A series of boronic acids and their preparation and use

Abstract

This invention provides a series of cycloboronic acid compounds, their preparation methods, and applications, belonging to the fields of medicinal chemistry and pharmaceuticals. This invention prepares a series of cycloboronic acid compounds, with specific structures shown in Formula I. These compounds exhibit significant inhibitory efficacy against serine and metallo-β-lactamases. The compounds prepared in this invention have good application potential in the preparation of highly effective and safe inhibitors of serine and metallo-β-lactamases. Formula I

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceuticals, specifically relating to a series of cycloboronic acid compounds, their preparation methods, and applications. Background Technology

[0002] β-lactam antibiotics, as the most widely used antibacterial drugs in clinical practice, exert their bactericidal effect by competitively binding to penicillin-binding proteins (PBPs) to inhibit bacterial cell wall synthesis. However, the emergence of bacterial resistance has severely weakened their clinical efficacy. Currently known resistance mechanisms mainly include: mutations at PBP target sites, expression of efflux pumps, altered outer membrane permeability, and the production of β-lactamases. Among these, Gram-negative bacteria primarily mediate resistance through the production of β-lactamases, which specifically hydrolyze the β-lactam ring, leading to antibiotic inactivation.

[0003] According to the Ambler molecular classification system, β-lactamases can be divided into four categories: A, B, C, and D. Categories A, C, and D belong to serine β-lactamases (SBLs), whose active site contains a key serine residue; category B consists of metallo-β-lactamases (MBLs), characterized by zinc ion-dependent carbapenemase activity. Four novel β-lactamase inhibitors approved in recent years (avibactam, vaborbactam, relebactam, and durlobactam) are effective against most SBLs, but have no inhibitory effect on MBLs (except for vaborbactam, which exhibits weak activity), highlighting the urgent need for MBL inhibitor development. Bicyclic borate compounds VNRX-5133 (which has completed Phase III clinical trials) and QPX-7728... Although possessing broad-spectrum inhibitory activity, the former (QPX-7728) exhibits strong selectivity for VIM-type MBLs but is ineffective against IMP-type MBLs, while the latter's efficacy is limited by its high plasma protein binding rate, which may affect its efficacy. The IC50 of QPX-7728 against different metalloenzymes is disclosed in the literature (DOI:10.1021 / acs.jmedchem.9b01976). 50 The values ​​were: IMP-1: 0.22 ± 0.05 μM; NDM-1: 0.032 ± 0.014 μM, and their inhibitory activity against metalloenzymes needs to be further improved.

[0004] Therefore, developing novel MBL inhibitors that combine high efficacy and safety remains an important research direction in the field of anti-infectives. Summary of the Invention

[0005] In view of the problems existing in the prior art, the purpose of this invention is to provide a series of cycloboronic acid compounds, their preparation methods and applications.

[0006] This invention provides compounds of Formula I, or salts thereof, or stereoisomers thereof, or solvates thereof, or their crystal forms thereof: Formula I Where R is selected from 0 to 3 R A The following groups are substituted: phenyl, phenyl 5-6 membered unsaturated heterocycle, phenyl 5-6 membered saturated heterocycle, 5-6 membered unsaturated heterocycle, naphthyl, 5-6 membered unsaturated heterocycle, and 5-6 membered unsaturated heterocycle; R A Each is independently selected from halogens, -LSO2R B amino, hydroxyl, C 1~5 Alkyl group, -CONR C R D amino-substituted C 1~5 Alkyl, C 1~5 Alkyl, halogen-substituted C 1~5 C-substituted alkyl, cyano, oxo, phenyl, or hydroxyl groups 1~5 Alkyl, 3-6 membered saturated cycloalkyl, 5-6 membered saturated heterocycle, -NHCOR E nitro, carboxyl, -L 1 NR 1 R 2 ; L is selected from none, C 1~5 Alkylene, NH; R B Selected from C 1~5 Alkyl, C 1~5 alkoxy- or halogen-substituted C 1~5 Alkyl, hydroxyl substituted C 1~5 alkyl; R C R D Each is independently selected from hydrogen and C. 1~5 alkyl; R E Selected from amino-substituted C 1~5 Alkyl, C 1~5 alkoxy- or halogen-substituted C 1~5 Alkyl, hydroxyl substituted C 1~5 alkyl; L 1 Selected from C 1~5 Alkylene; R 1 R 2 Each is independently selected from hydrogen and C. 1~5 alkyl.

[0007] Furthermore, R is selected from 0 to 3 Rs. AThe following groups are substituted: phenyl, phenyl 5-6 membered unsaturated heterocycle, phenyl 5-6 membered saturated heterocycle, 5-6 membered unsaturated heterocycle, naphthyl, 5-6 membered unsaturated heterocycle, and 5-6 membered unsaturated heterocycle; R A Each is independently selected from halogens, -LSO2R B amino, hydroxyl, C 1~3 Alkyl group, -CONR C R D amino-substituted C 1~3 Alkyl, C 1~3 Alkyl, halogen-substituted C 1~3 C-substituted alkyl, cyano, oxo, phenyl, or hydroxyl groups 1~3 Alkyl, 3-6 membered saturated cycloalkyl, 5-6 membered saturated heterocycle, -NHCOR E nitro, carboxyl, -L 1 NR 1 R 2 ; L is selected from none, C 1~3 Alkylene, NH; R B Selected from C 1~3 alkyl; R C R D Each is independently selected from hydrogen and C. 1~3 alkyl; R E Selected from amino-substituted C 1~3 alkyl; L 1 Selected from C 1~3 Alkylene; R 1 R 2 Each is independently selected from hydrogen and C. 1~3 alkyl.

[0008] Furthermore, R is selected from 0 to 3 Rs. A The following groups are substituted: , , , , , , , , , .

[0009] Furthermore, the structure of the compound is as shown in Formula II or Formula III: Formula II Formula III Among them, R A As mentioned above; m is selected from 0, 1, 2 or 3.

[0010] Furthermore, the structure of the compound is shown in Formula IV or Formula V: Formula IV Formula V Among them, R A As mentioned above; m is selected from 0, 1, 2 or 3.

[0011] Furthermore, the compound is selected from one of the following compounds: .

[0012] The present invention also provides the use of the above-mentioned compounds, or their salts, or their stereoisomers, or their solvates, or their crystal forms, in the preparation of serine enzyme inhibitors and / or metallo-β-lactamase inhibitors.

[0013] Furthermore, the inhibitor is an antibacterial adjuvant.

[0014] The present invention also provides the use of the above-mentioned compound, or its salt, or its stereoisomer, or its solvate, or its crystal form, in combination with an antibiotic in the preparation of an antibacterial agent; wherein the bacteria are preferably antibiotic-resistant Escherichia coli, Klebsiella pneumoniae, or Acinetobacter baumannii, and the antibiotic is preferably a β-lactam antibiotic.

[0015] The present invention also provides a pharmaceutical composition, which is a pharmaceutical preparation made by using the above-mentioned compound, or its salt, or its stereoisomer, or its solvate, or its crystal form as the active ingredient, plus pharmaceutically acceptable excipients.

[0016] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[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] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0019] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a- C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1~5 "Alkyl" refers to an alkyl group containing 1 to 5 carbon atoms.

[0020] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C 1~5 Alkyl groups are alkyl groups having 1 to 5 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. C 1~5 Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), and pentyl (n-pentyl, isopentyl and neopentyl).

[0021] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0022] The term "salt" refers to the above-mentioned compounds, acidic and / or basic salts formed with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts), and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromates, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0023] The term "solvate" refers to a complex formed by the combination of one or more solvent molecules with a compound. This includes, but is not limited to, hydrates.

[0024] Compared with the prior art, the present invention has achieved the following beneficial effects: This invention prepared a series of cycloboronic acid compounds. These compounds exhibit significant inhibitory efficacy against serine and metallo-β-lactamases. The compounds prepared in this invention have good application potential in the preparation of highly efficient and safe inhibitors of serine and metallo-β-lactamases. Specifically: 1. For Gram-negative bacteria producing serine and metallo-β-lactamases (SBLs / MBLs): The representative compound of this invention, when used in combination with meropenem (MEM), exhibits potent synergistic antibacterial activity against clinically multidrug-resistant isolates, including those producing broad-spectrum β-lactamases (ESBLs), carbapenemases (such as KPC, serine enzymes), and IMP and NDM-type metallo-β-lactamases. Its antibacterial spectrum is broader, and its antibacterial efficacy is significantly superior to the currently available clinical β-lactamase inhibitor Taniborbactam, effectively compensating for the latter's insufficient inhibitory efficacy against widely prevalent metalloenzymes such as IMP and NDM.

[0025] 2. For refractory Acinetobacter baumannii infection: The representative compound of this invention (such as compound 052) in combination with meropenem showed outstanding antibacterial efficacy against drug-resistant Acinetobacter baumannii clinical isolates, including those producing class D carbapenemase (OXA), which was significantly better than the combination of sulbactam / durlobactaml, providing a more promising new option for the treatment of Acinetobacter baumannii infection in critical situations such as ICU and ventilator-associated postoperative infections.

[0026] 3. Inhibitory efficacy and drug development potential: The half-maximal inhibitory concentration (IC50) of the compounds of this invention against the key metallo-β-lactamases IMP-1 and NDM-1 is... 50 The excellent levels of <0.1 μM and <0.01 μM, respectively, indicate that they possess potent enzyme inhibitory activity. Considering their comprehensive in vitro and in vivo antibacterial efficacy, the cycloboronic acid compounds of this invention demonstrate great application potential and clinical value in developing into a new generation of broad-spectrum, highly effective, and safe β-lactamase inhibitors to address the increasingly serious carbapenem-resistant Gram-negative bacterial infections.

[0027] 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.

[0028] 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 embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0029] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0030] Example 1: Preparation of the compound Route 1 is the preparation process of 001. Step a: At 65 °C, DMAP (39.3 g, 321.9 mmol) was added in portions to a solution of 3-bromo-2,6-dihydroxybenzoic acid (25 g, 107.3 mmol) and di-tert-butyl dicarbonate (117.1 g, 536.5 mmol) in THF (300 ml) and tert-butanol (150 ml) until a large number of bubbles were generated and the solution changed from turbid to clear, indicating complete conversion. The solution was concentrated to dryness, redissolved in DCM (500 ml), washed with dilute hydrochloric acid (0.2 N), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude product B2 containing excess di-tert-butyl dicarbonate, calculated according to quantitative yield.

[0031] Step b: To a solution of B2 (16.7 g, 34.1 mmol) in isopropanol (150 ml), potassium vinyltrifluoroborate (9.1 g, 68.3 mmol), triethylamine (5.2 g, 51.2 mmol), and Pd(dppf)Cl2 (1.25 g, 1.7 mmol) were added. The mixture was purged three times with a nitrogen balloon and stirred at 85 °C for 8 h. The solvent was removed by concentration, and the residue was resuspended in EA, washed with water, and the organic phase was concentrated to dryness. The solution was purified by column chromatography (1–15% ethyl acetate in hexane) to give a colorless oily substance B3 (8.6 g, 57.7%).

[0032] 1 H NMR (400 MHz, Chloroform- d ) δ 7.57 (d, J = 8.6 Hz, 1H), 7.10 (d, J =8.7, 0.5 Hz, 1H), 6.73 (dd, J = 17.6, 11.1 Hz, 1H), 5.74 (dd, J = 17.6, 1.0 Hz, 1H), 5.37 (dd, J = 11.1, 1.0 Hz, 1H), 1.57 (s, 9H), 1.54 (s, 9H), 1.52 (s, 9H). Steps c, d, and e: Add (Ir(COD)Cl)₂ (0.66 g, 0.98 mmol), DPPE (0.78 g, 1.97 mmol), and pinacol borane (3.8 g, 29.6 mmol) to a DCM (150 ml) solution of B3 (8.6 g, 19.7 mmol) and stir overnight at ambient temperature. After the starting material is completely consumed, concentrate to remove the solvent to obtain a crude product containing B4, which requires no further purification.

[0033] The crude B4 obtained in the previous step was redissolved in THF (100 ml), and (+)-pinanediol (5.0 g, 29.6 mmol) was added. The mixture was stirred at 60 °C for 4 hours. After TLC showed complete conversion of the starting material, the temperature was lowered to 30 °C, and tetrahydropyrrole (1.4 g, 19.7 mmol) was added at this temperature. The mixture was stirred for another hour. After TLC showed complete conversion of the starting material, the mixture was concentrated to dryness and purified by column chromatography (1-20% ethyl acetate in hexane solution) to obtain colorless oily substance B6 (6.2 g, 60.9%, 3 steps).

[0034] 1 H NMR (400 MHz, Chloroform- d ) δ 11.26 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.24 (dd, J = 8.8, 2.0 Hz, 1H), 3.46 – 3.17 (m,2H), 2.68 – 2.49 (m, 2H), 2.40 – 2.26 (m, 1H), 2.23 – 2.11 (m, 1H), 2.02 (t, J = 5.6 Hz, 1H), 1.94 – 1.86 (m, 1H), 1.86 – 1.75 (m, 1H), 1.61 (s, 9H), 1.54(s, 9H), 1.46 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H), 1.14 – 1.06 (m, 2H). Step f: At -78 °C, a DCM solution of trifluoromethanesulfonic anhydride (3.7 g, 13.2 mmol) in 5 ml of DCM was slowly added dropwise to a DCM solution of B6 (6.2 g, 12.0 mmol) and triethylamine (1.6 g, 15.6 mmol) in 70 ml of water. After the addition was complete, the mixture was slowly brought to room temperature and stirred at that temperature for 1 hour. The mixture was then concentrated to dryness, and the crude product was suspended in PE, filtered through a diatomaceous earth liner, and the filter cake was washed with PE. The filtrate was concentrated to dryness to obtain crude B7 (6.1 g, 78.4%), which did not require further purification.

[0035] Step g: B7 (300 mg, 0.46 mmol), phenylboronic acid (56 mg, 0.46 mmol), Pd(dppf)Cl2 (17 mg, 0.023 mmol), and K2CO3 (130 mg, 0.92 mmol) were added to a mixed solvent of 1,4-dioxane (4 mL) and H2O (1 mL). The mixture was purged three times with a nitrogen balloon, and stirred at 100 °C for 4 hours. The solvent was removed by concentration, and the residue was resuspended in EA, washed with water, and the organic phase was concentrated to dryness. The solution was purified by column chromatography (5–20% ethyl acetate in hexane) to give a colorless oily substance B8 (93 mg, 34.9%).

[0036] Step h: B8 (89 mg, 0.15 mmol) and isobutylboronic acid (31 mg, 0.3 mmol) were dissolved in acetonitrile (5 ml), and then 1,4-dioxane hydrochloride (4 N, 5 ml) was added. The mixture was stirred overnight at ambient temperature. TLC showed that the starting material was completely converted. The solution was concentrated to dryness, purified by prep-HPLC (mobile phase: acetonitrile, water containing 1‰ TFA), and lyophilized to give a white solid 001 (17 mg, 41.1%).

[0037] 001: 1 H NMR (400 MHz, Methanol- d 4) δ 7.69 – 6.80 (m, 7H), 2.83 (t, J =7.9 Hz, 2H), 1.13 (t, J = 7.8 Hz, 2H). Route 2 is the preparation process of 031. Step a: At 60 °C, DMAP (0.8 g, 6.6 mmol) was added in portions to a solution of 3-bromo-2-hydroxybenzoic acid (0.72 g, 3.3 mmol) and di-tert-butyl dicarbonate (2.9 g, 13.3 mmol) in THF (15 ml) and tert-butanol (8 ml), and the mixture was stirred at this temperature for 1 hour. The solution was concentrated to dryness, redissolved in DCM (60 ml), washed with dilute hydrochloric acid (0.2 N), and the organic phase was concentrated to dryness. The solution was purified by column chromatography (5–20% ethyl acetate in hexane) to give a colorless oil B10 (0.54 g, 43.6%).

[0038] Step b: To a solution of B10 (0.54 g, 1.45 mmol) in isopropanol (15 ml), potassium vinyltrifluoroborate (0.39 g, 2.9 mmol), triethylamine (0.22 g, 2.2 mmol), and Pd(dppf)Cl2 (53 mg, 0.07 mmol) were added. The mixture was purged three times with a nitrogen balloon and stirred at 85 °C for 8 h. The solvent was removed by concentration, and the residue was resuspended in EA, washed with water, and the organic phase was concentrated to dryness. The solution was purified by column chromatography (1–15% ethyl acetate in hexane) to give a colorless oily compound B11 (0.3 g, 64.7%).

[0039] 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 – 7.76 (m, 1H), 7.75 – 7.62 (m,1H), 7.25 – 7.19 (m, 1H), 7.01 – 6.76 (m, 1H), 5.84 – 5.60 (m, 1H), 5.50 –5.33 (m, 1H), 1.59 – 1.56 (m, 9H), 1.56 – 1.52 (m, 9H). Step c: Add (Ir(COD)Cl)2 (32 mg, 0.047 mmol), DPPE (37 mg, 0.094 mmol), and pinacol borane (0.18 g, 1.41 mmol) to a DCM (10 ml) solution of B11 (0.3 g, 0.94 mmol) and stir at ambient temperature for 2 hours. TLC showed that the starting material was completely consumed. The solution was concentrated to remove the solvent and purified by column chromatography (1-15% ethyl acetate in hexane) to obtain a pale green oily substance B12 (244 mg, 58.1%).

[0040] 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 – 7.55 (m, 1H), 7.53 – 7.35 (m,1H), 7.23 – 7.06 (m, 1H), 2.78 – 2.65 (m, 2H), 1.63 – 1.50 (m, 18H), 1.34 –1.12 (m, 12H), 1.16 – 1.01 (m, 2H). Step d: Following the synthesis step d in compound 001, compound 031 was prepared by prep-HPLC and lyophilized to obtain a white solid.

[0041] Following the preparation steps of route one or two, compounds 002-065 were prepared. The structures of 001-065 are as follows: .

[0042] 002: 1 H NMR (400 MHz, Methanol- d 4) δ 7.52 – 7.37 (m, 2H), 7.24 (d, J =7.8 Hz, 1H), 7.11 (t, J = 8.8 Hz, 2H), 7.04 – 6.87 (m, 1H), 2.83 (t, J = 7.8 Hz, 2H), 1.13 (t, J = 7.8 Hz, 2H). 003: 1 H NMR (400 MHz, Methanol- d 4) δ 7.56 (t, J = 7.8 Hz, 1H), 7.38 –7.25 (m, 3H), 7.02 (s, 1H), 4.55 (s, 2H), 2.99 (s, 3H), 2.87 (t, J = 7.9 Hz, 2H), 1.17 (t, J = 7.8 Hz, 2H). 004: 1 H NMR (400 MHz, Methanol- d 4) δ 9.31 (s, 1H), 8.14 (s, 1H), 8.12(d, J= 8.3 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.13 –6.99 (m, 1H), 2.89 (t, J = 7.9 Hz, 2H), 1.19 (t, J = 7.8 Hz, 2H). 005: 1 H NMR (400 MHz, Methanol- d 4) δ 7.48 – 6.72 (m, 5H), 2.83 (t, J =7.7 Hz, 2H), 1.13 (t, J = 7.9 Hz, 2H). 006: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.71 (d, J = 8.2 Hz, 1H), 7.57(d, J = 1.7 Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.72(d, J = 7.6 Hz, 1H), 2.74 (t, J = 7.1 Hz, 2H), 0.48 (t, J = 7.0 Hz, 2H). 007: 1 H NMR (400 MHz, Methanol- d 4) δ 7.51 – 7.35 (m, 1H), 7.06 – 6.87(m, 1H), 2.89 – 2.67 (m, 2H), 1.98 – 1.86 (m, 2H), 1.87 – 1.72 (m, 4H), 1.72– 1.58 (m, 2H), 1.56 – 1.34 (m, 1H), 1.09 (t, J = 7.9 Hz, 2H). 008: 1 H NMR (400 MHz, Methanol- d4) δ 7.43 – 7.36 (m, 2H), 7.29 – 7.20(m, 3H), 7.01 – 6.88 (m, 1H), 2.98 (s, 3H), 2.82 (t, J = 7.9 Hz, 2H), 1.12 (t, J = 7.8 Hz, 2H). 009: 1 H NMR (400 MHz, Methanol- d 4) δ 7.24 (d, J = 8.1 Hz, 2H), 7.19 (d, J =7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.86 – 6.65 (m, 2H), 2.81 (t, J = 7.8 Hz,2H), 1.12 (t, J = 7.8 Hz, 2H). 010: 1 H NMR (400 MHz, Methanol- d 4) δ 7.33 (d, J = 8.2 Hz, 2H), 7.20 (d, J =7.8 Hz, 1H), 7.00 – 6.76 (m, 3H), 3.81 (s, 3H), 2.82 (t, J = 7.9 Hz, 2H), 1.12(t, J = 7.8 Hz, 2H). 011: 1 H NMR (400 MHz, Methanol- d 4) δ 7.98 – 7.80 (m, 2H), 7.50 (d, J =8.0 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.05 – 6.88 (m, 1H), 2.84 (t, J = 7.8 Hz,2H), 1.14 (t, J = 7.8 Hz, 2H). 012: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.37 (d,J = 8.1 Hz, 2H), 7.26(d, J = 7.9 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 3.70 (s,2H), 2.59 (t, J = 7.1 Hz, 2H), 0.33 (t, J = 7.1 Hz, 2H). 013: 1 H NMR (400 MHz, Methanol- d 4) δ 7.38 (s, 4H), 7.25 (d, J = 7.8 Hz,1H), 6.94 (s, 1H), 2.83 (t, J = 7.9 Hz, 2H), 1.13 (t, J = 7.8 Hz, 2H). 014: 1 H NMR (400 MHz, Methanol- d 4) δ 7.29 (d, J = 7.8 Hz, 2H), 7.27 –7.16 (m, 3H), 6.98 – 6.89 (m, 1H), 2.82 (t, J = 7.8 Hz, 2H), 2.36 (s, 3H), 1.12(t, J = 7.8 Hz, 2H). 015: 1 H NMR (400 MHz, Methanol- d 4) δ 7.27 (d, J = 7.7 Hz, 1H), 7.06 –6.75 (m, 4H), 2.83 (t, J = 7.9 Hz, 2H), 1.13 (t, J = 7.9 Hz, 2H). 016: 1 H NMR (400 MHz, Methanol- d 4) δ 7.72 (d, J = 8.1 Hz, 2H), 7.69 –7.55 (m, 2H), 7.33 (d,J = 7.7 Hz, 1H), 7.06 – 6.92 (m, 1H), 2.88 (t, J = 7.9 Hz,2H), 1.18 (t, J = 7.9 Hz, 2H). 017: 1 H NMR (400 MHz, Methanol- d 4) δ 7.41 – 7.31 (m, 2H), 7.27 – 7.18(m, 3H), 7.03 – 6.77 (m, 1H), 2.92 (p, J = 7.0 Hz, 1H), 2.83 (t, J = 7.8 Hz, 2H),1.27 (d, J = 7.0 Hz, 6H), 1.13 (t, J = 7.8 Hz, 2H). 018: 1 H NMR (400 MHz, Methanol- d 4) δ 7.47 (t, J = 9.2 Hz, 4H), 7.27 (d, J =7.8 Hz, 1H), 7.05 – 6.82 (m, 1H), 3.11 (s, 3H), 3.04 (s, 3H), 2.84 (t, J = 7.9Hz, 2H), 1.13 (t, J = 7.8 Hz, 2H). 019: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.84 – 7.57 (m, 1H), 7.49 –7.21 (m, 2H), 7.05 – 6.82 (m, 1H), 6.56 (t, J = 7.2 Hz, 1H), 2.79 – 2.41 (m,2H), 0.54 – 0.15 (m, 2H). 020: 1 H NMR (400 MHz, Methanol- d4) δ 7.70 – 7.61 (m, 4H), 7.55 – 7.48(m, 2H), 7.47 – 7.40 (m, 2H), 7.38 – 7.30 (m, 1H), 7.26 (d, J = 7.7 Hz, 1H),7.06 – 6.94 (m, 1H), 2.84 (t, J = 7.9 Hz, 2H), 1.14 (t, J = 7.8 Hz, 2H). 021: 1 H NMR (400 MHz, Methanol- d 4) δ 7.48 – 7.35 (m, 4H), 7.25 (d, J =7.8 Hz, 1H), 7.00 – 6.89 (m, 1H), 4.67 (s, 2H), 2.83 (t, J = 7.8 Hz, 2H), 1.13(t, J = 7.8 Hz, 2H). 022: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.37 (d, J = 8.5 Hz, 2H), 7.03(d, J = 8.4 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.83 (t, J =4.8 Hz, 4H), 3.11 (t, J = 4.8 Hz, 4H), 2.58 (t, J = 7.1 Hz, 2H), 0.33 (t, J = 7.1Hz, 2H). 023: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.42 – 7.36 (m, 2H), 7.35 –7.28 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 2.87 (t, J= 6.6Hz, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.51 – 2.40 (m, 2H), 0.33 (t, J = 7.0 Hz, 2H). 024: 1 H NMR (400 MHz, Methanol- d 4) δ 9.25 (s, 1H), 8.19 – 8.02 (m, 2H),7.60 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.03 (s, 1H), 2.85 (t, J = 7.8Hz, 2H), 1.15 (t, J = 7.9 Hz, 2H). 025: 1 H NMR (400 MHz, Methanol- d 4) δ 7.51 (t, J = 8.3 Hz, 1H), 7.35 –7.14 (m, 3H), 7.06 – 6.88 (m, 1H), 3.02 (s, 3H), 2.83 (t, J = 7.8 Hz, 2H), 1.13(t, J = 7.8 Hz, 2H). 026: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.38 (d, J = 8.2 Hz, 2H), 7.05(d, J = 8.4 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 3.28 –2.99 (m, 4H), 2.97 – 2.74 (m, 4H), 2.59 (t, J = 7.0 Hz, 2H), 0.34 (t, J = 7.0 Hz,2H). 027: 1 H NMR (400 MHz, Methanol- d4) δ 7.44 – 7.22 (m, 3H), 7.21 – 7.13(m, 1H), 7.13 – 7.04 (m, 1H), 6.84 (s, 1H), 2.81 (t, J = 7.9 Hz, 2H), 1.14 (t, J = 7.8 Hz, 2H). 028: 1 H NMR (400 MHz, Methanol- d 4) δ 7.45 – 7.34 (m, 1H), 7.26 (d, J =7.8 Hz, 1H), 7.23 – 6.89 (m, 4H), 2.83 (t, J = 7.9 Hz, 2H), 1.13 (t, J = 7.8 Hz,2H). 029: 1 H NMR (400 MHz, Methanol- d 4) δ 7.46 – 7.39 (m, 2H), 7.27 – 7.21(m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.08 – 7.01 (m, 1H), 2.81 (t, J = 7.8 Hz, 2H),1.11 (t, J = 7.8 Hz, 2H). 030: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.78 (d, J = 8.0 Hz, 2H), 7.46(d, J = 8.0 Hz, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 2.62 (t, J =7.1 Hz, 2H), 0.36 (t, J = 7.1 Hz, 2H). 031: 1 H NMR (400 MHz, Methanol- d 4) δ 7.69 (d, J= 8.0, 1.8 Hz, 1H), 7.33(d, J = 7.4 Hz, 1H), 6.79 (t, J = 7.7 Hz, 1H), 2.70 (t, J = 8.1 Hz, 2H), 1.09 (t, J =8.1 Hz, 2H). 032: 1 H NMR (400 MHz, Methanol- d 4) δ 7.18 (d, J = 7.8 Hz, 1H), 7.06 (d, J =7.9 Hz, 1H), 6.99 (d, J = 14.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.24 (s, 3H),1.11 (t, J = 7.8 Hz, 2H). 033: 1 H NMR (400 MHz, Methanol- d 4) δ 7.22 (d, J = 7.9 Hz, 1H), 7.16 –7.05 (m, 1H), 7.06 – 6.96 (m, 1H), 6.87 – 6.71 (m, 1H), 2.82 (t, J = 7.9 Hz,2H), 2.08 (s, 3H), 1.13 (t, J = 7.8 Hz, 2H). 034: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.13 (dd, J = 5.7, 2.0 Hz, 1H),7.00 – 6.78 (m, 2H), 6.64 – 6.49 (m, 1H), 2.63 – 2.45 (m, 2H), 0.31 (t, J = 7.1Hz, 2H). 035: 1 H NMR (400 MHz, Deuterium Oxide) δ 6.73 – 6.64 (m, 2H), 6.63 –6.53 (m, 1H), 6.39 (d,J = 7.7 Hz, 1H), 2.32 (t, J = 7.1 Hz, 2H), 0.07 (t, J = 7.1Hz, 2H). 036: 1 H NMR (400 MHz, Methanol- d 4) δ 7.30 – 7.18 (m, 2H), 6.94 – 6.79(m, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.08 (s, 3H), 1.13 (t, J = 8.0 Hz, 2H). 037: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.46 – 7.39 (m, 1H), 7.39 –7.36 (m, 1H), 7.32 – 7.05 (m, 1H), 6.99 – 6.89 (m, 1H), 6.84 – 6.66 (m, 1H),2.59 (t, J = 7.0 Hz, 2H), 0.33 (t, J = 7.1 Hz, 2H). 038: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.38 – 7.21 (m, 1H), 7.17 –7.11 (m, 1H), 7.07 – 6.97 (m, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 7.7 Hz,1H), 2.57 (t, J = 7.1 Hz, 2H), 0.32 (t, J = 7.1 Hz, 2H). 039: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.77 (d, J = 7.9 Hz, 1H), 7.69(d, J= 7.8 Hz, 1H), 7.41 – 7.31 (m, 1H), 7.30 – 7.13 (m, 2H), 6.96 – 6.78 (m,1H), 6.78 – 6.62 (m, 1H), 2.62 – 2.44 (m, 2H), 0.26 (t, J = 7.0 Hz, 2H). 040: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.61 (d, J = 7.8 Hz, 2H), 7.35(t, J = 7.6 Hz, 2H), 7.31 – 7.21 (m, 2H), 7.19 – 7.09 (m, 1H), 6.99 – 6.86 (m,1H), 6.76 – 6.67 (m, 1H), 2.71 – 2.43 (m, 2H), 0.31 (t, J = 7.1 Hz, 2H). 041: 1 H NMR (400 MHz, Methanol- d 4) δ 7.37 – 7.20 (m, 4H), 7.16 (d, J =7.8 Hz, 1H), 6.84 (s, 1H), 2.73 (t, J = 7.9 Hz, 2H), 1.03 (t, J = 7.8 Hz, 2H). 042: 1 H NMR (400 MHz, Methanol- d 4) δ 7.99 – 7.86 (m, 1H), 7.62 (s, 1H),7.46 (s, 1H), 7.42 – 7.25 (m, 3H), 7.02 (s, 1H), 2.88 (t, J = 7.9 Hz, 2H), 1.19(t, J = 7.9 Hz, 2H). 043: 1 H NMR (400 MHz, Methanol- d 4) δ 7.10 (d, J= 7.7 Hz, 1H), 6.91 –6.65 (m, 4H), 5.86 (s, 2H), 2.71 (t, J = 7.8 Hz, 2H), 1.02 (t, J = 7.8 Hz, 2H). 044: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.53 (s, 1H), 7.44 – 7.34 (m,1H), 7.34 – 7.21 (m, 1H), 7.02 – 6.84 (m, 1H), 6.68 – 6.15 (m, 1H), 2.74 –2.45 (m, 2H), 0.53 – 0.09 (m, 2H). 045: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.31 – 7.21 (m, 2H), 7.16 –7.06 (m, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 2.52 (t, J = 7.1Hz, 2H), 2.22 (s, 3H), 0.27 (t, J = 7.1 Hz, 2H). 046: 1 H NMR (400 MHz, Methanol- d 4) δ 7.97 (d, J = 8.0 Hz, 2H), 7.79 –7.50 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.06 – 6.87 (m, 1H), 3.54 – 3.18 (m,3H), 2.84 (t, J = 7.8 Hz, 2H), 1.14 (t, J = 7.8 Hz, 2H). 047: 1H NMR (400 MHz, Deuterium Oxide) δ 7.78 – 7.60 (m, 2H), 7.58 –7.37 (m, 2H), 7.08 – 6.87 (m, 1H), 6.69 – 6.32 (m, 1H), 2.76 – 2.21 (m, 2H),0.76 – -0.34 (m, 2H). 048: 1 H NMR (400 MHz, Methanol- d 4) δ 7.81 (s, 1H), 7.70 – 7.44 (m, 2H),7.28 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 4.49 (s, 2H), 3.01 – 2.65 (m, 2H), 1.14(t, J = 7.9 Hz, 2H). 049: 1 H NMR (400 MHz, Deuterium Oxide) δ 8.13 (d, J = 8.5 Hz, 2H), 7.55(d, J = 8.4 Hz, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 2.68 –2.52 (m, 2H), 0.32 (t, J = 7.1 Hz, 2H). 050: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.96 – 7.74 (m, 4H), 7.55 (d, J = 8.7 Hz, 1H), 7.50 – 7.38 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 7.9Hz, 1H), 2.68 – 2.43 (m, 2H), 0.40 – 0.16 (m, 2H). 051: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 (d, J= 8.0 Hz, 2H), 7.23(d, J = 8.1 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.63 – 6.43 (m, 1H), 2.68 – 2.47(m, 2H), 2.40 (s, 3H), 0.38 – 0.24 (m, 2H). 052: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 (d, J = 8.0 Hz, 2H), 7.23(d, J = 8.1 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.63 – 6.43 (m, 1H), 2.68 – 2.47(m, 2H), 2.40 (s, 3H), 0.38 – 0.24 (m, 2H). 053: 1 H NMR (400 MHz, D2O) δ 7.51 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.56(dd, J = 7.6, 1.8 Hz, 1H), 6.31 (t, J = 1.9 Hz, 1H), 3.69 (d, J = 1.8 Hz, 3H), 2.68(t, J = 7.0 Hz, 2H), 0.42 (t, J = 7.1 Hz, 2H). 054: 1 H NMR (400 MHz, D2O) δ 7.63 (d, J = 18.6 Hz, 2H), 6.89 (d, J = 7.9Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 3.77 (s, 3H), 2.56 – 2.51 (m, 2H), 0.32 –0.28 (m, 2H). 055: 1 H NMR (400 MHz, D2O) δ 7.56 (s, 1H), 6.96 (d, J= 7.7 Hz, 1H), 6.79(d, J = 7.7 Hz, 1H), 6.50 (s, 1H), 2.59 (s, 2H), 0.33 (s, 2H). 056: 1 H NMR (400 MHz, D2O) δ 7.78 (s, 1H), 7.65 (s, 1H), 6.89 (d, J = 7.8Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 5.47 (s, 1H), 4.20 (s, 1H), 3.03 (d, J = 12.8Hz, 2H), 2.64 – 2.48 (m, 3H), 2.01 (d, J = 12.8 Hz, 2H), 1.81 – 1.67 (m, 2H),0.30 (t, J = 7.1 Hz, 2H). 057: 1 H NMR (400 MHz, D2O) δ 7.76 (s, 1H), 7.65 – 7.60 (m, 1H), 6.89(d, J = 7.8 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 3.58 – 3.49 (m, 1H), 2.56 (t, J =7.1 Hz, 2H), 1.03 – 0.90 (m, 4H), 0.32 (t, J = 7.1 Hz, 2H). 058: 1 H NMR (400 MHz, D2O) δ 7.41 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.48(d, J = 7.6 Hz, 1H), 3.70 (s, 3H), 2.56 (t, J = 7.1 Hz, 2H), 2.09 (s, 3H), 0.32(t, J = 7.0 Hz, 2H). 059: 1 H NMR (400 MHz, D2O) δ 6.92 (d, J= 7.6 Hz, 1H), 6.33 (d, J = 7.5 Hz,1H), 2.58 (t, J = 6.9 Hz, 2H), 1.98 (s, 6H), 0.33 (t, J = 7.1 Hz, 2H). 060: 1 H NMR (400 MHz, D2O) δ 7.75 (d, J = 2.4 Hz, 1H), 7.70 – 7.64 (m,1H), 6.91 (d, J = 7.7 Hz, 1H), 6.66 (dd, J = 7.6, 2.4 Hz, 1H), 4.34 – 4.02 (m,2H), 2.82 – 2.73 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.14 (s, 6H), 0.33 (t, J =7.1 Hz, 2H). 061: 1 H NMR (400 MHz, DMSO) δ 8.66 – 8.35 (m, 2H), 7.71 – 7.41 (m,2H), 7.08 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 1.4 Hz, 1H), 2.69 (t, J = 7.1 Hz, 2H),0.42 (t, J = 7.1 Hz, 2H). 062: 1 H NMR (400 MHz, D2O) δ 8.97 (s, 1H), 8.83 – 8.63 (m, 1H), 7.04(d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 2.63 (t, J = 7.1 Hz, 2H), 0.36 (t, J =7.1 Hz, 2H). 063: 1 H NMR (400 MHz, D2O) δ 6.86 (d, J= 7.6 Hz, 1H), 6.62 – 6.26 (m,1H), 5.72 – 5.64 (m, 1H), 3.28 – 3.15 (m, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.54(t, J = 7.0 Hz, 2H), 2.33 – 2.13 (m, 2H), 0.30 (t, J = 7.0 Hz, 2H). 064: 1 H NMR (400 MHz, D2O) δ 6.75 (d, J = 7.7 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 5.78 (d, J = 5.5 Hz, 1H), 3.60 – 3.37 (m, 2H), 2.75 – 2.48 (m, 1H), 2.43(t, J = 7.1 Hz, 2H), 1.93 (d, J = 17.5 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.68 – 1.39(m, 2H), 0.20 (t, J = 7.0 Hz, 2H). 065: 1 H NMR (400 MHz, D2O) δ 8.60 – 8.45 (m, 1H), 8.44 – 8.25 (m, 1H), 7.95 – 7.72 (m, 1H), 7.47 – 7.24 (m, 1H), 7.20 – 6.82 (m, 1H), 6.70 – 6.21(m, 1H), 2.86 – 2.45 (m, 2H), 0.62 – 0.19 (m, 0H). The following experimental examples demonstrate the beneficial effects of the present invention.

[0043] Experimental Example 1: Activity Test of Compounds 1. Experimental Methods (1) Enzyme activity experiment: ① Preparation of inhibitors: The inhibitors were dissolved in DMSO and diluted twice to ensure a final concentration range of 0.00195 nM to 2 nM, with 11 inhibitor concentrations.

[0044] ② Diluting the enzyme: Purify NDM1, IMP-1, VIM-1, VIM-2, OXA-48, and Ampc proteins, and dilute them to working concentrations with phosphate buffer. Prepare a mixture of enzyme and BSA.

[0045] ③ Preparation of FC-5 / cefotaxime (NCF): Dissolve FC-5 in DMSO and dilute with phosphate buffer to a final concentration of 5 μM. Dissolve NCF in DMSO and dilute with phosphate buffer to a final concentration of 100 μM.

[0046] ④ 96-well test: Add 25 μl of enzyme to wells 1 to 12 of the plate, then add 25 μl of different concentrations of inhibitor to wells 1 to 11 in sequence. Fill well 12 with phosphate buffer, mix well, and incubate at 37°C for 10 min.

[0047] ⑤ Instrumental Testing: The reaction was initiated at 37°C by adding 50 μl of FC-5 to each well for metalloenzymes. Fluorescence changes (λex = 380 nm and λem = 460 nm) were measured using a microplate reader. For serine enzymes, 50 μl of NCF (λ = 490 nm) was added to each well. This assay was performed three times. IC50 50 The values ​​were obtained using GraphPad Prism software.

[0048] (2) Antibacterial test: We strictly followed the operating procedures of the Clinical and Laboratory Standards Institute (CLSI). We used the microbroth dilution method to determine the MIC values ​​of various antimicrobial agents and BLI against resistant strains.

[0049] The antibiotic was diluted in cationic-regulated Mueller-Hinton II broth (CAMHB) medium, and then the compound or DMSO was added to 96-well plates. The final concentration of the antibiotic was adjusted to 64–0.03125 mg / ml using a two-fold dilution method, while the inhibitor was tested at a fixed concentration (4 μg / ml). The final concentration of the bacterial culture per well was approximately 5 × 10⁻⁶. 5 CFU / ml. 96-well plates were incubated at 37°C for 18-20 hours, and the minimum inhibitory concentration (MIC) was determined by observing bacterial growth.

[0050] ① MIC test of clinical isolates: Inhibitor dosage concentration was 4 μg / ml. MEM: Meropenem. CAZ: Ceftazidime. AVI: Avibactam. TAN: Taniborbactam.

[0051] ② MIC test of Acinetobacter baumannii clinical isolates: Inhibitor concentration was 4 μg / ml. SUL: Sulbactam. DUL: Dulobactam.

[0052] ③ MIC test of clinical isolates expressing metalloenzymes: the inhibitor concentration was 4 ug / ml.

[0053] 2. Experimental Results (1) Enzyme activity test results The compounds of this invention exhibit nanomolar to micromolar inhibitory activity against clinically common metallo-β-lactamases (IMP-1, NDM-1, VIM-1, VIM-2) and serine enzymes AmpC and OXA-48, with 0.19 (IC50 of NDM-1) showing the highest inhibitory activity. 50 (0.68nM), 004 (NDM-1 IC) 50 (1.58 nM), 006 (NDM-1 IC) 50 (3.4 nM), 048 (NDM-1 IC) 50 (1.1 nM) and 052 (NDM-1 IC) 50 The inhibitory efficacy of taniborbactam (6.9 nM) against NDM-1 was approximately 20 to 200 times greater than that of the positive control taniborbactam, and it maintained an IC50 of <30 nM against enzymes such as IMP-1 and VIM-2. 50 It exhibits broad-spectrum and highly efficient inhibition characteristics.

[0054] (2) Results of antibacterial activity test The compounds of this invention, when used in combination with meropenem, can significantly reduce the MIC of carbapenem-resistant Gram-negative bacteria: against NDM-1-producing Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, the meropenem MIC decreased from 32-64 µg / mL to ≤0.125-1 µg / mL (a 64-512-fold decrease in inhibitory concentration). Among them, 001, 004, 006, 019, 052, 054, 056, 060, and 061 showed a recovery of meropenem sensitivity at a fixed concentration of 4 µg / mL. Similarly, against Acinetobacter baumannii and Pseudomonas aeruginosa OXA-48 serine enzyme strains, a 4-32-fold reduction in MIC was achieved, indicating that this series of compounds can reverse carbapenem resistance and enhance the in vitro efficacy of meropenem.

[0055] In summary, this invention provides a series of cycloboronic acid compounds, their preparation methods, and applications. This invention prepares a series of cycloboronic acid compounds. These compounds exhibit significant inhibitory efficacy against serine and metallo-β-lactamases. The compounds prepared by this invention have good application potential in the preparation of highly efficient and safe inhibitors of serine and metallo-β-lactamases.

Claims

1. The compound of formula I, or its salt, its stereoisomer, its solvate, or its crystal form: Formula I in, R is selected from 0 to 3 R's. A The following groups are substituted: phenyl, phenyl 5-6 membered unsaturated heterocycle, phenyl 5-6 membered saturated heterocycle, 5-6 membered unsaturated heterocycle, naphthyl, 5-6 membered unsaturated heterocycle, and 5-6 membered unsaturated heterocycle; R A Each is independently selected from halogens, -LSO2R B amino, hydroxyl, C 1~5 Alkyl group, -CONR C R D amino-substituted C 1~5 Alkyl, C 1~5 Alkyl, halogen-substituted C 1~5 C-substituted alkyl, cyano, oxo, phenyl, or hydroxyl groups 1~5 Alkyl, 3-6 membered saturated cycloalkyl, 5-6 membered saturated heterocycle, -NHCOR E nitro, carboxyl, -L 1 NR 1 R 2 ; L is selected from none, C 1~5 Alkylene, NH; R B Selected from C 1~5 Alkyl, C 1~5 alkoxy- or halogen-substituted C 1~5 Alkyl, hydroxyl substituted C 1~5 alkyl; R C R D Each is independently selected from hydrogen and C. 1~5 alkyl; R E Selected from amino-substituted C 1~5 Alkyl, C 1~5 alkoxy- or halogen-substituted C 1~5 Alkyl, hydroxyl substituted C 1~5 alkyl; L 1 Selected from C 1~5 Alkylene; R 1 R 2 Each is independently selected from hydrogen and C. 1~5 alkyl.

2. The compound, or its salt, or its stereoisomer, or its solvate, or its crystal form according to claim 1, characterized in that, The R is selected from 0 to 3 Rs. A The following groups are substituted: phenyl, phenyl 5-6 membered unsaturated heterocycle, phenyl 5-6 membered saturated heterocycle, 5-6 membered unsaturated heterocycle, naphthyl, 5-6 membered unsaturated heterocycle, and 5-6 membered unsaturated heterocycle; R A Each is independently selected from halogens, -LSO2R B amino, hydroxyl, C 1~3 Alkyl group, -CONR C R D amino-substituted C 1~3 Alkyl, C 1~3 Alkyl, halogen-substituted C 1~3 C-substituted alkyl, cyano, oxo, phenyl, or hydroxyl groups 1~3 Alkyl, 3-6 membered saturated cycloalkyl, 5-6 membered saturated heterocycle, -NHCOR E nitro, carboxyl, -L 1 NR 1 R 2 ; L is selected from none, C 1~3 Alkylene, NH; R B Selected from C 1~3 alkyl; R C R D Each is independently selected from hydrogen and C. 1~3 alkyl; R E Selected from amino-substituted C 1~3 alkyl; L 1 Selected from C 1~3 Alkylene; R 1 R 2 Each is independently selected from hydrogen and C. 1~3 alkyl.

3. The compound, or its salt, or its stereoisomer, or its solvate, or its crystal form according to claim 1, characterized in that, The R is selected from 0 to 3 Rs. A The following groups are substituted: 、 、 、 、 、 、 、 、 、 。 4. The compound, or its salt, or its stereoisomer, or its solvate, or its crystal form according to claim 2, characterized in that, The structure of the compound is shown in Formula II or Formula III: Formula II Formula III Among them, R A As described in claim 2; m is selected from 0, 1, 2 or 3.

5. The compound, or its salt, or its stereoisomer, or its solvate, or its crystal form according to claim 2, characterized in that, The structure of the compound is shown in Formula IV or Formula V: Formula IV Formula V Among them, R A As described in claim 2; m is selected from 0, 1, 2 or 3.

6. The compound, or its salt, or its stereoisomer, or its solvate, or its crystal form according to any one of claims 1 to 5, characterized in that, The compound is selected from one of the following compounds: 。 7. Use of the compound, salt thereof, stereoisomer thereof, solvate thereof, or crystal form thereof according to any one of claims 1 to 6 in the preparation of serine enzyme inhibitors and / or metallo-β-lactamase inhibitors.

8. The use according to claim 7, characterized in that, The inhibitor is an antibacterial adjuvant.

9. The use of the compound, salt thereof, stereoisomer thereof, solvate thereof, or crystal form thereof as claimed in any one of claims 1 to 6, in combination with an antibiotic in the preparation of an antibacterial agent; wherein the bacteria are preferably antibiotic-resistant Escherichia coli, Klebsiella pneumoniae, or Acinetobacter baumannii, and the antibiotic is preferably a β-lactam antibiotic.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a pharmaceutical preparation made by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1 to 6, or a salt thereof, a stereoisomer thereof, a solvate thereof, or a crystal form thereof as the active ingredient.

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