CN104725381B

CN104725381B - Growth factor receptor inhibitor and its application

Info

Publication number: CN104725381B
Application number: CN201310705259.1A
Authority: CN
Inventors: 王勇; 丁晔; 张小猛; 张先; 王小伟; 廖文辉; 张迪; 张仓; 徐信
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Huicheng Pharmaceutical Co., Ltd.
Priority date: 2013-12-19
Filing date: 2013-12-19
Publication date: 2018-04-10
Anticipated expiration: 2033-12-19
Also published as: CN104725381A

Abstract

The invention belongs to chemical medicine, more particularly to the compound shown in Formulas I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, and the pharmaceutical composition containing these compounds and the application of these compounds or composition in medicine preparation.Described compound has good growth factor receptors inhibitory activity, can effectively reduce Tumor incidence, extend tumor patient life.

Description

Growth factor receptor inhibitor and its application

Technical field

The invention belongs to chemical medicine, and in particular to one kind have growth factor receptors inhibitory activity compound or Its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, and the pharmaceutical composition containing these compounds and The application of these compounds or composition in medicine preparation.

Background technology

Most cells growth factor receptors contains the peptide sequence of EGFR-TK, therefore this receptoroid is commonly referred to as tyrosine Kinases receptors.According to the similitude of peptide sequence, these acceptors are divided into some major classes at present：(1) EGF-R ELISA, Such as EGFR, HER2, HER3, HER4, height expression is common in epithelial cell tumour；(2) Insulin Receptor Family, as insulin by Body, IGF-1 (IGFR), insulin-related receptor (IRR), height expression are common in blood cell tumour； (3) platelet-derived growth factor receptors family, such as PDGFRa, PDGRRb, colony stimulating factor (CSF-1R), c-Kit, Height expression is common in brain tumor, blood cell tumour；(4) fibroblast growth factor acceptor (FGFR) family, such as FGFR1, FRFR2, FGFR3, FGFR4 and keratinocyte growth factor etc., play an important role in terms of angiogenesis；(5) blood vessel Endothelial cell growth factor receptor 2 body（VEGFR）, be angiogenesis important positivity regulatory factor；In addition, also hepatic cell growth Factor acceptor (HGFR), Fibronectin type IIIs acceptor and NFG acceptor (NGFR) etc..EGFR-TK Acceptor over-expresses in different type tumour respectively, causes its Intracellular signals to activate, and cell transformation, constantly propagation, promotes Generation, the development of tumour.

Vascular endothelial growth factor receptor (VEGFR）It is vascular endothelial growth factor (VEGF) specific film Acceptor, there is high-affinity, belong to typical cross-film integral protein, be divided into extracellular region, transmembrane region and film inner region three parts, with born of the same parents The EGFR-TK area opened between the supersecondary structures of outer 7 immunoglobulin-likes, intracellular 2 is its feature.According to its structure with The difference of function can be divided mainly into VEGFR-1, VEGFR-2 and VEGFR-3 totally 3 kinds of hypotypes.Wherein, VEGFR-1, VEGFR-2 master Chrotoplast to express in the blood vessels.Research shows, after VEGF is combined with VEGFR-2, causes the phosphorylation of acceptor itself, activates silk The protein kinase of former activation is split, realizes VEGF mitogen characteristic, the division growth of induction of vascular endothelial cell；VEGF with After VEGFR-1 is combined, increase vascular endothelial cell permeability, make endovascular protein extravasation, form the branch of endothelial cell migration The provisional matrix of frame and angiogenesis；VEGF can strengthen plasminogen activator activity simultaneously, improve plasminogen activation because Son and plasminogen activation factor inhibiting factor_mRNA level, promote extracellular proteolysis, be advantageous to capillary Generation；Furthermore VEGF can change the activated form of endothelial cell gene, inducing endothelial cell expressing protein hydrolase, interstitial collagen Enzyme and tissue factor promote angiogenesis.Numerous studies confirmation, the growth and transfer of entity tumor and VEGF-VEGFR signals Angiogenic growth caused by path excessive activation is closely related, and growth is rapid and has the vessel density of the tumour of transfer apparently higher than life The long slow and tumour without transfer.When VEGF signal is suppressed, the angiogenesis and tumour growth of tumour are contained.

Fibroblast growth factor acceptor (FGFR) is combined with its part fibroblast growth factor, and it is big to regulate and control one The process of class cell development, including Apoptosis, breed, divide a word with a hyphen at the end of a line and angiogenesis.Largely demonstrate,prove it was demonstrated that fibroblastic growth The factor and vascular endothelial growth factor collaboration promote angiogenesis.Because mutation or receptor-ligand overexpression cause The regulation and control of FGFR signal paths it is not normal, also it is verified that being present in kinds of tumor cells, and can be by adjusting tumour Angiogenesis directly stimulates tumour growth and played a significant role in the development process of tumour.

Therefore, medicine of the exploitation with growth factor receptors inhibitory activity, the particularly generation to blood vessel have important tune The VEGFR and/or FGFR of control effect, suppress the excessive activation of VEGFR signal paths and/or FGFR signal paths, will face There is good application prospect on bed.

The content of the invention

It is an object of the invention to provide the compound or its pharmacy that formula I one kind has growth factor receptors inhibitory activity Acceptable salt, isomers, solvate, crystallization or prodrug,

Wherein：

X is selected from O, S, N (R₄)、C_1-3Alkylidene；

Ring A is selected to be selected from containing 0-3 heteroatomic quaternarys, five yuan, hexa-atomic, seven yuan or octatomic rings, described hetero atom N、O、S；

R₁Selected from hydrogen, oxo, alkyl, alkoxy, haloalkyl, halogenated alkoxy ,-OH ,-NH₂, nitro, halogen, CN, list Alkyl amino, double alkyl aminos, acylamino-, ester group, cycloalkyl, Heterocyclylalkyl；

R₂Selected from hydrogen, alkyl, alkoxy, haloalkyl, halogenated alkoxy ,-OH ,-NH₂, nitro, halogen, CN, monoalkyl Amino, double alkyl aminos, acylamino-, ester group, cycloalkyl, Heterocyclylalkyl；

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, alkyl, nitro, alkoxy, alkoxyalkyl, ammonia Alkyl, acylamino-, acyl group, alkyl amido, alkyl acyl, cycloalkyl, Heterocyclylalkyl, described hydroxyl, carboxyl, amino, alkane Base, alkoxy, alkoxyalkyl, aminoalkyl, acylamino-, acyl group, alkyl amido, alkyl acyl, cycloalkyl, Heterocyclylalkyl can With by one or more halogens, hydroxyl, carboxyl, amino, cyano group, nitro, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxy alkyl, carboxylic Base alkyl, alkoxy, alkyl monosubstituted amino, double alkyl aminos, alkoxyacyl, acylamino-, alkyl monosubstituted amino acyl group, double alkyl ammonia Base acyl group, alkyl acyl, alkyl acyl epoxide, carboxyalkyl acyloxy, hydroxy alkyl acyloxy, alkyl sulphonyl, virtue Base sulfonyl, heterocyclyl sulfonyl, amino-sulfonyl, monoalkylaminosulfonyl, the substitution of double alkyl amino sulfonyls；

R₄Selected from hydrogen, alkyl；

N is selected from 1,2,3,4.

It is a further object to provide prepare the present invention compounds of formula I or its pharmaceutically acceptable salt, Isomers, solvate, the method for crystallization or prodrug.

It is also another object of the present invention to provide comprising the present invention compounds of formula I or its pharmaceutically acceptable salt, The composition of isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and the formula I comprising the present invention Compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and another kind or multiple protein tyrosine-kinase The composition of enzyme inhibitor.

The present invention's a further object is the compounds of formula I or its pharmaceutically acceptable salt, isomery for providing the present invention Body, solvate, crystallization or the method for prodrug treatment and/or pre- preventing tumor, and the compounds of formula I or its medicine of the present invention Acceptable salt, isomers, solvate, crystallization or prodrug are learned in preparing for the medicine for the treatment of and/or pre- preventing tumor Using.

For above-mentioned purpose, the present invention provides following technical scheme：

In a first aspect, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, knot Brilliant or prodrug,

Wherein：

X is selected from O, S, N (R₄)、C_1-3Alkylidene；

R₂Selected from hydrogen, alkyl, alkoxy, haloalkyl, halogenated alkoxy ,-OH ,-NH₂, halogen, nitro, CN, monoalkyl Amino, double alkyl aminos, acylamino-, ester group, cycloalkyl, Heterocyclylalkyl；

R₄Selected from hydrogen, alkyl；

N is selected from 1,2,3,4.

In some preferred embodiments, compound of the invention is compounds of formula I and its pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein：

Ring A is selected from the carbocyclic ring containing 4-8 carbon atom, for example, cyclobutane base, cyclobutane base, pentamethylene base, cyclopentenyl, Cyclohexyl, cyclohexenyl group, cycloheptyl alkyl, cycloheptenyl, cyclooctane base, cyclo-octene base, preferably containing 5-7 carbon atom Carbocyclic ring, such as pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl group, cycloheptyl alkyl, cycloheptenyl, more preferably contain There is the carbocyclic ring of 5-6 carbon atom, be still more preferably pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl group.

In other preferred embodiments, compound of the invention is compounds of formula I and its pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein：

Ring A is selected from containing 1-2 heteroatomic quaternarys, five yuan, hexa-atomic, seven yuan or eight circle heterocycles, preferably containing 1-2 Heteroatomic five-, six- or seven-membered heterocycle, it is described more preferably containing 1-2 heteroatomic five yuan or hexa-member heterocycles Hetero atom be selected from O, N, S, be still more preferably tetrahydrofuran ring group, nafoxidine ring group, oxinane ring group, piperidines Base.

R₁Selected from hydrogen, oxo, alkyl, haloalkyl, halogen, preferably hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, halogen, enter One step is preferably hydrogen, oxo, C_1-3Alkyl, halo C_1-3Alkyl, halogen are still more preferably hydrogen, oxo, methyl, ethyl, third Base, isopropyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine.

R₂Selected from hydrogen, alkyl, haloalkyl, halogen, preferably hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, halogen, further Preferably hydrogen, C_1-3Alkyl, halo C_1-3Alkyl, halogen, it is still more preferably hydrogen, methyl, ethyl, propyl group, isopropyl, trifluoro Methyl, trifluoroethyl, fluorine, chlorine.

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C_1-10Alkyl, nitro, C_1-10Alkoxy, C_1-10Alkane Epoxide C_1-10Alkyl, amino C_1-10Alkyl, acylamino-, acyl group, C_1-10Alkyl amido, C_1-10Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl, described hydroxyl, carboxyl, amino, C_1-10Alkyl, C_1-10Alkoxy, C_1-10Alkoxy C_1-10Alkyl, amino C_1-10Alkyl, acylamino-, acyl group, C_1-10Alkyl amido, C_1-10Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl can be by one Individual or multiple halogens, hydroxyl, carboxyl, amino, cyano group, nitro, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl, hydroxyl C_1-6Alkane Base, carboxyl C_1-6Alkyl, C_1-6Alkoxy, single C_1-6Alkyl amino, double C_1-6Alkyl amino, C_1-6Alkoxyacyl, acylamino-, list C_1-6Alkylaminoacyl, double C_1-6Alkylaminoacyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl epoxide, carboxyl C_1-6Alkyl acyl Epoxide, hydroxyl C_1-6Alkyl acyl epoxide, C_1-6Alkyl sulphonyl, aryl sulfonyl, C_1-6Heterocyclyl sulfonyl, amino-sulfonyl, Single C_1-6Alkyl amino sulfonyl, double C_1-6Alkyl amino sulfonyl, nafoxidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, four Hydrogen thiazolyl, Si Qing oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl substitution；

It is further preferred that

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C_1-6Alkyl, nitro, C_1-6Alkoxy, C_1-6Alcoxyl Base C_1-6Alkyl, amino C_1-6Alkyl, acylamino-, acyl group, C_1-6Alkyl amido, C_1-6Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocycle Alkyl, described hydroxyl, carboxyl, amino, cyano group, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, amino C_1-6Alkane Base, acylamino-, acyl group, C_1-6Alkyl amido, C_1-6Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl can be by one or more Individual halogen, hydroxyl, carboxyl, amino, cyano group, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl, hydroxyl C_1-6Alkyl, carboxyl C_1-6 Alkyl, C_1-6Alkoxy, single C_1-6Alkyl amino, double C_1-6Alkyl amino, C_1-6Alkoxyacyl, acylamino-, single C_1-6Alkyl amino Acyl group, double C_1-6Alkylaminoacyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl epoxide, carboxyl C_1-6Alkyl acyl epoxide, hydroxyl C_1-6Alkyl acyl epoxide, C_1-6Alkyl sulphonyl, aryl sulfonyl, C_1-6Heterocyclyl sulfonyl, amino-sulfonyl, single C_1-6Alkyl Amino-sulfonyl, double C_1-6Alkyl amino sulfonyl, nafoxidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, Si Qing oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl substitution；

It is further preferred that

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group ,-C_1-6Alkyl, nitro ,-O-C_1-6Alkyl ,-C_1-6 Alkyl-O-C_1-6Alkyl ,-O-C_1-6Alkyl-O-C_1-6Alkyl ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C_1-6Alkane Base-NH-C_1-6Alkyl ,-C_1-6Alkyl-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C (O)-O-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-O- C_1-6Alkyl ,-C (O)-NH₂、-C(O)-NH-C_1-6Alkyl ,-C (O)-NH-C_3-6Cycloalkyl ,-C (O)-N- (C_1-6Alkyl) (C_1-6Alkane Base) ,-C_1-6Alkyl-C (O)-NH₂、-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-N- (C_1-6Alkyl) (C_1-6 Alkyl) ,-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-C_1-6Alkyl ,-O-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6 Alkyl ,-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-OH ,-C_1-6Alkyl-NH₂、-C(O)-NH-C_1-6Alkyl-OH ,-C (O)-NH- C_1-6Alkyl-C (O)-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-C (O)- OH、-C_1-6Alkyl-O-C_1-6Alkyl-OH ,-C_1-6Alkyl-O-C_1-6Alkyl-O-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6Alkane Base-C (O)-OH ,-C_1-6Alkyl-O-C (O)-C_1-6Alkyl-OH ,-C_1-6Alkyl-tetrahydro pyrrolidine ,-C_1-6Alkyl-tetrahydrofuran ,- C_1-6Alkyl-thiophane ,-C_1-6Alkyl-tetrahydro-thiazoles ,-C_1-6Alkyl-Si Qing oxazoles ,-C_1-6Alkyl-piperidine ,-C_1-6Alkyl- Piperazine ,-C_1-6Alkyl-morpholine, described tetrahydro pyrrolidine, tetrahydrofuran, thiophane, tetrahydro-thiazoles, Si Qing oxazoles, piperidines, Piperazine morpholine can be substituted by one or more halogens, hydroxyl, alkyl, hydroxyalkyl, carboxyl, amino, cyano group, alkoxy.

X is selected from O, N (R₄), described R₄Selected from hydrogen, C_1-6Alkyl；Preferably O, N (R₄), described R₄Selected from hydrogen, C_1-3Alkane Base；More preferably NH, O.

When n is selected from 2,3,4, R₃Identical group can be selected from, different groups can also be selected from.

X is selected from O, S, N (R₄)、CH₂；

Ring A is selected from C_4-8Cycloalkyl or C_4-8Heterocyclylalkyl, described hetero atom are selected from N, O, S；

R₁Selected from hydrogen, oxo, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy ,-OH ,-NH₂, nitre Base, halogen, CN, single C_1-6Alkyl amino, double C_1-6Alkyl amino, acylamino-, ester group, C_1-6Cycloalkyl, C_1-6Heterocyclylalkyl；

R₂Selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy ,-OH ,-NH₂, nitro, halogen Element, CN, single C_1-6Alkyl amino, double C_1-6Alkyl amino, acylamino-, ester group, C_1-6Cycloalkyl, C_1-6Heterocyclylalkyl；

R₄Selected from hydrogen, C_1-6Alkyl；

N is selected from 1,2 and 3.

X is selected from O, S, NH；

Ring A is selected from C_5-7Cycloalkyl or C_5-7Heterocyclylalkyl, described hetero atom are selected from N, O, S；

R₁Selected from hydrogen, oxo, C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy ,-OH ,-NH₂, nitre Base, halogen, CN, single C_1-3Alkyl amino, double C_1-3Alkyl amino, acylamino-, ester group, C_1-3Cycloalkyl, C_1-3Heterocyclylalkyl；

R₂Selected from hydrogen, C_1-3Alkyl, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy ,-OH ,-NH₂, nitro, halogen Element, CN, single C_1-3Alkyl amino, double C_1-3Alkyl amino, acylamino-, ester group, C_1-3Cycloalkyl, C_1-3Heterocyclylalkyl；

R₄Selected from hydrogen, C_1-3Alkyl；

N is selected from 1 and 2.

Preferably, the present invention provides formula Ia compound or its pharmaceutically acceptable salt, isomers, solvate, knot Brilliant or prodrug,

Wherein：

X is selected from O, S, N (R₄)、C_1-3Alkylidene；

Ring A₁Selected from the carbocyclic ring containing 4-8 carbon atom；

R₄Selected from hydrogen, alkyl；

N is selected from 1,2,3,4.

In some preferred embodiments, compound of the invention is formula Ia compound and its pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein：

X is selected from N (R₄), O, described R₄Selected from hydrogen, C_1-6Alkyl；Preferably N (R₄), O, described R₄Selected from hydrogen, C_1-3Alkane Base；More preferably NH, O；

Ring A₁Selected from the carbocyclic ring containing 5-7 carbon atom, the more preferably carbocyclic ring containing 5-6 carbon atom, more enter One step is preferably pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl group；

R₁Selected from hydrogen, oxo, alkyl, haloalkyl, halogen, preferably hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, halogen, enter One step is preferably hydrogen, oxo, C_1-3Alkyl, halo C_1-3Alkyl, halogen are still more preferably hydrogen, oxo, methyl, ethyl, third Base, isopropyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine；

R₂Selected from hydrogen, alkyl, haloalkyl, halogen, preferably hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, halogen, further Preferably hydrogen, C_1-3Alkyl, halo C_1-3Alkyl, halogen, it is still more preferably hydrogen, methyl, ethyl, propyl group, isopropyl, trifluoro Methyl, trifluoroethyl, fluorine, chlorine；

It is further preferred that

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C_1-6Alkyl, nitro, C_1-6Alkoxy, C_1-6Alcoxyl Base C_1-6Alkyl, amino C_1-6Alkyl, acylamino-, acyl group, C_1-6Alkyl amido, C_1-6Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocycle Alkyl, described hydroxyl, carboxyl, amino, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, amino C_1-6Alkyl, acyl ammonia Base, acyl group, C_1-6Alkyl amido, C_1-6Alkyl acyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl can by one or more halogens, Hydroxyl, carboxyl, amino, cyano group, nitro, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Heterocyclylalkyl, hydroxyl C_1-6Alkyl, carboxyl C_1-6Alkane Base, C_1-6Alkoxy, single C_1-6Alkyl amino, double C_1-6Alkyl amino, C_1-6Alkoxyacyl, acylamino-, single C_1-6Alkyl amino acyl Base, double C_1-6Alkylaminoacyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl epoxide, carboxyl C_1-6Alkyl acyl epoxide, hydroxyl C_1-6 Alkyl acyl epoxide, C_1-6Alkyl sulphonyl, aryl sulfonyl, C_1-6Heterocyclyl sulfonyl, amino-sulfonyl, single C_1-6Alkyl ammonia Base sulfonyl, double C_1-6Alkyl amino sulfonyl, nafoxidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, four Qing oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl substitution；

It is further preferred that

R₄Selected from hydrogen, C_1-6Alkyl, preferably hydrogen, C_1-3Alkyl, further preferred hydrogen；

N is selected from 1,2,3, preferably 1 or 2.

Preferably, the present invention provides formula Ib compound or its pharmaceutically acceptable salt, isomers, solvate, knot Brilliant or prodrug,

Wherein：

X is selected from O, S, N (R₄)、CH₂；

Ring A₂Selected from 1-2 heteroatomic quaternarys, five yuan, hexa-atomic, seven yuan or eight circle heterocycles are contained, described hetero atom selects From N, O, S；

R₄Selected from hydrogen, alkyl；

N is selected from 1,2,3,4.

In some preferred embodiments, compound of the invention is formula Ib compound and its pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein：

Ring A₂It is further preferably self-contained selected from containing 1-2 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or eight circle heterocycles There are 1-2 heteroatomic five-, six- or seven-membered heterocycles, still more preferably from individual heteroatomic five yuan or hexa-atomic containing 1-2 Heterocycle, described hetero atom are selected from N, O, S；

It is further preferred that

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group ,-C_1-6Alkyl, nitro ,-O-C_1-6Alkyl ,-C_1-6 Alkyl-O-C_1-6Alkyl ,-O-C_1-6Alkyl-O-C_1-6Alkyl ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C_1-6Alkane Base-NH-C_1-6Alkyl ,-C_1-6Alkyl-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C (O)-O-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-O- C_1-6Alkyl ,-C (O)-NH₂、-C(O)-NH-C_1-6Alkyl ,-C (O)-NH-C_3-6Cycloalkyl ,-C (O)-N- (C_1-6Alkyl) (C_1-6Alkane Base) ,-C_1-6Alkyl-C (O)-NH₂、-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-N- (C_1-6Alkyl) (C_1-6 Alkyl) ,-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-C_1-6Alkyl ,-O-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6 Alkyl ,-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-OH ,-C_1-6Alkyl-NH₂、-C(O)-NH-C_1-6Alkyl-OH ,-C (O)-NH- C_1-6Alkyl-C (O)-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-C (O)- OH、-C_1-6Alkyl-O-C_1-6Alkyl-OH ,-C_1-6Alkyl-O-C_1-6Alkyl-O-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6Alkane Base-C (O)-OH ,-C_1-6Alkyl-O-C (O)-C_1-6Alkyl-OH ,-C_1-6Alkyl-tetrahydro pyrrolidine ,-C_1-6Alkyl-tetrahydrofuran ,- C_1-6Alkyl-thiophane ,-C_1-6Alkyl-tetrahydro-thiazoles ,-C_1-6Alkyl-Si Qing oxazoles ,-C_1-6Alkyl-piperidine ,-C_1-6Alkyl- Piperazine ,-C_1-6Alkyl-morpholine, described tetrahydro pyrrolidine, tetrahydrofuran, thiophane, tetrahydro-thiazoles, Si Qing oxazoles, piperidines, Piperazine morpholine can be substituted by one or more halogens, hydroxyl, alkyl, hydroxyalkyl, carboxyl, amino, cyano group, alkoxy；

N is selected from 1,2,3, preferably 1 or 2.

The invention provides compound in detail below：

Present invention also offers the following key intermediate for preparing the compounds of this invention：

On the other hand, the present invention provides the preparation method of the general formula compound of the present invention：

(1) key intermediate M1 preparation：

Wherein, n, R₃And ring A has the definition in formula I, Y is halogen；

Comprise the following steps that：

A) compound of formula 1 and SPTS and I₂The compound of formula 2 is made in reaction；

B) compound that formula 3 is made in elimination reaction occurs for the compound of formula 2；

C) compound of formula 4 is made with Methyl isocyanoacetate reaction for the compound of formula 3；

D) compound of formula 5 is made with diphenyl phosphono azanol reaction for the compound of formula 4；

E) compound of formula 6 is made with formamide for the compound of formula 5；

F) formula M1 key intermediate is made by halogenating reaction for the compound of formula 6.

(2) preparation of compound of Formula I：

Wherein, X, R₁、R₂、R₃、R₄, n and ring A there is definition in formula I, Y is halogen, X₁Selected from amino or hydroxyl.

Specific steps：

Formula M1 compound reacts the compound of obtained Formulas I, the choosing of described alkali with formula M2 compound in the basic conditions From sodium carbonate, potassium carbonate or triethylamine.

The third aspect, present invention offer pharmaceutical composition, its compound comprising the present invention or its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug.

In some embodiments, the present invention provides pharmaceutical composition, and it includes compound of the present invention, isomers, molten Agent compound, crystallization or prodrug, also include the one or more selected from following composition：Tyrosine protein enzyme inhibitor, EGFR suppress Agent, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, group egg White deacetylase inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..

Can by the present invention compound, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, Diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but unlimited In intracutaneous, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, example Such as by being transfused or injecting, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) is applied.Give Medicine can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including piece Agent, pill, granula, pulvis, capsule, syrup, emulsion, supensoid agent etc..The preparation can be by methods known in the art system It is standby, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.

Fourth aspect, the present invention provide compound, isomers, solvate, crystallization or the prodrug or the present invention of the present invention Medicine composite for curing or pre- preventing tumor method and the application in prevention or tumor is prepared, including to tumour Easily hair crowd or tumor patient apply compound, isomers, solvate, crystallization or the prodrug of the present invention or include the present invention Compound, isomers, solvate, the pharmaceutical composition of crystallization or prodrug, effectively to reduce Tumor incidence, extend tumour Patient vitals.

Term explanation

" alkyl " of the present invention refers to the saturated hydrocarbyl of straight or branched.

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

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

" haloalkyl " of the present invention refers to the alkyl at least substituted by a halogen.

" halogenated alkoxy " of the present invention refers to the alkoxy at least substituted by a halogen.

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

The present invention " acyl group " refer to-C (O)-.

" alkyl amido " of the present invention refers to-alkyl-C (O)-NH₂。

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

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

" carboxyalkyl " of the present invention refers to-alkyl-C (O) OH.

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

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

" the double alkylaminoacyls " of the present invention refers to-C (O)-N (alkyl) (alkyl).

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

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

" the carboxyalkyl acyloxy " of the present invention refers to-O-C (O)-alkyl-C (O) OH.

" alkyl sulphonyl " of the present invention refers to-S (O)₂- alkyl.

" aryl sulfonyl " of the present invention refers to-S (O)₂- aryl.

" heterocyclyl sulfonyl " of the present invention is-S (O)₂- heterocyclic radical.

" amino-sulfonyl " of the present invention refers to-S (O)₂- amino.

" monoalkylaminosulfonyl " of the present invention refers to-S (O)₂- NH- alkyl.

" the double alkyl amino sulfonyls " of the present invention refers to-S (O)₂- N (alkyl) (alkyl).

Herein, term " quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring " refers to 4 to 8 yuan of saturations, part insatiable hunger And/or it is all undersaturated monocyclic, it is without hetero atom or contains one or more hetero atoms selected from N, O and S, including C_4-8 Cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl.Herein, the cycloalkyl is understood to monocyclic, and it can be saturated rings or not Saturation, non-aromatic ring, it can include double bond in due course, and the Heterocyclylalkyl refers to saturation or unsaturation, non-aromatic monocyclic, It contains hetero atom N, O or S to substitute one or more carbon atoms.As described herein, it is described " quaternary, five yuan, it is hexa-atomic, seven yuan Or octatomic ring " be fused on pyrrole ring.

" aryl " of the present invention refers to the aromatic hydrocarbon group containing one or more phenyl ring.Suitable aryl includes phenyl, naphthalene Base.

" heteroaryl " of the present invention refers to the aromatic radical that at least one carbon atom is substituted by hetero atom in aryl.Institute The hetero atom stated is O, S, N.

" solvate " of the present invention refers to solute in a conventional sense（Such as reactive compound, the salt of reactive compound）With Solvent（Such as water）Combine the compound formed.Solvent refers to solvent that is known to those of skill in the art or easily determining.Such as Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..

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

Referring to " isomers " of the present invention includes compound along configuration structure body, rotamer and enantiomter.Configuration is different Structure body refers to the cis-trans-isomer of cis or trans configuration；Rotamer refers to due to alloisomerism caused by singly-bound rotation Body.

" prodrug " of the present 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 the compound of invention, i.e., the compound for the compound invented by conversion costs such as the oxidations, reduction, hydrolysis of enzyme And/or the compound of the compound of the conversion cost such as hydrolysis by hydrochloric acid in gastric juice etc. invention.

" the pharmaceutically acceptable salt " of the present invention refers to the pharmaceutically acceptable salt that the compound of the present invention is formed with acid, Described acid include but is not limited to 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 etc..

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

" pharmaceutically acceptable carrier " of the present invention refer to not cause obvious irritation to organism and do not disturb to Give the bioactivity of compound and the carrier of property, comprising solvent, diluent or other excipient, dispersant, surfactant, Isotonic agent, thickener or emulsifying agent, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention Compound is incompatible.Carbohydrate can be included, but are not limited to as some examples of pharmaceutically acceptable carrier, such as lactose, Portugal Grape sugar and sucrose；Starch, such as cornstarch and farina；Cellulose and its derivates, such as sodium carboxymethylcellulose and Cellulose and cellulose acetate；Malt, gelatin etc..

" excipient " of the present invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound. Excipient can include calcium carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, gelatin, plant Oil, polyethylene glycol.

The life for referring to that tumour can be suppressed " preparing the application in being used to treat or prevent the medicine of tumour " of the present invention Long, development and/or transfer, mainly given to required human or animal and control the compound of the invention for giving treatment effective dose to press down Make, slow down or reverse the growth, development or expanding of subject's tumour.

The compound of the present invention refers to all general formula compound of the present invention, including formula I, formula Ia and formula Ib any Compound and particular compound described in formula.

Embodiment

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

The chloro- rings of 6,7- dihydros -5H- penta of embodiment 14- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formic acid first The synthesis of ester

The synthesis of the iodo- 2- p-toluenesulfonyls -4- methyl formates-pentamethylene of step 11-

Under condition of ice bath, 10g3- cyclopentene -1- methyl formates and 21.2g SPTSs are weighed, is placed in reaction bulb In, it is 1 to add 500mL volume ratios:1 methylene chloride/water mixed solvent, after stirring 1h, 20g I are added portionwise₂, after adding, After room temperature reaction 3 hours, stratification, organic phase being taken, aqueous phase is extracted (2 times × 250mL) with dichloromethane, merges organic phase, Washed twice successively with aqueous solution of sodium bisulfite, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, anhydrous slufuric acid Sodium is dried, and filtering, is spin-dried for, is obtained title compound.It is not purified, it is directly used in and reacts in next step.

ESI-MS m/z:409[M+H]⁺,447[M+K]⁺。

The synthesis of step 21- p-toluenesulfonyls -4- methyl formates-cyclopentene

The compound of 31.8g steps 1 preparation is weighed in reaction bulb, 10g triethylamines, 600mL acetonitriles is slowly added to, heats To 70 DEG C, reaction is spin-dried for after 3 hours, is added the dissolving of 400mL ethyl acetate, is eaten successively with saturated sodium bicarbonate aqueous solution and saturation Aqueous salt solu-tion twice, anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains title compound.It is not purified, it is directly used in next Step reaction.

ESI-MS m/z:281[M+H]⁺。

The synthesis of the ring of step 32,4- dicarboxylic acid methyl esters-penta simultaneously [3,4] pyrroles

Under nitrogen protection, 2g NaH are weighed in reaction bulb, the anhydrous THF of 100mL is added, is cooled to 0 DEG C or so, are slowly added Enter the anhydrous THF solution of compound and 3.96g Methyl isocyanoacetate of the 200mL dissolved with the preparation of 5.6g steps 2, finish continuation After being reacted 1 hour under the conditions of 0 DEG C, 2~3mL absolute methanols are added, stirs 5 minutes, is spin-dried for, residue 200mL acetic acid second Ester is dissolved, and diatomite filtering, filter cake is washed 3 times with ethyl acetate, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate Dry, filtering, be spin-dried for, obtain dark oil thing, column chromatography purifying, obtain title compound.

ESI-MS m/z:224[M+H]⁺,262[M+K]⁺。

The synthesis of the ring of step 4N- amino -2,4- dicarboxylic acid methyl esters-penta simultaneously [3,4] pyrroles

Under nitrogen protection, 73mg NaH are weighed in reaction bulb, 3mL dry DMFs is added, is cooled to 0 DEG C or so, slowly drop Enter the anhydrous DMF solution for the compound that 5mL is prepared dissolved with 270mg steps 3, after keeping 0 DEG C of reaction 30min, be added portionwise 350mg diphenyl phosphono azanols, it is warming up to 20 DEG C of reaction 30min.Reaction finishes, and adds 30mL ethyl acetate and 30mL frozen water extraction Take, take organic layer, aqueous layer with ethyl acetate extraction (2 times × 15mL), merge organic layer, saturated aqueous common salt washed once, anhydrous Sodium sulphate is dried, and filtering, is spin-dried for, column chromatography purifies to obtain title compound.

ESI-MS m/z:239[M+H]⁺。

The rings of step 54- hydroxyl -6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formic acid first The synthesis of ester

The compound of 1.4g steps 4 preparation is weighed in reaction bulb, 5mL formyl amine solvents is added, is warming up to 180 DEG C of conditions Lower reaction 2 hours.Reaction is finished, and reaction solution is poured into 20mL frozen water, ethyl acetate extraction (3 × 20mL), merges organic layer, Saturated common salt water washing, anhydrous sodium sulfate drying, filtering, it is spin-dried for, column chromatography purifying, obtains title compound.

¹H NMR(300MHz,DMSO-d₆):δ12.44(s,1H),7.66(s,1H),7.28(s,1H),3.72-3.67(m, 1H),3.64(s,3H),3.22-3.02(m,4H)。

ESI-MS m/z:234[M+H]⁺。

The chloro- rings of 6,7- dihydros -5H- penta of step 64- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methyl formates Synthesis

The compound of 300mg steps 5 preparation is weighed in reaction bulb, the dissolving of 20mL toluene is added, sequentially adds 5 equivalents three Chlorethoxyfos (POCl3), 5 equivalent DIPEAs (DIPEA), 110 DEG C are warming up to, reacted 6 hours.Reaction finishes, and subtracts Pressure is evaporated off solvent and obtains dark oil thing, after adding the dissolving of 20mL ethyl acetate, is adjusted with 0~5 DEG C of saturated sodium bicarbonate aqueous solution PH value takes organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, is spin-dried for obtaining title compound to neutrality.ESI- MS m/z:252[M+H]⁺。

The synthesis of the chloro- 5,6,7,8- tetrahydrochysenes of embodiment 24--[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl formates

Using 3- cyclohexene -1- methyl formates as raw material, title compound is made in the method with embodiment 1.

ESI-MS m/z:266[M+H]⁺。

Embodiment 34- chlorine furans simultaneously [3', 4':3,4] synthesis of pyrrolo- [2,1-f] [1,2,4] triazine -7 (5H) -one

Using 2 (5H)-furanones as initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:210[M+H]⁺。

The chloro- 5H- piperazines of embodiment 44- are muttered simultaneously [3', 4':3,4] conjunction of pyrrolo- [2,1-f] [1,2,4] triazine -8 (6H) -one Into

With 5,6- dihydro -2H- pyran-2-ones for raw material, title compound is made in the method with embodiment 1.

ESI-MS m/z:224[M+H]⁺。

The synthesis of the chloro- rings of 6,7- dihydros -5H- penta of embodiment 54- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine

Using cyclopentene as initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:194[M+H]⁺。

The synthesis of the chloro- 5,6,7,8- tetrahydrochysenes of embodiment 64--[1,2,4] triazine simultaneously [6,1-a] iso-indoles

Using cyclohexene as initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:208[M+H]⁺。

The synthesis of the chloro- 5,6- dihydros of embodiment 74--[1,2,4] triazine simultaneously [6,1-a] iso-indoles

Using 2- cyclohexene -1- ketone as initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:206[M+H]⁺。

The synthesis of the chloro- 5,6- dihydros of embodiment 84,8- bis--[1,2,4] triazine simultaneously [6,1-a] iso-indoles

ESI-MS m/z:240[M+H]⁺。

The chloro- rings of 5H- penta of embodiment 94- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6,6 (7H)-dicarboxylic The synthesis of ester

With 3- cyclopentene -1,1- dicarboxylate for initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:338[M+H]⁺。

Embodiment 102- (the chloro- rings of 6,7- dihydros -5H- penta of 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) The synthesis of methyl acetate

Step 1：The synthesis of 2- cyclopentene -1- methyl acetates

1.12g2- cyclopentene -1- acetic acid is weighed in 50mL round-bottomed flasks, 10mL absolute methanols is added, it is dense to be added dropwise to 2 drops Sulfuric acid, 2h is heated to reflux, after reaction stops, depressurizing precipitation, add water, pH is adjusted to alkalescent, acetic acid with sodium bicarbonate aqueous solution Ethyl ester extracts, and depressurizes precipitation after anhydrous sodium sulfate drying organic phase, obtains target product.

ESI-MS m/z:141[M+H]⁺。

Step 2：2- (the chloro- rings of 6,7- dihydros -5H- penta of 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) second The synthesis of sour methyl esters

Using 2- cyclopentene -1- methyl acetates as initiation material, title compound is made in the method with embodiment 1.

ESI-MS m/z:280[M+H]⁺。

The rings of embodiment 114- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- methyl formates（B-47）Synthesis

The compound of the preparation of 319mg embodiments 1 is weighed, after adding 10mL DMF dissolvings, adds the fluoro- 5- hydroxyls of 96.5mg4- Base -2 methyl indole and 67.3mg Anhydrous potassium carbonates, after being stirred at room temperature 2 hours stop reaction, add 40mL ethyl acetate and 80mL water is extracted, and aqueous phase is extracted with ethyl acetate 2 times, merges organic phase, and saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate Dry, filtering, be spin-dried for, post purifying, title compound is made.

¹H NMR(500M Hz,DMSO-d₆)δ:11.34(s,1H),7.83(s,1H),7.52(s,1H),7.08-7.05 (m,1H),6.99-6.93(m,1H),6.33(s,1H),4.25-4.18(m,1H),3.49-3.43(m,2H),3.26-3.24 (m,2H),3.44（s,3H）,1.33-1.24(m,3H).ESI-MS(m/z):381[M+H]⁺。

- 5,6,7,8- tetrahydrochysenes-[1,2,4] triazine is simultaneously by embodiment 124- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) [6,1-a] iso-indoles -7- methyl formates（B-37）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 2, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.32(s,1H),7.88-7.80(m,1H),7.90(s,1H),7.15- 7.13(m,1H),6.99-6.96(m,1H),6.24(s,1H),3.75(s,2H),3.67-3.66(m,1H),3.39-2.96(m, 2H),2.92-2.89(m,3H),2.41(s,3H),2.24-2.19(m,1H),1.82-1.80(m,1H)。

ESI-MS(m/z):395[M+H]⁺。

Embodiment 134- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) furans simultaneously [3', 4':3,4] pyrrolo- [2, 1-f] [1,2,4] triazine -7 (5H) -one (B-34) synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 3, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.43(s,1H,N-H),8.71(s,1H),8.27(s,1H),7.16- 7.19(m,1H)7.01-7.03(m,1H),6.26(s,1H),5.66(s,2H),2.41(s,3H)。

ESI-MS(m/z):339[M+H]⁺。

Embodiment 144- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) piperazine is muttered simultaneously [3', 4':3,4] pyrrolo- [2, 1-f] [1,2,4] triazine -8 (6H) -one（B-31）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 4, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.41(s,1H,N-H),8.59(s,1H),8.17(s,1H),7.18- 7.15(m,1H),7.05-7.00(m,1H),6.26(s,1H),4.66-4.62(m,2H),3.33-3.32(m,2H),2.41(s, 3H)。

ESI-MS(m/z):353[M+H]⁺。

Embodiment 154- ((2- indolone -5- bases) epoxide) -5H- piperazines are muttered simultaneously [3', 4':3,4] pyrrolo- [2,1-f] [1, 2,4] triazine -8 (6H) -one（B-33）Synthesis

Compound and 5-OHi -2- ketone are made as raw material using embodiment 4, the method with embodiment 11 is made titled Compound.

¹H NMR(500M Hz,DMSO-d₆)δ:8.61(s,1H),8.22(s,1H),8.00(s,1H,N-H),6.98- 6.92(m,2H),6.20-6.18(m,1H),4.64-4.62(m,2H),3.65-3.63(m,2H),3.33-3.29(m,2H)。

ESI-MS(m/z):337[M+H]⁺。

The rings of embodiment 164- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine（B-44）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 5, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:12.13(s,1H,N-H),7.98(s,1H),7.80(s,1H),7.15- 7.12(m,1H),6.99-6.94(m,1H),6.23(s,1H),3.02(t,2H),2.87(t,2H),2.45-2.41(m,5H)。

ESI-MS(m/z):323[M+H]⁺。

- 5,6,7,8- tetrahydrochysenes-[1,2,4] triazine is simultaneously by embodiment 174- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) The synthesis of [6,1-a] iso-indoles (B-35)

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 6, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.30(s,1H,N-H),7.87(s,1H),7.77(s,1H),7.14- 7.12(m,1H),6.98-6.95(m,1H),6.23(s,1H),3.00(t,2H),2.73(t,2H),2.41(s,3H),1.82- 1.78(m,4H)。

ESI-MS(m/z):337[M+H]⁺。

Embodiment 184- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -5,6- dihydros-[1,2,4] triazine simultaneously [6, 1-a] iso-indoles（B-39）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 7, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500MHz,CDCl₃)δ:8.00(s,br,1H,N-H),7.80(s,1H),7.54(s,1H),7.10- 7.07(m,1H),7.02-6.96(m,1H),6.57(d,1H),6.35(s,1H),6.02-5.95(m,1H),3.22-3.14(m, 2H),2.61-2.59(m,2H),2.45(s,3H)。

ESI-MS(m/z):335[M+H]⁺。

Embodiment 194- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) chloro- 5,6- dihydros of -8--[1,2,4] triazine And [6,1-a] iso-indoles（B-42）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 8, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500MHz,CDCl₃)δ:8.01(s,1H,N-H),7.82(s,1H),7.55(s,1H),7.08-7.11 (m,1H),6.99-7.03(m,1H),6.59(d,1H),6.03-5.97(m,1H),3.24-3.16(m,2H),2.63-2.58 (m,2H),2.46(s,3H)。

ESI-MS(m/z):369[M+H]⁺。

The rings of embodiment 204- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -5H- penta simultaneously [3,4] pyrrolo- [2,1- F] [1,2,4] triazine -6,6 (7H)-dicarboxylate（B-61）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 9, with the method system of embodiment 11 Obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.35(s,1H,N-H),7.95(s,1H),7.83(s,1H),7.16- 7.13(m,1H),7.02-6.97(m,1H),6.25(s,1H),4.15-4.22(m,4H),3.66(s,2H),3.53(s,2H), 2.41(s,3H),1.20(t,6H).

ESI-MS(m/z):467[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 212- Pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) ethyl acetate（B-62）Synthesis

Compound and the fluoro- 5- hydroxy-2-methyls indoles of 4- are made as raw material using embodiment 10, with the method system of embodiment 11 Obtain title compound.

1H NMR(300M Hz,CDCl₃)δ:8.09(s,1H,N-H),7.83(s,1H),7.50(s,1H),7.06-7.04 (m,1H),6.98-6.95(m,1H),6.32(s,1H),3.98-3.94(m,1H),3.63(s,3H),3.60(t,2H),3.32- 3.28(m,1H),2.90-2.78(m,3H),2.58-2.53(m,2H),2.41(s,3H)。

ESI-MS(m/z):409[M+H]⁺。

The rings of embodiment 224- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- bases) methanol（B-48）Synthesis

In the 8mL 25mL single port bottles of tetrahydrofuran (THF) are filled, 18mg Lithium Aluminium Hydrides (LAH) are added, stir lower drip Add the tetrahydrofuran solution of compounds of the 7mL dissolved with the preparation of 190mg embodiments 11, after finishing, TLC, which is monitored to raw material, to disappear, Reaction is quenched, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase, filtering, is spin-dried for, title compound is made.

¹H NMR(500M Hz,DMSO-d₆)δ:11.34(s,1H,N-H),7.88(s,1H),7.78(s,1H),7.16- 7.13(m,1H),6.99-6.94(m,1H),6.24(s,1H),4.74-4.71(m,1H),3.51-3.47(m,2H),3.13- 3.08(m,1H),3.12-2.65(m,4H),2.41(s,3H)。

ESI-MS(m/z):353[M+H]⁺。

- 5,6,7,8- tetrahydrochysenes-[1,2,4] triazine is simultaneously by embodiment 234- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) [6,1-a] iso-indoles -7- methanol（B-43）Synthesis

Compound is made as raw material using embodiment 12, title compound is made in the method with embodiment 22.

¹H NMR(500M Hz,DMSO-d₆)δ:11.32(s,1H,N-H),7.88(s,1H),7.80(s,1H),7.14- 7.13(m,1H),6.99-6.96(m,1H),6.24(s,1H),4.59-4.58(m,1H),3.47-3.48(m,2H),3.29- 3.20(m,1H),2.93-2.84(m,2H),2.72-2.65(m,1H),2.41(s,3H),2.04-1.89(m,2H),1.60- 1.41(m,1H)。

ESI-MS(m/z):367[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 242- Pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) ethanol（B-65）Synthesis

Compound is made as raw material using embodiment 21, title compound is made in the method with embodiment 22.

¹H NMR(500M Hz,DMSO-d₆)δ:11.32 (s, 1H, N-H, heavy water disappear after exchanging), 7.89 (s, 1H), 7.79 (s, 1H), 7.13-7.16 (m, 1H), 6.98-6.93 (m, 1H), 6.24 (s, 1H), 4.41 (s, br, 1H ,-OH, heavy water friendships Disappeared after changing), 3.53-3.45 (m, 2H), 2.96-2.75 (m, 3H), 2.41 (s, 3H), 2.28-2.17 (m, 2H), 1.68- 1.66(m,1H),1.63-1.58(m,1H)。

ESI-MS(m/z):367[M+H]⁺。

(the rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole of embodiment 25 Cough up simultaneously [2,1-f] [1,2,4] triazine -6,6- diyls) dimethanol（B-66）Synthesis

Compound is made as raw material using embodiment 20, title compound is made in the method with embodiment 22.

¹H NMR(500M Hz,DMSO-d₆)δ:11.32(s,1H,N-H),7.86(s,1H),7.74(s,1H),7.12- 7.14(m,1H),6.98-6.95(m,1H),6.24(s,1H),4.69(s,br,2H,-OH),3.46(s,4H),2.88(s, 2H),2.71(s,2H),2.41(s,3H)。

ESI-MS(m/z):383[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 262- Pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) propan-2-ol（B-67）Synthesis

Compound prepared by 38mg embodiments 11 is dissolved in the anhydrous THF of 5mL, under argon gas protection, at room temperature, is slowly added to Dissolved with the THF solution of 29mg methyl-magnesium-chlorides.After reaction terminates, precipitation is depressurized, adds saturated aqueous common salt, ethyl acetate extraction 2 It is secondary, merge organic phase, anhydrous sodium sulfate drying, filtering, be spin-dried for, column chromatography purifying, title compound is made.

¹H NMR(500M Hz,DMSO-d6)δ:11.33(s,1H,N-H),7.87(s,1H),7.75(s,1H),7.12- 7.15(m,1H),6.94-6.99(m,1H),6.24(s,1H),4.31(s,1H,-OH),2.87-3.01(m,5H),2.41(s, 3H),1.17(s,6H)。

ESI-MS(m/z):381[M+H]⁺。

The rings of embodiment 274- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- formic acid（B-49）Synthesis

Compound made from 190mg embodiments 11 is weighed in 25mL single port bottles, it is 7 to add volume ratio:3 THF/ methanol Mixed solvent 10mL, be slowly added to 18mg lithium hydroxides, after completion of the reaction plus water quenching is gone out reaction, with 1M dilute hydrochloric acid solution tune PH to 5~6 is saved, ethyl acetate extraction, filters, is spin-dried for after drying organic phase, title compound is made.

¹H NMR(500M Hz,DMSO-d₆)δ:12.5(s,br,1H,COOH),11.34(s,1H,N-H),7.89(s, 1H),7.80(s,1H),7.13-7.11(m,1H),6.96-6.93(m,1H),6.22(s,1H),3.78-3.60(m,1H), 3.31-3.12(m,4H),2.39(s,3H)。

ESI-MS(m/z):365[M-H]^-。

- 5,6,7,8- tetrahydrochysenes-[1,2,4] triazine is simultaneously by embodiment 284- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) [6,1-a] iso-indoles -7- formic acid（B-40）Synthesis

Compound is made as raw material using embodiment 12, title compound is made in the method with embodiment 27.

¹H NMR(500M Hz,DMSO-d₆)δ:12.5(s,br,1H,COOH),11.34(s,1H,N-H),7.89-7.82 (m,1H),7.92(s,1H),7.16-7.14(m,1H),7.01-6.97(m,1H),6.26(s,1H),4.61-4.59(m,1H), 3.49-3.47(m,2H),3.33-3.31(m,1H),2.94-2.92(m,1H),2.71-2.66(m,2H),2.41(s,3H)。

ESI-MS(m/z):379[M-H]^-。

The rings of embodiment 294- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) amino) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- formic acid（B-59）Synthesis

Step 1 is using compound made from embodiment 1 and the fluoro- 5- amino-2-methyls indoles of 4- as raw material, with embodiment 11 The rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) amino) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1- is made in method F] [1,2,4] triazine -6- methyl formates.

For step 2 using compound made from step 1 as raw material, title compound is made in the method with embodiment 27.

¹H NMR(500M Hz,DMSO-d₆)δ:12.29(s,br,1H,COOH),11.23(s,1H,N-H),8.74(s, 1H,N-H),7.65(s,1H),7.45(s,1H),7.13-7.10(m,1H),7.04-6.99(m,1H),6.21(s,1H), 3.64-3.56(m,1H),3.31-3.27(m,2H),3.06-3.03(m,2H),2.40(s,3H)。

ESI-MS(m/z):364[M-H]^-。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 302- Pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) acetic acid（B-64）Synthesis

Using compound made from embodiment 21 as raw material, title compound is made in the method with embodiment 27.

¹H NMR(500M Hz,DMSO-d₆)δ:12.17(s,br,1H,COOH),11.34(s,1H,N-H),7.80(s, 1H),7.69

(s,1H),7.13-7.02(m,1H),6.99-6.97(m,1H),6.24(s,1H),3.09-3.04(m,1H), 2.88-2.74(m,4H),2.12-1.56(m,2H),2.41(s,3H)。

ESI-MS(m/z):379[M-H]^-。

Embodiment 313- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3, 4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methoxyl group) -3- oxygen subunit propionic acid（B-72）Synthesis

In 50mL round-bottomed bottles, 348mg DIPEAs (DIEA), 0.5mg4- dimethylamino pyrroles are sequentially added Pyridine (DMAP), dissolved with 5mL tetrahydrofurans (THF), be slowly added dropwise after stirring 10min under ice-water bath into 5mL dissolved with 175mg1- second The THF solution of base -3- (3- dimethylamine propyls) carbodiimide hydrochlorides (EDCI), 5mL is then added dropwise dissolved with 320mg embodiments 22 The THF solution of the compound of preparation, it is stirred at room temperature after question response terminates, depressurizes precipitation, add saturated aqueous common salt, ethyl acetate extraction Take 2 times, merge organic phase, filter, be spin-dried for after anhydrous sodium sulfate drying, column chromatography purifying, title compound is made.

¹H NMR(500MHz,DMSO-d₆)δ:12.41 (s, br, 1H, COOH, heavy water disappear after exchanging), 11.36 (s, 1H, Heavy water disappears after exchanging), 7.89 (s, 1H), 7.79 (s, 1H), 7.15-7.13 (m, 1H), 6.98-6.95 (m, 1H), 6.23 (s, 1H),4.10(s,2H),3.20-3.17(m,2H),3.06-3.00(m,3H),2.89-2.84(m,1H),2.73-2.69(m, 1H),2.41(s,3H)。

ESI-MS (m/z):[M-H]^-437。

The rings of embodiment 324- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- formamides（B-51）Synthesis

The compound of the preparation of 73mg embodiments 27 is weighed in 50mL round-bottomed bottles, adds 5mL DMF, 12mg4- dimethylaminos Pyridine (DMAP), 152mg2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), room temperature After stirring reaction 0.3h, 54mg NH are sequentially added₄Cl, 258mgN, N- diisopropylethylamine（DIPEA）, continue to be stirred at room temperature instead After answering 8.0h, it is 6~7 with 1MHCl regulations pH, then adds ethyl acetate and extract, merging organic phase, saturated common salt water washing, Anhydrous sodium sulfate drying, filtering are spin-dried for rear pillar chromatographic purifying, and title compound is made.

¹HNMR(500MHz,DMSO-d6)δ:11.3 (s, N-H, heavy water disappear after exchanging), 7.94 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H, N-H, heavy water disappear after exchanging), 7.19-7.16 (m, 1H), 7.01-6.93 (m, 2H), 6.26 (s, 1H), 3.69-3.61(m,1H),3.30-308(m,4H),2.53(s,3H)。

ESI-MS(m/z):366[M+H]⁺。

Embodiment 33N- methyl-(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) formamide

For the compound and methylamine prepared using embodiment 28 as raw material, title compound is made in the method with embodiment 32.

¹H NMR(500MHz,DMSO-d6)δ:11.32 (s, N-H, heavy water disappear after exchanging), 7.99 (s, 1H), 7.89 (s,1H),7.78(s,1H),7.12-7.15(m,1H),6.95-6.98(m,1H),6.24(s,1H),3.61-3.68(m,1H), 3.00-3.28(m,4H),2.63(s,3H),2.40(s,3H)。

ESI-MS(m/z):380[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 342- Pyrrolo- [2,1-f] [1,2,4] triazine -7- bases) acetamide（B-68）Synthesis

Using compound made from embodiment 30 as raw material, title compound is made in the method with embodiment 32.

¹H NMR(500M Hz,DMSO-d6)δ:11.34 (s, 1H, N-H, heavy water disappear after exchanging), 7.91 (s, 1H), 7.80 (s, 1H), 7.34 (s, 1H, N-H, heavy water disappear after exchanging), 7.16-7.13 (m, 1H), 7.02-6.96 (m, 1H), 6.81 (s, 1H, N-H, heavy water disappear after exchanging), 6.24 (s, 1H), 3.78-3.75 (s, 1H), 2.97-2.77 (m, 3H), 2.63- 2.57(m,1H),2.41(s,3H),2.29-2.01(m,2H)。

ESI-MS(m/z):380[M+H]⁺。

Embodiment 35N- ((S) -1- hydroxy propane -2- bases)-(4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) - The rings of 6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) formamide（B-50）Synthesis

Using compound made from embodiment 27 and L- aminopropanols as raw material, title compound is made in the method with embodiment 32 Thing.

¹H NMR(500M Hz,DMSO-d₆)δ:11.30 (s, br, 1H, N-H, heavy water disappear after exchanging), 7.89 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H, N-H, heavy water disappear after exchanging), 7.15-7.12 (m, 1H), 6.99-6.96 (m, 1H), 6.24 (s, 1H), 4.65 (s, 1H, O-H, heavy water disappear after exchanging) 3.81 (s, 1H), 3.62-3.60 (m, 1H), 3.38-3.35 (m, 3H),3.16-3.05(m,3H),2.40(s,3H),1.05(s,3H)。

ESI-MS(m/z):424[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 362- Pyrrolo- [2,1-f] [1,2,4] triazine -7- bases)-N- ((S) -1- hydroxy propane -2- bases) acetamide（B-69）Synthesis

Using compound made from embodiment 30 and L- aminopropanols as raw material, title compound is made in the method with embodiment 32 Thing.

1H NMR(300MHz,DMSO-d₆)δ:11.32(s,1H),7.90(s,1H),7.79(s,1H),7.63-7.61 (m,1H),7.15-7.13(d,1H),6.96-6.90(t,1H),6.24(s,1H),4.61-4.60(m,1H),3.79-3.75 (m,2H),3.22-3.16(m,2H),2.95-2.78(m,4H),2.41(s,3H),2.22-2.30(m,1H),2.11-2.05 (m,1H),1.01-0.98(t,3H)。

ESI-MS(m/z):438[M+H]⁺。

Embodiment 374- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6- ((2- methoxy ethoxies) methyl) - The rings of 6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine（B-57）Synthesis

By compound prepared by 35mg embodiments 22 with 3mL DMF dissolve after, add 20mg2- bromo-ethyl-methyl ethers and 20mg Anhydrous potassium carbonates, reaction solution stop reaction after being stirred at room temperature 2 hours, add ethyl acetate 40ml and water 80ml extractions, water Mutually it is extracted with ethyl acetate 2 times, merges organic phase, washed once with saturated sodium-chloride water solution, mistake after anhydrous sodium sulfate drying Filter, is spin-dried for, and column chromatography purifying, title compound is made.

¹H NMR(500M Hz,DMSO-d₆)δ:11.31 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.15-7.12 (m,1H),6.99-6.94(m,1H),6.24(s,1H),3.57-3.44(m,6H),3.13(s,3H),3.02-2.95(m,2H), 2.86-2.83(m,1H),2.80-2.76(m,1H),2.67-2.62(m,1H),2.40(s,3H)。

ESI-MS(m/z):411[M+H]⁺。

Embodiment 38N- (4- (the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) -6- ((2- methoxy ethoxies) methyl) -6,7- The rings of dihydro -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -4- amine（B-58）Synthesis

Step 1：The rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) amino) -6,7- dihydros -5H- penta simultaneously [3,4] pyrroles And the synthesis of [2,1-f] [1,2,4] triazine -6- methyl formates

Using compound made from embodiment 1 and the fluoro- 5- amino-2-methyls indoles of 4- as raw material, with the method for embodiment 11 The rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) amino) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] is made [1,2,4] triazine -6- methyl formates.

Step 2：The rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) amino) -6,7- dihydros -5H- penta simultaneously [3,4] pyrroles And [2,1-f] [1,2,4] triazine -6- methanol

Using compound made from step 1 as raw material, 4- ((the fluoro- 2- methyl isophthalic acids H- Yin of 4- are made in the method with embodiment 22 Diindyl -5- bases) amino) penta ring simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methanol of -6,7- dihydros -5H-.

Step 3：N- (4- (the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) -6- ((2- methoxy ethoxies) methyl) -6,7- two The synthesis of the rings of hydrogen -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -4- amine

Using compound made from step 2 and 2- bromo-ethyl-methyl ethers as raw material, the method with embodiment 37 is made titled Compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.22(s,1H),8.66(s,1H),7.63(s,1H),7.42(s,1H), 7.09-6.95(m,2H),6.20(s,1H),3.52-3.45(m,6H),3.25(s,3H),3.07-3.05(m,2H),2.92- 2.72(m,3H),2.40(s,3H)。

ESI-MS(m/z):410[M+H]⁺。

Embodiment 392- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3, 4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methoxyl group) ethanol（B-60）Synthesis

Using the compound of embodiment 22 and chlorethanol as raw material, title compound is made in the method with embodiment 37.

¹H NMR(500M Hz,DMSO-d6)δ:11.32 (s, 1H, N-H, heavy water disappear after exchanging), 7.88 (s, 1H), 7.78 (s, 1H), 7.14-7.13 (m, 1H), 6.98-6.97 (m, 1H), 6.24 (s, 1H), 4.56 (s, br, 1H, OH, heavy water friendships Disappeared after changing), 3.62-3.50 (m, 6H), 3.16-3.14 (m, 2H), 3.02-2.97 (m, 1H), 2.86-2.82 (m, 1H), 3.02-2.70(m,1H),2.41(s,3H)。

ESI-MS(m/z):397[M+H]⁺。

Embodiment 404- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6- (2- methoxy ethoxies) -6,7- two The rings of hydrogen -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine（B-63）Synthesis

Step 1：The synthesis of 4- (2- methoxy ethoxies) cyclopentene

0.84g3- cyclopentene -1- alcohol is weighed with reaction bulb, adding 1.66g K₂CO₃, 10mL acetonitriles, stirring at normal temperature 0.5h Afterwards, 2- bromo-ethyl-methyl ethers are added, reaction overnight, after reaction terminates, removal of solvent under reduced pressure, adds water, ethyl acetate extraction, done It is dry, filtering, it is spin-dried for, title compound is made, is directly used in and reacts in next step.

ESI-MS(m/z):143[M+H]⁺。

Step 2：The rings of 4- chlorine 6- (2- methoxy ethoxies) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1, 2,4] synthesis of triazine

Using compound made from step 1 as raw material, title compound is made in the method with embodiment 1.

ESI-MS(m/z):268[M+H]⁺。

Step 3：4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6- (2- methoxy ethoxies) -6,7- dihydros - The synthesis of the rings of 5H- penta simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine

Using compound made from step 2 as raw material, title compound is made in the method with embodiment 11.

¹H NMR(300M Hz,DMSO-d₆)δ:11.34(s,1H,N-H),7.90(s,1H),7.82(s,1H),7.15- 7.12(m,1H),7.00-6.95(m,1H),6.24(s,1H),4.70-4.66(m,1H),3.63(t,2H),3.60(t,2H), 3.47-3.43(m,2H),3.24(s,3H),3.00-2.81(m,2H),2.41(s,3H)。

ESI-MS(m/z):397[M+H]⁺。

(the rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole of embodiment 41 Cough up simultaneously [2,1-f] [1,2,4] triazine -6- bases) methylamine（B-70）Synthesis

For the compound prepared using embodiment 32 as raw material, title compound is made in the method with embodiment 22.¹H NMR (500M Hz,DMSO-d6)δ:11.51(s,1H,N-H),7.87(s,1H),7.76(s,1H),7.15-7.12(m,1H), 6.99-6.97 (m, 1H), 6.23 (s, 1H), 3.73 (s, 2H, N-H, heavy water disappear after exchanging), 3.17-3.11 (m, 1H), 3.01-2.50(m,6H),2.41(s,3H)。

ESI-MS(m/z):352[M+H]⁺。

The rings of embodiment 424- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrrole Cough up simultaneously [2,1-f] [1,2,4] triazine -6- formonitrile HCNs（B-71）Synthesis

Step 1：The synthesis of 4- cyano group cyclopentene

12.1g diallyls acetonitrile is weighed in 150mL single port bottles, adds 50mL dichloromethane stirring and dissolvings, is added about 0.5g (1,3- pairs-(2,4,6- trimethylbenzenes) -2- imidazolines) dichloro (benzylidene) (thricyclohexyl phosphorus) changes ruthenium（GRUBB‘S Second generation catalyst）, it is stirred overnight at room temperature, point plate tracking, after question response is complete, with 150mL saturated common salt water washings, organic phase After anhydrous sodium sulfate drying, precipitation is depressurized, obtains 4- itrile group cyclopentene.

Step 2：The conjunction of the chloro- rings of 6,7- dihydros -5H- penta of 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formonitrile HCNs Into

Using step 1 gains as raw material, title compound is made in the method with embodiment 1.

Step 3：The rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrroles And the synthesis of [2,1-f] [1,2,4] triazine -6- formonitrile HCNs

Using step 2 gains as raw material, title compound is made in the method with embodiment 11.

¹H NMR(500M Hz,DMSO-d₆)δ:11.35(s,1H,N-H),7.97(s,1H),7.89(s,1H),7.16- 7.13(m,1H),7.02-6.96(m,1H),6.24(s,1H),4.01-3.93(m,1H),3.57-3.49(m,1H),3.48- 3.42(m,1H),3.26-3.20(m,1H),3.18-2.13(m,1H),2.41(s,3H)。

ESI-MS(m/z):348[M+H]⁺。

The rings of embodiment 43N- cyclopropyl -4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta And [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- imidazole carboxamides

For the compound and cyclopropylamine prepared using embodiment 28 as raw material, title compound is made in the method with embodiment 32.

¹H NMR(500M Hz,DMSO-d₆)δ:11.33(s,1H,N-H),8.02-7.78(m,3H),7.15-7.12(d, 1H),6.99-6.95(t,1H),6.23(s,1H),3.57-3.52(m,1H),3.24-3.15(m,1H),3.06-3.04(m, 2H),2.89(s,1H),2.73-2.69(d,1H),2.41(s,3H),0.63-0.61(m,2H),0.44-0.43(m,2H)。

ESI-MS(m/z):406[M+H]⁺。

((2S) -1- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta of embodiment 44 And [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methyl) pyrroles -2- bases) methanol（B-85）

Step the 14- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3,4] pyrroles Cough up the synthesis of simultaneously [2,1-f] [1,2,4] triazine -6- formaldehyde

The compound of the preparation of 200mg embodiments 22 is weighed in 50ml single port bottles, adds ethyl acetate/DMSO mixed solutions 14mL(4:3) dissolve, lower addition 480mg o-iodobenzoic acids (IBX) are stirred at room temperature, 85 DEG C of reaction 15min, after reaction terminates, add Enter 20ml water, ethyl acetate extraction (3 × 30mL), merge organic phase, saturated common salt water washing, dry, filtering, column chromatography purifying Obtain title compound.

ESI-MS(m/z):351[M+H]⁺。

Step 2:(((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously by (2S) -1- [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methyl) pyrroles -2- bases) methanol（B-85）Synthesis

The compound of 120mg steps 1 preparation is weighed in 50ml single port bottles, adds 10mL toluene/ethanol mixed solvents（Body Product ratio 16：3）Dissolving, 52mgD- dried meat ammonia alcohol is added, 110 DEG C of reaction 6h, after reaction terminates, room temperature is cooled to, adds 218mg tri- Acetoxyl group sodium borohydride, 2h is stirred at room temperature, after reaction terminates, is directly added into 1ml water, prepares column chromatography and obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.37(s,1H,N-H),7.94(s,1H),7.87-7.7.86(d,1H), 7.17-7.15(d,1H),7.00-6.97(t,1H),6.26(s,1H),5.55-5.52(m,1H),3.80-3.58(m,5H), 3.38-3.34(m,3H),3.24-3.15(m,2H),2.97-2.90(m,1H),2.75-2.70(m,1H),2.45(s,3H), 2.17-2.09(m,1H),2.07-2.00(m,1H),1.92-1.88(m,1H),1.78-1.72(m,1H)。

ESI-MS(m/z):436[M+H]⁺。

Embodiment 45N- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3, 4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methyl) acetamide（B-86）

The compound of the preparation of 200mg embodiments 41 is weighed in 50ml there-necked flasks, adds the dissolving of 10ml anhydrous methylene chlorides, After 0-5 DEG C of stirring 10min, the dichloromethane solution that 5ml is dissolved with 80mg chloroacetic chlorides, 0-5 DEG C of reaction 1h is added dropwise, reaction terminates Afterwards, 20ml water is added, dichloromethane extraction (3 × 20mL), is dried, filtering, is spin-dried for, column chromatography purifies to obtain title compound.

¹H NMR(500M Hz,DMSO-d₆)δ:11.32(s,1H,N-H),8.00(s,1H),7.87(s,1H),7.78(s, 1H),7.14-7.11(d,1H),6.98-6.93(t,1H),6.23(s,1H),3.23-3.10(m,3H),3.01-2.92(m, 2H),2.82-2.71(m,1H),2.64-2.57(m,1H),2.49(s,3H),1.82(s,3H)。

ESI-MS(m/z):394[M+H]⁺。

Embodiment 46N- ((rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta simultaneously [3, 4] pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) methyl) Methanesulfomide（B-87）

For the compound and mesyl chloride prepared using embodiment 41 as raw material, title compound is made in the method with embodiment 45 Thing.

¹H NMR(500M Hz,DMSO-d₆)δ:11.33(s,1H,N-H),7.88(s,1H),7.80(s,1H),7.19- 7.13(m,2H),6.98-6.95(t,1H),6.23(s,1H),3.21-3.16(m,1H),3.11-3.10(m,2H),3.03- 3.00(m,2H),2.91(s,3H),2.87-2.83(m,1H),2.70-2.68(m,1H),2.41(s,3H)。

ESI-MS(m/z):430[M+H]⁺。

(rings of 4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) epoxide) -6,7- dihydros -5H- penta are simultaneously [3,4] by embodiment 471- Pyrrolo- [2,1-f] [1,2,4] triazine -6- bases) ethanol（B-88）

Weigh compound 4- ((4- ((the fluoro- 2- Methyl-1H-indoles -5- bases of 4-) oxygen of the step 1 of 40mg embodiments 44 preparation Base) simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formaldehyde in 25ml single port bottles, adds-the rings of 6,7- dihydros -5H- penta The anhydrous THF of 8ml dissolve, and at -50 DEG C, the CH of 1 equivalent is added dropwise₃MgCl, drop finish, and 30min is reacted at -50 DEG C, after reaction terminates, is added Enter NH₄Cl is quenched, and ethyl acetate extraction, dries, filtering, is spin-dried for, column chromatography purifies to obtain title compound.

¹H NMR(500M Hz,DMSO-d6)δ:11.33(s,1H,N-H),7.87(s,1H),7.76(s,1H),7.15- 7.12(d,1H),7.00-6.94(m,1H),6.24(s,1H),4.62(s,1H),3.75(s,1H),3.10-2.68(m,5H), 2.41(s,3H),1.14-1.12(d,3H)。

ESI-MS(m/z):367[M+H]⁺。

The Compound ira vitro enzymatic activity evaluation of the present invention of experimental example 1

1 experiment material

1.1 compound

Compound of the invention prepared by above example, after each compound is dissolved to 1.5mM with DMSO, 3 times successively Dilute, totally 11 concentration.

1.2 reagent

Vascular endothelial cell growth factor R-2（Vascular endothelial growth factor receptor2,VEGFR2）, purchased from Japanese Carna Biosciences companies；

Fibroblast growth factor acceptor 1（Fibroblast growth factor receptor1,FGFR1）, purchase From in Japanese Carna Biosciences companies；

Dimethyl sulfoxide (DMSO)（Dimethyl sulfoxide,DMSO）, purchased from Sigma Co., USA；

EDTA, purchased from Sigma Co., USA；

96 orifice plates（96well plate）, purchased from Corning companies of the U.S.；

384 orifice plates（384well plate）, purchased from Corning companies of the U.S..

1 × kinase buffer liquid（50mM HEPES,pH7.5,0.0015%Brij-35,10mM MgCl₂,2mM DTT）, face With preceding preparation；

Terminate liquid（100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating Reagent#3, 50mMEDTA）, prepared before use.

1.3 instrument

LabChip EZ Reader, purchased from Caliper companies of the U.S..

2 experimental methods

1) the μ l of compound solution 10 of each concentration are taken into 96 orifice plates, add 90 μ l1 × kinase buffer liquid；Set up simultaneously DMSO control groups and without enzyme activity control group, only contain 10 μ l DMSO and 90 μ l1 × kinase buffer liquid.Each group mixes at room temperature 10min, then respectively transferase 45 μ l into 384 orifice plates；

2) kinases VEGFR2 or FGFR1 are dissolved in 1 × kinase buffer liquid, are configured to 2.5 × kinase solution, then shift 10 μ l2.5 × kinase solution is into above-mentioned 384 orifice plates containing each concentration compound；It is molten that DMSO control groups add 10 μ l2.5 × kinases Liquid；1 × kinase buffer liquids of the 10 μ l without kinases is added without enzyme activity control group.10min is incubated at room temperature；

3) polypeptide of FAM marks and ATP are dissolved in 1 × kinase buffer liquid, are configured to 2.5 × substrate solution, then shift 10 μ l2.5 × substrate solution is into above-mentioned 384 orifice plate, 28 DEG C of incubation 1hr；

4) 25 μ l terminate liquid terminating reactions are added in each hole；

5) reading and converting rate data on LabChip EZ Reader are placed in, and calculate inhibiting rate I%, calculation formula be I%= (Max-Conversion)/(Max-Min) × 100, wherein Max are the conversion ratio of DMSO control groups, and Min is without enzyme activity control group Conversion ratio, Conversion be compound treatment group conversion ratio.Data are fitted to obtain IC through XLfit processing₅₀。IC₅₀It is worth table Show with not plus compared with compound treatment group, compound suppresses corresponding compound concentration during 50% enzyme activity.IC₅₀It the results are shown in Table 1.

Table 1

The compound that can be seen that the present invention from above experimental result there is preferably suppression to live VEGFR2 or FGFR1 Property.

Although being described in detail above 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.The interest field of the present 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,

Wherein：

X is selected from O, S, N (R₄) and C_1-3Alkylidene；

Ring A is selected from the carbocyclic ring containing 5 and 6 carbon atoms and contains 1-2 heteroatomic five yuan and hexa-member heterocycles, described miscellaneous original Son is selected from N, O, S；

R₁Selected from hydrogen, oxo, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy ,-OH ,-NH₂, nitro, halogen Element, CN, single C_1-6Alkyl amino and double C_1-6Alkyl amino；

R₂Selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy ,-OH ,-NH₂, nitro, halogen, CN, single C_1-6Alkyl amino and double C_1-6Alkyl amino；

R₃Selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group ,-C_1-6Alkyl, nitro ,-O-C_1-6Alkyl ,-C_1-6Alkyl- O-C_1-6Alkyl ,-O-C_1-6Alkyl-O-C_1-6Alkyl ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C_1-6Alkyl-NH- C_1-6Alkyl ,-C_1-6Alkyl-N (C_1-6Alkyl) (C_1-6Alkyl) ,-C (O)-O-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-O-C_1-6Alkane Base ,-C (O)-NH₂、-C(O)-NH-C_1-6Alkyl ,-C (O)-NH-C_3-6Cycloalkyl ,-C (O)-N- (C_1-6Alkyl) (C_1-6Alkyl) ,- C_1-6Alkyl-C (O)-NH₂、-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-N- (C_1-6Alkyl) (C_1-6Alkane Base) ,-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-C (O)-C_1-6Alkyl ,-O-C (O)-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6Alkane Base ,-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-OH ,-C_1-6Alkyl-NH₂、-C(O)-NH-C_1-6Alkyl-OH ,-C (O)-NH-C_1-6 Alkyl-C (O)-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-OH ,-C_1-6Alkyl-C (O)-NH-C_1-6Alkyl-C (O)-OH ,- C_1-6Alkyl-O-C_1-6Alkyl-OH ,-C_1-6Alkyl-O-C_1-6Alkyl-O-C_1-6Alkyl ,-C_1-6Alkyl-O-C (O)-C_1-6Alkyl-C (O)-OH、-C_1-6Alkyl-O-C (O)-C_1-6Alkyl-OH ,-C_1-6Alkyl-tetrahydro pyrrolidine ,-C_1-6Alkyl-tetrahydrofuran ,-C_1-6 Alkyl-thiophane ,-C_1-6Alkyl-tetrahydro-thiazoles ,-C_1-6Alkyl-Si Qing oxazoles ,-C_1-6Alkyl-piperidine ,-C_1-6Alkyl-piperazine Piperazine ,-C_1-6Alkyl-morpholine, described tetrahydro pyrrolidine, tetrahydrofuran, thiophane, tetrahydro-thiazoles, Si Qing oxazoles, piperidines, piperazine Piperazine, morpholine can be by one or more halogens, hydroxyl, C_1-6Alkyl, hydroxyl C_1-6Alkyl, carboxyl, amino, cyano group, C_1-6Alkoxy takes Generation；

R₄Selected from hydrogen and C_1-6Alkyl；

N is selected from 1,2,3 and 4.

2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein：

X is selected from O, S, N (R₄) and CH₂；

R₄Selected from hydrogen and C_1-6Alkyl；

N is selected from 1,2 and 3.

3. compound according to claim 1 or its pharmaceutically acceptable salt, its middle ring A is selected from pentamethylene base, cyclopentenyl, ring Hexyl and cyclohexenyl group.

4. compound according to claim 1 or its pharmaceutically acceptable salt, its middle ring A is selected from tetrahydrofuran ring group, tetrahydrochysene pyrrole Cough up ring group, oxinane ring group and piperidyl.

5. compound or its pharmaceutically acceptable salt according to any one of claim 2-4, wherein X are selected from N (R₄) and O, Described R₄Selected from hydrogen and C_1-6Alkyl.

6. compound according to claim 5 or its pharmaceutically acceptable salt, wherein X is selected from N (R₄) and O, described R₄Selected from hydrogen And C_1-3Alkyl.

7. compound according to claim 6 or its pharmaceutically acceptable salt, wherein X is selected from NH and O.

8. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from following Compound：

9. prepare the intermediate of the compound or its pharmaceutically acceptable salt described in any one of claim 1 to 8：

10. a kind of pharmaceutical composition, it includes compound described in any one of claim 1 to 8 or its is pharmaceutically acceptable Salt and pharmaceutical acceptable carrier.

11. the medicine described in compound or its pharmaceutically acceptable salt or claim 10 described in any one of claim 1-8 Compositions are preparing the application in being used to treat or prevent the medicine of tumour.