Azole quaternary ammonium salt as well as preparation method and application thereof

Abstract

The invention relates to an azole quaternary ammonium salt and a preparation method thereof and application of the azole quaternary ammonium salt in modification or marking of amino in molecules, the azole quaternary ammonium salt is a compound shown in the formula (III), and a stereoisomer, a tautomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound, the compound has high reaction activity and stability and good water solubility, and the compound can be used for preparing the compound. The oligo group is easy to modify and used for subsequent functional module connection, and can be used for modifying or marking amino groups in molecules. The method provided by the invention has the advantages of short reaction route, high total yield, mild preparation condition, simple reaction condition, convenience in operation, wide substrate selection range, easiness in large-scale preparation of the azole quaternary ammonium salt and the like, and has huge potential application value in the fields of drug molecule synthesis, biological probe and biomarker reagent development and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of biochemistry, and in particular to an azole quaternary ammonium salt and a preparation method and application thereof. Background Art

[0002] Quaternary ammonium salt compounds have extremely wide applications in the fields of biomedicine, pesticides, materials and petrochemicals, such as bactericides and disinfectants, fabric softeners and antistatic agents, corrosion inhibitors, surfactants, reactive dyes, injection molding additives, drag reducers, thickeners, phase transfer catalysts and flocculating demulsifiers.

[0003] Azole quaternary ammonium salts are similar to general quaternary ammonium salts, which are quaternary ammonium salts substituted with alkyl or aryl groups of azole compounds. Azole quaternary ammonium salts are also very important organic synthesis reagents, which can undergo nucleophilic substitution, carbene insertion, Michael addition and other reactions. The chemical selectivity of traditional azole quaternary ammonium salts in nucleophilic substitution reactions is complex, and the reaction conditions or reaction temperatures are high, which limits their application range; in addition, the solvents of multi-reaction systems have high requirements, and oxidation reactions tend to occur preferentially under water conditions, which greatly limits their application in biological products.

[0004] In order to explore the application scope of quaternary ammonium salts of azoles in biological products, the reactivity and chemical selectivity of quaternary ammonium salts of azoles can be improved by adjusting the electronic effect of quaternary ammonium salts of azoles. Gouriprasanna Roy et al. found in their previous research (Org. Biomol. Chem., 2018, 23: 4243-4260) that in the absence of metal catalysis, K 2 CO 3 / I 2 The mediated azole quaternary ammonium salts can undergo oxidation, imidization and amination reactions under specific reaction conditions. Although there are two examples of modifying benzylamine into imine under anhydrous conditions, the harsh reaction conditions limit its application, and the research results do not involve the amino coupling reaction of amino acids and polypeptide compounds.

[0005] The amino modification reagents developed at this stage mainly include NHS ester, benzoyl fluoride, sulfonyl fluoride, vinyl sulfonamide, allyl sulfonamide, aldehyde, o-dialdehyde, o-nitrobenzyl alcohol, thioisocyanate, diazonium salt, o-carbonylphenylboronic acid, oxazoline salt and imidazole-1-sulfonyl azide. Among them, NHS ester is a carboxylic acid activated by succinimide, and the purpose of amino modification is achieved by the amidation reaction between the activated carboxyl group and the amino group; benzoyl fluoride is a relatively stable acyl halide compound, which is easier to store than acyl chloride and can achieve the purpose of amide modification by amidation reaction with the amino group; sulfonyl fluoride is a reagent with higher activity than benzoyl fluoride and can undergo amidation reaction with the amino group; vinyl sulfonamide and allyl sulfonamide are very good Michael acceptors and can undergo Michael addition reaction with the amino group to achieve the purpose of amino modification; thioisocyanate (or isocyanic acid) Esters) can also efficiently undergo nucleophilic addition reactions with amino groups and be converted into corresponding thioureas (carbamates); aldehyde compounds easily react with amino groups to form imines, which can be further reduced to obtain stable amino compounds; similarly, diazo compounds can also undergo nucleophilic addition reactions with amino groups and be converted into stable benzotriazines to achieve the purpose of modifying the amino group; and o-carbonylboronic acid forms imines through the carbonyl and amino groups, and stabilizes the imine bond through the electronic conjugation between boron and nitrogen to achieve the modification of the amino group (Chem. Commun., 2021, 57: 10689-10702).

[0006] In addition, thiazolopyridine quaternary ammonium salts are a class of compounds that react with primary amines. Under weakly alkaline conditions, they react specifically and effectively with lysine residues (J.Med.Chem.2022,65:11840-11853) or aminosilane coatings to form covalent bonds. Its advantage is that it can specifically modify the amino groups of amino acids, and the water solubility of quaternary ammonium salts is good, but the stability of such compounds is poor, and they need to be prepared when needed, and are prone to hydrolysis or other transformations during storage, and there are certain structural requirements for the modification of polypeptides, which can meet the specific modification requirements of some short peptides. In addition, the further modification and application of such compounds have not been reported, and the application limitations are obvious.

[0007] In summary, azole quaternary ammonium salt compounds have high economic added value and are of great significance for the modification of peptides, coupling schemes of peptides with other functional structural units, protein sequencing, etc. It is necessary to fully explore the application breadth of azole quaternary ammonium salt compounds and design a class of reagents with fewer synthetic steps, high yield, high reaction activity, high thermal stability and water compatibility, while introducing a rich connector. Summary of the invention

[0008] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, the present invention provides an azole quaternary ammonium salt with high thermal stability, high reaction activity and good water solubility, and provides a preparation method with short reaction route, simple conditions and high yield, which is easy to prepare the azole quaternary ammonium salt in large quantities. The azole quaternary ammonium salt provided by the present invention can selectively and efficiently modify or label the amino group in biological macromolecules, not only has the advantage of site selectivity, but also has economy, and has huge potential application value in the fields of drug molecule synthesis, biological probe and biomarker reagent development.

[0009] To this end, the first aspect of the present invention provides a use of a compound in modifying or labeling an amino group in a molecule, wherein the compound is a compound represented by formula (III), and stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

[0010]

[0011] in:

[0012] R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C 6 -C 20 Aromatic amine, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl;

[0013] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted Rd Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0014] R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0015] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0016] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0017] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one Rg Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0018] R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0019] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0020] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0021] R h Selected from C 1 -C 3 alkyl;

[0022] Z - Selected from acid ions.

[0023] Most of the existing amino modification reagents have low conversion efficiency, long reaction time, poor chemical selectivity, and certain requirements for reaction solvents, and are not suitable for the modification of amino acids and peptides. Specifically, although NHS ester is a more commonly used amino modification reagent, it has poor compatibility in aqueous phase, is prone to hydrolysis to varying degrees, and has poor chemical selectivity. Its efficiency will decrease to varying degrees in low-concentration peptide detection; although imidazole-1-sulfonyl azide (Biopolymers, 2015, 4: 419-426) is completely water-soluble, the conversion requires copper salt catalysis, and the participation of copper ions is not conducive to the stability of the peptide and subsequent application. Thiazolopyridine quaternary ammonium salts have poor thermal stability and low efficiency in amino-specific modification. The reagents cannot be stored alone and need to be prepared temporarily, which is not conducive to commercialization. The modified reagents have poor water solubility, which is not conducive to the modification of biological products such as proteins and peptides.

[0024] To this end, the present invention utilizes the aforementioned compound, which has high reactivity and stability, can stably exist within 80°C, can quickly react specifically with primary amine compounds, has good water solubility, is easy to modify oligo groups and is used for subsequent functional module connection, can be used to modify or label amino groups in molecules, is easy to mass produce and easy to store and transport, and has great potential application value in the fields of drug molecule synthesis, biological probes and biomarker reagent development.

[0025] According to an embodiment of the present invention, the R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkylthio, C 1 -C 5 Alkylamino, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, C 6 -C 10 Arylthio, C 6 -C 10 Aromatic amino group, C 2 -C5 Alkenyl, C 2 -C 5 Alkynyl;

[0026] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0027] R a , R b are independently selected from H, C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0028] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0029] R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy.

[0030] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl.

[0031] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl.

[0032] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 Aryl.

[0033] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl;

[0034] R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0035] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl.

[0036] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl.

[0037] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl.

[0038] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from C 1 alkyl.

[0039] According to an embodiment of the present invention, X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace;

[0040] R h Selected from C 1 alkyl.

[0041] According to an embodiment of the present invention, X and Y are independently selected from O, S, and NH, and NH is replaced by an R h replace;

[0042] R h Selected from C 1 alkyl.

[0043] According to an embodiment of the present invention, the acid ions are selected from inorganic acid ions, organic acid ions or halide ions.

[0044] According to an embodiment of the present invention, the inorganic acid ions include nitrate ions, sulfate ions, phosphate ions, chlorate ions, iodate ions, perchlorate ions, periodate ions, tetrafluoroborate ions or hexafluorophosphate ions.

[0045] According to an embodiment of the present invention, the organic acid ions are selected from alkyl sulfonate ions, benzene sulfonate ions, acetate ions, tartrate ions, salicylate ions, maleate ions, succinate ions, citrate ions, glycerate ions or ascorbate ions.

[0046] According to an embodiment of the present invention, the halide ion is selected from fluoride ion, chloride ion, bromide ion or iodide ion.

[0047] According to an embodiment of the present invention, R 1 are two substituents on the azole ring, the two substituents are connected to each other and together with the atoms on the azole ring to form an unsubstituted or optionally substituted R d Substituted C 6 Aryl;

[0048] R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy;

[0049] R 2 , R 3 Selected from C 1 alkyl;

[0050] X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl;

[0051] Z - Selected from tetrafluoroborate ion and iodide ion.

[0052] According to an embodiment of the present invention, the compound is

[0053]

[0054] The second aspect of the present invention provides a method for modifying or labeling an amino group in a molecule, comprising using a compound to modify or label an amino group in a molecule, wherein the compound is a compound represented by formula (III), and stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

[0055]

[0056] in:

[0057] R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C 6 -C 20 Aromatic amino group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl;

[0058] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0059] R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C20 Aryl, 5-20 membered heteroaryl;

[0060] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0061] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0062] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0063] R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0064] Rg Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0065] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0066] R h Selected from C 1 -C 3 alkyl;

[0067] Z - Selected from acid ions.

[0068] According to an embodiment of the present invention, the R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkylthio, C 1 -C 5 Alkylamino, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, C 6 -C 10 Arylthio, C 6 -C 10 Aromatic amine, C2 -C 5 Alkenyl, C 2 -C 5 Alkynyl;

[0069] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0070] R a , R b are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0071] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0072] R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy.

[0073] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl.

[0074] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl.

[0075] According to an embodiment of the present invention, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 Aryl.

[0076] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl;

[0077] R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0078] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl.

[0079] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl.

[0080] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl.

[0081] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from C 1 alkyl.

[0082] According to an embodiment of the present invention, X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace;

[0083] R h Selected from C 1 alkyl.

[0084] According to an embodiment of the present invention, X and Y are independently selected from O, S, and NH, and NH is replaced by an R h replace;

[0085] R h Selected from C 1 alkyl.

[0086] According to an embodiment of the present invention, the acid ions are selected from inorganic acid ions, organic acid ions or halide ions.

[0087] According to an embodiment of the present invention, the inorganic acid ions include nitrate ions, sulfate ions, phosphate ions, chlorate ions, iodate ions, perchlorate ions, periodate ions, tetrafluoroborate ions or hexafluorophosphate ions.

[0088] According to an embodiment of the present invention, the organic acid ions are selected from alkyl sulfonate ions, benzene sulfonate ions, acetate ions, tartrate ions, salicylate ions, maleate ions, succinate ions, citrate ions, glycerate ions or ascorbate ions.

[0089] According to an embodiment of the present invention, the halide ion is selected from fluoride ion, chloride ion, bromide ion or iodide ion.

[0090] According to an embodiment of the present invention, R 1 are two substituents on the azole ring, the two substituents are connected to each other and together with the atoms on the azole ring to form an unsubstituted or optionally substituted R d Substituted C 6 Aryl;

[0091] R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy;

[0092] R 2 , R 3 Selected from C 1 alkyl;

[0093] X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl;

[0094] Z - Selected from tetrafluoroborate ion and iodide ion.

[0095] According to an embodiment of the present invention, the compound is

[0096]

[0097] According to an embodiment of the present invention, the molecule comprises an amino acid ester, an amino amide, a peptide or a protein.

[0098] According to an embodiment of the present invention, the method further comprises dissolving the compound in solvent A, adding the molecule to react, and obtaining a product in which the amino group in the molecule is labeled or modified.

[0099] According to an embodiment of the present invention, the solvent A includes at least one selected from dimethyl sulfoxide, n-butanol, tert-butanol, isopropanol, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, water, hexamethylphosphoramide, polyethylene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.

[0100] The third aspect of the present invention provides a compound, which is a compound represented by formula (IV), and its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0101]

[0102] in:

[0103] R 4 are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form a d Substituted C 6 Aryl, unsubstituted or optionally substituted with at least one R d Substituted with the following groups: C 7 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0104] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0105] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-ORf , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0106] R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0107] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0108] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0109] R h Selected from C 1 -C 3 alkyl;

[0110] Z - Selected from acid ions.

[0111] The compound provided by the present invention has high reactivity and stability, can stably exist within 80°C, can quickly react specifically with primary amine compounds, has good water solubility, is easy to modify oligo groups and is used for subsequent functional module connection, can be used to modify or label amino groups in molecules, is easy to mass produce and easy to store and transport, and has great potential application value in the fields of drug molecule synthesis, biological probes and biomarker reagent development.

[0112] According to an embodiment of the present invention, R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy.

[0113] According to an embodiment of the present invention, R 4 are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form a bond surrounded by 1-5 R d Substituted C 6 Aryl, unsubstituted or optionally substituted with 1-5 R d Substituted with the following groups: C 7 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl.

[0114] According to an embodiment of the present invention, R 4 There are two substituents on the azole ring, and the two substituents are connected to each other and form a bond with the skeleton atoms on the azole ring. d Substituted C 6 Aryl.

[0115] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl;

[0116] R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl;

[0117] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl.

[0118] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl.

[0119] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl.

[0120] According to an embodiment of the present invention, the R 2 , R 3 are independently selected from C 1 alkyl.

[0121] According to an embodiment of the present invention, X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace;

[0122] R h Selected from C 1 alkyl.

[0123] According to an embodiment of the present invention, X and Y are independently selected from O, S, and NH, and NH is replaced by an R h replace;

[0124] R h Selected from C 1 alkyl.

[0125] According to an embodiment of the present invention, the acid ions are selected from inorganic acid ions, organic acid ions or halide ions.

[0126] According to an embodiment of the present invention, the inorganic acid ions include nitrate ions, sulfate ions, phosphate ions, chlorate ions, iodate ions, perchlorate ions, periodate ions, tetrafluoroborate ions or hexafluorophosphate ions.

[0127] According to an embodiment of the present invention, the organic acid ions are selected from alkyl sulfonate ions, benzene sulfonate ions, acetate ions, tartrate ions, salicylate ions, maleate ions, succinate ions, citrate ions, glycerate ions or ascorbate ions.

[0128] According to an embodiment of the present invention, the halide ion is selected from fluoride ion, chloride ion, bromide ion or iodide ion.

[0129] According to an embodiment of the present invention, R 4 are two substituents on the azole ring, the two substituents are connected to each other and form a bond with at least one R d Substituted C 6 Aryl;

[0130] R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy;

[0131] R 2 , R 3 Selected from C 1 alkyl;

[0132] X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl;

[0133] Z - Selected from tetrafluoroborate ion and iodide ion.

[0134] According to an embodiment of the present invention, the compound is

[0135]

[0136] The fourth aspect of the present invention provides a method for preparing the compound described in the third aspect, the method comprising:

[0137] The compound represented by formula (II) and compound R 3 OZ reaction to obtain a compound represented by formula (IV);

[0138] Or the compound represented by formula (II) and compound R 3 -Z reaction to obtain a compound represented by formula (IV);

[0139]

[0140] The invention provides two different synthetic routes, and adopts different methods to effectively avoid the application limitation caused by single conditions in the synthesis of azole quaternary ammonium salt derivatives. The method has the advantages of short reaction route, high total yield, mild preparation conditions, simple reaction conditions, convenient operation, wide substrate selection range, easy preparation of azole quaternary ammonium salts in large quantities, etc.

[0141] According to an embodiment of the present invention, the method further comprises dissolving the compound represented by formula (II) in solvent B, adding compound R 3 OZ reaction to obtain the compound represented by formula (IV).

[0142] According to an embodiment of the present invention, the solvent B includes at least one selected from anhydrous dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, tetrahydrofuran, 1,4-dioxane, n-hexane, n-pentane, cyclohexane, chloroform, carbon tetrachloride, chlorobenzene, fluorobenzene, bromobenzene, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, benzene, toluene, xylene, acetonitrile, acetone, ethyl ether, methyl ethyl ether, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, ethylene glycol methyl ether, methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.

[0143] According to an embodiment of the present invention, the compound represented by formula (II) and compound R 3 The molar ratio of OZ is (1:10000)-(100:1), preferably (1:1)-(1:5).

[0144] According to an embodiment of the present invention, the method further comprises dissolving the compound represented by formula (II) in solvent C, adding compound R 3 -Z reaction to obtain the compound represented by formula (IV).

[0145] According to an embodiment of the present invention, the solvent C includes at least one selected from acetonitrile, acetone, and N,N-dimethylformamide.

[0146] According to an embodiment of the present invention, the compound represented by formula (II) and compound R 3 The molar ratio of -Z is (1:10000) to (100:1), preferably (1:1) to (1:5).

[0147] Compared with the prior art, the present invention has the following beneficial effects:

[0148] The present invention aims at the deficiencies of the prior art and provides an azole quaternary ammonium salt with few synthesis steps, high reaction activity, high thermal stability, water phase compatibility and easy storage and transportation. The quaternary ammonium salt can specifically react with amino acid residues and can be used as an amino group modifier. In addition, the present invention also provides two different synthetic routes of azole quaternary ammonium salts, which avoid the application limitations caused by single conditions in actual production. At the same time, the method has atom economy, simple operation, low cost, and is easy to mass produce, and has great potential application value in the fields of drug molecule synthesis, biological probe and biomarker reagent development.

[0149] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0150] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0151] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0152] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0153] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0154] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0155] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0156] Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of this application. The above techniques and methods can usually be implemented according to conventional methods well known in the art, according to the descriptions in the multiple general and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes a chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 .

[0157] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0158] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed by Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, including naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzylpenicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or organic salts formed by polyamine resins; Salts derived from inorganic and organic acids include, but are not limited to, organic salts formed from sulfuric, phosphoric, nitric, hydrobromic, hydrochloric, formic, acetic, propionic, benzenesulfonic, benzoic, phenylacetic, salicylic, alginic, anthranilic, camphoric, citric, ethylenesulfonic, formic, fumaric, furoic, gluconic, glucuronic, glutamic, glycolic, isethionic, lactic, maleic, malic, mandelic, mucic, pamoic, pantothenic, stearic, succinic, sulfanilic, tartaric, p-toluenesulfonic, malonic, 2-hydroxypropionic, oxalic, glycolic, glucuronic, galacturonic, citric, lysine, arginine, aspartic, cinnamic, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or trifluoromethanesulfonic acids.

[0159] In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of the compounds of the present invention.

[0160] The term "stereoisomer" refers to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformers. The stereochemical definitions and conventions used in the present invention are generally defined in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0161] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

[0162] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0163] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolution acid that is an optically active salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configurations can also be used to obtain any enantiomer or diastereomer of the compounds described in the present invention through stereo organic synthesis.

[0164] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0165] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0166] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0167] The term "C 1 -C 10 “Alkyl” is understood to mean a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the radical has 1, 2, 3, 4, 5, 6 carbon atoms (“C 1 -C 6 alkyl), for example methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly, the radical having 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0168] The term "C 1 -C 10 "Alkoxy" is understood to mean -O-(C 1 -C 10 alkyl), where "C 1 -C 10 "Alkyl" has the above definition.

[0169] The term "C 1 -C 10 "Alkylthio" is understood to mean -S-(C 1 -C 10 alkyl), where "C 1 -C 10 "Alkyl" has the above definition.

[0170] The term "C 1 -C10 "Alkylamino" is understood to mean -N-(C 1 -C 10 alkyl), where "C 1 -C 10 "Alkyl" has the above definition.

[0171] The term "C 6 -C 20 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C 6 -C 20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0172] The term "C 6 -C 20 "Aryloxy" is understood to mean -O-(C 6 -C 20 Aryl), wherein C 6 -C 20 Aryl has the above definition.

[0173] The term "C 6 -C 20 "Arylthio" is understood to mean -S-(C 6 -C 20 Aryl), wherein C 6 -C 20 Aryl has the above definition.

[0174] The term "C 6 -C 20 "Arylamine" is understood to mean -N-(C 6 -C 20 Aryl), wherein C 6 -C 20 Aryl has the above definition.

[0175] The term "C 2 -C 10 "Alkenyl" is understood to be a monovalent alkenyl radical which is chain or branched and contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0176] The term "C 2 -C10 "Alkynyl" is understood to be a linear or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0177] The term "C 3 -C 10 "Alkynyloxy" should be understood as -O-(C 3 -C 10 Alkynyl), where "C 3 -C 10 "Alkynyl" is understood to be a linear or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0178] The term "C 3 -C 12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 12 carbon atoms, including fused or bridged polycyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring such as a decalin ring. The term "C 3 -C 10 "Cycloalkyl" is understood to mean a saturated, monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, including fused or bridged polycyclic ring systems.

[0179] The term "5-20 membered heteroaryl" is understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contains 1 to 5, preferably 1 to 3, heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si, and, in each case, may additionally be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0180] The term "3-10 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 3 to 10 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and unless otherwise indicated, they may be attached via carbon or nitrogen, wherein -CH 2-The group is optionally replaced by -C(O)-; and wherein, unless otherwise specified to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the -NH in the ring is optionally substituted by acetyl, formyl, methyl or mesyl; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoimidazolidinyl.

[0181] The term "halogen" is to be understood as meaning fluorine, chlorine, bromine and iodine.

[0182] The term "Z - " should be understood as a negatively charged acid ion, and the charge number is not limited to 1. For example, the charge number can be 1, 2, 3 or 4.

[0183] The term "compound R 3 OZ" is understood to include the group R 3 , oxygen atoms and acid radical ions Z, for example, C 3 H 9 OBF 4 .

[0184] The term "compound R 3 -Z" is understood to include the group R 3 and an acid ion Z, for example, methyl iodide.

[0185] According to an embodiment of the present invention, the present invention provides a use of a compound in modifying or labeling an amino group in a molecule, wherein the compound is a compound represented by formula (III), and stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

[0186]

[0187] in:

[0188] R 1 is one or two substituents on the azole ring, each R 1Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C 6 -C 20 Aromatic amine, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl;

[0189] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0190] R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0191] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0192] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0193] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0194] R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0195] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0196] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0197] R h Selected from C 1 -C 3 alkyl;

[0198] Z - Selected from acid ions.

[0199] According to an embodiment of the present invention, the present invention also provides a method for modifying or labeling an amino group in a molecule, comprising using a compound to modify or label an amino group in a molecule, wherein the compound is a compound represented by formula (III), and stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

[0200]

[0201] in:

[0202] R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C6 -C 20 Aromatic amino group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl;

[0203] Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0204] R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0205] R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0206] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0207] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0208] R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0209] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0210] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0211] R h Selected from C 1 -C 3 alkyl;

[0212] Z - Selected from acid ions.

[0213] According to an embodiment of the present invention, the present invention further provides a compound, which is a compound represented by formula (IV), and its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0214]

[0215] in:

[0216] R 4 are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form a d Substituted C 6 Aryl, unsubstituted or optionally substituted with at least one R d Substituted with the following groups: C 7 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si;

[0217] R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy;

[0218] R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl;

[0219] R e , R f are independently selected from C1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0220] R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl;

[0221] X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace;

[0222] R h Selected from C 1 -C 3 alkyl;

[0223] Z - Selected from acid ions.

[0224] According to an embodiment of the present invention, the present invention also provides a method for preparing the aforementioned compound, comprising:

[0225] The compound represented by formula (II) and compound R 3 OZ reaction to obtain a compound represented by formula (IV);

[0226] Or the compound represented by formula (II) and compound R 3 -Z reaction to obtain a compound represented by formula (IV);

[0227]

[0228] Taking compound 2 as an example, the target compound of azole quaternary ammonium salt was prepared as follows:

[0229]

[0230] Step 1: Preparation of compound 2

[0231] Compound 2 can be prepared from commercial 2-chlorothiazole compounds as raw materials according to the method of reference Tetrahedron, 2004, 60, 6113, as follows:

[0232] The 2-chlorothiazole compound (compound shown in Formula 1) undergoes a nucleophilic substitution reaction in a DMF solution containing NaHS to obtain a 2-mercaptoquinoline intermediate (compound shown in Formula 2'). The intermediate needs to be separated and purified, and sodium iodide and potassium carbonate are directly added, and then a brominated alkane or alkyl iodide is added, and then the next step of nucleophilic substitution reaction occurs to obtain a thioether intermediate (compound shown in Formula 2). The reaction process can be expressed as:

[0233]

[0234] Among them, R 1 , R 2 The meaning is the same as above.

[0235] The specific operation method is preferably: dissolve 1.0 mol of 2-chlorothiazole compounds in anhydrous N, N-dimethylformamide. Under room temperature, add 1.1 mol of sodium hydrosulfide to the above solution at one time, stir at room temperature for 10 minutes, then heat to 80°C and continue stirring for 4 hours. Then, add 1.0 mol of sodium iodide and 1.5 mol of potassium carbonate to the reaction solution in sequence, and then add 1.5 mol of bromoalkane to continue the reaction. After the reaction is completed, slowly add water to the reaction system to quench the reaction, extract with ethyl acetate, wash with brine, dry with anhydrous sodium sulfate, evaporate the solvent, separate by silica gel column chromatography, and use a mixed solvent of petroleum ether and ethyl acetate as the eluent. The volume ratio of petroleum ether to ethyl acetate is 10:1 to obtain the key intermediate (the compound shown in Formula 2);

[0236] Step 2: Preparation of quaternary ammonium salt of azole

[0237] The key thioether intermediate (compound shown in Formula 2) can be reacted with a trialkyloxonium salt or an iodoalkane to obtain an azole quaternary ammonium salt (compound shown in Formula 3). The reaction process can be expressed as:

[0238]

[0239] There are two specific operation methods:

[0240] 1. Dissolve 1.0 mol of the thioether intermediate (compound shown in Formula 2) in dry dichloromethane, add 1.0 mol of a trialkyloxonium salt at room temperature, and after the reaction is complete at room temperature, remove the solvent by distillation under reduced pressure, wash three times with ether, and dry in vacuum to obtain a thiazole quaternary ammonium salt (compound shown in Formula 3);

[0241] 2. Dissolve 1.0 mol of the thioether intermediate (compound shown in Formula 2) in acetonitrile or DMF solution, add 1.5 mol of iodinated alkane at room temperature, stir at room temperature for 10 minutes, raise the temperature to 80°C and continue to react until the raw materials react, remove the solvent by distillation under reduced pressure, wash three times with ether, and dry in vacuum to obtain a thiazole quaternary ammonium salt (compound shown in Formula 3).

[0242] The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent replacements, or solvents, solvent combinations, and different ratios of solvent combinations that are equivalent to those described in the present invention are all considered to be included in the scope of the present invention.

[0243] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm).

[0244] The abbreviations of the present invention are defined as follows:

[0245] NHS: N-hydroxysuccinimide

[0246] DMF: N,N-dimethylformamide

[0247] NaHS: Sodium hydrosulfide

[0248] MeI: methyl iodide

[0249] MeCN: Acetonitrile

[0250] Acetone: Acetone

[0251] PPH 3 :Triphenylphosphine

[0252] DIAD: diethyl azodicarboxylate

[0253] THF: Tetrahydrofuran

[0254] TBAB: Tetrabutylammonium bromide

[0255] DCM: dichloromethane

[0256] TMSN 3 :Azidotrimethylsilane

[0257] TBAF: Tetrabutylammonium fluoride

[0258] Example 1: Preparation of Compound 1-1

[0259]

[0260] The specific steps are as follows:

[0261] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 2-methylmercaptobenzoxazole (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.65g, 10.0mmol), add ultra-dry dichloromethane (Annaiji Chemical, 50mL), add trimethyloxonium tetrafluoroborate (Annaiji Chemical, 1.48g, 10.0mmol) under stirring, and stir magnetically at room temperature for 2 hours. After the reaction is completed, filter and remove the solvent, wash three times with ether, and vacuum dry to obtain benzoxazolium tetrafluoroborate (1-1, white solid, 2.56g, yield 96%).

[0262] 1 H NMR (500 MHz, DMSO-d 6 )δ8.10-8.04(m,1H),8.04-8.00(m,1H),7.72(td,J=7.7,1.3Hz,1H),7.70-7.66(m,1H),3.94(s,3H),3.05(s,3H).

[0263] LC-MS(ESI):C 9 H 10 NOS + [M] + Calculated value: 180.0, measured value: 180.1.

[0264] Example 2: Preparation of Compound 1-2

[0265]

[0266] The specific steps are as follows:

[0267] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 2-methylmercaptobenzothiazole (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.81g, 10.0mmol), add acetonitrile or acetone (Annaiji Chemical, 50mL), add iodomethane (Annaiji Chemical, 2.13g, 15.0mmol) under stirring, after magnetic stirring at room temperature for 30 minutes, heat to 80°C and continue to react for 4 hours. After the reaction is completed, filter and remove the solvent, wash three times with ether, and vacuum dry to obtain benzothiazolium iodide salt (1-2, white solid, 3.20g, yield 99%).

[0268] 1 H NMR (400 MHz, DMSO-d 6)δ8.39(dd,J=8.1,1.2Hz,1H),8.18(dd,J=8.4,0.9Hz,1H),7.82(ddd,J=8.5, 7.3,1.2Hz,1H),7.70(ddd,J=8.3,7.3,1.1Hz,1H),4.09(s,3H),3.11(s,3H).

[0269] LC-MS(ESI):C 9 H 10 NS 2 + [M] + Calculated value: 196.0, measured value: 196.3.

[0270] Example 3: Preparation of Compound 1-3

[0271]

[0272] The specific steps are as follows:

[0273] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 1-methyl-2-methylmercaptobenzimidazole (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.78 g, 10.0 mmol), add acetonitrile or acetone (Annaiji Chemical, 50 mL), add iodomethane (Annaiji Chemical, 2.13 g, 15.0 mmol) under stirring, after magnetic stirring at room temperature for 30 minutes, heat to 80°C and continue to react for 4 hours. After the reaction is completed, filter and remove the solvent, wash three times with ether, and vacuum dry to obtain benzimidazolium iodide salt (1-3, white solid, 2.75 g, yield 86%).

[0274] 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(dd,J=6.3,3.2Hz,2H),7.69(dd,J=6.3,3.2Hz,2H),4.11(s,6H),2.70(s,3H).

[0275] LC-MS(ESI):C 10 H 13 N 2 S + [M] + Calculated value: 193.1, measured value: 193.3.

[0276] Example 4: Preparation of Compound 1-4

[0277]

[0278] The specific steps are as follows:

[0279] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 1-methyl-2-methylmercaptobenzimidazole (1.78g, 10.0mmol), add ultra-dry dichloromethane (Annaiji Chemical, 50mL), add trimethyloxonium tetrafluoroborate (Annaiji Chemical, 1.48g, 10.0mmol) under stirring, and stir magnetically at room temperature for 2 hours. After the reaction is completed, filter and remove the solvent, wash three times with ether, and vacuum dry to obtain benzimidazolium tetrafluoroborate (1-4, white solid, 2.55g, yield 91%).

[0280] 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(dd,J=6.3,3.1Hz,2H),7.70(dd,J=6.3,3.1Hz,2H),4.11(s,6H),2.69(s,3H).

[0281] LC-MS(ESI):C 10 H 13 N 2 S + [M] + Calculated value: 193.1, measured value: 193.2.

[0282] Example 5: Preparation of Compound 1-5

[0283]

[0284] The specific steps are as follows:

[0285] In a 250 mL round-bottom flask equipped with a magnetic stirrer, 2-(methylthio)benzo[d]thiazole-6-ol (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.97 g, 10.0 mmol), triphenylphosphine (Annaiji Chemical, 2.62 g, 10.0 mmol), 3-butyn-1-ol (Annaiji Chemical, 0.70 g, 10.0 mmol) and tetrahydrofuran (Annaiji Chemical, 50 mL) were added. After magnetic stirring at 0 ° C for 10 min, diethyl azodicarboxylate (Annaiji Chemical, 1.74 g, 10.0 mmol) was added dropwise, and the reaction was continued at room temperature until the reaction was completed. The solvent was removed by distillation under reduced pressure, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether:ethyl acetate was 10:1 to obtain a colorless, transparent, viscous intermediate. Acetonitrile or acetone (Annaiji Chemical, 50 mL) was added, and iodomethane (Annaiji Chemical, 2.13 g, 15.0 mmol) was added under stirring. After magnetic stirring at room temperature for 30 minutes, the temperature was raised to 80°C and the reaction was continued for 4 hours. After the reaction was completed, the solvent was removed by filtration, and the mixture was washed with ether three times and dried in vacuo to obtain benzothiazolium iodide salt (1-5, white solid, 3.44 g, yield 88%).

[0286] 1 H NMR (500 MHz, DMSO-d 6 )δ8.10(d,J=9.3Hz,1H),8.01(d,J=2.6Hz,1H),7.44(dd,J=9.3,2.6Hz,1H),4.18(t,J=6 .5Hz,2H),4.07(s,3H),3.10(s,3H),2.93(t,J=2.6Hz,1H),2.71(td,J=6.5,2.7Hz,2H).

[0287] LC-MS(ESI):C 13 H 14 NOS 2 + [M] + Calculated value: 264.1, measured value: 264.2.

[0288] Example 6: Preparation of Compound 1-6

[0289]

[0290] The specific steps are as follows:

[0291] The preparation method was the same as that of Example 5 to obtain benzothiazolium iodide (1-6, white solid, 3.72 g, yield 73%).

[0292] 1 H NMR (400 MHz, DMSO-d6 )δ8.08(d,J=9.3Hz,1H),7.97(d,J=2.6Hz,1H),7.43(dd,J=9.3,2.6Hz,1H),4.22-4.17(m,2H),4.11(d,J=2.4Hz,2H) ,4.05(s,3H),3.81-3.75(m,2H),3.58(td,J=4.0,1.1Hz,2H),3.54-3.48(m,6H),3.41(t,J=2.4Hz,1H),3.08(s,3H).

[0293] LC-MS(ESI):C 18 H 24 NO 4 S 2 + [M] + Calculated value: 382.1, measured value: 382.2.

[0294] Example 7: Preparation of Compound 1-7

[0295]

[0296] The specific steps are as follows:

[0297] In a 250mL round-bottom flask equipped with a magnetic stirrer, 2-(methylthio)benzo[d]thiazole-6-ol (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.97 g, 10.0 mmol), TBAB (Annaiji Chemical, 0.32 g, 1.0 mmol), and dichloromethane (Annaiji Chemical, 50 mL) were added. Under stirring, an aqueous NaOH solution (40 mL, 2.5 M) and 1,2-dibromoethane (Annaiji Chemical, 7.52 g, 40.0 mmol) were added. After reacting for 48 hours, dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was separated by silica gel column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate to obtain a white solid intermediate; the intermediate was dissolved in tetrahydrofuran (Annaiji Chemical, 50 mL), and TMSN was added. 3 (Annaiji Chemical, 1.27 g, 11.0 mmol), TBAF (Annaiji Chemical, 20 mL, 1.0 M tetrahydrofuran solution) was added under stirring, and the solvent was removed by reduced pressure distillation after the reaction was completed. The intermediate was separated by silica gel column chromatography to obtain a white solid intermediate. The subsequent preparation method was the same as in Example 2 to obtain benzothiazolium iodide salt (1-7, white solid, 2.65 g, total yield 65%).

[0298] 1 H NMR (400 MHz, DMSO-d 6)δ8.10(d,J=9.2Hz,1H),7.99(d,J=2.6Hz,1H),7.44(dd,J=9.2,2.6Hz,1H),4.27(t,J=4.7Hz,2H),4.06(s,3H),3.72(t,J=4.7Hz,2H),3.08(s,3H).

[0299] LC-MS(ESI):C 11 H 13 N 4 OS 2 + [M] + Calculated value: 281.1, measured value: 281.4.

[0300] Example 8: Preparation of Compound 1-8

[0301]

[0302]

[0303] The specific steps are as follows:

[0304] In a 250mL round-bottom flask equipped with a magnetic stirrer, 2-(methylthio)benzo[d]thiazole-6-ol (Shanghai Bid Pharmaceutical Technology Co., Ltd., 1.97 g, 10.0 mmol), TBAB (Annaiji Chemical, 0.32 g, 1.0 mmol), and dichloromethane (Annaiji Chemical, 50 mL) were added. Under stirring, an aqueous NaOH solution (40 mL, 2.5 M) and 1,2-dibromoethane (Annaiji Chemical, 7.52 g, 40.0 mmol) were added. After reacting for 48 hours, dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was separated by silica gel column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate to obtain a white solid intermediate; the intermediate was dissolved in tetrahydrofuran (Annaiji Chemical, 50 mL), and TMSN was added. 3 (Annaiji Chemical, 1.27g, 11.0mmol), TBAF (Annaiji Chemical, 20mL, 1.0M tetrahydrofuran solution) was added under stirring, and the solvent was removed by distillation under reduced pressure after the reaction was completed. The obtained white solid intermediate was transferred to a 250mL round-bottom flask equipped with a magnetic stirrer, and ultra-dry dichloromethane (Annaiji Chemical, 50mL) was added. Trimethyloxonium tetrafluoroborate (Annaiji Chemical, 1.48g, 10.0mmol) was added under stirring, and magnetic stirring was performed at room temperature for 2 hours. After the reaction was completed, the solvent was filtered out and washed with ether three times, and then dried in vacuo to obtain benzimidazolium tetrafluoroborate (1-8, white solid, 2.76g, yield 75%).

[0305] 1 H NMR (400 MHz, DMSO-d 6 )δ8.10(d,J=9.3Hz,1H),7.97(d,J=2.6Hz,1H),7.44(dd,J=9.3,2.6Hz,1H),4.27(t,J=4.8Hz,2H),4.06(s,3H),3.72(t,J=4.8Hz,2H),3.08(s,3H).

[0306] LC-MS(ESI):C 11 H 13 N 4 OS 2 + [M] + Calculated value: 281.1, measured value: 281.3.

[0307] Example 9: Reaction of quaternary pyridinium salts with biomolecules containing amino acid residues

[0308] Preparation of compound 2-1:

[0309]

[0310]

[0311] Compound 1-2a (same as compound 1-2, 96.9 mg, 0.3 mmol) was directly dissolved in dimethyl sulfoxide or n-butanol (5 ml), lysine (14.6 mg, 0.1 mmol) was added to the solution as an amine nucleophile, and triethylamine (20.2 mg, 0.2 mmol) was added, and the reaction was stirred at room temperature. After the reaction was completed, the reaction solution was separated by reverse phase preparative column to obtain the product (2-1, white solid, 68.2 mg, yield 98%).

[0312] 1 H NMR (400 MHz, Methanol-d 4 )δ7.87(t,J=8.7Hz,2H),7.66(dt,J=21.9,7.4Hz,4H),7.52-7.39(m,2H),4.34(dd,J=9.2,4.7Hz,1H),3.92(s,3H),3.81(s,3H),3.5 9(t,J=7.1Hz,2H),2.28(dt,J=9.4,4.5Hz,1H),2.16(dt,J=9.4,4.8Hz,1H),1.92(q,J=7.6Hz,2H),1.73(dq,J=17.1,8.5,7.3Hz,2H).

[0313] LC-MS(ESI):C 22 H 26 N 4 O 2 S 2 [M+H] 2+ Calculated value: 442.1, measured value: 221.3.

[0314] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. Use of a compound for modifying or labeling an amino group in a molecule, It is characterized in that The compound is a compound represented by formula (III), and its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: in: R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C 6 -C 20 Aromatic amino group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl; Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si; R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy; R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl; R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl; X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 -C 3 alkyl; Z - Selected from acid ions.

2. The use according to claim 1, It is characterized in that The R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkylthio, C 1 -C 5 Alkylamino, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, C 6 -C 10 Arylthio, C 6 -C 10 Aromatic amino group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl; Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si; R a , R b are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 Aryl.

3. The use according to claim 1, It is characterized in that The R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl; R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl; Optionally, the R 2 , R 3 are independently selected from C 1 alkyl.

4. The use according to claim 1, It is characterized in that The X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 alkyl; Optionally, the X and Y are independently selected from O, S, NH, and the NH is replaced by an R h replace; R h Selected from C 1 alkyl.

5. The use according to claim 1, It is characterized in that The acid ions include inorganic acid ions, organic acid ions or halide ions; Optionally, the inorganic acid ion comprises a nitrate ion, a sulfate ion, a phosphate ion, a chlorate ion, an iodate ion, a perchlorate ion, a periodate ion, a tetrafluoroborate ion or a hexafluorophosphate ion; Optionally, the organic acid ion includes an alkylsulfonate ion, a benzenesulfonate ion, an acetate ion, a tartrate ion, a salicylate ion, a maleate ion, a succinate ion, a citrate ion, a glycerate ion or an ascorbate ion; Optionally, the halide ion comprises fluoride ion, chloride ion, bromide ion or iodide ion.

6. The use according to claim 1, It is characterized in that R 1 are two substituents on the azole ring, the two substituents are connected to each other and together with the atoms on the azole ring to form an unsubstituted or optionally substituted R d Substituted C 6 Aryl; R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; R 2 , R 3 Selected from C 1 alkyl; X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl; Z - Selected from tetrafluoroborate ion and iodide ion.

7. The use according to claim 1, It is characterized in that The compound is 8. A method for modifying or labeling an amino group in a molecule, It is characterized in that The invention comprises using a compound to modify or label an amino group in a molecule, wherein the compound is a compound represented by formula (III), and stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof: in: R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylamino, C 6 -C 20 Aryl, C 6 -C 20 Aryloxy, C 6 -C 20 Arylthio, C 6 -C 20 Aromatic amino group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl; Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si; R a , R b are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy; R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl; R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl; X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 -C 3 alkyl; Z - Selected from acid ions; Optionally, the R 1 is one or two substituents on the azole ring, each R 1 Each independently selected from halogen, -OH, -CN, -NO 2 、-C(=O)R a 、-C(=O)-OR b , unsubstituted or optionally substituted with at least one R c Substituted with the following groups: -NH 2 , -SH, -C(=O)NH, C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkylthio, C 1 -C 5 Alkylamino, C 6 -C 10 Aryl, C 6 -C 10 Aryloxy, C 6 -C 10 Arylthio, C 6 -C 10 Aromatic amino group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl; Or, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si; R a , R b are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R c Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl; Optionally, when R 1 When there are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form an unsubstituted or optionally substituted R d Substituted with the following groups: C 6 Aryl; Optionally, the R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl; R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl; Optionally, the R 2 , R 3 are independently selected from C 1 alkyl; Optionally, X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 alkyl; Optionally, the X and Y are independently selected from O, S, NH, and the NH is replaced by an R h replace; R h Selected from C 1 alkyl; Optionally, the acid ions include inorganic acid ions, organic acid ions or halide ions; Optionally, the inorganic acid ion comprises a nitrate ion, a sulfate ion, a phosphate ion, a chlorate ion, an iodate ion, a perchlorate ion, a periodate ion, a tetrafluoroborate ion or a hexafluorophosphate ion; Optionally, the organic acid ion includes an alkylsulfonate ion, a benzenesulfonate ion, an acetate ion, a tartrate ion, a salicylate ion, a maleate ion, a succinate ion, a citrate ion, a glycerate ion or an ascorbate ion; Optionally, the halide ion comprises fluoride ion, chloride ion, bromide ion or iodide ion; Optionally, R 1 are two substituents on the azole ring, the two substituents are connected to each other and together with the atoms on the azole ring to form an unsubstituted or optionally substituted R d Substituted C 6 Aryl; R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; R 2 , R 3 Selected from C 1 alkyl; X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl; Z - Selected from tetrafluoroborate ion and iodide ion; Optionally, the compound is Optionally, the molecule comprises an amino acid ester, an amino amide, a peptide or a protein; Optionally, the method further comprises dissolving the compound in solvent A, adding the molecule to react, and obtaining a product in which the amino group in the molecule is labeled or modified; Optionally, the solvent A comprises at least one selected from dimethyl sulfoxide, n-butanol, tert-butanol, isopropanol, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, water, hexamethylphosphoramide, polyethylene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.

9. A compound, It is characterized in that The compound is a compound represented by formula (IV), and its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: in: R 4 are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form a d Substituted C 6 Aryl, unsubstituted or optionally substituted with at least one R d Substituted with the following groups: C 7 -C 20 Aryl, C 3 -C 12 Cycloalkyl, 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl contains 1-5 heteroatoms independently selected from O, S, Se, Te, Po, N, P, As, B or Si; R d Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, azido-substituted C 1 -C 10 Alkoxy, C 3 -C 10 Alkynyloxy; R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 10 Alkyl, C 6 -C 20 Aryl; R e , R f are independently selected from C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 20 Aryl, 5-20 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 6 -C 20 Aryl, 5-20 membered heteroaryl; X and Y are independently selected from O, S, Se, Te, Po, NH, PH, AsH, BH, SiH 2 、SO 2 , SO, NH, PH, AsH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 -C 3 alkyl; Z - Selected from acid ions; Optionally, R d Selected from C 1 -C 5 Alkyl, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 5 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; Optionally, R 4 are two substituents on the azole ring, the two substituents are connected to each other and together with the skeleton atoms on the azole ring form a bond surrounded by 1-5 R d Substituted C 6 Aryl, unsubstituted or optionally substituted with 1-5 R d Substituted with the following groups: C 7 -C 10 Aryl, C 5 -C 7 Cycloalkyl, 5-7 membered heteroaryl; Optionally, R 4 There are two substituents on the azole ring, and the two substituents are connected to each other and form a bond with the skeleton atoms on the azole ring. d Substituted C 6 Aryl; Optionally, the R 2 , R 3 are independently selected from -C(=O)R e 、-C(=O)-OR f , unsubstituted or optionally substituted with at least one R g Substituted with the following groups: -C(=O)NH, C 1 -C 5 Alkyl, C 6 -C 10 Aryl; R e , R f are independently selected from C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl; R g Selected from halogen, -OH, -CN, -NO 2 、-NH 2 , C 1 -C 5 Alkyl, C 3 -C 5 Cycloalkyl, 3-5 membered heterocyclic group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 5 Alkyl, C 6 -C 10 Aryl; Optionally, the R 2 , R 3 are independently selected from unsubstituted or optionally substituted with at least one R g Substituted with the following groups: C 1 -C 3 Alkyl, C 6 -C 8 Aryl; Optionally, the R 2 , R 3 are independently selected from C 1 alkyl; Optionally, X and Y are independently selected from O, S, Se, NH, BH, SiH 2 、SO 2 , SO, NH, BH, SiH 2 Optionally, at least one R h replace; R h Selected from C 1 alkyl; Optionally, the X and Y are independently selected from O, S, NH, and the NH is replaced by an R h replace; R h Selected from C 1 alkyl; Optionally, the acid ions include inorganic acid ions, organic acid ions or halide ions; Optionally, the inorganic acid ion comprises a nitrate ion, a sulfate ion, a phosphate ion, a chlorate ion, an iodate ion, a perchlorate ion, a periodate ion, a tetrafluoroborate ion or a hexafluorophosphate ion; Optionally, the organic acid ion includes an alkylsulfonate ion, a benzenesulfonate ion, an acetate ion, a tartrate ion, a salicylate ion, a maleate ion, a succinate ion, a citrate ion, a glycerate ion or an ascorbate ion; Optionally, the halide ion comprises fluoride ion, chloride ion, bromide ion or iodide ion; Optionally, R 4 are two substituents on the azole ring, the two substituents are connected to each other and form a bond with at least one R d Substituted C 6 Aryl; R d Selected from C 1 -C 2 Alkoxy, azido-substituted C 1 -C 2 Alkoxy, C 4 -C 9 Alkynyloxy; R 2 , R 3 Selected from C 1 alkyl; X and Y are independently selected from O, S, and NH, wherein NH is separated by an R h Replacement, R h Selected from C 1 alkyl; Z - Selected from tetrafluoroborate ion and iodide ion; Optionally, the compound is 10. A method for preparing the compound according to claim 9, It is characterized in that The method comprises: The compound represented by formula (II) and compound R 3 OZ reaction to obtain a compound represented by formula (IV); Or the compound represented by formula (II) and compound R 3 -Z reaction to obtain a compound represented by formula (IV); Optionally, the method further comprises dissolving the compound represented by formula (II) in solvent B, adding compound R 3 OZ reaction to obtain a compound represented by formula (IV); Optionally, the solvent B comprises at least one selected from anhydrous dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, tetrahydrofuran, 1,4-dioxane, n-hexane, n-pentane, cyclohexane, chloroform, carbon tetrachloride, chlorobenzene, fluorobenzene, bromobenzene, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, benzene, toluene, xylene, acetonitrile, acetone, ethyl ether, methyl ethyl ether, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, ethylene glycol methyl ether, methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide; Optionally, the compound represented by formula (II) and compound R 3 The molar ratio of OZ is (1:10000)-(100:1), preferably (1:1)-(1:5); Optionally, the method further comprises dissolving the compound represented by formula (II) in solvent C, adding compound R 3 -Z reaction to obtain a compound represented by formula (IV); Optionally, the solvent C comprises at least one selected from acetonitrile, acetone, and N,N-dimethylformamide; Optionally, the compound represented by formula (II) and compound R 3 The molar ratio of -Z is (1:10000) to (100:1), preferably (1:1) to (1:5).

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