CN105367495A

CN105367495A - Piper longum amide analogue containing seven-membered lactam ring and preparation method and application thereof

Info

Publication number: CN105367495A
Application number: CN201410437125.0A
Authority: CN
Inventors: 缪震元; 张万年; 吴岳林; 盛春泉; 庄春林; 闵啸; 姚建忠; 董国强
Original assignee: Second Military Medical University SMMU
Current assignee: Second Military Medical University SMMU
Priority date: 2014-08-29
Filing date: 2014-08-29
Publication date: 2016-03-02
Anticipated expiration: 2034-08-29
Also published as: CN105367495B

Abstract

The invention relates to the technical field of medicine, in particular to a substitutive piper longum amide analogue. The substitutive piper longum amide analogue comprises cis-trans-isomers thereof and any mixture in the form of cis-trans-isomers or pharmaceutical salt of the analogue. The structure of the substitutive piper longum amide analogue is shown in the formula (I). The invention further provides a preparation method of the substitutive piper longum amide compound and application of the substitutive piper longum amide compound to preparation of antitumor drugs.

Description

The similar thing of piperlongumine containing seven membered lactams rings and preparation and application thereof

Technical field

The present invention relates to medical art, be specifically related to a class similar thing of piperlongumine containing seven membered lactams rings and preparation method thereof, and the application in medicine.

Background technology

Piperlongumine (Piplartine) is a kind of alkaloid extracted from piperaceae Piper herbaceous perennial vine plant Piper longum, and its chemical structure is as follows:

Pharmacological testing shows that piperlongumine has multiple biological activity, as the treatment of neural system aspect disease, the treatment of cardiovascular and cerebrovascular diseases and antimycotic, antidepressant and antitumor action.WO2008147483 and WO2009038684 respectively describes the effect of the nervous tissue relative disease that piperlongumine and analogue thereof cause as Progressive symmetric erythrokeratodermia many stoves leukoencephalopathy and hippocampus damage in the multiple demyelinating disease for the treatment of Progressive symmetric erythrokeratodermia central nervous system.Piperlongumine has hypotensive effect, and be highly resistant to hematoblastic gathering, can be used for treatment (the AntiplateleteffectsofacidamidesisolatedfromthefruitsofPi perlongumL of cardiovascular and cerebrovascular diseases, Phytomedicine2007,14:853), CN200910243046.5 (publication number is CN101810612A) and CN201010033836.3 (publication number is CN101774875A) respectively describes the synthetic method of the similar thing of piperlongumine and the application at thrombus prevention and cure medicine thereof.In addition, piperlongumine also has good fungi restraining effect (AntifungalamidesfromPiperhispidumandPipertuberculatum, Phytochemistry, 2000,55:621), there is certain antidepressant effect (Piplartine, anamidealkaloidfromPipertuberculatum, presentsanxiolyticandantidepressanteffectsinmice, Phytomedicine, 2007,14:605).

WO2009114126 describes piperlongumine and analogue plays the effect for the treatment of tumour by affecting reactive oxygen species in tumour cell, and CN201010034289.0 (publication number is CN102125552A) reports the antitumor action of the piperlongumine alkoxyl group substitutive derivative after to piperlongumine structural modification subsequently.The similar thing of piperlongumine of these reports is active relatively not high, is therefore necessary to carry out structural modification on this basis, strengthens the activity of compound, reduces toxicity, therefrom find new antitumor drug.

Summary of the invention

The object of the present invention is to provide a class to contain the similar thing of piperlongumine of seven membered lactams rings, another object of the present invention is to provide the preparation method of the described similar thing of piperlongumine containing seven membered lactams rings, and is preparing the application in antitumor drug.

Existing piperlongumine structural modification mainly concentrates on phenyl ring alkoxyl group replacement part, double bond and hexa-atomic lactam nucleus and introduces substituting group, and it is relatively less for the transformation of piperlongumine self lactam nucleus, technical scheme of the present invention, mainly by hexa-atomic lactam nucleus ring expansion to seven membered lactams ring, obtains the similar thing of piperlongumine containing seven membered lactams rings of the brand-new skeleton of a class.

A first aspect of the present invention, provides the similar thing of piperlongumine that a class contains seven membered lactams rings, and comprise any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, structure is as shown in (I):

Wherein ring A is selected from following arbitrary: containing 1 or plural aromatic ring, containing 1 or plural fragrant heterocycle, containing saturated carbon ring or the fractional saturation carbocyclic ring of 3-7 carbon atom, containing the saturated bicyclic of 8-10 carbon atom or unsaturated dicyclo or aromatic ring, containing the 5-6 unit hetero-aromatic ring of 1-4 individual independently nitrogen or oxygen or sulphur atom, containing 4-7 unit's saturated bicyclic or the unsaturated dicyclo of 1-3 individual independently nitrogen or oxygen or sulphur atom, containing 7-10 unit's saturated bicyclic or the unsaturated dicyclo of 1-5 individual independently nitrogen or oxygen or sulphur atom, containing the two fragrant heterocycle of 8-10 unit of 1-5 individual independently nitrogen or oxygen or sulphur atom,

R ₁, R ₂, R ₃independently represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, diazanyl, azido-, low alkyl group, cycloalkyl, low-grade halogenated alkyl, low-grade alkenyl, lower cyanoalkyl, rudimentary 4-nitro alkyl, amide group, rudimentary amido alkyl, rudimentary diazanyl alkyl, rudimentary azido-alkyl, (CH ₂) _mnR ₅r ₅, (CH ₂) _moR ₅, (CH ₂) _msR ₅, (CH ₂) _mnR ₅c (O) R ₅, (CH ₂) _mc (O) R ₅, (CH ₂) _moC (O) R ₅, O (CH ₂) _mnR ₅r ₅, OC (O) NR ₅, OC (O) (CH ₂) _moC (O) R ₅or R ₁and R ₂or R ₁and R ₃or R ₂and R ₃form the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

Preferred R ₁, R ₂, R ₃independently represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, (CH ₂) _mnR ₅r ₅, (CH ₂) _moR ₅, (CH ₂) _mc (O) R ₅, (CH ₂) _moC (O) R ₅, O (CH ₂) _mnR ₅r ₅, or R ₁and R ₂or R ₁and R ₃or R ₂and R ₃form the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

R ₄represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, diazanyl, azido-, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy, (CH ₂) _n[N=X], OC (O) [N=X], (CH ₂) _moC (O) [N=X] (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH ₂, CH, NR ₅), substituted or unsubstituted loweraralkyl, wherein substituting group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy;

Preferred R ₄represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, cycloalkyl, (CH ₂) _n[N=X] (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH ₂, CH, NR ₅);

R ₅represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, diazanyl, azido-, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

Preferred R ₅represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

B is selected from:

R ₆represent following groups: hydrogen, amino, halogen, cyano group, amide group, azido-, diazanyl, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

Preferred R ₆represent following groups: hydrogen, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

R ₇represent following groups: hydrogen, amino, halogen, cyano group, amide group, azido-, diazanyl, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy, low-grade alkenyl, aryl, (CH ₂) _mnR ₅r ₅, (CH ₂) _moR ₅, (CH ₂) _msR ₅, (CH ₂) _mnR ₅c (O) R ₅, (CH ₂) _mc (O) R ₅, (CH ₂) _moC (O) R ₅, O (CH ₂) _mnR ₅r ₅, OC (O) NR ₅, OC (O) (CH ₂) _moC (O) R ₅or R ₇with R ₁or R ₂or R ₃form the chain of 5 or 6 yuan, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

Preferred R ₇represent following groups: hydrogen, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy, aryl or R ₇with R ₁or R ₂or R ₃form the chain of 5 or 6 yuan, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

M, n are the integers between 0 to 3;

Z is 0 or 1 or 2;

In this article, the term " rudimentary " relevant with alkyl, alkylthio and alkoxyl group refers to the straight or branched saturated fatty hydrocarbyl group containing 1 to 6 carbon atom, such as, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methylthio group, ethylmercapto group, methoxyl group and oxyethyl group, the term " rudimentary " relevant with term alkenyl or alkynyl group refers to the group containing 2 to 6 carbon atoms and one or more double bond or triple bond, such as: vinyl, allyl group, isoolefine propyl group, pentenyl, hexenyl, propenyl, ethynyl, proyl and butynyl.Term cycloalkyl refers to the ring containing 3 to 7 carbon, such as, and cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Term aryl refers to list, two or tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, each ring containing maximum 7 carbon atoms, such as, phenyl, naphthyl, anthryl, xenyl or indenyl.Term halogen refers to chlorine, bromine, iodine or fluorine.Corresponding to term low-grade halogenated alkyl, lower cyanoalkyl, rudimentary 4-nitro alkyl, rudimentary amido alkyl, rudimentary diazanyl alkyl, lower alkoxy loweralkyl, rudimentary azido-alkyl, loweraralkyl, Lower hydroxy alkyl, the group of lower alkylthio low alkyl group and the rudimentary Sulfonylalkyl of low alkyl group is respectively by one to three halogen, cyano group, nitro, amide group, diazanyl, alkoxyl group, azido-, aryl, hydroxyl, low alkyl group sulfenyl low alkyl group or rudimentary Sulfonylalkyl replace.Low-grade alkyl amino can contain one or two low alkyl group, such as, represent NHCH ₃, NHCH ₂cH ₃, N (CH ₃) ₂or CH ₃nCH ₂cH ₃.

Preferably, in formula (I):

R ₁, R ₂, R ₃independently represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, (CH ₂) _mnR ₅r ₅, (CH ₂) _moR ₅, (CH ₂) _mc (O) R ₅, (CH ₂) _moC (O) R ₅, O (CH ₂) _mnR ₅r ₅, or R ₁and R ₂or R ₁and R ₃or R ₂and R ₃form the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

R ₄represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, cycloalkyl, (CH ₂) _n[N=X] (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH ₂, CH, NR ₅);

R ₅represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

R ₆represent following groups: hydrogen, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy;

R ₇represent following groups: hydrogen, amino, halogen, cyano group, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy, aryl or R ₇with R ₁or R ₂or R ₃form the chain of 5 or 6 yuan, wherein the unit of this chain is selected from CH, CH ₂, O, S or NR ₅;

M, n are the integers between 0 to 3;

Z is 0 or 1 or 2;

The term " rudimentary " relevant with alkyl and alkoxyl group refers to the straight or branched saturated fatty hydrocarbyl group containing 1 to 6 carbon atom, cycloalkyl refers to the ring containing 3 to 7 carbon, aryl refers to list, two or tricyclic hydrocarbon compound, wherein at least one ring is aromatic nucleus, each ring is containing maximum 7 carbon atoms, halogen refers to chlorine, bromine, iodine or fluorine, corresponding to term low-grade halogenated alkyl, lower alkoxy loweralkyl, loweraralkyl, the group of Lower hydroxy alkyl is respectively by one to three halogen, alkoxyl group, aryl, hydroxyl replaces, low-grade alkyl amino can contain one or two low alkyl group.

More excellent, formula I is selected from:

(E) the chloro-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

1-(5,6,7-trimethoxy-1-Methyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

(E) the bromo-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the bromo-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the bromo-1-of-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the bromo-1-of-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the bromo-1-of-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

1-(5,6,7-trimethoxy-1-Methyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

(E) the chloro-1-of-3-(2-cyano group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the bromo-1-of-3-(2-cyano group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,4-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

(E) the chloro-1-of-3-(3-(3-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2,3-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2,6-dichlorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2,3,4-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,4,5-trifluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,4-dichlorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-aminomethyl phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-nitrophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3-aminomethyl phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2-bromophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(the fluoro-4-bromophenyl of 2-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(the bromo-4-fluorophenyl of 3-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2,5-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(4-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E)-1-(3-(benzo [d] [1,3] dioxole-5-base) acryl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-;

(E) the chloro-1-of-3-(3-(2,5-difluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(2 ,-4-difluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(the chloro-3-nitrophenyl of 4-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-methoxyl group-4-hydroxy phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(5-methoxyl group-3,4-dihydroxy phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-dimethoxy-4 '-(2-morpholine oxyethyl group) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-dimethoxy-4 '-(3-(N, N-dimethylamino) propoxy-) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-dimethoxy-4 '-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-dimethoxy-4 '-(2-piperidines oxyethyl group) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(3,5-dimethoxy-4 '-(2-(1-methylpyrrolidin-2-yl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The bromo-1-of 3-(1-butyl-6-hydroxyl-5,7-dimethoxy-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E)-4-(3-(6-chloro-7-oxo-2,3,4,7-tetrahydrochysene-1H-azatropylidene-1-base)-3-oxo third-1-thiazolinyl)-2,6-dimethoxy benzene yl acetates;

The chloro-1-of 3-(quinoline-3-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The bromo-1-of 3-(quinoline-3-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The chloro-1-of 3-(2-phenycyclopropyl carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

(E) the chloro-1-of-3-(3-(pyridin-3-yl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The bromo-1-of 3-(1-butyl-6-hydroxyl-5,7-dimethoxy-6-(2-(4-methylpiperazine-1-oxyethyl group)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The bromo-1-of 3-(1-butyl-6-hydroxyl-5,7-dimethoxy-6-(3-(N, N-dimethylamino) propoxy-)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one;

The bromo-1-of 3-(1-butyl-6-hydroxyl-5,7-dimethoxy-6-(2-morpholine oxyethyl group)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one.

Described pharmaceutical salts, refers to pharmaceutically acceptable various forms of salt, the salt that can be formed with organic acids such as mineral acid or toxilic acid, oxysuccinic acid, citric acid such as hydrochloric acid, nitric acid, Hydrogen bromides.

A second aspect of the present invention, is to provide the preparation method that a described class contains the similar thing of piperlongumine of seven membered lactams rings.

Described preparation method take hexanolactam as raw material, first synthesizes unsaturated seven membered lactams rings, then prepare various acyl chlorides, both reactions are prepared the similar thing of piperlongumine.

A third aspect of the present invention, is to provide the similar thing of piperlongumine that a described class contains seven membered lactams rings, and any mixture or its pharmaceutical salts that comprise its cis-trans-isomer and its these forms are preparing the application in antitumor drug.

Compound of the present invention has anti-tumor activity, they can be used for treating tumour, comprise the cancer that the positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system occur, and thyroid carcinoma, leukemia, suddenly king's evil, lymphoma and myelomatosis etc.

The pharmacologically active of the compounds of this invention makes it may be used for, and preparation is antitumor, antimycotic, platelet aggregation-against and anti-drugs for nervous, and therefore the present invention also comprises using these compounds and pharmaceutical salts thereof as the pharmaceutical composition of activeconstituents.This pharmaceutical composition can be solid form or liquid form.

Compound of the present invention, comprise any mixture of its cis-trans-isomer and its these forms or its pharmaceutical salts except preparing the application in antitumor drug, also can be used for preparing agents: antifungal drug, medicament for resisting platelet aggregation, antidepressant drug, anxiolytic medicament, analgesic, and the medicine etc. of other cardiovascular and cerebrovascular diseases and nervous system disorders.

Embodiment

Now in conjunction with the embodiments, the invention will be further described, but enforcement of the present invention is not limited in this.

The preparation of chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of embodiment 1:3-

22.6 grams of oenantholactam are dissolved in 200 milliliters of chloroforms, under ice bath, add 124.8 grams of phosphorus pentachlorides by part, continue reaction after adding 10 minutes, then back flow reaction 3 hours.Reaction solution is carefully poured in 500 milliliters of frozen water after being cooled to 0 to 5 degree by ice bath, with dichloromethane extraction 5 times, anhydrous sodium sulfate drying, adds sherwood oil and ethyl acetate mixed solvent after concentrated, separates out solid, filter, obtain 17 grams of solids, be directly used in the next step.

17 gram of 3,3-dichloro oenantholactam is dissolved in 70 milliliters of dry DMF, adds 4 grams lithium chlorides, 7 grams of Quilonum Retards successively, be warmed up to 130 degree and react 8 hours, boil off DMF, after column purification, obtain 10.5 grams of white solids, yield 77%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.72 (s, 1H), 6.61-6.66 (m, 1H), 3.27-3.31 (m, 2H), 2.34-2.39 (m, 2H), 1.94-1.98 (m, 2H).

The preparation of bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of embodiment 2:3-

11.3 grams of oenantholactam are dissolved in 200 milliliters of methylene dichloride, under ice bath, add 41.6 grams of phosphorus pentachlorides by part, continue reaction after adding 10 minutes.Add zinc iodide 1 gram under nitrogen protection, be warming up to room temperature reaction 1 hour.Then drip the dichloromethane solution (32 grams of bromines are dissolved in 100 milliliters of methylene dichloride) of bromine, dropwise rear stirring and spend the night.Ice bath is cooled to 0 to 5 degree, is carefully poured into by reaction solution in 500 milliliters of frozen water, with dichloromethane extraction 5 times, anhydrous sodium sulfate drying, adds sherwood oil and ethyl acetate mixed solvent after concentrated, separates out solid, filter to obtain 23.3 grams of solids, be directly used in the next step.

13.5 gram of 3,3-dibromo oenantholactam is dissolved in 70 milliliters of dry DMF, adds 4 grams lithium chlorides, 7 grams of Quilonum Retards successively, be warmed up to 130 degree react 8 hours after, boil off DMF, after column purification 7.1 grams of white solids, yield 75%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.37 (s, 1H), 6.86 (t, 1H), 3.26 (q, 2H), 2.34 (q, 2H), 1.91-2.00 (m, 2H).

The preparation of embodiment 3, the chloro-1-of (E)-3-(3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

By 119mg3,4,5-trimethoxy cinnamic acid is put in 254mg oxalyl chloride, reacts 4 hours under nitrogen protection.Pressure reducing and steaming solvent, add 5 milliliters of anhydrous tetrahydro furans, be cooled to 0 degree, drip 101mg triethylamine, stirring reaction is continued 15 minutes at 0 degree after dropwising, then drip chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 73mg3-be dissolved in 5 milliliters of anhydrous tetrahydro furans, dropwise rear stirred overnight at room temperature.Add 30 milliliters of DCM, respectively with saturated ammonium chloride and saturated brine washing, anhydrous sodium sulfate drying, concentrated, column purification obtains 134.2mg light yellow solid, yield 73.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.75 (d, 1H), 7.40 (d, 1H), 6.77-6.82 (m, 3H), 4.01 (t, 2H), 3.90 (s, 6H), 3.89 (s, 3H), 2.38 (q, 2H), 2.00-2.06 (m, 2H); EI-MS:m/z:366.11 [M+H] ⁺.

The preparation of embodiment 4, the chloro-1-of (E)-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with (E)-2-methyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 129.5mg light yellow solid, yield 68.2%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.85 (d, 1H), (6.78 s, 1H), 6.58 (s, 2H), 3.96 (t, 2H), (3.86 s, 9H), 2.38 (q, 2H), 2.14 (s, 3H), 2.02-2.08 (m, 2H); EI-MS:m/z:380.13 [M+H] ⁺.

The preparation of embodiment 5, the chloro-1-of (E)-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with (E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 129.4mg light yellow solid, yield 65.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.84 (t, 1H), 6.60 (s, 1H), 6.53 (s, 2H), (3.96 t, 2H), 3.86 (s, 9H), 2.57-2.67 (m, 2H), (2.49 q, 2H), 2.02-2.07 (m, 2H), δ 1.17 (t, 3H); EI-MS:m/z:394.14 [M+H] ⁺.

The preparation of embodiment 6, the chloro-1-of (E)-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with (E)-2-propyl group-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 121.1mg light yellow solid, yield 59.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.84 (t, 1H), 6.63 (s, 1H), 6.53 (s, 2H), (3.96 t, 2H), 3.86 (s, 9H), 3.80 (d, 2H), (2.45-2.62 m, 4H), 2.00-2.09 (m, 2H), 0.96 (t, 3H); EI-MS:m/z:408.16 [M+H] ⁺.

The preparation of embodiment 7, the chloro-1-of (E)-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with (E)-2-butyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 91.1mg light yellow solid, yield 43.2%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.84 (t, 1H), 6.62 (s, 1H), 6.53 (s, 2H), 3.96 (t, 2H), 3.86 (s, 3H), 3.85 (s, 6H), 2.45-2.62 (m, 4H), 2.02-2.07 (m, 2H), 1.55-1.62 (m, 2H), 1.29-1.38 (m, 2H), 0.89 (t, 3H); EI-MS:m/z:422.17 [M+H] ⁺.

The preparation of embodiment 8,1-(5,6,7-trimethoxy-1-Methyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 5,6,7-trimethoxy-1-Methyl-1H-indole-2-carboxylic acid, obtain 154.2mg light yellow solid, yield 78.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.92 (t, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 4.17 (s, 3H), 4.00 (s, 3H), 3.96-3.98 (m, 2H), 3.92 (s, 3H), (3.85 s, 3H), 2.58-2.63 (m, 2H), 2.04-2.09 (m, 2H); EI-MS:m/z:393.12 [M+H] ⁺.

The preparation of embodiment 9,1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 5,6,7-trimethoxy-1-ethyl-1H-Indoline-2-carboxylic acid, obtain 149.5mg light yellow solid, yield 73.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.93 (t, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 4.66 (q, 2H), 4.05 (s, 3H), 3.97 (t, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.63 (q, 2H), 2.05-2.07 (m, 2H), 1.45 (t, 3H); EI-MS:m/z:407.14 [M+H] ⁺.

The preparation of embodiment 10,1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 5,6,7-trimethoxy-1-propyl group-1H-Indoline-2-carboxylic acid, obtain 140.6mg light yellow solid, yield 66.8%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.93 (t, 1H), 6.73 (s, 1H), 6.62 (s, 1H), 4.56-4.61 (m, 2H), 4.04 (s, 3H), 3.96 (t, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.62 (q, 2H), 2.04-2.09 (m, 2H), 1.83-1.90 (m, 2H), 0.94 (t, 3H); EI-MS:m/z:421.15 [M+H] ⁺.

The preparation of embodiment 11,1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 5,6,7-trimethoxy-1-butyl-1H-Indoline-2-carboxylic acid, obtain 118.7mg light yellow solid, yield 54.6%, ¹hNMR (CDCl ₃, 300MHz) and δ: 6.93 (t, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 4.58-4.64 (m, 2H), 4.03 (s, 3H), 3.96 (t, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.62 (q, 2H), 2.04-2.09 (m, 2H), 1.81-1.86 (m, 2H), 1.35-1.43 (m, 2H), 0.95 (t, 3H); EI-MS:m/z:435.17 [M+H] ⁺.

The preparation of embodiment 12,1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 5,6,7-trimethoxy-1-benzyl-1H-Indoline-2-carboxylic acid, obtain 173.3mg light yellow solid, yield 73.9%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.05-7.25 (m, 5H), 6.91 (t, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 5.96 (s, 2H), 3.90 (t, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.53 (s, 3H), 2.58 (q, 2H), 2.00-2.04 (m, 2H); EI-MS:m/z:469.15 [M+H] ⁺.

The preparation of embodiment 13, the bromo-1-of (E)-3-(3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-for raw material with bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-, obtain 158.6mg light yellow solid, yield 77.3%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.74 (d, 1H), 7.42 (d, 1CH), 7.02 (t, 1H), (6.80 s, 2H), 4.01 (t, 2H), 3.90 (s, 6H), (3.89 s, 3H), 2.36 (q, 2H), 1.99-2.06 (m, 2H); EI-MS:m/z:412.06 [M+H] ⁺.

The preparation of embodiment 14, the bromo-1-of (E)-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and (E)-2-methyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 144.0mg light yellow solid, yield 67.9% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.09 (t, 1H), (6.78 s, 1H), 658 (s, 2H), 3.96 (t, 2H), (3.87 s, 9H), 2.46 (q, 2H), 2.14 (s, 3H), 2.02-2.06 (m, 2H); EI-MS:m/z:426.07 [M+H] ⁺.

The preparation of embodiment 15, the bromo-1-of (E)-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and (E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 137.4mg light yellow solid, yield 62.7% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.08 (t, 1H), 6.61 (s, 1H), 653 (s, 2H), (3.96 t, 2H), 3.86 (s, 9H), 2.60-2.67 (m, 2H), (2.43-2.50 m, 2H), 2.00-2.09 (m, 2H), 1.16 (t, 3H); EI-MS:m/z:438.09 [M+H] ⁺.

The preparation of embodiment 16, the bromo-1-of (E)-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and (E)-2-propyl group-3-(3,4,5-trimethoxyphenyl) vinylformic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 130.0mg light yellow solid, yield 57.5% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.07 (t, 1H), 6.63 (d, 1H), 6.54 (s, 2H), 3.96 (t, 2H), 3.86 (s, 9H), 2.54-2.62 (m, 2H), 2.42-2.50 (m, 2H), (2.02-2.09 m, 2H), 1.54-1.59 (m, 2H), 0.96 (t, 3H); EI-MS:m/z:452.10 [M+H] ⁺.

The preparation of embodiment 17, the bromo-1-of (E)-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and (E)-2-butyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 115.7mg light yellow solid, yield 49.6% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.08 (t, 1H), 6.63 (s, 1H), 6.54 (s, 2H), 3.96 (t, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.57-2.62 (m, 2H), 2.42-2.50 (m, 2H), 2.02-2.07 (m, 2H), 1.51-1.57 (m, 2H), 1.40-1.43 (m, 2H), 0.86 (t, 3H); EI-MS:m/z:466.12 [M+H] ⁺.

The preparation of embodiment 18,1-(5,6,7-trimethoxy-1-Methyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 5,6,7-trimethoxy-1-Methyl-1H-indole-2-carboxylic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 176.0mg light yellow solid, yield 80.5% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.16 (t, 1H), 6.73 (s, 1H), 6.62 (s, 1H), 4.17 (s, 3H), 4.00 (s, 3H), 3.96 (t, 2H), 3.92 (s, 3H), (3.85 s, 3H), 2.55-2.62 (m, 2H), 2.04-2.09 (m, 2H); EI-MS:m/z:439.37 [M+H] ⁺.

The preparation of embodiment 19,1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 5,6,7-trimethoxy-1-ethyl-1H-Indoline-2-carboxylic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 172.2mg light yellow solid, yield 76.3% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.18 (t, 1H), 6.74 (s, 1H), 6.62 (s, 1H), 4.66 (q, 2H), 4.05 (s, 3H), 3.95-3.99 (m, 2H), 3.92 (s, 3H), (3.86 s, 3H), 2.57-2.65 (m, 2H), 2.06-2.10 (m, 2H); EI-MS:m/z:453.13 [M+H] ⁺.

The preparation of embodiment 20,1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 5,6,7-trimethoxy-1-propyl group-1H-Indoline-2-carboxylic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 156.8mg light yellow solid, yield 67.4% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.54-4.60 (m, 2H), 4.03 (s, 3H), 3.94 (t, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.56-2.63 (m, 2H), 2.04-2.09 (m, 2H), 1.85 (q, 2H), 0.94 (t, 3H); EI-MS:m/z:466.97 [M+H] ⁺.

The preparation of embodiment 21,1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 5,6,7-trimethoxy-1-butyl-1H-Indoline-2-carboxylic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 144.8mg light yellow solid, yield 60.4% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), (6.72 s, 1H), 6.62 (s, 1H), 4.57-4.62 (m, 2H), (4.02 s, 3H), 3.95 (t, 2H), 3.90 (s, 3H), (3.85 s, 3H), 2.56-2.63 (m, 2H), 2.02-2.10 (m, 2H), 1.77-1.88 (m, 2H), 1.32-1.44 (m, 2H), 0.95 (t, 3H); EI-MS:m/z:481.29 [M+H] ⁺.

The preparation of embodiment 22,1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl) bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with 3-bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 5,6,7-trimethoxy-1-benzyl-1H-Indoline-2-carboxylic acid substitute 3-chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid is raw material, obtains 189.6mg light yellow solid, yield 73.9% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.30-7.40 (m, 1H), 7.04-7.25 (m, 5H), 6.77 (s, 1H), 6.74 (s, 1H), 5.95 (s, 2H), 3.90-3.92 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.52 (s, 3H), 2.52-2.59 (m, 2H), 2.00-2.06 (m, 2H); EI-MS:m/z:515.10 [M+H] ⁺.

The preparation of embodiment 23, the chloro-1-of (E)-3-(2-cyano group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with (E)-2-cyano group-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 55.5mg light yellow oil, yield 28.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.91 (s, 1H), 7.24 (s, 2H), 7.16 (t, 1H), 3.94-4.00 (m, 5H), 3.92 (s, 6H), 2.57 (q, 2H), 2.01-2.06 (m, 2H); EI-MS:m/z:391.31 [M+H] ⁺.

The preparation of embodiment 24, the bromo-1-of (E)-3-(2-cyano group-3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, with (E)-2-cyano group-3-(3,4,5-trimethoxyphenyl) vinylformic acid and bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-and substitute 3,4,5-trimethoxy cinnamic acid and chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-and be raw material, obtain 68.6mg light yellow oil, yield 31.5% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.90 (s, 1H), 7.24 (s, 2H), 7.18 (t, 1H), 3.94-4.00 (m, 5H), 3.91 (s, 6H), 2.55 (q, 2H), 2.01-2.06 (m, 2H); EI-MS:m/z:435.05 [M+H] ⁺.

The preparation of embodiment 25, the chloro-1-of (E)-3-(3-(3,5-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3,5-dimethoxy-cinnamic acid, obtain 50.2mg white solid, yield 29.9%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.75 (d, 1H), 7.46 (d, 1H), 6.81 (t, 1H), (6.73 s, 2H), 6.51 (s, 1H), 4.02 (t, 2H), (3.83 s, 6H), 2.39 (q, 2H), 2.00-2.05 (m, 2H).

The preparation of embodiment 26, the chloro-1-of (E)-3-(3-(4-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with the fluoro-styracin of 4-, obtain 53.6mg yellow solid, yield 36.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.79 (d, 1H), (7.57-7.61 m, 2H), 7.43 (d, 1H), 7.09 (t, 2H), (6.82 t, 1H), 4.02 (t, 2H), 2.39 (q, 2H), 2.01-2.08 (m, 2H).

The preparation of embodiment 27, the chloro-1-of (E)-3-(3-(3,4-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3,4-dimethoxy-cinnamic acid, obtain 60.1mg faint yellow solid, yield 35.8%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.80 (d, 1H), 7.40 (d, 1H), 7.10-7.22 (m, 2H), (6.88 d, 1H), 6.78 (t, 1H), 4.02 (t, 2H), (3.94 s, 6H), 2.39 (q, 2H), 2.01-2.07 (m, 2H).

The preparation of embodiment 28, the chloro-1-of (E)-3-(3-(2-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2-chloro-cinnamic acid, obtain 103.0mg Tan solid, yield 66.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.23 (d, 1H), 7.72-7.75 (m, 1H), 7.48 (d, 1H), (7.42-7.44 m, 1H), 7.30-7.35 (m, 2H), 6.82 (t, 1H), (4.03 t, 2H), 2.38 (q, 2H), 2.02-2.07 (m, 2H).

The preparation of embodiment 29, the chloro-1-of (E)-3-(3-(4-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 4-methoxy cinnamic acid, obtain 30.1mg brown solid, yield 19.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.81 (d, 1H), 7.56 (d, 2H), 7.40 (d, 1H), (6.91 d, 2H), 6.78 (t, 1H), 4.01 (t, 2H), (3.86 s, 3H), 2.38 (q, 2H), 2.00-2.05 (m, 2H).

The preparation of embodiment 30, the chloro-1-of (E)-3-(3-(3-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-chloro-cinnamic acid, obtain 15.5mg brown solid, yield 10.0%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.74 (d, 1H), 7.59 (s, 1H), 7.48 (d, 1H), (7.45-7.47 m, 1H), 7.35-7.38 (m, 2H), 6.83 (t, 1H), (4.02 t, 2H), 2.40 (q, 2H), 2.01-2.08 (m, 2H).

The preparation of embodiment 31, the chloro-1-of (E)-3-(3-(2-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2-methoxy cinnamic acid, obtain 81.6mg yellow solid, yield 53.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.18 (d, 1H), 7.59-7.62 (m, 1H), 7.55 (d, 1H), 7.33-7.39 (m, 1H), 6.91-6.98 (m, 2H), 6.78 (t, 1H), 4.00 (t, 2H), (3.90 s, 3H), 2.37 (q, 2H), 1.99-2.03 (m, 2H).

The preparation of embodiment 32, the chloro-1-of (E)-3-(3-(2,3-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,3-dimethoxy-cinnamic acid, obtain 66.7mg brown solid, yield 39.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.15 (d, 1H), 7.52 (d, 1H), 7.24-7.27 (m, 1H), 7.03-7.09 (m, 1H, Ph), 6.94-6.97 (m, 1H), 6.80 (t, 1H), 4.02 (t, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.38 (q, 2H), 2.01-2.06 (m, 2H).

The preparation of embodiment 33, the chloro-1-of (E)-3-(3-(2,6-dichlorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,6-dichloro-cinnamic acid, obtain 76.7mg brown solid, yield 44.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.92 (d, 1H), (7.59 d, 1H), 7.37 (d, 2H), 7.20-7.22 (m, 1H), (6.81 t, 1H), 4.03 (t, 2H), 2.40 (q, 2H), 2.03-2.10 (m, 2H).

The preparation of embodiment 34, the chloro-1-of (E)-3-(3-(3-p-methoxy-phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-methoxy cinnamic acid, obtain 74.3mg tawny oil, yield 48.6%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.80 (d, 1H), 7.49 (d, 1H), 7.31-7.34 (m, 1H), 7.18-7.21 (m, 1H), 7.11 (s, 1H), 6.94-6.97 (m, 1H), 6.81 (t, 1H), 4.02 (t, 2H), 3.86 (s, 3H), 2.39 (q, 2H), 2.01-2.06 (m, 2H).

The preparation of embodiment 35, the chloro-1-of (E)-3-(3-(3-bromophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-bromo-cinnamic acid, obtain 26.1mg yellow solid, yield 14.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.70-7.75 (m, 2H), 7.44-7.53 (m, 3H), 7.24-7.28 (m, 1H), 6.82 (t, 1H), 4.02 (t, 2H), 2.39 (q, 2H), 2.01-2.05 (m, 2H).

The preparation of embodiment 36, the chloro-1-of (E)-3-(3-(4-chloro-phenyl-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 4-chloro-cinnamic acid, obtain 62.5mg white solid, yield 40.3%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.76 (d, 1H), (7.53 d, 2H), 7.46 (d, 1H), 7.37 (d, 2H), (6.81 t, 1H), 4.02 (t, 2H), 2.39 (q, 2H), 2.00-2.05 (m, 2H).

The preparation of embodiment 37, the chloro-1-of (E)-3-(3-(2-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2-fluoro cinnamic acid, obtain 89.3mg pink solid, yield 60.8%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.98 (d, 1H), 7.64 (t, 1H), 7.55 (d, 1H), (7.34-7.41 m, 1H), 7.08-7.19 (m, 2H), 6.81 (t, 1H), (4.02 t, 2H), 2.40 (q, 2H), 1.99-2.08 (m, 2H).

The preparation of embodiment 38, the chloro-1-of (E)-3-(3-(2,3,4-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,3,4-trimethoxy cinnamic acid, obtain 15.5mg yellow oil, yield 8.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.05 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 6.79 (t, 1H), 6.69 (d, 1H), 4.02 (t, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 2.38 (q, 2H), 2.01-2.05 (m, 2H).

The preparation of embodiment 39, the chloro-1-of (E)-3-(3-(3,4,5-trifluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3,4,5-tri-fluoro cinnamic acid, obtain 36.1mg brown solid, yield 21.9%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.61 (d, 1H), 7.39 (d, 1H), 7.19-7.23 (m, 2H), 6.83 (t, 1H), 4.02 (t, 2H), 2.40 (q, 2H), 2.01-2.06 (m, 2H).

The preparation of embodiment 40, the chloro-1-of (E)-3-(3-(3,4-dichlorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3,4-dichloro-cinnamic acid, obtain 49.1mg yellow solid, yield 28.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.65-7.71 (m, 2H), 7.38-7.48 (m, 3H), 6.82 (t, 1H), 4.01 (t, 2H), 2.39 (q, 2H), 2.01-2.07 (m, 2H).

The preparation of embodiment 41, the chloro-1-of (E)-3-(3-(4-aminomethyl phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 4-tolyl acrylic acid, obtain 125.3mg yellow solid, yield 86.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.72 (d, 1H), 7.45-7.51 (m, 3H), 7.20 (d, 2H), 6.80 (t, 1H), 4.02 (t, 2H), 2.35-2.43 (m, 5H), 2.01-2.05 (m, 2H).

The preparation of embodiment 42, the chloro-1-of (E)-3-(3-(4-nitrophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 4-nitrocinnamic acid, obtain 93.7mg yellow solid, yield 58.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.25 (d, 2H), (7.79 d, 1H), 7.73 (d, 2H), 7.57 (d, 1H), (6.85 t, 1H), 4.03 (t, 2H), 2.41 (q, 2H), 2.03-2.09 (m, 2H).

The preparation of embodiment 43, the chloro-1-of (E)-3-(3-(3-aminomethyl phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-tolyl acrylic acid, obtain 60.1mg yellow oil, yield 41.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.81 (d, 1H), (7.49 d, 1H), 7.43 (s, 1H), 7.20-7.31 (m, 2H), (6.81 t, 1H), 4.02 (t, 2H), 2.34-2.43 (m, 5H), 2.01-2.07 (m, 2H).

The preparation of embodiment 44, the chloro-1-of (E)-3-(3-(2-bromophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2-bromo-cinnamic acid, obtain 66.7mg brown solid, yield 37.6%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.17 (d, 1H), 7.72 (dd, 1H), 7.63 (dd, 1H), 7.44 (d, 1H), 7.30-7.35 (m, 1H), 7.23-7.26 (m, 1H), 6.82 (t, 1H), (4.03 t, 2H), 2.40 (q, 2H), 2.02-2.07 (m, 2H).

The preparation of embodiment 45, the chloro-1-of (E)-3-(3-(the fluoro-4-bromophenyl of 2-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with the fluoro-4-bromo-cinnamic acid of 2-, obtain 61.1mg yellow solid, yield 32.8%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.11 (d, 1H), (7.69-7.74 m, 1H), 7.36-7.41 (m, 2H), 7.04-7.10 (m, 1H), (6.82 t, 1H), 4.03 (t, 2H), 2.37 (q, 2H), 2.02-2.07 (m, 2H).

The preparation of embodiment 46, the chloro-1-of (E)-3-(3-(the bromo-4-fluorophenyl of 3-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with the bromo-4-fluoro cinnamic acid of 3-, obtain 20.1mg yellow solid, yield 10.8%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.80-7.82 (m, 1H), 7.70 (d, 1H), 7.48-7.53 (m, 1H), (7.42 d, 1H), 7.15 (t, 1H), 6.83 (t, 1H), (4.02 t, 2H), 2.40 (q, 2H), 2.01-2.08 (m, 2H).

The preparation of embodiment 47, the chloro-1-of (E)-3-(3-(2,5-Dimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,5-dimethoxy-cinnamic acid, obtain 80.8mg brown solid, yield 48.1%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.17 (d, 1H), 7.53 (d, 1H), 7.13 (d, 1H), 6.92-6.96 (m, 1H), 6.86 (d, 1H), 6.79 (t, 1H), 4.02 (t, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 2.38 (q, 2H), 2.00-2.05 (m, 2H).

The preparation of embodiment 48, the chloro-1-of (E)-3-(3-(4-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 4-trifluoromethyl cinnamic acid, obtain 85.2mg yellow solid, yield 49.6%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.80 (d, 1H), 7.63-7.71 (m, 4H), 7.54 (d, 1H), 6.83 (t, 1H), 4.03 (t, 2H), 2.41 (q, 2H), 2.02-2.07 (m, 2H).

The preparation of embodiment 49, the chloro-1-of (E)-3-(3-(3-fluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-fluoro cinnamic acid, obtain 9.5mg brown solid, yield 6.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.74 (d, 1H), 7.46 (d, 1H), 7.33-7.36 (m, 2H), (7.29 s, 1H), 7.05-7.11 (m, 1H), 6.80 (t, 1H), (4.00 t, 2H), 2.33-2.42 (m, 2H), 1.97-2.06 (m, 2H).

The preparation of embodiment 50, the chloro-1-of (E)-3-(3-(3-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-methyl fluoride styracin, obtain 32.1mg yellow solid, yield 18.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.74-7.83 (m, 3H), (7.63-7.65 m, 1H), 7.49-7.54 (m, 2H), 6.82 (t, 1H), 4.02 (t, 2H), 2.36-2.44 (m, 2H), 2.01-2.08 (m, 2H).

The preparation of embodiment 51, (E)-1-(3-(benzo [d] [1,3] dioxole-5-base) acryl) chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of-3-

According to the method for embodiment 3, with benzo [d] [1,3] dioxole-5-base) vinylformic acid substitute 3,4,5-trimethoxy cinnamic acid for raw material, obtain 66.7mg yellow solid, yield 41.7%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.69 (d, 1H), (7.61 t, 1H), 7.08-7.11 (m, 2H), 6.78-6.82 (m, 2H), (6.01 s, 2H), 4.00 (t, 2H), 2.37 (q, 2H), 1.96-2.06 (m, 2H).

The preparation of embodiment 52, the chloro-1-of (E)-3-(3-(2,5-difluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,5-cinnamic acid difluoride, obtain 47.5mg yellow solid, yield 30.5%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.85 (d, 1H), (7.45 d, 1H), 7.28-7.31 (m, 1H), 7.02-7.06 (m, 2H), (6.80 t, 1H), 3.99 (t, 2H), 2.37 (q, 2H), 1.96-2.05 (m, 2H).

The preparation of embodiment 53, the chloro-1-of (E)-3-(3-(2-trifluoromethyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2-trifluoromethyl cinnamic acid, obtain 19.6mg brown solid, yield 11.4%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.08 (dd, 1H), (7.79 d, 1H), 7.69 (d, 1H), 7.44-7.59 (m, 3H), (5.84 t, 1H), 4.22 (t, 2H), 3.44-3.47 (m, 2H), 2.72-2.76 (m, 2H).

The preparation of embodiment 54, the chloro-1-of (E)-3-(3-(2 ,-4-difluorophenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 2,4-cinnamic acid difluoride, obtain 56.6mg yellow solid, yield 36.3%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.85 (d, 1H), (7.55-7.63 m, 1H), 7.44 (d, 1H), 6.82-6.91 (m, 2H), (6.78 t, 1H), 3.98 (t, 2H), 2.35 (q, 2H), 1.95-2.04 (m, 2H).

The preparation of embodiment 55, the chloro-1-of (E)-3-(3-(the chloro-3-nitrophenyl of 4-) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3,4,5-trimethoxy cinnamic acid for raw material with 3-nitro-4-chloro-cinnamic acid, obtain 50.1mg yellow solid, yield 28.2%, ¹hNMR (CDCl ₃, 300MHz) and δ: 8.02 (d, 1H), (7.69-7.72 m, 2H), 7.56-7.62 (m, 1H), 7.49 (d, 1H), (6.84 t, 1H), 4.01 (t, 2H), 2.39 (q, 2H), 2.03-2.04 (m, 2H).

The preparation of embodiment 56, the chloro-1-of (E)-3-(3-(3,5-methoxyl group-4-hydroxy phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

By the chloro-1-of 73mg (E)-3-(3-(3; 4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one are dissolved in 10mL methylene dichloride; be cooled to 0 DEG C; then add 267mg aluminum trichloride (anhydrous) by part, react 1.5 hours under room temperature, add frozen water cancellation reaction; dichloromethane extraction three times; concentrated, column purification obtains 46.5mg off-white color solid, yield 65.0%. ¹HNMR(CDCl ₃,300MHz)δ:7.76(d,1H),7.39(d,1H),6.83(s,2H),6.79(t,1H),5.8(s,1H),4.01(t,2H),3.94(s,6H),2.35-2.43(m,2H),2.00-2.04(m,2H)；EI-MS:m/z:352.3[M+H]+。

The preparation of embodiment 57, the chloro-1-of (E)-3-(3-(5-methoxyl group-3,4-dihydroxy phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

By the chloro-1-of 73mg (E)-3-(3-(3; 4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one are dissolved in 10mL methylene dichloride; be cooled to 0 DEG C; then add 267mg aluminum trichloride (anhydrous) by part, react 1.5 hours under room temperature, add frozen water cancellation reaction; dichloromethane extraction three times; concentrated, column purification obtains off-white color look solid, yield 25.0%. ¹HNMR(CDCl ₃,300MHz)δ:7.71(d,1H),7.36(d,1H),6.87(d,1H),6.79(t,1H),6.73(d,1H),5.69(s,1H),5.39(s,1H),4.00(t,2H),3.93(s,3H),2.38(q,2H),1.99-2.06(m,2H)；EI-MS:m/z:335.9[M-H] ^-。

The preparation of embodiment 58, the chloro-1-of (E)-3-(3-(3,5-dimethoxy-4 '-(2-morpholine oxyethyl group) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

By the chloro-1-of 70mg (E)-3-(3-(4-hydroxyl-3; 5-Dimethoxyphenyl) allyl acyl group)-6; after the mixing of 7-dihydro-1H-azepine-2 (5H)-one, 105mg triphenylphosphine, 52.5mgN-morpholine base ethanol; under nitrogen protection; add 8mL anhydrous tetrahydro furan; be cooled to 0 DEG C, drip 83mgDIAD.Be warming up to room temperature, stirring reaction spends the night, and concentrated, column purification obtains 44mg yellow solid, yield 44.2%. ¹HNMR(CDCl ₃,600MHz)δ:7.73(d,1H),7.36(d,1H),6.77-6.80(m,3H),4.14(t,2H),4.00(t,2H),3.86(s,6H),3.75-3.76(m,4H),2.81(t,2H),2.61-2.64(m,4H),2.35-2.39(m,2H),2.00-2.03(m,2H)；EI-MS:m/z:465.8[M+H] ⁺。

Embodiment 59, the chloro-1-of (E)-3-(3-(3; 5-dimethoxy-4 '-(3-(N; N-dimethylamino) propoxy-) phenyl) acryl) preparation of-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58, replace N-morpholine base ethanol for raw material with 3-(N, N-dimethyl) propyl alcohol, khaki color solid can be obtained, yield 37.6%. ¹HNMR(CDCl ₃,600MHz)δ:7.69(d,1H),7.35(d,1H),6.77(t,1H),6.75(s,2H),4.05(t,2H),3.97(t,2H),3.84(s,6H),3.36(t,2H),2.83(s,6H),2.34-2.36(m,2H),2.24-2.27(m,2H),1.97-2.00(m,2H)；EI-MS:m/z:437.6[M+H] ⁺。

Embodiment 60, the chloro-1-of (E)-3-(3-(3; 5-dimethoxy-4 '-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) acryl) preparation of-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58, replace N-morpholine base ethanol for raw material with 2-(4-methylpiperazine) ethanol, khaki color solid can be obtained, yield 23.5%. ¹HNMR(CDCl ₃,600MHz)δ:7.72(d,1H),7.38(d,1H),6.79(s,2H),6.73(t,1H),4.14-4.17(m,2H),4.00-4.02(m,2H),3.86(s,6H),2.93-3.02(m,10H),2.82(s,3H),2.36-2.41(m,2H),1.98-2.10(m,2H)；EI-MS:m/z:478.3[M+H] ⁺。

The preparation of embodiment 61, the chloro-1-of (E)-3-(3-(3,5-dimethoxy-4 '-(2-piperidines oxyethyl group) phenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58, replace N-morpholine base ethanol for raw material with N-piperidine ethanol, khaki color solid can be obtained, yield 23.9%. ¹HNMR(CDCl ₃,600MHz)δ:7.72(d,1H,),7.39(d,1H),6.80(t,1H),6.78(s,2H),4.43(t,2H),4.00(t,2H),3.88(s,6H),3.33-3.36(m,2H),2.36-2.40(m,2H),2.08-2.11(m,4H),1.99-2.02(m,2H),1.65-1.68(m,6H)；EI-MS:m/z:463.3[M+H] ⁺。

Embodiment 62, the chloro-1-of (E)-3-(3-(preparation of 3,5-dimethoxy-4 '-(2-(1-methylpyrrolidin-2-yl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58, replace N-morpholine base ethanol for raw material with 2-(1-crassitude 2-yl) ethanol, khaki color solid can be obtained, yield 17.3%, ¹hNMR (CDCl ₃, 300MHz) and δ: 7.68 (d, 1H), 7.35 (d, 1H), 6.77 (t, 1H), 6.74 (s, 2H), 4.18-4.24 (m, 2H), 3.96 (t, 2H), 3.83 (s, 6H), 2.82 (s, 3H), 2.44-2.47 (m, 3H), 2.20--2.31 (m, 2H), 2.03-2.10 (m, 2H), 1.91-2.00 (m, 2H), 1.20-1.30 (m, 4H); EI-MS:m/z:463.5 [M+H] ⁺.

The preparation of the bromo-1-of embodiment 63,3-(1-butyl-6-hydroxyl-5,7-dimethoxy-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 56; with the bromo-1-of 3-(1-butyl-5; 6,7-dimethoxy-1H-indole-2-carbonyl) the chloro-1-of-6,7-dihydro-1H-azatropylidene-2 (5H)-one replacement (E)-3-(3-(3; 4; 5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one are raw material, can obtain khaki color solid; yield 48.3% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.57-4.62 (m, 2H), 4.02 (s, 3H), 3.95 (t, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.56-2.63 (m, 2H), 2.02-2.10 (m, 2H, CH ₂), 1.77-1.88 (m, 2H), 1.32-1.44 (m, 2H), 0.95 (t, 3H); EI-MS:m/z:467.8 [M+H] ⁺.

The preparation of embodiment 64, (E)-4-(3-(6-chloro-7-oxo-2,3,4,7-tetrahydrochysene-1H-azatropylidene-1-base)-3-oxo third-1-thiazolinyl)-2,6-dimethoxy benzene yl acetates

By the chloro-1-of 70mg (E)-3-(3-(4-hydroxyl-3; 5-Dimethoxyphenyl) allyl acyl group)-6; 7-dihydro-1H-azepine-2 (5H)-one is dissolved in 10mL methylene dichloride, adds 22mg triethylamine, is cooled to 0 DEG C.Then drip 17.3mg Acetyl Chloride 98Min., stirring at room temperature reacts 1 hour.Add 20mL water, be separated organic layer, water layer dichloromethane extraction 2 times.Merge organic layer, salt is washed, anhydrous sodium sulfate drying, and concentrated, column purification obtains 46mg white solid, yield 58.3%. ¹HNMR(CDCl ₃,300MHz)δ:7.75(d,1H),7.4(d,1H),6.78-6.82(m,3H),4.02(t,2H),3.87(s,6H),2.36-2.41(m,5H)，2.00-2.05(m,2H)；EI-MS:m/z:394.1[M+H] ⁺。

The preparation of the chloro-1-of embodiment 65,3-(quinoline-3-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, replace 3,4,5-trimethoxy cinnamic acid for raw material with quinoline-3-carboxylic acid, obtain 120.9mg light yellow solid, yield 80.4%, ¹hNMR:(CDCl ₃, 300MHz) and δ: 8.95 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.91 (d, 1H), 7.79-7.85 (m, 1H), 7.60-7.65 (m, 1H), 6.97 (t, 1H), 4.14 (t, 2H), 2.62-2.70 (m, 2H), 2.10-2.19 (m, 2H); EI-MS:m/z:301.27 [M+H] ⁺.

The preparation of the bromo-1-of embodiment 66,3-(quinoline-3-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, substitute 3-chloro-6 with bromo-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-and quinoline-3-carboxylic acid, 7-dihydro-1H-azatropylidene-2 (5H)-one and 3,4,5-trimethoxy cinnamic acid are raw material, obtain 138.2mg light yellow solid, yield 80.1% ¹hNMR:(CDCl ₃, 300MHz) and δ: 8.94 (d, 1H), 8.40 (d, 1H), 8.14 (d, 1H), 7.81 (d, 1H), 7.59-7.64 (m, 1H), 7.18 (t, 1H), 4.12 (t, 2H), 2.57-2.64 (m, 2H), 2.10-2.17 (m, 2H); EI-MS:m/z:345.4 [M+H] ⁺.

The preparation of the chloro-1-of embodiment 67,3-(2-phenycyclopropyl carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, replace 3,4,5-trimethoxy cinnamic acid for raw material with 2-phenyl cyclopropyl carbocylic acid, obtain 101.7mg off-white color solid, yield 70.2%, ¹hNMR (300MHz, CDCl ₃) δ: 7.26-7.32 (2H, m), 7.16-7.21 (3H, m), 6.77 (t, 1H), 3.90-3.96 (m, 2H), 3.10-3.16 (m, 1H), 2.65-2.72 (m, 1H); 2.33-2.41 (m, 2H), 1.93-2.02 (m, 2H), 1.76-1.80 (m, 1H), 1.39-1.46 (m, 1H); EI-MS:m/z:316.1 [M+H2O] ^-.

The preparation of embodiment 68, the chloro-1-of (E)-3-(3-(pyridin-3-yl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, replace 3,4,5-trimethoxy cinnamic acid for raw material with 1-(3-pyridyl) vinylformic acid, obtain 98.7mg khaki color solid, yield 71.3%, ¹hNMR (300MHz, CDCl ₃) δ: 8.78 (s, 1H), 8.62 (d, 1H), 7.94 (d, 1H), 7.73 (d, 1H), (7.54 d, 1H), 7.33-7.37 (m, 1H), 6.82 (t, 1H), (4.02 t, 2H), 2.39 (q, 2H), 1.99-2.08 (m, 2H); EI-MS:m/z:277.4 [M+H] ⁺.

The preparation of embodiment 69, (E)-1-(3-(3,4,5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 3, replace chloro-6,7-dihydro-1H-azatropylidene-2 (5H)-one of 3-for raw material with 6,7-dihydro-1H-azatropylidene-2 (5H)-one, obtain 112.9mg khaki color solid, yield 67.8%, ¹hNMR:(CDCl ₃, 300MHz) and δ: 7.71 (d, 1H), 7.39 (d, 1H), 6.81 (s, 2H, Ph), 6.54-6.58 (m, 1H), 6.13 (d, 1H), 4.01 (t, 2H), 3.90 (s, 6H), 3.89 (s, 3H), 2.43 (q, 2H), 1.98-2.06 (m, 2H) .EI-MS:m/z:332.1 [M+H] ⁺.

The bromo-1-of embodiment 70, the 3-(preparation of 1-butyl-6-hydroxyl-5,7-dimethoxy-6-(2-(4-methylpiperazine-1-oxyethyl group)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58; with the bromo-1-of 3-(1-butyl-6-hydroxyl-5; 7-dimethoxy-1H-indole-2-carbonyl)-6; 7-dihydro-1H-azatropylidene-2 (5H)-one and 2-(4-methylpiperazine) ethanol replace the chloro-1-of (E)-3-(3-(4-hydroxyl-3; 5-Dimethoxyphenyl) allyl acyl group)-6; 7-dihydro-1H-azepine-2 (5H)-one and N-morpholine base ethanol are raw material; khaki color solid can be obtained; yield 17.9% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.57-4.62 (m, 2H), 4.02 (s, 3H), 3.95-4.12 (m, 4H), 3.90 (s, 3H), 3.85 (s, 3H), 2.93-3.02 (m, 10H), 2.56-2.63 (m, 2H), 2.36-2.41 (m, 2H), 2.02-2.10 (m, 2H, CH ₂), 1.77-1.88 (m, 2H), 1.32-1.44 (m, 2H), 0.95 (t, 3H).

The preparation of the bromo-1-of embodiment 71,3-(1-butyl-6-hydroxyl-5,7-dimethoxy-6-(3-(N, N-dimethylamino) propoxy-)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58; with the bromo-1-of 3-(1-butyl-6-hydroxyl-5; 7-dimethoxy-1H-indole-2-carbonyl)-6; 7-dihydro-1H-azatropylidene-2 (5H)-one and 3-(N; N-dimethyl) the chloro-1-of propyl alcohol replacement (E)-3-(3-(4-hydroxyl-3; 5-Dimethoxyphenyl) allyl acyl group)-6; 7-dihydro-1H-azepine-2 (5H)-one and N-morpholine base ethanol are raw material; khaki color solid can be obtained; yield 13.3% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.57-4.62 (m, 2H), 4.02 (m, 5H), 3.95 (t, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.83 (s, 6H), 2.56-2.63 (m, 4H), 1.97-2.10 (m, 4H), 1.77-1.88 (m, 2H), 1.32-1.44 (m, 2H), 0.95 (t, 3H).

The preparation of the bromo-1-of embodiment 72,3-(1-butyl-6-hydroxyl-5,7-dimethoxy-6-(2-morpholine oxyethyl group)-1H-indole-2-carbonyl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one

According to the method for embodiment 58; with the bromo-1-of 3-(1-butyl-6-hydroxyl-5; 7-dimethoxy-1H-indole-2-carbonyl)-6; 7-dihydro-1H-azatropylidene-2 (5H)-one replaces the chloro-1-of (E)-3-(3-(4-hydroxyl-3; 5-Dimethoxyphenyl) allyl acyl group)-6,7-dihydro-1H-azepine-2 (5H)-one are raw material, can obtain khaki color solid; yield 21.2% ¹hNMR (CDCl ₃, 300MHz) and δ: 7.17 (t, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.57-4.62 (m, 2H), 4.14 (t, 2H), 4.02 (s, 3H), 3.95 (t, 2H), 3.90 (s, 3H), 3.75-3.76 (m, 4H), 3.85 (s, 3H), 2.81 (t, 2H), 2.56-2.63 (m, 6H), 2.02-2.10 (m, 2H, CH ₂), 1.77-1.88 (m, 2H), 1.32-1.44 (m, 2H), 0.95 (t, 3H).

Embodiment 73: the anti-tumor activity test of the compounds of this invention

Carried out Cytostatic to tumor cell test to compound of the present invention, test method adopts conventional mtt assay (as Lv Qiujun chief editor " developmental pharmacology research method ", 2007:242-243).

Cell strain selects A549 (human lung carcinoma cell), MDA-MB-231 (human breast cancer cell), HCT116 (people's colon-cancer cell), Hep3B (human liver cancer cell), HepG2 (human liver cancer cell), Saos-2 (OS-732 cells), U2OS (human osteosarcoma cell), SK-Hep-1 (human liver cancer cell), HeLa (human cervical carcinoma cell), WI38 (human embryonic lung fibroblast).Frozen and go down to posterity by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room.Nutrient solution is that RPMI1640+15%NBS+ is dual anti-.

MTT solution preparation: take MTT0.5 gram, be dissolved in 100mL phosphoric acid buffer (PBS) or without in phenol red substratum, with 0.22 μm of membrane filtration to remove the bacterium in solution, put 4 DEG C and keep in Dark Place.

Sample liquid is prepared: after dissolving with DMSO (Merck), add PBS (-) and be made into the solution of 100 μ g/mL or uniform suspension, then use the PBS (-) of DMSO to dilute, ultimate density is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.To obtain antineoplastic compound piperlongumine (the reference literature Design of confirmation, synthesisandbiologicalactivityofpiperlonguminederivative sasselectiveanticanceragents.EurJMedChem.2014,82:545-51 method is synthesized) be made into reference substance solution with same condition.

Mtt assay: the 96 every holes of orifice plate add the cell suspension 100 μ L that concentration is 4-6 × 104/mL, put 37 DEG C, 5%CO ₂in incubator.After 24h, add sample liquid, 10 μ L/ holes, if three wells, 37 DEG C, 5%CO ₂effect 72h.Every hole adds the MTT solution 20 μ L of 5mg/ml, and add lysate after effect 4h, 100 μ L/ holes, put in incubator, surveys 570nmOD value after dissolving by the full-automatic microplate reader of MK-2.Calculation of half inhibitory concentration IC ₅₀.

Test-results is in table 1; wherein; sample refers to Piperlongumine compounds (the such as embodiment 14 i.e. bromo-1-of (E)-3-(2-methyl-3-(3 prepared in corresponding embodiment; 4; 5-trimethoxyphenyl) acryl)-6,7-dihydro-1H-azatropylidene-2 (5H)-one).

Table 1, first test compounds anti tumor activity in vitro

Note: Taxol represents taxol

Table 2, second batch test compounds anti tumor activity in vitro

Note: DOX represents Dx

Table 3, the 3rd BT(batch testing) Compound ira vitro anti-tumor activity

Note: DOX represents Dx

Table 4, the 4th BT(batch testing) Compound ira vitro anti-tumor activity

Above experimental result shows, compound of the present invention has good anti-tumor activity, and multiple compound is higher than existing antineoplastic compound piperlongumine, and therefore the compounds of this invention and its esters may be used for preparing antitumor drug.

More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims

1. a class contains the similar thing of piperlongumine of seven membered lactams rings, and comprise any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, it is characterized in that, the structure of the similar thing of described piperlongumine is as shown in (I):

R ₄represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, diazanyl, azido-, low alkyl group, cycloalkyl, low-grade halogenated alkyl, lower alkoxy, (CH ₂) _n[N=X], OC (O) [N=X], (CH ₂) _moC (O) [N=X], substituted or unsubstituted loweraralkyl, wherein substituting group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy; Wherein [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH ₂, CH, NR ₅;

B is selected from following structure formula II, (III), (IV) are arbitrary:

M, n are the integers between 0 to 3;

Z is 0 or 1 or 2.

2. a class according to claim 1 contains the similar thing of piperlongumine of seven membered lactams rings, comprises any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, it is characterized in that, in formula (I):

R ₄represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, cycloalkyl, (CH ₂) _n[N=X]; Wherein [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH ₂, CH, NR ₅;

M, n are the integers between 0 to 3;

Z is 0 or 1 or 2;

The rudimentary finger relevant with alkyl and alkoxyl group is containing the straight or branched saturated fatty hydrocarbyl group of 1 to 6 carbon atom; Cycloalkyl refers to the ring containing 3 to 7 carbon; Aryl refers to list, two or tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring is containing maximum 7 carbon atoms; Halogen refers to chlorine, bromine, iodine or fluorine; The group of low-grade halogenated alkyl, lower alkoxy loweralkyl, loweraralkyl, Lower hydroxy alkyl is replaced by one to three halogen, alkoxyl group, aryl, hydroxyl respectively, and low-grade alkyl amino contains one or two low alkyl group.

3. a class according to claim 1 contains the similar thing of piperlongumine of seven membered lactams rings, and comprise any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, it is characterized in that, formula (I) compound is selected from following arbitrary:

4. a class according to claim 1 contains the similar thing of piperlongumine of seven membered lactams rings, comprise any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, it is characterized in that, described pharmaceutical salts, refer to pharmaceutically acceptable various forms of salt.

5. a class as claimed in claim 1 contains the similar thing of piperlongumine of seven membered lactams rings, comprise any mixture of its cis-trans-isomer and its these forms or the preparation method of its pharmaceutical salts, it is characterized in that, described preparation method take hexanolactam as raw material, first unsaturated seven membered lactams rings are synthesized, then prepare various acyl chlorides, target compound is prepared in both reactions.

6. a class as claimed in claim 1 contains the similar thing of piperlongumine of seven membered lactams rings, and any mixture or its pharmaceutical salts that comprise its cis-trans-isomer and its these forms are preparing the application in antitumor drug.

7. a class according to claim 6 contains the similar thing of piperlongumine of seven membered lactams rings, the any mixture or its pharmaceutical salts that comprise its cis-trans-isomer and its these forms are preparing the application in antitumor drug, it is characterized in that, described tumour comprises esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, the cancer that brain and central nervous system occur, and thyroid carcinoma, leukemia, king's evil suddenly, lymphoma and myelomatosis.