CN105777464B - Hydroxamic acid derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses a hydroxamic acid derivative, a preparation method and application thereof₁M, n, X and R₂Is defined as described in the specification and claims. The hydroxamic acid derivative can inhibit the activity of LpxC deacetylase, has antibacterial activity, can particularly inhibit gram-negative bacteria, and is particularly suitable for preparing medicaments for preventing and/or treating related diseases caused by the gram-negative bacteria.

Description

Hydroxamic acid derivatives and preparation method and application thereof

technical field

The present invention belongs to the field of pharmaceutical compounds. In particular, the present invention relates to a new class of hydroxamic acid derivatives, or enantiomers, diastereomers, racemates or mixtures thereof, and pharmaceutically acceptable salts thereof, and The preparation method of the above-mentioned compound and the use of the above-mentioned compound as a biologically active substance for preparing a medicine.

Background technique

With the widespread use of antibacterial drugs, a large number of drug-resistant bacteria have appeared clinically, and the problem of bacterial drug resistance has become an important problem that threatens human public health. For Gram-negative bacterial infections, especially diseases caused by E. coli, P. aeruginosa, and A. baumannii, there are very limited therapeutic drugs.

The outer layer of the cell membrane of Gram-negative bacteria is composed of lipopolysaccharide (LPS), which acts as a permeable barrier to prevent antibiotics from entering the interior of the bacteria. Biological studies have shown that lipopolysaccharide is essential for bacterial cell growth and plays an important role in the folding process of membrane proteins [The Journal of Biological Chemistry, 274(8), 1999, 5114-5119]. Each lipopolysaccharide molecule is mainly composed of three main parts: O-type antigen, core polysaccharide and plasmoid A. Among them, lipid A is the link between lipopolysaccharide and the outer membrane, and is the key structure to maintain the stability of the cell membrane [J Lipid Res, 46(5), 2005, 839-861]. Plasmid A is synthesized in the cytoplasm on the inner surface of the inner membrane under the catalysis of nine specific and highly conserved biological enzymes. The first step is the acylation of UDP-glucose fatty acid, which is a one-step reversible reaction. The second step is the deacetylation catalyzed by LpxC[UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase], which is the rate controller for the biosynthesis of lipid A step. If the activity of LpxC deacetylase can be inhibited, the synthesis of lipid A can be blocked, thereby destroying the integrity of bacterial lipopolysaccharide, resulting in bacterial death.

LpxC deacetylase is a zinc ion protease, increasing or decreasing its content is lethal to bacteria, and widely exists in Gram-negative bacteria, has no common sequence with mammalian protein components, and is not prone to side effects . These advantages make it an important target for new anti-Gram-negative drugs.

A variety of LpxC inhibitors have been reported in the literature [Current Medicinal Chemistry, 2012, 19, 2038-2050]. Although most of them have good antibacterial activity in vitro, few compounds have entered clinical research due to their poor druggability. Only Achaogen's ACHN-975 entered Phase I clinical trials in 2012, but the study was terminated in 2013 due to problems with the injection site during injection administration [Bioorganic & Medicinal Chemistry Letters 24(2014) 3683–3689].

SUMMARY OF THE INVENTION

The object of the present invention is to provide an LpxC inhibitor.

The first aspect of the present invention provides a compound of formula I, its enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt,

In the formula, R ₁ is an unsubstituted or substituted C ₁ -C ₆ alkyl group, and the substitution refers to having a substituent selected from the group consisting of hydroxyl, amino, halogen, nitro, cyano, and mercapto;

m is an integer from 0 to 2, which is 0, 1 or 2;

n is an integer from 0 to 1;

X is -O-, -S-, -NH-, -NHCO- or -CONH-;

R ₂ is substituted C ₁ -C ₆ alkyl, the substitution means having a substituent selected from the group consisting of hydroxyl, mercapto, nitro, cyano, -SO ₂ (halogenated C ₁ -C ₃ alkyl ), -SO ₂ (C ₁ -C ₃ alkyl), -CONHOH,

Provided that the compound of formula I is not:

4,4'-(1,3-Butadiyn-1,4-diyl)bis[N-[(1S,2R)-2-hydroxy-1-[(hydroxyamino)acyl]propyl]benzyl amide;

N-[(1S,2R)-2-hydroxy-1-[(hydroxyamino)acyl]propyl]-N'-[(1R,2R)-2-hydroxy-1-[(hydroxyamino)acyl]propyl base]-[1,1'-biphenyl]-4,4'-dicarboxamide;

N-[(1S)-1-(Aminomethyl)-2-(hydroxyamino)-2-oxoethyl]-4-[2-[4-[2-(hydroxyamino)-2-oxo Ethoxy]phenyl]ethynyl]-benzamide.

In another preferred example, the definitions of R ₁ , m, n, X and R ₂ are as described above, provided that when X is -CONH- or -NHCO-, and R ₂ has two substituents, the substituents Not hydroxyl and -CONHOH; when X is -O-, the substituent on R ₂ is not -CONHOH.

In another preferred embodiment, the substitution is mono-substitution or polysubstitution. In another preferred embodiment, the substitution is mono-substitution, di-substitution, tri-substitution or tetra-substitution. In another preferred embodiment, the polysubstituted, disubstituted, trisubstituted or tetrasubstituted refers to having the same or different substituents.

In another preferred example, the C ₁ -C ₆ alkyl group has 1, 2, 3 or 4 substituents.

In another preferred embodiment, the configuration of each chiral carbon atom in the compound of formula I is independently R-type or S-type.

In another preferred embodiment, R ₁ is a hydroxy or amino substituted C ₁ -C ₄ alkyl group.

In another preferred example, R ₂ is a substituted C ₁ -C ₆ alkyl group, and the substitution refers to having a substituent selected from the group consisting of hydroxyl, -SO ₂ CH ₃ , -SO ₂ CF ₃ , -CONHOH ,

In another preferred example, R ₂ is a substituted C ₁ -C ₄ alkyl group, wherein the substituents on the C ₁ -C ₄ alkyl group are selected from: hydroxyl, -SO ₂ CH ₃ , -SO ₂ CF ₃ , - CONHOH,

In another preferred embodiment, the compound of formula I is any one of compounds 1-20 prepared in the examples.

In another preferred embodiment, the pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, ethyl acetate acid salt, oxalate, succinate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, essence acid or maleate.

The second aspect of the present invention provides the preparation method of the compound of formula I described in the first aspect, wherein m is 1 or 2; when n is 1, the method comprises the following steps:

(a) the compound of formula I-1 is condensed with the compound of formula I-2 to obtain the compound of formula I-3;

(b) the compound of formula I-3 reacts with the compound of formula I-4 to obtain the compound of formula I-5;

(c) compound of formula I-5 reacts with hydroxylamine to obtain compound of formula I,

In each formula, X is defined as above,

When m is 0; n is 0 or 1, and X is -O- or -S-, the method includes the following steps:

(i) the compound of formula II-1 is condensed with the compound of formula II-2 to obtain the compound of formula II-3, and q is 1 or 2;

(ii) the compound of formula II-3 is reacted with R ₂ OH to obtain the compound of formula II-4;

(iii) the compound of formula II-4 reacts with hydroxylamine to obtain the compound of formula I,

In each formula, R ₁ is protected or unprotected, unsubstituted or substituted C ₁ -C ₆ alkyl;

R ₂ is protected or unprotected substituted C ₁ -C ₆ alkyl;

Y is ethynyl or halogen;

Each of said substitutions independently refers to substitution with a group selected from the group consisting of hydroxy, amino, halogen, nitro, cyano, _-SO2CH3 , _-CONHOH ,

And when R ₁ is a protected, unsubstituted or substituted C ₁ -C ₆ alkyl and/or R ₂ is a protected substituted C ₁ -C ₆ alkyl, the method also includes removing the protecting group. Step, the protecting group is selected from: tert-butoxycarbonyl, p-methoxybenzyl, benzyl, benzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl , methoxymethyl, methylthiomethyl, methoxyethoxymethyl, benzyloxymethyl.

In another preferred example, when R ₁ is a protected, unsubstituted or substituted C ₁ -C ₆ alkyl group, the compound of formula II-4 is deprotected and reacted with hydroxylamine to obtain the compound of formula I.

In another preferred embodiment, when R ₂ is a protected substituted C ₁ -C ₆ alkyl group, the compound of formula II-4 is reacted with hydroxylamine to remove the protecting group to obtain the compound of formula I.

A third aspect of the present invention provides a pharmaceutical composition comprising:

The compound of formula I described in the first aspect, its enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt; and

A pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides the use of the compound of formula I described in the first aspect or the pharmaceutical composition described in the third aspect, for:

(1) preparing a drug that inhibits LpxC deacetylase;

(2) Preparation of medicines for preventing and/or treating bacterial infections;

(3) preparation of medicines for inhibiting bacterial growth;

(4) LpxC deacetylase inhibitor.

In another preferred embodiment, the bacteria are Gram-negative bacteria.

In another preferred embodiment, the Gram-negative bacteria are selected from: Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii.

A fifth aspect of the present invention provides a method for reducing bacterial pathogenicity or toxicity, comprising the steps of:

The bacteria are contacted with the compound of formula I according to the first aspect 1 or the pharmaceutical composition according to the third aspect, thereby reducing the pathogenicity or toxicity of the bacteria.

In another preferred embodiment, the bacteria are Gram-negative bacteria.

In another preferred embodiment, the Gram-negative bacteria are selected from: Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii.

In another preferred embodiment, the method is a non-therapeutic method.

In another preferred embodiment, the method is a therapeutic method.

In another preferred embodiment, the contacting results in an increase or decrease in the content of LpxC deacetylase in the bacteria.

The sixth aspect of the present invention provides a method for inhibiting LpxC deacetylase, by administering a safe and effective amount of the compound of formula I or the pharmaceutical composition described in the third aspect to a subject in need or to the environment.

The seventh aspect of the present invention provides an antibacterial method for administering a safe and effective amount of the compound of formula I or the pharmaceutical composition described in the third aspect to a desired subject or to the environment.

The eighth aspect of the present invention provides a method for treating bacterial infection, comprising the steps of: administering a safe and effective amount of the compound of formula I or the pharmaceutical composition of the third aspect to a subject infected with bacteria.

In another preferred embodiment, the compound of formula I or the pharmaceutical composition of the third aspect is contacted with bacteria and acts for a period of time, thereby reducing the pathogenicity and/or toxicity of bacteria.

In the present invention, the required object includes human or non-human mammal, preferably, human, mouse or rat.

In the present invention, the mode of administration to the subject is not particularly limited, including but not limited to oral administration, injection, inhalation, and topical use.

In the present invention, "safe and effective amount" refers to: the amount of the active ingredient (the compound of formula I) is sufficient to significantly improve the condition without causing serious side effects.

The hydroxamic acid derivative of the present invention can inhibit the activity of LpxC deacetylase, has bacteriostatic activity, especially can inhibit Gram-negative bacteria, and is especially suitable for preparing prophylactic and/or therapeutic bacteria, especially Gram-negative bacteria Drugs for related diseases caused by bacteria.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated here.

Detailed ways

After extensive and in-depth research, the inventors of the present application have developed a novel LpxC deacetylase inhibitor for the first time, which is a hydroxamic acid derivative. The hydroxamic acid derivative of the present invention has antibacterial activity, especially can inhibit Gram-negative bacteria. On this basis, the present invention has been completed.

Hydroxamic acid derivatives

In the present invention, hydroxamic acid derivatives, compounds of formula I, and compounds of formula I have the same meaning, and all refer to compounds with the following structures:

Wherein, the definitions of R ₁ , m, n, X and R ₂ are as described above.

In the present invention, the term "C ₁ -C ₆ alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl and Butyl etc. In the present invention, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

Preparation

The compound of the present invention can be produced by the following method, however the conditions of the method such as reactants, solvent, acid, base, amount of compound used, reaction temperature, reaction time, etc. are not limited to the following descriptions. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known to those skilled in the art, and those skilled in the art of the present invention can easily make the above combinations.

Route 1: m is 1 or 2; when n is 1, the method includes the following steps:

Route 2: when m is 0; when n is 0 or 1, the method includes the following steps:

In each formula, the definitions of X, R ₁ , R ₂ , Y, m, and n are as described above.

In a preferred embodiment, the compound of formula I-1 is reacted with the compound of formula I-2 in a polar solvent in the presence of a condensing agent and an organic base at room temperature for 4-16 hours to obtain the compound of formula I-3. The condensing agent can be 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT). The organic base can be triethylamine and diisopropylethylamine; the polar solvent can be dichloromethane and N,N-dimethylformamide.

In a preferred embodiment, the compound of formula I-3 and the compound of formula I-4 (Y is an ethynyl group) are catalyzed by a metal-containing copper catalyst, in a mixed solvent under basic conditions, and under the protection of an inert gas at room temperature to The reaction is carried out at 40°C for 12-24 hours to obtain the compound of formula I-4. The metal-containing copper catalyst may be copper acetate, and the mixed solvent under basic conditions may be a mixed solvent of pyridine and methanol.

In a preferred embodiment, the compound of formula I-3 and the compound of formula I-4 (Y is a halogen) are catalyzed by a metal-containing palladium catalyst, in a basic condition and a polar aprotic solvent, under the protection of an inert gas The reaction is carried out at room temperature to 40° C. for 2-12 hours to obtain the compound of formula I-5. The metal-containing palladium catalyst may be bis(triphenylphosphine)palladium dichloride and cuprous iodide. The bases used in the basic conditions can be: triethylamine, diisopropylethylamine, and pyridine. The polar aprotic solvent can be: 1,4-dioxane, dimethylformamide, tetrahydrofuran. The inert gas can be nitrogen or argon.

In a preferred embodiment, the compound of formula II-1 is reacted with the compound of formula II-2 in a polar solvent in the presence of a condensing agent and an organic base at room temperature for 4-16 hours to obtain the compound of formula II-3. The condensing agent can be 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT). The organic base can be triethylamine and diisopropylethylamine; the polar solvent can be dichloromethane and N,N-dimethylformamide.

In a preferred embodiment, the compound of formula II-3 is reacted with R ₂ OH in a polar solvent in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine at room temperature for 0.5-2 hours , the compound of formula II-4 is obtained. The polar solvent can be tetrahydrofuran, N,N-dimethylformamide.

In a preferred embodiment, the compound of formula I-5 or the compound of formula II-4 is reacted with an aqueous hydroxylamine solution (eg 50%) in a polar solvent at room temperature to 40° C. for 3-18 hours to obtain the compound of formula I. The polar solvent can be a mixed solution of methanol and dichloromethane. In a preferred embodiment, some compounds do not have a deprotection process, and hydroxylamine is directly the final product after replacing the methyl ester.

In a preferred embodiment, the compound of formula I-5 whose R ₂ has a protecting group or the compound of formula II-4 whose R ₂ has a protecting group is reacted with hydroxylamine in an acidic solvent at room temperature for 3-12 hours , the protecting group is removed to obtain the compound of formula I. The acidic solvent may be a mixed solution of trifluoroacetic acid and dichloromethane.

In a preferred embodiment, a compound of formula I- ₅ having a protecting group such as t-butoxycarbonyl for R or a compound of formula II- ₄ having a protecting group such as t-butoxycarbonyl for R is in an acidic solvent After deprotection, react with an aqueous hydroxylamine solution (eg, 50%) in a polar solvent at room temperature to 40° C. for 3-18 hours to obtain the compound of formula I. The acidic solvent may be a 1,4-dioxane solution of hydrogen chloride or an ethyl acetate solution. The polar solvent can be a mixed solution of methanol and dichloromethane.

pharmaceutical composition

The compound of formula I of the present invention can inhibit the activity of LpxC deacetylase, has bacteriostatic activity, and can especially inhibit Gram-negative bacteria.

The pharmaceutical composition provided by the present invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient; and a pharmaceutically acceptable carrier.

Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose. Preferably, the "one dose" is one tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

The solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like. Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

When using the pharmaceutical composition, a safe and effective amount of the compound of formula I of the present invention is suitable for mammals (such as human beings) in need of treatment, wherein the dose is a pharmaceutically considered effective dose when administered, for a person with a body weight of 60kg , the daily dosage is usually 1-2000mg, preferably 20-500mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All features disclosed in this specification may be used in combination with any composition, and each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

The benefits of the present invention are:

(1) The present invention provides hydroxamic acid derivatives with novel structures.

(2) The present invention provides a preparation method of the hydroxamic acid derivative, which is simple and efficient.

(3) The present invention discovers for the first time a new use of the hydroxamic acid derivative, which can be used for preparing antibacterial drugs, especially for preparing drugs for inhibiting Gram-negative bacteria.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to normal conditions such as people such as Sambrook, molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor LaboratoryPress, 1989), or according to manufacturer's recommended conditions. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

In all the examples, ¹ H-NMR was recorded with a Varian Mercury 300 or AVANCEIII 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); silica gel was used for separation, which was 200-300 mesh when not specified, and the proportions of the eluents were all is the volume ratio.

Preparation Examples

Example 1: N-((2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-4-((4-(3-(methylsulfonyl) Preparation of Propoxy)phenyl)1,3-butadiynyl-)aniline (Compound 1)

(a) 1-Iodo-4-(3-(methylsulfonyl)propoxy)benzene

Under argon protection, 3-methylsulfonyl propanol (200 mg, 1.447 mmol) and 4-iodophenol (382 mg, 1.737 mmol) were dissolved in 10 ml of anhydrous tetrahydrofuran, and triphenylphosphine ( 569 mg, 2.171 mmol) and diethyl azodicarboxylate (378 mg, 2.171 mmol), reacted for 1 h, TLC (PE/EA=2/1) detected the completion of the reaction of the raw materials, spin-dried the solution, column chromatography (PE/EA= 5/1-2/1) to obtain 400 mg of white solid with a yield of 81.3%.

¹ H NMR(400MHz, Chloroform-d)δ7.56(d,J=9.1Hz,2H),6.66(d,J=9.0Hz,2H),4.08(t,J=5.8Hz,2H),3.28- 3.18(m, 2H), 2.95(s, 3H), 2.40–2.28(m, 2H).

MS(ESI)m/z:[(M+Na) ⁺ ,263.0].

(b) Trimethyl((4-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)silane

Under argon, compound 1-iodo-4-(3-(methylsulfonyl)propoxy)benzene (400 mg, 1.176 mmol) prepared in (a) above and trimethylsilylacetylene (173 mg, 1.765 mmol) were dissolved in Ph(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.059 mmol), CuI (12 mg, 0.059 mmol), Et ₃ N (238 mg, 2.352 mmol) were added to 10 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 12 h. TLC (PE/EA=2/1) detected the disappearance of the raw materials, the solvent was spin-dried, redissolved in ethyl acetate, washed with saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution in turn, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (PE/EA=5/1-2/1) to obtain 330 mg of a yellow solid with a yield of 90.5%.

¹ H NMR(400MHz, Chloroform-d)δ7.40(d,J=8.7Hz,2H),6.80(d,J=8.8Hz,2H),4.11(t,J=5.8Hz,2H),3.31- 3.16(m, 2H), 2.95(s, 3H), 2.35(dq, J=11.4, 6.0Hz, 2H), 0.23(s, 9H).

MS(ESI) m/z: [(M+Cl) ^- ,344.8].

(c) 1-Ethynyl-4-(3-(methylsulfonyl)propoxy)benzene

The compound trimethyl((4-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)silane (330 mg, 1.063 mmol) prepared in (b) above was dissolved in 10 ml of anhydrous tetrahydrofuran and cooled to 0°C, slowly add tetra-n-butylamine fluoride (1M, 1.3ml), warm to room temperature, react for 1h, monitor the reaction by TLC (PE/EA=2/1), after the reaction is completed, add 10ml of water and 30ml of acetic acid ethyl ester, and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (PE/EA=5/1-2/1) to obtain 228 mg of white solid with a yield of 90.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (d, J=8.9 Hz, 2H), 6.82 (d, J=8.9 Hz, 2H), 4.12 (t, J=5.8 Hz, 2H), 3.25 (dd , J＝8.7,6.7Hz,2H),3.01(s,1H),2.96(s,3H),2.36(ddt,J＝11.6,7.6,5.7Hz,2H).MS(ESI)m/z:[ (M+Na) ⁺ ,263.0].

MS(ESI)m/z:[(M+Na) ⁺ ,261.1].

(d)(2S,3R)-3-Hydroxy-2-(4-((4-(3-(methylsulfonyl)propoxy)phenyl)-1,3-butadiyn-1-yl) benzamido) butyric acid methyl ester

Compound 1-ethynyl-4-(3-(methylsulfonyl)propoxy)benzene (228 mg, 0.957 mmol) prepared in (c) above was combined with (2S,3R)-2-(4-ethynylbenzyl) Acylamino)-3-hydroxybutyric acid methyl ester [Bioorganic & Medicinal Chemistry 19 (2011) 852–860] (500 mg, 1.914 mmol), dissolved in a mixed solvent of 8 ml of anhydrous methanol and 8 ml of pyridine, and copper acetate ( 348mg, 1.914mmol), stir at room temperature, react for 24h, monitor the reaction by TLC (PE/EA=2/1), after the reaction is completed, add 40ml of ethyl acetate to dissolve, and use dilute hydrochloric acid (1M) to wash away the pyridine in the solvent, It was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (PE/EA=5/1-2/1) to obtain 195 mg of white solid with a yield of 40.1%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.92 (d , J=8.8Hz, 1H), 6.87(d, J=8.8Hz, 2H), 4.84(dd, J=8.8, 2.2Hz, 1H), 4.50(s, 1H), 4.16(t, J=5.8Hz) ,2H),3.83(s,3H),3.38–3.22(m,2H),2.99(s,3H),2.39(dt,J=15.5,5.9Hz,2H),1.32(d,J=6.4Hz, 3H).

MS(ESI)m/z:[(M+Na) ⁺ ,520.1].

(e) N-((2S,3R)-3-hydroxy-1-(hydroxylamino)-1-oxobutan-2-yl)-4-((4-(3-(methylsulfonyl)propane) oxy)phenyl)1,3-butadiynyl-)aniline

The compound (2S,3R)-3-hydroxy-2-(4-((4-(3-(methylsulfonyl)propoxy)phenyl)-1,3-butadiyne prepared in the above (d) Methyl -1-yl)benzamido)butyrate (195mg, 0.392mmol) was dissolved in a mixed solution of 5ml of dichloromethane and 10ml of methanol, 50% aqueous hydroxylamine solution (1ml) was added dropwise at 0°C, and stirred at room temperature 12h, TLC (CH ₂ Cl ₂ /MeOH=20/1) detected the disappearance of raw materials. The solution was spin-dried and slurried with dichloromethane three times to obtain a pure product, which was 98 mg of off-white solid, and the yield was 50.1%.

¹ H NMR(400MHz, DMSO)δ10.70(s,1H),8.88(s,1H),8.22(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.71( d,J＝8.4Hz,2H),7.59(d,J＝8.8Hz,2H),7.02(d,J＝8.8Hz,2H),4.91(d,J＝6.4Hz,1H),4.25(dd, J=8.4, 5.6Hz, 1H), 4.15 (t, J=6.3Hz, 2H), 4.08–3.97 (m, 1H), 3.31–3.26 (m, 2H), 3.03 (s, 3H), 2.20–2.11 (m,2H),1.09(d,J＝6.3Hz,3H).

MS(ESI)m/z: [(MH) ^- ,497.0].

Example 2: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxybutan-2-yl)-4-((4-(((S)-3hydroxy- Preparation of 1-(hydroxylamine)-1-propoxy-2-yl)carbamoyl)phenyl)-1,3-butadiyn-1-yl)benzamide (compound 2)

(a) (S)-3-Hydroxy-2-amino-propionic acid methyl ester hydrochloride

L-threonine (1.0 g, 9.443 mmol) was suspended in 20 ml of methanol, thionyl chloride (1.3 g, 10.86 mmol) was added at 0 °C, stirred at room temperature for 24 h, and spin-dried to obtain 1.47 g of a gel, yield 100%.

¹ H NMR (400MHz, Deuterium Oxide) δ 4.17 (t, J=3.7Hz, 1H), 4.00 (dd, J=12.6, 4.2Hz, 1H), 3.89 (dd, J=12.3, 3.2Hz, 1H) ,3.75(s,3H).

(b) (S)-Methyl 2-(4-ethynylbenzoyl)-3-hydroxybutyrate

Compound (S)-3-hydroxy-2-amino-propionic acid methyl ester hydrochloride (256 mg, 1.642 mmol) prepared in (a) above and 4-ethynylbenzoic acid (200 mg, 1.369 mmol) were dissolved in 10 ml N , N-dimethylformamide, under argon protection, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.642 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.642 mmol), 1 -Hydroxybenzotriazole (222 mg, 1.642 mmol), diisopropylethylamine (708 mg, 5.476 mmol). Stir at room temperature for 20 h, TLC detected the reaction completion (CH ₂ Cl ₂ /MeOH=20/1), added 40 ml of ethyl acetate, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (CH ₂ Cl ₂ /MeOH=100/1-80/1) to obtain 165 mg of a yellow solid with a yield of 44.0%.

¹ H NMR(400MHz, Chloroform-d)δ7.82(d,J=8.0Hz,2H),7.58(d,J=8.0Hz,2H),7.15(d,J=7.2Hz,1H),4.89( dt, J＝7.1, 3.3Hz, 1H), 4.10(qd, J＝11.3, 5.5Hz, 2H), 3.85(s, 3H), 3.24(s, 1H), 2.63(t, J＝5.8Hz, 1H) ).

MS(ESI)m/z:[(M+H) ⁺ ,248.0].

(c)(2S,3R)-3-Hydroxy-2-(4-((4-(((S)-3-hydroxy-1-methoxy-1-propoxy-2-yl)aminomethane Acyl)phenyl)-1,3-butadiyn-1-yl)benzamido)butyric acid methyl ester

Compound (S)-methyl 2-(4-ethynylbenzoyl)-3-hydroxybutyrate (160 mg, 0.647 mmol) prepared in (b) above was combined with (2S,3R)-2-(4-acetylene) Benzamido)-3-hydroxybutyric acid methyl ester (254mg, 0.971mmol), dissolved in a mixed solvent of 8ml of anhydrous methanol and 8ml of pyridine, added copper acetate (348mg, 1.914mmol) under argon protection, room temperature Stir, react for 24 hours, monitor the reaction by TLC (CH ₂ Cl ₂ /MeOH=20/1), after the reaction is completed, add 40 ml of ethyl acetate to dissolve, use dilute hydrochloric acid (1M) to wash off the pyridine in the solvent, and then use saturated chlorine Washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (CH ₂ Cl ₂ /MeOH=80/1-20/1) to obtain 110 mg of a white solid with a yield of 33.6%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (d, J=7.4 Hz, 1H), 8.47 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.0 Hz, 4H), 7.76 (d, J=7.4Hz, 4H), 5.08 (t, J=6.2Hz, 1H), 4.99 (d, J=7.3Hz, 1H), 4.58–4.48 (m, 2H), 4.19 (h, J= 6.8Hz, 1H), 3.80(t, J=5.8Hz, 2H), 3.67(s, 3H), 3.66(s, 3H), 1.15(d, J=6.4Hz, 3H).

MS(EI)m/z: (M ⁺ ,506).

(d) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-propoxy-2-yl)-4-((4-((((S)-3hydroxy-1- (hydroxylamine)-1-oxobutan-2-yl)carbamoyl)phenyl)-1,3-butadiyn-1-yl)benzamide

The compound (2S,3R)-3-hydroxy-2-(4-((4-(((S)-3-hydroxy-1-methoxy-1-oxybutane- 2-yl)carbamoyl)phenyl)-1,3-butadiyn-1-yl)benzamido)butyric acid methyl ester (110 mg, 0.216 mmol) was dissolved in a mixture of 5 ml of dichloromethane and 10 ml of methanol To the solution, 50% hydroxylamine aqueous solution (1 ml) was added dropwise at 0°C, stirred at room temperature for 12 h, TLC (CH ₂ Cl ₂ /MeOH=20/1) detected the disappearance of the raw materials. The solution was spin-dried and slurried with dichloromethane three times to obtain pure product, which was 100 mg of off-white solid, and the yield was 91.0%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.72(s,1H), 10.71(s,1H), 8.89(s,1H), 8.87(s,1H), 8.49(d, J=7.9Hz, 1H), 8.24(d, J＝8.4Hz, 1H), 8.02-7.91(m, 4H), 7.81-7.70(m, 4H), 4.99(t, J＝5.8Hz, 1H), 4.91(d, J =6.3Hz,1H),4.42(q,J=6.6Hz,1H),4.26(dd,J=8.4,5.6Hz,1H),4.09-3.97(m,1H),3.69(hept,J=5.3Hz ,2H),1.10(d,J＝6.3Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,508.9].

Example 3: 4,4'-(1,2-ethynyl)bis(N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzene Formamide) (Compound 3) Preparation

(a) Methyl (2S,3R)-3-hydroxy-2-(4-iodobenzoyl)butyrate

The hydrochloride salt of threonine methyl ester (168 mg, 0.991 mmol) and 4-iodobenzoic acid (205 mg, 0.826 mmol) were dissolved in 10 ml of N,N-dimethylformamide, under argon protection, followed by Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 0.991 mmol), 1-hydroxybenzotriazole (134 mg, 0.991 mmol), diisopropylethyl acetate base amine (427 mg, 3.304 mmol). Stir at room temperature for 20 h, TLC detected the reaction completion (CH ₂ Cl ₂ /MeOH=20/1), added 40 ml of ethyl acetate, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (CH ₂ Cl ₂ /MeOH=100/1-80/1) to obtain 140 mg of a yellow solid with a yield of 38.9%.

¹ H NMR(400MHz, Chloroform-d)δ7.81(d,J=8.4Hz,2H),7.57(d,J=8.5Hz,2H),6.88(d,J=8.8Hz,2H),4.80( dd,J=8.8,2.4Hz,1H),4.47(ddd,J=6.7,4.5,2.4Hz,1H),3.81(s,3H),2.14(d,J=4.7Hz,1H),1.29(d ,J=6.4Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,386.0].

(b)(2S,2'S,3R,3'R)-2,2'-((4,4'-(1,2-ethynyl)bis(benzoyl))bis(3-hydroxybutyrate ester)

Compound (2S,3R)-3-hydroxy-2-(4-iodobenzoyl)butyric acid methyl ester (140 mg, 0.386 mmol) prepared in the above (a) and (2S,3R)-2-(4 -Ethynylbenzamido)-3-hydroxybutyric acid methyl ester (121mg, 0.463mmol) was dissolved in 15ml of anhydrous tetrahydrofuran solution, under argon protection, followed by adding triethylamine (78mg, 0.772mmol), Bis(triphenylphosphine) palladium dichloride (14mg, 0.019mmol) and cuprous iodide (4mg, 0.019mmol) were reacted at 40°C for 12h, and the reaction was completed by TLC detection (CH ₂ Cl ₂ /MeOH=20/ 1), 40 ml of ethyl acetate was added, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the solution was spin-dried for column chromatography (CH ₂ Cl ₂ /MeOH=100/1-80/1) to obtain 90 mg of a yellow solid with a yield of 47.0%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.1 Hz, 4H), 7.73 (d, J=8.1 Hz, 4H), 4.99 (d, J＝7.5Hz, 2H), 4.52(dd, J＝8.2, 4.2Hz, 2H), 4.20(td, J＝6.9, 4.4Hz, 2H), 3.67(s, 6H), 1.14(s, 3H)1.18(s,3H).

MS(EI)m/z: (M ⁺ ,496).

(c) 4,4'-(1,2-ethynyl)bis(N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzyl amide)

Compound (2S,2'S,3R,3'R)-2,2'-((4,4'-(1,2-ethynyl)bis(benzoyl))bis(3 -Methyl hydroxybutyrate) (90 mg, 0.216 mmol) was dissolved in a mixed solution of 5 ml of dichloromethane and 10 ml of methanol, 50% aqueous hydroxylamine solution (1 ml) was added dropwise at 0 °C, stirred at room temperature for 12 h, TLC (CH ₂ Cl ₂ /MeOH=20/1) to detect the disappearance of the raw material. The solution was spin-dried and slurried with dichloromethane three times to obtain a pure product, which was 80 mg of off-white solid, and the yield was 88.5%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.69(s, 2H), 8.87(s, 2H), 8.19(d, J=8.5Hz, 2H), 7.97(d, J=8.0Hz, 4H) ,7.70(d,J＝8.0Hz,4H),4.92(d,J＝6.3Hz,2H),4.27(dd,J＝8.4,5.5Hz,2H),4.03(q,J＝6.0Hz,2H) ,1.10(d,J=6.3Hz,6H).

MS(ESI)m/z:[(M+H) ⁺ ,521.1].

Example 4: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-(3-(methylsulfonyl)propane) Preparation of oxy)phenyl)ethynyl)benzamide (compound 4)

(a) (2S,3R)-Methyl 3-hydroxy-2-(4-((4-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)benzoyl)butyrate

Take compound 1-iodo-4-(3-(methylsulfonyl)propoxy)benzene (product of step (a) of Example 1) (237 mg, 0.498 mmol), (2S,3R)-2-(4- Ethynylbenzamido)-3-hydroxybutyric acid methyl ester (130 mg, 0.696 mmol), triethylamine (126 mg, 1.245 mmol), bis(triphenylphosphine)palladium dichloride (17 mg, 0.025 mmol) and Cuprous iodide (5 mg, 0.025 mmol), anhydrous tetrahydrofuran as solvent, according to the method described in (b) of Example 3, 200 mg of yellow solid was obtained with a yield of 84.9%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.9 Hz, 2H), 6.94-6.80 (m, 3H), 4.83 (d, J=11.1Hz, 1H), 4.56–4.41 (m, 1H), 4.15 (t, J=5.8Hz, 2H), 3.80 (s, 3H), 3.27 (dd, J=9.2, 6.1Hz, 2H), 2.97 (s, 3H), 2.42–2.33 (m, 2H), 2.10 (d, J=4.4Hz, 1H), 1.31 (d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,496.2].

(b) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-(3-(methylsulfonyl)propoxy) yl)phenyl)ethynyl)benzamide

Compound (2S,3R)-3-hydroxy-2-(4-((4-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)benzoyl)butyr prepared as above (a) Methyl acid (80 mg, 0.169 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 30 mg of white solid was obtained with a yield of 37.4%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.88 (s, 1H), 8.16 (d, J=8.5Hz, 1H), 7.94 (d, J=8.4Hz, 2H) ,7.63(d,J＝8.4Hz,2H),7.54(d,J＝8.7Hz,2H),7.02(d,J＝8.8Hz,2H),4.92(d,J＝6.4Hz,1H),4.26 (dd, J=8.5, 5.5Hz, 1H), 4.14(t, J=6.2Hz, 2H), 4.03(q, J=6.2Hz, 1H), 3.33–3.26(m, 2H), 3.03(s, 3H), 2.21–2.11(m, 2H), 1.10(d, J=6.3Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,475.0].

Example 5: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-(2-(methylsulfonyl)ethyl) Preparation of oxy)phenyl)ethynyl)benzamide (compound 5)

(a) 1-Iodo-4-(2-(methylsulfonyl)ethoxy)benzene

With compound 3-methylsulfonylethanol (200mg, 1.610mmol) and 4-iodophenol (425mg, 1.932mmol), triphenylphosphine (633mg, 2.415mmol) and diethyl azodicarboxylate (420mg, 2.415mmol) Using anhydrous tetrahydrofuran as a solvent, according to the method described in (a) of Example 1, 411 mg of white solid was obtained with a yield of 78.3%.

¹ H NMR(400MHz, Chloroform-d)δ7.60(d,J=9.0Hz,2H),6.69(d,J=9.0Hz,2H),4.41(t,2H),3.44(t,J=5.3 Hz,2H),3.05(s,3H).

MS(ESI) m/z: [(M+Cl) ^- ,360.5].

(b) (2S,3R)-Methyl 3-hydroxy-2-(4-((4-(2-(methylsulfonyl)ethoxy)phenyl)ethynyl)benzoyl)butyrate

Compounds prepared from (a) above 1-iodo-4-(3-(methylsulfonyl)ethoxy)benzene (411 mg, 0.984 mmol), (2S,3R)-2-(4-ethynylbenzoyl) amino)-methyl 3-hydroxybutyrate (280 mg, 1.073 mmol), triethylamine (298 mg, 2.952 mmol), bis(triphenylphosphine)palladium dichloride (35 mg, 0.049 mmol) and cuprous iodide ( 10 mg, 0.049 mmol), anhydrous tetrahydrofuran was used as a solvent, and according to the method described in (b) in Example 3, 328 mg of a yellow solid was obtained, with a yield of 72.5%.

¹ H NMR(400MHz, Chloroform-d)δ7.85(d,J=8.3Hz,2H),7.61(d,J=8.2Hz,2H),7.54(d,J=8.7Hz,2H),6.93( d, J=8.8Hz, 2H), 4.86 (dd, J=8.7, 2.4Hz, 1H), 4.65–4.36 (m, 3H), 3.84 (s, 3H), 3.49 (t, J=5.3Hz, 2H) ), 3.11(s, 1H), 1.33(d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,459.9].

(c) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-(2-(methylsulfonyl)ethoxy) yl)phenyl)ethynyl)benzamide

Compound (2S,3R)-3-hydroxy-2-(4-((4-(3-(methylsulfonyl)ethoxy)phenyl)ethynyl)benzoyl)butyr prepared as above (b) Methyl acid (100 mg, 0.217 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 30 mg of white solid was obtained with a yield of 30.0%.

¹ H NMR(400MHz,DMSO)δ10.69(s,1H),8.87(s,1H),8.15(d,J=8.5Hz,1H),7.94(d,J=8.4Hz,2H),7.63( d, J＝8.4Hz, 2H), 7.55(d, J＝8.8Hz, 2H), 7.07(d, J＝8.9Hz, 2H), 4.92(d, J＝6.4Hz, 1H), 4.40(t, J＝5.7Hz, 2H), 4.26(dd, J＝8.4, 5.6Hz, 1H), 4.03(dd, J＝12.2, 6.1Hz, 1H), 3.65(t, J＝5.6Hz, 2H), 3.09( s,3H),1.09(d,J＝6.3Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,460.8].

Example 6: (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4-((4-(2-(methylsulfone) Preparation of yl)ethoxy)phenyl)ethynyl)benzamide (compound 6)

(a) (S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl)ethoxy)phenyl)ethynyl ) benzamide) methyl butyrate

Compound 1-iodo-4-(3-(methylsulfonyl)ethoxy)benzene (product of step (a) of Example 5) (209 mg, 0.641 mmol), (S)-3-((tert-butoxy) Carbonyl)amino)-2-(4-ethynylbenzamide)-3-methylbutyric acid methyl ester (WO2013170030A1) (200mg, 0.534mmol), triethylamine (162mg, 1.602mmol), bis(triphenyl) phosphine) palladium dichloride (37mg, 0.053mmol) and cuprous iodide (10mg, 0.053mmol), anhydrous tetrahydrofuran was used as solvent, according to the method described in (b) in Example 3, 280mg of yellow solid was obtained, yield 91.6 %.

¹ H NMR(400MHz, Chloroform-d)δ9.13(s,1H),7.98-7.87(m,2H),7.65-7.55(m,2H),7.54-7.47(m,2H),6.90(d, J=8.8Hz, 2H), 4.74(d, J=8.0Hz, 1H), 4.70(s, 1H), 4.48(dd, J=5.8, 4.9Hz, 2H), 3.75(s, 3H), 3.49– 3.42(m, 2H), 3.08(d, J=0.8Hz, 3H), 1.53(s, 3H), 1.49(s, 3H), 1.46(s, 9H).

MS(ESI)m/z:[(M+H) ⁺ ,572.7].

(b) (S)-Methyl 3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl)ethoxy)phenyl)ethynyl)benzamide)butyrate ester

Compound (S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl)ethoxy)) prepared in (a) above Phenyl)ethynyl)benzamide)butyric acid methyl ester (280mg, 0.489mmol) was dissolved in 10ml of 1,4-dioxane solution, 5ml of 1,4-dioxane hydrogen chloride solution was added dropwise, Stir at room temperature for 5 hours, TLC (PE/EA=2/1) detects the reaction is complete, spin dry the solvent, add 40 ml of ethyl acetate to dissolve, wash off the residual acid with saturated aqueous sodium bicarbonate solution, then wash with saturated aqueous sodium chloride solution, acetic acid The ethyl ester layer was dried over anhydrous sodium sulfate. Filter and spin dry to obtain 185 mg of solid, yield 80.1%.

¹ H NMR(400MHz, DMSO-d6)δ8.41(s,1H),7.91(d,J=8.1Hz,2H),7.64(d,J=8.0Hz,2H),7.56(d,J=8.4 Hz, 2H), 7.07(d, J=8.5Hz, 2H), 4.42(s, 1H), 4.40(d, J=5.2Hz, 2H), 3.66(s, 3H), 3.64(d, 2H), 3.09(s, 3H), 1.15(s, 3H), 1.13(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,473.1]

(c) (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4-((4-(2-(methylsulfonyl) )ethoxy)phenyl)ethynyl)benzamide

Compound (S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl)ethoxy)phenyl)ethynyl)benzyl prepared with (b) above Amide) methyl butyrate (185 mg, 0.391 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 60 mg of white solid was obtained with a yield of 32.4%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.19(s, 1H), 9.26(s, 1H), 8.63(d, J=9.3Hz, 1H), 7.99(d, J=8.2Hz, 2H) ,7.65(d,J＝8.0Hz,2H),7.55(d,J＝8.7Hz,2H),7.07(d,J＝8.8Hz,2H),4.70(d,J＝9.3Hz,1H),4.40 (t, J=5.6Hz, 2H), 3.65(s, 2H), 3.09(s, 3H), 1.35(s, 3H), 1.31(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,474.1]

Example 7: (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4-((4-(3-(methylsulfone) Preparation of yl)propoxy)phenyl)ethynyl)benzamide (compound 7)

(a) (S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl)propoxy)phenyl)ethynyl ) benzamide) methyl butyrate

Take 1-iodo-4-(3-(methylsulfonyl)propoxy)benzene (product of Example 5, step (a)) (218 mg, 0.641 mmol), (S)-3-((tert-butoxycarbonyl) ) amino)-2-(4-ethynylbenzamide)-3-methylbutyric acid methyl ester (200 mg, 0.534 mmol), triethylamine (162 mg, 1.602 mmol), bis(triphenylphosphine)dichloro Palladium (37 mg, 0.053 mmol) and cuprous iodide (10 mg, 0.053 mmol), and anhydrous tetrahydrofuran as solvent, according to the method described in (b) in Example 3, 260 mg of yellow solid was obtained with a yield of 82.9%.

¹ H NMR (400MHz, Chloroform-d) δ 9.13 (s, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 4.82–4.67 (m, 2H), 4.17 (t, J=5.8Hz, 2H), 3.77 (s, 3H), 3.42–3.15 (m ,2H),2.99(s,3H),2.44–2.34(m,2H),1.55(s,3H),1.51(s,3H),1.48(s,9H).

MS(ESI)m/z:[(M+Na) ⁺ ,609.2].

(b) (S)-methyl 3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl)propoxy)phenyl)ethynyl)benzamide)butyric acid ester

(S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl)propoxy)benzene prepared in (a) above (260mg, 0.443mmol) was dissolved in 10ml of 1,4-dioxane solution, 5ml of 1,4-dioxane hydrogen chloride solution was added dropwise, room temperature Stir for 5h, TLC (PE/EA=2/1) detects the completion of the reaction, spin dry the solvent, add 40ml of ethyl acetate to dissolve, wash off the residual acid with saturated aqueous sodium bicarbonate solution, then wash with saturated aqueous sodium chloride solution, ethyl acetate The ester layer was dried over anhydrous sodium sulfate. Filter and spin dry to obtain 170 mg of solid with a yield of 78.9%.

¹ H NMR(400MHz, DMSO)δ8.54(s,1H),7.93(d,J=8.3Hz,2H),7.64(d,J=8.4Hz,2H),7.54(d,J=8.8Hz, 2H), 7.02(d, J＝8.8Hz, 2H), 4.53(d, J＝3.2Hz, 1H), 4.14(t, J＝6.2Hz, 2H), 3.67(s, 3H), 3.31–3.23( m, 2H), 3.03(s, 3H), 2.26–2.08(m, 2H), 1.20(s, 3H), 1.19(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,487.0].

(c) (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4-((4-(2-(methylsulfonyl) )propoxy)phenyl)ethynyl)benzamide

(S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl)propoxy)phenyl)ethynyl)benzamide prepared as (b) above ) methyl butyrate (170 mg, 0.349 mmol) was used as the raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) in Example 1, 60 mg of white solid was obtained with a yield of 35.3%.

¹ H NMR (300MHz, DMSO-d6) δ 11.24 (d, J=5.2Hz, 1H), 9.28 (d, J=13.9Hz, 1H), 8.55 (d, J=9.4Hz, 1H), 8.04 ( s, 2H), 7.95(d, J＝8.1Hz, 2H), 7.63(d, J＝8.0Hz, 2H), 7.52(d, J＝8.1Hz, 2H), 7.00(d, J＝9.2Hz, 2H), 4.69(d, J=9.1Hz, 1H), 4.32–3.97(m, 2H), 3.25(d, J=8.2Hz, 2H), 3.01(s, 3H), 2.11(s, 2H), 1.33(s, 3H), 1.28(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,488.0].

Example 8: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-((5-hydroxy-4-oxo Preparation of Hetero-1,4-dihydropyridin-2-yl)methyl)phenyl)ethynyl)benzamide (Compound 8)

(a) 2-((4-iodophenyl)methylene)-4,5-bis((4-methoxybenzyl)oxy)pyridine

With (4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methanol (WO2013150296A1) (500 mg, 1.311 mmol) and 4-iodophenol (346 mg, 1.573 mmol), triphenyl Phosphine (516 mg, 1.967 mmol) and diethyl azodicarboxylate (343 mg, 1.967 mmol) were used as raw materials, and anhydrous tetrahydrofuran was used as solvent, according to the method described in Example 1 (a) to obtain 400 mg of white solid, Yield 52.3%.

¹ H NMR (400MHz, Chloroform-d) δ8.11(s, 1H), 7.53(d, J=9.1Hz, 2H), 7.33-7.28(m, 4H), 7.04(s, 1H), 6.88(d , J=2.3Hz, 2H), 6.86(d, J=2.3Hz, 2H), 6.71(d, J=8.9Hz, 2H), 5.10(s, 2H), 5.08(s, 2H), 5.03(s ,2H),3.82(s,3H),3.80(s,3H).

MS(ESI)m/z:[(M+H) ⁺ ,584.4].

(b) (2S,3R)-2-(4-((4-((4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methoxy)phenyl) Ethynyl)benzamide)-3-hydroxybutyrate methyl ester

Compound 2-((4-iodophenyl)methylene)-4,5-bis((4-methoxybenzyl)oxy)pyridine (400mg, 0.686mmol), (2S, 3R)-2-(4-ethynylbenzamido)-3-hydroxybutyric acid methyl ester (215mg, 0.823mmol), triethylamine (208mg, 2.058mmol), bis(triphenylphosphine)dichloride Palladium (24 mg, 0.034 mmol) and cuprous iodide (7 mg, 0.034 mmol), and anhydrous tetrahydrofuran as solvent, according to the method described in (b) in Example 3, 300 mg of yellow solid was obtained with a yield of 61.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.7 Hz) ,2H),7.31(t,J=8.9Hz,4H),7.06(s,1H),6.92(d,J=8.8Hz,2H),6.87(m,5H),5.11(s,2H),5.10 (s, 4H), 4.83 (dd, J=8.6, 2.1Hz, 1H), 4.52–4.43 (m, 1H), 3.81 (s, 9H), 1.25 (d, J=2.5Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,739.4].

(c) 4-((4-((4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methoxy)phenyl)ethynyl)-N-((2S ,3R)-3hydroxy-1-(hydroxylamine)-1-oxybutan-2-yl)benzamide

Compound (2S,3R)-2-(4-(((4-((4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methoxy) prepared as above (b) base)phenyl)ethynyl)benzamide)-3-hydroxybutyric acid methyl ester (300mg, 0.419mmol) as raw material, dichloromethane and methanol as solvents, according to the method described in (e) in Example 1, 200 mg of white solid were obtained, and the yield was 66.5%.

¹ H NMR (400MHz, DMSO) δ 10.71(s, 1H), 8.87(s, 1H), 8.20(s, 1H), 8.16(d, J=8.3Hz, 1H), 7.94(d, J=8.4 Hz, 2H), 7.63(d, J＝8.4Hz, 2H), 7.53(d, J＝9.0Hz, 2H), 7.35(dd, J＝10.4, 8.2Hz, 4H), 7.30(s, 1H), 7.08(d,J=8.1Hz,2H),6.93(dd,J=8.7,4.2Hz,4H),5.14(s,2H),5.10(s,2H),5.08(s,2H),4.28–4.24 (m,1H),4.06–4.00(m,1H),3.76(s,3H),3.75(s,3H),1.10(d,J=6.0Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,718.0].

(d) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-((5-hydroxy-4-oxa -1,4-Dihydropyridin-2-yl)methyl)phenyl)ethynyl)benzamide

Compound 4-((4-((4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methoxy)phenyl)ethynyl)- N-((2S,3R)-3hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (200 mg, 0.279 mmol) was dissolved in 10 ml of dry dichloromethane, 0°C 0.2 ml of trifluoroacetic acid was added dropwise, moved to room temperature and stirred for 5 h after the addition, TLC (CH ₂ Cl ₂ /MeOH=10:1) detected the completion of the reaction, spin-dried, and slurried three times with ethyl acetate to obtain a solid with a yield of 82.7% .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.70(s, 1H), 8.15(d, J=8.4Hz, 1H), 7.95(d, J=8.1Hz, 2H), 7.65(s, 1H) ,7.63(d,J＝8.1Hz,2H),7.56(d,J＝8.3Hz,3H),7.09(d,J＝8.5Hz,2H),6.65(s,1H),5.07(s,2H) ,4.32–4.23(m,1H),4.09–3.99(m,1H),1.10(d,J=6.2Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,478.0].

Example 9: 4-((4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)ethynyl)-N-( Preparation of (2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (Compound 9)

(a) 1,5-bis(dibenzyloxy)-2-((4-iodophenoxy)methyl)pyridin-4(1H)-one

With compound 1,5-bis(dibenzyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one [Journal of Medicinal Chemistry 56(2013) 5541-5552] (500 mg, 1.021 mmol) and 4-iodophenol (270 mg, 1.225 mmol), triphenylphosphine (402 mg, 1.532 mmol) and diethyl azodicarboxylate (267 mg, 1.532 mmol) were used as raw materials, and anhydrous tetrahydrofuran was used as solvent, according to Example 1 According to the method described in (a), 390 mg of white solid was obtained in a yield of 55.2%.

¹ H NMR(400MHz, Chloroform-d)δ7.75-7.26(m,20H),7.19-7.15(m,2H),6.98(s,1H),6.43(d,J=3.2Hz,2H),6.40 (s,1H),6.22(s,1H),5.88(s,1H),4.50(s,2H).

MS(ESI)m/z:[(M+H) ⁺ ,714.2].

(b)(2S,3R)-2-(4-((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl) )Methoxy)phenyl)ethynyl)benzamido)-3-hydroxybutyric acid methyl ester

The compound 1,5-bis(dibenzyloxy)-2-((4-iodophenoxy)methyl)pyridin-4(1H)-one (390 mg, 0.564 mmol) of the above (a), (2S,3R)-Methyl 2-(4-ethynylbenzamido)-3-hydroxybutyrate (177 mg, 0.677 mmol), triethylamine (171 mg, 1.692 mmol), bis(triphenylphosphine) Palladium dichloride (20 mg, 0.028 mmol) and cuprous iodide (6 mg, 0.028 mmol), anhydrous tetrahydrofuran was used as solvent, according to the method described in Example 3 (b), 300 mg of yellow solid was obtained with a yield of 64.5%.

¹ H NMR (400MHz, Chloroform-d)δ7.96(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,1H),7.55(d,J=8.3Hz,2H),7.48– 7.25(m, 20H), 7.19–7.16(m, 2H), 6.96(s, 1H), 6.66(d, J=8.7Hz, 2H), 6.45(s, 1H), 6.02(s, 1H), 5.88 (s,1H),4.78(dd,J=8.2,3.2Hz,1H),4.60–4.50(m,2H),4.47(dd,J=6.5,3.3Hz,1H),3.80(s,3H), 1.29(d,J=6.4Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,825.0].

(c) 4-((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)acetylene yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compound (2S,3R)-2-(4-(((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydro) prepared with (b) above) Pyridin-2-yl)methoxy)phenyl)ethynyl)benzamido)-3-hydroxybutyric acid methyl ester (300mg, 0.363mmol) as raw material, dichloromethane and methanol as solvents, according to Example 1 The method described in (e) gave 200 mg of white solid with a yield of 66.7%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.88 (s, 1H), 8.16 (d, J=8.4Hz, 1H), 7.95 (d, J=8.4Hz, 2H) ,7.85(s,1H),7.64(d,J=8.4Hz,2H),7.48(d,J=8.7Hz,2H),7.44-7.30(m,16iH),7.24-7.21(m,4H), 6.78(d, J＝8.9Hz, 2H), 6.47(s, 1H), 6.39(s, 1H), 6.02(s, 1H), 4.92(d, J＝6.3Hz, 1H), 4.76(s, 2H) ), 4.27(dd, J＝8.5, 5.5Hz, 1H), 4.12(q, J＝5.3Hz, 1H), 4.03(q, J＝6.1Hz, 1H), 3.17(d, J＝5.2Hz, 3H ),1.10(d,J=6.3Hz,3H).

MS(ESI)m/z: [(MH) ^- ,824.2].

(d) 4-((4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)ethynyl)-N-(( 2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compounds prepared with (c) above 4-((4-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy )phenyl)ethynyl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (200mg, 0.242mmol) as starting material, Dichloromethane was used as solvent, and trifluoroacetic acid was used as debenzyl reagent. According to the method described in (d) of Example 8, 110 mg of solid was obtained, and the yield was 82.7%.

¹ H NMR(600MHz,DMSO)δ10.72(s,1H),8.90(s,1H),8.18(d,J=8.1Hz,1H),7.95(d,J=7.8Hz,2H),7.92( s, 1H), 7.64(d, J＝7.7Hz, 2H), 7.56(d, J＝7.8Hz, 2H), 7.10(d, J＝8.1Hz, 2H), 6.93(s, 1H), 5.22( s, 2H), 4.28–4.25 (m, 1H), 4.06–4.00 (m, 1H), 1.10 (d, J=5.7Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,494.1].

Example 10: 4-((4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)-1,3-butanedi Preparation of Alkynyl-1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (Compound 10)

(a) 1,5-bis(diphenylmethyloxy)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methylene)pyridin-4(1H)-one

Take compound 1,5-bis(dibenzyloxy)-2-((4-iodophenoxy)methyl)pyridin-4(1H)-one (product of Example 9, step (a)) ( 390 mg, 0.564 mmol), trimethylsilylacetylene (66 mg, 0.677 mmol), triethylamine (171 mg, 1.692 mmol), bis(triphenylphosphine)palladium dichloride (20 mg, 0.028 mmol) and cuprous iodide (6 mg, 0.028 mmol), anhydrous tetrahydrofuran was used as solvent, according to the method described in (b) of Example 3, 300 mg of yellow solid was obtained, and the yield was 80.4%.

¹ H NMR(400MHz, Chloroform-d)δ7.75-7.26(m,20H),7.19-7.15(m,2H),6.98(s,1H),6.43(d,J=3.2Hz,2H),6.40 (s,1H),6.22(s,1H),5.88(s,1H),4.50(s,2H),0.23(s,9H).

MS(ESI)m/z:[(M+H) ⁺ ,662.2].

(b) 1,5-bis(diphenylmethyloxy)-2-((4-ethynylphenoxy)methylene)pyridin-4(1H)-one

With the above (a) compound 1,5-bis(diphenylmethyloxy)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methylene)pyridine-4(1H)- Ketone (300mg, 0.453mmol) was used as raw material, tetra-n-butylamine fluoride (1M, 0.6ml) was used as detrimethylsilyl reagent, and tetrahydrofuran was used as solvent. According to the method described in (c) of Example 1, 240mg of white solid was obtained , the yield is 89.8%.

¹ H NMR(400MHz, Chloroform-d)δ7.75-7.26(m,20H),7.19-7.15(m,2H),6.98(s,1H),6.43(d,J=3.2Hz,2H),6.40 (s,1H),6.22(s,1H),5.88(s,1H),4.50(s,2H),3.01(s,1H).

MS(ESI)m/z:[(M+H) ⁺ ,662.2].

(c)(2S,3R)-2-(4-((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl) )methoxy)phenyl)-1,3-butadiyn-1-yl)benzamide)-3-hydroxybutyric acid methyl ester

Compound 1,5-bis(dibenzyloxy)-2-((4-ethynylphenoxy)methylene)pyridin-4(1H)-one (240 mg, 0.407) prepared with (b) above mmol), (2S,3R)-2-(4-ethynylbenzamido)-3-hydroxybutyric acid methyl ester (213mg, 0.813mmol), copper acetate (122mg, 0.813mmol) as raw materials, methanol and pyridine As a mixed solvent, according to the method described in (d) of Example 1, 138 mg of white solid was obtained, and the yield was 40.0%.

¹ H NMR (400MHz, Chloroform-d)δ7.84(d,J=8.3Hz,2H),7.75-7.26(m,22H),7.19-7.15(m,2H),6.98(s,1H),6.43 (d, J＝3.2Hz, 2H), 6.40(s, 1H), 6.22(s, 1H), 5.88(s, 1H), 4.84(dd, J＝8.8, 2.2Hz, 1H), 4.60(s, 1H), 4.50(s, 2H), 3.83(s, 3H), 1.32(d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,849.3].

(d) 4-((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)- 1,3-Butadiyn-1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compound (2S,3R)-2-(4-(((4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydro) prepared with (c) above) Pyridin-2-yl)methoxy)phenyl)-1,3-butadiyn-1-yl)benzamide)-3-hydroxybutyric acid methyl ester (138 mg, 0.163 mmol) as starting material, dichloromethane Using methanol as a solvent, according to the method described in (e) of Example 1, 120 mg of white solid was obtained with a yield of 87.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.70(s, 1H), 8.88(s, 1H), 8.16(d, J=8.4Hz, 1H), 7.85(d, J=8.4Hz, 2H) ,7.85(s,1H),7.66(d,J=8.4Hz,2H),7.48(d,J=8.7Hz,2H),7.44-7.30(m,16H),7.24-7.21(m,4H), 6.78(d, J＝8.9Hz, 2H), 6.47(s, 1H), 6.39(s, 1H), 6.02(s, 1H), 4.92(d, J＝6.3Hz, 1H), 4.76(s, 2H) ), 4.27(dd, J＝8.5, 5.5Hz, 1H), 4.12(q, J＝5.3Hz, 1H), 4.03(q, J＝6.1Hz, 1H), 3.17(d, J＝5.2Hz, 3H ),1.10(d,J=6.3Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,850.3].

(e) 4-((4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)phenyl)-1,3-butadiyne yl-1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compounds prepared with (d) above 4-((4-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy )phenyl)-1,3-butadiyn-1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzyl The amide (120 mg, 0.141 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (d) of Example 8, 58 mg of white solid was obtained with a yield of 80.2%.

¹ H NMR(600MHz,DMSO)δ10.72(s,1H),8.90(s,1H),8.18(d,J=8.1Hz,1H),7.95(d,J=7.8Hz,2H),7.92( s, 1H), 7.66(d, J＝7.7Hz, 2H), 7.56(d, J＝7.8Hz, 2H), 7.10(d, J＝8.1Hz, 2H), 6.93(s, 1H), 5.22( s, 2H), 4.28–4.25 (m, 1H), 4.06–4.00 (m, 1H), 1.10 (d, J=5.7Hz, 3H). MS(ESI) m/z: [(M+H) ⁺ ,494.1].

MS(ESI)m/z:[(M+H) ⁺ ,518.1].

Example 11: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-((5-hydroxy-4-oxo Preparation of Hetero-1,4-dihydropyridine-2-yl)methoxy)phenyl)-1,3-butadiyn-1-yl)benzamide (Compound 11)

(a) 4,5-bis((4-methoxybenzyl)oxy)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methylene)pyridine

Take compound 2-((4-iodophenyl)methylene)-4,5-bis((4-methoxybenzyl)oxy)pyridine (product of Example 8, step (a)) (420 mg, 0.720 mmol), trimethylsilylacetylene (106 mg, 1.080 mmol), triethylamine (218 mg, 2.160 mmol), bis(triphenylphosphine)palladium dichloride (25 mg, 0.036 mmol) and cuprous iodide (7 mg, 0.036 mmol), anhydrous tetrahydrofuran was used as solvent, according to the method described in Example 3 (b), 350 mg of yellow solid was obtained, the yield was 87.8%.

¹ H NMR (400MHz, Chloroform-d) δ 8.13 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.06(s, 1H), 6.94–6.84(m, 6H), 5.12(s, 2H), 5.11(s, 2H), 5.09(s, 2H), 3.84(s, 3H), 3.83 (s,3H),0.26(s,9H).

MS(ESI)m/z:[(M+H) ⁺ ,554.0].

(b) 2-((4-ethynylphenyl)methylene)-4,5-bis((4-methoxybenzyl)oxa)pyridine

With the above (a) compound 4,5-bis((4-methoxybenzyl)oxy)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methylene)pyridine (350mg , 0.632mmol) as raw material, tetra-n-butylamine fluoride (1M, 0.8ml) as detrimethylsilyl reagent, and tetrahydrofuran as solvent, according to the method described in (c) in Example 1, 270mg of white solid was obtained in a yield of 270mg. 88.8%.

¹ H NMR (400MHz, Chloroform-d) δ 8.15(s, 1H), 7.43(d, J=8.5Hz, 2H), 7.33(dd, J=10.5, 8.5Hz, 4H), 7.07(s, 1H) ),6.89(d,J＝8.1Hz,6H),5.13(s,2H),5.11(s,2H),5.10(s,2H),3.84(s,3H),3.83(s,3H),3.03 (s,1H).

MS(ESI)m/z: [(M+H) ⁺ 482.0].

(c) (2S,3R)-2-(4-((4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)phenyl) -1,3-Butadiyn-1-yl)benzamide)-3-hydroxybutyric acid methyl ester

Compound 2-((4-ethynylphenyl)methylene)-4,5-bis((4-methoxybenzyl)oxa)pyridine (270 mg, 0.561 mmol), ( 2S,3R)-2-(4-ethynylbenzamido)-3-hydroxybutyric acid methyl ester (293mg, 1.121mmol), copper acetate (168mg, 1.121mmol) as raw materials, methanol and pyridine as mixed solvents, According to the method described in (d) of Example 1, 162 mg of white solid was obtained, and the yield was 38.9%.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (d, J=8.1 Hz, 1H), 8.17 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.70 (d, J= 8.3Hz, 2H), 7.56 (d, J=8.7Hz, 2H), 7.33 (dd, J=8.6, 7.7Hz, 4H), 7.27 (s, 1H), 7.06 (d, J=8.8Hz, 2H) ,6.91(dd,J＝8.7,3.2Hz,4H),5.12(s,2H),5.07(s,4H),4.96(d,J＝7.4Hz,1H),4.48(dd,J＝8.2,4.2 Hz, 1H), 4.21–4.13(m, 1H), 3.74(s, 3H), 3.73(s, 3H), 3.64(s, 3H), 1.13(d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,741.0].

(d) 4-((4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)phenyl)-1,3-butadiyne- 1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compound (2S,3R)-2-(4-((4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy) prepared as above (c) yl)phenyl)-1,3-butadiyn-1-yl)benzamide)-3-hydroxybutyric acid methyl ester (162mg, 0.219mmol) as raw material, dichloromethane and methanol as solvents, according to Examples The method described in (e) in 1 gave 138 mg of a white solid with a yield of 85.0%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.69(s,1H),8.87(s,1H),8.22-8.18(m,2H),7.95(d,J=8.0Hz,2H),7.71( d, J=8.1Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.35 (dd, J=10.2, 8.3Hz, 4H), 7.29 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.97–6.89 (m, 4H), 5.14 (s, 2H), 5.09 (s, 4H), 4.90 (d, J=6.7Hz, 1H), 4.26 (dd, J=8.5, 5.5Hz) ,1H),4.03(q,J＝6.2Hz,1H),3.76(s,3H),3.75(s,3H),1.09(d,J＝6.3Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,742.1].

(e) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((4-((5-hydroxy-4-oxa -1,4-Dihydropyridine-2-yl)methoxy)phenyl)-1,3-butadiyn-1-yl)benzamide

Compounds prepared with (d) above 4-((4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)phenyl)-1,3 -Butadiyn-1-yl)-N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (138 mg, 0.186 mmol) as Raw material, dichloromethane and methanol were used as solvents, according to the method described in (d) of Example 8, 65 mg of white solid was obtained, and the yield was 69.7%.

¹ H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.21(d,J=8.4Hz,1H),7.98(s,1H),7.95(d,J=8.1Hz,2H), 7.71(d,J＝8.0Hz,2H),7.63(d,J＝8.2Hz,2H),7.11(d,J＝8.5Hz,2H),7.08(s,1H),5.24(s,2H), 4.26(dd,J=8.4,5.5Hz,1H),4.10–3.94(m,1H),1.09(d,J=6.2Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,502.1].

Example 12: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-(3-(methylsulfonyl)propoxy)benzene Preparation of formamide (compound 12)

(a) Methyl (2S,3R)-3-hydroxy-2-(4-hydroxybenzamide)butyrate

With p-hydroxybenzoic acid (114mg, 0.826mmol), threonine methyl ester hydrochloride (168mg, 0.991mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190mg, 0.991mmol), 1-hydroxybenzotriazole (134mg, 0.991mmol), diisopropylethylamine (427mg, 3.304mmol) as raw materials, N-N-dimethylformamide as solvent, according to the examples The method described in 2(b) gave 157 mg of white solid with a yield of 75.2%.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.78 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.66 (d, J=3.3 Hz, 1H), 4.37 ( dq,J=3.3,6.6Hz,1H),3.75(s,3H),1.22(d,J=6.6Hz,3H);

MS(ESI)m/z: [(MH) ^- ,252.0].

(b) Methyl (2S,3R)-3-hydroxy-2-(4-(3-(methylsulfonyl)propoxy)benzamide)butyrate

Compound (2S,3R)-methyl 3-hydroxy-2-(4-hydroxybenzamide)butyrate (157 mg, 0.620 mmol) prepared with the above (a), 3-methylsulfonylpropanol (129 mg, 0.930 mmol) and, triphenylphosphine (325mg, 1.240mmol), diethyl azodicarboxylate (216mg, 1.240mmol) as raw materials, anhydrous tetrahydrofuran as solvent, according to the method described in Example 1(a) to obtain 160 mg of white solid, yield 69.1%.

¹ H NMR(400MHz, Chloroform-d)δ7.82(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,1H),6.90(d,J=8.8Hz,2H),4.80( dd, J=8.7, 2.5Hz, 1H), 4.50–4.38 (m, 1H), 4.15 (t, J=5.8Hz, 2H), 3.79 (s, 3H), 3.32–3.22 (m, 2H), 2.98 (s, 3H), 2.86 (d, J=5.2Hz, 1H), 2.44–2.31 (m, 2H), 1.28 (d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,374.0].

(c) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-(3-(methylsulfonyl)propoxy)benzyl Amide

The compound (2S,3R)-3-hydroxy-2-(4-(3-(methylsulfonyl)propoxy)benzamide)butyric acid methyl ester (160 mg, 0.428 mmol) prepared in the above (b) was used as Raw material, dichloromethane and methanol were used as solvents, according to the method described in (e) of Example 1, 138 mg of white solid was obtained, and the yield was 86.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.65(s, 1H), 8.84(s, 1H), 7.93-7.80(m, 3H), 7.03(d, J=8.5Hz, 2H), 4.89( d, J=6.3Hz, 1H), 4.25 (dd, J=8.4, 5.3Hz, 1H), 4.16 (t, J=6.2Hz, 2H), 4.02 (q, J=6.1Hz, 1H), 3.32– 3.26(m, 2H), 3.03(s, 3H), 2.21–2.11(m, 2H), 1.08(d, J=6.3Hz, 3H).

MS(ESI)m/z: [(MH) ^- ,373.1].

Example 13: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-(3-(methylsulfonyl)ethoxy)benzene Preparation of formamide (compound 13)

(a) Methyl (2S,3R)-3-hydroxy-2-(4-(3-(methylsulfonyl)ethoxy)benzamide)butyrate

Compound (2S,3R)-methyl 3-hydroxy-2-(4-hydroxybenzamide)butyrate (product of step (a) of Example 12) (157 mg, 0.620 mmol), 3-methylsulfonylethanol (154 mg, 1.240 mmol) and, triphenylphosphine (325 mg, 1.240 mmol), diethyl azodicarboxylate (216 mg, 1.240 mmol) as raw materials, anhydrous tetrahydrofuran as solvent, according to Example 1(a) According to the method described above, 150 mg of white solid was obtained with a yield of 67.3%.

¹ H NMR(400MHz, Chloroform-d)δ7.86(d,J=8.8Hz,2H),6.96(d,J=8.7Hz,2H),6.91(d,J=8.8Hz,1H),4.83( dd, J=8.7, 2.4Hz, 1H), 4.55–4.44(m, 3H), 3.82(s, 3H), 3.50(t, J=5.3Hz, 2H), 3.10(s, 3H), 1.31(d ,J=6.4Hz,3H).

MS(ESI) m/z: [(M+Cl) ^- ,393.9].

(b) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-(3-(methylsulfonyl)ethoxy)benzyl Amide

The compound (2S,3R)-3-hydroxy-2-(4-(3-(methylsulfonyl)ethoxy)benzamide)butyric acid methyl ester (150 mg, 0.417 mmol) prepared in the above (a) was used as Raw material, dichloromethane and methanol were used as solvents, according to the method described in (e) of Example 1, 120 mg of white solid was obtained, and the yield was 79.8%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.65(s, 1H), 8.85(s, 1H), 7.98-7.83(m, 3H), 7.08(d, J=8.8Hz, 2H), 4.90( d, J＝6.2Hz, 1H), 4.42(t, J＝5.7Hz, 2H), 4.26(dd, J＝8.5, 5.4Hz, 1H), 4.02(q, J＝6.0Hz, 1H), 3.66( t, J=5.7Hz, 2H), 3.09(s, 3H), 1.08(d, J=6.3Hz, 3H).

MS(ESI) m/z: [(M-Cl) ^- ,358.9].

Example 14: N-((2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)propoxy) Preparation of -[1,1'-biphenyl]-4-carboxamide (Compound 14)

(a)(2S,3R)-Methyl 3-hydroxy-2-(4'-hydroxy-[1,1'-biphenyl]-4-formyl)butyrate

4'-Hydroxy-[1,1'-biphenyl]-4-carboxylic acid (177 mg, 0.826 mmol), threonine methyl ester hydrochloride (168 mg, 0.991 mmol), 1-(3-diphenylene) Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 0.991 mmol), 1-hydroxybenzotriazole (134 mg, 0.991 mmol), diisopropylethylamine (427 mg, 3.304 mmol) ) as the raw material, and N-N-dimethylformamide as the solvent, according to the method described in Example 2(b), 180 mg of white solid was obtained, with a yield of 66.2%.

¹ H NMR(400MHz, DMSO)δ9.70(s,1H),8.25(d,J=8.2Hz,1H),7.95(d,J=8.3Hz,2H),7.72(d,J=8.3Hz, 2H), 7.59(d, J＝8.6Hz, 2H), 6.88(d, J＝8.6Hz, 2H), 5.00(d, J＝7.8Hz, 1H), 4.52(dd, J＝8.2, 4.1Hz, 1H), 4.24–4.15(m, 1H), 3.67(s, 3H), 1.16(d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,330.0]

(b) (2S,3R)-3-Hydroxy-2-(4'-(3-methylsulfonyl)propoxy)-[1,1'-biphenyl]-4-formyl)butanoic acid methyl ester

Compound (2S,3R)-methyl 3-hydroxy-2-(4'-hydroxy-[1,1'-biphenyl]-4-formyl)butyrate (180 mg, prepared with the above (a)) 0.547 mmol), 3-methylsulfonyl propanol (151 mg, 1.094 mmol) and, triphenylphosphine (287 mg, 1.094 mmol), diethyl azodicarboxylate (191 mg, 1.094 mmol), as raw materials, anhydrous tetrahydrofuran As solvent, according to the method described in Example 1(a), 150 mg of white solid was obtained, and the yield was 61.0%.

¹ H NMR(400MHz, Chloroform-d)δ7.92(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.56(d,J=8.7Hz,1H),7.01( d, J=8.7Hz, 2H), 6.99 (d, J=8.7Hz, 2H), 4.87 (dd, J=8.7, 2.4Hz, 1H), 4.49 (td, J=6.9, 3.5Hz, 1H), 4.18(t,J=5.8Hz,2H),3.83(s,3H),3.37–3.26(m,2H),3.00(s,3H),2.45(d,J=3.7Hz,1H),2.43–2.36 (m, 2H), 1.33 (d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,449.9].

(c) N-((2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)propoxy)- [1,1'-Biphenylene]-4-carboxamide

Compound (2S,3R)-3-hydroxy-2-(4'-(3-methylsulfonyl)propoxy)-[1,1'-biphenyl]-4-prepared with (b) above Methyl formyl)butyrate (150 mg, 0.334 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 100 mg of solid was obtained with a yield of 66.7%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.69(s, 1H), 8.87(s, 1H), 8.04(d, J=8.3Hz, 1H), 7.97(d, J=8.4Hz, 2H) ,7.75(d,J＝8.4Hz,2H),7.71(d,J＝8.7Hz,2H),7.07(d,J＝8.7Hz,2H),4.93(d,J＝6.5Hz,1H),4.29 (dd, J=8.5, 5.3Hz, 1H), 4.16(t, J=6.2Hz, 2H), 4.04(h, J=6.1Hz, 1H), 3.34–3.27(m, 2H), 3.04(s, 3H), 2.22–2.12(m, 2H), 1.10(d, J=6.3Hz, 3H).

MS(ESI)m/z: [(MH) ^- ,448.9].

Example 15: N-((2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)ethoxy) Preparation of -[1,1'-biphenyl]-4-carboxamide (Compound 15)

(a)(2S,3R)-3-Hydroxy-2-(4'-(3-methylsulfonyl)ethoxy)-[1,1'-biphenyl]-4-formyl)butyric acid methyl ester

Take the compound (2S,3R)-methyl 3-hydroxy-2-(4'-hydroxy-[1,1'-biphenyl]-4-formyl)butyrate (Example 16, step (a)) product) (204 mg, 0.620 mmol), 3-methylsulfonylethanol (154 mg, 1.240 mmol) and, triphenylphosphine (325 mg, 1.240 mmol), diethyl azodicarboxylate (216 mg, 1.240 mmol) as starting materials , anhydrous tetrahydrofuran was used as solvent, according to the method described in Example 1(a), 190 mg of white solid was obtained, and the yield was 70.4%.

¹ H NMR(400MHz, Chloroform-d)δ7.92(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.56(d,J=8.7Hz,1H),7.01( d, J=8.7Hz, 2H), 6.99 (d, J=8.7Hz, 2H), 4.87 (dd, J=8.7, 2.4Hz, 1H), 4.49 (td, J=6.9, 3.5Hz, 1H), 4.42(t,J＝5.7Hz,2H),3.83(s,3H),3.66(t,J＝5.7Hz,2H),3.00(s,3H),2.45(d,J＝3.7Hz,1H), 1.33(d,J=6.4Hz,3H).

MS(EI)m/z: (M ⁺ ,435).

(b) N-((2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)ethoxy)- Preparation of [1,1'-biphenyl]-4-carboxamide

Compound (2S,3R)-3-hydroxy-2-(4'-(3-methylsulfonyl)ethoxy)-[1,1'-biphenyl]-4-prepared with (b) above Methyl formyl)butyrate (190 mg, 0.436 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 120 mg of solid was obtained with a yield of 63.1%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.69(s, 1H), 8.87(s, 1H), 8.04(d, J=8.3Hz, 1H), 7.97(d, J=8.4Hz, 2H) ,7.75(d,J＝8.4Hz,2H),7.71(d,J＝8.7Hz,2H),7.07(d,J＝8.7Hz,2H),4.93(d,J＝6.5Hz,1H),4.42 (t, J=5.7Hz, 2H), 4.29 (dd, J=8.5, 5.3Hz, 1H), 4.04 (h, J=6.1Hz, 1H), 3.66 (t, J=5.7Hz, 2H), 3.04 (s,3H),1.10(d,J＝6.3Hz,3H).

MS(EI)m/z: (M ⁺ ,436).

Example 16: (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)propane Preparation of oxy)-[1,1'-biphenyl]-4-carboxamide (Compound 16)

(a)(S)-3-((tert-butoxycarbonyl)amino)-2-(4'-hydroxy-[1,1'-biphenyl]-4-carboxamido)-3-methyl methyl butyrate

4'-Hydroxy-[1,1'-biphenyl]-4-carboxylic acid (177 mg, 0.826 mmol), (S)-2-amino-3-((tert-butoxycarbonyl)amino)-3 - Methyl butyrate (WO201231298A2) (244 mg, 0.991 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 0.991 mmol), 1-hydroxybenzoate Triazole (134 mg, 0.991 mmol) and diisopropylethylamine (427 mg, 3.304 mmol) were used as raw materials, and N-N-dimethylformamide was used as solvent. According to the method described in Example 2(b), 200 mg of white solid was obtained , the yield is 54.7%.

¹ H NMR (400MHz, Chloroform-d) δ 9.07 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 6.97(d, J=8.7Hz, 2H), 4.78(d, J=8.3Hz, 1H), 4.72(s, 1H), 3.74(s, 3H), 1.53(s, 3H), 1.49(s, 3H), 1.46(s, 9H).

MS(EI)m/z: (M ⁺ ,442)

(b) (S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4'-(3-(methylsulfonyl)propoxy)-[1,1'-bi Methyl diphenyl]-4-carboxamido)butyrate

Compound (S)-3-((tert-butoxycarbonyl)amino)-2-(4'-hydroxy-[1,1'-biphenyl]-4-carboxamido) prepared with (a) above - Methyl 3-methylbutyrate (200 mg, 0.452 mmol), 3-methylsulfonyl propanol (151 mg, 1.094 mmol) and triphenylphosphine (287 mg, 1.094 mmol), diethyl azodicarboxylate (191 mg) , 1.094 mmol), as raw material, and anhydrous tetrahydrofuran as solvent, according to the method described in Example 1(a), 180 mg of white solid was obtained with a yield of 70.8%.

¹ H NMR (400MHz, Chloroform-d) δ 9.07 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 6.97(d, J＝8.7Hz, 2H), 4.78(d, J＝8.3Hz, 1H), 4.72(s, 1H), 4.16(t, J＝5.8Hz, 2H), 3.74( s, 3H), 3.36–3.11 (m, 2H), 2.97 (s, J=0.7Hz, 3H), 2.43–2.16 (m, 2H), 1.53 (s, 3H), 1.49 (s, 3H), 1.46 (s, 9H).

MS(ESI)m/z:[(M+Na)+,585.2].

(c) (S)-3-Amino-3-methyl-2-(4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-4-methyl amide) methyl butyrate

Compound (S)-3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4'-(3-(methylsulfonyl)propoxy)-[1 prepared with (b) above ,1'-biphenyl]-4-carboxamido) butyric acid methyl ester (180mg, 0.320mmol) was used as raw material, and 1,4-dioxane of hydrogen chloride was used as solvent. According to the method described above, 126 mg of solid was obtained, and the yield was 85.0%.

¹ H NMR(400MHz, Chloroform-d)δ7.89(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),7.54(d,J=8.7Hz,2H),7.46( d, J=8.4Hz, 1H), 7.05–6.83 (m, 2H), 4.59 (d, J=8.3Hz, 1H), 4.16 (t, J=5.8Hz, 2H), 3.78 (d, J=0.8 Hz, 3H), 3.38–3.16 (m, 2H), 2.97 (s, 3H), 2.43–2.16 (m, 3H), 1.26 (s, 3H), 1.23 (s, 3H).

MS(ESI)m/z:[(M+H)+,463.1].

(d) (S)-N-(3-Amino-1-(hydroxylamine)-3-methyl-1-oxobutan-2-yl)-4'-(3-(methylsulfonyl)propoxy yl)-[1,1'-biphenyl]-4-carboxamide

Compound (S)-3-amino-3-methyl-2-(4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenylene] prepared with (c) above ]-4-Carboxamide) butyric acid methyl ester (126 mg, 0.320 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (e) of Example 1, 80 mg of solid was obtained with a yield of 63.5%.

¹ H NMR(400MHz, DMSO)δ8.12(s,1H),7.93(d,J=7.9Hz,2H),7.73(d,J=8.0Hz,2H),7.69(d,J=8.9Hz, 2H), 7.06(d, J＝8.2Hz, 2H), 6.29(s, 2H), 4.36(s, 1H), 4.15(t, J＝6.2Hz, 2H), 3.30(s, 2H), 3.03( s, 3H), 2.17(t, J=7.8Hz, 2H), 1.14(s, 3H), 1.06(s, 3H).

MS(ESI)m/z:[(M+H)+,464.0].

Example 17: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((5-hydroxy-4-oxa-1, Preparation of 4-dihydropyridin-2-yl)methoxy)benzamide (Compound 17)

(a) (2S,3R)-2-(4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)benzoyl)-3- methyl hydroxybutyrate

With compound (2S,3R)-methyl 3-hydroxy-2-(4-hydroxybenzamide)butyrate (product of step (a) of Example 12) (157 mg, 0.620 mmol), (4,5-di ((4-Methoxybenzyl)oxy)-2-pyridyl)methanol (WO2013150296A1) (354 mg, 0.930 mmol), triphenylphosphine (325 mg, 1.240 mmol), diethyl azodicarboxylate (216 mg, 1.240 mmol) as raw material, and anhydrous tetrahydrofuran as solvent, according to the method described in Example 1(a), 300 mg of white solid was obtained, and the yield was 78.5%.

¹ H NMR(400MHz, DMSO)δ8.19(s,1H),8.07(s,1H),7.88(d,J=8.8Hz,2H),7.36(d,J=13.0Hz,5H),7.11( d, J＝8.8Hz, 2H), 6.92(s, 4H), 5.14(s, 2H), 5.10(d, J＝5.3Hz, 4H), 4.94(s, 1H), 4.48(s, 1H), 4.16(s, 1H), 3.74(s, 6H), 3.65(s, 3H), 1.13(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,617.1]

(b) 4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy-1- (Hydroxyamine)-1-oxobutan-2-yl)benzamide

Compound (2S,3R)-2-(4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)benzyl prepared as (a) above Acyl)-methyl 3-hydroxybutyrate (300 mg, 0.486 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in Example 1 (e), 240 mg of solid was obtained with a yield of 80.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.63(s, 1H), 8.83(s, 1H), 8.19(s, 1H), 7.86(t, J=9.0Hz, 1H), 7.42-7.27( m, 4H), 7.09(d, J=8.8Hz, 2H), 6.92(dd, J=8.6, 5.2Hz, 4H), 5.13(s, 2H), 5.09(s, 4H), 4.88(s, 1H ), 4.23(s, 1H), 4.01(s, 1H), 3.74(s, 6H), 1.08(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,618.0].

(c) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4-((5-hydroxy-4-oxa-1,4 -Dihydropyridin-2-yl)methoxy)benzamide

Compounds prepared with (b) above 4-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)-N-((2S,3R)-3 -Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (240 mg, 0.389 mmol) was used as raw material, and dichloromethane and methanol were used as solvents, as described in Example 8 (d) method, 100 mg of white solid was obtained, and the yield was 68.2%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.64(s,1H), 8.85(s,1H), 7.97(s,1H), 7.89(s,3H), 7.11(d, J=8.8Hz, 3H), 5.25(s, 2H), 4.25(s, 1H), 4.01(s, 1H), 1.99(d, J=7.4Hz, 1H), 1.06(s, 3H).

MS(ESI)m/z: [(M+H) ⁺ , 378.0].

Example 18: 4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy- Preparation of 1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (Compound 18)

(a) (2S,3R)-2-(4-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy ) benzamide)-3-hydroxybutyrate methyl ester

Compound (2S,3R)-methyl 3-hydroxy-2-(4-hydroxybenzamide)butyrate (product of step (a) of Example 12) (157 mg, 0.620 mmol), 1,5-bis( Diphenylmethyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one [Journal of Medicinal Chemistry 56(2013) 5541-5552] (607 mg, 1.240 mmol), triphenylphosphine (325 mg, 1.240 mmol), diethyl azodicarboxylate (216 mg, 1.240 mmol) as raw materials, and anhydrous tetrahydrofuran as solvent, according to the method described in Example 1(a), 350 mg of white solid was obtained with a yield of 77.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J=8.2 Hz, 1H), 7.85-7.79 (m, 3H), 7.46-7.33 (m, 14H), 7.30 (dq, J=6.5 ,3.6,2.9Hz,2H),7.24–7.19(m,4H),6.83(d,J=8.8Hz,2H),6.46(s,1H),6.38(s,1H),6.03(s,1H) ,5.76(s,1H),4.94(d,J=7.6Hz,1H),4.77(s,2H),4.47(dd,J=8.2,4.1Hz,1H),4.17(ddd,J=7.7,6.3 ,4.1Hz,1H),3.65(s,3H),1.14(d,J=6.3Hz,2H).

MS(ESI)m/z: [(M+H) ⁺ ,725].

(b) 4-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S,3R )-3-hydroxy-1-(hydroxylamine)-1-oxybutan-2-yl)benzamide

Compound (2S,3R)-2-(4-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridine-2-) prepared with (a) above (base)methoxy)benzamide)-3-hydroxybutyric acid methyl ester (350mg, 0.482mmol) as raw material, dichloromethane and methanol as solvents, according to the method described in (e) in Example 1 to obtain a solid 250mg, yield 71.4%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.64(s,1H),8.85(s,1H),7.96-7.73(m,4H),7.45-7.34(m,13H),7.33-7.28(m ,2H),7.25–7.17(m,4H),6.81(d,J=8.8Hz,2H),6.46(s,1H),6.39(s,1H),6.02(s,1H),4.88(d, J=6.4Hz, 1H), 4.77(s, 2H), 4.25(dd, J=8.5, 5.4Hz, 1H), 4.02(q, J=6.1Hz, 1H), 1.08(d, J=6.3Hz, 3H).

MS(ESI)m/z:[(M+Na) ⁺ ,748.1].

(c) 4-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy-1 -(hydroxylamine)-1-oxobutan-2-yl)benzamide

Compounds prepared with (b) above 4-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N- ((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)benzamide (250mg, 0.344mmol) was used as raw material, and dichloromethane and methanol were used as solvents. According to the method described in (d) of Example 8, 100 mg of white solid was obtained, and the yield was 73.9%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.66(s, 1H), 10.24(d, J=2.5Hz, 2H), 8.84(s, 4H), 8.03-7.81(m, 2H), 7.11( d, J=8.7Hz, 1H), 6.95(s, 1H), 5.25(s, 2H), 4.23(s, 1H), 4.02(s, 1H), 1.07(s, 3H).

MS(ESI)m/z:[(M+H) ⁺ ,394.0].

Example 19: N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-((5-hydroxy-4-oxa-1 Preparation of ,4-dihydropyridin-2-yl)methoxy)-[1,1'-biphenyl]-4-carboxamide (Compound 19)

(a)(2S,3R)-2-(4'-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)-[1,1' -Methyl biphenyl]-4-ylformyl)-3-hydroxybutyrate

Take the compound (2S,3R)-methyl 3-hydroxy-2-(4'-hydroxy-[1,1'-biphenyl]-4-formyl)butyrate (Example 16, step (a)) product) (204 mg, 0.620 mmol), (4,5-bis((4-methoxybenzyl)oxy)-2-pyridyl)methanol (354 mg, 0.930 mmol), triphenylphosphine (325 mg, 1.240 mmol) ), diethyl azodicarboxylate (216 mg, 1.240 mmol) as raw materials, and anhydrous tetrahydrofuran as solvent, according to the method described in Example 1(a), 310 mg of white solid was obtained with a yield of 72.2%.

¹ H NMR(400MHz, DMSO)δ8.27(d,J=8.2Hz,1H),8.20(s,1H),7.97(d,J=8.4Hz,2H),7.77(d,J=8.4Hz, 2H), 7.70(d, J＝8.8Hz, 2H), 7.37(d, J＝8.6Hz, 2H), 7.34(d, J＝8.6Hz, 2H), 7.31(s, 1H), 7.13(d, J＝8.8Hz, 2H), 6.92(dd, J＝8.6, 2.0Hz, 4H), 5.14(s, 2H), 5.10(d, J＝7.6Hz, 4H), 4.99(d, J＝7.7Hz, 1H), 4.52(dd, J=8.2, 4.1Hz, 1H), 4.25–4.14(m, 1H), 3.74(s, 3H), 3.72(s, 3H), 3.67(s, 3H), 1.16(d ,J=6.4Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,692.9].

(b) 4'-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy-1 -(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-benzamide

Compound prepared as (a) above (2S,3R)-2-(4'-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)- [1,1'-Biphenyl]-4-ylformyl)-3-hydroxybutyric acid methyl ester (310 mg, 0.447 mmol) was used as raw material, and dichloromethane and methanol were used as solvents. ) to obtain 270 mg of solid with a yield of 87.1%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.68(s, 1H), 8.86(s, 1H), 8.19(s, 1H), 8.02(d, J=8.6Hz, 1H), 7.96(d, J=8.5Hz, 2H), 7.75(d, J=8.4Hz, 2H), 7.69(d, J=8.8Hz, 2H), 7.37(d, J=8.7Hz, 2H), 7.34(d, J= 8.7Hz, 2H), 7.31(s, 1H), 7.12(d, J=8.8Hz, 2H), 6.92(dd, J=8.7, 2.0Hz, 4H), 5.14(s, 2H), 5.09(s, 4H), 4.92(d, J＝6.4Hz, 1H), 4.29(dd, J＝8.5, 5.3Hz, 1H), 4.04(q, J＝6.1Hz, 1H), 3.74(s, 3H), 3.72( s,3H),1.10(d,J＝6.3Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,694.1].

(c) N-((2S,3R)-3-hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-4'-((5-hydroxy-4-oxa-1, 4-Dihydropyridin-2-yl)methoxy)-[1,1'-biphenyl]-4-carboxamide

Compounds prepared with (b) above 4'-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)methoxy)-N-((2S,3R)- 3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-benzamide (270 mg, 0.389 mmol) as starting material, dichloro Methane and methanol were used as solvents, according to the method described in (d) of Example 8, 100 mg of white solid was obtained, and the yield was 68.2%.

¹ H NMR(400MHz, DMSO)δ10.69(s,1H),8.04(d,J=8.5Hz,1H),7.98(d,J=8.1Hz,2H),7.94(s,1H),7.75( t, J＝7.8Hz, 4H), 7.16(d, J＝8.6Hz, 2H), 7.05(s, 1H), 5.24(s, 2H), 4.29(dd, J＝8.4, 5.5Hz, 1H), 4.08–4.02(m,1H),1.11(d,J=6.2Hz,3H).

MS(ESI)m/z:[(M+H) ⁺ ,454.2].

Example 20: 4'-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy - Preparation of 1-(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-carboxamide (compound 20)

(a)(2S,3R)-2-(4'-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy yl)-[1,1'-biphenyl]-4-ylbenzamido)-3-hydroxybutyric acid methyl ester

Take the compound (2S,3R)-methyl 3-hydroxy-2-(4'-hydroxy-[1,1'-biphenyl]-4-formyl)butyrate (Example 16, step (a)) product) (304 mg, 0.620 mmol), 1,5-bis(diphenylmethyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one (607 mg, 1.240 mmol), triphenylphosphine ( 325 mg, 1.240 mmol), diethyl azodicarboxylate (216 mg, 1.240 mmol) were used as raw materials, and anhydrous tetrahydrofuran was used as solvent. According to the method described in Example 1(a), 350 mg of white solid was obtained with a yield of 69.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.43 (d , J＝8.7Hz, 2H), 7.33(d, J＝8.7Hz, 2H), 7.17(s, 1H), 7.06(d, J＝8.7Hz, 2H), 6.89(d, J＝8.7Hz, 2H) ),6.85(d,J=8.7Hz,2H),6.75(d,J=8.7Hz,2H),6.48(s,1H),4.99(s,2H),4.98(s,2H),4.83(dd , J=8.5, 3.0Hz, 1H), 4.62(s, 2H), 4.53–4.46(m, 1H), 3.80(s, 3H), 3.78(s, 3H), 3.77(s, 3H), 1.34( d, J=6.4Hz, 3H).

MS(ESI)m/z:[(M+Na) ⁺ ,731.2].

(b) 4'-((1,5-bis(dibenzyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S, 3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-carboxamide

Compound (2S,3R)-2-(4'-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridine-2) prepared with (a) above -yl)methoxy)-[1,1'-biphenyl]-4-ylbenzamido)-3-hydroxybutyric acid methyl ester (350mg, 0.436mmol) as raw material, dichloromethane and methanol As solvent, according to the method described in Example 1 (e), 280 mg of solid was obtained, and the yield was 80.1%.

¹ H NMR (400MHz, DMSO) δ 10.68(s, 1H), 8.86(s, 1H), 8.11(s, 1H), 8.03(d, J=8.4Hz, 1H), 7.98(d, J=8.3 Hz, 2H), 7.76(d, J＝8.4Hz, 2H), 7.71(d, J＝8.3Hz, 2H), 7.39(d, J＝7.0Hz, 4H), 7.05(d, J＝8.5Hz, 2H), 6.98(d, J＝5.6Hz, 2H), 6.96(d, J＝5.7Hz, 2H), 6.19(s, 1H), 5.28(s, 2H), 5.05(s, 2H), 4.96( s, 2H), 4.92(d, J=6.4Hz, 1H), 4.30(dd, J=8.2, 5.6Hz, 1H), 4.09–4.02(m, 1H), 3.77(s, 3H), 3.76(s ,3H),1.11(d,J＝6.3Hz,3H).

MS(ESI)m/z: [(MH) ^- ,708.0]

(c) 4'-((1,5-Dihydroxy-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N-((2S,3R)-3-hydroxy- 1-(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-carboxamide

Compounds prepared with (b) above 4'-((1,5-bis(diphenylmethyloxy)-4-oxa-1,4-dihydropyridin-2-yl)methoxy)-N -((2S,3R)-3-Hydroxy-1-(hydroxylamine)-1-oxobutan-2-yl)-[1,1'-biphenyl]-4-carboxamide (280 mg, 0.349 mmol) as raw materials, and dichloromethane and methanol as solvents, according to the method described in (d) in Example 8, 100 mg of white solid was obtained with a yield of 61.0%.

¹ H NMR(400MHz, DMSO)δ10.69(s,1H),8.03(d,J=8.5Hz,1H),7.97(d,J=7.9Hz,2H),7.80(s,1H),7.75( d, J＝8.2Hz, 2H), 7.71(d, J＝8.3Hz, 2H), 7.12(d, J＝8.4Hz, 2H), 6.84(s, 1H), 5.20(s, 2H), 4.34– 4.25(m,1H),4.09–3.98(m,1H),1.11(d,J=6.2Hz,3H).

MS(ESI)m/z: [(MH) ^- ,468.1].

Biological activity test

1. Antibacterial test

Test method: The MIC (Minimum inhibitory concentration, minimum inhibitory concentration) value of each compound was tested three times by the following method.

The method used 96-well plates and LB medium containing 5% DMSO. Compounds were prepared at different concentrations, and 100 μL were placed on a 96-well plate (Corning Costar 3596, flat bottom with lid, polystyrene well). In a two-fold dilution series, the ranges were 0.0005-1 μg/mL, 0.0025-5 μg/mL, and 0.014-5 μg/mL. Bacterial cells, grown to OD600=0.6, were diluted 100-fold with fresh LB medium, and 100 μL of the diluted cells were added to each well. The inoculated plates were incubated at 37°C for 22h. After the incubation, 50uL of 1 mg/mL 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide (MTT) was added, and the plate was incubated for 3 hours. The MIC value is based on the lowest concentration without obvious discoloration (from yellow to black).

The positive control drug is CHIR-090, a classic LpxC inhibitor, which can effectively inhibit the growth of Pseudomonas aeruginosa and Escherichia coli.

It can be seen from the data in Table 2 that the compounds of the present invention have good biological activities, such as compounds 4, 5, 6, and 7, which have strong in vitro inhibition of Pseudomonas aeruginosa and Escherichia coli, especially compound 4, which has significantly better bacteriostatic activity for the positive drug CHIR-090.

Table 2. Inhibitory activity data of some compounds against Pseudomonas aeruginosa and Escherichia coli (unit: μg/ml)

2. In vitro liver microsome stability test of the present invention

Test method: SD rat liver microsomes and ICR mouse liver microsomes were used in this experiment. The incubation method is as follows: microsomes are placed in 0.1M tris(hydroxymethyl)aminomethane/hydrochloric acid buffer (pH 7.4) to a final concentration of 0.33mg/ml microsomal protein, followed by the addition of cofactors _MgCl2 (5mM), Test compounds (final concentration 0.1 μM, co-solvent 0.01% DMSO, 0.005% BSA) and NADPH (1 mM) were incubated at 37° C. for 60 min. The reaction begins upon addition of liver microsomes, test compound or NADPH. Samples were taken at 0, 7, 17, 30 and 60 min of incubation and the enzymatic reaction was stopped by adding methanol to precipitate proteins. After centrifugation, samples were analyzed using LC/MS/MS. This method evaluates the metabolic stability of the test compound by detecting its in vitro half-life and hepatic microsomal clearance.

Table 3 Data of some compounds in in vitro liver microsome stability experiments

It can be seen from the data in Table 3 that the compounds 4 and 5 of the present invention have good stability in the in vitro stability test of liver microsomes, and are obviously better than the control drug CHIR-090.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (17)

1. A compound of formula I, its enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt,

In the formula, R ₁ is a substituted C ₁ -C ₆ alkyl group, and the substitution refers to having a substituent selected from the group consisting of hydroxyl and amino; m is 1; n is 1; X is -O-; R ₂ is -SO ₂ (C ₁ -C ₃ alkyl) substituted C ₁ -C ₆ alkyl. 2 . The compound of formula I according to claim 1 , wherein the configuration of each chiral carbon atom in the compound of formula I is independently R-type or S-type. 3 . 3. The compound of formula I according to claim 1, wherein R ₁ is hydroxy or amino substituted C ₁ -C ₄ alkyl. 4. The compound of formula I according to claim 1, wherein R ₂ is -SO ₂ CH ₃ substituted C ₁ -C ₆ alkyl. 5. The compound of formula I according to claim 1, wherein R ₂ is -SO ₂ CH ₃ substituted C ₁ -C ₄ alkyl. 6. The compound of formula I according to claim 1, wherein the compound of formula I is:

or

7. the preparation method of formula I compound as claimed in claim 1, is characterized in that, described method comprises the following steps:

(a) the compound of formula I-1 is condensed with the compound of formula I-2 to obtain the compound of formula I-3; (b) the compound of formula I-3 reacts with the compound of formula I-4 to obtain the compound of formula I-5; (c) compound of formula I-5 reacts with hydroxylamine to obtain compound of formula I, Wherein, the definition of X is as described in claim 1, In each formula, R ₁ is a protected or unprotected, substituted C ₁ -C ₆ alkyl group, and the substitution refers to having a substituent selected from the group consisting of hydroxyl and amino; R ₂ is C ₁ -C ₆ alkyl substituted with protected or unprotected -SO ₂ (C ₁ -C ₃ alkyl); Y is ethynyl or halogen; And when R ₁ is a protected, substituted C ₁ -C ₆ alkyl and/or R ₂ is a protected -SO ₂ (C ₁ -C ₃ alkyl) substituted C ₁ -C ₆ alkyl, The method also includes the step of removing a protecting group selected from the group consisting of: tert-butoxycarbonyl, p-methoxybenzyl, benzyl, benzyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl, allyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, benzyloxymethyl. 8. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: The compound of formula I of claim 1, its enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt; and A pharmaceutically acceptable carrier. 9. the compound of formula I as claimed in claim 1 or the purposes of the pharmaceutical composition of claim 8, is characterized in that, is used for: (1) preparing a drug that inhibits LpxC deacetylase; (2) Preparation of medicines for preventing and/or treating bacterial infections; (3) Preparation of drugs for inhibiting bacterial growth. 10. The use of claim 9, wherein the bacterial infection is a Gram-negative bacterial infection. 11. The use of claim 10, wherein the Gram-negative bacteria are selected from the group consisting of: Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. 12. A method for reducing bacterial pathogenicity or toxicity for non-therapeutic purposes in vitro, comprising the steps of: The bacteria are contacted with the compound of formula I of claim 1 or the pharmaceutical composition of claim 8, thereby reducing bacterial pathogenicity or toxicity. 13. The method of claim 12, wherein the bacteria are Gram-negative bacteria. 14. The method of claim 13, wherein the Gram-negative bacteria are selected from the group consisting of: Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. 15. The method of claim 12, wherein the contacting results in an increase or decrease in the amount of LpxC deacetylase in the bacteria. 16. A method of inhibiting LpxC deacetylase in vitro for non-therapeutic purposes by administering the compound of formula I of claim 1 or the pharmaceutical composition of claim 8 to a subject in need thereof or to the environment. 17. An in vitro non-therapeutic method of antibacterial administration of the compound of formula I of claim 1 or the pharmaceutical composition of claim 8 to a subject in need or to the environment.