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WO2022022616A1 - 2,4,4-三取代二氢噁唑衍生物及其制备方法和用途 - Google Patents

2,4,4-三取代二氢噁唑衍生物及其制备方法和用途 Download PDF

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WO2022022616A1
WO2022022616A1 PCT/CN2021/109144 CN2021109144W WO2022022616A1 WO 2022022616 A1 WO2022022616 A1 WO 2022022616A1 CN 2021109144 W CN2021109144 W CN 2021109144W WO 2022022616 A1 WO2022022616 A1 WO 2022022616A1
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methyl
dihydrooxazole
triazol
phenyl
thiophen
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PCT/CN2021/109144
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English (en)
French (fr)
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赵冬梅
赵立雨
程卯生
孙楠楠
田霖丰
孙印
郑阳
张储
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • 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.
  • 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 finger (toe) nail 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.
  • superficial fungal infection is mainly caused by ringworm, such as skin, hair and finger (toe) nail 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.
  • 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.
  • azoles block the synthesis of ergosterol by inhibiting the activity of lanosterol 14 ⁇ -demethylase (CYP51), and are the most active and mature targets in the field of antifungal research.
  • 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).
  • imidazoles such as Miconazole, Clotrimazole, Ketoconazole
  • triazoles such as fluconazole ( Fluconazole), Itraconazole (Itraconazole), Voriconazole (Voriconazole) and Posaconazole (Posaconazole).
  • 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.
  • 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:
  • 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;
  • 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 heteroatoms 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 substituted by hydroxy, amino or halogen, or (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 ) alkyl acyl, carbamoyl; substituted by mono or di(C 1
  • R 2 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, phenyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy optionally substituted by hydroxy, amino or halogen; by mono- or di(C 1 -C ) 6 alkyl) substituted amino, (C 1 -C 6 ) alkyl amido; free, salified, esterified or amidated carboxyl; (C 1 -C 6 ) alkylsulfinyl, sulfonic Acyl.
  • 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 prodrugs thereof:
  • 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;
  • 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, benzyl, -(CHF)Ph or -( CF2 )Ph, and said aryl or heteroaryl or benzyl, -(CHF)Ph or -
  • the benzene ring of (CF 2 )Ph is optionally substituted by 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 heteroatoms 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 substituted by hydroxy, amino or halogen, or (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, (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 ) alkyl acyl; carbamoyl
  • R 2 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, phenyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylacyl; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkane optionally substituted by hydroxy, amino or halogen oxy; mono- or di(C 1 -C 6 alkyl) substituted amino, (C 1 -C 6 )alkylamido; free, salified, esterified or amidated carboxyl; (C 1 ) -C 6 ) alkylsulfinyl, (C 1 -C 6 ) alkylsulfonyl.
  • 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,
  • 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,
  • Y is O
  • 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,
  • Y is O
  • 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,
  • 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,
  • Y is O
  • 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 or indolyl, and Ar is optionally substituted with 0-3 identical or different Ms.
  • Ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuranyl, benzothiazolyl, benzothienyl, benzopyrazole or indolyl, and Ar is optionally substituted with 1-3 identical or different M.
  • 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,
  • M is phenyl, furyl, thienyl, dioxanyl, oxadiazolyl or piperazinyl.
  • 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,
  • M is phenyl, furyl, thienyl, dioxanyl, oxadiazolyl.
  • 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:
  • compositions 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.
  • 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 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.
  • 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 , o
  • 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.
  • 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 above shows a general synthetic route for the preparation of compound I , wherein Ar, M, R1 and MBG are as claimed.
  • 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, lithium tetrahydrogen reduces the ester group of intermediate A5 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 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.
  • 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.
  • Mass spectrometry used for compound structure confirmation was 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 2 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
  • Example 3 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-cyclopropyl-4,5-dihydro oxazole
  • Example 7 4-((1H-1,2,4-triazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl -4,5-Dihydrooxazole
  • 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.
  • 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.
  • 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.
  • step d the intermediate 5-4 (2 mmol) was dissolved in methanol (10 mL) solution, Pd/C was added, H 2 was added, the reaction was carried out at room temperature, TLC detected the reaction was complete, filtered, and the solvent was evaporated under reduced pressure to obtain the intermediate Body 5-5.
  • 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 drying agent was filtered off and concentrated under reduced pressure to obtain intermediate 5-7.
  • step g add intermediate 5-8 (5mmol), SOCl 2 (25mmol) and triethylamine (25mmol) in methylene chloride, stir the reaction at room temperature, TLC detects that the reaction is complete, evaporate the organic solvent, dissolve in ethyl acetate , 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.
  • 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.
  • Example 7 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
  • Example 11 4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-2-(5-phenylthiophen-2-yl)-4,5 - Dihydrooxazole
  • Example 12 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-(furan-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole
  • Example 13 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(thiophen-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole
  • Example 14 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(naphthalen-2-yl)-4-phenyl-4,5-dihydrooxane azole
  • Example 18 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(benzyloxy)phenyl)-4-phenyl-4,5 - Dihydrooxazole
  • 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
  • Example 22 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 23 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 24 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 25 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 26 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 27 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 28 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 29 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole
  • 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
  • Example 31 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 32 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • 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
  • 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
  • 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
  • Example 36 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 37 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • 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
  • 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
  • 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
  • Example 41 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 42 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Example 56 4-((1H-Tetrazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl)- 4,5-Dihydrooxazole
  • Experimental methods refer to the conventional 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).
  • RPMI-1640 medium 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 0.22 ⁇ m microporous membrane, and stored at 4°C for later use.
  • 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.
  • Use a spectrophotometer to adjust the concentration of the bacterial solution, and adjust the A value to 0.3-0.5; then dilute it 50 times with the medium to serve as the inoculated bacterial suspension.
  • Spheroids C. albicans, Candida tropicalis, Candida glabrata and Cryptococcus neoformans.
  • the activated strains were inoculated on the Sabouraud solid medium plate by the partition and streak method, and cultivated at a constant temperature of 32 °C for 2-3 days. 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 sterilized distilled water in sequence, and mix well. The concentration of the prepared medicinal solution was 0.64 mg/mL.
  • Step 1 add RPMI-1640 medium: Add 180 ⁇ L RPMI-1640 medium to the first well of each row, 100 ⁇ L RPMI-1640 medium to wells 2-11, and 200 ⁇ L RPMI-1640 medium to 12 wells.
  • the second step adding the drug sample: add 20 ⁇ L of the drug to be tested to the first well, mix with a pipette, and draw 100 ⁇ L to the second well, and then dilute it 2-fold to the tenth well, mix well and discard 100 ⁇ L.
  • the third step, adding bacterial suspension add 100 ⁇ L of inoculating bacterial suspension to each of wells 1-11.
  • Well 11 is a growth control
  • well 12 is a blank medium control.
  • test concentration ( ⁇ g/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.
  • 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.
  • a pharmaceutically acceptable carrier depends on the desired route of administration and standard pharmaceutical practice.
  • Various drugs of this type of compound are used below.

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Abstract

本发明涉及2,4,4-三取代二氢噁唑衍生物及其制备方法和用途，属于药物合成技术领域。具体地，本发明涉及一类2,4,4-三取代二氢噁唑衍生物及其药学上可接受的盐、水合物、溶剂化物或其前药，它们的制备方法以及其作为治疗由真菌感染引起的各类疾病的药物中的用途。本发明所述的2,4,4-三取代二氢噁唑衍生物及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药的通式如(I)所示：其中，MBG、X、Y、M、R1如权利要求和说明书所述。

Description

2,4,4-三取代二氢噁唑衍生物及其制备方法和用途 技术领域
本发明属于药物合成技术领域，涉及一类2,4,4-三取代二氢噁唑衍生物及其药学上可接受的盐、水合物、溶剂化物或其前药，它们的制备方法以及其作为治疗由真菌感染引起的各类疾病的药物中的用途。
背景技术
真菌感染可分为浅表真菌感染和深部真菌感染，其中浅表真菌感染主要由癣菌引起，如皮肤，毛发和指(趾)甲等真菌感染；深部真菌感染主要由白色念珠菌、新生隐球菌和烟曲霉菌引起，如皮下组织、内膜等深部组织的感染。近三十年，随着免疫缺陷的患者越来越多，真菌感染率急剧飙升，严重威胁人类健康，寻找新结构类型的抗真菌药物迫在眉睫。
目前临床上抗真菌药物根据作用机制的不同，可以分为抑制麦角甾醇合成的唑类药物；破坏细胞壁的棘白霉素类抗真菌药物、造成细胞膜泄漏的多烯类药物和作用于核酸的抗代谢类抗真菌药物。其中，唑类药物通过抑制羊毛甾醇14α-去甲基化酶(CYP51)的活性，阻断麦角甾醇的合成，是抗真菌药物领域研究最活跃，最成熟的靶点。目前临床上的唑类抗真菌药物主要分为两类：咪唑类药物如咪康唑(Miconazole)、克霉唑(Clotrimazole)、酮康唑(Ketoconazole)；三氮唑类药物如氟康唑(Fluconazole)、伊曲康唑(Itraconazole)、伏立康唑(Voriconazole)和泊沙康唑(Posaconazole)。尽管唑类药物在临床上发挥着不可替代的作用，但是该类药物严重的毒副作用和耐药菌株的产生，督促着药物化学家开发更多结构类型、高效低毒、给药方式多样的抗真菌药物。
发明内容
本发明的目的是针对现有技术的不足，提供一类2,4,4-三取代二氢噁唑衍生物，以及所述衍生物的药学可接受的盐、水合物、溶剂化合物或前 药，并提供所述衍生物的制备方法以及所述衍生物的用途；同时提供含有所述2,4,4-三取代二氢噁唑衍生物的药物组合物。本发明在参考文献的基础上，设计并合成了一系列2,4,4-三取代二氢噁唑衍生物，该类化合物经体外抗真菌活性测试表明，该类化合物具有较强的抗真菌活性，在治疗真菌感染疾病中具有较大研究价值。
为实现上述目的，本发明提供通式I所示的2,4,4-三取代二氢噁唑衍生物及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
Figure PCTCN2021109144-appb-000001
其中：
MBG是取代或未取代的四唑基、取代或未取代的三唑基、取代或未取代的咪唑基、或取代或未取代的吡啶基；所述的取代基为：氢、C1-C4烷基、C1-C4烷氧基；
Y为O或S；
X为CH、CH 2、N、NH、或O；
Figure PCTCN2021109144-appb-000002
为单键或双建；
R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、(C 1-C 4)烷氧基、羧基、-COOR 2、-CON(R 2) 2、5-10元芳基或者5-10元杂芳基，且所述芳基或杂芳基任选地被0-3个相同或不同的R 2取代；
Ar环为C3-C6环烷基、5-10元杂环基、C 6-C 10芳基或C 5-C 10杂芳基，其中，所述杂环基、杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选地被0-3个相同或不同的M取代；
M为氢、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、(C 1-C 6)烷基硫基；任选被羟基、氨基或卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基或(C 1-C 6)烷基硫基；被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的和酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、磺酰基；(C 1-C 6)烷基酰基、氨基甲酰基；被单或二(C 1-C 6烷基)取代的氨基甲酰基；除了M为所连接的供 电、吸电基团外，M也可以为5-10元杂环基、C 6-C 12芳基或C 5-C 12杂芳基，所述杂环基和杂芳基含有1-3个选自O、N和S的杂原子；并且M任选被0-3个相同或不同的R 2取代；
R 2为氢、羟基、卤素、硝基、氨基、氰基、苯基、(C 1-C 6)烷基、(C 1-C 6)烯基、(C 1-C 6)炔基、(C 1-C 6)烷氧基；任选被羟基、氨基或卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基；被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的或酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、磺酰基。
本发明提供通式I所示的2,4,4-三取代二氢噁唑衍生物及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
Figure PCTCN2021109144-appb-000003
其中：
MBG是取代或未取代的四唑基、取代或未取代的三唑基、取代或未取代的咪唑基、或取代或未取代的吡啶基；所述的取代基为：氢、C1-C4烷基、C1-C4烷氧基；
Y为O或S；
X为CH、CH 2、N、NH、或O；
Figure PCTCN2021109144-appb-000004
为单键或双建；
R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、(C 1-C 4)烷氧基、羧基、-COOR 2、-CON(R 2) 2、5-10元芳基或者5-10元杂芳基、苄基、-(CHF)Ph或-(CF 2)Ph，且所述芳基或杂芳基或者苄基、-(CHF)Ph或-(CF 2)Ph的苯环上任选地被0-3个相同或不同的R 2取代；
Ar环为C3-C6环烷基、5-10元杂环基、C 6-C 10芳基或C 5-C 10杂芳基，其中，所述杂环基、杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选地被0-3个相同或不同的M取代；
M为氢、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、(C 1-C 6)烷基硫基；任选被羟基、氨基或 卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基或(C 1-C 6)烷基硫基；被单或二(C 1-C 6烷基)取代的氨基；(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的和酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基；(C 1-C 6)烷基酰基；氨基甲酰基；被单或二(C 1-C 6烷基)取代的氨基甲酰基；或者M为5-10元杂环基、C 6-C 12芳基或C 5-C 12杂芳基，所述杂环基和杂芳基含有1-3个选自O、N和S的杂原子；并且M任选被0-3个相同或不同的R 2取代；
R 2为氢、羟基、卤素、硝基、氨基、氰基、苯基、(C 1-C 6)烷基、(C 1-C 6)烯基、(C 1-C 6)炔基、(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基；任选被羟基、氨基或卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基；被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的或酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
MBG选自以下结构：
Figure PCTCN2021109144-appb-000005
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
Figure PCTCN2021109144-appb-000006
为双键，X为N。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
Figure PCTCN2021109144-appb-000007
为双键，X为N；
MBG选自以下结构：
Figure PCTCN2021109144-appb-000008
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、苄基、-(CHF)Ph、-(CF 2)Ph或苯基，且苄基、-(CHF)Ph、-(CF 2)Ph和苯基的苯环上任选0-3个R 2取代。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
Figure PCTCN2021109144-appb-000009
为双键，X为N；
R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、苄基、-(CHF)Ph、-(CF 2)Ph或苯基，且苄基、-(CHF)Ph、-(CF 2)Ph和苯基的苯环上任选0-3个R 2取代；
MBG为以下结构之一：
Figure PCTCN2021109144-appb-000010
Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选被0-3个相同或不同的M取代。
Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选被1-3个相同或不同的M取代。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
M为苯基、呋喃基、噻吩基、二噁烷基、噁二唑基或哌嗪基。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
M为苯基、呋喃基、噻吩基、二噁烷基、噁二唑基。
本发明优选如下化合物及其药学上可接受的盐、水合物、溶剂化物或前药，但这些化合物并不意味着对本发明的任何限制：
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)苯甲酰胺
1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯 基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯 基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
而且，按照本发明所属领域的一些通常方法，本发明中通式I的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式I所示的化合物可以以非溶剂化形式和含有药学上可接受的溶 剂(如水、乙醇等)的溶剂化形式。通式I所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式I所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“亚烷基”是指直链或支链的亚烷基；“芳基”是指除去芳烃中的一个或不同位置的两个氢原子而得到的有机基团，如苯基、萘基；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，该环状体系是指具有芳香性的，并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团，如噻唑基，咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基，吲哚基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹啉基，异喹啉基，苯并咪唑基，苯并噁唑基等。
本发明可以含有通式I的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋形剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋形剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明通式I的化合物可以通过包括化学领域众所周知的方法来合 成，尤其根据本发明的说明来制备；本发明中的室温指环境温度，为10℃至30℃。
应当理解的是，本文所述的实施例和反应方案仅为例举说明目的，本领域技术人员可以据此进行各种修改和改变，并且这些修饰和改变均包括在本发明的主旨和范围内以及所附权利要求的范围内。
化合物制备的一般反应方案
本发明的化合物及其药学上可接受的盐可由如下物质制备：(a)原料一般可以从商业来源获取的或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备，(b)可由文献记载的方法制备的已知起始物质，(c)本文的方案和实验过程中所描述的新中间体。本发明中的化合物可以通过以下反应方案及描述合成。
方案I
Figure PCTCN2021109144-appb-000011
上述方案I展示出了制备化合物I的一般合成路线，其中Ar、M、R 1和MBG如权利要求书所述。
将D-丝氨酸甲酯盐酸盐A1与原料A2发生酰胺反应得到中间体A3，-80℃条件下，中间体A3与SOCl 2发生反应得到中间体A4，中间体A4在碱性条件下与R 1-X(X为卤素)发生取代反应得到中间体A5，四氢铝锂还原中间体A5的酯基得到中间体A6，A6与SOCl 2发生取代反应得到中 间体A7，A7与MBG发生取代反应得到目标化合物I。
方案II
Figure PCTCN2021109144-appb-000012
上述方案II展示出了制备化合物R 1为
Figure PCTCN2021109144-appb-000013
时，化合物的一般合成路线，其中Ar、M、R 1、R 2和MBG如权利要求书所述。
原料B1与AgNO 2发生取代反应得到中间体B2，中间体B2与甲醛发生双羟甲基化反应得到中间体B3，中间体B3与2,2-二甲氧基丙烷发生反应得到中间体B4，中间体B4与Pd/C发生还原反应得到中间体B5，中间体B5与原料B6发生酰胺反应得到中间体B7，中间体B7在酸性条件下脱去保护基得到中间体B8，中间体B8与SOCl 2发生取代反应，得到中间体B9，中间体B9与MBG发生取代反应，得到目标化合物B10。
本发明的积极进步效果在于：本发明提供了2,4,4-三取代二氢噁唑衍生物，其制备方法、药物组合物和应用。本发明的2,4,4-三取代二氢噁唑衍生物对各种浅表和深部真菌具有良好的抗真菌活性，与现有临床应用的抗真菌药物相比，具有高效、低毒、抗真菌谱广等优点，可用于制备抗真菌药物。
本发明提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下属实例和制备例的范围并不以任何方式限制 本发明的范围。本发明的通式I的化合物，可按照方案I和方案II的合成方法制备得来，这些路线中应用的全部可变因数如权利要求中的定义。
具体实施方式
不需要进一步详细说明，认为本领域熟练技术人员借助于前面的描述，可以最大程度的利用本发明。因此下面提供的实施例旨在阐述而不是限制本发明的范围。
原料一般可以从商业来源获取的或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。
化合物结构确证所用的质谱用Agilent 1100LC/MS测定。柱层析纯化产物使用的是青岛海洋化工厂生产的100-200目或者200-300目硅胶。
实施例1：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000014
步骤a中：将原料1-1(1.1mmol)、联苯甲酸1-2(1.1mmol)和PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(1.2mmol)加入到DMF中，室温搅拌反应8h，TLC检测反应完毕，加水，乙酸乙酯萃取， 饱和食盐水洗涤有机层，无水硫酸钠干燥过夜。滤除干燥剂，减压浓缩得中间体1-3。
步骤b中：将中间体1-3(5mmol)、SOCl 2(12.5mmol)和三乙胺(12.5mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体1-4。
步骤c中：将中间体1-4(5mmol)溶于无水THF中，缓慢滴加LiN(Pr-i) 2(10mmol)的THF溶液，反应约1h，加入CH 3I(10mmol)，TLC检测反应完全，升至室温，加饱和NH 4Cl溶液淬灭，减压蒸除有机溶剂，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩得中间体1-5。
步骤d中：冰浴条件下，将中间体1-5(5mmol)溶于THF中，分批加入四氢铝锂(10mmol)，TLC检测反应完全，加饱和NH 4Cl溶液淬灭反应，减压蒸除有机溶剂，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩得中间体1-6。
在步骤e中：将中间体1-6(5mmol)、SOCl 2(20mmol)和三乙胺(20mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体1-7。
在步骤f中：冰浴条件下，将咪唑(15mmol)加入DMF中，加入NaH(20mmol)，搅拌30min后加入中间体1-7(5mmol)，继续反应，TLC检测反应完毕，将反应液倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得目标化合物1。 1H-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)calcd for C 20H 19N 3O,[M+H] +,318.1601；found 318.1632.
按照实施例1的方法，分别使用相应的卤代烷，制备得到实施例2-6。
实施例2：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5- 二氢噁唑
Figure PCTCN2021109144-appb-000015
ESI-MS[M+H] +(m/z):346.1。
实施例3：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000016
ESI-MS[M+H] +(m/z):344.1。
实施例4：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000017
1H-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 26H 23N 3O,[M+H] +,394.1914；found 394.1949.
实施例5：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000018
HRMS(ESI,m/z)calcd for C 26H 22FN 3O,[M+H] +,412.1820；found 412.1857.
实施例6：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基) 甲基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000019
1H-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 26H 21F 2N 3O,[M+H] +,430.1725；found 430.1727.
实施例7：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000020
步骤a中：将AgNO 2(10mmol)加入乙醚(30mL)中，室温搅拌，滴加溴苄(5mmol)，避光搅拌反应5h，将反应液倾入水中，用乙醚萃取3次，减压蒸除乙醚得淡黄色油状液体，柱层析得中间体5-2。
步骤b中：将中间体5-2(4mmol)溶于乙醇中，加入甲醛溶液(24mmol)、NaOH(4mmol)，室温搅拌反应，TLC检测反应完毕，减压蒸除有机溶剂，加水，乙酸乙酯萃取3次，合并有机层，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-3。
步骤c中：将2,2-二甲氧基丙烷(4.5mmol)加入中间体5-3(3mmol)的丙酮溶液中，加入对甲基苯磺酸(0.6mmol)，室温反应，TLC检测反应完全，减压蒸除溶剂，柱层析得中间体5-4。
在步骤d中：将中间体5-4(2mmol)溶于甲醇(10mL)溶液中，加入Pd/C，通入H 2，室温反应，TLC检测反应完全，过滤，减压蒸除溶剂得中间体5-5。
步骤e中：将原料联苯甲酸5-6(1.1mmol)、中间体5-5(1.1mmol)和PyBOP(1.2mmol)加入DMF(10mL)中，室温搅拌反应8h，TLC检测反应完毕，加水，乙酸乙酯萃取，饱和食盐水洗涤有机层，无水硫酸钠干燥过夜。滤除干燥剂，减压浓缩得中间体5-7。
步骤f中：将中间体5-7(5mmol)加入到冰乙酸/水(V:V＝3:1)中，40℃反应，TLC检测反应完全，倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-8。
步骤g中：将中间体5-8(5mmol)、SOCl 2(25mmol)和三乙胺(25mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-9。
步骤h中：冰浴条件下，将唑(15mmol)加入DMF(10mL)中，加入NaH(20mmol)，搅拌30min后加入中间体5-9(5mmol)，继续反应，TLC检测反应完毕，将反应液倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na 2SO 4干燥过夜。滤除干燥剂，减压浓缩、柱层析得目标化合物7。 1H-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 24H 20N 4O,[M+Na] +,403.1529；found 403.1563.
按照实施例7的方法，分别使用相应的原料制备得到实施例8-56。
实施例8：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000021
1H-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 25H 21N 3O,[M+H] +,380.1757；found 380.1796.
实施例9：4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000022
1H-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 23H 19N 5O,[M+Na] +,404.1482；found 404.1514.
实施例10：3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
Figure PCTCN2021109144-appb-000023
1H-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 21H 17N 5O 2,[M+Na] +,394.1274；found 394.1315.
实施例11：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000024
1H-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 22H 18N 4OS,[M+Na] +,409.1094；found 409.1134.
实施例12：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000025
1H-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 for C 22H 18N 4O 2,[M+Na] +,393.1322；found 393.1356.
实施例13：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000026
1H-NMR(600MHz,DMSO-d 6)δ8.31(s,1H),8.04(dd,J＝2.9,1.3Hz,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＝7.7Hz,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 22H 18N 4OS,[M+Na] +,409.1094；found 409.1140.
实施例14：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000027
1H-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 22H 18N 4O,[M+Na] +,377.1373；found 377.1403.
实施例15：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000028
1H-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 for C 20H 16N 4O 2,[M+Na] +,367.1165；found 367.1203.
实施例16：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000029
1H-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 19H 15N 5OS,[M+Na] +,384.0890；found 384.0923.
实施例17：4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000030
1H-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 18H 16N 4O,[M+Na] +,327.1216；found 327.1248.
实施例18：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000031
1H-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 25H 22N 4O 2,[M+H] +,411.1816；found 411.1856.
实施例19：N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)苯甲酰胺
Figure PCTCN2021109144-appb-000032
1H-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 25H 21N 5O 2,[M+Na] +,446.1587；found 446.1640.
实施例20：1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
Figure PCTCN2021109144-appb-000033
1H-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 for C 24H 26N 6O 2,[M+Na] +,453.2009；found 453.2050.
实施例21：2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
Figure PCTCN2021109144-appb-000034
1H-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 26H 20N 6O 2,[M+Na] +,471.1540；found 471.1577.
实施例22：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000035
1H-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 22H 17FN 4O 2,[M+Na] +,411.1228；found 411.1264.
实施例23：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000036
ESI-MS[M+H] +(m/z):405.1。
实施例24：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000037
ESI-MS[M+H] +(m/z):407.1。
实施例25：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000038
ESI-MS[M+H] +(m/z):439.1。
实施例26：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000039
ESI-MS[M+H] +(m/z):405.1。
实施例27：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000040
ESI-MS[M+H] +(m/z):421.1。
实施例28：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000041
ESI-MS[M+H] +(m/z):423.1。
实施例29：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000042
ESI-MS[M+H] +(m/z):455.1。
实施例30：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000043
ESI-MS[M+H] +(m/z):481.1。
实施例31：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000044
1H-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 20H 14F 2N 4OS,[M+Na] +,419.0749；found 419.0778.
实施例32：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000045
ESI-MS[M+H] +(m/z):413.1。
实施例33：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000046
1H-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 20H 13F 3N 4OS,[M+Na] +,437.0654；found 437.0688.
实施例34：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000047
ESI-MS[M+H] +(m/z):415.1。
实施例35：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000048
ESI-MS[M+H] +(m/z):447.1。
实施例36：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000049
1H-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 20H 14ClFN 4OS,[M+Na] +,435.0453；found 435.0480.
实施例37：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000050
1H-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 20H 14Cl 2N 4OS,[M+Na] +,451.0158；found 451.0195.
实施例38：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000051
1H-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 20H 13ClF 2N 4OS,[M+Na] +,453.0359；found 453.0383.
实施例39：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000052
1H-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＝14.1Hz,1H),4.55(d,J＝9.1Hz,1H).HRMS(ESI,m/z)calcd for C 20H 13ClF 2N 4OS,[M+Na] +,453.0359；found 453.0383.
实施例40：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2- 基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000053
ESI-MS[M+H] +(m/z):463.1。
实施例41：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000054
1H-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 20H 14BrFN 4OS,[M+Na] +,478.9948；found 480.9957.
实施例42：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000055
1H-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。
实施例43：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2- 基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000056
1H-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＝9.1,2.6Hz,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 20H 13BrF 2N 4OS,[M+Na] +,496.9854；found 498.9869.
实施例44：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000057
1H-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＝9.1Hz,1H).HRMS(ESI,m/z)calcd for C 20H 13BrF 2N 4OS,[M+Na] +,496.9854；found 498.9869.
实施例45：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000058
ESI-MS[M+H] +(m/z):507.1。
实施例46：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000059
1H-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 24H 18F 2N 4O,[M+Na] +,439.1341；found 439.1382.
实施例47：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000060
1H-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 24H 18ClFN 4O,[M+Na] +,455.1045；found 455.1093.
实施例48：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000061
1H-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 24H 17F 3N 4O,[M+Na] +,457.1247；found 457.1282.
实施例49：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000062
1H-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 24H 17F 3N 4O,[M+Na] +,457.1247；found 457.1281.
实施例50：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000063
ESI-MS[M+H] +(m/z):467.1。
实施例51：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000064
1H-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 24H 18F 2N 4O,[M+Na] +,439.1341；found 439.1390.
实施例52：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000065
1H-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 24H 18ClFN 4O,[M+Na] +,455.1045；found 455.1083.
实施例53：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000066
1H-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＝9.1,1.6Hz,1H).HRMS(ESI,m/z)calcd for C 24H 17F 3N 4O,[M+Na] +,457.1247；found 457.1286.
实施例54：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000067
1H-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 24H 17F 3N 4O,[M+Na] +,457.1247；found 457.1279.
实施例55：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000068
ESI-MS[M+H] +(m/z):467.1。
实施例56：4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
Figure PCTCN2021109144-appb-000069
1H 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。
本发明部分产物的药理研究。
实验方法:参考常规的体外抑菌试验方法(Reference method for broth dilution antifungal susceptibility testing of yeasts and filamentous fungi； Approved Standard M27-A3 and M38-A2)。
实验材料和方法:
(1)实验菌株：
本实验选用了以下5种常见的人体致病标准真菌菌株作为筛选对象，真菌菌株由沈阳药科大学提供。
表1实验所用菌种及其编号
菌种名称 Species 菌株选择
白色念珠菌 Candida albicans SC5314
白色念珠菌 Candida albicans CPCC400523
新生隐球菌 Cryptococcus neofrmans GIM 2.209
热带假丝酵母菌 Candida tropicalis cgmcc 2.3739
烟曲霉菌 Aspergillus fumigatus cgmcc 3.7795
(2)试验方法：
RPMI-1640培养基的配制：RPMI-1640 10g,NaHCO 3 2.0g，三氮吗啡琳丙磺酸(sigma)34.5g，加800mL无菌蒸馏水溶解，lmol/L NaOH调整pH至7.0后，定容至1000mL，0.22μm微孔滤膜过滤除菌后放置4℃保存备用。
丝状真菌菌悬液的制备：丝状真菌(红色毛癣菌、疵状毛癣菌、石膏样小抱子菌和烟曲霉菌)等连续两次传代接种于沙氏培养基平板，在35℃培养箱中培养48h，菌落上加入0.85％生理盐水5mL，制备菌液。用分光光度计调整菌液浓度，A值调整至0.3-0.5；再用培养基稀释50倍作为接种菌悬液。
球状真菌菌悬液的制备：球状菌(白色念珠菌、热带假丝酵母菌、光滑假丝酵母菌和新生隐球菌)。将活化后的菌株用分区划线法接种于沙氏固体培养基平板上，于32℃恒温培养2-3天，取适量单菌落接入含l0mL0.85％无菌生理盐水的三角瓶中，震荡15分钟，用灭菌枪头取少量菌液于血细胞计数板上，显微镜下计数。加RPMI-1640培养基稀释，使最终菌悬液的浓度为1x10 6个/mL。
药液制备：称取上述化学合成药各6.40mg，依次加入l.0mL二甲基亚砜(DMSO),l.0mL吐温-20和8.0mL灭菌蒸馏水，混匀。配成药液浓 度为0.64mg/mL。以相同方法配制阳性对照药氟康唑、伏立康唑。
接种：第一步，加RPMI-1640培养基：每行的第1孔加入180μL RPMI-1640培养基，2-11孔加入100μL RPMI-1640培养基，12孔加入200μL RPMI-1640培养基。第二步，加药样：向第1孔中加入20μL待测药液，用移液枪混匀后吸取100μL至2孔，依次进行2倍稀释至第10孔后混匀弃去100μL。第三步，加菌悬液：向1-11孔中各加100μL接种菌悬液。第11孔为生长对照，第12孔为空白培养基对照。阳性对照药物不设空白药物对照，即从第1孔开始做倍比梯度稀释直至第10孔，测试浓度(μg/mL)范围32、16、8、4、2、1、0、5、0.25、0.125、0.0625。
培养和检测：以空白对照无菌生长，阳性对照生长良好作为判断试验操作是否合格的标准。每板测试8个样品，每个菌均设置阳性药物对照。待测药物稀释法同上。
表2.实例化合物最低抑菌浓度((MIC,μg/ml)
Figure PCTCN2021109144-appb-000070
Figure PCTCN2021109144-appb-000071
Figure PCTCN2021109144-appb-000072
从上述试验结果可以清楚地看出，本发明所要保护的通式I的化合物及其盐类具有良好的抗真菌活性，多个化合物的抗真菌活性强于对照药，与现有的抗真菌药物相比，具有结构新颖、低毒、高效、广谱等优点，因此本发明的化合物具有很好的工业应用前景。
本发明中通式I的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
片剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
胶囊剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。
注射剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g， 按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
气雾剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
栓剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。
膜剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
滴丸剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
外用搽剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
软膏剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。

Claims (11)

  1. 通式(I)所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
    Figure PCTCN2021109144-appb-100001
    其中：
    MBG是取代或未取代的四唑基、取代或未取代的三唑基、取代或未取代的咪唑基、或取代或未取代的吡啶基；所述的取代基为：氢、C1-C4烷基、C1-C4烷氧基。
    Y为O或S；
    X为CH、CH 2、N、NH、或O；
    Figure PCTCN2021109144-appb-100002
    为单键或双建；
    R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、(C 1-C 4)烷氧基、羧基、-COOR 2、-CON(R 2) 2、5-10元芳基或者5-10元杂芳基、苄基、-(CHF)Ph或-(CF 2)Ph，且所述芳基或杂芳基或者苄基、-(CHF)Ph或-(CF 2)Ph的苯环上任选0-3个相同或不同的R 2取代；
    Ar环为C3-C6环烷基、5-10元杂环基、C 6-C 10芳基或C 5-C 10杂芳基，其中，所述杂环基、杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选0-3个相同或不同的M取代；
    M为氢、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、(C 1-C 6)烷基硫基；任选被羟基、氨基或卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基或(C 1-C 6)烷基硫基；被单或二(C 1-C 6烷基)取代的氨基；(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的和酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基；(C 1-C 6)烷基酰基；氨基甲酰基；被单或二(C 1-C 6烷基)取代的氨基甲酰基；或者M为5-10元杂环基、C 6-C 12芳基或C 5-C 12杂芳基，所述杂环基和杂芳基含有1-3个选自O、N和S的杂原子；并且M任选被0-3个相同或不同的R 2 取代；
    R 2为氢、羟基、卤素、硝基、氨基、氰基、苯基、(C 1-C 6)烷基、(C 1-C 6)烯基、(C 1-C 6)炔基、(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基；任选被羟基、氨基或卤素取代的(C 1-C 6)烷基或(C 1-C 6)烷氧基；被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基；游离的、成盐的、酯化的或酰胺化的羧基；(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基。
  2. 如权利要求1所述的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
    其中，MBG选自以下结构：
    Figure PCTCN2021109144-appb-100003
  3. 如权利要求1或2所述化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：其中，
    Y为O；
    Figure PCTCN2021109144-appb-100004
    为双键，X为N。
  4. 如权利要求1-3任何一项所述的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：其中，
    R 1为(C 1-C 5)烷基、(C 3-C 6)环烷基、苄基、-(CHF)Ph、-(CF 2)Ph或苯基，且苄基、-(CHF)Ph、-(CF 2)Ph和苯基的苯环上任选0-3个R 2取代。
  5. 如权利要求1-4任何一项所述的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：其中：
    Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选被0-3个相同或不同的M取代。
  6. 如权利要求1-5任何一项所述的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：其中：
    M为苯基、呋喃基、噻吩基、二噁烷基、噁二唑基或哌嗪基
  7. 如下的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，选自：
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基)甲基)-4,5-二氢噁唑
    4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
    4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
    3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
    N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基) 苯甲酰胺
    1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
    2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟 苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟 苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
    4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
    4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑。
  8. 一种药用组合物，包含权利要求1-7中任何一项的化合物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
  9. 如权利要求1所述的化合物，及其药学上可接受的盐的制备方法：
    Figure PCTCN2021109144-appb-100005
    路线I
    Figure PCTCN2021109144-appb-100006
    路线II
    其中，Ar、M、R 1和MBG如权利要求1所述。
  10. 权利要求1-7中任何一项的化合物及其药学上可接受的盐、水合 物、溶剂化物或前药或权利要求8所述的药用组合物在制备治疗真菌感染疾病药物中的应用。
  11. 如权利要求10所述的应用，其中所述的真菌感染疾病与一种或多种以下致病真菌有关：伞状犁头霉(Absidia corymbifera)、荚膜阿耶罗菌(Ajellomyces capsulatus)、皮炎阿耶罗菌((Ajellomyces dermatitidis)、苯黑末节皮真菌(Arthroderma benhamiae)、粉节皮菌(Arthroderma fulvum)、石膏样节皮菌(Arthroderma gypseum)、内弯节皮菌(Arthroderma incurvatum)、太田节皮菌(Arthroderma otae)、万博节皮菌(Arthroderma vanbreuseghemii)、黄曲霉(Aspergillus flavus)、烟曲霉(Aspergillus fumigatus)、黑曲霉(Aspergillus niger)、皮炎芽生菌(Blastomyces dermatitidis)、白色念珠菌(Candida albicans)、光滑念珠菌(Candida glabrata)、季也蒙念珠菌(Candida guilliermondii)、克鲁斯念珠菌(Candida krusei)、近平滑念珠菌(Candida parapsilosis)、热带假丝念珠菌(Candida tropicalis)、菌膜假丝酵母(Candida pelliculosa)、卡氏枝抱瓶霉(Cladophialophora carrionii)、粗球孢子菌(Coccidioides immitis)、新生隐球菌(Cryptococcus neoformans)、小克银汉霉菌属(Cunninghamella sp.)、絮状表皮癣菌(Epidermophyton floccosum)、皮炎外瓶霉(Exophiala dermatitidis)、新型线黑粉菌(Filobasidiella neoformans)、佩德罗索氏着色芽生菌(Fonsecaea pedrosoi)、腐皮镰刀菌(Fusarium solani)、白地霉(Geotrichum candidum)、荚膜组织胞浆菌(Histoplasma capsulatum)、威尼克外瓶霉(Hortaea werneckii)、东方伊萨酵母(工ssatschenkia orientalis)、灰马杜拉分枝菌(Madurella grisae)、糠批马拉色菌(Malassezia fur fur)、球形马拉色菌(Malassezia globosa)、钝形马拉色菌(Malassezia obtusa)、厚皮马拉色菌(Malassezia pachydermatis)、限制性马拉色菌(Malassezia restricta)、斯洛非马拉色菌(Malassezia slooffiae)、合轴马拉色菌(Malassezia sympodialis)、犬小孢子菌(Microsporum cams)、黄褐色小孢子菌(Microsporum fulvum)、石膏样小孢子菌(Microsporum gypseum)、卷枝毛霉菌(Mucor circinelloides)、红球丛赤壳(Nectria haematococca)、宛氏拟青霉(Paecilomyces variotii)、巴西副球孢子菌(Paracoccidioides brasiliensis)、马尔尼菲青霉菌(Peniciliium marneffei)、异常毕赤酵母(Pichia anomala)、季也蒙毕赤酵母(Pichia guilliermondii)、卡氏 肺孢子虫(Pneumocystis carinii)、波氏假阿利什菌(Pseudallescheria boydii)、稻根霉菌(Rhizopus oryzae)、深红酵母(Rhodotorula rubra)、尖端赛多孢子菌(Scedosporium apiospernium)、裂褶菌(Schizophyllum commune)、申克孢子丝菌(Sporothrix schenckii)、须发癣菌(Trichophyton mentagrophytes)、红色毛癣菌(Trichophyton rubrum)、疵状癣菌(Trichophyton verrucosum)、紫色毛癣菌(Trichophyton violaceum)、阿萨希毛孢子菌(Trichosporon asahii)、皮肤毛孢子菌(Trichosporon cutaneum)、墨毛孢子菌(Trichosporon inkin)、粘状毛孢子菌(Trichosporon mucoides)、耳念珠菌(Candida auris)。
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