CN109568323B

CN109568323B - Antibacterial composition and use thereof

Info

Publication number: CN109568323B
Application number: CN201710912114.7A
Authority: CN
Inventors: 史澂空
Original assignee: Beijing Tianxinyuan Pharmaceutical Science And Technology Development Co ltd; Beijing Sihuan Pharmaceutical Co Ltd; Beijing Ao He Research Institute Co Ltd
Current assignee: Beijing Tianxinyuan Pharmaceutical Science And Technology Development Co ltd; Beijing Sihuan Pharmaceutical Co Ltd; Beijing Ao He Research Institute Co Ltd
Priority date: 2017-09-29
Filing date: 2017-09-29
Publication date: 2022-09-30
Anticipated expiration: 2037-09-29
Also published as: CN109568323A

Abstract

The invention relates to the technical field of medicines, in particular to a pharmaceutical product which comprises a compound (a), or a pharmaceutically acceptable salt, ester or solvent compound thereof, or a stereoisomer thereof, and at least one beta-lactam antibiotic or a derivative thereof, wherein the compound (a) has a structure shown in a formula (I). Also relates to the use of said pharmaceutical product for the preparation of a medicament for the treatment and/or prevention of bacterial infectious diseases, preferably said bacteria have a resistance caused by a beta-lactamase.

Description

Antibacterial composition and use thereof

Technical Field

The invention belongs to the technical field of medicines. In particular, the invention relates to a pharmaceutical product, in particular to an antibacterial pharmaceutical composition containing a diazabicyclooctanone compound and a beta-lactam antibiotic, and an application thereof in preparing a medicament for preventing and/or treating infectious diseases caused by bacteria.

Background

The rapid development of antibiotics has great significance in modern medical history. The first successful clinical application of β -lactam drugs was penicillin G, which indicated direction for the subsequent clinical application of β -lactam antibiotics. The beta-lactam antibiotics refer to a large class of antibiotics with a beta-lactam ring in the chemical structure, and comprise the penicillin, the cephalosporin, the carbapenem, the monocyclic beta-lactam and the like which are most commonly used in clinic. The medicines still belong to the most extensive, safe and effective medicines for resisting bacterial infection, however, with the continuous use and the gradual deepening of the research and development of the antibiotics, the beta-lactam antibiotics are easy to be hydrolyzed by beta-lactamase generated by pathogenic bacteria to generate increasingly serious drug resistance. One approach for solving the drug resistance is to adopt a beta-lactamase inhibitor to reduce or inhibit the activity of the beta-lactamase, recover the original antibacterial activity and antibacterial spectrum of the antibiotic and improve the clinical curative effect of the antibiotic.

According to molecular junctionBeta-lactamase differs in amino acid sequence in the structure, and is largely classified into two categories: one is A, C, D with serine as the active site, and the second is a metal ion (especially Zn) ²⁺ Ions) are active sites. Clinically used beta-lactamase inhibitors are Clavulanic acid (Clavulanic acid), Sulbactam (Sulbactam) and Tazobactam (Tazobactam).

Clavulanic acid, sulbactam and tazobactam are structural analogues of penicillin, are irreversible suicide enzyme inhibitors and have short maintenance action time. The main enzyme spectrum of clavulanic acid is partial class A beta-lactamase (such as CTX-M, TEM-1, SHV-1), and the combined effect is not good for the drug resistance triggered by newly generated class A beta-lactamase (such as KPC), class B metalloenzyme (such as IMP, NDM-1, VIM), class C enzyme (such as AmpC) or class D enzyme (such as OXA). Sulbactam and tazobactam mainly improve the inhibition effect of partial C (such as AmpC), D (such as OXA) and other enzymes, but still have no good inhibition activity on newly generated A-class beta-lactamase (such as KPC) and B-class metalloenzyme (such as IMP, NDM-1, VIM). Avibatan (Avibacam, AVI) and MK-7655 are diazabicyclooctanone compounds, and the structures are shown in the specification. Compared with clavulanic acid, sulbactam and tazobactam, the avibactam has long-acting enzyme inhibition effect, solves part of drug resistance problem mediated by A-class beta-lactamase (such as KPC), but still can not effectively solve the drug resistance caused by B-class metalloenzyme, and has limited clinical application. MK-7655 has a broader antimicrobial spectrum, but similarly does not show good efficacy against B-type metalloenzyme-producing strains. Furthermore, the half-lives (T) of Avermentan and MK-7655 _1/2 ) Short, and cannot be effectively matched with the half-life of antibiotics, so that the clinical application of the antibiotics is limited.

Patent WO2017045510 discloses that a novel diazabicyclooctanone compound independently developed by Shandongxuan bamboo medicine science and technology limited company has good beta-lactamase inhibitory activity and certain antibacterial effect, and the medicine can effectively solve the problem of bacterial drug resistance caused by one or more beta-lactamases, particularly the problem of drug resistance mediated by B-type metalloenzymes, effectively makes up the defects of similar medicines, and has very urgent and realistic clinical requirements.

Disclosure of Invention

The invention aims to solve one of the technical problems, and solves the problem of bacterial drug resistance caused by beta-lactamase, in particular to the problem of bacterial drug resistance caused by B-type metal beta-lactamase. The present application provides a pharmaceutical product comprising a diazabicyclooctanone compound and a beta-lactam antibiotic, which is useful for the prevention and/or treatment of bacterial infectious diseases.

In one aspect, the present application provides a pharmaceutical product comprising compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and at least one beta-lactam antibiotic or a derivative thereof, wherein compound (a) has a structure according to formula (I),

wherein the content of the first and second substances,

R ₁ is-SO ₃ M，-OSO ₃ M，-SO ₂ NH ₂ ，-PO ₃ M，-OPO ₃ M，-CH ₂ CO ₂ M，-CF ₂ CO ₂ M or-CF ₃ ；

M is selected from H or a pharmaceutically acceptable cation;

ring a is selected from the following optionally substituted with substituents: 5-15 membered bridged ring group, 5-15 membered spiro ring group, 5-15 membered bridged heterocyclic group or 5-15 membered spiro heterocyclic group, said substituent being selected from halogen, amino, carboxyl, hydroxyl, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 An alkylcarbonyl group;

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkoxy radical C _1-6 Alkyl, halo C _1-6 Alkoxy, halo C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _1-6 Alkylcarbonyl, halogeno C _1-6 Alkylcarbonyl, halo C _1-6 Alkyl carbonyl group C _1-6 Alkyl radical, C _1-6 Alkylcarbonyloxy, C _1-6 Alkoxycarbonyl radical, C _1-6 Alkylcarbonyloxy C _1-6 Alkyl radical, C _1-6 Alkylamido radical, C _1-6 Alkylaminocarbonyl, di (C) _1-6 Alkyl) aminocarbonyl, C _1-6 Alkylsulfinyl radical, C _1-6 Alkylsulfonyl radical, C _1-6 Alkylsulfonyl radical C _1-6 Alkyl radical, C _1-6 Alkylsulfonylamino, C _1-6 Alkylsulfonyloxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl-C _1-6 Alkyl, 6-8 membered aryl, 6-15 membered fused aryl, 4-15 membered fused cyclic group, 5-15 membered bridged cyclic group, 5-15 membered spiro cyclic group, 3-8 membered heterocyclic group-C _1-6 Alkyl, 5-8 membered heteroaryl, 5-15 membered fused heteroaryl, 4-15 membered fused heterocyclyl, 5-15 membered bridged heterocyclyl or 5-15 membered spiroheterocyclyl.

In certain embodiments, ring a is a 5-15 membered bridged ring group optionally substituted with a substituent. In certain embodiments, ring a is a 5-15 membered spirocyclic group optionally substituted with a substituent. In certain embodiments, ring a is a 5-15 membered bridged heterocyclic group optionally substituted with a substituent. In certain embodiments, ring a is a 5-15 membered spiroheterocyclyl optionally substituted with substituents.

In certain embodiments, the compound (a) has the structure shown in formula (II),

wherein R is ₁ 、R ₂ Ring A is as defined above.

In certain embodiments, the compound (a) has the structure shown in formula (III),

wherein the content of the first and second substances,

ring a is selected from the following optionally substituted with substituents: 5-15 membered spiro ring group, 5-15 membered nitrogen bridge heterocyclic group or 5-15 membered nitrogen containing spiro heterocyclic group, wherein the substituent is selected from halogen, amino, carboxyl, hydroxyl, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 An alkylcarbonyl group;

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkoxy radical C _1-6 Alkyl, halo C _1-6 Alkoxy, halo C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylamino radical C _1-6 Alkyl radical, C _1-6 Alkylcarbonyl, halogeno C _1-6 Alkylcarbonyl, halo C _1-6 Alkyl carbonyl radical C _1-6 Alkyl radical, C _1-6 Alkylcarbonyloxy, C _1-6 Alkoxycarbonyl radical, C _1-6 Alkylcarbonyloxy C _1-6 Alkyl radical, C _1-6 Alkylamido radical, C _1-6 Alkylaminocarbonyl, di (C) _1-6 Alkyl) aminocarbonyl, C _1-6 Alkylsulfinyl radical, C _1-6 Alkylsulfonyl radical, C _1-6 Alkylsulfonyl radical C _1-6 Alkyl radical, C _1-6 Alkylsulfonylamino group, C _1-6 Alkylsulfonyloxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl-C _1-6 Alkyl, 4-10 membered fused ring radicals5-10 membered bridged ring group, 5-10 membered spiro ring group, 3-8 membered heterocyclic group-C _1-6 Alkyl, 4-10 membered fused heterocyclic group, 5-10 membered bridged heterocyclic group or 5-10 membered spiro heterocyclic group;

m is selected from H, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, ammonium ion, or tetra (C) _1-6 Alkyl) quaternary ammonium ions.

In certain embodiments, ring a is a 5-15 membered nitrogen containing bridged heterocyclic group optionally substituted with a substituent. In certain embodiments, ring a is a 5-15 membered nitrogen containing spiroheterocyclyl optionally substituted with substituents.

In certain embodiments, in the compound (a),

ring a is selected from the following optionally substituted with substituents: 7-9 membered spirocyclyl, 7-9 membered nitrogen containing bridged heterocyclyl or 7-9 membered nitrogen containing spiroheterocyclyl, said substituents being selected from the group consisting of halogen, amino, carboxyl, hydroxyl, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 An alkoxy group;

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylcarbonyl, halo C _1-6 Alkylcarbonyl group, C _1-6 Alkylcarbonyloxy, C _1-6 Alkylamido radical, C _1-6 Alkylsulfinyl radical, C _1-6 Alkylsulfonyl radical, C _1-6 Alkylsulfonylamino, 3-8 membered cycloalkyl-C _1-6 Alkyl, 3-8 membered heterocyclyl-C _1-6 Alkyl, a 5-9 membered fused heterocyclic group, a 6-9 membered bridged heterocyclic group or a 6-9 membered spiroheterocyclic group;

m is selected from H, sodium ion, potassium ion, zinc ion or tetrabutylammonium ion.

In certain embodiments, ring a is a 7-9 membered spirocyclic group optionally substituted with a substituent. In certain embodiments, ring a is a 7-9 membered nitrogen containing bridged heterocyclic group optionally substituted with a substituent. In certain embodiments, ring a is a 7-9 membered nitrogen containing spiroheterocyclyl optionally substituted with a substituent.

In certain embodiments, in the compound (a),

ring a is selected from the following optionally substituted with substituents: 7-9 membered spirocyclyl, 7-9 membered nitrogen containing bridged heterocyclyl or 7-9 membered nitrogen containing spiroheterocyclyl, said substituents being selected from the group consisting of halogen, amino, carboxyl, hydroxyl, cyano, C _1-4 Alkyl, halo C _1-4 Alkyl or C _1-4 An alkoxy group;

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-4 Alkyl, halo C _1-4 Alkyl, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy radical, C _1-4 Alkylamino, di (C) _1-4 Alkyl) amino, C _1-4 Alkylcarbonyl, halo C _1-4 Alkylcarbonyl group, C _1-4 Alkylcarbonyloxy, C _1-4 Alkylamido radical, C _1-4 Alkylsulfinyl radical, C _1-4 Alkylsulfonyl radical, C _1-4 Alkylsulfonylamino, 3-6 membered cycloalkyl-C _1-4 Alkyl, 3-6 membered heterocyclyl-C _1-4 An alkyl group;

In certain embodiments, ring a is attached to the nitrogen atom of the amide group in compound (a) through a ring carbon atom.

In certain embodiments, in the compound (a),

ring A is selected from the group consisting of 2-azabicyclo [2.2.1] heptanyl, 7-azabicyclo [2.2.1] heptanyl, 3-azabicyclo [3.2.1] octanyl, 8-azabicyclo [3.2.1] octanyl, 2-azabicyclo [2.2.2] octanyl, 2, 5-diazabicyclo [2.2.1] heptanyl, 3, 8-diazabicyclo [3.2.1] octanyl, 2-oxa-5-azabicyclo [2.2.1] heptanyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3, 8-diazabicyclo [3.2.1] oct-6-enyl, 3, 9-diazabicyclo [3.3.1] nonanyl, 5-azaspiro [2.4] heptanyl, 2-azaspiro [3.3] heptanyl optionally substituted with substituents, 2-azaspiro [3.5] nonanyl group, 7-azaspiro [3.5] nonanyl group, 2, 6-diazaspiro [3.3] heptanyl group, 2-oxa-6-azaspiro [3.3] heptanyl group, 6-oxa-2-azaspiro [3.4] octanyl group, 6-azaspiro [3.4] octanyl group, 2-azaspiro [4.4] nonanyl group, 2-oxa-7-azaspiro [4.4] nonanyl group, 6-azaspiro [3.4] oct-7-enyl group, 2-oxa-6-azaspiro [3.4] oct-7-enyl group, 2-azaspiro [4.4] non-7-enyl group or spiro [3.3] heptanyl group, the substituent being selected from a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, methyl, ethyl or propyl;

R ₂ selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, a methyl group, an ethyl group, a butyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, an acetyl group, a methanesulfonyl group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, a cyclohexyl group, a cyclohexylmethyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a piperidinyl group or a morpholinyl group.

In certain embodiments, in the compound (a),

ring A is selected from the group consisting of 3-azabicyclo [3.2.1] octanyl, 8-azabicyclo [3.2.1] octanyl, 3, 9-diazabicyclo [3.3.1] nonanyl, 2-azaspiro [3.3] heptanyl, 2-azaspiro [3.5] nonanyl, 7-azaspiro [3.5] nonanyl or spiro [3.3] heptanyl, optionally substituted;

R ₂ selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, a methyl group, an ethyl group, a butyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, an acetyl group, a methanesulfonyl group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, a cyclohexyl group, a cyclohexylmethyl group, a pyrrolidinyl group, a piperidinyl group or a morpholinyl group.

In certain embodiments, in the compound (a),

ring A is selected from 2-azaspiro [3.3] heptanyl optionally substituted with a substituent selected from a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, a methyl group, an ethyl group or a propyl group;

R ₂ selected from hydrogen atom, fluorine atom, chlorine atom, amino group, hydroxyl group, methyl group, ethyl group, butyl group, trifluoromethyl group, methoxy group, trisFluoromethoxy, acetyl, methylsulfonyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, pyrrolidinyl, piperidinyl or morpholinyl.

In certain embodiments, the compound (a) has the structure shown in formula (IV):

wherein R is ₂ Selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, a methyl group, an ethyl group, a butyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, an acetyl group, a methanesulfonyl group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, a cyclohexyl group, a cyclohexylmethyl group, a pyrrolidinyl group, a piperidinyl group or a morpholinyl group;

In certain embodiments, the compound (a) is selected from the following compounds 1 through 15-2:

in certain embodiments, the compound (a) is selected from

In certain embodiments, the beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams;

the penicillin antibiotic is selected from: penicillin G, penicillin G potassium, penicillin G sodium, penicillin V, long-acting penicillin, oxacillin, cloxacillin, methicillin, oxacillin, nafcillin, flucloxacillin, dicloxacillin, ampicillin, amoxicillin, hydracillin, methicillin, phthalacillin, pivampicillin, bacampicillin, carbenicillin, piperacillin, sulbenicillin, furbenicillin, ticarcillin, azlocillin, mezlocillin, apacillin, mezlocillin, pimecrillin, temocillin or any combination thereof;

the cephalosporin antibiotics are selected from: cefazolin, cefoselin, cefaclor, cefprozil, ceforotid, cefotiam, cefaclor, cefletaxetin, cefepime, ceftriazine, ceftezole, cefcapene, cefadroxil, cephalexin, ceflorentm, cefetamide, cefixime, cephradine, ceftriaxone, ceftriazole, cephalothin, cefuroxime, chlorocepham, cefcapene, cefprozil, cefaclor, cefdaxime, cefmetazole, cefbuperazone, cefotetan, cefotiam, cefotaxime, cefonicid, cefurotin, ceftriaxone, cefotaxime, ceftizoxime, cefpodoxime, ceftiofur, cefminox, cefoperazone, cefotaxime, cefuroxime, ceftriaxone, cefotetan, latamoxef, ceftibuten, cefimidazole, cefsulodin, cefdinir, cefodizime, cefmenoxime, ceftizoxime, cefcapene, cefetamet, cefteram, cefditoren, cefepime, cefixime, cefquinome, cefozopran, cefpirome, flomoxef, cefradine, cefotiam, cefoselis, cefpirome, ceftriaxone, or any combination thereof;

the carbapenem antibiotic is selected from the following group: banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem or any combination thereof.

The monocyclic beta lactam antibiotics are selected from: aztreonam, carumonam, or a combination thereof.

In certain embodiments, the beta lactam antibiotic is preferably a cephalosporin antibiotic, which is preferably: ceftazidime, ceftriaxone, cefepime, cefozopran, cefotaxime, cefoperazone, ceftaroline fosamil or any combination thereof.

In certain embodiments, the derivative of the β -lactam antibiotic is selected from an ester, a pharmaceutically acceptable salt, a stereoisomer, a prodrug, a solvate, a complex, or a metabolite of the β -lactam antibiotic.

In certain embodiments, the beta-lactam antibiotic is in a form that is clinically useful, e.g., the combination can be formed as the free base or as the sodium salt, etc. For example, the ceftriaxone in the combination product referred to in the present invention may refer to a free base compound thereof, and may also refer to a sodium salt thereof.

In certain embodiments, the pharmaceutical product wherein compound (a) is

The beta-lactam antibiotics are cephalosporin antibiotics, such as: ceftazidime, ceftriaxone, cefepime, cefozopran, cefotaxime, cefoperazone, ceftaroline fosamil or any combination thereof, or carbapenem antibiotics, for example: banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem or any combination thereof, or a monocyclic beta-lactam antibiotic, such as aztreonam.

In certain embodiments, the pharmaceutical product wherein compound (a) is

In certain embodiments, in the composition, compound (a) is

In certain embodiments, the β -lactam antibiotic is a cephalosporin antibiotic, such as: ceftazidime, ceftriaxone, cefepime, cefozopran, cefotaxime, cefoperazone, ceftaroline fosamil or any combination thereof, or carbapenem antibiotics, for example: banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem or any combination thereof, or a monocyclic beta-lactam antibiotic, such as aztreonam.

In certain embodiments, in the pharmaceutical product, compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and the beta-lactam antibiotic or derivative thereof are present in a prophylactically and/or therapeutically effective amount or unit dose.

In certain embodiments, the weight ratio of compound (a), or a pharmaceutically acceptable salt, ester, or solvate thereof, or a stereoisomer thereof, to the β -lactam antibiotic or derivative thereof is: 0.5-50: 0.5-50, such as 0.5-10: 0.5-50, 10-20: 0.5-50, 20-30: 0.5-50, 30-40: 0.5-50, 40-50: 0.5-50, 0.5-50: 0.5-10, 0.5-50: 10-20, 0.5-50: 20-30, 0.5-50: 30-40, 0.5-50: 40-50, 0.5-10: 0.5-10, 10-20: 10-20, 0.5-20: 0.5-20, 20-30: 20-30, 30-40: 30-40, 40-50: 40-50, 1-10: 1-10, 1-10: 1-20, 1-20: 1-10, 1-0.5-50, 1: 1-10: 0.5-50, 1: 1-32, 1: 0.5-16: 1-20, 1-20: 1.5-20: 0.5-20; for example, 0.5:0.5, 0.5:1, 0.5:1.5, 0.5:2, 0.5:2.5, 0.5:3, 0.5:3.5, 0.5:4, 0.5:4.5, 0.5:5, 0.5:5.5, 0.5:6, 0.5:6.5, 0.5:7, 0.5:7.5, 0.5:8, 0.5:8.5, 0.5:9, 0.5:9.5, 0.5:10, 0.5:10.5, 0.5:11, 0.5:11.5, 0.5:12, 0.5:12.5, 0.5:13, 0.5:13.5, 0.5:14, 0.5:14.5, 0.5:15, 0.5:1, 0.5: 5:12, 0.5: 5:12.5, 0.5:13, 0.5: 5:13, 0.5:14, 0.5:15, 0.5: 5:1, 0.5: 5:30, 0.5: 5: 0.5:20, 0.5:23, 0.5:20, 0.5: 5:20, 0.5: 5:20, 0.5:23, 0.5:20, 0.5:23, 0.5:20, 0.5:23, 0.5:20, 0.5:23, 0.5:20, 0.5:23, 0.5:20, 0.5:23, 0.5:20, 0.5, 0.5:32.5, 0.5:33, 0.5:33.5, 0.5:34, 0.5:34.5, 0.5:35, 0.5:35.5, 0.5:36, 0.5:36.5, 0.5:37, 0.5:37.5, 0.5:38, 0.5:38.5, 0.5:39, 0.5:39.5, 0.5:40, 0.5:40.5, 0.5:41, 0.5:41.5, 0.5:42, 0.5:42.5, 0.5:43, 0.5:43.5, 0.5:44, 0.5:44.5, 0.5:45, 0.5: 45.5: 46, 0.5:46.5, 0.5:47, 0.5:48, 0.5: 5:44.5, 0.5:5, 0.5: 5:45, 0.5: 5:46, 0.5: 5:47, 0.5:5, 0.5:5, 0.5:5, 0.5:47, 0.5:5, 0.5: 5:0.5, 0.5:5, 0.5: 5:0.5, 0.5: 5:0.5, 0.5:0.5, 0.5: 5: 0.5: 5:0.5, 0.5: 5:0.5, 0.5: 5:0.5, 0.5: 5:0.5, 0.5: 5:0.5, 0.5:33, 0.5: 5:9, 0.5: 5:0.5, 0.5:0.5, 0.5:33, 0.5:5, 0.5: 5:9, 0.5: 5: 0.5:5, 0.5: 5:9, 0.5:0.5, 0.5: 5:9, 0.5:5, 0.5:9, 0.5: 5:9, 0.5:5, 0.5:9, 0.5, 0, 16:0.5, 16.5:0.5, 17:0.5, 17.5:0.5, 18:0.5, 18.5:0.5, 19:0.5, 19.5:0.5, 20:0.5, 20.5:0.5, 21:0.5, 21.5:0.5, 22:0.5, 22.5:0.5, 23:0.5, 23.5:0.5, 24:0.5, 24.5:0.5, 25:0.5, 25.5:0.5, 26:0.5, 26.5:0.5, 27:0.5, 27.5:0.5, 28:0.5, 28.5:0.5, 29:0.5, 29.5:0.5, 30:0.5, 30.5:0.5, 31:0.5, 31.5:0.5, 31:0.5, 28.5:0.5, 45:0.5, 45:0.5, 33.5:0.5, 45:0.5, 45:0.5, 45, 48.5:0.5, 49:0.5, 49.5:0.5 or 50: 0.5. Optionally, the beta-lactam antibiotic is selected from: ceftazidime, ceftriaxone, cefepime, cefozopran, cefotaxime, cefoperazone, ceftaroline fosamil or combinations thereof. Optionally, the beta-lactam antibiotic is selected from: banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem or any combination thereof. Optionally, the beta-lactam antibiotic is selected from: aztreonam.

In certain embodiments, compound (a), or a pharmaceutically acceptable salt, ester, or solvate thereof, or a stereoisomer thereof, is present in an amount of 0.02g to 50g (e.g., 0.02g to 0.1g, 0.1g to 10g, 0.125g to 8g, 0.25g to 4g, 0.5g to 2g, 1g to 10g, 10g to 20g, 20g to 30g, 30g to 40g, or 40g to 50g, e.g., 0.02g, 0.03g, 0.04g, 0.05g, 0.06g, 0.07g, 0.08g, 0.09g, 0.1g, 0.11g, 0.12g, 0.13g, 0.14g, 0.15g, 0.16g, 0.17g, 0.18g, 0.19g, 0.34g, 0.31g, 0.34g, 0.26g, 0.30 g, 0.25g, or a pharmaceutically acceptable salt, or a stereoisomer thereof, per 1g of a beta-lactam antibiotic in a pharmaceutical product, 0.4g, 0.41g, 0.42g, 0.43g, 0.44g, 0.45g, 0.46g, 0.47g, 0.48g, 0.49g, 0.5g, 0.51g, 0.52g, 0.53g, 0.54g, 0.55g, 0.56g, 0.57g, 0.58g, 0.59g, 0.6g, 0.61g, 0.62g, 0.63g, 0.64g, 0.65g, 0.66g, 0.67g, 0.68g, 0.69g, 0.7g, 0.71g, 0.72g, 0.73g, 0.74g, 0.75g, 0.76g, 0.77g, 0.78g, 0.79g, 0.8g, 0.81g, 0.82g, 0.83g, 0.74g, 0.75g, 0.76g, 0.77g, 0.78g, 0.9g, 0.93g, 0.9g, 1g, 9g, 1.9 g, 9g, 1.93 g, 9g, 1.9 g, 1g, 1.9 g, 9g, 1.9 g, 1g, 9g, 0.93g, 9g, 1.9 g, 9g, 1.93 g, 9g, 1.9 g, 1.93 g, 9g, 1.93 g, 1.9 g, 9g, 1.93 g, 1.9 g, 9g, 1.93 g, 1.9 g, 1.96 g, 1.9 g, 1.93 g, 1.9 g, 9g, 1g, 9g, 1.93 g, 9g, 1.93 g, 9g, 1g, 9g, 1.9 g, 9g, 1.93 g, 1g, 1.93 g, 9g, 1.93 g, 9g, 1.93 g, 9g, 1.93 g, 9, 27g, 28g, 29g, 30g, 31g, 32g, 33g, 34g, 35g, 36g, 37g, 38g, 39g, 40g, 41g, 42g, 43g, 44g, 45g, 46g, 47g, 48g, 49g, or 50 g). Optionally, the beta-lactam antibiotic is selected from: ceftazidime, ceftriaxone, cefepime, cefozopran, cefotaxime, cefoperazone, ceftaroline fosamil or combinations thereof. Optionally, the beta-lactam antibiotic is selected from: banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem or any combination thereof. Optionally, the beta-lactam antibiotic is selected from: aztreonam.

In certain embodiments, the pharmaceutical product comprises:

(1)0.0625g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tipipenem or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or

(2)0.125g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or alternatively

(3)0.25g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebucipenem or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or

(4)0.33g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebucipenem, or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or alternatively

(5)0.5g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(6)1g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucipenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(7)2g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 2g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem, or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam; or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof

(8)0.03125g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebipenem or any combination thereof; e.g. a monobactam-lactam antibiotic such as aztreonam); or

(9)0.0625g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tipipenem or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or

(10)0.125g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebucipenem, or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or alternatively

(11)0.167g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebucipenem, or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or

(12)0.25g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(13)0.5g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbamine, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebucipenem, or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or alternatively

(14)1g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 1g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as banipenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucipenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(15)0.015625g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as bernanpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tipipenem or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(16)0.03125g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbampenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tebipenem, or any combination thereof; e.g. a monocyclic beta-lactam antibiotic such as aztreonam); or

(17)0.0625g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as bernanpenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tipipenem or any combination thereof; e.g. a monobactam antibiotic such as aztreonam); or

(18)0.125g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbampenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucipenem or any combination thereof; e.g. a monobactam-lactam antibiotic such as aztreonam); or

(19)0.25g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbampenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephapenem, tebucipenem or any combination thereof; e.g. a monobactam-lactam antibiotic such as aztreonam); or alternatively

(20)0.5g of compound (a), or a pharmaceutically acceptable salt, ester or solvate thereof, or a stereoisomer thereof, and 0.5g of a beta-lactam antibiotic or a derivative thereof (e.g. a cephalosporin antibiotic such as ceftazidime, ceftriaxone, cefotaxime, cefoperazone, cefepime, ceftaroline pivoxil; e.g. a carbapenem antibiotic such as berbampenem, imipenem, meropenem, ertapenem, biapenem, panipenem, doripenem, cephalopenem, tepiripenem, or any combination thereof; e.g. a monobactam antibiotic such as aztreonam).

Optionally, the pharmaceutical product further comprises one or more therapeutically active agents selected from antibacterial agents, beta-lactamase inhibitors, anti-anaerobes agents, antifungal agents, anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, anti-cancer agents, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins, anti-vascular hyperproliferation compounds, or any combination thereof.

In certain embodiments, the antibacterial agent is selected from tobramycin, levofloxacin, vancomycin, linezolid, tigecycline, or any combination thereof.

In certain embodiments, the beta-lactamase inhibitor is selected from clavulanic acid, tazobactam, sulbactam, or any combination thereof.

In certain embodiments, the anti-anaerobe agent is metronidazole and the antifungal agent is colistin.

In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, the beta-lactam antibiotic or derivative thereof, and the optional therapeutically active agent are present separately in the pharmaceutical product, e.g., in different formulations. In certain embodiments, the different formulations have the same or different dosage forms.

In certain embodiments, the dosage form is selected from the group consisting of a powder, tablet, granule, capsule, solution, emulsion, suspension, injection, spray, aerosol, powder cloud, lotion, liniment, ointment, plaster, paste, patch, gargle, or suppository.

In certain embodiments, the different formulations each comprise one active ingredient. For example, the pharmaceutical product comprises a first formulation having as an active ingredient the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and a second formulation having as an active ingredient the β -lactam antibiotic or a derivative thereof. For example, the pharmaceutical product comprises a first formulation having the active ingredient of said compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, a second formulation having the active ingredient of said β -lactam antibiotic or a derivative thereof, and a third formulation having the active ingredient of said therapeutically active agent.

In certain embodiments, the formulation may be administered to a patient or subject in need of prevention and/or treatment by any suitable administration, e.g., oral, parenteral, rectal, pulmonary, or topical administration. When used for oral administration, the formulations are oral formulations, e.g., oral solid formulations such as tablets, capsules, pills, granules, and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. The oral formulation may further comprise suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the formulations may be injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. For injections, the production can be carried out by conventional methods in the pharmaceutical field. When an injection is prepared, no additive can be added into the preparation, and an appropriate additive can be added according to the property of the medicine. When used for rectal administration, the formulations may be suppositories and the like. For pulmonary administration, the formulation may be an inhalant or a spray, etc. In the present application, the preferred mode of administration is intravenous, intramuscular or oral.

In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and the beta-lactam antibiotic or derivative thereof are present in the pharmaceutical product in the form of a pharmaceutical composition. In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and the therapeutically active agent are present in the pharmaceutical product in the form of a pharmaceutical composition. In certain embodiments, the β -lactam antibiotic or derivative thereof and the therapeutically active agent are present in the pharmaceutical product in the form of a pharmaceutical composition. In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, the beta-lactam antibiotic or derivative thereof, and the therapeutically active agent are present in the pharmaceutical product in the form of a pharmaceutical composition.

In certain embodiments, the pharmaceutical composition is formulated into any pharmaceutically acceptable dosage form, such as a powder, tablet, granule, capsule, solution, emulsion, suspension, injection, spray, aerosol, powder spray, lotion, liniment, ointment, plaster, paste, patch, gargle, or suppository, such as a powder, tablet, granule, capsule, solution, injection, ointment, gargle, or suppository.

In certain embodiments, the pharmaceutical composition may be administered to a patient or subject in need of prevention and/or treatment by any suitable administration, e.g., oral, parenteral, rectal, pulmonary, or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. When formulated into oral preparations, the pharmaceutical composition may further comprise suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical composition can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be manufactured by a conventional method in the existing pharmaceutical field. When preparing injection, the pharmaceutical composition can be added with no additive, or added with proper additive according to the nature of the medicine. When used for rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or a spray. In the present application, the preferred mode of administration is intravenous, intramuscular or oral.

In certain embodiments, the pharmaceutical product further comprises one or more pharmaceutically acceptable carriers.

In one aspect, the present application relates to the use of compound (a) as defined above, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, and a β -lactam antibiotic or a derivative thereof, for the preparation of a pharmaceutical product for the prevention and/or treatment of an infectious disease caused by a bacterium in a subject.

In certain embodiments, the bacterium has drug resistance caused by a beta-lactamase.

In certain embodiments, the beta-lactamase is selected from: class a beta-lactamase, class B metallo beta-lactamase, class C beta-lactamase, class D beta-lactamase, or any combination thereof.

In certain embodiments, the beta-lactamase is a class B beta-lactamase.

In certain embodiments, the beta-lactamase is selected from: CTX-M, TEM, SHV, KPC, NDM, IMP, VIM, AmpC, OXA, extended spectrum beta-lactamases (ESBLs), or any combination thereof.

In certain embodiments, the beta-lactam antibiotic is selected from a cephalosporin antibiotic or a monobactam antibiotic.

In certain embodiments, the bacteria are selected from gram positive bacteria, gram negative bacteria, or any combination thereof.

In certain embodiments, the bacterium is a gram-negative bacterium.

In certain embodiments, the gram-positive bacterium is selected from: staphylococcus aureus, Staphylococcus epidermidis, Streptococcus agalactiae, enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, enterococcus, Clostridium difficile, or any combination thereof.

In certain embodiments, the gram-negative bacteria are selected from: citrobacter, Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Salmonella, Serratia marcescens, Shigella, Pseudomonas aeruginosa, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria gonorrhoeae, Acinetobacter, Burkholderia, Campylobacter, helicobacter pylori, Vibrio cholerae, klebsiella, Haemophilus influenzae, Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium ulcerosa, Chlamydia pneumoniae, Chlamydia trachomatis, Haemophilus influenzae, Streptococcus pyogenes, beta-hemolytic streptococcus, Acinetobacter baumannii, Pseudomonas aeruginosa, Bacteroides fragilis, Bacillus cereus, stenotrophomonas maltophilia, Enterobacter huoshi, Klebsiella oxytoca or any combination thereof.

In certain embodiments, the infectious disease caused by a bacterium is selected from the group consisting of: upper respiratory tract infections, lower respiratory tract infections, complicated urinary tract infections and other urinary tract infections, central nervous system infections, ear infections, pleuropneumoniae and bronchial infections, tuberculosis, complicated or non-complicated urinary tract infections, intra-abdominal infections, cardiovascular infections, bloodstream infections, septicemia, bacteremia, CNS infections, skin or soft tissue infections, GI infections, bone and joint infections, genital infections, eye infections, granuloma infections, complicated or non-complicated skin and skin structure infections, catheter infections, pharyngitis, sinusitis, otitis externa, otitis media, bronchitis, pyothorax, pneumonia, community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, respirator-related pneumonia, diabetic foot infections, vancomycin-resistant enterococcus infections, cystitis and pyelonephritis, kidney stones, prostatitis, urinary tract infections, and other urinary tract infections, and other infections, and the like, Peritonitis, complicated intraperitoneal and other intraperitoneal infections, dialysis-related peritonitis, visceral abscesses, endocarditis, myocarditis, pericarditis, infusion-related sepsis, meningitis, encephalitis, brain abscesses, osteomyelitis, arthritis, genital ulcers, urethritis, vaginitis, cervicitis, gingivitis, conjunctivitis, keratitis, endophthalmitis, infections in cystic fibrosis patients, infections in febrile neutropenic patients, or any combination thereof.

In certain embodiments, the subject is a mammal, e.g., a bovine, equine, ovine, porcine, canine, feline, rodent, primate; among these, particularly preferred subjects are humans.

In one aspect, the present application relates to a method for the prevention and/or treatment of an infectious disease caused by bacteria in a subject, comprising administering to the subject a prophylactically and/or therapeutically effective amount of compound (a), or a pharmaceutically acceptable salt, ester, solvate compound, or stereoisomer thereof, as defined above, and at least one β -lactam antibiotic or derivative thereof.

In certain embodiments, the beta-lactamase is a class B beta-lactamase.

In certain embodiments, the β -lactam antibiotic is selected from a cephalosporin antibiotic or a mono-lactam antibiotic.

In certain embodiments, the compound (a), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a stereoisomer thereof, the beta-lactam antibiotic or a derivative thereof, and optionally the therapeutically active agent are administered to the subject simultaneously or sequentially, e.g., the therapeutically active agent may be administered before, simultaneously or after administration of the compound (a), or a pharmaceutically acceptable salt, ester, solvate thereof, or stereoisomer thereof. For example, the therapeutically active agent may be administered before, simultaneously with or after the administration of the β -lactam antibiotic or derivative thereof.

In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and the beta-lactam antibiotic or derivative thereof are administered to the subject concurrently in the form of a pharmaceutical composition. In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and the therapeutically active agent are administered to the subject simultaneously in the form of a pharmaceutical composition. In certain embodiments, the β -lactam antibiotic or derivative thereof and the therapeutically active agent are administered to the subject simultaneously in the form of a pharmaceutical composition. In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, the beta-lactam antibiotic or derivative thereof, and the therapeutically active agent are administered to the subject simultaneously in the form of a pharmaceutical composition.

In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, is administered to the subject by intravenous administration, intramuscular administration, or oral administration. In certain embodiments, the compound (a), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, is administered to the subject 1,2,3, or 4 times daily.

In certain embodiments, the β -lactam antibiotic or derivative thereof is administered to the subject by intravenous, intramuscular, or oral administration. In certain embodiments, the beta-lactam antibiotic or derivative thereof is administered to the subject 1,2,3, or 4 times per day.

In certain embodiments, the therapeutically active agent is administered to the subject by intravenous administration, intramuscular administration, or oral administration. In certain embodiments, the therapeutically active agent is administered to the subject 1,2,3, or 4 times daily.

In another aspect, the present application also relates to a method of preparing the compound (a), a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, comprising the steps of:

step (1): preparation of intermediate 1

Dissolving the raw materials 1 and 2 in an organic solvent, preferably a polar organic solvent, adding an organic base, a carboxyl activating reagent and a water shrinking agent or adding an organic base and a polypeptide condensing agent, reacting for several hours at 10-80 ℃ under the protection of nitrogen, preferably at 25 ℃, preferably for 12-20 hours, and after the reaction is finished, purifying to obtain the intermediate 1.

Step (2): preparation of Compound (a)

Dissolving the intermediate 1 in organic solvent and/or water mixed solvent, adding organic base and SO ₃ Reacting M complex (such as sulfur trioxide trimethylamine complex) with palladium carbon at room temperature for several hours, preferably 1-20 hours, in a hydrogen environment, adding organic acid and/or organic acid salt for acidification after the reaction is finished, reacting at room temperature for several hours, and purifying after the reaction is finished to obtain the compound (a).

The organic solvent is selected from one or more of the following: halogenated hydrocarbon solvents selected from dichloromethane, trichloromethane, and the like; amide solvents selected from N, N-dimethylformamide, N-dimethylacetamide and the like; alcohol solvent selected from methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, ethylene glycol and glycerol; ketone solvents selected from acetone, methyl butyl ketone, methyl isobutyl ketone, and the like; the ester solvent is selected from methyl acetate, ethyl acetate, dimethyl phthalate, propyl acetate, etc.

The organic base is selected from: organic amine bases such as dimethylamine, diethylamine, triethylamine, N-diisopropylethylamine, isopropylamine, hexamethylenediamine, etc.; alkali metal salts of alcohols are selected from lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, etc.

The carboxyl activating reagent is selected from: 1-hydroxy benzotriazole (HOBt) and 1-hydroxy-7-azo benzotriazole (HOAt).

The water reducing agent is selected from: 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDC. HCl), N-Dicyclohexylcarbodiimide (DCC).

The polypeptide condensing agent is selected from: o-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU); 2- (7-Azobenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU).

In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.

In the present application, unless otherwise indicated, scientific and technical terms used herein have the meanings that are commonly understood by those of skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.

The term "halo" as used herein means substituted with "halogen atom" which means fluorine atom, chlorine atom, bromine atom or iodine atom.

Said "C" of the present invention _1-6 Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C _1-5 Alkyl group "," C _1-4 Alkyl group "," C _1-3 Alkyl group "," C _1-2 Alkyl group "," C _2-6 Alkyl group "," C _2-5 Alkyl group and C _2-4 Alkyl group and C _2-3 Alkyl group and C _3-6 Alkyl group "," C _3-5 Alkyl group "," C _3-4 Alkyl group and C _4-6 Alkyl group "," C _4-5 Alkyl group and C _5-6 Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention _1-4 Alkyl "means C _1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.

The "halo C" of the present invention _1-6 Alkyl "refers to one or more halogen atoms substituted for C _1-6 One or more of alkylA group derived from a hydrogen atom, said "halogen atom" and "C _1-6 Alkyl "is as defined above. "halo C" as described in this invention _1-4 Alkyl "denotes halogeno C _1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.

The "hydroxyl group C" of the present invention _1-6 Alkyl "refers to one or more hydroxy-substituted C _1-6 A group derived from one or more hydrogen atoms of an alkyl group, said "C _1-6 Alkyl "is as defined above. The "hydroxy group C" of the present invention _1-4 Alkyl "means hydroxy C _1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.

"amino C" according to the invention _1-6 Alkyl "refers to one or more amino substituted C _1-6 A group derived from one or more hydrogen atoms of an alkyl group, said "C _1-6 Alkyl "is as defined above. "amino group C" according to the invention _1-4 Alkyl means amino C _1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.

"C" according to the invention _2-6 Alkenyl "means a straight, branched or cyclic alkenyl group having 2 to 6 carbon atoms containing at least one double bond, and includes, for example," C _2-5 Alkenyl group and C _2-4 Alkenyl group "," C _2-3 Alkenyl group "," C _3-6 Alkenyl group "," C _3-5 Alkenyl group and C _3-4 Alkenyl group "," C _4-6 Alkenyl group "," C _4-5 Alkenyl group "," C _5-6 Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like.

"C" according to the invention _2-6 Alkynyl "refers to a straight or branched chain alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, for example," C _2-5 Alkynyl and C _2-4 Alkynyl and C _2-3 Alkynyl group "," C _3-6 Alkynyl radical”、“C _3-5 Alkynyl group "," C _3-4 Alkynyl group "," C _4-6 Alkynyl group "," C _4-5 Alkynyl group "," C _5-6 Alkynyl "and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl and the like.

"four (C) according to the invention _1-6 Alkyl) Quaternary ammonium ion "means a plurality of identical or different C _1-6 Alkyl substituted quaternary ammonium ion (H) ₄ N ⁺ ) A group derived from four hydrogen atoms of the group "C _1-6 Alkyl "is as defined above.

"C" according to the invention _1-6 Alkoxy radical, C _1-6 Alkoxy radical C _1-6 Alkyl, halo C _1-6 Alkoxy, halo C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Alkylcarbonyl group, C _1-6 Alkylcarbonyloxy, C _1-6 Alkoxycarbonyl radical, C _1-6 Alkylcarbonyloxy C _1-6 Alkyl radical, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, C _1-6 Alkylamino radical C _1-6 Alkyl, halo C _1-6 Alkylcarbonyl, halo C _1-6 Alkyl carbonyl group C _1-6 Alkyl radical, C _1-6 Alkylamido radical, C _1-6 Alkylaminocarbonyl, di (C) _1-6 Alkyl) aminocarbonyl, C _1-6 Alkylsulfinyl radical, C _1-6 Alkylsulfonylamino, C _1-6 Alkylsulfonyloxy, C _1-6 Alkylsulfonyl radical C _1-6 Alkyl radical, C _1-6 Alkylsulfonyl "means with C _1-6 alkyl-O-, C _1-6 alkyl-O-C _1-6 Alkyl-, halo-C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-C _1-6 Alkyl-, C _1-6 alkyl-C (O) -, C _1-6 alkyl-C (O) -O-, C _1-6 alkyl-O-C (O) -, C _1-6 alkyl-C (O) -O-C _1-6 Alkyl-, C _1-6 alkyl-NH-, (C) _1-6 Alkyl radical) ₂ -N-，C _1-6 alkyl-NH-C _1-6 Alkyl-, halo-C _1-6 alkyl-C (O) -, halo-C _1-6 alkyl-C (O) -C _1-6 Alkyl-, C _1-6 alkyl-C (O) -NH-, C _1-6 alkyl-NH-C (O) -, (C) _1-6 Alkyl radical) ₂ -NH-C(O)-，C _1-6 alkyl-SO-, C _1-6 alkyl-SO ₂ -NH-，C _1-6 alkyl-SO ₂ -O-，C _1-6 alkyl-SO ₂ -C _1-6 Alkyl-, C _1-6 alkyl-SO ₂ A group attached by a formula wherein "C _1-6 Alkyl, halo C _1-6 Alkyl "is as defined above. "C" according to the invention _1-4 Alkoxy radical, C _1-4 Alkoxy radical C _1-4 Alkyl, halo C _1-4 Alkoxy, halo C _1-4 Alkoxy radical C _1-4 Alkyl radical, C _1-4 Alkylcarbonyl group, C _1-4 Alkylcarbonyloxy, C _1-4 Alkoxycarbonyl radical, C _1-4 Alkylcarbonyloxy C _1-4 Alkyl radical, C _1-4 Alkylamino, di (C) _1-4 Alkyl) amino, C _1-4 Alkylamino radical C _1-4 Alkyl, halo C _1-4 Alkylcarbonyl, halogeno C _1-4 Alkyl carbonyl radical C _1-4 Alkyl radical, C _1-4 Alkylamido radical, C _1-4 Alkylaminocarbonyl, di (C) _1-4 Alkyl) aminocarbonyl, C _1-4 Alkylsulfinyl radical, C _1-4 Alkylsulfonylamino group, C _1-4 Alkylsulfonyloxy, C _1-4 Alkylsulfonyl radical C _1-4 Alkyl radical, C _1-4 Alkylsulfonyl "refers to specific examples of the above examples in which the alkyl group contains 1 to 4 carbon atoms.

The "pharmaceutically acceptable cation" of the present invention may be a monovalent or divalent metal cation having a valence of the periodic Table of elements, such as Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、Fe ²⁺ (ii) a The organic cation can also be ammonium ions or nitrogen-containing organic cations, and the nitrogen-containing organic cations comprise the following components: (1) a plurality of C _1-6 Formed by alkyl radicals substituting for hydrogen of ammonium ions _1-6 Alkyl radical) ₄ N ⁺ Said plurality of C _1-6 The alkyl groups, which may be identical or different, are as defined above, and are preferably (C) _1-4 Alkyl radical) ₄ N ⁺ (ii) a (2) Organic compounds formed from nitrogen-containing organic heterocyclic or heteroaromatic ringsThe cation, preferably a 3-to 8-membered nitrogen-containing heterocyclic cation and a 5-to 6-membered nitrogen-containing heteroaromatic ring cation, may be, for example

And so on.

The "3-to 8-membered cycloalkyl group" referred to herein means a saturated cyclic alkyl group having 3 to 8 carbon atoms, and includes, for example, "3-to 4-membered cycloalkyl group", "3-to 5-membered cycloalkyl group", "3-to 6-membered cycloalkyl group", "3-to 7-membered cycloalkyl group", "4-to 5-membered cycloalkyl group", "4-to 7-membered cycloalkyl group", "4-to 8-membered cycloalkyl group", "5-to 6-membered cycloalkyl group", "5-to 7-membered cycloalkyl group", "5-to 8-membered cycloalkyl group", "6-to 8-membered cycloalkyl group", "7-to 8-membered cycloalkyl group" and the like. Specific examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. "5-6 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 5-6 carbon atoms.

The "6-to 8-membered aryl" as referred to herein means a monocyclic aryl group having 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like.

The "6-15 membered fused aryl" group according to the present invention means an unsaturated aromatic cyclic group having 6 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms with each other. Specific examples include, but are not limited to: naphthyl, anthryl, phenanthryl, and the like. The 6-10 membered fused aryl refers to a specific example of 6-10 ring atoms in the 6-15 membered fused aryl.

The "4-to 15-membered fused ring group" as referred to herein means a cyclic structure containing 4 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms with each other, and includes, for example, "4-to 12-membered fused ring group", "4-to 11-membered fused ring group", "5-to 10-membered fused ring group", "6-to 11-membered fused ring group", "5-to 9-membered fused ring group", "7-to 10-membered fused ring group", "4-to 12-membered fused ring group", "8-to 9-membered fused ring groupCyclyl group "," 9-to 10-membered fused cyclic group ", and the like, and optionally, a carbon atom in the cyclic structure may be oxo. Examples thereof include, but are not limited to:

and the like. The 4-to 10-membered fused ring group "means a specific example of the 4-to 15-membered fused ring group containing 4 to 10 ring atoms.

The "5-15 membered spirocyclic group" as used herein means a cyclic structure containing 5 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing one carbon atom with each other. Optionally, the carbon atom in the cyclic structure may be oxo. The "5-15-membered spiro ring group" includes, for example, "4-11-membered spiro ring group", "6-11-membered spiro ring group", "5-10-membered spiro ring group", "7-10-membered spiro ring group", "6-9-membered spiro ring group", "7-8-membered spiro ring group", "9-10-membered spiro ring group" and the like. Specific examples include, but are not limited to:

and so on. The "7-9-membered spirocyclic group" or "5-10-membered spirocyclic group" means a specific example in which 7 to 9 or 5 to 10 ring atoms are contained in 5-15-membered spirocyclic group.

The "5-15 membered bridged cyclic group" as used herein means a cyclic structure containing 5 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. Optionally, the carbon atom in the cyclic structure may be oxo. "5-15 membered bridged ring group" includes, for example, "5-11 membered bridged ring group", "6-11 membered bridged ringThe group "5-10 bridge ring group", "7-10 bridge ring group", "6-9 bridge ring group", "7-8 bridge ring group", "9-10 bridge ring group", etc. Specific examples include, but are not limited to:

and so on. The "5-to 10-membered bridged ring group" means a specific example in which the 5-to 15-membered bridged ring group contains 5 to 10 ring atoms.

The "3-to 8-membered heterocyclic group" as used herein means a saturated or partially saturated cyclic group having at least one hetero atom which is a nitrogen atom, an oxygen atom and/or a sulfur atom and having 3 to 8 ring atoms. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "3-to 8-membered heterocyclic group" includes, for example, "3-to 7-membered heterocyclic group", "3-to 6-membered heterocyclic group", "4-to 7-membered heterocyclic group", "4-to 6-membered heterocyclic group", "6-to 8-membered heterocyclic group", "5-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "3-to 8-membered oxygen-containing heterocyclic group", "3-to 6-membered oxygen-containing heterocyclic group", "5-to 6-membered saturated oxygen-containing heterocyclic group", "3-to 8-membered nitrogen-containing heterocyclic group", "5-to 6-membered saturated nitrogen-containing heterocyclic group" and the like, preferably "5-to 6-membered heterocyclic group". Specific examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diazaziridinyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidinonyl, tetrahydropyridinonyl, dihydropiperidinonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, diazo, and dihydropyrrolyl, Oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like. The "5-6 membered heterocyclic group" refers to a specific example containing 5 to 6 ring atoms in a 3-8 membered heterocyclic group.

The "4-15 membered fused heterocyclic group" as used herein means a cyclic structure containing 4 to 15 ring atoms (at least one of which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "4-15-membered fused heterocyclic group" includes, for example, "4-12-membered fused heterocyclic group", "4-10-membered fused heterocyclic group", "5-9-membered fused heterocyclic group", "6-11-membered fused heterocyclic group", "7-9-membered fused heterocyclic group", "9-10-membered fused heterocyclic group", "4-15-membered nitrogen-containing fused heterocyclic group", "4-10-membered nitrogen-containing fused heterocyclic group", "5-12-membered nitrogen-containing fused heterocyclic group", "5-10-membered nitrogen-containing fused heterocyclic group", "6-10-membered nitrogen-containing fused heterocyclic group", "7-9-membered nitrogen-containing fused heterocyclic group" and the like. Specific examples include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl cyclobutyl, pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, pyrrolidinyl morpholinyl, piperidinyl morpholinyl, pyrrolidinyl, tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, pyrrolidinyl cyclopropyl, piperidinyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroquinazolinyl, 2H-chromenyl, 4-one, 4H-1, 3-d, 4-d, and the like, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, benzimidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydrocyclopenta [ c ] pyrrolyl, indolinyl, dihydroisoindolyl, benzoxazolinyl, benzothiazolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 4H-1, 3-benzoxazinyl, and the like.

The "5-to 15-membered spiroheterocyclic group" as used herein means a saturated or partially saturated cyclic structure containing 5 to 15 ring atoms (at least one of which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more cyclic structures sharing one ring atom with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-to 15-membered spiroheterocyclic group" includes, for example, "5-to 11-membered spiroheterocyclic group", "6-to 11-membered spiroheterocyclic group", "5-to 10-membered spiroheterocyclic group", "6-to 9-membered spiroheterocyclic group", "7-to 9-membered spiroheterocyclic group", "9-to 10-membered spiroheterocyclic group", "7-to 9-membered saturated spiroheterocyclic group", "5-to 15-membered nitrogen-containing spirocyclic group", "5-to 10-membered nitrogen-containing spiroheterocyclic group", "7-to 11-membered nitrogen-containing spiroheterocyclic group", "7-to 9-membered saturated nitrogen-containing spiroheterocyclic group" and the like. Specific examples include, but are not limited to:

and the like. The "5-to 10-membered spiroheterocyclic group" means a specific example containing 5 to 10 ring atoms in the 5-to 15-membered spiroheterocyclic group. The "7-to 9-membered nitrogen-containing spiroheterocyclic group" refers to a specific example in which 7 to 9 ring atoms are contained in a 5-to 15-membered spiroheterocyclic group, and at least one ring atom thereof is a nitrogen atom.

The term "5-15 membered bridged heterocyclic group" as used herein means a group containing 5 to 15 ring atoms (of which up to and includingAt least one ring atom being a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-to 15-membered bridged heterocyclic group" includes, for example, "5-to 10-membered bridged heterocyclic group", "6-to 11-membered bridged heterocyclic group", "6-to 10-membered bridged heterocyclic group", "6-to 9-membered bridged heterocyclic group", "7-to 10-membered bridged heterocyclic group", "7-to 9-membered saturated bridged heterocyclic group", "5-to 15-membered nitrogen-containing bridged heterocyclic group", "5-to 9-membered nitrogen-containing bridged heterocyclic group", "7-to 8-membered nitrogen-containing bridged heterocyclic group", "7-to 9-membered saturated nitrogen-containing bridged heterocyclic group" and the like. Specific examples include, but are not limited to:

and the like. The "5-to 10-membered bridged heterocyclic group" means a specific example containing 5 to 10 ring atoms in the 5-to 15-membered bridged heterocyclic group. The "7-to 9-membered nitrogen bridged heterocyclic group" refers to a specific example of a 5-to 15-membered bridged heterocyclic group containing 7 to 9 ring atoms, at least one of which is a nitrogen atom.

The "5-to 8-membered heteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered heteroaryl" includes, for example, "5-7 membered heteroaryl", "5-6 membered heteroaryl", and the like. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyltrienyl, 1, 3-diazacycloheptyltrienyl, azocyclotetrazinyl, and the like. The "5-6 membered heteroaryl" refers to a specific example containing 5 to 6 ring atoms in the 5-8 membered heteroaryl.

The "5-to 15-membered fused heteroaryl group" according to the present invention means an unsaturated aromatic cyclic structure containing 5 to 15 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-15 membered thick heteroaryl" includes, for example, "5-10 membered thick heteroaryl", "7-10 membered thick heteroaryl", "9-10 membered thick heteroaryl", and the like. Specific examples include, but are not limited to: benzofuranyl, benzoisotropfuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl, and the like. The "5-to 10-membered fused heteroaryl group" refers to a specific example containing 5 to 10 ring atoms in a 5-to 14-membered fused heteroaryl group.

The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed ₂ The structure of (1).

The term "optionally substituted with a substituent" as used herein means substituted or unsubstituted with a substituent.

"pharmaceutically acceptable salts" of the compound (a) of the present invention refer to acidic functional groups (e.g., -COOH, -OH, -SO) present in the compound (a) ₃ H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts,and salts with nitrogen-containing organic bases; and basic functional groups (e.g. -NH) present in the compound (a) ₂ Etc.) with a suitable inorganic or organic anion (acid), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).

The "ester" of the compound (a) of the present invention means an ester which can be formed by esterification with an alcohol in the presence of a carboxyl group in the compound (a), and an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like in the presence of a hydroxyl group in the compound (a). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.

The "stereoisomers" of the compounds of the present invention are classified into conformational isomers and configurational isomers, and configurational isomers are also classified into cis-trans isomers and optical isomers (enantiomers). Conformational isomerism is a stereoisomerism phenomenon in which organic molecules having a certain configuration are rotated or twisted due to carbon and carbon single bonds, so that atoms or atom groups of the molecules generate different arrangement modes in space, and the common structures include structures of alkanes and cycloalkanes, such as chair conformation and ship conformation which appear in cyclohexane structure. "optical isomers" (enantiomers) "refers to compounds of the present invention which contain one or more asymmetric centers and thus can be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention. All enantiomers, diastereomers, racemates, meso-isomers, cis-trans-isomers, tautomers, geometrical isomers, epimers, mixtures thereof and the like of the compound (a) are claimed and are included in the scope of the present invention.

The "solvent compound" in the present invention refers to a complex formed by the interaction of a compound (such as beta-lactam antibiotics) and water or an organic solvent through non-covalent bonds; the organic solvent includes all kinds understood by those skilled in the art, such as alcohols, ethers, esters, aromatic hydrocarbons or aliphatic hydrocarbons, and the like.

The compound is an aggregate which is formed by combining a compound (such as beta-lactam antibiotics) and one or more other medicinal auxiliary molecules and has certain (physiological and chemical) functions or obvious (physicochemical) characteristics; such as substances obtained by improving the crystallization properties, formulation properties, etc. of compounds using pharmaceutical molecules.

The term "metabolite" as used herein refers to a substance produced by a compound (e.g., a β -lactam antibiotic) during in vivo metabolism, which may or may not have a higher or lower biological activity than the original compound.

The term "dosage form" as used herein refers to a form suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections, and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles, or suppositories, and more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles, or suppositories.

The "carrier" of the present invention includes, but is not limited to, fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, solubilizers; for example, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins, such as human serum protein, buffer substances, such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene block polymers, wool fat or any combination thereof.

The compound preparation is a preparation containing two or more main components, namely a preparation formed by mixing a plurality of different types of medicines.

The 'beta-lactamase' of the invention refers to a protein capable of inactivating beta-lactam antibiotics. Beta-lactamases are enzymes that can catalyze the hydrolysis of the beta-lactam ring of beta-lactam antibiotics. The invention mainly relates to microbial beta-lactamase which can be divided into 'A class', 'B class', 'C class' and 'D class' beta-lactamase. See in particular Waley, The Chemistry of beta-lactamase, Page Ed., Chapman & Hall, London, (1992) 198-228. Beta-lactamases of particular interest in the present invention include class C beta-lactamases produced by Pseudomonas aeruginosa (Pesudomonas pyocyaneum), Citrobacter freundii or Enterobacter cloacae (Eenterbacter cloacae); b-type metal beta-lactamase produced by Bacteroides fragilis (CcrA), Klebsiella pneumoniae, Escherichia coli (Escherichia coli), Enterobacter cloacae, Citrobacter freundii, Bacillus cereus (BcII) or stenotrophomonas maltophilia (L1); class A beta-lactamase produced by Klebsiella oxytoca, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Citrobacter freundii or Enterobacter hophilgenum; and class D beta-lactamases produced by Klebsiella pneumoniae or Escherichia coli.

The term "beta-lactamase inhibitor" as used herein refers to a compound capable of reducing or inhibiting the activity of beta-lactamase. Beta-lactamase activity refers to the activity of A, B, C and/or class D beta-lactamases. For antimicrobial applications, preferred half-effective inhibitory concentrations are no greater than 100. mu.g/mL, or no greater than 50. mu.g/mL, or no greater than 25. mu.g/mL, preferably no greater than 8. mu.g/mL, more preferably no greater than 4. mu.g/mL.

"antibiotic" as used herein refers to a compound or composition that reduces microbial viability or inhibits microbial growth or proliferation, and the term "inhibit growth or proliferation" refers to an increase in the passage time (i.e., the time required for bacterial cell division or population doubling) of at least about 2-fold. Preferred antibiotics are those capable of increasing passage time by at least about 10-fold or more (e.g., at least about 100-fold or even unlimited in total cell death). The antibiotics used in the present invention also include antimicrobial, bacteriostatic or bacteriocidal agents. Examples of antibiotics suitable for use in the present invention include beta-lactams, preferably penicillins, cephalosporins, carbapenems, monobactams.

An "effective amount" as referred to herein is an amount sufficient to obtain, or at least partially obtain, the desired effect. For example, a prophylactically effective amount (e.g., a disease associated with a bacterial infection) refers to an amount sufficient to prevent, or delay the onset of a disease (e.g., a disease associated with a bacterial infection); a disease-treating effective amount is an amount sufficient to cure or at least partially arrest the disease and its complications in the patient. It is well within the ability of those skilled in the art to determine such effective amounts, as may be judged by clinical trial results, model animal infection studies, and/or in vitro assays. The amount effective for therapeutic use will depend, inter alia, on the severity of the disease to be treated, the general state of the patient's own immune system, the patient's personality characteristics (e.g., age, weight, and sex), the mode of administration of the drug, and other treatments administered concurrently. For prophylactic treatment, a prophylactically effective amount is an amount that will be effective in preventing a bacterial infection.

"synergistic" or "synergistic effect" as used herein means that two or more drugs interact such that their combined effect is superior to their respective effects.

The "pharmaceutical product" according to the present invention, which comprises two or more main ingredients, such as the compound (a) of the present invention, or a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof, or a stereoisomer thereof, and a β -lactam antibiotic or a derivative thereof, may be present separately, for example, separately packaged to be present in separate formulations, or mixed with each other to be present in the form of a pharmaceutical composition.

All references cited in this application are intended to be included within the scope of the disclosure and are intended to be illustrative of the invention.

Advantageous effects of the invention

Compared to the prior art, the pharmaceutical product of the present application has one or more of the following advantages:

(1) the medicine product has excellent antibacterial activity, effectively reduces the bacteriostatic concentration of beta-lactam antibiotics, reduces toxic and side effects caused by high dosage of medicines, and has excellent treatment effect on infectious diseases caused by bacteria resistant to the beta-lactam antibiotics;

(2) the pharmaceutical products of the present application are effective in inhibiting the activity of one or more beta-lactamase enzymes, and can be used to treat diseases caused by drug-resistant bacterial infections caused by bacteria that produce beta-lactamase enzymes, particularly those caused by bacteria that produce class B beta-lactamase enzymes (e.g., Bacteroides fragilis (CcrA), Klebsiella pneumoniae, Escherichia coli or Enterobacter cloacae, Citrobacter freundii, Bacillus cereus (BcII), or stenotrophomonas maltophilia (L1), reducing longer stays, higher mortality, and more treatment costs caused by infections caused by drug-resistant bacteria;

(3) each component of the drug product has good pharmaceutical properties in pharmacokinetics and/or pharmacodynamics, such as good in vivo and in vitro antibacterial effects, higher exposure, better bioavailability, and/or longer half-life period, and the pharmaceutical properties of each component can be well matched, so that the drug product has good clinical application value;

(4) in the pharmaceutical product of the present application, the compound (a), a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof can exert therapeutic effects as a β -lactamase inhibitor and/or an antibiotic, and has a synergistic effect in combination with a β -lactam antibiotic. When the beta-lactamase inhibitor is used as a beta-lactamase inhibitor, the beta-lactamase inhibitor can inhibit all or part of beta-lactamase, effectively improve the antibacterial concentration of beta-lactam antibiotics and enhance the pharmacodynamic activity of the beta-lactam antibiotics; when used as an antibiotic, it has the effect of killing or inhibiting the growth of bacteria, and can synergistically enhance the antibacterial activity with a beta-lactam antibiotic. The technical effects possessed by the compound (a), a pharmaceutically acceptable salt, an ester, a solvate, or a stereoisomer thereof may be present simultaneously or separately on different strains.

Detailed Description

The present invention is further illustrated by the following specific embodiments, which are not intended to limit the invention. Modifications and improvements may be made by persons skilled in the art in light of the teachings of the invention without departing from the basic concept and scope of the invention.

The synthesis of the compound (a) of the present invention can be found in the method disclosed in patent WO2017045510, and all the technical contents cited in the present application are included in the disclosure of the present application.

Experimental protocol

The following provides some exemplary experimental protocols of the present invention to demonstrate the beneficial activity and beneficial technical effects of the pharmaceutical products of the present invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure. Those skilled in the art, having the benefit of the teachings of this specification, may effect numerous modifications thereto and changes may be made without departing from the scope and spirit of the invention in its aspects.

Experimental example 1 in vitro antibacterial Activity of Compound (a)

Test strains: the experimental enzyme-producing standard strains were purchased from ATCC and the clinically isolated CRE strains were purchased from southwest Hospital, third university of military medical science.

And (3) testing the sample: part of compound (a) or a salt of compound (a), the chemical name and the preparation method are shown in the preparation examples of each compound.

Control drug: abamebactam (AVI) sodium salt and MK-7655 are both manufactured by Shandongxuan bamboo medicine science and technology Limited company, and the structural formula is described in the background technology.

The experimental method comprises the following steps: agar dilution method, reference M100-S23: performance Standards for anti-microbial Suadaptability Testing; a minimum inhibitory concentration (MIC, minimum inhibitory concentration, μ g/mL) was calculated for the Twenty-Third information Supplement (Clinical And Laboratory Standards Institute, 2013).

The experimental results are as follows:

TABLE 1 in vitro antibacterial Activity of Compound (a) against ATCC enzyme-producing Standard Strain (. mu.g/mL)

Note: slash "/" indicates no measurement.

TABLE 2 Compound (a in vitro antibacterial Activity against clinically isolated CRE strains (. mu.g/mL)

Note: ESBLs stands for "extended spectrum beta-lactamases; slash "/" indicates no measurement.

TABLE 3 in vitro antibacterial Activity of Compound (a) against enzyme-producing strains (. mu.g/mL)

And (4) experimental conclusion:

the experimental results in tables 1,2 and 3 can judge that the inhibition effect of the compound (a) on drug-resistant bacteria caused by beta-lactamase is obviously better than that of a contrast drug, namely, Avibactam (AVI) sodium salt or MK-7655, particularly the problem of bacterial drug resistance caused by B-type metalloenzyme, and the compound (a) can solve the problem of antibiotic resistance caused by beta-lactamase; aiming at the test strains, the antibacterial activity is better, and the compound (a) or pharmaceutically acceptable salt, ester or solvent compound thereof or stereoisomer thereof has better clinical application potential.

Experimental example 2 in vitro enzymatic Activity experiment of Compound (a)

The experimental method comprises the following steps:

cefotaxime (Nitrocefin, a cephalosporin antibiotic) is sensitive to most beta-lactamases and undergoes a color change after hydrolysis. The rate of Nitrocefin hydrolysis was determined by recording the corresponding absorbance in real time in the reaction system. Beta-lactamase inhibitors inhibit the hydrolysis of Nitrocefin by the enzyme, reducing the rate of hydrolysis. Calculating the IC of the inhibitor by measuring the reaction rate in the same reaction system under different inhibitor concentrations ₅₀ (half maximal inhibitory concentration)。

1. Preparing a reagent:

nitrocefin was dissolved in DMSO at a concentration of 2mM and dispensed at-20 ℃. The purchased beta-lactamase stock solution was 1mg/mL, and the stock solution was dissolved in 50% glycerol. Taking part of the mother liquor to dilute 1000 times of the reaction solution, subpackaging and storing at-20 ℃.

2. Compound solution preparation:

test compounds were dissolved in DMSO to prepare a stock solution having a concentration of 10 mM. If not used on the same day, the mother liquor is stored at-20 ℃. The final concentration tested was: 100 μ M, 25 μ M, 6.25 μ M, 1.563 μ M, 390.6nM, 97.66nM, 24.41nM, 6.10nM, 1.53nM, 0.381nM, 0.095 nM. (EDTA-Na) ₂ The concentration was always 20mM as a control for NDM-1 testing).

3. Reaction system:

results of experiment 1:

TABLE 4 inhibitory Activity (IC) of Compound (a) against beta-lactamase ₅₀ )

Note: slash "/" indicates no measurement.

Results of experiment 2:

TABLE 5 inhibitory Activity (IC) of Compound (a) against beta-lactamase ₅₀ ,nM)

Experiment 3 results

TABLE 6 inhibitory Activity (IC) of Compound (a) against beta-lactamase ₅₀ )

And (4) experimental conclusion:

the above table shows that the compound (a) or the salt thereof has better inhibition effect on beta-lactamase and is superior to or equal to the inhibition activity of a control drug, namely Avibactam (AVI) sodium salt or MK-7655.

Experimental example 3 in vitro antibacterial Activity of Compound (a) in combination with ceftazidime

And (3) testing the sample: part of compound (a) or a salt of compound (a), the chemical name and the preparation method thereof are as described above.

Control drug: avibactam (AVI) sodium salt, purchased from denna new positive medicine science and technology ltd; MK-7655, made by self, with reference to the preparation method of WO2009091856A2 (published as 2009-07-23); ceftazidime (CAZ), purchased from shenglid biotechnology limited, tokyo.

Test strains: the experimental enzyme-producing standard strains are purchased from ATCC, and the clinical isolated CRE strains are purchased from third-military medical university

School southwest hospital.

The experimental method comprises the following steps: agar dilution method, reference M100-S23: performance Standards for anti-microbial Suadaptability Testing; a minute-Third information Supplement (Clinical And Laboratory Standards Institute,2013) fixes the concentration of the compound And calculates the minimum inhibitory concentration (MIC, μ g/mL).

The experimental results are as follows:

TABLE 7 MIC (μ g/mL) of the in vitro antibacterial Activity of the compositions of the invention against ATCC enzyme-producing Standard strains

Note: the dash "-" indicates no test was performed.

TABLE 8 MIC (μ g/mL) of the in vitro antibacterial Activity of the compositions of the invention against ATCC enzyme-producing Standard strains

TABLE 9 MIC (μ g/mL) of the in vitro antibacterial Activity of the compositions of the invention against ATCC enzyme-producing Standard strains

Note: the dash "-" indicates no test was performed.

TABLE 10 MIC (μ g/mL) of in vitro antibacterial Activity of the compositions of the invention against ATCC enzyme-producing Standard strains

Note: the dash "-" indicates no test was performed.

TABLE 11 MIC (μ g/mL) of the in vitro antibacterial Activity of the compositions of the invention against ATCC enzyme-producing Standard strains

Note: the dash "-" indicates no test was performed.

TABLE 12 MIC (μ g/mL) of in vitro antibacterial Activity of the compositions of the invention against clinically isolated CRE strains

Note: the dash "-" indicates no test was performed.

And (4) experimental conclusion:

from the experimental results in tables 7-13, it can be seen that the composition of the present invention has good antibacterial activity against the above drug-resistant bacteria caused by β -lactamase, and the inhibitory effect is superior to that of a single component of ceftazidime, a composition of Avibactam (AVI) sodium salt and ceftazidime, and/or a composition of MK-7655 and ceftazidime, especially for bacteria producing type B metalloenzymes, and can reduce the effective concentration of ceftazidime by more than 1000 times.

From the experimental results in tables 14 to 15, it can be seen that the compositions of the present invention with different ratios have good antibacterial effects on drug-resistant bacteria caused by β -lactamase, which are superior to the antibacterial effects of the ceftazidime mono-component, the composition of Avibactam (AVI) sodium salt and ceftazidime, and/or the composition of MK-7655 and ceftazidime, and especially for bacteria producing type B metalloenzymes, the effective concentration of ceftazidime is effectively reduced. In the compositions of the present invention with different ratios, the antibacterial effect is the best when the ratio of the compound to ceftazidime is 1:1, i.e. the lower the effective concentration of ceftazidime is.

From the above results, it can be seen that the compositions of the present invention are effective for bacterial resistance diseases caused by one or more beta-lactamases; particularly, the composition has better clinical application potential on bacterial drug-resistant diseases caused by B-type beta-lactam metalloenzyme.

Experimental example 4 in vitro antibacterial Activity of Compound (a) in combination with ceftriaxone sodium, cefotaxime sodium, cefoperazone, cefepime, ceftaroline fosamil

Test sample the partial compounds of the present invention, their chemical names and methods of preparation are as described above; ceftriaxone sodium, cefotaxime sodium, cefoperazone sodium, cefepime and cefprozil ester are all from commercial sources.

Comparison products: avibactam (Avibactam, AVI) sodium salt;

test strains: all experimental enzyme-producing standard strains are purchased from ATCC and total 11 strains;

concentration setting:

1. antibiotic concentration settings

Ceftriaxone sodium, cefotaxime sodium, cefoperazone sodium, cefepime and ceftaroline fosamil, the concentration range is 0.03-128 mug/ml when singly used, 13 gradients are totally obtained, the concentration range is 0.03-64 mug/ml when cefoperazone sodium and enzyme inhibitor are used together, 12 gradients are totally obtained, and the concentration ranges of other four antibiotics and enzyme inhibitor are used together, four antibiotics are 0.03-32 mug/ml, and 11 gradients are totally obtained.

2. Enzyme inhibitor concentration settings

The highest concentration of the compound 2, the compound 6 and the abamectin sodium salt when used singly is 64 mu g/ml, the highest concentration is 0.03 mu g/ml, and 12 gradients are formed;

the five antibiotics are combined with the compound 2, the compound 6 or the avibactam sodium salt according to a fixed proportion, wherein the proportion is 1:1, 2:1, 4:1, 6:1 and 8: 1.

3. Group of

The experiment is divided into an antibiotic group, an enzyme inhibitor group, an antibiotic-enzyme inhibitor group, a solvent control group and a blank control group.

Experimental method

1. The dilution method of the medicine comprises the following steps:

the antibiotic or enzyme inhibitor was formulated as a stock solution at a concentration of 1280. mu.g/ml.

Antibiotic group and enzyme inhibitor single group: diluting to different concentration gradients by a multiple dilution method, comprising the following steps:

2ml of sterile water for injection is added into each of the second test tube to the twelfth test tube, and 2ml of 1280. mu.g/ml liquid medicine is added into the first test tube (2 ml of 1280. mu.g/ml enzyme inhibitor +2ml of sterile water for injection). Adding 2ml of 1280 mu g/ml liquid medicine into the second test tube (adding 2ml of liquid medicine into the first test tube for the enzyme inhibitor), uniformly mixing, placing 2ml into the third test tube, carrying out two-time dilution on the solution, uniformly mixing the last test tube, taking out 2ml, and discarding the solution, wherein the minimum concentration of the solution is 0.3 mu g/ml;

and (3) combining the antibiotic group and the enzyme inhibitor in a fixed ratio, namely taking 2ml of prepared mother liquor with the required concentration of the two compounds respectively, uniformly mixing the mother liquor with the volume ratio of 1:1, and diluting the mother liquor by times to the required minimum concentration.

2. Preparation of drug-containing plate

Single-use group of drugs: first, 2ml of the prepared compound solution was added to the corresponding dishes in order. Finally, 18ml of MH agar medium (55 ℃) equilibrated in a water bath was added to each plate and mixed with each other. The liquid medicine in each plate is diluted 10 times, wherein the final concentration of the enzyme inhibitor single group is 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 and 0.03 mu g/ml from high to low, and the final concentration of the antibiotic single group is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 and 0.03 mu g/ml from high to low.

Drug combination group: the combination group with fixed proportion is that 2ml of mother liquor with the required concentration of the two prepared compounds are taken respectively, mixed evenly, diluted in multiple proportion and added into corresponding dishes in sequence. Finally, 18ml of MH agar medium (55 ℃) equilibrated in a water bath was added to each plate and mixed with each other. The liquid medicine in each plate is diluted 10 times, for example, in the case of a combination of ceftriaxone sodium/compound 6 in a fixed ratio of 2:1, the final concentrations of the compounds are 32(16), 16(8), 8(4), 4(2), 2(1), 1(0.5), 0.5(0.25), 0.25(0.125), 0.125(0.06), 0.06(0.03) and 0.03(0.015) μ g/ml from high to low.

3. Preparation of experimental bacteria liquid

From fresh colonies grown on non-selective medium for 18-20 hours, single colonies were picked, adjusted directly to 0.5# MAh turbidity (about 108cfu/ml) with sterile physiological saline, and diluted 10-fold with physiological saline for use.

4. Inoculating and culturing

And (3) inoculating 5 mu l of prepared bacterial liquid on the prepared medicine-containing plate by using an automatic bacteria inoculating instrument, inoculating 27 strains of bacteria on each plate at most, and marking the positions of the bacteria.

And (3) placing the plate inoculated with the bacteria into a biochemical incubator for culturing for 16-24 hours at 35 ℃.

A total of 11 strains were selected in this experiment and are shown in the following table:

strain numbering	Name of Strain	Enzyme production information
			BAA-2452 ^TM	Klebsiella pneumoniae	NDM-1
BAA-2524 ^TM	Klebsiella pneumoniae	OXA-48
			BAA-2523 ^TM	Klebsiella pneumoniae	OXA-48
BAA-2340 ^TM	Escherichia coli	KPC
			BAA-196 ^TM	Escherichia coli	TEM-10
BAA-2146 ^TM	Escherichia coli	NDM-1
			BAA-2341 ^TM	Escherichia coli	KPC
BAA-1900 ^TM	Enterobacter cloacae	KPC
			BAA-2468 ^TM	Enterobacter cloacae	NDM-1
ATCC-51983 ^TM	Enterobacter hollisae	SHV-5
			BAA-2082 ^TM	Klebsiella oxytoca	KPC

Results of the experiment

When the compound (a) is used alone, the MIC concentration of the compound (a) to the bacterial strain is 1-8 mu g/ml, and particularly the MIC concentration of the compound (a) to bacteria producing B-type metalloenzyme can be as low as 1 mu g/ml; the MIC concentration of the abamectin to the bacterial strain is more than 8-64 mu g/ml, and the MIC concentration of the abamectin to the bacteria producing the B-type metalloenzyme is more than 8 mu g/ml.

When ceftriaxone sodium, cefotaxime sodium, cefoperazone sodium, cefepime and cefprozil are used alone, strains producing A and D beta-lactamase, such as BAA-2524 ^TM 、BAA-2523 ^TM BAA-2340 ^TM 、BAA-196 ^TM 、BAA-2341 ^TM 、BAA-1900 ^TM 、ATCC-51983 ^TM 、BAA-2082 ^TM Certain or weak or no inhibiting effect; when the ceftriaxone sodium is combined with the compound (a) in the ratio of 1:1, 2:1, 4:1, 6:1 and 8:1 respectively, the MIC of the ceftriaxone sodium is obviously reduced and is more than 64 times better than that of the ceftriaxone sodium when the ceftriaxone sodium is combined with the compound 2 or the compound 6 in the ratio of 1:1 aiming at BAA-2523 ^TM The MIC value of (A) is reduced to 0.5 mu g/ml, which is about 256 times improved compared with the MIC (128 mu g/ml) of ceftriaxone sodium alone; ceftriaxone sodium in combination with compound 2 or compound 6 at a 1:1 ratio for BAA-2341 ^TM The MIC value of (A) is reduced to 1 mu g/ml, which is improved by about 64 times compared with the MIC (64 mu g/ml) of ceftriaxone sodium alone; the combination effect of each cephalosporin antibiotic and the compound (a) is better than that of each cephalosporin antibiotic and abamectinThe antibacterial effect after use is better or equivalent.

When ceftriaxone sodium, cefotaxime sodium, cefoperazone sodium, cefepime, and cefprozil are used alone, it can be used for strain producing B type metal beta-lactamase, such as BAA-2452 ^TM 、BAA-2146 ^TM 、BAA-2468 ^TM Almost no inhibitory effect; after the composition is respectively combined with the compound (a) in a ratio of 1:1, 2:1, 4:1, 6:1 and 8:1, the MIC of the composition is remarkably reduced and is about 4-128 times better than the effect of single use, and is about 2-8 times better than the antibacterial effect of each cephalosporin antibiotic combined with abamectin, and especially within a low proportion range (the cephalosporin antibiotics are 1: 1-4: 1) compared with the compound (a), the antibacterial effect of the composition is optimal.

Conclusion of the experiment

The composition can obviously reduce the effective concentration of the cephalosporin antibiotics, and solves the problem of bacterial drug resistance caused by beta-lactamase, in particular the drug resistance caused by B-type metalloenzyme.

Experimental example 5 in vivo Sterilization Effect test of the composition of the present invention in a neutropenia mouse thigh infection model

And (3) testing the sample: the chemical names and the preparation methods of the partial compounds of the invention are described above; antibacterial agents: ceftazidime (CAZ), commercially available.

Control drug: avibactam (AVI) sodium salt, purchased from denna new positive medicine science and technology ltd; MK-7655, which is prepared by self-made, refers to a preparation method in WO2009091856A2 (published as 2009-07-23).

The experimental method comprises the following steps:

1. in vitro antibacterial Activity test

Referring to the method of experimental example 1, the concentration of the compound was fixed, and the Minimum Inhibitory Concentration (MIC) of antibiotic inhibition (CAZ) was calculated, and the results are shown in table 16.

2. In vivo experiments in animals

Animal(s) production

Female CD-1(ICR) SPF grade mice weighing 25. + -.2 g were used in the experiments. Intraperitoneal injections were performed by two doses of cyclophosphamide: one induced granulocytopenia 4 days (150mg/kg) before infection experiments, and the other induced granulocytopenia 1 day (100mg/kg) before infection experiments.

Animals were raised in SPF level environment without restriction of water and grain.

Bacterial strains

Infection with disease

The concentration of the bacterial liquid is about 10 ⁵ -10 ⁷ The bacterial suspension in cfu/mL was inoculated intramuscularly in the thighs on both sides of neutropenic mice in a volume of 0.1mL per side.

Preparation of single-component or composite liquid medicine

Using 5% glucose injection or 1% Na ₂ CO ₃ The water solution dissolves corresponding medicines, is mixed evenly by vortex to prepare high-concentration solution, and then is diluted into other concentration solutions in sequence. For the combined liquid medicine, the two liquid medicines are mixed and uniformly mixed according to the ratio of 1:1(V/V) before administration, and the specific preparation concentration is shown in the following table:

administration of drugs

t is 0h, i.e. treatment is initiated 2h after infection is initiated or vehicle (control) at a dose of 10mL/kg, intravenously or subcutaneously, at a frequency of 2,4, 8 or 12 hour intervals (q2h, q4h, q8h or q12h) (over 24 h). Thighs were harvested from all animals 24 hours after treatment initiation, and mice that failed to survive 24 hours were harvested at the time of air deprivation. All study mice were harvested and sacrificed by cervical dislocation. After sacrifice, the thighs were removed, the leg bones removed, and each leg muscle was individually homogenized in physiological saline. The thigh muscle homogenate is subjected to a gradient dilution, howeverThe desired dilutions were then plated on nutrient agar for CFU determination. In addition to the treatment group and vehicle control group mentioned above, another group of 3 infected untreated mice was harvested at the beginning of the administration, and 3 mice were humanely sacrificed at t ═ 0h to determine the initial inoculum immediately prior to treatment. The effect of the medicine is determined as log10[ cfu/thigh ] when t is 24h and t is 0h]The difference between the values (Mean of 3 mice) is expressed as "Mean (logCFU/thigh) _change ". The results are shown in tables 17 to 19.

The experimental results are as follows:

TABLE 16 MIC (μ g/mL) of the Individual component or composition for the Strain in the study of drug action

TABLE 17 in vivo efficacy study of monocomponent or composition on class A beta-lactamase, extended spectrum enzyme producing bacteria in a neutropenic thigh infection model

Note: the slash "/" indicates no specific value — indicating that the data is not statistical.

TABLE 18 in vivo efficacy Studies of Single component or composition on B-or C-class beta-lactamase, extended spectrum enzyme producing bacteria in a neutropenic thigh infection model

Note: the slash "/" indicates no specific numerical value.

TABLE 19 in vivo efficacy study of monocomponent or composition on class D beta-lactamase, extended spectrum enzyme producing bacteria in a neutropenic thigh infection model

Note: slash "/" indicates no specific number.

And (4) experimental conclusion:

the experimental results in table 16 show that the inhibition effect of the composition of the present invention on drug-resistant bacteria caused by beta-lactamase is significantly better than that of a ceftazidime single component, a compound single component, and/or a composition of Avibactam (AVI) sodium salt and ceftazidime, and particularly, the inhibition effect on bacteria producing metal-B enzymes (NDM-1, IMP, VIM) is significantly better than that of a composition of Avibactam (AVI) sodium salt and ceftazidime.

From the experimental results in table 17, it can be determined that the in vivo pharmacodynamic activity of the composition of the present invention is superior to that of a ceftazidime monocomponent, a compound monocomponent, and/or a ceftazidime-avibactam sodium salt composition, in terms of a standard strain and a clinical strain producing class a beta-lactamase (KPC, SHV), an extended-spectrum enzyme, in a neutropenic thigh infection model; wherein, the in vivo pharmacodynamic activity of the ceftazidime + compound 2 is increased in proportion dependence, and the combination of the ceftazidime + compound 2 with the ratio of 4:1 or more has more advantages on treating the infection caused by the bacterial strain; the pharmacodynamic activity of the ceftazidime + compound 6 in a 4:1 combined mode is weaker than that of the ceftazidime + compound 2 in the same proportion, but is obviously better than that of the ceftazidime alone.

As can be seen from the experimental results in table 18, in the neutropenic thigh infection model, for the B-class metal beta-lactamase (IMP, NDM-1), C-class beta-lactamase (AmpC), standard strains and clinical strains of extended spectrum enzymes, the pharmacodynamic activity of the composition of the present invention is superior to that of a composition of a ceftazidime monocomponent, a compound monocomponent, and/or a ceftazidime-avibactam sodium salt; wherein the in vivo pharmacodynamic activity of the ceftazidime + compound 2 is increased in a ratio dependence manner and is enhanced along with the increase of the administration frequency, and the combination of the ceftazidime + compound 2 with the ratio of 4:1 or more is more advantageous for treating the infection caused by the bacterial strain; the pharmacodynamic activity of the ceftazidime + compound 6 is obviously superior to that of the ceftazidime alone.

As can be seen from the experimental results in table 19, the pharmacodynamic activity of the composition of the present invention is superior to that of the composition of ceftazidime monocomponent, compound monocomponent, and/or ceftazidime-avibactam sodium salt against D-class beta-lactamase (OXA), clinical strains of extended spectrum enzyme in the neutropenia thigh infection model; wherein the 2:1 combination of ceftazidime + compound 2 is more advantageous for treating infections caused by the above strains.

Thus, the compositions of the present invention can solve the problem of bacterial resistance caused by one or more beta-lactamases, in particular bacterial resistance caused by B-type metalloenzymes.

Experimental example 6 in vivo Sterilization test of the composition of the present invention in a model of mouse septicemia caused by BAA-1705

And (3) testing the sample: compound 6, its chemical name and method of preparation are as described above; ceftazidime (CAZ) is supplied by shandongxan bamboo medicine technology ltd.

The preparation method of the compound 6 comprises the following steps:

solvent: 5% glucose injection

Preparation: dissolving the compound in 5% glucose injection, filtering with 0.22 μm filter membrane for sterilization, and diluting with solvent to desired concentration.

CAZ preparation method

Solvent: 1% Na2CO3 aqueous solution

Preparation: the compound was dissolved in 1% aqueous Na2CO3 solution, sterilized by filtration through a 0.22 μm filter and then diluted with solvent to the desired concentration.

Combining the medicinal liquids, mixing the two medicinal solutions at a ratio of 1:1(V/V) before administration, and using.

Test animal

The SPF-grade Kunming mouse with the animal qualification certificate weighs 18-22 g, and is half male and half female.

Animals were kept in an SPF-grade environment.

Test strains

The strain name: klebsiella pneumoniae;

the strain number is as follows: BAA-1705;

enzyme production information: KPC;

the source is as follows: ATCC (American ginseng).

The in vitro minimal inhibitory concentrations of compound 6 and CAZ for this BAA-1705 are shown in the table below.

MIC values of Compound 6 with CAZ for BAA-1705

Infection with viral infection

The concentration of 100% Minimum Lethal Dose (MLD) of the bacteria solution is about 107CFU/ml, namely 2.0# M turbidity bacteria solution is diluted 5 times by 0.5% dry yeast solution to be used as injection bacteria solution, and mice (0.5 ml/mouse) are infected by the intraperitoneal injection bacteria solution.

Administration dose setting and administration

The test sets up 2 model control groups (100% MLD and 1/10MLD groups), 1 solvent group, and 10 dosing groups for the test drug. After fasting, the weight of the Kunming mice is 18-22 g, the Kunming mice are randomly divided into 8 mice each group, the male and female mice are half of the weight of the Kunming mice, and the experimental animals are divided into 18 groups.

Dose setting

The test animals were administered subcutaneously once each 1h and 4h after infection with the bacteria in a volume of 10mL/kg per mouse. Observation of results

After the administration, the observation was carried out day by day for 7 consecutive days. On day 7 after administration, the number of deaths of mice in each group was counted and statistically processed in comparison with the control group, and the survival rate was used as an index for evaluating the drug efficacy.

Results of the experiment

TABLE 20 in vivo protection of BAA-1705 induced mouse septicemia by Compound 6 and CAZ

ED 50: means the amount of drug that can protect 50% of the experimental animals from surviving in the dose-response of the test model of the fixed ratio of ceftazidime to compound 6 (ceftazidime: compound 6 ═ 2:1) for treating septicemia.

It can be seen from table 20 that the control group of the test model: the 100% MLD and 1/10MLD mortality rates are both 100%, which indicates that the molding is successful and the amount of the infected bacteria is slightly larger in the test.

The results of the in vivo antibacterial effect test are combined and analyzed as follows:

when CAZ is used singly, the administration dose is 512mg/kg, and the CAZ has no protective effect on infected mice;

the ED50 of the combination of CAZ and the compound 6 is 25.13/12.56mg/kg, the protection effect on the infected mice is poor and only 12.5 percent when the administration dose is less than or equal to 16/8mg/kg, and the protection effect on the infected mice can reach 100 percent when the administration dose is 256/128 mg/kg.

Conclusion of the experiment

Compared with the single use of CAZ, the composition provided by the invention has the advantages that the survival rate of mice with septicemia caused by BAA-1705 is obviously improved, the effective concentration of ceftazidime is reduced, and the composition has a good protection effect on infected mice. The above test protocol and effect of the composition of the present invention on animals can effectively guide the clinical test protocol of the composition and predict the clinical test effect.

EXAMPLE 7 in vitro antibacterial Activity of Compounds of the present invention

And (3) testing the sample: the chemical names and preparation methods of the partial compounds of the invention are described above.

Control drug: AVI is self-made by Shandongxuan bamboo pharmaceutical science and technology Limited, and the structural formula is described in the background technology.

The experimental method comprises the following steps: agar dilution method, reference M100-S23: performance Standards for anti-microbial Suadaptability Testing; Twenty-Third information Supplement (Clinical And Laboratory Standards Institute,2013)

Experimental results and conclusions:

TABLE 21 MIC (μ g/mL) of in vitro antibacterial Activity of the Compounds of the invention against ATCC enzyme-producing Standard strains

Note that: when the antibacterial concentration of the composition is measured, the concentration of the compound is fixed, and the MIC of meropenem is measured, as follows.

"-" indicates not measured, the same applies below.

TABLE 22 MIC (μ g/mL) of in vitro antibacterial Activity of the Compounds of the present invention against ATCC enzyme-producing Standard strains

TABLE 23 MIC (μ g/mL) of in vitro antibacterial Activity of Compounds of the invention against clinically isolated CRE strains

TABLE 24 in vitro antibacterial Activity MIC (μ g/mL) of meropenem in combination with a fixed ratio of the Compound of the present invention against ATCC enzyme-producing Standard strains

[ Note ]: the 2:1 and the 4:1 are both the compound 6 or the compound 2 of the meropenem, and the following are the same.

TABLE 25 in vitro antibacterial Activity MIC (μ g/mL) of meropenem in combination with a fixed ratio of the compound of the invention against clinically isolated CRE strains

The experimental results in tables 21-25 show that the compound has better antibacterial activity on bacteria producing beta-lactamase when combined with meropenem and is obviously better than the single-component antibacterial effect of meropenem, particularly, the compound has good antibacterial effect on bacteria producing KPC enzyme and B-type metalloenzyme, the MIC concentration of meropenem is effectively reduced, and the compound has the potential of solving the drug resistance problem of carbapenem antibiotics.

EXAMPLE 8 in vitro antibacterial Activity of the Compound of the present invention with Aztreonam composition

And (3) testing the sample: the chemical name, the structural formula and the preparation method of the compound 6 are shown in PCT/CN 2016/095837.

Control drug: OP-0595 is made by Shandongxuan bamboo science and technology Limited, and its structural formula is described in the background.

Experimental results and conclusions:

TABLE 26 in vitro antibacterial Activity of the Compounds of the invention against ATCC enzyme-producing Standard strains (. mu.g/mL)

TABLE 27 in vitro antibacterial Activity of Compounds of the invention against clinically isolated CRE strains (. mu.g/mL)

TABLE 28 in vitro antibacterial Activity (μ g/mL) of aztreonam in fixed ratio with the Compounds of the invention against ATCC enzyme-producing Standard strains

[ Note ]: the 2:1 and the 4:1 both refer to aztreonam compound 6 or compound 2, and the same holds true below.

TABLE 29 in vitro antibacterial Activity of aztreonam in combination with the Compound of the invention on clinically isolated CRE strains (μ g/mL)

The experimental results shown in tables 26-29 show that the compound has better antibacterial activity on bacteria producing beta-lactamase when combined with aztreonam and is obviously better than the antibacterial effect of a single component of aztreonam, particularly, the compound has good antibacterial effect on bacteria producing KPC enzyme and B-type metalloenzyme, the MIC concentration of aztreonam is effectively reduced, and the compound has better antibacterial activity in a low proportion (such as the compound of the invention: aztreonam 1: 1-2) when combined with aztreonam, which indicates that the compound has the potential of solving the problem of antibiotic resistance.

The present invention is described in further detail with reference to the experimental examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the above-described embodiments. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Claims

1. A pharmaceutical product comprising compound (a), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and at least one β -lactam antibiotic or derivative thereof, wherein the β -lactam antibiotic or derivative thereof is aztreonam;

the compound (a) has a structure shown in a formula (I),

wherein the content of the first and second substances,

R ₁ is-OSO ₃ M；

M is selected from H, sodium ion, potassium ion, zinc ion or tetrabutylammonium ion;

ring A is selected from 7-9 membered spiro ring group, 7-9 membered nitrogen bridge heterocyclic group or 7-9 membered nitrogen spiro heterocyclic group;

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylcarbonyl group, C _1-6 Alkylsulfonyl, 3-to 8-membered cycloalkyl or 3-to 8-membered cycloalkyl-C _1-6 An alkyl group.

2. A pharmaceutical product according to claim 1, wherein compound (a) has the structure of formula (II),

wherein R is ₁ 、R ₂ Ring a is as defined in claim 1.

3. A pharmaceutical product according to claim 1, wherein compound (a) has the structure of formula (III),

wherein the content of the first and second substances,

R ₂ selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkyl carbonyl group, C _1-6 Alkylsulfonyl or 3-8 membered cycloalkyl;

m is selected from H, sodium ion or tetrabutylammonium ion;

the ring A is attached to the nitrogen atom of the amide group in compound (a) via a ring carbon atom.

4. The pharmaceutical product of claim 1, wherein in compound (a),

ring A is selected from 2-azabicyclo [2.2.1] heptanyl, 7-azabicyclo [2.2.1] heptanyl, 3-azabicyclo [3.2.1] octanyl, 8-azabicyclo [3.2.1] octanyl, 2-azabicyclo [2.2.2] octanyl, 2, 5-diazabicyclo [2.2.1] heptanyl, 3, 8-diazabicyclo [3.2.1] octanyl, 3, 9-diazabicyclo [3.3.1] nonanyl, 5-azaspiro [2.4] heptanyl, 2-azaspiro [3.3] heptanyl, 2-azaspiro [3.5] nonanyl, 7-azaspiro [3.5] nonanyl, 2, 6-diazaspiro [3.3] heptanyl, 2-azaspiro [4.4] nonanyl or spiro [3.3] heptanyl;

R ₂ selected from a hydrogen atom, a fluorine atom, a chlorine atom, an amino group, a hydroxyl group, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, a cyclohexyl group or a cyclohexylmethyl group.

5. The pharmaceutical product of claim 1, wherein in compound (a),

ring A is selected from 2-azaspiro [3.3] heptylalkyl, 2-azaspiro [3.5] nonanyl, 7-azaspiro [3.5] nonanyl or spiro [3.3] heptanyl;

R ₂ selected from hydrogen atom, fluorine atom, chlorine atom, amino group, methyl group, ethyl group, butyl group, acetyl group, methylsulfonyl group, cyclopropyl group or cyclopropylmethyl group;

m is selected from H or sodium ion.

6. The pharmaceutical product of claim 5, wherein in Compound (a),

ring A is selected from 2-azaspiro [3.3] heptanyl;

R ₂ selected from hydrogen, amino, methyl, ethyl, butyl, acetyl, methylsulfonyl, cyclopropyl or cyclopropylmethyl;

m is selected from H or sodium ion.

7. The pharmaceutical product of claim 6, wherein compound (a) has the structure of formula (IV):

wherein R is ₂ Selected from hydrogen, amino, methyl, ethyl, butyl, acetyl, methylsulfonyl, cyclopropyl or cyclopropylmethyl;

m is selected from H or sodium ion.

8. The pharmaceutical product of claim 1, wherein compound (a) is selected from the group consisting of:

9. the pharmaceutical product of claim 8, wherein compound (a) is selected from

10. The pharmaceutical product of claim 1, further comprising one or more therapeutically active agents selected from an antibacterial agent, a beta-lactamase inhibitor, an anti-anaerobe agent, an antifungal agent, an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressive agent, an anticancer agent, an antiviral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, or an anti-vascular hyperproliferative compound;

the antibacterial agent is selected from tobramycin, levofloxacin, vancomycin, linezolid, tigecycline, or any combination thereof;

the beta-lactamase inhibitor is selected from clavulanic acid, tazobactam, sulbactam or any combination thereof;

the anti-anaerobe agent is metronidazole, and the antifungal agent is colistin;

said compound (a), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, said beta-lactam antibiotic or a derivative thereof and said therapeutically active agent are present in said pharmaceutical product in the form of a pharmaceutical composition.

11. Use of a pharmaceutical product according to claim 1 for the preparation of a pharmaceutical product for the prevention and/or treatment of an infectious disease caused by bacteria in a subject;

the bacterium has drug resistance caused by beta-lactamase;

the beta-lactamase is selected from: class A beta-lactamase, class B metallo beta-lactamase, class C beta-lactamase, class D beta-lactamase, or any combination thereof; the bacteria are selected from gram positive bacteria, gram negative bacteria or any combination thereof;

the gram-positive bacteria are selected from: staphylococcus aureus, staphylococcus epidermidis, streptococcus agalactiae, enterococcus faecalis, streptococcus pneumoniae, streptococcus pyogenes, enterococcus, clostridium difficile or any combination thereof;

the gram-negative bacteria are selected from: citrobacter, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Salmonella, Serratia marcescens, Shigella shigella, Pseudomonas aeruginosa, Moraxella mucosae, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria gonorrhoeae, Acinetobacter, Burkholderia, Campylobacter, helicobacter pylori, Vibrio cholerae, Klebsiella, Haemophilus influenzae, Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium ulcerae, Chlamydia pneumoniae, Chlamydia trachomatis, Streptococcus pyogenes, beta-hemolyticus, Pseudomonas aeruginosa, Bacteroides fragilis, Bacillus cereus, stenotrophomonas maltophilia, Enterobacter holtzeri, Klebsiella oxytoca or any combination thereof;

the infectious disease caused by bacteria is selected from: upper respiratory tract infections, lower respiratory tract infections, complicated urinary tract infections, central nervous system infections, ear infections, intra-abdominal infections, cardiovascular infections, bloodstream infections, skin or soft tissue infections, bone and joint infections, genital infections, eye infections, diabetic foot infections, gingivitis, or any combination thereof;

the subject is a mammal selected from bovine, equine, ovine, porcine, canine, feline, rodent, or primate.

12. The use of claim 11, wherein the beta-lactamase is a class B beta-lactamase; the bacteria are gram-negative bacteria; the subject is a human.

13. The use of claim 11, wherein the beta-lactamase is selected from the group consisting of: CTX-M, TEM, SHV, KPC, NDM, IMP, VIM, AmpC, OXA, extended spectrum beta-lactamase ESBLs, or any combination thereof.

14. Use of the pharmaceutical product of claim 1 for the preparation of a pharmaceutical product for the prevention and/or treatment of an infectious disease caused by bacteria in a subject, wherein the infectious disease caused by bacteria is selected from pharyngitis, bronchitis, pneumonia, empyema, meningitis, encephalitis, cerebral abscess, otitis externa, otitis media, peritonitis, visceral abscess, endocarditis, myocarditis, pericarditis, septicemia, bacteremia, osteomyelitis, arthritis, cystitis, pyelonephritis, pericardial ulcer, vaginitis, cervicitis, conjunctivitis, or keratitis.