CN109400573B - Benzo [ d ] [1,3] dioxole compound, preparation method and application thereof - Google Patents

Abstract

The invention discloses a benzo[d][1,3]dioxole compound, a preparation method and its application. The benzo[d][1,3]dioxole provided by the invention Pentenes have obvious synergistic effect on drug-resistant Candida albicans 103 produced by fluconazole.

Description

Benzo[d][1,3]dioxole compounds, preparation methods and applications thereof

Technical Field

The present invention relates to benzo[d][1,3]dioxole compounds, preparation methods and applications thereof.

Background Art

Since the 1980s, due to the extensive use of broad-spectrum antibiotics, HIV infection, cancer chemotherapy and the increase in immunosuppressed patients caused by organ transplantation, invasive fungal infections have increased year by year, mainly Candida albicans, Cryptococcus neoformans, and Aspergillus. Among them, Candida albicans has the highest incidence. Statistics show that Candida albicans infection ranks fourth among nosocomial pathogenic microbial infections. The mortality rate of invasive fungal infections is high, and most statistical literature shows that the mortality rate of fungal infections is higher than 50%.

There are relatively few clinical antifungal drugs, including only limited types and varieties such as azoles, polyenes, and echinocandins. Among them, azole drugs are the most widely used, such as fluconazole, voriconazole, and posaconazole. In recent years, with the widespread and large-scale use of azole antifungal drugs, strains resistant to azole antifungal drugs have appeared in clinical practice. Among them, resistance to fluconazole is the most serious and widespread. Fungal resistance has become one of the main reasons for the failure of clinical antifungal infection treatment.

There are not many treatment strategies for drug-resistant fungal infections. In addition to increasing the dose of antifungal drugs and changing the drug type, clinical trials have tried combination therapy. However, among the limited drug types, the effect of combination therapy in treating drug-resistant fungi is not significant or even ineffective. In recent years, the focus of research has been on screening non-antifungal drugs that can work in synergy with antifungal drugs.

Summary of the invention

The technical problem solved by the present invention is to overcome the strong drug resistance of antifungal drugs in the prior art and the poor or ineffective effect of antifungal combination drugs, thereby providing a benzo[d][1,3]dioxole compound, a preparation method and application thereof. The benzo[d][1,3]dioxole compound provided by the present invention has a significant synergistic effect on fluconazole-resistant Candida albicans 103.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides a benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as shown in Formula I:

Where n ¹ is 0, 1, 2 or 3;

噻吩基、呋喃基、C₂～C₄的炔基、

R¹与R²连接成

R³为C₁～C₃的烷基；R is a substituted or unsubstituted C ₆ ～C ₁₀ aryl group, a C ₃ ～C ₆ cycloalkyl group,

Thienyl, furyl, C ₂ -C ₄ alkynyl,

^R1 and ^R2 are connected to form

R ³ is a C ₁ to C ₃ alkyl group;

中的A为C₃～C₆的环烷基，并与苯环形成并环结构；Said

A is a C ₃ to C ₆ cycloalkyl group, and forms a ring structure with the benzene ring;

The number of substituents of the substituted or unsubstituted C ₆ -C ₁₀ aryl group is one or more (e.g., 2), and the substituents are one or more of halogen (e.g., fluorine, chlorine, bromine or iodine) or C ₁ -C ₆ alkyl (e.g., C ₁ -C ₃ alkyl, and methyl). When there is one substituent, the position of the substituent may be ortho, para or meta. When there are two substituents, the position of the substituents may be ortho-ortho, ortho-para, ortho-meta, meta-meta or meta-para.

The benzo[d][1,3]dioxole compounds shown in formula I do not include compounds shown in the following structures:

In the present invention, the substituted or unsubstituted C ₆ ～C ₁₀ aryl group may be a phenyl group;

The C ₃ -C ₆ cycloalkyl group may be cyclopropyl, cyclopentyl or cyclohexyl;

可为

Said

Can

可为

The C ₂ -C ₄ alkynyl group may be an ethynyl group;

Can

例如

In the present invention, preferably, when n=0, the R is

For example

所述取代或未取代的C₆～C₁₀的芳基的取代基的数目可为一个或多个(例如2个)，所述取代基为卤素(例如氟、氯、溴或碘)；When n=1, R is a substituted or unsubstituted C ₆ ～C ₁₀ aryl, C ₄ ～C ₆ cycloalkyl, thienyl, furyl, or

The number of substituents of the substituted or unsubstituted C ₆ -C ₁₀ aryl group may be one or more (eg, 2), and the substituent is a halogen (eg, fluorine, chlorine, bromine or iodine);

When n=2, R is a substituted or unsubstituted C ₆ -C ₁₀ aryl group; the substituted or unsubstituted C ₆ -C ₁₀ aryl group may have one or more substituents (e.g., 2), and the substituents are one or more of halogen (e.g., fluorine, chlorine, bromine or iodine) or C ₁ -C ₆ alkyl (e.g., C ₁ -C ₃ alkyl, e.g., methyl).

In the present invention, the R can be selected from any of the following structures:

The benzo[d][1,3]dioxole compound represented by formula I can be selected from any of the following compounds:

Compound 5, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromobenzyl)propionamide, structural formula:

Compound 12, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-bromobenzyl)propionamide, structural formula:

Compound 13, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromobenzyl)propionamide, structural formula:

Compound 14, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3,4-dichlorobenzyl)propionamide, structural formula:

Compound 15, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluorobenzyl)propionamide, structural formula:

Compound 18, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)propionamide, structural formula:

Compound 21, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-3-methyl)propionamide, structural formula:

Compound 26, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methylphenethyl)propionamide, structural formula:

Compound 30, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromophenethyl)propionamide, structural formula:

Compound 32, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-chlorophenylpropyl)propionamide, structural formula:

The present invention also provides a benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as shown in Formula II:

Where n ² is 1, 2 or 3;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, or a substituted or unsubstituted phenyl or aromatic hetero group; and at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is a substituted or unsubstituted phenyl or aromatic hetero group; the aromatic hetero group is pyridyl, furyl, thienyl, imidazolyl or oxazolyl; for example, only one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is a substituted or unsubstituted phenyl or aromatic hetero group, and the others are hydrogen;

)；The substituent of the substituted or unsubstituted phenyl or aromatic hetero group is C ₁ -C ₃ alkyl (e.g. methyl), halogen (e.g. fluorine, chlorine, bromine or iodine), haloalkyl (e.g. -CF ₃ ) or halogen-substituted phenoxy (e.g.

);

The benzo[d][1,3]dioxole compound as shown in formula II does not include the compound shown in the following structure:

In the present invention, when R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen at the same time, R ⁸ may be

例如

When R ⁶ , R ⁷ and R ⁸ are hydrogen at the same time, one of R ⁴ and R ⁵ is hydrogen and the other can be

For example

例如

When R ⁴ , R ⁵ and R ⁸ are hydrogen at the same time, one of R ⁶ and R ⁷ is hydrogen and the other can be

For example

)；In the present invention, preferably, when n ² = 1, the substituent of the substituted or unsubstituted phenyl or aromatic hetero group is a C ₁ -C ₃ alkyl group (such as methyl), a halogen group (such as fluorine, chlorine, bromine or iodine), or a halogen-substituted phenoxy group (such as

);

When n ² =2 or 3, the substituent of the substituted or unsubstituted phenyl or aromatic hetero group is halogen (eg, fluorine, chlorine, bromine or iodine).

In the present invention, the benzo[d][1,3]dioxole compound as shown in Formula II can be selected from any of the following compounds:

Compound 33, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 34, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 35, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-trifluoromethyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 36, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 37, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 39, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 40, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 41, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 42, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylmethyl)propionamide, structural formula:

Compound 44, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(pyridin-4-yl)benzyl)propionamide, structural formula:

Compound 45, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-2-yl)benzyl)propionamide, structural formula:

Compound 46, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-3-yl)benzyl)propionamide, structural formula:

Compound 47, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(furan-2-yl)benzyl)propionamide, structural formula:

Compound 48, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-2-yl)methyl)propionamide, structural formula:

Compound 49, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-2-yl)methyl)propionamide, structural formula:

Compound 50, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-2-ylmethyl)propionamide, structural formula:

Compound 51, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-3-yl)methyl)propionamide, structural formula:

Compound 52, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-3-yl)methyl)propionamide, structural formula:

Compound 53, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-3-ylmethyl)propionamide, structural formula:

Compound 54, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)ethyl)propionamide, structural formula:

Compound 55, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)ethyl)propionamide, structural formula:

Compound 56, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylethyl)propionamide, structural formula:

The present invention also provides a use of a benzo[d][1,3]dioxole compound as shown in formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of an antifungal pharmaceutical composition;

Where n ¹ is 0, 1, 2 or 3;

噻吩基、呋喃基、C₂～C₄的炔基、

R¹与R²连接成

R³为C₁～C₃的烷基；R is a substituted or unsubstituted C ₆ ～C ₁₀ aryl group, a C ₃ ～C ₆ cycloalkyl group,

Thienyl, furyl, C ₂ -C ₄ alkynyl,

^R1 and ^R2 are connected to form

R ³ is a C ₁ to C ₃ alkyl group;

中的A为C₃～C₆的环烷基，并与苯环形成并环结构；Said

A is a C ₃ to C ₆ cycloalkyl group, and forms a ring structure with the benzene ring;

The substituted or unsubstituted C ₆ -C ₁₀ aryl group may have one or more substituents (eg, 2), and the substituents are one or more of halogen (eg, fluorine, chlorine, bromine or iodine) or C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, such as methyl).

In the present invention, the substituted or unsubstituted C ₆ ～C ₁₀ aryl group may be a phenyl group;

The C ₃ -C ₆ cycloalkyl group may be cyclopropyl, cyclopentyl or cyclohexyl;

可为

Said

Can

The C ₂ to C ₄ alkynyl group may be an ethynyl group;

可为

Said

Can

In the present invention, the R can be selected from any of the following structures:

例如

In the present invention, preferably, when n=0, the R is

For example

所述取代或未取代的C₆～C₁₀的芳基的取代基的数目可为一个或多个(例如2个)，所述取代基为卤素(例如氟、氯、溴或碘)；When n=1, R is a substituted or unsubstituted C ₆ ～C ₁₀ aryl, C ₄ ～C ₆ cycloalkyl, thienyl, furyl, or

The number of substituents of the substituted or unsubstituted C ₆ -C ₁₀ aryl group may be one or more (eg, 2), and the substituent is a halogen (eg, fluorine, chlorine, bromine or iodine);

When n=2, R is a substituted or unsubstituted C ₆ -C ₁₀ aryl group; the substituted or unsubstituted C ₆ -C ₁₀ aryl group may have one or more substituents (e.g., 2), and the substituents are one or more of halogen (e.g., fluorine, chlorine, bromine or iodine) or C ₁ -C ₆ alkyl (e.g., C ₁ -C ₃ alkyl, e.g., methyl).

The structure of the benzo[d][1,3]dioxole compound represented by formula I can be selected from any of the following structures:

Compound 1, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorophenyl)propionamide, structural formula:

Compound 2, chemical name: (R)-3-(Benzo[d][1,3]dioxol-5-yl)-N-indaneamide, structural formula:

Compound 3, chemical name: (S)-3-(Benzo[d][1,3]dioxol-5-yl)-N-indaneamide, structural formula:

Compound 4, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorobenzyl)propionamide, structural formula:

Compound 5, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromobenzyl)propionamide, structural formula:

Compound 6, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-chlorobenzyl)propionamide, structural formula:

Compound 7, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(Benzo[d][1,3]dioxol-5-methyl)propionamide, structural formula:

Compound 8, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-chlorobenzyl)propionamide, structural formula:

Compound 9, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-chlorobenzyl)propionamide, structural formula:

Compound 10, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluorobenzyl)propionamide, structural formula:

Compound 11, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-methylbenzyl)propionamide, structural formula:

Compound 12, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-bromobenzyl)propionamide, structural formula:

Compound 13, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromobenzyl)propionamide, structural formula:

Compound 14, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3,4-dichlorobenzyl)propionamide, structural formula:

Compound 15, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluorobenzyl)propionamide, structural formula:

Compound 16, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-propyn-1-yl)propionamide, structural formula:

Compound 17, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclopropylmethyl)propionamide, structural formula:

Compound 18, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)propionamide, structural formula:

Compound 19, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(furan-2-methyl)propionamide, structural formula:

Compound 20, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-2-methyl)propionamide, structural formula:

Compound 21, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-3-methyl)propionamide, structural formula:

Compound 22, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(pyridine-2-methyl)propionamide, structural formula:

Compound 24, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-methyl)propionamide, structural formula:

Compound 25, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(phenethyl)propionamide, structural formula:

Compound 26, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methylphenethyl)propionamide, structural formula:

Compound 27, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(Benzo[d][1,3]dioxol-5-ethyl)propionamide, structural formula:

Compound 28, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorophenethyl)propionamide, structural formula:

Compound 29, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-methylphenethyl)propionamide, structural formula:

Compound 30, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromophenethyl)propionamide, structural formula:

Compound 31, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(phenylpropyl)propionamide, structural formula:

Compound 32, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-chlorophenylpropyl)propionamide, structural formula:

In the application, the pharmaceutical composition comprises a benzo[d][1,3]dioxole compound as shown in Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and fluconazole.

The present invention also provides a use of a benzo[d][1,3]dioxole compound as shown in formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of an antifungal pharmaceutical composition;

Where n ² is 1, 2 or 3;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, or a substituted or unsubstituted phenyl or aromatic hetero group; and at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is a substituted or unsubstituted phenyl or aromatic hetero group; the aromatic hetero group is pyridyl, furyl, thienyl, imidazolyl or oxazolyl; for example, only one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is a substituted or unsubstituted phenyl or aromatic hetero group, and the others are hydrogen;

)。The substituent of the substituted or unsubstituted phenyl or aromatic hetero group is C ₁ -C ₃ alkyl (e.g. methyl), halogen (e.g. fluorine, chlorine, bromine or iodine), haloalkyl (e.g. -CF ₃ ) or halogen-substituted phenoxy (e.g.

).

)；In the present invention, preferably, when n ² = 1, the substituent of the substituted or unsubstituted phenyl or aromatic hetero group is a C ₁ -C ₃ alkyl group (such as methyl), a halogen group (such as fluorine, chlorine, bromine or iodine), or a halogen-substituted phenoxy group (such as

);

When n ² =2 or 3, the substituent of the substituted or unsubstituted phenyl or aromatic hetero group is halogen (eg, fluorine, chlorine, bromine or iodine).

In the present invention, when R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen at the same time, R ⁸ may be

例如

When R ⁶ , R ⁷ and R ⁸ are hydrogen at the same time, one of R ⁴ and R ⁵ is hydrogen and the other can be

For example

例如

When R ⁴ , R ⁵ and R ⁸ are hydrogen at the same time, one of R ⁶ and R ⁷ is hydrogen and the other can be

For example

In the present invention, the structure of the benzo[d][1,3]dioxole compound as shown in Formula II can be selected from any of the following structures:

Compound 33, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 34, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 35, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-trifluoromethyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 36, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 37, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 39, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 40, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 41, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propionamide, structural formula:

Compound 42, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylmethyl)propionamide, structural formula:

Compound 43, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(4-fluorophenoxy)benzyl)propionamide, structural formula:

Compound 44, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(pyridin-4-yl)benzyl)propionamide, structural formula:

Compound 45, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-2-yl)benzyl)propionamide, structural formula:

Compound 46, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-3-yl)benzyl)propionamide, structural formula:

Compound 47, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(furan-2-yl)benzyl)propionamide, structural formula:

Compound 48, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-2-yl)methyl)propionamide, structural formula:

Compound 49, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-2-yl)methyl)propionamide, structural formula:

Compound 50, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-2-ylmethyl)propionamide, structural formula:

Compound 51, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-3-yl)methyl)propionamide, structural formula:

Compound 52, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-3-yl)methyl)propionamide, structural formula:

Compound 53, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-3-ylmethyl)propionamide, structural formula:

Compound 54, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)ethyl)propionamide, structural formula:

Compound 55, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)ethyl)propionamide, structural formula:

Compound 56, chemical name: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylethyl)propionamide, structural formula:

In the application, the pharmaceutical composition comprises a benzo[d][1,3]dioxole compound as shown in Formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof and fluconazole.

The present invention also provides a method for preparing a benzo[d][1,3]dioxole compound as shown in formula I, which comprises the following steps: in a solvent, under the action of a base and a condensation agent, subjecting piperonyl propionic acid and a compound as shown in formula I-1 to a condensation reaction as shown below;

In the condensation reaction, the condensation agent may be a condensation agent commonly used in the condensation reaction of an acid and an amine, such as PyBOP; the base may be a condensation agent commonly used in the condensation reaction of an acid and an amine, such as DIEA; and the solvent may be DMF.

In the condensation reaction, the molar ratio of the piperonyl propionic acid to the compound represented by formula I-1 can be a conventional ratio in the art for condensation reaction of an acid and an amine, for example, 1:1.

In the condensation reaction, the molar ratio of the condensing agent to the capryloyl propionic acid can refer to the conventional amounts used in this type of reaction in the art, for example, 1:1.

In the condensation reaction, the molar ratio of the base to the piperylpropionic acid can refer to the conventional amounts used in this type of reaction in the art, for example, 3:1 to 5:1.

The temperature of the condensation reaction may be 20-35°C.

The condensation reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The disappearance of capsyl propionic acid or the compound represented by formula I-1 is generally regarded as the reaction endpoint, and the reaction time is generally 2h to 3h.

After the condensation reaction is completed, post-treatment may be further performed, and the post-treatment may be selected from one or more post-treatment methods selected from quenching, extraction, washing, drying, filtration, column chromatography and recrystallization.

Water can be used for the quenching; ethyl acetate can be used for the extraction; saturated sodium chloride aqueous solution can be used for the washing; anhydrous sodium sulfate can be used for the drying; and methanol and water can be used for the recrystallization.

The present invention also provides a method for preparing a benzo[d][1,3]dioxole compound as shown in formula II, which comprises the following steps: in a solvent, under the action of a base and a catalyst, subjecting the compound shown in formula II-1 and the compound shown in formula II-2 to a coupling reaction as shown below:

R ^4' , R ^5' , R ^6' , R ^7' and R ^8' are each independently hydrogen, substituted or unsubstituted phenyl or aromatic hetero group, or halogen; and one of R ^4' , R ^5' , R ^6' , R ^7' and R ^8' must be halogen; the aromatic hetero group is pyridyl, furyl, thienyl, imidazolyl or oxazolyl;

The Ar is a substituted or unsubstituted phenyl group or an aromatic hetero group; the aromatic hetero group is a pyridyl group, a furyl group, a thienyl group, an imidazolyl group or an oxazolyl group.

The catalyst may be a catalyst commonly used in coupling reactions in the art, such as bistriphenylphosphine palladium dichloride.

The base may be a base commonly used in coupling reactions in the art, such as potassium carbonate.

The solvent may be DMF.

In the coupling reaction, the molar ratio of the compound of formula II-1 to the compound of formula II-2 can be a conventional ratio for such reactions in the art, such as 5:6.

In the coupling reaction, the molar ratio of the compound of formula II-1 to the catalyst can refer to the conventional ratio of this type of reaction in the art, for example, 20:1.

In the coupling reaction, the molar ratio of the compound of formula II-1 and the base can refer to the conventional ratio of this type of reaction in the art, for example, 1:2.

The temperature of the coupling reaction may be 80°C.

The coupling reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The reaction endpoint is generally determined when the amount of the compound represented by formula II-1 or the compound represented by formula II-2 detected by HPLC is less than 5%. The reaction time is generally 6 to 8 hours.

After the coupling reaction is completed, post-treatment may be further performed, and the post-treatment may be selected from one or more post-treatment methods selected from quenching, extraction, washing, drying, filtration, column chromatography and recrystallization.

Water can be used for the quenching; ethyl acetate can be used for the extraction; saturated sodium chloride aqueous solution can be used for the washing; anhydrous sodium sulfate can be used for the drying; ethyl acetate and n-hexane can be used for the recrystallization.

The method for preparing the benzo[d][1,3]dioxole compound as shown in formula II may further comprise the following steps: in a solvent, under the action of a base and a condensing agent, subjecting piperonyl propionic acid and the compound as shown in formula I-1 to a condensation reaction as shown below;

In the condensation reaction, the condensation agent may be a condensation agent commonly used in acid and condensation reaction, such as PyBOP; the base may be a condensation agent commonly used in acid and amine condensation reaction, such as DIEA.

In the condensation reaction, the molar ratio of the piperonyl propionic acid to the compound represented by formula III can be a conventional ratio in the art for condensation reaction of an acid and an amine, for example, 1:1.

In the condensation reaction, the molar ratio of the condensing agent to the capryloyl propionic acid can refer to the conventional amounts used in this type of reaction in the art, for example, 1:1.

In the condensation reaction, the molar ratio of the base to the piperylpropionic acid can refer to the conventional amounts used in this type of reaction in the art, for example, 3:1 to 5:1.

The temperature of the condensation reaction may be 20-35°C.

The condensation reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The disappearance of capsyl propionic acid or the compound represented by formula III is generally regarded as the reaction endpoint, and the reaction time is generally 2 to 3 hours.

After the condensation reaction is completed, post-treatment may be further performed, and the post-treatment may be selected from one or more post-treatment methods selected from quenching, extraction, washing, drying, filtration, column chromatography and recrystallization.

Water can be used for the quenching; ethyl acetate can be used for the extraction; saturated sodium chloride aqueous solution can be used for the washing; anhydrous sodium sulfate can be used for the drying; and methanol and water can be used for the recrystallization.

In the present invention, the room temperature refers to 20°C to 35°C.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effect of the present invention is that the benzo[d][1,3]dioxole compounds provided by the present invention have a significant synergistic effect on Candida albicans 103 resistant to fluconazole.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Embodiment 1:

Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorophenyl)propionamide (E)-N-(Compound 1)

The raw carboxylic acid and the raw amine were dissolved in DMF in a molar ratio of 1:1, and 1.1 equivalents of PyBOP and 3 equivalents of DIEA were added. The mixture was reacted at room temperature for 2-3 hours and followed by TLC. After the reaction was complete, the reaction solution was poured into water for quenching, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin drying. The mixture was purified by column chromatography and recrystallized from methanol and water (volume ratio of 1:1 to 1:2) to obtain a white solid 1 (yield: 61%, purity greater than 98%). ¹ HNMR (300MHz, DMSO-d6): δ967 (s, 2H), 784 (m, 2H), 729–707 (m2H), 6.89–6.77 (m, 2H), 6.71 (d, J = 7.8Hz, 2H), 5.96 (s, 2H), 2.83 (t, J = 7.5Hz, 2H), 2.65 (t ,J＝7.5Hz,2H).[M+H] ⁺ :288.1

Example 2: Preparation of (R)-3-(Benzo[d][1,3]dioxol-5-yl)-N-indaneamide (Compound 2)

The preparation process of compound 2 is similar to that of compound 1. By changing the type of amine, a white solid 2 is finally obtained (yield: 63%, purity greater than 98%). The chiral center involved in the product is brought in by the reaction raw materials. Since the reaction process does not involve chiral changes, the chiral purity does not need to be tested again. ¹ H NMR (300MHz, DMSO-d ₆ ): δ8.18(d,J＝8.1Hz,1H),7.32–7.06(m,3H),6.99(d,J＝7.0Hz,1H),6.84(d,J＝6.8Hz,2H),6.70(d,J＝7.8Hz,1H),5.98(s,2H),5. 28(dd,J＝15.8,7.9Hz,1H),2.97–2.66(m,4H),2.39(dd,J＝17.1,9.8Hz,3H),1.83–1.62(m,1H).[M+H] ⁺ :310.1

Example 3: Preparation of (S)-3-(Benzo[d][1,3]dioxol-5-yl)-N-indaneamide (Compound 3)

The preparation process of compound 3 is similar to that of compound 1, and a white solid 3 is finally obtained (yield: 58%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.19(d,J＝8.1Hz,1H),7.31–7.07(m,3H),6.99(d,J＝6.9Hz,1H),6.84(d ,J＝6.3Hz,2H),6.70(d,J＝7.8Hz,1H),5.98(s,2H),5.28(q,J＝7.8Hz,1H),3.07–2.67(m,4H),2.39 (dd,J＝17.4,10.0Hz,3H),1.82–1.61(m,1H).[M+H] ⁺ :310.1

Example 4: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorobenzyl)propionamide (Compound 4)

The preparation process of compound 4 is similar to that of compound 1, and a white solid 4 is finally obtained (yield: 55%; purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.31 (t, J＝5.7Hz, 1H), 7.28 (dt, J＝11.5, 4.2Hz, 1H), 7.21–6.95 (m, 3H), 6.84 –6.71(m,2H),6.65(dd,J＝8.0,1.3Hz,1H),5.96(s,2H),4.27(d,J＝5.8Hz,2H),2.75(t,J＝7.5Hz, 2H),2.41(t,J＝7.5Hz,2H).[M+H] ⁺ :302.1

Example 5: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromobenzyl)propionamide (Compound 5)

The preparation process of compound 5 is similar to that of compound 1, and a white solid 5 is finally obtained (yield: 63%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.34 (t, J＝5.8Hz, 1H), 7.50–7.39 (m, 1H), 7.37–7.23 (m, 1H), 7.11 (dd, J＝ 18.0,8.5Hz,2H),6.79(dd,J＝7.6,4.7Hz,2H),6.65(dd,J＝7.9,1.7Hz,1H),5.96(s,2H),4.21(t,J＝5.9 Hz,2H),2.76(t,J＝7.5Hz,2H),2.39(d,J＝7.3Hz,2H).[M+H] ⁺ :362.0

Example 6: Preparation of propionamide 3-(benzo[d][1,3]dioxol-5-yl)-N-(4-chlorobenzyl)propionamide (Compound 6)

The preparation process of compound 6 is similar to that of compound 1, and a white solid 6 is finally obtained (yield: 64%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.33 (t, J = 5.6 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.79(dd,J＝6.5,4.6Hz,2H),6.65(d,J＝7.9Hz,1H),5.96(s,2H),4.22(d,J＝5.9Hz,2H),2.76(t,J ＝7.5Hz,2H),2.40(t,J＝7.5Hz,2H).[M+H] ⁺ :318.0

Example 7: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(Benzo[d][1,3]dioxol-5-methyl) (Compound 7)

The preparation process of compound 7 is similar to that of compound 1, and white solid 7 is finally obtained (yield: 59%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.21 (t, J = 5.8 Hz, 1H), 6.86–6.74 (m, 3H), 6.69 (s, 1H), 6.63 (dd, J = 10.1, 3.7Hz,2H),5.95(d,J＝5.9Hz,4H),4.13(d,J＝5.9Hz,2H),2.74(t,J＝7.5Hz,2H),2.37(t,J＝7.6Hz ,2H).[M+H] ⁺ :328.1

Example 8: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-chlorobenzyl)propionamide (Compound 8)

The preparation process of compound 8 is similar to that of compound 1, and a white solid 8 is finally obtained (yield: 62%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.34 (s, 1H), 7.15 (dt, J = 17.3, 7.8Hz, 4H), 6.82 (d, J = 9.3Hz, 2H), 6.67 (d ,J＝7.8Hz,1H),5.98(s,2H),4.24(d,J＝5.5Hz,2H),2.78(t,J＝7.3Hz,2H),2.42(t,J＝7.4Hz,2H ).[M+H] ⁺ :302.1

Example 9: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-chlorobenzyl)propionamide (Compound 9)

The preparation process of compound 9 is similar to that of compound 1, and a white solid 9 is finally obtained (yield: 57%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.36 (s, 1H), 7.44 (d, J = 7.0Hz, 1H), 7.35–7.17 (m, 2H), 7.09 (d, J = 6.8Hz ,1H),6.83(d,J＝6.8Hz,2H),6.68(d,J＝7.8Hz,1H),5.99(s,2H),4.32(d,J＝5.5Hz,2H),2.80(t ,J＝7.3Hz,2H),2.64–2.47(m,3H).[M+H] ⁺ :318.1

Example 10: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluorobenzyl)propionamide (Compound 10)

The preparation process of compound 10 is similar to that of compound 1, and white solid 10 is finally obtained (yield: 54%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.38 (brs, 1H), 7.33 (dd, J＝14.4, 7.2Hz, 1H), 7.01 (dt, J＝30.0, 10.6Hz, 3H), 6.81 (s,2H),6.67(d,J＝7.9Hz,1H),5.98(s,2H),4.28(d,J＝5.6Hz,2H),2.79(t,J＝7.3Hz,2H),2.44 (t,J＝7.3Hz,2H).[M+H] ⁺ :302.1

Example 11: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-methylbenzyl)propionamide (Compound 11)

The preparation process of compound 11 is similar to that of compound 1, and white solid 11 is finally obtained (yield: 61%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.14 (brs, 1H), 7.25–6.93 (m, 4H), 6.77 (d, J = 5.6Hz, 2H), 6.63 (d, J = 8.0Hz ,1H),5.93(s,2H),4.18(d,J＝5.4Hz,2H),2.74(t,J＝7.5Hz,2H),2.39(t,J＝7.5Hz,2H),2.18(s ,3H).[M+H] ⁺ :298.1

Example 12: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-bromobenzyl)propionamide (Compound 12)

The preparation process of compound 12 is similar to that of compound 1, and white solid 12 is finally obtained (yield: 63%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.33 (t, J = 5.5 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.31–7.09 (m, 2H), 7.01 (d, J＝7.5Hz,1H),6.78(d,J＝6.6Hz,2H),6.64(d,J＝7.9Hz,1H),5.94(s,2H),4.23(d,J＝5.7Hz,2H) ,2.76(t,J＝7.4Hz,2H),2.45(d,J＝7.7Hz,2H).[M+H] ⁺ :362.0

Example 13: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromobenzyl)propionamide (Compound 13)

The preparation process of compound 13 is similar to that of compound 1, and white solid 13 is finally obtained (yield: 59%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.34 (t, J = 5.7 Hz, 1H), 7.44–7.31 (m, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.10 (d, J＝7.6Hz,1H),6.76(d,J＝6.9Hz,2H),6.62(d,J＝8.0Hz,1H),5.93(s,2H),4.21(d,J＝5.9Hz,2H) ,2.73(t,J＝7.5Hz,2H),2.39(t,J＝7.5Hz,2H).[M+H] ⁺ :362.0

Example 14: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3,4-dichlorobenzyl)propionamide (Compound 14)

The preparation process of compound 14 is similar to that of compound 1, and white solid 14 is finally obtained (yield: 58%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.40 (t, J = 5.4Hz, 1H), 7.55 (d, J = 8.2Hz, 1H), 7.41 (s, 1H), 7.14 (d, J =8.2Hz,1H),6.81(d,J＝8.2Hz,2H),6.66(d,J＝7.9Hz,1H),5.97(s,2H),4.25(d,J＝5.7Hz,2H), 2.78(t,J＝7.4Hz,2H),2.44(t,J＝7.4Hz,2H).[M+H] ⁺ :352.0

Example 15: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluorobenzyl)propionamide (Compound 15)

The preparation process of compound 15 is similar to that of compound 1, and white solid 15 is finally obtained (yield: 61%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.34(t,J＝5.3Hz,1H),7.34–7.13(m,2H),7.01(t,J＝8.4Hz,1H),6.81(d ,J＝8.9Hz,2H),6.66(d,J＝7.9Hz,1H),5.97(s,2H),4.25(d,J＝5.4Hz,2H),2.76(t,J＝7.5Hz,2H ),2.41(t,J＝7.5Hz,2H).[M+H] ⁺ :320.1

Example 16: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-propyn-1-yl)propionamide (Compound 16)

The preparation process of compound 16 is similar to that of compound 1, and white solid 16 is finally obtained (yield: 56%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.90 (s, 1H), 6.81 (d, J = 7.9Hz, 2H), 6.67 (d, J = 7.8Hz, 1H), 5.97 (s, 2H ),2.74(t,J＝7.5Hz,2H),2.33(t,J＝7.5Hz,2H),1.85(d,J＝7.3Hz,1H).[M+H] ⁺ :218.1

Example 17: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclopropylmethyl)propionamide (Compound 17)

The preparation process of compound 17 is similar to that of compound 1, and white solid 17 is finally obtained (yield: 59%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.90 (s, 1H), 6.81 (d, J = 7.9Hz, 2H), 6.67 (d, J = 7.8Hz, 1H), 5.97 (s, 2H ),2.93(t,J＝5.7Hz,2H),2.74(t,J＝7.5Hz,2H),2.33(t,J＝7.5Hz,2H),0.85(m,1H),0.39(d,J ＝7.4Hz,2H),0.13(d,J＝4.0Hz,2H).[M+H] ⁺ :248.1

Example 18: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)propionamide (Compound 18)

The preparation process of compound 18 is similar to that of compound 1, and white solid 18 is finally obtained (yield: 51%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.75 (s, 1H), 6.80 (d, J = 8.5Hz, 2H), 6.65 (d, J = 7.8Hz, 1H), 5.96 (s, 2H) ),2.86(t,J＝6.0Hz,2H),2.73(t,J＝7.4Hz,2H),2.33(t,J＝7.4Hz,2H),1.58(m,5H),1.30(m,1H ),1.15(m,3H),0.81(m,2H).[M+H] ⁺ :290.2

Example 19: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(furan-2-methyl)propionamide (Compound 19)

The preparation process of compound 19 is similar to that of compound 1, and white solid 19 is finally obtained (yield: 57%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.30 (s, 1H), 7.58 (s, 1H), 6.81 (d, J = 7.6Hz, 2H), 6.66 (d, J = 7.9Hz, 1H ),6.39(s,1H),6.18(s,1H),5.97(s,2H),4.25(d,J＝5.4Hz,2H),2.75(t,J＝7.6Hz,2H),2.38(t ,J＝7.6Hz,2H).[M+H] ⁺ :274.1

Example 20: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-2-methyl)propionamide (Compound 20)

The preparation process of compound 20 is similar to that of compound 1, and a white solid 20 is finally obtained (yield: 59%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.46 (s, 1H), 7.39 (d, J = 4.7Hz, 1H), 7.04–6.87 (m, 2H), 6.80 (s, 2H), 6.67 (d,J＝7.8Hz,1H),5.97(s,2H),4.43(d,J＝5.5Hz,2H),2.77(t,J＝7.5Hz,2H),2.39(t,J＝7.5Hz ,2H).[M+H] ⁺ :290.1

Example 21: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-3-methyl)propionamide (Compound 21)

The preparation process of compound 21 is similar to that of compound 1, and a white solid 21 is finally obtained (yield: 56%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.29 (s, 1H), 7.47 (d, J = 2.4Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.81 (s ,2H),6.68(d,J＝7.1Hz,1H),5.98(s,2H),4.25(d,J＝4.1Hz,2H),2.77(d,J＝6.3Hz,2H),2.41(t ,J＝6.5Hz,2H).[M+H] ⁺ :290.1

Example 22: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(pyridine-2-methyl)propionamide (Compound 22)

The preparation process of compound 22 is similar to that of compound 1, and a white solid 22 is finally obtained (yield: 61%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.46 (d, J = 6.1 Hz, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.47–7.32 (m, 1H), 6.80 (d ,J＝7.2Hz,2H),6.66(d,J＝7.9Hz,1H),5.98(s,2H),4.29(d,J＝5.6Hz,2H),2.77(t,J＝7.4Hz,2H ),2.43(t,J＝7.4Hz,2H).[M+H] ⁺ :285.1

Example 23: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(pyridine-3-methyl)propionamide (Compound 23)

The preparation process of compound 23 is similar to that of compound 1, and a white solid 23 is finally obtained (yield: 58%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.46 (d, J = 6.1 Hz, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.47–7.32 (m, 1H), 6.80 (d ,J＝7.2Hz,2H),6.66(d,J＝7.9Hz,1H),5.98(s,2H),4.29(d,J＝5.6Hz,2H),2.77(t,J＝7.4Hz,2H ),2.43(t,J＝7.4Hz,2H).[M+H] ⁺ :285.1

Example 24: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-methyl)propionamide (Compound 24)

The preparation process of compound 24 is similar to that of compound 1, and white solid 24 is finally obtained (yield: 62%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.75 (s, 1H), 6.80 (d, J = 8.5Hz, 2H), 6.65 (d, J = 7.8Hz, 1H), 5.96 (s, 2H) ),2.86(t,J＝6.0Hz,2H),2.73(t,J＝7.4Hz,2H),2.33(t,J＝7.4Hz,2H),1.58(m,5H),1.30(m,1H ),1.15(m,3H),0.81(m,2H).[M+H] ⁺ :290.2

Example 25: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(phenethyl)propionamide (Compound 25)

The preparation process of compound 25 is similar to that of compound 1, and a white solid 25 is finally obtained (yield: 61%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.90 (s, 1H), 7.45–7.24 (m, 2H), 7.20 (d, J = 7.0Hz, 3H), 6.92–6.71 (m, 2H) ,6.62(d,J＝7.8Hz,1H),5.98(s,2H),3.31–3.14(m,2H),2.81(t,J＝7.5Hz,2H),2.60(t,J＝7.0Hz, 2H),2.36(t,J＝7.6Hz,2H).[M+H] ⁺ :298.1

Example 26: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methylphenethyl)propionamide (Compound 26)

The preparation process of compound 26 is similar to that of compound 1, and a white solid 26 is finally obtained (yield: 58%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.88 (s, 1H), 7.08 (s, 4H), 6.89–6.70 (m, 2H), 6.61 (d, J = 7.8Hz, 1H), 5.98 (s,2H),3.22(d,J＝6.3Hz,2H),2.76(t,J＝7.5Hz,2H),2.60(t,J＝7.0Hz,2H),2.33(t,J＝7.7Hz ,2H),2.27(s,3H).[M+H] ⁺ :312.1

Example 27: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(Benzo[d][1,3]dioxol-5-ethyl)propionamide (Compound 27)

The preparation process of compound 27 is similar to that of compound 1, and white solid 27 is finally obtained (yield: 61%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.33 (t, J = 5.6 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.79(dd,J＝6.5,4.6Hz,2H),6.65(d,J＝7.9Hz,1H),5.96(s,2H),4.22(d,J＝5.9Hz,2H),2.76(t,J ＝7.5Hz,2H),2.40(t,J＝7.5Hz,2H).[M+H] ⁺ :318.0

Example 28: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluorophenethyl)propionamide (Compound 28)

The preparation process of compound 28 is similar to that of compound 1, and white solid 28 is finally obtained (yield: 56%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.84 (t, J＝5.4Hz, 1H), 7.28–7.12 (m, 2H), 7.07 (ddd, J＝8.9, 5.8, 2.5Hz, 2H) ,6.76(dd,J＝9.2,4.7Hz,2H),6.62(dd,J＝7.9,1.7Hz,1H),5.94(s,2H),3.20(dt,J＝10.4,6.1Hz,2H), 2.67(dt,J＝14.5,7.2Hz,4H),2.28(t,J＝7.7Hz,2H).[M+H] ⁺ :316.1

Example 29: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-methylphenethyl)propionamide (Compound 29)

The preparation process of compound 29 is similar to that of compound 1, and a white solid 29 is finally obtained (yield: 59%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.13 (t, J＝5.5Hz, 1H), 7.17–6.95 (m, 4H), 6.78 (dd, J＝4.7, 3.0Hz, 2H), 6.64 (dd,J＝7.9,1.6Hz,1H),5.95(s,2H),4.20(d,J＝5.6Hz,2H),2.75(t,J＝7.5Hz,2H),2.40(t,J＝ 7.5Hz,2H),2.20(s,3H).[M+H] ⁺ :298.1

Example 30: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromophenethyl)propionamide (Compound 30)

The preparation process of compound 30 is similar to that of compound 1, and a white solid 30 is finally obtained (yield: 61%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.84 (t, J＝5.4Hz, 1H), 7.51–7.33 (m, 2H), 7.10 (d, J＝8.3Hz, 2H), 6.76 (dd ,J＝9.5,4.7Hz,2H),6.61(dd,J＝7.9,1.6Hz,1H),5.94(s,2H),3.21(dt,J＝13.5,6.7Hz,2H),2.66(dt, J＝17.7,7.2Hz,4H),2.28(t,J＝7.6Hz,2H).[M+H] ⁺ :376.0

Example 31: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(phenylpropyl)propionamide (Compound 31)

The preparation process of compound 31 is similar to that of compound 1, and white solid 31 is finally obtained (yield: 63%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.80 (t, J = 5.2 Hz, 1H), 7.35–7.19 (m, 2H), 7.14 (t, J = 5.7 Hz, 3H), 6.76 (d, J＝7.1Hz,2H),6.62(d,J＝8.0Hz,1H),5.89(s,2H),3.00(dd,J＝12.7,6.5Hz,2H),2.70(t,J＝7.5Hz, 2H),2.48(d,J＝7.0Hz,2H),2.29(t,J＝7.6Hz,2H),1.71–1.53(m,2H).[M+H] ⁺ :312.1

Example 32: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-chlorophenylpropyl)propionamide (Compound 32)

The preparation process of compound 32 is similar to that of compound 1, and finally a white solid 31 is obtained (yield: 62%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.79 (t, J = 5.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.75 (d,J＝7.1Hz,2H),6.62(d,J＝8.0Hz,1H),5.89(s,2H),2.98(q,J＝6.5Hz,2H),2.70(t,J＝7.5Hz ,2H),2.53–2.46(m,2H),2.29(t,J＝7.6Hz,2H),1.65–1.48(m,2H).[M+H] ⁺ :346.1

Example 33: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 32)

Compound 5 (10 mmol) and p-toluene boronic acid (12 mmol) were dissolved in 20 ml DMF, and then bistriphenylphosphine palladium dichloride (0.5 mmol) and potassium carbonate (20 mmol) were added. The reaction was carried out at 80°C for 6 hours under nitrogen protection. After the raw material was less than 5% by HPLC, the reaction was terminated. After the reaction solution was cooled to room temperature, 30 ml of water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Column chromatography was used for purification, and recrystallization with ethyl acetate and n-hexane was performed to obtain a gray solid, namely compound 32 (yield: 41%, purity greater than 98%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.35 (t, J＝5.4Hz, 1H), 7.66–7.51 (m, 4H), 7.25 (dd, J＝18.0, 7.9Hz, 4H), 6.83 ( d,J＝7.5Hz,2H),6.69(d,J＝7.8Hz,1H),5.97(s,2H),4.29(d,J＝5.6Hz,2H),2.80(t,J＝7.4Hz, 2H),2.44(t,J＝7.4Hz,2H),2.36(s,3H).[M+H] ⁺ :374.2

Example 34: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 34)

The preparation process of compound 34 is similar to that of compound 33, and white solid 33 is finally obtained (yield: 44%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ )) δ: 8.37 (brs, 1H), 7.82–7.30 (m, 5H), 7.28–6.98 (m, 3H), 6.83 (d, J = 7.1Hz, 2H) ,6.69(d,J＝7.3Hz,1H),5.98(s,2H),4.30(d,J＝5.3Hz,2H),2.75(t,J＝7.4Hz,2H),2.43(t,J＝ 7.2Hz,2H),2.39(s,3H).[M+H] ⁺ :374.2

Example 35: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-trifluoromethyl-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 35)

The preparation process of compound 35 is similar to that of compound 33, and white solid 35 is finally obtained (yield: 37%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.39 (t, J = 5.6 Hz, 1H), 7.86 (dd, J = 18.3, 8.3 Hz, 4H), 7.68 (d, J = 7.9 Hz, 2H) ,7.29(d,J＝7.9Hz,2H),6.83(d,J＝7.8Hz,2H),6.69(d,J＝7.9Hz,1H),5.98(s,2H),4.32(d,J＝ 5.7Hz,2H),2.80(t,J＝7.4Hz,2H),2.45(t,J＝7.5Hz,2H).[M+H] ⁺ :427.1

Example 36: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 36)

The preparation process of compound 36 is similar to that of compound 33, and white solid 36 is finally obtained (yield: 39%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.38 (t, J = 5.5 Hz, 1H), 7.58–7.38 (m, 4H), 7.39–7.20 (m, 4H), 6.96–6.80 (m, 2H) ),6.69(d,J＝7.7Hz,1H),5.97(s,2H),4.32(d,J＝5.6Hz,2H),2.80(t,J＝7.4Hz,2H),2.45(t,J ＝7.5Hz,2H).[M+H] ⁺ :378.1

Example 37: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 37)

The preparation process of compound 37 is similar to that of compound 33, and white solid 37 is finally obtained (yield: 45%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.37 (t, J = 5.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 5.6 Hz, 3H), 7.37 –7.11(m,3H),6.84(d,J＝8.0Hz,2H),6.69(d,J＝7.9Hz,1H),5.97(s,2H),4.31(d,J＝5.7Hz,2H) ,2.80(t,J＝7.4Hz,2H),2.44(t,J＝7.5Hz,2H).[M+H] ⁺ :378.1

Example 38: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-cyano-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 38)

The preparation process of compound 38 is similar to that of compound 33, and white solid 38 is finally obtained (yield: 42%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.35 (t, J = 5.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 4H), 7.64 (d, J = 8.0 Hz, 2H), 7.24 (d,J＝8.0Hz,2H),6.78(d,J＝8.1Hz,2H),6.64(d,J＝8.0Hz,1H),5.92(s,2H),4.27(d,J＝5.7Hz ,2H),2.75(t,J＝7.5Hz,2H),2.40(t,J＝7.5Hz,2H).[M+H] ⁺ :385.2

Example 39: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 39)

The preparation process of compound 39 is similar to that of compound 33, and white solid 39 is finally obtained (yield: 43%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.38 (t, J = 5.6 Hz, 1H), 7.80–7.32 (m, 5H), 7.23 (dd, J = 13.6, 8.2 Hz, 3H), 6.89– 6.75(m,2H),6.69(d,J＝7.7Hz,1H),5.97(s,2H),4.31(d,J＝5.7Hz,2H),2.80(t,J＝7.4Hz,2H), 2.44(t,J＝7.5Hz,2H).[M+H] ⁺ :396.1

Example 40: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 40)

The preparation process of compound 40 is similar to that of compound 33, and white solid 40 is finally obtained (yield: 46%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.33 (t, J = 5.6 Hz, 1H), 7.65 (dd, J = 8.4, 5.6 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H) ,7.35–7.12(m,4H),6.77(dd,J＝9.8,4.6Hz,2H),6.64(d,J＝7.6Hz,1H),5.93(s,2H),4.25(d,J＝5.7 Hz,2H),2.75(t,J＝7.3Hz,2H),2.39(t,J＝7.3Hz,2H).[M+H] ⁺ :378.1

Example 41: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide (Compound 41)

The preparation process of compound 41 is similar to that of compound 33, and white solid 41 is finally obtained (yield: 41%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.35 (t, J＝5.4Hz, 1H), 7.66–7.51 (m, 4H), 7.25 (dd, J＝18.0, 7.9Hz, 4H), 6.83 ( d,J＝7.5Hz,2H),6.69(d,J＝7.8Hz,1H),5.97(s,2H),4.29(d,J＝5.6Hz,2H),2.80(t,J＝7.4Hz, 2H),2.64(t,J＝7.2Hz,2H),2.44(t,J＝7.4Hz,2H),2.36(s,3H).[M+H] ⁺ :388.2

Example 42: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylmethyl)propionamide (Compound 42)

The preparation process of compound 42 is similar to that of compound 33, and white solid 42 is finally obtained (yield: 45%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.11 (s, 1H), 7.61 (dd, J = 20.2, 7.7Hz, 4H), 7.46 (t, J = 7.5Hz, 2H), 7.33 (dd ,J＝18.6,7.6Hz,3H),6.87–6.70(m,2H),6.62(d,J＝7.8Hz,1H),5.95(s,2H),3.42(s,2H),3.25(dd, J＝12.8,6.7Hz,2H),2.63(t,J＝7.0Hz,2H).[M+H] ⁺ :360.1

Example 43: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(4-fluorophenoxy)benzyl)propionamide (Compound 43)

The preparation process of compound 43 is similar to that of compound 33, and white solid 43 is finally obtained (yield: 38%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.30 (t, J = 5.5 Hz, 1H), 7.18 (t, J = 8.7 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 6.98 (dd,J＝8.9,4.5Hz,2H),6.85(d,J＝7.7Hz,2H),6.74(d,J＝7.4Hz,2H),6.61(d,J＝8.0Hz,1H),5.87 (s,2H),4.17(d,J＝5.7Hz,2H),2.72(t,J＝7.4Hz,2H),2.36(t,J＝7.4Hz,2H).[M+H] ⁺ :394.1

Example 44: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(pyridin-4-yl)benzyl)propanamide (Compound 44)

The preparation process of compound 44 is similar to that of compound 33, and white solid 44 is finally obtained (yield: 36%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.60 (s, 2H), 8.36 (t, J = 5.7Hz, 1H), 7.68 (dd, J = 10.3, 6.9Hz, 4H), 7.25 (d, J＝8.0Hz,2H),6.79(d,J＝8.0Hz,2H),6.64(d,J＝8.0Hz,1H),5.93(s,2H),4.28(d,J＝5.8Hz,2H) ,2.75(t,J＝7.4Hz,2H),2.40(t,J＝7.5Hz,2H).[M+H] ⁺ :361.2

Example 45: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-2-yl)benzyl)propionamide (Compound 45)

The preparation process of compound 45 is similar to that of compound 33, and white solid 45 is finally obtained (yield: 36%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.32 (t, J = 5.6 Hz, 1H), 7.62–7.39 (m, 4H), 7.11 (dd, J = 10.0, 6.4 Hz, 3H), 6.78 ( d,J＝8.1Hz,2H),6.64(d,J＝7.9Hz,1H),5.93(s,2H),4.22(d,J＝5.8Hz,2H),2.75(t,J＝7.4Hz, 2H),2.39(t,J＝7.5Hz,2H).[M+H] ⁺ :366.2

Example 46: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-3-yl)benzyl)propionamide (Compound 46)

The preparation process of compound 46 is similar to that of compound 33, and white solid 46 is finally obtained (yield: 39%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.31 (t, J＝5.5Hz, 1H), 7.80 (s, 1H), 7.60 (d, J＝7.5Hz, 3H), 7.51 (d, J＝ 4.9Hz,1H),7.15(d,J＝8.0Hz,2H),6.78(d,J＝7.8Hz,2H),6.64(d,J＝7.7Hz,1H),5.93(s,2H),4.23 (d,J＝5.7Hz,2H),2.75(t,J＝7.4Hz,2H),2.39(t,J＝7.4Hz,2H).[M+H] ⁺ :366.2

Example 47: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(furan-2-yl)benzyl)propanamide (Compound 47)

The preparation process of compound 47 is similar to that of compound 33, and white solid 47 is finally obtained (yield: 41%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.31 (t, J = 5.3 Hz, 1H), 7.69–7.47 (m, 4H), 7.14 (d, J = 8.0 Hz, 2H), 6.87 (d, J＝3.1Hz,1H),6.78(d,J＝8.1Hz,2H),6.64(d,J＝7.6Hz,1H),5.93(s,2H),4.22(d,J＝5.7Hz,2H) ,2.74(t,J＝7.3Hz,2H),2.39(t,J＝7.3Hz,2H).[M+H] ⁺ :350.1

Example 48: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-2-yl)methyl)propanamide (Compound 48)

The preparation process of compound 48 is similar to that of compound 33, and white solid 48 is finally obtained (yield: 43%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.18 (t, J = 5.2 Hz, 1H), 7.37–7.06 (m, 8H), 6.83–6.70 (m, 2H), 6.62 (d, J = 7.8 Hz,1H),5.93(s,2H),4.12(d,J＝5.4Hz,2H),2.71(t,J＝7.3Hz,2H),2.37(m,2H),2.32(s,3H). [M+H] ⁺ :374.2

Example 49: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-2-yl)methyl)propanamide (Compound 49)

The preparation process of compound 49 is similar to that of compound 33, and white solid 49 is finally obtained (yield: 41%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.19 (t, J = 5.3 Hz, 1H), 7.46–7.08 (m, 8H), 6.86–6.70 (m, 2H), 6.62 (d, J = 7.9 Hz,1H),5.93(s,2H),4.11(d,J＝5.3Hz,2H),2.70(t,J＝7.5Hz,2H),2.35(t,J＝7.5Hz,2H).[M +H] ⁺ :378.2

Example 50: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-2-ylmethyl)propionamide (Compound 50)

The preparation process of compound 50 is similar to that of compound 33, and white solid 50 is finally obtained (yield: 42%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.19 (t, J = 5.3 Hz, 1H), 7.46–7.08 (m, 8H), 6.86–6.70 (m, 2H), 6.62 (d, J = 7.9 Hz,2H),5.93(s,2H),4.11(d,J＝5.3Hz,2H),2.70(t,J＝7.5Hz,2H),2.35(t,J＝7.5Hz,2H).[M +H] ⁺ :360.2

Example 51: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-3-yl)methyl)propanamide (Compound 51)

The preparation process of compound 51 is similar to that of compound 33, and white solid 51 is finally obtained (yield: 45%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.33 (t, J = 5.5 Hz, 1H), 7.62–7.40 (m, 4H), 7.38–7.19 (m, 3H), 7.07 (d, J = 7.5 Hz,1H),6.82–6.68(m,2H),6.63(d,J＝8.0Hz,1H),6.01–5.85(m,2H),4.30(t,J＝8.3Hz,2H),3.33(s ,2H),2.84–2.66(m,2H),2.38(dd,J＝14.4,7.0Hz,2H),2.31(s,3H).[M+H] ⁺ :374.2

Example 52: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-3-yl)methyl)propanamide (Compound 52)

The preparation process of compound 52 is similar to that of compound 33, and white solid 52 is finally obtained (yield: 38%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.33 (t, J = 5.6 Hz, 1H), 7.63 (dd, J = 8.4, 5.6 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H) ,7.41–7.16(m,3H),7.10(d,J＝7.6Hz,1H),6.81–6.69(m,2H),6.62(d,J＝7.9Hz,1H),5.91(s,2H), 4.29(d,J＝5.8Hz,2H),2.74(t,J＝7.5Hz,2H),2.38(d,J＝7.4Hz,2H).[M+H] ⁺ :378.2

Example 53: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-3-ylmethyl)propionamide (Compound 53)

The preparation process of compound 53 is similar to that of compound 33, and white solid 53 is finally obtained (yield: 39%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.11 (s, 1H), 7.61 (dd, J = 20.2, 7.7Hz, 4H), 7.46 (t, J = 7.5Hz, 2H), 7.33 (dd ,J＝18.6,7.6Hz,3H),6.87–6.70(m,2H),6.62(d,J＝7.8Hz,1H),5.95(s,2H),3.42(s,2H),3.25(dd, J＝12.8,6.7Hz,2H),2.63(t,J＝7.0Hz,2H).[M+H] ⁺ :360.1

Example 54: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)ethyl)propanamide (Compound 54)

The preparation process of compound 54 is similar to that of compound 33, and white solid 54 is finally obtained (yield: 36%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.35 (t, J＝5.4Hz, 1H), 7.66–7.51 (m, 4H), 7.25 (dd, J＝18.0, 7.9Hz, 4H), 6.83 ( d,J＝7.5Hz,2H),6.69(d,J＝7.8Hz,1H),5.97(s,2H),4.29(d,J＝5.6Hz,2H),2.80(t,J＝7.4Hz, 2H),2.44(t,J＝7.4Hz,2H),2.36(s,3H).[M+H] ⁺ :388.2

Example 55: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)ethyl)propanamide (Compound 55)

The preparation process of compound 55 is similar to that of compound 33, and white solid 55 is finally obtained (yield: 36%. Purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.33 (t, J = 5.6 Hz, 1H), 7.65 (dd, J = 8.4, 5.6 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H) ,7.35–7.12(m,4H),6.77(dd,J＝9.8,4.6Hz,2H),6.64(d,J＝7.6Hz,1H),5.93(s,2H),4.25(d,J＝5.7 Hz,2H),2.75(t,J＝7.3Hz,2H),2.39(t,J＝7.3Hz,2H).[M+H] ⁺ :392.1

Example 56: Preparation of 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylethyl)propionamide (Compound 56)

The preparation process of compound 56 is similar to that of compound 33, and white solid 56 is finally obtained (yield: 38%, purity greater than 98%)

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.11 (s, 1H), 7.61 (dd, J = 20.2, 7.7Hz, 4H), 7.46 (t, J = 7.5Hz, 2H), 7.33 (dd ,J＝18.6,7.6Hz,3H),6.87–6.70(m,2H),6.62(d,J＝7.8Hz,1H),5.95(s,2H),3.42(s,2H),3.25(dd, J＝12.8,6.7Hz,2H),2.63(t,J＝7.0Hz,2H).[M+H] ⁺ :374.1

Effect Example

1. Experimental Materials

1. Strains:

Clinically isolated drug-resistant Candida albicans 103 was donated by the Strain Conservation Center of Changhai Hospital (it can also be purchased from the Institute of Cell Biology, Chinese Academy of Sciences).

Culture conditions: All experimental strains were activated by streaking on Sandcastle Dextrose Agar (SDA) medium. After culturing at 30°C for 2 weeks, single clones were picked out and streaked again for activation. The single clones obtained for the second time were placed on SDA slants, cultured using the above method, and stored at 4°C for later use.

2. Culture medium:

RPMI 1640 liquid culture medium: RPMI1640 (Gibco BRL) 10g, NaHCO3 2.0g, morpholinepropanesulfonic acid (MOPS) (Sigma) 34.5g (0.165M), add 900ml of triple-distilled water to dissolve, adjust the pH to 7.0 (25°C) with 1N NaOH, make up to 1000ml with triple-distilled water, filter and sterilize with a 0.22μm microporous filter membrane, and store at 4°C for later use.

Sandburg Dextrose Agar Solid Medium (SDA): 10 g of peptone, 40 g of glucose, and 18 g of agar are dissolved in 900 ml of triple-distilled water, and the pH is adjusted to 7.0. The volume is made up to 1000 ml with triple-distilled water, and the mixture is sterilized at high pressure (121°C, 15 min) and stored at 4°C for later use.

YEPD culture medium: 10 g yeast extract, 20 g peptone, 20 g glucose, add 900 ml triple distilled water to dissolve, make up to 1000 ml with triple distilled water, sterilize by high pressure (121°C, 15 min), and store at 4°C for later use.

3. Reagents:

Fluconazole (FCZ) injection was provided by Dalian Pfizer Pharmaceutical Co., Ltd., and forsythiaside A was provided by Shanghai Changhai Hospital (also available from Chengdu Mansite Biotechnology Co., Ltd.). Dimethyl sulfoxide (DMSO) was produced by Shanghai Chemical Reagent Company of China National Pharmaceutical Group

4. Instruments and equipment:

Multiskan MK3 ELISA Analyzer (Labsystems, Finland)

Water-insulated electric constant temperature incubator (Shanghai Yuejin Medical Equipment Factory)

MJX Intelligent Mold Incubator (Ningbo Jiangnan Instrument Factory)

THZ-82A desktop constant temperature oscillator (Shanghai Yuejin Medical Equipment Factory)

SW-CT-IF ultra-clean workbench (Suzhou Antai Air Technology Co., Ltd.)

Inverted microscope (Amersham Pharmacia product)

Micropipette (Finland Finnpette product)

96-well cell culture plate (Nunclon, Denmark)

2. Experimental Methods

1. Preparation of fungal suspension:

Before the experiment, a small amount of Candida albicans was picked from the SDA medium stored at 4°C with an inoculation loop and inoculated into 1ml YEPD culture medium. The culture was cultured at 30°C and 200rpm with shaking for 16 hours to make the fungus in the late exponential growth phase. The bacterial solution was added to 1ml YEPD culture medium and activated again using the above method. After 16 hours, the cells were counted with a hemocytometer and the concentration of the bacterial solution was adjusted to 1×10 ³ -5×10 ³ CFU/ml with RPMI1640 culture medium.

2. Preparation of drug sensitivity plate:

Take a sterile 96-well plate, add 100μl of RPMI 1640 liquid culture medium to well 1 of each row as a blank control; add 100μl of freshly prepared bacterial solution to wells 3 to 12; add 160μl of bacterial solution and 40μl of test compound solution to well 2; well 12 does not contain drugs, but only adds 100μl of bacterial solution as a positive growth control. Wells 2 to 11 are diluted in multiples so that the final drug concentrations in each well are 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125μg/ml, respectively, and the DMSO content in each well is less than 1%. Prepare a quality control bacterial drug sensitivity plate at the same time as the drug sensitivity plate is prepared each time, and each drug sensitivity plate is cultured in a constant temperature box at 30℃.

3. Determination of minimum inhibitory concentration (MIC value):

After Candida was cultured for 24 hours in a 30°C incubator, the OD value of each well was measured at 620nm using an enzyme-labeled analyzer. The OD value of the positive control well was controlled at about 0.2. Compared with the positive control well, the drug concentration in the lowest concentration well where the OD value dropped by more than 80% was the MIC ₈₀ (the drug concentration when the fungal growth was inhibited by 80%). When the MIC ₈₀ value of the drug exceeded the measured concentration range, statistics were performed according to the following method: when the MIC ₈₀ value was higher than the highest concentration of 64μg/ml, it was counted as ">64μg/ml"; when the MIC ₈₀ value was the lowest concentration or below the lowest concentration, no distinction was made and it was counted as "≤0.125μg/ml". The above experiments were all performed in parallel 2 to 3 times. When the MIC ₈₀ value could be accurately repeated or only differed by one concentration, it was accepted and the higher concentration was used as the MIC ₈₀ value; when the MIC ₈₀ value differed by more than two concentrations, the experiment needed to be repeated until it met the requirements.

Referring to standard J (M27-A scheme) proposed by the National Committee for Clinical Trials Standards (NCCLS) of the United States in 1997: the MIC of AmB was determined as follows: compared with the growth control wells, the lowest drug concentration corresponding to 100% complete inhibition of growth and clear culture medium was the MIC of AmB; compared with the growth control wells, the lowest drug concentration corresponding to ≥80% growth inhibition was the MIC ₈₀ of fluconazole and forsythiaside A.

4. Quality control bacteria:

According to the recommendations of the NCCLS M27-A scheme, we used Candida parapsilosis ATCC18062 as the quality control bacteria. Each time the drug sensitivity plate was prepared, a quality control bacteria drug sensitivity plate was prepared. The MIC reference values were as follows: FCZ: MIC ₈₀ value 0.25-1.0 μg/ml; AmB: MIC value 0.5-2.0 μg/ml. Each test used this strain as the reference strain. Only when its MIC value was within the above range, the test operation was considered accurate and reliable. If the test strain grew well at the same time, the test was considered successful and the results were acceptable.

5. Evaluation of the effect of combined medication:

The fractional inhibitory concentration index (FICI) is the main parameter for evaluating the interaction between two drugs in combination. The fractional inhibitory concentration (FIC) is the ratio of the minimum inhibitory concentration (MIC) required for combined inhibition of each drug to the MIC when used alone. The FIC index (FICI) is equal to the sum of the FICs of the two drugs. When the MIC value is higher than the upper limit of detection, the FICI is calculated as twice the upper limit concentration. Many literature reports that when FICI≤0.5, the interaction between the two drugs is determined to be synergistic, and the smaller the FIC index, the stronger the synergistic effect; when 0.5<FICI≤1, the interaction between the two drugs is determined to be additive; when 1<FICI≤4, it is irrelevant; when FICI>4, the two drugs produce antagonism. This topic uses the latest standards currently used in foreign journals: when FICI≤0.5, the interaction between the two drugs is determined to be synergistic; when 0.5<FICI≤4, it is irrelevant; when FICI>4, the two drugs produce antagonism. This topic uses the latest standards currently used in foreign journals: when FICI≤0.5, the interaction between the two drugs is determined to be synergistic; when 0.5<FICI≤4, it is irrelevant; when FICI>4, the two drugs produce antagonism.

3. Experimental Results

1. FICI and MIC ₈₀ results of compounds 1 to 56 in combination with fluconazole against resistant Candida albicans 103 strains; the same test was also performed on the known compound A, the structure of which is:

Experimental conclusion:

The checkerboard dilution method was used to test the synergistic effect of the above compounds 1 to 56 on fluconazole-resistant Candida albicans 103. It was found that except for compounds 23 and 38, all compounds had obvious synergistic effects on fluconazole-resistant Candida albicans 103, and they can be used as synergists for antifungal drugs against resistant fungi. The synergistic effect of compound 4 is due to the synergistic effect of compound A.

The embodiments described herein are for illustration only (as examples), and various modifications or changes made by technicians should also be included in the essence and scope of the patent application and the scope of the appended claims.

Claims (16)

1. A benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof as shown in Formula I:

Where n ¹ is 0, 1, 2 or 3; R is a substituted or unsubstituted phenyl group, a C ₃ to C ₆ cycloalkyl group,

C ₂ to C ₄ alkynyl,

The number of substituents of the substituted or unsubstituted phenyl group is one or two, and the substituents are halogen or C ₁ -C ₃ alkyl; The benzo[d][1,3]dioxole compounds shown in formula I do not include compounds shown in the following structures:

2. The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine; and/or, the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclopentyl or cyclohexyl; And/or, the C ₂ -C ₄ alkynyl group is ethynyl. 3 . The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the C ₁ -C ₃ alkyl group is a methyl group. 4. The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein when n ¹ = 0, R is

When n ¹ = 1, R is a substituted or unsubstituted phenyl group, a C ₄ -C ₆ cycloalkyl group,

The number of substituents of the substituted or unsubstituted phenyl group is one or two; the substituent is halogen; When n ¹ =2, R is a substituted or unsubstituted phenyl group; the number of substituents of the substituted or unsubstituted phenyl group is one or two; and the substituents are halogen or C ₁ -C ₃ alkyl groups. 5 . The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 4 , wherein when n ¹ =1, the substituent is fluorine, chlorine, bromine or iodine. 6 . The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 4 , wherein when n ¹ =2, the halogen is fluorine, chlorine, bromine or iodine. 7. The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from any of the following structures:

8. The benzo[d][1,3]dioxole compound of formula I as claimed in claim 1 is selected from any of the following compounds: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromobenzyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-bromobenzyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromobenzyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3,4-dichlorobenzyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluorobenzyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(thiophene-3-methyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methylphenethyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromophenethyl)propionamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-chlorophenylpropyl)propionamide. 9. A benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof as shown in Formula II:

Where n ² is 1, 2 or 3; When R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen at the same time, R ⁸ is

Or, when R ⁶ , R ⁷ and R ⁸ are all hydrogen, one of R ⁴ and R ⁵ is hydrogen and the other is

Or, when R ⁴ , R ⁵ and R ⁸ are all hydrogen, one of R ⁶ and R ⁷ is hydrogen and the other is

The benzo[d][1,3]dioxole compound shown in formula II does not include the compound shown in the following structure:

10. The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein when R ⁶ , R ⁷ and R ⁸ are all hydrogen, one of R ⁴ and R ⁵ is hydrogen and the other is

11. The benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein when R ⁴ , R ⁵ and R ⁸ are all hydrogen, one of R ⁶ and R ⁷ is hydrogen and the other is

12. The benzo[d][1,3]dioxole compound of formula II as claimed in claim 9 is selected from any of the following compounds: 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-trifluoromethyl-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-difluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methyl-(1,1'-biphenyl)-4-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylmethyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(pyridin-4-yl)benzyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-2-yl)benzyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(thiophen-3-yl)benzyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(furan-2-yl)benzyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-2-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-2-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-2-ylmethyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-3-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-3-yl)methyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-3-ylmethyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-(1,1'-biphenyl)-4-yl)ethyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-fluoro-(1,1'-biphenyl)-4-yl)ethyl)propanamide; 3-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1'-biphenyl-4-ylethyl)propanamide. 13. Use of a benzo[d][1,3]dioxole compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition against Candida albicans;

Where n ¹ is 0, 1, 2 or 3; R is a substituted or unsubstituted phenyl group, a C ₃ to C ₆ cycloalkyl group,

C ₂ to C ₄ alkynyl,

The number of substituents of the substituted or unsubstituted phenyl group is one or two, and the substituents are halogen or C ₁ -C ₃ alkyl. 14. Use of a benzo[d][1,3]dioxole compound or a pharmaceutically acceptable salt thereof as shown in formula II in the preparation of a pharmaceutical composition for use against Candida albicans:

Where n ² is 1, 2 or 3; When R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen at the same time, R ⁸ is

Or, when R ⁶ , R ⁷ and R ⁸ are all hydrogen, one of R ⁴ and R ⁵ is hydrogen and the other is

Or, when R ⁴ , R ⁵ and R ⁸ are all hydrogen, one of R ⁶ and R ⁷ is hydrogen and the other is

15. A method for preparing a benzo[d][1,3]dioxole compound as shown in formula I, characterized in that it comprises the following steps: in a solvent, under the action of a base and a condensing agent, subjecting piperonyl propionic acid and a compound as shown in formula I-1 to a condensation reaction as shown below;

ⁿ¹ and R are as defined in any one of claims 1 to 7. 16. A method for preparing a benzo[d][1,3]dioxole compound as shown in formula II, characterized in that it comprises the following steps: in a solvent, under the action of a base and a catalyst, subjecting the compound shown in formula II-1 and the compound shown in formula II-2 to a coupling reaction as shown below:

n ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in any one of claims 9-11.