Cyp51-targeted azole compound and use thereof

Abstract

The present invention belongs to the technical field of drug synthesis. Specifically, disclosed are an azole derivative as shown in general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, a preparation method therefor, and the use thereof in the preparation of a drug for preventing or treating various diseases caused by fungal infections.

Description

A class of azole compounds targeting CYP51 and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese application No. 202410300921.3, filed on March 15, 2024. Said application No. 202410300921.3 is hereby incorporated by reference in its entirety. Technical Field

[0003] The present invention belongs to the technical field of drug synthesis, and specifically relates to an azole derivative and its pharmaceutically acceptable salt, hydrate, solvate and prodrug, a preparation method thereof and its use in preparing drugs for treating various diseases caused by fungal infections. Background Art

[0004] Fungal infections can be divided into superficial and deep fungal infections. Deep fungal infections, also known as invasive fungal infections, are a class of diseases with high morbidity and mortality. Every year, hundreds of millions of patients worldwide are infected with pathogens, resulting in at least 1.5 to 2 million deaths. In recent years, the widespread use of organ transplants and the growing number of HIV-infected people have led to a growing number of immunocompromised individuals, resulting in a yearly increase in the incidence of invasive fungal infections.

[0005] Candida, Cryptococcus, and Aspergillus are the three major pathogens of invasive fungal infections. Despite the significant threat posed to humans by fungal infections, effective clinical treatments for these infections remain limited. Currently, clinically available antifungal drugs can be divided into three categories, based on their mechanisms of action: azoles that inhibit ergosterol synthesis; echinocandins that disrupt cell walls; polyenes that cause cell membrane leakage; and antimetabolites that act on nucleic acids. Azoles exert their antibacterial effects by inhibiting the activity of lanosterol 14α-demethylase (CYP51), thereby blocking the synthesis of ergosterol, a key component of fungal cell membranes. Currently, azole antifungal drugs in clinical practice are mainly divided into three categories: imidazole drugs, such as miconazole and ketoconazole; triazole drugs, such as fluconazole, itraconazole, voriconazole and posaconazole; and tetrazole drugs, such as oteconazole.

[0006] Although azole drugs play an irreplaceable role in clinical practice, they still have certain shortcomings, such as a narrow antibacterial spectrum, drug-drug interactions, and the emergence of drug resistance. This makes the development of new, broad-spectrum, highly effective, and low-toxic antifungal drugs of great significance. Summary of the Invention

[0007] The object of the present invention is to provide a novel azole derivative and a preparation method thereof and use thereof as a medicine, especially as a CYP51 inhibitor.

[0008] To achieve the above purpose, the present invention adopts the following technical solutions:

[0009] An azole derivative, wherein the derivative is a compound represented by general formula I, or a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0010] wherein MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, or an optionally substituted pyrazolyl, wherein the optionally substituted refers to a C1-4 alkyl substitution or a C1-4 alkoxy substitution;

[0011] X is carbonyl, sulfoxide or sulfone, or CH2, NH, O or S;

[0012] R 1 is H, -P(O)(OH)2, -CH2-OP(O)(OH)2, or -C(O)alkyl optionally substituted by amino, wherein the alkyl is a C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0013] R 2 The phenyl ring is substituted, the substituent may be located at the ortho, meta or para position, may be monosubstituted or polysubstituted, and the substituent is selected from halogen, wherein the halogen is F, Cl, Br or I;

[0014] R 3 is hydrogen, halogen, alkyl or haloalkyl, wherein the alkyl is a C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0015] R 4 Selected from i, ii or iii, wherein the substituents may be located at the ortho, meta or para position and may be monosubstituted or polysubstituted;

[0016] i. halogen, wherein the halogen is F, Cl, Br or I;

[0017] ii. a C1-6 straight chain or branched alkyl group, which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0018] iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, methoxy, ethoxy, phenyl, amino or alkynyl.

[0019] In a preferred embodiment, MBG is selected from the following structures: X is CH2.

[0020] In a preferred embodiment, wherein R 1 and R 3 is hydrogen; R 2 It is 2,4-difluorophenyl.

[0021] In a preferred embodiment, wherein R4 is selected from i, ii or iii, wherein the substituent position may be located at the ortho, meta or para position, and may be monosubstituted or polysubstituted;

[0022] i. halogen, wherein the halogen is F, Cl, Br or I;

[0023] ii. a C1-6 straight chain or branched alkyl group, which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0024] iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, methoxy, ethoxy, phenyl, amino or alkynyl.

[0025] In a preferred embodiment, the derivative is a compound represented by general formula I, or a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, selected from:

[0026] 1-((4-(4-Benzylpiperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0027] 2-(2,4-Difluorophenyl)-1-((4-(4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0028] 1-((4-(4-(4-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0029] 1-((4-(4-(4-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0030] 2-(2,4-Difluorophenyl)-1-((4-(4-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0031] 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0032] 2-(2,4-Difluorophenyl)-1-((4-(4-methoxybenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0033] 2-(2,4-Difluorophenyl)-1-((4-(4-isopropylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0034] 1-((4-(4-(4-(4-tert-butyl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0035] 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-nitrobenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0036] 4-((4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)methyl)benzonitrile

[0037] 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0038] 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0039] 1-((4-((1,1'-biphenyl)-4-ylmethyl)piperazin-1-yl)benzyl(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0040] 1-((4-(4-(4-aminobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0041] 2-(2,4-Difluorophenyl)-1-((4-(4-ethynylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0042] 2-(2,4-Difluorophenyl)-1-((4-(2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0043] 2-(2,4-Difluorophenyl)-1-((4-(3-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0044] 1-((4-(4-(2-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0045] 1-((4-(4-(3-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0046] 1-((4-(4-(2-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0047] 1-((4-(4-(3-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0048] 1-((4-(4-(2-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0049] 1-((4-(4-(3-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0050] 1-((4-(4-(2-bromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0051] 1-((4-(4-(2-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0052] 1-((4-(4-(2-bromo-6-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0053] 1-((4-(4-(2-bromo-4-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0054] 1-((4-(4-(2-bromo-5-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0055] 1-((4-(4-(2-bromo-6-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0056] 1-((4-(4-(2,4-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0057] 1-((4-(4-(2,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0058] 1-((4-(4-(2,6-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0059] 1-((4-(4-(2-bromo-4-(trifluoromethyl)benzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0060] 1-((4-(4-(2,6-dibromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0061] 1-((4-(4-(2-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0062] 1-((4-(4-(2-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0063] 2-(2,4-Difluorophenyl)-1-((4-(4-(2-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0064] 1-((4-(4-(3-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0065] 1-((4-(4-(tert-Butyl)benzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0066] 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(tetrafluoromethyl)benzyl)piperazin-1-yl)benzyl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0067] 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-(tetrafluoromethoxy)benzyl)piperazin-1-yl)benzylamino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0068] 1-((4-(4-(2-bromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0069] 1-((4-(4-(2-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0070] 1-((4-(4-(2-bromo-4-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0071] 1-((4-(4-(2,4-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0072] 1-((4-(4-(2-bromo-6-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0073] 1-((4-(4-(3-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0074] 1-((4-(4-(3-bromo-5-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0075] 1-((4-(4-(3,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0076] 1-((4-(4-(5-bromo-2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0077] 1-((4-(4-(5-bromo-2-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0078] 1-((4-(4-(2,5-Dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol.

[0079] Furthermore, according to common methods in the field of the present invention, some compounds of general formula I of the present invention have basic groups and can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.

[0080] In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula I that may have weak or even no activity themselves, but after administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or other means).

[0081] The compounds of Formula I may be in unsolvated forms and solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.). The compounds of Formula I may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemic mixtures), are included within the scope of the present invention.

[0082] The compounds of formula I may exist in different tautomeric forms, all of which are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that interconvert via a low energy barrier.

[0083] In the definition of compounds of general formula I given above, the terms used are generally defined as follows:

[0084] Optionally substituted substituents: C1-C4 alkyl, C1-C4 alkoxy.

[0085] Halogen: refers to fluorine, chlorine, bromine or iodine.

[0086] Alkyl: a straight or branched chain alkyl group, preferably, the alkyl group is a C1-6 straight or branched chain alkyl group, for example, it can be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl.

[0087] Cycloalkyl: a substituted or unsubstituted cyclic alkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents include methyl, halogen, etc.

[0088] Haloalkyl: a straight-chain or branched alkyl group, in which the hydrogen atoms may be partially or completely replaced by halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.

[0089] Alkoxy: a straight or branched chain alkyl group, the hydrogen atom of the hydroxyl group may be substituted by these straight or branched chain alkyl groups, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, etc. Aliphatic ring containing 1-2 heteroatoms, such as cyclic alkyl groups of N, O, and S, such as tetrahydrofuranyl, piperidinyl, piperazinyl, etc.

[0090] The present invention may contain derivatives of Formula I, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to form compositions, and then prepared into clinically acceptable dosage forms. The pharmaceutically acceptable excipients described above refer to any diluent, adjuvant, and / or carrier useful in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.

[0091] The pharmaceutical composition of the present invention can be formulated into several dosage forms, wherein the pharmaceutical composition contains some commonly used excipients in the pharmaceutical field. The above-mentioned several dosage forms can be injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, ointments and other dosage forms.

[0092] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, preservatives, solubilizers and bases, etc. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0093] The compounds of formula I of the present invention can be synthesized by methods well known in the chemical field, especially prepared according to the description of the present invention; room temperature in the present invention refers to ambient temperature, which is 25°C.

[0094] The preparation method of the derivative represented by the above general formula I is as follows:

[0095] Starting from 2'-chloro-2,4-difluoroacetophenone, a substitution reaction with triazole or tetrazole under alkaline conditions is performed to obtain intermediate 2. Intermediate 2 is then cyclized with trimethylsulfoxide iodide under alkaline conditions to obtain intermediate 3. Intermediate 4 undergoes a substitution reaction with N-Boc-piperazine under high temperature and alkaline conditions to obtain intermediate 5. Intermediate 5 undergoes reductive amination with methylamine to obtain intermediate 6. Intermediate 6 is then subjected to ring opening with intermediate 3 under alkaline conditions to obtain intermediate 7. Subsequently, the Boc protection is removed under acidic conditions to obtain intermediate 8. Finally, the product 9 is reacted with the corresponding substituted benzyl bromide under alkaline conditions. Target compounds with similar structures can also be prepared according to the above general method.

[0096] In the above preparation process, MBG and R 4 , as defined above.

[0097] Furthermore, 2'-chloro-2,4-difluoroacetophenone is used as a starting material, and a substitution reaction occurs with triazole or tetrazole under alkaline conditions to obtain intermediate 2, and the reaction temperature is 0-70°C, preferably 25°C; the base in the reaction can be sodium hydride, triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably potassium carbonate; the catalyst in the reaction can be benzyltriethylammonium chloride, tetraethylammonium bromide, benzyltrimethylammonium chloride, polyethylene glycol, and the most preferred is benzyltriethylammonium chloride; the reaction solvent can be acetonitrile, tetrahydrofuran, toluene, dichloromethane, N,N-dimethylformamide, preferably dichloromethane. Intermediate 2 is cyclized with trimethylsulfoxide iodide under high temperature alkaline conditions to obtain intermediate 3. The reaction solvent can be toluene / water, dichloromethane / water, acetonitrile / water, preferably dichloromethane / water; the reaction temperature is 30-80°C, preferably 50°C; the catalyst in the reaction can be hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetrabutylammonium bromide, tetraethylammonium bromide, benzyltrimethylammonium chloride, preferably benzyltrimethylammonium chloride; the base in the reaction can be sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine , N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, etc., preferably sodium hydroxide; Intermediate 4 reacts with N-Boc-piperazine under alkaline and high temperature conditions to produce Intermediate 5, the reaction temperature being 90-150°C, preferably 135°C; the reaction solvent can be dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably N-methylpyrrolidone; the base can be potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate. Intermediate 5 undergoes reductive amination with methylamine to produce Intermediate 5, the reaction temperature being 0-50°C, preferably 25°C; the reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., preferably methanol; the reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 3 and Intermediate 6 undergo ring opening under alkaline conditions to produce Intermediate 7. The reaction solvent can be ethanol or N,N-dimethylformamide, preferably ethanol. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine. The reaction temperature is 50-120°C, preferably 80°C. The Boc protecting group is removed under acidic conditions to produce Intermediate 8. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, preferably ethyl acetate. The reaction temperature is 0-70°C, preferably 25°C. The acid in the reaction can be a saturated solution of hydrogen chloride in ethyl acetate, a solution of hydrogen chloride in ethanol, a solution of hydrogen chloride in 1,4-dioxane, a solution of hydrogen chloride in methanol, an aqueous solution of hydrogen chloride, p-toluenesulfonic acid, trifluoroacetic acid, etc., preferably a saturated solution of hydrogen chloride in ethyl acetate.Finally, a substitution reaction with the corresponding benzyl bromide is carried out to obtain the final product 9. The reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, methanol, etc., preferably acetonitrile; the reaction temperature is 0-70°C, preferably 25°C; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine.

[0098] The present invention relates to the use of azole derivatives, compounds represented by general formula I, and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in the preparation of drugs for preventing or treating diseases related to fungal infections.

[0099] The use of the azole derivatives represented by general formula I, and their stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of antifungal drugs.

[0100] A pharmaceutical composition comprises an azole derivative represented by general formula I and its stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs as active ingredients and a pharmaceutically acceptable excipient.

[0101] The composition is used in preparing medicines for preventing or treating diseases related to fungal infection.

[0102] The invention relates to an application of the composition in preparing antifungal drugs.

[0103] The present invention provides novel azole derivatives, their preparation methods, pharmaceutical compositions, and applications. These azole derivatives exhibit excellent antifungal activity against various superficial and deep-seated fungi. Compared with existing clinically used antifungal drugs, they possess advantages such as high efficacy, low toxicity, and a broad antifungal spectrum, and can be used to prepare antifungal drugs. DETAILED DESCRIPTION

[0104] The examples are intended to illustrate rather than limit the scope of the present invention. The H NMR spectra of the compounds were determined using a Bruker ARX-600; all reagents used were of analytical or chemical purity.

[0105] The specific embodiment structure is as follows:

[0106] The preparation route of Example 1 is as follows:

[0107] The specific synthesis steps are as follows:

[0108] Synthesis of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one (2)

[0109] 1,2,4-Triazole (20.00 g, 0.29 mol), benzyltriethylammonium chloride (2.20 g, 0.01 mmol), and potassium carbonate (41.42 g, 0.30 mmol) were added to a dichloromethane solution. A dichloromethane solution of Intermediate 1 (2.00 g, 0.19 mmol) was added dropwise under an ice bath. After completion of the addition, the mixture was stirred at room temperature for 12 hours. TLC (DCM:MeOH = 50:1) confirmed complete reaction. The mixture was filtered, the filter cake washed with dichloromethane, and the organic phase concentrated and isolated by column chromatography to yield a white solid in 80% yield.

[0110] Synthesis of 1-((2-(2,4-difluorophenyl)oxirane-2-yl)methyl)-1H-1,2,4-triazole (3)

[0111] Trimethylsulfoxide iodide (28.29 g, 0.13 mol) was dissolved in aqueous NaOH and allowed to react at room temperature for 2 h. Intermediate 2 (25.00 g, 0.11 mol), benzyltrimethylammonium chloride (0.99 g, 0.005 mol), and dichloromethane were then added and allowed to react at 55°C for 6 h. TLC (DCM:MeOH = 50:1) confirmed the complete reaction. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The mixture was separated by column chromatography to afford a pale yellow solid in a 75% yield.

[0112] Synthesis of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (5)

[0113] Intermediate 4 (10.00 g, 0.080 mol), N-Boc-piperazine (16.57 g, 0.089 mol), and potassium carbonate (22.11 g, 0.16 mol) were added to an N-methylpyrrolidone solution and reacted at 135°C for 18 h. TLC monitoring (PE:EA = 10:1) indicated complete reaction. The reaction solution was added to 300 mL of water, resulting in the precipitation of a brownish-yellow solid. This solid was filtered and separated by column chromatography to afford a white solid in a 68% yield.

[0114] Synthesis of tert-butyl 4-((methylamino)methyl)phenyl)piperazine-1-carboxylate (6)

[0115] Intermediate 5 (10.00 g, 0.034 mol) and aqueous methylamine (1.28 g, 0.041 mol) were added to a methanol solution and allowed to react at room temperature for 30 minutes. The reducing agent, sodium borohydride (1.95 g, 0.051 mol), was then added and the reaction continued at room temperature for 1 hour. TLC (DCM:MeOH = 20:1) confirmed complete reaction. The mixture was concentrated under reduced pressure and isolated by column chromatography to yield a yellow oil in an 86% yield.

[0116] Synthesis of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)phenyl)piperazine-1-carboxylate (7)

[0117] Intermediate 3 (10.00 g, 0.042 mol), intermediate 6 (14.81 g, 0.048 mol), and triethylamine (21.32 g, 0.21 mol) were added to anhydrous ethanol at room temperature and refluxed for 6 hours. TLC (DCM:MeOH = 30:1) confirmed complete reaction. The mixture was concentrated under reduced pressure and isolated by column chromatography to afford a white solid in a 78% yield.

[0118] Synthesis of 2-(2,4-difluorophenyl)-1-(methyl(4-(piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (8)

[0119] Intermediate 7 (10.00 g, 0.018 mol) was dissolved in 20 mL of a saturated solution of hydrogen chloride in ethyl acetate and allowed to react at room temperature for 2 h. TLC (DCM:MeOH = 10:1) confirmed complete reaction. The mixture was concentrated under reduced pressure to afford a white solid, which was used in the next step without purification in a 95% yield.

[0120] Preparation of 1-((4-(4-benzylpiperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (Example 1)

[0121] Intermediate 8 (0.050 g, 0.11 mmol) was dissolved in 5 mL of acetonitrile, and benzyl bromide (0.021 g, 0.12 mmol) and triethylamine (0.022 g, 0.22 mmol) were added. The mixture was stirred at room temperature for 1 hour. TLC (DCM:MeOH = 10:1) confirmed the reaction was complete. The mixture was concentrated under reduced pressure and separated on a preparative thin-layer plate (DCM:MeOH = 30:1) to afford a white solid in a 79% yield. 1H NMR(600MHz,DMSO-d6)δ8.27(s,1H),7.73(s,1H),7.40(d,J=6.9Hz,1H),7.33(s,4H),7.27 (s,1H),7.16–7.11(m,1H),6.95(td,J=8.4,2.4Hz,1H),6.91(d,J=8.2Hz,2H),6.79(d,J=8 .2Hz,2H),5.68(s,1H),4.53–4.46(m,2H),3.51(s,2H),3.40(d,J=13.0Hz,1H),3.29(d,J= 13.6Hz,1H),3.08(s,4H),2.95(d,J=13.7Hz,1H),2.73(d,J=13.4Hz,1H),2.03(s,3H).HRMS calcd for C 30 H 34 F2N6O,[M+Na] + ,555.2660;found 555.2653.

[0122] According to the method of Example 1, corresponding raw materials were used to prepare Examples 2-33.

[0123] Example 2: 2-(2,4-difluorophenyl)-1-((4-(4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0124] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.73(s,1H),7.43–7.39(m,1H),7.36(t,J=6.8Hz,2H),7. 14(q,J=12.7,10.5Hz,3H),6.96(d,J=6.5Hz,1H),6.91(d,J=8.2Hz,2H),6.79(d,J=8.2Hz,2H), 5.69(s,1H),4.50(q,J=14.3Hz,2H),3.50(s,2H),3.41(d,J=13.0Hz,1H),3.29(d,J=13.0Hz,1 H),3.08(s,4H),2.96(d,J=13.6Hz,1H),2.74(d,J=13.7Hz,1H),2.48(s,4H),2.03(s,3H).HRMS calcd for C 30 H 33 F3N6O,[M+Na] +,573.2566;found 573.2531.

[0125] Example 3: 1-((4-(4-(4-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0126] 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),8.00(s,1H),7.84(s,1H),7.72(s,1H),7.32( s,3H),7.01(d,J=8.0Hz,2H),6.80(dd,J=16.7,7.7Hz,4H),4.89(s,1H),4.79(d,J=14.2 Hz,1H),4.65(d,J=14.1Hz,1H),4.43(s,1H),4.38(d,J=11.9Hz,1H),3.58(s,1H),3.40( s,1H),3.23(s,4H),3.05(d,J=13.4Hz,1H),2.81(s,1H),2.64(s,4H),2.04(s,3H).HRMS calcd for C 30 H 33 ClF2N6O,[M+Na] + ,589.2270;found 589.2291.

[0127] Example 4: 1-((4-(4-(4-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0128] 1H NMR (600MHz, DMSO-d6) δ8.27(s,1H),7.73(s,1H),7.40(d,J=6.9Hz,1H),7.33(s,3H),7.2 7(s,1H),7.16–7.11(m,1H),6.96(d,J=6.9Hz,1H),6.91(d,J=8.2Hz,2H),6.79(d,J=8.2Hz ,2H),5.68(s,1H),4.53–4.46(m,2H),3.51(s,2H),3.40(d,J=12.9Hz,1H),3.30(s,1H),3 .08(s,4H),2.95(d,J=13.7Hz,1H),2.73(d,J=13.4Hz,1H),2.50(s,4H),2.03(s,3H).HRMS calcd for C 30 H 33 BrF2N6O,[M+Na] + ,635.1745;found 635.1836.

[0129] Example 5: 2-(2,4-difluorophenyl)-1-((4-(4-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0130] 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.72(s,1H),7.66(d,J=8.2Hz,2H),7.57(q, J=8.7Hz,1H),7.13(d,J=7.9Hz,2H),7.01(d,J=8.2Hz,2H),6.80(dd,J=18.3,8.4Hz,4H ),4.47–4.40(m,2H),3.53(s,2H),3.40(d,J=12.8Hz,1H),3.28(d,J=12.8Hz,1H),3.20 (s,4H),3.05(d,J=13.5Hz,1H),2.81(d,J=13.5Hz,1H),2.61(s,4H),2.01(s,3H).HRMS calcd for C 30 H 33 F2IN6O,[M+Na] + ,681.1626;found 681.1640.

[0131] Example 6: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0132] 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.72(s,1H),7.56(s,1H),7.30(s,2H),7.1 7(d,J=7.6Hz,2H),7.00(d,J=8.1Hz,2H),6.84–6.76(m,5H),5.34(s,1H),4.79(d,J=1 4.2Hz,1H),4.65(d,J=14.2Hz,1H),4.46–4.36(m,3H),3.65(s,1H),3.39(d,J=12.9Hz ,1H),3.28(s,4H),3.04(d,J=13.4Hz,1H),2.72(s,4H),2.35(s,3H),2.00(s,3H).HRMS calcd for C 31 H 36 F2N6O,[M+Na] + ,569.2816;found 569.2820.

[0133] Example 7: 2-(2,4-difluorophenyl)-1-((4-(4-methoxybenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0134] 1H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.73(s,1H),7.41(q,J=8.9Hz,1H),7.25(t,J=7.7Hz,1H),7.13( t,J=9.5Hz,1H),6.96(d,J=9.2Hz,1H),6.93–6.88(m,4H),6.83(d,J=8.4Hz,1H),6.79(d,J=8.2Hz,2H) ,5.72(s,1H),4.50(q,J=14.3Hz,2H),3.74(s,3H),3.50(s,4H),3.39(s,2H),3.37(d,J=10.4Hz,1H), 3.29(d,J=12.9Hz,1H),3.09(s,4H),2.96(d,J=13.7Hz,1H),2.74(d,J=13.7Hz,1H),2.03(s,3H).HRMS calcd for C 31 H 36 F2N6O2,[M+Na] + ,585.2766;found 585.2783.

[0135] Example 8: 2-(2,4-difluorophenyl)-1-((4-(4-isopropylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0136] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.73(s,1H),7.41(d,J=6.9Hz,1H),7.23(d,J=7.9Hz,2H),7.19(d,J=8.0Hz, 2H),7.14–7.11(m,1H),6.95(dd,J=8.5,2.6Hz,1H),6.91(d,J=8.4Hz,2H),6.78(d,J=8.5Hz,2H),5.71(s,1H),4.5 3(d,J=14.3Hz,1H),4.48(d,J=14.3Hz,1H),3.47(s,2H),3.41(s,1H),3.29(d,J=13.0Hz,1H),3.07(s,4H),2.96( d,J=13.7Hz,1H),2.88–2.84(m,1H),2.74(d,J=13.6Hz,1H),2.48(s,4H),2.03(s,3H),1.19(d,J=6.9Hz,6H).HRMS calcd for C 33 H40 F2N6O,[M+H] + ,575.3310;found 575.3352.

[0137] Example 9: 1-((4-(4-(4-(4-tert-butyl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0138] 1 H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.74(s,1H),7.42(q,J=8.5Hz,1H),7.35(d,J=7.9Hz,2H),7.25 (d,J=7.9Hz,2H),7.16–7.11(m,1H),6.98–6.94(m,1H),6.92(d,J=8.1Hz,2H),6.79(d,J=8.2Hz,2H), 5.71(s,1H),4.51(q,J=14.3Hz,2H),3.49(s,2H),3.42(s,1H),3.30(d,J=13.0Hz,1H),3.08(s,4H), 2.96(d,J=13.6Hz,1H),2.75(d,J=13.7Hz,1H),2.50(d,J=9.1Hz,4H),2.04(s,3H),1.28(s,9H).HRMS calcd for C 34 H 42 F2N6O,[M+H] + ,589.3466;found 589.3478.

[0139] Example 10: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-nitrobenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0140] 1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),8.22(d,J=8.7Hz,2H),7.74(s,1H),7.63(d,J=8.7Hz,2H),7.43–7 .39(m,1H),7.16–7.12(m,1H),6.96(td,J=8.5,2.6Hz,1H),6.92(d,J=8.7Hz,2H),6.80(d,J=8.7Hz,2H ),5.69(s,1H),4.54–4.46(m,2H),3.67(s,2H),3.41(d,J=12.9Hz,1H),3.30(d,J=13.0Hz,1H),3.11(t ,J=4.9Hz,4H),2.96(d,J=14.6Hz,1H),2.74(d,J=13.7Hz,1H),2.53(t,J=5.0Hz,4H),2.04(s,3H). calcd for C 30 H 33 F2N7O3,[M+Na] + ,600.2511;found 600.2551.

[0141] Example 11: 4-((4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)methyl)benzonitrile

[0142] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.81(d,J=8.3Hz,2H),7.74(s,1H),7.55(d,J=8.0Hz,2H),7. 41(d,J=6.9Hz,1H),7.16–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.3Hz,2H),6.80(d,J=8.8Hz ,2H),5.69(s,1H),4.50(q,J=14.2Hz,2H),3.61(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=13.0Hz ,1H),3.10(s,4H),2.96(d,J=15.5Hz,1H),2.74(d,J=13.7Hz,1H),2.51(s,4H),2.04(s,3H).HRMS calcd for C 31 H 33 F2N7O,[M+Na] +,580.2612;found 580.2656.

[0143] Example 12: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0144] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.74(s,1H),7.70(d,J=8.0Hz,2H),7.57(d,J=7.9Hz,2H),7 .44–7.39(m,1H),7.16–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.5Hz,2H),6.80(d,J=8.8Hz, 2H),5.70(s,1H),4.50(q,J=14.3Hz,2H),3.61(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=13.0Hz ,1H),3.10(s,4H),2.96(d,J=13.7Hz,1H),2.74(d,J=13.6Hz,1H),2.51(s,4H),2.04(s,3H).HRMS calcd for C 31 H 33 F5N6O,[M+Na] + ,623.2534;found 623.2582.

[0145] Example 13: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0146] 1H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.74(s,1H),7.46(d,J=8.4Hz,2H),7.44–7.39(m,1H),7.33(d ,J=8.1Hz,2H),7.16–7.11(m,1H),6.95(td,J=8.6,2.8Hz,1H),6.92(d,J=8.3Hz,2H),6.79(d,J=8. 4Hz,2H),5.70(s,1H),4.51(q,J=14.3Hz,2H),3.55(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=13.0 HRMS calcd for C 31 H 33 F5N6O2,[M+Na] + ,639.2483;found 639.2493.

[0147] Example 14: 1-((4-([1,1'-biphenyl]-4-ylmethyl)piperazin-1-yl)benzyl(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0148] 1 H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.74(s,1H),7.67(d,J=7.1Hz,2H),7.64(d,J=7.8Hz,2H),7.47(t,J=7. 7Hz,2H),7.42(d,J=8.0Hz,3H),7.36(t,J=7.4Hz,1H),7.17–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.3Hz ,2H),6.80(d,J=8.3Hz,2H),5.69(s,1H),4.51(q,J=14.3Hz,2H),3.56(s,2H),3.41(d,J=13.0Hz,1H),3.30( HRMS calcd for C 36 H 38F2N6O,[M+H] + ,609.3153;found 609.3142.

[0149] Example 15: 1-((4-(4-(4-aminobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0150] 1 H NMR (600MHz, DMSO-d6) δ8.35(s,1H),7.78(s,1H),7.46(d,J=7.1Hz,1H),7.19(t,J=9.1Hz,1H) ,7.08(s,2H),7.02–7.00(m,1H),6.97(d,J=8.1Hz,2H),6.85(d,J=8.1Hz,2H),6.59(d,J=7.8H z,2H),5.79(s,1H),4.59–4.52(m,2H),3.46(d,J=10.9Hz,2H),3.35(d,J=12.8Hz,2H),3.11(q ,J=7.2Hz,4H),3.02(d,J=13.7Hz,1H),2.78(d,J=13.3Hz,1H),2.56(s,4H),2.08(s,3H).HRMS calcd for C 30 H 35 F2N7O,[M+H] + ,548.2949;found 548.2949.

[0151] Example 16: 2-(2,4-difluorophenyl)-1-((4-(4-ethynylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0152] 1H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.75(s,1H),7.45(d,J=7.8Hz,2H),7.42–7.39(m,1H),7.35(d, J=7.9Hz,2H),7.16–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.2Hz,2H),6.79(d,J=8.7Hz,2H),5. 69(s,1H),4.50(q,J=14.3Hz,2H),4.15(s,1H),3.53(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=13.1 HRMS calcd for C 32 H 34 F2N6O,[M+Na] + ,579.2660;found 579.2698.

[0153] Example 17: 2-(2,4-difluorophenyl)-1-((4-(2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0154] 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.72(s,1H),7.59–7.54(m,1H),7.46(s,1H),7. 27(d,J=7.1Hz,1H),7.14(t,J=7.4Hz,1H),7.06(t,J=8.8Hz,1H),7.01(d,J=8.0Hz,2H),6.8 3–6.76(m,4H),4.47–4.40(m,2H),3.72(s,2H),3.40(d,J=11.7Hz,1H),3.28(s,1H),3.24( s,4H),3.05(d,J=13.0Hz,1H),2.81(d,J=13.1Hz,1H),2.77–2.64(m,4H),2.01(s,3H).HRMS calcd for C 30 H 33 F3N6O,[M+Na] + ,573.2566;found 573.2594.

[0155] Example 18: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0156] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.73(s,1H),7.43–7.36(m,2H),7.17(d,J=7.7Hz,1H),7.15 (d,J=9.4Hz,2H),7.11–7.06(m,1H),6.97–6.94(m,1H),6.92(d,J=8.3Hz,2H),6.79(d,J=8.3Hz, 2H),5.70(s,1H),4.51(q,J=14.3Hz,2H),3.54(s,2H),3.41(d,J=12.9Hz,1H),3.30(d,J=13.0Hz ,1H),3.09(s,4H),2.96(d,J=13.6Hz,1H),2.74(d,J=13.7Hz,1H),2.49(s,4H),2.04(s,3H).HRMS calcd for C 30 H 33 F3N6O,[M+Na] + ,573.2566;found 573.2586.

[0157] Example 19: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0158] 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.73(s,1H),7.60–7.54(m,1H),7.39(s,1H),7.28(s,1H),7.24(s,2H),7.02(d,J=8.0Hz,2H),6.84–6 .75(m,4H),4.44(q,J=14.2Hz,2H),3.58(s,2H),3.40(s,1H),3.29(s,1H ),3.23(s,4H),3.05(s,1H),2.82(s,1H),2.64(s,4H),2.01(s,3H).HRMS calcd for C 30 H 33 ClF2N6O,[M+Na]+ ,589.2270;found 589.2294

[0159] Example 20: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0160] 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.73(s,1H),7.60–7.54(m,1H),7.39(s,1H),7.28(s,1H),7.24(s,2H),7.02(d,J=8.0Hz,2H),6.84–6 .75(m,4H),4.44(q,J=14.2Hz,2H),3.58(s,2H),3.40(s,1H),3.29(s,1H ),3.23(s,4H),3.05(s,1H),2.82(s,1H),2.64(s,4H),2.01(s,3H).HRMS calcd for C 30 H 33 ClF2N6O,[M+H] + ,567.2451;found 567.2487

[0161] Example 21: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0162] 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.73(s,1H),7.57(dd,J=13.8,8.4Hz,3H), 7.31(t,J=7.5Hz,1H),7.13(t,J=7.4Hz,1H),7.02(d,J=8.0Hz,2H),6.84–6.75(m,4H) ,4.48–4.40(m,2H),3.70(s,2H),3.40(d,J=12.6Hz,1H),3.28(d,J=12.2Hz,1H),3.23 (s,4H),3.06(d,J=13.5Hz,1H),2.82(d,J=13.3Hz,1H),2.72(s,4H),2.01(s,3H).HRMS calcd for C 30 H 33BrF2N6O,[M+Na] + ,635.1745;found 635.1736.

[0163] Example 22: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0164] 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.73(s,1H),7.59–7.55(m,1H),7.53(s,1H),7.41(d ,J=7.9Hz,1H),7.30(d,J=7.6Hz,1H),7.20(t,J=7.8Hz,1H),7.01(d,J=8.1Hz,2H),6.81(dd,J=2 1.8,8.3Hz,4H),4.44(d,J=7.5Hz,2H),3.55(s,2H),3.40(d,J=13.1Hz,1H),3.28(d,J=13.0Hz, 1H),3.21(s,4H),3.05(d,J=13.5Hz,1H),2.81(d,J=13.4Hz,1H),2.62(s,4H),2.01(s,3H).HRMS calcd for C 30 H 33 BrF2N6O,[M+H] + ,611.1946;found 611.1985.

[0165] Example 23: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0166] 1H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.87(d,J=7.8Hz,1H),7.74(s,1H),7.45(d,J=8.0Hz,1H),7.40(q,J= 7.9,6.9Hz,2H),7.14(t,J=10.7Hz,1H),7.04(t,J=7.7Hz,1H),6.96(d,J=5.9Hz,1H),6.93(d,J=8.1Hz,2H) ,6.80(d,J=8.2Hz,2H),5.70(s,1H),4.51(q,J=14.3Hz,2H),3.52(s,2H),3.41(d,J=12.9Hz,1H),3.30(d, J=13.0Hz,1H),3.10(s,4H),2.96(d,J=13.5Hz,1H),2.75(d,J=13.8Hz,1H),2.57(s,4H),2.04(s,3H).HRMS calcd for C 30 H 33 F2IN6O,[M+Na] + ,681.1626;found 681.1672.

[0167] Example 24: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0168] 1 H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.72(d,J=19.2Hz,2H),7.63(d,J=7.8Hz,1H),7.42(q,J=8. 9Hz,1H),7.35(d,J=7.6Hz,1H),7.14(q,J=9.4,8.2Hz,2H),6.98–6.90(m,3H),6.79(d,J=8.2Hz, 2H),5.70(s,1H),4.51(q,J=14.3Hz,2H),3.48(s,2H),3.41(d,J=12.9Hz,1H),3.30(d,J=13.0Hz ,1H),3.09(s,4H),2.96(d,J=13.7Hz,1H),2.75(d,J=13.5Hz,1H),2.49(s,4H),2.04(s,3H).HRMS calcd for C 30 H 33 F2IN6O,[M+Na] +,681.1626;found 681.1614.

[0169] Example 25: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0170] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.74(s,1H),7.59–7.52(m,2H),7.44–7.39(m,1H),7.27(t d,J=8.5,2.7Hz,1H),7.17–7.11(m,1H),6.98–6.90(m,3H),6.80(d,J=8.8Hz,2H),5.70(s,1H), 4.51(q,J=14.3Hz,2H),3.57(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=13.0Hz,1H),3.13–3.06 (m,4H),2.96(d,J=15.4Hz,1H),2.75(d,J=13.7Hz,1H),2.56(t,J=4.9Hz,4H),2.04(s,3H).HRMS calcd for C 30 H 32 BrF3N6O,[M+Na] + ,653.1650;found 653.1665.

[0171] Example 26: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0172] 1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.74(s,1H),7.66(dd,J=8.8,5.3Hz,1H),7.44–7.39(m,1H),7 .36(dd,J=9.8,3.2Hz,1H),7.17–7.10(m,2H),6.98–6.92(m,3H),6.81(d,J=8.7Hz,2H),5.70(s,1H ),4.51(q,J=14.3Hz,2H),3.59(s,2H),3.42(d,J=13.0Hz,1H),3.30(d,J=13.0Hz,1H),3.12(t,J=4 .9Hz,4H),2.96(d,J=14.7Hz,1H),2.75(d,J=13.6Hz,1H),2.59(t,J=5.0Hz,4H),2.04(s,3H).HRMS calcd for C 30 H 32 BrF3N6O,[M+Na] + ,653.1650;found 653.1584.

[0173] Example 27: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0174] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.74(d,J=2.1Hz,1H),7.73(s,1H),7.53(d,J=8.3Hz,1H),7.47(dd,J =8.3,2.2Hz,1H),7.43–7.39(m,1H),7.16–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.3Hz,2H),6.80(d, J=8.6Hz,2H),5.69(s,1H),4.50(q,J=14.3Hz,2H),3.58(s,2H),3.41(d,J=13.0Hz,1H),3.30(d,J=12.9Hz ,1H),3.10(s,4H),2.96(d,J=15.4Hz,1H),2.74(d,J=13.7Hz,1H),2.56(t,J=4.9Hz,4H),2.04(s,3H).HRMS calcd for C 30 H 32 BrClF2N6O,[M+Na]+ ,669.1355;found 669.1393.

[0175] Example 28: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0176] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.73(s,1H),7.64(d,J=8.5Hz,1H),7.55(d,J=2.7Hz,1H),7.43–7.39 (m,1H),7.31(dd,J=8.5,2.7Hz,1H),7.14(t,J=9.2Hz,1H),6.97–6.94(m,1H),6.92(d,J=8.7Hz,2H),6.81 (d,J=8.8Hz,2H),5.69(s,1H),4.50(q,J=14.3Hz,2H),3.59(s,2H),3.41(d,J=12.9Hz,1H),3.31–3.29(m, 1H),3.11(s,4H),2.96(d,J=15.6Hz,1H),2.74(d,J=13.7Hz,1H),2.58(t,J=5.0Hz,4H),2.04(s,3H).HRMS calcd for C 30 H 32 BrClF2N6O,[M+Na] + ,669.1355;found 669.1359.

[0177] Example 29: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0178] 1H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.73(s,1H),7.65(d,J=8.0Hz,1H),7.52(d,J=8.0Hz,1H),7.41(q, J=8.4Hz,1H),7.26(t,J=8.0Hz,1H),7.17–7.11(m,1H),6.96(d,J=7.7Hz,1H),6.91(d,J=8.1Hz,2H),6.7 9(d,J=8.1Hz,2H),5.69(s,1H),4.50(q,J=14.3Hz,2H),3.75(s,2H),3.40(d,J=13.0Hz,1H),3.30(d,J= 13.3Hz,1H),3.04(s,4H),2.96(d,J=13.8Hz,1H),2.74(d,J=13.6Hz,1H),2.62(s,4H),2.03(s,3H).HRMS calcd for C 30 H 32 BrClF2N6O,[M+Na] + ,669.1355;found 669.1389.

[0179] Example 30: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0180] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.85(d,J=2.1Hz,1H),7.73(s,1H),7.60(dd,J=8.3,2.1Hz,1H), 7.47(d,J=8.2Hz,1H),7.40(t,J=7.9Hz,1H),7.16–7.12(m,1H),6.97–6.94(m,1H),6.92(d,J=8.0Hz,2 H),6.80(d,J=8.4Hz,2H),5.69(s,1H),4.50(d,J=14.7Hz,2H),3.56(s,2H),3.40(s,1H),3.30(d,J=12 .9Hz,1H),3.10(s,4H),2.96(d,J=13.8Hz,1H),2.74(d,J=13.7Hz,1H),2.56(s,4H),2.04(s,3H).HRMS calcd for C 30 H 32 Br2F2N6O,[M+Na]+ ,713.0850;found 713.0872.

[0181] Example 31: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0182] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.73(s,1H),7.68(s,1H),7.58(d,J=8.5Hz,1H),7.43– 7.39(m,2H),7.14(t,J=9.2Hz,1H),6.96(dd,J=8.9,2.5Hz,1H),6.92(d,J=8.3Hz,2H),6.81( d,J=8.2Hz,2H),5.69(s,1H),4.50(d,J=14.3Hz,2H),3.59(s,2H),3.40(s,1H),3.29(s,1H) ,3.11(s,4H),2.96(d,J=13.7Hz,1H),2.74(d,J=13.7Hz,1H),2.58(s,4H),2.04(s,3H).HRMS calcd for C 30 H 32 Br2F2N6O,[M+Na] + ,713.0850;found 713.0910.

[0183] Example 32: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0184] 1H NMR (600MHz, DMSO-d6) δ8.25(s,1H),7.96(s,1H),7.74(t,J=8.3Hz,2H),7.71(s,1H),7.38(q ,J=8.6Hz,1H),7.13–7.09(m,1H),6.94(dd,J=8.2,2.5Hz,1H),6.90(d,J=8.3Hz,2H),6.78(d, J=8.2Hz,2H),5.66(s,1H),4.51–4.44(m,2H),3.65(s,2H),3.39(d,J=12.9Hz,1H),3.26(s,1H ),3.10(s,4H),2.93(d,J=13.7Hz,1H),2.72(d,J=13.5Hz,1H),2.57(s,4H),2.01(s,3H).HRMS calcd for C 31 H 32 BrF5N6O,[M+Na] + ,701.1639;found 701.1657.

[0185] Example 33: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0186] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.74–7.68(m,3H),7.43–7.38(m,1H),7.16–7.12(m ,1H),6.97–6.93(m,1H),6.91(d,J=8.6Hz,2H),6.79(d,J=8.8Hz,2H),5.68(s,1H),4.54 –4.46(m,2H),3.74(s,2H),3.40(d,J=13.0Hz,1H),3.29(d,J=13.0Hz,1H),3.04(s,4H), 2.95(d,J=15.4Hz,1H),2.74(d,J=13.7Hz,1H),2.61(t,J=5.0Hz,4H),2.03(s,3H).HRMS calcd for C 30 H 31 Br2F3N6O,[M+Na] + ,731.0755;found 731.0711.

[0187] Referring to the method of Preparation Example 1, triazole was replaced by tetrazole, and corresponding raw materials were used to prepare Examples 34-51, respectively.

[0188] Example 34: 1-((4-(4-(2-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0189] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.61(d,J=7.9Hz,1H),7.52(d,J=6.0Hz,1H),7.38(t,J=7. 4Hz,1H),7.34–7.30(m,1H),7.23–7.18(m,2H),6.98–6.96(m,2H),6.94(dd,J=8.3,2.6Hz,1H), 6.82(d,J=8.4Hz,2H),5.93(s,1H),4.81(s,2H),3.60(s,2H),3.43(d,J=13.0Hz,1H),3.35(s,1 H),3.11(s,4H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.7Hz,1H),2.57(s,4H),2.10(s,3H).HRMS calcd for C 31 H 36 F2N6O,[M+Na] + ,634.1717;found 634.1693.

[0190] Example 35: 1-((4-(4-(2-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0191] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.52(dd,J=7.5,1.8Hz,1H),7.44(dd,J=7.8,1.4Hz,1H),7.34 (s,1H),7.30(q,J=8.0,7.6Hz,2H),7.21–7.17(m,1H),6.97(d,J=8.5Hz,2H),6.94(dd,J=8.5,2.6H z,1H),6.82(d,J=8.4Hz,2H),5.94(s,1H),4.81(s,2H),3.62(s,2H),3.43(d,J=13.0Hz,1H),3.35( s,1H),3.11(s,4H),2.95(d,J=14.6Hz,1H),2.84(d,J=13.8Hz,1H),2.57(s,4H),2.10(s,3H).HRMS calcd for C 29 H 32 ClF2N7O,[M+H] + ,568.2403;found 568.2442.

[0192] Example 36: 2-(2,4-difluorophenyl)-1-((4-(4-(2-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0193] 1 H NMR (600MHz, DMSO-d6) δ9.03(s,1H),7.79(d,J=7.8Hz,1H),7.37(d,J=6.0Hz,1H),7.32(t,J=7.4Hz,1H ),7.24(q,J=8.4Hz,1H),7.14–7.09(m,1H),6.96(t,J=7.6Hz,1H),6.90(d,J=8.5Hz,2H),6.86(dd,J=8 .6,2.6Hz,1H),6.74(d,J=8.2Hz,2H),5.86(s,1H),4.73(s,2H),3.45(s,2H),3.36(d,J=13.1Hz,1H),3 .28(s,1H),3.03(s,4H),2.88(d,J=13.8Hz,1H),2.77(d,J=13.8Hz,1H),2.49(s,4H),2.03(s,3H).HRMS calcd for C 29 H 32 F2IN7O,[M+H] +,660.1759;found 660.1805.

[0194] Example 37: 1-((4-(4-(3-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0195] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.53(s,1H),7.46(d,J=7.5Hz,1H),7.34(d,J=7.4Hz,1H),7. 31(q,J=7.6,6.9Hz,2H),7.21–7.16(m,1H),6.96(d,J=8.3Hz,2H),6.94(dd,J=8.6,2.6Hz,1H),6.8 1(d,J=8.3Hz,2H),5.93(s,1H),4.81(s,2H),3.51(s,2H),3.43(d,J=13.0Hz,1H),3.36(d,J=12.8H z,1H),3.09(s,4H),2.95(d,J=13.9Hz,1H),2.84(d,J=13.8Hz,1H),2.49(s,4H),2.10(s,3H).HRMS calcd for C 29 H 32 BrF2N7O,[M+H] + ,614.1878;found 614.1886.

[0196] Example 38: 1-((4-(4-(tert-Butyl)benzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0197] 1H NMR(600MHz,DMSO-d6)δ9.10(s,1H),7.34(d,J=8.0Hz,2H),7.30(t,J=8.2Hz,1H),7.23(d,J=7 .9Hz,2H),7.18(d,J=10.2Hz,1H),6.95(d,J=8.1Hz,2H),6.93(d,J=8.4Hz,1H),6.79(d,J=8.2 Hz,2H),5.92(s,1H),4.80(s,2H),3.46(s,2H),3.42(d,J=13.1Hz,1H),3.34(s,1H),3.07(s,4 H),2.94(d,J=13.8Hz,1H),2.83(d,J=13.8Hz,1H),2.47(s,4H),2.09(s,3H),1.27(s,9H).HRMS calcd for C 33 H 41 F2N7O,[M+H] + ,590.3419;found 590.3419.

[0198] Example 39: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0199] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.70(d,J=7.9Hz,2H),7.57(d,J=7.8Hz,2H),7.32(q, J=8.9Hz,1H),7.21–7.16(m,1H),6.97(d,J=8.4Hz,2H),6.94(dd,J=8.6,2.6Hz,1H),6.82(d ,J=8.2Hz,2H),5.93(s,1H),4.81(s,2H),3.61(s,2H),3.43(d,J=13.0Hz,1H),3.35(s,1H), 3.11(s,4H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.7Hz,1H),2.51(s,4H),2.10(s,3H).HRMS calcd for C 30 H 32 F5N7O,[M+H] + ,602.2667;found 602.2686.

[0200] Example 40: 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0201] 1 H NMR(600MHz,DMSO-d6)δ9.04(s,1H),7.39(s,2H),7.25(s,3H),7.11(s,1H),6.89(s,3H),6.74(s,2H),5.87(s,1 H),4.73(s,2H),3.47(s,2H),3.34(s,2H),3.02(s,4H),2.87(s,1H),2.78(s,1H),2.42(s,4H),2.03(s,3H).HRMS calcd for C 30 H 32 F5N7O2,[M+H] + ,618.2616;found 618.2638.

[0202] Example 41: 1-((4-(4-(2-bromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0203] 1 H NMR (600MHz, DMSO-d6) δ9.10(s,1H),7.65(s,1H),7.33(dd,J=23.6,9.1Hz,2H),7.19(d,J=9.7Hz,1H),7.12(d,J=8.6Hz,1H),6.97(d,J=8.2Hz,3H), 6.82(d,J=8.1Hz,2H),5.93(s,1H),4.80(s,2H),3.58(s,2H),3.43(d,J=1 2.7Hz,2H),3.12(s,4H),2.97–2.82(m,2H),2.58(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrF3N7O,[M+Na] + ,654.1603;found 654.1642.

[0204] Example 42: 1-((4-(4-(2-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0205] 1 H NMR (600MHz, DMSO-d6) δ9.10(s,1H),7.65(s,1H),7.33(dd,J=23.6,9.1Hz,2H),7.19(d,J=9.7Hz,1H),7.12(d,J=8.6Hz,1H),6.97(d,J=8.2Hz,3H), 6.82(d,J=8.1Hz,2H),5.93(s,1H),4.80(s,2H),3.58(s,2H),3.43(d,J=1 2.7Hz,2H),3.12(s,4H),2.97–2.82(m,2H),2.58(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrF3N7O,[M+Na] + ,654.1603;found 654.1636.

[0206] Example 43: 1-((4-(4-(2-bromo-4-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0207] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.74(d,J=2.2Hz,1H),7.53(d,J=8.3Hz,1H),7.47(dd,J=8.3 ,2.2Hz,1H),7.34–7.29(m,1H),7.21–7.17(m,1H),6.97(d,J=8.3Hz,2H),6.94(dd,J=8.5,2.6Hz, 1H),6.82(d,J=8.4Hz,2H),5.92(s,1H),4.80(s,2H),3.57(s,2H),3.43(d,J=12.9Hz,1H),3.37(s ,1H),3.11(s,4H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.7Hz,1H),2.56(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31BrClF2N7O,[M+Na] + ,670.1307;found 670.1303.

[0208] Example 44: 1-((4-(4-(2,4-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0209] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.85(d,J=2.1Hz,1H),7.60(dd,J=8.2,2.1Hz,1H),7.46(d,J =8.3Hz,1H),7.31(q,J=8.6Hz,1H),7.21–7.16(m,1H),6.97(d,J=8.4Hz,2H),6.94(dd,J=8.5,2.6H z,1H),6.82(d,J=8.3Hz,2H),5.93(s,1H),4.80(s,2H),3.56(s,2H),3.43(d,J=13.0Hz,1H),3.37( s,1H),3.11(s,4H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.8Hz,1H),2.56(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 Br2F2N7O,[M+Na] + ,714.0802;found 714.0847.

[0210] Example 45: 1-((4-(4-(2-bromo-6-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0211] 1H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.51 (d, J = 7.4Hz, 1H), 7.30 (q, J = 8. 8Hz,1H),7.26(t,J=8.0Hz,1H),7.21–7.16(m,1H),6.95(d,J=8.5Hz,2H),6.93(d,J=2.7Hz,1H) ,6.80(d,J=8.5Hz,2H),5.92(s,1H),4.80(s,2H),3.75(s,2H),3.42(d,J=13.0Hz,1H),3.36(s, 1H),3.04(s,4H),2.94(d,J=13.8Hz,1H),2.83(d,J=13.8Hz,1H),2.62(s,4H),2.09(s,3H).HRMS calcd for C 29 H 31 BrClF2N7O,[M+H] + ,648.1488;found 648.1531.

[0212] Example 46: 1-((4-(4-(3-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0213] 1 H NMR(600MHz,DMSO-d6)δ9.10(s,1H),7.44(d,J=8.4Hz,1H),7.40(s,1H),7.31(d,J=6.7H z, 1H), 7.21 (t, J = 9.2Hz, 2H), 6.96 (d, J = 8.4Hz, 2H), 6.94 (d, J = 8.4Hz, 1H), 6.81 (d, J = 8. 4Hz,2H),5.92(s,1H),4.80(s,2H),3.55(s,2H),3.43(d,J=12.9Hz,1H),3.37(s,1H),3. 10(s,4H),2.94(d,J=13.8Hz,1H),2.83(d,J=13.8Hz,1H),2.51(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrF3N7O,[M+H] + ,632.1783;found 632.1786.

[0214] Example 47: 1-((4-(4-(3-bromo-5-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0215] 1 H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.31 (d, J = 9. 0Hz,1H),7.19(d,J=10.4Hz,1H),6.96(d,J=8.2Hz,2H),6.93(d,J=7.2Hz,1H),6.81(d,J= 6.2Hz,2H),5.92(s,1H),4.80(s,2H),3.53(s,2H),3.43(d,J=12.9Hz,1H),3.35(s,1H),3 .10(s,4H),2.94(d,J=13.7Hz,1H),2.83(d,J=13.8Hz,1H),2.51(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrClF2N7O,[M+H] + ,648.1488;found 648.1476.

[0216] Example 48: 1-((4-(4-(3,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0217] 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.73(s,1H),7.56(d,J=1.9Hz,2H),7.32(q,J=8.7H z,1H),7.21–7.17(m,1H),6.96(d,J=8.5Hz,2H),6.94(dd,J=8.6,2.6Hz,1H),6.81(d,J=8 .3Hz,2H),5.92(s,1H),4.80(s,2H),3.53(s,2H),3.43(d,J=13.0Hz,1H),3.37(s,1H),3. 10(s,4H),2.95(d,J=13.1Hz,1H),2.84(d,J=13.8Hz,1H),2.51(s,4H),2.10(s,3H).HRMS calcd for C 29H 31 Br2F2N7O,[M+H] + ,692.0983;found 692.0989.

[0218] Example 49: 1-((4-(4-(5-bromo-2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0219] 1 H NMR(600MHz,DMSO-d6)δ9.14(s,1H),7.64–7.61(m,1H),7.54–7.50(m,1H),7.32(q,J= 8.6Hz,1H),7.22–7.17(m,2H),6.96(d,J=8.1Hz,2H),6.93(s,1H),6.80(d,J=8.2Hz,2 H),5.99(s,1H),4.82(s,2H),3.57(s,2H),3.44(d,J=13.0Hz,1H),3.35(s,1H),3.09( s,4H),2.96(d,J=13.8Hz,1H),2.84(d,J=13.8Hz,1H),2.53(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrF3N7O,[M+H] + ,630.1804;found 630.1873.

[0220] Example 50: 1-((4-(4-(5-bromo-2-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0221] 1H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 7.69 (d, J = 2.5Hz, 1H), 7.50 (dd, J = 8.5, 2.5Hz, 1H), 7.42 (d, J = 8.5Hz ,1H),7.33–7.29(m,1H),7.19(ddd,J=11.8,9.1,2.7Hz,1H),6.97(d,J=8.3Hz,2H),6.94(dd,J=8.5,2.6Hz ,1H),6.82(d,J=8.7Hz,2H),5.92(s,1H),4.80(s,2H),3.61(s,2H),3.43(d,J=13.0Hz,1H),3.35(s,1H),3 .11(t,J=4.9Hz,4H),2.95(d,J=13.7Hz,1H),2.84(d,J=13.7Hz,1H),2.59–2.56(m,4H),2.10(s,3H).HRMS calcd for C 29 H 31 BrClF2N7O,[M+Na] + ,670.1307;found 670.1320.

[0222] Example 51: 1-((4-(4-(2,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol

[0223] 1 H NMR(600MHz,DMSO-d6)δ9.10(s,1H),7.68(d,J=2.6Hz,1H),7.57(d,J=8.4Hz,1H),7.42(dd,J=8.5 ,2.6Hz,1H),7.33–7.29(m,1H),7.21–7.17(m,1H),6.97(d,J=8.4Hz,2H),6.94(dd,J=8.5,2.6Hz, 1H),6.82(d,J=8.6Hz,2H),5.92(s,1H),4.80(s,2H),3.59(s,2H),3.43(d,J=13.0Hz,1H),3.37(s ,1H),3.12(s,4H),2.94(d,J=13.7Hz,1H),2.83(d,J=13.8Hz,1H),2.58(s,4H),2.10(s,3H).HRMS calcd for C 29 H 31 Br2F2N7O,[M+Na] +,714.0802;found 714.0830.

[0224] Pharmacodynamic studies on some products of the present invention.

[0225] Experimental method: Refer to the conventional in vitro antifungal test method (Reference method for broth dilution antifungal susceptibility testing of yeasts and filamentous fungi; Approved Standard M27-A3 and M38-A2).

[0226] Materials and methods

[0227] (1) Experimental strains: This experiment used the following three common human pathogenic fungal strains as screening objects. The fungal strains were provided by Shenyang Pharmaceutical University.

[0228] Table 1 Strains used in the experiment and their numbers

[0229] (2) Experimental methods:

[0230] Preparation of RPMI-1640 medium: RPMI-1640 10.0 g, NaHCO 3 2.0 g, triazamorphine propanesulfonic acid (Sigma) 34.5 g, add 800 mL of sterile distilled water to dissolve, adjust the pH to 7.0 with 1 mol / L NaOH, dilute to 1000 mL, filter through a 0.22 μm microporous filter to sterilize, and store at 4°C until use.

[0231] Preparation of coccal fungal suspension: Coccal fungi (Candida albicans, Candida tropicalis, Cryptococcus neoformans). Activate the strains by streaking onto Sabouraud solid medium plates and incubate at 32°C for 2-3 days. Transfer an appropriate number of colonies to a flask containing 10 mL of 0.85% sterile saline. Shake for 15 minutes. Use a sterile pipette tip to transfer a small amount of the suspension onto a hemocytometer and count under a microscope. Dilute with RPMI-1640 medium to a final concentration of 1x10 6 pieces / mL.

[0232] Solution Preparation: Weigh 6.40 mg of each compound prepared in the above examples, add 1.0 mL of dimethyl sulfoxide (DMSO), 1.0 mL of Tween-20, and 8.0 mL of sterile distilled water, and mix thoroughly. The resulting solution concentration is 0.64 mg / mL. Positive controls fluconazole, voriconazole, and itraconazole are prepared in the same manner.

[0233] Inoculation: Step 1, add RPMI-1640 medium: add 180 μL RPMI-1640 medium to the first well of each row, add 100 μL RPMI-1640 medium to wells 2-11, and add 200 μL RPMI-1640 medium to well 12. Step 2, add drug sample: add 20 μL of the test solution (i.e., the compound obtained in each example) to well 1, mix with a pipette, and then draw 100 μL to well 2, dilute 2-fold to well 10, and then mix and discard 100 μL. Step 3, add bacterial suspension: add 100 μL of inoculated bacterial suspension to each well 1-11. Well 11 is the growth control, and well 12 is the blank culture medium control. There is no blank drug control for the positive control drug. That is, a serial dilution is performed starting from well 1 to well 10, and the test concentration (μg / mL) range is 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625.

[0234] Cultivation and Testing: The blank control should show no growth and the positive control should show good growth. Eight samples should be tested per plate, and a positive drug control should be included for each bacterium. The dilution method for the test drug should be the same as above.

[0235] Table 2 Minimum inhibitory concentration of the compounds in the examples (μg / mL)

[0236] The above experimental results indicate that the compounds of Formula I and their salts as claimed in the present invention have excellent antifungal activity, with many of the compounds exhibiting stronger antifungal activity than the positive control drug. Compared with existing antifungal drugs, they possess advantages such as novel structure, low toxicity, high efficacy, and a broad spectrum. Therefore, the compounds of the present invention have promising application prospects.

[0237] The compounds of formula I of the present invention can be administered alone, but are generally administered in admixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier should be based on the desired route of administration and standard pharmaceutical practice. The following describes the preparation methods of various pharmaceutical dosage forms of such compounds, such as tablets, capsules, injections, aerosols, suppositories, films, pills, topical liniments, and ointments, to illustrate their new applications in the pharmaceutical field.

[0238] Example 52: Tablets.

[0239] 10 g of the compound of Example 30 was added with 20 g of excipients according to the general pharmaceutical tableting method, mixed evenly, and compressed into 100 tablets, each weighing 300 mg.

[0240] Example 53: Capsules.

[0241] 10 g of the compound of Example 30 was mixed with 20 g of excipients according to the requirements of pharmaceutical capsules and filled into hollow capsules. Each capsule weighed 300 mg.

[0242] Example 54: Injection.

[0243] 10 g of the compound of Example 30 was adsorbed on activated carbon according to conventional pharmaceutical methods, filtered through a 0.65 μm microporous filter membrane, and then filled into a nitrogen tank to prepare an aqueous injection preparation, each containing 2 mL, for a total of 100 bottles.

[0244] Example 55: Aerosol.

[0245] 10 g of the compound of Example 30 was dissolved in an appropriate amount of propylene glycol, and then distilled water and other raw materials were added to prepare 500 mL of a clear solution.

[0246] Example 56: Suppository.

[0247] 10 g of the compound of Example 30 was ground into powder and added with an appropriate amount of glycerol. After grinding evenly, melted glycerol gelatin was added and ground evenly. The mixture was poured into a mold coated with a lubricant to prepare 50 suppositories.

[0248] Example 57: Film.

[0249] 10 g of the compound of Example 30 was stirred and expanded with polyvinyl alcohol, medicinal glycerin, water, etc., and then heated to dissolve. The mixture was filtered through an 80-mesh sieve. The compound of Example 30 was then added to the filtrate and stirred to dissolve. 100 films were made using a film coating machine.

[0250] Example 58: Drop pills.

[0251] 10 g of the compound of Example 30 was heated to melt and mixed with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin to prepare 1000 dropping pills.

[0252] Example 59: Liniment for external use.

[0253] 10 g of the compound of Example 30 was mixed and ground with 2.5 g of auxiliary materials such as an emulsifier according to conventional pharmaceutical methods, and then distilled water was added to 200 mL to prepare the product.

[0254] Example 60: Ointment.

[0255] The compound of Example 30 (10 g) was ground into powder and then mixed with 500 g of an oily base such as vaseline to obtain the product.

[0256] While the present invention has been described with reference to specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

Claims

1. An azole derivative represented by general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, characterized in that: wherein MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, or an optionally substituted pyrazolyl, wherein the optionally substituted refers to a C1-4 alkyl substitution or a C1-4 alkoxy substitution; X is carbonyl, sulfoxide or sulfone, or CH2, NH, O or S; R 1 is H, -P(O)(OH)2, -CH2-OP(O)(OH)2, or -C(O)alkyl optionally substituted by amino, wherein the alkyl is a C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl; R 2 The phenyl ring is substituted, the substituent may be located at the ortho, meta or para position, may be monosubstituted or polysubstituted, and the substituent is selected from halogen, wherein the halogen is F, Cl, Br or I; R 3 is hydrogen, halogen, alkyl or haloalkyl, wherein the alkyl is a C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl; R 4 Selected from i, ii or iii, wherein the substituents may be located at the ortho, meta or para position and may be monosubstituted or polysubstituted; i. halogen, wherein the halogen is F, Cl, Br or I; ii. C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl; iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, methoxy, ethoxy, phenyl, amino or alkynyl.

2. The azole derivative of general formula I according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: in, MBG is selected from the following structures: X is CH2.

3. The azole derivative of general formula I according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: R 1 and R 3 is hydrogen; R 2 It is 2,4-difluorophenyl.

4. The azole derivative of general formula I according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: R 4 Selected from i, ii, or iii, wherein the substituents may be located at the ortho, meta, or para position and may be monosubstituted or polysubstituted; i. halogen, wherein the halogen is F, Cl, Br or I; ii. C1-6 straight or branched chain alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl; iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, methoxy, ethoxy, phenyl, amino or alkynyl.

5. The azole derivative of general formula I according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: Selected from: 1-((4-(4-Benzylpiperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(4-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(4-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-methoxybenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-isopropylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(4-(4-tert-butyl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-nitrobenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 4-((4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)methyl)benzonitrile 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-((1,1'-biphenyl)-4-ylmethyl)piperazin-1-yl)benzyl(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(4-aminobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-ethynylbenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(3-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(3-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(3-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(3-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-6-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-4-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-5-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-6-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2,4-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2,6-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-4-(trifluoromethyl)benzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2,6-dibromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-((4-(4-(2-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-((4-(4-(2-iodobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(3-bromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(tert-Butyl)benzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 2-(2,4-difluorophenyl)-1-(methyl(4-(4-(tetrafluoromethyl)benzyl)piperazin-1-yl)benzyl)amino)-3-(1H-tetrazol-1-yl)propan-2-ol 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-(tetrafluoromethoxy)benzyl)piperazin-1-yl)benzylamino)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-4-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-4-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2,4-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2-bromo-6-chlorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(3-bromo-5-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(3-bromo-5-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(3,5-dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(5-bromo-2-fluorobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(5-bromo-2-chlorophenyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol 1-((4-(4-(2,5-Dibromobenzyl)piperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)propan-2-ol.

6. A pharmaceutical composition, characterized in that: It comprises an azole derivative represented by general formula I according to any one of claims 1 to 5, or a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.

7. A pharmaceutical preparation, characterized in that: It comprises the azole derivative represented by general formula I according to any one of claims 1 to 5, or its stereoisomer or pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 6 as an active ingredient.

8. Use of the azole derivative represented by general formula I according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or the pharmaceutical composition according to claim 6, or the pharmaceutical preparation according to claim 7 in the preparation of an antifungal drug.

9. The use according to claim 8, characterized in that: The fungus is Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Cryptococcus neoformans, Microsporum gypseum or Trichophyton rubrum.

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