CN1566065A - Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof - Google Patents

Abstract

The present invention relates to γ-butyronic acid derivatives containing γ-aryl-α-substituted amino-β-substituents represented by the general formula (I), their preparation methods, pharmaceutical compositions containing them, and as medicines, Especially as a medicine for treating osteoarthritis and tumors.

Description

γ-aryl butanonic acid derivatives substituted by α-position heteroatoms, their preparation methods, pharmaceutical compositions and uses thereof

technical field

The present invention relates to butyronic acid derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as medicine for treating osteoarthritis and tumor.

Background technique

Matrix metalloproteinases (Matrix Metalloproteinases, MMPs) is a general term for a class of endopeptidases with zinc ions in their active sites, which exist on the extracellular matrix and membrane surfaces. It is mainly secreted by fibroblasts, neutrophils, macrophages and tumor cells in the form of inactive zymogen, and activated by corresponding enzymes in the extracellular matrix (Extra Cellular Matrix, ECM). MMPs can hydrolyze different protein substrates, such as: collagen, gelatin, proteoglycan, fibroblast, elastin, etc. It is regulated in three ways in vivo: mediated by cytokines and growth factors; activation of zymogens; and participation of endogenous inhibitors (TIMPs, Tissue Inhibitors of Matrix Metalloproteinase). Under normal physiological conditions, it shows the degradation of joint soft tissue, promotes the metabolism of articular cartilage, promotes the attachment and adhesion of cells, and has the effect of promoting angiogenesis. According to different hydrolysis substrates, MMPs can be divided into four categories: gelatin protease, collagen protease, interstitial lytic enzyme and membrane type matrix metalloprotease. So far, about 24 kinds of matrix metalloproteinases have been discovered, and their three-dimensional structures have been basically determined by X-ray and nuclear magnetic resonance techniques. The study of gene molecular biology shows that the homology of these MMPs subtypes is 40%-60%. In recent years, pathological studies have found that MMPs are highly expressed in inflammatory cells, especially in bone and joint inflammatory cells and in the process of tumor invasion and metastasis. It shows that osteoarthritis and tumor invasion and metastasis are related to the overexpression of MMPs. Studies have also shown that osteoarthritis may be related to MMP-1 and MMP-3, while tumors are not only related to MMP-1 and MMP-3, but also closely related to MMP-2 and MMP-9.

Drug design based on structure and hydrolysis mechanism is currently the most widely used method for the design of MMPs inhibitors. Many literatures and patents have published and reported some designed and synthesized MMPs inhibitors, such as peptidomimetic MMPs inhibitors: Marimastat BB-2516 (British BiotechReport and Accounts 1994; Drug Discovery Today, 1996, 1, 16-26) , Barimastat BB-94 (Patent No. EP498665; WO9213831), Trocade Ro32-3555 (Patent No. EP684240; JP95291938), etc.; non-peptide MMPs inhibitor PrinomastatAG-3340 (Patent No. US5753653), Bay12-9566 (Patent No. 9615096), CGS-27023A (Patent No. EP606046; JP94256293) etc. But so far, no antineoplastic and anti-inflammatory drugs targeting MMPs have been approved for marketing, and even many MMPs inhibitors that have entered clinical phase III have stopped clinical trials and terminated clinical development. Clinical trials have found that many antineoplastic or anti-inflammatory drugs currently used as MMPs inhibitors have no significant curative effect compared with placebo in the test, and there is no obvious anti-tumor or anti-inflammatory effect when used alone, and they generally have adverse effects on skeletal muscle and Joint damage, mainly manifested as muscle soreness and joint stiffness. Therefore, it is an urgent need in this field to design and develop new MMPs inhibitors as anti-tumor or anti-inflammatory drugs.

Contents of the invention

In order to overcome the deficiencies in the prior art, the purpose of the present invention is to provide a new derivative;

Another object of the present invention is to provide a new preparation method of derivatives;

Another object of the present invention is to provide a new composition containing derivatives;

Another object of the present invention is to provide a new derivative and its application in anti-tumor or anti-inflammatory drugs prepared from the derivative.

In order to accomplish the purpose of the present invention, the present invention takes following technical scheme:

One aspect of the present invention relates to compounds as shown in general formula (I) and pharmaceutically acceptable salts thereof

Wherein, R1 is selected from C _1～8 linear or branched alkyl and alkoxy, alkylthio, alkylamino; cycloalkyl; halogen, nitro, cyano, hydroxyl; -COOR ⁵ ,- OCOR ⁶ , -NHCOR ⁷ , -CONHR ⁸ , wherein R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently selected from C ₁ to C ₄ alkyl, cycloalkyl or phenyl

or

M is an oxygen atom, a sulfur atom, an amino group, a methylene phenyl group, a phenoxy group, a phenylthio group, an anilino group, and a benzyl group;

^R is selected from C _1-4 alkyl, alkoxy, alkylthio, alkylamino, hydroxyl, amino, halogen-substituted phenyl, phenoxy, phenylthio, anilino, benzyl; selected from heterocyclyl and substituted heterocyclyl;

R2 is selected from O, S, =NR ⁹ , =NOR ¹⁰ , wherein R ⁹ and R ¹⁰ are independently selected from H, C _1-4 alkyl or cycloalkyl, and phenyl;

Z is selected from H, NH, O, S, = _CH2 ;

When Z=NH, O, S, R3 is selected from H, C _1～6 straight chain or branched alkyl; cycloalkyl; phenyl and substituted phenyl; heterocyclic and substituted heterocyclic; -COR ¹¹ , wherein R ¹¹ is selected from C _1-4 alkyl, cycloalkyl, phenyl and substituted phenyl.

When Z=CH ₂ , R3 is selected from phthaloyl-2-yl, succinyl-2-yl, hydantoin-3-yl, R ¹² W[R ¹² is selected from H, C _{1～ 6} Alkyl _{; Cycloalkyl} ; Phenyl and substituted phenyl; ^{Heterocyclic and} substituted heterocyclic; ); W is selected from O, S, NH;

Y is selected from NH, O, S;

R4 is selected from H, C _1～6 linear or branched alkyl, cycloalkyl; phenyl and substituted phenyl; benzyl and phenylalkyl; -COR ¹⁴ , wherein R ¹⁴ is selected from C ₁ ～C ₄ Alkyl, phenyl, phenylalkyl and substituted phenyl, phenylalkyl; also can be selected from heterocyclic group;

X is selected from OH, NHOH.

Wherein, the heterocyclic group is selected from pyridyl, pyrrolyl, furyl, thienyl, pyryl, pyridyl, piperazinyl.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Ia)

Wherein, R1 and R4 are as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Ib)

Wherein, R1 and R4 are as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Ic)

Wherein, R1 is as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Id)

Wherein, R1 is as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Ie)

Wherein, R1 and R4 are as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (If)

Wherein, R1, R3 and R4 are as defined above.

According to the present invention, preferred compounds of general formula (I) include but are not limited to compounds represented by formula (Ig)

Wherein, R1 is as defined above.

According to the present invention, more preferred compounds include, but are not limited to, compounds of the formula

2-(2-Hydroxyethylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

2. 2-Benzylamino-4-oxo-4-(4'-biphenyl)butanoic acid

2-n-Butylamino-4-oxo-4-(4'-biphenyl)butanoic acid

2-n-octylamino-4-oxo-4-(4'-biphenyl)butanoic acid

2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

2-Cyclohexylamino-4-oxo-4-(4'-biphenyl)butanoic acid

2-Cyclopropylamino-4-oxo-4-(4'-biphenyl)butanoic acid

2-(3-Phenylpropylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(4-Hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(4-Morpholinyl)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(4-Hydroxy-N-piperidinyl)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(2-Hydroxyethylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-Benzylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-n-Butylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-n-octylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-Cyclohexylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-Cyclopropylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(3-Phenylpropylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(4-Hydroxybutylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(4-Morpholinyl)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(4-Piperidinyl)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid

2-(2-Hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-Benzylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-n-Butylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-n-octylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-Cyclohexylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-Cyclopropylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(3-Phenylpropylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(4-Hydroxybutylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(4-Morpholinyl)-4-oxo-4-(4'-methoxyphenyl)butanoic acid

2-(2-Hydroxyethylthio)-4-oxo-4-(4'-biphenyl)butanoic acid

N-Hydroxy-2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)butanamide

N-Hydroxy-2-[2-(N-succinimidyl)ethylthio]-4-oxo-4-(4'-biphenyl)butanamide

2-Propylthio-4-oxo-4-(4'-biphenyl)butanoic acid

2-(2-Hydroxyethylthio)-2-methyl-4-oxo-4-(4'-biphenyl)butanoic acid

N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)butanamide

N-Hydroxy-2-benzylamino-4-oxo-4-(4'-biphenyl)butanamide

N-Hydroxy-2-benzylamino-4-oxo-4-(4'-methoxyphenyl)butanamide

N-Hydroxy-2-octylamino-4-oxo-4-(4'-methoxyphenyl)butanamide

N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4'-phenoxyphenyl)butanamide

N-Hydroxy-2-benzylamino-4-oxo-4-(4'-phenoxyphenyl)butanamide

N-Hydroxy-2-(4-hydroxybutylamino)-4-oxo-4-(4'-phenoxyphenyl)butanamide

2-(4-Morpholinyl)-4-oxo-4-[4'-(4"-chloro)biphenyl]butanoic acid

2-(2-Hydroxyethylamino)-4-oxo-4-[4'-(4"-chloro)biphenyl]butanoic acid

2-(4-Methylphenylthio)-4-oxo-4-(4'-biphenyl)butanoic acid

2-(2-Aminoethylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

N-hydroxy-2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butyramide and pharmacodynamically acceptable hydrochloride.

N-hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl)butyramide and pharmacodynamically acceptable hydrochloride.

N-Hydroxy-2-hydroxy-3-acetamido 4-oxo-4-(4'-biphenyl)butanamide.

N-Hydroxy-2-[2-(4-nitrophenoxy)ethylthio]-4-oxo-4-(4'-biphenyl)butanamide

2-(2-Hydroxyethylamino)-4-phenoxy-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-benzylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-n-octylamino-4-phenoxy-3-(4'-bibenzoyl)butyric acid and pharmacodynamically acceptable hydrochloride.

2-(2-N,N'-Dimethylaminoethylamino)-4-phenoxy-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride .

2-n-butylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-cyclohexylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-(2-hydroxyethylamino)-4-(4-tolylthio)-3-(4'-bibenzoyl)butyric acid and pharmacodynamically acceptable hydrochloride.

2-benzylamino-4-(4-tolylthio)-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-(2-N,N'-dimethylaminoethylamino)-4-(4-tolylthio)-3-(4'-bibenzoyl)butanoic acid and pharmacodynamically acceptable hydrochloride.

2-n-octylamino-4-(4-tolylthio)-3-(4'-bibenzoyl)butyric acid and pharmacodynamically acceptable hydrochloride.

4-(4-Biphenyl)-2-(2-hydroxyethylthio)-4-hydroxyiminobutanoic acid.

4-(4-Biphenyl)-2-(2-propylthio)-4-hydroxyiminobutanoic acid

4-(4-Biphenyl)-2-(4-methylphenylthio)-4-hydroxyiminobutanoic acid

According to the present invention also relates to the method for preparing compound of the present invention, can comprise respectively: Method 1:

(A) Michael addition of α, β unsaturated γ aryl butanonic acid cis-trans mixtures obtained by Friedel-Crafts reaction with various primary amines or thiols in an appropriate solvent to obtain the corresponding addition products.

Described solvent comprises: various linear ethers (such as: ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monomethyl ether ), tetrahydrofuran, benzene or substituted benzene (such as: toluene, xylene, chlorobenzene), acetone, butanone, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol and the above mixture of solvents.

Method 2:

(A) 4-(4-substituted phenyl)-2-(substituted amino)-4-oxobutanoic acid in alcohol and thionyl chloride at an appropriate temperature to prepare 4-(4-substituted phenyl) -2-(substituted amino)-4-oxobutyrate hydrochloride;

(B) The obtained ester hydrochloride is reacted with hydroxylamine hydrochloride and alkali in alcohol to generate the corresponding hydroxamic acid.

The alcohol described in the step (A) includes methanol and ethanol, and the temperature range includes room temperature to the reflux temperature of the solvent; the alcohol described in the step (B) corresponds to the alcohol described in (A), and the alkali includes potassium hydroxide, Sodium hydroxide, potassium alkoxide or sodium alkoxide (the alcohol corresponds to that described in (A)).

Method 3:

(A) In an appropriate solvent, react 2-(2-hydroxyethylmercapto)-4-oxo-4-(4'-substituted phenyl)butanoic acid with methyl iodide or dimethyl sulfate and potassium carbonate to prepare get the corresponding methyl ester;

(B) Mitsunobu reaction, under the action of triphenylphosphine and diethyl azodicarboxylate, the 2-(2-hydroxyethylmercapto)-4-oxo-4-(4'-biphenyl group obtained in the previous step ) methyl butyrate reacts with succinimide or phthalimide or substituted phenols to generate the corresponding product 2-[2-(2-succinimide) ethylmercapto]-4-oxo -4-(4'-substituted phenyl) methyl butyrate or 2-[2-(2-phthalimido)ethylmercapto]-4-oxo-4-(4'-biphenyl base) butyric acid methyl ester or 2-[2-(4”-nitrophenoxy) ethyl mercapto]-4-oxo-4-(4’-biphenyl) butyric acid methyl ester;

(C) reacting the methyl butyrate obtained above with hydroxylamine hydrochloride and alkali in methanol to generate the corresponding hydroxamic acid.

The alkali described in step (C) includes potassium hydroxide, sodium hydroxide, potassium methylate, sodium methylate.

Method 4:

(A) Addition of mercaptoethanol to trans-alpha methyl-alpha, beta unsaturated gamma aryl butanonic acid in an alcohol solution of alkali to prepare the corresponding addition product.

The alkali includes potassium hydroxide, sodium hydroxide, potassium methylate, sodium methylate; the alcohol includes methanol and ethanol.

Method 5:

(A) In alcohol, substituted acetophenone, glyoxylic acid monohydrate and various amines undergo Mannich condensation to generate corresponding Mannich condensation products.

The alcohols include methanol and ethanol, and the temperature range includes room temperature to the reflux temperature of the solvent used.

Method 6:

(A) 3-(4'-substituted benzoyl)-3-butenoic acid is subjected to bromine addition to obtain 3,4-dibromo 3-(4'-substituted benzoyl)butanoic acid;

(B) Protect the hydroxyl group of the obtained 3,4-dibromo-3-(4'-substituted benzoyl)butanoic acid to obtain 3,4-dibromo-3-(4'-substituted benzoyl)butyric acid acid derivatives;

(C) β elimination of the obtained 3,4-dibromo-3-(4'-substituted benzoyl)butyrate to generate 4-bromo-3-(4'-substituted benzoyl)-2-butene acid derivatives;

(D) Reaction of the obtained 4-bromo-3-(4'-substituted benzoyl)-2-butenoic acid derivative with R3H to obtain the corresponding 4-substituted-3-(4'-substituted benzoyl) - 2-butenoic acid derivatives;

(E) deprotecting the substituted crotonate obtained in (D) into the corresponding acid;

(F) Add the resulting 4-substituted-3-(4'-substituted benzoyl)-2-butenoic acid to the corresponding primary amine to prepare 2-substituted amino-4-substituted-3-(4 '-substituted benzoyl)-2-butanoic acid.

The used solvent of step (A) comprises dichloromethane, chloroform, carbon tetrachloride, 1,2-ethylene dichloride, chlorobenzene, acetic acid, various linear ethers, or be selected from their mixture; Preferably The linear ethers are diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and more preferred solvents are.

The protection reaction in step (B) is preferably 3,4-dibromo-3-(4'-substituted benzoyl) butanoic acid and alcohol carry out esterification reaction; The esterification reaction is preferably under the catalysis of concentrated sulfuric acid; Preferred alcohol Includes methanol and ethanol.

Step (C) 3,4-dibromo-3-(4'-substituted benzoyl) butyrate undergoes β-elimination, preferably under the action of a base, preferably under the action of an organic base, and the preferred organic base includes triethyl Amines, pyridine, N-methylmorpholine, DBU, DBN.

The solvent used for the reaction is preferably an aprotic polar solvent, and the preferred aprotic polar solvent includes dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, various linear Ethers; preferred linear ethers are diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, diglyme;

The preferred R3H of step (D) includes substituted phenol, substituted thiophenol, phthalamide, succinimide. The reaction is preferably carried out under alkaline conditions, and the preferred base includes potassium carbonate, sodium carbonate, potassium hydroxide, Sodium Hydroxide, DBU, DBN.

Preferred solvents include DMF,

The deprotection of the ester in step (E) is preferably carried out under the action of a base, and the preferred base includes potassium hydroxide, sodium hydroxide, and lithium hydroxide.

The solvent described in step (F) is the same as method 1 (A). Used solvents include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, acetic acid, various linear ethers, or their mixtures; preferred linear ethers The most preferred solvents are diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether.

Method 7:

(A) Methylation of the carboxylic acid hydroxyl group of 2-hydroxy-3-acetamido-4-oxo-4-(4'-substituted phenyl)butanoic acid.

(B) 2-Hydroxy-3-acetamido-4-oxo-4-(4'-substituted phenyl)butyric acid methyl ester was prepared into the corresponding hydroxamic acid by the method described in method 2(B).

Preferred methylating reagents in step (A) include methyl iodide, dimethyl sulfate, methylation is preferably under alkaline conditions, and the preferred base is potassium carbonate; the preferred solvent for the reaction is DMF;

Method 8:

(A) In alcohol solution, 2-thioether substituted-4-(4'-biphenyl)-4 oxobutanoic acid reacts with hydroxylamine hydrochloride and alkali to make corresponding condensation products.

The alcohols include methanol, ethanol, t-butanol. The base includes potassium hydroxide, sodium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide.

The preferred reaction schemes of various methods are as follows:

method 1

Method 2

Method 3

Method 4

Method 5

Method 6:

Method 7:

Method 8:

The present invention therefore also relates to pharmaceutical compositions comprising, as active ingredient, an effective dose of at least one compound of general formula (I) and/or a stereoisomer thereof together with customary pharmaceutical excipients or adjuvants. Usually the pharmaceutical composition of the present invention contains 0.1-90% by weight of the compound of general formula (I) and/or its physiologically acceptable salt.

Pharmaceutical compositions can be prepared according to methods known in the art. When used for this purpose, if necessary, the compound of general formula (I) and/or stereoisomers can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to make it available as human medicine or an appropriate administration form or dosage form for veterinary use.

The compound of general formula (I) of the present invention or the pharmaceutical composition containing it can be administered in unit dose form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal cavity, oral mucosa, skin , peritoneum or rectum, etc. Dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc., can be common preparations, sustained release preparations, controlled Release formulations and various microparticle drug delivery systems. Various carriers known in the art can be widely used for tableting unit dosage forms. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin paste, sodium carboxymethylcellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbate Sugar alcohol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers , such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. In order to formulate a dosage unit into a pellet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethylcellulose, etc. In order to formulate the administration unit into a suppository, various carriers known in the art can be widely used. Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like. In order to form a dosage unit into a capsule, the active ingredient compound of general formula (I) or its stereoisomer is mixed with the above-mentioned various carriers, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of general formula (I) or its stereoisomers can also be made into microcapsules, suspended in an aqueous medium to form a suspension, and can also be packed into hard capsules or made into injections for application. In order to prepare the dosage unit into injection preparations, such as solutions, emulsions, lyophilized powder injections and suspensions, all diluents commonly used in this field can be used, for example, water, ethanol, polyethylene glycol, 1,3 - Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added.

In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

The dosage of the compound of general formula (I) of the present invention or its stereoisomer depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight and individual response of the patient or animal, the used Specific compound, route of administration and frequency of administration, etc. Usually, for patients with a body weight of about 75 kg, the daily dose of the compound of general formula (I) given is 0.001 mg/kg body weight to 100 mg/kg body weight, preferably 0.01 mg/kg body weight to 20 mg/kg body weight, more preferably 0.1 mg/kg Body weight - 5 mg/kg body weight. The above dose can be administered in a single dose or divided into several, eg two, three or four doses.

The present invention carries out in vitro enzyme inhibition test on established MMP1, MMP2, MMP9 enzyme activity screening models, and shows that this type of compound has the activity of inhibiting MMP-1, MMP-2 and MMP-9, and has the ability to MMP-2 or MMP -9 selective inhibition. Osteoarthritis and tumor invasion and metastasis are related to the overexpression of MMPs. Osteoarthritis is related to MMP-1 and MMP-3; tumors are not only related to MMP-1 and MMP-3, but also closely related to MMP-2 and MMP-9. Therefore, the compound of the present invention can be used in the preparation of medicines for treating osteoarthritis and tumors.

Detailed ways

The following examples are used to further illustrate the present invention, but this does not imply any limitation to the present invention.

Example 1:

2-(2-Hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-butyric acid (A): Preparation of 3-(4-phenylbenzoyl)acrylic acid:

Dissolve 23.13 grams of biphenyl and 14.71 grams of maleic anhydride in 300 milliliters of dichloromethane, add 40.00 grams of anhydrous aluminum trichloride in four batches under cooling in an ice-water bath, slowly rise to room temperature, continue to react for 5 hours, and concentrate To dryness, add a mixture of crushed ice and concentrated hydrochloric acid to the obtained viscous liquid, carry out hydrolysis, filter the obtained yellow solid, wash with water until neutral, then wash several times with petroleum ether, after draining, recrystallize with glacial acetic acid to obtain 37.26 gram of yellow crystals, yield: 93.19%, melting point: 168-170°C (literature value: 172-175°C).

(B): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-butyric acid:

Suspend 5.045 grams of 3-(4-phenylbenzoyl)acrylic acid in 100 milliliters of benzene, add 10 milliliters of acetone solution of 1.222 grams of ethanolamine, react at room temperature for 1 hour, filter the white precipitate generated, wash with benzene and acetone respectively, The obtained crude product was soaked in hot ethanol and washed to obtain 6.811 g of white powdery solid, yield: 86.94%, melting point: 185-187° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.827 (t, 2H, J: 5.4Hz), 2.999 (t, 2H, J: 5.4Hz), 3.570 (m, 3H), 7.491 (m, 3H, J: 7.5 Hz), 7.749 (d, 2H, J: 7.5 Hz), 7.835 (d, 2H, J: 8.7 Hz), 8.029 (d, 2H, J: 8.7 Hz).

Example 2:

2-Benzylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 5.434 grams of 3-(4-phenylbenzoyl) acrylic acid, 2.308 grams of benzylamine, and 100 milliliters of ether are used as solvent to obtain 6.877 grams of white powdery solid, yield: 88.83%, melting point: 177-179°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.361 (dd, 1H, J: 7.5Hz, 17.1Hz), 3.456 (dd, 1H, J: 5.4Hz, 17.1Hz), 3.654 (t, 1H, J : 5.4Hz, 6.9Hz), 3.87 (d, 1H, J: 13.5Hz), 3.968 (d, 1H, J: 13.2Hz), 7.159-8.055 (m, 14H).

Example 3:

2-n-Butylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid is used, 0.366 grams of n-butylamine, and 25 milliliters of ether are used as solvents to obtain 1.502 grams of white powdery solids, yield : 92.32%, melting point: 172.6-174.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.867 (t, 3H, J: 7.5Hz), 1.303 (q, 2H, J: 7.5Hz), 1.541 (m, 2H), 2.742 (t, 1H, J: 7.5Hz), 2.883(dd, 1H, J: 7.2Hz, 13.2Hz), 3.552(m, 2H), 3.679(m, 1H), 7.486(m, 3H, J: 7.5Hz), 7.745(d , 2H, J: 7.5), 7.836 (d, 2H, J: 8.4Hz), 8.039 (d, 2H, J: 8.4Hz).

Example 4:

2-n-octylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid is used, 0.646 grams of n-octylamine, and 25 milliliters of ether are used as solvents to obtain 1.676 grams of white powdery solids, yield : 87.86%, melting point: 122.4-126.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.833 (t, 3H, J: 6.6Hz), 1.224 (s, 10H), 1.510 (dd, 2H, J: 7.5Hz, 13.5Hz), 2.776 (m , 2H), 3.326 (dd, 1H, J: 7.2Hz, 18.3Hz), 3.478 (dd, 1H, J: 4.2Hz, 18.3Hz), 3.631 (dd, 1H, J: 4.5Hz, 7.2Hz), 7.024 -8.015 (m, 9H), 8.20 (w, 1H).

Example 5:

2-(2-N,N’-Dimethylaminoethylamino)-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.371 grams of 2-N, N'-dimethylaminoethylamine, and 25 milliliters of benzene are used as solvent , to obtain 1.655 g of white powdery solid, yield: 97.23%, melting point: 140.0-143.0° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.213 (s, 6H), 2.393 (m, 1H), 2.830 (t, 1H), 2.996 (t, 2H, J: 6.0Hz), 3.402-3.692 ( m, 3H), 7.49 (m, 3H, J: 7.5Hz), 7.746 (d, 2H, 7.5Hz), 7.835 (d, 2H, J: 8.4Hz), 8.045 (d, 2H, J: 8.4Hz) .

Embodiment 6:

2-Cyclohexylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid is used, 0.496 grams of cyclohexylamine, and 25 milliliters of ether are used as solvents to obtain 1.494 grams of white powdery solids, yield : 85.03%, melting point: 178.6-180.1°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.196 (m, 4H), 1.289 (d, 1H, J: 11.7Hz), 1.561 (d, 1H, J: 11.7Hz), 1.701 (m, 2H) , 1.932(m, 2H), 2.93(m, 1H), 3.430(m, 2H), 3.797(s, 1H), 7.50(m, 3H, J: 7.5Hz), 7.757(d, 2H, J: 7.5 Hz), 7.850 (d, 2H, J: 8.4 Hz), 8.043 (d, 2H, J: 8.4 Hz).

Embodiment 7:

2-Cyclopropylamino-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.285 grams of cyclopropylamine, and 25 milliliters of ether are used as solvents to obtain 1.476 grams of white powdery solids, yield: 95.42%, melting point: 143.2-146.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.737 (m, 2H), 0.885 (m, 2H), 2.809 (q, 1H, J: 3.6Hz), 3.857 (dd, 1H, J: 5.1Hz, 18.6Hz), 3.927(dd, 1H, J: 4.2Hz, 18.6Hz), 4.525(t, 1H, J: 4.8Hz), 7.506(m, 3H, J: 7.8Hz), 7.764(d, 2H, J : 7.5), 7.881 (d, 2H, J: 8.4Hz), 8.089 (d, 2H, J: 8.4Hz).

Embodiment 8:

2-(3-Phenylpropylamino)-4-oxo-4-(4’-biphenyl)butanoic acid

The method is the same as in Example 1 (B), using 0.757 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.406 grams of γ-amphetamine, and 25 milliliters of ether as solvents to obtain 1.051 grams of white powdery solids, yield: 90.45% , Melting point: 169-170.4°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.974 (m, 2H), 2.641 (t, 2H, J: 7.5Hz), 3.056 (m, 2H), 3.816 (dd, 1H, J: 5.1Hz, 18.9Hz), 3.891(dd, 1H, J: 7.5Hz, 18.9Hz), 4.460(t, 1H, J: 7.5Hz), 7.245(m, 5H), 7.506(m, 3H), 7.765(d, 2H , J: 7.2Hz), 7.882 (d, 2H, J: 8.7Hz), 8.082 (d, 2H, J: 8.4Hz).

Embodiment 9:

2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-biphenyl)butanoic acid

The method is the same as in Example 1 (B), using 2.523 grams of 3-(4-phenylbenzoyl) acrylic acid, 1.022 grams of 3-N, N'-dimethylaminopropylamine, and 50 milliliters of benzene as a solvent to obtain a white powder shaped solid. The obtained solid was dissolved in 15 ml of saturated methanol solution of hydrogen chloride, and 50 ml of anhydrous ether was added to precipitate 4.209 g of white solid, yield: 98.49% (calculated as hydrochloride), melting point: 138-141° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.151 (t, 2H, J: 7.5Hz), 2.727 (s, 6H), 3.184 (m, 4H), 3.881 (dd, 1H, J: 4.8Hz, 18.9Hz), 3.994(dd, 1H, J: 4.8Hz, 18.9Hz), 4.459(t, 1H, J: 4.8Hz), 7.504(m, 3H, J: 7.8Hz), 7.764(d, 2H, J : 7.8Hz), 7.879 (d, 2H, J: 8.4Hz), 8.087 (d, 2H, J: 8.4Hz), 10-11 (w, 2H).

Example 10:

2-(4-Hydroxybutylamino)-4-oxo-4-(4’-biphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 2.523 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.891 grams of 4-hydroxy-n-butylamine, and 50 milliliters of benzene are used as solvents to obtain a white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, 3.017 g of white solid, yield: 79.84% (calculated as hydrochloride), melting point: 139-142° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.455 (p, 2H, J: 7.5Hz), 1.720 (p, 2H, J: 7.5Hz), 3.047 (m, 2H), 3.378 (m, 2H) , 3.833(dd, 1H, J: 5.1Hz, 18.3Hz), 3.871(dd, 1H, J: 4.5Hz, 18.3Hz), 4.428(t, 1H, J: 4.8Hz), 7.504(m, 3H, J : 7.5Hz), 7.764 (d, 2H, J: 7.2Hz), 7.88 (d, 2H, J: 8.4Hz), 8.806 (d, 2H, J: 8.4Hz), 9.2 (w, 1H).

Example 11:

2-(N-morpholinyl)-4-oxo-4-(4’-biphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.436 grams of morpholine, and 25 milliliters of benzene are used as a solvent to obtain 1.29 grams of white powdery solids, yield: 76.0%, melting point: 183-186°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.454 (m, 4H), 2.729 (m, 2H), 3.165 (dd, 1H, J: 3.6Hz, 16.8Hz), 3.614 (dd, 1H, J: 4.2Hz, 16.2Hz), 3.582-3.750(m, 3H), 7.458(m, 3H), 7, 741(dd, 2H, J: 7.8Hz), 7.811(d, 2H, J: 8.4Hz), 8.069 (d, 2H, J: 8.4 Hz).

Example 12:

2-(4-Hydroxy-N-piperidinyl)-4-oxo-4-(4’-biphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.261 grams of 3-(4-phenylbenzoyl) acrylic acid, 0.506 grams of 4-hydroxypiperidine, and 25 milliliters of benzene are used as solvent to obtain 1.158 grams of white powdery solids. Yield: 65.53%, melting point: 134-137°C (decomposition).

¹ HNMR (300MHz, DMSO): 6 (ppm) = 1.384-1.588 (m, 2H), 1.726-1.879 (m, 2H), 2.391 (t, 1H, J: 9.6Hz), 2.675 (t, 1H, J : 9.3Hz), 2.797-2.981(m, 2H), 3.139(m, 1H), 3.678(m, 2H), 3.765(m, 1H), 7.478(m, 3H, J: 7.5Hz), 7.729(d , 2H, J: 7.5Hz), 7.789 (d, 2H, J: 8.4Hz), 8.026 (d, 2H, J: 8.4Hz).

Example 13:

2-(2-Hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl)-butyric acid

(A) Preparation of 3-(4-phenoxybenzoyl)acrylic acid:

Method is the same as embodiment 1 (A), and difference is to use 17.02 gram diphenyl ethers, 9.806 gram maleic anhydrides, and 26.66 gram aluminum chloride, 300 milliliters of methylene dichlorides, gained pale yellow solid with dichloromethane/petroleum ether Recrystallized to obtain 22.69 g of product, yield: 84.59%, melting point: 115-117°C (literature value: 121°C, recrystallized from benzene).

(B) Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl)-butyric acid:

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid is used, 0.305 grams of ethanolamine, and 25 milliliters of benzene are used as solvent to obtain 1.521 grams of white powdery solid, yield: 92.36%, melting point: 155.0-157.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.961 (t, 2H, J: 5.4Hz), 3.398 (dd, 1H, J: 7.8Hz, 18.0Hz), 3.503 (dd, 1H, J: 4.2Hz , 18.0Hz), 3.582(t, 2H, J: 4.8Hz, 3.9Hz), 3.675(dd, 1H, J: 4.5Hz), 7.021(d, 2H, J: 11.7Hz), 7.105(d, 2H, J: 7.8 Hz), 7.233 (t, 1H, 7.5 Hz), 7.447 (t, 2H, J: 7.8 Hz), 7.975 (d, 2H, J: 11.7 Hz).

Example 14:

2-Benzylamino-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.536 grams of benzylamine, and 25 milliliters of ether are used as solvents to obtain 1.523 grams of white powdery solids, yield : 81.13%, melting point: 173.0-174.4°C (decomposition).

¹ H NMR (300MHz, DMSO): δ (ppm) = 3.299 (dd, 1H, J: 6.9Hz, 17.4Hz), 3.382 (dd, 1H, J: 5.4Hz, 17.4Hz), 3.628 (t, 1H, J : 4.2Hz) 3.863 (d, 1H, J: 13.2Hz), 3.956 (d, 1H, J: 13.5Hz), 7.032-8.013 (m, 14H).

Example 15:

2-n-Butylamino-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.366 grams of n-butylamine, and 25 milliliters of ether are used as solvents to obtain 0.904 grams of white powdery solids. Yield: 52.96%, melting point: 164.0-167.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.848 (t, 3H, J: 7.2Hz), 1.283 (q, 2H, J: 14.4Hz), 1.510 (p, 2H, J: 7.2Hz), 2.731 (t, 1H, J: 7.5Hz), 2.838 (dd, 1H, J: 7.5Hz, 13.5Hz), 3.345 (dd, 1H, J: 7.8Hz, 18.0Hz), 3.481 (dd, 1H, J: 4.5 Hz, 18.0 Hz), 3.652 (dd, 1H, J: 4.5 Hz), 6.998-7.993 (m, 9H), 8.25 (w, 1H).

Example 16:

2-n-octylamino-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.646 grams of n-octylamine, and 25 milliliters of ether are used as solvents to obtain 0.888 grams of white powdery solids. Yield: 44.68%, melting point: 164.0-166.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.830 (t, 3H, J: 6.3Hz), 1.223 (s, 10H), 1.505 (dd, 2H, J: 7.5Hz, 13.5Hz), 2.723 (t , 1H, J: 7.5Hz), 2.824 (dd, 1H, J: 7.2Hz, 13.2Hz), 3.332 (dd, 1H, J: 7.8Hz, 18.3Hz), 3.480 (dd, 1H, J: 4.2Hz, 18.3Hz), 3.641 (dd, 1H, J: 4.5Hz, 7.2Hz), 7.014-7.988 (m, 9H), 8.25 (w, 1H).

Example 17:

2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

Method is the same as embodiment 1 (B), and difference is to use 1.341 gram 3-(4-phenoxybenzoyl) acrylic acid, 0.371 gram 2-N, N'-dimethylaminoethylamine, 25 milliliters of benzene do solvent to obtain 1.569 g of white powdery solid, yield: 88.04%, melting point: 137.0-139.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.143 (s, 3H), 2.195 (s, 3H), 2.456 (m, 2H), 2.959 (t, 2H, J: 5.7Hz), 3.373 (dd, 1H, J: 7.5Hz, 18.0Hz), 3.485 (dd, 1H, J: 4.2Hz, 18.0Hz), 3.627 (dd, 1H, J: 4.2Hz, 7.5Hz), 7.026 (d, 2H, J: 8.7 Hz), 7.102 (d, 2H, J: 7.8Hz), 7.232 (t, 1H, J: 7.5Hz), 7.446 (t, 2H, J: 7.8Hz), 7.972 (d, 2H, J: 8.7Hz) .

Example 18:

2-Cyclohexylamino-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.496 grams of cyclohexylamine, and 25 milliliters of ether are used as solvents to obtain 1.024 grams of white powdery solids. Yield: 55.74%, melting point: 184.0-186.5°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.149 (m, 4H), 1.275 (d, 1H, J: 11.7Hz), 1.548 (d, 1H, J: 11.7Hz), 1.681 (m, 2H) , 1.919(m, 2H), 2.894(m, 1H), 3.351(dd, 1H, J: 7.8Hz, 18.0Hz), 3.428(dd, 1H, J: 4.2Hz, 18.0Hz), 3.752(dd, 1H , J: 4.2Hz, 7.8Hz), 6.641-7.980 (m, 9H), 8.2 (w, 1H).

Example 19:

2-Cyclopropylamino-4-oxo-4-(4-phenoxyphenyl)-butanoic acid

The method is the same as Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid is used, 0.285 grams of cyclopropylamine, and 25 milliliters of ether are used as solvents to obtain 0.458 grams of white powdery solids, yield : 28.15%, melting point: 171.2-173.2°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.320 (m, 4H), 2.240 (p, 1H, J: 3.6Hz), 3.255 (d, 2H, J: 6.6Hz), 3.700 (t, 1H, J: 6.6Hz), 7.022 (d, 2H, J: 8.4Hz), 7.11 (d, 2H, J: 8.4Hz), 7.232 (t, 1H, J: 7.5Hz), 7.446 (t, 2H, J: 7.8 Hz), 7.951 (d, 2H, J: 9.0 Hz).

Example 20:

2-(3-Phenylpropylamino)-4-oxo-4-(4-phenoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 2.683 grams of 3-(4-phenoxybenzoyl) acrylic acid, 1.352 grams of γ-amphetamine, and 50 milliliters of ether are used as solvents to obtain a white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, white solid 2.944 g, yield: 66.92% (calculated as hydrochloride), melting point: 140-142° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.971 (p, 2H, J: 7.5Hz), 2.628 (t, 2H, J: 7.5Hz), 3.029 (m, 2H), 3.731 (dd, 1H, J: 5.1Hz, 18.9Hz), 3.809 (dd, 1H, J: 4.5Hz, 18.9Hz), 7.081 (d, 2H, J: 8.7Hz), 7.130 (d, 2H, J: 7.5Hz), 7.194- 7.445 (m, 6H), 7.472 (t, 2H, J: 7.8Hz), 8.018 (d, 2H, J; 8.7Hz), 9.2 (w, 1H).

Example 21:

2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4-phenoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.511 grams of 3-N, N'-dimethylaminopropylamine, and 25 milliliters of benzene are used as solvent , a white powdery solid was obtained. The solid was made into hydrochloride according to the method described in Example 9, white solid 1.225 g, yield: 55.26% (calculated as hydrochloride), melting point: 160-162° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.902 (p, 2H, J: 7.2Hz), 2.654 (s, 6H), 2.893 (m, 2H), 3.021 (t, 2H, J: 7.2Hz) , 3.456(m, 2H), 3.750(m, 1H), 7.048(d, 2H, J: 9.0Hz), 7.117(d, 2H, J: 8.1Hz), 7.248(t, 1H, J: 7.8Hz) , 7.46 (t, 2H, J: 7.8Hz), 7.986 (d, 2H, J: 9.0Hz).

Example 22:

2-(4-Hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 2.683 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.891 grams of 4-hydroxyl-n-butylamine, and 50 milliliters of benzene are used as solvents to obtain a white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, 2.417 g of white solid, yield: 61.37% (calculated as hydrochloride), melting point: 130-133° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.452 (m, 2H), 1.695 (m, 2H), 3.022 (dd, 2H, J: 8.1Hz), 3.373 (m, 2H), 3.764 (m, 2H), 4.391(m, 1H), 7.081(d, 2H, J: 8.7Hz), 7.130(d, 2H, J: 7.8Hz), 7.258(t, 1H, J: 7.5Hz), 7.469(t, 2H, J: 7.8 Hz), 8.023 (d, 2H, J: 8.7 Hz), 9.2 (w, 1H).

Example 23:

2-(N-morpholino)-4-oxo-4-(4-phenoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid is used, 0.436 grams of morpholine, and 25 milliliters of benzene are used as a solvent to obtain white powdery solids, with a yield of 1.157 : 65.11%, melting point: 176-178°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.452 (m, 2H), 2.699 (m, 2H), 2.878 (t, 1H, J: 4.8Hz), 3.102 (dd, 2H, J: 4.2Hz, 17.4Hz), 3.628(dd, 2H, J: 3.9Hz, 9.6Hz), 3.698(dd, 2H, J: 4.5Hz, 9.6Hz), 7.033(d, 2H, J: 8.7Hz), 7.118(d, 2H, J; 8.1 Hz), 7.239 (t, 1H, J: 7.5 Hz), 7.454 (t, 2H, J: 7.8 Hz), 8.015 (d, 2H, J: 8.7 Hz).

Example 24:

2-(N-piperidinyl)-4-oxo-4-(4’phenoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.341 grams of 3-(4-phenoxybenzoyl) acrylic acid, 0.426 grams of piperidine, and 25 milliliters of anhydrous ether are used as solvents to obtain 0.201 grams of white powdery solids. Yield: 11.37%, melting point: 146.5-149.5°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.364-1.599 (m, 8H), 2.568 (t, 1H, J: 5.7Hz), 2.769 (t, 1H, J: 5.7Hz), 2.907 (t, 2H, J: 5.1Hz), 3.671(s, 1H), 7.031(d, 2H, J: 8.7Hz), 7.111(d, 2H, J: 8.1Hz), 7.233(t, 1H, J: 7.5Hz) , 7.451 (t, 2H, J: 8.1 Hz), 7.996 (d, 2H, J: 8.7 Hz).

Example 25:

2-(2-Hydroxyethylamino)-4-oxo-4-(4-methoxyphenyl)-butyric acid

(A): Preparation of 3-(4-methoxybenzoyl)acrylic acid:

Method is the same as Example 1 (A), and difference is to use 10.81 gram anisole, 9.806 gram maleic anhydride, and 26.66 gram aluminum chloride, 300 milliliters of methylene dichloride, gained light yellow solid is with ethyl acetate/petroleum ether Recrystallized to obtain 15.32 g of product, yield: 74.29%, melting point: 119-122°C (literature value: 108-110°C).

(B): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4-methoxyphenyl)-butyric acid:

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.305 grams of ethanolamine, and 25 milliliters of benzene are used as solvents to obtain 1.258 grams of white powdery solids, yield: 94.16%, melting point: 165.2-168.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.956 (t, 2H, J: 5.4Hz), 3.391 (dd, 1H, J: 7.8Hz, 18.3Hz), 3.483 (dd, 1H, J: 4.5Hz , 18.3Hz), 3.570(dd, 2H, J: 5.1Hz, 8.7Hz), 3.656(dd, 1H, J: 4.5Hz, 7.8Hz), 3.819(s, 3H), 7.023(d, 2H, 9.0Hz ), 7.924 (d, 2H, J: 9.0 Hz).

Example 26:

2-Benzylamino-4-oxo-4-(4-methoxyphenyl)-butyric acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.536 grams of benzylamine, and 25 milliliters of ether are used as solvents to obtain 1.408 grams of white powdery solids, yield : 89.87%, melting point: 175.7-177.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.298 (dd, 1H, J: 6.9Hz, 17.4Hz), 3.370 (dd, 1H, J: 5.4Hz, 17.4 Hz), 3.617 (t, 1H, J : 5.4Hz), 3.831(s, 3H), 3.867(d, 1H, J: 13.5Hz), 3.96(d, 1H, 13.5Hz), 7.004-7.955(m, 9H).

Example 27:

2-n-Butylamino-4-oxo-4-(4-methoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.366 grams of n-butylamine, and 25 milliliters of ether are used as solvents to obtain 0.632 grams of white powdery solids. Yield: 45.25%, melting point: 162.6-165.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.852 (t, 3H, J: 7.2Hz, 7.5Hz), 1.284 (q, 2H, J: 7.2Hz, 7.5Hz), 1.533 (p, 2H), 2.837(m, 2H), 3.324(dd, 1H, J: 7.8Hz, 18.0Hz), 3.478(dd, 1H, J: 4.2Hz, 18.0Hz), 3.628(dd, 1H, J: 4.2Hz, 3.9Hz ), 3.825 (s, 3H), 7.033 (d, 2H, J: 11.7Hz), 7.933 (d, 2H, 11.7Hz), 8.2 (w, 1H).

Example 28:

2-n-octylamino-4-oxo-4-(4-methoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.646 grams of n-octylamine, and 25 milliliters of ether are used as solvents to obtain 0.96 grams of white powdery solids. Yield: 57.24%, melting point: 166.0-168.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.836 (t, 3H, J: 6.0Hz, 6.9Hz), 1.225 (s, 10H), 1.514 (t, 2H, J: 6.9Hz, 7.2Hz), 2.778(m, 2H), 3.320(dd, 1H, J: 8.1Hz, 18.0Hz), 3.475(dd, 1H, J: 3.6Hz, 18.0Hz), 3.621(dd, 1H, J: 3.9Hz, 4.2Hz , 7.8Hz), 3.824(s, 3H), 7.033(d, 2H, J: 9.0Hz), 7.934(d, 2H, J: 9.0Hz), 8.15(w, 1H).

Example 29:

2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4-methoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.371 grams of 2-N, N'-dimethylaminoethylamine, and 25 milliliters of benzene are used to make solvent to obtain 1.310 g of white powdery solid, yield: 89.01%, melting point: 126.3-128.7°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.189 (s, 6H), 2.455 (m, 2H), 2.956 (t, 2H, J: 6.0Hz), 3.374 (dd, 1H, J: 7.5Hz, 18.0Hz), 3.465(dd, 1H, J: 4.2Hz, 18.0Hz), 3.611(dd, 1H, J: 3.9Hz, 4.2Hz), 3.819(s, 3H), 7.022(d, 2H, J: 9.0 Hz), 7.4 (w, 1H), 7.919 (d, 2H, J: 8.4Hz).

Example 30:

2-Cyclohexylamino-4-oxo-4-(4-methoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.496 grams of cyclohexylamine, and 25 milliliters of ether are used as solvents to obtain 1.221 grams of white powdery solids. Yield: 79.97%, melting point: 160.0-162.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.155 (m, 3H), 1.392 (t, 2H, J: 10.8Hz), 1.579 (d, 1H, J: 12.0Hz), 1.748 (d, 2H, J: 12.0Hz), 2.084(m, 2H), 3.119(m, 1H), 3.732(d, 2H, J: 5.1Hz), 3.848(s, 3H), 4.497(t, 1H, J: 4.8Hz) , 7.079 (d, 2H, J: 8.7Hz), 7.967 (d, 2H, J: 8.7Hz), 9.00 (w, 1H).

Example 31:

2-Cyclopropylamino-4-oxo-4-(4-methoxyphenyl)-butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid is used, 0.285 grams of cyclopropylamine, and 25 milliliters of ether are used as solvents to obtain 1.257 grams of white powdery solids, yield : 95.48%, melting point: 157.5-159.0°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.338 (m, 4H), 2.242 (p, 1H, J: 3.0Hz, 3.3Hz, 3.6Hz), 3.245 (d, 2H, J: 6.0Hz), 3.696 (t, 1H, J: 6.0Hz), 3.819 (s, 3H), 7.023 (d, 2H, J: 6.9Hz), 7.907 (d, 2H, J: 6.9Hz).

Example 32:

2-(3-Phenylpropylamino)-4-oxo-4-(4-methoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 2.062 grams of 3-(4-methoxybenzoyl) acrylic acid, 1.352 grams of γ-amphetamine, and 50 milliliters of ether are used as solvents to obtain a white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, white solid 2.715 g, yield: 71.85% (calculated as hydrochloride), melting point: 125-128° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.959 (t, 2H, J: 7.5Hz), 2.624 (t, 2H, J: 7.5Hz), 3.026 (d, 2H, J: 7.8Hz), 3.730 (t, 2H, J: 6.3Hz), 3.820 (s, 3H), 4.401 (t, 1H, J: 4.5Hz), 7.082 (d, 2H, J: 8.7Hz), 7.207 (d, 3H, J: 7.5Hz), 7.291 (t, 2H, J: 7.5Hz), 7.972 (d, 2H, J: 8.7Hz), 9.0 (w, 1H).

Example 33:

2-(3-N,N'-Dimethylpropylamino)-4-oxo-4-(4-methoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.031 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.511 grams of 3-N, N'-dimethylaminopropylamine, and 25 milliliters of benzene are used as solvent , to obtain a white powdery solid, which is made into hydrochloride according to the method described in Example 9, to obtain 1.304 grams of white solid, yield: 68.37% (calculated as hydrochloride), melting point: 120-123 ° C (decomposition ).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.672 (p, 2H, J: 6.6Hz), 2.113 (s, 3H), 2.167 (s, 3H), 2.268 (t, 1H, J: 6.6Hz) , 2.373(t, 1H, J: 6.3Hz), 2.791(t, 1H, J: 7.2Hz), 2.912(t, 1H, J: 6.6Hz), 3.462-3.579(m, 3H), 3.841(s, 3H), 7.05 (d, 2H, J: 9.0 Hz), 7.944 (d, 2H, J: 9.0 Hz).

Example 34:

2-(4-Hydroxybutylamino)-4-oxo-4-(4-methoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 2.062 grams of 3-(4-methoxybenzoyl) acrylic acid, 0.891 grams of 4-hydroxy-n-butylamine, and 50 milliliters of ether are used as solvents to obtain a white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, white solid 2.434 g, yield: 62.03% (calculated as hydrochloride), melting point: 150-152° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.427 (p, 2H, J: 7.2Hz), 1.599 (dd, 2H, J: 7.5Hz, 15.3Hz), 2.867 (dd, 2H, J: 7.2Hz , 13.2Hz), 3.290-3.477(m, 4H), 3.628(m, 1H), 3.836(s, 3H), 7.045(d, 2H, J: 9.0Hz), 7.943(d, 2H, J: 8.7Hz ).

Example 35:

2-(N-morpholino)-4-oxo-4-(4-methoxyphenyl)butanoic acid

The method is the same as in Example 1 (B), except that 1.031 gram of 3-(4-methoxybenzoyl) acrylic acid is used, 0.436 gram of morpholine, and 50 milliliters of ether are used as solvent to obtain 0.747 gram of white powdery solid, yield : 50.93%, melting point: 167-169°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.445 (m, 2H), 2.705 (m, 2H), 3.085 (dd, 1H, J: 4.2Hz, 17.1Hz), 3.540 (dd, 1H, J: 16.2Hz, 11.1Hz), 3.617-3.714 (m, 3H), 3.833 (s, 3H), 7.026 (d, 2H, J: 8.7Hz), 7.967 (d, 2H, J: 8.7Hz).

Example 36:

2-(2-Hydroxyethylthio)-4-oxo-4-(4’-biphenyl)-butanoic acid

Suspend 12.61 g of 3-(4-phenylbenzoyl)acrylic acid in 150 ml of ether, add 19.53 g of mercaptoethanol, react overnight at room temperature, filter the resulting white precipitate, wash with ether, and drain to obtain a white powdery solid 11.56 g, yield: 69.96%, melting point: 127.6-129.6°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.964 (dt, 1H, J: 6.0Hz, 14.4Hz), 3.083 (dt, 1H, J: 5.4Hz, 14.4Hz), 3.45 (dd, 1H, J : 6.0Hz, 118.3Hz), 3.712 (dd, 1H, J: 8.4Hz, 18.3Hz), 3.952 (t, 2H, J: 5.7Hz), 4.047 (dd, 1H, J: 6.0Hz, 8.4Hz), 7.464 (m, 3H, J: 7.5Hz), 7.625 (d, 2H, J: 7.5Hz), 7.698 (d, 2H, J: 8.1Hz), 8.044 (d, 2H, J: 8.1Hz).

Example 37:

2-(2-Hydroxyethylthio)-4-oxo-4-(4’-biphenyl)-N-hydroxybutyramide

(A): Preparation of 2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)-butyric acid methyl ester:

Dissolve 14.06 g of 2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)-butyric acid in 50 ml of DMF, add 7.046 g of anhydrous potassium carbonate, stir for a while , add 12.08 grams of methyl iodide, react at room temperature until the raw material is consumed (TLC monitoring), the reaction solution is diluted with 400 milliliters of ethyl acetate, washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness, acetic acid Ethyl ester/petroleum ether was recrystallized to obtain 12.44 g of white solid, yield: 84.86%, melting point: 108.5-110.5°C.

¹ HNMR (300MHz, CDCl ₃ ): δ (ppm) = 2 (w, 1H), 2.894 (m, 1H), 3.036 (m, 1H), 3.429 (dd, 1H, J: 5.7Hz, 18.0Hz), 3.718(dd, 1H, J: 9.0Hz, 18.0Hz), 3.798(s, 3H), 3.865(m, 2H), 4.005(dd, 1H, J: 5.7Hz, 8.7Hz), 7.470(m, 3H, J: 7.2 Hz), 7.630 (d, 2H, J: 7.2 Hz), 7.703 (d, 2H, J: 8.4 Hz), 8.044 (d, 2H, J: 8.4 Hz).

(B): Preparation of 2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)-N-hydroxybutanamide:

The ice-water bath was lowered to 0°C, 0.505 gram of potassium hydroxide was added to 5 milliliters of methanol solution of 0.417 gram of hydroxylamine hydrochloride, reacted at this temperature for 1 hour, and the white solid generated was removed by filtration, and 1.033 gram of 2-(2-hydroxyethylsulfide Base)-4-oxo-4-(4'-biphenyl)butanoic acid methyl ester was added to the filtrate and reacted overnight at room temperature. The resulting insoluble matter was filtered off, the filtrate was concentrated, the residue was dissolved in water, and the aqueous phase was extracted with ether. The aqueous solution was acidified with concentrated hydrochloric acid to pH=3, and a solid precipitated out. After filtering and washing with water until neutral, the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain 655 mg of white solid, yield: 63.22%, melting point: 138-140°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.643 (td, 2H, J: 2.4Hz, 6.6Hz), 3.161 (d, 2H, J: 7.8Hz), 3.425 (t, 2H, J: 7.2Hz ), 3.651(t, 1H, J: 7.8Hz), 7.379(m, 1H), 7.468(t, 2H, J: 7.2Hz), 7.7(m, 6H), 11.5(w, 1H), 12.6(w , 1H).

Example 38:

2-[2-(N-succinimido)ethylthio]-4-oxo-4-(4’-biphenyl)-N-hydroxybutyramide

(A): Preparation of 2-[2-(N-succinimide) ethylmercapto]-4-oxo-4-(4'-biphenyl)-butyric acid methyl ester:

Dissolve 0.495 g of succinimide, 1.722 g of 2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)-butyric acid methyl ester and 1.312 g of triphenylphosphine In 10 ml of tetrahydrofuran, 10 ml of a tetrahydrofuran solution of 0.871 g of ethyl azodicarboxylate was added dropwise at room temperature. React overnight at room temperature. The precipitated white solid was filtered and washed with ether to obtain 1.49 g of white solid, yield: 70.02%, melting point: 145.8-147°C.

¹ HNMR (300MHz, CDCl ₃ ): δ (ppm) = 2.746 (s, 4H), 2.925 (dt, 1H, J: 7.2Hz, 13.8Hz), 3.038 (dt, 1H, J: 6.0Hz, 13.8Hz) , 3.334(dd, 1H, J: 4.2Hz, 18.0Hz), 3.718(dd, 1H, 10.8Hz, 18.0Hz), 3.798(s, 3H), 3.856(t, 2H, 6.9Hz), 3.975(dd, 1H, J: 4.2Hz, 10.5Hz), 7.466 (m, 3H, J: 7.5Hz), 7.630 (d, 2H, J: 7.5Hz), 7.695 (d, 2H, J: 8.4Hz), 8.04 (d , 2H, J: 8.7Hz).

(B) Preparation of 2-[2-(N-succinimide) ethylthio]-4-oxo-4-(4'-biphenyl)-N-hydroxybutyramide:

The method is the same as in Example 37 (B), except that 1.39 grams of 2-[2-(N-succinimide) ethylmercapto]-4-oxo-4-(4'-biphenyl)-butyl Acid methyl ester reacted with 454 mg of hydroxylamine hydrochloride and 550 mg of potassium hydroxide to obtain 340 mg of 2-[2-(N-succinimide) ethylthio]-4-oxo-4-(4'-linked Phenyl)-N-hydroxybutyramide, yield: 24.41%, melting point: 179-181°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.526 (s, 4H), 2.639-3.140 (m, 2H), 3.334-3.718 (m, 2H), 3.856 (t, 2H, 6.9Hz), 3.975 ( m, 1H), 7.466 (m, 3H, J: 7.5Hz), 7.630 (d, 2H, J: 7.5Hz), 7.695 (d, 2H, J: 8.4Hz), 8.04 (d, 2H, J: 8.7 Hz), 10.5(w, 1H), 12.9(w, 1H).

Example 39:

2-Propylthio-4-oxo-4-(4’-biphenyl)-butanoic acid

The method is the same as in Example 36, except that 5.045 g of 3-(4-phenylbenzoyl)acrylic acid is added to 2.5 equivalents of propanethiol to obtain 4.929 g of white solid, yield: 75.04%, melting point: 115-117°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.925 (t, 3H, J: 7.2Hz), 1.564 (hd, 2H, J: 3.0Hz, 7.2Hz), 2.668 (t, 2H, J: 7.2Hz ), 3.327(s, 1H), 3.618(d, 1H, J: 10.2Hz), 3.692(d, 1H, J: 10.2Hz), 7.484(m, 3H, J: 7.5Hz), 7.737(d, 2H , J: 7.5Hz), 7.816 (d, 2H, J: 8.7Hz), 8.055 (d, 2H, J: 8.7Hz).

Example 40:

2-Methyl-2-(2-hydroxyethylthio)-4-oxo-4-(4’-biphenyl)-butanoic acid

(A): Preparation of 2-methylene-4-oxo-4-(4'-biphenyl)-butyric acid:

The method is the same as Example 1 (A), except that 15.42 grams of biphenyl are used, 11.21 grams of itaconic anhydride, 26.66 grams of aluminum trichloride, and 300 milliliters of dichloroethane are used as solvent, and the gained crude product is recrystallized with dioxane, 18.06 g of light yellow solid was obtained, yield: 67.81%, melting point: 181.6-183.6°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 4.062 (s, 2H), 5.742 (s, 1H), 6.216 (s, 1H), 7.486 (m, 3H, J: 7.5Hz), 7.741 (d, 2H, J: 7.5Hz), 7.826 (d, 2H, J: 8.4Hz), 8.057 (d, 2H, J: 8.4Hz), 12.456 (w, 1H).

(B): Preparation of 2-methyl-3-(4-phenylbenzoyl)acrylic acid:

Suspend 15.98 g of 2-methylene-4-(4'-biphenyl)-4-oxo-butyric acid in 180 ml of dry ether, add 36.43 g of triethylamine, and react at room temperature for nearly 70 hours until the reaction liquid Separate the layers, add 180 ml of water to the reaction solution, stir vigorously to dissolve the oily substance in water, separate the water phase, wash the ether layer with 60 ml of water again, combine the water phases, acidify with concentrated hydrochloric acid to PH=3, filter and precipitate The yellow solid was washed with water until neutral, and the crude product was recrystallized from ethanol/water to obtain 12.56 g of bright yellow solid, yield: 78.62%, melting point: 164-167°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.045 (s, 3H), 7.485 (m, 3H, J: 7.5Hz), 7.699 (s, 1H), 7.733 (d, 2H, J: 7.5Hz) , 7.848 (d, 2H, J: 8.4Hz), 8.002 (d, 2H, J: 8.4Hz), 13.077 (w, 1H).

(C): Preparation of 2-methyl-2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl)-butanoic acid:

Dissolve 10.29 grams of 2-methyl-3-(4-phenylbenzoyl)acrylic acid in 100 ml of methanol solution containing 2.6 grams of potassium hydroxide, add 15.09 grams of mercaptoethanol, heat and reflux for 4 hours, cool, and precipitate white The crystals were filtered, washed with a small amount of methanol, and after being drained, the solid was dissolved in 150 ml of water, acidified with concentrated hydrochloric acid under ice bath cooling, the white solid separated out was filtered, washed with water until neutral, and dried to obtain 10.32 g of a white solid. The yield : 77.55%, melting point: 149-152°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.524 (s, 3H), 2.673-2.824 (m, 2H), 3.440 (d, 1H, J: 17.4Hz), 3.74 (d, 1H, J: 18.3 Hz), 4.824(s, 1H), 7.487(m, 3H, J: 8.1Hz), 7.734(d, 2H, J: 8.1Hz), 7.815(d, 2H, J: 8.7Hz), 8.039(d, 2H, J: 8.7Hz), 12.319 (w, 1H).

Example 41:

2-(2-Hydroxyethylamino)-4-oxo-4-(4’-biphenyl)-N-hydroxybutyramide

(A): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)butyric acid methyl ester hydrochloride:

The ice-salt bath was lowered below -10°C, and 1 ml (about 2 equivalents) of thionyl chloride was added dropwise to 20 ml of anhydrous methanol to keep the inner temperature below -10°C. After dropping, stir at room temperature for 1 hour, add 1.567 g of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)butanoic acid, the raw material dissolves rapidly, and stir at room temperature for 3 hours Then, heat to reflux for 40 minutes. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from methanol/ether to give white crystals: 1.658 g, yield: 91.15%, melting point: 154-156°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.18 (m, 2H), 3.704 (t, 2H, J: 5.4Hz), 3.739 (s, 3H), 3.861 (dd, 1H, J: 5.1Hz, 18.9Hz), 3.964(dd, 1H, J: 4.8Hz, 18.9Hz), 4.638(t, 1H, J: 5.1Hz), 7.508(m, 3H, J: 7.8Hz), 7.767(d, 2H, J : 7.5Hz), 7.886 (d, 2H, J: 8.1Hz), 8.074 (d, 2H, J: 8.7Hz).

(B): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-N-hydroxybutanamide:

The method is the same as in Example 37 (B), except that 1.553 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl) methyl butyrate hydrochloride and 0.593 647 mg of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-N-hydroxybutyramide was reacted with 0.958 gram of potassium hydroxide, white solid, Yield: 46.15%, melting point: 218.9-222°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.798 (dd, 2H, J: 6.0Hz, 13.5Hz), 3.167 (t, 2H, J: 7.5Hz), 3.497 (m, 4H), 7.376 (d , 1H, J: 7.2Hz), 7.466 (t, 2H, J: 7.5Hz), 7.672 (d, 2H, J: 8.4Hz), 7.685 (d, 2H, J: 6.9Hz), 7.786 (d, 2H , J: 8.7Hz) 11-12 (w, 2H).

Example 42:

2-Benzylamino-4-oxo-4-(4’-biphenyl)-N-hydroxybutyramide

(A): Preparation of 2-benzylamino-4-oxo-4-(4'-biphenyl)butyric acid methyl ester hydrochloride:

The method is the same as in Example 41 (A), except that 1.797 gram of 2-benzylamino-4-oxygen-4-(4'-biphenyl) butanoic acid and 1 milliliter of thionyl chloride are made into 1.773 gram of 2 -Benzylamino-4-oxo-4-(4'-biphenyl)butanoic acid methyl ester hydrochloride, yield: 86.49%, melting point: 142.5-144°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.735 (s, 3H), 3.837 (d, 1H, J: 5.4Hz), 3.899 (m, 1H), 4.276 (d, 1H, J: 13.2Hz) , 4.335(d, 1H, J: 13.2Hz), 4.394-4.512(m, 1H), 7.433-7.567(m, 5H), 7.504(m, 3H, J: 7.8Hz), 7.764(d, 2H, J : 7.5Hz), 7.881 (d, 2H, J: 8.1Hz), 8.064 (d, 2H, J: 8.4Hz).

(B): Preparation of 2-benzylamino-4-oxo-4-(4'-biphenyl)-N-hydroxybutyramide:

The method is the same as in Example 37 (B), except that 1.67 gram of 2-benzylamino-4-oxo-4-(4'-biphenyl) methyl butyrate hydrochloride and 0.566 gram of hydroxylamine hydrochloride and 0.914 686 mg of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-biphenyl)-N-hydroxybutanamide was reacted with gram of potassium hydroxide, white solid, yield: 44.95% , Melting point: 218-220°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.116 (m, 2H), 3.2-4.0 (w, 1H), 3.463 (t, 1H, J: 7.5Hz), 3.639 (d, 1H, J: 13.8 Hz), 3.820(d, 1H, J: 13.8Hz), 7.225(s, 5H), 7.379(t, 1H, J: 7.2Hz), 7.471(t, 2H, J: 7.5Hz), 7.640-7.755( m, 6H).

Example 43:

2-Benzylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide

(A): Preparation of 2-benzylamino-4-oxo-4-(4-methoxyphenyl)butanoic acid methyl ester hydrochloride:

The method is the same as in Example 41 (A), except that 1.567 grams of 2-benzylamino-4-oxo-4-(4-methoxyphenyl) butanoic acid and 2 equivalents of thionyl chloride are made into 1.335 grams 2-Benzylamino-4-oxo-4-(4-methoxyphenyl)butanoic acid methyl ester hydrochloride, yield: 73.39%, melting point: 128-130°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.706 (s, 3H), 3.757-3.828 (m, 2H), 3.848 (s, 3H), 4.258 (d, 1H, J: 13.2Hz), 4.303 ( d, 1H, J: 13.2Hz), 4.444(t, 1H, J: 3.3Hz), 7.080(d, 2H, J: 8.7Hz), 7.423(m, 3H), 7.580(m, 2H), 7.953( d, 2H, J: 8.7 Hz).

(B): Preparation of 2-benzylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide:

The method is the same as in Example 37 (B), except that 1.230 gram of 2-benzylamino-4-oxygen-4-(4-methoxyphenyl) butyric acid methyl ester hydrochloride and 0.470 gram of hydroxylamine hydrochloride and 0.759 grams of potassium hydroxide reacted to produce 341 mg of 2-benzylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide, white solid, yield: 30.72%, melting point: 192.8-195°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.035 (dd, 1H, J: 6.6Hz, 18.3Hz), 3.075 (dd, 1H, J: 7.8Hz, 18.3Hz), 3.389 (t, 1H, J : 7.2Hz), 3.652(d, 1H, J: 13.8Hz), 3.812(d, 1H, J: 13.8Hz), 3.759(s, 3H), 6.905(d, 2H, J: 9.0Hz), 7.236( s, 5H), 7.584 (d, 2H, J: 9.0 Hz), 11.2 (w, 1H).

Example 44:

2-n-octylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide

(A): Preparation of 2-n-octylamino-4-oxo-4-(4-methoxyphenyl) methyl butyrate hydrochloride:

The method is the same as in Example 41 (A), except that 1.677 grams of 2-n-octylamino-4-oxo-4-(4-methoxyphenyl) butanoic acid and 2 equivalents of thionyl chloride are made into 1.457 grams 2-n-octylamino-4-oxo-4-(4-methoxyphenyl)butanoic acid methyl ester hydrochloride, yield: 75.5%, melting point: 122.5-125°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.850 (t, 3H, J: 6.6Hz), 1.245 (s, 10H), 1.632 (m, 2H), 2.965 (d, 1H, J: 6.9Hz) , 3.010(d, 1H, J: 7.2Hz), 3.714(s, 3H), 3.781(d, 1H, J: 4.8Hz), 3.835(d, 1H, J: 4.8Hz), 3.853(s, 3H) , 4.482 (t, 1H, J: 4.8Hz), 7.086 (d, 2H, J: 8.7Hz), 7.967 (d, 2H, J: 8.7Hz).

(B): Preparation of 2-n-octylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide:

The method is the same as in Example 37 (B), except that 485 mg of 2-n-octylamino-4-oxo-4-(4-methoxyphenyl) butyric acid methyl ester hydrochloride and 175 mg of hydroxylamine hydrochloride and 70 mg of 2-n-octylamino-4-oxo-4-(4-methoxyphenyl)-N-hydroxybutanamide was reacted with 282 mg of potassium hydroxide, white solid, yield: 15.08%, melting point: 196-200°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.836 (t, 3H, J: 6.0Hz, 6.9Hz), 1.225 (s, 10H), 1.514 (t, 2H, J: 6.9Hz, 7.2Hz), 2.778(m, 2H), 3.320(dd, 1H, J: 8.1Hz, 18.0Hz), 3.475(dd, 1H, J: 3.6Hz, 18.0Hz), 3.621(dd, 1H, J: 3.9Hz, 4.2Hz , 7.8Hz), 3.824(s, 3H), 7.033(d, 2H, J: 9.0Hz), 7.934(d, 2H, J: 9.0Hz), 9.2(w, 1H), 11.6(w, 1H).

Example 45:

2-(2-Hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutyramide

(A): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl) methyl butyrate hydrochloride:

The method is the same as in Example 41 (A), and the difference is that 1.573 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl) butyric acid and 2 equivalents of dichloroethylene Sulfone was made into 1.525 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride, yield: 84.06%, melting point: 133- 135°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.164 (m, 2H), 3.687 (t, 2H, J: 5.4Hz), 3.723 (s, 3H), 3.793 (d, 1H, J: 5.4Hz) , 3.849 (d, 1H, J: 4.5Hz), 4.598 (t, 1H, J: 4.8Hz), 7.085 (d, 2H, J: 9.0Hz), 7.131 (d, 2H, J: 8.1Hz), 7.264 (t, 1H, J: 7.2 Hz), 7.473 (t, 2H, J: 8.1 Hz), 8.009 (d, 2H, J: 9.0 Hz).

(B): Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutanamide:

The method is the same as in Example 37 (B), except that 1.418 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride and 0.519 gram of hydroxylamine hydrochloride and 0.838 gram of potassium hydroxide react to obtain 509 mg of 2-(2-hydroxyethylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutyramide, white Solid, yield: 39.58%, melting point: 187.5-190.5°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.800 (m, 2H), 3.077 (dd, 1H, J: 6.0Hz, 14.1Hz), 3.155 (dd, 1H, J: 7.5Hz, 14.1Hz), 3.483(m, 3H), 6.976(d, 2H, J: 8.4Hz), 7.040(d, 2H, J: 8.1Hz), 7.160(t, 1H, J: 7.5Hz), 7.403(t, 2H, J : 7.8Hz), 7.706 (d, 2H, J: 8.7Hz), 10.9 (w, 1H), 11.4 (w, 1H).

Example 46:

2-Benzylamino-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutanamide

(A): Preparation of 2-benzylamino-4-oxo-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride:

The method is the same as in Example 41 (A), except that 1.877 gram of 2-benzylamino-4-oxo-4-(4'-biphenyl) butanoic acid and 2 equivalents of thionyl chloride are made into 1.698 gram of 2 -Benzylamino-4-oxo-4-(4-phenoxyphenyl)butanoic acid methyl ester hydrochloride, yield: 79.73%, melting point: 244-250°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.457 (dd, 1H, J: 6.9Hz, 17.4Hz), 3.540 (dd, 1H, J: 5.4Hz, 17.4Hz), 3.726 (s, 3H), 3.785 (t, 1H, J: 4.2Hz), 4.020 (d, 1H, J: 13.2Hz), 4.113 (d, 1H, J: 13.5Hz), 7.189-8.170 (m, 14H).

(B): Preparation of 2-benzylamino-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutanamide:

The method is the same as in Example 37 (B), except that 1.278 gram of 2-benzylamino-4-oxygen-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride and 0.417 gram of hydroxylamine hydrochloride and 130 mg of 2-benzylamino-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutanamide was reacted with 0.673 gram of potassium hydroxide, white solid, yield: 11.10%, melting point: 165-168°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.043 (m, 2H), 3.649 (d, 1H, J: 13.8Hz), 3.820 (d, 1H, J: 13.8Hz), 3.998 (s, 1H) , 6.957(d, 2H, J: 8.7Hz), 7.023(d, 2H, J: 8.1Hz), 7.160(t, 1H, J: 7.8Hz), 7.234(s, 5H), 7.405(t, 2H, J: 7.8Hz), 7.656 (d, 2H, J: 8.7Hz), 7.980 (d, 1H, 8.7Hz).

Example 47:

2-(4-Hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutyramide

(A): Preparation of 2-(4-hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride:

The method is the same as in Example 41 (A), except that 10.536 grams of 2-(4-hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl) butanoic acid and 2 equivalents of thionyl chloride Make 10.06 grams of 2-(4-hydroxybutanyl)-4-oxo-4-(4-phenoxyphenyl) butyric acid methyl ester hydrochloride, yield: 83.73%, melting point: 129.4-131.4 ℃ (decomposition ).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.444 (p, 2H, J: 6.9Hz), 1.698 (m, 2H), 3.025 (m, 2H), 3.391 (t, 2H, J: 6.3Hz) , 3.798(dt, 1H, J: 4.8Hz, 18.6Hz), 3.907(dt, 1H, J: 5.4Hz, 18.6Hz), 4.510(t, 1H, J: 4.8Hz), 7.083(d, 2H, J : 8.7Hz), 7.132 (d, 2H, J: 7.8Hz), 7.261 (t, 1H, J: 7.5Hz), 7.471 (t, 2H, J: 7.8Hz), 8.014 (d, 2H, J: 8.7 Hz).

(B): Preparation of 2-(4-hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutyramide:

The method is the same as in Example 37 (B), except that 2.039 grams of 2-(4-hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl) methyl butyrate hydrochloride is mixed with 0.695 1.737 grams of 2-(4-hydroxybutylamino)-4-oxo-4-(4-phenoxyphenyl)-N-hydroxybutyramide were reacted with 1.122 grams of potassium hydroxide, yield: 93.29%, melting point: 179.6-181.6°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.383 (m, 2H), 1.507 (m, 2H), 2.742 (t, 2H, J: 7.5Hz), 3.052 (dd, 1H, J: 6.3Hz, 13.8Hz), 3.167(dd, 1H, J: 7.5Hz, 13.8Hz), 3.376(m, 3Hz), 6.970(d, 2H, J: 8.7Hz), 7.037(d, 2H, J: 8.7Hz), 7.159 (, t, 1H, J: 7.5Hz), 7.401 (t, 2H, J: 8.1Hz), 7.703 (d, 2H, J: 8.7Hz), 10.9 (w, 1H), 11.5 (w, 1H) .

Example 48:

2-(N-Morpholinyl)-4-oxo-4-[4’-(4”-chloro)biphenyl]butanoic acid

Dissolve 2.307 g of glyoxylic acid monohydrate in 20 ml of absolute ethanol, and cool in an ice bath to below 4°C. Under stirring, 20 ml of ethanol solution of 1.742 g of morpholine was added dropwise, so that the internal temperature did not exceed 4°C. After dropping, the resulting clear solution was stirred at room temperature for a while, and then 2.307 g of 4-chlorobiphenone was added. Raise the temperature to 60°C and react for 5 hours until all the solids are dissolved. Cool to room temperature, filter the precipitated pale yellow solid, recrystallize from ethanol to obtain 0.708 g of off-white solid, yield: 18.94%, melting point: 194-196°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.429-2.487 (m, 1H), 2.735 (m, 2H), 2.912 (t, 1H, J: 4.8Hz), 3.145 (d, 1H, J: 4.2 Hz), 3.546(m, 4H), 3.651(t, 1H, J: 4.8Hz), 3.731(d, 1H, J: 4.2Hz), 7.556(d, 2H, J: 8.4Hz), 7.784(d, 2H, J: 8.4Hz), 7.825 (d, 2H, J: 8.7Hz), 8.076 (d, 2H, J: 8.7Hz).

Example 49:

2-(2-Hydroxyethylamino)-4-oxo-4-[4’-(4”-chloro)biphenyl]butanoic acid

The method is the same as in Example 1 (B), except that 0.634 grams of 3-[4-(4'-chlorophenyl)benzoyl]acrylic acid, 0.135 grams of 2-hydroxyethylamine, and 25 milliliters of benzene are used as solvents to obtain white powdery solid. The solid was made into hydrochloride according to the method described in Example 9, 0.664 g of white solid, yield: 78.15% (calculated as hydrochloride), melting point: 137-140° C. (decomposition).

¹ H NMR (300MHz, DMSO): δ (ppm) = 3.135 (dt, 1H, J: 7.2Hz, 12.6Hz), 3.209 (dt, 1H, J: 7.2Hz, 12.6Hz), 3.706 (t, 2H, J : 7.2Hz), 3.823(dd, 1H, J: 4.8Hz, 18.6Hz), 3.916(dd, 1H, 4.8Hz, 18.6Hz), 4.524(t, 1H, J: 4.8Hz), 7.570(d, 2H , J: 8.4Hz), 7.802 (d, 2H, 8.4Hz), 7.884 (d, 2H, J: 8.4Hz), 8.079 (d, 2H, J: 8.4Hz).

Example 50:

2-(4-Methylphenylthio)-4-oxo-4-(4’-biphenyl)butanoic acid

The method is the same as in Example 36, except that 1.261 g of 3-(4-phenylbenzoyl)acrylic acid is added to 2.5 equivalents of p-cresylthiol to obtain 1.086 g of white solid, yield: 57.70%, melting point: 160- 162°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.295 (s, 3H), 3.477 (dd, 1H, J: 4.8Hz, 18.0Hz), 3.584 (dd, 1H, J: 9.6Hz, 18.0Hz), 4.069 (dd, 1H, J: 4.8Hz, 9.6Hz), 7.190 (d, 2H, J: 8.1Hz), 7.420 (d, 2H, J: 8.1Hz), 7.491 (m, 3H, J: 7.5Hz) , 7.739 (d, 2H, J: 7.5Hz), 7.821 (d, 2H, J: 8.4Hz), 8.017 (d, 2H, J: 8.4Hz).

Example 51:

2-(2-Aminoethylamino)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid

Method is the same as embodiment 1 (B) with embodiment method, and difference is to use 1.341 gram 3-(4-phenoxybenzoyl) acrylic acid, the methanol solution of 1 equivalent ethylenediamine monohydrochloride (by 0.665 gram ethyl alcohol) Diamine dihydrochloride and 1 equivalent of potassium hydroxide (prepared at 0° C.), 25 ml of benzene as solvent, obtained 0.811 g of off-white solid, yield: 44.46%, melting point: 167.1-169.1° C. (decomposition). The solid was made into hydrochloride according to the method described in Example 9 to obtain 0.746 g of white solid, yield: 37.18% (calculated as hydrochloride), melting point: 139-142° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.219-3.608 (m, 4H), 3.855 (dd, 1H, J: 4.5Hz, 15.0Hz), 3.921 (dd, 1H, J: 3.9Hz, 15.0Hz ), 4.478 (t, 1H, J: 4.2Hz), 7.090 (d, 2H, J: 8.7Hz), 7.140 (d, 2H, J: 7.8Hz), 7.269 (t, 1H, J: 7.5), 7.478 (t, 2H, J: 7.8Hz), 8.035 (d, 2H, J: 8.7Hz).

Example 52:

N-Hydroxy-2-(4-hydroxybutylamino)-4-oxo-4-(4’-biphenyl)butanamide

(A) Preparation of 2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl) methyl butyrate hydrochloride:

The method is the same as in Example 41 (A), except that 1.889 grams of 2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butyrate hydrochloride and 1 milliliter of di Thionyl chloride is made into 1.538 grams of white crystals of 2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butyric acid methyl ester hydrochloride, yield: 78.47%, melting point: 142-145°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.454 (p, 2H, J: 7.5Hz), 1.706 (p, 2HmJ: 7.5Hz), 3.060 (m, 2H), 3.401 (t, 2H, J: 7.5Hz) 6.3Hz), 3.743(s, 3H), 3.845(dd, 1H, J: 5.1Hz, 18.9Hz), 3.931(dd, 1H, J: 4.5Hz, 18.9Hz), 4.555(t, 1H, J: 4.8 Hz), 7.507(m, 3H, J: 7.5Hz), 7.766(d, 2H, J: 7.2Hz), 7.887(d, 2H, J: 8.4Hz), 8.084(d, 2H, J: 8.4Hz) .

(B) Preparation of N-hydroxyl-2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butyramide:

The method is the same as in Example 37 (B), except that 1.476 grams of 2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl) methyl butyrate hydrochloride and 0.523 grams Hydroxylamine hydrochloride and 0.844 gram of potassium hydroxide react to obtain 686 mg of N-hydroxyl-2-(4-hydroxybutylamino)-4-oxo-4-(4'-biphenyl)butanamide white solid 306 mg, received Yield: 44.95%, melting point: 218-220°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.403 (m, 2H), 1.533 (m, 2H), 2.774 (t, 2H, J: 7.5Hz), 3.126 (dd, 1H, J: 6.6Hz, 14.1Hz), 3.228(dd, 1H, J: 7.2Hz, 14.1Hz), 3.352(t, 2H, J: 6.3Hz), 3.441(t, 1H, J: 6.9Hz), 7.463(m, 3H, J : 7.5Hz), 7.697 (d, 2H, J: 7.5Hz), 7.681 (d, 2H, J: 8.4Hz), 7.798 (d, 2H, J: 8.4Hz).

Example 53:

N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4’-methoxyphenyl)butanamide

(A) Preparation of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl) methyl butyrate hydrochloride:

The method is the same as in Example 41 (A), except that 1.277 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl) butanoic acid and ₁ milliliter of SOCl are prepared 1.307 g of white crystals of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl) butyric acid methyl ester hydrochloride, yield: 86.10%, melting point: 124- 126°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.149 (m, 2H, CH ₂ OH), 3.690 (t, 2H, J: 5.1 Hz, CH ₂ NH), 3.714 (s, 3H, CH ₃ OAr) , 3.768(dd, 1H, J: 5.1Hz, 18.3Hz, COCH ₂ ), 3.875(dd, 1H, J: 5.4Hz, 18.3Hz, COCH ₂ ), 3.852(s, 3H, COOCH ₃ ), 4.579(t , 1H, J: 5.1Hz, CHCOOCH ₃ ), 7.084 (d, 2H, J: 8.7Hz, ArH), 7.963 (d, 2H, J: 8.7Hz, ArH).

(B) Preparation of N-hydroxyl-2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl) butyramide:

The method is the same as in Example 37 (B), except that 1.200 grams of 2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl) methyl butyrate hydrochloride is mixed with 0.525 grams of hydroxylamine hydrochloride and 0.848 grams of potassium hydroxide were reacted to obtain 136 mg of white solid N-hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4'-methoxyphenyl)butyramide , yield: 12.76%, melting point: 176-178°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.809 (m, 2H, J: 5.4Hz), 3.087 (dd, 1H, J: 5.7Hz, 14.1Hz), 3.168 (dd, 1H, J: 7.8Hz , 14.1Hz), 3.414 (t, 1H, J: 6.6Hz), 3.495 (t, 2H, J: 5.7Hz), 6.936 (d, 2H, J: 8.7Hz), 7.648 (d, 2H, J: 8.7 Hz).

Example 54:

N-Hydroxy-2-hydroxy-3-acetamido 4-oxo-4-(4’-biphenyl)butanamide

(A) Preparation of 2-hydroxyl-3-acetamido 4-oxo-4-(4'-biphenyl)butanoic acid:

Method reference patent US4453003.

(B) Preparation of 2-hydroxyl-3-acetamido 4-oxo-4-(4'-biphenyl)butyric acid methyl ester:

Dissolve 4.729 g of 2-hydroxy-3-acetamido 4-oxo-4-(4'-biphenyl)butanoic acid in 30 ml of DMF, add 2 g of anhydrous potassium carbonate, stir at room temperature, and add 2 equivalents Iodomethane, reacted for 3 hours. The reaction solution was diluted with 200 ml of ethyl acetate, washed with water and saturated brine successively, and the organic phase was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness, and the solid was recrystallized from ethyl acetate/petroleum ether to obtain 4.758 g of white crystals, yield: 96.45%, 147-149°C.

(C) N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4'-biphenyl)butanamide preparation:

The method is the same as in Example 37 (B), except that 2-hydroxyl-3-acetamido 4-oxo-4-(4'-biphenyl)butanoic acid methyl ester, 0.525 g of hydroxylamine hydrochloride and 0.848 g of potassium hydroxide N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4'-biphenyl)butyramide 0.551 gram was obtained by reaction, yield: 53.65%, melting point: 150.6-153.0°C (decomposition ).

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.507 (s, 3H), 4.100 (d, 1H, J: 3.6Hz), 5.004 (s, 1H), 5.538 (d, 1H, J: 4.2Hz) , 7.437 (m, 3H, J: 7.5Hz), 7.558 (d, 2H, J: 8.4Hz), 7.671 (d, 2H, J: 7.5Hz), 7.672 (d, 2H, J: 8.4Hz), 10.986 (s, 1H), 11.490 (s, 1H).

Example 55:

N-Hydroxy-2-[2-(4-nitrophenoxy)ethylthio]-4-oxo-4-(4’-biphenyl)butanamide

(A) Preparation of 2-[2-(4-nitrophenoxy) ethylthio]-4-oxo-4-(4'-biphenyl)butyric acid methyl ester:

The method is the same as in Example 38 (A), except that 0.696 gram p-nitrophenol, 1.722 gram 2-(2-hydroxyethylthio)-4-oxo-4-(4'-biphenyl) butyric acid methyl The ester reacted with 1.312 grams of triphenylphosphine and 0.871 grams of ethyl azodicarboxylate, and purified by column chromatography (petroleum ether/ethyl acetate=4:1) to obtain 2-[2-(4-nitrophenoxy 2.008 g of light yellow semi-solid, yield: 86.25%.

(B) Preparation of N-hydroxyl-2-[2-(4-nitrophenoxy) ethylthio]-4-oxo-4-(4'-biphenyl)butyramide:

The method is the same as in Example 37 (B), with 2.008 grams of 2-[2-(4-nitrophenoxy) ethylthio]-4-oxo-4-(4'-biphenyl)butyric acid methyl ester and 0.6 g of hydroxylamine hydrochloride and 0.726 g of potassium hydroxide were reacted to obtain 1.056 g of light yellow solid, yield: 52.49%, melting point: 162-164°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 3.179 (t, 2H, J: 6.0Hz), 3.536 (d, 2H, J: 9.9Hz), 4.373 (t, 2H, J: 6.0Hz), 4.862 (t, 1H, J: 9.6Hz), 7.151(d, 2H, J: 9.3Hz), 7.468(m, 3H, J: 7.5Hz), 7.715(d, 2H, J: 7.5Hz), 7.755( s, 5H), 8.165 (d, 2H, J: 9.3Hz).

Example 56:

2-(2-Hydroxyethylamino)-4-phenoxy-3-(4’-bibenzoyl)butanoic acid

(A): Preparation of 3-(4-phenylbibenzoyl) propionic acid:

Dissolve 61.68 grams of biphenyl and 42.03 grams of succinic anhydride in 700 milliliters of benzene, and add 112 grams of aluminum trichloride in four batches under cooling in an ice-water bath. Dry, add a mixture of crushed ice and concentrated hydrochloric acid for hydrolysis, filter the resulting white solid, wash with water until neutral, and then wash several times with petroleum ether, recrystallize the crude product with glacial acetic acid to obtain 83.92 g of white crystals, yield: 82.50%, melting point : 173-175°C (literature value: 176-178°C).

(B): Preparation of 3-(4-bibenzoyl)-3-butenoic acid:

Mix 50.46 grams of 3-(4-phenylbenzoyl)propionic acid and 8.8 grams of paraformaldehyde with 25 milliliters of pyridine, heat to 55-60° C., add 1 milliliter of morpholine, and continue the reaction at this temperature for 6 hours. Cool to room temperature, dilute with 800 ml ethyl acetate, wash twice with 6 mol/L hydrochloric acid, then wash several times with water and saturated saline until neutral, dry over anhydrous magnesium sulfate, filter, wash with ethyl acetate, and the filtrate Combined and concentrated to dryness under reduced pressure, the obtained white crude product was recrystallized with dichloromethane/petroleum ether to obtain 40.43 g of white solid, yield: 75.90%, melting point: 128-130°C.

(C): Preparation of 3-(4-bibenzoyl)-3,4-dibromo-butyric acid:

Dissolve 40 grams of 3-(4-phenylbenzoyl)-3-butenoic acid in 500 milliliters of chloroform, add 24 grams of liquid bromine dropwise under stirring at room temperature, stir for 1 hour after the dripping, and concentrate to dryness under reduced pressure. The resulting white crude product was recrystallized from toluene to give a white product, 46.39 g, yield: 72.49%, melting point: 126.4-128.0 °C.

(D): Preparation of 3-(4-bibenzoyl)-3,4-dibromo-butyric acid methyl ester:

Dissolve 42.61 g of 3-(4-phenylbenzoyl)-3,4-dibromo-butyric acid in 500 ml of anhydrous methanol, add 8 ml of concentrated sulfuric acid, heat to reflux for 5 hours, cool to room temperature, and precipitate white The solid was filtered, washed with methanol, and dried to obtain 32 g of product, yield: 72.71%, melting point: 65.3-67°C. Without purification, the next reaction was carried out directly.

(E): Preparation of 3-(4-bibenzoyl)-4-bromo-2-butenoic acid methyl ester:

Dissolve 32 grams of 3-(4-phenylbenzoyl)-3,4-dibromo-butyric acid methyl ester in 500 milliliters of ether, add 14.71 grams of triethylamine, react at room temperature for 4 hours, dilute with ether to 700 ml, washed twice with 6 mol/L hydrochloric acid, then washed several times with water and saturated brine until neutral, dried over anhydrous magnesium sulfate, filtered, washed with ether, combined filtrates, concentrated to dryness under reduced pressure, the resulting light orange The crude product was recrystallized from absolute ethanol to obtain 14.24 g of the product, yield: 54.50%, melting point: 106-109°C.

¹ HNMR (300MHz, CDCl ₃ ): δ(ppm)=3.832(s, 3H), 4.937(s, 2H), 6.166(s, 1H), 7.484(m, 3H, J: 6.5Hz), 7.637(d , 2H, J: 6.5Hz), 7.721 (d, 2H, J: 9.0Hz), 7.955 (d, 2H, J: 9.0Hz).

(F): Preparation of 4-phenoxy-3-(4-bibenzoyl)-2-butenoic acid methyl ester:

Dissolve 1.179 g of phenol in 15 ml of DMF suspension of 2.6 g of anhydrous potassium carbonate, add a catalytic amount of triethylbenzyl ammonium chloride (TEBAC), stir for a while and add 4.5 g of 3-(4-bibenzoyl )-4-bromo-2-butenoic acid methyl ester DMF solution 15ml, react at room temperature until the raw material disappears (TLC detection). The reaction solution was diluted with 250 ml of ethyl acetate, washed several times with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness, dissolved in dichloromethane, and then filtered through silica gel. After the filtrate was concentrated, the resulting solid was recrystallized with methanol to obtain 4.388 g of flesh-colored solid, yield: 94.06%, melting point: 110-115°C.

(G): Preparation of 4-phenoxy-3-(4-bibenzoyl)-2-butenoic acid:

Add 4.388 g of 4-phenoxy-3-(4-bibenzoyl)-2-butenoic acid methyl ester into 10 ml of NaOH solution (8%), and heat to reflux until the suspension is completely dissolved. The solution was homogeneous, and the reaction took about 1 hour. Cool to room temperature, carefully acidify with concentrated hydrochloric acid, extract 200ml of ethyl acetate three times, combine the extracts, wash with water and saturated brine in turn until neutral, and dry over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness to obtain 4.05 g of a brown oil, yield: 96.09%. It was directly put into the next step reaction without purification.

(H): Preparation of 2-(2-hydroxyethylamino)-4-phenoxy-3-(4'-bibenzoyl)butanoic acid:

Suspend 844.6 mg of 4-phenoxy-3-(4-bibenzoyl)-2-butenoic acid in 10 ml of benzene, add 1 equivalent of ethanolamine, and react overnight at room temperature. The precipitated solid was collected by filtration, washed with acetone and dried to obtain 416 mg of off-white solid, yield: 48.55%, melting point: 80-83°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.767 (s, 2H), 2.695 (t, 2H, J: 5.4Hz), 3.450 (t, 2H, J: 5.4Hz), 6.915 (d, 2H, J: 8.1Hz), 6.942 (t, 1H, J: 7.2Hz), 7.285 (t, 2H, J: 8.1Hz), 7.403 (t, 1H, J: 7.2Hz), 7.496 (t, 2H, J: 7.2Hz), 7.496 (t, 2H, J: 7.5Hz), 7.720(d, 2H, J: 7.5Hz), 7.775(d, 2H, J: 8.4Hz), 7.882(d, 2H, J: 8.4Hz).

Example 57:

2-Benzylamino-4-phenoxy-3-(4’-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that diethyl ether is used as solvent to obtain 421 mg of off-white solid, yield: 38.38%, melting point: 174-177°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.760 (s, 2H), 3.795 (s, 2H), 6.915-6.976 (m, 3H), 7.262-7.332 (m, 3H), 7.313 (s, 5H) ), 7.470 (m, 3H, 7.2Hz), 7.698 (d, 2H, J: 7.2Hz), 7.761 (d, 2H, J: 8.4Hz), 7.866 (d, 2H, J: 8.4Hz).

Example 58:

2-n-octylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that diethyl ether is used as solvent to obtain 453 mg of white solid, yield: 39.42%, melting point: 158-161°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.824 (t, 3H, J: 6.9Hz), 1.147 (s, 10H), 1.207 (p, 2H, J: 6.9Hz), 1.756 (s, 2H) , 2.483(m, 2H), 6.904(d, 2H, J: 7.8Hz), 6.933(t, 1H, J: 7.2Hz), 7.273(t, 2H, J: 7.8Hz), 7.394(t, 1H, J: 7.2Hz), 7.485 (t, 2H, J: 7.2Hz), 7.711 (d, 2H, J: 7.2Hz), 7.759 (d, 2H, J: 8.7Hz), 7.872 (d, 2H, J: 8.7Hz), 7.872 (d, 2H, J: 8.7Hz).

Example 59:

2-(2-N,N'-Dimethylaminoethylamino)-4-phenoxy-3-(4'-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that benzene is used as solvent to obtain 407 mg of white solid, yield: 42.92%, melting point: 15.2-154°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 1.756 (s, 2H), 2.084 (s, 6H), 2.281 (t, 2H, J: 6.0Hz), 2.690 (t, 2H, J: 6.0Hz) , 6.917(d, 2H, J: 8.1Hz), 6.943(t, 1H, J: 7.5Hz), 7.283(t, 2H, J: 8.1Hz), 7.401(t, 1H, J: 7.2Hz), 7.495 (t, 2H, J: 7.5Hz), 7.716 (d, 2H, J: 8.1Hz), 7.763 (d, 2H, J: 8.4Hz), 7.870 (d, 2H, J: 8.4Hz).

Example 60:

2-n-Butylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), using diethyl ether as solvent to obtain 375 mg of white solid, yield: 44.49%, melting point: 175-178°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.767 (t, 3H, J: 7.2Hz), 1.164 (h, 2H, J: 7.2Hz), 1.320 (p, 2H, J: 7.2Hz), 1.762 (s, 2H), 2.510 (t, 2H, J: 7.2Hz), 6.907 (d, 2H, J: 7.8Hz), 6.931 (t, 1H, J: 7.8Hz), 7.274 (t, 2H, J: 7.8Hz), 7.274 (t, 2H, J: 7.8Hz), 7.393(t, 1H, J: 7.2Hz), 7.486(t, 2H, J: 7.2Hz), 7.708(d, 2H, J: 7.2Hz), 7.761(d, 2H, J: 8.4Hz ), 7.880 (d, 2H, J: 8.4Hz).

Example 61:

2-Cyclohexylamino-4-phenoxy-3-(4’-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that diethyl ether is used as solvent to obtain 543 mg of white solid, yield: 69.16%, melting point: 216-219°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.955-1.191 (m, 5H), 1.469-1.726 (m, 5H), 1.756 (s, 2H), 2.708 (td, 1H, J: 3.6Hz, 10.5 Hz), 6.898(d, 2H, J: 7.8Hz), 6.925(t, 1H, J: 7.5Hz), 7.269(t, 2H, J: 7.8Hz), 7.391(t, 1H, J: 7.2Hz) , 7.486 (t, 2H, J: 7.5Hz), 7.706 (d, 2H, J: 7.2Hz), 7.757 (d, 2H, J: 8.4Hz), 7.877 (d, 2H, J: 8.4Hz).

Example 62:

2-(2-Hydroxyethylamino)-4-(4-methylthio)-3-(4’-bibenzoyl)butanoic acid

(A) Preparation of 4-(4-tolylthio)-3-(4'-bibenzoyl)-2-butenoic acid methyl ester:

The method is the same as in Example 56 (F), using 1.556 grams of p-cresol and 4.5 grams of 3-(4-bibenzoyl)-4-bromo-2-butenoic acid methyl ester to react to obtain 4-(4- Tolylthio)-3-(4'-bibenzoyl)-2-butenoic acid methyl ester, 4.639 g of orange oil, yield: 92.01%, was directly put into the next reaction without purification.

(B) Preparation of 4-(4-tolylthio)-3-(4'-bibenzoyl)-2-butenoic acid:

The method is the same as in Example 56 (G), except that 4.367 grams of 4-(4-tolylthio)-3-(4'-bibenzoyl)-2-butenoic acid methyl ester is hydrolyzed to obtain brown oil 4.05 g, yield: 96.09%, directly put into the next reaction without purification.

(C) Preparation of 2-(2-hydroxyethylamino)-4-(4-tolylthio)-3-(4'-bibenzoyl) butanoic acid:

The method is the same as in Example 56(H), using benzene as solvent to obtain 336 mg of off-white solid, yield: 28.80%, melting point: 102.2-105.2°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.230 (s, 3H), 3.210 (s, 2H), 2.680 (t, 2H, J: 5.4Hz), 3.109 (t, 2H, J: 5.4Hz) , 7.114(s, 1H), 7.374-7.714(m, 13H).

Example 63:

2-Benzylamino-4-(4-tolylthio)-3-(4’-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that diethyl ether is used as solvent to obtain 495 mg of white solid, yield: 38.32%, melting point: 120-122°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.235 (s, 3H), 3.365 (s, 2H), 3.822 (s, 2H), 7.043 (s, 1H), 7.173 (d, 2HJ: 8.7Hz) , 7.247-7.386(m, 5H), 7.322(d, 2H, J: 8.7Hz), 7.457(m, 3H, J: 7.8Hz), 7.698(d, 2H, J: 7.8Hz), 7.759(s, 4H).

Example 64:

2-(2-N,N'-Dimethylaminoethylamino)-4-(4-methylthio)-3-(4'-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), using benzene as a solvent to obtain 350 mg of off-white solid, yield: 40.75%, melting point: 94.6-98°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.115 (s, 6H), 2.233 (s, 3H), 2.325 (t, 2H, J: 6.3Hz), 2.728 (t, 2H, J: 6.3Hz) , 3.317(s, 2H), 3.617(w, 3H), 6.971(s, 1H), 7.166(d, 2H, J: 8.4Hz), 7.307(d, 2H, 8.1Hz), 7.384(t, 1H, J: 7.2Hz), 7.468(t, 2H, H: 7.2Hz), 7.696(d, 2H, J: 7.2Hz), 7.758(s, 4H).

Example 65:

2-n-octylamino-4-(4-tolylthio)-3-(4’-bibenzoyl)butanoic acid

The method is the same as in Example 56(H), except that diethyl ether is used as solvent to obtain 160 mg of off-white solid, yield: 18.13%, melting point: 130-133°C.

¹ HNMR (300MHz, DMSO): δ (ppm) = 0.815 (t, 3H, J: 6.3Hz), 1.201 (s, 10H), 1.434 (p, 2H, J: 6.9Hz), 2.232 (s, 3H) , 2.628(t, 2H, J: 7.5Hz), 3.179(s, 2H), 6.918(s, 1H), 7.165(d, 2H, J: 8.1Hz), 7.299(d, 2H, J: 8.1Hz) , 7.384(t, 1H, J: 7.2Hz), 7.468(t, 2H, J: 7.2Hz), 7.697(d, 2H, J: 7.2Hz), 7.760(s, 4H).

Example 66:

4-(4-Biphenyl)-2-(2-Hydroxyethylthio)-4-Hydroxyiminobutanoic Acid

Add 6 mmol of hydroxylamine hydrochloride to 10 ml of anhydrous methanol, add 9 mmol of potassium hydroxide under cooling in an ice-water bath, and react at this temperature for 1 hour. Filter, wash the solid with a small amount of methanol, add the filtrate to 3 mmol 2-(2-hydroxyethylthio)-(4'-biphenyl)-4-oxobutanoic acid, and react overnight at room temperature. The reaction solution was concentrated to dryness, the residue was dissolved in water, carefully acidified with concentrated hydrochloric acid, the precipitated white precipitate was filtered, washed with water until neutral, and dried to obtain 1.031 g of white solid, yield: 99.52%, melting point: 138-140°C (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.641 (td, 2H, J: 2.4Hz, 6.9Hz, CH ₂ S), 3.160 (d, 2H, J: 7.8Hz, COCH ₂ ), 3.423 (t , 2H, J: 7.2Hz, _CH2OH ), 3.651 (t, 1H, J: 7.8Hz, CHS), 7.366 (t, 1H, J: 7.2Hz, ArH), 7.466 (t, 2H, J: 7.5 Hz, ArH), 7.663-7.735 (m, 6H, ArH).

Example 67: 4-(4-Biphenyl)-2-(2-propylthio)-4-hydroxyiminobutanoic acid

The method was the same as in Example 66 to obtain 0.639 g of white solid, yield: 93.03%, melting point: 128-131° C. (decomposition).

¹ HNMR (300MHz, CDCl ₃ ): δ (ppm) = 0.924 (t, 3H, J: 7.5Hz, CH ₃ ), 1.553 (p, 2H, J: 6.9Hz, CH ₂ CH ₃ ), 2.585 (dt, 1H, J: 4.8Hz, 12.6Hz, SCH ₂ ), 2.655 (dt, 1H, J: 6.3Hz, 12.6Hz, SCH ₂ ), 3.304 (dd, 1H, J: 7.8Hz, 14.1Hz, COCH ₂ ), 3.426(dd, 1H, J: 7.8Hz, 14.1Hz, COCH ₂ ), 3.893(t, 1H, J: 7.8Hz, CHS), 7.422(m, 3H, J: 7.5Hz, ArH), 7.579(d, 2H, J: 7.5Hz, ArH), 7.613 (d, 2H, J: 8.4Hz, ArH), 7.644 (d, 2H, J: 8.4Hz, ArH).

Example 68: 4-(4-Biphenyl)-2-(4-methylphenylthio)-4-hydroxyiminobutanoic acid

The method is the same as in Example 66, except that 0.774 g of white solid is obtained, yield: 98.86%, melting point: 122-125° C. (decomposition).

¹ HNMR (300MHz, DMSO): δ (ppm) = 2.242 (s, 3H, CH ₃ ), 3.174 (d, 2H, J: 7.5Hz, COCH ₂ ), 3.949 (t, 1H, J: 7.5Hz, CHS ), 7.077(d, 2H, J: 8.1Hz, ArH), 7.218(d, 2H, J: 8.1Hz, ArH), 7.361(t, 1H, J: 7.5Hz, ArH), 7.462(t, 2H, J: 7.5Hz, ArH), 7.627-7.692 (m, 6H, ArH).

Compound structures and physical constants are shown in Table 3.2.1.

Table 3.2.1

No. Structural Formula Molecular Formula Molecular Weight Melting Point (°C)

           C₁₈H₁₈N₂O₅        342.35          150.6-153Gyy21010

C ₁₈ H ₁₈ N ₂ O ₅ 342.35 150.6-153

Gyy10904 C ₁₈ H ₁₈ O ₄ S 330.40 127.6-129.6

Gyy11112 C ₁₉ H ₂₀ O ₄ S 344.42 149-152

            C₁₉H₂₀O₃S          328.43           115-117Gyy20604

C ₁₉ H ₂₀ O ₃ S 328.43 115-117

Gyy30104 C ₂₃ H ₂₀ O ₃ S 376.47 160-162

         C₁₈H₁₉NO₄S         345.41           138-140Gyy21009

C ₁₈ H ₁₉ NO ₄ S 345.41 138-140

      C₂₂H₂₂N₂O₅S       426.49           179-181Gyy21106

C ₂₂ H ₂₂ N ₂ O ₅ S 426.49 179-181

Gyy21121 C ₂₄ H ₂₂ N ₂ O ₆ S 466.51 106-108

          C₁₈H₁₉NO₄S         345.41           138-140Gyy30314

C ₁₈ H ₁₉ NO ₄ S 345.41 138-140

        C₂₃H₂₁NO₃S         391.48           122-125Gyy30315

C ₂₃ H ₂₁ NO ₃ S 391.48 122-125

            C₁₉H₂₁NO₃S         343.44           128-131Gyy30316

C ₁₉ H ₂₁ NO ₃ S 343.44 128-131

            C₂₀H₂₁NO₄          339.39           183-186Gyy10404

C ₂₀ H ₂₁ NO ₄ 339.39 183-186

Gyy10407 C ₂₃ H ₂₁ NO ₃ 359.42 191.5-193.5

                  C₂₁H₂₃NO₄         353.42            171.4-172.4Gyy10408

C ₂₁ H ₂₃ NO ₄ 353.42 171.4-172.4

Gyy10906 C ₁₈ H ₁₉ NO ₄ 313.35 185-187

                   C₂₀H₂₃NO₃         325.41            173.3-175Gyy20201

C ₂₀ H ₂₃ NO ₃ 325.41 173.3-175

Gyy20204 C ₂₄ H ₃₁ NO ₃ 381.52 122.4-126.0

Gyy20205 C ₂₂ H ₂₅ NO ₃ 351.44 178.6-180.1

               C₂₀H₂₄N₂O₃       340.42            142-143.8Gyy20202

C ₂₀ H ₂₄ N ₂ O ₃ 340.42 142-143.8

Gyy20206 C ₁₉ H ₁₉ NO ₃ 309.36 143.2-146

                C₂₅H₂₅NO₃         387.48            169-170.4Gyy20605

C ₂₅ H ₂₅ NO ₃ 387.48 169-170.4

Gyy21112 C ₂₀ H ₂₄ ClNO ₄ 377.87 139-142

Gyy21113 C ₂₁ H ₂₈ Cl ₂ N ₂ O ₃ 427.37 138-141

Gyy20123 C ₁₈ H ₁₉ NO ₅ 329.35 155-157

                  C₂₄H₃₁NO₄         397.51            164-166Gyy20207

C ₂₄ H ₃₁ NO ₄ 397.51 164-166

                    C₂₀H₂₃NO₄         341.41            164-167Gyy20208

C ₂₀ H ₂₃ NO ₄ 341.41 164-167

Gyy20209 C ₂₂ H ₂₅ NO ₄ 367.44 184-186.5

Gyy20210 C ₁₉ H ₁₉ NO ₄ 325.36 171.2-173.2

               C₂₃H₂₁NO₄         375.42            173-174.4Gyy20211

C ₂₃ H ₂₁ NO ₄ 375.42 173-174.4

Gyy20215 C ₂₀ H ₂₄ N ₂ O ₄ 356.42 137-139

                    C₂₀H₂₁NO₅         355.39            176-178Gyy20217

C ₂₀ H ₂₁ NO ₅ 355.39 176-178

                    C₂₁H₂₃NO₄         353.42            146.5-149.5Gyy20218

C ₂₁ H ₂₃ NO ₄ 353.42 146.5-149.5

               C₂₁H₂₆N₂O₄      370.45            160-162.7Gyy20501

C ₂₁ H ₂₆ N ₂ O ₄ 370.45 160-162.7

Gyy21110 C ₂₅ H ₂₆ ClNO ₄ 439.94 140-142

                C₁₈H₂₁ClN₂O₄    364.82            167.1-169.1Gyy30305

C ₁₈ H ₂₁ ClN ₂ O ₄ 364.82 167.1-169.1

                C₂₀H₂₄ClNO₅       393.87            130-133Gyy21111

C ₂₀ H ₂₄ ClNO ₅ 393.87 130-133

Gyy20213 C ₁₈ H ₁₉ NO ₄ 313.35 175.7-177

Gyy20113 C ₁₃ H ₁₇ NO ₅ 267.28 165.2-168

                    C₁₉H₂₉NO₄         335.44            166-168Gyy20114

C ₁₉ H ₂₉ NO ₄ 335.44 166-168

Gyy20118 C ₁₅ H ₂₁ NO ₄ 279.34 162.6-165

Gyy20120 C ₁₅ H ₂₂ N ₂ O ₄ 294.35 126.3-128.7

Gyy20214 C ₁₇ H ₂₃ NO ₄ 305.37 160-162

                       C₁₄H₁₇NO₄         263.29            157.5-159Gyy20216

C ₁₄ H ₁₇ NO ₄ 263.29 157.5-159

             C₁₅H₁₉NO₅          293.32            167-169Gyy20219

C ₁₅ H ₁₉ NO ₅ 293.32 167-169

         C₁₆H₂₄N₂O₄        308.38            148-150.3Gyy20502

C ₁₆ H ₂₄ N ₂ O ₄ 308.38 148-150.3

Gyy21108 C ₂₀ H ₂₄ ClNO ₄ 377.87 125-128

        C₁₇H₂₅NO₇          355.39            150-152Gyy21109

C ₁₇ H ₂₅ NO ₇ 355.39 150-152

          C₂₀H₂₀ClNO₄        373.83            194-196Gyy10403

C ₂₀ H ₂₀ ClNO ₄ 373.83 194-196

Gyy30105 C ₁₈ H ₁₈ ClNO ₄ 347.80 175-177

          C₂₃H₂₂N₂O₃        374.44            218-222Gyy20918

C ₂₃ H ₂₂ N ₂ O ₃ 374.44 218-222

          C₁₈H₂₀N₂O₄        328.37            218.9-222Gyy20919

C ₁₈ H ₂₀ N ₂ O ₄ 328.37 218.9-222

Gyy30308 C ₂₀ H ₂₄ N ₂ O ₄ 356.42 205.6-208

Gyy20923 C ₁₈ H ₂₀ N ₂ O ₅ 344.37 187.5-190.5

Gyy21011 C ₂₃ H ₂₂ N ₂ O ₄ 390.44 165-168

Gyy20922 C ₁₃ H ₁₈ N ₂ O ₅ 282.30 176-178

Gyy21013 C ₁₈ H ₂₀ N ₂ O ₄ 328.37 192.8-195

Gyy21014 C ₁₉ H ₃₀ N ₂ O ₄ 350.46 196-200

Gyy21132 C ₂₀ H ₂₄ N ₂ O ₅ 372.42 179.6-181.6

Gyy20414 C ₃₀ H ₂₇ NO ₄ 465.55 174-177

Gyy20415 C ₃₁ H ₃₇ NO ₄ 487.64 158-161

Gyy20417 C ₂₅ H ₂₅ NO ₅ 419.48 80-83

            C₂₇H₃₀N₂O₄      446.55            151.2-154Gyy20418

C ₂₇ H ₃₀ N ₂ O ₄ 446.55 151.2-154

Gyy20419 C ₂₇ H ₂₉ NO ₄ 431.53 175-178

Gyy20422 C ₂₉ H ₃₁ NO ₄ 457.57 216-219

           C₂₆H₂₇NO₄S       449.56            102.2-105.2Gyy20411

C ₂₆ H ₂₇ NO ₄ S 449.56 102.2-105.2

               C₃₁H₂₉NO₃S       495.64            120-122Gyy20412

C ₃₁ H ₂₉ NO ₃ S 495.64 120-122

               C₃₂H₃₉NO₃S       517.73            130-133Gyy20421

C ₃₂ H ₃₉ NO ₃ S 517.73 130-133

Gyy20420 C ₂₈ H ₃₂ N ₂ O ₃ S 476.63 94.6-98

activity evaluation

Experimental principle

In the MMPs hydrolysis activity inhibition experiment, the selected hydrolysis substrate contains both a highly fluorescent 7-methoxycoumarin group and a quencher group, and the activated MMPs can cleave the peptide between the fluorescent group and the quencher group bond to enhance the fluorescence of the substrate. The inhibitory effect of the sample on MMPs was observed according to the change of fluorescence intensity.

Materials and Methods

Instrument: Fluostar galaxy microplate optical measuring instrument and supporting fluorescence measuring 384-well plate (product of BMG company).

Reagent

1. Recombinant human MMP-1, MMP-2, MMP-3, MMP-9, fluorescent substrate II

ProMMP-1: the stock solution concentration is 132 μg/ml, TCN is dissolved, and the final concentration is 0.1 μg/ml.

ProMMP-2: The stock solution concentration is 50 μg/ml, TCN is dissolved, and the final concentration is 0.018 μg/ml.

ProMMP-3: The stock solution concentration is 100 μg/ml, TCN is dissolved, and the final concentration is 0.4 μg/ml.

ProMMP-9: The stock solution concentration is 66 μg/ml, TCN is dissolved, and the final concentration is 0.1 μg/ml.

Fluorescent substrate II: the concentration of the stock solution is 2mM, dissolved in DMSO, and the final concentration is 10mM.

Activator APMA (p-aminophenylmercuric acetate): 100mM dissolved in DMSO, the use concentration is 1mM.

2. TCN buffer: 50mM Tris, PH=7.5, 10mM CaCl ₂ , 150mM NaCl

3. The sample to be screened: the compound to be tested was dissolved in DMSO, diluted with TCN, and used at a final concentration of 10 μg/ml, ready for use.

experimental method

1. Activation of MMPs:

MMP-1: Add APMA to 132 μg/ml ProMMP-1 solution so that the final concentration of APMA is 1 mM, and incubate at 37°C for 2.5 hours. Dilute with TCN buffer when used.

MMP-2: Add APMA to 50 μg/ml ProMMP-2 solution so that the final concentration of APMA is 1 mM, and incubate at 37°C for 2.5 hours. Dilute with TCN buffer before use.

MMP-3: Add APMA to 100 μg/ml ProMMP-3 solution to make the final concentration of APMA 1 mM, and incubate at 37°C for 24 hours. Dilute with TCN buffer when used.

MMP-9: Add APMA to 66 μg/ml ProMMP-9 solution so that the final concentration of APMA is 1 mM, and incubate at 37°C for 25 hours. Dilute with TCN buffer when used.

2. Determination of compound inhibitory activity:

(1) 8 wells in a 384-well plate are used as controls. Among them, A1-D1 uses physiological saline instead of samples to reflect the maximum activity of the enzyme, which is used as an enzyme value control (Ke); E1-H1 uses physiological saline instead of samples, and reaction buffer instead of enzymes, as a positive control (Kc).

(2) Add 5 μl of samples to be tested at different concentrations and 40 μl of activating enzyme (final concentration: 0.4 μg/ml) to the remaining wells, and measure the obtained enzyme activity as the experimental value (Ks).

(3) After 10 minutes, 5 μl of fluorescent substrate II (final concentration: 10 μM) was added at low temperature, and centrifuged quickly and briefly at low temperature.

(4) Fluorescence was measured at Ex320nm and EM405nm, and the reaction temperature was 35°C. One cycle every 2 minutes, a total of 20 cycles were measured. Remove the first two time points (to exclude the influence of low starting temperature on the reaction), and calculate the change slope of the fluorescence value as the value reflecting the enzyme activity.

Inhibition rate% of the sample=[(Ke-Kc)-(Ks-Kc)]/(Ke-Kc)×100%. Dilute the sample to be tested into 5 different concentrations (10, 1, 0.1, 0.01, 0.001 μg/ml) respectively, measure the inhibition rate of the sample to the enzyme under different concentrations, and make a dose-effect curve according to the inhibition rate and sample concentration, Calculation of _IC50 (results are listed in the table below).

List of target MMPs inhibitory activities

IC ₅₀ (μM) IC(μM)

compound compound compound

MMP-1 MMP-2 MMP-3 MMP-9 MMP-1 MMP-2 MMP-3 MMP-9

Gyy21010 * 3.45 * * Gyy20217 * 46.70 * *

Gyy10904 * 3.71 * 18.49 Gyy20218 * 3.189 * 14.22

Gyy11112 11.73 4.94 * 53.21 Gyy20501 * 10.32 * 64.76

Gyy20604 15.69 1.86 * * * Gyy21110 5.53 4.12 * 14.95

Gyy30104 * 5.94 * 9.496 Gyy30305 * 11.57 * 2.27

Gyy21009 * 0.796 * 46.06 Gyy21111 * 90.71 *

Gyy21106 Untested Untested Untested Untested Gyy20213 * * 22.90 *

Gyy21121 * 2.700 * 53.03 Gyy20113 53.86 45.72 * 77.15

Gyy30314 * 6.47 54.72 79.64 Gyy20114 * 13.25 *

Gyy30315 37.18 3.07 * 4.626 Gyy20118 * * * * *

Gyy30316 * 6.95 * 14.04 Gyy20120 * * * * *

Gyy10404 * 4.63 64.23 * Gyy20214 45.65 11.47 * 86.96

Gyy010407 * 5.79 * * * Gyy20216 82.01 13.77 * 31.26

Gyy10408 33.59 5.63 * 17.69 Gyy20219 * 16.52 *

Gyy10906 * 2.645 * 23.64 Gyy20502 9.961 6.04 * 15.01

Gyy20201 * * 2.35 46.65 15.16 Gyy21108 * * * * *

Gyy20204 Untested Untested Untested Untested Gyy21109 * 31.06 * * *

Gyy20205 * 3.12 * 8.494 Gyy10403 * 5.26 * 18.06

Gyy20202 * 1.06 * 13.99 Gyy30105 * 0.364 2.218

Gyy20206 * 2.14 * 15.07 Gyy20918 53.41 75.05 *

Gyy20605 15.57 9.10 * 12.96 Gyy20919 15.13 5.73 *

Gyy21112 3.313 4.50 * * 9.07 Gyy30308 * 15.91 * *

Gyy21113 2.066 0.709 1.872 9.88 Gyy20923 * 13.52 * 17.47

Gyy20123 * 26.27 * * Gyy21011 * 0.526 69.38 15.93

Gyy20207 * * * * * * * Gyy20922 * * * * * *

Gyy20208 * 29.74 * 12.40 Gyy21013 * 8.64 71.81 *

Gyy20209 71.68 40.63 * 63.82 Gyy21014 * 17.58 * 86.88

Gyy20210 * 14.04 * 75.84 Gyy21132 * 0.79 * 28.04

Gyy20211 * 10.78 * * Gyy20414 * 2.84 *

Gyy20215 * 57.63 * * Gyy20415 * 1.14 * *

Gyy20417 Untested Untested Untested Untested Gyy20411 Untested Untested Untested Untested

Gyy20418 15.14 3.11 * 57.95 Gyy20412 * 2.37 * *

Gyy20419 10.62 1.24 * 29.08 Gyy20421 * 2.50 * *

Gyy20422 17.59 2.95 * 75.71 Gyy20420 * 2.73 * *

Note: * in the table indicates no inhibitory activity

The in vitro enzyme inhibition test on the established MMP1, MMP2, MMP9 enzyme activity screening models shows that this type of compound has different degrees of inhibitory activity on MMP-1, MMP-2, MMP-3 and MMP-9, and has Different degrees of selective inhibition of MMP-2.

Claims (14)

1. Compounds represented by general formula (I) and pharmacodynamically acceptable salts thereof

Wherein, R1 is selected from C _1～8 linear or branched alkyl and alkoxy, alkylthio, alkylamino; cycloalkyl; halogen, nitro, cyano, hydroxyl; -COOR ⁵ ,- OCOR ⁶ , -NHCOR ⁷ , -CONHR ⁸ ; R ⁵ , R ⁶ , R ⁷ , R ⁸ are independently selected from C ₁ -C ₄ alkyl, cycloalkyl or phenyl, or

M is an oxygen atom, a sulfur atom, an amino group, a methylene phenyl group, a phenoxy group, a phenylthio group, an anilino group, and a benzyl group; ^R is selected from C _1-4 alkyl, alkoxy, alkylthio, alkylamino, hydroxyl, amino, halogen-substituted phenyl, phenoxy, phenylthio, anilino, benzyl; selected from heterocyclyl and substituted heterocyclyl; R2 is selected from O, S, =NR ⁹ , =NOR ¹⁰ ; R ⁹ and R ¹⁰ are independently selected from H, C _1~4 alkyl or cycloalkyl, phenyl; Z is selected from H, NH, O, S, = _CH2 ; When Z=NH, O, S, R3 is selected from H, C _1～6 straight chain or branched alkyl; cycloalkyl; phenyl and substituted phenyl; heterocyclic and substituted heterocyclic; -COR ¹¹ , wherein R ¹¹ is selected from C _1-4 alkyl, cycloalkyl, phenyl and substituted phenyl. When Z=CH ₂ , R3 is selected from phthaloyl-2-yl, succinyl-2-yl, hydantoin-3-yl, R ¹² W[R ¹² is selected from H, C _{1～ 6} Alkyl; Cycloalkyl _; Phenyl and substituted _phenyl ; ^Heterocyclyl and substituted heterocyclyl ^; Base; W is selected from O, S, NH; Y is selected from NH, O, S; R4 is selected from H, C _1～6 linear or branched alkyl, cycloalkyl; phenyl and substituted phenyl; benzyl and phenylalkyl; -COR ¹⁴ , wherein R ¹⁴ is selected from C ₁ ～C ₄ Alkyl, phenyl, phenylalkyl and substituted phenyl, phenylalkyl; also can be selected from heterocyclic group; X is selected from OH, NHOH. 2. The compound according to claim 1, wherein said heterocyclic group is selected from pyridyl, pyrrolyl, furyl, thienyl, pyranyl, pyridyl, piperazinyl. 3. The compound according to claim 1, characterized in that said compound is Wherein, R1 and R4 are as defined in claim 1. 4. The compound according to claim 1, characterized in that said compound is

Wherein, R1 and R4 are as defined in claim 1. 5. The compound according to claim 1, characterized in that said compound is

Wherein, R1 is as defined in claim 1. 6. The compound according to claim 1, characterized in that said compound is Wherein, R1 is as defined in claim 1. 7. The compound according to claim 1, characterized in that said compound is

Wherein, R1 and R4 are as defined in claim 1. 8. The compound according to claim 1, characterized in that said compound is

Wherein, R1, R3 and R4 are as defined in claim 1. 9. The compound according to claim 1, characterized in that said compound is Wherein, R1 is as defined in claim 1. 10. Compounds according to claims 1-9, characterized in that said compounds are selected from 2-(2-Hydroxyethylamino)-4-oxo-4-(4’-biphenyl)butanoic acid 2-Benzylamino-4-oxo-4-(4’-biphenyl)butanoic acid 2-n-Butylamino-4-oxo-4-(4’-biphenyl)butanoic acid 2-n-octylamino-4-oxo-4-(4’-biphenyl)butanoic acid 2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-biphenyl)butanoic acid 2-Cyclohexylamino-4-oxo-4-(4’-biphenyl)butanoic acid 2-Cyclopropylamino-4-oxo-4-(4’-biphenyl)butanoic acid 2-(3-Phenylpropylamino)-4-oxo-4-(4’-biphenyl)butanoic acid 2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-biphenyl)butanoic acid 2-(4-Hydroxybutylamino)-4-oxo-4-(4’-biphenyl)butanoic acid 2-(4-Morpholinyl)-4-oxo-4-(4’-biphenyl)butanoic acid 2-(4-Hydroxy-N-piperidinyl)-4-oxo-4-(4’-biphenyl)butanoic acid 2-(2-Hydroxyethylamino)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-Benzylamino-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-n-Butylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-n-octylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-Cyclohexylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-Cyclopropylamino-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-(3-Phenylpropylamino)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-phenoxyphenyl)butanoic acid 2-(4-Hydroxybutylamino)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-(4-Morpholinyl)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-(4-Piperidinyl)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid 2-(2-Hydroxyethylamino)-4-oxo-4-(4’-methoxyphenyl)butanoic acid 2-Benzylamino-4-oxo-4-(4’-methoxyphenyl)butanoic acid 2-n-Butylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-n-octylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-(2-N,N'-Dimethylaminoethylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-Cyclohexylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-Cyclopropylamino-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-(3-Phenylpropylamino)-4-oxo-4-(4’-methoxyphenyl)butanoic acid 2-(3-N,N'-Dimethylaminopropylamino)-4-oxo-4-(4'-methoxyphenyl)butanoic acid 2-(4-Hydroxybutylamino)-4-oxo-4-(4’-methoxyphenyl)butanoic acid 2-(4-Morpholinyl)-4-oxo-4-(4’-methoxyphenyl)butanoic acid 2-(2-Hydroxyethylthio)-4-oxo-4-(4’-biphenyl)butanoic acid N-Hydroxy-2-(2-hydroxyethylthio)-4-oxo-4-(4’-biphenyl)butanamide N-Hydroxy-2-[2-(N-succinimido)ethylthio]-4-oxo-4-(4’-biphenyl)butanamide 2-Propylthio-4-oxo-4-(4’-biphenyl)butanoic acid 2-(2-Hydroxyethylthio)-2-methyl-4-oxo-4-(4’-biphenyl)butanoic acid N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4’-biphenyl)butanamide N-Hydroxy-2-benzylamino-4-oxo-4-(4’-biphenyl)butanamide N-Hydroxy-2-benzylamino-4-oxo-4-(4’-methoxyphenyl)butanamide N-Hydroxy-2-octylamino-4-oxo-4-(4'-methoxyphenyl)butanamide N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4’-phenoxyphenyl)butanamide N-Hydroxy-2-benzylamino-4-oxo-4-(4’-phenoxyphenyl)butanamide N-Hydroxy-2-(4-hydroxybutylamino)-4-oxo-4-(4’-phenoxyphenyl)butanamide 2-(4-Morpholinyl)-4-oxo-4-[4’-(4”-chloro)biphenyl]butanoic acid 2-(2-Hydroxyethylamino)-4-oxo-4-[4’-(4”-chloro)biphenyl]butanoic acid 2-(4-Methylphenylthio)-4-oxo-4-(4’-biphenyl)butanoic acid 2-(2-Aminoethylamino)-4-oxo-4-(4’-phenoxyphenyl)butanoic acid N-Hydroxy-2-(4-hydroxybutylamino)-4-oxo-4-(4’-biphenyl)butanamide N-Hydroxy-2-(2-hydroxyethylamino)-4-oxo-4-(4’-methoxyphenyl)butanamide N-Hydroxy-2-hydroxy-3-acetamido 4-oxo-4-(4’-biphenyl)butanamide N-Hydroxy-2-[2-(4-nitrophenoxy)ethylthio]-4-oxo-4-(4’-biphenyl)butanamide 2-(2-Hydroxyethylamino)-4-phenoxy-3-(4’-bibenzoyl)butanoic acid 2-Benzylamino-4-phenoxy-3-(4’-bibenzoyl)butanoic acid 2-n-octylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid 2-(2-N,N'-Dimethylaminoethylamino)-4-phenoxy-3-(4'-bibenzoyl)butanoic acid 2-n-Butylamino-4-phenoxy-3-(4'-bibenzoyl)butanoic acid 2-Cyclohexylamino-4-phenoxy-3-(4’-bibenzoyl)butanoic acid 2-(2-Hydroxyethylamino)-4-(4-tolylthio)-3-(4’-bibenzoyl)butanoic acid 2-Benzylamino-4-(4-tolylthio)-3-(4’-bibenzoyl)butanoic acid 2-(2-N,N'-Dimethylaminoethylamino)-4-(4-methylthio)-3-(4'-bibenzoyl)butanoic acid 2-n-octylamino-4-(4-tolylthio)-3-(4’-bibenzoyl)butanoic acid 4-(4-Biphenyl)-2-(2-Hydroxyethylthio)-4-Hydroxyiminobutanoic Acid 4-(4-Biphenyl)-2-(2-propylthio)-4-hydroxyiminobutanoic acid 4-(4-Biphenyl)-2-(4-methylphenylthio)-4-hydroxyiminobutanoic acid 11. A method for preparing the compound and its intermediates described in claim 1, characterized in that it is selected from the following methods Method 1: (A) Michael addition of α, β unsaturated γ aryl butanonic acid cis-trans mixtures obtained by Friedel-Crafts reaction with various primary amines or thiols in an appropriate solvent to obtain the corresponding addition products ; Method 2: (A) Prepare 2-substituted amino-4-oxo-4-(4'-substituted phenyl)butanoic acid in alcohol and thionyl chloride at an appropriate temperature to prepare 2-substituted amino-4 - Oxy-4-(4'-substituted phenyl) butyrate hydrochloride; (B) the obtained ester hydrochloride reacts with hydroxylamine hydrochloride and alkali in alcohol to generate corresponding hydroxamic acid; Method 3: (A) react 2-(2-hydroxyethylmercapto)-4-oxo-4-(4'-substituted phenyl)butanoic acid with methyl iodide or dimethyl sulfate and potassium carbonate to prepare the corresponding Methyl ester; (B) Mitsunobu reaction, under the effect of triphenylphosphine and diethyl azodicarboxylate or dibenzyl azodicarboxylate or diisopropyl azodicarboxylate, 2-(2-hydroxyethyl mercapto )-4-oxo-4-(4'-substituted phenyl) butyric acid methyl ester reacts with succinimide or phthalimide or substituted phenol to generate the corresponding product 2-[2-(2- Succinimidyl)ethylmercapto]-4-oxo-4-(4'-substituted phenyl)butanoic acid methyl ester or 2-[2-(2-phthalimido)ethyl Mercapto]-4-oxo-4-(4'-substituted phenyl) methyl butyrate or 2-[2-(4"-nitrophenoxy)ethylmercapto]-4-oxo-4-(4 '-substituted phenyl) methyl butyrate; (C) reacting the above-mentioned gained methyl butyrate with hydroxylamine hydrochloride and alkali in methanol to generate corresponding hydroxamic acid; Method 4: (A) Add mercaptoethanol to trans-α methyl-α, β unsaturated γ aryl butanonic acid in an alkaline alcohol solution to obtain the corresponding addition product; Method 5: (A) Mannich condensation of substituted acetophenone, glyoxylic acid monohydrate and various amines in alcohol to generate corresponding Mannich condensation products; Method 6: (A) Bromine addition of 3-(4'-substituted benzoyl)-3-butenoic acid to prepare 3,4-dibromo 3-(4'-substituted benzoyl)butanoic acid ; (B) Protect the hydroxyl group of the obtained 3,4-dibromo-3-(4'-substituted benzoyl)butanoic acid to obtain 3,4-dibromo-3-(4'-substituted benzoyl)butyric acid acid derivatives; (C) β elimination of the obtained 3,4-dibromo-3-(4'-substituted benzoyl)butyrate to generate 4-bromo-3-(4'-substituted benzoyl)-2-butene acid derivatives; (D) Reaction of the obtained 4-bromo-3-(4'-substituted benzoyl)-2-butenoic acid derivative with R3H to obtain the corresponding 4-substituted-3-(4'-substituted benzoyl) - 2-butenoic acid derivatives; (E) deprotecting the substituted crotonate obtained in (D) into the corresponding acid; (F) Add the resulting 4-substituted-3-(4'-substituted benzoyl)-2-butenoic acid to the corresponding primary amine to prepare 2-substituted amino-4-substituted-3-(4 '-substituted benzoyl)-2-butanoic acid; Method 7: (A) methylating the carboxylic acid hydroxyl group of 2-hydroxyl-3-acetamido-4-oxo-4-(4'-substituted phenyl) butanoic acid; (B) 2-hydroxyl-3-acetamido-4-oxo-4-(4'-substituted phenyl) butyric acid methyl ester is prepared into corresponding hydroxamic acid by the method described in method 2(B); Method 8: (A) React 2-thioether-substituted-4-(4'-biphenyl)-4-oxobutyric acid with hydroxylamine hydrochloride and base in alcohol solution to produce 2-thioether-substituted-4, a condensation product of 4-hydroxylamine -(4'-Biphenyl)-4-hydroxyiminobutanoic acid. 12. A pharmaceutical composition, characterized by comprising an effective dose of any compound as claimed in claims 1-10, and a pharmacodynamically acceptable carrier. 13. The pharmaceutical composition according to claim 12, characterized in that the pharmaceutical composition can be tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations and various particle delivery systems. 14. Use of the compound according to any one of claims 1-10 in the preparation of drugs for treating osteoarthritis and tumors.