Beta-lactamase inhibitor containing urea tricyclic ring as well as preparation method and application of beta-lactamase inhibitor

Abstract

The invention provides a beta-lactamase inhibitor containing urea tricyclic ring as well as a preparation method and application of the beta-lactamase inhibitor, and belongs to the technical field of medicinal chemistry. The beta-lactamase inhibitor containing the urea tricyclic ring is a compound as shown in a formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. The invention also provides a beta-lactamase inhibitor with a brand new structure, when the molecule is combined with the traditional beta-lactamase antibiotic for application, the problem of drug resistance of most bacteria to the beta-lactamase antibiotic due to expression of beta-lactamase can be reversed, and the beta-lactamase inhibitor has a good application prospect in clinical treatment of bacterial infection. # imgabs0 #

Description

A β-lactamase inhibitor containing urea tricycle, its preparation method and use Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a urea tricyclic beta-lactamase inhibitor, a preparation method thereof and use thereof. Background Art

[0002] Since Fleming's discovery of penicillin in the 1920s, the invention and clinical application of antibiotics have profoundly transformed human healthcare and quality of life, significantly increasing life expectancy worldwide. However, the development of resistance among pathogens to currently used antibiotics has long been a scientific reality. Penicillin-resistant Streptococcus pneumoniae isolates were reported in 1967, followed by the discovery of penicillinase-producing Neisseria gonorrhoeae isolates in 1976. The extended-spectrum cephalosporin cefuroxime was released in 1980, and three years later, an extended-spectrum beta-lactamase-producing Escherichia coli isolate was identified. With the passage of time, the continuous introduction of new antibiotics into clinical practice, and especially the expansion of antibiotic use, the emergence of clinical pathogen resistance appears to be accelerating.

[0003] Biologically, antibiotic resistance is the natural result of the interaction between environmental selection pressures imposed by antibiotic use and the adaptive capacity of pathogens dictated by genetic mutation. While widespread antibiotic use is undoubtedly a key factor in the development and spread of antibiotic resistance, a problem and crisis, recent research suggests that resistance to antibiotic compounds first isolated from nature is a natural phenomenon that predates their industrial production. Known resistance mechanisms broadly include: ① Chemical alteration and inactivation of antibiotics, primarily through hydrolysis by β-lactamases; ② Modification of the drug-binding sites of penicillin-binding proteins (PBPs); ③ Reduced intracellular drug accumulation, such as through active efflux pumps; ④ Loss of bacterial outer membrane porins, which restrict drug influx; and ⑤ Formation of resistant bacterial biofilms.

[0004] Hydrolytic degradation of β-lactam antibiotics by β-lactamases represents the most clinically relevant mechanism of pathogen resistance. The majority of resistant bacteria on the WHO and US CDC priority or urgent threat lists express β-lactamases as a primary mechanism of resistance. β-lactam antibiotics target penicillin-binding proteins (PBPs) on the bacterial cell membrane. These proteins biochemically target enzymes involved in the biosynthesis and degradation of bacterial cell wall peptidoglycan (PG), including DD-transpeptidases (TPs), carboxypeptidases (DD-carboxy-peptidases), and endopeptidases (DD-endopeptidases). The β-lactam heterobicyclic nucleus of typical β-lactam antibiotics closely resembles the D-alanyl-D-alanine (D-ala-D-ala) moiety of the bacterial cell wall peptidoglycan tetrapeptide side chains, which serve as substrates for PBPs. The normal number and composition of PBPs are essential for bacteria to maintain normal cell morphology and function, and to complete cell division and morphogenesis during the cell cycle. β-lactam antibiotics, through irreversible covalent binding to PBPs, effectively interfere with the normal physiological cycle of cell wall biosynthesis and degradation, directly undermining the bacterial cell wall's protective function against osmotic shock, leading to bacterial cell disintegration and death. However, some Gram-negative bacteria and a few Gram-positive bacteria produce β-lactamases that are structurally similar to PBPs. These enzymes also have an exceptionally high affinity for many β-lactam antibiotics, but they can hydrolyze and destroy the four-membered β-lactam ring of the bound antibiotic, conferring drug resistance. The diverse β-lactamases, evolving at an astonishing rate, possess enormous molecular diversity, with over 7,000 distinct β-lactamase protein molecules currently known worldwide. Many pathogenic bacteria can express multiple β-lactamases with different specificities. At the same time, some β-lactamases have evolved extended-spectrum hydrolytic activities (ESBLs, carbapenemases, etc.), thus forming a pathway for acquiring multidrug resistance (MDR, XDR, PDR, etc.).

[0005] A straightforward strategy to address these resistance mechanisms is to develop small molecule inhibitors (BLIs) of β-lactamases and, through combination therapy, restore the antibacterial activity of resistant β-lactam antibiotics. For example, patent publication number CN104364254B discloses heterobicyclic compounds as β-lactamase inhibitors, providing a class of heterobicyclic compounds that, when used in combination with traditional β-lactam antibiotics, can reverse the resistance of most bacteria to β-lactam antibiotics due to the expression of β-lactamases.

[0006] However, the effects of the above-mentioned β-lactamase inhibitors still need to be further improved, and therefore it is necessary to design β-lactamase inhibitors with new molecular structures.

[0007] Summary of the Invention

[0008] In view of the problems in the prior art, the present invention provides a β-lactamase inhibitor containing a urea tricycle, a preparation method thereof and its use, with the aim of providing a new class of β-lactamase inhibitors.

[0009] The present invention provides a compound represented by Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:

[0010] in,

[0011] R1 is selected from

[0012] R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR 10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 、-CH2NR7C(O)R9;

[0013] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 The cycloalkyl, heterocycloalkyl, cycloketone group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0014] R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0015] R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, the saturated ring being optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0016] R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0017] R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0018] R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0019] R 13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0020] R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0021] m are independently selected from 1, 2, 3, and 4;

[0022] M is selected from hydrogen, a metal ion or an organic cation.

[0023] Furthermore,

[0024] R2 is selected from hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR 10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 、-CH2NR7C(O)R9;

[0025] R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, the saturated ring being optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0026] R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0027] R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0028] R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0029] m is selected from 1, 2, 3, and 4.

[0030] Furthermore, the compound is represented by Formula IA:

[0031] in,

[0032] R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -C(O)NR7R8, -CH2NR7R8, -C(O)OR9, -CH2NR7C(O)R9;

[0033] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0034] R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitriloethyl, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazolyl, oxadiazolyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0035] R7 and R8 are independently selected from H, C 1-6 Alkyl, piperidinyl;

[0036] R9 is selected from H, C 1-6 alkyl;

[0037] R 13 、R 14 、R 15 With R 16 are independently selected from H, C 1-6 alkyl;

[0038] M is selected from hydrogen or sodium ion.

[0039] Furthermore, the compound is represented by Formula IB:

[0040] in,

[0041] R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -C(O)NR7R8, -CH2NR7R8, -C(O)OR9, -CH2NR7C(O)R9;

[0042] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0043] R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitriloethyl, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16The phenyl, imidazole, oxadiazole group is optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0044] R7 and R8 are independently selected from H, C 1-6 Alkyl, piperidinyl;

[0045] R9 is selected from H, C 1-6 alkyl;

[0046] R 13 、R 14 、R 15 With R 16 are independently selected from H, C 1-6 alkyl.

[0047] Furthermore, the compound is represented by Formula IC:

[0048] in,

[0049] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0050] R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitriloethyl, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazole, oxadiazole group is optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0051] R 13 、R 14 、R 15 With R 16 are independently selected from H, C 1-6 alkyl.

[0052] Furthermore, the compound is one of the following compounds:

[0053] Furthermore, the compound is represented by Formula II:

[0054] in,

[0055] R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 、-CH2NR7C(O)R9;

[0056] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 The cycloalkyl, heterocycloalkyl, cycloketone group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0057] R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0058] R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, the saturated ring being optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0059] R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0060] R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0061] R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl;

[0062] R13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0063] R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0064] m is selected from 1, 2, 3, and 4;

[0065] M is selected from hydrogen, a metal ion or an organic cation.

[0066] Furthermore, the compound is represented by formula III:

[0067] in,

[0068] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 The cycloalkyl, heterocycloalkyl, cycloketone group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0069] R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0070] R13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen;

[0071] R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2 aryl, -SO2 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxy, halogen.

[0072] Furthermore, the compound is represented by Formula IV:

[0073] in,

[0074] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ;

[0075] R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitriloethyl, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazole, oxadiazole group is optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ;

[0076] R 13 、R 14 、R 15 With R 16 are independently selected from H, C 1-6 alkyl.

[0077] Furthermore, the compound is one of the following compounds:

[0078] The present invention also provides a method for preparing the aforementioned compound, which comprises the following steps:

[0079] Step 1: Using the bicyclic compound M1 as a raw material, a reduction reaction, a Mitsunobu reaction, a substitution reaction, a deprotection reaction, and a ring closure reaction are performed to obtain a tricyclic intermediate M2;

[0080] Step 2: Using the tricyclic intermediate M2 as a raw material, deprotection reaction, substitution reaction, and ion exchange are performed to obtain the target compound TM;

[0081] Wherein, R1, R2, R3, R4, and R5 are as described above;

[0082] PG1 is selected from a hydroxyl protecting group.

[0083] Furthermore, the preparation method of the compound M1 comprises the following steps:

[0084] Using compound M0 as the raw material, intermediate M3 is prepared through Friedel-Crafts reaction, substitution reaction, and reduction reaction, and then the ring is closed to obtain bicyclic intermediate M4. M4 is then subjected to protection, oxidation, and deprotection reaction to obtain intermediate M1.

[0085] Wherein, R2 is as described above.

[0086] The present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of β-lactamase inhibitors.

[0087] The present invention also provides use of the aforementioned compound, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of a medicament for treating bacterial infection.

[0088] Furthermore, the drug is a drug for treating infection caused by drug-resistant bacteria expressing β-lactamase.

[0089] The present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of a drug for enhancing the sensitivity of bacteria to antibiotics.

[0090] Furthermore, the drug is a drug that enhances the sensitivity of β-lactamase-producing drug-resistant bacteria to β-lactam antibiotics.

[0091] The present invention also provides a drug for treating bacterial infections and / or enhancing bacterial sensitivity to antibiotics, which is a preparation comprising the aforementioned compound, its pharmaceutically acceptable salt, its stereoisomer or its solvate as an active ingredient, and pharmaceutically acceptable excipients or auxiliary ingredients.

[0092] Furthermore, the drug is a drug for treating infection caused by drug-resistant bacteria expressing β-lactamase and / or the drug is a drug for enhancing the sensitivity of drug-resistant bacteria producing β-lactamase to β-lactam antibiotics.

[0093] The present invention also provides a combined drug for treating bacterial infection, which comprises the aforementioned drug and at least one β-lactam antibiotic.

[0094] The present invention also provides a compound preparation for treating bacterial infection, which is a compound preparation prepared by using the aforementioned combined drug as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0095] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0096] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0097] "Substitution" means that a hydrogen atom in a molecule is replaced by another different atom or molecule. "Substitution" can mean substitution by one group or by at least two groups.

[0098] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a-b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0099] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, C 1-6Alkyl refers to an alkyl group having 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group may be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may optionally be substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl, etc. The alkyl group may also be part of other groups, such as C 1-6 Alkoxy.

[0100] "Alkenyl" is used to refer to a straight or branched hydrocarbon group containing at least one olefinic bond, such as C 2-12 Alkenyl refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one olefinic bond.

[0101] "Alkynyl" is used to refer to a straight or branched chain hydrocarbon group containing at least one acetylenic bond, such as C 2-12 Alkynyl refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one acetylenic bond.

[0102] "Cycloalkenyl" refers to a non-aromatic carbocyclic group containing at least one olefinic bond, including cyclized alkenyl groups. Cycloalkenyl groups can include bicyclic, polycyclic, and spirocyclic ring systems. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl.

[0103] "Alkoxy" is used to represent a saturated chain hydrocarbon group or a cyclic hydrocarbon group connected to the substituted atom through an oxygen atom. Examples of alkoxy include but are not limited to methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyloxy, and cyclobutyloxy.

[0104] "Alkylthio" is used to indicate a saturated chain hydrocarbon group or a cyclic hydrocarbon group connected to a substituted atom through a sulfur atom. Examples of alkylthio include, but are not limited to, methylthio, ethylthio, isopropylthio, tert-butylthio, cyclopropylthio, and cyclobutylthio.

[0105] " Cycloalkyl " refers to a cyclic group of a saturated or partially saturated all-carbon monocycle or polycyclic (including condensed rings, spirocycles or bridged rings) without a conjugated π electron system. For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, when the point of attachment is located at a non-aromatic carbon atom, the term " cycloalkyl " (e.g., 5,6,7,8,-tetralin-5-yl) is used. The term " cycloalkyl " includes cycloalkenyl groups, such as cyclohexenyl. The example of a cycloalkyl group includes, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.

[0106] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, such as O, N or S, including but not limited to:

[0107] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to

[0108] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, such as O, N or S, including but not limited to:

[0109] "Cycloketo" refers to a cycloalkyl or heterocycloalkyl group with at least one carbon being replaced by C=O, including but not limited to:

[0110] "A saturated ring containing 1 or 2 heteroatoms" refers to a heterocycloalkyl group containing 1 or 2 heteroatoms.

[0111] In the present invention, -SO2C 1-6 The structure of the alkyl group is Where R' is C 1-6 Alkyl. Similarly, -SO2C 3-6 R' in cycloalkyl, -SO2 aryl, -SO2 heteroaryl is C 3-6 Cycloalkyl, aryl, heteroaryl.

[0112] In the present invention, -C(O)C 1-6 The structure of the alkyl group is Where R' is C 1-6 Alkyl. Similarly, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 In alkenyl, -C(O)aryl, -C(O)heteroaryl, R" is C 3-6 Cycloalkyl, C 2-6 Alkenyl, aryl, heteroaryl.

[0113] In the present invention, -C(O)OC 1-6 The structure of the alkyl group is Where R' is C 1-6 alkyl.

[0114] In the present invention, -OC 1-6 The structure of the alkyl group is Where R' is C 1-6 alkyl.

[0115] In the present invention, the structure of -C(O)NR7R8 is The structure of -CH2NR7R8 is The structure of -C(NH)NR7R8 is The structure of -C(O)OR9 is The structure of -C(NH)OR9 is -C(O)NR 10 The structure of NR7R8 is -C(O)NR 10 NR 11 C(O)R 12 The structure is C(O)NR 10 The structure of OR9 is C(NH)NR 10 The structure of OR9 is -C(O)NR 10 (CH2) m The structure of NR7R8 is -C(O)NR 10 (CH2) m NR 11 C(O)R 12 The structure is The structure of -SO2NR7R8 is The structure of NR7R8 is

[0116] "Stereoisomers" include enantiomers and diastereomers.

[0117] The hydrogen atoms in the compounds of the present invention may be various isotopes of hydrogen, such as protium ( 1 H), deuterium ( 2 H) or tritium ( 3 H).

[0118] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0119] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0120] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0121] The present invention provides a class of β-lactamase inhibitors with a novel structure. When used in combination with traditional β-lactam antibiotics, these molecules can reverse the drug resistance of most bacteria to β-lactam antibiotics due to the expression of β-lactamases, and have great application prospects in the clinical treatment of bacterial infections.

[0122] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0123] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0124] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0125] Example 1

[0126] Synthesis route:

[0127] Synthesis of Intermediate 2 (Step a):

[0128] Aluminum chloride (17.69 g, 132.69 mmol) was dissolved in DCM (300 ml) under nitrogen. Chloroacetyl chloride (10.56 mL, 132.69 mmol) was added and stirred at room temperature until the reaction solution turned pale yellow. Compound 1 (25 g, 120.63 mmol) was added all at once under nitrogen and stirred at room temperature overnight. The reaction was quenched with 25% wt sodium bicarbonate solution (250 mL) under ice-cooling. The organic phase was separated and the solvent was evaporated to obtain the crude product, which was purified by column chromatography to yield the title compound (25 g, 73%).

[0129] Synthesis of intermediate 3 (step b):

[0130] Intermediate 2 (11 g, 38.77 mmol) was dissolved in acetonitrile (200 mL), and sodium diformamide (4.4 g, 46.52 mmol) was added. The mixture was refluxed overnight, and another portion of sodium diformamide (2.2 g, 23.26 mmol) was added. Reflux was continued for 2 h. The acetonitrile was dried and filtered through EA slurry. The filter cake was washed with EA (100 mL x 3). The organic phase was dried and concentrated to obtain the crude product, which was purified by column chromatography to afford the title compound (9.5 g, 76.5%).

[0131] Synthesis of intermediate 4 (step c):

[0132] Intermediate 3 (16.62 g, 51.89 mmol) was dissolved in 200 mL of THF / MT (9 / 1), stirred and cooled at -20°C for 0.5 h. Ethanol (15 mL, 2.6 mol) was added, and sodium borohydride (2.35 g, 62.27 mmol) was slowly added portionwise. After the addition of sodium borohydride, the reaction was continued at -20°C for 2 h. The temperature was slowly raised to 0°C and the reaction was continued for 30 min. The sodium borohydride was quenched with water under ice-bath conditions, and the mixture was spin-dried. The inorganic salts were filtered by slurrying with EA, and the filter cake was washed with EA (100 mL x 3). The organic phase was dried and concentrated to obtain the crude product, which was used directly in the next reaction.

[0133] Synthesis of Intermediate 5 (Step d):

[0134] Intermediate 4 (7 g, 21.72 mmol) was dissolved in HCl / EtOH (1 M, 200 mL), stirred at room temperature overnight, dried, slurried with EA, filtered, and the filter cake was washed with EA (100 mL x 3). The filter cake was dried at low temperature and used directly in the next reaction.

[0135] Synthesis of Intermediate 6 (Step e):

[0136] Intermediate 5 (9.43 g, 35.42 mmol) was dissolved in DMF (150 mL). TFA (7.9 mL, 106.62 mmol) was added portionwise at room temperature. Paraformaldehyde (1.5 g, 8.5 mmol) was added and stirred at room temperature overnight. Excess paraformaldehyde was filtered and the filter cake was washed with DCM (100 mL x 2). The DCM was removed at low temperature and used directly in the next reaction.

[0137] Synthesis of intermediate 7 (step f):

[0138] To a DMF solution of intermediate 6 (150 mL) was added TEA (24.62 mL, 177.1 mmol), stirred for 30 min, and then Boc anhydride (12.21 mL, 53.13 mmol) was added and stirred at room temperature overnight. Diluted with water (100 mL), extracted with EA (100 mL x 4), and the organic phases were combined and washed with water (100 mL x 5). The organic phases were dried and concentrated to give the crude product, which was purified by column chromatography to afford the title compound (9.2 g, 70%). 1 H NMR (400MHz, DMSO-d6) δ7.93(s,2H),7.79(t,J=7.4Hz,1H),7.68(t,J=7.8Hz,2H),7.33(d,J=3.3Hz,1H),6.36(d,J=3 .4Hz,1H),5.26(d,J=5.7Hz,1H),4.52(s,2H),4.40(d,J=5.4Hz,1H),3.59(s,1H),3.18(d,J=5.3Hz,1H),1.40(s,9H).

[0139] Synthesis of intermediate 8 (step g):

[0140] Intermediate 7 (1 g, 2.64 mmol), NsNHOBn (814 mg, 2.64 mmol), and triphenylphosphine (1.038 g, 3.96 mmol) were dissolved in toluene (30 mL). Under nitrogen, DIAD (777 μL, 3.96 mmol) dissolved in toluene (3 mL) was added dropwise under an ice bath. The mixture was stirred at room temperature overnight. The reaction mixture was removed to obtain a crude product, which was purified by column chromatography to afford the title compound (1.28 g, 73%).

[0141] Synthesis of Intermediate 9 (Step h):

[0142] Intermediate 8 (5.3 g, 7.93 mmol) was dissolved in methanol (20 mL), potassium carbonate (5.48 g, 39.65 mmol) and TGA (1.37 mL, 19.82 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was spin-dried, dissolved in water (30 mL), and extracted with EA (50 mL x 4). The organic phases were combined, washed with water (20 mL x 3), dried, and concentrated to obtain a crude product, which was purified by column chromatography to afford the title compound (2.8 g, 73%).

[0143] Synthesis of intermediate 10 (step i):

[0144] Intermediate 9 (2.8 g) was dissolved in HCl / EA (2 M, 20 mL) under ice-bath and stirred at room temperature overnight. The reaction solution was neutralized with saturated sodium bicarbonate solution under ice-bath until weakly alkaline and extracted with EA (40 mL x 3). The organic phase was removed and purified by column chromatography to give the title compound (1.7 g, 70%).

[0145] Synthesis of intermediate 11 (step j):

[0146] Intermediate 10 (314 mg, 0.82 mmol) was dissolved in ACN (72 mL) at -25°C. DIPEA (542 μL, 3.28 mmol) was added and stirred for 30 min. Triphosgene (97 mg, 0.33 mmol) was dissolved in acetonitrile (5 mL) and slowly added dropwise to the reaction mixture. Stirring was continued at -25°C for 2 h. The mixture was then slowly warmed to room temperature and stirred at room temperature overnight. The product was concentrated to dryness and purified by column chromatography to afford the title compound (235 mg, 70%).

[0147] Synthesis of intermediate 12 (step k):

[0148] Intermediate 11 (294 mg, 0.72 mmol) was dissolved in methanol (20 mL). Pd / C (121 mg, 1.14 mmol) and palladium hydroxide (121 mg, 0.86 mmol) were added. The mixture was replaced with hydrogen three times and allowed to react overnight at room temperature under a hydrogen atmosphere. The palladium-carbon residue was filtered through celite, quickly dried at low temperature, and used directly in the next reaction.

[0149] Synthesis of intermediate 13 (step 1):

[0150] Intermediate 12 (100 mg, 0.31 mmol) was dissolved in pyridine (5 mL), and sulfur trioxide-pyridine (296 mg, 1.86 mmol) was added. The mixture was stirred at room temperature overnight under nitrogen. The mixture was filtered and washed with DCM (10 mL x 3). The organic phase was concentrated, purified by prep-HPLC, and lyophilized to obtain the title compound (30 mg, 24%).

[0151] Synthesis of the compound of Example 1 (step m):

[0152] Intermediate 13 was dissolved in 5 mL of purified water and sodium ion exchange resin was added and stirred for 4 h. After filtration, the filter cake was washed with water, acetone / water (1 / 1), and water in sequence. The filtrate was lyophilized to obtain the title compound (5 mg, white solid). 1 H NMR (400MHz, DMSO-d6) δ7.97–7.90(m,2H),7.83–7.74(m,1H),7.70–7.62(m,2H),7.24(d,J=3.3Hz,1H),6.33(d ,J=3.3Hz,1H),4.56(d,J=2.7Hz,1H),4.43(d,J=16.8Hz,1H),4.32(d,J=17.0Hz,1H),2.89(s,1H),2.73(s,1H).

[0153] Example 2

[0154] Synthesis route:

[0155] Synthesis of intermediate 14 (step n):

[0156] Intermediate 7 (50 mg, 0.13 mmol) was dissolved in EA (8 mL), and IBX (73 mg, 0.26 mmol) was added. The mixture was refluxed overnight, filtered, and the filter cake was washed with EA (5 mL x 3), dried, and purified by column chromatography to give the title compound (40 mg, 80%).

[0157] Synthesis of intermediate 15 (step o):

[0158] Intermediate 14 (8 g, 21.25 mmol) was dissolved in ethanol (50 mL), and KOH (12 g, 212.5 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then dried, dissolved in water (50 mL), and extracted with EA (50 mL x 3). The organic phases were combined, concentrated, and purified by column chromatography to afford the title compound (4.25 g, 84%).

[0159] Synthesis of intermediate 16 (step p):

[0160] Intermediate 15 (50 mg, 0.21 mmol) was dissolved in ultra-dry DMF (3 mL) under nitrogen atmosphere and stirred on ice for 10 min. NaH (28 mg) was added and stirred on ice for 30 min. MsCl (50 μL) was added and the mixture was allowed to react on ice for 1 h. The reaction mixture was then allowed to warm to room temperature and allowed to react for 4 h. Water was added to quench the NaH in the ice bath, and the mixture was extracted with EA (10 mL x 4). The organic phases were combined and washed with water (20 mL x 5). The organic phase was then dried and purified by column chromatography to afford the title compound (60 mg, 90%).

[0161] Synthesis of intermediate 17 (step q):

[0162] Intermediate 16 (1.5 g, 5.99 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (340 mg, 8.98 mmol) was added in portions under ice bath. The temperature was slowly raised to room temperature and the reaction was carried out at room temperature for 2 h. The sodium borohydride was quenched with water, the solvent was dried, and the residue was dissolved in EA. The organic phase was washed with water (50 mL x 2), dried, and purified by column chromatography to give the title compound (1 g, 60%).

[0163] Synthesis of intermediate 18 (step r):

[0164] Intermediate 17 (325 mg, 1.03 mmol), NsNHOBn (318 mg, 1.03 mmol), and triphenylphosphine (540 mg, 2.06 mmol) were dissolved in toluene (15 mL). Under nitrogen, DIAD (417 uL, 2.06 mmol) dissolved in toluene (3 mL) was added dropwise under an ice bath and stirred at room temperature overnight. The reaction mixture was concentrated to dryness and purified by column chromatography to afford the title compound (440 mg, 70%).

[0165] Synthesis of intermediate 19 (step s):

[0166] Intermediate 18 (440 mg, 0.73 mmol) was dissolved in methanol (8 mL), and potassium carbonate (508 mg, 3.65 mmol) and TGA (127 μl, 1.82 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was spin-dried, dissolved in water (10 mL), and extracted with EA (10 mL x 4). The organic phases were combined, washed with water (10 mL x 3), dried, concentrated, and purified by column chromatography to give the title compound (200 mg, 65%).

[0167] Synthesis of intermediate 20 (step t):

[0168] Intermediate 19 (200 mg, 0.47 mmol) was dissolved in HCl / EA (2 M, 7 mL) under ice-bath and stirred at room temperature overnight. The reaction solution was neutralized with saturated sodium bicarbonate solution to make it weakly alkaline under ice-bath and extracted with EA (20 mL x 3). The organic phase was dried, concentrated to dryness, and purified by column chromatography to give the title compound (143 mg, 94%).

[0169] Synthesis of intermediate 21 (step u):

[0170] Intermediate 20 (143 mg, 0.44 mmol) was dissolved in ACN (40 mL) at -25°C. DIPEA (291 μL, 1.76 mmol) was added and stirred for 30 min. Triphosgene (52 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL) and slowly added dropwise to the reaction mixture. Stirring was continued at -25°C for 2 h. The mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated and purified by column chromatography to afford the title compound (100 mg, 65%).

[0171] Synthesis of intermediate 22 (step v):

[0172] Intermediate 21 (100 mg, 0.29 mmol), Pd / C (70 mg, 0.66 mmol), TEA (200 uL, 2.9 mmol), and triethylamine sulfur trioxide (120 mg, 0.87 mmol) were dissolved in IPA / EA / H2O = 1:2:3 (6 mL), and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction was quenched with 1 M potassium dihydrogen phosphate solution (2 mL), Pd / C was filtered through celite, and the filter cake was washed with water (10 mL), IPA / water = 1:1 (10 mL), and water (10 mL) in sequence. The aqueous phase was washed with isopropyl acetate (10 mL x 2), and tetrabutylammonium acetate (4 eq) was added to the aqueous phase. The mixture was stirred at room temperature for 30 min, and extracted with dichloromethane (10 mL x 2) and dichloromethane:isopropanol = 5:1 (10 mL x 2) in sequence. The organic phase was concentrated at 25 ° C and used directly in the next reaction.

[0173] Synthesis of Example 2 Compound (Step w):

[0174] 2 g of Dowex ion exchange resin was suspended in a 2 M NaOH solution (20 mL) and slowly stirred for 1 hour. After filtration, the product was loaded onto a column and rinsed with copious amounts of water until the pH was neutral. Intermediate 22 obtained in the previous step was dissolved in water (5 mL) at room temperature and added to the treated Dowex ion exchange resin. The mixture was slowly stirred for 4 hours, filtered, and washed three times with water (5 mL). The collected fractions were lyophilized to yield the title compound (15 mg, 14.3%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.98(d,J=3.3Hz,1H),6.27(d,J=3.3Hz,1H),4.55(d,J=2.7Hz,1H),4.46–4. 34(m,1H),4.23(d,J=16.8Hz,1H),3.40(dd,J=10.9,2.9Hz,1H),3.36(s,3H),3.17(d,J=10.9Hz,1H).

[0175] Example 3-Example 12 General Synthesis Route:

[0176] The general synthetic methods for Examples 3 to 12 are as described above. Common intermediate 15 is used as the starting material. Intermediate A is obtained by sulfonation with different sulfonyl chlorides, followed by asymmetric reduction to obtain secondary alcohol B. B undergoes a Mitsunobu reaction to obtain a conformationally flipped intermediate C. This is followed by a two-step deprotection process to remove the o-nitrobenzenesulfonyl and tert-butyloxycarbonyl groups to obtain intermediate E. E is cyclized with triphosgene in acetonitrile to obtain tricyclic intermediate F. The benzyl group of the intermediate F is removed under palladium-carbon catalysis and sulfonated to obtain tetrabutylammonium sulfonate G. Finally, the sodium salts of Examples 3 to 12 are prepared by passing through a sodium ion exchange resin.

[0177] The specific preparation method is described below using Example 3 as an example. The preparation methods of Examples 4 to 12 are similar to those of Example 3.

[0178] Example 3

[0179] Synthesis route:

[0180] Compound 3A, namely Compound 16 in Example 2, was prepared according to the method of Compound 16 in Example 2.

[0181] Synthesis of intermediate 3B

[0182] Under nitrogen, intermediate 3A (i.e., compound 16, 5.0 g, 15.91 mmol) and (S)-MeCBS (15.91 mL, 2 M, 15.91 mmol) catalyst were dissolved in ultra-dry dichloromethane (50 mL). The temperature was cooled to -50°C and, while maintaining the temperature, borane dimethyl sulfide (7.96 mL, 15.91 mmol) was slowly added dropwise over approximately 1 hour. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was continued for approximately 1 hour. The reaction was quenched by the addition of isopropanol. The reaction solution was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to afford compound 3B (4.5 g, 89.4%, enantiomeric excess (ee%) = 84.4% by chiral HPLC).

[0183] Recrystallization: Heat to 50°C, dissolve 4.5 g of the product in 10 mL of ethyl acetate, add about 50 mL of petroleum ether, slowly cool to room temperature, precipitate crystals, and filter to obtain 2.5 g of pure product. The enantiomeric excess (ee%) measured by chiral HPLC analysis is 99.1%.

[0184] LCMS: calculated value: C 13 H 19 N2O5S, [MH] - =315.1015, measured value: 315.2.

[0185] 1 H NMR (400MHz, CDCl3) δ = 7.07-7.06 (d, J = 3.2Hz, 1H), 6.34-6.33 (d, J = 3.6Hz, 1H), 4.59- 4.44(m,3H), 3.70(s,1H), 3.61-3.58(d,J=11.6Hz,1H),3.35(m,3H),1.39(s,9H)ppm.

[0186] Synthesis of intermediate 3C

[0187] Intermediate 3B (2.4 g, 7.59 mmol), NsNHOBn (2.58 g, 8.35 mmol), and tributylphosphine (2.27 mL, 9.11 mmol) obtained in the previous step were dissolved in toluene (50 mL) at room temperature. Diisopropyl azodicarboxylate (1.80 mL, 9.11 mmol) was slowly added dropwise at 0°C. The reaction was stirred at room temperature for 4 hours. The toluene was distilled off under reduced pressure, and the crude product was concentrated. Compound 3C (4.0 g, yield 86.9%, enantiomeric excess ee% = 94.3%) was obtained by silica gel column chromatography.

[0188] LCMS: calculated value: C 26 H 30 N4O9S2Na, [M+Na] + =629.1352, measured value: 629.2.

[0189] Synthesis of intermediate 3D

[0190] Intermediate 3C (250 g, 412.1 mmol) obtained in the previous step and zinc bromide (464.1 g, 2.06 mol) were dissolved in dichloromethane (5 L) and reacted at room temperature for approximately 4 hours. After the reaction, approximately 3 L of water was slowly added to the reaction solution. The organic phase was collected and extracted once more with dichloromethane. The combined organic phases were washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was distilled off under reduced pressure to obtain the crude product, compound 3D (208 g), which was used directly in the next reaction.

[0191] LCMS: calculated value: C 21 H 22 N4O7S2, [M+H] + =507.09, measured value: 506.9.

[0192] Synthesis of intermediate 3E

[0193] Intermediate 3D (208 g, 410.6 mmol) obtained in the previous step was dissolved in a 1 / 1 acetonitrile / methanol solution (2 L). p-Toluenethiophenol (204.0 g, 1.64 mol) and potassium carbonate (227.0 g, 1.64 mol) were added and stirred at 50°C for approximately 3 hours. After completion of the reaction, the solvent was removed by concentration, and the mixture was extracted and washed with 2 L of water and 2 L of ethyl acetate. The organic phase was separated and collected, and the aqueous phase was extracted once again with 1 L of ethyl acetate. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The concentrated organic phases yielded a crude product, which was purified by silica gel column chromatography to yield compound 3E (100 g, 75.8% yield over two steps). The enantioselectivity of the product was maintained at 85-90% ee. LCMS: Calculated value: C 15 H 19 N3O3S, [M+H] + =322.11, measured value: 322.0.

[0194] Synthesis of intermediate 3F

[0195] Intermediate 3E (50 g, 155.6 mmol), diisopropylethylamine (80.4 mL, 622.3 mmol), and acetonitrile (5 L) were mixed at room temperature. Triphosgene (18.5 g, 62.3 mmol) was dissolved in 1 L of acetonitrile and slowly added dropwise to the mixture with stirring at 0°C over approximately 1 hour. The mixture was allowed to warm to room temperature and allowed to react overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the reaction solution was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to afford compound 3F (35 g, 64.7% yield).

[0196] Recrystallization: Heat to 50°C, dissolve 70 g of the product in 70 mL of ethyl acetate, add 20 mL of petroleum ether, and slowly cool to room temperature to precipitate crystals to obtain 33 g (yield 47.1%) of a white solid with an enantioselectivity of 99.5% ee.

[0197] 1 H NMR (400 MHz, CDCl3) δ = 7.43-7.35 (m, 5H), 7.05-7.04 (d, J = 3.2 Hz, 1H), 6.37-6.36 (d, J = 3.6 Hz, 1H), 4.89 (s, 2H), 4.48-4.41 (m, 2H), 4.31-4.27 (d, J = 16.8 Hz, 1H), 3.41 (s, 3H), 3.24-3.21 (d, J = 10.4 Hz, 1H) ppm. LCMS: calculated: C 16 H 18 N3O4S, [M+H] + =348.10, measured value: 348.1.

[0198] Synthesis of intermediate 3G

[0199] Intermediate 3F (33.0 g, 94.99 mmol), sulfur trioxide (51.6 g, 284.97 mmol), palladium on carbon (3 g, 31.35 mmol, 10%), and triethylamine (28.84 g, 284.97 mmol) were dissolved in isopropanol (50 mL), ethyl acetate (100 mL), and water (150 mL) at room temperature. The atmosphere was replaced with hydrogen and the mixture was allowed to react at room temperature for approximately 4 hours. The reaction was monitored to confirm the completion of both the debenzylation and sulfonation reactions. After the reaction, the solids were removed by filtration under reduced pressure, and the aqueous phase was separated and collected. The organic phase was extracted again with 100 mL of water. The combined aqueous phases were washed again with 100 mL of ethyl acetate, and the aqueous phase was collected. Tetrabutylammonium hydrogen sulfate (322.5 g, 949.9 mmol) was added directly to the aqueous phase and stirred for two hours. The stirred liquid was extracted twice with 200 mL of dichloromethane, and the organic phases were combined, washed three times with water and once with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography to obtain compound 3G (48.4 g, yield 87.8%). The purity of the compound was 98.6% by HPLC.

[0200] 1 H NMR (400MHz, CDCl3) δ = 7.05-7.04 (d, J = 3.2Hz, 1H), 6.34-6.33 (d, J = 3.2Hz, 1H), 4.62-4.61 (d, J = 2.4Hz, 1H), 4.47-4.43 (d, J = 16.8Hz, 1H), 4.32-4.2 7(d,J=16.8Hz,1H),3.48-3.44(dd,J1=11.2Hz,J1=3.2Hz,1H),3.42(s,3H ),3.25-3.22(d,J=11.2Hz,1H),3.12-3.06(q,J=7.2,8H),1.19-1.16(t,J =7.2,12H)ppm. LCMS: calculated value: C9H 10 N3O7S2, [MH] - =335.9966, measured value: 336.0.

[0201] Synthesis of Example 3

[0202] Intermediate 3G (51 g) was dissolved in 500 mL of purified water, and sodium ion exchange resin was added and stirred for 4 h. After filtration, the filter cake was washed with water, acetone / water (1 / 1), and water in sequence, and lyophilized to obtain the target compound Example 3 (22.5 g, yield 71.2%, HPLC purity 97.8%).

[0203] 1H NMR (400 MHz, CDCl3) δ = 7.05-7.04 (d, J = 3.2 Hz, 1H), 6.34-6.33 (d, J = 3.2 Hz, 1H), 4.62-4.61 (d, J = 2.4 Hz, 1H), 4.47-4.43 (d, J = 16.8 Hz, 1H), 4.32-4.27 (d, J = 16.8 Hz, 1H), 3.48-3.44 (dd, J1 = 11.2 Hz, J1 = 3.2 Hz, 1H), 3.42 (s, 3H), 3.25-3.23 (d, J = 11.2 Hz, 1H) ppm. LCMS: calculated value: C9H 10 N3O7S2, [MH] - =335.9966, measured value: 336.0.

[0204] Example 4

[0205] 1 H NMR: (400 MHz, DMSO-d6), δ 7.05 (d, J = 2.7 Hz, 1H), 6.36 (d, J = 3.1 Hz, 1H), 4.62 (s, 1H), 4.43 (d, J = 17.0 Hz, 1H), 4.30 (d, 16.7 Hz, 2H), 3.56 (q, 8.0 Hz, 2H), 3.47 (d, J = 8.2 Hz, 2H), 3.25 (d, J = 10.9 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). LCMS: calculated value: C 10 H 12 N3NaO7S2, [M-Na] - =350.3, measured value: 350.2.

[0206] Example 5

[0207] 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J = 3.3 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 4.63 (t, J = 2.7 Hz, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 3.53 (t, 2H), 3.48 (dd, J = 11.0, 2.9 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 1.66–1.41 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). LCMS: calculated value: C 11 H 14 N3O7S2 - Na +,[M-Na + ] - =364.03, measured value: 364.0.

[0208] Example 6

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J = 3.3 Hz, 1H), 6.37 (d, J = 3.3 Hz, 1H), 4.63 (t, J = 2.6 Hz, 1H), 4.40 (d, J = 16.9 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 3.79–3.66 (m, 1H), 3.47 (dd, J = 10.9, 2.9 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H). LCMS: calculated for C11H14N3O7S2 - Na + ,[M-Na + ] - =364.03, measured value: 364.1.

[0210] Example 7

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J = 3.3 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H), 4.64 (d, J = 2.6 Hz, 1H), 4.46 (d, J = 16.8 Hz, 1H), 4.32 (d, J = 16.7 Hz, 1H), 3.49 (dd, J = 10.9, 2.9 Hz, 1H), 3.26 (d, J = 10.9 Hz, 1H), 3.17–3.00 (m, 2H), 1.29–1.05 (m, 6H). LCMS: calculated value: C 11 H 12 N3O7S2 - Na + ,[M-Na + ] - =362.01, measured value: 361.9.

[0212] Example 8

[0213] LCMS: calculated value: C 12 H 14 N3O7S2, [M-Na] -=376.03, measured value: 376.01.

[0214] Example 9

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 7.01 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 4.62 (d, J = 2.6 Hz, 1H), 4.43-4.22 (m, 2H), 3.54 (ddd, J = 11.5, 8.0, 3.3 Hz, 1H), 3.47 (dd, J = 11.0, 2.9 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 1.93-1.55 (m, 5H), 1.43-1.03 (m, 5H). LCMS: calculated value: C 14 H 18 N3O7S2 - , [M-Na] - =404.06, measured value: 404.03.

[0216] Example 10

[0217] 1H NMR (400MHz, DMSO) δ9.13(d,J=2.2Hz,1H),8.94(d,J=4.8Hz,1H),8.38(d,J=8.2Hz,1H),7.71(dd,J=8.2,4.9Hz,1H),7.34(d,J=3.2Hz,1H), 6.38 (d, J = 3.2Hz, 1H), 4.58 (d, J = 2.4Hz, 1H), 4.49 (d, J = 16.9Hz, 1H), 4.35 (d, J = 16.9Hz, 1H), 3.45 (d, J = 2.6Hz, 1H), 3.21 (d, J = 11.0Hz, 1H). LCMS: Calculated value C 13 H 11 N4O7S2, [M-Na]- = 399.37. Actual value 400.1

[0218] Example 11

[0219] 1H NMR (400 MHz, CDCl3) δ = 8.62 (s, 1H), 8.00 (s, 1H), 7.12-7.11 (d, J = 3.2 Hz, 1H), 6.31-6.30 (d, J = 3.2 Hz, 1H), 4.57-4.57 (d, J = 2.4 Hz, 1H), 4.45-4.32 (q, J = 16.8 Hz, 2H), 3.88 (s, 3H), 3.45-3.42 (m, 1H), 3.21-3.18 (d, J = 10.8, 1H) ppm. LCMS: calculated value: C 12 H 12 N5O7S2, [M+H] + =402.0184, measured value: 402.2.

[0220] Example 12

[0221] 1 H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 4.64 (d, J = 2.6 Hz, 1H), 4.46–4.21 (m, 2H), 3.49 (dd, J = 11.0, 2.9 Hz, 1H), 3.29 (d, J = 10.9 Hz, 1H), 2.77 (s, 6H). LCMS: calculated value: C 10 H 13 N4O7S2 - Na + ,[M-Na + ] - =365.02, measured value: 364.9.

[0222] Example 13-Example 15 General Synthesis Route:

[0223] The general synthetic methods for Examples 13 to 15 are as described above. Common intermediate 5 is used as the starting material. Intermediate H is obtained by ring closure with ethyl formaldehyde, followed by Boc protection to obtain intermediate I. Intermediate I is oxidized with IBX to obtain ketone J, which is then deprotected in a methanol / water solution of sodium hydroxide to obtain key intermediate K. Intermediate K is amidated with ammonium chloride to obtain intermediate L, which is then sulfonylated with various sulfonyl chlorides to obtain various intermediates M. Intermediate M is then reduced with sodium borohydride, followed by a Mitsunobu reaction and a two-step deprotection reaction to obtain intermediate Q. Q is ring-closed with triphosgene in acetonitrile to obtain tricyclic intermediate R. The benzyl group of intermediate R is removed under palladium-carbon catalysis and sulfonated to obtain tetrabutylammonium sulfonate. Finally, the sodium salts of Examples 13 to 15 are prepared by sodium ion exchange resin.

[0224] The specific preparation method is described below using Example 13 as an example. The preparation methods of Examples 14 and 15 are similar to those of Example 13.

[0225] Example 13

[0226] Synthesis route:

[0227] Synthesis of intermediate H

[0228] To a 10 L reaction flask, intermediate 5 (230 g, 759.6 mmol), tetrahydrofuran (2.3 L), and a 50% ethyl glyoxylate solution in toluene (264.5 g, 1.30 mol) were added sequentially. The mixture was cooled to 0-5°C in an ice bath and trifluoroacetic acid (246.2 g, 2.16 mol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 16 hours. LCMS monitoring confirmed the presence of product and the absence of starting material. After completion of the reaction, the reaction was directly carried out to the next step.

[0229] 1 HNMR(400MHz, DMSO-d6)δ=1.20~1.26(t,J=4.0Hz,3H),2.43~2.49(m, 1H),2.93~2.98(m,1H),4.05~4.17(m,2H),4.37~4.39(m,1H),4.71(s,1H),4.96(s,1H),5.18(s,1H), 6.41 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H), 7.64 ~ 7.69 (m, 2H), 7.74 ~ 7.78 (m, 1H), 7.87 ~ 7.93 (m, 2H). LCMS:C 16 H 18 N2O5S, theoretical value [M] = 350.0, measured value [M+H] + =351.1.

[0230] Synthesis of intermediate I

[0231] In a 10L four-necked flask, the reaction mixture containing the intermediate H obtained above (estimated to be 300g, 856mmol) was cooled to 0-5°C and triethylamine (434g, 4.29mol) was slowly added dropwise. The reaction mixture was then allowed to warm to room temperature, followed by the dropwise addition of di-tert-butyl dicarbonate (374g, 1.71mol). The mixture was stirred at room temperature for 16 hours. LCMS monitoring indicated that no starting material remained and product was formed. After completion of the reaction, the mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (500mL x 3) and discarded. The filtrate was concentrated and purified on a silica gel column to afford 147g of a yellow solid in a 38.1% yield.

[0232] 1H NMR (400MHz, DMSO-d6) δ=0.96~1.05(m,3H),1.25(s,9H),4.03~4.06(m,2H),4.06~4.08(m,1H),4.24~4.33(m,1 H), 5.43 (s, 1H), 5.67 ~ 5.96 (m, 1H), 6.26 ~ 6.29 (m, 1H), 7.22 ~ 7.47 (m, 1H), 7.47 ~ 7.59 (m, 3H), 7.69 ~ 7.74 (m, 2H). LCMS:C 21 H 26 N2O7S, theoretical value [M] = 450.1, measured value [M+H] + =451.1.

[0233] Synthesis of intermediate J

[0234] To a 500 mL reaction flask, add Intermediate I (18 g, 39.95 mmol), dissolve in 180 mL of ethyl acetate, and add 2-iodoacylbenzoic acid (22.37 g, 79.9 mmol). Heat under reflux and react for 8 hours. Monitor the reaction by LCMS until completion. The reaction solution is cooled to room temperature and filtered. The filter cake is washed with 100 mL of ethyl acetate, and the filtrate is concentrated and purified by silica gel chromatography to obtain 15.5 g of a white solid in an 86% yield.

[0235] NMR: 1 HNMR (400MHz, CDCl3): δ1.28~1.43(m,3H), 1.47~1.62(m,9H), 3.64~3.81(m,1H), 4.24~4.28(m ,2H),4.62~4.82(m,1H),6.54~6.80(m,2H),7.21(s,1H),7.59~7.72(m,3H),7.97~8.02(m,2H). LCMS:C 21 H 24 N2O7S, theoretical value [M] = 448.1, measured value [M+H] + =449.1.

[0236] Synthesis of key intermediate K

[0237] In a 500mL reaction flask, intermediate J (15.5g, 34.6mmol), 210mL of methanol and 21mL of water were added, ventilated three times with a nitrogen balloon, cooled to 0-5°C in an ice bath, sodium hydroxide (8.3g, 207.5mmol) was added in one portion, ventilated three times with a nitrogen balloon, and slowly returned to room temperature for 2h. LCMS monitoring was performed until no starting material remained. Cooled to 0-5°C in an ice bath, the pH was adjusted to 1-2 with 2M aqueous hydrochloric acid solution, concentrated at 40°C to remove methanol, and redissolved with 300mL of ethyl acetate. The aqueous phase was saturated with sodium chloride, stirred evenly, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (100mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain a total of 10g of yellow solid with a yield of 106%. LCMS: C 13 H 16 N2O5, theoretical value [M] = 280.1, measured value [M+H] + =281.0.

[0238] Synthesis of intermediate L:

[0239] To a 500 mL reaction flask, intermediate K (10 g, 35.68 mmol), DMF (120 mL), HATU (27.13 g, 71.36 mmol), and ammonium chloride (5.73 g, 107.04 mmol) were added. The mixture was purged with a nitrogen balloon three times and cooled to 0-5°C in an ice bath. N,N-diisopropylethylamine (23.59 g, 142.72 mmol) was added dropwise. The mixture was returned to room temperature and stirred overnight. LCMS monitoring confirmed no residual starting material. To the reaction mixture, 150 mL of saturated brine, 150 mL of water, and 300 mL of ethyl acetate were added while stirring. The mixture was stirred until uniform and allowed to stand. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 7.1 g of the desired product in a 71% yield.

[0240] 1 HNMR (400MHz, DMSO-d6): δ1.43(s,9H),4.13~4.30(m,2H),5.60~5.68(m,1H),6.35(s,1H),6.95( s, 1H), 7.41 ~ 7.45 (d, J = 16.0Hz, 1H), 7.54 ~ 7.56 (d, J = 8.0Hz, 1H), 11.38 ~ 11.51 (d, J = 12.0Hz, 1H). LCMS:C 13 H 17 N3O4, theoretical value [M] = 279.1, measured value [M+H] + =280.2.

[0241] Synthesis of intermediate 13M:

[0242] To a 250 mL reaction flask, intermediate L (7 g, 25.06 mmol), THF (70 mL), N,N-diisopropylethylamine (9.72 g, 75.18 mmol), N,N-dimethylaminopyridine (0.31 g, 2.51 mmol), and pyridine 3-sulfonyl chloride (6.68 g, 37.59 mmol) were added sequentially. The mixture was stirred at room temperature overnight and monitored by LCMS until no starting material remained. 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture, stirred evenly, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 7.9 g of the desired product as a yellow solid in a 75% yield.

[0243] 1 HNMR(400MHz,DMSO-d6): δ1.44(s,9H),3.73(br,1H),4.44(br,1H),6.43(br,1H), 6.71(s,1H),7.67~7.79(m,4H),8.50~8.53(m,1H),8.97~8.99(m,1H),9.26(s,1H). LCMS:C 18 H 20 N4O6S, theoretical value [M] = 420.1, measured value [M+H] + =421.1.

[0244] Synthesis of intermediate 13N:

[0245] To a 250 mL reaction flask, intermediate 13M (8 g, 19.03 mmol), THF (100 mL), and methanol (10 mL) were added. The mixture was cooled to 0-5°C in an ice bath. Sodium borohydride (0.86 g, 22.84 mmol) was added in two portions. The reaction was continued for 0.5 h after the addition was complete. TLC monitoring was performed until no starting material remained. The reaction solution was quenched with 30 mL of water and concentrated to remove the methanol. 200 mL of ethyl acetate was added, followed by the addition of sodium chloride-saturated aqueous phase. The mixture was stirred evenly, allowed to stand, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 8 g of the crude target product as a yellow solid in a 99% yield.

[0246] LCMS:C 18 H 22 N4O6S, theoretical value [M] = 422.1, measured value [M-H2O+H] + =405.1.

[0247] Synthesis of intermediate 13O:

[0248] To a 250 mL reaction flask, intermediate 13N (7.9 g, 18.7 mmol), toluene (120 mL), BnONHNs (11.53 g, 37.4 mmol), and tri-n-butylphosphine (7.57 g, 37.4 mmol) were added. The mixture was cooled to 0-5°C in an ice bath, and DEAD (6.51 g, 37.4 mmol) was added dropwise. The mixture was allowed to react overnight at room temperature. LCMS monitoring was performed until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to obtain 12.3 g of the desired product as an orange oil in a 92% yield.

[0249] NMR: 1 HNMR(400MHz, DMSO-d6)δ=1.25~1.50(m,9H),4.03~4.08(m,4H),4.88~4.89(m,1H),5.99~ 6.00(m,1H),6.59~6.64(m,2H),7.15~7.34(m,6H),7.92~8.45(m,5H),8.83~9.24(m,2H). LCMS:C 31 H 32 N6O 10 S2, theoretical value [M] = 712.2, measured value [M+H] + =713.4.

[0250] Synthesis of intermediate 13P:

[0251] To a 250 mL reaction flask, intermediate 13O (11.8 g, 16.56 mmol) was added, followed by a solution of TFA (20 mL) in DCM (100 mL). The mixture was allowed to react at room temperature for 1 h, monitored by LCMS until no starting material remained. The reaction solution was concentrated, and 100 mL of saturated sodium bicarbonate and 200 mL of ethyl acetate were added. After stirring, the mixture was allowed to stand for separation. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 11.4 g of the crude target product as a yellow oil. The yield was 112%.

[0252] NMR: 1 HNMR (400MHz, DMSO-d6) δ1.25~1.50(m,9H),4.03~4.08(m,4H),4.88~4.89(m,1H),5.99~ 6.00(m,1H),6.59~6.64(m,2H),7.15~7.34(m,6H),7.92~8.45(m,5H),8.83~9.24(m,2H). LCMS:C 31 H 32 N6O 10 S2, theoretical value [M] = 712.2, measured value [M+H] + =713.4.

[0253] Synthesis of intermediate 13Q:

[0254] To a 250 mL reaction flask, intermediate 13O (11.4 g, 18.61 mmol), p-toluenethiophenol (6.93 g, 55.83 mmol), and potassium carbonate (7.72 g, 55.83 mmol) were added. The reaction was allowed to react at room temperature for 3 h. LCMS monitoring was performed until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to obtain 3 g of the desired product as a yellow oil in a 37% yield.

[0255] NMR: 1 HNMR (400MHz, DMSO-d6) δ2.62~2.68(m,1H),2.95(m,1H),3.06~3.09(m,1H), 3.60~3.62(m,1H),4.61(s,2H),4.66~4.69(m,1H),6.33(s,1H),6.51(d,J=8. 0Hz, 1H), 7.28 (s, 1H), 7.30~7.44 (m, 7H), 7.62~7.66 (d, J=8.0Hz, 1H), 8.33~8 .36(dd,J=12.0,4.0Hz,1H),8.85~8.87(dd,J=12.0,4.0Hz,1H),9.09(s,1H). LCMS:C 20 H 21 N5O4S, theoretical value [M] = 427.2, measured value [M+H] + =428.2.

[0256] Synthesis of intermediate 13R:

[0257] To a 250 mL reaction flask, add intermediate 13Q (3 g, 7.02 mmol), acetonitrile (200 mL), and N,N-diisopropylethylamine (3.63 g, 28.08 mmol). The mixture was cooled to 0-5°C in an ice bath. A solution of triphosgene in acetonitrile (0.83 g of triphosgene dissolved in 50 mL of acetonitrile) was added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. LCMS monitoring was performed until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to obtain 2.9 g of the desired product as a light yellow solid in a 91% yield.

[0258] NMR: 1HNMR (400MHz, DMSO-d6)δ=3.16~3.20(m,1H),3.46~3.48(m,1H),4.43(s,1H),4.89(s,2H),5.17(s,1H),6.46( s,1H),7.37~7.68(m,7H),7.68~7.70(m,1H),8.11(s,1H),8.36~8.39(m,1H),8.90~8.92(m,1H),9.11(s,1H). LCMS:C 21 H 19 N5O5S, theoretical value [M] = 453.2, measured value [M+H] + =454.2.

[0259] Synthesis of Example 13:

[0260] To a 50 mL reaction flask was added intermediate 13R (518 mg, 1.14 mmol), isopropanol (12 mL) and water (8 mL), followed by triethylamine (58 mg, 0.57 mmol), triethylamine sulfur trioxide complex (52 mg, 2.85 mmol) and palladium on carbon (1 g, 9.4 mmol). The mixture was replaced three times under hydrogen protection and allowed to react at room temperature overnight. LCMS monitoring showed that the remaining raw material was about 16%, which was then post-treated. 1. The reaction mixture was filtered through a pad of celite, the filter cake was washed with 10 mL of isopropanol, and concentrated to dryness at 40°C to obtain a crude product. 2. The crude product was passed through a reverse phase column to obtain a water and acetonitrile solution of the desired product, which was concentrated at 40°C to remove the acetonitrile. 3. 4 g of Dowex 50WX8 resin was added to 20 mL of a 2M aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 h and filtered. The filter cake was washed with deionized water until the pH was neutral. The filter cake was transferred to an aqueous solution of the desired product and stirred at room temperature for 1 day. 4. The mixture was filtered and the filtrate was lyophilized. The sodium salt of the desired product was prepared by analysis and a total of 51 mg as a white solid.

[0261] 1 HNMR (400MHz, DMSO-d6)δ=3.26~3.29(m,1H),3.38~3.51(m,1H),4.61(s,1H),5.17(s,1H),6.40(s,1H),7.42~ 7.46(m,2H),7.66~7.69(dd,J=8.0,4.0Hz,1H),8.11(s,1H),8.36(d,J=8.0Hz,1H),8.90(m,1H),9.10(s,1H). LCMS:C 14 H 13 N5O8S2, theoretical value [M] = 443.1, measured value [MH] - =442.0. HPLC: purity: 94.9%.

[0262] Example 14

[0263] 1 HNMR (DMSO-d6, 400 MHz): δ 3.29-3.32 (m, 2H), 3.47 (s, 3H), 4.64 (d, J = 4.0 Hz, 1H), 5.08 (s, 1H), 6.36 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.53 (s, 1H), 8.05 (s, 1H). LCMS: theoretical value C 10 H 11 N4NaO8S2, [M-Na] - =379.0, actual measured value 379.0.

[0264] Example 15

[0265] 1 HNMR (400 MHz, DMSO-d6) δ 1.08-1.27 (m, 5H), 3.20-3.23 (m, 1H), 3.37-3.40 (m, 1H), 4.64 (s, 1H), 5.10 (s, 1H), 6.34 (d, J = 4.0 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.47 (s, 1H), 8.04 (s, 1H). LCMS: theoretical value C 12 H 13 N4O8S2, [M-Na] - 405.02, measured value 405.0.

[0266] Example 16

[0267] Synthesis of intermediate 16B

[0268] In a three-necked round-bottom flask, intermediate 16A (15 g, 86.43 mmol) was added and dissolved in tetrahydrofuran (300 mL) and ice-bathed for 15 minutes. Simultaneously, lithium hydroxide monohydrate (2.12 g, 50.46 mmol) was dissolved in tetrahydrofuran (100 mL) and ice-bathed for 15 minutes. While maintaining the ice bath, the lithium hydroxide aqueous solution was added to the reaction solution. The reaction solution was then slowly returned to room temperature and stirred for 1 hour. The reaction was monitored by TLC until completion. 1 M dilute hydrochloric acid was slowly added to the reaction solution while cooling it to an ice bath to adjust the pH to 2-3. Ethyl acetate (500 mL) was added, along with a small amount of solid sodium chloride until solid precipitated in the aqueous phase. The reaction solution was allowed to stand and separated. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford crude intermediate 16B (14 g, 100% yield) as a yellow solid, which was used directly in the next reaction.

[0269] Synthesis of intermediate 16C

[0270] In a round-bottom flask, compound 16B (6 g, 16.74 mmol) was added and dissolved in acetonitrile (60 mL). Cesium carbonate (8.18 g, 25.11 mmol) was added and stirred at room temperature for 5 minutes. Subsequently, iodomethane (4.75 g, 33.4 mmol) was added dropwise using a rubber-tipped dropper and stirred at room temperature for 6 hours. LCMS monitoring showed that no starting material remained.

[0271] The reaction solution was slowly added to water (200 mL) at room temperature and stirred for 10 minutes. Ethyl acetate (150 mL) was added and stirring was continued for 5 minutes. The reaction solution was allowed to stand and then separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow oily crude product, which was purified by silica gel chromatography to obtain intermediate 16C (4.17 g, yield 66.8%) as a yellow oil.

[0272] 1 H NMR(400MHz,DMSO-d6)δ1.46(s,9H),3.71(s,3H),3.76-3.88(m,3H),3.93-3.94(m ,1H),4.42-4.49(m,1H),4.94(s,1H),6.72(d,J=4.0Hz,1H),7.53(d,J=4.0Hz,1H).

[0273] Synthesis of intermediate 16D

[0274] To a round-bottom flask, intermediate 16C (8 g, 21.48 mmol), tetrahydrofuran (80 mL), and methanol (8 mL) were added. The mixture was cooled to 0-5°C in an ice bath. Sodium borohydride (1 g, 26.42 mmol) was added in two portions. The reaction was continued for 0.5 hours after the addition was complete. TLC monitoring was performed until no starting material remained. The reaction mixture was quenched with water (100 mL) and concentrated to remove the methanol. Ethyl acetate (300 mL) was added, followed by the addition of sodium chloride-saturated aqueous phase. The mixture was stirred until uniformly distributed. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude intermediate 16D (8 g, 99% yield) as a white solid, which was used directly in the next step.

[0275] Synthesis of intermediate 16E

[0276] To a round-bottom flask, intermediate 16D (8 g, 21.36 mmol), toluene (100 mL), BnONHNs (12.5 g, 40.54 mmol), and tri-n-butylphosphine (8.2 g, 40.54 mmol) were added. The mixture was cooled to 0-5°C in an ice bath, and DIAD (8.2 g, 40.54 mmol) was added dropwise. The mixture was allowed to react overnight at room temperature and monitored by LCMS until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford intermediate 16E (10 g, 82.9% yield) as a yellow oil.

[0277] Synthesis of intermediate 16F

[0278] To a round-bottom flask, intermediate 16E (4.6 g, 6.92 mmol) and a dichloromethane solution of TFA (12.5 mL of TFA dissolved in 50 mL of dichloromethane) were added. The mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC until no starting material remained. The reaction solution was concentrated and repeatedly rinsed with dichloromethane (50 mL) three times. Saturated sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL) were added, stirred until uniform, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of intermediate 16F (3.76 g, 96.23% yield) as a yellow solid, which was used directly in the next reaction.

[0279] LCMS: C 23 H 25 N4O9S2, theoretical value [M+H] + =565.1, measured value [M+H] + =565.0.

[0280] Synthesis of intermediate 16G

[0281] To a round-bottom flask, intermediate 16F (3.76 g, 6.66 mmol), acetonitrile (56 mL), p-toluenethiophenol (2.48 g, 19.98 mmol), and potassium carbonate (2.76 g, 19.98 mmol) were added. The mixture was allowed to react at room temperature for 3 hours. LCMS was used to monitor the reaction until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford intermediate 16G (1.48 g, 58.57% yield) as a yellow solid.

[0282] LCMS: C 17 H 22 N3O5S, theoretical value [M+H] + =380.1, measured value [M+H] + =380.1.

[0283] Synthesis of intermediate 16H

[0284] To a round-bottom flask, add Intermediate 16G (1.48 g, 3.90 mmol), acetonitrile (150 mL), and N,N-diisopropylethylamine (2.02 g, 15.6 mmol). The mixture was cooled to 0-5°C in an ice bath. A solution of triphosgene in acetonitrile (0.46 g, 1.56 mmol, dissolved in 74 mL of acetonitrile) was added dropwise. The reaction was allowed to react overnight at room temperature, monitored by LCMS, until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford Intermediate 16H (1.45 g, 91.69% yield) as a yellow solid.

[0285] 1 H NMR (400MHz, DMSO-d6) δ3.25-3.31(m,2H),3.42(s,3H),3.79(s,3H),4.55(d,J=4.0Hz,1H),4. 93-4.94(m,2H),5.10(s,1H),6.50(d,J=4.0Hz,1H),7.26(d,J=4.0Hz,1H),7.39-7.46(m,5H).

[0286] LCMS: C 18 H 20 N3O6S, theoretical value [M+H] + =406.1, measured value [M+H] + =406.1.

[0287] Synthesis of intermediate 16I

[0288] To a round-bottom flask were added intermediate 16H (300 mg, 0.74 mmol), isopropanol (4 mL), ethyl acetate (2 mL), and water (2 mL), followed by triethylamine (220 mg, 2.22 mmol), triethylamine sulfur trioxide complex (400 mg, 2.22 mmol), and palladium on carbon (60 mg, 0.56 mmol). The mixture was replaced three times under hydrogen protection, and the reaction was allowed to react at room temperature overnight. The reaction was monitored by LCMS until no starting material remained.

[0289] The reaction mixture was filtered through a pad of celite, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was concentrated to dryness below 30°C to obtain the crude product. The crude product was subjected to reverse phase preparation to obtain a water and acetonitrile solution of the desired product, which was concentrated below 30°C to remove the acetonitrile. The aqueous solution of intermediate 16I was retained and used directly in the next reaction.

[0290] Synthesis of Example 16

[0291] Dowex 50WX8 resin (10 g) was weighed and added to a 2 M aqueous sodium hydroxide solution (200 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The filter cake was washed with deionized water until the pH was neutral. The filter cake was transferred to an aqueous solution of intermediate 16I and stirred at room temperature for 4 hours. The reaction solution was then filtered and the filtrate was lyophilized to obtain Example 16 (40 mg, total yield of the two-step reaction was 13.67%) as a light yellow solid.

[0292] 1 H NMR (400MHz, DMSO-d6) δ3.27-3.30(m,2H),3.42(s,3H),3.79(s,3H),4.72(d,J=4.0Hz,1H),5.09(s,1H),6.45(d,J=4.0Hz,1H),7.25(d,J=4.0Hz,1H). 13 C NMR(150MHz,DMSO-d6)δ169.28,166.77,125.25,121.81,121.10,112.24,62.36,57.80,53.04,47.03,42.10.HRMS(ESI) - :calcd for C 11 H 11 N3O9S2[M-Na] - :394.0020,found:394.0003.

[0293] Example 17

[0294] Synthesis of intermediate 17B

[0295] To a round-bottom flask, intermediate 16A (2 g, 5.18 mmol), tetrahydrofuran (50 mL), and methanol (5 mL) were added. The mixture was cooled to 0-5°C in an ice bath. Sodium borohydride (0.1 g, 2.59 mmol) was added in two portions. The reaction was continued for 0.5 h after the addition was complete. The reaction was monitored by TLC until no starting material remained. The reaction solution was quenched by the addition of water (50 mL). The tetrahydrofuran and methanol were removed by concentration, followed by the addition of ethyl acetate (150 mL). The aqueous phase was saturated with sodium chloride and stirred until uniformly mixed. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude intermediate 17B (2 g, 99% yield) as a white oil, which was used directly in the next reaction.

[0296] Synthesis of intermediate 17C

[0297] To a round-bottom flask, intermediate 17B (2 g, 5.15 mmol), toluene (30 mL), BnONHNs (3.18 g, 10.3 mmol), and tri-n-butylphosphine (2.08 g, 10.3 mmol) were added. The mixture was cooled to 0-5°C in an ice bath, and DIAD (2.08 g, 10.3 mmol) was added dropwise. The mixture was allowed to react overnight at room temperature and monitored by LCMS until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford intermediate 17C (2.9 g, 83% yield) as a yellow oil.

[0298] 1 H NMR(400MHz,DMSO-d6)δ0.82-.085(m,3H),1.14-1.21(m,9H),3.58(s,3H),4.12-4.17(m,2H),4.18-4 .95(m,2H),4.95(s,1H),6.06-6.24(m,1H),6.80-6.88(m,2H),7.18-7.38(m,5H),7.70-7.98(m,4H).

[0299] Synthesis of intermediate 17D

[0300] To a round-bottom flask, intermediate 17C (2.9 g, 4.27 mmol) and a dichloromethane solution of TFA (10 mL of TFA dissolved in 40 mL of dichloromethane) were added. The mixture was allowed to react at room temperature for 3 hours. The reaction was monitored by TLC until no starting material remained. The reaction solution was concentrated and repeatedly rinsed with dichloromethane (100 mL) five times. Saturated sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL) were added. After stirring, the mixture was allowed to stand for separation. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford crude intermediate 17D (2.67 g, 108% yield) as a yellow oil, which was used directly in the next reaction.

[0301] LCMS:C 24 H27 N4O9S2, theoretical value [M+H] + =579.1, measured value [M+H] + =579.1.

[0302] Synthesis of intermediate 17E

[0303] To a round-bottom flask, Intermediate 17D (2.67 g, 4.61 mmol), acetonitrile (100 mL), p-toluenethiophenol (1.72 g, 13.83 mmol), and potassium carbonate (1.91 g, 13.83 mmol) were added. The mixture was allowed to react at room temperature for 6 hours. LCMS was used to monitor the reaction until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford Intermediate 17E (1 g, 55% yield) as a yellow oil.

[0304] 1 H NMR (400MHz, DMSO-d6) δ1.18-1.23(m,3H),2.64-2.67(m,1H),3.03-3.13(m,2H),3.73-3.75(m,1H),4.02-4.10( m,2H),4.67-4.69(m,3H),6.37(d,J=4.0Hz,1H),6.49(d,J=8.0Hz,1H),7.13(d,J=4.0Hz,1H),7.31-7.37(m,5H).

[0305] LCMS:C 18 H 23 N4O4S, theoretical value [M+H] + =394.0, measured value [M+H] + =394.0.

[0306] Synthesis of intermediate 17F

[0307] To a round-bottom flask, add Intermediate 17E (1 g, 2.54 mmol), acetonitrile (70 mL), and N,N-diisopropylethylamine (1.31 g, 10.16 mmol). The mixture was cooled to 0-5°C in an ice bath. A solution of triphosgene in acetonitrile (0.3 g of triphosgene dissolved in 30 mL of acetonitrile) was added dropwise. The reaction was allowed to react overnight at room temperature, monitored by LCMS, until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to afford Intermediate 17F (0.75 g, 70% yield) as a white solid.

[0308] 1H NMR (400MHz, DMSO-d6) δ1.25-1.28(m,3H),3.25-3.30(m,2H),3.42(s,3H),4.18-4.31(m,2H),4.54(s ,1H),4.93-4.94(m,2H),5.07(s,1H),6.49(d,J=4.0Hz,1H),7.24(d,J=4.0Hz,1H),7.39-7.46(m,5H).

[0309] LCMS:C 19 H 21 N4O5S, theoretical value [M+H] + =420.1, measured value [M+H] + =420.1.

[0310] Synthesis of intermediate 17G

[0311] To a round-bottom flask, intermediate 17F (300 mg, 0.72 mmol), isopropanol (4 mL), ethyl acetate (2 mL), and water (2 mL) were added, followed by triethylamine (220 mg, 2.22 mmol), triethylamine sulfur trioxide complex (400 mg, 2.22 mmol), and palladium on carbon (60 mg, 0.56 mmol). The mixture was replaced three times under hydrogen protection and allowed to react overnight at room temperature. LCMS monitoring was used to monitor the reaction until no starting material remained. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (20 mL), and concentrated to dryness below 30°C to obtain the crude product. The crude product was subjected to reverse phase column chromatography to obtain a water and acetonitrile solution of the target product. The acetonitrile was removed by concentration below 30°C, and the aqueous solution of intermediate 17G was retained and used directly in the next reaction.

[0312] Synthesis of Example 17

[0313] Dowex 50WX8 resin (10 g) was weighed and added to a 2 M aqueous sodium hydroxide solution (200 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The filter cake was washed with deionized water until the pH was neutral. The filter cake was transferred to an aqueous solution of intermediate 17G and stirred at room temperature for 4 hours. The reaction solution was then filtered and the filtrate was lyophilized to obtain Example 17 (30 mg, total yield of the two-step reaction was 10.25%) as a light yellow solid.

[0314] 1H NMR(400MHz,DMSO-d6)δ1.26-1.29(m,3H),3.28-3.35(m,2H),3.42(s,3H),4.19-4.32(m,2H) ,4.72(d,J=4.0Hz,1H),5.07(s,1H),6.45(d,J=4.0Hz,1H),7.25(d,J=4.0Hz,1H).HRMS(ESI) - :calcd for C 12 H 13 N3O9S2[M-Na] - :408.0177,found:408.0158.

[0315] Example 18

[0316] Synthesis of Intermediate 18B:

[0317] To a 250 mL eggplant-shaped flask, 10 g of intermediate 16B (27.9 mmol), THF (100 mL), HATU (13.79 g, 36.27 mmol), and N,N-diisopropylethylamine (7.21 g, 55.8 mmol) were added and stirred at room temperature for 0.5 h. 4-Amino-1-benzylpiperidine (5.84 g, 30.69 mmol) was added and stirred at room temperature overnight. LCMS confirmed no residual starting material. 100 mL of water and 200 mL of ethyl acetate were added to the reaction mixture, stirred thoroughly, and allowed to stand for separation. The organic phase was washed sequentially with 100 mL of 1 M aqueous hydrochloric acid, 100 mL of saturated aqueous sodium bicarbonate, and 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The desired product was purified by silica gel chromatography to obtain 4.4 g of a gray solid in a yield of 29.7%.

[0318] LCMS: calculated value C 26 H 34 N4O6S, [M] = 530.22; measured value [M+H] + =531.5.

[0319] Synthesis of intermediate 18C:

[0320] To a 250 mL eggplant-shaped flask, intermediate 18B (4.4 g, 8.29 mmol), THF (45 mL), and methanol (5 mL) were added. The mixture was cooled to 0-5°C in an ice bath. Sodium borohydride (0.38 g, 9.95 mmol) was added in two portions. The reaction was continued for 2 h after the addition was complete. TLC monitoring was performed until no starting material remained. The reaction solution was quenched by adding 50 mL of water and concentrated to remove THF and methanol. 150 mL of ethyl acetate was added, and the aqueous phase saturated with sodium chloride was added. The mixture was stirred evenly, allowed to stand, and the layers separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 4.2 g of the crude target product as a yellow solid in a 95% yield.

[0321] 1 HNMR (400MHz, DMSO-d6) δ: 1.43 (s, 9H), 1.59 ~ 1.72 (m, 6H), 2.13 ~ 2.20 (m, 2H), 2.75 ~ 2.82 (m, 3H), 3.47 ~ 3. 69(m,5H),4.38~4.53(m,1H),5.53~5.80(m,1H),6.40~6.67(m,3H),7.29~7.60(m,6H),8.14~8.25(m,1H).

[0322] Synthesis of intermediate 18D:

[0323] To a 100 mL eggplant-shaped flask, intermediate 18C (4.2 g, 7.89 mmol), toluene (45 mL), BnONHNs (4.87 g, 15.78 mmol), and tri-n-butylphosphine (3.19 g, 15.78 mmol) were added. The mixture was cooled to 0-5°C in an ice bath, and DIAD (3.19 g, 15.78 mmol) was added dropwise. The mixture was allowed to react overnight at room temperature and monitored by LCMS until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to obtain 3.1 g of the desired product as a yellow oil in a 47% yield.

[0324] LCMS: calculated value C 39 H 46 N6O 10 S2, [M] = 822.27, measured value [M+H] + =823.3.

[0325] Synthesis of intermediate 18E:

[0326] To a 100 mL eggplant-shaped flask, intermediate 18D (3.1 g, 3.77 mmol) and a TFA solution in DCM (8 mL TFA dissolved in 40 mL DCM) were added. The mixture was allowed to react at room temperature for 3 h. The reaction was monitored by TLC until no starting material remained. The reaction solution was concentrated and rinsed five times with 100 mL of DCM. 50 mL of saturated sodium bicarbonate and 100 mL of ethyl acetate were added. After stirring, the mixture was allowed to stand for separation. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2.1 g of the crude target product as a yellow oil in a 77% yield.

[0327] LCMS: calculated value C 34 H 38 N6O8S2, [M] = 722.22; Found [M+H] + =723.0.

[0328] Synthesis of intermediate 18F:

[0329] To a 100 mL eggplant-shaped flask, intermediate 18E (2.1 g, 2.91 mmol), 10 mL of acetonitrile, 10 mL of methanol, p-toluenethiophenol (1.08 g, 8.73 mmol), and potassium carbonate (1.21 g, 8.73 mmol) were added. The mixture was allowed to react at room temperature for 3 h. LCMS monitoring was performed until no starting material remained. The reaction solution was concentrated and purified by silica gel chromatography to obtain 1.1 g of the desired product as a yellow oil in a 70% yield.

[0330] LCMS: calculated value C 28 H 35 N5O4S, [M] = 537.24; Found [M+H] + =538.0.

[0331] Synthesis of intermediate 18G:

[0332] To a 250 mL eggplant-shaped flask, intermediate 18F (1.1 g, 2.05 mmol), acetonitrile (70 mL), and N,N-diisopropylethylamine (1.06 g, 8.2 mmol) were added. The mixture was cooled to 0-5°C in an ice bath. A solution of triphosgene in acetonitrile was added dropwise (one drop every 2-3 seconds, 0.24 g of triphosgene dissolved in 30 mL of acetonitrile). After the addition was complete, the reaction was allowed to proceed overnight at room temperature. LCMS monitoring was performed until no starting material remained. The reaction solution was concentrated and purified on a preparative plate to obtain 0.61 g of the desired product as a light yellow solid in a 53% yield.

[0333] 1HNMR (400MHz, DMSO-d6) δ1.48~1.55(m,2H),1.68~1.74(m,2H),2.01~2.03(m,2H),2.77~2.80(m,2H),3.20~3.38(m,1H),3.51~3.57(m,4 H),4.48(s,1H),4.88~4.95(m,2H),5.08(s,1H),6.41(d,J=4.0Hz,1H),7.12(d,J=4.0Hz,1H),7.26~7.45(m,10H),8.55(d,J=4.0Hz,1H).

[0334] LCMS: calculated value C 29 H 33 N5O5S, [M] = 563.22; measured value [M+H] + =564.3.

[0335] Synthesis of intermediate 18H:

[0336] To a 100 mL eggplant-shaped flask was added Intermediate 18G (0.5 g, 0.89 mmol), ethanol (10 mL), ethyl acetate (10 mL), di-tert-butyl dicarbonate (0.29 g, 1.33 mmol), and palladium on carbon (167 mg, 1.58 mmol). The mixture was replaced five times under hydrogen protection and allowed to react overnight at room temperature. LCMS monitoring was performed until no starting material remained. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with 20 mL of ethyl acetate and 20 mL of ethanol. The mixture was concentrated below 30°C and purified on a preparative plate to obtain 45 mg of the desired product as a yellow oil in a 10% yield.

[0337] LCMS:C 20 H 29 N5O7S, theoretical value [M] = 483.18; measured value [M+H] + =484.1.

[0338] Synthesis of intermediate 18I:

[0339] To a 25 mL eggplant-shaped flask, add intermediate 18H (45 mg, 0.093 mmol), triethylamine sulfur trioxide complex (40 mg, 0.22 mmol), isopropyl alcohol (1 mL), ethyl acetate (1 mL), water (0.2 mL), triethylamine (28 mg, 0.28 mmol), and palladium on carbon (51 mg, 0.28 mmol). Nitrogen was replaced three times. The reaction was allowed to react at room temperature overnight. LCMS monitoring was performed until no starting material remained. 1. The reaction solution was concentrated below 30°C to obtain crude product 1. 10 mL of water and 10 mL of ethyl acetate were added to the crude product 1, stirred evenly, and then allowed to stand. The liquid was separated, and the aqueous phase was extracted once with 10 mL of ethyl acetate. Tetrabutylammonium hydrogen sulfate (315 mg, 0.93 mmol) was added to the aqueous phase, stirred at room temperature for 0.5 h, extracted with DCM (30 mL x 2 each time), and the organic phase was concentrated to dryness to obtain the crude product 2; the crude product 2 was sent to HPLC for preparative separation and lyophilized to obtain 25 mg of the target product as a white solid in a yield of 33%.

[0340] 1 HNMR (400MHz, DMSO-d6) δ0.93~0.97(m,14H),1.28~1.37(m,11H),1.55(m ,12H),1.58~1.63(m,9H),1.70~1.75(m,2H),2.87(br,2H),3.16~3.20(m, 10H), 3.41~3.44(m,4H),3.77~3.91(m,3H),4.65(d,J=4.0Hz,1H),5.07(s ,1H),6.36(d,J=4.0Hz,1H),7.13(d,J=4.0Hz,1H),8.63(d,J=8.0Hz,1H).

[0341] LCMS: calculated value C 20 H 29 N5O 10 S2, [M] = 563.14; measured value [MH] - =562.1.

[0342] Synthesis of Example 18:

[0343] To a 25 mL eggplant-shaped flask, intermediate 18I (23 mg, 0.041 mmol) and a solution of TFA in DCM (1 mL TFA in 5 mL DCM) were added. The mixture was allowed to react at room temperature for 1 h. LCMS was used to monitor the reaction until no starting material remained. The reaction solution was concentrated, washed five times with 100 mL of DCM, concentrated, and separated by preparative HPLC column chromatography. The product was then lyophilized to yield 3.5 mg of the desired product as a white solid in an 18% yield.

[0344] 1HNMR (400 MHz, DMSO-d6) δ 1.67-1.69 (m, 2H), 1.91-2.00 (m, 3H), 2.50 (m, 1H), 2.68-2.70 (m, 1H), 3.87-3.91 (m, 2H), 4.65 (d, J = 4.0 Hz, 1H), 5.09 (s, 1H), 6.38 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 8.23 ​​(br, 1H), 8.82 (d, J = 8.0 Hz, 1H). LCMS: calculated value C 15 H 21 N5O8S2, [M] = 463.08; measured value [MH] - =462.1.

[0345] Example 19

[0346] The synthesis method of Example 19 is similar to that of Example 18. 1 H NMR (400 MHz, DMSO) δ 7.14 (d, J = 6.0 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H), 5.36 (s, 1H), 4.67 (d, J = 1.6 Hz, 1H), 3.40 (s, 3H), 3.20 (s, 3H), 2.94 (s, 3H). LCMS: calculated value C 12 H 15 N4O8S2 - , [M-Na] - It is 407.03; the measured value is 407.1.

[0347] General Synthetic Route of Examples 20-23

[0348] Example 20

[0349] Synthesis of intermediate 20B:

[0350] The raw material intermediate 15R (1.40 g, 3.36 mmol) was dissolved in 14 mL of dichloromethane, and triethylamine (33.6 mmol, 3.4 g) was added. The reaction temperature was cooled to 0-5°C, and trifluoroacetic anhydride (6.72 mmol, 1.41 g) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at this temperature for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction solution was poured into ice water (30 mL) to quench the mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by prep-TLC to obtain intermediate 20B (860 mg, 64.2% yield) as a white foamy solid.

[0351] 1 H NMR (400MHz, DMSO-d6) δ7.48-7.35(m,5H),7.36(d,J=3.3Hz,1H),6.54(d,J=3.3Hz,1H),5.63(s,1H) ,5.00–4.88(m,2H),4.61(d,J=2.1Hz,1H),3.61–3.49(m,2H),3.17–3.04(m,1H),1.36–1.15(m,4H).

[0352] LCMS: calculated value C 19 H 18 N4O4S, M=398.10; measured value [M+H] + =399.0.

[0353] Synthesis of intermediate 20C:

[0354] The raw material intermediate 20B (400 mg, 1.0 mmol) was dissolved in methanol (8 mL), di-tert-butyl dicarbonate (436 mg, 2.0 mmol) was added, and then Raney nickel (200 mg) was added. The hydrogen was replaced three times and the reaction was stirred at room temperature for 6 hours. LCMS monitored the reaction. After the reaction was completed, the mixture was filtered through celite and the filter cake was washed with methanol (10 mL x 3). The filter cake was discarded and quenched with dilute hydrochloric acid. The filtrate was concentrated to remove the solvent to obtain a crude product. The crude product was purified by prep-TLC to give intermediate 20C (200 mg, 39.6%) as a yellow solid.

[0355] 1 H NMR (400MHz, DMSO-d6) δ7.49–7.34(m,5H),7.14(d,J=3.2Hz,1H),6.96(t,J=5.7Hz,1H),6.42(d,J=3.3Hz,1H),4.91(s,2H),4. 59-4.50(m,1H),4.41(d,J=1.9Hz,1H),3.81-3.7(m,1H),3.53–3.38(m,2H),3.17–2.88(m,2H),1.41(s,9H),1.26–1.04(m,4H).

[0356] LCMS: calculated value C 24 H 30 N4O6S, M=502.19; measured value [M+H] + =503.1.

[0357] Synthesis of intermediate 20D:

[0358] Compound 20C (250 mg, 0.50 mmol) was dissolved in 3 mL of methanol in a 10 mL three-necked flask. Palladium catalyst (100 mg) was added and stirred at room temperature under a hydrogen atmosphere. After 2 h, the reaction was complete as monitored by LCMS. The reaction solution was filtered under reduced pressure, and the filtrate was directly concentrated to give a crude yellow oil. Column purification was performed to give 180 mg of a white solid, with a yield of 89.3%. LCMS: Calculated value C 17 H 24 N4O6S, M=412.14: measured value [M+1] + =413.0

[0359] The above white solid (180 mg, 0.44 mmol) and sulfur trioxide pyridine (208 mg, 1.3 mmol) were added to a 25 mL three-necked round-bottom flask, 3 mL of ultra-dry pyridine was added, and the mixture was stirred at room temperature under nitrogen protection. The solution became a yellow suspension.

[0360] The reaction was complete after overnight LCMS monitoring. The mixture was concentrated at room temperature to remove pyridine. Dichloromethane was added to the reaction solution to dissolve the product. The solid was removed by filtration under reduced pressure. The filtrate was collected and concentrated to obtain 300 mg of crude compound 20D as a brown oil. The crude product was used directly in the next reaction without further purification.

[0361] LCMS: calculated value C 17 H 24 N4O9S2, M=492.10, measured value [MH] - =491.0

[0362] Synthesis of Example 20:

[0363] The crude product of compound 20D (300 mg) was added to a 25 mL three-necked flask, and 3 mL of dichloromethane was added to dissolve it. The mixture was cooled to 0°C in an ice bath, and trifluoroacetic acid (2 mL) was slowly added dropwise. After the addition was complete, the mixture was naturally warmed to room temperature and stirred. The solution became a brown clear liquid.

[0364] The reaction was complete after 30 min of LCMS monitoring. Low-temperature concentration afforded a crude brown oil. 5 mL of acetonitrile was added to the concentrate, stirred, and a solid precipitated. The filter cake was collected by vacuum filtration and washed with dichloromethane, methanol, and acetonitrile to afford 90 mg of Example 20 as a white powdery solid. HPLC analysis revealed a purity of 96.8%.

[0365] 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 3H), 7.23 (d, J = 3.3 Hz, 1H), 6.46 (d, J = 3.3 Hz, 1H), 4.77 (dd, J = 11.2, 3.7 Hz, 1H), 4.70 (d, J = 2.5 Hz, 1H), 3.57 (d, J = 11.6 Hz, 1H), 3.54–3.47 (m, 1H), 3.35–3.28 (m, 2H), 3.00–2.90 (m, 1H), 1.30–1.02 (m, 4H). LCMS: calculated value C 12 H 16 N4O7S2, M=392.05, measured value [MH] - =391.0

[0366] Example 21

[0367] The synthesis method of Example 21 is similar to that of Example 20.

[0368] 1 H NMR (400MHz, DMSO) δ7.76(s,3H),7.22(d,J=3.2Hz,1H),6.45(d,J=3.3Hz,1H),4.74(dd,J=11.0,3 .8Hz,1H),4.69(d,J=2.5Hz,1H),3.66–3.51(m,2H),3.44(s,4H),3.30(d,J=2.6Hz,2H).LCMS:M=C 10 H 14 N4O7S, theoretical value [MH] - =365.03; measured value [MH] - =365.1.

[0369] Example 22

[0370] Synthesis of compound 21B:

[0371] Compound 14R (3.7 g, 9.48 mmol) was added to a 100 mL three-necked flask and dissolved in 40 mL of dichloromethane. Triethylamine (9.8 g, 94.80 mmol) was added to the reaction solution, resulting in a yellow clear liquid. The mixture was cooled to 0°C and stirred for 5 minutes. Trifluoroacetic anhydride (4.0 g, 18.9 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture was naturally warmed to room temperature and stirred, resulting in a yellow clear liquid. After 1 hour of reaction, LCMS detected that the reaction was complete. 40 mL of water was added to the reaction solution, stirred for 10 minutes, and the dichloromethane phase was separated and collected. The aqueous phase was extracted again with 30 mL of dichloromethane. The combined dichloromethanes were washed with water and saturated brine, dried over anhydrous NaSO4, and concentrated to obtain a yellow oily crude product. The crude product was purified by silica gel chromatography to obtain 3.0 g of compound 21B as a brown foamy solid in an 85.2% yield.

[0372] 1 H NMR (400MHz, DMSO-d6) δ7.48–7.33(m,5H),7.31(d,J=4.0,1H),6.54(d,J=3.3Hz ,1H),5.66(s,1H),4.97-4.88(m,,2H),4.61(d,J=2.1Hz,1H),3.60–3.47(m,5H).

[0373] LCMS: M=C 17 H 16 N4O4S, theoretical value [M+H] + =373.09; measured value [M+H] + =373.1.

[0374] Synthesis of compound 22F

[0375] Intermediate 21B (200 mg, 0.54 mmol) was added to methanol (4 mL) at room temperature and stirred to dissolve. Acetic anhydride (110 mg, 1.18 mmol) and Raney nickel (95 mg, 1.62 mmol) were then added, respectively. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at room temperature overnight. LCMS monitoring revealed the disappearance of the starting material. The reaction solution was filtered, the filtrate concentrated, and purified by column chromatography to afford 102 mg (45.1%) of a white product.

[0376] LCMS: calculated value: C 19 H 22 N4O5S, [M] = 518.13, found: [M+H] + =419.1.

[0377] Synthesis of Example 22

[0378] Intermediate 22F (0.1 g, 0.24 mmol) was dissolved in isopropanol (1.5 mL) and ethyl acetate (1.5 mL) at room temperature, and palladium carbon (0.097 g, 0.91 mmol), triethylamine sulfur trioxide complex (0.087 g, 0.48 mmol), and triethylamine (0.061 g, 0.60 mmol) were added and stirred to dissolve. The hydrogen gas was replaced three times. After 3 hours of reaction, the reaction progress was monitored by LCMS to observe the disappearance of the raw material. The reaction solution was filtered at room temperature, washed with deionized water (5 mL), and the filtrate was concentrated at low temperature to obtain a crude product. The crude product was dissolved with deionized water (5 mL), and impurities were extracted with ethyl acetate (5 mL). 10 eq of tetrabutylammonium hydrogen sulfate solid was added and stirred for 1 hour. The mixture was extracted with dry dichloromethane (5 mL) and concentrated at low temperature. 10 mg of the freeze-dried product was prepared and isolated. 2 g of Dowex cation exchange resin was activated with sodium hydroxide (20 mL, 2 M) for 1 hour and filtered. The filter cake was the exchange resin and washed with deionized water until the pH of the filtrate was neutral. The freeze-dried product and the ion exchange resin were dissolved in 5 mL of deionized water and stirred at room temperature for 5 hours. The mixture was then rinsed 5 times in a silica gel column. The obtained mobile phase was freeze-dried to obtain the target compound Example 22 (6 mg, 5.8%).

[0379] 1 H NMR (400MHz, DMSO-d6) δ = 8.02 (s, 1H), 7.07 (d, J = 0Hz, 1H), 6.29 (d, J = 4Hz, 1H), 4.53 (d, J = 4Hz, 1 H), 4.42 (t, J = 16Hz, 1H), 3.42 (d, J = 12Hz, 2H), 3.35 (s, 3H), 3.12 (d, J = 8Hz, 2H), 1.79 (s, 3H) ppm.

[0380] LCMS: calculated value: C 12 H 15 N4NaO8S2, [MH] - =407.03, measured value: 407.1.

[0381] Example 23

[0382] The synthesis method of Example 23 is the same as that of Example 22. 1H-NMR (DMSO-d6, 400MHz): δ1.83~1.90(m,3H), 3.17~3.21(m,1H), 3.44~3.51(m,2H), 3.80~3.86(m,1H), 4.51~4.55(m,1H), 4.57~4.59(m,1H), 6. 43(d,J=4.0Hz,1H),7.43(d,J=4.0Hz,1H),7.70~7.73(m,1H),8.12~8.15 (m,1H),8.27~8.30(m,1H),8.95(d,J=4.0Hz,1H),9.11(d,J=4.0Hz,1H).

[0383] LCMS:C 16 H 16 N5O8S2 - , theoretical value [M-Na] - =470.04, measured value [M-Na] - =470.

[0384] General Synthetic Route of Examples 24-26

[0385] Example 24

[0386] Preparation of intermediate 24B

[0387] To a solution of intermediate 9 (52 g, 107.53 mmol) in triethylamine (500 ml) was added di-tert-butyl dicarbonate (117.34 g, 537.65 mmol). The mixture was refluxed at 100°C for 7 h. TLC monitoring indicated complete reaction of the starting material. The system was concentrated and purified by silica gel column chromatography to afford 24B (30 g, 47.8%) as a yellow oil.

[0388] LC-MS: calculated C 30 H 37 N3O7S ， M=583.24, measured value [M+H] + =584.4.

[0389] Preparation of intermediate 24C

[0390] Intermediate 24B (28 g, 47.97 mmol) was dissolved in a mixed solution of methanol and water (methanol / water = 10:1, methanol: 300 ml, water: 30 mL). Potassium hydroxide (13.4 g, 240 mmol) was added to the mixed solution under nitrogen protection and reacted at 70°C for 3 h. LC-MS showed that the starting material was completely reacted. Dilute hydrochloric acid was added to neutralize the system and the methanol was concentrated under reduced pressure. Ethyl acetate (150 mL) was added to extract the solution. After separation of the organic phase, the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 24C (16.4 g, 77.1%) as a yellow oil.

[0391] LC-MS: calculated C 24 H 33 N3O5, M=443.24, measured value [M+H] + =444.3.

[0392] Preparation of intermediate 24D

[0393] To a solution of Intermediate 24C (1 g, 2.25 mmol), sodium hydroxide (0.09 g, 2.25 mmol), and tetrabutylammonium hydrogen sulfate (0.038 g, 0.11 mmol) in dichloromethane (30 mL) was slowly added dropwise cyclopropaneyl chloride (0.35 g, 0.31 mL, 23.38 mmol) at 0°C. The reaction solution was warmed to room temperature and stirred overnight. TLC monitoring indicated complete reaction of the starting material. The product was extracted with water, separated, and the organic phase was concentrated. Silica gel column chromatography afforded Intermediate 24D (0.42 g, 36.41%) as a yellow oil.

[0394] LC-MS: calculated C 28 H 37 N3O6, M=511.27, measured value [M+H] + =512.3.

[0395] 1 H NMR (400MHz, DMSO-d6): δ7.72(d,J=3.5Hz,1H),7.29(s,3H),7.17-7.08(m,2H),6.32-6.28(m,1H),4.96(s,1H),4.85 –4.41(m,4H),3.92–3.77(m,1H),3.71–3.45(m,1H),2.66–2.57(m,1H),1.51(s,9H),1.35(s,9H),1.15–1.05(m,4H).

[0396] Preparation of intermediate 24E

[0397] Zinc bromide (2.64 g, 11.7 mmol) was added to a solution of Intermediate 24D (0.6 g, 1.17 mmol) in DCM (30 mL). After 3 hours of reaction at room temperature, TLC monitoring indicated complete reaction. A sodium bicarbonate suspension was added to the reaction solution, stirred for 1 hour, and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford Intermediate 24E (0.37 g, 100%) as a yellow oil, which was used directly in the next reaction.

[0398] LC-MS: calculated C 18 H 21 N3O2, M=311.16, measured value [M+H] + =312.1.

[0399] 1 H NMR (400MHz, DMSO-d6): δ7.55(d,J=3.4Hz,1H),7.40–7.26(m,5H),6.58(d,J=8.0Hz,1H),6.29(d,J=3.3Hz,1H),4.66(s,2H),3.94(d ,J=17.7Hz,1H),3.82–3.73(m,2H),3.01(dd,J=13.3,3.1Hz,1H),2.67(dd,J=13.3,3.6Hz,1H),2.58–2.52(m,1H),1.06–0.98(m,4H).

[0400] Preparation of intermediate 24F

[0401] Triphosgene (0.14 g, 0.48 mmol) was dissolved in acetonitrile (5 mL) at room temperature and added dropwise to a solution of Intermediate 24E (0.37 g, 1.19 mmol) and DIPEA (0.62 g, 0.79 mL, 4.76 mmol) in acetonitrile (10 mL) at -20°C. After 2 hours of reaction at room temperature, LC-MS indicated complete reaction. Ethyl acetate (10 mL) and water (10 mL) were added for extraction. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. Silica gel column chromatography afforded Intermediate 24F (0.26 g, 63%) as a yellow oil.

[0402] LC-MS: calculated C 19 H 19 N3O3, M=337.14, measured value [M+H] + =338.1.

[0403] 1H NMR (400MHz, DMSO-d6): δ7.61(d,J=3.4Hz,1H),7.41(m,7.46-7.35Hz,5H),6.36(d,J=3.4Hz,1H),4.91(s ,2H),4.46–4.32(m,3H),3.40–3.35(m,1H),3.22(d,J=10.9Hz,1H),2.63–2.54(m,1H),1.15–0.97(m,4H).

[0404] Preparation of intermediate 24G

[0405] To a solution of Intermediate 24F (260 mg, 0.76 mmol) in acetonitrile (20 mL) was added palladium on carbon (10 wt%, 260 mg). The mixture was replaced twice with a double-layer hydrogen balloon. After stirring at ambient temperature for 5 hours, LCMS monitoring indicated complete reaction. After filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 24G (0.15 g, 80%) as a white solid, which was used directly in the next reaction.

[0406] LC-MS: calculated C 12 H 13 N3O3, M=247.1, measured value [M+H] + =248.1.

[0407] 1 H NMR (400MHz, DMSO-d6) δ9.44 (s, 1H), 7.59 (d, J = 3.4Hz, 1H), 6.36 (d,J=3.4Hz,1H),4.37(s,2H),4.28(d,J=2.7Hz,1H),3.45-3.42(m,1H),3.1 7(d,J=10.7Hz,1H),2.61-2.55(m,1H),1.10-1.02(m,J=8.0,4.8,4.1Hz,4H).

[0408] Preparation of intermediate 24H

[0409] To a solution of Intermediate 24G (0.15 g, 0.61 mmol) in DCM (10 mL) at room temperature were added triethylamine (0.19 g, 0.25 mL, 1.83 mmol) and sulfur trioxide triethylamine complex (0.33 g, 1.83 mmol). After 3 hours of reaction at room temperature, LCMS monitoring indicated complete reaction of the starting materials. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 0-10%) to afford Intermediate 24H as a white solid.

[0410] LC-MS: calculated C 12 H 12 N3O- 6S, MH=326.04, measured value [MH] - =326.0.

[0411] Preparation of Example 24

[0412] Intermediate 24H was dissolved in a mixture of acetonitrile (10 mL) and water (5 mL), and sodium ion exchange resin was added. The mixture was stirred at ambient temperature for 3 hours, filtered, and the filter cake was washed with water and acetone. The filtrate was lyophilized, purified by prep-HPLC, and lyophilized to afford Example 24 (135 mg, 64%) as a white solid.

[0413] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 3.4 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 4.62 (d, J = 2.6 Hz, 1H), 4.45–4.32 (m, 2H), 3.47 (dd, J = 10.9, 2.9 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 2.63–2.57 (m, 1H), 1.12–1.01 (m, 4H). LC-MS: calculated value C 12 H 12 N3O6S - , [M-Na] - =326.04, measured value 326.0.

[0414] Example 25

[0415] The synthesis method of Example 25 is similar to that of Example 24. LC-MS: calculated value C 10 H 10 N3O6S, [M-Na] - =300.0, measured value 300.03.

[0416] Example 26

[0417] The synthesis method of Example 26 is similar to that of Example 24. LC-MS: calculated value C 13 H 12 N5O6S, [M-Na] - =366.05, measured value 366.02.

[0418] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0419] Test Example 1: Antibacterial activity test

[0420] The National Committee for Clinical and Laboratory Standards Institute (CLSI, formerly NCCLs) antimicrobial susceptibility testing protocol (Methods for Dilution Antimicrobial Succeptibility Tests for Bacteria That Grow Aerobically; Approved Standard-tenth Edition M07-A10, 2015) was used to test the minimum inhibitory concentration (MIC) of the Example compounds (at a concentration of 4 mg / L) in combination with β-lactam antibiotics (ceftazidime, cefepime, meropenem, imipenem, and aztreonam). The specific test materials and procedures are as follows.

[0421] Source of strain:

[0422] The standard strains used in this experiment were purchased from ATCC. The clinical strains used were isolated and identified in domestic public hospitals as resistant to some or all marketed β-lactam antibiotics, and the β-lactamases they expressed were determined. Each bacterial strain was purified by streaking a single colony on an agar plate before the experiment. Fresh cultures were incubated overnight at 37°C and appropriately diluted for use in the experiment.

[0423] Culture medium and culture conditions

[0424] CAMHB (Cation Adjusted Mueller-Hinton) medium, incubate at 35-37°C in air for 16-20 h.

[0425] CAMHB formula: acid hydrolyzed casein (17.5g / L), beef powder (3.0g / L), soluble starch (1.5g / L), calcium ions (20-25mg / L), magnesium ions (10-12.5mg / L).

[0426] Preparation of test samples

[0427] CAMHB broth was used to prepare 4-fold working concentration stock solutions of antibiotics (ceftazidime, cefepime, meropenem, aztreonam) combined with the example compounds. The final concentrations of the antibiotics in the stock solutions were 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.125 mg / L, respectively. The final concentration of avibactam, lelibactam, or the example compounds was 4 mg / L.

[0428] Preparation of inoculum

[0429] Select several colonies from the agar plate cultured for 18-24 hours and prepare a bacterial suspension directly in sterile saline. Adjust the concentration of the bacterial suspension to 0.5 McFarland units. Dilute the corrected bacterial suspension with CAMHB broth to (4-8) × 10 5 CFU / mL, ready for use.

[0430] Sample addition and inoculation

[0431] Test group: 50 μL of the stock solution of antibiotics (ceftazidime, cefepime, meropenem, imipenem, aztreonam) and 50 μL of the stock solution of β-lactamase inhibitors (avibactam, lelibactam, or example compounds) were added to wells 1 to 12 of a sterilized 96-well polystyrene plate. 100 μL of CAMHB containing the test bacteria solution was then added to each well, for a total volume of 200 μL per well. The final drug concentrations in the wells were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 mg / L, respectively. The final concentration of the example compounds or known β-lactamase inhibitors was 4 mg / L. The final concentration of the bacterial solution was (2-4) × 10 5 CFU / mL.

[0432] Ceftazidime single-drug group: The addition method was the same as above, and each well contained only ceftazidime. The final concentrations were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 mg / L, respectively. The final concentration of the bacterial solution was (2-4) × 10 5 CFU / mL, without β-lactamase inhibitors.

[0433] Bacteria control group: only bacterial solution was inoculated into the wells, with a final concentration of (2-4)×10 5 CFU / mL, drug-free.

[0434] Incubation

[0435] Seal the 96-well polystyrene plate after adding the sample and place it in a 35-37°C incubator for 16-20 hours to determine the results.

[0436] MIC endpoint interpretation

[0437] The lowest drug concentration that completely inhibited bacterial growth in the wells was defined as the minimum inhibitory concentration (MIC) by visual observation.

[0438] Table 1. Antibacterial activity MIC of the example compounds in combination with ceftazidime 50 (mg / L) Note: “+++” indicates MIC50 ≤0.1mg / L; “++” means 0.1mg / L <MIC 50 ≤1mg / L; “+” means 1mg / L <MIC 50 ≤10mg / L; “-” indicates MIC 50 >10mg / L.

[0439] As can be seen from Table 1 above, when multiple Example compounds are used in combination with the β-lactam antibiotic ceftazidime, the MIC of ceftazidime against several β-lactamase-producing resistant bacteria can be reduced several times, indicating that the Example compounds can effectively enhance the sensitivity of β-lactamase-producing resistant bacteria to β-lactam antibiotics. Among them, compared with avibactam, Example 2, Example 3, Example 20 and Example 21 can more effectively enhance the antibacterial activity of ceftazidime against different Gram-negative bacteria, especially significantly enhancing the activity of ceftazidime against various Enterobacteriaceae expressing different β-lactamases.

[0440] Table 2. Antibacterial activity MIC of the compounds in the examples combined with different antibiotics 50 (mg / L) Note: “+++” indicates MIC 50 ≤0.1mg / L; “++” means 0.1mg / L <MIC 50 ≤1mg / L; “+” means 1mg / L <MIC 50 ≤10mg / L; “-” indicates MIC 50 >10mg / L.

[0441] As can be seen from Table 2 above, when the example compounds are used in combination with different β-lactam antibiotics (ceftazidime, aztreonam, meropenem, cefepime), the MICs of the above antibiotics against several β-lactamase-producing resistant bacteria can be reduced by several times, indicating that the example compounds can effectively enhance the sensitivity of β-lactamase-producing resistant bacteria to β-lactam antibiotics. Compared to the avibactam / ceftazidime combination or the lelibactam / imipenem combination, Examples 3 and 20 can show better antibacterial activity against different resistant Gram-negative bacteria when combined with ceftazidime, aztreonam, meropenem or cefepime. It is suggested that the embodiments of the present invention can be developed into a drug combination scheme with a variety of β-lactam antibiotics for the treatment of infections caused by resistant Gram-negative bacteria.

[0442] Table 3. Antibacterial activity MIC of the example compounds in combination with different antibiotics against clinical drug-resistant strains 50 (mg / L) Note: “+++” indicates MIC 50≤0.1mg / L; “++” means 0.1mg / L <MIC 50 ≤1mg / L; “+” means 1mg / L <MIC 50 ≤10mg / L; “-” indicates MIC 50 >10mg / L.

[0443] As shown in Table 3 above, when the compound of Example 3 or the compound of Example 20 is used in combination with different β-lactam antibiotics (ceftazidime or cefepime), the MICs of the above antibiotics against β-lactamase-producing (including serine hydrolase KPC-2 and metallo-β-lactamases NDM-1 and NDM-5)-resistant bacteria are reduced several-fold, significantly superior to the avibactam / ceftazidime combination. This indicates that the compounds of the examples can effectively enhance the sensitivity of β-lactamase-producing resistant bacteria to β-lactam antibiotics.

[0444] Test Example 2: β-lactamase inhibition activity test

[0445] The IC50 assay for β-lactamase inhibitors against β-lactamase uses nitrocefin as a substrate. The enzyme is incubated with a serial dilution of the β-lactamase inhibitor in 50 mM phosphate buffer (containing 0.1 mg / mL bovine serum albumin) at 37°C for 10 minutes. The reaction is initiated by the addition of 100 μM nitrocefin, and the reaction temperature is set to 37°C. The absorbance at 490 nm is recorded every minute for 1 hour. The initial reaction rate is calculated, and the IC is calculated in GraphPad Prsim software. 50 .

[0446] Table 4. IC values ​​of compounds against β-lactamase 50 (mg / L) Note: “+++” means IC 50 ≤1μM; “++” means 1μM <IC 50 ≤10μM; “+” indicates 10μM <IC 50 ≤100μM; “-” indicates MIC 50 >100 μM; “NT” means not tested.

[0447] As can be seen from the above table, the example compounds can exhibit good inhibitory activity against the selected three categories A / C / D, a total of 5 β-lactamases, suggesting that the compounds of the present invention can enhance the sensitivity of bacteria to existing β-lactam antibiotics by inhibiting β-lactamase.

[0448] The above embodiments and experimental examples show that the present invention provides a class of β-lactamase inhibitors that, when used in combination with traditional β-lactam antibiotics, can reverse the problem of bacterial resistance to β-lactam antibiotics due to the expression of β-lactamases, and have good application prospects in the clinical treatment of bacterial infections.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof: in, R1 is selected from R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR 10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 , -CH2NR7C(O)R9; R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 The cycloalkyl, heterocycloalkyl, cycloketo group is optionally substituted by zero, one or more substituents independently selected from the following: 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; m is independently selected from 1, 2, 3, and 4; M is selected from hydrogen, a metal ion or an organic cation.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: R2 is selected from hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR 10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 , -CH2NR7C(O)R9; R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; m is selected from 1, 2, 3, and 4.

3. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is represented by Formula IA: in, R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -C(O)NR7R8, -CH2NR7R8, -C(O)OR9, -CH2NR7C(O)R9; R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, ethyl nitrile, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazolyl, oxadiazolyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R7 and R8 are independently selected from H, C 1-6 Alkyl, piperidinyl; R9 is selected from H, C 1-6 alkyl; R 13 , R 14 , R 15 With R 16 are independently selected from H, C 1-6 alkyl; M is selected from hydrogen or sodium ion.

4. The compound according to claim 3, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is represented by formula IB: in, R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -C(O)NR7R8, -CH2NR7R8, -C(O)OR9, -CH2NR7C(O)R9; R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, ethyl nitrile, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazolyl, oxadiazolyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R7 and R8 are independently selected from H, C 1-6 Alkyl, piperidinyl; R9 is selected from H, C 1-6 alkyl; R 13 , R 14 , R 15 With R 16 are independently selected from H, C 1-6 alkyl.

5. The compound according to claim 4, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is represented by formula IC: in, R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, ethyl nitrile, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazolyl, oxadiazolyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R 13 , R 14 , R 15 With R 16 are independently selected from H, C 1-6 alkyl.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is one of the following compounds:

7. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is shown in formula II: in, R2 is selected from hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)NR7R8, -CH2NR7R8, -C(NH)NR7R8, -C(O)OR9, -C(NH)OR9, -C(O)NR 10 NR7R8, -C(O)NR 10 NR 11 C(O)R 12 、-C(O)NR 10 OR9, -C(NH)NR 10 OR9, -C(O)NR 10 (CH2) m NR7R8, -C(O)NR 10 (CH2) m NR 11 C(O)R 12 , -CH2NR7C(O)R9; R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group, The heterocycloalkyl and cycloketone groups are optionally substituted by zero, one or more substituents independently selected from the following: 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R7 and R8 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 or R7 and R8 form a saturated ring with the N atom containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R9 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 10 With R 11 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 12 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl; R 13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; m is selected from 1, 2, 3, 4; M is selected from hydrogen, a metal ion or an organic cation.

8. The compound according to claim 7, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is shown in formula III: in, R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 3-6 Cyclic keto, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)aryl, -C(O)heteroaryl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 The cycloalkyl, heterocycloalkyl, cycloketo group is optionally substituted by zero, one or more substituents independently selected from the following: 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 and R5 are independently selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, nitrileethyl, aryl, heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The aryl and heteroaryl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R 13 With R 14 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 13 and R 14 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxyl, halogen; R 15 With R 16 are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-7 Heterocycloalkyl, aryl, heteroaryl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2aryl, -SO2heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)aryl, -C(O)heteroaryl; or R 15 and R 16 Together with the N atom, it forms a saturated ring containing 1 or 2 heteroatoms, wherein the saturated ring is optionally substituted by zero, one or more substituents independently selected from the following: hydrogen, C 1-6 Alkyl, hydroxy, halogen.

9. The compound according to claim 8, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is shown in formula IV: in, R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 2-6 alkenyl, -C(O)phenyl, -C(O)pyrazolyl, -C(O)NR 13 R 14 、-SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -SO2phenyl, -SO2pyridyl, -SO2pyrazolyl, -SO2NR 13 R 14 The alkyl and alkenyl groups are optionally substituted by zero, one or more substituents independently selected from the following: halogen, hydroxyl, C 3-6 Cycloalkyl, piperidinyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 13 R 14 、-C(O)OC 1-6 Alkyl, -C(O)NR 13 R 14 The pyrazolyl, phenyl, pyridyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 13 R 14 , the cycloalkyl group is optionally substituted by zero, one or more substituents independently selected from the following: C 1-6 Alkyl, hydroxyl, halogen, NR 13 R 14 ; R4 is selected from hydrogen, halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl, acetyl, cyano, ethyl nitrile, phenyl, imidazolyl, oxadiazolyl, -C(O)OC 1-6 Alkyl, -C(O)NR 15 R 16 The phenyl, imidazolyl, oxadiazolyl are optionally substituted by zero, one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NR 15 R 16 ; R 13 , R 14 , R 15 With R 16 are independently selected from H, C 1-6 alkyl.

10. The compound according to any one of claims 7 to 9, its pharmaceutically acceptable salt, its stereoisomer or its solvate, characterized in that: The compound is one of the following compounds:

11. The method for preparing the compound according to any one of claims 1 to 10, characterized in that: It includes the following steps: Step 1: Using the bicyclic compound M1 as a raw material, a reduction reaction, a Mitsunobu reaction, a substitution reaction, a deprotection reaction, and a ring-closure reaction are performed to obtain a tricyclic intermediate M2; Step 2, using the tricyclic intermediate M2 as a raw material to carry out deprotection reaction, substitution reaction, and ion exchange to obtain the target compound TM; Wherein, R1, R2, R3, R4, and R5 are as described in any one of claims 1 to 10; PG1 is selected from a hydroxyl protecting group.

12. The preparation method according to claim 11, characterized in that: The preparation method of the compound M1 comprises the following steps: Using compound M0 as a raw material, intermediate M3 is prepared through Friedel-Crafts reaction, substitution reaction, and reduction reaction, and then the bicyclic intermediate M4 is obtained through ring closure. M4 is then subjected to protection, oxidation, and deprotection reaction to obtain intermediate M1; Wherein, R2 is as described in any one of claims 1-10.

13. Use of the compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of a β-lactamase inhibitor.

14. Use of the compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of a medicament for treating bacterial infection.

15. The use according to claim 14, characterized in that: The drug is a drug for treating infection by drug-resistant bacteria expressing β-lactamase.

16. Use of the compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer or its solvate in the preparation of a medicament for enhancing the sensitivity of bacteria to antibiotics.

17. The use according to claim 16, characterized in that: The drug is a drug for enhancing the sensitivity of β-lactamase-producing drug-resistant bacteria to β-lactam antibiotics.

18. A drug for treating bacterial infection and / or for enhancing bacterial sensitivity to antibiotics, characterized in that: The invention relates to a preparation which uses the compound described in any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer or its solvate as an active ingredient and adds pharmaceutically acceptable excipients or auxiliary ingredients.

19. The drug according to claim 18, characterized in that: The drug is a drug for treating infection by drug-resistant bacteria expressing β-lactamase and / or the drug is a drug for enhancing the sensitivity of drug-resistant bacteria producing β-lactamase to β-lactam antibiotics.

20. A combined drug for treating bacterial infection, characterized in that: It comprises the drug according to claim 18 or 19 and at least one β-lactam antibiotic.

21. A compound preparation for treating bacterial infection, characterized in that: It is a compound preparation prepared by using the combined drug described in claim 20 as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

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