Diazabicyclo beta-lactamase inhibitor and application thereof

Abstract

The invention discloses a beta-lactamase inhibitor, which is selected from a compound with a structure shown as a formula I or pharmaceutically acceptable salts, isomers or deuterated substances 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.

Description

[0001] This application is a divisional application of the invention entitled "Diazabicyclic β-lactamase inhibitor and its application", filed on January 6, 2025, with application number 2025100152873. Technical Field

[0002] This invention belongs to the field of medicinal chemistry and relates to novel diazabicyclic β-lactamase inhibitors, pharmaceutical compositions thereof, and their use in treating bacterial infections. Background Technology

[0003] The rapid development of antibiotics has been of great significance in the history of modern medicine. Antibiotics can effectively treat infectious diseases caused by bacteria, bringing great convenience to clinical practice. However, the irrational use and even abuse of antibiotics has accelerated the development of bacterial resistance, posing a significant challenge to human health. β-lactam antibiotics, as one of the oldest, most widely used, and most frequently used antibiotics in clinical practice, have also encountered increasingly serious resistance problems.

[0004] Bacterial β-lactamases hydrolyze antibiotics with a β-lactam ring structure, rendering them inactive. This is the most common mechanism of bacterial resistance to β-lactam antibiotics. Based on differences in the amino acid sequence of their molecular structure, β-lactamases can be mainly divided into two categories: one is the A, C, and D type, which uses serine as the active site; the other is the type that uses metal ions (especially Zn). 2＋ Metalloenzymes with ) as active sites.

[0005] In 1976, the first β-lactamase preparation (clavulanic acid) was discovered and later commercialized as an oral / intravenous medication in combination with a β-lactam antibiotic (amoxicillin). β-lactamase inhibitors, while lacking significant antibiotic activity on their own, protect β-lactam antibiotics from degradation by microbially produced enzymes (β-lactamases). Since the 1980s, the β-lactamase inhibitor / antibiotic combination has become a standard part of treatment.

[0006] In the mid-1990s, a new and important non-β-lactamase inhibitor, avibactam, was discovered. Belonging to the diazabicyclic class of compounds (DBOs), it is a reversible β-lactamase inhibitor. Compared to classic β-lactamase inhibitors (such as clavulanic acid, sulbactam, and tazobactam), avibactam possesses long-lasting action, reversible covalent binding to the enzyme, and does not induce β-lactamase production. In recent years, medicinal chemists have continued their in-depth research based on avibactam, successfully discovering a series of diazabicyclic derivatives such as dulobactam, relebactam, and nacubactam, all of which exhibit similar β-lactamase inhibitory activity to avibactam. However, because diazabicyclic β-lactamase inhibitors contain sulfonic acid groups in their 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 limits the clinical use of this type of β-lactamase inhibitor.

[0007]

[0008] A prodrug is a compound that has no biological activity itself, but can release a pharmacologically active metabolite or original drug through chemical or enzymatic conversion in the body. Prodrug design is a commonly used and effective strategy to improve the lipid solubility of compounds, increase oral absorption, and enhance bioavailability.

[0009] Therefore, designing prodrugs for diazabicyclic β-lactamase inhibitors to improve their oral bioavailability and enable oral administration has significant clinical value. Summary of the Invention

[0010] The purpose of this 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, which can significantly improve the oral bioavailability of the diazabicyclic β-lactamase inhibitor.

[0011] The objective of this invention is achieved through the following technical solution:

[0012] β-lactamase inhibitors are selected from compounds with the structure shown in Formula I or their pharmaceutically acceptable salts, isomers or deuterated derivatives:

[0013]

[0014] I

[0015] in, Indicates a single bond or a double bond;

[0016] R1 is selected from H, , ;

[0017] R2 is selected from H or CH3;

[0018] L1 is selected from those that are not substituted or are replaced by one or more R. 1a Substituted -(CH2) m -, m is selected from 1, 2, 3, 4 or 5, R 1a The substituents are selected from halogens, hydroxyl groups, cyano groups, NH2, substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups containing at least one N, O, or S atom, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, and C1-C8 hydrocarbon groups. C1-C8 heteroalkyl group, C3-C8 cyclic alkyl group, C3-C8 heterocyclic alkyl group, C3-C8 cyclic alkyl hydrocarbon group, C3-C8 heterocyclic alkyl hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic alkyl group, substituted C3-C8 cyclic alkyl hydrocarbon group, substituted C3-C8 heterocyclic alkyl hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0019] R3 and R4 are independently selected from H, halogen, hydroxyl, cyano, sulfonyl, and so on. , , , , The substituents of C1-C8 hydrocarbon groups (substituted or unsubstituted), C1-C8 heterocyclic hydrocarbon groups (substituted or unsubstituted), C3-C8 cyclic hydrocarbon groups (substituted or unsubstituted), C3-C8 heterocyclic hydrocarbon groups (substituted or unsubstituted) containing at least one atom selected from N, O, or S, C6-C8 aryl groups (substituted or unsubstituted), and C5-C8 heteroaryl groups (substituted or unsubstituted) can be independently selected from halogens, hydroxyl groups, cyano groups, and C1-C8 hydrocarbon groups. C1-C8 heteroalkyl group, C3-C8 cyclic alkyl group, C3-C8 heterocyclic alkyl group, C3-C8 cyclic alkyl hydrocarbon group, C3-C8 heterocyclic alkyl hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-10 aryl hydrocarbon group, C5-10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic alkyl group, substituted C3-C8 cyclic alkyl hydrocarbon group, substituted C3-8 heterocyclic alkyl hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0020] R5 is selected from , , , , ;

[0021] X1 and X2 are independently selected from O, S, and Se, respectively; R 6a R 6b The substituents are independently selected from substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, C1-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups. C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group or ;

[0022] R7a R 7b The substituents are independently selected from substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, C1-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups. C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0023] R 8a R 8b The substituents are independently selected from substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, C1-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups. C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0024] R9 is selected from ;R 11The substituents selected from substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 alkoxy groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups, can be independently selected from halogens, hydroxyl groups, cyano groups, and C1-C8 heteroaryl groups. -C8 hydrocarbon group, C1-C8 heterohydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon hydrocarbon group, C3-C8 heterocyclic hydrocarbon hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0025] R 10 The substituents are selected from substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C1-C8 hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, and C1-C8 heteroaryl groups. Hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group or ;

[0026] L2, L3, and L4 are each independently selected from unsubstituted or R-type molecules. 1b Substituted -(CH2) n -, n is selected from 1, 2, 3, 4 or 5, R 1bThe substituents are selected from halogens, hydroxyl groups, cyano groups, NH2, substituted or unsubstituted C1-C8 hydrocarbon groups, substituted or unsubstituted C1-C8 heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 cyclic hydrocarbon groups containing at least one N, O, or S atom, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents for C1-C8 hydrocarbon groups, C1-C8 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, C1-C8 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 cyclic hydrocarbon groups. Heteroaryl, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl, substituted C5-C8 heteroaryl, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0027] Ring A is selected from substituted or unsubstituted C3-C8 cyclic hydrocarbon groups, substituted or unsubstituted C3-C8 heterocyclic hydrocarbon groups containing at least one atom selected from N, O, or S, substituted or unsubstituted C6-C8 aryl groups, and substituted or unsubstituted C5-C8 heteroaryl groups. The substituents of the C3-C8 cyclic hydrocarbon groups, C3-C8 heterocyclic hydrocarbon groups, C6-C8 aryl groups, and C5-C8 heteroaryl groups can be independently selected from halogens, hydroxyl groups, cyano groups, C1-C8 hydrocarbon groups, C1-C8 heterocyclic hydrocarbon groups, C3-C8 cyclic hydrocarbon groups, and C3-C8 heterocyclic hydrocarbon groups. Hydrocarbon group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic hydrocarbon group, C6-C8 aryl group, C5-C8 heteroaryl group, C7-C10 aryl hydrocarbon group, C5-C10 heteroaryl hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, substituted C5-C10 heteroaryl hydrocarbon group;

[0028] The substituents of the aforementioned substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C3-C8 cyclic hydrocarbon group, substituted C3-C8 heterocyclic hydrocarbon group, substituted C6-C8 aryl group, substituted C5-C8 heteroaryl group, substituted C7-C10 aryl hydrocarbon group, and substituted C5-C10 heteroaryl hydrocarbon group are each independently selected from halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, acyl, sulfonyl, sulfonamide, sulfinimide, urea, and guanidine.

[0029] But not including: Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R5 is selected from ; Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R5 is selected from ; Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R5 is selected from .

[0030] Further preferred, Indicates a single bond or a double bond;

[0031] R1 is selected from H, , ;

[0032] R2 is selected from H or CH3;

[0033] L1 is selected from -CH2-;

[0034] R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl;

[0035] R4 is selected from methyl, , , , X1 is selected from O, S; R 6a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7a 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, and benzyl;

[0036] R5 is selected from , , , R9 is selected from X2 is selected from O, S; R 6b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl; R 7b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L3 is selected from -CH2-, R 8bSelected 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, and benzyl;

[0037] But not including: Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R5 is selected from ; Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R5 is selected from .

[0038] Further optimized Indicates a single bond or a double bond;

[0039] R1 is selected from H, , ;

[0040] R2 is selected from H or CH3;

[0041] L1 is selected from -CH2-;

[0042] R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl;

[0043] R4 is selected from methyl, , , X1 is selected from O;R 6a Selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl; L2 is selected from -CH2-, R 8a Selected from isopropyl and tert-butyl;

[0044] R5 is selected from , , , R9 is selected from X2 is selected from O;R 6b Selected from methyl, ethyl, and isopropyl; R 7b Selected from isopropyl; L3 is selected from -CH2-, R 8b Selected from isopropyl and tert-butyl; L4 is selected from -CH2- and R 11 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and isopropoxy;

[0045] But not including: Indicates a single bond, R1 is selected from H, R2 is selected from H, L1 is selected from -CH2-, R3 is selected from CH3, and R4 is selected from... R4 is selected from .

[0046] As a further preferred embodiment of the β-lactamase inhibitor described in this invention, the β-lactamase inhibitor is selected from compounds with structures as shown in Formula II or their pharmaceutically acceptable salts or isomers:

[0047]

[0048] II

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

[0050] As a further preferred embodiment of the β-lactamase inhibitor described in this invention, the β-lactamase inhibitor is selected from compounds with structures as shown in Formula III or their pharmaceutically acceptable salts, isomers, or deuterated derivatives:

[0051]

[0052] III

[0053] R3, R4, and R5 are as described above.

[0054] As a further preferred embodiment of the β-lactamase inhibitor described in this invention, the β-lactamase inhibitor is selected from compounds with structures as shown in Formula IV or their pharmaceutically acceptable salts, isomers, or deuterated derivatives:

[0055]

[0056] IV

[0057] R3, R4, and R5 are as described above.

[0058] As a further preferred embodiment of the β-lactamase inhibitor described in this invention, the β-lactamase inhibitor is selected from compounds with structures as shown in Formula V or their pharmaceutically acceptable salts, isomers, or deuterated derivatives:

[0059]

[0060] V

[0061] R3, R4, and R5 are as described above.

[0062] Specifically, the β-lactamase inhibitors of this invention are selected from the following compounds or their pharmaceutically acceptable salts or isomers, deuterated derivatives:

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] Terminology Explanation

[0075] "Hydrocarbon group" refers to a saturated or unsaturated, branched or straight-chain monovalent hydrocarbon group resulting from the removal of a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of hydrocarbon groups include: methyl; ethyls, such as ethane, vinyl, and ethynyl; propyls, such as propyl-1-yl, propyl-2-yl, propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), etc. The term "hydrocarbon group" specifically includes groups with any degree or level of saturation, i.e., groups having only carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having combinations of carbon-carbon single, double, and triple bonds. The terms alkyl, alkenyl, and ynyl are used when a specific level of saturation is desired.

[0076] "Aryl" refers to a monovalent aromatic hydrocarbon group resulting from the removal of a hydrogen atom from a single carbon atom in a parent aromatic ring system. Aryl groups include 5- and 6-membered carbocyclic aromatic rings, such as benzene; bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthalene, indene, and tetrahydronaphthalene; and tricyclic systems, such as fluorene, where at least one ring is a carbocyclic and aromatic. Aryl groups also include polycyclic systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, a cycloalkyl ring, or a heterocyclic alkyl ring. For example, aryl groups include a phenyl ring fused to a 5- to 7-membered heterocyclic alkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic systems where only one ring is a carbocyclic aromatic ring, the radical carbon atom may be located on either the carbocyclic aromatic ring or the heterocyclic alkyl ring. Examples of aryl groups include those derived from acethracene, acenaphthene, indene, indene, naphthalene, octylbenzene, octylphenene, cyclooctadiene, olebenzene, pentacene, cyclopentadiene, dibenzophenanthrene, perylene, phenaene, etc. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined separately herein.

[0077] "Arylalkyl group" refers to a non-cyclic hydrocarbon group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Examples of arylalkyl groups include: benzyl, 2-phenylethyl-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, 2-naphthyl

[0078] Arylvinyl-1-yl, naphthylbenzyl, and 2-naphthophenyl-1-yl. The term arylalkyl is used when a specific hydrocarbon moiety is intended.

[0079] alkyl, aryl-alkenyl or aryl-ynyl.

[0080] "Cyclic hydrocarbon group" refers to a saturated or partially unsaturated cyclic hydrocarbon group, which can also be a spiro ring or a bridged ring.

[0081] "Cycloalkylalkyl group" refers to a non-cyclic hydrocarbon group in which a hydrogen atom bonded to a carbon atom is replaced by a cycloalkyl group as defined herein. For the specific hydrocarbon moiety, the terms cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylynyl are used.

[0082] A "heteroalkyl group" refers to a hydrocarbon group in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced by the same or different heteroatoms. Examples of heteroatoms in heteroalkyl groups include: -O-, -S-, -NH-, -N (-CH3)-, -SO-, and -SO2-.

[0083] "Halogen" refers to fluorine, chlorine, bromine, or iodine groups.

[0084] "Heteroarylene hydrocarbon group" refers to an arylene hydrocarbon group in which one carbon atom (and some associated hydrogen atoms) is replaced by a heteroatom.

[0085] "Heterocyclic hydrocarbon group" itself or as part of another substituent refers to a saturated or unsaturated cyclic hydrocarbon group in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or different heterocyclic atoms; or it refers to a parent aromatic ring system in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or different heteroatoms, thereby violating Hückel's rule, and can also be a spiroheterocycle or a bridged heterocycle.

[0086] "Heterocyclic hydrocarbon group" refers to a cyclic hydrocarbon group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cyclic hydrocarbon ring are replaced by the same or different heteroatoms.

[0087] "Sulfonyl" refers to a group containing -S(O)(O)-. Examples of sulfonyl groups include p-toluenesulfonyl, sulfonylimide, and methanesulfonyl.

[0088] Another object of the present invention is to provide a pharmaceutical composition comprising the β-lactamase inhibitor described herein or a pharmaceutically acceptable salt thereof or an isomer or deuterated thereof, and a pharmaceutically acceptable carrier.

[0089] The pharmaceutical composition further comprises an antibiotic; furthermore, the antibiotic is a β-lactam antibiotic, such as penicillins, cephalosporins, cephamycins, and carbapenems.

[0090] The pharmaceutical composition is in the form of an oral preparation; the oral preparation includes solid dosage forms and liquid dosage forms 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.

[0091] The pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that the components in the composition can interact with and blend with the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier components 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, glycerin, mannitol, sorbitol, etc.), emulsifiers, fillers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0092] Another object of the present invention is to provide the use of the β-lactamase inhibitor or the pharmaceutical composition thereof in the preparation of β-lactamase inhibitors.

[0093] Another object of the present invention is to provide the use of the β-lactamase inhibitor or the pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to bacterial infections.

[0094] The bacteria mentioned are bacteria capable of producing β-lactamases, including but not limited to Enterobacter, Citrobacter, Profedenella, Serratia, or Morganella.

[0095] The beneficial effects of this invention are:

[0096] This invention relates to a β-lactamase inhibitor that, through the action of biological enzymes in vivo, rapidly and completely releases its active metabolites, such as avibactam, dulobactam, relebactam, and nakubactam, which are diazabicyclic β-lactamase inhibitors. It also exhibits rapid onset of action, effectively improving the oral bioavailability of these β-lactamase inhibitors and enabling oral administration, thus solving the problem of low oral bioavailability of diazabicyclic β-lactamase inhibitors. This invention's β-lactamase inhibitor is suitable for oral administration and has a broad spectrum, effectively addressing the lack of broad-spectrum oral β-lactamase inhibitors in clinical practice and overcoming the narrow antibacterial spectrum of existing oral β-lactamase inhibitors. Detailed Implementation

[0097] Example 1

[0098] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid (neopentyloxy)methyl ester (compound 1)

[0099]

[0100]

[0101] Step 1: Synthesis of Compound 1b

[0102] Compound 1a (20.0 g, 72.6 mmol) was dissolved in ethyl acetate (200 mL) at room temperature, followed by the addition of 10% palladium on carbon (5.60 g). The mixture was purged three times with hydrogen, and the reaction was carried out at room temperature under a hydrogen atmosphere for 3 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness to give 13.0 g of compound 1b, with a yield of 96.6%. LCMS (ESI): [M+H] + =186.2. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.49 – 7.15 (m, 2H), 3.64 (d, J = 7.2 Hz, 1H), 3.17 (d, J = 3.2 Hz, 1H), 3.00 – 2.99 (m, 1H), 2.87(d, J = 11.6 Hz, 1H), 2.10 – 2.07 (m, 1H), 2.10 – 2.05 (m, 1H), 1.79 – 1.67(m, 1H), 1.66 – 1.55 (m, 1H).

[0103] Step 2: Synthesis of Compound 1d

[0104] 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), methyl tert-pentanoate (15.2 g, 101.6 mmol), and potassium iodide (7.0 g, 42.3 mmol) were added at room temperature, and the reaction was carried out at 45 °C for 16 h. After the reaction was complete, 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 over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate == 8 / 1 V / V) to give 1.0 g of compound 1d, with a yield of 5.1%. 1 H NMR (400 MHz, CDCl3) δ 5.78 (s, 2H), 3.57 (s,2H), 1.21 – 1.20 (m, 15H).

[0105] Step 3: Synthesis of compound 1e

[0106] At room temperature, sulfonyl chloride (628 mg, 4.66 mmol) was dissolved in diethyl ether (9 mL). The mixture was purged three times with argon gas 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 diethyl ether (0.9 mL) was slowly added dropwise. The mixture was stirred at -78 °C for 2 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 500 mg of compound 1e, with a yield of 38.9%. 1H NMR (400 MHz, CDCl3) δ 5.80 (s, 2H), 4.50 (s, 2H), 1.33 (s, 6H), 1.21 (s, 9H).

[0107] Step 4: Synthesis of Compound 1

[0108] At room temperature, compound 1b (100 mg, 0.54 mmol) was dissolved in a mixed solvent of ultradry tetrahydrofuran (1 mL) and N,N-dimethylpropenylurea (1 mL). Under nitrogen protection, sodium bis(trimethylsilyl)amino (0.3 mL, 2M tetrahydrofuran solution, 0.59 mmol) was added at -78 °C. The reaction was continued with stirring at -78 °C for 10 min, and then compound 1e (270 mg, 0.81 mmol) was slowly added. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was allowed to proceed for 2 h at room temperature. After the reaction was complete, 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 C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 19.32 mg of compound 1, yield 7.5%. LCMS (ESI): [M+H] + = 480.3. 1 H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.81 (d, J =5.6 Hz, 1H), 5.77 (d, J = 5.6 Hz, 1H), 5.52 (s, 1H), 4.74 (d, J = 9.2 Hz,1H), 4.59 (d, J = 9.2 Hz, 1H), 4.17 (d, J = 2.2 Hz, 1H), 4.05 (d, J = 7.1 Hz,1H), 3.35 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.45 (dd, J =14.8, 6.7 Hz, 1H), 2.15 – 2.13 (m, 1H), 1.91 – 1.88 (m, 2H), 1.29 (d, J = 5.3Hz, 6H), 1.20 (s, 9H).

[0109] Example 2

[0110] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid (isobutyryloxy)methyl ester (compound 2)

[0111]

[0112] The synthesis method is the same as for compound 1, except that chloromethyl isobutyrate is used to replace chloromethyl pivalate in an equivalent amount. LCMS (ESI): [M+H] + = 466.4. 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 5.81 (d, J = 5.6 Hz,1H), 5.77 (d, J = 5.6 Hz, 1H), 5.59 (s, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.59(d, J = 9.2 Hz, 1H), 4.19 – 4.15 (m, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.38 –3.31 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.66 – 2.55 (m, 1H), 2.50 – 2.40 (m,1H), 2.21 – 2.12 (m, 1H), 2.01 – 1.91 (m, 1H), 1.89 – 1.81 (m, 1H), 1.30 (d,J = 5.6 Hz, 6H), 1.18 (d, J = 5.6 Hz, 6H).

[0113] Example 3

[0114] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid acetoxymethyl ester (compound 3)

[0115]

[0116] The synthetic method is the same as for compound 1, except that chloromethyl acetate is substituted in equal amounts for chloromethyl pivalate. LCMS (ESI): [M+H] + = 438.3. 1H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.80 (d, J = 5.6 Hz, 1H), 5.76 (d, J = 5.6 Hz, 1H), 5.51 (s, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.59 (d, J= 9.2 Hz, 1H), 4.17 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.35 (d, J= 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.49 – 2.41 (m, 1H), 2.21 – 2.13(m, 1H), 2.12 (s, 3H), 2.00 – 1.90 (m, 1H), 1.89 – 1.80 (m, 1H), 1.30 (d, J =4.8 Hz, 6H).

[0117] Example 4

[0118] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid-1-(isobutyryloxy)ethyl ester (compound 4)

[0119]

[0120] The synthetic method is the same as for compound 1, except that methyl tervastatin is replaced by an equivalent amount of (1-chloroethyl) isobutyrate. LCMS (ESI): [M+H] + = 480.5. 1H NMR (400 MHz, CDCl3) δ 6.92 – 6.80 (m, 1H), 6.50 (s,1H), 5.55 (s, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.64 – 4.55 (m, 1H), 4.17 (s,1H), 4.05 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 12.4 Hz, 1H), 3.02 (d, J = 10.4Hz, 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 = 9.2 Hz, 3H), 1.30 – 1.24 (m, 6H), 1.17 (dd, J =7.2, 2.0 Hz, 6H).

[0121] Example 5

[0122] Synthesis of (1R,2R)-2-(1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)cyclopropane-1-carboxylic acid ethyl ester (compound 5)

[0123]

[0124]

[0125] Step 1: Synthesis of compound 5b

[0126] Compound 5a (6.0 g, 52.57 mmol) was dissolved in diethyl ether (60 mL) at 0 °C, and then lithium aluminum hydride (23.2 mL, 57.8 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and sodium sulfate decahydrate (20.0 g) was slowly added. The mixture was filtered, and the filter cake was washed with diethyl ether (100 mL). The organic phases were combined and concentrated to dryness at 0 °C to give 3.9 g of compound 5b, with a yield of 74.1%. 1 H NMR (400 MHz, CDCl3) δ 5.83 – 5.70 (m, 1H), 5.15 – 5.00 (m, 2H), 3.34 (d, J = 6.4 Hz, 2H), 1.02 (s, 6H).

[0127] Step 2: Synthesis of compound 5c

[0128] Compound 5b (3.9 g, 38.94 mmol) was dissolved in tetrahydrofuran (39 mL) at room temperature. Sodium hydride (2.34 g, 58.41 mmol) was added under ice bath conditions, and the reaction was maintained on ice for 30 minutes. Then, benzyl bromide (9.99 g, 58.41 mmol) was added, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 5.5 g of compound 5c, with a yield of 74.2%. 1 H NMR (400 MHz, CDCl3) δ 7.39 –7.17 (m, 5H), 5.88 (dd, J = 17.6, 10.8 Hz, 1H), 5.09 – 4.89 (m, 2H), 4.52 (s,2H), 3.20 (s, 2H), 1.04 (s, 6H).

[0129] Step 3: Synthesis of Compound 5D

[0130] Compound 5c (4.2 g, 22.07 mmol) was dissolved in 1,2-dichloroethane (42 mL) at room temperature. Under nitrogen protection, the mixture was placed in an ice bath and cooled with stirring. Rhodium(II) dimer acetate (97 mg, 0.22 mmol) was added, followed by the slow dropwise addition of ethyl 2-diazoacetate (4.74 g, 66.21 mmol). After the addition was complete, the reaction mixture was heated to 45 °C and the reaction was continued for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (100 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 rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 1.0 g of compound 5d, with a yield of 16.4%. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.24 (m, 5H), 4.51 (s, 2H), 4.13 – 4.07 (m,2H), 3.22 – 3.19 (m, 2H), 1.59 – 1.52 (m, 1H), 1.50 – 1.43 (m, 1H), 1.27 –1.21 (m, 3H), 0.96 – 0.92 (m, 1H), 0.90 – 0.85 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H).

[0131] Step 4: Synthesis of compound 5e

[0132] Compound 5d (1.0 g, 3.62 mmol) was dissolved in methanol (10 mL) at room temperature, followed by the addition of 10% palladium on carbon (300 mg). The mixture was purged three times with hydrogen gas, and stirred for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 450 mg of crude compound 5e, which was directly used for the next reaction. LCMS (ESI) [M+H] + = 187.0.

[0133] Step 5: Synthesis of compound 5f

[0134] At room temperature, sulfonyl chloride (490 mg, 3.63 mmol) was dissolved in ether (10 mL), and the mixture was purged three times with argon gas and stirred at -78 °C for 10 min. A solution of compound 5e (450 mg, 2.42 mmol) and pyridine (287 mg, 3.63 mmol) in ether (1.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 500 mg of crude compound 5f, which was directly used in the next reaction step.

[0135] Step Six: Preparation of Compound 5

[0136] 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-dimethylpropenylurea (2.4 mL), and the mixture was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amino (0.82 mL, 2 M tetrahydrofuran solution, 1.94 mmol) was added dropwise, and the mixture was kept at -78 °C for 10 minutes. Then, compound 5f (500 mg, 1.76 mmol) was added, and the mixture was kept at -78 °C with stirring for 10 minutes. The mixture was then gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was complete, 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 brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was subjected to prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60%–70%) to give 68.47 mg of compound 5, with a yield of 8.97%. LCMS (ESI): [M+H] + = 434.2. 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 5.50 (s, 1H), 4.57 (d, J= 8.8 Hz, 1H), 4.27 (dd, J = 9.2, 3.2 Hz, 1H), 4.20 – 4.15 (m, 1H), 4.15 –4.09 (m, 2H), 4.05 (d, J = 7.6 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.01 (d, J= 12.0 Hz, 1H), 2.48 – 2.43 (m, 1H), 2.21 – 2.13 (m, 1H), 1.99 – 1.80 (m,2H), 1.48 – 1.41 (m, 1H), 1.30 – 1.23 (m, 4H), 1.14 – 1.06 (m, 1H), 0.93 –0.88 (m, 7H).

[0137] Example 6

[0138] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-methyl-2-p-toluenesulfonylpropionate isopropyl ester (compound 6)

[0139]

[0140] Step 1: Synthesis of compound 6b

[0141] 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. After the addition was complete, the mixture was gradually brought to room temperature and the reaction continued for 16 hours. At the end of the reaction, water (50 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 15.0 g of compound 6b, with a yield of 78.9%. LCMS (ESI): [M+H] + = 195.2. 1 H NMR (400 MHz, CDCl3) δ 5.15 – 4.99 (m,1H), 4.33 (q, J = 6.8 Hz, 1H), 1.81 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.4 Hz,6H).

[0142] Step 2: Synthesis of compound 6c

[0143] 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) at room temperature. Then, tetrabutylammonium iodide (666 mg, 1.80 mmol) and sodium 4-methylbenzenesulfinate (6.88 g, 38.66 mmol) were added sequentially, and the mixture was heated to 80 °C for 16 hours. After the reaction was complete, water (50 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to give 5.6 g of compound 6c, yield 80.6%. 1H NMR(400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 5.04 –4.89 (m, 1H), 3.99 (q, J = 7.2 Hz, 1H), 2.44 (s, 3H), 1.56 (d, J = 8.4 Hz, 3H), 1.22 – 1.08 (m, 6H).

[0144] Step 3: Synthesis of compound 6d

[0145] Compound 6c (1.0 g, 3.70 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (3 mL) at room temperature. 37% formaldehyde aqueous solution (330 mg, 4.07 mmol) and sodium bicarbonate (31 mg, 0.37 mmol) were added sequentially at 0 °C, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, water (50 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 1.1 g of compound 6d, with a yield of 82.7%. LCMS (ESI): [M+H] + = 301.2.

[0146] Step 4: Synthesis of compound 6e

[0147] At room temperature, sulfonyl chloride (450 mg, 3.33 mmol) was dissolved in diethyl ether (5 mL). The mixture was purged three times with argon gas, and the temperature was lowered to -78 °C with stirring for 10 min. A solution of compound 6d (500 mg, 1.67 mmol) and pyridine (264 mg, 3.33 mmol) in diethyl ether (0.5 mL) was slowly added dropwise at -78 °C. After the addition was complete, the temperature was gradually raised to room temperature, and the reaction was continued with stirring at room temperature for 4 h. After the reaction was complete, 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 reaction.

[0148] Step 5: Synthesis of Compound 6

[0149] Compound 1b (310 mg, 1.67 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (6 mL) and N,N-dimethylpropenylurea (2.4 mL) at room temperature. The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (0.92 mL, 2 M tetrahydrofuran solution, 1.84 mmol) was added dropwise. After the addition was complete, the temperature was maintained at -78 °C for 10 minutes, and then compound 6e (667 mg, 1.67 mmol) was slowly added. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was allowed to proceed for 2 hours. At the end of the reaction, water (100 mL) was added to quench the reaction mixture, and the solution 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 purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 55%–70%) to give 75.46 mg of compound 6, yield 8.24%. LCMS (ESI): [M+H] + = 548.4. 1 H NMR (400 MHz, CDCl3) δ7.83 – 7.66 (m, 2H), 7.37 (d, J = 9.2 Hz, 2H), 6.46 (s, 1H), 5.56 (s, 1H),5.29 – 4.81 (m, 3H), 4.15 (s, 1H), 4.07 (t, J = 6.8 Hz, 1H), 3.30 (t, J =10.8 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.54 – 2.39 (m, 4H), 2.15 (d, J =10.0 Hz, 1H), 1.99 – 1.83 (m, 2H), 1.66 (d, J = 13.2 Hz, 3H), 1.24 (t, J =6.0 Hz, 6H).

[0150] Example 7

[0151] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-carbonyl-1,6-diazabicyclo[3.2.1]octane-6-yl)oxo)sulfonyl)oxo)methyl)-2-methylmalonic acid diisopropyl ester (compound 7)

[0152]

[0153] Step 1: Synthesis of compound 7b

[0154] Compound 7a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at room temperature, followed by the addition of isopropanol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol). The mixture was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added. The reaction was continued at room temperature for 16 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 14.0 g of compound 7b, with a yield of 81.8%. 1 H NMR (400 MHz, CDCl3) δ 5.14 – 5.00(m, 2H), 3.83 (q, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.30 – 1.17 (m,12H).

[0155] Step 2: Synthesis of compound 7c

[0156] Compound 7b (7.0 g, 34.61 mmol) was dissolved in a mixed solvent of ethanol (35 mL) and water (35 mL) at room temperature. 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 complete, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 3 / 1 V / V) to give 3.7 g of compound 7c, with a yield of 46.1%. 1 H NMR (400 MHz, CDCl3) δ 5.13 – 5.02 (m, 2H), 3.83 (d, J = 7.2 Hz, 2H), 1.42 (s, 3H), 1.30 – 1.19 (m, 12H).

[0157] Step 3: Synthesis of compound 7d

[0158] At room temperature, sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in diethyl ether (10 mL). The mixture was purged three times with argon. A solution of compound 7c (1.0 g, 4.31 mmol) and pyridine (375 mg, 4.74 mmol, 1.1 equivalents) in diethyl ether (1 mL) was added at -78 °C. The mixture was stirred at -78 °C for 0.5 hours and then gradually raised 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 give 1.0 g of compound 7d, with a yield of 96.4%. 1 H NMR (400 MHz, CDCl3) δ 5.12 – 5.06 (m, 2H), 4.79 (s, 2H), 1.57 (s, 3H), 1.26 (d,J = 7.2 Hz, 12H).

[0159] Step 4: Synthesis of Compound 7

[0160] At room temperature, compound 1b (300 mg, 1.60 mmol) was dissolved in ultra-dry tetrahydrofuran (6 mL) and N,N-dimethylpropenylurea (2.2 mL). Under argon protection, sodium bis(trimethylsilyl)amino (0.9 mL, 2M tetrahydrofuran solution, 1.8 mmol) was added to the mixture at -78 °C. After the addition was complete, the mixture was stirred for 10 min at -78 °C. Then, compound 7d (642 mg, 1.95 mmol) was slowly added to the mixture. After the addition was complete, the reaction temperature was gradually raised to room temperature, and the reaction continued for 2 h at room temperature. Upon completion of the reaction, 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. The organic phases were 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 C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 95.26 mg of compound 7, yield 12.2%. LCMS (ESI): [M+H] + = 480.3. 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H),5.68 (s, 1H), 5.09 – 5.06 (m, 3H), 4.90 (d, J = 9.4 Hz, 1H), 4.16 (s, 1H),4.06 (d, J = 7.4 Hz, 1H), 3.32 (d, J = 12.1 Hz, 1H), 3.02 (d, J = 12.1 Hz,1H), 2.46 – 2.41 (m, 1H), 2.24 – 2.12 (m, 1H), 2.05 – 1.78 (m, 2H), 1.53 (s,3H), 1.26 (d, J = 5.4 Hz, 12H).

[0161] Example 8

[0162] Synthesis of dimethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid dimethyl ester (compound 8)

[0163]

[0164] The synthetic method is similar to that of compound 7, except that isopropanol is replaced by an equimolar amount of methanol. LCMS (ESI): [M+H] + =424.2. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.57 (s, 1H), 5.04 (d, J = 9.6Hz, 1H), 4.89 (d, J = 9.6 Hz, 1H), 4.16 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.2Hz, 1H), 3.78 (d, J = 5.6 Hz, 6H), 3.33 (d, J = 12.0 Hz, 1H), 3.07 – 2.99 (m,1H), 2.53 – 2.39 (m, 1H), 2.21 – 2.12 (m, 1H), 2.01 – 1.92 (m, 1H), 1.91 –1.82 (m, 1H), 1.58 (s, 3H).

[0165] Example 9

[0166] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid di-tert-butyl ester (compound 9)

[0167]

[0168] Step 1: Synthesis of compound 9b

[0169] Compound 9a (30.0 g, 138.72 mmol) was dissolved in tetrahydrofuran (300 mL) at room temperature. The solution was cooled to 0 °C, and sodium hydride (5.5 g, 138.72 mmol) was slowly added. After the addition was complete, the reaction was allowed to proceed at 0 °C for 0.5 h. Then, iodomethane (19.7 g, 138.72 mmol) was added at 0 °C. After the addition was complete, the solution was gradually heated to room temperature and the reaction was allowed to continue at room temperature for 2 h. After the reaction was complete, water (200 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1 V / V) to give 30.5 g of compound 9b, with a yield of 95.5%. 1 H NMR (400 MHz, CDCl3) δ 3.26 (q, J = 7.3 Hz, 1H), 1.46 (s,18H), 1.32 (d, J = 7.3 Hz, 3H).

[0170] Step 2: Synthesis of compound 9c

[0171] Compound 9b (20.0 g, 86.96 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature. The solution was cooled to 0 °C, and sodium hydride (5.2 g, 130.43 mmol) was slowly added. After the addition was complete, the solution was reacted at 0 °C for 0.5 h. Then, tetrabutylammonium iodide (16.1 g, 43.48 mmol) and benzyl chloromethyl ether (13.6 g, 86.96 mmol) were added. After the addition was complete, the solution was heated to 90 °C and reacted for 4 h. After the reaction was complete, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 28.0 g of compound 9c, with a yield of 91.9%. LCMS (ESI): [M+Na] + = 373.2. 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 5H), 4.53 (s, 2H), 3.74 (s, 2H), 1.45 (d, J = 2.5Hz, 6H), 1.43 (s, 15H).

[0172] Step 3: Synthesis of compound 9d

[0173] Compound 9c (1.0 g, 2.86 mmol) was dissolved in ethyl acetate (10 mL) at room temperature. 10% palladium on carbon (500 mg) was added. The reaction mixture was purged three times with hydrogen gas, and the mixture was heated to 50 °C and stirred for 16 h under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give 550 mg of compound 9d, with a yield of 74.0%. LCMS (ESI): [M+Na] + =283.1.

[0174] Step 4: Synthesis of compound 9e

[0175] At room temperature, sulfonyl chloride (568 mg, 4.21 mmol) was dissolved in diethyl ether (7 mL), and the mixture was cooled to -78 °C under nitrogen protection. A solution of compound 9d (730 mg, 2.81 mmol) and pyridine (244 mg, 3.09 mmol) in diethyl ether (1 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 3 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 520 mg of crude compound 9e, which was used directly in the next reaction step.

[0176] Step 5: Synthesis of Compound 9

[0177] At room temperature, compound 1b (268 mg, 1.45 mmol) was dissolved in a mixed solvent of dry tetrahydrofuran (6 mL) and N,N-dimethylpropenylurea (2.2 mL). The mixture was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amino (0.8 mL, 2 M tetrahydrofuran solution, 1.60 mmol) was slowly added. After the addition was complete, the mixture was stirred at -78 °C for 10 min. Then, compound 9e (520 mg, 1.45 mmol) was slowly added. After the addition was complete, the mixture was gradually heated to room temperature and the reaction was continued at room temperature for 2 h. After the reaction was complete, 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 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%–70%) to give 141.38 mg of compound 9, yield 19.2%. LCMS (ESI): [M + Na] + = 530.2. 1 H NMR (400 MHz, CDCl3) δ6.48 (s, 1H), 5.60 (s, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.86 (d, J = 9.3 Hz, 1H), 4.16 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 7.4 Hz, 1H), 3.32 (d, J = 11.8Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.44 (dd, J = 15.1, 6.9 Hz, 1H), 2.21 –2.12 (m, 1H), 1.90 – 1.88 (m, 2H), 1.57 – 1.42 (m, 21H).

[0178] Example 10

[0179] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid diethyl ester (compound 10)

[0180]

[0181] Step 1: Synthesis of Compound 10b

[0182] Compound 10a (10.0 g, 53.2 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (20 mL) at room temperature. 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 complete, the reaction was continued at room temperature for 16 hours. At the end of the reaction, water (50 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 9.2 g of compound 10b, with a yield of 79.3%. LCMS (ESI): [M+H] + = 219.1.

[0183] Step 2: Synthesis of compound 10c

[0184] At room temperature, sulfonyl chloride (1.86 g, 13.76 mmol) was dissolved in diethyl ether (20 mL), and the mixture was purged three times with argon gas and stirred at -78 °C for 10 min. Then, a solution of compound 10b (2.0 g, 9.17 mmol) and pyridine (943 mg, 11.93 mmol) in diethyl ether (2.0 mL) was slowly added dropwise at -78 °C. After the addition was complete, the temperature was gradually raised to room temperature, and the reaction was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 2.0 g of compound 10c, with a yield of 69.2%. 1 HNMR (400 MHz, CDCl3) δ 4.81 (s, 2 H), 4.25 (q, J = 6.8 Hz, 4H), 1.97 (q, J =7.6 Hz, 2H), 1.30 (t, J = 6.8 Hz, 6H), 0.95 (t, J = 6.8 Hz, 3H).

[0185] Step 3: Synthesis of Compound 10

[0186] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (6 mL) and N,N-dimethylpropenylurea (2.4 mL). Under nitrogen protection, sodium bis(trimethylsilyl)amino (0.89 mL, 2 M tetrahydrofuran solution, 1.78 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction was maintained at -78 °C for 10 minutes. Then, compound 10c (1025 mg, 3.24 mmol) was added dropwise. After the addition was complete, the temperature of the reaction solution was slowly raised to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, 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: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 28.11 mg of compound 10, yield 3.73%. LCMS (ESI): [M+H] + = 466.5. 1 H NMR (400 MHz, CDCl3) δ 6.47(s, 1H), 5.54 (s, 1H), 5.10 (d, J = 10.0 Hz, 1H), 4.95 (d, J = 10.0 Hz, 1H),4.29 – 4.20 (m, 4H), 4.15 (d, J = 2.0 Hz, 1H), 4.07 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.50 – 2.39 (m, 1H), 2.18 –2.02 (m, 3H), 1.99 – 1.82 (m, 2H), 1.30 – 1.25 (m, 6H), 0.92 (t, J = 7.8 Hz, 3H).

[0187] Example 11

[0188] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid diisopropyl ester (compound 11)

[0189]

[0190] The synthetic method is the same as for compound 10, except that compound 10a is replaced by an equivalence of diisopropyl 2-ethylmalonate. LCMS (ESI): [M+H] + = 494.2. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.54 (s, 1H), 5.14 – 5.04 (m, 3H), 4.95 (d, J = 9.6 Hz, 1H), 4.17 – 4.12 (m, 1H), 4.07 (d,J = 7.2 Hz, 1H), 3.31 (d, J = 11.6 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.49 –2.40 (m, 1H), 2.20 – 1.80 (m, 5H), 1.27 – 1.23 (m, 12H), 0.92 (t, J = 7.6 Hz, 3H).

[0191] Example 12

[0192] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid dithioethyl ester (compound 12)

[0193]

[0194] Step 1: Synthesis of Compound 12a

[0195] Compound 7a (10.0 g, 84.75 mmol) was dissolved in dichloromethane (100 mL) at room temperature. Then, oxaloyl chloride (32.28 g, 254.23 mmol) and N,N-dimethylformamide (619 mg, 8.47 mmol) were added at 0 °C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to give 13.0 g of compound 12a, with a yield of 99.0%. 1 HNMR (400 MHz, CDCl3) δ 4.36 – 4.19 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H).

[0196] Step 2: Synthesis of compound 12b

[0197] Compound 12a (13.0 g, 84.4 mmol) was dissolved in dichloromethane (130 mL) at room temperature. Triethylamine (25.57 g, 253.2 mmol) and ethanethiol (15.95 g, 253.2 mmol) were added sequentially at 0 °C, and the reaction was allowed to proceed for 16 hours at room temperature. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 3.8 g of compound 12b, with a yield of 21.8%. 1 HNMR (400 MHz, CDCl3) δ 3.88 – 3.78 (m, 1H), 2.95 – 2.89 (m, 4H), 1.46 (d, J =7.1 Hz, 3H), 1.29 – 1.24 (m, 6H).

[0198] Step 3: Synthesis of compound 12c

[0199] Compound 12b (3.8 g, 18.44 mmol) was dissolved in ethanol (16 mL) and water (8 mL) at room temperature. 37% formaldehyde aqueous solution (1.65 g, 20.3 mmol) and sodium bicarbonate (155 mg, 1.84 mmol equivalent) were added at 0 °C. After the addition was complete, the mixture was brought to room temperature and reacted for 16 hours. Upon completion of the reaction, water (50 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phases were 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 rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 3.3 g of compound 12c, with a yield of 75.8%. LCMS (ESI): [M+H] + = 237.0.

[0200] Step 4: Synthesis of compound 12d

[0201] At room temperature, sulfonyl chloride (172 mg, 1.27 mmol) was dissolved in diethyl ether (2 mL). The mixture was purged three times with argon gas and stirred at -78 °C for 10 min. Then, a solution of compound 12c (200 mg, 0.85 mmol) and pyridine (87 mg, 1.10 mmol) in diethyl ether (0.2 mL) was slowly added dropwise at -78 °C. After the addition was complete, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 289 mg of crude compound 12d, which was used directly in the next reaction.

[0202] Step 5: Synthesis of Compound 12

[0203] Compound 1b (160 mg, 0.86 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (3.2 mL) and N,N-dimethylpropenylurea (1.4 mL) at room temperature. The solution was cooled to -78 °C under argon protection. Sodium bis(trimethylsilyl)amino (0.47 mL, 0.95 mmol in 2 M tetrahydrofuran solution) was added dropwise. The mixture was stirred at -78 °C for 10 minutes. Then, compound 12d (289 mg, 0.86 mmol) was added. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 2 hours at room temperature. After the reaction was complete, 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 C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 24.87 mg of compound 12, yield 59.6%. LCMS (ESI): [M+H] + = 484.1. 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 5.52 (s, 1H), 5.13 – 4.99 (m, 2H), 4.16 (s, 1H), 4.07 (d, J = 7.6 Hz, 1H), 3.33 (d, J =11.2 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.99 – 2.90 (m, 4H), 2.50 – 2.39 (m,1H), 2.21 – 2.11 (m, 1H), 1.99 – 1.83 (m, 2H), 1.71 (s, 3H), 1.29 – 1.24 (m,6H).

[0204] Example 13

[0205] Synthesis of diethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-benzylmalonic acid (compound 13)

[0206]

[0207] Step 1: Synthesis of Compound 13b

[0208] Compound 13a (10.0 g, 62.43 mmol) was dissolved in ethanol (100 mL) at room temperature. Potassium carbonate (11.22 g, 81.16 mmol) and benzyl bromide (21.36 g, 124.86 mmol) were added sequentially, and the mixture was heated to 65 °C for 8 hours. After the reaction was complete, the mixture was quenched with pure water (100 mL), extracted with dichloromethane (100 mL × 3), and the organic phases were combined. The organic phases were washed with sodium bicarbonate (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 6.7 g of compound 13b, with a yield of 42.9%. 1 HNMR (400 MHz, CDCl3) δ 7.30 – 7.16 (m, 5H), 4.24 – 4.07 (m, 4H), 3.69– 3.58 (m, 1H), 3.22 (d, J = 8.0 Hz, 2H), 1.26 – 1.14 (m, 6H).

[0209] Step 2: Synthesis of compound 13c

[0210] At room temperature, 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), and the reaction was carried out at 80 °C for 24 hours. After the reaction was completed, the reaction solution was concentrated directly to dryness, and the residue was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate = 3 / 1 V / V) to give 4.0 g of compound 13c, with a yield of 53.3%. LCMS (ESI): [M+H] + = 281.2.

[0211] Step 3: Synthesis of compound 13d

[0212] At room temperature, sulfonyl chloride (1.08 g, 8.03 mmol) was dissolved in diethyl ether (10 mL). The mixture was purged three times with argon gas, and stirred at -78 °C for 10 minutes. A solution of compound 13c (1.5 g, 5.35 mmol) and pyridine (635 mg, 8.03 mmol, 1.5 equivalents) in diethyl ether (1.0 mL) was added dropwise. After the addition was complete, the reaction was carried out 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 1.5 g of crude compound 13d, which was directly used for the next reaction.

[0213] Step 4: Synthesis of Compound 13

[0214] Compound 1b (734 mg, 3.96 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (16 mL) and N,N-dimethylpropenylurea (6.4 mL) at room temperature under nitrogen protection. Sodium bis(trimethylsilyl)amino (2.2 mL, 2M tetrahydrofuran solution, 4.36 mmol) was added at -78 °C, and the reaction was stirred for another 10 min at -78 °C. Then, diethyl 2-benzyl-2-(((chlorosulfonyl)oxy)methyl)malonate (1.50 g, 3.96 mmol) was slowly added. After the addition was complete, 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 complete, 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: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–60%) to give 185.06 mg of compound 13, yield 8.86%. LCMS (ESI): [M+H] + =528.6. 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.26 (m, 3H), 7.19 – 7.12 (m, 2H), 6.47 (s, 1H), 5.59 (s, 1H), 4.94 (d, J = 10.0 Hz, 1H), 4.78 (d, J = 10.0 Hz, 1H), 4.30 –4.14 (m, 5H), 4.07 (d, J = 7.2 Hz, 1H), 3.39 (d, J = 2.8 Hz, 2H), 3.35 – 3.28(m, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.48 – 2.37 (m, 1H), 2.20 – 2.10 (m, 1H), 2.02 – 1.79 (m, 2H), 1.25 (q, J = 7.2 Hz, 6H).

[0215] Example 14

[0216] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-phenylmalonate diethyl ester (compound 14)

[0217]

[0218] The synthetic method is similar to that of compound 13, except that compound 13b is replaced by an equivalence of diethyl 2-phenylmalonate. LCMS (ESI): [M+H] + = 514.2. 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.31 (m, 5H), 6.45 (s,1H), 5.51 (s, 1H), 5.38 (d, J = 9.6 Hz, 1H), 5.14 (d, J = 9.6 Hz, 1H), 4.44 –4.21 (m, 4H), 4.03 (s, 2H), 3.24 (d, J = 11.6 Hz, 1H), 2.97 (d, J = 12.0 Hz,1H), 2.49 – 2.35 (m, 1H), 2.17 – 2.07 (m, 1H), 1.96 – 1.76 (m, 2H), 1.33 –1.24 (m, 6H).

[0219] Example 15

[0220] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylmalonic acid diisopropyl ester (compound 15)

[0221]

[0222] Step 1: Synthesis of Compound 15b

[0223] Compound 15a (10.0 g, 99.88 mmol) was dissolved in dichloromethane (15 mL) at room temperature, followed by the addition of isopropanol (9.0 g, 149.82 mmol) and 4-dimethylaminopyridine (1.2 g, 9.99 mmol). The mixture was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (30.9 g, 149.82 mmol) was added. The reaction was allowed to proceed at room temperature for 16 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness to give 10 g of compound 15b, with a yield of 70.4%. 1 H NMR (400 MHz, CDCl3) δ 4.86 (dt, J = 12.5, 6.3 Hz, 1H), 2.01 (d, J = 7.1 Hz, 2H), 1.08 (dd, J = 6.3, 1.2Hz, 6H), 0.43 – 0.32 (m, 2H), -0.00 (t, J = 4.8 Hz, 2H).

[0224] Step 2: Synthesis of compound 15c

[0225] Diisopropylaminolithium (88 mL, 175.8 mmol) was dissolved in dry tetrahydrofuran (100 mL) at -78 °C under nitrogen protection. Compound 15b (10.0 g, 70.32 mmol) was added at -78 °C, and the reaction was carried out at -78 °C for 30 min. Then, di-tert-butyl dicarbonate (18.4 g, 84.39 mmol) was added, and the reaction was continued at room temperature for 4 h. After the reaction was completed, water (50 mL) was added to quench the reaction mixture, 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 to give 10.0 g of compound 15c, with a yield of 58.7%. 1H NMR (400 MHz, CDCl3) δ 5.14 – 4.99 (m, 1H), 2.48 (d, J = 10.0 Hz,1H), 1.43 (s, 9H), 1.26 (d, J = 6.3 Hz, 6H), 0.63 (dd, J = 8.1, 2.9 Hz, 2H),0.30 (dd, J = 4.9, 1.1 Hz, 2H).

[0226] Step 3: Synthesis of compound 15d

[0227] Compound 15c (8.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature, cooled to 0 °C under nitrogen atmosphere, and then sodium hydride (2.1 g, 52.7 mmol) was added. The reaction was carried out at 0 °C for 0.5 h, followed by the addition of ((chloromethoxy)methyl)benzene (5.5 g, 35.1 mmol) and tetrabutylammonium iodide (6.5 g, 17.6 mmol), and the reaction was carried out at 90 °C for 0.5 h. After the reaction was completed, water (100 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 8 / 1 V / V) to give 3.0 g of compound 15d, with a yield of 32.2%. LCMS (ESI): [M+Na] + = 385.3.

[0228] Step 4: Synthesis of compound 15e

[0229] Compound 15d (1.5 g, 4.14 mmol) was dissolved in dichloromethane (15 mL) at room temperature, followed by the addition of trifluoroacetic acid (3 mL), and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was concentrated directly to dryness, and the residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 1 / 1 V / V) to give 3.0 g of compound 15e, with a yield of 32.2%. LCMS (ESI): [M+H] + = 307.2.

[0230] Step 5: Synthesis of compound 15f

[0231] Compound 15e (1.0 g, 3.26 mmol) was dissolved in dichloromethane (10 mL) at room temperature. 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, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated directly to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 8 / 1V / V) to give 600 mg of compound 15f, with a yield of 52.8%. LCMS (ESI): [M+H] + = 349.3.

[0232] Step Six: Synthesis of 15g of Compound

[0233] Compound 15f (600 mg, 1.72 mmol) was dissolved in ethyl acetate (6 mL) at room temperature, and 10% palladium on carbon (60 mg) was added. The mixture was purged with hydrogen three times, and the reaction was stirred at room temperature for 1.5 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness to give 350 mg of compound (15 g), yield 69.7%. LCMS (ESI): [M+H] + = 259.2.

[0234] Step 7: Synthesis of compound 15h

[0235] Sulfonyl chloride (272 mg, 2.03 mmol) was dissolved in dry diethyl ether (3 mL) and cooled to -78°C. A solution of 15 g (350 mg, 1.36 mmol) of compound and pyridine (161 mg, 2.03 mmol) in dry diethyl ether (2 mL) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 5 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 350 mg of the crude compound (15 h). This crude compound was used directly in subsequent reactions without further purification. 1 H NMR (400 MHz, 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).

[0236] Step 8: Synthesis of Compound 15

[0237] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropenylurea (1 mL). The solution was cooled to -78 °C under nitrogen atmosphere, and sodium bis(trimethylsilyl)amino (973 μL, 2 M tetrahydrofuran solution, 1.95 mmol) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 10 minutes. Then, compound 15h (577 mg, 1.62 mmol) was added, and the solution was gradually heated to room temperature. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, 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: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 47.94 mg of compound 15, yield 5.86%. LCMS (ESI): [M+H] + = 506.4. 1 H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.52(s, 1H), 5.19 – 4.97 (m, 3H), 4.89 (d, J = 12.8 Hz, 1H), 4.16 (s, 1H), 4.07(d, J = 7.2 Hz, 1H), 3.30 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.54 – 2.36 (m, 1H), 2.18 – 2.13 (m, 1H), 2.00 – 1.82 (m, 2H), 1.51 -1.44 (m,1H), 0.64 (d, J = 7.2 Hz, 2H), 0.55 - 0.44 (m, 2H).

[0238] Example 16

[0239] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylmalonic acid-1-tert-butyl-3-ethyl ester (compound 16)

[0240]

[0241] The synthetic method follows steps two, three, six, seven, and eight of the synthesis of compound 15, with ethyl 2-cyclopropyl acetate replacing compound 15b in an equivalent amount. LCMS (ESI): [M+Na] + = 528.1. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.53 (s, 1H), 5.98 (d, J = 8.4 Hz, 1H), 4.87 (d, J =8.4 Hz, 1H), 4.25 – 4.16 (m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.31 (d, J = 12.0Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.46 – 2.41 (m, 1H), 2.22 – 2.09 (m, 1H), 2.02 – 1.80 (m, 2H), 1.46 (d, J = 6.0 Hz, 10H), 1.28 (q, J = 7.2 Hz, 3H), 0.64 (d, J = 8.4 Hz, 2H), 0.49 -0.48 (m, 2H).

[0242] Example 17

[0243] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-cyclopropylmalonic acid-1-ethyl-3-isopropyl ester (compound 17)

[0244]

[0245] The synthetic method is similar to that of compound 15, except that compound 15b is replaced by an equivalence of ethyl 2-cyclopropyl. LCMS (ESI): [M+H] + = 492.3. 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 5.67 (s, 1H), 5.18 – 4.97 (m, 2H), 4.89 (d, J = 9.6 Hz, 1H), 4.30 – 4.12 (m, 3H), 4.07 (d,J = 7.2 Hz, 1H), 3.36 – 3.26 (m, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.51 – 2.37(m, 1H), 2.24 – 2.09 (m, 1H), 2.01 – 1.82 (m, 2H), 1.53 – 1.44 (m, 1H), 1.36– 1.19 (m, 9H), 0.65 (d, J = 8.8 Hz, 2H), 0.57 – 0.42 (m, 2H).

[0246] Example 18

[0247] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diylbis(2-methylpropionate) (compound 18)

[0248]

[0249] Step 1: Synthesis of Compound 18b

[0250] Compound 18a (10.0 g, 83.23 mmol) was dissolved in dichloromethane (100 mL) at room temperature. Then, pyridine (9.88 g, 124.85 mmol), isobutyric anhydride (26.33 g, 166.46 mmol), and 4-dimethylaminopyridine (202.8 mg, 1.66 mmol) were added at room temperature, and the reaction was allowed to proceed for 16 hours. After the reaction was complete, water (50 mL) was added to quench the reaction mixture. 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 7.0 g of compound 18b, in 32.3% yield. 1H NMR (400MHz, CDCl3) δ 4.02 (d, J = 11.6 Hz, 4H), 3.40 (s, 2H), 2.60 – 2.55 (m, 2H), 1.18 (d, J = 7.2 Hz, 12H), 0.97 (s, 3H).

[0251] Step 2: Synthesis of compound 18c

[0252] At room temperature, sulfonyl chloride (778 mg, 5.76 mmol) was dissolved in diethyl ether (8 mL). The mixture was purged three times with argon gas and stirred at -78 °C for 10 min. Then, a solution of compound 18b (1.0 g, 3.84 mmol) and pyridine (456 mg, 5.76 mmol) in diethyl ether (0.8 mL) was slowly added dropwise at -78 °C, and the reaction was stirred at -78 °C for 2 h. After the reaction was complete, 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 reaction.

[0253] Step 3: Synthesis of Compound 18

[0254] At room temperature, compound 1b (413 mg, 2.23 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (8 mL) and N,N-dimethylpropenylurea (3.2 mL). Under argon protection, sodium bis(trimethylsilyl)amino (1.2 mL, 2M tetrahydrofuran solution, 2.45 mmol) was added to the mixture at -78 °C. The reaction was then stirred for 10 min at -78 °C. Compound 18c (1.20 g, 3.34 mmol) was then slowly added. After the addition was complete, the reaction was gradually brought to room temperature and allowed to proceed for 2 hours. Upon completion, water (50 mL) was added to quench the reaction mixture, and the solution 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 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%–70%) to give 115.1 mg of compound 18, yield 10.17%. LCMS (ESI): [M+H+MeCN] + = 508.3. 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 5.61 (s,1H), 4.74 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.16 (s, 1H), 4.11 –3.98 (m, 5H), 3.34 (d, J = 11.6 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.65 –2.56 (m, 2H), 2.50 – 2.38 (m, 1H), 2.23 – 2.10 (m, 1H), 2.00 – 1.80 (m, 2H),1.19 (dd, J = 7.2, 2.0 Hz, 12H), 1.09 (s, 3H).

[0255] Example 19

[0256] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)phospho)bis(oxy))bis(methylene)bis(2-methylpropionate) (Compound 19)

[0257]

[0258]

[0259] Step 1: Synthesis of Compound 19b

[0260] Compound 19a (35.0 g, 147.0 mmol) was dissolved in tetrahydrofuran (350 mL) at room temperature. Sodium hydride (5.3 g, 220.4 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. Iodomethane (31.3 g, 220.4 mmol) was then added, and the mixture was stirred at room temperature for 5 h until the reaction was complete. The reaction was monitored by LCMS until completion. After the reaction was complete, water (200 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 30.0 g of compound 19b, with a yield of 81.1%. LCMS (ESI): [M+H] + =253.1. 1H NMR (400 MHz, CDCl3) δ 4.25 – 4.10 (m,6H), 1.47 (d, J = 16.4 Hz, 6H), 1.34 – 1.24 (m, 9H).

[0261] Step 2: Synthesis of compound 19c

[0262] Compound 19b (24.0 g, 95.2 mmol) was dissolved in tetrahydrofuran (300 mL) at room temperature. The solution was cooled to 0 °C, and lithium borohydride (5.3 g, 220.4 mmol) was added. After the addition was complete, the mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete, water (200 mL) was added to quench the reaction mixture, and the solution 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 1 / 1 V / V) to give 15.0 g of compound 19c, yield 75.0%. LCMS (ESI): [M+H] + =211.1. 1 H NMR (400 MHz, CDCl3) δ 4.19 – 4.08 (m,5H), 3.68 – 3.51 (m, 2H), 1.36 – 1.29 (m, 6H), 1.18 (d, J = 16.8, 6H).

[0263] Step 3: Synthesis of compound 19d

[0264] Compound 19c (8.0 g, 38.1 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature. Sodium hydride (1.4 g, 57.1 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. Benzyl bromide (9.8 g, 57.1 mmol) was then added, and the mixture was stirred at room temperature for 5 h. After the reaction was complete, water (50 mL) was added to quench the reaction mixture, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 3 / 1V / V) to give 5.5 g of compound 19d, with a yield of 48.2%. LCMS (ESI): [M+H] + =301.2. 1HNMR (400 MHz, CDCl3) δ 7.43 – 7.24 (m, 5H), 4.53 (s, 2H), 4.10 – 4.05 (m,4H), 3.49 (d, J = 12.4 Hz, 2H), 1.36 – 1.14 (m, 12H).

[0265] Step 4: Synthesis of compound 19e

[0266] Compound 19d (1.5 g, 5.0 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and trimethylbromosilane (3.9 g, 25.0 mmol) was added at 0 °C. The mixture was stirred at 55 °C for 2 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.2% formic acid / water, mobile phase B: acetonitrile, gradient: 40%–60%) to give 1.2 g of compound 19e, with a yield of 97.6%. LCMS (ESI) [M+H] + = 245.0. 1 H NMR (400 MHz, CDCl3) δ 7.37 –7.28 (m, 5H), 4.55 (s, 2H), 3.49 (d, J = 14.8 Hz, 2H), 1.23 (d, J = 16.4 Hz, 6H).

[0267] Step 5: Synthesis of compound 19f

[0268] Compound 19e (1.2 g, 4.9 mmol) was dissolved in acetone (15 mL) at room temperature. A mixture of cesium carbonate (4.8 g, 14.8 mmol), iodomethyl isobutyrate (3.37 g, 14.8 mmol), and methane (0.237 g, 14.8 mmol) was added, and the mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness. The residue was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate = 3 / 1 V / V) to give 1.0 g of compound 19f, with a yield of 45.9%. LCMS (ESI) [M+H] + =445.2. 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.24(m, 5H), 5.74 – 5.57 (m, 4H), 4.53 (s, 2H), 3.48 (d, J = 14.8 Hz, 2H), 2.62 –2.55 (m, 2H), 1.29 – 1.16 (m, 18H).

[0269] Step Six: Synthesis of Compound 19g

[0270] Compound 19f (800 mg, 1.8 mmol) was dissolved in ethyl acetate (16 mL) at room temperature, followed by the addition of 10% palladium on carbon (400 mg). The mixture was purged three times with hydrogen, and the reaction was continued for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 600 mg of compound 19f, with a yield of 94.2%. LCMS (ESI) [M+H] + = 355.1.

[0271] Step 7: Synthesis of compound 19h

[0272] At room temperature, sulfonyl chloride (315 mg, 2.3 mmol) was dissolved in diethyl ether (6 mL). The solution was cooled to -78 °C under nitrogen atmosphere, and a solution of 19 g (550 mg, 1.6 mmol) of compound and pyridine (184 mg, 2.3 mmol) in diethyl ether (1 mL) was added dropwise. After the addition was complete, the solution was gradually warmed 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 give 650 mg of compound 19h, with a yield of 92.6%, which was directly used for the next reaction.

[0273] Step 8: Synthesis of Compound 19

[0274] At room temperature, compound 1b (250 mg, 1.4 mmol) was dissolved in a mixed solution of tetrahydrofuran (7.5 mL) and N,N-dimethylpropenylurea (2.0 mL). The solution was cooled to -78 °C under nitrogen atmosphere, and sodium bis(trimethylsilyl)amino (0.8 mL, 2 M tetrahydrofuran solution, 1.54 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 10 minutes. Then, compound 19h (610 mg, 1.4 mmol) was added dropwise. After the addition was complete, the mixture was gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was complete, water (20 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 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%–65%) to give 57.39 mg of compound 19, yield 7.1%. LCMS (ESI) [M+H] + =602.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.40 (s, 1H), 5.63 (d,J = 12.4 Hz, 4H), 4.64 – 4.58 (m, 1H), 4.45 – 4.40 (m, 1H), 4.12 (s, 1H), 3.91 (d, J = 6.4 Hz, 1H), 3.19 (s, 2H), 2.65 – 2.58 (m, 2H), 2.14 – 2.09 (m, 1H), 1.97 – 1.92 (m, 1H), 1.86 – 1.82 (m, 1H), 1.79 – 1.64(m, 1H), 1.21 – 1.08 (m, 18H).

[0275] Example 20

[0276] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)phospho)bis(oxy))bis(methylene)diacetate (compound 20)

[0277]

[0278] The synthesis method is similar to that of compound 19, except that iodomethyl isobutyrate is replaced by an equivalent amount of iodomethyl acetate in step five. LCMS (ESI) [M+H] + =546.2. 1 H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 5.74 – 5.65 (m, 4H), 5.56 (s, 1H), 4.76 (dd, J = 12.8, 9.2 Hz, 1H), 4.52 (t, J = 10.0 Hz, 1H), 4.17 (s, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.35 (d, J = 12.0 Hz, 1H), 3.02(d, J = 12.0 Hz, 1H), 2.54 – 2.40 (m, 1H), 2.15 (s, 7H), 2.01 – 1.85 (m, 2H),1.30 (dd, J = 17.2, 10.0 Hz, 6H).

[0279] Example 21

[0280] Synthesis of (((1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-methylprop-2-yl)phospho)bis(oxy))bis(methylene)dipentanoate (compound 21)

[0281]

[0282] The synthetic method is as described for compound 19, except that iodomethyl isobutyrate is replaced by an equivalent amount of iodomethyl pentovalinate in step five. LCMS (ESI): [M+H] + = 630.4. 1 H NMR (400 MHz, CDCl3) δ 6.50 (s, 1H), 5.82 –5.59 (m, 5H), 4.82 – 4.70 (m, 1H), 4.52 (t, J = 9.6 Hz, 1H), 4.17 (s, 1H),4.05 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.03 (d, J = 12.0 Hz,1H), 2.41 – 2.40 (m, 1H), 2.23 – 2.09 (m, 1H), 2.02 – 1.83 (m, 2H), 1.34 –1.19 (m, 24H).

[0283] Example 22

[0284] Synthesis of 2-(bis((isopropoxycarbonyl)oxy)methoxy)phosphoryl)-2-methylpropyl((2S,5R)-2-carbonyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)sulfate (compound 22)

[0285]

[0286] The synthetic method is similar to that of compound 19, except that iodomethyl isobutyrate methyl carbonate is replaced by an equivalent amount in step five. LCMS (ESI): [M+H] + = 634.5. 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 5.70 (d, J = 12.3 Hz, 4H), 5.62 (s, 1H), 5.00 – 4.87 (m, 2H), 4.83 – 4.71 (m, 1H), 4.53 (t, J = 9.9 Hz, 1H), 4.17 (s, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.35 (d, J= 11.9 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.43 (d, J = 15.4 Hz, 1H), 2.14(s, 1H), 1.90 – 1.84 (m, 2H), 1.31 – 1.28 (m, 18H).

[0287] Example 23

[0288] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid bis((neopentyloxy)methyl) ester (compound 23)

[0289]

[0290] Step 1: Synthesis of compound 23b

[0291] Compound 23a (20.0 g, 114.8 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, cooled to 0 °C, and sodium hydride (4.10 g, 173.2 mmol) was slowly added. The reaction was carried out 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, and the mixture was heated to 90 °C and stirred for 2 h. After the reaction was complete, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 28.0 g of compound 23b, with a yield of 82.8%. LCMS (ESI): [M+H] + = 295.1. 1 H NMR (400 MHz, CDCl3)δ 7.34 – 7.26 (m, 5H), 4.54 (s, 2H), 4.16 (q, J = 7.2 Hz, 4H), 3.81 (s, 2H), 1.53 (s, 3H), 1.22 (t, J = 7.2 Hz, 6H).

[0292] Step 2: Synthesis of compound 23c

[0293] Compound 23b (18.0 g, 61.2 mmol) was dissolved in a mixed solvent of ethanol (90 mL) and water (90 mL) at room temperature. Sodium hydroxide (9.8 g, 244.9 mmol) was slowly added at room temperature, and the reaction mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 45%–65%) to obtain 15.0 g of compound 23c, which was directly used in the next reaction. LCMS (ESI): [M+Na] + = 261.1.

[0294] Step 3: Synthesis of compound 23d

[0295] Compound 23c (2.0 g, 8.40 mmol) was dissolved in dichloromethane (20 mL) at room temperature, followed by the addition of methyl iodide pentovalinate (4.48 g, 18.5 mmol) and cesium carbonate (6.02 g, 18.58 mmol). The reaction was allowed to proceed for 16 h at room temperature. After the reaction was complete, water (100 mL) was added to quench the reaction mixture, 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 rapid chromatography (Silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 2.3 g of compound 23d, with a yield of 63.6%. LCMS (ESI): [M+Na] + = 489.2.

[0296] Step 4: Synthesis of compound 23e

[0297] Compound 23d (800 mg, 1.72 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. 10% palladium on carbon (120 mg) was added, and the mixture was purged three times with hydrogen. The reaction mixture was stirred for 1.5 h at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 500 mg of compound 23e, with a yield of 77.3%. LCMS (ESI): [M+Na] + =399.2.

[0298] Step 5: Synthesis of compound 23f

[0299] At room temperature, sulfonyl chloride (215 mg, 1.59 mmol) was dissolved in ether (10 mL). The mixture was purged three times with argon gas and stirred at -78 °C for 10 min. Then, a solution of compound 23e (500 mg, 1.33 mmol) and pyridine (105 mg, 1.33 mmol) in ether (1.7 mL) was slowly added dropwise at -78 °C. The temperature was gradually raised to room temperature, and the reaction was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 680 mg of compound 23f, which was directly used in the next reaction.

[0300] Step Six: Synthesis of Compound 23

[0301] Compound 1b (220 mg, 1.18 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropenylurea (1 mL) at room temperature. The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (713 μL, 1.42 mmol in 2 M tetrahydrofuran solution) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 10 minutes. Compound 23f (676 mg, 1.43 mmol) was then slowly added to the solution. After the addition was complete, the solution was gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated directly to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 54.65 mg of compound 23, yield 9.86%. LCMS (ESI): [M+H] + = 624.6. 1 H NMR (400 MHz, CDCl3) δ 6.49 (s,1H), 5.67 (s, 1H), 5.18 – 4.97 (m, 2H), 4.89 (d, J = 9.6 Hz, 1H), 4.23 – 4.20(m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.03 (d, J =12.0 Hz, 1H), 2.44 (dd, J = 15.2, 6.8 Hz, 1H), 2.24 – 2.09 (m, 1H), 2.01 –1.82 (m, 2H), 1.55 – 1.43 (m, 1H), 1.36 – 1.19 (m, 9H), 0.65 (d, J = 8.8 Hz, 2H), 0.50 – 0. 46 (m, 2H).

[0302] Example 24

[0303] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-cyclohexyl-3-ethyl ester (compound 24)

[0304]

[0305] Step 1: Synthesis of compound 24a

[0306] Compound 23b (25.0 g, 85.0 mmol) was dissolved in ethanol (250 mL) and water (250 mL) at room temperature. Sodium hydroxide (6.80 g, 170 mmol) was slowly added at room temperature, and the mixture was stirred at 50 °C for 2 h. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by reverse-phase synthesis (0.1% FA, ACN) to give 17.0 g of compound 24a, with a yield of 75.1%. LCMS (ESI): [M+H] + = 267.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.26 (m,5H), 4.54 – 4.46 (m, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.76 (d, J = 8.8 Hz, 1H), 3.68 (d, J = 8.8 Hz, 1H), 1.39 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H).

[0307] Step 2: Synthesis of compound 24b

[0308] Compound 24a (2.0 g, 7.5 mmol) was dissolved in dichloromethane (20 mL) at room temperature, followed by the sequential addition of cyclohexanol (1.1 g, 11.3 mmol) and 4-dimethylaminopyridine (92 mg, 0.75 mmol). The reaction was allowed to proceed for 16 hours at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 1.8 g of compound 24b, with a yield of 69.2%. LCMS (ESI) [M+H] + =349.2. 1 H NMR (400 MHz, CDCl3) δ 7.32–7.26 (m, 5H), 4.88–4.77 (m, 1H), 4.54–4.53 (m, 2H), 4.19–4.14 (m, 2H), 3.82 (s, 2H), 1.84–1.71 (m, 2H), 1.72–1.61(m, 2H), 1.53 (s, 3H), 1.46–1.26 (m, 6H), 1.22 (t, J = 7.2 Hz, 3H).

[0309] Step 3: Synthesis of compound 24c

[0310] Compound 24b (1.8 g, 5.2 mmol) was dissolved in ethanol (40 mL) at room temperature, followed by the addition of 10% palladium on carbon (1.0 g). The mixture was purged three times with hydrogen, and the reaction was continued at 50 °C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 1.1 g of compound 24c, with a yield of 82.7%. LCMS (ESI) [M+Na] + =281.2. 1 H NMR (400 MHz, CDCl3) δ 4.93–4.81 (m, 1H), 4.23–4.21 (m, 2H), 3.85 (s,2H), 1.89–1.77 (m, 2H), 1.77–1.64 (m, 2H), 1.54–1.47 (m, 3H), 1.44 (s, 3H), 1.43–1.30 (m, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0311] Step 4: Synthesis of compound 24d

[0312] At room temperature, sulfonyl chloride (392 mg, 2.9 mmol) was dissolved in diethyl ether (5 mL). The solution was cooled to -78 °C under a nitrogen atmosphere, and a solution of compound 24c (500 mg, 1.9 mmol) and pyridine (229 mg, 2.9 mmol) in diethyl ether (0.5 mL) was added dropwise. After the addition was complete, the solution was gradually warmed to room temperature and 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 give 600 mg of compound 24d (yield 86.8%). 1 H NMR (400 MHz, CDCl3) δ 4.94 – 4.83(m, 1H), 4.81 (s, 2H), 4.27 – 4.22 (m, 2H), 1.83 – 1.80 (m, 3H), 1.70 (d, J =6.0 Hz, 2H), 1.59 (s, 3H), 1.53 – 1.37 (m, 5H), 1.28 (t, J = 7.2 Hz, 3H).

[0313] Step 5: Synthesis of Compound 24

[0314] At room temperature, compound 1b (300 mg, 1.62 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and N,N-dimethylpropenylurea (2.4 mL). The mixture was cooled to -78 °C under nitrogen atmosphere, and sodium bis(trimethylsilyl)amino (0.9 mL, 2 M tetrahydrofuran solution, 1.80 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78 °C for 10 minutes. Then, compound 24d (579 mg, 1.62 mmol) was slowly added dropwise. After the addition was complete, the mixture was gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated directly to dryness. The residue was purified by reversed-phase prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 65%–75%), yielding 115.22 mg of compound 24 (yield 14.1%). LCMS (ESI) [M+H] + =506.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.40 (s, 1H), 4.92 (d, J = 9.6 Hz, 1H), 4.81 – 4.77 (m,2H), 4.20 – 4.12 (m, 2H), 4.10 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.23 – 3.15 (m, 2H), 2.10 (dd, J = 15.6, 6.8 Hz, 1H), 2.01 – 1.91 (m, 1H), 1.88 – 1.82 (m, 1H), 1.78 – 1.66 (m, 3H), 1.59 (s, 2H), 1.49 – 1.27 (m, 9H), 1.18 (t, J = 7.2 Hz, 3H).

[0315] Example 25

[0316] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-benzyl-3-ethyl ester (compound 25)

[0317]

[0318] Step 1: Synthesis of Compound 25b

[0319] Compound 25a (900 mg, 6.16 mmol) was dissolved in dichloromethane (10 mL) at room temperature. 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 sequentially, and the reaction was allowed to proceed for 16 h at room temperature. After the reaction was complete, the reaction mixture 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 1.0 g of compound 25b, with a yield of 68.9%. LCMS (ESI): [M+H] + = 237.1. 1 H NMR(400 MHz, CDCl3) δ 7.45 – 7.30 (m, 5H), 5.15 (s, 2H), 4.19 – 4.13 (m, 2H), 3.48 (q, J = 7.2 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0320] Step 2: Synthesis of compound 25c

[0321] Compound 25b (1.0 g, 4.23 mmol) was dissolved in ethanol (10 mL) and water (3 mL) at room temperature. A 37% aqueous formaldehyde solution (514 mg, 4.66 mmol) and sodium bicarbonate (48 mg, 0.42 mmol) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 V / V) to give 1.0 g of compound 25c, with a yield of 88.4%. LCMS (ESI): [M+H] + = 267.1. 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.30 (m,5H), 5.20 (s, 2H), 4.17 (q, J = 6.4 Hz, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.48(d, J = 5.2 Hz, 1H), 2.82 (t, J = 7.2 Hz, 1H), 1.47 (s, 3H), 1.18 (t, J =7.2Hz, 3H).

[0322] Step 3: Synthesis of compound 25d

[0323] At room temperature, sulfonyl chloride (377 mg, 2.82 mmol) was dissolved in dry diethyl ether (5 mL) and cooled to -78°C. A solution of compound 25c (500 mg, 1.88 mmol) and pyridine (222 mg, 2.82 mmol) in diethyl ether (2 mL) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 5 hours. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness to obtain 500 mg of crude compound 25d, which was used directly in the next reaction step.

[0324] Step 4: Synthesis of Compound 25

[0325] Compound 1b (200 mg, 1.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and N,N-dimethylpropenylurea (1 mL) at room temperature. The mixture was cooled to -78 °C under nitrogen atmosphere and stirred for 10 minutes. Sodium bis(trimethylsilyl)amino (648 μL, 2 M tetrahydrofuran solution, 1.19 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -78 °C for 10 minutes. Compound 25d (500 mg, 1.30 mmol) was then slowly added dropwise. After the addition was complete, the mixture was gradually heated to room temperature and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated directly to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 62%–78%) to give 54.65 mg of compound 25, yield 9.86%. LCMS (ESI): [M+H] + = 514.2. 1H NMR(400 MHz, CDCl3) δ 7.34 – 7.31 (m, 5H), 6.45 (s, 1H), 5.55 (s, 1H), 5.22 (s,2H), 5.04 (d, J = 6.3 Hz, 1H), 4.91 (d, J = 13.7 Hz, 1H), 4.18 – 4.15 (m,3H), 4.06 (d, J = 6.4 Hz, 1H), 3.29 (d, J = 11.6 Hz, 1H), 3.03 (d, J = 16.6Hz, 1H), 2.50 – 2.38 (m, 1H), 2.15 – 2.13 (m, 1H), 1.99 – 1.83 (m, 2H), 1.58(s, 3H), 1.17 (t, J = 7.2 Hz, 3H).

[0326] Example 26

[0327] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-n-butyl-3-ethyl ester (compound 26)

[0328]

[0329] The synthetic method is similar to that of compound 24, except that n-butanol is used to replace cyclohexanol in step two by an equimolar amount. LCMS (ESI): [M+H] + = 480.5. 1 H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.63 (s, 1H), 5.07 –4.98 (m, 1H), 4.95 – 4.86 (m, 1H), 4.25 – 4.14 (m, 5H), 4.06 (d, J = 7.2 Hz,1H), 3.32 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.50 – 2.38 (m,1H), 2.21 – 2.11 (m, 1H), 2.02 – 1.80 (m, 2H), 1.66 – 1.60 (m, 2H), 1.56 (s,3H), 1.41 – 1.33 (m, 2H), 1.30 – 1.24 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0330] Example 27

[0331] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid bis((isobutyryloxy)methyl) ester (compound 27)

[0332]

[0333] The synthetic method is similar to that of compound 23, except that iodomethyl isobutyrate is used to replace iodomethyl tervastatin in step three in an equivalent amount. LCMS (ESI): [M+H] + = 596.5. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.82 (t, J= 5.2 Hz, 2H), 5.79 – 5.75 (m, 2H), 5.51 (s, 1H), 5.04 (d, J = 9.6 Hz, 1H), 4.87 (d, J = 9.6 Hz, 1H), 4.15 (s, 1H), 4.05 (d, J = 7.2 Hz, 1H), 3.34 (d, J= 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 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).

[0334] Example 28

[0335] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-((isobutyryloxy)methyl)-3-isopropyl ester (compound 28)

[0336]

[0337] Step 1: Synthesis of compound 28a

[0338] Compound 7b (20.0 g, 98.89 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature. Sodium hydride (5.93 g, 148.34 mmol) was slowly added to the solution at 0 °C. After the addition was complete, the reaction was allowed to proceed 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 complete, 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 28 g of compound 28a, with a yield of 87.9%. LCMS (ESI): [M+H] + =323.1.

[0339] Step 2: Synthesis of compound 28b

[0340] Compound 28a (20.0 g, 62.03 mmol) was dissolved in isopropanol (200 mL) and water (200 mL) at room temperature. Sodium hydroxide (4.96 g, 124.06 mmol) was slowly added at room temperature. After the addition was complete, the reaction mixture was heated to 50 °C and stirred for 2 h. After the reaction was complete, the reaction solution 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%–80%) to give 6.2 g of compound 28b, yield 36.7%. LCMS (ESI): [M+H] + =281.0.

[0341] Step 3: Synthesis of compound 28c

[0342] Compound 28b (3.4 g, 12.13 mmol) was dissolved in acetone (34 mL) at room temperature. Cesium carbonate (5.93 g, 18.2 mmol) and methyl isobutyrate (4.15 g, 18.2 mmol) were added, and the mixture was heated to 50 °C for 16 hours. After the reaction was complete, water (100 mL) was added to quench the reaction mixture, 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 rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 1.2 g of compound 28c, with a yield of 26.1%. 1 H NMR (400 MHz, CDCl3) δ 7.35 – 7.24 (m, 5H), 5.76 (dd, J = 15.2,5.6 Hz, 2H), 5.08 – 4.98 (m, 1H), 4.52 (s, 2H), 3.81 (dd, J = 23.2, 8.8 Hz,2H), 2.59 – 2.47 (m, 1H), 1.55 – 1.51 (m, 3H), 1.20 (dd, J = 12.0, 6.4 Hz,6H), 1.15 (dd, J = 7.2, 1.6 Hz, 6H).

[0343] Step 4: Synthesis of compound 28d

[0344] Compound 28c (1.2 g, 3.15 mmol) was dissolved in isopropanol (12 mL) at room temperature, followed by the addition of 10% palladium on carbon (500 mg). The mixture was purged three times with hydrogen and heated to 50 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 800 mg of compound 28d, with a yield of 87.5%. 1 H NMR (400 MHz, CDCl3) δ 5.82 – 5.78 (m, 2H), 5.12 – 5.03 (m, 1H), 3.92 – 3.79 (m, 2H), 2.67 – 2.54 (m, 1H), 1.44 (s, 3H), 1.27 – 1.23 (m, 6H), 1.19 (d, J = 7.2 Hz, 6H).

[0345] Step 5: Synthesis of compound 28e

[0346] At room temperature, sulfonyl chloride (558 mg, 4.13 mmol) was dissolved in diethyl ether (6 mL). The mixture was purged three times with argon gas and stirred at -78 °C for 10 min. Then, a solution of compound 28d (800 mg, 2.76 mmol) and pyridine (338 mg, 4.13 mmol) in diethyl ether (0.6 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 2 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 700 mg of compound 28e, which was directly used for the next reaction. 1 H NMR (400MHz, CDCl3) δ 7.45 – 7.30 (m, 5H), 5.20 (s, 2H), 4.17 (q, J = 6.4 Hz, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.48 (d, J = 5.2 Hz, 1H), 2.82 (t, J = 7.2 Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

[0347] Step Six: Synthesis of Compound 28

[0348] Compound 1b (350 mg, 1.89 mmol) was dissolved in a mixed solvent of dry tetrahydrofuran (7 mL) and N,N-dimethylpropenylurea (2.8 mL) at room temperature. The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (1.0 mL, 2M tetrahydrofuran solution, 2.00 mmol) was added. After the addition was complete, the mixture was stirred at -78 °C for 10 min. Then, compound 28e (700 mg, 1.80 mmol) was 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. At the end of the reaction, water (50 mL) was added 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 analyzed by prep-HPLC (Waters). Purification was performed using a 3767 / QDA column (SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%), yielding 19.32 mg of compound 28, in 7.5% yield. LCMS (ESI): [M+H] + = 538.4. 1H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 5.84 –5.76 (m, 2H), 5.58 (s, 1H), 5.10 – 4.99 (m, 2H), 4.92 – 4.85 (m, 1H), 4.15(s, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.33 (d, J = 12.0 Hz, 1H), 3.02 (d, J =12.0 Hz, 1H), 2.64 – 2.55 (m, 1H), 2.48 – 2.39 (m, 1H), 2.20 – 2.12 (m, 1H),2.01 – 1.90 (m, 1H), 1.91 – 1.81 (m, 1H), 1.56 (d, J = 1.2 Hz, 3H), 1.28 –1.24 (m, 6H), 1.18 (dd, J = 7.0, 0.8 Hz, 6H).

[0349] Example 29

[0350] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-n-butyl-3-isopropyl ester (compound 29)

[0351]

[0352] Synthetic methods are as follows, for compound 24, with compound 24a replaced by an equivalent amount of compound 24b and cyclohexanol replaced by an equivalent amount of n-butanol. LCMS (ESI): [M+H] + = 494.4. 1H NMR (400 MHz, CDCl3) δ 6.56 (s, 1H), 5.99 (s, 1H), 5.13 – 5.03 (m, 1H), 5.01 (d, J = 9.2 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.20 – 4.14 (m, 3H), 4.07 (d, J = 7.2 Hz, 1H), 3.33 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.0 Hz, 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).

[0353] Example 30

[0354] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid 1-cyclohexyl-3-isopropyl ester (compound 30)

[0355]

[0356] Synthetic methods are similar to those used for compound 24, except that compound 24a is replaced by an equivalent amount of compound 28b. LCMS (ESI) [M+H] + =520.2. 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.55 (s, 1H), 5.12 – 5.00 (m,2H), 4.97 – 4.82 (m, 2H), 4.16 (s, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.32 (d, J= 12.0 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 2.51 – 2.37 (m, 1H), 2.22 – 2.11(m, 1H), 2.00 – 1.81 (m, 4H), 1.73 – 1.68 (m, 4H), 1.54 (s, 3H), 1.48 – 1.36 (m, 4H), 1.27 – 1.22 (m, 6H).

[0357] Example 31

[0358] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxo)sulfonyl)oxo)methyl)-2-methylmalonic acid-1-ethyl-3-isopropyl ester (compound 31)

[0359]

[0360] Synthetic methods are similar to those used for compound 24, except that isopropanol is equivalently replaced with cyclohexanol. LCMS (ESI): [M+H] + =466.1. 1 H NMR (400 MHz, CDCl3) δ 6.48 (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 = 7.4 Hz, 1H), 3.32(d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.1 Hz, 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).

[0361] Example 32

[0362] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-tert-butyl-3-isopropyl ester (compound 32)

[0363]

[0364] Synthetic methods include compound 24, where compound 24a is replaced by an equivalent amount of compound 24b, and cyclohexanol is replaced by an equivalent amount of tert-butanol. LCMS (ESI): [M+Na] + = 516.2. 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 5.51 (s, 1H), 5.12 – 5.04 (m, 1H), 5.00 – 4.96 (m, 1H), 4.88 (d, J = 9.6 Hz, 1H), 4.16 (d, J = 2.4 Hz, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.32 (d, J = 12.0 Hz,1H), 3.02 (d, J = 12.0 Hz, 1H), 2.47 – 2.42 (m, 1H), 2.18 – 2.14 (m, 1H), 1.99 – 1.84 (m, 2H), 1.48 (dd, J = 14.0, 2.4 Hz, 12H), 1.28 – 1.24 (m, 6H).

[0365] Example 33

[0366] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxo)sulfonyl)oxo)methyl)-2-methylmalonic acid-1-tert-butyl-3-ethyl ester (compound 33)

[0367]

[0368] Synthetic methods are similar to those used for compound 24, except that cyclohexanol is replaced by an equimolar amount of tert-butanol. LCMS (ESI): [M+Na] + =502.4. 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.53 (s, 1H), 5.08 – 4.93 (m,1H), 4.87 (d, J = 8.3 Hz, 1H), 4.23 – 4.16 (m, 3H), 4.07 (d, J = 7.3 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.44 (dd, J = 14.3, 5.8Hz, 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).

[0369] Example 34

[0370] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-tert-butyl-3-n-butyl ester (compound 34)

[0371] Step 1: Synthesis of Compound 34a

[0372] Compound 9c (41 g, 117.0 mmol) was dissolved in dichloromethane (800 mL) at room temperature, followed by the addition of trifluoroacetic acid (26.7 g, 234.3 mmol). The reaction mixture was allowed to react at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated directly to dryness, and the residue was purified by rapid chromatography (200-300 mesh silica gel, dichloromethane:methanol (10 / 1 V / V)) to give 13.5 g of compound 34a, with a yield of 39.2%. LCMS (ESI): [M+Na] + = 317.2. 1 H NMR (400 MHz, 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).

[0373] Step 2: Synthesis of Compound 34b

[0374] Compound 34a (1.5 g, 5.10 mmol) was dissolved in dichloromethane (15 mL) at room temperature, followed by the sequential addition of butanol (567 mg, 7.65 mmol) and 4-dimethylaminopyridine (63 mg, 0.51 mmol) at room temperature. The reaction mixture was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (1.58 g, 7.65 mmol) was added. The reaction mixture was allowed to continue reacting at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate (5 / 1 V / V)) to give 1.4 g of compound 34b, yield: 78.4%. LCMS (ESI): [M+H] + = 373.3, t R = 2.151 min.

[0375] Step 3: Synthesis of compound 34c

[0376] Compound 34b (1.4 g, 4 mmol) was dissolved in isopropanol (14 mL) at room temperature, followed by the addition of 10% palladium on carbon (700 mg). This mixture was then purged three times with hydrogen. The reaction mixture was reacted at 50 °C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give 1.0 g of compound 34c, yield: 96.1%. LCMS (ESI): [M+Na] + = 283.3.

[0377] Step 4: Synthesis of compound 34d

[0378] At room temperature, sulfonyl chloride (1038 mg, 7.69 mmol) was dissolved in ether (10 mL), the mixture was purged with nitrogen, and the temperature was lowered to -78 °C and stirred for 10 min. A solution of 1-(tert-butyl)-3-butyl 2-(hydroxymethyl)-2-methylmalonic acid (1.0 g, 3.85 mmol) and pyridine (608 mg, 7.69 mmol) in ether (1 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was gradually brought to room temperature and stirred for 4 h. After the reaction was complete, the reaction solution was directly filtered, and the filtrate was concentrated to dryness to give 600 mg of the crude compound (34 days), which was directly used in the next reaction.

[0379] Step 5: Synthesis of Compound 34

[0380] 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-dimethylpropenylurea (2.4 mL). The mixture was cooled to -78°C under nitrogen protection, and sodium bis(trimethylsilyl)amino (0.89 mL, 2 M tetrahydrofuran solution, 1.78 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 10 min. Then, compound 34d (700 mg, 1.80 mmol) was 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. At the end of the reaction, water (50 mL) was added 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 analyzed by prep-HPLC (Waters). 3767 / QDA column: SunFire C18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%). Purification yielded 162.79 mg of compound 34, yield: 19.8%. LCMS (ESI): [M+Na] + = 530.5. 1 H NMR (400 MHz, CDCl3) δ 6.47 (s,1H), 5.60 (s, 1H), 5.04 – 4.80 (m, 2H), 4.17 – 4.16 (m, 3H), 4.06 (d, J = 6.8Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 3.02 (d, J = 12.4 Hz, 1H), 2.50 – 2.36(m, 1H), 2.25 – 2.07 (m, 1H), 2.01 – 1.77 (m, 2H), 1.64 – 1.62 (m, 2H), 1.51– 1.49 (m, 3H), 1.47 – 1.32 (m, 11H), 1.00 – 0.83 (m, 3H).

[0381] Example 35

[0382] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxo)sulfonyl)oxo)methyl)-2-ethylmalonic acid-1-ethyl-3-isopropyl ester (compound 35)

[0383]

[0384] The first step of the synthesis method is the same as that for compound 23, except that compound 23a is replaced by an equivalence of diethyl ethylmalonate. Subsequent synthesis is similar to that for compound 24, except that compound 23b is replaced by the product obtained in step one, and cyclohexanol is replaced by an equivalence of isopropanol. LCMS (ESI): [M+Na] + = 502.2. 1 H NMR (400 MHz, CDCl3) δ6.47 (s, 1H), 5.59 (s, 1H), 5.10 – 5.08 (m, 2H), 4.95 (d, J = 9.9 Hz, 1H), 4.34 – 4.01 (m, 4H), 3.32 (d, J = 11.9 Hz, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.45 – 2.42 (m, 1H), 2.25 – 1.79 (m, 5H), 1.30 – 1.23 (m, 9H), 0.92 (t, J = 7.5 Hz, 3H).

[0385] Example 36

[0386] Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2-((isobutyryloxy)methyl)-2-methylpropionic acid isopropyl ester (compound 36)

[0387]

[0388] Step 1: Synthesis of compound 36a

[0389] Compound 28b (3.5 g, 12.5 mmol) was dissolved in dichloromethane (35 mL) at room temperature. Triethylamine (3.78 g, 37.5 mmol) and isobutyl carbamate (3.41 g, 25 mmol) were added sequentially, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 3.3 g of compound 36a, with a yield of 69.5%. LCMS (ESI): [M+Na] + = 403.3. 1H NMR (400 MHz, 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 – 3.26 (m, 1H), 2.15 – 1.85 (m, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.27 – 1.15 (m, 6H), 1.15 – 1.06 (m, 3H), 1.01 – 0.87 (m, 3H).

[0390] Step 2: Synthesis of compound 36b

[0391] Compound 36a (3.3 g, 8.68 mmol) was dissolved in methanol (33 mL) at room temperature. The solution was cooled to 0 °C, and sodium borohydride (363 mg, 9.55 mmol) was added in portions. After the addition was complete, the solution was gradually warmed to room temperature and the reaction was continued for 1 hour. At the end of the reaction, water (100 mL) was added to quench the reaction mixture, and the solution 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 1.7 g of compound 36b, with a yield of 73.6%. LCMS (ESI): [M+H] + = 267.3. 1 H NMR (400 MHz, CDCl3) δ 7.37 – 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 = 9.2 Hz, 1H), 2.62 – 2.50 (m, 1H), 1.26 – 1.22 (m, 6H), 1.17 (s, 3H).

[0392] Step 3: Synthesis of compound 36c

[0393] Compound 36b (1.7 g, 6.40 mmol) was dissolved in dichloromethane (17 mL) at room temperature. Pyridine (758 mg, 9.58 mmol) and isobutyryl chloride (817 mg, 7.67 mmol) were added sequentially, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, water (50 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5 / 1V / V) to give 2.0 g of compound 36c, with a yield of 93.4%. LCMS (ESI): [M+H] + = 337.3. 1 H NMR (400 MHz, 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 = 7.2 Hz, 6H).

[0394] Step 4: Synthesis of compound 36d

[0395] Compound 36c (2.0 g, 5.95 mmol) was dissolved in isopropanol (20 mL) at room temperature, followed by the addition of 10% palladium on carbon (1.0 g). The mixture was purged three times with hydrogen, and the reaction was continued at 50 °C under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 1.4 g of compound 36d, with a yield of 95.8%. LCMS (ESI): [M+H] + =247.3. 1 H NMR (400 MHz, CDCl3) δ 5.12 – 4.98 (m, 1H), 4.34 – 4.15 (m, 2H), 3.76 – 3.57 (m, 2H), 2.65 – 2.46 (m, 2H), 1.27 – 1.23 (m, 6H), 1.22 – 1.12 (m,9H).

[0396] Step 5: Synthesis of compound 36e

[0397] At room temperature, sulfonyl chloride (220 mg, 1.62 mmol) was dissolved in diethyl ether (2 mL). The mixture was purged three times with argon gas, cooled to -78 °C, and stirred for 10 min. Then, a solution of compound 36d (200 mg, 0.813 mmol) and pyridine (129 mg, 1.62 mmol) in diethyl ether (1 mL) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was gradually brought to room temperature and the reaction continued for 4 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 279 mg of crude compound 36e, which was directly used in the next reaction.

[0398] Step Six: Synthesis of Compound 36

[0399] At room temperature, compound 1b (150 mg, 0.81 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (3 mL) and N,N-dimethylpropenylurea (1.2 mL). The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (0.45 mL, 2 M tetrahydrofuran solution, 0.89 mmol) was added dropwise. After the addition was complete, the reaction was maintained at -78 °C for 10 minutes, and then compound 36e (2790 mg, 0.81 mmol) was slowly added. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was continued for 2 hours. At the end of the reaction, water (100 mL) was added to quench the reaction mixture, and the solution was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 27.07 mg of compound 36, yield 6.77%. LCMS (ESI): [M+Na] + = 494.2. 1H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H),5.67 (s, 1H), 5.09 – 5.02 (m, 1H), 4.91 – 4.84 (m, 1H), 4.76 – 4.68 (m, 1H),4.30 – 4.24 (m, 1H), 4.22 – 4.15 (m, 2H), 4.06 (d, J = 7.2 Hz, 1H), 3.33 (d,J = 11.2 Hz, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.49 – 2.40(m, 1H), 2.19 – 2.14 (m, 1H), 2.00 – 1.81 (m, 2H), 1.28 – 1.24 (m, 9H), 1.18 – 1.15 (m, 6H).

[0400] Example 37

[0401] Synthesis of 2-((((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid diisopropyl ester (compound 37)

[0402]

[0403]

[0404] Step 1: Synthesis of Compound 37b

[0405] Compound 37a (2.0 g, 7.24 mmol) was dissolved in dichloromethane (20 mL) at room temperature. The solution was cooled to 0 °C, and tert-butyl 4-amino-1-piperidincarnate (1.4 g, 7.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.8 g, 7.24 mmol), and N,N-diisopropylethylamine (936 mg, 7.24 mmol) were added sequentially. After the addition was complete, the solution was gradually warmed to room temperature and the reaction was continued for 16 h. After the reaction was completed, water (100 mL) was added to quench the reaction mixture, and the solution was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography on 200-300 mesh silica gel (petroleum ether:ethyl acetate = 1 / 1 V / V) to give 3.0 g of compound 37b, in 90.4% yield. LCMS (ESI): [M+H] + =459.4.

[0406] Step 2: Synthesis of compound 37c

[0407] Compound 37b (2.0 g, 4.37 mmol) was dissolved in methanol (20 mL) at room temperature. 10% palladium on carbon (500 mg) was added, and the mixture was purged three times with hydrogen. The reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 1.4 g of compound 37c, with a yield of 87.5%. LCMS (ESI): [M+Na] + = 391.3.

[0408] Step 3: Synthesis of compound 37d

[0409] At room temperature, compound 37c (1.0 g, 2.7 mmol) was dissolved in a mixed solution of dry tetrahydrofuran (20 mL) and N,N-dimethylpropenylurea (9 mL). The solution was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (1.5 mL, 2M tetrahydrofuran solution, 3.0 mmol) was added. After the addition was complete, the mixture was stirred at -78 °C for 10 min. Then, compound 7d (986 mg, 3.0 mmol) was slowly added. After the addition was complete, the mixture was gradually heated to room temperature and the reaction was continued for 2 h. After the reaction was completed, water (100 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60%–80%) to give 100 mg of the compound after 37 days, in a yield of 5.6%. LCMS (ESI): [M+Na] + = 685.3.

[0410] Step 4: Synthesis of Compound 37

[0411] Compound 37d (60 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL) at room temperature, cooled to -10 °C, and trifluoroacetic acid (1 mL) was added. After the addition was complete, the mixture was stirred at -10 °C for 0.5 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 50%–70%) to give 21.90 mg of compound 37d, yield 43.0%. LCMS (ESI): [M+H] + = 563.5.

[0412] Example 38

[0413] Synthesis of 2-((((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid diisopropyl ester (compound 38)

[0414]

[0415] Step 1: Synthesis of compound 38b

[0416] 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), and triethylamine (11.26 g, 111.5 mmol) was added. The mixture was heated to 70 °C and reacted for 20 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness. The residue was diluted with ethyl acetate (100 mL) and washed thoroughly with 1N dilute hydrochloric acid, saturated sodium bicarbonate solution, and water in sequence. The organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 5.5 g of crude compound 38b, which was directly used in the next reaction.

[0417] Step 2: Synthesis of compound 38c

[0418] Compound 38b (2.5 g, 8.16 mmol) was dissolved in ethanol (25 mL) at room temperature, and hydrazine hydrate (0.5 mL, 12.2 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed three times with ethyl acetate (50 mL × 3). The filtrates were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 1.2 g of compound 38c, with a yield of 83.5%. 1 H NMR (400 MHz, CDCl3) δ 3.70 (t, J = 4.8 Hz, 2H), 3.36 – 3.32 (m, 2H), 1.45 (s, 9H).

[0419] Step 3: Synthesis of compound 38d

[0420] Compound 37a (1.2 g, 4.3 mmol) was dissolved in dichloromethane (12 mL) at room temperature. Compound 38c (1.1 g, 6.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.6 g, 4.3 mmol), and N,N-diisopropylethylamine (561 mg, 4.3 mmol) were added sequentially. After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 hours. Upon completion of the reaction, water (100 mL) was added to quench the reaction mixture, 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 rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 1 / 1 V / V) to give 1.5 g of the compound after 38 days, with a yield of 79.4%. LCMS (ESI): [M+H] + = 435.3.

[0421] Step 4: Synthesis of compound 38e

[0422] Compound 38d (800 mg, 1.84 mmol) was dissolved in ethyl acetate (20 mL) at room temperature, followed by the addition of 10% palladium on carbon (600 mg). The mixture was purged three times with hydrogen, and the reaction was continued for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 400 mg of compound 38e, with a yield of 63.1%. LCMS (ESI): [M+Na] + = 367.3. 1 H NMR (400 MHz, MeOD) δ 4.12–4.07 (m, 1H), 3.92–3.75 (m, 3H), 3.70 (s, 1H), 3.28 (s, 1H), 3.17–2.97 (m, 2H), 2.24–2.20 (m, 1H), 2.07–2.04 (m,1H), , 1.98–1.87 (m, 1H), 1.85–1.73 (m, 1H), 1.44 (s, 9H).

[0423] Step 5: Synthesis of compound 38f

[0424] Compound 38e (400 mg, 1.16 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and N,N-dimethylpropenylurea (3 mL) at room temperature. The mixture was cooled to -78 °C under nitrogen protection, and sodium bis(trimethylsilyl)amino (0.6 mL, 2 M tetrahydrofuran solution, 1.28 mmol) was added dropwise. After the addition was complete, the reaction was maintained at -78 °C for 10 minutes, followed by the addition of compound 7d (767 mg, 2.33 mmol). After the addition was complete, the mixture was gradually warmed to room temperature and the reaction was continued for 2 hours. At the end of the reaction, water (20 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19×250 mm, 10 μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, gradient: 60%–80%) to give 200 mg of crude compound 38f, which was directly used in the next reaction. LCMS (ESI): [M+H] + = 539.2.

[0425] Step Six: Synthesis of Compound 38

[0426] Compound 38f (100 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (2 mL) was slowly added dropwise at -10 °C. The mixture was stirred at -10 °C for 30 min. After the reaction was complete, the reaction solution was concentrated to dryness, and 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%–70%) to give 9.94 mg of compound 38, with a yield of 12.1%. LCMS (ESI): [M+H] + = 539.5. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 2H), 5.09 –5.05 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 9.6 Hz, 1H), 4.30 – 4.08(m, 3H), 3.27 (s, 2H), 3.13 (d, J = 11.2 Hz, 1H), 2.29 – 2.24 (m, 1H), 2.13 –2.10 (m, 1H), 2.00 – 1.90 (m, 2H), 1.50 (s, 3H), 1.24 (s, 12H).

[0427] Example 39

[0428] Synthesis of 2-((((((2S,5R)-2-aminoacyl-7-oxo-1,6-diazoheterocyclic[3.2.1]octane-6-acyl(oxo)sulfonyl(oxo)methyl)-2-(cyclopropylmethyl)malonic acid-1-isopropyl-3-methyl ester (compound 39)

[0429]

[0430] Step 1: Synthesis of compound 39b

[0431] Compound 39a (10 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at 0 °C. 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 sequentially under nitrogen protection, and the mixture was heated to 25 °C and reacted for 12 hours. After the reaction was complete, 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 rapid chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1V / V) to give 11.0 g of compound 39b, with a yield of 81.1%.

[0432] Step 2: Synthesis of compound 39c

[0433] Compound 39b (4.00 g, 24.97 mmol) was dissolved in THF (20 mL) at 0 °C. Sodium hydroxide (4.55 g, 24.97 mmol, 60% in mineral oil) was slowly added under nitrogen atmosphere, and stirring was continued for 30 minutes. Then, (iodomethyl)cyclopropane (1.1 g, 27.47 mmol) was added, and the mixture was heated to 50 °C and reacted for 5 hours. After the reaction was complete, the reaction mixture was quenched at 0 °C with saturated ammonium chloride aqueous solution (100 mL), and 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 3.0 g of compound 39c, yield 56.07%. 1 H NMR (400 MHz, CDCl3) δ 5.06 (dt, J = 12.4, 6.4 Hz, 1H), 3.72 (s,3H), 3.43 (t, J = 7.6Hz, 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).

[0434] Step 3: Synthesis of compound 39d

[0435] Compound 39c (1.0 g, 4.67 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (10 mL) at room temperature. Under nitrogen protection, the mixture was cooled 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 sequentially. The reaction was allowed to proceed for 16 hours at room temperature. After the reaction was complete, the reaction mixture was quenched with water (100 mL) at 25 °C and 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1V / V) to give 1.0 g of compound 39d, yield 87.71%. 1H NMR (400 MHz, CDCl3) δ 5.17 – 4.99 (m, 1H), 4.11 – 4.01 (m, 2H), 3.76 (s, 3H), 2.34 (s, 1H), 1.93 – 1.80 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 0.75 – 0.60 (m, 1H), 0.55 – 0.39 (m, 2H), 0.18 – 0.00 (m, 2H).

[0436] Step 4: Synthesis of compound 39e

[0437] At room temperature, sulfonyl chloride (332 mg, 2.46 mmol) was dissolved in diethyl ether (4 mL), and the solution was cooled to -78 °C under nitrogen atmosphere. A solution of compound 39d (400 mg, 2.46 mmol) and pyridine (194 mg, 2.46 mmol, 1.5 equivalents) in diethyl ether (2 mL) was added dropwise. After the addition was complete, the solution was gradually heated to room temperature, and the reaction was allowed to proceed for 4 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 561 mg of compound 39e, which was used directly in the next reaction without further purification.

[0438] Step 5: Synthesis of Compound 39

[0439] At room temperature, compound 1b (151 mg, 0.82 mmol) was dissolved in a mixed solvent of THF (12 mL) and N,N-dimethylpropenylurea (4.6 mL). The mixture was cooled to -78 °C under nitrogen atmosphere, and then sodium bis(trimethylsilyl)amino (0.45 mL, 2 M tetrahydrofuran solution, 0.9 mmol) was added dropwise. The mixture was reacted at -78 °C for 10 minutes, and then compound 39e (561 mg, 1.64 mmol) was added dropwise. After the addition was complete, the mixture was gradually heated to room temperature and reacted at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL) at 0 °C and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and 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%–70%) to give 45 mg of compound 39, yield 11%. LCMS (ESI) [M+H] + =492.3. 1H NMR (400 MHz, DMSO-d6) δ 7.67 – 7.32 (m, 2H), 5.10 (d,J = 9.8 Hz, 1H), 5.03 – 4.94 (m, 1H), 4.94 – 4.87 (m, 1H), 4.10 (s, 1H), 3.97– 3.89 (m, 1H), 3.72 (d, J = 2.6 Hz, 3H), 3.26 – 3.12 (m, 2H), 2.16 – 2.05(m, 1H), 1.99 – 1.90 (m, 1H), 1.89 – 1.69 (m, 4H), 1.21 – 1.16 (m, 6H), 0.67– 0.55 (m, 1H), 0.53 – 0.37 (m, 2H), 0.14 – 0.02 (m, 2H).

[0440] Example 40

[0441] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-ethyl-3-methyl ester (compound 40)

[0442]

[0443] The synthetic method is similar to that of compound 39, except that isopropanol is replaced by an equimolar amount of ethanol. LCMS (ESI) [M+H] + =478.3. 1 HNMR (400 MHz, DMSO-d6) δ 7.61-7.33 (m, 2H), 5.10 (d, J = 9.8 Hz, 1H), 4.95-4.86 (m, 1H), 4.25 – 4.14 (m, 2H), 4.11-4.07(m, 1H), 3.96-3.90 (m, 1H), 3.72(d, J = 3.6 Hz, 3H), 3.25-3.14 (m, 2H), 2.17-2.05 (m, 1H), 1.99-1.68 (m, 5H), 1.22-1.15 (m, 3H), 0.68-0.55 (m, 1H), 0.49-0.38 (m, 2H), 0.14-0.03 (m, 2H).

[0444] Example 41

[0445] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid diisopropyl ester (compound 41)

[0446]

[0447] Synthetic methods are similar to those used for compound 39, with compound 39b replaced by an equivalent amount of diisopropyl malonate. LCMS (ESI) [M+H] + =520.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 58.0 Hz, 2H), 5.08 (d, J =9.6 Hz, 1H), 5.01-4.94 (m, 1H), 4.88 (dd, J = 9.6, 2H), 4.09 (s, 1H), 3.92(d, J = 7.2 Hz, 1H), 3.23-3.13 (m, 2H), 2.13-2.07 (m, 1H), 1.99 – 1.66 (m,5H), 1.18 (d, J = 5.6 Hz, 12H), 0.64-0.52 (m, 1H), 0.46-0.38 (m, 2H), 0.11–0.04 (m, 2H).

[0448] Example 42

[0449] Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-ethyl-3-isopropyl ester (compound 42)

[0450]

[0451] The synthetic method is similar to that of compound 39, except that compound 39a is replaced by an equivalence of monoethyl malonate. LCMS(ESI) [M+H] + =506.4. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 58.0 Hz, 2H), 5.00 (d, J =10.0 Hz, 1H), 5.03-4.93 (m, 1H), 4.90 (dd, J = 9.6, 2.8Hz, 1H), 4.23 – 4.13(m, 2H), 4.10 (s, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.24-3.14 (m, 2H), 2.13-2.07(m, 1H), 1.99-1.69 (m, 5H), 1.21-1.17 (m, 9H), 0.64-0.55 (m, 1H), 0.47-0.40(m, 2H), 0.12-0.05(m, 2H).

[0452] Example 43

[0453] Synthesis of 2-((((((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)sulfonyl)oxy)methyl)-2-(cyclopropylmethyl)malonic acid-1-ethyl-3-methyl ester (compound 43)

[0454]

[0455] Step 1: Synthesis of compound 43b

[0456] Compound 43a (0.21 g, 0.73 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, followed by the addition of 10% palladium on carbon (0.1 g). The mixture was then purged three times with hydrogen gas, and the reaction was carried out at room temperature under a hydrogen atmosphere for 3 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated directly to dryness to give 0.14 g of compound 43b, with a yield of 97.2%. LCMS (ESI): [M+H] + =198.2.

[0457] Step 2: Synthesis of compound 43c

[0458] Compound 39a (10 g, 84.75 mmol) was dissolved in dichloromethane (100 mL) at 0°C. Under nitrogen protection, 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 sequentially. After the addition was complete, the reaction mixture was heated to 25°C and reacted for 12 hours. After the reaction was complete, 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 rapid chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1V / V) to give 8 g of compound 43c, with a yield of 64.64%. 1 H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.39 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0459] Step 3: Synthesis of compound 43d

[0460] Compound 43c (4 g, 27.38 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) at 0°C. Sodium hydroxide (1.2 g, 30.12 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. Then, (iodomethyl)cyclopropane (5 g, 27.38 mmol) was added to the reaction mixture. After the addition was complete, the reaction mixture was heated to 50°C and reacted for 5 hours. After the reaction was complete, the reaction mixture was quenched at 0°C with saturated ammonium chloride aqueous solution (100 mL), 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 rapid chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 92 / 8 V / V) to give 4.1 g of compound 43d, with a yield of 74.81%. 1H NMR (400 MHz, CDCl3) δ4.20 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.46 (t, J = 7.6 Hz, 1H), 1.81 (t, J= 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.78-0.67 (m, 1H), 0.48-0.41 (m, 2H), 0.13-0.09 (m, 2H).

[0461] Step 4: Synthesis of compound 43e

[0462] Under nitrogen protection and at 0°C, compound 43d (4.1 g, 20.45 mmol) was dissolved in a mixture of ethanol (40 mL) and water (20 mL), followed by the sequential addition of sodium bicarbonate (172 mg, 2.05 mmol) and 37% formaldehyde aqueous solution (1.83 g, 22.50 mmol). After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 hours. At the end of the reaction, the reaction mixture was quenched by adding water (100 mL) at 25°C, and 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 purified by rapid chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 V / V) to give 3.3 g of compound 43e, in 70.0% yield.

[0463] Step 5: Synthesis of compound 43f

[0464] At room temperature, sulfonyl chloride (2.47 g, 18.24 mmol) was dissolved in diethyl ether (30 mL), and the solution was cooled to -78°C under nitrogen protection. A solution of compound 43e (2.8 g, 12.16 mmol) and pyridine (1.45 g, 18.24 mmol) in diethyl ether (2 mL) was added dropwise. After the addition was complete, the solution was gradually warmed to room temperature, and the reaction was allowed to proceed for 4 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to give 3.9 g of compound 43f, which was used directly in the next reaction step.

[0465] Step Six: Synthesis of Compound 43

[0466] Compound 43b (130 mg, 0.66 mmol) was dissolved in a mixed solvent of THF (10 mL) and N,N-dimethylpropenylurea (4 mL) at room temperature. The solution was cooled to -78 °C under nitrogen atmosphere, and then sodium bis(trimethylsilyl)amino (0.37 mL, 2 M tetrahydrofuran solution, 0.74 mmol) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 10 minutes. Then, compound 43f (452.3 mg, 1.32 mmol) was 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 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 and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated to dryness. The residue was subjected to prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1%). Purification was performed using formic acid / water (mobile phase B: acetonitrile, gradient: 50%–70%) to give 32 mg of compound 43, yield 9.6%. LCMS (ESI) [M+H] + =490.2. 1 H NMR (400 MHz, CDCl3) δ 7.12(s, 1H),5.43(s, 1H),5.16 (t, J = 5.0Hz, 1H),5.04 (t, J = 4.0Hz, 1H),4.38-4.35(m, 1H),4.24-4.21(m, 2H),3.77-3.74 (m, 3H),3.60-3.57(m, 1H),2.99 (d, J = 8.0 Hz, 1H),2.78 (d, J = 20.0 Hz, 1H),2.39-2.33(m, 1H),2.25(s, 3H),2.01-1.97(m, 2H),1.27-1.25(m, 3H),0.68-0.60(m, 1H),0.51-0.45(m, 2H),0.13-0.07(m, 2H).

[0467] Example 44

[0468] Synthesis of 2-((((((2S,5R)-2-dicarbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid diisopropyl ester (compound 44)

[0469]

[0470] Step 1: Synthesis of Compound 44

[0471] Compound 43b (150 mg, 0.76 mmol) was dissolved in a mixed solvent of THF (10 mL) and N,N-dimethylpropenylurea (4 mL) at room temperature. The solution was cooled to -78 °C under nitrogen atmosphere, and then sodium bis(trimethylsilyl)amino (0.42 mL, 2 M tetrahydrofuran solution, 0.84 mmol) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 10 minutes. Then, compound 7d (502.8 mg, 1.52 mmol) was 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 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 and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated to dryness. The residue was subjected to prep-HPLC (Waters 3767 / QDA column: SunFire C18, 19 × 250 mm, 10 μm; mobile phase A: 0.1%). Purification was performed using formic acid / water (mobile phase B: acetonitrile, gradient: 50%–70%) to give 29 mg of compound 44, yield 7.8%. LCMS (ESI) [M+H] + =492.2. 1 H NMR (400 MHz, CDCl3) δ 7.12(s, 1H), 5.43(s, 1H), 5.10–5.07 (m, 2H), 4.41(s, 1H), 4.38-4.35(m, 1H), 4.29-4.26(m, 1H), 4.11-4.07 (m, 1H), 3.96-3.90 (m, 1H), 3.59 – 3.49 (m, 1H), 3.47 – 3.39 (m, 1H), 1.78-1.75 (m, 3H), 1.53 (s, 3H), 1.26 (d, J = 5.4 Hz, 12H).

[0472] Example 45

[0473] "Native drug" refers to the active drug released from the metabolism of prodrugs, specifically avibactam, relebactam, nakubactam, and dulobactam in this embodiment.

[0474] Test Example 1: Oral Bioavailability in Rats

[0475] Male Sprague-Dawley (SD) rats were administered the parent drug (e.g., avibactam, relebactam, nakubactam, dulobactam) via intravenous injection (IV) and oral administration (PO), respectively, and the test compound was administered orally (PO). Pharmacokinetic (PK) studies were conducted, and the oral bioavailability (%F) of the parent drug was determined by comparing the AUC after oral administration with the AUC after IV administration.

[0476] 1.1 Drug Preparation

[0477] 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 each prepared into a 1.0 mg / mL solution using 2% DMSO + 10% polyethylene glycol-15 hydroxystearate + 88% physiological saline for oral administration.

[0478] 1.2 Administration

[0479] 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.

[0480] 1.3 Operation

[0481] Blood samples were collected via jugular sinus puncture at 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after drug administration, and anticoagulated with heparin sodium. Blood samples were placed on ice after collection, and plasma separation was completed within 30 minutes of collection (centrifugation conditions: 6800g, 6 minutes, 2-8℃). The supernatant was then transferred for LC / MS / MS analysis to determine the original drug concentration.

[0482] 1.3 Pharmacokinetic Parameter Results

[0483] In male rats, the oral bioavailability of the drug after equimolar conversion between the compound and the drug is shown in Table 1 below, where A indicates (%F)>90%, B indicates 50<(%F)≤90%, C indicates 20<(%F)≤50%, and D indicates (%F)≤20%.

[0484] The results showed that compounds 8, 12, 13, 21, 24, 29, 31, 33, 35, and 40 exhibited oral bioavailability of greater than 90% for the parent drug; compounds 11, 16, 19, 23, 32, 42, and 44 showed oral bioavailability of the parent drug between 50% and 90%; and compounds 37, 38, 39, 41, and 43 showed oral bioavailability of the parent drug between 20% and 50%. These experimental results demonstrate that the compounds of this invention all exhibit good oral bioavailability of the parent drug and are suitable for oral administration.

[0485] Table 1. Pharmacokinetic parameters of the compounds in rats

[0486]

[0487] Test Example 2: Oral bioavailability of the compound in beagle dogs

[0488] Male beagle dogs were given the parent drug (e.g., avibactam, relebactam, nakubactam, dulobactam) intravenously (IV) and orally (PO), and the test compound was administered orally. Pharmacokinetic (PK) studies were conducted to determine the plasma concentration of the parent drug and the oral bioavailability (%F) of the test compound.

[0489] 2.1 Drug Preparation

[0490] Avibactam was dissolved in pH 7.5 phosphate-buffered saline (PBS) to prepare a solution of 2.0 mg / mL for intravenous injection; avibactam, compounds 31, 33, and 35 were each prepared into a solution of 2.0 mg / mL using 2% DMSO + 10% Solutol + 88% Saline for oral administration.

[0491] 2.2 Administration

[0492] 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.

[0493] 2.3 Operation

[0494] Blood samples were collected via jugular sinus puncture at 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after drug administration, and anticoagulated with heparin sodium. Blood samples were placed on ice after collection, and plasma separation was completed within 30 minutes of collection (centrifugation conditions: 2200g, 10 minutes, 2-8ºC). The supernatant was then transferred for LC / MS / MS analysis to determine the original drug concentration.

[0495] 2.4 Pharmacokinetic Parameter Results

[0496] In the pharmacokinetic study of beagle dogs, the oral bioavailability of the parent drug after converting the compound to the parent drug in equimolar amounts is shown in Table 2 below, where A indicates (%F)>90%, B indicates 50<(%F)≤90%, C indicates 20<(%F)≤50%, and D indicates (%F)≤20%.

[0497] The results showed that the oral bioavailability of the compound of the present invention in beagle dogs was greater than 90%, which effectively improved the oral bioavailability of the original drug and could solve the problem of poor oral absorption of the original drug.

[0498] Table 2. Pharmacokinetic parameters of the compounds in beagle dogs

[0499]

[0500] Test Example 3: Hepatocyte Stability Test

[0501] 3.1 Hepatocytes

[0502] Rat hepatocytes.

[0503] 3.2 Preparation of Compound Solutions

[0504] Weigh a certain amount of the compound and add DMSO to prepare a 10 mM stock solution. Take a certain volume of the stock solution and dilute it with DMSO to prepare a working solution with a concentration of 100 μM.

[0505] 3.3 Sample incubation

[0506] Take 2 μL of the working solution of the 100 μM compound and add it to 198 μL of hepatocyte suspension. Incubate at 37 °C. At time points of 0, 5, 15, 30, and 60 min, add the above mixture to the stop solution and mix well. Vortex vigorously for 10 min, then centrifuge at 6000 rpm and 4 °C for 20 min. Collect the supernatant and analyze it by LC-MS / MS.

[0507] 3.4. Results

[0508] Experimental results demonstrate that all avibactam prodrugs of this invention are completely converted to the original avibactam in rat hepatocytes. Among them, compounds 31, 33, and 35 can be rapidly and completely converted to the original avibactam in rat hepatocytes, while compounds 37, 38, and 43 are converted and released into retribactam, nakubactam, and dulobactam, respectively, in rat hepatocytes.

[0509] The metabolic data of the compounds of the present invention in rat hepatocytes are shown in Table 3; the data on the conversion and release of the original drug by the compounds of the present invention in rat hepatocytes are shown in Table 4.

[0510] Table 3. Metabolic data of the compounds in rat hepatocytes

[0511]

[0512] Note: BLOD indicates below the detection limit.

[0513] Table 4. Data on the conversion and release of the parent drug in rat hepatocytes

[0514]

Claims

1. β-lactamase inhibitors, selected from compounds with the structure shown in Formula II or their pharmaceutically acceptable salts or isomers: ； II; in, R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl; R4 is selected from , , , X1 is selected from O, S; R 6a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl; R 7a 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, and benzyl; R5 is selected from , , , R9 is selected from X2 is selected from O, S; R 6b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl; R 7b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L3 is selected from -CH2-, R 8b 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, and benzyl; However, it does not include: R3 selected from CH3, R4 selected from R5 is selected from R3 is selected from CH3, and R4 is selected from R5 is selected from .

2. The β-lactamase inhibitor according to claim 1, characterized in that: R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl; R4 is selected from , , X1 is selected from O;R 6a 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 Selected from methyl, ethyl, and isopropyl; R 7b Selected from isopropyl; L3 is selected from -CH2-, R 8b Selected from isopropyl and tert-butyl; L4 is selected from -CH2- and R 11 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and isopropoxy; However, it does not include: R3 selected from CH3, R4 selected from R4 is selected from .

3. β-lactamase inhibitors, selected from compounds with the structure shown in Formula III or their pharmaceutically acceptable salts, isomers, or deuterated derivatives: ； III; in, R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl; R4 is selected from X1 is selected from O, S; R 6a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl; R5 is selected from X2 is selected from O, S; R 6b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

4. β-lactamase inhibitors, selected from compounds with structures shown in Formula IV or their pharmaceutically acceptable salts, isomers, or deuterated derivatives: ； IV; in, R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl; R4 is selected from X1 is selected from O, S; R 6a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl; R5 is selected from X2 is selected from O, S; R 6b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. β-lactamase inhibitors, selected from compounds with the structure shown in Formula V or their pharmaceutically acceptable salts, isomers, or deuterated derivatives: ； V； in, R3 is selected from methyl, phenyl, benzyl, cyclopropyl, and cyclopropylmethyl; R4 is selected from X1 is selected from O, S; R 6a Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R5 is selected from X2 is selected from O, S; R 6b Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

6. β-lactamase inhibitors, selected from the following compounds or their pharmaceutically acceptable salts or isomers, deuterated derivatives: ； ； ； ； ； ； ； ； ； ； 。 7. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises a β-lactamase inhibitor as described in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an isomer or deuterated thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that: The pharmaceutical composition further comprises an antibiotic.

9. The pharmaceutical composition according to claim 8, characterized in that: The antibiotics mentioned are β-lactam antibiotics, including penicillins, cephalosporins, cephamycins, and carbapenems.

10. The use of the β-lactamase inhibitor according to any one of claims 1-6 or the pharmaceutical composition according to claim 10 in the preparation of a β-lactamase inhibitor, or in the preparation of a medicament for treating diseases related to bacterial infections.

11. The application according to claim 10, characterized in that: The bacteria mentioned are those capable of producing β-lactamase.

12. The application according to claim 11, characterized in that: The bacteria mentioned are Enterobacter, Citrobacter, Prof., Serratia, or Morganella, etc.

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