A furan aromatic diamide neuraminidase inhibitor and its preparation method and application

Abstract

The present invention relates to a furan aromatic diamide neuraminidase inhibitor, its preparation method, and application. The preparation method specifically comprises: reacting ethyl 4-aminobenzoate with chloroacetyl chloride in a solvent to obtain the neuraminidase inhibitor; or reacting N-BOC-4-aminobenzoic acid with furfural amine in a solvent to obtain the neuraminidase inhibitor. Compared with the prior art, the inhibitor of the present invention employs a furan aromatic diamide compound structure for the first time, and the resulting inhibitor has good neuraminidase inhibitory activity and excellent neuraminidase inhibitory effect, and can be used to prepare a drug for inhibiting neuraminidase activity.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a furan aromatic diamide neuraminidase inhibitor, and a preparation method and application thereof. Background Art

[0002] Influenza viruses are highly contagious pathogens capable of causing seasonal epidemics and pandemics worldwide. High genomic variability is a hallmark of influenza viruses, and this variability causes the effectiveness of vaccines and antiviral drugs to vary over time. Traditional anti-influenza drugs, such as oseltamivir and zanamivir, work primarily by inhibiting viral replication and transmission, but their effectiveness is often diminished by the development of viral resistance.

[0003] In recent years, researchers have been dedicated to identifying new anti-influenza strategies to overcome the limitations of existing drugs. These strategies include developing drugs that target different stages of the viral life cycle and exploring new targets for viral-host cell interactions. With the development of computer-aided drug design technology, researchers can more rapidly identify and optimize new antiviral compounds that may possess stronger antiviral activity and reduce the risk of drug resistance.

[0004] Patent CN112079744B discloses the use of an aromatic acylhydrazone derivative in the preparation of a neuraminidase inhibitor. The aromatic acylhydrazone derivative has a good inhibitory effect on neuraminidase. The IC of the aromatic acylhydrazone derivative having the structure shown in formula (a) is 50 The value is 5.99 μg / mL (23.39 μM), which has good neuraminidase inhibitory activity. Patent CN108530439B discloses furancarboxamide derivatives and their use as NA inhibitors, wherein the structure shown in formula (b) also has relatively good neuraminidase inhibitory activity (IC 50 =33.5 μM).

[0005]

[0006] While existing technologies have demonstrated excellent performance in inhibiting neuraminidase activity, there is still room for improvement. Therefore, the development of novel anti-influenza virus inhibitors, particularly those with innovative backbones, is crucial. These novel compounds are expected to not only provide more effective treatment options but also offer new avenues for future influenza virus prevention and treatment. Summary of the Invention

[0007] The purpose of the present invention is to provide a furan aromatic diamide neuraminidase inhibitor and its preparation method and application in order to solve at least one of the above problems, thereby solving the problem of preparing neuraminidase inhibitors based on furan aromatic diamide compounds. The inhibitor has a novel structure and has good neuraminidase inhibitory activity as shown by experiments. It can be used to prepare drugs that inhibit neuraminidase activity.

[0008] The purpose of the present invention is achieved through the following technical solutions:

[0009] A furan aromatic diamide neuraminidase inhibitor, wherein the chemical structural formula of the neuraminidase inhibitor is shown in Formula I:

[0010]

[0011] In formula I, Ar is an aryl group.

[0012] Preferably, Ar in Formula I is selected from any one of the following structural formulas:

[0013]

[0014] Preferably, the chemical structural formula of the neuraminidase inhibitor is selected from one of the following structural formulas:

[0015]

[0016]

[0017] Preferably, the neuraminidase inhibitor is:

[0018] Furthermore, the chemical structure of the neuraminidase inhibitor with the best neuraminidase inhibitory effect is: Its IC 50 The value was 0.34±0.02μM, which showed very excellent neuraminidase inhibitory activity.

[0019] The present invention also provides a method for preparing a furan aromatic diamide neuraminidase inhibitor, comprising the following steps:

[0020] S1: ethyl 4-aminobenzoate reacts with chloroacetyl chloride in a first solvent to obtain a first intermediate;

[0021] S2: The first intermediate undergoes a second reaction with a substituted phenol in a second solvent to obtain a second intermediate;

[0022] S3: The second intermediate undergoes a third reaction in an alkaline solution to obtain a third intermediate;

[0023] S4: The third intermediate reacts with furfural in a second solvent to produce the neuraminidase inhibitor;

[0024] or:

[0025] T1: N-BOC-4-aminobenzoic acid reacts with furfural in a second solvent to produce a fifth intermediate;

[0026] T2: The fifth intermediate undergoes a sixth reaction in an acidic solution to obtain a sixth intermediate;

[0027] T3: the sixth intermediate reacts with chloroacetyl chloride in the first solvent to obtain a seventh intermediate;

[0028] T4: the seventh intermediate undergoes an eighth reaction with a substituted phenol in a second solvent to obtain the neuraminidase inhibitor;

[0029] The substituent in the substituted phenol is an aryl group.

[0030] Preferably, in step S1, potassium carbonate is used as a catalyst, the molar ratio of ethyl 4-aminobenzoate to chloroacetyl chloride is 15-20:22-30, the temperature of the first reaction is 0-30° C., and the time is 1-10 h.

[0031] More preferably, in step S1, the addition ratio of potassium carbonate, the first solvent, ethyl 4-aminobenzoate and chloroacetyl chloride is 24 mmol: (15-20) mL: (10-20) mmol: (20-40) mmol, preferably 24 mmol: 20 mL: 20 mmol: 30 mmol.

[0032] More preferably, in step S1, the temperature of the first reaction is preferably 0° C., and the time is preferably 1.5 h.

[0033] Preferably, in step S1, after the first reaction, post-treatment is performed to obtain a first intermediate, and the specific process is: the reaction liquid after the first reaction is extracted with dichloromethane, the organic phase is collected, and the organic phase is washed with a saturated sodium bicarbonate solution, a 1N hydrochloric acid solution and a saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate, the solvent is removed by distillation under reduced pressure, and the purified first intermediate is obtained by column chromatography.

[0034] Preferably, in step S2, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the first intermediate to the substituted phenol is 2-4:2-4, the temperature of the second reaction is 30-90° C., and the time is 5-10 h.

[0035] More preferably, in step S2, the addition ratio of the first intermediate, substituted phenol, potassium carbonate, potassium iodide and the second solvent is (2-4) mmol: (2-4) mmol: (2-4) mmol: 0.01 mmol: (2-5) mL, preferably 2 mmol: 2.2 mmol: 3 mmol: 0.01 mmol: 3 mL.

[0036] More preferably, in step S2, the temperature of the second reaction is preferably 85° C., and the time is preferably 7 h.

[0037] Preferably, in step S2, after the second reaction, post-treatment is performed to obtain a second intermediate, and the specific process is: distilled water is added to the reaction solution after the second reaction to quench the reaction to obtain a precipitate, the second intermediate is separated by reduced pressure filtration, washed with saturated brine, and then purified by column chromatography to obtain a pure second intermediate.

[0038] Preferably, in step S3, sodium hydroxide is used as the alkaline solution, the molar ratio of the second intermediate to sodium hydroxide is 1.5:10-15, the hydrolysis temperature is 0-30° C., and the time is 1-10 h.

[0039] More preferably, in step S3, the third reaction is carried out in a third solvent.

[0040] More preferably, in step S3, the addition ratio of the second intermediate, sodium hydroxide and the third solvent is 1.5 mmol: (10-15) mmol: (12-18) mL, preferably 1.5 mmol: 12 mmol: 15 mL.

[0041] More preferably, in step S3, the temperature of the third reaction is preferably 25° C., and the time is preferably 4 hours.

[0042] Preferably, in step S3, after the third reaction, post-treatment is performed to obtain a third intermediate, and the specific process is: adding distilled water to the reaction solution after the third reaction, adjusting the pH of the solution to 1 with concentrated hydrochloric acid solution, filtering and washing with saturated brine to obtain a crude product, and the crude product is recrystallized and purified from water to obtain a pure third intermediate.

[0043] More preferably, in step S3, the concentration of the sodium hydroxide solution is 10 mol / L, and the concentration of the concentrated hydrochloric acid is 1 mol / L.

[0044] Preferably, in step S4, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of the third intermediate to furfural is 1-3:1.5-3, the temperature of the fourth reaction is 0-30°C, and the time is 1-10h.

[0045] More preferably, in step S4, the addition ratio of the third intermediate, furfural, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is (1-3) mmol: (1.5-3) mmol: 2 mmol: 3.5 mmol, preferably 1 mmol: 1.5 mmol: 2 mmol: 3.5 mmol.

[0046] More preferably, in step S4, the temperature of the fourth reaction is preferably 25° C., and the time is preferably 6 h.

[0047] Preferably, in step S4, after the fourth reaction, post-treatment is performed to obtain the neuraminidase inhibitor. The specific process is: the reaction liquid after the fourth reaction is filtered and washed with saturated brine to obtain a crude product, and the crude product is recrystallized using 90% ethanol solution to obtain the pure neuraminidase inhibitor.

[0048] Preferably, the first solvent is dichloromethane, the second solvent is N,N-dimethylformamide, and the third solvent is ethanol.

[0049] Preferably, the preparation steps S1-S4 are as shown in the following reaction steps:

[0050]

[0051] Wherein, Formula I is a neuraminidase inhibitor, Formula II is a first intermediate, Formula III is a second intermediate, and Formula IV is a third intermediate.

[0052] Preferably, in step T1, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of N-BOC-4-aminobenzoic acid to furfural is 5-10:8-10, the temperature of the fifth reaction is 20-35° C., and the time is 5-10 h.

[0053] More preferably, in step T1, the addition ratio of the 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-BOC-4-aminobenzoic acid and furfural is (10-15) mmol: (20-25) mmol: (5-10) mmol: (8-10) mmol, preferably 12 mmol: 21 mL: 6 mmol: 9 mmol.

[0054] More preferably, in step T1, the temperature of the fifth reaction is preferably 25° C., and the time is preferably 6 hours.

[0055] Preferably, in step T1, a post-treatment is performed after the fifth reaction to obtain a fifth intermediate. The specific process is: the reaction liquid after the fifth reaction is filtered and washed with saturated brine to obtain a pure fifth intermediate.

[0056] Preferably, in step T2, concentrated hydrochloric acid is used as the acidic solution, the molar ratio of the fifth intermediate to concentrated hydrochloric acid is 5-10:7-8, the sixth reaction temperature is 0-25° C., and the reaction time is 10-12 h.

[0057] More preferably, in step T2, the sixth reaction is carried out in a fourth solvent.

[0058] More preferably, in step T2, the addition ratio of the fifth intermediate, concentrated hydrochloric acid and the fourth solvent is (5-10) mmol: (7-8) mL: (13-18) mL, preferably 6 mmol: 7.5 mL: 15 mL.

[0059] More preferably, in step T2, the temperature of the sixth reaction is preferably 0° C., and the time is preferably 12 h.

[0060] Preferably, in step T2, a post-treatment is performed after the sixth reaction to obtain a sixth intermediate, and the specific process is: filtering and separating the reaction liquid after the sixth reaction to obtain the sixth intermediate.

[0061] Preferably, in step T3, triethylamine is used as an acid-binding agent, the molar ratio of the sixth intermediate to chloroacetyl chloride is 5:7-8, and the temperature of the seventh reaction is 0-35° C. and the time is 2-5 h.

[0062] More preferably, in step T3, the addition ratio of the sixth intermediate, chloroacetyl chloride, triethylamine and the first solvent is 5 mmol: (7-8) mmol: (12-18) mmol: (9-15) mL, preferably 5 mmol: 7.5 mmol: 15 mmol: 10 mL.

[0063] More preferably, in step T3, the temperature of the seventh reaction is preferably 0° C., and the reaction time is preferably 3 h.

[0064] Preferably, in step T3, after the seventh post-reaction, post-treatment is performed to obtain the seventh intermediate. The specific process is: distilled water is added to the reaction solution after the seventh reaction to quench the reaction, and dichloromethane is used for extraction. The organic phase is collected, and the organic phase is washed with a saturated sodium bicarbonate solution, a 1N hydrochloric acid solution, and a saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and purified by column chromatography to obtain a pure seventh intermediate.

[0065] Preferably, in step T4, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the seventh intermediate to the substituted phenol is 1-2:1-2, and the temperature of the eighth reaction is 60-90° C. and the time is 6-8 h.

[0066] More preferably, in step T4, the addition ratio of the seventh intermediate, substituted phenol, potassium iodide, potassium carbonate and the second solvent is (1-2) mmol: (1-2) mmol: 0.01 mmol: (2-4) mmol: (2-5) mL, preferably 1 mmol: 1.1 mmol: 0.01 mmol: 3 mmol: 2 mL.

[0067] More preferably, in step T4, the temperature of the eighth reaction is preferably 85° C., and the reaction time is preferably 7 h.

[0068] Preferably, in step T4, after the eighth reaction, post-treatment is performed to obtain the neuraminidase inhibitor. The specific process is: the reaction solution after the eighth reaction is filtered and washed with saturated brine to obtain a crude product, and the crude product is purified by column chromatography to obtain a pure neuraminidase inhibitor.

[0069] Preferably, the first solvent is dichloromethane, the second solvent is N,N-dimethylformamide, and the fourth solvent is 1,4-dioxane.

[0070] Preferably, the preparation steps T1-T4 are as shown in the following reaction steps:

[0071]

[0072] Wherein, Formula I is a neuraminidase inhibitor, Formula V is the fifth intermediate, Formula VI is the sixth intermediate, and Formula VII is the seventh intermediate.

[0073] In addition, the present invention also provides a use of the above-mentioned furan aromatic diamide neuraminidase inhibitor in the preparation of a drug for inhibiting neuraminidase activity.

[0074] The present invention uses a receptor-based molecular docking virtual screening method to screen 10,000 compounds from the database and obtain a compound with theoretical neuraminidase inhibitory activity. Then, the compound is modified to design more reasonable compounds. Fourteen of the compounds are tested for neuraminidase activity, with oseltamivir carboxlate (OSC) as a positive control. The IC of OSC is 50 The value is 0.31 μM.

[0075] IC values ​​of the following four compounds synthesized by the present invention are 50The values ​​are all close to 0.31μM:

[0076] Among them, the compound with the best inhibitory effect is: Its IC 50 The value was 0.34±0.02μM, which showed very excellent neuraminidase inhibitory activity.

[0077] Compared with the prior art, the present invention provides a neuraminidase inhibitor with a new skeleton structure, a preparation method thereof, and an application thereof. Firstly, in terms of structure, furan aromatic diamide compounds have not been reported before for inhibiting neuraminidase. Secondly, the prepared inhibitor has good neuraminidase inhibitory activity and excellent neuraminidase inhibitory effect, and can be used to prepare drugs that inhibit neuraminidase activity. DETAILED DESCRIPTION

[0078] The present invention is described in detail below with reference to specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0079] In the examples described below, unless otherwise specified, the reagents used are conventional commercially available products, and the methods used are well known in the art.

[0080] A furan aromatic diamide neuraminidase inhibitor, wherein the chemical structural formula of the neuraminidase inhibitor is shown in Formula I:

[0081]

[0082] In formula I, Ar is an aryl group.

[0083] Wherein, Ar in Formula I is selected from any one of the following structural formulas:

[0084]

[0085] The chemical structural formula of the neuraminidase inhibitor is selected from one of the following structural formulas:

[0086]

[0087]

[0088] Among them, the chemical structure of the neuraminidase inhibitor with the best inhibitory effect on neuraminidase is: Its IC 50 The value was 0.34±0.02μM, which showed very excellent neuraminidase inhibitory activity.

[0089] The present invention also provides a method for preparing a furan aromatic diamide neuraminidase inhibitor, comprising the following steps:

[0090] S1: ethyl 4-aminobenzoate reacts with chloroacetyl chloride in a first solvent to obtain a first intermediate;

[0091] S2: The first intermediate undergoes a second reaction with a substituted phenol in a second solvent to obtain a second intermediate;

[0092] S3: The second intermediate undergoes a third reaction in an alkaline solution to obtain a third intermediate;

[0093] S4: The third intermediate reacts with furfural in a second solvent to produce the neuraminidase inhibitor;

[0094] or:

[0095] T1: N-BOC-4-aminobenzoic acid reacts with furfural in a second solvent to produce a fifth intermediate;

[0096] T2: The fifth intermediate undergoes a sixth reaction in an acidic solution to obtain a sixth intermediate;

[0097] T3: the sixth intermediate reacts with chloroacetyl chloride in the first solvent to obtain a seventh intermediate;

[0098] T4: the seventh intermediate undergoes an eighth reaction with a substituted phenol in a second solvent to obtain the neuraminidase inhibitor;

[0099] The substituent in the substituted phenol is an aryl group.

[0100] In step S1, potassium carbonate is used as a catalyst, the molar ratio of ethyl 4-aminobenzoate to chloroacetyl chloride is 15-20:22-30, the temperature of the first reaction is 0-30° C., and the time is 1-10 hours;

[0101] The addition ratio of the potassium carbonate, the first solvent, ethyl 4-aminobenzoate and chloroacetyl chloride is 24 mmol: (15-20) mL: (10-20) mmol: (20-40) mmol, preferably 24 mmol: 20 mL: 20 mmol: 30 mmol;

[0102] The temperature of the first reaction is preferably 0°C and the time is preferably 1.5h;

[0103] After the first reaction, post-treatment is performed to obtain a first intermediate. The specific process is as follows: the reaction liquid after the first reaction is extracted with dichloromethane, the organic phase is collected, and the organic phase is washed with a saturated sodium bicarbonate solution, a 1N hydrochloric acid solution and a saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate. The solvent is removed by reduced pressure distillation, and the purified first intermediate is obtained by column chromatography.

[0104] In step S2, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the first intermediate to the substituted phenol is 2-4:2-4, the temperature of the second reaction is 30-90°C, and the time is 5-10 hours;

[0105] The addition ratio of the first intermediate, substituted phenol, potassium carbonate, potassium iodide and the second solvent is (2-4) mmol: (2-4) mmol: (2-4) mmol: 0.01 mmol: (2-5) mL, preferably 2 mmol: 2.2 mmol: 3 mmol: 0.01 mmol: 3 mL;

[0106] The temperature of the second reaction is preferably 85°C and the time is preferably 7h;

[0107] After the second reaction, post-treatment is performed to obtain a second intermediate. The specific process is: distilled water is added to the reaction solution after the second reaction to quench the reaction to obtain a precipitate, the second intermediate is separated by reduced pressure filtration, washed with saturated brine, and then purified by column chromatography to obtain a pure second intermediate.

[0108] In step S3, a third solvent is added to the third reaction, sodium hydroxide is used as the alkaline solution, ethanol is used as the third solvent, the molar ratio of the second intermediate to sodium hydroxide is 1.5:10-15, the hydrolysis temperature is 0-30° C., and the time is 1-10 hours;

[0109] The addition ratio of the second intermediate, sodium hydroxide and the third solvent is 1.5 mmol: (10-15) mmol: (12-18) mL, preferably 1.5 mmol: 12 mmol: 15 mL;

[0110] The temperature of the third reaction is preferably 25°C, and the time is preferably 4 hours;

[0111] After the third reaction, post-treatment is performed to obtain a third intermediate, specifically, the process is as follows: adding distilled water to the reaction solution after the third reaction, adjusting the pH of the solution to 1 with concentrated hydrochloric acid solution, filtering and washing with saturated brine to obtain a crude product, and the crude product is purified by recrystallization from water to obtain a pure third intermediate;

[0112] The concentration of the sodium hydroxide solution is 10 mol / L, and the concentration of the concentrated hydrochloric acid is 1 mol / L.

[0113] In step S4, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of the third intermediate to furfural is 1-3:1.5-3, and the temperature of the fourth reaction is 0-30° C. and the time is 1-10 hours;

[0114] The addition ratio of the third intermediate, furfural, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is (1-3) mmol: (1.5-3) mmol: 2 mmol: 3.5 mmol, preferably 1 mmol: 1.5 mmol: 2 mmol: 3.5 mmol;

[0115] The temperature of the fourth reaction is preferably 25°C and the time is preferably 6 hours;

[0116] After the fourth reaction, post-treatment is performed to obtain the neuraminidase inhibitor. The specific process is as follows: the reaction solution after the fourth reaction is filtered and washed with saturated brine to obtain a crude product, and the crude product is recrystallized using 90% ethanol solution to obtain the pure neuraminidase inhibitor.

[0117] The first solvent is dichloromethane, and the second solvent is N,N-dimethylformamide.

[0118] The preparation steps of S1-S4 are shown in the following reaction steps:

[0119]

[0120] Wherein, Formula I is a neuraminidase inhibitor, Formula II is a first intermediate, Formula III is a second intermediate, and Formula IV is a third intermediate.

[0121] In step T1, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of N-BOC-4-aminobenzoic acid to furfural is 5-10:8-10, the temperature of the fifth reaction is 20-35° C., and the reaction time is 5-10 hours;

[0122] The addition ratio of the 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-BOC-4-aminobenzoic acid and furfural is (10-15) mmol: (20-25) mmol: (5-10) mmol: (8-10) mmol, preferably 12 mmol: 21 mL: 6 mmol: 9 mmol;

[0123] The temperature of the fifth reaction is preferably 25°C and the time is preferably 6 hours;

[0124] After the fifth reaction, post-treatment is performed to obtain a fifth intermediate. The specific process is: the reaction liquid after the fifth reaction is filtered and washed with saturated brine to obtain a pure fifth intermediate.

[0125] In step T2, the fourth solvent is added to the sixth reaction, concentrated hydrochloric acid is used as the acidic solution, 1,4-dioxane is used as the fourth solvent, the molar ratio of the fifth intermediate to concentrated hydrochloric acid is 5-10:7-8, the sixth reaction temperature is 0-25° C., and the reaction time is 10-12 h;

[0126] The addition ratio of the fifth intermediate, concentrated hydrochloric acid and the fourth solvent is (5-10) mmol: (7-8) mL: (13-18) mL, preferably 6 mmol: 7.5 mL: 15 mL;

[0127] The temperature of the sixth reaction is preferably 0°C, and the time is preferably 12 hours;

[0128] After the sixth reaction, post-treatment is performed to obtain a sixth intermediate. The specific process is: the reaction liquid after the sixth reaction is filtered and separated to obtain the sixth intermediate.

[0129] In step T3, triethylamine is used as an acid-binding agent, the molar ratio of the sixth intermediate to chloroacetyl chloride is 5:7-8, and the temperature of the seventh reaction is 0-35°C and the time is 2-5 hours;

[0130] The addition ratio of the sixth intermediate, chloroacetyl chloride, triethylamine and the first solvent is 5 mmol: (7-8) mmol: (12-18) mmol: (9-15) mL, preferably 5 mmol: 7.5 mmol: 15 mmol: 10 mL;

[0131] The temperature of the seventh reaction is preferably 0°C, and the reaction time is preferably 3h;

[0132] After the seventh post-reaction, post-treatment is performed to obtain the seventh intermediate. The specific process is as follows: distilled water is added to the reaction solution after the seventh reaction to quench the reaction, and dichloromethane is used for extraction. The organic phase is collected, and the organic phase is washed with a saturated sodium bicarbonate solution, a 1N hydrochloric acid solution, and a saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and purified by column chromatography to obtain a pure seventh intermediate.

[0133] In step T4, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the seventh intermediate to the substituted phenol is 1-2:1-2, the temperature of the eighth reaction is 60-90°C, and the time is 6-8 hours;

[0134] The addition ratio of the seventh intermediate, substituted phenol, potassium iodide, potassium carbonate and the second solvent is (1-2) mmol: (1-2) mmol: 0.01 mmol: (2-4) mmol: (2-5) mL, preferably 1 mmol: 1.1 mmol: 0.01 mmol: 3 mmol: 2 mL;

[0135] The temperature of the eighth reaction is preferably 85°C, and the reaction time is preferably 7h;

[0136] After the eighth reaction, post-treatment is performed to obtain the neuraminidase inhibitor. The specific process is as follows: the reaction solution after the eighth reaction is filtered and washed with saturated brine to obtain a crude product, and the crude product is purified by column chromatography to obtain a pure neuraminidase inhibitor.

[0137] The first solvent is dichloromethane, and the second solvent is N,N-dimethylformamide.

[0138] The preparation steps of T1-T4 are shown in the following reaction steps:

[0139]

[0140] Wherein, Formula I is a neuraminidase inhibitor, Formula V is the fifth intermediate, Formula VI is the sixth intermediate, and Formula VII is the seventh intermediate.

[0141] The prepared inhibitor was tested for neuraminidase activity inhibition. The specific test method is as follows:

[0142] 1. Experimental instruments and materials

[0143] Multifunctional fluorescence microplate reader, SP-Max 3500FL, Shanghai Shanpu Biotechnology Co., Ltd.;

[0144] Clean bench;

[0145] Bond A3 Pipette manual single-channel adjustable pipette: 0.5-10 μL, 10-100 μL, 100-1000 μL, purchased from Titan Technology;

[0146] 96-well ELISA plate (black), sterilized, Corning;

[0147] H5N1 neuraminidase was purchased from Beijing Sino Biological Technology Co., Ltd.; the fluorogenic substrate 2'-(4-methylumbelliferyl)-α-D-acetylneuraminic acid sodium hydrate (4-MUNANA) (Sigma, M8639) used in enzyme inhibition experiments was purchased from Sigma; 2-(N-morpholino)ethanesulfonic acid (MES), calcium chloride, sodium hydroxide, and anhydrous ethanol were purchased from Titan Technology.

[0148] Positive control drug, Oseltamivir carboxlate (OSC), Shanghai Hekang Biotechnology Co., Ltd.

[0149] 2. Experimental Methods

[0150] The positive control drug and the target compound prepared in the example were dissolved in DMSO to an initial concentration of 1000 μmol / L, which was then diluted into six concentration gradients in the order of 500 μmol / L, 250 μmol / L, 125 μmol / L, 62.5 μmol / L, 31.25 μmol / L, and 15.625 μmol / L. Three groups were prepared for each concentration gradient.

[0151] 2.1 Sample testing preparation

[0152] a. Add 70 μL of buffer (33 mM MES, 4 mM CaCl2) to each well of a 96-well ELISA plate;

[0153] b. Add 10 μL of neuraminidase to each well;

[0154] c. Add 10 μL of the prepared neuraminidase inhibitor sample or positive control drug sample to each well, and set up three sets of blank control samples;

[0155] d. Add 10 μL of neuraminidase substrate (100 μM 4-MUNANA) to each well.

[0156] 2.2 Detection

[0157] a. Place the 96-well microplate in a multifunctional fluorescence microplate reader and shake for 1 minute;

[0158] b. Set the temperature to 37°C and incubate for 5 minutes to allow the neuraminidase and the test sample to fully mix and interact;

[0159] c. Remove the 96-well plate and add 10 μL of neuraminidase fluorescent substrate to each well;

[0160] d. Place the sample in the multifunctional fluorescence microplate reader again and shake to mix for 1 minute;

[0161] e. Incubate at 37°C for 30 minutes. Remove the plate and add 150 μL of stop solution (14 mM NaOH in 83% ethanol) to each well. Place the plate back in the multi-functional fluorescence microplate reader and vortex to mix for 1 minute. Set the excitation wavelength to 355 nm and the emission wavelength to 460 nm. After the incubation period, begin measuring the fluorescence intensity (RFU).

[0162] f. Repeat the above steps and perform 3 sets of parallel experiments.

[0163] Note: The first well in the 96-well ELISA plate is used as a blank group. No sample is added, and 10 μL DMSO solution is added. The average inhibition rate of each sample at each gradient concentration in each parallel experiment is calculated, and then the corresponding IC is fitted. 50 value.

[0164] The positive control drug and the target compound were prepared in DMSO solution to an initial concentration of 1000 μmol / L. These two mixed solutions were then diluted in series to form six concentration gradients: 500 μmol / L, 250 μmol / L, 125 μmol / L, 62.5 μmol / L, 31.25 μmol / L, and 15.625 μmol / L. Three groups were prepared for each concentration gradient. In a 96-well black fluorescent microplate, 70 μL of neuraminidase buffer, 10 μL of neuraminidase, and the positive control drug sample at each gradient concentration to be tested were added. Three blank control groups were also set up. Mix by shaking for 1 minute in a multifunctional fluorescence microplate reader and incubate at 37°C for 5 minutes; take out the 96-well microplate, add 10 μL of neuraminidase substrate to each well, shake for 1 minute to mix, incubate at 37°C for 30 minutes, take out, add 150 μL of stop solution (14 mM NaOH in 83% ethanol aqueous solution) to each well, place it in a multifunctional fluorescence microplate reader again, shake and mix for 1 minute, set the excitation wavelength to 355 nm, set the emission wavelength to 460 nm, and start the fluorescence intensity (RFU) measurement after the incubation. Perform three experiments in parallel, calculate the average inhibition rate of the sample at each gradient concentration in each parallel experiment, and then fit the corresponding IC 50 value.

[0165] The above embodiments are described in more detail below with reference to specific examples:

[0166] Example 1

[0167] 4-(2-(3,5-dimethoxyphenoxyacetamido)-N-(furan-2-ylmethyl)benzamide, the structural formula of which is shown below:

[0168]

[0169] The specific synthesis steps are as follows:

[0170] (1) 1.42 g (6 mmol) of N-BOC-4-aminobenzoic acid, 0.84 mL (9 mmol) of furfural, 1.62 g (12 mmol) of 1-hydroxybenzotriazole (HOBT) and 4.02 g (21 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDCl) were added to a 100 mL round-bottom flask. 8 mL of N,N-dimethylformamide (DMF) was added to the flask and stirred at room temperature (25°C) for 6 hours under nitrogen protection to react. After the reaction was completed, 15 mL of distilled water was added to the system for quenching, and then filtered and washed with saturated brine to obtain the pure intermediate of formula V.

[0171] (2) Place 1.90 g (6 mmol) of the intermediate of Formula V in a 100 mL three-necked round-bottom flask, add 15 mL of 1,4-dioxane solvent, and slowly add 7.5 mL of 4N HCl solution dropwise in an ice bath under N2 protection. Stir overnight. After the reaction is complete, filter to obtain the pure intermediate of Formula VI.

[0172] (3) 1.26 g (5 mmol) of the intermediate of formula VI was added to a 100 mL three-necked flask, followed by the addition of 2.08 mL (15 mmol) of triethylamine and 10 mL of dichloromethane (DCM). After being allowed to stand at room temperature for 1 hour, 0.6 mL (7.5 mmol) of chloroacetyl chloride was slowly added using a constant pressure titration funnel under ice bath cooling. The reaction was stirred at 0°C for 3 hours to complete the reaction. After the reaction was completed, 10 mL of distilled water was added to the reaction mixture to quench the reaction, and then the mixture was extracted with dichloromethane and the organic phase was collected. The organic phase was then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid solution and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the purified intermediate of formula VII was obtained by column chromatography.

[0173] (4) To a 25 mL round-bottom flask, 0.29 g (1 mmol) of the intermediate of formula VII, 0.17 g (1.1 mmol) of 3,5-dimethoxyphenol, and 2 mL of DMF solvent were added, followed by the addition of 0.41 g (3 mmol) of potassium carbonate and a trace amount of potassium iodide. The mixture was stirred at 85°C for 7 hours, and the reaction was monitored by TLC. After the reaction was completed, 5 mL of distilled water was added to the reaction solution to quench the reaction. Solids precipitated and were filtered, and the filter cake was retained. The crude product was washed with saturated brine to obtain the product shown in Example 1. Finally, it was purified by column chromatography to obtain the product shown in Example 1.

[0174] Experimental results:

[0175] 4-(2-(3,5-dimethoxyphenoxyacetamido)-N-(furan-2-ylmethyl)benzamide, white solid, yield 89%, its IC 50 The IC value of the positive control drug OSC was 0.34 μM. 50 The value is 0.31 μM.

[0176] 1 H NMR (401MHz, DMSO-d6) δ10.27(s,1H),8.88(s,1H),7.88(d,J=8.7Hz,2H),7.75(d,J=8.8Hz,2H),7.58(d,J=2.1 Hz,1H),6.41(s,1H),6.29(d,J=3.3Hz,1H),6.25-6.12(m,3H),4.70(s,2H),4.48(d,J=5.8Hz,2H),3.73(s,6H). 13 C NMR(100MHz,DMSO-d6)δ167.33,166.03,161.67,160.08,153.04,142.44,141.52,129.64,128.68,119.3 9,110.96,107.32,94.19,93.97,67.78,55.73,40.65,40.44,40.23,40.03,39.82,39.61,39.40,36.51.

[0177] Example 2

[0178] N-(furan-2-ylmethyl)-4-(2-phenoxyacetamido)benzamide, its structural formula is as follows:

[0179]

[0180] The specific synthesis steps are as follows:

[0181] (1) 3.30 g (20 mmol) of ethyl 4-aminobenzoate (Compound 7) was added to a 100 mL three-necked flask, followed by the addition of 3.32 g (24 mmol) of potassium carbonate and 20 mL of dichloromethane (DCM). Under ice-cooling conditions, 2.42 mL (30 mmol) of chloroacetyl chloride was slowly added using a constant pressure titration funnel. The reaction was stirred at 0°C for 1.5 hours to complete the reaction. After the reaction was completed, 20 mL of distilled water was added to the reaction mixture to quench the reaction, and then the mixture was extracted with dichloromethane and the organic phase was collected. The organic phase was then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid solution and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate and removing the solvent by reduced pressure distillation. Finally, the purified intermediate of Formula II was obtained by column chromatography.

[0182] (2) To a 25 mL round-bottom flask, 0.48 g (2 mmol) of the intermediate of formula II and 0.21 g (2.2 mmol) of phenol were added, followed by the addition of 0.41 g (3 mmol) of potassium carbonate, 0.01 mmol of potassium iodide, and 3 mL of dimethylformamide (DMF). The mixture was stirred at 85° C. for 7 hours. After the reaction was completed, 5 mL of distilled water was added to the reaction mixture to quench the reaction, and the mixture was filtered. The intermediate of formula III was obtained by washing with saturated brine and finally purified by column chromatography.

[0183] (3) 0.45 g (1.5 mmol) of the ester compound of formula III intermediate was placed in a 50 mL round-bottom flask and 15 mL of ethanol was added. Then, 0.67 g (12 mmol) of sodium hydroxide solution dissolved in 2 mL of distilled water was slowly added to the flask under ice bath conditions. The reaction was stirred at room temperature of 25°C for 4 hours. After the reaction was completed, 10 mL of distilled water was added to the reaction mixture, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. The crude product was obtained by filtration and washed with saturated brine. Finally, it was recrystallized from water for purification to obtain a pure intermediate of formula IV.

[0184] (4) 0.27 g (1 mmol) of intermediate compound 10, 1.5 mmol of furfural, 0.27 g (2 mmol) of 1-hydroxybenzotriazole (HOBT) and 0.67 g (3.5 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDCl) were added to a 25 mL round-bottom flask. 2 mL of dimethylformamide (DMF) was added to the flask, and the mixture was stirred at room temperature of 25°C for 6 hours under nitrogen protection to react. After the reaction was completed, 4 mL of distilled water was added to the system for quenching, and then the system was filtered and washed with saturated brine to obtain a crude product. The product shown in Example 2 was finally obtained by recrystallization using 90% ethanol solution.

[0185] Experimental results:

[0186] N-(Furan-2-ylmethyl)-4-(2-phenoxyacetamido)benzamide, white solid, yield 84%, its IC 50 The value was 46.66 μM.

[0187] 1H NMR(100MHz,)δ10.30(s,1H),8.83(d,J=5.3Hz,1H),7.96-7.52(m,5H),7.33(t,J=7.6H z,2H),7.01(d,J=7.5Hz,3H),6.33(d,J=8.4Hz,2H),4.73(s,2H),4.46(d,J=5.8Hz,2H).

[0188] Example 3

[0189] N-(Furan-2-ylmethyl)-4-(2-(4-methoxyphenoxyacetamido)benzamide was prepared using a method similar to that of Example 2, and its structural formula is as follows:

[0190]

[0191] White solid, yield 80%, its IC 50 The value was 47.38 μM.

[0192] 1 H NMR (401MHz, DMSO-d6) δ10.20(s,1H),8.81(t,J=5.8Hz,1H),7.81(d,J=8.8Hz,2H),7.69(d,J=8.8Hz,2H),7.52(s,1H),6.91(d,J= 9.1Hz,2H),6.84(d,J=9.3Hz,2H),6.35(dd,J=3.2,1.8Hz,1H),6.24–6.21(m,1H),4.61(s,2H),4.41(d,J=5.7Hz,2H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ167.76,166.02,154.41,153.07,152.32,142.50,141.60,129.58,128.68,119.37 ,116.25,115.15,111.00,107.35,68.42,55.90,40.69,40.48,40.27,40.06,39.85,39.65,39.44,36.52.

[0193] Example 4

[0194] N-(Furan-2-ylmethyl)-4-(2-(3-methoxyphenoxyacetamido)benzamide was prepared using a method similar to that of Example 1. Its structural formula is as follows:

[0195]

[0196] White solid, yield 87%, its IC 50 The value is 16.20 μM.

[0197] 1 H NMR (401MHz, DMSO-d6) δ10.28(s,1H),8.86(t,J=5.8Hz,1H),7.86(d,J=8.8Hz,2H),7.73(d,J=8.9Hz,2H),7.56(s,1H),7.21(t,J= 8.5Hz,1H),6.62–6.53(m,3H),6.39(dd,J=3.2,1.9Hz,1H),6.27(d,J=3.6Hz,1H),4.71(s,2H),4.45(d,J=5.7Hz,2H),3.73(s,3H). 13 C NMR(100MHz,DMSO-d6)δ172.16,170.76,165.72,164.24,157.79,146.29,134.35,133.43,124.11,115.72 ,112.18,112.07,112.01,106.43,72.46,60.40,45.40,45.20,44.99,44.78,44.57,44.36,44.15,41.25.

[0198] Example 5

[0199] N-(Furan-2-ylmethyl)-4-(2-(2-methoxyphenoxyacetamido)benzamide was prepared using a method similar to that of Example 1. Its structural formula is as follows:

[0200]

[0201] White solid, yield 85%, IC 50 The value is 31.60 μM.

[0202] 1 H NMR (401MHz, DMSO-d6) δ10.28(s,1H),8.87(t,J=5.8Hz,1H),7.88(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),7.58(s,1H),7 .10–6.94(m,3H),6.93–6.85(m,1H),6.41(s,1H),6.28(d,J=3.5Hz,1H),4.72(s,2H),4.47(d,J=5.7Hz,2H),3.82(s,3H). 13C NMR(100MHz,DMSO-d6)δ167.66,166.00,153.05,149.82,147.93,142.46,141.56,129.56,128.74,122.68,121.22 ,119.15,115.24,113.06,110.97,107.32,69.07,56.11,40.67,40.46,40.25,40.04,39.84,39.63,39.42,36.52.

[0203] Example 6

[0204] 4-(2-(3-chlorophenoxyacetamido)-N-(furan-2-ylmethyl)benzamide was prepared using a method similar to Example 2, and its structural formula is as follows:

[0205]

[0206] White solid, yield 75%, its IC 50 The value was 95.21 μM.

[0207] 1 H NMR (401MHz, DMSO-d6) δ10.30(s,1H),8.86(t,J=5.8Hz,1H),7.86(d,J=8.7Hz,2H),7.71(d,J=8.7Hz,2H),7.57(s,1H),7.34(t,J=8.2Hz,1H),7 .11(t,J=2.2Hz,1H),7.04(d,J=8.0Hz,1H),6.99(dd,J=8.3,2.5Hz,1H),6.39(s,1H),6.26(d,J=3.3Hz,1H),4.78(s,2H),4.45(d,J=5.7Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ167.08,166.00,159.27,153.06,142.50,141.52,134.19,131.46,129.65,128.73,121 .72,119.35,115.53,114.20,111.00,107.35,67.70,40.69,40.48,40.27,40.07,39.85,39.65,39.44,36.52.

[0208] Example 7

[0209] 4-(2-(4-(tert-butyl)phenoxyacetamido)-N-(furan-2-ylmethyl)benzamide was prepared using a method similar to that of Example 1. Its structural formula is as follows:

[0210]

[0211] White solid, yield 82%, its IC 50 The value was 14.69 μM.

[0212] 1 H NMR (401MHz, DMSO-d6) δ10.32(s,1H),8.89(t,J=5.8Hz,1H),7.90(d,J=8.9Hz,2H),7.77(d,J=8.8Hz,2H),7.59(s,1H), 7.34(d,J=8.9Hz,2H),6.95(d,J=8.9Hz,2H),6.41(s,1H),6.30(s,1H),4.72(s,2H),4.49(d,J=5.7Hz,2H),1.27(s,9H). 13 C NMR(100MHz,DMSO-d6)δ167.68,166.03,156.08,155.42,153.04,143.96,142.45,141.60,129.57,128.68,126.64,126.41,1 19.34,115.17,114.65,110.97,107.33,67.70,40.65,40.44,40.23,40.02,39.82,39.61,39.40,36.52,34.31,31.95,31.82.

[0213] Example 8

[0214] 4-(2-(5-bromo-2-methoxyphenoxyacetamido)-N-(furan-2-ylmethyl)benzamide was prepared using a method similar to that of Example 1. Its structural formula is as follows:

[0215]

[0216] White solid, yield 84%, its IC 50 The value was 13.37 μM.

[0217] 1H NMR (401MHz, DMSO-d6) δ10.30(s,1H),8.86(t,J=5.8Hz,1H),7.87(d,J=8.8Hz,2H),7.70(d,J=8.8Hz,2H),7.56(s,1H),7.19– 7.08(m,2H),6.97(d,J=8.7Hz,1H),6.42–6.35(m,1H),6.27(d,J=3.6Hz,1H),4.76(s,2H),4.46(d,J=5.8Hz,2H),3.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.16,166.01,153.03,149.22,148.81,142.45,141.52,128.77,124.88,119.13,11 7.74,114.57,111.99,110.97,107.32,68.80,56.35,40.65,40.44,40.23,40.02,39.81,39.61,39.40,36.52.

[0218] Example 9

[0219] 4-(2-(4-fluorophenoxyacetamido)-N-(furan-2-ylmethyl)benzamide was prepared using a method similar to that of Example 1. Its structural formula is as follows:

[0220]

[0221] White solid, yield 89%, its IC 50 The value was 55.83 μM.

[0222] 1 H NMR (401MHz, DMSO-d6) δ10.30(s,1H),8.87(t,J=6.2Hz,1H),7.88(d,J=8.7Hz,2H),7.74(d,J=8.7Hz,2H),7. 58(s,1H),7.17(t,J=8.8Hz,2H),7.05(s,2H),6.41(s,1H),6.28(s,1H),4.73(s,2H),4.47(d,J=5.8Hz,2H). 13C NMR(100MHz,DMSO-d6)δ167.38,166.00,154.64,153.04,142.46,141.53,129.60,128.67,119.35,116.64 ,116.56,116.49,116.27,110.97,107.32,68.18,40.65,40.44,40.24,40.03,39.82,39.61,39.40,36.50.

[0223] Example 10

[0224] N-(Furan-2-ylmethyl)-4-(2-(4-nitrophenoxyacetamido)benzamide was prepared by a method similar to that of Example 1, and its structural formula is as follows:

[0225]

[0226] Green solid, yield 77%, its IC 50 The value was 86.80 μM.

[0227] 1 H NMR (401MHz, DMSO-d6) δ10.43(s,1H),8.88(t,J=5.8Hz,1H),8.26(d,J=9.3Hz,2H),7.88(d,J=8.8Hz,2H),7.72(d ,J=8.8Hz,2H),7.59(s,1H),7.23(d,J=9.3Hz,2H),6.41(s,1H),6.29(s,1H),4.96(s,2H),4.47(d,J=5.7Hz,2H). 13 CNMR(100MHz,DMSO-d6)δ166.49,166.00,163.63,153.02,142.46,141.81,141.46,129.67,128.73,12 6.34,119.31,115.83,110.97,107.34,67.77,40.65,40.45,40.24,40.03,39.82,39.61,39.40,36.51.

[0228] Example 11

[0229] 4-(2-(4-Acetamidophenoxyacetamido)-N-(furan-2-ylmethyl)benzamide was prepared by a method similar to that of Example 1, and its structural formula is as follows.

[0230]

[0231] White solid, yield 88%, its IC 50 The value was 2.78 μM.

[0232] 1 H NMR (401MHz, DMSO-d6) δ9.83(s,1H),8.86(t,J=6.1Hz,1H),7.95(s,1H),7.86(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),7.56(s ,1H),7.50(d,J=9.0Hz,2H),6.94(d,J=9.0Hz,2H),6.39(s,1H),6.27(s,1H),4.68(s,2H),4.46(d,J=5.4Hz,2H),2.00(s,3H). 13 CNMR(100MHz,DMSO-d6)δ168.37,167.59,166.05,162.84,154.03,153.04,142.43,141.60,133.71,129.56,128.64,121. 03,119.38,115.27,110.95,107.31,67.98,40.63,40.43,40.22,40.01,39.80,39.59,39.38,36.51,36.27,31.27,24.26.

[0233] Table 1: Comparative Example (OSC) and Examples 1-11 for neuraminidase half-inhibitory concentration (IC 50 )

[0234] sample Yield <![CDATA[IC 50 ]]> OSC (Comparative Example) ———— 0.31μM Example 1 89％ 0.34 μM Example 2 84％ 46.66μM Example 3 80％ 47.38μM Example 4 87％ 16.20μM Example 5 85％ 31.60μM Example 6 75％ 95.21μM Example 7 82％ 14.69μM Example 8 84％ 13.37μM Example 9 89％ 55.83μM Example 10 77％ 86.80μM Example 11 88％ 2.78μM

[0235] As shown in Table 1, the half-inhibitory concentration of the furan aromatic diamide neuraminidase inhibitor Example 1 prepared by the preparation method of the present invention on neuraminidase is close to that of the positive control OSC (IC 50 =0.31 μM).

[0236] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A furan aromatic diamide neuraminidase inhibitor, characterized in that: The chemical structural formula of the neuraminidase inhibitor is selected from one of the following structural formulas: 、 、 、 or .

2. A furan aromatic diamide neuraminidase inhibitor according to claim 1, characterized in that: The chemical structural formula of the neuraminidase inhibitor is selected from one of the following structural formulas: 、 or .

3. A furan aromatic diamide neuraminidase inhibitor according to claim 2, characterized in that: The chemical structural formula of the neuraminidase inhibitor is: 。 4. A method for preparing the furan aromatic diamide neuraminidase inhibitor according to any one of claims 1 to 3, characterized in that: The steps include: S1: ethyl 4-aminobenzoate reacts with chloroacetyl chloride in a first solvent to obtain a first intermediate; S2: The first intermediate undergoes a second reaction with a substituted phenol in a second solvent to obtain a second intermediate; S3: The second intermediate undergoes a third reaction in an alkaline solution to obtain a third intermediate; S4: The third intermediate reacts with furfural in a second solvent to produce the neuraminidase inhibitor; or: T1: N-BOC-4-aminobenzoic acid reacts with furfural in a second solvent to produce a fifth intermediate; T2: The fifth intermediate undergoes a sixth reaction in an acidic solution to obtain a sixth intermediate; T3: the sixth intermediate reacts with chloroacetyl chloride in the first solvent to obtain a seventh intermediate; T4: the seventh intermediate undergoes an eighth reaction with a substituted phenol in a second solvent to obtain the neuraminidase inhibitor; The substituted phenol is 3,5-dimethoxy-1-phenol, 3-chloro-1-phenol, 5-bromo-2-methoxy-1-phenol, 4-fluoro-1-phenol or 4-acetamido-1-phenol; The first solvent is dichloromethane, and the second solvent is N,N-dimethylformamide.

5. The method for preparing a furan aromatic diamide neuraminidase inhibitor according to claim 4, characterized in that: Include at least one of the following: 1) In step S1, potassium carbonate is used as a catalyst, the molar ratio of ethyl 4-aminobenzoate to chloroacetyl chloride is 15-20:22-30, the temperature of the first reaction is 0-30°C, and the time is 1-10 hours; 2) In step S2, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the first intermediate to the substituted phenol is 2-4:2-4, and the temperature of the second reaction is 30-90°C and the time is 5-10 hours; 3) In step S3, sodium hydroxide is used as the alkaline solution, the molar ratio of the second intermediate to sodium hydroxide is 1.5:10-15, the temperature of the third reaction is 0-30°C, and the time is 1-10 hours; 4) In step S4, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of the third intermediate to furfural is 1-3:1.5-3, and the temperature of the fourth reaction is 0-30° C. and the time is 1-10 hours.

6. The method for preparing a furan aromatic diamide neuraminidase inhibitor according to claim 4, characterized in that: Include at least one of the following: 1) In step T1, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are used as condensation agents, the molar ratio of N-BOC-4-aminobenzoic acid to furfural is 5-10:8-10, and the temperature of the fifth reaction is 20-35° C. and the reaction time is 5-10 hours; 2) In step T2, concentrated hydrochloric acid is used as the acidic solution, the molar ratio of the fifth intermediate to concentrated hydrochloric acid is 5-10:7-8, the sixth reaction temperature is 0-25°C, and the reaction time is 10-12 hours; 3) In step T3, triethylamine is used as an acid-binding agent, the molar ratio of the sixth intermediate to chloroacetyl chloride is 5:7-8, and the temperature of the seventh reaction is 0-35°C and the time is 2-5 hours; 4) In step T4, potassium iodide and potassium carbonate are used as acid binding agents, the molar ratio of the seventh intermediate to the substituted phenol is 1-2:1-2, and the temperature of the eighth reaction is 60-90°C and the time is 6-8 hours.

7. Use of the furan aromatic diamide neuraminidase inhibitor according to any one of claims 1 to 3 in the preparation of a medicament for inhibiting neuraminidase activity.

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