Diazabicyclo beta-lactamase inhibitor and application thereof

Abstract

The invention discloses a beta-lactamase inhibitor which is selected from a compound with a structure as shown in a formula I or pharmaceutically acceptable salt, isomer or deuterated substance of the compound. The invention discloses an application of the beta-lactamase inhibitor in preparation of the beta-lactamase inhibitor. The invention also discloses application of the beta-lactamase inhibitor in preparation of medicines for treating diseases related to bacterial infection. The bacteria are bacteria capable of producing beta-lactamase. The beta-lactamase inhibitor disclosed by the invention can quickly and completely release active metabolites such as avibactam, dulobactam, relebactam, nacchabactam and other diazabicyclo beta-lactamase inhibitors in vivo, and can quickly take effect, so that the oral bioavailability of the beta-lactamase inhibitor is effectively improved, the bioavailability of the beta-lactamase inhibitor is improved, and the bioavailability of the beta-lactamase inhibitor is improved. Therefore, the diazabicyclo beta-lactamase inhibitor can be orally taken, and the problem of low oral bioavailability of the diazabicyclo beta-lactamase inhibitor is solved. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a novel diazabicyclic beta-lactamase inhibitor and a pharmaceutical composition thereof and use thereof in treating bacterial infection. Background Art

[0002] The rapid development of antibiotics is of great significance in the history of modern medicine. Antibiotics can effectively treat infectious diseases caused by bacteria, which has brought great convenience to clinical practice. However, the irrational use and even abuse of antibiotics has accelerated the development of bacterial resistance and brought great challenges to human health. As one of the antibiotics with the longest history, the widest range of use, and the most commonly used in clinical practice, the problem of drug resistance of β-lactam antibiotics has also arisen and is becoming increasingly serious.

[0003] β-lactamase produced by bacteria can hydrolyze antibiotics with β-lactam ring structure and inactivate them. This is the most common mechanism of bacterial resistance to β-lactam antibiotics. β-lactamase can be divided into two major categories based on the difference in amino acid sequence in the molecular structure: one is A, C, D type with serine as the active site, and the other is A, C, D type with metal ions (especially Zn 2+ ) as the active site of metalloenzymes.

[0004] In 1976, the first β-lactamase inhibitor (clavulanic acid) was discovered and later commercialized as an oral / intravenous drug in combination with a β-lactam antibiotic (amoxicillin). β-lactamase inhibitors, while lacking significant antibiotic activity themselves, protect β-lactam antibiotics from being inactivated by enzymes (β-lactamases) produced by microorganisms. β-lactamase inhibitor / antibiotic combinations have become a standard part of treatment since the 1980s.

[0005] In the mid-1990s, a new and important non-β-lactam β-lactamase inhibitor, Avibactam, was discovered. It belongs to the diazabicyclic compounds (DBOs), a class of reversible β-lactamase inhibitors. Compared with classical β-lactamase inhibitors (such as clavulanic acid, sulbactam, and tazobactam), Avibactam has the characteristics of long-term effect and reversible covalent binding to the enzyme, and does not induce the production of β-lactamase. In recent years, medicinal chemists have continued to conduct in-depth research based on Avibactam and successfully discovered a series of diazabicyclic derivatives such as Durlobactam, Relebactam, and Nacubactam, all of which have similar β-lactamase inhibitory effects as Avibactam. However, since diazabicyclic β-lactamase inhibitors contain a sulfonic acid structure, they are highly water-soluble but have very low lipid solubility, resulting in poor oral absorption. They are not suitable for oral administration and can only be used for intravenous injection, which also limits the clinical use of this type of β-lactamase inhibitors.

[0006]

[0007] Prodrug refers to a compound that has no biological activity itself, but can release pharmacologically active metabolites or original drugs through chemical or enzymatic conversion in vivo. Prodrug design is a common and effective strategy to improve the lipid solubility of compounds, increase oral absorption, and improve bioavailability.

[0008] Therefore, it is of great clinical value to design prodrugs of diazabicyclic β-lactamase inhibitors to improve the oral bioavailability of such β-lactamase inhibitors and enable them to be administered orally. Summary of the invention

[0009] The object of the present invention is to provide a class of diazabicyclic β-lactamase inhibitors, wherein the β-lactamase inhibitor is a prodrug of the diazabicyclic β-lactamase inhibitor and can significantly improve the oral bioavailability of the diazabicyclic β-lactamase inhibitor.

[0010] The objective of the present invention is achieved through the following technical solutions:

[0011] The β-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] in, represents a single bond or a double bond;

[0014] R1 is selected from H,

[0015] R2 is selected from H, CH3;

[0016] L1 is selected from unsubstituted or substituted with one or more R 1a Substituted -(CH2) m -, m is selected from 1, 2, 3, 4 or 5, R 1a is selected from halogen, hydroxyl, cyano, NH2, substituted or unsubstituted C1-C8 hydrocarbon group, substituted or unsubstituted C1-C8 heteroalkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group, and the substituents of C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group can be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group , C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0017] R3 and R4 are independently selected from H, halogen, hydroxyl, cyano, sulfonyl, Substituted or unsubstituted C1-C8 hydrocarbon group, substituted or unsubstituted C1-C8 heteroalkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group, the substituents of C1-C8 hydrocarbon group, C1-C8 heteroalkyl group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group can be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0018] R5 is selected from

[0019] X1, X2 are independently selected from O, S, Se; R 6a , R 6b The substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group can be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterocyclic hydrocarbon group, C3-C8 aryl group and C5-C8 heteroaryl group. C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl or

[0020] R 7a , R 7b The substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group can be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterocyclic hydrocarbon group, C3-C8 aryl group and C5-C8 heteroaryl group. C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0021] R 8a , R8b The substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group can be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterocyclic hydrocarbon group, C3-C8 aryl group and C5-C8 heteroaryl group. C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0022] R9 is selected from R 11 The substituents of the C1-C8 hydrocarbon group, C1-C8 alkoxy group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group, or C1-C8 alkyl group may be independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 alkoxy group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, or C5-C8 heteroaryl group. -C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0023] R 10The substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group, or C1-C8 hydrocarbon group may be independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterocycloalkyl group, or C3-C8 cycloalkyl group. alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl or

[0024] L2, L3, L4 are independently selected from unsubstituted or substituted with one or more R 1b Substituted -(CH2) n -, n is selected from 1, 2, 3, 4 or 5, R 1b The substituents of C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl may be independently selected from halogen, hydroxyl, cyano, NH2, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C5-C8 heteroaryl. The substituents of C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl may be independently selected from halogen, hydroxyl, cyano, C1-C8 C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0025] Ring A is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C5-C8 heteroaryl, and the substituents of C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, and C5-C8 heteroaryl can be independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, alkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl;

[0026] The substituents of the above-mentioned substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl are each independently selected from halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamido, sulfenimide, urea, guanidino;

[0027] But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from

[0028] More preferably, represents a single bond or a double bond;

[0029] R1 is selected from H,

[0030] R2 is selected from H, CH3;

[0031] L1 is selected from -CH2-;

[0032] R3 is selected from methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl;

[0033] R4 is selected from methyl, X1 is selected from O, S; R 6a is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7a is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L2 is selected from -CH2-, R 8a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl;

[0034] R5 is selected from R9 is selected from X2 is selected from O, S; R 6b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L3 is selected from -CH2-, R 8b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; L4 is selected from -CH2-, R 11 Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl;

[0035] But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from

[0036] More preferably, represents a single bond or a double bond;

[0037] R1 is selected from H,

[0038] R2 is selected from H, CH3;

[0039] L1 is selected from -CH2-;

[0040] R3 is selected from methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl;

[0041] R4 is selected from methyl, X1 is selected from O; R 6a is selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl; L2 is selected from -CH2-, R 8a Selected from isopropyl and tert-butyl;

[0042] R5 is selected from R9 is selected from X2 is selected from O; R 6b is selected from methyl, ethyl, isopropyl; R 7b isopropyl; L3 is selected from -CH2-, R 8b isopropyl, tert-butyl; L4 is selected from -CH2-, R 11 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isopropoxy;

[0043] But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R4 is selected from

[0044] As a further preferred embodiment of the β-lactamase inhibitor of the present invention, the β-lactamase inhibitor is selected from a compound having a structure as shown in Formula II or a pharmaceutically acceptable salt or isomer thereof:

[0045]

[0046] Among them, R3, R4, and R5 are as described above.

[0047] As a further preferred embodiment of the β-lactamase inhibitor of the present invention, the β-lactamase inhibitor is selected from a compound having a structure as shown in Formula III or a pharmaceutically acceptable salt, isomer, or deuterated product thereof:

[0048]

[0049] Among them, R3, R4, and R5 are as described above.

[0050] As a further preferred embodiment of the β-lactamase inhibitor of the present invention, the β-lactamase inhibitor is selected from a compound having a structure as shown in Formula IV or a pharmaceutically acceptable salt, isomer, or deuterated product thereof:

[0051]

[0052] Among them, R3, R4, and R5 are as described above.

[0053] As a further preferred embodiment of the β-lactamase inhibitor of the present invention, the β-lactamase inhibitor is selected from a compound having a structure as shown in Formula V or a pharmaceutically acceptable salt, isomer, or deuterated product thereof:

[0054]

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

[0056] Specifically, the β-lactamase inhibitor of the present invention is selected from the following compounds or pharmaceutically acceptable salts or isomers or deuterated derivatives thereof:

[0057]

[0058]

[0059]

[0060] Explanation of terms

[0061] "Hydrocarbyl" refers to a saturated or unsaturated, branched or straight-chain, monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of hydrocarbyl groups include: methyl; ethyls, e.g., ethyl, ethenyl, and ethynyl; propyls, e.g., prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and the like. The term "hydrocarbyl" specifically includes groups having any degree or level of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having combinations of single, double, and triple carbon-carbon bonds. Where a specific level of saturation is intended, the terms alkyl, alkenyl, and alkynyl are used.

[0062] "Aryl" refers to a monovalent aromatic hydrocarbon radical produced by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic systems in which at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic systems in which at least one ring is carbocyclic and aromatic, for example, fluorene. Aryl includes polycyclic systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes a phenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic ring systems in which only one ring is a carbocyclic aromatic ring, the radical carbon atom may be located in the carbocyclic aromatic ring or the heterocycloalkyl ring. Examples of aryl groups include those derived from aceanthrene, acenaphthylene, indane, indene, naphthalene, octylene, octylphene, octylene, octylene, pentylene, pentylene, diphenylphenanthrene, perylene, phenalene, etc. However, aryl groups do not in any way encompass or overlap with heteroaryl groups defined separately herein.

[0063] "Arylalkyl" refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by 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-naphthophenyleth-1-yl. If a specific alkyl moiety is intended, the terms arylalkyl, arylalkenyl, or arylalkynyl are used.

[0064] The "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group, which may be a spiro ring or a bridged ring.

[0065] "Cycloalkylalkyl" refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group as defined herein. If a specific alkyl moiety is intended, the term cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl is used.

[0066] "Heteroalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more carbon atoms (and some associated hydrogen atoms) of the alkyl group are independently replaced by the same or different heteroatoms. Examples of heteroatoms in heteroalkyl groups include: -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-.

[0067] "Halogen" refers to a fluoro, chloro, bromo or iodo radical.

[0068] "Heteroarylalkyl" refers to an arylalkyl group in which one carbon atom (and some associated hydrogen atoms) is replaced by a heteroatom.

[0069] "Heterocycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cycloalkyl group in which one or more carbon atoms (and some of the associated hydrogen atoms) are independently replaced by the same or different heteroatoms; or refers to a parent aromatic ring system in which one or more carbon atoms (and some of the associated hydrogen atoms) are independently replaced by the same or different heteroatoms, so that the ring system violates Hückel's rule and can also be a spiro heterocycle or a bridged heterocycle.

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

[0071] The "sulfonyl group" refers to a group containing -S(O)(O)-. Examples of the sulfonyl group include p-toluenesulfonyl, sulfonylimide, and methanesulfonyl.

[0072] Another object of the present invention is to provide a pharmaceutical composition, which comprises the β-lactamase inhibitor of the present invention or a pharmaceutically acceptable salt or an isomer or deuterated product thereof, and a pharmaceutically acceptable carrier.

[0073] The pharmaceutical composition further comprises an antibiotic; further, the antibiotic is a β-lactam antibiotic, such as penicillins, cephalosporins, cephamycins and carbapenem antibiotics.

[0074] The dosage form of the pharmaceutical composition is an oral preparation; the oral preparation includes a solid dosage form for oral administration and a liquid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.

[0075] The pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, fillers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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

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

[0078] The bacteria are bacteria that can produce β-lactamase, including but not limited to bacteria of the genus Enterobacter, Citrobacter, Prufidenella, Serratia marcescens or Morganella.

[0079] Beneficial effects of the present invention:

[0080] The β-lactamase inhibitor of the present invention can quickly and completely release active metabolites such as avibactam, dulobactam, relebactam, nakubactam and other diazabicyclic β-lactamase inhibitors through the action of biological enzymes in vivo, and can quickly take effect, effectively improve the oral bioavailability of such β-lactamase inhibitors, so that they can be orally administered, solving the problem of low oral bioavailability of diazabicyclic β-lactamase inhibitors. The β-lactamase inhibitor of the present invention 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 1: Synthesis of compound 1b

[0086] At room temperature, compound 1a (20.0 g, 72.6 mmol) was dissolved in ethyl acetate (200 mL), and then 10% palladium carbon (5.60 g) was added thereto. The mixture was replaced with hydrogen three times and reacted for 3 hours at room temperature in a hydrogen atmosphere. After the reaction was completed, the reaction solution 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 (400MHz, DMSO-d6) δ9.70 (s, 1H), 7.49-7.15 (m, 2H), 3.64 (d, J = 7.2Hz, 1H), 3.17 (d, J = 3.2Hz, 1H), 3.00-2. 99(m,1H),2.87(d,J=11.6Hz,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 2: 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, and the mixture was reacted at 45°C for 16 h. After the reaction, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated brine (200 mL×2), dried with 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==8 / 1 V / V) to obtain 1.0 g of compound 1d with a yield of 5.1%. 1 H NMR (400MHz, CDCl3) δ5.78 (s, 2H), 3.57 (s, 2H), 1.21-1.20 (m, 15H).

[0089] Step 3: Synthesis of compound 1e

[0090] At room temperature, sulfonyl chloride (628 mg, 4.66 mmol) was dissolved in ether (9 mL), the mixed solution was replaced with argon three times, and stirred at -78 ° C for 10 min. Then, at -78 ° C, a solution of compound 1d (900 mg, 3.88 mmol) and pyridine (338 mg, 4.27 mmol) in ether (0.9 mL) was slowly added dropwise, and the mixed solution was stirred at -78 ° C for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 500 mg of compound 1e with a yield of 38.9%. 1 H NMR (400MHz, CDCl3) δ5.80 (s, 2H), 4.50 (s, 2H), 1.33 (s, 6H), 1.21 (s, 9H).

[0091] Step 4: Synthesis of compound 1

[0092] At room temperature, compound 1b (100 mg, 0.54 mmol) was dissolved in a mixed solvent of ultra-dry tetrahydrofuran (1 mL) and N,N-dimethylpropylene urea (1 mL), and sodium bis(trimethylsilyl)amide (0.3 mL, 2M tetrahydrofuran solution, 0.59 mmol) was added at -78°C under nitrogen protection; the reaction was continued with stirring at -78°C for 10 min, and compound 1e (270 mg, 0.81 mmol) was slowly added. After the addition was completed, the temperature was gradually raised to room temperature and reacted at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 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 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 19.32 mg of compound 1 with a yield of 7.5%. LCMS (ESI): [M+H] + =480.3. 1 H NMR (400MHz, CDCl3) δ6.48(s,1H),5.81(d,J=5.6Hz,1H),5.77(d,J=5.6Hz,1H),5.5 2(s,1H),4.74(d,J=9.2Hz,1H),4.59(d,J=9.2Hz,1H),4.17(d,J=2.2Hz,1H),4.05( d,J=7.1Hz,1H),3.35(d,J=12.0Hz,1H),3.02(d,J=12.1Hz,1H),2.45(dd,J=14.8,6 .7Hz,1H),2.15-2.13(m,1H),1.91-1.88(m,2H),1.29(d,J=5.3Hz,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] The synthesis method is the same as compound 1, except that chloromethyl isobutyrate is used in place of chloromethyl pivalate. LCMS (ESI): [M+H] + =466.4.1 H NMR (400MHz, CDCl3) δ6.51(s,1H),5.81(d,J=5.6Hz,1H),5.77(d,J=5.6Hz,1H),5.59(s,1H ),4.73(d,J=9.2Hz,1H),4.59(d,J=9.2Hz,1H),4.19-4.15(m,1H),4.06(d,J=7.2Hz,1H),3 .38-3.31(m,1H),3.02(d,J=12.0Hz,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=5.6Hz,6H),1.18(d,J=5.6Hz,6H).

[0097] Example 3

[0098] 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 acetoxymethyl ester (Compound 3)

[0099]

[0100] The synthesis method is the same as compound 1, except that chloromethyl acetate is used in place of chloromethyl pivalate. LCMS (ESI): [M+H] + =438.3. 1 H NMR (400MHz, CDCl3) δ6.48(s,1H),5.80(d,J=5.6Hz,1H),5.76(d,J=5.6Hz,1H),5.51( s,1H),4.73(d,J=9.2Hz,1H),4.59(d,J=9.2Hz,1H),4.17(d,J=2.0Hz,1H),4.06(d,J= 7.2Hz,1H),3.35(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,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=4.8Hz,6H).

[0101] Example 4

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

[0103]

[0104] The synthesis method is the same as compound 1, except that 1-chloroethyl isobutyrate is used in an equivalent amount to replace chloromethyl pivalate. LCMS (ESI): [M+H] + =480.5. 1 H NMR (400MHz, CDCl3) δ6.92-6.80(m,1H),6.50(s,1H),5.55(s,1H),4.70(d,J=9.2Hz,1H),4.64-4.55(m,1H) ,4.17(s,1H),4.05(d,J=7.2Hz,1H),3.34(d,J=12.4Hz,1H),3.02(d,J=10.4Hz,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=9.2Hz,3H),1.30-1.24(m,6H),1.17(dd,J=7.2,2.0Hz,6H).

[0105] Example 5

[0106] Synthesis of ethyl (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-carboxylate (Compound 5)

[0107]

[0108]

[0109] Step 1: Synthesis of compound 5b

[0110] At 0°C, compound 5a (6.0 g, 52.57 mmol) was dissolved in ether (60 mL), and 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 organic phases were combined and concentrated to dryness at 0°C to obtain 3.9 g of compound 5b with a yield of 74.1%.1 H NMR (400MHz, CDCl3) δ5.83-5.70 (m, 1H), 5.15-5.00 (m, 2H), 3.34 (d, J = 6.4Hz, 2H), 1.02 (s, 6H).

[0111] Step 2: Synthesis of compound 5c

[0112] At room temperature, compound 5b (3.9 g, 38.94 mmol) was dissolved in tetrahydrofuran (39 mL), sodium hydride (2.34 g, 58.41 mmol) was added in an ice bath, the reaction was kept in an ice bath for 30 minutes, then benzyl bromide (9.99 g, 58.41 mmol) was added, the ice bath was removed, and the reaction was kept at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (100 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL × 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 (400MHz, CDCl3) δ7.39-7.17(m,5H),5.88(dd,J=17.6,10.8Hz,1H),5.09-4.89(m,2H),4.52(s,2H),3.20(s,2H),1.04(s,6H).

[0113] Step 3: Synthesis of compound 5d

[0114] At room temperature, compound 5c (4.2 g, 22.07 mmol) was dissolved in 1.2-dichloroethane (42 mL), and placed in an ice bath under nitrogen protection, stirred and cooled, and dimerized rhodium acetate (II) (97 mg, 0.22 mmol) was added thereto, and ethyl 2-diazoacetate (4.74 g, 66.21 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was heated to 45°C and continued to react for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (100 mL×3) was used for extraction. The organic phases were 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 (400MHz, CDCl3) δ7.35-7.24(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=6.4Hz,6H).

[0115] Step 4: Synthesis of compound 5e

[0116] At room temperature, compound 5d (1.0 g, 3.62 mmol) was dissolved in methanol (10 mL), and then 10% palladium carbon (300 mg) was added, replaced with hydrogen three times, and stirred 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 450 mg of crude compound 5e, which was directly used for the next step. LCMS (ESI) [M+H] + =187.0.

[0117] Step 5: Synthesis of compound 5f

[0118] At room temperature, sulfonyl chloride (490 mg, 3.63 mmol) was dissolved in ether (10 mL), the mixture was replaced with argon three times, and stirred at -78 ° C for 10 min; compound 5e (450 mg, 2.42 mmol) and pyridine (287 mg, 3.63 mmol) in ether (1.0 mL) were slowly added dropwise, and the mixture was stirred 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 500 mg of crude compound 5f, which was directly used in the next step.

[0119] Step 6: Preparation of compound 5

[0120] At room temperature, compound 1b (326 mg, 1.76 mmol) was added to a mixed solution of ultra-dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.4 mL), and the mixture was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (0.82 mL, 2M tetrahydrofuran solution, 1.94 mmol) was added dropwise, and the mixture was kept at -78 °C for 10 minutes. Compound 5f (500 mg, 1.76 mmol) was then added thereto, and the mixture was stirred at -78 °C for 10 minutes. The mixture was gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, 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, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% to 70%) to obtain 68.47 mg of compound 5 with a yield of 8.97%. LCMS (ESI): [M+H] + =434.2. 1 HNMR (400MHz, CDCl3) δ6.46 (s, 1H), 5.50 (s, 1H), 4.57 (d, J = 8.8Hz, 1H), 4.27 (dd, J = 9. 2,3.2Hz,1H),4.20-4.15(m,1H),4.15-4.09(m,2H),4.05(d,J=7.6Hz,1H),3.34(d,J= 12.0Hz,1H),3.01(d,J=12.0Hz,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-toluenesulfonylpropionate (Compound 6)

[0123]

[0124] Step 1: Synthesis of compound 6b

[0125] Compound 6a (15.0 g, 98 mmol) was added to isopropanol (50 mL) at room temperature, cooled to 0°C, and thionyl chloride (14 g, 117.6 mmol) was added thereto; after the addition was completed, the temperature was gradually raised to room temperature and the reaction was continued for 16 hours; after the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted three times with ethyl acetate (100 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 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 (400MHz, CDCl3) δ5.15-4.99 (m, 1H), 4.33 (q, J = 6.8Hz, 1H), 1.81 (d, J = 6.8Hz, 3H), 1.28 (d, J = 6.4Hz, 6H).

[0126] Step 2: Synthesis of compound 6c

[0127] At room temperature, compound 6b (5.0 g, 25.77 mmol) was added to a mixed solution of water (10 mL), toluene (7.5 mL) and acetone (7.5 mL), and then tetrabutylammonium iodide (666 mg, 1.80 mmol) and sodium 4-methylbenzenesulfinate (6.88 g, 38.66 mmol) were added thereto in sequence, and the mixture was heated to 80°C 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 three times with ethyl acetate (100 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 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 (400MHz, CDCl3) δ7.77(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),5.04-4.89(m, 1H), 3.99 (q, J = 7.2Hz, 1H), 2.44 (s, 3H), 1.56 (d, J = 8.4Hz, 3H), 1.22-1.08 (m, 6H).

[0128] Step 3: Synthesis of compound 6d

[0129] At room temperature, compound 6c (1.0 g, 3.70 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (3 mL), and 37% formaldehyde aqueous solution (330 mg, 4.07 mmol) and sodium bicarbonate (31 mg, 0.37 mmol) were added in sequence at 0°C, and the reaction was continued at room temperature 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 three times with ethyl acetate (100 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 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 4: Synthesis of compound 6e

[0131] At room temperature, sulfonyl chloride (450 mg, 3.33 mmol) was dissolved in ether (5 mL), the mixture was replaced with argon three times, cooled to -78 °C and stirred for 10 min. At -78 °C, a solution of compound 6d (500 mg, 1.67 mmol) and pyridine (264 mg, 3.33 mmol) in ether (0.5 mL) was slowly added dropwise. After the addition was complete, the temperature was gradually raised to room temperature and 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 667 mg of crude compound 6e, which was directly used for the next step.

[0132] Step 5: Synthesis of compound 6

[0133] At room temperature, compound 1b (310 mg, 1.67 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.4 mL), cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amide (0.92 mL, 2M tetrahydrofuran solution, 1.84 mmol) was added dropwise. After the addition was completed, the temperature was kept at -78 °C for 10 minutes, and then compound 6e (667 mg, 1.67 mmol) was slowly added thereto. After the addition was completed, the temperature was gradually raised to room temperature and reacted 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 ethyl acetate (100 mL×3) was used for extraction three times. The organic phases were combined, washed with a 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: SunFireSunFireC18, 19×250 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, yield, 8.24%. LCMS (ESI): [M+H] + =548.4. 1 H NMR (400MHz, CDCl3) δ7.83-7.66 (m, 2H), 7.37 (d, J = 9.2Hz, 2H), 6.46 (s, 1H) ,5.56(s,1H),5.29-4.81(m,3H),4.15(s,1H),4.07(t,J=6.8Hz,1H),3.30(t ,J=10.8Hz,1H),3.02(d,J=12.0Hz,1H),2.54--2.39(m,4H),2.15(d,J=10. 0Hz, 1H), 1.99--1.83 (m, 2H), 1.66 (d, J = 13.2Hz, 3H), 1.24 (t, J = 6.0Hz, 6H).

[0134] Example 7

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

[0136]

[0137] Step 1: Synthesis of compound 7b

[0138] At room temperature, compound 7a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL), and isopropanol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol) were added in sequence. The temperature was lowered to 0°C, and N,N'-dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added thereto. The reaction was allowed to react at room temperature for 16 h. 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 14.0 g of compound 7b with a yield of 81.8%. 1 H NMR (400MHz, CDCl3) δ5.14--5.00(m,2H),3.83(q,J=7.2Hz,1H),1.42(d,J=7.2Hz,3H),1.30--1.17(m,12H).

[0139] Step 2: Synthesis of compound 7c

[0140] At room temperature, compound 7b (7.0 g, 34.61 mmol) was dissolved in a mixed solvent of ethanol (35 mL) and water (35 mL), and formaldehyde aqueous solution (3.12 g, 38.07 mmol) and sodium bicarbonate (291 mg, 3.46 mmol, 0.1 equivalent) were added at room temperature, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 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 with a yield of 46.1%. 1 H NMR (400MHz, CDCl3) δ5.13--5.02(m,2H),3.83(d,J=7.2Hz,2H),1.42(s,3H),1.30--1.19(m,12H).

[0141] Step 3: Synthesis of compound 7d

[0142] At room temperature, sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in ether (10 mL), and the mixed solution was replaced with argon three times. A solution of compound 7c (1.0 g, 4.31 mmol) and pyridine (375 mg, 4.74 mmol, 1.1 equivalent) in ether (1 mL) was added at -78°C. The mixed solution was stirred at -78°C for 0.5 hour and then gradually warmed to room temperature. The reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 1.0 g of compound 7d with a yield of 96.4%.1 H NMR (400MHz, CDCl3) δ5.12-5.06 (m, 2H), 4.79 (s, 2H), 1.57 (s, 3H), 1.26 (d, J = 7.2Hz, 12H).

[0143] Step 4: Synthesis of compound 7

[0144] At room temperature, compound 1b (300 mg, 1.60 mmol) was dissolved in ultra-dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.2 mL). Under argon protection, sodium bis(trimethylsilyl)amide (0.9 mL, 2M tetrahydrofuran solution, 1.8 mmol) was added thereto at -78 °C. After the addition was completed, the reaction was continued to stir at -78 °C for 10 min, and compound 7d (642 mg, 1.95 mmol) was slowly added thereto. After the addition was completed, the reaction temperature was gradually raised to room temperature, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction. The resulting solution was extracted with ethyl acetate (200 mL×3), and the organic phases were combined, washed with saturated brine (200 mL×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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 95.26 mg of compound 7 with a yield of 12.2%. LCMS (ESI): [M+H] + =480.3. 1 H NMR (400MHz, CDCl3) δ6.49(s,1H),5.68(s,1H),5.09-5.06(m,3H),4.90(d,J=9.4Hz,1H),4.16(s,1H),4.06(d,J=7.4Hz,1H),3.32(d, J=12.1Hz,1H),3.02(d,J=12.1Hz,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=5.4Hz,12H).

[0145] Example 8

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

[0147]

[0148] The synthesis method is the same as compound 7, except that methanol is used in place of isopropanol. LCMS (ESI): [M+H] + =424.2. 1 HNMR (400MHz, CDCl3) δ6.47(s,1H),5.57(s,1H),5.04(d,J=9.6Hz,1H),4.89(d,J=9.6Hz,1H),4.16(d,J=2.0Hz,1H),4.06(d,J=7.2Hz,1H),3.78(d ,J=5.6Hz,6H),3.33(d,J=12.0Hz,1H),3.07-2.99(m,1H),2.53-2.39(m,1 H),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 1: Synthesis of compound 9b

[0153] At room temperature, compound 9a (30.0 g, 138.72 mmol) was dissolved in tetrahydrofuran (300 mL), cooled to 0°C, and sodium hydride (5.5 g, 138.72 mmol) was slowly added thereto. After the addition was completed, the mixture was reacted at 0°C for 0.5 h. Then, iodomethane (19.7 g, 138.72 mmol) was added at 0°C. After the addition was completed, the mixture was gradually warmed to room temperature and continued to react 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 the mixture was extracted with ethyl acetate (200 mL×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 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, CDCl3) δ3.26 (q, J=7.3Hz, 1H), 1.46 (s, 18H), 1.32 (d, J=7.3Hz, 3H).

[0154] Step 2: Synthesis of compound 9c

[0155] At room temperature, compound 9b (20.0 g, 86.96 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0°C, and sodium hydride (5.2 g, 130.43 mmol) was slowly added thereto. After the addition was completed, the mixture was reacted at 0°C for 0.5 h. Tetrabutylammonium iodide (16.1 g, 43.48 mmol) and benzyl chloromethyl ether (13.6 g, 86.96 mmol) were then added thereto. After the addition was completed, the mixture was heated to 90°C for 4 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL×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 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 with a yield of 91.9%. LCMS(ESI):[M+Na] + =373.2. 1 H NMR (400MHz, CDCl3) δ7.32-7.28 (m, 5H), 4.53 (s, 2H), 3.74 (s, 2H), 1.45 (d, J = 2.5Hz, 6H), 1.43 (s, 15H).

[0156] Step 3: Synthesis of compound 9d

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

[0158] Step 4: Synthesis of compound 9e

[0159] At room temperature, sulfonyl chloride (568 mg, 4.21 mmol) was dissolved in ether (7 mL), cooled to -78 °C under nitrogen protection, and a solution of compound 9d (730 mg, 2.81 mmol) and pyridine (244 mg, 3.09 mmol) in ether (1 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 3 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 520 mg of crude compound 9e, which was directly used in the next step.

[0160] Step 5: Synthesis of compound 9

[0161] At room temperature, compound 1b (268 mg, 1.45 mmol) was dissolved in a mixed solvent of dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.2 mL), and the temperature was lowered to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (0.8 mL, 2M tetrahydrofuran solution, 1.60 mmol) was slowly added thereto. After the addition was completed, the reaction was continued at -78 °C with stirring for 10 min. Compound 9e (520 mg, 1.45 mmol) was slowly added thereto. After the addition was completed, the temperature was gradually raised 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 the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with a 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 141.38 mg of compound 9 with a yield of 19.2%. LCMS (ESI): [M+Na] + =530.2. 1 H NMR (400MHz, CDCl3) δ6.48(s,1H),5.60(s,1H),4.95(d,J=9.3Hz,1H),4.86(d,J=9.3Hz,1H),4.16(d,J=2.0Hz,1H),4.06(d,J=7.4Hz,1H) ,3.32(d,J=11.8Hz,1H),3.02(d,J=12.1Hz,1H),2.44(dd,J=15.1,6.9Hz,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 diethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonate (Compound 10)

[0164]

[0165] Step 1: Synthesis of compound 10b

[0166] At room temperature, compound 10a (10.0 g, 53.2 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (20 mL), and 37% formaldehyde aqueous 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 the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 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 2: Synthesis of compound 10c

[0168] At room temperature, sulfonyl chloride (1.86 g, 13.76 mmol) was dissolved in ether (20 mL), the mixture was replaced with argon three times, and stirred at -78 ° C for 10 min; then compound 10b (2.0 g, 9.17 mmol) and pyridine (943 mg, 11.93 mmol) in ether (2.0 mL) were slowly added dropwise at -78 ° C. After the addition was completed, the temperature was gradually raised to room temperature, and the reaction was stirred 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 2.0 g of compound 10c with a yield of 69.2%. 1 H NMR (400MHz, CDCl3) δ4.81 (s, 2H), 4.25 (q, J = 6.8Hz, 4H), 1.97 (q, J = 7.6Hz, 2H), 1.30 (t, J = 6.8Hz, 6H), 0.95 (t, J = 6.8Hz, 3H).

[0169] Step 3: Synthesis of compound 10

[0170] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.4 mL). Under nitrogen protection, sodium bis(trimethylsilyl)amide (0.89 mL, 2M tetrahydrofuran solution, 1.78 mmol) was added dropwise at -78°C. After the addition was complete, the temperature was kept at -78°C for 10 minutes, and then compound 10c (1025 mg, 3.24 mmol) was added. After the addition was complete, the temperature of the reaction solution was slowly raised to room temperature and reacted 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 mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 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: SunFireSunFireC18, 19 × 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 with a yield of 3.73%. LCMS (ESI): [M+H] + =466.5. 1 H NMR (400MHz, CDCl3) δ6.47 (s, 1H), 5.54 (s, 1H), 5.10 (d, J = 10.0Hz, 1H), 4.95 (d,J=10.0Hz,1H),4.29-4.20(m,4H),4.15(d,J=2.0Hz,1H),4.07(d,J=7.2H z,1H),3.32(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,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=7.8Hz,3H).

[0171] Embodiment 11

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

[0173]

[0174] The synthesis method is the same as compound 10, except that compound 10a is replaced by an equivalent amount of diisopropyl 2-ethylmalonate. LCMS (ESI): [M+H] + =494.2.1 H NMR (400MHz, CDCl3) δ6.47(s,1H),5.54(s,1H),5.14--5.04(m,3H),4.95(d,J=9.6Hz,1H),4.17-4.12(m,1H),4.07(d,J=7.2Hz,1H ), 3.31 (d, J = 11.6Hz, 1H), 3.02 (d, J = 12.0Hz, 1H), 2.49-2.40 (m, 1H), 2.20-1.80 (m, 5H), 1.27-1.23 (m, 12H), 0.92 (t, J = 7.6Hz, 3H).

[0175] Example 12

[0176] 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 bisthioethyl ester (Compound 12)

[0177]

[0178] Step 1: Synthesis of compound 12a

[0179] At room temperature, compound 7a (10.0 g, 84.75 mmol) was dissolved in dichloromethane (100 mL), and then oxalyl chloride (32.28 g, 254.23 mmol) and N,N-dimethylformamide (619 mg, 8.47 mmol) were added at 0°C and reacted 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 (400MHz, CDCl3) δ4.36-4.19 (m, 1H), 1.67 (d, J = 7.2Hz, 3H).

[0180] Step 2: Synthesis of compound 12b

[0181] At room temperature, compound 12a (13.0 g, 84.4 mmol) was dissolved in dichloromethane (130 mL), triethylamine (25.57 g, 253.2 mmol) and ethanethiol (15.95 g, 253.2 mmol) were added thereto in sequence at 0°C, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was directly concentrated to dryness, and 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 (400MHz, CDCl3) δ3.88-3.78(m,1H),2.95-2.89(m,4H),1.46(d,J=7.1Hz,3H),1.29-1.24(m,6H).

[0182] Step 3: Synthesis of compound 12c

[0183] At room temperature, compound 12b (3.8 g, 18.44 mmol) was dissolved in ethanol (16 mL) and water (8 mL), and 37% formaldehyde aqueous solution (1.65 g, 20.3 mmol) and sodium bicarbonate (155 mg, 1.84 mmol equivalent) were added thereto at 0°C; after addition, the mixture was heated to room temperature and reacted at room temperature 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 × 3). The organic phases were combined, washed with saturated brine (100 mL × 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 3.3 g of compound 12c with a yield of 75.8%. LCMS (ESI): [M+H] + =237.0.

[0184] Step 4: Synthesis of compound 12d

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

[0186] Step 5: Synthesis of compound 12

[0187] At room temperature, compound 1b (160 mg, 0.86 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (3.2 mL) and N,N-dimethylpropylene urea (1.4 mL), cooled to -78°C under argon protection, sodium bis(trimethylsilyl)amide (0.47 mL, 2M tetrahydrofuran solution, 0.95 mmol) was added dropwise, stirred at -78°C for 10 minutes, and compound 12d (289 mg, 0.86 mmol) was added. After addition, the temperature was slowly raised to room temperature and reacted 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 mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 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 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 24.87 mg of compound 12 with a yield of 59.6%. LCMS (ESI): [M+H] + =484.1. 1 H NMR (400MHz, CDCl3) δ6.46 (s, 1H), 5.52 (s, 1H), 5.13-4.99 (m, 2H), 4.16 (s, 1H), 4.07 (d, J = 7.6Hz, 1H), 3.33 (d, J = 11.2Hz, 1H), 3. 02(d,J=12.0Hz,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 diethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-benzylmalonate (Compound 13)

[0190]

[0191] Step 1: Synthesis of compound 13b

[0192] At room temperature, compound 13a (10.0 g, 62.43 mmol) was dissolved in ethanol (100 mL), potassium carbonate (11.22 g, 81.16 mmol) and benzyl bromide (21.36 g, 124.86 mmol) were added thereto in sequence, and the mixture was heated to 65°C for 8 hours. After the reaction was completed, pure water (100 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with sodium bicarbonate (100 mL×2), dried with 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 (400MHz, CDCl3) δ 7.30-7.16 (m, 5H), 4.24-4.07 (m, 4H), 3.69--3.58 (m, 1H), 3.22 (d, J = 8.0Hz, 2H), 1.26-1.14 (m, 6H).

[0193] Step 2: Synthesis of compound 13c

[0194] Potassium hydroxide (5 mg, 0.094 mmol) and paraformaldehyde (1.22 g, 40.16 mmol) were added to compound 13b (6.7 g, 26.77 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 3: Synthesis of compound 13d

[0196] At room temperature, sulfonyl chloride (1.08 g, 8.03 mmol) was dissolved in ether (10 mL), the mixed solution was replaced with argon three times, stirred at -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 ether (1.0 mL) was added dropwise. After the addition was complete, the mixture was reacted at -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 of reaction.

[0197] Step 4: Synthesis of compound 13

[0198] At room temperature, compound 1b (734 mg, 3.96 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (16 mL) and N,N-dimethylpropylene urea (6.4 mL), and under nitrogen protection, sodium bis(trimethylsilyl)amide (2.2 mL, 2M tetrahydrofuran solution, 4.36 mmol) was added thereto at -78°C, and the mixture was stirred and reacted for 10 min at -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 raised to room temperature, and the reaction was carried out 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 the mixture was extracted with ethyl acetate (1000 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 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: SunFireSunFireC18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 60%) to obtain 185.06 mg of compound 13, with a yield of 8.86%. LCMS (ESI): [M+H] + =528.6. 1 H NMR (400MHz, CDCl3) δ7.33-7.26(m,3H),7.19-7.12(m,2H),6.47(s,1H),5.59(s ,1H),4.94(d,J=10.0Hz,1H),4.78(d,J=10.0Hz,1H),4.30-4.14(m,5H),4.07(d ,J=7.2Hz,1H),3.39(d,J=2.8Hz,2H),3.35-3.28(m,1H),3.03(d,J=12.0Hz,1H) ,2.48-2.37(m,1H),2.20-2.10(m,1H),2.02-1.79(m,2H),1.25(q,J=7.2Hz,6H).

[0199] Embodiment 14

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

[0201]

[0202] The synthesis method is the same as compound 13, except that diethyl 2-phenylmalonate is used in place of compound 13b. LCMS (ESI): [M+H] + =514.2. 1 H NMR (400MHz, CDCl3) δ7.47-7.31(m,5H),6.45(s,1H),5.51(s,1H),5.38(d,J=9.6Hz,1H),5.14(d,J=9.6Hz,1H),4.44-4.21(m,4H),4. 03(s,2H),3.24(d,J=11.6Hz,1H),2.97(d,J=12.0Hz,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] Embodiment 15

[0204] Synthesis of diisopropyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylmalonate (Compound 15)

[0205]

[0206] Step 1: Synthesis of compound 15b

[0207] At room temperature, compound 15a (10.0 g, 99.88 mmol) was dissolved in dichloromethane (15 mL), isopropanol (9.0 g, 149.82 mmol) and 4-dimethylaminopyridine (1.2 g, 9.99 mmol) were added, 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 hours. 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 (400MHz, CDCl3) δ4.86 (dt, J = 12.5, 6.3Hz, 1H), 2.01 (d, J = 7.1Hz, 2H), 1.08 (dd, J = 6.3, 1.2Hz, 6H), 0.43-0.32 (m, 2H), -0.00 (t, J = 4.8Hz, 2H).

[0208] Step 2: Synthesis of compound 15c

[0209] At -78°C, lithium diisopropylamide (88 mL, 175.8 mmol) was dissolved in dry tetrahydrofuran (100 mL) under nitrogen protection, and compound 15b (10.0 g, 70.32 mmol) was added at -78°C, and the mixture was reacted at -78°C for 30 min, and then di-tert-butyl dicarbonate (18.4 g, 84.39 mmol) was added, and the mixture was heated to room temperature and continued to react for 4 h. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 mL×3), and 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 to obtain 10.0 g of compound 15c with a yield of 58.7%. 1 HNMR (400MHz, CDCl3) δ5.14-4.99 (m, 1H), 2.48 (d, J = 10.0Hz, 1H), 1.43 (s, 9H), 1.26(d,J=6.3Hz,6H), 0.63(dd,J=8.1,2.9Hz,2H), 0.30(dd,J=4.9,1.1Hz,2H).

[0210] Step 3: Synthesis of compound 15d

[0211] At room temperature, compound 15c (8.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C under nitrogen, and then sodium hydride (2.1 g, 52.7 mmol) was added, and the mixture was reacted 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 mixture was reacted at 90°C for 0.5 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 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 separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate=8 / 1 V / V) to obtain 3.0 g of compound 15d with a yield of 32.2%. LCMS (ESI): [M+Na] + =385.3.

[0212] Step 4: Synthesis of compound 15e

[0213] At room temperature, compound 15d (1.5 g, 4.14 mmol) was dissolved in dichloromethane (15 mL), and then trifluoroacetic acid (3 mL) was added and reacted 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 5: Synthesis of compound 15f

[0215] At room temperature, compound 15e (1.0 g, 3.26 mmol) was dissolved in dichloromethane (10 mL), and isopropanol (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 thereto, and the reaction was allowed to proceed overnight at room temperature. 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 6: Synthesis of compound 15g

[0217] At room temperature, compound 15f (600 mg, 1.72 mmol) was dissolved in ethyl acetate (6 mL), 10% palladium on carbon (60 mg) was added, the mixture was replaced with hydrogen three times, and the reaction was stirred 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 7: 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 addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 5 hours. 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 subsequent reactions without further purification. 1H NMR (400MHz, CDCl3) δ5.12-5.08(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 8: Synthesis of compound 15

[0221] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), and the temperature was cooled to -78 °C in a nitrogen environment. Sodium bis(trimethylsilyl)amide (973 uL, 2M tetrahydrofuran solution, 1.95 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78 °C for 10 minutes. Then, compound 15h (577 mg, 1.62 mmol) was added, the temperature was gradually raised to room temperature, and the mixture was 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×3). The organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 47.94 mg of compound 15 with a yield of 5.86%. LCMS (ESI): [M+H] + =506.4. 1 H NMR (400MHz, CDCl3) δ6.48(s,1H),5.52(s,1H),5.19-4.97(m,3H),4.89(d,J=12.8Hz,1H),4.16(s,1H),4.07(d,J=7.2 Hz,1H),3.30(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,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=7.2Hz,2H),0.55-0.44(m,2H).

[0222] Example 16

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

[0224]

[0225] The synthesis method is the same as step 2, step 3, step 6, step 7, and step 8 of the synthesis of compound 15, and ethyl 2-cyclopropylacetate is used to replace compound 15b. LCMS (ESI): [M+Na] + =528.1. 1 H NMR (400MHz, CDCl3) δ6.47 (s, 1H), 5.53 (s, 1H), 5.98 (d, J = 8.4Hz, 1H), 4.87 (d ,J=8.4Hz,1H),4.25-4.16(m,3H),4.07(d,J=7.2Hz,1H),3.31(d,J=12.0Hz,1H ),3.02(d,J=12.0Hz,1H),2.46-2.41(m,1H),2.22-2.09(m,1H),2.02-1.80(m, 2H),1.46(d,J=6.0Hz,10H),1.28(q,J=7.2Hz,3H),0.64(d,J=8.4Hz,2H),0.49 -0.48(m,2H).

[0226] Embodiment 17

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

[0228]

[0229] The synthesis method is the same as compound 15, except that ethyl 2-cyclopropylacetate is used in place of compound 15b. LCMS (ESI): [M+H] + =492.3. 1 H NMR (400MHz, CDCl3) δ6.49 (s, 1H), 5.67 (s, 1H), 5.18-4.97 (m, 2H), 4.89 (d, J= 9.6Hz,1H),4.30-4.12(m,3H),4.07(d,J=7.2Hz,1H),3.36-3.26(m,1H),3.03 (d,J=12.0Hz,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=8.8Hz,2H),0.57-0.42(m,2H).

[0230] Embodiment 18

[0231] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl bis(2-methylpropionate) (Compound 18)

[0232]

[0233] Step 1: Synthesis of compound 18b

[0234] At room temperature, compound 18a (10.0 g, 83.23 mmol) was dissolved in dichloromethane (100 mL), and 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 reacted at room temperature 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 three times with dichloromethane (100 mL × 3). The organic phases were combined, washed with sodium bicarbonate (100 mL × 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 (400MHz, CDCl3) δ4.02 (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 2: Synthesis of compound 18c

[0236] At room temperature, sulfonyl chloride (778 mg, 5.76 mmol) was dissolved in ether (8 mL), the mixture was replaced with argon three times, stirred at -78 ° C for 10 min, and then slowly added a solution of compound 18b (1.0 g, 3.84 mmol) and pyridine (456 mg, 5.76 mmol) in ether (0.8 mL) at -78 ° C, and stirred at -78 ° C for 2 h. After the reaction was completed, the reaction solution 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 step.

[0237] Step 3: Synthesis of compound 18

[0238] At room temperature, compound 1b (413 mg, 2.23 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (8 mL) and N,N-dimethylpropylene urea (3.2 mL). Under argon protection, sodium bis(trimethylsilyl)amide (1.2 mL, 2M tetrahydrofuran solution, 2.45 mmol) was added thereto 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 slowly added. After the addition was completed, the reaction temperature was gradually raised to room temperature, and the reaction was continued at room temperature for 2 hours. When the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 mL×3). The organic phases were combined, washed with a 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, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 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 (400MHz, CDCl3) δ6.49(s,1H),5.61(s,1H),4.74(d,J=9.2Hz,1H),4.48(d,J=9.2Hz,1H),4.16(s,1H),4.11-3.98(m,5H),3.34(d,J=11.6Hz,1 H),3.02(d,J=12.0Hz,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=7.2,2.0Hz,12H),1.09(s,3H).

[0239] Embodiment 19

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

[0241]

[0242]

[0243] Step 1: Synthesis of compound 19b

[0244] At room temperature, compound 19a (35.0 g, 147.0 mmol) was dissolved in tetrahydrofuran (350 mL), sodium hydride (5.3 g, 220.4 mmol) was added at 0°C, the reaction was stirred at room temperature for 1 h, and iodomethane (31.3 g, 220.4 mmol) was added thereto. After the addition was complete, the reaction was stirred at room temperature for 5 hours, and the reaction was completed by monitoring by LCMS. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (500 mL×3) was used for extraction three times. 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 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 (400MHz, CDCl3) δ4.25-4.10 (m, 6H), 1.47 (d, J = 16.4Hz, 6H), 1.34-1.24 (m, 9H).

[0245] Step 2: Synthesis of compound 19c

[0246] At room temperature, compound 19b (24.0 g, 95.2 mmol) was dissolved in tetrahydrofuran (300 mL), cooled to 0°C, and lithium borohydride (5.3 g, 220.4 mmol) was added thereto. After the addition was complete, the mixture was heated to 50°C and stirred for 16 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (300 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 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 (400MHz, CDCl3) δ4.19-4.08(m,5H), 3.68-3.51(m,2H), 1.36-1.29(m,6H), 1.18(d,J=16.8,6H).

[0247] Step 3: Synthesis of compound 19d

[0248] At room temperature, compound 19c (8.0 g, 38.1 mmol) was dissolved in tetrahydrofuran (100 mL), 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 thereto, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (100 mL×3) was used for extraction three times. 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 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 with a yield of 48.2%. LCMS (ESI): [M+H] + =301.2. 1 H NMR (400MHz, CDCl3) δ7.43-7.24(m,5H),4.53(s,2H),4.10-4.05(m,4H),3.49(d,J=12.4Hz,2H),1.36-1.14(m,12H).

[0249] Step 4: Synthesis of compound 19e

[0250] Under room temperature, compound 19d (1.5 g, 5.0 mmol) was dissolved in dichloromethane (30 mL), trimethylsilyl bromide (3.9 g, 25.0 mmol) was added at 0°C, and the mixture was stirred at 55°C for 2 h. After the reaction, the reaction solution was filtered, and the filtrate was directly concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.2% formic acid / water, mobile phase B: acetonitrile, gradient: 40% to 60%) to obtain 1.2 g of compound 19e with a yield of 97.6%. LCMS (ESI) [M+H] + =245.0. 1 H NMR (400MHz, CDCl3) δ7.37-7.28 (m, 5H), 4.55 (s, 2H), 3.49 (d, J = 14.8Hz, 2H), 1.23 (d, J = 16.4Hz, 6H).

[0251] Step 5: Synthesis of compound 19f

[0252] At room temperature, compound 19e (1.2 g, 4.9 mmol) was dissolved in acetone (15 mL), and a mixture of cesium carbonate (4.8 g, 14.8 mmol) and iodomethyl isobutyrate (3.37 g, 14.8 mmol) and methane (0.237 g, 14.8 mmol) was added thereto, and the mixture 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 (400MHz, CDCl3) δ7.45-7.24(m,5H),5.74-5.57(m,4H),4.53(s,2H),3.48(d,J=14.8Hz,2H),2.62-2.55(m,2H),1.29-1.16(m,18H).

[0253] Step 6: Synthesis of compound 19g

[0254] At room temperature, compound 19f (800 mg, 1.8 mmol) was dissolved in ethyl acetate (16 mL), and then 10% palladium carbon (400 mg) was added. The mixed solution was replaced with hydrogen three times, and the reaction was continued for 16 hours at room temperature under hydrogen atmosphere. 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 7: Synthesis of compound 19h

[0256] At room temperature, sulfonyl chloride (315 mg, 2.3 mmol) was dissolved in ether (6 mL), cooled to -78 °C in a nitrogen environment, and a solution of compound 19g (550 mg, 1.6 mmol) and pyridine (184 mg, 2.3 mmol) in ether (1 mL) was added dropwise. After the addition was complete, the temperature was gradually raised to room temperature, and 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 for the next step.

[0257] Step 8: Synthesis of compound 19

[0258] At room temperature, compound 1b (250 mg, 1.4 mmol) was dissolved in a mixed solution of tetrahydrofuran (7.5 mL) and N,N-dimethylpropylene urea (2.0 mL), and the temperature was lowered to -78 °C in a nitrogen environment. Sodium bis(trimethylsilyl)amide (0.8 mL, 2M tetrahydrofuran solution, 1.54 mmol) was added dropwise. After the addition was complete, the reaction was stirred at -78 °C for 10 minutes. Compound 19h (610 mg, 1.4 mmol) was continued to be added dropwise. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction three times. The organic phases were combined, washed with a 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 65%) to obtain 57.39 mg of compound 19 with a yield of 7.1%. LCMS (ESI) [M+H] + =602.2. 1 H NMR (400MHz, DMSO-d6) δ7.55(s,1H),7.40(s,1H),5.63(d,J=12.4Hz,4H),4.64-4.58(m,1H),4.45-4.40(m,1H),4.12(s,1H),3.91(d,J=6. 4Hz,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] Embodiment 20

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

[0261]

[0262] The synthesis method is the same as compound 19, except that iodomethyl acetate is used in place of iodomethyl isobutyrate in step 5. LCMS (ESI) [M+H] + =546.2. 1H NMR (400MHz, CDCl3) δ6.49(s,1H),5.74-5.65(m,4H),5.56(s,1H),4.76(dd,J=12.8,9.2Hz,1H),4.52(t,J=10.0Hz,1H),4.17(s,1H),4.05(d,J =7.6Hz,1H),3.35(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,1H),2.54-2.40(m,1H),2.15(s,7H),2.01-1.85(m,2H),1.30(dd,J=17.2,10.0Hz,6H).

[0263] Embodiment 21

[0264] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2-methylpropan-2-yl)phosphoryl)bis(oxy))bis(methylene)dipivalerate (Compound 21)

[0265]

[0266] The synthesis method is the same as compound 19, except that iodomethyl pivalate is used in place of iodomethyl isobutyrate in step 5. LCMS (ESI): [M+H] + =630.4. 1 H NMR (400MHz, CDCl3) δ6.50(s,1H),5.82-5.59(m,5H),4.82-4.70(m,1H),4.52(t,J=9.6Hz,1H),4.17(s,1H),4.05(d,J=7.2Hz,1 H), 3.34 (d, J = 12.0Hz, 1H), 3.03 (d, J = 12.0Hz, 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] Embodiment 22

[0268] Synthesis of 2-(bis((isopropoxycarbonyl)oxy)methoxy)phosphoryl)-2-methylpropyl((2S,5R)-2-carbonyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)sulfate (Compound 22)

[0269]

[0270] The synthesis method is the same as compound 19, except that iodomethyl isopropyl carbonate is used in place of iodomethyl isobutyrate in step 5. LCMS (ESI): [M+H] + =634.5. 1 H NMR (400MHz, CDCl3) δ6.51(s,1H),5.70(d,J=12.3Hz,4H),5.62(s,1H),5.00-4.87(m,2H),4.83-4.71(m,1H),4.53(t,J=9.9Hz,1H),4.17(s,1H), 4.05(d,J=6.8Hz,1H),3.35(d,J=11.9Hz,1H),3.02(d,J=12.1Hz,1H),2. 43(d,J=15.4Hz,1H),2.14(s,1H),1.90-1.84(m,2H),1.31-1.28(m,18H).

[0271] Embodiment 23

[0272] Synthesis of bis((pivaloyloxy)methyl)2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 23)

[0273]

[0274] Step 1: Synthesis of compound 23b

[0275] At room temperature, compound 23a (20.0 g, 114.8 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0°C, sodium hydride (4.10 g, 173.2 mmol) was slowly added thereto, reacted at 0°C for 0.5 h, then tetrabutylammonium iodide (21.2 g, 57.4 mmol) and ((chloromethoxy)methyl)benzene (18.0 g, 114.8 mmol) were added at 0°C, heated to 90°C and stirred for 2 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and 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 (400MHz, CDCl3) δ7.34-7.26 (m, 5H), 4.54 (s, 2H), 4.16 (q, J = 7.2Hz, 4H), 3.81 (s, 2H), 1.53 (s, 3H), 1.22 (t, J = 7.2Hz, 6H).

[0276] Step 2: Synthesis of compound 23c

[0277] At room temperature, compound 23b (18.0 g, 61.2 mmol) was dissolved in a mixed solvent of ethanol (90 mL) and water (90 mL), sodium hydroxide (9.8 g, 244.9 mmol) was slowly added at room temperature, and the mixture was stirred at 50°C for 16 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 45% to 65%) to obtain 15.0 g of compound 23c, which was directly used in the next step. LCMS (ESI): [M+Na] + =261.1.

[0278] Step 3: Synthesis of compound 23d

[0279] At room temperature, compound 23c (2.0 g, 8.40 mmol) was dissolved in dichloromethane (20 mL), and then iodomethyl pivalate (4.48 g, 18.5 mmol) and cesium carbonate (6.02 g, 18.58 mmol) were added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (100 mL×3) was used for extraction. 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 separated and purified by flash chromatography (Silicagel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 2.3 g of compound 23d with a yield of 63.6%. LCMS (ESI): [M+Na] + =489.2.

[0280] Step 4: Synthesis of compound 23e

[0281] At room temperature, compound 23d (800 mg, 1.72 mmol) was dissolved in ethyl acetate (8 mL), 10% palladium on carbon (120 mg) was added, the mixed solution was replaced with hydrogen three times, and stirred at room temperature in a hydrogen atmosphere for 1.5 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 500 mg of compound 23e with a yield of 77.3%. LCMS (ESI): [M+Na]+ =399.2.

[0282] Step 5: Synthesis of compound 23f

[0283] At room temperature, sulfonyl chloride (215 mg, 1.59 mmol) was dissolved in ether (10 mL), the mixture was replaced with argon three times, stirred at -78 ° C for 10 min, and then slowly added a solution of compound 23e (500 mg, 1.33 mmol) and pyridine (105 mg, 1.33 mmol) in ether (1.7 mL) at -78 ° C, gradually warmed to room temperature, and stirred 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 680 mg of compound 23f, which was directly used in the next step.

[0284] Step 6: Synthesis of compound 23

[0285] At room temperature, compound 1b (220 mg, 1.18 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), and the temperature was lowered to -78°C under nitrogen protection. Sodium bis(trimethylsilyl)amide (713 uL, 2M tetrahydrofuran solution, 1.42 mmol) was added dropwise. After the addition was completed, the mixture was reacted at -78°C for 10 minutes. Compound 23f (676 mg, 1.43 mmol) was slowly added thereto. After the addition was completed, the temperature was gradually raised to room temperature and the mixture was 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×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 54.65 mg of compound 23 with a yield of 9.86%. LCMS (ESI): [M+H] + =624.6. 1H NMR (400MHz, CDCl3) δ6.49 (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=7.2Hz,1H),3.29(d,J=12.0Hz,1H),3.03(d, J=12.0Hz,1H),2.44(dd,J=15.2,6.8Hz,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=8.8Hz,2H),0.50-0.46(m,2H).

[0286] Embodiment 24

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

[0288]

[0289] Step 1: Synthesis of compound 24a

[0290] At room temperature, compound 23b (25.0 g, 85.0 mmol) was dissolved in ethanol (250 mL) and water (250 mL), sodium hydroxide (6.80 g, 170 mmol) was slowly added at room temperature, and the mixture was stirred 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 reverse phase preparation (0.1% FA, ACN) to obtain 17.0 g of compound 24a with a yield of 75.1%. LCMS (ESI): [M+H] + =267.1. 1 H NMR (400MHz, DMSO-d6) δ7.42-7.26(m,5H),4.54-4.46(m,2H),4.15(q,J=7.2Hz,2H ),3.76(d,J=8.8Hz,1H),3.68(d,J=8.8Hz,1H),1.39(s,3H),1.15(t,J=7.2Hz,3H).

[0291] Step 2: Synthesis of compound 24b

[0292] At room temperature, compound 24a (2.0 g, 7.5 mmol) was dissolved in dichloromethane (20 mL), and then cyclohexanol (1.1 g, 11.3 mmol) and 4-dimethylaminopyridine (92 mg, 0.75 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, and 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 (400MHz, CDCl3) δ7.32-7.26(m,5H),4.88-4.77(m,1H),4.54-4.53(m,2H),4.19-4.14(m,2H),3.8 2(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=7.2Hz,3H).

[0293] Step 3: Synthesis of compound 24c

[0294] At room temperature, compound 24b (1.8 g, 5.2 mmol) was dissolved in ethanol (40 mL), and then 10% palladium carbon (1.0 g) was added. The mixed solution was replaced with hydrogen three times, and the reaction was continued at 50°C 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 1.1 g of compound 24c with a yield of 82.7%. LCMS (ESI) [M+Na] + =281.2. 1 HNMR(400MHz, CDCl3)δ4.93-4.81(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=7.2Hz,3H).

[0295] Step 4: Synthesis of compound 24d

[0296] At room temperature, sulfonyl chloride (392 mg, 2.9 mmol) was dissolved in ether (5 mL), cooled to -78 °C under nitrogen atmosphere, and a solution of compound 24c (500 mg, 1.9 mmol) and pyridine (229 mg, 2.9 mmol) in ether (0.5 mL) was added dropwise. After the addition was completed, the temperature was gradually raised to room temperature and the mixture was reacted 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 with a yield of 86.8%). 1 H NMR (400MHz, CDCl3) δ4.94-4.83(m,1H),4.81(s,2H),4.27-4.22(m,2H),1.83-1.80( m, 3H), 1.70 (d, J = 6.0Hz, 2H), 1.59 (s, 3H), 1.53-1.37 (m, 5H), 1.28 (t, J = 7.2Hz, 3H).

[0297] Step 5: Synthesis of compound 24

[0298] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.4 mL), and the temperature was cooled to -78 °C in a nitrogen environment. Sodium bis(trimethylsilyl)amide (0.9 mL, 2M tetrahydrofuran solution, 1.80 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78 °C for 10 minutes. Compound 24d (579 mg, 1.62 mmol) was then slowly added thereto. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted 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×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by reverse phase prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 65% to 75%) to obtain 115.22 mg of compound 24, yield 14.1%). LCMS (ESI) [M+H] + =506.3. 1H NMR(400MHz,DMSO-d6)δ7.54(s,1H),7.40(s,1H),4.92(d,J=9.6Hz,1H),4.81- 4.77(m,2H),4.20-4.12(m,2H),4.10(d,J=2.0Hz,1H),3.92(d,J=6.0Hz,1H),3. 23-3.15(m,2H),2.10(dd,J=15.6,6.8Hz,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=7.2Hz,3H).

[0299] Embodiment 25

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

[0301]

[0302] Step 1: Synthesis of compound 25b

[0303] At room temperature, compound 25a (900 mg, 6.16 mmol) was dissolved in dichloromethane (10 mL), 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 thereto in sequence, and the mixture was reacted 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×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 (400MHz, CDCl3) δ7.45-7.30(m,5H),5.15(s,2H),4.19-4.13(m,2H),3.48(q,J=7.2Hz,1H),1.44(d,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H).

[0304] Step 2: Synthesis of compound 25c

[0305] At room temperature, compound 25b (1.0 g, 4.23 mmol) was dissolved in ethanol (10 mL) and water (3 mL), and 37% aqueous formaldehyde solution (514 mg, 4.66 mmol) and sodium bicarbonate (48 mg, 0.42 mmol) were added thereto, and the mixture was reacted 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×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 25c with a yield of 88.4%. LCMS (ESI): [M+H] + =267.1. 1 H NMR (400MHz, CDCl3) δ7.45-7.30 (m, 5H), 5.20 (s, 2H), 4.17 (q, J = 6.4Hz, 2H), 3.87 (d, J = 7. 2Hz, 2H), 3.48 (d, J = 5.2Hz, 1H), 2.82 (t, J = 7.2Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.2Hz, 3H).

[0306] Step 3: Synthesis of compound 25d

[0307] At room temperature, sulfonyl chloride (377 mg, 2.82 mmol) was dissolved in dry ether (5 mL) 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 completed, the mixture was heated to room temperature and stirred at room temperature for 5 hours. 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 step.

[0308] Step 4: Synthesis of compound 25

[0309] At room temperature, compound 1b (200 mg, 1.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), cooled to -78 °C in a nitrogen environment, stirred for 10 minutes, sodium bis(trimethylsilyl)amide (648 uL, 2M tetrahydrofuran solution, 1.19 mmol) was added dropwise, and the mixture was reacted at -78 °C for 10 minutes. Compound 25d (500 mg, 1.30 mmol) was slowly added thereto, and the temperature was gradually raised to room temperature after the addition was completed, and the mixture was 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×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 62% to 78%) to obtain 54.65 mg of compound 25, with a yield of 9.86%. LCMS (ESI): [M+H] + =514.2. 1 H NMR (400MHz, CDCl3) δ7.34-7.31(m,5H),6.45(s,1H),5.55(s,1H),5.22(s,2 H),5.04(d,J=6.3Hz,1H),4.91(d,J=13.7Hz,1H),4.18-4.15(m,3H),4.06(d, J=6.4Hz,1H),3.29(d,J=11.6Hz,1H),3.03(d,J=16.6Hz,1H),2.50-2.38(m,1 H), 2.15-2.13 (m, 1H), 1.99-1.83 (m, 2H), 1.58 (s, 3H), 1.17 (t, J = 7.2Hz, 3H).

[0310] Embodiment 26

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

[0312]

[0313] The synthesis method is the same as compound 24, except that cyclohexanol in step 2 is replaced by an equivalent amount of n-butanol. LCMS (ESI): [M+H] + =480.5. 1H NMR (400MHz, CDCl3) δ6.48(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=7.2Hz,1H),3.32(d,J=12.0Hz,1H),3.02(d,J= 12.0Hz,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=7.2Hz,3H).

[0314] Embodiment 27

[0315] Synthesis of bis((isobutyryloxy)methyl)2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 27)

[0316]

[0317] The synthesis method is the same as compound 23, except that iodomethyl isobutyrate is used in place of iodomethyl pivalate in step 3. LCMS (ESI): [M+H] + =596.5. 1 H NMR (400MHz, CDCl3) δ6.47 (s, 1H), 5.82 (t, J = 5.2Hz, 2H), 5.79-5.75 (m, 2H), 5.51 (s,1H),5.04(d,J=9.6Hz,1H),4.87(d,J=9.6Hz,1H),4.15(s,1H),4.05(d,J=7.2 Hz,1H),3.34(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,1H),2.65-2.56(m,2H),2.48- 2.40(m,1H),2.14(s,1H),1.98-1.82(m,2H),1.58(s,3H),1.19(d,J=7.2Hz,12H).

[0318] Embodiment 28

[0319] 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-((isobutyryloxy)methyl)-3-isopropyl ester (Compound 28)

[0320]

[0321] Step 1: Synthesis of compound 28a

[0322] At room temperature, compound 7b (20.0 g, 98.89 mmol) was dissolved in tetrahydrofuran (200 mL), and sodium hydride (5.93 g, 148.34 mmol) was slowly added thereto at 0°C. After the addition was complete, the mixture was reacted at 0°C for 0.5 h. Then, tetrabutylammonium iodide (18.27 g, 59.45 mmol) and ((chloromethoxy)methyl)benzene (9.31 g, 59.45 mmol) were added at 0°C. After the addition was complete, the mixture was heated to 90°C and stirred for 2 h. After the reaction was completed, water (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with a 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 2: Synthesis of compound 28b

[0324] At room temperature, compound 28a (20.0 g, 62.03 mmol) was dissolved in isopropanol (200 mL) and water (200 mL), and sodium hydroxide (4.96 g, 124.06 mmol) was slowly added at room temperature. After the addition was complete, the reaction was heated to 50°C and stirred 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% to 80%) to obtain 6.2 g of compound 28b, with a yield of 36.7%. LCMS (ESI): [M+H] + =281.0.

[0325] Step 3: Synthesis of compound 28c

[0326] At room temperature, compound 28b (3.4 g, 12.13 mmol) was dissolved in acetone (34 mL), cesium carbonate (5.93 g, 18.2 mmol) and iodomethyl isobutyrate (4.15 g, 18.2 mmol) were added thereto, and the mixture was heated to 50°C for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×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 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 (400MHz, CDCl3) δ7.35-7.24(m,5H),5.76(dd,J=15.2,5.6Hz,2H),5.08-4.98(m,1H),4.52(s,2H),3.81(dd,J =23.2,8.8Hz,2H),2.59-2.47(m,1H),1.55-1.51(m,3H),1.20(dd,J=12.0,6.4Hz,6H),1.15(dd,J=7.2,1.6Hz,6H).

[0327] Step 4: Synthesis of compound 28d

[0328] At room temperature, compound 28c (1.2 g, 3.15 mmol) was dissolved in isopropanol (12 mL), and 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 (400MHz, CDCl3) δ5.82-5.78(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 = 7.2Hz, 6H).

[0329] Step 5: Synthesis of compound 28e

[0330] At room temperature, sulfonyl chloride (558 mg, 4.13 mmol) was dissolved in ether (6 mL), the mixture was replaced with argon three times, stirred at -78 ° C for 10 min, and then slowly added a solution of compound 28d (800 mg, 2.76 mmol) and pyridine (338 mg, 4.13 mmol) in ether (0.6 mL) to it. After the addition was complete, the mixture 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 used for the next step. 1 H NMR (400MHz, CDCl3) δ7.45-7.30 (m, 5H), 5.20 (s, 2H), 4.17 (q, J = 6.4Hz, 2H), 3.87 (d, J = 7. 2Hz, 2H), 3.48 (d, J = 5.2Hz, 1H), 2.82 (t, J = 7.2Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.2Hz, 3H).

[0331] Step 6: Synthesis of compound 28

[0332] At room temperature, compound 1b (350 mg, 1.89 mmol) was dissolved in a mixed solvent of dry tetrahydrofuran (7 mL) and N,N-dimethylpropylene urea (2.8 mL), 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 thereto. After the addition was complete, the reaction was continued to react at -78 °C with stirring for 10 min. Compound 28e (700 mg, 1.80 mmol) was then slowly added to the reaction solution. After the addition was complete, the mixture was gradually warmed 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 the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×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: SunFireSunFireC18, 19×250mm, 10μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 19.32 mg of compound 28, with a yield of 7.5%. LCMS (ESI): [M+H] + =538.4. 1H NMR (400MHz, CDCl3) δ6.48(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=7.2Hz,1H),3.33(d,J=12.0Hz,1H),3.02(d,J=1 2.0Hz,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=1.2Hz,3H),1.28-1.24(m,6H),1.18(dd,J=7.0,0.8Hz,6H).

[0333] Embodiment 29

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

[0335]

[0336] The synthesis method is the same as compound 24, with compound 28b replacing compound 24a in equivalent amount, and n-butanol replacing cyclohexanol in equivalent amount. LCMS (ESI): [M+H] + =494.4. 1 H NMR (400MHz, CDCl3) δ6.56 (s, 1H), 5.99 (s, 1H), 5.13-5.03 (m, 1H), 5.01 (d, J = 9.2Hz, 1H), 4 .95-4.86(m,1H),4.20-4.14(m,3H),4.07(d,J=7.2Hz,1H),3.33(d,J=12.0Hz,1H),3.02(d ,J=12.0Hz,1H),2.48-2.37(m,1H),2.21-2.09(m,1H),2.02-1.91(m,1H),1.90-1.80(m,1H) ),1.66-1.59(m,2H),1.55(s,3H),1.41-1.33(m,2H),1.28-1.23(m,6H),0.97-0.88(m,3H).

[0337] Embodiment 30

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

[0339]

[0340] The synthesis method is the same as compound 24, except that compound 28b is used to replace compound 24a in equivalent amounts. LCMS (ESI) [M+H] + =520.2. 1 H NMR(400MHz, CDCl3)δ6.47(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=7.6Hz,1H),3.32(d,J=12.0Hz,1H),3. 00(d,J=9.2Hz,1H),2.51-2.37(m,1H),2.22-2.11(m,1H),2.00-1.81(m,4 H),1.73-1.68(m,4H),1.54(s,3H),1.48-1.36(m,4H),1.27-1.22(m,6H).

[0341] Embodiment 31

[0342] 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-ethyl-3-isopropyl ester (Compound 31)

[0343]

[0344] The synthesis method is the same as compound 24, except that cyclohexanol is replaced by an equivalent amount of isopropanol. LCMS (ESI): [M+H] + =466.1. 1 HNMR(400MHz,CDCl3)δ6.48(s,1H),5.63(s,1H),5.13-4.99(m,2H),4.91-4.89(m,1H),4.29-4.14(m,3H),4.06(d,J=7.4Hz,1H),3.3 2(d,J=12.0Hz,1H),3.02(d,J=12.1Hz,1H),2.45-2.42(m,1H),2.15-2.13(m,1H),2.00-1.81(m,2H),1.55(s,3H),1.27-1.24(m,9H).

[0345] Embodiment 32

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

[0347]

[0348] The synthesis method is the same as compound 24, with compound 28b replacing compound 24a in an equivalent amount, and tert-butanol replacing an equivalent amount of cyclohexanol. LCMS (ESI): [M+Na] + =516.2. 1 H NMR(400MHz, CDCl3)δ6.46(s,1H),5.51(s,1H),5.12-5.04(m,1H),5.00-4.9 6(m,1H),4.88(d,J=9.6Hz,1H),4.16(d,J=2.4Hz,1H),4.06(d,J=7.6Hz,1H), 3.32(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,1H),2.47-2.42(m,1H),2.18-2.14 (m,1H),1.99-1.84(m,2H),1.48(dd,J=14.0,2.4Hz,12H),1.28-1.24(m,6H).

[0349] Embodiment 33

[0350] Synthesis of 1-tert-butyl-3-ethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 33)

[0351]

[0352] The synthesis method is the same as compound 24, except that cyclohexanol is replaced by an equivalent amount of tert-butyl alcohol. LCMS (ESI): [M+Na] + =502.4. 1HNMR (400MHz, CDCl3) δ6.47(s,1H),5.53(s,1H),5.08-4.93(m,1H),4.87(d,J=8.3Hz,1H),4.23-4.16(m,3H),4.07(d,J=7.3Hz,1H),3.31(d,J= 12.2Hz,1H),3.02(d,J=12.1Hz,1H),2.44(dd,J=14.3,5.8Hz,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] Embodiment 34

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

[0355]

[0356] Step 1. Synthesis of compound 34a

[0357] At room temperature, compound 9c (41 g, 117.0 mmol) was dissolved in dichloromethane (800 mL), and then trifluoroacetic acid (26.7 g, 234.3 mmol) was added, and the reaction solution was reacted at room temperature for 16 h. 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, dichloromethane: methanol (10 / 1 V / V)) to obtain 13.5 g of compound 34a, with a yield of 39.2%. LCMS (ESI): [M+Na] + =317.2. 1 H NMR (400MHz, CDCl3) δ7.35-7.22(m,5H),4.55(s,2H),3.84-3.74(m,2H),1.48(s,3H),1.44(s,9H).

[0358] Step 2: Synthesis of compound 34b

[0359] At room temperature, compound 34a (1.5 g, 5.10 mmol) was dissolved in dichloromethane (15 mL), and then butanol (567 mg, 7.65 mmol) and 4-dimethylaminopyridine (63 mg, 0.51 mmol) were added in sequence at room temperature. The reaction solution was cooled to 0°C, and N,N'-dicyclohexylcarbodiimide (1.58 g, 7.65 mmol) was added thereto. The reaction solution continued to react for 16 hours at room temperature. After the reaction was completed, the reaction solution 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 =2.151min.

[0360] Step 3. Synthesis of compound 34c

[0361] At room temperature, compound 34b (1.4 g, 4 mmol) was dissolved in isopropanol (14 mL), and then 10% palladium carbon (700 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution was reacted 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 1.0 g of compound 34c, with a yield of 96.1%. LCMS (ESI): [M+Na] + =283.3.

[0362] Step 4. Synthesis of compound 34d

[0363] At room temperature, sulfonyl chloride (1038 mg, 7.69 mmol) was dissolved in ether (10 mL), the mixture was replaced with nitrogen, cooled to -78 ° C and stirred for 10 min. 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 ether (1 mL) were slowly added dropwise. After the addition was completed, the reaction gradually warmed to room temperature and stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was directly filtered and the filtrate was concentrated to dryness to obtain 600 mg of crude compound 34d, which was directly used in the next step.

[0364] Step 5: Synthesis of compound 34

[0365] At room temperature, compound 1b (300 mg, 1.62 mmol) was added to a mixed solution of ultra-dry tetrahydrofuran (6 mL) and N,N-dimethylpropylene urea (2.4 mL), and the mixture was cooled to -78°C under nitrogen protection. Sodium bis(trimethylsilyl)amide (0.89 mL, 2M tetrahydrofuran solution, 1.78 mmol) was added dropwise thereto. After the addition was completed, the reaction was continued to react at -78°C with stirring for 10 min. Compound 34d (700 mg, 1.80 mmol) was then slowly added to the reaction solution. After the addition was completed, the mixture was gradually warmed 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 the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×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: SunFireSunFireC18, 19×250mm, 10μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%), to obtain 162.79mg compound 34, yield: 19.8%. LCMS (ESI): [M+Na] + =530.5. 1 H NMR (400MHz, CDCl3) δ6.47(s,1H),5.60(s,1H),5.04-4.80(m,2H),4.17-4.16(m,3H),4.06(d,J=6.8Hz,1H),3.31(d,J=12.0Hz,1H),3.02(d,J=12 .4Hz,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] Embodiment 35

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

[0368]

[0369] Synthesis method step 1 is the same as compound 23 synthesis step 1, using diethyl ethylmalonate to replace compound 23a, and the subsequent synthesis method is the same as compound 24, using the product obtained in step 1 to replace compound 23b, and using isopropanol to replace cyclohexanol. LCMS (ESI): [M+Na] + =502.2. 1 H NMR (400MHz, CDCl3) δ6.47(s,1H),5.59(s,1H),5.10-5.08(m,2H),4.95(d,J=9.9Hz,1H),4.34-4.01(m,4H),3.32(d,J =11.9Hz,1H),3.02(d,J=12.1Hz,1H),2.45-2.42(m,1H),2.25-1.79(m,5H),1.30-1.23(m,9H),0.92(t,J=7.5Hz,3H).

[0370] Embodiment 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 1: Synthesis of compound 36a

[0374] At room temperature, compound 28b (3.5 g, 12.5 mmol) was dissolved in dichloromethane (35 mL), triethylamine (3.78 g, 37.5 mmol) and isobutyl phosgene (3.41 g, 25 mmol) were added thereto in sequence, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (50 mL × 3) was used for extraction three times. 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 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 (400MHz, CDCl3) δ7.35-7.24(m,5H),5.08-4.92(m,1H),4.59-4.41(m,2H),3.80-3.75(m,3H),3.30-3.2 6(m,1H),2.15-1.85(m,1H),1.53(d,J=6.4Hz,3H),1.27-1.15(m,6H),1.15-1.06(m,3H),1.01-0.87(m,3H).

[0375] Step 2: Synthesis of compound 36b

[0376] At room temperature, compound 36a (3.3 g, 8.68 mmol) was dissolved in methanol (33 mL), cooled to 0 ° C, and sodium borohydride (363 mg, 9.55 mmol) was added in batches; after addition, the temperature was gradually raised to room temperature and the reaction was continued for 1 hour. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (100 mL × 3) was used for extraction three times. 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 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 (400MHz, CDCl3) δ7.37-7.26(m,5H),5.10-4.98(m,1H),4.58-4.43(m,2H),3.93-3.83(m,1H) ),3.76-3.61(m,2H),3.48(d,J=9.2Hz,1H),2.62-2.50(m,1H),1.26-1.22(m,6H),1.17(s,3H).

[0377] Step 3: Synthesis of compound 36c

[0378] At room temperature, compound 36b (1.7 g, 6.40 mmol) was dissolved in dichloromethane (17 mL), and pyridine (758 mg, 9.58 mmol) and isobutyryl chloride (817 mg, 7.67 mmol) were added thereto in sequence. After addition, the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (40 mL × 3) was used for extraction three times. 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 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 (400MHz, CDCl3) δ7.40-7.16(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 = 7.2Hz, 6H).

[0379] Step 4: Synthesis of compound 36d

[0380] At room temperature, compound 36c (2.0 g, 5.95 mmol) was dissolved in isopropanol (20 mL), and then 10% palladium carbon (1.0 g) was added. The mixed solution was replaced with hydrogen three times, and the reaction was continued in a hydrogen atmosphere at 50°C for 16 hours. After the reaction was completed, the reaction solution 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 (400MHz, CDCl3) δ5.12-4.98(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 5: Synthesis of compound 36e

[0382] At room temperature, sulfonyl chloride (220 mg, 1.62 mmol) was dissolved in ether (2 mL), the mixture was replaced with argon three times, cooled to -78 °C and stirred for 10 min, and then slowly added a solution of compound 36d (200 mg, 0.813 mmol) and pyridine (129 mg, 1.62 mmol) in ether (1 mL) at -78 °C. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was continued 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 6: Synthesis of compound 36

[0384] At room temperature, compound 1b (150 mg, 0.81 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1.2 mL), cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amide (0.45 mL, 2M tetrahydrofuran solution, 0.89 mmol) was added dropwise. After the addition was completed, the reaction was maintained at -78 °C for 10 minutes, and then compound 36e (2790 mg, 0.81 mmol) was slowly added thereto. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was continued for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction three times. The organic phases were combined, washed with a 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 27.07 mg of compound 36, with a yield of 6.77%. LCMS (ESI): [M+Na] + =494.2. 1 H NMR(400MHz, CDCl3)δ6.51(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=7.2Hz,1H ),3.33(d,J=11.2Hz,1H),3.02(d,J=12.0Hz,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] Embodiment 37

[0386] Synthesis of diisopropyl 2-((((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 37)

[0387]

[0388]

[0389] Step 1: Synthesis of compound 37b

[0390] At room temperature, compound 37a (2.0 g, 7.24 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C, and tert-butyl 4-amino-1-piperidinylcarboxylate (1.4 g, 7.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.8 g, 7.24 mmol) and N,N-diisopropylethylamine (936 mg, 7.24 mmol) were added in sequence. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was continued for 16 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction three times. The organic phases were combined, washed with a 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 3.0 g of compound 37b with a yield of 90.4%. LCMS (ESI): [M+H] + =459.4.

[0391] Step 2: Synthesis of compound 37c

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

[0393] Step 3: 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-dimethylpropylene urea (9 mL), cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amide (1.5 mL, 2M tetrahydrofuran solution, 3.0 mmol) was added thereto; after addition, the mixture was stirred at -78 °C for 10 min, and then compound 7d (986 mg, 3.0 mmol) was slowly added thereto; after addition, 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 the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (50 mL×3), the organic phases were combined, washed with a 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: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% to 80%) to obtain 100 mg of compound 37d with a yield of 5.6%. LCMS (ESI): [M+Na] + =685.3.

[0395] Step 4: Synthesis of compound 37

[0396] At room temperature, compound 37d (60 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), cooled to -10 ° C, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at -10 ° C for 0.5 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 21.90 mg of compound 37, with a yield of 43.0%. LCMS (ESI): [M+H] + =563.5.

[0397] Embodiment 38

[0398] Synthesis of diisopropyl 2-((((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (Compound 38)

[0399]

[0400] Step 1: Synthesis of compound 38b

[0401] At room temperature, tert-butyl (2-bromoethyl)carbamate (10.0 g, 44.6 mmol) and N-hydroxyphthalimide (7.28 g, 44.6 mmol) were dissolved in acetonitrile (100 mL), triethylamine (11.26 g, 111.5 mmol) was added thereto, and the mixture was heated to 70°C for 20 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was diluted with ethyl acetate (100 mL), and washed with 1N dilute hydrochloric acid, saturated sodium bicarbonate solution and water in sequence. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 5.5 g of crude compound 38b, which was directly used in the next step.

[0402] Step 2: Synthesis of compound 38c

[0403] At room temperature, compound 38b (2.5 g, 8.16 mmol) was dissolved in ethanol (25 mL), hydrazine hydrate (0.5 mL, 12.2 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction liquid was filtered, the filter cake was washed three times with ethyl acetate (50 mL × 3), the filtrate was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 1.2 g of compound 38c, with a yield of 83.5%. 1 H NMR (400MHz, CDCl3) δ3.70 (t, J = 4.8Hz, 2H), 3.36-3.32 (m, 2H), 1.45 (s, 9H).

[0404] Step 3: Synthesis of compound 38d

[0405] At room temperature, compound 37a (1.2 g, 4.3 mmol) was dissolved in dichloromethane (12 mL), and 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-diisopropylethylamine (561 mg, 4.3 mmol) were added thereto in sequence. After addition, the mixture was reacted at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 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 separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 1 / 1 V / V) to obtain 1.5 g of compound 38d with a yield of 79.4%. LCMS(ESI):[M+H] + =435.3.

[0406] Step 4: Synthesis of compound 38e

[0407] At room temperature, compound 38d (800 mg, 1.84 mmol) was dissolved in ethyl acetate (20 mL), and then 10% palladium carbon (600 mg) was added. The mixed solution was replaced with hydrogen three times, and the reaction was continued for 16 hours at room temperature in a hydrogen atmosphere. 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)δ4.12-4.07(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 5: Synthesis of compound 38f

[0409] At room temperature, compound 38e (400 mg, 1.16 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and N,N-dimethylpropylene urea (3 mL), cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amide (0.6 mL, 2M tetrahydrofuran solution, 1.28 mmol) was added dropwise. After the 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 raised to room temperature and the reaction was continued for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted three times with ethyl acetate (50 mL×3). The organic phases were combined, washed with a 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, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60% to 80%) to obtain 200 mg of crude compound 38f, which was directly used in the next step. LCMS (ESI): [M+H] + =539.2.

[0410] Step 6: 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 slowly added dropwise at -10°C, and the mixture was stirred at -10°C for 30 min. After the reaction, the reaction solution was concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 9.94 mg of compound 38 with a yield of 12.1%. LCMS (ESI): [M+H] + =539.5. 1 H NMR (400MHz, CDCl3) δ8.22(s,2H),5.09-5.05(m,2H),4.94(d,J=8.8Hz,1H),4.84(d,J=9.6Hz,1H),4.30-4.08(m,3H),3 .27(s,2H),3.13(d,J=11.2Hz,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] Embodiment 39

[0413] Synthesis of 2-((((((2S,5R)-2-aminoacyl-7-oxo-1,6-diazoheterocyclo[3.2.1]octane-6-acyl(oxy)sulfonyl(oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-isopropyl-3-methyl ester (Compound 39)

[0414]

[0415] Step 1: Synthesis of compound 39b

[0416] At 0°C, compound 39a (10 g, 84.68 mmol) was dissolved in dichloromethane (100 mL), and isopropanol (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 in sequence under nitrogen protection, and the temperature was raised to 25°C 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 the mixture was extracted with dichloromethane (300 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 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 11.0 g of compound 39b. The yield was 81.1%.

[0417] Step 2: Synthesis of compound 39c

[0418] Compound 39b (4.00 g, 24.97 mmol) was dissolved in THF (20 mL) at 0°C, and sodium hydrogen (4.55 g, 24.97 mmol, 60% in mineral oil) was slowly added under nitrogen atmosphere, and stirring was continued for 30 minutes, and then (iodomethyl)cyclopropane (1.1 g, 27.47 mmol) was added, and the temperature was raised to 50°C for reaction 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, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, backwashed with saturated brine (100 mL×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 3.0 g of compound 39c with a yield of 56.07%. 1 H NMR(400MHz, CDCl3)δ5.06(dt,J=12.4,6.4Hz,1H),3.72(s,3H),3.43(t,J=7.6Hz,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 3: Synthesis of compound 39d

[0420] At room temperature, compound 39c (1.0 g, 4.67 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (10 mL). Under nitrogen protection, the temperature was lowered to 0 ° C, and sodium bicarbonate (39.21 mg, 0.467 mmol) and 37% formaldehyde aqueous solution (416.6 mg, 5.13 mmol) were added thereto in sequence, and the mixture was reacted 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 the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 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 1.0 g of compound 39d with a yield of 87.71.%. 1 H NMR (400MHz, CDCl3) δ5.17-4.99(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 4: Synthesis of compound 39e

[0422] At room temperature, sulfonyl chloride (332 mg, 2.46 mmol) was dissolved in ether (4 mL), and the temperature was lowered to -78 °C under nitrogen; a solution of compound 39d (400 mg, 2.46 mmol) and pyridine (194 mg, 2.46 mmol, 1.5 equivalents) in ether (2 mL) was added dropwise, and the temperature was gradually raised to room temperature after the addition was completed, and 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 collected and concentrated under reduced pressure to obtain 561 mg of compound 39e, which was directly used in the next step without further purification.

[0423] Step 5: Synthesis of compound 39

[0424] At room temperature, compound 1b (151 mg, 0.82 mmol) was dissolved in a mixed solvent of THF (12 mL) and N,N-dimethylpropylene urea (4.6 mL), cooled to -78 °C in a nitrogen environment, and then sodium bis(trimethylsilyl)amide (0.45 mL, 2M tetrahydrofuran solution, 0.9 mmol) was added dropwise, and the reaction was carried out at -78 °C for 10 minutes. Compound 39e (561 mg, 1.64 mmol) was then added dropwise. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 45 mg of compound 39 with a yield of 11%. LCMS (ESI) [M+H] + =492.3. 1 H NMR(400MHz, DMSO-d6)δ7.67-7.32(m,2H),5.10(d,J=9.8Hz,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=2.6Hz,3 H),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] Embodiment 40

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

[0427]

[0428] The synthesis method is the same as compound 39, except that isopropanol is replaced by an equivalent amount of ethanol. LCMS (ESI) [M+H] + =478.3. 1HNMR(400MHz,DMSO-d6)δ7.61-7.33(m,2H),5.10(d,J=9.8Hz,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=3.6Hz,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] Embodiment 41

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

[0431]

[0432] The synthesis method is the same as compound 39, with diisopropyl malonate replacing compound 39b in an equivalent amount. LCMS (ESI) [M+H] + =520.4. 1 H NMR (400MHz, DMSO-d6) δ7.46(d,J=58.0Hz,2H),5.08(d,J=9.6Hz,1H),5.01-4.94(m,1H),4.88(dd,J=9.6,2H),4.09(s,1H),3.92(d,J=7.2Hz, 1H),3.23-3.13(m,2H),2.13-2.07(m,1H),1.99-1.66(m,5H),1.18(d,J =5.6Hz,12H),0.64-0.52(m,1H),0.46-0.38(m,2H),0.11-0.04(m,2H).

[0433] Embodiment 42

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

[0435]

[0436] The synthesis method is the same as compound 39, except that compound 39a is replaced by an equivalent amount of monoethyl malonate. LCMS (ESI) [M+H] + =506.4. 1 H NMR(400MHz,DMSO-d6)δ7.47(d,J=58.0Hz,2H),5.00(d,J=10.0Hz,1H),5.03 -4.93(m,1H),4.90(dd,J=9.6,2.8Hz,1H),4.23-4.13(m,2H),4.10(s,1H),3. 93(d,J=6.8Hz,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] Embodiment 43

[0438] Synthesis of 1-ethyl-3-methyl 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)malonate (Compound 43)

[0439]

[0440] Step 1: Synthesis of compound 43b

[0441] At room temperature, compound 43a (0.21 g, 0.73 mmol) was dissolved in ethyl acetate (5 mL), and then 10% palladium carbon (0.1 g) was added thereto. The mixture was replaced with hydrogen three times and reacted for 3 hours at room temperature in a hydrogen atmosphere. After the reaction was completed, the reaction solution 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 2: Synthesis of compound 43c

[0443] At 0°C, compound 39a (10 g, 84.75 mmol) was dissolved in dichloromethane (100 mL), and ethanol (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 thereto in sequence under nitrogen protection. After the addition was completed, the reaction solution was heated 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 the mixture was extracted with dichloromethane (300 mL×3). The organic phases were combined, washed with saturated brine (300 mL×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 8 g of compound 43c with a yield of 64.64%. 1 HNMR (400MHz, CDCl3) δ4.21 (q, J=6.8Hz, 2H), 3.76 (s, 3H), 3.39 (s, 2H), 1.29 (t, J=7.2Hz, 3H).

[0444] Step 3: Synthesis of compound 43d

[0445] At 0°C, compound 43c (4 g, 27.38 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and sodium hydrogen (1.2 g, 30.12 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was completed, the temperature was kept at 0°C and stirred for 30 minutes. Then (iodomethyl)cyclopropane (5 g, 27.38 mmol) was added to the above reaction solution. After the addition was completed, the reaction solution was heated 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, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, backwashed with saturated brine (100 mL×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 = 92 / 8 V / V) to obtain 4.1 g of compound 43d with a yield of 74.81%. 1 H NMR (400MHz, CDCl3) δ4.20 (q, J=7.2Hz, 2H), 3.72 (s, 3H), 3.46 (t, J=7.6Hz, 1H), 1.81 (t, J= 7.2Hz,2H),1.27(t,J=7.2Hz,3H),0.78-0.67(m,1H),0.48-0.41(m,2H),0.13-0.09(m,2H).

[0446] Step 4: Synthesis of compound 43e

[0447] Under nitrogen protection, at 0°C, compound 43d (4.1 g, 20.45 mmol) was dissolved in a mixed solution of ethanol (40 mL) and water (20 mL), and sodium bicarbonate (172 mg, 2.05 mmol) and 37% formaldehyde aqueous solution (1.83 g, 22.50 mmol) were added thereto in sequence. After the addition was completed, the mixture was reacted 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 the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×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 5: Synthesis of compound 43f

[0449] At room temperature, sulfonyl chloride (2.47 g, 18.24 mmol) was dissolved in ether (30 mL) and cooled to -78°C under nitrogen protection. Compound 43e (2.8 g, 12.16 mmol) and pyridine (1.45 g, 18.24 mmol) in ether (2 mL) were added dropwise. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and 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.

[0450] Step 6: Synthesis of compound 43

[0451] At room temperature, compound 43b (130 mg, 0.66 mmol) was dissolved in a mixed solvent of THF (10 mL) and N,N-dimethylpropylene urea (4 mL), cooled to -78°C in a nitrogen environment, and then sodium bis(trimethylsilyl)amide (0.37 mL, 2M tetrahydrofuran solution, 0.74 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78°C for 10 minutes, and compound 43f (452.3 mg, 1.32 mmol) was added dropwise. After the addition was complete, the mixture was gradually warmed to room temperature and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250mm, 10μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50% to 70%) to obtain 32 mg of compound 43, with a yield of 9.6%. LCMS (ESI) [M+H] + =490.2. 1H NMR (400MHz, CDCl3) δ7.12 (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=8.0Hz,1H), 2.78(d,J=20.0Hz,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] Embodiment 44

[0453] Synthesis of diisopropyl 2-((((((2S,5R)-2-diaminoformyl-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 1: Synthesis of compound 44

[0456] At room temperature, compound 43b (150 mg, 0.76 mmol) was dissolved in a mixed solvent of THF (10 mL) and N,N-dimethylpropylene urea (4 mL), cooled to -78°C in a nitrogen environment, and then sodium bis(trimethylsilyl)amide (0.42 mL, 2M tetrahydrofuran solution, 0.84 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78°C for 10 minutes. Compound 7d (502.8 mg, 1.52 mmol) was added dropwise. After the addition was complete, the mixture was gradually warmed to room temperature and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFireSunFireC18, 19×250mm, 10μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%~70%) to obtain 29 mg of compound 44, with a yield of 7.8%. LCMS (ESI) [M+H] + =492.2. 1H NMR (400MHz, CDCl3) δ7.12(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=5.4Hz,12H).

[0457] Embodiment 45

[0458] The "original drug" refers to the active drug released by the metabolism of the prodrug, and in this embodiment specifically refers to avibactam, relebactam, nacubactam, and dulobactam.

[0459] Test Example 1: Oral Bioavailability in Rats

[0460] Pharmacokinetic (PK) studies were conducted in male Sprague-Dawley (SD) rats with intravenous (IV) and oral (PO) administration of the parent drug (e.g., avibactam, relebactam, navibactam, dulobactam) and oral (PO) administration of the test compound. The oral bioavailability (%F) of the parent drug was determined by comparing the AUC after oral administration with the AUC after IV administration.

[0461] 1.1 Drug preparation

[0462] The original drug was dissolved in pH 7.5 phosphate buffered saline (PBS) to prepare a 0.4 mg / mL solution for intravenous injection; compounds 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 respectively prepared with 2% DMSO + 10% polyethylene glycol-15 hydroxystearate + 88% saline to prepare a 1.0 mg / mL solution for oral administration.

[0463] 1.2 Administration

[0464] The intravenous dose is 2 mg / kg and the oral dose is 10 mg / kg; the intravenous and oral dose volumes are 5 mL / kg and 10 mL / kg, respectively.

[0465] 1.3 Operation

[0466] Blood was collected by jugular sinus puncture at 0h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration, and heparin sodium was used for anticoagulation. Blood samples were placed on ice after collection, and plasma separation was completed within 30 minutes after collection (centrifugation conditions: 6800g, 6 minutes, 2-8°C), and the supernatant was removed for LC / MS / MS analysis to determine the original drug concentration.

[0467] 1.3 Pharmacokinetic parameter results

[0468] In male rats, after the compound and the original drug were converted to equimolar, the oral bioavailability of the original drug is shown in Table 1 below, where A represents (%F)>90%, B represents 50<(%F)≤90%, C represents 20<(%F)≤50%, and D represents (%F)≤20%.

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

[0470] Table 1. Pharmacokinetic parameters of 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 compounds in beagle dogs

[0473] Pharmacokinetic (PK) studies were conducted in male beagle dogs with parent drug (e.g., avibactam, relebactam, nacubactam, dulobactam) administered intravenously (IV) and orally (PO), and with test compound administered orally to determine parent drug concentration in plasma and oral bioavailability (%F) of test compound.

[0474] 2.1 Drug preparation

[0475] Avibactam was dissolved in pH 7.5 phosphate buffered saline (PBS) to prepare 2.0 mg / mL for intravenous injection; avibactam, compounds 31, 33, and 35 were respectively prepared into 2.0 mg / mL solutions with 2% DMSO+10% Solutol+88% Saline for oral administration.

[0476] 2.2 Administration

[0477] The intravenous dose is 10 mg / kg and the oral dose is 20 mg / kg; the intravenous and oral dose volumes are 5 mL / kg and 10 mL / kg, respectively.

[0478] 2.3 Operation

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

[0480] 2.4 Pharmacokinetic parameter results

[0481] In the beagle dog pharmacokinetic study, the oral bioavailability of the original drug after the compound and the original drug were converted to equimolar ratio is shown in Table 2 below, 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 of the present invention 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 compounds in beagle dogs

[0484] Compound Oral bioavailability (%F) Avibatan 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 Compound solution preparation

[0489] Weigh a certain amount of compound, add DMSO to prepare a 10 mM stock solution, take a certain volume of the stock solution, and dilute it with DMSO to a working solution with a concentration of 100 μM.

[0490] 3.3 Sample incubation

[0491] Take 2 μL of the working solution of 100 μM compound and add it to 198 μL of hepatocyte suspension, and pre-incubate in a 37°C incubator; at 0, 5, 15, 30, and 60 min, take the above mixture and add it to the stop solution to mix well; vortex vigorously for 10 min, centrifuge at 6000 rpm and 4°C for 20 min. Collect the supernatant and analyze it by LC-MS / MS.

[0492] Results

[0493] The experimental results show that all avibactam prodrugs of the present invention are completely converted into the original drug avibactam in rat hepatocytes, among which compounds 31, 33, and 35 can be quickly and completely converted into the original drug avibactam in rat hepatocytes, and compounds 37, 38, and 43 are converted and released into relebactam, nacubactam, and dulobactam in rat hepatocytes, respectively.

[0494] The metabolism data of the compounds of the present invention in rat hepatocytes are shown in Table 3; the data of the conversion and release of the original drug of the compounds of the present invention in rat hepatocytes are shown in Table 4.

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

[0496]

[0497] Note: BLOD means below the limit of detection;

[0498] Table 4. Data on the conversion and release of the original drug in rat hepatocytes

[0499]

Claims

1. A β-lactamase inhibitor selected from a compound having a structure as shown in Formula I or a pharmaceutically acceptable salt, isomer or deuterated product thereof: in, represents a single bond or a double bond; R1 is selected from H, R2 is selected from H, CH3; L1 is selected from unsubstituted or substituted with one or more R 1a Substituted -(CH2) m -, m is selected from 1, 2, 3, 4 or 5, R 1a selected from halogen, hydroxyl, cyano, NH2, substituted or unsubstituted C1-C8 hydrocarbon group, substituted or unsubstituted C1-C8 heteroalkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group, the substituents of C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group are independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; R3 and R4 are independently selected from H, halogen, hydroxyl, cyano, sulfonyl, Substituted or unsubstituted C1-C8 hydrocarbon group, substituted or unsubstituted C1-C8 heteroalkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group, the substituents of C1-C8 hydrocarbon group, C1-C8 heteroalkyl group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group and C5-C8 heteroaryl group are independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C C3-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-C10 heteroarylalkyl; R5 is selected from X1, X2 are independently selected from O, S, Se; R 6a , R 6b The substituents of the C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl and C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heterocycloalkyl, C3-C8 aryl and C5-C8 heteroaryl. C3-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl or R 7a , R 7b The substituents of the C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl and C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heterocycloalkyl, C3-C8 aryl and C5-C8 heteroaryl. 8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; R 8a , R 8b The substituents of the C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl and C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heterocycloalkyl, C3-C8 aryl and C5-C8 heteroaryl. 8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; R9 is selected from R 11 The substituents of the C1-C8 hydrocarbon group, C1-C8 alkoxy group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group are selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group, and C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group are selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group. C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; R 10 The substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, C5-C8 heteroaryl group, and C1-C8 hydrocarbon group are selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterohydrocarbon group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group, and the substituents of the C1-C8 hydrocarbon group, C3-C8 cycloalkyl group, C3-C8 heterocycloalkyl group, C6-C8 aryl group, and C5-C8 heteroaryl group are independently selected from halogen, hydroxyl, cyano, C1-C8 hydrocarbon group, C1-C8 heterohydrocarbon group, substituted or unsubstituted C3-C8 heterocycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl group, substituted or unsubstituted C5-C8 heteroaryl group. C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl or L2, L3, L4 are independently selected from unsubstituted or substituted with one or more R 1b Substituted -(CH2) n -, n is selected from 1, 2, 3, 4 or 5, R 1b The substituents of C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, NH2, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C5-C8 heteroaryl. The substituents of C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; Ring A is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing at least one atom selected from N, O or S, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C5-C8 heteroaryl, and the substituents of C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C8 aryl, and C5-C8 heteroaryl are independently selected from halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl C3-C8 cycloalkylalkyl, C3-C8 heterocycloalkylalkylalkyl, C6-C8 aryl, C5-C8 heteroaryl, C7-C10 arylalkyl, C5-C10 heteroarylalkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl; The substituents of the above-mentioned substituted C3-C8 cycloalkyl, substituted C3-C8 heterocycloalkyl, substituted C3-C8 cycloalkylalkyl, substituted C3-C8 heterocycloalkylalkyl, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 arylalkyl, substituted C5-C10 heteroarylalkyl are each independently selected from halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamido, sulfenimide, urea, guanidino; But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from 2. The β-lactamase inhibitor according to claim 1, characterized in that: represents a single bond or a double bond; R1 is selected from H, R2 is selected from H, CH3; L1 is selected from -CH2-; R3 is selected from methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl; R4 is selected from methyl, X1 is selected from O, S; R 6a is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7a is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L2 is selected from -CH2-, R 8a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R5 is selected from R9 is selected from X2 is selected from O, S; R 6b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L3 is selected from -CH2-, R 8b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; L4 is selected from -CH2-, R 11 Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R5 is selected from 3. The β-lactamase inhibitor according to claim 3, characterized in that: represents a single bond or a double bond; R1 is selected from H, R2 is selected from H, CH3; L1 is selected from -CH2-; R3 is selected from methyl, phenyl, benzyl, cyclopropyl, cyclopropylmethyl; R4 is selected from methyl, X1 is selected from O; R 6a is selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl; L2 is selected from -CH2-, R 8a Selected from isopropyl and tert-butyl; R5 is selected from R9 is selected from X2 is selected from O; R 6b is selected from methyl, ethyl, isopropyl; R 7b isopropyl; L3 is selected from -CH2-, R 8b isopropyl, tert-butyl; L4 is selected from -CH2-, R 11 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isopropoxy; But not included: represents a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, R4 is selected from R4 is selected from 4. β-lactamase inhibitors selected from compounds having a structure as shown in Formula II or pharmaceutically acceptable salts and isomers thereof: in, R3, R4, and R5 are as described in any one of claims 1 to 3.

5. A β-lactamase inhibitor selected from a compound having a structure as shown in Formula III or a pharmaceutically acceptable salt, isomer, or deuterated product thereof: in, R3, R4, and R5 are as described in any one of claims 1 to 3.

6. A β-lactamase inhibitor selected from a compound having a structure as shown in Formula IV or a pharmaceutically acceptable salt, isomer, or deuterated product thereof: in, R3, R4, and R5 are as described in any one of claims 1 to 3.

7. A β-lactamase inhibitor selected from a compound having a structure as shown in Formula V or a pharmaceutically acceptable salt, isomer, or deuterated product thereof: in, R3, R4, and R5 are as described in any one of claims 1 to 3.

8. A β-lactamase inhibitor selected from the following compounds or pharmaceutically acceptable salts or isomers or deuterated derivatives thereof:

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the β-lactamase inhibitor according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or an isomer or deuterated product thereof, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises an antibiotic; further preferably, the antibiotic is a β-lactam antibiotic, and the β-lactam antibiotic is a penicillin, cephalosporin, cephamycin and carbapenem antibiotic.

10. Use of the β-lactamase inhibitor according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a β-lactamase inhibitor, or in the preparation of a medicament for treating diseases related to bacterial infection; preferably, the bacteria are bacteria capable of producing β-lactamase; more preferably, the bacteria are bacteria of the genus Enterobacter, Citrobacter, Prufidenella, Serratia marcescens or Morganella.

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