A class of azole compounds targeting CYP51 and their uses

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and specifically discloses a azole derivative represented by general formula I, or its stereoisomer or its pharmaceutically acceptable salt, hydrate, solvate or prodrug, a preparation method thereof, and its use in the preparation of a drug for preventing or treating various diseases caused by fungal infections.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a azole derivative and its pharmaceutically acceptable salts, hydrates, solvates and prodrugs, a preparation method thereof, and its use in the preparation of drugs for treating various diseases caused by fungal infections. Background Art

[0002] Fungal infections can be divided into superficial fungal infections 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 are infected with pathogenic bacteria worldwide, and at least 1.5 - 2 million people die from it every year. In recent years, with the widespread development of organ transplantation and the continuous expansion of the HIV-infected population, the number of immunocompromised people has been increasing, resulting in an increasing incidence of invasive fungal infections year by year.

[0003] Candida, Cryptococcus and Aspergillus are the three major pathogenic bacteria of invasive fungal infections. Although fungal infections have posed a great threat to humans, the effective drugs for clinical treatment of fungal infections are still very limited. Currently, clinically used antifungal drugs can be classified into azole drugs that inhibit ergosterol synthesis according to different mechanisms of action; echinocandin antifungal drugs that destroy the cell wall, polyene drugs that cause cell membrane leakage, and antimetabolic antifungal drugs that act on nucleic acids. Among them, azole drugs inhibit the activity of lanosterol 14α-demethylase (CYP51), thereby blocking the synthesis of ergosterol, an important component of the fungal cell membrane, and exerting an antibacterial effect. Currently, clinically used azole antifungal drugs 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 Oteseconazole.

[0004] Although azole drugs play an irreplaceable role clinically, there are still certain deficiencies in this class of drugs, such as narrow antibacterial spectrum, drug-drug interactions and the emergence of drug resistance. Therefore, it is of great significance to develop new, broad-spectrum, highly effective and low-toxic antifungal drugs. Summary of the Invention

[0005] The purpose of the present invention is to provide a novel azole derivative, a preparation method thereof, and its application as a drug, especially as a CYP51 inhibitor.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] An azole derivative, which is a compound represented by the general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0008]

[0009] Wherein, MBG is an optionally substituted tetrazolyl group, an optionally substituted triazolyl group, or an optionally substituted pyrazolyl group, and the term "optionally substituted" refers to being substituted by a C1-4 alkyl group or a C1-4 alkoxy group;

[0010] X is a carbonyl group, a sulfoxide group or a sulfone group, or CH2, NH, O or S;

[0011] R 1 is H, -P(O)(OH)2, -CH2-O-P(O)(OH)2, or -C(O)alkyl optionally substituted by an amino group, and the alkyl group is a C1-6 straight-chain or branched-chain alkyl group, which is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0012] R 2 is a substituted benzene ring, and the substituent position can be ortho, meta or para, and it can be mono-substituted or multi-substituted, and the substituents are selected from halogens, and the halogens are F, Cl, Br or I;

[0013] R 3 is hydrogen, a halogen, an alkyl group or a haloalkyl group, and the alkyl group is a C1-6 straight-chain or branched-chain alkyl group, which is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0014] R 4 is selected from i, ii or iii, wherein the substituent position can be ortho, meta or para, and it can be mono-substituted or multi-substituted;

[0015] i. A halogen, and the halogens are F, Cl, Br or I;

[0016] ii. A C1-6 straight-chain or branched-chain alkyl group, which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0017] iii. A cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, a formyl group, a methoxy group, an ethoxy group, a phenyl group, an amino group or an alkynyl group.

[0018] In a preferred embodiment, MBG is selected from the following structures: X is CH2.

[0019] In a preferred embodiment, wherein, R1 and R 3 is hydrogen; R 2 is 2,4-difluorophenyl.

[0020] In a preferred embodiment, R4 is selected from i, ii or iii, wherein the substituent position can be ortho, meta or para, and can be mono-substituted or multi-substituted;

[0021] i. a halogen, and the halogen is F, Cl, Br or I;

[0022] ii. a C1-6 straight-chain or branched-chain alkyl group, which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0023] iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, methoxy, ethoxy, phenyl, amino or alkynyl.

[0024] In a preferred embodiment, the derivative is a compound represented by the general formula I, or its stereoisomer or its pharmaceutically acceptable salt, hydrate, solvate or prodrug, selected from:

[0025] 1-((4-(4-Benzylpiperazin-1-yl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0026] 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

[0027] 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

[0028] 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

[0029] 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

[0030] 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

[0031] 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

[0032] 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

[0033] 1-((4-(4-(4-(tert-butyl)benzyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0034] 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

[0035] 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

[0036] 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

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

[0038] 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

[0039] 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

[0040] 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

[0041] 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

[0042] 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

[0043] 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

[0044] 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

[0045] 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

[0046] 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

[0047] 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

[0048] 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

[0049] 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

[0050] 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

[0051] 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

[0052] 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

[0053] 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

[0054] 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

[0055] 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

[0056] 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

[0057] 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

[0058] 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

[0059] 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

[0060] 1 - ((4 - (4 - (2 - bromobenzyl)piperazin - 1 - yl)benzyl)(methyl)amino) - 2 - (2,4 - difluorophenyl) - 3 - (1H - tetrazol - 1 - yl)propan - 2 - ol

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

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

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

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

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

[0066] 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-(tetrafluoromethoxy)benzyl)piperazin-1-yl)benzylamino)-3-(1H-tetrazol-1-yl)propan-2-ol

[0067] 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

[0068] 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

[0069] 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

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

[0071] 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

[0072] 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

[0073] 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

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

[0075] 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

[0076] 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

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

[0078] Moreover, according to some common methods in the field to which the present invention pertains, some of the compounds of general formula I in the present invention have basic groups and can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the salts formed 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, etc.

[0079] In addition, the present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are derivatives of general formula I, which may themselves have weak activity or even no activity, but after administration, they are converted into the corresponding bioactive forms under physiological conditions (such as through metabolism, solvolysis or other means).

[0080] The compounds represented by General Formula I can exist in non-solvated form and solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.). The compounds represented by General Formula I may contain asymmetric or chiral centers and thus can exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereoisomers, enantiomers and atropisomers, as well as mixtures thereof (such as racemic mixtures), are included within the scope of the present invention.

[0081] The compounds represented by General Formula I can exist in different tautomeric forms, and all these forms 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 low energy barriers.

[0082] In the definitions of the compounds of General Formula I given above, the terms used are generally defined as follows:

[0083] Optionally substituted substituents: C1-C4 alkyl, C1-C4 alkoxy.

[0084] Halogen: refers to fluorine, chlorine, bromine or iodine.

[0085] Alkyl: straight-chain or branched-chain alkyl. Preferably, the alkyl is a C1-6 straight-chain or branched-chain alkyl. For example, it can be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl.

[0086] Cycloalkyl: substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, etc.

[0087] Halogenated alkyl: straight-chain or branched-chain alkyl, on which the hydrogen atoms can be partially or completely replaced by halogen atoms. For example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.

[0088] Alkoxy: straight-chain or branched-chain alkyl, on which the hydrogen atom of the hydroxyl group can be replaced by these straight-chain or branched-chain alkyls. For example, methoxy, ethoxy, propoxy, isopropoxy, etc. A saturated aliphatic ring containing 1-2 heteroatoms such as N, O, S, such as tetrahydrofuranyl, piperidinyl, piperazinyl, etc.

[0089] The present invention may contain derivatives of General Formula I, and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs as active ingredients, which are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and formulated into a clinically acceptable dosage form. The above-mentioned pharmaceutically acceptable excipients refer to any diluents, adjuvants and / or carriers that can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0090] The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The several dosage forms described above can adopt dosage form drugs such as injections, tablets, capsules, aerosols, suppositories, membranes, dripping pills, external liniments, ointments, etc.

[0091] The carriers for the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, non-pigments, flavoring agents, preservatives, solubilizing agents, and matrices, etc. The pharmaceutical preparation can be administered orally or parenterally (such as intravenously, subcutaneously, intraperitoneally or topically). If some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0092] The compound of general 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; the room temperature in the present invention refers to the ambient temperature, which is 25 °C.

[0093] The preparation method of the derivative shown in the above general formula I, the preparation reaction of the derivative shown in the general formula I is as follows:

[0094]

[0095] Using 2'-chloro-2,4-difluoroacetophenone as the starting material, a substitution reaction occurs with triazole or tetrazole under alkaline conditions to obtain intermediate 2. Intermediate 2 undergoes cyclization with trimethylsulfoxonium iodide under alkaline conditions to obtain intermediate 3. Intermediate 4 undergoes a substitution reaction with N-Boc-piperazine under high-temperature alkaline conditions to obtain intermediate 5. Intermediate 5 undergoes reductive amination with methylamine to obtain intermediate 6. Intermediate 6 then undergoes 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, it reacts with the corresponding substituted benzyl bromide under alkaline conditions to obtain the final product 9. Target compounds with similar structures can also be prepared according to the above general formula method.

[0096] The definitions of MBG and R 4 in the above preparation process flow are as described above.

[0097] Furthermore, starting from 2'-chloro-2,4-difluoroacetophenone, a substitution reaction is carried out with triazole or tetrazole under basic conditions to obtain intermediate 2. 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 most preferably benzyltriethylammonium chloride; the reaction solvent can be acetonitrile, tetrahydrofuran, toluene, dichloromethane, N,N-dimethylformamide, preferably dichloromethane. Intermediate 2 is cyclized with dimethylsulfoxide iodide under high-temperature basic 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 cetyltrimethylammonium 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 undergoes a substitution reaction with N-Boc-piperazine under high-temperature basic conditions to obtain intermediate 5. The reaction temperature is 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 obtain intermediate 5. The reaction temperature is 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 basic conditions to obtain intermediate 7. The reaction solvent can be ethanol, 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 obtain 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 ethyl acetate solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, an aqueous solution of hydrogen chloride, p-toluenesulfonic acid, trifluoroacetic acid, etc., preferably a saturated ethyl acetate solution of hydrogen chloride.Finally, it undergoes a substitution reaction with the corresponding benzyl bromide to obtain the final product 9. The reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, methanol, etc., with acetonitrile being preferred; 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., with triethylamine being preferred.

[0098] Use of the azole derivative of the present invention, the compound represented by the general formula I, and its stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of a drug for preventing or treating diseases related to fungal infections.

[0099] Use of the azole derivative represented by the general formula I, and its stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of an antifungal drug.

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

[0101] Use of the composition in the preparation of a drug for preventing or treating diseases related to fungal infections.

[0102] Use of the composition in the preparation of an antifungal drug.

[0103] The beneficial effects of the present invention are as follows: The present invention provides a novel azole derivative, its preparation method, drug combination and application. The azole derivative of the present invention has good antifungal activity against various superficial and deep fungi. Compared with the existing clinically used antifungal drugs, it has the advantages of high efficiency, low toxicity, broad antibacterial spectrum, etc., and can be used to prepare antifungal drugs. Detailed implementation manners

[0104] The examples are intended to illustrate rather than limit the scope of the present invention. The nuclear magnetic resonance hydrogen spectrum of the compound was measured with a Bruker ARX-600; all the reagents used were of analytical purity or chemical purity.

[0105] The specific example structures are as follows:

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

[0107]

[0108] The specific synthesis steps are as follows: 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 dichloromethane solution. Under ice bath conditions, a dichloromethane solution of intermediate 1 (2.00 g, 0.19 mmol) was added dropwise thereto. After the addition was complete, the mixture was stirred at room temperature for 12 h. TLC monitoring (DCM:MeOH = 50:1) showed that the raw materials had completely reacted. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phase was concentrated and separated by column chromatography to obtain a white solid with a yield of 80%.

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

[0111] Trimethylsulfoxonium iodide (28.29 g, 0.13 mol) was dissolved in an aqueous NaOH solution and reacted at room temperature for 2 h. Then, intermediate 2 (25.00 g, 0.11 mol), benzyltrimethylammonium chloride (0.99 g, 0.005 mol), and dichloromethane were added, and the reaction was carried out at 55 °C for 6 h. TLC monitoring (DCM:MeOH = 50:1) showed that the raw materials had completely reacted. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and separated by column chromatography to obtain a pale yellow solid with a yield of 75%.

[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 the reaction was carried out at 135 °C for 18 h. TLC monitoring (PE:EA = 10:1) showed that the raw materials had completely reacted. The reaction solution was added to 300 mL of water, and a brownish-yellow solid precipitated. The solid was filtered by suction to obtain a brownish-yellow solid, which was separated by column chromatography to obtain a white solid with a yield of 68%.

[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 solution (1.28 g, 0.041 mol) were added to a methanol solution, and the reaction was carried out at room temperature for 30 min. Subsequently, sodium borohydride (1.95 g, 0.051 mol), a reducing agent, was added, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 20:1) showed that the raw materials had completely reacted. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a yellow oil, with a yield of 86%. 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)

[0116] 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 an anhydrous ethanol solution at room temperature, and the reaction was refluxed for 6 h. TLC monitoring (DCM:MeOH = 30:1) showed that the raw materials had completely reacted. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a white solid, with a yield of 78%.

[0117] 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)

[0118] Intermediate 7 (10.00 g, 0.018 mol) was dissolved in 20 mL of a saturated ethyl acetate solution of hydrogen chloride, and the reaction was carried out at room temperature for 2 h. TLC monitoring (DCM:MeOH = 10:1) showed that the raw materials had completely reacted. The mixture was concentrated under reduced pressure to obtain a white solid, which was directly used in the next step without purification, with a yield of 95%.

[0119] 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)

[0120] Intermediate 8 (0.050 g, 0.11 mmol) was dissolved in 5 mL of acetonitrile. After adding benzyl bromide (0.021 g, 0.12 mmol) and triethylamine (0.022 g, 0.22 mmol), the mixture was stirred at room temperature for 1 h. TLC monitoring (DCM:MeOH = 10:1) showed that the reaction was complete. The mixture was concentrated under reduced pressure and separated by preparative thin-layer chromatography (DCM:MeOH = 30:1) to obtain a white solid, with a yield of 79%. 11H NMR (600 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.33 (s, 4H), 7.27 (s, 1H), 7.16–7.11 (m, 1H), 6.95 (td, J = 8.4, 2.4 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 5.68 (s, 1H), 4.53–4.46 (m, 2H), 3.51 (s, 2H), 3.40 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H), 3.08 (s, 4H), 2.95 (d, J = 13.7 Hz, 1H), 2.73 (d, J = 13.4 Hz, 1H), 2.03 (s, 3H). HRMS calcd for C 30 H 34 F2N6O, [M+Na] + , 555.2660; found 555.2653.

[0121] According to the method of Example 1, Examples 2 - 33 were prepared using the corresponding raw materials respectively.

[0122] 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

[0123]

[0124] 1 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.43–7.39 (m, 1H), 7.36 (t, J = 6.8 Hz, 2H), 7.14 (q, J = 12.7, 10.5 Hz, 3H), 6.96 (d, J = 6.5 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 5.69 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 3.50 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 13.0 Hz, 1H), 3.08 (s, 4H), 2.96 (d, J = 13.6 Hz, 1H), 2.74 (d, J = 13.7 Hz, 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]

[0127] 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 = 14.2Hz,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.

[0128] 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

[0129]

[0130] 11H NMR (600 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.33 (s, 3H), 7.27 (s, 1H), 7.16–7.11 (m, 1H), 6.96 (d, J = 6.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 5.68 (s, 1H), 4.53–4.46 (m, 2H), 3.51 (s, 2H), 3.40 (d, J = 12.9 Hz, 1H), 3.30 (s, 1H), 3.08 (s, 4H), 2.95 (d, J = 13.7 Hz, 1H), 2.73 (d, J = 13.4 Hz, 1H), 2.50 (s, 4H), 2.03 (s, 3H). HRMS calcd for C 30 H 33 BrF2N6O, [M+Na] + , 635.1745; found 635.1836.

[0131] 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

[0132]

[0133] 1 1H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.72 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.57 (q, J = 8.7 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 6.80 (dd, J = 18.3, 8.4 Hz, 4H), 4.47–4.40 (m, 2H), 3.53 (s, 2H), 3.40 (d, J = 12.8 Hz, 1H), 3.28 (d, J = 12.8 Hz, 1H), 3.20 (s, 4H), 3.05 (d, J = 13.5 Hz, 1H), 2.81 (d, J = 13.5 Hz, 1H), 2.61 (s, 4H), 2.01 (s, 3H). HRMS calcd for C 30 H 33 F2IN6O, [M+Na] + , 681.1626; found 681.1640.

[0134] 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

[0135]

[0136] 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.72(s,1H),7.56(s,1H),7.30(s,2H),7.17(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=14.2Hz,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.

[0137] 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

[0138]

[0139] 11H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.41 (q, J = 8.9 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 9.5 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 6.93–6.88 (m, 4H), 6.83 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 2H), 5.72 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 3.74 (s, 3H), 3.50 (s, 4H), 3.39 (s, 2H), 3.37 (d, J = 10.4 Hz, 1H), 3.29 (d, J = 12.9 Hz, 1H), 3.09 (s, 4H), 2.96 (d, J = 13.7 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.03 (s, 3H). HRMS calcd for C 31 H 36 F2N6O2, [M+Na] + , 585.2766; found 585.2783.

[0140] 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

[0141]

[0142] 11H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.14–7.11 (m, 1H), 6.95 (dd, J = 8.5, 2.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.71 (s, 1H), 4.53 (d, J = 14.3 Hz, 1H), 4.48 (d, J = 14.3 Hz, 1H), 3.47 (s, 2H), 3.41 (s, 1H), 3.29 (d, J = 13.0 Hz, 1H), 3.07 (s, 4H), 2.96 (d, J = 13.7 Hz, 1H), 2.88–2.84 (m, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.48 (s, 4H), 2.03 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H). HRMS calcd for C 33 H 40 F2N6O, [M+H] + , 575.3310; found 575.3352.

[0143] 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

[0144]

[0145] 1 1H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.74 (s, 1H), 7.42 (q, J = 8.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.16–7.11 (m, 1H), 6.98–6.94 (m, 1H), 6.92 (d, J = 8.1 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 5.71 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.49 (s, 2H), 3.42 (s, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.08 (s, 4H), 2.96 (d, J = 13.6 Hz, 1H), 2.75 (d, J = 13.7 Hz, 1H), 2.50 (d, J = 9.1 Hz, 4H), 2.04 (s, 3H), 1.28 (s, 9H). HRMS calcd for C34 H 42 F2N6O, [M+H] + , 589.3466; found 589.3478.

[0146] 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

[0147]

[0148] 1 H 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). HRMS calcd for C 30 H 33 F2N7O3, [M+Na] + , 600.2511; found 600.2551.

[0149] 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

[0150]

[0151] 11H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 6.9 Hz, 1H), 7.16–7.12 (m, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.69 (s, 1H), 4.50 (q, J = 14.2 Hz, 2H), 3.61 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.10 (s, 4H), 2.96 (d, J = 15.5 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.51 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 31 H 33 F2N7O, [M+Na] + , 580.2612; found 580.2656.

[0152] Example 12: 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)amino

[0153] )-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0154]

[0155] 1 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.44–7.39 (m, 1H), 7.16–7.12 (m, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 3.61 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.10 (s, 4H), 2.96 (d, J = 13.7 Hz, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.51 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 31 H 33F5N6O, [M+Na] + , 623.2534; found 623.2582.

[0156] Example 13: 2-(2,4-Difluorophenyl)-1-(methyl(4-(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0157]

[0158] 1 H 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 = 13.0Hz, 1H), 3.09(s, 4H), 2.96(d, J = 13.7Hz, 1H), 2.74(d, J = 13.7Hz, 1H), 2.50(s, 4H), 2.04(s, 3H). HRMS calcd for C 31 H 33 F5N6O2, [M+Na] + , 639.2483; found 639.2493.

[0159] 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

[0160]

[0161] 11H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.74 (s, 1H), 7.67 (d, J = 7.1 Hz, 2H), 7.64 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 8.0 Hz, 3H), 7.36 (t, J = 7.4 Hz, 1H), 7.17–7.12 (m, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H), 5.69 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.56 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.11 (s, 4H), 2.96 (d, J = 13.0 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.53 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 36 H 38 F2N6O, [M+H] + , 609.3153; found 609.3142.

[0162] Example 15: 1 - ((4 - (4 - (4 - aminobenzyl)piperazin - 1 - yl)benzyl)(methyl)amino)-2-(2,4 - difluoroben

[0163] zyl)-3-(1H - 1,2,4 - triazol - 1 - yl)propan - 2 - ol

[0164]

[0165] 1 1H NMR (600 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.78 (s, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.19 (t, J = 9.1 Hz, 1H), 7.08 (s, 2H), 7.02–7.00 (m, 1H), 6.97 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.59 (d, J = 7.8 Hz, 2H), 5.79 (s, 1H), 4.59–4.52 (m, 2H), 3.46 (d, J = 10.9 Hz, 2H), 3.35 (d, J = 12.8 Hz, 2H), 3.11 (q, J = 7.2 Hz, 4H), 3.02 (d, J = 13.7 Hz, 1H), 2.78 (d, J = 13.3 Hz, 1H), 2.56 (s, 4H), 2.08 (s, 3H). HRMS calcd for C30 H 35 F2N7O, [M+H] + , 548.2949; found 548.2949.

[0166] Example 16: 2-(2,4-Difluorophenyl)-1-((4-(4-ethynylbenzyl)piperazin-1-yl)benzyl)(methyl)amino

[0167] -3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0168]

[0169] 1 H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.75 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.42–7.39 (m, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.16–7.12 (m, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.69 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 4.15 (s, 1H), 3.53 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.1 Hz, 1H), 3.09 (s, 4H), 2.96 (d, J = 13.6 Hz, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.49 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 32 H 34 F2N6O, [M+Na] + , 579.2660; found 579.2698.

[0170] 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

[0171]

[0172] 11H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.72 (s, 1H), 7.59–7.54 (m, 1H), 7.46 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.83–6.76 (m, 4H), 4.47–4.40 (m, 2H), 3.72 (s, 2H), 3.40 (d, J = 11.7 Hz, 1H), 3.28 (s, 1H), 3.24 (s, 4H), 3.05 (d, J = 13.0 Hz, 1H), 2.81 (d, J = 13.1 Hz, 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.

[0173] 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

[0174]

[0175] 1 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.43–7.36 (m, 2H), 7.17 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 9.4 Hz, 2H), 7.11–7.06 (m, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.3 Hz, 2H), 5.70 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.54 (s, 2H), 3.41 (d, J = 12.9 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.09 (s, 4H), 2.96 (d, J = 13.6 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.49 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 30 H 33 F3N6O, [M+Na] + , 573.2566; found 573.2586.

[0176] 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

[0177]

[0178] 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;found589.2294

[0179] 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

[0180]

[0181] 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

[0182] 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

[0183]

[0184] 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 33 BrF2N6O,[M+Na] + ,635.1745; found 635.1736.

[0185] 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

[0186]

[0187] 11H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.73 (s, 1H), 7.59–7.55 (m, 1H), 7.53 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.81 (dd, J = 21.8, 8.3 Hz, 4H), 4.44 (d, J = 7.5 Hz, 2H), 3.55 (s, 2H), 3.40 (d, J = 13.1 Hz, 1H), 3.28 (d, J = 13.0 Hz, 1H), 3.21 (s, 4H), 3.05 (d, J = 13.5 Hz, 1H), 2.81 (d, J = 13.4 Hz, 1H), 2.62 (s, 4H), 2.01 (s, 3H). HRMS calcd for C 30 H 33 BrF2N6O, [M+H] + , 611.1946; found 611.1985.

[0188] 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

[0189]

[0190] 1 1H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 (q, J = 7.9, 6.9 Hz, 2H), 7.14 (t, J = 10.7 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 5.9 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 5.70 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.52 (s, 2H), 3.41 (d, J = 12.9 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.10 (s, 4H), 2.96 (d, J = 13.5 Hz, 1H), 2.75 (d, J = 13.8 Hz, 1H), 2.57 (s, 4H), 2.04 (s, 3H). HRMS calcd for C 30 H 33F2IN6O, [M+Na] + , 681.1626; found 681.1672.

[0191] 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

[0192]

[0193] 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.

[0194] 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

[0195]

[0196] 11H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.74 (s, 1H), 7.59–7.52 (m, 2H), 7.44–7.39 (m, 1H), 7.27 (td, J = 8.5, 2.7 Hz, 1H), 7.17–7.11 (m, 1H), 6.98–6.90 (m, 3H), 6.80 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.57 (s, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.13–3.06 (m, 4H), 2.96 (d, J = 15.4 Hz, 1H), 2.75 (d, J = 13.7 Hz, 1H), 2.56 (t, J = 4.9 Hz, 4H), 2.04 (s, 3H). HRMS calcd for C 30 H 32 BrF3N6O, [M+Na] + , 653.1650; found 653.1665.

[0197] 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

[0198]

[0199] 1 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.74 (s, 1H), 7.66 (dd, J = 8.8, 5.3 Hz, 1H), 7.44–7.39 (m, 1H), 7.36 (dd, J = 9.8, 3.2 Hz, 1H), 7.17–7.10 (m, 2H), 6.98–6.92 (m, 3H), 6.81 (d, J = 8.7 Hz, 2H), 5.70 (s, 1H), 4.51 (q, J = 14.3 Hz, 2H), 3.59 (s, 2H), 3.42 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 3.12 (t, J = 4.9 Hz, 4H), 2.96 (d, J = 14.7 Hz, 1H), 2.75 (d, J = 13.6 Hz, 1H), 2.59 (t, J = 5.0 Hz, 4H), 2.04 (s, 3H). HRMS calcd for C 30 H 32 BrF3N6O, [M+Na] +,653.1650; found 653.1584.

[0200] 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

[0201]

[0202] 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).HRMScalcd for C 30 H 32 BrClF2N6O,[M+Na] + ,669.1355; found 669.1393.

[0203] 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

[0204]

[0205] 11H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.43–7.39 (m, 1H), 7.31 (dd, J = 8.5, 2.7 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97–6.94 (m, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.69 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 3.59 (s, 2H), 3.41 (d, J = 12.9 Hz, 1H), 3.31–3.29 (m, 1H), 3.11 (s, 4H), 2.96 (d, J = 15.6 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.58 (t, J = 5.0 Hz, 4H), 2.04 (s, 3H). HRMS calcd for C 30 H 32 BrClF2N6O, [M+Na] + , 669.1355; found 669.1359.

[0206] 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

[0207]

[0208] 1 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (q, J = 8.4 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.17–7.11 (m, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 8.1 Hz, 2H), 6.79 (d, J = 8.1 Hz, 2H), 5.69 (s, 1H), 4.50 (q, J = 14.3 Hz, 2H), 3.75 (s, 2H), 3.40 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.3 Hz, 1H), 3.04 (s, 4H), 2.96 (d, J = 13.8 Hz, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.62 (s, 4H), 2.03 (s, 3H). HRMS calcd for C 30H 32 BrClF2N6O, [M+Na] + , 669.1355; found 669.1389.

[0209] 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

[0210]

[0211] 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, 2H), 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.

[0212] 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

[0213]

[0214] 11H 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;found713.0910.

[0215] Example32:2-(2,4-Difluorophenyl)-1-(methyl(4-(4-methylbenzyl)piperazin-1-yl)benzyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

[0216]

[0217] 1 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;found701.1657.

[0218] 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

[0219]

[0220] 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.

[0221] Referring to the method of Preparation Example 1, the triazole was replaced with tetrazole, and Examples 34-51 were prepared by using the corresponding raw materials respectively.

[0222] 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

[0223]

[0224] 11H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 7.4 Hz, 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, 2.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.93 (s, 1H), 4.81 (s, 2H), 3.60 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.35 (s, 1H), 3.11 (s, 4H), 2.95 (d, J = 13.8 Hz, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.57 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 31 H 36 F2N6O, [M+Na] + , 634.1717; found 634.1693.

[0225] 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

[0226]

[0227] 1 1H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.52 (dd, J = 7.5, 1.8 Hz, 1H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H), 7.34 (s, 1H), 7.30 (q, J = 8.0, 7.6 Hz, 2H), 7.21–7.17 (m, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.94 (dd, J = 8.5, 2.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 4.81 (s, 2H), 3.62 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.35 (s, 1H), 3.11 (s, 4H), 2.95 (d, J = 14.6 Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H), 2.57 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 32 ClF2N7O, [M+H] +,568.2403; found 568.2442.

[0228] 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

[0229]

[0230] 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 forC 29 H 32 F2IN7O,[M + H] + ,660.1759; found 660.1805.

[0231] 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

[0232]

[0233] 11H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.31 (q, J = 7.6, 6.9 Hz, 2H), 7.21–7.16 (m, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.94 (dd, J = 8.6, 2.6 Hz, 1H), 6.81 (d, J = 8.3 Hz, 2H), 5.93 (s, 1H), 4.81 (s, 2H), 3.51 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.36 (d, J = 12.8 Hz, 1H), 3.09 (s, 4H), 2.95 (d, J = 13.9 Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H), 2.49 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 32 BrF2N7O, [M+H] + , 614.1878; found 614.1886.

[0234] 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

[0235]

[0236] 1 1H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.2 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 10.2 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.4 Hz, 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 = 13.1 Hz, 1H), 3.34 (s, 1H), 3.07 (s, 4H), 2.94 (d, J = 13.8 Hz, 1H), 2.83 (d, J = 13.8 Hz, 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.

[0237] 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

[0238]

[0239] 1 H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.32 (q, J = 8.9 Hz, 1H), 7.21–7.16 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.94 (dd, J = 8.6, 2.6 Hz, 1H), 6.82 (d, J = 8.2 Hz, 2H), 5.93 (s, 1H), 4.81 (s, 2H), 3.61 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.35 (s, 1H), 3.11 (s, 4H), 2.95 (d, J = 13.8 Hz, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.51 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 30 H 32 F5N7O, [M+H] + ,602.2667; found 602.2686.

[0240] 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

[0241]

[0242] 1 H NMR (600 MHz, DMSO-d6) δ 9.04 (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, 1H), 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 32F5N7O2, [M+H] + , 618.2616; found 618.2638.

[0243] 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

[0244]

[0245] 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 = 12.7Hz, 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.

[0246] 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

[0247]

[0248] 11H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.65 (s, 1H), 7.33 (dd, J = 23.6, 9.1 Hz, 2H), 7.19 (d, J = 9.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 3H), 6.82 (d, J = 8.1 Hz, 2H), 5.93 (s, 1H), 4.80 (s, 2H), 3.58 (s, 2H), 3.43 (d, J = 12.7 Hz, 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.

[0249] 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

[0250]

[0251] 1 1H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.3, 2.2 Hz, 1H), 7.34–7.29 (m, 1H), 7.21–7.17 (m, 1H), 6.97 (d, J = 8.3 Hz, 2H), 6.94 (dd, J = 8.5, 2.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 4.80 (s, 2H), 3.57 (s, 2H), 3.43 (d, J = 12.9 Hz, 1H), 3.37 (s, 1H), 3.11 (s, 4H), 2.95 (d, J = 13.8 Hz, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.56 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 31 BrClF2N7O, [M+Na] + , 670.1307; found 670.1303.

[0252] 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

[0253]

[0254] 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=8.5,2.6Hz,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.

[0255] 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

[0256]

[0257] 11H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.30 (q, J = 8.8 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.21–7.16 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 5.92 (s, 1H), 4.80 (s, 2H), 3.75 (s, 2H), 3.42 (d, J = 13.0 Hz, 1H), 3.36 (s, 1H), 3.04 (s, 4H), 2.94 (d, J = 13.8 Hz, 1H), 2.83 (d, J = 13.8 Hz, 1H), 2.62 (s, 4H), 2.09 (s, 3H). HRMS calcd for C 29 H 31 BrClF2N7O, [M+H] + , 648.1488; found 648.1531.

[0258] 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

[0259]

[0260] 1 1H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.21 (t, J = 9.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 4.80 (s, 2H), 3.55 (s, 2H), 3.43 (d, J = 12.9 Hz, 1H), 3.37 (s, 1H), 3.10 (s, 4H), 2.94 (d, J = 13.8 Hz, 1H), 2.83 (d, J = 13.8 Hz, 1H), 2.51 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 31 BrF3N7O, [M+H] + , 632.1783; found 632.1786.

[0261] 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

[0262]

[0263] 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.

[0264] 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

[0265]

[0266] 11H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 1.9 Hz, 2H), 7.32 (q, J = 8.7 Hz, 1H), 7.21–7.17 (m, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.94 (dd, J = 8.6, 2.6 Hz, 1H), 6.81 (d, J = 8.3 Hz, 2H), 5.92 (s, 1H), 4.80 (s, 2H), 3.53 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.37 (s, 1H), 3.10 (s, 4H), 2.95 (d, J = 13.1 Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H), 2.51 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 31 Br2F2N7O, [M+H] + , 692.0983; found 692.0989.

[0267] 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

[0268]

[0269] 1 1H NMR (600 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.64–7.61 (m, 1H), 7.54–7.50 (m, 1H), 7.32 (q, J = 8.6 Hz, 1H), 7.22–7.17 (m, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 6.80 (d, J = 8.2 Hz, 2H), 5.99 (s, 1H), 4.82 (s, 2H), 3.57 (s, 2H), 3.44 (d, J = 13.0 Hz, 1H), 3.35 (s, 1H), 3.09 (s, 4H), 2.96 (d, J = 13.8 Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H), 2.53 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 31 BrF3N7O, [M+H] + , 630.1804; found 630.1873.

[0270] 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

[0271]

[0272] 1 H 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).HRMScalcd for C 29 H 31 BrClF2N7O,[M+Na] + ,670.1307;found 670.1320.

[0273] 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

[0274]

[0275] 11H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.5, 2.6 Hz, 1H), 7.33–7.29 (m, 1H), 7.21–7.17 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.94 (dd, J = 8.5, 2.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 5.92 (s, 1H), 4.80 (s, 2H), 3.59 (s, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.37 (s, 1H), 3.12 (s, 4H), 2.94 (d, J = 13.7 Hz, 1H), 2.83 (d, J = 13.8 Hz, 1H), 2.58 (s, 4H), 2.10 (s, 3H). HRMS calcd for C 29 H 31 Br2F2N7O, [M+Na] + , 714.0802; found 714.0830.

[0276] Pharmacodynamic study of some products of the present invention.

[0277] Experimental method: Refer to the conventional in vitro antibacterial test method (Reference method for broth dilution antifungal susceptibility testing of yeasts and filamentous fungi; Approved Standard M27-A3 and M38-A2).

[0278] Experimental materials and methods:

[0279] (1) Experimental strains: The following three common human pathogenic standard fungal strains were used as screening objects in this experiment, and the fungal strains were provided by Shenyang Pharmaceutical University.

[0280] Table 1 Strains used in the experiment and their numbers

[0281] Strain name Genus and species Strain Candida albicans Candida albicans SC5314 Candida tropicalis Candida tropicalis CGMCC 2.3739 Cryptococcus neoformans Cryptococcus neoformans GIM 2.209

[0282] (2) Experimental method:

[0283] Preparation of RPMI-1640 medium: 10.0 g of RPMI-1640, 2.0 g of NaHCO3, 34.5 g of 3-(N-morpholino)propanesulfonic acid (sigma). Dissolve in 800 mL of sterile distilled water. Adjust the pH to 7.0 with 1 mol / L NaOH, then make up the volume to 1000 mL. Filter through a 0.22 μm microporous membrane to sterilize and store at 4°C for later use.

[0284] Preparation of spherical fungal suspension: Spherical fungi (Candida albicans, Candida tropicalis, Cryptococcus neoformans). Inoculate the activated strains on Sabouraud solid medium plates by the method of quadrant streaking, and incubate at 32°C for 2 - 3 days. Take an appropriate amount of single colonies and inoculate them into a triangular flask containing 10 mL of 0.85% sterile normal saline, shake for 15 minutes. Take a small amount of the bacterial liquid with a sterilized pipette tip and count it under a microscope on a hemocytometer. Dilute with RPMI-1640 medium to make the final concentration of the bacterial suspension 6 1×10

[0285] Preparation of the drug solution: 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 in sequence, and mix well. Prepare a drug solution with a concentration of 0.64 mg / mL. Prepare positive control drugs fluconazole, voriconazole, and itraconazole in the same way.

[0286] Inoculation: First step, add RPMI-1640 medium: Add 180 μL of RPMI-1640 medium to the first well in each row, add 100 μL of RPMI-1640 medium to wells 2 - 11, and add 200 μL of RPMI-1640 medium to the 12th well. Second step, add the drug sample: Add 20 μL of the test drug solution (i.e., the compounds obtained in each example) to the first well, mix well with a pipette gun and then aspirate 100 μL to the second well, and perform 2-fold dilution in sequence until the 10th well and then mix well and discard 100 μL. Third step, add the bacterial suspension: Add 100 μL of the inoculated bacterial suspension to each of wells 1 - 11. The 11th well is the growth control, and the 12th well is the blank medium control. For the positive control drug, no blank drug control is set, that is, perform serial dilution from the first well until the 10th well, and the test concentration (μg / mL) range is 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625.

[0287] Culture and detection: Take the blank control with no sterile growth and the positive control with good growth as the criteria for judging whether the test operation is qualified. Test 8 samples per plate, and set positive drug controls for each bacterium. The dilution method of the test drug is the same as above.

[0288] Table 2 Minimum inhibitory concentration (μg / mL) of the compounds in the examples

[0289]

[0290]

[0291] As can be seen from the above experimental results, the compounds of general formula I and their salts to be protected by the present invention have good antifungal activity. The antifungal activities of multiple compounds are stronger than those of the positive control drug. Compared with the existing antifungal drugs, they have the advantages of novel structure, low toxicity, high efficiency, and broad spectrum. Therefore, the compounds of the present invention have good application prospects.

[0292] The compounds of general formula I in the present invention can be administered alone, but are usually administered in a mixture with a pharmaceutical carrier. The selection of the pharmaceutical carrier should be based on the desired route of administration and standard pharmaceutical practice. The following are the preparation methods of various pharmaceutical dosage forms of such compounds, such as tablets, capsules, injections, aerosols, suppositories, membranes, dripping pills, external liniments, and ointments, to illustrate their new applications in the pharmaceutical field.

[0293] Example 52: Tablets.

[0294] 10 g of the compound of Example 30 was mixed with 20 g of excipients according to the general tabletting method in pharmacy, and then compressed into 100 tablets, each tablet weighing 300 mg.

[0295] Example 53: Capsules.

[0296] 10 g of the compound of Example 30 was mixed with 20 g of excipients according to the requirements of pharmacy for capsules, and then filled into hollow capsules, each capsule weighing 300 mg.

[0297] Example 54: Injections.

[0298] 10 g of the compound of Example 30 was adsorbed with activated carbon according to the conventional method in pharmacy, filtered through a 0.65 μm microporous membrane, and then filled into a nitrogen tank to prepare an aqueous injection preparation, with each vial containing 2 mL and a total of 100 vials filled.

[0299] Example 55: Aerosols.

[0300] 10 g of the compound of Example 30 was dissolved in an appropriate amount of propylene glycol, and then distilled water and other excipients were added to prepare a 500 mL clear solution.

[0301] Example 56: Suppositories.

[0302] 10 g of the compound of Example 30 was ground fine, an appropriate amount of glycerol was added, and after grinding evenly, the melted glycerogelatin was added and ground evenly. Then it was poured into a mold coated with a lubricant to prepare 50 suppositories.

[0303] Example 57: Membranes.

[0304] For Example 30, 10 g of the compound was taken, and polyvinyl alcohol, medicinal glycerol, water, etc. were stirred and swollen and then heated for dissolution. After filtration through an 80-mesh sieve, the above compound of Example 30 was added to the filtrate and stirred for dissolution. 100 tablets were prepared by a film coating machine.

[0305] Example 58: Pills.

[0306] For Example 30, 10 g of the compound was heated and melted and mixed evenly with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin. A total of 1000 pills were prepared.

[0307] Example 59: Topical liniment.

[0308] For Example 30, 10 g of the compound 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 make up to 200 mL.

[0309] Example 60: Ointment.

[0310] For Example 30, 10 g of the compound was ground finely and then ground evenly with 500 g of an oily matrix such as vaseline.

[0311] Although the present invention has been described by specific embodiments, modifications and equivalent changes are obvious to those skilled in the art, and they are all included in the scope of the present invention.

Claims

1. An azole derivative represented by the general formula I or a pharmaceutically acceptable salt thereof, characterized in that: General formula I wherein MBG is an optionally substituted tetrazolyl group, an optionally substituted triazolyl group, or an optionally substituted pyrazolyl group, and the said substitution means C1-4 alkyl substitution or C1-4 alkoxy substitution; X is a carbonyl group, a sulfoxide group, or a sulfone group, or CH2, NH, O, or S; R 1 is H, -P(O)(OH)2, -CH2-O-P(O)(OH)2, or -C(O)alkyl optionally substituted with an amino group, where the alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl; R 2 is a substituted benzene ring, and the substituent position can be ortho, meta or para, and can be mono-substituted or multi-substituted. The substituent is selected from halogens, and the halogen is F, Cl, Br or I; R 3 is hydrogen, halogen, alkyl or haloalkyl, and the alkyl in the alkyl or the haloalkyl is 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 substituent position is ortho, meta or para; i. A halogen, and the said halogen is F, Cl, Br, or I; ii. 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 or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Among them, MBG is selected from the following structures: ; X is CH2.

3. The azole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 and R 3 is hydrogen; R 2 is 2,4-difluorophenyl.

4. The azole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 4 selected from i, ii, or iii, where the substituent position is ortho, meta, or para; i. A halogen, and the said halogen is F, Cl, Br, or I; ii. 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. A triazole derivative or a pharmaceutically acceptable salt thereof, characterized in that, The said azole derivative is 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-(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-(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-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-Bromo-5-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-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 contains the azole derivative described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient.

7. A pharmaceutical preparation, characterized in that: It contains the azole derivative described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 6 as an active ingredient.

8. Use of the azole derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6, or the pharmaceutical preparation according to claim 7, for the preparation of an antifungal drug, characterized in that: The fungi are Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Cryptococcus neoformans, Microsporum gypseum or Trichophyton rubrum.

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