CN116478070A

CN116478070A - Compound, pharmaceutical composition and application thereof in field of vasodilation or antiviral

Info

Publication number: CN116478070A
Application number: CN202310463286.6A
Authority: CN
Inventors: 李荀; 郑昌博; 解春雨; 庞攀攀; 乔冠荣; 李忠; 卫娟娜; 辛国斌; 张瑛
Original assignee: Shandong First Medical University and Shandong Academy of Medical Sciences
Current assignee: Shandong First Medical University and Shandong Academy of Medical Sciences
Priority date: 2022-06-23
Filing date: 2022-06-23
Publication date: 2023-07-25
Also published as: CN115093359B; CN115093359A

Abstract

The invention relates to a compound, a pharmaceutical composition and application thereof in the field of vasodilation or antiviral. The invention provides a series of compounds with the structure shown in the following formulas I-III:the compound can be used as an HDAC6 inhibitor, has vasodilation activity and latent HIV virus activation activity, and is expected to be developed into a clinical medicine with higher therapeutic index.

Description

Compound, pharmaceutical composition and application thereof in field of vasodilation or antiviral

The scheme is a divisional application of application number 202210718885.3 (application date: 2022, 6 and 23 days, and the invention creative name: a compound, a pharmaceutical composition and application thereof in the field of vasodilation or antiviral).

Technical Field

The invention belongs to the technical field of vasodilation active compounds, and particularly relates to a compound, a pharmaceutical composition containing the compound and application of the compound in the field of vasodilation or antiviral.

Background

The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.

Hypertension refers to the measurement of 3 times of blood pressure in a resting state of not the same day without using any antihypertensive drug clinically, with a systolic pressure of 140mmHg or more and/or a diastolic pressure of 90mmHg or more. It is a complex disease caused by genetic and environmental risk factors, and is the most common cause of death and high incidence of disease in the elderly population. Hypertension is one of the most important risk factors for cardiovascular disease, including stroke and heart failure. Over 10 million people worldwide suffer from hypertension and the associated medical costs are increasing annually. In China, hypertension patients have a trend of low age, the prevalence rate of hypertension in people 18 years old and older is 27.9%, and the number of patients with senile hypertension is about 60-70% of the total number of patients.

To date, 18 HDAC subtypes have been identified in mammals, which can be divided into four classes based on their sequence homology to yeast protein homologs: class I (HDAC 1, 2, 3, 8), class IIa (HDAC 4, 5, 7, 9), class IIb (HDAC 6, 10) and class IV (HDAC 11), all three of which are Zn employing arginase-deacetylase folding ²⁺ A dependent enzyme; whereas class III HDACs (sirtuins 1-7) are NAD using uncorrelated folding ⁺ A dependent enzyme. Studies have shown that histone deacetylase 6 (HDAC 6), which belongs to the class IIb HDAC family, plays a role in the pathophysiology of hypertension-related vascular diseases. Unlike other HDAC family members, HDAC6 also mediates deacetylation of non-histone substrates present in the cytoplasm, such as α -tubulin, heat shock protein 90 (HSP 90), and cortical proteins. Researchers can improve hypertension and exert cardioprotection by studying inhibitors and/or knocking out genes to inactivate HDAC 6. Therefore, HDAC6 is considered as a promising target for cardiovascular disease drug development.

Furthermore, it is well known that high-potency antiviral therapies, while reducing the HIV-1/AIDS viral load to very low detection limit levels, still fail to completely eliminate the HIV-1 virus, largely due to the presence of the latent HIV-1 virus, the "latent viral pool", which becomes the major bottleneck in curing HIV-1. These latent viruses do not express viral proteins on the cell surface and are therefore not recognized by the host immune system and are therefore not available for antiviral drugs or the immune system. The use of safe and effective latent virus activators is critical to the currently widely accepted and used "activate and kill" strategies. The study demonstrates that HDAC6 is a potential target for developing HIV latent virus activators, which are all HDAC inhibitors (HDACi) currently entering the clinical stage of research.

Typical characteristics of HDAC inhibitors include a Cap group (Cap) that interacts with the enzyme surface region, a zinc ion binding group (ZBG) that interacts with the zinc ion in the catalytic pocket, and a Linker group (Linker) that acts as a bridge between the Cap group and the zinc ion binding group. Currently, four HDAC inhibitors, including Vorinostat (SAHA), romidepsin, belinostat and Panobinostat, have been approved by the united states Food and Drug Administration (FDA) for marketing. Vorinostat (SAHA, trade name:) Is a hydroxamic acid broad-spectrum HDAC inhibitor with a linear structure, and is approved by FDA for treating Cutaneous T Cell Lymphoma (CTCL) in 10 th 2006. In deoxycorticosterone acetate (DOCA) -saline hypertensive rats, SAHA significantly reduced systolic blood pressure and significantly reduced collagen deposition, diastolic stiffness and increased pro-inflammatory markers due to hypertension. Therefore, it is of great importance to develop HDAC 6-specific inhibitors with vasodilatory activity.

Disclosure of Invention

Aiming at the requirements of the prior art, the invention aims to provide a series of compounds with vasodilation and HIV latent virus activation activity, which not only have remarkable vasodilation and HIV latent virus activation effects, but also have stronger HDAC6 inhibition activity and better clinical application prospect.

Specifically, the invention provides the following technical scheme:

in a first aspect of the present invention, there is provided a compound having a structure represented by formula I, formula II or formula III, or pharmaceutically acceptable salts, solvates and hydrates thereof;

wherein R is selected from hydroxamic acid groups, methylene hydroxamic acid groups; x, Y, Z are selected from nitrogen or carbon, R ¹ Selected from hydrogen, methyl or hydroxymethyl; r is R ² Selected from the group consisting of-OH, -NH-NH ₂ 。

Preferably, R is selected from 3-CONHOH, 4-CONHOH, 3-CH ₂ CONHOH、4-CH ₂ CONHOH。

Preferably, the pharmaceutically acceptable salts of the compounds are those of the compounds which have been modified with groups which are intended to improve the physical properties of the compounds, typically with inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, and with organic acids such as methanesulfonic acid, toluenesulfonic acid, citric acid or trifluoroacetic acid.

Further, the compound of formula I is specifically as follows:

3- (2- (1H-indol-3-yl) acetamido) -N-hydroxybenzoyl (code XCY-A1);

4- (2- (1H-indol-3-yl) acetamido) -N-hydroxybenzoyl (code XCY-A2);

2- (3- (2- (1H-indol-3-yl) acetamido) phenyl) -N-hydroxyacetamide (code XCY-A3);

2- (4- (2- (1H-indol-3-yl) acetamido) phenyl) -N-hydroxyacetamide (code XCY-A4).

Further, the synthetic route for the compounds of formula I is as follows:

the specific synthesis steps are as follows:

will contain R ⁴ Reflux reaction of substituted aminobenzene derivative and sulfoxide chloride, extraction of the product with ethyl acetate to obtain compoundObject 2; reacting compound 2 with 2- (1H-indol-3-yl) acetic acid for a period of time at room temperature under EDCI and DMAP conditions, and purifying the product to obtain a compound shown in a formula I; wherein R is ⁴ Selected from 3-COOH,4-COOH,3-CH ₂ COOH，4-CH ₂ COOH。

Preferably, the compound of formula II is specifically as follows:

n-hydroxy-3- (2- (naphthalen-2-yl) acetamido) benzamide (code XCY-C1);

n-hydroxy-4- (2- (naphthalen-2-yl) acetamido) benzamide (code XCY-C2);

n-hydroxy-2- (3- (2- (naphthalen-2-yl) acetamido) phenyl) acetamide (code XCY-C3);

n-hydroxy-2- (4- (2- (naphthalen-2-yl) acetamido) phenyl) acetyl (code XCY-C4);

further, the synthetic route of the compound shown in the formula II is as follows:

the specific synthesis steps are as follows:

will contain R ⁴ Reflux reaction of the amino benzene derivative of the substituent group and thionyl chloride, and extraction of the product by adopting ethyl acetate to obtain a compound 2; reacting the compound 2 with 2-naphthylacetic acid for a period of time at room temperature under EDCI and DMAP conditions, purifying a product to obtain a compound 4, and reacting the compound 4 with hydroxylamine hydrochloride for a period of time at room temperature under the protection of inert gas to obtain a compound shown in a formula II; wherein R is ⁴ Selected from 3-COOH,4-COOH,3-CH ₂ COOH，4-CH ₂ COOH。

Preferably, the compound of formula III is specifically as follows:

methyl 4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) benzoate (code XCY-D1);

4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) benzoic acid (code XCY-D2);

4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) -N-methylbenzamide (code XCY-D3);

1- (4- (hydrazinocarbonyl) phenyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (code XCY-D4);

n-hydroxy-4- (2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetamido) benzamide (code XCY-D5);

n-hydroxy-4- (2- ((3 '-methoxy- [1,1' -biphenyl ] -4-yl)) amino) -2-oxoethyl) benzamide (code XCY-D6);

N ¹ -hydroxy-N ⁴ - (3 '-methoxy- [1,1' -biphenyl)]-4-yl) terephthalamide (code XCY-D7);

n-hydroxy-4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzamide (code XCY-D8);

4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid (code XCY-D9);

1- (4- (hydrazinocarbonyl) benzyl) -1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (code XCY-D10);

4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) -N-hydroxybenzoamide (code XCY-D11);

4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid (code XCY-D12);

1-butyl-1- (4- (hydrazinocarbonyl) benzyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (code XCY-D13).

Further, the synthetic route for the compound of formula III is as follows:

according to the above synthetic route, the specific synthetic scheme of the above compound XCY-D5 is as follows:

3-Methoxyphenylboronic acid (Compound 9), 4-bromophenylacetic acid, ph (PPh) ₃ ) ₄ And K ₂ CO ₃ Dissolving in dioxane aqueous solution, reflux reacting under inert gas protection for a period of time to obtain compound 12, dissolving compound 12 in anhydrous dichloromethane, sequentially adding DCC and 4-aminobenzoic acidStirring methyl ester and DMAP at room temperature for reaction to obtain a compound 13, dissolving the compound 13 in a mixed solution of dichloromethane and methanol, adding hydroxylamine hydrochloride and KOH, and stirring at room temperature for reaction for a period of time under the protection of inert gas to obtain the compound XCY-D5.

The specific synthesis mode of the compound XCY-D1 is as follows:

3-Methoxyphenylboronic acid (Compound 9), 1-bromo-4-nitrobenzene, ph (PPh) ₃ ) ₄ And K ₂ CO ₃ Dissolving in dioxane aqueous solution, and carrying out reflux reaction for a period of time under the protection of inert gas to obtain the compound 10. Dissolving the compound 10, zinc powder and ammonium chloride in aqueous solution of tetrahydrofuran and ethanol, carrying out reflux reaction under the protection of inert gas to obtain a compound 11, dissolving the compound 11 and triethylamine in dichloromethane, and then adding the compound 6 to react for a period of time at room temperature.

The specific synthetic modes of the compounds XCY-D2-D4 are as follows:

adding the compound XCY-D1 into alcohol or amine solutions with different R substituents, and carrying out reflux reaction for a period of time.

The specific synthesis mode of the compound XCY-D6 is as follows:

reacting 2-naphthylacetic acid with a compound 2a for a period of time at room temperature under EDCI and DMAP conditions to obtain a compound 14a; the compound 14a is dissolved in a mixed solution of dichloromethane and methanol, hydroxylamine hydrochloride and KOH are added, and the mixture is reacted for a period of time under the protection of inert gas.

The specific synthesis mode of the compound XCY-D7 is as follows:

compound 11 was dissolved in an anhydrous dichloromethane solution, DCC, monomethyl terephthalate, and DMAP were added in this order, and the mixture was stirred at room temperature for reaction for a while to give compound 14b. The compound 14b is dissolved in a mixed solution of dichloromethane and methanol, hydroxylamine hydrochloride and KOH are added, and the mixture is reacted for a period of time at room temperature under the protection of inert gas.

The specific synthetic modes of the compound XCY-D8 and the compound XCY-D11 are as follows:

under the ice bath condition, triphosgene is dissolved in ethyl acetate, and then an ethyl acetate solution of the compound 11 and triethylamine is slowly added dropwise for reaction at room temperature to obtain a compound 15; dissolving the compound 8 and triethylamine in dichloromethane, slowly dropwise adding a dichloromethane solution of the compound 15, and reacting at room temperature for a period of time to obtain a compound 16; the compound 16 is dissolved in a mixed solution of dichloromethane and methanol, hydroxylamine hydrochloride and KOH are added, and stirring reaction is carried out at room temperature under the protection of nitrogen.

The specific synthesis modes of the compound XCY-D9 and the compound XCY-D12 are as follows:

compound 16 was dissolved in methanol, and KOH was added to react.

The specific synthesis modes of the compound XCY-D10 and the compound XCY-D13 are as follows:

dissolving the compound 16 in ethanol, adding hydrazine hydrate, and carrying out reflux reaction under the protection of inert gas.

In the above-described mode of compound synthesis, the compound 6, the compound 7, and the compound 8 may be synthesized as follows:

in a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the first aspect and, optionally, a pharmaceutical carrier.

The above pharmaceutical composition is administered to a subject for the purpose of preventing, ameliorating or treating a disease, and the above compound should be in a synergistically effective dose, which can be confirmed according to the subject and the purpose of administration based on conventional technical means in the art; in a preferred embodiment, the subject is a mammal, such as a human, monkey, rabbit, dog, or mouse; further preferred, the subject is a human.

Preferably, the pharmaceutical composition further comprises a pharmaceutically necessary pharmaceutical carrier; such pharmaceutical carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances (e.g., phosphates), glycerol, sorbitol, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, and the like; the pharmaceutical carrier may be present in the pharmaceutical composition in an amount of from 1% to 98% by weight, typically about to 80% by weight.

Preferably, the pharmaceutical composition may be administered by: oral, spray inhalation, rectal, nasal, vaginal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous modes of administration being more preferred.

Preferably, the dosage form of the pharmaceutical composition may be a liquid dosage form, a solid dosage form; wherein the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension; the solid dosage forms comprise tablets, capsules, dripping pills, aerosols, pills, powders, emulsions, granules, suppositories, freeze-dried powder injection, inclusion compounds, landfill agents, patches, liniment and the like.

In a third aspect of the invention, there is provided the use of a compound according to the first aspect, a pharmaceutical composition according to the second aspect, as an HDAC inhibitor.

Preferably, the use as HDAC inhibition includes, but is not limited to, any of the following:

(1) A model agent for preparing an HDAC inhibition model;

(2) For preventing, ameliorating or treating a disease associated with HDAC;

(3) Is used for preparing the therapeutic drugs for diseases related to HDAC.

In the above aspect (1), the model agent is used for preparing a disease model, and may be a cell, tissue or animal model.

In the above (2) and (3), the HDAC-related disease means a disease in which HDAC is a therapeutic target, or abnormal high expression of HDAC occurs in disease characterization; specific examples are lymphoma, triple negative breast cancer, non-small cell lung cancer, myeloma, colon cancer, prostate cancer, AIDS, hypertension, etc.

In a fourth aspect of the present invention there is provided a vasodilator medicament comprising a compound of the first aspect and/or a pharmaceutical composition of the second aspect.

In a fifth aspect of the present invention there is provided a medicament for reducing blood pressure comprising a compound according to the first aspect and/or a pharmaceutical composition according to the second aspect.

In a sixth aspect of the invention there is provided a method of vasodilating blood vessels comprising administering to a subject in need thereof a compound according to the first aspect and/or a pharmaceutical composition according to the second aspect.

In a seventh aspect, the present invention provides the use of a compound according to the first aspect, a pharmaceutical composition according to the second aspect as an HIV latent virus activator.

In a verified embodiment of the present invention, the compound according to the first aspect is further the compound XCY-D6, and in a preferred embodiment, the use according to the seventh aspect is the compound XCY-D6, the use of a pharmaceutical composition comprising the compound XCY-D6 as an HIV latent virus activator.

Preferably, the above-mentioned uses as activators of HIV latent viruses include, but are not limited to, any of the following:

(1) For activating latent HIV virus to undergo transcription;

(2) For ameliorating or treating HIV virus-related diseases;

(3) Is used for preparing anti-AIDS medicines.

The invention verifies that the compound XCY-D6 can effectively activate latent HIV virus to enable the latent HIV virus to be transcribed, and the aim of clearing HIV-1 latent virus library is fulfilled by combining the compound with high-efficiency antiretroviral therapy (highly active antiretroviral therapy, HAART) and combining with an autoimmune system of cells; in one embodiment of the above aspect (1), the compound and the pharmaceutical composition are used for activating latent HIV virus expression in a disease model, and the activation purpose may be to screen effective anti-HIV virus drugs.

In a seventh aspect of the present invention, there is provided a medicament for the treatment of AIDS, wherein the compound XCY-D6 is as an active ingredient.

The medicine for treating AIDS comprises other active ingredients except the compound XCY-D6, wherein the other active ingredients are antiviral medicines or immune activating medicines; wherein the antiviral drug is a nucleoside reverse transcriptase inhibitor, such as lamivudine, zidovudine, tenofovir or emtricitabine; specific examples of the immune activating drugs include BCG, interleukin-2, transfer factor, thymus peptide, levamisole, etc.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.

FIG. 1 illustrates exposure of an exemplary compound of the present invention to 1X 10 in the aortic segment of a mouse ^-6 mol/L phenylephrine (Phe) to induce systolic vasodilatory activity results.

FIG. 2 illustrates the results of vasodilatory activity of exemplary compounds of the present invention in mice aortic segments exposed to 60mM KCl to induce contraction.

FIG. 3 shows the results of HIV-1 latent virus activating activity of an exemplary compound of the invention XCY-D6.

FIG. 4 illustrates a graph of modes of action of exemplary compounds of the invention XCY-A2 with HDAC 6;

Wherein, the left graph is a graph of the action mode of the compound XCY-A2 and the key amino acid of the target HDAC 6;

the right figure is a schematic representation of the compound XCY-A2 extending into the active binding cavity of the target HDAC 6.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.

In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.

Example 1Preparation of the Compounds

The compound of the formula I can be prepared through the following reaction route:

the reagents used in the preparation flow are respectively as follows: a: thionyl chloride; methanol; 75 ℃;12h; b:2- (1H-indol-3-yl) acetic acid; EDCI; DMAP; dichloromethane; room temperature; c: hydroxylamine hydrochloride; KOH; dichloromethane/methanol; room temperature; 3h.

In particular, the present invention gives some of the schematic compound preparation procedures and effect verification data in the examples.

(1) Preparation of intermediate methyl 3-aminobenzoate (2 a)

3-aminobenzoic acid 1a (1.00 g,7.29 mmol) was dissolved in 20mL of methanol under ice-bath conditions, and thionyl chloride (2.17 g,18.23 mmol) was slowly added dropwise. After the completion of the dropwise addition, the mixture was refluxed and stirred for reaction for 12 hours. After the reaction mixture was concentrated, a saturated sodium hydrogencarbonate solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, dried over anhydrous MgSO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.99g of a yellow oil in 90% yield.

(2) Preparation of intermediate methyl 4-aminobenzoate (2 b)

Under ice bath condition, 4-aminobenzoic acid1b (1.00 g,7.29 mmol) was dissolved in 20mL of methanol and thionyl chloride (2.17 g,18.23 mmol) was slowly added dropwise. After the completion of the dropwise addition, the mixture was refluxed and stirred for reaction for 12 hours. After the reaction mixture was concentrated, a saturated sodium hydrogencarbonate solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, dried over anhydrous MgSO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.98g of a pale pink solid in 89% yield. Melting point: 109-111 ℃. MS (ESI) m/z calcd.for C ₈ H ₉ NO ₂ [2M+Na] ⁺ :325.15,found:325.33。

(3) Preparation of intermediate methyl 3-aminophenylacetate (2 c)

3-aminophenylacetic acid 1c (1.00 g,6.62 mmol) was dissolved in 20mL of methanol under ice-bath conditions, and thionyl chloride (1.97 g,16.54 mmol) was slowly added dropwise. After the completion of the dropwise addition, the mixture was refluxed and stirred for reaction for 12 hours. After the reaction mixture was concentrated, a saturated sodium hydrogencarbonate solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, dried over anhydrous MgSO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.87g of a yellow oil in 87% yield.

(4) Preparation of intermediate methyl 2- (4-aminophenyl) acetate (2 d)

Under ice-bath conditions, 4-aminophenylacetic acid 1d (1.00 g,6.62 mmol) was dissolved in 20mL of methanol, and thionyl chloride (1.97 g,16.54 mmol) was slowly added dropwise. After the completion of the dropwise addition, the mixture was refluxed and stirred for reaction for 12 hours. After the reaction mixture was concentrated, a saturated sodium hydrogencarbonate solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, dried over anhydrous MgSO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.85g of yellow oil in 85% yield.

(5) Preparation of intermediate methyl 3- (2- (1H-indol-3-yl) acetamido) benzoate (3 a)

2- (1H-indol-3-yl) acetic acid (0.50 g,2.85 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.60 g,3.14 mmol) was added and the reaction stirred at room temperature for 1H. Intermediate 2a (0.47 g,3.14 mmol) and DMAP (0.04 g,0.29 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). Combining the organic phasesAnd, using anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, column chromatography on silica gel (dichloromethane: methanol=200:1) gave 0.60g of yellow oil in 71% yield. MS (ESI) m/z calcd.for C ₁₈ H ₁₆ N ₂ O ₃ [M+H] ⁺ :309.12,found:309.18。

(6) Preparation of intermediate methyl 4- (2- (1H-indol-3-yl) acetamido) benzoate (3 b)

2- (1H-indol-3-yl) acetic acid (0.50 g,2.85 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.60 g,3.14 mmol) was added and the reaction stirred at room temperature for 1H. Intermediate 2b (0.47 g,3.14 mmol) and DMAP (0.04 g,0.29 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, and column chromatography on silica gel (dichloromethane: methanol=200:1) gave 0.61g of yellow solid in 69% yield. Melting point: 94-96 ℃. MS (ESI) m/z calcd.for C ₁₈ H ₁₆ N ₂ O ₃ [M-H] ^- :307.12,found:307.36。

(7) Preparation of intermediate methyl 2- (3- (2- (1H-indol-3-yl) acetamido) phenylacetate (3 c)

2- (1H-indol-3-yl) acetic acid (0.50 g,2.85 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.60 g,3.14 mmol) was added and the reaction stirred at room temperature for 1H. Intermediate 2c (0.52 g,3.14 mmol) and DMAP (0.04 g,0.29 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=200:1) afforded 0.60g of a yellow solid in 66% yield. Melting point: 139-141 ℃. MS (ESI) m/z calcd.for C ₁₉ H ₁₈ N ₂ O ₃ [M+Cl] ^- :357.58,found:358.06。

(8) Preparation of intermediate methyl 2- (4- (2- (1H-indol-3-yl) acetamido) phenylacetate (3 d)

2- (1H-indol-3-yl) acetic acid (0.50 g,2.85 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.60 g,3.14 mmol) was added and the reaction stirred at room temperature for 1H. Intermediate 2d (0.52 g,3.14 mmol) and DMAP (0.04 g,0.29 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, and column chromatography on silica gel (dichloromethane: methanol=200:1) gave 0.46g of yellow solid in 50% yield. Melting point: 136-138 ℃. MS (ESI) m/z calcd.for C ₁₉ H ₁₈ N ₂ O ₃ [M+Cl] ^- :357.58,found:358.02。

(9) Preparation of 3- (2- (1H-indol-3-yl) acetamido) -N-hydroxybenzoyl (XCY-A1)

Intermediate 3a (0.20 g,0.65 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.35 g,19.46 mmol) and KOH (1.13 g,20.15 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.12g of a white solid in 59% yield. Melting point: 195-197 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.17(s,1H,NH),10.92(s,1H,OH),10.24(s,1H,ArH),9.01(s,1H,ArH),8.01(s,1H,ArH),7.79(d,J＝7.1Hz,1H,NH),7.60(dd,J＝23.5,7.7Hz,1H,NH),7.34(dd,J＝22.6,13.3Hz,4H,ArH),7.04(dt,J＝34.2,7.2Hz,2H,ArH),3.76(s,2H,CH ₂ )； ¹³ CNMR(100MHz,DMSO-d ₆ ):δ170.39,164.80,140.00,136.61,133.99,129.15,127.75,124.40,122.06,121.58,121.48,119.15,118.90,118.63,111.85,108.91,34.31；MS(ESI)m/z:calcd.for C ₁₇ H ₁₅ N ₃ O ₃ [2M+H] ⁺ :619.22,found:618.78。

(10) Preparation of 4- (2- (1H-indol-3-yl) acetamido) -N-hydroxybenzoyl (XCY-A2)

Will be inIntermediate 3b (0.20 g,0.65 mmol) was dissolved in a mixture of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.35 g,19.46 mmol) and KOH (1.13 g,20.15 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.11g of a white solid in 56% yield. Melting point: 251-253 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.09(s,1H,NH),10.92(s,1H,OH),10.31(s,1H,ArH),8.92(s,1H,ArH),7.76–7.65(m,4H,ArH),7.61(d,J＝7.8Hz,1H,NH),7.37(d,J＝8.1Hz,1H,ArH),7.28(s,1H,ArH),7.08(t,J＝7.4Hz,1H,ArH),6.99(t,J＝7.4Hz,1H,NH),3.77(s,2H,CH ₂ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ170.56,164.41,142.39,136.60,128.15,127.68,127.56(2C),124.40,121.49(2C),119.11,118.90,118.82,111.86,108.79,34.33；MS(ESI)m/z:calcd.for C ₁₇ H ₁₅ N ₃ O ₃ [M-H] ^- :308.11,found:308.12。

(11) Preparation of 2- (3- (2- (1H-indol-3-yl) acetamido) phenyl) -N-hydroxyacetamide (XCY-A3)

Intermediate 3c (0.20 g,0.62 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.29 g,18.61 mmol) and KOH (1.08 g,19.22 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.10g of a white solid in 53% yield. Melting point: 159-161 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.92(s,1H,NH),10.67(s,1H,OH),10.10(s,1H,ArH),8.84(s,1H,ArH),7.63(d,J＝7.8Hz,1H,ArH),7.56–7.48(m,2H,ArH),7.37(d,J＝8.1Hz,1H,NH),7.27(d,J＝1.7Hz,1H,ArH),7.21(t,J＝7.8Hz,1H,ArH),7.09(t,J＝7.4Hz,1H,ArH),7.00(t,J＝7.4Hz,1H,ArH),6.94(d,J＝7.5Hz,1H,NH),3.74(s,2H,CH ₂ ),3.25(s,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ170.22,167.45,139.73,136.95,136.62,128.92,127.71,124.32(2C),121.49,120.23,119.17,118.90,117.90,111.85,109.10,69.11,34.28；MS(ESI)m/z:calcd.for C ₁₈ H ₁₇ N ₃ O ₃ [2M+H] ⁺ :647.26,found:646.80。

(12) Preparation of 2- (4- (2- (1H-indol-3-yl) acetamido) phenyl) -N-hydroxyacetamide (XCY-A4)

Intermediate 3d (0.20 g,0.62 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.29 g,18.61 mmol) and KOH (1.08 g,19.22 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (pure ethyl acetate) gave 0.10g of a white solid in 50% yield. Melting point: 183-185 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.91(s,1H,NH),10.63(s,1H,OH),10.10(s,1H,ArH),8.80(s,1H,ArH),7.61(d,J＝7.8Hz,1H,ArH),7.54(d,J＝7.9Hz,2H,ArH),7.36(d,J＝8.0Hz,1H,NH),7.26(s,1H,ArH),7.17(d,J＝8.2Hz,2H,ArH),7.07(t,J＝7.4Hz,1H,ArH),6.98(t,J＝7.4Hz,1H,NH),3.73(s,2H,CH ₂ ),3.29–3.18(m,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ170.06,167.63,138.32,136.63,131.13,129.56(2C),127.74,124.30(2C),121.43,119.54,119.15,118.84,111.83,109.11,39.27,34.24；MS(ESI)m/z:calcd.for C ₁₈ H ₁₇ N ₃ O ₃ [2M+Na] ⁺ :669.26,found:668.19。

The compound of the formula II can be prepared through the following reaction route:

the reagents used in the preparation flow are respectively as follows: a: thionyl chloride; methanol; 75 ℃;12h; b:2- (1H-indol-3-yl) acetic acid; EDCI; DMAP;

dichloromethane; room temperature; c: hydroxylamine hydrochloride; KOH; dichloromethane/methanol; room temperature; 3h.

(1) Preparation of intermediate methyl 3- (2- (naphthalen-2-yl) acetamido) benzoate (4 a)

2-naphthylacetic acid (0.50 g,2.69 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.57 g,2.95 mmol) was added, and the reaction was stirred at room temperature for 1h. Intermediate 2a (0.45 g,2.95 mmol) and DMAP (0.03 g,0.27 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.53g of a yellow solid in 62% yield. Melting point: 142-144 ℃. MS (ESI) m/z calcd.for C ₂₀ H ₁₇ NO ₃ [M+Cl] ^- :354.57,found:354.89。

(2) Preparation of intermediate methyl 4- (2- (naphthalen-2-yl) acetamido) benzoate (4 b)

2-naphthylacetic acid (0.50 g,2.69 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.57 g,2.95 mmol) was added, and the reaction was stirred at room temperature for 1h. Intermediate 2b (0.45 g,2.95 mmol) and DMAP (0.03 g,0.27 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.47g of a white solid in 55% yield. Melting point: 155-157 ℃. MS (ESI) m/z calcd.for C ₂₀ H ₁₇ NO ₃ [M+Cl] ^- :354.57,found:354.89。

(3) Preparation of intermediate methyl 2- (3- (2- (naphthalen-2-yl) acetamido) phenyl) acetate (4 c)

2-naphthylacetic acid (0.50 g,2.69 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.57 g,2.95 mmol) was added, and the reaction was stirred at room temperature for 1h. Intermediate 2c (0.49 g,2.95 mmol) and DMAP (0.03 g,0.27 mmol) were added and the reaction stirred at room temperature for 3h. Reaction completionAfter that, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10min. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo afforded 0.53g of a yellow solid in 59% yield. Melting point: 135-137 deg.c. MS (ESI) m/z calcd.for C ₂₁ H ₁₉ NO ₃ [M+Cl] ^- :368.59,found:368.95。

(4) Preparation of intermediate methyl 2- (4- (2- (naphthalen-2-yl) acetamido) phenyl) acetate (4 d)

2-naphthylacetic acid (0.50 g,2.69 mmol) was dissolved in 50mL of anhydrous dichloromethane, EDCI (0.57 g,2.95 mmol) was added, and the reaction was stirred at room temperature for 1h. Intermediate 2d (0.49 g,2.95 mmol) and DMAP (0.03 g,0.27 mmol) were added and the reaction stirred at room temperature for 3h. After the reaction was completed, 2M hydrochloric acid (50 mL) was added thereto, and the mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was concentrated and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.54g of a white solid in 61% yield. Melting point: 124-126 ℃. MS (ESI) m/z calcd.for C ₂₁ H ₁₉ NO ₃ [M+Cl] ^- :368.59,found:368.99。

(5) Preparation of N-hydroxy-3- (2- (naphthalen-2-yl) acetamido) benzamide (XCY-C1)

Intermediate 4a (0.20 g,0.63 mmol) was dissolved in a mixture of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.31 g,18.79 mmol) and KOH (1.09 g,19.53 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.10g of a white solid in 52% yield. Melting point: 189-191 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.19(s,1H,OH),10.41(s,1H,ArH),9.03(s,1H,ArH),8.02(s,1H,NH),7.91–7.83(m,4H,ArH),7.79(d,J＝7.4Hz,1H,NH),7.57–7.44(m,3H,ArH),7.45–7.31(m,2H,ArH),3.85(s,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ170.11,164.60,142.13,133.79,133.46,132.35,128.25,128.19,128.06,127.96,127.94(2C),127.88(2C),127.71,126.67,126.17,119.08,43.87；MS(ESI)m/z:calcd.for C ₁₉ H ₁₆ N ₂ O ₃ [M+Cl] ^- :355.57,found:354.92。

(6) Preparation of N-hydroxy-4- (2- (naphthalen-2-yl) acetamido) benzamide (XCY-C2)

Intermediate 4b (0.20 g,0.63 mmol) was dissolved in a mixture of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.31 g,18.79 mmol) and KOH (1.09 g,19.53 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.12g of a white solid in 60% yield. Melting point: 241-243 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.11(s,1H,OH),10.47(s,1H,ArH),8.95(s,1H,NH),7.89(d,J＝8.0Hz,3H,ArH),7.84(s,1H,NH),7.71(q,J＝8.8Hz,4H,ArH),7.49(ddd,J＝8.5,7.4,4.8Hz,3H,ArH),3.86(s,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ169.79,164.77,139.75,133.97,133.48,132.35,129.24,128.22,128.09,127.96,127.92(2C),127.89(2C),126.63,126.12,122.23,121.86,43.90；MS(ESI)m/z:calcd.for C ₁₉ H ₁₆ N ₂ O ₃ [M+Cl]-:355.57,found:354.90。

(7) Preparation of N-hydroxy-2- (3- (2- (naphthalen-2-yl) acetamido) phenyl) acetamide (XCY-C3)

Intermediate 4c (0.12 g,0.36 mmol) was dissolved in a mixed solution of 8mL of dichloromethane and 8mL of methanol, hydroxylamine hydrochloride (0.75 g,10.80 mmol) and KOH (0.62 g,11.16 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.06g of a white solid in 49% yield. Melting point: 189-191 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.65(s,1H,OH),10.24(s,1H,ArH),7.89(dd,J＝8.6,2.7Hz,3H,ArH),7.84(s,1H,NH),7.49(ddd,J＝9.9,8.5,7.0Hz,6H,ArH),7.22(t,J＝7.8Hz,1H,ArH),6.95(d,J＝7.5Hz,1H,NH),3.82(s,2H,CH ₂ ),3.25(s,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ169.55,167.42,139.52,137.01,134.16,133.48,132.33,128.98,128.19,128.09,127.96,127.88,127.86,126.61,126.09,124.53,120.31,117.97,43.90,39.52；MS(ESI)m/z:calcd.for C ₂₀ H ₁₈ N ₂ O ₃ [M+Cl]-:369.58,found:368.95。

(8) Preparation of N-hydroxy-2- (4- (2- (naphthalen-2-yl) acetamido) phenyl) acetamide (XCY-C4)

Intermediate 4d (0.15 g,0.45 mmol) was dissolved in a mixture of 10mL dichloromethane and 10mL methanol, hydroxylamine hydrochloride (0.94 g,13.50 mmol) and KOH (0.78 g,13.95 mmol) were added and the reaction was stirred at room temperature under nitrogen for 3h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.08g of a white solid in 51% yield. Melting point: 193-195 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.64(s,1H,OH),10.22(s,1H,ArH),8.83(s,1H,ArH),7.88(s,3H,ArH),7.52(s,6H,ArH),7.19(s,2H,NH),3.82(s,2H,CH ₂ ),3.24(s,2H,CH ₂ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ169.42,167.63,138.11,134.17,133.47,132.32,131.35,129.65(2C),128.18,128.15,127.96(2C),127.89,126.61,126.08,119.59(2C),43.86,39.25；MS(ESI)m/z:calcd.for C ₂₀ H ₁₈ N ₂ O ₃ [M+Cl] ^- :369.58,found:368.95。

The compound of formula III of the invention can be prepared by the following reaction route:

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the reagents used in the preparation flow are respectively as follows: a: triphosgene; triethylamine; ethyl acetate; room temperature; 5h; b: i: 4-amino-1-butanol/n-butylamine; absolute ethyl alcohol; 95 ℃;5h; ii: sodium borohydride; methanol; 0 ℃;2h; c: 1-bromo-4-nitrobenzene; tetrakis (triphenylphosphine) palladium; potassium carbonate; 1, 4-dioxane/water; 95 ℃ for 12 hours; d: zinc; ammonium chloride; tetrahydrofuran/ethanol/water; 75 ℃;4h; e: triethylamine; dichloromethane; room temperature; 3h; f: i: potassium hydroxide; methanol; 80 ℃;6h; ii: aqueous methylamine solution; 60 ℃;2h; iii: hydrazine hydrate; 90 ℃;7h; g: p-bromophenylacetic acid; tetrakis (triphenylphosphine) palladium; potassium carbonate; 1, 4-dioxane/water; 95 ℃ for 12 hours; h: DCC; DMAP; dichloromethane; room temperature; 3h; i: hydroxylamine hydrochloride; KOH; dichloromethane/methanol; room temperature; 3h; j:2- (4-methoxycarbonylphenyl) acetic acid/monomethyl terephthalate; DCC; DMAP; dichloromethane; room temperature; 3h; k: hydroxylamine hydrochloride; KOH; dichloromethane/methanol; room temperature; 3h; l: triphosgene; triethylamine; ethyl acetate; room temperature; 5h; m: triethylamine; dichloromethane; room temperature; 3h; n: hydroxylamine hydrochloride; KOH; dichloromethane/methanol; room temperature; 3h.

(1) Preparation of intermediate methyl 4-isocyanatobenzoate (6)

Triphosgene (0.20 g,0.66 mmol) was dissolved in 10mL of ethyl acetate under ice-bath conditions, followed by slow dropwise addition of 10mL of a solution of methyl 4-aminobenzoate 5 (0.20 g,1.32 mmol) and triethylamine (0.13 g,1.32 mmol) in ethyl acetate. After the completion of the dropwise addition, the reaction was stirred at room temperature for 5 hours. The reaction solution was filtered and concentrated to a yellow oil which was directly put into the next step.

(2) Preparation of intermediate methyl 4- (((4-hydroxybutyl) amino) methyl) benzoate (8 a)

4-amino-1-butanol (0.28 mL,6.10 mmol) and methyl 4-formylbenzoate 7 (0.50 g,3.05 mmol) were dissolved in 25mL absolute ethanol and reacted under reflux with stirring for 2h. The reaction solution was cooled to room temperature and concentrated in vacuo, and the crude product was used directly in the next step. Ice bathUnder the condition that the crude product is dissolved in 50mL of methanol, naBH is added in portions over 10min ₄ (0.12 g,3.10 mmol) was stirred at room temperature for 2h. The reaction mixture was quenched with water, concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.63g of a colourless oil in 87% yield in two steps. MS (ESI) m/z calcd.for C ₁₃ H ₁₉ NO ₃ [M+H] ⁺ :238.14,found:238.20。

(3) Preparation of intermediate 4- ((butylamino) methyl) benzoic acid methyl ester (8 b)

N-butylamine (0.45 g,6.10 mmol) and methyl 4-formylbenzoate 7 (0.50 g,3.05 mmol) were dissolved in 25mL absolute ethanol and reacted for 2h under reflux with stirring. The reaction solution was cooled to room temperature and concentrated in vacuo, and the crude product was used directly in the next step. The crude product was dissolved in 50mL of methanol under ice bath conditions and NaBH was added in portions over 10min ₄ (0.12 g,3.10 mmol) was stirred at room temperature for 2h. The reaction mixture was quenched with water, concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 0.54g of a colourless oil in 80% yield in two steps.

(4) Preparation of intermediate 3-methoxy-4 '-nitro-1, 1' -biphenyl (10)

3-Methoxyphenylboronic acid 9 (0.90 g,5.94 mmol), 1-bromo-4-nitrobenzene (1.00 g,4.95 mmol), ph (PPh) ₃ ) ₄ (0.29 g,0.25 mmol) and K ₂ CO ₃ (2.05 g,14.85 mmol) was dissolved in a mixed solution of 40mL dioxane and 8mL water, and the mixture was stirred under reflux under nitrogen for 12h. The reaction mixture was cooled, added with an appropriate amount of water, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, filtered through celite, anhydrous Na ₂ SO ₄ And (5) drying. Filtration and concentration in vacuo gave 1.85g of a reddish brown oil which was taken directly to the next step.

(5) Preparation of intermediate 3 '-methoxy- [1,1' -biphenyl ] -4-amine (11)

Intermediate 10 (1.85 g,8.08 mmol), zinc powder (2.64 g,40.38 mmol) and ammonium chloride (432g,80.75 mmol) was dissolved in a mixture of 20mL tetrahydrofuran, 20mL ethanol and 6mL water, and the mixture was refluxed and stirred under nitrogen for 4h. The reaction solution was cooled, filtered through celite, and extracted three times with ethyl acetate (3×50 mL) with an appropriate amount of water. The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, column chromatography on silica gel (petroleum ether: ethyl acetate=50:1) afforded 1.05g of a yellow solid in 65% yield. Melting point: 109-111 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.36(d,J＝8.4Hz,2H,ArH),7.27(t,J＝7.9Hz,1H,ArH),7.09(t,J＝7.5Hz,1H,ArH),7.05(s,1H,ArH),6.78(dd,J＝8.1,1.9Hz,1H,ArH),6.64(d,J＝8.4Hz,2H,ArH),5.25(s,2H,NH ₂ ),3.79(s,3H,CH ₃ )；MS(ESI)m/z:calcd.for C ₁₃ H ₁₃ NO[M+H] ⁺ :200.10,found:200.07。

(6) Preparation of intermediate 2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid (12)

3-Methoxyphenylboronic acid 9 (0.85 g,5.58 mmol), 4-bromophenylacetic acid (1.00 g,4.65 mmol), ph (PPh) ₃ ) ₄ (0.27 g,0.23 mmol) and K ₂ CO ₃ (1.93 g,13.95 mmol) was dissolved in a mixed solution of 40mL dioxane and 8mL water, and the mixture was stirred under reflux under nitrogen for 12h. The reaction solution was cooled, filtered through celite, and extracted three times with ethyl acetate (3×50 mL) with an appropriate amount of water. The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) gave 0.82g of yellow oil in 73% yield. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.39(s,1H,OH),7.61(d,J＝7.9Hz,2H,ArH),7.36(dd,J＝13.7,7.8Hz,3H,ArH),7.26–7.15(m,2H,ArH),6.93(d,J＝7.1Hz,1H,ArH),3.82(s,3H,CH ₃ ),3.62(s,2H,CH ₂ )。

(7) Preparation of intermediate methyl 4- (2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetamido) benzoate (13)

Intermediate 12 (0.50 g,2.06 mmol) was dissolved in 20mL of anhydrous dichloromethane and DCC (0.56 g,2.68 mmol), methyl 4-aminobenzoate (0.34 g,2.27 mmol) and DMAP (0.02 g,0.21 mmol) were added sequentially and the reaction stirred at room temperature for 3h. After the reaction is finished, addThe mixture was extracted three times with dichloromethane (3X 50 mL) with an appropriate amount of water. The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (petroleum ether: ethyl acetate=9:1) afforded 0.50g of a white solid in 65% yield. Melting point: 129-131 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.92(d,J＝8.5Hz,2H,ArH),7.75(d,J＝8.6Hz,2H,ArH),7.63(d,J＝7.9Hz,2H,ArH),7.50–7.31(m,3H,ArH),7.29–7.09(m,2H,ArH),6.93(d,J＝6.7Hz,1H,ArH),5.58(d,J＝6.8Hz,1H,NH),3.82(s,6H,CH ₃ CH ₃ ),3.73(s,2H,CH ₂ )；MS(ESI)m/z:calcd.for C ₂₃ H ₂₁ NO ₄ [2M+Cl] ^- :785.75,found:784.63。

(8) Preparation of intermediate methyl 3- (2- (naphthalen-2-yl) acetamido) benzoate (14 a)

(9) Preparation of intermediate methyl 4- ((3 '-methoxy- [1,1' -biphenyl ] -4-yl) carbamoyl) benzoate (14 b)

Intermediate 11 (0.12 g,0.61 mmol) was dissolved in 20mL of anhydrous dichloromethane, DCC (0.15 g,0.73 mmol), monomethyl terephthalate (0.10 g,0.56 mmol) and DMAP (0.01 g,0.06 mmol) were added sequentially and the reaction was stirred at room temperature for 3h. After the reaction, an appropriate amount of water was added thereto, and the mixture was extracted three times with methylene chloride (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (petroleum ether: ethyl acetate=9:1) afforded 0.17g of a white solid in 85% yield. Melting point: 147-149 ℃. MS (ESI) m/z calcd.for C ₂₂ H ₁₉ NO ₄ [M-H] ^- :360.13,found:360.20。

(10) Preparation of intermediate 4 '-isocyanato-3-methoxy-1, 1' -biphenyl (15)

Triphosgene (0.15 g,0.50 mmol) was dissolved in 10mL of ethyl acetate under ice-bath conditions, and 10mL of ethyl acetate solution of intermediate 11 (0.20 g,1.00 mmol) and triethylamine (0.15 g,1.50 mmol) were slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at room temperature for 5 hours. The reaction solution was filtered and concentrated to a yellow oil which was directly put into the next step.

(11) Preparation of intermediate 4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoate (16 a)

Intermediate 8a (0.24 g,1.00 mmol) and triethylamine (0.31 g,3.00 mmol) were dissolved in 15mL of dichloromethane under ice-bath conditions, and a solution of intermediate 15 (0.45 g,2.00 mmol) in 15mL of dichloromethane was slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, an appropriate amount of water was added thereto, and extraction was performed three times with ethyl acetate (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, column chromatography on silica gel (dichloromethane: methanol=200:1) gave 0.40g of yellow oil in 64% yield. MS (ESI) m/z calcd.for C ₂₇ H ₃₀ N ₂ O ₅ [M-H] ^- :461.22,found:461.19。

(12) Preparation of intermediate methyl 4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoate (16 b)

Intermediate 8b (0.22 g,1.00 mmol) and triethylamine (0.31 g,3.00 mmol) were dissolved in 15mL of dichloromethane under ice-bath conditions, and a solution of intermediate 15 (0.45 g,2.00 mmol) in 15mL of dichloromethane was slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, an appropriate amount of water was added thereto, and extraction was performed three times with ethyl acetate (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, column chromatography on silica gel (dichloromethane: methanol=200:1) gave 0.31g of yellow oil in 69% yield. MS (ESI) m/z calcd.for C ₂₇ H ₃₀ N ₂ O ₄ [M-H] ^- :445.22,found:445.12。

(13) Preparation of methyl 4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) benzoate (XCY-D1)

Intermediate 11 (0.18 g,0.88 mmol) and triethylamine (0.27 g,2.65 mmol) were dissolved in 10mL of dichloromethane under ice-bath conditions, followed by slow dropwise addition of 5mL of a dichloromethane solution of intermediate 6 (0.23 g,1.32 mmol). After the completion of the dropwise addition, the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=200:1) afforded 0.30g of a white solid in 60% yield. Melting point: 173-175 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.13(s,1H,NH),8.93(s,1H,NH),7.91(d,J＝8.7Hz,2H,ArH),7.61(dt,J＝19.3,7.6Hz,6H,ArH),7.35(t,J＝7.9Hz,1H,ArH),7.25–7.14(m,2H,ArH),6.90(dd,J＝8.1,1.9Hz,1H,ArH),3.83(s,6H,CH ₃ CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ166.43,160.25,152.61,144.79,141.78,139.37,134.35,130.88(2C),130.39,127.61(2C),123.03,119.23(2C),119.00,117.87(2C),112.96,112.16,55.57,52.23；MS(ESI)m/z:calcd.for C ₂₂ H ₂₀ N ₂ O ₄ [M+Cl] ^- :411.59,found:410.90。

(14) Preparation of 4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) benzoic acid (XCY-D2)

The target compound XCY-D1 (0.10 g,0.27 mmol) was dissolved in 10mL of methanol, KOH (0.15 g,2.67 mmol) was added, and the reaction was stirred under reflux for 6h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.07g of a white solid in 67% yield. Melting point: 255-257 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.35(s,1H,OH),9.18(s,1H,NH),7.90(d,J＝8.6Hz,2H,ArH),7.61(q,J＝8.6Hz,6H,ArH),7.41–7.27(m,1H,NH),7.24–7.09(m,2H,ArH),6.89(dd,J＝8.1,1.7Hz,1H,ArH),3.81(d,J＝9.3Hz,3H,CH ₃ )； ¹³ CNMR(150MHz,DMSO-d ₆ ):δ167.91,160.24,152.77,144.32,141.81,139.56,134.20,130.97(2C),130.38,127.59(2C),124.75,119.17(2C),119.00,117.73(2C),112.92,112.14,55.56；MS(ESI)m/z:calcd.for C ₂₁ H ₁₈ N ₂ O ₄ [M-H] ^- :361.13,found:361.36。

(15) Preparation of 4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) -N-methylbenzamide (XCY-D3)

The target compound XCY-D1 (0.15 g,0.40 mmol) was dissolved in 5mL aqueous methylamine solution, and the reaction was stirred under reflux for 2h under nitrogen protection. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.07g of a white solid in 46% yield. Melting point: 239-241 deg.c. ¹ H NMR(600MHz,DMSO-d ₆ ):δ8.95(s,1H,NH),8.87(s,1H,NH),8.28(q,J＝4.3Hz,1H,NH),7.80(d,J＝8.7Hz,2H,ArH),7.65–7.59(m,2H,ArH),7.55(dd,J＝12.3,8.8Hz,4H,ArH),7.35(t,J＝7.9Hz,1H,ArH),7.23–7.20(m,1H,ArH),7.18–7.16(m,1H,ArH),6.92–6.87(m,1H,ArH),3.82(s,3H,CH ₃ ),2.78(d,J＝4.5Hz,3H,CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ166.76,160.25,152.77,142.71,141.81,139.55,134.18,130.39,128.49(2C),128.23,127.60(2C),119.13(2C),118.99,117.73(2C),112.93,112.15,55.57,26.65；MS(ESI)m/z:calcd.for C ₂₂ H ₂₁ N ₃ O ₃ [M+Cl] ^- :410.61,found:411.07。

(16) Preparation of 1- (4- (hydrazinocarbonyl) phenyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (XCY-D4)

The target compound XCY-D1 (0.12 g,0.32 mmol) was dissolved in 10mL of ethanol, hydrazine hydrate (0.10 g,1.60 mmol) was added, and the mixture was stirred under reflux under nitrogen for 7h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.07g of a white solid in 46% yield. Melting point：251–253℃。 ¹ H NMR(600MHz,DMSO-d ₆ ):δ9.62(s,1H,NH),8.96(s,1H,NH),8.89(s,1H,NH),7.79(d,J＝8.6Hz,2H,ArH),7.62(d,J＝8.7Hz,2H,ArH),7.55(dd,J＝15.0,8.6Hz,4H,ArH),7.35(t,J＝7.9Hz,1H,ArH),7.21(d,J＝7.9Hz,1H,ArH),7.19–7.11(m,1H,ArH),6.90(dd,J＝8.2,2.3Hz,1H,ArH),4.47(s,2H,NH ₂ ),3.82(s,3H,CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ166.20,160.24,152.77,142.79,141.80,139.54,134.19,130.39,128.39(2C),127.60(2C),126.90,119.15(2C),118.99,117.80(2C),112.93,112.14,55.57；MS(ESI)m/z:calcd.for C ₂₁ H ₂₀ N ₄ O ₃ [2M+H] ⁺ :753.30,found:752.56。

(17) Preparation of N-hydroxy-4- (2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetamido) benzamide (XCY-D5)

Intermediate 13 (0.20 g,0.53 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.11 g,15.98 mmol) and KOH (0.94 g,16.74 mmol) were added, and the reaction was stirred at room temperature under nitrogen atmosphere for 2h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.05g of a white solid in 23% yield. Melting point: 179-181 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.16(d,J＝38.9Hz,1H,OH),10.38(d,J＝35.3Hz,1H,NH),8.95(s,1H,ArH),7.79–7.59(m,6H,ArH),7.49–7.30(m,3H,ArH),7.25–7.13(m,2H,ArH),6.93(d,J＝7.0Hz,1H,NH),3.82(s,3H,CH ₃ ),3.68(d,J＝34.0Hz,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ169.93,164.45,160.23,142.17,141.95,138.95,135.60,130.45(2C),130.13(2C),128.18,127.76,127.22(2C),119.39(2C),118.94,113.38,112.60,55.59,43.44；MS(ESI)m/z:calcd.for C ₂₂ H ₂₀ N ₂ O ₄ [M+Cl] ^- :410.59,found:409.96。

(18) N-hydroxy-4- (2- ((3 '-methoxy- [1,1' -biphenyl)]Preparation of-4-yl) amino) -2-oxoethyl-benzamide (XCY-D6) intermediate 14a (0.25 g,0.67 mmol) was dissolved inTo a mixed solution of 10mL of methylene chloride and 10mL of methanol were added hydroxylamine hydrochloride (1.39 g,19.98 mmol) and KOH (1.16 g,20.77 mmol), and the reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.08g of a white solid in 32% yield. Melting point: 191-193 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.19(s,1H,OH),10.31(s,1H,NH),9.02(s,1H,ArH),7.71(dd,J＝14.7,8.2Hz,4H,ArH),7.63(d,J＝8.5Hz,2H,ArH),7.43(d,J＝7.9Hz,2H,ArH),7.35(t,J＝7.9Hz,1H,ArH),7.21(d,J＝7.7Hz,1H,ArH),7.17(s,1H,ArH),6.90(d,J＝6.6Hz,1H,NH),3.82(s,3H,CH ₃ ),3.74(s,2H,CH ₂ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ169.22,164.72,160.24,141.64,139.65,139.13,135.35,131.61,130.41,129.62(2C),127.49(2C),127.40,119.98(2C),119.08(2C),113.13,112.21,55.58,43.56；MS(ESI)m/z:calcd.for C ₂₂ H ₂₀ N ₂ O ₄ [M+Cl] ^- :410.59,found:410.92。

(19)N ¹ -hydroxy-N ⁴ - (3 '-methoxy- [1,1' -biphenyl)]Preparation of-4-yl) terephthalamide (XCY-D7)

Intermediate 14b (0.16 g,0.43 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (0.90 g,12.95 mmol) and KOH (0.75 g,13.33 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 2h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.06g of a white solid in 40% yield. Melting point: 267-269 ℃. ¹ H NMR(600MHz,DMSO-d ₆ ):δ11.33(s,1H,OH),10.38(s,1H,NH),9.11(s,1H,ArH),7.98(d,J＝7.9Hz,2H,ArH),7.83(t,J＝8.7Hz,4H,ArH),7.63(d,J＝8.4Hz,2H,ArH),7.30(t,J＝7.8Hz,1H,NH),7.21–7.10(m,2H,ArH),6.85(dd,J＝8.0,1.7Hz,1H,ArH),3.76(s,3H,CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ165.39,163.94,160.27,141.66,139.06,137.59,135.86,130.43,128.24(2C),127.40(4C),121.16(3C),119.15,113.22,112.30,55.61；MS(ESI)m/z:calcd.for C ₂₁ H ₁₈ N ₂ O ₄ [M-H] ^- :361.13,found:361.20。

(20) Preparation of N-hydroxy-4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzamide (XCY-D8)

Intermediate 16a (0.16 g,0.43 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.74 g,24.95 mmol) and KOH (1.46 g,26.04 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 2h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.18g of a white solid in 48% yield. Melting point: 113-115 ℃. ¹ H NMR(600MHz,DMSO-d ₆ ):δ11.18(s,1H,OH),9.01(s,1H,NH),8.52(s,1H,NH),7.74(d,J＝7.4Hz,2H,ArH),7.58(s,4H,ArH),7.35(d,J＝7.6Hz,3H,ArH),7.24–7.11(m,2H,ArH),6.88(d,J＝7.2Hz,1H,ArH),4.64(s,2H,CH ₂ ),4.51(s,1H,OH),3.82(s,3H,CH ₃ ),3.49–3.36(m,4H,CH ₂ ,CH ₂ ),1.57(s,2H,CH ₂ ),1.43(s,2H,CH ₂ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ164.59,160.22,155.66,142.77,141.94,140.68,133.81,131.93,130.34,127.52(2C),127.48(2C),127.05(2C),120.53(2C),118.95,112.81,112.07,61.12,55.55,49.46,46.78,29.77,25.11；MS(ESI)m/z:calcd.for C ₂₆ H ₂₉ N ₃ O ₅ [M+Cl] ^- :498.66,found:497.75。

(21) Preparation of 4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid (XCY-D9)

Intermediate 16a (0.22 g,0.48 mmol) was dissolved in 20mL of methanol, KOH (0.27 g,4.80 mmol) was added and the reaction stirred at reflux for 6h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtering, trueAir concentration and silica gel column chromatography (dichloromethane: methanol=100:1) gave 0.09g of a white solid in 42% yield. Melting point: 67-69 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.86(s,1H,OH),8.54(s,1H,NH),7.94(d,J＝8.0Hz,2H,ArH),7.63–7.54(m,4H,ArH),7.40(d,J＝8.0Hz,2H,ArH),7.34(t,J＝7.9Hz,1H,ArH),7.20(d,J＝7.7Hz,1H,ArH),7.16(s,1H,ArH),6.88(d,J＝8.0Hz,1H,ArH),4.68(s,2H,CH ₂ ),4.52(s,1H,OH),3.82(s,3H,CH ₃ ),3.39(d,J＝17.3Hz,4H,CH ₂ CH ₂ ),1.56(dd,J＝13.9,7.1Hz,2H,CH ₂ ),1.43(dd,J＝13.7,6.6Hz,2H,CH ₂ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ167.66,160.20,155.65,144.75,141.92,140.65,133.82,130.33,129.99(2C),129.89,127.63(2C),127.04(2C),120.54(2C),118.94,112.81,112.05,61.12,55.54,49.56,46.85,29.86,25.11；MS(ESI)m/z:calcd.for C ₂₆ H ₂₈ N ₂ O ₅ [2M-H] ^- :895.40,found:894.73。

(22) Preparation of 1- (4- (hydrazinocarbonyl) benzyl) -1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (XCY-D10)

Intermediate 16a (0.16 g,0.35 mmol) was dissolved in 15mL of ethanol, hydrazine hydrate (0.09 g,1.73 mmol) was added and the reaction was stirred under reflux under nitrogen for 7h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.07g of a white solid in 43% yield. Melting point: 165-167 ℃. ¹ H NMR(600MHz,DMSO-d ₆ ):δ9.01(s,1H,NH),8.52(s,1H,NH),7.74(d,J＝7.4Hz,2H,ArH),7.58(s,4H,ArH),7.35(d,J＝7.6Hz,3H,ArH),7.24–7.11(m,2H,ArH),6.88(d,J＝7.2Hz,1H,ArH),4.64(s,4H,CH ₂ ,NH ₂ ),4.51(s,1H,OH),3.82(s,3H,CH ₃ ),3.49–3.36(m,4H,CH ₂ CH ₂ ),1.57(s,2H,CH ₂ ),1.43(s,2H,CH ₂ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ167.20,161.10,155.10,144.75,141.92,140.65,133.82,130.33,129.99(2C),129.89,127.63(2C),127.04(2C),120.54(2C),118.94,112.81,112.05,61.12,55.54,49.56,46.85,29.86,25.11；MS(ESI)m/z:calcd.for C ₂₆ H ₃₀ N ₄ O ₄ [M-H] ^- :461.23,found:461.12。

(23) Preparation of 4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) -N-hydroxybenzoamide (XCY-D11)

Intermediate 16b (0.31 g,0.69 mmol) was dissolved in a mixed solution of 10mL of dichloromethane and 10mL of methanol, hydroxylamine hydrochloride (1.44 g,20.68 mmol) and KOH (1.20 g,21.39 mmol) were added, and the reaction was stirred at room temperature under nitrogen for 2h. The reaction mixture was concentrated, and extracted three times with ethyl acetate (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=40:1) afforded 0.16g of a pale red solid in 52% yield. Melting point: 101-103 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.19(s,1H,OH),9.01(s,1H,NH),8.49(s,1H,NH),7.74(d,J＝7.9Hz,2H,ArH),7.59(d,J＝9.3Hz,4H,ArH),7.34(t,J＝7.4Hz,3H,ArH),7.20(d,J＝7.7Hz,1H,ArH),7.15(s,1H,ArH),6.88(d,J＝8.0Hz,1H,ArH),4.65(s,2H,CH ₂ ),3.82(s,3H,CH ₃ ),3.32(d,J＝7.3Hz,2H,CH ₂ ),1.51(dd,J＝14.2,7.2Hz,2H,CH ₂ ),1.30–1.24(m,2H,CH ₂ ),0.87(t,J＝7.3Hz,3H,CH ₃ )； ¹³ C NMR(100MHz,DMSO-d ₆ ):δ164.57,160.22,155.66,142.76,141.94,140.68,133.81,131.95,130.34,127.53(2C),127.48(2C),127.03(2C),120.58(2C),118.95,112.81,112.06,55.55,49.55,46.65,30.45,19.94,14.27；MS(ESI)m/z:calcd.for C ₂₆ H ₂₉ N ₃ O ₄ [M+Cl] ^- :482.67,found:481.68。

(24) Preparation of 4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid (XCY-D12)

Intermediate 16b (0.20 g,0.45 mmol) was dissolved in 20mL of methanol, KOH (0.25 g,4.50 mmol) was added and the reaction stirred at reflux for 6h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, vacuum concentration, silica gel column chromatography (dichloromethane:methanol=100: 1) 0.08g of white solid was obtained in 40% yield. Melting point: 125-127 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.87(s,1H,OH),8.51(s,1H,NH),7.94(d,J＝8.1Hz,2H,ArH),7.58(s,4H,ArH),7.40(d,J＝8.0Hz,2H,ArH),7.34(t,J＝7.9Hz,1H,ArH),7.20(d,J＝7.6Hz,1H,ArH),7.15(s,1H,ArH),6.94–6.81(m,1H,ArH),4.68(s,2H,CH ₂ ),3.82(s,3H,CH ₃ ),3.26(s,2H,CH ₂ ),1.49(dd,J＝14.3,7.5Hz,2H,CH ₂ ),1.25(dd,J＝14.1,6.7Hz,2H,CH ₂ ),0.87(t,J＝7.3Hz,3H,CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ167.62,160.25,155.69,144.72,141.98,140.67,133.88,130.31,129.96(2C),127.65(2C),127.01(2C),120.62(2C),120.52,118.97,112.84,112.12,55.58,49.71,46.75,30.45,19.92,14.22；MS(ESI)m/z:calcd.for C ₂₆ H ₂₈ N ₂ O ₄ [M+H] ⁺ :433.20,found:433.12。

(25) Preparation of 1-butyl-1- (4- (hydrazinocarbonyl) benzyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea (XCY-D13)

Intermediate 16b (0.20 g,0.45 mmol) was dissolved in 15mL of ethanol and hydrazine hydrate (0.11 g,2.25 mmol) was added and the reaction was stirred under reflux under nitrogen for 7h. The reaction mixture was concentrated, and then, an appropriate amount of water was added thereto, followed by extraction with ethyl acetate three times (3X 50 mL). The organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ And (5) drying. Filtration, concentration in vacuo, silica gel column chromatography (dichloromethane: methanol=100:1) afforded 0.09g of a white solid in 45% yield. Melting point: 145-147 ℃. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.01(s,1H,NH),8.49(s,1H,NH),7.74(d,J＝7.9Hz,2H,ArH),7.59(d,J＝9.3Hz,4H,ArH),7.34(t,J＝7.4Hz,3H,ArH),7.20(d,J＝7.7Hz,1H,ArH),7.15(s,2H,ArH),6.88(d,J＝8.0Hz,2H,NH ₂ ),4.65(s,2H,CH ₂ ),3.82(s,3H,CH ₃ ),3.32(d,J＝7.3Hz,2H,CH ₂ ),1.51(dd,J＝14.2,7.2Hz,2H,CH ₂ ),1.30–1.24(m,2H,CH ₂ ),0.87(t,J＝7.3Hz,3H,CH ₃ )； ¹³ C NMR(150MHz,DMSO-d ₆ ):δ166.71,160.25,157.80,147.56,142.00,140.13,133.47,130.29,129.46(2C),128.45(2C),127.34(2C),118.91(2C),118.89,112.76,112.09,55.55,53.15,52.39,48.89,32.16,20.42,14.35；MS(ESI)m/z:calcd.for C ₂₆ H ₃₀ N ₄ O ₃ [M+Cl] ^- :481.68,found:481.68。

Example 2Inhibition activity detection of HDAC6 by Compounds

The compounds described in example 1 were tested for HDAC6 inhibitory activity using 7-amino-4-methylcoumarin (AMC) fluorescence assay. Compared with the traditional ultraviolet analysis method, the method has higher sensitivity and smaller error. The detection principle is mainly divided into two steps: in the first step, a special peptide fluorogenic substrate (Boc-Lys (acetyl) -AMC) is used, which comprises an acetyl lysine residue and a fluorophore 7-amino-4-methylcoumarin (AMC), which is deacetylated by the action of an HDAC6 enzyme and a test compound, and which is activated after deacetylation to release the pancreatin hydrolysis substrate Boc-Lys-AMC. In the second step, boc-Lys-AMC is hydrolyzed by pancreatin to release the fluorophore 7-amino-4-methylcoumarin (AMC), and the fluorescence intensity of AMC is measured at 355nm/460nm of emission wavelength/excitation wavelength. Because of different inhibition effects of the compound, different numbers of fluorophores are generated, and therefore, the absorbance is different, and the inhibition rate of the compound on the HDAC6 enzyme can be obtained according to the absorbance.

(1) Preparation of Buffer (Buffer): 1 Xbuffer (containing 15mM Tris-HCl (pH 8.0), 250. Mu.M EDTA,250mM NaCl,10% glycerol) was prepared.

(2) Preparation of HDAC6 enzyme solution: the enzyme solution was diluted appropriately with 1 Xbuffer.

(3) Preparing a compound solution to be tested: about 2.0mg of the target compound and the positive control SAHA were dissolved in 100% DMSO of different volumes, and diluted with 1 Xbuffer, with a final DMSO ratio of 1%.

(4) Preparation of a fluorogenic substrate solution: stock solutions were dissolved in DMSO to make up 30mM, and diluted to 300. Mu.M with 1 Xbuffer.

(5) Pancreatin (Trypsin) solution: the pancreatin solution contained 10mg/mL pancreatin, 50mM Tris-HCl (pH 8.0), 100mM NaCl, 2. Mu.M TSA.

(6) And (3) adding 50 mu L of compound solution to be detected into a 384-well plate, setting 3 compound wells at each concentration, adding 50 mu L of buffer solution into a negative control group and a blank group respectively, then adding 10 mu L of prepared HDAC6 enzyme solution into an experimental group and a negative control group respectively, adding 10 mu L of buffer solution into the blank group, and shaking for 5min at a constant temperature of 37 ℃ after the addition, so that the compound and the HDAC6 are fully combined.

(7) mu.L of the prepared fluorogenic substrate solution was pipetted into each well and incubated at 37℃for 30min on a constant temperature shaker to allow the substrate to react well with HDAC 6.

(8) mu.L of prepared TSA stop solution containing pancreatin was pipetted into each well and shaken for 20min at 37 ℃.

(9) After the reaction, the intensity of the emitted light at a wavelength of 460nm was measured at an excitation wavelength of 355 nm.

(10) Experimental data processing: inhibition ratio = (negative control fluorescence value-experimental fluorescence value)/(negative control fluorescence value-blank fluorescence value) ×100%.

The results of the inhibition of HDAC6 enzyme by the compounds described in example 1 are shown in table 1 below:

TABLE 1

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Experimental results: the results in Table 1 show that at a concentration of 1. Mu.M, the inhibition ratios of the above-mentioned compounds to HDAC6 enzymes were all over 70% for XCY-A1, XCY-A2, XCY-A4, XCY-C1, XCY-C4, XCY-D5, XCY-D6, XCY-D7, XCY-D8, XCY-D11, indicating that the above-mentioned compounds have good enzyme inhibitory activities; furthermore, the inhibition rate of the compounds XCY-A2, XCY-A4, XCY-C2, XCY-C4, XCY-D5, XCY-D6, XCY-D8 and XCY-D11 exceeds 95 percent, which is equivalent to that of a positive drug SAHA.

Example 3Vasodilation Activity assay

Experimental principle: the ex vivo vascular ring assay is an assay that studies vasomotor function and uses this assay to detect the vasodilatory activity of a compound on blood vessels. With the continued development of experimental devices, 620M multichannel ex vivo vascular tensiometry systems (DMT corporation, denmark) are now in wide use. The detection principle is as follows: firstly, separating blood vessels, rapidly removing connective tissues and adipose tissues around the blood vessels, cutting into blood vessel rings with the length of 2-3mm, then penetrating the blood vessel rings through metal wires or tungsten wires and hanging the blood vessel rings in a tension bath, connecting a tension transducer and a computer, and measuring and recording the vasomotor activity of isolated blood vessels, wherein the blood vessel is commonly used for researching the functions of micro blood vessels such as rat mesenteric arteries, rat cerebral basilar arteries, mouse mesenteric arteries, mouse aorta, iliac arteries, carotid arteries, renal arteries and the like.

Experimental materials and instruments: male C57BL/6 mice for 4-6 weeks, phenylephrine (Phe, sigma-Aldrich), KCl, L-nitroarginine methyl ester (L-NAME, sigma-Aldrich), methylene blue (Sigma-Aldrich), dimethyl sulfoxide (DMSO, sigma-Aldrich), acetylcholine (Ach), test compounds, animal dissecting tables, surgical dissecting microscopes, 620M-type multichannel ex vivo vascular tensiometers, oxygen cylinders, micro-vacuum pumps, petri dishes, water baths, common animal surgical instruments, and the like.

The experimental method comprises the following steps:

(1) Taking 4-6 week old male C57BL/6 mice, killing by cervical dislocation, rapidly opening thoracic cavity, taking thoracic aorta, and filling 100% O ₂ Soaking in Krebs-Henseleit (K-H) solution (pH=7.4) pre-cooled at 4deg.C to maintain vascular activity and wash off blood stains. Micromanipulation removes perivascular connective tissue and adipose tissue. The K-H solution comprises the following components in percentage by weight: naCl 119.0, naHCO ₃ 25.0，MgCl ₂ 1.0，KCl 4.7，KH ₂ PO ₄ 1.2，CaCl ₂ 2.5，D-glucose 11.0。

(2) Each thoracic aorta can be cut into 4 vascular rings with the length of 2mm, a vascular ring specimen is connected with a DMT vascular tension measurement system through two thin steel wires, the vascular ring specimen is horizontally hung in a constant-temperature bath tank containing K-H liquid with the length of 5mL, and the change of vascular tension is recorded by using a Power Lab data acquisition and analysis system. The basal tension was adjusted to 3mN, equilibrated for 60min, and K-H solution was changed every 20min during this period, and the tension was maintained at 3mN. Throughout the experiment, the K-H solution in the bath was continuously fed with 100% O ₂ The temperature was controlled at 37.+ -. 0.5 ℃.

(3) After stabilization of vascular tension, the K-H solution in the bath was replaced with 60mM KCl (NaCl 63.7, naHCO) ₃ 25.0，MgCl ₂ 1.0，KCl 60.0，KH ₂ PO ₄ 1.2，CaCl ₂ 2.5, D-glucose 11.0), and the reactivity of blood vessels was examined. The high potassium caused the thoracic aorta to undergo a contractile response, which was maintained for 10min, then rinsed thoroughly (3 times at 10min intervals) to baseline, and after 30min the above experiment was repeated.

(4) After the front and back high potassium stimulation, the difference of the amplitude of the vasoconstriction is less than 10%, which indicates that the vasoactivity is good.

(5) The vascular ring was rebalanced for 30min with the vasoconstrictor Phe (1X 10) ^-6 M) causing vascular persistence to contract, and adding vasodilator Ach (1×10) ^-5 M), detecting the integrity of vascular endothelium. If the vasodilation amplitude of the blood vessel>60% of the total endothelium is considered to be intact and can be used for subsequent experiments.

(6) Separately with the receptor-dependent shrinking agent Phe (1X 10) ^-6 M) or a non-receptor dependent contractile agent KCl (60 mM) to pre-contract the complete vascular ring of the endothelium, and after the vascular tension reaches a stable platform, adding a compound to be tested dissolved in DMSO at an accumulated concentration, and calculating the vasodilation rate. An equal volume of DMSO was added as a control, depending on the time of addition of the test compound.

(7) Vasodilation rate (%) = (maximum systolic vascular ring tension induced by Phe or 60mM KCl-vascular ring tension after administration of the compound)/(maximum systolic vascular ring tension induced by Phe or 60mM KCl-vascular ring basal tension) ×100%.

Experimental results: FIG. 1 shows a partial compound exposure of 1X 10 in the aortic segment of mice ^-6 The alpha-adrenergic receptor agonist phenylephrine (Phe) at mol/L to induce a systolic vasodilatory activity result. Wherein XCY-A3, XCY-C1, XCY-D7, XCY-D8, XCY-D10 can effectively relax Phe-induced vasoconstriction in a concentration range of 3 mu M to 300 mu M. The maximum diastolic rate of XCY-A3 is 39.7%, the maximum diastolic rate of XCY-C1 is 11.2%, the maximum diastolic rate of XCY-D7 is 23.6%, the maximum diastolic rate of XCY-D8 is 21.61%, and the maximum diastolic rate of XCY-D10 is 36.83%.

FIG. 2 shows the results of vasodilatory activity of a fraction of compounds exposed to 60mM KCl in the aortic segment of mice to induce contraction. Wherein, XCY-A3, XCY-A4, XCY-C1, XCY-C2, XCY-C4, XCY-D10 and XCY-D13 can effectively relax the vasoconstriction induced by 60mM KCl in the concentration range of 3 mu M to 300 mu M. The maximum diastolic rate of XCY-A3 is 13.96%, the maximum diastolic rate of XCY-A4 is 16.01%, the maximum diastolic rate of XCY-C1 is 23.49%, the maximum diastolic rate of XCY-C2 is 22.35%, the maximum diastolic rate of XCY-C4 is 21.93%, the maximum diastolic rate of XCY-D10 is 72.49%, and the maximum diastolic rate of XCY-D13 is 60.26%.

Example 4Results of HIV latent Virus activation Activity of Compound XCY-D6

Experimental principle: this example establishes a J-Lat cell model for high throughput screening to initially evaluate the effect of compounds to activate HIV latent virus. J-Lat10.6 cells were GFP negative cells selected after infection of Jurkat cells with HIV-1 pseudovirus, and the GFP expression of the cells was rapidly increased after treatment with the latent activator. In this example, GFP expression was observed under a fluorescence microscope after 48 hours of treatment of cells with different compounds. The stronger the expression of GFP the higher the fluorescence intensity, indicating that the compound is a latent activator.

Experimental results: the results showed that GFP expression was up-regulated to varying degrees in GFP-positive J-Lat cells after XCY-D6 (1000 IU/ml), especially at 12. Mu.M concentration, indicating that the compound is a potential latent virus activator (FIG. 3).

Example 5Docking study of Compounds with HDAC6

Experimental principle: SYBYL is computer molecular simulation software developed by the American Tripos company, wherein a Surflex-Dock molecular docking module adopts a unique experience scoring function and a proprietary search engine (a search engine based on molecular similarity) to Dock ligand molecules to binding sites of proteins, belongs to a flexible docking technology, supports docking taking flexibility of biomacromolecule protein residues into consideration, is a main consideration factor for screening virtual activity of compounds, and can provide theoretical support and technical guidance for discovering novel HDAC6 target lead compounds and structural modification and modification thereof.

The experimental steps are as follows: 1) HDAC6 complex crystal structure 6CW8 was downloaded from the protein database. 2) Ligand optimization: ligand molecules were drawn in the docking software and further optimization was performed in the SYBYL ligand preparation module (ligand structure preparation). Firstly, hydrotreating ligand molecules; then, energy optimization is performed, and parameters are set as follows: the force field is set as a Tripos force field, the energy optimization calculation method is Powell, and the gradient isThe maximum number of iterations is 10000. 3) Receptor optimization: the 6CW8 was optimized at a SYBYL Surflex-Dock protein preparation module (prepare protein structure). Firstly, extracting the ligand in the complex crystal structure, and carrying out hydrotreatment on the protein. And then generating a prototype molecule, namely a docking pocket by taking the coordinates of the ligand molecules in the complex crystal structure as the center, and storing the file generated at present for the next molecular docking operation. 4) Ligand molecule docking with HDAC6 protein molecule: to examine the docking effect of the molecular docking software and to further determine the appropriate parameters for the HDAC6 inhibitor to Dock with the protein, the ligand molecule was docked back to the protein active pocket at the SYBYL Surflex-Dock module. Selecting a Surflex-Dock docking mode, introducing the receptor molecules and the ligand molecules after treatment, and setting docking parameters as follows: the maximum generated conformation (Max conformations per Fragment) of each fragment is 20, the maximum output conformation (Maximum Number of Poses per Ligand) of each ligand molecule is 20, and finally R between the docking conformations is preserved MSD value (Minimum RMSD Between Final Poses) is +.>To compare the difference between the docking conformation and the crystalline conformation, 6CW8 was set.

Analysis of results: as shown in FIG. 4, the ZBG region of the compound XCY-A2 is reacted with hydrated catalytic metal Zn ²⁺ Chelation, hydrogen bond interaction is formed between OH in ZBG region and amino acid residue H574, hydrogen bond interaction is formed between NH in Linker region amide group and key amino acid residue S531, cap region occupies surface recognition region, stable hydrophobic interaction is formed, which explains excellent HDAC6 inhibition activity of the compound to a certain extent.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound, characterized in that the compound has a structure represented by formula III or pharmaceutically acceptable salts, solvates and hydrates thereof;

wherein X, Y is selected from nitrogen or carbon, R ¹ Selected from hydrogen, methyl or hydroxymethyl; r is R ² Selected from the group consisting of-OH, -NH-NH ₂ 。

2. The compound of claim 1, wherein the pharmaceutically acceptable salt of the compound is a salt of the compound with an inorganic acid, which is hydrochloric acid, sulfuric acid, nitric acid, or hydrobromic acid, or an organic acid, which is methanesulfonic acid, toluenesulfonic acid, or trifluoroacetic acid.

3. The compound of claim 1, wherein the compound of formula III is specifically as follows:

methyl 4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) benzoate, code XCY-D1;

4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) benzoic acid, code XCY-D2;

4- (3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) -N-methylbenzamide, code XCY-D3;

1- (4- (hydrazinocarbonyl) phenyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea, code XCY-D4;

n-hydroxy-4- (2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetamido) benzamide, code XCY-D5;

n-hydroxy-4- (2- ((3 '-methoxy- [1,1' -biphenyl ] -4-yl)) amino) -2-oxoethyl) benzamide, code XCY-D6;

N ¹ -hydroxy-N ⁴ - (3 '-methoxy- [1,1' -biphenyl)]-4-yl) terephthalamide, code XCY-D7;

n-hydroxy-4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzamide, code XCY-D8;

4- ((1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid, code XCY-D9;

1- (4- (hydrazinocarbonyl) benzyl) -1- (4-hydroxybutyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea, code XCY-D10;

4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) -N-hydroxybenzoamide, code XCY-D11;

4- ((1-butyl-3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) ureido) methyl) benzoic acid, code XCY-D12;

1-butyl-1- (4- (hydrazinocarbonyl) benzyl) -3- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) urea, code XCY-D13.

4. A compound according to claim 3, wherein the compound of formula III is synthesized according to the following route:

the specific synthesis mode of the compound XCY-D5 is as follows:

3-Methoxyphenylboronic acid, 4-bromophenylacetic acid, ph (PPh) ₃ ) ₄ And K ₂ CO ₃ Dissolving in dioxane aqueous solution, carrying out reflux reaction for a period of time under the protection of inert gas to obtain a compound 12, dissolving the compound 12 in anhydrous dichloromethane, sequentially adding DCC, methyl 4-aminobenzoate and DMAP, stirring at room temperature to obtain a compound 13, dissolving the compound 13 in a mixed solution of dichloromethane and methanol, adding hydroxylamine hydrochloride and KOH, and stirring at room temperature under the protection of inert gas to obtain the compound XCY-D5;

the specific synthesis mode of the compound XCY-D1 is as follows:

3-Methoxyphenylboronic acid, 1-bromo-4-nitrobenzene, ph (PPh) ₃ ) ₄ And K ₂ CO ₃ Dissolving in dioxane aqueous solution, carrying out reflux reaction for a period of time under the protection of inert gas to obtain a compound 10, dissolving the compound 10, zinc powder and ammonium chloride in aqueous solution of tetrahydrofuran and ethanol, carrying out reflux reaction under the protection of inert gas to obtain a compound 11, dissolving the compound 11 and triethylamine in dichloromethane, and then adding a compound 6 to react for a period of time at room temperature to obtain the catalyst;

the specific synthesis modes of the compounds XCY-D2-D4 are as follows:

adding the compound XCY-D1 into alcohol or amine solutions with different R substituents, and carrying out reflux reaction for a period of time to obtain the compound;

the specific synthesis mode of the compound XCY-D6 is as follows:

reacting 2-naphthylacetic acid with a compound 2a for a period of time at room temperature under EDCI and DMAP conditions to obtain a compound 14a; dissolving a compound 14a in a mixed solution of dichloromethane and methanol, adding hydroxylamine hydrochloride and KOH, and reacting for a period of time under the protection of inert gas;

the specific synthesis mode of the compound XCY-D7 is as follows:

dissolving a compound 11 in an anhydrous dichloromethane solution, sequentially adding DCC, monomethyl terephthalate and DMAP, stirring at room temperature for reacting for a period of time to obtain a compound 14b, dissolving the compound 14b in a mixed solution of dichloromethane and methanol, adding hydroxylamine hydrochloride and KOH, and reacting at room temperature under the protection of inert gas for a period of time to obtain the compound;

under the ice bath condition, triphosgene is dissolved in ethyl acetate, and then an ethyl acetate solution of the compound 11 and triethylamine is slowly added dropwise for reaction at room temperature to obtain a compound 15; dissolving the compound 8 and triethylamine in dichloromethane, slowly dropwise adding a dichloromethane solution of the compound 15, and reacting at room temperature for a period of time to obtain a compound 16; dissolving a compound 16 in a mixed solution of dichloromethane and methanol, adding hydroxylamine hydrochloride and KOH, and stirring at room temperature under the protection of nitrogen to react to obtain the compound;

dissolving the compound 16 in methanol, and adding KOH for reaction to obtain the compound;

the specific synthesis modes of the compound XCY-D10 and the compound XCY-D113 are as follows:

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and optionally a pharmaceutical carrier;

the pharmaceutical composition is administered to a subject for the purpose of preventing, ameliorating or treating a disease; the subject is a mammal, such as a human, monkey, rabbit, dog, or mouse;

Or, the pharmaceutical composition also comprises a pharmaceutically necessary pharmaceutical carrier;

or, the dosage form of the pharmaceutical composition is a liquid dosage form or a solid dosage form; wherein the liquid dosage form is selected from true solutions, colloids, microparticles, emulsions, and suspensions; the solid dosage forms are selected from tablet, capsule, dripping pill, aerosol, pill, powder, emulsion, granule, suppository, lyophilized powder for injection, clathrate, landfill, patch, and liniment.

6. Use of a compound according to any one of claims 1 to 4, a pharmaceutical composition according to claim 5 as an HDAC inhibitor in the following manner:

(1) A model agent for preparing an HDAC inhibition model;

(2) For preventing, ameliorating or treating a disease associated with HDAC;

(3) For the preparation of a therapeutic agent for a disease associated with HDAC;

in the above (1), the model agent is used for preparing a disease model, including a cell, a tissue or an animal model;

in the above aspects (2) and (3), the HDAC-related disease means a disease in which HDAC is a therapeutic target, or abnormal high expression of HDAC occurs in disease characterization.

7. The use of a compound, pharmaceutical composition as claimed in claim 6 as an HDAC inhibitor, wherein the HDAC-related disease is lymphoma, triple negative breast cancer, non-small cell lung cancer, myeloma, colon cancer, prostate cancer, aids or hypertension.

8. A vasodilator or antihypertensive drug comprising a compound according to any one of claims 1 to 4 and a pharmaceutical composition according to claim 5.

9. Use of a compound, pharmaceutical composition according to any one of claims 1-4 as an HIV latent virus activator, wherein the compound is XCY-D6, including but not limited to any one of the following:

(1) For activating latent HIV virus to undergo transcription;

(2) For ameliorating or treating HIV virus-related diseases;

(3) Is used for preparing anti-AIDS medicines.

10. A medicament for the treatment of AIDS, characterized in that in the medicament, the compound XCY-D6 is as active ingredient;

the medicine comprises other active ingredients besides the compound XCY-D6, wherein the other active ingredients are antiviral medicines or immune activation medicines;

the antiviral drug is one or the combination of more than one of lamivudine, zidovudine, tenofovir or emtricitabine;

the immune activating medicine is one or a combination of several of BCG vaccine, interleukin-2, transfer factor, thymus peptide and levamisole.