Boric acid derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a boric acid derivative, and a preparation method therefor and the use thereof. The boric acid derivative is as shown in formula I, formula II or formula III, and has relatively strong antibacterial activity when used in combination with an antibacterial agent. After a single intravenous administration in mice, the in vivo exposure of the derivative is more than 5 times the exposure of QPX-7728, which is beneficial to reducing the administration dose while maintaining comparable efficacy, thereby reducing toxic side effects of the drug.

Description

Boric acid derivatives, methods of making and uses thereof

[0001] Priority claim

[0002] The present application is related to and claims priority to Chinese Patent Application No. 202411375487.1, filed on September 30, 2024, the entire contents of which are incorporated herein for all purposes to the extent not inconsistent with the present specification. TECHNICAL FIELD

[0003] The present application relates to the field of medicinal chemistry, in particular to a series of boric acid derivatives, methods of making and uses thereof. BACKGROUND

[0004] β-lactam antibiotics are the most widely used and the best anti-infective effect of a class of antibacterial drugs in clinical. The most important antibiotics available at present are several classes of compounds containing β-lactam ring, including penicillins, penems, carbapenems, cephalosporins, monobactams and sulfactams. This kind of antibiotics has the advantages of strong bactericidal activity, low toxicity, wide indications and good clinical efficacy. The mechanism of action of β-lactam antibiotics is similar, which inhibits the synthesis of cell wall muropeptide synthase, i.e. penicillin binding protein (PBP), thereby hindering the synthesis of cell wall muropeptide, causing bacterial cell wall defects, and bacterial lysis.

[0005] Although β-lactam antibiotics are still very important worldwide, the resistance to β-lactamase antibiotics in various infectious pathogens reduces the therapeutic effect on bacterial infections. One of the main mechanisms of bacterial resistance to β-lactam antibiotics is the production of β-lactamase, which can decompose β-lactam antibiotics, resulting in inactivation of antibacterial activity. So far, more than 2800 β-lactamases have been reported. They have many differences in source, substrate, inhibitor, structure, etc. In 1980, Ambler classified β-lactamases into four classes based on amino acid sequence analysis: class A is penicillinase, class B is metallo-β-lactamase (MBL), class C is cephalosporinase, and class D is oxacillinase. Among them, the active groups of classes A, C and D are serine (SBL), and class B is metal zinc ion (MBL).

[0006] β-lactamase inhibitors can bind to β-lactamase to inactivate the enzyme, thereby restoring the antibacterial activity of β-lactam antibiotics. Clinically, the combination of β-lactamase inhibitors with β-lactam antibiotics can inhibit drug-resistant bacteria, reduce the amount of use, expand the antibacterial spectrum and enhance the antibacterial activity. So far, the β-lactamase inhibitors on the market all have great limitations, and none of them can effectively treat MBL-mediated superbug resistance. Clavulanic acid, sulbactam and tazobactam can only inhibit part of class A SBL; avibactam inhibits class A, C and D SBLs, but has no effect on pathogenic bacteria resistant to MBL. MBLs can hydrolyze all β-lactam antibiotics except monobactams, including penicillins, cephalosporins, extended-spectrum cephalosporins, and carbapenems.

[0007] In recent years, new β-lactamase inhibitors have become a development hotspot. A class of compounds represented by phenylboronic acid has attracted widespread attention for its significant inhibitory effect on metallo-β-lactamase (MBLs). For example, QPX-7728 and the like. SUMMARY

[0008] The purpose of the present application is to provide a new type of β-lactamase inhibitor which has a significant inhibitory effect on four types of β-lactamase.

[0009] The present application provides a compound represented by formula I or formula II or a compound represented by formula III or a pharmaceutically acceptable salt thereof or an isomer thereof or a deuterated product thereof,

[0010] In formula I, represents a single bond or a double bond;

[0011] L1 is selected from -CH2-, -O-, -S-, -Se-, -CH2CH2-, -CH2O-, -CH2S-, -CH2Se-, -CH=CH-;

[0012] A is selected from a benzene ring or one or two 5-6 membered heteroaromatic rings selected from N, O or S;

[0013] R0, R1are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -Si(R C )3, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isostere, wherein the double bond connecting R0and R1to the ring is cis or trans; preferably, R0is H and R1is H, methyl, ethyl or -Si(CH3)3;

[0014] R A , R B , R Ceach independently selected from hydrogen, deuterium, amino, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic;

[0015] R2is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, alkenyl, alkynyl, carboxyl, acyl, sulfonyl, urea, guanidine, unsubstituted or substituted with one or more R D substituted C1-C6alkyl and C1-C6heteroalkyl, -O-R D , -S-R D , -Se-R D , or Preferably, R2is selected from H, halogen;

[0016] R3is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, alkenyl, alkynyl, carboxyl, acyl, sulfonyl, urea, guanidine, unsubstituted or substituted with one or more R H substituted C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -O-(CH2) n -R E1 , -S-R E2 , -Se-R E3 , or Preferably, R3is selected from H, halogen, -OH, unsubstituted or substituted with one or more R H substituted C1-C6alkyl, -O-(CH2) n -R E1 , -S-R E2 , -Se-RE3 , or

[0017] R D , R H each independently is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, wherein the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino, carboxylic acid isostere, or Preferably, R H is selected from halogen, -OH, -NH2, -COOH, B is selected from a 4-12 membered heterocyclic or heteroaryl ring having one, two, or three members selected from N, O, or S; L6is selected from a covalent bond or -(CH2) y -; y is selected from 0, 1, or 2; R k is selected from H, -COOH, -OH, -NH2, phenyl, C3-C6cycloalkyl, a 4-6 membered heterocyclic or heteroaryl ring having one, two, or three members selected from N, O, or S;

[0018] Preferably, RE1 R E2 R E3 each independently is selected from hydrogen or from an unsubstituted or substituted C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 4- to 6-membered heterocyclic ring having one or two heteroatoms selected from N, O, or S; preferably, R E substituted C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 4- to 6-membered heterocyclic ring having one or two heteroatoms selected from N, O, or S; preferably, R 10 substituted C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 4- to 6-membered heterocyclic ring having one or two heteroatoms selected from N, O, or S; preferably, R E halogen, -OH, -NH2, -NO, -COOH;

[0019] R b R c each independently is selected from substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, substituted by deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aryl ring, fused heteroaryl ring, bridged ring, bridged heterocyclic ring, -NR A R B -C(O)R C -C(O)OR C -C(O)SR C -C(S)R C -S(O)R C -S(O)OR C -S(O)(O)R C amino and carboxylic acid electronic isostere; or R b R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; preferably, R b R c each independently is selected from C1-C4alkyl or R b R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring;

[0020] R d R e each independently is selected from hydroxyl, -O-R F -S-R FSubstituent or unsubstituted C1-C6 hydrocarbon groups, C1-C6 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups. Substituents can be deuterium, halogens, hydroxyl groups, amino groups, cyano groups, nitro groups, carboxyl groups, acyl groups, sulfonyl groups, sulfonamide groups, sulfinimides, urea groups, guanidinyl groups, C1-C6 hydrocarbon groups, C1-C6 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, C5-C8 heteroaryl groups, and C7-C8 heteroaryl groups. 10 aryl hydrocarbon group, C5-C 10 Heteroaryl hydrocarbon group, spirocarbocyclic ring, spiroheterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heterocyclic ring, bridged ring, bridged heterocyclic ring, -NR A R B -C(O)R C -C(O)OR C -C(O)SR C -C(S)R C -S(O)R C -S(O)OR C -S(O)(O)R C Isosteres of amino and carboxylic acids;

[0021] Or R d R e Together with the atoms attached to it, it forms a 4- to 6-membered heterocycle, having one atom selected from N, O, S, or NR. F 4-6 quintile heterocyclic rings; preferably, R d R e Each alkyl group is independently selected from C1-C4;

[0022] R f Selected from O, NH or NR F Preferred, R f Selected from O or NH;

[0023] R4is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R4is selected from H, -COOH, the following groups unsubstituted or substituted with one or more R C1 C1-C6alkyl, C3-C6cycloalkyl, 5-10 membered heteroaromatic ring, 4-6 membered heterocyclic ring having one, two or three members selected from N, O or S, phenyl ring; R C1 is selected from H, halogen, -OH, -NH2, keto (=O), C1-C6alkyl unsubstituted or substituted with one or more R D C1-C6alkyl; R D is selected from H, halogen, -OH, -NH2, phenyl, C3-C6cycloalkyl, 5-6 membered heteroaromatic ring, 4-6 membered heterocyclic ring having one, two or three members selected from N, O or S;

[0024] L3is selected from a covalent bond, -(CH2) x -, -(CH2) n -NH-, -(CH2)n -N(R F )-, -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -Se-, -(CH2) n -, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)(O)-, Preferably, L3 is selected from the group consisting of a covalent bond, -CH2-, -C(O)-, -C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-,

[0025] n is selected from 0, 1, 2; preferably, n is selected from 0 or 1; x is 1 or 2 or 3;

[0026] L4 is selected from -CH2-, -N(R F )-, NH, O, S, Se;

[0027] L5 is selected from -CH2-, -CH2-CH2-, -CH(CH3)-, -CH(CH3)CH2-, -C(CH3)2CH2-, -N(R F )-, NH, O, S, Se;

[0028] R F is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic, bridged cyclic, bridged heterocyclic, substituted with deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isostere;

[0029] or R2, R3 together with the atoms to which they are attached form an optionally unsubstituted or substituted ring system selected from the group consisting of carbocyclic, heterocyclic, aryl, heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic; preferably, R2, R3 together with the atoms to which they are attached form a heterocyclic ring of 4 to 6 members selected from N, O or S.

[0030] R a1 is selected from the group consisting of R a1 is selected from the group consisting of

[0031] R b , R c are each independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl, the substituents being selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, urea, guanidine, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C2-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isostere; preferably, R b , Rc Each independently selected from C1-C4 alkyl or R b R c Together with the atoms attached to it, they form 4- to 6-membered heterocycles;

[0032] Or R b R c Together with the atoms attached to it, they form 4- to 6-membered heterocycles;

[0033] R d R e Each is independently selected from hydroxyl, -OR F -SR F Substituent or unsubstituted C1-C6 hydrocarbon groups, C1-C6 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups. Substituents can be deuterium, halogens, hydroxyl groups, amino groups, cyano groups, nitro groups, carboxyl groups, acyl groups, sulfonyl groups, sulfonamide groups, sulfinimides, urea groups, guanidinyl groups, C1-C6 hydrocarbon groups, C1-C6 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, C5-C8 heteroaryl groups, and C7-C8 heteroaryl groups. 10 aryl hydrocarbon group, C5-C 10 Heteroaryl hydrocarbon group, spirocarbocyclic ring, spiroheterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heterocyclic ring, bridged ring, bridged heterocyclic ring, -NR A R B -C(O)R C -C(O)OR C -C(O)SR C -C(S)R C -S(O)R C -S(O)OR C -S(O)(O)R C Isosteres of amino and carboxylic acids; preferably, R d R e Each alkyl group is independently selected from C1-C4;

[0034] Or R d R e Together with the atoms attached to it, it forms a 4- to 6-membered heterocycle, having one atom selected from N, O, S, or NR. F 4-6 quintile heterocyclic rings;

[0035] R f Selected from O, NH or NR F ;

[0036] In Formula III: Indicates a single bond or a double bond;

[0037] L2is selected from -CH2-, -0-, -S-, -Se-, -CH2CH2-, -CH2O-, -CH2S-, -CH2Se-, -CHCH-, =CHCH2-;

[0038] R a2 selected from halogen, R a2 selected from halogen,

[0039] R b , R c each independently selected from substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R b , R c each independently selected from C1-C4alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring;

[0040] or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring;

[0041] R d , R e each independently selected from hydroxyl, -O-R F , -S-R F, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR 10 , substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR 10 , substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR A , -C(O)R B , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , -NR C , amino and carboxylic acid electronic isosteres; preferably, R d , R e are each independently selected from C1-C4alkyl;

[0042] or R d , R e together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring, a 4- to 6-membered heterocyclic ring having one member selected from N, O, S or NR F ;

[0043] R f is selected from O, NH or NR F ;

[0044] R F is selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, the substituents can be deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C2-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C2-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isostere.

[0045] The present application also provides a compound represented by Formula I-1, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0046] wherein:

[0047] L1is selected from -CH2-, -O-, -S-, -Se-;

[0048] R0is selected from H; R1is selected from H, methyl or -Si(CH3)3; wherein the double bond connecting R0to the ring is cis or trans;

[0049] R2is selected from H, F, Cl, Br;

[0050] R3is selected from H, halogen, -OH, the following groups which are unsubstituted or substituted by one or more R H substituted C1-C6 alkyl, C1-C6 haloalkyl, -O-(CH2) n -R E1 , -S-R E2 , -Se-R E3 , or

[0051] n is selected from 0, 1, 2 or 3;

[0052] R H is selected from halogen, -OH, -NH2, -COOH,

[0053] B is selected from L6 is selected from covalent bonds or -(CH2). y -; y is selected from 0, 1, or 2; R k Selected from H, -COOH, -OH, -NH2, phenyl, C3-C6 cycloalkyl, having one, two or three 4- to 6-membered heterocycles or heteroaryl groups selected from N, O or S;

[0054] R E1 R E2 R E3 Each is independently selected from hydrogen or unsubstituted or by one or more R E Substitutes C1-C6 alkyl, C3-C6 cycloalkyl, or benzene rings, having one, two, or three 4- to 6-membered heterocycles selected from N, O, or S; R E Selected from halogens, -OH, -NH2, -NO, -COOH;

[0055] R b R c Each independently selected from C1-C4 alkyl or R b R c Together with the S atom it is attached to, it forms a 4- to 6-membered heterocycle; R d R e Each alkyl group is independently selected from C1-C4; R f Selected from O or NH;

[0056] R4 is selected from H, -COOH, -OH, -NH2, unsubstituted or substituted with one or more R4 groups. C1 The following groups are substituted: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C8 aryl, 5-10 membered heteroaromatic ring, having one, two or three 4- to 6 membered heterocycles selected from N, O or S;

[0057] L3 is selected from covalent bonds, -(CH2). x -, -C(O)-, -C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-, x is 1, 2, or 3;

[0058] R C1 Selected from H, halogen, -OH, -NH2, ketone group (=O), unsubstituted or with one or more R groups. D Substituted C1-C6 alkyl groups; R D Selected from H, halogens, -OH, -NH2, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaromatic rings, and having one or two 4- to 6 membered heterocycles selected from N, O or S;

[0059] Alternatively, R2 and R3 together with the attached atoms form a 4- to 6-membered heterocycle selected from one or two N, O, or S.

[0060] In some preferred instances, L1 is -CH2-.

[0061] In some preferred examples, R0 and R1 are H.

[0062] In some preferred examples, R2 is H, F, or Cl.

[0063] In some preferred embodiments, R3 is selected from H, halogen, -OH, unsubstituted, or substituted by one or more R H Substituted C1-C3 alkyl groups, C1-C3 haloalkyl groups, -O-(CH2) n -R E1 -SR E2 ,or

[0064] In some preferred instances, n is selected from 0 or 1;

[0065] In some preferred instances, R H Selected from halogens, -OH, -NH2, -COOH,

[0066] B is selected from L6 is selected from covalent bonds or -(CH2). y -; y is selected from 0, 1, or 2; R k It is selected from H, -COOH, -OH, -NH2, phenyl, C3-C6 cycloalkyl, having one, two or three 4- to 6-membered heterocycles or heteroaryl groups selected from N, O or S.

[0067] In some better instances, R H Selected from halogens, -OH, -NH2, and -COOH.

[0068] In some preferred instances, R E1 R E2 Each is independently selected from hydrogen or unsubstituted or by one or more R E Substituted C1-C3 alkyl, C3-C6 cycloalkyl, benzene ring, having one, two, or three 4- to 6-membered heterocycles selected from N, O, or S; R E Selected from halogens, -OH, -NH2, and -COOH. In some specific examples, R... E2 Selected from methyl or ethyl;

[0069] In some preferred instances, R b R ceach independently selected from C1-C4 alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; R d , R e each independently selected from C1-C4 alkyl, C1-C4 alkyl preferably being methyl, ethyl; R f is selected from O or NH.

[0070] In some preferred embodiments, R4 is selected from H, -OH, -NH2, the following groups, which are unsubstituted or substituted by one or more R C1 C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic ring having one, two or three members selected from N, O or S, phenyl ring. In some preferred embodiments, R C1 is selected from H, halogen, -OH, -NH2, keto (=0).

[0071] In some preferred embodiments, L3 is selected from a covalent bond, -(CH2) x -, -C(O)-, -C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-; x is 1 or 2.

[0072] In some preferred embodiments, R2, R3 together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring having one or two members selected from N, O or S.

[0073] The present application also provides a compound represented by Formula II-1, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0074] R a1 is selected from

[0075] R b , R c each independently selected from C1-C4 alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; R d , R e each independently selected from C1-C4 alkyl; R f is selected from NH.

[0076] a compound represented by any one of the following structures, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0077] In some embodiments of the present application, the pharmaceutically acceptable salt is an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt, including a disodium salt.

[0078] In some embodiments of the present application, the pharmaceutically acceptable salt of the compound is as follows: wherein, R0, R1, R2, R3, L1, A, R a1 , R a2 , L2r are as described above.

[0079] The present application also provides a compound as shown in any of the following structures, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated compound thereof,

[0080] The present application also provides a pharmaceutical composition comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated compound thereof, and one or more other drugs selected from antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, or anti-allergic agents; the composition can further comprise a pharmaceutically acceptable carrier.

[0081] In some embodiments of the present application, the other drug is an antibacterial agent, for example, meropenem.

[0082] The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated compound thereof, in the preparation of a beta-lactamase inhibitor drug.

[0083] The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a drug for treating diseases related to bacterial infection. The bacteria can be, for example, Klebsiella pneumoniae, Escherichia coli, or Enterobacter cloacae, etc.

[0084] The present application further provides a method for treating bacterial infection in a mammal, which can be a human, or can be a non-human mammal, for therapeutic purposes, comprising administering to the mammal a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated compound thereof, or a pharmaceutical composition.

[0085] Technical effects:

[0086] The present application discloses a series of novel boronic acid beta-lactamase inhibitors, which have strong antibacterial activity when combined with antibacterial agents. The in vivo exposure amount after a single intravenous administration in mice is more than 5 times the exposure amount of QPX-7728, which is conducive to reducing the dosage and reducing the side effects of the drug in the case of obtaining similar efficacy.

[0087] Explanation of terms

[0088] "Hydrocarbon group" refers to the saturated hydrocarbon group formed by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne.

[0089] A monovalent hydrocarbon group that is either unsaturated, branched, or straight-chain. Examples of hydrocarbon groups include: methyl; ethyls, such as ethane, vinyl, and ethynyl; propyls, such as propyl-1-yl, propyl-2-yl, propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), etc. The term "hydrocarbon group" specifically includes groups having any degree or level of saturation, i.e., groups having only carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having combinations of carbon-carbon single, double, and triple bonds. The terms alkyl, alkenyl, and ynyl are used when a specific level of saturation is intended.

[0090] "Aryl" refers to a single carbon atom from the parent aromatic ring system.

[0091] A aryl group is a monovalent aromatic group formed by removing a hydrogen atom from a carbon ring. Aryl groups include 5- and 6-membered carbocyclic aromatic rings, such as benzene; bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthalene, indene, and tetrahydronaphthalene; and tricyclic systems, such as fluorene, wherein at least one ring is a carbocyclic and aromatic. Aryl groups include polycyclic systems having at least one carbocyclic aromatic ring fused with at least one carbocyclic aromatic ring, a cycloalkyl ring, or a heterocyclic alkyl ring. For example, aryl groups include a phenyl ring fused with a 5- to 7-membered heterocyclic alkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic systems where only one ring is a carbocyclic aromatic ring, the radical carbon atom may be located on the carbocyclic aromatic ring or the heterocyclic alkyl ring. Examples of aryl groups include those derived from acethracene, acenaphthene, indene, indene, naphthalene, octylbenzene, octylphenene, cyclooctadiene, olebenzene, pentacene, cyclopentadiene, dibenzophenanthrene, perylene, phenaene, etc. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined separately herein.

[0092] "Arylalkyl" refers to a non-cyclic hydrocarbon group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Examples of arylalkyl groups include: benzyl, 2-phenylethyl-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, 2-naphthylvinyl-1-yl, naphthylbenzyl, and 2-naphthophenylethyl-1-yl. The terms arylalkyl, arylalenyl, or arylynyl are used when the specific hydrocarbon moiety is intended.

[0093] "Cyclic hydrocarbon group" refers to a saturated or partially unsaturated cyclic hydrocarbon group.

[0094] "Cycloalkylalkyl" refers to a non-cyclic alkyl group in which one of the carbon atoms bonded to a hydrogen atom is replaced by a cycloalkyl group as defined herein. If a specific alkyl moiety is intended, the term cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl is used.

[0095] "Heteroalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom group. Examples of heteroatom groups in heteroalkyl groups are: -0-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, among others.

[0096] "Halo" refers to a fluoro, chloro, bromo, or iodo group.

[0097] "Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and certain associated hydrogen atoms) is replaced by a heteroatom.

[0098] "Heterocycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated ring system in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom; or to a parent aromatic ring system in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom, thereby violating the Hückel rule.

[0099] "Heterocycloalkylalkyl" refers to a cycloalkylalkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are replaced with the same or different heteroatom.

[0100] "Spiro" refers to a polycyclic group in which single rings share a carbon atom (referred to as a spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Spiroalkyl groups are classified as mono-, bi-, or polyspiroalkyl groups, preferably mono- and bi-spiroalkyl groups, according to the number of rings that share a spiro atom. "Spirocarbocyclic" refers to the ring system in a spiroalkyl group.

[0101] "Fused" refers to a percarbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Fused alkyl groups are classified as bicyclo-, tricyclo-, tetracyclo-, or polycyclo-fused alkyl groups, preferably bicyclo- or tricyclo-fused alkyl groups, according to the number of rings that make up the ring system. "Fusedcarbocyclic" refers to the ring system in a fused alkyl group.

[0102] "Bridged ring" refers to a polycarbocyclic ring system in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Depending on the number of rings, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring alkyl group, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic.

[0103] "Spiro heterocycle" refers to a polycyclic ring system in which the single rings share a single carbon atom (referred to as the spiro atom), in which one or more ring atoms are a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system.

[0104] "Fused heterocycle" refers to a polycarbocyclic ring system in which each ring shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, in which one or more ring atoms are a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.

[0105] "Bridged heterocycle" refers to a polycarbocyclic ring system in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, in which one or more ring atoms are a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. DETAILED DESCRIPTION

[0106] The following examples facilitate a better understanding of the present application, but do not limit the present application. The experimental methods in the following examples are conventional methods, unless otherwise specified. The experimental materials used in the following examples are commercially available from conventional biochemical reagent stores, unless otherwise specified.

[0107] The free compound of the present application can be obtained by converting the salt compound into the free compound by the following method: dissolving the salt compound in water, adjusting the pH of the obtained aqueous solution to 6 with an acid (the acid can be selected from, but is not limited to, hydrochloric acid, sulfuric acid), directly preparing the obtained solution by Prep-HPLC (10%-90% ACN), concentrating the prepared solution to remove part of the acetonitrile and water, and freeze-drying the remaining material to obtain the target free compound.

[0108] Example 1: Preparation of compound 1j

[0109] 7-ethoxy-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0110] Step one: Preparation of compound 1b

[0111] Zinc powder (4.2 g, 64.2 mmol) was dissolved in dry tetrahydrofuran (19.3 mL) at room temperature, diisobutylaluminum hydride (0.7 mL, 1 M in n-hexane) was added, and then compound 1a (4.0 g, 20.0 mmol) was slowly added dropwise, the reaction temperature was controlled at 40 °C during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at room temperature for 2 h under nitrogen protection. A 1 M tetrahydrofuran solution of compound 1b was obtained, which was directly used in the next step.

[0112] Step two: Preparation of compound 1d

[0113] Compound 1c (6.0 g, 15.4 mmol) was dissolved in DMF (20 mL) at room temperature, K2CO3 (3.15 g, 22.8 mmol) and iodoethane (24.0 g, 154 mmol) were added in turn, and the reaction system was stirred at room temperature for 12 h under nitrogen protection. The reaction was monitored by TLC. Water (50 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 1d (3.5 g, yield 55%). 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.06-4.04 (m, 2H), 1.59 (s, 9H), 1.57 (s, 9H), 1.43-1.40 (m, 3H).

[0114] Step three: Preparation of compound 1e

[0115] Compound 1d (3.5 g, 8.4 mmol) was dissolved in trifluoroacetic acid (10 mL) at room temperature, and the reaction was carried out at room temperature for 1 h, and the reaction was monitored by TLC. The reaction solution was directly concentrated to dryness to obtain compound 1e (2.0 g, yield 95%). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 4.05 (d, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0116] Step four: Preparation of compound 1f

[0117] Compound 1e (2.0 g, 7.66 mmol) was dissolved in trifluoroacetic acid (10 mL) at room temperature, trifluoroacetic anhydride (5 mL), DMF (1 mL) and acetone (20 mL) were added successively, the reaction was stirred at 75 °C for 12 h under nitrogen protection. TLC monitoring showed that the reaction was completed, the excess trifluoroacetic acid was removed by direct concentration of the reaction solution, saturated sodium carbonate aqueous solution (50 mL) was slowly added to the residue, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 1f (1.0 g, yield 44%). 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.2 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 4.20-4.17 (m, 2H), 1.77 (s, 6H), 1.54 (t, J = 7.2 Hz, 3H).

[0118] Step five: Preparation of compound 1g

[0119] Compound 1f (350 mg, 1.16 mmol) was dissolved in THF (15 mL) at room temperature, bis(tri-tert-butylphosphine)palladium (60 mg, 0.12 mmol) was added, then the system was raised to 50 °C, and compound 1b (7 ml, 1M / THF) was added dropwise. After the addition was completed, the system was stirred at 50 °C for 0.5 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, saturated ammonium chloride (50 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) and Prep-HPLC (0.1% TFA, 60% ~ 95% ACN) to give compound 1g (0.12 g, yield 32%). 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.8, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.20-4.18 (m, 2H), 3.51 (s, 2H), 1.73 (s, 6H), 1.54 (t, J = 7.2 Hz, 3H), 0.21 (s, 9H).

[0120] Step six: Preparation of compound 1h

[0121] Compound 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (40 mg, 0.12 mmol) was dissolved in THF (1 mL) at room temperature, CuCl (10 mg, 0.10 mmol) and sodium tert-butoxide (35 mg, 0.40 mmol) were added, and the mixture was stirred at room temperature for 0.5 h under nitrogen protection. Pinacol diboronic acid (220 mg, 1.0 mmol) in THF (1 mL) was added to the above reaction solution and stirred for 15 min, then compound 1g (150 mg, 0.5 mmol) was directly added to the above reaction system, and the mixture was stirred at room temperature for 3 h after the addition was completed. After the reaction was completed, saturated ammonium chloride (50 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 8 / 1) and Prep-HPLC (0.1% TFA, 65%-90% ACN) to obtain compound 1h (0.1 g, yield 50%). LCMS (ESI): [M+H] + = 461.3.

[0122] Step seven: preparation of compound 1i

[0123] Compound 1h (40 mg, 0.087 mmol) was dissolved in trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 1i (20 mg, yield 58%). LCMS (ESI): [M+H] + = 389.3.

[0124] Step eight: preparation of compound 1j

[0125] Compound 1i (20 mg, 0.051 mmol, 1.0 eq) was dissolved in dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, and NaOH (3N, 0.1 mL) was added. The reaction was carried out at room temperature for 30 min, and LCMS showed that the starting material was completely reacted. The reaction was stopped, and the compound was prepared by Prep-HPLC (0.1% TFA, 15%-40% ACN). The preparation liquid was concentrated to remove part of the acetonitrile and water, and the residue was freeze-dried. NaOH (0.1N) was added again to make the pH = 8-9, and freeze-drying was carried out again to obtain compound 1j (2.3 mg, yield 18%). LCMS (ESI): [M+H] + = 249.1. 1H NMR (400 MHz, D20) δ 6.83 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.04 - 5.02 (m, 1H), 4.93 - 4.90 (m, 1H), 3.99 - 3.95 (m, 2H), 3.29 (s, 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0126] Example 2: Preparation of compound 2e

[0127] 7-Fluoro-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylic acid disodium salt

[0128] Step one, preparation of compound 2b

[0129] Zinc powder (2.05 g, 31.4 mmol) was placed in a 50 mL three-necked flask, tetrahydrofuran (20 mL) was added, the resulting reaction solution was replaced with nitrogen three times, stirred at room temperature, diisobutylaluminum hydride (0.5 mL, 1 M n-hexane solution) and compound 1a (2.0 g, 10.46 mmol) were added dropwise successively, after the addition was completed, the reaction was stirred at room temperature for 1 hour. The above reaction solution was added to compound 2a (1.0 g, 3.64 mol) and bis(tri-tert-butylphosphine)palladium (200 mg, 0.364 mmol) in tetrahydrofuran (10 mL) at room temperature, the resulting reaction solution was protected with nitrogen, heated to 50°C for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (100 mL), the resulting solution was extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 50 / 1) to obtain compound 2b (750 mg, yield 68%). 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (dd, J = 8.6, 5.7 Hz, 1H), 6.89 - 6.80 (m, 1H), 3.52 (s, 2H), 1.75 (s, 6H), 0.19 (s, 9H).

[0130] Step two, preparation of compound 2c

[0131] Compound 2b (100 mg, 0.326 mmol) in tetrahydrofuran (0.5 mL) was added dropwise, and stirring was continued at room temperature for 1 hour. After the reaction was completed, ethyl acetate (50 mL) was added for dilution, and the obtained solution was washed with water (20 mL x 3), saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 2c (60 mg, yield 42%). LCMS (ESI): [M+H] + = 435.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.28 (dd, J = 8.7, 5.9 Hz, 1H), 6.99 (dd, J = 10.2, 8.7 Hz, 1H), 6.65 (s, 1H), 3.44 (s, 2H), 1.71 (s, 6H), 1.03 (s, 12H), 0.11 (s, 9H).

[0132] Step three: Preparation of compound 2d

[0133] Compound 2c (60 mg, 0.138 mmol) was dissolved in DCM (0.5 mL) at 0°C, and the reaction solution was stirred at room temperature, and trifluoroacetic acid (0.5 mL) was slowly added thereto. After the addition was completed, the reaction was heated to 30°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness, and compound 2d (30 mg, yield 60%) was prepared by prep-TLC (PE / EA = 20 / 1). LCMS (ESI): [M+H] + = 363.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.39 (dd, J = 8.6, 5.8 Hz, 1H), 6.75 (dd, J = 9.9, 8.6 Hz, 1H), 5.89 - 5.84 (m, 1H), 5.56 - 5.49 (m, 1H), 3.39 (s, 2H), 1.71 (s, 6H), 1.21 (s, 12H).

[0134] Step four: Preparation of compound 2e

[0135] Compound 2d (30 mg, 0.083 mmol, 1.0 eq) was dissolved in dioxane / H20 (1 mL, 1 / 1) at room temperature, sodium hydroxide (3 M, 0.5 mL) was added, the reaction was carried out at room temperature for 30 minutes, the reaction solution was reversed phase preparation (C18, 0.05% HC1, 5%~35% ACN) and then freeze-dried, the solid was dissolved in 1 mL of water and the pH was adjusted to 8~9 with 0.1 N sodium hydroxide, and then freeze-dried to obtain compound 2e (4.5 mg, yield 25%). LCMS (ESI): [M+H] + = 223.1. 1 H NMR (400 MHz, Deuterium Oxide) δ 6.86 (t, J = 7.8 Hz, 1H), 6.38 (t, J = 8.7 Hz, 1H), 5.03 (s, 1H), 4.93 (s, 1H), 3.31 (s, 2H).

[0136] Example 3: Preparation of compound 3a

[0137] 2-Hydroxy-7-methoxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid disodium salt

[0138] The preparation method is as in Example 1. Compound 3a (17.3 mg, 37%) was prepared by replacing iodoethane with iodomethane. LCMS (ESI): [M+H] + = 235.2. 1 H NMR (400 MHz, D20) δ 6.85 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.91 (d, J = 4.0 Hz, 1H), 3.67 (s, 3H), 3.29 (s, 2H).

[0139] Example 4: Preparation of compound 4a

[0140] 7-Fluoro-2-hydroxy-3-((trimethylsilyl)methylene)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0141] Step one: Preparation of compound 4a

[0142] Compound 2c (40 mg, 0.09 mmol) was dissolved in dioxane (0.2 mL) and water (0.1 mL) at room temperature, NaOH (3 N, 0.1 mL) was added, the reaction was carried out for 1 h, after the reaction was completed, hydrochloric acid (1 N) was added to adjust pH = 8, the compound was prepared by Prep-HPLC (TFA 0.1%, 15%~40% CAN), after freeze-drying, NaOH (0.1 N) was added again to adjust pH = 8~9, freeze-drying again to obtain compound 4a (3.6 mg, yield 11%). LCMS (ESI): [M+H] + = 295.1. 1 H NMR (400 MHz, D20) δ 6.90-6.88 (m, 1H), 6.39-6.37 (m, 1H), 5.65 (s, 1H), 3.48 (s, 2H), 0.05 (s, 9H).

[0143] Example 5: Preparation of compound 5g

[0144] 3-ethylidene-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0145] Step one: Preparation of compound 5b

[0146] Zinc powder (2.50 g, 38.24 mmol) was placed in a 50 mL three-necked flask, tetrahydrofuran (15 mL) was added, the resulting reaction solution was replaced with nitrogen three times, stirred at room temperature, diisobutylaluminum hydride (0.5 mL, 1 M n-hexane solution) and compound 5a (2.0 g, 15.04 mmol) were added dropwise, after the dropwise addition was completed, the reaction was stirred at room temperature for 1 h. A 1 M tetrahydrofuran solution of compound 5b was obtained, which was directly used in the next step reaction.

[0147] Step two: Preparation of compound 5d

[0148] Compound 5c (1.2 g, 4.1 mmol) was dissolved in DCM (10 mL) at room temperature, SEM-Cl (1.0 g, 6.0 mmol) and DIEA (1.6 g, 12.3 mmol) were added in turn, the reaction system was stirred at room temperature under nitrogen protection for 12 h. After the reaction was completed, water (50 mL) was added to the system, the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 50 / 1) to obtain compound 5d (1.2 g, yield 69%).

[0149] Step three: Preparation of compound 5e

[0150] Compound 5d (1.2 g, 2.8 mmol) was dissolved in THF (10 mL) at room temperature, bis(tri-tert-butylphosphine)palladium (143 mg) was added, the system was warmed to 50 °C, compound 5b (14.8 mL, 1M in THF) was added dropwise and stirred for 0.5 hours. After the reaction was completed, the system was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 50 / 1) to obtain compound 5e (170 mg, yield 15%).

[0151] Step four: preparation of compound 5f

[0152] Compound 5f (22 mg, 0.05 mmol) was dissolved in dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, 3N NaOH aqueous solution (0.1 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the compound was prepared by Prep-HPLC (0.1% NH4HCO3, 10% ~ 15% ACN), and the prepared solution was freeze-dried. 0.1N NaOH aqueous solution was added to adjust the pH to 8 ~ 9, and the obtained solution was freeze-dried again to obtain compound 5g (2.1 mg, yield 18%). LCMS (ESI): [M+H] = 237.1.

[0153] Step five: preparation of compound 5g

[0154] Compound 5f (22 mg, 0.05 mmol) was dissolved in dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, 3N NaOH aqueous solution (0.1 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the compound was prepared by Prep-HPLC (0.1% NH4HCO3, 10% ~ 15% ACN), and the prepared solution was freeze-dried. 0.1N NaOH aqueous solution was added to adjust the pH to 8 ~ 9, and the obtained solution was freeze-dried again to obtain compound 5g (2.1 mg, yield 18%). LCMS (ESI): [M+H] = 237.1. + 1 ​H NMR (400 MHz, D20) δ 7.21-7.12 (m, 1H), δ 6.59-6.50 (m, 1H), 5.10 (s, 1H), 3.41-3.19 (m, 2H), 1.59 (s, 3H).

[0155] Example 6: Preparation of compound 6i

[0156] 2-hydroxy-3-methylene-7-(2,2,2-trifluoroethoxy)-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid disodium salt

[0157] Step one: Preparation of compound 6a

[0158] Compound lc (6.0 g, 15.4 mmol) was dissolved in DMF (20 mL) at room temperature, K2CO3(3.19 g, 23.1 mmol) and iodomethane (21.9 g, 154 mmol) were added successively, and the reaction system was stirred at room temperature for 12 h under nitrogen protection. After the reaction was completed, water (50 mL) was added to the system, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 6a (3.0 g, yield 48%). 1 H NMR (400 MHz, CDC13) δ 7.53 (d, J = 9.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 1.59 (s, 9H), 1.58 (s, 9H).

[0159] Step two: Preparation of compound 6b

[0160] Compound 6a (3.0 g, 7.44 mmol) was dissolved in TFA (10 mL) at room temperature, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction liquid was directly concentrated to dryness to obtain compound 6b (1.75 g, yield 95%). 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H).

[0161] Step three: Preparation of compound 6c

[0162] Compound 6b (2.0 g, 8.1 mmol) was dissolved in TFA (10 mL) at room temperature, TFAA (5 mL), DMF (1 mL) and acetone (20 mL) were added successively, the reaction was stirred at 75 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, saturated aqueous sodium carbonate solution (50 mL) was added to the residue, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 6c (0.9 g, yield 39%). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 9.2 Hz, 1H), 3.98 (s, 3H), 1.78 (s, 6H).

[0163] Step one: preparation of compound 6d

[0164] Compound 6c (2.0 g, 6.97 mmol) was dissolved in DCM (20 mL) at room temperature, and the temperature was lowered to -50 °C. Boron trichloride (1 M in DCM, 14 mL, 14.0 mmol) was slowly added dropwise under nitrogen protection, and the mixture was stirred at -50 °C for 2 h after the addition was completed. After the reaction was completed, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 6d (1.8 g, yield 94%). 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 6.68 (d, J = 9.2 Hz, 1H), 1.73 (s, 6H).

[0165] Step two: preparation of compound 6e

[0166] Compound 6d (0.9 g, 3.3 mmol) was dissolved in DMF (10 mL) at room temperature, K2CO3 (912 mg, 6.6 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.92 g, 8.25 mmol) were added successively, and the reaction system was heated to 80 °C and stirred for 2 h under nitrogen protection. After the reaction was completed, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 6e (1.0 g, 85%).1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 4.89-4.87 m, 2H), 1.71 (s, 6H).

[0167] Step three: Preparation of compound 6f

[0168] Compound 6e (0.5 g, 1.4 mmol) was dissolved in THF (5 mL) at room temperature, Pd(t-Bu)3P)2 (144 mg, 0.28 mmol) was added, stirred for 10 minutes at room temperature, then compound 1b (5.6 mL, 1M in THF) was added, protected by nitrogen, stirred for 1 hour at room temperature. After the reaction was completed, it was cooled to room temperature, saturated ammonium chloride (40 mL) was added to the system, extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 6f (265 mg, yield 49%). 1 H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.50-4.47 (m, 2H), 3.51 (s, 2H), 1.75 (s, 6H), 0.21 (s, 9H).

[0169] Step four: Preparation of compound 6g

[0170] Compound (1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride) (100 mg, 0.29 mmol) was dissolved in THF (1 mL) at room temperature, CuCl (23 mg, 0.23 mmol) and sodium tert-butoxide (90 mg, 0.93 mmol) were added, stirred for 0.5 hours at room temperature under nitrogen protection. Compound bis(pinacolato)diboron (884 mg, 3.48 mmol) was dissolved in THF (3 mL), added to the above reaction solution and stirred for 15 minutes, then compound 6f (450 mg, 1.16 mmol) was directly added to the above reaction solution, stirred for 3 hours at room temperature. After the reaction was completed, saturated ammonium chloride (50 mL) was added to the system, extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) and Prep-HPLC (0.1% TFA, 65% ~ 90% ACN) respectively to obtain compound 6g (80 mg, yield 13%). LCMS (ESI): [M+H] += 515.4.

[0171] Step five: Preparation of compound 6h

[0172] Compound 6g (50 mg, 0.097 mmol) was dissolved in TFA (1 mL) at room temperature, stirred for 16 hours under nitrogen protection at room temperature. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 6h (40 mg, yield 93%). LCMS (ESI): [M+H] + = 443.3.

[0173] Step six: Preparation of compound 6i

[0174] Compound 6h (40 mg, 0.09 mmol) was dissolved in dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, 3N NaOH aqueous solution (0.1 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the compound was prepared by Prep-HPLC (0.1% NH4HCO3, 15%~40% ACN), the preparation solution was concentrated under reduced pressure to remove most of the acetonitrile and water, the residue was freeze-dried, and the pH was adjusted to 8~9 with 0.1N NaOH aqueous solution, and the obtained solution was freeze-dried again to obtain compound 6i (7.4 mg, yield 22%). LCMS (ESI): [M+H] + = 303.1. 1 H NMR (400 MHz, D2O) δ 6.86 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.42-4.40 (m, 2H), 3.30 (s, 2H).

[0175] Example 7: Preparation of compound 7a

[0176] 7-(2,2-difluoroethoxy)-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0177] The preparation method is as in Example 1. Compound 7a (2.1 mg, 5.3%) was prepared by replacing iodoethane with 1,1-difluoro-2-iodoethane. LCMS (ESI): [M+H] + = 285.08. 1H NMR (400 MHz, D20) δ 6.86 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.23 - 5.96 (t, J = 52 Hz, 1H), 5.03 (s, 1H), 4.92 (s, 1H), 4.16 (td, J = 14.4, 3.8 Hz, 2H), 3.30 (s, 2H).

[0178] Example 8: Preparation of compound 8i

[0179] 2-hydroxy-3-methylene-7-(trifluoromethoxy)-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid disodium salt

[0180] Step one: Preparation of compound 8b

[0181] Compound 8a (4.0 g, 15.6 mmol) was dissolved in DCM (40 mL) at room temperature, and Boc20 (3.6 g, 16.3 mmol) and DMAP (95 mg, 0.78 mmol) were added successively. The reaction was stirred at room temperature for 1 h under nitrogen protection. After the reaction was completed, water (50 mL) was added to the system, and then 1 M HC1 was added to adjust pH = 7-8. Extraction was performed with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 8b (5.0 g, 90%).

[0182] Step two: Preparation of compound 8c

[0183] Compound 8b (5.0 g, 14.0 mmol) was dissolved in THF (40 mL) at room temperature, and the temperature was lowered to -78 °C using a dry ice acetone bath. LDA (2 M / THF, 13.5 mL, 27.0 mmol) was added dropwise slowly, and the temperature was controlled below -55 °C during the addition. After the addition was completed, the system was slowly warmed to room temperature and stirred for 1 h. After the reaction was completed, water (50 mL) was added to the system, and then 1 M dilute hydrochloric acid was added to adjust pH = 7-8. Extraction was performed with ethyl acetate (50 mL x 3), and the organic phase was combined. The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 8c (3.0 g, yield 60%).

[0184] Step three: Preparation of compound 8d

[0185] Compound 8c (3.0 g, 8.4 mmol) was dissolved in TFA (20 mL) at room temperature, and stirred for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was slurried with petroleum ether (30 mL) to obtain compound 8d (1.5 g, yield 60%). LCMS (ESI): [M-H] - = 288.9.

[0186] Step four: Preparation of compound 8e

[0187] Compound 8d (1.5 g, 5.0 mmol) was dissolved in TFA (5 mL) at room temperature, and TFAA (5 mL), DMF (1 mL) and acetone (10 mL) were added in sequence, and stirred for 12 hours under nitrogen protection and at 65°C. After the reaction was completed, the reaction solution was concentrated and rotary evaporated, and saturated aqueous sodium carbonate solution (50 mL) was added at room temperature, and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 8e (1.2 g, yield 70%). LCMS (ESI): [M+H] + = 341.02.

[0188] Step five: Preparation of compound 8f

[0189] Compound 8e (1.2 g, 3.5 mmol) was dissolved in THF (6 mL) at room temperature, and Pd(t-Bu)3P)2 (357 mg, 0.7 mmol) was added first, and then compound 1b (17.5 mL, 1M in THF) was added dropwise, and stirred for 0.5 hours at room temperature under nitrogen protection. After the reaction was completed, the system was cooled to room temperature, and saturated ammonium chloride solution (50 mL) was added, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 8f (0.2 g, yield 15%). LCMS (ESI): [M+H] + = 373.09.

[0190] Step six: Preparation of compound 8g

[0191] Compound (1, 3-bis(2, 4, 6-trimethylphenyl) imidazole hydrochloride) (70 mg, 0.2 mmol) was dissolved in THF (1 mL) at room temperature, CuCl (16 mg, 0.16 mmol) and sodium tert-butoxide (62 mg, 0.64 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours under nitrogen protection. Pinacol diboronic acid ester (610 mg, 2.4 mmol) in THF (3 mL) was added to the above reaction solution, and the mixture was stirred for 15 minutes. Then, compound 8f (300 mg, 0.8 mmol) was directly added to the above reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) and Prep-HPLC (0.1% TFA, 65% to 90% ACN) to obtain compound 8g (80 mg, yield 20%). LCMS (ESI): [M+H] + = 501.3.

[0192] Step seven: preparation of compound 8h

[0193] Compound 8g (80 mg, 0.16 mmol) was dissolved in TFA (1 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain compound 8h (60 mg, yield 88%). LCMS (ESI): [M+H] + = 429.1.

[0194] Step eight: preparation of compound 8i

[0195] Compound 8h (40 mg, 0.09 mmol) was dissolved in dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, and 3N aqueous NaOH solution (0.1 mL) was added, and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the compound was prepared by Prep-HPLC (0.1% NH4HCO3, 15% to 40% ACN), the preparation liquid was concentrated to remove the solvent, and the residue was freeze-dried. NaOH (0.1N) was added again to make the pH = 8-9, and freeze-drying was performed again to obtain 8i (9.4 mg, yield 29%). LCMS (ESI): [M+H] + = 289.0. 1 H NMR (400 MHz, D2O) δ 6.92 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.04 (d, J = 4.0 Hz, 1H), 4.93 (d, J = 4.0 Hz, 1H), 3.34 (s, 2H).

[0196] Example 9: Preparation of compound 9a

[0197] 7-(Cyclopropylmethoxy)-2-hydroxy-3-methylene-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0198] The preparation method is as in Example 1, using (iodomethyl)cyclopropane instead of iodoethane to prepare compound 9a (2.1 mg, 13%). LCMS (ESI): [M+H] + = 275.1. 1 H NMR (400 MHz, Deuterium Oxide) δ 6.82 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 8.2 Hz, 1H), 5.02 (s, 1H), 4.91 (s, 1H), 3.73 (d, J = 7.0 Hz, 2H), 3.28 (s, 2H), 1.13 (dd, J = 15.7, 7.4 Hz, 1H), 0.54 - 0.43 (m, 2H), 0.23 (dt, J = 6.2, 4.4 Hz, 2H).

[0199] Example 10: Preparation of compound 10f

[0200] 6-Fluoro-2-hydroxy-7-methoxy-3-methylene-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0201] Step one: Preparation of compound 10b

[0202] Compound 10a (2.0 g, 7.55 mmol) was dissolved in acetone (4.7 g, 79.3 mmol) and DMF (0.5 mL) in a 100 mL single-necked flask, and replaced with nitrogen three times, and trifluoroacetic anhydride (10.9 g, 51.8 mmol) and trifluoroacetic acid (3 mL) were added dropwise at 0 °C, and the reaction was carried out at 105 °C for 24 hours. After cooling to room temperature, the reaction solution was quenched with saturated sodium carbonate solution (500 mL), extracted with ethyl acetate (300 mL x 3), the combined organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 10b (400 mg, 17%). 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 10.6 Hz, 1H), 4.05 (s, 3H), 1.74 (s, 6H).

[0203] Step 2: Preparation of compound 10c

[0204] Compound 10b (400 mg, 1.31 mmol) and bis(tri-tert-butylphosphine)palladium (134 mg, 0.262 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, followed by the dropwise addition of 1b (8 mL, 1 M in THF). The reaction was carried out under nitrogen protection at 25 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 40 / 1) to give compound 10c (80 mg, 18%). 1 H NMR (400MHz, Chloroform-d) δ7.53–7.48(m,1H),4.04(s,3H),3.51(s,2H),1.70(s,6H),0.20(s,9H).

[0205] Step 3: Preparation of compound 10d

[0206] At room temperature, 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (21 mg, 0.0595 mmol), CuCl (5.0 mg, 0.0476 mmol), and t-BuONa (20 mg, 0.191 mmol) were dissolved in tetrahydrofuran (0.5 mL), and the mixture was purged with nitrogen three times. The reaction was carried out at room temperature for 30 minutes. A tetrahydrofuran (0.5 mL) solution of bis-pinacolborate (121 mg, 0.476 mmol) was added dropwise to the reaction system. After stirring at room temperature for 30 minutes, a tetrahydrofuran (0.5 mL) solution of compound 10c (80 mg, 0.238 mmol) and methanol (15.3 mg, 0.476 mmol) were added dropwise to the reaction system. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 10d (74 mg, 67%). LCMS (ESI): [M + H) + =465.4.

[0207] Step 4: Preparation of compound 10e

[0208] Compound 10d (74 mg, 0.159 mmol) was dissolved in TFA (1.0 mL) at 0 °C, and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 10e (20 mg, 32%). LCMS (ESI): [M+H] + = 393.2.

[0209] Step five: preparation of compound 10f

[0210] Compound 10e (20 mg, 0.051 mmol) was dissolved in dioxane / H2O (0.5 mL, 1 / 1) at room temperature, and 3M aqueous sodium hydroxide solution (0.2 mL) was added. The reaction was carried out at room temperature for 30 minutes. The reaction solution was freeze-dried after being prepared by Prep-HPLC (C18, 5%~10% ACN). The residue was dissolved in water (1 mL), and the pH was adjusted to 8-9 with 0.1N sodium hydroxide. After freeze-drying, compound 10f (2.8 mg, yield 17%) was obtained. LCMS (ESI): [M+H] + = 253.1. 1 1H NMR (400 MHz, Deuterium Oxide) δ 6.73 (d, J = 12.1 Hz, 1H), 5.06 (s, 1H), 4.96 (m, 1H), 3.78 (d, J = 0.9 Hz, 3H), 3.30 (s, 2H).

[0211] Example 11: preparation of compound 11e

[0212] 7-(Difluoromethoxy)-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0213] Step one: preparation of compound 11a

[0214] Compound 6d (600 mg, 2.2 mmol) was dissolved in DMF (8 mL) in a 50 mL three-necked flask, and nitrogen was replaced three times. Sodium difluoro chloroacetate (670 mg, 4.4 mol) and potassium carbonate (608 mg, 4.4 mmol) were added in turn, and the reaction was carried out at 80 °C for 1 hour. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 11a (600 mg, yield 85%).

[0215] Step two: Preparation of compound 11b

[0216] Compound 11a (600 mg, 1.86 mmol), bis(tri-tert-butylphosphine)palladium (190 mg, 0.37 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, then 1b (10.8 mL, 1M in THF) was added dropwise, and the reaction was carried out at 25 °C for 1 hour under nitrogen protection. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 11b (240 mg, yield 36%). LCMS (ESI): [M+H] + = 355.3.

[0217] Step three: Preparation of compound 11c

[0218] 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (59 mg, 0.17 mmol), CuCl (13 mg, 0.136 mmol), t-BuONa (52 mg, 0.54 mmol) were dissolved in tetrahydrofuran (0.5 mL) at room temperature, and the reaction was carried out at room temperature for 30 minutes under nitrogen protection. Bis(pinacolato)diboron (259 mg, 1.02 mmol) was dissolved in tetrahydrofuran (0.5 mL) and added dropwise to the reaction system, which was stirred at room temperature for 30 minutes. Then compound 11b (240 mg, 0.68 mmol) dissolved in tetrahydrofuran (0.5 mL) was added dropwise to the reaction system, which was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 11c (200 mg, yield 61%). LCMS (ESI): [M+H] + = 483.3.

[0219] Step four: Preparation of compound 11d

[0220] Compound 11c (200 mg, 0.41 mmol) was dissolved in TFA (1 mL) at 0 °C, and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 11d (100 mg, yield 59%). LCMS (ESI): [M+H] + = 411.2.

[0221] Step five: Preparation of compound 11e

[0222] Compound 11d (50 mg, 0.12 mmol) was dissolved in dioxane / H20 (0.5 mL, 1 / 1) at room temperature, sodium hydroxide (3 M, 0.4 mL) was added, and the reaction was stirred at room temperature for 30 min. The reaction solution was prepared by Prep-HPLC (C18, 5%~10% ACN) and then lyophilized. The residue was dissolved in water (1 mL), and the pH was adjusted to 8-9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 11e (2.1 mg, yield 5.3%). LCMS (ESI): [M+H] + = 271.13. 1 H NMR (400 MHz, D20) δ 6.91 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.81-6.43 (t, J = 76 Hz, 1H), 5.06 (s, 1H), 4.95 (s, 1H), 3.35 (s, 2H).

[0223] Example 12: Preparation of compound 12g

[0224] 2-Hydroxy-7-methyl-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8- carboxylic acid disodium salt

[0225] Step one: Preparation of compound 12b

[0226] Compound 12a (3 g, 0.016 mol) was dissolved in DCM (30 mL) at room temperature, then DMAP (20.0 mg, 0.16 mmol), Boc20 (3.92 g, 0.018 mol) were added, and the reaction was stirred at room temperature for 1 h. The reaction was complete, and the reaction solution was directly concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 30 / 1) to obtain compound 12b (4.0 g, yield 87%). 1 H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.05-7.01 (m, 1H), 2.35 (s, 3H), 1.55 (s, 9H).

[0227] Step two: Preparation of compound 12c

[0228] Compound 12b (2.5 g, 8.7 mmol) was dissolved in THF (30 mL) at room temperature, then the reaction was cooled to -78 °C, and LDA (5.2 mL, 10.4 mmol, 2M in THF) was added dropwise. After the addition was completed, the reaction was gradually warmed to room temperature, and stirred for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 12c (0.6 g, yield 24%). 1 H NMR (400 MHz, CD3OD) δ 7.51 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.4, 0.8 Hz, 1H), 2.47 (s, 3H), 1.66 (s, 9H).

[0229] Step three: preparation of compound 12d

[0230] Compound 12c (0.6 g, 2.09 mmol) was dissolved in DCM (10 mL) at room temperature, then DMAP (2.6 mg, 0.02 mmol), Boc20 (502 mg, 2.3 mmol) were added, and stirred at room temperature for 1 h. After the reaction was completed, the reaction was directly concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 30 / 1) to obtain compound 12d (0.6 g, yield 74%). 1 H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 2.34 (s, 3H), 1.60 (s, 9H), 1.55 (s, 9H).

[0231] Step four: preparation of compound 12e

[0232] Compound 12d (0.6 g, 1.55 mmol) was dissolved in THF (8 mL) at room temperature, to the resulting solution was added Pd(t-Bu)3P)2(80 mg, 0.155 mmol), after the addition was completed, compound 1b (7.8 mL, 7.75 mmol, 1 Min THF) was added dropwise into the reaction, under nitrogen protection, the reaction was carried out at 60 °C for 0.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added to the system, the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 12e (0.12 g, yield 18.4%). LC-MS: [M+Na] = 441.27. +

[0233] Step five: preparation of compound 12f

[0234] Compound (1,3-bis(2,4,6-trimethylphenyl)imidazole hydrochloride) (25 mg, 0.07 mmol) was dissolved in THF (1 mL) at room temperature, CuCl (5.8 mg, 0.06 mmol) and sodium tert-butoxide (22 mg, 0.23 mmol) were added, stirred at room temperature for 0.5 h under nitrogen protection. To the above reaction solution was added bis(pinacolato)diboron (147 mg, 0.58 mmol) in THF (3 mL), after the addition was completed, stirred for 15 min, compound 12e (120 mg, 0.29 mmol) and methanol (0.3 mL) were added, stirred at room temperature for 3 h. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the system, the resulting solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 12f (55 mg, yield 35%). LC-MS: [M+Na] = 569.32. +

[0235] Step six: preparation of compound 12g

[0236] Compound 12f (50 mg, 0.09 mmol, 1.0 eq) was dissolved in TFA (1 mL) at room temperature, the reaction was carried out in an ice bath for 0.5 h, after the reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%~20% ACN) and freeze-dried, the residue was dissolved in water (1 mL), the pH was adjusted to 8-9 with 0.1 N sodium hydroxide, and then freeze-dried to obtain compound 12g (10 mg, yield 39.6%). LC-MS: [M+H]​​+ = 219.14. 1 H NMR (400 MHz, D20) δ 6.83 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 4.94 (d, J = 4.0 Hz, 1H), 3.34 (s, 2H), 2.12 (s, 3H).

[0237] Example 13: Preparation of compound 13e

[0238] 6-chloro-2-hydroxy-7-methoxy-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8- carboxylic acid disodium salt

[0239] Step one: Preparation of compound 13a

[0240] 6c (1.0 g, 3.48 mmol) was placed in a 50 mL single-necked flask, to which DMF (10 mL) and NCS (604 mg, 4.53 mmol) were added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure to remove DMF, and the residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 2 (1.0 g, 89.5%). LCMS (ESI): [M+H] + = 322.99.

[0241] Step two: Preparation of compound 13b

[0242] Compound 13a (1.0 g, 3.11 mmol), bis(tri-tert-butylphosphine)palladium (316.9 mg, 0.62 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask at room temperature, which was replaced with nitrogen for 3 times, and compound lb (15.55 mL, 15.55 mmol, 1M in THF) was added dropwise under nitrogen protection, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 100 / 1) to obtain compound 13b (380 mg, 34.7%). LCMS (ESI): [M+H] + = 353.13.

[0243] Step three: Preparation of compound 13c

[0244] Compound 13b (380 mg, 1.078 mmol) in tetrahydrofuran (2 mL) and methanol (0.4 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered with celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 4 (87 mg, 16.8%). LCMS (ESI): [M+H] = 481.24. +

[0245] Step four: preparation of compound 13d

[0246] Compound 13c (87 mg, 0.181 mmol) was dissolved in trifluoroacetic acid (1.0 mL) at 0°C, and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was prepared by Prep-HPLC (TFA 0.1%, 15% to 40% ACN) to obtain compound 13d (57 mg, 77.2%). LCMS (ESI): [M+H] = 409.21. +

[0247] Step five: preparation of compound 13e

[0248] Compound 13d (57 mg, 0.14 mmol) was dissolved in isopropanol (0.5 mL) at room temperature, and sodium hydroxide (2M, 0.35 mL) was added. The mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was prepared by Prep-HPLC (NH4HCO3 0.1%, 1% to 35% ACN) and then lyophilized. The residual solid was dissolved in 1 mL of water, and the pH was adjusted to 8-9 with 0.1N sodium hydroxide. After lyophilization, compound 13e (8 mg, 17.3%) was obtained. LCMS (ESI): [M+H] = 269.10. + 1 H NMR (400 MHz, D2O) δ 7.14 (s, 1H), 5.24 (s, 1H), 5.14 (s, 1H), 3.95 (s, 3H), 3.50 (s, 2H).

[0249] Example 14: preparation of compound 14f

[0250] ​​​2,7-dihydroxy-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8-carboxylic acid disodium salt

[0251] Step one: Preparation of compound 14a

[0252] Compound 6c (4.0 g, 13.9 mmol) was dissolved in DCM (40 mL) at room temperature, and boron trichloride (27.8 mL, 27.8 mmol) was slowly added at -40 °C. The reaction was gradually warmed to -20 °C under nitrogen protection and stirred for 3 hours. After the reaction was completed, saturated aqueous sodium carbonate solution was slowly added to the solution under ice bath until the pH was 7-8. The resulting solution was extracted with DCM (150 mL x 3), and the organic phase was combined and washed with saturated brine (600 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 14a (2.2 g, 58.0%).

[0253] Step two: Preparation of compound 14b

[0254] Compound 14a (5.0 g, 18.3 mmol) was dissolved in DCM (50 mL) at room temperature, and DMAP (223 mg) and Boc20 (4.8 g, 21.9 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated to dryness, and the residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 14b (6.0 g, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 1.73 (s, 6H), 1.47 (s, 9H).

[0255] Step three: Preparation of compound 14c

[0256] Compound 14b (4.0 g, 10.7 mmol) was dissolved in THF (40 mL) at room temperature, and bis(tri-tert-butylphosphine)palladium (1.1 g, 2.14 mmol) was added, followed by dropwise addition of compound 1b (32.1 mL, 32.1 mmol, 1M in THF). The reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (100 mL) was added to the system. The resulting solution was extracted with ethyl acetate (150 mL x 3). The organic phase was combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 14c (2.4 g, 55.5%). LC-MS: [M+Na] +=427.22.

[0257] Step 4: Preparation of compound 14d

[0258] 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (321 mg, 0.93 mmol) was dissolved in 1 mL of THF at room temperature. CuCl (73 mg, 0.74 mmol) and sodium tert-butoxide (181 mg, 1.89 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours under nitrogen protection. A 1 mL solution of diboronpinacol ester (2818 mg, 11.1 mmol) in THF was added to the above reaction solution. After the addition was complete, the mixture was stirred for 15 minutes. Compound 14c (1.5 g, 3.71 mmol) and methanol (0.2 mL) were added sequentially to the above reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (90 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 8 / 1) to give compound 14d (0.8 g, 40.5%). LC-MS: [M + Na] + =555.21.

[0259] Step 5: Preparation of compound 14e

[0260] Compound 14d (700 mg, 1.31 mmol) was dissolved in 10 mL of TFA at room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was then subjected to Prep-HPLC (0.1% TFA, 60%–95% ACN) to obtain compound 14e (125 mg, 26.5%). LC-MS: [M+H] + =361.23.

[0261] Step Six: Preparation of Compound 14f

[0262] Compound 14e (25 mg, 0.07 mmol) was dissolved in 1,4-dioxane / H₂O (0.2 mL / 0.1 mL) at room temperature. NaO aqueous solution (3 N, 0.1 mL) was added, and the mixture was reacted at room temperature for 30 minutes. After the reaction was complete, the reaction solution was directly prepared by Prep-HPLC (NH₄HCO₃ 0.1%, 1%–35% ACN). The prepared solution was lyophilized, and the residual solid was dissolved in 1 mL of water. The pH was adjusted to 8–9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 14f (10.0 mg, 51.1%). LC-MS: [M+H] + =221.10. 1H NMR (400 MHz, D20) δ 7.29 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 4.0 Hz, 1H), 5.55-5.33 (m, 2H), 3.54 (s, 2H).

[0263] Example 15: Preparation of compound 15b

[0264] 2-Hydroxy-7-isopropoxy-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8- carboxylic acid disodium salt

[0265] Step one: Preparation of compound 15a

[0266] Compound 14e (25 mg, 0.07 mmol) was dissolved in DMF (1 mL) at room temperature, to which K2CO3 (25 mg, 0.18 mmol) and iodoisopropane (35.7 mg, 0.21 mmol) were added, and the reaction was heated to 80 °C for 2 hours. After the reaction was completed, the reaction was directly concentrated to dryness, and the residue was prepared by Prep-HPLC (0.1% TFA, 60%~95% ACN, 15 min). The prepared solution was lyophilized, and compound 15a (15 mg, 53%) was obtained. LC-MS: [M+H] + = 403.16.

[0267] Step two: Preparation of compound 15b

[0268] Compound 15a (15 mg, 0.037 mmol) was dissolved in 1,4-dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, and aqueous NaOH (3N, 0.1 mL) was added. The reaction was allowed to react at room temperature for 30 minutes, and after the reaction was completed, the reaction was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%~20% ACN). The prepared solution was lyophilized, and the residue was dissolved in 1 mL of water, and the pH was adjusted to 8~9 with 0.1N sodium hydroxide, and then lyophilized to obtain compound 15b (10.0 mg, 83.4%). LC-MS: [M+H] + = 263.16. 1 H NMR (400 MHz, D20) δ 7.07 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.28 (s, 1H), 5.17 (d, J = 4.2 Hz, 1H), 4.66-4.61 (m, 1H), 3.55 (s, 2H), 1.44 (d, J = 6.1 Hz, 6H).

[0269] Example 16: Preparation of compound 16a

[0270] 7-benzyloxy-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid disodium salt

[0271] Preparation method as in Example 15, using benzyl bromide instead of isopropyl iodide, to give compound 16a (2.1 mg, 17.1%). LC-MS: [M+H] + = 311.19. 1 H NMR (400 MHz, D20) δ 7.70 - 7.55 (m, 5H), 7.07 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.30 (s, 1H), 5.18 (s, 1H), 5.03 (s, 2H), 3.55 (s, 2H).

[0272] Example 17: Preparation of compound 17a

[0273] 7-benzyloxy-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid disodium salt

[0274] Preparation method as in Example 15, using n-butyl iodide instead of isopropyl iodide, to give compound 17a (10.0 mg, 55.8%). LC-MS: [M+H] + = 277.12. 1 H NMR (400 MHz, D20) δ 7.08 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 5.27 (s, 1H), 5.16 (s, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.54 (s, 2H), 1.90 - 1.82 (m, 2H), 1.65 - 1.57 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).

[0275] Example 18: Preparation of compound 18a

[0276] 7-benzyloxy-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid disodium salt

[0277] Preparation method as in Example 15, using 1-bromo-2-fluoroethane instead of isopropyl iodide, to give compound 18a (6.0 mg, 41.6%). LC-MS: [M+H] + = 267.10. 1H NMR (400 MHz, D20) δ 7.09 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.27 (s, 1H), 5.15 (d, J = 4.0 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.40 - 4.32 (m, 2H), 3.54 (s, 2H).

[0278] Example 19: Preparation of compound 19a

[0279] 2-Hydroxy-3-methylene-7-(3-oxetanyloxy)-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8- carboxylic acid disodium salt

[0280] Preparation method as in example 15. Replace iodine isopropyl with 3-iodooxetane to give compound 19a (1.8 mg, 4.3%). LCMS (ESI): [M+H] + = 277.1. 1 H NMR (400 MHz, D20) δ 7.09 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.27 (s, 1H), 5.15 (d, J = 4.0 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.40 - 4.32 (m, 2H), 3.54 (s, 2H).

[0281] Example 20: Preparation of compound 20a

[0282] 7-Cyclobutoxy-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8- carboxylic acid disodium salt

[0283] Preparation method as in example 15. Replace iodine isopropyl with bromo cyclobutane to give compound 20a (10.0 mg, 62.0%). LC-MS: [M+H] + = 275.15. 1 H NMR (400 MHz, D20) δ 7.06 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.28 (s, 1H), 5.18 (s, 1H), 4.81 (m, 1H), 3.55 (s, 2H), 2.53 (m, 2H), 2.27 (m, 2H), 1.95 (m, 1H), 1.79 (m, 1H).

[0284] Example 21: Preparation of compound 21a

[0285] 7-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-2-hydroxy-3-methylene-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0286] The compound 21a (8.0 mg, 37.7%) was prepared according to the procedure described in example 15, using 1-Boc-3-iodoazetidine instead of iodoisopropane. LC-MS: [M+Na] + = 398.2. 1 H NMR (400 MHz, D20) δ 7.08 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.29 (s, 1H), 5.18 (s, 1H), 5.12 - 5.11 (m, 1H), 4.50 (t, J = 8.4 Hz, 2H), 4.19 (d, J = 9.6 Hz, 2H), 3.55 (s, 2H), 1.63 (s, 9H).

[0287] Example 22: Preparation of compound 22c

[0288] 7-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-2-hydroxy-3-methylene-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0289] Step one: Preparation of compound 22b

[0290] Compound 22a (90 mg, 0.17 mmol) was dissolved in TFA (1 mL) at room temperature and the reaction was allowed to proceed for 2 hours at room temperature. Upon completion of the reaction, the compound was prepared by Prep-HPLC (0.1% TFA, 60% ACN to 95% ACN, 15 min) and the prepared solution was lyophilized directly to give compound 22b (45 mg, 63.7%). LC-MS: [M+H] + = 416.29.

[0291] Step two: Preparation of compound 22c

[0292] Compound 22b (40 mg, 0.096 mmol) was dissolved in 1,4-dioxane / H2O (0.2 mL / 0.1 mL) at room temperature, and an aqueous NaOH solution (3 N, 0.1 mL) was added thereto. The reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly subjected to Prep-HPLC preparation (0.1% NH4HCO3, 1% to 35% ACN). The preparation solution was lyophilized, and the residual solid was dissolved in 1 mL of water, adjusted to pH = 8 to 9 with 0.1 N sodium hydroxide, and lyophilized to obtain compound 22c (25 mg, 77.3%). LC-MS: [M+H] + = 276.16. 1 H NMR (400 MHz, D2O) δ 7.06 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.28 (s, 1H), 5.06 (s, 1H), 4.37 (m, 1H), 4.14 - 3.89 (m, 4H), 3.54 (s, 2H).

[0293] Example 23: Preparation of compound 23a

[0294] 7-((1-acetylazetidin-3-yl)oxy)-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid disodium salt

[0295] Step one: Preparation of compound 23a

[0296] Compound 22 (15 mg, 0.054 mmol) was dissolved in H2O (1 mL) at room temperature, and potassium carbonate (74.6 mg, 0.54 mol) and acetyl chloride (21.0 mg, 0.27 eq) were added thereto at 0°C. After the addition was completed, the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was directly subjected to Prep-HPLC preparation (0.1% NH4HCO3, 1% to 35% ACN). The preparation solution was lyophilized, and the residual solid was dissolved in 1 mL of water, adjusted to pH = 8 to 9 with 0.1 N sodium hydroxide, and lyophilized to obtain compound 23a (8.2 mg, 40%). LC-MS: [M+H] + = 318.16. 1 H NMR (400 MHz, D2O) δ 7.07 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.27 (s, 1H), 5.17 (s, 1H), 4.75 (m, 1H), 4.54 (m, 2H), 4.47 (m, 1H), 4.19 (m, 1H), 3.54 (s, 2H), 2.08 (s, 3H).

[0297] Example 24: Preparation of compound 24a

[0298] 7-((1 -Methanesulfonylazetidin-3-yl)oxy)-2-hydroxy-3-methylene-3,4-dihydro-2H- benzo [e] [1,2]oxaborinin-8-carboxylic acid disodium salt

[0299] Step one: preparation of compound 24a

[0300] Compound 22 (15 mg, 0.054 mmol) was dissolved in H20 (1 mL) at room temperature, potassium carbonate (74.6 mg, 0.54 mmol), MsCl (31.0 mg, 0.27 mmol) were added at 0 °C. After the addition was completed, the reaction was stirred at 0 °C for 1 h. The reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 1%~35% ACN), the preparation solution was lyophilized, the residual solid was dissolved in 1 mL water, 0.1 N sodium hydroxide was used to adjust pH = 8~9, and then lyophilized to obtain compound 24a (8.0 mg, 35.7%). LC-MS: [M+H] + = 354.16. 1 H NMR (400 MHz, D20) δ 6.82 (d, J = 8.2 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 5.02 (s, 1H), 4.93 (m, 2H), 4.34 - 4.21 (m, 2H), 3.99 (m, 2H), 3.28 (s, 3H), 3.08 (s, 2H).

[0301] Example 25: preparation of compound 25j

[0302] 7-Ethoxy-6-fluoro-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8- carboxylic acid disodium salt

[0303] Step one, preparation of compound 25b

[0304] Compound 25a (3.9 g, 25.3 mmol) was placed in a 100 mL single-necked flask, to which DME (20 mL), DMAP (158.6 mg, 1.3 mmol) and acetone (1.8 g, 32.9 mmol) were added, and SOCl2(3.9 g, 32.9 mmol) was added dropwise at 0 °C. After the dropwise addition was completed, the reaction solution was gradually warmed to room temperature and stirred for 1 hour. After the reaction was completed, water (30 mL) was added to quench the reaction, and the resulting solution was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 25b (3.27 g, 66%). LCMS (ESI): [M+H] + = 195.10.

[0305] Step two: Preparation of compound 25c

[0306] Compound 25b (39.2 g, 202.26 mmol) was placed in a 250 mL single-necked flask, to which acetonitrile (150 mL) and select-F (78.7 g, 222.26 mmol) were added. After the addition was completed, the reaction solution was heated to 60 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, water (50 mL) was added to the residue, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 100 / 1) to obtain compound 25c (14.58 g, 34%). 1 H NMR (400 MHz, Chloroform-d) δ 10.34 (s, 1H), 6.42 (dd, J = 8.8, 3.2 Hz, 1H), 1.77 (s, 6H), 1.59 (s, 1H).

[0307] Step three: Preparation of compound 25d

[0308] Compound 25c (3.58 g, 16.88 mmol) was placed in a 100 mL single-necked flask, to which DCM (25 mL) and NBS (3.6 g, 20.26 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100 / 1) to obtain compound 25d (3.61 g, 73%). 1H NMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 7.53 (d, J = 10.0 Hz, 1H), 1.58 (s, 6H).

[0309] Step four: Preparation of compound 25e

[0310] Compound 25d (3.61 g, 12.49 mmol) was placed in a 100 mL single-necked flask, to which DCM (30 mL), DMAP (15.26 mg, 0.12 mmol) and Boc20 (3.27 g, 14.99 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 25e (4.82 g, yield 99%). 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H), 1.60 (s, 9H), 1.55 (s, 6H).

[0311] Step five: Preparation of compound 25f

[0312] Compound 1b (7.71 mL, 1M in THF) was added to compound 25e (1.0 g, 2.57 mmol) and bis(tri-tert-butylphosphine)palladium (262.6 mg, 0.51 mmol) in tetrahydrofuran (10 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 25f (258 mg, yield 24%). LCMS (ESI): [M-100] + = 323.17.

[0313] Step six: Preparation of compound 25g

[0314] Compound 25g (210 mg, yield 13%) was obtained by the method described above. LC-MS: [M+H]=451.22. +

[0315] Step seven: Preparation of compound 25h

[0316] Compound 25g (87 mg, 0.181 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0 °C, and the reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was prepared by Prep-HPLC (TFA 0.1%, 15%~40% ACN) to obtain compound 25h (184 mg, 29%). LC-MS: [M+H]=379.18. +

[0317] Step eight: Preparation of compound 25i

[0318] Compound 25h (17 mg, 0.045 mmol) was dissolved in DMF (1 mL) at room temperature, and K2CO3 (62 mg, 0.45 mmol), iodoethane (70 mg, 0.45 mmol) were added thereto in sequence. After the addition was completed, the reaction solution was heated to 60 °C and reacted for 4 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was prepared by Prep-HPLC (0.1% TFA, 60%~95% ACN) to obtain compound 25i (15 mg, 82.1%). LC-MS: [M+H]=407.20. +

[0319] Step nine: Preparation of compound 25j

[0320] ​​​Compound 25i (15 mg, 0.037 mmol) was dissolved in isopropanol (0.2 mL) at room temperature, to which was added an aqueous NaOH solution (2 N, 0.2 mL), and after the addition was complete, the reaction was allowed to proceed at room temperature for 30 minutes. After the reaction was complete, the reaction solution was directly subjected to Prep-HPLC preparation (0.1% NH4HCO3, 10% to 20% ACN), and the preparation solution was lyophilized. The residual solid was dissolved in 1 mL of water, and the pH was adjusted to 8 to 9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 25j (5 mg, 41.2%). LC-MS: [M+H] + = 267.10. 1 H NMR (400 MHz, D2O) δ 6.92 (d, J = 11.8 Hz, 1H), 5.26 (s, 1H), 4.17 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.49 (s, 2H), 1.53 - 1.35 (m, 3H).

[0321] Example 26: Preparation of compound 26a

[0322] 7-butoxy-6-fluoro-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8- carboxylic acid disodium salt

[0323] The preparation method was as in Example 25, except that 1-iodobutane was used instead of iodoethane, to prepare compound 26a (5 mg, 38.0%). LC-MS: [M+H] + = 295.10. 1 H NMR (400 MHz, D2O) δ 6.92 (d, J = 12.0 Hz, 1H), 5.24 (s, 1H), 5.05 (s, 1H), 4.09 (t, J = 6.6 Hz, 2H), 3.50 (s, 2H), 1.82 (m, 2H), 1.57 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H).

[0324] Example 27: Preparation of compound 27a

[0325] 6-fluoro-7-(2-fluoroethoxy)-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8- carboxylic acid disodium salt

[0326] The preparation method was as in Example 25, except that 1-bromo-2-fluoroethane was used instead of iodoethane, to prepare compound 27a (6 mg, 45.6%). LC-MS: [M+H] + = 285.10. 1H NMR (400 MHz, D20) δ 6.93 (d, J = 11.9 Hz, 1H), 5.23 (s, 1H), 5.13 (s, 1H), 4.50 - 4.30 (m, 2H), 4.40 - 4.31 (m, 2H), 3.49 (s, 2H).

[0327] Example 28: Preparation of compound 28a

[0328] 6-Fluoro-2-hydroxy-3-methylene-7-propoxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8- carboxylic acid disodium salt

[0329] Preparation method as example 25, replace iodoethane with iodopropane, to prepare compound 28a (6 mg, 48.7%). LC-MS: [M+H] + = 281.10. 1 H NMR (400 MHz, D20) δ 6.96 - 6.85 (d, J = 11.9 Hz, 1H), 5.33 (s, 1H), 5.13 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.49 (s, 2H), 1.83 (q, J = 7.1 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H).

[0330] Example 29: Preparation of compound 29b

[0331] 7-(Carboxymethoxy)-6-fluoro-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][l,2]oxaborinin-8- carboxylic acid trisodium salt

[0332] Step one: Preparation of compound 29a

[0333] Compound 25h (17 mg, 0.045 mmol) was dissolved in DMF (1 mL) at room temperature, K2CO3 (62 mg, 0.45 mmol), methyl chloroacetate (49 mg, 0.45 mmol) were added successively, after the addition was completed, the reaction liquid was heated to 60 °C for 4 hours. After the reaction was completed, the compound was prepared by Prep-HPLC (0.1% TFA, 60% ~ 95% ACN) to obtain compound 29a (15 mg, 74.1%). LC-MS: [M+H] + = 451.20.

[0334] Step two: Preparation of compound 29b

[0335] Compound 29a (15 mg, 0.033 mmol) was dissolved in isopropanol (0.2 mL) at room temperature, and aqueous NaOH (2 N, 0.2 mL) was added. After the addition was completed, the reaction was allowed to proceed at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10% to 20% ACN). The preparation solution was directly freeze-dried. The residual solid was dissolved in 1 mL of water, and the pH was adjusted to 8 to 9 with 0.1 N sodium hydroxide. After freeze-drying, compound 29b (5 mg, 39.9%) was obtained. LC-MS: [M+H]=297.10. + 1 H NMR (400 Hz, D2O) δ 6.91 (d, J = 12.3 Hz, 1H), 5.24 (s, 1H), 5.14 (s, 1H), 4.53 (s, 2H), 3.49 (s, 2H).

[0336] Example 30: Preparation of compound 30f

[0337] 2-Hydroxy-3-methylene-7-(methylsulfonylimino)-3,4-dihydro-2H-benzo[e][1,2]oxa- naphthalene-8-carboxylic acid disodium salt

[0338] Step one: Preparation of compound 30b

[0339] Compound 30a (5.0 g, 12.8 mmol) was dissolved in DMF (20 mL) at room temperature, and sodium thiomethoxide (2.69 g, 38.4 mmol) was added thereto. The reaction solution was stirred at room temperature for 64 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by column chromatography (PE / EA = 5 / 1) to obtain compound 30b (2.3 g, 42.9%).

[0340] Step two: Preparation of compound 30c

[0341] ​Compound 30b (0.5 g, 1.19 mmol) was dissolved in methanol (5 mL) at room temperature, to which iodobenzene diacetate (766 mg, 2.38 mmol) and ammonium carbonate (229 mg, 2.38 mmol) were added, and after completion of the addition, stirring was performed at room temperature for 1 h. After completion of the reaction, water (30 mL) was added to the system, and the obtained solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 30c (0.35 g, 65.1%). LC-MS: [M+H] = 452.18. +

[0342] Step three: Preparation of compound 30d

[0343] Compound 30c (0.3 g, 0.66 mmol) was dissolved in THF (3 mL) at room temperature, to which bis(tri-tert-butylphosphine)palladium (68 mg, 0.13 mmol, 0.2 eq) and compound 1b (3.3 mL, 3.3 mmol, 1M in THF) were sequentially added, and the reaction solution was heated to 40°C under nitrogen protection for 0.5 h. After completion of the reaction, the reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (30 mL) was added to the system, and the obtained solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 30d (0.12 g, 37.7%). LC-MS: [M+H] = 482.58. +

[0344] Step four: Preparation of compound 30e

[0345] ​​1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (21 mg, 0.06 mmol) was dissolved in THF (1 mL) at room temperature. CuCl (5.0 mg, 0.05 mmol) and sodium tert-butoxide (19 mg, 0.2 mmol) were added sequentially, and the mixture was stirred at room temperature for 0.5 hours under nitrogen protection. A THF solution of pinacol diborate (127 mg, 0.5 mmol) in 2 mL was then added. After the addition was complete, the mixture was stirred at room temperature for 15 minutes. Compound 30d (120 mg, 0.25 mmol) and methanol (0.3 mL) were added sequentially, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (30 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 30e (75 mg, 49.2%). LC-MS: [M+H] + =610.45.

[0346] Step 5: Preparation of compound 30f

[0347] Compound 30e (20 mg, 0.03 mmol) was dissolved in 0.3 mL of TFA at room temperature and reacted in an ice bath for 0.5 h. After the reaction was complete, the reaction solution was concentrated to dryness. The residue was prepared by Prep-HPLC (0.1% NH4HCO3, 10%–20% ACN). The prepared solution was directly lyophilized, and the residual solid was dissolved in 1 mL of water, the pH was adjusted to 8–9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 30f (2.5 mg, 23%). LC-MS: [M+H] + =282.12. 1 H NMR (400MHz, D2O) δ7.29 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H), 5.11 (s, 1H), 3.58 (s, 2H), 3.32 (s, 3H).

[0348] Example 31: Preparation of compound 31c

[0349] 2-Hydroxy-3-methylene-7-(methylthio)-3,4-dihydro-2H-benzo[e][1,2]oxoborane-8-carboxylic acid disodium salt

[0350] Step 1: Preparation of compound 31a

[0351] Compound 30b (0.5 g, 1.19 mmol) was dissolved in THF (5 mL) at room temperature, and bis(tri-tert-butylphosphine)palladium (62 mg, 0.12 mmol, 0.1 eq) and compound 1b (6 mL, 5.95 mmol, 1M in THF) were added successively. The reaction was heated to 40°C for 0.5 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (20 mL) was added to the system. The resulting solution was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 31a (0.2 g, 37.3%). LC-MS: [M-H] - = 449.13.

[0352] Step two: Preparation of compound 31b

[0353] 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (38 mg, 0.11 mmol) was dissolved in THF (1 mL) at room temperature, and CuCl (8.8 mg, 0.09 mmol) and sodium tert-butoxide (34 mg, 0.35 mmol) were added successively. It was stirred at room temperature for 0.5 h under nitrogen protection. Bis(pinacolato)diboron (224 mg, 0.88 mmol) in THF (2 mL) was added, and it was stirred at room temperature for 15 min after the addition was completed. Compound 31a (200 mg, 0.44 mmol) and methanol (0.3 mL) were added successively, and it was stirred at room temperature for 3 h. After the reaction was completed, water (20 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 31b (110 mg, 43%). LC-MS: [M+Na] + = 601.13.

[0354] Step three: Preparation of compound 31c

[0355] Compound 31b (40 mg, 0.07 mmol) was dissolved in TFA (0.4 mL) at room temperature, and it was reacted in an ice bath for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was prepared by Prep-HPLC (0.1% NH4HCO3, 15%~30% ACN). The preparation liquid was directly freeze-dried, and the residual solid was dissolved in 1 mL of water, adjusted to pH = 8~9 with 0.1N sodium hydroxide, and freeze-dried to obtain compound 31c (12 mg, 55%). LC-MS: [M+H] += 251.10. 1 H NMR (400 MHz, D20) δ 7.15 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.27 (s, 1H), 5.16 (s, 1H), 3.56 (s, 2H), 2.58 (s, 3H).

[0356] Example 32: Preparation of compound 32d

[0357] 2-hydroxy-3-methylene-7-(methylsulfonyl)-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8- carboxylic acid disodium salt

[0358] Step one: Preparation of compound 32a

[0359] Compound 30b (0.5 g, 1.19 mmol) was dissolved in DCM (5 mL) at room temperature, then m-chloroperoxybenzoic acid (966 mg, 4.76 mmol, 85%) was added, stirred at room temperature for 1 h. Saturated aqueous sodium sulfite solution (30 mL) was added to the reaction solution, the resulting solution was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 3 / 1) to give compound 32a (0.33 g, 61.5%). LC-MS: 475.08 [M+Na] + = 475.08.

[0360] Step two: Preparation of compound 32b

[0361] Compound 32a (0.28 g, 0.62 mmol) was dissolved in THF (3 mL) at room temperature, then bis(tri-tert-butylphosphine)palladium (31 mg, 0.06 mmol) and compound 1b (3.1 mL, 3.1 mmol, 1M in THF) were added successively, and the reaction solution was heated to 40°C under nitrogen protection for 0.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 32b (0.25 g, 83.6%). LC-MS: [M+Na] + = 505.20.

[0362] Step three: Preparation of compound 32c

[0363] 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (54 mg, 0.16 mmol) was dissolved in 2 mL of THF at room temperature. CuCl (12.3 mg, 0.12 mmol) and sodium tert-butoxide (48 mg, 0.5 mmol) were added sequentially, and the mixture was stirred at room temperature for 0.5 h under nitrogen protection. A 3 mL solution of pinacol diborate (315 mg, 1.24 mmol, 2.0 eq) in THF was then added, and the mixture was stirred at room temperature for 15 min. Compound 32b (300 mg, 0.62 mmol) and methanol (0.6 mL) were added sequentially, and the mixture was stirred at room temperature for 3 h. After the reaction was complete, 30 mL of saturated ammonium chloride aqueous solution was added to the system, and the resulting solution was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give compound 32c (150 mg, 39.6%). LC-MS: [M+Na] + =633.24.

[0364] Step 4: Preparation of compound 32d

[0365] Compound 32c (70 mg, 0.11 mmol) was dissolved in 1 mL of TFA at room temperature and reacted in an ice bath for 0.5 h. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was prepared by Prep-HPLC (0.1% NH4HCO3, 10%–20% ACN). The prepared solution was directly lyophilized, and the residual solid was dissolved in 1 mL of water, the pH was adjusted to 8–9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 32d (11 mg, 29.1%). LC-MS: [M+H] + =283.05. 1 H NMR (400MHz, D2O) δ7.29-7.25(m,2H),5.22(s,1H),5.12–5.11(m,1H),3.58(s,2H),3.32(s,3H).

[0366] Example 33: Preparation of compound 33g

[0367] 7-Chloro-2-hydroxy-3-methylene-3,4-dihydro-2H-benzo[e][1,2]oxoborane-8-carboxylic acid disodium salt

[0368] Step 1: Preparation of compound 33b

[0369] Compound 33a (5.8 g, 14.2 mmol) was placed in a 100 mL single-necked flask, to which DCM (30 mL) and TFA (30 mL) were added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 33b (3.4 g, 95.1%).

[0370] Step two: Preparation of compound 33c

[0371] Compound 33b (3.4 g, 13.54 mmol) was dissolved in TFA (2.5 mL) at room temperature, and TFAA (14 mL), DMF (0.5 mL), and acetone (15 mL) were added in sequence. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 h. After the reaction was completed, the reaction solution was gradually cooled to room temperature, and saturated aqueous sodium carbonate solution (50 mL) was added to it. The resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 33c (1.97 g, 50.0%).

[0372] Step three: Preparation of compound 33d

[0373] Compound 33c (500 mg, 1.71 mmol) and bis(tri-tert-butylphosphine)palladium (175 mg, 0.34 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, and compound 1b (5.1 mL, 5.1 mmol, 1M in THF) was added dropwise. After the dropwise addition was completed, the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL), and the resulting solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 50 / 1) to obtain compound 33d (160 mg, 29.0%). + LCMS (ESI): [M+H] = 323.12.

[0374] Step four: Preparation of compound 33e

[0375] 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (42.4 mg, 0.12 mmol), CuCl (9.8 mg, 0.09 mmol), and sodium tert-butoxide (38.2 mg, 0.39 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. The reaction was carried out under nitrogen protection at room temperature for 30 minutes. A THF solution of pinacol diborate (252.3 mg, 0.99 mmol) in 1.0 mL was added dropwise, and the mixture was stirred at room temperature for another 10 minutes. Then, a THF solution of compound 33d (160 mg, 0.49 mmol) in 2 mL and methanol (0.2 mL) were added dropwise, and the mixture was stirred at room temperature for another 1 hour. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by column chromatography (PE / EA = 50 / 1) to give compound 33e (63 mg, 28.2%). LCMS(ESI):[M+H] + =451.20.

[0376] Step 5: Preparation of compound 33f

[0377] Compound 33e (63 mg, 0.14 mmol) was dissolved in TFA (1 mL) at 0 °C and reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly to dryness to obtain crude compound 33f (100 mg), which was directly used in the next reaction. LC-MS (ESI): [M+H] + =379.25.

[0378] Step 5: Preparation of 33g of compound

[0379] Compound 33f (80 mg, 0.21 mmol) was dissolved in 0.5 mL of 1,4-dioxane at room temperature, and 0.53 mL of 4 M sodium hydroxide aqueous solution was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%–35% ACN). The prepared solution was directly lyophilized, and the residual solid was dissolved in 1 mL of water, the pH was adjusted to 8–9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 33 g (10 mg, 15.9%). LC-MS (ESI): [M+H] + =239.20. 1 H NMR (400MHz, D2O) δ7.07 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.29 (d, J = 2.8 Hz, 1H), 5.19 (d, J = 2.8 Hz, 1H), 3.54 (s, 2H).

[0380] Example 34: Preparation of compound 34h

[0381] 2-hydroxy-3-methylene-3,4,7,8-tetrahydro-2H-[1,4]dioxino[1,2-e][1,2]oxaborinin-10- carboxylic acid disodium salt

[0382] Step one: Preparation of compound 34b

[0383] Compound 34a (2 g, 0.013 mol) was dissolved in DCM (30 mL) at room temperature, and DMAP (16 mg, 0.13 mmol) and Boc20 (3.12 g, 0.014 mol) were added successively. After the addition was completed, the reaction was stirred at room temperature for 1 h. The reaction was directly concentrated to dryness, and the residue was purified by column chromatography (PE / EA = 30 / 1) to obtain compound 34b (3.0 g, 87%). 1 HNMR (400 MHz, Chloroform-d) δ 6.85 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.66 (dd, J = 8.8, 2.8 Hz, 1H), 4.25 (s, 4H), 1.56 (s, 9H).

[0384] Step two: Preparation of compound 34c

[0385] Compound 34b (3.0 g, 11.9 mmol) was dissolved in THF (30 mL) at room temperature, and the reaction was cooled to -78 °C. LDA (7.1 mL, 14.2 mmol, 2M in THF) was added dropwise, and the reaction was gradually warmed to room temperature and stirred for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to the system, and the resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 34c (2.1 g, 70.0%). 1 HNMR (400 MHz, Chloroform-d) δ 10.96 (s, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 4.33-4.27 (m, 2H), 4.25-4.15 (m, 2H), 1.62 (s, 9H).

[0386] Step three: Preparation of compound 34d

[0387] Compound 34c (2.1 g, 8.33 mmol) was dissolved in DCM (30 mL) at room temperature, the reaction solution was cooled to 0 °C, and NBS (1.48 g, 8.33 mmol) was added thereto. After the addition was completed, the reaction solution was stirred at 0 °C for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was separated by column chromatography (PE / EA = 20 / 1) to obtain compound 34d (1.0 g, 36.3%).

[0388] Step four: Preparation of compound 34e

[0389] Compound 34d (1.0 g, 3.02 mmol) was dissolved in DCM (10 mL) at room temperature, and DMAP (3.7 mg, 0.03 mmol) and Boc20 (724 mg, 3.32 mmol) were added thereto in sequence. After the addition was completed, the reaction solution was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was purified by column chromatography (PE / EA = 30 / 1) to obtain compound 34e (1.0 g, 76.8%).

[0390] Step five: Preparation of compound 34f

[0391] Compound 34e (1.0 g, 2.32 mmol) was dissolved in THF (15 mL) at room temperature, and bis(tri-tert-butylphosphine)palladium (236 mg, 0.46 mmol) was added thereto. After the addition was completed, the reaction solution was heated to 50 °C under nitrogen protection, and compound 1b (8 mL, 1M in THF) was added dropwise thereto and stirred for 0.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (50 mL) was added to the system. The obtained solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 34f (0.23 g, yield 21.5%).

[0392] Step six: Preparation of compound 34g

[0393] 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (42.4 mg, 0.12 mmol), CuCl (9.8 mg, 0.09 mmol), and sodium tert-butoxide (38.2 mg, 0.39 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature under nitrogen protection and reacted for 30 minutes at room temperature. A THF solution of pinacol diborate (252.3 mg, 0.99 mmol) in 1.0 mL was added dropwise, and the mixture was stirred at room temperature for another 10 minutes. Then, a THF solution of compound 34f (230 mg, 0.49 mmol) in 2 mL and methanol (0.2 mL) were added dropwise, and the mixture was stirred at room temperature for another hour. After the reaction was complete, the reaction solution was filtered directly through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 50 / 1) to obtain 34g of the compound (100mg, 34.6%).

[0394] Step 7: Preparation of the compound over 34 hours

[0395] 34 g (100 mg, 0.17 mmol) of the compound was dissolved in 1 mL of TFA at room temperature and reacted in an ice bath for 0.5 h. After the reaction was complete, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%–20% ACN). The prepared solution was directly lyophilized, and the residual solid was dissolved in 1 mL of water, the pH was adjusted to 8–9 with 0.1 N sodium hydroxide, and then lyophilized to obtain compound 34 h (10 mg, 18.1%). LC-MS: [M+H] + =263.20. 1 H NMR (400MHz, D2O) δ6.76(s,1H),5.34(s,1H),5.25(s,1H),4.43(s,4H),3.54(s,2H).

[0396] Example 35: Preparation of compound 35a

[0397] 2-Hydroxy-3-methylene-3,4-dihydro-2H-[1,3]dioxacyclopenteno[4',5',4,5]benzo[1,2-e][1,2]oxaboronehepten-9-carboxylic acid disodium salt

[0398] The preparation method is as described in Example 34, except that compound 34a was prepared by replacing compound 34a with 3,4-methylenedioxyphenol, yielding compound 35a (15 mg, 25.2%). LCMS (ESI): [M+H] += 249.10.1H NMR (400 MHz, D2O) δ 6.54 (s, 1H), 6.03 (d, J = 8.4 Hz, 1H), 5.78 (s, 2H), 5.06 (s, 1H), 5.01 (s, 1H), 3.26 (s, 2H).

[0399] Example 36: Preparation of compound 36i

[0400] 7-[(1H-1,2,4-triazol-1-yl)methyl]-2-hydroxy-3-methylene-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid disodium salt

[0401] Step one: Preparation of compound 36b

[0402] Compound 36a (4.0 g, 13.9 mmol) was placed in a 100 mL single-necked flask, to which DCM (20 mL) and TFA (10 mL) were added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was directly concentrated to dryness to obtain compound 36b (3.3 g) as a crude product, which was directly used in the next reaction.

[0403] Step two: Preparation of compound 36c

[0404] Compound 36b (3.0 g, 12.9 mmol) was dissolved in TFA (3 mL) at room temperature, to which TFAA (2 mL), DMF (2 mL) and acetone (12 mL) were sequentially added, and the reaction was heated to 100°C under nitrogen protection and stirred for 16 hours. After the reaction was completed, saturated sodium carbonate aqueous solution (50 mL) was added to the residue at room temperature, and the obtained solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 36c (2.8 g, 80.0%). LCMS (ESI): [M+H] + = 271.15.

[0405] Step three: Preparation of compound 36d

[0406] Compound 36c (2.9 g, 10.7 mmol), NBS (2.2 g, 12.3 mmol), dibenzoyl peroxide (210 mg) were dissolved in carbon tetrachloride at room temperature, and stirred at 85 °C for 16 h under nitrogen protection. After the reaction was completed, water (30 mL) was added to the reaction solution, and the resulting solution was extracted with DCM (150 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE / EA = 20 / 1) to obtain compound 36d (2.0 g, 53.4%).

[0407] Step four: Preparation of compound 36e

[0408] Compound 36d (1.7 g, 4.86 mmol) and triazole (470 mg, 6.81 mmol) were dissolved in DMF (15 mL), and potassium carbonate (1.35 g, 9.78 mol) was added thereto. After stirring at room temperature for 8 h under nitrogen protection, the reaction was filtered, and the filtrate was directly subjected to prep-HPLC (0.1% TFA, 30% to 80% ACN) to obtain compound 36e (1.0 g, 60.9%). LCMS (ESI): [M+H] + = 338.08.

[0409] Step five: Preparation of compound 36f

[0410] Compound 36e (500 mg, 1.35 mmol) and bis(tri-tert-butylphosphine)palladium (138 mg, 0.27 mmol) were dissolved in tetrahydrofuran (8 mL) at room temperature, and compound 1b (4.05 mL, 4.05 mmol) was added dropwise thereto. After stirring at room temperature for 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL), and the resulting solution was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 36f (300 mg, 60.2%). LCMS (ESI): [M+H] + = 370.18.

[0411] Step six: Preparation of compound 36g

[0412] Compound 36g (900 mg, 2.43 mmol) in THF (10 mL) and methanol (0.2 mL) was added dropwise, and stirring was continued at room temperature for 1 h after the addition was completed. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by column chromatography (PE / EA = 50 / 1) to obtain compound 36g (650 mg, yield 53.8%). LC-MS (ESI): [M+H] = 498.31. +

[0413] Step Seven: Preparation of compound 36h

[0414] Compound 36g (350 mg, 0.70 mmol) was dissolved in TFA (5 mL) at 0 °C, and reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by prep-HPLC preparation (0.1% TFA, 30% to 80% ACN) to obtain compound 36h (180 mg, 60.5%). LC-MS (ESI): [M+H] = 426.20. +

[0415] Step Eight: Preparation of compound 36i

[0416] Compound 36h (70 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL) at room temperature, and aqueous sodium hydroxide solution (2 M, 1 mL) was added thereto. Stirring was carried out at room temperature for 1 h, and the reaction was completed. The reaction solution was directly subjected to Prep-HPLC preparation (0.1% NH4HCO3, 1% to 35% ACN), and the preparation solution was directly freeze-dried. After the residual solid was dissolved in 1 mL of water and adjusted to pH = 8 to 9 with 0.1 N sodium hydroxide, freeze-drying was performed to obtain compound 36i (20 mg, 36.0%). LC-MS (ESI): [M+H] = 286.11. + 1 H NMR (400 MHz, D2O) δ 8.30 (s, 1H), 7.94 (s, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 5.23 (s, 2H), 5.04 (s, 1H), 4.94 - 4.92 (m, 1H), 3.35 (s, 2H).​​​

[0417] Example 37: Preparation of compound 37g

[0418] 7-(dimethylphosphoryl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid disodium salt

[0419] Step one: Preparation of compound 37b

[0420] Compound 37a (2.35 g, 5.89 mmol) was dissolved in acetonitrile (25 mL), potassium carbonate (2.43 g, 8.83 mmol) and benzyl bromide (1.21 g, 7.07 mmol) were added, after the addition was completed, the reaction was heated to 80 °C for 8 hours. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 100 / 1) to obtain compound 37b (2.53 g, 88%).

[0421] Step one: Preparation of compound 37b

[0422] Compound 37b (510 mg, 1.04 mmol) was dissolved in 1,4-dioxane (10 mL), dimethyl phosphine oxide (250 mg, 3.13 mmol), tris(dibenzylideneacetone)dipalladium (95 mg, 0.10 mmol), triethylamine (317 mg, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.21 mmol) were added in turn, after the addition was completed, the reaction was heated to 90 °C for 40 hours under nitrogen protection. After the reaction was completed, the reaction was filtered with diatomite, and the filtrate was directly concentrated to dryness, and the residue was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 37c (210 mg, 27%). 1 H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.4, 2.4 Hz, 1H), 7.62-7.49 (m, 3H), 7.44-7.31 (m, 3H), 5.12 (s, 2H), 1.83 (s, 3H), 1.80 (s, 3H), 1.51 (s, 9H).

[0423] Step three: Preparation of compound 37d

[0424] Compound 37c (200 mg, 0.46 mmol) and pinacol vinylborate (175 mg, 1.14 mmol) were dissolved in DMF (5 mL). Triethylamine (161 mg, 1.59 mmol) and bis(tri-tert-butylphosphine)palladium (24 mg, 0.046 mmol) were added sequentially. After the addition was complete, the reaction mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated directly to dryness. The residue was prepared by Prep-HPLC (0.1% HCOOH, 10%–20% ACN) to obtain compound 37d (110 mg, 63%). 1 H NMR (400MHz, CDCl3) δ7.67(d,J=2.8Hz,1H),7.65(s,1H),7.48–7.42(m,2H),7.42–7.36(m,2H),7.36–7.30(m,1H),6.98(dd,J=17 .6,11.2Hz,1H),5.88(dd,J=17.6,1.2Hz,1H),5.43(dd,J=11.2,1.2Hz,1H),4.98(s,2H),1.83(s,3H),1.80(s,3H),1.52(s,9H).

[0425] Step 4: Preparation of compound 37e

[0426] Compound 37d (110 mg, 0.29 mmol) was dissolved in methanol (5 mL). Pinaryl diborate (110 mg, 0.43 mmol), cuprous oxide (6 mg, 0.04 mmol), triphenylphosphine (11 mg, 0.04 mmol), and dipotassium hydrogen phosphate (75 mg, 0.43 mmol) were added sequentially. After the addition was complete, the reaction mixture was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was directly concentrated to dryness. A 10 / 1 (5 mL) mixture of dichloromethane and methanol was added to the residue, and the mixture was stirred for 10 minutes. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 37e (270 mg), which was directly used in the next reaction. LC-MS: [M+H] + =515.27.

[0427] Step 5: Preparation of compound 37f

[0428] Compound 37e (215 mg, 0.42 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (540 mg) was added. The reaction was carried out at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 37f (120 mg), which was directly used in the next reaction. LC-MS: [M+H] + =325.16.

[0429] Step Six: Preparation of 37g of Compound

[0430] Compound 37f (120 mg, 0.37 mmol) was dissolved in 10 mL of dichloromethane. The reaction solution was cooled to 0 °C, and a dichloromethane solution of boron trichloride (1.5 mL, 1 M in DCM) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the dichloromethane. The residue was cooled to -78 °C, and 5 mL of ethanol was added dropwise. The resulting solution was adjusted to pH approximately 7 with 2 M sodium hydroxide aqueous solution. The solution was then concentrated to dryness. The residue was prepared by Prep-HPLC (0.1% NH4HCO3, 10%–20% ACN). The prepared solution was directly lyophilized. The remaining solid was dissolved in 1 mL of water, and the pH was adjusted to 8–9 with 0.1 N sodium hydroxide before lyophilization to obtain compound 37 g (10 mg, 8.2%). LC-MS: [M+H] + =269.10. 1 H NMR (400MHz, D2O) δ7.17(dd,J=7.6,3.2Hz,1H),7.09(dd,J=12.4,7.6Hz,1H),2.71(t,J=7.2Hz,2H),1.84(s,3H),1.80(s,3H),0.42(t,J=7.2Hz,2H).

[0431] Example 38: Preparation of compound 38e

[0432] 2-Hydroxy-5-[(1-oxo-1λ] 6 [-Thiobutane-1-yl)amino]-1,1a,2,7b-tetrahydrobenzo[e]cyclopropano[c][1,2]oxaborone-hepten-4-carboxylic acid disodium salt

[0433] Step 1: Preparation of compound 38b

[0434] Compound 38a (1.50 g, 5.57 mmol) and 1-aminomethylenethiabutyronane 1-oxide (0.94 g, 8.92 mmol) were dissolved in dioxane (20 mL). Tris(dibenzylacetone)dipalladium (0.26 mg, 0.28 mmol), cesium carbonate (3.63 g, 11.14 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.32 g, 0.56 mmol) were added sequentially. The reaction was carried out under nitrogen protection and heated to 100 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 1 / 2) to give compound 38b (950 mg, 58%). 1H NMR (400 MHz, CDC13) δ 7.58 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.34 - 4.25 (m, 2H), 4.19 - 4.09 (m, 3H), 2.42 - 2.22 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H).

[0435] Step two: Preparation of compound 38c

[0436] Compound 38b (0.95 g, 3.24 mmol) was dissolved in tetrahydrofuran (12 mL) / ethanol (0.6 mL), pinacol diboronic acid (1.23 g, 4.86 mmol, 1.5 eq), cesium carbonate (3.17 g, 9.72 mmol, 3.0 eq) and dichlorobis(triphenylphosphine) nickel(II) (0.09 g, 0.16 mmol, 0.05 eq) were added, and the reaction was stirred at 65 °C for 1 hour under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 38c (500 mg, 48%). LC-MS: [M+H] + = 322.17.

[0437] Step three: Preparation of compound 38d

[0438] Zinc powder (407 mg, 6.23 mmol), cuprous chloride (62 mg, 0.62 mmol) and dibromomethane (271 mg, 1.56 mmol) were dispersed in tetrahydrofuran (10 mL), and acetyl chloride (12 mg, 0.16 mmol) was added. The reaction was heated to 50 °C, and a tetrahydrofuran (10 mL) solution of compound 38c (500 mg, 1.56 mmol) and dibromomethane (1.35 g, 7.78 mmol) were added. After the addition was completed, the reaction was heated to 60 °C and reacted for 1.5 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated to dryness under reduced pressure. The residue was prepared by Prep-HPLC (0.1% NH4HCO3, 10% to 20% ACN) to obtain compound 38d (30 mg, 6%). LC-MS: [M+H] + = 336.14.

[0439] Step four: Preparation of compound 38e

[0440] Compound 38d (30 mg, 0.09 mmol) was dissolved in methanol (1.3 mL), and an aqueous sodium hydroxide solution (4 M, 0.7 mL) was added. The reaction solution was heated to 60 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%~20% ACN). The prepared solution was directly freeze-dried, and the residual solid was dissolved in 1 mL of water, adjusted to pH = 8~9 with 0.1 N sodium hydroxide, and freeze-dried to obtain compound 38e (10 mg, 30%). LC-MS: [M+H] + = 308.12. 1 HNMR (400MHz, D2O) δ 7.03 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 4.36-4.24 (m, 1H), 4.22-4.09 (m, 2H), 2.44-2.24 (m, 2H), 1.89-1.74 (m, 1H), 0.92-0.78 (m, 1H), 0.35-0.30 (m, 1H), 0.29-0.21 (m, 1H).

[0441] Example 39: Preparation of compound 39d

[0442] 2-hydroxy-5-[(dimethyl oxo-λ 6 sulfanylidenyl)amino]-1,1a,2,7b-tetrahydrobenzo[e]cyclopropa[c][1,2]oxaboralene-4-carboxylic acid disodium salt

[0443] Step one: Preparation of compound 39a

[0444] Compound 38a (2.5 g, 9.29 mmol) and dimethyl sulfoximine (1.64 g, 17.61 mmol) were dissolved in 1,4-dioxane (40 mL), and tris(dibenzylideneacetone)dipalladium (0.43 mg, 0.46 mmol), cesium carbonate (6.05 g, 18.57 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.54 g, 0.93 mmol) were sequentially added. After completion of the addition, the reaction solution was heated to 100 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 39a (2.2 g, 85%). LC-MS: [M+H] + = 282.07.

[0445] Step one: Preparation of compound 39b

[0446] Compound 39a (1.1 g, 3.91 mmol) was dissolved in tetrahydrofuran (18 mL) / ethanol (0.9 mL), to which pinacol diboronic acid (1.49 g, 5.86 mmol), cesium carbonate (3.82 g, 11.73 mmol) and dichlorobis(triphenylphosphine) nickel(II) (0.10 g, 0.20 mmol) were sequentially added, and the reaction was carried out at 65°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 39d (1.1 g, 91%). LC-MS: [M+H] + = 310.19.

[0447] Step three: Preparation of compound 39c

[0448] Zinc powder (1.86 g, 28.48 mmol), cuprous chloride (282 mg, 2.85 mmol) and dibromomethane (1.24 g, 7.12 mmol) were dispersed in tetrahydrofuran (20 mL), to which acetyl chloride (42 mg, 0.54 mmol) was added, and the reaction was heated to 50°C, to which a tetrahydrofuran (20 mL) solution of compound 39b (2.2 g, 7.12 mmol) was sequentially added and then dibromomethane (6.18 g, 35.60 mmol) was added, and after the addition was completed, the reaction was warmed to 60°C for 2 hours. The reaction was filtered through diatomite, and the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 39c (1.8 g, 80%). LC-MS: [M+H] + = 324.14.

[0449] Step five: Preparation of compound 39d

[0450] Compound 39c (200 mg, 0.62 mmol) was dispersed in aqueous sodium hydroxide solution (4M, 32 mL), and the reaction was carried out at 60°C for 16 hours. After the reaction was completed, the reaction solution was directly prepared by Prep-HPLC (0.1% NH4HCO3, 10%~20% ACN), and the preparation solution was directly freeze-dried, and the residual solid was dissolved in 1 mL of water, and the pH was adjusted to 8~9 with 0.1N sodium hydroxide, and then freeze-dried to obtain compound 39d (78.3 mg, 35.4%). LC-MS: [M+H] + = 296.18. 1 H NMR (400 MHz, D2O) δ 7.11 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.29-3.16 (m, 6H), 2.08-1.95 (m, 1H), 1.11-0.97 (m, 1H), 0.46-0.29 (m, 2H).

[0451] Test Example 1: Beta-lactamase inhibition

[0452] Enzyme activity reaction buffer preparation: 50 mM sodium phosphate, 300 mM NaCl, 0.1 mg / ml BSA, pH 7.0.

[0453] Compound working solution preparation: QPX-7728 (synthesized according to WO2018005662A1) and test compounds were diluted with DMSO and buffer to 5X working solution.

[0454] Test procedure:

[0455] 1.1 Dilute enzyme to 20 nM as 4x working solution using buffer, take 50 μL / well to add to clear 96-well plate reaction wells, add Reaction Buffer to blank wells, centrifuge at 1000 rpm for 1 min;

[0456] 1.2 Add 40 μL buffer to each well in clear 96-well plate, centrifuge at 1000 rpm for 1 min;

[0457] 1.3 Add 10 μL / well of compound working solution to clear 96-well plate reaction wells, add 10 μL / well of 20% DMSO to blank wells, centrifuge at 1000 rpm for 1 min, and incubate in a 37°C incubator for 10 min;

[0458] 1.4 Dilute substrate Nitrocefin to 2x Nitrocefin working solution (100 μM) using buffer, add 100 μL / well to clear 96-well plate;

[0459] 1.5 Perform absorbance detection at 490 nm on a plate reader;

[0460] 1.6 IC 50 Calculation: Calculate the half maximal inhibitory concentration IC50 of the compound according to the formula % Enzyme Activity = (OD sample - OD Blank ) / (OD Control - OD Blank ) x 100%, see Table 1 below. Where A represents IC 50 > 10000 nM, B represents IC 50 1000-10000 nM, C represents IC 50 200-1000 nM, and D represents IC 50 < 200 nM.

[0461] Table 1: IC of compounds in β-lactamase inhibition experiment 50 Values (nM)

[0462] As shown in Table 1, both the compound of the present application and compound QPX7728 can effectively inhibit the activities of the four clinically very important β-lactamases of class A (KPC-2, SHV-12, TEM-10), class B (NDM-1, VIM-1), class C (Ampc), and class D (OXA-48).

[0463] Test Example 2: In vitro bacteriostatic experiment

[0464] In order to determine the ability of the test compound to enhance the inhibition of the growth of β-lactamase-producing bacterial strains, a classic cell-based bouillon microdilution MIC test was used. The β-lactamase-producing bacterial strains used were: Klebsiella pneumoniae expressing class A KPC-2, Escherichia coli expressing class A SHV-12, Escherichia coli expressing class B NDM-1, Enterobacter cloacae expressing class C Ampc, and Klebsiella pneumoniae expressing class D OXA-48.

[0465] 1.1 Preparation of bacterial solution

[0466] Fresh nutrient agar slants of the test strains were inoculated into 2 mL of CAMHB medium, which was incubated at 37°C for 6 h, and then turbidimetrically diluted with a No. 0.5 McFarland turbidity tube. The concentration was adjusted to about (2-4) x 10 5 CFU / mL.

[0467] 1.2 Experimental procedure

[0468] For the meropenem / test compound combination, the final concentration of the test compound in the wells was 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, and 0.03 μg / mL. The final concentration of meropenem was 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, and 0.03 μg / mL.

[0469] For meropenem, 100 μL of the above-described solution at different concentrations was taken into a sterile 96-well plate, and 100 μL of the bacterial suspension was added to each well. The concentration of the bacteria was about (1-2) x 10 5 CFU / mL.

[0470] Positive control wells were also set up: 100 μL of the bacterial solution + 100 μL of the medium; and negative control wells: 200 μL of the medium. The plates were incubated at 37°C for 16-20 h, and the results were observed. The minimum inhibitory concentrations for different bacterial strains are shown in Table 2 below.

[0471] Table 2

[0472] The results show that the E. coli and K. pneumoniae resistant to meropenem, and the compounds of Examples 3, 8, 10, 27, 34, 38 and QPX-7728 can significantly restore the antibacterial activity of meropenem.

[0473] Test Example 3: Compound mouse pharmacokinetics experiment

[0474] 3.1 Experimental materials

[0475] The compound QPX7728 and Examples 3, 8, 10 were accurately weighed and diluted with normal saline to the administration concentration, and prepared for immediate use.

[0476] 3.2 Experimental steps

[0477] Single intravenous injection was performed in CD1 mice according to the grouping mode in Table 3 as follows, and blood was collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, 48h, 72h after administration. The blood drug concentration at different time points was determined by establishing a biological analysis method, and the pharmacokinetic parameters were calculated.

[0478] Table 3

[0479] The results are shown in Table 4 below.

[0480] Table 4

[0481] The results show that the exposure of Examples 3, 8, 10, 27, 34, 38 after single intravenous administration in mice is significantly higher than that of QPX7728, and the exposure of Examples 3, 8, 10, 27, 34 is more than 5 times that of QPX7728. High exposure of the compound in vivo is conducive to reducing the administration dose and reducing drug side effects while obtaining similar efficacy.

[0482] Test Example 4: Drug protection effect experiment on immunocompromised mouse thigh muscle infection model

[0483] 4.1 Immunocompromised mouse thigh muscle infection

[0484] According to the results of the model establishment experiment, the infection bacteria concentration was determined, and the bacterial suspension was injected into the thigh muscle of the immunocompromised mice (except for the blank group). 0.1 mL of bacterial suspension was injected intramuscularly into the left and right legs.

[0485] 4.2 Drug preparation

[0486] 4.3 Administration

[0487] Each group is given the compound of the application and the antibacterial agent 2 hours after infection, with a dosage of 0.5 mL / 20 g per mouse.

[0488] 4.5 Sample collection

[0489] The mice are sacrificed 24 hours after infection, and the tissues are weighed and immediately immersed in 5 mL of pre-cooled sterile normal saline for homogenization.

[0490] 4.5 Homogenate colony count

[0491] Five randomly selected mice from each group are used for homogenate colony count. The tissues are weighed and immersed in 5 mL of sterile pre-cooled normal saline prepared in advance for homogenization, and the homogenate is diluted 10 times with sterile normal saline. 1 mL of the diluted homogenate is taken and placed in a sterile plate, and agar medium is added for mixing. After incubation in a 35-37°C incubator for 36-48 hours, the colony count is performed. The results show that the compound of the application can significantly restore the antibacterial activity of the antibacterial agent.

[0492] Test Example 5: Protection effect experiment of the drug on the lung infection model of immunocompromised mice

[0493] 5.1 Lung infection of immunocompromised mice

[0494] According to the results of the model establishment experiment, the infection bacteria concentration is determined, and the immunocompromised mice (except for the blank group) are infected by tracheal intubation and instillation of the bacterial suspension (25 μL).

[0495] 5.2 Drug preparation

[0496] 5.3 Drug administration

[0497] Each group is given the compound of the application and the antibacterial agent 2 hours after infection, with a dosage of 0.5 mL / 20 g per mouse.

[0498] 5.4 Sample collection

[0499] The mice are sacrificed 24 hours after infection, and the tissues are weighed and immediately immersed in 5 mL of pre-cooled sterile normal saline for homogenization.

[0500] 5.5 Homogenate colony count

[0501] Five randomly selected mice from each group are used for homogenate colony count. The tissues are weighed and immersed in 5 mL of sterile pre-cooled normal saline prepared in advance for homogenization, and the homogenate is diluted 10 times with sterile normal saline. 1 mL of the diluted homogenate is taken and placed in a sterile plate, and agar medium is added for mixing. After incubation in a 35-37°C incubator for 36-48 hours, the colony count is performed. The results show that the compound of the application can significantly restore the antibacterial activity of the antibacterial agent.

Claims

1. A compound represented by Formula I or Formula II or a compound represented by Formula III or a pharmaceutically acceptable salt thereof or an isomer thereof or a deuterated form thereof, In formula I: represents a single or double bond; L1is selected from -CH2-, -O-, -S-, -Se-, -CH2CH2-, -CH2O-, -CH2S-, -CH2Se-, -CH=CH-; A is selected from a phenyl ring or also one or two 5-6 membered heteroaromatic rings selected from N, O or S; R0 and R1 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfinimide, urea, guanidinyl, substituted or unsubstituted C1-C6 hydrocarbon group, C1-C6 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C2-C8 heterocyclic hydrocarbon group, C6-C8 aryl, C5-C8 heteroaryl, spirocarbocyclic, spiroheterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic ring. Fused aromatic rings, bridged rings, and bridged heterocycles; substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfinimide, urea, guanidine, C1-C6 hydrocarbon group, C1-C6 heterohydrocarbon group, C3-C8 cyclic hydrocarbon group, C2-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C2-C8 heterocyclic hydrocarbon group, C6-C8 aryl, C5-C8 heteroaryl, C7-C 10 aryl hydrocarbon group, C5-C 10 Heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C2-C8 heterocyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C2-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C 10 aryl hydrocarbon group, substituted C5-C 10 Heteroaryl hydrocarbon group, spirocarbocyclic ring, spiroheterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heterocyclic ring, bridged ring, bridged heterocyclic ring, -Si(R) C 3. -NR A R B -C(O)R C -C(O)OR C -C(O)SR C -C(S)R C -S(O)R C -S(O)OR C -S(O)(O)R C The amino and carboxylic acid isosteres, wherein the double bonds of R0 and R1 connected to the ring are cis or trans; preferably, R0 is H, and R1 is H, methyl, ethyl or -Si(CH3)3; R A , R B , R C each independently is selected from hydrogen, deuterium, amino, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, wherein the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic; R2is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, alkenyl, alkynyl, carboxyl, acyl, sulfonyl, urea, guanidine, unsubstituted or substituted Ci-C6hydrocarbyl and Ci-C6heterohydrocarbyl, -0-R D unsubstituted or substituted Ci-C6hydrocarbyl and Ci-C6heterohydrocarbyl, -0-R D , -S-R D , -Se-R D or Preferably, R2is selected from H, halogen; R3is selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, alkenyl, alkynyl, carboxyl, acyl, sulfonyl, urea, guanidine, unsubstituted or substituted Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -0-(CH2)q-OR H substituted Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -0-(CH2)q-OR n -R E1 , -S-R E2 , -Se-R E3 , or Preferably, R3 is selected from H, halogen, -OH, unsubstituted or substituted by one or more R H Substituted C1-C6 alkyl groups, -O-(CH2) n -R E1 -SR E2 -Se-R E3 ,or R D R H Each group is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfinimide, urea, guanidinyl, substituted or unsubstituted C1-C6 hydrocarbon groups, C1-C6 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C2-C8 heterocyclic hydrocarbon groups, C6-C8 aryl, C5-C8 heteroaryl, spirocarbocyclic, spiroheterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic ring, fused heteroaromatic ring. Bridged rings and bridged heterocycles, with substituents including deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfinimide, urea, guanidine, C1-C6 hydrocarbon group, C1-C6 heterohydrocarbon group, C3-C8 cyclic hydrocarbon group, C2-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C2-C8 heterocyclic hydrocarbon group, C6-C8 aryl, C5-C8 heteroaryl, and C7-C8 heteroaryl. 10 aryl hydrocarbon group, C5-C 10 Heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C2-C8 heterocyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C2-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C 10 aryl hydrocarbon group, substituted C5-C 10 Heteroaryl hydrocarbon group, spirocarbocyclic ring, spiroheterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heterocyclic ring, bridged ring, bridged heterocyclic ring, -NR A R B -C(O)R C -C(O)OR C -C(O)SR C -C(S)R C -S(O)R C -S(O)OR C -S(O)(O)R C Isosteres of amino and carboxylic acids Preferably, R H selected from halogen, -OH, -NH2, -COOH, B is selected from a 4- to 12-membered heterocyclic or heteroaromatic ring having one, two or three members selected from N, O or S; L6is selected from a covalent bond or -(CH2) y -; y is selected from 0, 1 or 2; R k is selected from H, -COOH, -OH, -NH2, phenyl, C3-C6cycloalkyl, a 4- to 6-membered heterocyclic or heteroaromatic ring having one, two or three members selected from N, O or S; R E1 , R E2 , R E3 are each independently selected from hydrogen or from an unsubstituted or by one or more R E substituted C1-C6alkyl, C3-C6cycloalkyl, C6-C 10 aromatic ring, heterocyclic ring having one or two 4-6 membered rings selected from N, O or S; R E is selected from halogen, -OH, -NH2, -NO, -COOH; R b , R c each independently is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, ureido, guanidino, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; preferably, R b , R c each independently is selected from the group consisting of C1-C4alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; R d , R e each independently is selected from the group consisting of hydroxyl, -O-R F , -S-R F , substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, wherein the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino, and carboxylic acid electronic isostere; or R d , R e together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring having one 4- to 6-membered heterocyclic ring selected from N, O, S or NR F ; preferably, R d , R e are each independently selected from C1-C4alkyl; R f selected from O, NH or NR F ; preferably, R f is selected from O or NH; R4is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R4is selected from H, -COOH, the following groups unsubstituted or substituted with one or more R C1 C1-C6alkyl, C3-C6cycloalkyl, 5-10 membered heteroaromatic ring, 4-6 membered heterocyclic ring having one, two or three members selected from N, O or S, phenyl ring; R C1 is selected from H, halogen, -OH, -NH2, keto (=O), C1-C6alkyl unsubstituted or substituted with one or more R D C1-C6alkyl; R D is selected from H, halogen, -OH, -NH2, phenyl, C3-C6cycloalkyl, 5-6 membered heteroaromatic ring, 4-6 membered heterocyclic ring having one, two or three members selected from N, O or S; L3is selected from a covalent bond, -(CH2) x - -(CH2) n - -(CH2) n - -(CH2) F - -(CH2) n - -(CH2) n - -(CH2) n - -(CH2) n - -(CH2) Preferably, L3is selected from a covalent bond, -CH2-, -C(O)-, -C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-, n is selected from 0, 1, 2; preferably, n is selected from 0 or 1; x is 1 or 2 or 3; L4is selected from -CH2-, -N(R F )-, NH, O, S, Se; L5is selected from -CH2-, -CH2-CH2-, -CH(CH3)-, -CH(CH3)CH2-, -C(CH3)2CH2-, -N(R F )-, NH, O, S, Se; R F selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, a substituent can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamidyl, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; or R2, R3together with the atoms to which they are attached form an optionally unsubstituted or substituted ring system selected from a carbocyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a spiro carbocyclic ring, a spiro heterocyclic ring, a fused carbocyclic ring, a fused heterocyclic ring, a fused aromatic ring, a fused heteroaromatic ring, a bridged ring, a bridged heterocyclic ring; preferably, R2, R3together with the atoms to which they are attached form a heterocyclic ring selected from one or two 4-6 membered rings selected from N, O or S; In formula II: R a1 selected from Preferably, R a1 selected from R b , R c each independently is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, ureido, guanidino, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic ring, spiro heterocyclic ring, fused carbocyclic ring, fused heterocyclic ring, fused aromatic ring, fused heteroaromatic ring, bridged ring, bridged heterocyclic ring, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R b , R c each independently is selected from the group consisting of C1-C4alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; or R b , R c with the atom to which it is attached forms a 4-6 membered heterocyclic ring; R d , R e each independently selected from the group consisting of hydroxyl, -O-R F , -S-R F , substituted or unsubstituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl, the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C2-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R d , R e each independently selected from the group consisting of C1-C4 alkyl; or R d , R e together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring having one 4- to 6-membered heterocyclic ring selected from N, O, S or NR F ; R f selected from O, NH or NR F ; in formula III: represents a single or double bond; L2is selected from -CH2-, -O-, -S-, -Se-, -CH2CH2-, -CH2O-, -CH2S-, -CH2Se-, -CHCH-, =CHCH2-; R a2 selected from halogen, Preferably, R a2 selected from halogen, R b , R c each independently is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, the substituents being selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R b , R c each independently is selected from the group consisting of C1-C4alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; R d , R e each independently is selected from the group consisting of hydroxyl, -O-R F , -S-R F , substituted or unsubstituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl, wherein the substituents can be deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfoximine, urea, guanidine, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic, bridged cyclic, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino and carboxylic acid electronic isosteres; preferably, R d , R e each independently is selected from the group consisting of C1-C4alkyl; or R d , R e together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring having one 4- to 6-membered heterocyclic ring selected from N, O, S or NR F ; R f selected from O, NH or NR F ; R F substituted C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C2-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C2-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C2-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C 10 arylalkyl, C5-C 10 heteroarylalkyl, spiro carbocyclic, spiro heterocyclic, fused carbocyclic, fused heterocyclic, fused aryl, fused heteroaryl, bridged ring, bridged heterocyclic, -NR A R B , -C(O)R C , -C(O)OR C , -C(O)SR C , -C(S)R C , -S(O)R C , -S(O)OR C , -S(O)(O)R C , amino, and carboxylic acid electronic isosteres.

2. A compound represented by Formula I-1 or a pharmaceutically acceptable salt thereof or an isomer thereof or a deuterated product thereof, wherein: L1is selected from -CH2-, -O-, -S-, -Se-; R0is selected from H; R1is selected from H, methyl or -Si(CH3)3; wherein the double bond to which R0is attached to the ring is cis or trans; R2is selected from H, F, Cl, Br; R3 is selected from H, halogen, -OH, unsubstituted or substituted with one or more R H The following groups are substituted: C1-C6 alkyl, C1-C6 haloalkyl, -O-(CH2) n -R E1 -SR E2 -Se-R E3 ,or n is selected from 0, 1, 2 or 3; R H selected from halogen, -OH, -NH2, -COOH, B is selected from L6is selected from a covalent bond or -(CH2) y -; y is selected from 0, 1 or 2; R k is selected from H, -COOH, -OH, -NH2, phenyl, C3-C6cycloalkyl, a 4-6 membered heterocyclic or heteroaryl having one, two or three members selected from N, O or S; R E1 R E2 R E3 Each is independently selected from hydrogen or unsubstituted or by one or more R E Substitutes C1-C6 alkyl, C3-C6 cycloalkyl, or benzene rings, having one, two, or three 4- to 6-membered heterocycles selected from N, O, or S; R E Selected from halogens, -OH, -NH2, -NO, -COOH; R b , R c each independently selected from C1-C4 alkyl or R b , R c form together with the S atom to which they are attached a 4- to 6-membered heterocyclic ring; R d , R e each independently selected from C1-C4 alkyl; R f is selected from O or NH; R4is selected from H, -COOH, -OH, -NH2, unsubstituted or substituted with one or more R C1 substituted with one, two or three heteroatoms selected from N, O or S; L3is selected from a covalent bond, -(CH2) x - C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-, x is 1 or 2 or 3; R C1 selected from H, halogen, -OH, -NH2, keto (=0), unsubstituted or substituted C1-C6 alkyl; R D selected from H, halogen, -OH, -NH2, keto (=0), unsubstituted or substituted C1-C6 alkyl; R D selected from H, halogen, -OH, -NH2, keto (=0), unsubstituted or substituted C1-C6 alkyl; R or R2, R3together with the atoms to which they are attached form a heterocyclic ring selected from one or two 4-6 membered rings selected from N, O or S.

3. The compound of formula I-1 according to claim 2, or a pharmaceutically acceptable salt thereof, or isomer thereof, or deuterated product thereof, characterized in that, L1is -CH2-; preferably, R0, R1are H; preferably, R2is H, F, Cl; preferably, R3is selected from H, halogen, -OH, unsubstituted or substituted C1-C3alkyl, C1-C3haloalkyl, -0-(CH2) H unsubstituted or substituted C1-C3alkyl, C1-C3haloalkyl, -0-(CH2) n -R E1 , -S-R E2 , or preferably, R H is selected from halogen, -OH, -NH2, -COOH, more preferably, R H is selected from halogen, -OH, -NH2, -COOH; preferably, n is selected from 0 or 1 ; preferably, B is selected from L6is selected from a covalent bond or -(CH2) y -; y is selected from 0, 1 or 2; R k is selected from H, -COOH, -OH, -NH2, phenyl, C3-C6cycloalkyl, a 4- to 6- membered heterocyclic or heteroaromatic ring having one, two or three members selected from N, O or S; preferably, R2, R3together with the atoms to which they are attached form a 4- to 6- membered heterocyclic ring selected from one or two members selected from N, O or S.

4. The compound of formula I-1 according to claim 2, or a pharmaceutically acceptable salt thereof, or isomer thereof, or deuterated product thereof, characterized in that, R E1 , R E2 each independently is selected from hydrogen or unsubstituted or by one or more R E substituted C1-C3 alkyl, C3-C6 cycloalkyl, phenyl ring, heterocyclic ring having one, two or three 4-6 membered rings selected from N, O or S; preferably R E is selected from halogen, -OH, -NH2, -COOH; preferably R E2 is selected from methyl or ethyl; preferably R b , R c each independently is selected from C1-C4 alkyl or R b , R c together with the atom to which they are attached form a 4-6 membered heterocyclic ring; preferably R d , R e each independently is selected from C1-C4 alkyl, C1-C4 alkyl preferably such as methyl, ethyl; preferably R f is selected from O or NH.

5. The compound of formula I-1 according to claim 2, or a pharmaceutically acceptable salt thereof, or isomer thereof, or deuterated product thereof, characterized in that, R4is selected from H, -OH, -NH2, unsubstituted or substituted with one or more R C1 substituted with one, two or three 4 to 6 membered heterocycles having one, two or three members selected from N, O or S, a phenyl ring; in some preferred examples, R C1 selected from H, halogen, -OH, -NH2, keto (=0).

6. The compound of formula I-1 according to claim 2, or a pharmaceutically acceptable salt thereof, or isomer thereof, or deuterated product thereof, characterized in that, L3is selected from a covalent bond, -(CH2) x - -C(O)CH2-, -C(O)O-, -C(O)OCH2-, -C(O)NH-, -C(O)NHCH2-, -S(O)(O)-; x is 1 or 2.

7. A compound represented by Formula II-1, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, wherein: R a1 selected from R b , R c each independently is selected from the group consisting of C1-C4 alkyl or R b , R c together with the atom to which they are attached form a 4- to 6-membered heterocyclic ring; R d , R e each independently is selected from the group consisting of C1-C4 alkyl; R f is selected from NH.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, The pharmaceutically acceptable salt of the compound is an alkali metal salt; preferably a sodium salt; more preferably a disodium salt; most particularly as follows: wherein, R0, R1, R2, R3, L1, A, Ra1, Ra2, L2r are as described in any one of claims 1-7.

9. A compound as depicted in any one of the following structures, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, 10. A pharmaceutical composition, characterized by, A composition comprising the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, and one or more other drugs selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent; preferably, the antibacterial agent is meropenem; preferably, the composition further comprises a pharmaceutically acceptable carrier.

11. Use of the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, in the manufacture of a medicament for inhibiting beta-lactamase.

12. Use of the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, in the manufacture of a medicament for treating a disease associated with bacterial infection; preferably, the bacteria comprises Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae.

13. A compound as depicted in any one of the following structures, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, 14. A pharmaceutical composition, characterized by, A composition comprising the compound of claim 13, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, and one or more other drugs selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent; preferably, the antibacterial agent is meropenem; preferably, the composition further comprises a pharmaceutically acceptable carrier.

15. Use of the compound of claim 13, or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a deuterated form thereof, in the manufacture of a medicament for inhibiting beta-lactamase.

16. Use of the compound of claim 13 or a pharmaceutically acceptable salt thereof or isomer thereof or deuterated product thereof in the preparation of a medicament for treating a disease associated with a bacterial infection; preferably, the bacteria comprises Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae.

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