Diazabicyclic beta-lactamase inhibitors and uses thereof

Abstract

The application discloses a beta-lactamase inhibitor selected from a compound shown in a structure as shown in formula I or a pharmaceutically acceptable salt, isomer or deuterated product thereof. The application discloses application of the beta-lactamase inhibitor in preparation of a beta-lactamase inhibitor. The application also discloses application of the beta-lactamase inhibitor in preparation of a drug for treating diseases related to bacterial infection. The bacteria are bacteria capable of producing beta-lactamase. The beta-lactamase inhibitor of the application can rapidly and completely release an active metabolite such as avibactam, dorobactam, relebactam, nacubactam and other dinitrogen heterocyclic beta-lactamase inhibitors in the body, can rapidly take effect, effectively improves oral bioavailability of the beta-lactamase inhibitor, enables oral administration of the beta-lactamase inhibitor and solves the problem of low oral bioavailability of the dinitrogen heterocyclic beta-lactamase inhibitor.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and relates to novel diazabicyclic beta-lactamase inhibitors, pharmaceutical compositions thereof and uses for treating bacterial infections. BACKGROUND

[0002] The rapid development of antibiotics has great significance in the history of modern medicine. Antibiotics can effectively treat infectious diseases caused by bacteria, bringing great convenience to the clinic. However, the irrational use and even abuse of antibiotics has accelerated the development process of bacterial drug resistance, posing a great challenge to human health. As one of the oldest, most widely used and most commonly used antibiotics in clinical practice, the problem of drug resistance has also arisen and is becoming increasingly serious.

[0003] The beta-lactamase produced by bacteria can hydrolyze antibiotics with a beta-lactam ring structure, rendering the antibiotics inactive, which is the most common mechanism of bacterial resistance to beta-lactam antibiotics. Beta-lactamases can be mainly divided into two categories according to the difference in amino acid sequence in the molecular structure: one is A, C, D class with serine as the active site, and the other is metalloenzyme class with metal ions (especially Zn 2+ ) as the active site.

[0004] In 1976, the first beta-lactamase preparation (clavulanic acid) was discovered, which was later combined with beta-lactam antibiotics (amoxicillin) as an oral / intravenous drug commercialized. Beta-lactamase inhibitors, although lacking significant antibiotic activity, can protect beta-lactam antibiotics from being inactivated by microbial enzymes (beta-lactamase). Since the 1980s, beta-lactamase inhibitor / antibiotic combinations have become a standard part of therapy.

[0005] In the mid-1990s, a new important non-beta-lactam beta-lactamase inhibitor, avibactam, was discovered, which belongs to the class of diazabicyclo compounds (DBOs), a class of reversible beta-lactamase inhibitors. Compared with classic beta-lactamase inhibitors (such as clavulanic acid, sulbactam, and tazobactam), avibactam has the characteristics of long-acting and reversible covalent binding with enzymes, and does not induce beta-lactamase production. In recent years, medicinal chemists have continuously conducted in-depth research on the basis of avibactam, and successfully discovered a series of diazabicyclo derivatives such as durlobactam, relebactam, and nacubactam, which have similar beta-lactamase inhibitory effects as avibactam. However, due to the presence of sulfonic acid group structure in the structure of diazabicyclo beta-lactamase inhibitors, the water solubility is large, and the lipid solubility is too low, resulting in poor oral absorption, which is not suitable for oral administration, and can only be used for intravenous injection, which also limits the clinical use of this kind of beta-lactamase inhibitors.

[0006]

[0007] A prodrug refers to a compound that has no biological activity itself, but can release a metabolite or a drug with pharmacological activity through in vivo chemical or enzymatic conversion. Prodrug design is a commonly used effective strategy to improve the lipid solubility, increase the oral absorption, and improve the bioavailability of compounds.

[0008] Therefore, the design of diazabicyclo beta-lactamase inhibitor prodrugs to improve the oral bioavailability of such beta-lactamase inhibitors so that they can be orally administered has important clinical value. SUMMARY

[0009] The purpose of the present application is to provide a class of diazabicyclo beta-lactamase inhibitors, which are diazabicyclo beta-lactamase inhibitor prodrugs, and can significantly improve the oral bioavailability of diazabicyclo beta-lactamase inhibitors.

[0010] The purpose of the present application is achieved by the following technical solutions:

[0011] The beta-lactamase inhibitor is selected from a compound having a structure as shown in formula I or a pharmaceutically acceptable salt, isomer or deuterated product thereof:

[0012]

[0013] wherein, represents a single bond or a double bond;

[0014] R1 is selected from H,

[0015] R2 is selected from H and CH3;

[0016] L1 is selected from those that are not substituted or are replaced by one or more R. 1a Substituted -(CH2) m -, m is selected from 1, 2, 3, 4 or 5, R 1a The substituents are selected from halogens, hydroxyl groups, cyano groups, NH2, substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups containing at least one N, O, or S atom, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, and C1-C8 hydrocarbon groups. C1-C8 heteroalkyl group, C3-C8 cyclic alkyl group, C3-C8 heterocyclic alkyl group, C3-C8 cyclic alkyl hydrocarbon group, C3-C8 heterocyclic alkyl hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic alkyl group, substituted C3-C8 cyclic alkyl hydrocarbon group, substituted C3-C8 heterocyclic alkyl hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0017] R3 and R4 are independently selected from H, halogen, hydroxyl, cyano, sulfonyl, and so on. The substituents of the C1-C8 hydrocarbon group, the C1-C8 heterocyclic hydrocarbon group, the C3-C8 cyclic hydrocarbon group, the C3-C8 heterocyclic hydrocarbon group containing at least one atom selected from N, O, or S, the C6-C8 aryl group, and the C5-C8 heteroaryl group, whether substituted or unsubstituted, can be independently selected from halogens, hydroxyl groups, cyano groups, and C1-C8 hydrocarbon groups. C1-C8 heteroalkyl group, C3-C8 cyclic alkyl group, C3-C8 heterocyclic alkyl group, C3-C8 cyclic alkyl hydrocarbon group, C3-C8 heterocyclic alkyl hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-10 aryl hydrocarbon group, C5-10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic alkyl group, substituted C3-C8 cyclic alkyl hydrocarbon group, substituted C3-8 heterocyclic alkyl hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0018] R5is selected from

[0019] X1, X2are independently selected from O, S, Se; R 6a , R 6b are independently selected from substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, substituents of C1-C8alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from halogen, hydroxyl, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl, or

[0020] R 7a , R 7b are independently selected from substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, substituents of C1-C8alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from halogen, hydroxyl, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl;

[0021] R 8a , R8b The substituents of the independently selected group consisting of substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from the group consisting of N, O, or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, C1-C8alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl;

[0022] R9is selected from the group consisting of R 11 The substituents of the independently selected group consisting of substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from the group consisting of N, O, or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, C1-C8alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl;

[0023] R 10The substituents selected from substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from the group consisting of N, O or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from halogen, hydroxy, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl or

[0024] L2, L3, L4are independently selected from unsubstituted or substituted -(CH2) 1b substituted -(CH2) n n is selected from 1, 2, 3, 4 or 5, R 1b The substituents selected from halogen, hydroxy, cyano, NH2, substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from the group consisting of N, O or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from halogen, hydroxy, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl;

[0025] Ring A is selected from substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl having at least one atom selected from N, O or S, substituted or unsubstituted C6-C8aryl, substituted or unsubstituted C5-C8heteroaryl, the substituents of C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C8aryl, C5-C8heteroaryl can be independently selected from halogen, hydroxy, cyano, C1-C8alkyl, C1-C8heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C3-C8cycloalkylalkyl, C3-C8heterocycloalkylalkyl, C6-C8aryl, C5-C8heteroaryl, C7-C10arylalkyl, C5-C10heteroarylalkyl, substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl;

[0026] the substituents of the above substituted C3-C8cycloalkyl, substituted C3-C8heterocycloalkyl, substituted C3-C8cycloalkylalkyl, substituted C3-C8heterocycloalkylalkyl, substituted C6-C8aryl, substituted C5-C8heteroaryl, substituted C7-C10arylalkyl, substituted C5-C10heteroarylalkyl are each independently selected from halogen, hydroxy, thio, amino, cyano, nitro, carboxy, acyl, sulfonyl, sulfonamido, sulfoximine, ureido, guanidino;

[0027] but not including: represents a single bond, R1is selected from H, R2is selected from H, L1is selected from -CH2-, R3is selected from CH3, R4is selected from R5is selected from represents a single bond, R1is selected from H, R2is selected from H, L1is selected from -CH2-, R3is selected from CH3, R4is selected from R5is selected from represents a single bond, R1is selected from H, R2is selected from H, L1is selected from -CH2-, R3is selected from CH3, R4is selected from R5is selected from

[0028] further preferred, represents a single bond or a double bond;

[0029] R1is selected from H,

[0030] R2is selected from H, CH3;

[0031] L1is selected from -CH2-;

[0032] R3is selected from the group consisting of methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl;

[0033] R4is selected from the group consisting of methyl, X1is selected from the group consisting of O, S; R 6a R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7a R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L2is selected from the group consisting of -CH2-, R 8a R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R

[0034] R5is selected from the group consisting of R9is selected from the group consisting of X2is selected from the group consisting of O, S; R 6b R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7b R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L3is selected from the group consisting of -CH2-, R 8b R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; L4is selected from the group consisting of -CH2-, R 11 R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R

[0035] but not including: R1is selected from the group consisting of H, R2is selected from the group consisting of H, L1is selected from the group consisting of -CH2-, R3is selected from the group consisting of CH3, R4is selected from the group consisting of R5is selected from the group consisting of R1is selected from the group consisting of H, R2is selected from the group consisting of H, L1is selected from the group consisting of -CH2-, R3is selected from the group consisting of CH3, R4is selected from the group consisting of R5is selected from the group consisting of

[0036] more preferred, R1is selected from the group consisting of H, R2is selected from the group consisting of H, L1is selected from the group consisting of -CH2-, R3is selected from the group consisting of CH3, R4is selected from the group consisting of

[0037] R1is selected from the group consisting of H,

[0038] R2is selected from the group consisting of H, CH3;

[0039] L1is selected from the group consisting of -CH2-;

[0040] R3is selected from the group consisting of methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl;

[0041] R4is selected from the group consisting of methyl, X1is selected from O; R 6a is selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl; L2is selected from -CH2-, R 8a is selected from isopropyl, tert-butyl;

[0042] R5is selected from R9is selected from X2is selected from O; R 6b is selected from methyl, ethyl, isopropyl; R 7b is selected from isopropyl; L3is selected from -CH2-, R 8b is selected from isopropyl, tert-butyl; L4is selected from -CH2-, R 11 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isopropoxy;

[0043] but not including: represents a single bond, R1is selected from H, R2is selected from H, L1is selected from -CH2-, R3is selected from CH3, R4is selected from R4is selected from

[0044] As a further preferred embodiment of the beta-lactamase inhibitor according to the present application, the beta-lactamase inhibitor is selected from a compound of the structure according to Formula II or a pharmaceutically acceptable salt, isomer, deuteride thereof:

[0045]

[0046] wherein R3, R4, R5are as previously described.

[0047] As a further preferred embodiment of the beta-lactamase inhibitor according to the present application, the beta-lactamase inhibitor is selected from a compound of the structure according to Formula III or a pharmaceutically acceptable salt, isomer, deuteride thereof:

[0048]

[0049] wherein R3, R4, R5are as previously described.

[0050] As a further preferred embodiment of the beta-lactamase inhibitor according to the present application, the beta-lactamase inhibitor is selected from a compound of the structure according to Formula IV or a pharmaceutically acceptable salt, isomer, deuteride thereof:

[0051]

[0052] wherein R3, R4, R5are as previously described.

[0053] As a further preferred embodiment of the β-lactamase inhibitor described in this invention, the β-lactamase inhibitor is selected from compounds with structures as shown in Formula V or their pharmaceutically acceptable salts, isomers, or deuterated derivatives:

[0054]

[0055] R3, R4, and R5 are as described above.

[0056] Specifically, the β-lactamase inhibitors of this invention are selected from the following compounds or their pharmaceutically acceptable salts or isomers, deuterated derivatives:

[0057]

[0058]

[0059]

[0060] Terminology Explanation

[0061] "Hydrocarbon group" refers to a saturated or unsaturated, branched or straight-chain monovalent hydrocarbon group resulting from the removal of a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. 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 with 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 desired.

[0062] "Aryl" means a monovalent aromatic carbocyclic group derived by removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups include 5- and 6-membered carbocyclic aromatic rings, such as, for example, benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as, for example, naphthalene, indane, and tetrahydronaphthalene; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as, for example, fluorene. Aryl groups include polycyclic ring systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, a cycloalkyl ring, or a heterocycloalkyl ring. For example, aryl groups include phenyl rings fused to 5- to 7-membered heterocycloalkyl rings containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic ring systems having only one ring that is carbocyclic and aromatic, the radical carbon atom can be located on either the carbocyclic aromatic ring or the heterocycloalkyl ring. Examples of aryl groups include those derived from acanthrylene, acenaphthylene, indane, indene, naphthalene, octalene, octaphene, octalene, ovalene, pentacene, pentalene, picene, pyranthrene, pyran, and phenalene. However, aryl groups do not encompass or overlap with heteroaryl groups, which are separately defined herein.

[0063] "Arylalkyl" means an acyclic alkyl group in which one of the hydrogen atoms has been replaced with an aryl group. Examples of arylalkyl groups include benzyl, 2-phenyleth-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, 2-naphthylethen-1-yl, naphthylbenzyl, and 2-naphthobenzyleth-1-yl. The term arylalkyl is used if a specific alkyl moiety is intended.

[0064] "Cycloalkyl" means a saturated or partially unsaturated cyclic hydrocarbon group, which can also be spiro, bridged.

[0065] "Cycloalkylalkyl" means an acyclic alkyl group in which one of the hydrogen atoms has been replaced with a cycloalkyl group as defined herein. The term cycloalkylalkyl is used if a specific alkyl moiety is intended.

[0066] "Heteroalkyl" by itself or as part of another substituent means a hydrocarbon group in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatoms. Examples of heteroatoms in heteroalkyl groups are -O-, -S-, -NH-, -N(-CH3)-, -SO-, -SO2-, and the like.

[0067] "Halo" means a fluoro, chloro, bromo, or iodo group.

[0068] "Heteroarylalkyl" means an arylalkyl group in which one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom.

[0069] "Heterocycloalkyl" by itself or as part of another substituent group means a saturated or unsaturated ring alkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom; or a parent aromatic ring system in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom such that the ring system violates the Hückel rule, and can also be a spiroheterocyclic, bridged heterocyclic ring.

[0070] "Heterocycloalkylalkyl" means a cycloalkylalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are replaced with the same or different heteroatom.

[0071] "Sulfonyl" means a group containing -S(O)(O)-. Examples of sulfonyl groups are p-toluenesulfonyl, sulfonimidoyl, mesyl, and the like.

[0072] Another object of the present application is to provide a pharmaceutical composition comprising the β-lactamase inhibitor according to the present application or a pharmaceutically acceptable salt thereof or an isomer or deuterated form thereof, and a pharmaceutically acceptable carrier.

[0073] The pharmaceutical composition further comprises an antibiotic; further, the antibiotic is a β-lactam antibiotic, such as a penicillin, a cephalosporin, a cephamycin, and a carbapenem antibiotic.

[0074] The pharmaceutical composition is in the form of an oral preparation; the oral preparation includes a solid dosage form for oral administration, a liquid dosage form for oral administration. The solid dosage form for oral administration includes a capsule, a tablet, a pill, a powder, and a granule. The liquid dosage form for oral administration includes a pharmaceutically acceptable emulsion, a solution, a suspension, a syrup, or a tincture.

[0075] The pharmaceutically acceptable carrier means one or more compatible solid or liquid filler or gel materials, which are suitable for human use, and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that the components of the composition are capable of being commingled with the active ingredients of the present application, and with each other, without any chemical incompatibility resulting in, for example, a degradation of the active ingredient. Examples of suitable pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, fillers, wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0076] Another object of the present application is to provide the use of the β-lactamase inhibitor or the pharmaceutical composition in the preparation of a β-lactamase inhibitor.

[0077] Another object of the present application is to provide the use of the β-lactamase inhibitor or the pharmaceutical composition in the preparation of a drug for treating diseases related to bacterial infection.

[0078] The bacteria can be bacteria capable of producing β-lactamase, including but not limited to bacteria of Enterobacter, Citrobacter, Providencia, Serratia or Morganella, etc.

[0079] The present application has the following advantages:

[0080] The β-lactamase inhibitor of the present application can release active metabolites such as avibactam, dorobactam, relebactam, and nacubactam, etc. by the action of biological enzymes in vivo, and can quickly take effect, effectively improve the oral bioavailability of such β-lactamase inhibitors, so that it can be orally administered, solving the problem of low oral bioavailability of dinitrogen heterocyclic β-lactamase inhibitors. The β-lactamase inhibitor of the present application is suitable for oral administration and has a broad spectrum, effectively solving the problem of lack of broad-spectrum oral β-lactamase inhibitors in clinical practice, and making up for the shortcomings of narrow antibacterial spectrum of existing oral β-lactamase inhibitors. DETAILED DESCRIPTION

[0081] Example 1

[0082] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid (pivaloyloxy)methyl ester (Compound 1)

[0083]

[0084]

[0085] Step one: synthesis of compound 1b

[0086] Compound 1a (20.0 g, 72.6 mmol) was dissolved in ethyl acetate (200 mL) at room temperature, then 10% palladium-carbon (5.60 g) was added, the mixture was replaced with hydrogen three times, and the reaction was carried out at room temperature under hydrogen atmosphere for 3 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was directly concentrated to dryness to obtain 13.0 g of compound 1b with a yield of 96.6%. LCMS (ESI): [M+H] + = 186.2. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.49 - 7.15 (m, 2H), 3.64 (d, J = 7.2 Hz, 1H), 3.17 (d, J = 3.2 Hz, 1H), 3.00 - 2.99 (m, 1H), 2.87 (d, J = 11.6 Hz, 1H), 2.10 - 2.07 (m, 1H), 2.10 - 2.05 (m, 1H), 1.79 - 1.67 (m, 1H), 1.66 - 1.55 (m, 1H).

[0087] Step two: synthesis of compound 1d

[0088] Compound 1c (10.0 g, 84.7 mmol) was dissolved in acetonitrile (100 mL) at room temperature, potassium carbonate (17.5 g, 127.0 mmol), chloromethyl pivalate (15.2 g, 101.6 mmol) and potassium iodide (7.0 g, 42.3 mmol) were added at room temperature, the mixture was stirred at 45 °C for 16 h. The reaction was completed, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL x 3), the organic phase was combined, washed with saturated brine (200 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 8 / 1 V / V) to give 1.0 g of compound 1d, yield 5.1%. 1 H NMR (400 MHz, CDCl3) δ 5.78 (s, 2H), 3.57 (s, 2H), 1.21 - 1.20 (m, 15H).

[0089] Step three: synthesis of compound 1e

[0090] Sulfonyl chloride (628 mg, 4.66 mmol) was dissolved in ether (9 mL) at room temperature, the mixture was replaced with argon three times, stirred at temperature -78 °C for 10 min. Compound 1d (900 mg, 3.88 mmol) and pyridine (338 mg, 4.27 mmol) were slowly added dropwise at temperature -78 °C, and the mixture was stirred at temperature -78 °C for 2 h. The reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 500 mg of compound 1e, yield 38.9%. 1 H NMR (400 MHz, CDCl3) δ 5.80 (s, 2H), 4.50 (s, 2H), 1.33 (s, 6H), 1.21 (s, 9H).

[0091] Step four: synthesis of compound 1

[0092] Compound 1b (100 mg, 0.54 mmol) was dissolved in a mixture solvent of super dry tetrahydrofuran (1 mL) and N,N-dimethylacrylurea (1 mL) at room temperature, sodium bis(trimethylsilyl)amide (0.3 mL, 2M tetrahydrofuran solution, 0.59 mmol) was added at temperature -78 °C under nitrogen protection; continue to stir the reaction at temperature -78 °C for 10 min, slowly add compound 1e (270 mg, 0.81 mmol). After dropwise addition, gradually increase to room temperature and react at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated brine (200 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Purification of the residue by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) gave 19.32 mg of compound 1, with a yield of 7.5%. LCMS (ESI): [M+H] + = 480.3. 1 H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.81 (d, J = 5.6 Hz, 1H), 5.77 (d, J = 5.6 Hz, 1H), 5.52 (s, 1H), 4.74 (d, J = 9.2 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.17 (d, J = 2.2 Hz, 1H), 4.05 (d, J = 7.1 Hz, 1H), 3.35 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.45 (dd, J = 14.8, 6.7 Hz, 1H), 2.15-2.13 (m, 1H), 1.91-1.88 (m, 2H), 1.29 (d, J = 5.3 Hz, 6H), 1.20 (s, 9H).

[0093] Example 2

[0094] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid (isobutyryloxy)methyl ester (Compound 2)

[0095]

[0096] Synthesis method as compound 1, only isobutyric acid chloromethyl ester is used instead of tert-butyl chloromethyl ester. LCMS (ESI): [M+H] + = 466.4.1 H NMR (400 MHz, CDC13) δ 6.51 (s, 1H), 5.81 (d, J = 5.6 Hz, 1H), 5.77 (d, J = 5.6 Hz, 1H), 5.59 (s, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.19 - 4.15 (m, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.38 - 3.31 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.66 - 2.55 (m, 1H), 2.50 - 2.40 (m, 1H), 2.21 - 2.12 (m, 1H), 2.01 - 1.91 (m, 1H), 1.89 - 1.81 (m, 1H), 1.30 (d, J = 5.6 Hz, 6H), 1.18 (d, J = 5.6 Hz, 6H).

[0097] Example 3

[0098] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid ethoxymethyl ester (Compound 3)

[0099]

[0100] Synthetic procedure was like Compound 1, only use chloromethyl acetate instead of chloromethyl pivalate. LCMS (ESI): [M+H] = 438.3. + = 438.3. 1 H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.80 (d, J = 5.6 Hz, 1H), 5.76 (d, J = 5.6 Hz, 1H), 5.51 (s, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.17 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.35 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.21 - 2.13 (m, 1H), 2.12 (s, 3H), 2.00 - 1.90 (m, 1H), 1.89 - 1.80 (m, 1H), 1.30 (d, J = 4.8 Hz, 6H).

[0101] Example 4

[0102] 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)- 2,2-dimethylpropanoic acid-1-(isobutyryloxy)ethyl ester (Compound 4)

[0103]

[0104] The synthesis method is as that of Compound 1, only using isobutyric acid (1- chloroethyl) ester instead of chloromethyl pivaloate in equivalent amount. LCMS (ESI): [M+H] + = 480.5. 1 H NMR (400 MHz, CDC13) δ 6.92-6.80 (m, 1H), 6.50 (s, 1H), 5.55 (s, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.64-4.55 (m, 1H), 4.17 (s, 1H), 4.05 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 12.4 Hz, 1H), 3.02 (d, J = 10.4 Hz, 1H), 2.56-2.51 (m, 1H), 2.47-2.43 (m, 1H), 2.17-2.15 (m, 1H), 2.03-1.79 (m, 2H), 1.48 (d, J = 9.2 Hz, 3H), 1.30-1.24 (m, 6H), 1.17 (dd, J = 7.2, 2.0 Hz, 6H).

[0105] Example 5

[0106] Synthesis of (1R,2R)-2-(1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2-methylpropan-2-yl)cyclopropane-1-carboxylic acid ethyl ester (Compound 5)

[0107]

[0108]

[0109] Step one: synthesis of compound 5b

[0110] Compound 5a (6.0 g, 52.57 mmol) was dissolved in ether (60 mL) at a temperature of 0 °C, then lithium aluminum hydride (23.2 ml, 57.8 mmol) was added dropwise thereto, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, sodium sulfate decahydrate (20.0 g) was slowly added thereto, filtered, and the filter cake was washed with ether (100 mL). The combined organic phase was concentrated to dryness at a temperature of 0 °C to obtain 3.9 g of compound 5b at a yield of 74.1%.1 H NMR (400 MHz, CDC13) δ 5.83-5.70 (m, 1H), 5.15-5.00 (m, 2H), 3.34 (d, J = 6.4 Hz, 2H), 1.02 (s, 6H).

[0111] Step two: synthesis of compound 5c

[0112] Compound 5b (3.9 g, 38.94 mmol) was dissolved in tetrahydrofuran (39 mL) at room temperature, sodium hydride (2.34 g, 58.41 mmol) was added under ice bath, the ice bath was kept for 30 minutes, then benzyl bromide (9.99 g, 58.41 mmol) was added, the ice bath was removed, the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 5.5 g of compound 5c with a yield of 74.2%. 1 H NMR (400 MHz, CDC13) δ 5.83-5.70 (m, 1H), 5.15-5.00 (m, 2H), 3.34 (d, J = 6.4 Hz, 2H), 1.02 (s, 6H).

[0113] Step three: synthesis of compound 5d

[0114] Compound 5c (4.2 g, 22.07 mmol) was dissolved in 1,2-dichloroethane (42 mL) at room temperature, stirred and cooled in an ice bath under nitrogen protection, then 2-diazomethane ethyl acetate (4.74 g, 66.21 mmol) was slowly added after adding rhodium (II) dimeric acetate (97 mg, 0.22 mmol), the reaction solution was warmed to 45°C and the reaction was continued for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 1.0 g of compound 5d with a yield of 16.4%. 1H NMR (400 MHz, CDC13) δ 7.35 - 7.24 (m, 5H), 4.51 (s, 2H), 4.13 - 4.07 (m, 2H), 3.22 - 3.19 (m, 2H), 1.59 - 1.52 (m, 1H), 1.50 - 1.43 (m, 1H), 1.27 - 1.21 (m, 3H), 0.96 - 0.92 (m, 1H), 0.90 - 0.85 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H).

[0115] Step four: synthesis of compound 5e

[0116] Compound 5d (1.0 g, 3.62 mmol) was dissolved in methanol (10 mL) at room temperature, then 10% palladium carbon (300 mg) was added, and the mixture was replaced with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 450 mg of crude compound 5e, which was directly used in the next reaction. LCMS (ESI) [M+H] + = 187.0.

[0117] Step five: synthesis of compound 5f

[0118] Sulfonyl chloride (490 mg, 3.63 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and the mixture was replaced with argon three times. Compound 5e (450 mg, 2.42 mmol) and pyridine (287 mg, 3.63 mmol) in diethyl ether (1.0 mL) were slowly added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 500 mg of crude compound 5f, which was directly used in the next reaction.

[0119] Step six: preparation of compound 5

[0120] Compound 1b (326 mg, 1.76 mmol) was added to a mixture of super dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (0.82 mL, 2 M in tetrahydrofuran, 1.94 mmol) was added dropwise under nitrogen protection at -78 °C. The reaction was kept at -78 °C for 10 minutes, and then compound 5f (500 mg, 1.76 mmol) was added. The reaction was kept at -78 °C for 10 minutes, and then gradually warmed to room temperature and reacted at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and then extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% to 70%) to give 68.47 mg of compound 5, in a yield of 8.97%. LCMS (ESI): [M+H] + = 434.2. 1 HNMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 5.50 (s, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.27 (dd, J = 9.2, 3.2 Hz, 1H), 4.20-4.15 (m, 1H), 4.15-4.09 (m, 2H), 4.05 (d, J = 7.6 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.01 (d, J = 12.0 Hz, 1H), 2.48-2.43 (m, 1H), 2.21-2.13 (m, 1H), 1.99-1.80 (m, 2H), 1.48-1.41 (m, 1H), 1.30-1.23 (m, 4H), 1.14-1.06 (m, 1H), 0.93-0.88 (m, 7H).

[0121] Example 6

[0122] Synthesis of isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2-methyl-2-p-tolylsulfonylpropanoate (Compound 6)

[0123]

[0124] Step one: synthesis of compound 6b

[0125] Compound 6a (15.0 g, 98 mmol) was added into isopropyl alcohol (50 mL) at room temperature, and the mixture was cooled to 0 °C, and thionyl chloride (14 g, 117.6 mmol) was added thereto; after the addition was completed, the mixture was gradually warmed to room temperature and reacted for 16 hours; after the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3) three times, and the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness; the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 15.0 g of compound 6b, with a yield of 78.9%. LCMS (ESI): [M+H] + = 195.2. 1 H NMR (400 MHz, CDCl3) δ 5.15-4.99 (m, 1H), 4.33 (q, J = 6.8 Hz, 1H), 1.81 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.4 Hz, 6H).

[0126] Step two: synthesis of compound 6c

[0127] Compound 6b (5.0 g, 25.77 mmol) was added to a mixture of water (10 mL), toluene (7.5 mL), and acetone (7.5 mL) at room temperature, and then tetrabutylammonium iodide (666 mg, 1.80 mmol) and sodium 4-methylbenzenesulfinate (6.88 g, 38.66 mmol) were sequentially added thereto, and the mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3) three times, and the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness; the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate (V / V = 5 / 1)) to obtain 5.6 g of compound 6c, with a yield of 80.6%. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 5.04-4.89 (m, 1H), 3.99 (q, J = 7.2 Hz, 1H), 2.44 (s, 3H), 1.56 (d, J = 8.4 Hz, 3H), 1.22-1.08 (m, 6H).

[0128] Step three: synthesis of compound 6d

[0129] Compound 6c (1.0 g, 3.70 mmol) was dissolved in a mixture solvent of ethanol (6 mL) and water (3 mL) at room temperature, 37% aqueous formaldehyde solution (330 mg, 4.07 mmol) and sodium bicarbonate (31 mg, 0.37 mmol) were added successively at temperature 0 °C, the reaction was continued at room temperature for 16 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL x 3) for three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 1.1 g of compound 6d, with a yield of 82.7%. LCMS (ESI): [M+H] + = 301.2.

[0130] Step four: synthesis of compound 6e

[0131] Sulfonyl chloride (450 mg, 3.33 mmol) was dissolved in diethyl ether (5 mL) at room temperature, the mixture was replaced with argon for three times, and cooled to -78 °C for 10 min. Compound 6d (500 mg, 1.67 mmol) and pyridine (264 mg, 3.33 mmol) in diethyl ether (0.5 mL) were added slowly dropwise at temperature -78 °C, after the addition was completed, it was gradually warmed to room temperature and the reaction was continued to stir at room temperature for 4 h. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated to dryness to obtain 667 mg of compound 6e crude product, which was directly used for the next reaction.

[0132] Step five: synthesis of compound 6

[0133] Compound 1b (310 mg, 1.67 mmol) was dissolved in a mixture of dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and sodium bis(trimethylsilyl)amide (0.92 mL, 2M in tetrahydrofuran, 1.84 mmol) was added dropwise to the solution under nitrogen protection at -78 °C. After the dropwise addition was completed, the temperature was maintained at -78 °C for 10 minutes, and then compound 6e (667 mg, 1.67 mmol) was slowly added to the solution. After the addition was completed, the temperature was gradually increased to room temperature, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and the organic phase was extracted with ethyl acetate (100 mL x 3) three times. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 55% to 70%) to obtain 75.46 mg of compound 6, in a yield of 8.24%. LCMS (ESI): [M+H] + 548.4. 1 H NMR (400 MHz, CDCl3) δ 7.83-7.66 (m, 2H), 7.37 (d, J = 9.2 Hz, 2H), 6.46 (s, 1H), 5.56 (s, 1H), 5.29-4.81 (m, 3H), 4.15 (s, 1H), 4.07 (t, J = 6.8 Hz, 1H), 3.30 (t, J = 10.8 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.54-2.39 (m, 4H), 2.15 (d, J = 10.0 Hz, 1H), 1.99-1.83 (m, 2H), 1.66 (d, J = 13.2 Hz, 3H), 1.24 (t, J = 6.0 Hz, 6H).

[0134] Example 7

[0135] Synthesis of diisopropyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 7)

[0136]

[0137] Step one: synthesis of compound 7b

[0138] Compound 7a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at room temperature, and isopropyl alcohol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol) were added successively, and the mixture was cooled to 0 °C. N,N'-Dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added thereto, and the mixture was reacted at room temperature for 16 h. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 14.0 g of compound 7b at a yield of 81.8%. 1 H NMR (400 MHz, CDCl3) δ 5.14-5.00 (m, 2H), 3.83 (q, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.30-1.17 (m, 12H).

[0139] Step two: synthesis of compound 7c

[0140] Compound 7b (7.0 g, 34.61 mmol) was dissolved in a mixed solvent of ethanol (35 mL) and water (35 mL) at room temperature, and aqueous formaldehyde (3.12 g, 38.07 mmol) and sodium bicarbonate (291 mg, 3.46 mmol, 0.1 equivalent) were added thereto at room temperature. The mixture was stirred at room temperature for 16 h. After the completion of the reaction, the reaction solution was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 3 / 1 V / V) to obtain 3.7 g of compound 7c at a yield of 46.1%. 1 H NMR (400 MHz, CDCl3) δ 5.13-5.02 (m, 2H), 3.83 (d, J = 7.2 Hz, 2H), 1.42 (s, 3H), 1.30-1.19 (m, 12H).

[0141] Step three: synthesis of compound 7d

[0142] Sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and the mixture was replaced with argon three times. Compound 7c (1.0 g, 4.31 mmol) and pyridine (375 mg, 4.74 mmol, 1.1 equivalent) in diethyl ether (1 mL) were added to the mixture at -78 °C, and the mixture was stirred at -78 °C for 0.5 h, and then gradually warmed to room temperature. The reaction was continued at room temperature for 2 h. After the completion of the reaction, the reaction solution was directly concentrated to dryness to obtain 1.0 g of compound 7d at a yield of 96.4%.1 H NMR (400 MHz, CDC13) δ 5.12-5.06 (m, 2H), 4.79 (s, 2H), 1.57 (s, 3H), 1.26 (d, J = 7.2 Hz, 12H).

[0143] Step four: synthesis of compound 7

[0144] Compound 1b (300 mg, 1.60 mmol) was dissolved in super dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.2 mL) at room temperature, and sodium bis(trimethylsilyl)amide (0.9 mL, 2M tetrahydrofuran solution, 1.8 mmol) was added to it under argon protection at -78 °C. After the addition was completed, the reaction was continued to stir for 10 min at -78 °C, and compound 7d (642 mg, 1.95 mmol) was slowly added to it. After the addition was completed, the reaction temperature was gradually increased to room temperature, and the reaction was continued to react for 2 h at room temperature. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and the obtained solution was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 95.26 mg of compound 7, with a yield of 12.2%. LCMS (ESI): [M+H] + = 480.3. 1 H NMR (400 MHz, CDC13) δ 6.49 (s, 1H), 5.68 (s, 1H), 5.09-5.06 (m, 3H), 4.90 (d, J = 9.4 Hz, 1H), 4.16 (s, 1H), 4.06 (d, J = 7.4 Hz, 1H), 3.32 (d, J = 12.1 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.46-2.41 (m, 1H), 2.24-2.12 (m, 1H), 2.05-1.78 (m, 2H), 1.53 (s, 3H), 1.26 (d, J = 5.4 Hz, 12H).

[0145] Example 8

[0146] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methyl propanedioic acid dimethyl ester (compound 8)

[0147]

[0148] The synthetic method is as compound 7, only isopropanol is replaced by methanol. LCMS (ESI): [M+H] + = 424.2. 1 HNMR (400MHz, CDC13) δ 6.47 (s, 1H), 5.57 (s, 1H), 5.04 (d, J = 9.6 Hz, 1H), 4.89 (d, J = 9.6 Hz, 1H), 4.16 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.78 (d, J = 5.6 Hz, 6H), 3.33 (d, J = 12.0 Hz, 1H), 3.07-2.99 (m, 1H), 2.53-2.39 (m, 1H), 2.21-2.12 (m, 1H), 2.01-1.92 (m, 1H), 1.91-1.82 (m, 1H), 1.58 (s, 3H).

[0149] Example 9

[0150] Synthesis of di-tert-butyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 9)

[0151]

[0152] Step one: synthesis of compound 9b

[0153] Compound 9a (30.0 g, 138.72 mmol) was dissolved in tetrahydrofuran (300 mL) at room temperature, and sodium hydride (5.5 g, 138.72 mmol) was slowly added to it at 0 °C. After the addition was completed, the reaction was continued at 0 °C for 0.5 h, and then methyl iodide (19.7 g, 138.72 mmol) was added at 0 °C. After the addition was completed, the temperature was gradually increased to room temperature, and the reaction was continued at room temperature for 2 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and extraction was performed with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 30.5 g of compound 9b with a yield of 95.5%. 1 HNMR (400MHz, CDC13) δ 3.26 (q, J = 7.3 Hz, 1H), 1.46 (s, 18H), 1.32 (d, J = 7.3 Hz, 3H).

[0154] Step two: synthesis of compound 9c

[0155] Compound 9b (20.0 g, 86.96 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, and sodium hydride (5.2 g, 130.43 mmol) was slowly added thereto at 0 °C. After the addition was completed, the reaction was allowed to react at 0 °C for 0.5 h, and tetrabutylammonium iodide (16.1 g, 43.48 mmol) and benzyl chloromethyl ether (13.6 g, 86.96 mmol) were further added thereto. After the addition was completed, the reaction was allowed to react at 90 °C for 4 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and extraction was performed with ethyl acetate (200 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 28.0 g of compound 9c at a yield of 91.9%. LCMS (ESI): [M+Na] = 373.2. + 1 H NMR (400 MHz, CDCl3) d 7.32-7.28 (m, 5H), 4.53 (s, 2H), 3.74 (s, 2H), 1.45 (d, J = 2.5 Hz, 6H), 1.43 (s, 15H).

[0156] Step three: synthesis of compound 9d

[0157] Compound 9c (1.0 g, 2.86 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, and 10% palladium-carbon (500 mg) was added thereto. The reaction solution was replaced with hydrogen three times, and the reaction was allowed to react at 50 °C for 16 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 550 mg of compound 9d at a yield of 74.0%. LCMS (ESI): [M+Na] = 283.1. +

[0158] Step four: synthesis of compound 9e

[0159] Sulfonyl chloride (568 mg, 4.21 mmol) was dissolved in diethyl ether (7 mL) at room temperature, and a solution of compound 9d (730 mg, 2.81 mmol) and pyridine (244 mg, 3.09 mmol) in diethyl ether (1 mL) was added dropwise thereto under nitrogen protection at -78 °C. After the dropwise addition was completed, the reaction was allowed to react at -78 °C for 3 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 520 mg of compound 9e as a crude product, which was directly used in the next reaction.

[0160] Step five: synthesis of compound 9 ​​

[0161] Compound 1b (268 mg, 1.45 mmol) was dissolved in dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.2 mL) mixed solvent at room temperature, and under nitrogen protection, the temperature was lowered to -78 °C, and then sodium bis(trimethylsilyl)amide (0.8 mL, 2M tetrahydrofuran solution, 1.60 mmol) was slowly added. After the addition was completed, the reaction was continued to stir at -78 °C for 10 min, and then compound 9e (520 mg, 1.45 mmol) was slowly added. After the addition was completed, the temperature was gradually increased to room temperature and the reaction was continued to react at room temperature for 2 h. After the reaction was completed, water (200 mL) was added to quench the reaction, and then extracted with ethyl acetate (200 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% ~ 70%) to obtain 141.38 mg of compound 9, with a yield of 19.2%. LCMS (ESI): [M+Na] = 530.2. + 1 H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.60 (s, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.86 (d, J = 9.3 Hz, 1H), 4.16 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.4 Hz, 1H), 3.32 (d, J = 11.8 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.44 (dd, J = 15.1, 6.9 Hz, 1H), 2.21-2.12 (m, 1H), 1.90-1.88 (m, 2H), 1.57-1.42 (m, 21H).

[0162] Example 10

[0163] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethyl propanedioic acid diethyl ester (Compound 10)

[0164]

[0165] Step one: synthesis of compound 10b

[0166] ​Compound 10a (10.0 g, 53.2 mmol) was dissolved in a mixture solvent of ethanol (40 mL) and water (20 mL) at room temperature, 37% aqueous formaldehyde solution (4.74 g, 58.5 mmol) and sodium bicarbonate (447 mg, 5.32 mmol) were added at 0 °C, after the addition was completed, the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 9.2 g of compound 10b with a yield of 79.3%. LCMS (ESI): [M+H] + = 219.1.

[0167] Step two: synthesis of compound 10c

[0168] Sulfonyl chloride (1.86 g, 13.76 mmol) was dissolved in diethyl ether (20 mL) at room temperature, and the mixture was replaced with argon three times, stirred at -78 °C for 10 min; then a solution of compound 10b (2.0 g, 9.17 mmol) and pyridine (943 mg, 11.93 mmol) in diethyl ether (2.0 mL) was slowly added dropwise at -78 °C, and the dropwise addition was completed. The temperature was gradually increased to room temperature, and the reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated to dryness to obtain 2.0 g of compound 10c with a yield of 69.2%. 1 H NMR (400 MHz, CDCl3) δ 4.81 (s, 2H), 4.25 (q, J = 6.8 Hz, 4H), 1.97 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 6.8 Hz, 6H), 0.95 (t, J = 6.8 Hz, 3H).

[0169] Step three: synthesis of compound 10

[0170] Compound 1b (300 mg, 1.62 mmol) was dissolved in a mixture of dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and sodium bis(trimethylsilyl)amide (0.89 mL, 2M in tetrahydrofuran, 1.78 mmol) was added dropwise thereto under nitrogen protection at -78°C. After the dropwise addition was completed, the reaction was maintained at -78°C for 10 minutes, and then compound 10c (1025 mg, 3.24 mmol) was added dropwise thereto. After the dropwise addition was completed, the temperature of the reaction liquid was slowly increased to room temperature, and the reaction was performed at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction liquid to quench the reaction, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 28.11 mg of compound 10 at a yield of 3.73%. LCMS (ESI): [M+H] + = 466.5. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.54 (s, 1H), 5.10 (d, J = 10.0 Hz, 1H), 4.95 (d, J = 10.0 Hz, 1H), 4.29-4.20 (m, 4H), 4.15 (d, J = 2.0 Hz, 1H), 4.07 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.18-2.02 (m, 3H), 1.99-1.82 (m, 2H), 1.30-1.25 (m, 6H), 0.92 (t, J = 7.8 Hz, 3H).

[0171] Example 11

[0172] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid diisopropyl ester (Compound 11)

[0173]

[0174] The synthesis method is as that of compound 10, except that 2-ethylmalonic acid diisopropyl ester is used instead of compound 10a. LCMS (ESI): [M+H] + = 494.2.1 H NMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.54 (s, 1H), 5.14 - 5.04 (m, 3H), 4.95 (d, J = 9.6 Hz, 1H), 4.17 - 4.12 (m, 1H), 4.07 (d, J = 7.2 Hz, 1H), 3.31 (d, J = 11.6 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.49 - 2.40 (m, 1H), 2.20 - 1.80 (m, 5H), 1.27 - 1.23 (m, 12H), 0.92 (t, J = 7.6 Hz, 3H).

[0175] Example 12

[0176] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid bisethyl ester (Compound 12)

[0177]

[0178] Step one: Synthesis of compound 12a

[0179] Compound 7a (10.0 g, 84.75 mmol) was dissolved in dichloromethane (100 mL) at room temperature, then oxalyl chloride (32.28 g, 254.23 mmol) and N,N- dimethylformamide (619 mg, 8.47 mmol) were added at 0 °C, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 13.0 g of compound 12a with a yield of 99.0%. 1 H NMR (400 MHz, CDC13) δ 4.36 - 4.19 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H).

[0180] Step two: Synthesis of compound 12b

[0181] Compound 12a (13.0 g, 84.4 mmol) was dissolved in dichloromethane (130 mL) at room temperature, and triethylamine (25.57 g, 253.2 mmol) and ethanethiol (15.95 g, 253.2 mmol) were sequentially added thereto at 0 °C, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 3.8 g of compound 12b with a yield of 21.8%. 1H NMR (400 MHz, CDC13) δ 3.88-3.78 (m, 1H), 2.95-2.89 (m, 4H), 1.46 (d, J = 7.1 Hz, 3H), 1.29-1.24 (m, 6H).

[0182] Step three: synthesis of compound 12c

[0183] Compound 12b (3.8 g, 18.44 mmol) was dissolved in ethanol (16 mL) and water (8 mL) at room temperature, 37% aqueous formaldehyde solution (1.65 g, 20.3 mmol) and sodium bicarbonate (155 mg, 1.84 mmol equivalent) were added into the mixture at 0 °C; after addition, the mixture was warmed to room temperature and reacted for 16 hours at room temperature. After reaction, water (50 mL) was added into the reaction mixture to quench the reaction, extracted with ethyl acetate (100 mL x 3), the organic phase was combined and washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness, the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to give 3.3 g of compound 12c with a yield of 75.8%. LCMS (ESI): [M+H] + = 237.0.

[0184] Step four: synthesis of compound 12d

[0185] Sulfonyl chloride (172 mg, 1.27 mmol) was dissolved in diethyl ether (2 mL) at room temperature, the mixture was replaced with argon for three times, stirred at -78 °C for 10 min, then a solution of compound 12c (200 mg, 0.85 mmol) and pyridine (87 mg, 1.10 mmol) in diethyl ether (0.2 mL) was slowly added dropwise at -78 °C, after dropwise addition, the mixture was gradually warmed to room temperature and stirred at room temperature for 4 h. After reaction, the reaction mixture was filtered, and the filtrate was directly concentrated to dryness to give 289 mg of compound 12d crude which was directly used in the next step reaction.

[0186] Step five: synthesis of compound 12

[0187] Compound 1b (160 mg, 0.86 mmol) was dissolved in a mixture solution of dry tetrahydrofuran (3.2 mL) and N,N-dimethylacrylamide (1.4 mL) at room temperature, argon protection, cooling to -78 °C, then sodium bis(trimethylsilyl)amide (0.47 mL, 2M in tetrahydrofuran, 0.95 mmol) was added dropwise, stirred at -78 °C for 10 minutes, then compound 12d (289 mg, 0.86 mmol) was added. After addition, slowly warmed to room temperature, and reacted at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% ~ 70%) to give 24.87 mg of compound 12, with a yield of 59.6%. LCMS (ESI): [M+H] + = 484.1. 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 5.52 (s, 1H), 5.13-4.99 (m, 2H), 4.16 (s, 1H), 4.07 (d, J = 7.6 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.99-2.90 (m, 4H), 2.50-2.39 (m, 1H), 2.21-2.11 (m, 1H), 1.99-1.83 (m, 2H), 1.71 (s, 3H), 1.29-1.24 (m, 6H).

[0188] Example 13

[0189] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-benzylmalonic acid diethyl ester (Compound 13)

[0190]

[0191] Step one: synthesis of compound 13b

[0192] Compound 13a (10.0 g, 62.43 mmol) was dissolved in ethanol (100 mL) at room temperature, and potassium carbonate (11.22 g, 81.16 mmol) and benzyl bromide (21.36 g, 124.86 mmol) were added thereto in sequence, and heated to 65 °C for 8 hours. After the reaction was completed, pure water (100 mL) was added for quenching, extracted with dichloromethane (100 mL x 3), and the combined organic phase was washed with sodium bicarbonate (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 6.7 g of compound 13b, with a yield of 42.9%. 1 HNMR (400 MHz, CDC13) δ 7.30-7.16 (m, 5H), 4.24-4.07 (m, 4H), 3.69-3.58 (m, 1H), 3.22 (d, J = 8.0 Hz, 2H), 1.26-1.14 (m, 6H).

[0193] Step two: synthesis of compound 13c

[0194] Compound 13b (6.7 g, 26.77 mmol) was added with potassium hydroxide (5 mg, 0.094 mmol) and paraformaldehyde (1.22 g, 40.16 mmol) at room temperature, and reacted at 80 °C for 24 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate = 3 / 1 V / V) to obtain 4.0 g of compound 13c, with a yield of 53.3%. LCMS (ESI): [M+H] + = 281.2.

[0195] Step three: synthesis of compound 13d

[0196] Sulfonyl chloride (1.08 g, 8.03 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and the mixture was replaced with argon three times, stirred at a temperature of -78 °C for 10 minutes, and a solution of compound 13c (1.5 g, 5.35 mmol) and pyridine (635 mg, 8.03 mmol, 1.5 equivalents) in diethyl ether (1.0 mL) was added dropwise. After the dropwise addition was completed, the reaction was reacted at a temperature of -78 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 1.5 g of crude compound 13d, which was directly subjected to the next step.

[0197] Step four: synthesis of compound 13

[0198] Compound 1b (734 mg, 3.96 mmol) was dissolved in a mixture of dry tetrahydrofuran (16 mL) and N,N-dimethylacrylamide (6.4 mL) at room temperature, and sodium bis(trimethylsilyl)amide (2.2 mL, 2M tetrahydrofuran solution, 4.36 mmol) was added thereto under nitrogen protection at a temperature of -78°C, and the reaction was continued to be stirred for 10 min at a temperature of -78°C, and then 2-benzyl-2-(((chlorosulfonyl)oxy)methyl)malonic acid diethyl ester (1.50 g, 3.96 mmol) was slowly added. After the addition was completed, the reaction temperature was gradually increased to room temperature, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and extraction was performed with ethyl acetate (1000 mL x 3), and the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% ~ 60%) to obtain 185.06 mg of compound 13 at a yield of 8.86%. LCMS (ESI): [M+H] + = 528.6. 1 H NMR (400 MHz, CDCl3) δ 7.33-7.26 (m, 3H), 7.19-7.12 (m, 2H), 6.47 (s, 1H), 5.59 (s, 1H), 4.94 (d, J = 10.0 Hz, 1H), 4.78 (d, J = 10.0 Hz, 1H), 4.30-4.14 (m, 5H), 4.07 (d, J = 7.2 Hz, 1H), 3.39 (d, J = 2.8 Hz, 2H), 3.35-3.28 (m, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.48-2.37 (m, 1H), 2.20-2.10 (m, 1H), 2.02-1.79 (m, 2H), 1.25 (q, J = 7.2 Hz, 6H).

[0199] Example 14

[0200] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-phenylpropanoic acid diethyl ester (Compound 14)

[0201]

[0202] The synthetic method is as compound 13, only use 2-phenylmalonic acid diethyl ester instead of compound 13b. LCMS (ESI): [M+H] + = 514.2. 1 H NMR (400 MHz, CDC13) δ 7.47 - 7.31 (m, 5H), 6.45 (s, 1H), 5.51 (s, 1H), 5.38 (d, J = 9.6 Hz, 1H), 5.14 (d, J = 9.6 Hz, 1H), 4.44 - 4.21 (m, 4H), 4.03 (s, 2H), 3.24 (d, J = 11.6 Hz, 1H), 2.97 (d, J = 12.0 Hz, 1H), 2.49 - 2.35 (m, 1H), 2.17 - 2.07 (m, 1H), 1.96 - 1.76 (m, 2H), 1.33 - 1.24 (m, 6H).

[0203] Example 15

[0204] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylpropanedioic acid diisopropyl ester (Compound 15)

[0205]

[0206] Step one: synthesis of compound 15b

[0207] Compound 15a (10.0 g, 99.88 mmol) was dissolved in dichloromethane (15 mL) at room temperature, isopropyl alcohol (9.0 g, 149.82 mmol) and 4-dimethylaminopyridine (1.2 g, 9.99 mmol) were added, and the temperature was lowered to 0 °C, N,N'-dicyclohexylcarbodiimide (30.9 g, 149.82 mmol) was added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 10 g of compound 15b with a yield of 70.4%. 1 H NMR (400 MHz, CDC13) δ 4.86 (dt, J = 12.5, 6.3 Hz, 1H), 2.01 (d, J = 7.1 Hz, 2H), 1.08 (dd, J = 6.3, 1.2 Hz, 6H), 0.43 - 0.32 (m, 2H), -0.00 (t, J = 4.8 Hz, 2H).

[0208] Step two: synthesis of compound 15c

[0209] Compound 15b (10.0 g, 70.32 mmol) was added at -78 °C, and the reaction was continued at -78 °C for 30 min, then di-tert-butyl dicarbonate (18.4 g, 84.39 mmol) was added, and the reaction was continued at room temperature for 4 h. The reaction was quenched by adding water (50 mL) to the reaction solution, and the product was extracted with ethyl acetate (100 mL x 3). The organic phase was combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 10.0 g of compound 15c in a yield of 58.7%. 1 HNMR (400 MHz, CDC13) δ 5.14-4.99 (m, 1H), 2.48 (d, J = 10.0 Hz, 1H), 1.43 (s, 9H), 1.26 (d, J = 6.3 Hz, 6H), 0.63 (dd, J = 8.1, 2.9 Hz, 2H), 0.30 (dd, J = 4.9, 1.1 Hz, 2H).

[0210] Step three: synthesis of compound 15d

[0211] Compound 15c (8.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature, and the solution was cooled to 0 °C under nitrogen, then sodium hydride (2.1 g, 52.7 mmol) was added, and the reaction was continued at 0 °C for 0.5 h, then ((chloromethoxy)methyl)benzene (5.5 g, 35.1 mmol) and tetrabutylammonium iodide (6.5 g, 17.6 mmol) were added, and the reaction was continued at 90 °C for 0.5 h. The reaction was quenched by adding water (100 mL) to the reaction solution, and the product was extracted with ethyl acetate (100 mL x 3). The organic phase was combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 8 / 1 V / V) to give 3.0 g of compound 15d in a yield of 32.2%. LCMS (ESI): [M+Na] = 385.3. +

[0212] Step four: synthesis of compound 15e

[0213] ​Compound 15d (1.5 g, 4.14 mmol) was dissolved in dichloromethane (15 mL) at room temperature, then trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 1 / 1 V / V) to obtain 3.0 g of compound 15e, with a yield of 32.2%. LCMS (ESI): [M+H] + = 307.2.

[0214] Step five: synthesis of compound 15f

[0215] Compound 15e (1.0 g, 3.26 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and isopropyl alcohol (1.0 g, 4.90 mmol), N,N'-dicyclohexylcarbodiimide (1.0 g, 4.90 mmol) and 4-dimethylaminopyridine (39 mg, 0.326 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 8 / 1 V / V) to obtain 600 mg of compound 15f, with a yield of 52.8%. LCMS (ESI): [M+H] + = 349.3.

[0216] Step six: synthesis of compound 15g

[0217] Compound 15f (600 mg, 1.72 mmol) was dissolved in ethyl acetate (6 mL) at room temperature, and 10% palladium-carbon (60 mg) was added, and the mixture was replaced with hydrogen gas three times, and the reaction was allowed to proceed at room temperature for 1.5 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 350 mg of compound 15g, with a yield of 69.7%. LCMS (ESI): [M+H] + = 259.2.

[0218] Step seven: synthesis of compound 15h

[0219] Sulfonyl chloride (272 mg, 2.03 mmol) was dissolved in dry ether (3 mL) and cooled to -78°C, and a solution of compound 15g (350 mg, 1.36 mmol) and pyridine (161 mg, 2.03 mmol) in dry ether (2 mL) was added dropwise. After the dropwise addition was completed, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 350 mg of crude compound 15h, which was directly used in the subsequent reaction without further purification. 1H NMR (400 MHz, CDC13) δ 5.12-5.08 (m, 2H), 4.81 (s, 2H), 1.52-1.50 (m, 1H), 1.27-1.25 (m, 12H), 0.74-0.65 (m, 2H), 0.51-0.48 (m, 2H).

[0220] Step eight: synthesis of compound 15

[0221] Compound lb (300 mg, 1.62 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen. Sodium bis(trimethylsilyl)amide (973 uL, 2M tetrahydrofuran solution, 1.95 mmol) was added dropwise, and the reaction was allowed to proceed for 10 minutes at -78 °C. Compound 15h (577 mg, 1.62 mmol) was then added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was completed, and the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 pm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 47.94 mg of compound 15, with a yield of 5.86%. LCMS (ESI): [M+H] + = 506.4. 1 H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.52 (s, 1H), 5.19-4.97 (m, 3H), 4.89 (d, J = 12.8 Hz, 1H), 4.16 (s, 1H), 4.07 (d, J = 7.2 Hz, 1H), 3.30 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.54-2.36 (m, 1H), 2.18-2.13 (m, 1H), 2.00-1.82 (m, 2H), 1.51-1.44 (m, 1H), 0.64 (d, J = 7.2 Hz, 2H), 0.55-0.44 (m, 2H).

[0222] Example 16

[0223] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropyl propanedioic acid- 1-tert-butyl-3-ethyl ester (Compound 16)

[0224]

[0225] The synthetic method was like the synthesis of compound 15, step two, step three, step six, step seven, step eight, with 2-cyclopropylacetic acid ethyl ester instead of compound 15b. LCMS (ESI): [M+Na] + = 528.1. 1 H NMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.53 (s, 1H), 5.98 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 8.4 Hz, 1H), 4.25 - 4.16 (m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.46 - 2.41 (m, 1H), 2.22 - 2.09 (m, 1H), 2.02 - 1.80 (m, 2H), 1.46 (d, J = 6.0 Hz, 10H), 1.28 (q, J = 7.2 Hz, 3H), 0.64 (d, J = 8.4 Hz, 2H), 0.49 - 0.48 (m, 2H).

[0226] Example 17

[0227] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylpropanedioic acid- 1 -ethyl-3- isopropyl ester (Compound 17)

[0228]

[0229] The synthetic method was like the synthesis of compound 15, with 2-cyclopropylacetic acid ethyl ester instead of compound 15b. LCMS (ESI): [M+H] + = 492.3. 1 H NMR (400 MHz, CDC13) δ 6.49 (s, 1H), 5.67 (s, 1H), 5.18 - 4.97 (m, 2H), 4.89 (d, J = 9.6 Hz, 1H), 4.30 - 4.12 (m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.36 - 3.26 (m, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.51 - 2.37 (m, 1H), 2.24 - 2.09 (m, 1H), 2.01 - 1.82 (m, 2H), 1.53 - 1.44 (m, 1H), 1.36 - 1.19 (m, 9H), 0.65 (d, J = 8.8 Hz, 2H), 0.57 - 0.42 (m, 2H).

[0230] Example 18

[0231] 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-l,3-diyl bis(2-methylpropanoate) (Compound 18) was synthesized

[0232]

[0233] Step one: synthesis of compound 18b

[0234] Compound 18a (10.0 g, 83.23 mmol) was dissolved in dichloromethane (100 mL) at room temperature, then pyridine (9.88 g, 124.85 mmol), isobutyric anhydride (26.33 g, 166.46 mmol,) and 4-dimethylaminopyridine (202.8 mg, 1.66 mmol) were added at room temperature, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane (100 mL x 3), the organic phases were combined, washed with sodium bicarbonate (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 7.0 g of compound 18b, with a yield of 32.3%. 1 H NMR (400 MHz, CDC13) δ 4.02 (d, J = 11.6 Hz, 4H), 3.40 (s, 2H), 2.60-2.55 (m, 2H), 1.18 (d, J = 7.2 Hz, 12H), 0.97 (s, 3H).

[0235] Step two: synthesis of compound 18c

[0236] Sulfonyl chloride (778 mg, 5.76 mmol) was dissolved in diethyl ether (8 mL) at room temperature, the mixture was replaced with argon three times, stirred at -78°C for 10 min, and then a solution of compound 18b (1.0 g, 3.84 mmol) and pyridine (456 mg, 5.76 mmol) in diethyl ether (0.8 mL) was slowly added dropwise at -78°C, and the mixture was stirred at -78°C for 2 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated to dryness to obtain 1.2 g of crude compound 18c, which was directly used in the next reaction.

[0237] Step three: synthesis of compound 18

[0238] Compound 1b (413 mg, 2.23 mmol) was dissolved in a mixture of dry tetrahydrofuran (8 mL) and N,N-dimethylacrylamide (3.2 mL) at room temperature, and sodium bis(trimethylsilyl)amide (1.2 mL, 2M tetrahydrofuran solution, 2.45 mmol) was added to the mixture under argon protection at -78 °C. The reaction was continued to stir at -78 °C for 10 min, and compound 18c (1.20 g, 3.34 mmol) was added slowly. After the addition was completed, the reaction was gradually raised to room temperature, and the reaction was continued at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (100 mL x 3) three times. The organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 115.1 mg of compound 18, with a yield of 10.17%. LCMS (ESI): [M+H+MeCN] + = 508.3. 1 H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 5.61 (s, 1H), 4.74 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.16 (s, 1H), 4.11-3.98 (m, 5H), 3.34 (d, J = 11.6 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.65-2.56 (m, 2H), 2.50-2.38 (m, 1H), 2.23-2.10 (m, 1H), 2.00-1.80 (m, 2H), 1.19 (dd, J = 7.2, 2.0 Hz, 12H), 1.09 (s, 3H).

[0239] Example 19

[0240] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)phosphoryl)bis(oxy))bis(methylene)bis(2- methylpropanoate) (Compound 19)

[0241]

[0242]

[0243] Step one: Synthesis of compound 19b

[0244] Compound 19a (35.0 g, 147.0 mmol) was dissolved in tetrahydrofuran (350 mL) at room temperature, sodium hydride (5.3 g, 220.4 mmol) was added at 0 °C, the reaction was stirred at room temperature for 1 h, then methyl iodide (31.3 g, 220.4 mmol) was added, after the addition was completed, the reaction was stirred at room temperature for 5 h, and the reaction was monitored by LCMS. After the reaction was completed, water (200 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (500 mL x 3) three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 30.0 g of compound 19b, with a yield of 81.1%. LCMS (ESI): [M+H] + = 253.1. 1 H NMR (400 MHz, CDCl3) δ 4.25-4.10 (m, 6H), 1.47 (d, J = 16.4 Hz, 6H), 1.34-1.24 (m, 9H).

[0245] Step two: synthesis of compound 19c

[0246] Compound 19b (24.0 g, 95.2 mmol) was dissolved in tetrahydrofuran (300 mL) at room temperature, and lithium borohydride (5.3 g, 220.4 mmol) was added at 0 °C, and the reaction was stirred at 50 °C for 16 h. After the reaction was completed, water (200 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (300 mL x 3) three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 1 / 1 V / V) to obtain 15.0 g of compound 19c, with a yield of 75.0%. LCMS (ESI): [M+H] + = 211.1. 1 H NMR (400 MHz, CDCl3) δ 4.19-4.08 (m, 5H), 3.68-3.51 (m, 2H), 1.36-1.29 (m, 6H), 1.18 (d, J = 16.8, 6H).

[0247] Step three: synthesis of compound 19d

[0248] Compound 19c (8.0 g, 38.1 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, sodium hydride (1.4 g, 57.1 mmol) was added at 0 °C, the reaction was stirred at 0 °C for 1 h, benzyl bromide (9.8 g, 57.1 mmol) was added to it and the reaction was stirred at room temperature for 5 h. The reaction was completed, water (50 mL) was added to the reaction to quench the reaction and extracted with ethyl acetate (100 mL x 3) for three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, the residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 3 / 1 V / V) to obtain 5.5 g of compound 19d, the yield was 48.2%. LCMS (ESI): [M+H] + = 301.2. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.24 (m, 5H), 4.53 (s, 2H), 4.10-4.05 (m, 4H), 3.49 (d, J = 12.4 Hz, 2H), 1.36-1.14 (m, 12H).

[0249] Step four: synthesis of compound 19e

[0250] Compound 19d (1.5 g, 5.0 mmol) was dissolved in dichloromethane (30 mL) at room temperature, trimethylsilyl bromide (3.9 g, 25.0 mmol) was added at 0 °C, the reaction was stirred at 55 °C for 2 h. The reaction was completed, the reaction was filtered, the filtrate was directly concentrated to dryness, the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.2% formic acid / water, mobile phase B: acetonitrile, gradient: 40% ~ 60%) to obtain 1.2 g of compound 19e, the yield was 97.6%. LCMS (ESI) [M+H] + = 245.0. 1 H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 4.55 (s, 2H), 3.49 (d, J = 14.8 Hz, 2H), 1.23 (d, J = 16.4 Hz, 6H).

[0251] Step five: synthesis of compound 19f

[0252] Compound 19e (1.2 g, 4.9 mmol) was dissolved in acetone (15 mL) at room temperature, to which a mixture of cesium carbonate (4.8 g, 14.8 mmol) and isobutyric acid iodo methyl ester (3.37 g, 14.8 mmol) with methane (0.237 g, 14.8 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate = 3 / 1 V / V) to obtain 1.0 g of compound 19f, with a yield of 45.9%. LCMS (ESI) [M+H] + = 445.2. 1 H NMR (400 MHz, CDC13) δ 7.45-7.24 (m, 5H), 5.74-5.57 (m, 4H), 4.53 (s, 2H), 3.48 (d, J = 14.8 Hz, 2H), 2.62-2.55 (m, 2H), 1.29-1.16 (m, 18H).

[0253] Step six: synthesis of compound 19g

[0254] Compound 19f (800 mg, 1.8 mmol) was dissolved in ethyl acetate (16 mL) at room temperature, then 10% palladium carbon (400 mg) was added, and the mixture was replaced with hydrogen three times. The reaction was continued at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 600 mg of compound 19g, with a yield of 94.2%. LCMS (ESI) [M+H] + = 355.1.

[0255] Step seven: synthesis of compound 19h

[0256] Sulfonyl chloride (315 mg, 2.3 mmol) was dissolved in diethyl ether (6 mL) at room temperature, and the solution was cooled to -78 °C under a nitrogen atmosphere. To this, a solution of compound 19g (550 mg, 1.6 mmol) and pyridine (184 mg, 2.3 mmol) in diethyl ether (1 mL) was added dropwise, and the temperature was gradually increased to room temperature. The reaction was continued at room temperature for 6 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 650 mg of compound 19h, with a yield of 92.6%, which was directly used in the next reaction.

[0257] Step eight: synthesis of compound 19

[0258] Compound 1b (250 mg, 1.4 mmol) was dissolved in a mixture solution of tetrahydrofuran (7.5 mL) and N,N-dimethylacrylamide (2.0 mL) at room temperature, and cooled to -78 °C under nitrogen atmosphere, then sodium bis(trimethylsilyl)amide (0.8 mL, 2M in tetrahydrofuran, 1.54 mmol) was added dropwise, and the reaction was stirred at -78 °C for 10 minutes, then compound 19h (610 mg, 1.4 mmol) was added dropwise, and the reaction was gradually warmed to room temperature, and reacted at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL x 3) three times, and the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% ~ 65%) to obtain 57.39 mg of compound 19, with a yield of 7.1%. LCMS (ESI) [M+H] + = 602.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.40 (s, 1H), 5.63 (d, J = 12.4 Hz, 4H), 4.64-4.58 (m, 1H), 4.45-4.40 (m, 1H), 4.12 (s, 1H), 3.91 (d, J = 6.4 Hz, 1H), 3.19 (s, 2H), 2.65-2.58 (m, 2H), 2.14-2.09 (m, 1H), 1.97-1.92 (m, 1H), 1.86-1.82 (m, 1H), 1.79-1.64 (m, 1H), 1.21-1.08 (m, 18H).

[0259] Example 20

[0260] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)oxy)phosphoryl)bis(oxy))bis(methylene) diacetate (Compound 20)

[0261]

[0262] Synthesis method as compound 19, only use methyl iodide acetate instead of isobutyric acid methyl iodide in step five. LCMS (ESI) [M+H] + = 546.2. 1H NMR (400 MHz, CDC13) δ 6.49 (s, 1H), 5.74-5.65 (m, 4H), 5.56 (s, 1H), 4.76 (dd, J = 12.8, 9.2 Hz, 1H), 4.52 (t, J = 10.0 Hz, 1H), 4.17 (s, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.35 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.54-2.40 (m, 1H), 2.15 (s, 7H), 2.01-1.85 (m, 2H), 1.30 (dd, J = 17.2, 10.0 Hz, 6H).

[0263] Example 21

[0264] Synthesis of (((l-(((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2-methylpropan-2-yl)phosphoryl)bis(oxy))bis(methylene) di- pivalate (Compound 21)

[0265]

[0266] Synthetic procedure as for Compound 19, using iodo methyl pivalate instead of iodo methyl isobutyrate in step five. LCMS (ESI): [M+H] + = 630.4. 1 H NMR (400 MHz, CDC13) δ 6.50 (s, 1H), 5.82-5.59 (m, 5H), 4.82-4.70 (m, 1H), 4.52 (t, J = 9.6 Hz, 1H), 4.17 (s, 1H), 4.05 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.41-2.40 (m, 1H), 2.23-2.09 (m, 1H), 2.02-1.83 (m, 2H), 1.34-1.19 (m, 24H).

[0267] Example 22

[0268] Synthesis of 2-(bis((isopropoxycarbonyl)oxy)methoxy)phosphoryl)-2-methylpropyl ((2S,5R)-2-carbonyl-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl) sulfate (Compound 22)

[0269]

[0270] The synthetic method is as compound 19, only replace isobutyl iodomethyl carbonate with equivalent amount of iodomethyl isopropyl carbonate in step five. LCMS (ESI): [M+H] + = 634.5. 1 H NMR (400 MHz, CDC13) δ 6.51 (s, 1H), 5.70 (d, J = 12.3 Hz, 4H), 5.62 (s, 1H), 5.00 - 4.87 (m, 2H), 4.83 - 4.71 (m, 1H), 4.53 (t, J = 9.9 Hz, 1H), 4.17 (s, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.35 (d, J = 11.9 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.43 (d, J = 15.4 Hz, 1H), 2.14 (s, 1H), 1.90 - 1.84 (m, 2H), 1.31 - 1.28 (m, 18H).

[0271] Example 23

[0272] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid bis((neopentanoyloxy)methyl) ester (Compound 23)

[0273]

[0274] Step one: synthesis of compound 23b

[0275] Compound 23a (20.0 g, 114.8 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, and sodium hydride (4.10 g, 173.2 mmol) was slowly added thereto at 0 °C. After reaction at 0 °C for 0.5 h, ((chloromethoxy)methyl)benzene (18.0 g, 114.8 mmol) and tetrabutylammonium iodide (21.2 g, 57.4 mmol) were added at 0 °C, and reaction was performed by stirring at 90 °C for 2 h. After reaction, water (200 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 28.0 g of compound 23b, with a yield of 82.8%. LCMS (ESI): [M+H] + = 295.1. 1H NMR (400 MHz, CDC13) δ 7.34-7.26 (m, 5H), 4.54 (s, 2H), 4.16 (q, J = 7.2 Hz, 4H), 3.81 (s, 2H), 1.53 (s, 3H), 1.22 (t, J = 7.2 Hz, 6H).

[0276] Step two: synthesis of compound 23c

[0277] Compound 23b (18.0 g, 61.2 mmol) was dissolved in a mixture solvent of ethanol (90 mL) and water (90 mL) at room temperature, sodium hydroxide (9.8 g, 244.9 mmol) was added slowly at room temperature, the reaction was stirred at 50 °C for 16 h. The reaction was finished, the reaction liquid was directly concentrated to dryness, the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 45%~65%) to give 15.0 g of compound 23c, which was directly used in the next reaction. LCMS (ESI): [M+Na] = 261.1. +

[0278] Step three: synthesis of compound 23d

[0279] Compound 23c (2.0 g, 8.40 mmol) was dissolved in dichloromethane (20 mL) at room temperature, then iodomethyl pivalate (4.48 g, 18.5 mmol) and cesium carbonate (6.02 g, 18.58 mmol) were added, the reaction was stirred at room temperature for 16 h. The reaction was finished, water (100 mL) was added to the reaction liquid to quench the reaction, and extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to give 2.3 g of compound 23d, with a yield of 63.6%. LCMS (ESI): [M+Na] = 489.2. +

[0280] Step four: synthesis of compound 23e

[0281] Compound 23d (800 mg, 1.72 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, 10% palladium-carbon (120 mg) was added thereto, the mixture was replaced with hydrogen gas three times, and the reaction was stirred at room temperature in a hydrogen atmosphere for 1.5 h. The reaction was finished, the reaction liquid was filtered, and the filtrate was concentrated to dryness to give 500 mg of compound 23e, with a yield of 77.3%. LCMS (ESI): [M+Na] = 489.2.​​+ = 399.2.

[0282] Step five: synthesis of compound 23f

[0283] Sulfonyl chloride (215 mg, 1.59 mmol) was dissolved in diethyl ether (10 mL) at room temperature, the mixture was replaced with argon for three times, stirred at -78 °C for 10 min, then a solution of compound 23e (500 mg, 1.33 mmol) and pyridine (105 mg, 1.33 mmol) in diethyl ether (1.7 mL) was added dropwise at -78 °C, gradually warmed to room temperature, and stirred at room temperature for 4 h. The reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 680 mg of compound 23f, which was directly used in the next step.

[0284] Step six: synthesis of compound 23

[0285] Compound 1b (220 mg, 1.18 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylacrylurea (1 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (713 uL, 2M in tetrahydrofuran, 1.42 mmol) was added dropwise, and the reaction was stirred at -78 °C for 10 min. Compound 23f (676 mg, 1.43 mmol) was slowly added, and the reaction was gradually warmed to room temperature. After 2 h, the reaction was completed, and the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was directly concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 pm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 54.65 mg of compound 23, with a yield of 9.86%. LCMS (ESI): [M+H] + = 624.6. 1H NMR (400 MHz, CDC13) δ 6.49 (s, 1H), 5.67 (s, 1H), 5.18-4.97 (m, 2H), 4.89 (d, J = 9.6 Hz, 1H), 4.23-4.20 (m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.44 (dd, J = 15.2, 6.8 Hz, 1H), 2.24-2.09 (m, 1H), 2.01-1.82 (m, 2H), 1.55-1.43 (m, 1H), 1.36-1.19 (m, 9H), 0.65 (d, J = 8.8 Hz, 2H), 0.50-0.46 (m, 2H).

[0286] Example 24

[0287] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1 -cyclohexyl-3-ethyl ester (Compound 24)

[0288]

[0289] Step one: Synthesis of compound 24a

[0290] Compound 23b (25.0 g, 85.0 mmol) was dissolved in ethanol (250 mL) and water (250 mL) at room temperature, sodium hydroxide (6.80 g, 170 mmol) was added slowly at room temperature, the reaction was stirred at 50 °C for 2 h. The reaction was concentrated to dryness directly, the residue was purified by reverse phase preparation (0.1% FA, ACN) to give 17.0 g of compound 24a in 75.1% yield. LCMS (ESI): [M+H] + = 267.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.26 (m, 5H), 4.54-4.46 (m, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.76 (d, J = 8.8 Hz, 1H), 3.68 (d, J = 8.8 Hz, 1H), 1.39 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H).

[0291] Step two: Synthesis of compound 24b

[0292] Compound 24a (2.0 g, 7.5 mmol) was dissolved in dichloromethane (20 mL) at room temperature, then cyclohexanol (1.1 g, 11.3 mmol) and 4-dimethylaminopyridine (92 mg, 0.75 mmol) were added successively, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 1.8 g of compound 24b, with a yield of 69.2%. LCMS (ESI) [M+H] + = 349.2. 1 H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 5H), 4.88-4.77 (m, 1H), 4.54-4.53 (m, 2H), 4.19-4.14 (m, 2H), 3.82 (s, 2H), 1.84-1.71 (m, 2H), 1.72-1.61 (m, 2H), 1.53 (s, 3H), 1.46-1.26 (m, 6H), 1.22 (t, J = 7.2 Hz, 3H).

[0293] Step three: synthesis of compound 24c

[0294] Compound 24b (1.8 g, 5.2 mmol) was dissolved in ethanol (40 mL) at room temperature, then 10% palladium-carbon (1.0 g) was added, and the mixture was replaced with hydrogen three times. The reaction was continued at 50°C under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 1.1 g of compound 24c, with a yield of 82.7%. LCMS (ESI) [M+Na] + = 281.2. 1 H NMR (400 MHz, CDCl3) δ 4.93-4.81 (m, 1H), 4.23-4.21 (m, 2H), 3.85 (s, 2H), 1.89-1.77 (m, 2H), 1.77-1.64 (m, 2H), 1.54-1.47 (m, 3H), 1.44 (s, 3H), 1.43-1.30 (m, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0295] Step four: synthesis of compound 24d

[0296] Sulfonyl chloride (392 mg, 2.9 mmol) was dissolved in diethyl ether (5 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen atmosphere. A solution of compound 24c (500 mg, 1.9 mmol) and pyridine (229 mg, 2.9 mmol) in diethyl ether (0.5 mL) was added dropwise, and the solution was gradually warmed to room temperature. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 600 mg of compound 24d (yield 86.8%). 1 H NMR (400 MHz, CDC13) δ 4.94-4.83 (m, 1H), 4.81 (s, 2H), 4.27-4.22 (m, 2H), 1.83-1.80 (m, 3H), 1.70 (d, J = 6.0 Hz, 2H), 1.59 (s, 3H), 1.53-1.37 (m, 5H), 1.28 (t, J = 7.2 Hz, 3H).

[0297] Step five: synthesis of compound 24

[0298] Compound 1b (300 mg, 1.62 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen atmosphere. Sodium bis(trimethylsilyl)amide (0.9 mL, 2M tetrahydrofuran solution, 1.80 mmol) was added dropwise, and the solution was gradually warmed to room temperature. After 10 minutes, compound 24d (579 mg, 1.62 mmol) was slowly added, and the solution was gradually warmed to room temperature. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was directly concentrated to dryness, and the residue was purified by reverse phase prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 65% ~ 75%) to obtain 115.22 mg of compound 24 (yield 14.1%). + = 506.3. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.40 (s, 1H), 4.92 (d, J = 9.6 Hz, 1H), 4.81-4.77 (m, 2H), 4.20-4.12 (m, 2H), 4.10 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.23-3.15 (m, 2H), 2.10 (dd, J = 15.6, 6.8 Hz, 1H), 2.01-1.91 (m, 1H), 1.88-1.82 (m, 1H), 1.78-1.66 (m, 3H), 1.59 (s, 2H), 1.49-1.27 (m, 9H), 1.18 (t, J = 7.2 Hz, 3H).

[0299] Example 25

[0300] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1 -benzyl-3-ethyl ester (Compound 25)

[0301]

[0302] Step one: Synthesis of compound 25b

[0303] Compound 25a (900 mg, 6.16 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and benzyl alcohol (998 mg, 9.25 mmol), N,N'-dicyclohexylcarbodiimide (1.09 g, 9.25 mmol) and 4-dimethylaminopyridine (75 mg, 0.62 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 1.0 g of compound 25b, with a yield of 68.9%. LCMS (ESI): [M+H] = 237.1. + 1 H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 5.15 (s, 2H), 4.19-4.13 (m, 2H), 3.48 (q, J = 7.2 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0304] Step two: Synthesis of compound 25c​

[0305] Compound 25b (1.0 g, 4.23 mmol) was dissolved in ethanol (10 mL) and water (3 mL) at room temperature, 37% aqueous formaldehyde solution (514 mg, 4.66 mmol) and sodium bicarbonate (48 mg, 0.42 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined and washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 1.0 g of compound 25c with a yield of 88.4%. LCMS (ESI): [M+H] + = 267.1. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 5.20 (s, 2H), 4.17 (q, J = 6.4 Hz, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.48 (d, J = 5.2 Hz, 1H), 2.82 (t, J = 7.2 Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

[0306] Step three: synthesis of compound 25d

[0307] Sulfonyl chloride (377 mg, 2.82 mmol) was dissolved in dry ether (5 mL) at room temperature and cooled to -78 °C, and a solution of compound 25c (500 mg, 1.88 mmol) and pyridine (222 mg, 2.82 mmol) in ether (2 mL) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 500 mg of crude compound 25d, which was directly used in the next reaction.

[0308] Step four: synthesis of compound 25

[0309] Compound 1b (200 mg, 1.08 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1 mL) at room temperature, cooled to -78 °C under nitrogen atmosphere, stirred for 10 minutes, added dropwise sodium bis(trimethylsilyl)amide (648 uL, 2M tetrahydrofuran solution, 1.19 mmol), after dropwise addition, reacted at -78 °C for 10 minutes, slowly added compound 25d (500 mg, 1.30 mmol) thereto, after dropwise addition, gradually increased to room temperature, reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was directly concentrated to dryness, the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 pm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 62%~78%) to obtain 54.65 mg of compound 25, yield 9.86%. LCMS (ESI): [M+H] + = 514.2. 1 H NMR (400 MHz, CDCl3) δ 7.34-7.31 (m, 5H), 6.45 (s, 1H), 5.55 (s, 1H), 5.22 (s, 2H), 5.04 (d, J = 6.3 Hz, 1H), 4.91 (d, J = 13.7 Hz, 1H), 4.18-4.15 (m, 3H), 4.06 (d, J = 6.4 Hz, 1H), 3.29 (d, J = 11.6 Hz, 1H), 3.03 (d, J = 16.6 Hz, 1H), 2.50-2.38 (m, 1H), 2.15-2.13 (m, 1H), 1.99-1.83 (m, 2H), 1.58 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H).

[0310] Example 26

[0311] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-n-butyl-3-ethyl ester (Compound 26)

[0312]

[0313] Synthesis method as compound 24, only use n-butanol equivalent instead of cyclohexanol in step two. LCMS (ESI): [M+H] + = 480.5. 1H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.63 (s, 1H), 5.07-4.98 (m, 1H), 4.95-4.86 (m, 1H), 4.25-4.14 (m, 5H), 4.06 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.50-2.38 (m, 1H), 2.21-2.11 (m, 1H), 2.02-1.80 (m, 2H), 1.66-1.60 (m, 2H), 1.56 (s, 3H), 1.41-1.33 (m, 2H), 1.30-1.24 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0314] Example 27

[0315] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid bis((isobutyryloxy)methyl) ester (Compound 27)

[0316]

[0317] Synthetic procedure was like that of Compound 23, using isobutyric acid iodomethyl ester instead of pivalic acid iodomethyl ester in step three. LCMS (ESI): [M+H] + = 596.5. 1 H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.63 (s, 1H), 5.07-4.98 (m, 1H), 4.95-4.86 (m, 1H), 4.25-4.14 (m, 5H), 4.06 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.50-2.38 (m, 1H), 2.21-2.11 (m, 1H), 2.02-1.80 (m, 2H), 1.66-1.60 (m, 2H), 1.56 (s, 3H), 1.41-1.33 (m, 2H), 1.30-1.24 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0318] Example 28

[0319] 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1-((isobutyryloxy)methyl)-3-isopropyl ester (Compound 28)

[0320]

[0321] Step one: synthesis of compound 28a

[0322] Compound 7b (20.0 g, 98.89 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, sodium hydride (5.93 g, 148.34 mmol) was slowly added into the solution at 0 °C, after the addition was completed, the reaction was carried out at 0 °C for 0.5 h, then ((chloromethoxy)methyl)benzene (9.31 g, 59.45 mmol) and tetrabutylammonium iodide (18.27 g, 59.45 mmol) were added at 0 °C, after the addition was completed, the reaction was carried out at 90 °C for 2 h. After the reaction was completed, water (200 mL) was added into the reaction solution to quench the reaction, and the reaction was extracted with ethyl acetate (200 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 28 g of compound 28a, with a yield of 87.9%. LCMS (ESI): [M+H] + = 323.1.

[0323] Step two: synthesis of compound 28b

[0324] Compound 28a (20.0 g, 62.03 mmol) was dissolved in isopropyl alcohol (200 mL) and water (200 mL) at room temperature, sodium hydroxide (4.96 g, 124.06 mmol) was slowly added into the solution at room temperature, after the addition was completed, the reaction was carried out at 50 °C for 2 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% ~ 80%) to obtain 6.2 g of compound 28b, with a yield of 36.7%. LCMS (ESI): [M+H] + = 281.0.

[0325] Step three: synthesis of compound 28c

[0326] Compound 28b (3.4 g, 12.13 mmol) was dissolved in acetone (34 mL) at room temperature, to which cesium carbonate (5.93 g, 18.2 mmol) and isobutyric acid iodo methyl ester (4.15 g, 18.2 mmol) were added, heated to 50 °C for 16 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 1.2 g of compound 28c, with a yield of 26.1%. 1 HNMR (400 MHz, CDC13) δ 7.35-7.24 (m, 5H), 5.76 (dd, J = 15.2, 5.6 Hz, 2H), 5.08-4.98 (m, 1H), 4.52 (s, 2H), 3.81 (dd, J = 23.2, 8.8 Hz, 2H), 2.59-2.47 (m, 1H), 1.55-1.51 (m, 3H), 1.20 (dd, J = 12.0, 6.4 Hz, 6H), 1.15 (dd, J = 7.2, 1.6 Hz, 6H).

[0327] Step four: synthesis of compound 28d

[0328] Compound 28c (1.2 g, 3.15 mmol) was dissolved in isopropyl alcohol (12 mL) at room temperature, then 10% palladium-carbon (500 mg) was added, the mixture was replaced with hydrogen three times, and heated to 50 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 800 mg of compound 28d, with a yield of 87.5%. 1 H NMR (400 MHz, CDC13) δ 5.82-5.78 (m, 2H), 5.12-5.03 (m, 1H), 3.92-3.79 (m, 2H), 2.67-2.54 (m, 1H), 1.44 (s, 3H), 1.27-1.23 (m, 6H), 1.19 (d, J = 7.2 Hz, 6H).

[0329] Step five: synthesis of compound 28e

[0330] Sulfonyl chloride (558 mg, 4.13 mmol) was dissolved in diethyl ether (6 mL) at room temperature, the mixture was replaced with argon for three times, stirred at -78 °C for 10 min, then a solution of compound 28d (800 mg, 2.76 mmol) and pyridine (338 mg, 4.13 mmol) in diethyl ether (0.6 mL) was added dropwise slowly, after the addition was completed, the reaction was stirred at -78 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 700 mg of compound 28e, which was directly subjected to the next step reaction. 1 H NMR (400 MHz, CDC13) δ 7.45-7.30 (m, 5H), 5.20 (s, 2H), 4.17 (q, J = 6.4 Hz, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.48 (d, J = 5.2 Hz, 1H), 2.82 (t, J = 7.2 Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

[0331] Step six: synthesis of compound 28

[0332] Compound 1b (350 mg, 1.89 mmol) was dissolved in a mixture of dry tetrahydrofuran (7 mL) and N, N-dimethylacrylamide (2.8 mL) at room temperature, and the mixture was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (1.0 mL, 2M tetrahydrofuran solution, 2.00 mmol) was added to the mixture, and the mixture was stirred at -78 °C for 10 min. Compound 28e (700 mg, 1.80 mmol) was then added slowly to the reaction solution, and the mixture was gradually warmed to room temperature. The reaction was continued at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% ~ 70%) to obtain 19.32 mg of compound 28 with a yield of 7.5%. LCMS (ESI): [M+H] + = 538.4. 1H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.84-5.76 (m, 2H), 5.58 (s, 1H), 5.10-4.99 (m, 2H), 4.92-4.85 (m, 1H), 4.15 (s, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.33 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.64-2.55 (m, 1H), 2.48-2.39 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.90 (m, 1H), 1.91-1.81 (m, 1H), 1.56 (d, J = 1.2 Hz, 3H), 1.28-1.24 (m, 6H), 1.18 (dd, J = 7.0, 0.8 Hz, 6H).

[0333] Example 29

[0334] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1 -n-butyl-3 -isopropyl ester (Compound 29)

[0335]

[0336] Synthetic method as for Compound 24, replace compound 24a with compound 28b, replace cyclohexanol with n-butanol. LCMS (ESI): [M+H] + = 494.4. 1 H NMR (400 MHz, CDC13) δ 6.48 (s, 1H), 5.84-5.76 (m, 2H), 5.58 (s, 1H), 5.10-4.99 (m, 2H), 4.92-4.85 (m, 1H), 4.15 (s, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.33 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.64-2.55 (m, 1H), 2.48-2.39 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.90 (m, 1H), 1.91-1.81 (m, 1H), 1.56 (d, J = 1.2 Hz, 3H), 1.28-1.24 (m, 6H), 1.18 (dd, J = 7.0, 0.8 Hz, 6H).

[0337] Example 30

[0338] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid 1-cyclohexyl-3-isopropyl ester (Compound 30)

[0339]

[0340] Synthesis method is as compound 24, only with compound 28b and so on equivalent replacement compound 24a. LCMS (ESI) [M+H] + = 520.2. 1 H NMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.55 (s, 1H), 5.12-5.00 (m, 2H), 4.97-4.82 (m, 2H), 4.16 (s, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 2.51-2.37 (m, 1H), 2.22-2.11 (m, 1H), 2.00-1.81 (m, 4H), 1.73-1.68 (m, 4H), 1.54 (s, 3H), 1.48-1.36 (m, 4H), 1.27-1.22 (m, 6H).

[0341] Example 31

[0342] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid 1-cyclohexyl-3-isopropyl ester (Compound 30)

[0343]

[0344] Synthesis method is as compound 24, only with compound 28b and so on equivalent replacement compound 24a. LCMS (ESI) [M+H] + = 520.2. 1 H NMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.55 (s, 1H), 5.12-5.00 (m, 2H), 4.97-4.82 (m, 2H), 4.16 (s, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 2.51-2.37 (m, 1H), 2.22-2.11 (m, 1H), 2.00-1.81 (m, 4H), 1.73-1.68 (m, 4H), 1.54 (s, 3H), 1.48-1.36 (m, 4H), 1.27-1.22 (m, 6H).

[0345] Example 32

[0346] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1 -tert-butyl-3- isopropyl ester (Compound 32)

[0347]

[0348] Synthetic procedure was like Compound 24, with one equivalent of compound 28b replacing compound 24a, tert-butanol replacing one equivalent of cyclohexanol. LCMS (ESI): [M+Na] + = 516.2. 1 H NMR (400 MHz, CDC13) δ 6.46 (s, 1H), 5.51 (s, 1H), 5.12 - 5.04 (m, 1H), 5.00 - 4.96 (m, 1H), 4.88 (d, J = 9.6 Hz, 1H), 4.16 (d, J = 2.4 Hz, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.47 - 2.42 (m, 1H), 2.18 - 2.14 (m, 1H), 1.99 - 1.84 (m, 2H), 1.48 (dd, J = 14.0, 2.4 Hz, 12H), 1.28 - 1.24 (m, 6H).

[0349] Example 33

[0350] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1 -tert-butyl-3- isopropyl ester (Compound 32)

[0351]

[0352] Synthetic procedure was like Compound 24, with one equivalent of compound 28b replacing compound 24a, tert-butanol replacing one equivalent of cyclohexanol. LCMS (ESI): [M+Na] + = 516.2. 1HNMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.53 (s, 1H), 5.08-4.93 (m, 1H), 4.87 (d, J = 8.3 Hz, 1H), 4.23-4.16 (m, 3H), 4.07 (d, J = 7.3 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.44 (dd, J = 14.3, 5.8 Hz, 1H), 2.18-2.16 (m, 1H), 2.02-1.80 (m, 2H), 1.46-1.43 (m, 12H), 1.28-1.27 (m, 3H).

[0353] Example 34

[0354] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid- 1-tert-butyl-3-n-butyl ester (Compound 34)

[0355]

[0356] Step one, synthesis of compound 34a

[0357] Compound 9c (41 g, 117.0 mmol) was dissolved in dichloromethane (800 mL) at room temperature, then trifluoroacetic acid (26.7 g, 234.3 mmol) was added, the reaction was stirred at room temperature for 16 h. The reaction was directly concentrated to dryness, the residue was separated and purified by flash chromatography (200-300 mesh silica gel, dichloromethane:methanol (10 / 1 V / V)) to give 13.5 g of compound 34a, yield 39.2%. LCMS (ESI): [M+Na] = 317.2. + = 317.2. 1 H NMR (400 MHz, CDC13) δ 6.47 (s, 1H), 5.53 (s, 1H), 5.08-4.93 (m, 1H), 4.87 (d, J = 8.3 Hz, 1H), 4.23-4.16 (m, 3H), 4.07 (d, J = 7.3 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.44 (dd, J = 14.3, 5.8 Hz, 1H), 2.18-2.16 (m, 1H), 2.02-1.80 (m, 2H), 1.46-1.43 (m, 12H), 1.28-1.27 (m, 3H).

[0358] Step two, synthesis of compound 34b

[0359] Compound 34a (1.5 g, 5.10 mmol) was dissolved in dichloromethane (15 mL) at room temperature, then butanol (567 mg, 7.65 mmol) and 4-dimethylaminopyridine (63 mg, 0.51 mmol) were added successively at room temperature. The reaction was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (1.58 g, 7.65 mmol) was added. The reaction was continued to react at room temperature for 16 h. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness. The crude product was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate (5 / 1 V / V)) to obtain 1.4 g of compound 34b, with a yield of 78.4%. LCMS (ESI): [M+H] + = 373.3, t R = 2.151 min.

[0360] Step three, synthesis of compound 34c

[0361] Compound 34b (1.4 g, 4 mmol) was dissolved in isopropanol (14 mL) at room temperature, then 10% palladium-carbon (700 mg) was added, and the mixture was replaced with hydrogen three times. The reaction was continued to react at 50 °C under a hydrogen atmosphere for 16 h. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 1.0 g of compound 34c, with a yield of 96.1%. LCMS (ESI): [M+Na] + = 283.3.

[0362] Step four, synthesis of compound 34d

[0363] Sulfonyl chloride (1038 mg, 7.69 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and the mixture was replaced with nitrogen and cooled to -78 °C for 10 min. A solution of 2-(hydroxymethyl)-2-methylmalonic acid 1-(tert-butyl) 3-butyl ester (1.0 g, 3.85 mmol) and pyridine (608 mg, 7.69 mmol) in diethyl ether (1 mL) was slowly added dropwise, and the reaction was gradually warmed to room temperature. The reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction was directly filtered, and the filtrate was concentrated to dryness to obtain 600 mg of compound 34d crude, which was directly used in the next reaction.

[0364] Step five: synthesis of compound 34

[0365] Compound 1b (300 mg, 1.62 mmol) was added to a mixed solution of super dry tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (0.89 mL, 2M tetrahydrofuran solution, 1.78 mmol) was added dropwise thereto under nitrogen protection and cooling to -78 °C. After the addition was completed, the reaction was continued to stir at -78 °C for 10 min, and then compound 34d (700 mg, 1.80 mmol) was slowly added to the reaction solution. After the addition was completed, the reaction was continued to stir at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 162.79 mg of compound 34, yield: 19.8%. LCMS (ESI): [M+Na] + = 530.5. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.60 (s, 1H), 5.04-4.80 (m, 2H), 4.17-4.16 (m, 3H), 4.06 (d, J = 6.8 Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.4 Hz, 1H), 2.50-2.36 (m, 1H), 2.25-2.07 (m, 1H), 2.01-1.77 (m, 2H), 1.64-1.62 (m, 2H), 1.51-1.49 (m, 3H), 1.47-1.32 (m, 11H), 1.00-0.83 (m, 3H).

[0366] Example 35

[0367] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid-1-ethyl-3-isopropyl ester (Compound 35)

[0368]

[0369] Synthesis method step one as compound 23 synthesis step one, with ethyl malonic acid diethyl ester equivalent instead of compound 23a, the follow-up synthesis method as compound 24, with the product obtained in step one instead of compound 23b, with isopropanol equivalent instead of cyclohexanol. LCMS (ESI): [M+Na] + = 502.2. 1 H NMR (400MHz, CDCI3) δ 6.47 (s, 1H), 5.59 (s, 1H), 5.10-5.08 (m, 2H), 4.95 (d, J = 9.9 Hz, 1H), 4.34-4.01 (m, 4H), 3.32 (d, J = 11.9 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.45-2.42 (m, 1H), 2.25-1.79 (m, 5H), 1.30-1.23 (m, 9H), 0.92 (t, J = 7.5 Hz, 3H).

[0370] Example 36

[0371] Synthesis of isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1 ]octan-6- yl)oxy)sulfonyl)oxy)-2-((isobutyryloxy)methyl)-2-methylpropanoate (Compound 36)

[0372]

[0373] Step one: synthesis of compound 36a

[0374] Compound 28b (3.5 g, 12.5 mmol) was dissolved in dichloromethane (35 mL) at room temperature, and triethylamine (3.78 g, 37.5 mmol) and isobutyl chloroformate (3.41 g, 25 mmol) were added successively, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL x 3) three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 3.3 g of compound 36a, with a yield of 69.5%. LCMS (ESI): [M+Na] + = 403.3. 1H NMR (400 MHz, CDC13) δ 7.35 - 7.24 (m, 5H), 5.08 - 4.92 (m, 1H), 4.59 - 4.41 (m, 2H), 3.80 - 3.75 (m, 3H), 3.30 - 3.26 (m, 1H), 2.15 - 1.85 (m, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.27 - 1.15 (m, 6H), 1.15 - 1.06 (m, 3H), 1.01 - 0.87 (m, 3H).

[0375] Step two: synthesis of compound 36b

[0376] Compound 36a (3.3 g, 8.68 mmol) was dissolved in methanol (33 mL) at room temperature, and sodium borohydride (363 mg, 9.55 mmol) was added portionwise at 0 °C; after addition, the reaction was gradually warmed to room temperature and continued to react for 1 hour. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3) three times. The organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 1.7 g of compound 36b with a yield of 73.6%. LCMS (ESI): [M+H] + = 267.3. 1 H NMR (400 MHz, CDC13) δ 7.35 - 7.24 (m, 5H), 5.08 - 4.92 (m, 1H), 4.59 - 4.41 (m, 2H), 3.80 - 3.75 (m, 3H), 3.30 - 3.26 (m, 1H), 2.15 - 1.85 (m, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.27 - 1.15 (m, 6H), 1.15 - 1.06 (m, 3H), 1.01 - 0.87 (m, 3H).

[0377] Step three: synthesis of compound 36c

[0378] Compound 36b (1.7 g, 6.40 mmol) was dissolved in dichloromethane (17 mL) at room temperature, pyridine (758 mg, 9.58 mmol) and isobutyryl chloride (817 mg, 7.67 mmol) were added successively, after the addition was completed, the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL x 3) for three times, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 5 / 1 V / V) to obtain 2.0 g of compound 36c, with a yield of 93.4%. LCMS (ESI): [M+H] + = 337.3. 1 H NMR (400 MHz, CDCl3) δ 7.40-7.16 (m, 5H), 5.10-4.94 (m, 1H), 4.51 (s, 2H), 4.25 (q, J = 10.8 Hz, 2H), 3.66-3.47 (m, 2H), 2.58-2.40 (m, 1H), 1.25-1.17 (m, 9H), 1.12 (d, J = 7.2 Hz, 6H).

[0379] Step four: synthesis of compound 36d

[0380] Compound 36c (2.0 g, 5.95 mmol) was dissolved in isopropyl alcohol (20 mL) at room temperature, then 10% palladium-carbon (1.0 g) was added, the mixture was replaced with hydrogen gas for three times, and the reaction was continued in the hydrogen atmosphere at 50°C for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated to dryness to obtain 1.4 g of compound 36d, with a yield of 95.8%. LCMS (ESI): [M+H] + = 247.3. 1 H NMR (400 MHz, CDCl3) δ 5.12-4.98 (m, 1H), 4.34-4.15 (m, 2H), 3.76-3.57 (m, 2H), 2.65-2.46 (m, 2H), 1.27-1.23 (m, 6H), 1.22-1.12 (m, 9H).

[0381] Step five: synthesis of compound 36e

[0382] Sulfonyl chloride (220 mg, 1.62 mmol) was dissolved in ether (2 mL) at room temperature, the mixture was replaced with argon for three times, cooled to -78 °C and stirred for 10 min, then a solution of compound 36d (200 mg, 0.813 mmol) and pyridine (129 mg, 1.62 mmol) in ether (1 mL) was added dropwise at -78 °C. After the addition was completed, the reaction was continued at room temperature for 4 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 279 mg of crude compound 36e which was directly used in the next step.

[0383] Step six: synthesis of compound 36

[0384] Compound 1b (150 mg, 0.81 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1.2 mL) at room temperature, and sodium bis(trimethylsilyl)amide (0.45 mL, 2M solution in tetrahydrofuran, 0.89 mmol) was added dropwise at -78 °C under nitrogen protection. After the addition was completed, the reaction was continued at -78 °C for 10 min, then compound 36e (2790 mg, 0.81 mmol) was slowly added. After the addition was completed, the reaction was continued at room temperature for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (50 mL x 3) three times, the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 27.07 mg of compound 36, with a yield of 6.77%. LCMS (ESI): [M+Na] = 494.2. + = 494.2. 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 5.67 (s, 1H), 5.09-5.02 (m, 1H), 4.91-4.84 (m, 1H), 4.76-4.68 (m, 1H), 4.30-4.24 (m, 1H), 4.22-4.15 (m, 2H), 4.06 (d, J = 7.2 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.61-2.53 (m, 1H), 2.49-2.40 (m, 1H), 2.19-2.14 (m, 1H), 2.00-1.81 (m, 2H), 1.28-1.24 (m, 9H), 1.18-1.15 (m, 6H).

[0385] Example 37

[0386] 2-((((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid diisopropyl ester (Compound 37) was synthesized according to the following procedure:

[0387]

[0388]

[0389] Step one: synthesis of compound 37b

[0390] Compound 37a (2.0 g, 7.24 mmol) was dissolved in dichloromethane (20 mL) at room temperature, and then 4-amino-1-piperidinecarboxylic acid tert-butyl ester (1.4 g, 7.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.8 g, 7.24 mmol) and N,N-diisopropyl ethylamine (936 mg, 7.24 mmol) were added successively at 0 °C. After the addition was completed, the mixture was gradually warmed to room temperature and the reaction was continued for 16 h. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3) three times. The combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (200-300 mesh, petroleum ether: ethyl acetate = 1 / 1 V / V) to give 3.0 g of compound 37b with a yield of 90.4%. LCMS (ESI): [M+H] = 459.4. +

[0391] Step two: synthesis of compound 37c

[0392] Compound 37b (2.0 g, 4.37 mmol) was dissolved in methanol (20 mL) at room temperature, and then 10% palladium-carbon (500 mg) was added. The mixture was replaced with hydrogen three times, and the reaction was stirred at room temperature for 2 h in a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give 1.4 g of compound 37c with a yield of 87.5%. LCMS (ESI): [M+Na] = 391.3. +

[0393] Step three: synthesis of compound 37d

[0394] ​​At room temperature, compound 37c (1.0 g, 2.7 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (20 mL) and N,N-dimethylpropenylurea (9 mL). The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (1.5 mL, 2 M tetrahydrofuran solution, 3.0 mmol) was added. After the addition was complete, the mixture was stirred at -78 °C for 10 min. Then, compound 7d (986 mg, 3.0 mmol) was slowly added. After the addition was complete, the mixture was gradually heated to room temperature and the reaction was continued for 2 h. After the reaction was completed, water (100 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60%–80%) to give 100 mg of the compound after 37 days, in a yield of 5.6%. LCMS (ESI): [M+Na] + =685.3.

[0395] Step 4: Synthesis of Compound 37

[0396] Compound 37d (60 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL) at room temperature, cooled to -10 °C, and trifluoroacetic acid (1 mL) was added. After the addition was complete, the mixture was stirred at -10 °C for 0.5 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 21.90 mg of compound 37, yield 43.0%. LCMS (ESI): [M+H] + =563.5.

[0397] Example 38

[0398] Synthesis of 2-((((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid diisopropyl ester (compound 38)

[0399]

[0400] Step 1: Synthesis of compound 38b

[0401] Compound 38b (2.5 g, 8.16 mmol) was dissolved in ethanol (25 mL) at room temperature, hydrazine hydrate (0.5 mL, 12.2 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (50 mL x 3), the combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 1.2 g of compound 38c in a yield of 83.5%.

[0402] Step two: synthesis of compound 38c

[0403] Compound 38b (2.5 g, 8.16 mmol) was dissolved in ethanol (25 mL) at room temperature, hydrazine hydrate (0.5 mL, 12.2 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (50 mL x 3), the combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 1.2 g of compound 38c in a yield of 83.5%. 1 H NMR (400 MHz, CDCl3) δ 3.70 (t, J = 4.8 Hz, 2H), 3.36-3.32 (m, 2H), 1.45 (s, 9H).

[0404] Step three: synthesis of compound 38d

[0405] Compound 37a (1.2 g, 4.3 mmol) was dissolved in dichloromethane (12 mL) at room temperature, compound 38c (1.1 g, 6.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.6 g, 4.3 mmol), and N,N-diisopropyl ethylamine (561 mg, 4.3 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 1 / 1 V / V) to give 1.5 g of compound 38d in a yield of 79.4%. LCMS (ESI): [M+H] + = 435.3.

[0406] Step four: synthesis of compound 38e

[0407] Compound 38d (800 mg, 1.84 mmol) was dissolved in ethyl acetate (20 mL) at room temperature, then 10% palladium carbon (600 mg) was added, the mixture was replaced with hydrogen three times, and the reaction was continued at room temperature in a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 400 mg of compound 38e with a yield of 63.1%. LCMS (ESI): [M+Na] + = 367.3. 1 HNMR (400MHz, MeOD) δ 4.12-4.07 (m, 1H), 3.92-3.75 (m, 3H), 3.70 (s, 1H), 3.28 (s, 1H), 3.17-2.97 (m, 2H), 2.24-2.20 (m, 1H), 2.07-2.04 (m, 1H),, 1.98-1.87 (m, 1H), 1.85-1.73 (m, 1H), 1.44 (s, 9H).

[0408] Step five: synthesis of compound 38f

[0409] Compound 38e (400 mg, 1.16 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and N, N-dimethylacrylurea (3 mL) at room temperature, and under nitrogen protection, the temperature was lowered to -78°C, and then sodium bis (trimethylsilyl) amide (0.6 mL, 2M tetrahydrofuran solution, 1.28 mmol) was added dropwise. After the dropwise addition was completed, the reaction was maintained at -78°C for 10 minutes, and then compound 7d (767 mg, 2.33 mmol) was added. After the addition was completed, the temperature was gradually increased to room temperature, and the reaction was continued for 2 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and extraction was performed three times with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% ~ 80%) to obtain 200 mg of crude compound 38f, which was directly used in the next step reaction. LCMS (ESI): [M+H] + = 539.2.

[0410] Step six: synthesis of compound 38

[0411] Compound 38f (100 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) at room temperature, trifluoroacetic acid (2 mL) was added slowly dropwise at -10 °C, the reaction was stirred at -10 °C for 30 min. The reaction was completed, the reaction was concentrated to dryness, the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to give 9.94 mg of compound 38, yield 12.1%. LCMS (ESI): [M+H] + = 539.5. 1 H NMR (400 MHz, CDC13) δ 8.22 (s, 2H), 5.09-5.05 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 9.6 Hz, 1H), 4.30-4.08 (m, 3H), 3.27 (s, 2H), 3.13 (d, J = 11.2 Hz, 1H), 2.29-2.24 (m, 1H), 2.13-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.50 (s, 3H), 1.24 (s, 12H).

[0412] Example 39

[0413] 2-((((((2S,5R)-2-aminoacyl-7-oxo-l,6-diazabicyclo[3.2.1]octane-6-yl (oxo)sulfonyl(oxo)methyl)-2-(cyclopropylmethyl)propanedioic acid-1-isopropyl-3-methyl ester (Compound 39) Synthesis

[0414]

[0415] Step one: Synthesis of compound 39b

[0416] Compound 39a (10 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at 0 °C, and isopropyl alcohol (7.63 g, 127.02 mmol), N,N'-dicyclohexylcarbodiimide (26.21 g, 127.02 mmol) and 4-dimethylaminopyridine (1.03 g, 8.47 mmol) were added successively under nitrogen protection, and the mixture was warmed to 25 °C and reacted for 12 hours. After the reaction was completed, water (200 mL) was added to the reaction mixture at 25 °C to quench the reaction, and dichloromethane (300 mL x 3) was used for extraction. The organic phase was combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 11.0 g of compound 39b, with a yield of 81.1%.

[0417] Step two: synthesis of compound 39c

[0418] Compound 39b (4.00 g, 24.97 mmol) was dissolved in THF (20 mL) at 0 °C, and sodium hydride (4.55 g, 24.97 mmol, 60% in mineral oil) was slowly added under nitrogen protection, and stirring was continued for 30 minutes, then (iodomethyl)cyclopropane (1.1 g, 27.47 mmol) was added, and the mixture was warmed to 50 °C and reacted for 5 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture at 0 °C to quench the reaction, and ethyl acetate (80 mL x 3) was used for extraction. The organic phase was combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 3.0 g of compound 39c, with a yield of 56.07%. 1 H NMR (400 MHz, CDCl3) δ 5.06 (dt, J = 12.4, 6.4 Hz, 1H), 3.72 (s, 3H), 3.43 (t, J = 7.6 Hz, 1H), 1.84-1.74 (m, 2H), 1.26 (s, 3H), 1.23 (s, 3H), 0.79-0.65 (m, 1H), 0.55-0.39 (m, 2H), 0.18-0.02 (m, 2H).

[0419] Step three: synthesis of compound 39d

[0420] Compound 39c (1.0 g, 4.67 mmol) was dissolved in a mixture solvent of ethanol (20 mL) and water (10 mL) at room temperature, and then sodium bicarbonate (39.21 mg, 0.467 mmol) and 37% formaldehyde aqueous solution (416.6 mg, 5.13 mmol) were added successively under nitrogen protection at 0 °C. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture at 25 °C to quench the reaction, and then extracted with ethyl acetate (80 mL x 3). The organic phase was combined and washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 1.0 g of compound 39d with a yield of 87.71%. 1 H NMR (400 MHz, CDCl3) δ 5.17-4.99 (m, 1H), 4.11-4.01 (m, 2H), 3.76 (s, 3H), 2.34 (s, 1H), 1.93-1.80 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 0.75-0.60 (m, 1H), 0.55-0.39 (m, 2H), 0.18-0.00 (m, 2H).

[0421] Step four: synthesis of compound 39e

[0422] Sulfonyl chloride (332 mg, 2.46 mmol) was dissolved in diethyl ether (4 mL) at room temperature and cooled to -78 °C under nitrogen protection; a solution of compound 39d (400 mg, 2.46 mmol) and pyridine (194 mg, 2.46 mmol, 1.5 eq) in diethyl ether (2 mL) was added dropwise, and then gradually warmed to room temperature. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction liquid was filtered, the filtrate was collected and concentrated under reduced pressure to obtain 561 mg of compound 39e, which was used directly in the next step without further purification.

[0423] Step five: synthesis of compound 39

[0424] Compound 1b (151 mg, 0.82 mmol) was dissolved in THF (12 mL) and N,N- dimethylacrylamide (4.6 mL) at room temperature, cooled to -78 °C under nitrogen, then added sodium bis(trimethylsilyl)amide (0.45 mL, 2 M in tetrahydrofuran, 0.9 mmol) dropwise, reacted for 10 minutes at -78 °C, then added compound 39e (561 mg, 1.64 mmol) dropwise, gradually warmed to room temperature, and reacted for 3 hours at room temperature. After the reaction was completed, the reaction solution was poured into a 0 °C saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined and concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 45 mg of compound 39, with a yield of 11%. LCMS (ESI) [M+H] + = 492.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.67-7.32 (m, 2H), 5.10 (d, J = 9.8 Hz, 1H), 5.03-4.94 (m, 1H), 4.94-4.87 (m, 1H), 4.10 (s, 1H), 3.97-3.89 (m, 1H), 3.72 (d, J = 2.6 Hz, 3H), 3.26-3.12 (m, 2H), 2.16-2.05 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.69 (m, 4H), 1.21-1.16 (m, 6H), 0.67-0.55 (m, 1H), 0.53-0.37 (m, 2H), 0.14-0.02 (m, 2H).

[0425] Example 40

[0426] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)propanedioic acid-1-ethyl-3- methyl ester (Compound 40)

[0427]

[0428] Synthesis method as compound 39, only replace isopropanol with ethanol equivalent. LCMS (ESI) [M+H] + = 478.3. 1H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.33 (m, 2H), 5.10 (d, J = 9.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.25 - 4.14 (m, 2H), 4.11 - 4.07 (m, 1H), 3.96 - 3.90 (m, 1H), 3.72 (d, J = 3.6 Hz, 3H), 3.25 - 3.14 (m, 2H), 2.17 - 2.05 (m, 1H), 1.99 - 1.68 (m, 5H), 1.22 - 1.15 (m, 3H), 0.68 - 0.55 (m, 1H), 0.49 - 0.38 (m, 2H), 0.14 - 0.03 (m, 2H).

[0429] Example 41

[0430] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6- yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid diisopropyl ester (Compound 41)

[0431]

[0432] Synthetic method as Compound 39, replace compound 39b with diisopropyl malonate equivalent. LCMS (ESI) [M+H] + = 520.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 58.0 Hz, 2H), 5.08 (d, J = 9.6 Hz, 1H), 5.01 - 4.94 (m, 1H), 4.88 (dd, J = 9.6, 2H), 4.09 (s, 1H), 3.92 (d, J = 7.2 Hz, 1H), 3.23 - 3.13 (m, 2H), 2.13 - 2.07 (m, 1H), 1.99 - 1.66 (m, 5H), 1.18 (d, J = 5.6 Hz, 12H), 0.64 - 0.52 (m, 1H), 0.46 - 0.38 (m, 2H), 0.11 - 0.04 (m, 2H).

[0433] Example 42

[0434] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6- yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-ethyl-3-isopropyl ester (Compound 42)

[0435]

[0436] The synthetic method is as compound 39, only monomethyl malonate is used as equivalent replacement of compound 39a. LCMS (ESI) [M+H] + = 506.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 58.0 Hz, 2H), 5.00 (d, J = 10.0 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.90 (dd, J = 9.6, 2.8 Hz, 1H), 4.23 - 4.13 (m, 2H), 4.10 (s, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.24 - 3.14 (m, 2H), 2.13 - 2.07 (m, 1H), 1.99 - 1.69 (m, 5H), 1.21 - 1.17 (m, 9H), 0.64 - 0.55 (m, 1H), 0.47 - 0.40 (m, 2H), 0.12 - 0.05 (m, 2H).

[0437] Example 43

[0438] Synthesis of 2-((((((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6- yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-ethyl-3-methyl ester (Compound 43)

[0439]

[0440] Step one: synthesis of compound 43b

[0441] Compound 43a (0.21 g, 0.73 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, then 10% palladium carbon (0.1 g) was added thereto, the mixture was replaced with hydrogen gas for three times, and the reaction was carried out at room temperature in hydrogen atmosphere for 3 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was directly concentrated to dryness to obtain 0.14 g of compound 43b, with a yield of 97.2%. LCMS (ESI): [M+H] + = 198.2.

[0442] Step two: synthesis of compound 43c

[0443] Compound 39a (10 g, 84.75 mmol) was dissolved in dichloromethane (100 mL) at 0 °C, and then ethyl alcohol (3.9 g, 84.75 mmol), N,N'-dicyclohexylcarbodiimide (19.2 g, 93.22 mmol) and 4-dimethylaminopyridine (1 g, 8.43 mmol) were added successively under nitrogen protection. After the addition was completed, the reaction solution was warmed to 25 °C and reacted for 12 hours. After the reaction was completed, water (200 mL) was added to the reaction mixture at 25 °C to quench the reaction, and dichloromethane (300 mL x 3) was used for extraction. The organic phase was combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 8 g of compound 43c with a yield of 64.64%. 1 H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.39 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0444] Step three: synthesis of compound 43d

[0445] Compound 43c (4 g, 27.38 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) at 0 °C, and then sodium hydride (1.2 g, 30.12 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was completed, the reaction solution was kept at 0 °C and stirred for 30 minutes, and then (iodomethyl)cyclopropane (5 g, 27.38 mmol) was added. After the addition was completed, the reaction solution was warmed to 50 °C and reacted for 5 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (100 mL) was added to the reaction mixture at 0 °C to quench the reaction, and ethyl acetate (100 mL x 3) was used for extraction. The organic phase was combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 92 / 8 V / V) to obtain 4.1 g of compound 43d with a yield of 74.81%. 1 H NMR (400 MHz, CDCl3) δ 4.20 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.46 (t, J = 7.6 Hz, 1H), 1.81 (t, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.78-0.67 (m, 1H), 0.48-0.41 (m, 2H), 0.13-0.09 (m, 2H).

[0446] Step four: synthesis of compound 43e

[0447] Compound 43d (4.1 g, 20.45 mmol) was dissolved in a mixture of ethanol (40 mL) and water (20 mL) at 0 °C under nitrogen protection, and sodium bicarbonate (172 mg, 2.05 mmol) and 37% aqueous formaldehyde solution (1.83 g, 22.50 mmol) were added successively. After the addition was completed, the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture at 25 °C to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 3.3 g of compound 43e, with a yield of 70.0%.

[0448] Step five: synthesis of compound 43f

[0449] Sulfonyl chloride (2.47 g, 18.24 mmol) was dissolved in diethyl ether (30 mL) at room temperature under nitrogen protection, and the temperature was lowered to -78 °C. A solution of compound 43e (2.8 g, 12.16 mmol) and pyridine (1.45 g, 18.24 mmol) in diethyl ether (2 mL) was added dropwise, and the temperature was gradually raised to room temperature. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction liquid was filtered, the filtrate was collected and concentrated under reduced pressure to obtain 3.9 g of compound 43f, which was directly used in the next step reaction.

[0450] Step six: synthesis of compound 43

[0451] Compound 43b (130 mg, 0.66 mmol) was dissolved in a mixture of THF (10 mL) and N,N-dimethylacrylamide (4 mL) at room temperature under nitrogen protection, and the temperature was lowered to -78 °C. Then sodium bis(trimethylsilyl)amide (0.37 mL, 2M tetrahydrofuran solution, 0.74 mmol) was added dropwise, and the reaction was carried out at -78 °C for 10 minutes. Compound 43f (452.3 mg, 1.32 mmol) was added dropwise, and the temperature was gradually raised to room temperature. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction liquid was poured into a saturated aqueous sodium bicarbonate solution (20 mL) at 0 °C, extracted with ethyl acetate (50 mL x 2), and the organic phase was combined and concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 32 mg of compound 43, with a yield of 9.6%. LCMS (ESI) [M+H] + 490.2.1 H NMR (400 MHz, CDC13) δ 7.12 (s, 1H), 5.43 (s, 1H), 5.16 (t, J = 5.0 Hz, 1H), 5.04 (t, J = 4.0 Hz, 1H), 4.38-4.35 (m, 1H), 4.24-4.21 (m, 2H), 3.77-3.74 (m, 3H), 3.60-3.57 (m, 1H), 2.99 (d, J = 8.0 Hz, 1H), 2.78 (d, J = 20.0 Hz, 1H), 2.39-2.33 (m, 1H), 2.25 (s, 3H), 2.01-1.97 (m, 2H), 1.27-1.25 (m, 3H), 0.68-0.60 (m, 1H), 0.51-0.45 (m, 2H), 0.13-0.07 (m, 2H)

[0452] Example 44

[0453] Synthesis of diisopropyl 2-((((((2S,5R)-2-dicarbamoyl-3-methyl-7-oxo-1,6- diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 44)

[0454]

[0455] Step one: synthesis of compound 44

[0456] Compound 43b (150 mg, 0.76 mmol) was dissolved in THF (10 mL) and N,N- dimethylacrylamide (4 mL) mixed solvent at room temperature, cooled to -78 °C under nitrogen, then added dropwise sodium bis(trimethylsilyl)amide (0.42 mL, 2M in tetrahydrofuran, 0.84 mmol, dropwise, 10 min at -78 °C, then dropwise compound 7d (502.8 mg, 1.52 mmol), dropwise, gradually to room temperature, 3 h at room temperature. The reaction was completed, the reaction liquid was poured into 0 °C sodium bicarbonate saturated aqueous solution (20 mL), extracted with ethyl acetate (50 mL x 2), the organic phase was combined and concentrated to dryness, the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 x 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to give 29 mg of compound 44, yield 7.8%. LCMS (ESI) [M+H] + = 492.2. 1H NMR (400 MHz, CDC13) δ 7.12 (s, 1H), 5.43 (s, 1H), 5.10-5.07 (m, 2H), 4.41 (s, 1H), 4.38-4.35 (m, 1H), 4.29-4.26 (m, 1H), 4.11-4.07 (m, 1H), 3.96-3.90 (m, 1H), 3.59-3.49 (m, 1H), 3.47-3.39 (m, 1H), 1.78-1.75 (m, 3H), 1.53 (s, 3H), 1.26 (d, J = 5.4 Hz, 12H).

[0457] Example 45

[0458] “Prodrug” refers to an active drug that is metabolically released from a prodrug, and in the present embodiment specifically refers to avibactam, relebactam, nacubactam, and dulobactam.

[0459] Test Example 1: Oral bioavailability in rats

[0460] Male Sprague-Dawley (SD) rats were administered intravenously (IV) and orally (PO) with prodrugs (e.g., avibactam, relebactam, nacubactam, and dulobactam) and orally (PO) with test compounds, and pharmacokinetic (PK) studies were performed. Oral bioavailability (%F) of the prodrugs was determined by comparing the AUC after oral administration and the AUC after IV administration.

[0461] 1.1 Drug preparation

[0462] The prodrugs were dissolved in pH 7.5 phosphate buffered saline (PBS) to prepare a 0.4 mg / mL solution for intravenous injection. Compound 8, 11, 12, 13, 16, 19, 21, 23, 24, 26, 29, 31, 32, 33, 35, 37, 38, 39, 40, 41, 42, 43, and 44 were each dissolved in 2% DMSO + 10% polyethylene glycol-15 hydroxystearate + 88% normal saline to prepare a 1.0 mg / mL solution for oral administration.

[0463] 1.2 Dosing

[0464] The intravenous dose was 2 mg / kg, and the oral dose was 10 mg / kg. The dose volume was 5 mL / kg for intravenous administration and 10 mL / kg for oral administration.

[0465] 1.3 Procedure

[0466] Blood samples were collected at 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h post-dose via jugular sinus puncture and anticoagulated with sodium heparin. Blood samples were placed on ice and plasma was separated (centrifugation conditions: 6800 g, 6 min, 2-8 °C) within 30 min of collection and the supernatant was removed for LC / MS / MS analysis to determine the concentration of the parent drug.

[0467] 1.3 Pharmacokinetic parameter results

[0468] The oral bioavailability of the parent drug in male rats after equimolar conversion of the compound to the parent drug is shown in Table 1 below, where A indicates (>90%) B indicates 50

[0469] The results show that compounds 8, 12, 13, 21, 24, 29, 31, 33, 35, 40 show oral bioavailability of the parent drug greater than 90%, compounds 11, 16, 19, 23, 32, 42, 44 show oral bioavailability of the parent drug between 50% and 90%, and compounds 37, 38, 39, 41, 43 show oral bioavailability of the parent drug between 20% and 50%. The experimental results demonstrate that the compounds of the present application all show good oral bioavailability of the parent drug, suitable for oral administration.

[0470] Table 1. Pharmacokinetic parameters of the compounds in rats

[0471] Compound Oral bioavailability (%F) Compound Oral bioavailability (%F) 8 A 32 B 11 B 33 A 12 A 35 A 13 A 37 C 16 B 38 C 19 B 39 C 21 A 40 A 23 B 41 C 24 A 42 B 26 A 43 C 29 A 44 B 31 A

[0472] Test Example 2: Oral bioavailability of the compounds in beagle dogs

[0473] Male beagle dogs were administered intravenously (IV) and orally (PO) with the parent drug (e.g. avibactam, relebactam, nacubactam, dorbactam) and orally with the test compounds, and pharmacokinetic (PK) studies were performed to determine the concentration of the parent drug in plasma and the oral bioavailability (%F) of the test compounds.

[0474] 2.1 Drug preparation

[0475] Avibactam was dissolved in pH 7.5 phosphate buffered saline (PBS) and prepared as a 2.0 mg / mL solution for IV administration; avibactam, compounds 31, 33, 35 were prepared as 2.0 mg / mL solutions for oral administration using 2% DMSO + 10% Solutol + 88% Saline.

[0476] 2.2 Dosing

[0477] The dosage of intravenous administration is 10 mg / kg, and the dosage of oral administration is 20 mg / kg; the dosage volume of intravenous and oral administration is 5 mL / kg and 10 mL / kg, respectively.

[0478] 2.3 Operation

[0479] At 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after the end of administration, blood samples were collected through jugular sinus puncture, and sodium heparin was used for anticoagulation. After the blood sample was collected, it was placed on ice, and plasma separation was completed within 30 minutes after the collection (centrifugation condition: 2200 g, 10 minutes, 2-8°C), and the supernatant was removed for LC / MS / MS analysis to determine the concentration of the original drug.

[0480] 2.4 Pharmacokinetic parameter results

[0481] In the pharmacokinetic test of beagle dogs, the oral bioavailability of the original drug after the compound is converted into the original drug in equimolar amount is shown in Table 2, wherein A represents (%F)>90%, B represents 50<(%F)≤90%, C represents 20<(%F)≤50%, and D represents (%F)≤20%.

[0482] The results show that the oral bioavailability of the original drug of the compound in beagle dogs is greater than 90%, which effectively improves the oral bioavailability of the original drug and can well solve the problem of poor oral absorption of the original drug.

[0483] Table 2. Pharmacokinetic parameters of the compound in beagle dogs

[0484] Compound Oral bioavailability (%F) Avibactam D 31 A 33 A 35 A 40 A

[0485] Test Example 3: Hepatocyte stability test

[0486] 3.1 Hepatocytes

[0487] Rat hepatocytes.

[0488] 3.2 Preparation of compound solution

[0489] A certain amount of compound was weighed and dissolved in DMSO to prepare a 10 mM stock solution, and a certain volume of the stock solution was diluted with DMSO to prepare a working solution with a concentration of 100 μM.

[0490] 3.3 Incubation of samples

[0491] 2 μL of the working solution of 100 μM compound was taken and added to 198 μL of hepatocyte suspension, and pre-incubated in a 37°C incubator; at 0, 5, 15, 30 and 60 min, the above mixture was added to the termination solution and mixed; vortexed for 10 min, centrifuged at 6000 rpm and 4°C for 20 min. The supernatant was collected and analyzed by LC-MS / MS.

[0492] 3.4. Results

[0493] The experimental results prove that all the avibactam prodrugs of the present application are completely converted into the original drug avibactam in rat hepatocytes, wherein compounds 31, 33, 35 can be rapidly and completely converted into the original drug avibactam in rat hepatocytes, and compounds 37, 38, 43 release rebaqatan, nacubactam, durbactam, respectively.

[0494] The metabolism data of the compounds of the present application in rat hepatocytes are shown in Table 3, and the data of the compounds of the present application in rat hepatocytes converting to release the original drug are shown in Table 4.

[0495] Table 3. Metabolism data of compounds in rat hepatocytes

[0496]

[0497] Note: BLOD represents below the detection limit;

[0498] Table 4. Data of compounds in rat hepatocytes converting to release the original drug

[0499]

Claims

1. A β-lactamase inhibitor selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: ； ； ； ； 。 2. A pharmaceutical composition, characterized by:

2. A pharmaceutical composition comprising the β-lactamase inhibitor of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein:

3. The pharmaceutical composition of claim 2, further comprising an antibiotic.

4. The pharmaceutical composition of claim 3, wherein:

4. The antibiotic of claim 3 is a β-lactam antibiotic, and the β-lactam antibiotic is a penicillin, a cephalosporin, a cephamycin, and a carbapenem antibiotic.

5. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 for the manufacture of a β-lactamase inhibitor.

6. Use of the β-lactamase inhibitor of claim 1 or the pharmaceutical composition of claim 2 for the manufacture of a medicament for the treatment of a disease associated with a bacterial infection, and the bacteria is a β-lactamase producing bacteria.

Images