Vancomycin derivative and preparation method therefor, pharmaceutical composition, and use

Abstract

A vancomycin derivative having a structure as shown in formula (I), a preparation method therefor, a pharmaceutical composition, and a use. A variety of sulfonium or sulfur-containing structural fragments having aromatic linkers are introduced at four positions of a vancomycin parent nucleus, which significantly enhances the antibacterial activity and shows the potential for the intrinsic resistance against Gram-negative bacteria while achieving high safety. Furthermore, the vancomycin derivative also shows antiviral activity.

Description

Vancomycin derivatives, methods of making, pharmaceutical compositions, and uses thereof TECHNICAL FIELD

[0001] The present invention belongs to the field of medicinal chemistry and medicine, and relates to vancomycin derivatives, in particular sulfonium derivatives, and pharmaceutically acceptable salts thereof, methods of making the vancomycin derivatives, pharmaceutical compositions comprising the vancomycin derivatives or pharmaceutically acceptable salts thereof, and uses of the vancomycin derivatives and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with Gram-positive and / or Gram-negative bacterial infection. BACKGROUND

[0002] Vancomycin, as the most representative member of the glycopeptide antibiotic family, has been widely used in clinic for more than 60 years. Its main mechanism of action is to inhibit the biosynthesis of peptidoglycan in the cell wall of Gram-positive bacteria. It is currently mainly used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, and is hailed as the "last line of defense" against stubbornly drug-resistant positive bacterial infections, with the reputation of "ace antibiotic". However, with the first case of vancomycin-resistant Enterococcus (VRE) reported in France in 1986, followed by the first case of vancomycin-intermediate Staphylococcus aureus (VISA) reported in Japan in 1996, and the first case of vancomycin-resistant Staphylococcus aureus (VRSA) reported in 2002, the "last line of defense" is in danger. The emergence of more and more vancomycin-resistant strains has once again posed a huge challenge and threat to us. Therefore, it is urgent to develop effective strategies against vancomycin-resistant strains.

[0003] In our previous work, we reported a class of alkyl sulfonium-modified vancomycin derivatives that are effective against vancomycin-resistant strains. The main mechanism is to increase the interaction between the vancomycin derivative and the bacterial cell membrane through the modification of the lipophilic alkyl sulfonium fragment, thereby overcoming drug resistance. The corresponding results have been published (Angew. Chem. Int. Ed. 2019, 58, 6678-6682) and applied for a patent (Application No. 201811109378.X, Application Publication No. CN 110938114 A). However, the types of sulfonium fragments in the previous work were less studied, and the corresponding structure-activity relationship needs to be further studied. Therefore, in the present invention, we focus on introducing diversified sulfonium or sulfur-containing structural fragments with aromatic linkers at four positions of the vancomycin nucleus. This is not only a further application of the sulfonium modification strategy, but also will develop more effective candidate drug molecules against vancomycin-resistant strains. SUMMARY

[0004] An object of the present application is to provide a class of vancomycin derivatives, in particular vancomycin sulfonium derivatives, or pharmaceutically acceptable salts thereof.

[0005] Another object of the present application is to provide a method for preparing the above vancomycin derivatives.

[0006] Another object of the present application is to provide a pharmaceutical composition comprising the above vancomycin derivatives and / or pharmaceutically acceptable salts thereof.

[0007] Still another object of the present application is to provide the use of the above vancomycin derivatives and / or pharmaceutically acceptable salts thereof, or the above pharmaceutical composition in the preparation of antibacterial drugs.

[0008] To achieve the above objects, the present application adopts the following technical solutions:

[0009] In a first aspect, the present application provides a vancomycin derivative or a pharmaceutically acceptable salt thereof as shown in the following formula (I):

[0010] Wherein:

[0011] R1 is selected from -OH, -NH-X1-S + (R a )-X2-R b , -NH-X1-S-X2-R b ;

[0012] R2 is selected from -H, -X1-S + (R a )-X2-R b , -X1-S-X2-R b ;

[0013] R3 is selected from -H, -X1-NH-X1-R c , -X1-NH-X1-S + (R a )-X2-R b , -X1-NH-X1-S-X2-R b ;

[0014] R4 is selected from -H, -X1-S + (R a )-X2-R b ;

[0015] And at least one of R1, R1, R3, R4 contains -S + (R a )-X2-R b or -S-X2-R b structural fragment;

[0016] X1 is independently selected from -(CH2) n - Substituted or unsubstituted C6-C 20 aryl, wherein the substitution refers to being replaced by one or more substituents selected from the following: halogen, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, halogenated C1-C 10 Alkyl groups; wherein n is independently an integer selected from 0 to 6, for example 0, 1, 2, 3, 4, 5, 6; preferably, each X1 is independently selected from -(CH2). n -or phenyl, wherein n is independently 1, 2, or 3;

[0017] X2 is independently selected from -(CH2). m - Substituted or unsubstituted C6-C 20 aryl, wherein the substitution refers to being replaced by one or more substituents selected from the following: halogen, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, halogenated C1-C 10 Alkyl group; wherein, -(CH2) m - In this context, m is independently an integer selected from 0 to 6, for example, 0, 1, 2, 3, 4, 5, 6; preferably, m is independently 2, 3, 4; -(CH2) m One or more hydrogens in X2 are optionally replaced by -OH; preferably, X2 is -CH2CH(OH)CH2- or phenyl.

[0018] R a Each is independently selected from C1-C6 alkyl or halogen-substituted C1-C6 alkyl, preferably from C1-C4 alkyl or halogen-substituted C1-C4 alkyl, more preferably methyl;

[0019] R b Each is independently selected from substituted or unsubstituted C6-C. 20 aryl, substituted or unsubstituted C6-C 20 The aryloxy group, or the substituted or unsubstituted ring containing one or more heteroatoms selected from N, O, and S, is a 5-10 membered heteroaryloxy group; the substitution refers to being substituted by one or more substituents selected from the following: halogen, C1-C... 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, halogenated C1-C 10 Alkoxy, substituted or unsubstituted C6-C10 aryl, wherein said "substituted C6-C 10 aryl" means said C6-C 10 aryl contains one or more substituents selected from the group consisting of halogen, C1-C 10 alkyl, halogen-C1-C 10 alkyl, C1-C 10 alkoxy, halogen-C1-C 10 alkoxy; preferably, R b each independently is selected from the group consisting of substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy containing one or more heteroatoms selected from the group consisting of N, O and S in the ring; said substitution means substitution by one or more substituents selected from the group consisting of halogen, C1-C6alkyl, halogen-C1-C6alkyl, C1-C6alkoxy, halogen-C1-C6alkoxy, substituted or unsubstituted phenyl, wherein said "substituted phenyl" means said phenyl contains one or more substituents selected from the group consisting of halogen, C1-C6alkyl, halogen-C1-C6alkyl, C1-C6alkoxy, halogen-C1-C6alkoxy; more preferably, R b each independently is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy, said substitution means substitution by one or more groups selected from the group consisting of halogen (e.g. chlorine, bromine), t-butyl, trifluoromethyl, methoxy, phenyl, trifluoromethyl-substituted phenyl, halogen (e.g. chlorine)-substituted phenyl;

[0020] R c is selected from the group consisting of preferably is

[0021] In a preferred embodiment of the present application, in formula (I) only one of R1, R2, R3, R4contains the structural fragment -S + (R a )-X2-R b or S-X2-R b In a preferred embodiment of the present application, in formula (I) only one of R1, R2, R3, R4contains the structural fragment -S + (R a )-X2-R b In a preferred embodiment of the present application, in formula (I) only one of R1, R2, R3, R4contains the structural fragment -S

[0022] In a preferred embodiment of the present application, in formula (I) X1is each independently selected from the group consisting of -(CH2) n - or phenyl, wherein n is independently 1, 2, 3.

[0023] In a preferred embodiment of the present application, in formula (I), X2, m is independently 2, 3, 4; preferably, X2is -CH2CH(OH)CH2- or phenyl.

[0024] In a preferred embodiment of the present application, in formula (I), R a each is independently selected from C1-C4 linear or branched alkyl or halogen-substituted C1-C4 linear or branched alkyl, more preferably methyl.

[0025] In a preferred embodiment of the present application, in formula (I), R b each is independently selected from substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy containing one or more heteroatoms selected from N, O and S in the ring; the substitution means substituted with one or more substituents selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, substituted or unsubstituted phenyl, wherein the "substituted phenyl" means the phenyl contains one or more substituents selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy; preferably, R b each is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy, the substitution means substituted with one or more groups selected from halogen (e.g. chloro, bromo), t-butyl, trifluoromethyl, methoxy, phenyl, trifluoromethyl-substituted phenyl, halogen (e.g. chloro)-substituted phenyl.

[0026] In a preferred embodiment of the present application, in formula (I), R c is

[0027] In another preferred embodiment of the present application, the vancomycin derivative represented by formula (I) is selected from the following compounds:

[0028] The vancomycin derivative represented by formula (I) of the present application can be generally prepared by a preparation method comprising the following steps:

[0029] The vancomycin hydrochloride is reacted by an amide condensation reaction, a reductive amination reaction or a Mannich reaction to obtain a vancomycin derivative intermediate with a sulfur atom modification, and then reacted with an excess of an epoxide to obtain a vancomycin aromatic sulfonium derivative of the present application through an SN2 ring-opening substitution reaction. The vancomycin aromatic sulfonium derivative can be further reacted with a pyrrolidine dithioformate ammonium salt to obtain an aromatic sulfur derivative.

[0030] The preparation of specific compounds can be carried out according to the specific reaction conditions in the examples. The amide condensation reaction, the reductive amination reaction or the Mannich reaction can be carried out at room temperature to 80°C. In the SN2 ring-opening substitution reaction of the vancomycin derivative intermediate and the epoxide, the equivalent ratio of the epoxide to the vancomycin intermediate can be 10-40 times, and the reaction solvent can be glacial acetic acid.

[0031] In some embodiments, the preparation method can be one of the following four preparation methods:

[0032] Method I:

[0033] (1) The vancomycin derivative intermediate (II-1) with a sulfur atom modification is reacted with an excess of an epoxide to obtain a vancomycin aromatic sulfonium derivative represented by formula (I-1-a) through an SN2 ring-opening substitution reaction;

[0034] (2) The vancomycin sulfonium derivative represented by formula (I-1-a) is reacted with a pyrrolidine dithioformate ammonium salt (APDC) to obtain a vancomycin derivative represented by formula (I-1-b);

[0035] wherein, R 1a is -NH-X1-S + (R a )-CH2-CH(OH)-CH2-R b , R 1b is -NH-X1-S-CH2-CH(OH)-CH2-R b ;

[0036] X1, R a , R b are as defined above;

[0037] Method II:

[0038] (1) The vancomycin derivative intermediate (II-2) with a sulfur atom modification is reacted with an excess of an epoxide to obtain a vancomycin aromatic sulfonium derivative represented by formula (I-2-a) through an SN2 ring-opening substitution reaction;

[0039] (2) the vancomycin sulfonium derivative represented by formula (I-2-a) reacts with ammonium pyrrolidine dithioformate (APDC) to obtain a vancomycin derivative represented by formula (I-2-b);

[0040] (3) the vancomycin sulfonium derivative represented by formula (I-2-a) reacts with NH2-X1-R c , formaldehyde to obtain a vancomycin derivative represented by formula (I-2-c);

[0041] wherein, R 2a is -X1-S + (R a )-CH2-CH(OH)-CH2-R b , R 2b is -X1-S-CH2-CH(OH)-CH2-R b ;

[0042] X1, R a , R b , R c are defined as described above;

[0043] Method three:

[0044] (1) the vancomycin derivative intermediate (II-3) with sulfur atom modification reacts with excess epoxide to undergo SN2 ring-opening substitution reaction to obtain a vancomycin aromatic sulfonium derivative represented by formula (I-3-a);

[0045] (2) the vancomycin sulfonium derivative represented by formula (I-3-a) reacts with ammonium pyrrolidine dithioformate (APDC) to obtain a vancomycin derivative represented by formula (I-3-b);

[0046] wherein, R 3a is -X1-NH-X1-S + (R a )-CH2-CH(OH)-CH2-R b , R 3b is -X1-NH-X1-S-CH2-CH(OH)-CH2-R b ;

[0047] X1, R a , R b are defined as described above;

[0048] Method four:

[0049] (1) the vancomycin derivative intermediate (II-4) with sulfur atom modification reacts with excess epoxide The SN2 ring-opening substitution reaction occurs to obtain a vancomycin aromatic sulfonium derivative shown in formula (I-4-a);

[0050] wherein, R 4a is -X1-S + (R a )-CH2-CH(OH)-CH2-R b ;

[0051] X1, R a , R b are defined as described above.

[0052] In the above-mentioned methods one to four, the SN2 ring-opening substitution reaction in step (1) is preferably carried out in the presence of a reaction solvent, which can be glacial acetic acid.

[0053] The reaction of step (2) is preferably carried out in the presence of a reaction solvent, which can be an aqueous ethanol solution, wherein the mass fraction of ethanol is 60-90%.

[0054] The reaction of step (3) is preferably carried out in the presence of a reaction solvent, which can be a mixed solvent of acetonitrile-water, and the ratio thereof can be 1:1.

[0055] The present application also provides a pharmaceutical composition comprising a vancomycin derivative shown in formula (I) or a pharmaceutically acceptable salt thereof.

[0056] The present application also provides the use of a vancomycin derivative shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease or disorder associated with Gram-positive bacterial and / or Gram-negative bacterial infection.

[0057] The Gram-positive bacteria include but are not limited to Staphylococcus aureus, Enterococcus.

[0058] The Gram-negative bacteria include but are not limited to Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa.

[0059] Diseases or conditions associated with Gram-positive and / or Gram-negative bacterial infections include: respiratory tract infections (upper respiratory tract infections such as pharyngitis, lower respiratory tract infections including tracheitis, bronchitis, pneumonia caused by Enterobacter spp. and Serratia marcescens such as community-acquired pneumonia, ventilator-associated pneumonia, hospital-acquired pneumonia, bronchiectasis), pulmonary tuberculosis and pulmonary infections complicated by pulmonary fibrosis, urinary tract infections (including uncomplicated and complicated pyelonephritis, recurrent cystitis, complicated urinary tract infections, uncomplicated pyelonephritis, etc.). Infections include: urethral infections, central nervous system infections (encephalitis, meningitis, brain abscess), ear infections (otitis externa, otitis media), abdominal infections including peritonitis, cardiovascular infections (blood infections such as sepsis or bacteremia, endocarditis, myocarditis, pericarditis), skin or soft tissue infections, bone and joint infections (arthritis, osteomyelitis), genital infections (genital ulcers, vaginitis, cervicitis), eye infections (conjunctivitis, keratitis, endophthalmitis), and oral infections (including gingivitis, periodontitis).

[0060] Terminology Explanation

[0061] In this invention, the term "C1-C" x "Alkyl" refers to a straight-chain or branched alkyl group having 1 to x carbon atoms in its main chain, such as "C1-C". 10 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms in its main chain, preferably C1-C6 alkyl or C1-C4 alkyl, examples of which include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, etc.

[0062] In this invention, the term "aryl" refers to an aromatic cyclic group that does not contain heteroatoms, such as phenyl or naphthyl.

[0063] In this invention, the term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from N, O, and S, such as pyrroleyl, imidazolyl, oxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, etc.

[0064] The term "pharmaceutically acceptable salt" in this invention refers to salts formed with inorganic acids such as phosphoric acid, sulfuric acid, and hydrochloric acid, or organic acids such as acetic acid, tartaric acid, citric acid, malic acid, and trifluoroacetic acid, or acidic amino acids such as aspartic acid and glutamic acid, or salts formed with the above acids as esters or amides and then with inorganic bases, such as sodium, potassium, calcium, aluminum, and ammonium salts.

[0065] Pharmaceutically acceptable salts of the compounds of this invention specifically refer to the trifluoroacetate salts of vancomycin aromatic thionium derivatives represented by formula (I). Attached Figure Description

[0066] Figure 1 is the results of cytotoxicity experiments in biological test example 2, wherein a) is a column chart of the cytotoxicity test of the compounds of the present application on AML12 cells; b) is a column chart of the cytotoxicity test of the compounds of the present application on H9C2 cells; c) is a column chart of the cytotoxicity test of the compounds of the present application on HEK293 cells.

[0067] Figure 2 is a graph of the hemolytic toxicity test of the compounds of the present application in biological test example 3.

[0068] Figure 3 is a graph of the survival rate of mice in a single dose administration of S. aureus USA300 LAC strain model in biological test example 5.

[0069] Figure 4 is a graph of the survival rate of mice in a vancomycin-resistant Enterococcus VRE strain model in biological test example 5, wherein a) is a graph of the survival rate of mice in a 20 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model; b) is a graph of the survival rate of mice in a 10 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model; c) is a graph of the survival rate of mice in a 5 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model; d) is a graph of the survival rate of mice in a 2.5 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model; e) is a graph of the survival rate of mice in a 1.25 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model; f) is a graph of the survival rate of mice in a 0.625 mg / kg administration group of the vancomycin-resistant Enterococcus VRE strain model.

[0070] Figure 5 is the results of the mechanism of action of the compounds of the present application in biological test example 6, wherein a) is a graph of the cell membrane permeability test against S. aureus USA300; b) is a graph of the cell membrane depolarization test against S. aureus USA300.

[0071] Figure 6 is the results of the Park nucleotide detection experiment in biological test example 7, wherein a) is a graph of the wavelength 260 nm ultraviolet absorption detection of Park nucleotide; b) is a graph of the HPLC detection of Park nucleotide; c) is a graph of the HRMS detection of Park nucleotide.

[0072] Figure 7 is the results of the antiviral activity test in biological test example 8, wherein a) is a column chart of the antiviral activity of the compounds of the present application against RSV-ON1 virus and cytotoxicity detection; b) is a column chart of the antiviral activity of the compounds of the present application against XBB virus. DETAILED DESCRIPTION

[0073] The present application will be further illustrated in the following examples. These examples are only for illustrating the present application, but not in any way limit the scope of protection of the present application.

[0074] For the following examples, standard procedures and purification methods known to those skilled in the art can be used. Unless otherwise specified, the starting materials are generally available from commercial sources such as Bide Pharmatech Co., Ltd. and Shanghai Titan Technology Co., Ltd. Commercially available solvents and reagents are generally used without further purification, anhydrous solvents are treated by standard methods, and other reagents are commercially available analytical pure. Vancomycin hydrochloride is purchased from Titan Technology Co., Ltd., batch number 011073672. Linezolid is purchased from Titan Technology Co., Ltd., batch number P1571508. Daptomycin is purchased from Shanghai Coupling Pharmaceutical Technology Co., Ltd., batch number 202307019KK07. Oritavancin diphosphate is purchased from Shanghai Hanjing Chemical Co., Ltd., batch number HJ20210718. Unless otherwise specified, all temperatures are in °C (degrees Celsius), and room temperature or ambient temperature refers to 20-25°C. The structure of the compound is determined by nuclear magnetic resonance spectrum (NMR) and / or mass spectrum (MS).

[0075] The nuclear magnetic resonance hydrogen spectrum displacement (δ) is given in units of parts per million (ppm). The nuclear magnetic resonance hydrogen spectrum is determined by Bruker Avance III HD 500MHz / 600MHz and AscEndTM-600MHz type nuclear magnetic resonance instrument, deuterated methanol (CD3OD), deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6), deuterium water (D2O) as solvent, tetramethylsilane (TMS) as internal standard.

[0076] High-resolution mass spectrometry is measured by Agilent 6230 series TOF LC-MS, if the intensity of the ion containing chlorine or bromine is described, the expected intensity ratio is observed (about 3:1 for ions containing 35Cl / 37Cl, 1:1 for ions containing 79Br / 81Br), and only the intensity of the lower mass ion is given.

[0077] HPLC: -3030 analytical high performance liquid chromatography system (Shanghai Tongwei Analysis Technology Co., Ltd.), -3050 preparative high performance liquid chromatography system (Shanghai Tongwei Analysis Technology Co., Ltd.), LC3000 analytical high performance liquid chromatography system (Beijing Innovative Tongheng Technology Co., Ltd.), LC3000 preparative high performance liquid chromatography system (Beijing Innovative Tongheng Technology Co., Ltd.). Analytical high performance liquid chromatography conditions: C18 column (Welch 5 μm, 4.6 x 250 mm) with UV detection at 214 nm and 254 nm and elution conditions of 2-90% acetonitrile (containing 0.1% v / v TFA) gradient over 30 minutes. Preparative HPLC conditions: C18 column (Welch 5 μm, 21.2 x 250 mm) with UV detection at 214 nm and 254 nm and elution conditions of 2-90% acetonitrile (containing 0.1% v / v TFA) gradient over 30 minutes.

[0078] In the above discussion and the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0079] DCM: dichloromethane;

[0080] DIPEA: N,N-diisopropylethylamine;

[0081] DMF: N,N-dimethylformamide;

[0082] DMSO: dimethylsulfoxide;

[0083] HATU: O-(pyridin-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0084] MTBE: methyl tert-butyl ether;

[0085] TFA: trifluoroacetic acid;

[0086] TLC: thin layer chromatography.

[0087] Preparation of starting materials

[0088] Preparation 1 Preparation of 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxirane (1)

[0089] First Step: Preparation of 4-[4-(trifluoromethyl)phenyl]phenol (1a)

[0090] Commercially available 4-trifluoromethylphenylboronic acid (2 g, 10.23 mmol), 4-bromophenol (1.21 g, 7.02 mmol), potassium carbonate (2.91 g, 21.06 mmol) and palladium acetate (0.078 g, 0.35 mmol) were dissolved in a single-mouth reaction flask containing 200 mL of water and stirred at room temperature overnight, TLC detection until the reaction did not continue. Then filter the reaction solution with diatomite, extract the filtrate with ethyl acetate for 3 times, separate the organic layer after washing with water, 1 mol / L HC1, saturated brine, dry the organic layer with anhydrous sodium sulfate, and separate and purify with a fast preparation column machine to obtain the target product la (1.35 g, yield 81%).

[0091] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 4.40 (dd, J = 11.4, 2.6 Hz, 1H), 3.90 (dd, J = 11.4, 2.6 Hz, 1H), 3.41 - 3.35 (m, 1H), 2.86 (t, J = 4.7 Hz, 1H), 2.73 (dd, J = 5.1, 2.6 Hz, 1H).

[0092] Second step: preparation of 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxirane (1)

[0093] Weigh la (1 g, 4.20 mmol), commercially available 2-(chloromethyl)oxirane (2.331 g, 25.20 mmol), commercially available potassium carbonate (4.645 g, 33.61 mmol) into a single-mouth reaction flask, add 33.33 mL of acetone and stir, reflux at 65°C under nitrogen protection overnight, TLC detection until the reaction does not continue. Quench the reaction with NH4C1 and adjust the pH to acidic, extract with ethyl acetate for 3 times, separate the organic layer, dry the organic layer with anhydrous sodium sulfate, and separate and purify with a fast preparation column machine to obtain the target product 1 (0.821 g, yield 66.5%).

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 4.40 (dd, J = 11.4, 2.6 Hz, 1H), 3.90 (dd, J = 11.4, 2.6 Hz, 1H), 3.41 - 3.35 (m, 1H), 2.86 (t, J = 4.7 Hz, 1H), 2.73 (dd, J = 5.1, 2.6 Hz, 1H).

[0095] Preparation of 2 2-({[4-(4-chlorophenyl)phenyl]oxy}methyl)oxirane (2)

[0096] Replace 4-[4-(trifluoromethyl)phenyl]phenol in the second step of Preparation 1 with commercially available 4-(4-chlorophenyl)phenol (2a), and the rest of the required starting materials, reagents and preparation methods are the same as Preparation 1 to give solid 2 (362 mg, yield 57%).

[0097] 1 H NMR (600 MHz, DMSO-d6) δ 7.64 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.38 (dd, J = 11.4, 2.6 Hz, 1H), 3.88 (dd, J = 11.4, 6.6 Hz, 1H), 2.86 (t, J = 4.7 Hz, 1H), 2.73 (dd, J = 5.1, 2.6 Hz, 1H).

[0098] Preparation 3 2-{[(4-phenylphenyl)oxy]methyl}oxirane (3)

[0099] Replace 4-[4-(trifluoromethyl)phenyl]phenol in the second step of Preparation 1 with commercially available 4-phenylphenol (3a), and the rest of the required starting materials, reagents and preparation methods are the same as Preparation 1 to give solid 3 (443 mg, yield 67%).

[0100] 1 H NMR (600 MHz, DMSO-d6) δ 7.63-7.61 (m, 2H), 7.61-7.58 (m, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.33-7.29 (m, 1H), 7.05 (d, J = 8.6 Hz, 2H), 4.37 (dd, J = 11.3, 2.6 Hz, 1H), 3.87 (dd, J = 11.3, 6.5 Hz, 1H), 2.86 (dd, J = 5.1, 4.2 Hz, 1H), 2.73 (t, J = 5.1, 4.2 Hz, 1H).

[0101] Preparation 4 2-{[(2-chlorophenyl)oxy]methyl}oxirane (4)

[0102] Replace 4-[4-(trifluoromethyl)phenyl]phenol in the second step of Preparation 1 with commercially available 2-chlorophenol (4a), and the rest of the required starting materials, reagents and preparation methods are the same as Preparation 1 to give solid 4 (168.7 mg, yield 40%).

[0103] 1H NMR (500 MHz, Methanol-d4) δ 7.36 (dd, J = 7.9, 1.6 Hz, 1H), 7.24 (ddd, J = 8.2, 7.5, 1.6 Hz, 1H), 7.08 (dd, J = 8.2, 1.4 Hz, 1H), 6.93 (ddd, J = 7.9, 1.4 Hz, 1H), 4.38 (dd, J = 11.4, 2.5 Hz, 1H), 3.96 (dd, J = 11.4, 5.9 Hz, 1H), 3.42 - 3.34 (m, 1H), 2.89 (t, J = 5.1, 4.3 Hz, 1H), 2.81 (dd, J = 5.1, 2.7 Hz, 1H).

[0104] Preparation 5 2-{[(3-chlorophenyl)oxy]methyl}oxirane (5)

[0105] Using commercially available 3-chlorophenol (5a) instead of 4-[4- (trifluoromethyl)phenyl]phenol in the second step of Preparation 1, and the rest of the required starting materials, reagents and preparation methods are the same as Preparation 1, to give solid 5 (249.3 mg, yield 58%).

[0106] 1 H NMR (500 MHz, Chloroform-d) δ 7.20 (t, J = 8.1 Hz, 1H), 6.95 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H), 6.92 (t, J = 2.2 Hz, 1H), 6.82 (ddd, J = 8.4, 2.5, 0.9 Hz, 1H), 4.23 (dd, J = 11.0, 3.0 Hz, 1H), 3.93 (dd, J = 11.0, 5.7 Hz, 1H), 3.37 - 3.32 (m, 1H), 2.91 (dd, J = 4.9, 4.1 Hz, 1H), 2.75 (dd, J = 4.9, 2.6 Hz, 1H).

[0107] Preparation 6 2-{[(4-chlorophenyl)oxy]methyl}oxirane (6)

[0108] Using commercially available 4-chlorophenol (6a) instead of 4-[4- (trifluoromethyl)phenyl]phenol in the second step of Preparation 1, and the rest of the required starting materials, reagents and preparation methods are the same as Preparation 1, to give solid 6 (165 mg, yield 38%).

[0109] 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.21 (dd, J = 11.0, 3.0 Hz, 1H), 3.91 (dd, J = 11.0, 5.8 Hz, 1H), 3.38 - 3.28 (m, 1H), 2.91 (dd, J = 4.9, 4.1 Hz, 1H), 2.75 (dd, J = 4.9, 2.6 Hz, 1H).

[0110] Preparation 7 2-({[4-(trifluoromethyl)phenyl]oxy}methyl)oxirane (7)

[0111] Using commercially available 4-(trifluoromethyl)phenol (7a) instead of 4-[4- (trifluoromethyl)phenyl]phenol in the second step of Preparation 1, and using the same starting materials, reagents and preparation procedures as in Preparation 1, solid 7 (53.7 mg, 14% yield) was obtained.

[0112] 1 H NMR (500 MHz, Methanol-d4) δ 7.58 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 4.39 (dd, J = 11.3, 2.5 Hz, 1H), 3.91 (dd, J = 11.3, 6.3 Hz, 1H), 3.39 - 3.32 (m, 1H), 2.88 (t, J = 4.6 Hz, 1H), 2.75 (dd, J = 5.0, 2.7 Hz, 1H).

[0113] Example 1

[0114] First step: Dissolve commercially available vancomycin hydrochloride (150 mg, 0.1 mmol) in a single-mouth reaction vial containing DMSO / DMF (1 / 1 (v / v), 5 mL), and add 3- methylthiopropylamine (12.4 μL, 0.11 mmol), DIPEA (52.3 μL, 0.3 mmol) sequentially while stirring, then add HATU (38 mg, 0.1 mmol) previously dissolved in 1 mL of DMF dropwise into the above system, continue stirring at room temperature for 2 hours until the reaction no longer continues as detected by analytical RP-HPLC, then quench the reaction by adding an appropriate amount of TFA to adjust the pH to weakly acidic. Add methyl tert-butyl ether (MTBE) to precipitate a white solid, centrifuge to obtain a white solid crude product, then wash once with acetonitrile. After centrifugation, dissolve the lower crude product precipitate with an appropriate amount of water and acetonitrile, and separate and purify by preparative RP-HPLC, then collect the target component and lyophilize to obtain a white fluffy solid vana (74.8 mg, 49% yield).

[0115] R.T. = 10.221 min (analytical RP-HPLC). 1 H NMR (500 MHz, DMSO-d6 with 20 μL D20) δ 7.85 (s, 1H), 7.58 - 7.50 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 6.73 - 6.63 (m, 2H), 6.37 (d, J = 2.3 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 5.75 (d, J = 7.9 Hz, 1H), 5.60 (s, 1H), 5.30 - 5.21 (m, 3H), 5.18 (s, 2H), 4.92 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.45 (d, J = 5.5 Hz, 1H), 4.37 (d, J = 5.7 Hz, 1H), 4.27 - 4.14 (m, 2H), 4.00 - 3.90 (m, 1H), 3.67 (d, J = 11.0 Hz, 1H), 3.59 - 3.50 (m, 2H), 3.30 - 3.14 (m, 5H), 2.47 (t, J = 7.3 Hz, 2H), 2.19 - 2.09 (m, 1H), 2.05 (s, 3H), 1.91 (d, J = 11.9 Hz, 1H), 1.79 - 1.69 (m, 3H), 1.69 - 1.60 (m, 2H), 1.60 - 1.50 (m, 1H), 1.30 (s, 3H), 1.07 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 70 H 84 Cl2N 10 O 23 S theoretical value [M+2H] 2+ m / z 768.2478, actual value m / z 768.2510.

[0116] Second step, take vana (20 mg, 0.013 mmol) dispersed in 5 mL centrifuge tube containing 2 mL glacial acetic acid, vortex to the system uniform, 2-{[(4-phenylphenyl)oxy]methyl}oxirane (3) (29.39 mg, 0.13 mmol) is added to the above reaction system, 40 ℃ constant temperature shaking bed for 24 h, until the analytical RP-HPLC monitoring reaction is basically completed. Nitrogen blowing instrument to remove glacial acetic acid, add water and acetonitrile to dissolve the crude product, directly with preparative RP-HPLC separation and purification, after collecting the target component freeze-drying to get white fluffy solid van001 trifluoroacetate (11.2 mg, yield 49%).

[0117] R.T. = 16.168 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.57 (s, 1H), 8.23 (s, 1H), 7.82 (s, 1H), 7.65-7.58 (m, 4H), 7.58-7.50 (m, 2H), 7.48-7.41 (m, 3H), 7.34-7.29 (m, 2H), 7.28 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.10-7.04 (m, 2H), 6.81-6.76 (m, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 5.76 (d, J = 7.7 Hz, 1H), 5.59 (s, 1H), 5.29 (s, 1H), 5.28-5.21 (m, 2H), 5.18 (s, 2H), 4.92 (s, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.49 (s, 1H), 4.42-4.33 (m, 1H), 4.34-4.30 (m, 1H), 4.29-4.23 (m, 1H), 4.14-4.02 (m, 2H), 3.97 (s, 1H), 3.68 (d, J = 10.9 Hz, 1H), 3.38-3.30 (m, 1H), 3.29-3.23 (m, 2H), 3.24-3.19 (m, 1H), 3.18 (s, 1H), 2.96-2.90 (m, 3H), 2.63 (s, 3H), 2.17-2.07 (m, 1H), 2.00-1.84 (m, 3H), 1.73 (d, J = 13.1 Hz, 1H), 1.71-1.59 (m, 2H), 1.60-1.52 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI+ )C 85 H 99 Cl2N 10 O 25 S + Theoretical [M+H] 2+ m / z 881.2974, found m / z 881.2952.

[0118] Example 2

[0119] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 1 with 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxirane (1), and the rest of the required starting materials, reagents and preparation methods are the same as Example 1 to obtain the trifluoroacetic acid salt of van002 (8.5 mg, yield 43%).

[0120] R.T. = 18.260 min (analytical HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.73 (s, 1H), 8.55 (s, 1H), 8.42 (t, J = 7.8 Hz, 2H), 7.95 - 7.90 (m, 4H), 7.88 - 7.83 (m, 3H), 7.78 (d, J = 8.2 Hz, 2H), 7.71 (dd, J = 8.9, 3.0 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.35 - 7.29 (m, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.78 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 5.79 - 5.69 (m, 1H), 5.58 (s, 1H), 5.36 (d, J = 4.1 Hz, 1H), 5.24 (s, 2H), 5.20 (d, J = 5.0 Hz, 2H), 4.92 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.47 (s, 1H), 4.41 - 4.33 (m, 1H), 4.30 (d, J = 4.9 Hz, 1H), 4.28 - 4.17 (m, 1H), 3.95 (s, 1H), 3.67 (d, J = 10.9 Hz, 1H), 3.29 - 3.22 (m, 2H), 3.19 (s, 1H), 2.98 - 2.93 (m, 3H), 2.63 (s, 3H), 2.18 - 2.08 (m, 1H), 2.04 - 1.94 (m, 2H), 1.90 (d, J = 10.8 Hz, 1H), 1.74 (d, J = 13.1 Hz, 1H), 1.71 - 1.66 (m, 1H), 1.66 - 1.55 (m, 2H), 1.32 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI+) C 86 H 98 Cl2F3N 10 O 25 S + Theoretical [M+H] 2+ m / z 915.2911, found m / z 915.2926.

[0121] Example 3

[0122] The second step in Example 1 was replaced with 2-({[4-(4-chlorophenyl)phenyl]oxy}methyl)oxirane (2) instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents and preparation methods were the same as Example 1 to give the trifluoroacetate salt of van003 (13.8 mg, 59% yield).

[0123] R.T. = 17.573 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.77 - 8.68 (m, 1H), 8.54 (s, 1H), 7.83 (s, 1H), 7.64 (dd, J = 8.4, 5.8 Hz, 5H), 7.55 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 10.1 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.8 Hz, 1H), 6.75 - 6.68 (m, 2H), 6.41 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.75 (d, J = 7.2 Hz, 1H), 5.60 (s, 1H), 5.29 (d, J = 6.8 Hz, 2H), 5.18 (s, 1H), 5.16 (s, 1H), 5.11 (s, 1H), 4.92 (s, 1H), 4.71 - 4.59 (m, 1H), 4.45 (d, J = 5.5 Hz, 1H), 4.43 (d, J = 5.6 Hz, 1H), 4.40 - 4.34 (m, 1H), 4.19 (s, 2H), 4.12 - 4.03 (m, 2H), 3.96 (s, 1H), 3.68 (d, J = 10.7 Hz, 1H), 3.31 - 3.19 (m, 3H), 2.96 (d, J = 9.2 Hz, 3H), 2.88 (s, 1H), 2.62 (s, 3H), 2.19 - 2.01 (m, 3H), 1.99 - 1.90 (m, 1H), 1.83 (d, J = 13.1 Hz, 1H), 1.72 - 1.59 (m, 2H), 1.59 - 1.50 (m, 1H), 1.36 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 85 H 98 Cl3N 10 O 25 S +Theoretical value [M+H] 2+ m / z 898.2782, actual value m / z 898.2755.

[0124] Example 4

[0125] Example 1, except that 2-{[(4-phenylphenyl)oxy]methyl}oxirane was replaced by 2-[(phenyloxy)methyl]oxirane, and the other required starting materials, reagents and methods of preparation were the same as in Example 1, to give van004 trifluoroacetate salt (10.5 mg, 47.8% yield).

[0126] R.T. = 14.333, 14.390 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.73 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.46 - 7.41 (m, 1H), 7.35 - 7.28 (m, 3H), 7.26 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.00 - 6.91 (m, 3H), 6.78 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 5.74 (s, 1H), 5.59 (s, 1H), 5.32 - 5.25 (m, 2H), 5.23 (d, J = 4.0 Hz, 1H), 5.20 - 5.13 (m, 2H), 4.91 (s, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.47 (s, 1H), 4.39 - 4.32 (m, 1H), 4.31 (d, J = 4.7 Hz, 1H), 4.23 (d, J = 33.8 Hz, 1H), 4.05 - 3.99 (m, 2H), 3.95 (s, 1H), 3.70 (d, J = 1.3 Hz, 1H), 3.68 (s, 1H), 3.66 (s, 1H), 3.37 - 3.29 (m, 2H), 3.28 - 3.24 (m, 2H), 3.24 - 3.20 (m, 2H), 3.18 (s, 2H), 2.97 - 2.85 (m, 3H), 2.62 (s, 4H), 2.20 - 2.08 (m, 1H), 1.94 (s, 2H), 1.90 (d, J = 6.0 Hz, 1H), 1.73 (d, J = 12.9 Hz, 1H), 1.70 - 1.66 (m, 1H), 1.65 - 1.59 (m, 1H), 1.59 - 1.50 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H). High resolution mass spectrometry (ESI + )C 79 H 95 Cl2N 10 O25S + Theoretical [M+H] 2+ m / z 843.2818, found m / z 843.2822.

[0127] Example 5

[0128] The second step in Example 1 was replaced with (2S)-2-[(phenyloxy)methyl]oxirane in place of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 1 to give the trifluoroacetate salt of van005 (8.8 mg, 40% yield).

[0129] R.T. = 11.24 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.72 (s, 1H), 8.54 (s, 1H), 8.25-8.16 (m, 1H), 7.81 (dd, J = 3.8, 1.9 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.52-7.45 (m, 4H), 7.44 (dd, J = 8.1, 1.8 Hz, 1H), 7.34-7.28 (m, 3H), 7.27 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.00-6.92 (m, 3H), 6.78 (dd, J = 8.3, 2.0 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 5.27 (d, J = 8.4 Hz, 2H), 5.23 (d, J = 4.1 Hz, 1H), 5.18 (t, J = 3.8 Hz, 2H), 4.90 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.47 (d, J = 5.2 Hz, 1H), 4.34 (dq, J = 7.2, 3.5, 2.4 Hz, 1H), 4.31 (d, J = 5.2 Hz, 1H), 4.26 (s, 2H), 4.01 (dd, J = 6.3, 3.7 Hz, 2H), 3.67 (d, J = 10.3 Hz, 1H), 3.57-3.54 (m, 2H), 3.53-3.48 (m, 1H), 3.37-3.29 (m, 3H), 3.26 (d, J = 8.0 Hz, 1H), 3.18 (d, J = 10.6 Hz, 2H), 2.99-2.84 (m, 4H), 2.72 (s, 1H), 2.63-2.52 (m, 3H), 2.19-2.09 (m, 1H), 2.00-1.92 (m, 2H), 1.90 (s, 1H), 1.77-1.70 (m, 1H), 1.64 (s, 2H), 1.53 (s, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI +)C 79 H 95 Cl2N 10 O 25 S + Theoretical [M+H] 2+ m / z 843.2818, found m / z 843.2820.

[0130] Example 6

[0131] The second step of Example 1 was replaced by (2R)-2-[(phenyloxy)methyl]oxirane instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the rest of the required starting materials, reagents and preparation methods were the same as Example 1 to give van006 trifluoroacetate salt (22.1 mg, yield 34%).

[0132] R.T. = 11.32 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.73 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.57-7.47 (m, 2H), 7.45-7.41 (m, 1H), 7.34-7.29 (m, 3H), 7.27 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.99-6.95 (m, 3H), 6.78 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 5.75 (s, 1H), 5.59 (s, 1H), 5.27 (d, J = 8.6 Hz, 2H), 5.25-5.21 (m, 1H), 5.18 (s, 2H), 4.90 (s, 1H), 4.66 (q, J = 6.6 Hz, 1H), 4.48 (s, 1H), 4.38-4.32 (m, 1H), 4.30 (d, J = 4.8 Hz, 1H), 4.26 (s, 1H), 4.09-3.94 (m, 3H), 3.67 (d, J = 11.4 Hz, 1H), 3.58-3.55 (m, 1H), 3.54-3.51 (m, 2H), 3.51 (d, J = 3.5 Hz, 1H), 3.35-3.30 (m, 1H), 3.26 (d, J = 7.8 Hz, 2H), 3.23 (d, J = 10.8 Hz, 1H), 3.17 (s, 2H), 2.95-2.87 (m, 5H), 2.72 (s, 1H), 2.61 (s, 3H), 2.13 (d, J = 8.7 Hz, 1H), 1.98-1.91 (m, 2H), 1.89 (s, 1H), 1.76-1.69 (m, 1H), 1.64 (s, 2H), 1.54 (s, 1H), 1.30 (s, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + ) 79 95 10 25 + Theoretical [M+H] 2+ m / z 843.2818, found m / z 843.2811.

[0133] Example 7

[0134] ​​​​The second step in Example 1 was replaced by 2-{[(2-chlorophenyl)oxy]methyl}oxirane (4) instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the other required starting materials, reagents and preparation methods were the same as in Example 1 to give the trifluoroacetate salt of van007 (48.1 mg, 43% yield).

[0135] R.T. = 11.992 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ8.72 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.52-7.46 (m, 1H), 7.45-7.41 (m, 2H) , 7.34-7.29 (m, 2H), 7.27 (s, 1H), 7.21 (d, J=8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.03-6.96 (m, 1H), 6.78 (dd, J=8.4, 2.0H z, 1H), 6.71 (d, J = 8.4Hz, 1H), 6.38 (d, J = 2.6Hz, 1H), 6.23 (d, J = 2.6Hz, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 5.27 (d, J = 8.9Hz , 2H), 5.23 (d, J=4.0Hz, 1H), 5.17 (d, J=4.2Hz, 2H), 4.91 (s, 1H), 4.67 (q, J=6.6Hz, 1H), 4.47 (s, 1H), 4.38 (hept, J=4.0H z, 1H), 4.31 (dt, J=5.3, 3.0Hz, 1H), 4.26 (s, 1H), 4.16-4.03 (m, 3H), 3.67 (d, J=11.2Hz, 1H), 3.59-3.55 (m, 2H), 3.55-3 .52(m,2H),3.50(s,1H),3.38-3.30(m,1H),3.29-3.25(m,2H),3.24-3.21(m,1H),3.18(s,2H),2.97-2.91(m,3H),2.88 (s, 1H), 2.72(s, 1H), 2.63–2.55(m, 3H), 2.13(d, J = 9.0 Hz, 1H), 1.93(d, J = 15.7 Hz, 2H), 1.90(s, 1H), 1.75–1.70(m, 1H), 1.64(s, 2H), 1.54(s, 1H), 1.30(s, 3H), 1.05(d, J = 6.8 Hz, 3H), 0.90(d, J = 6.0 Hz, 3H), 0.86(d, J = 6.1 Hz, 3H). High-resolution mass spectrometry (ESI) + C 79 H 94 Cl3N 10 O 25 S + Theoretical value [M+H] 2+ m / z 860.2623, the actual value is m / z 860.2623.

[0136] Example 8

[0137] The second step in Example 1 was replaced with 2-{[(3- chlorophenyl)oxy]methyl}oxirane (5), and the remaining starting materials, reagents, and preparation methods were the same as in Example 1 to give the trifluoroacetate salt of van008 (69.2 mg, 62% yield).

[0138] R.T. = 12.479 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.73 (s, 1H), 8.56 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.46 - 7.40 (m, 1H), 7.34 - 7.30 (m, 1H), 7.30 - 7.26 (m, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.93 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.71 (s, 1H), 5.56 (s, 1H), 5.27 (d, J = 8.2 Hz, 2H), 5.22 (s, 1H), 5.16 (s, 2H), 4.88 (s, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.46 (s, 1H), 4.37 - 4.27 (m, 2H), 4.24 (s, 1H), 4.11 - 3.95 (m, 3H), 3.57 (d, J = 1.0 Hz, 1H), 3.53 - 3.47 (m, 3H), 3.43 (d, J = 7.0 Hz, 2H), 3.40 (s, 1H), 3.32 - 3.28 (m, 1H), 3.25 (d, J = 5.0 Hz, 2H), 3.21 (s, 1H), 3.19 - 3.16 (m, 2H), 2.92 - 2.88 (m, 3H), 2.71 (s, 2H), 2.58 - 2.53 (m, 3H), 2.11 (d, J = 12.1 Hz, 1H), 1.93 (s, 2H), 1.89 (d, J = 7.3 Hz, 1H), 1.74 (d, J = 3.6 Hz, 1H), 1.63 (s, 2H), 1.53 (s, 1H), 1.30 (s, 3H), 1.05 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI +)C 79 H 94 Cl3N 10 O 25 S + Theoretical [M+H] 2+ m / z 860.2623, found m / z 860.2630.

[0139] Example 9

[0140] Example 1, using 2-{[(4-chlorophenyl)oxy]methyl}oxirane (6) in place of 2-{[(4- phenylphenyl)oxy]methyl}oxirane in the second step of Example 1, and the remaining required starting materials, reagents and methods of preparation as in Example 1, to give van009 trifluoroacetate salt (70.3 mg, 63% yield).

[0141] R.T. = 12.478 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.72 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.78 (s, 1H), 7.57-7.52 (m, 1H), 7.51 (s, 1H), 7.41-7.35 (m, 1H), 7.34-7.30 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.01-6.93 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.71 (s, 1H), 5.59-5.52 (m, 1H), 5.26 (d, J = 9.1 Hz, 2H), 5.22 (s, 1H), 5.18-5.13 (m, 2H), 4.88 (s, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.46 (s, 1H), 4.37-4.31 (m, 1H), 4.29 (d, J = 4.4 Hz, 1H), 4.24 (s, 1H), 4.03-3.93 (m, 2H), 3.65 (d, J = 10.9 Hz, 1H), 3.58-3.52 (m, 2H), 3.51-3.45 (m, 2H), 3.41 (s, 1H), 3.33-3.27 (m, 1H), 3.25 (d, J = 4.8 Hz, 2H), 3.21 (s, 1H), 3.17 (s, 2H), 2.92-2.85 (m, 4H), 2.71 (d, J = 0.7 Hz, 1H), 2.55 (s, 3H), 2.18-2.05 (m, 1H), 1.91 (s, 2H), 1.89 (d, J = 6.9 Hz, 1H), 1.73 (d, J = 12.9 Hz, 1H), 1.61 (dd, J = 12.7, 6.6 Hz, 2H), 1.53 (s, 1H), 1.30 (s, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.84 (d, J = 6.0 Hz, 3H). High resolution mass spectrometry (ESI + ) 79 94 10 25 + Theoretical [M+H] 2+ m / z 860.2623, found m / z 860.2628.

[0142] Example 10 ​​​​

[0143] The second step in Example 1 was replaced with 2-{[(4-bromophenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 1 to give van010 trifluoroacetate salt (18 mg, 16% yield).

[0144] R.T. = 12.862 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.72 (s, 1H), 8.55 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.45-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.98-6.88 (m, 2H), 6.78 (dd, J = 44.6, 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.71 (s, 1H), 5.55 (s, 1H), 5.27 (d, J = 9.2 Hz, 2H), 5.24-5.20 (m, 1H), 5.16 (s, 2H), 4.88 (s, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.46 (s, 1H), 4.38-4.31 (m, 1H), 4.30-4.27 (m, 1H), 4.24 (s, 1H), 3.99 (qq, J = 10.3, 5.0 Hz, 2H), 3.65 (d, J = 10.4 Hz, 1H), 3.59-3.56 (m, 1H), 3.55-3.48 (m, 3H), 3.42 (q, J = 7.0 Hz, 2H), 3.30 (dd, J = 13.6, 6.9 Hz, 1H), 3.25 (d, J = 5.1 Hz, 2H), 3.21 (s, 1H), 3.17 (s, 2H), 2.94-2.85 (m, 5H), 2.71 (s, 1H), 2.54 (s, 3H), 2.12 (t, J = 9.2 Hz, 1H), 1.92 (d, J = 8.1 Hz, 2H), 1.89 (s, 1H), 1.76-1.73 (m, 1H), 1.62 (s, 2H), 1.52 (s, 1H), 1.30 (s, 3H), 1.05 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.1 Hz, 3H), 0.84 (d, J = 6.0 Hz, 3H). High resolution mass (ESI + ) C79 H 94 BrCl2N 10 O 25 S + Theoretical [M+H] 2+ m / z 882.237, actual m / z 882.2316.

[0145] Example 11

[0146] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 1 with 2-({[4-(trifluoromethyl)phenyl]oxy}methyl)oxirane, and the rest of the required starting materials, reagents and preparation methods are the same as Example 1 to obtain the trifluoroacetic acid salt of van011 (33.8 mg, yield 30%).

[0147] R.T. = 13.274 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.73 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.81 (d, J = 4.7 Hz, 1H), 7.68 - 7.66 (m, 2H), 7.60 - 7.47 (m, 2H), 7.47 - 7.38 (m, 1H), 7.34 - 7.28 (m, 1H), 7.27 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.18 - 7.14 (m, 2H), 6.78 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.4, 2.3 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 5.27 (d, J = 6.3 Hz, 2H), 5.24 (d, J = 4.1 Hz, 1H), 5.17 (d, J = 4.7 Hz, 2H), 4.90 (s, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.48 (s, 1H), 4.40 - 4.33 (m, 1H), 4.30 (t, J = 4.6 Hz, 1H), 4.26 (s, 1H), 4.11 (tt, J = 11.5, 5.9 Hz, 2H), 3.72 - 3.65 (m, 1H), 3.60 - 3.54 (m, 2H), 3.53 (d, J = 2.3 Hz, 2H), 3.51 (s, 1H), 2.97 - 2.90 (m, 3H), 2.88 (s, 1H), 2.72 (s, 1H), 2.63 - 2.53 (m, 3H), 2.13 (d, J = 9.5 Hz, 1H), 1.93 (s, 2H), 1.92 - 1.85 (m, 1H), 1.75 - 1.70 (m, 1H), 1.64 (s, 2H), 1.53 (s, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + ) 80 94 Cl2F3N 10 25 S + Theoretical [M+H] 2+ m / z 877.2754, found m / z 877.2767.

[0148] Example 12

[0149] ​​The second step in Example 1 was replaced with 2-{[(4-tert- butylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 1 to give the trifluoroacetate salt of van012 (52.6 mg, 46% yield).

[0150] R.T. = 14.678 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.73 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.45-7.41 (m, 1H), 7.34-7.28 (m, 3H), 7.27 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.90-6.86 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 5.75 (s, 1H), 5.59 (s, 1H), 5.28 (s, 2H), 5.24 (s, 1H), 5.18 (s, 2H), 4.90 (s, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.48 (s, 1H), 4.37-4.29 (m, 2H), 4.26 (s, 1H), 4.05-3.93 (m, 3H), 3.67 (d, J = 10.9 Hz, 1H), 3.61-3.54 (m, 2H), 3.52 (s, 2H), 3.49 (s, 1H), 3.32 (q, J = 6.9 Hz, 1H), 3.26 (d, J = 7.3 Hz, 2H), 3.24 (s, 1H), 3.17 (s, 2H), 2.92 (t, J = 8.3 Hz, 3H), 2.88 (s, 1H), 2.72 (s, 1H), 2.61 (s, 3H), 2.13 (d, J = 11.7 Hz, 1H), 1.93 (s, 2H), 1.90 (s, 1H), 1.73 (d, J = 13.4 Hz, 1H), 1.65 (s, 2H), 1.54 (s, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 83 H 103 Cl2N 10 O 25 S + Theoretical [M+H]2+ m / z 871.3131, actual value m / z 871.3136.

[0151] Example 13

[0152] Example 1, except that 2-{[(4-methoxyphenyl)oxy]methyl}oxirane was used instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane. The other required starting materials, reagents and methods of preparation were the same as in Example 1 to give van013 trifluoroacetate salt (6.4 mg, 11% yield).

[0153] R.T. = 11.36 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ8.74 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.55 (d, J = 8.0Hz, 2H), 7.45-7.41 (m, 1H), 7.37-7.30 (m, 1 H), 7.27 (s, 1H), 7.21 (d, J=8.0Hz, 1H), 6.94-6.89 (m, 2H), 6.88-6.84 (m, 2H), 6.78 (d, J=8.6Hz, 1H), 6.71 (d, J=8.6Hz , 1H), 6.39 (d, J=2.2Hz, 1H), 6.24 (t, J=1.8Hz, 1H), 5.76 (d, J=7.7Hz, 1H), 5.60 (s, 1H), 5.27 (d, J=8.8Hz, 2H), 5.24 (d , J=4.1Hz, 1H), 5.18 (s, 2H), 4.91 (s, 1H), 4.67 (q, J=6.6Hz, 1H), 4.49 (s, 1H), 4.31 (q, J=4.6Hz, 2H), 4.26 (s, 1H), 4.0 0-3.93 (m, 3H), 3.70 (t, J = 0.8Hz, 3H), 3.68 (d, J = 10.4Hz, 1H), 3.57 (d, J = 5.7Hz, 1H), 3.53 (d, J = 3.1Hz, 2H), 3.51 (d, J=13.0Hz, 1H), 3.38-3.30(m, 2H), 3.26(d, J=6.8Hz, 2H), 3.24-3.19(m, 2H), 3.18(s, 1H), 2.96-2.88(m, 3H), 2.62(d, J = 4.9 Hz, 3H), 2.13 (d, J = 13.8 Hz, 1H), 1.97–1.92 (m, 2H), 1.91 (d, J = 6.6 Hz, 1H), 1.73 (d, J = 13.1 Hz, 1H), 1.69–1.62 (m, 2H), 1.59–1.53 (m, 1H), 1.31 (s, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H). High-resolution mass spectrometry (ESI) + C 80 H 97 Cl2N 10 O 26 S + Theoretical value [M+H] 2+ m / z 858.2870, actual value is m / z 858.2872.

[0154] Example 14

[0155] The second step in Example 1 was replaced by 2-benzyloxirane instead of 2-{[(4- phenylphenyl)oxy]methyl}oxirane, and the rest of the required starting materials, reagents and preparation methods were the same as in Example 1 to give the trifluoroacetate salt of van014 (15.9 mg, 28% yield).

[0156] R.T. = 11.122 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.54 (s, 1H), 8.21 (s, 1H), 7.80 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 3.3 Hz, 1H), 7.25-7.23 (m, 3H), 7.22 (s, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 6.20 (d, J = 2.5 Hz, 1H), 5.71 (s, 1H), 5.56 (s, 1H), 5.27 (s, 2H), 5.22 (s, 1H), 5.16 (s, 2H), 4.87 (s, 1H), 4.65 (d, J = 6.8 Hz, 1H), 4.47 (s, 1H), 4.30 (d, J = 5.1 Hz, 1H), 4.24 (s, 1H), 4.15 (d, J = 7.6 Hz, 1H), 3.54 (d, J = 8.7 Hz, 1H), 3.51 (d, J = 13.4 Hz, 1H), 3.43 (d, J = 7.0 Hz, 2H), 3.41 (d, J = 7.0 Hz, 2H), 3.36 (d, J = 5.2 Hz, 1H), 3.25 (d, J = 6.1 Hz, 3H), 3.17 (s, 2H), 2.89-2.84 (m, 3H), 2.82 (d, J = 7.6 Hz, 2H), 2.79-2.71 (m, 2H), 2.61 (q, J = 1.9 Hz, 1H), 2.56 (d, J = 21.5 Hz, 3H), 2.11 (d, J = 8.7 Hz, 1H), 1.89 (d, J = 11.2 Hz, 3H), 1.73 (d, J = 13.0 Hz, 1H), 1.63 (s, 2H), 1.53 (s, 1H), 1.31 (d, J = 6.2 Hz, 3H), 1.05 (t, J = 3.3 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI+) C 79 H 95Cl2N 10 O 24 S + Theoretical value [M+H] 2+ m / z 835.2843, actual value m / z 835.2830.

[0157] Example 15

[0158] van002 (10 mg, 0.0055 mmol) was weighed into a 2 mL centrifuge tube containing 1 mL 75% ethanol, and ammonium pyrrolidine dithio-carbonate (APDC) (9 mg, 0.055 mmol) was added. The system became white turbid, and the reaction continued overnight on a shaker. After the reaction was substantially complete, as monitored by analytical RP-HPLC, a suitable amount of TFA was added to adjust the pH to weakly acidic. The reaction solution was directly separated and purified by preparative RP-HPLC, and the collected target component was freeze-dried to obtain the trifluoroacetate salt of van015 (8.5 mg, yield 43%) as a white fluffy solid.

[0159] R.T. = 18.568 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 7.85 (d, J = 3.6 Hz, 2H), 7.84 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.72 - 7.65 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.46 - 7.43 (m, 1H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 7.21 - 7.17 (m, 2H), 7.11 - 7.06 (m, 2H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.75 (d, J = 7.8 Hz, 1H), 5.60 (s, 1H), 5.26 (d, J = 7.8 Hz, 1H), 5.24 (d, J = 3.9 Hz, 2H), 5.17 (t, J = 3.3 Hz, 2H), 4.91 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.44 (d, J = 5.4 Hz, 1H), 4.38 (d, J = 5.6 Hz, 1H), 4.20 (s, 1H), 4.06 (dd, J = 9.7, 4.2 Hz, 1H), 4.01 (t, J = 4.8 Hz, 1H), 3.99 - 3.93 (m, 2H), 3.67 (d, J = 10.9 Hz, 1H), 3.55 (d, J = 8.8 Hz, 1H), 3.53 (d, J = 4.3 Hz, 1H), 3.51 (s, 1H), 3.43 - 3.40 (m, 1H), 3.26 (d, J = 6.4 Hz, 2H), 3.21 (td, J = 13.2, 12.8, 6.5 Hz, 2H), 3.17 (s, 1H), 2.74 (dd, J = 13.5, 5.8 Hz, 1H), 2.67 - 2.64 (m, 1H), 2.62 (d, J = 5.5 Hz, 3H), 2.57 (t, J = 7.3 Hz, 2H), 2.54 (s, 1H), 2.13 (d, J = 12.3 Hz, 1H), 1.90 (d, J = 10.4 Hz, 1H), 1.74 (p, J = 8.7, 7.8 Hz, 3H), 1.70 - 1.65 (m, 1H), 1.64 - 1.60 (m, 1H), 1.58 - 1.53 (m, 1H), 1.29 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H). High resolution mass spectrometry (ESI + ) 85 H 95 Cl2F3N 10 O 25S, Theoretical [M+2H] 2+ m / z 908.2833, actual m / z 908.2854.

[0160] Example 16

[0161] First step: Commercial vancomycin hydrochloride (800 mg, 0.54 mmol), 3- methylthiopropanal (168.3 μL, 1.62 mmol) and DIPEA (422 μL, 2.42 mmol) were added sequentially to a single-mouth reaction flask containing 100 mL of DMF, the reaction system was transferred to 50 °C and stirred for 2 hours until the analytical RP-HPLC monitoring reaction no longer changed further, then the reaction system was returned to room temperature, sodium cyanoborohydride (135.3 mg, 2.15 mmol) dissolved in 1.6 mL of methanol was slowly added to the reaction flask, and a small amount of TFA was added to the above reaction system to adjust the pH to about 3-4, and the reaction was continued for 2 hours to fully reduce the carbon-nitrogen double bond of the formed Schiff base to a carbon-nitrogen single bond, and the reaction was monitored by analytical RP-HPLC. After the reaction was completed, 30 mL of ethyl acetate was added to the reaction system to precipitate the crude product three times, centrifuged and discarded the supernatant, and the lower crude precipitate was dissolved with an appropriate amount of water and acetonitrile and directly separated and purified by preparative RP-HPLC, and the collected target compound components were freeze-dried to obtain white fluffy solid vanb (423.1 mg, yield 52%).

[0162] R.T. = 11.823 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 7.84 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.48 - 7.45 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.78 (dd, J = 8.4, 2.0 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 11.5 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.74 (d, J = 7.9 Hz, 1H), 5.60 (s, 1H), 5.30 (d, J = 7.8 Hz, 1H), 5.28 (d, J = 4.2 Hz, 1H), 5.19 (d, J = 3.7 Hz, 1H), 5.16 (d, J = 2.0 Hz, 1H), 5.12 (s, 1H), 4.93 (s, 1H), 4.64 (q, J = 6.7 Hz, 1H), 4.45 (d, J = 7.0 Hz, 1H), 4.43 (d, J = 5.7 Hz, 1H), 4.19 (d, J = 11.4 Hz, 1H), 3.97 (dd, J = 152.5, 4.4 Hz, 1H), 3.68 (d, J = 10.8 Hz, 1H), 3.48 - 3.41 (m, 2H), 3.32 - 3.24 (m, 3H), 2.91 - 2.84 (m, 1H), 2.84 - 2.76 (m, 1H), 2.63 (s, 3H), 2.20 - 2.11 (m, 1H), 2.03 (s, 3H), 2.00 - 1.95 (m, 1H), 1.88 - 1.76 (m, 3H), 1.72 - 1.65 (m, 1H), 1.64 - 1.60 (m, 1H), 1.60 - 1.53 (m, 1H), 1.34 (s, 3H), 1.09 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H). High resolution mass spectrometry (ESI+) C 70 H 83 Cl2N9O 24 S Theoretical [M+2H] 2+ m / z 768.7403, found m / z 768.7391.

[0163] Second step: vanb (20 mg, 0.013 mmol) was taken in a 5 mL centrifuge tube containing 2 mL of glacial acetic acid, vortexed until the system was homogeneous, 2-{[(4-phenylphenyl)oxy]methyl}oxirane (3) (29.39 mg, 0.13 mmol) was added to the above reaction system, and the reaction was carried out at 40 °C constant temperature shaker for 24 h until the reaction was basically completed by monitoring with analytical RP-HPLC. The glacial acetic acid was removed by nitrogen blowing instrument, and the crude product was dissolved in water and acetonitrile, and then directly separated and purified by preparative RP-HPLC. After the target component was collected, it was freeze-dried to obtain the trifluoroacetic acid salt of van016 (10.5 mg, yield 46%) as a white fluffy solid.

[0164] R.T. = 15.733 min and 15.844 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.74 (s, 1H), 8.54 (s, 1H), 7.83 (s, 1H), 7.69-7.58 (m, 5H), 7.57-7.50 (m, 2H), 7.49-7.39 (m, 4H), 7.33 (t, J = 7.0 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.8 Hz, 1H), 6.76-6.68 (m, 2H), 6.41 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.75 (s, 1H), 5.60 (s, 1H), 5.35-5.25 (m, 2H), 5.19-5.17 (m, 1H), 5.16 (s, 1H), 5.10 (s, 1H), 4.92 (s, 1H), 4.67 (s, 1H), 4.47-4.44 (m, 1H), 4.43 (d, J = 5.6 Hz, 1H), 4.39-4.33 (m, 1H), 4.26-4.14 (m, 1H), 4.12-4.03 (m, 2H), 3.68 (d, J = 10.7 Hz, 1H), 3.32-3.21 (m, 3H), 2.97 (d, J = 9.2 Hz, 3H), 2.88 (s, 1H), 2.63-2.57 (m, 3H), 2.19-2.01 (m, 3H), 1.96 (d, J = 9.2 Hz, 1H), 1.83 (d, J = 13.0 Hz, 1H), 1.72-1.60 (m, 2H), 1.56 (s, 1H), 1.36 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 5.9 Hz, 3H). High resolution mass spectrometry (ESI + )C85 H 98 Cl2N9O 26 S + Theoretical [M+H] 2+ m / z 881.7894, actual m / z 881.7850.

[0165] Example 17

[0166] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 16 with 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxirane (1) and the rest of the required starting materials, reagents and preparation methods are the same as Example 16 to give the trifluoroacetic acid salt of van017 (62.7 mg, 59% yield).

[0167] R.T. = 17.875 min and 17.945 min (analytical HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.74 (s, 1H), 8.55 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.82 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.49 - 7.43 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 5.60 (s, 1H), 5.33 - 5.24 (m, 2H), 5.18 (s, 1H), 5.15 (s, 1H), 5.11 (s, 1H), 4.90 (s, 1H), 4.69 - 4.59 (m, 1H), 4.48 - 4.43 (m, 1H), 4.42 (d, J = 5.6 Hz, 1H), 4.40 - 4.34 (m, 1H), 4.23 - 4.13 (m, 2H), 4.09 (d, J = 4.9 Hz, 2H), 3.99 - 3.90 (m, 1H), 3.47 - 3.41 (m, 2H), 3.35 (s, 1H), 3.29 - 3.22 (m, 3H), 2.96 (d, J = 10.1 Hz, 3H), 2.88 (s, 1H), 2.61 (s, 3H), 2.07 (d, J = 34.6 Hz, 3H), 1.94 (s, OH), 1.83 (d, J = 12.9 Hz, 1H), 1.71 - 1.59 (m, 2H), 1.58 - 1.52 (m, 1H), 1.36 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI+) C 86 H 97 Cl2F3N9O 26 S + Theoretical [M+H] 2+ m / z 915.7834, found m / z 915.7825.

[0168] Example 18

[0169] The second step in Example 16 was replaced with 2-({[4-(4-chlorophenyl)phenyl]oxy}methyl)oxirane (2) instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 16 to give the trifluoroacetate salt of van018 (6.3 mg, 27% yield).

[0170] R.T. = 17.141 min and 17.245 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.89 - 8.80 (m, 4H), 8.72 (s, 1H), 8.54 (s, 1H), 8.48 - 8.40 (m, 2H), 7.97 - 7.91 (m, 4H), 7.84 (s, 1H), 7.67 - 7.60 (m, 5H), 7.56 (s, 1H), 7.53 - 7.41 (m, 4H), 7.36 - 7.29 (m, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.78 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.22 (d, J = 2.2 Hz, 1H), 5.81 - 5.72 (m, 1H), 5.58 (s, 1H), 5.36 (d, J = 4.1 Hz, 1H), 5.27 (d, J = 7.7 Hz, 1H), 5.26 - 5.22 (m, 1H), 5.21 - 5.15 (m, 2H), 4.93 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.47 (s, 1H), 4.41 - 4.33 (m, 1H), 4.30 (d, J = 4.9 Hz, 1H), 4.27 (s, 2H), 4.14 - 4.10 (m, 2H), 4.08 (h, J = 4.5, 3.9 Hz, 2H), 3.95 (s, 1H), 3.67 (d, J = 10.9 Hz, 1H), 3.29 - 3.21 (m, 3H), 3.19 (s, 1H), 3.00 - 2.88 (m, 3H), 2.63 (s, 3H), 2.18 - 2.09 (m, 1H), 1.99 (dd, J = 14.6, 7.5 Hz, 2H), 1.90 (d, J = 10.7 Hz, 1H), 1.75 (d, J = 13.2 Hz, 1H), 1.69 (q, J = 6.8, 5.7 Hz, 1H), 1.66 - 1.56 (m, 2H), 1.32 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 5.9 Hz, 3H), 0.87 (d, J = 5.9 Hz, 3H). High resolution mass spectrometry (ESI+ )C 85 H 97 Cl3N9O 26 S + Theoretical [M+H] 2+ m / z 898.7702, found m / z 898.7687.

[0171] Example 19

[0172] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 16 with 2-[(phenyloxy)methyl]oxirane, and the rest of the required starting materials, reagents and preparation methods are the same as Example 16 to give the trifluoroacetate salt of van019 (14 mg, yield 64%).

[0173] R.T. = 13.033 min and 13.100 min (analytical HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ 8.72 (s, 1H), 8.54 (s, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.55 (d, J = 8.6Hz, 2H), 7.47 (dd, J = 8.4, 1.8Hz, 1H), 7.33 (s, 1H), 7.3 2-7.30 (m, 2H), 7.19 (d, J=8.4Hz, 1H), 7.17 (d, J=1.9Hz, 1H), 7.00-6.96 (m, 2H), 6.96 (s, 1H), 6.78 (dd, J=8.5, 1.9Hz, 1H), 6 .73 (d, J=8.5Hz, 1H), 6.41 (d, J=2.3Hz, 1H), 6.25 (d, J=2.3Hz, 1H), 5.75 (d, J=7.5Hz, 1H), 5.61 (s, 1H), 5.31 (s, 1H), 5.30-5 .26 (m, 1H), 5.18 (d, J = 3.7Hz, 1H), 5.16 (s, 1H), 5.11 (s, 1H), 4.92 (s, 1H), 4.66 (d, J = 6.7Hz, 1H), 4.46 (d, J = 5.5Hz, 1H), 4.4 3 (d, J=5.7Hz, 1H), 4.38-4.31 (m, 1H), 4.21-4.17 (m, 1H), 4.06-3.99 (m, 2H), 3.96 (s, 1H), 3.68 (d, J=10.9Hz, 1H), 3.61 (d, J =4.1Hz, 1H), 3.60-3.57(m, 2H), 3.56(s, 0H), 3.41-3.32(m, 2H), 3.32-3.26(m, 3H), 3.24-3.20(m, 1H), 2.99-2.83(m, 5H), 2 0.63 (s, 4H), 2.19–2.11 (m, 1H), 2.08–2.02 (m, 1H), 1.96 (d, J = 11.8 Hz, 1H), 1.83 (d, J = 13.1 Hz, 1H), 1.76–1.71 (m, 1H), 1.70–1.61 (m, 2H), 1.60–1.53 (m, 1H), 1.36 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 6.1 Hz, 3H). High-resolution mass spectrometry (ESI) + C 79 H 94 Cl2N9O 26 S + Theoretical value [M+H] 2+ m / z 843.7738, actual value m / z 843.7738.

[0174] Example 20

[0175] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 16 with (2S)-2-[(phenyloxy)methyl]oxirane, and the rest of the required starting materials, reagents and preparation methods are the same as Example 16 to give the trifluoroacetate salt of van020 (10.1 mg, 46% yield).

[0176] R.T. = 10.503 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.23 (s, 1H), 9.15 (d, J = 12.0 Hz, 1H), 8.68 (s, 1H), 8.51 (d, J = 5.8 Hz, 1H), 7.83 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.48 - 7.44 (m, 3H), 7.32 (d, J = 7.8 Hz, 3H), 7.30 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.17 (s, 1H), 6.97 (dd, J = 12.2, 7.5 Hz, 3H), 6.77 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 6.39 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 6.01 - 5.97 (m, 2H), 5.75 (d, J = 7.7 Hz, 1H), 5.58 (s, 1H), 5.37 (d, J = 6.5 Hz, 1H), 5.29 (t, J = 7.1 Hz, 2H), 5.17 (t, J = 10.6 Hz, 3H), 5.10 (d, J = 6.6 Hz, 1H), 4.92 (s, 1H), 4.66 (p, J = 7.2, 6.8 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.37 - 4.32 (m, 1H), 4.19 (d, J = 11.6 Hz, 1H), 4.09 (d, J = 5.7 Hz, 1H), 4.05 - 3.97 (m, 2H), 3.70 - 3.66 (m, 2H), 3.61 (s, 4H), 3.28 (s, 4H), 2.96 (d, J = 8.5 Hz, 4H), 2.88 - 2.81 (m, 1H), 2.58 (s, 3H), 2.54 (s, 1H), 2.18 - 2.11 (m, 1H), 2.10 - 2.03 (m, 2H), 1.95 (d, J = 12.5 Hz, 1H), 1.82 (d, J = 12.9 Hz, 1H), 1.63 (q, J = 8.1, 7.0 Hz, 2H), 1.53 (dd, J = 14.8, 8.3 Hz, 1H), 1.34 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 5.8 Hz, 3H). High resolution mass spectrometry (ESI + ) 79 94 Cl2N9O 26 + Theoretical [M+H] 2+ m / z 843.7738, found m / z 843.7739.

[0177] ​​Example 21

[0178] The second step of Example 16 was replaced by (2R)-2-[(phenyloxy)methyl]oxirane instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the rest of the required starting materials, reagents and preparation methods were the same as Example 16 to give van021 trifluoroacetate salt (10.4 mg, 47% yield).

[0179] R.T. = 10.463 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.22 (s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.51 (d, J = 5.8 Hz, 1H), 7.83 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.34 - 7.29 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.03 - 6.94 (m, 4H), 6.77 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 1.9 Hz, 1H), 6.25 (d, J = 1.9 Hz, 1H), 5.98 (t, J = 6.6 Hz, 2H), 5.75 (d, J = 7.7 Hz, 1H), 5.59 (s, 1H), 5.36 (d, J = 5.7 Hz, 1H), 5.32 - 5.28 (m, 2H), 5.19 - 5.13 (m, 4H), 5.10 (d, J = 6.7 Hz, 1H), 4.93 (s, 1H), 4.67 (q, J = 6.8 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.35 (tt, J = 9.2, 4.6 Hz, 2H), 4.27 (s, 1H), 4.19 (d, J = 11.5 Hz, 2H), 4.09 (t, J = 5.5 Hz, 1H), 4.06 - 3.97 (m, 3H), 3.68 (dd, J = 10.5, 4.8 Hz, 2H), 3.65 - 3.60 (m, 4H), 3.28 (s, 4H), 2.96 (d, J = 6.0 Hz, 4H), 2.90 - 2.82 (m, 1H), 2.58 (s, 3H), 2.53 (d, J = 13.6 Hz, 1H), 2.15 (dd, J = 16.8, 6.5 Hz, 1H), 2.10 - 2.02 (m, 2H), 1.99 - 1.92 (m, 1H), 1.83 (d, J = 13.0 Hz, 1H), 1.64 (q, J = 7.6, 7.2 Hz, 2H), 1.53 (dd, J = 14.1, 7.5 Hz, 1H), 1.35 (s, 3H), 1.10 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 5.9 Hz, 3H). High resolution mass spectrometry (ESI + ) 79 94 Cl2N9O 26 + Theoretical [M+H] 2+ m / z 843.7738, found m / z 843.7738

[0180] ​​Example 22

[0181] Compound van017 (60 mg, 0.04 mmol) was dissolved in a single port reaction vial containing 1 mL H2O and 1 mL acetonitrile, to which was added slowly, with stirring, aminomethyl phosphonic acid (34.7 mg, 0.31 mmol) and DIPEA (136.1 μL, 0.781 mmol) in sequence, stirred at room temperature for 2 min, then the reaction was transferred to a low temperature reaction condition at -10 °C, after the reaction temperature dropped to -10 °C, a 37% formaldehyde solution (3.7 μL, 0.049 mmol) was added dropwise to the above reaction system, stirred overnight, the reaction progress was monitored by analytical RP-HPLC, when the reaction no longer continued, the reaction was quenched with TFA to weakly acidic pH. Directly purified by preparative RP-HPLC, the target component was collected by freeze-drying to obtain the trifluoroacetate salt of van022 (12.8 mg, yield 25%) as a white fluffy solid.

[0182] R.T. = 17.260 min and 17.332 min (analytical HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.77 (s, 1H), 8.62 (s, 1H), 7.85 (d, J = 8.4 Hz, 3H), 7.79 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.15 (s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.82 - 6.78 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 5.76 (s, 1H), 5.63 (s, 1H), 5.33 - 5.27 (m, 2H), 5.20 - 5.15 (m, 1H), 5.14 (s, 1H), 5.11 (s, 1H), 4.88 (s, 1H), 4.70 - 4.62 (m, 1H), 4.48 - 4.44 (m, 1H), 4.43 (d, J = 5.7 Hz, 1H), 4.40 - 4.35 (m, 1H), 4.34 - 4.24 (m, 1H), 4.21 - 4.13 (m, 1H), 4.13 - 4.06 (m, 2H), 3.68 (d, J = 10.7 Hz, 1H), 3.28 (d, J = 7.7 Hz, 4H), 2.97 (d, J = 9.7, 1.6 Hz, 3H), 2.92 - 2.81 (m, 1H), 2.71 - 2.62 (m, 2H), 2.60 (s, 3H), 2.15 - 2.00 (m, 2H), 1.99 - 1.90 (m, 0H), 1.83 (d, J = 13.1 Hz, 1H), 1.73 - 1.62 (m, 2H), 1.59 - 1.49 (m, 1H), 1.37 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H). High resolution mass spectrometry (ESI + ) 88 103 Cl2F3N 10 O 29 PS + Theoretical [M+H] 2+ m / z 977.2876, found m / z 977.2888.

[0183] Example 23

[0184] ​The first step in Example 22 was replaced with aminoethyl β-D-galactopyranoside, and the remaining starting materials, reagents and preparation methods were the same as Example 22 to give the trifluoroacetate salt of van023 (22.4 mg, 33% yield).

[0185] R.T. = 16.997 min and 17.079 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.82 (s, 1H), 8.64 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.82-7.78 (m, 3H), 7.74-7.70 (m, 2H), 7.63 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.84-6.77 (m, 2H), 6.55 (s, 1H), 5.74 (d, J = 7.2 Hz, 1H), 5.70 (s, 1H), 5.34-5.26 (m, 2H), 5.16-5.12 (m, 2H), 5.11 (s, 1H), 4.83 (s, 1H), 4.50-4.45 (m, 1H), 4.43 (d, J = 5.7 Hz, 1H), 4.38 (dt, J = 8.6, 4.2 Hz, 1H), 4.23-4.12 (m, 3H), 4.12-4.05 (m, 3H), 4.05-3.95 (m, 2H), 3.85-3.78 (m, 1H), 3.68 (d, J = 10.5 Hz, 1H), 3.65-3.59 (m, 2H), 3.40 (t, J = 6.3 Hz, 1H), 3.36-3.24 (m, 5H), 3.12 (s, 2H), 2.97 (d, J = 9.2, 1.4 Hz, 3H), 2.89 (s, 1H), 2.59 (s, 3H), 2.17-2.01 (m, 3H), 1.99-1.92 (m, 1H), 1.84 (d, J = 12.9 Hz, 1H), 1.70-1.62 (m, 2H), 1.57-1.47 (m, 1H), 1.37 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 95 H 114 Cl2F3N 10 O 32S + Theoretical [M+H] 2+ m / z 1033.3362, actual m / z 1033.3378.

[0186] Example 24

[0187] Example 15 was repeated using van 017 as starting material instead of van 002, and the other required materials, reagents and procedures as described in Example 15 to give the trifluoroacetate salt of van 024 (17.4 mg, 59% yield).

[0188] R.T. = 19.628 min (analytical HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ8.73 (s, 1H), 8.56 (s, 1H), 7.85 (d, J = 8.3Hz, 3H), 7.78 (d, J = 8.3Hz, 2H), 7.71-7.66 (m, 2H), 7.53 (d, J = 8 .3Hz, 1H), 7.49-7.43 (m, 1H), 7.32 (d, J=8.3Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 7.16 (s, 1H), 7.10-7.01 (m, 2H), 6 .78 (dd, J=8.4, 1.9Hz, 1H), 6.72 (d, J=8.6Hz, 2H), 6.40 (d, J=2.3Hz, 1H), 6.25 (d, J=2.3Hz, 1H), 5.75 (d, J=7. 0Hz, 1H), 5.61 (s, 1H), 5.31 (d, J=7.7Hz, 1H), 5.29-5.23 (m, 1H), 5.18 (s, 1H), 5.16 (s, 1H), 5.11 (s, 1H), 4.91 (s, 1H), 4.63 (d, J = 6.7Hz, 1H), 4.45 (d, J = 5.5Hz, 1H), 4.43 (d, J = 5.6Hz, 1H), 4.19 (d, J = 11.3Hz, 2H), 4.06-3. 91 (m, 3H), 3.68 (d, J = 10.8Hz, 1H), 3.31-3.22 (m, 3H), 2.87 (s, 1H), 2.82 (s, 1H), 2.74 (ddd, J = 13.4, 5.4, 2.0H z, 1H), 2.67–2.56 (m, 6H), 2.19–2.09 (m, 1H), 1.97 (d, J = 11.7 Hz, 1H), 1.90–1.76 (m, 3H), 1.71–1.60 (m, 2H), 1.59–1.50 (m, 1H), 1.34 (s, 3H), 1.09 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.1 Hz, 3H). High-resolution mass spectrometry (ESI) + C 85 H 94 Cl2F3N9O 26 Theoretical value of S [M+2H] 2+ m / z 908.7758, actual value is m / z 908.7780.

[0189] Example 25

[0190] First Step: Dissolve commercially available vancomycin hydrochloride (400 mg, 0.269 mmol) in a single-mouth reaction vial containing 7 mL H2O and 7 mL acetonitrile, slowly add 3- methylthiopropylamine (241.54 μL, 2.154 mmol) and DIPEA (937.8 μL, 5.384 mmol) sequentially while stirring, stir at room temperature for 2 min, then transfer the reaction system to a low-temperature reaction condition of -10 °C, after the temperature of the reaction system drops to -10 °C, add 37% formaldehyde solution (26.3 μL, 0.337 mmol) dropwise to the above reaction system, stir overnight, monitor the reaction progress by analytical RP-HPLC, when the reaction no longer continues, quench the reaction by adjusting the pH of the reaction system to weakly acidic with TFA. Directly separate and purify with preparative RP-HPLC, freeze-dry the collected target component to obtain white fluffy solid vanc (175 mg, yield 42%).

[0191] R.T. = 11.453 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 7.82 (s, 1H), 7.58 (s, 1H), 7.55-7.50 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 11.3 Hz, 1H), 6.55 (s, 1H), 5.72 (d, J = 7.6 Hz, 1H), 5.66 (s, 1H), 5.30-5.21 (m, 2H), 5.16 (d, J = 4.5 Hz, 2H), 5.12 (d, J = 2.0 Hz, 1H), 4.85 (s, 1H), 4.67 (q, J = 6.6 Hz, 1H), 4.49-4.41 (m, 2H), 4.17-4.07 (m, 4H), 4.04-3.98 (m, 1H), 3.30-3.24 (m, 2H), 3.19 (s, 1H), 3.00 (t, J = 7.8 Hz, 2H), 2.61 (s, 3H), 2.04 (s, 3H), 1.98-1.85 (m, 3H), 1.74 (d, J = 13.1 Hz, 1H), 1.71-1.60 (m, 2H), 1.58-1.48 (m, 1H), 1.31 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 71 H86 Cl2N 10 O 24 S[M+2H] 2+ Theoretical m / z 783.2535, found m / z 783.2526.

[0192] Second step: vanc (20 mg, 0.0128 mmol) was dispersed in a 5 mL centrifuge tube containing 2 mL of glacial acetic acid, vortexed until the system was uniform, and 2-{[(4-phenylphenyl)oxy]methyl}oxirane (3) (28.94 mg, 0.128 mmol) was added to the above reaction system. The reaction was carried out on a constant temperature shaker at 40°C for 24 h until the reaction was basically completed as monitored by analytical RP-HPLC. The glacial acetic acid was removed by nitrogen blowing, and water and acetonitrile were added to dissolve the crude product. The crude product was directly separated and purified by preparative RP-HPLC, and after the target component was collected, it was freeze-dried to obtain the trifluoroacetate salt of van025 (5.8 mg, yield 25%) as a white fluffy solid.

[0193] R.T. = 15.236 min (analytical HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 7.81 (s, 1H), 7.67 - 7.58 (m, 5H), 7.51 (d, J = 8.6 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 8.1, 6.3 Hz, 2H), 7.21 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 9.1 Hz, 2H), 6.56 (s, 1H), 5.74 (d, J = 7.1 Hz, 1H), 5.70 (s, 1H), 5.31 - 5.22 (m, 2H), 5.14 (s, 2H), 5.11 (s, 1H), 4.81 (s, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.51 - 4.45 (m, 1H), 4.44 (d, J = 5.7 Hz, 1H), 4.42 - 4.33 (m, 1H), 4.18 - 4.00 (m, 8H), 3.70 - 3.57 (m, 4H), 3.30 - 3.23 (m, 2H), 3.17 (s, 1H), 3.13 - 3.03 (m, 1H), 2.98 (d, J = 8.9 Hz, 3H), 2.58 (s, 3H), 2.25 - 2.16 (m, 2H), 2.16 - 2.05 (m, 1H), 1.92 (d, J = 10.7 Hz, 1H), 1.73 (d, J = 13.1 Hz, 1H), 1.70 - 1.61 (m, 2H), 1.57 - 1.48 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H). High resolution mass spectrometry (ESI + ) 86 101 10 26 + Theoretical [M+H] 2+ m / z 896.3030, found m / z 896.3028.

[0194] Example 26

[0195] ​​​​The second step in Example 25 was replaced with 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxirane (1) and the remaining starting materials, reagents and procedures were the same as in Example 25 to give the trifluoroacetate salt of van026 (117 mg, 62% yield).

[0196] R.T. = 17.243 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 7.85 (d, J = 8.1 Hz, 2H), 7.81 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.9 Hz, 2H), 6.56 (s, 1H), 5.74 (d, J = 7.0 Hz, 1H), 5.70 (s, 1H), 5.29 - 5.22 (m, 2H), 5.14 (s, 2H), 5.11 (s, 1H), 4.81 (s, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.49 - 4.45 (m, 1H), 4.43 (d, J = 5.7 Hz, 1H), 4.40 - 4.33 (m, 1H), 4.19 - 4.00 (m, 8H), 3.67 (d, J = 10.5 Hz, 1H), 3.65 - 3.58 (m, 1H), 3.31 - 3.22 (m, 2H), 3.17 (s, 1H), 3.13 - 3.05 (m, 2H), 2.98 (d, J = 9.3 Hz, 3H), 2.58 (s, 3H), 2.20 (s, 2H), 2.16 - 2.05 (m, 1H), 1.92 (d, J = 13.6 Hz, 1H), 1.73 (d, J = 13.2 Hz, 1H), 1.69 - 1.62 (m, 3H), 1.56 - 1.48 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 5.9 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 87 H 100 Cl2F3N 10 O 26 S +Theoretical [M+H] 2+ m / z 930.2967, actual m / z 930.2934.

[0197] Example 27

[0198] Example 25, the second step of 2-{[(4-phenylphenyl)oxy]methyl}oxirane was replaced by 2-({[4-(4-chlorophenyl)phenyl]oxy}methyl)oxirane (2), and the rest of the required starting materials, reagents and preparation methods were the same as in Example 25, to obtain the trifluoroacetate salt of van027 (8.6 mg, yield 37%).

[0199] R.T. = 16.558 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 7.81 (s, 1H), 7.67-7.59 (m, 6H), 7.53-7.44 (m, 5H), 7.32 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H), 6.56 (s, 1H), 5.74 (d, J = 7.1 Hz, 1H), 5.70 (s, 1H), 5.30-5.21 (m, 2H), 5.14 (s, 2H), 5.11 (s, 1H), 4.81 (s, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.49-4.45 (m, 1H), 4.43 (d, J = 5.8 Hz, 1H), 4.42-4.32 (m, 1H), 4.16-4.00 (m, 8H), 3.67 (d, J = 10.8 Hz, 1H), 3.65-3.58 (m, 2H), 3.30-3.23 (m, 2H), 3.17 (s, 1H), 3.09 (s, 2H), 2.98 (d, J = 9.1 Hz, 3H), 2.58 (s, 3H), 2.24-2.16 (m, 2H), 2.16-2.09 (m, 1H), 1.90 (d, J = 12.1 Hz, 1H), 1.73 (d, J = 13.1 Hz, 1H), 1.68-1.62 (m, 2H), 1.56-1.47 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 6.1 Hz, 3H). High resolution mass spectrometry (ESI + )C 86 H 100 Cl3N10 O 26 S + Theoretical [M+H] 2+ m / z 913.2832, actual m / z 913.2843.

[0200] Example 28

[0201] Example 25, except that 2-{[(4-phenylphenyl)oxy]methyl}oxirane was replaced by 2-[(phenyloxy)methyl]oxirane, and the remaining starting materials, reagents and methods of preparation were the same as in Example 25, to give van028 trifluoroacetate salt (6.1 mg, 27.8% yield).

[0202] R.T. = 13.323 min and 13.410 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ 8.80 (s, 1H), 8.64 (s, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.2Hz, 1H), 7.47 (d, J = 8.6Hz, 1H), 7.31 (d, J=8.4Hz, 3H), 7.29(s, 1H), 7.21(dd, J=8.4, 7.8Hz, 1H), 7.12(s, 1H), 6.98(s, 1H), 6.95(d, J=7.8Hz, 2H), 6.86(d , J=8.5Hz, 1H), 6.80 (d, J=8.5Hz, 1H), 6.56 (s, 1H), 5.73 (d, J=6.3Hz, 1H), 5.69 (s, 1H), 5.29-5.21 (m, 2H), 5.14 ( s, 2H), 5.11 (s, 1H), 4.80 (s, 1H), 4.66 (q, J=6.7Hz, 1H), 4.50-4.45 (m, 1H), 4.43 (d, J=5.9Hz, 1H), 4.39-4.30 (m, 1 H), 4.13 (s, 1H), 4.06 (s, 1H), 4.01 (d, J=7.6Hz, 3H), 3.67 (d, J=11.2Hz, 1H), 3.64-3.61 (m, 1H), 3.59 (s, 1H), 3.3 8 (s, 1H), 3.26 (d, J=6.0Hz, 2H), 3.17 (s, 1H), 3.07 (s, 2H), 2.97 (d, J=8.6Hz, 3H), 2.72 (s, 1H), 2.58 (s, 3H), 2.26 -2.15 (m, 2H), 2.11 (s, 1H), 1.90 (d, J = 8.8 Hz, 1H), 1.73 (d, J = 13.1 Hz, 1H), 1.65 (q, J = 7.3, 5.7 Hz, 2H), 1.52 (s, 1H), 1.30 (s, 3H), 1.27-1.21 (m, 2H), 1.05 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 6.0 Hz, 3H). High-resolution mass spectrometry (ESI) + C 80 H 97 Cl2N 10 O 26 S + Theoretical value [M+H] 2+ m / z 858.2870, actual value is m / z 858.2869.

[0203] Example 29

[0204] The second step in Example 25 was replaced with (2S)-2-[(phenyloxy)methyl]oxirane instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 25 to give the trifluoroacetate salt of van029 (4.2 mg, 38.2% yield).

[0205] R.T. = 11.923 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.80 (s, 2H), 8.64 (s, 2H), 7.81 (s, 1H), 7.65-7.61 (m, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.3, 1.8 Hz, 1H), 7.34-7.28 (m, 3H), 7.23-7.18 (m, 1H), 7.12 (s, 1H), 6.99-6.93 (m, 4H), 6.87 (dd, J = 8.5, 1.9 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.56 (s, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 5.28-5.23 (m, 2H), 5.16-5.08 (m, 3H), 4.80 (s, 1H), 4.66 (q, J = 6.6 Hz, 1H), 4.47 (d, J = 5.6 Hz, 1H), 4.43 (d, J = 5.8 Hz, 1H), 4.40-4.31 (m, 1H), 4.16-4.08 (m, 3H), 4.05-3.99 (m, 3H), 3.67 (d, J = 10.8 Hz, 1H), 3.61-3.58 (m, 1H), 3.55-3.52 (m, 1H), 3.50-3.48 (m, 1H), 3.40-3.37 (m, 1H), 3.29-3.23 (m, 2H), 3.17 (s, 1H), 3.10-3.04 (m, 2H), 2.97 (d, J = 7.0 Hz, 3H), 2.58 (s, 3H), 2.54 (s, 1H), 2.24-2.09 (m, 4H), 1.90 (d, J = 10.7 Hz, 1H), 1.72 (d, J = 13.1 Hz, 1H), 1.69-1.62 (m, 2H), 1.53 (q, J = 5.3, 4.8 Hz, 2H), 1.30 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H). High resolution mass spectrometry (ESI + )C 80 H 97 Cl2N 10 O26 S + Theoretical [M+H] 2+ m / z 858.2870, actual m / z 858.2858.

[0206] Example 30

[0207] Replace 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 25 with (2R)-2-[(phenyloxy)methyl]oxirane, and the rest of the required starting materials, reagents and preparation methods are the same as Example 25 to give van030 trifluoroacetate salt (5 mg, 45% yield).

[0208] R.T. = 11.705 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D20) δ 8.81 (s, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.00 - 6.93 (m, 3H), 6.87 (dd, J = 8.5, 2.0 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.56 (s, 1H), 5.74 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 5.28 - 5.23 (m, 2H), 5.16 - 5.08 (m, 3H), 4.80 (s, 1H), 4.66 (q, J = 6.6 Hz, 1H), 4.46 (d, J = 5.0 Hz, 1H), 4.43 (d, J = 5.8 Hz, 1H), 4.38 - 4.33 (m, 1H), 4.12 (d, J = 15.0 Hz, 2H), 4.06 - 3.97 (m, 4H), 3.66 (d, J = 9.6 Hz, 1H), 3.61 - 3.58 (m, 1H), 3.53 (d, J = 7.9 Hz, 1H), 3.49 (d, J = 7.4 Hz, 1H), 3.26 (d, J = 6.4 Hz, 2H), 3.17 (s, 1H), 3.12 - 3.03 (m, 3H), 2.97 (d, J = 9.9 Hz, 3H), 2.58 (s, 3H), 2.54 (s, 1H), 2.24 - 2.08 (m, 4H), 1.90 (d, J = 12.7 Hz, 1H), 1.72 (d, J = 13.0 Hz, 1H), 1.69 - 1.63 (m, 2H), 1.56 - 1.47 (m, 2H), 1.30 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 6.2 Hz, 4H). High resolution mass spectrometry (ESI + ) 80 97 10 26 + Theoretical [M+H] 2+ m / z 858.2870, found m / z 858.2864.

[0209] Example 31

[0210] ​​​​The starting material van002 in Example 15 was replaced by van026, and the other required starting materials, reagents and preparation methods were the same as in Example 15 to obtain the trifluoroacetate salt of van031 (29.1 mg, yield 49%).

[0211] R.T. = 19.058 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.81 (s, 1H), 8.65 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.83-7.80 (m, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.70-7.68 (m, 2H), 7.63 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.09-7.04 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 5.77-5.71 (m, 1H), 5.69 (s, 1H), 5.28-5.21 (m, 2H), 5.14 (s, 2H), 5.11 (s, 1H), 4.81 (s, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.48-4.39 (m, 2H), 4.16-4.07 (m, 4H), 4.04 (dd, J = 9.4, 4.2 Hz, 1H), 4.02-3.95 (m, 2H), 3.67 (d, J = 10.8 Hz, 1H), 3.32-3.21 (m, 2H), 3.17 (s, 1H), 3.00 (s, 2H), 2.76 (dd, J = 13.5, 5.2 Hz, 2H), 2.70-2.60 (m, 3H), 2.57 (s, 3H), 2.15-2.07 (m, 1H), 1.99-1.86 (m, 3H), 1.73 (d, J = 13.1 Hz, 1H), 1.69-1.61 (m, 2H), 1.55-1.46 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H). High resolution mass spectrometry (ESI + )C 86 H 97 Cl2F3N 10 O 26 S[M+2H] 2+ m / z 923.2891, actual value m / z 923.2882.

[0212] Example 32

[0213] First Step: Weigh commercially available vancomycin hydrochloride (300 mg, 0.2 mmol), 3-methylthiopropionaldehyde (145.8 mg, 1.4 mmol) into a single-mouth reaction vial containing 4 mL water and 4 mL acetonitrile and stir to dissolve, add 400 μL acetic acid and sodium cyanoborohydride (251.4 mg, 4 mmol) sequentially, transfer the reaction system to an oil bath at 70 °C, and stop the reaction after monitoring by analytical RP-HPLC that the reaction no longer changes further. Directly purify by preparative RP-HPLC, and lyophilize the collected target compound fraction to obtain white fluffy solid vand (95.2 mg, 31% yield).

[0214] R.T. = 13.037 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.76 (br s, 1H), 8.56 (br s, 1H), 7.84 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 6.78 (dd, J = 8.5, 2.0 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 6.40 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.77 (d, J = 7.8 Hz, 1H), 5.61 (s, 1H), 5.26 - 5.21 (m, 2H), 5.17 (d, J = 11.2 Hz, 2H), 5.11 (s, 1H), 4.89 (s, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.20 - 4.06 (m, 2H), 3.67 (d, J = 11.0 Hz, 1H), 3.26 (d, J = 5.2 Hz, 2H), 3.17 (s, 1H), 2.87 (s, 3H), 2.08 (s, 3H), 2.06 (s, 1H), 1.90 (d, J = 11.6 Hz, 1H), 1.84 - 1.76 (m, 1H), 1.73 (d, J = 13.0 Hz, 1H), 1.67 - 1.57 (m, 1H), 1.56 - 1.47 (m, 1H), 1.28 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 2.08 (d, J = 5.0 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H). High resolution mass spectrometry (ESI + ) C70 H 83 Cl2N9O 24 S theoretical value [M+2H] 2+ m / z 768.7403, actual value m / z 768.7401.

[0215] Second step: vanc (10 mg, 0.013 mmol) was dispersed in a 5 mL centrifuge tube containing 2 mL of glacial acetic acid, vortexed until the system was uniform, and 2-{[(4-phenylphenyl)oxy]methyl}oxirane (3) (14.7 mg, 0.13 mmol) was added to the above reaction system. The reaction was carried out on a constant temperature shaker at 40°C for 24 h until the reaction was basically completed as monitored by analytical RP-HPLC. The glacial acetic acid was removed by nitrogen blowing, and water and acetonitrile were added to dissolve the crude product. Directly, preparative RP-HPLC was used for separation and purification. After the target component was collected, it was freeze-dried to obtain the trifluoroacetate salt of van032 (14.6 mg, yield 63%) as a white fluffy solid.

[0216] R.T. = 16.299 min (analytical HPLC). 1H NMR (600MHz, DMSO-d6 with 20μL D2O) δ7.84 (s, 1H), 7.64-7.59 (m, 5H), 7.54 (d, J = 8.4Hz, 1H), 7.49-7.46 (m, 1H), 7.44 (t, J =7.7Hz, 2H), 7.36-7.30 (m, 2H), 7.16 (s, 1H), 7.06 (d, J = 8.6Hz, 2H), 6.78 (dd, J = 8.4, 1.9Hz , 1H), 6.72 (d, J=8.6Hz, 1H), 6.40 (d, J=2.3Hz, 1H), 6.25 (d, J=2.3Hz, 1H), 5.75 (d, J=7.8H z, 1H), 5.58 (s, 1H), 5.24 (dd, J=9.0, 5.8Hz, 2H), 5.18 (d, J=5.1Hz, 2H), 5.11 (s, 1H), 4.88 ( s, 1H), 4.67 (q, J=6.7Hz, 1H), 4.49-4.41 (m, 2H), 4.41-4.34 (m, 1H), 4.23-4.13 (m, 1H), 4. 12-4.03 (m, J=4.6Hz, 2H), 3.67 (d, J=10.0Hz, 1H), 3.47-3.39 (m, 1H), 3.31-3.21 (m, 2H), 3. 17 (s, 1H), 3.00 (d, J = 8.4 Hz, 3H), 2.19–2.04 (m, 2H), 1.93–1.86 (m, 1H), 1.74 (t, J = 12.9 Hz, 1H), 1.55 (s, 2H), 1.28 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.86 (s, 3H). High-resolution mass spectrometry (ESI) + C 85 H 98 Cl2N9O 26 S + Theoretical value [M+2H] 2+ m / z 881.7897, actual value is m / z 881.7890.

[0217] Example 33

[0218] In the second step of Example 32, 2-{[(4-phenylphenyl)oxy]methyl}oxetine was replaced with 2-[({4-[4-(trifluoromethyl)phenyl]phenyl}oxy)methyl]oxetine (1), and the other required raw materials, reagents and preparation methods were the same as in Example 32, to obtain the trifluoroacetate of van033 (5.9 mg, yield 25%).

[0219] R.T. = 18.278 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 7.87-7.83 (m, 3H), 7.79 (d, J = 8.3 Hz, 2H), 7.75-7.70 (m, 2H), 7.53 (d, J = 8.5 Hz, IH), 7.50-7.45 (m, IH), 7.35 (d, J = 8.3 Hz, IH), 7.21 (s, IH), 7.15 (s, IH), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.6 Hz, IH), 6.72 (d, J = 8.4 Hz, IH), 6.40 (d, J = 2.3 Hz, IH), 6.25 (d, J = 2.3 Hz, IH), 5.76 (d, J = 7.7 Hz, IH), 5.60 (s, IH), 5.28-5.21 (m, 2H), 5.17 (s, 2H), 5.11 (s, IH), 4.87 (s, IH), 4.67 (d, J = 6.9 Hz, IH), 4.47-4.42 (m, 2H), 4.39 (s, IH), 4.23-4.14 (m, IH), 4.10 (s, 2H), 3.67 (d, J = 10.2 Hz, IH), 3.30-3.21 (m, 2H), 3.17 (s, IH), 3.00 (d, J = 8.9 Hz, 3H), 2.18-2.05 (m, IH), 1.90 (d, J = 12.0 Hz, IH), 1.72 (d, J = 13.1 Hz, IH), 1.56 (s, IH), 1.28 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (s, 3H), 0.87 (s, 3H). High resolution mass spectrometry (ESI + )C 86 H 97 Cl2F3N9O 26 S + Theoretical [M+H] 2+ m / z 915.7834, found m / z 915.7823.

[0220] Example 34

[0221] Example 32, replacing 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step with 2-({[4-(4-chlorophenyl)phenyl]oxy}methyl)oxirane (2), and using the remaining starting materials, reagents, and methods described in Example 32, to give van034 trifluoroacetate salt (10.3 mg, 44% yield).

[0222] R.T. = 17.610 min (analytical HPLC). 1 H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 7.84 (s, 1H), 7.64 (dd, J = 8.5, 6.3 Hz, 4H), 7.53 (d, J = 8.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.47 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81-6.75 (m, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.76 (d, J = 7.8 Hz, 1H), 5.60 (s, 1H), 5.28-5.22 (m, 2H), 5.17 (s, 2H), 5.11 (s, 1H), 4.87 (s, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.48-4.41 (m, 2H), 4.41-4.34 (m, 1H), 4.22-4.13 (m, 2H), 4.08 (s, 2H), 3.67 (d, J = 10.7 Hz, 1H), 3.26 (d, J = 10.5 Hz, 2H), 3.17 (s, 1H), 3.00 (d, J = 8.8 Hz, 3H), 2.20-2.01 (m, 1H), 1.94-1.84 (m, 1H), 1.72 (d, J = 13.1 Hz, 1H), 1.62-1.44 (m, 1H), 1.28 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (s, 3H), 0.87 (s, 3H). High resolution mass spectrometry (ESI + )C 85 H 97 Cl3N9O 26 S + Theoretical [M+H] 2+ m / z 898.7699, found m / z 898.7706.

[0223] Example 35

[0224] Example 32, except that 2-{[(4-phenylphenyl)oxy]methyl}oxirane in the second step of Example 32 was replaced with 2-[(phenyloxy)methyl]oxirane, and the remaining starting materials, reagents, and methods of preparation were the same as in Example 32, to give van035 trifluoroacetate salt (7.2 mg, 32.8% yield).

[0225] R.T. = 14.730 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6with 20 μL D2O) δ 8.72 (s, 1H), 8.54 (s, 1H), 7.83 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.33-7.32 (m, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.15 (s, 1H), 6.99-6.91 (m, 3H), 6.77 (dd, J = 8.5, 2.0 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.75 (d, J = 7.4 Hz, 1H), 5.59 (s, 1H), 5.27-5.22 (m, 2H), 5.17 (s, 2H), 5.11 (s, 1H), 4.89-4.82 (m, 1H), 4.66 (q, J = 6.7 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 4.35 (s, 1H), 4.17 (s, 1H), 4.01 (dt, J = 9.9, 5.3 Hz, 3H), 3.67 (s, 1H), 3.66 (s, 1H), 3.59 (d, J = 18.2 Hz, 2H), 3.54 (d, J = 8.9 Hz, 2H), 3.42 (s, 3H), 3.29-3.21 (m, 2H), 3.16 (s, 1H), 2.98 (d, J = 8.1 Hz, 3H), 2.25-2.03 (m, 3H), 1.89 (d, J = 12.4 Hz, 1H), 1.72 (d, J = 13.2 Hz, 2H), 1.55 (s, 2H), 1.28 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.91 (s, 3H), 0.86 (d, J = 5.6 Hz, 3H). High resolution mass spectrometry (ESI + )C 79 H 94 Cl2N9O 26 S + Theoretical [M+H] 2+ m / z 843.7738, found m / z 843.7737.

[0226] Example 36

[0227] The second step in Example 32 was replaced with (2S)-2-[(phenyloxy)methyl]oxirane instead of 2-{[(4-phenylphenyl)oxy]methyl}oxirane, and the remaining starting materials, reagents, and preparation methods were the same as in Example 32 to give the trifluoroacetate salt of van036 (2.8 mg, 13% yield).

[0228] R.T. = 12.778 min (analytical RP-HPLC). 1 H NMR (600 MHz, DMSO-d6with 20 μL D2O) δ 8.67 (s, 1H), 8.51 (s, 1H), 7.83 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.28 (d, J = 1.8 Hz, 2H), 7.27 (d, J = 1.7 Hz, 2H), 7.26 (s, 1H), 7.15 (s, 1H), 6.92 (s, 3H), 6.77 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.73 (d, J = 8.0 Hz, 1H), 5.55 (s, 1H), 5.28 - 5.22 (m, 2H), 5.17 (d, J = 12.0 Hz, 2H), 5.10 (s, 1H), 4.85 (s, 1H), 4.66 (d, J = 6.6 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 4.34 (s, 1H), 4.18 (s, 1H), 4.00 (s, 2H), 3.97 (dd, J = 9.8, 4.2 Hz, 3H), 3.84 - 3.81 (m, 2H), 3.77 (dd, J = 5.9, 4.2 Hz, 2H), 3.67 (d, J = 10.6 Hz, 1H), 3.52 (d, J = 6.5 Hz, 3H), 3.39 - 3.21 (m, 4H), 3.15 (d, J = 2.4 Hz, 1H), 2.96 (d, J = 7.4 Hz, 3H), 2.11 (d, J = 34.2 Hz, 1H), 2.00 - 1.90 (m, 2H), 1.88 (s, 1H), 1.72 (d, J = 13.1 Hz, 1H), 1.55 (s, 2H), 1.36 (s, 1H), 1.28 (s, 3H), 1.23 (d, J = 4.3 Hz, 3H), 0.86 (d, J = 18.4 Hz, 6H). High resolution mass spectrometry (ESI + )C 79 H 94 Cl2N9O 26 S +Theoretical [M+H] 2+ m / z 843.7738, found m / z 843.7745.

[0229] Example 37

[0230] Example 32, using (2R)-2-[(phenyloxy)methyl]oxirane instead of 2-{[(4- phenylphenyl)oxy]methyl}oxirane in the second step, and the remaining starting materials, reagents and methods of preparation are the same as in Example 32, to give the trifluoroacetate salt of van037 (2.5 mg, 11% yield).

[0231] R.T. = 12.747 min (analytical RP-HPLC). 1H NMR (600 MHz, DMSO-d6 with 20 μL D2O) δ 8.67 (s, 1H), 8.51 (s, 1H), 7.83 (s, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.29 (d, J = 5.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 6.93 - 6.91 (m, 3H), 6.77 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.73 (d, J = 8.8 Hz, 1H), 5.54 (s, 1H), 5.31 - 5.21 (m, 2H), 5.17 (d, J = 13.8 Hz, 2H), 5.10 (s, 1H), 4.85 (s, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 4.33 (s, 2H), 4.18 (s, 1H), 4.01 (s, 2H), 3.97 (dd, J = 9.8, 4.2 Hz, 2H), 3.83 (dd, J = 9.8, 6.2 Hz, 2H), 3.80 - 3.74 (m, 2H), 3.67 (d, J = 10.7 Hz, 2H), 3.37 - 3.23 (m, 3H), 3.15 (d, J = 2.5 Hz, 1H), 2.96 (d, J = 11.7 Hz, 3H), 2.19 - 2.07 (m, 1H), 2.02 - 1.91 (m, 2H), 1.89 (d, J = 12.6 Hz, 1H), 1.82 - 1.75 (m, 1H), 1.72 (d, J = 13.1 Hz, 1H), 1.53 (dd, J = 15.1, 7.6 Hz, 2H), 1.28 (s, 3H), 1.22 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H). High resolution mass spectrometry (ESI + )C 79 H 94 Cl2N9O 26 S + Theoretical [M+H] 2+ m / z 843.7738, found m / z 843.7747.

[0232] Activity test:

[0233] Biological test example 1 In vitro antibacterial activity test

[0234] The in vitro antibacterial activity of vancomycin, daptomycin, oritavancin, linezolid and 37 compounds of the present application (all the compounds of the present application used in the following biological test examples 1 and 2-8 are trifluoroacetate salts of the corresponding numbered compounds, for convenience, only the compound number is recorded; the vancomycin used is vancomycin hydrochloride, and the oritavancin used is a diphosphate salt, for convenience, only the drug prototype name is recorded) was tested. According to the U.S. Clinical Laboratory Standards Committee (CLSI) drug sensitivity test standard, based on WS / T 639-2018 Technical Requirements for Antimicrobial Sensitivity Test and CLSI M-100 Execution Standard for Antimicrobial Sensitivity Test, the minimal inhibitory concentration (MIC) of the compounds was determined.

[0235] The test strains were vancomycin-sensitive Staphylococcus aureus (Staphylococcus aureus Newman strain, referred to as Newman strain), vancomycin-intermediate Staphylococcus aureus (Staphylococcus aureus Mu50 strain, referred to as Mu50 strain), methicillin-resistant Staphylococcus aureus (Staphylococcus aureus USA300 strain, referred to as USA300 strain), and vancomycin-resistant Enterococcus faecium (VRE, VanA phenotype Efm-HS0649 strain, VanM phenotype Efm-HS08257 strain, and VanB phenotype VanB(R) strain) and vancomycin-resistant Enterococcus faecalis (VRE, VanB phenotype). The antibacterial activity of the compounds on 5 strains of gram-negative bacteria was also tested, and the test strains were Escherichia coli (Escherichia coli, AB1157 strain), Acinetobacter baumannii 1 (Acinetobacter baumannii, clinical isolate), Acinetobacter baumannii 2 (Acinetobacter baumannii, ATCC19606), Klebsiella pneumoniae (clinical isolate), Pseudomonas aeruginosa PAO1. The above-mentioned related strains were derived from Shanghai Renji Hospital.

[0236] In the test, 100 μL of each different concentration (256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 mg / L) of the test drug solution was taken into the first to the twelfth holes of a sterilized 96-hole polystyrene plate, and 100 μL of the test bacterial solution (200 μL per hole) was added to each hole, with a final concentration of about 10 5 CFU / mL, so that the final drug concentration was 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 mg / L and lower 2-fold dilution concentration (diluted to an additional 96-hole polystyrene plate). Each test was set with 1 duplicate well. After sealing, it was placed in a 35-37°C incubator for 16-24h, and the results were judged. The lowest drug concentration that completely inhibited bacterial growth in the small hole was its minimal inhibitory concentration (MIC). The results are shown in Tables 1, 2 and 3.

[0237] Table 1 Test results of the antibacterial activity of the compounds of the present application in vitro against Staphylococcus aureus

[0238] Table 2 Test results of the antibacterial activity of the compounds of the present application in vitro against Enterococcus

[0239] Table 3 Test results of the antibacterial activity of the compounds of the present application in vitro against Gram-negative bacteria

[0240] The above in vitro antibacterial activity studies show that the vancomycin analogs represented by the examples of the present application have antibacterial activity against vancomycin-resistant Staphylococcus aureus and drug-resistant Enterococcus, most of which is higher than that of vancomycin, and the antibacterial activity of some compounds is more than 64 times that of vancomycin, and individual strains show an activity of 10 orders of magnitude higher than that of vancomycin. In terms of Gram-negative bacteria, the activity of some preferred compounds is enhanced by 4-32 times compared with vancomycin. The antibacterial experiment shows that the novel vancomycin analogs involved in the present application can significantly enhance their antibacterial activity and show the potential of inherent resistance to Gram-negative bacteria.

[0241] Biological test example 2 cytotoxicity and acute toxicity evaluation experiment in mice

[0242] In order to investigate the toxicity of the compounds, we verified the safety of the cytotoxicity and the safety of the single intravenous administration of mice.

[0243] Cell cytotoxicity experiments were performed using the compounds van017 and van024 of the present application, with N V - trifluoromethylbiphenylmethylvancomycin 3m (compound from J. Med. Chem. 2018, 61, 286-304), vancomycin, and oritavancin as control compounds. The selected cells were AML12: mouse liver cells, H9C2: rat myocardial cells, and HEK293: human embryonic kidney cells. The above cells were from Shandong Second Medical University. Three groups of experiments were set up according to the different cells. Cell viability was determined using the Cell Counting Kit-8 (CCK8) method.

[0244] Cells in the logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density (about 5000 cells) and 90 μL per well. After overnight culture, the drug solution concentrations of van017, van024, 3m, vancomycin, and oritavancin were set at 25 mg / L, 50 mg / L, and 100 mg / L, respectively, and 10 μL of drug solution was added to each well for 24 h. Three replicate wells were set up for each concentration, and the corresponding concentration of normal saline vehicle control and cell-free zeroing wells were set up. After the end of the action, 10 μL of CCK8 detection solution was added to each well, and the plates were placed in a 37°C cell incubator for about 1.5 h. The optical density (OD value) at 450 nm wavelength was determined using a VERSMax enzyme marker. The OD value was converted to cell viability value

conversion formula: cell viability value = OD C / OD C＝0 × 100, where C represents the concentration

[0245] The cytotoxicity showed that the compound van017 still showed cell viability comparable to the vancomycin group at a concentration of 100 mg / L, proving that this type of aromatic sulfonium-modified derivative has high safety. And the cell viability value of van017 at 50 mg / L and 100 mg / L in HEK293 cells was higher than that of 3m and oritavancin, showing that the safety is better than that of 3m and oritavancin.

[0246] In the toxicity evaluation experiment, we further investigated the safety of the compound van017 group and the van026 group in mice. The positive control was the oritavancin group. Each group of 3 healthy ICR mice was subjected to acute toxicity test, and the mice were directly injected with drugs (slowly injected with drug solution) via the tail vein. The drug dose of each administration group was 40 mg / kg, and the drug volume for each mouse was 0.1 mL / 10 g. The physical changes of the mice were observed and recorded within 7 days, and the safety of the drugs was evaluated. The results showed that all the mice survived, indicating that the minimum lethal dose of van017 and van026 in mice was higher than 40 mg / kg.

[0247] Hemolytic toxicity test

[0248] To verify the hemolytic toxicity of the compounds, fresh rat blood was extracted to test the hemolysis of the compounds. First, the fresh blood was diluted 4 times with PBS buffer (Solarbio, China), centrifuged at 3000 rpm for 10 minutes, repeated 5-6 times until the supernatant was colorless and transparent, to collect the red blood cells. The washed red blood cells were configured into an 8% red blood cell suspension with PBS buffer. The compounds were diluted into different concentration gradients (10 mg / L, 20 mg / L, 30 mg / L) and added to the prepared red blood cell suspension, incubated at 37°C for 1 hour. Blank control (only red blood cells) and positive control (red blood cells containing 0.1% Triton X-100) were set as references. After 1 hour, centrifuged at 3000 rpm for 3 minutes, the hemolysis effect was observed directly by taking pictures, and then the supernatant was carefully transferred to a 96-well plate to obtain the absorbance at 540 nm. t , Ab p and Ab n are defined as the absorbance values of the test, positive control and negative control, respectively. The calculation method of hemolysis rate is: hemolysis rate = [(Ab t - Ab n ) / (Ab p - Ab n )] x 100. As shown in Figure 2.

[0249] The above experiments prove that the compounds van017 and van026 have no hemolytic toxicity at a drug concentration of 30 mg / L.

[0250] Example 4: In vivo pharmacokinetic experiment in mice

[0251] The compounds van017 and van026 of the present application and the positive compound vancomycin were selected for the in vivo pharmacokinetic experiment in mice, wherein the male mice (CD-1 mice) used were all from the Shanghai Laboratory Animal Center of the Chinese Academy of Sciences, and were grown to 20-22 g under the conditions of 18-29°C and humidity range of 30-70%.

[0252] The solution of the above-mentioned corresponding compound was injected into the tail vein, and blood samples were taken at 0.05 h, 0.25 h, 0.75 h, 2 h, 4 h, 8 h and 24 h (femoral vein blood collection) for a total of 7 time points. The drug concentrations (ng / mL) in the plasma of the mice at different times were detected by LC-MS / MS, and the pharmacokinetic software WinNonlin 6.4 was used to obtain the corresponding half-life T 1 / 2 , the area under the drug concentration-time curve AUC, the plasma clearance CL, the mean residence time MRT, and the distribution volume Vss calculated when the drug reached steady state in the body. The specific results are shown in Table 4.

[0253] From the results of Table 4, the two compounds of the present application have longer half-life T 1 / 2 than vancomycin, and the area under the concentration-time curve AUC is 20-30 times larger than that of vancomycin. In terms of plasma clearance CL, the two compounds of the present application are slower than vancomycin, showing good drugability parameters superior to the positive compound.

[0254] Table 4 Experimental results of mouse in vivo pharmacokinetics of representative compounds of the present application

[0255] Note: AUC last : Area under the concentration-time curve from the start of dosing to the last point; AUC INF_obs : Area under the concentration-time curve from the start of dosing to the theoretical extrapolation to infinity; MRT INF_obs : Mean residence time from the start of dosing to the theoretical extrapolation to infinity; V SS_obs : Volume of distribution at steady state in humans (the higher the plasma protein binding, the smaller the Vss); obs is observed, i.e. measured, and INF is infinity.

[0256] Biological Test Example 5 In vivo efficacy experiment in mice

[0257] In order to determine the in vivo efficacy of the preferred compounds, we carried out in vivo protection experiments in a systemic infection model of two resistant strains (MRSA strain, VRE strain) to evaluate the in vivo efficacy of vancomycin derivatives.

[0258] In the in vivo efficacy experiment of MRSA strain (USA300 LAC) infection, we carried out in vivo efficacy experiments using a single dose of administration. Forty 8-week-old female BALB / c mice were randomly divided into four groups (van017 group, van026 group, blank group, control vancomycin group), 10 mice in each group, and challenged with 1x10 8 CFU of USA300 LAC strain, and administered 1 hour later at a drug dose of 7 mg / kg, and the survival rate was observed for 7 days, and it was found that the mice did not die, and the results are shown in Figure 3.

[0259] In the in vivo efficacy experiment of VRE strain (SC-2022-D2-059, VanA phenotype) infection, we carried out in vivo efficacy experiments using multiple doses of administration.

[0260] Take 72 healthy ICR mice, randomly divided into groups, 6 mice in each group, half male and half female (3 males and 3 females each). Different dilution concentrations of bacterial solution were taken and injected into the mice intraperitoneally, 0.5 mL per mouse. After infection, observe for 7 days and record the number of dead mice. The minimum amount of bacteria that causes 100% mortality of mice is used as the minimum lethal dose, and the amount of bacteria is used as the infection amount of the in vivo protection test. According to the results of the MLD experiment, use 4.5x10 8 CFU / mL of bacteria as the infection amount of the in vivo protection test.

[0261] Take 72 healthy ICR mice, randomly divided into groups, 6 mice in each group, half male and half female (3 males and 3 females each). According to the results of the MLD experiment, use 5% gastric mucosa to prepare the initial inoculation bacterial suspension to the MLD bacterial concentration. The compounds van017, van026 and vancomycin of the present application are respectively dissolved in sterile water to prepare a solution, and the drug doses of van017 and van026 are set to 20 mg / kg, 10 mg / kg, 5 mg / kg, 2.5 mg / kg, 1.25 mg / kg, 0.625 mg / kg, and the drug dose of vancomycin is set to 20 mg / kg, 10 mg / kg, and the drug dose of oritavancin is set to 2.5 mg / kg, 0.625 mg / kg. On the day of infection, all groups except the blank group were infected with MLD bacterial solution (10 8 CFU / mL) intraperitoneally. Each administration group was injected with the designed dose of drug intravenously 1 hour after infection (each mouse was slowly injected with drug solution), and the volume of drug administered to each mouse was 0.1 mL / 10 g. The mortality of mice was observed and recorded within 7 days. The results are shown in Figure 4.

[0262] The results show that the survival rate of mice in the compound van017 (2.5 / 5 / 10 / 20 mg / kg) group reached 100%, the survival rate of mice in the compound van017 (1.25 mg / kg) group reached 66.7%, and the survival rate of mice in the compound van017 (0.625 mg / kg) group reached 33.3%. The survival rate of mice in the compound van026 (2.5 mg / kg) group was 0%, the survival rate of mice in the compound van026 (5 mg / kg) group was 50%, and the survival rate of mice in the compound van026 (10 / 20 mg / kg) group reached 100%. The survival rate of mice in the vancomycin hydrochloride (20 / 10 mg / kg) group was 0%. The survival rate of mice in the oritavancin (2.5 mg / kg) group reached 83.3%, and the survival rate of mice in the oritavancin (0.625 mg / kg) group reached 33.3%.

[0263] The above in vivo pharmacodynamic studies show that van017 and van026 of the present application have significant in vivo protective benefits on the above two drug-resistant bacteria systemic infection models, and the in vivo efficacy is much better than that of vancomycin. Among them, the in vivo efficacy of compound van017 is better than that of van026 in the VRE infection protection model, and is equivalent to or better than that of oritavancin.

[0264] Biological test example 6 mechanism of action verification experiment

[0265] Next, the mechanism of action of the compounds of the present application was studied, and the effect on the integrity of the bacterial cell membrane was evaluated and verified mainly through cell membrane permeability and depolarization test experiments.

[0266] The specific steps of the permeability experiment are as follows: the overnight culture of vancomycin-resistant Enterococcus faecium (VanA, Efm-HS-0649) and methicillin-resistant Staphylococcus aureus (USA300 LAC) was transferred to fresh tryptone soybean broth (TSB) and cultured for 3 hours (USA300 LAC) or 6 hours (Efm-HS-0649) to reach the exponential growth phase of the strain. The bacterial cells were collected and washed once with sterile PBS buffer, then suspended in 5mM glucose and 5mM HEPES buffer (1:1, 500mL, pH=7.2) and the OD value was adjusted to 0.6. 130μL of bacterial suspension was added to a 96-well black Costar plate, followed by the addition of 10μL of propidium iodide dye (PI, 150μM DMSO stock solution), and different concentrations of test compound were added to each well, 10μL per well, and mixed several times with a pipette. Each sample was tested three times. The fluorescence intensity was detected and recorded with an enzyme marker for the next 40 minutes, recording once every minute, with an excitation wavelength of 510nm and an emission wavelength of 620nm. The experimental results are shown in Figure 5a. 600

[0267] The specific steps of the cell membrane depolarization experiment are as follows: the cell membrane site is mainly through DiSC 35 ​The fluorescence intensity was measured by a fluorescence plate reader (FLUOstar OPTIMA, BMG LABTECH) at 665 nm emission wavelength and 595 nm excitation wavelength. The results are shown in Figure 5(b).

[0268] The above experiments prove that compounds van017 and van026 can increase the permeability of bacterial cell membrane and cause depolarization. Mechanism experiments prove the possible mechanism of action of this kind of sulfonium ion modified vancomycin derivatives: vancomycin binds to the terminal dipeptide of Lipid II, enabling the sulfonium ion it carries to form electrostatic interactions with the negative charge components on the surface of the bacterial cell membrane phospholipids, while the hydrophobic fragment connected to the sulfonium ion takes the opportunity to insert into the phospholipid bilayer of the bacterial cell membrane, causing an increase in cell membrane permeability and depolarization, and destroying the integrity of the cell membrane. Under the action of cell wall biosynthesis and cell membrane destruction, the bacteria disintegrate and die.

[0269] Biological test example 7 Park nucleotide detection experiment

[0270] In order to study whether the new vancomycin derivatives have an inhibitory effect on cell wall (peptidoglycan) biosynthesis, we compared the accumulation of UDP-MurNAc-pp caused by screening drugs and vancomycin treatment of Staphylococcus aureus USA300 strain (referred to as USA300).

[0271] During the bacterial culture stage, Staphylococcus aureus USA300 was inoculated in TSB liquid medium and cultured overnight, and the OD 600= 0.1 to 100 mL TSB (250 mL conical flask) 37°C, 250 rpm, incubate for 2 h; termination of translation stage, add 130 pg / mL chloramphenicol to the bacterial solution after the incubation is completed, incubate at 37°C for 15 min; drug loading stage, after the bacterial solution is dispensed, add test compounds van017, van026 and vancomycin 5 pg / mL respectively, and set up a negative control group without adding drugs, incubate at 37°C for 2 h; post-treatment stage, test the OD value of each sample, then centrifuge at 7500 rpm for 5 min, wash with sterile water to remove the antibacterial drugs, discard the waste liquid after centrifugation, repeat twice. Finally, resuspend in sterile water (based on the lowest OD value sample, calculate the amount of sterile water needed for other samples in turn), boil in boiling water for 30 min, vortex evenly and ultrasonic for 30 min, centrifuge and freeze-dry the supernatant. Detection stage, dissolve the obtained freeze-dried powder with 200 pL of pure water, centrifuge and take the supernatant, take 20 pL respectively for LCMS analysis of the cell wall precursors connected with UDP in the solution, monitor the ultraviolet absorption peak at 260 nm, and confirm the MS, the results are shown in Figure 6.

[0272] Compared with the vancomycin group, van017 and van026 have stronger absorption intensity at 260 nm, which corresponds to the accumulation of UDP MurNAc-pp, and is confirmed by high-resolution mass spectrometry

UDP-MurNAc-pp (C 40 H 65 N9O 26 P2) theoretical value 1150.3589 [M+H] + ; actual value 1150.3634

[0273] Antiviral activity test of biological test example 8

[0274] In order to explore the in vitro antiviral activity of this class of vancomycin derivatives, we tested the inhibitory activity of compounds van017 and van026 on respiratory syncytial virus (RSV-ON1-GFP) and new crown pseudovirus (XBB Pseudovirus), and tested the cytotoxicity at the working concentration of drugs. The above viruses are derived from the Guangzhou laboratory.

[0275] Hep-2 cells in the logarithmic growth phase were diluted to 0.3 x 10 6Vero cells (African green monkey kidney cells) in logarithmic growth phase were inoculated into 24-well culture plates at an appropriate density (about 100,000 cells) and 500 μL per well. After overnight culture, van017, van026 or vancomycin hydrochloride at a concentration of 10 mM (working concentration 10 μM) was added for 1 h, and then 1000 TCID50 of XBB spike pseudovirus with Renilla luciferase tag (50 μL per well) was added to each well, with three replicate wells for each concentration and DMSO control wells at the corresponding concentration. After about 24 h in a 37°C cell incubator, the cells were lysed and the luciferase activity was detected using a Renilla luciferase luciferase detection kit (Bi Yun Tian RG066M).

[0276] Vero cells (African green monkey kidney cells) in logarithmic growth phase were inoculated into 24-well culture plates at an appropriate density (about 100,000 cells) and 500 μL per well. After overnight culture, van017, van026 or vancomycin hydrochloride at a concentration of 10 mM (working concentration 10 μM) was added for 1 h, and then 1000 TCID50 of XBB spike pseudovirus with Renilla luciferase tag (50 μL per well) was added to each well, with three replicate wells for each concentration and DMSO control wells at the corresponding concentration. After about 24 h in a 37°C cell incubator, the cells were lysed and the luciferase activity was detected using a Renilla luciferase luciferase detection kit (Bi Yun Tian RG066M).

[0277] The working concentration of the drugs van017, van026, and vancomycin hydrochloride was 10 μM, 100 μL was added to the wells with about 30,000 Hep-2 cells for 36 h and 40,000 A549 cells for 24 h, and DMSO control and culture medium control groups were set up, with four replicate wells for each group. After co-culture, 10 μL of CCK8 reagent was added to each well according to the CCK-8 detection kit (Solebao CA1210), and the absorbance value was measured at OD 450 nm after 1.5 h of reaction at 37°C. The OD value was converted to cell viability value

conversion formula: cell viability value = [A (drug) - A (blank)] / [A (0 drug) - A (blank)] where A (0 drug): DMSO control group, A (blank): culture medium control group

[0278] The above experiments show that the compound van017 of the application has good inhibitory effect on the proliferation of RSV-ON1 virus in Hep-2 cells, and the drug has no toxicity in Hep-2 cells at a concentration of 10 muM; the compound van026 has good inhibitory effect on the proliferation of new crown XBB pseudovirus in Vero cells.

[0279] The above is only a schematic description of the application, and those skilled in the art should know that various improvements can be made to the application without departing from the working principle of the application, which all belong to the protection scope of the application.

Claims

1. A vancomycin derivative of the following formula (I) or a pharmaceutically acceptable salt thereof: ###0001### (I) wherein: R1is selected from -OH, -NH-X1-S + (R a )-X2-R b , -NH-X1-S-X2-R b ; R2is selected from -H, -X1-S + (R a )-X2-R b , -X1-S-X2-R b ; R3is selected from -H, -X1-NH-X1-R c , -X1-NH-X1-S + (R a )-X2-R b , -X1-NH-X1-S-X2-R b ; R4is selected from -H, -X1-S + (R a )-X2-R b ; and at least one of R1, R2, R3, R4 contains -S + (R a )-X2-R b or -S-X2-R b structural fragment; each X1is independently selected from the group consisting of -(CH2) n -, substituted or unsubstituted C6-C 20 aryl, the substitution means substituted with one or more substituents selected from the group consisting of halogen, C1-C 10 alkyl, halogenated C1-C 10 alkyl, C1-C 10 alkoxy, halogenated C1-C 10 alkoxy; wherein n is independently an integer selected from 0-6; X2is each independently selected from the group consisting of -(CH2) m -, substituted or unsubstituted C6-C 20 aryl, the substitution means substituted with one or more substituents selected from the group consisting of halogen, C1-C 10 alkyl, halogenated C1-C 10 alkyl, C1-C 10 alkoxy, halogenated C1-C 10 alkoxy; wherein, -(CH2) m -; m is independently an integer selected from the group consisting of 0-6, -(CH2) m ; one or more hydrogens in -(CH2) m - are optionally replaced with -OH; R a each independently is selected from C1-C6alkyl or halogen-substituted C1-C6alkyl; R b each independently is selected from substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C6-C 20 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy containing one or more heteroatoms selected from N, O and S in the ring; said substitution means substituted with one or more substituents selected from halogen, C1-C 10 alkyl, halo C1-C 10 alkyl, C1-C 10 alkoxy, halo C1-C 10 alkoxy, substituted or unsubstituted C6-C 10 aryl, wherein said "substituted C6-C 10 aryl" means said C6-C 10 aryl contains one or more substituents selected from halogen, C1-C 10 alkyl, halo C1-C 10 alkyl, C1-C 10 alkoxy, halo C1-C 10 alkoxy; R c selected from 2. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein In formula (I) only one of R1, R2, R3, R4 contains -S + (R a )-X2-R b or S-X2-R b structural fragment, preferably containing -S + (R a )-X2-R b structural fragment.

3. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein In formula (I), each X1is independently selected from -(CH2) n - or phenyl, wherein n is independently 1, 2, 3; and / or In X2, m is independently 2, 3, 4; preferably, X2 is -CH2CH(OH)CH2- or phenyl.

4. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein In formula (I), R a each independently is selected from C1-C4 linear or branched alkyl or halogen-substituted C1-C4 linear or branched alkyl, more preferably methyl.

5. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein In formula (I), R b each independently selected from substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy containing one or more heteroatoms selected from N, O and S in the ring; the substitution means substituted by one or more substituents selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, substituted or unsubstituted phenyl, wherein the "substituted phenyl" means the phenyl contains one or more substituents selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy; Preferably, R b each independently is selected from substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy, the substitution meaning substitution with one or more groups selected from halogen (e.g. chlorine, bromine), tert-butyl, trifluoromethyl, methoxy, phenyl, trifluoromethyl-substituted phenyl, halogen (e.g. chlorine)-substituted phenyl.

6. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein In formula (I), R c is 7. The vancomycin derivative of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, The vancomycin derivative of formula (I) is selected from the following compounds:

8. The method for preparing the vancomycin derivative of formula (I) according to any one of claims 1-7, which is prepared by a preparation method comprising the following steps: The vancomycin hydrochloride is reacted by amide condensation reaction, reductive amination reaction or Mannich reaction to obtain a vancomycin derivative intermediate with sulfur atom modification, and then reacted with excess epoxide to obtain the vancomycin aromatic sulfonium derivative of the present application by SN2 ring-opening substitution reaction; Further, the vancomycin aromatic sulfonium derivative is reacted with pyrrolidine dithioformate salt to obtain the aromatic sulfur derivative.

9. A pharmaceutical composition comprising the vancomycin derivative of formula (I) according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

10. Use of the vancomycin derivative of formula (I) according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating and / or preventing a disease or disorder associated with infection of gram-positive bacteria and / or gram-negative bacteria. Preferably, the gram-positive bacteria include: Staphylococcus aureus, Enterococcus; Preferably, the gram-negative bacteria include: Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa; Preferably, the disease or disorder associated with infection of gram-positive bacteria and / or gram-negative bacteria include: respiratory tract infection, including upper respiratory tract infection such as pharyngitis, lower respiratory tract infection including tracheitis, bronchitis, pneumonia caused by Enterobacter and Serratia marcescens such as community-acquired pneumonia, ventilator-acquired pneumonia, hospital-acquired pneumonia, bronchiectasis, pulmonary tuberculosis and pulmonary infection complicated with pulmonary fibrosis; urinary tract infection, including simple and complicated pyelonephritis, recurrent cystitis, complicated urinary tract infection, simple urinary tract infection; central nervous system infection, including encephalitis, meningitis, brain abscess; ear infection, including otitis externa, otitis media; abdominal cavity infection, including peritonitis; cardiovascular infection, including blood infection such as sepsis or bacteremia, endocarditis, myocarditis, pericarditis; skin or soft tissue infection; bone and joint infection, including arthritis, osteomyelitis; genital infection, including genital ulcer, vaginitis, cervicitis; eye infection, including conjunctivitis, keratitis, endophthalmitis; oral cavity infection, including gingivitis, periodontitis.

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