Azole alcohol derivative containing difluorophenyl structure and use thereof

Abstract

The present invention belongs to the technical field of medicinal chemistry, and specifically relates to an azole alcohol derivative containing a difluorophenyl structure and the use thereof in the preparation of a drug for treating various diseases caused by fungal infection. The derivative is a compound represented by formula I, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. Further provided are 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

Difluorophenyl-containing azole alcohol derivatives and their applications Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to an azole derivative containing a difluorophenyl structure and its application in the preparation of drugs for treating various diseases caused by fungal infections. Background Technology

[0002] Fungal infections can be divided into superficial fungal infections and deep fungal infections. Deep fungal infections, also known as invasive fungal infections, are a 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.

[0003] Candida, Cryptococcus, and Aspergillus are the three major pathogens of invasive fungal infections. Although fungal infections pose a significant threat to humans, the number of effective drugs for treating them clinically remains very limited. Currently, antifungal drugs in clinical practice can be classified according to their mechanisms of action into azoles (which inhibit ergosterol synthesis), echinocandins (which disrupt cell walls), allylamines (which inhibit fungal cell membrane synthesis), polyenes (which cause cell membrane leakage), and antimetabolites (which act on nucleic acids). Among these, azoles are widely used first-line drugs in clinical practice, acting by acting on lanosterol 14... α - The activity of demethylase (CYP51) inhibits the synthesis of fungal cell membranes, thus exerting an antifungal effect. Currently, clinically available azole antifungal drugs are mainly divided into three categories: imidazole drugs, such as miconazole and ketoconazole; triazole drugs, such as fluconazole, itraconazole, voriconazole, and posaconazole; and tetraazole drugs, such as oteseconazole.

[0004] 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

[0005] The purpose of this invention is to overcome the defects and deficiencies in the prior art and to provide a difluorophenyl azole derivative and its application in the preparation of drugs for treating various diseases caused by fungal infections, especially as a CYP51 inhibitor.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A difluorophenyl azole derivative, characterized in that: the derivative is a compound of Formula I, its stereoisomer, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug;

[0008] In the formula,

[0009] MBG is selected from unsubstituted or substituted tetrazolium, triazolium, and pyrazolium, wherein the substituent is C1-4 alkyl or C1-4 alkoxy.

[0010] M is

[0011] Ring A is a phenyl group, a 5-7 membered heteroaryl group, a 5-7 membered heterocyclic alkyl group, a 5-7 membered heteroaryl group containing a ketone carbonyl group, a 5-7 membered heterocyclic alkyl group containing a ketone carbonyl group, a five-membered aryl-hexa-aryl group, or a six-membered aryl-hexa-aryl group, wherein the heteroaryl group, heterocyclic alkyl group, ketone carbonyl group, or ketone carbonyl group mentioned contains 1-3 heteroatoms selected from N, O, or S;

[0012] The B ring is a phenyl group substituted with 1-4 identical or different R1s, an unsubstituted 5-7 membered heteroaryl group or a 5-7 membered heterocyclic alkyl group substituted with 1-4 identical or different R1s, wherein the mentioned heteroaryl group or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O or S.

[0013] R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0014] R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4 phenyl or benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0015] R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy.

[0016] n is an integer from 1 to 7;

[0017] m is an integer from 1 to 6;

[0018] P is an integer from 1 to 4;

[0019] X is hydrogen, halogen, C1-4 alkyl, or C1-4 haloalkyl;

[0020] Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group.

[0021] Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl, carbonyl, or sulfonyl;

[0022] W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazinyl group, a methylpiperazinyl group, or a carbonylpiperazinyl group;

[0023] R4 is a halogen, including nitro, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0024] Preferably, the derivative is, where M is When the derivative is as shown in Formula II;

[0025] The M is When the derivative is shown in formula Ш;

[0026] The M is When the derivative is as shown in Formula IV;

[0027] In the above general formulas,

[0028] MBG is selected from unsubstituted or substituted tetrazolium, triazolium, and pyrazolium, wherein the substituent is C1-4 alkyl or C1-4 alkoxy.

[0029] X is hydrogen, halogen, C1-4 alkyl, or C1-4 haloalkyl;

[0030] Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group.

[0031] Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl, carbonyl, or sulfonyl;

[0032] W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazinyl group, a methylpiperazinyl group, or a carbonylpiperazinyl group;

[0033] R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0034] R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4 phenyl or benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0035] R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy.

[0036] R4 is a halogen, including nitro, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0037] n is 1, 2, 3, 4, 5, 6, or 7;

[0038] m is 1, 2, 3, 4, 5, or 6;

[0039] P is 1, 2, 3, or 4;

[0040] The carbon atom marked with * is either a chiral carbon atom or a non-chiral carbon atom;

[0041] Ring A is a phenyl group, a 5-7 membered heteroaryl group, a 5-7 membered heterocyclic alkyl group, a 5-7 membered heteroaryl group containing a ketone carbonyl group, a 5-7 membered heterocyclic alkyl group containing a ketone carbonyl group, a five-membered aryl-hexa-aryl group, or a six-membered aryl-hexa-aryl group, wherein the heteroaryl group, heterocyclic alkyl group, ketone carbonyl group, or ketone carbonyl group mentioned contains 1-3 heteroatoms selected from N, O, or S;

[0042] The B ring is a phenyl group substituted with 1-4 identical or different R1 atoms, an unsubstituted 5-7 membered heteroaryl group or a 5-7 membered heterocyclic alkyl group substituted with 1-4 identical or different R1 atoms, wherein the mentioned heteroaryl group or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O or S.

[0043] Further preferably, in the general formula of the derivative,

[0044] MBG is selected from the following structures:

[0045] X is hydrogen, a C1-4 alkyl group, or a C1-4 haloalkyl group;

[0046] Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group.

[0047] Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl or carbonyl;

[0048] W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazinyl group, a methylpiperazinyl group, or a carbonylpiperazinyl group;

[0049] Ring A can be a benzene ring, piperidine ring, pyrrole ring, pyridine ring, pyridinone ring, pyridazinone ring, pyrimidinone ring, oxazole ring, thiophene ring, furan ring, or thiazole ring;

[0050] The B ring is an unsubstituted phenyl, 5-7-membered heteroaryl, or 5-7-membered heterocyclic alkyl group, which may be substituted with 1-4 identical or different R1 groups, wherein the heteroaryl or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, or S.

[0051] R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0052] R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4 phenyl or benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups;

[0053] R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy.

[0054] R4 is a substituent that can be located at the ortho, meta, or para position, and can be a halogen, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl, or isopentyl.

[0055] n is 1, 2, 3, 4, 5, 6, or 7;

[0056] m is 1, 2, 3, 4, 5, or 6;

[0057] P is 1, 2, 3, or 4;

[0058] The carbon atom marked with * is either a chiral carbon atom or a non-chiral carbon atom.

[0059] Further preferred, in the derivative formula II,

[0060] MBG is selected from the following structures:

[0061] X is hydrogen or a C1-4 alkyl group;

[0062] Ring A can be a piperidine ring, a piperidone ring, a pyridinone ring, a pyridazinone ring, or a pyrimidinone ring;

[0063] Ring B is a benzene ring;

[0064] R1 is selected from halogens, C1-C5 alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino, or hydroxyl.

[0065] n is 1, 2, 3, 4, 5, 6, or 7.

[0066] Further preferred, in the derivative formula Ш,

[0067] W is an S atom, and is a vinyl, unsubstituted or substituted phenyl, benzyloxy, piperazine or methylpiperazine;

[0068] R4 is a substituent that can be located at the ortho, meta, or para position, and can be a halogen, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl, or isopentyl.

[0069] Y is methyl or deuterated methyl;

[0070] Z represents hydrogen or carbonyl group;

[0071] R2 is selected from halogens, C1-C5 alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, phenyl, amino or hydroxyl, unsubstituted or benzyloxy group substituted with at least one halogen;

[0072] P is 1, 2, 3, or 4;

[0073] m can be 1, 2, 3, 4, 5, or 6.

[0074] More preferably, the derivative is a compound, its stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0075] 2-(2,4-Difluorophenyl)-1-(6-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0076] 2-(2,4-Difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0077] 1-(6-bromo-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0078] 2-(2,4-Difluorophenyl)-1-[6-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0079] 2-(2,4-Difluorophenyl)-1-[6-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0080] 1-[6-(2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0081] 1-[6-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0082] 1-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0083] 2-(2,4-Difluorophenyl)-1-[6-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0084] 2-(2,4-Difluorophenyl)-1-[6-(4-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0085] 2-(2,4-Difluorophenyl)-1-{6-[4-(prop-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0086] 1-[6-(4-tert-butylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0087] 2-(2,4-Difluorophenyl)-1-[6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0088] 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol;

[0089] 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol;

[0090] 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol;

[0091] 4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile;

[0092] 1-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0093] 1-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol;

[0094] (2R,3R)-3-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0095] (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol;

[0096] (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol;

[0097] 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile;

[0098] (2R,3R)-3-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0099] (2R,3R)-3-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol;

[0100] 6-(4-Chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydroisoquinoline-1-one;

[0101] 6-(4-chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydrophthalazin-1-one;

[0102] 7-(4-Chlorophenyl)-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-3,4-dihydroquinazolin-4-one;

[0103] 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydroisoquinoline-6-yl}benzyl nitrile;

[0104] 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydrophthalazine-6-yl}benzylnitrile;

[0105] 4-{3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzyl nitrile;

[0106] 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydroisoquinoline-1-one;

[0107] 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one;

[0108] 7-(4-Chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-3,4-dihydroquinazolin-4-one;

[0109] 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazo-1-yl)propyl]-1,2-dihydroisoquinoline-1-one;

[0110] 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one;

[0111] 7-(4-Chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazo-1-yl)propyl]-3,4-dihydroquinazolin-4-one;

[0112] 1-({4-[4-(3-bromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0113] 1-({4-[4-(3-bromo-5-chlorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0114] 1-({4-[4-(3-bromo-5-fluorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0115] 1-({4-[4-(3,5-dibromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0116] (3-Bromophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl}methyl ketone;

[0117] (3-Bromo-5-chlorophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl}methyl ketone;

[0118] (E)-2-(2,4-difluorophenyl)-1-{methyl[4-(4-nitrostyryl)benzyl]amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0119] (E)-2-(2,4-difluorophenyl)-1-[methyl(4-styrylbenzyl)amino]-3-(1H-tetrazol-1-yl)prop-2-ol;

[0120] (E)-2-(2,4-difluorophenyl)-1-{[4-(4-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0121] (E)-2-(2,4-difluorophenyl)-1-{[4-(4-chlorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0122] (E)-2-(2,4-difluorophenyl)-1-{[4-(2-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0123] (E)-2-(2,4-difluorophenyl)-1-{[4-(3-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0124] (E)-1-{[4-(4-bromostyryl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0125] (E)-2-(2,4-difluorophenyl)-1-{[4-(4-iodostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0126] 2-(2,4-Difluorophenyl)-1-{[4-(4-{4-[(4-fluorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol;

[0127] 1-{[4-(4-{4-[(4-chlorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol;

[0128] 4-({4-[4-(4-{[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl)amino}methyl)phenyl)piperazin-1-yl]phenoxy}methyl)benzylnitrile;

[0129] 2-(2,4-Difluorophenyl)-1-(methyl{4-[4-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)piperazin-1-yl]benzyl}amino)-3-(1H-tetrazol-1-yl)prop-2-ol.

[0130] Furthermore, according to some common methods in the field to which this invention pertains, some compounds of general formulas I and II 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 add to 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.

[0131] 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.

[0132] In the definitions of general formula compounds given above, the terms used in the compilation are generally defined as follows:

[0133] Optional substituents: C1-C4 alkyl, C1-C4 alkoxy.

[0134] Halogens: refer to fluorine, chlorine, bromine or iodine.

[0135] Alkyl: Straight-chain or branched alkyl, preferably, the alkyl is a C1-6 straight-chain or branched alkyl, for example, it may be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl or isopentyl.

[0136] Cycloalkyl: Substituted or unsubstituted cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents include methyl, halogen, etc.

[0137] 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.

[0138] 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.

[0139] Heteroaryl groups containing ketone carbonyl groups, for example: Heterocyclic alkyl groups containing ketone carbonyl groups, for example:

[0140] A pharmaceutical composition characterized in that the composition comprises a derivative of the general formula I or II, a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0141] A pharmaceutical formulation wherein the derivative or the composition is the active ingredient.

[0142] The use of the derivative, the composition, or the pharmaceutical preparation thereof, and the use of the derivative, the composition, or the pharmaceutical preparation thereof in the preparation of drugs for various diseases caused by fungal infections.

[0143] The fungus is selected from one or more of the following pathogenic fungi: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fullvum*, *Arthrodermagypseum*, *Arthrodermaincurvatum*, *Arthrodermaotae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, *Candida albicans*, and *Candida glabrata*. Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaeapedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum *Capsulatum*, *Hortaeawerneckii*, *Issa mesaschenkia orientalis*, *Madurellagrisae*, *Malassezia furfur*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum cams, Microsporum fullvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Peniciliium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apispernium, Schizophyllum commune, Sporothrix chenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum The fungi include *Trichosporon violaceum*, *Trichosporonasahii*, *Trichosporoncutaneum*, *Trichosporoninkin*, *Trichosporonmucoides*, and *Candida auris*.

[0144] Furthermore, the present invention also includes prodrugs derived from the present invention. These prodrugs may themselves have weak or even no activity, but after administration, they are converted into their corresponding biologically active forms under physiological conditions (e.g., through metabolism, solvation, or other means).

[0145] Compounds of Formula I can exist in both unsolvable 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 stereoisomeric forms. 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.

[0146] This invention provides a method for preparing a clinically acceptable dosage form by mixing a derivative of general formula I, and its pharmaceutically acceptable salt, hydrate, solvate, or prodrug as an active ingredient, with a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0147] The pharmaceutical compositions 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.

[0148] 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.

[0149] The compounds of the general formula of this invention can be synthesized by methods well known in the field of chemistry, and especially prepared according to the description of this invention; room temperature in this invention refers to ambient temperature, which is 25°C.

[0150] The preparation method of the derivatives represented by the above general formula, wherein the derivatives represented by the general formula are obtained by the following reaction:

[0151] Starting with 2'-chloro-2,4-difluoroacetophenone, a substitution reaction under basic conditions yields intermediate 2. Intermediate 2, under basic conditions, undergoes cyclization with trimethyl sulfoxide to yield intermediate 3. Intermediate 4 or intermediate 5 undergoes ring-opening with intermediate 3 under basic conditions to yield intermediate 6 or the target compound 7. Subsequently, intermediate 6 undergoes a Suzuki coupling reaction with phenylboronic acid containing different substituents to yield the target compound 8.

[0152] The definitions of MBG, A ring, and R1 in the above preparation process are as described above.

[0153] 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 undergoes cyclization with trimethyl sulfoxide under high-temperature alkaline conditions to yield intermediate 3. The reaction solvent can be toluene / water, dichloromethane / water, or 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, or benzyltrimethylammonium chloride, preferably benzyltrimethylammonium chloride; the base in the reaction can be sodium hydride. Sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, etc., preferably sodium hydroxide; intermediate 3 and intermediate 4 or intermediate 5 undergo ring-opening under alkaline conditions to obtain intermediate 6 or target compound 7, the reaction solvent can be ethanol, N,N-dimethylformamide, preferably ethanol; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine; the reaction temperature is 50-120℃, preferably 80℃. Intermediate 6 undergoes coupling reactions with phenylboronic acids of different substituents to yield target compound 8. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, 1,4-dioxane / water, isopropanol, or ethanol, preferably 1,4-dioxane / water. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, or sodium bicarbonate, preferably cesium carbonate. The catalyst in the reaction can be tetra-triphenylphosphine palladium, bis(triphenylphosphine) palladium dichloride, or chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-diphenylphosphine). The reaction mixture is phenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II), palladium acetate, preferably chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); the ligand may be triphenylphosphine, 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, preferably 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl; the reaction temperature is 50–120 °C, preferably 100 °C.

[0154] Starting with 9, the intermediate 10 was obtained by ring-opening with 1-[(2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxymethyl]-1H-[1,2,4]triazole under alkaline conditions. Subsequently, the intermediate 10 was obtained by Suzuki coupling reaction with phenylboronic acid with different substituents to obtain the target compound 11.

[0155] The definitions of ring A and R1 in the above preparation process are as described above.

[0156] Furthermore, starting with 9, intermediate 10 is obtained by ring-opening with 1-[(2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxymethyl]-1H-[1,2,4]triazole. The reaction temperature is 50-150℃, preferably 120℃. The solvent can be acetonitrile, tetrahydrofuran, N-methylpyrrolidone, tert-butanol, toluene, isopropanol, preferably N-methylpyrrolidone. The base in the reaction can be magnesium hydroxide, magnesium carbonate, sodium hydroxide, potassium carbonate, cesium carbonate, lithium tert-butoxide, magnesium tert-butoxide, preferably cesium carbonate; intermediate 10 undergoes a Suzuki coupling reaction with phenylboronic acid of different substituents to obtain final product 11. The reaction solvent can be tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, ethylene glycol dimethyl ether, 1,4-dioxane, isopropanol, ethanol, preferably ethylene glycol dimethyl ether. 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℃, preferably 85℃.

[0157] Starting with 2'-chloro-2,4-difluoroacetophenone, a substitution reaction with tetrazolium under alkaline conditions yielded intermediate 12. Intermediate 12 was then cyclized with trimethyl sulfoxide under alkaline conditions to give intermediate 13. Intermediate 14 underwent a substitution reaction with N-Boc-piperazine under high-temperature alkaline conditions to give intermediate 15. Intermediate 15 underwent reductive amination with methyl-d3-amine hydrochloride to give intermediate 16. Intermediate 16 then underwent ring-opening with intermediate 13 under alkaline conditions to give intermediate 17. Subsequently, Boc protection was removed under acidic conditions to give intermediate 18. Finally, intermediates 17 and 18 were reacted with the corresponding substituted benzyl bromo or benzoic acid under alkaline conditions to give final products 19 and 20, respectively. Similar target compounds can also be prepared using the above general formula method.

[0158] The definition of R2 in the above preparation process is as described above.

[0159] Furthermore, using 2'-chloro-2,4-difluoroacetophenone as the starting material, a substitution reaction is carried out with tetrazolium under alkaline conditions to obtain intermediate 12. 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 12 is cyclized with trimethyl sulfoxide under high-temperature alkaline conditions to give intermediate 13. 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, or triethylamine. The intermediate 14 is prepared by reacting N-Boc-piperazine with N-Boc-piperazine under alkaline high-temperature conditions to obtain intermediate 15. The reaction temperature is 90–150 °C, preferably 135 °C. The reaction solvent can be dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, with N-methylpyrrolidone being preferred as a base. The base can be potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., with potassium carbonate being preferred. Intermediate 15 is then reductively aminationd with methyl-d3-amine hydrochloride to obtain intermediate 16. The reaction temperature is 0–50 °C, preferably 25 °C. The reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., with methanol being preferred. The reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., with sodium borohydride being preferred. Intermediate 13 and intermediate 16 undergo ring-opening under alkaline conditions to yield intermediate 17. The reaction solvent can be ethanol or N,N-dimethylformamide, preferably ethanol. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine. The reaction temperature is 50–120°C, preferably 80°C. Under acidic conditions, the Boc protecting group is removed to yield intermediate 18. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, preferably ethyl acetate. The reaction temperature is 0–70°C, preferably 25°C. The acid in the reaction can be a saturated solution of hydrogen chloride in ethyl acetate, an ethanol solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, an aqueous solution of hydrogen chloride, p-toluenesulfonic acid, trifluoroacetic acid, etc., preferably a saturated solution of hydrogen chloride in ethyl acetate.Finally, a substitution reaction with the corresponding benzyl bromodiphenyl ether yields final product 19. The reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, methanol, etc., preferably acetonitrile; the reaction temperature is 0–70℃, preferably 25℃; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine. A condensation reaction with the corresponding benzoic acid yields final product 20. The reaction solvent can be tetrahydrofuran, dichloromethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., preferably N,N-dimethylformamide; the reaction temperature is 0–90℃, preferably 25℃; the condensing agent in the reaction can be dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, O-(7-azabenzotriazol-1-yl)-di(dimethyl... The reagents include (amino)carbomony hexafluorophosphate, O-(benzotriazol-1-yl)-di(dimethylamino)carbomony hexafluorophosphate, benzotriazol-1-yloxy-tris(tetrahydropyrrol)phosphonium hexafluorophosphate, etc., preferably benzotriazol-1-yloxy-tris(tetrahydropyrrol)phosphonium hexafluorophosphate; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, etc., preferably 4-dimethylaminopyridine.

[0160] Starting with 4-vinylbenzaldehyde, it undergoes a Heck coupling reaction with a correspondingly substituted iodobenzene to give intermediate 22. Intermediate 22 undergoes reductive amination with methylamine to give intermediate 23. Intermediate 23 and intermediate 13 undergo ring-opening under alkaline conditions to give final product 24. Target compounds with similar structures can also be prepared according to the above general formula method.

[0161] The definition of R2 in the above preparation process is as described above.

[0162] Furthermore, intermediate 22 is obtained by Heck coupling reaction of 4-vinylbenzaldehyde as the starting material with a correspondingly substituted iodobenzene. The reaction temperature is 80–150 °C, preferably 100 °C. The reaction solvent can be N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, preferably toluene. The reaction catalyst can be palladium acetate, palladium chloride, tetra-triphenylphosphine palladium, bis(diphenylphosphine)ferrocene palladium chloride, preferably palladium acetate. Intermediate 22 is reductively amination with methylamine to obtain intermediate 23. The reaction temperature is 0–50 °C, preferably 25 °C. The reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., preferably methanol. The reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 13 and intermediate 23 undergo ring-opening under alkaline conditions to obtain final product 24. The reaction solvent can be ethanol or N,N-dimethylformamide, preferably ethanol. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine. The reaction temperature is 50-120℃, preferably 80℃.

[0163] Starting with 4-piperazinylphenol, it reacts with Boc anhydride to give intermediate 26. Intermediate 26 reacts with benzyl bromo to give intermediate 27. Intermediate 27 is deprotected from Boc under acidic conditions to give intermediate 28. Intermediate 28 undergoes a nucleophilic substitution reaction with 4-fluorobenzaldehyde to give intermediate 29. Intermediate 29 undergoes a reductive amination reaction with methylamine to give intermediate 30. Intermediate 30 and intermediate 13 undergo ring-opening under basic conditions to give intermediate 31. Intermediate 31 is deprotected from benzyl group under acidic conditions to give intermediate 32. Intermediate 32 undergoes substitution reaction with benzyl bromo with different substituents under basic conditions to give final product 33. Target compounds with similar structures can also be prepared according to the above general formula method.

[0164] The definition of R2 in the above preparation process is as described above.

[0165] Furthermore, using 4-piperazinylphenol as the starting material, intermediate 26 is obtained by reacting it with Boc anhydride at a reaction temperature of -10 to 25°C, preferably 25°C. The reaction solvent can be methanol, dichloromethane, or tetrahydrofuran, preferably methanol. The base can be sodium hydroxide, potassium carbonate, sodium carbonate, or triethylamine, preferably triethylamine. Intermediate 26 reacts with benzyl bromide to obtain intermediate 27 at a reaction temperature of 25 to 80°C, preferably 50°C. The reaction solvent can be tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, or acetone, preferably N,N-dimethylformamide. The base can be sodium hydroxide, potassium carbonate, sodium carbonate, or triethylamine, preferably potassium carbonate. Intermediate 27 is deprotected from Boc protection under acidic conditions to obtain intermediate 28. The reaction solvent can be methanol, ethanol, or isopropanol. The reaction mixture contains n-propanol, tert-butanol, sec-butanol, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and ethyl acetate, preferably dichloromethane; the reaction temperature is 0–70°C, preferably 25°C; the acid in the reaction can be a saturated solution of hydrogen chloride in ethyl acetate, an ethanol solution of hydrogen chloride, a solution of hydrogen chloride in 1,4-dioxane, a methanol solution of hydrogen chloride, an aqueous solution of hydrogen chloride, p-toluenesulfonic acid, trifluoroacetic acid, etc., preferably trifluoroacetic acid. Intermediate 28 undergoes a nucleophilic substitution reaction with 4-fluorobenzaldehyde to give intermediate 29, the reaction temperature is 90–150°C, preferably 135°C; the reaction solvent can be dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably the base N-methylpyrrolidone; the base can be potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, etc., preferably potassium carbonate. Intermediate 29 reacts with methylamine via a reductive amination reaction to yield intermediate 30. The reaction temperature is 0–50°C, preferably 25°C. The reaction solvent can be methanol, ethanol, dichloromethane, tetrahydrofuran, etc., preferably methanol. The reducing agent can be sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, tetraisopropyl titanate, etc., preferably sodium borohydride. Intermediate 13 reacts with intermediate 30 under alkaline conditions for ring-opening to yield intermediate 31. The reaction solvent can be ethanol, N,N-dimethylformamide, preferably ethanol. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine. The reaction temperature is 50–120°C, preferably 80°C. Intermediate 31 is deprotected by benzyl group under acidic conditions to obtain intermediate 32. The reaction temperature can be -40 to 80°C, preferably -20°C. The reaction solvent can be ethanol, acetonitrile, acetone, dichloromethane, tetrahydrofuran, etc., preferably dichloromethane. The deprotecting agent can be hydrogen palladium on carbon, boron trichloride, polyphosphoric acid and hydrochloric acid, 2,3-dichloro-5,6-diacetonitrile-1,4-benzoquinone and tert-butyl nitrite, etc., preferably boron trichloride.Intermediate 32 undergoes a substitution reaction with benzyl bromowith different substituents under alkaline conditions to give final product 33. The reaction temperature is 25–80 °C, preferably 50 °C. The reaction solvent can be tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, or acetone, with N,N-dimethylformamide being the preferred solvent. The base can be sodium hydroxide, potassium carbonate, sodium carbonate, or triethylamine, with potassium carbonate being the preferred base.

[0166] This invention provides the use of azole derivatives, specifically compounds of general formula I, 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.

[0167] The use of the compound represented by general formula I, its stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs in the preparation of antifungal drugs.

[0168] The beneficial effects of this invention are as follows: This invention provides a novel azole derivative, its preparation method, a pharmaceutical composition comprising the derivative, a pharmaceutical formulation, and its 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

[0169] 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.

[0170] The specific implementation structure is as follows:

[0171] The preparation route of Example 1 is shown below:

[0172] The specific synthesis steps are as follows:

[0173] Synthesis of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl-1-one (2)

[0174] 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 separation was performed by column chromatography (DCM:MeOH = 500:1) to obtain a white solid in 80% yield.

[0175] Synthesis of 1-{[2-(2,4-difluorophenyl)ethyleneoxy-2-yl]methyl}-1H-1,2,4-triazole(3)

[0176] 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 proceeds were complete. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. Separation by column chromatography (DCM:MeOH = 300:1) yielded a pale yellow solid with a yield of 75%.

[0177] Synthesis of 1-(6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol (5)

[0178] Intermediate 4 (12.58 g, 0.060 mol) and intermediate 3 (7.12 g, 0.030 mol) were dissolved in anhydrous ethanol, and triethylamine (8.34 mL, 0.059 mol) was added. The reaction was carried out at 80 °C for 5 h. TLC monitoring (DCM:MeOH = 30:1) showed that the reaction proceeds were complete. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. Separation was carried out by column chromatography (PE:EA = 1:1) to give a white solid in 81% yield.

[0179] Preparation of 1-[6-phenyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol (Example 1)

[0180] Intermediate 5 was dissolved in 6 mL of 1,4-dioxane / water (v:v = 5:1), followed by the sequential addition of phenylboronic acid, cesium carbonate, and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) under argon protection and stirring at 100 °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 32% yield. NMR(600MHz,Chloroform-d)δ8.18(s,1H),7.81(s,1H),7.58(q,J=8.4Hz,1H),7.53 (d,J=7.7Hz,2H),7.41(t,J=7.6Hz,2H),7.33(dd,J=7.0,4.6Hz,2H),7.28(s,1H),6 .92(d,J=7.9Hz,1H),6.84(t,J=8.9Hz,2H),5.31(d,J=34.8Hz,1H),4.62–4.54(m,2 H),3.57(q,J=14.9Hz,2H),3.27(d,J=13.5Hz,1H),2.89–2.79(m,3H),2.67(s,2H).

[0181] Following the method of Example 1, Examples 2-26 were prepared using the corresponding raw materials.

[0182] Example 2: 2-(2,4-difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinoline-2-yl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0183] 1H NMR(600MHz,DMSO-d6)δ8.33(s,1H),7.76(s,1H),7.44(td,J=8.9,6.7Hz,1H), 7.17–7.13(m,1H),7.08–7.05(m,2H),7.03–7.01(m,1H),6.98–6.94(m,1H),6.9 4–6.92(m,1H),5.77(s,1H),4.62(d,J=2.1Hz,2H),3.63(s,2H),3.05(dd,J=13. 8,1.6Hz,1H),2.86(d,J=13.9Hz,1H),2.77–2.73(m,1H),2.65(d,J=2.8Hz,3H).

[0184] Example 3: 1-(6-bromo-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0185] 1H NMR (600MHz, DMSO-d6) δ8.30(s,1H),7.75(s,1H),7.41(td,J=9.0,6.8Hz,1H),7.24(d,J= 9.9Hz, 2H), 7.16 (ddd, J=11.9, 9.1, 2.6Hz, 1H), 6.95 (td, J=8.4, 2.6Hz, 1H), 6.92 (d, J=8. 0Hz,1H),5.75(s,1H),4.59(d,J=2.3Hz,2H),3.58(s,2H),3.03(dd,J=13.8,1.6Hz,1H),2 .83(d,J=13.8Hz,1H),2.75–2.70(m,1H),2.64(dt,J=6.9,3.8Hz,2H),2.63–2.58(m,1H).

[0186] Example 4: 2-(2,4-difluorophenyl)-1-[6-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0187] 1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.76(s,1H),7.48–7.42(m,2H),7.38(dt,J=7.6,3.4H z,1H),7.29–7.24(m,3H),7.21(s,1H),7.18(td,J=9.3,4.6Hz,1H),7.05(d,J=8.0Hz,1H),6 .97(td,J=8.5,2.4Hz,1H),5.77(s,1H),4.61(s,2H),3.68(s,2H),3.07(d,J=14.3Hz,1H), 2.86(d,J=13.8Hz,1H),2.78(dd,J=10.3,5.8Hz,1H),2.72–2.70(m,2H),2.68–2.65(m,1H).

[0188] Example 5: 2-(2,4-difluorophenyl)-1-[6-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0189] 1H NMR(600MHz,DMSO-d6)δ8.33(s,1H),7.77(s,1H),7.47–7.44(m,3H),7.43(s,1H),7. 40(d,J=8.2Hz,1H),7.38(s,1H),7.18–7.16(m,1H),7.16–7.14(m,1H),7.04(d,J=7. 9Hz,1H),6.97(t,J=7.4Hz,1H),5.79(s,1H),4.62(s,2H),3.68(s,2H),3.07(d,J=13 .7Hz,1H),2.87(d,J=13.7Hz,1H),2.81–2.77(m,1H),2.73(s,2H),2.70–2.66(m,1H).

[0190] Example 6: 2-(2,4-difluorophenyl)-1-[6-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0191] 1H NMR(600MHz,DMSO-d6)δ8.35(s,1H),7.77(s,1H),7.63(s,2H),7.48–7.42(m,1H),7 .34(d,J=7.2Hz,1H),7.30(s,1H),7.25(t,J=7.9Hz,2H),7.17(t,J=9.3Hz,1H),7.02 (d,J=7.4Hz,1H),6.97(s,1H),5.82(s,1H),4.63(s,2H),3.66(s,2H),3.07(d,J=13. 6Hz,1H),2.87(d,J=13.6Hz,1H),2.81–2.76(m,1H),2.72(s,2H),2.69–2.64(m,1H).

[0192] Example 7: 1-[6-(2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0193] 1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.76(s,1H),7.48–7.45(m,1H),7.42(d,J=7.4Hz,1H), 7.39–7.37(m,1H),7.25(s,2H),7.24(s,1H),7.21(s,1H),7.16(dd,J=5.8,3.3Hz,1H),7.05 (d,J=8.1Hz,1H),6.95(s,1H),5.77(s,1H),4.62(s,2H),3.68(s,1H),3.58(s,1H),3.07(d, J=14.4Hz,1H),2.85(d,J=8.0Hz,1H),2.68(s,1H),2.64(d,J=4.5Hz,2H),2.63–2.60(m,1H).

[0194] Example 8: 1-[6-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0195] 1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.75(s,1H),7.46(d,J=3.9Hz,2H),7.43(s,1H),7.3 8(s,1H),7.25(s,1H),7.17–7.14(m,2H),7.04(d,J=8.0Hz,1H),6.95(s,1H),6.92(d,J=8. 0Hz,1H),5.76(s,1H),4.61(s,2H),3.67(s,1H),3.58(s,1H),3.07(d,J=14.1Hz,1H),2.8 4(d,J=5.1Hz,1H),2.78(dd,J=10.6,5.5Hz,1H),2.73–2.71(m,2H),2.64(d,J=5.7Hz,1H).

[0196] Example 9: 1-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0197] 1H NMR (600MHz, DMSO-d6) δ8.32(d,J=4.1Hz,1H),7.77(d,J=2.7Hz,1H),7.73(t,J=8.7Hz,2H),7.63–7.62(m,1H),7 .48–7.47(m,1H),7.43(td,J=5.1,4.4,2.2Hz,1H),7.41–7.36(m,1H),7.35–7.32(m,1H),7.17(ddt,J=9.3,6.4, 3.4Hz,1H),7.04(d,J=8.3Hz,1H),6.98–6.95(m,1H),5.77(d,J=11.7Hz,1H),4.62(d,J=5.3Hz,2H),3.67(d,J=9 .5Hz,2H),3.07(dd,J=14.7,6.6Hz,1H),2.87(dd,J=13.8,6.9Hz,1H),2.72(dddd,J=34.0,25.6,9.9,4.7Hz,4H).

[0198] Example 10: 2-(2,4-difluorophenyl)-1-[6-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0199] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.76(s,1H),7.48(d,J=8.0Hz,2H),7.43(d,J=7.1Hz,1H),7.33 (d,J=7.9Hz,1H),7.30(s,1H),7.23(d,J=8.0Hz,2H),7.17(t,J=9.4Hz,1H),7.00(d,J=8.0Hz,1H),6 .96(dt,J=8.5,4.2Hz,1H),5.77(s,1H),4.61(s,2H),3.65(s,2H),3.06(d,J=13.9Hz,1H),2.86(d,J =13.8Hz,1H),2.77(dd,J=10.4,5.5Hz,1H),2.71(s,2H),2.66(dd,J=10.4,5.4Hz,1H),2.32(s,3H).

[0200] Example 11: 2-(2,4-difluorophenyl)-1-[6-(4-ethylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0201] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.76(s,1H),7.50(d,J=8.1Hz,2H),7.43(d,J=7.1Hz,1H),7.33 (d,J=7.9Hz,1H),7.30(s,1H),7.26(d,J=8.1Hz,2H),7.19–7.15(m,1H),7.01(d,J=8.0Hz,1H),6.96( dt,J=8.5,4.2Hz,1H),5.77(s,1H),4.61(s,2H),3.65(s,2H),3.06(d,J=14.0Hz,1H),2.86(d,J=13.8 Hz,1H),2.79–2.76(m,1H),2.71(s,2H),2.67–2.65(m,1H),2.63–2.60(m,2H),1.19(d,J=7.6Hz,3H).

[0202] Example 12: 2-(2,4-difluorophenyl)-1-{6-[4-(prop-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0203] 1H NMR (600MHz, DMSO-d6) δ8.33(s,1H),7.77(s,1H),7.50(d,J=8.1Hz,2H),7.45(d,J=7.2Hz,1H),7 .33(d,J=7.9Hz,1H),7.28(d,J=8.4Hz,3H),7.19–7.14(m,1H),7.00(d,J=8.0Hz,1H),6.96(td,J= 8.5,2.2Hz,1H),5.79(s,1H),4.63(s,2H),3.66(s,2H),3.07(d,J=14.0Hz,1H),2.92–2.85(m,2H ),2.78(dt,J=10.3,4.9Hz,1H),2.72(s,2H),2.67(dd,J=10.6,5.4Hz,1H),1.21(d,J=6.9Hz,6H).

[0204] Example 13: 1-[6-(4-tert-butylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0205] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.76(s,1H),7.51(d,J=8.4Hz,2H),7.44(d,J=8.4Hz ,3H),7.34–7.32(m,1H),7.30(s,1H),7.19–7.15(m,1H),7.01(d,J=8.0Hz,1H),6.98–6.95 (m,1H),5.77(s,1H),4.61(s,2H),3.66(s,2H),3.07(d,J=14.0Hz,1H),2.86(d,J=13.8Hz ,1H),2.77(dd,J=10.6,5.5Hz,1H),2.72(d,J=5.1Hz,2H),2.68–2.65(m,1H),1.30(s,9H).

[0206] Example 14: 2-(2,4-difluorophenyl)-1-[6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0207] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.76(s,1H),7.53(d,J=8.7Hz,2H),7.43(d,J=7.1Hz,1H ),7.30(d,J=8.0Hz,1H),7.27(s,1H),7.19–7.15(m,1H),6.99(d,J=8.7Hz,3H),6.96(dd,J=8. 5,2.2Hz,1H),5.77(s,1H),4.61(s,2H),3.78(s,3H),3.65(s,2H),3.06(d,J=14.0Hz,1H),2. 86(d,J=13.8Hz,1H),2.77(dd,J=10.3,5.5Hz,1H),2.71(s,2H),2.66(dd,J=10.3,5.3Hz,1H).

[0208] Example 15: 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol

[0209] 1H NMR (600MHz, DMSO-d6) δ8.34(s,1H),7.83(d,J=8.2Hz,2H),7.77(d,J=6.7Hz,3H),7.44(dd ,J=17.2,8.5Hz,3H),7.17(ddd,J=11.7,9.2,2.4Hz,1H),7.08(d,J=8.0Hz,1H),6.97(td,J= 8.5,2.4Hz,1H),5.80(s,1H),4.63(s,2H),3.69(s,2H),3.08(d,J=14.1Hz,1H),2.88(d,J= 13.8Hz,1H),2.79(dd,J=10.5,5.5Hz,1H),2.76–2.72(m,2H),2.68(dd,J=10.7,5.6Hz,1H).

[0210] Example 16: 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol

[0211] 1H NMR (600MHz, DMSO-d6) δ8.34(s,1H),7.78(s,1H),7.72(d,J=8.7Hz,2H),7.46(d,J=6.9Hz,1H),7 .41(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,1H),7.35(s,1H),7.19–7.14(m,1H),7.05(d,J=8.0Hz,1H) ,6.97(td,J=8.5,2.3Hz,1H),5.80(s,1H),4.63(s,2H),3.68(s,2H),3.10–3.05(m,1H),2.88(d, J=13.8Hz,1H),2.79(dd,J=10.7,5.6Hz,1H),2.73(q,J=4.5Hz,2H),2.68(dd,J=11.0,5.7Hz,1H).

[0212] Example 17: 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol

[0213] 1H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.77(s,1H),7.57(d,J=8.7Hz,2H),7.44(q,J=8.8Hz,1H),7.3 3(d,J=7.9Hz,1H),7.30(s,1H),7.19–7.15(m,1H),7.12(d,J=8.7Hz,2H),7.00(d,J=8.0Hz,1H),6. 99–6.94(m,1H),5.78(s,1H),4.79(q,J=8.9Hz,2H),4.62(s,2H),3.65(s,2H),3.07(d,J=13.9Hz,1 H),2.86(d,J=13.8Hz,1H),2.77(dd,J=10.4,5.5Hz,1H),2.71(s,2H),2.67(dd,J=10.4,5.3Hz,1H).

[0214] Example 18: 4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile 1H NMR (600MHz, DMSO-d6) δ8.33(s,1H),7.88(d,J=8.4Hz,2H),7.82(d,J=8.4Hz,2H),7.77(s,1H) ,7.46–7.43(m,2H),7.43(s,1H),7.17(ddd,J=11.7,9.2,2.4Hz,1H),7.08(d,J=8.0Hz,1H),6.9 7(td,J=8.5,2.3Hz,1H),5.79(s,1H),4.62(s,2H),3.69(s,2H),3.08(d,J=14.1Hz,1H),2.87(d ,J=13.8Hz,1H),2.79(dd,J=10.7,5.6Hz,1H),2.75–2.72(m,2H),2.68(dd,J=10.7,5.5Hz,1H).

[0215] Example 19: 1-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0216] 1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.77(s,1H),7.59(s,1H),7.51–7.49 (m,1H),7.44(s,2H),7.35(d,J=7.4Hz,1H),7.27–7.21(m,1H),7.18(d,J= 16.9Hz,1H),7.10–7.04(m,1H),6.97(s,1H),5.78(s,1H),4.62(s,2H),3. 68(s,2H),3.07(d,J=11.4Hz,1H),2.88(s,1H),2.79(s,1H),2.71(s,3H).

[0217] Example 20: 1-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol

[0218] 1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.43–7.39(m,2H),7.25 (s,2H),7.17–7.14(m,1H),6.97–6.94(m,1H),6.92(d,J=8.0Hz,1H),5.76 (s,1H),4.59(s,2H),3.58(s,2H),3.03(d,J=14.0Hz,1H),2.83(d,J=13.9 Hz,1H),2.75–2.70(m,2H),2.68–2.62(m,3H),2.61(dd,J=7.5,4.2Hz,1H).

[0219] Example 21: 6-(4-chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydroisoquinoline-1-one

[0220] 1H NMR (400MHz, DMSO-d6) δ8.34(s,1H),8.26(d,J=7.8Hz,1H),8.00(s,1H),7.89(s,1H),7.84(s ,1H),7.78(d,J=8.1Hz,2H),7.56(s,1H),7.38(d,J=7.6Hz,1H),7.30(d,J=7.0Hz,1H),7.24–7 .20(m,1H),6.88(s,1H),6.67(d,J=8.2Hz,1H),6.44(d,J=6.7Hz,1H),5.32(q,J=7.6,5.0Hz, 1H), 4.90 (d, J = 14.5Hz, 1H), 4.73–4.67 (m, 1H), 4.56 (d, J = 3.9Hz, 1H), 4.34 (d, J = 14.2Hz, 1H).

[0221] Example 22: 6-(4-chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one

[0222] 1H NMR (600MHz, DMSO-d6) δ8.29(s,1H),8.25(s,1H),8.14(s,1H),8.04(d,J=8.4Hz, 1H),7.99(d,J=8.6Hz,1H),7.88(dd,J=5.3,2.0Hz,2H),7.62(s,1H),7.69(t,J=2 .2Hz,1H),7.68(t,J=2.2Hz,1H),7.25–7.21(m,2H),6.89–6.86(m,1H),6.39(s,1 H), 4.98 (d, J = 14.6Hz, 1H), 4.57 (dd, J = 14.4, 12.0Hz, 2H), 4.41 (d, J = 14.2Hz, 1H).

[0223] Example 23: 7-(4-chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-3,4-dihydroquinazolin-4-one

[0224] 1H NMR (600MHz, DMSO-d6) δ8.28(s,1H),8.25(s,1H),8.14(s,1H),8.04(d,J=8.4Hz, 1H),7.99(d,J=8.6Hz,1H),7.88(dd,J=5.3,2.0Hz,2H),7.73(s,1H),7.69(t,J=2 .2Hz,1H),7.68(t,J=2.2Hz,1H),7.25–7.21(m,2H),6.89–6.86(m,1H),6.39(s,1 H), 4.86 (d, J = 14.6Hz, 1H), 4.57 (dd, J = 14.4, 12.0Hz, 2H), 4.41 (d, J = 14.2Hz, 1H).

[0225] Example 24: 6-(4-chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-1,2-dihydroisoquinoline-1-one

[0226] 1H NMR (400MHz, DMSO-d6) δ9.10(d,J=2.8Hz,1H),8.28(t,J=8.1Hz,1H),8.00(d,J=22.7Hz,1H),7.91(d, J=5.9Hz,1H),7.84–7.80(m,2H),7.57(dd,J=12.9,8.2Hz,2H),7.44–7.40(m,1H),7.34–7.28(m,1H), 7.21(d,J=8.5Hz,1H),6.91(td,J=8.5,8.0,4.1Hz,1H),6.73–6.67(m,1H),6.62(d,J=5.3Hz,1H),5.2 3(dd,J=14.6,3.3Hz,1H), 4.86(d,J=7.6Hz,1H), 4.72(dd,J=14.6,3.6Hz,1H), 4.27(d,J=14.0Hz,1H).

[0227] Example 25: 6-(4-chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one

[0228] 1H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.45–8.42(m,1H),8.34(d,J=5.9Hz,2H),8.25(d,J=7.9Hz,1H),7.88(d,J=3.8Hz,1H),7.81(s,1H),7.56(d ,J=5.1Hz,1H),7.22(s,1H),6.89(s,1H),6.43(s,1H),5.32(t,J=5.0Hz ,1H),5.23(d,J=14.5Hz,1H),4.90–4.85(m,2H),4.58(d,J=13.8Hz,1H).

[0229] Example 26: 7-(4-chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-3,4-dihydroquinazolin-4-one

[0230] 1H NMR (600MHz, DMSO-d6) δ9.07(d,J=1.8Hz,1H),8.31(d,J=3.2Hz,1H),8.20(dd,J=8.3,3.9Hz,1 H),8.01(dd,J=6.4,1.8Hz,1H),7.95–7.92(m,2H),7.82–7.78(m,2H),7.56–7.55(m,1H),7.35 –7.31(m,1H),7.17(td,J=6.4,3.3Hz,1H),6.91(ddd,J=8.5,5.8,2.6Hz,1H),6.61(d,J=2.4Hz ,1H),5.20(dd,J=14.5,2.3Hz,1H),4.76(td,J=10.9,9.5,2.9Hz,2H),4.37(d,J=14.2Hz,1H).

[0231] The preparation route of Example 27 is shown below:

[0232] The specific synthesis steps are as follows:

[0233] Synthesis of 6-bromo-2-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl)isoquinoline-1(2H)-one (9)

[0234] 6-Bromoisoquinoline-1(2H)-one (3.00 g, 0.013 mol) and 1-[(2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxymethyl]-1H-[1,2,4]triazole (2.77 g, 0.011 mol) were dissolved in N-methylpyrrolidone, and cesium carbonate (9.12 g, 0.028 mol) was added. The mixture was stirred at 120 °C for 6 h. TLC monitoring (DCM:MeOH = 15:1) showed that the reaction was complete. The mixture was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and column chromatography (DCM:MeOH = 300:1) was used to separate the solid into a white solid with a yield of 72%.

[0235] Preparation of 6-(4-chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydroisoquinoline-1-one (Example 27):

[0236] Intermediate 9 was dissolved in ethylene glycol dimethyl ether, and 4-chlorophenylboronic acid, cesium carbonate, and tetrakis(triphenylphosphine)palladium were added sequentially. The mixture was stirred at 85°C for 5 h under argon protection. TLC monitoring (DCM:MeOH = 30:1) showed the reaction was complete. The mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure, and separated by thin-layer chromatography (DCM:MeOH = 30:1) to give a white solid in 45% yield. ¹H NMR (600 MHz, DMSO-d6) δ 8.38 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 8.04–8.02 (m, 1H), 7.85 (d, J = 8.5 Hz, 3H), 7.63 (d, J = 7.6 Hz, 1H), 7.61–7.58 (m, 3H), 7.34–7.30 (m, 1H), 7.27 (t) ,J=9.3Hz,1H),6.96(dt,J=8.5,4.2Hz,1H),6.83(d,J=7.6Hz,1H),6.16(s,1H),6.05 –6.02(m,1H),4.97(d,J=14.6Hz,1H),4.10(d,J=14.5Hz,1H),1.14(d,J=7.2Hz,3H).

[0237] Following the method of Example 27, Examples 27-38 were prepared using the corresponding raw materials.

[0238] Example 28: 6-(4-chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydrophthalazin-1-one

[0239] 1H NMR(600MHz,DMSO-d6)δ8.65(s,1H),8.40–8.37(m,2H),8.23(d,J=10.4Hz,2 H),7.91–7.89(m,2H),7.65–7.63(m,2H),7.56(s,1H),7.34(q,J=8.2Hz,1H), 7.24–7.20(m,1H),6.93(td,J=8.4,2.6Hz,1H),5.95(s,1H),4.94(d,J=14.5 Hz, 1H), 4.32 (d, J = 14.4Hz, 1H), 3.17 (d, J = 5.2Hz, 1H), 1.23 (d, J = 5.7Hz, 3H).

[0240] Example 29: 7-(4-chlorophenyl)-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-3,4-dihydroquinazolin-4-one

[0241] 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),8.14(s,1H),8.04(d,J=8.5Hz,1H),7.89(d,J=1. 9Hz,1H),7.87(s,1H),7.69(dd,J=8.5,2.0Hz,1H),7.64–7.61(m,3H),7.58–7.54(m,2 H),7.22–7.18(m,1H),7.06(td,J=8.5,6.5Hz,1H),6.94(td,J=8.5,2.6Hz,1H),4.75( d,J=14.8Hz,1H),4.66(d,J=14.8Hz,1H),3.24(q,J=5.5Hz,1H),1.59(d,J=5.6Hz,3H).

[0242] Example 30: 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydroisoquinoline-6-yl}benzyl nitrile

[0243] 1H NMR (600MHz, DMSO-d6) δ8.42(d,J=8.4Hz,1H),8.24(s,1H),8.12(d,J=1.9Hz,1H),8.02(d,J=7.0Hz, 2H),7.91(dd,J=8.4,1.9Hz,1H),7.66(d,J=7.5Hz,1H),7.64–7.62(m,1H),7.61(s,1H),7.35–7.31( m,1H),7.30–7.26(m,1H),6.97(dt,J=8.4,4.1Hz,1H),6.85(d,J=7.6Hz,1H),6.18(s,1H),6.05(d,J =7.2Hz,1H),4.99(d,J=14.6Hz,1H),4.13–4.10(m,1H),3.19(d,J=5.2Hz,1H),1.15(d,J=7.2Hz,3H).

[0244] Example 31: 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydrophthalazine-6-yl}benzyl nitrile

[0245] 1H NMR(600MHz, Methanol-d4)δ8.29(s,1H),7.84(s,1H),7.66–7.64(m,2H),7.64–7.62(m,2H),7.57–7.53(m,3H),7.06(td,J=8.5,6.4Hz,1H),6.92(ddd ,J=10.6,9.0,2.5Hz,1H),6.82–6.78(m,1H),4.90(d,J=14.9Hz,1H),4.61( d,J=14.9Hz,1H),3.43(s,1H),3.20(q,J=5.6Hz,1H),1.63(d,J=5.6Hz,3H).

[0246] Example 32: 4-{3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzyl nitrile

[0247] 1H NMR (600MHz, DMSO-d6) δ8.48(s,1H),8.35(d,J=8.3Hz,1H),8.22(s,1H),8.10(d,J=1 .9Hz,1H),8.08–8.06(m,2H),8.02–8.00(m,2H),7.98(dd,J=8.3,2.0Hz,1H),7.58(s ,1H),7.34–7.29(m,2H),6.97(td,J=8.4,2.6Hz,1H),6.70(d,J=8.4Hz,1H),5.90(q, J=7.4Hz,1H),4.87(d,J=14.6Hz,1H),4.23(d,J=14.5Hz,1H),1.23(d,J=7.2Hz,3H).

[0248] Example 33: (2R,3R)-3-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0249] 1H NMR(600MHz,DMSO-d6)δ8.27(s,1H),7.68(s,1H),7.66(s,1H),7.66(s,1H),7.50(s,1H),7.49(s,1H ),7.42(d,J=7.2Hz,2H),7.35(d,J=6.9Hz,1H),7.17(d,J=8.0Hz,1H),7.16–7.11(m,1H),6.95–6.91( m,1H),5.57(s,1H),4.83(d,J=2.6Hz,2H),4.01(d,J=15.1Hz,1H),3.80(d,J=15.2Hz,1H),3.27–3.2 3(m,1H),3.06–3.01(m,1H),2.87(d,J=16.0Hz,1H),2.61(s,1H),1.23(s,1H),0.86(d,J=6.9Hz,3H).

[0250] Example 34: (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol

[0251] 1H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.87(d,J=8.1Hz,2H),7.80(d,J=8.2Hz,2H),7.66(s,1H),7.50(d,J= 8.3Hz,2H),7.36(d,J=7.0Hz,1H),7.21(d,J=7.8Hz,1H),7.15(t,J=9.4Hz,1H),6.93(dt,J=8.5,4.3Hz,1H ),5.58(s,1H),4.84(d,J=3.0Hz,2H),4.03(dd,J=11.2,3.9Hz,1H),3.82(d,J=15.3Hz,1H),3.36(d,J=6.7 Hz,1H),3.28–3.25(m,1H),3.08–3.03(m,1H),2.90(d,J=16.0Hz,1H),2.63(s,1H),0.87(d,J=6.9Hz,3H).

[0252] Example 35: (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol

[0253] 1H NMR (600MHz, DMSO-d6) δ8.28 (s, 1H), 7.76 (d, J = 8.7Hz, 2H), 7.66 (s1H), 7.43 (d, J = 6.8Hz, 4H), 7.3 6(d,J=7.1Hz,1H),7.18(d,J=8.4Hz,1H),7.16–7.12(m,1H),6.93(dt,J=8.5,4.3Hz,1H),5.58(s,1 H),4.84(d,J=3.1Hz,2H),4.02(d,J=15.1Hz,1H),3.81(d,J=15.3Hz,1H),3.35(d,J=6.8Hz,1H),3. 28–3.23(m,1H),3.04(d,J=8.4Hz,1H),2.88(d,J=15.7Hz,1H),2.62(s,1H),0.87(d,J=6.8Hz,3H).

[0254] Example 36: 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile

[0255] 1H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.90(d,J=8.4Hz,2H),7.86(d,J=8.4Hz,2H),7.68(s,1H),7.50( d,J=8.4Hz,2H),7.40–7.35(m,1H),7.21(d,J=7.8Hz,1H),7.14(ddd,J=11.7,9.1,2.4Hz,1H),6.95–6. 92(m,1H),5.60(s,1H),4.85(s,2H),4.03(d,J=15.3Hz,1H),3.82(d,J=15.4Hz,1H),3.35(q,J=6.9Hz, 1H),3.29–3.23(m,1H),3.08–3.03(m,1H),2.89(d,J=16.0Hz,1H),2.62(s,1H),0.87(d,J=6.9Hz,3H).

[0256] Example 37: (2R,3R)-3-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0257] 1H NMR(600MHz,Chloroform-d)δ8.01(s,1H),7.80(s,1H),7.52–7.48(m,1H),7.35(t,J=8.3Hz,1H),7.2 9(s,1H),7.24(d,J=2.0Hz,1H),7.18(t,J=8.5Hz,1H),6.98(d,J=119.2Hz,1H),6.81–6.75(m,2H),5. 35(t,J=4.8Hz,1H),4.94–4.83(m,2H),3.96(dd,J=58.0,14.9Hz,1H),3.63(dd,J=39.7,19.8Hz,1H), 3.12(s,2H),2.93(d,J=60.2Hz,2H),2.64–2.53(m,1H),2.01(d,J=6.5Hz,1H),0.88(t,J=6.8Hz,3H).

[0258] Example 38: (2R,3R)-3-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol

[0259] 1H NMR (600MHz, DMSO-d6) δ8.27(s,1H),7.73(dd,J=11.0,2.0Hz,1H),7.66(s,1H),7.64(d,J=8.1Hz,1H),7.54(dd ,J=8.4,1.8Hz,1H),7.49–7.47(m,2H),7.35(d,J=7.0Hz,1H),7.18(d,J=8.0Hz,1H),7.15(td,J=9.2,4.5Hz,1H ),6.95–6.92(m,1H),5.57(s,1H),4.84–4.82(m,2H),4.01(d,J=15.2Hz,1H),3.81(d,J=15.3Hz,1H),3.35(d,J =6.9Hz,1H),3.28–3.23(m,1H),3.06–3.01(m,1H),2.88(d,J=16.2Hz,1H),2.62(s,1H),0.86(d,J=6.9Hz,3H).

[0260] The preparation routes for Examples 39 and 43 are shown below:

[0261] The specific synthesis steps are as follows:

[0262] Synthesis of 1-(2,4-difluorophenyl)-2-(1H-tetrazol-1-yl)ethyl-1-one (12)

[0263] Tetrazazole (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 75% yield.

[0264] Synthesis of 1-{[2-(2,4-difluorophenyl)ethyleneoxy-2-yl]methyl}-1H-tetrazole (13)

[0265] Trimethyl sulfoxide (28.29 g, 0.13 mol) was dissolved in NaOH aqueous solution and reacted at room temperature for 2 h. Then, intermediate 12 (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 60 °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 65% yield.

[0266] Synthesis of 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (15)

[0267] Intermediate 14 (10.00 g, 0.080 mol), N-Boc-piperazine (16.57 g, 0.089 mol), and potassium carbonate (22.11 g, 0.16 mol) were added to an N-methylpyrrolidone solution and reacted at 135 °C for 18 h. TLC monitoring (PE:EA = 10:1) showed complete reaction of the starting materials. The reaction solution was added to 300 mL of water, resulting in the precipitation of a brownish-yellow solid. The brownish-yellow solid was filtered and separated by column chromatography to obtain a white solid, with a yield of 68%.

[0268] Synthesis of 4-(4-{[(methyl-d3)amino]methyl}phenyl)piperazine-1-carboxylic acid tert-butyl ester (16)

[0269] Intermediate 15 (10.00 g, 0.034 mol) and methyl-d3-amine hydrochloride (2.89 g, 0.041 mol) were added to a methanol solution and reacted at room temperature for 30 min. Then, sodium borohydride (1.95 g, 0.051 mol) was added as a reducing agent, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 20:1) indicated complete reaction of the starting material. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a yellow oily substance in 87% yield.

[0270] Synthesis of 4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (17)

[0271] Intermediate 13 (10.00 g, 0.042 mol), intermediate 16 (14.81 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 obtain a white solid in 78% yield.

[0272] Synthesis of 2-(2,4-difluorophenyl)-1-{(methyl-d3)[4-(piperazin-1-yl)benzyl]amino}-3-(1H-tetrazol-1-yl)prop-2-ol (18)

[0273] Intermediate 17 (10.00 g, 0.018 mol) was dissolved in 20 mL of a saturated solution of hydrogen chloride in ethyl acetate, and the reaction was carried out at room temperature for 2 h. TLC monitoring (DCM:MeOH = 10:1) showed that the reaction was complete. The solution was concentrated under reduced pressure to give a white solid, which could be used directly in the next step without purification, with a yield of 95%.

[0274] Preparation of 1-({4-[4-(3-bromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol (Example 39)

[0275] Intermediate 18 (0.050 g, 0.11 mmol) was dissolved in 5 mL of acetonitrile, and benzyl bromide (0.021 g, 0.12 mmol) and triethylamine (0.022 g, 0.22 mmol) were added. The mixture was stirred at room temperature for 1 h. TLC monitoring (DCM:MeOH = 10:1) confirmed the reaction was complete. The mixture was concentrated under reduced pressure and separated by thin-layer chromatography (DCM:MeOH = 30:1) to give a white solid in 75% yield. 1HNMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.8Hz, 1H), 7.34 (d, J = 7.8Hz, 1H), 7. 30(t,J=7.8Hz,2H),7.18(td,J=9.1,4.5Hz,1H),6.96(d,J=8.4Hz,2H),6.94(dd,J=8.4,2.6Hz,1H),6 .81(d,J=8.6Hz,2H),5.91(s,1H),4.80(s,2H),3.52(s,2H),3.42(d,J=13.0Hz,1H),3.37(s,1H),3.1 0(t,J=4.9Hz,4H),2.94(dd,J=13.7,1.6Hz,1H),2.83(d,J=13.8Hz,1H),2.51(dd,J=3.9,2.0Hz,4H).

[0276] Following the method of Example 39, Examples 40-42 were prepared using the corresponding raw materials.

[0277] Example 40: 1-({4-[4-(3-bromo-5-chlorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0278] 1H NMR (600MHz, DMSO-d6) δ9.10(s,1H),7.62(s,1H),7.52(d,J=1.6Hz,1H),7.43(t,J=1.6Hz,1H ),7.32–7.29(m,1H),7.21–7.17(m,1H),6.96(d,J=8.6Hz,2H),6.94(dd,J=8.5,2.6Hz,1H),6. 82–6.80(m,2H),5.92(s,1H),4.80(s,2H),3.54(s,2H),3.42(d,J=13.1Hz,1H),3.37(s,1H), 3.10(t,J=4.7Hz,4H),2.95–2.92(m,1H),2.83(d,J=13.8Hz,1H),2.49(dd,J=3.9,2.0Hz,4H).

[0279] Example 41: 1-({4-[4-(3-bromo-5-fluorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0280] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.43(s,1H),7.40(s,1H),7.31(dd,J=9.1,6.7Hz, 1H),7.22–7.17(m,2H),6.97(d,J=8.4Hz,2H),6.94(dd,J=8.4,2.6Hz,1H),6.81(d,J=8. 3Hz,2H),5.92(s,1H),4.80(s,2H),3.55(s,2H),3.43(d,J=12.9Hz,1H),3.37(s,1H),3 .11(t,J=4.8Hz,4H),2.94(d,J=13.8Hz,1H),2.83(d,J=13.8Hz,1H),2.52–2.50(m,4H).

[0281] Example 42: 1-({4-[4-(3,5-dibromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0282] 1H NMR (600MHz, DMSO-d6) δ9.11 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 1.8Hz2H), 7.33–7.29 (m, 1H) ,7.18(td,J=9.1,4.5Hz,1H),6.97(d,J=8.4Hz,2H),6.94(dd,J=8.5,2.6Hz,1H),6.81(d,J =8.4Hz,2H),5.92(s,1H),4.80(s,2H),3.55(s,2H),3.43(d,J=12.9Hz,1H),3.37(s,1H), 3.11–3.08(m,4H),2.96–2.92(m,1H),2.83(d,J=13.8Hz,1H).2.49(dd,J=3.9,2.0Hz,4H).

[0283] Preparation of (3-bromophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl} methyl ketone (Example 43)

[0284] 3-Bromobenzoic acid (0.050 g, 0.11 mmol) was dissolved in 5 mL of N,N-dimethylformamide. Benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate and 4-dimethylaminopyridine were added sequentially. The mixture was stirred at room temperature for 30 min, then intermediate 18 was added, and the mixture was stirred at room temperature for 4 h. TLC monitoring (DCM:MeOH = 20:1) indicated the reaction 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 65% yield. 1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.67(s,1H),7.64(s,1H),7.46–7.41(m,2H),7.33( td,J=8.9,6.6Hz,1H),7.19(ddd,J=11.8,9.0,2.7Hz,1H),7.00(d,J=8.1Hz,2H),6.95(td ,J=8.5,2.6Hz,1H),6.85(d,J=8.2Hz,2H),5.94(s,1H),4.82(s,2H),3.75(s,2H),3.41(d d,J=40.7,9.0Hz,4H),3.21–3.07(m,4H),2.96(d,J=13.8Hz,1H),2.84(d,J=13.8Hz,1H).

[0285] Example 44 was prepared using the corresponding raw materials according to the method of Example 43.

[0286] Example 44: (3-Bromo-5-chlorophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl}methyl ketone

[0287] 1H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.84(d,J=2.0Hz,1H),7.64(d,J=1.6Hz,1H),7.56(d,J=1.7H z,1H),7.32(td,J=8.9,6.6Hz,1H),7.19(ddd,J=11.9,9.0,2.6Hz,1H),6.99(d,J=8.2Hz,2H),6.95 (dt,J=8.5,4.2Hz,1H),6.85(d,J=8.2Hz,2H),5.93(s,1H),4.81(s,2H),3.74(s,2H),3.44(d,J=1 3.2Hz,2H),3.38(s,2H),3.20(s,2H),3.10(s,2H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.7Hz,1H).

[0288] The preparation route of Example 45 is shown below:

[0289] The specific synthesis steps are as follows:

[0290] Synthesis of (E)-4-(4-nitrostyryl)benzaldehyde (22)

[0291] 4-Vinylbenzaldehyde (0.50 g, 3.79 mmol), 4-nitrobenzene (1.41 g, 5.68 mmol), and potassium carbonate (1.57 g, 11.36 mmol) were added to 20 mL of toluene. Under argon protection, palladium acetate and triphenylphosphine were added sequentially, and the reaction was carried out at 100 °C for 10 h. TLC monitoring (DCM:MeOH = 50:1) showed that the starting material reaction was complete. The organic phase was concentrated and separated by column chromatography to obtain a white solid with a yield of 65%.

[0292] Synthesis of (E)-N-methyl-4-(4-nitrostyryl)benzamide (23)

[0293] Intermediate 22 (0.20 g, 0.79 mmol) and methylamine hydrochloride (0.08 g, 1.18 mmol) were added to a methanol solution and reacted at room temperature for 30 min. Then, sodium borohydride (0.06 g, 1.57 mmol) was added as a reducing agent, and the reaction was continued at room temperature for 1 h. TLC monitoring (DCM:MeOH = 20:1) indicated complete reaction of the starting material. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a yellow oily substance in 87% yield.

[0294] Preparation of (E)-2-(2,4-difluorophenyl)-1-{methyl[4-(4-nitrostyryl)benzyl]amino}-3-(1H-tetrazol-1-yl)prop-2-ol (Example 45)

[0295] Intermediate 13 (0.15 g, 0.65 mmol), intermediate 23 (0.16 g, 0.59 mmol), and triethylamine (0.18 g, 1.79 mmol) 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 58% yield. 1HNMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 7.53 (d, J = 7.7Hz, 2H), 7.44 (d, J = 7. 7Hz,2H),7.31(d,J=7.4Hz,2H),7.22(d,J=7.1Hz,2H),7.16(s,2H),7.05(d, J=7.8Hz,2H),6.90(s,1H),6.00(s,1H),4.78(s,2H),3.52(d,J=13.2Hz,1H ),3.39(d,J=13.0Hz,1H),2.95(s,1H),2.80(d,J=13.6Hz,1H),2.08(s,3H).

[0296] Following the method of Example 45, Examples 46-52 were prepared using the corresponding raw materials.

[0297] Example 46: (E)-2-(2,4-difluorophenyl)-1-[methyl(4-styrylbenzyl)amino]-3-(1H-tetrazol-1-yl)prop-2-ol

[0298] 1H NMR (600MHz, DMSO-d6) δ9.12(s,1H),7.59(d,J=7.6Hz,2H),7.50(d,J=7.8Hz,2H),7.38(t, J=7.6Hz,2H),7.34(d,J=7.9Hz,1H),7.27(d,J=7.3Hz,1H),7.23(s,2H),7.20(d,J=9.6Hz,1 H),7.13(d,J=7.7Hz,2H),6.96(d,J=8.5Hz,1H),6.00(s,1H),4.84(s,2H),3.57(d,J=13.3H z,1H),3.46(d,J=13.2Hz,1H),3.01(d,J=14.0Hz,1H),2.87(d,J=13.5Hz,1H),2.15(s,3H).

[0299] Example 47: (E)-2-(2,4-difluorophenyl)-1-{[4-(4-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol

[0300] 1H NMR (600MHz, DMSO-d6) δ9.11 (s, 1H), 7.69–7.57 (m, 2H), 7.48 (d, J = 8.1Hz, 2H), 7.35 (dq,J=25.3,7.8Hz,2H),7.22(s,1H),7.21(s,2H),7.19(d,J=5.5Hz,1H),7.12(d,J= 7.7Hz,2H),6.96(t,J=7.8Hz,1H),5.98(s,1H),4.83(s,2H),3.57(d,J=13.2Hz,1H), 3.46(d,J=13.2Hz,1H), 3.00(d,J=14.0Hz,1H), 2.86(d,J=13.7Hz,1H), 2.14(s,3H).

[0301] Example 48: (E)-2-(2,4-difluorophenyl)-1-{[4-(4-chlorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol

[0302] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.62(d,J=8.1Hz,2H),7.50(d,J=7.8Hz,2H),7.4 3(d,J=8.2Hz,1H),7.40–7.30(m,2H),7.25–7.22(m,2H),7.20(d,J=9.5Hz,1H),7.12(d ,J=7.8Hz,2H),6.96(t,J=7.6Hz,1H),5.98(s,1H),4.83(s,2H),3.57(d,J=13.3Hz,1H ),3.46(d,J=13.4Hz,1H),3.00(d,J=13.9Hz,1H),2.86(d,J=13.8Hz,1H),2.14(s,3H).

[0303] Example 49: (E)-2-(2,4-difluorophenyl)-1-{[4-(2-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol

[0304] 1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.52(d,J=8.0Hz,2H),7.39–7.35(m,1H),7.33(s,1H) ),7.29(d,J=15.0Hz,2H),7.25(d,J=3.0Hz,1H),7.23(d,J=3.0Hz,2H),7.21(d,J=4.7Hz,1 H),7.14(d,J=8.2Hz,2H),6.98–6.95(m,1H),5.99(s,1H),4.83(s,2H),3.58(d,J=13.4Hz ,1H),3.47(d,J=13.5Hz,1H),3.01(d,J=13.9Hz,1H),2.87(d,J=13.7Hz,1H),2.15(s,3H).

[0305] Example 50: (E)-2-(2,4-difluorophenyl)-1-{[4-(3-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol

[0306] 1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.50(d,J=7.7Hz,2H),7.44–7.39(m,2H),7.36(dd,J=14 .3,7.2Hz,1H),7.31(d,J=16.6Hz,2H),7.22(d,J=4.8Hz,1H),7.21–7.17(m,1H),7.14(d,J=7 .8Hz,2H),7.10(d,J=8.7Hz,1H),6.98–6.95(m,1H),5.99(s,1H),4.83(s,2H),3.58(d,J=13. 5Hz,1H),3.47(d,J=13.2Hz,1H),3.01(d,J=13.7Hz,1H),2.87(d,J=13.7Hz,1H),2.15(s,3H).

[0307] Example 51: (E)-1-{[4-(4-bromostyryl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0308] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.56(s,4H),7.50(d,J=7.8Hz,2H),7.34–7 .30(m,1H),7.27(d,J=16.4Hz,1H),7.23–7.19(m,2H),7.12(d,J=7.8Hz,2H),6. 96(td,J=8.5,2.7Hz,1H),5.98(s,1H),4.82(s,2H),3.57(d,J=13.2Hz,1H),3.4 6(d,J=13.3Hz,1H),3.00(d,J=13.9Hz,1H),2.86(d,J=13.7Hz,1H),2.14(s,3H).

[0309] Example 52: (E)-2-(2,4-difluorophenyl)-1-{[4-(4-iodostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol

[0310] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.73(d,J=8.1Hz,1H),7.60(s,1H),7.50(d,J=7.8Hz,2H),7 .41(s,1H),7.37(s,1H),7.32(d,J=7.6Hz,1H),7.28–7.25(m,1H),7.22(d,J=6.8Hz,2H),7.20(d ,J=11.7Hz,1H),7.12(d,J=7.8Hz,2H),6.98–6.94(m,1H),5.98(s,1H),4.83(s,2H),3.57(d,J=1 3.3Hz, 1H), 3.46 (d, J = 13.3Hz, 1H), 3.00 (d, J = 13.9Hz, 1H), 2.86 (d, J = 13.5Hz, 1H), 2.14 (s, 3H).

[0311] The preparation route of Example 53 is shown below:

[0312] The specific synthesis steps are as follows:

[0313] Synthesis of 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (26)

[0314] Intermediate 25 (5.00 g, 0.028 mol), di-tert-butyl dicarbonate (7.35 g, 0.034 mol), and triethylamine (8.52 g, 0.084 mol) were added to a methanol solution at room temperature and reacted for 1 h at room temperature. 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 solid in 98% yield.

[0315] Synthesis of 4-[4-(benzyloxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (27)

[0316] Intermediate 26 (6.00 g, 0.022 mol), benzyl bromide (3.68 g, 0.022 mol), and potassium carbonate (2.98 g, 0.022 mol) were added to an N,N-dimethylformamide solution at room temperature and reacted at 50 °C for 12 h. TLC monitoring (DCM:MeOH = 30:1) showed complete reaction of the starting materials. The reaction solution was added to ice water, and a yellow solid precipitated. This solid was filtered and separated by column chromatography to obtain a white solid, with a yield of 54%.

[0317] Synthesis of 1-[4-(benzyloxy)phenyl]piperazine (28)

[0318] Intermediate 27 (4.00 g, 0.011 mol) was added to a trifluoroacetic acid solution at room temperature and reacted for 2 h at room temperature. TLC monitoring (PE:EA = 4:1) showed the reaction was complete. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain a white solid in 93% yield.

[0319] Synthesis of 4-{4-[4-(benzyloxy)phenyl]piperazin-1-yl}benzaldehyde (29)

[0320] Intermediate 28 (2.00 g, 7.4 mmol), p-fluorobenzaldehyde (1.84 g, 8.9 mmol), and potassium carbonate (1.49 g, 0.011 mol) were added to an N,N-dimethylformamide solution at room temperature and refluxed for 3 h. TLC monitoring (DCM:MeOH = 15:1) indicated complete reaction of the starting materials. Upon addition of the reaction solution to ice water, a pale yellow solid precipitated. This solid was filtered and separated by column chromatography to obtain a white solid in 67% yield.

[0321] Synthesis of 1-(4-{4-[4-(benzyloxy)phenyl]piperazin-1-yl}phenyl)-N-methylmethylamine (30)

[0322] Intermediate 29 (1.00 g, 5.4 mmol) and aqueous methylamine (1.2 mL, 0.011 mol) were added to a methanol solution and reacted at room temperature for 1 h. Then, sodium borohydride (0.42 g, 0.011 mol) was added as a reducing agent, and the reaction was continued at room temperature for another 1 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 obtain a white powdery solid in 89% yield.

[0323] Synthesis of 1-[(4-{4-[4-(benzyloxy)phenyl]piperazin-1-yl}benzyl)(methyl)amino]-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol (31)

[0324] Intermediate 30 (1.00 g, 2.6 mmol), intermediate 13 (0.62 g, 2.6 mmol), and triethylamine (0.78 g, 7.7 mmol) 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 solution was concentrated under reduced pressure and separated by column chromatography to give a white solid in 62.5% yield. 1H NMR (600MHz, DMSO-d6) δ9.11(s,1H),7.44(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H),7.32(t,J= 7.6Hz,2H),7.20(t,J=9.3Hz,1H),7.00(d,J=8.0Hz,2H),6.94(q,J=8.8Hz,5H),6.89(d,J=8.1 Hz,2H),5.93(s,1H),5.04(s,2H),4.81(s,2H),3.45(d,J=13.0Hz,1H),3.39(s,1H),3.26–3. 21(m,4H),3.14(t,J=5.1Hz,4H),2.96(d,J=13.8Hz,1H),2.84(d,J=13.8Hz,1H),2.11(s,3H).

[0325] Synthesis of 4-{4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl)amino}methyl)phenyl]piperazin-1-yl}phenol (32)

[0326] Intermediate 31 (1.00 g, 1.5 mmol) was added to anhydrous dichloromethane solution at room temperature. Boron tribromide was added dropwise at -20 °C. After the addition was complete, the mixture was transferred to room temperature and the reaction was allowed to proceed for 2 h. TLC monitoring (DCM:MeOH = 30:1) showed that the reaction proceeded completely. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The resulting product was separated by column chromatography to give a white solid in 40.3% yield.

[0327] Preparation of 2-(2,4-difluorophenyl)-1-{[4-(4-{4-[(4-fluorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol (Example 53)

[0328] Intermediate 32 (80 mg, 0.15 mmol), 4-fluorobenzyl bromide (34 mg, 0.18 mmol), and potassium carbonate (31 mg, 0.22 mmol) were added to an N,N-dimethylformamide solution at room temperature and reacted at 50 °C for 6 h. TLC monitoring (DCM:MeOH = 30:1) indicated complete reaction of the starting materials. Upon addition of the reaction solution to ice water, a yellow solid precipitated. This solid was filtered and separated by preparative thin-layer chromatography to obtain a white solid, with a yield of 52%. 1H NMR(400MHz, DMSO-d6)δ9.10(s,1H),7.48(dd,J=8.4,5.6Hz,2H),7.31(d,J=8.1Hz,1H) ,7.24–7.20(m,2H),7.19(s,2H),6.99(d,J=8.3Hz,2H),6.93(d,J=5.1Hz,4H),6.88(d,J =8.7Hz,2H),5.91(s,1H),5.02(s,2H),4.80(s,2H),3.45(d,J=13.0Hz,1H),3.39(s,1H) ,3.23(s,4H),3.15(s,4H),2.96(d,J=13.7Hz,1H),2.84(d,J=13.6Hz,1H),2.10(s,3H).

[0329] Example 54: 1-{[4-(4-{4-[(4-chlorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol

[0330] 1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.45(s,5H),7.32(d,J=8.1Hz,1H),7.21(d,J=10.4 Hz,1H),7.00(d,J=7.7Hz,2H),6.95(d,J=8.8Hz,2H),6.92(d,J=8.3Hz,2H),6.89(d,J=8 .3Hz,2H),5.93(s,1H),5.04(s,2H),4.81(s,2H),3.45(d,J=13.0Hz,1H),3.25–3.22(m, 4H), 3.15 (d, J = 5.2Hz, 4H), 2.96 (d, J = 13.8Hz, 1H), 2.84 (d, J = 13.8Hz, 1H), 2.11 (s, 3H).

[0331] Example 55: 4-({4-[4-(4-{[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl)amino}methyl)phenyl)piperazin-1-yl]phenoxy}methyl)benzylnitrile)

[0332] 1H NMR(600MHz,DMSO-d6)δ9.10(s,1H),7.81(d,J=8.0Hz,2H),7.55(d,J=7.9Hz,2H),7.32–7.29 (m,1H),7.19(t,J=2.9Hz,1H),7.09–7.07(m,2H),6.96–6.94(m,3H),6.90–6.88(m,2H),6.80( d,J=8.4Hz,2H),5.94(s,1H),4.79(s,2H),3.63(s,2H),3.48(s,1H),3.42(d,J=13.0Hz,1H),3 .10(t,J=5.0Hz,4H),2.95(d,J=13.8Hz,1H),2.85(s,1H),2.53(d,J=5.0Hz,4H),2.13(s,3H).

[0333] Example 56: 2-(2,4-difluorophenyl)-1-(methyl{4-[4-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)piperazin-1-yl]benzyl}amino)-3-(1H-tetrazol-1-yl)prop-2-ol

[0334] 1H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 7.75 (d, J = 8.0Hz, 2H), 7.65 (d, J = 8.0Hz, 2H), 7.32–7. 29(m,1H),7.20(t,J=2.7Hz,1H),6.99(d,J=8.1Hz,2H),6.94(d,J=6.4Hz,5H),6.88(d,J=8 .1Hz,2H),5.92(s,1H),5.16(s,2H),4.80(s,2H),3.45(d,J=13.0Hz,1H),3.24–3.21(m,4H ),3.14(dd,J=6.8,3.6Hz,4H),2.95(d,J=13.8Hz,1H),2.84(d,J=13.7Hz,1H),2.10(s,3H).

[0335] Pharmacodynamic studies of some products of this invention:

[0336] Experimental methods:

[0337] Refer to the standard in vitro antibacterial test methods (Reference method for broth dilution antifungal susceptibility testing of yeasts and filamentous fungi; Approved Standard M27-A3 and M38-A2).

[0338] Experimental materials and methods:

[0339] (1) Experimental strains: The following seven common human pathogenic standard fungal strains were used as screening targets in this experiment. Each human pathogenic standard fungal strain was provided by Shenyang Pharmaceutical University.

[0340] Table 1. Strains used in the experiment and their numbers.

[0341] (2) Experimental methods:

[0342] 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.

[0343] 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 amount of single colonies 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 diluted with RPMI-1640 medium to a final concentration of 1 x 10⁶ cells / mL.

[0344] 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-80, 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.

[0345] 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. No blank control was set up for the positive control drug; that is, serial dilutions were performed starting from well 1 up to well 10, with test concentrations (μg / mL) ranging from 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, to 0.0625. Based on this, for compounds with superior activity, we further diluted the test concentrations to explore the activity limits of the compounds, specifically by diluting them tenfold, extending the test concentration (μg / mL) range to 3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, 0.025, 0.0125, to 0.00625.

[0346] 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.

[0347] Table 2. Minimum inhibitory concentrations (μg / mL) of the compounds in the examples.

[0348] Table 3. Minimum inhibitory concentrations (μg / mL) of compounds in preferred embodiments.

[0349] The experimental results above show that the compounds of general formulas I and II 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.

[0350] The general formula compounds of 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 practices. 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.

[0351] Example 57: Tablets.

[0352] Example 21: 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.

[0353] Example 58: Capsules.

[0354] Example 21: 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.

[0355] Example 59: Injection.

[0356] Example 21: 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.

[0357] Example 60: Aerosol.

[0358] Example 21: 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.

[0359] Example 61: Suppositories.

[0360] Example 21: 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.

[0361] Example 62: Film-forming agent.

[0362] In Example 21, 10g of compound 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 compound from Example 27 was added to the filtrate and stirred until dissolved. 100 films were then made using a coating machine.

[0363] Example 63: Droplets.

[0364] Example 21: 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.

[0365] Example 64: Topical liniment.

[0366] Example 21: 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.

[0367] Example 65: Ointment.

[0368] Example 21: 10g of compound was finely ground and then mixed with 500g of oily matrix such as petrolatum to obtain the product.

[0369] 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 alcohol derivative containing difluorophenyl structure, characterized by: Derivatives are compounds of Formula I, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; In the formula, MBG is selected from unsubstituted or substituted tetrazolium, triazolium, and pyrazolium, wherein the substituent is C1-4 alkyl or C1-4 alkoxy. M is Ring A is a phenyl group, a 5-7 membered heteroaryl group, a 5-7 membered heterocyclic alkyl group, a 5-7 membered heteroaryl group containing a ketone carbonyl group, a 5-7 membered heterocyclic alkyl group containing a ketone carbonyl group, a five-membered aryl-hexa-aryl group, or a six-membered aryl-hexa-aryl group, wherein the heteroaryl group, heterocyclic alkyl group, ketone carbonyl group, or ketone carbonyl group mentioned contains 1-3 heteroatoms selected from N, O, or S; The B ring is a phenyl group substituted with 1-4 identical or different R1s, an unsubstituted 5-7 membered heteroaryl group or a 5-7 membered heterocyclic alkyl group substituted with 1-4 identical or different R1s, wherein the mentioned heteroaryl group or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O or S. R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4 phenyl or benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy. n is an integer from 1 to 7; m is an integer from 1 to 6; P is an integer from 1 to 4; X is hydrogen, halogen, C1-4 alkyl, or C1-4 haloalkyl; Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group. Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl, carbonyl, or sulfonyl; W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazine group, a methylpiperazine group, or a carbonylpiperazine group; R4 is a halogen, including nitro, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

2. The azole alcohol derivative containing difluorophenyl structure according to claim 1, characterized by: The M is When the derivative is of formula II; The M is When the derivative is shown in formula Ш; The M is at the time, the derivative is represented by formula IV; In the above general formulas, MBG is selected from unsubstituted or substituted tetrazolium, triazolium, and pyrazolium, wherein the substituent is C1-4 alkyl or C1-4 alkoxy. X is hydrogen, halogen, C1-4 alkyl, or C1-4 haloalkyl; Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group. Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl, carbonyl, or sulfonyl; W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazine group, a methylpiperazine group, or a carbonylpiperazine group; R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4 phenyl or benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy. R4 is a halogen, including nitro, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. n is 1, 2, 3, 4, 5, 6, or 7; m is 1, 2, 3, 4, 5, or 6; P is 1, 2, 3, or 4; The carbon atom marked with * is either a chiral carbon atom or a non-chiral carbon atom; Ring A is a phenyl group, a 5-7 membered heteroaryl group, a 5-7 membered heterocyclic alkyl group, a 5-7 membered heteroaryl group containing a ketone carbonyl group, a 5-7 membered heterocyclic alkyl group containing a ketone carbonyl group, a five-membered aryl-hexa-aryl group, or a six-membered aryl-hexa-aryl group, wherein the heteroaryl group, heterocyclic alkyl group, ketone carbonyl group, or ketone carbonyl group mentioned contains 1-3 heteroatoms selected from N, O, or S; The B ring is a phenyl group substituted with 1-4 identical or different R1 atoms, an unsubstituted 5-7 membered heteroaryl group or a 5-7 membered heterocyclic alkyl group substituted with 1-4 identical or different R1 atoms, wherein the mentioned heteroaryl group or heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O or S.

3. The azole alcohol derivative containing difluorophenyl structure according to claim 2, characterized by: In the general formula of the derivatives MBG is selected from the following structures: X is hydrogen, a C1-4 alkyl group, or a C1-4 haloalkyl group; Y is hydrogen, a C1-4 alkyl group, or a C1-4 deuterated alkyl group. Z is hydrogen, C1-4 alkyl, C1-4 haloalkyl or carbonyl; W is an N, O, or S atom, a C2-4 alkenyl group, a phenyl group, a piperazine group, a methylpiperazine group, or a carbonylpiperazine group; Ring A can be a benzene ring, piperidine ring, pyrrole ring, pyridine ring, pyridinone ring, pyridazinone ring, pyrimidinone ring, oxazole ring, thiophene ring, furan ring, or thiazole ring; Ring B is an unsubstituted phenyl group or a 5-7 membered heteroaryl group or a 5-7 membered heterocyclic alkyl group substituted with 1-4 identical or different R1 groups, wherein... The mentioned heteroaryl and heterocycloalkyl groups contain 1-3 heteroatoms selected from N, O or S; R1 is a halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R2 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one identical or different hydroxyl, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one identical or different R4, benzyloxy, benzyloxy, C1-C6 alkoxy, unsubstituted or free, salt-forming, esterified and amidated carboxyl groups; R3 is hydrogen, halogen, nitro, amino, cyano, aldehyde, C2-C6 alkenyl, C1-C6 alkyl acyl, C1-C3 alkylene dioxy, unsubstituted or substituted with at least one of the same or different hydroxyl groups, amino or halogenated C1-C6 alkyl, unsubstituted or substituted with at least one halogen phenyl, benzyloxy, C1-C6 alkoxy. R4 is a halogen, and can be nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl, or isopentyl. n is 1, 2, 3, 4, 5, 6, or 7; m is 1, 2, 3, 4, 5, or 6; P is 1, 2, 3, or 4; The carbon atom marked with * is either a chiral carbon atom or a non-chiral carbon atom.

4. The azole alcohol derivative containing difluorophenyl structure according to claim 3, characterized by: In the derivative formula II MBG is selected from the following structures: X is hydrogen or a C1-4 alkyl group; Ring A can be a piperidine ring, a piperidone ring, a pyridinone ring, a pyridazinone ring, or a pyrimidinone ring; Ring B is a benzene ring; R1 is selected from halogens, C1-C5 alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, benzyloxy, phenyl, amino, or hydroxyl. n is 1, 2, 3, 4, 5, 6, or 7.

5. The azole alcohol derivative containing difluorophenyl structure according to claim 3, characterized by: In the derivative formula Ш W represents an S atom, which can be vinyl, phenyl, piperazinyl, methylpiperazinyl, or carbonylpiperazinyl. R4 is a halogen, and can be nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, tert-pentyl, sec-pentyl, or isopentyl. Y is methyl or deuterated methyl; Z represents hydrogen or carbonyl; R2 is selected from halogens, C1-C5 alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, formyl, acetyl, methoxy, phenyl, amino or hydroxyl, unsubstituted or benzyloxy substituted with at least one of the same or different R4; P is 1, 2, 3, or 4; m can be 1, 2, 3, 4, 5, or 6.

6. The azole alcohol derivative containing difluorophenyl structure according to any one of claims 1 to 5, characterized by: The derivative is a compound, its stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. 2-(2,4-Difluorophenyl)-1-(6-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-(6-bromo-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-[6-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-[6-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-[6-(2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-[6-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-[6-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-[6-(4-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-{6-[4-(prop-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-[6-(4-tert-butylphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-[6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol; 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol; 2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}prop-2-ol; 4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile; 1-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; 1-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)prop-2-ol; (2R,3R)-3-[6-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol; (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-{6-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-2-yl}but-2-ol; 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2,3,4-tetrahydroisoquinoline-6-yl}benzylnitrile; (2R,3R)-3-[6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol; (2R,3R)-3-[6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol; 6-(4-Chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydroisoquinoline-1-one; 6-(4-chlorophenyl)-2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1,2-dihydrophthalazin-1-one; 7-(4-Chlorophenyl)-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-3,4-dihydroquinazolin-4-one; 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydroisoquinoline-6-yl}benzyl nitrile; 4-{2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-1-oxo-1,2-dihydrophthalazine-6-yl}benzylnitrile; 4-{3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzyl nitrile; 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydroisoquinoline-1-one; 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one; 7-(4-Chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-3,4-dihydroquinazolin-4-one; 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazo-1-yl)propyl]-1,2-dihydroisoquinoline-1-one; 6-(4-Chlorophenyl)-2-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-1,2-dihydrophthalazin-1-one; 7-(4-Chlorophenyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,3,4-tetrazo-1-yl)propyl]-3,4-dihydroquinazolin-4-one; 1-({4-[4-(3-bromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; 1-({4-[4-(3-bromo-5-chlorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; 1-({4-[4-(3-bromo-5-fluorobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; 1-({4-[4-(3,5-dibromobenzyl)piperazin-1-yl]benzyl}(methyl-d3)amino)-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; (3-Bromophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl}methyl ketone; (3-Bromo-5-chlorophenyl){4-[4-({[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl-d3)amino}methyl)phenyl]piperazin-1-yl}methyl ketone; (E)-2-(2,4-difluorophenyl)-1-{methyl[4-(4-nitrostyryl)benzyl]amino}-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-[methyl(4-styrylbenzyl)amino]-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-{[4-(4-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-{[4-(4-chlorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-{[4-(2-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-{[4-(3-fluorostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-1-{[4-(4-bromostyryl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; (E)-2-(2,4-difluorophenyl)-1-{[4-(4-iodostyryl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; 2-(2,4-Difluorophenyl)-1-{[4-(4-{4-[(4-fluorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-3-(1H-tetrazol-1-yl)prop-2-ol; 1-{[4-(4-{4-[(4-chlorobenzyl)oxy]phenyl}piperazin-1-yl)benzyl](methyl)amino}-2-(2,4-difluorophenyl)-3-(1H-tetrazol-1-yl)prop-2-ol; 4-({4-[4-(4-{[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-tetrazol-1-yl)propyl](methyl)amino}methyl)phenyl)piperazin-1-yl]phenoxy}methyl)benzylnitrile; 2-(2,4-Difluorophenyl)-1-(methyl{4-[4-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)piperazin-1-yl]benzyl}amino)-3-(1H-tetrazol-1-yl)prop-2-ol.

7. A pharmaceutical composition, characterized by: The composition comprises the derivative of general formula I or II as claimed in claim 1, its stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

8. A pharmaceutical preparation, characterized by: The formulation uses the derivative of claim 1 or the composition of claim 7 as the active ingredient.

9. Use of a derivative according to claim 1, a composition according to claim 7, or a pharmaceutical preparation according to claim 8, characterized in that: The use of the derivative of claim 1, the composition of claim 7, or the pharmaceutical preparation of claim 8 in the preparation of remedies for various diseases caused by fungal infections.

10. Use according to claim 9, characterized in that: The fungus is selected from one or more of the following pathogenic fungi: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fullvum*, *Arthrodermagypseum*, *Arthrodermaincurvatum*, *Arthrodermaotae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, *Candida albicans*, and *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, Fonsecaeapedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum *Capsulatum*, *Hortaeawerneckii*, *Issa mesaschenkia orientalis*, *Madurellagrisae*, *Malassezia furfur*fur), Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, 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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