CN111848600B - 2,4, 4-trisubstituted dihydrooxazole derivative and application thereof - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and relates to 2,4, 4-trisubstituted dihydro-oxazole derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method thereof and application thereof as drugs for treating various diseases caused by fungal infection. The general formula of the 2,4, 4-trisubstituted dihydro-oxazole derivative and the stereoisomer thereof or the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is shown as (I): wherein, MBG, X, Y, M, R¹As described in the claims and specification.

Description

2,4,4-Tri-substituted dihydrooxazole derivatives and their uses

technical field

The invention belongs to the technical field of drug synthesis, and relates to a class of 2,4,4-trisubstituted dihydrooxazole derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, their preparation methods and their preparations. Use as a medicament for the treatment of various diseases caused by fungal infections.

Background technique

Fungal infection can be divided into superficial fungal infection and deep fungal infection, among which superficial fungal infection is mainly caused by ringworm, such as skin, hair and nail (toe) fungal infection; deep fungal infection is mainly caused by Candida albicans, Cryptophytes Cocci and Aspergillus fumigatus cause infections of deep tissues such as subcutaneous tissue and intima. In the past three decades, with the increasing number of patients with immunodeficiency, the rate of fungal infection has soared, which seriously threatens human health. It is urgent to find new structural types of antifungal drugs.

At present, clinical antifungal drugs can be divided into azole drugs that inhibit ergosterol synthesis according to different mechanisms of action; echinocandicin antifungal drugs that destroy cell walls, polyene drugs that cause cell membrane leakage, and antifungal drugs that act on nucleic acids. Metabolic antifungal drugs. Among them, azoles block the synthesis of ergosterol by inhibiting the activity of lanosterol 14α-demethylase (CYP51), and are the most active and mature targets in the field of antifungal research. Currently clinical azole antifungal drugs are mainly divided into two categories: imidazoles such as Miconazole, Clotrimazole, Ketoconazole; triazoles such as fluconazole ( Fluconazole), Itraconazole (Itraconazole), Voriconazole (Voriconazole) and Posaconazole (Posaconazole). Although azole drugs play an irreplaceable role in clinical practice, these drugs have serious side effects and drug-resistant strains. , urging medicinal chemists to develop antifungal drugs with more structural types, high efficiency and low toxicity, and various modes of administration.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a class of 2,4,4-trisubstituted dihydrooxazole derivatives, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the derivatives in view of the deficiencies of the prior art , and provide the preparation method of the derivative and the use of the derivative; and also provide the pharmaceutical composition containing the 2,4,4-trisubstituted dihydrooxazole derivative. The present invention designs and synthesizes a series of 2,4,4-tri-substituted dihydrooxazole derivatives on the basis of the references. The in vitro antifungal activity test shows that these compounds have strong antifungal properties. It has great research value in the treatment of fungal infections.

In order to achieve the above purpose, the present invention provides 2,4,4-trisubstituted dihydrooxazole derivatives represented by general formula I and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates or pro-forms thereof. medicine:

in:

MBG is substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyridyl; the substituents are: hydrogen, C1-C4 alkane base, C1-C4 alkoxy.

Y is O or S;

X is CH, _CH2 , N, NH, or O;

为单键或双建；

For single-key or double-build;

R ¹ is (C ₁ -C ₅ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -COOR ² , -CON(R ² ) ₂ , 5 -10-membered aryl or 5-10-membered heteroaryl, and the aryl or heteroaryl is optionally substituted with 0-3 identical or different R ² ;

The Ar ring is a C3-C6 cycloalkyl group, a 5-10 membered heterocyclic group, a _C6 - _C10 aryl group or a _C5 - _C10 heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 a heteroatom selected from N, O or S, and Ar is optionally substituted with 0-3 identical or different M;

M is hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₁ - C ₆ )alkoxy, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy optionally hydroxy, amino or halo (C ₁ -C ₆ )alkylthio, mono- or di(C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido, free, salified, esterified and amidated carboxyl, (C ₁ -C ₆ ) alkylsulfinyl, sulfonyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) Substituents of alkylacyl, carbamoyl, mono- or di( _C1 - _C6 alkyl) substituted carbamoyl, ( _{C1 -} C3) alkylenedioxy; except that M is the attached power , in addition to the charge-absorbing group, M can also be a 5-10 membered heterocyclic group, a C ₆ -C ₁₂ aryl group or a C ₅ -C ₁₂ heteroaryl group, and the heterocyclic group and the heteroaryl group contain 1-3 A heteroatom selected from O, N and S, and the heterocyclic group, aryl group or heteroaryl group is optionally substituted by 0-3 identical or different R ² ;

R ² is hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkenyl, (C ₁ -C ₆ )alkynyl, (C ₁ ) -C ₆ )alkoxy, optionally hydroxy, amino or halogenated (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, mono or di(C ₁ -C ₆ alkyl) ) substituted amino, (C ₁ -C ₆ ) alkylamido, free, salified, esterified and amidated carboxyl, (C ₁ -C ₆ ) alkylsulfinyl, sulfonyl, ( C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, amino substituted with mono or di(C ₁ -C ₆ alkyl) Formyl, (C ₁ -C ₃ )alkylenedioxy.

The present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

in,

MBG is selected from the following structures:

The present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

in,

Y is O;

为双键，X为N。

is a double bond, and X is N.

The present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

in,

Y is O;

为双键，X为N；

is a double bond, and X is N;

MBG is selected from the following structures:

The present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

in,

R ¹ is (C ₁ -C ₅ )alkyl, (C ₃ -C ₆ )cycloalkyl, benzyl, -(CHF)Ph, -(CF ₂ )Ph, or phenyl, and benzyl, -(CHF )Ph, -(CF ₂ )Ph and the phenyl ring of phenyl are optionally substituted with 0-3 R ² .

The present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

in,

Y is O;

为双键，X为N；

is a double bond, and X is N;

R ¹ is (C ₁ -C ₅ )alkyl, (C ₃ -C ₆ )cycloalkyl, benzyl, -(CHF)Ph, -(CF ₂ )Ph, or phenyl, and benzyl, -(CHF ) Ph, -(CF ₂ )Ph and optional 0-3 R ² substitutions on the benzene ring of phenyl;

MBG is one of the following structures:

Ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuranyl, benzothiazolyl, benzothienyl, benzopyrazole group or indolyl group, and Ar is optionally substituted with 1-3 same or different M.

The present invention preferably the following compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, but these compounds do not mean any limitation to the present invention:

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-methyl-4,5-dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-isopropyl-4,5-dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-cyclopropyl-4,5-dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-benzyl-4,5-dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-5-(fluoro(phenyl)methyl)-4,5- Dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-5-(difluoro(phenyl)methyl)-4,5 - Dihydrooxazole

4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5 - Dihydrooxazole

4-((1H-Tetrazol-2-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5-dihydrooxazole

3-(4-((1H-1,2,4-Triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazol-2-yl)-5-phenyl Isoxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-phenyl-2-(5-phenylthiophen-2-yl)-4,5-dihydrooxane azole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(furan-3-yl)phenyl)-4-phenyl-4,5-di Hydroxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(thiophen-3-yl)phenyl)-4-phenyl-4,5-di Hydroxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(naphthalen-2-yl)-4-phenyl-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(benzofuran-2-yl)-4-phenyl-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydro oxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(benzo[d]thiazol-2-yl)-4-phenyl-4,5-dihydro oxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2,4-diphenyl-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(benzyloxy)phenyl)-4-phenyl-4,5-dihydrooxane azole

N-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl ) benzamide

1-(4-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazol-2-yl )phenyl)piperazin-1-yl)ethanone

2-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl )-5-phenyl-1,3,4-oxadiazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(furan-3-yl)phenyl)- 4,5-Dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(furan-3-yl)phenyl)- 4,5-Dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(furan-3-yl)benzene base)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(furan-3-yl)benzene base)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(thiophen-3-yl)phenyl)- 4,5-Dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(thiophen-3-yl)phenyl)- 4,5-Dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(thiophen-3-yl)benzene base)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(thiophen-3-yl)benzene base)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(5-(trifluoromethoxy)benzene [b]thiophen-2-yl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4-chlorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2,4-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(3,5-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2,4-di chlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-chlorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2,4-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(3,5-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2,4-di chlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4-chlorophenyl )-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2,4-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(3,5-di Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2,4-di chlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 4-Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 4-Chlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 2,4-Difluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 3,5-Difluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 2,4-Dichlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 4-Fluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 4-Chlorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 2,4-Difluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 3,5-Difluorophenyl)-4,5-dihydrooxazole

4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-( 2,4-Dichlorophenyl)-4,5-dihydrooxazole

4-((1H-Tetrazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl)-4,5- Dihydrooxazole

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

Furthermore, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula I, which themselves may have weak or even no activity, but after administration, are destroyed under physiological conditions (eg by metabolism, solvolysis or otherwise) by into the corresponding biologically active form.

Compounds of formula I can be in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds represented by the general formula I may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (eg, racemic mixtures), are included within the scope of the present invention Inside.

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

In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to straight-chain or branched alkyl; "alkylene" refers to straight-chain or branched alkylene; " "Aryl" refers to an organic group obtained by removing two hydrogen atoms at one or different positions in an aromatic hydrocarbon, such as phenyl and naphthyl; "heteroaryl" refers to an organic group containing one or more selected from N, O, S heteroatom monocyclic or polycyclic ring system, the ring system refers to an organic group which is aromatic and obtained by removing two hydrogen atoms in one or different positions in the ring system, such as thiazole base, imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl , oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, etc.

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

The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. Several of the above-mentioned dosage forms can be used as injections, tablets, capsules, aerosols, suppositories, films, drop pills, external liniments, ointments and other dosage forms.

The carriers used in the pharmaceutical compositions of the present invention are of the common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, colorless, flavoring agents , preservatives, solubilizers and substrates, etc. Pharmaceutical formulations may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric-coated tablets.

The compounds of general formula I of the present invention can be synthesized by methods including well-known methods in the field of chemistry, especially prepared according to the description of the present invention; room temperature in the present invention refers to ambient temperature, which is 10°C to 30°C.

It should be understood that the examples and reaction schemes described herein are for illustrative purposes only, and those skilled in the art can make various modifications and changes accordingly, and these modifications and changes are all included within the spirit and scope of the present invention and within the scope of the appended claims.

General reaction scheme for compound preparation

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared from the following materials: (a) The starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described in the present invention , (b) known starting materials that can be prepared by methods described in the literature, (c) new intermediates described in the schemes and experimental procedures herein. The compounds of the present invention can be synthesized by the following reaction schemes and descriptions.

Scheme I

Scheme I above shows a general synthetic route for the preparation of compound ^I , wherein Ar, M, R1 and MBG are as claimed.

The amide reaction of D-serine methyl ester hydrochloride A1 and raw material A2 is carried out to obtain intermediate A3. Under the condition of -80 °C, intermediate A3 reacts with SOCl ₂ to obtain intermediate A4. Intermediate A4 reacts with R under alkaline conditions. ¹ -X (X is halogen) undergoes a substitution reaction to obtain intermediate A5, the ester group of intermediate A5 is reduced by lithium aluminum tetrahydrogen to obtain intermediate A6, A6 undergoes a substitution reaction with SOCl ₂ to obtain intermediate A7, and A7 undergoes a substitution reaction with MBG The target compound I was obtained.

Scheme II

时，化合物的一般合成路线，其中Ar、M、R¹、R²和MBG如权利要求书所述。Scheme II above shows the preparation ^of compound R1 as

, the general synthetic route for compounds in which Ar, M, R ¹ , R ² and MBG are as described in the claims.

Substitution reaction between raw material B1 and AgNO ₂ to obtain intermediate B2, intermediate B2 and formaldehyde undergo bismethylolation reaction to obtain intermediate B3, and intermediate B3 reacts with 2,2-dimethoxypropane to obtain intermediate B4, Intermediate B4 undergoes reduction reaction with Pd/C to obtain intermediate B5, intermediate B5 undergoes amide reaction with raw material B6 to obtain intermediate B7, intermediate B7 is deprotected under acidic conditions to obtain intermediate B8, intermediate B8 and SOCl _2. Substitution reaction occurs to obtain intermediate B9, and intermediate B9 undergoes substitution reaction with MBG to obtain target compound B10.

The positive progress effect of the present invention is that the present invention provides 2,4,4-trisubstituted dihydrooxazole derivatives, its preparation method, pharmaceutical composition and application. The 2,4,4-trisubstituted dihydrooxazole derivatives of the present invention have good antifungal activity against various superficial and deep fungi, and have high efficiency, low toxicity, It has the advantages of broad antifungal spectrum, etc., and can be used to prepare antifungal drugs.

The examples and preparations provided herein further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations do not limit the scope of the invention in any way. The compounds of general formula I of the present invention can be prepared according to the synthetic methods of Scheme I and Scheme II, all variables used in these schemes are as defined in the claims.

Detailed ways

Without further elaboration, it is believed that one skilled in the art can, with the help of the preceding description, utilize the present invention to its fullest extent. The examples provided below are therefore intended to illustrate rather than limit the scope of the present invention.

The starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described herein. Unless otherwise specified, all reagents used are of analytical or chemical grade.

The mass spectra used for compound structure confirmation were determined with an Agilent 1100 LC/MS. The purified product by column chromatography used 100-200 mesh or 200-300 mesh silica gel produced by Qingdao Ocean Chemical Factory.

Example 1: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-methyl-4,5-dihydrooxane azole

In step a: the raw materials 1-1 (1.1 mmol), bibenzoic acid 1-2 (1.1 mmol) and PyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate) (1.2 mmol) were combined ) was added to DMF, stirred at room temperature for 8 h, TLC detected the reaction completion, added water, extracted with ethyl acetate, washed the organic layer with saturated brine, and dried over anhydrous sodium sulfate overnight. The desiccant was filtered off and concentrated under reduced pressure to obtain Intermediate 1-3.

In step b: intermediate 1-3 (5 mmol), SOCl ₂ (12.5 mmol) and triethylamine (12.5 mmol) were added to dichloromethane, the reaction was stirred at room temperature, TLC detected that the reaction was complete, the organic solvent was evaporated, ethyl acetate The ester was dissolved, washed three times with water, the organic layer was washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 1-4.

In step c: the intermediate 1-4 (5 mmol) was dissolved in anhydrous THF, the THF solution of LiN(Pr-i) ₂ (10 mmol) was slowly added dropwise, the reaction was carried out for about 1 h, CH ₃ I (10 mmol) was added, TLC The reaction was detected to be complete, warmed to room temperature, quenched by adding saturated NH ₄ Cl solution, the organic solvent was evaporated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The drying agent was filtered off and concentrated under reduced pressure to obtain Intermediate 1-5.

In step d: under ice bath condition, the intermediate 1-5 (5 mmol) was dissolved in THF, and lithium tetrahydroaluminum (10 mmol) was added in batches. TLC detected the reaction to be complete, and saturated NH ₄ Cl solution was added to quench the reaction. The organic solvent was evaporated under pressure, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off and concentrated under reduced pressure to obtain Intermediate 1-6.

In step e: intermediate 1-6 (5mmol), SOCl ₂ (20mmol) and triethylamine (20mmol) were added to dichloromethane, the reaction was stirred at room temperature, TLC detected that the reaction was complete, the organic solvent was evaporated, ethyl acetate Dissolved, washed three times with water, washed the organic layer with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 1-7.

In step f: under ice bath conditions, imidazole (15mmol) was added to DMF, NaH (20mmol) was added, intermediate 1-7 (5mmol) was added after stirring for 30min, the reaction was continued, TLC detected the completion of the reaction, and the reaction solution was poured into It was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure, and the target compound 1 was obtained by column chromatography. ¹ H-NMR (400MHz, DMSO-d ₆ )δ7.90(d, J=8.4Hz, 2H), 7.77(d, J=8.4Hz, 2H), 7.74-7.70(m, 2H), 7.59(s ,1H),7.50(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),7.14(s,1H),6.81(s,1H),4.31(d,J＝8.9Hz ,1H),4.22–4.14(m,2H),4.12(d,J=8.9Hz,1H),1.31(s,3H).HRMS(ESI,m/z)calcdforC ₂₀ H ₁₉ N ₃ O,[M +H] ⁺ ,318.1601; found 318.1632.

According to the method of Example 1, the corresponding haloalkanes were respectively used to prepare Examples 2-6.

Example 2: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-isopropyl-4,5-dihydro oxazole

ESI-MS [M+H] ⁺ (m/z): 346.1.

Example 3: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-cyclopropyl-4,5-dihydro oxazole

ESI-MS [M+H] ⁺ (m/z): 344.1.

Example 4: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-benzyl-4,5-dihydrooxane azole

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.81(d,J=8.5Hz,2H),7.75-7.68(m,4H),7.61(s,1H),7.49(t,J=7.5Hz ,2H),7.41(t,J＝7.3Hz,1H),7.28–7.14(m,6H),6.81(s,1H),4.31(s,2H),4.23(d,J＝9.2Hz,1H) ,4.16(d,J=9.2Hz,1H),3.04(d,J=13.5Hz,1H),2.91(d,J=13.5Hz,1H).HRMS(ESI,m/z)calcd for C ₂₆ H ₂₃ N ₃ O, [M+H] ⁺ , 394.1914; found 394.1949.

Example 5: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-5-(fluoro(phenyl)methyl)- 4,5-Dihydrooxazole

HRMS(ESI,m/z)calcd for C ₂₆ H ₂₂ FN ₃ O,[M+H] ⁺ , 412.1820; found 412.1857.

Example 6: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-5-(difluoro(phenyl)methyl) -4,5-Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ7.84(d,J=8.4Hz,2H),7.76(d,J=8.3Hz,2H),7.71(d,J=7.4Hz,2H), 7.69–7.62(m, 3H), 7.55–7.48(m, 5H), 7.42(t, J=7.4Hz, 1H), 7.14(s, 1H), 6.76(s, 1H), 4.69(d, J= 10.1Hz,1H),4.59(d,J=14.2Hz,1H),4.36–4.29(m,2H).HRMS(ESI,m/z)calcd for C ₂₆ H ₂₁ F ₂ N ₃ O,[M+ H] ⁺ , 430.1725; found 430.1727.

Example 7: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl -4,5-Dihydrooxazole

In step a: AgNO ₂ (10 mmol) was added to ether (30 mL), stirred at room temperature, benzyl bromide (5 mmol) was added dropwise, stirred for 5 h in the dark, the reaction solution was poured into water, extracted with ether for 3 times, and evaporated under reduced pressure. Remove ether to obtain light yellow oily liquid, and column chromatography obtains intermediate 5-2.

In step b: the intermediate 5-2 (4 mmol) is dissolved in ethanol, formaldehyde solution (24 mmol) and NaOH (4 mmol) are added, the reaction is stirred at room temperature, the completion of the reaction is detected by TLC, the organic solvent is evaporated under reduced pressure, water is added, ethyl acetate The ester was extracted three times, and the organic layers were combined, washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure and subjected to column chromatography to obtain Intermediate 5-3.

In step c: add 2,2-dimethoxypropane (4.5mmol) to the acetone solution of intermediate 5-3 (3mmol), add p-toluenesulfonic acid (0.6mmol), react at room temperature, and detect the reaction by TLC Complete, the solvent was evaporated under reduced pressure, and the intermediate 5-4 was obtained by column chromatography.

In step d: the intermediate 5-4 (2 mmol) was dissolved in methanol (10 mL) solution, Pd/C was added, H ₂ was introduced, the reaction was carried out at room temperature, and the reaction was completed by TLC, filtered, and the solvent was evaporated under reduced pressure to obtain the intermediate Body 5-5.

In step e: the raw material bibenzoic acid 5-6 (1.1 mmol), intermediate 5-5 (1.1 mmol) and PyBOP (1.2 mmol) were added to DMF (10 mL), and the reaction was stirred at room temperature for 8 h. TLC detected the reaction and added water. , extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate overnight. The desiccant was filtered off and concentrated under reduced pressure to obtain intermediate 5-7.

In step f: intermediate 5-7 (5 mmol) was added to glacial acetic acid/water (V:V=3:1), reacted at 40° C., TLC detected that the reaction was complete, poured into water, extracted with ethyl acetate, saturated NaCl The organic layer was washed and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 5-8.

In step g: intermediate 5-8 (5mmol), SOCl ₂ (25mmol) and triethylamine (25mmol) are added in methylene chloride, the reaction is stirred at room temperature, TLC detects that the reaction is complete, the organic solvent is evaporated, and ethyl acetate is dissolved , washed three times with water, washed the organic layer with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 5-9.

In step h: under ice bath conditions, add azole (15mmol) to DMF (10mL), add NaH (20mmol), add intermediate 5-9 (5mmol) after stirring for 30min, continue the reaction, TLC detects the completion of the reaction, and the reaction The liquid was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na ₂ SO ₄ overnight. The desiccant was filtered off, concentrated under reduced pressure, and the target compound 7 was obtained by column chromatography. ¹ H-NMR (600MHz, DMSO-d ₆ )δ8.32(s, 1H), 7.96(d, J=8.4Hz, 2H), 7.90(s, 1H), 7.79(d, J=8.3Hz, 2H) ), 7.73(d, J=7.5Hz, 2H), 7.53-7.49(m, 4H), 7.44-7.39(m, 3H), 7.32(t, J=7.3Hz, 1H), 5.13(d, J= 8.9Hz,1H),4.74(d,J=14.2Hz,1H),4.61(d,J=14.1Hz,1H),4.46(d,J=8.9Hz,1H).HRMS(ESI,m/z) calcd for C ₂₄ H ₂₀ N ₄ O, [M+Na] ⁺ , 403.1529; found403.1563.

According to the method of Example 7, the corresponding raw materials were used to prepare Examples 8-56.

Example 8: 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5-dihydrooxane azole

¹ H-NMR (600MHz, DMSO-d ₆ )δ7.99(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.74(d,J=7.2Hz,2H), 7.55-7.49(m, 5H), 7.44-7.39(m, 3H), 7.32(t, J=7.3Hz, 1H), 7.09(s, 1H), 6.75(s, 1H), 4.82(d, J= 9.1Hz,1H),4.52(d,J=14.2Hz,1H),4.43(d,J=9.1Hz,1H),4.35(d,J=14.2Hz,1H).HRMS(ESI,m/z) calcd for C ₂₅ H ₂₁ N ₃ O, [M+H] ⁺ , 380.1757; found380.1796.

Example 9: 4-((1H-Tetrazol-2-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5-di Hydroxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ9.26(s,1H),7.98(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),7.75-7.73(m ,2H),7.54–7.50(m,4H),7.44–7.39(m,3H),7.33(t,J=7.3Hz,1H),5.08(d,J=14.2Hz,1H),5.03(d, J=9.2Hz,1H),4.96(d,J=14.2Hz,1H),4.49(d,J=9.2Hz,1H).HRMS(ESI,m/z)calcd for C ₂₃ H ₁₉ N ₅ O, [M+Na] ⁺ , 404.1482; found 404.1514.

Example 10: 3-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazol-2-yl)- 5-Phenylisoxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.34(s,1H),8.00-7.98(m,2H),7.92(s,1H),7.59-7.56(m,4H),7.49(dd, J=8.2, 1.0Hz, 2H), 7.41(t, J=7.6Hz, 2H), 7.34(t, J=7.3Hz, 1H), 5.19(d, J=9.1Hz, 1H), 4.78(d, J=14.2Hz, 1H), 4.67(d, J=14.2Hz, 1H), 4.55(d, J=9.1Hz, 1H).HRMS(ESI,m/z)calcd for C ₂₁ H ₁₇ N ₅ O ₂ ,[M+Na] ⁺ ,394.1274; found 394.1315.

Example 11: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-2-(5-phenylthiophen-2-yl)-4,5 - Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.28(s,1H),7.92(s,1H),7.77-7.74(m,2H),7.57(d,J=0.8Hz,2H),7.49 –7.46(m, 4H), 7.40(t, J=7.7Hz, 3H), 7.33(t, J=7.3Hz, 1H), 5.12(d, J=8.8Hz, 1H), 4.73(d, J= 14.2Hz,1H),4.60(d,J=14.2Hz,1H),4.46(d,J=8.8Hz,1H).HRMS(ESI,m/z)calcd for C ₂₂ H ₁₈ N ₄ OS,[M +Na] ⁺ ,409.1094; found 409.1134.

Example 12: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-(furan-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.31(d,J=12.2Hz,2H),7.88(d,J=5.0Hz,2H),7.86(s,1H),7.79(t,J =1.7Hz,1H),7.74(d,J=8.4Hz,2H),7.53–7.49(m,2H),7.39(t,J=7.7Hz,2H),7.32(t,J=7.3Hz,1H) ), 7.06–7.02(m, 1H), 5.11(d, J=8.9Hz, 1H), 4.72(d, J=14.2Hz, 1H), 4.59(d, J=14.1Hz, 1H), 4.44(d , J=8.9Hz, 1H).HRMS(ESI,m/z)calcd forC ₂₂ H ₁₈ N ₄ O ₂ , [M+Na] ⁺ , 393.1322; found 393.1356.

Example 13: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(thiophen-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.04 (dd, J=2.9, 1.3 Hz, 1H), 7.92-7.87 (m, 3H), 7.84 (d, J= 8.5Hz, 2H), 7.69 (dd, J=5.0, 2.9Hz, 1H), 7.63 (dd, J=5.0, 1.3Hz, 1H), 7.53–7.50 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.32(t, J＝7.3Hz, 1H), 5.11(d, J＝8.9Hz, 1H), 4.73(d, J＝14.2Hz, 1H), 4.60(d, J＝14.1Hz, 1H), 4.44 (d, J=8.9Hz, 1H).HRMS(ESI, m/z) calcd for C ₂₂ H ₁₈ N ₄ OS, [M+Na] ⁺ , 409.1094; found 409.1140.

Example 14: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(naphthalen-2-yl)-4-phenyl-4,5-dihydrooxane azole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.43(s, 1H), 8.33(s, 1H), 8.08(d, J=7.9Hz, 1H), 8.03(d, J=0.9Hz, 2H ),8.00(d,J=8.1Hz,1H),7.88(s,1H),7.66-7.63(m,1H),7.62-7.59(m,1H),7.55(dd,J=8.2,1.1Hz, 2H), 7.41(t, J＝7.7Hz, 2H), 7.33(t, J＝7.3Hz, 1H), 5.18(d, J＝8.8Hz, 1H), 4.76(d, J＝14.2Hz, 1H) ,4.63(d,J=14.2Hz,1H),4.50(d,J=8.8Hz,1H).HRMS(ESI,m/z)calcd for C ₂₂ H ₁₈ N ₄ O,[M+Na] ⁺ , 377.1373; found 377.1403.

Example 15: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(benzofuran-2-yl)-4-phenyl-4,5-di Hydroxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.30(s, 1H), 7.91(s, 1H), 7.78-7.72(m, 2H), 7.53-7.48(m, 4H), 7.40(t, J=7.6Hz, 2H), 7.37–7.32 (m, 2H), 5.17 (d, J=8.9Hz, 1H), 4.74 (d, J=14.2Hz, 1H), 4.63 (d, J=14.2Hz, 1H), 4.50(d, J=8.9Hz, 1H).HRMS(ESI,m/z)calcd forC ₂₀ H ₁₆ N ₄ O ₂ , [M+Na] ⁺ , 367.1165; found 367.1203.

Example 16: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(benzo[d]thiazol-2-yl)-4-phenyl-4, 5-Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.33(s,1H),8.26-8.22(m,1H),8.15(dd,J=7.3,1.7Hz,1H),7.91(s,1H) ,7.63(pd,J=7.1,1.3Hz,2H),7.53–7.48(m,2H),7.43(t,J=7.7Hz,2H),7.35(t,J=7.3Hz,1H),5.29( d,J＝9.0Hz,1H),4.81(d,J＝14.2Hz,1H),4.69(d,J＝14.2Hz,1H),4.62(d,J＝9.0Hz,1H).HRMS(ESI, m/z) calcd for C ₁₉ H ₁₅ N ₅ OS, [M+Na] ⁺ , 384.0890; found 384.0923.

Example 17: 4-((1H-1,2,4-triazol-1-yl)methyl)-2,4-diphenyl-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.30(s, 1H), 7.90-7.85(m, 3H), 7.58(t, J=7.4Hz, 1H), 7.51-7.48(m, 4H) ,7.39(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),5.11(d,J＝9.0Hz,1H),4.72(d,J＝14.1Hz,1H),4.60 (d, J=14.1Hz, 1H), 4.44 (d, J=9.0Hz, 1H). HRMS(ESI, m/z) calcd for C ₁₈ H ₁₆ N ₄ O, [M+Na] ⁺ , 327.1216; found 327.1248.

Example 18: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(benzyloxy)phenyl)-4-phenyl-4,5 - Dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.27(s,1H),7.88(s,1H),7.82(d,J=8.9Hz,2H),7.49(d,J=7.2Hz,2H) ), 7.46(d, J＝7.2Hz, 2H), 7.42–7.33(m, 5H), 7.30(t, J＝7.3Hz, 1H), 7.10(d, J＝8.9Hz, 2H), 5.18(s ,2H),5.06(d,J＝8.9Hz,1H),4.69(d,J＝14.1Hz,1H),4.56(d,J＝14.1Hz,1H),4.39(d,J＝8.9Hz,1H) ).HRMS(ESI,m/z)calcd for C ₂₅ H ₂₂ N ₄ O ₂ , [M+H] ⁺ , 411.1816; found 411.1856.

Example 19: N-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazole-2- yl)phenyl)benzamide

¹ H-NMR (600MHz, DMSO-d ₆ )δ10.52(s, 1H), 8.30(s, 1H), 7.98(d, J=7.9Hz, 2H), 7.92(d, J=8.8Hz, 2H) ), 7.90–7.86(m, 3H), 7.62(t, J=7.3Hz, 1H), 7.56(t, J=7.5Hz, 2H), 7.51(d, J=7.2Hz, 2H), 7.39(t , J=7.7Hz, 2H), 7.32(t, J=7.3Hz, 1H), 5.09(d, J=8.9Hz, 1H), 4.71(d, J=14.1Hz, 1H), 4.59(d, J =14.1Hz,1H),4.43(d,J=8.9Hz,1H).HRMS(ESI,m/z)calcd for C ₂₅ H ₂₁ N ₅ O ₂ , [M+Na] ⁺ , 446.1587; found 446.1640.

Example 20: 1-(4-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazole -2-yl)phenyl)piperazin-1-yl)ethanone

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.25(s,1H),7.87(s,1H),7.71(d,J=9.0Hz,2H),7.50-7.47(m,2H),7.37 (t, J=7.7Hz, 2H), 7.30 (t, J=7.3Hz, 1H), 6.98 (d, J=9.0Hz, 2H), 5.02 (d, J=8.9Hz, 1H), 4.67 (d , J=14.1Hz, 1H), 4.54 (d, J=14.1Hz, 1H), 4.35 (d, J=8.9Hz, 1H), 3.59–3.57 (m, 4H), 3.35–3.31 (m, 4H) ,2.04(s,3H).HRMS(ESI,m/z)calcd forC ₂₄ H ₂₆ N ₆ O ₂ ,[M+Na] ⁺ ,453.2009;found 453.2050.

Example 21: 2-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazole-2- yl)phenyl)-5-phenyl-1,3,4-oxadiazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.33(s, 1H), 8.26(d, J=8.5Hz, 2H), 8.17(dd, J=8.0, 1.5Hz, 2H), 8.11(d , J=8.5Hz, 2H), 7.89(s, 1H), 7.69-7.64(m, 3H), 7.54-7.51(m, 2H), 7.41(t, J=7.7Hz, 2H), 7.33(t, J=7.3Hz, 1H), 5.18 (d, J=8.9Hz, 1H), 4.76 (d, J=14.2Hz, 1H), 4.63 (d, J=14.2Hz, 1H), 4.51 (d, J= 8.9Hz, 1H).HRMS(ESI,m/z)calcd for C ₂₆ H ₂₀ N ₆ O ₂ , [M+Na] ⁺ , 471.1540; found 471.1577.

Example 22: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.32(d, J=8.0Hz, 2H), 7.90-7.84(m, 3H), 7.79(t, J=1.7Hz, 1H), 7.74(d , J=8.5Hz, 2H), 7.55–7.52(m, 2H), 7.21(t, J=8.9Hz, 2H), 7.04(dd, J=1.8, 0.8Hz, 1H), 5.09(d, J= 9.0Hz,1H),4.72(d,J=14.1Hz,1H),4.59(d,J=14.1Hz,1H),4.43(d,J=9.0Hz,1H).HRMS(ESI,m/z) calcd for C ₂₂ H ₁₇ FN ₄ O ₂ , [M+Na] ⁺ , 411.1228; found411.1264.

Example 23: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 405.1.

Example 24: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 407.1.

Example 25: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 439.1.

Example 26: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 405.1.

Example 27: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole

ESI-MS[M+H] ⁺ (m/z): 421.1.

Example 28: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 423.1.

Example 29: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 455.1.

Example 30: 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(5-(trifluoromethyl) Oxy)benzo[b]thiophen-2-yl)-4,5-dihydrooxazole

ESI-MS[M+H] ⁺ (m/z): 481.1.

Example 31: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.29(s, 1H), 8.02-7.96(m, 2H), 7.91(d, J＝16.4Hz, 2H), 7.55-7.50(m, 2H) ,7.35(td,J＝9.0,2.5Hz,1H),7.23(t,J＝8.9Hz,2H),5.17(d,J＝8.9Hz,1H),4.75(d,J＝14.2Hz,1H) ,4.62(d,J=14.2Hz,1H),4.50(d,J=8.9Hz,1H).HRMS(ESI,m/z)calcd for C ₂₀ H ₁₄ F ₂ N ₄ OS,[M+Na] ⁺ ,419.0749; found 419.0778.

Example 32: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 413.1.

Example 33: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.34(s, 1H), 8.04-7.99(m, 2H), 7.97(s, 1H), 7.87(s, 1H), 7.67-7.61(m, 1H), 7.40–7.34 (m, 2H), 7.13 (td, J=8.5, 2.5Hz, 1H), 5.18 (dd, J=9.1, 2.6Hz, 1H), 4.65 (d, J=14.3Hz, 1H) ),4.59(d,J=14.3Hz,1H),4.52(dd,J=9.0,1.5Hz,1H).HRMS(ESI,m/z)calcd for C ₂₀ H ₁₃ F ₃ N ₄ OS,[M +Na] ⁺ ,437.0654; found 437.0688.

Example 34: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 415.1.

Example 35: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 447.1.

Example 36: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.29(s,1H),8.24(d,J=1.3Hz,1H),7.97(d,J=8.6Hz,1H),7.94(s,1H) ), 7.90 (s, 1H), 7.54–7.49 (m, 3H), 7.25–7.21 (m, 2H), 5.17 (d, J=8.9Hz, 1H), 4.75 (d, J=14.2Hz, 1H) ,4.62(d,J=14.2Hz,1H),4.51(d,J=8.9Hz,1H).HRMS(ESI,m/z)calcd for C ₂₀ H ₁₄ ClFN ₄ OS,[M+Na] ⁺ , 435.0453; found 435.0480.

Example 37: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.30(s, 1H), 8.24(d, J=1.9Hz, 1H), 7.97(d, J=8.5Hz, 1H), 7.95(d, J =0.4Hz,1H),7.89(s,1H),7.51–7.45(m,5H),5.17(d,J=8.9Hz,1H),4.76(d,J=14.2Hz,1H),4.63(d , J=14.2Hz, 1H), 4.51 (d, J=9.0Hz, 1H).HRMS (ESI, m/z) calcd for C ₂₀ H ₁₄ Cl ₂ N ₄ OS, [M+Na] ⁺ , 451.0158; found 451.0195.

Example 38: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.34(s, 1H), 8.26(d, J=1.8Hz, 1H), 7.99(d, J=7.4Hz, 2H), 7.86(s, 1H) ), 7.66–7.60 (m, 1H), 7.51 (dd, J=8.6, 1.9Hz, 1H), 7.40–7.34 (m, 1H), 7.12 (td, J=8.5, 2.4Hz, 1H), 5.18 ( dd, J=9.1, 2.5Hz, 1H), 4.65 (d, J=14.3Hz, 1H), 4.59 (d, J=14.3Hz, 1H), 4.53 (dd, J=8.9, 1.3Hz, 1H). HRMS (ESI, m/z) calcd for C ₂₀ H ₁₃ ClF ₂ N ₄ OS, [M+Na] ⁺ , 453.0359; found 453.0383.

Example 39: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.32(s, 1H), 8.25(d, J=1.8Hz, 1H), 7.98(d, J=8.0Hz, 2H), 7.90(s, 1H) ), 7.50(dd, J=8.6, 2.0Hz, 1H), 7.24–7.18(m, 3H), 5.15(d, J=9.1Hz, 1H), 4.80(d, J=14.2Hz, 1H), 4.67 (d, J=14.1 Hz, 1H), 4.55 (d, J=9.1 Hz, 1H). HRMS(ESI, m/z) calcd for C ₂₀ H ₁₃ ClF ₂ N ₄ OS, [M+Na] ⁺ , 453.0359; found 453.0383.

Example 40: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 463.1.

Example 41: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.39(d, J=1.7Hz, 1H), 8.28(s, 1H), 7.93(s, 1H), 7.92-7.88(m, 2H), 7.62 (dd, J=8.5, 1.8Hz, 1H), 7.53–7.50(m, 2H), 7.23(t, J=8.9Hz, 2H), 5.17(d, J=8.9Hz, 1H), 4.75(d, J=14.2Hz,1H),4.62(d,J=14.2Hz,1H),4.51(d,J=8.9Hz,1H).HRMS(ESI,m/z)calcd for C ₂₀ H ₁₄ BrFN ₄ OS, [M+Na] ⁺ ,478.9948; found 480.9957.

Example 42: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.40-8.37(m,1H),8.30(s,1H),7.94(s,1H),7.92-7.89(m,2H),7.62(dd, J=8.5, 1.8Hz, 1H), 7.50(d, J=8.7Hz, 2H), 7.46(d, J=8.7Hz, 2H), 5.17(d, J=8.9Hz, 1H), 4.76(d, J=14.2Hz, 1H), 4.63 (d, J=14.2Hz, 1H), 4.51 (d, J=8.9Hz, 1H). ESI-MS [M+H] ⁺ (m/z): 473.1.

Example 43: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.40(d, J=1.7Hz, 1H), 8.34(s, 1H), 7.97(s, 1H), 7.92(d, J=8.5Hz, 1H) ), 7.86 (s, 1H), 7.65–7.61 (m, 2H), 7.39–7.35 (m, 1H), 7.12 (td, J=8.5, 2.5Hz, 1H), 5.18 (dd, J=9.1, 2.6 Hz,1H),4.65(d,J＝14.3Hz,1H),4.59(d,J＝14.3Hz,1H),4.53(dd,J＝9.0,1.5Hz,1H).HRMS(ESI,m/z )calcd for C ₂₀ H ₁₃ BrF ₂ N ₄ OS, [M+Na] ⁺ , 496.9854; found 498.9869.

Example 44: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.39(s,1H),8.32(s,1H),7.97(s,1H),7.93-7.88(m,2H),7.64-7.59(m, 1H), 7.25–7.18(m, 3H), 5.15(d, J=9.1Hz, 1H), 4.80(d, J=14.2Hz, 1H), 4.67(d, J=14.1Hz, 1H), 4.55( d, J=9.1 Hz, 1 H). HRMS (ESI, m/z) calcd for C ₂₀ H ₁₃ BrF ₂ N ₄ OS, [M+Na] ⁺ , 496.9854; found 498.9869.

Example 45: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 507.1.

Example 46: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Fluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.34(s,1H),7.99-7.96(m,2H),7.90(s,1H),7.68(dd,J=8.3,1.4Hz,2H) ,7.59(td,J=7.9,1.6Hz,1H),7.57-7.54(m,2H),7.50-7.46(m,1H),7.37-7.33(m,2H),7.23(t,J=8.9Hz ,2H),5.13(d,J＝9.0Hz,1H),4.74(d,J＝14.2Hz,1H),4.61(d,J＝14.1Hz,1H),4.46(d,J＝9.0Hz,1H) ).HRMS(ESI,m/z)calcd for C ₂₄ H ₁₈ F ₂ N ₄ O,[M+Na] ⁺ , 439.1341; found 439.1382.

Example 47: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Chlorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.35(s,1H),7.98(d,J=8.4Hz,2H),7.90(s,1H),7.68(dd,J=8.3,1.4Hz ,2H),7.61–7.58(m,1H),7.54(d,J=8.6Hz,2H),7.50–7.47(m,1H),7.46(d,J=8.6Hz,2H),7.34(dd, J=10.7, 4.4Hz, 2H), 5.12(d, J=9.0Hz, 1H), 4.75(d, J=14.2Hz, 1H), 4.62(d, J=14.1Hz, 1H), 4.45(d, J=9.0Hz, 1H). HRMS (ESI, m/z) calcd for C ₂₄ H ₁₈ ClFN ₄ O, [M+Na] ⁺ , 455.1045; found 455.1093.

Example 48: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.39(s, 1H), 8.00(d, J=8.5Hz, 2H), 7.87(s, 1H), 7.72-7.68(m, 3H), 7.60 (td, J=7.9, 1.6Hz, 1H), 7.50–7.46 (m, 1H), 7.39–7.33 (m, 3H), 7.11 (td, J=8.5, 2.5Hz, 1H), 5.15 (dd, J ＝9.2,2.5Hz,1H),4.64(d,J＝14.3Hz,1H),4.58(d,J＝14.3Hz,1H),4.48(dd,J＝9.1,1.6Hz,1H).HRMS(ESI ,m/z)calcd for C ₂₄ H ₁₇ F ₃ N ₄ O,[M+Na] ⁺ ,457.1247; found 457.1282.

Example 49: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(3,5-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.37(s,1H),7.99(d,J=8.5Hz,2H),7.90(s,1H),7.69(dd,J=8.3,1.4Hz ,2H),7.59(td,J＝7.9,1.6Hz,1H),7.50-7.46(m,1H),7.38-7.33(m,2H),7.26(dd,J＝8.6,2.2Hz,2H), 7.21(tt,J＝9.1,2.3Hz,1H),5.11(d,J＝9.2Hz,1H),4.79(d,J＝14.2Hz,1H),4.66(d,J＝14.1Hz,1H), 4.50(d, J=9.2Hz, 1H).HRMS(ESI,m/z)calcd for C ₂₄ H ₁₇ F ₃ N ₄ O, [M+Na] ⁺ , 457.1247; found 457.1281.

Example 50: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Dichlorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 467.1.

Example 51: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Fluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.33(s, 1H), 7.96(d, J=8.5Hz, 2H), 7.89(s, 1H), 7.84(d, J=8.5Hz, 2H) ), 7.62–7.59 (m, 2H), 7.57–7.53 (m, 3H), 7.28–7.20 (m, 3H), 5.13 (d, J=9.0Hz, 1H), 4.74 (d, J=14.2Hz, 1H),4.61(d,J=14.1Hz,1H),4.45(d,J=9.0Hz,1H).HRMS(ESI,m/z)calcd for C ₂₄ H ₁₈ F ₂ N ₄ O,[M+ Na] ⁺ ,439.1341; found 439.1390.

Example 52: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Chlorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.34(s, 1H), 7.96(d, J=8.4Hz, 2H), 7.89(s, 1H), 7.84(d, J=8.4Hz, 2H) ), 7.61–7.59 (m, 2H), 7.55–7.52 (m, 3H), 7.46 (d, J=8.6Hz, 2H), 7.26 (td, J=8.1, 1.5Hz, 1H), 5.12 (d, J＝9.0Hz,1H),4.74(d,J＝14.2Hz,1H),4.62(d,J＝14.1Hz,1H),4.45(d,J＝9.0Hz,1H).HRMS(ESI,m/ z) calcd for C ₂₄ H ₁₈ ClFN ₄ O, [M+Na] ⁺ , 455.1045; found 455.1083.

Example 53: 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.38(s, 1H), 7.98(d, J=8.5Hz, 2H), 7.88-7.84(m, 3H), 7.71(td, J=8.7, 6.8Hz, 1H), 7.63–7.60 (m, 2H), 7.55 (td, J=8.1, 6.2Hz, 1H), 7.40–7.35 (m, 1H), 7.29–7.25 (m, 1H), 7.11 (td , J=8.5, 2.5Hz, 1H), 5.14 (dd, J=9.1, 2.5Hz, 1H), 4.64 (d, J=14.3Hz, 1H), 4.58 (d, J=14.3Hz, 1H), 4.47 (dd, J=9.1, 1.6 Hz, 1H). HRMS(ESI, m/z) calcd for C ₂₄ H ₁₇ F ₃ N ₄ O, [M+Na] ⁺ , 457.1247; found 457.1286.

Example 54: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(3,5-Difluorophenyl)-4,5-dihydrooxazole

¹ H-NMR (600MHz, DMSO-d ₆ )δ8.37(s, 1H), 7.97(d, J=8.5Hz, 2H), 7.90(s, 1H), 7.84(d, J=8.5Hz, 2H) ), 7.62–7.59 (m, 2H), 7.57–7.53 (m, 1H), 7.29–7.24 (m, 3H), 7.23–7.19 (m, 1H), 5.11 (d, J=9.2Hz, 1H), 4.79(d,J=14.2Hz,1H),4.65(d,J=14.1Hz,1H),4.50(d,J=9.2Hz,1H).HRMS(ESI,m/z)calcd for C ₂₄ H ₁₇ F ₃ N ₄ O, [M+Na] ⁺ , 457.1247; found 457.1279.

Example 55: 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole

ESI-MS [M+H] ⁺ (m/z): 467.1.

Example 56: 4-((1H-Tetrazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl)- 4,5-Dihydrooxazole

¹ H NMR(600MHz,DMSO)δ9.19(s,1H),8.26(d,J=1.9Hz,1H),7.99(t,J=4.3Hz,2H),7.56-7.47(m,3H), 7.24(t,J=8.9Hz,2H),5.12-5.06(m,2H),4.97(d,J=14.2Hz,1H),4.54(d,J=9.2Hz,1H).ESI-MS[M +H] ⁺ (m/z): 414.1.

Pharmacological studies of some products of the present invention.

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

Experimental materials and methods:

(1) Experimental strains:

In this experiment, the following five common human pathogenic standard fungal strains were selected as screening objects, and the fungal strains were provided by Shenyang Pharmaceutical University.

Table 1 Bacteria used in the experiment and their numbers

strain name Species strain selection Candida albicans Candida albicans SC5314 Candida albicans Candida albicans CPCC400523 Cryptococcus neoformans Cryptococcus neofrmans GIM 2.209 Candida tropicalis Candida tropicalis cgmcc 2.3739 Aspergillus fumigatus Aspergillus fumigatus cgmcc 3.7795

(2) Test method:

Preparation of RPMI-1640 medium: RPMI-1640 10g, NaHCO ₃ 2.0g, sigma 34.5g, add 800mL sterile distilled water to dissolve, adjust the pH to 7.0 with 1mol/L NaOH, and make up to volume to 1000mL, sterilized by filtration with a 0.22μm microporous membrane, and stored at 4°C for later use.

Preparation of filamentous fungal suspension: Filamentous fungi (Trichophyton rubrum, Trichophyton blemishes, Microsporum gypsum and Aspergillus fumigatus) etc. were successively inoculated on Sabouraud medium plates for two consecutive passages, and were incubated at 35 Cultivate in an incubator for 48 hours, and add 5 mL of 0.85% physiological saline to the colony to prepare a bacterial solution. Adjust the concentration of the bacterial solution with a spectrophotometer, and adjust the A value to 0.3-0.5; then dilute it 50 times with the medium as the inoculated bacterial suspension.

Preparation of Spherical Fungal Suspension: Spheroids (C. albicans, Candida tropicalis, Candida glabrata and Cryptococcus neoformans). The activated strains were inoculated on Sabouraud's solid medium plate by partition and streak method, cultured at 32°C for 2-3 days, and an appropriate amount of single colony was taken into a conical flask containing 10 mL of 0.85% sterile saline. Shake for 15 minutes, use a sterilized pipette tip to take a small amount of bacterial solution on a hemocytometer, and count under a microscope. Add RPMI-1640 medium to dilute so that the final bacterial suspension concentration is 1×10 ⁶ cells/mL.

Liquid preparation: Weigh 6.40 mg of each of the above chemically synthesized drugs, add 1.0 mL of dimethyl sulfoxide (DMSO), 1.0 mL of Tween-20 and 8.0 mL of sterile distilled water in sequence, and mix well. The concentration of the drug solution is 0.64mg/mL. The positive control drugs, fluconazole and voriconazole, were prepared in the same way.

Inoculation: Step 1, add RPMI-1640 medium: add 180 μL RPMI-1640 medium to the first well of each row, 100 μL RPMI-1640 medium to wells 2-11, and 200 μL RPMI-1640 medium to 12 wells. The second step, adding the drug sample: add 20 μL of the drug to be tested to the first well, mix with a pipette, and draw 100 μL to the second well, and then dilute it 2-fold to the tenth well, mix well and discard 100 μL. The third step, adding bacterial suspension: add 100 μL of inoculating bacterial suspension to each of wells 1-11. Well 11 is a growth control, and well 12 is a blank medium control. There is no blank drug control for the positive control drug, that is, the doubling gradient dilution from the first well to the 10th well, the test concentration (μg/mL) range is 32, 16, 8, 4, 2, 1, 0, 5, 0.25 , 0.125, 0.0625.

Cultivation and detection: Aseptic growth of blank control and good growth of positive control are the criteria for judging whether the test operation is qualified. Eight samples were tested per plate, and positive drug controls were set for each bacteria. The dilution method of the drug to be tested is the same as above.

Table 2 Example compound minimum inhibitory concentration ((MIC, μg/ml)

It can be clearly seen from the above test results that the compounds of the general formula I to be protected by the present invention and their salts have good antifungal activities, and the antifungal activities of many compounds are stronger than those of the control drugs, which are in line with the existing antifungal drugs. In comparison, it has the advantages of novel structure, low toxicity, high efficiency, broad spectrum, etc. Therefore, the compound of the present invention has a good industrial application prospect.

The compounds of general formula I in the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier. The choice of the pharmaceutically acceptable carrier depends on the desired route of administration and standard pharmaceutical practice. Various drugs of this type of compound are used below. The preparation methods of dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, drop pills, external liniments and ointments, illustrate their new applications in the pharmaceutical field.

Example 17: Tablets.

Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), adding 20 g of auxiliary materials according to the general pharmaceutical tableting method, and mixing, then compressed into 100 tablets, each weighing 300 mg.

Example 18: Capsules.

Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), mix 20 g of the auxiliary materials according to the requirements of pharmaceutical capsules, and then put them into hollow capsules, each capsule weighing 300 mg.

Example 19: Injection.

Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), according to the conventional method of pharmacy, carry out activated carbon adsorption, filter through a 0.65 μm microporous membrane, fill in a nitrogen tank to prepare a water injection preparation, Each bottle contains 2mL, and a total of 100 bottles are filled.

Example 20: Aerosol.

10 g of the compound containing the compound in claim 1 (take the compound of Example 31 as an example) is dissolved in an appropriate amount of propylene glycol, and distilled water and other materials are added to prepare a 500 mL clear solution.

Example 21: Suppositories.

Use 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), grind it into a fine amount and add an appropriate amount of glycerol, grind it evenly, add the melted glycerin gelatin, grind it evenly, and pour it into a model that has been coated with lubricant , 50 suppositories were prepared.

Example 22: Film formulation.

With 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), polyvinyl alcohol, medicinal glycerin, water, etc. are stirred and expanded, heated and dissolved, filtered through an 80-mesh sieve, and then the compound of Example 18 is added. Stir in the filtrate to dissolve, and coat 100 membranes by machine.

Example 23: Dropping pills.

10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example) was heated, melted and mixed with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin to prepare 1000 dripping pills.

Example 24: External liniment.

Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), mix and grind 2.5 g of auxiliary materials such as emulsifiers according to conventional pharmaceutical methods, and then add distilled water to 200 mL to prepare.

Example 25: Ointment.

Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 31 as an example), grind it finely with 500 g of an oily base such as vaseline to make it.

While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (7)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

MBG is

、

；

Y is O;

x is N;

“

"is a double construction;

R¹is C₃-C₆Cycloalkyl, benzyl, - (CHF) Ph, - (CF)₂) Ph or phenyl, and benzyl, - (CHF) Ph, - (CF)₂) Ph and optionally 0-3R on the phenyl ring of the phenyl group²Substitution;

ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuryl, benzothiazolyl, benzothienyl, benzopyrazolyl or indolyl, and Ar is optionally substituted with 1-3 of the same or different M;

m is hydroxy, halogen, nitro, amino, cyano, C₁-C₆Alkyl, 5-10 membered heterocyclic group, C₆-C₁₂Aryl or C₅-C₁₂Heteroaryl, said heterocyclyl and heteroaryl containing 1-3 heteroatoms selected from O, N and S, and said heterocyclyl, aryl or heteroaryl optionally containing 0-3R, which may be the same or different²Substitution;

R²is hydroxy, halogen, nitro, amino, cyano, C₁-C₆Alkyl radical, C₁-C₆An alkyl acyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof: wherein:

the Ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuryl, benzothiazolyl, benzothienyl, benzopyrazolyl or indolyl, and Ar is optionally substituted with 1-3 of the same or different M.

3. A compound selected from:

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-methyl-4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-isopropyl-4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-cyclopropyl-4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-benzyl-4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -5- (fluoro (phenyl) methyl) -4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -5- (difluoro (phenyl) methyl) -4, 5-dihydrooxazole

4-((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-tetrazol-2-yl) methyl) -2- ([1,1' -biphenyl]-4-yl) -4-phenyl-4, 5-dihydrooxazole

3-(4-((1H-1,2, 4-triazol-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazol-2-yl) -5-phenylisoxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4-phenyl-2- (5-phenylthiophen-2-yl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (4- (furan-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (4- (thiophen-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (naphthalen-2-yl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (benzofuran-2-yl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (benzo [ b ]]Thiophene-2-yl)-4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (benzo [ d ] methyl]Thiazol-2-yl) -4-phenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2, 4-diphenyl-4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (4- (benzyloxy) phenyl) -4-phenyl-4, 5-dihydrooxazole

N-(4-(4-((1H-1,2, 4-triazol-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazol-2-yl) phenyl) benzamide

1-(4-(4-(4-((1H-1,2, 4-triazol-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazol-2-yl) phenyl) piperazin-1-yl) ethanone

2-(4-(4-((1H-1,2, 4-triazol-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazol-2-yl) phenyl) -5-phenyl-1, 3, 4-oxadiazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-difluorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (thiophen-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (thiophen-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-difluorophenyl) -2- (4- (thiophen-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (thiophen-3-yl) phenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-difluorophenyl) -2- (5- (trifluoromethyl)Oxy) benzo [ b]Thien-2-yl) -4, 5-dihydrooxazoles

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-fluorobenzo [ b]Thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-fluorobenzo [ b]Thien-2-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-fluorobenzo [ b]Thiophen-2-yl) -4- (2, 4-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-fluorobenzo [ b]Thiophen-2-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-fluorobenzo [ b]Thiophen-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thien-2-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thiophen-2-yl) -4- (2, 4-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thiophen-2-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thiophen-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b]Thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b]Thien-2-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b]Thiophen-2-yl) -4- (2, 4-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b]Thien-2-yl) -4- (3, 5-difluorophenyl) -4,5-Dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b]Thiophen-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (2, 4-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (2, 4-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole

4-((1H-1,2, 4-triazol-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole

4-((1H-tetrazol-1-yl) methyl) -2- (6-chlorobenzo [ b]Thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient.

5. A process for preparing a compound of claim 1, and pharmaceutically acceptable salts thereof:

route I

Route II

Wherein Ar, M, R¹、R²And MBG as claimed in claim 1.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of fungal infection.

7. The use according to claim 6, wherein the fungal infection disease is associated with one or more of the following pathogenic fungi: absidia umbellata (Absidia coreybifera), yarrowia capsulata (Ajlomyces capsulatus), Arjothrix dermatitidis (Ajlomyces dermatitidis), Arthrobacter nigra (Arthroderma benthamiae), Arthrobacter farinosus (Arthroderma fulvum), Arthrobacter gypti (Arthroderma gypseum), Arthrobacter inquinans (Arthroderma incarnatum), Arthrobacter terrestris (Arthroderma incarnatum), Dermatophthora paniculata (Arthroderma atroviride), Aspergillus flavus (Aspergillus flavus), Aspergillus fumigatus (Aspergillus fumigatus), Aspergillus niger (Aspergillus niger), Pseudomonas glabra (Candida glabrata), Candida albicans (Candida albicans), Candida albicans (Candida albicans), Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida, Microcorium sp, Epidermophyton floccosum (Epidermophyton floccosum), Exophyton dermatum (Exophiala dermatitidis), Blastomyces dermatitidis (Exophiala dermatitidis), Filobasidiella neoformans (Filobasidiella neoformans), Verbascum pernicifluum (Fonscexaea fruosoi), Fusarium solani (Fusarium solani), Geotrichum candidum (Geotrichum candidum), Histoplasma capsulatum (Histoplasma capsulatum), Exophyton veneckii (Horteaceae), Trichosporon orientalis, Mycobacterium griseula (Madurella griseula), Malassezia furfur (Maseula furiosula furiosum), Sarcopsis (Malcinia glabra), Sarcophyllum septoria (Malpighia), Sarcoporia glauca sp), Microsporum melanogassum (Malvaceae), Microsporum melanogassum purpurea (Malvacea), Microsporum griseula melanogassum (Malvacea), Microsporum griseula aestivum furiosum, Microsporum (Malvacea viridae), Microsporum (Malvacea), Microsporum griseula furiosum canis (Malvacea), Microsporum furiosum (Malvaceae), Microsporum (Malvacea), Microsporum furiosum (Malvaceae), Microsporum (Malvacea (Malvaceae), Microsporum furiosum, Microsporum (Malvacrum (Malvaceum strain (Malvacea), Microsporum (Malvacea, Microsporum furiosum (Malvaccum) and Microsporum, Microsporum, Mucor circinelloides, Monascus ruber (Nectria haemata), Paecilomyces variotii (Paecilomyces variotii), Paracoccus braziliani (Paracoccus brazilians), Penicillium marneffei (Penicillium marneffei), Pichia anomala (Pichia anomala), Pichia quaternary (Pichia guieriillonidii), Pneumocystis carinii (Pneumocystis carinii), Pseudoleishmania Boehmerina (Pseudoallomyces boydii), Rhizopus oryzae (Rhizopus oryzae), Rhodotorula rubra (Rhodotorula rubra), Polyporus cuspidatus (Scedosporium), schizophyllum commune (Schizophyllum commune), Trichophyton schenckii (Sporothrix schenckii), Trichophyton mentagrophytes (Trichophyton mentagrophytes), Trichophyton rubrum (Trichophyton rubrum), Trichophyton mentagrophytes (Trichophyton verrucosum), Trichophyton purpureus (Trichophyton violaceum), Trichophyton assamium (Trichosporon asahii), Trichosporon dermatum (Trichosporon cutaneum), Trichosporon trichothecium (Trichosporon okinin), Trichosporon mucosae (Trichosporon mucoides), and Candida auriculata (Candida auris).