Biphenyl hydroxime derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a biphenyl hydroxime amine derivative as shown in a general formula I, a stereoisomer and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and substituent groups X, Ar and R are defined in the specification. The invention also relates to a method for preparing the compound shown in the general formula I, a medicinal composition containing the compound and application of the compound and the medicinal composition in preparation of medicines for treating and preventing superficial bacteria and deep gram-negative bacteria infection diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and relates to novel biphenyl hydroxime derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, and preparation methods and applications of biphenyl hydroxime derivatives. Background Art

[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 the quality of life, but also lead to serious complications, including sepsis and organ failure. According to statistics from the World Health Organization (WHO), about 14 million people die from bacterial infections each year worldwide. Among them, Gram-negative bacterial infections (accounting for about 45% of the high mortality rate) are receiving increasing attention. The current therapeutic arsenal mainly consists of antibiotics, sulfonamides and quinolones. However, the frequent emergence of adverse reactions and drug-resistant strains continues to restrict its application prospects. Therefore, the development of efficient and safe new antibacterial drugs for Gram-negative bacterial infections has become a top priority.

[0003] Lipopolysaccharide, as an indispensable outer membrane component of Gram-negative bacteria, is essential for maintaining the normal physiological functions of bacteria and their ability to invade hosts. In this biosynthesis process, the LpxC enzyme (UDP-3-O-acyl-N-acetylglucosamine deacetylase) plays a core role, catalyzing specific chemical reactions to generate UDP-3-O-acylglucosamine, a key precursor that is essential for the synthesis of lipopolysaccharide. Therefore, LpxC has become a key target for exploring new antibacterial strategies. In recent years, the scientific community has successfully developed several small molecule LpxC inhibitors, which effectively inhibit the proliferation of Gram-negative bacteria by interfering with the activity of LpxC and then destroying the biosynthesis chain of lipopolysaccharide. However, bacteria are highly adaptable and can circumvent the effects of these drugs through gene mutations or enhanced drug efflux mechanisms. In addition, 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, especially 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. They reactivate immune responses and promote pathogen clearance by blocking PD-L1 / PD-1 interactions. However, the use of antimicrobial drugs or ICIs alone has obvious limitations. To overcome these limitations, we proposed an innovative dual-target (LpxC / PD-L1) drug design strategy that aims to simultaneously inhibit bacterial growth and activate host immunity. This design is expected to work synergistically and enhance the therapeutic effect, while reducing the side effects and drug resistance problems that may occur during single-drug treatment, opening up new avenues for the treatment of Gram-negative infections.

[0004] The inventors designed and synthesized a series of novel biphenyl hydroxime derivatives based on the receptor structure of dual targets (LpxC / PD-L1) by skeleton splicing. In vitro activity screening showed that the compounds had high antibacterial activity. Summary of the invention

[0005] In view of the problems existing in the prior art, the present invention provides a class of novel biphenyl hydroxylamine derivatives and their uses; the present invention relates to the strong antibacterial effect of biphenyl hydroxylamine derivatives, and also relates to the preparation of such compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs for treating Gram-negative bacterial infectious diseases.

[0006] In order to achieve the above object, the present invention provides biphenyl hydroxamate compounds represented by general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[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-oxopyrrolidinyl;

[0010] X is a methyl group or a hydrogen group;

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

[0012] The present invention preferably relates to biphenyl hydroxamate compounds represented by general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:

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

[0014] X is a methyl group or a hydrogen group;

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

[0016] The compound of the above general formula I, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs are selected from:

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

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

[0019] N-Hydroxy-3-methyl-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butanamide 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)propanamide N,3-dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propanamide 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butanamide N-hydroxy-3-methyl-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butanamide 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-dihydroxypropanamide

[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-methylbutanamide

[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)piperidine-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-oxobutan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-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-oxopropan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide

[0027] N-(3-Hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide

[0028] N-(1-(Hydroxyamino)-3-methyl-1-oxobutan-2-yl)-1-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)piperidine-3-carboxamide

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

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

[0031] 1-([1,1'-biphenyl]-3-ylmethyl)-N-(1-(hydroxyamino)-3-methyl-1-oxobutan-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 corresponding to the above 24 compounds are as follows:

[0034]

[0035] According to some common methods in the field to which the present invention belongs, the derivatives of the above formula I in the present invention can be reacted with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0036] In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of the general formula I, which may have weak or even no activity themselves, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0037] The present invention may contain the derivative of formula I above, and its pharmaceutically acceptable salt, hydrate, solvate or prodrug as active ingredient, mixed with pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The derivative of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.

[0038] The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The above-mentioned several dosage forms can be injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, ointments and other dosage forms.

[0039] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, preservatives, solubilizers and bases, etc. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

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

[0041] The active compound of the present invention or its pharmaceutically acceptable salt and solvate can be used as an antibacterial drug.

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

[0043] According to the compounds of formula I Y-1 to Y12 of the present invention, intermediate 2 can be prepared from the corresponding starting material 1 through Suzuki coupling reaction according to the method of route 1; at the same time, its hydroxyl group is subjected to chlorination reaction 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 intermediates (4, 5, 6), and the intermediates are condensed and reduced with amino acid methyl ester hydrochloride to obtain intermediates (7a-d, 8a-d, 9a-d); the reduction product is subjected to hydroxylamine hydrochloride to undergo hydroxylamine hydrochloride hydroximation reaction 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 compounds of formula I Y-13 to Y20 of the present invention, the corresponding starting intermediate 3 can be reacted with a piperidine carboxylate to prepare an intermediate 10 through a nucleophilic substitution reaction according to the method of route 2; at the same time, its carboxyl group is hydrolyzed to generate an intermediate 11, and the intermediate is condensed and reduced with an amino acid methyl ester hydrochloride to obtain an intermediate (12a-d, 13a-d); the reduction product is subjected to a hydroxylamine hydrochloride hydroximation reaction to obtain the 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 compound of formula I of the present invention, Y-21 to Y24 can be prepared from the corresponding starting materials phenylboronic acid 1 and 3-bromobenzaldehyde by Suzuki reaction to generate intermediate 14 according to the method of route 3. Intermediate 14 undergoes reductive amination reaction with L-glutamic acid to obtain intermediate 15. Subsequently, intramolecular cyclization and dehydration are carried out in refluxing ethanol to generate intermediate 16. Subsequently, the key intermediate can react with amino acid methyl ester hydrochloride through amidation reaction to obtain intermediate 17a-d. Finally, the target compound Y-21 to Y24 is generated through 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 invention relates to the use of the biphenylhydroxyoxime derivatives and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of drugs for treating or preventing fungal diseases; the fungal diseases are diseases caused by pathogenic Gram-negative bacteria; the pathogenic Gram-negative bacteria are Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium or Pseudomonas aeruginosa.

[0054] The anti-negative bacteria compound of the present invention has shown a significant technological leap compared to the prior art. It is unique in that it has a wider antibacterial spectrum and can effectively inhibit a variety of pathogens including resistant negative strains, significantly improving the success rate of antibacterial treatment. At the same time, the compound exhibits lower toxicity and higher biocompatibility, reduces side effects during treatment, and provides patients with a safer treatment option. In addition, its synthetic route is simple and efficient, cost-controlled, conducive to large-scale production and application, and provides a powerful tool for solving global public health challenges. In summary, the antibacterial compound of the present invention has achieved major breakthroughs in anti-negative bacteria effect, safety and economy. DETAILED DESCRIPTION

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

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

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

[0058] Phenylboronic 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 into dioxane. The reaction system was heated to reflux and stirred for 5 hours. After the reaction was completed, the mixed solution 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 reduced pressure 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 dichloromethane solution under ice bath conditions. The reaction system was then heated to reflux and stirred for 5 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure 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 to the DMF solution in sequence. The reaction system was heated to 80°C and stirred for 3.0 hours. After the reaction was completed, 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 evaporated under reduced pressure to obtain intermediate 4.

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

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

[0065] Step 5 N,3-dihydroxy-2-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propanamide (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 a methanol solution and stirred at room temperature for 4.0 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure to obtain the desired compound Y-1, which was then purified and separated by column chromatography.

[0067] Yield: 59.9%; mp: 112.4.2-114.6°C. 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] According to the preparation method of Example 1, Example 2 (Y-2) to Example 12 (Y-12) were prepared.

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

[0070] Yield: 62.4%; mp: 118.6-120.1°C. 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)butanamide (Y-3)

[0072] Yield: 60.9%; mp: 115.4-117.2°C. 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°C. 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 5N, 3-dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)propanamide (Y-5)

[0076] Yield: 70.3%; mp: 118.1-120.3°C. 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 6N, 3-dihydroxy-2-((3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)butanamide (Y-6)

[0078] Yield: 62.2%; mp: 121.5-123.4°C. 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)butanamide (Y-7)

[0080] Yield: 58.6%; mp: 117.3-119.1°C. 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°C. 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°C. 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°C. 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-methylbutanamide (Y-11)

[0088] Yield: 64.5%; mp: 134.6-135.9°C. 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°C. 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-carboxylate (10)

[0093] Intermediate 3 (0.04 mol, 1.0 equivalent), piperidine-4-carboxylic acid methyl ester (1.0 equivalent) and sodium hydride (1.2 equivalent) were added to a dichloromethane solution in sequence. The reaction system was heated to reflux for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure 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 2N sodium hydroxide solution (30 mL) and stirred at 60°C for 2.0 hours. After the reaction was completed, the pH value of the mixture was further adjusted to 2-3 using a dilute hydrochloric acid solution to form a white solid precipitate. The intermediate 11 was separated by suction filtration and dried.

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

[0097] Intermediate 11 (0.03 mol, 1.0 eq.), EDCI (2.0 eq.) and HOBt (2.0 eq.) were dissolved in DMF solution and stirred at room temperature for 2.0 h. Serine methyl ester hydrochloride (1.1 eq.) and DIEA (3.0 eq.) were then introduced into the reaction system and heated at 80 °C for 6.0 h. After the reaction was completed, 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 evaporated under reduced pressure to obtain intermediate 12a.

[0098] Step 4 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)

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

[0100] Yield: 67.1%; mp: 131.4-133.6°C. 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, Example 14 (Y-14) to Example 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°C. 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-oxobutan-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°C. 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°C. 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°C. 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-oxobutan-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°C. 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-oxobutan-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°C. 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°C. 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] Phenylboronic 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 system was heated to reflux for 5 hours. After the reaction was completed, the mixed solution was poured into ice water. The organic layer was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by reduced pressure to obtain intermediate 14.

[0119] Step 2 Preparation of 2-(([1,1'-biphenyl]-3-ylmethyl)amino)pentanedioic 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 further added to the mixture, and stirring was continued for 4 hours. After the reaction was completed, the organic solvent was removed by vacuum evaporation, and the pH value was adjusted to 4-5, thereby forming 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 ethanol solution. The reaction system was heated to reflux conditions and maintained for 5.0 hours. After the reaction was completed, 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-carboxamido)-3-hydroxypropanoate (17a)

[0124] Intermediate 16 (0.02 moL, 1.0 equiv), EDCI (2.0 equiv) and HOBt (2.0 equiv) were added to the DMF solution and stirred at 25°C for 2.0 hours. Then the key intermediate 6a (1.2 equiv) and DIEA (4.0 equiv) were introduced into the reaction system and heated at 80°C for 6 hours. After the reaction was completed, 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 reduced pressure to isolate 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 solution and stirred at room temperature for 4.0 hours. After the reaction was completed, the mixture was evaporated in vacuo. 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°C. 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] According to the preparation method of Example 21, Example 22 (Y-22) to Example 24 (Y-24) were prepared.

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

[0130] Yield: 61.6%; mp: 145.8-147.4°C. 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-oxobutan-2-yl)-5-oxopyrrolidine-2-carboxamide (Y-23)

[0132] Yield: 68.1%; mp: 157.1-159.4°C. 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°C. 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 on some products of the present invention.

[0136] In vitro antimicrobial activity test.

[0137] The antibacterial activity of the target compounds was tested separately. The in vitro minimum inhibitory concentration (MIC) 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 with 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 state of Gram-negative bacteria was observed under 35°C culture conditions; the in vitro antibacterial activity test of the compounds prepared in the above examples is shown in Table 1.

[0138] Table 1. In vitro antibacterial activity test 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] Preferred compounds Y-2, Y-5, Y-6, Y-16, Y-18 and Y-20 have excellent broad-spectrum antibacterial effects. In order to further explore their mechanism of action, corresponding dual-target inhibition experiments were conducted, and the experimental results are shown in Table 2. The IC 50 The values ​​ranged from 0.071±0.015μM to 11.9±2.4μM, indicating that its molecular structure effectively exhibited significant dual-target inhibition ability. Among them, the dual-target inhibition effects of compounds Y-6 and Y-18 were more balanced. In particular, the dual-target inhibition activity of compound Y-6 was better than that of other compounds.

[0145] Table 2. Dual-target (LpxC / PD-L1) inhibitory activity of some preferred compounds.

[0146]

[0147] It can be clearly seen from the above test results that the compound of general formula I to be protected by the present invention has good in vitro antibacterial activity, and therefore the compound of the present invention has a good industrial application prospect.

[0148] The compounds of general formula I in the present invention can be administered alone, but are usually administered in admixture with a pharmaceutical carrier. The selection of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. The following is a preparation method of various pharmaceutical dosage forms of such compounds, such as tablets, capsules, injections, aerosols, suppositories, films, pills, external liniments and ointments, to illustrate their new applications in the pharmaceutical field.

[0149] Example 25: Tablets.

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

[0151] Example 26: Capsules.

[0152] 10 g of a compound containing the compound of claim 1 (using the compound of Example Y-1 as an example) is mixed with 20 g of auxiliary materials according to the requirements of pharmaceutical capsules and then filled into hollow capsules. Each capsule weighs 300 mg.

[0153] Example 27: Injection.

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

[0155] Example 28: Aerosol.

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

[0157] Example 29: Suppository.

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

[0159] Example 30: Film.

[0160] Use 10g of a compound containing the compound of claim 1 (using the compound of Example Y-1 as an example), stir and swell polyvinyl alcohol, medicinal glycerin, water, etc., heat to dissolve, filter with an 80-mesh sieve, add the compound of Example 18 to the filtrate, stir and dissolve, and use a film coating machine to make 100 films.

[0161] Example 31: Drop pills.

[0162] 10 g of a compound containing the compound of claim 1 (for example, the compound of Example Y-1) is heated and melted with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin to prepare 1000 dripping pills.

[0163] Example 32: External use liniment.

[0164] The preparation method is prepared by mixing 10 g of a compound containing the compound of claim 1 (for example, the compound of Example Y-1) with 2.5 g of auxiliary materials such as an emulsifier according to conventional pharmaceutical methods, and then adding distilled water to 200 mL.

[0165] Example 33: Ointment.

[0166] 10 g of a compound containing the compound of claim 1 (for example, the compound of Example Y-1) is ground into powder and then mixed with 500 g of an oily base such as vaseline to obtain the product.

[0167] Although the present invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

Claims

1. Biphenyl hydroxime derivatives represented by general formula I, and their geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in: 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-oxopyrrolidinyl; X is a methyl group or a hydrogen group; R is hydroxymethyl, 2-hydroxyethyl, isopropyl or cyclopropyl.

2. The biphenyl hydroxamate derivative of general formula I as claimed in claim 1, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in Ar is p-methylphenol, 3-methylphenol, 4-formyl-piperidinyl, 3-formyl-piperidinyl, 3,5-methoxy-4-methylphenol, 2-formaldehyde-5-oxopyrrolidinyl; X is a methyl group or a hydrogen group; R is hydroxymethyl, 2-hydroxyethyl, isopropyl or cyclopropyl.

3. The biphenyl hydroxime derivative represented by the general formula I according to any one of claims 1 to 2, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, selected from:

4. A method for synthesizing the derivative of any one of claims 1 to 3, specifically comprising: obtaining the target product through Suzuki coupling, chlorination, substitution, condensation reduction and hydroxylation reaction; or obtaining the target product through Suzuki coupling, chlorination, substitution, hydrolysis, amidation and hydroxylation reaction; or obtaining the target product through Suzuki coupling, condensation reduction, cyclization, amidation and hydroxylation reaction.

5. A pharmaceutical composition comprising the derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.

6. Use of the derivative according to any one of claims 1 to 3 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug in the preparation of a drug for treating or preventing fungal diseases.

7. Use of the derivative according to any one of claims 1 to 3 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug in the preparation of a drug for treating or preventing pathogenic Gram-negative bacterial infections.

8. The use of the biphenylhydroxyoxime derivatives as claimed in claim 7 in the preparation of drugs for treating or preventing pathogenic Gram-negative bacterial infections, characterized in that: The pathogenic Gram-negative bacteria are Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium or Pseudomonas aeruginosa.

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