Pleuromutilin derivative with arylboronic acid or arylboronic acid ester fragment as well as preparation method and application of pleuromutilin derivative

Abstract

The invention belongs to the field of pharmacy, and relates to pleuromutilin derivatives with arylboronic acid or arylboronic acid ester fragments as well as a preparation method and application of the pleuromutilin derivatives. The pleuromutilin derivative with the arylboronic acid or arylboronic acid ester fragment has a structure as shown in formulas (Ia), (Ib) and (Ic) or a pharmaceutically acceptable salt of the pleuromutilin derivative. The compound disclosed by the invention has excellent antibacterial activity and can be used as an active substance for treating infectious diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmacy, and particularly relates to a class of pleuromutilin derivatives having an arylboronic acid or arylboronic acid ester fragment, and a preparation method and use thereof. Background Art

[0002] Pleuromutilin is a tricyclic diterpenoid antibiotic isolated from the higher fungi Basidiomycetes Pleurotus mutilis and Pleurotus passeckeranius. Its main skeleton is composed of a five-membered ring, a six-membered ring and an eight-membered ring fused together, having a tricyclic rigid structure. Pleuromutilin and its derivatives mainly have good inhibitory activities against Gram-positive bacteria and mycoplasma pathogens, and have good application prospects in veterinary and human antibiotics. Pleuromutilin antibiotics mainly act antibacterial by selectively binding to the ribosome of prokaryotic microorganisms and inhibiting the activity of peptidyl transferase, thereby hindering the protein synthesis of prokaryotic cells. Due to the specific binding of pleuromutilin to bacterial ribosomes, it has high antibacterial activity, high selectivity, and is less likely to produce drug resistance compared to other types of antibiotics. Currently, no cross-resistance of pleuromutilin to drugs such as mupirocin, β-lactam antibiotics, macrolide antibiotics or quinolones has been found.

[0003] It has been nearly 60 years since pleuromutilin-type antibiotics were marketed. The marketed veterinary pleuromutilin-type antibiotics are tiamulin (approved in 1979) and valnemulin (approved in the EU in 1999), which are mainly used for the prevention and treatment of swine dysentery and have a broad antibacterial spectrum; retapamulin is a 1% ointment (trade name Altabax) developed by GlaxoSmithKline for topical use, mainly used for the treatment of skin infectious diseases such as impetigo. It was approved for marketing by the US FDA in 2007 and was approved by the European Medicines Agency (EMA) for the short-term treatment of secondary epidermal infections in the same year. Retapamulin is the first new topical prescription antibiotic; Lefamulin (BC-3781) is a semi-synthetic antibiotic developed by Austrian Nabriva Therapeutics for the treatment of community-acquired pneumonia (CABP). It was approved for marketing by the FDA in 2019. This new drug is an antibiotic with an innovative mechanism of action approved by the FDA in the past 20 years, providing a new treatment option for the treatment of CABP.

[0004]

[0005] The tricyclic diterpene nucleus of pleuromutilin is the key part for its antibacterial activity. However, due to its poor water solubility and low oral bioavailability, it cannot be directly used as a drug and needs to be structurally modified. (Cui Ge. Synthesis of Novel Derivatives of Pleuromutilin [D]. Hebei University of Science and Technology, 2021. DOI: 10.27107 / d.cnki.ghbku.2021.000190.) During the process of structurally modifying pleuromutilin, researchers found that the C14-side chain of pleuromutilin is the main site for chemical modification, and its ester group structure is usually an essential group for activity. Domestic and foreign researchers usually modify the C14-side chain while retaining the ester group, and introduce various groups to improve its antibacterial activity and bioavailability. (Wang Qian, Xia Yuxiang. Patent Analysis of Side Chain Improvement of Pleuromutilin Drugs [J]. Science & Technology Vision, 2019(20): 27-28. DOI: 10.19694 / j.cnki.issn2095-2457.2019.20.011.)

[0006]

[0007] The clinical compound under investigation, BC-7013, introduced a phenylthioether fragment at the C22 position and showed strong activity against common Gram-positive bacterial pathogens. In addition, Fang Binghu (Chem Biol Drug Des. 2015; 86: 239-245), Tang Youzhi (Chem Biol Drug Des. 2018; 92: 1627-1637; European Journal of Medicinal Chemistry 181(2019)111594; European Journal of Medicinal Chemistry 204(2020)112604) and others from South China Agricultural University also extended the use of phenylthioether fragments at the C22 position and found that the presence of the phenylthioether structure could enhance the anti-Staphylococcus aureus activity of pleuromutilin compounds, but did not pay attention to the antibacterial activity against other Gram-positive bacteria.

[0008] The borate group is a strong Lewis acid. The two hydroxyl groups on it have four sets of lone pair electrons and two hydrogen bond donors at the same time, and have the ability to provide rich hydrogen bond binding forces. The central boron atom contains an empty p orbital, enabling it to undergo reversible covalent binding with a variety of nucleophilic groups such as hydroxide anions, geminal diol structures in sugar skeletons, and hydroxyl groups in amino acid residues under physiological conditions. It also has a neutral trigonal planar structure and an anionic tetrahedral structure. In addition, the borate structure can form coordination bonds with zinc ions and other substances, providing complexing forces. Due to its rich binding modes and force types, the borate group has received attention in the treatment of various diseases in recent years and has been gradually proven to have good in vivo safety and stability. As of now, five drugs containing borate structures have been launched (bortezomib, tavaborole, ixazomib, crisaborole, faropenem sodium). In the present invention, the borate structure is introduced into the pleuromutilin skeleton to discover highly efficient and broad-spectrum antibiotics against Gram-positive bacterial infections.

[0009] Summary of the Invention

[0010] In order to solve the deficiencies of the existing technology, the main object of the present invention is to provide a pleuromutilin derivative with an arylboronic acid or arylboronic acid ester fragment.

[0011] Another object of the present invention is to provide a preparation method for the above-mentioned pleuromutilin derivative with an arylboronic acid or arylboronic acid ester fragment.

[0012] Another object of the present invention is to provide the use of a pleuromutilin derivative with an arylboronic acid or arylboronic acid ester fragment or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating infectious diseases, especially infectious diseases caused by Staphylococcus aureus, drug-resistant Staphylococcus aureus, Staphylococcus epidermidis, drug-resistant Staphylococcus epidermidis, Streptococcus pneumoniae, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa or Mycoplasma, or infectious diseases caused by multi-drug resistant bacteria.

[0013] The object of the present invention is achieved by the following technical solutions:

[0014] A pleuromutilin derivative with an arylboronic acid fragment represented by formula (Ia) or a pharmaceutically acceptable salt thereof:

[0015]

[0016] Wherein,

[0017] Selected from When L is CO, ring C is selected from a benzene ring, a six-membered nitrogen-containing heterocycle, a five-membered oxygen-containing heterocycle, a five-membered sulfur-containing heterocycle, R 1Selected from hydrogen, fluorine, chlorine, trifluoromethyl, nitro, amino, methyl, methoxy, n is selected from 1, 2, 3, 4; L is selected from CH 2 , CH 2 When CO, ring C is a benzene ring, R 1 is hydrogen and n is 4.

[0018] A pleuromutilin derivative having an aryl borate fragment represented by formula (Ib) or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Wherein,

[0021] Selected from

[0022] Selected from

[0023] A pleuromutilin derivative having an aryl borate fragment represented by formula (Ic) or a pharmaceutically acceptable salt thereof:

[0024]

[0025] Wherein,

[0026] Selected from

[0027] t is selected from 1, 2.

[0028] More preferably, the pleuromutilin derivatives having an aryl boronic acid or aryl borate fragment are selected from the following:

[0029]

[0030]

[0031]

[0032]

[0033] The method for preparing the above-mentioned pleuromutilin derivative having an aryl boronic acid or aryl borate fragment comprises the following steps:

[0034]

[0035] (1) Pleuromutilin undergoes a sulfonylation reaction with p-toluenesulfonyl chloride, dichloromethane as the solvent and triethylamine as the acid-binding agent, and the reaction is carried out at room temperature to obtain intermediate (II), and the molar ratio of p-toluenesulfonyl chloride to pleuromutilin is 1.1:1;

[0036] (2) Using intermediate (II) as a raw material, it undergoes a nucleophilic substitution reaction with o / m / p-aminothiophenol. N,N-dimethylformamide is used as a solvent, and potassium carbonate is used as an acid-binding agent. The reaction is heated to obtain intermediate (III). The molar ratio of intermediate (II) to o / m / p-aminothiophenol is 1:1.3;

[0037]

[0038] (3) In Examples 1-25 and 29-40, L is CO or CH 2 For CO, an amide condensation reaction occurs according to the operation in step (3A); in Examples 26-28, when L is CH 2 a nucleophilic substitution reaction occurs according to the operation in step (3B);

[0039] Compounds 1-25 and 29-40 are prepared using step (3A). In this reaction, intermediate (III) undergoes an amide condensation reaction with boronic acid-based aryl acids or boronic ester-based aryl acids. N,N-dimethylformamide is used as a solvent, HATU is used as a condensing agent, N,N-diisopropylethylamine is used as an acid-binding agent, and a catalytic amount of DMAP is added to activate the carboxyl group. The reaction is carried out at room temperature to obtain pleuromutilin derivatives with arylboronic acid or arylboronic ester fragments having the structures shown in formulas (Ia), (Ib), and (Ic). The molar ratio of intermediate (III) to boronic acid-based aryl acids or boronic ester-based aryl acids is 1:2.

[0040] Compounds 26-28 are prepared using step (3B). In this reaction, intermediate (III) undergoes a nucleophilic substitution reaction with boronic acid-based bromobenzyl. Acetonitrile is used as a solvent, potassium iodide is used as a catalyst, and the reaction is heated to obtain pleuromutilin derivatives with arylboronic acid fragments having the structure shown in formula (Ia). The molar ratio of intermediate (III) to boronic acid-based bromobenzyl is 1:1.

[0041] Beneficial technical effects

[0042] The present invention provides a class of novel pleuromutilin compounds with structures as shown in formulas (Ia), (Ib), and (Ic). By modifying the 22-position of pleuromutilin with boronic acid-based or boronic ester-based arylamide benzenethiol, the antibacterial activities against various standard and drug-resistant Gram-positive bacteria are superior to those of the same type of marketed drugs. The pleuromutilin derivatives having arylboronic acid or arylboronic ester fragments and their pharmaceutically acceptable salts can be used as novel antibacterial drugs for the treatment of bacterial infections in animals or humans.

[0043] Abbreviation description

[0044] Abbreviation Full name HATU N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate TEA Triethylamine DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide Description of the drawings

[0045] Figure 1 is the bactericidal curve of Compound 14 Detailed implementation mode

[0046] The present invention will be further described below in conjunction with embodiments, but the implementation modes of the present invention are not limited thereto.

[0047] In all embodiments, 1 1H-NMR was recorded using a Bruker AVANCE III 400 nuclear magnetic resonance spectrometer, a Bruker AVANCEIII 500 nuclear magnetic resonance spectrometer or a QOne 400 nuclear magnetic resonance spectrometer, and the chemical shift was expressed in δ (ppm); low-resolution mass spectrometry was determined using a Waters H-Class-SQD type mass spectrometer.

[0048] Unless otherwise specified, the experimental materials and reagents used in the following experimental examples and embodiments can all be obtained from commercial channels.

[0049] The pleuromutilin nucleus described in the present invention is numbered as follows:

[0050]

[0051] Experimental Example 1

[0052] Preparation of Intermediate II

[0053]

[0054] Weigh 10 g of pleuromutilin (26 mmol) and dissolve it in 60 mL of dichloromethane solution. Add 5.5 g of p-toluenesulfonyl chloride (28.9 mmol) and 7.3 mL of TEA (98.8 mmol). After stirring at room temperature for 12 h, add 100 mL of saturated ammonium chloride aqueous solution to quench the reaction solution. Separate and recover the organic phase. Extract the aqueous phase three times with 30 mL of dichloromethane each time. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 12 g of Intermediate II with a yield of 85%. ESI-MS (m / z): 533.69 [M+H] + . 11H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.81 (d, J = 8.5 Hz, 1H), 5.37 (d, J = 11.0 Hz, 1H), 5.23 (d, J = 17.4 Hz, 1H), 4.52 (s, 2H), 3.38 (s, 1H), 2.49 (s, 3H), 2.35 - 2.17 (m, 3H), 2.15 - 2.04 (m, 2H), 1.79 (dq, J = 14.9, 3.0 Hz, 1H), 1.70 - 1.62 (m, 3H), 1.55 - 1.42 (m, 6H), 1.39 (dq, J = 14.5, 3.7 Hz, 1H), 1.29 (d, J = 16.1 Hz, 1H), 1.20 (s, 3H), 0.91 (d, J = 6.9 Hz, 3H), 0.66 (d, J = 7.1 Hz, 3H).

[0055] Preparation of Intermediate Ⅲ-A

[0056]

[0057] Weigh 2 g of Intermediate Ⅱ (3.8 mmol) and dissolve it in 10 mL of DMF. Add 612 mg of 2-aminothiophenol (4.9 mmol) and 1.6 g of potassium carbonate (11.3 mmol). After stirring at room temperature for 12 h, add 15 mL of saturated ammonium chloride aqueous solution to quench the reaction solution. Extract the aqueous phase three times with 15 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1.5 g of Intermediate Ⅲ-A with a yield of 83%. ESI-MS (m / z): 486.26 [M + H] + ; 11H NMR (500 MHz, Chloroform-d) δ 7.43 (dd, J = 7.7, 1.5 Hz, 1H), 7.17 (td, J = 7.7, 1.6 Hz, 1H), 6.99 (dd, J = 7.7, 1.6 Hz, 1H), 6.80 (td, J = 7.6, 1.5 Hz, 1H), 6.44 (dd, J = 17.4, 11.0 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 11.0, 1.6 Hz, 1H), 5.18 (dd, J = 17.4, 1.6 Hz, 1H), 3.46 (d, J = 15.5 Hz, 1H), 3.40 (d, J = 15.5 Hz, 1H), 3.32 (d, J = 6.5 Hz, 1H), 2.30 (m, 1H), 2.26 - 2.13 (m, 2H), 2.05 (s, 1H), 1.98 (dd, J = 16.1, 8.5 Hz, 1H), 1.75 (dd, J = 14.8, 3.3 Hz, 1H), 1.68 - 1.57 (m, 2H), 1.55 - 1.40 (m, 2H), 1.38 (s, 3H), 1.34 - 1.24 (m, 2H), 1.14 (s, 3H), 1.09 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H), 0.57 (d, J = 7.0 Hz, 3H). Preparation of Intermediate Ⅲ-B

[0058]

[0059] Weigh 2 g of Intermediate Ⅱ (3.8 mmol) and dissolve it in 10 mL of DMF. Add 612 mg of 3-aminobenzenethiol (4.9 mmol) and 1.6 g of potassium carbonate (11.3 mmol). After stirring at room temperature for 12 h, add 15 mL of saturated ammonium chloride aqueous solution to quench the reaction solution. Extract the aqueous phase three times with 15 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1.6 g of Intermediate Ⅲ-B with a yield of 86%. ESI-MS (m / z): 486.33 [M + H] + . 11H NMR (400 MHz, Chloroform-d) δ 7.18 (t, J = 7.9 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.02 (dd, J = 7.9, 2.1 Hz, 1H), 6.90 (dt, J = 8.0, 1.3 Hz, 1H), 6.40 (dd, J = 17.4, 11.0 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 5.30 (dd, J = 11.0, 1.6 Hz, 1H), 5.15 (dd, J = 17.4, 1.6 Hz, 1H), 3.58 (s, 2H), 3.33 (d, J = 6.4 Hz, 1H), 2.34 - 2.15 (m, 3H), 2.10 - 1.95 (m, 2H), 1.75 (dd, J = 14.3, 3.1 Hz, 1H), 1.68 - 1.56 (m, 2H), 1.54 - 1.46 (m, 2H), 1.41 (s, 3H), 1.38 - 1.16 (m, 3H), 1.12 (s, 3H), 0.86 (d, J = 7.1 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H).

[0060] Preparation of Intermediate Ⅲ-C

[0061]

[0062] Weigh 2 g of Intermediate Ⅱ (3.8 mmol) and dissolve it in 10 mL of DMF. Add 612 mg of 4-aminothiophenol (4.9 mmol) and 1.6 g of potassium carbonate (11.3 mmol). After stirring at room temperature for 12 h, add 15 mL of saturated ammonium chloride aqueous solution to quench the reaction solution. Extract the aqueous phase three times with 15 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1.4 g of Intermediate Ⅲ-C with a yield of 79%. ESI-MS (m / z): 486.35 [M + H] + . 11H NMR (500 MHz, Chloroform-d) δ 7.25 (d, J = 7.9 Hz, 2H), 6.57 (d, J = 8.1 Hz, 2H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 5.19 (d, J = 17.4 Hz, 1H), 3.41 (d, J = 14.7 Hz, 1H), 3.36 (d, J = 14.5 Hz, 1H), 3.33 (d, J = 6.6 Hz, 1H), 2.31 (m, 1H), 2.28 - 2.12 (m, 2H), 2.06 (s, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 1.68 - 1.58 (m, 2H), 1.56 - 1.41 (m, 2H), 1.39 (s, 3H), 1.35 (m, 1H), 1.18 (d, J = 16.0 Hz, 1H), 1.14 (s, 3H), 1.10 (m, 1H), 0.86 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 6.9 Hz, 3H).

[0063] Example 1 Preparation of 14 - O - [2 - (1,3 - Dihydro - 1 - hydroxy - 2,1 - benzoxaborol - 6 - carboxamido)phenyl]thioacetylmurin (Compound 1)

[0064]

[0065] Weigh 74.7 mg of 1 - hydroxy - 1,3 - dihydrobenzo[c][1,2]oxaborolane - 6 - carboxylic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - A (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 87.9 mg of Compound 1 with a yield of 65%. ESI - MS (m / z): 668.70 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 7.8, 1.5 Hz, 1H), 7.31 (td, J = 7.6, 1.5 Hz, 1H), 7.20 (td, J = 7.6, 1.5 Hz, 1H), 6.02 (dd, J = 17.8, 11.2 Hz, 1H), 5.48 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H), 4.96 - 4.86 (m, 2H), 3.83 (d, J = 16.0 Hz, 1H), 3.73 (d, J = 16.0 Hz, 1H), 3.36 (d, J = 5.9 Hz, 1H), 2.34 (s, 1H), 2.19 - 1.95 (m, 4H), 1.59 (m, 2H), 1.44 (s, 1H), 1.28 (s, 3H), 1.21 (m, 3H), 1.12 (m, 1H), 0.98 (s, 3H), 1.03 - 0.90 (m, 1H), 0.78 (d, J = 7.0 Hz, 3H), 0.49 (d, J = 6.9 Hz, 3H).

[0066] Example 2 Preparation of 14 - O - [3 - (3 - (dihydroxyboryl)benzamido)phenyl]thioacetyl moxalactam (Compound 2)

[0067]

[0068] Weigh 69.7 mg of 3 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, and wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution. Combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate twice. Combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (methylene chloride:methanol = 20:1) to obtain 83.6 mg of Compound 2 with a yield of 63%. ESI - MS (m / z): 656.83 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.33 (t, J = 1.6 Hz, 1H), 8.21 (s, 2H), 7.95 (ddt, J = 18.0, 7.9, 1.4 Hz, 2H), 7.85 (t, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.3, 2.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.08 - 5.97 (m, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.00 - 4.90 (m, 2H), 4.48 (d, J = 6.0 Hz, 1H), 3.84 (d, J = 15.7 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.37 (t, J = 6.1 Hz, 1H), 2.36 (s, 1H), 2.12 - 1.94 (m, 4H), 1.68 - 1.54 (m, 2H), 1.50 - 1.29 (m, 1H), 1.32 (s, 3H), 1.28 - 1.19 (m, 3H), 1.07 - 0.92 (m, 1H), 0.98 (s, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0069] Example 3 Preparation of 14 - O - [3 - (3 - (4,4,5,5 - Tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzamido)phenyl]thioacetylmurin (Compound 3)

[0070]

[0071] Weigh 104.2 mg of 3 - carboxyphenylboronic acid pinacol ester (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, and wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution. Combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate twice. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 85.4 mg of Compound 3 with a yield of 57%. ESI - MS (m / z): 738.48 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (t, J = 1.5 Hz, 1H), 8.05 (dt, J = 7.9, 1.6 Hz, 1H), 7.87 (dt, J = 7.5, 1.3 Hz, 1H), 7.84 (t, J = 1.2 Hz, 1H), 7.64 (dt, J = 8.0, 1.3 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.09 (dt, J = 8.0, 1.1 Hz, 1H), 6.03 (dd, J = 17.8, 11.2 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 4.98 - 4.95 (m, 1H), 4.93 (s, 1H), 4.48 (d, J = 6.1 Hz, 1H), 3.84 (d, J = 15.8 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.37 (t, J = 6.1 Hz, 1H), 2.36 (s, 1H), 2.23 - 1.93 (m, 4H), 1.61 (m, 2H), 1.50 - 1.34 (m, 2H), 1.33 (s, 12H), 1.31 (s, 3H), 1.30 - 1.11 (m, 3H), 1.03 (m, 1H), 0.97 (s, 3H), 0.79 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H).

[0072] Example 4 Preparation of 14 - O - [3 - (3 - (dihydroxyboryl) - 4 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 4)

[0073]

[0074] Weigh 77.3 mg of 5 - carboxy - 2 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (methylene chloride:methanol = 20:1) to obtain 95.6 mg of Compound 4 with a yield of 70%. ESI - MS (m / z): 674.69 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.40 (s, 2H), 8.17 (dd, J = 5.7, 2.5 Hz, 1H), 8.00 (dd, J = 8.2, 2.5 Hz, 1H), 7.84 (t, J = 1.9 Hz, 1H), 7.62 (dd, J = 7.8, 2.0 Hz, 1H), 7.26 (m, 2H), 7.09 (dd, J = 7.9, 2.2 Hz, 1H), 6.03 (m, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.00 - 4.90 (m, 2H), 4.48 (s, 1H), 3.84 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.37 (m, 1H), 2.36 (s, 1H), 2.27 - 1.92 (m, 4H), 1.68 - 1.53 (m, 2H), 1.52 - 1.35 (m, 2H), 1.32 (s, 3H), 1.28 - 1.12 (m, 3H), 0.97 (s, 3H), 0.95 - 0.82 (m, 1H), 0.80 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0075] Example 5 Preparation of 14 - O - [3 - (3 - (Dihydroxyboranyl) - 5 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 5)

[0076]

[0077] Weigh 77.3 mg of 3 - carboxy - 5 - fluorophenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 77.8 mg of Compound 5 with a yield of 57%. ESI - MS (m / z): 674.43 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.42 (m, 1H), 8.22 (m, 1H), 7.85 (m, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.63 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.03 (dd, J = 17.7, 11.2 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 4.99 - 4.90 (m, 2H), 4.48 (d, J = 6.0 Hz, 1H), 3.84 (d, J = 15.7 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.38 (d, J = 5.7 Hz, 1H), 2.36 (s, 1H), 2.21 - 2.00 (m, 4H), 1.62 (m, 2H), 1.44 (m, 2H), 1.31 (s, 3H), 1.24 (m, 3H), 0.97 (s, 3H), 0.93 (m, 1H), 0.79 (d, J = 6.8 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0078] Example 6 Preparation of 14 - O - [3 - (5 - (dihydroxyboryl) - 2 - fluorobenzamido)phenyl]thioacetyl mirincin (Compound 6)

[0079]

[0080] Weigh 77.3 mg of 3 - carboxy - 5 - fluorophenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (dichloromethane:methanol = 20:1) to obtain 75.0 mg of Compound 6 with a yield of 55%. ESI - MS (m / z): 674.51 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.06 (m, 1H), 7.81 (t, J = 4.1 Hz, 1H), 7.53 (m, 1H), 7.32 - 7.25 (m, 2H), 7.11 (m, 1H), 6.03 (dd, J = 17.8, 11.2 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 4.95 (m, 2H), 3.85 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.38 (m, 1H), 2.36 (s, 1H), 2.26 - 1.81 (m, 4H), 1.68 - 1.54 (m, 2H), 1.38 (m, 2H), 1.32 (s, 3H), 1.30 - 1.20 (m, 3H), 0.99 (s, 3H), 0.92 (m, 1H), 0.79 (s, 3H), 0.58 (s, 3H).

[0081] Example 7 Preparation of 14 - O - [3 - (3 - (dihydroxyboranyl) - 5 - (trifluoromethyl)benzamido)phenyl]thioacetyl moxilin (Compound 7)

[0082]

[0083] Weigh 98.2 mg of 3 - boronic acid - 5 - (trifluoromethyl)benzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of III - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 88.2 mg of Compound 7 with a yield of 60%. ESI - MS (m / z): 724.88 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.63 (m, 1H), 8.36 - 8.17 (m, 2H), 7.87 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.05 (dd, J = 17.6, 11.3 Hz, 1H), 5.53 (d, J = 8.0 Hz, 1H), 5.02 - 4.91 (m, 2H), 4.50 (s, 1H), 3.91 - 3.73 (m, 2H), 3.40 (m, 1H), 2.37 (s, 1H), 2.24 - 1.93 (m, 4H), 1.61 (m, 2H), 1.52 - 1.42 (m, 2H), 1.41 (s 3H), 1.33 (m, 3H), 1.03 (m, 1H), 0.99 (s, 3H), 0.81 (dd, J = 7.2, Hz, 3H), 0.60 (dd, J = 7.0, Hz, 3H).

[0084] Example 8 Preparation of 14 - O - [3 - (3 - amino - 5 - (dihydroxyboryl)benzamido)phenyl]thioacetyl moxilin (Compound 8)

[0085]

[0086] Weigh 76.0 mg of 3 - aminocarboxybenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 96.5 mg of Compound 8 with a yield of 71%. ESI - MS (m / z): 671.41 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (d, J = 8.0, 2.0 Hz, 1H), 6.03 (dd, J = 18.0, 11.1 Hz, 1H), 5.51 (d, J = 7.9 Hz, 1H), 4.99 - 4.89 (m, 2H), 4.48 (d, J = 5.9 Hz, 1H), 3.83 (m, 2H), 3.38 (m, 1H), 2.35 (s, 1H), 2.23 - 1.97 (m, 4H), 1.68 - 1.55 (m, 2H), 1.52 - 1.36 (m, 2H), 1.32 (s, 3H), 1.21 - 1.11 (m, 3H), 1.02 (m, 1H), 0.97 (s, 3H), 0.79 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0087] Example 9 Preparation of 14 - O - [3 - (3 - (dihydroxyboryl) - 4 - methylbenzamido)phenyl]thioacetyl moxilin (Compound 9)

[0088]

[0089] Weigh 82.3 mg of 5 - carboxylic acid - 2 - methylphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (dichloromethane:methanol = 20:1) to obtain 80.0 mg of Compound 9, with a yield of 59%. ESI - MS (m / z): 670.72 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.19 (s, 2H), 8.17 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1.9, 1H), 7.84 (dd, J = 8.0, 2.4 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.05 (dd, J = 17.6, 11.3 Hz, 1H), 5.53 (d, J = 8.3 Hz, 1H), 5.02 - 4.92 (m, 2H), 4.50 (d, J = 6.0 Hz, 1H), 3.86 (d, J = 15.6 Hz, 1H), 3.79 (d, J = 15.7 Hz, 1H), 2.48 (s, 3H), 2.38 (m, 1H), 2.09 (m, 4H), 1.69 - 1.57 (m, 2H), 1.53 - 1.35 (m, 2H), 1.34 (s, 3H), 1.33 - 1.19 (m, 3H), 1.00 (s, 3H), 1.00 - 0.95 (m, 1H), 0.82 (d, J = 6.9 Hz, 3H), 0.60 (d, J = 6.7 Hz, 3H).

[0090] Example 10 Preparation of 14 - O - [3 - (3 - (dihydroxyboryl) - 5 - methylbenzamido)phenyl]thioacetyl moxilin (Compound 10)

[0091]

[0092] Weigh 75.6 mg of 3 - carboxy - 5 - methylphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 90.9 mg of Compound 10 with a yield of 67%. ESI - MS (m / z): 670.61 [M + Na] + . 11H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.10 (s, 2H), 7.81 (d, J = 3.1 Hz, 1H), 7.78 - 7.68 (m, 3H), 7.60 (dd, J = 8.0 Hz, 3.0 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.05 (dd, J = 8.0 Hz, 2.8 Hz, 1H), 6.02 (dt, J = 17.6, 9.6 Hz, 1H), 5.48 (d, J = 8.3 Hz, 1H), 5.14 - 4.82 (m, 2H), 4.43 (d, J = 6.0 Hz, 1H), 3.80 (d, J = 15.6 Hz, 1H), 3.73 (d, J = 15.6 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 1H), 2.20 - 1.86 (m, 2H), 1.66 - 1.36 (m, 2H), 1.29 (s, 3H), 1.27 - 1.08 (m, 3H), 0.95 (s, 3H), 0.91 (m, 1H), 0.77 (d, J = 7.0 Hz, H), 0.57 (dd, J = 16.0, 6.7 Hz, 3H).

[0093] Example 11 Preparation of 14 - O - [3 - (3 - (dihydroxyboryl) - 4 - methoxybenzamido)phenyl]thioacetyl moxilin (Compound 11)

[0094]

[0095] Weigh 82.3 mg of 3 - boric acid - 4 - methoxybenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution in sequence, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 91.7 mg of Compound 11 with a yield of 66%. ESI - MS (m / z): 686.53 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.88 (s, 2H), 7.85 - 7.83 (m, 1H), 7.63 (dd, J = 7.9, 2.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.11 - 7.05 (m, 2H), 6.03 (dd, J = 18.5, 10.5 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 4.98 - 4.90 (m, 2H), 4.48 (d, J = 6.0 Hz, 1H), 4.04 (d, J = 7.1 Hz, 1H), 4.01 (d, J = 7.1 Hz, 1H), 3.87 (s, 3H), 2.36 (s, 1H), 2.18 - 1.90 (m, 4H), 1.69 - 1.53 (m, 2H), 1.50 - 1.28 (m, 2H), 1.32 (s, 3H), 1.31 - 1.20 (m, 3H), 1.08 - 0.91 (m, 1H), 0.97 (s, 3H), 0.80 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0096] Example 12 Preparation of 14 - O - [3 - (3 - (dihydroxyboranyl) - 5 - methoxybenzamido)phenyl]thioacetyl moxilin (Compound 12)

[0097]

[0098] Weigh 82.3 mg of 3 - boronic acid - 5 - methoxybenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (methylene chloride:methanol = 20:1) to obtain 97.3 mg of Compound 12 with a yield of 70%. ESI - MS (m / z): 686.49 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.03 (dd, J = 16.7, 10.7 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 5.00 - 4.91 (m, 2H), 3.90 - 3.71 (m, 5H), 3.37 (t, J = 6.2 Hz, 1H), 2.36 (s, 1H), 2.23 - 1.88 (m, 4H), 1.68 - 1.53 (m, 2H), 1.51 - 1.38 (m, 2H), 1.32 (s, 3H), 1.29 - 1.21 (m, 3H), 0.98 (s, 3H), 0.94 (m, 1H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0099] Example 13 Preparation of 14 - O - [3 - (5 - (dihydroxyboryl) - 2 - methoxybenzamido)phenyl]thioacetylmurin (Compound 13)

[0100]

[0101] Weigh 82.3 mg of 5 - boric acid - 2 - methoxybenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (dichloromethane:methanol = 20:1) to obtain 94.5 mg of Compound 13 with a yield of 68%. ESI - MS (m / z): 686.40 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.96 (d, J = 7.1 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.06 (dd, J = 17.9, 11.0 Hz, 1H), 5.53 (d, J = 8.1 Hz, 1H), 5.02 - 4.94 (m, 2H), 4.51 (d, J = 5.9 Hz, 1H), 4.39 (d, J = 5.3 Hz, 1H), 3.92 (s, 3H), 3.86 (d, J = 15.7 Hz, 1H), 3.79 (d, J = 15.6 Hz, 1H), 2.38 (s, 1H), 2.26 - 1.96 (m, 4H), 1.71 - 1.55 (m, 2H), 1.50 - 1.36 (m, 2H), 1.35 (s, 3H), 1.33 - 1.15 (m, 3H), 1.01 (s, 3H), 0.98 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H), 0.61 (d, J = 6.7 Hz, 3H).

[0102] Example 14 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl)benzamido)phenyl]thioacetyl moxilin (Compound 14)

[0103]

[0104] Weigh 69.7 mg of 4 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain 84.9 mg of Compound 14 with a yield of 64%. ESI - MS (m / z): 656.58 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.27 (s, 1H), 7.96 - 7.87 (m, 4H), 7.64 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.03 (dd, J = 17.7, 11.3 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 5.00 - 4.90 (m, 2H), 4.48 (d, J = 5.9 Hz, 1H), 3.84 (d, J = 15.9 Hz, 2H), 3.77 (d, J = 15.7 Hz, 1H), 3.38 (d, J = 6.2 Hz, 1H), 2.36 (s, 1H), 2.21 - 1.92 (m, 4H), 1.67 - 1.56 (m, 2H), 1.50 - 1.41 (m, 2H), 1.32 (s, 3H), 1.28 - 1.24 (m, 3H), 0.97 (s, 3H), 0.93 (m, 1H), 0.80 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0105] Preparation of 14 - O - [3 - (4 - (4,4,5,5 - Tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzamido)phenyl]thioacetylmurin (Compound 15) in Example 15

[0106]

[0107] Weigh 104.2 mg of 4 - carboxyphenylboronic acid pinacol ester (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 106.5 mg of Compound 15 with a yield of 71%. ESI - MS (m / z): 738.78 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.86 (t, J = 2.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.64 (dd, J = 8.6, 2.1 Hz, 1H), 7.27 (t, J = 8.0, 1H), 7.09 (dd, J = 8.8, 1.9 Hz, 1H), 6.02 (dd, J = 18.5, 10.6 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 4.97 - 4.91 (m, 2H), 3.83 (d, J = 15.7 Hz, 1H), 3.76 (d, J = 15.7 Hz, 1H), 3.37 (m, 1H), 2.34 (s, 1H), 2.22 - 1.90 (m, 4H), 1.60 (m, 2H), 1.47 - 1.37 (m, 2H), 1.31 (s, 12H), 1.30 (s, 3H), 1.06 (m, 4H), 0.96 (s, 3H), 0.79 (d, J = 7.0 Hz, 3H), 0.57 (d, J = 6.7 Hz, 3H).

[0108] Example 16 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 3 - fluorobenzamido)phenyl]thioacetylmurin (Compound 16)

[0109]

[0110] Weigh 77.3 mg of 3 - carboxy - 5 - fluorophenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 90.1 mg of Compound 16 with a yield of 66%. ESI - MS (m / z): 674.49 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.41 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.64 (m, 3H), 7.29 (t, J = 8.0 Hz, 1H), 7.10 (dd, J = 7.8, 2.3 Hz, 1H), 6.03 (dd, J = 17.5, 11.5 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 4.99 - 4.90 (m, 2H), 4.48 (d, J = 6.0 Hz, 1H), 3.85 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.37 (t, J = 5.8 Hz, 1H), 2.36 (s, 1H), 2.22 - 1.93 (m, 4H), 1.61 (m, 2H), 1.51 - 1.35 (m, 2H), 1.32 (s, 3H), 1.27 - 1.22 (m, 3H), 0.97 (s, 3H), 0.95 - 0.83 (m, 1H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0111] Example 17 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 2 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 17)

[0112]

[0113] Weigh 77.3 mg of 4 - carboxy - 3 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and purified by column chromatography (methylene chloride:methanol = 20:1) to obtain 92.8 mg of Compound 17 with a yield of 68%. ESI - MS (m / z): 674.92 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 8.41 (s, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.82 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H), 6.05 (dd, J = 17.8, 11.1 Hz, 1H), 5.52 (d, J = 8.1 Hz, 1H), 5.02 - 4.92 (m, 2H), 4.51 (d, J = 6.1 Hz, 1H), 3.86 (d, J = 15.3 Hz, 1H), 3.78 (d, J = 15.8 Hz, 1H), 3.65 - 3.51 (m, 1H), 2.38 (s, 1H), 2.21 - 1.94 (m, 4H), 1.71 - 1.57 (m, 2H), 1.52 - 1.36 (m, 2H), 1.34 (d, J = 3.5 Hz, 3H), 1.25 - 1.18 (m, 3H), 1.01 (s, 3H), 1.06 - 0.93 (m, 1H), 0.82 (d, J = 6.9 Hz, 3H), 0.60 (d, J = 6.7 Hz, 3H).

[0114] Example 18 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 3 - chlorobenzamido)phenyl]thioacetyl mirimicin (Compound 18)

[0115]

[0116] Weigh 84.0 mg of 2 - chloro - 4 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 85.3 mg of Compound 18 with a yield of 61%. ESI - MS (m / z): 690.28 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.49 (s, 2H), 7.92 (d, J = 7.1 Hz, 1H), 7.85 (m, 2H), 7.63 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 8.3 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.03 (dd, J = 17.6, 11.3 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 4.98 - 4.91 (m, 2H), 4.48 (s, 1H), 3.84 (d, J = 15.7 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.43 (t, J = 7.0 Hz, 1H), 2.36 (s, 1H), 2.27 - 1.94 (m, 4H), 1.62 (m, 2H), 1.41 (m, 2H), 1.32 (s, 3H), 1.25 (m, 3H), 1.07 - 1.03 (m, 1H), 0.97 (s, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 7.2 Hz, 3H).

[0117] Example 19 Preparation of 14 - O - [3 - (4 - (dihydroxyboranyl) - 2 - chlorobenzamido)phenyl]thioacetyl moxilin (Compound 19)

[0118]

[0119] Weigh 84.0 mg of 3 - chloro - 4 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain 89.5 mg of Compound 19 with a yield of 64%. ESI - MS (m / z): 690.47 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.39 (s, 2H), 7.88 (d, J = 7.2 Hz, 1H), 7.80 (m, 2H), 7.51 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.03 (dd, J = 18.1, 10.9 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 4.98 - 4.91 (m, 2H), 4.50 (s, 1H), 3.84 (d, J = 15.4 Hz, 1H), 3.76 (d, J = 15.7 Hz, 1H), 2.36 (s, 1H), 2.23 - 1.98 (m, 4H), 1.70 - 1.55 (m, 2H), 1.49 - 1.39 (m, 2H), 1.32 (s, 3H), 1.29 - 1.23 (m, 3H), 0.99 (s, 3H), 0.94 (m, 1H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0120] Example 20 Preparation of 14 - O - [3 - (4 - (dihydroxyboranyl) - 3 - nitrobenzamido)phenyl]thioacetyl moxilin (Compound 20)

[0121]

[0122] Weigh 88.6 mg of 4 - carboxy - 2 - nitrobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (dichloromethane:methanol = 20:1) to obtain 83.9 mg of Compound 20 with a yield of 59%. ESI - MS (m / z): 701.55 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.78 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 7.87 - 7.83 (m, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.03 (dd, J = 18.7, 10.1 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 4.99 - 4.90 (m, 2H), 4.48 (d, J = 5.9 Hz, 1H), 3.86 (d, J = 15.8 Hz, 1H), 3.79 (d, J = 15.7 Hz, 1H), 3.38 (d, J = 6.0 Hz, 1H), 2.36 (s, 1H), 2.23 - 1.94 (m, 4H), 1.69 - 1.53 (m, 2H), 1.50 - 1.34 (m, 2H), 1.32 (s, 3H), 1.29 - 1.20 (m, 3H), 1.01 (d, J = 4.2 Hz, 1H), 0.97 (s, 3H), 0.79 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0123] Example 21 Preparation of 14 - O - [3 - (4 - (dihydroxyboranyl) - 2 - nitrobenzamido)phenyl]thioacetyl moxilin (Compound 21)

[0124]

[0125] Weigh 88.6 mg of 3 - nitro - 4 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 89.5 mg of Compound 21, with a yield of 63%. ESI - MS (m / z): 701.79 [M + Na] + . 11H NMR (500 MHz, DMSO) δ 10.53 (s, 1H), 7.95 (s, 1H), 7.76 - 7.70 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.04 (dd, J = 17.6, 11.3 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.01 - 4.93 (m, 2H), 3.82 (d, J = 15.7 Hz, 1H), 3.76 (d, J = 15.7 Hz, 1H), 3.39 (d, J = 5.8 Hz, 1H), 2.37 (s, 1H), 2.18 (dd, J = 18.9, 11.2 Hz, 1H), 2.11 - 1.93 (m, 3H), 1.69 - 1.56 (m, 2H), 1.51 - 1.34 (m, 2H), 1.32 (s, 3H), 1.22 (m, 3H), 1.00 (s, 3H), 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.9 Hz, 3H).

[0126] Example 22 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 3 - methoxybenzamido)phenyl]thioacetyl moxilin (Compound 22)

[0127]

[0128] Weigh 82.3 mg of 4 - borono - 3 - methoxybenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution. Wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution. Combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 93.3 mg of Compound 22 with a yield of 67%. ESI - MS (m / z): 686.31 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.25 (s, 2H), 7.95 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 2.6 Hz, 1H), 7.49 (t, J = 2.1 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.06 (dd, J = 17.7, 11.2 Hz, 1H), 5.53 (d, J = 8.2 Hz, 1H), 5.02 - 4.93 (m, 2H), 4.50 (d, J = 6.0 Hz, 1H), 3.88 - 3.80 (m, 5H), 3.41 (d, J = 6.1 Hz, 1H), 2.38 (s, 1H), 2.26 - 1.94 (m, 4H), 1.71 - 1.58 (m, 2H), 1.53 - 1.36 (m, 2H), 1.35 (s, 3H), 1.31 - 1.14 (m, 3H), 1.00 (s, 3H), 0.98 (m, 1H), 0.82 (d, J = 6.9 Hz, 3H), 0.61 (d, J = 6.8 Hz, 3H).

[0129] Example 23 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 3,5 - difluorobenzamido)phenyl]thioacetyl mirimicin (Compound 23)

[0130]

[0131] Weigh 84.8 mg of 4 - boric acid - 3,5 - difluorobenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain 79.9 mg of Compound 23 with a yield of 57%. ESI - MS (m / z): 692.58 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.61 (dd, J = 7.5, 1.8 Hz, 1H), 7.55 (t, J = 2.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.14 (dd, J = 7.9, 1.8 Hz, 2H), 6.04 (dd, J = 17.8, 11.2 Hz, 1H), 5.52 (d, J = 8.2 Hz, 1H), 5.01 - 4.91 (m, 2H), 4.51 (d, J = 6.0 Hz, 1H), 3.86 (d, J = 15.8 Hz, 1H), 3.79 (d, J = 15.8 Hz, 1H), 2.37 (s, 1H), 2.25 - 1.93 (m, 4H), 1.62 (m, 2H), 1.53 - 1.35 (m, 2H), 1.33 (s, 3H), 1.31 - 1.15 (m, 4H), 0.98 (s, 3H), 0.81 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H).

[0132] Example 24 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl) - 2,3 - difluorobenzamido)phenyl]thioacetyl mialine (Compound 24)

[0133]

[0134] Weigh 91.6 mg of 4 - boro - 2,3 - difluorobenzoic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (dichloromethane:methanol = 20:1) to obtain 84.1 mg of Compound 24 with a yield of 60%. ESI - MS (m / z): 692.67 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 7.82 (s, 1H), 7.64 (q, d, J = 8.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.09 - 6.00 (m, 1H), 5.52 (d, J = 8.2 Hz, 1H), 5.01 - 4.92 (m, 2H), 4.57 - 4.51 (m, 1H), 3.86 (d, J = 15.7 Hz, 1H), 3.79 (d, J = 15.7 Hz, 1H), 3.41 (d, J = 6.0 Hz, 1H), 2.38 (s, 1H), 2.26 - 1.95 (m, 4H), 1.64 (t, J = 13.2 Hz, 2H), 1.46 (d, J = 14.6 Hz, 2H), 1.34 (s, 3H), 1.25 (s, 4H), 1.00 (s, 4H), 1.06 - 0.93 (m, 1H), 0.82 (d, J = 7.0 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H).

[0135] Example 25 Preparation of 14 - O - [3 - (1,3 - Dihydro - 1 - hydroxy - 2,1 - benzoxaborol - 6 - carboxamido)phenyl]thioacetyl moxilin (Compound 25)

[0136]

[0137] Weigh 74.7 mg of 1 - hydroxy - 1,3 - dihydrobenzo[c][1,2]oxaborolane - 6 - carboxylic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (methylene chloride:methanol = 20:1) to obtain 74.4 mg of Compound 25 with a yield of 55%. ESI - MS (m / z): 668.70 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 9.35 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.02 (dd, J = 17.7, 11.3 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 5.07 (s, 2H), 4.98 - 4.90 (m, 2H), 4.47 (d, J = 6.0 Hz, 1H), 3.85 (d, J = 15.7 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.60 (m, 1H), 2.35 (s, 1H), 2.16 (dd, J = 18.1, 11.0 Hz, 1H), 2.11 - 1.91 (m, 3H), 1.68 - 1.52 (m, 2H), 1.47 - 1.36 (m, 2H), 1.32 (s, 3H), 1.23 - 1.12 (m, 3H), 1.04 - 0.91 (m, 1H), 0.97 (s, 3H), 0.79 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H).

[0138] Example 26 Preparation of 14 - O - [3 - (2 - (dihydroxyboryl)benzylamino)phenyl]thioacetyl mirincin (Compound 26)

[0139]

[0140] Weigh 100 mg of Ⅲ - B (0.21 mmol) and 45 mg of 2 - (bromomethyl)phenylboronic acid (0.21 mmol), dissolve them in 2 mL of acetonitrile, and add 10 mg of KI (0.07 mmol). The reaction system is stirred overnight under reflux conditions. After the reaction is completed, the organic solvent in the system is removed by distillation under reduced pressure to obtain the crude product. The crude product is dispersed with 5 mL of ethyl acetate and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 75.2 mg of Compound 26 with a yield of 58%. ESI - MS (m / z): 620.52 [M + H] + . 1 1H NMR (500 MHz, DMSO - D 6)δ9.45(s,1H),7.85(dt,J=7.3,1.1Hz,1H),7.53(t,J=2.0Hz,1H),7.46(dd,J=8.2,2.3Hz,1H),7.44-7.42(m,2H),7.36-7.26(m,1H),7.21(t,J=8.0Hz,1H),6.89(dd,J=7.7,1.8Hz,1H),6.02(dd,J=18.2,10.7Hz,1H),5.50(d,J=8.3Hz,1H),5.02-4.89(m,2H),4.51(s,2H),4.46(s,1H),3.85(d,J=15.6Hz,1H),3.78(d,J=15.6Hz,1H),2.36(s,1H),2.15(m,1H),2.10-1.89(m,3H),1.67-1.53(m,2H),1.52-1.35(m,2H),1.32(s,3H),1.29-1.17(m,3H),1.00(m,1H),0.94(s,3H),0.79(d,J=7.0Hz,3H),0.60(d,J=7.0Hz,3H).

[0141] Example 27 Preparation of 14-O-[3-(3-(Dihydroxyboranyl)benzamido)phenyl]thioacetyl moxilin (Compound 27)

[0142]

[0143] Weigh 100 mg of Ⅲ-B (0.21 mmol) and 45 mg of 3-bromomethylphenylboronic acid (0.21 mmol), dissolve them in 2 mL of acetonitrile, and add 10 mg of KI (0.07 mmol). The reaction system was stirred overnight under reflux conditions. After the reaction was completed, the organic solvent in the system was removed by distillation under reduced pressure to obtain a crude product. The crude product was dispersed in 5 mL of ethyl acetate and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 84.3 mg of Compound 27 with a yield of 65%. ESI-MS (m / z): 620.57 [M+H] + . 1 H NMR(500MHz,DMSO-D 6)δ 7.98 (s, 2H), 7.77 (t, J = 1.3 Hz, 1H), 7.66 (dt, J = 7.3, 1.3 Hz, 1H), 7.36 (dd, J = 6.9, 1.1 Hz, 1H), 7.27 (t, J = 6.8, Hz, 1H), 6.95 (t, J = 7.9 Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 6.47 (dd, J = 7.7, 1.8 Hz, 1H), 6.41 (dd, J = 8.2, 2.3 Hz, 1H), 6.07 (dd, J = 17.1, 11.9 Hz, 1H), 5.50 (d, J = 8.3 Hz, 1H), 5.03 - 4.94 (m, 2H), 4.50 (d, J = 6.1 Hz, 1H), 4.21 (d, J = 5.8 Hz, 2H), 3.71 (d, J = 15.6 Hz, 1H), 3.64 (d, J = 15.5 Hz, 1H), 3.39 (m, 1H), 2.37 (s, 1H), 2.23 - 1.94 (m, 4H), 1.62 (m, 2H), 1.52 - 1.38 (m, 2H), 1.33 (s, 3H), 1.25 (m, 3H), 1.01 (s, 3H), 0.99 (m, 1H), 0.81 (d, J = 7.0 Hz, 3H), 0.59 - 0.57 (m, 3H).

[0144] Example 28 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl)benzylamino)phenyl]thioacetyl moxilin (Compound 28)

[0145]

[0146] Weigh 100 mg of Ⅲ - B (0.21 mmol), dissolve 45 mg of 4 - (bromomethyl)phenylboronic acid (0.21 mmol) in 2 mL of acetonitrile, and add 10 mg of KI (0.07 mmol). The reaction system was stirred overnight under reflux conditions. After the reaction was completed, the organic solvents in the system were removed by distillation under reduced pressure to obtain the crude product. The crude product was dispersed in 5 mL of ethyl acetate and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 99.9 mg of Compound 28 with a yield of 77%. ESI - MS (m / z): 620.87 [M + H] + . 11H NMR (400 MHz, DMSO) δ 7.95 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 6.94 (t, J = 7.9 Hz, 1H), 6.55 (s, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 6.06 (dd, J = 17.8, 11.2 Hz, 1H), 5.50 (d, J = 8.2 Hz, 1H), 5.02 - 4.94 (m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 4.24 (d, J = 5.9 Hz, 2H), 3.70 (d, J = 15.2 Hz, 1H), 3.64 (d, J = 15.6 Hz, 1H), 3.40 (d, J = 6.1 Hz, 1H), 2.36 (s, 1H), 2.20 - 1.93 (m, 2H), 1.63 (t, J = 15.1 Hz, 2H), 1.45 (d, J = 10.7 Hz, 2H), 1.38 (s, 1H), 1.28 (d, J = 35.3 Hz, 5H), 1.22 - 1.09 (m, 1H), 1.01 (s, 1H), 1.01 (s, 2H), 0.95 (d, J = 9.6 Hz, 1H), 0.81 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.9 Hz, 3H).

[0147] Example 29 Preparation of 14 - O - [3 - (3 - (dihydroxyboranyl)phenylacetamido)phenyl]thioacetyl moxilin (Compound 29)

[0148]

[0149] Weigh 75.6 mg of 3 - (carboxymethyl)phenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution in sequence, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry them over anhydrous sodium sulfate, and purify them by column chromatography (methylene chloride:methanol = 20:1) to obtain 78.7 mg of Compound 29 with a yield of 58%. ESI - MS (m / z): 670.85 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 7.99 (s, 1H), 7.76 - 7.63 (m, 3H), 7.41 - 7.18 (m, 4H), 7.03 (t, J = 7.2 Hz, 1H), 6.09 (dd, J = 17.8, 11.2 Hz, 1H), 5.52 (d, J = 8.0 Hz, 1H), 5.03 (m, 2H), 4.44 (d, J = 5.8 Hz, 1H), 3.87 - 3.69 (m, 2H), 3.61 (s, 2H), 3.37 (m, 1H), 2.35 (s, 1H), 2.25 - 1.83 (m, 4H), 1.69 - 1.52 (m, 2H), 1.41 (m, 2H), 1.33 (s, 3H), 1.27 - 1.19 (m, 3H), 1.19 - 1.07 (m, 1H), 0.95 (s, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.57 (d, J = 6.7 Hz, 3H).

[0150] Example 30 Preparation of 14 - O - [3 - (4 - (dihydroxyboryl)phenylacetamido)phenyl]thioacetyl moxilin (Compound 30)

[0151]

[0152] Weigh 75.6 mg of 4 - (carboxymethyl)phenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 82.7 mg of Compound 30 with a yield of 61%. ESI - MS (m / z): 670.57 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.03 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 2.3 Hz, 1H), 7.21 (d, J = 7.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.03 (dd, J = 8.0, 3.0 Hz, 1H), 6.84 (dd, J = 7.5, 3.1 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 5.84 (dd, J = 18.5, 10.7 Hz, 1H), 5.30 (d, J = 8.1 Hz, 1H), 4.79 - 4.75 (m, 2H), 4.79 - 4.71 (m, 2H), 4.30 (d, J = 5.2 Hz, 1H), 3.61 (d, J = 15.8 Hz, 1H), 3.54 (d, J = 15.7 Hz, 1H), 3.43 (m, 2H), 3.19 (d, J = 5.9 Hz, 1H), 2.13 (s, 1H), 2.00 - 1.81 (m, 4H), 1.49 - 1.35 (m, 2H), 1.27 - 1.15 (m, 2H), 1.12 (s, 3H), 1.09 - 0.90 (m, 4H), 0.80 (s, 3H), 0.61 (d, J = 7.2 Hz, 3H), 0.37 (d, J = 7.2 Hz, 3H).

[0153] Example 31 Preparation of 14 - O - [3 - (5 - (dihydroxyboryl) - 3 - pyridinecarboxamido)phenyl]thioacetyl moxilin (Compound 31)

[0154]

[0155] Weigh 70.1 mg of 5 - carboxypyridine - 3 - boronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain 71.8 mg of Compound 31 with a yield of 30%. ESI - MS (m / z): 635.77 [M + H]+. 11H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 8.79 (d, J = 4.4 Hz, 2H), 8.56 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 8.4, 4.4 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.05 (dd, J = 17.8, 11.2 Hz, 3H), 5.53 (d, J = 8.1 Hz, 2H), 5.01 - 4.92 (m, 2H), 3.87 (d, J = 15.7 Hz, 1H), 3.81 (d, J = 15.7 Hz, 1H), 2.38 (s, 1H), 2.23 - 2.01 (m, 4H), 1.71 - 1.53 (m, 2H), 1.51 - 1.38 (m, 2H), 1.33 (s, 3H), 1.29 - 1.23 (m, 3H), 0.99 (m, 4H), 0.82 (d, J = 7.0 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H).

[0156] Example 32 Preparation of 14 - O - [3 - (5 - (dihydroxyboryl) - 2 - furanecarboxamido)phenyl]thioacetyl moxilin (Compound 32)

[0157]

[0158] Weigh 65.5 mg of 5 - boronic acid furan - 2 - carboxylic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 67.9 mg of Compound 32 with a yield of 52%. ESI - MS (m / z): 646.68 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.05 (dd, J = 17.7, 11.3 Hz, 1H), 5.52 (d, J = 8.2 Hz, 1H), 4.98 (d, J = 6.3 Hz, 1H), 4.94 (s, 1H), 3.86 (d, J = 15.7 Hz, 1H), 3.79 (d, J = 15.7 Hz, 1H), 3.40 (d, J = 5.2 Hz, 1H), 2.38 (s, 1H), 2.19 (dd, J = 19.2, 10.7 Hz, 1H), 2.14 - 1.91 (m, 2H), 1.70 - 1.55 (m, 2H), 1.50 - 1.36 (m, 2H), 1.33 (s, 3H), 1.29 - 1.20 (m, 3H), 0.99 (s, 3H), 1.06 - 0.89 (m, 1H), 0.82 (d, J = 6.9 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H).

[0159] Example 33 Preparation of 14 - O - [3 - (5 - (dihydroxyboryl) - 2 - thiophenecarboxamido)phenyl]thioacetyl moxilin (Compound 33)

[0160]

[0161] Weigh 72.2 mg of 5 - boronic acid furan - 2 - carboxylic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - B (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and purified by column chromatography (methylene chloride:methanol = 20:1) to obtain 76.4 mg of Compound 33, with a yield of 57%. ESI - MS (m / z): 662.77 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.45 (d, J = 3.8 Hz, 1H), 7.96 (t, J = 4.3 Hz, 1H), 7.80 (m, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.03 (dd, J = 17.7, 11.2 Hz, 1H), 5.50 (d, J = 8.0 Hz, 1H), 4.99 - 4.89 (m, 2H), 4.48 (d, J = 6.0 Hz, 1H), 3.84 (d, J = 15.8 Hz, 1H), 3.77 (d, J = 15.8 Hz, 1H), 3.38 (d, J = 6.3 Hz, 1H), 2.36 (s, 1H), 2.28 - 1.88 (m, 4H), 1.71 - 1.55 (m, 2H), 1.52 - 1.39 (m, 2H), 1.32 (s, 3H), 1.29 - 1.15 (m, 3H), 0.97 (s, 3H), 0.92 (m, 1H), 0.79 (d, J = 6.8 Hz, 3H), 0.659 (d, J = 6.8 Hz, 3H).

[0162] Example 34 Preparation of 14 - O - [4 - (3 - (dihydroxyboryl)benzamido)phenyl]thioacetyl mirimicin (Compound 34)

[0163]

[0164] Weigh 69.7 mg of 3 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 74.3 mg of Compound 34 with a yield of 56%. ESI - MS (m / z): 656.30 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), δ 7.94 (t, J = 1.5 Hz, 1H), 7.75 (dd, J = 8.1, 2.1 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.36 (dd, J = 8.2, 1.6 Hz, 2H), 6.06 (dd, J = 18.4, 11.9 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.04 - 4.96 (m, 2H), 3.79 (d, J = 15.5 Hz, 1H), 3.72 (d, J = 15.4 Hz, 1H), 3.39 (d, J = 5.9 Hz, 1H), 2.38 (s, 1H), 2.19 - 1.96 (m, 4H), 1.68 - 1.65 (m, 2H), 1.49 - 1.36 (m, 2H), 1.33 (s, 3H), 1.29 - 1.21 (m, 3H), 1.16 - 1.02 (m, 1H), 1.01 (s, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.59 (dd, J = 6.9, 2.3 Hz, 3H).

[0165] Example 35 Preparation of 14 - O - [4 - (3 - (dihydroxyboryl) - 4 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 35)

[0166]

[0167] Weigh 77.3 mg of 3 - carboxy - 2 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of III - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 66.9 mg of Compound 35 with a yield of 49%. ESI - MS (m / z): 674.49 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.40 (s, 2H), 8.17 (dd, J = 5.7, 2.6 Hz, 1H), 8.00 (m, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.29 - 7.17 (m, 1H), 6.07 (dd, J = 16.9, 12.0 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.06 - 4.94 (m, 2H), 3.79 (d, J = 15.5 Hz, 1H), 3.72 (d, J = 15.5 Hz, 1H), 3.57 (s, 1H), 2.37 (s, 1H), 2.23 - 1.96 (m, 4H), 1.68 - 1.55 (m, 2H), 1.50 - 1.33 (m, 2H), 1.33 (s, 3H), 1.28 - 1.19 (m, 3H), 1.01 (s, 3H), 0.97 (m, 1H), 0.80 (d, J = 7.0 Hz, 3H), 0.58 (d, J = 6.9 Hz, 3H).

[0168] Example 36 Preparation of 14 - O - [4 - (5 - (dihydroxyboryl) - 2 - fluorobenzamido)phenyl]thioacetyl mirincamycin (Compound 36)

[0169]

[0170] Weigh 77.3 mg of 3 - carboxy - 4 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 81.9 mg of Compound 36 with a yield of 60%. ESI - MS (m / z): 674.77 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.27 (d, J = 2.9 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.98 (m, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.44 - 7.24 (m, 3H), 6.08 (dd, J = 16.9, 10.5 Hz, 1H), 5.54 (d, J = 8.2 Hz, 1H), 5.06 - 4.97 (m, 2H), 4.52 (d, J = 6.3 Hz, 1H), 3.81 (d, J = 15.3 Hz, 1H), 3.74 (d, J = 15.4 Hz, 1H), 3.41 (t, J = 6.1 Hz, 1H), 2.40 (s, 1H), 2.25 - 1.96 (m, 4H), 1.73 - 1.58 (m, 2H), 1.54 - 1.38 (m, 2H), 1.35 (s, 3H), 1.28 - 1.24 (m, 3H), 1.03 (s, 3H), 0.97 (m, 1H), 0.83 (d, J = 6.9 Hz, 3H), 0.62 - 0.58 (d, J = 7.0 Hz, 3H).

[0171] Example 37 Preparation of 14 - O - [4 - (4 - (dihydroxyboryl)benzamido)phenyl]thioacetyl moxilin (Compound 37)

[0172]

[0173] Weigh 69.7 mg of 4 - carboxyphenylboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol), dissolve them in 2 mL of DMF, stir at room temperature for 30 min, then add 100 mg of III - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 71.7 mg of Compound 37 with a yield of 54%. ESI - MS (m / z): 656.65 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 7.94 - 7.87 (m, 4H), 7.79 (dd, J = 7.2 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 6.09 (dd, J = 17.7, 11.3 Hz, 1H), 5.54 (d, J = 8.1 Hz, 1H), 5.06 - 4.97 (m, 2H), 4.51 (s, 1H), 3.81 (d, J = 15.5 Hz, 1H), 3.74 (d, J = 15.4 Hz, 1H), 2.39 (s, 1H), 2.09 (m, 4H), 1.71 - 1.55 (m, 2H), 1.52 - 1.44 (m, 2H), 1.35 (s, 3H), 1.30 - 1.22 (m, 4H), 1.03 (s, 3H), 0.82 (d, J = 6.9 Hz, 3H), 0.60 (d, J = 6.9 Hz, 3H).

[0174] Example 38 Preparation of 14 - O - [4 - (4 - (dihydroxyboranyl) - 3 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 38)

[0175]

[0176] Weigh 77.3 mg of 4 - carboxy - 2 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 80.5 mg of Compound 38 with a yield of 59%. ESI - MS (m / z): 674.59 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.41 (m, 1H), 7.35 (d, J = 8.5 Hz, 2H), 6.07 (dd, J = 17.7, 11.2 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 5.05 - 4.96 (m, 2H), 3.78 (d, J = 15.4 Hz, 1H), 3.71 (d, J = 15.5 Hz, 1H), 3.39 (d, J = 5.8 Hz, 1H), 2.38 (s, 1H), 2.20 - 1.94 (m, 4H), 1.69 - 1.55 (m, 2H), 1.51 - 1.36 (m, 2H), 1.34 (s, 3H), 1.28 - 1.24 (m, 3H), 1.01 (s, 3H), 0.96 (m, 1H), 0.81 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H).

[0177] Example 39 Preparation of 14 - O - [4 - (4 - (dihydroxyboranyl) - 2 - fluorobenzamido)phenyl]thioacetyl moxilin (Compound 39)

[0178]

[0179] Weigh 77.3 mg of 4 - carboxy - 3 - fluorobenzeneboronic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of III - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system, and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 87.4 mg of Compound 39 with a yield of 77%. ESI - MS (m / z): 674.78 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 8.38 (s, 2H), 7.72 - 7.65 (m, 3H), 7.60 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.3 Hz, 2H), 6.07 (dd, J = 17.7, 10.5 Hz, 1H), 5.51 (d, J = 8.2 Hz, 1H), 5.03 - 4.94 (m, 2H), 3.79 (d, J = 15.1 Hz, 1H), 3.72 (d, J = 15.4 Hz, 1H), 3.39 (d, J = 5.9 Hz, 1H), 2.37 (s, 1H), 2.23 - 2.02 (m, 4H), 1.70 - 1.54 (m, 2H), 1.45 (d, J = 10.1 Hz, 2H), 1.33 (s, 3H), 1.27 - 1.22 (m, 3H), 1.01 (s, 3H), 0.95 (s, 1H), 0.80 (d, J = 6.9 Hz, 4H), 0.58 (d, J = 6.8 Hz, 3H).

[0180] Example 40 Preparation of 14 - O - [4 - (1,3 - Dihydro - 1 - hydroxy - 2,1 - benzoxaborol - 6 - carboxamido)phenyl]thioacetylmurin (Compound 40)

[0181]

[0182] Weigh 74.7 mg of 1 - hydroxy - 1,3 - dihydrobenzo[c][1,2]oxaborole - 6 - carboxylic acid (0.42 mmol), 121.7 mg of HATU (0.32 mmol), and 25.7 mg of DMAP (0.21 mmol) and dissolve them in 2 mL of DMF. After stirring at room temperature for 30 min, add 100 mg of Ⅲ - C (0.21 mmol) and 70 μL of DIPEA (0.44 mmol) to the reaction system and stir at room temperature for 6 h. After the reaction is completed, add 5 mL of ethyl acetate to dilute the reaction solution, wash the reaction solution successively with 5 mL of 1 M hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, combine the aqueous phases and extract the aqueous phases with 10 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 82.5 mg of Compound 40 with a yield of 62%. ESI - MS (m / z): 668.43 [M + Na] + . 11H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 9.36 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.03 (dd, J = 8.0, 1.7 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.06 (dd, J = 16.4, 10.9 Hz, 1H), 5.52 (d, J = 8.2 Hz, 1H), 5.07 (s, 2H), 5.05 - 4.93 (m, 2H), 4.49 (d, J = 6.1 Hz, 1H), 3.79 (d, J = 15.4 Hz, 1H), 3.72 (d, J = 15.4 Hz, 1H), 3.39 (t, J = 6.1 Hz, 1H), 2.37 (s, 1H), 2.20 - 1.94 (m, 4H), 1.68 - 1.53 (m, 2H), 1.50 - 1.34 (m, 2H), 1.33 (s, 3H), 1.30 - 1.14 (m, 3H), 1.01 (s, 3H), 0.97 (m, 1H), 0.80 (d, J = 6.9 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H).

[0183] Effect Example: In vitro antibacterial experiment

[0184] Experimental method

[0185] The microbroth dilution method was used to evaluate the in vitro antibacterial activity of the compound against different strains. The specific operation steps are as follows: Place the sterilized 96-well plate in the laminar flow hood. Add 200 μL of the bacterial solution diluted with CAMHB medium to the first column (about 5×10 5(CFU / mL). Starting from the second column, add 100 μL of the bacterial solution to each column. Take 4 μL of the test sample solution dissolved in DMSO at a concentration of 6.4 mg / mL and add it to each well in the first column in sequence. At the same time, set up a blank control group (without adding samples) and a positive drug group (tiamulin at a concentration of 6.4 mg / mL), and repeat each sample three times. After adding the samples, use an 8-channel micropipette to take 100 μL of the sample from the previous column and add it to the next column for 2-fold serial dilution. When adding the sample to the last well, after adding and mixing the liquid, then aspirate 100 μL of the liquid. The compound concentrations in each well after dilution are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 μg / mL respectively. Place the 96-well plate in an incubator at 37 °C for 18 - 20 h, and observe the growth status of the bacteria in each well. For each compound, starting from the well where the sample was added and counting backward, the compound concentration corresponding to the first well where no bacteria growth is observed is the minimum inhibitory concentration (MIC) of the compound. The strains used in the experiment are 8 strains of Staphylococcus aureus, 5 strains of Streptococcus pneumoniae, and 6 strains of Staphylococcus epidermidis.

[0186] The following table shows the MIC test results

[0187] Table - 1 In vitro antibacterial data of compounds

[0188]

[0189]

[0190] All target compounds showed good antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis, approaching or superior to the four marketed pleuromutilin drugs and other reported C22 - phenylthioether substituted derivatives. Among them, compounds 14 and 25 showed the best antibacterial activities against the above two strains.

[0191] Table - 2 In vitro antibacterial spectrum data of compounds 14 and 25

[0192]

[0193]

[0194] The above data indicate that the antibacterial activities of compounds 14 and 25 against standard or drug - resistant Staphylococcus aureus, Streptococcus pneumoniae, and Staphylococcus epidermidis are superior to the marketed drug Lefamulin in 2019.

[0195] Effect example: In vitro bactericidal curve

[0196] Experimental method

[0197] The original bacterial liquid in the logarithmic growth phase (OD 600 = 0.5) was diluted 100 times with CAMHB broth medium to obtain the bacterial liquid to be tested (about 5×10 5 CFU / mL), and it was added to a sterilized 96-well plate in a laminar flow hood. Prepare the sample solutions to be tested with the mother liquor concentrations of 25×, 50×, 100×, 200×, 400× MIC. Pipette 4 μL of each of the above sample solutions with different concentrations to be tested and add them to the bacterial liquid to be tested to obtain the medicated bacterial liquid containing the sample to be tested with the working concentrations of 0.5×, 1×, 2×, 4×, 8× MIC. At the same time, set up a blank control group (the bacterial liquid to be tested without the sample) and a positive drug group (the bacterial liquid containing tylosin at the working concentrations of 1×, 4× MIC). All the above samples were repeated three times. Place the 96-well plate in an incubator at 37 °C and take samples at the incubation times of 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h. After sampling, dilute step by step by 10 0 times to 10 -6 times. Pipette 100 μL and spread it on a TSA agar plate. After 24 hours, count the colonies, and the colony count is expressed as CFU / mL. The strain used in the experiment was Staphylococcus aureus MRSA strain USA300.

[0198] The experimental results are shown in Figure 1

[0199] The above embodiments are preferred implementation methods of the present invention, but the implementation methods of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A pleuromutilin derivative having an arylboronic acid fragment represented by formula (Ⅰa) or a pharmaceutically acceptable salt thereof: Wherein, Selected from L is selected from CH 2 , CO or CH 2 CO; Ring C is selected from a benzene ring, a six-membered nitrogen-containing heterocycle, a five-membered oxygen-containing heterocycle, and a five-membered sulfur-containing heterocycle; R 1 selected from hydrogen, fluorine, chlorine, trifluoromethyl, nitro, amino, methyl, methoxy; n is selected from 1, 2, 3, 4.

2. A pleuromutilin derivative having an arylboronic ester fragment represented by formula (Ⅰb) or a pharmaceutically acceptable salt thereof: Wherein, Selected from Selected from 3. A pleuromutilin derivative having an arylboronic ester fragment represented by formula (Ⅰc) or a pharmaceutically acceptable salt thereof: Wherein, Selected from t is selected from 1, 2.

4. The pleuromutilin derivative having an arylboronic acid fragment or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, in the pleuromutilin derivative having an arylboronic acid fragment represented by formula (Ⅰa), When L is CO, ring C is selected from a benzene ring, a six-membered nitrogen-containing heterocycle, a five-membered oxygen-containing heterocycle, a five-membered sulfur-containing heterocycle, R 1 is selected from hydrogen, fluorine, chlorine, trifluoromethyl, nitro, amino, methyl, methoxy, and n is selected from 1, 2, 3, 4; L is selected from CH 2 , CH 2 CO, when ring C is a benzene ring, R 1 is hydrogen and n is 4.

5. The pleuromutilin derivative having an arylboronic acid or arylboronic ester fragment according to any one of claims 1-4, characterized in that, the compound is selected from the following:

6. The preparation method of the pleuromutilin derivative having an arylboronic acid or arylboronic ester fragment according to any one of claims 1-5, characterized in that, comprises the following steps: (1) React pleuromutilin with p-toluenesulfonyl chloride, using dichloromethane as a solvent and triethylamine as an acid-binding agent to carry out a sulfonylation reaction to obtain intermediate (Ⅱ); (2) Use intermediate (Ⅱ) as a raw material, using potassium carbonate as an acid-binding agent, and carry out a nucleophilic substitution reaction with o / m / p-aminothiophenol in an aprotic dipolar solvent to obtain intermediate (Ⅲ); (3) When L is CO or CH 2 CO, an amide condensation reaction occurs by operating according to step (3A). When L is CH 2 , a nucleophilic substitution reaction occurs by operating according to step (3B) to obtain formula (Ia), (Ⅰb), the pleuromutilin derivative having an arylboronic acid or arylboronic ester fragment with the structure shown in (Ⅰc); (3A) Use intermediate (Ⅲ) as a raw material, using an aprotic dipolar solvent as a solvent, under the action of HATU condensing agent, N,N-diisopropylethylamine and DMAP, carry out an amide condensation reaction with boronic acid-based aryl acid or boronic ester-based aryl acid to obtain the pleuromutilin derivative having an arylboronic acid or arylboronic ester fragment with the structure shown in formula (Ⅰa), (Ⅰb), (Ⅰc). (3B) Use intermediate (Ⅲ) as a raw material, using acetonitrile as a solvent, react with boronic acid-based bromobenzyl overnight in the presence of potassium iodide to obtain the pleuromutilin derivative having an arylboronic acid fragment with the structure shown in formula (Ⅰa).

7. A pharmaceutical composition comprising a therapeutically effective amount of one or more pleuromutilin derivatives having an arylboronic acid or arylboronic ester fragment according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof as the main active ingredient, and pharmaceutically acceptable excipients.

8. The use of the pleuromutilin derivative having an arylboronic acid or arylboronic ester fragment according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating infectious diseases, wherein the infectious diseases are infections caused by Staphylococcus aureus, drug-resistant Staphylococcus aureus, Staphylococcus epidermidis, drug-resistant Staphylococcus epidermidis, Streptococcus pneumoniae, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Mycoplasma pneumoniae or Chlamydia pneumoniae, or infectious diseases caused by multi-drug resistant bacteria.

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