CN102911117B

CN102911117B - Naphthylamine derivative and purpose thereof

Info

Publication number: CN102911117B
Application number: CN201210430633.7A
Authority: CN
Inventors: 郭朋; 刘田; 陈琦; 徐林; 杨青; 钱旭红
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2012-11-01
Filing date: 2012-11-01
Publication date: 2014-08-20
Anticipated expiration: 2032-11-01
Also published as: CN102911117A

Abstract

The inventor of the invention utilizes the medicinal chemical principle to design and synthetize a series of novel naphthylamine derivatives, and performs an inhibitory activity test of the kind of derivative on human N-acetyl amino glycosidase. The test result shows that the inhibitory activity effect is good, and the inhibition effect of some compounds is obviously higher than that of reference compounds reported in literatures. According to the invention, the naphthylamine derivative is free of a glycosyl structure; and the synthesis method is relatively simpler. Therefore, the naphthylamine derivative lays foundation for the development of new medicines used for curing illness relative to human Beta-N-acetyl amino glycosidase.

Description

Naphthalimide derivative and uses thereof

Technical field

The present invention relates to a kind of naphthalimide derivative and uses thereof (as the application of mankind's beta-N-acetylhexosaminidase inhibitor).

Background technology

Carbohydrate is brought into play critical function in vivo, not only in energy metabolism, occupies core status, and participate in comprising maintain that organism structure is complete, multiple physiology and the pathologic process such as the diffusion of cell recognition, signal conduction, inflammatory reaction and cancer cells.The physiological process participating in due to carbohydrate is so complicated, and therefore, the enzyme that participates in carbohydrate metabolic process is also of a great variety.The enzyme of the participation carbohydrate hydrolysis up to the present, having been found that just adheres to 114 families separately.

Beta-N-acetylhexosaminidase (β-N-acetyl-D-hexosaminidase, EC3.2.1.52) in the mankind and Mammals lysosome participates in the hydrolysis of glycosylation part in multiple saccharide complex.Human body contains 3 kinds of beta-N-acetylhexosaminidases, is all the dimers that are made up of α-subunit and β-subunit.Wherein, beta-N-acetylhexosaminidase A is by a α-subunit and a different poly-binary that β-subunit forms.Beta-N-acetylhexosaminidase is the enzyme of being responsible for being hydrolyzed the N-acetylhexosamine that is positioned at various saccharide complex non-reducing ends.Because this enzyme is widely distributed and participate in much important physiology and pathologic process in organism, therefore always by different field investigators are paid close attention to, the physiology that hope participates in this enzyme by the adjusting realization to this enzyme activity or the regulation and control of pathologic process.There is certain difference in beta-N-acetylhexosaminidase, therefore, completely likely utilizes the inhibitor of these difference design alternatives aspect physiological distribution, structure and catalytic mechanism, to reach the object of particular physiological function in regulation and control organism.

This enzyme is at the auxiliary lower hydrolysis physiology substrate Ganglioside GM2 of GM2 activator, and this physiological process is most important for human health.The sudden change of associated protein can cause the accumulation of Sphingolipids,sialo in neurone lysosome, causes serious gangliosidosis, as Tay-Sachs disease and Sandhoff disease etc.

Although this class disease sickness rate is low, but very large to the destructiveness of human body, the research of drug molecule companion in this class disease is more. and the drug molecule companion of sudden change lysosomal enzyme is generally the competitive inhibitor of this fermentoid, can be incorporated into active centre with mutant enzyme, assist it correctly folding in endoplasmic reticulum, thereby avoid degradation pathway, correctly be transported to lysosome, there is the metabolism substrate of high density in lysosome, be at war with the drug molecule that is incorporated into mutant enzyme, zymoprotein and drug molecule are dissociated, act on eubolism substrate.

Adopt drug molecule companion to treat lysosomal storage disease, its application prospect is very wide. and drug molecule companion therapy is by oral lysosomal enzyme inhibitor, directly recover the function of endogenous lysosomal enzyme, and drug molecule can pass through hemato encephalic barrier treatment central nervous system relevant store up disease, easier than existing other treatment method (as: enzyme replacement treatment and substrate reduce therapy), be more suitable for long-term treatment.Enzyme strengthens therapy and is attempted being used for the treatment of multiple inherited disease.Often only need to recover the enzyme activity of 5-10% and just can cure because many lysosomes store up disease, therefore be considered to more potential.

So far, the human amino hexoside enzyme inhibitors of reporting is all the structure based on glycosyl, in structure of modification and actual application, may run into a lot of problems, therefore has investigator exploring aspect the non-glycosyl inhibition agent of screening.The people such as Tropak utilize the method for high flux screening to obtain several not brand-new inhibitor structures based on glycosyl, and wherein a kind of inhibition of bisnaphthalimides is best, but because its clinical toxicity is larger, can not be used for the treatment of research.

Given this, the exploitation of the novel human hexosaminidase inhibitor based on non-glycosyl and initiative just seem very necessary.

Summary of the invention

The present inventor uses pharmaceutical chemistry principle, has designed and synthesized the naphthalimide derivative of series of novel, and do the inhibition active testing of this analog derivative to mankind's N-acetyl hexosaminidase, test result shows: the naphthalimide analog derivative that the present invention designs and invents demonstrates good inhibition activity to mankind's N-acetyl hexosaminidase, and part of compounds inhibition is apparently higher than the control compound of bibliographical information.Due to the not sugary based structures of naphthalimide derivative that the present invention designs and synthesizes, its synthetic method is relatively simple, and thus, the new drug initiative that is used for the treatment of the disease relevant to mankind's beta-N-acetylhexosaminidase for exploitation is laid a good foundation.

One object of the present invention is, a kind of naphthalimide derivative of novelty is provided, and described naphthalimide derivative is compound shown in formula I, or it is at pharmacologically acceptable salts:

In formula I, R ¹for hydrogen (H), C ₁～C ₄alkoxyl group, C ₁～C ₄alkyl replace amino ( r ³and R ⁴independently be selected from respectively C ₁～C ₄a kind of in alkyl), or halogen (F, Cl, Br or I);

R ²for hydrogen (H), hydroxyl (OH) or amino (NH ₂) replace C ₁～C ₄alkyl, or group shown in formula II:

In formula II, X is O, S, and NH, or m is 0～6 integer; N is 0 or 1;

A is phenyl, substituted-phenyl, and the nitrogenous quinary heterocyclic radical (specifically seeing group shown in formula III or formula IV) of nitrogenous quinary heterocyclic radical or replacement:

Wherein, R ⁵～R ⁹independently be selected from respectively: H, C ₁～C ₄alkoxyl group, C ₁～C ₄fluoroalkoxy, halogen (F, Cl, Br or I), nitro (NO ₂) or formic acid carbalkoxy (as: COOCH ₃(methyl-formiate base) etc.) middle a kind of, or R ⁵～R ⁹two of middle arbitrary neighborhoods be combined as divalence phenyl or (described divalence phenyl or with female ring phenyl be the relation of " also "), all the other are H,

R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C ₁～C ₄phenyl or naphthyl (phenyl of described divalence, C that alkoxyl group replaces ₁～C ₄phenyl or naphthyl and the nitrogenous five-membered ring (female ring) that alkoxyl group replaces is the relation of " also "), all the other are and R ¹⁰～R ¹³in have at least one to be

Another object of the present invention is, disclose a kind of purposes of above-mentioned naphthalimide derivative (compound shown in formula I or its at pharmacologically acceptable salts), be the application of naphthalimide derivative provided by the present invention in the medicine for the preparation of the treatment disease relevant to mankind's beta-N-acetylhexosaminidase, in other words, naphthalimide derivative provided by the present invention is as the application of mankind's beta-N-acetylhexosaminidase inhibitor.

Embodiment

In preferred technical scheme of the present invention, R ¹for H, C ₁～C ₂alkoxyl group, Cl, Br, I or wherein R ³independently be selected from respectively C with R4 ₁～C ₂a kind of in alkyl;

Preferred technical scheme is: R ¹for H, methoxyl group (CH ₃o-) amino (N (CH that, Br or dimethyl replace ₃) ₂).

In another preferred technical scheme of the present invention, R ²for H, or hydroxyl (OH) or amino (NH ₂) replace C ₁～C ₂alkyl.

In a further preferred technical solution of the present invention, R ²for group shown in formula II, and A is group shown in formula III,

Wherein R ⁵～R ⁹independently be selected from respectively: H, C ₁～C ₂alkoxyl group, C ₁～C ₂fluoroalkoxy, halogen (F, Cl, Br or I), nitro (NO ₂) or-COOCH ₃middle one,

Or

In R5～R9 two of arbitrary neighborhoods be combined as divalence phenyl or (described divalence phenyl or with female ring phenyl be the relation of " also "), all the other are H;

Preferred technical scheme is: R ²for group shown in formula II, and A is group shown in formula III,

Wherein R ⁵～R ⁹independently be selected from respectively: H, methoxyl group, trifluoromethoxy, Cl ,-NO ₂or-COOCH ₃middle one, or

R ⁵～R ⁹two of middle arbitrary neighborhoods be combined as divalence phenyl or (described divalence phenyl or with female ring phenyl be the relation of " also "), all the other are H.

In a further preferred technical solution of the present invention, R ²for group shown in formula II, and A is group shown in formula IV,

Wherein R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C ₁～C ₂phenyl or naphthyl (phenyl of described divalence, C that alkoxyl group replaces ₁～C ₂phenyl or naphthyl and the nitrogenous five-membered ring (female ring) that alkoxyl group replaces is the relation of " also "), all the other are and R ¹⁰～R ¹³in have at least one to be

Preferred technical scheme is: R ²for group shown in formula II, and A is group shown in formula IV,

Wherein R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, the phenyl or naphthyl (relation that the phenyl of described divalence, the phenyl or naphthyl of methoxy substitution and nitrogenous five-membered ring (female ring) are " also ") of methoxy substitution, all the other are and R ¹⁰～R ¹³in have at least one to be

In another preferred technical scheme of the present invention, m is 0,1,2 or 3.

In sum, the R that the present invention recommends ²be selected from following groups a kind of:

In addition, the present invention also provides the method for compound shown in a kind of preparation formula I, its key step (synthesis strategy) is: with 1,8-naphthalene acid anhydride or derivatives thereof (compound shown in formula V) is raw material, by compound shown in formula V with corresponding amine through sub-amidate action, obtain one of target compound (brief note is A series compound); The compound in A series compound with terminal amino group is carried out to alkane amination reaction with a series of compounds with end alkyl bromine again, or form azomethine with a series of benzaldehyde compounds, two (brief note is B series compound) that obtain target compound through reduction, concrete steps are referring to appended embodiment.

The present invention is further elaborated by the following examples, and these embodiment are only for illustrating the present invention and understanding better content of the present invention, the protection domain that it does not limit the present invention in any way.

Embodiment 1

2-(2-amino-ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (Al) synthetic

In 25mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (2g, 10.1mmol), 50mL dehydrated alcohol and quadrol (1.35mL, 20.2mmol), mixture heating reflux reaction 2 hours, after completion of the reaction, reduction vaporization falls solvent and excessive quadrol, and thick product obtains faint yellow solid product A 1 (1.8g), productive rate 74% with dehydrated alcohol recrystallization.

Fusing point: 141-142 DEG C.

¹h NMR (400MHz, DMSO-d ₆): δ=8.34 (d, J=7.6Hz, 2H), 8.31 (d, J=8.0Hz, 2H), 7.75 (dd, J=8.0,7.6Hz, 2H), 4.01 (t, J=6.8Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.62ppm (br, 2H); ¹³cNMR (100MHz, DMSO-d ₆): δ=163.9,134.4,131.5,130.9,127.7,127.4,122.4,43.2,40.2ppm; HRMS-ESI (m/z): calculated value: C ₁₄h ₁₃n ₂o ₂[M+H] ⁺, 241.0977; Experimental value, 241.0978.

Embodiment 2

2-(2-((2-hydroxyethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A2) synthetic

In 25mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (198mg, 1.00mmol), 10mL dehydrated alcohol and hydroxyethylethylene diamine (140mg, 1.00mmol), mixture heating reflux reaction 2 hours, after completion of the reaction, reduction vaporization falls solvent, and thick product obtains white solid product A2 (241mg), productive rate 85% with dehydrated alcohol recrystallization.

¹H?NMR(CDCl ₃，400MHz)：δ＝8.55(d，J＝7.2Hz，2H)，8.17(d，J＝8.0Hz，2H)，7.71(dd，J＝8.0，7.2Hz，2H)，4.32(t，J＝6.0Hz，2H)，3.61(t，J＝4.4Hz，2H)，3.02(t，J＝6.0Hz，2H)，2.84(t，J＝4.4Hz，2H)，2.2ppm(br，2H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝164.5，134.0，131.5，131.3，128.1，126.9，122.5，61.0，50.9，47.4，40.1ppm.EI?MS(m/e)：285.4(M+1，100).

Embodiment 3

2-(2-((2-amino-ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A3) synthetic

In 50mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (198mg, 1.0mmol), 20mL dehydrated alcohol and 2mL diethylenetriamine (excessive), mixture heating reflux reaction 2 hours, after completion of the reaction, filter, collect filtrate, reduction vaporization falls solvent, washing, uses dichloromethane extraction three times, collected organic layer, reduction vaporization falls solvent, obtain white solid, thick product obtains white solid product A3 (189mg), productive rate 67% with dehydrated alcohol recrystallization.

¹H?NMR(CDCl ₃，400MHz)：δ＝8.54(d，J＝6.8Hz，2H)，8.17(d，J＝8.0Hz，4H)，7.71(t，J＝7.6Hz，2H)，4.32(t，J＝6.0Hz，2H)，3.01(t，J＝6.4Hz，2H)，2.77ppm(s，4H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝164.0，133.6，131.2，130.9，127.8，126.6，122.2，51.8，47.2，41.4，39.7ppm.EIMS(m/e)：284.6(M+1，100).

Embodiment 4

2-(2-amino-ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A4) synthetic

The quadrol (165mg, 1.0mmol) of monolateral Boc protection joins 4-nitro-1, in the 10mL ethanolic soln of 8-naphthalene acid anhydride (125mg, 0.5mmol).This mixture return stirring 3 hours, raw material dissolves completely.Question response liquid is down to room temperature, filters, and filtration cakes torrefaction obtains yellow solid 200mg, productive rate 100%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.83(d，J＝8.0Hz，1H)，8.74(d，J＝8.0Hz，1H)，8.70(d，J＝8.0Hz，1H)，8.41(d，J＝8.0Hz，1H)，7.99(dd，J＝8.0，8.0Hz，1H)，4.93(br，1H)，4.38(t，J＝5.6Hz，2H)，3.50-3.60(m，2H)，1.25(s，9H)； ¹³C?NMR(100MHz，CDCl3)：δ＝163.6，162.8，156.1，149.6，132.5，129.9，129.8，129.3，129.2，126.9，123.8，123.7，122.9，79.3，40.5，39.2，28.2ppm.

Getting above-mentioned yellow solid (50mg, 130 μ mol) is mixed in 15mL methyl alcohol and 2mLDMF with salt of wormwood (100mg, 725 μ mol).This mixture is heated to 60 DEG C, stirs 4 hours.Suction filtration while hot, filtrate decompression evaporate to dryness.Thick product silica gel column chromatography (elutriant: DCM) separates and obtains solid 30mg, productive rate 62%.

2mL trifluoroacetic acid joins in the 10mL dichloromethane solution of above-mentioned solid (30mg, 81 μ mol), and stirring at room temperature is after 4 hours, and removal of solvent under reduced pressure obtains light green solid (A4) 22mg, fusing point: 205-206 DEG C, productive rate 100%.

¹h NMR (400MHz, DMSO-d ₆): δ=8.54 (dd, J=1.2,8.4Hz, 1H), 8.49 (dd, J=1.2,7.6Hz, 1H), 8.44 (d, J=8.4Hz, 1H), 7.95 (br, 2H), 7.82 (dd, J=7.6,8.4Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 4.30 (t, J=6.0Hz, 2H), 4.14 (s, 3H), 3.16 (t, J=6.0Hz, 2H); ¹³c NMR (100MHz, DMSO-d ₆): δ=164.7,163.9,160.9,133.7,131.4,129.2,128.8,126.8,123.2,122.6,114.9,106.7,57.1,38.1,37.8ppm; HRMS-ESI (m/z): calculated value C ₁₅h ₁₅n ₂o ₃[M+H] ⁺, 271.1083; Experimental value, 271.1092.

Embodiment 5

2-(2-amino-ethyl)-6-dimethyl amido-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A5) synthetic

The quadrol (165mg, 1.0mmol) of monolateral Boc protection joins 4-nitro-1, in the 10mL ethanolic soln of 8-naphthalene acid anhydride (125mg, 0.5mmo1).This mixture return stirring 3 hours, raw material dissolves completely.Question response liquid is down to room temperature, filters, and filtration cakes torrefaction obtains yellow solid 200mg, productive rate 100%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.83(d，J＝8.0Hz，1H)，8.74(d，J＝8.0Hz，1H)，8.70(d，J＝8.0Hz，1H)，8.41(d，J＝8.0Hz，1H)，7.99(dd，J＝8.0，8.0Hz，1H)，4.93(br，1H)，4.38(t，J＝5.6Hz，2H)，3.50-3.60(m，2H)，1.25(s，9H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝163.6，162.8，156.1，149.6，132.5，129.9，129.8，129.3，129.2，126.9，123.8，123.7，122.9，79.3，40.5，39.2，28.2pp?m.

Get in the mixing solutions that above-mentioned yellow solid (50mg, 130 μ mol) joins 2mL DMF and 10mL 40% dimethylamine agueous solution composition.This mixture stirring at room temperature is after 12 hours, and all solvents are removed in decompression.Thick product silica gel column chromatography (elutriant: methylene chloride/methanol 40: 1 (v/v)) separates and obtains solid 30mg, productive rate: 60%.

2mL trifluoroacetic acid joins in the 10mL dichloromethane solution of above-mentioned solid (30mg, 80 μ mol), and stirring at room temperature is after 4 hours, and removal of solvent under reduced pressure obtains orange solid (A5) 22mg, fusing point: 172-174 DEG C, productive rate 99%.

¹H?NMR(400MHz，DMSO-d ₆)：δ＝8.53(d，J＝8.4Hz，1H)，8.46(d，J＝7.6Hz，1H)，8.34(d，J＝8.0Hz，1H)，7.99(br，2H)，7.75(dd，J＝7.6，8.4Hz，1H)，7.22(d，J＝8.0Hz，1H)，4.30(t，J＝6.0Hz，2H)，3.15(t，J＝6.0Hz，2H)，3.11(s，3H)，3.09ppm(s，3H)；

¹³c NMR (100MHz, DMSO-d ₆): δ=164.8,164.0,157.2,132.7,132.1,131.0,130.3,125.4,124.6,123.0,113.9,113.3,44.9,38.2,37.7ppm; HRMS-ESI (m/z): calculated value C ₁₆h ₁₈n ₃o ₂[M+H] ⁺, 284.1399; Experimental value, 284.1399.

Embodiment 6

2-(2-amino-ethyl) the bromo-1H-benzo of-6-[de] isoquinoline 99.9-1,3 (2H)-diketone (A6) synthetic

Divided by 4-nitro-1,1 in 8-naphthalene acid anhydride alternative embodiment 1, outside 8-naphthalene acid anhydride, other condition and step are identical with embodiment 1, obtain compd A 6, white solid, fusing point: 151-152 DEG C, productive rate 70%.

¹h NMR (400MHz, DMSO-d ₆): δ=8.53 (d, J=8.4Hz, 1H), 8.49 (d, J=7.6Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 8.18 (d, J=8.0Hz, 1H), 7.96 (dd, J=7.6,8.4Hz, 1H), 4.07 (t, J=6.8Hz, 2H), 2.85 (t, J=6.8Hz, 2H), 2.51ppm (br, 2H); ¹³c NMR (100MHz, DMSO-d6): δ=163.6,163.5,132.9,131.9,131.8,131.3,130.2,129.4,129.2,128.8,123.4,122.6,42.9,39.9ppm; HRMS-ESI (m/z): calculated value C ₁₄h ₁₂n ₂o ₂br[M+H] ⁺, 319.0082; Experimental value, 319.0079.

Embodiment 7

2-(2-((2-(4-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B1) synthetic

In 50mL round-bottomed flask, add successively compd A 1 (450mg; 1.87mmol); 20mL acetonitrile; 1-(2-bromine oxethyl)-4-anisole (430mg; 1.87mmol) and salt of wormwood (530mg; 3.75mmol), under argon shield, back flow reaction 12 hours.After completion of the reaction, cooling, filter removal of solvent under reduced pressure, thick product silica gel column chromatography (CH ₂cl ₂/ CH ₃oH, 30: 1, v/v) obtain faint yellow solid product B 1 (400mg), fusing point: 107-109 DEG C, productive rate 54%.

¹h NMR (400MHz, CDCl ₃): δ=8.61 (d, J=7.6Hz, 2H), 8.22 (d, J=8.0Hz, 2H), 7.77 (dd, J=7.6,8.0Hz, 2H), 6.86-6.76 (m, 4H), 4.40 (t, J=6.4Hz, 2H), 4.03 (t, J=5.2Hz, 2H), 3.77 (s, 3H), 3.16-3.06 (m, 4H), 1.97ppm (br, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=164.0,153.7,152.9,133.7,131.3,127.8,126.7,122.3,115.4,114.5,68.0,55.6,48.6,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₃n ₂o ₄[M+H] ⁺, 391.1658; Experimental value, 391.1656.

Embodiment 8

2-(2-((2-(3-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B2) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-3-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 2), fusing point 79-80 DEG C, productive rate 50%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.58(d，J＝7.2Hz，2H)，8.19(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，7.13(t，J＝8.0Hz，1H)，6.52-6.42(m，3H)，4.37(t，J＝6.4Hz，2H)，4.05(t，J＝5.2Hz，2H)，3.77(s，3H)，3.14-3.06(m，4H)，1.93ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,160.7,160.1,133.9,131.6,131.2,129.8,128.2,126.9,122.6,106.6,106.5,100.9,67.3,55.2,48.5,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₃n ₂o ₄[M+H] ⁺, 391.1658; Experimental value, 391.1654.

Embodiment 9

2-(2-((2-(2-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B3) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-2-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 3), fusing point 116-118 DEG C, productive rate 65%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.56(d，J＝7.6Hz，2H)，8.17(d，J＝8.0Hz，2H)，7.72(dd，J＝7.6，8.0Hz，2H)，6.88(m，4H)，4.36(t，J＝6.8Hz，2H)，4.12(t，J＝5.2Hz，2H)，3.81(s，3H)，3.13(t，J＝5.2Hz，2H)，3.08(t，J＝6.8Hz，2H)，1.89ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.3,149.7,148.4,133.9,131.5,131.2,128.1,128.9,122.6,121.4,120.8,114.1,111.9,68.8,56.8,48.5,47.4,40.0ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₃n ₂o ₄[M+H] ⁺, 391.1658; Experimental value, 391.1653.

Embodiment 10

2-(2-((2-(4-anisole sulfenyl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B4) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine ethylmercapto group)-4-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 4), productive rate 55%.

¹h NMR (400MHz, CDCl ₃): δ=8.61 (d, J=7.2Hz, 2H), 8.22 (d, J=8.4Hz, 2H), 7.77 (dd, J=7.2,8.4Hz, 2H), 7.35 (d, J=8.8Hz, 2H), 6.81 (d, J=8.8Hz, 2H), 4.34 (t, J=6.4Hz, 2H), 3.79 (s, 3H), 3.01 (t, J=6.4Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 2.88 (t, J=6.0Hz, 2H), 1.85ppm (br, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=164.2,158.9,133.8,133.3,131.4,131.1,128.0,126.8,125.8,122.5,114.5,55.3,48.0,47.1,40.0,36.0ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₃n ₂o ₃s[M+H] ⁺, 407.1429; Experimental value, 407.1429.

Embodiment 11

2-(2-((3-(4-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B5) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine propoxy-)-4-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 5), fusing point 110-111 DEG C, productive rate 72%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.59(d，J＝7.6Hz，2H)，8.21(d，J＝8.0Hz，2H)，6.78(m，4H)，4.38(t，J＝6.4Hz，2H)，3.97(t，J＝6.4Hz，2H)，3.77(s，3H)，3.05(t，J＝6.4Hz，2H)，2.90(t，J＝6.4Hz，2H)，1.96(tt，J＝6.4，6.4Hz，2H)，1.75ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,153.6,153.1,134.0,131.6,131.3,128.2,126.9,122.6,115.3,114.5,67.0,55.7,47.7,46.7,40.0,29.7ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₅n ₂o ₄[M+H] ⁺, 405.1814; Experimental value, 405.1812.

Embodiment 12

2-(2-((3-(3-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B6) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine propoxy-)-3-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compound B-26), fusing point: 85-86 DEG C, productive rate 70%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.57(d，J＝7.6Hz，2H)，8.19(d，J＝8.4Hz，2H)，7.73(dd，J＝7.6，8.4Hz，2H)，7.12(dd，J＝7.6，8.0Hz，1H)，6.50-6.42(m，3H)，4.36(t，J＝6.4Hz，2H)，4.00(t，J＝6.4Hz，2H)，3.76(s，3H)，3.05(t，J＝6.4Hz，2H)，2.90(t，J＝6.8Hz，2H)，1.96(dt，J＝6.4，6.8Hz，2H)，1.54ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,160.8,160.2,133.9,131.6,131.2,129.7,128.2,126.9,122.6,106.6,106.3,100.9,66.3,55.2,47.7,46.6,40.0,29.7ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₅n ₂o ₄[M+H] ⁺, 405.1814; Experimental value, 405.1818.

Embodiment 13

2-(2-((3-(4-anisole sulfenyl) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B7) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine rosickyite base)-4-anisole alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 7), fusing point: 97-98 DEG C, productive rate 65%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.56(d，J＝7.6Hz，2H)，8.18(d，J＝8.0Hz，2H)，7.72(dd，J＝7.6，8.0Hz，2H)，7.30(d，J＝8.8Hz，2H)，6.80(d，J＝8.8Hz，2H)，4.31(t，J＝6.4Hz，2H)，3.77(s，3H)，2.98(t，J＝6.4Hz，2H)，2.84(t，7.2Hz，2H)，2.78(t，J＝6.8Hz，2H)，1.74(dt，J＝6.8，7.2Hz，2H)，1.35ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.3,158.7,133.9,133.0,131.5,131.2,128.1,126.9,126.6,122.6,114.5,55.3,48.3,47.740.0,33.5,29.7ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₅n ₂o ₃s[M+H] ⁺, 421.1586; Experimental value 421.1583.

Embodiment 14

2-(2-((2-(benzo [d] [1,3] methylene-dioxy-5-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B8) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in Compound C 1 alternative embodiment 7, other condition and step are identical with embodiment 7, obtain yellow solid (compd B 8), fusing point: 119-120 DEG C, productive rate 44%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.61(d，J＝7.6Hz，2H)，8.22(d，J＝8.0Hz，2H)，7.77(dd，J＝7.6，8.0Hz，2H)，6.65(d，J＝8.4Hz，1H)，6.46(d，J＝1.2Hz，1H)，6.29(dd，J＝1.2，8.4Hz，1H)，5.91(s，2H)，4.39(t，J＝6.4Hz，2H)，3.99(t，J＝5.2Hz，2H)，3.18-.3.00(m，4H)，1.92ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,154.3,148.1,141.6,134.0,131.6,131.3,128.2,126.9,122.6,107.8,105.6,101.1,98.1,68.2,48.5,47.4 39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₁n ₂o ₅[M+H] ⁺, 405.1450; Experimental value 405.1455.

Embodiment 15

2-(2-((2-(3,4-dimethoxy phenoxy group) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B9) synthetic

Divided by 1-(2-bromine oxethyl)-3, beyond 1-in 4-dimethoxy benzene alternative embodiment 7 (2-bromine oxethyl)-4-anisole, other condition and step are identical with embodiment 7, obtain yellow solid (compd B 9), fusing point: 119-121 DEG C, productive rate 45%. ¹h NMR (400MHz, CDCl ₃): δ=8.59 (d, J=7.6Hz, 2H), 8.20 (d, J=8.0Hz, 2H), 7.74 (dd, J=7.6,8.0Hz, 2H), 6.73 (d, J=8.8Hz, 1H), 6.51 (d, J=2.4Hz, 1H), 6.37 (dd, J=2.4,8.8Hz, 1H), 4.40 (t, J=6.4Hz, 2H), 4.04 (t, J=5.2Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.15-3.08 (m, 4H), 2.39 (br, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=164.4,153.5,149.8,143.6,133.9,131.6,131.2,128.2,126.9,122.6,111.9,103.9,101.0,67.8,56.5,55.8,48.5,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₅n ₂o ₅[M+H] ⁺, 421.1763; Experimental value 421.1760.

Embodiment 16

2-(2-((2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B10) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-Trifluoromethyl phenyl ether alternative embodiment 7, other condition and step are identical with embodiment 7, obtain yellow solid (compound B-11 0), fusing point: 93-94 DEG C, productive rate 50%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.62(d，J＝7.6Hz，2H)，8.23(d，J＝8.4Hz，2H)，7.77(dd，J＝7.6，8.4Hz，2H)，7.10(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，2H)，4.40(t，J＝6.4Hz，2H)，4.05(t，J＝5.2Hz，2H)，3.15-3.05(m，4H)，1.90ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,157.4,142.7,134.0,131.6,131.3,128.2,126.9,122.6,122.3,115.3,67.9,48.3,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₀n ₂o ₄f ₃[M+H] ⁺, 445.1375; Experimental value 445.1375.

Embodiment 17

Synthesizing of 4-(2-((2-(1,3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) oxyethyl group) methyl benzoate (B11)

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-methyl-formiate base benzene alternative embodiment 7, other condition and step are identical with embodiment 7, obtain white solid (compound B-11 1), fusing point: 107-109 DEG C, productive rate 53%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.61(d，J＝8.0Hz，2H)，8.22(d，J＝8.4Hz，2H)，7.93(d，J＝7.2Hz，2H)，7.75(dd，J＝8.0，8.4Hz，2H)，6.87(d，J＝8.4Hz，2H)，4.39(t，J＝6.4Hz，2H)，4.12(t，J＝5.2Hz，2H)，3.89(s，3H)，3.15-3.08(m，4H)，1.94(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=166.8,164.4,162.6,134.0,131.6,131.5,131.3,128.2,126.9,122.6,114.1,67.5,51.8,48.2,47.4,39.8ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₃n ₂o ₅[M+H] ⁺, 419.1607; Experimental value 419.1607.

Embodiment 18

2-(2-((2-(4-chlorophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B12) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-chlorobenzene alternative embodiment 7, other condition and step are identical with embodiment 7, obtain yellow solid (compound B-11 2), fusing point: 106-107 DEG C.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.58(d，J＝7.2Hz，2H)，8.20(d，J＝8.4Hz，2H)，7.74(dd，J＝7.2，8.4Hz，2H)，7.16(d，J＝8.8Hz，2H)，6.77(d，J＝8.8Hz，2H)，4.37(t，J＝6.4Hz，2H)，4.01(t，J＝5.2Hz，2H)，3.11-3.05(m，4H)，1.77ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,157.5,134.0,131.6,131.2,129.2,128.2,126.9,125.5,122.6,115.7,67.7,48.3,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₂h ₁₀n ₂o ₃cl[M+H] ⁺, 395.1162; Experimental value 395.1154.

Embodiment 19

2-(2-((2-(4-nitrophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B13) synthetic

beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-oil of mirbane alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compound B-11 3), fusing point: 158-160 DEG C, productive rate 60%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.59(d，J＝7.6Hz，2H)，8.22(d，J＝8.4Hz，2H)，8.11(d，J＝9.2Hz，2H)，7.76(dd，J＝7.6，8.4Hz，2H)，6.89(d，J＝9.2Hz，2H)，4.38(t，J＝6.4Hz，2H)，4.13(t，J＝5.2Hz，2H)，3.16-3.08(m，4H)，1.69ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,163.9,141.4,134.0,131.6,131.3,128.2,126.9,125.8,122.5,114.4,68.4,48.0,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₂h ₂₀n ₃o ₅[M+H] ⁺, 406.1403; Experimental value 406.1404.

Embodiment 20

2-(2-((2-((4-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B14) synthetic

In 25mL round-bottomed flask, add successively the bromo-4-anisole of 1-(5g, 26.7mmol), cuprous iodide (510mg, 2.7mmol), L-PROLINE (615mg, 5.4mmol) and salt of wormwood (7.4g, 53.5mmol), oxyethylamine (4.8mL, 80.2mmol) and DMSO (20mL).After degassed, under this mixture argon shield, 60 DEG C stir 24 hours complete to raw material reaction.Reactant imports in 100mL water, ethyl acetate (100mL) extraction three times.Organic phase merges, and dry, evaporated under reduced pressure obtains thick product.Separate (CH through silica gel column chromatography ₂cl ₂/ CH ₃oH, 30: 1, v/v) obtain red oil (3.5g), productive rate 78%.

Under room temperature, Tetrabutyl amonium bromide is joined to 2,3-bis-chloro-5, the dichloromethane solution of 6-dicyan para benzoquinone (48mg, 2.1mmol) and triphenylphosphine (562mg, 2.1mmol).Get above-mentioned red oil (240mg, 1.4mmol) and add this mixture, solution changes scarlet into by yellow at once.After stirring at room temperature 30 minutes, the direct evaporated under reduced pressure of reaction solution, thick product silica gel column chromatography separates and obtains corresponding brominated product, yellow oil (270mg), productive rate 82%.

In 50mL round-bottomed flask, add successively compd A 1 (450mg; 1.87mmol); 20mL acetonitrile; N-(2-bromotrifluoromethane)-4-anisidine (431mg; 1.87mmol) and salt of wormwood (518mg; 3.75mmol), under argon shield, back flow reaction 12 hours.After completion of the reaction, cooling, filter removal of solvent under reduced pressure, thick product column chromatography (CH ₂cl ₂/ CH ₃oH, 30: 1, v/v) obtain 405mg red solid product (compound B-11 4), fusing point: 100-101 DEG C, productive rate 55%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.58(d，J＝7.2Hz，2H)，8.20(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，6.69(d，J＝9.2Hz，2H)，6.50(d，J＝9.2Hz，2H)，4.41(t，J＝6.4Hz，2H)，3.72(s，3H)，3.20(t，J＝6.0Hz，2H)，3.13(t，J＝6.4Hz，2H)，3.04ppm(t，J＝6.0Hz，2H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.5,152.0,142.6,134.1,134.0,131.6,131.4,131.3,128.2,126.9,126.8,122.5,119.3,114.8,114.2,113.9,55.8,48.1,47.2,43.8,39.2ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₄n ₃o ₃[M+H] ⁺, 290.1818; Experimental value, 290.1819.

Embodiment 21

2-(2-((2-((3-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B15) synthetic

Beyond the bromo-4-anisole of 1-in the bromo-3-anisole of 1-alternative embodiment 20, other condition and step are identical with embodiment 20, obtain yellow solid (compound B-11 5), fusing point: 148-149 DEG C, productive rate 70%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.60(dd，J＝0.8，7.6Hz，2H)，8.21(dd，J＝0.8，8.4Hz，2H)，7.75(dd，J＝7.6，8.4Hz，2H)，7.01(dd，J＝8.0，8.4Hz，1H)，6.23(dd，J＝2.0，8.0Hz，1H)，6.14(dd，J＝1.6，8.4Hz，1H)，6.11(dd，J＝1.6，2.0Hz，1H)，4.36(t，J＝6.4Hz，2H)，4.22(br，1H)，3.75(s，3H)，3.17(m，2H)，3.06(t，J＝6.4Hz，2H)，2.98(t，J＝5.6Hz，2H)，1.46ppm(br，1H)；

¹³c NMR (100MHz, CDCl3): δ=164.5,160.7,150.0,134.0,131.6,131.3,129.8,128.2,126.9,122.6,105.9,102.4,98.6,55.0,48.1,47.4,43.5,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₄n ₃o ₃[M+H] ⁺, 290.1818; Experimental value, 290.1819.

Embodiment 22

2-(2-((2-((2,4-Dimethoxyphenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B16) synthetic

Bromo-2 divided by 1-, in 3-dimethoxy benzene alternative embodiment 20, beyond the bromo-4-anisole of 1-, other condition and step are identical with embodiment 20, obtain red solid (compound B-11 6), fusing point: 96-97 DEG C, productive rate 68%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.59(d，J＝7.2Hz，2H)，8.21(d，J＝7.6Hz，2H)，7.75(dd，J＝7.2，7.6Hz，2H)，6.52(d，J＝8.4Hz，1H)，6.40-6.35(m，2H)，4.37(t，J＝6.8Hz，2H)，3.75(s，3H)，3.68(s，3H)，3.20(t，J＝6.0Hz，2H)，3.07(t，J＝6.8Hz，2H)，3.00ppm(t，J＝6.0Hz，2H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,151.8,148.1,133.9,132.8,131.6,131.2,128.2,126.9,122.7,110.3,103.8,99.2,55.8,55.3,48.6,47.5,44.2,40.0ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₆n ₃o ₄[M+H] ⁺, 420.1923; Experimental value 420.1922.

Embodiment 23

2-(2-((4-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B17) synthetic

In 50mL round-bottomed flask, add compd A 1 (500mg, 2.1mmol), 4-methoxybenzaldehyde (280mg, 2.1mmol) and 20mL methyl alcohol.This mixture stirred overnight at room temperature, suction filtration, filter cake IR bake is dry, obtains white solid.

Again sodium triacetoxy borohydride (530mg, 2.5mmol) is joined to the 20mL1 of above-mentioned solid and acetic acid (0.12mL, 2.1mmol), 2-dichloroethane solution.After stirred overnight at room temperature, pour in 50mL water, methylene dichloride (50mL) extraction three times, merges organic phase, dry organic phase, and pressurization is steamed except organic solvent, and resistates separates (CH through silica gel column chromatography ₂cl ₂/ CH ₃oH, 30: 1, v/v) obtain pale solid (compound B-11 7) 380mg, fusing point: 142-143 DEG C, productive rate 50%.

¹h NMR (400MHz, CDCl ₃): δ=8.59 (d, J=7.2Hz, 2H), 8.22 (d, J=7.6Hz, 2H), 7.76 (dd, J=7.2,7.6Hz, 2H), 7.26 (d, J=8.8Hz, 2H), 6.80 (d, J=8.8Hz, 2H), 3.39 (t, J=6.4Hz, 2H), 3.85 (s, 2H), 3.76 (s, 3H), 3.06 (t, J=6.4Hz, 2H), 1.49ppm (br, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=164.4,158.5,133.9,132.6,131.6,131.2,129.3,128.2,126.9,122.7,113.7,55.2,52.9,47.0,40.0ppm; HRMS-ESI (m/z): calculated value C ₂₂h ₂₁n ₂o ₃[M+H] ⁺, 361.1552; Experimental value, 361.1551.

Embodiment 24

2-(2-((3-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B18) synthetic

Beyond 4-methoxybenzaldehyde in m-methoxybenzaldehyde alternative embodiment 23, other condition and step are identical with embodiment 23, obtain white solid (compound B-11 8).Fusing point: 110-112 DEG C, productive rate 65%.

¹h NMR (400MHz, CDCl ₃): δ=8.58 (d, J=7.2Hz, 2H), 8.20 (d, J=8.0Hz, 2H), 7.74 (dd, J=7.2,8.0Hz, 2H), 7.17 (t, J=8.0Hz, 1H), 7.91-6.86 (m, 2H), 6.76-6.71 (m, 1H), 4.38 (t, J=6.4Hz, 2H), 3.85 (s, 2H), 3.75 (s, 3H), (3.05 t, J=6.4Hz, 2H), 1.65ppm (br, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=164.4,159.7,142.1,133.9,131.6,131.2,129.3,128.2,126.9,122.7,120.4,113.3,112.6,55.1,53.5,47.1,40.0ppm; HRMS-ESI (m/z): calculated value C ₂₂h ₂₁n ₂o ₃[M+H] ⁺, 361.1552; Experimental value 361.1554.

Embodiment 25

2-(2-((3,4-Dimethoxyphenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B19) synthetic

Beyond 4-methoxybenzaldehyde in Veratraldehyde alternative embodiment 23, other condition and step are identical with embodiment 23, obtain white solid (compound B-11 9).Fusing point: 142-143 DEG C, productive rate 62%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.59(d，J＝7.2Hz，2H)，8.21(d，J＝8.0Hz，2H)，7.75(dd，J＝7.2，8.0Hz，2H)，6.88(d，J＝1.6Hz，1H)，6.83(dd，J＝1.6，8.4Hz，1H)，6.75(d，J＝8.4Hz，1H)，4.38(t，J＝6.4Hz，2H)，3.83(s，3H)，3.81(s，2H)，3.80(s，3H)，3.04(t，J＝6.4Hz，2H)，1.76ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,148.9,147.9,133.9,133.0,131.6,131.2,128.2,126.9,122.6,120.2,111.4,110.9,55.9,55.7,53.2,46.9,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₃h ₂₃n ₂o ₄[M+H] ⁺, 391.1658; Experimental value 391.1656.

Embodiment 26

2-(2-((2-(1,3-dioxoisoindolin) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B20) synthetic

By phthalic imidine (1.0g, 10mL DMF solution 6.8mmol) joins and is equipped with 1, 2-ethylene dibromide (3mL, 34.0mmol), salt of wormwood (1.9g, 14.0mmol) and in the 50mL round-bottomed flask of 20mLDMF, after stirring at room temperature 2 hours, the about 20mLDMF of pressure reducing and steaming, surplus materials is poured in 100mL water, methylene dichloride 100mL extraction three times, merge organic phase, dry, filter, remove organic solvent in gained filtrate under reduced pressure, resistates separates (AcOEt/PE through silica gel column chromatography, 1: 5, v/v) obtain white solid (Compound C 2) 750mg, productive rate: 43%,

Compound C 2 and compd A 1 are pressed to the condition described in embodiment 7 and step reaction, obtain white solid (compd B 20), fusing point: 172-174 DEG C, productive rate 70%.

¹h NMR (400MHz, CDCl ₃): δ=8.49 (d, J=7.2Hz, 2H), 8.21 (d, J=8.0Hz, 2H), 7.72 (dd, J=7.2,8.0Hz, 2H), 7.63 (s, 4H), 4.32 (t, J=6.0Hz, 2H), 3.80 (t, J=6.0Hz, 2H), 3.07 (t, J=6.0Hz, 2H), 3.02 (t, J=6.0Hz, 2H), 1.59ppm (s, 1H); ¹³c NMR (100MHz, CDCl ₃): δ=168.4,164.4,133.8,133.6,132.1,126.9,123.0,122.7,47.4,47.2,39.7,37.6ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₁₉n ₃o ₄[M+H] ⁺, 414.1454; Experimental value 414.1456.

Embodiment 27

2-(2-((2-(2-oxygen benzo [cd] indoles-1 (1H)-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B21) synthetic:

Outside phthalic imidine in Compound C 3 alternate embodiments 26, other condition and step are identical with embodiment 26, obtain yellow look solid (compd B 21), productive rate 62%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.64(d，J＝7.2Hz，2H)，8.21(d，J＝8.0Hz，2H)，8.11(d，J＝7.2Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.76(dd，J＝8.0，7.6Hz，2H)，7.62(t，J＝7.6Hz，1H)，7.42(t，J＝7.6Hz，1H)，7.34(d，J＝8.4Hz，1H)，6.69(d，J＝7.2Hz，1H)，4.70(t，J＝7.2Hz，2H)，4.22(t，J＝7.2Hz，2H)，4.08(t，J＝4.4Hz，2H)，3.93(t，J＝4.4Hz，2H)，1.65ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,158.4,142.7,133.9,131.6,131.3,130.1,128.9,128.8,128.4,128.2,126.9,126.3,125.5,125.2,122.7,117.2,101.6,63.2,47.7,45.7,41.2ppm; HRMS-ESI (m/z): calculated value C ₂₇h ₂₂n ₃o ₃[M+H] ⁺, 436.1661; Experimental value 436.1659.

Embodiment 28

Synthesizing of N-(2-((2-(1,3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) ethyl)-4-methoxy benzamide (B22)

At 0 DEG C, thionyl chloride (4.8mL, 65.7mmol) is added drop-wise in the 20mL benzole soln of anisic acid (2.0g, 13.2mmol).After reflux 8 hours, be cooled to room temperature, underpressure distillation goes out desolventizing and excessive thionyl chloride obtains anisoyl chloride, colourless liquid 2.2g.

Get aforesaid liquid 60mg (0.35mmol) and be dissolved in 10mL methylene dichloride, be slowly added drop-wise to the 10mL dichloromethane solution of compound A-13 (150mg, 0.53mmol) and pyridine (2mL).Stirring at room temperature is to after reacting completely, and reaction solution is poured in 50mL water, and methylene dichloride 50mL extraction three times, merges organic phase, dry, filters, and filtrate decompression is steamed and desolventized, and resistates separates (CH through silica gel column chromatography ₂cl ₂/ CH ₃oH, 30: 1, v/v), obtain yellow solid (compd B 22) 100mg, productive rate 68%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.39(d，J＝6.8Hz，2H)，8.10(d，J＝7.2Hz，2H)，7.65-7.56(m，4H)，7.04(s，1H)，6.70(d，J＝6.4Hz，2H)，4.26(t，J＝6.0Hz，2H)，3.75(s，3H)，3.80(t，J＝6.0Hz，2H)，3.07(t，J＝6.0Hz，2H)，3.02(t，J＝6.0Hz，2H)，1.59ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=167.2,164.4,161.8,133.9,131.4,131.2,128.8,127.9,127.0,126.8,122.3,113.4,77.5,77.4,77.2,76.9,55.3,47.9,47.4,39.7ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₄n ₃o ₄[M+H] ⁺, 418.1767; Experimental value 418.1770.

Embodiment 29

2-(2-((2-(naphthalene-1-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B23) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-naphthalene alternative embodiment 7, other condition and step are identical with embodiment 7, obtain white solid (compd B 23), productive rate 65%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.51(d，J＝7.2Hz，2H)，8.19(d，J＝8.0Hz，1H)，8.09(d，J＝8.0Hz，2H)，7.72(d，J＝8.0Hz，1H)，7.64(dd，J＝8.0，7.2Hz，2H)，7.42(dt，J＝7.4，1.2Hz，1H)，7.35(m，2H)，7.26(m，1H)，6.74(d，J＝7.6Hz，1H)，4.38(t，J＝6.8Hz，2H)，4.20(t，J＝5.2Hz，2H)，3.22(t，J＝5.2Hz，2H)，3.15(t，J＝6.8Hz，2H)，1.90ppm(br，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=164.4,154.5,134.4,133.9,131.5,131.2,128.1,127.4,126.8,126.3,125.8,125.6,125.1,122.5,122.0,120.3,104.7,67.7,48.5,47.6,40.0ppm; HRMS-ESI (m/z): calculated value C ₂₆h ₂₃n ₂o ₃[M+H] ⁺, 411.1709; Experimental value, 411.1722.

Embodiment 30

2-(2-((2-(naphthalene-1-amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B24) synthetic

Beyond 1-(2-bromine oxethyl)-4-anisole in 1-((2-bromotrifluoromethane) amino)-naphthalene alternative embodiment 7, other condition and step are identical with embodiment 7, obtain faint yellow solid (compd B 24), productive rate 50%.

¹h NMR (400MHz, CDCl ₃): δ=8.56 (d, J=7.2Hz, 2H), 8.15 (d, J=8.0Hz, 1H), 7.69 (m, 4H), 7.35 (t, J=7.2Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.13 (m, 2H), 6.52 (d, J=7.6Hz, 1H), 5.01 (br, 1H), 4.39 (t, J=6.0Hz, 2H), 3.30 (t, J=4.8Hz, 2H), 3.13 (m, 4H), 1.42ppm (br, 1H); ¹³cNMR (100MHz, CDCl ₃): δ=164.6,143.9,134.2,134.0,131.5,131.3,128.4,128.2,126.9,126.6,125.5,124.3,123.5,122.5,120.1,117.0,104.1,47.9,47.5,43.6,39.9ppm; HRMS-ESI (m/z): calculated value C ₂₆h ₂₄n ₃o ₂[M+H] ⁺, 410.1869; Experimental value, 410.1862.

Embodiment 31

2-(2-((2-(5-methoxyl group-2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B25) synthetic

5-methoxyl group isatin (Compound C 4) (1.0g, 5.64mmol), neopentyl glycol (589mg, 5.64mmol) and tosic acid (49mg, 0.28mmol) mix and be dissolved in 30mL toluene, be heated to reflux, stir 8 hours.Reaction solution is down to room temperature, filters, and filtrate decompression evaporate to dryness, resistates separates (AcOEt/PE, 2: 3, v/v) through silica gel column chromatography and obtains white solid (Compound C 5) 1.25g, productive rate 84%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.20(s，1H)，7.06(d，J＝2.4Hz，1H)，6.82(dd，J＝2.4，8.0Hz，1H)，6.70(d，J＝8.0Hz，1H)，4.73(d，J＝10.8Hz，2H)，3.80(s，3H)，3.55(d，J＝10.8Hz，2H)，1.43(s，3H)，0.91ppm(s，3H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝173.7，156.3，133.5，128.4，116.4，110.9，110.4，93.7，71.3，55.9，30.3，23.0，22.1ppm.

Under sodium hydride (304mg, 7.60mmol) ice bath, join in the 10mLDMF solution of Compound C 5 (1.0g, 3.80mmol) in batches.Under 30 DEG C of conditions, stir after 30 minutes, add glycol dibromide (0.66mL, 7.60mmol).Be warming up to 40 DEG C, continue to be stirred to and react completely.Reaction solution is poured in 50mL ethyl acetate, 50mL washing three times.Dry organic phase, filters, filtrate decompression evaporate to dryness, and resistates separates (AcOEt/PE, 1: 3, v/v) through silica gel column chromatography and obtains yellow oil (Compound C 6) 1.3g, productive rate: 92%.

¹H?NMR(400MHz，CDCl ₃)：δ＝7.07(d，J＝2.8Hz，1H)，6.87(dd，J＝2.8，8.4Hz，1H)，6.74(d，J＝8.4Hz，1H)，4.72(d，J＝10.8Hz，2H)，3.99(t，J＝7.2Hz，2H)，3.81(s，3H)，3.55-3.48(m，4H)，1.42(s，3H)，0.89ppm(s，3H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝171.1，156.6，135.0，127.9，116.0，110.8，109.1，93.3，71.4，55.9，41.2，30.3，27.0，23.0，22.1ppm.

Condition and step reaction that Compound C 6 and compd A 1 are pressed to embodiment 7, obtain yellow solid (Compound C 7).Productive rate 55%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.55(d，J＝7.2Hz，2H)，8.18(d，J＝7.6Hz，2H)，7.72(dd，J＝7.2，7.6Hz，2H)，7.00(d，J＝1.6Hz，1H)，6.82-6.72(m，2H)，4.67(d，J＝11.2Hz，2H)，4.32(d，J＝6.4Hz，2H)，3.77(s，3H)，3.70(t，J＝6.4Hz，2H)，3.43(d，J＝11.2Hz，2H)，3.06(d，J＝6.4Hz，2H)，2.98(d，J＝6.4Hz，2H)，1.95(s，1H)，1.38(s，3H)，0.83ppm(s，3H)； ¹³C?NMR(100MHz，CDCl ₃)：δ＝171.4，164.3，156.3，135.8，133.9，131.5，131.2，128.1，127.9，126.9，122.6，115.9，110.5，109.5，93.4，71.2，56.9，47.3，46.5，39.7，39.6，30.2，23.0，22.1ppm。

Compound C 7 is joined to hydrochloric acid/acetic acid (v/v=3: in mixing solutions 1), after stirring at room temperature 10 minutes, slowly pour the saturated solution of sodium bicarbonate into, dichloromethane extraction three times, merge organic phase, dry, filter, filtrate decompression evaporate to dryness, resistates separates (CH through silica gel column chromatography ₃oH/CH ₂cl ₂, 30: 1, v/v), obtain red solid (compd B 25) 1.3g, fusing point: 169-170 DEG C, productive rate 90%.

¹H?NMR(400MHz，CDCl ₃)：δ＝8.52(d，J＝7.2Hz，2H)，8.20(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，7.04-6.97(m，2H)，6.95(d，J＝8.0Hz，1H)，4.31(t，J＝6.4Hz，2H)，3.79(t，J＝6.4Hz，2H)，3.76(s，3H)，3.14-3.00(m，4H)，2.31ppm(s，1H)；

¹³c NMR (100MHz, CDCl ₃): δ=183.7,164.4,158.6,156.2,145.1,134.0,131.5,131.3,128.1,126.9,124.6,122.4,117.9,111.6,109.3,55.9,47.4,46.5,40.3,39.4ppm; HRMS-ESI (m/z): calculated value C ₂₅h ₂₂n ₃o ₅[M+H] ⁺, 444.1559; Experimental value, 444.1560.

Embodiment 32

2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B26) synthetic

Outside the Compound C 4 in Compound C 4a alternative embodiment 31, other condition and step are identical with embodiment 31, can obtain orange solid (compd B 26).Fusing point: 82-84 DEG C.

¹h NMR (400MHz, CDCl ₃): δ=8.56 (d, J=7.6Hz, 2H), 8.23 (d, J=8.0Hz, 2H), 7.77 (dd, J=7.6,8.0Hz, 2H), 7.51 (d, J=7.6Hz, 1H), 7.46 (dd, J=7.2,7.6Hz, 1H), 7.05-6.95 (m, 2H), 4.32 (t, J=6.4Hz, 2H), 3.82 (t, J=6.4Hz, 2H), 3.00-3.10ppm (m, 4H); ¹³c NMR (100MHz, CDCl ₃): δ=183.4,164.5,158.5,151.2,138.2,134.0,131.6,131.3,128.2,127.0,125.1,123.4,122.5,117.6,110.5,47.5,46.5,40.5,39.6ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₂₀n ₃o ₄[M+H] ⁺, 414.1454; Experimental value 414.1454.

Embodiment 33

2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B27) synthetic

Beyond compd A 1 in compd A 4 alternative embodiments 32, other condition and step are identical with embodiment 32, can obtain yellow solid (compd B 27).

¹h NMR (400MHz, CDCl ₃): δ=8.61-8.51 (m, 2H), 8.50 (d, J=8.4Hz, 1H), 7.70 (dd, J=7.6,8.0Hz, 1H), 7.50 (d, J=7.2Hz, 1H), 7.45 (dd, J=7.6,8.0Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 7.02-6.96 (m, 2H), 4.28 (t, J=6.0Hz, 2H), 4.14 (s, 3H), 3.80 (t, J=6.0Hz, 2H), 3.10-2.97ppm (m, 4H); ¹³c NMR (100MHz, CDCl ₃): δ=183.4,164.8,164.2,161.0,158.5,151.3,138.2,133.6,131.6,129.4,128.8,126.0,125.1,123.5,123.4,122.2,117.6,114.9,110.5,105.2,56.2,47.6,46.5,40.5,39.5ppm; HRMS-ESI (m/z): calculated value C ₂₅h ₂₂n ₃o ₅(M+H), 444.1559; Experimental value, 444.1564.

Embodiment 34

2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-dimethyl amine-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B28) synthetic

Beyond compd A 1 in compound A-45 alternative embodiment 32, other condition and step are identical with embodiment 32, can obtain red solid (compd B 28).

¹h NMR (400MHz, CDCl ₃): δ=8.53 (d, J=7.2Hz, 1H), 8.40-8.50 (m, 2H), 7.68 (dd, J=7.6,8.0Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.49 (dd, J=7.6,8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 7.00-7.40 (m, 2H), 4.31 (t, J=6.0Hz, 2H), 3.85 (t, J=6.0Hz, 2H), 3.14 (s, 6H), 3.07ppm (t, J=6.0Hz, 4H); ¹³c NMR (100MHz, CDCl3): δ=Gp-156-125; HRMS-ESI (m/z): calculated value C ₂₆h ₂₅n ₄o ₄[M+H] ⁺, 457.1876; Experimental value, 457.1877.

Embodiment 35

2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl) the bromo-1H-benzo of-6-[de] isoquinoline 99.9-1,3 (2H)-diketone (B29) synthetic

Beyond compd A 1 in compd A 6 alternative embodiments 32, other condition and step are identical with embodiment 32, can obtain orange solid (compd B 29), fusing point: 90-92 DEG C.

¹h NMR (400MHz, CDCl ₃): δ=8.65-8.55 (m, 2H), 8.37 (d, J=7.6Hz, 1H), 8.06 (d, J=8.0Hz, 1H), 7.87 (dd, 7.6,8.0Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.47 (dd, J=7.6,8.0Hz, 1H), 7.05-6.95 (m, 2H), 4.31 (t, J=6.0Hz, 2H), 3.81 (t, J=6.4Hz, 2H), 3.10-3.00ppm (m, 4H); ¹³cNMR (100MHz, CDCl ₃): δ=183.4,163.9,158.5,151.2,138.1,133.4,132.1,131.3,131.1,130.7,130.4,129.1,128.1,125.2,123.4,123.0,122.1,117.6,110.4,47.4,46.5,40.5,39.7ppm; HRMS-ESI (m/z): calculated value C ₂₄h ₁₉n ₃o ₄br[M+H] ⁺, 492.0559; Experimental value, 492.0563.

Embodiment 36

The inhibition active testing of compound provided by the invention to mankind's N-acetyl hexosaminidase:

All test compounds are all dissolved in the aqueous solution of 20% ethanol, and concentration is 0.1mM.Taking M-31850 (Product Name: β-Hexosaminidase Inhibitor) as control compound.Suppressing active testing uses mankind's beta-N-acetylhexosaminidase purchased from Sigma-Aldrich company (CAS Number:9012-33-3).Enzymic activity test is used substrate for 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide (being abbreviated as 4MU-β-GlcNAc), purchased from Sigma-Aldrich company.Probe temperature is 37 DEG C.

Test procedure: preculture 10 minutes in the citrate buffer solution that is first 50mM by the inhibitor of mankind's beta-N-acetylhexosaminidase and different concns in concentration (pH=4.25); Then add respectively 4MU-β-GlcNAc to be respectively 8 μ M and 16 μ M to final concentration, initiation enzymatic reaction; Finally add 0.5M sodium carbonate solution 100 μ l termination reactions.Utilize fluorescence spectrophotometer to measure the fluorescence intensity of hydrolysate 4MU, excitation wavelength is 360nm, and emission wavelength is 405nm.Suppressing constant (Ki) utilizes Dixon plots linear regression data to calculate.The results are shown in Table 1.

As shown in Table 1, this type of naphthalimide derivative has obvious inhibition activity to mankind's beta-N-acetylhexosaminidase.Compare known non-glycosyl STRUCTURE DEPRESSION agent M-31850, this compounds can reach better or equal inhibition.Due to the clinical toxicity of M-31850, make it can not serve as pharmacological agent relative disease.But the active compound in the present invention is the new non-glycosyl mankind beta-N-acetylhexosaminidase inhibitor of exploitation, the relevant human body diseases for the treatment of has been opened up new direction.

Table 1

Nd: inhibitor concentration suppresses activity and is less than 50% in the time of 0.05mM.

Claims

1. a naphthalimide derivative, is characterized in that, described naphthalimide derivative is compound shown in formula I, or it is at pharmacologically acceptable salts:

In formula I, R ¹for H, C ₁～C ₄alkoxyl group, or halogen, wherein R ³and R ⁴independently be selected from respectively C ₁～C ₄a kind of in alkyl;

R ²for H, hydroxyl or the amino C replacing ₁～C ₄alkyl, or group shown in formula II:

In formula II, X is O, S, and NH, or m is 0～6 integer; N is 0 or 1;

A is group shown in formula III or formula IV:

Wherein, R ⁵～R ⁹independently be selected from respectively: H, C ₁～C ₄alkoxyl group, C ₁～C ₄a kind of in fluoroalkoxy, halogen, nitro or formic acid carbalkoxy, or R ⁵～R ⁹two of middle arbitrary neighborhoods be combined as divalence phenyl or all the other are H,

R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C ₁～C ₄phenyl or naphthyl that alkoxyl group replaces, all the other are and R ¹⁰～R ¹³in have at least one to be

But, do not comprise following compounds:

2-(2-amino-ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-hydroxyethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-amino-ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-amino-ethyl)-6-dimethyl amido-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone or 2-(2-amino-ethyl) the bromo-1H-benzo of-6-[de] isoquinoline 99.9-1,3 (2H)-diketone.

2. naphthalimide derivative as claimed in claim 1, is characterized in that, wherein R ¹for H, C ₁～C ₂alkoxyl group, Cl, Br, I or wherein R ³and R ⁴independently be selected from respectively C ₁～C ₂a kind of in alkyl.

3. naphthalimide derivative as claimed in claim 2, is characterized in that, wherein R ¹for H, CH ₃o-, Br or-N (CH ₃) ₂.

4. naphthalimide derivative as claimed in claim 1, is characterized in that, wherein R ²for H, or hydroxyl or the amino C replacing ₁～C ₂alkyl.

5. the naphthalimide derivative as described in claim 3 or 4, is characterized in that, described naphthalimide derivative is: 2-(2-amino-ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone.

6. naphthalimide derivative as claimed in claim 1, is characterized in that, wherein R ²for group shown in formula II, and A is group shown in formula III; M is 0,1,2 or 3;

Wherein R ⁵～R ⁹independently be selected from respectively: H, C ₁～C ₂alkoxyl group, C ₁～C ₂fluoroalkoxy, halogen, nitro or-COOCH ₃middle one,

Or

R ⁵～R ⁹two of middle arbitrary neighborhoods be combined as divalence phenyl or all the other are H.

7. naphthalimide derivative as claimed in claim 6, is characterized in that, wherein R ⁵～R ⁹independently be selected from respectively: H, methoxyl group, trifluoromethoxy, Cl ,-NO ₂or-COOCH ₃middle one.

8. naphthalimide derivative as claimed in claim 7, is characterized in that, wherein R ²be selected from: a kind of in following groups:

9. the naphthalimide derivative as described in claim 3 or 8, it is characterized in that, described naphthalimide derivative is: 2-(2-((2-(4-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(3-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(2-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(4-anisole sulfenyl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((3-(4-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((3-(3-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((3-(4-anisole sulfenyl) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H) diketone, 2-(2-((2-(benzo [d] [1, 3] methylene-dioxy-5-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(3, 4-dimethoxy phenoxy group) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 4-(2-((2-(1, 3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) oxyethyl group) methyl benzoate, 2-(2-((2-(4-chlorophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(4-nitrophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-((4-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-((3-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-((2, 4-Dimethoxyphenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((4-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((3-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((3, 4-Dimethoxyphenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, N-(2-((2-(1, 3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) ethyl)-4-methoxy benzamide, 2-(2-((2-(naphthalene-1-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, or 2-(2-((2-(naphthalene-1-amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone.

10. naphthalimide derivative as claimed in claim 1, is characterized in that, wherein R ²for group shown in formula II, and A is group shown in formula IV; M is 0,1,2 or 3;

Wherein R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C ₁～C ₂phenyl or naphthyl that alkoxyl group replaces, all the other are and R ¹⁰～R ¹³in have at least one to be

11. naphthalimide derivatives as claimed in claim 10, is characterized in that, wherein R ¹⁰～R ¹³two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, the phenyl or naphthyl of methoxy substitution, all the other are and R ¹⁰～R ¹³in have at least one to be

12. naphthalimide derivatives as claimed in claim 11, is characterized in that, wherein R ²be selected from: a kind of in following groups:

or

13. naphthalimide derivatives as described in claim 3 or 11, it is characterized in that, described naphthalimide derivative is: 2-(2-((2-(1, 3-dioxoisoindolin) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(2-oxygen benzo [cd] indoles-1 (1H)-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(5-methoxyl group-2, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(2, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(2, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-(2, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-dimethyl amine-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, or 2-(2-((2-(2, 3-dioxo indoline-1-yl) ethyl) amino) ethyl) the bromo-1H-benzo of-6-[de] isoquinoline 99.9-1, 3 (2H)-diketone.

14. application of naphthalimide derivative in the medicine for the preparation of the treatment disease relevant to mankind's beta-N-acetylhexosaminidase as described in any one in claim 1～13.

The application in the medicine for the preparation of the treatment disease relevant to mankind's beta-N-acetylhexosaminidase of 15. 1 kinds of naphthalimide derivatives;

Wherein, described naphthalimide derivative is: 2-(2-amino-ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-hydroxyethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-((2-amino-ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone, 2-(2-amino-ethyl)-6-dimethyl amido-1H-benzo [de] isoquinoline 99.9-1, 3 (2H)-diketone or 2-(2-amino-ethyl) the bromo-1H-benzo of-6-[de] isoquinoline 99.9-1, 3 (2H)-diketone.