CN111848600A - 2,4, 4-trisubstituted dihydrooxazole derivative and application thereof - Google Patents

2,4, 4-trisubstituted dihydrooxazole derivative and application thereof Download PDF

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CN111848600A
CN111848600A CN202010749278.4A CN202010749278A CN111848600A CN 111848600 A CN111848600 A CN 111848600A CN 202010749278 A CN202010749278 A CN 202010749278A CN 111848600 A CN111848600 A CN 111848600A
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methyl
dihydrooxazole
phenyl
triazole
trichosporon
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CN111848600B (en
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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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Shenyang Pharmaceutical University
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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

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-trisubstituted dihydrooxazole derivative and application thereof
Technical Field
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.
Background
Fungal infections can be divided into superficial fungal infections and deep fungal infections, wherein superficial fungal infections are mainly caused by ringworm, such as fungal infections of skin, hair and nails; deep fungal infections are mainly caused by candida albicans, cryptococcus neoformans and aspergillus fumigatus, such as infections of deep tissues like subcutaneous tissue and intima. In recent thirty years, with more and more patients with immunodeficiency, the fungal infection rate is sharply increased, the human health is seriously threatened, and the search for antifungal medicines with new structural types is urgent.
Currently, clinical antifungal drugs can be classified into azole drugs for inhibiting ergosterol synthesis according to different action mechanisms; echinocandin antifungal drugs which destroy cell walls, polyene drugs which cause cell membrane leakage, and antimetabolite antifungal drugs which act on nucleic acids. The azole drugs block the synthesis of ergosterol by inhibiting the activity of lanosterol 14 alpha-demethylase (CYP51), and are the most active and mature targets for the field of antifungal drugs. Currently, clinical azole antifungal drugs are mainly classified into two types: imidazoles such as Miconazole (Miconazole), Clotrimazole (Clotrimazole), Ketoconazole (Ketoconazole); triazole drugs such as Fluconazole (Fluconazole), Itraconazole (Itraconazole, Voriconazole (Voriconazole) and Posaconazole (Posaconazole)) although azole drugs play irreplaceable roles in clinic, serious toxic and side effects and drug-resistant strains of the drugs are generated, and pharmacochemists are urged to develop antifungal drugs with more structural types, high efficiency, low toxicity and various administration modes.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a2, 4, 4-trisubstituted dihydrooxazole derivative, a pharmaceutically acceptable salt, a hydrate, a solvent compound or a prodrug of the derivative, a preparation method of the derivative and application of the derivative; also provides a medicine composition containing the 2,4, 4-trisubstituted dihydro oxazole derivative. According to the invention, a series of 2,4, 4-trisubstituted dihydro oxazole derivatives are designed and synthesized on the basis of reference documents, and the compounds have strong antifungal activity and great research value in treatment of fungal infection diseases as shown by in vitro antifungal activity tests.
In order to achieve the above objects, the present invention provides a2, 4, 4-trisubstituted dihydrooxazole derivative represented by the general formula I and a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
Figure BDA0002609486550000011
wherein:
MBG is a substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyridyl; the substituent is as follows: hydrogen, C1-C4 alkyl, C1-C4 alkoxy.
Y is O or S;
x is CH, CH2N, NH, or O;
Figure BDA0002609486550000021
is a single bond or a double bond;
R1is (C)1-C5) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C4) Alkoxy, carboxyl, -COOR2、-CON(R2)25-10 membered aryl or 5-10 membered heteroaryl, and said aryl or heteroaryl is optionally 0-3 of the same or different R2Substitution;
ar ring is C3-C6 cycloalkyl, 5-10 member heterocyclyl, C6-C10Aryl or C5-C10Heteroaryl, wherein said heterocyclyl, heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 0-3, the same or different M;
m is hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group; in addition to M being a bonded electron-donating, electron-withdrawing group, M may also be a 5-to 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 hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)1-C6) Alkenyl, (C)1-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, freeSalified, esterified and amidated carboxyl groups, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably selects the compound shown in the general formula I, and stereoisomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
MBG is selected from the following structures:
Figure BDA0002609486550000022
the invention preferably selects the compound shown in the general formula I, and stereoisomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
y is O;
Figure BDA0002609486550000031
is a double bond, and X is N.
The invention preferably selects the compound shown in the general formula I, and stereoisomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
y is O;
Figure BDA0002609486550000032
is a double bond, X is N;
MBG is selected from the following structures:
Figure BDA0002609486550000033
the invention preferably selects the compound shown in the general formula I, and stereoisomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
R1is (C)1-C5) Alkyl, (C)3-C6) Cycloalkyl, 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 group2And (4) substitution.
The invention preferably selects the compound shown in the general formula I, and stereoisomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
y is O;
Figure BDA0002609486550000034
is a double bond, X is N;
R1is (C)1-C5) Alkyl, (C)3-C6) Cycloalkyl, 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;
MBG is one of the following structures:
Figure BDA0002609486550000035
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.
The following compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are preferred in the present invention, but these compounds are not meant to limit the invention in any way:
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-triazole-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-triazole-1-yl) methyl) -4-phenyl-2- (5-phenylthiophen-2-yl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (furan-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (thiophene-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (naphthalene-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzofuran-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzo [ b ] thiophen-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzo [ d ] thiazol-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2, 4-diphenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (benzyloxy) phenyl) -4-phenyl-4, 5-dihydrooxazole
N- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) benzamide
1- (4- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) piperazine-1-yl) ethanone
2- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) -5-phenyl-1, 3, 4-oxadiazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (thiophene-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-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-difluorophenyl) -2- (5- (trifluoromethoxy) benzo [ b ] thiophen-2-yl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-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-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-chlorphenyl) -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-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-difluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-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
Furthermore, some of the compounds of formula I of the present invention have basic groups and can form pharmaceutically acceptable salts with acids according to conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid 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, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The compounds of formula I may be in unsolvated form as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds of formula I may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the present invention.
The compounds of formula I may exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are mutually converted via a low energy barrier.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "aryl" refers to an organic group derived from an aromatic hydrocarbon by removal of two hydrogen atoms at one or different positions, such as phenyl, naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which refers to an organic group having aromatic character and obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, and the like.
The invention can contain the derivative of the general formula I, and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredients, and the derivative is mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may 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 containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., 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 formula I of the present invention may be synthesized by methods well known in the chemical arts, including, inter alia, the preparation of compounds according to the teachings of the present invention; the room temperature in the present invention means an ambient temperature of 10 ℃ to 30 ℃.
It is understood that the examples and reaction schemes described herein are for illustrative purposes only and that various modifications and changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this invention and scope of the appended claims.
General reaction scheme for the preparation of Compounds
The compounds of the present invention and pharmaceutically acceptable salts thereof may be prepared from: (a) the starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art or in accordance with the methods described herein, (b) known starting materials which may be prepared by literature procedures, (c) the novel 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
Figure BDA0002609486550000071
Scheme I above showsA general synthetic route to compound I is shown, wherein Ar, M, R1And MBG as described in the claims.
Performing amide reaction on D-serine methyl ester hydrochloride A1 and raw material A2 to obtain intermediate A3, and reacting the intermediate A3 and SOCl at-80 DEG C2Reacting to obtain intermediate A4, and reacting intermediate A4 with R under alkaline condition1Carrying out substitution reaction on-X (X is halogen) to obtain an intermediate A5, reducing ester group of the intermediate A5 by lithium aluminum hydride to obtain an intermediate A6, and reacting A6 with SOCl2Carrying out substitution reaction to obtain an intermediate A7, and carrying out substitution reaction between A7 and MBG to obtain a target compound I.
Scheme II
Figure BDA0002609486550000081
Scheme II above demonstrates the preparation of Compound R1Is composed of
Figure BDA0002609486550000082
General synthetic route to compounds, where Ar, M, R1、R2And MBG as described in the claims.
Feedstock B1 with AgNO2Carrying out substitution reaction to obtain an intermediate B2, carrying out dihydroxymethylation reaction on the intermediate B2 and formaldehyde to obtain an intermediate B3, carrying out reaction on the intermediate B3 and 2, 2-dimethoxypropane to obtain an intermediate B4, carrying out reduction reaction on the intermediate B4 and Pd/C to obtain an intermediate B5, carrying out amide reaction on the intermediate B5 and a raw material B6 to obtain an intermediate B7, removing a protecting group from the intermediate B7 under an acidic condition to obtain an intermediate B8, and carrying out deprotection reaction on the intermediate B8 and SOCl to obtain an intermediate B82Carrying out substitution reaction to obtain an intermediate B9, and carrying out substitution reaction between the intermediate B9 and MBG to obtain a target compound B10.
The positive progress effects of the invention are as follows: the invention provides a2, 4, 4-trisubstituted dihydro oxazole derivative, a preparation method, a pharmaceutical composition and application thereof. The 2,4, 4-trisubstituted dihydro oxazole derivative has good antifungal activity on various superficial and deep fungi, has the advantages of high efficiency, low toxicity, wide antifungal spectrum and the like compared with the antifungal medicines in the prior clinical application, and can be used for preparing antifungal medicines.
The examples and preparations provided herein further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of general formula I according to the invention can be prepared according to the synthetic methods of scheme I and scheme II, all the variables used in these routes being as defined in the claims.
Detailed Description
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The examples provided below are therefore intended to illustrate but not to limit the scope of the invention.
The starting materials may 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. The reagents used are, without particular reference, analytically or chemically pure.
Mass spectra used for structural confirmation of compounds were determined by Agilent 1100 LC/MS. The column chromatography purification product adopts silica gel of 100-200 meshes or 200-300 meshes produced by Qingdao ocean chemical plant.
Example 1: 4- ((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl ] -4-yl) -4-methyl-4, 5-dihydrooxazole
Figure BDA0002609486550000091
In the step a: adding raw materials 1-1(1.1mmol), 1-2(1.1mmol) of diphenic acid and PyBOP (1H-benzotriazole-1-base oxygen tripyrrolidinyl hexafluorophosphate) (1.2mmol) into DMF, stirring at room temperature for reaction for 8H, detecting the reaction by TLC, adding water, extracting with ethyl acetate, washing an organic layer with saturated saline solution, and drying over night with anhydrous sodium sulfate. Filtering to remove the drying agent, and concentrating under reduced pressure to obtain intermediate 1-3.
In the step b: intermediate 1-3(5mmol), SOCl2Adding (12.5mmol) and triethylamine (12.5mmol) into dichloromethane, stirring at room temperature for reaction, and detecting by TLC that the reaction is completeEvaporating to remove organic solvent, dissolving in ethyl acetate, washing with water for 3 times, washing organic layer with saturated NaCl, and removing anhydrous Na2SO4Dry overnight. Filtering to remove drying agent, concentrating under reduced pressure, and performing column chromatography to obtain intermediate 1-4.
In the step c: dissolving the intermediates 1 to 4(5mmol) in anhydrous THF, and slowly adding LiN (Pr-i) dropwise2(10mmol) in THF, reacted for about 1h, CH was added3I (10mmol), TLC detection reaction is completed, the temperature is raised to room temperature, saturated NH is added4Quenching with Cl solution, evaporating to remove organic solvent under reduced pressure, extracting with ethyl acetate, washing organic layer with saturated NaCl, and collecting anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, and concentrating under reduced pressure to obtain intermediate 1-5.
In the step d: under the ice-bath condition, dissolving the intermediate 1-5(5mmol) in THF, adding lithium aluminum hydride (10mmol) in batches, detecting the reaction completion by TLC, adding saturated NH4Quenching reaction with Cl solution, evaporating under reduced pressure to remove organic solvent, extracting with ethyl acetate, washing organic layer with saturated NaCl, and adding anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, and concentrating under reduced pressure to obtain intermediate 1-6.
In step e: intermediate 1-6(5mmol), SOCl2Adding (20mmol) and triethylamine (20mmol) into dichloromethane, stirring at room temperature for reaction, detecting by TLC to complete the reaction, evaporating to remove organic solvent, dissolving with ethyl acetate, washing with water for 3 times, washing the organic layer with saturated NaCl, and adding anhydrous Na2SO4Dry overnight. Filtering to remove drying agent, concentrating under reduced pressure, and performing column chromatography to obtain intermediate 1-7.
In step f: under the ice bath condition, imidazole (15mmol) is added into DMF, NaH (20mmol) is added, after stirring for 30min, intermediate 1-7(5mmol) is added, the reaction is continued, TLC detection reaction is finished, reaction liquid is poured into water, ethyl acetate extraction is carried out, saturated NaCl is used for washing an organic layer, and anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, concentrating under reduced pressure, and performing column chromatography to obtain the target compound 1.1H-NMR(400MHz,DMSO-d6)7.90(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)calcdforC20H19N3O,[M+H]+,318.1601；found 318.1632.
Examples 2-6 were prepared according to the procedure for example 1, using the corresponding alkyl halides, respectively.
Example 2: 4- ((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl ] -4-yl) -4-isopropyl-4, 5-dihydrooxazole
Figure BDA0002609486550000103
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-dihydrooxazole
Figure BDA0002609486550000101
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-dihydrooxazole
Figure BDA0002609486550000102
1H-NMR(400MHz,DMSO-d6)7.81(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 C26H23N3O,[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
Figure BDA0002609486550000111
HRMS(ESI,m/z)calcd for C26H22FN3O,[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
Figure BDA0002609486550000112
1H-NMR(600MHz,DMSO-d6)7.84(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 C26H21F2N3O,[M+H]+,430.1725；found 430.1727.
Example 7: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- ([1,1' -biphenyl ] -4-yl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000113
In the step a: mixing AgNO2Adding (10mmol) into diethyl ether (30mL), stirring at room temperature, dropwise adding benzyl bromide (5mmol), stirring away from light for 5h, pouring the reaction solution into water, extracting with diethyl ether for 3 times, evaporating under reduced pressure to remove diethyl ether to obtain light yellow oily liquid, and performing column chromatography to obtain intermediate 5-2.
In the step b: dissolving intermediate 5-2(4mmol) in ethanol, adding formaldehyde solution (24mmol) and NaOH (4mmol), stirring at room temperature for reaction, TLC detecting reaction, evaporating under reduced pressure to remove organic solvent, adding water, extracting with ethyl acetate for 3 times, mixing organic layers, washing with saturated NaCl, and collecting anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, concentrating under reduced pressure, and performing column chromatography to obtain intermediate 5-3.
In the step c: adding 2, 2-dimethoxypropane (4.5mmol) into acetone solution of intermediate 5-3(3mmol), adding p-toluenesulfonic acid (0.6mmol), reacting at room temperature, detecting by TLC to complete reaction, evaporating under reduced pressure to remove solvent, and performing column chromatography to obtain intermediate 5-4.
In step d: dissolve intermediate 5-4(2mmol) in methanol (10mL), add Pd/C, and pass H2Reacting at room temperature, detecting by TLC to complete reaction, filtering, and evaporating under reduced pressure to remove the solvent to obtain an intermediate 5-5.
In the step e: the raw materials, 5-6(1.1mmol) of diphenic acid, 5-5(1.1mmol) of intermediate and PyBOP (1.2mmol) are added into DMF (10mL), stirred at room temperature for reaction for 8h, after TLC detection reaction, water is added, ethyl acetate is extracted, the organic layer is washed with saturated saline, and dried over anhydrous sodium sulfate overnight. Filtering to remove the drying agent, and concentrating under reduced pressure to obtain intermediate 5-7.
In the step f: adding the intermediate 5-7(5mmol) into glacial acetic acid/water (V: V ═ 3:1), reacting at 40 ℃, detecting by TLC that the reaction is complete, pouring into water, extracting by ethyl acetate, washing an organic layer by saturated NaCl, and anhydrous Na2SO4Dry overnight. Filtering to remove desiccant, concentrating under reduced pressure, and performing column chromatography to obtain intermediate 5-8.
Step g: intermediate 5-8(5mmol), SOCl2Adding (25mmol) and triethylamine (25mmol) into dichloromethane, stirring at room temperature for reaction, detecting by TLC to complete reaction, evaporating to remove organic solvent, dissolving with ethyl acetate, washing with water for 3 times, washing organic layer with saturated NaCl, and adding anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, concentrating under reduced pressure, and performing column chromatography to obtain intermediate 5-9.
In the step h: under the ice bath condition, adding oxazole (15mmol) into DMF (10mL), adding NaH (20mmol), stirring for 30min, adding intermediate 5-9(5mmol), continuing to react, after TLC detection reaction is finished, pouring the reaction solution into water, extracting with ethyl acetate, washing an organic layer with saturated NaCl, and adding anhydrous Na2SO4Dry overnight. Filtering to remove the drying agent, concentrating under reduced pressure, and performing column chromatography to obtain the target compound 7.1H-NMR(600MHz,DMSO-d6)8.32(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 C24H20N4O,[M+Na]+,403.1529；found403.1563.
Examples 8-56 were prepared according to the procedure for example 7, using the corresponding starting materials, respectively.
Example 8: 4- ((1H-imidazol-1-yl) methyl) -2- ([1,1' -biphenyl ] -4-yl) -4-phenyl-4, 5-dihydrooxazole
1H-NMR(600MHz,DMSO-d6)7.99(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 C25H21N3O,[M+H]+,380.1757；found380.1796.
Example 9: 4- ((1H-tetrazol-2-yl) methyl) -2- ([1,1' -biphenyl ] -4-yl) -4-phenyl-4, 5-dihydrooxazole
1H-NMR(600MHz,DMSO-d6)9.26(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 C23H19N5O,[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
Figure BDA0002609486550000131
1H-NMR(600MHz,DMSO-d6)8.34(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 C21H17N5O2,[M+Na]+,394.1274；found 394.1315.
Example 11: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-2- (5-phenylthiophen-2-yl) -4, 5-dihydrooxazole
Figure BDA0002609486550000132
1H-NMR(600MHz,DMSO-d6)8.28(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 C22H18N4OS,[M+Na]+,409.1094；found 409.1134.
Example 12: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (furan-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000141
1H-NMR(600MHz,DMSO-d6)8.31(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 forC22H18N4O2,[M+Na]+,393.1322；found 393.1356.
Example 13: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (thiophene-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000142
1H-NMR(600MHz,DMSO-d6)8.31(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 C22H18N4OS,[M+Na]+,409.1094；found 409.1140.
Example 14: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (naphthalene-2-yl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000143
1H-NMR(600MHz,DMSO-d6)8.43(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 C22H18N4O,[M+Na]+,377.1373；found 377.1403.
Example 15: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzofuran-2-yl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000151
1H-NMR(600MHz,DMSO-d6)8.30(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 forC20H16N4O2,[M+Na]+,367.1165；found 367.1203.
Example 16: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzo [ d ] thiazol-2-yl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000152
1H-NMR(600MHz,DMSO-d6)8.33(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 C19H15N5OS,[M+Na]+,384.0890；found 384.0923.
Example 17: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2, 4-diphenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000153
1H-NMR(600MHz,DMSO-d6)8.30(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 C18H16N4O,[M+Na]+,327.1216；found 327.1248.
Example 18: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (benzyloxy) phenyl) -4-phenyl-4, 5-dihydrooxazole
Figure BDA0002609486550000154
1H-NMR(600MHz,DMSO-d6)8.27(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 C25H22N4O2,[M+H]+,411.1816；found 411.1856.
Example 19: n- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) benzamide
Figure BDA0002609486550000161
1H-NMR(600MHz,DMSO-d6)10.52(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 C25H21N5O2,[M+Na]+,446.1587；found 446.1640.
Example 20: 1- (4- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) piperazine-1-yl) ethanone
Figure BDA0002609486550000162
1H-NMR(600MHz,DMSO-d6)8.25(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 forC24H26N6O2,[M+Na]+,453.2009；found 453.2050.
Example 21: 2- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) -5-phenyl-1, 3, 4-oxadiazole
Figure BDA0002609486550000171
1H-NMR(600MHz,DMSO-d6)8.33(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 C26H20N6O2,[M+Na]+,471.1540；found 471.1577.
Example 22: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000172
1H-NMR(600MHz,DMSO-d6)8.32(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 C22H17FN4O2,[M+Na]+,411.1228；found411.1264.
Example 23: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000173
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
Figure BDA0002609486550000181
ESI-MS[M+H]+(m/z):407.1。
Example 25: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000182
ESI-MS[M+H]+(m/z):439.1。
Example 26: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000183
ESI-MS[M+H]+(m/z):405.1。
Example 27: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000184
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- (thiophen-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000185
ESI-MS[M+H]+(m/z):423.1。
Example 29: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000191
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- (trifluoromethoxy) benzo [ b ] thiophen-2-yl) -4, 5-dihydrooxazole
Figure BDA0002609486550000192
ESI-MS[M+H]+(m/z):481.1。
Example 31: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000193
1H-NMR(600MHz,DMSO-d6)8.29(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 C20H14F2N4OS,[M+Na]+,419.0749；found 419.0778.
Example 32: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000194
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
Figure BDA0002609486550000201
1H-NMR(600MHz,DMSO-d6)8.34(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 C20H13F3N4OS,[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
Figure BDA0002609486550000202
ESI-MS[M+H]+(m/z):415.1。
Example 35: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000203
ESI-MS[M+H]+(m/z):447.1。
Example 36: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000204
1H-NMR(600MHz,DMSO-d6)8.29(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 C20H14ClFN4OS,[M+Na]+,435.0453；found 435.0480.
Example 37: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-chlorphenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000211
1H-NMR(600MHz,DMSO-d6)8.30(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)calcdfor C20H14Cl2N4OS,[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
Figure BDA0002609486550000212
1H-NMR(600MHz,DMSO-d6)8.34(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 C20H13ClF2N4OS,[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
Figure BDA0002609486550000213
1H-NMR(600MHz,DMSO-d6)8.32(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 C20H13ClF2N4OS,[M+Na]+,453.0359；found 453.0383.
Example 40: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000221
ESI-MS[M+H]+(m/z):463.1。
Example 41: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000222
1H-NMR(600MHz,DMSO-d6)8.39(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 C20H14BrFN4OS,[M+Na]+,478.9948；found 480.9957.
Example 42: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (4-chlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000223
1H-NMR(600MHz,DMSO-d6)8.40–8.37(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
Figure BDA0002609486550000231
1H-NMR(600MHz,DMSO-d6)8.40(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 C20H13BrF2N4OS,[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
Figure BDA0002609486550000232
1H-NMR(600MHz,DMSO-d6)8.39(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 C20H13BrF2N4OS,[M+Na]+,496.9854；found 498.9869.
Example 45: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000233
ESI-MS[M+H]+(m/z):507.1。
Example 46: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000241
1H-NMR(600MHz,DMSO-d6)8.34(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 C24H18F2N4O,[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
Figure BDA0002609486550000242
1H-NMR(600MHz,DMSO-d6)8.35(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 forC24H18ClFN4O,[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
Figure BDA0002609486550000243
1H-NMR(600MHz,DMSO-d6)8.39(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 C24H17F3N4O,[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
Figure BDA0002609486550000251
1H-NMR(600MHz,DMSO-d6)8.37(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 C24H17F3N4O,[M+Na]+,457.1247；found 457.1281.
Example 50: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000252
ESI-MS[M+H]+(m/z):467.1。
Example 51: 4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (3 '-fluoro- [1,1' -biphenyl ] -4-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
Figure BDA0002609486550000253
1H-NMR(600MHz,DMSO-d6)8.33(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 C24H18F2N4O,[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
Figure BDA0002609486550000254
1H-NMR(600MHz,DMSO-d6)8.34(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 C24H18ClFN4O,[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
Figure BDA0002609486550000261
1H-NMR(600MHz,DMSO-d6)8.38(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 C24H17F3N4O,[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
Figure BDA0002609486550000262
1H-NMR(600MHz,DMSO-d6)8.37(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 C24H17F3N4O,[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
Figure BDA0002609486550000263
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
Figure BDA0002609486550000271
1H NMR(600MHz,DMSO)9.19(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。
The invention also relates to the pharmacological research of the partial product.
Experimental methods Reference is made to the conventional in vitro bacteriostatic test methods (Reference method for the diagnosis of bacterial infection and bacterial infection testing of the ages and filtrations fungi; Approved Standard M27-A3 and M38-A2).
Experimental materials and methods:
(1) experimental strains:
the following 5 common human pathogenic standard fungal strains were selected as screening targets in the experiment, and the fungal strains are provided by Shenyang pharmaceutical university.
TABLE 1 strains used in the experiments and their numbering
Bacterial species 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) The test method comprises the following steps:
preparation of RPMI-1640 medium: RPMI-164010 g, NaHCO32.0g and 34.5g of triazorphyrin propanesulfonic acid (sigma), dissolving with 800mL of sterile distilled water, adjusting the pH to 7.0 with lmol/L NaOH, diluting to 1000mL, filtering with a 0.22 mu m microporous membrane for sterilization, and storing at 4 ℃ for later use.
Preparing filamentous fungus suspension: filamentous fungi (Trichophyton rubrum, Trichophyton matsutake, Trichophyton gypseum and Aspergillus fumigatus) and the like are continuously subcultured twice on a Shake's medium plate, cultured in an incubator at 35 ℃ for 48h, and 5mL of 0.85% physiological saline is added to bacterial colonies to prepare a bacterial liquid. Adjusting the concentration of the bacterial liquid by using a spectrophotometer, and adjusting the value A to 0.3-0.5; then diluted 50 times with culture medium to obtain inoculum suspension.
Preparing a globular fungus suspension: coccoid bacteria (candida albicans, candida tropicalis, candida glabrata, and cryptococcus neoformans). Inoculating the activated strain on a solid Sha's medium plate by a partition-streaking method, culturing at a constant temperature of 32 ℃ for 2-3 days, taking a proper amount of single colony to a triangular flask containing l 0mL of 0.85% sterile physiological saline, shaking for 15 minutes, taking a small amount of bacterial liquid on a blood cell counting plate by a sterilized gun head, and counting under a microscope. Adding RPMI-1640 medium to dilute to obtain final bacterial suspension with concentration of 1X106one/mL.
Preparing a liquid medicine: 6.40mg of each of the above chemically synthesized drugs was weighed, and l.0mL of dimethyl sulfoxide (DMSO), l.0mL of Tween-20 and 8.0mL of sterilized distilled water were sequentially added thereto and mixed well. The concentration of the prepared liquid medicine is 0.64 mg/mL. Positive control drugs fluconazole and voriconazole are prepared by the same method.
Inoculation: first, adding RPMI-1640 culture medium: the 1 st well of each row was filled with 180. mu.L of RPMI-1640 medium, the 2-11 wells were filled with 100. mu.L of RPMI-1640 medium, and the 12 wells were filled with 200. mu.L of RPMI-1640 medium. Secondly, adding a medicine sample: adding 20 mu L of liquid medicine to be detected into the 1 st hole, uniformly mixing by using a liquid transfer gun, sucking 100 mu L to 2 holes, sequentially diluting by 2 times to the 10 th hole, uniformly mixing, and discarding 100 mu L. Step three, adding bacterial suspension: 100. mu.L of each inoculum suspension was added to wells 1-11. Well 11 is growth control and well 12 is blank medium control. The positive control drug is not provided with a blank drug control, i.e., a dilution is performed in a multiple gradient from the 1 st well to the 10 th well, and the test concentrations (μ g/mL) are in the ranges of 32, 16, 8, 4, 2, 1, 0, 5, 0.25, 0.125 and 0.0625.
Culturing and detecting: and (4) taking the blank control aseptic growth and the positive control good growth as the standard for judging whether the test operation is qualified. Each plate tested 8 samples, and each bacteria was provided with a positive drug control. The test drug dilution method was as above.
TABLE 2 minimal inhibitory concentration of the exemplified compounds ((MIC, μ g/ml)
Figure BDA0002609486550000281
Figure BDA0002609486550000291
From the test results, it is clear that the compound of the general formula I and the salt thereof to be protected have good antifungal activity, the antifungal activity of a plurality of compounds is stronger than that of a reference drug, and compared with the existing antifungal drugs, the compound has the advantages of novel structure, low toxicity, high efficiency, broad spectrum and the like, so that the compound has good industrial application prospect.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms of the compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, as appropriate.
Example 17: and (4) tablets.
10g of the compound of claim 1 (in the case of the compound of example 31) was mixed with 20g of excipients according to a usual pharmaceutical tableting method and compressed into 100 tablets each weighing 300 mg.
Example 18: and (4) capsules.
10g of the compound containing the compound in claim 1 (taking the compound in the embodiment 31 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.
Example 19: can be made into injection.
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example 31), activated carbon adsorption was carried out according to a conventional pharmaceutical method, and after filtration through a 0.65 μm microporous membrane, the mixture was filled in a nitrogen tank to prepare water-acupuncture preparations (2 mL each) and 100 bottles in total.
Example 20: an aerosol formulation.
Dissolving 10g of the compound of claim 1 (example 31) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 21: a suppository.
50 suppositories were prepared by grinding 10g of the compound of claim 1 (example 31) with the appropriate amount of glycerin, mixing well, adding melted glycerin gelatin, grinding well, pouring into lubricant-coated molds.
Example 22: and (3) film agent.
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example 31), polyvinyl alcohol, medicinal glycerin, water and the like were swollen with stirring and then dissolved by heating, and then the compound of example 18 was added to the filtrate and dissolved with stirring, and 100 sheets were formed into a film by a film coating machine.
Example 23: a dripping pill.
10g of the compound containing the compound of claim 1 (taking the compound in example 31 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 24: liniment for external use.
The compound of claim 1 (example 31) 10g is mixed with adjuvants such as emulsifier 2.5g, and then ground, and added with distilled water to 200 mL.
Example 25: and (3) ointment.
Prepared by grinding 10g of the compound containing the compound of claim 1 (taking the compound in example 31 as an example) and then uniformly grinding the ground product with 500g of an oily base such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (10)

1. A compound of formula (I), and stereoisomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
Figure FDA0002609486540000011
wherein:
MBG is a substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyridyl; the substituent is as follows: hydrogen, C1-C4 alkyl, C1-C4 alkoxy.
Y is O or S;
x is CH, CH2N, NH, or O;
Figure FDA0002609486540000012
is a single bond or a double bond;
R1is (C)1-C5) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C4) Alkoxy, carboxyl, -COOR2、-CON(R2)25-10 membered aryl or 5-10-membered heteroaryl, and optionally 0-3 of the same or different R2Substitution;
ar ring is C3-C6 cycloalkyl, 5-10 member heterocyclyl, C6-C10Aryl or C5-C10Heteroaryl, wherein said heterocyclyl, heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 0-3, the same or different M;
m is hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group; in addition to M being a bonded electron-donating, electron-withdrawing group, M may also be a 5-to 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 hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)1-C6) Alkenyl, (C)1-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
2. The compound of claim 1, and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:
wherein MBG is selected from the following structures:
Figure FDA0002609486540000021
3. the compound of claim 1 or 2, and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof: wherein the content of the first and second substances,
y is O;
Figure FDA0002609486540000022
is a double bond, and X is N.
4. The compound of any one of claims 1-3, and stereoisomers or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof: wherein the content of the first and second substances,
R1is (C)1-C5) Alkyl, (C)3-C6) Cycloalkyl, 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 group2And (4) substitution.
5. The compound of any one of claims 1-4, and stereoisomers or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs 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.
6. A compound selected from the group consisting of:
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-triazole-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-triazole-1-yl) methyl) -4-phenyl-2- (5-phenylthiophen-2-yl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (furan-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (thiophene-3-yl) phenyl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (naphthalene-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzofuran-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzo [ b ] thiophen-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (benzo [ d ] thiazol-2-yl) -4-phenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2, 4-diphenyl-4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (4- (benzyloxy) phenyl) -4-phenyl-4, 5-dihydrooxazole
N- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) benzamide
1- (4- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) piperazine-1-yl) ethanone
2- (4- (4- ((1H-1,2, 4-triazole-1-yl) methyl) -4-phenyl-4, 5-dihydrooxazole-2-yl) phenyl) -5-phenyl-1, 3, 4-oxadiazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (furan-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-fluorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -4- (4-chlorophenyl) -2- (4- (thiophene-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-triazole-1-yl) methyl) -4- (2, 4-dichlorophenyl) -2- (4- (thiophene-3-yl) phenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazol-1-yl) methyl) -4- (2, 4-difluorophenyl) -2- (5- (trifluoromethoxy) benzo [ b ] thiophen-2-yl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-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-triazole-1-yl) methyl) -2- (6-fluorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (4-chlorphenyl) -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-triazole-1-yl) methyl) -2- (6-chlorobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (4-fluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-difluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazol-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophen-2-yl) -4- (3, 5-difluorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (6-bromobenzo [ b ] thiophene-2-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-1-yl) methyl) -2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) -4- (2, 4-dichlorophenyl) -4, 5-dihydrooxazole
4- ((1H-1,2, 4-triazole-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-triazole-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.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient together with a pharmaceutically acceptable excipient.
8. A process for preparing a compound of claim 1, and pharmaceutically acceptable salts thereof:
Figure FDA0002609486540000041
route I
Figure FDA0002609486540000051
Route II
Wherein Ar, M, R1、R2And MBG as claimed in claim 1.
9. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition of claim 7 for the manufacture of a medicament for the treatment of fungal infection.
10. The use according to claim 9, wherein the fungal infection disease is associated with one or more of the following pathogenic fungi: absidia umbellata (Absidia corymbiofera), yarrowia capsulata (Ajlomyces capsulatus), Arjothrix dermatitidis (Ajlomyces dermatitidis), Arthrobacter nigra (Arthroderma benthamiana), Arthroderma farinosa (Arthroderma fulvum), Arthroderma gypti (Arthroderma gypseum), Arthroderma incarnatum (Arthroderma incarnatum), Arthroderma terrestris (Arthroderma incarnatum), Arthroderma gangrenosum (Arthroderma atroviride), Aspergillus fumigatus (Aspergillus flavus), Aspergillus fumigatus (Aspergillus fumigatus), Aspergillus niger (Aspergillus niger), Pseudomonas glabra (Candida glabrata), Candida albicans (Candida albicans), Candida glabrata (Candida albicans), Candida glabrata (Candida glabrata, Candida glabrata, Candida glabrata, Candida glabrata, Candida, Epidermophyton floccosum (Epidermophyton floccosmosum), Exophytum dermatum (Exophiala dermatitidis), Ustilago virens (Filobasidiella neoformans), Euglena pigmented Germinatum (Fonscexaea pedosoi), Fusarium solani (Fusarium solani), Geotrichum candidum (Geotrichum candidum), Histoplasma capsulatum (Histoplasma capsulatum), Exophyton venenum (Hortya wereckii), Issatchenkia orientalis (Issatchenkia orientalis), Mycobacterium glaucae (Madurella grisea), Malassezia glauca (Malassezia fura furiosum), Microsella globosa (Malassezia glauca), Microsella globosa (Malasse flava), Microsella globosa (Malassezia globosa), Microsella viridula (Malassezia), Microsella viridula viridis (Malasse), Microsella viridis (Mallota), Microsella viridis (Microsella), Microsella globosa (Microsella globosa), Microsella viridis (Microsella globosa), Microsella globosa (Microsella globosa), Microsella glob, Paecilomyces variotii (Paecilomyces variotii), Paracoccidioides brasiliensis (Paracoccus brasiliensis), Penicillium marneffei (Penicillium marneffei), Pichia anomala (Pichia anomala), Pichia quaternary (Pichia williaminormidis), Pneumocystis carinii (Pneumocystis carinii), Pseudoalisma pombe (Pseudolasia boidinii), Rhizopus oryzae (Rhizopus oryzae), Rhodotorula rubra (Rhodotorula rubra), Polyporus oxysporum (Scedosporium), Schizophyllum schizophyllum (Schizophyllum commune), Trichosporon scherzerianum (Sporotrichomonkii), Trichosporon Trichophyton (Trichosporon Trichophyton), Trichosporon Trichophyton (Trichosporon), Trichosporon Trichophyton (Trichosporon Trichophyton), Trichosporon Trichophyton (Trichosporon Trichophyton), Trichosporon Trichophyton (Trichosporon Trichophyton (Trichosporon), Trichosporon Trichophyton (Trichosporon Trichophyton), Trichosporon Trichophyton (Trichosporon Trichophyton), Trichosporon Trichophyton (Trichosporon), Trichosporon trichon (Trichosporon), Trichosporon trichon (Trichosporon), Trichosporon trichon (Trichosporon), Trichosporon trichon.
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CN114605282A (en) * 2022-03-22 2022-06-10 宿迁盛基医药科技有限公司 Preparation method of montelukast sodium side chain intermediate

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CN114605282A (en) * 2022-03-22 2022-06-10 宿迁盛基医药科技有限公司 Preparation method of montelukast sodium side chain intermediate

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