Benzophenone compounds and preparation method and application thereof

Abstract

The present application provides a benzophenone compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in Formula I: #imgabs0# wherein X is ‑(C=O)‑NH‑ or ‑NH‑(C=O)‑; n is an integer from 1 to 10; R1, R2, and R3 represent one or more substituents, which may be the same or different, and R1, R2, and R3 are each independently selected from hydrogen, halogen, C 1‑5 Alkyl, C 1‑5 One or more of alkoxy, hydroxyl, nitro, cyano and amino. The compounds of the present invention can regulate K v 11.1 channel, restore or reverse the effect of astemizole on K v The inhibition of 11.1 channels reduces the cardiotoxicity of astemizole and has the pharmaceutical activity of alleviating acquired LQTS, making it a potential drug for the treatment of acquired LQTS.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a benzophenone compound and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to increase the understanding of the overall background of the application, and should not be necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art that has been known to ordinary technicians in the field.

[0003] K v 11.1 channel protein is expressed in human brain, heart, endocrine system, spleen, liver and other tissues, and is most expressed in myocardial cells. v 11.1 is often closely related to diseases such as arrhythmia, cancer, schizophrenia and endocrine disorders; among them, arrhythmia is caused by K v 11.1 It is caused by abnormal expression of channel protein in myocardial cells or drug blocking of the channel.

[0004] Arrhythmia refers to abnormalities in the frequency, rhythm, site of origin, conduction velocity, and order of activation of the heart's electrical impulses. Long QT syndrome (LQTS) is a type of arrhythmia. Loss-of-function mutations in the hERG gene (KCNH2) or blockage of the channel by external drugs can lead to a prolongation of the patient's cardiomyocyte action potential (APD), that is, a prolongation of the QT interval in the electrocardiogram. Abnormal T waves induce LQTS, resulting in ventricular arrhythmias, torsades de Pointes (TdP), ventricular fibrillation (VF), and even sudden death. LQTS can be divided into congenital and acquired types. Congenital LQTS is caused by K v Loss-of-function mutations in 11.1 channels cause I kr Abnormalities in the molecular structure of the channel protein reduce the outflow of the rapid delayed rectifier potassium ion current, leading to arrhythmias. On the other hand, people use some antiarrhythmic drugs (such as amiodarone, sotalol, brombenzylamine, ibuteri and dofetilide, etc.) or drugs for treating other diseases (such as antiallergic drugs, antipsychotic drugs, prokinetic agents, antitumor drugs, antibacterial drugs, etc.), which block K v 11.1 channels, resulting in reduced potassium ion efflux and thus acquired LQTS. Summary of the invention

[0005] The present invention provides a benzophenone compound and a preparation method and application thereof. The benzophenone compound provided by the present invention can regulate K v11.1 channel activity, which is manifested by the compounds of the present invention having an effect on K v 11.1 channels mediate activation or inhibition of potassium currents; at the same time, K v Compounds with strong activation effects on the 11.1 channel can be used to reverse the potassium ion outflow reduction effect caused by the channel blocker astemizole and increase channel function; in addition, the compounds of the present invention also have an effect on cardiac conduction velocity and can significantly shorten the side effect of prolonged cardiac conduction time caused by astemizole blocking the channel; finally, the present invention studies the activation and inactivation mechanism of the compounds, and the compounds can shift the steady-state activation curve to the left and the channel inactivation curve to the right. Therefore, the compounds can make K v 11.1 channels are more easily activated and less likely to be inactivated. Therefore, the benzophenone compounds or pharmaceutically acceptable salts thereof provided by the present invention, or pharmaceutical compositions or pharmaceutical preparations comprising these compounds, can significantly alleviate the cardiotoxicity of astemizole, and have high application value in the field of treatment of acquired LQTS.

[0006] Specifically, the present invention provides the following technical features, and a combination of one or more of the following technical features constitutes the technical solution of the present invention.

[0007] In the first aspect of the present invention, the present invention provides a benzophenone compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in Formula I:

[0008]

[0009] wherein X is -(C=O)-NH- or -NH-(C=O)-; n is an integer of 1-10;

[0010] R1, R2, and R3 represent one or more substituents, which may be the same or different. R1, R2, and R3 are each independently selected from hydrogen, halogen, C 1-5 Alkyl, C 1-5 one or more of alkoxy, hydroxy, nitro, cyano and amino;

[0011] Preferably, in some embodiments of the present invention, the structure of the compound is as shown in Formula II or III:

[0012]

[0013] Wherein, n is an integer of 1-3, and R1 and R2 are the same as defined above. Wherein, in formula II, when n=1, R1 and R2 are not H at the same time.

[0014] In some embodiments of the present invention, R1 represents one or two substituents selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3one or more of alkoxy, hydroxy, nitro, cyano and amino;

[0015] R2 is a substituent on the benzene ring selected from hydrogen, halogen, C 1-3 Alkyl and C 1-3 Alkoxy.

[0016] Wherein, in the compound of formula III, when R2 is hydrogen, the compound of formula III is G4:

[0017]

[0018] In some embodiments of the present invention, the structure of the compound of the present invention is shown in G1:

[0019]

[0020] Wherein, R1 and R2 are as defined above.

[0021] In some preferred embodiments, R1 is H; R2 is hydrogen, chlorine, fluorine, bromine, iodine, methyl, ethyl or isopropyl.

[0022] In some preferred embodiments, R1 is selected from one or two of methyl, ethyl, propyl (isopropyl), methoxy, nitro, cyano, fluorine, chlorine, bromine and iodine substituents.

[0023] In some preferred embodiments, R2 is fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, isopropyl, nitro, amino or cyano; and R1 is selected from one or two of fluorine, chlorine, bromine and iodine substituents.

[0024] In some embodiments of the present invention, the structure of the compound of the present invention is shown in II-1:

[0025]

[0026] Wherein, R1 and R2 are as defined above;

[0027] In some preferred embodiments, R2 is hydrogen; R1 is selected from one or two of fluorine, chlorine, bromine and iodine substituents, that is, the structure of the compound is G2:

[0028]

[0029] In some embodiments of the present invention, the structure of the compound of the present invention is shown in II-2:

[0030]

[0031] Wherein, R1 and R2 are as defined above;

[0032] In some preferred embodiments, R2 is hydrogen; R1 is selected from one or two of fluorine, chlorine, bromine and iodine substituents, that is, the structure of the compound is G3:

[0033]

[0034] In some embodiments of the present invention, the structure of the compound of the present invention is shown in III-1:

[0035]

[0036] Wherein, R1 and R2 are as defined above;

[0037] In some preferred embodiments, R2 is hydrogen; R1 is selected from one or two of fluorine, chlorine, bromine and iodine substituents.

[0038] In some embodiments of the present invention, the structure of the compound of the present invention is shown in III-2:

[0039]

[0040] Wherein, R1 and R2 are as defined above.

[0041] In some preferred embodiments, R2 is hydrogen; R1 is selected from one or two of fluorine, chlorine, bromine and iodine substituents.

[0042] As an example, the present invention provides a series of examples of the above compounds, which are selected from the following compounds:

[0043] SDUY400: 2-(4-(4-iodobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0044] SDUY401: 2-(4-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0045] SDUY403: 2-(4-(2-methylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0046] SDUY404: 2-(4-(3-methylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0047] SDUY405: 2-(4-benzoyl-2-chlorophenoxy)-N-(pyridin-3-yl)acetamide;

[0048] SDUY406: 2-(4-(3-nitrobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0049] SDUY408: 2-(4-(3-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0050] SDUY409: 2-(4-(2-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0051] SDUY410: 2-(4-(4-nitrobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0052] SDUY415: 2-(4-(3-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0053] SDUY417: 2-(4-(4-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0054] SDUY418: 2-(4-(2-bromo-4-fluorobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0055] SDUY420: 2-(4-(2-bromo-5-iodobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0056] SDUY421: 2-(4-(2-bromo-4-chlorobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide;

[0057] SDUY424: 2-(4-(2-bromo-3-chlorobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide;

[0058] SDUY425: 2-(4-(2-bromo-4-iodobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide;

[0059] SDUY429: 2-(4-(2-bromo-3-iodobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide;

[0060] SDUY432: 2-(4-(2-bromobenzoyl)-3-methylphenoxy)-N-(pyridin-3-yl)acetamide;

[0061] SDUY431: 2-(4-(2-bromobenzoyl)-2-methylphenoxy)-N-(pyridin-3-yl)acetamide;

[0062] SDUY436: 2-(4-(2-bromobenzoyl)-2-chlorophenoxy)-N-(pyridin-3-yl)acetamide;

[0063] SDUY437: 2-(4-(2-ethylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0064] SDUY438: 2-(4-(4-ethylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0065] SDUY439: 2-(4-(4-isopropylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0066] SDUY440: 2-(4-(2-bromobenzoyl)-2-ethylphenoxy)-N-(pyridin-3-yl)acetamide;

[0067] SDUY441: 2-(4-(4-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0068] SDUY428: 2-(4-(2-bromobenzoyl)-3-fluorophenoxy)-N-(pyridin-3-yl)acetamide;

[0069] SDUY411: 4-(4-(2-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)butanamide;

[0070] SDUY426: 4-(4-(2-bromo-5-chlorobenzoyl)phenoxy)-N-(pyridin-3-yl)butanamide;

[0071] SDUY430: 3-(4-(2-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acrylamide;

[0072] SDUY427: 3-(4-(2-bromo-5-chlorobenzoyl)phenoxy)-N-(pyridin-3-yl)acrylamide;

[0073] SDUY422: N-(2-(4-(2-bromobenzoyl)phenoxy)ethyl)nicotinamide:

[0074] SDUY434: N-(3-(4-(2-bromobenzoyl)phenoxy)propyl)nicotinamide;

[0075] SDUY435: (3-(4-(2-bromo-5-chlorobenzoyl)phenoxy)propyl)nicotinamide;

[0076] SDUY423: N-(2-(4-(2-bromo-5-chlorobenzoyl)phenoxy)ethyl)nicotinamide;

[0077] SDUY412: 2-(4-(3-aminobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0078] SDUY413: 2-(4-(4-aminobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0079] SDUY414: 2-(4-(3-hydroxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0080] SDUY416: 2-(4-(4-hydroxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide;

[0081] SDUY419: 2-(4-(2-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide.

[0082] Pharmaceutically acceptable salts described in the present application refer to the acidic and / or basic salts of the compound of formula I or its stereoisomer, formed with inorganic and / or organic acids and bases, also include zwitterionic salts (inner salts), also include quaternary ammonium salts, such as: alkylammonium salts. These salts can be directly obtained in compound separation and purification, and can also be obtained by mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base appropriately (such as: equivalent). These salts can be obtained by trying the following methods, for example: forming a precipitation in a solution and collecting it with a filtering method, or recovering it after solvent evaporation, or freeze-drying it after reaction in an aqueous medium.

[0083] In some embodiments of the present application, the pharmaceutically acceptable salt described in the present application can be a hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, formate, acetate, propionate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate, or p-toluenesulfonate of a compound of formula I.

[0084] In the second aspect of the present invention, the present invention provides a method for preparing the compound described in the first aspect or a pharmaceutically acceptable salt thereof, comprising: using R1-substituted benzoic acid A1 and anisole containing an R2 substituent as starting materials, and finally obtaining the compound of formula I of the present application through chloroacylation reaction of carboxylic acid, Friedel-Crafts acylation reaction, demethylation reaction, substitution reaction, hydrolysis reaction and amide condensation reaction.

[0085] Specifically, in some embodiments of the present invention, the preparation method of the present invention is as shown in route 1:

[0086] Route 1:

[0087]

[0088] Wherein, R1 and R2 are as defined above.

[0089] In an embodiment of the present invention, the method of route 1 comprises:

[0090] Step a: dissolve the R1-substituted benzoic acid in dichloromethane, add a catalytic amount of N,N-dimethylformamide, and slowly add oxalyl chloride under nitrogen protection and ice bath conditions, and stir to react at room temperature. After the reaction is complete, the reaction mixture is concentrated and dried under reduced pressure to obtain intermediate B1;

[0091] Step b: Dissolve B1 in dichloromethane, add anisole substituted by R2, add anhydrous aluminum chloride under ice bath conditions, and slowly return to room temperature for reaction. After the reaction is complete, add 5% citric acid solution to the reaction solution, extract with dichloromethane three times, combine the organic phases, wash twice with saturated brine, wash once with water, dry over anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain intermediate C1;

[0092] Step c: C1 was dissolved in toluene solution, anhydrous aluminum chloride was slowly added, and the mixture was refluxed at 130° C. After the reaction was complete, the reactant was cooled to room temperature, quenched by adding 3M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain intermediate D1;

[0093] Step d: D1 was dissolved in N,N-dimethylformamide, anhydrous potassium carbonate and methyl bromoacetate were added, the mixed solution was stirred at 65°C for reaction, and the reaction was monitored by TLC until completion, cooled to room temperature, washed with a large amount of water, extracted with ethyl acetate three times, the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain intermediate E1;

[0094] Step e: E1 was dissolved in tetrahydrofuran / methanol (1:1), 1 M lithium hydroxide aqueous solution was added, and the mixture was reacted at 100° C. The reaction was monitored by TLC until completion, and the mixture was cooled to room temperature. The pH was adjusted to pH=1 using 3 M hydrochloric acid, the precipitate was collected by filtration, and the mixture was washed with water and petroleum ether for multiple times to obtain intermediate F1;

[0095] Step f: F1 was dissolved in N,N-dimethylformamide, triethylamine, 3-aminopyridine and HATU were added in sequence, the reaction was stirred at room temperature overnight, and the reaction was monitored by TLC until completion. The mixture was cooled to room temperature, washed with a large amount of water, extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100:1) to obtain the final product G1.

[0096] In some embodiments of the present invention, the preparation method of the present invention is as shown in Scheme 2:

[0097] Route 2:

[0098]

[0099] wherein R1 is as defined above and R2 is hydrogen.

[0100] In an embodiment of the present invention, the method of route 2 comprises:

[0101] Step a: Dissolve the intermediate D2 in N,N-dimethylformamide, add anhydrous potassium carbonate and ethyl 4-bromobutyrate, stir the mixed solution at 65°C for reaction, monitor by TLC until the reaction is complete, cool to room temperature, wash with water, extract with ethyl acetate three times, combine the organic phases, wash twice with saturated brine, wash once with water, dry over anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain the intermediate E2;

[0102] Step b: E2 was dissolved in tetrahydrofuran / methanol (1:1) solution, 1M lithium hydroxide aqueous solution was added, and the reaction was carried out at 100°C. TLC was monitored until the reaction was complete, and the reaction was cooled to room temperature. 3M hydrochloric acid was added to adjust the pH to 1, and the precipitate was collected by filtration. Water and petroleum ether were added to wash the mixture several times to obtain intermediate F2;

[0103] Step c: F2 was dissolved in N,N-dimethylformamide, triethylamine, 3-aminopyridine and HATU were added in sequence, the reaction was stirred at room temperature overnight, and the reaction was monitored by TLC until the reaction was complete. The mixture was cooled to room temperature, washed with a large amount of water, extracted with ethyl acetate three times, the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the final product G2;

[0104] Wherein, in some embodiments of the present invention, the molar ratio of the intermediate D2, ethyl 4-bromobutyrate and anhydrous potassium carbonate in step a is 1:2:2, the solvent is N,N-dimethylformamide, and the amount of the solvent is 3 mL of N,N-dimethylformamide per mmol of the intermediate D2;

[0105] In some embodiments of the present invention, the molar ratio of the intermediate E2 to lithium hydroxide in step b is 1:5, the solvent is a mixed solution of tetrahydrofuran and anhydrous methanol (1:1), and the amount of the solvent is 3 mL of solvent per mmol of the intermediate E2;

[0106] In some embodiments of the present invention, the molar ratio of the intermediate F2, 3-aminopyridine, triethylamine and HATU in step c is 1:1.5:1.5:1.5, the solvent is N,N-dimethylformamide, and the amount of the solvent is 2 mL of solvent per mmol of intermediate F2.

[0107] In some embodiments of the present invention, the preparation method of the present invention is carried out according to route three:

[0108] Route 3:

[0109]

[0110] wherein R1 is as defined above and R2 is hydrogen.

[0111] In an embodiment of the present invention, the method of route three comprises:

[0112] Step a: Take intermediate D3 as the starting material and dissolve it in acetonitrile, add 3-bromo-1-propanol and anhydrous potassium carbonate, reflux at 65°C, monitor by TLC until the reaction is complete, cool to room temperature, filter the reaction mixture and extract it three times with ethyl acetate, combine the organic phases, wash it twice with saturated brine, wash it once with water, dry it over anhydrous sodium sulfate, and concentrate it by rotary evaporation to obtain intermediate E3;

[0113] Step b: E3 was dissolved in acetone, Jones reagent was added dropwise under ice bath condition, stirred at room temperature overnight, monitored by TLC until the reaction was complete, water was added to the mixed solution, extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine and once with water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain intermediate F3;

[0114] Step c: F3 was dissolved in N,N-dimethylformamide, triethylamine, 3-aminopyridine and HATU were added in sequence, and the mixture was stirred at room temperature for overnight reaction. The reaction was monitored by TLC until completion, and the mixture was cooled to room temperature, washed with water, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine twice, washed with water once, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The residue was chromatographed on a silica gel column (dichloromethane:methanol=100:1) to obtain the final product G3;

[0115] Wherein, in some embodiments of the present invention, the molar ratio of the intermediate D3, 3-bromo-1-propanol, and anhydrous potassium carbonate in step a is 1:3.3:1.1, and the solvent is acetonitrile, and the amount of the solvent is 3 mL of acetonitrile per mmol of the intermediate D3;

[0116] In some embodiments of the present invention, the intermediate E3 and Jones reagent (6 mL Jones reagent is used for 1 mmol E3) in step b are used as the solvent, and the amount of the solvent is acetone, and each mmol of the intermediate E3 is dissolved in 3 mL of the solvent.

[0117] In some embodiments of the present invention, the molar ratio of the intermediate F3, 3-aminopyridine, triethylamine and HATU in step c is 1:1.5:1.5:1.5, the solvent is N,N-dimethylformamide, and the amount of the solvent is 2 mL of solvent per mmol of intermediate F3.

[0118] In some embodiments of the present invention, the preparation method of the present invention is carried out according to route 4:

[0119] Route 4:

[0120]

[0121] wherein R1 is as defined above and R2 is hydrogen.

[0122] In an embodiment of the present invention, the method of route 4 comprises:

[0123] Step a: intermediate D4 is used as a starting material and dissolved in tetrahydrofuran, tert-butyl (2-hydroxyethyl) carbamate or tert-butyl (3-hydroxypropyl) carbamate and triphenylphosphine are added, diethyl azodicarboxylate is added dropwise in an ice bath under nitrogen protection, and the temperature is restored to room temperature for reaction after the addition is completed. After the reaction is completed as monitored by TLC, the reaction is quenched with ice water, extracted three times with ethyl acetate, the organic phases are combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the residue is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain intermediate E4;

[0124] Step b: E4 was dissolved in dichloromethane, trifluoroacetic acid was added and reacted at room temperature. After the reaction was complete, the mixture was concentrated by rotary evaporation and the pH was adjusted to 8 with saturated sodium bicarbonate to obtain intermediate F4;

[0125] Step c: Dissolve F4 in N,N-dimethylformamide, add triethylamine, 3-aminopyridine and HATU in sequence, stir overnight at room temperature, and monitor the reaction by TLC. Add water and ethyl acetate to the reaction system for separation and extraction, extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash the organic phases twice with saturated brine, wash once with water, dry over anhydrous sodium sulfate, and concentrate by rotary evaporation. The residue is chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain the final product G4. Wherein, in some embodiments of the present invention, the molar ratio of the intermediate D4, tert-butyl (2-hydroxyethyl) carbamate or tert-butyl (3-hydroxypropyl) carbamate, diethyl azodicarboxylate, and triphenylphosphine in step a is 1:1:3:2, the solvent is tetrahydrofuran, and the amount of the solvent is 3 mL of tetrahydrofuran per millimole of the intermediate D4;

[0126] In some embodiments of the present invention, in step b, 1 mmol of E4 uses 6 mL of Jones reagent, the solvent is dichloromethane, and the amount of the solvent is 3 mL of solvent per mmol of intermediate E4.

[0127] In some embodiments of the present invention, the molar ratio of the intermediate F4, nicotinic acid, triethylamine and HATU in step c is 1:1.5:1.5:1.5, the solvent is N,N-dimethylformamide, and the amount of the solvent is 2 mL of solvent per mmol of intermediate F4.

[0128] In some embodiments of the present invention, the preparation method of the present invention is carried out according to route 5:

[0129] Route 5:

[0130]

[0131] Among them, R1 is nitro or amino, preferably 3-NH2 or 4-NH2, and R2 is hydrogen.

[0132] In an embodiment of the present invention, the method of route 5 comprises: using F5 (3-NO2 or 4-NO2) as a raw material, dissolving ammonium chloride in a mixed solution of isopropanol / water (2:1), adding iron powder and reacting under reflux at 90°C, monitoring the reaction to be complete by TLC, filtering while hot, extracting the filtrate with ethyl acetate three times, combining the organic phases, washing twice with saturated brine, washing once with water, drying over anhydrous sodium sulfate, and concentrating by rotary evaporation. The residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100:1) to obtain the final product G5. Wherein, in some embodiments of the present invention, the molar ratio of F5 (3-NO2 or 4-NO2), iron powder and ammonium chloride is 1:5:5, the solvent is isopropanol and water, and the amount of the solvent is 2 mL of solvent per millimole of the raw material.

[0133] In some embodiments of the present invention, the preparation method of the present invention is carried out according to route 6:

[0134] Route 6:

[0135]

[0136] Among them, R1 is hydroxyl, preferably 3-OH or 4-OH, and R2 is hydrogen.

[0137] In an embodiment of the present invention, the method of route six comprises:

[0138] Step a: Take F6 (3-Br or 4-Br) as a raw material and dissolve it in 1,4-dioxane, add bis(2-boron), potassium acetate and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, and reflux at 110° C. for 4 hours under nitrogen protection to obtain a borate ester intermediate;

[0139] Step b: The borate intermediate was dissolved in tetrahydrofuran, 4-methylmorpholine-4-oxide was added, and the mixture was refluxed at 70°C for two hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered, the residue was washed with ethyl acetate, and the filtrate was collected. The filtrate was washed twice with saturated brine and once with water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain the final product G6;

[0140] Wherein, in some embodiments of the present invention, the molar ratio of F6 (3-Br or 4-Br), bis(boron), potassium acetate, and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride in step a is 1:2:3:0.1, the solvent is 1,4-dioxane, and the amount of the solvent is 2 mL of solvent per mmol of the raw material.

[0141] In some embodiments of the present invention, the molar ratio of the intermediate to 4-methylmorpholine-4-oxide in step b is 1:3, the solvent is tetrahydrofuran, and the amount of the solvent is 2 mL of solvent per mmol of the intermediate.

[0142] In some embodiments of the present invention, the preparation method of the present invention is carried out according to route 7:

[0143] Route 7:

[0144]

[0145] In an embodiment of the present invention, the method of route seven comprises: using F7-1 as a raw material, adding K4[Fe(CN)6]·3H2O, anhydrous sodium carbonate and palladium acetate to N,N-dimethylacetamide, refluxing at 120°C under nitrogen protection, monitoring the reaction to be complete by TLC, filtering while hot, washing the filter residue with ethyl acetate, collecting the filtrate, washing the filtrate twice with saturated brine, washing once with water, drying over anhydrous sodium sulfate, and concentrating by rotary evaporation. The residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the final product SDUY419;

[0146] In some embodiments of the present invention, the molar ratio of F7-1, K4[Fe(CN)6]·3H2O, sodium carbonate and palladium acetate is 1:0.4:1:0.1, the solvent is N,N-dimethylacetamide, and the amount of the solvent is 2 mL of solvent per mmol of raw material.

[0147] In the fourth aspect of the present invention, the present invention provides a pharmaceutical composition or pharmaceutical preparation, which comprises the compound or a pharmaceutically acceptable salt thereof described in the first aspect above; and, further, the pharmaceutical preparation also comprises at least one pharmaceutically acceptable excipient or pharmaceutical carrier.

[0148] The pharmaceutical composition or pharmaceutical preparation described in the present application may contain one or more of the compounds of formula I or pharmaceutically acceptable salts thereof described in the first aspect above, such as the compound of formula I, or the hydrochloride of the compound of formula I, or the compound of formula I and the hydrochloride of the compound of formula I, etc. In some embodiments of the present application, the pharmaceutical composition or pharmaceutical preparation may be administered enterally or parenterally, and the dosage form includes but is not limited to tablets, capsules, pills, injections, etc.

[0149] In the embodiment of the present application, the pharmaceutical adjuvant or drug carrier should first be compatible with the compound described in the first aspect of the present application and not react, and secondly, the adjuvant or drug carrier complies with the relevant provisions in the pharmacopoeia and ICH. The adjuvant described in the present application can be an excipient, such as a binder, a filler, a wetting agent, a disintegrant, etc., which can be added and used as needed in tablets, capsules and pills for oral administration. And, if necessary, the pharmaceutical composition or preparation described in the present application may also contain other adjuvants such as flavorings, colorants, stabilizers, lubricants, or suitable dosage forms may also be coated using methods known in pharmacy.

[0150] In some embodiments of the present application, a method for producing a pharmaceutical composition or a pharmaceutical preparation is provided, the method comprising mixing one or more of the compounds described in the first aspect of the present application or a pharmaceutically acceptable salt thereof with a pharmaceutical excipient or a pharmaceutical carrier. For example, in some embodiments, a solid or liquid preparation can be prepared by uniformly mixing the active compound with a liquid and / or a finely pulverized solid excipient in a desired ratio, and then, if necessary, the resulting mixture is formed into a desired shape. The dosage form for parenteral administration is prepared, for example, as follows: the compound described in the first aspect of the present application is dissolved in a suitable liquid vehicle, the solution is filtered and sterilized, and then filled into a suitable vial or ampoule and sealed, and if necessary, such as considering transportation and storage, freeze-drying can also be attempted. Of course, in addition to this, the skilled person can also use other techniques or methods known in the art to formulate the compounds of the present application into pharmaceutical compositions or pharmaceutical preparations. For example, the preparation of pharmaceutical preparations can be carried out according to the modern pharmaceutical preparation series edited by Shenyang Pharmaceutical University. And, in addition to those mentioned in the present application, suitable pharmaceutical excipients may also be other types known in the art, such as those recorded in the Handbook of Pharmaceutical Excipients compiled by Paul JSheskey et al., which has been revised to the eighth edition.

[0151] In the fifth aspect of the present invention, the present invention provides a method for preparing a method for regulating K v11.1 Application of drugs or reagents in the channel.

[0152] In some embodiments of the present invention, the compounds of the present invention can activate or inhibit K v 11.1 channel, so the drug or preparation is K v 11.1 Channel Activators or K v 11.1 Channel inhibitors.

[0153] In the sixth aspect of the present invention, the present invention provides use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of an astemizole antagonist drug or reagent.

[0154] In some embodiments of the present invention, the antagonism of the present invention is to restore or reverse the effect of astemizole on K v The inhibition of 11.1 channels reduces the cardiotoxicity of astemizole and has the efficacy of alleviating acquired LQTS.

[0155] In the seventh aspect of the present invention, the present invention provides use of the compound or a pharmaceutically acceptable salt thereof described in the first aspect in the preparation of a medicament for treating acquired LQTS.

[0156] In the eighth aspect of the present invention, the present invention provides use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of an antiarrhythmic drug.

[0157] In the ninth aspect of the present invention, the present invention provides a method for activating or inhibiting K v 11.1 A method of treating a patient's condition, comprising administering to a subject an effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt thereof.

[0158] In the tenth aspect of the present invention, the present invention provides a method for treating acquired LQTS, comprising administering to a subject a therapeutically effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt thereof.

[0159] By using the above technical means, the following beneficial effects can be achieved: the compounds of the present invention have an effect on K v 11.1 channel has good activation activity; in the microscale thermophoresis experiment (MST experiment), some compounds interacted with K v 11.1 channel protein showed good binding affinity. In in vitro functional experiments (whole-cell patch clamp electrophysiological experiments), some compounds had good binding affinity to K v The 11.1 channel-mediated potassium current showed strong activation activity and could reverse the K v11.1 channel blocking and enhancing channel function; at the same time, some compounds of the present invention also have an effect on cardiac conduction velocity and can significantly alleviate the prolonged cardiac conduction time caused by astemizole; compound activation and inactivation mechanism studies have shown that some compounds can shift the steady-state activation curve to the left and the channel inactivation curve to the right, thereby making K v 11.1 channel is easier to activate and less likely to be inactivated. Therefore, the compound of formula I structure, pharmaceutical salt or pharmaceutically acceptable pharmaceutical composition with these compounds as main active ingredients described in the present invention can be used to prepare antiarrhythmic drugs, and has high application value in alleviating drug hERG cardiotoxicity and acquired LQTS. BRIEF DESCRIPTION OF THE DRAWINGS

[0160] The drawings constituting part of the present application are used to provide a further understanding of the present application. The illustrative embodiments and descriptions of the present application are used to explain the present application and do not constitute an improper limitation on the present application. The implementation scheme of the present application is described in detail below in conjunction with the drawings, wherein:

[0161] Figure 1 :The target compound of the present invention has an effect on K v Activation diagram of 11.1 channel, including: (a) current activation diagram before and after administration of compound SDUY403; (b) current activation diagram before and after administration of compound SDUY414; (c) K v 11.1 Potassium current amplification graph.

[0162] Figure 2 : Representative K v 11.1 Dose-effect curve of channel activator.

[0163] Figure 3 :Compounds inhibit K of astemizole v 11.1 Channel current recovery diagram, where: (a) Different concentrations of astemizole affect K v 11.1 Effect of astemizole on channel current; (b) Astemizole concentration-current relationship; (c) Astemizole dose-effect curve; (d) Effect of compound SDUY403 on the inhibition of K by different concentrations of astemizole v 11.1 Effects of the channel current; (e) Effects of compound SDUY403 on the inhibition of K by different concentrations of astemizole v 11.1 Concentration-current relationship of channel current; (f) Effect of compound SDUY436 on the inhibition of K by different concentrations of astemizole v 11.1 Concentration-current relationship of channel current; (g) Effect of compound SDUY424 on the inhibition of K by different concentrations of astemizole v 11.1 Concentration-current relationship diagram of channel current; (h) Effect of compound SDUY415 on the inhibition of K by different concentrations of astemizole v11.1 Concentration-current relationship of channel current; (i) Effect of compound SDUY437 on the inhibition of K by different concentrations of astemizole v 11.1 Concentration-current relationship diagram of channel current.

[0164] Figure 4 : The restorative effect of compounds on the prolongation of cardiac excitation conduction time by 100 nM astemizole, wherein: (ad) show the effects of 100 nM astemizole and 5 μM SDUY403, SDUY436, SDUY424 and SDUY437 on cardiac conduction time under 8 Hz stimulation.

[0165] Figure 5 :Compound SDUY403 has an effect on K v 11.1 Effect diagrams of channel activation and inactivation gating characteristics, including: (a) activation segment current change diagram before administration of compound SDUY403; (b) activation segment current change diagram after administration of compound SDUY403; (c) activation curve diagram; (d) inactivation segment current change diagram before administration of compound SDUY403; (e) inactivation segment current change diagram after administration of compound SDUY403; (f) inactivation curve diagram.

[0166] Figure 6 :Compound SDUY436 has an effect on K v 11.1 Effect diagrams of channel activation and inactivation gating characteristics, including: (a) activation segment current change diagram before administration of compound SDUY436; (b) activation segment current change diagram after administration of compound SDUY436; (c) activation curve diagram; (d) inactivation segment current change diagram before administration of compound SDUY436; (e) inactivation segment current change diagram after administration of compound SDUY436; (f) inactivation curve diagram. DETAILED DESCRIPTION

[0167] The present application is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0168] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. The reagents or raw materials used in this application can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in this application are used in a conventional manner in the art or in accordance with the product instructions. In addition, any method and material similar to or equivalent to the content described herein can be applied to the method of this application. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0169] Preparation Example :Synthesis of target compound

[0170] 1. Experimental instruments and reagents: The low-resolution mass spectrometry data of the compound was determined by the Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, and the high-resolution mass spectrometry was determined by the Public Experimental Research Center of Xuzhou Medical University using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. 1 H NMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR was measured by the Analysis and Testing Center of the School of Pharmacy of Shandong University. The solvent used was deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3), tetramethylsilane (TMS) was used as the internal standard, the chemical shift was expressed in δ (ppm), the coupling constant was expressed in J (Hz), and the various types of peaks mainly included: s-singlet, d-doublet, t-triplet, m-multiplet, etc.

[0171] The raw materials used in this experiment were used directly in the reaction without purification unless otherwise specified. The raw materials were mainly purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Beijing Inokai Technology Co., Ltd., Beijing Myrida Co., Ltd., Jinan Zhaoxu Co., Ltd., Beijing Bailingwei Reagent Co., Ltd., Shandong Chengchuan Reagent Co., Ltd., Jinan Saibo Reagent Co., Ltd., Jinan Zhizun Reagent Co., Ltd., Beijing Myril Co., Ltd. and other reagent companies. The solvents used were analytical grade, and standard methods were used for purification and drying when necessary.

[0172] 2. Synthesis of target compound:

[0173] Preparation of 2-(4-(4-iodobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY400)

[0174] 4-iodobenzoic acid A1-1 (3.00 g, 12.09 mmol) was dissolved in 100 mL of dichloromethane, and 5 drops of N,N-dimethylformamide were added. Oxalyl chloride (3.07 g, 24.19 mmol) was slowly added under nitrogen protection and ice bath conditions, and stirred at room temperature for 2 hours. The reaction was completed after TLC monitoring. The reaction solution was concentrated to obtain 3.00 g of intermediate B1-1; B1-1 (3.00 g, 11.30 mmol) and anisole (1.52 g, 14.10 mmol) were dissolved in dichloromethane, and anhydrous aluminum chloride (1.88 g, 14.10 mmol) was slowly added under ice bath conditions. The reaction was reacted at room temperature for 1 hour. The reaction was completed after TLC monitoring. 50 mL of 5% citric acid solution, extracted with dichloromethane three times (50mL×3), combined organic phases, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate C1-1; C1-1 (2.00 g, 5.91 mmol) was dissolved in 15 mL of toluene solution, anhydrous aluminum chloride (1.97 g, 14.80 mmol) was slowly added at room temperature, refluxed at 130°C for 2 hours, and the reaction was complete after TLC monitoring. The reaction solution was cooled to room temperature and quenched by adding 3M hydrochloric acid. The reaction solution was extracted with ethyl acetate three times (50 mL×3), combined organic phases, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain intermediate D1-1; D1-1 (1.50 g, 4.63 mmol) was dissolved in 15 mL Anhydrous potassium carbonate (1.28 g, 9.26 mmol) and methyl bromoacetate (1.42 g, 4.63 mmol) were added to N,N-dimethylformamide, and the mixture was stirred at 65°C for 2 hours. The reaction was complete after monitoring by TLC. The reaction solution was cooled to room temperature, and saturated brine was added. The mixture was extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate E1-1. E1-1 (0.61 g, 1.54 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (8 mL:8 mL), and 1 M aqueous lithium hydroxide solution was added. The mixture was refluxed at 100°C for 4 hours. The reaction was complete after monitoring by TLC. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 3 M hydrochloric acid. The reaction solution was filtered, the residue was collected, and the residue was washed with water and petroleum ether to obtain intermediate F1-1. F1-1 (0.30 g, 0.79 mmol) was dissolved in 10 mL Triethylamine (0.09 g, 0.86 mmol), 3-aminopyridine (0.08 g, 0.86 mmol) and HATU (0.45 g, 1.19mmol), stirred at room temperature overnight, TLC monitored the reaction to be complete, added saturated brine, extracted with ethyl acetate three times (50mL×3), combined the organic phases, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.30g of brown solid SDUY400, yield: 83%. Melting point: 195-196℃. . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.79(dd,J=2.6,0.8Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.07(ddd,J=8.3,2.6,1.5Hz,1 H),7.98-7.89(m,2H),7.80-7.74(m,2H),7.51-7.44(m,2H),7.38(ddd,J=8.3,4.7,0.8Hz,1H),7.21-7.13(m,2H),4.89(s,2H); 13 C NMR(151MHz,DMSO-d6)δ194.21,167.10,162.05,145.22,141.88,137.87,137.45 ,135.47,132.57,131.54,130.20,127.29,124.12,115.18,100.70,67.49.HR-MS m / z:calcdfor C 20 H 15 IN2O3[(MH) - ],457.0049;found,457.0082.

[0175] Preparation of 2-(4-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY401)

[0176] 4-Bromobenzoic acid A1-2 (1.00 g, 4.60 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.00 g of intermediate B1-2; B1-2 (1.00 g, 4.55 mmol) was dissolved in dichloromethane, anisole (0.62 g, 5.68 mmol) and anhydrous aluminum chloride (0.76 g, 5.68 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction was completed after TLC monitoring, 50 mL of 5% citric acid solution was added to the reaction solution, and the mixture was extracted with dichloromethane three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain The intermediate obtained 1.15g of intermediate C1-2; C1-2 (1.00g, 3.43mmol) was dissolved in toluene, anhydrous aluminum chloride (0.57g, 4.29mmol) was added, and the mixture was refluxed at 110°C for 2 hours. The reaction was completed after TLC monitoring. The reaction solution was cooled to room temperature and quenched by adding 3M hydrochloric acid. The reaction solution was extracted with ethyl acetate three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain 0.80g of intermediate D1-2; D1-2 (0.80g, 2.89mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (0.88 g, 5.77mmol) and anhydrous potassium carbonate (0.80g, 5.77mmol), reflux at 65℃ for 2 hours, the reaction is complete after TLC monitoring, the reaction solution is cooled to room temperature, saturated brine is added, extracted with ethyl acetate three times (50mL×3), the organic phases are combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.00g of intermediate E1-2; E1-2 (1.00g, 2.86mmol) is dissolved in a mixed solution of tetrahydrofuran / methanol (1:1), 1M lithium hydroxide aqueous solution is added, refluxed at 100℃ for 4 hours, the reaction is complete after TLC monitoring, the reaction solution is cooled to room temperature, adjusted to pH=1 with 3M hydrochloric acid, the reaction solution is filtered, the filter residue is collected, and washed with water and petroleum ether The residue was filtered to obtain 0.90 g of intermediate F1-2; F1-2 (0.50 g, 1.49 mmol) was dissolved in N,N-dimethylformamide, and triethylamine (0.17 g, 1.64 mmol), 3-aminopyridine (0.15 g, 1.64 mmol) and HATU (0.85 g, 1.64 mmol) were added in sequence, and stirred at room temperature overnight. The reaction was completed after monitoring by TLC, and saturated brine was added. The mixture was extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain 0.47 g of light yellow solid SDUY401, with a yield of 77%.Melting point: 170-171℃. 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.80(dd,J=2.6,0.8Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.07(ddd,J=8.4,2.6 ,1.5Hz,1H),7.83-7.72(m,4H),7.68-7.59(m,2H),7.38(ddd,J=8.3,4.7,0.8Hz,1H),7.21-7.14(m,2H),4.90(s,2H); 13 CNMR(151MHz,DMSO-d6)δ193.92,167.10,162.08,145.21,141.87,137.18,135.4 8,132.59,132.02,131.76,130.19,127.30,126.52,124.12,115.20,67.49.HR-MS m / z:calcd forC 20 H 15 BrN2O3[(MH) - ],409.0188;found,409.0217.

[0177] Preparation of 2-(4-(2-methylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY403)

[0178] 2-Methylbenzoic acid A1-3 (1.50 g, 11.03 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.50 g of intermediate B1-3; B1-3 (1.50 g, 9.70 mmol) was dissolved in dichloromethane, anisole (1.31 g, 12.10 mmol) and anhydrous aluminum chloride (1.61 g, 12.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.95 g of intermediate C1-3; C1-3 (1.95 g, 8.62 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.87 g, 21.50 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.91 g of intermediate D1-3; D1-3 (1.91 g, 9.00 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (2.75 g, 18.00 mmol) and anhydrous potassium carbonate (2.49 g, 18.00 mmol) were added, and refluxed at 65°C for 2 hours to obtain 1.50 g of intermediate E1-3; E1-3 (1.50 g, 5.28 mmol) was dissolved in A 1M lithium hydroxide aqueous solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.00 g of intermediate F1-2; F1-3 (0.50 g, 1.85 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.21 g, 2.03 mmol), 3-aminopyridine (0.19 g, 2.03 mmol) and HATU (1.06 g, 2.78 mmol) were added in sequence, and stirred at room temperature overnight to obtain 0.45 g of light yellow solid SDUY403. The above post-treatment method was the same as compound SDUY400, with a yield of 70%. Melting point: 62-63°C. 1 H NMR (600MHz, DMSO-d6) δ10.38(s,1H),8.83-8.72(m,1H),8.30(dd,J=4.7,1.5Hz,1H),8.05(ddd,J=8.3,2.6,1.5Hz,1H),7.75-7.62(m,2H), 7.44(td,J=7.5,1.6Hz,1H),7.40-7.33(m,2H),7.33-7.29(m,1H),7.27(dd,J=7.6,1.6Hz,1H),7.17-7.12(m,2H),4.87(s,2H),2.20(s,3H); 13C NMR(151MHz,DMSO-d6)δ196.73,167.04,162.44,145.21,141.88,139.34,135.70,135.45,13 2.42,131.20,130.87,130.36,127.94,127.31,125.89,124.10,115.35,67.47,19.71.HR-MS m / z:calcd for C 21 H 18 N2O3[(MH) - ],345.1239;found,345.1262.

[0179] Preparation of 2-(4-(3-methylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY404)

[0180] 3-Methylbenzoic acid A1-4 (1.50 g, 11.03 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.50 g of intermediate B1-4; B1-4 (1.50 g, 9.70 mmol) was dissolved in dichloromethane, anisole (1.31 g, 12.10 mmol) and anhydrous aluminum chloride (1.61 g, 12.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 2.00 g of intermediate C1-4; C1-4 (2.00 g, 8.84 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.95 g, 22.10 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 1.52 g of intermediate D1-4; D1-4 (1.52 g, 7.16 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (2.19 g, 14.32 mmol) and anhydrous potassium carbonate (2.00 g, 14.32 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 1.50 g of intermediate E1-4; E1-4 (1.50 g, 5.28 mmol) was dissolved in A 1M lithium hydroxide aqueous solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.00 g of intermediate F1-4; F1-4 (0.50 g, 1.85 mmol) was dissolved in N,N-dimethylformamide, and triethylamine (0.21 g, 2.03 mmol), 3-aminopyridine (0.19 g, 2.03 mmol) and HATU (1.06 g, 2.78 mmol) were added in sequence, and stirred at room temperature overnight to obtain 0.56 g of light yellow solid SDUY404. The above post-treatment method was the same as compound SDUY400, with a yield of 88%. Melting point: 122-123°C. 1H NMR (600MHz, DMSO-d6) δ10.38(s,1H),8.81(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.08(ddd,J=8.3,2.6,1.5Hz,1H),7.8 3-7.72(m,2H),7.54-7.50(m,1H),7.50-7.41(m,3H),7.38(dd,J=8.3,4.7Hz,1H),7.23-7.11(m,2H),4.89(s,2H),2.39(s,3H); 13 C NMR(151MHz,DMSO-d6)δ195.01,167.14,161.87,145.22,141.90,138.35,138.23,135.47,13 3.23,132.51,130.71,130.05,128.78,127.31,127.00,124.10,115.11,67.50,21.35.HR-MS m / z:calcd for C 21 H 18 N2O3[(MH) - ],345.1239;found,345.1260.

[0181] Preparation of 2-(4-benzoyl-2-chlorophenoxy)-N-(pyridin-3-yl)acetamide (SDUY405)

[0182] Benzoic acid (1.50 g, 12.29 mmol) was dissolved in dichloromethane, 4 drops of N,N-dimethylformamide were added, oxalyl chloride (3.11 g, 24.58 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 h to obtain 1.50 g of intermediate benzoyl chloride; benzoyl chloride (1.50 g, 12.48 mmol) was dissolved in dichloromethane, 2′-chloroanisole (2.22 g, 15.60 mmol) and anhydrous aluminum chloride (1.61 g, 12.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 2.00 g of intermediate C1-5; C1-5 (2.00 g, 8.10 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.69 g, 20.25 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 2.00 g of intermediate D1-5; D1-5 (2.00 g, 8.60 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (2.63 g, 17.20 mmol) and anhydrous potassium carbonate (2.38 g, 17.20 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 2.66 g of intermediate E1-5; E1-5 (2.66 g, 8.73 mmol) was dissolved in tetrahydrofuran A 1M lithium hydroxide aqueous solution was added to a mixed solution of furan / methanol (1:1), and refluxed at 100°C for 4 hours to obtain 3.70 g of intermediate F1-5; F1-5 (3.70 g, 12.70 mmol) was dissolved in N,N-dimethylformamide, triethylamine (1.42 g, 14.00 mmol), 3-aminopyridine (1.32 g, 14.00 mmol) and HATU (7.26 g, 19.10 mmol) were added in sequence, and stirred at room temperature overnight to obtain 2.00 g of light yellow solid SDUY405. The above post-treatment method was the same as compound SDUY400, with a yield of 44%. Melting point: 132-133°C. 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.81(d,J=2.5Hz,1H),8.34(dd,J=4.7,1.5Hz,1H),8.09(dt,J=8.6,1.9Hz,1H),7.83 (d,J=2.1Hz,1H),7.74-7.65(m,4H),7.57(t,J=7.6Hz,2H),7.43(dd,J=8.4,4.8Hz,1H),7.26(d,J=8.7Hz,1H),5.06(s,2H); 13C NMR(151MHz,DMSO-d6)δ193.88,166.62,157.39,144.60,140.89,137.51,135.73,133.00 ,131.81,131.27,131.14,129.83,129.06,127.65,124.48,122.18,114.00,67.99.HR-MS m / z:calcd for C 20 H 15 ClN2O3[(M+Na) + ],389.0669;found,389.0647.

[0183] Preparation of 2-(4-(3-nitrobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY406)

[0184] 3-Nitrobenzoyl chloride B1-6 (4.00 g, 21.6 mmol) was dissolved in dichloromethane, and methyl phenoxyacetate (1.79 g, 21.6 mmol) and anhydrous aluminum chloride (5.76 g, 43.2 mmol) were added under ice bath, and reacted at room temperature for 1 hour. The reaction was completed after TLC monitoring. A 5% citric acid solution was added to the reaction solution, and the dichloromethane was extracted three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate E1- 6; E1-6 (4.12 g, 13.03 mmol) was dissolved in a tetrahydrofuran / methanol (10 mL:10 mL) mixed solution, 1 M lithium hydroxide (1.56 g, 65.30 mmol) aqueous solution was added, and the mixture was reacted at 100 ° C for 4 hours. The reaction was completed after TLC monitoring. The reaction solution was cooled to room temperature, adjusted to pH = 1 with 3 M hydrochloric acid, the reaction solution was filtered, the filter residue was collected, and the filter residue was washed with water and petroleum ether to obtain intermediate F1-6; F1-6 (2.00 g, 6.64 mmol) was dissolved in 15 mL Triethylamine (0.74 g, 7.30 mmol), 3-aminopyridine (0.69 g, 7.30 mmol) and HATU (3.79 g, 9.96 mmol) were added to N,N-dimethylformamide in sequence, stirred at room temperature overnight, and the reaction was complete after TLC monitoring. Saturated brine was added, and ethyl acetate was extracted three times (50 mL × 3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 1.98 g of yellow solid SDUY406, with a yield of 79%. Melting point: 210-211 ° C. 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.83(d,J=2.6Hz,1H),8.58(d,J=4.3Hz,1H),8.49(dd,J=8.3,2.4Hz,1H),8.30(dd,J=4.7,1.5Hz,1H),8.14(d t,J=7.7,1.4Hz,1H),8.09(dt,J=8.3,2.0Hz,1H),7.85-7.81(m,2H),7.39 (dd,J=4.7,2.1Hz,1H),7.38-7.35(m,1H),7.25-7.14(m,2H),4.95(s,2H); 13 C NMR(151MHz,DMSO-d6)δ192.83,167.08,162.55,148.18,145.09,141.78,140.06,139.49,135.79 ,134.98,132.83,130.83,129.52,128.38,127.11,126.87,124.13,120.12,115.35,67.44.HR-MS m / z:calcd for C 20 H 15 N3O5[(MH) - ],376.0933;found,376.0946.

[0185] Preparation of 2-(4-(3-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY408)

[0186] 3-Methoxybenzoyl chloride B1-7 (4.00 g, 23.40 mmol) was dissolved in dichloromethane, and methyl phenoxyacetate (4.29 g, 25.74 mmol) and anhydrous aluminum chloride (4.69 g, 35.10 mmol) were added under ice bath, and reacted at room temperature for 1 hour. The reaction was completed after TLC monitoring. A 5% citric acid solution was added to the reaction solution, and the dichloromethane was extracted three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.60 g of the intermediate. E1-7; E1-7 (2.60 g, 8.66 mmol) was dissolved in a tetrahydrofuran / methanol (10 mL:10 mL) mixed solution, 1 M lithium hydroxide aqueous solution was added, and the mixture was reacted at 100 ° C for 4 hours. The reaction was completed after TLC monitoring. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 3 M hydrochloric acid. The reaction solution was filtered, the filter residue was collected, and the filter residue was washed with water and petroleum ether to obtain 1.40 g of intermediate F1-7; F1-7 (1.40 g, 4.89 mmol) was dissolved in 15 mL Triethylamine (0.54 g, 5.38 mmol), 3-aminopyridine (0.51 g, 5.38 mmol) and HATU (2.79 g, 7.34 mmol) were added to N,N-dimethylformamide in sequence, stirred at room temperature overnight, and the reaction was complete after TLC monitoring. Saturated brine was added, and ethyl acetate was extracted three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 1.31 g of light yellow solid SDUY408, with a yield of 74%. Melting point: 120-121°C. 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.82(d,J=2.6Hz,1H),8.33(dd,J=4.7,1.5Hz,1H),8.10(ddd,J=8.4,2.6,1.5Hz,1H),7.90 -7.70(m,2H),7.47(t,J=7.8Hz,1H),7.41(dd,J=8.3,4.7Hz,1H),7.27-7.19(m,3H),7.19-7.13(m,2H),4.90(s,2H),3.82(s,3H); 13 C NMR(151MHz,DMSO-d6)δ194.59,167.17,161.93,159.63,144.90,141.52,139.56,135.59,13 2.56,130.54,130.07,127.67,124.27,122.18,118.49,115.12,114.49,67.49,55.81.HR-MS m / z:calcd for C21 H 18 N2O4[(MH) - ],361.1188;found,361.1193.

[0187] Preparation of 2-(4-(2-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY409)

[0188] 2-Methoxybenzoyl chloride B1-8 (4.00 g, 23.40 mmol) was dissolved in dichloromethane, and methyl phenoxyacetate (4.29 g, 25.74 mmol) and anhydrous aluminum chloride (4.69 g, 35.10 mmol) were added under ice bath, and reacted at room temperature for 1 hour. The reaction was completed after TLC monitoring. A 5% citric acid solution was added to the reaction solution, and the dichloromethane was extracted three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.20 g of the intermediate. E1-8; E1-8 (3.20 g, 10.66 mmol) was dissolved in a tetrahydrofuran / methanol (10 mL:10 mL) mixed solution, 1 M lithium hydroxide aqueous solution was added, and the mixture was reacted at 100 ° C for 4 hours. The reaction was completed after TLC monitoring. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 3 M hydrochloric acid. The reaction solution was filtered, the filter residue was collected, and the filter residue was washed with water and petroleum ether to obtain 2.79 g of intermediate F1-8; F1-8 (2.79 g, 9.96 mmol) was dissolved in 15 mL Triethylamine (1.11 g, 10.96 mmol), 3-aminopyridine (1.03 g, 10.95 mmol) and HATU (5.69 g, 14.94 mmol) were added to N,N-dimethylformamide in sequence, stirred at room temperature overnight, and the reaction was complete after TLC monitoring. Saturated brine was added, and ethyl acetate was extracted three times (50 mL × 3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 2.00 g of light yellow solid SDUY409, with a yield of 56%. Melting point: 124-125°C. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.79(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.06(dt,J=8.5,1.9Hz,1H),7.78-7.65(m,2H), 7.52(ddd,J=8.8,7.4,1.8Hz,1H),7.38(dd,J=8.3,4.7Hz,1H),7.27(dd,J=7.5,1.8Hz,1H),7.20-7.04(m,4H),4.86(s,2H),3.69(s,3H);13 C NMR(151MHz,DMSO-d6)δ194.59,167.10,162.26,156.85,145.12,141.78,135.49,132.09,13 2.01,131.06,129.32,128.85,127.42,124.15,120.99,115.13,112.41,67.47,56.04.HR-MS m / z:calcd forC 21 H 18 N2O4[(MH) - ],361.1188;found,361.1193.

[0189] Preparation of 2-(4-(4-nitrobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY410)

[0190] 4-Nitrobenzoyl chloride B1-9 (2.00 g, 10.80 mmol) was dissolved in dichloromethane, and methyl phenoxyacetate (1.79 g, 10.80 mmol) and anhydrous aluminum chloride (2.88 g, 21.60 mmol) were added under ice bath, and reacted at room temperature for 1 hour. The reaction was complete after TLC monitoring. 50 mL of 5% citric acid solution, extracted with dichloromethane three times (50mL×3), combined the organic phases, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate E1-9; E1-9 (4.20 g, 13.23 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (10 mL:10 mL), added to a 1M aqueous solution of lithium hydroxide (1.59 g, 66.67 mmol), reacted at 100°C for 4 hours, and the reaction was complete after TLC monitoring. The reaction solution was cooled to room temperature, adjusted to pH=1 with 3M hydrochloric acid, filtered, and the residue was collected. The residue was washed with water and petroleum ether to obtain intermediate F1-9; F1-9 (3.90 g, 1 2.90mmol) was dissolved in 20mL N,N-dimethylformamide, triethylamine (1.43g, 14.20mmol), 3-aminopyridine (1.34g, 14.20mmol) and HATU (7.36g, 19.35mmol) were added in sequence, stirred at room temperature overnight, and the reaction was complete after TLC monitoring. The reaction solution was cooled to room temperature, saturated brine was added, and ethyl acetate was extracted three times (50mL×3). The organic phases were combined, washed twice with saturated brine, once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 3.38g of yellow solid SDUY410, with a yield of 70%. Melting point: 190-191°C. 1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.82(d,J=2.6Hz,1H),8.40-8.34(m,2H),8.32(dd,J=4.8,1.5Hz,1H),8.09(ddd,J =8.3,2.6,1.6Hz,1H),7.96-7.89(m,2H),7.85-7.78(m,2H),7.40(dd,J=8.3,4.7Hz,1H),7.23-7.17(m,2H),4.92(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.54,167.05,162.58,149.65,145.00,143.82,141.61 ,135.59,132.85,130.80,129.59,127.42,124.20,124.09,115.37,67.47.HR-MS m / z:calcd for C 20 H 15 N3O5[(M+H) + ],378.1090;found,378.1085.

[0191] Preparation of 2-(4-(3-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY415)

[0192] 3-Cyanobenzoic acid A1-10 (3.00 g, 20.40 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (5.18 g, 40.80 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 4.50 g of intermediate B1-10; B1-10 (4.50 g, 33.90 mmol) was dissolved in dichloromethane, anisole (3.67 g, 33.90 mmol) and anhydrous aluminum chloride (4.52 g, 33.90 mmol) were added, and stirred at room temperature for 1 hour to obtain 3.38 g of intermediate C1-10; C1-10 (3.38 g, 14.20 mmol) was dissolved in toluene, anhydrous aluminum chloride (4.74 g, 35.6 mmol) was added, and refluxed at 110°C for 2 hours to obtain 2.00 g of intermediate D1-10; D1-10 (1.39 g, 6.23 mmol) was dissolved in N, N-dimethylformamide, tert-butyl bromoacetate (1.90 g, 12.45 mmol) and anhydrous potassium carbonate (1.72 g, 12.45 mmol) were added, and refluxed at 65°C for 2 hours to obtain 1.82 g of intermediate E1-10; E1-10 (1.82 g, 6.16 mmol) was dissolved in dichloromethane, and slowly Slowly add TFA (10 mL), stir at room temperature for 2 hours, monitor the reaction by TLC, concentrate by rotary evaporation, adjust pH to 1 with saturated sodium bicarbonate solution, and obtain 1.22 g of intermediate F1-10; F1-10 (1.22 g, 4.34 mmol) is dissolved in N, N-dimethylformamide, triethylamine (0.48 g, 4.77 mmol), 3-aminopyridine (0.45 g, 4.77 mmol) and HATU (2.48 g, 6.51 mmol) are added in sequence, and stirred at room temperature overnight to obtain 1.00 g of light pink solid SDUY415. The above post-treatment method is the same as compound SDUY400, and the yield is 65%. Melting point: 190-191 ° C. 1 HNMR(400MHz, DMSO-d6)δ10.40(s,1H),8.80(d,J=2.5Hz,1H),8.31(d,J=4.5Hz,1H),8.18-8.03(m,3H),7.99(dt, J=7.9,1.5Hz,1H),7.79(dd,J=15.0,8.1Hz,3H),7.38(dd,J=8.3,4.7Hz,1H),7.19(d,J=8.5Hz,2H),4.91(s,2H); 13CNMR(151MHz,DMSO-d6)δ193.11,167.05,162.41,145.23,141.87,139.28,135.76,135.47,13 4.00,133.06,132.85,130.30,129.64,127.28,124.11,118.63,115.34,112.24,67.50.HR-MS m / z:calcd for C 21 H 15 N3O3[MH] - ,356.1035;found,356.1030.

[0193] Preparation of 2-(4-(4-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY417)

[0194] 4-Cyanobenzoic acid A1-11 (3.00 g, 20.40 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (5.18 g, 40.80 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 3.43 g of intermediate B1-11; B1-11 (3.43 g, 20.70 mmol) was dissolved in dichloromethane, anisole (2.80 g, 25.88 mmol) and anhydrous aluminum chloride (3.45 g, 25.88 mmol) were added, and stirred at room temperature for 1 hour to obtain 3.12 g of intermediate C1-11; C1-11 (3.12 g, 13.20 mmol) was dissolved in toluene, anhydrous aluminum chloride (4.39 g, 32.90 mmol) was added, and refluxed at 110°C for 2 hours to obtain 2.02 g of intermediate D1-11; D1-11 (2.02 g, 9.05 mmol) was dissolved in N,N-dimethylformamide, tert-butyl bromoacetate (2.76 g, 18.09 mmol) and anhydrous potassium carbonate (2.50 g, 18.09 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.56 g of intermediate E1-11; E1-11 (2.56 g, 6.16 mmol) was dissolved in dichloromethane, and slowly added Add TFA (10 mL), stir at room temperature for 2 hours, monitor the reaction by TLC, concentrate by rotary evaporation, adjust pH to 1 with saturated sodium bicarbonate solution, and obtain 2.65 g of intermediate F1-11; F1-11 (2.65 g, 9.42 mmol) was dissolved in N, N-dimethylformamide, triethylamine (1.05 g, 10.40 mmol), 3-aminopyridine (0.98 g, 10.40 mmol) and HATU (5.93 g, 15.60 mmol) were added in sequence, and stirred at room temperature overnight to obtain 2.65 g of light pink solid SDUY417. The above post-treatment method was the same as compound SDUY400, with a yield of 60%. Melting point: 180-181°C. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.80(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.07(ddd,J=8.4,2.6 ,1.5Hz,1H),8.05-8.00(m,2H),7.90-7.75(m,4H),7.38(dd,J=8.3,4.7Hz,1H),7.25-7.14(m,2H),4.91(s,2H); 13C NMR(151MHz,DMSO-d6)δ193.53,167.24,162.03,161.25,145.21,141.90,135.49 ,132.64,132.06,131.54,128.90,127.31,124.11,115.61,114.92,65.95.HR-MS m / z:calcd for C 21 H 15 N3O3[(MH) - ],356.1035;found,356.1017.

[0195] Preparation of 2-(4-(2-bromo-4-fluorobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY418)

[0196] 2-Bromo-4-fluorobenzoic acid A1-12 (2.00 g, 9.13 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.32 g, 9.14 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 2.17 g of intermediate B1-12; B1-12 (2.17 g, 9.14 mmol) was dissolved in dichloromethane, anisole (1.24 g, 11.42 mmol) and anhydrous aluminum chloride (1.52 g, 11.42 mmol) were added, and stirred at room temperature for 1 hour to obtain 2.38 g of intermediate C1-12; C1-12 (2.38 g, 7.71 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.57 g, 19.27 mmol) was added, and refluxed at 110°C for 2 hours to obtain 2.16 g of intermediate D1-12; D1-12 (2.16 g, 7.34 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (2.25 g, 14.69 mmol) and anhydrous potassium carbonate (2.03 g, 14.69 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.97 g of intermediate E1-12; E1-12 (2.97 g, 8.09 mmol) Dissolve in a tetrahydrofuran / methanol (1:1) mixed solution, add 1M lithium hydroxide aqueous solution, reflux at 100°C for 4 hours to obtain 2.30g of intermediate F1-12; F1-12 (2.30g, 6.51mmol) is dissolved in N,N-dimethylformamide, triethylamine (0.72g, 7.16mmol), 3-aminopyridine (0.67g, 7.16mmol) and HATU (3.71g, 9.77mmol) are added in sequence, and stirred at room temperature overnight to obtain 2.51g of light yellow solid SDUY418. The above post-treatment method is the same as compound SDUY400, yield: 90%. Melting point: 176-177°C. 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.79(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.06(ddd,J=8.3,2.6,1.5Hz,1H),7.93- 7.66(m,3H),7.53(dd,J=8.5,6.0Hz,1H),7.43(dd,J=8.5,2.5Hz,1H),7.38(dt,J=8.3,4.4Hz,1H),7.28-7.08(m,2H),4.90(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.41,166.97,162.92,161.86,145.21,141.85,137.63,13 5.45,132.65,131.02,129.50,127.31,124.12,120.69,119.82,115.56,67.47.HR-MS m / z:calcd for C 20 H 14 BrFN2O3[(MH) - ],427.0094;found,427.0075.

[0197] Preparation of 2-(4-(2-bromo-5-iodobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY420)

[0198] 2-Bromo-5-iodobenzoic acid A1-13 (2.00 g, 6.12 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (1.55 g, 12.24 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 2.11 g of intermediate B1-13; B1-13 (2.11 g, 6.12 mmol) was dissolved in dichloromethane, anisole (0.83 g, 7.65 mmol) and anhydrous aluminum chloride (1.02 g, 7.65 mmol) were added, and stirred at room temperature for 1 hour to obtain 2.46 g of intermediate C1-13; C1-13 (2.46 g, 5.90 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.97 g, 14.75 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.80 g of intermediate D1-13; D1-13 (1.80 g, 4.47 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (1.37 g, 8.93 mmol) and anhydrous potassium carbonate (1.23 g, 8.93 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.77 g of intermediate E1-13; E1-13 (2.77 g, 5.83 mmol) was dissolved In a tetrahydrofuran / methanol (1:1) mixed solution, add 1M lithium hydroxide aqueous solution, reflux at 100°C for 4 hours to obtain 2.00g of intermediate F1-13; F1-13 (2.00g, 4.34mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.48g, 4.77mmol), 3-aminopyridine (0.45g, 4.77mmol) and HATU (1.82g, 4.77mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.89g of light yellow solid SDUY420. The above post-treatment method is the same as compound SDUY400, yield: 82%. Melting point: 196-197°C. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.78(d,J=2.6Hz,1H),8.31(dd,J=4.6,1.5Hz,1H),8.06(dt,J=8.3,1.9Hz,1H),7.8 1(d,J=8.0Hz,2H),7.74-7.68(m,2H),7.54(d,J=8.1Hz,1H),7.38(dd,J=8.3,4.7Hz,1H),7.18-7.12(m,2H),4.89(s,2H); 13C NMR(151MHz,DMSO-d6)δ192.48,166.94,163.04,145.21,143.05,141.85,140.44,137.0 2,135.45,135.14,132.69,129.06,127.30,124.11,118.65,115.63,94.16,67.47.HR-MS m / z:calcd for C 20 H 14 BrIN2O3[(MH) - ],536.9134;found,536.9108.

[0199] Preparation of 2-(4-(2-bromo-4-chlorobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide (SDUY421)

[0200] 2-Bromo-4-chlorobenzoic acid A1-14 (2.00 g, 8.49 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.16 g, 16.99 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 2.16 g of intermediate B1-14; B1-14 (2.16 g, 8.50 mmol) was dissolved in dichloromethane, anisole (1.15 g, 10.63 mmol) and anhydrous aluminum chloride (1.42 g, 10.63 mmol) were added, and stirred at room temperature for 1 hour to obtain 2.87 g of intermediate C1-14; C1-14 (2.87 g, 8.81 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.94 g, 22.04 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.50 g of intermediate D1-14; D1-14 (1.50 g, 4.81 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (1.47 g, 9.63 mmol) and anhydrous potassium carbonate (1.33 g, 9.63 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.47 g of intermediate E1-14; E1-14 (2.47 g, 6.44 mmol) was dissolved In a tetrahydrofuran / methanol (1:1) mixed solution, 1M lithium hydroxide aqueous solution was added, and refluxed at 100°C for 4 hours to obtain 1.51g of intermediate F1-14; F1-14 (1.51g, 4.09mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.45g, 4.49mmol), 3-aminopyridine (0.42g, 4.49mmol) and HATU (1.71g, 4.49mmol) were added in sequence, and stirred at room temperature overnight to obtain 0.70g of light yellow solid SDUY421. The above post-treatment method was the same as compound SDUY400, with a yield of 39%. Melting point: 202-203°C. 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.79(d,J=2.6Hz,1H),8.31(dd,J=4.8,1.4Hz,1H),8.06(ddd,J=8.3,2.5,1.5Hz,1H),7.92(d,J=2.0 Hz,1H),7.77-7.69(m,2H),7.63(dd,J=8.2,2.0Hz,1H),7.49(d,J=8.2Hz,1H),7.38(dd,J=8.3,4.7Hz,1H),7.20-7.13(m,2H),4.90(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.28,166.95,163.01,145.18,141.81,139.92,135.55,135.46 ,132.68,132.66,130.49,129.25,128.49,127.34,124.13,119.82,115.61,67.47.HR-MS m / z:calcd forC 20 H 14 BrClN2O3[(MH) - ],444.9778;found,444.9756.

[0201] Preparation of 2-(4-(2-bromo-3-chlorobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide (SDUY424)

[0202] 2-Bromo-3-chlorobenzoic acid A1-15 (1.00 g, 4.25 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (1.08 g, 8.49 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 1.08 g of intermediate B1-15; B1-15 (1.08 g, 4.25 mmol) was dissolved in dichloromethane, anisole (0.58 g, 5.31 mmol) and anhydrous aluminum chloride (0.71 g, 5.31 mmol) were added, and stirred at room temperature for 1 hour to obtain 1.14 g of intermediate C1-15; C1-15 (1.14 g, 3.51 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.17 g, 8.77 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.50 g of intermediate D1-15; D1-15 (1.50 g, 4.81 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (1.47 g, 9.63 mmol) and anhydrous potassium carbonate (1.33 g, 9.63 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.47 g of intermediate E1-15; E1-15 (2.47 g, 6.44 mmol) was dissolved in A 1M aqueous lithium hydroxide solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.51 g of intermediate F1-15; F1-15 (1.19 g, 3.22 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.37 g, 3.54 mmol), 3-aminopyridine (0.33 g, 3.54 mmol) and HATU (1.35 g, 3.54 mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.21 g of light yellow solid SDUY424. The above post-treatment method was the same as compound SDUY400, with a yield of 81%. Melting point: 82-83°C. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.78(d,J=2.6Hz,1H),8.31(dd,J=4.6,1.5Hz,1H),8.06(ddd,J=8.3,2.6,1.5Hz,1H),7.80(dd ,J=8.0,1.5Hz,1H),7.76-7.68(m,2H),7.56(t,J=7.8Hz,1H),7.43-7.38(m,1H),7.39-7.35(m,1H),7.22-7.12(m,2H),4.90(s,2H); 13C NMR(151MHz,DMSO-d6)δ193.13,166.94,163.07,145.22,143.72,141.86,135.44,134.78 ,132.68,131.73,129.89,128.94,127.29,127.26,124.10,118.81,115.67,67.47.HR-MS m / z:calcd for C 20 H 14 BrClN2O3[(MH) - ],444.9778;found,444.9735.

[0203] Preparation of 2-(4-(2-bromo-4-iodobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide (SDUY425)

[0204] 2-Bromo-4-iodobenzoic acid A1-16 (1.00 g, 3.06 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (0.78 g, 6.12 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.06 g of intermediate B1-16; B1-16 (1.06 g, 3.06 mmol) was dissolved in dichloromethane, anisole (0.42 g, 3.84 mmol) and anhydrous aluminum chloride (0.51 g, 3.84 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.25 g of intermediate C1-16; C1-16 (1.25 g, 3.00 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.00 g, 7.49 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.06 g of intermediate D1-16; D1-16 (1.06 g, 2.63 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (0.80 g, 5.26 mmol) and anhydrous potassium carbonate (0.73 g, 5.26 mmol) were added, and refluxed at 65°C for 2 hours to obtain 1.33 g of intermediate E1-16; E1-16 (1.33 g, 2.80 mmol) was dissolved in A 1M aqueous lithium hydroxide solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.21 g of intermediate F1-16; F1-16 (1.21 g, 2.62 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.29 g, 2.89 mmol), 3-aminopyridine (0.27 g, 2.89 mmol) and HATU (1.10 g, 2.89 mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.16 g of light yellow solid SDUY425. The above post-treatment method was the same as compound SDUY400, with a yield of 83%. Melting point: 176-177°C. 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.78(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.16(d,J=1.6Hz,1H),8.06(ddd,J=8.3,2.6,1.5 Hz,1H),7.90(dd,J=8.0,1.5Hz,1H),7.79-7.65(m,2H),7.38(dd,J=8.3,4.7Hz,1H),7.24(d,J=7.9Hz,1H),7.20-7.11(m,2H),4.89(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.46,166.95,162.99,145.20,141.84,140.66,140.52,137.0 6,135.45,132.65,130.60,129.21,127.34,124.12,119.84,115.60,97.56,67.47.HR-MS m / z:calcd for C 20 H 14 BrIN2O3[(MH) - ],534.9154;found,534.9114.

[0205] Preparation of 2-(4-(2-bromo-3-iodobenzoyl)phenoxy)-N-pyridin-3-yl)acetamide (SDUY429)

[0206] 2-Bromo-3-iodobenzoic acid A1-17 (1.00 g, 3.06 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (0.78 g, 6.12 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 1.06 g of intermediate B1-17; B1-17 (1.06 g, 3.06 mmol) was dissolved in dichloromethane, anisole (0.42 g, 3.84 mmol) and anhydrous aluminum chloride (0.51 g, 3.84 mmol) were added, and stirred at room temperature for 1 hour to obtain 1.35 g of intermediate C1-17; C1-17 (0.94 g, 2.26 mmol) was dissolved in toluene, anhydrous aluminum chloride (0.75 g, 5.65 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 0.81 g of intermediate D1-17; D1-17 (0.81 g, 2.01 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (0.61 g, 4.02 mmol) and anhydrous potassium carbonate (0.56 g, 4.02 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 1.13 g of intermediate E1-17; E1-17 (1.13 g, 2.38 mmol) was dissolved in A 1M lithium hydroxide aqueous solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.48 g of intermediate F1-17; F1-17 (1.48 g, 3.21 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.36 g, 3.53 mmol), 3-aminopyridine (0.33 g, 3.53 mmol) and HATU (1.34 g, 3.53 mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.55 g of light yellow solid SDUY429. The above post-treatment method was the same as compound SDUY400, with a yield of 90%. Melting point: 142-143°C. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.78(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.11(dd,J=7.8,1.5Hz,1H),8.06(ddd,J=8.3,2.6,1 .5Hz,1H),7.75-7.69(m,2H),7.42(dd,J=7.5,1.5Hz,1H),7.38(dd,J=8.3,4.7Hz,1H),7.28(t,J=7.7Hz,1H),7.19-7.11(m,2H),4.89(s,2H); 13CNMR(151MHz,DMSO-d6)δ193.56,166.94,162.99,145.22,142.90,141.88,141.52,135.4 4,132.65,129.76,128.73,128.17,127.31,125.57,124.10,115.66,104.77,67.48.HR-MS m / z:calcd forC 20 H 14 BrIN2O3[(MH) - ],534.9154;found,534.9101.

[0207] Preparation of 2-(4-(2-bromobenzoyl)-3-methylphenoxy)-N-(pyridin-3-yl)acetamide (SDUY432)

[0208] 2-Bromobenzoic acid (2.00 g, 9.95 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.53 g, 19.90 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.09 g of intermediate 2-bromobenzoyl chloride; 2-bromobenzoyl chloride (1.09 g, 4.97 mmol) was dissolved in dichloromethane, 3-methylanisole (0.76 g, 6.21 mmol) and anhydrous aluminum chloride (0.83 g, 6.21 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.63 g of intermediate C1-18; C1-18 (1.63 g, 5.34 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.78 g, 13.35 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 0.77 g of intermediate D1-18; D1-18 (0.77 g, 2.65 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (0.81 g, 5.28 mmol) and anhydrous potassium carbonate (0.73 g, 5.28 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 1.27 g of intermediate E1-18; E1-18 (1.27 g, 3.50 mmol) was dissolved In a tetrahydrofuran / methanol (1:1) mixed solution, 1M lithium hydroxide aqueous solution was added, and refluxed at 100°C for 4 hours to obtain 1.29g of intermediate F1-18; F1-18 (1.29g, 3.69mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.41g, 4.06mmol), 3-aminopyridine (0.38g, 4.06mmol) and HATU (1.54g, 4.06mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.17g of light yellow solid SDUY432. The above post-treatment method was the same as compound SDUY400, with a yield of 75%. Melting point: 144-145°C. 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.79(d,J=2.5Hz,1H),8.30(dd,J=4.7,1.5Hz,1 H),8.06(ddd,J=8.3,2.6,1.5Hz,1H),7.72(dd,J=7.8,1.2Hz,1H),7.52(td,J=7.4,1.3 Hz, 1H), 7.44 (ddd, J=15.8, 7.5, 1.9Hz, 2H), 7.37 (dd, J=8.3, 4.7Hz, 1H), 7.25 (d, J=8. 7Hz,1H),7.06(d,J=2.6Hz,1H),6.90(dd,J=8.7,2.6Hz,1H),4.85(s,2H),2.58(s,3H); 13 C NMR(151MHz,DMSO-d6)δ196.13,167.06,161.31,145.21,142.96,142.45,141.90,135.45,135.35,13 3.35,131.90,129.42,129.14,128.26,127.32,124.09,119.04,118.91,112.14,67.37,22.08.HR-MS m / z:calcd for C 21 H 17 BrN2O3[(MH) - ],423.0344;found,423.0301.

[0209] Preparation of 2-(4-(2-bromobenzoyl)-2-methylphenoxy)-N-(pyridin-3-yl)acetamide (SDUY431)

[0210] 2-Bromobenzoic acid (2.00 g, 9.95 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.53 g, 19.90 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.09 g of intermediate 2-bromobenzoyl chloride; 2-bromobenzoyl chloride (1.09 g, 4.97 mmol) was dissolved in dichloromethane, 2-methylanisole (0.76 g, 6.21 mmol) and anhydrous aluminum chloride (0.83 g, 6.21 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 0.96 g of intermediate C1-19; C1-19 (0.96 g, 3.15 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.05 g, 7.88 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 0.93 g of intermediate D1-19; D1-19 (0.93 g, 3.19 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (0.98 g, 6.38 mmol) and anhydrous potassium carbonate (0.88 g, 6.38 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 1.36 g of intermediate E1-19; E1-19 (1.36 g, 3.74 mmol) was dissolved in A 1M aqueous lithium hydroxide solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.11 g of intermediate F1-19; F1-19 (1.11 g, 3.18 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.35 g, 3.50 mmol), 3-aminopyridine (0.33 g, 3.50 mmol) and HATU (1.33 g, 3.50 mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.12 g of light yellow solid SDUY431. The above post-treatment method was the same as compound SDUY400, with a yield of 83%. Melting point: 90-91°C. 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.77(d,J=2.5Hz,1H),8.30(dd,J=4.7,1.5Hz,1H),8.08-8.00(m,1H),7.75(dd,J=7.8,1.2Hz,1H),7.63 (d,J=2.3Hz,1H),7.56-7.44(m,3H),7.42(dd,J=7.3,1.9Hz,1H),7.37(dd,J=8.3,4.7Hz,1H),7.03(d,J=8.6Hz,1H),4.92(s,2H),2.29(s,3H); 13C NMR(151MHz,DMSO-d6)δ194.19,167.03 161.27,145.17,141.72,141.18,135.50,133.25,132.21,131.81,130.98,1 29.05,128.19,127.47,127.14,124.12,118.83,111.86,67.69,16.56.HR-MS m / z:calcdfor C 21 H 17 BrN2O3[(MH) - ],423.0344;found,423.0301.

[0211] Preparation of 2-(4-(2-bromobenzoyl)-2-chlorophenoxy)-N-(pyridin-3-yl)acetamide (SDUY436)

[0212] 2-Bromobenzoic acid (1.00 g, 4.97 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (1.26 g, 9.95 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.09 g of intermediate 2-bromobenzoyl chloride; 2-bromobenzoyl chloride (1.09 g, 4.97 mmol) was dissolved in dichloromethane, 2-chloroanisole (0.89 g, 6.21 mmol) and anhydrous aluminum chloride (0.83 g, 6.21 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.28 g of intermediate C1-20; C1-20 (1.28 g, 3.92 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.31 g, 9.80 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 1.20 g of intermediate D1-20; D1-20 (1.20 g, 3.84 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (1.17 g, 7.68 mmol) and anhydrous potassium carbonate (1.06 g, 7.68 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 1.69 g of intermediate E1-20; E1-20 (1.69 g, 4.41 mmol) was dissolved in A 1M aqueous lithium hydroxide solution was added to a tetrahydrofuran / methanol (1:1) mixed solution, and refluxed at 100°C for 4 hours to obtain 1.58 g of intermediate F1-20; F1-20 (1.58 g, 4.28 mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.47 g, 4.71 mmol), 3-aminopyridine (0.44 g, 4.71 mmol) and HATU (1.79 g, 4.71 mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.44 g of light yellow solid SDUY436. The above post-treatment method was the same as compound SDUY400, with a yield of 76%. Melting point: 120-121°C.1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.75(d,J=2.6Hz,1H),8.30(dd,J=4.7,1.4Hz,1H),8.03(dt,J=8.3,2.0 Hz,1H),7.84-7.68(m,2H),7.62-7.44(m,4H),7.37(dd,J=8.3,4.7Hz,1H),7.25(d,J=8.7Hz,1H),5.05(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.22,166.36,158.40,145.19,141.55,140.31,135.48,133.37,132.25 ,131.41,131.38,130.04,129.27,128.35,126.98,124.16,122.62,118.80,114.42,67.99.HR-MS m / z:calcd for C 20 H 14 BrClN2O3[(MH) - ],444.9778;found,444.9731.

[0213] Preparation of 2-(4-(2-ethylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY437)

[0214] 2-Ethylbenzoic acid A1-21 (1.50 g, 9.99 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.54 g, 19.98 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 1.68 g of intermediate B1-21; B1-21 (1.68 g, 9.96 mmol) was dissolved in dichloromethane, anisole (1.35 g, 12.45 mmol) and anhydrous aluminum chloride (1.66 g, 12.45 mmol) were added, and stirred at room temperature for 1 hour to obtain 2.67 g of intermediate C1-21; C1-21 (2.67 g, 11.11 mmol) was dissolved in toluene, anhydrous aluminum chloride (3.70 g, 27.78 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.77 g of intermediate D1-21; D1-21 (1.77 g, 7.81 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (2.39 g, 15.63 mmol) and anhydrous potassium carbonate (2.16 g, 15.63 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.50 g of intermediate E1-21; E1-21 (2.50 g, 8.40 mmol) Dissolve in a tetrahydrofuran / methanol (1:1) mixed solution, add 1M lithium hydroxide aqueous solution, reflux at 100°C for 4 hours to obtain 1.90g of intermediate F1-21; F1-21 (1.90g, 6.69mmol) is dissolved in N,N-dimethylformamide, triethylamine (0.74g, 7.36mmol), 3-aminopyridine (0.69g, 7.36mmol) and HATU (2.80g, 7.36mmol) are added in sequence, and stirred at room temperature overnight to obtain 2.04g of light yellow solid SDUY437. The above post-treatment method is the same as compound SDUY400, yield: 85%. Melting point: 70-71°C. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.80(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz, 1H),8.07(dt,J=8.4,2.0Hz,1H),7.82-7.62(m,2H),7.47(td,J=7.4,1.5Hz,1H),7.4 1-7.38(m,1H),7.38-7.34(m,1H),7.31(td,J=7.4,1.3Hz,1H),7.24(dd,J=7.6,1.5H z,1H),7.19-7.11(m,2H),4.89(s,2H),2.54(q,J=7.6Hz,2H),1.06(t,J=7.5Hz,3H); 13C NMR(151MHz,DMSO-d6)δ196.82,167.03,162.48,145.20,142.07,141.88,139.02,135.46,132.4 3,131.02,130.44,129.73,127.81,127.34,125.87,124.10,115.32,67.49,26.17,16.27.HR-MS m / z:calcd for C 22 H 20 N2O3[(M+H) + ],361.1552;found,361.1539.

[0215] Preparation of 2-(4-(4-ethylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY438)

[0216] 4-Ethylbenzoic acid A1-22 (1.50 g, 9.99 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.54 g, 19.98 mmol) was slowly added under nitrogen protection, and stirred at room temperature for 2 hours to obtain 1.68 g of intermediate B1-22; B1-22 (1.68 g, 9.96 mmol) was dissolved in dichloromethane, anisole (1.35 g, 12.45 mmol) and anhydrous aluminum chloride (1.66 g, 12.45 mmol) were added, and stirred at room temperature for 1 hour to obtain 2.79 g of intermediate C1-22; C1-22 (2.79 g, 11.11 mmol) was dissolved in toluene, anhydrous aluminum chloride (3.89 g, 29.00 mmol) was added, and refluxed at 110°C for 2 hours to obtain 2.27 g of intermediate D1-22; D1-22 (2.27 g, 10.03 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (1.53 g, 20.06 mmol) and anhydrous potassium carbonate (2.79 g, 20.06 mmol) were added, and refluxed at 65°C for 2 hours to obtain 3.42 g of intermediate E1-22; E1-22 (3.42 g, 8.40 mmol) was dissolved In a tetrahydrofuran / methanol (1:1) mixed solution, 1M lithium hydroxide aqueous solution was added, and refluxed at 100°C for 4 hours to obtain 2.62g of intermediate F1-22; F1-22 (2.62g, 9.22mmol) was dissolved in N,N-dimethylformamide, triethylamine (1.02g, 10.14mmol), 3-aminopyridine (0.95g, 10.14mmol) and HATU (3.86g, 10.14mmol) were added in sequence, and stirred at room temperature overnight to obtain 3.02g of light yellow solid SDUY438. The above post-treatment method was the same as compound SDUY400, and the yield was 91%. Melting point: 112-113°C.1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.82(d,J=2.6Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.09(ddd,J=8.4,2.6,1.5Hz,1H),7.81-7.71(m,2H),7 .64(d,J=8.0Hz,2H),7.39(d,J=4.3Hz,2H),7.37(d,J=4.5Hz,1H),7.22 -7.12(m,2H),4.89(s,2H),2.70(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ194.57,167.15,161.73,149.03,145.22,141.91,135.67,135.4 7,132.41,130.90,130.09,128.32,127.32,124.09,115.07,67.53,28.63,15.62.HR-MS m / z:calcdfor C 22 H 20 N2O3[(MH) - ],359.1396;found,359.1351.

[0217] Preparation of 2-(4-(4-isopropylbenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY439)

[0218] 4-isopropylbenzoic acid A1-23 (1.50 g, 9.14 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (2.32 g, 18.27 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.67 g of intermediate B1-23; B1-23 (1.67 g, 9.14 mmol) was dissolved in dichloromethane, anisole (1.24 g, 11.43 mmol) and anhydrous aluminum chloride (1.52 g, 11.43 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.88 g of intermediate C1-23; C1-23 (1.88 g, 7.38 mmol) was dissolved in toluene, anhydrous aluminum chloride (2.46 g, 18.45 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.85 g of intermediate D1-23; D1-23 (1.85 g, 7.69 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (2.35 g, 15.38 mmol) and anhydrous potassium carbonate (2.13 g, 15.38 mmol) were added, and refluxed at 65°C for 2 hours to obtain 2.63 g of intermediate E1-23; E1-23 (2.63 g, 8.42 mmol) Dissolve in a tetrahydrofuran / methanol (1:1) mixed solution, add 1M lithium hydroxide aqueous solution, reflux at 100°C for 4 hours to obtain 2.51g of intermediate F1-23; F1-23 (2.51g, 8.42mmol) is dissolved in N,N-dimethylformamide, triethylamine (0.94g, 9.26mmol), 3-aminopyridine (0.87g, 9.26mmol) and HATU (3.52g, 9.26mmol) are added in sequence, and stirred at room temperature overnight to obtain 2.90g of light yellow solid SDUY439. The above post-treatment method is the same as compound SDUY400, with a yield of 92%. Melting point: 104-105°C. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.82(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.09(ddd,J=8.3,2.5,1.5Hz,1H),7.82-7.73(m,2H),7.6 5(d,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),7.38(dd,J=8.3,4.7Hz,1H),7.2 3-7.13(m,2H),4.89(s,2H),2.99(p,J=6.9Hz,1H),1.25(d,J=6.9Hz,6H); 13C NMR(151MHz,DMSO-d6)δ194.54,167.15,161.73,153.54,145.22,141.91,135.81,135.4 7,132.43,130.87,130.13,127.32,126.90,124.10,115.07,67.52,33.95,24.02.HR-MS m / z:calcdfor C 23 H 22 N2O3[(MH) - ],373.1552;found,373.1508.

[0219] Preparation of 2-(4-(2-bromobenzoyl)-2-ethylphenoxy)-N-(pyridin-3-yl)acetamide (SDUY440)

[0220] 2-Bromobenzoic acid (1.00 g, 4.97 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (1.26 g, 9.95 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.09 g of intermediate 2-bromobenzoyl chloride; 2-bromobenzoyl chloride (1.02 g, 4.97 mmol) was dissolved in dichloromethane, 2-ethylanisole (0.80 g, 5.84 mmol) and anhydrous aluminum chloride (0.78 g, 5.84 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 1.31 g of intermediate C1-24; C1-24 (1.31 g, 4.10 mmol) was dissolved in toluene, anhydrous aluminum chloride (1.37 g, 10.25 mmol) was added, and refluxed at 110°C for 2 hours to obtain 1.09 g of intermediate D1-24; D1-24 (1.09 g, 3.56 mmol) was dissolved in N, N-dimethylformamide, methyl bromoacetate (1.09 g, 7.11 mmol) and anhydrous potassium carbonate (0.98 g, 7.11 mmol) were added, and refluxed at 65°C for 2 hours to obtain 1.55 g of intermediate E1-24; E1-24 (1.55 g, 4.12 mmol) was dissolved In a tetrahydrofuran / methanol (1:1) mixed solution, add 1M lithium hydroxide aqueous solution, reflux at 100°C for 4 hours to obtain 1.38g of intermediate F1-24; F1-24 (1.38g, 3.79mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.42g, 4.17mmol), 3-aminopyridine (0.39g, 4.17mmol) and HATU (1.59g, 4.17mmol) were added in sequence, and stirred at room temperature overnight to obtain 1.44g of light yellow solid SDUY440. The above post-treatment method is the same as compound SDUY400, yield: 87%. Melting point: 126-127°C. 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.76(d,J=2.6Hz,1H),8.30(dd,J=4.6,1. 4Hz,1H),8.05(dt,J=8.4,2.0Hz,1H),7.75(dd,J=7.7,1.2Hz,1H),7.67(d,J=2.3 Hz,1H),7.47(dddd,J=25.6,16.9,7.3,1.6Hz,4H),7.37(dd,J=8.3,4.7Hz,1H), 7.03(d,J=8.7Hz,1H),4.93(s,2H),2.72(q,J=7.4Hz,2H),1.19(t,J=7.5Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ194.18,166.98,160.96,145.12,141.60,141.18,135.54,133.24,133.21,131.8 2,131.14,130.43,129.13,129.09,128.19,127.08,124.15,118.84,111.96,67.60,23.14,14.16.HR-MS m / z:calcd for C 22 H 19 BrN2O3[(M+Na) + ],461.0456;found,461.0415.

[0221] Preparation of 2-(4-(4-methoxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY441)

[0222] 4-Methoxybenzoyl chloride B1-25 (0.50 g, 2.94 mmol) was dissolved in dichloromethane, methyl phenoxyacetate (0.49 g, 2.94 mmol) and anhydrous aluminum chloride (0.59 g, 4.41 mmol) were added under ice bath, and the mixture was reacted at room temperature for 1 hour. The reaction was complete after monitoring by TLC. A 5% citric acid solution was added to the reaction solution, and the mixture was extracted with dichloromethane three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.78 g of intermediate E1-25; E1-25 (0.78 g, 2.60 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (10 mL:10 mL), 1 M aqueous lithium hydroxide solution was added, the mixture was reacted at 100°C for 4 hours, the reaction was complete after monitoring by TLC, the reaction solution was cooled to room temperature, and 3 M hydrochloric acid was adjusted to pH = 1, the reaction solution was filtered, the filter residue was collected, and the filter residue was washed with water and petroleum ether to obtain 0.70g of intermediate F1-25; F1-25 (0.70g, 2.32mmol) was dissolved in 15mL N,N-dimethylformamide, triethylamine (0.26g, 2.56mmol), 3-aminopyridine (0.24g, 2.56mmol) and HATU (0.97g, 2.56mmol) were added in sequence, and stirred at room temperature overnight. TLC monitored the reaction to be complete, saturated brine was added, and ethyl acetate was extracted three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.50g of light yellow solid SDUY441, yield: 60%. Melting point: 146-147°C. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.81(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.12–8.01 (m,1H),7.81-7.65(m,4H),7.38(dd,J=8.3,4.7Hz,1H),7.22-7.04(m,4H),4.88(s,2H),3.86(s,3H); 13 C NMR(151MHz,DMSO-d6)δ193.62,167.19,163.10,161.47,145.22,141.92,135.48,13 2.31,132.18,131.28,130.44,127.32,124.09,115.00,114.29,67.53,56.01.HR-MS m / z:calcd for C 21 H 18 N2O4[(MH) -],361.1188;found,361.1136.

[0223] Preparation of 2-(4-(2-bromobenzoyl)-3-fluorophenoxy)-N-(pyridin-3-yl)acetamide (SDUY428)

[0224] 2-Bromobenzoic acid (1.00 g, 4.97 mmol) was dissolved in dichloromethane, 5 drops of N,N-dimethylformamide were added, oxalyl chloride (1.26 g, 9.95 mmol) was slowly added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours to obtain 1.00 g of intermediate 2-bromobenzoyl chloride; 2-bromobenzoyl chloride (1.00 g, 4.97 mmol) was dissolved in dichloromethane, 3-fluoroanisole (0.78 g, 6.21 mmol) and anhydrous aluminum chloride (0.83 g, 6.21 mmol) were added, and the mixture was stirred at room temperature for 1 hour to obtain 0.64 g of intermediate C1-26; C1-26 (0.64 g, 2.07 mmol) was dissolved in toluene, anhydrous aluminum chloride (0.69 g, 5.18 mmol) was added, and the mixture was refluxed at 110°C for 2 hours to obtain 0.53 g of intermediate D1-26; D1-26 (0.53 g, 1.80 mmol) was dissolved in N,N-dimethylformamide, methyl bromoacetate (0.50 g, 3.59 mmol) and anhydrous potassium carbonate (0.55 g, 3.59 mmol) were added, and the mixture was refluxed at 65°C for 2 hours to obtain 0.67 g of intermediate E1-26; E1-26 (0.67 g, 1.83 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (1:1), 1 M lithium hydroxide aqueous solution was added, and the mixture was refluxed at 100°C for 4 hours to obtain 0.60 g of intermediate Intermediate F1-26: Dissolve F1-26 (0.60 g, 1.70 mmol) in N,N-dimethylformamide, add triethylamine (0.19 g, 1.87 mmol), 3-aminopyridine (0.18 g, 1.87 mmol) and HATU (0.71 g, 1.87 mmol) in sequence, stir at room temperature overnight, monitor the reaction to be complete by TLC, add saturated brine, extract with ethyl acetate three times (50 mL×3), combine the organic phases, wash twice with saturated brine, wash once with water, dry over anhydrous sodium sulfate, filter, concentrate, and the residue is chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.51 g of light yellow solid SDUY428. The above post-treatment method is the same as compound SDUY400, yield: 71%. Melting point: 156-157°C. 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.78(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.06(dt,J=8.6,1. 9Hz,1H),7.75-7.66(m,2H),7.55-7.43(m,3H),7.38(dd,J=8.3,4.7Hz,1H),7.08-6.97(m,2H),4.92(s,2H); 13 C NMR(151MHz,DMSO-d6)δ191.20,166.65,164.32,162.32,145.26,142.36,141.87,135.41,133.65 ,133.24,132.16,129.02,128.36,127.30,124.12,118.46,112.38,103.78,103.61,67.79.HR-MS m / z:calcd for C 20 H 14 BrFN2O3[(MH) - ],427.0094;found,427.0047.

[0225] Preparation of 4-(4-(2-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)butanamide (SDUY411)

[0226] (2-Bromophenyl)(4-hydroxyphenyl)methane (1.51 g, 5.77 mmol) was dissolved in N,N-dimethylformamide, ethyl 4-bromobutyrate (2.09 g, 11.55 mmol) and anhydrous potassium carbonate (1.60 g, 11.55 mmol) were added, and the mixture was refluxed at 65°C for 2 hours. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, filtered, and extracted with ethyl acetate three times (50 mL × 3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.94 g of intermediate E2-1; E2-1 (2.94 g, 7.80 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (1:1), 1 M aqueous lithium hydroxide solution was added, and the mixture was refluxed at 100°C for 4 hours. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, Adjust the pH to 1 with 3M hydrochloric acid, filter the reaction solution, collect the residue, wash the residue with water and petroleum ether to obtain 1.93g of intermediate F2-1; F2-1 (1.93g, 5.31mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.59g, 5.85mmol), 3-aminopyridine (0.55g, 5.85mmol) and HATU (3.03g, 7.97mmol) were added in sequence and stirred at room temperature overnight. TLC monitored the reaction to be complete, saturated brine was added to the reaction solution, and ethyl acetate was extracted three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 1.42g of light yellow solid SDUY411, yield: 61%. Melting point: 104-105°C. 1 H NMR(400MHz,Chloroform-d)δ8.61(d,J=2.6Hz,1H),8.41(s,1H),8.30(d,J=4.8Hz,1H),8.20(dt,J=8.5,1.9Hz,1H),7.78-7.69(m,2H),7.62(dd,J=7.9, 1.1Hz,1H),7.43-7.36(m,1H),7.31(dtd,J=15.1,7.6,2.2Hz,3H),6.97-6.7 9(m,2H),4.11(t,J=5.9Hz,2H),2.62(t,J=7.1Hz,2H),2.22(p,J=6.5Hz,2H); 13C NMR(151MHz,DMSO-d6)δ194.00,171.69,163.73,144.04,141.16,140.73,136.46,133.26,132.6 4,131.84,129.08,128.85,128.23,126.98,124.26,118.83,115.26,67.96,33.01,24.78.HR-MS m / z:calcd for C 22 H 19 BrN2O3[(M+Na) + ],461.0477;found,461.0430.

[0227] Preparation of 4-(4-(2-bromo-5-chlorobenzoyl)phenoxy)-N-(pyridin-3-yl)butanamide (SDUY426)

[0228] (2-bromo-5-chlorophenyl)(4-hydroxyphenyl)methane (1.00 g, 3.22 mmol) was dissolved in N,N-dimethylformamide, ethyl 4-bromobutyrate (1.17 g, 6.44 mmol) and anhydrous potassium carbonate (0.89 g, 6.44 mmol) were added, and the mixture was refluxed at 65°C for 2 hours. The reaction was completed after monitoring by TLC. The reaction solution was cooled to room temperature, filtered, and extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.70 g of intermediate E2-2; E2-2 (1.70 g, 4.13 mmol) was dissolved in a mixed solution of tetrahydrofuran / methanol (1:1), 1 M aqueous lithium hydroxide solution was added, and the mixture was refluxed at 100°C for 4 hours. The reaction was completed after monitoring by TLC, and the reaction solution was cooled to room temperature. , adjusted to pH=1 with 3M hydrochloric acid, filtered the reaction solution, collected the residue, washed with water and petroleum ether to obtain 1.58g of intermediate F2-2; F2-2 (1.58g, 3.98mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.44g, 4.37mmol), 3-aminopyridine (0.41g, 4.37mmol) and HATU (1.67g, 4.37mmol) were added in sequence and stirred at room temperature overnight. TLC monitored the reaction to be complete, saturated brine was added to the reaction solution, extracted with ethyl acetate three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 1.22g of light yellow solid SDUY426, yield: 65%. Melting point: 140-141°C. 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.73(d,J=2.6Hz,1H),8.25(dd,J=4.8,1.5Hz,1H),8.04(dt,J=8.4,2.0Hz,1H),7.77(d,J=8.6Hz,1H),7.74- 7.64(m,2H),7.63-7.52(m,2H),7.33(dd,J=8.3,4.7Hz,1H),7.18-7.02(m ,2H),4.16(t,J=6.3Hz,2H),2.55(t,J=7.3Hz,2H),2.08(p,J=6.8Hz,2H); 13 C NMR(151MHz,DMSO-d6)δ192.48,171.63,163.95,144.44,142.86,141.20,136.32,134.99,133.2 8,132.78,131.67,128.71,128.36,126.53,124.05,117.29,115.37,68.02,32.99,24.78.HR-MS m / z:calcd for C 22 H 18 BrClN2O3[(M+Na) + ],497.0067;found,497.0014.

[0229] Preparation of 3-(4-(2-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acrylamide (SDUY430)

[0230] (2-Bromophenyl)(4-hydroxyphenyl)methane (1.00 g, 3.61 mmol) was dissolved in acetonitrile, 3-bromo-1-propanol (1.66 g, 11.91 mmol) and anhydrous potassium carbonate (0.55 g, 3.97 mmol) were added, and the mixture was refluxed at 65°C for 2 hours. The reaction was completed after monitoring by TLC. The reaction solution was cooled to room temperature, filtered, and extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.10 g of intermediate E3-1. E3-1 (1.00 g, 2.98 mmol) was dissolved in acetone, 15 mL of Jones reagent was added dropwise under ice bath conditions, stirred for 15 minutes, the ice bath was removed, and stirred at room temperature overnight. The reaction was completed after monitoring by TLC. Water was added to the reaction solution to quench the reaction, and extracted with ethyl acetate three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.77 g of intermediate F3-1; F3-1 (0.77 g, 2.21 mmol) was dissolved in N, N-dimethylformamide, triethylamine (0.25 g, 2.43 mmol), 3-aminopyridine (0.23 g, 2.43 mmol) and HATU (0.92 g, 2.43 mmol) were added in sequence, stirred at room temperature overnight, and the reaction was complete after TLC monitoring. Saturated brine was added to the reaction solution, and ethyl acetate was extracted three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.62 g of light yellow solid SDUY430, with a yield of 67%. Melting point: 136-137°C. 1 HNMR (400MHz, DMSO-d6) δ10.33(s,1H),8.76(d,J=2.6Hz,1H),8.27(dd,J=4.7,1.5Hz,1H),8.06(dt,J=8.5,1.9Hz,1H),7.81-7.71(m,3 H),7.71-7.63(m,2H),7.36(dt,J=8.4,4.2Hz,1H),7.32-7.27(m,1H),7.15-7.08(m,2H),4.40(t,J=5.9Hz,2H),2.88(t,J=5.9Hz,2H); 13C NMR(151MHz,DMSO-d6)δ194.02,169.49,163.52,144.71,141.24,141.14,133.26,132.64,13 1.86,129.09,128.99,128.24,126.53,124.11,118.82,115.31,115.16,64.75,36.42.HR-MS m / z:calcd for C 21 H 17 BrN2O3[(M+Na) + ],449.0300;found,449.0253.

[0231] Preparation of 3-(4-(2-bromo-5-chlorobenzoyl)phenoxy)-N-(pyridin-3-yl)acrylamide (SDUY427)

[0232] (2-bromo-5-chlorophenyl)(4-hydroxyphenyl)methane (1.00 g, 3.23 mmol) was dissolved in acetonitrile, 3-bromo-1-propanol (1.48 g, 10.63 mmol) and anhydrous potassium carbonate (0.49 g, 3.54 mmol) were added, and the mixture was refluxed at 65°C for 2 hours. The reaction was completed after monitoring by TLC. The reaction solution was cooled to room temperature, filtered, and extracted with ethyl acetate three times (50 mL × 3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.00 g of intermediate E3-2; E3-2 (2.00 g, 5.41 mmol) was dissolved in acetone, 18 mL of Jones reagent was added dropwise under ice bath conditions, stirred for 15 minutes, the ice bath was removed, and stirred at room temperature overnight. The reaction was completed after monitoring by TLC. Water was added to the reaction solution to quench the reaction, and extracted with ethyl acetate three times ( 50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.77g of intermediate F3-2; F3-2 (1.46g, 3.81mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.42g, 4.19mmol), 3-aminopyridine (0.39g, 4.19mmol) and HATU (1.59g, 4.19mmol) were added in sequence and stirred at room temperature overnight. The reaction was completed after TLC monitoring. Saturated brine was added to the reaction solution, and ethyl acetate was extracted three times (50mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 1.13g of light yellow solid SDUY427, yield: 65%. Melting point: 160-161°C. 1HNMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.76 (d, J = 2.5Hz, 1H), 8.27 (dd, J = 4. 7,1.4Hz,1H),8.06(dt,J=8.3,2.1Hz,1H),7.78(d,J=8.6Hz,1H),7.72-7.66 (m,2H),7.61(d,J=2.6Hz,1H),7.56(dd,J=8.6,2.6Hz,1H),7.36(dd,J=8.3, 4.7Hz,1H),7.16-7.07(m,2H),4.40(t,J=5.9Hz,2H),2.88(t,J=5.9Hz,2H); 13 C NMR(151MHz,DMSO-d6)δ192.51,169.48,163.75,144.65,142.83,141.18,136.17,135.00,13 3.29,132.78,131.69,128.73,128.51,126.59,124.13,117.29,115.41,64.79,36.40.HR-MS m / z:calcd for C 21 H 16 BrClN2O3[(M+Na) + ],482.9910;found,482.9857.

[0233] Preparation of N-(2-(4-(2-bromobenzoyl)phenoxy)ethyl)nicotinamide (SDUY422)

[0234] (2-Bromophenyl)(4-hydroxyphenyl)methane (1.00 g, 3.61 mmol) was dissolved in tetrahydrofuran, tert-butyl(2-hydroxyethyl)carbamate (0.58 g, 3.61 mmol) and triphenylphosphine (1.89 g, 7.22 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. Under nitrogen protection, diethyl azodicarboxylate (10.83 g, 1.89 mmol) was added dropwise under ice bath conditions, and the reaction was allowed to react at room temperature for 4 hours. After TLC monitoring, the reaction was complete, and the reaction solution was quenched with ice water, extracted with ethyl acetate three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1.20 g of intermediate E4-1; E4-1 (0.50 g, 1.19 mmol) was dissolved in dichloromethane and added 10 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 hours. The reaction was complete after TLC monitoring. The mixture was concentrated by rotary evaporation, adjusted to pH=8 with saturated sodium bicarbonate, and filtered to obtain 0.36 g of intermediate F4-1. F4-1 (0.36 g, 1.12 mmol) was dissolved in N,N-dimethylformamide, and triethylamine (0.13 g, 1.24 mmol), nicotinic acid (0.15 g, 1.24 mmol) and HATU (0.64 g, 1.69 mmol) were added in sequence and stirred at room temperature overnight. The reaction was complete after TLC monitoring. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.21 g of light yellow solid SDUY422, with a yield of 44%. Melting point: 134-135°C. 1 HNMR(400MHz,DMSO-d6)δ9.04-8.99(m,1H),8.91(t,J=5.5Hz,1H),8.71(dd,J=4.8,1.7Hz,1H),8.19(dt,J=8.0,2.0Hz,1H),7.75(dd,J=7.9,1 .2Hz,1H),7.71-7.62(m,2H),7.58-7.46(m,3H),7.42(dd,J=7.3,1.9Hz,1H),7.20-7.06(m,2H),4.26(t,J=5.6Hz,2H),3.70(q,J=5.6Hz,2H); 13C NMR(151MHz,DMSO-d6)δ194.00,165.66,163.61,152.39,148.87,141.13,135.41,133.26,13 2.64,131.85,130.18,129.07,129.00,128.24,123.89,118.82,115.35,66.97,39.30.HR-MS m / z:calcd for C 21 H 17 BrN2O3[(M+Na) + ],447.0320,found,447.0291.

[0235] Preparation of N-(3-(4-(2-bromobenzoyl)phenoxy)propyl)nicotinamide (SDUY434)

[0236] (2-Bromophenyl)(4-hydroxyphenyl)methane (0.77 g, 2.78 mmol) was dissolved in tetrahydrofuran, and tert-butyl (3-hydroxypropyl)carbamate (0.49 g, 2.78 mmol) and triphenylphosphine (1.46 g, 5.56 mmol) were added. The mixture was stirred at room temperature for 15 minutes. Under nitrogen protection, diethyl azodicarboxylate (1.45 g, 8.34 mmol) was added dropwise under ice bath conditions. The mixture was reacted at room temperature for 4 hours. The reaction was completed after TLC monitoring. The reaction solution was quenched with ice water, extracted with ethyl acetate three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 0.70 g of intermediate E4-2; E4-2 (0.70 g, 1.63 mmol) was dissolved in dichloromethane, 4 mL trifluoroacetic acid, react at room temperature for 2 hours, TLC monitoring reaction is complete, rotary evaporation concentration, adjusted to pH = 8 with saturated sodium bicarbonate solution, filtered to obtain 0.60g intermediate F4-2; F4-2 (0.60g, 1.80mmol) was dissolved in N, N-dimethylformamide, triethylamine (0.21g, 1.97mmol), nicotinic acid (0.24g, 1.97mmol) and HATU (1.03g, 2.70mmol) were added in sequence and stirred at room temperature overnight, TLC monitoring reaction is complete, saturated brine was added to the reaction solution, ethyl acetate was extracted three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain 0.52g light yellow solid SDUY434, yield: 67%. Melting point: 110-111℃. 1H NMR(400MHz,DMSO-d6)δ9.00(d,J=2.3Hz,1H),8.77(dt,J=9.2,3.6Hz,1H),8.7 0(dd,J=4.8,1.7Hz,1H),8.18(dt,J=8.0,2.0Hz,1H),7.75(dd,J=8.0,1.2Hz,1 H),7.72-7.64(m,2H),7.57-7.46(m,3H),7.42(dd,J=7.3,1.9Hz,1H),7.13-7. 06(m,2H),4.17(t,J=6.1Hz,2H),3.46(q,J=6.5Hz,2H),2.03(p,J=6.5Hz,2H); 13 C NMR(151MHz,DMSO-d6)δ192.49,165.39,164.03,152.22,148.82,142.88,135.36,135.00,133.2 8,132.76,131.67,130.51,128.70,128.34,123.85,117.28,115.39,66.46,36.68,29.08.ESI-MS m / z:calcd for C 22 H 19 BrN2O3[(M+H) + ],439.06,found,439.05.

[0237] Preparation of (3-(4-(2-bromo-5-chlorobenzoyl)phenoxy)propyl)nicotinamide (SDUY435)

[0238] (2-bromo-5-chlorophenyl)(4-hydroxyphenyl)methane (0.81 g, 2.61 mmol) was dissolved in tetrahydrofuran, and tert-butyl (3-hydroxypropyl)carbamate (0.46 g, 2.61 mmol) and triphenylphosphine (1.37 g, 5.22 mmol) were added. The mixture was stirred at room temperature for 15 minutes. Under nitrogen protection, diethyl azodicarboxylate (1.36 g, 7.82 mmol) was added dropwise under ice bath conditions. The mixture was reacted at room temperature for 4 hours. After TLC monitoring, the reaction was complete. The reaction solution was quenched with ice water, extracted with ethyl acetate three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 0.80 g of intermediate E4-3. E4-3 (0.80 g, 1.71 mmol) was dissolved in dichloromethane and added 8 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 hours. The reaction was complete after TLC monitoring. The mixture was concentrated by rotary evaporation, adjusted to pH=8 with saturated sodium bicarbonate solution, and filtered to obtain 0.92 g of intermediate F4-3. F4-3 (0.92 g, 2.50 mmol) was dissolved in N,N-dimethylformamide, and triethylamine (0.28 g, 2.75 mmol), nicotinic acid (0.34 g, 2.75 mmol) and HATU (1.43 g, 3.75 mmol) were added in sequence, and stirred at room temperature overnight. The reaction was complete after TLC monitoring. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (50 mL×3). The organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.80 g of light yellow solid SDUY435, with a yield of 68%. Melting point: 76-77°C. 1 HNMR(400MHz,DMSO-d6)δ9.06-8.95(m,1H),8.75(t,J=5.6Hz,1H),8.70(dd,J=4.9 ,1.7Hz,1H),8.17(dt,J=7.9,2.0Hz,1H),7.78(d,J=8.5Hz,1H),7.72-7.66(m,2H), 7.60(d,J=2.6Hz,1H),7.55(dd,J=8.5,2.6Hz,1H),7.50(dd,J=8.0,4.8Hz,1H),7.1 9-7.04(m,2H),4.17(t,J=6.1Hz,2H),3.46(q,J=6.5Hz,2H),2.03(p,J=6.7Hz,2H); 13C NMR(151MHz,DMSO-d6)δ194.00,165.39,163.81,152.21,148.82,141.18,135.35,133.25,132.6 2,131.83,130.51,129.06,128.83,128.23,123.85,118.82,115.29,66.41,36.69,29.09.ESI-MS m / z:calcd for C 22 H 18 BrClN2O3[(M+H) + ],473.03,found,472.99.

[0239] Preparation of N-(2-(4-(2-bromo-5-chlorobenzoyl)phenoxy)ethyl)nicotinamide (SDUY423)

[0240] (2-bromo-5-chlorophenyl)(4-hydroxyphenyl)methane (1.00 g, 3.22 mmol) was dissolved in tetrahydrofuran, and tert-butyl (2-hydroxyethyl)carbamate (0.52 g, 3.22 mmol) and triphenylphosphine (1.27 g, 4.83 mmol) were added. The mixture was stirred at room temperature for 15 minutes. Under nitrogen protection, diethyl azodicarboxylate (0.67 g, 3.86 mmol) was added dropwise under ice bath conditions. The mixture was reacted at room temperature for 4 hours. After TLC monitoring, the reaction was complete. The reaction solution was quenched with ice water, extracted with ethyl acetate three times (50 mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1.20 g of intermediate E4-4. E4-4 (0.50 g, 1.10 mmol) was dissolved in dichloromethane and added 10mL trifluoroacetic acid, react at room temperature for 2 hours, TLC monitoring reaction is complete, rotary evaporation concentration, adjusted to pH=8 with saturated sodium bicarbonate solution, filtered to obtain 0.35g intermediate F4-4; F4-4 (0.35g, 0.97mmol) was dissolved in N,N-dimethylformamide, triethylamine (0.11g, 1.07mmol), nicotinic acid (0.13g, 1.07mmol) and HATU (0.56g, 1.46mmol) were added in sequence and stirred at room temperature overnight, TLC monitoring reaction is complete, saturated brine was added to the reaction solution, ethyl acetate was extracted three times (50mL×3), the organic phases were combined, washed twice with saturated brine, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was chromatographed on a silica gel column (dichloromethane: methanol = 100: 1) to obtain 0.28g light yellow solid SDUY423, yield: 64%. Melting point: 110-111℃. 1H NMR (400MHz, DMSO-d6) δ9.00(d,J=2.3Hz,1H),8.91(t,J=5.4Hz,1H),8.71(dd,J=4.9,1.6Hz,1H),8.19(dt,J=8.0,2.0Hz,1H),7.77(d,J=8. 6Hz,1H),7.73-7.64(m,2H),7.61-7.53(m,2H),7.51(dd,J=8.0,4.8Hz,1H),7.16-7.10(m,2H),4.27(t,J=5.6Hz,2H),3.70(q,J=5.6Hz,2H); 13 C NMR(151MHz,DMSO-d6)δ192.49,165.67,163.84,152.39,148.86,142.83,135.41,135.00,13 3.29,132.77,131.68,130.18,128.71,128.51,123.90,117.28,115.45,67.02,39.29.HR-MS m / z:calcd for C 21 H 16 BrClN2O3[(M+Na) + ],482.9910,found,482.9870.

[0241] Preparation of 2-(4-(3-aminobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY412)

[0242] SDUY406 (1.00 g, 2.65 mmol) was dissolved in a mixed solution of isopropanol / water (8 mL:8 mL), iron powder (0.74 g, 13.25 mmol) and ammonium chloride (0.72 g, 13.25 mmol) were added, and the mixture was prepared according to route 5 to obtain 0.64 g of yellow solid SDUY412, with a yield of 70%. Melting point: 104-105°C. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.81(s,1H),8.31(d,J=4.7Hz,1H),8.08(d,J=8.3Hz,1H),7.75( d,J=8.3Hz,2H),7.47-7.31(m,1H),7.17(t,J=8.6Hz,3H),6.98-6.74(m,3H),5.38(s,2H),4.88(s,2H); 13C NMR(151MHz,DMSO-d6)δ195.50,167.19,161.64,149.22,145.20,141.87,138.88,135.48 ,132.36,131.10,129.28,127.32,124.12,117.95,117.35,114.94,114.74,67.47.HR-MS m / z:calcdfor C 20 H 17 N3O3[(MH) - ],346.1192;found,346.1184.

[0243] Preparation of 2-(4-(4-aminobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY413)

[0244] SDUY410 (1.00 g, 2.65 mmol) was dissolved in a mixed solution of isopropanol / water (8 mL:8 mL), iron powder (0.74, 13.25 mmol) and ammonium chloride (0.72 g, 13.25 mmol) were added, and the preparation was carried out according to route 5 to obtain 0.61 g of yellow solid SDUY413, with a yield of 67%. Melting point: 206-207°C. 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.83(s,1H),8.30(d,J=4.6Hz,1H),8.09(d,J=8.3Hz,1H),7.65(d,J=8.2Hz,2 H),7.51(d,J=8.2Hz,2H),7.43-7.31(m,1H),7.12(d,J=8.3Hz,2H),6.61(d,J=8.3Hz,2H),6.10(s,2H),4.87(s,2H); 13 C NMR(151MHz,DMSO-d6)δ192.77,167.34,160.69,153.89,145.18,141.90,135.52 ,132.78,132.46,131.62,127.29,124.72,124.10,114.74,113.00,67.51.HR-MS m / z:calcd for C20H17N3O3[(MH)-],346.1192; found,346.1185.

[0245] Preparation of 2-(4-(3-hydroxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY414)

[0246] The final product of 2-(4-(3-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (1.05 g, 2.56 mmol) was dissolved in 1,4-dioxane, and bisborane (1.30 g, 5.12 mmol), potassium acetate (0.75 g, 7.68 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.19 g, 0.26 mmol) were added in sequence to obtain 0.53 g of intermediate borate according to route 6. The intermediate borate (0.53 g, 1.16 mmol) was dissolved in tetrahydrofuran, and 4-methylmorpholine-4-oxide (0.41 g, 3.47 mmol) was added to obtain 0.23 g of brown solid SDUY414, yield: 58%. Melting point: 200-201°C. 1 HNMR (400MHz, DMSO-d6) δ10.39(s,1H),9.79(s,1H),8.80(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.07(ddd,J=8.3,2.6,1.5Hz,1H),7.80-7. 72(m,2H),7.38(dd,J=8.2,4.6Hz,1H),7.33(d,J=7.8Hz,1H),7.18-7.13( m,2H),7.12-7.05(m,2H),7.03(ddd,J=8.1,2.5,1.0Hz,1H),4.88(s,2H); 13 C NMR(151MHz,DMSO-d6)δ194.80,167.15,161.81,157.77,145.22,141.89,139.42,135.47 ,132.45,130.73,130.01,127.31,124.11,120.63,119.74,116.23,115.04,67.48.HR-MS m / z:calcd for C 20 H 16 N2O4[(M+H) + ],349.1188;found,349.1184.

[0247] Preparation of 2-(4-(4-hydroxybenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY416)

[0248] The final product of 2-(4-(4-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (1.00 g, 2.44 mmol) was dissolved in 1,4-dioxane, and bisborane (1.24 g, 4.88 mmol), potassium acetate (0.72 g, 7.68 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.18 g, 0.24 mmol) were added in sequence to obtain 2.00 g of intermediate borate according to route 6. The intermediate borate was dissolved in tetrahydrofuran, and 4-methylmorpholine-4-oxide (1.92 g, 16.38 mmol) was added to obtain 1.20 g of light yellow solid SDUY416, with a yield of 63%. Melting point: 170-171°C. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.81(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.08(dt,J=8.3,2.0Hz,1H),7.7 1(d,J=8.7Hz,2H),7.67-7.58(m,2H),7.38(dd,J=8.3,4.7Hz,1H),7.21-7.10(m,2H),6.88(d,J=8.5Hz,2H),4.87(s,2H); 13 C NMR(151MHz,DMSO-d6)δ193.53,167.24,162.03,161.25,145.21,141.90,135.49 ,132.64,132.06,131.54,128.90,127.31,124.11,115.61,114.92,65.95.HR-MS m / z:calcd for C 20 H 16 N2O4[(MH) - ],347.1032; found,347.1017.

[0249] Preparation of 2-(4-(2-cyanobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (SDUY419)

[0250] 2-(4-(2-bromobenzoyl)phenoxy)-N-(pyridin-3-yl)acetamide (0.70 g, 1.71 mmol) was dissolved in N,N-dimethylacetamide, K4[Fe(CN)6].3H2O (0.29 g, 0.68 mmol), anhydrous sodium carbonate (0.18 g, 1.71 mmol) and palladium acetate (0.04 g, 0.17 mmol) were added in sequence, and prepared according to route 7 to obtain 0.30 g of light pink solid SDUY419, yield: 50%. Melting point: 136-137°C.1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.80(d,J=2.5Hz,1H),8.31(dd,J=4.7,1.5Hz,1H),8.11-8.06(m,1H),8.07-8.0 4(m,1H),7.89-7.76(m,4H),7.72(dd,J=7.6,1.5Hz,1H),7.38(dd,J=8.3,4.7Hz,1H),7.25-7.17(m,2H),4.92(s,2H); 13 C NMR(151MHz,DMSO-d6)δ192.70,166.95,162.97,145.23,142.11,141.87,135.46,134.63,13 3.41,133.02,131.93,129.84,129.33,127.30,124.12,117.63,115.53,110.58,67.51.HR-MS m / z:calcd for C 21 H 15 N3O3[(MH) - ],356.1035;found,356.1020.

[0251] Experimental Example 1 :Activation of Kv11.1 channels by compounds

[0252] 1. Experimental principle: Patch clamp is an electrophysiological technique used to detect the activity of cell membrane ion channels. It can be divided into voltage clamp and current clamp according to the working mode. Voltage patch clamp can be divided into four modes: whole-cell, cell-attached or (on cell), inside-out, and outside-out. This experiment uses the whole-cell working mode in voltage clamp.

[0253] 2. Experimental materials and instruments

[0254] Experimental materials: DMEM (Gibco, USA), Australian fetal bovine serum (Hyclone, USA), 0.25% trypsin-EDTA (Gibco, USA), PBS (Sigma, USA), EGTA (Sigma, USA), HEPES (Sigma, USA), glucose (Sigma, USA), sodium chloride (Sigma, USA), potassium chloride (Sigma, USA), magnesium chloride (Sigma, USA), calcium chloride (Sigma, USA), potassium hydroxide (Sigma, USA), Mg-ATP (Sigma, USA), dipotassium hydrogen phosphate (Sigma, USA), sodium pyruvate (Sigma, USA), sodium bicarbonate (Sigma, USA).

[0255] Experimental instruments: Axonpatch 200B patch clamp amplifier (Axon Corporation, USA), Digidata 1550 digital-to-analog converter (Axon Corporation, USA), computer (Molecular Devices, Sunnyvale, CA), CO2 incubator (ThermoScientific), peristaltic pump (Baoding Lange Constant Flow Pump Co., Ltd.), -80℃ refrigerator (Thermo Scientific), Sutter electrode pulling instrument (Sutter Corporation, USA), Sutter micromanipulator (Sutter Corporation, USA), peristaltic pump (Baoding Lange Constant Flow Pump Co., Ltd.), pH meter (Beijing Yiyuan Electronic Instrument Technology Co., Ltd.), analytical balance (Sartorius Company, Germany), constant temperature water bath (Changzhou Huaguan Instrument Manufacturing Co., Ltd.), clean bench (Beijing Donglian Har Instrument Manufacturing Co., Ltd.), magnetic stirrer (IKA Company, Germany).

[0256] 3. Experimental methods

[0257] Preparation of DMEM complete medium: Add 10% fetal bovine serum, 400 Ug / mL G418 and 1% penicillin / streptomycin (final concentration is 100 U / mL) to DMEM medium and store in a 4°C refrigerator.

[0258] Preparation of internal and external solutions of the electrode: The external solution of the electrode contains 140mM NaCl, 5mM KCl, 1mM MgCl2, 2mM CaCl2, 10mM D-Glucose, 10mM HEPES, and the pH is adjusted to 7.4 with NaOH. The internal solution of the electrode contains 130mM KCl, 1mM MgCl2, 5mM EGTA, 5mM Mg-ATP, 10mM HEPES, and the pH is adjusted to 7.3 with KOH.

[0259] The 39 newly synthesized compounds were dissolved in DMSO solution to prepare a 10 mM concentrated stock solution, which was stored in a -20°C refrigerator and diluted with the electrode external solution to the required dosing concentration when used.

[0260] Cell culture and subculture: Cells grow by adhering to the wall. When the cell density reaches about 90% of the culture dish, subculture, remove the culture dish, use a pipette to suck away the culture medium in the culture dish, wash with PBS 2-3 times, add trypsin to digest for about 1 minute, and observe under a microscope. When the cells become round, the intercellular gap increases, and the cells fall off under the microscope, immediately add DMEM culture medium to terminate the digestion, and gently blow with a pipette to form a dispersed single cell suspension. Transfer the cell suspension to a 15mL centrifuge tube, place it in a low-speed centrifuge at 1200rpm / min for 1.5min, discard the supernatant, add DMEM to resuspend the cells, transfer to the culture dish at a ratio of 1:3, add DMEM complete culture medium, and culture in a 37℃, 5% CO2 incubator.

[0261] Preparation of cell smears: remove the culture dish, remove the culture medium with a pipette, wash 2-3 times with PBS, add trypsin to digest for 1 min, add DMEM culture medium to terminate digestion, disperse the cells, transfer the single cell suspension to a 15 mL centrifuge tube, centrifuge in a low-speed centrifuge at 1200 rpm / min for 1.5 min, discard the supernatant, add DMEM to resuspend the cells, plate at a low density on an 8 mm glass slide, and perform patch clamp recording after 48 hours.

[0262] Whole-cell patch clamp recording process: First, use a puller to pull a borosilicate hard glass blank electrode, polish it before use, fill the electrode with electrode liquid, fix it on the probe of the amplifier, place the cell smear in a bath filled with extracellular fluid, and select a single cell for the experiment. First, give the electrode positive pressure, use a micromanipulator to put the electrode into the liquid, the water impedance is 1.5-2.5MΩ, push the electrode to contact the slide, slowly approach the cell, release the positive pressure after the electrode contacts the cell (if it cannot be sealed by itself, slowly suck it), gradually form a GΩ seal, compensate for the electrode capacitance and apply negative pressure, when a large capacitive current suddenly appears and the impedance remains above GΩ, it indicates that the membrane is broken successfully, the Whole-Cell mode is formed, and the potassium current is recorded. The current signal is transmitted and stored in the computer through the Axonpatch 200B amplifier and the digital-to-analog converter. The experimental process is controlled by the pCLAMP10.6 software and the 200B software equipped with the amplifier. The digital-to-analog converter completes the generation of stimulation signals and the collection of feedback signals. All experimental data are expressed as mean ± standard deviation (Mean ± SEM). The dose-effect relationship curve was fitted by the logistic formula in Origin, and the formula is as follows: y = (A1-A2) / (1+(x / x0) p)+A2. (A1: the maximum value of y when x approaches infinity or is infinitely small; A2: the minimum value of y when x approaches infinity or is infinitely small; x: the inflection point of the curve; p: the slope of the curve at the inflection point).

[0263] K v 11.1 Potassium current recording procedure: The recording procedure uses a single step method, where the cell is clamped at -80 mV, depolarized to +40 mV for 3000 ms, and then repolarized to -40 mV to induce K v 11.1 Tail Current.

[0264] 4. Experimental results: This experiment used whole-cell patch clamp experiments to determine the effects of all target compounds on potassium currents at a concentration of 10 μM. The experimental results are as follows Figure 1 As shown in Table 1, the 16 compounds have a positive effect on K v The compounds SDUY403, SDUY424, SDUY429, SDUY436 and SDUY437 had a significant activation effect on the channel. Among them, the activation effect of the compound SDUY403, SDUY424, SDUY429, SDUY436 and SDUY437 on the channel was significantly better than that of the lead compound ML-T531. Compared with the activation current of ML-T531, I kr The effects of SDUY414, SDUY416, SDUY422, SDUY434, SDUY411 and SDUY410 on K v The activation of 11.1 channel was lower than that of ML-T531. In addition, SDUY435 and SDUY423 had a negative effect on K v 11.1 channel has a significant inhibitory effect. kr Reducing to 47% and 34% of normal values ​​respectively.

[0265] Table 1K v 111 Current Amplification

[0266]

[0267]

[0268] To further evaluate the activation of K v 11.1 Dose-effect relationship of channel current. In this experiment, nine concentrations of 0.01, 0.1, 0.3, 0.5, 1, 3, 5, 10 and 100 μM were selected to record the effect of the compound on I kr The impact of Figure 2 As shown in Table 2, the activities of SDUY403, SDUY424, SDUY429 and SDUY436 were significantly higher than those of ML-T531, and the EC 50The values ​​were 1.9, 3.0, 1.9 and 2.7 μM, respectively, while compounds SDUY415 and SDUY437 were comparable to ML-T531 in terms of activity, with their EC 50 The values ​​were 3.7 and 3.8 μM, respectively. In addition, the activities of compounds SDUY406, SDUY418, SDUY420, and SDUY432 were relatively low, and their activation I kr EC 50 The values ​​were all greater than 25 μM. max In terms of SDUY403 and SDUY437, respectively, at high concentrations, v 11.1 Potassium current increased to 18 and 28 times before administration, much higher than that of the lead compound ML-T531 (E max =5.0).

[0269] Table 2K v EC of 111 channel activators 50 Value and E max value

[0270]

[0271] Experimental Example 2 :Compounds inhibit K of astemizole v 11.1 Effect of Channel Current

[0272] 1. Experimental principle: Astemizole blocks K v 11.1 channel, resulting in prolonged QT interval and severe cardiac toxicity, and was withdrawn from the market. In this experimental example, astemizole was used to inhibit channel current to construct an acquired LQTS model, and the whole-cell patch clamp experiment was used to evaluate the reversal effect of active compounds on channel inhibition, thereby evaluating the efficacy of the compounds in alleviating acquired LQTS at the cellular level.

[0273] 2. Experimental instruments: MultiClamp 700A amplifier, 1550A digital-to-analog converter, pClamp 10.6 acquisition and analysis software (Molecular devices, USA).

[0274] 3. Experimental methods

[0275] Preparation of internal and external solutions of the electrode: The external solution of the electrode contains 130mM NaCl, 10mM HEPES, 5mM KCl, 1mM MgCl2.6H2O, 1mM CaCl2.H2O and 12.5mM D-Glucose, and the pH is adjusted to 7.4 with 5M NaOH. The internal solution of the electrode contains 65mM KCl, 75mM KF, 10mM HEPES, 5mM EGTA and 2mM MgCl2.6H2O, and the pH is adjusted to 7.3 with 1M KOH.

[0276] Drug preparation: Astemizole was dissolved in DMSO to prepare a 10 mM stock solution and stored in a -20°C refrigerator. When used, it was diluted to different dosing concentrations in the electrode external solution.

[0277] Experimental protocol: The voltage was clamped at -80 mV for 200 ms, then depolarized to +40 mV for 3000 ms, repolarized to -40 mV for 2000 ms, tail current was induced, then clamped at -80 mV, and the sweep interval was 6 s.

[0278] 4. Experimental results: In this experiment, the five most active compounds were selected and tested at a concentration of 5 μM for further pharmacodynamic evaluation at the cellular level. Figure 3 Part A and Figure 3 As shown in part b, astemizole significantly inhibited K v 11.1-mediated potassium current, at 1 μM concentration I kr The dose-effect relationship analysis showed that the inhibitory effect of astemizole on the channel was concentration-dependent, and the IC 50 The value was 1.9±0.7nM( Figure 3 When astemizole and compound SDUY403 were administered simultaneously, compound SDUY403 could significantly enhance the potassium current inhibited by astemizole and reverse the effect of astemizole on K v 11.1 Inhibition of channel. Astemizole completely inhibited channel current at 1 μM concentration, and 5 μM SDUY403 had difficulty in restoring the inhibited channel current. Similarly, compounds SDUY436, SDUY424, SDUY415, and SDUY437 could significantly alleviate the effects of astemizole on K v Inhibition of 11.1 channels. Among them, compounds SDUY403, SDUY436, SDUY424 and SDUY437 are more active than compound SDUY415.

[0279] In summary, compounds SDUY403, SDUY424, SDUY436 and SDUY437 can significantly reverse the inhibition of K by astemizole. v 11.1-mediated potassium current reduces the cardiotoxic effects of astemizole at the cellular level and has pharmacological activity in alleviating acquired LQTS.

[0280] Experimental Example 3 :Effects of compounds on astemizole-induced prolongation of overall cardiac conduction time

[0281] 1. Experimental principle: Multi-channel matrix cardiac electrophysiological mapping technology (MEA) is a system that can synchronously and accurately record electrical signals in multiple parts of the heart. Electrical mapping detects and collects information on the excitation of myocardial cells by directly placing electrodes in relevant parts of the heart, and then uses computer graphics to achieve three-dimensional dynamic mapping of the heart. This experimental example constructed an animal in vitro experimental model of acquired LQTS. The astemizole inhibitor was first given to induce prolonged cardiac conduction time, and then the compounds SDUY403, SDUY436, SDUY424 and SDUY437 were given. The therapeutic effect of the compounds on acquired LQTS was evaluated by electrical mapping.

[0282] 2. Experimental animals: 4-5 month old male mice (C57) were obtained from the Experimental Animal Center of Southwest Medical University. Three mice were kept normally in each cage, with a total of four cages. Rearing conditions: quiet and clean environment, normal day and night, controlled room temperature at 20-25℃, good ventilation, free food and water.

[0283] 3. Experimental methods

[0284] Preparation of Tyrode's solution: 1.8 mM CaCl2, 132 mM NaCl, 5.4 mM KCl, 1 mM MgCl2, 10 mM D-Glucose and 10 mM HEPES, filled with 100% O2 for 30 minutes, and adjusted to pH 7.4 with NaOH.

[0285] Preparation of KH solution: 119mM NaCl, 25mM NaHCO3, 4mM KCl, 1.2mM KH2PO4, 1mM MgCl2, 1.8mM CaCl2, 10mM Glucose and 2mM sodium pyruvate, filled with 100% O2 for 30 minutes, and adjusted to pH 7.2 with KOH.

[0286] Langendorff perfusion of isolated heart: Take out the pre-prepared benchtop solution from the constant temperature water bath, place it in the reflux device, and pass 95% O2 and 5% CO2 into the device until saturated. Control the perfusion rate to 2-2.5mL / min under the constant temperature of 37℃. Mix sodium heparin and sodium pentobarbital, anesthetize the male rat by intraperitoneal injection, open the chest cavity, cut it at the distal end of the aortic root to obtain a longer aorta, remove the heart, place the heart in the pre-prepared refrigerated KH solution, remove the connective tissue and pericardium around the heart under a stereo microscope, free the aortic root, immediately cannulate the aorta, fix it with surgical thread, start perfusion, and start recording after the heart stabilizes for 20 minutes. Stick the electric marker pen to the surface of the heart, adjust the position, and ensure that each electrode can record the signal as much as possible. Fix the position and keep the position of the marker pen from moving during the subsequent recording process. After the signal stabilizes, record the signal before drug administration. Perfuse the drug, and after the drug flows into the heart, record the post-drug administration signal in different time periods.

[0287] In this experimental example, 64 channels were selected to synchronously record the same heartbeat at different positions of the heart. The maximum descending branches at different sites have a temporal sequence. We selected the maximum descending branch for plotting. The red part represents the first excited site of the heart, and the blue part represents the second excited site of the heart. Excitation is transmitted from red to blue.

[0288] 4. Experimental results: Figure 4 Part A and Figure 4 The results in part b show that when astemizole and compounds SDUY403 and SDUY436 were given simultaneously, we found that compounds SDUY403 and SDUY436 could significantly shorten the conduction time prolonged by astemizole, with the conduction time shortened by 2.33 and 22.36 ms, respectively. Compounds SDUY429 and SDUY437 had no significant effect on cardiac conduction time.

[0289] In summary, in the acquired LQTS in vitro animal model, compounds SDUY403 and SDUY436 can significantly reduce the drug's hERG cardiotoxicity and alleviate acquired LQTS, but the efficacy of compounds SDUY424 and SDUY437 in the animal model is not ideal. Therefore, compounds SDUY403 and SDUY436 are expected to become potential drugs for the treatment of acquired LQTS through combined use.

[0290] Experimental Example 4 :Compounds for K v 11.1 Effects of channel dynamics

[0291] 1. Experimental method: To study K v11.1 Mechanism of action of channel activators. In this experimental example, whole-cell patch clamp experiments were used to evaluate the effects of compounds SDUY403 and SDUY436 on channel activation and inactivation kinetics. The concentration of the tested compounds was 5 μM.

[0292] Experimental plan for compound activation curve: cells were clamped at -80 mV, and the voltage was stepped from -50 mV to +50 mV in 10 mV steps for 3 s. Tail current was then activated by -40 mV, and the interval between single sweeps was 10 s.

[0293] Experimental plan for compound inactivation curve: The cells were clamped at -80 mV, then depolarized to +40 mV for 2 s, then gradually increased from -130 mV to +40 mV in 10 mV steps for 10 ms, then continued to be depolarized at +40 mV for 1 s, and finally restored to -80 mV, with a single sweep interval of 6 s.

[0294] The activation and inactivation curves were fitted using the Boltzmann equation, with the following formula: y = A2 + (A1 - A2) / [1 + e (x - x0) / dx]. (A1 is the initial value, A2 is the final value, x0 is the center, and dx is the time constant.)

[0295] 2. Experimental results: Figure 5 As shown, compound SDUY403 significantly affected K v 11.1 Channel activation and inactivation gating characteristics. In the presence of SDUY403, the channel activation curve shifted to the left, the half-activation voltage dropped from -5.3mV to -14mV, and the channel was more easily activated; on the contrary, the channel inactivation curve shifted to the right, the half-inactivation voltage increased from -35mV to -21mV, and the channel inactivation slowed down. Figure 6 As shown, the V of the activation curve before and after administration of compound SDUY436 1 / 2 From -5.3mV to -10mV, and its steady-state inactivation effect is relatively weak. It can be seen that the target compound of the present invention mainly exerts the pharmacological effect of enhancing potassium current and treating LQTS by accelerating channel activation and delaying channel inactivation.

[0296] In short, the compounds prepared by the present invention are good K v 11.1 channel activator, and showed excellent pharmacological activity in both in vitro and ex vivo experiments. v The structural modification and optimization of 11.1 channel activators have pointed out the direction and laid the foundation for the clinical transformation and application research of this type of compounds in controlling drug hERG cardiotoxicity and alleviating LQTS.

[0297] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. Although the present application is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A benzophenone compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from: 。 2. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof; Furthermore, the pharmaceutical preparation further comprises at least one pharmaceutically acceptable excipient or carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of one or more of the following drugs or reagents: 1) Regulating K v 11.1 Channel drugs or reagents; 2) Antiarrhythmic drugs.

4. The use according to claim 3, characterized in that The drug is K v 11.1 Channel inhibitors.

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