Biphenylic hydroxamic acid derivatives, processes for their preparation and uses thereof

Abstract

The present application belongs to the technical field of medicine, and relates to a diphenyl hydroxylamine derivative shown in general formula I, a stereoisomer and a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein the substituent groups X, Ar and R have the definitions given in the specification. The present application also relates to a method for preparing the compound of general formula I, a pharmaceutical composition containing the compound, and the use of the compound and the pharmaceutical composition in the preparation of a medicament for treating and preventing diseases caused by superficial bacterial and deep Gram-negative bacterial infections.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis. It relates to novel biphenyl hydroxyoxime derivatives and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, as well as methods for preparing and using biphenyl hydroxyoxime derivatives. Background Technology

[0002] With the deterioration of the external environment and the decline of human immunity, bacterial infections are increasingly becoming a serious public health problem. They not only affect quality of life but also lead to serious complications, including sepsis and organ failure. According to statistics from the World Health Organization (WHO), approximately 14 million people die from bacterial infections globally each year. Among these, Gram-negative bacterial infections (accounting for about 45% of the high mortality rate) are receiving increasing attention. Current treatment arsenals mainly consist of antibiotics, sulfonamides, and quinolones. However, adverse reactions and the frequent emergence of drug-resistant strains are constantly limiting their application prospects. Therefore, developing highly effective and safe new antibacterial drugs for Gram-negative bacterial infections has become an urgent priority.

[0003] Lipopolysaccharide (LPS), an indispensable outer membrane component of Gram-negative bacteria, is crucial for maintaining normal bacterial physiological functions and their ability to invade the host. In this biosynthetic process, LpxC enzyme (UDP-3-O-acyl-N-acetylglucosamine deacetylase) plays a central role, catalyzing a specific chemical reaction to generate UDP-3-O-acylglucosamine, a key precursor essential for LPS synthesis. Therefore, LpxC has become a key target for exploring novel antibacterial strategies. In recent years, the scientific community has successfully developed several small-molecule LpxC inhibitors. These inhibitors effectively inhibit the proliferation of Gram-negative bacteria by interfering with LpxC activity, thereby disrupting the LPS biosynthetic chain. However, bacteria are highly adaptable and can evade these drugs through gene mutations or enhanced drug efflux mechanisms. Furthermore, bacterial infection is not only related to the characteristics of the bacteria themselves but also profoundly affects the host's immune response. Infection-induced immunosuppression, particularly the high expression of PD-L1 (programmed death-ligand 1), weakens the immune system's ability to clear pathogens. To address this challenge, immune checkpoint inhibitors (ICIs) have emerged, which reactivate the immune response and promote pathogen clearance by blocking PD-L1 / PD-1 interactions. However, using antibacterial drugs or ICIs alone has significant limitations. To overcome these limitations, we propose an innovative dual-target (LpxC / PD-L1) drug design strategy designed to simultaneously inhibit bacterial growth and activate host immunity. This design is expected to have a synergistic effect, enhancing therapeutic efficacy while reducing the side effects and drug resistance issues that may arise with monotherapy, opening new avenues for the treatment of Gram-negative bacterial infections.

[0004] Starting from the dual-target (LpxC / PD-L1) receptor structure, the inventors designed and synthesized a series of novel biphenyl hydroxyoxime derivatives through scaffold assembly. In vitro activity screening showed that these compounds possess high antibacterial activity. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a novel class of biphenyl hydroxyoxime derivatives and their uses; this invention relates to the strong antibacterial activity of biphenyl hydroxyoxime amine derivatives, and also to the use of such compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of treatments for Gram-negative bacterial infections.

[0006] To achieve the above objectives, the present invention provides biphenyl hydroxyoxime compounds of general formula I and their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs.

[0007]

[0008] in:

[0009] Ar is p-methylphenol, 3-methylphenol, 4-formyl-piperidinyl, 3-formyl-piperidinyl, 3,5-methoxy-4-methylphenol, 3-methoxy-4-methylphenol or 2-formaldehyde-5-oxopyrrolyl.

[0010] X is a methyl or hydrogen group;

[0011] R is hydroxymethyl, 2-hydroxyethyl, isopropyl, or cyclopropyl.

[0012] This invention preferably relates to biphenyl hydroxyoxime compounds of general formula I and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, wherein:

[0013] Ar is p-methylphenol, 3-methylphenol, 4-formyl-piperidinyl, 3-formyl-piperidinyl, 3,5-methoxy-4-methylphenol or 2-formaldehyde-5-oxopyrrolyl.

[0014] X is a methyl or hydrogen group;

[0015] R is hydroxymethyl, 2-hydroxyethyl, isopropyl, or cyclopropyl.

[0016] The compounds of general formula I above, their geometric isomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, are selected from:

[0017] N,3-Dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide;

[0018] N,3-Dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide;

[0019] N-Hydroxy-3-methyl-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide N-Hydroxy-1-(4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide N,3-Dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide N,3-Dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide N,3-Dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide N,3-Dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide [Benzene]-3-yl)methoxy)benzyl)amino)butyramide N-hydroxy-3-methyl-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide N-hydroxy-1-(3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide 2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N,3-dihydroxypropionamide

[0020] 2-((2,6-Dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N,3-dihydroxybutyramide

[0021] 2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N-hydroxy-3-methylbutyramide

[0022] 1-(2,6-Dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-hydroxypyrrolidine-2-carboxamide

[0023] N-(3-hydroxy-1-(hydroxyamino)-1-oxopropan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidin-4-carboxamide

[0024] N-(3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxamide

[0025] N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidin-4-carboxamide

[0026] N-hydroxy-1-(1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carbonyl)pyrrolidine-2-carboxamide N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide

[0027] N-(3-hydroxy-1-(hydroxyamino)-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-carboxamide

[0028] N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-carboxamide

[0029] N-hydroxy-1-(1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide 1-([1,1'-biphenyl]-3-ylmethyl)-N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-5-oxopyrrolidine-2-carboxamide

[0030] 1-([1,1'-biphenyl]-3-ylmethyl)-N-(3-hydroxy-1-(hydroxyamino)-1-oxobut-2-yl)-5-oxopyrrolidine-2-carboxamide

[0031] 1-([1,1'-biphenyl]-3-ylmethyl)-N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-5-oxopyrrolidine-2-carboxamide

[0032] 1-(1-([1,1'-biphenyl]-3-ylmethyl)-5-oxopyrrolidine-2-carbonyl)-N-hydroxypyrrolidine-2-carboxamide

[0033] The structural formulas of the above 24 compounds are as follows:

[0034]

[0035] According to some common methods in the field to which this invention pertains, the derivatives of Formula I above can react with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include addition salts of inorganic and organic acids, with salts reacting with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0036] Furthermore, the present invention also includes prodrugs derived from the present invention. These prodrugs are derivatives of general formula I, which may themselves have weak or no activity, but are converted into their corresponding biologically active forms under physiological conditions (e.g., through metabolism, solvation, or other means) after administration.

[0037] This invention can contain derivatives of Formula I above, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare compositions, and formulated into clinically acceptable dosage forms. The aforementioned pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0038] The pharmaceutical compositions of the present invention can be formulated into several dosage forms, containing some commonly used excipients in the pharmaceutical field. The dosage forms described above can be injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, ointments, and other dosage forms.

[0039] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solvents, and matrices. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0040] In vitro antibacterial activity tests showed that the derivatives of general formula I of the present invention have antibacterial activity, and therefore the compounds of the present invention can be used to prepare drugs for the treatment and / or prevention of various Gram-negative bacterial diseases.

[0041] The active compounds of the present invention, or their pharmaceutically acceptable salts and solvates thereof, can be used as antibacterial agents.

[0042] The general formulas and examples for the preparation of derivatives of I provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the present invention in any way.

[0043] According to the present invention, compounds Y-1 to Y12 of formula I can all be prepared from the corresponding starting material 1 via Suzuki coupling reaction according to the method of route 1 to prepare intermediate 2; at the same time, its hydroxyl group is chlorinated to generate intermediate 3, intermediate 3 and 4-hydroxy-benzaldehyde (3-hydroxy-benzaldehyde, 4-hydroxy-2,6-dimethoxybenzaldehyde) are subjected to nucleophilic substitution reaction to obtain intermediate (4, 5, 6), which is condensed and reduced with amino acid methyl ester hydrochloride to obtain intermediate (7a-d, 8a-d, 9a-d); the reduction product undergoes hydroxyoxime reaction with hydroxylamine hydrochloride to obtain target compounds Y-1 to Y12.

[0044] All variable factors used in these schematic diagrams are as defined in the claims.

[0045]

[0046] Synthetic route 1: (a) (3-bromo-2-methylphenyl) methanol, Pd (PPh3) 4, K2CO3, 1,4-dioxane, reflux, 5.0h; (b) Thionyl chloride, DCM, reflux, 5.0h; (c) 4-hydroxybenzaldehyde or 4-hydroxy-2,6-dimethoxyben-zaldehyde, K2CO3, DMF, 80℃, 3.0h; (d) Serine Methyl Hydrochloride (Threonine Methyl Hydrochloride, CysteineMethyl Hydrochloride, Proline Methyl Hydrochloride), Sodium cyanoborohydride, glacial acetic acid, 25℃, 5.0h; (e) Hydroxylamine hydrochloride,potassiumhydroxide,methanol,25℃,4.0h.

[0047] According to the present invention, compounds Y-13 to Y20 of formula I can all be prepared by nucleophilic substitution reaction of the corresponding starting intermediate 3 with piperidine carboxylate according to route 2; at the same time, its carboxyl group is hydrolyzed to generate intermediate 11, which is condensed and reduced with amino acid methyl ester hydrochloride to obtain intermediates (12a-d, 13a-d); the reduction product undergoes hydroxyoxime reaction with hydroxylamine hydrochloride to obtain target compounds Y-13 to Y20.

[0048]

[0049] Synthetic route 2: (a) Methyl piperidine-3-carboxylate (Methyl piperidine-3-carboxylate, sodium hydride), DCM, reflux, 4.0h; (b) Sodium hydroxide aqueous, 60℃, 2.0h; (c) 1-Hydroxybenzotriazole (HOBT), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI), N, N-diisopropylethylamine (DIEA), DMF, 80℃, 6.0h; (d) Hydroxylamine hydrochloride, potassium hydroxide, methanol, 80℃, 4.0h.

[0050] According to the present invention, compounds Y-21 to Y24 of Formula I can all be generated from the corresponding starting materials phenylboronic acid 1 and 3-bromobenzaldehyde via the Suzuki reaction according to Route 3 to produce intermediate 14. Intermediate 14 undergoes a reductive amination reaction with L-glutamic acid to give intermediate 15. Subsequently, intramolecular cyclization and dehydration are carried out in refluxed ethanol to generate intermediate 16. Subsequently, the key intermediate can be reacted with amino acid methyl ester hydrochloride via an amidation reaction to give intermediates 17a-d. Finally, the target compounds Y-21 to Y24 are generated by a substitution reaction of hydroxylamine hydrochloride.

[0051]

[0052] Synthetic route 3: (a) 3-bromobenzaldehyde, Pd(PPh3)4, K2CO3, 1,4-dioxane, reflux, 5.0h; (b) L-glutamic acid, NaOH, NaBH4, HCl / H2O, 4.0h; (c) Ethanol, reflux, 4.0h; (d) HOBT, EDCI, DIEA, DMF, 80℃, 6.0h; (e) Hydroxylamine hydrochloride, potassiumhydroxide, methanol, 25℃, 4.0h.

[0053] The present invention relates to the use of biphenyl hydroxyoxime derivatives and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of drugs for the treatment or prevention of fungal diseases; wherein the fungal diseases are infections caused by pathogenic Gram-negative bacteria; wherein the pathogenic Gram-negative bacteria are Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium or Pseudomonas aeruginosa.

[0054] The antimicrobial compound of this invention represents a significant technological leap compared to existing technologies. Its unique feature lies in its broader antimicrobial spectrum, effectively inhibiting a variety of pathogens, including drug-resistant antimicrobial strains, and significantly improving the success rate of antimicrobial therapy. Simultaneously, this compound exhibits lower toxicity and higher biocompatibility, reducing side effects during treatment and providing patients with a safer treatment option. Furthermore, its synthetic route is simple, efficient, and cost-controllable, facilitating large-scale production and application, and providing a powerful tool for addressing global public health challenges. In summary, the antimicrobial compound of this invention represents a major breakthrough in antimicrobial efficacy, safety, and cost-effectiveness. Detailed Implementation

[0055] The following examples are intended to illustrate, but not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-400, and the mass spectra were determined using an Agilent 1100 LC / MS; all reagents used were analytical grade or chemically pure.

[0056] Example 1: Preparation of N,3-dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide (Y-1)

[0057] Step 1: Preparation of (2-methyl-[1,1'-biphenyl]-3-yl)methanol (2)

[0058] Phenylacetic acid 1 (0.05 mol, 1.0 equivalent), (3-bromo-2-methylphenyl)methanol (1.1 equivalent), potassium carbonate (1.5 equivalent), and tetrakis(triphenylphosphine)palladium (0.1 equivalent) were dissolved to form dioxane. The reaction system was heated to reflux and stirred for 5 hours. After the reaction was complete, the mixture was poured into ice water, and the organic layer was extracted with ethyl acetate. Subsequently, the organic phase was dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain intermediate 2.

[0059] Step 2 Preparation of 3-chloromethyl-2-methyl-1,1'-biphenyl (3)

[0060] Intermediate 2 (0.03 mol, 1.0 equivalent) and thionyl chloride (3.0 equivalent) were added to a solution of dichloromethane under ice bath conditions. The reaction system was then heated under reflux and stirred for 5 hours. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain intermediate 3.

[0061] Step 3 Preparation of 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (4)

[0062] Intermediate 3 (0.03 mol; 1.0 equivalent), 4-hydroxybenzaldehyde (1.0 equivalent), and potassium carbonate (2.0 equivalent) were added sequentially to a DMF solution. The reaction mixture was heated to 80 °C and stirred for 3.0 hours. After the reaction was complete, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain intermediate 4.

[0063] Step 4: Methyl 3-hydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionate (7a)

[0064] Key intermediate 4 (0.02 mol, 1.0 equivalent), serine methyl ester hydrochloride (1.1 equivalent), and sodium cyanoborohydride (1.5 equivalent) were sequentially added to glacial acetic acid solution (30 mL). The mixture was stirred at room temperature for 5.0 hours. After the reaction was complete, the mixture was concentrated to obtain crude intermediate 7a. Subsequently, it was purified and separated by silica gel column chromatography (CH2Cl2:MeOH = 10:1).

[0065] Step 5N, 3-dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide (Y-1)

[0066] Intermediate 7a (0.02 mol, 1.0 equivalent), hydroxylamine hydrochloride (2.0 equivalent), and potassium hydroxide (2.0 equivalent) were dissolved in methanol solution and stirred at room temperature for 4.0 hours. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain the desired compound Y-1, which was then purified by column chromatography.

[0067] Yield: 59.9%; mp: 112.42-114.6℃. 1 H NMR (500MHz, DMSO-d6) δ11.25(s,1H),9.38(s,1H),7.48(d,J=9.3Hz,4H),7.37(t,J=7.2Hz,2H),7.33–7.26(m,4H),7.19(d,J=7.3H z,1H),7.11(s,1H),7.10(s,1H),5.16(s,2H),5.02(s,1H),4.04(s,2H),3.79(d,J=5.3Hz,2H),3.63(d,J=5.2Hz,1H),2.19(s,3H). 13CNMR(126MHz,DMSO-d6)δ163.17,159.42,142.66,141.79,135.88,134.32,132.42,131.10,130. 10,129.64,128.73,128.34,127.45,126.02,115.25,68.97,60.02,58.65,48.74,16.28.ESI-MS m / z:405[MH] + ;407[M+H] + ;429[M+Na] + .

[0068] Following the preparation method of Example 1, Examples 2 (Y-2) to 12 (Y-12) were prepared.

[0069] Example 2N,3-dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide (Y-2)

[0070] Yield: 62.4%; mp: 118.6-120.1℃. 1 H NMR (500MHz, DMSO-d6) δ10.52(s,1H),8.90(s,1H),7.46(t,J=7.6Hz,4H),7.38(t,J=7.4Hz,2H),7.34–7.28(m,4H),7.27(d,J=7.9Hz,1H),7.22–7. 17(m,1H),7.01(d,J=8.3Hz,1H),5.12(s,2H),4.63(s,1H),3.69(d,J=13. 1Hz,1H),3.67–3.59(m,2H),2.77–2.72(m,1H),2.19(s,3H),1.04(s,3H). 13 C NMR (126MHz, DMSO) δ169.22,157.88,142.61,141.83,136.19,134.26,130.00,129.71,129.64,128. 72,128.29,127.43,125.99,114.91,68.87,67.87,65.97,50.96,20.32,16.25.ESI-MSm / z:419[MH] + ;421[M+H] + ;443[M+Na] + .

[0071] Example 3: N-hydroxy-3-methyl-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide (Y-3)

[0072] Yield: 60.9%; mp: 115.4-117.2℃. 1 H NMR(500MHz,DMSO-d6)δ11.18(s,1H),9.39(s,1H),7.52–7.44(m,6H),7.39( d,J=7.5Hz,1H),7.29(dd,J=19.5,7.2Hz,4H),7.20(d,J=6.1Hz,1H),7.11(d ,J=8.7Hz,2H),5.17(s,2H),4.01(d,J=13.3Hz,1H),3.89(d,J=13.2Hz,1H), 2.20(s,3H),1.28–1.21(m,1H),0.97(d,J=6.9Hz,3H),0.93(d,J=6.8Hz,3H). 13 C NMR (126MHz, DMSO-d6)159.40,142.68,141.81,135.90,134.32,132.41,130.10,129.63,128. 72,128.33,127.44,126.00,115.22,68.97,62.11,49.23,29.36,19.71,18.24,16.28.ESI-MS m / z:417[MH] + ;419[M+H] + ;441[M+Na] + .

[0073] Example 4: N-hydroxy-1-(4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide (Y-4)

[0074] Yield: 52.1%; mp: 109.7-111.2℃. 11H NMR(500MHz,DMSO-d6)δ10.39(s,1H),8.77(s,1H),7.45(d,J=7.5Hz,4H),7.3 8(t,J=7.4Hz,1H),7.32(d,J=7.0Hz,1H),7.27(d,J=3.8Hz,4H),7.22–7.17(m, 1H),7.00(d,J=8.3Hz,1H),5.12(s,2H),3.76(d,J=12.9Hz,2H),3.03–2.98(m, 1H), 2.20 (s, 3H), 2.00–1.90 (m, 2H), 1.75 (d, J = 6.0Hz, 2H), 1.81–1.63 (m, 2H). 13 C NMR(126MHz,DMSO-d6)δ170.25,157.93,142.62,141.86,136.21,134.26,131.62,130.29,129.64, 128.70,128.30,127.41,125.97,114.82,68.87,65.41,57.77,52.91,29.69,23.45,16.26.ESI-MS m / z:415[MH] + ;417[M+H] + ;439[M+Na] + .

[0075] Example 5: N,3-dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propionamide (Y-5)

[0076] Yield: 70.3%; mp: 118.1-120.3℃. 1 H NMR (500MHz, DMSO-d6) δ10.54(s,1H),8.88(s,1H),7.45(d,J=7.0Hz,4H),7. 39(d,J=7.3Hz,2H),7.32(d,J=7.2Hz,4H),7.10(d,J=2.1Hz,1H),6.95(d,J=2 .6Hz,1H),6.93(d,J=2.0Hz,1H),5.13(s,2H),4.86(d,J=18.0Hz,1H),4.01(d ,J=25.0Hz,2H),3.76(d,J=13.7Hz,1H),3.59(d,J=13.7Hz,2H),2.20(s,3H). 13C NMR(126MHz,DMSO-d6)δ169.72,159.03,142.62,141.85,136.17,134.30,130.03,129.64, 128.71,127.42,126.00,121.00,114.76,68.79,64.25,62.74,61.60,51.08,16.28.ESI-MS m / z:405[MH] + ;407[M+H] + ;429[M+Na] + .

[0077] Example 6: N,3-dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide (Y-6)

[0078] Yield: 62.2%; mp: 121.5-123.4℃. 1 H NMR(500MHz,DMSO)δ10.51(s,1H),8.83(s,1H),7.46(dd,J=8.1,6.8Hz,4H),7 .39(d,J=7.4Hz,2H),7.33–7.23(m,4H),7.22–7.17(m,1H),7.09(s,1H),6.94 (d,J=2.3Hz,1H),6.92(s,1H),5.13(s,2H),4.60(dd,J=5.6,2.5Hz,1H),3.75 (d,J=13.7Hz,1H),3.51(d,J=13.7Hz,2H),2.20(s,3H),1.06(d,J=6.3Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ169.37,159.05,142.68,142.63,141.87,136.21,134.28,129.99,129.67,129.64, 128.70,128.32,127.41,125.98,120.82,114.59,113.46,68.79,67.99,66.15,51.48,20.37,16.27.ESI-MS m / z:419[MH] + ;421[M+H] + ;443[M+Na] + .

[0079] Example 7: N-hydroxy-3-methyl-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butyramide (Y-7)

[0080] Yield: 58.6%; mp: 117.3-119.1℃. 1 H NMR(500MHz,DMSO-d6)δ10.46(s,1H),8.84(s,1H),7.46(d,J=2.0Hz,4H),7.4 1–7.34(m,2H),7.32(d,J=6.9Hz,4H),7.20(d,J=1.4Hz,1H),7.05(s,1H),5.12 (d,J=1.7Hz,2H),5.10(s,1H),3.73(d,J=13.9Hz,2H),3.44(s,1H),2.19(s,3 H), 1.69 (dt, J=13.6, 6.8Hz, 1H), 0.93 (d, J=6.7Hz, 3H), 0.84 (d, J=6.7Hz, 3H). 13 C NMR(126MHz,DMSO-d6)δ170.66,159.02,142.98,142.63,141.87,136.21,134.21,129.97,129.64,128.70, 128.23,127.41,125.98,120.71,114.35,113.42,68.74,64.91,51.24,31.64,19.97,19.72,16.24.ESI-MS m / z:417[MH] + ;419[M+H] + ;441[M+Na] + .

[0081] Example 8: N-hydroxy-1-(3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide (Y-8)

[0082] Yield: 64.5%; mp: 115.3-117.5℃. 1 H NMR (500MHz, DMSO-d6) δ10.43 (s, 1H), 8.78 (s, 1H), 7.45 (d, J = 7.9Hz, 4H), 7. 30(d,J=6.0Hz,2H),7.18(d,J=3.0Hz,4H),7.08(s,1H),6.93(d,J=8.1Hz,1H) ,5.14(s,2H),3.81(d,J=13.4Hz,2H),3.04(dd,J=8.8,5.2Hz,1H),2.21(s,3 H), 2.14 (d, J = 3.6Hz, 2H), 1.99 (td, J = 8.8, 4.3Hz, 2H), 1.73 (d, J = 7.9Hz, 2H). 13C NMR (126MHz, DMSO-d6) δ170.25,158.98,142.59,141.85,136.20,134.32,129.99,129.63,128.70,128.67,128 .42,127.40,125.92,122.02,115.41,113.57,68.81,58.46,53.10,29.72,26.81,23.54,16.30,16.24.ESI-MS m / z:415[MH] + ;417[M+H] + ;439[M+Na] + .

[0083] Example 9 2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N,3-dihydroxypropionamide (Y-9)

[0084] Yield: 57.3%; mp: 139.2-140.5℃. 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),7.49–7.39(m,4H),7.39(d,J=7.5Hz,2H),7.31(d,J=7.5Hz,2H),7.24(d,J=7.6Hz,1H),7.16(d,J =7.6Hz,2H),6.74(s,1H),6.68(s,2H),4.93(s,2H),3.77(s,6H),3.76–3.70(m,2H),3.69(s,1H),3.01(t,J=5.9Hz,1H),2.27(s,3H). 13 C NMR (126MHz, DMSO-d6) δ169.48,153.53,153.49,142.37,142.12,136.99,136.81,135.28,134.45,129.80,129 .61,128.83,128.68,127.32,125.68,105.46,105.36,72.98,63.05,61.88,56.38,56.34,51.56,16.11.ESI-MS m / z:465[MH] + ;467[M+H] + ;489[M+Na] + .

[0085] Example 10 2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N,3-dihydroxybutyramide (Y-10)

[0086] Yield: 60.9%; mp: 141.4-142.8℃. 1 H NMR(500MHz, DMSO-d6)δ8.76(s,1H),7.38(d,J=7.6Hz,4H),7.31(d,J=7.3Hz,2H),7.24(d,J=1.5Hz,2H),7.23(s,1H),7.17(t,J=7.6Hz,1H),7 .09(d,J=6.3Hz,2H),6.65(d,J=4.9Hz,1H),6.61(s,2H),4.85(s,2H),4.55(s,1H),3.69(s,6H),3.59(d,J=6.5Hz,1H),0.99(d,J=6.2Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ169.40,153.49,142.37,142.12,136.99,136.81,135.29,134.44,129.80,129 .61,128.84,128.68,127.33,125.68,105.44,72.98,68.01,66.05,56.34,51.68,20.44,16.12.ESI-MS m / z:479[MH] + ;481[M+H] + ;503[M+Na] + .

[0087] Example 11 2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N-hydroxy-3-methylbutyramide (Y-11)

[0088] Yield: 64.5%; mp: 134.6-135.9℃. 1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),7.45(t,J=7.5Hz,4H),7.38(d,J=7.5Hz ,2H),7.33–7.28(m,2H),7.24(t,J=7.6Hz,1H),7.16(dd,J=7.6,1.5Hz,2H),6 .65(s,2H),4.92(s,2H),4.44(s,1H),3.75(d,J=4.4Hz,6H),3.70(s,1H),2.2 7(s,3H),1.72(q,J=6.8Hz,1H),0.96(d,J=6.7Hz,3H),0.86(d,J=6.7Hz,3H). 13 CNMR(126MHz,DMSO-d6)δ170.68,153.47,142.37,142.12,137.10,136.99,135.21,134.44,129.81,129.61,12 8.85,128.68,127.32,125.68,105.18,72.98,64.74,56.31,56.27,51.34,31.66,20.04,19.73,16.11.ESI-MS m / z:477[MH] + ;479[M+H] + ;501[M+Na] + .

[0089] Example 12 1-(2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-hydroxypyrrolidine-2-carboxamide (Y-12)

[0090] Yield: 64.5%; mp: 132.3-133.6℃. 1 H NMR (500MHz, DMSO-d6) δ8.77(s,1H),7.48–7.41(m,9H),7.38(d,J=7.4Hz,6H),7.31(d,J=7.5Hz,6H),7.19–7.12(m,5H),6.67(s,3H),4.93(s ,4H),3.77(s,8H),3.72(d,J=1.6Hz,3H),3.69–3.65(m,12H),2.26–2. 20(m,9H),1.78–1.72(m,3H),1.36–1.24(m,3H),1.24(d,J=7.8Hz,3H). 13C NMR (126MHz, DMSO-d6) δ170.31,153.45,142.35,142.12,137.00,135.47,135.31,134.41,129.78,129.60,12 8.81,128.67,127.31,125.66,106.26,72.94,65.58,58.90,56.42,56.32,53.29,29.81,23.56,16.10.ESI-MS m / z:460[MH] + ;462[M+H] + ;484[M+Na] + .

[0091] Example 13: Preparation of N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxamide (Y-13)

[0092] Step 1: Preparation of methyl 1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid (10)

[0093] Intermediate 3 (0.04 mol, 1.0 equivalent), methyl piperidine-4-carboxylate (1.0 equivalent), and sodium hydride (1.2 equivalent) were added sequentially to a dichloromethane solution. The reaction system was heated under reflux for 4 hours. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain intermediate 10.

[0094] Step 2 Preparation of 1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid (11)

[0095] Intermediate 10 (0.03 mol, 1.0 equivalent) was introduced into 30 mL of 2 N sodium hydroxide solution and stirred at 60 °C for 2.0 h. After the reaction was complete, the pH of the mixture was further adjusted to 2-3 using dilute hydrochloric acid solution, resulting in the formation of a white solid precipitate. This precipitate was separated by filtration and dried to obtain intermediate 11.

[0096] Step 3: Preparation of methyl 3-hydroxy-2-(1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidin-4-carboxamido)propionate (12a)

[0097] Intermediate 11 (0.03 mol, 1.0 equivalent), EDCI (2.0 equivalent), and HOBt (2.0 equivalent) were dissolved in DMF solution and stirred at room temperature for 2.0 h. Then, serine methyl ester hydrochloride (1.1 equivalent) and DIEA (3.0 equivalent) were introduced into the reaction system, and the mixture was heated at 80 °C for 6.0 h. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain intermediate 12a.

[0098] Preparation of step 4, N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxamide (Y-13)

[0099] Intermediate 12a (0.02 mol, 1.0 equivalent), hydroxylamine hydrochloride (2.0 equivalent), and potassium hydroxide (2.0 equivalent) were dissolved in methanol solution and stirred at room temperature for 4.0 hours. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain the crude compound. Then, the crude compound was purified by column chromatography to obtain the desired compound Y-13.

[0100] Yield: 67.1%; mp: 131.4-133.6℃. 1 H NMR(500MHz,DMSO-d6)δ10.63(s,1H),8.88(s,1H),7.93(s,1H),7.44(d,J=7.8Hz,2H), 7.42(s,1H),7.39–7.32(m,1H),7.31–7.26(m,3H),7.24(d,J=7.3Hz,1H),7.15(d,J=7. 4Hz,1H),5.00(s,1H),4.19(d,J=7.1Hz,2H),3.81(d,J=13.8Hz,2H),3.13–3.03(m,3H) ,2.88(s,1H),2.30(s,2H),2.22(d,J=4.3Hz,2H),1.91(s,2H),1.73(d,J=27.2Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ174.43,167.51,162.88,142.82,142.07,135.41,129.62,128.74 ,128.67,127.38,125.77,62.00,53.55,52.51,36.29,31.26,27.58,21.57,16.94.ESI-MS m / z:410[MH] + ;412[M+H] +;434[M+Na] + .

[0101] According to the preparation method of Example 13, Examples 14 (Y-14) to 20 (Y-20) were prepared.

[0102] Example 14: N-(3-hydroxy-1-(hydroxyamino)-1-oxobutane-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxamide (Y-14)

[0103] Yield: 69.1%; mp: 134.1-136.9℃. 1 H NMR (500MHz, DMSO-d6) δ10.49(s,1H),8.83(s,1H),7.55(d,J=8.8Hz,1H),7.43(dd,J=8.1,6.8Hz ,2H),7.39–7.34(m,1H),7.31–7.25(m,3H),7.20(d,J=7.7Hz,1H),7.11–7.06(m,1H),4.79(s,1H ),4.07(d,J=8.7Hz,1H),3.94–3.86(m,1H),3.35(s,2H),2.89–2.81(m,2H),2.34–2.26(m,1H),2 .19(s,3H),2.01–1.94(m,2H),1.70–1.62(m,2H),1.56(d,J=12.2Hz,2H),1.01(d,J=6.2Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ175.13,167.68,142.50,142.30,137.73,134.69,129.66,129.23,128.88,12 8.61,127.22,125.45,66.97,61.59,56.87,53.50,53.37,42.37,29.51,28.85,20.54,16.40.ESI-MS m / z:424[MH] + ;426[M+H] + ;448[M+Na] + .

[0104] Example 15: N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carboxamide (Y-15)

[0105] Yield: 60.8%; mp: 124.9-127.2℃. 1H NMR(500MHz,DMSO-d6)δ10.68(s,1H),8.86(s,1H),7.46(t,J=7.5Hz,2H),7.4 2–7.35(m,1H),7.34–7.28(m,3H),7.23(s,1H),4.36(s,1H),3.96(t,J=8.6Hz, 2H),3.08–3.02(m,2H),2.31(s,1H),2.27(s,3H),1.91(d,J=7.0Hz,2H),1.88 (d,J=7.0Hz,2H),1.82(s,2H),1.33–1.17(m,2H),0.83(dd,J=6.8,2.4Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ174.97,168.13,144.81,141.91,138.36,133.71,133.56,129.60,128.72,12 7.55,124.58,124.13,65.34,62.79,56.02,51.91,43.37,30.88,26.33,19.59,19.02,16.37.ESI-MS m / z:422[MH] + ;424[M+H] + ;446[M+Na] + .

[0106] Example 16: N-hydroxy-1-(1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-4-carbonyl)pyrrolidine-2-carboxamide (Y-16)

[0107] Yield: 58.7%; mp: 131.1-132.6℃. 1 H NMR (500MHz, DMSO-d6) δ10.45(s,1H),8.76(s,1H),7.43(d,J=7.5Hz,2H),7.37(d,J=7.3Hz,1H ),7.32–7.27(m,3H),7.19(d,J=7.5Hz,1H),7.10(d,J=1.4Hz,1H),4.17–4.11(m,1H),3.65–3.6 0(m,2H),3.46(d,J=7.6Hz,2H),2.86(d,J=3.8Hz,3H),2.43(td,J=9.5,5.8Hz,1H),2.06–1.99 (m,2H),1.91(s,2H),1.66–1.63(m,2H),1.52(dd,J=13.8,10.0Hz,2H),1.25(d,J=11.1Hz,2H).13 C NMR(126MHz,DMSO-d6)δ173.41,169.43,142.53,142.30,137.71,134.72,129.66,129.31,128.92,12 8.61,127.24,125.46,61.59,57.86,53.34,46.98,32.74,29.83,28.41,24.82,21.52,16.41.ESI-MS m / z:420[MH] + ;422[M+H] + ;444[M+Na] + .

[0108] Example 17 N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide (Y-17)

[0109] Yield: 64.5%; mp: 106.3-108.1℃. 1 H NMR (500MHz, DMSO-d6) δ10.55(s,1H),8.82(s,1H),7.91(dd,J=18.0,8.2Hz,1H),7.43(t,J=7.5Hz,2H), 7.36(d,J=7.4Hz,1H),7.32–7.26(m,3H),7.19(t,J=7.5Hz,1H),7.11–7.06(m,1H),4.87(s,1H),4.17(d d,J=8.3,6.3Hz,1H),3.49(d,J=4.7Hz,2H),3.45(d,J=4.7Hz,2H),2.80–2.64(m,2H),2.20(d,J=7.2Hz, 3H), 2.17 (d, J = 6.3Hz, 2H), 2.03 (q, J = 12.8Hz, 1H), 1.62 (d, J = 3.9Hz, 2H), 1.41 (dd, J = 19.4, 9.8Hz, 2H). 13 C NMR (126MHz, DMSO-d6) δ173.97,167.44,142.51,142.31,137.51,134.76,129.67,129.46,129.39,128.98 ,128.94,128.60,127.22,125.47,62.07,61.65,56.54,53.97,53.16,42.73,27.93,24.65,16.45.ESI-MS m / z:410[MH] + ;412[M+H]+ ;434[M+Na] + .

[0110] Example 18: N-(3-hydroxy-1-(hydroxyamino)-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide (Y-18)

[0111] Yield: 59.7%; mp: 120.5-122.2℃. 1 H NMR (500MHz, DMSO-d6) δ10.57(s,1H),8.86(s,1H),7.82(d,J=9.2Hz,1H),7.46–7.39(m,2H),7.36(d,J =7.3Hz,1H),7.29(dd,J=7.5,1.5Hz,3H),7.19(t,J=7.6Hz,1H),7.09(d,J=1.6Hz,1H),4.85(s,1H),4. 12–4.03(m,1H),3.89(t,J=6.1Hz,1H),3.55(s,2H),2.75(d,J=68.6Hz,2H),2.21(s,2H),2.19(d,J=3. 5Hz,3H),2.02(d,J=12.0Hz,1H),1.63(d,J=4.1Hz,2H),1.50–1.33(m,2H),1.01(dd,J=6.4,1.5Hz,3H). 13 CNMR(126MHz,DMSO-d6)δ174.10,167.67,142.48,142.30,134.69,129.66,129.46,129.00,128.96,1 28.60,127.22,125.48,66.90,61.55,57.03,56.95,56.51,53.74,27.64,20.64,20.56,16.50.ESI-MS m / z:424[MH] + ;426[M+H] + ;448[M+Na] + .

[0112] Example 19: N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide (Y-19)

[0113] Yield: 64.5%; mp: 107.9-109.3℃. 1H NMR (500MHz, DMSO-d6) δ10.61(s,1H),8.82(s,1H),8.02(d,J=9.2Hz,1H),7.43(t,J=7.5Hz,2H),7.35(t,J=7.4 Hz,1H),7.27(dd,J=13.9,7.2Hz,3H),7.19(t,J=7.5Hz,1H),7.09(d,J=5.9Hz,1H),3.91(t,J=8.7Hz,1H),3.45( d,J=4.7Hz,2H),2.65(d,J=10.7Hz,2H),2.33(d,J=18.0Hz,1H),2.21(d,J=16.9Hz,3H),2.15(d,J=8.6Hz,1H), 1.82–1.77(m,2H),1.64(d,J=32.2Hz,2H),1.43(d,J=10.2Hz,2H),0.79(d,J=6.6Hz,3H),0.74(d,J=6.7Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ174.10,167.67,142.48,142.30,137.37,134.69,129.66,129.50,129.46,128.96,1 28.60,127.22,125.48,66.90,61.55,57.03,56.51,53.74,42.82,27.64,24.56,20.46,19.02,16.50.ESI-MS m / z:422[MH] + ;424[M+H] + ;446[M+Na] + .

[0114] Example 20: N-hydroxy-1-(1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide (Y-20)

[0115] Yield: 62.9%; mp: 108.1-110.4℃. 1H NMR (500MHz, DMSO-d6) δ10.40(s,1H),8.82(s,1H),7.42(d,J=7.5Hz,2H),7.36(d,J=7.5Hz,1H ),7.30–7.24(m,3H),7.22–7.16(m,1H),7.08(d,J=8.9Hz,1H),4.14–4.08(m,1H),3.61(d,J=9 .8Hz,2H),3.46(d,J=8.6Hz,2H),2.86–2.76(m,2H),2.18(s,3H),1.97–1.89(m,2H),1.82–1.7 7(m,2H),1.65(d,J=2.9Hz,2H),1.50(d,J=16.6Hz,1H),1.31–1.23(m,2H),0.88–0.82(m,2H). 13 C NMR (126MHz, DMSO-d6) δ172.30,169.23,142.30,137.67,134.74,129.64,129.26,129.10,128.85,12 8.60,127.23,125.45,61.70,61.45,57.99,56.03,54.10,53.96,27.27,24.82,22.20,16.44.ESI-MS m / z:420[MH] + ;422[M+H] + ;444[M+Na] + .

[0116] Example 21 Preparation of 1-([1,1'-biphenyl]-3-ylmethyl)-N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-5-oxopyrrolidine-2-carboxamide (Y-21)

[0117] Step 1: Preparation of [1,1'-biphenyl]-3-carboxaldehyde (14)

[0118] Phenylacetic acid 1 (0.04 mol, 1.0 equivalent), 3-bromobenzaldehyde (1.1 equivalent), potassium carbonate (1.5 equivalent), and tetrakis(triphenylphosphine)palladium (0.1 equivalent) were dissolved in dioxane. The reaction mixture was heated under reflux for 5 hours. After the reaction was complete, the mixture was poured into ice water. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to give intermediate 14.

[0119] Step 2 Preparation of 2-(([1,1'-biphenyl]-3-ylmethyl)amino)glutaric acid (15)

[0120] Intermediate 14 (0.03 mol, 1.0 equivalent), L / D-glutamic acid (1.1 equivalent), and sodium hydroxide (2.0 equivalent) were dissolved in ethanol-water (1:1), and the mixture was stirred at room temperature for 1.0 hour. Subsequently, sodium borohydride (1.5 equivalent) was added to the mixture, and stirring continued for 4 hours. After the reaction was complete, the organic solvent was removed by vacuum evaporation, and the pH was adjusted to 4-5, resulting in a white solid precipitate. Acid intermediate 15 was obtained by suction filtration.

[0121] Step 3 Preparation of 1-([1,1'-biphenyl]-3-ylmethyl)-5-oxopyrrolidine-2-carboxylic acid (16)

[0122] Intermediate 15 (0.02 mol, 1.0 equivalent) was dissolved in an ethanol solution. The reaction system was heated to reflux and maintained for 5.0 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the desired intermediate 16.

[0123] Step 4 Preparation of methyl 2-(1-([1,1'-biphenyl]-3-ylmethyl)-5-oxopyrrolidine-2-carbamate)-3-hydroxypropionate (17a)

[0124] Intermediate 16 (0.02 mol, 1.0 equivalent), EDCI (2.0 equivalent), and HOBt (2.0 equivalent) were added to a DMF solution and stirred at 25 °C for 2.0 h. Then, key intermediate 6a (1.2 equivalent) and DIEA (4.0 equivalent) were introduced into the reaction system, and the mixture was heated at 80 °C for 6 h. After the reaction was complete, the mixture was cooled, poured into ice water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to separate the desired intermediate 17a.

[0125] Step 5: Preparation of 1-([1,1'-biphenyl]-3-ylmethyl)-N-(3-hydroxy-1-(hydroxyamino)-1-oxopropane-2-yl)-5-oxopyrrolidine-2-carboxamide (Y-21)

[0126] Intermediate 17a (0.01 mol, 1.0 equivalent), hydroxylamine hydrochloride (2.0 equivalent), and potassium hydroxide (2.0 equivalent) were dissolved in methanol and stirred at room temperature for 4.0 hours. After the reaction was complete, the mixture was evaporated under vacuum. The crude product was then purified by column chromatography to obtain the desired compound Y-21.

[0127] Yield: 56.3%; mp: 114.3-116.2℃. 1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.24(s,1H),7.92(d,J=7.8Hz,1H),7.72(dd,J =62.1,7.5Hz,2H),7.64(s,1H),7.56(d,J=7.7Hz,1H),7.48(dd,J=16.8,7.9Hz,4H) ,7.21(t,J=8.2Hz,1H),5.09(s,1H),4.90(d,J=15.3Hz,1H),4.16–4.05(m,2H),3.9 2(t,J=5.9Hz,1H),2.33–2.16(m,2H),1.23(d,J=4.0Hz,2H),1.05(d,J=6.3Hz,2H). 13 CNMR(126MHz,DMSO-d6)δ175.44,171.92,166.84,140.96,140.50,138.22,129.64,129.43, 127.97,127.35,126.52,126.24,126.08,67.04,59.75,55.16,44.87,29.74,20.57.ESI-MS m / z:396[MH] + 398[M+H] + ; 420[M+Na] + .

[0128] Following the preparation method of Example 21, Examples 22 (Y-22) to 24 (Y-24) were prepared.

[0129] Example 22 1-([1,1'-biphenyl]-3-ylmethyl)-N-(3-hydroxy-1-(hydroxyamino)-1-oxobut-2-yl)-5-oxopyrrolidine-2-carboxamide (Y-22)

[0130] Yield: 61.6%; mp: 145.8-147.4℃. 1H NMR(500MHz,DMSO-d6)δ10.65(s,1H),8.90(s,1H),8.31(s,1H),7.66(d,J=7.0Hz,2 H),7.60–7.54(m,1H),7.52(d,J=7.6Hz,1H),7.49–7.41(m,4H),7.21(d,J=7.6Hz,1 H),4.98(t,J=5.5Hz,1H),4.91(d,J=15.3Hz,1H),4.27–4.15(m,2H),3.74(d,J=15. 3Hz, 1H), 3.55 (d, J = 5.3Hz, 1H), 2.36–2.28 (m, 2H), 1.91–1.81 (m, 2H), 1.12 (s, 3H). 13 CNMR(126MHz,DMSO-d6)δ175.38,171.75,167.09,140.99,140.49,138.12,129.66,129.42,127 .98,127.38,127.28,126.59,126.12,61.98,59.56,53.64,44.82,29.74,23.42,19.92.ESI-MS m / z:410[MH] + ;412[M+H] + ;434[M+Na] + .

[0131] Example 23 1-([1,1'-biphenyl]-3-ylmethyl)-N-(1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-5-oxopyrrolidine-2-carboxamide (Y-23)

[0132] Yield: 68.1%; mp: 157.1-159.4℃. 1 H NMR (500MHz, DMSO-d6) δ10.74(s,1H),8.96(s,1H),8.43(d,J=8.9Hz,1H),7.69(d,J =8.2Hz,2H),7.61(d,J=8.7Hz,1H),7.53(d,J=7.6Hz,1H),7.50–7.41(m,4H),7.22(d ,J=7.8Hz,1H),4.95(d,J=15.1Hz,1H),4.29–4.01(m,2H),3.79(d,J=15.3Hz,1H),2 .43–2.33(m,2H),2.28–2.18(m,1H),1.85(d,J=35.2Hz,2H),0.86(d,J=12.4Hz,6H). 13C NMR(126MHz,DMSO-d6)δ175.36,171.39,167.76,140.96,140.49,137.76,129.66,129.39,128 .01,127.38,127.24,126.75,126.21,59.37,56.25,45.13,30.83,29.80,23.30,19.02.ESI-MS m / z:408[MH] + ;410[M+H] + ;432[M+Na] + .

[0133] Example 24 1-(1-([1,1'-biphenyl]-3-ylmethyl)-5-oxopyrrolidine-2-carbonyl)-N-hydroxypyrrolidine-2-carboxamide (Y-24)

[0134] Yield: 58.3%; mp: 146.9-148.2℃. 1 H NMR (500MHz, DMSO-d6) δ10.54(s,1H),8.84(s,1H),7.65(d,J=7.3Hz,1H),7.58(d,J=7.7Hz ,2H),7.48(d,J=7.2Hz,1H),7.45(d,J=13.1Hz,1H),7.38(t,J=7.3Hz,4H),7.21(d,J=7.6Hz ,1H),4.83(d,J=14.8Hz,1H),4.25(d,J=5.2Hz,2H),3.92(d,J=14.8Hz,1H),2.31(d,J=6.7H z,2H),2.25(d,J=15.0Hz,2H),1.94–1.86(m,2H),1.83(d,J=8.0Hz,2H),1.71–1.64(m,2H). 13 C NMR(126MHz,DMSO-d6)δ175.32,169.69,168.92,140.87,140.39,137.63,129.66,129.44, 128.05,127.64,127.16,127.04,126.20,57.96,46.66,45.42,29.52,24.75,22.39.ESI-MS m / z:406[MH] + ;408[M+H] + 430[M+Na] + .

[0135] Pharmacological studies of some of the products of this invention.

[0136] In vitro antibacterial activity test.

[0137] The antibacterial activity of the target compounds was tested separately. The minimum inhibitory concentration (MIC) in vitro was determined using the standard guidelines described in the National Committee for Clinical Laboratory Standards (NCCLS). The MIC value is defined as the lowest concentration of an antibacterial inhibitor that has an inhibitory effect. In the experiment, CHIR090 was selected as a positive control drug; all compounds were dissolved in DMSO and serially diluted into growth medium. The proliferation of Gram-negative bacteria was observed under incubation conditions at 35°C; the in vitro antibacterial activity tests of the compounds prepared in the above examples are shown in Table 1.

[0138] Table 1. In vitro antibacterial activity tests of some compounds (MIC) 50 (μg / mL)

[0139]

[0140]

[0141] Abbreviations:Nor:Norfloxacin;K.Pne.,Klebsiella pneumoniae ATCC13883;E.Coli.,

[0142] Escherichia coli ATCC 8739; S.Typ., Salmonella Typhimurium ATCC14028; P.Aer., Pseudomonas aeruginosa ATCC9027.

[0143] In vitro dual-target inhibition assay

[0144] Compounds Y-2, Y-5, Y-6, Y-16, Y-18, and Y-20 exhibited excellent broad-spectrum antibacterial activity. To further explore their mechanism of action, corresponding dual-target inhibition experiments were conducted, and the results are shown in Table 2. The IC50 values ​​of these preferred compounds are... 50 The values ​​ranged from 0.071±0.015 μM to 11.9±2.4 μM, indicating that the molecular structure effectively exhibited significant dual-target inhibitory capabilities. Compounds Y-6 and Y-18 showed more balanced dual-target inhibitory effects. In particular, compound Y-6 exhibited superior dual-target inhibitory activity compared to the other compounds.

[0145] Table 2. Inhibitory activity of some preferred compounds targeting two sites (LpxC / PD-L1).

[0146]

[0147] The above experimental results clearly show that the compound of general formula I to be protected by this invention has good in vitro antibacterial activity, and therefore the compound of this invention has good prospects for industrial application.

[0148] In this invention, compounds of general formula I can be administered alone, but are usually given in mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practices. The following describes the new applications of this type of compound in the pharmaceutical field using various pharmaceutical dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, drops, liniments, and ointments.

[0149] Example 25: Tablets.

[0150] 10g of a compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) was mixed with 20g of excipients according to the general pharmaceutical tableting method and then compressed into 100 tablets, each weighing 300mg.

[0151] Example 26: Capsules.

[0152] 10g of a compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) and 20g of excipients were mixed in accordance with the requirements for pharmaceutical capsules and then filled into empty capsules, each capsule weighing 300mg.

[0153] Example 27: Injection.

[0154] 10g of the compound (taking compound Y-1 in Example as an example) was adsorbed onto activated carbon according to conventional pharmaceutical methods, filtered through a 0.65μm microporous membrane, and then filled into a nitrogen tank to prepare an aqueous injection preparation, each containing 2mL, for a total of 100 bottles.

[0155] Example 28: Aerosol.

[0156] 10g of a compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) is dissolved in an appropriate amount of propylene glycol, and then distilled water and other additives are added to prepare a 500mL clear solution.

[0157] Example 29: Suppositories.

[0158] 10g of a compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) was finely ground, and an appropriate amount of glycerin was added. After grinding evenly, melted glycerin gelatin was added, and the mixture was ground evenly. The mixture was then poured into a mold coated with lubricant to prepare 50 suppositories.

[0159] Example 30: Film-forming agent.

[0160] Using 10g of a compound containing the compound of claim 1 (taking compound Y-1 in Example as an example), polyvinyl alcohol, pharmaceutical glycerin, water, etc. are stirred and expanded, then heated and dissolved. The mixture is filtered through an 80-mesh sieve, and then compound of Example 18 is added to the filtrate and stirred and dissolved. 100 films are made by coating the film.

[0161] Example 31: Droplets.

[0162] 10g of a compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) was heated and melted with 50g of a matrix such as gelatin and mixed evenly. The mixture was then dropped into low-temperature liquid paraffin to prepare 1000 pellets.

[0163] Example 32: Topical liniment.

[0164] The compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) is mixed and ground with 2.5g of excipients such as emulsifiers according to conventional pharmaceutical methods, and then distilled water is added to 200mL to obtain the product.

[0165] Example 33: Ointment.

[0166] The compound containing the compound of claim 1 (taking the compound of Example Y-1 as an example) was ground into a fine powder and then mixed with 500g of an oily matrix such as petrolatum.

[0167] Although the invention has been described with reference to specific embodiments, modifications and equivalent variations will be apparent to those skilled in the art, and they are all included within the scope of the invention.

Claims

1. A biphenyl hydroxyoxime derivative, characterized in that, Its structural formula is selected from: 。 2. The use of the biphenyl hydroxyoxime derivative of claim 1 in the preparation of medicaments for treating or preventing Gram-negative bacterial infections.

3. The use of the biphenyl hydroxyoxime derivative as described in claim 2 in the preparation of drugs for treating or preventing Gram-negative bacterial infections, characterized in that, The Gram-negative bacteria mentioned are Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium, or Pseudomonas aeruginosa.

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