CN105693609A - Polysubstitution phenyl alkyl amino acridine-4-amide compound and preparing method and purpose thereof - Google Patents

Abstract

The invention provides a polysubstitution phenyl alkyl amino acridine-4-amide compound and a preparing method and purpose thereof. The compound is the polysubstitution phenyl alkyl amino acridine-4-amide compound having the structural formula shown as the formula I or salt or ester or solvate acceptable in pharmacy, wherein R1, R2, R3 and n are defined in the description. The compound can effectively inhibit expression of Survivin protein in tumor cells, inhibit activity of DNA topoisomerase, inhibit eukaryote tumor cell proliferation and prevent and/or treat tumor.

Description

Polysubstituted phenyl alkylamino acridone-4-amides compound and its production and use

Technical field

The present invention relates to field of medicaments, in particular it relates to polysubstituted phenyl alkylamino acridone-4-amides compound and its production and use compound and its production and use。

Background technology

Cancer has become as the second largest factor of serious threat human health。Over nearly 30 years, although the understanding of cancer has been had and largely improves by the mankind, but but there is not the improvement of same amplitude for the treatment of cancer。For this, the innovation of necessity and improving is carried out for the ways and means for the treatment of of cancer and is just particularly important。The novel targets finding cancer therapy drug is currently a focus for the treatment of of cancer。Such as, survivin Survivin is more and more higher in recent years in the attention rate in cancer therapy drug field。Survivin, as a frontier of oncotherapy, furthers investigate the short history less than 20 years from starting to be found to。Although small-molecule drug YM155 and the NSC80467 anticancer mechanism around Survivin research and development is also indefinite, but experiment confirms that they all can effectively suppress the expression of Survivin albumen in multiple cancerous cell, and kinds of tumor cells demonstrates significantly high active anticancer。

Summary of the invention

It is contemplated that one of technical problem solved at least to a certain extent in correlation technique。For this, it is an object of the present invention to propose a kind of can effectively suppress the expression of Survivin albumen in tumor cell, suppress topoisomerase, suppress eukaryote tumor cell proliferation or prevention and/or treatment tumor means。

In one aspect of the invention, the invention provides a kind of polysubstituted phenyl alkylamino acridone-4-amides compound。According to embodiments of the invention, this compound is polysubstituted phenyl alkylamino acridone-4-amides compound or its pharmaceutically acceptable salt, ester or the solvate with structural formula shown in Formulas I,

Wherein, R₁Be each independently H, haloalkyl that alkoxyl that carbon number is 1～5, halogen, carbon number are 1～5, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

R₂For alkoxyl that carbon number is 1～5 or optionally substituted amido；

R₃Be each independently for H, carbon number be 1～5 alkoxyl, carbon number be 1～5 haloalkyl, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

The integer of m=1-4；

The integer of n=1～5；

The integer of p=1-4。

Inventor have found that, this compound of the present invention can effectively suppress the expression of Survivin albumen in tumor cell, suppresses the activity of DNA topoisomerase, suppress eukaryote tumor cell proliferation or prevention and/or treatment tumor。

According to embodiments of the invention, R₁It is each independently as H, OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH₂CH₃、F、Cl、Br、CF₃、NO₂、NH₂Or carbon number is the straight chained alkyl of 1-5,

R₂For NH₂、N(CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-NH₂、-NO₂、-CF₃、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃, or-CH₂CH₂CH₂CH₃,

The integer of m=1-4；

The integer of n=1-4；

The integer of p=1-4。

According to embodiments of the invention, R₁It is each independently as OCH₃、Cl、NO₂, or CH₃,

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-CF₃, or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3。

Some concrete examples according to the present invention, compound according to embodiments of the present invention is one of following:

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((3-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9, the preparation of 10-acridan-4-amide,

N-(3-(dimethylamino) propyl group) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

5,7-bis-chloro-N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((3-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-Ethylbenzyl) amino)-5-nitro-9-oxo-acridan-4-amide。

In another aspect of this invention, the invention provides a kind of method preparing compound noted earlier。According to embodiments of the invention, the method includes: (1) makes compound shown in Formula II react with compound shown in formula III, in order to obtain compound shown in formula IV；(2) compound shown in formula IV and strong sulfuric acid response are made, in order to obtain compound shown in formula V；(3) compound shown in formula V is made to react with kiber alkyl amine compounds, in order to obtain compound shown in formula VI；(4) compound shown in formula VI is made to react with Multi substituted benzenes pheynylalkylamine compounds, in order to obtain compound shown in Formulas I,

Wherein, R₁、R₂、R₃, m, n, p as defined above。Inventor have found that, utilize the method for the present invention can fast and effeciently prepare foregoing compound, and the method is simple, convenient fast, target compound yield is higher, is suitable to large-scale production。

According to embodiments of the invention, kiber alkyl amine compounds has the structure shown in one of formula 1-formula 3。Multi substituted benzenes pheynylalkylamine compounds has structure shown below:

Some concrete examples according to the present invention, Multi substituted benzenes pheynylalkylamine compounds has the structure shown in one of formula 4-formula 9。Thereby, it is possible to effectively obtain foregoing compound。

According to embodiments of the invention, in step (1), using copper be catalyst, potassium carbonate as alkali, make compound shown in compound shown in Formula II and formula III react in anhydrous dimethyl formamide, in order to compound shown in acquisition formula IV。Concrete example according to the present invention, in step (1), at 100-130 DEG C, using copper be catalyst, potassium carbonate as alkali, make compound shown in compound shown in Formula II and formula III react 1-12 hour in anhydrous dimethyl formamide according to the ratio that mol ratio is 1:1.5。

According to embodiments of the invention, in step (2), at 50-100 DEG C, make compound shown in formula IV and strong sulfuric acid response 1-5 hour。

According to embodiments of the invention, in step (3), at 0-50 DEG C, with N, N'-carbonyl dimidazoles as condensing agent, compound shown in formula V and kiber alkyl amine compounds is made to react 10-30 hour in anhydrous dimethyl formamide。Thus, being conducive to reaction to carry out, reduce the generation of side reaction, improving productivity, thus fast and effeciently obtaining foregoing compound。

According to embodiments of the invention, in step (4), at 50-100 DEG C, compound shown in formula VI is made to react 10-30 hour with Multi substituted benzenes pheynylalkylamine compounds。Thereby, it is possible to make each reactant react under the conditions such as optimal temperature, proportioning, advantageously reduce side reaction, improve productivity and reaction efficiency。

In another aspect of the invention, the invention provides a kind of pharmaceutical composition。According to embodiments of the invention, this pharmaceutical composition contains foregoing compound。Inventor have found that, the pharmaceutical composition of the present invention can effectively suppress the expression of Survivin albumen in tumor cell, suppresses the activity of DNA topoisomerase, suppress eukaryote tumor cell proliferation, prevention and/or treatment tumor, and then can be effective to the treatment of cancer。

According to embodiments of the invention, topoisomerase is topoisomerase II。

According to embodiments of the invention, eukaryote is mammal；Tumor cell is cancerous cell；Further, cancerous cell is leukaemia cancer cell, breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell, wherein, the former leukaemia of the chronic marrow of the preferred people of leukaemia cancer cell, the preferred human liver cancer cell of hepatoma carcinoma cell。

In still another aspect of the invention, the invention provides foregoing compound or the pharmaceutical composition purposes in preparing medicine。According to embodiments of the invention, this medicine may be used for effectively suppressing the expression of Survivin albumen in tumor cell, suppresses the activity of DNA topoisomerase, suppresses eukaryote tumor cell proliferation or prevention and/or treatment tumor。

Accompanying drawing explanation

Fig. 1 shows according to one embodiment of present invention, and compound 16 suppresses the detected through gel electrophoresis result figure of topoisomerase II。

Fig. 2 shows according to one embodiment of present invention, the protein electrophoresis figure of compound 16。

Detailed description of the invention

Embodiments of the invention are described below in detail。The embodiments described below is illustrative of, and is only used for explaining the present invention, and is not considered as limiting the invention。Unreceipted concrete technology or condition in embodiment, technology or condition described by the document in this area or carry out according to product description。Agents useful for same or the unreceipted production firm person of instrument, be can pass through city available from conventional products。

In this article, " shown in formula N compound " in this article otherwise referred to as " compound N ", N is the arbitrary integer of 1-17 in this article, for instance " shown in formula 16 compound " can also be called " compound 16 " in this article。

As described in the present invention, substituent group is drawn the member ring systems (as shown in Formula II) that key is connected on the ring at center to be formed and is represented substituent R₁Can replace any commutable position on ring。Such as, Formula II represents any position being likely to be replaced on phenyl ring and all can be replaced。

In addition, it is necessary to illustrate, unless otherwise explicitly pointed out, the describing mode that adopts in the whole text in this article " ... it is each independently ", represent in identical group, do not affect mutually between concrete option expressed between same-sign。Such as, m R in compound shown in Formula II₁Between be independent of each other。

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention。Pharmaceutically acceptable salt at art for known to the skilled person which。

" solvate " of the present invention refers to the associated complex that the compound of one or more solvent molecule and the present invention is formed。The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and ethylaminoethanol。

In one aspect of the invention, the invention provides a kind of compound。According to embodiments of the invention, this compound is compound or its pharmaceutically acceptable salt, ester or the solvate with structural formula shown in Formulas I,

Wherein, R₁Be each independently H, haloalkyl that alkoxyl that carbon number is 1～5, halogen, carbon number are 1～5, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

R₂For alkoxyl that carbon number is 1～5 or optionally substituted amido；

R₃Be each independently for H, carbon number be 1～5 alkoxyl, carbon number be 1～5 haloalkyl, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

The integer of m=1-4；

The integer of n=1～5；

The integer of p=1-4。

Inventor have found that, this compound of the present invention can effectively suppress the expression of Survivin albumen in tumor cell, suppresses the activity of DNA topoisomerase, suppress eukaryote tumor cell proliferation or prevention and/or treatment tumor。

According to embodiments of the invention, R₁It is each independently as H, OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH₂CH₃、F、Cl、Br、CF₃、NO₂、NH₂Or carbon number is the straight chained alkyl of 1-5,

R₂For NH₂、N(CH₃)₂Or OCH₃,

R₃It is each independently H ,-OCH₃、-NH₂、-NO₂、-CF₃、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃, or-CH₂CH₂CH₂CH₃,

The integer of m=1-4；

The integer of n=1-4；

The integer of p=1-4。

According to embodiments of the invention, R₁It is each independently as OCH₃、Cl、NO₂, or CH₃,

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-CF₃, or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3。

Some concrete examples according to the present invention, compound according to embodiments of the present invention is one of following:

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((3-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9, the preparation of 10-acridan-4-amide,

N-(3-(dimethylamino) propyl group) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

5,7-bis-chloro-N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((3-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-Ethylbenzyl) amino)-5-nitro-9-oxo-acridan-4-amide。

Compound provided by the invention (includes hepatoma carcinoma cell through the test of kinds of tumor cells system, breast cancer cell etc.) and DNA connection experiment, topoisomerase active suppresses test, the downward etc. of protein electrophoresis experiment detection Survivin protein expression, prove that the compound of the present invention is a kind of potential antitumor drug suppressing Survivin protein expression in tumor cell and topoisomerase II having certain inhibitory activity, can effectively suppress the expression of Survivin albumen in tumor cell, suppress the activity of DNA topoisomerase, suppress eukaryote tumor cell proliferation, or prevention and/or treatment tumor。Raw materials of compound provided by the invention is easy to get, and preparation method is simple, and experiment proves that it has good anticancer effect, and designing research and development field at antitumor drug has good application prospect。

In another aspect of this invention, the invention provides a kind of method preparing compound noted earlier。According to embodiments of the invention, the method comprises the following steps:

(1) compound shown in Formula II is made to react with compound shown in formula III, in order to obtain compound shown in formula IV。

According to embodiments of the invention, the condition that compound shown in Formula II reacts with compound shown in formula III is not particularly limited。In one embodiment of the invention, using copper be catalyst, potassium carbonate as alkali, make compound shown in compound shown in Formula II and formula III react in anhydrous dimethyl formamide, in order to compound shown in acquisition formula IV。In another embodiment of the present invention, at 100-130 DEG C, using copper be catalyst, potassium carbonate as alkali, make compound shown in compound shown in Formula II and formula III react 1-12 hour in anhydrous dimethyl formamide according to the ratio that mol ratio is 1:1.5, in order to compound shown in acquisition formula IV。Be conducive to improving reaction efficiency thereby, it is possible to react at optimal temperature and conditions of mixture ratios, reduce side reaction, improve productivity。

(2) compound shown in formula IV and strong sulfuric acid response are made, in order to obtain compound shown in formula V。

According to embodiments of the invention, at 50-100 DEG C, make compound shown in formula IV and strong sulfuric acid response 1-5 hour。Thereby, it is possible to react under most suitable condition, be conducive to improving reaction efficiency, reduce side reaction, improve productivity。

(3) compound shown in formula V is made to react with kiber alkyl amine compounds, in order to obtain compound shown in formula VI。

According to embodiments of the invention, the condition that compound shown in formula V and kiber alkyl amine compounds react is not particularly limited, and those skilled in the art can select flexibly according to practical situation。In one embodiment of the invention, compound shown in formula V and kiber alkyl amine compounds is made to react in anhydrous dimethyl formamide, in order to obtain compound shown in formula VI。In another embodiment of the present invention, at 0-50 DEG C, with N, N'-carbonyl dimidazoles as condensing agent, compound shown in formula V and kiber alkyl amine compounds is made to react 10-30 hour in anhydrous dimethyl formamide。Thereby, it is possible to make each reactant react under the conditions such as optimal temperature, proportioning, advantageously reduce side reaction, improve productivity and reaction efficiency。

According to embodiments of the invention, the kind of described kiber alkyl amine compounds is not particularly limited, as long as foregoing compound can effectively be prepared, those skilled in the art can select flexibly according to physical condition。According to embodiments of the invention, described kiber alkyl amine compounds has the structure shown in formula 1-formula 3。

(4) compound shown in formula VI is made to react with Multi substituted benzenes pheynylalkylamine compounds (including but not limited to single (double; two) pyridine first (second) aminated compounds), in order to obtain compound shown in Formulas I。According to embodiments of the invention, the condition that compound shown in formula VI and Multi substituted benzenes pheynylalkylamine compounds react is not particularly limited, and those skilled in the art can select flexibly according to practical situation。In one embodiment of the invention, at 50-100 DEG C, compound shown in formula VI is made to react 10-30 hour with Multi substituted benzenes pheynylalkylamine compounds。Thereby, it is possible to react under most suitable condition, be conducive to improving reaction efficiency, reduce side reaction, improve productivity。

According to embodiments of the invention, the kind of described Multi substituted benzenes pheynylalkylamine compounds is not particularly limited。According to some embodiments of the present invention, described Multi substituted benzenes pheynylalkylamine compounds has structure shown below:

According to some currently preferred embodiments of the present invention, described Multi substituted benzenes pheynylalkylamine compounds has the structure shown in one of formula 4-formula 9。Thereby, it is possible to effectively obtain foregoing compound。

Wherein, R₁、R₂、R₃With n as defined above。

Inventor have found that, utilize the method for the present invention can fast and effeciently prepare foregoing compound, and the method is simple, convenient fast, yield is higher, is suitable to large-scale production。

In another aspect of the invention, the invention provides a kind of pharmaceutical composition。According to embodiments of the invention, this pharmaceutical composition contains foregoing compound。Inventor have found that, the pharmaceutical composition of the present invention can effectively suppress the expression of Survivin albumen in tumor cell, suppresses the activity of DNA topoisomerase, suppresses eukaryote tumor cell proliferation, prevention and/or treat effect of tumor。

In still another aspect of the invention, the invention provides compound noted earlier or the pharmaceutical composition purposes in preparing medicine。According to embodiments of the invention, described medicine is for effectively suppressing the expression of Survivin albumen in tumor cell, suppress the activity of DNA topoisomerase, suppressing effect of eukaryote tumor cell proliferation, prevention and/or treatment tumor。

It should be noted that the said medicine of the present invention can pass through injection, injection, collunarium, eye drip, infiltration, absorption, the method that physically or chemically mediates import body, such as muscle, Intradermal, subcutaneous, vein, mucosal tissue；Also body can be imported after being mixed by other materials or wrap up。When needing, said medicine can also add one or more pharmaceutically acceptable carriers。Described carrier includes the conventional diluent of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant etc.。It addition, the medicine of the present invention can make the various ways such as injection, tablet, powder, granule, capsule, oral liquid, unguentum, cream。The medicine of above-mentioned various dosage form all can be prepared according to the conventional method of pharmaceutical field。

According to embodiments of the invention, described topoisomerase is topoisomerase II。

According to embodiments of the invention, described eukaryote is mammal；Described tumor cell is cancerous cell；Described cancerous cell is leukaemia cancer cell, breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell, wherein, the former leukaemia of the chronic marrow of the preferred people of described leukaemia cancer cell, the preferred human liver cancer cell of described hepatoma carcinoma cell。

Embodiments of the invention are described below in detail。

The preparation of embodiment 1:1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-acridan-4-amide

1, preparation 2-((2-carbonyl-5-chlorphenyl) amino)-3-ar-Toluic acid

Dimethylformamide (50ml) adds 2,4-dichlorobenzoic acid (4.05mmol), 2-amino-3-ar-Toluic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), then stir overnight at 130 DEG C, then join in 200ml water after obtained reactant mixture cooling, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, the precipitation obtained also is dried by sucking filtration, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chlorphenyl) amino)-3-ar-Toluic acid, productivity 91.5%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 13.10 (s, 2H), 9.90 (s, 1H), 7.86 (d, J=8.2Hz, 1H), 7.72 (d, J=7.2Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 6.74 (d, J=7.5Hz, 1H), 6.08 (s, 1H), 2.12 (s, 3H).

2, the preparation chloro-5-methyl-9-oxo-acridan-4-carboxylic acid of 1-

2-((2-carbonyl-5-chlorphenyl) the amino)-3-ar-Toluic acid (1.19mmol) obtained in step 1 is joined in concentrated sulphuric acid (10ml), reflux 5 hours in 80 DEG C, then it is slowly added in frozen water (50mL) after obtained reactant liquor cooling, it is adjusted to pH value by NaOH solution subsequently and is about 5, after mixed liquor continues to be stirred at room temperature 30 minutes, there is a large amount of Precipitation。The precipitation obtained also is dried by sucking filtration, obtains pressed powder, i.e. 1-chloro-5-methyl-9-oxo-9,10-acridan-4-carboxylic acid。Productivity 95.0%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 12.59 (s, 1H), 8.32 (d, J=8.3Hz, 1H), 8.05 (d, J=8.0Hz, 1H), 7.66 (d, J=6.8Hz, 1H), 7.32 (d, J=8.3Hz, 1H), 7.24 (dd, J=7.9,7.3Hz, 1H), 2.54 (s, 3H).

3, the preparation chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide

The 1-chloro-5-methyl-9-oxo-9 that will obtain in step 2,10-acridan-4-carboxylic acid (3.48mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (5.22mmol) (10.00ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1，2-diaminoethane (10.44mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide。Productivity 65.3%。Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 12.93 (s, 1H), 8.27 (d, J=8.0Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.19 (t, J=7.7Hz, 1H), 7.15 (d, J=8.1Hz, 1H), 3.57 (dd, J=10.9,5.3Hz, 2H), 2.64-2.59 (m, 2H), 2.58 (s, 3H), 2.33 (s, 6H).

4, the preparation of 1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methyl-9-oxo-9 that step 3 is obtained, 10-dihydropyridine-4-amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 60.9%, fusing point 144-146 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.58 (s, 1H), 11.41 (s, 1H), 8.22 (d, J=8.1Hz, 1H), 7.60 (d, J=8.9Hz, 1H), 7.46 (d, J=6.9Hz, 1H), 7.39 (d, J=7.3Hz, 2H), 7.34 (t, J=7.5Hz, 2H), 7.28-7.24 (m, 1H), 7.15 (t, J=7.6Hz, 1H), 6.89 (s, 1H), 6.14 (d, J=8.7Hz, 1H), 4.55 (d, J=5.5Hz, 2H), 3.50 (dd, J=10.6,5.2Hz, 2H), 2.60 (s, 3H), 2.53 (t, J=5.8Hz, 2H), 2.27 (s, 6H)；¹³CNMR(100MHz,DMSO-d₆) δ 180.40,169.34,154.61,144.56,138.88,138.45,135.06,134.12,129.11,127.82,127.64,125.14,123.72,121.70,121.48,106.22,101.52,100.32,58.61,46.39,45.66,37.63,16.97；HR-MS (ESI): Calcdfor [M+H]⁺429.2291；Found:429.2300.

The preparation of embodiment 2:N-(2-(dimethylamino) ethyl) 1-((3-methoxy-benzyl) amino)-5-methyl-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methyl-9-oxo-9 that will obtain in case study on implementation 1,10-dihydropyridine-4-amide (0.42mmol), 3-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 27.3%, fusing point 164-166 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.58 (s, 1H), 11.43 (s, 1H), 8.24 (d, J=8.1Hz, 1H), 7.63 (d, J=8.9Hz, 1H), 7.48 (d, J=7.0Hz, 1H), 7.28-7.24 (m, 1H), 7.16 (t, J=7.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.93 (s, 2H), 6.81 (dd, J=8.1, 2.0Hz, 1H), 6.17 (d, J=8.9Hz, 1H), 4.55 (d, J=5.7Hz, 2H), 3.80 (d, J=13.0Hz, 3H), 3.53 (dd, J=10.8, 5.2Hz, 2H), 2.62 (s, 3H), 2.57 (t, J=5.8Hz, 2H), 2.30 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 181.24,169.38,160.07,155.25,144.74,139.79,138.55,133.56,133.43,129.79,124.88,123.85,121.87,121.37,119.36,112.76,112.73,106.81,101.32,99.98,57.69,55.23,46.83,45.05,36.74,17.10；HR-MS (ESI): Calcdfor [M+H]⁺459.2396；Found:459.2408.

The preparation of embodiment 3:N-(2-(dimethylamino) ethyl) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methyl-9-oxo-9 that will obtain in case study on implementation 1,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 54.6%, fusing point 225-227 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.59 (s, 1H), 11.34 (s, 1H), 8.22 (d, J=8.0Hz, 1H), 7.66 (d, J=9.0Hz, 1H), 7.47 (d, J=7.0Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 7.15 (t, J=7.6Hz, 1H), 6.98 (s, 1H), 6.88 (d, J=8.5Hz, 2H), 6.18 (d, J=9.0Hz, 1H), 4.48 (d, J=5.5Hz, 2H), 3.79 (s, 3H), 3.53 (dd, J=10.7,5.2Hz, 2H), 2.61 (s, 3H), 2.56 (t, J=5.7Hz, 2H), 2.29 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 181.20,169.42,158.94,155.13,144.76,138.53,133.53,133.47,130.00,128.40,124.87,123.82,121.86,121.35,114.24,106.73,101.14,99.86,57.81,55.30,46.32,45.08,36.79,17.09；HR-MS (ESI): Calcdfor [M+H]⁺459.2396；Found:459.2401.

The preparation of embodiment 4:N-(3-(dimethylamino) propyl group) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-acridan-4-amide

1, the preparation chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide

The 1-chloro-5-methyl-9-oxo-9 that will obtain in case study on implementation 1,10-acridan-4-carboxylic acid (1.74mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.61mmol) (10ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1,3-propane diamine (5.22mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide。Productivity 61.9%。Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 13.34 (s, 1H), 9.65 (s, 1H), 8.29 (d, J=8.1Hz, 1H), 7.65 (d, J=8.3Hz, 1H), 7.51 (d, J=7.1Hz, 1H), 7.21-7.15 (m, 2H), 3.64 (dd, J=10.2,5.8Hz, 2H), 2.67-2.62 (m, 2H), 2.61 (s, 3H), 2.39 (s, 6H), 1.85 (dt, J=11.4,5.8Hz, 2H).

2, the preparation of N-(3-(dimethylamino) propyl group) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-acridan-4-amide

The chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-methyl-9-oxo-9 that will obtain in step 1,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 22.4%, fusing point 185-187 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.82 (s, 1H), 11.32 (s, 1H), 8.68 (s, 1H), 8.22 (d, J=7.8Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.47 (d, J=6.1Hz, 1H), 7.33 (d, J=7.7Hz, 2H), 7.16 (d, J=7.2Hz, 1H), 6.89 (d, J=7.6Hz, 2H), 6.20 (d, J=8.8Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.59 (br, 2H), 2.62 (br, 5H), 2.39 (s, 6H), 1.84 (br, 2H)；¹³CNMR(100MHz,CDCl₃) δ 181.22,169.51,158.95,154.97,144.86,138.59,133.48,133.37,130.01,128.48,124.92,123.80,121.82,121.26,114.23,106.74,101.37,99.81,59.07,55.31,46.34,45.13,40.05,24.88,17.18；HR-MS (ESI): Calcdfor [M+H]⁺473.2552；Found:473.2571.

The preparation of embodiment 5:1-benzamido group-N-(2-methoxy ethyl)-5-methyl-9-oxo-acridan-4-amide

1, the preparation chloro-N-of 1-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide

The 1-chloro-5-methyl-9-oxo-9 that will obtain in case study on implementation 1,10-acridan-4-carboxylic acid (1.74mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.61mmol) (10.00ml), 30 minutes it are stirred at room temperature after dropwising, then dimethoxy ethylenediamine (5.22mmol) is added in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-dihydropyridine-4-amide。Productivity 59.6%。Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 12.79 (s, 1H), 8.27 (d, J=8.1Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.51 (d, J=7.0Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.14 (d, J=8.2Hz, 1H), 6.90 (s, 1H), 3.74 (dd, J=9.7,4.8Hz, 2H), 3.65 (t, J=4.8Hz, 2H), 3.45 (s, 3H), 2.58 (s, 3H).

2, the preparation of 1-benzamido group-N-(2-methoxy ethyl)-5-methyl-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-the methoxy ethyl)-5-methyl-9-oxo-9 that will obtain in step 1,10-dihydropyridine-4-amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 62.1%, fusing point 191-193 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.50 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.60 (d, J=8.8Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.41 (d, J=7.3Hz, 2H), 7.36 (t, J=7.4Hz, 2H), 7.30 (d, J=7.2Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 6.49 (s, 1H), 6.18 (d, J=8.8Hz, 1H), 4.58 (s, 2H), 3.67 (br, 2H), 3.59 (t, J=4.7Hz, 2H), 3.42 (d, J=8.1Hz, 3H), 2.62 (s, 3H)；¹³CNMR(100MHz,CDCl₃) δ 181.23,169.30,155.24,144.73,138.49,137.92,133.65,133.27,128.80,127.35,127.16,124.89,123.85,121.85,121.49,106.77,101.13,99.97,71.27,58.90,46.88,39.38,17.13；HR-MS (ESI): Calcdfor [M+H]⁺416.1974；Found:416.1980.

The preparation of embodiment 6:N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methyl-9-oxo-9 that will obtain in case study on implementation 1,10-dihydropyridine-4-amide (0.42mmol), 3,4,5-trimethoxy benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 33.1%, fusing point 195-197 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.61 (s, 1H), 11.38 (s, 1H), 8.23 (d, J=8.1Hz, 1H), 7.71 (d, J=8.9Hz, 1H), 7.49 (d, J=6.9Hz, 1H), 7.23-7.13 (m, 1H), 7.06 (s, 1H), 6.62 (s, 2H), 6.18 (d, J=8.9Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 3.84 (s, 9H), 3.56 (dd, J=10.6,5.1Hz, 2H), 2.62 (br, 5H), 2.35 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 181.26,169.40,155.21,153.61,144.72,138.54,137.25,133.77,133.62,133.59,124.92,123.79,121.84,121.44,106.78,104.11,101.36,100.07,60.84,57.83,56.19,47.24,45.01,36.62,17.11；HR-MS (ESI): Calcdfor [M+H]⁺519.2607；Found:519.2623.

The preparation of embodiment 7:1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-acridan-4-amide

1, preparation 2-((2-carbonyl-5-chlorphenyl) amino)-3-methoxybenzoic acid

Dimethylformamide (50ml) adds 2,4-dichlorobenzoic acid (4.05mmol), 2-amino-3-methoxybenzoic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), then stir overnight at 130 DEG C, then join in 200ml water after obtained reactant mixture cooling, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, the precipitation obtained also is dried by sucking filtration, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chlorphenyl) amino)-3-methoxybenzoic acid, productivity 98.9%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 13.12 (s, 2H), 10.07 (s, 1H), 7.85 (d, J=5.4Hz, 1H), 7.48 (d, J=5.2Hz, 1H), 7.41-7.21 (m, 2H), 6.76 (d, J=5.4Hz, 1H), 6.28 (s, 1H), 3.79 (s, 3H).

2, preparation 1-chloro-5-methoxyl-9-oxo-acridan-4-carboxylic acid

2-((2-carbonyl-5-chlorphenyl) the amino)-3-methoxybenzoic acid (1.19mmol) obtained in step 1 is joined in concentrated sulphuric acid (10ml), reflux 5 hours in 80 DEG C, then it is slowly added in frozen water (50mL) after obtained reactant liquor cooling, it is adjusted to pH value by NaOH solution subsequently and is about 5, after mixed liquor continues to be stirred at room temperature 30 minutes, there is a large amount of Precipitation。The precipitation obtained also is dried by sucking filtration, obtains pressed powder, i.e. 1-chloro-5-methyl-9-oxo-9,10-acridan-4-carboxylic acid。Productivity 92.7%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 13.97 (s, 1H), 12.56 (s, 1H), 8.26 (d, J=8.2Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.28 (d, J=8.2Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 4.02 (s, 3H).

3, the preparation chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-amide

1-chloro-5-methoxyl-9-the oxo-9 that will obtain in step 2,10-acridan-4-carboxylic acid (1.65mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (D10.00ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1，2-diaminoethane (4.95mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-amide。Productivity 58.7%。Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 12.90 (s, 1H), 7.97 (dd, J=8.2,0.9Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.19 (dt, J=8.1,3.8Hz, 2H), 7.11 (dd, J=7.8,1.1Hz, 1H), 4.08 (s, 3H), 3.60 (dd, J=11.2,5.0Hz, 2H), 2.65-2.56 (m, 2H), 2.32 (s, 6H)；¹³CNMR(100MHz,DMSO-d₆)δ176.02,168.82,155.70,147.73,144.89,132.92,130.22,123.41,121.16,117.57,112.37,109.91,105.48,104.58,58.68,56.80,45.76,43.80,37.73.

4, the preparation of 1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methoxyl group-9-oxo-9 that will obtain in step 3,10-dihydropyridine-4-amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 57.1%, fusing point 230-231 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.61 (s, 1H), 11.44 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.67 (d, J=8.9Hz, 1H), 7.42 (d, J=7.2Hz, 2H), 7.36 (t, J=7.3Hz, 2H), 7.30 (d, J=7.2Hz, 1H), 7.18 (t, J=7.9Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.97 (s, 1H), 6.17 (d, J=8.9Hz, 1H), 4.57 (d, J=5.4Hz, 2H), 4.09 (s, 3H), 3.56 (d, J=5.2Hz, 2H), 2.56 (t, J=5.5Hz, 2H), 2.29 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 180.86,169.14,155.19,147.95,144.19,138.08,133.58,131.04,128.78,127.29,127.16,122.48,121.10,117.14,111.31,107.24,101.79,99.82,57.85,56.27,46.87,45.11,36.84；HR-MS (ESI): Calcdfor [M+H]⁺445.2240；Found:445.2252.

The preparation of embodiment 8:N-(2-(dimethylamino) ethyl)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-methoxyl group-9-oxo-9 that will obtain in case study on implementation 7,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 70.8%, fusing point 245-246 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.57 (s, 1H), 11.36 (s, 1H), 7.92 (d, J=8.1Hz, 1H), 7.67 (d, J=8.9Hz, 1H), 7.32 (d, J=8.4Hz, 2H), 7.17 (t, J=8.0Hz, 1H), 7.07 (d, J=7.5Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=8.5Hz, 2H), 6.20 (d, J=8.9Hz, 1H), 4.49 (d, J=5.4Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 3.61-3.48 (m, 2H), 2.60 (t, J=5.6Hz, 2H), 2.33 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 180.79,169.14,158.93,155.16,147.92,144.21,1] 33.59,131.00,130.01,128.42,122.49,121.04,117.13,114.23,111.25,107.17,101.56,99.82,57.86,56.25,55.30,46.35,45.03,36.64；HR-MS (ESI): Calcdfor [M+H]⁺475.2345；Found:475.2336.

The preparation of embodiment 9:N-(3-(dimethylamino) propyl group)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-acridan-4-amide

1, the preparation chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-amide

1-chloro-5-methoxyl-9-the oxo-9 that will obtain in case study on implementation 7,10-acridan-4-carboxylic acid (1.65mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1,3-propane diamine (5.22mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(3-(dimethylamino) propyl group)-5-methoxyl group-9-oxo-9,10-dihydropyridine-4-amide。Productivity 60.5%。Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 13.27 (s, 1H), 9.51 (s, 1H), 7.97 (d, J=8.4Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.18 (t, J=8.4Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 4.08 (s, 3H), 3.65 (dd, J=10.0,5.7Hz, 2H), 2.69 2.57 (m, 2H), 2.36 (s, 6H), 1.83 (dt, J=11.3,5.8Hz, 2H).

2, the preparation of N-(3-(dimethylamino) propyl group)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-acridan-4-amide

The chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-methoxyl group-9-oxo-9 that will obtain in step 1,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 63.4%, fusing point 260-261 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 13.84 (s, 1H), 11.32 (s, 1H), 8.66 (s, 1H), 7.91 (d, J=8.1Hz, 1H), 7.53 (d, J=8.9Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.16 (t, J=8.0Hz, 1H), 7.07 (d, J=7.5Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 6.18 (d, J=8.9Hz, 1H), 4.49 (d, J=5.4Hz, 2H), 4.07 (s, 3H), 3.80 (s, 3H), 3.60 (dd, J=10.4, 5.4Hz, 2H), 2.59-2.50 (m, 2H), 2.33 (s, 6H), 1.84-1.72 (m, 2H)；¹³CNMR(100MHz,CDCl₃) δ 180.84,169.12,158.88,154.90,147.97,144.28,133.26,131.04,130.00,128.49,122.38,120.97,117.01,114.19,111.14,107.17,101.89,99.63,59.65,56.24,55.33,46.35,45.48,40.66,24.95；HR-MS (ESI): Calcdfor [M+H]⁺489.2502；Found:489.2493.

The preparation of the chloro-N-of embodiment 10:5,7-bis-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-9-oxo-acridan-4-amide

1, preparation 2-((2-carbonyl-5-chlorphenyl) amino)-3,5-dichlorobenzoic acid

Dimethylformamide (50ml) adds 2,4-dichlorobenzoic acid (04.05mmol), 2-amino-3,5-dichlorobenzoic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), then stir overnight at 130 DEG C, then join in 200ml water after obtained reactant mixture cooling, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, the precipitation obtained also is dried by sucking filtration, obtains faint yellow solid, i.e. 2-((2-carbonyl-5-chlorphenyl) amino)-3,5-dichlorobenzoic acid, productivity 45.6%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 13.36 (s, 2H), 10.10 (s, 1H), 7.99 (d, J=2.4Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.86 (d, J=2.4Hz, 1H), 6.85 (dd, J=8.5,1.9Hz, 1H), 6.34 (d, J=1.8Hz, 1H).

2, the preparation chloro-9-oxo of 1,5,7-tri--acridan-4-carboxylic acid

The 2-((2-carbonyl-5-chlorphenyl) amino)-3 that will obtain in step 1,5-dichlorobenzoic acid (1.19mmol) joins in concentrated sulphuric acid (10ml), reflux 5 hours in 80 DEG C, then it is slowly added in frozen water (50mL) after obtained reactant liquor cooling, it is adjusted to pH value by NaOH solution subsequently and is about 5, after mixed liquor continues to be stirred at room temperature 30 minutes, there is a large amount of Precipitation。The precipitation obtained also is dried by sucking filtration, obtains pressed powder, i.e. 1,5,7-tri-chloro-9-oxo-9,10-acridan-4-carboxylic acid。Productivity 90.5%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆)δ13.60(s,1H),8.30(s,1H),8.13-8.04(m,2H),8.02(s,1H),7.35-7.33(m,1H).

3, the preparation chloro-N-of 1,5,7-tri-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-amide

1 will obtained in step 2,5, the chloro-9-oxo-9 of 7-tri-, 10-acridan-4-carboxylic acid (2.35mmol) is slowly added dropwise into (10ml) in the dimethyl formamide solution to N, N '-carbonyl dimidazoles (3.52mmol), is stirred at room temperature 30 minutes after dropwising, then by N, N-dimethyl-1，2-diaminoethane (7.04mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, is spin-dried for, and gained residue obtains pressed powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, namely 1,5,7-tri-chloro-N-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-amide。Productivity 49.2%。

Compound structure confirmation data are:¹HNMR(400MHz,CDCl₃) δ 13.43 (s, 1H), 8.28 (d, J=2.3Hz, 1H), 7.83 (d, J=8.3Hz, 1H), 7.72 (d, J=2.3Hz, 1H), 7.39 (d, J=8.3Hz, 1H), 7.25 (s, 1H), 3.60 (dd, J=10.0,5.2Hz, 2H), 2.68-2.56 (m, 2H), 2.33 (s, 6H).

4, the preparation of the chloro-N-of 5,7-bis-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-9-oxo-acridan-4-amide

1 will obtained in step 3,5, the chloro-N-of 7-tri-(2-(dimethylamino) ethyl)-9-oxo-9,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 69.6%, fusing point 238-240 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 11.11 (d, J=5.1Hz, 1H), 8.23 (d, J=2.3Hz, 1H), 7.70-7.67 (m, 2H), 7.32 (d, J=8.6Hz, 2H), 7.02 (s, 1H), 6.91 (dd, J=6.7,4.8Hz, 2H), 6.25 (d, J=9.0Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 3.81 (s, 3H), 3.56 (dd, J=10.7,5.3Hz, 2H), 2.62-2.55 (m, 2H), 2.32 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 179.19,168.93,159.06,154.89,144.56,135.35,134.02,132.49,129.58,128.41,126.67,124.38,123.42,122.49,114.31,106.73,101.45,100.86,57.73,55.32,46.41,45.05,36.72；HR-MS (ESI): Calcdfor [M+H]⁺513.1460；Found:513.1467.

The preparation of embodiment 11:1-benzamido group-N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-acridan-4-amide

1, preparation 2-((2-carbonyl-5-chlorphenyl) amino)-3-nitrobenzoic acid

Dimethylformamide (50ml) adds 2,4-dichlorobenzoic acid (4.05mmol), 2-amino-3-nitrobenzoic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), then stir overnight at 130 DEG C, then join in 200ml water after obtained reactant mixture cooling, the mixture hydrochloric acid obtained is adjusted to pH value and is about 3, the precipitation obtained also is dried by sucking filtration, obtain faint yellow solid, i.e. 2-((2-carbonyl-5-chlorphenyl) amino)-3-nitrobenzoic acid, productivity 59.6%。Compound structure confirmation data are:¹HNMR(400MHz,DMSO-d₆) δ 13.12 (s, 2H), 10.07 (s, 1H), 7.85 (d, J=5.4Hz, 1H), 7.48 (d, J=5.2Hz, 1H), 7.41-7.21 (m, 2H), 6.76 (d, J=5.4Hz, 1H), 6.28 (s, 1H), 3.79 (s, 3H).

1, the preparation chloro-5-nitro-9-oxo-acridan-4-carboxylic acid of 1-

2-((2-carbonyl-5-chlorphenyl) the amino)-3-nitrobenzoic acid (1.19mmol) obtained in step 1 is joined in concentrated sulphuric acid (10.00ml), reflux 5 hours in 80 DEG C, then it is slowly added in frozen water (50mL) after obtained reactant liquor cooling, it is adjusted to pH value by NaOH solution subsequently and is about 5, after mixed liquor continues to be stirred at room temperature 30 minutes, there is a large amount of Precipitation。The precipitation obtained also is dried by sucking filtration, obtains red solid powder, i.e. 1-chloro-5-nitro-9-oxo-9,10-acridan-4-carboxylic acid, productivity 73.9%。Compound structure data characterization is:¹HNMR(400MHz,d₆-DMSO) δ 14.62 (s, 1H), 8.72 (dd, J=8.1,1.4Hz, 1H), 8.60 (d, J=7.8Hz, 1H), 8.35 (d, J=8.3Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.42 (d, J=8.3Hz, 1H).

2, the preparation chloro-N-of 1-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-9,10-dihydropyridine-4-amide

The 1-chloro-5-nitro-9-oxo-9 that will obtain in step 2,10-acridan-4-carboxylic acid (1.65mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1，2-diaminoethane (4.95mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains red solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-9,10-dihydropyridine-4-amide。Productivity 61.5%。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 8.67 (dd, J=13.7,7.9Hz, 2H), 7.83 (d, J=8.2Hz, 1H), 7.32 (t, J=7.9Hz, 1H), 7.27-7.25 (m, 1H), 3.63-3.61 (m, 2H), 2.61 (t, J=5.5Hz, 2H), 2.32 (s, 6H).

4, the preparation of 1-benzamido group-N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-nitro-9-oxo-9 that will obtain in step 3,10-dihydropyridine-4-amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 33.8%, fusing point 243-245 DEG C。Compound structure data characterization is:¹HNMR(400MHz,DMSO-d₆) δ 15.00 (s, 1H), 10.92 (s, 1H), 8.65 (d, J=7.2Hz, 1H), 8.57 (d, J=7.2Hz, 1H), 8.46 (s, 1H), 8.03 (d, J=8.8Hz, 1H), 4.40-7.37 (m, 5H), 7.29 (d, J=6.5Hz, 1H), 6.45 (d, J=8.6Hz, 1H), 4.61 (s, 2H), 2.53 (br, 2H), 2.27 (s, 6H)；¹³CNMR(100MHz,d₆-DMSO) δ 178.84,168.23,154.26,138.67,135.93,135.24,134.43,131.72,129.15,127.81,127.72,124.24,120.66,106.50,103.23,102.50,58.41,46.41,45.40,37.33；HR-MS (ESI): Calcdfor [M+H]⁺460.1985；Found:460.2000.

The preparation of embodiment 12:N-(2-(dimethylamino) ethyl)-1-((3-methoxy-benzyl) amino)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-nitro-9-oxo-9 that will obtain in case study on implementation 11,10-dihydropyridine-4-amide (0.42mmol), 3-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 19.8%, fusing point 155-157 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.02 (s, 1H), 11.08 (s, 1H), 8.71 (d, J=7.6Hz, 1H), 8.66 (d, J=8.0Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.30-7.26 (m, 2H), 6.98 (d, J=7.4Hz, 2H), 6.92 (s, 1H), 6.83 (d, J=7.6Hz, 1H), 6.29 (d, J=8.9Hz, 1H), 4.54 (d, J=5.3Hz, 2H), 3.80 (s, 3H), 3.59 (d, J=4.6Hz, 2H), 2.65-2.56 (m, 2H), 2.31 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 179.39,168.17,160.09,154.66,144.06,139.31,135.01,134.85,134.52,134.42,131.18,129.95,124.60,119.77,119.33,112.87,112.75,107.06,103.29,102.19,57.75,55.29,46.90,45.11,36.82；HR-MS (ESI): Calcdfor [M+H]⁺490.2090；Found:490.2070.

The preparation of embodiment 13:N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-nitro-9-oxo-9 that will obtain in case study on implementation 11,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 27.7%, fusing point 228-230 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.01 (s, 1H), 10.99 (s, 1H), 8.69 (d, J=6.8Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.31 (d, J=7.5Hz, 2H), 7.12 (s, 1H), 6.90 (d, J=7.3Hz, 2H), 6.31 (d, J=8.2Hz, 1H), 4.48 (s, 2H), 3.80 (s, 3H), 3.62 (br, 2H), 2.65 (br, 2H), 2.37 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 179.27,168.23,159.06,154.56,144.07,134.96,134.79,134.52,134.44,131.08,129.49,128.45,124.58,119.70,114.30,106.93,103.00,102.11,57.94,55.32,46.43,45.00,36.61；HR-MS (ESI): Calcdfor [M+H]⁺490.2090；Found:490.2099.

The preparation of embodiment 14:N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide

The chloro-N-of 1-(2-(dimethylamino) the ethyl)-5-nitro-9-oxo-9 that will obtain in case study on implementation 11,10-dihydropyridine-4-amide (0.42mmol), 3,4,5-trimethoxy benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains yellow solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 49.4%, fusing point 243-244 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.04 (s, 1H), 11.01 (s, 1H), 8.68 (dd, J=15.5,7.3Hz, 2H), 7.71 (d, J=8.7Hz, 1H), 7.30-7.28 (m, 1H), 6.95 (s, 1H), 6.61 (s, 2H), 6.30 (d, J=8.7Hz, 1H), 4.48 (d, J=4.0Hz, 2H), 3.85 (s, 9H), 3.59 (br, 2H), 2.57 (br, 2H), 2.31 (s, 6H)；¹³CNMR(100MHz,CDCl₃) δ 179.39,168.12,154.58,153.68,144.01,137.41,135.04,134.81,134.42,134.38,133.24,131.15,124.56,119.77,107.04,104.17,103.44,102.14,60.86,57.74,56.23,47.35,45.10,36.82；HR-MS (ESI): Calcdfor [M+H]⁺550.2302；Found:550.2308.

The preparation of embodiment 15:1-benzamido group-N-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-acridan-4-amide

1, the preparation chloro-N-of 1-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-9,10-dihydropyridine-4-amide

The 1-chloro-5-nitro-9-oxo-9 that will obtain in case study on implementation 11,10-acridan-4-carboxylic acid (1.65mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), 30 minutes it are stirred at room temperature after dropwising, then by N, N-dimethyl-1,3-propane diamine (5.22mmol) adds in reaction system, stirred overnight at room temperature。After reaction terminates, extract with dichloromethane (50mL), gained organic phase washed with water (40mL) washes three times, dry organic facies, it is spin-dried for, gained residue obtains red solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, i.e. the chloro-N-of 1-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-9,10-dihydropyridine-4-amide。Productivity 28.6%。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 14.78 (s, 1H), 9.53 (s, 1H), 8.77 (d, J=7.6Hz, 1H), 8.70 (d, J=7.9Hz, 1H), 7.72 (d, J=8.1Hz, 1H), 7.33 (dd, J=14.3,7.9Hz, 2H), 3.69 (br, 2H), 2.63 (br, 2H), 2.37 (s, 6H), 1.85 (br, 2H).

2, the preparation of 1-benzamido group-N-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-nitro-9-oxo-9 that will obtain in step 1,10-dihydropyridine-4-amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains red solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 73.7%, fusing point 222-224 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.25 (s, 1H), 11.06 (s, 1H), 8.71 (d, J=7.6Hz, 2H), 8.65 (d, J=7.9Hz, 1H), 7.61 (d, J=9.0Hz, 1H), 7.46-7.33 (m, 4H), 7.33-7.26 (m, 2H), 6.31 (d, J=8.9Hz, 1H), 4.57 (d, J=5.3Hz, 2H), 3.64 (br, 2H), 2.58 (br, 2H), 2.35 (s, 6H), 1.82 (br, 2H)；¹³CNMR(100MHz,CDCl₃) δ 179.41,168.14,154.50,144.20,137.58,135.08,134.86,134.40,134.12,131.07,128.86,127.50,127.15,124.59,119.59,107.07,103.57,101.96,59.42,46.94,45.30,40.47,24.94；HR-MS (ESI): Calcdfor [M+H]⁺474.2141；Found:474.2126.

The preparation of embodiment 16:N-(3-(dimethylamino) propyl group)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-nitro-9-oxo-9 that will obtain in case study on implementation 15,10-dihydropyridine-4-amide (0.42mmol), 4-methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains red solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 63.9%, fusing point 251-252 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.27 (s, 1H), 10.97 (s, 1H), 8.76 (s, 1H), 8.70 (d, J=7.6Hz, 1H), 8.65 (d, J=7.9Hz, 1H), 7.59 (d, J=9.0Hz, 1H), 7.33 (d, J=8.2Hz, 2H), 7.27-7,24 (m, 1H), 6.91 (d, J=8.3Hz, 2H), 6.32 (d, J=8.9Hz, 1H), 4.49 (d, J=5.1Hz, 2H), 3.81 (s, 3H), 3.64 (br, 2H), 2.56 (br, 2H), 2.35 (s, 6H), 1.80 (br, 2H)；¹³CNMR(100MHz,CDCl₃) δ 179.36,168.12,159.09,154.38,144.21,135.05,134.85,134.39,134.08,131.07,129.52,128.49,124.58,119.58,114.31,106.99,103.43,101.91,59.61,55.33,46.45,45.41,40.67,24.92；HR-MS (ESI): Calcdfor [M+H]⁺504.2247；Found:504.2245.

The preparation of embodiment 17:N-(3-(dimethylamino) propyl group)-1-((4-Ethylbenzyl) amino)-5-nitro-9-oxo-acridan-4-amide

The chloro-N-of 1-(3-(dimethylamino) the propyl group)-5-nitro-9-oxo-9 that will obtain in case study on implementation 15,10-dihydropyridine-4-amide (0.42mmol), 4-ethyl benzyl amine (2.10mmol) and triethylamine (0.50mL) are dissolved in cellosolvo solvent (10mL) successively, and reaction system stirs overnight under 90 DEG C of heating conditions。Reactant liquor is cooled to room temperature, has Precipitation after terminating by TLC detection reaction。Sucking filtration obtains solid powdery head product, dry after washing with water (40mL), obtains sterling。If without Precipitation after reactant liquor cooling, in reaction system, then add DCM (50mL) and water (50mL), after extraction, gained organic facies is washed with water three times (40mL × 3), dry organic facies rotation are evaporated off organic solvent, gained residue obtains red solid powder through column chromatography (eluant: ethyl acetate/ethanol (9:1v/v)) purification, productivity 24.0%, fusing point 266-267 DEG C。Compound structure data characterization is:¹HNMR(400MHz,CDCl₃) δ 15.27 (s, 1H), 11.03 (s, 1H), 8.79-8.71 (m, 1H), 8.66 (dd, J=8.1,1.4Hz, 1H), 7.69 (d, J=9.0Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.28 (d, J=8.1Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 6.35 (d, J=9.1Hz, 1H), 4.53 (d, J=5.5Hz, 2H), 3.66-3.65 (m, 2H), 2.68-2.66 (m, 2H), 2.65-2.63 (m, 2H), 2.41 (s, 6H), 1.86-1.85 (m, 2H), 1.24 (t, J=7.6Hz, 3H)；¹³CNMR(100MHz,CDCl₃) δ 179.39,168.28,154.55,144.25,143.60,135.06,134.88,134.71,134.44,134.31,131.06,128.36,127.24,124.63,119.59,107.02,103.29,102.09,59.00,46.77,45.04,39.97,28.53,24.82,15.54；HR-MS (ESI): Calcdfor [M+H]⁺502.2454；Found:502.2467.

Embodiment 18:MTT method cell inhibitory effect screening active ingredients

By mtt assay, adopting the human hepatocellular carcinoma HepG2 cell and the MCF-7 Human Breast Cancer Cells that are in exponential phase, the body outer cell proliferation inhibitory activity of the compound that detection embodiment 1-17 prepares, wherein, positive control drug selects YM155。Human hepatocellular carcinoma HepG2 cell and MCF-7 Human Breast Cancer Cells are attached cell, with containing the DMEM culture fluid that volume fraction is 10% hyclone, in 37 DEG C, volume fraction be the CO of 5%₂Cellar culture under condition；Test additionally, carried out the in vitro toxicity to normal liver cell QGY-7701 for compound 16。Wherein, normal liver cell QGY-7701 is attached cell, with containing the DMEM culture fluid that volume fraction is 10% hyclone, in 37 DEG C, volume fraction be the CO of 5%₂Cellar culture under condition；Concrete operations are as follows:

First, the compound (i.e. sample) prepared by embodiment 1-17 is configured to DMSO (dimethyl sulfoxide) solution that compound concentration is 5mM/L respectively, then by the solution of acquisition through gradient dilution, the sample solution of a series of Concentraton gradient is obtained。Then, take the logarithm trophophase human hepatocellular carcinoma HepG2 cell and MCF-7 Human Breast Cancer Cells, respectively with 6 × 10³The cell density of individual/mL is inoculated in 96 orifice plates, 99 μ L/ holes, first has at 37 DEG C, the CO of 5%₂Incubator in cultivate 12 hours, make after cell attachment followed by adding sample solution 1 μ L to every hole, make sample effect final concentration respectively 0.1 μM, 1 μM, 5 μMs, 10 μMs, 25 μMs and 50 μMs。Every kind of sample, each concentration set three multiple holes, and arrange a positive control and blank, wherein, positive controls add positive control medicine cisplatin with the sample solution solution with concentration, blank group is not added with sample solution。MTT solution is added after effect 48h, 10 μ L/ holes, after continuing cultivation 4 hours, dimethyl sulfoxide (DMSO) is added after sucking supernatant, 100 μ L/ holes, it is incubated about 10 minutes in 37 DEG C, then vibrate about 5 minutes with micro oscillator, crystallization is made to dissolve completely, by microplate reader in 490nm place measurement OD value, it is calculated as follows cell proliferation inhibition rate (InhibitionRate, IR%): IR%=(positive control OD-sample OD)/(positive control OD-blank OD) × 100%, part of test results is in Table 1。Again, the normal liver cell QGY-7701 of trophophase of taking the logarithm, with 6 × 10³The cell density of individual/mL is inoculated in 96 orifice plates, 99 μ L/ holes, in 37 DEG C, and the CO of 5%₂About 12 hours are cultivated under condition。Then every hole adds the DMSO solution 1 μ L of compound 16, makes the effect final concentration respectively 0.1 μM, 1 μM, 5 μMs, 10 μMs, 25 μMs and 50 μMs of this compound。Each concentration sets three multiple holes, and arranges blank, and wherein blank group is not added with sample solution。MTT solution is added after effect 48h, 10 μ L/ holes, after continuing cultivation 4 hours, dimethyl sulfoxide (DMSO) is added after sucking supernatant, 100 μ L/ holes, it is incubated about 10 minutes in 37 DEG C, then vibrate about 5 minutes with micro oscillator, crystallization is made to dissolve completely, by microplate reader in 490nm place measurement OD value, it is calculated as follows cell proliferation inhibition rate (InhibitionRate, IR%): IR%=(positive control OD-sample OD)/(positive control OD-blank OD) × 100%, experimental result is in Table 2。

The screening active ingredients result of the acridones compound that table 1 benzylamine replaces

Note: IC₅₀Represent half-inhibition concentration。

Table 2 compound 16 Toxic test results to normal liver cell QGY-7701

Note: IC₅₀Represent half-inhibition concentration。

Table 1 is shown that the MTT result of the acridones compound replaced containing benzamido group。It can be seen that R from result₃When substituent group is 4-methoxyl group, compound activity performance is comparatively prominent。The such as compound 3 IC to HepG2 cell₅₀Reach 2.11 μMs, and the IC that compound 13 is to MCF-7 cell₅₀Also 1.05 μMs can be reached。It addition, data are it can be seen that the compound external activity IC to HepG2 cell from table 1₅₀It is worth the activity also more satisfactory (IC of the MCF-7 cell less than the 4 of 4 μMs compounds (compound 2,3,15 and 16) its correspondence₅₀It is between 2.92 to 6.84 μMs)。As can be seen from the table, compound 13 is best to the antiproliferative activity of MCF-7 cell simultaneously, and the IC of the HepG2 cell of compound 13 correspondence₅₀Value also can reach 4.50 μMs。These phenomenons describe benzamido group acridones compound, and the inhibition of two kinds of solid tumor cells is basically identical。It should be noted that the length of the compound 13 and 16 only 4-position amide side chains of acridone parent of the difference in chemical constitution (i.e. methylene number n, in this patent, n selects 2 and 3) is different, and these two kinds of compounds IC to HepG2 cell₅₀It is worth basically identical。As can be seen here, the length of amide side chains is little on anti-tumor activity impact。

Table 2 is for the compound 16 in vitro toxicity test result to normal liver cell QGY-7701。As can be known from the table data, compound 16 is lower than the inhibitory activity value of HepG2 cell more than 11 times to normal hepatocellular toxicity。This phenomenon indicates compound 16 good external hypotoxicity。

Embodiment 24:DNA topoisomerase enzyme test

The present invention tests DNA topoisomerase II (english abbreviation TopoII) the activity Inhibition test of compound 16。Find that compound 16 property of can select that suppresses the activity of TopoII。From Fig. 1, (wherein, Dox10 is the doxorubicin of 10 μMs of concentration；Dox1 is the doxorubicin of 1 μM of concentration；8u is the testing compound 16 of 50 μMs of concentration；NC is non-processor group；KDNA is kinetoplast dna blank group) in it can be seen that TopoII can be had certain inhibitory activity (average inhibition of two times result is 10.99%) by compound 16。The doxorubicin DMSO solution of 1 μM and 10 μMs is selected in the positives comparison of this experiment。Based on described above, the inhibitory activity of TopoII is had certain selectivity by compound 16。This shows 16 damages that can indirectly be caused DNA by suppression TopoII activity, thus causing cancer cell-apoptosis。

Embodiment 25: protein electrophoresis is tested

In order to verify that compound 16 can in tumor cell suppresses the expression of Survivin, the present invention has carried out protein electrophoresis experiment。From figure 2 it can be seen that along with compound concentration from 1 μM increase to 10 μMs time, in human hepatocellular carcinoma HepG2 cell, the expression of Survivin albumen is substantially to lower。This phenomenon illustrates that compound 16 can effectively suppress the expression of Survivin in tumor cell。It addition, along with the increase of compound concentration, the expression of IAP Bcl2 has obvious downward, and Caspase-7 and PARP expresses and has rise trend。Thus it is inferred that compound 16 can induce HepG2 apoptosis。

In the description of this specification, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means in conjunction with this embodiment or example describe are contained at least one embodiment or the example of the present invention。In this manual, the schematic representation of above-mentioned term is necessarily directed to identical embodiment or example。And, the specific features of description, structure, material or feature can combine in one or more embodiments in office or example in an appropriate manner。Additionally, when not conflicting, the feature of the different embodiments described in this specification or example and different embodiment or example can be carried out combining and combining by those skilled in the art。

Although above it has been shown and described that embodiments of the invention, it is understandable that, above-described embodiment is illustrative of, it is impossible to be interpreted as limitation of the present invention, and above-described embodiment can be changed, revises, replace and modification by those of ordinary skill in the art within the scope of the invention。

Claims (10)

1. a compound, it is characterised in that described compound is polysubstituted phenyl alkylamino acridone-4-amides compound or its pharmaceutically acceptable salt, ester or the solvate with structural formula shown in Formulas I,

Wherein, R₁Be each independently H, haloalkyl that alkoxyl that carbon number is 1～5, halogen, carbon number are 1～5, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

R₂For alkoxyl that carbon number is 1～5 or optionally substituted amido；

R₃Be each independently for H, carbon number be 1～5 alkoxyl, carbon number be 1～5 haloalkyl, nitro, amido or straight chained alkyl that carbon number is 1～5 or branched alkyl；

The integer of m=1-4；

The integer of n=1～5；

The integer of p=1-4。

2. compound according to claim 1, it is characterised in that R₁It is each independently as H, OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、OCH₂CH₂CH₂CH₃、F、Cl、Br、CF₃、NO₂、NH₂Or carbon number is the straight chained alkyl of 1-5,

R₂For NH₂、N(CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-NH₂、-NO₂、-CF₃、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃, or-CH₂CH₂CH₂CH₃,

The integer of m=1-4；

The integer of n=1-4；

The integer of p=1-4。

3. compound according to claim 2, it is characterised in that R₁It is each independently as OCH₃、Cl、NO₂, or CH₃,

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-CF₃, or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3。

4. compound according to claim 1, it is characterised in that for one of following:

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((3-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9, the preparation of 10-acridan-4-amide,

N-(3-(dimethylamino) propyl group) 1-((4-methoxy-benzyl) amino)-5-methyl-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-methoxy ethyl)-5-methyl-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methyl-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-methoxyl group-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-5-methoxyl group-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

5,7-bis-chloro-N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-9-oxo-9,10-acridan-4-amide,

1-benzamido group-N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((3-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(2-(dimethylamino) ethyl)-5-nitro-9-oxo-1-((3,4,5-trimethoxy benzyl) amino)-9,10-acridan-4-amide,

1-benzamido group-N-(3-(dimethylamino) propyl group)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-methoxy-benzyl) amino)-5-nitro-9-oxo-9,10-acridan-4-amide,

N-(3-(dimethylamino) propyl group)-1-((4-Ethylbenzyl) amino)-5-nitro-9-oxo-acridan-4-amide。

5. the method preparing compound according to any one of claim 1-4, it is characterised in that including:

(1) compound shown in Formula II is made to react with compound shown in formula III, in order to obtain compound shown in formula IV；

(2) compound and strong sulfuric acid response shown in described formula IV are made, in order to obtain compound shown in formula V；

(3) compound shown in described formula V is made to react with kiber alkyl amine compounds, in order to obtain compound shown in formula VI；

(4) compound shown in described formula VI is made to react with Multi substituted benzenes pheynylalkylamine compounds, in order to obtain compound shown in Formulas I,

6. method according to claim 5, it is characterised in that described kiber alkyl amine compounds has the structure shown in one of formula 1-formula 3:

Optionally, described Multi substituted benzenes pheynylalkylamine compounds has structure shown below:

Preferably, described Multi substituted benzenes pheynylalkylamine compounds has the structure shown in one of formula 4-formula 9:

7. method according to claim 5, it is characterized in that, in step (1), using copper be catalyst, potassium carbonate is as alkali, compound shown in described Formula II is made to react in anhydrous dimethyl formamide with compound shown in described formula III, in order to obtain compound shown in described formula V；

Optionally, in step (3), with N, N'-carbonyl dimidazoles as condensing agent, compound shown in described formula V and kiber alkyl amine compounds is made to react in anhydrous dimethyl formamide, in order to obtain compound shown in described formula VI。

8. method according to claim 7, it is characterized in that, in step (1), at 100-130 DEG C, using copper be catalyst, potassium carbonate as alkali, make compound shown in compound shown in described Formula II and described formula III react 1-12 hour in anhydrous dimethyl formamide according to the ratio that mol ratio is 1:1.5；

Optionally, in step (2), at 50-100 DEG C, make compound shown in described IV and strong sulfuric acid response 1-5 hour；

Optionally, in step (3), at 0-50 DEG C, with N, N'-carbonyl dimidazoles as condensing agent, compound shown in described formula V and kiber alkyl amine compounds is made to react 10-30 hour in anhydrous dimethyl formamide；

Optionally, in step (4), at 50-100 DEG C, compound shown in described formula VI is made to react 10-30 hour with described Multi substituted benzenes pheynylalkylamine compounds。

9. a pharmaceutical composition, it is characterised in that containing the compound according to any one of claim 1-4,

Optionally, described pharmaceutical composition is used for:

1) expression of Survivin albumen in tumor cell is suppressed；

2) suppressing topoisomerase, optionally, described topoisomerase is topoisomerase II；

3) eukaryote tumor cell proliferation is suppressed,

Optionally, described eukaryote is mammal, optionally, described tumor cell is cancerous cell, optionally, described cancerous cell is leukaemia cancer cell, breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell, the former leukaemia of the chronic marrow of the preferred people of described leukaemia cancer cell, the preferred human liver cancer cell of described hepatoma carcinoma cell；Or

4) prevention and/or treatment tumor。

10. the compound according to any one of claim 1-4 or the pharmaceutical composition described in claim 9 purposes in preparing medicine, described medicine is used for:

1) expression of Survivin albumen in tumor cell is suppressed；

2) topoisomerase is suppressed；

3) eukaryote tumor cell proliferation is suppressed；Or

4) prevention and/or treatment tumor。