CN106749267A

CN106749267A - New epidermal growth factor receptor inhibitor and its application

Info

Publication number: CN106749267A
Application number: CN201611025615.5A
Authority: CN
Inventors: 王勇; 张小猛; 赵立文; 王小伟; 韩璐薇; 戴雪娟
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2015-11-23
Filing date: 2016-11-22
Publication date: 2017-05-31
Anticipated expiration: 2036-11-22
Also published as: TW201718583A; CN106749267B; WO2017088746A1

Abstract

The invention belongs to medicinal chemistry arts, and in particular to the new epidermal growth factor receptor inhibitor of a class, the pharmaceutical composition containing the inhibitor, and the inhibitor or pharmaceutical composition are used as cancer prevention and/or the purposes of medicine.Such compound shows good EGFR inhibitory activity, and in particular for the EGFR of mutation, being expected to turn into confrontation EGFR mutation causes the tumour of resistance to have special curative effect and the less medicine of side effect.

Description

New epidermal growth factor receptor inhibitor and its application

Technical field

The invention belongs to medicinal chemistry arts, and in particular to the new epidermal growth factor receptor inhibitor of a class, contain this The pharmaceutical composition of inhibitor, and the inhibitor or pharmaceutical composition are used as the purposes of cancer treatment drugs.

Background technology

EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) is proto-oncogene C- The expression product of erbB-1, is one of EGFR family members.EGFR families include EGFR (HER-1), ERBB2 (HER-2), Four members of ERBB3 (HER-3) and ERBB4 (HER-4).Have shown that EGFR overexpression or mutation can typically trigger tumour.EGFR Mutation causes the continuous activation of EGFR, and the effect enhancing of autocrine loop, receptor down-regulated mechanisms damage, abnormal signal conduction path swashs It is living, played an important role in the evolution of tumour.

Non-small cell lung cancer is had become for EGFR using EGFR- tyrosine kinase inhibitors (EGFR-TKI) treatment to control Goldstandard in treatment field.But, Clinical practice finds that most of patients can press down in EGFR-TKI such as Gefitinib, Tarcevas There is different degrees of resistance phenomenon, and then cause the reduction evident in efficacy of medicine, tumour progression within 6-12 month after preparation for treating. The generation of research display EGFR-TKI drug resistances is relevant with the secondary mutation of EGFR gene, and most common of which mutation is EGFR bases Because of the mutation in the site of 20 exon the 790th, i.e. T790M gene mutations.Because methionine is bigger than the occupy-place of threonine space, because This forms steric hindrance, changes the compatibility of EGFR kinases area ATP, causes EGFR-TKI small-molecule drugs effectively to block EGFR activation signalses, cause the generation of drug resistance.Meanwhile, first generation EGFR inhibitor lacks Wild type EGFR and mutant egf R Selectivity, the side effect such as generally existing fash, diarrhoea influences patient compliance.

Therefore, exploitation because bis- mutation of EGFR produce the effective medicine of the tumor patient of resistance, particularly exploitation to that can enter One step is improved to Wild type EGFR and mutant egf R selectivity, is heightened the effect of a treatment, and the medicine of side effect is reduced, by with good Application prospect.

The content of the invention

It is an object of the invention to provide the egf inhibitor of formula I or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, such compound show good EGFR inhibitory activity, in particular for the EGFR of mutation,

It is a further object to provide compounds of formula II or its pharmaceutically acceptable salt, isomers, solvent Compound, crystallization or prodrug, with the compounds of formula II as key intermediate, prepare compounds of formula I, reaction condition temperature With, yield and purity are higher,

Third object of the present invention is to provide compounds of formula III or its salt, is with the compounds of formula III Key intermediate, prepares compounds of formula I, and reactions steps are few, and mild condition, yield and purity are higher,

Fourth object of the present invention is to provide and prepares the compound or its pharmacy of formula I, II or III of the invention and can connect The method of salt, isomers, solvate, crystallization or the prodrug received.

5th purpose of the invention be to provide comprising compounds of formula I of the invention or its pharmaceutically acceptable salt, The pharmaceutical composition of isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier and comprising formula I of the invention Compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and another tumor inhibitor medicine Composition.

6th purpose of the invention is to provide compounds of formula I of the invention or its pharmaceutically acceptable salt, isomery The method of body, solvate, crystallization or prodrug and medicine composite for curing of the invention and/or pre- anti-cancer and its preparing For the application in the medicine for the treatment of and/or pre- anti-cancer.

For foregoing invention purpose, the present invention provides following technical scheme：

In a first aspect, the present invention provides compound or its pharmaceutically acceptable salt, isomers, the solvent conjunction shown in formula I Thing, crystallization or prodrug,

Wherein,

Ring A is C₄-C₈Nitrogen heterocycle, its optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, Alkoxy, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, monoalkyl ammonia Base alkyl, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, two The substitution of alkylaminoacyl, aryl, heteroaryl and Heterocyclylalkyl, when replacing base to have two or more, two adjacent substitution bases Substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or connection can together be constituted with atom in connection The atom that two substitution bases on same atom can jointly be connected with them forms substituted or unsubstituted cycloalkyl, miscellaneous Cycloalkyl；

X₁、X₂、X₃And X₄It is each independently selected from C (R₁) and N；

R₁、R_2a、R_2b、R_3a、R_3bAnd R_3cBe each independently selected from hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, Halogenated alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, Dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group and dialkyl amino Base acyl group；

R₄、R₅And R₆It is each independently selected from hydrogen, halogen, cyano group, alkyl, alkoxy and cycloalkyl, described alkyl, alkane Epoxide and cycloalkyl are optionally by one or more halogens, alkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, monoalkyl The substitution of amino, dialkyl amido, hydroxyl, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl or hydroxy alkyl；

R₇Selected from hydrogen, alkyl, cycloalkyl and haloalkyl；With

R₈Selected from hydrogen, alkyl and cycloalkyl, described alkyl and cycloalkyl are optionally by one or more halogens, alkyl, halogen The substitution of substituted alkyl, alkoxy, amino, alkyl monosubstituted amino, dialkyl amido or hydroxyl；Or

R₇、R₈And its N atoms of connection constitute nitrogen heterocyclic ring alkyl together, described nitrogen heterocyclic ring alkyl is optionally by one Or multiple halogens, alkyl, haloalkyl, alkoxy, amino, alkyl monosubstituted amino, dialkyl amido, hydroxyl, aminoalkyl, single alkane The substitution of base aminoalkyl, dialkyl aminoalkyl or hydroxy alkyl.

Second aspect, the present invention provide compounds of formula II or its pharmaceutically acceptable salt, isomers, solvate, Crystallization or prodrug,

Its middle ring A, X₁、X₂、X₃、X₄、R_2a、R_2b、R_3a、R_3b、R_3c、R₇And R₈With the definition in formula I.

The third aspect, the present invention provides compounds of formula III or its pharmaceutically acceptable salt,

Its middle ring A, X₁、X₂、X₃、X₄、R_2a、R_2bWith the definition in formula I, M is halogen.

In some embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, its middle ring A are C₄-C₈The monocyclic alkyl of nitrogen-containing hetero, it is optionally by one or more Halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, monoalkyl ammonia Base, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl The substitution of acyl group, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and Heterocyclylalkyl, works as substitution When base has two or more, two adjacent substitution bases can together be constituted substituted or unsubstituted cycloalkanes with atom in connection Base, Heterocyclylalkyl, aryl, heteroaryl, or two substitution bases being connected on same atom can jointly be connected with them Atom forms substituted or unsubstituted cycloalkyl, Heterocyclylalkyl.

In some embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, its middle ring A are to comprise only a C for nitrogen-atoms₄-C₈The monocyclic alkyl of nitrogen-containing hetero, Its optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, Hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxyl alkane Base, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and miscellaneous Cycloalkyl replaces, and when replacing base to have two or more, two adjacent substitution bases can together be constituted with atom in connection Substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or two substitution bases being connected on same atom can Substituted or unsubstituted cycloalkyl, Heterocyclylalkyl are formed with the atom that they are connected jointly.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isN is selected from selected from 1,2,3,4,5 and 6, m 1st, 2,3 and 4, R_aSelected from hydrogen, C_1-6Alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, nitro, Cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, Two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, list C_1-6 Alkylaminoacyl, two C_1-6Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-8Heterocyclylalkyl, when m is selected from 2,3 and 4 When, two R on two neighboring carbon atom_aC is constituted together with the carbon atom that can be connected with them_3-8Cycloalkyl or C_3-8Heterocycle Two R on alkyl, or same carbon atom_aC is constituted together with the carbon atom that can be jointly connected with them_3-8Cycloalkyl or C_3-8 Heterocyclylalkyl.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isN is selected from 1,2,3 selected from 1,2,3 and 4, m With 4, R_aSelected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkoxy, nitro, cyano group, Hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3 Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl, list C_1-3Alkyl ammonia Base acyl group, two C_1-3Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-6Heterocyclylalkyl is adjacent when m is selected from 2,3 and 4 Two R on two carbon atoms_aC is constituted together with the carbon atom that can be connected with them_3-6Cycloalkyl or C_3-6Heterocyclylalkyl, or Two R on same carbon atom_aC is constituted together with the carbon atom that can be jointly connected with them_3-6Cycloalkyl or C_3-6Heterocycle alkane Base.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, its middle ring A is to contain two C of nitrogen-atoms₄-C₈The monocyclic alkyl of nitrogen-containing hetero, Its optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, Hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxyl alkane Base, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and miscellaneous Cycloalkyl replaces, and when replacing base to have two or more, two adjacent substitution bases can together be constituted with atom in connection Substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or two substitution bases being connected on same atom can Substituted or unsubstituted cycloalkyl, Heterocyclylalkyl are formed with the atom that they are connected jointly.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isM is selected from 0,1 selected from 1,2,3 and 4, p 0,1 and 2, R are selected from 2, q_aSelected from hydrogen, C_1-6Alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alcoxyl Base, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl Base, list C_1-6Alkylaminoacyl, two C_1-6Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-8Heterocyclylalkyl, when m choosings From 2,3 and 4 when, two R on two neighboring atom_aC is constituted together with the atom that can be connected with them_3-8Cycloalkyl or C_3-8 Two R on Heterocyclylalkyl, or same atom_aC is constituted together with the atom that can be jointly connected with them_3-8Cycloalkyl or C_3-8 Heterocyclylalkyl.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isM is selected from 0,1 selected from 1,2,3 and 4, p 0,1 and 2, R are selected from 2, q_aSelected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alcoxyl Base, nitro, cyano group, hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl Base, list C_1-3Alkylaminoacyl, two C_1-3Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-6Heterocyclylalkyl, when m choosings From 2,3 and 4 when, two R on two neighboring atom_aC is constituted together with the atom that can be connected with them_3-6Cycloalkyl or C_3-6 Two R on Heterocyclylalkyl, or same atom_aC is constituted together with the atom that can be jointly connected with them_3-6Cycloalkyl or C_3-6 Heterocyclylalkyl.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, its middle ring A is the C containing a nitrogen-atoms and an oxygen atom₄-C₈It is nitrogenous Miscellaneous monocyclic alkyl, it is optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy Base, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl amino Base alkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, virtue The substitution of base, heteroaryl and Heterocyclylalkyl, when replacing base to have two or more, two adjacent substitution bases can be with connection Atom constitutes substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl together, or is connected on same atom The atom that two substitution bases can jointly be connected with them forms substituted or unsubstituted cycloalkyl, Heterocyclylalkyl.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isM is selected from 0,1 and selected from 1,2,3 and 4, p 2, q are selected from 0,1 and 2, R_aSelected from hydrogen, C_1-6Alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, Nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6 Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, Single C_1-6Alkylaminoacyl, two C_1-6Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-8Heterocyclylalkyl, when m be selected from 2, When 3 and 4, two R on two neighboring atom_aC is constituted together with the atom that can be connected with them_3-8Cycloalkyl or C_3-8Heterocycle Two R on alkyl, or same atom_aC is constituted together with the atom that can be jointly connected with them_3-8Cycloalkyl or C_3-8Heterocycle Alkyl.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, its middle ring A isM is selected from 0,1 selected from 1,2,3 and 4, p 0,1 and 2, R are selected from 2, q_aSelected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alcoxyl Base, nitro, cyano group, hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl Base, list C_1-3Alkylaminoacyl, two C_1-3Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-6Heterocyclylalkyl, when m choosings From 2,3 and 4 when, two R on two neighboring atom_aC is constituted together with the atom that can be connected with them_3-6Cycloalkyl or C_3-6 Two R on Heterocyclylalkyl, or same atom_aC is constituted together with the atom that can be jointly connected with them_3-6Cycloalkyl or C_3-6 Heterocyclylalkyl.In some embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, its middle ring A are the C containing a nitrogen-atoms and a sulphur atom₄-C₈Nitrogen-containing hetero Monocyclic alkyl, its optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, Nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl amido Alkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, virtue The substitution of base, heteroaryl and Heterocyclylalkyl, when replacing base to have two or more, two adjacent substitution bases can be with connection Atom constitutes substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl together, or is connected on same atom The atom that two substitution bases can jointly be connected with them forms substituted or unsubstituted cycloalkyl, Heterocyclylalkyl.

In some embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein X₁、X₂、X₃And X₄It is C (R₁)。

In some specific embodiments, the present invention provide below general formula Ia, IIa and the compound shown in IIIa or its Pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,

Its middle ring A, R₁、R_2a、R_2b、R_3a、R_3b、R_3c、R₄、R₅、R₆、R₇、R₈During there is formula above I, II and III with M Definition, n is selected from 1,2,3 and 4 integer.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein X₁、X₂、X₃And X₄In at least one be N.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein X₁、X₂、X₃And X₄In have two for N.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein X₁、X₂、X₃And X₄In have three for N.

In other embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein X₁、X₂、X₃And X₄It is N.

In some embodiments, the present invention provides compound shown in formula I, II or III or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₁、R_2aAnd R_2bIt is each independently selected from hydrogen, halogen, C_1-6Alkyl, C_3-8 Cycloalkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, Two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkane Base, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, list C_1-6Alkylaminoacyl and two C_1-6Alkyl amino acyl Base.

In some preferred embodiments, the compound or its pharmacy that the present invention is provided shown in formula I, II or III can The salt of receiving, isomers, solvate, crystallization or prodrug, wherein each R₁、R_2aAnd R_2bIndependently of one another independently selected from hydrogen, halogen Element, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkoxy, nitro, cyano group, hydroxyl, amino, Single C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-6Alkyl, two C_1-3Alkyl amino C_1-3 Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl, list C_1-3Alkylaminoacyl and two C_1-3Alkylaminoacyl.

In other preferred embodiments, the present invention provides the compound or its pharmacy shown in formula I, II or III Acceptable salt, isomers, solvate, crystallization or prodrug, wherein R₁、R_2aAnd R_2bBe each independently selected from hydrogen, fluorine, chlorine, bromine, Iodine, methyl, ethyl, propyl group, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, trifluoroethyl, difluoro first Base, two fluoro ethyls, methoxyl group, ethyoxyl, propoxyl group, trifluoromethyl epoxide, nitro, cyano group, hydroxyl, amino, methylamino, second ammonia Base, the third amino, isopropylamino, dimethylamino, lignocaine, dipropyl amino, diisopropylaminoethyl, N- methyl-N-ethylaminos, N- methyl-N-propylaminos, N- methyl-N-isoproylaminos, N- ethyl-N- propylcarbamics, N- ethyl-N-iso-propylaminos, N- propyl group-N- isopropylaminos, amino methyl, amino-ethyl, aminopropyl, Methyaminomethyl, methylaminoethyl, ethylamino first Base, ethylaminoethyl, dimethylamino methyl, dimethylaminoethyl, Diethylaminomethyl, diethyllaminoethyl, methylol, hydroxyl second Base, methoxy, ethoxyl methyl, propoxy methyl, methoxy ethyl and ethoxyethyl group.

In other preferred embodiments, the present invention provides the compound or its pharmacy shown in formula I, II or III Acceptable salt, isomers, solvate, crystallization or prodrug, wherein R₁、R_2aAnd R_2bBe each independently selected from hydrogen, fluorine, chlorine, bromine, Methyl, ethyl, propyl group, isopropyl, trifluoromethyl, trifluoroethyl, methoxyl group, ethyoxyl, hydroxyl, amino, methylamino, second ammonia Base, the third amino, dimethylamino, lignocaine, amino methyl, amino-ethyl, aminopropyl, Methyaminomethyl, methylaminoethyl, Ethylaminomethyl, ethylaminoethyl, dimethylamino methyl, Diethylaminomethyl, methylol and ethoxy.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, halogen, C_1-6Alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl ammonia Base, two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, list C_1-6Alkylaminoacyl and two C_1-6Alkyl ammonia Base acyl group.

In other preferred embodiments, the compound or its pharmacy that the present invention provides shown in formula I or II can connect Salt, isomers, solvate, crystallization or the prodrug received, wherein each R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, halogen, C_1-3Alkane Base, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-3Alkane Base amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-6Alkyl, two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl Base C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl, list C_1-3Alkylaminoacyl and two C_1-3Alkyl Aminoacyl.

In other preferred embodiments, the compound or its pharmacy that the present invention provides shown in formula I or II can connect Salt, isomers, solvate, crystallization or the prodrug received, wherein R_3a、R_3bAnd R_3cBe each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, Methyl, ethyl, propyl group, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, trifluoroethyl, difluoromethyl, Two fluoro ethyls, methoxyl group, ethyoxyl, propoxyl group, trifluoromethyl epoxide, nitro, cyano group, hydroxyl, amino, methylamino, ethylamino, Third amino, isopropylamino, dimethylamino, lignocaine, dipropyl amino, diisopropylaminoethyl, N- methyl-N-ethylaminos, N- Methyl-N-propylamino, N- methyl-N-isoproylaminos, N- ethyl-N- propylcarbamics, N- ethyl-N-iso-propylaminos, N- Propyl group-N- isopropylaminos, amino methyl, amino-ethyl, aminopropyl, Methyaminomethyl, methylaminoethyl, ethylamino first Base, ethylaminoethyl, dimethylamino methyl, dimethylaminoethyl, Diethylaminomethyl, diethyllaminoethyl, methylol, hydroxyl second Base, methoxy, ethoxyl methyl, propoxy methyl, methoxy ethyl and ethoxyethyl group.

In other preferred embodiments, the compound or its pharmacy that the present invention provides shown in formula I or II can connect Salt, isomers, solvate, crystallization or the prodrug received, wherein R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, fluorine, chlorine, bromine, first Base, ethyl, propyl group, isopropyl, trifluoromethyl, trifluoroethyl, methoxyl group, ethyoxyl, hydroxyl, amino, methylamino, ethylamino, Third amino, dimethylamino, lignocaine, amino methyl, amino-ethyl, aminopropyl, Methyaminomethyl, methylaminoethyl, second Amino methyl, ethylaminoethyl, dimethylamino methyl, Diethylaminomethyl, methylol and ethoxy.

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt shown in formula I or II, different Structure body, solvate, crystallization or prodrug, wherein R₇Selected from hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl and halo C_1-6Alkyl.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₇Selected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl and halo C_1-3Alkyl.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₇Selected from hydrogen, methyl, ethyl, propyl group, isopropyl, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl and trifluoromethyl.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₇It is methyl.

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt shown in formula I or II, different Structure body, solvate, crystallization or prodrug, wherein R₈Selected from hydrogen, C_1-6Alkyl and C_3-6Cycloalkyl, described C_1-6Alkyl and C_3-6Ring Alkyl is optionally by one or more halogens, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino or hydroxyl replace.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₈Selected from hydrogen, C_1-3Alkyl and C_3-6Cycloalkyl, described C_1-3Alkyl And C_3-6Cycloalkyl is optionally by one or more halogens, C_1-3Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy, amino, list C_1-3Alkyl Amino, two C_1-3Alkyl amino or hydroxyl replace.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₈Selected from hydrogen, C_1-3Alkyl and C_3-6Cycloalkyl, described C_1-3Alkyl And C_3-6Cycloalkyl is optionally by one or more halogens, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, difluoromethyl, trifluoro Ethyl, methoxyl group, ethyoxyl, propoxyl group, isopropyl epoxide, amino, methylamino, ethylamino, the third amino, dimethylamino, diethyl The substitution of amido, dipropyl amino, methylethylamine, methylpropylamino, ethylpropylamino or hydroxyl.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₈Selected from hydrogen, methyl, ethyl and propyl group, described methyl, ethyl With propyl group optionally by one or more amino, methylamino, ethylamino, the third amino, dimethylamino, diethylin, dipropyl amino, first The substitution of base ethylamino, methylpropylamino or ethylpropylamino.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₈It is the ethyl replaced by dimethylamino.

In other embodiments, the present invention provide compound or its pharmaceutically acceptable salt shown in formula I or II, Isomers, solvate, crystallization or prodrug, wherein R₇、R₈And its N of connection constitutes four to eight yuan of azacycloalkyls, described four To eight yuan of azacycloalkyls optionally by one or more halogens, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, amino, list C_1-6 Alkyl amino, two C_1-6Alkyl amino, hydroxyl, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6 Alkyl or hydroxy alkyl replace.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₇、R₈And its N of connection constitutes four to eight yuan of azacycloalkyls, institute Four to the eight yuan of azacycloalkyls stated are optionally by one or more halogens, C_1-3Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy, ammonia Base, list C_1-3Alkyl amino, two C_1-3Alkyl amino, hydroxyl, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3Alkane Base amino C_1-3Alkyl or hydroxy alkyl replace.

In some preferred embodiments, the present invention provides compound shown in formula I or II or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein R₇、R₈And its N of connection constitutes five to six-membered heterocycle alkyl, institute Five to the six-membered heterocycle alkyl stated is optionally by one or more halogens, C_1-3Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy, ammonia Base, list C_1-3Alkyl amino, two C_1-3Alkyl amino, hydroxyl, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3Alkane Base amino C_1-3Alkyl or hydroxy alkyl replace.

In some embodiments, the present invention provides the compound or its pharmaceutically acceptable salt, isomery shown in formula I Body, solvate, crystallization or prodrug, wherein R₄、R₅And R₆It is each independently selected from hydrogen, halogen, cyano group, C_1-6Alkyl, C_1-6Alcoxyl Base, C_3-8Cycloalkyl, described C_1-6Alkyl, C_1-6Alkoxy and cycloalkyl are optionally by one or more halogens, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, hydroxyl, amino C_1-6 Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl and hydroxyl C_1-6Alkyl replaces.

In some preferred embodiments, the present invention provide compound or its pharmaceutically acceptable salt shown in formula I, Isomers, solvate, crystallization or prodrug, wherein R₄、R₅And R₆It is each independently selected from hydrogen, halogen, cyano group, C_1-3Alkyl, C_1-3 Alkoxy, C_3-6Cycloalkyl, described C_1-3Alkyl, C_1-3Alkoxy and C_3-6Cycloalkyl is optionally by one or more halogens, C_1-3Alkane Base, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkoxy, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, hydroxyl, Amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, two C_1-3Alkyl amino C_1-3Alkyl or hydroxyl C_1-3Alkyl replaces.

In some preferred embodiments, the present invention provide compound or its pharmaceutically acceptable salt shown in formula I, Isomers, solvate, crystallization or prodrug, wherein R₄、R₅And R₆It is hydrogen.

In some embodiments, the present invention provides the compound or its pharmaceutically acceptable salt shown in general formula III, wherein M is selected from fluorine, chlorine, bromine and iodine.

In some preferred embodiments, the present invention provides the compound shown in general formula III or its is pharmaceutically acceptable Salt, wherein M are selected from chlorine, bromine and iodine.

In some specific embodiments, the compound or its pharmaceutically acceptable salt provided shown in formula I of the invention, Isomers, solvate, crystallization or prodrug, wherein

Ring A is

N is selected from 1,2,3 and 4；

M is selected from 1,2,3 and 4；

R_aSelected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkoxy, nitro, Cyano group, hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl amino C_1-3Alkyl, Two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, aminoacyl, list C_1-3 Alkylaminoacyl, two C_1-3Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-6Heterocyclylalkyl, when m is selected from 2,3 and 4 When, two R on two neighboring carbon atom_aC is constituted together with the carbon atom that can be connected with them_3-6Cycloalkyl or C_3-6Heterocycle Two R on alkyl, or same carbon atom_aC is constituted together with the carbon atom that can be jointly connected with them_3-6Cycloalkyl or C_3-6 Heterocyclylalkyl；

R₁、R_2a、R_2b、R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, halogen, C_1-3Alkyl, halo C_1-3Alkyl, C_1-3Alcoxyl Base, halo C_1-3Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, Single C_1-3Alkyl amino C_1-6Alkyl, two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkane Base acyl group, aminoacyl, list C_1-3Alkylaminoacyl and two C_1-3Alkylaminoacyl；

R₄、R₅And R₆It is hydrogen；

R₇It is methyl；

R₈It is the ethyl replaced by dimethylamino.

In other specific embodiments, the present invention provides compound shown in formula I or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein

Ring A is

M is selected from 1,2,3 and 4；

P is selected from 0,1 and 2；

Q is selected from 0,1 and 2；R_aSelected from hydrogen, C_1-3Alkyl, C_3-6Cycloalkyl, halo C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3 Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-3Alkyl amino, two C_1-3Alkyl amino, amino C_1-3Alkyl, list C_1-3Alkyl Amino C_1-3Alkyl, two C_1-3Alkyl amino C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkyl acyl, ammonia Base acyl group, list C_1-3Alkylaminoacyl, two C_1-3Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-6Heterocyclylalkyl, when When m is selected from 2,3 and 4, two R on two neighboring atom_aC is constituted together with the atom that can be connected with them_3-6Cycloalkyl or C_3-6Two R on Heterocyclylalkyl, or same atom_aC is constituted together with the atom that can be jointly connected with them_3-6Cycloalkyl or C_3-6Heterocyclylalkyl；

R₄、R₅And R₆It is hydrogen；

R₇It is methyl；

R₈It is the ethyl replaced by dimethylamino.

Ring A is

M is selected from 1,2,3 and 4；

P is selected from 0,1 and 2；

R₄、R₅And R₆It is hydrogen；

R₇It is methyl；

R₈It is the ethyl replaced by dimethylamino.

In some specific embodiments, the invention provides following compound or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug：

In other specific embodiments, the invention provides following compound or its pharmaceutically acceptable salt, different Structure body, solvate, crystallization or prodrug：

Fourth aspect, the present invention provides the preparation method of the compound of formula I, II and III of the invention, including following step Suddenly：

A) there is the intermediate that necleophilic reaction is obtained formula III in the raw material of the raw material of formula 1 and formula 2；

B) intermediate of formula 4 is obtained with the raw material reaction of formula 3 for the intermediate of formula III；

C) intermediate of formula 5 is obtained by necleophilic reaction for the intermediate of formula 4；

D) intermediate of Formula II is obtained by reduction reaction for the intermediate of formula 5；

E) compound of Formulas I is obtained with the raw material reaction of formula 6 for the intermediate of Formula II.

Above-mentioned ring A, X₁、X₂、X₃、X₄、R_2a、R_2b、R_3a、R_3b、R_3c、R₄、R₅、R₆、R₇、R₈During there is formula I, II, III with M Definition.

In some embodiments, the present invention provides the preparation method for preparing compounds of formula I of the invention, the side Method includes using compounds of formula II of the invention.

In some embodiments, the present invention provides the preparation method for preparing compounds of formula I of the invention, the side Method includes using compounds of formula III of the invention.

5th aspect, the present invention provides pharmaceutical composition, and it includes compounds of formula I of the present invention or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.

In some embodiments, the present invention provides pharmaceutical composition, and it includes compounds of formula I of the present invention, isomery Body, solvate, crystallization or prodrug, also comprising one or more compound selected from following composition：Gefitinib, Lip river in distress are replaced Buddhist nun, Lapatinib, Afatinib, ZD6474, Canertinib, Ah handkerchief replace for Buddhist nun, Dacca for Buddhist nun (dacomitinib), training profit Buddhist nun (pelitinib), WZ4002, AG-490, AZD8931, AZD9291 etc..

Can by compounds of formula I of the present invention, isomers, solvate, crystallization or prodrug with it is pharmaceutically acceptable Carrier is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but are not limited to intracutaneous, flesh Interior, intraperitoneal, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as by defeated Note or inject, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) is applied.Being administered to be It is whole body or part.The example of oral administration preparation includes solid or liquid dosage form, specifically, including tablet, pill, grain Agent, pulvis, capsule, syrup, emulsion, supensoid agent etc..The preparation can be prepared by methods known in the art, and comprising medicine The conventional use of carrier of thing formulation art.

6th aspect, the present invention provides compounds of formula I of the present invention, isomers, solvate, crystallization or prodrug or sheet The medicine composite for curing of invention and/or the method for prevention of tumor and the application in treatment and/or prevention of tumor medicine is prepared, Compounds of formula I of the present invention, isomers, solvate, crystallization or preceding are applied including easily sending out crowd or tumor patient to tumour Medicine or the pharmaceutical composition comprising compounds of formula I of the present invention, isomers, solvate, crystallization or prodrug, effectively to drop Low Tumor incidence, extension tumor patient life.

In some embodiments, the present invention provides compounds of formula I of the invention, isomers, solvate, crystallization Or the method that prodrug or medicine composite for curing of the invention have drug-fast tumour, including suffer to drug-fast tumour Person applies compounds of formula I of the present invention, isomers, solvate, crystallization or the prodrug of therapeutically effective amount or comprising this hair The pharmaceutical composition of bright compounds of formula I, isomers, solvate, crystallization or prodrug.

In other embodiments, the present invention provides compounds of formula I of the invention, isomers, solvate, knot The application of brilliant or prodrug or pharmaceutical composition of the invention in medicine of the treatment with drug-fast tumour is prepared.It is described to have Drug-fast tumour can have drug-fast tumour to multi-medicament, the tumour of the anti-medicine of preferred pair EGFR inhibitor, for example To first, second, third generation EGFR inhibitor, for example, have to Gefitinib, Tarceva and Lapatinib drug-fast swollen Knurl.The tumour includes but is not limited to solid tumor, preferably lung cancer, head and neck neoplasm, colorectal cancer, carcinoma of urinary bladder, cancer of pancreas, breast Gland cancer, prostate cancer, stomach cancer, carcinoma of mouth, liver cancer, oophoroma.It is highly preferred that the tumour is non-small cell lung cancer.At some In embodiment, the present invention provides the treatment of compounds of formula I of the invention, isomers, solvate, crystallization or prodrug to be had The method of drug-fast tumour, wherein the tumour carries EGFR mutators.In one embodiment, the tumour is carried EGFR mutators be the 20th exon exist T790M mutation.In another embodiment, the tumour is carried EGFR mutators are that the 21st exon has L858R mutation and/or missing/insertion mutation.In another embodiment, The EGFR mutators that the tumour is carried are T790M and L858R double mutations.In other embodiments, the present invention is carried For compounds of formula I of the invention, isomers, solvate, crystallization or prodrug or medicine of the invention for treating tumour Compositions, wherein treatment function of tumor shows prominent curative effect, the selectivity of height and/or less side effect.Again In some embodiments, the present invention provides compounds of formula I of the invention, isomers, solvate, crystallization or prodrug or sheet The method of the medicine composite for curing tumour of invention, methods described includes giving the present invention for needing its bacterium Compounds of formula I, isomers, solvate, crystallization or prodrug or pharmaceutical composition of the invention, produced treatment swells Effect in terms of knurl shows prominent curative effect, the selectivity of height and/or less side effect.

Term is defined

Unless otherwise defined, all technologies used herein and scientific terminology have and common skill of the art The identical implication that art personnel are generally understood that.

" isomers " of the invention includes the cis-trans-isomer of cis or trans configuration, the mapping for also being produced including chiral carbon Isomers and diastereoisomer.

" pharmaceutically acceptable salt " of the invention refers to compound of the present invention pharmaceutically acceptable with what acid was formed Salt, described acid may be selected from：Phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, butanedioic acid, Fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam etc..

" solvate " of the invention refers to this hair by being coordinated the complex to form solid-state or liquid with solvent molecule The form of bright compound.Hydrate is the special shape of solvate, wherein being coordinated with water.Within the scope of the present invention, it is molten Agent compound is preferably hydrate.

" crystallization " of the invention refers to the various solid forms that compound of the present invention is formed, including crystal formation, nothing are calmly Shape.

" prodrug " of the invention refer under the physiological condition of organism, due to the reaction such as enzyme, hydrochloric acid in gastric juice and conversion cost The compound of invention, i.e., change into compound of the invention and/or by hydrochloric acid in gastric juice etc. by the oxidation of enzyme, reduction, hydrolysis etc. Hydrolysis etc. changes into the compound of compound of the invention.

" pharmaceutical composition " of the invention refer to comprising any compound as herein described, including isomers, prodrug, Solvate, pharmaceutically acceptable salt or its chemical forms of protection, and one or more pharmaceutically acceptable carrier is mixed Compound.

" application in the medicine for treatment and/or prevention of tumor is prepared " of the invention refers to that can suppress tumour Growth, development and/or transfer, mainly give the compound of the invention for the treatment of effective dose to press down to required human or animal Make, slow down or reverse growth, development or the diffusion of subject's tumour.

Term " alkyl " refers to the saturated hydrocarbyl of straight or branched, the alkyl below preferably 6 carbon atoms.The implementation of alkyl Example include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, just oneself Base, isohesyl, 2,2- methyl butyls and 2,3- dimethylbutyls.Term " C_1-6Alkyl " refers to contain the 1-6 straight chain of carbon atom Or the saturated hydrocarbyl of side chain.Term " C_1-3Alkyl " refers to contain the 1-3 saturated hydrocarbyl of the straight or branched of carbon atom.

" cycloalkyl " of the invention refers to saturation, fractional saturation the alkyl of ring-type, below preferably 12 carbon atoms Cycloalkyl, the cycloalkyl below further preferred 8 carbon atoms, the cycloalkyl below still more preferably 6 carbon atoms.Cycloalkanes The embodiment of base includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl." C of the invention_3-8Cycloalkyl " refer to containing The 3-8 saturated hydrocarbyl of the ring-type of carbon atom.

" alkoxy " of the invention refers to-O- alkyl.

" oxo " of the invention refers to O=, and such as carbon atom is replaced to be formed by oxo groupSulphur atom is by an oxygen Formed for substituent groupSulphur atom is replaced to be formed by two oxo groups

" halogen " of the invention refers to fluorine, chlorine, bromine, iodine.

" haloalkyl " of the invention refers at least by an alkyl for halogen atom substitution.

" halogenated alkoxy " of the invention refers at least by an alkoxy for halogen substitution, preferably at least by a halogen The C of element substitution_1-6Alkoxy, more preferably at least by a C for halogen substitution_1-3Alkoxy, suitable halo C_1-3Alcoxyl Base is chloromethane epoxide, fluorine methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy；Two chloroethoxies, Difluoroethoxy, tri-chloroethoxy base, trifluoro ethoxy.

" alkyl monosubstituted amino " of the invention refers to-NH- alkyl, preferably-NH-C_1-6Alkyl, more preferably-NH- C_1-3Alkyl.

" dialkyl amido " of the invention refers to-N- (alkyl) (alkyl), preferably-N- (C_1-6Alkyl) (C_1-6Alkyl), More preferably-N- (C_1-3Alkyl) (C_1-3Alkyl).

" aminoalkyl " of the invention refers to-alkyl-NH₂。

" Mono-alkylaminoalkyl " of the invention refers to-alkyl-NH-alkyl.

" dialkyl aminoalkyl " of the invention refers to-alkyl-N- (alkyl) (alkyl).

" hydroxy alkyl " of the invention refers to-alkyl-OH.

" alkyl acyl " of the invention refers to-C (O)-alkyl.

" aminoacyl " of the invention refers to-C (O)-NH₂。

" alkyl monosubstituted amino acyl group " of the invention refers to-C (O)-NH- alkyl.

" dialkyl amido acyl group " of the invention refers to-C (O)-N- (alkyl) (alkyl).

" Heterocyclylalkyl " of the invention refers to that substituted or unsubstituted at least containing heteroatomic saturation, part is full The cyclic alkyl of sum, described hetero atom is selected from N, O, S.

" aryl " of the invention refer to can comprising the aromatic series of the monocyclic or multi-fused rings such as aromatic rings of two rings or three rings, A part for the ring that wherein at least is condensed forms the aromatic series of conjugation, and it contains 5 to 50 carbon atoms, preferably from about 6 to about 14 Carbon atom.Suitable aryl includes but is not limited to phenyl, naphthyl, xenyl, anthryl, tetralyl, fluorenyl, indanyl, sub- connection Phenyl and acenaphthenyl." C of the invention₆-C₁₀Aryl " refers to contain the 6-10 aromatic series of carbon atom.

" heteroaryl " of the invention refers at least one carbon atom quilt of aromatic monocyclic or multi-fused rings such as two rings or three rings The aromatic radical that hetero atom is substituted, described hetero atom is O, S, N.Suitable heteroaryl includes but is not limited to imidazole radicals, benzene And imidazole radicals, imidazopyridyl, quinazoline ketone group, pyrrole radicals, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl, Thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, triazolyl etc.." C of the invention₅-C₁₀Heteroaryl " refers to contain 5-10 The heteroaryl of individual atom.

" C of the invention₄-C₈Nitrogen heterocycle " refers to substituted or unsubstituted saturation, portion containing at least one nitrogen-atoms Point saturation and the heterocyclic group that complete undersaturated total annular atom number is 4,5,6,7 or 8, such as C₄Nitrogen heterocycle refers to substitution Or unsubstituted saturation, fractional saturation and completely undersaturated total annular atom number be 4 nitrogen heterocyclic ring group." C of the invention₄- C₈The monocyclic alkyl of nitrogen-containing hetero " refers to the substituted or unsubstituted saturation containing at least one nitrogen-atoms, fractional saturation and completely not Total annular atom number of saturation is 4,5,6,7 or 8 single Heterocyclylalkyl, and suitable example is including but not limited to substituted or unsubstituted Azelidinyl, azepine cyclopenta, piperidyl, azacycloheptyl, azocanyl, nitrogen oxocyclopentyl, nitrogen oxa- ring Hexyl, nitrogen oxepane base, nitrogen oxa- cyclooctyl, nitrogen thia cyclopenta, nitrogen thia cyclohexyl, nitrogen thia suberyl, nitrogen thia Cyclooctyl, diazacyclo amyl group, diazacyclo hexyl, diazacyclo heptyl or diazacyclo octyl group；And substitution or unsubstituted Nitrogenous heteroaryl, such as substituted or unsubstituted pyridine radicals, imidazole radicals, pyrazolyl, pyrrole radicals, pyridazinyl, pyrimidine radicals, pyrazine Base, wherein the substitution base is selected from alkyl, oxo, cycloalkyl, hydroxyl, hydroxyalkyl, alkoxy, amino, alkyl monosubstituted amino, double alkane Base amino, acylamino-, alkyl amido, acrylamido, heteroarylamido, halogen, haloalkyl, halogenated alkoxy.This Wen Zhong, the C₄-C₈Nitrogen heterocycle constitutes azacyclo- diindyl structure with indole ring, for example, suitable azacyclo- diindyl knot Structure is included but is not limited to Deng.

Specific embodiment

Representational embodiment is in order to the present invention is better described, not for limitation protection model of the invention below Enclose.

The N- of embodiment 1 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2,3- bis- Hydrogen -1H- pyrrolo-es [1,2-a]-indoles -9- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

The synthesis of step a 1- (3- bromopropyls) -1H- indoles

In 100ml reaction bulbs, NaH (60% content, 1.23g, 30.73mmol) and DMF (10ml), room temperature are sequentially added 0-4 DEG C is cooled to after stirring 5min, the DMF solution that 10mL is dissolved with indoles (3g, 25.61mmol) is slowly added to, finished, risen to Room temperature reaction 20min is obtained indoles activated solution.

It is another to take 250ml reaction bulbs, add 1,3- dibromopropanes (15.51g, 76.82mmol) and DMF (50ml).At 0-4 DEG C Indoles activated solution obtained above is slowly added dropwise, drop finishes, and 0.5h is reacted at room temperature.After reaction terminates, water (100ml) is added to quench Go out reaction, ethyl acetate extraction, combined ethyl acetate layer, anhydrous sodium sulfate drying, filtering, concentration, column chromatography purifies to obtain title Compound.

ESI-Ms m/z:239.1[M+H]。

The synthesis of step b 1- (3- iodine propyl group) -1H- indoles

In 250ml reaction bulbs, sequentially add step a gains 1- (3- bromopropyls) -1H- indoles (4.72g, 19.83mmol), sodium iodide (13.39g, 89.93mmol) and acetonitrile (100ml), backflow is overnight.After reaction terminates, add water, second Acetoacetic ester is extracted, and combined ethyl acetate layer, anhydrous sodium sulfate drying, filtering, concentrate drying obtains title thing, is directly used in next Step.

ESI-Ms m/z:286.1[M+H]。

The synthesis of step c 2,3- pyrrolin simultaneously [1,2-a] indoles

In 250ml three-necked bottles, sequentially add step b gains 1- (3- iodine propyl group) -1H- indoles (5.44g, 19.83mmol), potassium phosphate (8.4g, 39.67mmol), four triphenyl phosphorus palladiums (2.3g, 1.98mmol) and Isosorbide-5-Nitrae-dioxane (80ml), argon gas protection, flow back reaction overnight.After reaction terminates, add water and reaction is quenched, ethyl acetate extraction merges acetic acid second Ester layer, anhydrous sodium sulfate drying, filtering, concentration, column chromatography purifies to obtain title compound.

ESI-Ms m/z:158.1[M+H]。

The synthesis of step d 9- (2- chlorine pyrimidine-4-yl) -2,3- pyrrolin simultaneously [1,2-a] indoles

In 100ml reaction bulbs, sequentially add alchlor (2.18g, 16.35mmol), glycol dimethyl ether (50ml), 2,4- dichloro pyrimidines (2.44g, 16.35mmol) and step c gains 2,3- pyrrolin simultaneously [1,2-a] indoles (2.57g, 16.35mmol), back flow reaction 2h.After reaction terminates, reaction solution is cooled to room temperature, filtering, filter cake washing, and title is obtained after drying Thing.

ESI-Ms m/z:270.4[M+H]。

Step e N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (2,3- pyrrolin simultaneously [1,2-a] indoles -9- Base)-pyrimidine -2- amine synthesis

In 250ml reaction bulbs, step d gained 9- (2- chlorine pyrimidine-4-yl) -2,3- pyrrolin is added simultaneously [1,2-a] The fluoro- 2- methoxyl groups -5- nitroanilines (1.86g, 10mmol) of indoles (2.69g, 10mmol), 4- and p-methyl benzenesulfonic acid (1.71g, 10mmol), the dissolving of 50mL sec-butyl alcohols is added, 110 DEG C of reaction 2h after reaction terminates, are cooled to room temperature, filter, sec-butyl alcohol washing, Dry title compound.

ESI-Ms m/z:420.4[M+H]。

Step f N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) -4- The synthesis of (2,3- pyrrolin simultaneously [1,2-a] indoles -9- bases)-pyrimidine -2- amine

In 50ml reaction bulbs, sequentially add step e gains N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (2, 3- pyrrolin simultaneously [1,2-a] indoles -9- bases)-pyrimidine -2- amine (2.5g, 6mmol), N, N, N '-trimethyl ethylenediamine (0.61g, 6mmol), diisopropylethylamine (2.3g, 18mmol) and 10ml dioxane, 110 DEG C of back flow reaction 3h, reaction knot Shu Hou, concentration, column chromatography purifies to obtain title compound.

ESI-Ms m/z:502.4[M+H]。

Step g N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- aminophenyls) -4- The synthesis of (2,3- pyrrolin simultaneously [1,2-a] indoles -9- bases)-pyrimidine -2- amine

In 50ml reaction bulbs, step f gains N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia is sequentially added Base) -2- methoxyl group -5- nitrobenzophenones) -4- (2,3- pyrrolin simultaneously [1,2-a] indoles -9- bases)-pyrimidine -2- amine (2.5g, 5mmol), 10%Pd-C (20mg) and 30ml methyl alcohol, in 1 normal atmosphere pressure, hydrogen reducing 1h after reaction terminates, is filtered, Title compound is concentrated to give, next step is directly used in.

ESI-Ms m/z:472.6[M+H]。

Step h N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methyl -4- (2, 3- dihydro -1H- pyrrolo-es [1,2-a]-indoles -9- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

In 150ml single port bottles, addition step g gains N- (4- ((2- (dimethylamino) ethyl) (methyl) amino)- 2- methoxyl group -5- aminophenyls) -4- (2,3- pyrrolin simultaneously [1,2-a] indoles -9- bases)-pyrimidine -2- amine (2g, 4.2mmol), diisopropylethylamine (0.53g, 4.2mmol) and 20ml anhydrous methylene chlorides, are slowly added to 5ml dissolvings after dissolving There is the dichloromethane solution of pi-allyl acyl chlorides (0.37g, 4.2mmol), react 10min, after reaction terminates, concentration, column chromatography is pure Change to obtain title compound.

¹H NMR(300MHz,DMSO-d₆):δ10.17(s,1H),8.69(s,1H),8.28-8.25(d,2H),8.02(s, 1H), 7.37-7.35 (d, 1H), 7.15-6.97 (m, 4H), 6.44-6.35 (m, 1H), 6.21-6.15 (m, 1H), 5.74-5.70 (d,1H),4.1-4.10(t,2H),3.81(s,3H),3.35(s,1H),3.30-3.25(t,1H),2.90(s,2H),2.73 (s,3H),2.60-2.56(m,2H),2.33(s,2H),2.22(s,6H)。

ESI-Ms m/z:526.4[M+H]。

The N- of embodiment 2 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8, 9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

The synthesis of step a 1- (4- brombutyls) -1H- indoles

In 100mL reaction bulbs, NaH (60% content, 1.23g, 30.73mmol), DMF (10mL), room temperature are sequentially added 0-4 DEG C is cooled to after stirring 5min, the DMF solution that 10mL is dissolved with indoles (3g, 25.61mmol) is slowly added to, finished, risen to Room temperature reaction 20min is obtained indoles activated solution.

It is another to take 250mL reaction bulbs, add Isosorbide-5-Nitrae-dibromobutane (16.59g, 76.82mmol), DMF (50mL).At 0-4 DEG C Indoles activated solution obtained above is slowly added dropwise, drop finishes, and 0.5h is reacted at room temperature.After reaction terminates, water (100mL) is added to quench Go out, ethyl acetate extraction, combined ethyl acetate layer, anhydrous sodium sulfate drying, filtering, concentration, column chromatography purifies to obtain title compound Thing.

ESI-Ms m/z:252.1[M+H]。

The synthesis of step b 1- (4- iodine butyls) -1H- indoles

In 250mL reaction bulbs, sequentially add step a gains 1- (4- brombutyls) -1H- indoles (5g, 19.83mmol), sodium iodide (13.39g, 89.93mmol), acetonitrile (100mL), backflow is overnight.After reaction terminates, add water, acetic acid Ethyl ester is extracted, and combined ethyl acetate layer, anhydrous sodium sulfate drying, filtering, concentrate drying obtains title thing, is directly used in next step.

ESI-Ms m/z:300.0[M+H]。

The synthesis of step c 6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles

In 250mL three-necked bottles, (5.93g is pressed to sequentially add step b gains 1- (4- iodine butyls) -1H- indoles 19.83mmol), potassium phosphate (8.4g, 39.67mmol), four triphenyl phosphorus palladiums (2.3g, 1.98mmol), Isosorbide-5-Nitrae-dioxane (80mL), argon gas protection, flow back reaction overnight.After reaction terminates, add water and reaction is quenched, ethyl acetate extraction merges acetic acid second Ester layer, anhydrous sodium sulfate drying, filtering, concentration, column chromatography purifies to obtain title compound.

ESI-Ms m/z:172.1[M+H]。

The synthesis of step d 10- (2- chlorine pyrimidine-4-yl) -6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles

In 100mL reaction bulbs, sequentially add alchlor (2.18g, 16.35mmol), glycol dimethyl ether (50mL), 2,4- dichloro pyrimidines (2.44g, 16.35mmol), step c gains 6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles (2.8g, 16.35mmol), back flow reaction 2h.After reaction terminates, reaction solution is cooled to room temperature, filtering, filter cake washing, and title is obtained after drying Thing.

ESI-Ms m/z:284.1[M+H]。

Step e N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8,9- Tetrahydropyridine simultaneously [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With step d gains 10- (2- chlorine pyrimidine-4-yl) -6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles, the fluoro- 2- of 4- Methoxyl group -5- nitroanilines, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides be raw material, according to step e, f of embodiment 1, g and The method of h is obtained title compound.

¹H NMR(300MHz,DMSO-d₆)δ10.20(s,1H),8.65(s,1H),8.34(d,1H),8.11(s,1H), 8.06(d,1H),7.43(d,1H),7.19-7.03(m,3H),6.98(s,1H),6.57-6.41(m,1H),6.28-6.15(m, 1H),5.82-5.71(m,1H),4.09(t,2H),3.84(s,3H),3.18(t,2H),3.06-2.92(m,2H),2.66(s, 3H),2.47-2.40(m,2H),2.27(s,6H),2.08-1.96(m,2H),1.87-1.74(m,2H)。

ESI-Ms m/z:540.3[M+H]。

The N- of embodiment 3 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methyl -4- (6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) and allyl acid amides synthesis

The synthesis of step a 10- (the chloro- 5- methylpyrimidines -4- bases of 2-) -6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles

With the step c gains 6,7,8,9- tetrahydropyridines of embodiment 2, simultaneously [1,2-a] indoles and 5- methyl -2,4- dichloros are phonetic Pyridine is raw material, and title compound is obtained according to the method for the step d of embodiment 2.

Step b N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methyl -4- (6, 7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With step a gains 10- (the chloro- 5- methylpyrimidines -4- bases of 2-) -6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles, The fluoro- 2- methoxyl groups -5- nitroanilines of 4-, N, N, N '-trimethyl ethylenediamine and pi-allyl acyl chlorides be raw material, according to the step of embodiment 1 The method of rapid e, f, g and h is obtained title compound.

¹H NMR(300MHz,DMSO-d₆)δ10.02(s,1H),δ8.84(s,1H),8.33(s,1H),7.77(s,1H), 7.42(d,1H),7.26(d,1H),7.10-7.13(m,1H),7.04-7.07(m,1H),6.95(s,1H),6.34-6.39(m, 1H),6.19-6.22(m,1H),5.73(d,1H),4.11(t,2H),3.83(s,3H),2.99(s,2H),2.83(t,2H), 2.67(s,3H),2.25(t,2H),2.17(s,6H),2.07(s,3H),2.04(m,2H),1.79(m,2H)。

ESI-Ms m/z:554.3[M+H]。

The N- of embodiment 4 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8, 9- tetrahydropyridines simultaneously [1,2-a] -5- fluoro indole -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, 5- fluoro indoles, 1,4- dibromobutanes, N, N, N ' - Trimethyl ethylenediamine, pi-allyl acyl chlorides are raw material, and title compound is obtained according to the method for embodiment 1.

¹H NMR(300MHz,DMSO-d₆):δ9.62(s,1H),9.42(s,1H),8.3-8.27(d,2H),7.87(s, 1H),7.49(d,1H),7.14(d,1H),7.06(s,2H),6.71-6.63(m,1H),6.22-6.16(m,1H)5.73(d, 1H),4.13(s,2H),3.84(s,3H),3.32(s,4H),3.22-3.20(t,2H),2.83(s,6H),2.64(s,3H), 2.02(s,2H),1.85(s,2H)。

ESI-Ms m/z:558.4[M+H]。

The N- of embodiment 5 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- ((2,3- bis- Hydrogen -1H- pyrrolo- [1,2-a] -5- fluoro indole -9- bases) the chloro- pyrimidine -2-bases of -5-) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4,5- trichloropyrimidines, 5- fluoro indoles, 1,3- dibromopropanes, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides are raw material, and title compound is obtained according to the method for embodiment 1.

1H NMR(300MHz,DMSO-d6)δ：9.99(s,1H),8.48(s,1H),8.42(s,2H),7.41-7.34(m, 2H),6.98-6.91(m,2H),6.44–6.39(m,1H),6.17(m,1H),5.61(d,1H),4.14(t,2H),3.82(s, 3H),3.16–3.11(m,2H),2.91-2.87(m,2H),2.68(s,3H),2.57–2.54(m,2H),2.39–2.35(m, 2H),2.23(s,6H).

ESI-Ms m/z:578.2[M+H]。

The N- of embodiment 6 (2-((2-(dimethylamino) ethyl) (methyl) amino)-4- methoxyl groups-5-((4- (2,3- bis- Hydrogen -1H- pyrrolo- [1,2-a] -5- fluoro indole -9- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, 5- fluoro indoles, 1,3- dibromopropanes, N, N, N ' - Trimethyl ethylenediamine, pi-allyl acyl chlorides are raw material, and title compound is obtained according to the method for embodiment 1.

1H NMR(300MHz,DMSO-d6)δ10.07(s,1H),8.65(s,1H),8.25(d,1H),8.05–8.02(m, 1H),7.36-7.34(m,2H),7.01(s,1H),6.90–6.97(m,2H),6.36-6.34(m,1H),6.17-6.15(m, 1H),5.69-5.67(d,1H),4.13(t,2H),3.79(s,3H),2.89–2.88(t,2H),2.73(s,3H),2.62– 2.60(t,2H),2.51–2.50(t,2H),2.32-2.30(t,2H),2.21(s,6H).

ESI-Ms m/z:544.4[M+H]。

The N of embodiment 7-(2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl groups-5- ((4- (3,4- bis- Hydrogen -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

The synthesis of step a 2- skatoxyls

In 100ml reaction bulbs, Lithium Aluminium Hydride (902.63mg, 23.78mmol), THF (30ml) are sequentially added, room temperature is stirred Ice bath after 5min is mixed, indole -2-carboxylic ethyl ester (3g, 15.86mmol) is slowly added to, finished, be warmed to room temperature reaction 2h.Reaction knot Shu Hou, 0 DEG C is cooled to by system, is then added thereto 20ml THF and 1.7ml20%KOH, is filtered after stirring 10min, Filter cake is washed with 20ml THF, filtrate is washed once with saturation NaCl (10ml), anhydrous sodium sulfate drying, filtered, concentrate drying is obtained Title thing 2.3g, is directly used in next step.

ESI-Ms m/z:148.1[M+H]。

The step b 3,4- dihydros -1H- [synthesis of 1,4] oxazines simultaneously [4,3-a] indoles

In 500ml reaction bulbs, step a gained 2- skatoxyls (300mg, 2.04mmol), KOH are sequentially added (285.91mg,5.10mmol)、CH₂Cl₂(160ml), ice bath is cooled to 0 DEG C or so, nitrogen protection, after stirring 10min.Will 40mL is dissolved with Diphenyl (vinyl) sulfonium trifluoromethanesulfonate (888.86mg, 2.45mmol) CH₂Cl₂Solution is added dropwise in above-mentioned reaction system, is finished, and is warmed to room temperature reaction.After TLC monitoring raw materials disappear, reaction knot Shu Hou, adds water and reaction is quenched, ethyl acetate extraction, combined ethyl acetate layer, anhydrous sodium sulfate drying, filtering, concentration, column chromatography Purify to obtain title thing 300mg.

ESI-Ms m/z:174.1[M+H]。

Step c N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- dihydros - 1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, step b gained 3,4- dihydros -1H- [1,4] Evil Piperazine simultaneously [4,3-a] indoles, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides be raw material, and mark is obtained according to the method for embodiment 1 Topic compound.

1H NMR(300MHz,DMSO-d6)δ10.04(s,1H),8.61(s,1H),8.35(d,1H),8.06(d,1H), 8.03(s,1H),7.50-7.49(d,1H),7.24–7.19(m,2H),7.12-7.11(d,1H),7.00(s,1H),6.45(s, 1H),6.22–6.19(d,1H),5.73-5.71(d,1H),5.07(s,2H),4.16–4.14(t,2H),4.06–4.04(t, 2H),3.81(s,3H),2.96(s,2H),2.70(s,3H),2.30(s,6H),2.35(m,2H).

ESI-Ms m/z:542.2[M+H]。

The N- of embodiment 8 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8, 9- tetrahydropyridines simultaneously [1,2-a] -7- chloro-indole -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, 7- chloro-indoles, Isosorbide-5-Nitrae-dibromobutane, N, N, N ' - Trimethyl ethylenediamine, pi-allyl acyl chlorides are raw material, and title compound is obtained according to the method for embodiment 1.

1H NMR(300MHz,DMSO-d6)δ：10.04(s,1H),8.69(s,1H),8.38–8.36(d,1H),8.26 (s,1H),8.00(s,2H),7.14–7.12(m,1H),7.03–6.98(m,2H),6.43–6.35(m,1H),6.17–6.16 (d,1H),5.71–5.70(d,1H),4.66–4.62(m,2H),3.34–3.21(m,3H),2.90–2.86(m,3H),2.70 (s,4H),2.33–2.31(m,2H),2.20(s,6H),2.20–2.19(m,2H),1.78–1.76(m,2H),

ESI-Ms m/z:575.2[M+H]。

The N- of embodiment 9 (5- ((4- (1,1- dimethyl -2,3- dihydro -1H- pyrrolo- [1,2-a] indoles -9- bases) pyrimidine - 2- yls) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) and acrylamide synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, the bromo- 3- methybutanes of 1,3- bis-, indoles, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides are raw material, and title compound is obtained according to the method for embodiment 1.

1H NMR(300MHz,DMSO-d6)δ10.00(s,1H),8.58(s,1H),8.36–8.58(m,1H),7.91– 7.96(m,2H),7.35–7.40(m,1H),7.09–7.40(m,4H),6.36–6.45(m,1H),6.18–6.23(m,1H), 5.71–5.74(m,1H)4.12–4.19(m,2H),3.80(s,3H),2.93(s,2H),2.69(s,3H),2.37–2.44(m, 2H),2.28(s,6H),1.56(s,2H),1.37(s,6H).

ESI-Ms m/z:554.3[M+H]。

The N- of embodiment 10 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8, 9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases) the chloro- pyrimidine -2-bases of -5-) amino) phenyl) allyl acid amides synthesis

With the step c gains 6,7,8,9- tetrahydropyridines of the embodiment 2 simultaneously fluoro- 2- methoxyl groups -5- nitre of [1,2-a] indoles, 4- Base aniline, 2,4,5- trichloropyrimidines, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides be raw material, according to the method for embodiment 1 Title compound is obtained.

1H NMR(300MHz,DMSO-d6)δ：9.63(s,1H),9.47(s,1H),8.3–8.30(d,2H),7.85(s, 1H), 7.5 (d, 1H), 7.12 (d, 1H), 7.04 (s, 2H), 6.72-6.61 (m, 1H), 6.23-6.15 (m, 1H), 5.7,5 (d, 1H),4.12(s,2H),3.86(s,3H),3.34(s,4H),3.20–3.17(t,2H),2.86(s,6H),2.66(s,3H), 2.01(s,2H),1.86(s,2H).

ESI-Ms m/z:575.2[M+H]。

The N- of embodiment 11 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6,7,8, 9- tetrahydropyridines simultaneously [1,2-a] -5- Methoxv-indole -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, 5- methoxy-Indoles, 1,4- dibromobutanes, N, N, N '-trimethyl ethylenediamine, pi-allyl acyl chlorides be raw material, according to embodiment 1 method be obtained title compound.

1H NMR(300MHz,DMSO-d6)δ：10.02(s,1H),9.53(s,1H),8.40–8.45(d,2H),7.92 (s,1H),7.52(d,1H),7.18(d,1H),7.10(s,2H),6.76–6.70(m,1H),6.28–6.20(m,1H)5.72 (d,1H),4.12(s,2H),3.85(s,3H),3.72(s,3H),3.32(s,4H),3.21–3.19(t,2H),2.83(s, 6H),2.65(s,3H),2.02(s,2H),1.86(s,2H).

ESI-Ms m/z:570.4[M+H]。

The N- of embodiment 12 (2- ((2- (dimethylamino) ethyl) (methyl) amino-4-methoxyl -5- ((4- (1,1a, 2, 8b- tetrahydrochysenes cyclopropyl [3,4] pyrrolo- [1,2-a] indoles -8- bases) pyrimidine -2-base) amino) phenyl) acrylamide synthesis

The synthesis of step a 1- pi-allyl -1H- indoles -2- formaldehyde：

In 100mL bottle with two necks, 25ml dry DMFs are added, be cooled to 0-5 DEG C, be slowly added to 662mg NaH, stirred 10min.10mL is slowly dropped into above-mentioned reaction solution dissolved with the anhydrous DMF solution of 2g 1H- indoles -2- formaldehyde, bubble is produced, Solution colour is changed into furvous, persistently stirs 15min, and the dry DMF for being then slowly added into 5mL dissolved with 1.82g 3- bromopropenes is molten Liquid, room temperature reaction 3h adds 50mL water, and 3X60ml ethyl acetate extraction, concentration is dried, and column chromatography obtains title thing 2.0g.

ESI-Ms m/z:186.0[M+H]

Step b：The synthesis of N- ((1- acrylic -1H- indoles -2- bases) methene) -4- Methyl benzenesulfonyl hydrazines：

In 100mL single port bottles, sequentially add step a gained 1- pi-allyl -1H- indoles -2- formaldehyde (1.85g, 10mmol), to Methyl benzenesulfonyl hydrazine (1.86g, 10mmol), 50mL methyl alcohol, 85 DEG C of back flow reaction 2h of oil bath.It is concentrated to give title thick Product 3.6g, is directly used in next step.

Step c：The synthesis of 1,1a, 2,8b- tetrahydrochysene cyclopropyl [3,4] pyrrolo- [1,2-a] indoles：

In 250mL there-necked flasks, step b gained N- ((1- acrylic -1H- indoles -2- bases) methene) -4- methyl is added Benzene sulfonyl hydrazide (2.2g, 6.23mmol), potassium carbonate (1.29g, 9.35mmol), 60ml dioxane, 100 DEG C of back flow reactions of oil bath 12h.Filtering, concentration adds 50ml water, 3X 40ml ethanol extraction, 30ml washings, concentration, column chromatography to obtain 1.0g title products, It is directly used in next step.

Step d：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino-4-methoxyl -5- ((4 (1,1a, 2,8b- Tetrahydrochysene cyclopropyl [3,4] pyrrolo- [1,2-a] indoles -8- bases) pyrimidine -2-base) amino) phenyl) acrylamide synthesis

With the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, 2,4- dichloro pyrimidines, step c gained 1,1a, 2,8b- tetrahydrochysene cyclopropyl [3,4] pyrrolo- [1,2-a] indoles, N, N, N '-trimethyl ethylenediamine and pi-allyl acyl chlorides be raw material, synthesize according to embodiment 1 Method is obtained title compound.

¹H-NMR(300MHz,DMSO-d₆)δ:10.03(s,1H),8.70(s,1H),8.32-8.33(d,1H),8.24- 8.26(d,1H),8.01(s,1H),7.21-7.28(m,2H),7.10-7.13(m,1H),7.03-7.06(m,2H),6.41- 6.47(m,1H),6.20-6.23(d,1H),5.74-5.76(d,1H),4.19-4.28(m,2H),3.86(s,3H),2.97(s, 2H),2.95(s,2H),2.74(s,3H),2.29-2.5(m,8H),1.44-1.45(m,1H),0.70-0.71(m,1H)。

ESI-Ms m/z:537.9[M+H]

The N- of embodiment 13 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (6- oxygen Generation -6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:554.4[M+H]

((((6- is fluoro- for 4- for -4- methoxyl groups -5- for 2- ((2- (dimethylamino) ethyl) (methyl) amino) for the N- of embodiment 14 6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:558.3[M+H]

((((9- is fluoro- for 4- for -4- methoxyl groups -5- for 2- ((2- (dimethylamino) ethyl) (methyl) amino) for the N- of embodiment 15 6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:558.5[M+H]

The N- of embodiment 16 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (9,9- bis- Fluoro- 6,7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:575.3[M+H]

The N- of embodiment 17 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1,2- bis- Hydrogen diazete simultaneously [1,2-a] indoles -8- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:511.6[M+H]

((((1- is fluoro- for 4- for -4- methoxyl groups -5- for 2- ((2- (dimethylamino) ethyl) (methyl) amino) for the N- of embodiment 18 2,3- dihydro -1H- pyrrolo-es [1,2-a]-indoles -9- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:543.8[M+H]

The N- of embodiment 19 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2- oxygen Generation -1,2- dihydros diazete simultaneously [1,2-a] indoles -8- bases)-pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:525.4[M+H]

The N- of embodiment 20 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1,1- bis- Oxo -3,4- dihydros -2H- [1,2] thiazine [2,3-a] indoles -5- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:590.4[M+H]

The N- of embodiment 21 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2,3- bis- Methyl isophthalic acid, 2,3,4- tetrahydrochysenes pyrazine [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:569.5[M+H]

The N- of embodiment 22 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- oxygen Generation -1,2,3,4- tetrahydrochysenes pyrazine [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:555.7[M+H]

The N- of embodiment 23 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2- first Base -1,2,3,4- tetrahydrochysenes pyrazine [1,2-a] indoles -10- bases) pyrimidine -2-base) amino) phenyl) allyl acid amides synthesis

ESI-Ms m/z:554.8[M+H]

The vitro kinase activity evaluation of experimental example 1

1 experiment material

1.1 enzymes

EGFR^WTKinases, is purchased from Carna companies；

EGFR^T790M/L858RKinases, is purchased from Invitrogen companies.

1.2 reagents

Atriphos (ATP), is purchased from Sigma companies；

Peptide (Peptide FAM-P22), is purchased from GL Biochem companies；

Ethylenediamine tetra-acetic acid (EDTA), is purchased from Sigma companies.

1.3 instruments

Caliper EZ reader micro-fluidic chip instruments, are purchased from Caliper Life Sciences, Inc.

2 experimental techniques

2.1 prepare 1 × kinases basis buffer and stop buffer

1 × kinases basis buffer is (for EGFR^WT)：50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl₂, 10mM MnCl₂, 2mM DTT；

1 × kinases basis buffer is (for EGFR^T790M/L858R)：50mM HEPES, pH7.5,0.0015%Brij-35, 10mM MgCl₂, 2mM DTT；

Stop buffer：100mM HEPES, pH7.5,0.0015%Brij-35,0.2%Coating Reagent#3, 50mM EDTA。

2.2 prepare compound

Compound of the invention is dissolved to 10mM respectively with 100%DMSO, then 50 μM are diluted to complete medium, so After being diluted to 5 μM with the complete medium containing 0.1%DMSO afterwards, 3 times of dilutions successively, totally 10 concentration are (for EGFR^WT)；

Compound of the invention is dissolved to 10mM respectively with 100%DMSO, then 50 μM are diluted to complete medium, so After being diluted to 1 μM with the complete medium containing 0.1%DMSO afterwards, 3 times of dilutions successively, totally 10 concentration are (for EGFR^T790M ^/L858R)；

100 μ l 100%DMSO are added in empty hole for being formulated with kinases without compound control group and without kinases without change Compound control group；

It is to carry out source plate to mark 96 orifice plate used above.

2.3 prepare intermediate plate

10 μ l solution are always shifted in source plate in 96 new orifice plates, as intermediate plate, 90 μ is added in intermediate plate is per hole 1 × kinase buffer liquids of l, vibration mixes 10min.

2.4 preparing experiment plates

From 96 hole intermediate plates, in every hole transferase 45 μ l solution to 384 orifice plates.

2.5 kinase reactions

2.5.1. 2.5 × kinase solution is prepared：By EGFR^WTKinases and EGFR^T790M/L858RKinases stoste is separately added into 1 × In basis buffer, 2.5 × kinase solution is configured to；

2.5.2. 2.5 × peptide solution is prepared：The peptide and ATP that FAM is marked are added in 1 × basis buffer, It is configured to 2.5 × peptide solution；

2.5.3. shift in 10 2.5 × kinase solutions of μ l to 384 hole brassboards, be incubated at room temperature 10min；

2.5.4. in shifting 10 μ 2.5 × peptides of l solution to 384 hole brassboards, when being incubated one section under the conditions of 28 DEG C Between, add 25 μ l stop buffer terminating reactions.

Set simultaneously and (include DMSO, 1 × basis buffer and 2.5 × peptide solution without compound control group without kinases And have kinases without compound control group (including DMSO, 2.5 × kinase solution and 2.5 × peptide solution).

2.5.5.Caliper instrument readings, matched curve, calculates inhibiting rate

Data are read on Caliper instruments, and conversion data are obtained from Caliper programs, according to following Formula calculates inhibiting rate：

Inhibiting rate %=(max-com)/(max-min) × 100 calculate inhibiting rate, wherein " max " is represented has kinases without change Compound control group, " com " represents test-compound group, and " min " is represented without kinases without compound control group.

2.5.6. IC is calculated using the data processing softwares of Graphpad 5.0₅₀Value.The results are shown in Table 1.

Table 1

Knowable to experimental result, compound of the invention is to mutant egf R kinases, such as EGFR^L858R/T790MKinases has Good inhibitory activity, IC₅₀Value is less than 1nM, influences small to Wild type EGFR kinases, with preferable selectivity.

The cell in vitro activity rating of experimental example 2

2. experiment material

1.1 cells and positive control drug

Experiment cell line NCI-H1975 (the double mutant cells of EGFR, be mutated with L858R and T790M) and A431 (EGFR Wild-type cell), purchased from ATCC.

The efficient selective of listing, the irreversibility EGFR mutant inhibitor produced using Astrazeneca AB , used as positive control drug, synthetic method is referring to PCT/GB2012/051783 (patent No. WO2013/014448) explanation for AZD9291 Book embodiment 28, and composed by hydrogen and mass spectrum confirmation.

1.2 reagents

Cell Titer-Glo luminescent cell viability assay, purchased from Promega companies；

RPMI1640medium, purchased from Invitrogen companies；

DMEM medium, purchased from Invitrogen companies；

Hyclone, purchased from Invitrogen companies；

DMSO, purchased from Sigma companies；

NCI-H1975 cell culture in containing 10% inactivation hyclone (GIBCO) RPMI1640 culture mediums in, containing green grass or young crops The mycin 100IU/mL and μ g/mL of streptomysin 100；

A431 cell culture in containing 10% inactivation hyclone (GIBCO) DMEM culture mediums in, containing penicillin The 100IU/mL and μ g/mL of streptomysin 100.

2 experimental techniques

2.1 experimentations (CTG assay)

After by the NCI-H1975 cells and A431 cell dissociations of exponential phase, single cell suspension is blown and beaten into, be inoculated in 96 Well culture plate, per the μ L of hole culture medium 100, various 3 piece of 96 orifice plate of each cell line, wherein NCI-H1975 cell per wells inoculation 3X 10³Individual cell, A431 cell per wells inoculation 4X 10³Individual cell.By postvaccinal NCI-H1975 cells and A431 cells 5% CO₂Cultivated 16-24 hours in incubator, after after cell attachment, (compound exists to add test-compound by following concentration requirement Highest test concentrations on NCI-H1975 cells are 4 μM, 3 times of dilutions, totally 9 concentration；Highest test on A431 cells is dense It is 10 μM to spend, 3 times of dilutions, totally 9 concentration), it is further cultured in incubator 72 hours.Blank control group is set simultaneously (only to train Base is supported, cell and DMSO solution is not added with) and DMSO control groups (cell and 0.5% DMSO solution are added in culture medium).Add The CTG solution of 100 μ L, lucifuge vibration 2min, is incubated 10min.2.2 readings, calculate IC₅₀Value

Culture plate is put intoMulti-mode micropore board detector read plate, records luminescence readings results, and Inhibiting rate is calculated according to below equation：

Inhibitor (%)=(1- (RLU_com-RLU_blank)/(RLU_DMSO–RLU_blank)) × 100%,

Wherein RLU_comRepresent the light absorption value of test-compound group, RLU_blankRepresent the light absorption value of blank control group, RLU_DMSO The light absorption value of DMSO control groups is represented,

Drug effect inhibiting rate curve is drawn using XLFit curve fitting softwares and calculate IC₅₀Value, the results are shown in Table 2.

Table 2

In vitro cell experiment result shows that suppression of the compound of the invention to double-mutant cell (NCI-H1975) is made With preferable and small to the suppression of EGFR wild-type cells (A431), selectivity is similar to AZD9291 or is substantially better than AZD9291. One of major side effects of EGFR inhibitor of known current listing are fash, diarrhoea etc., these all with the EGFR quilts of wild type Suppress, poor selectivity is relevant.Therefore, compound of the invention is expected to turn into resist EGFR and be mutated causes the tumour of resistance with spy Different curative effect and the less medicine of side effect.

The blood sugar influence of experimental example 3 is detected

1 experiment material

1.1 compounds

The compound of the invention citric acid-sodium citrate buffer (pH4.5) of 25mM is dissolved, being configured to concentration is The settled solution of 1.25mg/mL, is set to test-compound group；It is set to the citric acid-sodium citrate buffer (pH4.5) of 25mM Vehicle control group；

1.2 animals

Female BAl BIc/C mice, every group each 5, body weight 18-22g, the western pul-Bi Kai experimental animals Co., Ltd in Shanghai carries For.The environment laundering period of 2~4 days is given before test mice experiment, fasting 8-12h before administration.

2 experimental techniques

2.1 mouse fasting but can free water 12 hours；

2.2 take the mouse 5 in step 2.1, and gavage (intragastric administration, I.G.) gives this The compound 25mg/kg of invention；

2.3 detect dynamic in 0min after gavage, the blood sampling of 15min, 30min, 1h, 2h eye socket using Roche brilliance type blood glucose meter Thing blood glucose value A, according to formula AUC=[(A_15min+A₀)×7.5]+[(A_30min+A_15min)×7.5]+[(A_60min+A_30min)×15] +[(A_120min+A_60min) × 30] AUC is calculated, and %=[(AUC are increased according to formula AUC_Compound- AUC_Solvent)/AUC_Solvent]× 100% calculates AUC growth rates, wherein " A₀" represent the blood glucose value of 0min after gavage, " A_15min" represent the blood after gavage 15min Sugar value, " A_30min" represent the blood glucose value after gavage 30min, " A_60min" represent the blood glucose value after gavage 60min, " A_120min" represent Blood glucose value after gavage 120min, " AUC_Compound" represent the AUC of test-compound, " AUC_Solvent" represent the AUC of vehicle control group Value, the results are shown in Table 3.

Table 3

Known EGFR inhibitor may result in the side effect such as body hyperglycaemia and impaired insulin signal transduction.Root According to Experimental report, the Rociletinib (CO1686) of AZD9291 and Clovis Oncology companies has certain journey to blood sugar Rising side effect (the Management of hyperglycemia from epidermal growth factor of degree receptor(EGFR)tyrosine kinase inhibitors(TKIs)targeting T790M-mediated resistance,Jeryl Villadolid,et al.Translational Lung Cancer Research(2015),4 (5),576-583).More than of the invention test result indicate that, compound of the invention is smaller to blood sugar influence, is expected to overcome existing The hyperglycaemia side effect that some EGFR inhibitors have, so as to help to reduce adverse reaction and improve patient compliance.

The drug metabolism of experimental example 4 is tested

1 experiment material

1.1 compounds

Compound of the invention is configured to oral and two kinds of injection to medicine composition.Wherein, ORAL FORMULATION is 25mM Citric acid-sodium citrate buffer (pH4.5) dissolving, be made 1.25mg/mL settled solutions；Tail vein injection pharmaceutical formulation is Citric acid-sodium citrate buffer (pH4.5) is 1 with physiological saline volume ratio：1 mixed solution, is made 0.2mg/mL solution.

1.2 animals

Female BAl BIc/C mice, every group each 5, body weight 18-22g, the western pul-Bi Kai experimental animals Co., Ltd in Shanghai carries For.The environment laundering period of 2~4 days is given before test mice experiment, fasting 8-12h before administration feeds water after administration 2h, is given after 4h Food.

1.3 reagents

Methyl alcohol (chromatographically pure)：Spectrum companies produce；

Acetonitrile (chromatographically pure)：Spectrum companies produce；

It is pure that remaining reagent is commercially available analysis.

1.4 instruments

The triple level Four bar LC-MS instrument of the types of American AB company API 4500, equipped with electric spray ion source (ESI), LC- 30AD double pumps；SIL-30AC automatic samplers；CTO-30AC column ovens；DGU-20A3R degassers；Analyst QS A01.01 Chromatographic work station；Milli-Q Superpure water machines (Millipore Inc)；Qilinbeier Vortex-5 oscillators；HITACHI The table-type high-speed refrigerated centrifuges of CF16R Ⅹ II.

2 experimental techniques

2.1 mouse fasting but can free water after 12 hours, take 0 moment blank plasma；

2.2 take the mouse 5 in step 2.1, and gavage (intragastric administration, I.G.) gives this Invention compound 25mg/kg；

The mouse 5 in step 2.1 is taken, tail vein (Intravenous administration, I.V.) give this hair Bright compound 2mg/kg；

2.3, in 5min, 15min, 30min, 1h, 2h, 4h, 10h, 24h after gavage, are placed in from eyeground vein clump continuous blood sampling It is distributed with the EP pipes of heparin, upper plasma is taken after 8000rpm/min centrifugations 5min, -20 DEG C freezes, and treat that LC-MS/MS is analyzed；

It is continuous from eyeground vein clump in 5min, 15min, 30min, 1h, 2h, 4h, 10h, 24h after tail vein injection administration Take blood to be placed in the EP pipes that heparin is distributed with, upper plasma is taken after 8000rpm/min centrifugations 5min, -20 DEG C freeze, and treat LC-MS/ MS is analyzed；

The 2.4 blood concentration-time data according to obtained by step 2.3, calculation pharmacokinetics is sought using WinNonlin softwares Parameter, is shown in Table 4.

Table 4

Compound of the invention has preferable pharmacokinetic data, should have preferable potential applicability in clinical practice.

Although being below described in detail to the present invention, however it is understood by skilled practitioners that without departing from this hair On the premise of bright spirit and scope various modifications and changes can be carried out to the present invention.Interest field of the invention is not limited to The detailed description made above, and claims should be belonged to.

Claims

1. compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,

Wherein：

Ring A is C₄-C₈Nitrogen heterocycle, it is optionally by one or more halogens, oxo, alkyl, cycloalkyl, haloalkyl, alcoxyl Base, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, alkyl monosubstituted amino alkane Base, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl group The substitution of aminoacyl, aryl, heteroaryl and Heterocyclylalkyl, when replacing base to have two or more, adjacent two substitution bases can be with Atom in connection constitutes substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl together, or is connected to same The atom that two substitution bases on one atom can jointly be connected with them forms substituted or unsubstituted cycloalkyl, heterocycle alkane Base；

R₁、R_2a、R_2b、R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, halo Alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dioxane Base aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, alkyl monosubstituted amino acyl group and dialkyl amido acyl Base；

R₄、R₅And R₆It is each independently selected from hydrogen, halogen, cyano group, alkyl, alkoxy and cycloalkyl, described alkyl, alkoxy With cycloalkyl optionally by one or more halogens, alkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl monosubstituted amino, The substitution of dialkyl amido, hydroxyl, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl or hydroxy alkyl；

R₇Selected from hydrogen, alkyl, cycloalkyl and haloalkyl；With

R₈Selected from hydrogen, alkyl and cycloalkyl, described alkyl and cycloalkyl are optionally by one or more halogens, alkyl, alkyl halide The substitution of base, alkoxy, amino, alkyl monosubstituted amino, dialkyl amido or hydroxyl；Or

R₇、R₈And its N atoms of connection constitute nitrogen heterocyclic ring alkyl together, described nitrogen heterocyclic ring alkyl is optionally by one or many Individual halogen, alkyl, haloalkyl, alkoxy, amino, alkyl monosubstituted amino, dialkyl amido, hydroxyl, aminoalkyl, monoalkyl ammonia The substitution of base alkyl, dialkyl aminoalkyl or hydroxy alkyl.

2. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, its In：

Ring A is to comprise only a C for nitrogen-atoms₄-C₈The monocyclic alkyl of nitrogen-containing hetero, it is optionally by one or more halogens, oxo, alkane Base, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amino Base, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl Base, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and Heterocyclylalkyl substitution, when substitution base has two or more When, adjacent two substitution bases can with atom in connection constituted together substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, Aryl, heteroaryl, or the atom that two substitution bases being connected on same atom can jointly be connected with them form substitution Or unsubstituted cycloalkyl, Heterocyclylalkyl；

Preferably,

Ring A isN is selected from 1,2,3 and 4, R selected from 1,2,3,4,5 and 6, m_aSelected from hydrogen, C_1-6Alkyl, C_3-8Cycloalkyl, halogen For C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl Amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkane Epoxide C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, list C_1-6Alkylaminoacyl, two C_1-6Alkylaminoacyl, C_6-10Virtue Base, C_5-10Heteroaryl and C_3-8Heterocyclylalkyl, when m is selected from 2,3 and 4, two R on two neighboring carbon atom_aCan be with them The carbon atom for being connected constitutes C together_3-8Cycloalkyl or C_3-8Two R on Heterocyclylalkyl, or same carbon atom_aCan be with it The carbon atom of common connection constitute C together_3-8Cycloalkyl or C_3-8Heterocyclylalkyl.

3. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, its In：

Ring A is to contain two C of nitrogen-atoms₄-C₈The monocyclic alkyl of nitrogen-containing hetero, its optionally by one or more halogens, oxo, alkyl, Cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, Aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, aminoacyl, The substitution of alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and Heterocyclylalkyl, when replacing base to have two or more, Two adjacent substitution bases can together be constituted substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, virtue with atom in connection Base, heteroaryl, or the atom that can be jointly connected with them of two substitution bases being connected on same atom formed substitution or Unsubstituted cycloalkyl, Heterocyclylalkyl；

Preferably,

Ring A isM is selected from 0,1 and 2, R selected from 1,2,3 and 4, p selected from 0,1 and 2, q_aSelected from hydrogen, C_1-6Alkyl, C_3-8Ring Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkane Base, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, list C_1-6Alkylaminoacyl, two C_1-6Alkylaminoacyl, C_6-10Aryl, C_5-10Heteroaryl and C_3-8Heterocyclylalkyl, when m is selected from 2,3 and 4, two R on two neighboring atom_aCan be with The atom that they are connected constitutes C together_3-8Cycloalkyl or C_3-8Two R on Heterocyclylalkyl, or same atom_aCan be with it The atom of common connection constitute C together_3-8Cycloalkyl or C_3-8Heterocyclylalkyl.

4. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, its In：

Ring A is the C containing a nitrogen-atoms and an oxygen atom₄-C₈The monocyclic alkyl of nitrogen-containing hetero, it is optionally by one or more halogen Element, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, nitro, cyano group, hydroxyl, amino, monoalkyl ammonia Base, dialkyl amido, aminoalkyl, Mono-alkylaminoalkyl, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl The substitution of acyl group, aminoacyl, alkyl monosubstituted amino acyl group, dialkyl amido acyl group, aryl, heteroaryl and Heterocyclylalkyl, works as substitution When base has two or more, two adjacent substitution bases can together be constituted substituted or unsubstituted cycloalkanes with atom in connection Base, Heterocyclylalkyl, aryl, heteroaryl, or two substitution bases being connected on same atom can jointly be connected with them Atom forms substituted or unsubstituted cycloalkyl, Heterocyclylalkyl；

Preferably,

5. the compound of any one according to claim 1-4 or its pharmaceutically acceptable salt, isomers, solvate, crystallization Or prodrug, wherein：

X₁、X₂、X₃And X₄It is each independently selected from C (R₁) and N；With

R₁、R_1a、R_1b、R_2a、R_2b、R_3a、R_3bAnd R_3cIt is each independently selected from hydrogen, halogen, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkane Epoxide, halo C_1-6Alkoxy, nitro, cyano group, hydroxyl, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, amino C_1-6Alkane Base, list C_1-6Alkyl amino C_1-6Alkyl, two C_1-6Alkyl amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6 Alkyl acyl, aminoacyl, list C_1-6Alkylaminoacyl and two C_1-6Alkylaminoacyl；

R₇Selected from hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl and halo C_1-6Alkyl；Preferably, R_aSelected from hydrogen, methyl, ethyl, propyl group, different Propyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and trifluoromethyl；With

R₈Selected from hydrogen, C_1-6Alkyl and C_3-6Cycloalkyl, described C_1-6Alkyl and C_3-6Cycloalkyl optionally by one or more halogens, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino or hydroxyl replace；It is preferred that Ground, R_bSelected from hydrogen, C_1-3Alkyl and C_3-6Cycloalkyl, described C_1-3Alkyl and C_3-6Cycloalkyl optionally by one or more halogens, Methyl, ethyl, propyl group, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxyl group, ethyoxyl, propoxyl group, isopropyl Epoxide, amino, methylamino, ethylamino, the third amino, dimethylamino, diethylin, dipropyl amino, methylethylamine, methyl-prop The substitution of base amino, ethylpropylamino or hydroxyl；With

R₄、R₅And R₆It is each independently selected from hydrogen, halogen, cyano group, C_1-6Alkyl, C_1-6Alkoxy, C_3-8Cycloalkyl, described C_1-6 Alkyl, C_1-6Alkoxy and cycloalkyl are optionally by one or more halogens, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, list C_1-6Alkyl amino, two C_1-6Alkyl amino, hydroxyl, amino C_1-6Alkyl, list C_1-6Alkyl amino C_1-6 Alkyl, two C_1-6Alkyl amino C_1-6Alkyl and hydroxyl C_1-6Alkyl replaces.

6. compound according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, described Compound is following compound：

7. a kind of pharmaceutical composition, the compound of its any one for including claim 1-6 or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.

8. the compound of any one of claim 1-6 or the composition of claim 7 are being prepared for treating and/or preventing to swell Application in the medicine of knurl, it is preferable that the tumour is with drug-fast tumour, it is highly preferred that the tumour is to EGFR Inhibitor has drug-fast tumour.

9. compounds of formula II or its pharmaceutically acceptable salt,

Its middle ring A, X₁、X₂、X₃、X₄、R_2a、R_2b、R_3a、R_3b、R_3c、R₇And R₈With the definition in claim 1-5.

10. compounds of formula III or its pharmaceutically acceptable salt,

Its middle ring A, X₁、X₂、X₃、X₄、R_2a、R_2bWith the definition in claim 1-5, M is halogen.