CN107382862A - Sulphur/oxo naphthoyl imide compounds and its application - Google Patents

Sulphur/oxo naphthoyl imide compounds and its application Download PDF

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CN107382862A
CN107382862A CN201710580365.XA CN201710580365A CN107382862A CN 107382862 A CN107382862 A CN 107382862A CN 201710580365 A CN201710580365 A CN 201710580365A CN 107382862 A CN107382862 A CN 107382862A
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phenyl
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sulphur
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张志超
王紫千
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Dalian University of Technology
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Abstract

The invention provides a kind of sulphur/oxo naphthoyl imide compounds and its application, described compound has formula I structure.Compound, so as to inducing cell apoptosis, can be a kind of activity very high inducer of apoptosis and antitumoral compounds in vitro with intracellular competitive binding and antagonism Bcl 2 and the albumen of Mcl 1.In addition, the derivative designed using based on it can be as bifunctional molecule, in vitro and intracellular identification, separation, enrichment and the family proteins of fluoroscopic examination Bcl 2；Or the difunctional complexs of PROTAC degradation selectivity Bcl 2 and the albumen of Mcl 1 in the cell are enough used as, so as to regulate and control the level of the family proteins of Bcl 2 in living cells.

Description

Sulphur/oxo naphthoyl imide compounds and its application
Technical field
The present invention relates to a kind of sulphur/oxo naphthoyl imide compounds, more particularly to 4- benzene coloured glaze base -1,8- naphthalimide And its derivative.More particularly to the competitive binding and antagonism Bcl-2 and Mcl-1 albumen of these compounds in vitro, internal, from And inducing cell apoptosis effect and the application as anticancer compound；Some of compounds are as the molecular probe based on activity In vitro and intracellular identification, separation, enrichment and the application of fluoroscopic examination Bcl-2 family proteins；And some of compounds As PROTAC (Proteolysis Targeting Chimera) difunctional complex degradation selectivity Bcl-2 in the cell With the application of Mcl-1 albumen.
Background technology
Bcl-2 family proteins (B-cell lymphoma 2family of proteins) are in apoptotic mitochondrial The summit of source path and core factor, it is a kind of key family protein of regulating cell apoptosis.Its family member includes three Subtribe：Bcl-2 family proteins with anti-apoptotic function (can be further divided into Bcl-2-like eggs according to architectural difference degree White and Mcl-1-like albumen)；Bax with apoptotic function, Bak；BH3-only albumen only containing BH3 regions, such as Bad, Bim etc..This three albuminoid is interacted by its shared BH3 domain, and the BH3-only albumen such as Bad, Bim passes through competing Strive with reference to the albumen with anti-apoptotic function, " executor "-Bax, Bak of release apoptosis, start apoptosis pathway.Therefore, pass through The antagonism of small molecule while high-affinity can be with single-minded induced tumor cell in Bcl-2-like albumen and Mcl-1-like albumen Apoptosis, realize high selectivity, the target of safe efficient, low painful anticancer.
But up to the present, the small molecule of specific antagonist Bcl-2 albumen is broadly divided into three classes.Natural products gossypol (Gossypol), ABT-263 classes compound and Terphenyls compound.They are all BH3 analogs, but they are all present Serious deficiency.Gossypol BH3 are not special BH3 analogs, therefore, have certain poison is secondary to make similar to degree deficiency With.Although ABT-263 is BH3 analogs, but can not be acted on Mcl-1, it is impossible to which wide spectrum suppresses Bcl-2 family proteins, experiment During find the undesirable and serious resistance of the effect that cancer cell of its expression high to Mcl-1 is shown.And Terphenyls Compound only shows the affinity of micromole's rank in competitive binding experiment in vitro, and such affinity is far from height The inducing cell apoptosis of effect.Therefore, exploitation is a kind of efficient, selective, the Bcl-2/Mcl-1 inhibitor of wide spectrum can gram The defects of taking above-mentioned molecule, realize safe efficient, the low painful treatment to cancer.
In addition, Bcl-2 family proteins are as regulating cell apoptosis and a kind of key family protein of tumor development, The discovery of the new protein member of its family, the detection of protein level and regulate and control treatment and research all to tumour in different cell lines It is significant.At present, Small-molecule probe the discovery of functional protein group newcomer, separation, enrichment and Function detection with And the application in the field such as level modulation to specific protein in living cells is increasingly extensive.Compared to traditional Western blotting, it is immunized Co-precipitation and the methods of gene knockout, Small-molecule probe have that cost is low, experimental period is short, experimental repeatability is strong and to living cells The advantages that interference is few.Wherein, it is that one kind has using the molecular probe (Activity-based Probes, ABPs) based on activity The Small-molecule probe for finding, separating, be enriched with and detect new albumen of effect；And PROTAC (Proteolysis Targeting Chimera) bifunctional complex is goal of regulation and control albumen Small-molecule probe horizontal in living cells.
Molecular probe based on activity refers to that one kind can be in the Proteomics of complexity and the activated centre of target proteinses The chemical small molecule that specific covalent combines.Its structure mainly includes three parts：Reactive group, linking group and reporter group, Linking group is generally alkane chain or polyglycol chain, and reactive group is connected together with reporter group.Reactive group is general For the compound that can be specifically bound with specific protein, the inhibitor molecules of such as target point protein, the function base in compound With the amino acid residue at protein active center covalent reaction should can occur for group, be allowed to irreversible and be incorporated in target proteinses On.Reporter group mainly has two kinds:One kind is fluorophor, such as fluorescein, rhodamine, Cy3/Cy5；When what is marked by probe After protein group on SDS-PAGE by separating, specific fluorescence signal can be shown by the albumen that probe combines.Another kind is Biotin group (Biotin), utilizes the specific binding of biotin and Streptavidin, it is possible to achieve the egg marked by probe White separation and enrichment.Isolated target point protein can both be detected by Western blot, can also pass through biological big point Sub- mass spectrum is analyzed, and determines these protein ingredients marked by probe.We can pass through transformation and optimization reactive group part Design synthesizes the probe molecule with finer selection, efficiently acts on target point protein, detects the structure and work(of target point protein Energy.Using the specific chemicals Small-molecule probe based on target proteinses activity come detecting function protein group, in Small-molecule probe Reactive group and the specific combination of target proteinses so as to specifically " fishing takes " GAP-associated protein GAP out of, complexity protein group, from And biochemical information interested is obtained, this is a kind of strategy for effectively finding unknown target spot.
PROTAC (Proteolysis Targeting Chimera) refers to a kind of bifunctional complex, including two kinds Part, centre are connected by connector.For example, one of which part is connected with E3 ubiquitin ligases, another side part and destination protein It is connected, promotes both spatially close, simulate the specificity knot of destination protein and ubiquitination E3 ligases by this way Close, promote more ubiquitinations of destination protein, and then destination protein is degraded by proteasome, so as to realize target protein level Regulation and control, reduce the level of target protein in cell.
Therefore, based on Bcl-2 family protein inhibitors, point based on activity for Bcl-2 family proteins is designed and developed Sub- probe and PROTAC bifunctional complex, it can apply to discovery, separation, enrichment and the work(of the new protein member of Bcl-2 families Energy detection and the level modulation field to Bcl-2 family proteins in living cells (such as Bcl-2 and Mcl-1), to realizing tumour Treatment and research it is significant.
The content of the invention
It is contemplated that obtain following three quasi-molecules：More can well target Bcl-2 family proteins (including Bcl-2 and Mcl-1 albumen) micromolecular inhibitor；Applied to the discovery of the new protein member of Bcl-2 families, separation, enrichment and Function detection Based on activity molecular probe；Promote the PROTAC bifunctional complex of Bcl-2 family proteins degraded in living cells.
One aspect of the present invention provides a kind of sulphur/oxo naphthoyl imide compounds, has formula I structure：
Wherein：
R1The phenyl arbitrarily substituted selected from phenyl or by following radicals：OH、OCH3、I、Br、Cl、NO2、NHCH3、N(CH3)2、 CN, phenyl or C1-4Alkyl；
X is selected from S or O；
R2Selected from H, R3、ZR3, piperidyl, piperidone base, piperidine dione base, pyrrolidinyl, pyrrolidone-base, pyrrolidines two Ketone group, C1-6Alkyl or substitution C1-6Alkyl；
Described R3Selected from substituted or unsubstituted phenyl, naphthyl, benzofuranyl, thienyl or indyl, (i.e. phenyl Or substituted-phenyl, naphthyl or substituted naphthyl, benzofuranyl or substitution benzofuranyl, thienyl or substituted thiophene, indyl Or substituted indolyl) described in substitution be arbitrarily to be substituted by following radicals：C1-4Alkyl, C1-4Alkenyl, C1-4Alkynyl, phenyl, OH, I、Br、Cl、NO2、NHCH3、N(CH3)2、CN、CF3、COOH、SO3H、COOR6、CONHR6、SO3R6、SO2NHR6Or OR6；It is therein R6Selected from C1-4Alkyl, C1-4Alkenyl, C1-4Alkynyl, phenyl, benzyl, CH2COOH or CH2CONH2, n is 1-3 integer；
Described Z is selected from (CH2)m、(CH2)mCONH、(CH2)mNHCO、(CH2)mOCO、(CH2)mNHSO2、(CH2)mOSO2、 (CH2)mCONH(CH2)nO、(CH2)mNHCO(CH2)nO, carbonyl or sulfonyl, m, n are 1-3 integer；
Described substitution C1-6Alkyl is the C arbitrarily substituted by following radicals1-6Alkyl：OH、OCH3、I、Br、Cl、NO2、 NH2、NHCH3、N(CH3)2、CH(OCH3)2、CHO、CN、COOH、COOCH3、COOC2H5Or R3。
On the other hand, the present invention provides a kind of functional molecular based on above-claimed cpd structure, i.e. sulphur/oxo naphthoyl is sub- The derivative of aminated compounds is above-mentioned sulphur/oxo naphthoyl imide compounds by L-R4Or L-R5The derivative obtained after substitution Thing；Wherein,
Described L is selected from L1~L6:
Wherein, p is 1-3 integer, and q is 1-10 integer；
Described R4Group selected from formula i~vi：
Described R5Group selected from formula vii or viii：
In formula vii, l is 2-10 integer.
For above-mentioned sulphur/oxo naphthoyl imide compounds, the BH3 that the present invention have detected them by multiple means is similar Degree, and their rejection abilities to Mcl-1 and Bcl-2.As a result show, the above-mentioned vulcanization with formula I of the invention is closed Thing can effectively suppress Mcl-1 and Bcl-2 albumen.The present invention have detected them to kinds of tumor cells system by cell experiment Inhibitory action.As a result show, sulphur of the present invention/oxo naphthoyl imide compounds can efficient induced various types of tumors Cell line apoptosis, and there is no lethal effect to normal cell.Based on this, the present invention further provides described sulphur/oxo naphthoyl Application of the imine compound in Bcl-2 family protein inhibitors are prepared, especially preparing Bcl-2 family protein inhibitors Application in kind anti-cancer drugs thing.Described Bcl-2 family protein inhibitors or corresponding antineoplastic can be compounds Simple substance formulation can also be that the formula I of effective dose sulphur/oxo naphthoyl imide compounds mix shape with appropriate medicinal adjuvant Into combination preparation.
For the R of sulphur of the present invention/oxo naphthoyl imide compounds4Substitutive derivative, the present invention pass through gel It is thin with work in vitro that fluorescence imaging, live cell fluorescent imaging and biotin/Streptavidin system enrichment experiment have detected them Intracellular mark, separation, the ability of enrichment Bcl-2 family proteins.As a result show, the analog derivative can be effectively in vitro and living Cell inner mark, separation, enrichment Bcl-2 and Mcl-1 albumen.To sulphur of the present invention/oxo naphthoyl imide compounds R5Substitutive derivative, the present invention have detected them by immunoblot experiment and regulate and control Bcl-2 family proteins level in the cell Ability.As a result show, the analog derivative can effectively promote the degraded of Bcl-2 and Mcl-1 albumen in living cells, so as to drop The level of low Bcl-2 and Mcl-1 albumen.
Based on above-mentioned discovery, the present invention further provides the derivative of described sulphur/oxo naphthoyl imide compounds to exist The application in functional reagent is prepared, described functional reagent is used for the identification of Bcl-2 family proteins, mark and regulation and control.More Specifically, wherein described R4The derivative of substituted sulphur/oxo naphthoyl imide compounds can be as the molecule based on activity Probe application is in the discovery of the new protein member of Bcl-2 families, separation, enrichment and Function detection.Wherein described R5Substituted sulphur/ The derivative of oxo naphthoyl imide compounds can be used as PROTAC (Proteolysis Targeting Chimera) double work( Can complex degradation selectivity Bcl-2 and Mcl-1 albumen in the cell.
Brief description of the drawings
The width of accompanying drawing 4 of the present invention：
Fig. 1 is flow cytometry analysis result of the compound 7 to induction U937 Apoptosis, and wherein A, B, C figure is respectively Add Apoptosis result when 0 μm of ol, 5 μm of ol, 10 μm of ol compound 7；
Fig. 2 is the cytotoxicity experiment result that compound 7 relies on Bax/Bak, and wherein A figures are that addition is non-specific positive right According to Gossypol cytotoxicity result, B figures are the cytotoxicity result for adding compound 7.
Fig. 3 be compound 18 and 20 in vitro with fluorescence labeling in MCF-7 cells, separation and enrichment Bcl-2 and Mcl-1 Experimental result, wherein a, b are respectively 10 μM of compounds 18 fluorescence labeling Bcl-2 in the presence of 0 μM, 50 μM of competitive inhibitors 12 With Mcl-1 gel fluorescence results, the coomassie brilliant blue staining result of each protein content in c, d a, b identical experiment systems, e, F is 50 μM of 20 separation and enrichment Bcl-2 and Mcl-1 silver staining knot in the presence of 0 μM, 200 μM of competitive inhibitors 12 of compound Fruit.
Fig. 4 is that compound 24 and 26 regulates and controls the horizontal immunoblot experiment results of Bcl-2 and Mcl-1 into the cell in MCF-7.
Embodiment
Sulphur provided by the present invention/oxo naphthoyl imide compounds, there is formula I structure
Wherein：
Described R1The phenyl arbitrarily substituted selected from phenyl or by following radicals：OH、OCH3、I、Br、Cl、NO2、NHCH3、N (CH3)2, CN, phenyl or C1-4Alkyl；It is preferred that R1The phenyl arbitrarily substituted selected from phenyl or by following radicals：Cl、Br、I、OCH3、 N(CH3)2Or C1-3Alkyl；It is further preferable that described R1Selected from phenyl or by the mono-substituted phenyl of following radicals：Cl、Br、I、 OCH3、N(CH3)2Or C1-3Alkyl；Contraposition in phenyl preferably occurs for these substitutions.More in specific embodiment, Described R1Selected from phenyl, 4- chlorphenyls, 4- bromophenyls, 4- iodophenyls, 4- methoxyphenyls, 4- dimethylamino phenyls, 4- first Base phenyl, 4- ethylphenyls, 4- isopropyl phenyls.Particularly preferred 4- bromophenyls, 4- aminomethyl phenyls and 4- isopropyl phenyls.
Described X is selected from S or O；It is preferred that X is S.
Described R2Selected from H, R3、ZR3, piperidyl, piperidone base, piperidine dione base, pyrrolidinyl, pyrrolidone-base, pyrrole Cough up alkane diketo, C1-6Alkyl or substitution C1-6Alkyl；The described substitution C1-6Alkyl is the C arbitrarily substituted by following radicals1-6 Alkyl：OH、OCH3、I、Br、Cl、NO2、NH2、NHCH3、N(CH3)2、CH(OCH3)2、CHO、CN、COOH、COOCH3、COOC2H5Or R3.As preferable technical scheme, described R2Selected from R3、ZR3, piperidone base, piperidine dione base, substitution C1-6Alkyl and by The C that following radicals arbitrarily substitute1-6Alkyl：CHO、COOH、COOCH3Or COOC2H5；It is further preferred that described R2Selected from R3、 ZR3, piperidine dione base or CHO substitution C1-6Alkyl.
Described in above-mentioned technical proposal and R3Selected from substituted or unsubstituted phenyl, naphthyl, benzofuranyl, thienyl Or indyl, i.e., phenyl or substituted-phenyl, naphthyl or substituted naphthyl, benzofuranyl or substitution benzofuranyl, thienyl or Substituted thiophene, indyl or substituted indolyl.It is wherein described and substitution be arbitrarily to be substituted by following radicals：C1-4Alkyl, C1-4 Alkenyl, C1-4Alkynyl, phenyl, OH, I, Br, Cl, NO2、NHCH3、N(CH3)2、CN、CF3、COOH、SO3H、COOR6、CONHR6、 SO3R6、SO2NHR6Or OR6；In preferable technical scheme, described R3Selected from substituted or unsubstituted phenyl, naphthyl, benzo furan Mutter base, thienyl or indyl, described substitution is any substitution of 1~3 substituent.In more preferred technical scheme, Described R3Selected from phenyl, naphthyl, indyl or the phenyl or indyl arbitrarily substituted by following radicals：C1-4Alkyl, C1-3Alkene Base, C1-3Alkynyl, COOH, OH, I, Br, Cl or OR6.R therein6Selected from C1-4Alkyl, C1-4Alkenyl, C1-4Alkynyl, phenyl, benzyl, CH2COOH or CH2CONH2.In highly preferred technical scheme, described R3Selected from phenyl, naphthyl, indyl, 2- methylbenzenes Base, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 3- isopropyl phenyls, 4- isopropyl phenyls, 4- tert-butyl-phenyls, 2- Carboxyl phenyl, 3- carboxyl phenyls, 4- carboxyl phenyls, 2- hydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls, 3,4,5- trihydroxies Phenyl, 2- iodophenyls, 4- iodophenyls, 6- chloro-indoles base, 6- bromo indoles base and 5- methyl indol bases.
Described in above-mentioned technical proposal and Z be selected from (CH2)m、(CH2)mCONH、(CH2)mNHCO、(CH2)mOCO、(CH2)mNHSO2、(CH2)mOSO2、(CH2)mCONH(CH2)nO、(CH2)mNHCO(CH2)nO, carbonyl or sulfonyl, m, n are the whole of 1-3 Number.
More specifically in technical scheme, sulphur of the present invention/oxo naphthoyl imide compounds, selected from following structures Compound：
The present invention further provides the preparation method of the sulphur of the invention described above/oxo naphthoyl imide compounds, including such as Lower step：
(1) the bromo- naphthalic anhydrides of 4- and R1XH is in the presence of acid binding agent according to mol ratio 1:1.2-1.5 reacts, and obtains chemical combination Thing III, reaction time 6-12h, reaction temperature are 80-150 DEG C, and reaction dissolvent DMF, acid binding agent is triethylamine；The step It is preferred that carry out under nitrogen protection；
(2) compound III and NH2、C1-6Alkylamine or (OH, OCH3、I、Br、Cl、NO2、NH2、NHCH3、N(CH3)2、CH (OCH3)2、CN、COOCH3、COOC2H5、R3) substitution C1-6Alkylamine is in the presence of acid binding agent according to molar ratio 1:2-1:5 is anti- Should, compound I, R therein is made2(corresponding difference) is H, C1-6Alkyl or (OH, OCH3、I、Br、Cl、NO2、NH2、NHCH3、N (CH3)2、CH(OCH3)2、CN、COOCH3、COOC2H5、R3) substitution C1-6Alkyl；Reaction time is 4-10h, and reaction temperature is 60-80 DEG C, reaction dissolvent is ethanol, and acid binding agent is triethylamine；
(3) R obtained by step (2)2For CH (OCH3)2Substitute C1-6Alkyl or COOCH3Substitute C1-6The formula I's of alkyl Compound hydrolyzes in the basic conditions, and R is made respectively2Substitute C for CHO1-6Alkyl or COOH substitutions C1-6The chemical combination of the Formulas I of alkyl Thing；The step is preferably carried out under nitrogen protection；
(4) R obtained by above-mentioned steps2For H, (CH2)mNH2、(CH2)mOH and (CH2)mCOOH compound I with R3COOH、R3COCl、R3SO2Cl and R3NH2R is made by acylated and sulfonylation2For ZR3Compound I；
(R2For (CH2)mNH2、(CH2)mOH and (CH2)mCOOH compound I is included in step (2), (3) obtained R2For NH2, OH, COOH substitution C1-6In the range of the compound I of alkyl.(CH2)mIt is included in C1-6In alkyl chain)
(5) compound III and R3NH2According to molar ratio 1:2-1:5 reactions, obtain R2For R3Formulas I compound, instead It is 10-24h between seasonable, reaction temperature is 120-160 DEG C, and reaction dissolvent is acetic acid：DMF=1:5 mixed solvent.
On the basis of the sulphur/oxo naphthoyl imide compounds of the invention described above, the present invention further provides a series of The derivative of functional molecular based on above-claimed cpd, i.e. sulphur/oxo naphthoyl imide compounds.This series of derivative be On the basis of sulphur with the general formula I/oxo naphthoyl imide compounds of the invention described above, via L-R4Or L-R5After substitution The derivative obtained；
Wherein, described L is linking group, is connected to the derivative of formula I sulphur/oxo naphthoyl imide compounds On, selected from L1~L6:
Wherein, p is 1-3 integer, and q is 1-10 integer；
Described R4Group selected from formula i~vi：
Described R5Group selected from formula vii or viii：
In formula vii, l is 2-10 integer.
As specific embodiment, described derivative has formula ix, x, xi or xii structure：
In above-mentioned formula ix, x, xi or xii, the selection of substituent and preferably with this specification hereinbefore described one Cause.
More specifically preferred embodiment, the derivative of described sulphur/oxo naphthoyl imide compounds is selected from as follows Compound：
Further, the present invention provides the preparation method of the derivative of above-mentioned sulphur/oxo naphthoyl imide compounds, this method Based on the preparation method of the hereinbefore described compound with general formula I, comprise the following steps：
(1) methyl ester derivation of compound I and L containing active hydrogen are subjected to amidatioon, sulfanilamide (SN) or reacted into ether etc., Or reacted (2) condition of compound III and L methyl ester derivation according to claim 8, obtain compound I-L-OCH3；
(2) compound I-L-OCH3Hydrolyze in the basic conditions, products therefrom further with R4NH2Or R5NH2According to feeding intake Mol ratio 1:1-1:2 carry out reaction amidation process, obtain the derivative of sulphur/oxo naphthoyl imide compounds；Wherein hydrolyze institute It is NaOH, solvent THF with alkali：H2O=3:1 mixed solvent；Amidation process addition active ester is HATU, and acid binding agent is DIEA。
The present invention it is described above and all technical schemes in, the term " alkyl " used includes straight chained alkyl and branched alkane Base.As mentioned by single alkyl such as " propyl group ", then straight chained alkyl is only refered in particular to, as mentioned by single branched alkyl such as " isopropyl ", then only Refer in particular to branched alkyl.And for example " C1-4Alkyl " includes C1-3Alkyl, methyl, ethyl, n-propyl, isopropyl and the tert-butyl group.Similar Rule is also applied for the other groups used in this specification.
Following non-limiting examples can make one of ordinary skill in the art be more fully understood the present invention, but not with Any mode limits the present invention.In following embodiments, unless otherwise specified, used experimental method is conventional method, institute With raw material and reagent etc. can chemically or biological reagent company purchase or from published method prepare.
Embodiment 1：The preparation of N- ethyls -4- (4- methylbenzene coloured glazes base) -1,8- naphthalimides (compound 1)
(1) synthesis of intermediate A 1
Take bromo- 1, the 8- naphthalic anhydrides of 1.39g (5mmol) 4- respectively, 0.682g (5.5mmol) toluene-ω-thiol, 0.556g triethylamines, 15mL DMF are added, 85 DEG C of reaction 6h, pours into 150mL water, filters after being cooled to room temperature.Solid Intermediate A 1 (4- (4- methylbenzenes sulfydryl) -1,8- naphthalic anhydrides) is recrystallized to obtain with petrol ether/ethyl acetate, is consolidated for yellow Body, yield 78%.
(2) synthesis of compound 1
320mg intermediate As 1,225mg ethamine and 506mg triethylamines are taken respectively, adds 10mL ethanol, and nitrogen is protected next time Stream, point plate tracking reaction (about reacting 5h), cooling, solid, filtering being separated out, solid is recrystallized with methanol/water, obtains compound 1, Yield 53%.
Compound 11H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H) .7.24 (d, J=7.6Hz, 2H), 3.20 (q, J= 6.4Hz, 2H), 2.32 (s, 3H), 1.19 (t, J=6.4Hz, 2H) .TOF MS (EI+):C21H17NO2S, theoretical value：347.1, it is real Measured value：347.1.
Embodiment 2：The preparation of N- normal-butyls -4- (4- bromobenzene coloured glazes base) -1,8- naphthalimides (compound 2)
(1) synthesis of intermediate A 2
Take bromo- 1, the 8- naphthalic anhydrides of 1.39g (5mmol) 4- respectively, 0.940g (5.5mmol) to bromo thiophenol, 0.556g (5.5mmol) triethylamine, 15mL DMF are added, 85 DEG C of reaction 6h, pours into 150mL water, filters after being cooled to room temperature. Solid recrystallize to obtain intermediate A 2 (4- (4- bromobenzenes sulfydryl) -1,8- naphthalic anhydrides) with petrol ether/ethyl acetate, for Huang Color solid, yield 75%.
(2) synthesis of compound 2
384mg (1mmol) intermediate A 2,365mg (5mmol) n-butylamines and 506mg (5mmol) triethylamine are taken respectively, are added Enter 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling separates out solid, filtering, and solid is used Methanol/water recrystallizes, and obtains compound 2, yield 58%.
Compound 21H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.52 (t, J=7.6Hz, 1H), 8.37 (t, J=7.6Hz, 1H), 8.31 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H) .7.24 (d, J=7.6Hz, 2H), 3.13 (t, J= 6.4Hz, 2H), 1.54 (m, J=6.4Hz, 2H), 1.29 (m, J=6.4Hz, 2H), 0.91 (t, J=6.4Hz, 2H) .TOF MS (EI+):C22H18BrNO2S, theoretical value：439.0,441.0, measured value：439.0,441.0.
Embodiment 3：The preparation of N- benzyls -4- (4- methoxybenzene coloured glazes base) -1,8- naphthalimides (compound 3)
(1) synthesis of intermediate A 1
Method according to the step of embodiment 1 (1) is prepared into intermediate A 1.
(2) synthesis of compound 3
320mg (1mmol) intermediate A 1,535mg (5mmol) benzylamines and 506mg (5mmol) triethylamine are taken respectively, are added 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling, separates out solid, filtering, solid first Alcohol/water recrystallization, obtains compound 3, yield 49%.
Compound 31H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H) .7.32-7.27 (m, 5H), 7.24 (d, J=7.6Hz, 2H),4.30(s,2H),2.32(s,3H).TOF MS(EI+):C26H19NO2S, theoretical value：409.1, measured value：409.2.
Embodiment 4：The preparation of N- phenethyls -4- (4- bromobenzene coloured glazes base) -1,8- naphthalimides (compound 4)
(1) synthesis of intermediate A 4
Bromo- 1, the 8- naphthalic anhydrides of 1.39g (5mmol) 4-, 0.946g (5.5mmol) p bromophenol, 0.556g are taken respectively Triethylamine, 15mL DMF are added, 150 DEG C of reaction 12h, pours into 150mL water, filters after being cooled to room temperature.Solid stone Oily ether/re-crystallizing in ethyl acetate obtains intermediate A 4 (4- (4- bromobenzenes epoxide) -1,8- naphthalic anhydrides), is yellow solid, yield 54%.
(2) synthesis of compound 4
368mg (1mmol) intermediate A 4,605mg (5mmol) phenyl ethylamines and 506mg (5mmol) triethylamine are taken respectively, are added Enter 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling separates out solid, filtering, and solid is used Methanol/water recrystallizes, and obtains compound 3, yield 42%.
Compound 41H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.53 (t, J=7.2Hz, 1H), 8.38 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.25-7.19 (m, 5H), 3.41 (t, J=6.8Hz, 2H), 2.32 (t, J=6.8Hz, 2H) .TOF MS (EI+):C26H18BrNO3, theoretical value： 471.0,473.0, measured value：471.2,473.2.
Embodiment 5：3- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base)-N- (4- aminomethyl phenyls)-propionamide (compound 5)
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of intermediate B 5
384mg (1mmol) intermediate A 2,698mg (5mmol) 3- aminopropanoates and 506mg (5mmol) three are taken respectively Ethamine, 10mL ethanol being added, nitrogen protection is lower to flow back, and puts plate tracking reaction (about reacting 5h), cooling, separates out solid, filters, Solid is recrystallized with methanol/water, obtains intermediate B 5, yield 51%.
(3) intermediate C5 synthesis
235mg (0.5mmol) intermediate B 5 is taken respectively, 200mg (5.0mmol) NaOH, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate C5, yield 95%.
(4) synthesis of compound 5
Take 91mg (0.2mmol) intermediates C5 to be dissolved in 10mL DMF, sequentially add 23.5mg (0.22mmol) to methyl Aniline, HATU 91mg (0.24mmol) are added after 52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, and point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 5, yield 70%.
Compound 51H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 9.82 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.44 (d, J=7.2Hz, 2H), 7.10 (d, J=7.2Hz, 2H), 4.36 (t, J=6.8Hz, 2H), 2.34 (t, J=6.8Hz, 2H),2.32(s,3H).TOF MS(EI+):C28H21BrN2O3S, theoretical value：544.0,546.0, measured value：543.9,546.0.
Embodiment 6：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -3,4,5- trimethoxies The preparation of benzamide (compound 6)
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of intermediate B 6
384mg (1mmol) intermediate A 2,300mg (5mmol) ethylenediamines and 506mg (5mmol) triethylamine are taken respectively, are added Enter 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling separates out solid, filtering, and solid is used Methanol/water recrystallizes, and obtains intermediate B 6, yield 61%.
(3) synthesis of compound 6
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 46.6mg (0.22mmol) to 3,4, 5- trimethoxybenzoic acids, HATU 91mg (0.24mmol), point are added after 52mg (0.4mmol) DIPEA, stirring at normal temperature 5min Plate tracking reaction (about reacting 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, is obtained Compound 6, yield 81%.
Compound 61H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.82 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.17 (s, 2H), 3.69 (t, J=6.8Hz, 2H), 3.36 (t, J=6.8Hz, 2H), 3.78 (s, 9H) .TOF MS (EI+): C30H25BrN2O6S, theoretical value：620.1,622.1, measured value：620.1,622.1.
Embodiment 7：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -2- naphthalenecarboxamide (chemical combination Thing 7) preparation
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) synthesis of compound 7
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 37.8mg (0.22mmol) to 2- naphthalenes Formic acid, HATU 91mg (0.24mmol) are added after 52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, and point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 7, yield 77%.
Compound 71H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.94 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.40 (m, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x= 8.4Hz, 1H), 8.15-8.05 (m, 3H), 7.87 (t, J=7.2Hz, 1H), 7.75 (m, J=7.2Hz, 1H), 7.72 (d, J= 7.6Hz, 2H), 7.66 (m, J=7.2Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 3.69 (t, J=6.8Hz, 2H), 3.36 (t, J=6.8Hz, 2H) .TOF MS (EI+):C31H21BrN2O3S, theoretical value：580.0,582.0, Measured value：580.1,582.1.
Embodiment 8：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -2- indole carboxamides (are changed Compound 8) preparation
(1) synthesis of intermediate A 8
Take bromo- 1, the 8- naphthalic anhydrides of 1.39g (5mmol) 4- respectively, 0.838g (5.5mmol) p-isopropyl benzenethiol, 0.556g (5.5mmol) triethylamine, 15mL DMF are added, 85 DEG C of reaction 6h, pours into 150mL water, filters after being cooled to room temperature. Solid recrystallize to obtain intermediate A 8 with petrol ether/ethyl acetate, be yellow solid, yield 79%.
(2) synthesis of intermediate B 8
348mg (1mmol) intermediate A 8,300mg (5mmol) ethylenediamines and 506mg (5mmol) triethylamine are taken respectively, are added Enter 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling separates out solid, filtering, and solid is used Methanol/water recrystallizes, and obtains intermediate B 8, yield 66%.
(2) synthesis of compound 8
Take 78mg (0.2mmol) intermediate B 8 to be dissolved in 10mL DMF, sequentially add 35.5mg (0.22mmol) to 2- Yin Diindyl formic acid, HATU 91mg (0.24mmol), point plate tracking reaction are added after 52mg (0.4mmol) DIPEA, stirring at normal temperature 5min (about reacting 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, compound 8 is obtained, produced Rate 62%.
Compound 81H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 11.55 (s, 1H), 8.94 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x= 8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.64 (q, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 2H), 3.68 (t, J=6.8Hz, 2H), 3.34 (t, J=6.8Hz, 2H), 2.87 (m, J=6.4Hz, 1H), 1.21 (d, J=6.4Hz, 6H) .TOF MS(EI+):C32H27N3O3S, theoretical value：533.2, measured value：522.1.
Embodiment 9：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -4- methyl benzoic acid first The preparation of ester (compound 9)
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of intermediate B 9
384mg (1mmol) intermediate A 2,300mg (5mmol) 2 hydroxy ethylamines and the second of 506mg (5mmol) three are taken respectively Amine, 10mL ethanol being added, nitrogen protection is lower to flow back, and puts plate tracking reaction (about reacting 5h), cooling, separates out solid, filters, Gu Body is recrystallized with methanol/water, and it is crocus solid to obtain intermediate B 9, yield 60%.
(3) synthesis of compound 9
Take 470mg (1.1mmol) intermediate B 9 to be dissolved in 10mL THF respectively, add 339mg (2.2mmol) 4- methylbenzenes Sulfonic acid chloride and 223mg (2.2mmol) triethylamine, backflow, point plate tracking reaction (about reacting 2h).Water quenching is added to go out, ethyl acetate Extraction, anhydrous sodium sulfate drying, vacuum are spin-dried for obtaining crude product, use petroleum ether：Ethyl acetate=1:1 post separation, obtain compound 9 For yellow solid, yield 84%.
Compound 91H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.94 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.64 (q, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 2H), 4.50 (t, J=6.8Hz, 2H), 3.37 (t, J=6.8Hz, 2H), 2.0 (s, J=6.8Hz, 3H) .TOF MS (EI+):C28H20BrNO4S, theoretical value： 545.03,547.03, measured value：545.00,546.98.
Embodiment 10：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -4- toluene sulfonic acide first The preparation of ester (compound 10)
(1) synthesis of intermediate B 9
Intermediate B 9 is prepared into according to the step of embodiment 9 (1), the method for (2).
(2) synthesis of compound 10
Take 470mg (1.1mmol) intermediate B to be dissolved in 10mL THF respectively, add paratoluensulfonyl chloride 419mg (2.2mmol) and 223mg (2.2mmol) triethylamine, backflow, point plate tracking reaction (about reacting 2h).Water quenching is added to go out, acetic acid second Ester extracts, and anhydrous sodium sulfate drying, vacuum is spin-dried for obtaining crude product, uses petroleum ether：Ethyl acetate=1:1 post separation, obtains chemical combination Thing 10, yield 84%.
Compound 101H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.45 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.64 (q, J=7.6Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 2H), 3.84 (t, J=6.8Hz, 2H), 3.40 (t, J=6.8Hz, 2H), 1.98 (s, J=6.8Hz, 3H) .TOF MS (EI+):C27H20BrNO5S2, theoretical value： 581.0,582.99, measured value：580.89,583.01.
Embodiment 11：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -4- methyl benzenesulfonamides The preparation of (compound 11)
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).(2) synthesis of compound 11
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 38mg (0.22mmol) to toluene sulphur Acid, HATU 91mg (0.24mmol) are added after 52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (about React 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, it is yellow to obtain compound 11 Solid, yield 62%.
Compound 111H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 7.91 (t, 1H), 8.44 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.13 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.40 (q, J=7.6Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 2H), 3.61 (t, J=6.8Hz, 2H), 3.32 (t, J=6.8Hz, 2H), 2.43 (s, J=6.8Hz, 3H) .TOF MS (EI+):C27H21BrN2O4S2, theoretical value： 580.01,582.01, measured value：579.99,582.02.
Embodiment 12：The system of N- (4- hydroxy phenyls) -4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides (compound 12) It is standby
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of compound 12
Take 76.8mg (0.2mmol) intermediate A 2 to be dissolved in 10mL DMF, add 27mg (0.24mmol) PAP, And 2mL AcOH are added, nitrogen protects 100 DEG C of back flow reactions, point plate tracking reaction (about reacting 16h), adds 100mL water quenchings to go out, Filter, obtain solid.Crude product petroleum ether：Ethyl acetate=2:1 post separation, obtain compound 12, yield 62%.
Compound 121H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 9.25 (s, 1H), 8.50 (s, 1H), 8.34 (t, J=7.2Hz, 1H), 8.27 (t, J=7.2Hz, 1H), 7.98 (d, J x= 8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.61 (q, J=7.6Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.51 (t, J=7.6Hz, 1H), 7.01 (d, J=7.6Hz, 2H), 6.99 (t, J=7.6Hz, 2H) .TOF MS(EI+):C24H14BrNO3S, theoretical value：474.99,476.99, measured value：475.05,476.56.
Embodiment 13：N- (4- Phenoxyphenyls) -4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides (compound 13) Prepare
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of compound 13
Take 76.8mg (0.2mmol) intermediate A 2 to be dissolved in 10mL DMF, add 44.5mg (0.24mmol) 4- amino two Phenylate, and 2mL AcOH are added, nitrogen protects 100 DEG C of back flow reactions, point plate tracking reaction (about reacting 16h), adds 100mL water It is quenched, filters, obtain solid.Crude product petroleum ether：Ethyl acetate=2:1 post separation, obtain compound 13, yield 62%.
Compound 131H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.49 (s, 1H), 8.30 (s, 1H), 8.28 (t, J=7.2Hz, 1H), 7.89 (t, J=7.2Hz, 1H), 7.72 (d, J x= 8.4Hz, 1H), 7.72 (t, J=7.2Hz, 1H), 7.65 (d, J=7.6Hz, 2H), 7.55 (q, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.42 (t, J=7.6Hz, 1H), 7.15 (d, J=7.6Hz, 2H), 7.15 (t, J=7.6Hz, 2H), 7.04 (t, J=6.8Hz, 2H), 6.99 (t, J=6.8Hz, 2H) .TOF MS (EI+):C30H18BrNO3S, theoretical value：551.02, 553.02, measured value：550.99,553.02.
Embodiment 14：2- (2- (4- (4- bromobenzenes sulfydryl)-N-1,8- naphthalimides base) phenoxy group) acetic acid (compound 14) preparation
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) synthesis of intermediate B 14
Take 384mg (1mmol) intermediate A 2 to be dissolved in 10mL DMF, add 131mg (1.2mmol) Ortho-Aminophenol, and 2mL AcOH are added, nitrogen protects 100 DEG C of back flow reactions, point plate tracking reaction (about reacting 16h), adds 100mL water quenchings to go out, take out Filter, obtains solid.Crude product petroleum ether：Ethyl acetate=2:1 post separation, it is crocus solid to obtain intermediate B 14, yield 62%.
(3) intermediate C14 synthesis
Take 95mg (0.2mmol) intermediate B 14 to be dissolved in 10mL DMF, add 40mg (0.24mmol) (27 μ L) bromoacetic acid Ethyl ester, and 110mg (0.8mmol) potassium carbonate is added, 65 DEG C of back flow reactions, point plate tracking reaction (about reacting 2h), add 100mL Water quenching is gone out, and separates out solid, is filtered, is obtained intermediate C14, yield 98%.
(4) synthesis of compound 14
112mg (0.2mmol) intermediates C14 is taken to be dissolved in 10mL THF, sodium hydroxide 80mg is dissolved in 2mL water, is added dropwise to In reaction mixture, it is stirred overnight at room temperature, point plate tracking reaction (about reacting 12h), THF vacuum is spin-dried for, adds about 2mL HCl adjusts PH, adds 100mL elutriations and goes out solid, and it is yellow solid that suction filtration, which obtains compound 14, yield 89%.
Compound 141H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 12.05 (s, 1H), 8.94 (s, 1H), 8.50 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x= 8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.64 (q, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 2H), 4.68 (s, J=6.8Hz, 2H) .TOF MS (EI+):C26H16BrNO5S, theoretical value：532.99,535.06, measured value：533.02, 534.89.
Embodiment 15：The preparation of N- normal-butyls -4- (4- bromobenzene coloured glazes base) -1,8- naphthalimides (compound 15)
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2
(2) synthesis of intermediate B 15
384mg (1mmol) intermediate A 2,556mg (5mmol) aminoacetaldehyde dimethyl acetals and 506mg (5mmol) are taken respectively Triethylamine, 10mL ethanol is added, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling, separates out solid, mistake Filter, solid are recrystallized with methanol/water, obtain intermediate B 15, yield 68%.
(3) synthesis of compound 15
Take 472mg (1mmol) intermediate B 15 to be dissolved in 5mL dichloromethane, 5mL trifluoroacetic acids, point plate tracking are added under normal temperature React (about reacting 0.5h), decompression is outstanding to boil off solvent, and solid is recrystallized with methanol/water, obtains compound 15, yield 88%.
Compound 151H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 9.72 (t, J=8.0Hz, 1H), 8.52 (t, J=7.6Hz, 1H), 8.37 (t, J=7.6Hz, 1H), 8.31 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.24 (d, J= 7.6Hz, 2H), 4.31 (d, J=8.0Hz, 2H) .TOF MS (EI+):C20H12BrNO3S, theoretical value：425.0,427.0, survey Value：425.0,427.0.
Embodiment 16：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides) ethyl) -2- (1- epoxides naphthalene) formamide The preparation of (compound 16)
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) intermediate C16 synthesis
Take 1- naphthalene phenol 120mg (0.80mmol) to be dissolved in 10mL DMF, add 160mg (0.96mmol) (108 μ L) bromine second Acetoacetic ester, and 440mg (3.20mmol) potassium carbonate is added, 65 DEG C of back flow reactions, TLC tracking reactions (about reacting 2h), add 100mL water quenchings are gone out, and separate out solid, are filtered, are obtained intermediate C16, yield 98%.
(3) intermediate D16 synthesis
120mg (0.56mmol) intermediates C, 222mg (5.60mmol) NaOH is taken respectively, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate D16, yield 95%.
(4) synthesis of compound 16
Take 110mg (0.26mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add among 56.60mg (0.22mmol) After body D16,68.00mg (0.53mmol) DIPEA, stirring at normal temperature 5min add HATU 119.80mg (0.32mmol), TLC with Track reacts (about reacting 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtains chemical combination Thing 16, yield 76%..
Compound 161H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.94 (s, 1H), 8.50 (t, J=7.2Hz, 2H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 2H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.64 (q, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 1H), 6.19 (t, J=6.8Hz, 1H), 5.01 (s, J=6.8Hz, 1H), 3.80 (t, J=6.8Hz, 2H), 3.36 (t, J=6.8Hz, 2H) .TOF MS (EI+): C32H23BrN2O4S, theoretical value：610.03,611.51, measured value：610.06,612.00.
Embodiment 17：3-N- (piperidine-2,6-diones) -- 4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides (compound 17) Prepare
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A.
(2) synthesis of compound 17
Take 350mg (0.88mmol) intermediate A 2 to be dissolved in 10mL THF, add 150mg (0.87mmol) 3- amino piperazines Pyridine -2,6- dione hydrochloride, 1.20mL triethylamines, 120 DEG C of backflows, TLC tracking reactions (about reacting 20h) is added dropwise.It is spin-dried for molten Agent, crude product flow back 20min in acetic anhydride, and temperature adds 5mL absolute ethyl alcohols when being reduced to 80 DEG C, stirs 30min, and cooling is taken out Filter, is washed 3 times with ethyl acetate, obtains yellow solid.Crude product dichloromethane：Methanol=40：1 post separation purifies, yield 84%.
The 1H NMR measurement results and mass spectroscopy result of compound 17 are as follows：1H NMR(400MHz,DMSO-d6)δ: 11.20 (S, J=7.6Hz, 1H), 8.52 (t, J=7.6Hz, 1H), 8.37 (t, J=7.6Hz, 1H), 8.31 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H) .7.24 (d, J= 7.6Hz, 2H), 4.78 (t, J=6.4Hz, 1H), 2.26 (m, J=6.4Hz, 2H), 1.98 (m, J=6.4Hz, 2H) .TOF MS (EI+):C23H15BrN2O4S, theoretical value：494.0,496.3, measured value：494.0,496.2.
Embodiment 18：3- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base)-N- ('-aziridino -6- heptyne of 3- bis- Base)-propionamide (compound 18) preparation
(1) intermediate C5 synthesis
Method according to the step of embodiment 5 (1), (2), (3) is prepared into intermediate C5.
(2) synthesis of compound 18
Take 91mg (0.2mmol) intermediates C5 to be dissolved in 10mL DMF, sequentially add 30.1mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after D18,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 18, yield 55%.
Compound 181H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.52 (t, J=7.2Hz, 1H), 8.36 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.68 (t, J=6.0Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.52 (t, J= 7.6Hz, 1H), 4.26 (t, J=6.8Hz, 2H), 3.42 (t, J=6.0Hz, 2H), 2.78 (t, J=6.4Hz, 1H), 2.70 (t, J=6.8Hz, 2H), 2.46 (t, J=6.4Hz, 2H), 1.51 (t, J=6.0Hz, 2H), 1.39 (t, J=6.4Hz, 2H) .TOF MS(EI+):C28H23BrN4O3S, theoretical value：574.1,576.1, measured value：574.2,576.2.
Embodiment 19：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) two '-aziridinos of -3- are pungent The preparation of acid amides -7- alkynes (compound 19)
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) synthesis of compound 19
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 36.6mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after C19,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 19, yield 61%.
Compound 191H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.52 (t, J=7.2Hz, 1H), 8.36 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.01 (t, J=6.0Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.52 (t, J= 7.6Hz, 1H), 3.70 (t, J=6.8Hz, 2H), 3.32 (t, J=6.8Hz, 2H), 2.34 (t, J=6.0Hz, 2H), 1.60 (t, J=6.0Hz, 2H), 1.41 (t, J=6.4Hz, 2H) .TOF MS (EI+):C28H23BrN4O3S, theoretical value：574.0,576.0, Measured value：574.0,576.0.
Embodiment 20：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) -4- (3- trifluoromethyls Two '-aziridinos) benzamide (compound 20) preparation
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) synthesis of compound 20
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 50.6mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after C20,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 20, yield 76%.
Compound 201H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.82 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.78 (d, J=7.2Hz, 2H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.51 (d, J=7.6Hz, 2H), 7.38 (d, J=7.2Hz, 2H), 4.36 (t, J=6.8Hz, 2H), 2.34 (t, J=6.8Hz, 2H),2.32(s,3H).TOF MS(EI+):C29H18BrF3N4O3S, theoretical value：638.0,640.0, measured value：638.0, 640.0.
Embodiment 21：N- (3- (4- benzoylphenyls)-N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides Base) ethyl) -2- propionamido-s) and pentanamide -4- alkynes (compound 21) preparation
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) synthesis of compound 21
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 76.8mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after C21,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 21, yield 63%.
Compound 211H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.53 (t, J=7.2Hz, 1H), 8.32 (s, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x=8.4Hz, 1H), 8.12 (s, 1H), 7.87 (t, J=7.2Hz, 1H), 7.81 (d, J=7.6Hz, 2H), 7.78 (d, J=7.2Hz, 2H), 7.72 (m, 4H), 7.61 (m, 1H), 7.55-7.51 (m, 5H), 7.38 (d, J=7.2Hz, 2H), 6.93 (d, J=7.6Hz, 2H), 4.92 (d, J=6.8Hz, 1H), 3.50 (t, J=6.4Hz, 2H), 3.32 (t, J=6.4Hz, 2H), 3.19 (t, J=6.8Hz, 2H), 2.90 (s, 1H), 2.35 (t, J=6.0Hz, 2H), 2.31 (t, J=6.0Hz, 2H) .TOF MS (EI+):C41H32BrN3O5S, reason By value：757.1,759.1, measured value：757.0,759.0.
Embodiment 22：N- (2- (4- (4- bromobenzenes the sulfydryl) -1,8- naphthalimides base) ethyl)-N '-(aziridine of 3- bis- Base -6- heptynyls) succinamide (compound 22) preparation
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) intermediate C22 synthesis
Take 170mg (0.4mmol) intermediate B 6 and 81mg (0.8mmol) triethylamine to be dissolved in 20mL THF, dripped under ice bath Add 90mg (0.6mmol) succinic acid list formyl chloride, stirring at normal temperature 12h, washing, dichloromethane extraction, crude product dichloromethane： Methanol=15:1 post separation, obtain intermediate C22, yield 80%.
(3) intermediate D22 synthesis
162mg (0.3mmol) intermediates C22,120mg (3.0mmol) NaOH is taken respectively, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate D22, yield 98%.
(4) synthesis of compound 22
Take 85mg (0.2mmol) intermediates D22 to be dissolved in 10mL DMF, sequentially add 36.6mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after E22,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 22, yield 67%.
Compound 221H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 8.52 (t, J=7.2Hz, 1H), 8.36 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.01 (t, J=6.0Hz, 1H), 7.87 (t, J=7.2Hz, 1H), 7.72 (d, J=7.6Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.52 (t, J= 7.6Hz, 1H), 3.70 (t, J=6.8Hz, 2H), 3.32 (t, J=6.8Hz, 2H), 2.52 (m, 4H), 2.34 (t, J=6.0Hz, 2H), 1.60 (t, J=6.0Hz, 2H), 1.41 (t, J=6.4Hz, 2H) .TOF MS (EI+):C31H28BrN5O4S, theoretical value： 645.1,647.1, measured value：645.3,647.3.
Embodiment 23：N- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl)-N '-(4- (4- pentynes Amide groups)-benzoylphenyl) succinamide (compound 23) preparation
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) synthesis of compound 23
Take 85mg (0.2mmol) intermediate B 6 to be dissolved in 10mL DMF, sequentially add 86.3mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after C23,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 23, yield 53%.
Compound 231H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 10.03 (s, 1H), 9.32 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J x= 8.4Hz, 1H), 8.01 (s, 1H), 7.87 (t, J=7.2Hz, 1H), 7.85 (d, J=7.2Hz, 4H), 7.81 (d, J=7.6Hz, 2H), 7.78 (d, J=7.2Hz, 2H), 7.74-7.72 (m, 6H), 7.61 (m, 1H), 7.55 (m, 3H), 7.38 (d, J= 7.2Hz, 2H), 3.70 (t, J=6.4Hz, 2H), 3.32 (t, J=6.4Hz, 2H), 2.90 (s, 1H), 2.60 (t, J=6.8Hz, 2H), 2.45 (t, J=6.8Hz, 2H), 2.35 (t, J=6.0Hz, 2H), 2.31 (t, J=6.0Hz, 2H) .TOF MS (EI+): C42H33BrN4O6S, theoretical value：800.1,802.1, measured value：800.1,802.1.
Embodiment 24：N- (2- (2- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) ethyoxyl) second Epoxide)-N '-((2S) -1- ((4R) -4- hydroxyls -2- ((4- (4- methyl-5-thiazoles base) benzyl) carbamoyl) -1- pyrroles Alkyl) -3,3 dimethyl -1- oxo -2- butyl) succinamide (compound 24) preparation
(1) synthesis of intermediate A 2
Method according to the step of embodiment 2 (1) is prepared into intermediate A 2.
(2) intermediate C24 synthesis
384mg (1mmol) intermediate A 2 is taken respectively, 1310mg (5mmol) B22 and 506mg (5mmol) triethylamine, is added 10mL ethanol, nitrogen protection is lower to flow back, and point plate tracking reaction (about reacting 5h), cooling, separates out solid, filtering, solid first Alcohol/water recrystallization, obtains intermediate C24, yield 61%.
(3) intermediate D24 synthesis
189mg (0.3mmol) intermediates C24,120mg (3.0mmol) NaOH is taken respectively, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate D24, yield 98%.
(4) synthesis of compound 24
Take 123mg (0.2mmol) intermediates D24 to be dissolved in 10mL DMF, sequentially add 92mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after E24,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 24, yield 48%.
Compound 241H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 10.03 (s, 1H), 9.32 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J= 8.4Hz, 1H), 8.01 (s, 1H), 7.87 (m, J=7.2Hz, 1H), 7.83 (s, 1H), 7.72 (d, J=7.2Hz, 2H), 7.69 (d, J=8.0Hz, 2H), 7.57 (t, J=7.2Hz, 1H), 7.55 (d, J=7.2Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 7.38 (d, J=7.2Hz, 2H), 5.01 (s, 1H), 4.40 (m, J=6.4Hz, 3H), 4.24 (s, 1H), 4.07 (m, J= 6.4Hz, 1H), 3.71 (m, J=6.4Hz, 4H), 3.52 (m, J=6.4Hz, 4H), 3.48 (m, J=6.4Hz, 2H), 3.39 (t, J=6.4Hz, 2H), 3.28 (t, J=6.4Hz, 2H), 2.77 (s, 3H), 2.50 (t, J=6.0Hz, 2H), 2.48 (m, J= 6.4Hz, 2H), 2.35 (t, J=6.0Hz, 2H), 0.94 (s, 9H) .TOF MS (EI+):C50H55BrN6O9S2, theoretical value： 1026.3,1028.3 measured value：1026.3,1028.3.
Embodiment 25：N- (2- (2- (2- (4- (4- bromobenzenes sulfydryl) -1,8- naphthalimides base) ethyl) ethyoxyl) second Epoxide)-N '-(2- ((N- (2,6- dioxo -3- piperidyls) -3- phthalimide-baseds) amino) ethyl) succinamide The preparation of (compound 25)
(1) intermediate D24 synthesis
Method according to the step of embodiment 24 (1), (2), (3) is prepared into intermediate D24.
(2) synthesis of compound 25
Take 123mg (0.2mmol) intermediates D24 to be dissolved in 10mL DMF, sequentially add 70mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after E25,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 25, yield 46%.
Compound 251H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 11.17 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.87 (m, J=7.2Hz, 1H), 7.72 (d, J=7.2Hz, 2H), 7.59 (m, J=8.0Hz, 2H), 7.57 (t, J=7.2Hz, 1H), 7.55 (d, J=7.2Hz, 2H), 7.25 (t, J=8.0Hz, 2H), 7.00 (t, J= 8.0Hz, 2H), 6.79 (s, 1H), 4.44 (t, J=6.4Hz, 1H), 3.71 (m, J=6.4Hz, 4H), 3.63 (m, J=6.4Hz, 2H), 3.52 (m, J=6.4Hz, 4H), 3.41 (m, J=6.4Hz, 2H), 3.39 (t, J=6.4Hz, 2H), 3.28 (t, J= 6.4Hz, 2H), 2.77 (s, 3H), 2.50 (t, J=6.0Hz, 2H), 2.35 (t, J=6.0Hz, 2H), 2.15-2.11 (m, 4H) .TOF MS(EI+):C43H41BrN6O10S2, theoretical value：912.2,914.2, measured value：912.2,914.2.
Embodiment 26：The preparation of compound 26
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) intermediate C26 synthesis
Take 170mg (0.4mmol) intermediate B 6,70mg (0.44mmol) adipic acid monomethyl esters and 104mg (0.8mmol) DIEA is dissolved in 15ml dichloromethane, adds 182mg (0.48mmol) HATU, stirring at normal temperature 12h after stirring at normal temperature 5min, washes, Dichloromethane extracts, crude product dichloromethane：Methanol=15:1 post separation, obtain intermediate C26, yield 86%.
(3) intermediate D26 synthesis
175mg (0.3mmol) intermediates C26,120mg (3.0mmol) NaOH is taken respectively, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate D26, yield 97%.
(4) synthesis of compound 26
Take 114mg (0.2mmol) intermediates D26 to be dissolved in 10mL DMF, sequentially add 82mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after E26,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 22, yield 77%.
Compound 261H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 11.17 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.87 (m, J=7.2Hz, 1H), 7.72 (d, J=7.2Hz, 2H), 7.70 (s, 1H), 7.59 (m, J =8.0Hz, 2H), 7.57 (t, J=7.2Hz, 1H), 7.55 (d, J=7.2Hz, 2H), 7.25 (t, J=8.0Hz, 2H), 7.00 (t, J=8.0Hz, 2H), 6.79 (s, 1H), 4.44 (t, J=6.4Hz, 1H), 3.70 (t, J=6.4Hz, 4H), 3.32 (t, J= 6.4Hz, 2H), 3.30 (t, J=6.8Hz, 2H), 2.13 (t, J=6.0Hz, 2H), 2.15-2.11 (m, 4H), 1.58 (t, J= 6.0Hz, 2H), 1.53 (t, J=6.0Hz, 2H), 1.38 (t, J=6.0Hz, 2H), 1.32 (t, J=6.0Hz, 2H), 1.28 (t, J=6.0Hz, 2H) .TOF MS (EI+):C45H45BrN6O8S, theoretical value：908.2,910.2, measured value：908.2,910.2.
Embodiment 27：The preparation of compound 27
(1) synthesis of intermediate B 6
Intermediate B 6 is prepared into according to the step of embodiment 6 (1), the method for (2).
(2) intermediate C27 synthesis
Take 170mg (0.4mmol) intermediate B 6,117mg (0.44mmol) L-N-Boc- phenylalanines and 104mg (0.8mmol) DIEA is dissolved in 15ml dichloromethane, and 182mg (0.48mmol) HATU, stirring at normal temperature are added after stirring at normal temperature 5min 12h, washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain intermediate C27, yield 85%.
(3) synthesis of intermediate E 27
269mg (0.4mmol) intermediates C27 is taken to be dissolved in 8ml dichloromethane：Trifluoroacetic acid=1:1 mixed solvent, normal temperature Stir 30min, it is outstanding solvent is evaporated off to obtain intermediate D27.It is directly added into 70mg (0.44mmol) adipic acid monomethyl esters and 104mg (0.8mmol) DIEA is dissolved in 15ml dichloromethane, and 182mg (0.48mmol) HATU, stirring at normal temperature are added after stirring at normal temperature 5min 12h, washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain intermediate E 27, two step total yields Rate 78%.
(4) intermediate F27 synthesis
215mg (0.3mmol) intermediate E 27 is taken respectively, 120mg (3.0mmol) NaOH, adds THF：H2O=3:1 it is mixed Bonding solvent 10mL, stirring at normal temperature 12h, reaction solution are poured into 100mL cold water, and PH=2 is acidified to hydrochloric acid, filter to obtain intermediate F27, yield 97%.
(4) synthesis of compound 27
Take 140mg (0.2mmol) intermediates F27 to be dissolved in 10mL DMF, sequentially add 82mg (0.22mmol) raw material HATU 91mg (0.24mmol) are added after G27,52mg (0.4mmol) DIPEA, stirring at normal temperature 5min, point plate tracking reaction is (big About react 2h), washing, dichloromethane extraction, crude product dichloromethane：Methanol=15:1 post separation, obtain compound 27, yield 71%.
Compound 271H NMR measurement results and mass spectroscopy result are as follows：1H NMR(400MHz,DMSO-d6)δ: 11.17 (s, 1H), 8.53 (t, J=7.2Hz, 1H), 8.37 (t, J=7.2Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.87 (m, J=7.2Hz, 1H), 7.72 (d, J=7.2Hz, 2H), 7.70 (s, 1H), 7.59 (m, J =8.0Hz, 2H), 7.57 (t, J=7.2Hz, 1H), 7.55 (d, J=7.2Hz, 2H), 7.25 (t, J=8.0Hz, 2H), 7.19 (t, J=8.4Hz, 1H), 7.14 (m, 4H), 7.00 (t, J=8.0Hz, 2H), 6.79 (s, 1H), 4.92 (t, J=7.0Hz, 1H), 4.44 (t, J=6.4Hz, 1H), 3.70 (t, J=6.4Hz, 4H), 3.32 (t, J=6.4Hz, 2H), 3.30 (t, J= 6.8Hz, 2H), 3.19 (d, J=7.0Hz, 2H), 2.13 (t, J=6.0Hz, 2H), 2.15-2.11 (m, 4H), 1.58 (t, J= 6.0Hz, 2H), 1.53 (t, J=6.0Hz, 2H), 1.38 (t, J=6.0Hz, 2H), 1.32 (t, J=6.0Hz, 2H), 1.28 (t, J=6.0Hz, 2H) .TOF MS (EI+):C54H54BrN7O9S, theoretical value：1055.3,1057.3 measured value：1055.3, 1057.3.
Embodiment 28：Suppress the ability of Bcl-2 and Mcl-1 albumen in vitro by Fluorescence Polarization assay detection compound
One Bid BH3 peptide fragment (amino acid with 21 amino acid of synthesis：79-99： QEDIIRNIARHLAQVGDSMDR), and 6- Fluoresceincarboxylic acids succinimide ester (FAM) is used as fluorescence labels on N-terminal mark (FAM-Bid).Reaction system used is GST-Bcl-2 albumen (40nM) or Mcl-1 albumen (40nM) in competion experiment, (100mM K are dissolved in reaction buffer with FAM-Bid polypeptides (5nM)3PO4,pH 7.5；100 μ g/mL ox γ albumin； 0.02% sodium azide).In 96 orifice plates, 100 μ L reaction systems are added per hole, then add being dissolved in for 1 μ L various concentrations The mother liquor (10mM) of DMSO compound to be detected, final concentration of 100 μM.Two control groups are set up simultaneously, a control group is Comprise only Bcl-2 or Mcl-1 and FAM-Bid (equivalent to 0% inhibiting rate) in reaction system, the reaction system in another control group Comprise only FAM-Bid peptide fragments.96 orifice plates after the lucifuge of 4 hours is incubated detect on ELIASA.Fluorescence polarization value (mP) measured under 485nm launch wavelengths caused by being excited by 530nm wavelength.KiThe accounting equation that value passes through Wang et al. reports Obtain.Calculate KiProgram can pass through the free acquisition of following network address：http://sw16.im.med.umich.edu/ software/calc ki/。
The BH3 of other compounds is detected similar to degree according to above-mentioned identical test method, they and Bcl-2 and Mcl-1 Competition binding constant (the K of albumeni) also it is being mostly nM levels, using (-)-Gossypol as positive control, the naphthoyl that 4- amino takes is sub- Amine is negative control.Concrete outcome is as shown in table 1.
The Fluorescence Polarization assay experimental result of the compounds of this invention of table 1.
The result of table 1 understands that compound 1-27 is shown to anti-apoptotic proteins-Mcl-1 and Bcl-2 albumen-sub-micro Mole level affinity, wherein, compound 7,8,12,14,15,16,17 shows the best parent to Mcl-1 and Bcl-2 albumen And power.The sulphur for illustrating to be related in the present invention/oxo naphthalimide skeleton series compound can efficiently dissociate anti-wither in vitro The interaction of albumen and BH3-only albumen is died, and the naphthoyl imide compounds of relevant position nitrogen substitution then can not.
Embodiment 25：The apoptosis situation of MCF-7 cell lines is induced by Flow Cytometry detection compound 7
This experiment passes through Annexin-V/propidium iodide staining by flow cytometry kits It is thin that (the green skies, Suzhou, Chinese C1063) detection compound 7 (5 μM and 10 μM) acts on human leukemia U937 cell lines 24h Born of the same parents' apoptosis situation.
Experimental procedure is as follows：
1. cell is collected：Suspension cell is directly collected into 10mL centrifuge tube, is 5 × 10 per sample cell number6/ mL, 1000r/min centrifuges 5min, discards nutrient solution；
2. washed 1 time with incubation buffer, 500~1000r/min centrifugations 5min；
3. cell is resuspended with 100 μ L label solution, lucifuge is incubated 10~15min at room temperature；
4.500~1000r/min centrifugations 5min sedimentation cell incubation buffers are washed 1 time；
5. adding at 4 DEG C of fluorescence (SA-FLOUS) solution and being incubated 20min, lucifuge is simultaneously vibrated frequently, by flow cytometer, Apoptosis situation of the detection compound 7 to induction U937 cells.Not add detection compound as a control group.
Flow cytometry analysis：Flow cytometer excitation wavelength 488nm, the passband filter for being 515nm with a wavelength Detect FITC fluorescence, filter detection PI of another wavelength more than 560nm.
As a result judge：Apoptotic cell has anti-metachromia to all dyestuff such as PI for cytoactive identification, and non-viable non-apoptotic cell is then Can not.The DNA that cell membrane has the cell of damage can dye by PI and produce red fluorescence, and the cell that cell membrane remains intact is then not Have red fluorescence generation.Therefore, Apoptosis early stage PI will not dye without red fluorescent.Normal live cells Similarly.On the scatter diagram of bivariate flow cytometer, left lower quadrant shows living cells, is (FITC-/PI-)；Upper right as Limit is non-living cell, i.e. non-viable non-apoptotic cell, is (FITC+/PI+)；And right lower quadrant is apoptotic cell, show (FITC+/PI-) (see Fig. 1).Fig. 1 result shows that, relative to control group (control), the apoptotic cell for adding the U937 cells of compound 7 is obvious Increase, and also increase with the increase apoptotic cell of compound concentration, during 24h, 5 μM, 10 μM of compound 7 induces 35% respectively With the apoptosis of 60% human leukemia U937 cell line cells.
The compound 1-27 of the present invention, also being capable of efficient induced tumor for other tumour cells such as K562, KU812 etc. Apoptosis.
Embodiment 26：Compound relies on Bax/Bak cytotoxicity experiment
Coprecipitation of calcium phosphate transfects 3 μ g Bax/Bak interference plasmids, and (Santa Bio Inc.USA Bax/Bak sequences are distinguished For GCTCTGAGCAGATCATGAA and CCCATTCACTACAGGTGAA) into U937 cells, after transfecting 24 hours, collect thin Born of the same parents, Bax/Bak protein expression situations after Western detection RNA interference, the groups of cells of same treatment plasmid-free transfection are set to compare Group.Cell after transfection is inoculated in (1 × 10 in 96 orifice plates5Individual/hole), it is parallel carry out untransfected plasmid cell group to according to the facts Test, empirically design concentration gradient adds compound 7 to be detected, and after acting on 24 hours, MTT detection cell viabilities, experiment is simultaneously MTT detects toxicity of the various concentrations compound 7 to the normal cell HEk293 cells of untransfected Bax/Bak interference plasmids, as a result As shown in Figure 2, Gossypol contrasts parallel processing as non-specific BH3 analogs and the compound of the present invention, it is seen that Gossypol does not have difference (Fig. 2A) to the toxicity of U937 cells in untransfected and transfectional cell, but the compounds of this invention 7 exists Obvious difference (death rate to U937 cells is respectively 90% and 10% or so) is shown in untransfected and transfectional cell, is said Bright compound 7 has absolute dependence Bax/Bak cytotoxicity, HEk293 cell base of the compound 7 to untransfected interference plasmid This does not show lethality (cell mortality is 10% or so during 50 μM of compound concentration) (Fig. 2 B).
Other 26 compounds are detected by above-mentioned identical test method, by contrasting detection compound effects in transfectional cell With the IC of non-transfected cells50Value changes, illustrate institute's detection compound be also respectively provided with absolute dependence Bax/Bak action character (see Table 2).And the naphthalimide of 4- amino substitution acts on the IC of transfectional cell and non-transfected cells50Value is basically unchanged, and illustrates 4- ammonia The naphthalimide of base substitution is not relying on Bax/Bak action character (being shown in Table 2).
The compounds of this invention of table 2. relies on Bax/Bak cytotoxicity experiment result
The result of table 2 shows that the toxicity for the cell that compound 1-27 of the invention is infected Bax/Bak interference plasmids is notable Less than non-transfected cells, it is known that the compounds of this invention is to rely on the realization of Bax/Bak albumen to the toxicity of the cell of cancer cell. The toxicity of cell that the naphthalimide compound of amino substitution is infected Bax/Bak interference plasmids and non-transfected cells almost phase Together, it is known that the naphthalimide compound of amino substitution is not dependent on the realization of Bax/Bak albumen to the toxicity of the cell of cancer cell 's.
The result of table 2 shows that compound 1-27 of the invention shows as 50 μM of ＞ IC to normal cell HEk29350, base This does not show lethality.The naphthalimide compound of amino substitution shows as IC to normal cell HEk29350=7.9 μM, Lethality is even above the cell to the infection of Bax/Bak interference plasmids.Confirm compound of the present invention compared to similar Killing of the naphthalimide compound of amino substitution to tumour cell has preferably specificity, and the killing to normal cell is made With small.
Embodiment 27：By running gel image checking compound in vitro with fluorescence labeling, separation, enrichment in living cells The ability of Bcl-2 and Mcl-1 albumen
10 μM of compounds 18 are separately added into experimental group and control group contains 5 μM of Bcl-2,5 μM of MDM2 and 5 μM of BSA eggs In white PBS (0.5M NaCl, 0.04M PBS), control group adds 12 50 μM of Reverse transcriptase immunomodulator compounds. Stationary incubation 2h at 4 DEG C, using 365nm ultra violet lamp 30min, experimental group and control group are then subjected to SDS-PAGE respectively Electrophoresis, fluorescence gel imaging, coomassie brilliant blue staining.
As a result as shown in Figure 3A, Bcl-2 protein bands in the experimental group of compound 18 are added to show in fluorescence imaging Fluorescence signal, and the Bcl-2 albumen of other reference proteins and addition competitive inhibitor does not show fluorescence signal (Fig. 3 A) then.Knot Fruit shows that compound 18 can selective fluorescence labeling Bcl-2 albumen in vitro.
50 μM of compounds 20 are separately added into experimental group and the MCF-7 cell lines of control group, it is same in cellular control unit system When add 200 μM of Reverse transcriptase immunomodulator compounds 12, be incubated 24h at 37 DEG C.With the new culture without compound and to change liquid clear Wash cell 3 times, then using 365nm ultra violet lamp 30min, collect cell and crack.In cell pyrolysis liquid respectively successively Add 200 μM of biotin-N3, 2.5mM sodium ascorbates, 600 μM of THPTA and 100 μM of copper sulphate.Incubated under 25 DEG C of mechanical oscillation Educate 2h, ultrafiltration is gone out unreacted biotin-N3, the sepharose 4B of marked by streptavidin is added into sample, 4 DEG C were incubated Night.Supernatant is removed, sepharose 4B is washed 3 times with PBS, is added 1X SDS loading buffer and is boiled sample, then will Experimental group and control group carry out SDS-PAGE electrophoresis, silver staining and gel imaging respectively.
As a result as shown in Figure 3 B, the experimental group for adding compound 20 contains Bcl-2 albumen and Mcl-1 in gel imaging figure Band, and it is practically free of the band of other albumen.After adding competitive inhibitor, Bcl-2 albumen in gel imaging figure and Mcl-1 bands shoal (Fig. 3 B).As a result show that compound 20 can apply to separation selective in the cell and enrichment Bcl-2 Family protein.
The compound 17-23 of the present invention can selective fluorescence labeling and separation selective in the cell in vitro With enrichment Bcl-2 family proteins.
Embodiment 28：Bcl-2 and Mcl-1 albumen is regulated and controled in living cells by Western blot detection compound 24,26 Horizontal ability
MCF-7 cells 24h is handled at 25 DEG C respectively with 10 μM of compounds 24,26 and pure DMSO respectively.It is thin using 150 μ l Cellular lysate liquid cracks 5*106 tumour cell.After lysate ice bath 30min cracking completely, 4 DEG C, 12000rpm centrifugation 30min, Take supernatant to produce total protein, protein quantification is carried out using Bradford methods, determines protein concentration.Corresponding amount is added in total protein 5X Loading Buffer, 100 DEG C of boiling water boiling 5min, make protein sample be denatured completely, and -20 DEG C of preservations are stand-by；
Total protein (l00 μ g) is taken to be separated by electrophoresis by SDS-PAGE, by the gel after separation with wet robin by albumen Electricity is gone on pvdf membrane；Then, pvdf membrane 2h is closed using 5% skimmed milk power room temperature；After closing, add respectively on pvdf membrane Enter corresponding slow shake of BCL-2, MCL-1,4 DEG C of primary antibody to stay overnight, incubation finishes, and is washed 3 times with PBS, adds corresponding secondary antibody, and room temperature is slow Shake and be incubated 2h, incubation finishes, then is washed 3 times with PBS, finally, is incubated with SuperSignalWest Femto chemical illuminating reagents 5min, it is exposed.
As a result as shown in figure 4, the experimental group for adding compound 24 and 26 contains Bcl-2 albumen and Mcl-1 in image Band substantially shoals (Fig. 4) compared to control group.As a result show that compound 24 and 26 can degradation selectivity Bcl-2 in the cell With Mcl-1 albumen, so as in living cells regulate and control Bcl-2 family proteins level.

Claims (14)

1. sulphur/oxo naphthoyl imide compounds, there is formula I structure：
Wherein：
R1The phenyl arbitrarily substituted selected from phenyl or by following radicals：OH、OCH3、I、Br、Cl、NO2、NHCH3、N(CH3)2、CN、 Phenyl or C1-4Alkyl；
X is selected from S or O；
R2Selected from H, R3、ZR3, piperidyl, piperidone base, piperidine dione base, pyrrolidinyl, pyrrolidone-base, pyrrolidine-diones Base, C1-6Alkyl or substitution C1-6Alkyl；
Described R3Selected from substituted or unsubstituted phenyl, naphthyl, benzofuranyl, thienyl or indyl, (phenyl or take For phenyl, naphthyl or substituted naphthyl, benzofuranyl or substitution benzofuranyl, thienyl or substituted thiophene, indyl or take For indyl) described in substitution be arbitrarily to be substituted by following radicals：C1-4Alkyl, C1-4Alkenyl, C1-4Alkynyl, phenyl, OH, I, Br, Cl、NO2、NHCH3、N(CH3)2、CN、CF3、COOH、SO3H、COOR6、CONHR6、SO3R6、SO2NHR6Or OR6；R therein6It is selected from C1-4Alkyl, C1-4Alkenyl, C1-4Alkynyl, phenyl, benzyl, CH2COOH or CH2CONH2, n is 1-3 integer；
Described Z is selected from (CH2)m、(CH2)mCONH、(CH2)mNHCO、(CH2)mOCO、(CH2)mNHSO2、(CH2)mOSO2、(CH2)mCONH(CH2)nO、(CH2)mNHCO(CH2)nO, carbonyl or sulfonyl, m, n are 1-3 integer；
Described substitution C1-6Alkyl is the C arbitrarily substituted by following radicals1-6Alkyl：OH、OCH3、I、Br、Cl、NO2、NH2、 NHCH3、N(CH3)2、CH(OCH3)2、CHO、CN、COOH、COOCH3、COOC2H5Or R3。
2. sulphur according to claim 1/oxo naphthoyl imide compounds, it is characterised in that described R1Selected from phenyl or The phenyl arbitrarily substituted by following radicals：Cl、Br、I、OCH3、N(CH3)2Or C1-3Alkyl.
3. sulphur according to claim 2/oxo naphthoyl imide compounds, it is characterised in that described R1Selected from phenyl, 4- chlorphenyls, 4- bromophenyls, 4- iodophenyls, 4- methoxyphenyls, 4- dimethylamino phenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 4- isopropyl phenyls.
4. sulphur according to claim 1/oxo naphthoyl imide compounds, it is characterised in that described R3Selected from phenyl, Naphthyl, indyl or the phenyl or indyl arbitrarily substituted by following radicals：C1-4Alkyl, C1-3Alkenyl, C1-3Alkynyl, COOH, OH, I, Br, Cl or OR6。
5. sulphur according to claim 4/oxo naphthoyl imide compounds, it is characterised in that described R3Selected from phenyl, Naphthyl, indyl, 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 3- isopropyl phenyls, 4- isopropyls Phenyl, 4- tert-butyl-phenyls, 2- carboxyl phenyls, 3- carboxyl phenyls, 4- carboxyl phenyls, 2- hydroxy phenyls, 3- hydroxy phenyls, 4- hydroxyls Base phenyl, 3,4,5- trihydroxies phenyl, 2- iodophenyls, 4- iodophenyls, 6- chloro-indoles base, 6- bromo indoles base, 5- methyl indol bases.
6. sulphur/oxo naphthoyl imide compounds according to claim 1 or 3, it is characterised in that described R2Selected from R3、 ZR3, piperidone base, piperidine dione base, substitution C1-6Alkyl and the C arbitrarily substituted by following radicals1-6Alkyl：CHO、COOH、 COOCH3Or COOC2H5。
7. sulphur according to claim 6/oxo naphthoyl imide compounds, it is characterised in that described R2Selected from R3、 ZR3, piperidine dione base or CHO substitution C1-6Alkyl.
8. sulphur/oxo according to claim 1 is for naphthoyl imide compounds, it is characterised in that described X is S.
9. sulphur according to claim 1/oxo naphthoyl imide compounds, is selected from：
10. the derivative of sulphur/oxo naphthoyl imide compounds, it is characterised in that be sulphur/oxo naphthalene described in claim 1 Imide analog compounds are by L-R4Or L-R5The derivative obtained after substitution；Wherein,
Described L is selected from L1~L6:
Wherein, p is 1-3 integer, and q is 1-10 integer；
Described R4Group selected from formula i~vi：
Described R5Group selected from formula vii or viii：
In formula vii, l is 2-10 integer.
11. the derivative of sulphur according to claim 10/oxo naphthoyl imide compounds, it is characterised in that described Derivative has formula ix, x, xi or xii structure：
12. the derivative of sulphur according to claim 11/oxo naphthoyl imide compounds, is selected from：
13. the answering in Bcl-2 family protein inhibitors are prepared of sulphur/oxo naphthoyl imide compounds described in claim 1 With.
14. the derivative of sulphur/oxo naphthoyl imide compounds described in claim 6 answering in functional reagent is prepared With described functional reagent is used for the identification of Bcl-2 family proteins, mark and regulation and control.
CN201710580365.XA 2017-07-17 2017-07-17 Sulphur/oxo naphthoyl imide compounds and its application Pending CN107382862A (en)

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WO2020027225A1 (en) 2018-07-31 2020-02-06 ファイメクス株式会社 Heterocyclic compound
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CN111171025A (en) * 2020-01-15 2020-05-19 四川大学华西医院 Preparation of targeted eEF2K degradation agent and application thereof in resisting breast cancer
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CN111675696A (en) * 2020-06-08 2020-09-18 西安交通大学 Light affinity probe molecule based on triazole active molecule and preparation method and application thereof
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CN113402530A (en) * 2021-06-22 2021-09-17 济南大学 Hypochlorous acid fluorescent probe with function of distinguishing cancer cells from normal cells, preparation method and application
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EP3813834A4 (en) * 2018-06-29 2022-03-09 Dana Farber Cancer Institute, Inc. New crbn modulators
WO2020027225A1 (en) 2018-07-31 2020-02-06 ファイメクス株式会社 Heterocyclic compound
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CN109400530A (en) * 2018-12-05 2019-03-01 安庆北化大科技园有限公司 Suitable for the naphthalimide aromatic sulfide type photoinitiator and preparation method of UV-LED photocuring and application
CN109400530B (en) * 2018-12-05 2022-04-12 安庆北化大科技园有限公司 Naphthalimide aryl thioether type photoinitiator suitable for UV-LED photocuring, and preparation method and application thereof
WO2020151229A1 (en) * 2019-01-26 2020-07-30 中国药科大学 Proteolysis targeting chimeric molecule, preparation method, and application
CN112010838A (en) * 2019-05-31 2020-12-01 中国科学院化学研究所 Naphthalimide-indole derivative-based intracellular reticulum fluorescent probe and application thereof
CN112010838B (en) * 2019-05-31 2021-07-13 中国科学院化学研究所 Naphthalimide-indole derivative-based intracellular reticulum fluorescent probe and application thereof
CN112125885A (en) * 2019-06-25 2020-12-25 中国药科大学 Benzoindole bifunctional molecular derivative and preparation method and application thereof
CN110804039A (en) * 2019-11-13 2020-02-18 大连理工大学 Phthalimide-containing 1, 8-naphthalic anhydride derivatives, pharmaceutically acceptable salts thereof and application of anti-tumor drugs thereof
CN111171025A (en) * 2020-01-15 2020-05-19 四川大学华西医院 Preparation of targeted eEF2K degradation agent and application thereof in resisting breast cancer
CN111675696A (en) * 2020-06-08 2020-09-18 西安交通大学 Light affinity probe molecule based on triazole active molecule and preparation method and application thereof
CN113402530A (en) * 2021-06-22 2021-09-17 济南大学 Hypochlorous acid fluorescent probe with function of distinguishing cancer cells from normal cells, preparation method and application

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