An oxabenzohexadiene borate compound, a preparation method and use thereof

Abstract

This invention relates to an oxobenzohexacyclic borate ester compound, its preparation method, and its uses, belonging to the pharmaceutical field. The derivatives of this invention are compounds represented by Formula I, or their salts, conformational isomers, or optical isomers. The oxobenzohexacyclic borate ester derivatives provided by this invention exhibit good, broad-spectrum inhibitory activity against clinically common metallo-β-lactamases (MBL) and serine β-lactamases (SBL), and show good antibacterial activity against various drug-resistant bacteria when used in combination with the β-lactam antibiotic meropenem. Therefore, the series of derivatives provided by this invention have great potential in the preparation of dual broad-spectrum inhibitors of MBL and SBL and in drugs to overcome β-lactam antibiotic-resistant bacteria. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial drug research, specifically relating to an oxobenzohexacyclic borate ester compound, its preparation method, and its uses. Background Technology

[0002] β- Lactam antibiotics are the most widely used small-molecule antibacterial drugs in clinical practice, with carbapenems often referred to as the "last line of defense against infection." However, an increasing number of pathogens have developed resistance, and the main reason for this resistance is... β- The production of lactamases is essential for the antibacterial function of antibiotics by hydrolyzing their components. β- The lactam ring. Depending on the different mechanisms of enzymatic hydrolysis of antibiotics, β- Lactamases are mainly divided into metalloenzymes. β- Lactamases (MBLs) and serine β- SBLs (Spiritual Breast Lambs) and MBLs primarily attack water molecules by activating one or two zinc ions at their active sites. β- The lactam ring is cleaved, and SBLs primarily attack the active site via nucleophilic serine residues. β-- The lactam ring is deactivated.

[0003] Currently, eight SBL inhibitors—clavulanic acid, sulbactam, avibactam, tazobactam, faborbactam, levobactam, dulobactam, and emmetzobactam—have been successfully approved for clinical use. However, these SBL-targeting drugs are almost ineffective against MBL-expressing resistant bacteria. In recent years, MBL-resistant bacteria have continued to emerge and spread, and are effective against almost all... β- Resistance to lactam antibiotics has become a global threat to human health. Although numerous MBL inhibitors have been reported, and some have shown promising in vitro and in vivo activity, none have yet been approved for clinical use, and very few have entered clinical trials. Currently, only two six-membered borate esters—VNRX-5133 and QPX-7728—are in Phase III and Phase I clinical trials, respectively. Therefore, developing dual-action inhibitors targeting both MBL and SBL / MBL remains a key focus of current research in the field of antimicrobial drugs.

[0004] The successful clinical trials of VNRX-5133 and QPX-7728 have revealed the superior potential of this type of backbone as a dual inhibitor of SBL / MBL. Therefore, this study aims to further explore the potential of six-membered cyclic borate esters and improve their enzyme and antibacterial spectra, which is of great significance for the development of antibacterial drugs. Summary of the Invention

[0005] To address the problems of existing technologies, this invention provides an oxobenzohexacyclic borosilicate ester compound, its preparation method, and its uses. The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof:

[0006] Formula I Wherein, R is selected from hydrogen, halogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C2-C10 ether, substituted or unsubstituted phenoxy, substituted or unsubstituted 4-10 heterocyclic alkoxy, substituted or unsubstituted 4-10 heterocyclic alkyl, substituted or unsubstituted spirocyclic; wherein, the substituent is selected from halogen, C1-C10 alkyl, C1-C5 alkoxy, amino, 4-10 heterocyclic alkyl, amidine, C1-C10 amino, C3-C10 aminocycloalkyl, C2-C10 ether.

[0007] Furthermore, the structure of the oxobenzo six-membered ring borate ester compound is shown in Formula II:

[0008] Formula II Wherein, R1 is selected from hydrogen, halogen, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2-C 10 The group is an ether group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted 4-membered azacycloalkoxy group; wherein the substituent is selected from fluorine, C1-C4 alkyl, methoxy, amino, amidoyl, C1-C3 amino, and C4-C6 aminocycloalkyl.

[0009] Furthermore, the structure of the oxobenzo six-membered ring borate ester compound is shown in Formula III:

[0010] Formula III Wherein, R1 is selected from hydrogen, halogen, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2-C 10 The group is an ether group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted 4-membered azacycloalkoxy group; wherein the substituent is selected from fluorine, C1-C4 alkyl, methoxy, amino, amidoyl, C1-C3 amino, and C4-C6 aminocycloalkyl.

[0011] Furthermore, the oxobenzocycloboronic ester compound is selected from:

[0012] Further, the salt is a sodium salt, and the salt of the oxobenzo six-membered ring borate ester compound is selected from:

[0013] The present invention also provides a pharmaceutical composition, which is a formulation prepared by adding pharmaceutically acceptable excipients to the above-mentioned oxobenzo six-membered ring borate esters, their stereoisomers or their salts as active ingredients.

[0014] This invention also provides the above-mentioned oxobenzohexacyclic borate esters, their stereoisomers, or salts thereof in the preparation of... β- Uses of lactamase inhibitors.

[0015] This invention also provides the use of the above-mentioned oxobenzohexacyclic borate esters, their stereoisomers, or salts thereof in combination with carbapenem antibiotics in the preparation of drugs against carbapenem-resistant bacteria; preferably, the carbapenem antibiotic is meropenem, and / or, the carbapenem-resistant bacteria are expressing... β- Drug-resistant bacteria of lactamase.

[0016] Furthermore, the aforementioned β- Lactamases are metalloenzymes β- Lactamase, serine β- Lactamase or metal β- Lactamase and serine β- Lactamase; preferably, the metal β- Lactamases are B1 subclass metalloids β- Lactamase, more preferably, the B1 subclass metalloenzyme. β- The lactamase is selected from VIM-1, VIM-2, NDM-1, NDM-5, IMP-1, and IMP-4; the serine... β- The lactamases were selected from class A (KPC-2, TEM-1, SHV-12, CTX-M-14), class C (AmpC), and class D (OXA-48).

[0017] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0018] The innovation of this invention lies in the successful application of PET technology to the field of antibacterial drugs, introducing radionuclides into the antibacterial skeleton benzohexacyclic borate ester, which has demonstrated excellent activity at both the enzyme and bacterial levels, and has also demonstrated efficacy in animals.

[0019] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0020] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0021] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0022] The following are the preparation methods for intermediate compounds:

[0023] Step 1: Synthesis of ethyl 3-bromo-2-hydroxy-6-methylbenzoate (A-2) Raw material B-1 (10 g, 43 mmol) was dissolved in dry DCM (64 ml), and tert-butyltrichloroacetylimide ester (11.5 ml, 64.3 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 2 h, filtered through diatomaceous earth, the filtrate was concentrated, n-pentane (50 ml) was added, and the mixture was filtered again. The filtrate was collected, and the solvent was evaporated to obtain intermediate B-2 (6 g, 48%).

[0024] Step 2: Synthesis of ethyl 3-bromo-2-hydroxy-6-methylbenzoate (A) Intermediate B-2 (6 g, 20.7 mmol) was dissolved in dry DMF (62 ml), and PMBCl (2.8 ml, 20.7 mmol) was added. The mixture was reacted at room temperature for 16 h, extracted with ethyl acetate and water, and the organic layers were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. Column chromatography was used to obtain intermediate compound B (4 g, 47%).

[0025] The following are examples of implementing the compounds of the present invention: Example 1: 7-(aminotriazolin-3-oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-1)

[0026] Step 1: Synthesis of tert-butyl 3-(4-bromo-2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)phenoxy)oxazoline-1-carboxylic acid ester (B-1) Starting material A (1 g, 2.44 mmol), N-Boc-3-hydroxyazacyclobutane (634 mg, 3.66 mmol), and CMBP (1.92 ml, 7.32 mmol) were dissolved in toluene (12.5 ml). The reaction was carried out overnight at 100 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The intermediate D-9 (620 mg, 45%) was obtained by column chromatography.

[0027] Step 2: Synthesis of tert-butyl 3-(2-(tert-butoxycarboxyl)-3-((4-methoxybenzyl)oxy)-4-vinylphenoxy)azabutane-1-carboxylic acid ester (C-1) Intermediate B-1 (620 mg, 1.1 mmol), n-tributylvinyltin (0.65 ml, 2.2 mmol), and Pd(PPh3)2Cl2 (77 mg, 0.11 mmol) were dissolved in dry Dioxane (3 ml). The reaction was carried out at 100 °C for 4 h under an argon atmosphere. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The solution was then removed by column chromatography to obtain intermediate C-1 (300 mg, 53%).

[0028] Step 3: Synthesis of tert-butyl 3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)phenoxy)azabutane-1-carboxylic acid ester (D-1) Intermediate C-1 (300 mg, 0.59 mmol), pinacol borane (0.13 ml, 0.71 mmol), dppe (19 mg, 0.047 mmol), and [IrCl(COD)]2 (16 mg, 0.024 mmol) were dissolved in dry DCM (5 ml) and reacted at room temperature under argon atmosphere for 16 h. The reaction was monitored by TLC until complete. The solvent was removed by evaporation, and intermediate D-1 (280 mg, 74%) was obtained by column chromatography.

[0029] Step 4: Synthesis of 7-(aminotriazolin-3-oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-1) Intermediate D-1 (280 mg, 0.44 mmol) was dissolved in Dioxane (2 ml), and TFA (3 ml) and TES (0.5 ml) were added. The mixture was reacted overnight at room temperature. The solvent was then evaporated, and the mixture was slurried with methanol and diethyl ether. The mixture was filtered to obtain a white solid crude product, which was purified by HPLC to obtain the final product L-1 (20 mg, 12%). ESI-MS: [M+H + ]: 264.1.

[0030] Example 2: 7-trans-3-aminocyclobutoxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-2)

[0031] Step 1: Synthesis of tert-butyl 3-bromo-6-((trans-(3-((tert-butylcarboxyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)benzoate (B-2) Intermediate B-2 (700 mg, 50%) was obtained by using cis-3-BOC aminocyclobutanol (686 mg, 3.66 mmol) as a starting material, following a similar synthetic method to intermediate B-1.

[0032] Step 2: Synthesis of tert-butyl 6-((trans-3-((tert-butoxycarbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-2) Using intermediate B-2 (700 mg, 1.21 mmol) as a starting material, intermediate C-2 (500 mg, 79%) was obtained by a similar synthetic method to intermediate C-1.

[0033] Step 3: Synthesis of tert-butyl 6-((trans-3-((tert-butoxycarbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (D-2) Using intermediate C-2 (500 mg, 0.95 mmol) as a starting material, intermediate D-2 (400 mg, 64%) was obtained by a similar synthetic method to intermediate D-1.

[0034] Step 4: Synthesis of 7-trans-3-aminocyclobutoxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-2) Using intermediate D-2 (400 mg, 0.61 mmol) as a starting material, L-2 (25 mg, 10%) was obtained by a similar synthetic method to that used for the final product L-1. 1 H NMR (400 MHz, D2O) δ 6.78 (d, J = 7.9 Hz, 1H), 6.07 (d, J = 7.5 Hz, 1H), 4.08-3.83 (m, 0.5H), 3.67-3.53 (m, 0.5H), 2.47 (t, J = 7.2 Hz, 2H), 2.42 – 2.29 (m, 2H), 2.26 – 2.09 (m, 2H), 0.26 (t, J = 7.2 Hz, 2H). 13 CNMR (101 MHz, D2O) δ 179.25, 166.76, 156.63, 153.56, 129.56, 125.66, 105.06,72.83, 45.13, 39.45, 28.78. ESI-MS: [M+H + ]: 278.1.

[0035] Example 3: 7-cis-3-aminocyclobutoxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-3)

[0036] Step 1: Synthesis of tert-butyl 3-bromo-6-(cis-(3-((tert-butylcarboxyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)benzoate (B-3) Intermediate B-3 (600 mg, 42%) was obtained by following a similar synthetic method to intermediate B-1, using trans-3-BOC aminocyclobutanol (686 mg, 3.66 mmol) as the starting material.

[0037] Step 2: Synthesis of tert-butyl 6-((cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-3) Intermediate C-3 (420 mg, 78%) was obtained by using intermediate B-3 (600 mg, 1.03 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0038] Step 3: Synthesis of tert-butyl 6-((cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (D-3) Using intermediate C-3 (420 mg, 0.80 mmol) as a starting material, intermediate D-3 (360 mg, 69%) was obtained by a similar synthetic method to intermediate D-1.

[0039] Step 4: Synthesis of 7-cis-3-aminocyclobutoxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-3) L-3 (15 mg, 6.9%) was obtained from intermediate D-3 (360 mg, 0.55 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 278.10.

[0040] Example 4: 7-((trans-4-aminocyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-4)

[0041] Step 1: Synthesis of tert-butyl-3-bromo-6-((trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)benzoate (B-4) Intermediate B-4 (400 mg, 27%) was obtained by using cis-N-4-BOC-aminocyclohexanol (788 mg, 3.66 mmol) as a starting material, following a similar synthetic method to intermediate B-1.

[0042] Step 2: Synthesis of tert-butyl 6-((trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-4) Intermediate C-4 (280 mg, 77%) was obtained by using intermediate B-3 (400 mg, 0.66 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0043] Step 3: Synthesis of tert-butyl 6-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)benzoate (D-4) Intermediate D-4 (180 mg, 52%) was obtained from intermediate C-4 (280 mg, 0.51 mmol) using a similar synthetic method as intermediate D-1.

[0044] Step 4: Synthesis of 7-((trans-4-aminocyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-4) Using intermediate D-4 (180 mg, 0.26 mmol) as a starting material, L-4 (10 mg, 9.1%) was obtained by a similar synthetic method to that used for the final product L-1. 1 H NMR (400 MHz, D2O) δ 6.84 (d, J = 7.0 Hz, 1H), 6.34(d, J = 7.8 Hz, 1H), 4.20-3.97 (m, 1H), 2.88-2.76 (m, 1H), 2.53 (t, J = 6.8 Hz,2H), 2.12-1.95 (m, 2H), 1.94-1.80 (m, 2H), 1.52-1.32 (m, 2H), 1.12-1.00 (m,2H), 0.32 (t, J = 6.8 Hz, 2H). ESI-MS: [M+H + ]: 306.1.

[0045] Example 5: 7-((cis-4-aminocyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-5)

[0046] Step 1: Synthesis of tert-butyl-3-bromo-6-((cis-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)benzoate (B-5) Intermediate B-5 (500 mg, 34%) was obtained from trans-N-4-BOC-aminocyclohexanol (788 mg, 3.66 mmol) using a similar synthetic method as intermediate B-1.

[0047] Step 2: Synthesis of tert-butyl 6-((cis-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-5) Intermediate C-5 (320 mg, 71%) was obtained by using intermediate B-5 (500 mg, 0.82 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0048] Step 3: Synthesis of tert-butyl 6-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)benzoate (D-5) Intermediate D-5 (200 mg, 50%) was obtained from intermediate C-5 (320 mg, 0.58 mmol) using a similar synthetic method as intermediate D-1.

[0049] Step 4: Synthesis of 7-((trans-4-aminocyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-5) L-5 (15 mg, 12%) was synthesized from intermediate D-5 (200 mg, 0.29 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 306.1.

[0050] Example 6: 7-((cis-4-aminocyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-6)

[0051] Step 1: Synthesis of benzyl 3-(4-bromo-2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)phenoxy)azacyclobut-1-carboxylic acid ester (B-6) Using intermediate A (4 g, 9.77 mmol) and 1-benzyloxycarbonyl-3-hydroxyazacyclobutane (3.24 g, 14.65 mmol) as starting materials, intermediate B-6 (3 g, 51%) was obtained by a similar synthetic method to intermediate B-1.

[0052] Step 2: Synthesis of benzyl 3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-vinylphenoxy)azacyclobut-1-carboxylate (C-6) Intermediate C-6 (1.5 g, 55%) was obtained from intermediate B-6 (3 g, 5 mmol) using a similar synthetic method as intermediate C-1.

[0053] Step 3: Synthesis of 3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)ethyl)phenoxy)azacyclobut-1-carboxylic acid ester (D-6) Using intermediate C-6 (1.5 g, 2.75 mmol) as a starting material, D-6 (1.2 g, 65%) was obtained by a similar synthetic method to that used for intermediate D-1.

[0054] Step 4: Synthesis of tert-butyl-6-(azatidine-3-yloxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)ethyl)benzoate (E-6) Intermediate D-6 (1.2 g, 1.78 mmol) was dissolved in methanol (9 ml) and ethyl acetate (9 ml), and 10% Pd / C (120 mg) was added. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by TLC until it was complete. The mixture was filtered, and the filtrate was evaporated to dryness to give intermediate E-6 (800 mg, 83%).

[0055] Step 5: Synthesis of tert-butyl(Z)-6-((1-(N,N'-bis(tert-butyloxycarbonyl)guanidinyl)aza-tetracyclic-3-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-6) Intermediate E-6 (500 mg, 0.92 mmol) was dissolved in THF (4 ml), and triethylamine (0.28 ml) and N,N'-di-BOC-S-methylisothiourea (348 mg, 1.02 mmol) were added. The mixture was reacted overnight at 50 °C. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate and water, and the organic phases were combined, washed with sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to column chromatography to obtain intermediate F-6 (150 mg, 21%).

[0056] Step 6: Synthesis of 7-((1-(2-fluoroethyl)azazolylbutyrate-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxazine-8-carboxylic acid (L-6) L-6 (15 mg, 0.19 mmol) was synthesized from intermediate F-6 (150 mg, 0.19 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 306.1.

[0057] Example 7: (S)-2-hydroxy-7-((1-prolyl-azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboron-8-carboxylic acid (L-7)

[0058] Step 1: Synthesis of tert-butyl(S)-2-(3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)phenoxy)azabutane-1-carboxyl)pyrrolidine-1-carboxylic acid ester (F-7) Intermediate E-6 (500 mg, 0.92 mmol), BOC-L-proline (198 mg, 0.92 mmol), EDCI (264 mg, 1.38 mmol), and HOBT (149 mg, 1.1 mmol) were dissolved in dry DMF (4.5 ml), and the mixture was reacted overnight at room temperature under an argon atmosphere. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate and water, and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain intermediate F-7 (350 mg, 52%).

[0059] Step 2: Synthesis of (S)-2-hydroxy-7-((1-prolyl-azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboron-8-carboxylic acid (L-7) L-7 (25 mg, 11%) was synthesized from intermediate F-7 (350 mg, 0.48 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 360.2.

[0060] Example 8: (R)-2-hydroxy-7-((1-prolyl-azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboron-8-carboxylic acid (L-8)

[0061] Step 1: Synthesis of tert-butyl(R)-2-(3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)phenoxy)azabutane-1-carboxyl)pyrrolidine-1-carboxylic acid ester (F-8) Using intermediate E-6 (500 mg, 0.92 mmol) and Boc-D-proline (198 mg, 0.92 mmol) as starting materials, intermediate F-8 (300 mg, 45%) was obtained by a similar synthetic method as intermediate F-7.

[0062] Step 2: Synthesis of (R)-2-hydroxy-7-((1-prolyl-azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboron-8-carboxylic acid (L-8) Using intermediate F-8 (300 mg, 0.41 mmol) as a starting material, L-8 (20 mg, 10%) was obtained by a similar synthetic method to that used for the final product L-1. 1 H NMR (400 MHz, D2O) δ 6.85 (d, J = 8.0 Hz, 1H), 6.11-5.95 (m, 1H), 5.05-4.92 (m, 1H), , 4.43-4.29 (m, 2H), 4.28-4.13 (m, 2H), 4.01(t, J = 13.6 Hz, 2H), 3.40 – 3.20 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.27-2.07(m, 1H), 1.93-1.74 (m, 3H), 0.33 (t, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, D2O) δ176.47, 175.70, 162.56, 154.38, 150.20, 127.14, 123.94, 101.24, 66.35, 58.23,57.34, 55.74, 46.98, 30.19, 26.27, 24.13, 23.73. ESI-MS: [M+H + ]: 360.2.

[0063] Example 9: 7-((1-(2-aminoethyl)azazolylbutyrate-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxazine-8-carboxylic acid (L-9)

[0064] Step 1: Synthesis of tert-butyl 6-((1-(N-(2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)tetra-3-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-9) Using intermediate E-6 (600 mg, 1.1 mmol) and tert-butyl((tert-butoxycarbonyl)amino(methylthio)methyl(2-aminoethyl)carbamate (572 mg, 1.32 mmol) as starting materials, intermediate F-9 (200 mg, 25%) was obtained by a similar synthetic method to intermediate F-6.

[0065] Step 2: Synthesis of 7-((1-(2-aminoethyl)azazolylbutyrate-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxazine-8-carboxylic acid (L-9) L-9 (15 mg, 8%) was synthesized from intermediate F-9 (200 mg, 0.41 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 349.2.

[0066] Example 10: 7-((1-(2-aminoethyl)azazolylbutyrate-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxazine-8-carboxylic acid (L-10)

[0067] Step 1: Synthesis of tert-butyl 6-((1-(N-(tert-butoxycarbonyl)sulfonamido)azabutane-3-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-10) Intermediate E-6 (560 mg, 1.04 mmol) and tert-butyl (chlorosulfonyl) carbamate (224 mg, 1.04 mmol) were dissolved in Py (6 ml) and reacted overnight at room temperature. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate and water, and the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to column chromatography to give intermediate F-10 (200 mg, 27%).

[0068] Step 2: Synthesis of 2-hydroxy-7-((1-sulfonamide azole butane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-10) L-10 (20 mg, 0.28 mmol) was synthesized from intermediate F-10 (200 mg, 0.28 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 343.1.

[0069] Example 11: (Z)-7-((1-(2-(2-aminothiazol-4-yl)-2-(methoxynitrile)acetyl)azabutane-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoroporin-8-carboxylic acid (L-11)

[0070] Step 1: Synthesis of tert-butyl(Z)-6-((1-(2-(2-aminothiazolyl-4-yl)-2-(methoxyimino)acetyl)azabutane-3-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)benzoate (F-11) Intermediate E-6 (500 mg, 0.92 mmol), AE-active ester (484 mg, 1.38 mmol), Et3N (0.26 ml, 1.84 mmol), and Py (0.15 ml, 1.84 mmol) were dissolved in DCM (4.5 ml) and EtOH (4.5 ml) and reacted overnight at room temperature. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate and water, and the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to column chromatography to give intermediate F-11 (260 mg, 39%).

[0071] Step 2: Synthesis of (Z)-7-((1-(2-(2-aminothiazolyl-4-yl)-2-(methoxynitrile)acetyl)azabutane-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoroporin-8-carboxylic acid (L-11) L-11 (16 mg, 10%) was synthesized from intermediate F-11 (260 mg, 0.36 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 447.1.

[0072] Example 12: 2-Hydroxy-7-((1-(thiophene-2-carboxyl)azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-12)

[0073] Step 1: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)-6-((1-(thiophene-2-carbonyl)azabutane-3-yl)oxy)benzoate (F-12) Using intermediate E-6 (500 mg, 0.92 mmol) and thiophene-2-carboxylic acid (484 mg, 0.92 mmol) as starting materials, intermediate F-12 (260 mg, 37%) was obtained by a similar synthetic method as intermediate F-7.

[0074] Step 2: Synthesis of 2-hydroxy-7-((1-(thiophene-2-carboxyl)azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoronine-8-carboxylic acid (L-12) L-12 (20 mg, 16%) was synthesized from intermediate F-12 (260 mg, 0.34 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 374.1.

[0075] Example 13: 2-Hydroxy-7-((1-(2-(thiophen-2-yl)acetyl)azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-13)

[0076] Step 1: Synthesis of tert-butyl-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)-6-((1-(2-(thiophene-2-yl)acetyl)azabutane-3-yl)oxy)benzoate (F-13) Using intermediate E-6 (500 mg, 0.92 mmol) and 2-thiopheneacetic acid (131 mg, 0.92 mmol) as starting materials, intermediate F-13 (220 mg, 36%) was obtained by a similar synthetic method to intermediate F-7.

[0077] Step 2: Synthesis of 2-hydroxy-7-((1-(2-(thiophen-2-yl)acetyl)azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-13) L-13 (10 mg, 8%) was synthesized from intermediate F-13 (220 mg, 0.33 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 388.1.

[0078] Example 14: 7-((1-(2-(trans-4-aminocyclohexyl)acetyl)azabutane-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoborene-8-carboxylic acid (L-14)

[0079] Step 1: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)-6-((1-(2-(thiophene-2-yl)acetyl)azabutane-3-yl)oxy)benzoate (F-14) Intermediate E-6 (500 mg, 0.92 mmol), trans-(N-BOC-4-aminocyclohexyl)acetic acid (284 mg, 1.1 mmol), PyBOP (574 mg, 1.1 mmol), and Et3N (0.38 ml, 2.76 mmol) were dissolved in DCM (2 ml), reacted overnight at room temperature, and the reaction was monitored by TLC until complete. The solution was evaporated to dryness and column chromatography was used to obtain intermediate F-14 (220 mg, 36%).

[0080] Step 2: Synthesis of 2-hydroxy-7-((1-(2-(thiophen-2-yl)acetyl)azabutane-3-yl)oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-14) L-14 (10 mg, 8%) was synthesized from intermediate F-14 (220 mg, 0.33 mmol) using a similar synthetic method to that used for the final product L-1. ESI-MS: [M+H + ]: 403.2.

[0081] Example 15: 7-((1-(2-aminoethyl)azabutane-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-15)

[0082] Step 1: Synthesis of tert-butyl 6-((1-(2-((tert-butoxycarbonyl)amino)ethyl)azacyclobutyl-3-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-15) Intermediate E-6 (600 mg, 1.08 mmol) and N-Boc-bromoethylamine (292 mg, 1.3 mmol) were dissolved in DMF (5 ml), and K2CO3 (300 mg, 2.16 mmol) was added. The mixture was reacted overnight at 50 °C. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was extracted with ethyl acetate and water. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography was used to obtain intermediate F-15 (180 mg, 24%).

[0083] Step 2: Synthesis of 7-((1-(2-aminoethyl)azabutane-3-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-15) Using intermediate F-15 (220 mg, 0.33 mmol) as a starting material, L-15 (14 mg, 10%) was obtained by a similar synthetic method to that used for the final product L-1. 1 H NMR (400 MHz, D2O) δ 6.82 (d, J = 8.1 Hz, 1H), 6.04(d, J = 7.8 Hz, 1H), 3.69 (t, J = 6.0 Hz, 2H), 3.24 – 3.16 (m, 2H), 2.98 (t, J =5.5 Hz, 1H), 2.63 – 2.56 (m, 2H), 2.52 (t, J = 5.5 Hz, 2H), 0.31 (t, J = 6.3Hz, 2H). 13 C NMR (101 MHz, D2O) δ 176.59, 164.45, 154.17, 150.49, 127.10, 123.53, 101.66, 67.47, 60.48, 57.92, 39.22, 26.22, 23.75. ESI-MS: [M+H + ]:307.1.

[0084] Example 16: 7-(trans-3-guanidinocyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-16)

[0085] Step 1: Synthesis of tert-butyl 6-(trans-3-((benzyloxy)carbonyl)amino)cyclobutoxy)-3-bromo-2-((4-methoxybenzyl)oxy)benzoate (B-7) Intermediate B-7 (2.7 g, 60%) was obtained from cis-benzyl 3-hydroxycyclobutylcarbamate (1.63 g, 7.35 mmol) using a similar synthetic method as intermediate B-1.

[0086] Step 2: Synthesis of tert-butyl 6-(trans-3-((benzyloxy)carbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-7) Using intermediate B-7 (2.7 g, 4.4 mmol) as a starting material, intermediate C-7 (1.53 g, 62%) was obtained by following a similar synthetic method to intermediate C-1.

[0087] Step 3: Synthesis of tert-butyl 6-(trans-3-((benzyloxy)carbonyl)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)benzoate (D-7) Intermediate D-7 (1.1 g, 58%) was obtained from intermediate C-7 (1.53 g, 2.74 mmol) using a similar synthetic method as intermediate D-1.

[0088] Step 4: Synthesis of tert-butyl 6-(trans-3-aminocyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)ethyl)benzoate (E-7) Using intermediate D-7 (1.1 g, 1.6 mmol) as a starting material, intermediate E-7 (700 mg, 79%) was obtained by a similar synthetic method to intermediate E-6.

[0089] Step 5: Synthesis of tert-butyl 6-(trans-3-((E)-2,3-bis(tert-butoxycarbonyl)guanidinyl)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-16) Using intermediate E-7 (700 mg, 1.26 mmol) as a starting material, intermediate F-16 (200 mg, 20%) was obtained by following a similar synthetic method to intermediate F-7.

[0090] Step 6: Synthesis of 7-(trans-3-guanidinocyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-16) Intermediate L-16 (15 mg, 14%) was obtained from intermediate F-16 (200 mg, 0.25 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 320.1.

[0091] Example 17: 7-(trans-3-guanidinocyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-17)

[0092] Step 1: Synthesis of tert-butyl 6-(trans-3-((E)-2,3-bis(tert-butoxycarbonyl)-3-(2-((tert-butoxycarbonyl)amino)ethyl)guanidinyl)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-17) Using intermediate E-7 (700 mg, 1.26 mmol) as a starting material, intermediate F-17 (150 mg, 13%) was obtained by following a similar synthetic method to intermediate F-7.

[0093] Step 2: Synthesis of 7-(trans-3-guanidinocyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-17) Intermediate L-17 (16 mg, 21%) was synthesized from intermediate F-17 (150 mg, 0.16 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 363.2.

[0094] Example 18: 2-Hydroxy-7-(trans-3-((S)-pyrrolidine-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-18)

[0095] Step 1: Synthesis of tert-butyl(S)-2-((trans-3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)phenoxy)cyclobutyl)carbamoyl)pyrrolidine-1-carboxylic acid ester (F-18) Using intermediate E-7 (500 mg, 0.9 mmol) as a starting material, intermediate F-18 (250 mg, 37%) was obtained by following a similar synthetic method to intermediate F-7.

[0096] Step 2: Synthesis of 2-hydroxy-7-(trans-3-((S)-pyrrolidine-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-18) Intermediate L-18 (20 mg, 12%) was synthesized from intermediate F-18 (250 mg, 0.33 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 375.2.

[0097] Example 19: 2-Hydroxy-7-(trans-3-((R)-pyrrolidine-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-19)

[0098] Step 1: Synthesis of tert-butyl(R)-2-((trans-3-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)phenoxy)cyclobutyl)carbamoyl)pyrrolidine-1-carboxylic acid ester (F-19) Using intermediate E-7 (500 mg, 0.9 mmol) as a starting material, intermediate F-19 (220 mg, 37%) was obtained by following a similar synthetic method to intermediate F-7.

[0099] Step 2: Synthesis of 2-hydroxy-7-(trans-3-((R)-pyrrolidine-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-19) Intermediate L-19 (12 mg, 8%) was obtained from intermediate F-19 (220 mg, 0.29 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H +]: 375.2.

[0100] Example 20: 2-Hydroxy-7-(trans-3-(thiophene-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-20)

[0101] Step 1: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaprozil-2-yl)ethyl)-6-(trans-3-(thiophene-2-carboxamide)cyclobutoxy)benzoate (F-20) Using intermediate E-7 (500 mg, 0.9 mmol) and thiophene-2-carboxylic acid (115 mg, 0.9 mmol) as starting materials, intermediate F-20 (230 mg, 39%) was obtained by following a similar synthetic method to intermediate F-7.

[0102] Step 2: Synthesis of 2-hydroxy-7-(trans-3-(thiophene-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-19) Intermediate L-20 (18 mg, 13%) was obtained from intermediate F-20 (230 mg, 0.35 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 388.1.

[0103] Example 21: 2-Hydroxy-7-(trans-3-(thiophene-2-carboxamido)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-21)

[0104] Step 1: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)-6-(trans-3-(2-(thiophene-2-yl)acetamido)cyclobutoxy)benzoate (F-21) Using intermediate E-7 (500 mg, 0.9 mmol) and 2-thiopheneacetic acid (128 mg, 0.9 mmol) as starting materials, intermediate F-21 (200 mg, 33%) was obtained by following a similar synthetic method to intermediate F-7.

[0105] Step 2: Synthesis of 2-hydroxy-7-(trans-3-(2-(thiophen-2-yl)acetamide)cyclobutoxy)-3,4-dihydro-2H-phenyl[e][1,2]oxoboroline-8-carboxylic acid (L-21) Using intermediate F-21 (200 mg, 0.3 mmol) as a starting material, intermediate L-21 (21 mg, 17%) was synthesized using a similar method to intermediate L-1. ESI-MS: [M+H + ]: 402.1.

[0106] Example 22: 7-(trans-3-((Z)-2-(2-aminothiazolyl-4-yl)-2-(methyleneoxyimine)acetamyl)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-22)

[0107] Step 1: Synthesis of tert-butyl 6-(trans-3-((Z)-2-(2-aminothiazo-4-yl)-2-(methoxyoxime)acetamido)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)benzoate (F-22) Using intermediate E-7 (500 mg, 0.9 mmol) and AE-active ester (473 mg, 1.35 mmol) as raw materials, intermediate F-22 (300 mg, 45%) was obtained by a similar synthetic method as intermediate F-11.

[0108] Step 2: Synthesis of 7-(trans-3-((Z)-2-(2-aminothiazolyl-4-yl)-2-(methyleneoxyimine)acetamyl)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-22) Intermediate L-22 (25 mg, 13%) was synthesized from intermediate F-22 (300 mg, 0.4 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 460.1.

[0109] Example 23: 2-Hydroxy-7-(trans-3-(sulfonamide)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-23)

[0110] Step 1: Synthesis of tert-butyl 6-(trans-3-((N-(tert-butoxycarbonyl)sulfonylamino)amino)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)ethyl)benzoate (F-23) Intermediate F-23 (180 mg, 27%) was obtained by using intermediate E-7 (500 mg, 0.9 mmol) and tert-butyl (chlorosulfonyl) carbamate (194 mg, 0.9 mmol) as starting materials, following a similar synthetic method to intermediate F-10.

[0111] Step 2: Synthesis of 2-hydroxy-7-(trans-3-(sulfonamide)cyclobutoxy)-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-23) Intermediate L-23 (20 mg, 23%) was obtained from intermediate F-23 (180 mg, 0.24 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 357.1.

[0112] Example 24: 7-(trans-3-(trans-4-aminocyclohexyl)acetamido)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzene[e][1,2]oxoboroline-8-carboxylic acid (L-24)

[0113] Step 1: Synthesis of tert-butyl 6-(trans-3-(2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetamyl)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)benzoate (F-24) Using intermediate E-7 (500 mg, 0.9 mmol) and trans-(N-BOC-4-aminocyclohexyl)acetic acid (284 mg, 1.1 mmol) as starting materials, intermediate F-24 (230 mg, 32%) was obtained by a similar synthetic method to intermediate F-14.

[0114] Step 2: Synthesis of 7-(trans-3-(trans-4-aminocyclohexyl)acetamyl)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoboroline-8-carboxylic acid (L-24) Intermediate L-24 (26 mg, 17%) was synthesized from intermediate F-24 (230 mg, 0.29 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 417.2.

[0115] Example 25: 7-(trans-3-(trans-4-aminocyclohexyl)acetamyl)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzene[e][1,2]oxoboroline-8-carboxylic acid (L-25)

[0116] Step 1: Synthesis of tert-butyl 6-(trans-3-(2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetamyl)cyclobutoxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)benzoate (F-25) Using intermediate E-7 (600 mg, 1.08 mmol) and N-Boc-bromoethylamine (292 mg, 1.3 mmol) as starting materials, intermediate F-25 (165 mg, 22%) was obtained by a similar synthetic method as intermediate F-15.

[0117] Step 2: Synthesis of 7-(trans-3-(trans-4-aminocyclohexyl)acetamyl)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoboroline-8-carboxylic acid (L-25) Intermediate L-25 (14 mg, 13%) was synthesized from intermediate F-25 (165 mg, 0.24 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 321.2.

[0118] Example 26: 7-(trans-3-(trans-4-aminocyclohexyl)acetamido)cyclobutoxy)-2-hydroxy-3,4-dihydro-2H-benzene[e][1,2]oxoboroline-8-carboxylic acid (L-26)

[0119] Step 1: Synthesis of benzyl 4-(4-bromo-2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)phenoxy)piperidine-1-carboxylic acid ester (B-8) Using benzyl 4-hydroxypiperidine-1-carboxylic acid ester (1.72 g, 7.33 mmol) as the starting material, intermediate B-8 (2.5 g, 82%) was obtained by a similar synthetic method to intermediate B-1.

[0120] Step 2: Synthesis of benzyl 4-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-vinylphenoxy)piperidine-1-carboxylic acid ester (C-8) Intermediate C-8 (1.7 g, 74%) was obtained by using intermediate B-8 (2.5 g, 4 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0121] Step 3: Synthesis of benzyl 4-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)phenoxy)piperidine-1-carboxylic acid ester (D-8) Intermediate D-8 (1.5 g, 72%) was obtained from intermediate C-8 (1.7 g, 2.96 mmol) using a similar synthetic method as intermediate D-1.

[0122] Step 4: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-6-(piperidin-4-oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (E-8) Using intermediate D-8 (1.5 g, 2.13 mmol) as a starting material, intermediate E-8 (1 g, 83%) was obtained by a similar synthetic method to intermediate E-6.

[0123] Step 5: Synthesis of tert-butyl 6-((1-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-26) Using intermediate E-8 (700 mg, 1.23 mmol) as a starting material, intermediate F-26 (200 mg, 23%) was obtained by a similar synthetic method to intermediate F-15.

[0124] Step 6: Synthesis of 7-((1-(2-aminoethyl)piperidin-4-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboroline-8-carboxylic acid (L-26) Intermediate L-26 (30 mg, 24%) was obtained from intermediate F-16 (200 mg, 0.28 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 335.2.

[0125] Example 27: 2-Hydroxy-7-(piperidin-4-oxy)-3,4-dihydro-2H-benzo[e][1,2]oxoborane-8-carboxylic acid (L-27)

[0126] Intermediate L-26 (25 mg, 12%) was obtained from intermediate E-8 (300 mg, 0.53 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 292.1.

[0127] Example 28: 7-((trans-4-((2-aminoethyl)amino)cyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoboridine-8-carboxylic acid (L-28)

[0128] Step 1: Synthesis of tert-butyl 6-((trans-4-(((benzyloxycarbonyl)amino)cyclohexyl)oxy)-3-bromo-2-((4-methoxybenzyl)oxy)benzoate (B-9) Using cis-N-Cbz-4-aminocyclohexanol (1.83 g, 7.33 mmol) as the starting material, intermediate B-9 (1.8 g, 58%) was obtained by a similar synthetic method to intermediate B-1.

[0129] Step 2: Synthesis of tert-butyl 6-((trans-4-(((benzyloxy)carbonyl)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-9) Intermediate C-9 (1.2 g, 73%) was obtained by using intermediate B-9 (1.8 g, 2.81 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0130] Step 3: Synthesis of tert-butyl 6-((trans-4-(((benzyloxycarbonyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)benzoate (D-9) Intermediate D-9 (1.1 g, 76%) was obtained from intermediate C-9 (1.2 g, 2.04 mmol) using a similar synthetic method as intermediate D-1.

[0131] Step 4: Synthesis of tert-butyl 6-((trans-4-aminocyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (E-9) Using intermediate D-9 (1.1 g, 1.53 mmol) as a starting material, intermediate E-9 (700 mg, 79%) was obtained by a similar synthetic method to intermediate E-6.

[0132] Step 5: Synthesis of tert-butyl-6-((trans-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)cyclohexyl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (F-28) Using intermediate E-8 (700 mg, 1.20 mmol) as a starting material, intermediate F-28 (120 mg, 14%) was obtained by a similar synthetic method to intermediate F-15.

[0133] Step 6: Synthesis of 7-((trans-4-((2-aminoethyl)amino)cyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoboridine-8-carboxylic acid (L-28) Intermediate L-28 (20 mg, 27%) was obtained from intermediate F-16 (120 mg, 0.16 mmol) using a similar synthetic method to intermediate L-1. ESI-MS: [M+H + ]: 349.2.

[0134] Example 29: 7-((6-aminospiro[3.3]heptane-2-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-29)

[0135] Step 1: Synthesis of tert-butyl 3-bromo-6-((6-((tert-butylcarboxyl)amino)spirocyclic[3.3]heptane-2-yl)oxy)-2-((4-methoxybenzyl)oxy)benzoate (B-10) Intermediate A (1 g, 2.44 mmol), 2-(BOC-amino)-6-hydroxyspiro[3.3]heptane (610 mg, 2.68 mmol), PPh3 (832 mg, 3.2 mmol) and DIAD (0.62 ml, 3.2 mmol) were dissolved in THF (15 ml) to give intermediate B-10 (500 mg, 33%).

[0136] Step 2: Synthesis of tert-butyl 6-((6-((tert-butyloxycarbonyl)amino)spiro[3.3]heptane-2-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-vinylbenzoate (C-10) Intermediate C-10 (250 mg, 55%) was obtained by using intermediate B-10 (500 mg, 0.81 mmol) as a starting material, following a similar synthetic method to intermediate C-1.

[0137] Step 3: Synthesis of tert-butyl 6-((6-((tert-butyloxycarbonyl)amino)spiro[3.3]hept-2-yl)oxy)-2-((4-methoxybenzyl)oxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)benzoate (D-10) Using intermediate C-10 (250 mg, 0.44 mmol) as a starting material, intermediate D-10 (217 mg, 71%) was obtained by a similar synthetic method to intermediate D-1.

[0138] Step 4: Synthesis of 7-((6-aminospiro[3.3]heptane-2-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-29) Using intermediate F-16 (217 mg, 0.31 mmol) as a starting material, intermediate L-29 (14 mg, 10%) was obtained by a similar synthetic method to intermediate L-1. 1 H NMR (400 MHz, D2O) δ 7.14-6.91 (m, 1H), 6.58-6.40 (m, 1H), 4.33-3.73 (m, 1H), 3.72-3.32 (m, 1H), 2.69 (t, J = 6.8 Hz, 1H),2.48 – 2.35 (m, 2H), 2.31-2.19 (m, 3H), 2.18 – 2.11 (m, 2H), 1.95 – 1.67 (m,2H), 0.48 (t, J= 8.0 Hz, 1H). ESI-MS: [M+H + ]: 318.1.

[0139] Example 30: 7-((trans-4-((2-aminoethyl)amino)cyclohexyl)oxy)-2-hydroxy-3,4-dihydro-2H-phenyl[e][1,2]oxoboridine-8-carboxylic acid (L-30)

[0140] Step 1: Synthesis of tert-butyl 6-(4-bromo-2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid ester (B-11) Using intermediate A (1 g, 2.44 mmol) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (571 mg, 2.68 mmol) as starting materials, intermediate B-11 (600 mg, 41%) was obtained by a similar synthetic method to intermediate B-10.

[0141] Step 2: Synthesis of tert-butyl 6-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-vinylphenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid ester (C-11) Using intermediate B-11 (600 mg, 0.99 mmol) as a starting material, intermediate C-11 (400 mg, 73%) was obtained by a similar synthetic method to intermediate C-1.

[0142] Step 3: Synthesis of tert-butyl 6-(2-(tert-butoxycarbonyl)-3-((4-methoxybenzyl)oxy)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)ethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid ester (D-11) Using intermediate C-11 (400 mg, 0.72 mmol) as a starting material, intermediate D-11 (350 mg, 76%) was obtained by a similar synthetic method to intermediate D-1.

[0143] Step 4: Synthesis of 7-((6-aminospiro[3.3]heptane-2-yl)oxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxoboridine-8-carboxylic acid (L-29) Using intermediate F-16 (350 mg, 0.51 mmol) as a starting material, intermediate L-30 (15 mg, 7%) was obtained by a similar synthetic method to intermediate L-1. 1H NMR (400 MHz, D2O) δ 6.84 (s, 1H), 6.16 (s, 1H), 4.56 (s, 1H), 3.98 (d, J = 11.4 Hz, 2H), 3.82 (d, J = 20.6 Hz, 2H), 2.80-2.43(m, 4H), 2.40-2.15 (m, 2H), 0.34 (s, 2H). ESI-MS: [M+H + ]: 304.1 The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0144] Experimental Example 1: Inhibitory activity of the compounds of the present invention against MBL and SBL 1. Test Methods The principle of the activity assay is that MBL and SBL enzymes catalyze the reaction of fluorescent substrates to produce fluorescent groups, and the fluorescence intensity reflects the enzyme activity. The activity assay is performed in a black 96-well microplate with a total reaction volume of 60 µL. The specific operating steps are as follows: (1) Prepare a stock solution of 100 mM by using DMSO to prepare a stock solution of the solid compound to be tested. Dilute the stock solution to 600 µM by using MBL activity test buffer (20 mM Tris-HCl pH 7.5, 200 mM NaCl, 0.01% Triton X-100) or SBL activity test buffer (PBS, 0.01% Triton X-100 or 50 mM HEPES, pH 7.2, 200 mM NaCl, 1 µg / ml BSA, 0.01% Triton X-100). Then dilute the working solution three times with the test buffer to obtain 10 working solutions of different concentrations.

[0145] (2) Prepare enzyme solutions of appropriate concentration using activity test buffer for the MBL enzymes to be tested (including VIM-2, NDM-1 and IMP-1) and SBL enzymes (KPC-2 and OXA-48).

[0146] (3) Prepare a 5 µM substrate solution of fluorescent substrate FC-5 with test buffer for later use.

[0147] (4) In a 96-well microplate, add 10 µL of the compound working solution obtained in step (1), 30 µL of test buffer and 10 µL of enzyme solution to each well, and incubate at room temperature for 10 minutes.

[0148] (5) After incubation, add 10 µL of fluorescent substrate solution to each well of a 96-well microplate and continuously monitor the fluorescence value change over 6 minutes using a microplate reader. The excitation wavelength λ for fluorescence detection is [not specified]. ex The emission wavelength is 380 nm, λ em It is 460 nm.

[0149] (6) Each experiment included a control well without the compound, and all measurements included three sets of parallel experiments.

[0150] Based on the changes in fluorescence intensity measured by the microplate reader, the residual enzyme activity in each well was calculated using the formula: Residual activity (%) = (ΔF1) / (ΔF2) × 100, where ΔF1 is the fluorescence change value in wells containing the test compound within a certain time period, and ΔF2 is the fluorescence change value in control wells without the compound within the same time period. The processed data were then fitted using GraphpadPrism 9.5 software to calculate the half-maximal inhibitory activity (IC50) of the enzyme. 50 value).

[0151] 2. Test Results The inhibitory activity of the compounds of this invention against MBL and SBL enzymes is shown in Table 1: Table 1. Inhibitory activities of the compounds of the present invention against MBL and SBL enzymes. a

[0152] a Note: +++++: IC 50 <10nM; ++++: 10nM <IC 50 <1 µM; +++: 1 µM <IC 50 <100 µM; ++: IC 50 >100µM.

[0153] The above experimental results demonstrate that the compounds of this invention exhibit good and broad-spectrum inhibitory activity against clinically important MBL enzymes (including NDM-1, IMP-1, and VIM-2). Specifically, compounds L-2, L-30, L-19, L-8, L-15, L-1, and L-4 show nanomolar inhibitory activity against NDM-1; compounds L-30 and L-19 show nanomolar inhibitory activity against IMP-1; and compounds L-30, L-19, L-8, L-15, L-1, and L-4 show nanomolar inhibitory activity against VIM-2. Compared with existing drugs tazobactam and avibactam, the compounds of this invention exhibit comparable or better inhibitory activity against the tested MBL enzymes; several compounds of this invention show comparable MBL inhibitory activity to taniborbactam, which is currently in the clinical evaluation stage. Similarly, the compounds of this invention exhibit good and broad-spectrum inhibitory activity against clinically important SBL enzymes (including KPC-2 and OXA-48). In this invention, almost all compounds (such as L-2 and L-30) exhibited nanomolar inhibitory activity against KPC-2 and OXA-48, demonstrating superior activity compared to the control drug tazobactam and comparable to avibactam and taniborbactam. In summary, the compounds of this invention exhibit good inhibitory effects against both MBL and SBL enzymes and can be used to prepare inhibitors with dual inhibitory effects on both MBL and SBL enzymes.

[0154] Test Example 2: Antibacterial activity of the compound of the present invention in combination with meropenem 1. Test Methods (1) Resuscitate the strain: Resuscitate the strain from the -80℃ refrigerator, streak it on non-resistant LB plates with an inoculation loop, and incubate at 37℃ for 18-20 h.

[0155] (2) Drug dilution: Weigh meropenem solid and dissolve it in DMSO to prepare a stock solution of 12.8 mg / mL. Dilute the stock solution with CAMHB medium to a working solution of 512 μg / mL. Add 100 µL of CAMHB to a clear 96-well plate, then add 100 µL of meropenem working solution. Then dilute 2-fold to obtain 9 concentrations and set up growth control wells without meropenem. Add 2 µL of the compound at a concentration of 1 mM to each well.

[0156] (3) Bacterial suspension dilution: Pick a single colony from the plate with an inoculation loop and place it in physiological saline, adjusting the OD600 to 0.08-0.13 (equivalent to 1×10⁻⁶). 8 (CFU / mL) This bacterial culture was diluted 100-fold with CAMHB, and 100 µL was added to each well. At this point, the meropenem concentration ranged from 128 μg / mL to 0.25 μg / mL, and the enzyme inhibitor concentration was 10 μM.

[0157] (4) Static incubation and result determination: Place the 96-well plate in a 37℃ incubator and incubate statically for 16-20 h. Observe the results the next day, and take the lowest concentration that can completely or significantly inhibit bacterial growth as the minimum inhibitory concentration (MIC) of meropenem.

[0158] 2. Test Results The antibacterial activity of the compounds of this invention in combination with meropenem against clinical isolates is shown in Tables 2 and 3: Table 2. Antibacterial activity of the compounds of the present invention in combination with meropenem against clinical isolates expressing SBL. a

[0159] Table 3. Antibacterial activity of the compounds of this invention in combination with meropenem against clinical isolates expressing MBL. a

[0160] a Note: ++++: MIC ≤ 4μg / ml; +++: 4μg / ml<MIC ≤ 16 μg / ml;++:MIC> 16 μg / ml.

[0161] The above experimental results demonstrate that the compounds of this invention, when used in combination with meropenem, exhibit good antibacterial activity against clinically isolated drug-resistant strains such as Klebsiella pneumoniae expressing KPC-2 and NDM-1, Escherichia coli expressing IMP-1, and Acinetobacter baumannii expressing OXA-23. For example, compounds L-2, L-30, L-19, L-8, L-15, L-4, L-27, L-3, L-9, L-22, and L-17, when used with meropenem, showed MIC values ​​less than or equal to 4 μg / ml against the tested clinically isolated drug-resistant bacteria, Klebsiella pneumoniae and Escherichia coli. These compounds showed antibacterial activity against Klebsiella pneumoniae expressing KPC-2 comparable to the control drug avibactam, while their antibacterial activity against Escherichia coli expressing IMP-1 and Klebsiella pneumoniae expressing NDM-1 was significantly superior to avibactam. Some compounds (such as L-9) could also restore the sensitivity of Acinetobacter baumannii expressing OXA-23 to meropenem.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that, The structural formula of the oxobenzohexacyclic borate ester is shown in Formula I: Formula I in, R is selected from hydrogen, halogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C2-C10 ether, substituted or unsubstituted phenoxy, substituted or unsubstituted 4-10 heterocyclic alkoxy, substituted or unsubstituted 4-10 heterocyclic alkyl, substituted or unsubstituted spirocyclic; wherein the substituent is selected from halogen, C1-C10 alkyl, C1-C5 alkoxy, amino, 4-10 heterocyclic alkyl, amidine, C1-C10 amino, C3-C10 aminocycloalkyl, C2-C10 ether.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that: The structural formula of the compound is shown in Formula II: Formula II Wherein, R1 is selected from hydrogen, halogen, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2-C 10 The group is an ether group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted 4-membered azacycloalkoxy group; wherein the substituent is selected from fluorine, C1-C4 alkyl, methoxy, amino, amidoyl, C1-C3 amino, and C4-C6 aminocycloalkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that, The structural formula of the compound is shown in Formula III: Formula III Wherein, R1 is selected from hydrogen, halogen, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2-C 10 The group is an ether group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted 4-membered azacycloalkoxy group; wherein the substituent is selected from fluorine, C1-C4 alkyl, methoxy, amino, amidoyl, C1-C3 amino, and C4-C6 aminocycloalkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that, The compound represented by Formula I has one of the following structures: 。 5. The oxobenzohexacyclic borate ester compound, its stereoisomer, or its salt according to claim 4, characterized in that, The salt is a sodium salt, and the salt of the compound is selected from: 。 6. A pharmaceutical composition, characterized in that, It is a formulation made with the oxobenzo six-membered ring borate ester compound, its stereoisomer or salt thereof as the active ingredient, plus pharmaceutically acceptable excipients.

7. The oxobenzohexacyclic borate ester compound, its stereoisomer, or its salt as described in any one of claims 1-5, in the preparation of β- Uses of lactamase inhibitors.

8. The use of the oxobenzohexacyclic borate ester compound, its stereoisomer, or a salt thereof as described in any one of claims 1-5, in combination with a carbapenem antibiotic in the preparation of a medicament against carbapenem-resistant bacteria; preferably, the carbapenem antibiotic is meropenem and / or the carbapenem-resistant bacteria are expressing... β- Drug-resistant bacteria of lactamase.

9. The use according to claim 6 or 7, characterized in that, The β- Lactamases are metalloenzymes β- Lactamase, serine β- Lactamase or metal β- Lactamase and serine β- Lactamase.

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