CN107151220B

CN107151220B - Phenol compound containing benzyloxy phenyl, preparation method and application thereof

Info

Publication number: CN107151220B
Application number: CN201610922561.6A
Authority: CN
Inventors: 汪小涧; 孙晨斌; 葛军; 席眉扬; 肖琼; 尹大力
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2015-10-19
Filing date: 2016-10-19
Publication date: 2021-07-20
Anticipated expiration: 2036-10-19
Also published as: CN107151220A

Abstract

The present invention discloses phenols containing benzyloxyphenyl groupsThe invention discloses a phenol compound (I) containing benzyloxy phenyl, and a preparation method and application thereof, and particularly discloses the phenol compound (I) containing benzyloxy phenyl. The compounds and medicinal preparations thereof can be used for preparing medicines for treating a series of cancers and inflammatory diseases, such as colon cancer, lung cancer, breast cancer, liver cancer, gastric cancer, inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. The invention also relates to a preparation method of the compounds.

Description

Phenol compound containing benzyloxy phenyl, preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a phenolic compound containing benzyloxy phenyl, a preparation method thereof, a pharmaceutical preparation containing the phenolic compound and medical application of the phenolic compound.

Background

Cancer is the second most serious disease worldwide that threatens human health, second only to cardiovascular and cerebrovascular diseases. The incidence of malignant tumors in China increases by about 2.5% each year, and the mortality rate increases at a rate of 1.3% each year. Inflammation is a major disease affecting human health. In recent years, the incidence in Asian regions has increased by 3-8.5 times more than a decade ago.

With intensive studies on the above diseases, SphK was found to be expressed at high levels (Biochimie 2010, 92, 707-715). SphK is divided into two subtypes, SphK1 and SphK2(J.Med.chem 2015, 58, 1879-1899). SphK inhibitors discovered at present are mainly sphingosine derivatives, wherein Safingol has entered phase I clinical research and is used for treating solid tumors, and related documents report that the SphK inhibitors can inhibit cell recruitment, reduce permeability of blood vessel walls and have an inhibiting effect on inflammation; another SphK inhibitor, the substrate sphingosine analogue DMS, was also reported to have similar activity, and has completed preclinical studies. In addition, the thiazole SphK inhibitor SKI-II can effectively inhibit the expression of inflammatory factors IL-1 beta, IL-6, IL-10 and the like (ACS Chem Biol 2015, 10, 225-233), and strongly proves that the SphK inhibitor can be used for treating certain diseases (FASEB J2009, 23, 143-52; Carcinogenesis 2010, 31, 1787-1793).

Since the incidence of cancer and inflammatory diseases tends to increase year by year and the mechanism of pathological process is very complicated, the discovery of structural diversity of SphK inhibitors to alleviate cancer and inflammatory bowel disease is urgent. Based on the research idea, researchers found that the phenolic compound containing the benzyloxy phenyl group has better inhibition effect on SphK than positive control DMS.

Disclosure of Invention

The invention aims to provide a triphenol compound containing benzyloxy phenyl, a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicines for preventing and/or treating Sphk dysfunction-related diseases.

In order to solve the technical problem, the invention provides the following technical scheme:

the first aspect of the technical scheme of the invention provides a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

represents phenyl, naphthyl or a five-membered or six-membered aromatic heterocyclic group containing 0, 1, 2 or 3 heteroatoms selected from nitrogen atoms, sulfur atoms or oxygen atomsA seed;

R₁selected from hydrogen, halogen, amino, hydroxyl, nitro, cyano, substituted or unsubstituted C₁～C₄Alkyl, substituted or unsubstituted C₁～C₄Alkoxy group of (C)₁～C₄Alkylamino group of (2), C₁～C₄Alkyl acyl of (2), C₁～C₄Alkanoylamino of (a), C₁～C₄An alkoxycarbonyl group of (a); wherein the substituent is selected from hydroxyl, amino, halogen, phenyl, five-membered or six-membered heterocyclic group containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, S; wherein R is₁Is mono-, di-, tri-, or tetra-substituted;

a is

Wherein R is₂Represents mono-, di-, tri-or tetra-substituted hydroxy;

x is O, S or NH.

Preferred compounds or pharmaceutically acceptable salts thereof are represented by the following general formula (Ia):

wherein:

represents phenyl, naphthyl or a five-membered or six-membered aromatic heterocyclic group containing 0, 1, 2 or 3 heteroatoms selected from nitrogen atoms, sulfur atoms or oxygen atoms; preferably phenyl;

R₁selected from hydrogen, halogen, amino, hydroxyl, nitro, cyano, substituted or unsubstituted C₁～C₄Alkyl, substituted or unsubstituted C₁～C₄Alkoxy group of (C)₁～C₄Alkylamino group of (2), C₁～C₄Alkyl acyl of (2), C₁～C₄Alkanoylamino of (a), C₁～C₄An alkoxycarbonyl group of (a); whereinThe substituent is selected from hydroxyl, amino, halogen, phenyl, five-membered or six-membered heterocyclic group containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, S; wherein R is₁Is mono-, di-, tri-, or tetra-substituted;

a is

Wherein R is₂Represents mono-, di-, tri-or tetra-substituted hydroxy;

x is O, S or NH, preferably O.

Preferred compounds or pharmaceutically acceptable salts thereof are represented by the following general formula (Ib):

wherein:

represents phenyl, naphthyl or a five-membered or six-membered aromatic heterocyclic group containing 0, 1, 2 or 3 heteroatoms selected from nitrogen atoms, sulfur atoms or oxygen atoms;

a is

Wherein R is₂Represents mono-, di-or tri-substitutionOr a tetra-substituted hydroxyl group;

x is O, S or NH.

Preferred compounds or pharmaceutically acceptable salts thereof are represented by the general formulae (I), (Ia) (Ib) wherein X is O,

is composed of

R₁Selected from halogen, amino, hydroxyl, nitro, cyano, substituted or unsubstituted C₁～C₄Alkyl, substituted or unsubstituted C₁～C₄Alkoxy group of (C)₁～C₄Alkylamino group of (2), C₁～C₄Alkyl acyl of (2), C₁～C₄Alkanoylamino of (a), C₁～C₄An alkoxycarbonyl group of (a); wherein the substituent is selected from hydroxyl, amino, halogen, phenyl, and five-membered or six-membered heterocyclic group containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, S, A is

Wherein R is₂Represents mono-, di-, tri-or tetra-substituted hydroxyl.

is composed of

R₁Selected from halogen, amino, hydroxyl, nitro, cyano, substituted or unsubstituted C₁～C₄Alkyl, substituted or unsubstituted C₁～C₄Alkoxy group of (C)₁～C₄Alkylamino group of (2), C₁～C₄Alkyl acyl of (2), C₁～C₄Alkanoylamino of (a), C₁～C₄An alkoxycarbonyl group of (a); wherein the substituent is selected from hydroxyl, amino, halogen, phenyl,A five-or six-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O, S, A is

Wherein R is₂Represents mono-, di-, tri-or tetra-substituted hydroxyl.

is composed of

Wherein R is₂Represents mono-, di-, tri-or tetra-substituted hydroxyl.

The above compound or a pharmaceutically acceptable salt thereof, wherein A is preferably

Halogen is selected from fluorine, chlorine, bromine, iodine, R₁Methyl, methoxy, tert-butyl, naphthyl, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy are preferred.

Most preferred compounds are selected from the group consisting of:

in a second aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, wherein the compound of the general formula (I) of the present invention is prepared by:

when in use

Is phenyl, A is R₂When X is O, S, NH, the preparation method of the compound comprises the following steps:

m- (or p-) hydroxybenzaldehyde with

Reacting to obtain a compound (II), reacting the compound (III) with hydrazine hydrate to obtain a compound (IV), and reacting the compound (IV) with the compound (II) to obtain a compound with a general formula (I).

M- (or p-) hydroxybenzaldehyde with

The reaction temperature is preferably 80 ℃, the reaction time is preferably 3 hours, the solvent used in the reaction is preferably DMF, and potassium carbonate is preferably added to the reaction solution as a base.

The reaction of the compound (III) and hydrazine hydrate is reflux reaction, the reaction time is preferably 36 hours, and the solvent used in the reaction is preferably ethanol.

The compound (IV) and the compound (II) are subjected to reflux reaction, the reaction time is preferably 6 hours, and the solvent used for the reaction is preferably ethanol.

When in use

Is phenyl, A is

The preparation method of the compound comprises the following steps:

m- (or p-) hydroxybenzaldehyde with

M- (or p-) hydroxybenzaldehyde with

The compound shown in the general formula (I) can be purified by adopting a common separation method, such as recrystallization, column chromatography and the like.

A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect.

The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.

The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.

The clinical dosage of the compound of the invention is 0.01-1000 mg/day, and the dosage can deviate from the range according to the severity of the disease or the dosage form.

The fourth aspect of the present invention provides a use of a compound according to the first aspect and a pharmaceutical composition according to the third aspect in the preparation of a medicament for preventing or treating a disease associated with SphK dysfunction. Wherein, the diseases related to SphK dysfunction comprise cancer and inflammatory diseases. The cancer comprises colon cancer, lung cancer, breast cancer, liver cancer and gastric cancer; the inflammatory disease comprises inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis or multiple sclerosis.

The beneficial technical effects are as follows:

the compound and the medicinal preparation thereof can be used for treating a series of diseases caused by SphK dysfunction, such as colon cancer, liver cancer, inflammatory bowel disease, hepatitis, asthma, primary sclerosis and the like. In addition, the preparation method provided by the invention has the characteristics of mild reaction conditions, abundant and easily-obtained raw materials, simple operation and post-treatment and the like.

Drawings

FIG. 1 inhibitory Activity of Compound syl1828 of the present invention for colitis

Detailed Description

Example 1

(E) -3, 4, 5-trihydroxy-N' - (3- (2-methylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (2-methylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of THF, 2-methylbenzyl bromide (1.66g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.5g, yield 81%, and melting point 35-38 deg.C.

¹H NMR(400MHz，CDCl₃)δ10.00(s，1H)，7.54-7.47(m，3H)，7.47-7.40(m，1H)，7.33-7.20(m，4H)，5.11(s，2H)，2.40(s，3H).

MS(ESI)m/z 227.1061(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.6g white solid with yield 57.81% and melting point greater than 250 deg.C.¹H NMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (2-methylbenzyloxy) benzaldehyde (0.307g, 1.36mmol) is dissolved in 15mL of ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.28g of gray solid is obtained, and the yield is 52.5%. Melting point 123-.

¹H NMR(400MHz，DMSO)δ11.53(s，1H)，9.13(s，2H)，8.82(s，1H)，8.37(s，1H)，7.42(d，J＝7.2Hz，1H)，7.37(d，J＝7.8Hz，1H)，7.33(d，J＝4.4Hz，1H)，7.29-7.16(m，4H)，7.07(m，1H)，6.91(s，2H)，5.12(s，2H)，2.33(s，3H).

HRMS calcd.For C22H21N2O5(M+H)⁺393.1445，found 393.1442.

Example 2

(E) -3, 4, 5-trihydroxy-N' - (3- (3-methylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (3-methylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, 3-methylbenzyl bromide (1.66g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain 1.6g of transparent oily substance with yield of 83%.

¹H NMR(400MHz，CDCl₃)δ9.97(s，1H)，7.50-7.40(m，3H)，7.32-7.20(m，4H)，7.15(d，J＝7.3Hz，1H)，5.08(s，3H)，2.37(s，3H).

MS(ESI)m/z 227.1061(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.6g white solid with yield 57.81% and melting point greater than 250 deg.C.

¹H NMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (3-methylbenzyloxy) benzaldehyde (0.307g, 1.36mmol) is dissolved in 15mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.3g of gray solid is obtained, and the yield is 56.2%. Melting point 155-.

¹H NMR(400MHz，DMSO)δ11.53(s，1H)，9.03(s，3H)，8.36(s，1H)，7.34(m，2H)，7.26(m，4H)，7.13(d，J＝6.7Hz，1H)，7.05(d，J＝8.1Hz，1H)，6.91(s，2H)，5.09(s，2H)，2.31(s，3H).

HRMS calcd.For C22H21N2O5(M+H)⁺393.1445，found 393.1441.

Example 3

(E) -3, 4, 5-trihydroxy-N' - (3- (4-methylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-methylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 4-methylbenzyl bromide (1.66g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.56g, yield 84.3%, and melting point 26-29 deg.C.

¹H NMR(400MHz，CDCl₃)δ9.97(s，1H)，7.47(m，3H)，7.33(d，J＝7.9Hz，2H)，7.28-7.22(m，1H)，7.21(d，J＝7.9Hz，2H)，5.09(s，2H)，2.37(s，3H).

MS(ESI)m/z 227.1061(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (4-methylbenzyloxy) benzaldehyde (0.307g, 1.36mmol) is dissolved in 15mL of ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.33g of gray solid is obtained, and yield is 61.9%. Melting point 213-.

¹H MR(400MHz，DMSO)δ11.52(s，1H)，9.13(s，2H)，8.81(s，1H)，8.35(s，1H)，7.38-7.31(m，3H)，7.29(s，1H)，7.24(d，J＝7.4Hz，1H)，7.19(d，J＝7.7Hz，2H)，7.04(d，J＝7.9Hz，1H)，6.90(s，2H)，5.09(s，2H)，2.29(s，3H).

HRMS calcd.ForC22H21N2O5(M+H)⁺393.1445，found 393.1441.

Example 4

(E) -3, 4, 5-trihydroxy-N' - (3- (2-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (2-trifluoromethylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 2-trifluoromethylbenzyl bromide (2.15g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain 1.78g of transparent oily substance with yield of 77%.

¹H NMR(400MHz，CDCl₃)δ9.97(s，1H)，7.71(t，J＝7.7Hz，2H)，7.57(t，J＝7.6Hz，1H)，7.52-7.40(m，4H)，7.26-7.20(m，1H)，5.31(s，2H).

MS(ESI)m/z 281.0775(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹H NMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

Dissolving 3- (2-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxy benzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.4g of gray solid by using an eluent dichloromethane and methanol which are 10: 1, wherein the yield is 66.6%, and the melting point is 206-.

¹H NMR(400MHz，DMSO)δ11.54(s，1H)，9.11(s，3H)，8.37(s，1H)，7.83-7.75(m，2H)，7.72(t，J＝7.6Hz，1H)，7.58(t，J＝7.6Hz，1H)，7.37(t，J＝7.8Hz，1H)，7.33-7.24(m，2H)，7.05(d，J＝7.8Hz，1H)，6.90(s，2H)，5.27(s，2H).

HRMS calcd.For C22H18F3N2O5(M+H)⁺447.1162，found 447.1162.

Example 5

(E) -3, 4, 5-trihydroxy-N' - (3- (3-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (3-trifluoromethylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 3-trifluoromethylbenzyl bromide (2.15g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain 1.82g of transparent oily substance with yield of 79%.

¹H NMR(400MHz，CDCl₃)δ9.99(s，1H)，7.73(s，1H)，7.62(t，J＝8.6Hz，2H)，7.50(m，4H)，7.30-7.23(m，1H)，5.17(s，2H).

MS(ESI)m/z 281.0775(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

Dissolving 3- (3-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.38g of gray solid by using dichloromethane and methanol at a ratio of 10: 1 as eluent, wherein the yield is 63.3%, and the melting point is 208-.

¹H NMR(400MHz，DMSO)δ11.55(s，1H)，9.06(s，3H)，8.37(s，1H)，7.83(s，1H)，7.79(d，J＝7.4Hz，1H)，7.70(d，J＝7.6Hz，1H)，7.64(m，1H)，7.43-7.31(m，2H)，7.27(d，J＝7.3Hz，1H)，7.08(d，J＝8.0Hz，1H)，6.91(s，2H)，5.25(s，2H).

HRMS calcd.For C22H18F3N2O5(M+H)⁺447.1162，found 447.1159.

Example 6

(E) -3, 4, 5-trihydroxy-N' - (3- (4-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-trifluoromethylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 4-trifluoromethylbenzyl bromide (2.15g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain transparent oily substance 1.5g, yield 65%.

¹H NMR(400MHz，CDCl₃)δ9.98(s，1H)，7.66(d，J＝8.0Hz，2H)，7.57(d，J＝8.0Hz，2H)，7.47(m，3H)，7.29-7.23(m，1H)，5.19(s，2H).

MS(ESI)m/z 281.0776(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

Dissolving 3- (4-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.28g of gray solid with eluent dichloromethane and methanol being 10: 1, the yield being 46.4%, and the melting point being 128-fold 131 ℃.

¹H NMR(400MHz，DMSO)δ11.54(s，1H)，9.12(s，3H)，8.36(s，1H)，7.75(d，J＝8.0Hz，2H)，7.69(d，J＝8.0Hz，2H)，7.41-7.30(m，2H)，7.26(d，J＝7.6Hz，1H)，7.07(m，1H)，6.91(s，2H)，5.27(s，2H).

HRMS calcd.For C22H18F3N2O5(M+H)⁺447.1162，found 447.1159.

Example 7

(E) -3, 4, 5-trihydroxy-N' - (3- (4-fluorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-fluorobenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 4-fluorobenzyl bromide (1.7g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.72g, yield 91%, and melting point 64-67 deg.C.

¹H NMR(400MHz，CDCl₃)δ9.98(s，1H)，7.51-7.45(m，3H)，7.42(m，2H)，7.29-7.20(m，1H)，7.09(t，J＝8.7Hz，2H)，5.09(s，2H).

MS(ESI)m/z 231.0811(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹H MR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

Dissolving 3- (4-fluorobenzyloxy) benzaldehyde (0.31g, 1.36mmol) in 15mL of ethanol, adding 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.33g of gray solid by using dichloromethane and methanol at a ratio of 10: 1 as eluent, wherein the yield is 61.3%, and the melting point is 202-.

¹H NMR(400MHz，DMSO)δ11.54(s，1H)，9.06(s，3H)，8.37(s，1H)，7.49-7.39(m，1H)，7.32m，5H)，7.15(t，J＝8.4Hz，1H)，7.06(d，J＝7.6Hz，1H)，6.92(s，2H)，5.17(s，2H).

HRMS calcd.For C21H18FN2O5(M+H)⁺397.1194，found 397.1193.

Example 8

(E) -3, 4, 5-trihydroxy-N' - (3- (3-chlorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (3-chlorooxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of THF, 3-chlorobenzyl bromide (1.84g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain transparent oily substance 1.5g, and obtaining yield 74%.

¹H NMR(400MHz，CDCl₃)δ9.98(s，1H)，7.48(m，4H)，7.32(s，3H)，7.28-7.19(m，1H)，5.09(s，2H).

MS(ESI)m/z 247.0517(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

Dissolving 3- (3-chlorobenzyloxy) benzaldehyde (0.33g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxy benzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.34g of gray solid by using dichloromethane and methanol at the ratio of 10: 1 as eluent, wherein the yield is 60.7%, and the melting point is 139-.

¹H NMR(400MHz，DMSO)δ11.54(s，1H)，9.02(s，3H)，8.36(s，1H)，7.53(s，1H)，7.42(m，2H)，7.40-7.29(m，3H)，7.26(d，J＝7.3Hz，1H)，7.06(m，1H)，6.91(s，2H)，5.16(s，2H).

HRMS calcd.For C21H18ClN2O5(M+H)⁺413.0899，found 413.0898.

Example 9

(E) -3, 4, 5-trihydroxy-N' - (3- (4-chlorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-chlorooxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 4-chlorobenzyl bromide (1.84g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.7g, yield 75%, and melting point 39-41 deg.C.

¹H NMR(400MHz，CDCl3)δ9.97(s，1H)，7.52-7.43(m，3H)，7.37(s，4H)，7.24(m，1H)，5.09(s，2H).

MS(ESI)m/z 247.0517(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

Dissolving 3- (4-chlorobenzyloxy) benzaldehyde (0.33g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxy benzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.3g of gray solid by using dichloromethane and methanol at a ratio of 10: 1 as eluent, wherein the yield is 53.5%, and the melting point is 199-202 ℃.

¹H NMR(400MHz，DMSO)δ11.54(s，1H)，9.10(s，2H)，8.36(s，1H)，7.49(d，J＝8.5Hz，2H)，7.44(d，J＝8.5Hz，2H)，7.34(m，2H)，7.25(d，J＝7.4Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.91(s，2H)，5.14(s，2H).

HRMS calcd.For C21H18ClN2O5(M+H)⁺413.0899，found 413.0898.

Example 10

(E) -3, 4, 5-trihydroxy-N' - (3- (4-cyanobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-cyanooxy) benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, 3-cyanobenzyl bromide (1.75g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.3g, yield 68.4%, and melting point 85-88 deg.C.

¹H NMR(400MHz，CDCl₃)δ9.99(s，1H)，7.77(s，1H)，7.68(d，J＝7.8Hz，1H)，7.64(d，J＝7.8Hz，1H)，7.52(m，3H)，7.48-7.44(m，1H)，7.26(m，1H)，5.16(s，3H).

MS(ESI)m/z 238.0858(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

Dissolving 3- (4-cyanobenzyloxy) benzaldehyde (0.32g, 1.36mmol) in 15mL ethanol, adding 3, 4, 5-trihydroxybenzoyl hydrazine (0.3g, 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, separating by column chromatography, and obtaining 0.33g of white solid by using an eluent dichloromethane and methanol at 10: 1, wherein the yield is 60.2%, and the melting point is 168-.

¹H NMR(400MHz，Acetone)δ10.77(s，1H)，8.45(s，1H)，8.17(s，2H)，7.94(s，1H)，7.88(d，J＝7.8Hz，1H)，7.76(d，J＝7.7Hz，1H)，7.65(t，J＝7.7Hz，1H)，7.48(s，1H)，7.37(t，J＝7.8Hz，1H)，7.32(d，J＝7.6Hz，1H)，7.10(m，J＝5.2Hz，3H)，5.27(s，2H).

HRMS calcd.For C25H26N2O5(M+H)⁺ 404.1236，found 404.1241.

Example 11

(E) -3, 4, 5-trihydroxy-N' - (3-naphthylmethyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3-naphthalene methoxy benzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 3-naphthylmethyloxybromide (1.97g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.5g, yield 69.7%, and melting point 44-46 deg.C.

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.10(d，J＝7.7Hz，1H)，8.01-7.90(m，2H)，7.68(d，J＝6.8Hz，1H)，7.62(m，1H)，7.60-7.48(m，5H)，7.45-7.39(m，1H)，5.63(s，2H).

MS(ESI)m/z 263.3018(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺

(3) Preparation of the title Compound

3-naphthalene methoxybenzaldehyde (0.36g, 1.36mmol) is dissolved in 15mL ethanol, 3, 4, 5-trihydroxy benzoyl hydrazine (0.3g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtration is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.1g of gray solid is obtained, yield is 17.1%, and melting point is 127-.

¹H NMR(400MHz，DMSO)δ11.55(s，1H)，9.02(s，3H)，8.39(s，1H)，8.11(d，J＝7.7Hz，1H)，7.96(m，2H)，7.70(d，J＝6.7Hz，1H)，7.64-7.47(m，3H)，7.44-7.35(m，2H)，7.30(s，1H)，7.15(d，J＝7.4Hz，1H)，6.92(s，2H)，5.60(s，2H).

HRMS calcd.For C22H21N2O6(M+H)⁺429.1445，found 429.1445.

Example 12

(E) -N' - ((3-benzylmethyloxy) benzylidene) benzimidazole-5-carbohydrazide

(1) Preparation of 3-benzyloxybenzaldehyde

3-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, benzyl bromide (1.52g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.5g, yield 85.7%, and melting point deg.C.

¹H NMR(400MHz，CDCl₃)δ9.97(s，1H)，7.42(m，8H)，7.25(m，1H)，5.13(s，2H).

MS(ESI)m/z 213.2406(M+H)⁺.

(2) Preparation of benzimidazole-5-carbohydrazide

Methyl benzimidazole-5-carboxylate (2.66g, 15.12mmol) is dissolved in 35mL ethanol, hydrazine hydrate (8.6mL, 120.9mmol) is added, reflux reaction is carried out at 80 ℃ for 36 hours, filtration is carried out to obtain white solid, and then ethyl acetate is used for beating three times (3X 15mL) to obtain 1.8g white solid, the yield is 67.7%, and the melting point is 236-239 ℃.

¹H NMR(400MHz，DMSO)δ12.48(s，1H)，9.69(s，1H)，8.28(s，1H)，8.07(s，1H)，7.68(d，J＝8.1Hz，1H)，7.58(s，1H)，4.47(s，2H).

MS(ESI)m/z 177.0768(M+H)⁺.

(3) Preparation of the title Compound

3-benzyloxybenzaldehyde (0.29g, 1.36mmol) was dissolved in 15mL of ethanol, and benzimidazole-5-carbohydrazide (0.29g, 1.63mmol) was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, filtered, concentrated, and separated by column chromatography using dichloromethane to methanol at 10: 1 as an eluent to obtain 0.31g of a white solid, yield 61.6%, melting point 222 and 225 ℃.

¹H NMR(400MHz，DMSO)δ12.74(s，1H)，11.86(s，1H)，8.44(s，1H)，8.36(s，1H)，8.23(s，1H)，7.80(d，J＝7.9Hz，1H)，7.67(d，J＝8.2Hz，1H)，7.47(m，2H)，7.36(m，5H)，7.08m，1H)，5.15(s，2H).

HRMS calcd.For C22H19N4O2(M+H)⁺371.1503，found 371.1496.

Example 13

(E) -4-hydroxy N' - (4- (benzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 4-benzyloxy-benzaldehyde

4-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and benzyl bromide (1.54, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, added with 15mL of distilled water, extracted twice with ethyl acetate (2X 20mL), washed with saturated sodium chloride solution 1 time, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.5g, yield 85.7%, and melting point deg.C.

¹H NMR(400MHz，CDCl₃)δ9.89(s，1H)，7.88-7.80(d，J＝8.7Hz，2H)，7.49-7.30(m，5H)，7.08(d，J＝8.7Hz，2H)，5.15(s，2H).

MS(ESI)m/z 213.2406(M+H)⁺.

(2) Preparation of the title Compound

4-benzyloxybenzaldehyde (0.29g, 1.36mmol) was dissolved in 15mL of ethanol, 4-hydroxybenzoyl hydrazine (0.3g, 1.97mmol) was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, filtered, the filtrate was concentrated, and separated by column chromatography, with an eluent of dichloromethane: methanol: 10: 1, to obtain 0.35g of a white solid, a yield of 73.8%, a melting point of 220-.

¹H NMR(400MHz，DMSO)δ11.50(s，1H)，10.08(s，1H)，8.36(s，1H)，7.79(d，J＝8.4Hz，2H)，7.64(d，J＝7.6Hz，2H)，7.45(d，J＝7.2Hz，2H)，740(t，J＝7.2Hz，2H)，7.37(m，1H)，7.08(d，J＝8.4Hz，2H)，6.84(d，J＝8.4Hz，2H)，，5.15(s，2H).

HRMS calcd.For C21H19N2O3(M+H)⁺347.1390，found 347.1380.

Example 14

(E) -3, 4, 5-trihydroxy-N' - (3- (2-chlorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (2-chlorobenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (0.50g, 4.06mmol) was dissolved in 8mL of THF, 2-chlorobenzyl bromide (1.00g, 4.87mmol), potassium carbonate (0.84g, 6.08mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 0.77g, yield 76.6%, and melting point 32-34 deg.C.

¹H NMR(400MHz，CDCl3)δ9.99(s，1H)，7.60-7.53(m，1H)，7.49(m，3H)，7.42m，1H)，7.32-7.24(m，3H)，5.23(s，2H).

MS(ESI)m/z 247.0509(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3.00g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.60g white solid, yield 57.81%, melting point greater than 250 deg.C.

1HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (2-chlorobenzyloxy) benzaldehyde (0.30g, 1.22mmol) is dissolved in 15mL of methanol, 3, 4, 5-trihydroxy benzoyl hydrazine (0.28g, 1.52mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.31g of gray solid is obtained, and yield is 61.8%. Melting point 208-.

¹H NMR(400MHz，DMSO-d₆)δ11.53(s，1H)，9.13(s，2H)，8.81(s，1H)，8.37(s，1H)，7.62(t，J＝4.8Hz，1H)，7.51(t，J＝5.2Hz，1H)，7.43-7.36(m，3H)，7.34(d，J＝9.6Hz，1H)，7.27(d，J＝7.7Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.90(s，2H)，5.19(s，2H).

HRMS calcd.For C₂₁H₁₈N₂O₅Cl(M+H)⁺413.0899，found 413.0886.

Example 15

(E) -3, 4, 5-trihydroxy-N' - (3- (3-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (2-chlorobenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (0.50g, 4.14mmol) was dissolved in 8mL of DMF, and 3-methoxybenzyl bromide (1.00g, 4.97mmol), potassium carbonate (0.86g, 6.22mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain colorless transparent oil 0.74g, with yield of 74.4%.

¹H NMR(400MHz，CDCl3)δ9.95(s，1H)，7.49-7.39(m，3H)，7.30(t，J＝7.9Hz，1H)，7.23(d，J＝8.0Hz，1H)，7.04-6.96(m，2H)，6.86(d，J＝8.4Hz，1H)，5.08(s，2H)，3.80(s，3H).

MS(ESI)m/z 243.1094(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (3-methoxybenzyloxy) benzaldehyde (0.30g, 1.24mmol) is dissolved in 15mL of methanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.28g, 1.55mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.31g of gray solid is obtained, and yield is 61.2%. Melting point 180-.

¹H NMR(400MHz，DMSO-d₆)δ11.52(s，1H)，9.04(s，3H)，8.35(s，1H)，7.39-7.21(m，4H)，7.09-6.97(m，3H)，6.96-6.85(m，3H)，5.12(s，2H)，3.75(s，3H).

HRMS calcd.For C₂₂H₂₁N₂O₆(M+H)⁺409.1394，found 409.1382.

Example 16

(E) -3, 4, 5-trihydroxy-N' - (3- (2-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 3- (2-cyanobenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (0.52g, 4.25mmol) was dissolved in 8mL of DMF, and 2-cyanobenzylbromide (1.00g, 5.10mmol), potassium carbonate (0.88g, 6.38mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 0.92g, yield 91.4%, and melting point 54-56 deg.C.

¹H NMR(400MHz，CDCl3)δ9.98(s，1H)，7.59-7.52(m，1H)，7.52-7.37(m，4H)，7.34-7.24(m，3H)，5.21(s，2H).

MS(ESI)m/z 238.0990(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (2-cyanobenzyloxy) benzaldehyde (0.30g, 1.26mmol) is dissolved in 15mL of methanol, 3, 4, 5-trihydroxy benzoyl hydrazine (0.29g, 1.58mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.30g of gray solid is obtained, and yield is 58.9%. Melting point 238-.

¹H NMR(400MHz， DMSO-d₆)δ11.54(s，1H)，9.07(s，3H)，8.37(s，1H)，7.90(d，J＝7.7Hz，1H)，7.75(d，J＝4.3Hz，2H)，7.62-7.51(m，1H)，7.45-7.24(m，3H)，7.09(d，J＝8.1Hz，1H)，6.90(s，2H)，5.28(s，2H).

HRMS calcd.For C₂₂H₁₈N₃O₅(M+H)⁺404.1241，found 404.1228.

Example 17

(E) -3, 4, 5-trihydroxy-N' - (3- (4-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 3- (4-cyanobenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (0.52g, 4.25mmol) was dissolved in 8mL of DMF, and 4-cyanobenzylbromide (1.00g, 5.10mmol), potassium carbonate (0.88g, 6.38mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 0.78g, yield 76.9%, and melting point 87-89 deg.C.

¹H NMR(400MHz，CDCl3)δ9.98(s，1H)，7.70(d，J＝8.0Hz，2H)，7.56(d，J＝8.0Hz，2H)，7.54-7.44(m，3H)，7.24(s，1H)，5.19(s，2H).

MS(ESI)m/z 238.0954(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (4-cyanobenzyloxy) benzaldehyde (0.30g, 1.26mmol) is dissolved in 15mL of methanol, 3, 4, 5-trihydroxy benzoyl hydrazine (0.29g, 1.58mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.35g of gray solid is obtained, and the yield is 68.6%. Melting point 242-245 ℃.

¹H NMR(400MHz，DMSO-d₆)δ11.53(s，1H)，9.13(s，2H)，8.81(s，1H)，8.36(s，1H)，7.86(d，J＝7.8Hz，2H)，7.66(d，J＝7.9Hz，2H)，7.42-7.21(m，3H)，7.06(d，J＝8.1Hz，1H)，6.90(s，2H)，5.27(s，2H).

HRMS calcd.For C₂₂H₁₈N₃O₅(M+H)⁺404.1241，found 404.1229.

Example 18

(E) -3, 4, 5-trihydroxy-N' - (3- (2-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (2-methoxybenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (0.50g, 4.14mmol) was dissolved in 8mL of DMF, and 2-methoxybenzyl bromide (1.00g, 4.97mmol), potassium carbonate (0.86g, 6.22mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 0.76g, yield 76.7%, and melting point 66-69 deg.C.

¹H NMR(400MHz，CDCl3)δ9.97(s，1H)，7.51(s，1H)，7.49-7.40(m，3H)，7.31(t，J＝7.9Hz，1H)，7.26(d，J＝7.6Hz，1H)，6.98(t，J＝7.5Hz，1H)，6.92(d，J＝8.2Hz，1H)，5.17(s，2H)，3.87(s，3H).

MS(ESI)m/z 227.1061(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

3- (2-methoxybenzyloxy) benzaldehyde (0.30g, 1.26mmol) is dissolved in 15mL of methanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.29g, 1.58mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.32g of gray solid is obtained, and yield is 63.2%. Melting point 162-165 ℃.

¹H NMR(400MHz，DMSO-d₆)δ11.52(s，1H)，9.13(s，2H)，8.81(s，1H)，8.36(s，1H)，7.41(d，J＝7.5Hz，1H)，7.36(d，J＝7.9Hz，1H)，7.32(d，J＝7.1Hz，2H)，7.23(d，J＝7.6Hz，1H)，7.09-7.00(m，1H)，6.96(t，J＝7.4Hz，1H)，6.90(s，2H)，5.10(s，2H)，3.84(s，3H).

HRMS calcd.For C₂₂H₂₁N₂O₆(M+H)⁺409.1394，found 409.1383.

Example 19

(E) -3, 4, 5-trihydroxy-N' - (4-benzyloxybenzylidene) benzoylhydrazine

(1) Preparation of 4-benzyloxy-benzaldehyde

4-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, benzyl bromide (1.53g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.44g, yield 83.0%, and melting point 65-67 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.84(d，J＝8.4Hz，2H)，7.47-7.30(m，5H)，7.08(d，J＝8.4Hz，2H)，5.15(s，2H).

MS(ESI)m/z 213.0903(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3.00g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.6g white solid, yield 57.81%, melting point greater than 250 deg.C.

(3) Preparation of the title Compound

4-benzyloxybenzaldehyde (0.29g, 1.36mmol) was dissolved in 45mL of ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, filtered, concentrated, and subjected to column chromatography to obtain a white solid (0.28g, yield 55.1%) using dichloromethane and methanol (10: 1 as eluent). Melting point 214-.¹H NMR(400MHz，DMSO-d₆)δ11.38(s，1H)，8.94(s，3H)，8.33(s，1H)，7.61(d，J＝8.2Hz，2H)，7.45(d，J＝7.4Hz，2H)，7.39(t，J＝7.4Hz，2H)，7.36-7.28(m，1H)，7.07(d，J＝8.1Hz，2H)，6.89(s，2H)，5.14(s，2H).

HRMS calcd.For C21H19O5N2(M+H)⁺379.1288，found 379.1277.

Example 20

(E) -3, 4, 5-trihydroxy N' - (4- (3-fluorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (3-fluorobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, 3-fluorobenzyl bromide (1.69g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.69g, yield 90.0%, and melting point 41-43 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.85(d，J＝8.4Hz，2H)，7.43-7.32(m，1H)，7.20(d，J＝7.7Hz，1H)，7.15(d，J＝9.7Hz，1H)，7.07(d，J＝8.4Hz，2H)，7.03(d，J＝10.4Hz，1H)，5.15(s，2H).

MS(ESI)m/z 231.0809(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

(3) Preparation of the title Compound

4- (3-fluorobenzyloxy) benzaldehyde (0.31g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.21g of white solid is obtained, and the yield is 54.1%. Melting point 206-.

¹H NMR(400MHz，DMSO-d₆)δ11.41(s，1H)，9.01(s，3H)，8.35(s，1H)，7.64(d，J＝8.2Hz，2H)，7.45(q，J＝7.4Hz，1H)，7.31(d，J＝7.3Hz，2H)，7.17(t，J＝8.6Hz，1H)，7.10(d，J＝8.1Hz，2H)，6.91(s，2H)，5.19(s，2H).

HRMS calcd.For C21H18O5N2F(M+H)⁺397.1194，found 397.1181.

Example 21

(E) -3, 4, 5-trihydroxy-N' - (4- (4-fluorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (4-fluorobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-fluorobenzyl bromide (1.69g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.71g, yield 91.0%, and melting point 95-97 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.85(d，J＝8.2Hz，2H)，7.48-7.35(m，2H)，7.18-6.97(m，4H)，5.11(s，2H).

MS(ESI)m/z 231.0810(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (4-fluorobenzyloxy) benzaldehyde (0.31g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.30g of white solid is obtained, and yield is 56.1%. Melting point 236-238 ℃.

¹H NMR(400MHz，DMSO-d₆)δ11.39(s，1H)，8.99(s，3H)，8.33(s，1H)，7.62(d，J＝8.3Hz，2H)，7.50(t，J＝6.9Hz，3H)，7.21(t，J＝8.7Hz，2H)，7.07(d，J＝8.3Hz，2H)，6.89(s，2H)，5.12(s，2H).

HRMS calcd.For C21H18O5N2F(M+H)⁺397.1194，found 397.1181.

Example 22

(E) -3, 4, 5-trihydroxy-N' - (4- (4-chlorobenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (4-chlorobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, 3-chlorobenzyl bromide (1.84g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.79g, yield 89.2%, and melting point 69-71 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.84(d，J＝8.4Hz，2H)，7.37(s，4H)，7.06(d，J＝8.4Hz，2H)，5.12(s，2H).

MS(ESI)m/z 247.0514(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

(3) Preparation of the title Compound

4- (4-chlorobenzyloxy) benzaldehyde (0.33g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.32g of white solid is obtained, and yield is 57.5%. Melting point 243-.

¹H NMR(400MHz，DMSO)δ11.42(s，1H)，9.14(s，2H)，8.80(s，1H)，8.35(s，1H)，7.64(d，J＝8.2Hz，2H)，7.48(q，J＝8.3Hz，4H)，7.09(d，J＝8.3Hz，2H)，6.92(s，2H)，5.16(s，2H).

HRMS calcd.For C21H18O5N2Cl(M+H)⁺413.0899，found 413.0888.

Example 23

(E) -3, 4, 5-trihydroxy-N' - (4- (2-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (2-trifluoromethylbenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 2-trifluoromethylbenzyl bromide (2.14g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.95g, yield 85.2%, and melting point 39-41 deg.C.

¹H NMR(400MHz，CDCl3)δ9.90(s，1H)，7.85(d，J＝8.3Hz，2H)，7.71(t，J＝7.9Hz，2H)，7.59(t，J＝7.6Hz，1H)，7.46(t，J＝7.7Hz，1H)，7.08(d，J＝8.3Hz，2H)，5.36(s，2H).

MS(ESI)m/z 281.0776(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.6g white solid with yield 57.81% and melting point greater than 250 deg.C.¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).

MS(ESI)m/z 185.0554(M+H)^+.

(3) Preparation of the title Compound

4- (2-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.30g of white solid is obtained, and yield is 50.0%. Melting point 190-.

¹H NMR(400MHz，DMSO)δ11.40(s，1H)，9.12(s，2H)，8.78(s，1H)，8.34(s，1H)，7.85-7.68(m，3H)，7.68-7.54(m，3H)，7.08(d，J＝8.3Hz，2H)，6.90(s，2H)，5.27(s，2H).

HRMS calcd.For C22H18O5N2F3(M+H)⁺447.1162，found447.1147.

Example 24

(E) -3, 4, 5-trihydroxy-N' - (4- (3-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (3-trifluoromethylbenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 3-trifluoromethylbenzyl bromide (2.14g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 2.08g, yield 91.0%, and melting point 39-41 deg.C.

¹H NMR(400MHz，CDCl3)δ9.91(s，1H)，7.86(d，J＝8.4Hz，2H)，7.71(s，1H)，7.63(d，J＝8.0Hz，2H)，7.53(t，J＝7.8Hz，1H)，7.09(d，J＝8.3Hz，2H)，5.20(s，2H).

MS(ESI)m/z 281.0775(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (3-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.32g of white solid is obtained, and yield is 53.3%. Melting point 188-.

1H NMR(400MHz，DMSO)δ11.40(s，1H)，9.11(s，2H)，8.80(s，1H)，8.34(s，1H)，7.82(s，1H)，7.77(d，J＝7.6Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.63(d，J＝7.8Hz，3H)，7.10(d，J＝8.3Hz，2H)，6.89(s，2H)，5.26(s，2H).

HRMS calcd.For C22H18O5N2F3(M+H)⁺447.1162，found 447.1148.

Example 25

(E) -3, 4, 5-trihydroxy-N' - (4- (4-trifluoromethylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (4-trifluoromethylbenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-trifluoromethylbenzyl bromide (2.14g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 2.11g, yield 92.0%, and melting point 50-52 deg.C.

¹H NMR(400MHz，CDCl3)δ9.90(s，1H)，7.85(d，J＝8.3Hz，2H)，7.67(d，J＝8.0Hz，2H)，7.56(d，J＝8.0Hz，2H)，7.08(d，J＝8.4Hz，2H)，5.21(s，2H).

MS(ESI)m/z 281.0778(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, and filtering to obtain whiteThe solid was slurried three times with ethyl acetate (3X 15mL) to give 1.6g of a white solid in 57.81% yield with a melting point greater than 250 ℃.¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H).

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (4-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.38g of white solid is obtained, and the yield is 62.0%. Melting point 248-.

¹H NMR(400MHz，DMSO)δ11.40(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.76(d，J＝7.9Hz，2H)，7.67(d，J＝8.2Hz，2H)，7.63(d，J＝8.2Hz，2H)，7.09(d，J＝8.3Hz，2H)，6.89(s，2H)，5.27(s，2H).

HRMS calcd.For C22H18O5N2F3(M+H)⁺447.1162，found 447.1148.

Example 26

(E) -3, 4, 5-trihydroxy-N' - (4- (2-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 4- (2-cyanobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 2-cyanobenzylbromide (1.76g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.65g, yield 85.2%, and melting point 92-94 deg.C.

¹H NMR(400MHz，CDCl3)δ9.91(s，1H)，7.88(d，J＝8.4Hz，2H)，7.74(d，J＝7.7Hz，1H)，7.70-7.61(m，2H)，7.54-7.43(m，1H)，7.12(d，J＝8.4Hz，2H)，5.35(s，2H).

MS(ESI)m/z 238.0857(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (2-cyanobenzyloxy) benzaldehyde (0.32g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.31g of white solid is obtained, and the yield is 57.5%. Melting point 259 ℃ C.

¹H NMR(400MHz，DMSO-d₆)δ11.41(s，1H)，9.12(s，2H)，8.78(s，1H)，8.35(s，1H)，7.91(s，1H)，7.74(s，2H)，7.65(s，2H)，7.58(s，1H)，7.12(s，2H)，6.90(s，2H)，5.29(s，2H).

HRMS calcd.For C22H18O5N3(M+H)⁺404.1241，found 404.1227.

Example 27

(E) -3, 4, 5-trihydroxy-N' - (4- (3-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 4- (3-cyanobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 3-cyanobenzylbromide (1.76g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.65g, yield 85.2%, and melting point 90-92 deg.C.

¹H NMR(400MHz，CDCl3)δ9.91(s，1H)，7.86(d，J＝8.4Hz，2H)，7.75(s，1H)，7.66(t，J＝9.0Hz，2H)，7.52(t，J＝7.8Hz，1H)，7.08(d，J＝8.4Hz，2H)，5.18(s，2H).

MS(ESI)m/z 238.0857(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (3-cyanobenzyloxy) benzaldehyde (0.32g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.32g of white solid is obtained, and yield is 58.3%. Melting point 257 ℃ and 259 ℃.

¹H NMR(400MHz，DMSO)δ11.40(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.93(s，1H)，7.80(s，2H)，7.62(s，3H)，7.09(s，2H)，6.89(s，2H)，5.21(s，3H).

HRMS calcd.For C22H18O5N3(M+H)⁺404.1241，found 404.1227.

Example 28

(E) -3, 4, 5-trihydroxy-N' - (4- (4-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 4- (4-cyanobenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-cyanobenzylbromide (1.76g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.85g, yield 89.5%, melting point 107-.

¹H NMR(400MHz，CDCl3)δ9.90(s，1H)，7.85(d，J＝8.3Hz，2H)，7.69(d，J＝8.0Hz，2H)，7.55(d，J＝8.0Hz，2H)，7.07(d，J＝8.4Hz，2H)，5.21(s，2H).

MS(ESI)m/z 238.0856(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (4-cyanobenzyloxy) benzaldehyde (0.32g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.32g of white solid is obtained, and yield is 58.5%. Melting point 265-.

¹H NMR(400MHz，DMSO)δ11.40(s，1H)，9.12(s，2H)，8.78(s，1H)，8.33(s，1H)，7.86(s，2H)，7.64(s，4H)，7.08(s，2H)，6.89(s，2H)，5.26(s，3H).

HRMS calcd.For C22H18O5N3(M+H)⁺404.1241，found 404.1226.

Example 29

(E) -3, 4, 5-trihydroxy-N' - (4- (4-methylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (4-methylbenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-methylbenzyl bromide (1.66g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 1.74g, yield 94.3%, and melting point 66-68 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.83(d，J＝8.5Hz，2H)，7.32(d，J＝7.7Hz，2H)，7.21(d，J＝7.8Hz，2H)，7.07(d，J＝8.5Hz，2H)，5.11(s，2H)，2.37(s，3H).

MS(ESI)m/z 227.1061(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (4-methylbenzyloxy) benzaldehyde (0.31g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtering is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.28g of white solid is obtained, and yield is 53.5%. Melting point 243-.

¹H NMR(400MHz，DMSO)δ11.38(s，1H)，9.11(s，2H)，8.77(s，1H)，8.32(s，1H)，7.60(d，J＝8.2Hz，2H)，7.33(d，J＝7.6Hz，2H)，7.19(d，J＝7.6Hz，2H)，7.05(d，J＝8.3Hz，2H)，6.89(s，2H)，5.09(s，2H)，2.29(s，3H).

HRMS calcd.For C₂₂H₂₁O₅N₂(M+H)⁺393.1445，found 393.1431.

Example 30

(E) -3, 4, 5-trihydroxy-N' - (4- (4-tert-butylbenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (4-tert-butylbenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-tert-butylbenzylbromide (2.03g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain white solid 2.110g, yield 94.3%, and melting point 72-74 deg.C.

¹H NMR(400MHz，CDCl3)δ9.89(s，1H)，7.84(d，J＝8.4Hz，2H)，7.44(d，J＝8.1Hz，2H)，7.37(d，J＝8.0Hz，2H)，7.09(d，J＝8.4Hz，2H)，5.12(s，2H)，1.34(s，9H).

MS(ESI)m/z 269.1528(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

Dissolving 4- (4-tert-butylbenzyloxy) benzaldehyde 0.36g and 1.36mmol) in 45mL ethanol, adding 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g and 1.63mmol), refluxing at 80 ℃ for 6 hours, filtering, concentrating the filtrate, and performing column chromatography separation to obtain a white solid with the eluent dichloromethane and methanol being 10: 1, wherein the white solid is 0.35g, and the yield is 60.0%. Melting point 232-.

¹H NMR(400MHz，DMSO)δ11.39(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.61(d，J＝8.2Hz，2H)，7.38(d，J＝6.3Hz，4H)，7.06(d，J＝8.2Hz，2H)，6.89(s，2H)，5.09(s，2H)，1.26(s，9H).

HRMS calcd.For C₂₅H₂₇O₅N₂(M+H)⁺435.1914，found 435.1899.

Example 31

(E) -3, 4, 5-trihydroxy-N' - (4- (2-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (2-methoxybenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 2-methoxybenzyl bromide (1.80g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain colorless oil 1.61g, with yield of 82.0%.

¹H NMR(400MHz，CDCl3)δ9.88(s，1H)，7.84(d，J＝8.3Hz，2H)，7.43(d，J＝7.5Hz，1H)，7.33(t，J＝7.9Hz，1H)，7.10(d，J＝8.4Hz，2H)，6.99(t，J＝7.5Hz，1H)，6.93(d，J＝8.3Hz，1H)，5.20(s，2H)，3.87(s，3H).

MS(ESI)m/z 243.1003(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (2-methoxybenzyloxy) benzaldehyde (0.33g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtration is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.31g of white solid is obtained, and yield is 55.3%. Melting point.

¹H NMR(400MHz，DMSO)δ11.38(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.61(s，2H)，7.36(d，J＝24.5Hz，2H)，7.05(s，3H)，6.95(s，1H)，6.89(s，2H)，5.09(s，2H)，3.82(s，4H).

HRMS calcd.For C₂₂H₂₁O₆N₂(M+H)⁺409.1394，found 409.1374.

Example 32

(E) -3, 4, 5-trihydroxy-N' - (4- (3-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (3-methoxybenzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 3-methoxybenzyl bromide (1.80g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain colorless oil 1.58g, with yield 80.0%.

¹H NMR(400MHz，CDCl3)δ9.88(s，1H)，7.83(d，J＝8.4Hz，2H)，7.32(t，J＝7.9Hz，1H)，7.07(d，J＝8.4Hz，2H)，7.00(d，J＝7.7Hz，1H)，6.98(s，1H)，6.89(dd，J＝8.3，2.4Hz，1H)，5.13(s，2H)，3.82(s，3H).

MS(ESI)m/z 243.1011(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80C for 36 h, filtering to obtain white solid, pulping with ethyl acetate three times (3X 15mL) to obtain 1.6g white solid, yield 57.81%, melting point greater than 250 ℃.¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (3-methoxybenzyloxy) benzaldehyde (0.33g, 1.36mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtration is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.30g of white solid is obtained, and yield is 53.4%. Melting point 202-.

¹H NMR(400MHz，DMSO)δ11.39(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.61(d，J＝8.3Hz，2H)，7.30(t，J＝8.0Hz，1H)，7.07(d，J＝8.4Hz，2H)，7.02(s，2H)，6.89(s，3H)，5.12(s，2H)，3.75(s，3H).

HRMS calcd.For C₂₂H₂₁O₆N₂(M+H)⁺409.1394，found 409.1379.

Example 33

(E) -4-hydroxy-N' - (4- (3-cyanobenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 4- (3-cyanobenzyloxy) benzaldehyde

MS(ESI)m/z 238.0857(M+H)⁺.

(2) Preparation of the title Compound

4- (2-cyanobenzyloxy) benzaldehyde (0.32g, 1.36mmol) was dissolved in 45mL of ethanol, 4-hydroxybenzoylhydrazine (0.25g, 1.63mmol) was added, the mixture was refluxed at 80 ℃ for 6 hours, filtered, the filtrate was concentrated, and the product was separated by column chromatography, with the eluent dichloromethane/methanol 10: 1, to give 0.35g of a white solid, with a yield of 69.5%. Melting point 237-.¹H NMR(400MHz，DMSO)δ11.44(s，1H)，10.00(s，1H)，8.36(s，1H)，7.91(s，1H)，7.79(d，J＝7.8Hz，4H)，7.71-7.54(m，3H)，7.09(d，J＝8.3Hz，2H)，6.84(d，J＝8.2Hz，2H)，5.21(s，2H).

HRMS calcd.For C₂₂H₁₈O₃N₃(M+H)⁺372.1343，found 372.1328.

Example 34

(E) -4-hydroxy-N' - (3- (3-trifluoromethylbenzyloxy) benzylidene) benzoyl hydrazine

(1) Preparation of 3- (3-trifluoromethylbenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, and 4-trifluoromethylbenzyl bromide (2.14g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain colorless oil 2.52g, yield 90.2%, and melting point 92-94 deg.C.

(2) Preparation of the title Compound

3- (3-trifluoromethylbenzyloxy) benzaldehyde (0.38g, 1.36mmol) was dissolved in 45mL of ethanol, 4-hydroxybenzoylhydrazine (0.25g, 1.63mmol) was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, filtered, concentrated, and subjected to column chromatography to obtain a white solid (0.42 g, 74.1% yield) using dichloromethane and methanol (20: 1). Melting point 188-.

¹H NMR(400MHz，DMSO)δ11.64(s，1H)，10.10(s，1H)，8.39(s，1H)，7.83(s，1H)，7.79(d，J＝8.2Hz，3H)，7.70(d，J＝7.7Hz，1H)，7.64(t，J＝7.8Hz，1H)，7.36(d，J＝7.8Hz，2H)，7.29(d，J＝7.7Hz，1H)，7.09(d，J＝8.2Hz，1H)，6.84(d，J＝8.3Hz，2H)，5.26(s，2H).

HRMS calcd.For C₂₀H₁₇O₃N₃F₃(M+H)⁺372.1318，found 372.1327.

Example 35

(E) -4-hydroxy-N' - (3- (3-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (3-methoxybenzyloxy) benzaldehyde

3-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of THF, 3-methoxybenzyl bromide (1.80g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out with anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain colorless oil 1.69g, yield 85.6%, and melting point 92-94 deg.C.

(2) Preparation of the title Compound

3- (3-methoxybenzyloxy) benzaldehyde (0.33g, 1.36mmol) was dissolved in 45mL of ethanol, 4-hydroxybenzoylhydrazine (0.25g, 1.63mmol) was added, the reaction was refluxed at 80 ℃ for 6 hours, filtered, the filtrate was concentrated, and the column chromatography was performed to obtain a white solid (0.36g, yield 71.1%) with an eluent of dichloromethane: methanol (20: 1). Melting point 174-.

¹H NMR(400MHz，DMSO)δ11.62(s，1H)，10.09(s，1H)，8.38(s，1H)，7.79(d，J＝8.2Hz，2H)，7.40-7.20(m，4H)，7.06(d，J＝8.2Hz，1H)，7.02(d，J＝4.9Hz，2H)，6.89(s，1H)，6.84(d，J＝8.2Hz，2H)，5.12(s，2H)，3.75(s，3H).

HRMS calcd.For C₂₂H₂₁O₄N₂(M+H)⁺377.1496，found 377.1481.

Example 36

(E) -4-hydroxy-N' - (3- (3-methoxybenzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 3- (4-tert-butyloxy) benzaldehyde

2-hydroxybenzaldehyde (1.0g, 8.2mmol) was dissolved in 15mL of DMF, and 4-tert-butylbenzylbromide (2.03g, 9.0mmol), potassium carbonate (1.35g, 9.8mmol) were added, reacted at 80 ℃ for 3 hours, 15mL of distilled water was added, extracted twice with ethyl acetate (2X 20mL), washed 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 3: 1 to obtain white solid 1.2g, yield 54.5%, and melting point 42-45 deg.C.

¹H NMR(400MHz，CDCl3)δ9.97(s，1H)，7.48(m，2H)，7.43(m，3H)，7.38(d，J＝8.4Hz，2H)，7.28-7.22(m，1H)，5.08(s，2H)，1.33(s，9H).

MS(ESI)m/z 269.1528(M+H)⁺.

(2) Preparation of the title Compound

3- (4-tert-butylbenzyloxy) benzaldehyde (0.36g, 1.36mmol) was dissolved in 15mL of ethanol, 4-hydroxybenzoylhydrazine (0.25g, 1.63mmol) was added, the mixture was refluxed at 80 ℃ for 6 hours, filtered, the filtrate was concentrated, and the product was separated by column chromatography, with the eluent dichloromethane and methanol being 10: 1, to give 0.28g of a white solid, yield 51.1%, melting point 163-.

¹H NMR(400MHz，DMSO-d₆)δ11.63(s，1H)，10.10(s，1H)，8.39(s，1H)，7.79(d，J＝8.3Hz，2H)，7.44-7.29(m，6H)，7.26(d，J＝7.5Hz，1H)，7.05(d，J＝8.2Hz，1H)，6.85(d，J＝8.3Hz，2H)，5.09(s，2H)，1.26(s，9H).

HRMS calcd.For C₂₅H₂₇O₃N₂(M+H)⁺403.2016，found 403.2000.

Example 37

(E) -3, 4, 5-trihydroxy-N' - (4-benzyloxy) benzylidene) benzoylhydrazines

(1) Preparation of 4- (3-benzyloxy) benzaldehyde

4-hydroxybenzaldehyde (1.00g, 8.2mmol) was dissolved in 15mL of DMF, bromobenzyl (1.80g, 10.5mmol), potassium carbonate (1.35g, 9.8mmol) were added, reaction was carried out at 80 ℃ for 3 hours, 15mL of distilled water was added, extraction was carried out twice with ethyl acetate (2X 20mL), washing was carried out 1 time with a saturated sodium chloride solution, and drying was carried out over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with petroleum ether and ethyl acetate at ratio of 5: 1 to obtain colorless oil 1.58g, with yield 80.0%.

¹H NMR(400MHz，CDCl3)δ9.88(s，1H)，7.83(d，J＝8.4Hz，2H)，7.32(t，J＝7.9Hz，1H)，7.07(d，J＝8.4Hz，2H)，7.00(d，J＝7.7Hz，1H)，6.98(s，1H)，6.89(dd，J＝8.3，2.4Hz，1H)，5.13(s，2H).

MS(ESI)m/z 212.3030(M+H)⁺.

(2) Preparation of 3, 4, 5-trihydroxy benzoyl hydrazine

Dissolving ethyl gallate (3g, 15.12mmol) in 35mL ethanol, adding hydrazine hydrate (8.6mL, 120.9mmol), refluxing at 80 deg.C for 36 hr, filtering to obtain white solid, and pulping with ethyl acetate three times (3 × 15mL) to obtain 1.6g white solid with yield 57.81% and melting point greater than 250 deg.C.¹HNMR(400MHz，DMSO)δ9.30(s，1H)，8.79(s，3H)，6.76(s，2H)，4.29(s，2H)。

MS(ESI)m/z 185.0554(M+H)⁺.

(3) Preparation of the title Compound

4- (3-benzyloxy) benzaldehyde (0.33g, 1.56mmol) is dissolved in 45mL ethanol, 3, 4, 5-trihydroxybenzoyl hydrazine (0.30g, 1.63mmol) is added, reflux reaction is carried out at 80 ℃ for 6 hours, filtration is carried out, filtrate is concentrated, column chromatography separation is carried out, eluent is dichloromethane and methanol is 10: 1, 0.31g of white solid is obtained, and the yield is 55.3%. Melting point 135-.

¹H NMR(400MHz，DMSO)δ11.38(s，1H)，9.11(s，2H)，8.78(s，1H)，8.33(s，1H)，7.61(s，2H)，7.36(d，J＝24.5Hz，2H)，7.05(s，3H)，6.95(s，1H)，6.89(s，2H)，5.09(s，2H).

HRMS calcd.For C₂₂H₂₁O₆N₂(M+H)⁺379.3867，found 379.4011.

Some of the pharmacological tests and results of the compounds of the invention are as follows:

experimental example 1: detection of inhibitory Effect of the Compounds of the present invention on SphK1 and SphK2

Experimental Material

Preparation of compound solution: accurately weighing 3-5mg of the above compound, placing in 1.5mL EP tube, and preparing with DMSOThe mother liquor concentration is 10^-2M, the concentration of the compound was 100. mu.M.

Experimental enzymes: human recombinant SphK1 and SphK2, supplied by life technologies, Inc., under the respective designations PV5214 and PV5216, were used at the respective action concentrations of 0.1 ng/. mu.L and 1 ng/. mu.L.

The instrument equipment comprises: perkinelmer envision enspire multimode reader, available from the pharmaceutical public laboratory of the chinese academy of medical sciences.

The experimental method comprises the following steps: human recombinant SphK1 (or SphK2) and a compound are incubated in a 384-well plate for 5min at room temperature, ATP and an enzyme substrate Sph are added, shaking is carried out at 1000rpm for 1min, incubation is carried out at 25 ℃ for 60min, Kinase Quench Buffer, anti-ADP Antibody and ADP Tracer Alexa Fluoro 488 are added, incubation is carried out for 1h at room temperature in a dark place, the fluorescence intensity under excitation light 488nm and emission light 519nm is detected, the inhibition rate under 100 mu M is calculated, and the experimental results are shown in Table 1.

TABLE 1 inhibitory Activity of the Compounds of the invention against SphK1 and SphK2

As shown in Table 1, the compounds of the present invention have strong SphK inhibitory effect, and the inhibitory activity of some compounds is better than that of positive control DMS.

Experimental example 2: detection of inhibition effect of compound SYl1828 on mouse colitis

Experimental Material

Preparation of compound solution: 50mg of the above compound was weighed out accurately and placed in a 100mL Erlenmeyer flask and made into a 1mg/mL solution with water at a concentration of 10 mg/kg.

Experiment mouse: c57BL/6 female mouse, 6-8 weeks old, 18-22g, supplied by Nanjing Qinglongshan animal farm.

The experimental method comprises the following steps: c57BL/6 female mice were randomly divided into 3 groups (Con group, DSS + syl1828 group), Con group was given normal water, DSS + syl1828 group was given 10mg/kg of liquid medicine per day by intraperitoneal injection, DSS group and DSS + syl1828 group were given 2.5% DSS water 5 days before, normal water 5 days after, 10 days after sacrifice, colons were removed, paraffin sections were made to monitor IL-6 secretion, and statistical results are shown in FIG. 1.

As can be seen from FIG. 1, compound syl1828 of the present invention has stronger colitis inhibition effect, and the inhibition activity is better than that of the positive control 5-ASA.

Experimental example 3: detection of antitumor Effect of Compound syl1828 of the present invention

Experimental Material

Preparation of compound solution: 50mg of the compound is accurately weighed and placed in a 100mL conical flask, and water is used for preparing a solution with the concentration of 1mg/mL, and the administration concentration is 10mg/kg and 40 mg/kg.

The experimental method comprises the following steps: after the C57BL/6 female mice are inoculated with tumor cells HepG 224 h, the female mice are randomly divided into 3 groups (blank control group, syl1828 low dose group and syl1828 high dose group), 10 female mice in each group are administered, the drug solution is injected into tail vein every 6h, the female mice are killed after 24h, the tumors are weighed, and the inhibition rate is calculated. The results are shown in Table 2.

TABLE 2 antitumor Activity of Compound syl1828 of the present invention

As shown in Table 2, compound syl1828 of the present invention has strong tumor-inhibiting effect.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

represents a phenyl group;

R₁selected from methoxy, trifluoromethyl; wherein R is₁Is monosubstituted;

a is

Wherein R is₂Representing a trihydroxy substitution;

x is O.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by being represented by the following general formula (Ia):

wherein

R₁A, X is as defined in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by being represented by the following general formula (Ib):

wherein

R₁A, X is as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that a is

5. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the prevention and/or treatment of a disease associated with SphK dysfunction.

8. The use according to claim 7, wherein the disease associated with SphK dysfunction comprises cancer or an inflammatory disease.

9. The use of claim 8, wherein said cancer comprises colon, lung, breast or liver cancer; the inflammatory disease comprises inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis or multiple sclerosis.