Quinoline derivative histone deacetylase inhibitor as well as preparation method and application thereof

Abstract

The present invention relates to a histone deacetylase inhibitor, which is a compound represented by a formula I or a pharmaceutically acceptable salt and a stereoisomer thereof, and the compound of the present invention has good HDAC inhibitory activity. In-vitro anti-tumor cell proliferation experiments show that the inhibitory activity of a plurality of compounds on a plurality of tumor cells exceeds that of a positive control drug SAHA. Therefore, part of the compounds have good HDACs inhibitory activity and anti-tumor cell proliferation activity, and can be used for guiding discovery of novel and efficient histone deacetylase inhibitors and anti-tumor active molecules. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a quinoline derivative histone deacetylase inhibitor and a preparation method and application thereof, belonging to the technical field of medicine. Background Art

[0002] Acetylation and deacetylation of histones are crucial for the modification of chromatin structure and are one of the most widely studied epigenetic modifications. The acetylation state of histones is regulated by two groups of enzymes: histone deacetylases (HDACs) and histone acetyltransferases (HATs). Based on differences in cellular localization and homology, the 18 members of the human HDACs family can be divided into Zn 2+ Dependent Class I (HDAC1,2,3,8), Class IIa (HDAC4,5,7,9), Class IIb (HDAC6,10), Class IV (HDAC11) and NAD + Class III (SIRT1-7)-dependent. In addition, more and more non-histone proteins have also been confirmed as substrates of HDACs. These include proteins associated with transcription complexes, which have important effects on the regulation of gene expression, cell proliferation, migration, death and angiogenesis. In the occurrence and development of cancer, HDACs can promote cancer cell proliferation and invasion and migration, accelerate angiogenesis in cancer tissues, enhance cancer cell resistance to chemotherapeutic drugs, and inhibit cancer cell differentiation and apoptosis. Therefore, HDACs have become an important target in the current research field of anti-tumor drugs.

[0003] A large number of clinical trials and basic research have confirmed that most of the current HDACs inhibitors have poor therapeutic effects on various solid tumors, which has limited the clinical application of this type of drugs; structural biology studies have confirmed that the catalytic pockets of zinc-dependent HDACs are similar and highly conservative, so many HDACs inhibitors have poor selectivity, and inhibiting subtypes that are not related to tumors may produce certain toxic side effects. Therefore, the development of new histone deacetylase inhibitors is of great significance for the treatment of tumors. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a histone deacetylase inhibitor and a preparation method and application thereof.

[0005] The technical solution of the present invention is as follows:

[0006] 1. A histone deacetylase inhibitor

[0007] A histone deacetylase inhibitor is a compound shown in the following formula I or a pharmaceutically acceptable salt or stereoisomer thereof;

[0008]

[0009] Wherein, R1 is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, and the ring part of the aryl, aralkyl, alkaryl, benzyl or heterocyclic is substituted by any substituent;

[0010] R2 is independently selected from positive amines of 1 to 6 carbon atoms, wherein the nitrogen atom forms an amide with the carbonyl group in the parent nucleus;

[0011] The R3 substituent is located at the terminal carbon atom; R3 is selected from aryl, heteroaryl, aralkyl, heteroaralkyl or cycloalkyl substituted with N-hydroxycarboxamide or N-hydroxycinnamic amide, or aryl, heteroaryl, aralkyl or heteroaralkyl substituted with N-o-aminobenzoyl, wherein the aryl, heteroaryl, aralkyl, heteroaralkyl or cycloalkyl is substituted with any substituent, or isohydroxamic acid, or carboxyl.

[0012] According to the present invention, the preferred histone deacetylase inhibitor is:

[0013] Histone deacetylase inhibitors having a hydroxamic acid structure, histone deacetylase inhibitors having an N-hydroxycinnamic amide structure, histone deacetylase inhibitors having an N-hydroxybenzamide structure or an N-anthranilamide structure.

[0014] According to the present invention, preferably, the histone deacetylase inhibitor is selected from one of the following:

[0015] 4-(Benzyloxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide;

[0016] N-(6-(Hydroxyamino)-6-oxohexyl)-4-phenylethoxyquinoline-2-carboxamide;

[0017] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide;

[0018] 4-((4-(tert-butyl)benzyl)oxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide;

[0019] 4-((4-chlorobenzyl)oxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide;

[0020] N-(7-(Hydroxyamino)-7-oxoheptyl)-4-phenylethoxyquinoline-2-carboxamide;

[0021] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide;

[0022] N-(7-(Hydroxyamino)-7-oxoheptyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide;

[0023] (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide;

[0024] (E)-4-(Benzyloxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0025] (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0026] (E)-4-((4-chlorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0027] (E)-4-((4-fluorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0028] (E)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-((4-methoxybenzyl)oxy)quinoline-2-carboxamide;

[0029] (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carboxamide;

[0030] (E)-N-(3-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide;

[0031] (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0032] (E)-4-((4-chlorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0033] (E)-4-((4-fluorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide;

[0034] (E)-N-(3-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carboxamide;

[0035] (E)-N-(3-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide;

[0036] N-(4-(Hydroxycarbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide;

[0037] 4-(Benzyloxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide;

[0038] 4-((4-(tert-butyl)benzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide;

[0039] 4-((4-chlorobenzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide;

[0040] N-(4-(Hydroxycarbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide;

[0041] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide;

[0042] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(benzyloxy)quinoline-2-carboxamide;

[0043] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide;

[0044] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-(tert-butylbenzyl)oxy)quinoline-2-carboxamide;

[0045] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-chlorobenzyl)oxy)quinoline-2-carboxamide;

[0046] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-fluorobenzyl)oxy)quinoline-2-carboxamide;

[0047] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide;

[0048] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(((2-aminophenyl)carbamoyl)benzyl)quinoline-2-carboxamide;

[0049] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide.

[0050] The terms and definitions used in the present invention have the following meanings:

[0051] The alkyl group of the present invention refers to a straight-chain or branched alkyl group derived from an alkane containing 1 to 10 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylbutyl, pentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, nonyl and decyl;

[0052] The cycloalkyl group in the present invention refers to a cyclic alkyl group derived from an alkane having 3 to 8 carbon atoms by removing a hydrogen atom, such as cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. 4-7 Cycloalkyl, C 4-6 Cycloalkyl and C 5-6 Cycloalkyl;

[0053] Examples of monocyclic heterocyclic groups are: oxirane, dioxirane, thiirane, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, oxaziridine, oxetanyl, 1,2-dioxetanyl, thietanyl, 1,2-dithiol, azetidinyl, 1,2-diazetidine, azetidinyl, 1,2-diazetidine, azetidinyl, 1,2-diazetidine, furanyl, tetrahydrofuranyl, thienyl, 2,5-dihydrothienyl, tetrahydrothienyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolanyl, 1,3-dioxol-2-one, 1,2-dithiol cyclopentenyl, 1,3-dithiolanyl, imidazolyl, 4,5-dihydroimidazolyl, imidazolidinyl, pyrazolyl, 4,5-dihydropyrazolyl, pyrazolidinyl, oxazolyl, 4,5-dihydrooxazolyl, isoxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiazolyl, 4,5-dihydrothiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, 4H-pyran 4H-1,4-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl, morpholinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl, morpholinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl, morpholinyl, 2H-1, 3-thiazinyl, 4H-1,3-thiazinyl, 5,6-dihydro-4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-1,4-thiazinyl, 4H-1,4-thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, oxepinyl, thiepinyl, 1,4-dioxocetinyl, azacycloheptinyl, 1,2-diazacycloheptinyl, 1,3-diazacycloheptinyl, 1,4-diazacycloheptinyl, azacyclooctatetraenyl, 1,4-dihydro-1,4-diazacyclooctatetraenyl, etc.;

[0054] Aryl refers to a substituent containing an aromatic ring, such as phenyl or benzyl, which is optionally fused to a cycloalkyl group, the cycloalkyl group preferably having 4-7 ring atoms, more preferably 5-6 ring atoms. Preferred aryl groups contain 5-15 carbon atoms;

[0055] Heteroaryl is an aromatic heterocyclic ring, which may be a monocyclic or bicyclic group. They contain one or more heteroatoms, preferably 1-3 heteroatoms, even more preferably 1-2 heteroatoms, independently selected from O, S and N. "Arylalkyl" refers to an aryl group connected to a C1-C4 alkylene group;

[0056] Arylalkyl refers to an aryl group connected to a C1-C4 alkylene group;

[0057] Heteroaralkyl refers to a heteroaryl group linked to a C1-C4 alkylene group;

[0058] According to the present invention, preferably, the compound represented by formula I or its pharmaceutically acceptable salt or stereoisomer is:

[0059] The pharmaceutically acceptable salt is a salt prepared by mixing the compound represented by Formula I with an acid or a base;

[0060] Acid addition salts are formed with acids which form non-toxic salts and are acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, bicarbonate, butyrate, camphorate, camphorsulfonate, carbonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, isethionate, e), lactate, maleate, malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, sucrose salt, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, hydrogen phosphate, dihydrogen phosphate, p-toluenesulfonate, trifluoroacetate or undecanoate;

[0061] Base addition salts are obtained during the final isolation and purification of the compounds by reacting the carboxylic acid-containing moiety with a base or with ammonia or an organic primary, secondary or tertiary amine. Base addition salts are based on cations of alkali metals or alkaline earth metals, non-toxic quaternary ammonium and amine cations, organic amines for the formation of base addition salts.

[0062] Preferably according to the present invention, the compound represented by formula I or a pharmaceutically acceptable salt or stereoisomer thereof, the stereoisomer is in the form of a stereoisomer of the compound represented by formula I or a physiological derivative thereof.

[0063] Unless otherwise specified, the chemical names of the compounds involved in the present invention include mixtures of all possible stereochemical forms, and the mixtures contain all enantiomers and diastereomers of the basic structural molecules, as well as substantially pure single isomer forms of the compounds, i.e., containing less than 10%, preferably less than 5%, especially less than 2%, and most preferably less than 1% of other isomers. Various stereoisomer forms of the peptidic compounds of the present invention are obviously included in the scope of the present invention;

[0064] The compound represented by Formula I may also exist in other protected forms or derivative forms, which are obvious to those skilled in the art and should be included in the scope of the present invention;

[0065] The substituents of the present invention may themselves be substituted with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979); substituents are selected from alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, aminoalkyl, cyano, halogen, carboxyl, thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

[0066] 2. Preparation method of histone deacetylase inhibitors with hydroxamic acid structure

[0067] The synthetic route is as follows:

[0068]

[0069] R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring part of the aryl, aralkyl, alkaryl, benzyl or heterocyclic is substituted by any substituent, and n=5 or 6;

[0070] (a) Aniline was dissolved in methanol, and dimethyl butynedioate was added dropwise at 0°C. The reaction solution was then heated to 80°C and refluxed for 8 hours. The solvent was removed by vortexing and purified by column chromatography to obtain a pure light yellow oily intermediate 2.

[0071] (b) Mix the light yellow oily intermediate 2 with polyphosphoric acid, slowly heat to 120° C., maintain the temperature for 2-3 hours, dissolve with 10% potassium carbonate solution until bubbles are no longer generated, filter, wash with water, and dry to obtain intermediate 3;

[0072] (c) Intermediate 3 is substituted with benzyl bromide, methyl iodide or 2-chlorohexylbenzene by K2CO3 in DMF to obtain intermediate 4;

[0073] (d) intermediate 4 and lithium hydroxide react in a mixed solution of tetrahydrofuran and water to obtain intermediate 5;

[0074] (e) intermediate 5 and 6-aminohexanoic acid hydrochloride or 7-aminoheptanoic acid hydrochloride are dissolved, HATU is dissolved in DMF, NMM is added, and the reaction is carried out at room temperature to obtain intermediate 6;

[0075] (f) Intermediate 6 is reacted with hydroxylamine methanol solution at room temperature to obtain the final product.

[0076] The specific operation steps will be described in detail in the examples. Those skilled in the art can change the above steps to increase the yield, design the synthesis route according to the basic knowledge in the art, such as selecting reactants, reaction solvents, reaction temperature, and can also use various protecting groups to avoid the occurrence of side reactions to improve the yield, see for example T. Green Protecting Groups in Organic Synthesis.

[0077] 3. Preparation method of histone deacetylase inhibitors with N-hydroxycinnamic acid structure

[0078]

[0079] wherein R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring portion of the aryl, aralkyl, alkaryl, benzyl or heterocyclic ring may be substituted with any substituent;

[0080] Reagents and conditions: (a) triethylamine, di-tert-butyl dicarbonate, reaction at room temperature for 8 hours; (b) methyl acrylate, triethylamine, tetrakistriphenylphosphine palladium, 130°C, 12 hours; (c) saturated solution of hydrogen chloride in ethyl acetate, room temperature; (d) compound 5, HATU, NMM, DMF, room temperature, 8 hours; (e) hydroxylamine hydrochloride, KOH, methanol, room temperature, overnight.

[0081] The specific operation steps will be described in detail in the examples. Those skilled in the art can change the above steps to increase the yield. They can design the synthesis route according to the basic knowledge in the art, such as selecting reactants, reaction solvents, reaction temperature, and can also use various protecting groups to avoid the occurrence of side reactions to improve the yield. These conventional protection methods can be found in, for example, T. Green Protecting Groups in Organic Synthesis.

[0082] 4. A method for preparing a histone deacetylase inhibitor having an N-hydroxybenzamide structure or an N-anthranilyl group, comprising the steps of:

[0083]

[0084] wherein R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring portion of the aryl, aralkyl, alkaryl, benzyl or heterocyclic ring may be substituted with any substituent;

[0085] Reagents and conditions: (a) Compound 5, HATU, NMM, DMF, room temperature, 8 h; (b) Hydroxylamine hydrochloride, KOH, methanol, room temperature, overnight; (c) LiOH, H2O / THF, room temperature; (d) o-phenylenediamine, HATU, NMM, DMF, room temperature, 8 h.

[0086] The specific operation steps will be described in detail in the examples. Those skilled in the art can change the above steps to increase the yield. They can design the synthesis route according to the basic knowledge in the art, such as selecting reactants, reaction solvents, reaction temperature, and can also use various protecting groups to avoid the occurrence of side reactions to improve the yield. These conventional protection methods can be found in, for example, T. Green Protecting Groups in Organic Synthesis.

[0087] The compounds of the present invention can be made into any pharmaceutical preparations by methods known in the art, and administered to patients who need such treatment by oral, parenteral, rectal or transpulmonary administration. When used for oral administration, conventional solid preparations such as tablets, capsules, pills, granules, etc. can be made, and oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. can also be made. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, injections can be made, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives may not be added, or suitable additives may be added according to the properties of the drug. When used for rectal administration, suppositories can be made, etc. When used for transpulmonary administration, inhalers or sprays can be made, etc.;

[0088] The dosage and frequency of administration of the compounds of the present invention can be adjusted according to the judgment of the clinician or pharmacist, taking into account factors such as the following: the age, health and size of the patient, and the severity of the symptoms to be treated. In general, the total daily dosage range of the compounds of the present invention is from about 0.1 to about 2000 mg per day, although there will be changes if necessary, depending on the purpose of treatment, the patient and the route of administration. In one embodiment, the dosage is from about 1 to about 200 mg / day, administered in a single dose or in 2-4 separated doses. In another embodiment, the dosage is from about 10 to about 2000 mg / day, administered in a single dose or in 2-4 separated doses. In another embodiment, the dosage is from about 100 to about 2000 mg / day, administered in a single dose or in 2-4 separated doses. In another embodiment, the dosage is from about 500 to about 2000 mg / day, administered in a single dose or in 2-4 separated doses. When the compound of the present invention, its pharmaceutically acceptable salt, ester or solvate or their prodrug or isomer is used in combination with other therapeutically active substances, they are administered simultaneously, separately or sequentially to prepare a pharmaceutical composition of a single administration method. The dosage of the other therapeutically active substances used in combination can be based on the amount used clinically, and can be appropriately selected according to the subject of administration, route of administration, disease, combination, etc. There is no particular restriction on the administration form of other therapeutically active substances, as long as the compound of the present invention and other therapeutically active substances are combined when administered.

[0089] A "pharmaceutical composition" refers to a preparation containing a therapeutically significant amount of an active pharmaceutical agent, which is prepared in a form suitable for administration to a patient. Thus, the preparation does not contain any one or more components in such an amount that a reasonably careful medical practitioner would find the preparation unsuitable for administration to an ordinary subject. In many cases, such a pharmaceutical composition is a sterile preparation.

[0090] The room temperature involved in the present invention is in the range of 20-30°C.

[0091] 5. Application of histone deacetylase inhibitors

[0092] The present invention also provides the use of the compound represented by formula I or its pharmaceutically acceptable salt or stereoisomer in the preparation of drugs for preventing or treating related mammalian diseases caused by abnormal expression or dysfunction of histone deacetylase, wherein the diseases include but are not limited to cancer, neurodegenerative diseases, inflammation, viral infection, diabetes, and malaria.

[0093] In addition, the present invention also includes a pharmaceutical composition suitable for oral administration to mammals, comprising the compound represented by the above formula I or a pharmaceutically acceptable salt, stereoisomer thereof, a pharmaceutically acceptable carrier, and optionally one or more pharmaceutically acceptable excipients.

[0094] In addition, the present invention also includes a pharmaceutical composition suitable for parenteral administration to mammals, comprising the compound represented by the above formula I or a pharmaceutically acceptable salt, stereoisomer thereof, a pharmaceutically acceptable carrier, and optionally one or more pharmaceutically acceptable excipients.

[0095] The enzyme inhibition activity and cell activity tests were performed to evaluate the biological activity of the compounds in vitro.

[0096] Fluorescence analysis was used to evaluate the inhibitory activity of compounds against histone deacetylase. When evaluating the inhibitory activity of compounds against HDAC deacetylases in vitro, the HDAC fluorescent substrate (containing an acetylated lysine side chain - Boc-Lys (acetyl) -AMC) was incubated with a sample containing HDAC activity (Hela cell nuclear extract) to deacetylate and activate the substrate. Boc-Lys-AMC was then hydrolyzed with trypsin to produce AMC fluorophore, and the fluorescence intensity was measured at the emission wavelength / excitation wavelength (390nm / 460nm). The fluorescence intensity is proportional to the HDACs inhibitory effect of the test compound. The data was processed using Prism GraphPad software to calculate the inhibition rate and IC of different target compounds against HDACs. 50 value.

[0097] The cell activity test of the compound used the MTT assay. The tumor cell suspension was inoculated in a 96-well plate, and different concentrations of the compound diluted with culture medium were added to each well. After incubation for 48 hours, the compound was stained with MTT. After incubation for another 4 hours, the absorbance OD value of each well was measured at 490 / 570 nm using an ELISA reader, and then the inhibition rate and IC were calculated. 50 The antiproliferative activity of the target compound was determined.

[0098] The results of the in vitro enzyme inhibition experiment show that the compounds of the present invention have good HDAC inhibitory activity. The in vitro anti-tumor cell proliferation experiment shows that the inhibitory activity of multiple compounds on multiple tumor cells exceeds that of the positive control drug SAHA. It can be seen that some of the compounds in the present invention have good HDACs inhibitory activity and anti-tumor cell proliferation activity, have great development prospects, and can be used to guide the discovery of new and efficient histone deacetylase inhibitors and anti-tumor active molecules. DETAILED DESCRIPTION

[0099] The present invention will be further described below with reference to the embodiments, but is not limited thereto.

[0100] Example 1

[0101] 2-(Phenylamino) dimethyl fumarate (2)

[0102] Dimethyl 2-(phenylamino)fumarate(2)

[0103] Aniline (20 g, 215 mmol) was dissolved in 40 mL of methanol, and dimethyl butynedioate (30.54 g, 215 mmol) was added dropwise at 0°C. Subsequently, the reaction solution was heated to 80°C and refluxed for 8 hours. The solvent was removed by vortexing to obtain a yellow oily product, which was purified by column chromatography (petroleum ether: ethyl acetate = 99:1) after being scavenged with silica gel to obtain a pure light yellow oily intermediate 2 with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),7.31(t,J=7.1Hz,2H),7.08(t,J=7.1Hz,1H),6.96(d,J=7.6Hz,2H),5.32(s,1H),3.67(s,6H).

[0104] 4-Hydroxyquinoline-2-carboxylic acid methyl ester (3)

[0105] Methyl 4-hydroxyquinoline-2-carboxylate(3)

[0106] 30g of intermediate 2 and 100g of polyphosphoric acid were mixed with mechanical stirring, slowly heated to 120°C, and the temperature was maintained for 2h after the reaction liquid gradually turned red. Subsequently, 10% potassium carbonate solution was slowly added dropwise to the reaction liquid until all the viscous liquid was dissolved and no more bubbles were generated. The suspension was filtered, the filter cake was washed with a small amount of water, and dried to obtain intermediate 3 with a yield of 75%. Brown powder, melting point: 224-226°C. 1H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.08(d,J=8.0Hz,1H),7.95(d,J=8.4Hz ,1H),7.72(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),6.63(s,1H),3.97(s,3H).

[0107] 4-Methoxyquinoline-2-carboxylic acid methyl ester (4a)

[0108] Methyl 4-methoxyquinoline-2-carboxylate(4a)

[0109] Intermediate 3 (2 g, 10 mmol), iodomethane (1.68 g, 11 mmol), potassium carbonate (4.08 g, 30 mmol) were dissolved in 50 mL DMF and heated to 70 °C for 8 h. After cooling to room temperature naturally, water was added to quench the reaction, and the solid was separated by filtration. The filter cake was washed with a small amount of water and dried to obtain 4a. Yield: 74%, brown powder, melting point: 224-226 °C. 1 H NMR (400MHz, DMSO-d6) δ8.23–8.17(m,1H),8.10(d,J=8.4Hz,1H),7.86(ddd,J=8.4, 6.8,1.5Hz,1H),7.72–7.68(m,1H),7.56(d,J=2.1Hz,1H),4.13(s,3H),3.96(s,3H).

[0110] 4-Ethoxyquinoline-2-carboxylic acid methyl ester (4b)

[0111] Methyl 4-ethoxyquinoline-2-carboxylate(4b)

[0112] Intermediate 3 (2 g, 10 mmol), ethyl bromide (1.09 g, 10 mmol), potassium carbonate (4.08 g, 30 mmol) were dissolved in 50 mL DMF and heated to 70 °C for 8 h. After cooling to room temperature naturally, water was added to quench the reaction, extracted with ethyl acetate, and the organic layer was washed once with water and saturated brine, dried over anhydrous magnesium sulfate, and spin-dried to obtain compound 4b. Yield: 65%, brown oil. 1H NMR (400MHz, DMSO-d6) δ8.21(d,J=8.4Hz,1H),8.09(d,J=8.3Hz,1H),7.84(d,J=7.9Hz,1H),7 .70(s,1H),7.52(d,J=2.1Hz,1H),4.41(d,J=6.8Hz,2H),3.95(s,3H),1.51(t,J=6.9Hz,3H).

[0113] 4-(Benzyloxy)quinoline-2-carboxylic acid methyl ester (4c)

[0114] Methyl 4-(benzyloxy)quinoline-2-carboxylate(4c)

[0115] The synthesis and purification methods are the same as 4b, except that the substrate is different. Yield: 68%, brown oil. 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.4Hz,1H),8.11(d,J=8.5Hz,1H),7.87(t,J=7.7Hz,1H ),7.74–7.68(m,2H),7.59(d,J=7.6Hz,2H),7.48–7.44(m,2H),5.51(s,2H),3.96(s,3H).

[0116] 4-((4-Bromobenzyl)oxy)quinoline-2-carboxylic acid methyl ester (4d)

[0117] Methyl 4-((4-bromobenzyl)oxy)quinoline-2-carboxylate(4d)

[0118] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 70%, white solid, melting point: 180-182°C. 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=8.4Hz,1H),8.11(d,J=8.5Hz,1H),7.87(t, J=7.8Hz,1H),7.74–7.65(m,4H),7.58–7.53(m,2H),5.49(s,2H),3.96(s,3H).

[0119] 4-((3-bromobenzyl)oxy)quinoline-2-carboxylic acid methyl ester (4e)

[0120] Methyl 4-((3-bromobenzyl)oxy)quinoline-2-carboxylate(4e)

[0121] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 72%, white solid, melting point: 176-178°C. 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.4Hz,1H),8.12(d,J=8.5Hz,1H),7.87(t,J=7.6Hz,1H),7.83–7.78(m,1H),7.72( t,J=7.7Hz,1H),7.67(d,J=1.8Hz,1H),7.61(t,J=6.4Hz,2H),7.43(td,J=7.9,1.8Hz,1H),5.51(s,2H),3.96(s,3H).

[0122] 4-((4-(tert-Butyl)benzyl)oxy)quinoline-2-carboxylic acid methyl ester (4f)

[0123] Methyl 4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxylate(4f)

[0124] The synthesis and purification methods are the same as 4b, except that the substrate is different. Yield: 65%, black oil. 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=8.4Hz,1H),8.11(d,J=8.6Hz,2H),7.86(t,J=7.6Hz,1 H),7.71(t,J=4.6Hz,2H),7.49(d,J=1.8Hz,3H),5.46(s,2H),3.96(s,3H),1.31(s,9H).

[0125] 4-((4-Chlorobenzyl)oxy)quinoline-2-carboxylic acid methyl ester (4 g)

[0126] Methyl 4-((4-chlorobenzyl)oxy)quinoline-2-carboxylate(4g)

[0127] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 68%, white solid, melting point: 220-222°C. 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=8.4Hz,1H),8.23(d,J=8.6Hz,1H),7.96(t,J=7.8H z,1H),7.84–7.73(m,2H),7.72–7.61(m,2H),7.54(s,2H),5.59(s,2H),3.96(s,3H).

[0128] 4-((4-Fluorobenzyl)oxy)quinoline-2-carboxylic acid methyl ester (4h)

[0129] Methyl 4-((4-fluorobenzyl)oxy)quinoline-2-carboxylate(4h)

[0130] The synthesis and purification methods are the same as 4b, except that the substrate is different. Yield: 68%, brown oil. 1 H NMR(400MHz, DMSO-d6)δ8.16(dd,J=8.4,1.4Hz,1H),7.87(d,J=8.4Hz,1H),7.80–7.71(m,2H),7. 70–7.62(m,2H),7.57(ddd,J=8.2,6.8,1.2Hz,1H),7.37–7.25(m,2H),5.46(s,2H),3.96(s,3H).

[0131] 4-((4-methoxybenzyl)oxy)quinoline-2-carboxylic acid methyl ester (4i)

[0132] Methyl 4-((4-methoxybenzyl)oxy)quinoline-2-carboxylate(4i)

[0133] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 75%, white solid, melting point: 190-192°C. 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=8.3Hz,1H),8.11–8.05(m,2H),7.66(dd,J=1 3.8, 6.7Hz, 2H), 7.50 (s, 2H), 7.00 (s, 2H), 5.29 (s, 2H), 3.78 (d, J = 2.2Hz, 6H).

[0134] 4-Phenylethoxyquinoline-2-carboxylic acid methyl ester (4j)

[0135] Methyl 4-phenethoxyquinoline-2-carboxylate(4j)

[0136] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 74%, white solid, melting point: 170-172°C. 1H NMR (400MHz, DMSO-d6) δ8.14(d,J=8.4Hz,1H),8.08(d,J=8.5Hz,1H),7.84(t,J=7.7Hz,1H),7.69(t,J=7.7Hz,1H),7.55(d,J=1 .9Hz,1H),7.43(d,J=7.5Hz,2H),7.38–7.31(m,2H),7.27–7.21(m,1H),4.56(t,J=6.5Hz,2H),3.94(s,3H),3.28–3.19(m,2H).

[0137] 4-([1,1'-Biphenyl]-4-ylmethoxy)quinoline-2-carboxylic acid methyl ester (4k)

[0138] Methyl 4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxylate(4k)

[0139] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 58%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=8.4,1.4Hz,1H),8.12(d,J=8.5Hz,1H),7.88(ddd,J=8.4,6.8,1.5Hz,2 H),7.75–7.68(m,7H),7.51–7.47(m,2H),7.39(dd,J=5.9,3.8Hz,1H),5.57(d,J=7.9Hz,2H),3.96(s,3H).

[0140] 4-(Naphthalen-1-ylmethoxy)quinoline-2-carboxylic acid methyl ester (4l)

[0141] Methyl 4-(naphthalen-1-ylmethoxy)quinoline-2-carboxylate(4l)

[0142] The synthesis and purification methods are the same as 4b, except that the substrate is different. Yield: 60%, yellow oil. 1 H NMR(400MHz, DMSO-d6)δ8.24–8.19(m,1H),8.12(dd,J=8.4,3.3Hz,2H),8.02(t,J=7.1Hz,2H),7.9 1(s,1H),7.84(t,J=7.6Hz,2H),7.63(dd,J=24.0,7.7Hz,4H),5.97(s,2H),3.98(d,J=1.6Hz,3H).

[0143] 4-(2-(Naphthalen-1-yloxy)ethoxy)quinoline-2-carboxylic acid methyl ester (4m)

[0144] Methyl 4-(2-(naphthalen-1-yloxy)ethoxy)quinoline-2-carboxylate(4m)

[0145] The synthesis and purification methods are the same as 4a, except that the substrate is different, yield: 60%, light yellow solid, melting point: 194-196°C. 1 H NMR (400MHz, DMSO-d6) δ8.20–8.09(m,4H),7.86(t,J=7.7Hz,2H),7.76(d,J=6.2Hz,1H),7.66(t,J=7.6Hz,1H) ,7.50(q,J=8.6,7.9Hz,4H),7.13(d,J=7.8Hz,1H),4.93–4.87(m,2H),4.69(q,J=8.5,6.3Hz,2H),3.98(s,3H).

[0146] 4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)quinoline-2-carboxylic acid methyl ester (4n)

[0147] Methyl 4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)quinoline-2-carboxylate(4n)

[0148] The synthesis and purification methods are the same as 4b, except that the substrate is different. Yield: 55%, brown oil. 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=12.7,8.5Hz,2H),7.85(t,J=7.7Hz,1H),7.68(t,J=7.8Hz,1H),7. 62(d,J=2.1Hz,1H),6.90(s,2H),4.69(t,J=4.8Hz,2H),4.53–4.45(m,2H),3.96(s,3H),2.30(s,6H).

[0149] 4-Methoxyquinoline-2-carboxylic acid (5a)

[0150] 4-methoxyquinoline-2-carboxylic acid(5a)

[0151] Intermediate 4a (1.5 g, 6.91 mmol) and lithium hydroxide (0.83 g, 34.53 mmol) were dissolved in 80 mL of tetrahydrofuran / water (2 / 1) solution and stirred at room temperature for 12 h. After the reaction was completed, tetrahydrofuran was removed by vortexing, the pH was adjusted to neutral with 2M hydrochloric acid, the precipitate was separated by filtration, the filter cake was washed with a small amount of water, dried, slurried with ethyl acetate, filtered, and dried to obtain product 5a. Yield: 85%, white solid, melting point: >300°C. 1 H NMR(400MHz, DMSO-d6)δ8.14(dd,J=8.4,1.4Hz,1H),7.91(d,J=8.4Hz,1H),7.76(ddd ,J=8.5,6.8,1.4Hz,1H),7.66(s,1H),7.58(ddd,J=8.1,6.8,1.2Hz,1H),4.11(s,3H).

[0152] 4-Ethoxyquinoline-2-carboxylic acid (5b)

[0153] 4-ethoxyquinoline-2-carboxylic acid(5b)

[0154] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 80%, yellow-white solid, melting point: 104-106°C. 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.4Hz,1H),7.87(d,J=8.4Hz,1H),7.77(t,J=7.7 Hz,1H),7.60(p,J=9.5,7.5Hz,2H),4.47–4.35(m,2H),1.50(td,J=7.0,2.0Hz,3H).

[0155] 4-(Benzyloxy)quinoline-2-carboxylic acid (5c)

[0156] 4-(benzyloxy)quinoline-2-carboxylic acid(5c)

[0157] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 75%, white solid, melting point: 272-274°C. 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=8.4Hz,1H),8.15(d,J=8.5Hz,1H),7.89(t,J=7.7Hz,1 H),7.81–7.67(m,2H),7.60(d,J=7.5Hz,2H),7.43(dt,J=26.5,7.4Hz,3H),5.53(s,2H).

[0158] 4-((4-Bromobenzyl)oxy)quinoline-2-carboxylic acid (5d)

[0159] 4-((4-bromobenzyl)oxy)quinoline-2-carboxylic acid(5d)

[0160] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 72%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),9.20(s,1H),8.23(d,J=8.3Hz,1H),8.04(d,J=8.4Hz ,1H),7.84(q,J=6.9,6.3Hz,1H),7.66(q,J=6.6Hz,4H),7.56(d,J=8.0Hz,2H),5.49(s,2H).

[0161] 4-((3-Bromobenzyl)oxy)quinoline-2-carboxylic acid (5e)

[0162] 4-((3-bromobenzyl)oxy)quinoline-2-carboxylic acid(5e)

[0163] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 78%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.13(s,1H),7.76(d,J=19.2Hz,2H),7.58(d,J=7.0Hz,5H),7.42(d,J=8.6Hz,1H),5.44(s,2H).

[0164] 4-((4-(tert-Butyl)benzyl)oxy)quinoline-2-carboxylic acid (5f)

[0165] 4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxylic acid(5f)

[0166] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 64%, brown solid, melting point: 286-288°C. 1H NMR (400MHz, DMSO-d6) δ8.26(d,J=8.4Hz,1H),8.19(d,J=8.5Hz,1H),7.92(t,J=7 .7Hz,1H),7.75(d,J=7.9Hz,2H),7.50(q,J=8.1Hz,4H),5.52(s,2H),1.31(s,9H).

[0167] 4-((4-Chlorobenzyl)oxy)quinoline-2-carboxylic acid (5 g)

[0168] 4-((4-chlorobenzyl)oxy)quinoline-2-carboxylic acid(5g)

[0169] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 70%, white solid, melting point: 254-256°C. 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=8.4Hz,1H),8.23(d,J=8.6Hz,1H),7.96(t,J=7.8Hz ,1H),7.84–7.73(m,2H),7.72–7.61(m,2H),7.54(dd,J=8.4,1.8Hz,2H),5.59(s,2H).

[0170] 4-((4-Fluorobenzyl)oxy)quinoline-2-carboxylic acid (5h)

[0171] 4-((4-fluorobenzyl)oxy)quinoline-2-carboxylic acid(5h)

[0172] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 78%, white solid, melting point: 272-274°C. 1 H NMR(400MHz, DMSO-d6)δ8.16(dd,J=8.4,1.4Hz,1H),7.87(d,J=8.4Hz,1H),7.80–7.71(m, 2H),7.70–7.62(m,2H),7.57(ddd,J=8.2,6.8,1.2Hz,1H),7.37–7.25(m,2H),5.46(s,2H).

[0173] 4-((4-Methoxybenzyl)oxy)quinoline-2-carboxylic acid (5i)

[0174] 4-((4-methoxybenzyl)oxy)quinoline-2-carboxylic acid(5i)

[0175] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 78%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=8.6Hz,1H),7.67(t,J=7.8Hz,1H),7.56–7.41(m,4H),6.99(d,J=8.3Hz,2H),5.28(s,2H),3.78(s,3H).

[0176] 4-Phenylethylquinoline-2-carboxylic acid (5j)

[0177] 4-phenethoxyquinoline-2-carboxylic acid(5j)

[0178] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 65%, white solid, melting point: 236-238°C. 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=8.3Hz,1H),7.86(d,J=8.5Hz,1H),7.75(t,J=7.7Hz,1H),7.62(s,1H),7.56(t,J=7.7H z,1H),7.43(d,J=7.5Hz,2H),7.33(t,J=7.5Hz,2H),7.23(t,J=7.5Hz,1H),4.54(t,J=6.7Hz,2H),3.22(t,J=6.6Hz,2H).

[0179] 4-([1,1'-Biphenyl]-4-ylmethoxy)quinoline-2-carboxylic acid (5k)

[0180] 4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxylic acid(5k)

[0181] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 60%, white solid, melting point: >300℃. 1 H NMR(400MHz, DMSO-d6)δ8.21(d,J=8.1Hz,1H),7.91(d,J=8.3Hz,1H),7.79–7.72(m,4H),7.6 9(d,J=3.2Hz,2H),7.65–7.58(m,2H),7.49(t,J=7.6Hz,2H),7.43–7.33(m,2H),5.53(s,2H).

[0182] 4-(Naphthalen-1-ylmethoxy)quinoline-2-carboxylic acid (5l)

[0183] 4-(naphthalen-1-ylmethoxy)quinoline-2-carboxylic acid(5l)

[0184] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 80%, white solid, melting point: >300℃. 1 H NMR(400MHz, DMSO-d6)δ8.20(dd,J=8.3,4.3Hz,1H),8.08(d,J=8.4Hz,1H),8.01(t ,J=7.8Hz,3H),7.94(s,1H),7.85–7.73(m,2H),7.58(t,J=8.2Hz,4H),5.95(s,2H).

[0185] 4-(2-(Naphthalen-1-yloxy)ethoxy)quinoline-2-carboxylic acid (5m)

[0186] 4-(2-(naphthalen-1-yloxy)ethoxy)quinoline-2-carboxylic acid(5m)

[0187] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 50%, yellow-white solid, melting point: 160-162°C. 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.4Hz,1H),8.12(d,J=8.3Hz,1H),7.91–7.84(m,2H),7.80(s,1H),7.74(t, J=7.6Hz,1H),7.47(tdd,J=19.3,9.2,7.0Hz,6H),7.13(d,J=7.4Hz,1H),4.92–4.81(m,2H),4.74–4.65(m,2H).

[0188] 4-(2-(4-Chloro-3,5-dimethylphenoxy)ethoxy)quinoline-2-carboxylic acid (5n)

[0189] 4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)quinoline-2-carboxylic acid(5n)

[0190] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 55%, yellow-white solid, melting point: 196-198°C.1 H NMR(400MHz,DMSO-d6)δ8.20(dd,J=12.8,8.5Hz,2H),7.99–7.90(m,1H),7.84–7.7 0(m,2H),6.91(s,2H),4.85–4.68(m,2H),4.52(dd,J=5.8,2.8Hz,2H),2.30(s,6H).

[0191] 6-(4-(Benzyloxy)quinoline-2-carboxamido)hexanoic acid methyl ester (6a)

[0192] Methyl 6-(4-(benzyloxy)quinoline-2-carboxamido)hexanoate(6a)

[0193] Under ice bath, 5c (0.28 g, 1 mmol), 6-aminohexanoic acid methyl ester hydrochloride (0.18 g, 1 mmol) and HATU (0.46 g, 1.2 mmol) were dissolved in DMF. NMM (0.35 ml, 3 mmol) was added. The mixture was stirred for 8 hours under nitrogen protection, poured into water, and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with 5% citric acid, saturated NaHCO3 solution and saturated brine. After drying over anhydrous MgSO4, the crude product was filtered and evaporated to dryness. The product 6a was obtained by recrystallization from ethyl acetate. Yield: 79%, light yellow solid, melting point: 254-256°C. 1 H NMR(400MHz, DMSO-d6)δ8.90(t,J=6.2Hz,1H),8.24(dd,J=8.5,1.4Hz,1H),8.08( d,J=8.4Hz,1H),7.85(ddd,J=8.5,6.8,1.5Hz,1H),7.72(s,1H),7.67(ddd,J=8.2 ,6.9,1.2Hz,1H),7.62–7.57(m,2H),7.49–7.44(m,2H),7.42–7.37(m,1H),5.51( s,2H),3.57(s,3H),2.32(t,J=7.4Hz,2H),1.61–1.54(m,4H),1.45–1.12(m,4H).

[0194] 6-(4-Phenylethoxyquinoline-2-carboxamido)hexanoic acid methyl ester (6b)

[0195] Methyl 6-(4-phenethoxyquinoline-2-carboxamido)hexanoate(6b)

[0196] The synthesis method is the same as 6a, except that the substrate is different and the purification method is recrystallization from anhydrous ethanol. Yield: 65%, white solid, melting point: 156-158°C. 1 H NMR(400MHz,DMSO-d6)δ8.86(t,J=6.2Hz,1H),8.13(dd,J=8.4,1.4Hz,1H),8.04(d,J =8.4Hz,1H),7.82(ddd,J=8.4,6.8,1.5Hz,1H),7.68–7.59(m,2H),7.47–7.40(m,2H), 7.34(t,J=7.5Hz,2H),7.29–7.20(m,1H),4.57(t,J=6.4Hz,2H),3.57(s,3H),3.22(t ,J=6.3Hz,2H),2.31(t,J=7.4Hz,2H),1.57(pd,J=7.5,2.3Hz,4H),1.52–1.11(m,4H).

[0197] 6-(4-([[1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)hexanoic acid methyl ester (6c)

[0198] Methyl 6-(4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)hexanoate(6c)

[0199] The synthesis method is the same as 6a, except that the substrate is different and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 10:1). Yield: 62%, light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.91(t,J=6.2Hz,1H),8.27(d,J=8.3Hz,1H),8.09(d,J=8.4Hz,1H),7.86(ddd,J=8.8,7.0,1.6Hz,2H),7.77–7.74(m,3H), 7.69(dd,J=10.9,7.9Hz,6H),7.43–7.34(m,2H),5.56(s,2H),3.57(s,3H ),2.32(t,J=7.4Hz,2H),1.58(td,J=7.5,4.1Hz,4H),1.52–1.08(m,4H).

[0200] 7-(4-((4-(tert-Butyl)benzyl)oxy)quinoline-2-carboxamido)heptanoic acid methyl ester (6d)

[0201] Methyl 7-(4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)heptanoate(6d)

[0202] The synthesis method is the same as 6a, except that the substrate is different and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether:ethyl acetate=5:1). Yield: 72%, brown oil. 1 H NMR (400MHz, DMSO-d6) δ8.88(t,J=6.2Hz,1H),8.25–8.21(m,1H),8.07(d,J=8.4Hz,1H),7.85(ddd,J=8.5,6.9,1.5Hz,1H),7.72(s,1H ),7.68–7.63(m,1H),7.53–7.46(m,4H),5.46(s,2H),3.57(s,3H),2.32(t,J=7.4Hz,2H),1.59(dp,J=11.1,3.0Hz,4H),1.30(s,13H).

[0203] 7-(4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)heptanoic acid methyl ester (6e)

[0204] Methyl 7-(4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)heptanoate(6e)

[0205] The synthesis method is the same as 6a, except that the substrate is different and the purification method is recrystallization from anhydrous ethanol. Yield: 70%, yellow-white solid, melting point: 80-82°C. 1 H NMR (400MHz, DMSO-d6) δ8.88(t,J=5.9Hz,1H),8.24(d,J=8.3Hz,1H),8.08(d,J=8.4Hz,1H),7.89–7.83(m,1H),7.70(s,1H),7.70–7.66(m,1 H),7.62(d,J=8.3Hz,2H),7.55–7.49(m,2H),5.51(s,2H),3.57(s,3H),2.28(dt,J=11.9,7.3Hz,2H),1.61–1.48(m,4H),1.39–1.18(m,6H).

[0206] 7-(4-Phenylethoxyquinoline-2-carboxamido)heptanoic acid methyl ester (6f)

[0207] Methyl 7-(4-phenethoxyquinoline-2-carboxamido)heptanoate(6f)

[0208] The synthesis method is the same as 6a, except that the substrate is different, and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1). Yield: 58%, yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.86(t,J=6.2Hz,1H),8.13(dd,J=8.4,1.4Hz,1H),8.04(d,J =8.4Hz,1H),7.82(ddd,J=8.4,6.8,1.5Hz,1H),7.68–7.59(m,2H),7.47–7.40(m,2H), 7.34(t,J=7.5Hz,2H),7.29–7.20(m,1H),4.57(t,J=6.4Hz,2H),3.57(s,3H),3.22(t ,J=6.3Hz,2H),2.31(t,J=7.4Hz,2H),1.57(pd,J=7.5,2.3Hz,4H),1.52–1.11(m,4H).

[0209] 7-(4-([[1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)heptanoic acid methyl ester (6j)

[0210] Methyl 7-(4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)heptanoate(6j)

[0211] The synthesis method is the same as 6a, except that the substrate is different, and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 5:1). Yield: 55%, white solid, melting point: 74-76°C. 1H NMR (400MHz, DMSO-d6) δ8.90(d,J=5.9Hz,1H),8.25(d,J=8.4Hz,1H),8.09(d,J=8 .4Hz,1H),7.95(s,1H),7.88–7.84(m,1H),7.75(dd,J=6.3,1.9Hz,2H),7.72–7.6 8(m,4H),7.67(s,1H),7.49(t,J=7.6Hz,2H),7.41–7.38(m,1H),5.56(s,2H),3.5 6(s,3H),2.33–2.26(m,2H),1.54(dd,J=15.2,7.6Hz,4H),1.32(d,J=4.0Hz,6H).

[0212] 7-(4-(Naphthalen-1-ylmethoxy)quinoline-2-carboxamido)heptanoic acid methyl ester (6k)

[0213] Methyl 7-(4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamido)heptanoate(6k)

[0214] The synthesis method is the same as 6a, except that the substrate is different and the purification method is recrystallization from anhydrous ethanol. Yield: 70%, white solid, melting point: 94-96°C. 1 H NMR(400MHz, DMSO-d6)δ8.92(d,J=6.4Hz,1H),8.25–8.18(m,2H),8.14–8.09(m,2H),8.01(s,1H),7.92(s,1H),7.86–7.81 (m,2H),7.59(d,J=8.8Hz,4H),5.97(s,2H),3.57(s,3H),2.33(d,J=7.3Hz,2H),1.71–1.53(m,6H),1.34(d,J=7.1Hz,4H).

[0215] 4-(Benzyloxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide (HI-1)

[0216] 4-(benzyloxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide(HI-1)

[0217] Take hydroxylamine hydrochloride (4.67g, 67mmol) and dissolve it in anhydrous methanol (24mL), and ultrasonically dissolve it to obtain solution A. Take potassium hydroxide (6.60g, 100mmol) and dissolve it in anhydrous methanol (14mL), and ultrasonically dissolve it to obtain solution B. In an ice bath, drop solution B into solution A drop by drop, continue stirring for 30min after all the drops are completed, and filter to obtain a methanol solution of potassium hydroxide and hydroxylamine. Take 6a (0.2g, 0.5mmol), add 5mL of methanol solution of potassium hydroxide and hydroxylamine and 5mL of DMF, and stir the reaction overnight. Spin dry methanol, add 1M hydrochloric acid to neutralize, filter the solid, and obtain a crude product. Recrystallize from anhydrous ethanol to obtain product HI-1. Yield: 25%, white solid, melting point: 164-166℃. 1 H NMR(400MHz, DMSO-d6)δ10.33(s,1H),8.87(t,J=6.0Hz,1H),8.68–8.62(m,1H), 8.24(d,J=7.7Hz,1H),8.08(d,J=8.5Hz,1H),7.88–7.82(m,1H),7.72(s,1H),7. 67(t,J=7.6Hz,1H),7.59(d,J=7.4Hz,2H),7.42(dt,J=27.3,7.3Hz,3H),5.51(s ,2H),1.96(t,J=7.3Hz,2H),1.54(dq,J=15.2,7.7Hz,4H),1.30(d,J=7.6Hz,2H). 13 C NMR (101MHz, DMSO) δ169.5,164.3,162.3,152.3,147.6,136.5,131.1,129.4,129. 1,128.6,128.1,127.7,122.2,121.8,99.6,70.5,32.6,29.4,26.5,25.3.HRMS(ESI + ):m / z calculated for C 23 H 25 N3O4 408.1918, found [M+H] + 408.1884.

[0218] N-(6-(Hydroxyamino)-6-oxohexyl)-4-phenylethoxyquinoline-2-carboxamide (HI-2)

[0219] N-(6-(hydroxyamino)-6-oxohexyl)-4-phenethoxyquinoline-2-carboxamide(HI-2)

[0220] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 30%, white solid, melting point: 156-157°C. 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.87(d,J=8.0Hz,1H),8.68(s,1H),8.28–8.02 (m,3H),7.86–7.81(m,1H),7.71–7.59(m,4H),7.52(d,J=8.2Hz,1H),7.43(d,J=7.6Hz ,2H),7.35(d,J=7.4Hz,1H),7.23(t,J=7.3Hz,1H),5.51(s,2H),4.56(d,J=7.9Hz,2H) ,3.22(t,J=6.5Hz,2H),1.98–1.91(m,2H),1.53(dd,J=15.2,7.5Hz,4H),1.30(s,4H). 13 C NMR (101MHz, DMSO) δ164.3,152.3,147.6,129.9,129.5,129.1,128.8,126.8,119.5,99.6,69.7.HRMS (ESI + ):m / z calculated for C 24 H 27 N3O4 422.2074, found[M+H] + 422.2035.

[0221] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide (HI-3)

[0222] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide(HI-3)

[0223] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 18%, white solid, melting point: 154-156°C. 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.90(t,J=6.2Hz,1H),8.27(dd,J=8.4,1.4Hz,1H),8.09(d,J=8.4Hz,1H),7.88–7.84(m,1H),7.77–7.74(m,3H) ,7.72–7.66(m,5H),7.49(t,J=7.6Hz,2H),7.39(t,J=7.3Hz,1H),5.56(s,3 H),1.96(t,J=7.3Hz,2H),1.56(dp,J=23.5,7.5Hz,5H),1.39–1.22(m,3H). 13 C NMR (101MHz, DMSO) δ169.49,164.3,162.4,152.3,147.6,140.5,140.2,135.6,131.1,129.4,1 28.7,128.0,127.7,127.4,127.2,122.2,121.8,99.6,70.3,32.7,29.4,26.5,25.4.HRMS(ESI + ):m / z calculated forC 29 H 29 N3O4 484.2231, found[M+H] + 484.2202.

[0224] 4-((4-(tert-butyl)benzyl)oxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide (HI-4)

[0225] 4-((4-(tert-butyl)benzyl)oxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide(HI-4)

[0226] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 35%, white solid, melting point: 234-236°C. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.89(t,J=6.1Hz,1H),8.67(s,1H),8.22(d,J=8.2Hz,1H),8.08(d,J=8.4Hz,1H),7.85(t,J=7.5Hz,1H),7.72(s ,1H),7.66(t,J=7.6Hz,1H),7.49(q,J=8.3Hz,4H),5.46(s,2H),1.96(t,J =7.3Hz,2H),1.54(dq,J=15.4,7.7Hz,4H),1.30(s,9H),1.28–1.02(m,4H). 13 C NMR (101MHz, DMSO) δ181.6,151.1,146.9,128.1,127.6,125.8,119.9,70.4,65.0,34.8,33.4,31.5.HRMS(ESI + ):m / z calculatedfor C 29 H 29 N3O4 464.2544, found[M+H] + 464.2514.

[0227] 4-((4-chlorobenzyl)oxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide (HI-5)

[0228] 4-((4-chlorobenzyl)oxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide(HI-5)

[0229] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 27%, white solid, melting point: 138-140°C. 1 H NMR (400MHz, DMSO-d6) δ10.33(d,J=3.1Hz,1H),8.89(t,J=6.1Hz,1H),8.24(dd,J=8.4,1.4Hz,1H),8.08(d,J=8.4Hz,1H),7 .86(ddd,J=8.4,6.8,1.5Hz,1H),7.73–7.61(m,4H),7.59–7.49(m,2H),5.51(s,2H),1.59–1.46(m,4H),1.35–1.21(m,6H). 13C NMR(101MHz,DMSO)δ164.3,162.2,152.3,147.6,135.5,133.2,131.2,129.9,129.4, 129.1,127.7,122.1,121.7,99.6,69.7,35.8,29.6,26.7,26.5,25.7,25.5.HRMS(ESI + ):m / z calculated for C 24 H 26 ClN3O4 456.1685, found[M+H] + 456.1686.

[0230] N-(7-(Hydroxyamino)-7-oxoheptyl)-4-phenylethoxyquinoline-2-carboxamide (HI-6)

[0231] N-(7-(hydroxyamino)-7-oxoheptyl)-4-phenethoxyquinoline-2-carboxamide(HI-6)

[0232] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 42%, white solid, melting point: 118-120°C. 1 H NMR(400MHz, DMSO-d6)δ10.35(s,1H),8.87(t,J=6.1Hz,1H),8.71(s,1H),8.19–8.10(m,1H), 8.05(d,J=8.4Hz,1H),7.82(ddd,J=8.5,6.9,1.5Hz,1H),7.69–7.58(m,2H),7.43(d,J=7.1Hz ,2H),7.34(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),4.57(t,J=6.4Hz,2H),3.22(t,J=6.4Hz,2 H), 1.94 (t, J = 7.4Hz, 2H), 1.54 (dq, J = 26.8, 7.1, 6.7Hz, 4H), 1.30 (qd, J = 7.8, 5.1, 4.4Hz, 4H). 13 C NMR(101MHz,DMSO)δ164.3,162.4,152.3,147.5,138.7,131.0,129.5,129.4,128.8, 127.5,126.8,122.0,121.7,99.0,69.6,35.0,32.6,29.6,28.8,26.6,25.5.HRMS(ESI +):m / z calculated for C 25 H 29 N3O4 436.2231, found[M+H] + 436.2219.

[0233] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide (HI-7)

[0234] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(7-(hydroxyamino)-7-oxoheptyl)

[0235] Quinoline-2-carboxamide(HI-7)

[0236] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 25%, white solid, melting point: 200-202°C. 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.27(d,J=8.3Hz,1H),8.09(d,J=8.4H z,1H),7.88–7.83(m,1H),7.75(t,J=4.0Hz,2H),7.69(dd,J=11.5,7.8Hz,4H ),7.49(t,J=7.4Hz,3H),7.39(d,J=7.4Hz,2H),5.56(s,2H),2.98(s,2H),2 .03(d,J=8.0Hz,1H),1.93(d,J=8.0Hz,1H),1.56–1.45(m,4H),1.30(s,4H). 13 C NMR (101MHz, DMSO) δ162.3,152.3,140.2,135.6,131.1,129.4,128.7,127.4,127.1,121.8,114.8,99.6,70.3,68.5,29.6,28.9,26.7.HRMS(ESI + ):m / z calculated for C 30 H 31 N3O4 498.2387, found[M+H] + 498.2386.

[0237] N-(7-(Hydroxyamino)-7-oxoheptyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide (HI-8)

[0238] N-(7-(hydroxyamino)-7-oxoheptyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide(HI-8)

[0239] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 15%, white solid, melting point: 224-226°C. 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.91(s,1H),8.20(s,1H),8.10(dd,J=12.8,8.3Hz,2H),8.01(t,J=7.8Hz,2H),7.92(s,1 H),7.85–7.79(m,2H),7.73(s,1H),7.59(q,J=8.7Hz,3H),5.97(s,2H),2.03–1.93(m,2H),1.54(d,J=35.5Hz,4H),1.31(s,4H). 13 CNMR(101MHz,DMSO)δ166.5,164.7,162.3,151.9,147.7,145.6,135.5,133.2 ,131.2,129.9,129.7,129.1,128.0,122.2,121.8,99.7,69.7,52.5.HRMS(ESI + ):m / z calculated forC 28 H 29 N3O4 472.2231, found[M+H] + 472.2227.

[0240] Tert-butyl (4-bromobenzyl)carbamate (8a)

[0241] tert-Butyl(4-bromobenzyl)carbamate(8a)

[0242] p-Bromobenzylamine (10 g, 53.75 mmol) and triethylamine (10.88 g, 107.5 mmol) were dissolved in 100 mL of dichloromethane, and di-tert-butyl dicarbonate (11.73 g, 53.75 mmol) was added dropwise. After the addition, the mixture was stirred for 2 h, the dichloromethane was dried by spin-drying, ethyl acetate was added, and the mixture was washed three times with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and spin-dried to obtain product 8a. Yield: 96%, white solid, melting point: 85-86°C. 1H NMR (400MHz, DMSO-d6) δ7.51(d,J=7.9Hz,2H),7.21–7.17(m,2H),4.09(d,J=6.2Hz,2H),1.39(s,9H).

[0243] Tert-butyl (3-bromobenzyl)carbamate (8b)

[0244] tert-Butyl(3-bromobenzyl)carbamate(8b)

[0245] The synthesis and purification methods are the same as 8a, except that the substrate is different, white solid, yield: 99%, melting point: 85-86°C. 1 H NMR (400MHz, DMSO-d6) δ7.50–7.42(m,2H),7.28(dd,J=16.1,8.5Hz,2H),4.12(d,J=6.3Hz,2H),1.39(s,9H).

[0246] (E)-3-(4-((((tert-butoxycarbonyl)amino)methyl)phenyl)acrylate (9a)

[0247] Methyl(E)-3-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)acrylate(9a)

[0248] Take 8a (10g, 34.94mmol), methyl acrylate (9.03g, 104.8mmol), triethylamine (10.61g, 104.83mmol), tetrakistriphenylphosphine palladium (0.1g) and dissolve in 50mL DMF, heat to 130℃ and reflux for 12h, cool naturally to room temperature, add 300mL ice water, extract 3 times with ethyl acetate, wash the combined organic layer with 5% citric acid, saturated NaHCO3 solution and saturated brine. After drying with anhydrous MgSO4, filter and evaporate to dryness to obtain a crude product. Purify by ethyl acetate and petroleum ether column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain product 9a. Yield: 75%, white solid, melting point: 66~68℃. 1 H NMR (400MHz, DMSO-d6) δ7.69–7.61(m,3H),7.44(t,J=6.1Hz,1H),7.27(d,J=7.9 Hz,2H),6.61(d,J=16.0Hz,1H),4.14(d,J=6.2Hz,2H),3.72(s,3H),1.39(s,9H).

[0249] (E)-methyl 3-(3-((((tert-butoxycarbonyl)amino)methyl)phenyl)acrylate (9b)

[0250] Methyl(E)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)acrylate(9b)

[0251] The synthesis method is the same as 9a, except that the substrate is different, and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 5:1). Yield: 65%, white solid, melting point: 90-92°C. 1 H NMR (400MHz, DMSO-d6) δ7.70–7.54(m,3H),7.47–7.27(m,3H),6.60(d,J=16.0Hz,1H),4.15(d,J=6.2Hz,2H),3.73(s,3H),1.40(s,9H).

[0252] (E)-(4-(3-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)methylammonium chloride (10a)

[0253] (E)-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)methanaminehydrochloride(10a)

[0254] Dissolve 9a (8.7 g, 30 mmol) in a saturated solution of hydrogen chloride in ethyl acetate, seal and stir for 2 h, filter and separate the solid, wash the filter cake with ethyl acetate, and dry to obtain 10a. Yield: 95%, white solid, melting point: 240-242°C. 1 H NMR (400MHz, DMSO-d6) δ8.47(s,3H),7.81–7.75(m,2H),7.67(d,J=16.1Hz,1H),7.60–7.49(m,2H),6.70(d,J=16.1Hz,1H),4.05(s,2H),3.73(s,3H).

[0255] (E)-(3-(3-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)methylammonium chloride (10b)

[0256] (E)-(3-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)methanaminium chloride(10b)

[0257] The synthesis and purification methods are the same as 10a, except that the substrate is different, yield: 90%, white solid, melting point: 216-218°C. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,3H),7.97–7.92(m,1H),7.71(d,J=7.9Hz,1H),7.66(d,J=16.0Hz,1 H),7.56(d,J=7.6Hz,1H),7.47(t,J=7.7Hz,1H),6.68(d,J=16.0Hz,1H),4.05(s,2H),3.74(s,3H).

[0258] (E)-3-(4-(((4-methoxyquinoline-2-carboxamido)methyl)phenyl)acrylate (11a)

[0259] Methyl(E)-3-(4-((4-methoxyquinoline-2-carboxamido)methyl)phenyl)acrylate(11a)

[0260] Under ice bath, 5a (0.20 g, 1 mmol), 10a (0.23 g, 1 mmol) and HATU (0.46 g, 1.2 mmol) were dissolved in DMF. NMM (0.35 ml, 3 mmol) was added. The mixture was stirred for 8 h under nitrogen protection, poured into water, and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with 5% citric acid, saturated NaHCO3 solution and saturated brine. After drying over anhydrous MgSO4, it was filtered and evaporated to dryness, and recrystallized from anhydrous ethanol to obtain product 11a. Yield: 70%, white solid, melting point: >300°C. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,J=6.4Hz,1H),8.20(dd,J=8.3,1.4Hz,1H),8.07(d,J=8.4Hz,1H),7.87–7.83(m,1H),7.75–7.66(m ,4H),7.63(d,J=3.1Hz,1H),7.41(d,J=8.0Hz,2H),6.62(dd,J=16.1,4.8Hz,1H),4.58(d,J=6.4Hz,2H),4.14(s,3H),3.72(s,3H).

[0261] (E)-3-(4-(((4-(Benzyloxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11b)

[0262] Methyl(E)-3-(4-((4-(benzyloxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11b)

[0263] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 66%, white solid, melting point: 128-130°C. 1 H NMR(400MHz,DMSO-d6)δ9.51(t,J=6.4Hz,1H),8.25(dd,J=8.5,1.4Hz,1H),8.09 (d,J=8.5Hz,1H),7.89–7.84(m,1H),7.75(d,J=4.0Hz,1H),7.68(s,3H),7.63(d, J=2.8Hz,1H),7.61–7.57(m,2H),7.48–7.44(m,2H),7.43–7.38(m,3H),7.31(d,J =8.2Hz,1H),6.63–6.59(m,1H),5.52(s,2H),4.58(d,J=6.4Hz,2H),3.72(s,3H).

[0264] (E)-methyl 3-(4-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11c)

[0265] Methyl(E)-3-(4-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11c)

[0266] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 60%, white solid, melting point: 162-164°C. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,J=6.4Hz,1H),8.23(dd,J=8.6,1.5Hz,1H),8.08(d,J=8.4Hz,1H),7.86(ddd,J=8.4,6.9,1.5Hz,1H),7.75(s,1H),7. 72–7.61(m,4H),7.49(q,J=8.5Hz,4H),7.41(d,J=8.0Hz,2H),6.61(d,J=1 6.0Hz,1H),5.46(s,2H),4.58(d,J=6.4Hz,2H),3.72(s,3H),1.30(s,9H).

[0267] (E)-3-(4-(((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11d)

[0268] Methyl(E)-3-(4-((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11d)

[0269] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 70%, white solid, melting point: 158-160°C. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,J=6.4Hz,1H),8.29–8.22(m,1H),8.09(d,J=8.4Hz,1H),7.86(ddd,J=8.5,6.9,1.5Hz,1H),7.73(s,1H),7.72–7. 66(m,3H),7.66–7.57(m,3H),7.57–7.49(m,2H),7.41(d,J=8.0Hz,2H), 6.61(d,J=16.0Hz,1H),5.52(s,2H),4.58(d,J=6.4Hz,2H),3.72(s,3H).

[0270] (E)-methyl 3-(4-(((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11e)

[0271] Methyl(E)-3-(4-((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11e)

[0272] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 64%, white solid, melting point: 147-149°C. 1H NMR (400MHz, DMSO-d6) δ9.51(t,J=6.4Hz,1H),8.25–8.21(m,1H),8.08(d,J=8.4Hz,1H),7.95(s,1H),7.86(ddd,J=8.4,6.8,1.5Hz,1 H),7.72–7.62(m,6H),7.44–7.39(m,2H),7.32–7.26(m,2H),6.61(d,J=16.1Hz,1H),5.49(s,2H),4.59(d,J=6.4Hz,2H),3.72(s,3H).

[0273] (E)-3-(4-(((4-((4-methoxybenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11f)

[0274] Methyl(E)-3-(4-((4-((4-methoxybenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11f)

[0275] The synthesis method is the same as 11a, except that the substrate is different. The purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether:ethyl acetate=5:1). Yield: 68%, brown oil. 1 H NMR (400MHz, DMSO-d6) δ9.48(t,J=6.4Hz,1H),8.25(dd,J=8.4,1.4Hz,1H),8.09(d,J=8.4Hz,1H),7.86(ddd,J=8.4,6.8,1.5Hz,1H),7.74(s,2H),7.7 2–7.65(m,3H),7.62(d,J=8.5Hz,3H),7.56–7.49(m,2H),7.47–7.37(m,2H ),6.61(d,J=16.0Hz,1H),5.51(s,2H),4.59(d,J=6.4Hz,2H),3.72(s,3H).

[0276] (E)-methyl 3-(4-(((4-phenylethoxyquinoline-2-carboxamido)methyl)phenyl)acrylate (11 g)

[0277] Methyl(E)-3-(4-((4-phenethoxyquinoline-2-carboxamido)methyl)phenyl)acrylate(11g)

[0278] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 55%, white solid, melting point: 118-120°C. 1 H NMR (400MHz, DMSO-d6) δ9.47(t,J=6.4Hz,1H),8.14(dd,J=8.5,1.4Hz,1H),8.05(d,J=8.4Hz,1H),7.83(ddd,J=8.4,6.9,1.5Hz,1H),7.73–7.60(m,5H), 7.48–7.38(m,4H),7.33(t,J=7.5Hz,2H),7.23(t,J=7.3Hz,1H),6.61(d,J=1 6.0Hz,1H),4.58(dt,J=6.5,3.3Hz,4H),3.72(s,3H),3.22(t,J=6.3Hz,2H).

[0279] (E)-methyl 3-(3-(((4-methoxyquinoline-2-carboxamido)methyl)phenyl)acrylate (11h)

[0280] Methyl(E)-3-(3-((4-methoxyquinoline-2-carboxamido)methyl)phenyl)acrylate(11h)

[0281] The synthesis method is the same as 11a, except that the substrate is different, and the purification method is ethyl acetate and petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1). Yield: 45%, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ9.49(t,J=6.4Hz,1H),8.25(dd,J=8.4,1.4Hz,1H),8.0 9(d,J=8.4Hz,1H),7.86(ddd,J=8.5,6.9,1.5Hz,1H),7.73(s,1H),7.72–7.70(m ,1H),7.69–7.66(m,1H),7.62(d,J=8.2Hz,2H),7.53–7.51(m,1H),7.43–7.38( m,1H),6.61(d,J=16.0Hz,1H),5.52(s,3H),4.59(d,J=6.4Hz,2H),3.72(s,3H).

[0282] (E)-methyl 3-(3-((4-((4-(4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11i)

[0283] Methyl(E)-3-(3-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11i)

[0284] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 56%, yellow-white solid, melting point: 140-142°C. 1 H NMR(400MHz,DMSO-d6)δ9.50(t,J=6.5Hz,1H),8.23(dd,J=8.4,1.4Hz,1H),8.11–8.0 6(m,1H),7.85(ddd,J=8.3,6.7,1.5Hz,1H),7.75(s,1H),7.68(t,J=3.7Hz,2H),7.65– 7.62(m,1H),7.51(dd,J=16.5,7.9Hz,4H),7.41(d,J=8.0Hz,2H),7.34–7.23(m,1H), 6.61(d,J=16.0Hz,1H),5.46(s,2H),4.59(d,J=6.4Hz,2H),3.72(s,3H),1.30(s,9H).

[0285] (E)-methyl 3-(3-(((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11j)

[0286] Methyl(E)-3-(3-((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11j)

[0287] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 60%, yellow-white solid, melting point: 150-152°C. 1H NMR (400MHz, DMSO-d6) δ9.47(t,J=6.4Hz,1H),8.25(dd,J=8.5,1.6Hz,1H),8.09(d,J =8.5Hz,1H),7.86(ddt,J=8.5,6.9,1.6Hz,1H),7.73(s,1H),7.71–7.70(m,1H),7.69 –7.66(m,1H),7.64–7.60(m,3H),7.52(dt,J=8.3,2.3Hz,2H),7.45–7.37(m,2H),6.6 1(dd,J=16.0,1.3Hz,1H),5.51(d,J=2.0Hz,2H),4.59(d,J=6.4Hz,2H),3.72(s,3H).

[0288] (E)-methyl 3-(3-(((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate (11k)

[0289] Methyl(E)-3-(3-((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)phenyl)acrylate(11k)

[0290] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 45%, white solid, melting point: 104-106°C. 1 H NMR (400MHz, DMSO-d6) δ9.49(t,J=6.4Hz,1H),8.23(dd,J=8.4,1.4Hz,1H),8.09(d,J=8.4Hz,1H),7.96(s,1H),7.86(ddd,J=8.4,6.8,1.5Hz,1H) ,7.75(s,1H),7.72–7.60(m,6H),7.47–7.37(m,2H),7.33–7.25(m,2H), 6.61(d,J=16.1Hz,1H),5.49(s,2H),4.60(d,J=6.4Hz,2H),3.72(s,3H).

[0291] (E)-3-(3-(((4-phenylethoxyquinoline-2-carboxamido)methyl)phenyl)acrylate (11l)

[0292] Methyl(E)-3-(3-((4-phenethoxyquinoline-2-carboxamido)methyl)phenyl)acrylate(11l)

[0293] The synthesis and purification methods are the same as 11a, except that the substrate is different. Yield: 52%, white solid, melting point: 116-118°C. 1 H NMR(400MHz, DMSO-d6)δ9.47(t,J=6.4Hz,1H),8.14(dd,J=8.3,1.4Hz,1H),8.05( d,J=8.4Hz,1H),7.83(ddd,J=8.4,6.9,1.5Hz,1H),7.67(dd,J=7.7,5.8Hz,3H),7. 62(d,J=1.9Hz,1H),7.53–7.37(m,4H),7.32(d,J=7.7Hz,1H),7.28–7.19(m,1H), 6.61(d,J=16.1Hz,1H), 4.59(d,J=6.2Hz,2H), 3.71(s,3H), 3.22(t,J=6.3Hz,2H).

[0294] (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide (HI-9)

[0295] (E)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxami de(HI-9)

[0296] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 35%, white solid, melting point: 158-160°C. 1 H NMR (400MHz, DMSO-d6) δ9.62(t,J=6.4Hz,1H),8.22(dd,J=8.3,1.4Hz,1H),8.12(d,J=8.4Hz,1H),7.94–7.87(m,1H),7.70( d,J=2.0Hz,1H),7.57(d,J=16.0Hz,1H),7.41(d,J=8.0Hz,1H),6.50(d,J=16.0Hz,1H),4.59(d,J=6.3Hz,2H),4.17(s,3H). 13 CNMR(101MHz,DMSO)δ168.0,164.0,144.1,142.1,133.3,131.5,128.7,128.4,127.9 ,127.9,122.2,122.2,121.7,119.2,119.2,101.6,98.8,98.8,57.0,42.9.HRMS(ESI+ ):m / z calculated for C 21 H 19 N3O4 378.1448, found[M+H] + 378.1455.

[0297] (E)-4-(Benzyloxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-10)

[0298] (E)-4-(benzyloxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)

[0299] quinoline-2-carboxamide(HI-10)

[0300] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 30%, white solid, melting point: 190-192°C. 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.25(d,J=8.3Hz,1H),8.08(d,J=8.5Hz,1H),7.95(s,1H),7.86(t,J=7.6Hz,1H),7.75(s,1H),7.68(t, J=7.6Hz,1H),7.59(d,J=7.4Hz,2H),7.52–7.25(m,6H),7.11(d,J=16.3Hz,1H),6.37(d,J=15.5Hz,1H),5.52(s,2H),4.55(d,J=6.2Hz,2H). 13 C NMR (101MHz, DMSO) δ164.5,162.4,152.1,147.6,136.5,131.2,129.4,129.1,12 8.6,128.3,128.1,127.7,127.1,122.2,121.9,99.7,70.6,70.6,70.5.HRMS(ESI + ):m / z calculated for C 27 H 23 N3O4 454.1761, found[M+H] + 454.1772.

[0301] (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-11)

[0302] (E)-4-((4-(tert-butyl)benzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quin oline-2-carboxamide(HI-11)

[0303] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 28%, white solid, melting point: 234-236°C. 1 H NMR (400MHz, DMSO-d6) δ9.45(d,J=10.8Hz,1H),8.22(d,J=7.6Hz,1H),8.07(q,J=6.7,5.6Hz,1H),7.83(q,J=8.2,7.2Hz,1H),7.75(q,J=4.4Hz ,1H),7.66(t,J=7.4Hz,1H),7.56–7.28(m,9H),6.43(dd,J=23.0,16.0Hz,1H),5.45(t,J=6.6Hz,2H),4.67–4.47(m,2H),1.29(d,J=4.0Hz,9H). 13 C NMR (101MHz, DMSO) δ162.5,152.1,151.2,147.6,133.4,131.2,129.4,128.4,128.1,127.8,125.8,121.9,99.6,70.4,42.8,34.8.HRMS (ESI + ):m / z calculated for C 31 H 31 N3O4510.2387, found[M+H] + 510.2383.

[0304] (E)-4-((4-chlorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-12)

[0305] (E)-4-((4-chlorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide(HI-12)

[0306] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 32%, white solid, melting point: 244-246°C. 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.45(d,J=16.2Hz,1H),8.25(d,J=8.5Hz,1H),8.08(d,J=8.8Hz,1H),7.86(t,J=7.6Hz,1H) ,7.82–7.58(m,5H),7.58–7.42(m,4H),7.35(dd,J=15.3,8.0Hz,2H),6.44(d,J=16.5Hz,1H),5.52(s,2H),4.56(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ187.6,166.8,165.9,130.0,129.1,128.9,128.9,127.3,99.7,80.9,70.0.HRMS (ESI + ):m / z calculated for C 27 H 22 ClN3O4 488.1372, found[M+H] + 488.1422.

[0307] (E)-4-((4-fluorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-13)

[0308] (E)-4-((4-fluorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide(HI-13)

[0309] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 36%, white solid, melting point: 294-296°C. 1H NMR (400MHz, DMSO-d6) δ9.57(t,J=6.3Hz,1H),8.24(dd,J=8.3,1.5Hz,1H),8.11(d,J=8.4Hz,1H),7.88(ddd,J=8.5,6.9,1.5Hz,1H),7.79(s,1H ),7.74–7.61(m,5H),7.57(d,J=16.0Hz,1H),7.41(d,J=8.1Hz,2H),7.29(td,J=8.6,2.1Hz,2H),6.50(d,J=16.0Hz,1H),4.59(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ168.0,163.8,161.3,151.3,144.1,142.0,133.4,132.5,132.4,131. 9,130.7,130.6,128.7,128.4,122.4,121.7,119.2,116.1,115.8,100.1,70.4.HRMS(ESI + ):m / z calculated for C 27 H 22 FN3O4472.1667, found [M+H] + 472.1692.

[0310] (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-((4-methoxybenzyl)oxy)quinoline-2-carboxamide (HI-14)

[0311] (E)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-((4-methoxybenzyl)oxy)quinoli ne-2-carboxamide(HI-14)

[0312] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 45%, white solid, melting point: 188-189°C. 1H NMR(400MHz,DMSO-d6)δ9.59(t,J=6.5Hz,1H),8.28–8.23(m,1H),8.09(d,J=8.5Hz,1 H),7.99–7.91(m,2H),7.87(ddd,J=8.4,6.8,1.5Hz,2H),7.73(s,1H),7.69(ddt,J=9. 9,7.2,2.2Hz,2H),7.62(d,J=8.3Hz,2H),7.53(d,J=2.0Hz,1H),7.50(dd,J=8.8,2.2H z,2H),7.34(dd,J=31.3,7.8Hz,1H),5.52(s,2H),4.64(d,J=6.4Hz,2H),3.84(s,3H). 13 C NMR (101MHz, DMSO) δ166.6,164.7,162.3,147.7,135.5,133.2,130.0,129.7 ,129.5,129.1,128.0,122.2,121.8,114.1,99.7,69.7,52.5,42.9.HRMS(ESI + ):m / z calculated for C 28 H 25 N3O5 484.1872, found [M+H] + 484.1894.

[0313] (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenylethoxyquinoline-2-carboxamide (HI-15)

[0314] (E)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carbox amide(HI-15)

[0315] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 15%, white solid, melting point: 150-152°C. 1H NMR(400MHz, DMSO-d6)δ9.44(s,1H),8.13(d,J=8.3Hz,1H),8.04(d,J=8.5Hz,1H),7.86–7.78(m,1H), 7.64(d,J=9.2Hz,2H),7.51–7.22(m,10H),6.45(d,J=15.8Hz,1H),4.56(s,4H),3.21(t,J=6.3Hz,2H). 13 C NMR (101MHz, DMSO) δ164.6,162.5,152.1,147.6,138.6,131.1,129.5,129.4 ,128.8,128.4,127.6,126.8,122.0,121.7,99.1,69.7,42.8,35.0.HRMS(ESI + ):m / z calculated for C 28 H 25 N3O4 468.1918, found[M+H] + 468.1894.

[0316] (E)-N-(3-(3-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide (HI-16)

[0317] (E)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxami de(HI-16)

[0318] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 18%, white solid, melting point: 144-146°C. 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.50(t,J=6.3Hz,1H),9.05(s,1H),8.20(dd,J=8.4,1.4Hz,1H),8.08(d,J=8.4Hz,1H),7.85(ddd ,J=8.4,6.9,1.5Hz,1H),7.71–7.62(m,2H),7.56(s,1H),7.53–7.29(m,4H),6.45(d,J=15.8Hz,1H),4.58(d,J=6.4Hz,2H),4.14(s,3H). 13C NMR (101MHz, DMSO) δ164.7,163.4,152.1,147.5,140.7,131.1,129.4,129.2,127.7,126.8,126.7,122.1,121.7,119.6,98.6,56.8,42.9.HRMS (ESI + ):m / z calculated for C 21 H 19 N3O4 378.1448, found[M+H] + 378.1414.

[0319] (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-17)

[0320] (E)-4-((4-(tert-butyl)benzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quin oline-2-carboxamide(HI-17)

[0321] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 25%, white solid, melting point: 260-262°C. 1 H NMR(400MHz, DMSO-d6)δ9.46(s,1H),8.22(d,J=8.5Hz,1H),8.07(d,J=8.1Hz,1H),7.85(s,1H),7.74(s,1H),7.66(s,1H),7 .48(dd,J=5.6,2.4Hz,5H),7.36(d,J=8.6Hz,5H),6.44(d,J=16.4Hz,1H),5.46(s,2H),4.55(s,2H),1.30(d,J=2.9Hz,9H). 13 CNMR(101MHz,DMSO)δ172.9,152.3,129.4,128.4,128.1,127.8,125.8,122.2,121.9,99.6,78.1,70.4,68.1,65.6,34.8,31.5.HRMS(ESI + ):m / z calculated for C 31 H 31 N3O4510.2387, found[M+H] + 510.2385.

[0322] (E)-4-((4-chlorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-18)

[0323] (E)-4-((4-chlorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide(HI-18)

[0324] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 22%, white solid, melting point: 148-150°C. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.48(s,1H),8.24(d,J=8.5Hz,1H),8.08(d,J=8.4Hz,1H),7.86(t,J=7.6Hz,1H),7.76–7 .60(m,5H),7.52(d,J=7.7Hz,2H),7.33(t,J=21.6Hz,4H),6.46(d,J=15.8Hz,1H),5.52(d,J=3.9Hz,2H),4.57(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ164.6,152.1,135.5,133.2,130.0,130.0,130.0,129.9,129.5,129.1,129.0,127.8,122.2,121.8,69.7.HRMS (ESI + ):m / z calculated forC 27 H 22 ClN3O4 488.1372, found[M+H] + 488.1393.

[0325] (E)-4-((4-fluorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide (HI-19)

[0326] (E)-4-((4-fluorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide(HI-19)

[0327] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 35%, white solid, melting point: 160-162°C. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,J=6.4Hz,1H),8.23(d,J=8.3Hz,1H),8.09(d,J=8.6Hz,1H),7.88–7.83(m,1H),7.76(s,1H),7 .72–7.55(m,5H),7.44–7.35(m,2H),7.29(dd,J=10.0,7.7Hz,2H),6.50(d,J=16.0Hz,1H),5.50(s,2H),4.59(d,J=6.5Hz,2H). 13 CNMR(101MHz,DMSO)δ167.9,144.2,140.5,134.7,130.7,130.7,130.7,130.6,130.5,129.8,129 .4,129.4,128.1,127.7,127.7,127.3,122.3,121.7,119.7,116.0,115.8,100.1,70.3.HRMS(ESI + ):m / z calculated for C 27 H 22 FN3O4 472.1667, found[M+H] + 472.1667.

[0328] (E)-N-(3-(3-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenylethoxyquinoline-2-carboxamide (HI-20)

[0329] (E)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carbox amide(HI-20)

[0330] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 32%, white solid, melting point: 150-152°C. 1H NMR (400MHz, DMSO-d6) δ9.52(t,J=6.5Hz,1H),8.18–8.12(m,1H),8.06(d,J=8.4Hz,1H),7.84(ddd,J=8.4,6.8,1 .4Hz,1H),7.70–7.61(m,2H),7.57(d,J=1.9Hz,1H),7.55–7.15(m,9H),4.65–4.50(m,4H),3.22(t,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ164.7,162.5,152.0,147.6,142.8,138.6,131.1,130.9,130.6,130.1,12 9.5,129.4,128.8,127.7,127.0,126.8,122.0,122.0,121.8,99.1,69.7,42.5,35.0.HRMS(ESI + ):m / z calculated for C 21 H 19 N3O4 468.1918, found[M+H] + 468.1899.

[0331] (E)-N-(3-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide (HI-21)

[0332] (E)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-(naphthalen-1-ylmethoxy)quin oline-2-carboxamide(HI-21)

[0333] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 24%, brown solid, melting point: 206-208°C. 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.51(s,1H),9.11(s,1H),8.34–8.19(s,1H), 8.09(s,1H),7.98–7.15(m,12H),6.46(d,J=15.3Hz,1H),5.52(s,2H),4.58(s,2H). 13CNMR(101MHz,DMSO)δ152.1,140.7,135.6,131.2,130.0,130.0,129.5,129.2,129.1,122.2,122.2,99.7,69.8,69.8.HRMS(ESI + ):m / z calculated for C 27 H 23 N3O4 454.1761, found[M+H] + 454.1771.

[0334] Methyl 4-((4-methoxyquinoline-2-carboxamido)methyl)benzoate (13a)

[0335] Methyl 4-((4-methoxyquinoline-2-carboxamido)methyl)benzoate(13a)

[0336] The synthesis and purification methods are the same as 6a, except that the substrate is different. Yield: 75%, brown solid, melting point: 102-104°C. 1 H NMR (400MHz, DMSO-d6) δ9.59(t,J=6.4Hz,1H),8.29–8.24(m,1H),8.09(d,J=8.4Hz,1H),7.95–7.92(m,1H),7.87(ddd,J=8.4,6.9, 1.5Hz,1H),7.73(s,1H),7.71–7.67(m,1H),7.63–7.61(m,1H),7.53–7.48(m,2H),5.52(s,3H),4.63(d,J=6.5Hz,2H),3.84(s,3H).

[0337] Methyl 4-((4-(Benzyloxy)quinoline-2-carboxamido)methyl)benzoate (13b)

[0338] Methyl 4-((4-(benzyloxy)quinoline-2-carboxamido)methyl)benzoate(13b)

[0339] The synthesis and purification methods are the same as those of 6a, except that the substrate is different, and the product is purified by ethyl acetate and petroleum ether column chromatography (petroleum ether:ethyl acetate=4:1). Yield: 80%, colorless oil. 1H NMR (400MHz, DMSO-d6) δ9.57(t,J=6.4Hz,1H),8.25(d,J=8.4Hz,1H),8.09(d,J=8.5Hz,1H),7.97–7.90(m,3H),7.88–7.84(m,1H),7.75(s ,1H),7.71–7.67(m,1H),7.59(d,J=7.4Hz,2H),7.50(d,J=8.1Hz,2H),7.47–7.41(m,2H),5.51(s,2H),4.64(d,J=6.5Hz,2H),3.84(s,3H).

[0340] Methyl 4-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)benzoate (13c)

[0341] Methyl 4-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)benzoate(13c)

[0342] The synthesis and purification methods are the same as 6a, except that the substrate is different. Yield: 65%, yellow-white solid, melting point: 102-104°C. 1 H NMR(400MHz,DMSO-d6)δ9.57(t,J=6.5Hz,1H),8.23(dd,J=8.4,1.4Hz,1H),8.09 (d,J=8.5Hz,1H),7.98–7.91(m,2H),7.86(ddd,J=8.4,6.8,1.6Hz,1H),7.76(s,1 H),7.67(ddd,J=8.2,6.8,1.2Hz,1H),7.50(td,J=9.5,8.5,6.9Hz,5H),7.36–7.1 9(m,1H),5.46(s,2H),4.64(d,J=6.4Hz,2H),3.84(s,3H),1.30(d,J=4.3Hz,9H).

[0343] Methyl 4-((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoate (13d)

[0344] Methyl 4-((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoate(13d)

[0345] The synthesis and purification methods are the same as 6a, except that the substrate is different. Yield: 67%, white solid, melting point: 188-190°C. 1 H NMR (400MHz, DMSO-d6) δ9.57(t,J=6.3Hz,1H),8.25(d,J=7.9Hz,1H),8.09(d,J=8.3Hz,1H),7.93(d,J=8.1Hz,2H),7.87(t,J=7.5Hz,1 H),7.73(s,1H),7.69(s,1H),7.62(d,J=8.3Hz,2H),7.51(dd,J=10.5,X`8.2Hz,4H),5.52(s,2H),4.64(d,J=6.4Hz,2H),3.84(s,3H).

[0346] Methyl 4-((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoate (13e)

[0347] Methyl 4-((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoate(13e)

[0348] The synthesis and purification methods are the same as 6a, except that the substrate is different. Yield: 72%, yellow-white solid, melting point: 160-162°C. 1 H NMR (400MHz, DMSO-d6) δ9.57(t,J=6.5Hz,1H),8.28–8.23(m,1H),8.09(d,J=8.4Hz,1H),7.93(d,J=8.3Hz,2H),7.89–7.84(m,1H),7.7 3(s,1H),7.69(t,J=7.6Hz,1H),7.62(d,J=8.4Hz,2H),7.51(dd,J=10.5,8.3Hz,4H),5.52(s,2H),4.64(d,J=6.4Hz,2H),3.84(s,3H).

[0349] Methyl 4-((4-phenethoxyquinoline-2-carboxamido)methyl)benzoate (13f)

[0350] Methyl 4-((4-phenethoxyquinoline-2-carboxamido)methyl)benzoate(13f)

[0351] The synthesis and purification methods are the same as 6a, except that the substrate is different. Yield: 76%, white solid, melting point: 142-144°C.1 H NMR(400MHz,DMSO-d6)δ9.54(t,J=6.4Hz,1H),8.14(dd,J=8.4,1.4Hz,1H),8 .05(d,J=8.4Hz,1H),7.98–7.90(m,2H),7.84(ddd,J=8.4,6.8,1.5Hz,1H),7. 69–7.61(m,2H),7.49(d,J=8.3Hz,2H),7.46–7.39(m,2H),7.33(t,J=7.6Hz,2 H),7.27–7.20(m,1H),4.69–4.55(m,4H),3.84(s,3H),3.23(t,J=6.4Hz,2H).

[0352] Methyl 4-((4-([[1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)methyl)benzoate (13 g)

[0353] Methyl 4-((4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)methyl)benzoate(13g)

[0354] The synthesis and purification methods are the same as 6a, except that the substrate is different, yield: 80%, white solid, melting point: 138-140°C. 1 H NMR (400MHz, DMSO-d6) δ9.60(t,J=6.4Hz,1H),8.28(dd,J=8.4,1.4Hz,1H),8.10(d,J=8.4Hz,1H),7.98–7.92(m,2H),7.88(ddd,J =8.4,6.8,1.5Hz,1H),7.80–7.66(m,8H),7.55–7.46(m,4H),7.42–7.37(m,1H),5.57(s,2H),4.64(d,J=6.4Hz,2H),3.84(s,3H).

[0355] N-(4-(Hydroxycarbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide (HI-22)

[0356] N-(4-(hydroxycarbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide(HI-22)

[0357] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 25%, white solid, melting point: 242-244°C.1 H NMR (400MHz, DMSO-d6) δ9.45 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 8.07 (d, J = 8.4Hz, 1H), 7.84 (t, J=7.8Hz,2H),7.79–7.59(m,4H),7.31(d,J=8.0Hz,2H),4.56(d,J=6.4Hz,2H),4.13(s,3H). 13 C NMR (101MHz, DMSO) δ164.1,163.4,152.3,148.1,147.5,131.1,129.4,129.1,127.6,126.7,122.0,121.7,114.2,98.5,56.8,42.7.HRMS(ESI + ):m / z calculatedfor C 19 H 17 N3O4 352.1292, found [M+H] + 352.1339.

[0358] 4-(Benzyloxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide (HI-23)

[0359] 4-(benzyloxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide(HI-23)

[0360] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 31%, white solid, melting point: 238-240°C. 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.24(d,J=8.4Hz,1H),8.08(d,J=8.6Hz,1H),7.85(t,J=7.6Hz,1H),7 .71(dd,J=18.6,10.5Hz,4H),7.59(d,J=7.3Hz,2H),7.53–7.19(m,7H),5.51(s,2H),4.55(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ145.4,144.9,134.2,133.6,132.8,132.2,131.9,127.1,126.4,104.7,75.6.HRMS (ESI + ):m / z calculated for C 25 H21 N3O4 428.1605, found[M+H] + 428.1607.

[0361] 4-((4-(tert-butyl)benzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide (HI-24)

[0362] 4-((4-(tert-butyl)benzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide(HI-24)

[0363] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 16%, white solid, melting point: 200-202°C. 1 H NMR (400MHz, DMSO-d6) δ9.46(d,J=22.0Hz,1H),8.23(d,J=8.5Hz,1H),8.08(d,J=8.5Hz,1H),7.96–7.83(m,2H),7.77–7 .62(m,3H),7.49(q,J=8.1Hz,4H),7.41–7.28(m,2H),5.46(s,2H),4.61(dd,J=24.7,6.4Hz,2H),1.30(t,J=1.0Hz,9H). 13 C NMR (101MHz, DMSO) δ162.5,151.2,147.7,133.4,131.2,129.7,129.4,129.1,128.1 ,128.0,126.9,125.8,122.2,121.9,114.1,99.6,70.4,52.5,34.8,31.5.HRMS(ESI + ):m / z calculated for C 29 H 29 N3O4 484.2231, found[M+H] + 484.2271.

[0364] 4-((4-chlorobenzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide (HI-25)

[0365] 4-((4-chlorobenzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide(HI-25)

[0366] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 20%, white solid, melting point: 160-162°C. 1 H NMR (400MHz, DMSO-d6) δ9.55(t,J=6.4Hz,1H),8.25(dd,J=8.3,1.4Hz,1H),8.09(d,J =8.4Hz,1H),7.87(ddd,J=8.4,6.8,1.5Hz,1H),7.73(s,1H),7.71–7.67(m,1H),7.65– 7.60(m,2H),7.57(t,J=1.8Hz,1H),7.55–7.50(m,2H),7.45(dt,J=7.8,1.5Hz,1H),7 .39(dd,J=7.7,1.5Hz,1H),7.30(t,J=7.8Hz,1H),5.52(s,2H),4.55(d,J=6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ164.7,162.3,151.9,147.7,142.8,135.5,133.2,131.2,131.0,130.6, 130.1,129.9,129.4,129.1,127.8,127.0,122.2,122.0,121.8,99.7,69.7,42.5.HRMS(ESI + ):m / z calculated for C 25 H 20 ClN3O4462.1221,found[M+H] + 462.1273.

[0367] N-(4-(Hydroxycarbamoyl)benzyl)-4-phenylethoxyquinoline-2-carboxamide (HI-26)

[0368] N-(4-(hydroxycarbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide(HI-26)

[0369] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 22%, white solid, melting point: 174-176°C. 1H NMR(400MHz,DMSO-d6)δ9.56(t,J=6.4Hz,1H),9.43(s,1H),8.16–8.12(m,1H), 8.07–8.04(m,1H),7.93(d,J=6.5Hz,1H),7.85–7.81(m,1H),7.73–7.66(m,2H), 7.63(s,1H),7.49(d,J=6.3Hz,1H),7.43(d,J=7.4Hz,2H),7.34(t,J=7.5Hz,3H ),7.24(d,J=7.5Hz,1H),4.65–4.55(m,4H),3.84(s,2H),3.22(t,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ166.6,164.8,162.5,152.0,147.6,145.6,138.7,131.1,129.7,129.5,129.4,12 9.0,128.8,128.6,128.0,127.7,126.8,122.0,121.8,114.1,99.1,69.7,52.5,42.8,35.0.HRMS(ESI + ):m / z calculated for C 26 H 23 N3O4442.1761, found [M+H] + 442.1815.

[0370] 4-([1,1'-Biphenyl]-4-ylmethoxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide (HI-27)

[0371] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide(HI-27)

[0372] The synthesis and purification methods are the same as those of HI-1, except that the substrate is different. Yield: 18%, white solid, melting point: 214-216°C. 1H NMR(400MHz, DMSO-d6)δ9.52–9.36(m,1H),8.27(t,J=8.6Hz,1H),8.09(t,J=7.9Hz,1H),7.97–7.92(m,1H),7.88–7.83(m,2H),7.7 7–7.66(m,8H),7.51–7.47(m,2H),7.43–7.35(m,2H),7.26(d,J=7.9Hz,1H),5.56(d,J=5.9Hz,2H),4.59(dd,J=21.1,12.1Hz,2H). 13 C NMR (101MHz, DMSO) δ164.5,162.4,152.1,147.7,145.6,140.5,140.2,135.6,131.2,129.7,129.6,129.5,129.4,12 9.1,128.8,128.0,127.7,127.4,127.2,127.1,127.0,126.7,122.2,121.9,114.1,99.7,70.3,52.5,36.2.HRMS(ESI + ):m / z calculated for C 31 H 25 N3O4 504.1923, found [M+H] + 504.1977.

[0373] 4-((4-(Benzyloxy)quinoline-2-carboxamido)methyl)benzoic acid (14a)

[0374] 4-((4-(benzyloxy)quinoline-2-carboxamido)methyl)benzoic acid(14a)

[0375] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 32%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),8.25(d,J=8.6Hz,1H),8.09(d,J=4.5Hz,1H),7.83(d,J=7.7Hz,3H),7.75(s,1H),7.67(d,J=3.5H z,1H),7.59(d,J=7.4Hz,2H),7.46(t,J=7.4Hz,2H),7.40(d,J=7.3Hz,1H),7.32(d,J=7.6Hz,2H),5.52(s,2H),4.58(d,J=6.5Hz,2H).

[0376] 4-((4-Methoxyquinoline-2-carboxamido)methyl)benzoic acid (14b)

[0377] 4-((4-methoxyquinoline-2-carboxamido)methyl)benzoic acid(14b)

[0378] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 50%, white solid, melting point: 256-258°C. 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.55(t,J=6.4Hz,1H),8.21(dd,J=8.4,1.4Hz,1H),8.08(d,J=8.4 Hz,1H),8.04–7.79(m,3H),7.79–7.61(m,2H),7.47(d,J=8.0Hz,2H),4.63(d,J=6.4Hz,2H),4.14(s,3H).

[0379] 4-((4-((4-(tert-Butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)benzoic acid (14c)

[0380] 4-((4-((4-(tert-butyl)benzyl)oxy)quinoline-2-carboxamido)methyl)benzoic acid(14c)

[0381] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 45%, white solid, melting point: 284-286°C. 1 H NMR (400MHz, DMSO-d6) δ9.39(t,J=6.4Hz,1H),8.23(dd,J=8.4,1.4Hz,1H),8.08(d,J=8.4Hz,1H),7.87–7.79(m,3H),7.76(s,1H ),7.66(ddd,J=8.2,6.8,1.3Hz,1H),7.53–7.46(m,4H),7.24(d,J=7.9Hz,2H),5.47(s,2H),4.56(d,J=6.1Hz,2H),1.30(s,9H).

[0382] 4-((4-((4-Chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoic acid (14d)

[0383] 4-((4-((4-chlorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoicacid(14d)

[0384] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 68%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ9.36(t,J=6.3Hz,1H),8.24(d,J=8.1Hz,1H),8.08(d,J=8.4Hz,1H),7.88–7.83(m,1H),7.82–7 .71(m,3H),7.66(dd,J=22.9,8.0Hz,3H),7.58–7.49(m,2H),7.21(d,J=7.9Hz,2H),5.52(s,2H),4.55(d,J=6.4Hz,2H).

[0385] 4-((4-((4-Fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoic acid (14e)

[0386] 4-((4-((4-fluorobenzyl)oxy)quinoline-2-carboxamido)methyl)benzoiccid(14e)

[0387] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 85%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ9.58(t,J=6.4Hz,1H),8.23(dd,J=8.5,3.8Hz,1H),8.08(dd,J=8.4,2.9Hz,1H),7.94(d,J=8.0Hz,1H),7.85(dt,J=1 6.2,7.6Hz,2H),7.75(d,J=4.8Hz,1H),7.67(p,J=6.7Hz,3H),7.50(d,J=8.0Hz,1H),7.35–7.20(m,3H),5.50(s,2H),4.60(d,J=6.4Hz,2H).

[0388] 4-((4-Phenylethoxyquinoline-2-carboxamido)methyl)benzoic acid (14f)

[0389] 4-((4-phenethoxyquinoline-2-carboxamido)methyl)benzoic acid(14f)

[0390] The synthesis and purification methods are the same as 5a, except that the substrate is different, yield: 76%, white solid, melting point: >300℃. 1 H NMR (400MHz, DMSO-d6) δ9.35(t,J=6.4Hz,1H),8.14(dd,J=8.4,1.4Hz,1H),8.05(d,J=8.4Hz,1H),7.81(ddd,J=20.3,10.5,5.6Hz,2H ),7.75–7.59(m,2H),7.53–7.40(m,2H),7.34(t,J=7.5Hz,2H),7.23(td,J=7.7,3.9Hz,2H),4.87–4.45(m,4H),3.23(t,J=6.4Hz,2H).

[0391] 4-((4-([[1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)methyl)benzoic acid (14 g)

[0392] 4-((4-([1,1'-biphenyl]-4-ylmethoxy)quinoline-2-carboxamido)methyl)benzoic acid(14g)

[0393] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 64%, yellow-white solid, melting point: 230-232°C. 1 H NMR (400MHz, DMSO-d6) δ9.39(t,J=6.4Hz,1H),8.27(d,J=8.3Hz,1H),8.09(d,J=8.5Hz,1H),7.84–7.78(m,3H),7.75(d,J=8.0Hz,2H ),7.72–7.66(m,5H),7.49(t,J=7.6Hz,2H),7.41(dq,J=14.3,7.5Hz,2H),7.25(d,J=7.9Hz,2H),5.57(s,2H),4.57(d,J=6.5Hz,2H).

[0394] 4-((4-(Naphthalen-1-ylmethoxy)quinoline-2-carboxamido)methyl)benzoic acid (14h)

[0395] 4-((4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamido)methyl)benzoicacid(14h)

[0396] The synthesis and purification methods are the same as 5a, except that the substrate is different. Yield: 68%, yellow-white solid, melting point: 296-298°C. 1 H NMR (400MHz, DMSO-d6) δ9.40(t,J=6.5Hz,1H),8.23–8.19(m,1H),8.10(dd,J=13.4,8.4Hz,2H),8.01(t,J=7.6Hz,2H),7.96(d ,J=3.5Hz,1H),7.82(d,J=7.4Hz,4H),7.58(dd,J=9.7,6.1Hz,4H),7.26(d,J=7.8Hz,2H),5.98(s,2H),4.58(d,J=6.4Hz,2H).

[0397] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(benzyloxy)quinoline-2-carboxamide (HI-28)

[0398] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(benzyloxy)quinoline-2-carboxamide(HI-28)

[0399] Under ice bath cooling, 14a (0.41 g, 1 mmol), o-phenylenediamine (0.11 g, 1 mmol) and HATU (0.45 g, 1.2 mmol) were dissolved in DMF, NMM (0.35 ml, 3 mmol) was added, the mixture was naturally warmed to room temperature, stirred for 8 hours under nitrogen protection, poured into water, and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with 5% citric acid, saturated NaHCO3 solution and brine. After drying over anhydrous MgSO4, the crude product was filtered and evaporated to obtain the crude product. The product was purified by ethyl acetate and petroleum ether column chromatography (petroleum ether: ethyl acetate = 8:1), and then purified by recrystallization from ethanol to obtain the final product. Yield: 65%, white solid, melting point: 204-206°C. 1H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 9.54 (t, J = 6.4Hz, 1H), 8.26 (d, J = 8.3Hz, 1H), 8.10 (d, J = 8.4 Hz,1H),7.94(d,J=8.0Hz,2H),7.87(t,J=8.0Hz,1H),7.75(s,1H),7.72–7.66(m,1H),7.59(d,J= 7.5Hz,2H),7.52–7.43(m,3H),7.39(t,J=7.2Hz,1H),7.16(d,J=7.8Hz,1H),6.96(t,J=7.6Hz,1H ),6.77(d,J=7.7Hz,1H),6.59(t,J=7.3Hz,1H),5.52(s,2H),4.87(s,2H),4.63(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ165.6,143.5,129.1,128.3,128.1,127.6,123.8,121.9,116.5,99.7,70.6.HRMS (ESI + ):m / z calculated for C 31 H 26 N4O3 503.2083, found [M+H] + 503.2041.

[0400] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide (HI-29)

[0401] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide(HI-29)

[0402] The synthesis method is the same as HI-28, except that the substrate is different, and it is purified by ethyl acetate, petroleum ether column chromatography (petroleum ether: ethyl acetate = 5:1), and then recrystallized from anhydrous ethanol. Yield: 68%, white solid, melting point: 208-210°C. 1HNMR(400MHz,DMSO-d6)δ9.62(s,1H),9.54(t,J=6.4Hz,1H),8.21(dd,J=8.4,1.5Hz,1H),8 .09(d,J=8.4Hz,1H),7.95(d,J=8.0Hz,2H),7.86(ddd,J=8.5,6.9,1.5Hz,1H),7.71–7.63(m ,2H),7.49(d,J=8.0Hz,2H),7.20–7.13(m,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8. 0,1.4Hz,1H),6.59(td,J=7.6,1.5Hz,1H),4.88(s,2H),4.64(d,J=6.4Hz,2H),4.14(s,3H). 13 C NMR (101MHz, DMSO) δ164.7,163.5,152.1,147.6,143.5,143.5,133.6,131.2,129.4,128.3, 127.7,127.6,127.1,126.9,123.8,122.1,121.8,116.7,116.5,98.6,56.8,42.9.HRMS(ESI + ):m / z calculated for C 25 H 22 N4O3 427.1765, found [M+H] + 427.1729.

[0403] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-(tert-butylbenzyl)oxy)quinoline-2-carboxamide (HI-30)

[0404] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-(tert-butyl)benzyl)oxy)

[0405] quinoline-2-carboxamide(HI-30)

[0406] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1), and anhydrous ethanol recrystallization. Yield: 52%, white solid, melting point: 164 ~ 166 ℃. 1HNMR(400MHz,DMSO-d6)δ9.61(s,1H),9.54(t,J=6.5Hz,1H),8.24(dd,J=8.5,1.4Hz,1H),8.09(d,J =8.4Hz,1H),7.95(d,J=8.0Hz,2H),7.86(ddd,J=8.4,6.9,1.5Hz,1H),7.76(s,1H),7.68(ddd,J=8. 2,6.9,1.2Hz,1H),7.48(dd,J=8.8,6.9Hz,6H),7.16(d,J=7.8Hz,1H),7.02–6.93(m,1H),6.78(dd, J=8.1,1.4Hz,1H),6.65–6.53(m,1H),5.47(s,2H),4.88(s,2H),4.64(d,J=6.4Hz,2H),1.30(s,9H). 13 C NMR (101MHz, DMSO) δ164.7,162.5,151.2,143.5,131.2,128.3,128.1,127.6,125.8,116.7,116.5,99.6,60.2,42.9,34.8.HRMS(ESI + ):m / z calculated for C 35 H 34 N4O3 559.2631, found [M+H] + 559.2663.

[0407] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-chlorobenzyl)oxy)quinoline-2-carboxamide (HI-31)

[0408] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-chlorobenzyl)oxy)quinoline-2-carboxamide(HI-31)

[0409] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1), and anhydrous ethanol recrystallization. Yield: 58%, white solid, melting point: 190 ~ 192 ℃. 1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.56(t,J=6.5Hz,1H),8.26(dd,J=8.4,1.4Hz,1 H),8.10(d,J=8.4Hz,1H),7.95(d,J=8.0Hz,2H),7.87(ddd,J=8.5,6.8,1.5Hz,1H),7. 82–7.44(m,8H),7.25–7.12(m,1H),6.98(td,J=7.6,1.5Hz,1H),6.80(dd,J=8.0,1.4 Hz,1H),6.62(td,J=7.5,1.4Hz,1H),5.52(s,2H),5.10(s,2H),4.64(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ165.6,164.7,162.3,152.0,147.7,143.5,135.5,133.6,133.2,131.3,129.9,129.4, 129.1,128.3,127.8,127.6,127.1,126.9,124.0,122.2,121.8,117.1,116.8,99.7,69.7,42.9.HRMS(ESI + ):m / z calculated for C 31 H 25 ClN4O3 537.1688, found[M+H] + 537.1661.

[0410] N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-fluorobenzyl)oxy)quinoline-2-carboxamide (HI-32)

[0411] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-fluorobenzyl)oxy)quinoline-2-carboxamide(HI-32)

[0412] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 5:1), and anhydrous ethanol recrystallization. Yield: 64%, white solid, melting point: 208 ~ 210 ℃. 1H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 9.56 (t, J=6.4Hz, 1H), 8.24 (dd, J=8.5, 1.4Hz, 1H), 8.10 (d, J= 8.4Hz,1H),7.96(d,J=8.0Hz,2H),7.87(ddd,J=8.5,6.8,1.5Hz,1H),7.76(s,1H),7.71–7.62(m,3H) ,7.49(d,J=8.0Hz,2H),7.34–7.26(m,2H),7.17(d,J=7.8Hz,1H),6.97(td,J=7.6,1.5Hz,1H),6.78( dd,J=8.0,1.4Hz,1H),6.60(td,J=7.6,1.4Hz,1H),5.50(s,2H),4.89(s,2H),4.64(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ165.6,164.7,162.3,152.1,147.7,143.5,143.4,133.7,132.7,132.7,131.2,130.5,130.4,129 .4,128.3,127.8,127.6,127.1,126.9,123.8,122.2,121.8,116.7,116.5,116.0,115.8,99.7,69.9,42.9.HRMS(ESI + ):m / z calculated for C 31 H 25 FN4O3521.1984, found [M+H] + 521.1942.

[0413] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-phenylethoxyquinoline-2-carboxamide (HI-33)

[0414] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide(HI-33)

[0415] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1), and anhydrous ethanol recrystallization. Yield: 69%, white solid, melting point: 188 ~ 190 ℃. 1H NMR (400MHz, DMSO-d6) δ9.62(s,1H),9.52(t,J=6.5Hz,1H),8.15(dd,J=8.3,1.4Hz,1H),8.07(d,J=8 .4Hz,1H),8.00–7.92(m,2H),7.84(ddd,J=8.4,6.9,1.5Hz,1H),7.70–7.62(m,2H),7.51–7.42(m,4H ),7.37–7.30(m,2H),7.27–7.21(m,1H),7.20–7.13(m,1H),6.97(td,J=7.6,1.6Hz,1H),6.78(dd,J= 8.0,1.4Hz,1H),6.59(td,J=7.5,1.4Hz,1H),4.89(s,2H),4.68–4.54(m,4H),3.23(t,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ164.7,162.5,152.1,147.6,143.5,138.7,133.6,131.1,129.5,129.4,128.8 ,128.3,127.6,127.1,126.8,123.8,122.0,121.8,116.7,116.5,99.1,69.7,42.8,35.0.HRMS(ESI + ):m / z calculated for C 32 H 28 N4O3 517.2234, found [M+H] + 517.2198.

[0416] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(((2-aminophenyl)carbamoyl)benzyl)quinoline-2-carboxamide (HI-34)

[0417] 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-((2-aminophenyl)carbamoyl)benzyl)

[0418] quinoline-2-carboxamide(HI-34)

[0419] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 8:1), and anhydrous ethanol recrystallization. Yield: 72%, white solid, melting point: 180 ~ 182 ℃. 1H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 9.56 (t, J = 6.5Hz, 1H), 8.23–8.19 (m, 1H), 8.16–8. 09(m,2H),8.01(dd,J=9.1,6.5Hz,2H),7.96(t,J=4.1Hz,3H),7.88–7.81(m,2H),7.64–7 .56(m,4H),7.50(d,J=8.0Hz,2H),7.17(d,J=7.8Hz,1H),7.00–6.94(m,1H),6.78(dd,J= 8.1,1.4Hz,1H),6.60(t,J=7.8Hz,1H),5.98(s,2H),4.88(s,2H),4.66(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ167.4,165.6,164.8,162.5,152.1,147.7,143.5,143.5,13 3.8,133.7,132.1,132.0,131.9,131.6,131.2,129.6,129.5,129.1,129.0,128 .3,127.8,127.6,127.5,127.1,126.9,126.6,125.9,124.4,123.8,122.1,121. 9,116.7,116.5,99.9,72.7,69.3,65.5,60.7,42.9,30.4,19.1,14.0.HRMS(ESI + ):m / z calculatedfor C 37 H 30 N4O3 579.2391, found [M+H] + 579.2353.

[0420] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide (HI-35)

[0421] N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(naphthalen-1-ylmethoxy)

[0422] quinoline-2-carboxamide(HI-35)

[0423] The synthesis method is the same as HI-28, except that the substrate is different, and the purification method is ethyl acetate, petroleum ether column chromatography purification (petroleum ether: ethyl acetate = 4:1), and anhydrous ethanol recrystallization. Yield: 52%, white solid, melting point: 258 ~ 260 ℃. 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 9.54 (t, J = 6.4Hz, 1H), 8.29 (d, J = 8.3Hz, 1H), 8.11(d,J=8.3Hz,1H),7.98–7.85(m,3H),7.80–7.65(m,7H),7.48(dd,J=8.2,6.4Hz ,4H),7.43–7.36(m,1H),7.16(d,J=7.8Hz,1H),7.01–6.92(m,1H),6.77(dd,J=7.9, 1.4Hz,1H),6.59(t,J=7.7Hz,1H),5.58(s,2H),4.87(s,2H),4.64(d,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO) δ164.7,162.4,140.5,135.6,133.7,132.0,131.2,129.4,129.1,12 8.7,128.3,127.6,127.4,127.2,116.7,116.5,65.5,42.9,30.4,19.1,14.0.HRMS(ESI + ):m / z calculated for C 35 H 28 N4O3 553.2234, found [M+H] + 553.2206.

[0424] Experimental example

[0425] Activity evaluation of target compounds

[0426] Experimental Example 1 The target compound inhibits histone deacetylase. The results are shown in Table 1

[0427] 1. [Materials]

[0428] Stock solutions of target compounds and positive controls SAHA and MS-275 (10 mM, dissolved in dimethyl sulfoxide); HeLa cell nuclear extract; Boc-Lys-AMC Substrate; HDAC Buffer; pancreatin; Trichostatin A (TSA, 0.3 mM, dissolved in dimethyl sulfoxide); 96-well plate; Thermo Varioskan Flash full-wavelength multi-function microplate reader;

[0429] 2. [Methods]

[0430] (1) Preparation of HDAC buffer

[0431] Weigh 60.57g of Tris, dissolve it in slightly less than 480mL of distilled water, adjust pH to 8 with concentrated hydrochloric acid, and then make up to 500mL with distilled water to obtain 1M Tris-HCl stock solution. Take 7.5mL of 1M Tris-HCl stock solution, add 0.0365g of EDTA, 7.31g of NaCl, and 50mL of glycerol, and make up to 500mL with distilled water to obtain HDAC buffer;

[0432] (2) Preparation of Trypsin solution

[0433] Take 25 mL of 1 M Tris-HCl stock solution, add 2.92 g of NaCl, make up to volume with distilled water, and then add appropriate amounts of trypsin and TSA (make the concentration of trypsin to 10 mg / mL and the concentration of TSA to 2 μM) before use.

[0434] (3) Preparation of substrate solution

[0435] The substrate was dissolved in DMSO to prepare a 30 mM stock solution, which was then diluted to 300 μM with HDAC buffer so that the DMSO content was about 1%.

[0436] (4) Dilution of enzyme solution

[0437] Dilute the enzyme solution with HDAC buffer at a ratio of 1:80.

[0438] (5) Preparation of compound solution

[0439] Dilute the compounds (test compounds and positive control drug SAHA) to 5× final concentration using HDAC buffer

[0440] (6) Preparation and determination of 100% and blank

[0441] ① Preparation and determination of 100% solution:

[0442] 50 μL HDAC buffer was mixed with 10 μL enzyme solution. After 5 min, 40 μL substrate was added and reacted at 37°C for 0.5 h. Then 100 μL Trypsin solution was added to terminate the reaction. After reacting at 37°C for 20 min, the fluorescence intensity was measured at (390 nm / 460 nm), which was 100% absorption.

[0443] ②Preparation and determination of blank solution:

[0444] Add 40 μL substrate to 60 μL HDAC buffer and react at 37°C for 1 h

[0445] Add 100 μL of Trypsin solution and react at 37°C for 1 h, then measure the fluorescence intensity at (390 nm / 460 nm) to obtain the blank absorption.

[0446] (2) Determination of the inhibitory activity of HDACs by compounds:

[0447] 50 μL of HDAC buffer containing drugs was mixed with 10 μL of enzyme solution and pre-incubated for 5 min. After adding 40 μL of substrate, the reaction was allowed to proceed at 37°C for 1 h. Then, 100 μL of Trypsin solution was added to terminate the reaction. After reacting at 37°C for 1 h, the fluorescence intensity was measured at (390 nm / 460 nm).

[0448] (3) Calculate inhibition rate and IC using software and formula 50 value

[0449] Terminology Note:

[0450] SAHA: vorinostat; M: mole / liter; mM: millimole / liter; μM: micromole / liter; mL: milliliter; μL: microliter; IC 50 : half inhibitory concentration; TSA: Trichostatin A, HDAC inhibitor; Substrate: 300μM Boc-Lys-AMC solution; Enzyme solution: a solution obtained by diluting HeLa cell nuclear extract 80 times with HDAC buffer.

[0451] Table 1 Results of in vitro inhibition of HDACs by target compounds

[0452]

[0453]

[0454] Experimental Example 2 Experiment on the inhibition of tumor cell proliferation by target compounds

[0455] The target compounds with good HDAC inhibitory activity were selected for in vitro tumor cell proliferation inhibition experiments. The results are shown in Table 2

[0456] 1. [Materials]

[0457] Tumor cell lines, MTT, 10% fetal bovine serum (Hyclone, USA), 2.5 g·L-1 trypsin (Gibco, USA), modified RPMI1640 medium (Hyclone, USA), positive control drug SAHA, 96-well plate;

[0458] 2. [Methods]

[0459] Culture cells routinely and collect logarithmically growing cells for experiments; dilute the logarithmically growing cells to 4×10 4 pc·mL -1 Then inoculate in a 96-well plate (100 μL per well), and the wells without cells are used as blank wells, and then cultured in a constant temperature incubator (37°C, 5% carbon dioxide) for 8 hours; add the target compound solution prepared with culture medium and the positive drug (SAHA) solution, and the wells without drugs are used as 100% wells. After culturing in a constant temperature incubator (37°C, 5% carbon dioxide) for 48 hours, 30 μL of MTT is added, and the liquid in the wells is removed after four hours (suspended cells need to be centrifuged), 150 μL of DMSO is added, and finally shaken in a constant temperature shaker for 10 minutes. The absorbance value of each well is measured at a wavelength of 570 nm using an enzyme reader to calculate the inhibition rate and IC 50 value;

[0460]

[0461]

[0462] The data in Table 2 are the average values ​​of three experiments, and the values ​​after “±” represent the standard deviation

[0463] in conclusion:

[0464] These compounds have good HDAC inhibitory activity, and the tested compounds all showed good anti-tumor cell proliferation activity. In the future, in-depth activity research can be carried out to develop more active compounds for the preparation of prevention and treatment of related mammalian diseases caused by abnormal histone deacetylase expression.

Claims

1. A histone deacetylase inhibitor, which is a compound represented by the following formula I or a pharmaceutically acceptable salt or stereoisomer thereof; in, R1 is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring part of the aryl, aralkyl, alkaryl, benzyl or heterocyclic is substituted by any substituent; R2 is independently selected from positive amines of 1 to 6 carbon atoms, wherein the nitrogen atom forms an amide with the carbonyl group in the parent nucleus; The R3 substituent is located at the terminal carbon atom; R3 is selected from aryl, heteroaryl, aralkyl, heteroaralkyl or cycloalkyl substituted with N-hydroxycarboxamide or N-hydroxycinnamic amide, or aryl, heteroaryl, aralkyl or heteroaralkyl substituted with N-o-aminobenzoyl, wherein the aryl, heteroaryl, aralkyl, heteroaralkyl or cycloalkyl is substituted with any substituent, or isohydroxamic acid, or carboxyl.

2. The histone deacetylase inhibitor according to claim 1, characterized in that Histone deacetylase inhibitors are: Histone deacetylase inhibitors having a hydroxamic acid structure, histone deacetylase inhibitors having an N-hydroxycinnamic amide structure, histone deacetylase inhibitors having an N-hydroxybenzamide structure or an N-anthranilamide structure.

3. The histone deacetylase inhibitor according to claim 1, characterized in that The histone deacetylase inhibitor is selected from one of the following: 4-(Benzyloxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide; N-(6-(Hydroxyamino)-6-oxohexyl)-4-phenylethoxyquinoline-2-carboxamide; 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide; 4-((4-(tert-butyl)benzyl)oxy)-N-(6-(hydroxyamino)-6-oxohexyl)quinoline-2-carboxamide; 4-((4-chlorobenzyl)oxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide; N-(7-(Hydroxyamino)-7-oxoheptyl)-4-phenylethoxyquinoline-2-carboxamide; 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(7-(hydroxyamino)-7-oxoheptyl)quinoline-2-carboxamide; N-(7-(Hydroxyamino)-7-oxoheptyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide; (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide; (E)-4-(Benzyloxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-4-((4-chlorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-4-((4-fluorobenzyl)oxy)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-N-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-((4-methoxybenzyl)oxy)quinoline-2-carboxamide; (E)-N-(4-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carboxamide; (E)-N-(3-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-methoxyquinoline-2-carboxamide; (E)-4-(((4-(tert-butyl)benzyl)oxy]-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-4-((4-chlorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-4-((4-fluorobenzyl)oxy)-N-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)quinoline-2-carboxamide; (E)-N-(3-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-phenethoxyquinoline-2-carboxamide; (E)-N-(3-(3-(Hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide; N-(4-(Hydroxycarbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide; 4-(Benzyloxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide; 4-((4-(tert-butyl)benzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide; 4-((4-chlorobenzyl)oxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide; N-(4-(Hydroxycarbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide; 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(hydroxycarbamoyl)benzyl)quinoline-2-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(benzyloxy)quinoline-2-carboxamide; N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-methoxyquinoline-2-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-((4-(tert-butylbenzyl)oxy)quinoline-2-carboxamide; N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-chlorobenzyl)oxy)quinoline-2-carboxamide; N-(4-(((2-aminophenyl)carbamoyl)benzyl)-4-((4-fluorobenzyl)oxy)quinoline-2-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-phenethoxyquinoline-2-carboxamide; 4-([1,1'-biphenyl]-4-ylmethoxy)-N-(4-(((2-aminophenyl)carbamoyl)benzyl)quinoline-2-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(naphthalen-1-ylmethoxy)quinoline-2-carboxamide.

4. The histone deacetylase inhibitor according to claim 1, characterized in that The compound represented by formula I or its pharmaceutically acceptable salt or stereoisomer, wherein the pharmaceutically acceptable salt is a salt prepared by mixing the compound represented by formula I with an acid or a base; Acid addition salts are formed with acids which form non-toxic salts and are acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, bicarbonate, butyrate, camphorate, camphorsulfonate, carbonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, isethionate, e), lactate, maleate, malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, sucrose salt, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, hydrogen phosphate, dihydrogen phosphate, p-toluenesulfonate, trifluoroacetate or undecanoate; Base addition salts are obtained during the final isolation and purification of the compounds by reacting the carboxylic acid-containing moiety with a base or with ammonia or an organic primary, secondary or tertiary amine. Base addition salts are based on cations of alkali metals or alkaline earth metals, non-toxic quaternary ammonium and amine cations, organic amines for the formation of base addition salts.

5. The histone deacetylase inhibitor according to claim 1, characterized in that The compound represented by formula I or its pharmaceutically acceptable salt, stereoisomer, the stereoisomer is the stereoisomer form of the compound represented by formula I or its physiological derivative.

6. A method for preparing the histone deacetylase inhibitor having a hydroxamic acid structure as claimed in claim 2, The synthetic route is as follows: R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring part of the aryl, aralkyl, alkaryl, benzyl or heterocyclic is substituted by any substituent, and n=5 or 6; (a) Aniline was dissolved in methanol, and dimethyl butynedioate was added dropwise at 0°C. The reaction solution was then heated to 80°C and refluxed for 8 hours. The solvent was removed by vortexing and purified by column chromatography to obtain a pure light yellow oily intermediate 2. (b) Mix the light yellow oily intermediate 2 with polyphosphoric acid, slowly heat to 120° C., maintain the temperature for 2-3 hours, dissolve with 10% potassium carbonate solution until bubbles are no longer generated, filter, wash with water, and dry to obtain intermediate 3; (c) Intermediate 3 is substituted with benzyl bromide, methyl iodide or 2-chlorohexylbenzene by K2CO3 in DMF to obtain intermediate 4; (d) intermediate 4 and lithium hydroxide react in a mixed solution of tetrahydrofuran and water to obtain intermediate 5; (e) intermediate 5 and 6-aminohexanoic acid hydrochloride or 7-aminoheptanoic acid hydrochloride are dissolved, HATU is dissolved in DMF, NMM is added, and the reaction is carried out at room temperature to obtain intermediate 6; (f) Intermediate 6 is reacted with hydroxylamine methanol solution at room temperature to obtain the final product.

7. A method for preparing the histone deacetylase inhibitor having an N-hydroxycinnamic amide structure as claimed in claim 2, in, R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring portion of the aryl, aralkyl, alkaryl, benzyl or heterocyclic can be substituted with any substituent; Reagents and conditions: (a) triethylamine, di-tert-butyl dicarbonate, reaction at room temperature for 8 hours; (b) methyl acrylate, triethylamine, tetrakistriphenylphosphine palladium, 130°C, 12 hours; (c) saturated solution of hydrogen chloride in ethyl acetate, room temperature; (d) compound 5, HATU, NMM, DMF, room temperature, 8 hours; (e) hydroxylamine hydrochloride, KOH, methanol, room temperature, overnight.

8. A method for preparing the histone deacetylase inhibitor having an N-hydroxybenzamide structure or an N-anthranilyl group as claimed in claim 2, comprising the steps of: in, R is independently selected from hydrogen, alkyl, cycloalkyl, alkaryl, aryl, 5-10 membered saturated or partially saturated heterocyclic or heteroaryl, benzyl, wherein the ring portion of the aryl, aralkyl, alkaryl, benzyl or heterocyclic can be substituted with any substituent; Reagents and conditions: (a) Compound 5, HATU, NMM, DMF, room temperature, 8 h; (b) Hydroxylamine hydrochloride, KOH, methanol, room temperature, overnight; (c) LiOH, H2O / THF, room temperature; (d) o-phenylenediamine, HATU, NMM, DMF, room temperature, 8 h.

9. Use of the compound of formula I according to claim 1 or its pharmaceutically acceptable salt or stereoisomer in the preparation of a drug for preventing or treating mammalian diseases caused by abnormal expression or dysfunction of histone deacetylase, wherein the disease is cancer, neurodegenerative disease, inflammation, viral infection, diabetes, or malaria.

10. A pharmaceutical composition suitable for oral administration to a mammal, comprising the compound of formula I according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutically acceptable carrier, and optionally one or more pharmaceutically acceptable excipients; A pharmaceutical composition suitable for parenteral administration to a mammal, comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.

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