Boric acid derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a boric acid derivative as well as a pharmaceutical composition and application thereof. The invention provides a compound shown in a formula I or pharmaceutically acceptable salt thereof. The compound provided by the invention has an inhibition effect on serine beta-lactamase (SBLs) and / or metal beta-lactamase (MBLs), and further, the compound provided by the invention can be combined with beta-lactam antibiotics to be used for treating bacterial infection. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to boric acid derivatives, their pharmaceutical compositions and their applications. Background Art

[0002] Antibiotics play an extremely important role in the treatment of bacterial infections. Due to the overuse of antibiotics, bacteria have continuously evolved various drug resistance mechanisms, resulting in a large number of drug-resistant bacteria.

[0003] β-lactam antibiotics are the most widely used antibacterial drugs in clinical practice, including penicillins and their derivatives, cephalosporins, monobactams, carbapenems, and penem enzyme inhibitors, etc., with a market share of more than 50%. Their mechanism of action is to bind to penicillin-binding proteins (PBPs), inhibit the synthesis of peptidoglycan, a component of the bacterial cell wall, and destroy the cell wall structure to achieve a bactericidal effect.

[0004] The expression of β-lactamase is one of the important drug resistance mechanisms of bacteria. β-lactamase inactivates β-lactam antibiotics by covalently binding to the carbonyl group on the β-lactam ring and hydrolyzing the amide bond to evade the killing of drugs. Bacteria have evolved various β-lactamases with different structures and functions during the evolution process. According to the Ambler classification method, they can be divided into serine enzymes (SBLs, including classes A, C, and D) and metalloenzymes (MBLs, class B). Clinically, carbapenem antibiotics are a special type of β-lactam drug. They have a broad antibacterial spectrum, strong antibacterial activity, and good stability against β-lactamases. They are the first-line drugs for the clinical treatment of severe, mixed infections, and drug-resistant bacteria, and are also known as the "last line of defense" against multi-drug resistant bacteria infections. In recent years, the rapid prevalence of carbapenem-resistant bacteria has brought great challenges to clinical treatment. Such bacteria usually carry β-lactamases that can hydrolyze carbapenem antibiotics. Common carbapenemases in clinical drug-resistant bacteria isolates in China include KPC-2 enzyme of class A, NDM-1 enzyme of class B, and OXA-48 type enzyme of class D, etc. According to the monitoring results reported by the China Bacterial Resistance Surveillance Network (CHINET) in 2023, the resistance rates of Klebsiella pneumoniae and Pseudomonas aeruginosa to the carbapenem antibiotic meropenem have reached 26% and 17.4% respectively. Once drug resistance occurs, the available treatment drugs are very limited, and there is an urgent need for new antibiotics against drug-resistant bacteria infections in clinical practice.

[0005] β-lactamase inhibitors can inhibit the hydrolytic activity of β-lactamases and restore β-lactam activity. Currently, β-lactamase inhibitors approved for marketing at home and abroad include clavulanic acid, sulbactam, tazobactam, avibactam, relebactam, and faropenem borate, etc. The inhibition spectrum of β-lactamases covers classes A, C, and D enzymes. For class B MBLs, there is no approved drug that can effectively inhibit them. MBLs can hydrolyze almost all β-lactam antibiotics except monocyclic β-lactams, including penicillins, cephalosporins, extended-spectrum cephalosporins, and carbapenems. The widespread dissemination of MBLs has posed a great challenge to clinical treatment. VNRX-5133 is the fastest progressing drug in clinical trials that can simultaneously inhibit SBLs and MBLs. It has completed phase III clinical trials, but its marketing application has been delayed due to CMC reasons. In addition, the emerging NDM-9 isolates in recent years have developed resistance to VNRX-5133. This subtype of MBL has been detected in Klebsiella pneumoniae, Escherichia coli, and even Acinetobacter baumannii. The rapid mutation of MBLs has also posed a great challenge to the research and development of antibacterial drugs.

[0006] In summary, for carbapenem-resistant bacteria, especially rapidly spreading MBL-resistant bacteria, existing β-lactamase inhibitors can no longer meet clinical needs. There is an urgent clinical need for new broad-spectrum β-lactamase inhibitors that can simultaneously inhibit SBLs and MBLs to cope with the increasingly severe clinical situation of anti-drug-resistant bacterial infections. Summary of the Invention

[0007] The technical problem to be solved by the present invention is the defect of the single structure of existing β-lactamase inhibitors. The present invention provides a boric acid derivative, its pharmaceutical composition, and its application. The compounds of the present invention have an inhibitory effect on serine β-lactamases (SBLs) and / or metallo-β-lactamases (MBLs). Further, the compounds of the present invention can be used in combination with β-lactam antibiotics for the treatment of bacterial infections.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof;

[0010]

[0011] Ring A is a C 3-10 aliphatic carbocyclic ring, a 3- to 12-membered aliphatic heterocyclic ring, a C 6-10 aryl ring, or a 5- to 12-membered heteroaryl ring;

[0012] R a independently is D, halogen, -OH, -CN, -NH2, -NO2, oxo (=O), C 1-6 alkyl, C1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, or C substituted with 1, 2, or 3 R 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0013] m is 0, 1, 2, or 3;

[0014] L1 is a linking bond, -CH2-, -CH2CH2-, C 3-6 Subcycloalkyl, 3- to 6-membered subheterocyclic group, or -CH2-, -CH2CH2-, C substituted with 1, 2, or 3 R 3-6 Subcycloalkyl, 3- to 6-membered subheterocyclic group;

[0015] X is

[0016] R 1 Is H, C 1-6 Alkyl or C substituted with 1, 2, or 3 R' 1-6 Alkyl;

[0017] R 2 Is H or C 1-6 Alkyl;

[0018] R 3 Is H, C 1-6 Alkyl, halogen, or C substituted with 1, 2, or 3 R' 1-6 Alkyl;

[0019] R is independently D, halogen, -OH, -CN, -NH2, -NO2, oxo(=O), C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0020] R' is independently D, halogen, -OH, -CN, -NH2, -NO2, -NH(Me) or -N(Me)2; Ring B is C 3-8 Aliphatic carbocyclic ring or C 6-10 Aromatic ring;

[0021] R b Is independently C 1-6 Alkyl, substituted with 1, 2, or 3 R b1 Substituted C 1-6 Alkyl;

[0022] R b1 Is independently -OH, -NH2, halogen, -O-C 1-6 Alkyl, -O-C 3-8Cycloalkyl, -O-C 3-8 Cycloalkenyl, -O-3- to 8-membered heterocyclic group, -O-C 6-10 Aryl, -O-5- to 12-membered heteroaryl, -S-C 1-6 Alkyl, -S-C 3-8 Cycloalkyl, -S-C 3-8 Cycloalkenyl, -S-3- to 8-membered heterocyclic group, -S-C 6-10 Aryl, -S-5- to 12-membered heteroaryl, -NR b2 -C 1-6 Alkyl, -NR b2 -C 3-8 Cycloalkyl, -NR b2 -C 3-8 Cycloalkenyl, -NR b2 -3- to 8-membered heterocyclic group, -NR b2 -C 6-10 Aryl, -NR b2 -5- to 12-membered heteroaryl, or -O-C b4 alkyl, -O-C 1-6 alkyl, -O-C 3-8 cycloalkyl, -O-C 3-8 cycloalkenyl, -O-3- to 8-membered heterocyclic group, -O-C 6-10 aryl, -O-5- to 12-membered heteroaryl, -S-C 1-6 alkyl, -S-C 3-8 cycloalkyl, -S-C 3-8 cycloalkenyl, -S-3- to 8-membered heterocyclic group, -S-C 6-10 aryl, -S-5- to 12-membered heteroaryl, -NR b2 -C 1-6 alkyl, -NR b2 -C 3-8 cycloalkyl, -NR b2 -C 3-8 cycloalkenyl, -NR b2 -3- to 8-membered heterocyclic group, -NR b2 -C 6-10 aryl, -NR b2 -5- to 12-membered heteroaryl,

[0023] R b2 is independently H or C 1-6 alkyl;

[0024] R b3 is independently -OH, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3- to 8-membered heterocyclic group, C 6-10Aryl or 5- to 12-membered heteroaryl;

[0025] R b4 are independently halogen, -OH, -NH2, -NR 5 R 6 , oxo (=O), C 6-10 Aryl, 5- to 12-membered heteroaryl, C 3-8 Cycloalkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic group;

[0026] n is 0, 1, 2 or 3;

[0027] Z is -NH2, C 1-6 Alkyl, Z2-NH-, NH2-Z1-NH-, NH2-Z1-, Z2-NH-Z1-, Z2-NH-Z1-NH-, Z2-C(=O)NH-, Z2- (C=O)NH-Z1-, Z2-(C=O)NH-Z1-NH-, Z2-NHC(=O)-, Z2-NH(C=O)-Z1-, Z2-NH(C=O)- Z1-NH-, NH2(C=O)NH-Z1-, NH2(C=O)NH-Z1-NH-, NH2(C=NH)NH-Z1-, NH2(C=NH)NH-Z1-NH-, Z2-NH(C=O)NH-, Z2-NH(C=O)NH-Z1-, Z2-NH(C=O)NH-Z1-NH- or by 1, 2 or 3 R Z1 Substituted -NH2, C 1-6 Alkyl, Z2-NH-, NH2-Z1-NH-, NH2-Z1-, Z2-NH-Z1-, Z2-NH-Z1-NH-, Z2-C(=O)NH-, Z 2-(C=O)NH-Z1-, Z2-(C=O)NH-Z1-NH-, Z2-NHC(=O)-, Z2-NH(C=O)-Z1-, Z2-NH( C=O)-Z1-NH-, NH2(C=O)NH-Z1-, NH2(C=O)NH-Z1-NH-, NH2(C=NH)NH-Z1-, NH2(C=NH)NH-Z1-NH-, Z2-NH(C=O)NH-, Z2-NH(C=O)NH-Z1-, Z2-NH(C=O)NH-Z1-NH-;

[0028] Z1 is independently C 1-6 Alkylene, C 3-6 Cycloalkylene, 5-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene;

[0029] Z2 is independently C 1-6 Alkyl, C3-6 a cycloalkyl group, a 5- to 12-membered heterocyclic group, a C 6-10 aryl group or a 5- to 12-membered heteroaryl group;

[0030] R Z1 is independently D, a halogen, -OH, -NR 5 R 6 , a C 1-6 alkyl group, a C 1-6 heteroalkyl group, a C 3-6 cycloalkyl group, a 3- to 8-membered heterocyclic group, or a C Z2 alkyl group, a C 1-6 heteroalkyl group, a C 1-6 cycloalkyl group or a 3- to 8-membered heterocyclic group substituted with one, two or three R 3-6 ;

[0031] R Z2 is independently a halogen, -OH, -CN or -NR 5 R 6 ;

[0032] R 5 and R 6 are independently H or a C 1-6 alkyl group;

[0033] In the aliphatic heterocycle, heterocyclic group and heterocyclene group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently one, two or three;

[0034] In the heteroaromatic ring, heteroaryl group and heteroarylene group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently one, two or three;

[0035] In the heteroalkyl group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently one, two or three.

[0036] In one embodiment, in the compound of formula I or a pharmaceutically acceptable salt thereof, the definitions of some groups can be as described below, and the definitions of other groups can be as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment"): Ring A is a C 3-10 aliphatic carbocycle, a 3- to 12-membered aliphatic heterocycle or a C 6-10 aryl ring.

[0037] In one embodiment, m is 0.

[0038] In one embodiment, L1 is -CH2-.

[0039] In one embodiment, X is

[0040] In one embodiment, R 1 is H.

[0041] In one embodiment, R 2 is H.

[0042] In one embodiment, R 3 is H.

[0043] In one embodiment, ring B is a saturated C 3-8 aliphatic carbocyclic ring.

[0044] In one embodiment, R b is independently C b1 alkyl substituted with one, two or three R 1-6 groups.

[0045] In one embodiment, R b1 is independently -OH, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR b2 -C 1-6 alkyl, or -NR b4 -C b2 alkyl substituted with one, two or three R 1-6 groups.

[0046] In one embodiment, R b2 is independently H.

[0047] In one embodiment, R b3 is independently C 1-6 alkyl.

[0048] In one embodiment, R b4 is independently C 6-10 aryl.

[0049] In one embodiment, n is 0 or 1.

[0050] In one embodiment, Z is NH2-Z1-NH- or NH2-Z1-.

[0051] In one embodiment, Z1 is independently C 1-6 alkylene.

[0052] In one embodiment, the C 3-10 aliphatic carbocyclic ring is a C 5-8 aliphatic carbocyclic ring, such as a C5 aliphatic carbocyclic ring, a C6 aliphatic carbocyclic ring, a C7 aliphatic carbocyclic ring or a C8 aliphatic carbocyclic ring.

[0053] In one embodiment, the C 3-10 aliphatic carbocyclic ring is a saturated C 3-10 aliphatic carbocyclic ring, such as the saturated C 3-10The aliphatic carbocycle is a monocyclic or bridged ring, for example

[0054] In one embodiment, the C 3-10 The aliphatic carbocycle is a saturated or unsaturated C 3-10 aliphatic carbocycle. For example, the unsaturated aliphatic carbocycle contains one carbon-carbon double bond. For example

[0055] In one embodiment, the C 3-8 The aliphatic carbocycle is a C 3-6 aliphatic carbocycle, such as a C3 aliphatic carbocycle, a C4 aliphatic carbocycle, a C5 aliphatic carbocycle or a C6 aliphatic carbocycle.

[0056] In one embodiment, the C 3-8 The aliphatic carbocycle is a saturated C 3-8 aliphatic carbocycle (i.e., C 3-8 cycloalkyl). For example, the saturated C 3-8 aliphatic carbocycle is a monocyclic ring.

[0057] In one embodiment, the 3-12 membered aliphatic heterocycle is a 5-8 membered aliphatic heterocycle, such as a 5-membered aliphatic heterocycle, a 6-membered aliphatic heterocycle, a 7-membered aliphatic heterocycle or an 8-membered aliphatic heterocycle.

[0058] In one embodiment, in the 3-12 membered aliphatic heterocycle, the heteroatoms are independently N, and the number of heteroatoms is independently 1, 2 or 3. For example

[0059] In one embodiment, the C 6-10 aryl ring is a benzene ring.

[0060] In one embodiment, the C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example, methyl.

[0061] In one embodiment, the C 1-6 alkylene is independently methylene, ethylene, propylene or butylene, for example ethylene.

[0062] In one embodiment, the halogen is independently F, Cl, Br or I; for example, F or Cl.

[0063] In one embodiment, the -O-C 1-6 alkyl, -S-C 1-6 alkyl and -NR b2 -C 1-6 alkyl in 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example, methyl.

[0064] In one embodiment, the C 3-6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl.

[0065] In one embodiment, is

[0066] In one embodiment, R b is independently

[0067] In one embodiment, is

[0068] In one embodiment, Z is In one embodiment, ring A is In one embodiment, is

[0069] In one embodiment, the compound represented by Formula I is as shown in Formula I-1:

[0070]

[0071] wherein q is 1, 2 or 3, and the definitions of other groups are as defined in any of the previous embodiments. For example, the compound represented by Formula I is as shown in Formula I-1-1 or Formula I-1-2:

[0072]

[0073] wherein the definitions of each group are as defined in any of the previous embodiments.

[0074] In one embodiment, q is 1.

[0075] In one embodiment, the compound represented by Formula I is as shown in Formula I-A:

[0076]

[0077] The definitions of each group are as defined in any of the previous embodiments;

[0078] For example, the compound represented by Formula I is as shown in Formula I-A-1:

[0079]

[0080] The definitions of each group are as defined in any of the previous embodiments;

[0081] For another example, the compound represented by Formula I is as represented by Formula I-A-1-1:

[0082]

[0083] The definitions of each group are as defined in any of the previous embodiments;

[0084] For another example, the compound represented by Formula I is as represented by Formula I-A-2-1:

[0085]

[0086] The definitions of each group are as defined in any of the previous embodiments.

[0087] In one embodiment, the compound represented by Formula I is selected from any of the following compounds:

[0088]

[0089]

[0090] In one embodiment, the compound represented by Formula I is any of the following compounds: The compound that elutes first under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 60:40 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes first is 6, and its retention time is 2.678min;

[0091] The compound that elutes last under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 60:40 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes last is 7, and its retention time is 3.037min;

[0092] The compound that elutes first under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.2% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 60:40 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes first is 8, and its retention time is 2.481min;

[0093] The compound that elutes later under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.2% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 60:40 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes later is 9, and its retention time is 2.665min;

[0094] The compound that elutes first under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 80:20 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes first is 11, and its retention time is 2.767min;

[0095] The compound that elutes later under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be 98:2 to 80:20 for linear gradient elution; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes later is 12, and its retention time is 3.054min;

[0096] The compound that elutes first under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 - 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be linearly gradient eluted from 98:2 to 60:40; From 11 - 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes first is 15 and its retention time is 2.241min;

[0097] The compound that elutes last under the following conditions: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 - 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be linearly gradient eluted from 98:2 to 60:40; From 11 - 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution; For example, the compound that elutes last is 16 and its retention time is 2.627min.

[0098] The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0099] The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof, and a β - lactam antibiotic.

[0100] In one embodiment, the β - lactam antibiotic is cefepime.

[0101] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0102] The present invention also provides the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of serine β - lactamase (SBLs) and / or metallo - β - lactamase (MBLs) inhibitors.

[0103] The present invention also provides the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in combination with a β - lactam antibiotic in the preparation of a drug for treating drug - resistant bacteria.

[0104] In one embodiment, the drug for treating drug - resistant bacteria is a drug for treating β - lactam antibiotic - resistant bacteria.

[0105] Glossary of terms:

[0106] The term "oxo (group)" refers to =O, where an oxygen atom replaces two hydrogens on the same carbon atom, that is, a carbonyl group replaces a methylene group, or it refers to replacing -S-.

[0107] The term "halogen" refers to F, Cl, Br, I, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br or 127 I.

[0108] The term "alkyl" refers to a saturated aliphatic hydrocarbon group; for example, an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc., and various branched isomers thereof, etc.

[0109] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon substituent; for example, the cycloalkyl contains 3 to 6 carbon atoms, more preferably contains 3 to 4 carbon atoms. Non-limiting examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, etc.

[0110] The term "-O-(alkyl)" refers to an alkoxy group, where the alkyl is defined as above. Non-limiting examples of the alkoxy group include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy.

[0111] The term "aliphatic carbocycle" refers to a monocyclic or polycyclic (bridged, spiro or fused) cyclic group having a specified number of carbon atoms (C 3-10 )), and the aliphatic carbocycle is a saturated aliphatic carbocycle or an unsaturated aliphatic carbocycle (for example, there is 1 carbon-carbon double bond on the ring of the unsaturated aliphatic carbocycle).

[0112] The term "aliphatic heterocycle" refers to a monocyclic or polycyclic cyclic group having a specified number of ring atoms (such as 3-12 membered), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S); the aliphatic heterocycle is a saturated aliphatic heterocycle or an unsaturated aliphatic heterocycle; for example, the aliphatic heterocycle contains 3 to 8 ring atoms; most preferably contains 3 to 6 ring atoms. In the present invention, "membered" represents the number of ring atoms, such as a 3-12 membered heterocyclic group means a heterocyclic group containing 3-12 ring atoms.

[0113] The term "heterocyclic group" refers to a monocyclic or polycyclic ring group having a specified number of ring atoms (e.g., 3-12 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S); the heterocyclic group is a heterocycloalkyl or heterocycloalkenyl; for example, the heterocyclic group contains 3 to 8 ring atoms; most preferably it contains 3 to 6 ring atoms. In the present invention, "membered" represents the number of ring atoms, such as a 3-12 membered heterocyclic group means a heterocyclic group containing 3-12 ring atoms.

[0114] The term "heterocycloalkyl" refers to a saturated, monocyclic or polycyclic ring group having a specified number of ring atoms (e.g., 3-12 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S).

[0115] The term "heterocycloalkenyl" refers to a monocyclic or polycyclic ring group having a specified number of ring atoms (e.g., 3-12 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S), and in which at least one ring contains one or more "double bonds", and the "heterocycloalkenyl" does not contain a closed cyclic conjugated system, only isolated π bonds or non-continuous conjugated π bonds.

[0116] The term "heteroaryl" or "heteroaromatic ring" refers to an aromatic group containing a specified number of ring atoms (e.g., 5-12 membered or 5-6 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S), which is monocyclic or polycyclic, and at least one ring has aromaticity (conforms to Hückel's rule).

[0117] The term "aromatic ring" or "aryl" refers to a cyclic group composed only of carbon atoms having a specified number of carbon atoms (e.g., C 6-10 ), which is monocyclic or polycyclic, and at least one ring has aromaticity (conforms to Hückel's rule). Aromatic rings (aryl) include but are not limited to benzene rings and naphthalene rings (phenyl and naphthyl), etc.

[0118] In the structural formulas of the groups described in this application, the means that the corresponding group is connected to other fragments and groups in the compound through this site. For example, in , when R is Cl, then

[0119] In addition, it should be noted that, unless otherwise explicitly stated, the description method “... independently is” adopted in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the description method “... independently is” can either mean that among different groups, the specific options expressed between the same symbols do not affect each other; or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0120] “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert biological activity.

[0121] “Pharmaceutically acceptable salt” refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0122] The term “therapeutically effective amount” refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art according to the circumstances.

[0123] The term “pharmaceutically acceptable carrier” refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions, and is all substances contained in a pharmaceutical preparation except the active ingredient. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0124] The term “treatment” refers to any of the following situations: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; (3) slowing down the development of one or more biological manifestations of a disease.

[0125] The term "patient" refers to any animal that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0126] Based on the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0127] The reagents and raw materials used in the present invention are all commercially available.

[0128] The positive and progressive effects of the present invention are as follows: The present invention provides boric acid derivatives, their pharmaceutical compositions and their applications. The compounds of the present invention have inhibitory effects on serine β-lactamases (SBLs) and / or metallo-β-lactamases (MBLs). Further, the compounds of the present invention can be used in combination with β-lactam antibiotics for the treatment of bacterial infections. Detailed Description of the Invention

[0129] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually carried out according to the conventional conditions of such reactions or according to the conditions recommended by the manufacturers. Unless otherwise specified, the percentages and parts are weight percentages and weight parts. Unless otherwise specified, the ratio of liquids is volume ratio.

[0130] The experimental materials and reagents used in the following examples can be obtained from commercial channels without special instructions.

[0131] The present invention uses the following abbreviations: Boc2O represents di-tert-butyl dicarbonate; DCM represents dichloromethane; DIBAL-H represents diisobutylaluminum hydride; DIPEA represents N,N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; IBX represents 2-iodoxybenzoic acid; LDA represents lithium diisopropylamide; LiAlH4 represents lithium aluminum hydride; LiHMDS represents lithium bis(trimethylsilyl)amide; m-CPBA represents meta-chloroperoxybenzoic acid; MsCl represents methanesulfonyl chloride; NaOAc represents sodium acetate; NaSMe represents sodium methanethiolate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; PCy3·HBF4 represents tricyclohexylphosphonium tetrafluoroborate; Pd(dppf)Cl2 represents dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium; Pd(OAc)2 represents palladium acetate; Pd(t-Bu3P)2 represents bis(tri-tert-butylphosphine)palladium; Sphos represents 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; TEA represents triethylamine; TES represents triethylsilane; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran; TsOH·H2O represents p-toluenesulfonic acid monohydrate.

[0132] Example 1: Synthesis of Compound 1

[0133]

[0134] Step 1: Preparation of Compound 1B

[0135] Dissolve Compound 1A (10 g, 0.055 mol) in 1,4-dioxane (100 mL). Under nitrogen protection, sequentially add bis(pinacolato)diboron (16.64 g, 0.066 mol), potassium acetate (16.08 g, 0.164 mol) and Pd(dppf)Cl2 (4 g, 0.006 mol) to the system. After the addition is complete, heat the reaction to 90 °C and stir for about 3 hours. Monitor the reaction by LC-MS. After the reaction is completed, concentrate the reaction solution under reduced pressure and purify it by column chromatography (100 / 1 petroleum ether / ethyl acetate) to obtain Compound 1B as a yellow oil (10 g, 80%). LC-MS m / z = 231.3 [M+H] + .

[0136] Step 2: Preparation of Compound 1C

[0137] Dissolve compound 1B (10 g, 0.044 mol) in EtOH (180 mL) and H2O (90 mL). Under nitrogen protection, add m-CPBA (9.01 g, 0.052 mol) to the system. After the addition, react at 25 °C for 16 hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction with saturated sodium bicarbonate solution, concentrate under reduced pressure, dilute with ethyl acetate, wash the organic phase with saturated sodium chloride solution, and dry the organic phase with anhydrous sodium sulfate. Filter, rotary evaporate under reduced pressure, and separate and purify by column chromatography (70 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 1C (3.5 g, 67%).

[0138] Step 3: Preparation of compound 1D

[0139] Dissolve compound 1C (3.2 g, 0.027 mol) in acetonitrile (50 mL). Under nitrogen protection, add NBS (4.73 g, 0.027 mol) to the system at 0 °C. After the addition, react at 0 °C for 5 hours. Monitor the reaction by TLC. After the reaction is completed, concentrate under reduced pressure to remove acetonitrile, and separate and purify by column chromatography (100 / 1 petroleum ether / ethyl acetate) to obtain yellow solid compound 1D (4.7 g, 89%). 1 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, 1H), 6.77 (s, 1H), 5.44 (s, 1H), 3.12 - 3.08 (m, 4H).

[0140] Step 4: Preparation of compound 1E

[0141] Dissolve compound 1D (4.7 g, 0.024 mol) in DCM (60 mL). Under nitrogen protection, add Boc2O (6.18 g, 0.028 mol) and DMAP (0.29 g, 0.002 mol) to the system in sequence at 25 °C. After the addition, react at 25 °C for 1.5 hours. Monitor the reaction by LC-MS. After the reaction is completed, concentrate under reduced pressure to remove DCM, and separate and purify by column chromatography (70 / 1 petroleum ether / ethyl acetate) to obtain white solid compound 1E (5.8 g, 82%). LC-MS m / z = 243.0 [M - 56 + H] + 。

[0142] Step 5: Preparation of compound 1F

[0143] Compound 1E (3.38 g, 0.011 mol) was dissolved in THF (35 mL). Under nitrogen protection, LDA (6.8 mL, 0.014 mol) was added dropwise to the system at -78 °C. After the addition was complete, the reaction was carried out at -78 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, diluted with ethyl acetate, concentrated under reduced pressure again, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After filtration and rotary evaporation under reduced pressure, it was separated and purified by column chromatography (70 / 1 petroleum ether / ethyl acetate) to obtain white solid compound 1F (2.52 g, 74%). LC-MS m / z = 243.1 [M - 56 + H] + 。

[0144] Step 6: Preparation of Compound 1G

[0145] Compound 1F (2.52 g, 0.008 mol) was dissolved in DCM (30 mL). Under nitrogen protection, Boc2O (2.2 g, 0.010 mol) and DMAP (0.1 g, 0.001 mol) were added dropwise to the system at -78 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, DCM was removed by concentration under reduced pressure, and it was separated and purified by column chromatography (100 / 1 petroleum ether / ethyl acetate) to obtain white solid compound 1G (3.13 g, 93%). 1 1H NMR (CDCl3, 400 MHz) δ 7.39 (s, 1H), 3.28 (m, 2H), 3.15 (m, 2H), 1.57 (s, 9H), 1.54 (s, 9H). LC-MS m / z = 243.0 [M - 100 - 56 + H] + 。

[0146] Step 7: Preparation of Compound 1I

[0147] Compound 1H (0.06 g, 0.0003 mol) and Zn (0.99 g, 0.015 mol) were successively dissolved in THF (15 mL). Under nitrogen protection, DIBAL-H (0.5 mL, 0.0005 mol, 1 M in n-Hexane) was added to the system at 25 °C. After the addition was complete, the reaction was carried out at 25 °C for 10 minutes. A solution of Compound 1H (1.34 g, 0.006 mol) in THF (5 mL) was added dropwise to the reaction system. Under nitrogen protection, the reaction was carried out at 50 °C for 1 hour. After the above reaction was cooled to room temperature, under nitrogen protection, the supernatant was taken and added to a solution of Compound 1G (1 g, 0.003 mol) and Pd(t-Bu3P)2 (0.1 g, 0.0002 mol) in THF (15 mL). Under nitrogen protection, the reaction was carried out at 25 °C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, THF was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography (20 / 1 petroleum ether / ethyl acetate) to obtain white solid Compound 1I (682 mg, 60%). LC-MS m / z = 483.0 [M+Na] + 。

[0148] Step 8: Preparation of Compound 1K

[0149] Compound 1I (682 mg, 1.481 mmol) and Compound 1J (1.261 g, 7.407 mmol) were successively dissolved in THF (20 mL). Under nitrogen protection, the reaction was carried out at 70 °C for 48 hours. After the reaction was completed, THF was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography (20 / 1 petroleum ether / ethyl acetate) to obtain white solid Compound 1K (721 mg, 95%). LC-MS m / z = 412.9 [M-100+H] + 。

[0150] Step 9: Preparation of Compound 1L

[0151] Under nitrogen protection, n-BuLi (0.8 mL, 2.026 mmol) was added dropwise to a solution of DCM (430.1 mg, 5.064 mmol) in THF (5 mL) at -78 °C, and the reaction was carried out at -78 °C for 0.5 h. Under the same conditions, a solution of compound 1K (519 mg, 1.013 mmol) in THF (2 mL) was added dropwise to the above mixture, and the reaction was carried out at -78 °C for 0.5 h. Then, under the same conditions, ZnCl2 (1.5 mL, 1.519 mmol, 1 M in THF) was added dropwise to the above mixture. After the addition was complete, the temperature was slowly restored to 25 °C, and the reaction was stirred at 25 °C for 16 h, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (30 / 1 petroleum ether / ethyl acetate) to obtain white solid compound 1L (400 mg, 69%). 1 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 4.39 - 4.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 3.64 - 3.60 (m, 1H), 3.31 - 3.26 (m, 2H), 3.23 - 3.17 (m, 1H), 3.11 - 3.07 (m, 2H), 3.03 - 2.97 (m, 1H), 2.37 - 2.31 (m, 1H), 2.24 - 2.17 (m, 1H), 2.09 - 2.04 (m, 1H), 1.93 - 1.86 (m, 2H), 1.55 (s, 9H), 1.53 (s, 9H), 1.39 (s, 3H), 1.29 (s, 3H), 1.14 (d, J = 11.2 Hz, 1H), 0.84 (s, 3H). LC-MS m / z = 461.0 [M - 100 + H] + 。

[0152] Step 10: Preparation of compound 1M

[0153] Under nitrogen protection, LiHMDS (1.3 mL, 1.285 mmol, 1 M in THF) was added dropwise to a solution of compound 1L (400 mg, 0.714 mmol) in THF (10 mL) at -78 °C, and the reaction was carried out at -78 °C for 16 h. After the reaction was completed, the reaction was quenched by adding water, concentrated under reduced pressure, diluted with DCM, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtered, the solvent was removed by concentration under reduced pressure to obtain the crude product of compound 1M. Without further purification, it was directly used for the next reaction.

[0154] Step 11: Preparation of compound 1O

[0155] First, dissolve compound 1N (900 mg, 2.247 mmol) in DCM (20 mL). Under nitrogen protection, slowly add thionyl chloride (534.7 mg, 4.494 mmol) dropwise to the reaction system at 0 °C, and stir the reaction at 0 °C for 2 hours. After the reaction is completed, concentrate under reduced pressure to obtain the crude acyl chloride intermediate of compound 1N. Without further purification, directly proceed to the next step of the reaction.

[0156] Next, dissolve the crude acyl chloride intermediate of compound 1N in DCM (5 mL). Under nitrogen protection, slowly add the above DCM solution dropwise to the DCM (10 mL) solution of compound 1M (489.3 mg, 0.714 mmol) and TEA (361.2 mg, 3.569 mmol) at 0 °C, and react at 25 °C for 16 hours. After the reaction is completed, add water to quench the reaction, concentrate under reduced pressure, dilute with DCM, wash with saturated sodium chloride solution, and dry the organic phase with anhydrous sodium sulfate. Filter, concentrate under reduced pressure to remove the solvent, obtain the crude product of compound 1O, and purify it by preparative HPLC to obtain the white solid compound 1O (87 mg, 13%). LC-MS m / z = 924.2 [M+H] + 。

[0157] Step 12: Preparation of compound 1

[0158] Dissolve compound 1O (87 mg, 0.094 mmol) in TFA (3 mL) and TES (0.5 mL). React at 0 °C for 1 hour. Monitor the reaction by LC-MS. After the reaction is completed, concentrate under reduced pressure to obtain the crude product of compound 1, and purify it by preparative HPLC to obtain the yellow solid compound 1 (5.9 mg, 15%). 1 1H NMR (D2O, 400 MHz) δ 7.03 (s, 1H), 3.35 - 3.26 (m, 4H), 3.23 - 3.00 (m, 5H), 2.91 - 2.80 (m, 3H), 2.31 - 2.26 (m, 1H), 2.05 - 2.00 (m, 1H), 1.93 - 1.89 (m, 1H), 1.80 - 1.77 (m, 1H), 1.43 - 1.39 (m, 1H), 1.31 - 1.12 (m, 2H), 1.01 - 0.91 (m, 1H), 0.73 - 0.56 (m, 3H). LC-MS m / z = 416.2 [M+H] + 。

[0159] Example 2: Synthesis of compound 2

[0160]

[0161] Step 1: Preparation of compound 2B

[0162] Ethyl 2-(diethoxyphosphoryl)acetate (13.59 g, 0.061 mol) was dissolved in THF (60 mL), and 60% NaH (1.62 g, 0.040 mol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under nitrogen protection. Then compound 2A (5 g, 0.020 mol) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (20 / 1 petroleum ether / ethyl acetate) to obtain a yellow oily compound 2B (6 g, 94%). LC-MS m / z = 318.2 [M+H] + .

[0163] Step 2: Preparation of compound 2C

[0164] Compound 2B (5.72 g, 0.018 mol) was dissolved in EtOH (80 mL), and Pd / C (2.87 g) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude yellow oily compound 2C (3.14 g, 94%). LC-MS m / z = 186.0 [M+H] + .

[0165] Step 3: Preparation of compound 2D

[0166] Compound 2C (3.14 g, 0.017 mol) was dissolved in DMF (30 mL), and TEA (8.53 g, 0.084 mol) and tert-butyl N-(2-bromoethyl)carbamate (7.57 g, 0.034 mol) were added. The reaction mixture was stirred at 50 °C for 5 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (40 / 1 DCM / MeOH) to obtain a yellow oily compound 2D (3 g, 54%). LC-MS m / z = 329.2 [M+H] + .

[0167] Step 4: Preparation of compound 2E

[0168] Compound 2D (1 g, 0.003 mol) was dissolved in MeOH (10 mL) and H2O (2 mL), and LiOH·H2O (0.38 g, 0.009 mol) was added. The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by flash column chromatography to obtain a yellow oily compound 2E (0.8 g, 90%). LC-MS m / z = 301.1 [M+H] +。

[0169] Step 5: Preparation of Compound 2F

[0170] Dissolve Compound 2E (643.0 mg, 2.142 mmol) in DMF (7 mL), add HATU (814.5 mg, 2.142 mmol) and DIPEA (276.8 mg, 2.142 mmol). The reaction mixture is reacted at 25 °C for 1 hour under nitrogen protection. After the reaction is complete, dissolve the crude Compound 1M in DMF (2 mL), add the above reaction mixture at 0 °C, and the reaction mixture is reacted at 25 °C for 16 hours under nitrogen protection. After the reaction is complete, the crude product is purified by flash column chromatography to obtain white solid Compound 2F (28 mg, 5%). LC-MS m / z = 824.6 [M+H] + 。

[0171] Step 6: Preparation of Compound 2

[0172] Prepared according to the synthetic scheme of Compound 1 in Example 1. White solid Compound 2 (5.1 mg, 25%) is obtained from Compound 2F (28 mg, 0.034 mmol). 1 1H NMR (D2O, 400 MHz) δ 7.06 (s, 1H), 3.44 - 3.04 (m, 13H), 2.95 - 2.85 (m, 2H), 2.44 - 2.38 (m, 1H), 2.31 - 2.11 (m, 1H), 1.79 - 1.31 (m, 6H), 0.80 - 0.61 (m, 1H). LC-MS m / z = 416.1 [M+H] + 。

[0173] Example 3: Synthesis of Compound 3

[0174]

[0175] Step 1: Preparation of Compound 3C

[0176] Prepared according to the synthetic scheme of Compound 2F in Example 2. White solid Compound 3B (58 mg, 55%) is obtained from the crude product of Compound 1M and Compound 3A (52 mg, 0.122 mmol). LC-MS m / z = 864.6 [M+H] + 。

[0177] Step 2: Preparation of Compound 3

[0178] Compound 3B (58 mg, 0.067 mmol) was dissolved in DCM (2 mL), and BCl3 (0.5 mL, 0.470 mmol, 1 M in DCM) was added at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with water at 0 °C, extracted with DCM, and the aqueous phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain white solid compound 3 (12.1 mg, 41%). 1 1H NMR (D2O, 400 MHz) δ 7.12 (s, 1H), 3.34 - 3.24 (m, 7H), 3.18 - 3.10 (m, 2H), 2.96 - 2.87 (m, 2H), 2.21 (d, J = 13.6 Hz, 1H), 2.06 (d, J = 13.6 Hz, 1H), 1.57 (s, 6H), 1.31 - 1.28 (m, 3H), 1.04 - 1.01 (m, 3H). LC-MS m / z = 442.1 [M + H] + 。

[0179] Example 4: Synthesis of Compound 4

[0180]

[0181] Step 1: Preparation of Compound 4B

[0182] Prepared according to the synthetic scheme of Compound 2F in Example 2. White solid compound 4B (180 mg, 68%) was obtained from the crude product of Compound 1M and Compound 4A (123 mg, 0.321 mmol). LC-MS m / z = 722.5 [M + H - 100] + 。

[0183] Step 2: Preparation of Compound 4

[0184] Prepared according to the synthetic scheme of Compound 3 in Example 3. White solid compound 4 (30 mg, 33%) was obtained from Compound 4B (180 mg, 0.219 mmol). 1 1H NMR (D2O, 400 MHz) δ 7.03 (s, 1H), 3.35 - 3.06 (m, 7H), 2.90 - 2.81 (m, 4H), 2.65 - 2.54 (m, 2H), 1.43 (d, J = 9.2 Hz, 3H), 1.33 (d, J = 9.2 Hz, 3H). LC-MS m / z = 400.1 [M + H] + 。

[0185] Example 5: Synthesis of Compound 5

[0186]

[0187] Step 1: Preparation of Compound 5B

[0188] Dissolve Compound 5A (5 g, 0.028 mol) in H2O (50 mL), add potassium periodate (6.54 g, 0.028 mol), and react the reaction solution at 25 °C for 2 hours. After the reaction is complete, filter the reaction solution, extract with DCM, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3.2 g of crude yellow oily Compound 5B.

[0189] Step 2: Preparation of Compound 5D

[0190] Dissolve Compound 5B (3.19 g, 0.020 mol), Compound 5C (3 g, 0.017 mol), and acetic acid (1 g, 0.017 mol) in MeOH (60 mL), react the reaction solution at 25 °C for 1 hour, then add sodium cyanoborohydride (1.05 g, 0.017 mol) portionwise at 0 °C, and react the reaction solution at 25 °C for 1 hour. After the reaction is complete, quench the reaction system with water, concentrate under reduced pressure, dilute with DCM, wash the organic phase with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent to obtain 5.38 g of crude yellow oily Compound 5D. LC-MS m / z = 323.2 [M+H] + 。

[0191] Step 3: Preparation of Compound 5E

[0192] Dissolve Compound 5D (6.5 g, 0.020 mol) in DCM (100 mL), add Boc2O (8.82 g, 0.040 mol), TEA (8.18 g, 0.081 mol), and DMAP (0.99 g, 0.008 mol), and react the reaction solution at 40 °C for 16 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a crude product, and purify the crude product by column chromatography (4 / 1 petroleum ether / ethyl acetate) to obtain yellow oily Compound 5E (5.84 g, 68%). LC-MS m / z = 423.2 [M+H] + 。

[0193] Step 4: Preparation of Compound 5F

[0194] Dissolve Compound 5E (4.73 g, 0.011 mol) in MeOH (35 mL) and H2O (5 mL), add LiOH·H2O (0.94 g, 0.022 mol), and react the reaction solution at 25 °C for 6 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by flash column to obtain white solid Compound 5F (1 g, 22%). LC-MS m / z = 395.2 [M+H] + 。

[0195] Step 5: Preparation of Compound 5G

[0196] Prepared according to the synthetic scheme of Compound 2F in Example 2. Compound 5G (30 mg, 9%) was obtained from the crude product of Compound 1M and Compound 5F (422.2 mg, 1.071 mmol). LC-MS m / z = 918.8 [M+H] + 。

[0197] Step 6: Preparation of Compound 5

[0198] Prepared according to the synthetic scheme of Compound 1 in Example 1. White solid Compound 5 (5.1 mg, 26%) was obtained from Compound 5G (30 mg, 0.032 mmol). 1 H NMR (D2O, 400 MHz) δ 6.93 (s, 1H), 6.61 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 3.45 - 3.42 (m, 2H), 3.39 - 3.38 (m, 2H), 3.23 - 3.18 (m, 3H), 3.15 - 3.10 (m, 2H), 3.06 - 3.02 (m, 2H), 2.86 - 2.82 (m, 2H). LC-MS m / z = 410.1 [M+H] + 。

[0199] Examples 6 and 7: Synthesis of Compounds 6 and 7

[0200]

[0201] Step 1: Preparation of Compound 6C

[0202] Dissolve Compound 6A (50 g, 0.233 mol), Compound 6B (23.73 g, 0.279 mol), ammonium acetate (1.79 g, 0.023 mol) and pyridine (110.34 g, 1.395 mol) in toluene (600 mL). Under nitrogen protection, stir and reflux for 12 hours. After the reaction is complete, cool, filter the reaction solution, dissolve the filter cake in water, neutralize it to neutral with dilute hydrochloric acid, and filter again to obtain the crude product of yellow solid Compound 6C (60 g, 82%). LC-MS m / z = 282.0, 284.0 [M+H] + 。

[0203] Step 2: Preparation of Compound 6D

[0204] Compound 6C (60 g, 0.213 mol) was dissolved in MeOH (200 mL). At 0 °C, saturated sodium bicarbonate solution was added until the reaction solution became alkaline, and then NaBH4 (16.08 g, 0.425 mol) was slowly added. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, quenched with water, adjusted to pH 3 - 4 with dilute hydrochloric acid, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of yellow solid compound 6D (50 g, 75%). LC-MS m / z = 284.0, 286.0 [M + H] + .

[0205] Step 3: Preparation of compound 6E

[0206] Compound 6D (50 g, 0.176 mol) was dissolved in DMF (500 mL). The reaction solution was stirred at 150 °C for 10 hours. After the reaction was complete, it was cooled, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (5 / 1 petroleum ether / ethyl acetate) to obtain compound 6E as a yellow oil (39 g, 83%). 1 1H NMR (CDCl3, 400 MHz) δ 7.14 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 3.71 (s, 3H), 2.95 (m, 2H), 2.56 (m, 2H). LC-MS m / z = 240.0 [M + H] + .

[0207] Step 4: Preparation of compound 6F

[0208] Compound 6E (17 g, 0.071 mol) was dissolved in THF (50 mL). At -78 °C, LDA (88.5 mL, 0.177 mol) was slowly added dropwise. The reaction solution was stirred at 25 °C for 12 hours under nitrogen protection. After the reaction was complete, it was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 6F as a black oil (12.5 g, 100%). 1 1H NMR (CDCl3, 400 MHz) δ 7.03 (d, J = 8.0 Hz, 1H), 6.89 - 6.87 (m, 1H), 6.80 (s, 1H), 4.19 - 4.17 (m, 1H), 3.79 (s, 3H), 3.62 - 3.57 (m, 1H), 3.49 - 3.45 (m, 1H). LC-MS m / z = 160.2 [M + H] + .

[0209] Step 5: Preparation of Compound 6G

[0210] Dissolve Compound 6F (12.5 g, 0.079 mol) in ACN (200 mL), slowly add NBS (25.15 g, 0.141 mol) at 0 °C, and stir the reaction solution at 25 °C for 12 hours. After the reaction is complete, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain yellow solid Compound 6G (11 g, 59%). LC-MS m / z = 237.9, 239.9 [M+H] + 。

[0211] Step 6: Preparation of Compound 6H

[0212] Dissolve Compound 6G (8 g, 0.034 mol) in EtOH (100 mL) and H2O (100 mL), add KOH (9.43 g, 0.168 mol), and stir the reaction solution at 80 °C for 2 hours. After the reaction is complete, cool, concentrate the reaction solution under reduced pressure, adjust the pH to 3 with 3 M dilute hydrochloric acid, and a solid precipitates. Filter, and dry the filter cake to obtain yellow solid crude Compound 6H (7 g, 73%). LC-MS m / z = 257.1, 259.1 [M+H] + 。

[0213] Step 7: Preparation of Compound 6I

[0214] Dissolve Compound 6H (4.7 g, 0.018 mol) in DCM (100 mL), slowly add BBr3 (9.17 g, 0.037 mol) at -78 °C, and stir the reaction solution at 25 °C for 2 hours. After the reaction is complete, quench the reaction solution with water at low temperature, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain yellow solid crude Compound 6I (4 g, 81%). LC-MS m / z = 243.1, 245.1 [M+H] + 。

[0215] Step 8: Preparation of Compound 6J

[0216] Dissolve Compound 6I (5 g, 0.021 mol) in THF (100 mL), slowly add LiAlH4 (24.7 mL, 0.025 mol, 1 M in THF) dropwise at 0 °C, and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. After the reaction is complete, quench the reaction solution with Na2SO4·10H2O, filter, and concentrate the filtrate under reduced pressure to obtain yellow oily crude Compound 6J (4.7 g, 90%). LC-MS m / z = 211.1, 213.1 [M+H-H2O] +。

[0217] Step 9: Preparation of Compound 6K

[0218] Dissolve Compound 6J (4.7 g, 0.021 mol) in DCM (100 mL), add Boc2O (13.42 g, 0.062 mol) and DMAP (2.5 g, 0.021 mol), and stir the reaction mixture at 25 °C for 3 hours. After the reaction is complete, add water to the reaction mixture, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain Compound 6K as a yellow oil (3.4 g, 37%). LC-MS m / z = 451.1, 453.1 [M+Na] + 。

[0219] Step 10: Preparation of Compound 6L

[0220] Prepared according to the synthesis protocol of Compound 1F in Example 1. Compound 6L as a yellow solid (1.8 g, 51%) was obtained from Compound 6K (3.4 g, 7.900 mmol). LC-MS m / z = 451.1, 453.1 [M+Na] + 。

[0221] Step 11: Preparation of Compound 6M

[0222] Dissolve Compound 6L (1.8 g, 4.200 mmol), CH3I (1.19 g, 8.400 mmol) and K2CO3 (1.16 g, 8.400 mmol) in ACN (50 mL), and stir the reaction mixture at 70 °C for 2 hours. After the reaction is complete, concentrate the reaction mixture under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain Compound 6M as a yellow oil (1 g, 50%). LC-MS m / z = 465.1, 467.1 [M+Na] + 。

[0223] Step 12: Preparation of Compound 6O

[0224] Compound 6M (1 g, 2.300 mmol), compound 6N (570 mg, 3.680 mmol), K3PO4 (1.95 g, 9.200 mmol), Sphos (90 mg, 0.230 mmol) and Pd(OAc)2 (30 mg, 0.115 mmol) were dissolved in 1,4-dioxane (40 mL) and H2O (4 mL). Under nitrogen protection, the mixture was stirred at 90 °C for 3 hours. After the reaction was complete, it was cooled, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain yellow solid compound 6O (810 mg, 86%). LC-MS m / z = 413.2 [M+Na] + .

[0225] Step 13: Preparation of Compound 6P

[0226] Compound 6O (800 mg, 2.049 mmol) was dissolved in DMF (2 mL) and H2O (0.2 mL) bubbled with nitrogen, and then PdCl2 (726.6 mg, 4.098 mmol) was added. The reaction solution was stirred at 25 °C for 16 hours. After the reaction was complete, it was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (4 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 6P (535 mg, 61%). LC-MS m / z = 429.2 [M+Na] + .

[0227] Step 14: Preparation of Compound 6R

[0228] Compound 6P (428 mg, 1.053 mmol), compound 6Q (153.2 mg, 1.264 mmol) and tris(2,2,2-trifluoroethyl) borate (389.1 mg, 1.264 mmol) were dissolved in THF (10 mL). The reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction was quenched with water. After concentration under reduced pressure, it was diluted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude yellow oily compound 6R (520 mg, 87%). LC-MS m / z = 532.4 [M+Na] + .

[0229] Step 15: Preparation of Compound 6T

[0230] PCy3·HBF4 (42.3 mg, 0.115 mmol) and CuSO4·5H2O (28.7 mg, 0.115 mmol) were dissolved in toluene (10 mL) and H2O (1 mL). The reaction solution was stirred at 0 °C for 10 minutes under nitrogen protection. Benzylamine (49.2 mg, 0.459 mmol) was added, and then compound 6R (585 mg, 1.148 mmol) and compound 6S (822 mg, 2.296 mmol) were added successively. The reaction solution was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with water. After concentration under reduced pressure, it was diluted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (1 / 1 petroleum ether / ethyl acetate) to obtain a yellow oily compound 6T (480 mg, 58%). LC-MS m / z = 690.4 [M+H] + 。

[0231] Step 16: Preparation of compound 6U

[0232] Compound 6T (130 mg, 0.189 mmol) was dissolved in 1,4-dioxane (0.4 mL), and a 1,4-dioxane solution of HCl (0.2 mL, 0.226 mmol, 1 M in 1,4-Dioxane) was added. The reaction solution was stirred at 25 °C for 15 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure at low temperature to obtain a crude product of yellow oily compound 6U (100 mg, 91%). Without further purification, the crude product was directly used for the next reaction. LC-MS m / z = 586.4 [M+H] + 。

[0233] Step 17: Preparation of compound 6V

[0234] Prepared according to the synthetic scheme of compound 2F in Example 2. White solid compound 6V (58 mg, 22%) was obtained from compound 6U (150 mg, 0.256 mmol). LC-MS m / z = 969.7 [M+H] + 。

[0235] Step 18: Preparation of compounds 6 and 7

[0236] Prepared according to the synthetic scheme of compound 3 in Example 3. White solid compound 6 (5.6 mg, 21%, HPLC retention time: 2.678 min) and compound 7 (9.0 mg, 34%, HPLC retention time: 3.037 min) were obtained from compound 6V (58 mg, 0.060 mmol).

[0237] HPLC purification conditions:

[0238] Chromatographic column: Xbridge C8 5μm 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be linearly gradient eluted from 98:2 to 60:40; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution.

[0239] Compound 6: 1 H NMR(D2O,400MHz)δ7.15(s,1H),4.08(dd,J=11.0,4.3Hz,1H),3.89 - 3.82(m,1H),3.77 - 3.72(m,1H),3.40 - 3.33(m,5H),3.28 - 3.20(m,2H),3.01 - 2.88(m,5H),2.01 - 1.81(m,2H),1.52 - 1.41(m,1H),1.39 - 1.16(m,2H),1.10 - 0.97(m,1H),0.82 - 0.58(m,3H).LC-MS m / z=446.1[M + H] + 。

[0240] Compound 7: 1 H NMR(D2O,400MHz)δ7.03(s,1H),4.03 - 3.99(m,1H),3.65 - 3.60(m,2H),3.38 - 3.32(m,3H),3.18 - 3.13(m,2H),2.96 - 2.90(m,1H),2.86 - 2.78(m,2H),2.71 - 2.68(m,1H),2.27 - 2.22(m,1H),2.06 - 2.00(m,1H),1.93 - 1.90(m,1H),1.84 - 1.81(m,1H),1.47 - 1.36(m,2H),1.20 - 0.68(m,6H).LC-MS m / z=446.1[M + H] + 。

[0241] Examples 8 and 9: Synthesis of Compounds 8 and 9

[0242]

[0243] Step 1: Preparation of Compound 8A

[0244] Prepared according to the synthesis scheme of Compound 6V in Example 6. The white solid Compound 8A (48 mg, 29%) was obtained from Compound 6U (100 mg, 0.171 mmol). LC-MS m / z = 953.0 [M+H] + 。

[0245] Step 2: Preparation of Compounds 8 and 9

[0246] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compound 8 (12.2 mg, 57%, HPLC retention time: 2.481 min) and Compound 9 (7.4 mg, 34%, HPLC retention time: 2.665 min) were obtained from Compound 8A (48 mg, 0.050 mmol).

[0247] HPLC purification conditions:

[0248] Column: Xbridge C8 5μm, 19*150 mm; Mobile phase: A: H2O (0.2% TFA), B: ACN; Wavelength: 214 nm; Flow rate: 15 mL / min; Gradient elution program: Set the volume ratio of the mobile phase A and the mobile phase B to be 98:2 to 60:40 for linear gradient elution at 0 - 10 minutes; Set the volume ratio of the mobile phase A and the mobile phase B to be 5:95 for isocratic elution at 11 - 15 minutes.

[0249] Compound 8: 1 H NMR (D2O, 400 MHz) δ 7.18 (s, 1H), 4.06 (dd, J = 11.1, 4.2 Hz, 1H), 3.87 (dd, J = 11.2, 6.8 Hz, 1H), 3.79 - 3.75 (m, 2H), 3.37 - 3.32 (m, 2H), 3.26 - 3.18 (m, 3H), 2.95 - 2.88 (m, 3H), 2.76 - 2.62 (m, 2H), 1.73 (d, J = 2.0 Hz, 3H), 1.62 (d, J = 2.0 Hz, 3H). LC-MS m / z = 430.1 [M+H] + 。

[0250] Compound 9: 11H NMR (D2O, 400 MHz) δ 7.14 (s, 1H), 4.02 (dd, J = 11.2, 5.0 Hz, 1H), 3.89 (dd, J = 10.9, 6.4 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.35 - 3.30 (m, 2H), 3.24 - 3.20 (m, 3H), 2.94 - 2.62 (m, 6H), 1.77 (d, J = 9.5 Hz, 3H), 1.69 (d, J = 9.6 Hz, 3H). LC-MS m / z = 430.1 [M + H] + 。

[0251] Example 10: Synthesis of Compound 10

[0252]

[0253] Step 1: Preparation of Compound 10B

[0254] Dissolve 10A (5 g, 0.027 mol) in toluene (100 mL) and DMSO (50 mL), add IBX (25.58 g, 0.041 mol), TsOH . H2O (1.54 g, 0.008 mol), stir the reaction at 55 °C for 48 hours. After the reaction is complete, cool it, add ether (150 mL) and saturated sodium bicarbonate solution (100 mL), filter the mixture through diatomaceous earth, combine the filtrates, extract with ethyl acetate, combine the organic phases and dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain the yellow oily compound 10B (3.5 g, 50%). 1 1H NMR (DMSO-d6, 400 MHz) δ 6.92 (dd, J = 0.8, 10.0 Hz, 1H), 5.89 (dd, J = 2.4, 10.0 Hz, 1H), 4.12 - 4.07 (q, J = 7.2 Hz, 2H), 2.88 - 2.83 (m, 1H), 2.58 - 2.52 (m, 1H), 2.47 - 2.35 (m, 3H), 2.07 - 2.02 (m, 1H), 1.71 - 1.63 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H).

[0255] Step 2: Preparation of Compound 10C

[0256] Compound 10B (3.4 g, 18.659 mmol) and CeCl3 (5.06 g, 20.525 mmol) were dissolved in MeOH (150 mL). Under the same conditions, NaBH4 (776.5 mg, 20.525 mmol) was added portionwise at 0 °C, and the total addition time was about 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction was quenched with acetone, concentrated under reduced pressure, diluted with DCM, the organic phase was washed with water, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 10C as a yellow oil (3.3 g, 91%). LC-MS m / z = 207.2 [M+Na] + 。

[0257] Step 3: Preparation of Compound 10D

[0258] Compound 10C (1.8 g, 9.770 mmol) was dissolved in DCM (20 mL), TEA (1.98 g, 19.541 mmol) and MsCl (1.12 g, 9.770 mmol) were added, and the reaction mixture was stirred at room temperature for 17 hours. After the reaction was complete, the reaction mixture was diluted with DCM, the organic phase was washed with water, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 10D as a yellow oil (2.5 g, 97%). LC-MS m / z = 167.2 [M-H-OMs+H] + 。

[0259] Step 4: Preparation of Compound 10F

[0260] Compound 10D (2.5 g, 0.010 mol) was dissolved in DMF (40 mL), 10E (4.57 g, 0.029 mol) and K2CO3 (5.25 g, 0.038 mol) were added, and the reaction mixture was stirred at room temperature for 17 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, the organic phase was washed with water, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 10F as a yellow oil (3 g, 96%). LC-MS m / z = 327.2 [M+H] + 。

[0261] Step 5: Preparation of Compound 10G

[0262] Compound 10F (2.95 g, 9.037 mmol) was dissolved in DCM (100 mL), and Boc2O (4.93 g, 22.593 mmol) and TEA (1.37 g, 13.556 mmol) were added. The reaction mixture was stirred at room temperature for 17 h. After completion of the reaction, the reaction mixture was washed twice with saturated brine (150 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (1 / 1 petroleum ether / ethyl acetate) to obtain compound 10G as a yellow oil (2.5 g, 62%). 1 1H NMR (DMSO-d6, 400 MHz) δ 5.70 - 5.65 (m, 2H), 4.55 (d, J = 6.4 Hz, 1H), 4.09 - 4.00 (q, J = 6.8 Hz, 2H), 3.92 - 3.91 (m, 1H), 3.06 - 2.93 (m, 4H), 2.47 - 2.43 (m, 2H), 2.32 - 2.27 (m, 1H), 2.25 - 2.12 (m, 2H), 1.97 - 1.92 (m, 2H), 1.40 - 1.35 (m, 18H), 1.18 (t, J = 6.8 Hz, 3H). LC-MS m / z = 449.4 [M+Na] + 。

[0263] Step 6: Preparation of compound 10H

[0264] Compound 10G (600 mg, 1.407 mmol) was dissolved in THF (10 mL), EtOH (10 mL) and water (10 mL), and LiOH . H2O (177.1 mg, 4.220 mmol) was added. The reaction mixture was stirred at room temperature for 17 h. After completion of the reaction, the pH was adjusted to 5 with 1 M citric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 10H as a white solid (350 mg, 56%). LC-MS m / z = 421.2 [M+Na] + 。

[0265] Step 7: Preparation of compound 10I

[0266] Prepared according to the synthetic scheme of compound 1O in Example 1. A white solid compound 10I (85 mg, 46%) was obtained from the crude product of compound 1M and compound 10H (88 mg, 0.220 mmol). LC-MS m / z = 837.0 [M+H] + 。

[0267] Step 8: Preparation of compound 10

[0268] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compound 10 (22 mg, 52%) was obtained from Compound 10I (85 mg, 0.102 mmol). 1 H NMR (400 MHz, D2O, the mixture of cis-trans isomerism) δ 7.08 (s, 1H), 7.06 (s, 1H), 5.71 - 5.64 (m, 1H), 5.63 - 5.53 (m, 1H), 5.50 - 5.39 (m, 1H), 3.78 - 3.71 (m, 2H), 3.61 - 3.53 (m, 1H), 3.41 - 3.34 (m, 8H), 3.28 - 3.18 (m, 8H), 3.14 - 3.04 (m, 4H), 2.97 - 2.84 (m, 4H), 2.58 - 2.43 (m, 2H), 2.38 - 2.08 (m, 4H), 2.00 - 1.88 (m, 1H), 1.79 - 1.55 (m, 1H), 1.51 - 1.38 (m, 1H), 1.37 - 1.18 (m, 1H), 0.85 - 0.69 (m, 2H). LC-MS m / z = 414.1 [M + H] + 。

[0269] Example 11 and 12: Synthesis of Compounds 11 and 12

[0270]

[0271] Step 1: Preparation of Compound 11A

[0272] Dissolve LiAlH4 (1.28 g, 0.034 mmol) in THF (65 mL), slowly drop H2SO4 (1.03 g, 0.011 mol) at 0 °C, stir the reaction solution at 0 °C for 1 hour, then slowly drop the THF (15 mL) solution of Compound 6G (5 g, 0.021 mol), and stir the reaction solution at 25 °C for 2 hours. After the reaction is complete, quench the reaction solution with Na2SO4·10H2O, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of yellow oily Compound 11A (4.2 g, 82%). LC-MS m / z = 242.1, 244.1 [M + H] + 。

[0273] Step 2: Preparation of Compound 11B

[0274] Compound 11A (4.1 g, 0.017 mol) was dissolved in DCM (150 mL), and then BBr3 (5.5 g, 0.022 mol) was slowly added dropwise at -78 °C. The reaction mixture was stirred at 25 °C for 10 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with methanol at low temperature, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (5 / 1 petroleum ether / ethyl acetate) to obtain yellow solid compound 11B (5 g, 80%). LC-MS m / z = 227.9 [M+H] + 。

[0275] Step 3: Preparation of compound 11C

[0276] Compound 11B (5 g, 0.022 mol) was dissolved in DCM (150 mL), Boc2O (14.34 g, 0.066 mol) and DMAP (10.7 g, 0.088 mol) were added at 0 °C, and the reaction mixture was stirred at 25 °C for 10 hours. After the reaction was complete, the reaction mixture was quenched with methanol, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (5 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 11C (2.2 g, 23%). LC-MS m / z = 450.8 [M+Na] + 。

[0277] Step 4: Preparation of compound 11D

[0278] Prepared according to the synthesis scheme of compound 1F in Example 1. Yellow oily compound 11D (1.3 g, 64%) was obtained from compound 11C (2 g, 4.700 mmol). 1 1H NMR (CDCl3, 400 MHz) δ 11.42 (s, 1H), 7.40 (s, 1H), 4.51 (s, 1H), 3.81 - 3.72 (m, 1H), 3.70 - 3.60 (m, 1H), 3.46 - 3.37 (m, 1H), 3.20 (dd, J = 13.8, 5.0 Hz, 1H), 2.81 (dd, J = 13.9, 2.2 Hz, 1H), 1.63 (s, 9H), 1.41 (s, 9H). LC-MS m / z = 428.0 [M+H] + 。

[0279] Step 5: Preparation of compound 11E

[0280] Prepared according to the synthesis scheme of compound 6M in Example 6. Yellow oily compound 11E (1.2 g, 90%) was obtained from compound 11D (1.3 g, 0.003 mol). 11H NMR (CDCl3, 400 MHz) δ 7.38 (s, 1H), 5.01 (s, 1H), 3.87 (s, 3H), 3.68 - 3.54 (m, 1H), 3.61 - 3.50 (m, 2H), 3.22 (dd, J = 14.4, 5.2 Hz, 1H), 2.83 - 2.79 (dd, J = 13.6, 2.0 Hz, 1H), 1.61 (s, 9H), 1.43 (s, 9H).

[0281] Step 6: Preparation of Compound 11F

[0282] Prepared according to the synthesis scheme of Compound 6O in Example 6. The yellow oily Compound 11F (2.4 g, 69%) was obtained from Compound 11E (4 g, 0.009 mol). 1 1H NMR (CDCl3, 300 MHz) δ 7.38 (s, 1H), 7.12 - 7.03 (m, 1H), 5.72 (d, J = 17.7 Hz, 1H), 5.32 (d, J = 11.1 Hz, 1H), 5.09 (m, 1H), 3.82 (s, 3H), 3.79 - 3.73 (m, 1H), 3.58 (m, 2H), 3.26 (dd, J = 5.4 Hz, 14.4 Hz, 1H), 2.86 (dd, J = 14.1, 2.5 Hz, 1H), 1.65 (s, 9H), 1.46 (s, 9H). LC-MS m / z = 390.0 [M + H] + .

[0283] Step 7: Preparation of Compound 11G

[0284] Dissolve Compound 11F (2.4 g, 0.006 mol) in DMF (30 mL), add 60% NaH (0.5 g, 0.012 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under nitrogen protection, then add CH3I (1.76 g, 0.012 mol), and the reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (5 / 1 petroleum ether / ethyl acetate) to obtain the yellow oily Compound 11G (2.3 g, 92%). LC-MS m / z = 426.4 [M + Na] + 。

[0285] Step 8: Preparation of Compound 11H

[0286] Prepared according to the synthesis scheme of Compound 6P in Example 6. The yellow oily Compound 11H (1.02 g, 42%) was obtained from Compound 11G (2.3 g, 0.006 mol). LC-MS m / z = 442.4 [M+Na] + 。

[0287] Step 9: Preparation of Compound 11I

[0288] Prepared according to the synthesis scheme of Compound 6R in Example 6. The yellow oily Compound 11I (1 g, 92%) was obtained from Compound 11H (870 mg, 2.074 mol). LC-MS m / z = 423.2 [M+H-100] + 。

[0289] Step 10: Preparation of Compound 11J

[0290] Prepared according to the synthesis scheme of Compound 6T in Example 6. The yellow oily Compound 11J (232 mg, 58%) was obtained from Compound 11I (21 mg, 0.057 mmol). LC-MS m / z = 703.4 [M+H] + 。

[0291] Step 11: Preparation of Compound 11K

[0292] Prepared according to the synthesis scheme of Compound 6U in Example 6. The crude yellow oily Compound 11K (150 mg, 98%) was obtained from Compound 11J (180 mg, 0.256 mmol). LC-MS m / z = 599.4 [M+H] + 。

[0293] Step 12: Preparation of Compound 11L

[0294] Prepared according to the synthesis scheme of Compound 2F in Example 2. The yellow oily Compound 11L (92 mg, 37%) was obtained from Compound 11K (150 mg, 0.251 mmol). LC-MS m / z = 981.6 [M+H] + 。

[0295] Step 13: Preparation of Compounds 11 and 12

[0296] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compounds 11 (7.6 mg, 20%, HPLC retention time: 2.767 min) and 12 (12 mg, 32%, HPLC retention time: 3.054 min) were obtained from Compound 11L (80 mg, 0.082 mmol).

[0297] HPLC purification conditions:

[0298] Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O(0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 - 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be linearly gradient eluted from 98:2 to 80:20; From 11 - 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution.

[0299] Compound 11: 1 H NMR(D2O, 400MHz) δ7.20(s, 1H), 3.98 - 3.90(m, 1H), 3.53 - 3.32(m, 8H), 3.29 - 3.25(m, 1H), 3.03 - 2.90(m, 4H), 2.76(s, 3H), 2.37 - 2.30(m, 1H), 2.10(dd, J = 14.0, 8.8Hz, 1H), 2.04 - 1.95(m, 1H), 1.91 - 1.82(m, 1H), 1.53 - 1.44(m, 1H), 1.28 - 1.16(m, 1H), 1.10 - 0.98(m, 1H), 0.93 - 0.80(m, 1H), 0.79 - 0.66(m, 2H). LC - MS m / z = 459.2[M + H] + 。

[0300] Compound 12: 1 H NMR(D2O, 400MHz) δ7.17(s, 1H), 3.96 - 3.89(m, 1H), 3.59(dd, J = 12.7, 7.3Hz, 1H), 3.43 - 3.26(m, 7H), 3.25 - 3.21(m, 1H), 3.13 - 3.03(m, 1H), 2.95 - 2.90(m, 2H), 2.90 - 2.83(m, 1H), 2.80(s, 3H), 2.22(dd, J = 16.8, 7.0Hz, 1H), 2.08 - 1.93(m, 2H), 1.62 - 1.52(m, 2H), 1.37 - 1.18(m, 3H), 1.05 - 0.86(m, 2H). LC - MS m / z = 459.2[M + H] + 。

[0301] Example 13: Synthesis of Compound 13

[0302]

[0303] Step 1: Preparation of Compound 13A

[0304] Compound 6M (1.1 g, 2.5 mmol) was dissolved in DCM (10 mL), and TFA (10 mL) was added at room temperature. The reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, it was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate was slowly added to the solution under ice bath until the solution was neutral. The mixture was extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of yellow solid compound 13A (600 mg, 84%). LC-MS m / z = 287.0, 289.0 [M+H] + 。

[0305] Step 2: Preparation of Compound 13B

[0306] Compound 13A (600 mg, 2.098 mmol) was dissolved in DMF (10 mL). 60% NaH (419.6 mg, 10.490 mmol) and CH3I (2.382 g, 16.784 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h under nitrogen protection. After completion of the reaction, it was quenched by slowly adding water under ice bath. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (6 / 1 petroleum ether / ethyl acetate) to obtain yellow solid compound 13B (550 mg, 79%). LC-MS m / z = 315.1, 317.1 [M+H] + 。

[0307] Step 3: Preparation of Compound 13D

[0308] Compound 13B (500 mg, 1.587 mmol), 13C (377.1 mg, 1.904 mmol), K2CO3 (657.8 mg, 4.760 mmol) and Pd(dppf)Cl2 (116.1 mg, 0.159 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was stirred at 90 °C for 3 h under nitrogen protection. After completion of the reaction, it was cooled, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 13D (325 mg, 64%). LC-MS m / z = 307.2 [M+H] + 。

[0309] Step 4: Preparation of Compound 13E

[0310] Compound 13D (360 mg, 1.175 mmol) was dissolved in ACN (10 mL), and 4 M dilute hydrochloric acid (4.4 mL, 17.627 mmol) was added dropwise. The reaction was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of yellow oily compound 13E (280 mg, 81%). LC-MS m / z = 279.2 [M+H] + 。

[0311] Step 5: Preparation of Compound 13F

[0312] Prepared according to the synthetic scheme of Compound 6R in Example 6. The crude product of yellow oily compound 13F (240 mg, 56%) was obtained from Compound 13E (280 mg, 1.006 mmol). LC-MS m / z = 382.2 [M+H] + 。

[0313] Step 6: Preparation of Compound 13G

[0314] Prepared according to the synthetic scheme of Compound 6T in Example 6. Yellow oily compound 13G (305 mg, 78%) was obtained from Compound 13F (240 mg, 0.629 mmol). LC-MS m / z = 562.3 [M+H] + 。

[0315] Step 7: Preparation of Compound 13H

[0316] Prepared successively according to the synthetic schemes of Compounds 6U and 6V in Example 6. White solid compound 13H (144 mg, 23%) was obtained from Compound 13G (305 mg, 0.543 mmol). LC-MS m / z = 840.5 [M+H] + 。

[0317] Step 8: Preparation of Compound 13I

[0318] Prepared according to the synthetic scheme of Compound 3 in Example 3. White solid compound 13I (72 mg, 89%) was obtained from Compound 13H (144 mg, 0.172 mmol). LC-MS m / z = 474.3 [M+H] + 。

[0319] Step 9: Preparation of Compound 13

[0320] Compound 13I (40 mg, 0.085 mmol) was dissolved in a mixed solvent of EtOH (0.5 mL), THF (1 mL) and H2O (1 mL), and LiOH was added .H2O (70.9 mg, 1.690 mmol) was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure at low temperature to obtain a crude product, which was purified by preparative HPLC to obtain white solid compound 13 (5 mg, 12%). 1 1H NMR (D2O, 400 MHz, a pair of epimers) δ 7.16 (s, 1H), 7.15 (s, 1H), 4.21 - 4.15 (m, 2H), 3.92 - 3.83 (m, 2H), 3.66 - 3.57 (m, 2H), 3.43 - 3.41 (m, 6H), 3.39 - 3.37 (m, 8H), 3.33 - 3.24 (m, 4H), 3.13 - 3.03 (m, 2H), 2.97 - 2.86 (m, 6H), 2.39 - 2.30 (m, 2H), 2.22 - 2.13 (m, 2H), 2.10 - 1.92 (m, 4H), 1.62 - 1.48 (m, 4H), 1.40 - 1.10 (m, 6H), 1.04 - 0.79 (m, 4H). LC-MS m / z = 460.1 [M + H] + 。

[0321] Example 14: Synthesis of Compound 14

[0322]

[0323] Step 1: Preparation of Compound 14A

[0324] 13A (2.1 g, 7.31 mmol), CH3I (5.2 g, 36.64 mmol) and K2CO3 (2.0 g, 14.47 mmol) were dissolved in ACN (20 mL), and the reaction solution was stirred at 70 °C for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (4 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 14A (1.5 g, 68%). LC-MS m / z = 301.1, 303.1 [M + H] + 。

[0325] Step 2: Preparation of Compound 14B

[0326] Compound 14A (1.5 g, 4.98 mmol) was dissolved in DCM (20 mL), and Et3N (1.01 g, 9.98 mmol) and MsCl (0.68 g, 5.97 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water, concentrated, diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (4 / 1 petroleum ether / ethyl acetate) to obtain yellow solid compound 14B (1.6 g, 76%). LC-MS m / z = 401.0, 403.0 [M+Na] + 。

[0327] Step 3: Preparation of Compound 14C

[0328] Compound 14B (1.6 g, 4.22 mmol) was dissolved in DMF (20 mL). Under nitrogen protection, NaSMe (0.59 g, 8.42 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled, quenched with water, concentrated, diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (5 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 14C (570 mg, 38%). LC-MS m / z = 302.9, 304.9 [M+H] + 。

[0329] Step 4: Preparation of Compound 14D

[0330] Compound 14C (570 mg, 1.67 mmol), CH3I (712.5 mg, 5.02 mmol) and K2CO3 (461.6 mg, 3.34 mmol) were dissolved in ACN (10 mL), and the reaction mixture was stirred at 70 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain yellow oily compound 14D (500 mg, 90%). LC-MS m / z = 330.9, 332.9 [M+H] + 。

[0331] Step 5: Preparation of Compound 14E

[0332] Prepared according to the synthesis scheme of compound 13D in Example 13. Yellow oily compound 14E (345 mg, 71%) was obtained from compound 14D (500 mg, 1.51 mmol). LC-MS m / z = 323.2 [M+H] + 。

[0333] Step 6: Preparation of Compound 14F

[0334] Prepared according to the synthesis scheme of Compound 13E in Example 13. The crude product of Compound 14F as a yellow oil (410 mg, 88%) was obtained from Compound 14E (510 mg, 1.58 mmol).

[0335] Step 7: Preparation of Compound 14G

[0336] Prepared according to the synthesis scheme of Compound 6R in Example 6. Compound 14G (450 mg, 77%) as a yellow oil was obtained from Compound 14F (410 mg, 1.39 mmol). LC-MS m / z = 398.1 [M+H] + 。

[0337] Step 8: Preparation of Compound 14H

[0338] Prepared according to the synthesis scheme of Compound 6T in Example 6. Compound 14H (310 mg, 45%) as a yellow oil was obtained from Compound 14G (450 mg, 1.13 mmol). LC-MS m / z = 578.2 [M+H] + 。

[0339] Step 9: Preparation of Compound 14I

[0340] Prepared successively according to the synthesis schemes of Compounds 6U and 6V in Example 6. Compound 14I (102 mg, 22%) as a white solid was obtained from Compound 14H (310 mg, 0.54 mmol). LC-MS m / z = 856.4 [M+H] + 。

[0341] Step 10: Preparation of Compound 14J

[0342] Dissolve Compound 14I (40 mg, 0.047 mmol) in EtOH (1 mL), THF (1 mL) and H2O (1 mL), and add LiOH . H2O (19.6 mg, 0.47 mmol), and stir the reaction at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution, dilute it with ethyl acetate, and wash the organic phase with water. Combine the organic phases and dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and purify the crude product by preparative HPLC to obtain Compound 14J (25 mg, 60%) as a white solid. LC-MS m / z = 842.5 [M+H] + 。

[0343] Step 11: Preparation of Compound 14

[0344] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compound 14 (2.9 mg, 19%) was obtained from Compound 14J (25 mg, 0.03 mmol). 1 H NMR (D2O, 400 MHz, a pair of epimers) δ 7.05 (s, 1H), 3.79 - 3.76 (m, 1H), 3.29 - 3.14 (m, 7H), 3.06 - 2.63 (m, 5H), 2.27 - 2.24 (m, 1H), 2.10 - 1.94 (m, 4H), 1.90 - 1.78 (m, 2H), 1.50 - 1.38 (m, 2H), 1.26 - 0.62 (m, 5H). LC-MS m / z = 476.2 [M + H] + 。

[0345] Example 15 and 16: Preparation of Compounds 15 and 16

[0346]

[0347] Step 1: Preparation of Compound 15A

[0348] 14I (52 mg, 0.06 mmol) and cumene hydroperoxide (9 mg, 0.06 mmol) were successively dissolved in ACN (20 mL), and then Ti(OiPr)4 (34 mg, 0.12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain the white solid Compound 15A (35 mg, 65%). LC-MS m / z = 888.4 [M + H] + 。

[0349] Step 2: Preparation of Compound 15B

[0350] Prepared according to the synthesis scheme of Compound 14J in Example 14. The white solid Compound 15B (25 mg, 73%) was obtained from Compound 15A (35 mg, 0.04 mmol). LC-MS m / z = 874.3 [M + H] + 。

[0351] Step 3: Preparation of Compounds 15 and 16

[0352] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compound 15 (3.2 mg, 21%, HPLC retention time: 2.241 min) and the white solid Compound 16 (3.3 mg, 22%, HPLC retention time: 2.627 min) were obtained from Compound 15B (25 mg, 0.03 mmol).

[0353] HPLC purification conditions:

[0354] Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; Flow rate: 15mL / min; Gradient elution program: From 0 to 10 minutes, set the volume ratio of mobile phase A and mobile phase B to be linearly gradient eluted from 98:2 to 60:40; From 11 to 15 minutes, set the volume ratio of mobile phase A and mobile phase B to be 5:95 for isocratic elution.

[0355] Compound 15: 1 H NMR (D2O, 400MHz) δ7.11 (s, 1H), 4.07 - 4.03 (d, J = 14.0Hz, 1H), 3.95 - 3.92 (m, 1H), 3.48 - 3.39 (m, 2H), 3.42 - 3.35 (m, 4H), 3.30 - 3.17 (m, 5H), 2.86 (s, 3H), 2.30 - 2.26 (m, 1H), 2.05 - 2.00 (m, 1H), 1.90 - 1.87 (m, 1H), 1.81 - 1.79 (m, 1H), 1.41 - 1.37 (m, 1H), 1.27 - 1.15 (m, 2H), 0.98 - 0.95 (m, 1H), 0.68 - 0.62 (m, 3H). LC-MS m / z = 508.1 [M+H] + 。

[0356] Compound 16: 1 H NMR (D2O, 400MHz) δ7.18 (s, 1H), 4.30 (d, J = 14.2Hz, 1H), 4.08 - 3.98 (m, 1H), 3.54 - 3.44 (m, 1H), 3.39 - 3.34 (m, 4H), 3.27 - 3.04 (m, 7H), 2.98 - 2.92 (m, 2H), 2.40 - 2.32 (m, 1H), 2.18 - 2.08 (m, 1H), 2.06 - 1.97 (m, 1H), 1.96 - 1.88 (m, 1H), 1.59 - 1.43 (m, 2H), 1.34 - 1.22 (m, 1H), 1.20 - 1.09 (m, 1H), 1.02 - 0.90 (m, 2H), 0.86 - 0.73 (m, 1H). LC-MS m / z = 508.1 [M+H] + 。

[0357] Example 17: Synthesis of Compound 17

[0358]

[0359] Step 1: Preparation of Compound 17B

[0360] Compound 17A (763 mg, 3.700 mmol) and NaOAc (607 mg, 7.400 mmol) were dissolved in acetic acid (20 mL). A solution of Br2 (562 mg, 3.515 mmol) in acetic acid (5 mL) was added dropwise at 80 °C. The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, it was cooled. The reaction mixture was quenched with saturated sodium sulfite solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate 10 / 1) to obtain white solid compound 17B (840 mg, 76%). LC-MS m / z = 267.1, 269.1 [M - 18 + H] + .

[0361] Step 2: Preparation of Compound 17C

[0362] Compound 17B (840 mg, 2.946 mmol) was dissolved in ACN (20 mL). K2CO3 (814 mg, 5.892 mmol) and CH3I (2.09 g, 14.730 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, it was cooled. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate 15 / 1) to obtain white solid compound 17C (620 mg, 67%). LC-MS m / z = 321.0, 323.0 [M + Na] + .

[0363] Step 3: Preparation of Compound 17D

[0364] Prepared according to the synthetic scheme of compound 13D in Example 13. Yellow oily compound 17D (450 mg, 72%) was obtained from compound 17C (620 mg, 2.073 mmol). LC-MS m / z = 291.2 [M + H] + .

[0365] Step 4: Preparation of Compound 17E

[0366] Prepared according to the synthetic scheme of compound 13E in Example 13. Yellow oily compound 17E (380 mg, 47%) was obtained from compound 17D (450 mg, 1.550 mmol). LC-MS m / z = 285.2 [M + Na] + .

[0367] Step 5: Preparation of Compound 17F

[0368] Prepared according to the synthetic scheme of Compound 6R in Example 6. Compound 17F (300 mg, 91%) was obtained as a yellow oil from Compound 17E (380 mg, 0.724 mmol). LC-MS m / z = 366.2 [M+H] + 。

[0369] Step 6: Preparation of Compound 17G

[0370] Prepared according to the synthetic scheme of Compound 6T in Example 6. Compound 17G (205 mg, 54%) was obtained as a yellow oil from Compound 17F (300 mg, 0.657 mmol). LC-MS m / z = 546.3 [M+H] + 。

[0371] Step 7: Preparation of Compound 17H

[0372] Prepared according to the synthetic scheme of Compound 6U in Example 6. Compound 17H (140 mg, 91%) was obtained as a yellow oil from Compound 17G (180 mg, 0.330 mmol). LC-MS m / z = 442.3 [M+H] + 。

[0373] Step 8: Preparation of Compound 17I

[0374] Prepared according to the synthetic scheme of Compound 2F in Example 2. Compound 17I (55 mg, 20%) was obtained as a white solid from Compound 17H (140 mg, 0.349 mmol). LC-MS m / z = 824.4 [M+H] + 。

[0375] Step 9: Preparation of Compound 17J

[0376] Prepared according to the synthetic scheme of Compound 13I in Example 13. Compound 17J (20 mg, 68%) was obtained as a white solid from Compound 17I (50 mg, 0.061 mmol). LC-MS m / z = 458.3 [M+H] + 。

[0377] Step 10: Preparation of Compound 17

[0378] Prepared according to the synthetic scheme of Compound 13 in Example 13. Compound 17 (1.1 mg, 8.8%) was obtained as a white solid from Compound 17J (12 mg, 0.026 mmol). 11H NMR (D2O, 400 MHz) δ 6.75 (s, 1H), 3.66 - 3.61 (m, 1H), 3.33 - 3.23 (m, 4H), 3.06 - 2.92 (m, 2H), 2.82 - 2.51 (m, 6H), 2.25 - 2.18 (m, 1H), 2.07 - 1.58 (m, 7H), 1.50 - 1.37 (m, 2H), 1.26 - 1.07 (m, 2H), 0.86 - 0.66 (m, 2H). LC-MS m / z = 444.1 [M + H] + 。

[0379] Example 18: Synthesis of Compound 18

[0380]

[0381] Step 1: Preparation of Compound 18B

[0382] Dissolve Compound 18A (3 g, 22.4 mmol) in acetic acid (80 mL) and DCM (20 mL), and dropwise add a solution of Br2 (3.4 g, 21.3 mmol) in acetic acid (30 mL) at 0 °C. Stir the reaction mixture at 0 °C for 1 hour. After the reaction is complete, quench the reaction mixture with saturated sodium sulfite solution, extract with ethyl acetate, wash the organic phase with saturated brine, combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (10 / 1 petroleum ether / ethyl acetate) to obtain yellow oily Compound 18B (4.1 g, 86%). LC-MS m / z = 213.0, 215.0 [M + H] + 。

[0383] Step 2: Preparation of Compound 18C

[0384] Prepared according to the synthesis protocol of Compound 1E in Example 1. Yellow oily Compound 18C (4.5 g, 75%) was obtained from Compound 18B (4.1 g, 19.2 mmol). LC-MS m / z = 257.0, 259.0 [M - 56 + H] + 。

[0385] Step 3: Preparation of Compound 18D

[0386] Prepared according to the synthesis protocol of Compound 1F in Example 1. Yellow oily Compound 18D (3.6 g, 80%) was obtained from Compound 18C (4.5 g, 14.4 mmol). LC-MS m / z = 257.0, 259.0 [M - 56 + H] + 。

[0387] Step 4: Preparation of Compound 18E

[0388] Prepared according to the synthesis scheme of Compound 17C in Example 17. The yellow oily Compound 18E (3.4 g, 90%) was obtained from Compound 18D (3.6 g, 11.5 mmol). LC-MS m / z = 271.0, 273.0 [M - 56 + H] + .

[0389] Step 5: Preparation of Compound 18F

[0390] Prepared according to the synthesis scheme of Compound 6O in Example 6. The yellow oily Compound 18F (1 g, 85%) was obtained from Compound 18E (1.4 g, 4.28 mmol). LC-MS m / z = 219.2 [M - 56 + H] + .

[0391] Step 6: Preparation of Compound 18G

[0392] Prepared according to the synthesis scheme of Compound 6P in Example 6. The yellow oily Compound 18G (300 mg, 28%) was obtained from Compound 18F (1 g, 3.6 mmol). LC-MS m / z = 235.1 [M - 56 + H] + .

[0393] Step 7: Preparation of Compound 18H

[0394] Prepared according to the synthesis scheme of Compound 6R in Example 6. The crude yellow oily Compound 18H (350 mg, 86%) was obtained from Compound 18G (300 mg, 1.03 mmol). LC-MS m / z = 394.1 [M + H] + .

[0395] Step 8: Preparation of Compound 18I

[0396] Prepared according to the synthesis scheme of Compound 6T in Example 6. The colorless oily Compound 18I (230 mg, 49%) was obtained from Compound 18H (320 mg, 0.81 mmol). LC-MS m / z = 574.2 [M + H] + .

[0397] Step 9: Preparation of Compound 18J

[0398] Prepared successively according to the synthesis schemes of Compounds 6U and 6V in Example 6. The white solid Compound 18J (70 mg, 22%) was obtained from Compound 18I (200 mg, 0.35 mmol). LC-MS m / z = 852.2 [M + H] + .

[0399] Step 10: Preparation of Compound 18

[0400] Prepared according to the synthesis scheme of Compound 3 in Example 3. The white solid Compound 18 (15 mg, 40%) was obtained from Compound 18J (70 mg, 0.08 mmol). 1 H NMR (D2O, 400 MHz) δ 7.25 (s, 1H), 3.44 - 3.31 (m, 4H), 3.28 - 3.23 (m, 1H), 3.15 - 3.08 (m, 2H), 2.96 - 2.78 (m, 5H), 2.38 - 2.30 (m, 1H), 2.11 - 1.99 (m, 3H), 1.97 - 1.90 (m, 1H), 1.83 - 1.73 (m, 1H), 1.49 - 1.41 (m, 1H), 1.36 - 1.13 (m, 2H), 1.04 - 0.88 (m, 1H), 0.80 - 0.53 (m, 3H). LC-MS m / z = 430.1 [M + H] + 。

[0401] Example 19: Synthesis of Compound 19

[0402]

[0403] Step 1: Preparation of Compound 19B

[0404] Dissolve Compound 11E (1.6 g, 3.60 mmol) in DMF (30 mL). Add 60% NaH (290 mg, 7.20 mmol) and Compound 19A (1.23 g, 7.20 mmol) to the mixture at 0 °C. Stir the reaction mixture at 25 °C for 1 hour. After the reaction is complete, quench the reaction with water in an ice bath, extract with ethyl acetate, wash the organic phase with saturated brine, combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product of Compound 19B. The crude product was purified by column chromatography (8 / 1 petroleum ether / ethyl acetate) to obtain Compound 19B as a yellow oil (1.3 g, 67%). LC-MS m / z = 532.1, 534.0 [M + H] + 。

[0405] Step 2: Preparation of Compound 19C

[0406] Prepared according to the synthesis scheme of Compound 11F in Example 11. The yellow oil Compound 19C (1.1 g, 96%) was obtained from Compound 19B (1.3 g, 2.40 mmol). LC-MS m / z = 480.2 [M + H] + 。

[0407] Step 3: Preparation of Compound 19D

[0408] Prepared according to the synthesis scheme of Compound 11H in Example 11. Compound 19D (700 mg, 61%) as a yellow oil was obtained from Compound 19C (1.1 g, 2.30 mmol). LC-MS m / z = 496.2 [M+H] + 。

[0409] Step 4: Preparation of Compound 19E

[0410] Prepared according to the synthesis scheme of Compound 11I in Example 11. Compound 19E (700 mg, 95%) as a yellow oil was obtained from Compound 19D (610 mg, 1.23 mmol). LC-MS m / z = 599.2 [M+H] + 。

[0411] Step 5: Preparation of Compound 19F

[0412] Prepared according to the synthesis scheme of Compound 11J in Example 11. Compound 19F (480 mg, 53%) as a yellow oil was obtained from Compound 19E (700 mg, 1.17 mmol). LC-MS m / z = 779.6 [M+H] + 。

[0413] Step 6: Preparation of Compound 19G

[0414] Prepared according to the synthesis scheme of Compound 11K in Example 11. Compound 19G (480 mg, 92%) as a yellow oil was obtained from Compound 19F (480 mg, 0.62 mmol). LC-MS m / z = 541.2 [M - 136 + 2H + H] + 。

[0415] Step 7: Preparation of Compound 19H

[0416] Prepared according to the synthesis scheme of Compound 11L in Example 11. Compound 19H (340 mg, 45%) as a yellow oil was obtained from Compound 19G (480 mg, 0.71 mmol). LC-MS m / z = 957.8 [M + H - 100] + 。

[0417] Step 8: Preparation of Compound 19

[0418] Prepared according to the synthesis scheme of Compound 3 in Example 3. Compound 19 (15.2 mg, 30%) as a white solid was obtained from Compound 19H (100 mg, 0.095 mmol). 11H NMR (D2O, 400 MHz) δ 7.53 - 7.48 (m, 5H), 7.18 (d, J = 14.9 Hz, 1H), 4.42 - 4.24 (m, 2H), 3.99 - 3.90 (m, 1H), 3.53 - 3.19 (m, 8H), 3.13 - 2.79 (m, 4H), 2.36 - 1.84 (m, 4H), 1.66 - 1.19 (m, 4H), 1.13 - 0.72 (m, 3H). LC-MS m / z = 535.2 [M+H] + 。

[0419] Test Example 1: Inhibition of Compounds against β-Lactamase IC 50 Test.

[0420] (1) Experimental Purpose: To detect the inhibitory activities of selected compounds against KPC-2, NDM-1, AmpC and OXA-48.

[0421] (2) Experimental Materials: Test compounds VNRX-5133, compounds 1, 6, 10 and selected β-lactamases. (See Table 1)

[0422] Table 1 β-Lactamases for Testing

[0423] Enzyme family β-lactamase Bacterial strain Class A KPC-2 K.pneumoniae / K.oxytoca Class B NDM-1 K.pneumoniae Class C AmpC-PA P.aeruginosa Class D OXA-48 K.pneumoniae

[0424] (3) Experimental Procedures:

[0425] ①: For class A β-lactamase KPC-2, class C β-lactamase AmpC-PA and class D β-lactamase OXA-48, PBS buffer (pH 7.4 1×PBS, 0.1 mg / mL BSA) was used as the reaction buffer, and cefoxitin was used as the substrate to detect the activity of β-lactamase.

[0426] ②: For class B β-lactamase NDM-1, HEPES buffer (pH 7.0 50 mM HEPES) was used as the reaction buffer, and imipenem was used as the substrate to detect the activity of β-lactamase.

[0427] ③: All test compounds were dissolved in DMSO to prepare a stock solution with a concentration of 10 mM. The final concentrations of the test compounds were: 25000 nM, 5000 nM, 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM, 0.0128 nM and 0 nM, and avibactam was used as the positive control.

[0428] ④: Cefoxitin is dissolved in DMSO to prepare a 16 mM stock solution, which is diluted to 2× the final concentration with buffer before use (for KPC-2 and AmpC-PA enzymes, the final substrate concentration is 100 μM; for OXA-48 enzyme, the final substrate concentration is 50 μM). Imipenem is dissolved in ultrapure water to prepare a stock solution with a concentration of 16 mM, and is diluted to 20× the final concentration with buffer before use (the final substrate concentration of imipenem is 200 μM).

[0429] ⑤: Dilute β-lactamase with the corresponding reaction buffer to 2× (for KPC-2, AmpC-PA, OXA-48) or 1.064× (for NDM-1) of the optimal reaction concentration.

[0430] Table 2 Final concentrations of β-lactamase reactions

[0431] β-lactamase Final test concentration (nM) KPC-2 2.49 AmpC-PA 0.82 OXA-48 1.16 NDM-1 14.98

[0432] ⑥: The reaction system is the same as in Table 3. Compounds are plated using an Echo liquid workstation, and then the diluted enzyme is added. Incubate at the corresponding temperature for 10 min, and then add the diluted substrate. For KPC-2, AmpC-PA, and OXA-48, cefoxitin is used as the reaction substrate, the test wavelength is 490 nm, and readings are taken after 40 min of reaction. For NDM-1, imipenem is used as the reaction substrate, the test wavelength is 294 nm, and readings are taken after 15 min of reaction. Each compound is tested in parallel twice on the same plate (two replicates for each concentration), and calculate IC 50 。

[0433] Table 3 β-lactamase reaction system

[0434]

[0435] ⑦: Perform a linear fit of the OD values at each compound concentration against the reaction time to calculate the substrate hydrolysis rate at that concentration.

[0436] ⑧: The inhibition rate calculation formula is as follows:

[0437] ZPE: (Zero effect control): Substrate hydrolysis rate in the DMSO + β-lactamase + substrate system;

[0438] HPE: (Full effect control): Substrate hydrolysis rate in the DMSO + Buffer + substrate system;

[0439] Test: Substrate hydrolysis rate in the compound + β-lactamase + substrate system;

[0440] ⑨: The formula built in GraphPad Prism was used in this experiment: log(inhibitor concentration) vs. response (inhibition rate %) - variable slope (four parameters). The relative inhibition rates at each concentration of the compound were substituted into the calculation of IC 50 。

[0441] (4) IC 50 Test results

[0442] Table 4 IC 50 values (nM)

[0443]

[0444]

[0445] As shown in Table 4, the marketed drug avibactam has good inhibitory effects on KPC-2 (class A), AmpC-PA (class C), and OXA-48 (class D) SBLs enzymes and is inactive against class B NDM-1 enzyme. Currently, there is no marketed drug that can effectively inhibit class B MBLs. The broad-spectrum inhibitor that can simultaneously inhibit SBLs and MBLs with the fastest clinical progress is VNRX-5133. Compounds 1, 6, and 10 in the present invention can effectively inhibit four types of enzymes, namely KPC-2, NDM-1, AmpC-PA, and OXA-48. Especially for NDM-1 type metalloenzymes, they all have high inhibitory activities, showing significant advantages compared with VNRX-5133. For AmpC and OXA-48 type enzymes, the inhibitory activities are also better than VNRX-5133. It is worth noting that compound 10 has broad-spectrum high inhibitory activities against four types of enzymes, and compound 6 has extremely low IC 50 value.

[0446] Test Example 2: Test of the minimum drug concentration (MIC) of compounds against bacterial growth inhibition

[0447] (1) Experimental purpose: To test the in vitro antibacterial activity of the combination of cefepime and the compound.

[0448] (2) Main experimental instruments

[0449] Table 5 Experimental instruments

[0450] Name Model Fixed asset number Manufacturer Autoclave mvs-83 38301028 ALPHAVITA Biological safety cabinet BSC-1604IIA2 3551529 Sujing Incubator ZXSD-B1270 2083348 Zhicheng Turbidimeter Harvard-80-2116-30 2622217 Harvard Analytical balance XS205 385414 Mettler Toledo

[0451] (3) Experimental materials and reagents

[0452] Table 6 Experimental consumables

[0453]

[0454]

[0455] (4) Experimental strains

[0456] Table 7 Information of experimental strains

[0457]

[0458] (5) Experimental procedures

[0459] ① Strain preparation: Take out the strains in Table 7 from -80°C, streak inoculate on CAMHA solid agar medium, and place in an incubator at 35 ± 2°C for 18 - 24 h.

[0460] ② Preparation of compound detection plate: Cefepime and the compound are dissolved in DMSO to prepare stock solutions. The concentration of the cefepime stock solution is 12.8 mg / mL, and the concentration of the compound stock solution is 0.8 mg / mL. Perform 2-fold serial dilution of cefepime in DMSO for 10 times to obtain 11 2-fold serial dilution solutions. Add 1 μL of the cefepime dilution solution to wells 1 - 11 in a 96-well plate in descending order of concentration, and add 1 μL of DMSO to well 12. Add 1 μL of different compound stock solutions to rows B - H in the 96-well plate in sequence to obtain the compound detection plate.

[0461] ③ Preparation of inoculum: Pick monoclonal colonies from the overnight cultured solid agar plate, dissolve in sterile normal saline, adjust the turbidity to 0.5 McFarland, and then dilute the inoculum 200-fold in the test medium to 5x10 5 CFU / ml to obtain the inoculum, and transfer 198 μL / well of the inoculum to the compound detection plate.

[0462] ④ MIC reading: Place the detection plate in an incubator at 36.5°C for 20 h, and then visually read the MIC. The MIC is the minimum antibiotic concentration at which bacterial growth can be completely inhibited by visual observation.

[0463] (6) Test results

[0464] Table 8 MIC values (μg / mL) of selected compounds combined with cefepime against different drug-resistant bacteria

[0465]

[0466]

[0467]

[0468] The meaning of "*" indicates that the concentration of the selected compound is 4 μg / mL.

[0469] As shown in Table 8, for the above-mentioned multiple drug-resistant strains, most of the compounds in the present invention are effective in combination with cefepime against most of these strains. The combination of Compound 1, Compound 6, and Compound 10 of the present invention with cefepime shows good antibacterial activity against the 4 selected drug-resistant strains (ATCC BAA-1705, ATCC BAA-2470, ARLG-1196, and ARLG-1019), and their antibacterial activity and antibacterial spectrum are comparable to or better than those of the combination of VNRX-5133 + cefepime. The combination of Compound 1, Compound 6, and Compound 10 with cefepime has high inhibitory activity against two drug-resistant bacteria carrying class B NDM-type metalloenzymes, ATCC BAA-2470 (NDM-1) and ARLG-1196 (CTX-M-1 group, SHV, NDM, TEM), showing a significant advantage compared to the combination of VNRX-5133 + cefepime. It is worth noting that Compound 6 of the present invention shows extremely high inhibitory activity against the two drug-resistant bacteria carrying class B NDM-type metalloenzymes.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof; Ring A is C 3-10 Aliphatic carbon ring, 3-12 membered aliphatic heterocyclic ring, C 6-10 Aromatic ring or 5-12 membered heteroaromatic ring; R a are independently D, halogen, -OH, -CN, -NH2, -NO2, oxo (=O), C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or C substituted by 1, 2 or 3 R 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; m is 0, 1, 2 or 3; L1 is a connecting bond, -CH2-, -CH2CH2-, C 3-6 Cycloalkylene, 3-6 membered heterocyclylene, or -CH2-, -CH2CH2-, C 3-6 Cycloalkylene, 3-6 membered heterocyclylene; X is R 1 H, C 1-6 Alkyl or C substituted by 1, 2 or 3 R' 1-6 alkyl; R 2 H or C 1-6 alkyl; R 3 H, C 1-6 Alkyl, halogen, or C substituted with 1, 2 or 3 R' 1-6 alkyl; R is independently D, halogen, -OH, -CN, -NH2, -NO2, oxo (=O), C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R' is independently D, halogen, -OH, -CN, -NH2, -NO2, -NH(Me) or -N(Me)2; Ring B is C 3-8 Aliphatic carbon ring or C 6-10 Aromatic rings; R b Independently for C 1-6 Alkyl, 1, 2 or 3 R b1 Substituted C 1-6 alkyl; R b1 are independently -OH, -NH2, halogen, -OC 1-6 Alkyl, -OC 3-8 Cycloalkyl, -OC 3-8 Cycloalkenyl, -O-3 to 8-membered heterocyclic group, -OC 6-10 Aryl, -O-5- to 12-membered heteroaryl, -SC 1-6 Alkyl, -SC 3-8 Cycloalkyl, -SC 3-8 Cycloalkenyl, -S-3 to 8-membered heterocyclic group, -SC 6-10 Aryl, -S-5 to 12-membered heteroaryl, -NR b2 -C 1-6 Alkyl, -NR b2 -C 3-8 Cycloalkyl, -NR b2 -C 3-8 Cycloalkenyl, -NR b2 -3 to 8-membered heterocyclic group, -NR b2 -C 6-10 Aryl, -NR b2 -5~12 membered heteroaryl, or by 1, 2 or 3 R b4 Replaced-OC 1-6 Alkyl, -OC 3-8 Cycloalkyl, -OC 3-8 Cycloalkenyl, -O-3 to 8-membered heterocyclic group, -OC 6-10 Aryl, -O-5- to 12-membered heteroaryl, -SC 1-6 Alkyl, -SC 3-8 Cycloalkyl, -SC 3-8 Cycloalkenyl, -S-3 to 8-membered heterocyclic group, -SC 6-10 Aryl, -S-5 to 12-membered heteroaryl, -NR b2 -C 1-6 Alkyl, -NR b2 -C 3-8 Cycloalkyl, -NR b2 -C 3-8 Cycloalkenyl, -NR b2 -3 to 8-membered heterocyclic group, -NR b2 -C 6-10 Aryl, -NR b2 -5~12 membered heteroaryl, R b2 are independently H or C 1-6 alkyl; R b3 are independently -OH, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3- to 8-membered heterocyclic group, C 6-10 Aryl or 5- to 12-membered heteroaryl; R b4 are independently halogen, -OH, -NH2, -NR 5 R 6 , oxo (=O), C 6-10 Aryl, 5- to 12-membered heteroaryl, C 3-8 Cycloalkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic group; n is 0, 1, 2 or 3; Z is -NH2, C 1-6 Alkyl, Z2-NH-, NH2-Z1-NH-, NH2-Z1-, Z2-NH-Z1-, Z2-NH-Z1-NH-, Z2-C(=O)NH-, Z2-(C=O)NH-Z1-, Z2-(C=O)NH-Z1-NH-, Z2-NHC(=O)-, Z2-NH(C=O)-Z1-, Z2-NH(C=O)-Z1-NH-, NH2(C=O)NH-Z1-, NH2(C=O)NH-Z1-NH-, NH2(C=NH)NH-Z1-, NH2(C=NH)NH-Z1-NH-, Z2- NH(C=O)NH-, Z2-NH(C=O)NH-Z1-, Z2-NH(C=O)NH-Z1-NH- or -NH2, C Z1 alkyl, Z2-NH-, NH2-Z1-NH-, NH2-Z1-, Z2-NH-Z1-, Z2-NH-Z1-NH-, Z2-C(=O)NH-, Z2-(C=O)NH-Z1-, Z2-(C=O)NH-Z1-NH-, Z2-NHC(=O)-, Z2-NH(C=O)-Z1-, Z2-NH(C=O)-Z1-NH-, NH2(C=O)NH-Z1-, NH2(C=O)NH-Z1-NH-, NH2(C=NH)NH-Z1-, NH2(C=NH)NH-Z1-NH-, Z2-NH(C=O)NH-, Z2-NH(C=O)NH-Z1-, Z2-NH(C=O)NH-Z1-NH-;​​ Z1 is independently C 1-6 Alkylene, C 3-6 Cycloalkylene, 5-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene; Z2 is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; R Z1 are independently D, halogen, -OH, -NR 5 R 6 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, or 1, 2 or 3 R Z2 Substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; R Z2 are independently halogen, -OH, -CN or -NR 5 R 6 ; R 5 and R 6 are independently H or C 1-6 alkyl; In the aliphatic heterocycle, heterocyclic group and heterocyclic group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3; In the heteroaromatic ring, heteroaryl group and heteroarylene group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3; In the heteroalkyl group, the heteroatoms are independently selected from N, O and S, and the number of the heteroatoms is independently 1, 2 or 3.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Ring A is C 3-10 Aliphatic carbon ring, 3-12 membered aliphatic heterocyclic ring or C 6-10 Aromatic rings; (2) m is 0; (3) L1 is -CH2-; (4)X is (5)R 1 is H; (6)R 2 is H; (7)R 3 is H; (8) Ring B is saturated C 3-8 Aliphatic carbon ring; (9)R b Independently, 1, 2 or 3 R b1 Substituted C 1-6 alkyl; (10)R b1 are independently -OH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NR b2 -C 1-6 alkyl, or by 1, 2 or 3 R b4 Substituted-NR b2 -C 1-6 alkyl; (11)R b2 independently H; (12)R b3 Independently for C 1-6 alkyl; (13)R b4 Independently for C 6-10 Aryl; (14)n is 0 or 1; (15) Z is NH2-Z1-NH- or NH2-Z1-; (16) Z1 is independently C 1-6 Alkylene.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: It meets one or more of the following conditions: (1) C 3-10 Aliphatic carbon ring is C 5-8 Aliphatic carbon ring, for example, C5 aliphatic carbon ring, C6 aliphatic carbon ring, C7 aliphatic carbon ring or C8 aliphatic carbon ring; (2) C 3-10 Aliphatic carbon ring is saturated C 3-10 Aliphatic carbon rings, such as the saturated C 3-10 The aliphatic carbon ring is a single ring or a bridged ring, for example (3) C 3-10 Aliphatic carbon ring or unsaturated C 3-10 Aliphatic carbocyclic rings, such as the unsaturated aliphatic carbocyclic rings containing one carbon-carbon double bond, are also (4) C 3-8 Aliphatic carbon ring is C 3-6 Aliphatic carbon ring, for example, C3 aliphatic carbon ring, C4 aliphatic carbon ring, C5 aliphatic carbon ring or C6 aliphatic carbon ring; (5) C 3-8 Aliphatic carbon ring is saturated C 3-8 Aliphatic carbon rings, such as the saturated C 3-8 Aliphatic carbon rings are single rings; (6) The 3-12-membered aliphatic heterocycle is a 5-8-membered aliphatic heterocycle, such as a 5-membered aliphatic heterocycle, a 6-membered aliphatic heterocycle, a 7-membered aliphatic heterocycle or an 8-membered aliphatic heterocycle; (7) In the 3-12 membered aliphatic heterocyclic ring, the heteroatom is independently N, and the number of heteroatoms is independently 1, 2 or 3, for example (8) C 6-10 The aromatic ring is a benzene ring; (9) C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example, methyl; (10) C 1-6 Alkylene is independently methylene, ethylene, propylene or butylene, for example ethylene; (11) The halogen is independently F, Cl, Br or I; for example, F or Cl; (12) -OC 1-6 Alkyl, -SC 1-6 Alkyl and -NR b2 -C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example, methyl; (13) C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) for (2)R b Independently (3) Z is (4) Ring A is 5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: It meets one or more of the following conditions: (1) for (2) for 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound represented by formula I is as shown in formula I-1: Wherein, q is 1, 2 or 3, and the other groups are defined as described in any one of claims 1 to 5; For example, the compound represented by formula I is represented by formula I-1-1 or formula I-1-2: Wherein, the definition of each group is as described in any one of claims 1-5; for example, q is 1.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound represented by formula I is represented by formula IA: The definition of each group is as described in any one of claims 1 to 5; For example, the compound represented by formula I is represented by formula IA-1: The definition of q is as described in claim 6; the definitions of the other groups are as described in any one of claims 1 to 5; For another example, the compound represented by formula I is represented by formula IA-1-1: The definition of q is as described in claim 6; the definitions of the other groups are as described in any one of claims 1 to 5; For another example, the compound represented by the formula I is represented by the formula IA-2-1: The definition of q is as described in claim 6; the definitions of other groups are as described in any one of claims 1-5.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is selected from any of the following compounds:

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is selected from any of the following compounds: The compounds that elute first under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 60:40, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the first eluting compound is 6, and its retention time is 2.678min; Compounds that elute later under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 60:40, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the compound eluting later is 7, and its retention time is 3.037min; The compounds that elute first under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.2% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 60:40, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the first eluting compound is 8, and its retention time is 2.481min; Compounds eluting later: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.2% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 60:40, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the compound 9 eluted later, and its retention time is 2.665min; Compounds eluting first: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 80:20, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the first eluting compound is 11, and its retention time is 2.767min; Compounds eluting later: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 80:20, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the compound eluting later is 12, and its retention time is 3.054min; Peak compounds: Chromatographic column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214nm; flow rate: 15mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 98:2 to 60:40, and linear gradient elution is performed; at 11-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is set to 5:95, and isocratic elution is performed; for example, the first eluting compound is 15, and its retention time is 2.241min; Compounds that elute later under the following conditions: Column: Xbridge C8 5μm, 19*150mm; Mobile phase: A: H2O (0.1% TFA), B: ACN; Wavelength: 214 nm; flow rate: 15 mL / min; gradient elution program: at 0-10 minutes, the volume ratio of the mobile phase A and the mobile phase B was set to 98:2 to 60:40, and linear gradient elution was performed; at 11-15 minutes, the volume ratio of the mobile phase A and the mobile phase B was set to 5:95, and isocratic elution was performed; for example, the last peak compound was 16, and its retention time was 2.627 min.

10. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a β-lactam antibiotic, for example, the β-lactam antibiotic is cefepime, and the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

12. Use of a compound of formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 1 in combination with a β-lactam antibiotic in the preparation of a drug against drug-resistant bacteria, for example, the drug against drug-resistant bacteria is a drug against β-lactam antibiotic-resistant bacteria.

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