Azole derivative having nitrogen-containing side chain substituent and use thereof in medicine

Abstract

The present invention belongs to the technical field of medicinal chemistry. Specifically disclosed are an azole derivative represented by general formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or 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 infection.

Description

Nitrogen-substituted azole derivatives and their pharmaceutical uses

[0001] Cross-references to related applications

[0002] This application claims the benefit of Chinese application number 2024109705815, filed on July 18, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry technology, specifically relating to an azole derivative and its pharmaceutically acceptable salts, hydrates, solvates and prodrugs, their preparation methods and their use in the preparation of drugs for treating various diseases caused by fungal infections. Background Technology

[0004] Fungal infections can be divided into superficial fungal infections and deep fungal infections. Deep fungal infections, also known as invasive fungal infections, are a type of disease with high morbidity and mortality. In recent years, the morbidity and mortality rates of invasive fungal infections in patients with immunodeficiency, cancer, organ transplantation, and other patient groups have been increasing year by year, exacerbating the treatment burden on patients and the medical industry.

[0005] Candida, Cryptococcus, and Aspergillus are the three major pathogens causing invasive fungal infections. Despite the significant threat fungal infections pose to humans, the number of effective drugs for clinical treatment remains very limited. Currently, antifungal drugs in clinical practice can be categorized based on their mechanisms of action: azole drugs that inhibit ergosterol synthesis; echinocandins that disrupt cell walls; allylamines that inhibit fungal cell membrane synthesis; polyenes that cause cell membrane leakage; and antimetabolites that act on nucleic acids. Among these, azole drugs are widely used first-line treatments in clinical practice. They exert their antifungal effect by inhibiting fungal cell membrane synthesis through their action on the activity of lanosterol 14α-demethylase (CYP51). Currently, azole antifungal drugs used 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 tetrazolazole drugs, such as oteseconazole.

[0006] Although azole drugs play an irreplaceable role in clinical practice, they suffer from problems such as low efficacy, narrow antibacterial spectrum, and potential drug interactions when administered in combination. This invention develops a new generation of novel nitrogen-substituted azole derivatives with potent antifungal effects to address these issues. Summary of the Invention

[0007] The purpose of this invention is to overcome the defects and deficiencies in the prior art and to provide a novel nitrogen-containing side-chain substituted azole derivative, its preparation method, and its application as an antifungal drug, especially as a CYP51 inhibitor.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides an azole derivative, said derivative being a compound of general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof:

[0010] Wherein, MBG is an optionally substituted tetrazolium, optionally substituted triazolium, or optionally substituted pyrazolium, and the optionally substituted refers to C. 1- 4-alkyl substitution or C 1-4 Alkyl substitution;

[0011] X represents hydrogen, halogen, or C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0012] Y represents a substituted benzene ring, with the substituent located at the ortho, meta, or para position, and the substitution being a monosubstituted or polysubstituted halogen.

[0013] Z represents hydrogen, C represents... 1-4 Alkyl, C 1-4 Halogenated alkyl, carbonyl, or sulfonyl groups;

[0014] R 1 For hydrogen, C 1-4 Alkyl or C 1-4 Deuterated alkyl groups;

[0015] R 2 Or R 3 It can be hydrogen or hydroxyl, halogen, nitro, amino, cyano, aldehyde, phenyl, benzyloxy, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, optionally hydroxyl, amino or halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated phenyl, halogenated benzyloxy, free, salt-forming, esterified and amidated carboxyl, C1-C6 alkylacyl, C1-C3 alkylenedioxy;

[0016] The carbon atom marked with * is either a chiral carbon atom or a non-chiral carbon atom;

[0017] Ring A is a phenyl, a 5-7 membered heteroaryl, a 5-7 membered heterocyclic alkyl, a five-membered aryl-hexa-aryl, or a six-membered aryl-hexa-aryl, wherein the heteroaryl or heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, or S, and ring A is optionally surrounded by 1-4 identical or different R atoms. 2 replace;

[0018] Ring B is a phenyl, a 5-7 membered heteroaryl, or a 5-7 membered heterocyclic alkyl group, wherein the heteroaryl or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, or S, and ring B is optionally surrounded by 1-4 identical or different R atoms. 3 replace.

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

[0020] In a preferred embodiment, X is hydrogen or methyl; Y is 2,4-difluorophenyl; Z is hydrogen or carbonyl.

[0021] In a preferred embodiment, ring A is a benzene ring, oxazole ring, pyridine ring, thiophene ring, furan ring, thiazole ring, pyrimidine ring, quinoline ring, benzothiophene ring, naphthyl ring, quinoxaline ring, or benzo[a]dioxane ring; R 2 It is either hydrogen or fluorine.

[0022] In a preferred embodiment, ring B is a benzene ring; R 3 Selected from i, ii, or iii, wherein the substituent is located at the ortho, meta, or para position, and the substitution is a single or multiple substitution;

[0023] i. A halogen, wherein the halogen is F, Cl, Br or I;

[0024] ii. The straight-chain or branched alkyl group with 1 to 6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0025] iii. Cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino or hydroxyl;

[0026] In a preferred embodiment, ring A is a benzene ring, ring B is a 5-6 membered heteroaryl group, and the heteroaryl group contains 1-2 heteroatoms selected from N, O or S; R 2 and R 3 It is either hydrogen or fluorine.

[0027] In a preferred embodiment, ring A is a benzene ring, and ring B is a benzene ring; R 2 It is hydrogen or fluorine; R 3Selected from i, ii, or iii, wherein the substituent is located at the ortho, meta, or para position, and the substitution is a single or multiple substitution;

[0028] i. A halogen, wherein the halogen is F, Cl, Br or I;

[0029] ii. The straight-chain or branched alkyl group with 1 to 6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0030] iii. Cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino, or hydroxyl.

[0031] In a preferred embodiment, ring A is a 5-6 membered heteroaryl group, the heteroaryl group containing 1-2 heteroatoms selected from N, O, or S, and ring B is a benzene ring; R 2 It is hydrogen; R 3 Selected from i, ii, or iii, wherein the substituent is located at the ortho, meta, or para position, and the substitution is a single or multiple substitution;

[0032] i. A halogen, wherein the halogen is F, Cl, Br or I;

[0033] ii. The straight-chain or branched alkyl group with 1 to 6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl;

[0034] iii. Cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino, or hydroxyl.

[0035] In a preferred embodiment, ring A is a five-membered arylhexane-aryl or a six-membered arylhexane-aryl, the aryl group contains 1-2 heteroatoms selected from N, O, or S, and ring B is absent; R 2 It is hydrogen;

[0036] In a preferred embodiment, the derivative is a compound of general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, selected from:

[0037] 2-(2,4-Difluorophenyl)-1-(methyl((5-phenylpyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0038] 2-(2,4-Difluorophenyl)-1-(((5-(2-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0039] 2-(2,4-Difluorophenyl)-1-(((5-(3-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0040] 2-(2,4-Difluorophenyl)-1-(((5-(4-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0041] 1-(((5-(2-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0042] 1-(((5-(3-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0043] 1-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0044] 2-(2,4-Difluorophenyl)-1-(((5-(2,4-difluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0045] 2-(2,4-Difluorophenyl)-1-(methyl((5-(p-tolyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0046] 2-(2,4-Difluorophenyl)-1-(((5-(4-methoxyphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0047] 2-(2,4-Difluorophenyl)-1-(((5-(4-ethylphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0048] 2-(2,4-Difluorophenyl)-1-(((5-(4-isopropylphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0049] 1-(((5-(4-(tert-butyl)phenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0050] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0051] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0052] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-((trifluoromethoxy)methyl)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0053] 4-(6-(((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)pyridin-3-yl)benzonitrile;

[0054] 1-(((5-([1,1'-biphenyl]-4-yl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0055] 1-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0056] 2-(2,4-Difluorophenyl)-1-(methyl((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0057] 2-(2,4-Difluorophenyl)-1-(methyl((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0058] 1-((4'-chloro-1,2-dihydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0059] 2-(2,4-Difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0060] 2-(2,4-Difluorophenyl)-1-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0061] 2-(2,4-Difluorophenyl)-1-(methyl((4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0062] 1-(((4-(4-chlorophenyl)thiazolyl-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0063] 2-(2,4-Difluorophenyl)-1-(methyl((4-(4-(trifluoromethyl)phenyl)thiazolyl-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0064] 2-(2,4-Difluorophenyl)-1-(methyl((4-(4-(trifluoromethoxy)phenyl)thiazolyl-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0065] 1-(((2-(4-chlorophenyl)thiazolyl-5-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0066] 2-(2,4-Difluorophenyl)-1-(methyl((2-(4-(trifluoromethyl)phenyl)thiazolyl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0067] 2-(2,4-Difluorophenyl)-1-(methyl((2-(4-(trifluoromethoxy)phenyl)thiazolyl-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0068] 1-(((5-(4-chlorophenyl)thiophen-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0069] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0070] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0071] 1-(((5-(4-chlorophenyl)furan-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0072] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0073] 2-(2,4-Difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0074] 1-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0075] 1-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0076] 1-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0077] 1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0078] 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0079] 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(cyclopropyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0080] 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0081] (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0082] (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0083] (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0084] (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0085] (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0086] (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0087] (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0088] (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0089] (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0090] (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0091] (2R,3R)-3-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0092] (2R,3R)-3-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0093] (2R,3R)-3-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0094] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0095] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0096] (2R,3R)-3-(((4'-chloro-2'-,3-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0097] (2R,3R)-3-(((4'-chloro-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0098] (2R,3R)-2-(2,4-difluorophenyl)-3-((3-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0099] (2R,3R)-1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0100] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0101] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0102] (2R,3R)-3-(((6-(4-chloro-2-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0103] (2R,3R)-3-(((6-(4-chloro-3-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0104] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0105] (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0106] 2-(2,4-Difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0107] 2-(2,4-Difluorophenyl)-1-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0108] 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0109] 1-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0110] 1-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0111] 4-(benzyloxy)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylbenzamide;

[0112] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-[1,1'-biphenyl]-4-carboxamide;

[0113] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenyl-1,2-oxazol-3-carboxamide;

[0114] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-6-phenylpyridine-3-carboxamide;

[0115] 4-Benzoyl-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylbenzamide;

[0116] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenylthiophene-2-carboxamide;

[0117] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenylfuran-3-carboxamide;

[0118] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-4-phenyl-1,3-thiazolyl-2-carboxamide;

[0119] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-2-phenylpyrimidine-5-carboxamide;

[0120] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide;

[0121] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-(4-methylphenyl)thiophene-2-carboxamide;

[0122] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(4-fluorophenyl)-N-methylthiophene-2-carboxamide;

[0123] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(2-fluorophenyl)-N-methylthiophene-2-carboxamide;

[0124] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(4-ethylphenyl)-N-methylthiophene-2-carboxamide;

[0125] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide;

[0126] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(3-fluorophenyl)-N-methylthiophene-2-carboxamide;

[0127] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(propyl-2-yl)phenyl]thiophene-2-carboxamide;

[0128] 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide;

[0129] 5-(4-chlorophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide;

[0130] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]thiophene-2-carboxamide;

[0131] 5-(4-chloro-3-fluorophenyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-methylthiophene-2-carboxamide;

[0132] 5-(4-chloro-2-fluorophenyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-methylthiophene-2-carboxamide;

[0133] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoline-3-carboxamide;

[0134] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide;

[0135] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylnaphthalene-2-carboxamide;

[0136] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoline-2-carboxamide;

[0137] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoxaloline-2-carboxamide;

[0138] N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-2H-1,3-benzodioxacyclopenten-5-carboxamide

[0139] Furthermore, according to some common methods in the field to which this invention pertains, some compounds of general formula I in this invention have basic groups and can react with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include addition salts of inorganic and organic acids, with salts that react with the following acids being 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.

[0140] Furthermore, the present invention also includes prodrugs derived from the present invention. These prodrugs are derivatives of general formula I, which may themselves have weak or even no activity, but are converted into their corresponding biologically active forms under physiological conditions (e.g., through metabolism, solvation, or other means) after administration.

[0141] Compounds of Formula I can exist in both non-solventized and solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.). Compounds of Formula I may contain asymmetric or chiral centers, and therefore can exist in different stereoisomers. All stereoisomers of this invention, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof (such as racemic mixtures), are included within the scope of this invention.

[0142] The compound represented by general formula I can exist in different tautomer forms, all of which are included within the scope of this invention. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert via low energy barriers.

[0143] In the definitions of compounds of general formula I given above, the terms used in the compilation are generally defined as follows:

[0144] Optional substituents: C1-C4 alkyl, C1-C4 alkoxy.

[0145] Halogens: refer to fluorine, chlorine, bromine or iodine.

[0146] Alkyl group: straight-chain or branched alkyl group, preferably, the alkyl group is C10. 1-6Straight-chain or branched alkyl groups, for example, may be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl.

[0147] Cycloalkyl: Substituted or unsubstituted cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents include methyl, halogen, etc.

[0148] Halogenated alkyl groups: straight-chain or branched alkyl groups in which hydrogen atoms may be partially or completely replaced by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.

[0149] Alkoxy: Straight-chain or branched alkyl groups, in which the hydrogen atom of the hydroxyl group can be replaced by these straight-chain or branched alkyl groups, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, etc.

[0150] In a second aspect, the present invention provides a composition comprising a derivative of general formula I, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof as active ingredients, which is then mixed with a pharmaceutically acceptable carrier or excipient to form a clinically acceptable dosage form. The aforementioned pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as allergic reactions.

[0151] In a third aspect, the pharmaceutical composition of the present invention can be formulated into several dosage forms, containing some commonly used excipients in the pharmaceutical field. The dosage forms described above can be injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, ointments, and other dosage forms of pharmaceutical drugs.

[0152] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solvents, and matrices. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0153] In the fourth aspect, the compounds of general formula I of the present invention can be synthesized by methods well known in the field of chemistry, and especially prepared according to the description of the present invention; room temperature in the present invention refers to ambient temperature, which is 25°C.

[0154] The preparation method of the derivative represented by general formula I above, wherein the preparation reaction of the derivative represented by general formula I is as follows:

[0155] Starting with 2'-chloro-2,4-difluoroacetophenone, a substitution reaction under basic conditions yielded intermediate 2. Intermediate 2, under basic conditions, cyclized with trimethyl sulfoxide to give intermediate 3. Intermediate 4 underwent reductive amination with ammonia, cyclopropylamine, methylamine hydrochloride, or methyl-d3-amine hydrochloride to give intermediate 5. Intermediate 3 then underwent ring-opening with intermediate 5 under basic conditions to give intermediate 6, which subsequently underwent a Suzuki coupling reaction with phenylboronic acid containing different substituents to give the target compound 7.

[0156] The above preparation process involves MBG, ring A, and R. 2 and R 3 The definition is as described above.

[0157] Furthermore, using 2'-chloro-2,4-difluoroacetophenone as the starting material, intermediate 2 is obtained by a substitution reaction with triazole or tetraazole under alkaline conditions. 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, preferably benzyltriethylammonium chloride. The reaction solvent can be acetonitrile, tetrahydrofuran, toluene, dichloromethane, N,N-dimethylformamide, preferably dichloromethane. Intermediate 2 is cyclized with trimethyl sulfoxide 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, or carbonate. Potassium, etc., preferably sodium hydroxide; intermediate 4 is reduced-amination with ammonia, cyclopropane ammonia solution, methylamine hydrochloride, or methyl-d3-amine hydrochloride to obtain intermediate 5, the reaction temperature is 0-50℃, preferably 25℃; the reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., preferably methanol; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably triethylamine; the reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 3 and intermediate 5 undergo ring-opening under alkaline conditions to obtain intermediate 6, 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℃, preferably 80℃. Intermediate 6 undergoes coupling reactions with phenylboronic acids of different substituents to obtain target compounds 7 and 8, respectively. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, 1,4-dioxane / water, isopropanol, ethanol, preferably 1,4-dioxane / water. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, preferably potassium carbonate. The catalyst in the reaction can be tetra-triphenylphosphine palladium, bis(triphenylphosphine) palladium dichloride, palladium acetate, preferably tetra-triphenylphosphine palladium. The reaction temperature is 50–100 °C, preferably 90 °C.

[0158] Starting from 9, intermediate 10 was obtained by Suzuki coupling reaction with phenylboronic acid with different substituents. Intermediate 10 was then subjected to reductive amination reaction with methylamine hydrochloride or methyl-d3-amine hydrochloride to obtain intermediate 11. Subsequently, under alkaline conditions, intermediate 11 was obtained by ring-opening with 1-[(2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxymethyl]-1H-[1,2,4]triazole to obtain target compound 12.

[0159] The above preparation process involves the A ring and R ring. 2 and R 3 The definition is as described above.

[0160] Furthermore, starting with 9, a Suzuki coupling reaction is carried out with phenylboronic acid of different substituents to obtain intermediate 10. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, 1,4-dioxane / water, isopropanol, ethanol, preferably 1,4-dioxane / water. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, preferably potassium carbonate. The catalyst in the reaction can be tetra-triphenylphosphine palladium, bis(triphenylphosphine) palladium dichloride, palladium acetate, preferably tetra-triphenylphosphine palladium. The reaction temperature is 50-100°C, preferably 90°C. Intermediate 10 is reductively amination with methylamine hydrochloride or methyl-d3-amine hydrochloride 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 base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably triethylamine. The reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 11 is ring-opened with 1-[(2R,3s)-2-(2,4-difluorophenyl)-3-methylepoxymethyl]-1H-[1,2,4]triazole to obtain target compound 12. The reaction temperature is 50–150 °C, preferably 120 °C. The solvent can be acetonitrile, tetrahydrofuran, tert-butanol, toluene, isopropanol, preferably isopropanol. The base in the reaction can be magnesium hydroxide, carbonic acid enzyme, sodium hydroxide, potassium carbonate, sodium carbonate, lithium tert-butoxide, magnesium tert-butoxide, preferably magnesium tert-butoxide; the Lewis acid can be lithium chloride, lithium bromide, magnesium chloride, lithium perchlorate, ferric chloride, zinc chloride, manganese chloride, preferably lithium perchlorate.

[0161] Starting with ethyl formate 13 containing different aromatic heterogroups, it undergoes a Suzuki coupling reaction with phenylboronic acid containing different substituents to give intermediate 14. Intermediate 14 is then hydrolyzed under alkaline conditions to give intermediate 15. Starting with 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole, it undergoes reductive amination with methylamine to give intermediate 17. Intermediate 17 then undergoes a condensation reaction with intermediate 15 to give the target compound 18.

[0162] The above preparation process involves ring A, ring B, and ring R. 3 and R 4 The definition is as described above.

[0163] Furthermore, using esters 13 containing different aromatic heterogroups as starting materials, intermediate 14 is obtained by a Suzuki coupling reaction with phenylboronic acid containing different substituents. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, 1,4-dioxane / water, isopropanol, ethanol, preferably 1,4-dioxane / water. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, preferably sodium carbonate. The catalyst in the reaction can be tetra-triphenylphosphine palladium, bis(triphenylphosphine) palladium dichloride, palladium acetate, preferably tetra-triphenylphosphine palladium. The reaction temperature is 50–100°C, preferably 80°C. Intermediate 14 is hydrolyzed under alkaline conditions to give intermediate 15. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, isopropanol, ethanol, preferably methanol. The base in the reaction can be potassium hydroxide, sodium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, preferably sodium hydroxide. The reaction temperature is 25-70℃, preferably 50℃. 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole is reductively amination with methylamine hydrochloride to obtain intermediate 17. The reaction temperature is 0–50 °C, preferably 25 °C. The reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., preferably ethanol. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably triethylamine. The reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 17 undergoes a condensation reaction with intermediate 15 to obtain target compound 18. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, 1,4-dioxane / water, isopropanol, ethanol, preferably N,N-dimethylformamide. The condensing agent can be dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc., preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The base can be 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably 4-dimethylaminopyridine. The reaction temperature is 0-50℃, preferably 25℃.

[0164] In a fifth aspect, the present invention provides the use of azole derivatives, specifically compounds of the general formula I, and their stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in the preparation of medicaments for the prevention or treatment of diseases related to fungal infections.

[0165] The use of the azole derivatives represented by general formula I, their stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs in the preparation of antifungal drugs.

[0166] A pharmaceutical composition comprising an azole derivative of general formula I and its stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs as an active ingredient and pharmaceutically acceptable excipients.

[0167] The pharmaceutical composition is used in the preparation of medicaments for the prevention or treatment of diseases related to fungal infections.

[0168] The pharmaceutical composition is used in the preparation of antifungal drugs.

[0169] The beneficial effects of this invention are as follows: This invention provides a novel azole derivative, its preparation method, pharmaceutical compositions comprising the derivative, pharmaceutical formulations, and uses. The azole derivative of this invention exhibits good antifungal activity against various superficial and deep fungi, and compared with existing clinically used antifungal drugs, it has the advantages of high efficiency, low toxicity, and broad antifungal spectrum, and can be used to prepare antifungal drugs. Detailed Implementation

[0170] The examples are intended to illustrate, and not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-600; all reagents used were analytical or chemically pure.

[0171] The specific implementation structure is as follows:

[0172] The preparation route of Example 1 is shown below:

[0173] The specific synthesis steps are as follows:

[0174] Synthesis of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl-1-one (2)

[0175] 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. Intermediate 1 (2.00 g, 0.19 mmol) in dichloromethane was then added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 12 h. TLC monitoring (DCM:MeOH = 50:1) confirmed complete reaction of the starting material. The mixture was filtered, the filter cake was washed with dichloromethane, the organic phase was concentrated, and column chromatography was used to separate a white solid in 80% yield.

[0176] Synthesis of 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole (3)

[0177] Trimethyl sulfoxide (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 reaction proceeded completely. The mixture was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and the solid was separated by column chromatography to obtain a pale yellow solid in 75% yield.

[0178] Synthesis of 1-(5-bromopyridin-2-yl)-N-methylmethylamine (5)

[0179] Intermediate 4 (12.58 g, 0.068 mol) and methylamine hydrochloride (2.56 g, 0.082 mol) were added to a methanol solution and reacted at room temperature for 30 min. Then, sodium borohydride (3.91 g, 0.102 mol) was added as a reducing agent, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 15:1) indicated complete reaction of the starting material. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and column chromatography was used to separate a pale yellow oily liquid, yielding 85%.

[0180] Synthesis of 1-(((5-bromopyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol (6)

[0181] Intermediate 3 (10.00 g, 0.042 mol), intermediate 5 (9.60 g, 0.048 mol), and triethylamine (21.32 g, 0.21 mol) were added to anhydrous ethanol solution at room temperature and refluxed for 6 h. TLC monitoring (DCM:MeOH = 30:1) indicated complete reaction of the starting material. The mixture was concentrated under reduced pressure and separated by column chromatography to give a white solid in 76% yield.

[0182] Preparation of 2-(2,4-difluorophenyl)-1-(methyl((5-phenylpyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol (Example 1)

[0183] Intermediate 6 was dissolved in 6 mL of 1,4-dioxane / water (v:v = 5:1), followed by the sequential addition of phenylboronic acid, potassium carbonate, and tetrakis(triphenylphosphine)palladium. The mixture was stirred at 90 °C for 5 h under argon protection. TLC monitoring (DCM:MeOH = 30:1) confirmed the reaction was complete. The mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure, and separated using a thin-layer chromatography (DCM:MeOH = 30:1) to give a white solid in 45% yield. 1H NMR (600MHz, DMSO-d6) δ8.77(d,J=2.3Hz,1H),8.31(s,1H),7.97(dd,J=8.1,2.4Hz,1H),7.73(s,2H),7.71( s,1H),7.52–7.48(m,2H),7.48–7.43(m,1H),7.43–7.39(m,1H),7.21(d,J=8.1Hz,1H),7.16(ddd,J=11.8,9. 1,2.6Hz,1H),6.96(td,J=8.4,2.6Hz,1H),6.19(s,1H),4.56(d,J=14.2Hz,1H),4.52(d,J=14.3Hz,1H),3.77 (d,J=14.4Hz,1H),3.66(d,J=14.3Hz,1H),3.10(d,J=13.7Hz,1H),2.88(d,J=13.9Hz,1H),2.16(s,3H). calcd for C 24 H 23 F2N5O,[M+Na] + ,458.1768; found 458.1739.

[0184] Following the method of Example 1, Examples 2-49 were prepared using the corresponding raw materials.

[0185] Example 2: 2-(2,4-difluorophenyl)-1-(((5-(2-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0186] 1H NMR(600MHz,DMSO-d6)δ8.71–8.64(m,1H),8.36(s,1H),7.91–7.87(m,1H),7.77(s,1H),7.62(td,J=7.8,1 .7Hz,1H),7.55–7.50(m,1H),7.48(ddd,J=7.1,4.5,1.8Hz,1H),7.38–7.34(m,2H),7.27(d,J=8.1Hz,1H),7 .17(ddd,J=11.8,9.1,2.6Hz,1H),6.98(td,J=8.5,2.6Hz,1H),6.21(s,1H),4.60(q,J=14.3Hz,2H),3.82( d,J=14.4Hz,1H),3.71(d,J=14.4Hz,1H),3.15(d,J=13.9Hz,1H),2.94(d,J=13.9Hz,1H),2.20(s,3H).HRMS calcd for C 24 H 22 F3N5O,[M+Na] + 476.1676; found 476.1679

[0187] Example 3: 2-(2,4-difluorophenyl)-1-(((5-(3-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0188] 1 H NMR (600MHz, CDCl3-d) δ8.74(d,J=2.4Hz,1H),8.16(s,1H),7.81(dd,J=7.9,2.4Hz,1H),7.71–7.65(m ,3H),7.48–7.45(m,2H),7.39(d,J=7.8Hz,1H),7.32–7.29(m,1H),7.18(d,J=8.0Hz,1H),7.12(td,J=8 .4,2.6Hz,1H),6.82(dd,J=7.7,2.4Hz,1H),4.60(d,J=14.2Hz,1H),4.46(d,J=14.1Hz,1H),3.81(d,J= 14.5Hz,1H),3.73(d,J=14.5Hz,1H),3.23(d,J=13.9Hz,1H),2.92(d,J=13.9Hz,1H),2.18(s,3H).HRMS calcd for C 24 H 22 F3N5O,[M+Na] +476.1674; found 476.1690

[0189] Example 4: 2-(2,4-difluorophenyl)-1-(((5-(4-fluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0190] 1 H NMR(600MHz,DMSO-d6)δ8.76(s,1H),8.31(s,1H),7.96(d,J=7.9Hz,1H),7.79–7.75(m,2H),7.73 (s,1H),7.47(dd,J=16.5,8.3Hz,1H),7.33(td,J=8.8,2.1Hz,2H),7.20(d,J=8.1Hz,1H),7.16(dd ,J=11.9,9.1Hz,1H),6.97(t,J=8.6Hz,1H),6.18(s,1H),4.54(q,J=14.3Hz,2H),3.76(d,J=14.3 Hz,1H),3.65(d,J=14.4Hz,1H),3.11(d,J=13.9Hz,1H),2.88(d,J=13.9Hz,1H),2.16(s,3H).HRMS calcd for C 24 H 23 F3N5O,[M+Na] + ,476.1674; found 476.1688.

[0191] Example 5: 1-(((5-(2-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0192] 1H NMR (600MHz, CDCl3-d) δ8.61(d,J=2.3Hz,1H),8.15(s,1H),7.76(dd,J=8.0,2.3Hz,1H),7.70(s,1H), 7.70–7.64(m,3H),7.55(td,J=7.4,1.6Hz,1H),7.51(dd,J=7.7,1.4Hz,1H),7.46(td,J=7.7,2.8Hz,2H ),7.41–7.33(m,4H),7.17(d,J=7.9Hz,1H),4.60(d,J=14.2Hz,1H),4.47(d,J=14.1Hz,1H),3.81(d,J= 14.6Hz,1H),3.73(d,J=14.6Hz,1H),3.23(d,J=13.9Hz,1H),2.92(d,J=13.9Hz,1H),2.19(s,3H).HRMS calcd for C 24 H 22 ClF₂N₅O,[M+Na] + 492.1379; found 492.1357

[0193] Example 6: 1-(((5-(3-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0194] 1 H NMR (600MHz, DMSO-d6) δ8.80(d,J=2.4Hz,1H),8.32(s,1H),8.02(dd,J=8.1,2.3Hz,1H),7.81(s,1H),7. 74(s,1H),7.70(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),7.50–7.44(m,2H),7.22(d,J=8.1Hz,1H),7.17( ddd,J=11.7,9.2,2.3Hz,1H),6.97(td,J=8.5,2.4Hz,1H),6.17(s,1H),4.55(q,J=14.3Hz,2H),3.78(d, J=14.4Hz,1H),3.66(d,J=14.4Hz,1H),3.11(d,J=14.2Hz,1H),2.88(d,J=13.9Hz,1H),2.16(s,3H).HRMS calcd for C 24 H 22 ClF₂N₅O,[M+Na] +492.1379; found 492.1345

[0195] Example 7: 1-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0196] 1 H NMR (600MHz, DMSO-d6) δ8.78(d,J=2.4Hz,1H),8.31(s,1H),7.98(dd,J=8.1,2.4Hz,1H),7.76(d,J=8.6H z,2H),7.73(s,1H),7.55(d,J=8.5Hz,2H),7.46(td,J=8.9,6.7Hz,1H),7.21(d,J=8.1Hz,1H),7.16(ddd, J=11.8,9.1,2.6Hz,1H),6.96(td,J=8.5,2.6Hz,1H),6.16(s,1H),4.54(q,J=14.3Hz,2H),3.77(d,J=14. 5Hz,1H),3.65(d,J=14.4Hz,1H),3.11(dd,J=13.8,1.7Hz,1H),2.88(d,J=13.8Hz,1H),2.16(s,3H).HRMS calcd for C 24 H 22 ClF₂N₅O,[M+Na] + 492.1381; found 492.1352

[0197] Example 8: 2-(2,4-difluorophenyl)-1-(((5-(2,4-difluorophenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0198] 1H NMR (600MHz, CDCl3-d) δ8.66(s,1H),8.16(s,1H),7.78(dt,J=8.1,2.0Hz,1H),7.69(d,J= 2.5Hz,2H),7.47(d,J=6.1Hz,1H),7.19(d,J=8.0Hz,1H),7.03(td,J=8.3,2.6Hz,1H),6.9 9–6.95(m,1H),6.84–6.78(m,2H),4.60(d,J=14.1Hz,1H),4.45(d,J=14.2Hz,1H),3.78(d d,J=50.4,14.5Hz,2H),3.25(d,J=14.0Hz,1H),2.93(d,J=14.2Hz,1H),2.19(s,3H).HRMS calcd for C 24 H 21 F4N5O,[M+Na] + 494.1580; found 494.1613

[0199] Example 9: 2-(2,4-difluorophenyl)-1-(methyl((5-(p-tolyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0200] 1 H NMR (600MHz, DMSO-d6) δ8.75(d,J=2.4Hz,1H),8.33(s,1H),7.94(dd,J=8.1,2.4Hz,1H),7.74(s,1H),7.61( d,J=8.2Hz,2H),7.48(td,J=8.9,6.8Hz,1H),7.30(d,J=7.9Hz,2H),7.20(d,J=8.1Hz,1H),7.16(ddd,J=11.8 ,9.1,2.6Hz,1H),6.97(td,J=8.5,2.6Hz,1H),6.24(s,1H),4.56(q,J=14.2Hz,2H),3.76(d,J=14.4Hz,1H), 3.66(d,J=14.3Hz,1H),3.11(dd,J=13.9,1.8Hz,1H),2.90(d,J=13.9Hz,1H),2.36(s,3H),2.17(s,3H).HRMS calcd for C 30 H 27 F2N5O,[M+Na] + 472.1927; found 472.1905

[0201] Example 10: 2-(2,4-difluorophenyl)-1-(((5-(4-methoxyphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0202] 1 H NMR(600MHz, CDCl3-d)δ8.72(d,J=2.3Hz,1H),8.16(s,1H),7.78(dd,J=7.9,2.4Hz,1H),7.69–7.6 6(m,3H),7.55–7.53(m,2H),7.47(dd,J=7.7,4.9Hz,1H),7.13(d,J=8.0Hz,1H),7.03(d,J=8.6Hz,2 H),6.81–6.79(m,1H),4.59(d,J=14.2Hz,1H),4.46(d,J=14.2Hz,1H),3.87(s,3H),3.79(d,J=14. 5Hz,1H),3.70(d,J=14.5Hz,1H),3.21(d,J=13.9Hz,1H),2.91(d,J=14.0Hz,1H),2.17(s,3H).HRMS calcd for C 25 H 25 F₂N₅O₂,[M+Na] + ,488.1876; found 488.1888

[0203] Example 11: 2-(2,4-difluorophenyl)-1-(((5-(4-ethylphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0204] 1H NMR (600MHz, DMSO-d6) δ8.75(d,J=2.4Hz,1H),8.33(s,1H),7.94(dd,J=8.1,2.5Hz,1H),7.73(s,1H),7.63(d,J=7. 4Hz,2H),7.57–7.54(m,1H),7.50–7.45(m,1H),7.33(d,J=7.8Hz,2H),7.20(d,J=8.1Hz,1H),7.18–7.14(m,1H),6. 97(td,J=8.4,2.7Hz,1H),6.24(s,1H),4.55(q,J=14.2Hz,2H),3.76(d,J=14.4Hz,1H),3.66(d,J=14.4Hz,1H),3.1 1(d,J=13.9Hz,1H),2.89(d,J=13.9Hz,1H),2.65(dd,J=15.2,7.6Hz,2H),2.16(s,3H),1.21(t,J=7.6Hz,3H).HRMS calcd for C 26 H 27 F2N5O,[M+Na] + 486.2081; found 486.2098

[0205] Example 12: 2-(2,4-difluorophenyl)-1-(((5-(4-isopropylphenyl)pyridin-2-yl)methyl)(methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0206] 1H NMR (600MHz, DMSO-d6) δ8.74(d,J=2.5Hz,1H),8.31(s,1H),7.94(dd,J=8.1,2.4Hz,1H),7.72(s,1H),7.64–7.6 2(m,2H),7.46(td,J=9.0,6.8Hz,1H),7.36(d,J=8.1Hz,2H),7.20(d,J=8.0Hz,1H),7.16(td,J=9.2,4.6Hz,1H) ,6.96(td,J=8.5,2.6Hz,1H),6.20(s,1H),4.53(t,J=12.6Hz,2H),3.75(d,J=14.4Hz,1H),3.65(d,J=14.3Hz,1 H),3.10(d,J=13.9Hz,1H),2.96–2.92(m,1H),2.88(d,J=13.7Hz,1H),2.16(s,3H),1.24(d,J=6.9Hz,6H).HRMS calcd for C 27 H 29 F2N5O,[M+Na] + 500.2240; found 500.2284

[0207] Example 13: 1-(((5-(4-(tert-butyl)phenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0208] 1 H NMR(600MHz,DMSO-d6)δ8.75(d,J=2.1Hz,1H),8.32(s,1H),7.94(dd,J=8.1,2.3Hz,1H),7.73(s,1H) ,7.64(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.47(d,J=7.0Hz,1H),7.21(d,J=8.1Hz,1H),7.18–7.1 4(m,1H),6.97(dd,J=8.4,6.1Hz,1H),6.21(s,1H),4.55(d,J=11.3Hz,2H),3.76(d,J=14.3Hz,1H),3 .66(d,J=14.3Hz,1H),3.11(d,J=13.6Hz,1H),2.89(d,J=13.9Hz,1H),2.16(s,3H),1.32(s,9H).HRMS calcd for C 28 H 31 F2N5O,[M+Na]+ ,514.2397; found 514.2402

[0209] Example 14: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0210] 1 H NMR (600MHz, DMSO-d6) δ8.84(s,1H),8.34(s,1H),8.03(d,J=6.7Hz,1H),7.93(d,J=7.0Hz, 2H),7.82(d,J=7.0Hz,2H),7.75(s,1H),7.50(d,J=7.0Hz,1H),7.25(d,J=7.5Hz,1H),7.13 (t,J=9.0Hz,1H),6.95(s,1H),6.21(s,1H),4.57(d,J=11.9Hz,2H),3.79(d,J=14.2Hz,1H) ,3.68(d,J=14.2Hz,1H),3.13(d,J=13.8Hz,1H),2.90(d,J=13.6Hz,1H),2.17(s,3H).HRMS calcd for C 25 H 22 F5N5O,[M+Na] + ,526.1645; found 526.1682

[0211] Example 15: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0212] 1H NMR(600MHz,DMSO-d6)δ8.80(d,J=2.5Hz,1H),8.32(s,1H),8.00(dd,J=8.1,2.5Hz,1H),7.86( d,J=8.4Hz,2H),7.74(s,1H),7.52–7.45(m,3H),7.23(d,J=8.1Hz,1H),7.17(ddd,J=11.9,9.0, 2.7Hz,1H),6.97(td,J=8.4,2.6Hz,1H),6.18(s,1H),4.55(q,J=14.3Hz,2H),3.78(d,J=14.4Hz ,1H),3.67(d,J=14.5Hz,1H),3.12(d,J=13.9Hz,1H),2.89(d,J=13.8Hz,1H),2.17(s,3H).HRMS calcd for C 25 H 22 F5N5O2,[M+Na] + ,542.1594; found 542.1557

[0213] Example 16: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-((trifluoromethoxy)methyl)phenyl)pyridin-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0214] 1 H NMR (600MHz, DMSO-d6) δ8.75(d,J=8.3Hz,1H),8.31(d,J=7.4Hz,1H),7.94(d,J=5.7Hz,1 H),7.71(dd,J=13.9,5.3Hz,3H),7.49–7.43(m,1H),7.18(d,J=8.3Hz,3H),6.97(d,J=8.3 Hz,1H),6.20(s,1H),4.86–4.80(m,2H),4.55(t,J=11.8Hz,2H),3.75(d,J=14.3Hz,1H), 3.64(d,J=14.3Hz,1H),3.10(d,J=13.9Hz,1H),2.87(d,J=13.9Hz,1H),2.15(s,3H).HRMS calcd for C 26 H 24 F5N5O2,[M+Na] + ,556.1748; found 556.1715

[0215] Example 17: 4-(6-(((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)pyridin-3-yl)benzonitrile

[0216] 1H NMR(600MHz,DMSO-d6)δ8.86(d,J=2.3Hz,1H),8.31(s,1H),8.07(dd,J=8.2,2.5Hz,1H),7.99–7 .94(m,4H),7.74(s,1H),7.47(td,J=9.0,6.7Hz,1H),7.25(d,J=8.2Hz,1H),7.17(ddd,J=11.8, 9.1,2.6Hz,1H),6.97(td,J=8.4,2.6Hz,1H),6.14(s,1H),4.55(q,J=14.3Hz,2H),3.80(d,J=14 .5Hz,1H),3.67(d,J=14.5Hz,1H),3.14–3.09(m,1H),2.88(d,J=13.9Hz,1H),2.17(s,3H).HRMS calcd for C25H22F2N6O,[M+Na]+,483.1723; found 483.1722

[0217] Example 18: 1-(((5-([1,1'-biphenyl]-4-yl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol)

[0218] 1 H NMR(600MHz,DMSO-d6)δ8.84(d,J=2.3Hz,1H),8.32(s,1H),8.04(dd,J=8.1,2.4Hz,1H),7.84–7.79(m,4H), 7.76–7.72(m,3H),7.52–7.49(m,2H),7.47(dd,J=9.0,6.8Hz,1H),7.41–7.38(m,1H),7.23(d,J=8.1Hz,1H) ,7.17(ddd,J=11.8,9.1,2.6Hz,1H),6.97(td,J=8.5,2.6Hz,1H),6.20(s,1H),4.55(q,J=14.2Hz,2H),3.78 (d,J=14.3Hz,1H),3.67(d,J=14.3Hz,1H),3.12(d,J=13.9Hz,1H),2.90(d,J=13.9Hz,1H),2.17(s,3H).HRMS calcd for C30 H 27 F2N5O,[M+Na] + ,534.2084; found 534.2080

[0219] Example 19: 1-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0220] 1H NMR (600MHz, DMSO-d6) δ8.29(d,J=2.2Hz,1H),8.24(s,1H),8.02(d,J=8.3Hz,1H),7.79( d,J=8.1Hz,1H),7.69(s,1H),7.47(dd,J=10.5,5.2Hz,1H),7.39(dd,J=9.1,2.2Hz,1H),7 .10–7.06(m,1H),6.93–6.90(m,1H),5.75(s,1H),4.52–4.45(m,1H),3.59(d,J=13.5Hz, 1H),3.39(d,J=13.6Hz,1H),3.02–2.99(m,1H),2.70(d,J=13.8Hz,1H),2.04(s,1H).HRMS calcd for C24H22ClF2N5O,[M+Na]+,492.1379; found 492.1379.

[0221] Example 20: 2-(2,4-difluorophenyl)-1-(methyl((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0222] 1H NMR (600MHz, DMSO-d6) δ8.35(d,J=2.2Hz,1H),8.25(s,1H),8.24(d,J=8.1Hz,1H),7.91(d,J= 8.1Hz,1H),7.79(d,J=8.2Hz,1H),7.71(s,1H),7.54(dd,J=8.1,2.3Hz,1H),7.42–7.38(m,1H ),7.12–7.08(m,1H),6.95–6.92(m,1H),5.76(s,1H),4.54–4.46(m,1H),3.63(d,J=13.6Hz,1 H),3.43(d,J=13.6Hz,1H),3.03(d,J=13.8Hz,1H),2.72(d,J=13.7Hz,1H),2.06(s,1H).HRMS calcd for C 25 H 22 F5N5O,[M+Na] + ,526.1642; found 526.1620

[0223] Example 21: 2-(2,4-difluorophenyl)-1-(methyl((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0224] 1 H NMR (600MHz, DMSO-d6) δ8.30(d,J=2.2Hz,1H),8.24(s,1H),8.12(dd,J=6.7,2.1Hz,1H),7. 82(d,J=8.1Hz,1H),7.69(s,1H),7.50–7.48(m,1H),7.39(ddd,J=9.1,4.6,3.1Hz,1H),7.10 –7.06(m,1H),6.91(q,J=2.6Hz,1H),5.74(s,1H),4.52–4.44(m,1H),3.60(d,J=13.6Hz,1H ),3.40(d,J=13.6Hz,1H),3.01(d,J=13.7Hz,1H),2.71(d,J=13.7Hz,1H),2.04(s,1H).HRMS calcd for C 25 H 22 F5N5O2,[M+Na] + ,542.1591; found 542.1612

[0225] Example 22: 1-((4'-chloro-1,2-dihydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0226] 1 H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.75(s,1H),7.68–7.66(m,2H),7.66–7.65(m,1H),7 .55–7.52(m,2H),7.50–7.47(m,1H),7.46–7.42(m,1H),7.16(t,J=4.2Hz,2H),6.97(dt,J= 8.5,2.6Hz,1H),5.76(s,1H),4.54(dd,J=29.1,14.3Hz,2H),3.60(d,J=13.4Hz,1H),3.43 (d,J=13.4Hz,1H),3.04(dd,J=13.6,2.0Hz,1H),2.77(d,J=13.7Hz,1H),2.08(s,3H).HRMS calcd for C 25 H 23 ClF₂N₄O,[M+Na] + 491.1426; found 491.1440

[0227] Example 23: 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0228] 1 H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.79(d,J=8.2Hz,2H),7.72–7.69(m,1H),7.54(d,J =8.1Hz,1H),7.39(dd,J=9.1,2.2Hz,1H),7.13(d,J=8.0Hz,1H),7.10–7.07(m,1H),6.90( dd,J=8.5,5.8Hz,1H),5.71(s,1H),4.49(d,J=15.4Hz,1H),3.55(d,J=13.4Hz,1H),3.39( d,J=13.5Hz,4H),2.99(dd,J=13.6,1.9Hz,1H),2.72(d,J=13.7Hz,1H),2.03(s,1H).HRMS calcd for C 26 H 23F5N4O,[M+Na] + 525.1690; found 525.1637

[0229] Example 24: 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0230] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.78–7.74(m,3H),7.56(d,J=7.8Hz,2H ),7.44(t,J=9.0Hz,3H),7.20–7.15(m,3H),6.98(td,J=8.6,2.5Hz,1H),5.7 7(s,1H),4.55(dd,J=30.3,14.3Hz,2H),3.61(d,J=13.4Hz,1H),3.45(d,J=1 3.4Hz,1H),3.05(d,J=13.7Hz,1H),2.78(d,J=13.7Hz,1H),2.10(s,3H).HRMS calcd for C 26 H 23 F5N4O2,[M+Na] + ,541.1639; found 541.1594

[0231] Example 25: 2-(2,4-difluorophenyl)-1-(methyl((4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0232] 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.75(s,1H),7.62(dd,J=6.5,2.2Hz,1H),7.50(d,J=8 .0Hz,2H),7.48–7.44(m,1H),7.13(dd,J=8.5,4.3Hz,5H),6.97(dt,J=8.5,2.6Hz,1H),5.77 (s,1H),4.79(dd,J=17.7,8.8Hz,2H),4.55(dd,J=28.7,14.3Hz,2H),3.58(d,J=13.3Hz,1H) ,3.43(d,J=13.3Hz,1H),3.04(dd,J=13.5,2.0Hz,1H),2.79(d,J=13.7Hz,1H),2.09(s,3H).

[0233] Example 26: 1-(((4-(4-chlorophenyl)thiazolyl-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0234] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.88–7.85(m,2H),7.76(s,1H),7.66(s,1H), 7.56–7.54(m,2H),7.43(dd,J=9.1,2.2Hz,1H),7.14(td,J=9.2,4.6Hz,1H),7.01–6 .98(m,1H),5.80(s,1H),4.56(d,J=6.8Hz,2H),3.85(d,J=14.5Hz,1H),3.72(d,J=1 4.5Hz,1H),3.05(dd,J=13.9,1.9Hz,1H),2.78(d,J=13.7Hz,1H),2.18(s,3H).HRMS calcd for C 22 H 20 ClF2N5OS,[M+Na] + 498.0943; found 498.0949

[0235] Example 27: 2-(2,4-difluorophenyl)-1-(methyl((4-(4-(trifluoromethyl)phenyl)thiazolyl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0236] 1H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.1Hz, 2H), 7.78 (s ,2H),7.77(s,1H),7.46–7.42(m,1H),7.20–7.16(m,1H),6.97(dt,J=8.5,2.6Hz, 1H), 5.90 (s, 1H), 4.57 (t, J = 12.2Hz, 2H), 4.06 (d, J = 15.3Hz, 1H), 3.82 (d, J = 15. 3Hz,1H),3.22(dd,J=13.7,2.1Hz,1H),2.88(d,J=13.8Hz,1H),2.25(s,3H).HRMS calcd for C 23 H 20 F5N5OS,[M+Na] + ,532.1206; found 532.1171

[0237] Example 28: 2-(2,4-difluorophenyl)-1-(methyl((4-(4-(trifluoromethoxy)phenyl)thiazolyl-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0238] 1 H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8.3Hz, 2H), 7.79 (s, 1H),7.46–7.43(m,1H),7.41(d,J=8.3Hz,2H),7.21–7.16(m,1H),6.98(td,J=8.5 ,2.6Hz,1H),5.90(s,1H),4.56(t,J=11.9Hz,2H),4.05(d,J=15.3Hz,1H),3.82(d ,J=15.3Hz,1H),3.22(d,J=13.9Hz,1H),2.89(d,J=13.8Hz,1H),2.25(s,3H).HRMS calcd for C 23 H 20 F5N5O2S,[M+Na] + ,548.1156; found 548.1152

[0239] Example 29: 1-(((2-(4-chlorophenyl)thiazolyl-5-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0240] 1 H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.86(d,J=8.1Hz,2H),7.77(s,1H),7.65(s, 1H),7.54(d,J=8.1Hz,2H),7.44(dd,J=16.3,8.2Hz,1H),7.19–7.10(m,1H),7.03– 6.95(m,1H),5.81(s,1H),4.56(q,J=14.1Hz,2H),3.85(d,J=14.5Hz,1H),3.72(d ,J=14.6Hz,1H),3.05(d,J=13.7Hz,1H),2.78(d,J=13.9Hz,1H),2.18(s,3H).HRMS calcd for C 22 H 20 ClF2N5OS,[M+Na] + 498.0943; found 498.0972

[0241] Example 30: 2-(2,4-difluorophenyl)-1-(methyl((2-(4-(trifluoromethyl)phenyl)thiazolyl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0242] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.05(d,J=8.1Hz,1H),7.83(d,J=8.3Hz ,1H),7.76(s,1H),7.72(s,1H),7.46–7.42(m,1H),7.15–7.11(m,1H),7.00– 6.96(m,1H),5.81(s,1H),4.59–4.53(m,1H),3.87(d,J=14.5Hz,1H),3.74(d ,J=14.5Hz,1H),3.07–3.04(m,1H),2.78(d,J=13.7Hz,1H),2.19(s,1H).HRMS calcd for C 23 H 20 F5N5OS,[M+Na] + ,532.1206; found 532.1244

[0243] Example 31: 2-(2,4-difluorophenyl)-1-(methyl((2-(4-(trifluoromethoxy)phenyl)thiazolyl-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0244] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.99–7.97(m,2H),7.77(s,1H),7.68(s,1H),7.4 9(d,J=8.3Hz,2H),7.46–7.42(m,1H),7.15(ddd,J=11.9,9.1,2.6Hz,1H),6.99(td,J= 8.4,2.6Hz,1H),5.81(s,1H),4.55(t,J=11.1Hz,2H),3.86(d,J=14.5Hz,1H),3.73(d, J=14.5Hz,1H),3.05(dd,J=13.7,1.9Hz,1H),2.78(d,J=13.8Hz,1H),2.19(s,3H).HRMS calcd for C 23 H 20 F5N5O2S,[M+Na] + ,548.1156; found 548.1187

[0245] Example 32: 1-(((5-(4-chlorophenyl)thiophen-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0246] 1 H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 7.76 (s, 1H), 7.59–7.56 (m, 1H), 7.43 (dt, J = 4. 7,2.7Hz,2H),7.32(d,J=3.6Hz,1H),7.16–7.12(m,1H),6.99–6.96(m,1H),6.85(d,J =3.7Hz,1H),5.76–5.75(m,1H),4.57(d,J=8.3Hz,2H),3.76(d,J=14.4Hz,1H),3.64 (d,J=14.3Hz,1H),3.03(d,J=13.8Hz,1H),2.80(d,J=13.8Hz,1H),2.18(s,1H).HRMS calcd for C 23 H 21 ClF₂N₄OS,[M+Na] + 497.0990; found 497.0987

[0247] Example 33: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0248] 1 H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.80–7.77(m,3H),7.74(d,J=8.2Hz,2H),7.48(d,J=3. 6Hz,1H),7.45(dd,J=9.1,2.2Hz,1H),7.16(ddd,J=11.9,9.1,2.7Hz,1H),6.99(td,J=8.5,2 .6Hz,1H),6.91(d,J=3.6Hz,1H),5.79(s,1H),4.60(t,J=11.6Hz,2H),3.80(d,J=14.4Hz,1H ),3.68(d,J=14.4Hz,1H),3.06(d,J=13.7Hz,1H),2.82(d,J=13.8Hz,1H),2.20(s,3H).HRMS calcd for C 24 H 21 F5N4OS,[M+Na] + ,531.1254; found 531.1284

[0249] Example 34: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0250] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.76(s,1H),7.69–7.66(m,2H),7.43(dt,J=9.0,6.8Hz ,1H),7.37(d,J=8.3Hz,2H),7.33(d,J=3.7Hz,1H),7.17–7.12(m,1H),6.98(dt,J=8.6,2.7Hz ,1H),6.86(d,J=3.7Hz,1H),5.76(s,1H),4.57(q,J=14.3Hz,2H),3.77(d,J=14.4Hz,1H),3. 65(d,J=14.3Hz,1H),3.03(dd,J=13.7,1.8Hz,1H),2.80(d,J=13.7Hz,1H),2.18(s,3H).HRMS calcd for C 24 H21 F5N4O2S,[M+Na] + ,547.1203; found 547.1156

[0251] Example 35: 1-(((5-(4-chlorophenyl)furan-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0252] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.73(s,1H),7.63(dd,J=6.6,2.0Hz,2H),7.47(dd,J=6.6 ,2.1Hz,2H),7.43–7.39(m,1H),7.11(ddd,J=11.8,9.1,2.7Hz,1H),6.98–6.94(m,1H),6.89(d ,J=3.3Hz,1H),6.31(d,J=3.3Hz,1H),5.71(s,1H),4.55(d,J=14.2Hz,1H),4.48(d,J=14.3Hz, 1H),3.60–3.54(m,2H),3.00(dd,J=13.8,1.7Hz,1H),2.79(d,J=13.9Hz,1H),2.21(s,3H).HRMS calcd for C 23 H 21 ClF₂N₄O₂,[M+Na] + ,481.1219; found 481.1231

[0253] Example 36: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0254] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.80–7.77(m,3H),7.74(d,J=8.2Hz,2H),7.48(d,J=3. 6Hz,1H),7.45(dd,J=9.1,2.2Hz,1H),7.16(ddd,J=11.9,9.1,2.7Hz,1H),6.99(td,J=8.5,2 .6Hz,1H),6.91(d,J=3.6Hz,1H),5.79(s,1H),4.60(t,J=11.6Hz,2H),3.80(d,J=14.4Hz,1H ),3.68(d,J=14.4Hz,1H),3.06(d,J=13.7Hz,1H),2.82(d,J=13.8Hz,1H),2.20(s,3H).HRMS calcd for C 24 H 21 F5N4O2,[M+Na] + ,515.1482; found 515.1508

[0255] Example 37: 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethoxy)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0256] 1 H NMR (600MHz, DMSO-d6) δ8.29 (s, 1H), 7.73 (dd, J = 6.8, 2.1Hz, 1H), 7.41 (s, 1 H),7.10(dt,J=11.9,4.5Hz,1H),6.97–6.94(m,1H),6.91(d,J=3.3Hz,1H),6 .32(d,J=3.3Hz,1H),5.71(s,1H),4.50(t,J=19.5Hz,2H),3.58(d,J=9.7Hz, 2H),3.01(dd,J=13.8,1.7Hz,1H),2.79(d,J=13.8Hz,1H),2.21(s,1H).HRMS calcd for C 24 H 21 F5N4O3,[M+Na] + ,531.1432; found 531.1493

[0257] Example 38: 1-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0258] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.75–7.70(m,3H),7.51(d,J=8.3Hz,2H),7.47(dd,J=11 .4,1.9Hz,1H),7.43–7.39(m,2H),7.23(t,J=7.9Hz,1H),7.14(ddd,J=11.8,9.1,2.6Hz,1H), 6.95(td,J=8.4,2.6Hz,1H),5.74(s,1H),4.53(dd,J=34.1,14.3Hz,2H),3.65(d,J=13.6Hz,1 H),3.55(d,J=13.6Hz,1H),3.05(d,J=13.4Hz,1H),2.82(d,J=13.7Hz,1H),2.13(s,3H).HRMS calcd for C 25 H 22 ClF3N4O,[M+Na] + ,509.1332; found 509.1367

[0259] Example 39: 1-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0260] 1 H NMR(600MHz, DMSO-d6)δ8.32(s,1H),7.77(t,J=14.8Hz,1H),7.73–7.71(m,2H),7.52–7.49(m,2H) ,7.46(dd,J=11.4,1.9Hz,1H),7.44–7.40(m,2H),7.23(t,J=7.9Hz,1H),7.13(ddd,J=11.8,9.0,2 .6Hz,1H),6.95(td,J=8.4,2.6Hz,1H),5.75(s,1H),4.55(dd,J=31.5,14.3Hz,2H),3.65(d,J=13. 6Hz,1H),3.55(d,J=13.6Hz,1H),3.05(d,J=11.8Hz,1H),2.83(d,J=13.7Hz,1H),2.13(s,3H).HRMS calcd for C 25 H 22 ClF3N4O,[M+Na] +,509.1332; found 509.1362

[0261] Example 40: 1-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0262] 1 H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.69(s,1H),7.50–7.43(m,2H),7.40–7.2 9(m,4H),7.11(d,J=8.1Hz,2H),7.08(d,J=10.5Hz,1H),6.91(t,J=8.6Hz,1H), 5.71(s,1H),4.49(dd,J=28.3,14.3Hz,2H),3.55(d,J=13.4Hz,1H),3.38(d,J= 13.4Hz,1H),2.99(d,J=13.7Hz,1H),2.72(d,J=13.7Hz,1H),2.03(s,3H).HRMS calcd for C 25 H 22 ClF3N4O,[M+Na] + ,509.1332; found 509.1367

[0263] Example 41: 1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0264] 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.77(s,1H),7.73(dd,J=11.0,2.1Hz,1H),7.63(t,J=8. 2Hz,1H),7.60(d,J=7.8Hz,2H),7.54(dd,J=8.4,2.0Hz,1H),7.47(dd,J=16.4,8.3Hz,1H),7. 20–7.14(m,3H),7.01–6.96(m,1H),5.79(s,1H),4.56(q,J=14.3Hz,2H),3.62(d,J=13.3Hz,1 H),3.45(d,J=13.4Hz,1H),3.07(d,J=13.7Hz,1H),2.79(d,J=13.7Hz,1H),2.10(s,3H).HRMS calcd for C 25 H 22 ClF3N4O,[M+Na] + 509.1332; found 509.1384

[0265] Example 42: 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0266] 1 H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.75(s,1H),7.68(dd,J=6.5,2.1Hz,2H),7 .60(d,J=8.1Hz,2H),7.52–7.49(m,2H),7.43(dd,J=9.1,2.2Hz,1H),7.35(d,J=7 .9Hz,2H),7.15(ddd,J=11.9,9.1,2.6Hz,1H),6.96(td,J=8.4,2.7Hz,1H),5.86 (s,1H),4.62(d,J=15.0Hz,2H),3.72(s,2H),2.97(dd,J=34.5,12.4Hz,2H).HRMS calcd for C 24 H 21 ClF₂N₄O,[M+Na] + 477.1270; found 477.1307

[0267] Example 43: 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(cyclopropyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0268] 1 H NMR (600MHz, DMSO-d6) δ8.26(s,1H),7.71(s,1H),7.61(d,J=8.4Hz,1H),7.47(d,J=7.9Hz,1H),7.43(d,J=8 .4Hz,1H),7.41–7.37(m,2H),7.13(t,J=6.1Hz,1H),7.09(d,J=8.0Hz,2H),6.92(td,J=8.5,2.6Hz,1H),5.56 (s,1H),4.48(s,1H),3.70(d,J=13.7Hz,1H),3.61(d,J=13.7Hz,1H),3.18(dd,J=13.9,1.7Hz,1H),2.92(d, J=14.0Hz,1H),1.76(dt,J=10.3,3.4Hz,1H),0.17(dt,J=6.3,3.1Hz,1H),-0.00(dd,J=6.5,3.4Hz,2H).HRMS calcd for C 27 H 25 ClF₂N₄O,[M+Na] + ,517.1583; found 517.1651

[0269] Example 44: 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0270] 1H NMR (600MHz, DMSO-d6) δ8.30(s,1H),7.75(s,1H),7.67(d,J=8.1Hz,2H),7.54(d,J=7.8 Hz,2H),7.50(d,J=8.1Hz,2H),7.44(dd,J=16.4,8.4Hz,1H),7.15(dd,J=16.1,5.4Hz,3H ),6.97(td,J=8.5,2.6Hz,1H),5.76(s,1H),4.54(dd,J=29.7,14.2Hz,2H),3.60(d,J=1 3.3Hz,1H),3.44(d,J=13.4Hz,1H),3.04(d,J=13.7Hz,1H),2.77(d,J=13.7Hz,1H).HRMS calcd for C 25 H 20 D3ClF2N4O,[M+Na] + 494.1614; found 494.1650

[0271] Example 45: 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-tetrazol-1-yl)prop-2-ol

[0272] 1 H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.88(d,J=8.1Hz,2H),7.80(d,J=8.2Hz,2H),7.63 (d,J=8.0Hz,2H),7.34(dd,J=15.8,8.8Hz,1H),7.25(d,J=8.0Hz,2H),7.23–7.19(m,1H) ,6.97(td,J=8.5,2.1Hz,1H),6.00(s,1H),4.84(d,J=14.9Hz,2H),3.64(d,J=13.4Hz,1 H), 3.52 (d, J = 13.4Hz, 1H), 3.05 (d, J = 13.9Hz, 1H), 2.87 (d, J = 13.8Hz, 1H), 2.15 (s, 3H).

[0273] Example 46: 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-tetrazol-1-yl)prop-2-ol

[0274] 1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.77(d,J=8.6Hz,2H),7.57(d,J=7.9Hz,2H),7.43 (d,J=8.2Hz,2H),7.35(dd,J=15.9,8.6Hz,1H),7.23(d,J=7.8Hz,2H),7.20(d,J=9.6Hz, 1H),6.97(dd,J=11.6,5.0Hz,1H),6.00(s,1H),4.89–4.83(m,2H),3.63(d,J=13.4Hz,1 H), 3.51 (d, J = 13.3Hz, 1H), 3.05 (d, J = 13.8Hz, 1H), 2.88 (d, J = 13.8Hz, 1H), 2.15 (s, 3H).

[0275] Example 47: 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0276] 1 H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.68(d,J=8.5Hz,2H),7.56(d,J=8.1Hz, 2H),7.50(d,J=8.5Hz,2H),7.36–7.32(m,1H),7.23–7.19(m,3H),6.96(td,J=8 .5,2.4Hz,1H),5.99(s,1H),4.83(d,J=12.8Hz,2H),3.63–3.60(m,1H),3.50( d,J=13.4Hz,1H),3.04(d,J=14.0Hz,1H),2.87(d,J=13.8Hz,1H),2.14(s,3H).

[0277] Example 48: 1-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0278] 1H NMR (600MHz, DMSO-d6) δ9.12 (s, 1H), 8.40 (d, J = 1.4Hz, 1H), 8.10 (d, J = 8.5Hz, 2H), 7.89 (d, J = 8. 1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.54(d,J=8.2Hz,2H),7.34(dd,J=15.9,8.8Hz,1H),7.20( dd,J=15.2,5.6Hz,1H),6.97(td,J=8.5,2.4Hz,1H),6.02(s,1H),4.87–4.82(m,2H),3.67(d,J=1 3.6Hz, 1H), 3.52 (d, J = 13.6Hz, 1H), 3.06 (d, J = 14.1Hz, 1H), 2.86 (d, J = 13.8Hz, 1H), 2.15 (s, 3H).

[0279] Example 49: 1-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0280] 1 H NMR(600MHz,DMSO-d6)δ9.16(s,1H),8.81(d,J=1.1Hz,1H),8.01(dd,J=8.0,1.7Hz,1H),7.77( d,J=8.3Hz,2H),7.56(d,J=8.3Hz,2H),7.37(dd,J=15.9,8.7Hz,1H),7.27(d,J=8.1Hz,1H),7. 21(t,J=9.6Hz,1H),6.96(t,J=7.4Hz,1H),6.49(s,1H),4.85(q,J=14.3Hz,2H),3.80(d,J=14. 4Hz,1H),3.71(d,J=14.4Hz,1H),3.12(d,J=14.0Hz,1H),2.97(d,J=13.9Hz,1H),2.21(s,3H).

[0281] The preparation route of Example 50 is shown below:

[0282] The specific synthesis steps are as follows:

[0283] Synthesis of 4'-chloro-[1,1'-biphenyl]-4-carboxaldehyde (10)

[0284] Intermediate 9 (10.00 g, 0.054 mol), (4-chlorophenyl)boric acid (12.64 g, 0.081 mol), potassium carbonate (22.39 g, 0.162 mol), and tetrakis(triphenylphosphine)palladium (5.78 g, 0.005 mol) were added to 6 mL of 1,4-dioxane / water solution at room temperature. The reaction was carried out at 90 °C for 6 h under argon protection. TLC monitoring (DCM:MeOH = 30:1) showed that the reaction proceeded completely. The mixture was extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to give a white solid in 62% yield.

[0285] Synthesis of 1-(4'-chloro-[1,1'-biphenyl]-4-yl)-N-methylmethylamine (11)

[0286] Intermediate 10 (7.23 g, 0.033 mol) and methylamine hydrochloride (4.46 g, 0.066 mol) were added to a methanol solution and reacted at room temperature for 30 min. Then, sodium borohydride (2.51 g, 0.066 mol) was added as a reducing agent, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 15:1) indicated complete reaction of the starting material. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a white powdery solid in 88% yield.

[0287] Preparation of (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol (Example 50):

[0288] Intermediate 11, intermediate 12, lithium perchlorate, and magnesium tert-butoxide were sequentially added to 2 ml of isopropanol solution, and stirred at 120 °C for 5 h. TLC monitoring (DCM:MeOH = 30:1) confirmed the reaction was complete. The mixture was extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and separated using a thin-layer chromatography (DCM:MeOH = 30:1) to give a white solid in 50% yield. 1H NMR(600MHz,MeOD-d)δ8.22(s,1H),7.69(s,1H),7.60(dd,J=12.0,7.9Hz,4H),7.47(d ,J=7.8Hz,2H),7.42(d,J=8.1Hz,2H),7.39–7.35(m,1H),6.84–6.79(m,1H),6.79–6.75 (m,1H),4.99(d,J=14.5Hz,1H),4.78(d,J=14.6Hz,1H),3.90(d,J=12.9Hz,1H),3.54(d ,J=13.2Hz,1H),3.36(dd,J=13.7,6.8Hz,1H),2.40(s,3H),0.91(d,J=6.9Hz,3H).HRMS calcd for C 26 H 25 ClF₂N₄O,[M+H] + 483.1763; found 483.1780

[0289] Example 51: (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0290] 1 H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.92(d,J=8.2Hz,2H),7.82(d,J=8.2Hz,2H),7.75(d,J=8.3Hz ,2H),7.64(s,1H),7.56(d,J=8.2Hz,2H),7.28(td,J=9.0,6.7Hz,1H),7.07(ddd,J=12.0,9.1,2.7H z,1H),6.89(td,J=8.4,2.6Hz,1H),5.56(s,1H),4.96(d,J=14.6Hz,1H),4.71(d,J=14.6Hz,1H),3. 92(d,J=13.5Hz,1H),3.58(d,J=13.3Hz,1H),3.40–3.33(m,1H),2.36(s,3H),0.80(d,J=6.9Hz,3H).

[0291] Example 52: (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0292] 1 H NMR (600MHz, DMSO-d6) δ8.29 (s, 1H), 7.83–7.79 (m, 2H), 7.69 (dd, J = 6.5, 1.7Hz, 2H), 7.64 (s, 1H), 7. 52(d,J=7.9Hz,2H),7.46(d,J=8.3Hz,2H),7.27(dd,J=15.9,9.0Hz,1H),7.07(ddd,J=11.9,9.0,2.6H z,1H),6.89(td,J=8.3,2.5Hz,1H),5.55(s,1H),4.95(d,J=14.5Hz,1H),4.70(d,J=14.6Hz,1H),3.90 (d,J=13.4Hz,1H),3.56(d,J=13.4Hz,1H),3.32(d,J=8.5Hz,1H),2.36(s,3H),0.79(d,J=6.9Hz,3H).

[0293] Example 53: (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0294] 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.65(s,1H),7.59(d,J=8.1Hz,2H),7.54(d,J=8.2Hz,2H),7 .52(d,J=7.8Hz,1H),7.37(dd,J=13.4,10.0Hz,2H),7.29(dd,J=16.4,8.3Hz,1H),7.12–7.05(m,1 H),6.92–6.86(m,1H),5.57(s,1H),4.94(d,J=14.2Hz,1H),4.76(d,J=14.6Hz,1H),3.92(d,J=13 .5Hz,1H),3.58(d,J=13.7Hz,1H),3.31(d,J=6.5Hz,1H),2.34(s,3H),0.80(d,J=6.9Hz,3H).HRMS calcd for C 26 H 24 ClF3N4O,[M+Na] + ,523.1488; found 523.1505

[0295] Example 54: (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0296] 1 H NMR (600MHz, DMSO-d6) δ8.33(s,1H),7.77(d,J=8.5Hz,2H),7.65(t,J=7.7Hz,2H),7.63(t,J=7.7Hz, 1H),7.56(t,J=7.6Hz,2H),7.53(d,J=8.5Hz,1H),7.26(dd,J=16.1,8.6Hz,1H),7.10–7.06(m,1H),6 .89(dd,J=11.5,5.3Hz,1H),5.54(s,1H),4.89(d,J=14.5Hz,1H),4.63(t,J=11.7Hz,1H),3.89(d,J= 12.8Hz,1H),3.65(d,J=13.4Hz,1H),3.35(d,J=9.1Hz,1H),2.38(s,3H),0.80(d,J=6.8Hz,3H).HRMS calcd for C 26 H 24 ClF3N4O,[M+Na] + ,523.1488; found 523.1538

[0297] Example 55: (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0298] 1H NMR (600MHz, DMSO-d6) δ8.91(d,J=1.6Hz,1H),8.31(s,1H),8.12(dd,J=8.1,2.3Hz,1H),7.80(d,J=8.5Hz, 2H),7.65(d,J=8.0Hz,2H),7.57(d,J=8.5Hz,2H),7.31(dd,J=16.0,8.9Hz,1H),7.10(ddd,J=11.4,9.1,2. 1Hz,1H),6.90(td,J=8.5,2.3Hz,1H),6.07(s,1H),4.94(d,J=14.5Hz,1H),4.72(d,J=14.6Hz,1H),4.09(d ,J=13.1Hz,1H),3.60(d,J=14.0Hz,1H),3.35(dd,J=11.7,4.7Hz,1H),2.39(s,3H),0.82(d,J=6.8Hz,3H).

[0299] Example 56: (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0300] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.73–7.64(m,5H),7.51(d,J=7.8Hz,4H), 7.29(dd,J=16.6,8.3Hz,1H),7.07(t,J=10.5Hz,1H),6.89(t,J=8.5Hz,1H),5. 56(s,1H),4.96(d,J=14.5Hz,1H),4.71(d,J=14.7Hz,1H),3.88(d,J=13.3Hz,1 H),3.56(d,J=13.4Hz,1H),3.33(d,J=12.8Hz,1H),0.79(d,J=6.8Hz,3H).HRMS calcd for C 26 H 22 D3ClF2N4O,[M+Na] + 508.1771; found 508.1794

[0301] Example 57: (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0302] 1 H NMR(600MHz,DMSO-d6)δ8.27(s,1H),7.78–7.76(m,2H),7.64–7.61(m,2H),7.58–7.57(m,1H), 7.56(s,1H),7.54–7.52(m,2H),7.26(dt,J=8.9,6.7Hz,1H),7.08(ddd,J=11.9,9.1,2.6Hz,1H ),6.88(td,J=8.5,2.7Hz,1H),5.54(s,1H),4.89(d,J=14.5Hz,1H),4.60(d,J=14.6Hz,1H),3. 88(d,J=13.4Hz,1H),3.65(d,J=13.4Hz,1H),3.34(d,J=7.2Hz,1H),0.79(d,J=6.8Hz,3H).HRMS calcd for C 26 H 21 D3ClF3N4O,[M+Na] + ,526.1677; found 526.1718

[0303] Example 58: (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0304] 1 H NMR (600MHz, DMSO-d6) δ8.30(s,1H),7.66(s,1H),7.60(d,J=7.0Hz,2H),7.55(d,J=8.6Hz,2H),7.5 3(d,J=8.1Hz,1H),7.38(dd,J=13.1,9.6Hz,2H),7.30(dt,J=9.1,6.7Hz,1H),7.09(ddd,J=11.8,9.1 ,2.6Hz,1H),6.90(td,J=8.4,2.6Hz,1H),5.58(s,1H),4.96(d,J=14.5Hz,1H),4.77(d,J=14.6Hz,1H ),3.92(d,J=13.7Hz,1H),3.59(d,J=13.7Hz,1H),3.32(q,J=6.9Hz,1H),0.81(d,J=6.9Hz,3H).HRMS calcd for C 26 H 21 D3ClF3N4O,[M+Na] +,526.1677; found 526.1707

[0305] Example 59: (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0306] 1 H NMR (600MHz, DMSO-d6) δ8.92 (s, 1H), 8.34 (s, 1H), 8.13 (d, J = 5.5Hz, 1H), 7.81 (d ,J=6.4Hz,2H),7.67(s,2H),7.57(d,J=6.2Hz,2H),7.34(d,J=6.0Hz,1H),7.10( s,1H),6.91(s,1H),6.11(s,1H),4.97(d,J=14.1Hz,1H),4.74(d,J=13.9Hz,1H) ,4.10(d,J=10.7Hz,1H),3.61(d,J=11.8Hz,1H),3.37(s,1H),0.84(s,3H).HRMS calcd for C 25 H 21 D3ClF2N5O,[M+Na] + ,509.1723; found 509.1794

[0307] Example 60: (2R,3R)-3-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0308] 1H NMR (600MHz, DMSO-d6) δ8.69(d,J=1.2Hz,1H),8.29(s,1H),8.14(d,J=8.6Hz,2H),8.00(d,J=8.1Hz,1 H),7.95(dd,J=8.1,1.8Hz,1H),7.64(s,1H),7.56(d,J=8.5Hz,2H),7.27(dd,J=16.0,8.9Hz,1H),7.0 9–7.05(m,1H),6.89(td,J=8.5,2.4Hz,1H),5.57(s,1H),4.94(d,J=14.5Hz,1H),4.68(d,J=13.0Hz,1 H),3.91(d,J=13.2Hz,1H),3.60(d,J=13.5Hz,1H),3.31(d,J=7.0Hz,1H),0.80(d,J=6.9Hz,3H).HRMS calcd for C 25 H 21 D3ClF2N5O,[M+Na] + ,509.1723; found 509.1794

[0309] Example 61: (2R,3R)-3-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0310] 1 H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.65(s,1H),7.59(t,J=8.5Hz,1H),7.56–7.53(m,5H), 7.40(dd,J=8.3,2.1Hz,1H),7.29(td,J=9.1,6.8Hz,1H),7.08(ddd,J=11.9,9.1,2.6Hz,1H) ,6.89(td,J=8.4,2.7Hz,1H),5.56(s,1H),4.96(d,J=14.5Hz,1H),4.73(d,J=14.6Hz,1H),3 .91(d,J=13.4Hz,1H),3.58(d,J=13.4Hz,1H),3.34–3.31(m,1H),0.80(d,J=6.9Hz,3H).HRMS calcd for C 26 H 21 D3ClF3N4O,[M+Na] + ,526.1677; found 526.1699

[0311] Example 62: (2R,3R)-3-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0312] 1 H NMR(600MHz, DMSO-d6)δ8.30(s,1H),7.77(dd,J=10.9,2.2Hz,1H),7.73(d,J=8.0Hz,2H),7.68–7.64(m ,2H),7.59(dd,J=8.4,2.1Hz,1H),7.53(d,J=7.9Hz,2H),7.29(td,J=9.0,6.7Hz,1H),7.07(ddd,J=11. 8,9.0,2.6Hz,1H),6.89(td,J=8.4,2.6Hz,1H),5.56(s,1H),4.96(d,J=14.5Hz,1H),4.72(d,J=14.6Hz ,1H),3.89(d,J=13.4Hz,1H),3.57(d,J=13.4Hz,1H),3.32(t,J=6.9Hz,1H),0.80(d,J=6.9Hz,3H).HRMS calcd for C 26 H 21 D3ClF3N4O,[M+Na] + ,526.1677; found 526.1703

[0313] Example 63: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0314] 1H NMR (600MHz, DMSO-d6) δ8.33(s,1H),7.92(d,J=8.0Hz,2H),7.82(d,J=8.1Hz,2H),7.75(d,J=7.8Hz, 2H),7.68(t,J=4.7Hz,1H),7.57(d,J=7.9Hz,2H),7.32(dd,J=16.4,8.3Hz,1H),7.07(ddd,J=11.9,9. 0,2.7Hz,1H),6.90(td,J=8.5,2.6Hz,1H),5.59(s,1H),4.99(d,J=14.6Hz,1H),4.75(d,J=14.6Hz,1 H),3.92(d,J=13.6Hz,1H),3.59(d,J=13.3Hz,1H),3.35(q,J=6.9Hz,1H),0.81(d,J=6.9Hz,3H).HRMS calcd for C 27 H 22 D3F5N4O,[M+H] + ,520.2215; found 520.2251

[0315] Example 64: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0316] 1 H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.81(d,J=8.2Hz,2H),7.69(d,J=7.9Hz,2H),7.67(s,1H) ,7.53(d,J=8.0Hz,2H),7.45(d,J=8.3Hz,2H),7.31(dd,J=16.5,8.4Hz,1H),7.09–7.05(m,1H) ,6.90(td,J=8.5,2.6Hz,1H),5.58(s,1H),4.98(d,J=14.5Hz,1H),4.74(d,J=14.6Hz,1H),3.9 0(d,J=13.4Hz,1H),3.57(d,J=13.3Hz,1H),3.35(q,J=6.8Hz,1H),0.81(d,J=6.8Hz,3H).HRMS calcd for C 27 H 22 D3F5N4O2,[M+Na] + ,558.1984; found 558.2022

[0317] Example 65: (2R,3R)-3-(((4'-chloro-2'-,3-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0318] 1 H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.68(d,J=9.7Hz,2H),7.64(t,J=8.5Hz,1H),7.55(d,J= 10.5Hz,1H),7.42(dd,J=17.8,7.4Hz,3H),7.32(dd,J=16.1,8.5Hz,1H),7.08(t,J=9.6Hz,1H) ,6.90(td,J=8.4,2.6Hz,1H),5.59(s,1H),4.94(d,J=14.6Hz,1H),4.69(d,J=14.5Hz,1H),3.9 3(d,J=12.1Hz,1H),3.68(d,J=13.4Hz,1H),3.38(q,J=6.7Hz,1H),0.83(d,J=6.8Hz,3H).HRMS calcd for C 26 H 20 D3ClF4N4O,[M+Na] + ,544.1583; found 544.1640

[0319] Example 66: (2R,3R)-3-(((4'-chloro-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0320] 1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.83(dd,J=10.9,2.1Hz,1H),7.69–7.65(m,2H),7.65–7 .63(m,2H),7.63–7.60(m,2H),7.32(dd,J=9.2,2.7Hz,1H),7.08(ddd,J=11.8,9.0,2.7Hz,1H) ,6.90(td,J=8.4,2.6Hz,1H),5.59(s,1H),4.94(d,J=14.5Hz,1H),4.67(d,J=14.6Hz,1H),3.9 1(d,J=13.5Hz,1H),3.67(d,J=13.5Hz,1H),3.37(q,J=6.9Hz,1H),0.83(d,J=6.7Hz,3H).HRMS calcd for C 26 H 20 D3ClF4N4O,[M+Na] + ,544.1583; found 544.1661

[0321] Example 67: (2R,3R)-2-(2,4-difluorophenyl)-3-((3-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0322] 1 H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.97(d,J=7.9Hz,2H),7.83(d,J=8.0Hz,2H),7.69 (t,J=7.8Hz,1H),7.67–7.62(m,3H),7.30(dd,J=16.3,8.4Hz,1H),7.11–7.06(m,1H),6. 92–6.88(m,1H),5.58(s,1H),4.93(d,J=14.5Hz,1H),4.65(d,J=14.6Hz,1H),3.92(d,J =13.5Hz,1H),3.68(d,J=13.5Hz,1H),3.38(d,J=8.2Hz,1H),0.82(d,J=7.0Hz,3H).HRMS calcd for C 27 H 21 D3F6N4O,[M+Na] + ,560.1941; found 560.1978

[0323] Example 68: (2R,3R)-1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0324] 1 H NMR(600MHz,DMSO-d6)δ8.27(s,1H),7.86(d,J=8.7Hz,2H),7.66–7.62(m,2H),7.60–7.56(m ,2H),7.47(d,J=8.2Hz,1H),7.26(dd,J=15.9,8.9Hz,1H),7.11–7.06(m,1H),6.88(td,J=8.5 ,2.6Hz,1H),5.54(s,1H),4.89(d,J=14.6Hz,1H),4.60(d,J=14.6Hz,1H),3.88(d,J=13.5Hz ,1H),3.65(d,J=13.4Hz,1H),3.36(t,J=4.6Hz,1H),3.33(s,1H),0.80(d,J=6.8Hz,3H).HRMS calcd for C 27 H 21 D3F6N4O2,[M+Na] + ,576.1890; found 576.1935

[0325] Example 69: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0326] 1 H NMR (600MHz, DMSO-d6) δ8.74(s,1H),8.33(s,3H),8.01(d,J=44.7Hz,2H),7.82(s,2H),7.68(s,1H),7.33(s,1H),7.10–6.98(m,1H),6.88(s,1 H),5.62(s,1H),4.98(d,J=11.1Hz,1H),4.75(d,J=14.7Hz,1H),3.93(d,J=13.3Hz,1H),3.59(d,J=13.8Hz,1H),3.33(s,1H),0.81(s,3H).HRMS calcd for C 26 H 21 D3F5N5O,[M+Na] +,543.1987; found 543.2060

[0327] Example 70: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0328] 1 H NMR(600MHz,DMSO-d6)δ8.91(d,J=2.4Hz,1H),8.29(s,1H),8.14(dd,J=8.1,2.4Hz,1H),7.91–7.88(m,2H ),7.67(d,J=8.1Hz,1H),7.64(s,1H),7.51(d,J=8.3Hz,2H),7.30(td,J=9.0,6.8Hz,1H),7.10(ddd,J=11. 9,9.1,2.6Hz,1H),6.89(td,J=8.5,2.6Hz,1H),6.66(s,1H),4.94(d,J=14.5Hz,1H),4.71(d,J=14.5Hz,1H ),4.08(d,J=14.4Hz,1H),3.61(d,J=14.1Hz,3H),3.36(dd,J=9.2,5.5Hz,7H),0.82(d,J=6.9Hz,2H).HRMS calcd for C 26 H 21 D3F5N5O2,[M+Na] + ,559.1936; found 559.2020

[0329] Example 71: (2R,3R)-3-(((6-(4-chloro-2-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0330] 1H NMR (600MHz, DMSO-d6) δ8.76(d,J=1.5Hz,1H),8.33(s,1H),8.05(t,J=8.6Hz,1H),8.00(dd,J=8.1,1.9Hz,1H),7.8 3(dd,J=8.1,2.1Hz,1H),7.68(s,1H),7.57(dd,J=11.1,1.9Hz,1H),7.44(dd,J=8.4,1.9Hz,1H),7.32(dd,J=15.9, 8.9Hz,1H),7.09(ddd,J=11.7,9.2,2.4Hz,1H),6.91(td,J=8.5,2.4Hz,1H),5.62(s,1H),4.99(d,J=14.5Hz,1H),4 .76(d,J=14.6Hz,1H),3.96(d,J=12.5Hz,1H),3.66–3.60(m,1H),3.35(q,J=6.9Hz,1H),0.83(d,J=6.9Hz,3H).HRMS calcd for C 25 H 20 D3ClF3N5O,[M+Na] + ,527.1629; found 527.1649

[0331] Example 72: (2R,3R)-3-(((6-(4-chloro-3-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0332] 1 H NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.30(s,1H),8.14(d,J=10.1Hz,1H),8.07(d,J=8.1Hz,1H),8.02(d ,J=8.3Hz,1H),7.98(d,J=7.7Hz,1H),7.71(t,J=8.1Hz,1H),7.65(s,1H),7.29(dd,J=15.9,8.6Hz,1H),7 .08(t,J=9.6Hz,1H),6.90(t,J=7.4Hz,1H),5.59(s,1H),4.95(d,J=14.5Hz,1H),4.70(d,J=14.5Hz,1H), 3.93(d,J=12.6Hz,1H),3.61(d,J=13.4Hz,1H),3.32(dd,J=13.9,6.9Hz,1H),0.81(d,J=6.7Hz,3H).HRMS calcd for C25 H 20 D3ClF3N5O,[M+Na] + ,527.1629; found 527.1642

[0333] Example 73: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0334] 1 H NMR (600MHz, DMSO-d6) δ8.74(s,1H),8.33(s,3H),8.01(d,J=44.7Hz,2H),7.82(s,2H),7.68(s,1H),7.33(s,1H),7.10–6.98(m,1H),6.88(s,1 H),5.62(s,1H),4.98(d,J=11.1Hz,1H),4.75(d,J=14.7Hz,1H),3.93(d,J=13.3Hz,1H),3.59(d,J=13.8Hz,1H),3.33(s,1H),0.81(s,3H).HRMS calcd for C 26 H 21 D3F5N5O,[M+Na] + ,543.1987; found 543.2008

[0335] Example 74: (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0336] 1H NMR (600MHz, DMSO-d6) δ8.71 (s, 1H), 8.31 (s, 1H), 8.24 (d, J = 7.4Hz, 2H), 8.02–7. 92(m,2H),7.67(s,1H),7.46(d,J=6.9Hz,2H),7.31(d,J=6.5Hz,1H),7.05(s,1H) ,6.88(s,1H),5.60(s,1H),4.97(d,J=14.3Hz,1H),4.73(d,J=14.0Hz,1H),3.91( s,1H),3.59(d,J=12.4Hz,1H),3.33(d,J=5.7Hz,1H),0.81(d,J=4.6Hz,3H).HRMS calcd for C 26 H 21 D3F5N5O2,[M+Na] + ,559.1936; found 559.1957

[0337] The preparation route of Example 75 is shown below:

[0338] The specific synthesis steps are as follows:

[0339] Synthesis of ethyl 4'-(benzyloxy)-[1,1'-biphenyl]-4-carboxylate (15)

[0340] Ethyl 4-bromobenzoate (10.00 g, 0.044 mol), (4'-(benzyloxy)-[1,1'-biphenyl]-4-yl)boronic acid (26.76 g, 0.088 mol), sodium carbonate (13.99 g, 0.132 mol), and tetrakis(triphenylphosphine)palladium (5.78 g, 0.005 mol) were added to 6 mL of 1,4-dioxane / water solution at room temperature. The reaction was carried out at 80 °C for 8 h under argon protection. TLC monitoring (DCM:MeOH = 30:1) showed that the reaction proceeds were complete. The mixture was extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to give a white solid in 70% yield.

[0341] Synthesis of 4'-(benzyloxy)-[1,1'-biphenyl]-4-carboxylic acid (16)

[0342] Intermediate 15 (10.23 g, 0.031 mol) was dissolved in methanol, and 4 N NaOH solution was added at room temperature. The mixture was then heated to 50 °C and reacted for 2 h. TLC monitoring (DCM:MeOH = 15:1) showed that the starting material reacted completely. The pH of the mixed solution was adjusted to acidic by adding 1 N HCl, and the mixture was filtered to obtain a white solid with a yield of 85%.

[0343] Synthesis of 2-(2,4-difluorophenyl)-1-(methylamino)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol (17)

[0344] 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole (10.00 g, 0.042 mol), methylamine hydrochloride (4.46 g, 0.066 mol), and triethylamine (6.68 g, 0.066 mol) were added to a methanol solution and reacted at room temperature for 30 min. Then, sodium borohydride (2.51 g, 0.066 mol) was added as a reducing agent, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 15:1) showed that the reaction was complete. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a white powdery solid in 68% yield.

[0345] Synthesis of 4-(benzyloxy)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylbenzamide (Example 75)

[0346] Intermediate 16 was dissolved in N,N-dimethylformamide, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 4-dimethylaminopyridine were added sequentially. The mixture was stirred at room temperature for 30 min, and then intermediate 17 was added, and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC until it was complete. The mixture was extracted with ethyl acetate, and the organic phases were combined. The solution was concentrated under reduced pressure and separated by column chromatography to give a white solid in 45% yield. 1 H NMR(600MHz,DMSO-d6)δ2.88(s,3H),3.95(s,2H),4.62(s,1H),4.76(s,1H),5.13(s,2 H),6.29(s,1H),7.09(d,J=108.8Hz,6H),7.32–7.49(m,6H),7.75(s,1H),8.34(s,1H).

[0347] Example 76: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-[1,1'-biphenyl]-4-carboxamide

[0348] 1H NMR(600MHz,DMSO-d6)δ2.91(s,3H),4.00(s,2H),4.66(d,J=14.3Hz,1H),4 .81(d,J=14.4Hz,1H),6.27(s,1H),7.00–7.03(m,1H),7.20(t,J=10.7Hz,1H ),7.30(d,J=7.7Hz,2H),7.40(d,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H),7.51 (d,J=7.9Hz,1H),7.63(s,1H),7.68–7.70(m,3H),7.78(s,1H),8.37(s,1H).

[0349] Example 77: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenyl-1,2-oxazol-3-carboxamide

[0350] 1 H NMR (600MHz, Methanol-d4) δ2.98(s,3H),3.97(d,J=14.2Hz,1H),4.25(d,J=15.2Hz,1H),4.43(d,J=15.2Hz,1H),4.71(d,J=14.2Hz,1H),6.68(s,1 H),6.78(ddd,J=2.5,8.8,11.7Hz,1H),6.98(ddd,J=2.5,8.8,11.6Hz,2H ),7.55(d,J=7.4Hz,4H),7.80(s,1H),7.87(d,J=3.0Hz,2H),8.39(s,1H).

[0351] Example 78: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-6-phenylpyridine-3-carboxamide

[0352] 1H NMR (600MHz, DMSO-d6) δ2.97(s,3H),4.02(s,2H),4.68(d,J=14.3Hz,1H),4.82(d,J=14.4Hz,1H),6.23(s,1H),7.03(d,J=7.5Hz,1H),7.18–7.23 (m,1H),7.48(d,J=7.1Hz,1H),7.51(t,J=7.6Hz,3H),7.74–7.80(m,2H) ,8.02(d,J=8.2Hz,1H),8.11(d,J=7.7Hz,2H),8.37(s,1H),8.51(s,1H).

[0353] Example 79: 4-Benzoyl-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylbenzamide

[0354] 1 H NMR (600MHz, DMSO-d6) δ2.90 (s, 3H), 3.99 (d, J = 13.9Hz, 1H), 4.02 (d, J = 14.1Hz, 1H), 4. 67(d,J=14.4Hz,1H),4.81(d,J=14.4Hz,1H),6.23(s,1H),7.02(dt,J=4.3,8.5Hz,1H), 7.20(ddd,J=2.6,9.0,12.0Hz,1H),7.38(d,J=7.7Hz,2H),7.50(q,J=8.3Hz,1H),7.57( t,J=7.6Hz,2H),7.69(q,J=7.6Hz,2H),7.74(s,2H),7.78(d,J=8.3Hz,2H),8.36(s,1H).

[0355] Example 80: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenylthiophene-2-carboxamide

[0356] 1H NMR (600MHz, DMSO-d6) δ3.23 (s, 3H), 3.94 (s, 1H), 4.11 (d, J = 14.2Hz, 1H), 4.5 9(d,J=14.3Hz,1H),4.75(s,1H),6.24(s,1H),6.98(t,J=8.5Hz,1H),7.17(s, 1H),7.35–7.41(m,2H),7.43(d,J=4.2Hz,1H),7.45(s,1H),7.46(d,J=1.8Hz, 1H),7.46–7.49(m,1H),7.69(dd,J=1.4,8.2Hz,2H),7.76(s,1H),8.33(s,1H).

[0357] Example 81: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-phenylfuran-3-carboxamide

[0358] 1 H NMR (600MHz, DMSO-d6) δ3.31(s,3H),3.84(s,1H),4.16(s,1H),4.59(d,J=14.3Hz,1H),4.77(s,1H),6.25(s,1H),6.94–6.97(m, 1H),7.14(d,J=54.1Hz,3H),7.38(t,J=7.4Hz,1H),7.42(d,J=8.3Hz,1H),7.47(t,J=7.7Hz,2H),7.74–7.77(m,3H),8.33(s,1H).

[0359] Example 82: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-4-phenyl-1,3-thiazolyl-2-carboxamide

[0360] 1H NMR(600MHz,DMSO-d6)δ3.02(s,3H),3.86(d,J=14.0Hz,1H),4.25(d,J=14.0Hz ,1H),4.68(d,J=14.5Hz,1H),4.82(d,J=14.5Hz,1H),6.19(s,1H),6.83(ddd,J =2.6,9.0,11.9Hz,1H),6.95(dd,J=2.9,5.6Hz,1H),7.19–7.22(m,1H),7.40–7 .43(m,2H),7.47(d,J=8.0Hz,2H),7.96–7.98(m,2H),8.34(s,1H),8.40(s,1H).

[0361] Example 83: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-2-phenylpyrimidine-5-carboxamide

[0362] 1 H NMR (600MHz, DMSO-d6) δ3.05(s,3H),3.97(s,1H),4.09(d,J=13.9Hz,1H),4.71(d,J=14.3Hz,1H),4.83(d,J=14.5Hz,1H),6.21(s,1H),7.04–7 .07(m,1H),7.19–7.23(m,1H),7.52(dd,J=10.6,14.7Hz,2H),7.57–7.6 3(m,4H),7.78(s,1H),8.37(s,1H),8.42(d,J=2.2Hz,1H),8.83(s,1H).

[0363] Example 84: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide

[0364] 1H NMR (600MHz, DMSO-d6) δ3.24(s,3H),3.96(s,1H),4.10(d,J=14.1Hz,1H),4.60(d,J=14.3Hz,1H),4.76(s,1H),6.23(s,1H),6.99(d ,J=8.8Hz,1H),7.17(s,1H),7.43–7.47(m,2H),7.64(s,1H),7.76(s,1H),7.80(d,J=8.1Hz,2H),7.92(d,J=8.1Hz,2H),8.34(s,1H).

[0365] Example 85: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-(4-methylphenyl)thiophene-2-carboxamide

[0366] 1 H NMR (600MHz, DMSO-d6) δ2.33(s,3H),3.22(s,3H),3.93(s,1H),4.11(d,J=14.1Hz,1H),4.59(d,J=14.3Hz,1H),4.75(s,1H),6.24(s ,1H),6.98(t,J=8.8Hz,1H),7.17(s,1H),7.25(d,J=7.8Hz,2H),7.38–7.47(m,3H),7.58(d,J=7.7Hz,2H),7.76(s,1H),8.34(s,1H).

[0367] Example 86: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(4-fluorophenyl)-N-methylthiophene-2-carboxamide

[0368] 1 H NMR (600MHz, DMSO-d6) δ3.23(s,3H),3.94(s,1H),4.10(d,J=14.1Hz,1H),4.59(d,J=14.3Hz,1H),4.75(s,1H),6.23(s,1H),6.99(d, J=8.1Hz,1H),7.14–7.20(m,1H),7.27–7.30(m,2H),7.37–7.42(m,1H),7.45(td,J=6.7,8.9Hz,2H),7.73–7.76(m,3H),8.33(s,1H).

[0369] Example 87: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(2-fluorophenyl)-N-methylthiophene-2-carboxamide

[0370] 1 H NMR (600MHz, DMSO-d6) δ3.25(s,3H),3.96(s,1H),4.12(d,J=14.0Hz,1H),4.61(d,J=14 .2Hz,1H),4.78(s,1H),6.25(s,1H),6.98(d,J=8.9Hz,1H),7.17(s,1H),7.31(t,J=7.5H z,1H),7.37(dd,J=8.1,11.6Hz,1H),7.43(s,1H),7.47(d,J=7.3Hz,1H),7.54–7.57(m,1 H),7.64(dd,J=7.6,10.8Hz,1H),7.77(s,1H),7.83(dt,J=4.0,7.9Hz,1H),8.35(s,1H).

[0371] Example 88: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(4-ethylphenyl)-N-methylthiophene-2-carboxamide

[0372] 1 H NMR(600MHz,DMSO-d6)δ1.19(t,J=7.6Hz,3H),2.62(t,J=7.6Hz,2H),3.93(s ,1H),4.12(d,J=14.1Hz,1H),4.60(d,J=14.3Hz,1H),4.75(s,1H),6.25(s,1 H),6.96–7.00(m,1H),7.17(t,J=10.2Hz,1H),7.27–7.29(m,2H),7.40(d,J= 16.2Hz,2H),7.44–7.47(m,1H),7.59–7.61(m,2H),7.76(s,1H),8.34(s,1H).

[0373] Example 89: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide

[0374] 1H NMR (600MHz, DMSO-d6) δ3.24(s,3H),3.95(s,1H),4.11(d,J=14.1Hz,1H),4.60(d,J=14.3Hz,1H),4.76(s,1H),6.24(s,1H),6.99 (d,J=8.8Hz,1H),7.15(d,J=19.5Hz,1H),7.45(dd,J=7.1,8.7Hz,4H),7.52(s,1H),7.76(s,1H),7.82–7.84(m,2H),8.34(s,1H).

[0375] Example 90: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-5-(3-fluorophenyl)-N-methylthiophene-2-carboxamide

[0376] 1 H NMR (600MHz, DMSO-d6) δ3.25(s,3H),3.96(s,1H),4.13(d,J=14.1Hz,1H),4.62(d,J=14.3Hz,1H),4.79(s,1H),6.27(s,1H),6.97–7.02(m,1H ),7.18(d,J=9.7Hz,1H),7.19–7.22(m,1H),7.42(s,1H),7.46–7.50(m ,2H),7.52–7.54(m,1H),7.56–7.61(m,2H),7.78(s,1H),8.36(s,1H).

[0377] Example 91: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(propyl-2-yl)phenyl]thiophene-2-carboxamide

[0378] 1H NMR(600MHz,DMSO-d6)δ1.21(s,3H),1.22(s,3H),2.89–2.93(m,1H),3.22(s,3H), 3.93(s,1H),4.12(d,J=14.1Hz,1H),4.59(d,J=14.4Hz,1H),4.75(s,1H),6.25(s, 1H),6.98(t,J=7.3Hz,1H),7.15(d,J=19.2Hz,1H),7.31(d,J=8.4Hz,2H),7.40(d, J=13.7Hz,2H),7.44–7.47(m,1H),7.61(d,J=8.3Hz,2H),7.76(s,1H),8.34(s,1H).

[0379] Example 92: 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide

[0380] 1 H NMR (600MHz, DMSO-d6) δ3.08–3.32(m,3H),3.95(s,1H),4.08(d,J=14.0Hz,1H),4.59(d,J=14.3Hz,1H),4.76(s,1 H),6.21(s,1H),6.98(s,1H),7.17(s,1H),7.40–7.50(m,2H),7.68(s,1H),7.75(s,1H),7.90(s,4H),8.33(s,1H).

[0381] Example 93: 5-(4-chlorophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide

[0382] 1 H NMR (600MHz, DMSO-d6) δ3.23(s,3H),3.94(s,1H),4.09(d,J=14.1Hz,1H),4.59(d,J=14.3Hz,1H),4.75(s,1H),6.23(s,1H) ,6.95–7.00(m,1H),7.13–7.20(m,1H),7.40(s,1H),7.43–7.46(m,1H),7.49–7.52(m,3H),7.71–7.76(m,3H),8.33(s,1H).

[0383] Example 94: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]thiophene-2-carboxamide

[0384] 1 H NMR (600MHz, DMSO-d6) δ3.22(s,3H),3.94(s,1H),4.10(d,J=14.1Hz,1H),4.59(d,J=14.3Hz,1H),4.75(s,1H),4.82(d,J=8.8Hz ,2H),6.24(s,1H),6.97(d,J=7.6Hz,1H),7.13(d,J=8.5Hz,3H),7.37–7.48(m,3H),7.66–7.69(m,2H),7.75(s,1H),8.33(s,1H).

[0385] Example 95: 5-(4-chloro-3-fluorophenyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-methylthiophene-2-carboxamide

[0386] 1 H NMR (600MHz, DMSO-d6) δ2.86 (s, 4H), 3.96 (s, 2H), 4.63 (d, J = 14.4Hz, 1H), 4.78 (d, J = 14.4Hz, 1H), 6.21 (s,1H),6.96–7.04(m,4H),7.18(t,J=10.6Hz,1H),7.46–7.50(m,1H),7.75–7.80(m,3H),8.34(s,1H).

[0387] Example 96: 5-(4-chloro-2-fluorophenyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-methylthiophene-2-carboxamide

[0388] 1H NMR (600MHz, DMSO-d6) δ3.23(s,3H),3.95(s,1H),4.09(d,J=14.0Hz,1H),4.60(d,J=14.2Hz,1H),4.76(s,1H),6.23(s,1H),6.98(d,J=8.7Hz,1H),7 .17(s,1H),7.40(dd,J=2.1,8.4Hz,1H),7.45(td,J=6.7,8.9Hz,1H),7.62 (dd,J=2.1,11.1Hz,1H),7.76(s,1H),7.87(t,J=8.5Hz,1H),8.33(s,1H).

[0389] Example 97: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoline-3-carboxamide

[0390] 1 H NMR (600MHz, DMSO-d6) δ2.97 (s, 3H), 3.99 (d, J = 13.4Hz, 1H), 4.05 (d, J = 13.9 Hz,1H),4.68(d,J=14.4Hz,1H),4.81(d,J=14.4Hz,1H),6.22(s,1H),7.00(t ,J=4.2Hz,1H),7.15–7.20(m,1H),7.48–7.52(m,1H),7.65(s,1H),7.74(s,1 H),7.80(s,1H),8.02(d,J=8.5Hz,2H),8.31(d,J=41.7Hz,2H),8.67(s,1H).

[0391] Example 98: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide

[0392] 1 H NMR (600MHz, DMSO-d6) δ3.25(s,3H),3.99(s,1H),4.10(s,1H),4.61(d,J=14.3Hz,1H),5.57(d,J=8.0Hz,1H),6.22(s,1H), 6.99(s,1H),7.18(s,1H),7.44(tt,J=7.6,12.6Hz,3H),7.74(s,2H),7.85–7.93(m,1H),7.98(d,J=7.4Hz,1H),8.34(s,1H).

[0393] Example 99: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylnaphthalene-2-carboxamide

[0394] 1 H NMR (600MHz, DMSO-d6) δ2.93 (s, 3H), 4.02 (t, J = 11.2Hz, 2H), 4.69 (d, J = 14.3Hz, 1H), 4.83 (d, J = 14.4Hz, 1H), 6.29 (s, 1H), 7.04 (d, J = 8. 9Hz,1H),7.20(d,J=10.6Hz,1H),7.31(d,J=8.3Hz,1H),7.53–7.58(m,3H),7.77(d,J=10.8Hz,2H),7.94(d,J=6.3Hz,3H),8.38(s,1H).

[0395] Example 100: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoline-2-carboxamide

[0396] 1 H NMR (600MHz, DMSO-d6) δ3.00 (s, 3H), 4.47 (d, J = 14.4Hz, 1H), 4.51 (d, J = 14.4 Hz,1H),4.69(d,J=14.4Hz,1H),4.89(d,J=14.4Hz,1H),6.26(s,1H),7.00(d t,J=4.5,8.9Hz,2H),7.45–7.48(m,2H),7.68(t,J=7.5Hz,1H),7.77(s,1H), 7.83(t,J=7.7Hz,1H),8.04–8.07(m,2H),8.38(s,1H),8.49(d,J=8.5Hz,1H).

[0397] Example 101: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylquinoxaline-2-carboxamide

[0398] 1H NMR (600MHz, DMSO-d6) δ2.88 (s, 3H), 4.15 (d, J = 15.3Hz, 1H), 4.33 (d, J = 15.4 Hz,1H),4.43(d,J=14.6Hz,1H),4.48(d,J=14.6Hz,1H),6.23(s,1H),6.78–6. 82(m,1H),7.04(dd,J=2.7,8.5Hz,1H),7.40–7.44(m,1H),7.47(s,1H),7.93– 7.96(m,2H),8.06–8.08(m,1H),8.14(s,1H),8.14–8.17(m,1H),8.69(s,1H).

[0399] Example 102: N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-2H-1,3-benzodioxane-5-carboxamide

[0400] 1 H NMR (600MHz, DMSO-d6) δ2.88 (s, 3H), 3.93 (d, J = 12.7Hz, 2H), 4.68 (d, J = 88.0Hz, 2H), 6.06 (s, 2H), 6.24 (s, 1H), 6.67–6. 79(m,2H),6.91(d,J=7.9Hz,1H),7.00(td,J=2.6,8.5Hz,1H),7.18(s,1H),7.42–7.51(m,1H),7.75(s,1H),8.33(s,1H).

[0401] Pharmacodynamic studies of some products of this invention:

[0402] Experimental methods:

[0403] Refer to the standard 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).

[0404] Experimental materials and methods:

[0405] (1) Experimental strains: The following seven common human pathogenic standard fungal strains were used as screening targets in this experiment. The fungal strains were provided by Shenyang Pharmaceutical University.

[0406] Table 1. Strains used in the experiment and their numbers.

[0407] (2) Experimental methods:

[0408] Preparation of RPMI-1640 medium: Dissolve 10.0g RPMI-1640, 2.0g NaHCO3, and 34.5g triazine propanesulfonic acid (Sigma) in 800mL of sterile distilled water. Adjust the pH to 7.0 with 1 mol / L NaOH, bring the volume to 1000mL, filter through a 0.22μm microporous membrane for sterilization, and store at 4℃ for later use.

[0409] Preparation of spherical fungal suspension: Spherical fungi (Candida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Candida glabrata, Candida krusei). Activated strains were inoculated onto Sabouraud dextrose agar plates using the streak plating method and incubated at 32°C for 2-3 days. A suitable single colony was inoculated into an Erlenmeyer flask containing 10 mL of 0.85% sterile physiological saline, shaken for 15 minutes, and a small amount of bacterial suspension was transferred using a sterile pipette tip onto a hemocytometer for microscopic counting. The suspension was then diluted with RPMI-1640 medium to a final concentration of 1 x 10⁻⁶. 6 per mL.

[0410] Drug solution preparation: Weigh 6.40 mg of each of the compounds obtained in the above examples, and add 1.0 mL of dimethyl sulfoxide (DMSO), 1.0 mL of Tween-20, and 8.0 mL of sterile distilled water sequentially, and mix well. The drug solution concentration is 0.64 mg / mL. Positive control drugs fluconazole, voriconazole, and itraconazole are prepared using the same method.

[0411] Inoculation: Step 1, add RPMI-1640 medium: Add 180 μL of RPMI-1640 medium to well 1 of each row, 100 μL of RPMI-1640 medium to wells 2-11, and 200 μL of RPMI-1640 medium to well 12. Step 2, add drug sample: Add 20 μL of the test drug solution (i.e., the compound obtained in each example) to well 1, mix well with a pipette, and then transfer 100 μL to well 2. Repeat this 2-fold dilution up to well 10, mixing well after each dilution and discarding the 100 μL. Step 3, add bacterial suspension: Add 100 μL of inoculation bacterial suspension to wells 1-11. Well 11 is the growth control, and well 12 is the blank medium control. The positive control drug does not have a blank control. That is, it is serially diluted from the first well to the tenth well, and the test concentration (μg / mL) ranges are 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625.

[0412] Culture and detection: The standard for judging whether the test procedure is qualified is the absence of sterile growth in the blank control and good growth in the positive control. Eight samples are tested per plate, and a positive drug control is set up for each bacterium. The dilution method of the test drug is the same as above.

[0413] Table 2. Minimum inhibitory concentrations (μg / mL) of the compounds in the examples.

[0414] The experimental results above show that the compounds of general formula I and their salts protected by this invention have good antifungal activity. The antifungal activity of many compounds is stronger than that of the positive control drug. Compared with existing antifungal drugs, they have advantages such as novel structure, low toxicity, high efficiency and broad spectrum. Therefore, the compounds of this invention have good application prospects.

[0415] The compounds of general formula I in this invention can be administered alone, but are usually administered in mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. The preparation methods of various pharmaceutical dosage forms of the compounds of this invention, such as tablets, capsules, injections, aerosols, suppositories, films, pellets, topical liniments and ointments, are given below to illustrate their new applications in the pharmaceutical field.

[0416] Example 103: Tablets.

[0417] Example 25: 10g of compound was mixed with 20g of excipients according to the general pharmaceutical tableting method and then compressed into 100 tablets, each weighing 300mg.

[0418] Example 104: Capsules.

[0419] Example 25: 10g of compound was mixed with 20g of excipients according to the requirements of pharmaceutical capsules and then filled into empty capsules, each weighing 300mg.

[0420] Example 105: Injection.

[0421] Example 25: 10g of compound was adsorbed onto activated carbon according to conventional pharmaceutical methods, filtered through a 0.65μm microporous membrane, and then filled into a nitrogen cylinder to prepare an aqueous injection preparation. Each injection contained 2mL, and a total of 100 bottles were filled.

[0422] Example 106: Aerosol.

[0423] Example 25: 10g of compound was dissolved in an appropriate amount of propylene glycol, and then distilled water and other additives were added to prepare a 500mL clear solution.

[0424] Example 107: Suppositories.

[0425] Example 25: 10g of compound was finely ground, and an appropriate amount of glycerin was added. After grinding evenly, melted glycerin gelatin was added, and the mixture was ground evenly. The mixture was then poured into a mold coated with lubricant to prepare 50 suppositories.

[0426] Example 108: Film Formulation.

[0427] 10g of compound 25 was mixed with polyvinyl alcohol, pharmaceutical glycerin, water, etc., stirred until it expanded, heated and dissolved, filtered through an 80-mesh sieve, and then the above-mentioned compound 25 was added to the filtrate and stirred until dissolved. 100 films were made by coating machine.

[0428] Example 109: Droplets.

[0429] In Example 25, 10g of compound was heated and melted with 50g of matrix such as gelatin and mixed evenly. The mixture was then dripped into low-temperature liquid paraffin to prepare 1000 pellets.

[0430] Example 110: Topical liniment.

[0431] Example 25: 10g of compound was mixed and ground with 2.5g of excipients such as emulsifier according to conventional pharmaceutical methods, and then distilled water was added to 200mL to obtain the product.

[0432] Example 111: Ointment.

[0433] Example 25: 10g of compound was finely ground and then mixed with 500g of an oily matrix such as petrolatum to obtain the product.

[0434] Although the invention has been described with reference to specific embodiments, modifications and equivalent variations will be apparent to those skilled in the art, and they are all included within the scope of the invention.

Claims

1. An azole derivative of general formula I, or its stereoisomer, or its pharmaceutically acceptable salt, hydrate, solvate, or prodrug, characterized in that: wherein MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, or an optionally substituted pyrazolyl, said optional substitution being with C 1- 4alkyl or C 1-4 alkoxy; X is hydrogen, halogen, C 1-4 alkyl or C 1-4 haloalkyl; Y is a substituted benzene ring, the substitution is located at ortho, meta or para position, the substitution is mono-substitution or multi-substitution halogen; Z is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, carbonyl or sulfonyl; R 1 is hydrogen, C 1-4 alkyl or C 1-4 deuteroalkyl; R 2 or R 3 is hydrogen or hydroxyl, halogen, nitro, amino, cyano, aldehydo, phenyl, benzyloxy, C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, C1-C6alkyl optionally substituted with hydroxyl, amino or halogen, halogenated C1-C6alkoxy, halogenated phenyl, halogenated benzyloxy, free, salified, esterified and amidated carboxyl, C1-C6alkylacyl, C1-C3alkylenedioxy; The carbon atom marked with * is a chiral carbon atom or an achiral carbon atom; A ring is phenyl, 5-7 membered heteroaryl, 5-7 membered heterocycloalkyl, five-membered heteroaryl and six-membered heteroaryl or six-membered heteroaryl and six-membered heteroaryl, wherein the heteroaryl, heterocycloalkyl contains 1-3 heteroatoms selected from N, O or S, and the A ring is optionally substituted with 1-4 same or different R 2 substituents; B ring is phenyl, 5-7 membered heteroaryl or 5-7 membered heterocycloalkyl, wherein heteroaryl, heterocycloalkyl contains 1-3 heteroatoms selected from N, O or S, and B ring is optionally substituted with 1-4 same or different R 3 substituents.

2. The azole derivative shown in general formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: wherein X is hydrogen or methyl; Y is 2,4-difluorophenyl; Z is hydrogen or carbonyl. wherein MBG is selected from the following structures:

3. The azole derivative shown in general formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: wherein A ring is a benzene ring, an oxazole ring, a pyridine ring, a thiophene ring, a furan ring, a thiazole ring, a pyrimidine ring, a quinoline ring, a benzothiophene ring, a naphthalene ring, a quinoxaline ring, or a benzodioxol ring; R 2 is hydrogen or fluorine. B ring is a benzene ring; wherein i. halogen, the halogen is F, Cl, Br or I; R 3 selected from i, ii or iii, wherein the substituent position is located in ortho, meta or para position, the substitution is mono- or polysubstitution; ii. straight-chain or branched alkyl of 1-6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or iso-pentyl; iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino or hydroxyl; or, wherein B ring is a 5-6 membered heteroaryl, the heteroaryl contains 1-2 heteroatoms selected from N, O or S; 4. The azole derivative shown in general formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: R 3 is hydrogen. wherein A ring is a benzene ring, B ring is a 5-6 membered heteroaryl, the heteroaryl contains 1-2 heteroatoms selected from N, O or S; 5. The azole derivative shown in general formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: R 2 and R 3 is hydrogen or fluorine. A ring is a benzene ring, B ring is a benzene ring; wherein i. halogen, the halogen is F, Cl, Br or I; R 2 is hydrogen or fluorine; R 3 selected from i, ii, or iii, wherein the substituent position is located at the ortho, meta, or para position, and the substitution is mono- or poly-substitution; ii. straight-chain or branched alkyl of 1-6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or iso-pentyl; iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino or hydroxyl.

6. The azole derivative shown in general formula I according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: A ring is a 5-6 membered heteroaryl, the heteroaryl contains 1-2 heteroatoms selected from N, O or S, B ring is a benzene ring; wherein i. halogen, the halogen is F, Cl, Br or I; R 2 is hydrogen; R 3 selected from i, ii, or iii, wherein the substituent position is located at the ortho, meta, or para position, and the substitution is mono- or poly-substitution; ii. straight-chain or branched alkyl of 1-6 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or iso-pentyl; iii. cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino or hydroxyl; or, wherein A ring is a five-membered aromatic heteroatom and a six-membered aromatic heteroatom or a six-membered aromatic heteroatom and a six-membered aromatic heteroatom, B ring is absent; selected from: R 2 is hydrogen.

7. The azole derivative according to claim 1 of the general formula I, or its stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized by: ​ 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol- 2-(2,4-difluorophenyl)-1-(methyl((5-(4-((trifluoromethoxy)methyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-((trifluoromethoxy)methyl)phenyl)pyridin-2- yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 4-(6-(((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)methyl)pyridin-3-yl)benzonitrile; 1-(((5-([1,1'-biphenyl]-4-yl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((5-([1,1'-biphenyl]-4-yl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((5-([1,1'-biphenyl]-4-yl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4-(4-chlorophenyl)thiazol-2-yl)methyl)(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-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((2-(4-chlorophenyl)thiazol-5-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((5-(4-chlorophenyl)thiophen-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((5-(4-chlorophenyl)furan-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((5-(4-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(cyclopropyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-(methyl((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-2'-,3-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((4'-chloro-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((3-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)(methyl-d3)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-1-(((4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((6-(4-chloro-3-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4- difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-3-(((6-(4-chloro-3-fluorophenyl)pyridin-3-yl)methyl)(methyl-d3)amino)-2-(2,4- difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-3-((methyl-d3)((6-(4-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)- 3-(1H-tetrazol-1-yl)propan-2-ol; 2-(2,4-difluorophenyl)-1-(methyl((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)amino)- 3-(1H-tetrazol-1-yl)propan-2-ol; 1-(((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- tetrazol-1-yl)propan-2-ol; 1-(((6-(4-chlorophenyl)pyridin-3-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- tetrazol-1-yl)propan-2-ol; 1-(((5-(4-chlorophenyl)pyridin-2-yl)methyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- tetrazol-1-yl)propan-2-ol; 4-(benzyloxy)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N- methylbenzamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-[1,1'- biphenyl]-4-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5- phenyl-1,2-oxazole-3-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-6- phenylpyridazine-3-carboxamide; 4-benzoyl-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N- methylbenzamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5- phenylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5- phenylfuran-3-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-4- phenyl-1,3-thiazole-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-2- phenylpyrimidine-5-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5-[4- (trifluoromethyl)phenyl]thiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5-(4- methylphenyl)thiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-5-(4-fluorophenyl)- N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-5-(2- fluorophenyl)-N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-5-(4- ethylphenyl)-N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5-[4- (trifluoromethoxy)phenyl]thiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-5-(3- fluorophenyl)-N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1 -yl)propyl]-N-methyl-5-[4- (propan-2-yl)phenyl]thiophene-2-carboxamide; 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide; 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]thiophene-2-carboxamide; 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide; 5-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methylthiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide; N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-N-methyl-1-benzothiophene-2-carboxamide.

8. A pharmaceutical composition, characterized by: A pharmaceutical composition comprising the azole derivative of the general formula I according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, as an active ingredient.

9. A pharmaceutical preparation, characterized by: A pharmaceutical composition comprising the azole derivative of the general formula I according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, or the pharmaceutical composition according to claim 8, as an active ingredient.

10. Use of the azole derivative of general formula I according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or the pharmaceutical composition according to claim 8 or the pharmaceutical preparation according to claim 9 for the manufacture of an antifungal medicament, characterized in that: Preferably, the fungus is selected from one or more of the following pathogenic fungi: Absidia corymbifera, Ajellomyces capsulatus, Ajellomyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae, Arthroderma vanbreuseghemii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum, Hortaea werneckii, Issatschenkia orientalis, Madurella grisae, Malassezia furfur, Malassezia pachydermatis, Malassezia oblonga, Malassezia nana, Malassezia globosa, Malassezia restricta, Malassezia sympodialis, Malassezia yamada, Mycoderma violaceum, Mycoderma stolicziae, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, Mycoderma sordellii, 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Malassezia slooffiae, Malassezia sympodialis, Microsporum cams, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Peniciliium marneffei, Pichia anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides, or Candida auris.

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