CN104725381A

CN104725381A - Growth factor receptor inhibitor and application thereof

Info

Publication number: CN104725381A
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: 2015-06-24
Anticipated expiration: 2033-12-19
Also published as: CN104725381B

Abstract

Belonging to the chemical pharmaceutical field, the invention in particular relates to a compound shown as formula I or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, and pharmaceutical compositions containing the compounds, and application of the compounds or compositions in drug preparation. The compound has good growth factor receptor inhibitory activity, and can effectively reduce the incidence of tumors and prolong the life of tumor patients. (formula I).

Description

Growth factor receptor inhibitor and application thereof

Technical field

The invention belongs to chemical medicine, be specifically related to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug that a class has growth factor receptors inhibit activities, and the application in medicine preparation with these compounds or composition of the pharmaceutical composition containing these compounds.

Background technology

Most cells growth factor receptors contains the peptide sequence of Tyrosylprotein kinase, therefore this receptoroid is commonly referred to as tyrosine kinase receptor.According to the similarity of peptide sequence, these acceptors are divided into some large classes at present: (1) EGF-R ELISA, and as EGFR, HER2, HER3, HER4, high expression level is common in epithelial cell tumour; (2) Insulin Receptor Family, as insulin receptor, IGF-1 (IGFR), insulin-related receptor (IRR), high expression level is common in blood cell tumour; (3) platelet-derived growth factor receptors family, as PDGFRa, PDGRRb, colony stimulating factor (CSF-1R), c-Kit etc., high expression level is common in cerebral tumor, blood cell tumour; (4) fibroblast growth factor acceptor (FGFR) family, as FGFR1, FRFR2, FGFR3, FGFR4 and keratinocyte growth factor etc., plays an important role in vasculogenesis; (5) vascular endothelial growth factor receptor (VEGFR) is the important positivity regulatory factor of vasculogenesis; In addition, hepatocyte growth factor receptor (HGFR), Fibronectin type III acceptor and NFG acceptor (NGFR) etc. are also had.Tyrosine kinase receptor is overexpression in dissimilar tumour respectively, causes its Intracellular signals to activate, and cell transformation, constantly breeds, and promotes the generation of tumour, development.

Vascular endothelial growth factor receptor (VEGFR) is vascular endothelial growth factor (VEGF) specific membrane receptor, there is high-affinity, belong to typical cross-film integral protein, be divided into extracellular region, cross-film district and film inner region three part, with the Tyrosylprotein kinase district opened between 2 in the supersecondary structure of outer 7 immunoglobulin-likes of born of the same parents, born of the same parents for its feature.VEGFR-1, VEGFR-2 and VEGFR-3 totally 3 kinds of hypotypes mainly can be divided into according to the difference of its structure and fuction.Wherein, VEGFR-1, VEGFR-2 mainly express at vascular endothelial cell.Research shows, VEGF and VEGFR-2 causes the phosphorylation of acceptor self, activates inhibition of mitogen-activated protein kinase, realize the mitogen characteristic of VEGF, the division growth of induction of vascular endothelial cell after combining; After VEGF and VEGFR-1 combines, increase vascular endothelial cell permeability, make endovascular protein extravasation, form the support of endothelial cell migration and the provisional matrix of vasculogenesis; Simultaneously VEGF can strengthen plasminogen activator activity, improves plasminogen activation factor and plasminogen activation factor supressor _mthe level of RNA, promotes extracellular proteolysis, is conducive to the generation of capillary vessel; Moreover VEGF can change the activated form of endothelial cell gene, inducing endothelial cell expressing protein lytic enzyme, interstitial collagenase and tissue factor promote vasculogenesis.Large quantity research confirms, the angiogenic growth that the growth of noumenal tumour and transfer and VEGF-VEGFR signal path excessive activation cause is closely related, and growth rapidly and have the vessel density of tumour of transfer apparently higher than poor growth with without the tumour shifted.When the signal of VEGF is suppressed, vasculogenesis and the tumor growth of tumour are contained.

Fibroblast growth factor acceptor (FGFR) is combined with its part fibroblast growth factor, regulates and controls the cytocerastic process of a large class, comprises apoptosis, breeds, divides a word with a hyphen at the end of a line and vasculogenesis.A large amount of evidence proves, fibroblast growth factor and vascular endothelial growth factor collaborative promotion blood vessel occur.The FGFR signal path regulation and control caused due to sudden change or receptor-ligand overexpression are not normal, also be proved and be present in kinds of tumor cells, and can by regulating tumor-blood-vessel growth or directly stimulating tumor growth and play a significant role in the development process of tumour.

Therefore, exploitation has the medicine of growth factor receptors inhibit activities, particularly the generation of blood vessel is had to VEGFR and/or FGFR of important regulating and controlling effect, suppress the excessive activation of VEGFR signal path and/or FGFR signal path, good application prospect will be had clinically.

Summary of the invention

The class that the object of this invention is to provide general formula I has compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of growth factor receptors inhibit activities,

Wherein:

X is selected from O, S, N (R ₄), C _1-3alkylidene group;

Ring A is selected from containing 0-3 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, and described heteroatoms is selected from N, O, S;

R ₁be selected from hydrogen, oxo, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-OH ,-NH ₂, nitro, halogen, CN, alkyl monosubstituted amino, two alkylamino, amido, ester group, cycloalkyl, Heterocyclylalkyl;

R ₂be selected from hydrogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-OH ,-NH ₂, nitro, halogen, CN, alkyl monosubstituted amino, two alkylamino, amido, ester group, cycloalkyl, Heterocyclylalkyl;

R ₃be selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, alkyl, nitro, alkoxyl group, alkoxyalkyl, aminoalkyl, amido, acyl group, alkyl amido, alkyl acyl, cycloalkyl, Heterocyclylalkyl, described hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, aminoalkyl, amido, acyl group, alkyl amido, alkyl acyl, cycloalkyl, Heterocyclylalkyl can by one or more halogen, hydroxyl, carboxyl, amino, cyano group, nitro, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyl group, alkyl monosubstituted amino, two alkylamino, alkoxyacyl, amido, alkyl monosubstituted amino acyl group, two alkylaminoacyl, alkyl acyl, alkyl acyl oxygen base, carboxyalkyl acyloxy, hydroxyalkyl acyloxy, alkyl sulphonyl, aryl sulfonyl, heterocyclyl sulfonyl, amino-sulfonyl, monoalkylaminosulfonyl, two alkyl amino sulfonyl replaces,

R ₄be selected from hydrogen, alkyl;

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

Another object of the present invention is to provide the method for the compound of preparing general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.

Another object of the present invention is to provide the composition of compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and the pharmaceutically acceptable carrier comprising general formula I of the present invention, and comprises the compound of general formula I of the present invention or the composition of its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and another kind or multiple protein tyrosine kinase inhibitor.

Also object of the present invention is to provide the method that the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug treat and/or prevent tumour, and the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug are for the preparation of the application treated and/or prevented in the medicine of tumour.

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

First aspect, the invention provides compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I,

Wherein:

X is selected from O, S, N (R ₄), C _1-3alkylidene group;

R ₂be selected from hydrogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-OH ,-NH ₂, halogen, nitro, CN, alkyl monosubstituted amino, two alkylamino, amido, ester group, cycloalkyl, Heterocyclylalkyl;

R ₄be selected from hydrogen, alkyl;

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

In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:

Ring A is selected from the carbocyclic ring containing 4-8 carbon atom, such as tetramethylene base, cyclobutene base, pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl, suberane base, cycloheptenyl, cyclooctane base, cyclooctene base, be preferably the carbocyclic ring containing 5-7 carbon atom, such as pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl, suberane base, cycloheptenyl, carbocyclic ring more preferably containing 5-6 carbon atom, is further preferably pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl.

In other preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:

Ring A is selected from containing 1-2 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or eight yuan of heterocycles, be preferably containing 1-2 heteroatomic five yuan, hexa-atomic or seven membered heterocyclic, more preferably containing 1-2 heteroatomic five yuan or hexa-member heterocycle, described heteroatoms is selected from O, N, S, is further preferably tetrahydrofuran (THF) cyclic group, Pyrrolidine cyclic group, tetrahydropyrans cyclic group, piperidyl.

R ₁be selected from hydrogen, oxo, alkyl, haloalkyl, halogen, be preferably hydrogen, C _1-6alkyl, halo C _1-6alkyl, halogen, more preferably hydrogen, oxo, C _1-3alkyl, halo C _1-3alkyl, halogen, be further preferably hydrogen, oxo, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine.

R ₂be selected from hydrogen, alkyl, haloalkyl, halogen, be preferably hydrogen, C _1-6alkyl, halo C _1-6alkyl, halogen, more preferably hydrogen, C _1-3alkyl, halo C _1-3alkyl, halogen, be further preferably hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine.

R ₃be selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C _1-10alkyl, nitro, C _1-10alkoxyl group, C _1-10alkoxy C _1-10alkyl, amino C _1-10alkyl, amido, acyl group, C _1-10alkyl amido, C _1-10alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, described hydroxyl, carboxyl, amino, C _1-10alkyl, C _1-10alkoxyl group, C _1-10alkoxy C _1-10alkyl, amino C _1-10alkyl, amido, acyl group, C _1-10alkyl amido, C _1-10alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl can by one or more halogen, hydroxyl, carboxyl, amino, cyano group, nitro, C _1-6alkyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, hydroxyl C _1-6alkyl, carboxyl C _1-6alkyl, C _1-6alkoxyl group, single C _1-6alkylamino, two C _1-6alkylamino, C _1-6alkoxyacyl, amido, single C _1-6alkylaminoacyl, two C _1-6alkylaminoacyl, C _1-6alkyl acyl, C _1-6alkyl acyl oxygen base, carboxyl C _1-6alkyl acyl oxygen base, hydroxyl C _1-6alkyl acyl oxygen base, C _1-6alkyl sulphonyl, aryl sulfonyl, C _1-6heterocyclyl sulfonyl, amino-sulfonyl, single C _1-6alkyl amino sulfonyl, two C _1-6alkyl amino sulfonyl, Pyrrolidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, thiazolidine base, four hydrogen oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl replace;

Further preferably,

R ₃be selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C _1-6alkyl, nitro, C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkyl, amino C _1-6alkyl, amido, acyl group, C _1-6alkyl amido, C _1-6alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, described hydroxyl, carboxyl, amino, cyano group, C _1-6alkyl, C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkyl, amino C _1-6alkyl, amido, acyl group, C _1-6alkyl amido, C _1-6alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl can by one or more halogen, hydroxyl, carboxyl, amino, cyano group, C _1-6alkyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, hydroxyl C _1-6alkyl, carboxyl C _1-6alkyl, C _1-6alkoxyl group, single C _1-6alkylamino, two C _1-6alkylamino, C _1-6alkoxyacyl, amido, single C _1-6alkylaminoacyl, two C _1-6alkylaminoacyl, C _1-6alkyl acyl, C _1-6alkyl acyl oxygen base, carboxyl C _1-6alkyl acyl oxygen base, hydroxyl C _1-6alkyl acyl oxygen base, C _1-6alkyl sulphonyl, aryl sulfonyl, C _1-6heterocyclyl sulfonyl, amino-sulfonyl, single C _1-6alkyl amino sulfonyl, two C _1-6alkyl amino sulfonyl, Pyrrolidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, thiazolidine base, four hydrogen oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl replace;

Still more preferably,

R ₃be selected 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 _1-6alkyl ,-C (O)-NH ₂,-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)-NH ₂,-C _1-6alkyl-C (O)-NH-C _1-6alkyl ,-C _1-6alkyl-C (O)-N-(C _1-6alkyl) (C _1-6alkyl) ,-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 _1-6alkyl ,-C _1-6alkyl-OH ,-C _1-6alkyl-C (O)-OH ,-C _1-6alkyl-NH ₂,-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 _1-6alkyl-C (O)-OH ,-C _1-6alkyl-O-C (O)-C _1-6alkyl-OH ,-C _1-6alkyl-tetrahydro pyrrolidine ,-C _1-6alkyl-tetrahydrofuran (THF) ,-C _1-6alkyl-tetramethylene sulfide ,-C _1-6alkyl-thiazolidine ,-C _1-6alkyl-Si Qing oxazole ,-C _1-6alkyl-piperidine ,-C _1-6alkyl-piperazin ,-C _1-6alkyl-morpholine, described tetrahydro pyrrolidine, tetrahydrofuran (THF), tetramethylene sulfide, thiazolidine, Si Qing oxazole, piperidines, piperazine morpholine can be replaced by one or more halogen, hydroxyl, alkyl, hydroxyalkyl, carboxyl, amino, cyano group, alkoxyl group.

X is selected from O, N (R ₄), described R ₄be selected from hydrogen, C _1-6alkyl; Be preferably O, N (R ₄), described R ₄be selected from hydrogen, C _1-3alkyl; More preferably NH, O.

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

X is selected from O, S, N (R ₄), CH ₂;

Ring A is selected from C _4-8cycloalkyl or C _4-8heterocyclylalkyl, described heteroatoms is selected from N, O, S;

R ₁be selected from hydrogen, oxo, C _1-6alkyl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group ,-OH ,-NH ₂, nitro, halogen, CN, single C _1-6alkylamino, two C _1-6alkylamino, amido, ester group, C _1-6cycloalkyl, C _1-6heterocyclylalkyl;

R ₂be selected from hydrogen, C _1-6alkyl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group ,-OH ,-NH ₂, nitro, halogen, CN, single C _1-6alkylamino, two C _1-6alkylamino, amido, ester group, C _1-6cycloalkyl, C _1-6heterocyclylalkyl;

R ₄be selected 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 heteroatoms is selected from N, O, S;

R ₁be selected from hydrogen, oxo, C _1-3alkyl, C _1-3alkoxyl group, halo C _1-3alkyl, halo C _1-3alkoxyl group ,-OH ,-NH ₂, nitro, halogen, CN, single C _1-3alkylamino, two C _1-3alkylamino, amido, ester group, C _1-3cycloalkyl, C _1-3heterocyclylalkyl;

R ₂be selected from hydrogen, C _1-3alkyl, C _1-3alkoxyl group, halo C _1-3alkyl, halo C _1-3alkoxyl group ,-OH ,-NH ₂, nitro, halogen, CN, single C _1-3alkylamino, two C _1-3alkylamino, amido, ester group, C _1-3cycloalkyl, C _1-3heterocyclylalkyl;

R ₄be selected from hydrogen, C _1-3alkyl;

N is selected from 1 and 2.

Preferably, the invention provides compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I a,

Wherein:

X is selected from O, S, N (R ₄), C _1-3alkylidene group;

Ring A ₁be selected from the carbocyclic ring containing 4-8 carbon atom;

R ₄be selected from hydrogen, alkyl;

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

In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I a, wherein:

X is selected from N (R ₄), O, described R ₄be selected from hydrogen, C _1-6alkyl; Be preferably N (R ₄), O, described R ₄be selected from hydrogen, C _1-3alkyl; More preferably NH, O;

Ring A ₁be selected from the carbocyclic ring containing 5-7 carbon atom, the carbocyclic ring more preferably containing 5-6 carbon atom, be further preferably pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl;

R ₁be selected from hydrogen, oxo, alkyl, haloalkyl, halogen, be preferably hydrogen, C _1-6alkyl, halo C _1-6alkyl, halogen, more preferably hydrogen, oxo, C _1-3alkyl, halo C _1-3alkyl, halogen, be further preferably hydrogen, oxo, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine;

R ₂be selected from hydrogen, alkyl, haloalkyl, halogen, be preferably hydrogen, C _1-6alkyl, halo C _1-6alkyl, halogen, more preferably hydrogen, C _1-3alkyl, halo C _1-3alkyl, halogen, be further preferably hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine;

Further preferably,

R ₃be selected from hydrogen, oxo, halogen, hydroxyl, carboxyl, amino, cyano group, C _1-6alkyl, nitro, C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkyl, amino C _1-6alkyl, amido, acyl group, C _1-6alkyl amido, C _1-6alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, described hydroxyl, carboxyl, amino, C _1-6alkyl, C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkyl, amino C _1-6alkyl, amido, acyl group, C _1-6alkyl amido, C _1-6alkyl acyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl can by one or more halogen, hydroxyl, carboxyl, amino, cyano group, nitro, C _1-6alkyl, C _3-6cycloalkyl, C _3-6heterocyclylalkyl, hydroxyl C _1-6alkyl, carboxyl C _1-6alkyl, C _1-6alkoxyl group, single C _1-6alkylamino, two C _1-6alkylamino, C _1-6alkoxyacyl, amido, single C _1-6alkylaminoacyl, two C _1-6alkylaminoacyl, C _1-6alkyl acyl, C _1-6alkyl acyl oxygen base, carboxyl C _1-6alkyl acyl oxygen base, hydroxyl C _1-6alkyl acyl oxygen base, C _1-6alkyl sulphonyl, aryl sulfonyl, C _1-6heterocyclyl sulfonyl, amino-sulfonyl, single C _1-6alkyl amino sulfonyl, two C _1-6alkyl amino sulfonyl, Pyrrolidine alkyl, tetrahydrofuran base, tetrahydro-thienyl, thiazolidine base, four hydrogen oxazolyls, piperidyl, piperazinyl, substituted piperazinyl, morpholinyl replace;

Still more preferably,

R ₄be selected from hydrogen, C _1-6alkyl, is preferably hydrogen, C _1-3alkyl, further preferred hydrogen;

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

Preferably, the invention provides compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I b,

Wherein:

X is selected from O, S, N (R ₄), CH ₂;

Ring A ₂be selected from containing 1-2 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or eight yuan of heterocycles, described heteroatoms is selected from N, O, S;

R ₄be selected from hydrogen, alkyl;

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

In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I b, wherein:

Ring A ₂be selected from containing 1-2 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or eight yuan of heterocycles, further preferably from containing 1-2 heteroatomic five yuan, hexa-atomic or seven membered heterocyclic, further preferably from containing 1-2 heteroatomic five yuan or hexa-member heterocycle, described heteroatoms is selected from N, O, S;

Further preferably,

Still more preferably,

R ₃be selected 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 _1-6alkyl ,-C (O)-NH ₂,-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)-NH ₂,-C _1-6alkyl-C (O)-NH-C _1-6alkyl ,-C _1-6alkyl-C (O)-N-(C _1-6alkyl) (C _1-6alkyl) ,-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 _1-6alkyl ,-C _1-6alkyl-OH ,-C _1-6alkyl-C (O)-OH ,-C _1-6alkyl-NH ₂,-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 _1-6alkyl-C (O)-OH ,-C _1-6alkyl-O-C (O)-C _1-6alkyl-OH ,-C _1-6alkyl-tetrahydro pyrrolidine ,-C _1-6alkyl-tetrahydrofuran (THF) ,-C _1-6alkyl-tetramethylene sulfide ,-C _1-6alkyl-thiazolidine ,-C _1-6alkyl-Si Qing oxazole ,-C _1-6alkyl-piperidine ,-C _1-6alkyl-piperazin ,-C _1-6alkyl-morpholine, described tetrahydro pyrrolidine, tetrahydrofuran (THF), tetramethylene sulfide, thiazolidine, Si Qing oxazole, piperidines, piperazine morpholine can be replaced by one or more halogen, hydroxyl, alkyl, hydroxyalkyl, carboxyl, amino, cyano group, alkoxyl group;

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

The invention provides following particular compound:

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

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

(1) preparation of key intermediate M1:

Wherein, n, R ₃and ring A has the definition in general formula I, Y is halogen;

Concrete steps are as follows:

A) compound of formula 1 and SPTS and I ₂the compound of the obtained formula 2 of reaction;

B) the compound generation eliminative reaction of formula 2 obtains the compound of formula 3;

C) compound of formula 3 and Methyl isocyanoacetate react the compound of obtained formula 4;

D) compound of formula 4 and phenylbenzene phosphono azanol reaction obtain the compound of formula 5;

E) compound of formula 5 and formamide obtain the compound of formula 6;

F) compound of formula 6 obtains the key intermediate of formula M1 through halogenating reaction.

(2) preparation of compound of Formula I:

Wherein, X, R ₁, R ₂, R ₃, R ₄, n and ring A has definition in general formula I, Y is halogen, X ₁be selected from amino or hydroxyl.

Concrete steps:

The compound of formula M1 and the compound of formula M2 react the compound of obtained formula I in the basic conditions, and described alkali is selected from sodium carbonate, salt of wormwood or triethylamine.

The third aspect, the invention provides pharmaceutical composition, and it comprises compound of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.

In some embodiments, the invention provides pharmaceutical composition, it comprises compound of the present invention, isomer, solvate, crystallization or prodrug, also comprises one or more that be selected from following composition: tyrosine protein enzyme inhibitors, EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc.

Compound of the present invention, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, thinner or mixed with excipients can be prepared into pharmaceutical preparation, to be suitable for per os or parenteral admin.Medication includes, but are not limited to intracutaneous, intramuscular, intraperitoneal, intravenously, subcutaneous, nose interior and peroral route.Described preparation can be used by any approach, such as, by infusion or inject, is used by the approach absorbed through epithelium or mucocutaneous (such as oral mucosa or rectum etc.).Administration can be whole body or local.The example of oral administration preparation comprises solid or liquid dosage form, specifically, comprises tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspensoid etc.Described preparation is prepared by methods known in the art, and comprises conventional carrier, thinner or the vehicle used of field of pharmaceutical preparations.

Fourth aspect, the invention provides the method for compound of the present invention, isomer, solvate, crystallization or prodrug or medicine composite for curing of the present invention or prophylaxis of tumours and the application in preparation prevention or tumor, comprise and easily send out the pharmaceutical composition that crowd or tumour patient use compound of the present invention, isomer, solvate, crystallization or prodrug or comprise compound of the present invention, isomer, solvate, crystallization or prodrug, effectively to reduce Tumor incidence, to extend tumour patient life to tumour.

Term explanation

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

" alkoxyl group " 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 at least by the alkyl of a halogen substiuted.

" halogenated alkoxy " of the present invention refers at least by the alkoxyl group of a halogen substiuted.

" amido " of the present invention refers to-C (O)-NH ₂.

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

" alkyl amido " of the present invention refers to-alkyl-C (O)-NH ₂.

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

" hydroxyalkyl " 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.

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

" two alkylaminoacyl " of the present invention refers to-C (O)-N (alkyl) (alkyl).

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

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

" 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.

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

In this article, term " quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring " refers to 4 to 8 yuan of saturated, part insatiable hungers and/or whole undersaturated monocycle, and it containing heteroatoms or containing one or more heteroatoms being selected from N, O and S, does not comprise C _4-8cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl.Herein, described cycloalkyl is understood to monocycle, and it can be saturated rings or undersaturated, non-aromatic ring, and it can comprise double bond in due course, and described Heterocyclylalkyl refers to saturated or unsaturated, non-aromatic monocyclic, it contains heteroatoms N, O or S to substitute one or more carbon atom.As described herein, described " quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring " is fused on pyrrole ring.

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

" heteroaryl " of the present invention refers in aryl the aromatic radical having at least a carbon atom to be substituted by heteroatoms.Described heteroatoms is O, S, N.

" solvate " of the present invention refers to the mixture that solute (salt as active compound, active compound) and solvent (as water) are combined to form in a conventional sense.Solvent refers to solvent that is known to those of skill in the art or that easily determine.If water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc.

" crystallization " of the present invention refers to the various solid form of compound formation of the present invention, comprises crystal formation, amorphous.

Refer to that " isomer " of the present invention comprises compound along configuration structure body, conformer and enantiomer.Configurational isomer refers to the cis-trans-isomer of cis or transconfiguration; Conformer refers to because singly-bound rotates the steric isomer produced.

" prodrug " of the present invention refers under the physiological condition of organism, change into the compound of compound of the present invention owing to reacting with enzyme, hydrochloric acid in gastric juice etc., namely change into the compound of compound of the present invention by the oxidation, reduction, hydrolysis etc. of enzyme and/or changed into the compound of compound of the present invention by the hydrolysis reaction etc. of hydrochloric acid in gastric juice etc.

" pharmacologically acceptable salts " of the present invention refers to the pharmacy acceptable salt that compound of the present invention is formed with acid, and described acid includes but not limited to phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid etc.

" pharmaceutical composition " of the present invention refers to and comprises any one compound as herein described, comprises the protection form of isomer, prodrug, solvate, pharmacy acceptable salt or its chemistry, and the mixture of one or more pharmaceutically acceptable carriers.

" pharmaceutically acceptable carrier " of the present invention refers to and does not cause obvious irritation to organism and do not disturb the biological activity of given compound and the carrier of character, comprises solvent, thinner or other vehicle, dispersion agent, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc.Unless any conventional carrier medium is incompatible with the compounds of this invention.Carbohydrate can be included, but are not limited to, as lactose, dextrose plus saccharose as some examples of pharmaceutically acceptable carrier; Starch, as W-Gum and yam starch; Cellulose and its derivates, as Xylo-Mucine and Mierocrystalline cellulose and rhodia; Fructus Hordei Germinatus, gelatin etc.

" vehicle " of the present invention refers to join in medicinal compositions to promote to give the inert substance of compound further.Vehicle can comprise calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil, polyoxyethylene glycol.

" application in the medicine for the preparation for the treatment of or prophylaxis of tumours " of the present invention refer to can the growth of Tumor suppression, development and/or transfer, mainly to required human or animal to controlling the compound of the present invention that gives treatment effective dose to suppress, to slow down or to reverse the growth of curee's tumour, development or expanding.

Compound of the present invention refers to the general formula compound that the present invention is all, comprises general formula I, general formula I a and the compound described in the arbitrary general formula of general formula I b and particular compound.

Embodiment

Representational embodiment is to better the present invention is described below, but not for limiting the scope of the invention.

The synthesis of chloro-6,7-dihydro-5H-penta rings of embodiment 14-also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate

The synthesis of the iodo-2-p-toluenesulfonyl of step 11--4-methyl-formiate-pentamethylene

Under condition of ice bath, take 10g3-cyclopentenes-1-methyl-formiate and 21.2g SPTS, be placed in reaction flask, add methylene dichloride/water mixed solvent that 500mL volume ratio is 1:1, after stirring 1h, add 20g I in batches ₂after adding, room temperature reaction is after 3 hours, stratification, get organic phase, aqueous phase, with dichloromethane extraction (2 times × 250mL), merges organic phase, washes twice successively with aqueous solution of sodium bisulfite, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain title compound.Not purified, be directly used in next step reaction.

ESI-MS m/z:409[M+H] ⁺,447[M+K] ⁺。

The synthesis of step 21-p-toluenesulfonyl-4-methyl-formiate-cyclopentenes

Take the compound of 31.8g step 1 preparation in reaction flask, slowly add 10g triethylamine, 600mL acetonitrile, be heated to 70 DEG C, react and be spin-dried for after 3 hours, add 400mL acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution and saturated common salt solution washing twice successively, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain title compound.Not purified, be directly used in next step reaction.

ESI-MS m/z:281[M+H] ⁺。

Step 32, the synthesis of 4-dicarboxylic acid methyl ester-penta ring also [3,4] pyrroles

Under nitrogen protection, take 2g NaH in reaction flask, add the anhydrous THF of 100mL, be cooled to about 0 DEG C, slowly add 200mL and be dissolved with the compound of 5.6g step 2 preparation and the anhydrous THF solution of 3.96g Methyl isocyanoacetate, finish and continue to react after 1 hour under 0 DEG C of condition, add 2 ~ 3mL anhydrous methanol, stir 5 minutes, be spin-dried for, residue 200mL acetic acid ethyl dissolution, diatomite filtration, filter cake ethyl acetate washs 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain dark oil thing, column chromatography purification, obtain title compound.

ESI-MS m/z:224[M+H] ⁺,262[M+K] ⁺。

The synthesis of amino-2,4-dicarboxylic acid methyl ester-penta rings of step 4N-also [3,4] pyrroles

Under nitrogen protection; take 73mg NaH in reaction flask; add 3mL dry DMF; be cooled to about 0 DEG C; slow instillation 5mL is dissolved with the anhydrous DMF solution of the compound of 270mg step 3 preparation; after keeping 0 DEG C to react 30min, add 350mg phenylbenzene phosphono azanol in batches, be warming up to 20 DEG C of reaction 30min.React complete, add 30mL ethyl acetate and the extraction of 30mL frozen water, get organic layer, aqueous layer with ethyl acetate extraction (2 times × 15mL), merge organic layer, saturated common salt water washing once, anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography purification obtains title compound.

ESI-MS m/z:239[M+H] ⁺。

The synthesis of step 54-hydroxyl-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate

The compound taking the preparation of 1.4g step 4, in reaction flask, adds 5mL methane amide and dissolves, and reacts 2 hours under being warming up to 180 DEG C of conditions.React complete, by reaction solution impouring 20mL frozen water, extraction into ethyl acetate (3 × 20mL), merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, filters, is spin-dried for, column chromatography purification, obtains title compound.

¹H NMR(300MHz,DMSO-d ₆):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 synthesis of chloro-6,7-dihydro-5H-penta rings of step 64-also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate

The compound taking the preparation of 300mg step 5 is in reaction flask, and add 20mL toluene and dissolve, add 5 equivalent phosphorus oxychloride (POCl3) successively, 5 equivalent DIPEAs (DIPEA), are warming up to 110 DEG C, react 6 hours.React complete, remove solvent under reduced pressure and obtain dark oil thing, after adding 20mL acetic acid ethyl dissolution, with the saturated sodium bicarbonate aqueous solution adjust pH of 0 ~ 5 DEG C to neutral, get organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, filters, is spin-dried for obtain title compound.ESI-MS m/z:252[M+H] ⁺。

The synthesis of chloro-5,6,7, the 8-tetrahydrochysenes of embodiment 24--[1,2,4] triazine also [6,1-a] isoindole-7-methyl-formiate

With 3-tetrahydrobenzene-1-methyl-formiate for raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:266[M+H] ⁺。

The synthesis of embodiment 34-chlorine furo [3', 4':3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7 (5H)-one

With 2 (5H)-furanones for starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:210[M+H] ⁺。

The chloro-5H-piperazine of embodiment 44-is muttered also the synthesis of [3', 4':3,4] pyrrolo-[2,1-f] [1,2,4] triazine-8 (6H)-one

With 5,6-dihydro-2H-pyran-2-one for raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:224[M+H] ⁺。

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

Take cyclopentenes as starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:194[M+H] ⁺。

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

Take tetrahydrobenzene as starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:208[M+H] ⁺。

The synthesis of chloro-5, the 6-dihydros of embodiment 74--[1,2,4] triazine also [6,1-a] isoindole

With 2-tetrahydrobenzene-1-ketone for starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:206[M+H] ⁺。

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

ESI-MS m/z:240[M+H] ⁺。

The synthesis of embodiment 94-chloro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6,6 (7H)-dicarboxylate

With 3-cyclopentenes-1,1-dicarboxylate for starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:338[M+H] ⁺。

The synthesis of embodiment 102-(chloro-6,7-dihydro-5H-penta rings of 4-also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) methyl acetate

The synthesis of step 1:2-cyclopentenes-1-methyl acetate

Take 1.12g2-cyclopentenes-1-acetic acid in 50mL round-bottomed flask, add 10mL anhydrous methanol, be added dropwise to 2 vitriol oils, reflux 2h, after reaction stops, decompression precipitation, add water, regulate pH to weakly alkaline with sodium bicarbonate aqueous solution, extraction into ethyl acetate, reduce pressure after anhydrous sodium sulfate drying organic phase precipitation, obtains target product.

ESI-MS m/z:141[M+H] ⁺。

The synthesis of step 2:2-(chloro-6,7-dihydro-5H-penta rings of 4-also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) methyl acetate

With 2-cyclopentenes-1-methyl acetate for starting raw material, the method with embodiment 1 obtains title compound.

ESI-MS m/z:280[M+H] ⁺。

The synthesis of embodiment 114-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate (B-47)

Take compound prepared by 319mg embodiment 1, after adding 10mL DMF dissolving, add 96.5mg4-fluoro-5-hydroxy-2-methyl indoles and 67.3mg Anhydrous potassium carbonate, stirring at room temperature is stopped reaction after 2 hours, add 40mL ethyl acetate and the extraction of 80mL water, aqueous phase is extracted with ethyl acetate 2 times, merges organic phase, saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, filters, is spin-dried for, column purification, obtained title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 124-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5,6,7,8-tetrahydrochysenes-[1,2,4] triazine also [6,1-a] isoindole-7-methyl-formiate (B-37)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 2, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 134-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base) furo [3', 4':3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7 (5H)-one (B-34)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 3, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-indole of 4--5-base) oxygen base) piperazine is muttered also the synthesis of [3', 4':3,4] pyrrolo-[2,1-f] [1,2,4] triazine-8 (6H)-one (B-31)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 4, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-base) oxygen base)-5H-piperazine is muttered also the synthesis of [3', 4':3,4] pyrrolo-[2,1-f] [1,2,4] triazine-8 (6H)-one (B-33)

Obtain compound and 5-OHi-2-ketone for raw material with embodiment 4, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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 synthesis of embodiment 164-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine (B-44)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 5, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 174-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5,6,7,8-tetrahydrochysenes-[1,2,4] triazine also [6,1-a] isoindole (B-35)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 6, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 184-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5,6-dihydros-[1,2,4] triazine also [6,1-a] isoindole (B-39)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 7, the method with embodiment 11 obtains title compound.

¹H NMR(500MHz,CDCl ₃)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] ⁺。

The synthesis of embodiment 194-((4-fluoro-2-Methyl-1H-indole-5-base) oxygen base) chloro-5, the 6-dihydros of-8--[1,2,4] triazine also [6,1-a] isoindole (B-42)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 8, the method with embodiment 11 obtains title compound.

¹H NMR(500MHz,CDCl ₃)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 synthesis of embodiment 204-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6,6 (7H)-dicarboxylate (B-61)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 9, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

Embodiment 212-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) synthesis of ethyl acetate (B-62)

Obtain compound and 4-fluoro-5-hydroxy-2-methyl indoles for raw material with embodiment 10, the method with embodiment 11 obtains title compound.

1H NMR(300M Hz,CDCl ₃)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] ⁺。

Embodiment 224-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) synthesis of methyl alcohol (B-48)

In the 25mL single port bottle of tetrahydrofuran (THF) (THF) filling 8mL, add 18mg Lithium Aluminium Hydride (LAH), stir the tetrahydrofuran solution that the lower 7mL of dropping is dissolved with compound prepared by 190mg embodiment 11, after finishing, TLC monitoring disappears to raw material, cancellation is reacted, extraction into ethyl acetate, anhydrous sodium sulfate drying organic phase, filters, be spin-dried for, obtained title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 234-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5,6,7,8-tetrahydrochysenes-[1,2,4] triazine also [6,1-a] isoindole-7-methyl alcohol (B-43)

Obtain compound for raw material with embodiment 12, the method with embodiment 22 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 242-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) ethanol (B-65)

Obtain compound for raw material with embodiment 21, the method with embodiment 22 obtains title compound.

¹h NMR (500M Hz, DMSO-d ₆) δ: 11.32 (s, 1H, N-H disappear after heavy water exchanges), 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, disappear after heavy water exchanges), 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] ⁺。

Embodiment 25 (4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6,6-bis-base) synthesis of dimethanol (B-66)

Obtain compound for raw material with embodiment 20, the method with embodiment 22 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

The synthesis of embodiment 262-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) propan-2-ol (B-67)

Compound prepared by 38mg embodiment 11 is dissolved in the anhydrous THF of 5mL, under argon shield, under room temperature, slowly adds the THF solution being dissolved with 29mg methylmagnesium-chloride.After reaction terminates, decompression precipitation, adds saturated aqueous common salt, extraction into ethyl acetate 2 times, merges organic phase, anhydrous sodium sulfate drying, filters, is spin-dried for, column chromatography purification, obtained title compound.

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 synthesis of embodiment 274-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formic acid (B-49)

Take the obtained compound of 190mg embodiment 11 in 25mL single port bottle, add the mixed solvent 10mL that volume ratio is the THF/ methyl alcohol of 7:3, slowly add 18mg lithium hydroxide, the cancellation that adds water after completion of the reaction is reacted, regulate pH to 5 ~ 6 with the dilute hydrochloric acid solution of 1M, extraction into ethyl acetate, filters after dry organic phase, be spin-dried for, obtained title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ^-。

The synthesis of embodiment 284-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-5,6,7,8-tetrahydrochysenes-[1,2,4] triazine also [6,1-a] isoindole-7-formic acid (B-40)

Obtain compound for raw material with embodiment 12, the method with embodiment 27 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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 synthesis of embodiment 294-((the fluoro-2-Methyl-1H-indole of 4--5-base) amino)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formic acid (B-59)

Step 1 with the obtained compound of embodiment 1 and 4-fluoro-5-amino-2-methyl indoles for raw material, method with embodiment 11 obtains 4-((the fluoro-2-Methyl-1H-indole of 4--5-base) is amino)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate.

Step 2 is with the obtained compound of step 1 for raw material, and the method with embodiment 27 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ^-。

The synthesis of embodiment 302-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) acetic acid (B-64)

The compound obtained with embodiment 21 is for raw material, and the method with embodiment 27 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methoxyl group) synthesis of-3-oxygen subunit propionic acid (B-72)

In 50mL round-bottomed bottle, add 348mg N successively, N-diisopropylethylamine (DIEA), 0.5mg4-Dimethylamino pyridine (DMAP), dissolve with 5mL tetrahydrofuran (THF) (THF), the THF solution that 5mL is dissolved with 175mg1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) is slowly added dropwise to after stirring 10min under ice-water bath, then the THF solution that 5mL is dissolved with compound prepared by 320mg embodiment 22 is dripped, after stirring at room temperature question response terminates, decompression precipitation, add saturated aqueous common salt, extraction into ethyl acetate 2 times, merge organic phase, filter after anhydrous sodium sulfate drying, be spin-dried for, column chromatography purification, obtained title compound.

¹h NMR (500MHz, DMSO-d ₆) δ: 12.41 (s, br, 1H, COOH, disappears after heavy water exchanges), 11.36 (s, 1H, disappears after heavy water exchanges), 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 synthesis of embodiment 324-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide (B-51)

Take the compound of 73mg embodiment 27 preparation in 50mL round-bottomed bottle, add 5mL DMF, 12mg4-Dimethylamino pyridine (DMAP), 152mg2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), after stirring at room temperature reaction 0.3h, add 54mg NH successively ₄cl, 258mgN, N-diisopropylethylamine (DIPEA), after continuing stirring at room temperature reaction 8.0h, regulates pH to be 6 ~ 7 with 1MHCl, then add extraction into ethyl acetate, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is spin-dried for rear column chromatography purification, obtained title compound.

¹hNMR (500MHz, DMSO-d6) δ: 11.3 (s, N-H disappear after heavy water exchanges), 7.94 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H, N-H disappear after heavy water exchanges), 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-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methane amide

The compound prepared with embodiment 28 and methylamine are for raw material, and the method with embodiment 32 obtains title compound.

¹h NMR (500MHz, DMSO-d6) δ: 11.32 (s, N-H disappear after heavy water exchanges), 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] ⁺。

The synthesis of embodiment 342-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) ethanamide (B-68)

The compound obtained with embodiment 30 is for raw material, and the method with embodiment 32 obtains title compound.

¹h NMR (500M Hz, DMSO-d6) δ: 11.34 (s, 1H, N-H, heavy water disappears after exchanging), 7.91 (s, 1H), 7.80 (s, 1H), 7.34 (s, 1H, N-H, heavy water disappears after exchanging), 7.16-7.13 (m, 1H), 7.02-6.96 (m, 1H), 6.81 (s, 1H, N-H, disappear after heavy water exchanges), 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-base)-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) synthesis of methane amide (B-50)

The compound obtained with embodiment 27 and L-aminopropanol are for raw material, and the method with embodiment 32 obtains title compound.

¹h NMR (500M Hz, DMSO-d ₆) δ: 11.30 (s, br, 1H, N-H, heavy water disappears after exchanging), 7.89 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H, N-H, heavy water disappears 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 disappears 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] ⁺。

Embodiment 362-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-7-base) synthesis of-N-((S)-1-hydroxy propane-2-base) ethanamide (B-69)

The compound obtained with embodiment 30 and L-aminopropanol are for raw material, and the method with embodiment 32 obtains title compound.

1H NMR(300MHz,DMSO-d ₆)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-indole of 4--5-base) oxygen base)-6-((2-methoxy ethoxy) methyl)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] synthesis of triazine (B-57)

After compound 3mL DMF 35mg embodiment 22 prepared dissolves, add 20mg2-bromo-ethyl-methyl ether and 20mg Anhydrous potassium carbonate, reaction solution stirring at room temperature is stopped reaction after 2 hours, and add ethyl acetate 40ml and water 80ml and extract, aqueous phase is extracted with ethyl acetate 2 times, merge organic phase, wash once with saturated sodium-chloride water solution, filter after anhydrous sodium sulfate drying, be spin-dried for, column chromatography purification, obtained title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-indole of 4--5-base)-6-((2-methoxy ethoxy) methyl)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] synthesis of triazine-4-amine (B-58)

The synthesis of step 1:4-((the fluoro-2-Methyl-1H-indole of 4--5-base) amino)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate

The compound obtained with embodiment 1 and 4-fluoro-5-amino-2-methyl indoles are for raw material, method with embodiment 11 obtains 4-((the fluoro-2-Methyl-1H-indole of 4--5-base) is amino)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl-formiate.

Step 2:4-((the fluoro-2-Methyl-1H-indole of 4--5-base) is amino)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl alcohol

With the obtained compound of step 1 for raw material, the method with embodiment 22 obtains 4-((the fluoro-2-Methyl-1H-indole of 4--5-base) is amino)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-methyl alcohol.

Step 3:N-(4-(the fluoro-2-Methyl-1H-indole of 4--5-base)-6-((2-methoxy ethoxy) methyl)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] synthesis of triazine-4-amine

The compound obtained with step 2 and 2-bromo-ethyl-methyl ether are for raw material, and the method with embodiment 37 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methoxyl group) synthesis of ethanol (B-60)

With the compound of embodiment 22 and chloroethanol for raw material, the method with embodiment 37 obtains title compound.

¹h NMR (500M Hz, DMSO-d6) δ: 11.32 (s, 1H, N-H, heavy water disappears 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, disappear after heavy water exchanges), 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-indole of 4--5-base) oxygen base)-6-(2-methoxy ethoxy)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] synthesis of triazine (B-63)

The synthesis of step 1:4-(2-methoxy ethoxy) cyclopentenes

Take in 0.84g3-cyclopentenes-1-alcohol and reaction flask, add 1.66g K ₂cO ₃, 10mL acetonitrile, after stirring at normal temperature 0.5h, add 2-bromo-ethyl-methyl ether, reaction is spent the night, and after reaction terminates, removal of solvent under reduced pressure, adds water, extraction into ethyl acetate, dry, filters, is spin-dried for, obtained title compound, is directly used in next step reaction.

ESI-MS(m/z):143[M+H] ⁺。

The synthesis of step 2:4-chlorine 6-(2-methoxy ethoxy)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine

The compound obtained with step 1 is for raw material, and the method with embodiment 1 obtains title compound.

ESI-MS(m/z):268[M+H] ⁺。

The synthesis of step 3:4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6-(2-methoxy ethoxy)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine

The compound obtained with step 2 is for raw material, and the method with embodiment 11 obtains title compound.

¹H NMR(300M Hz,DMSO-d ₆)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 synthesis of embodiment 41 (4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methylamine (B-70)

The compound prepared with embodiment 32 is for raw material, and the method with embodiment 22 obtains title compound. 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, disappears after heavy water exchanges), 3.17-3.11 (m, 1H), 3.01-2.50 (m, 6H), 2.41 (s, 3H).

ESI-MS(m/z):352[M+H] ⁺。

The synthesis of embodiment 424-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formonitrile HCN (B-71)

The synthesis of step 1:4-cyano group cyclopentenes

Take 12.1g diallyl acetonitrile in 150mL single port bottle, add 50mL methylene dichloride stirring and dissolving, add about 0.5g (1,3-two-(2,4,6-Three methyl Benzene)-2-tetrahydroglyoxaline) dichloro (α-tolylene) (thricyclohexyl phosphorus) changes ruthenium (GRUBB ' S s-generation catalyzer), stirred overnight at room temperature, point plate is followed the tracks of, after question response is complete, with the water washing of 150mL saturated common salt, organic phase is after anhydrous sodium sulfate drying, decompression precipitation, obtains 4-itrile group cyclopentenes.

The synthesis of chloro-6,7-dihydro-5H-penta rings of step 2:4-also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formonitrile HCN

With step 1 gains for raw material, the method with embodiment 1 obtains title compound.

The synthesis of step 3:4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formonitrile HCN

With step 2 gains for raw material, the method with embodiment 11 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

Embodiment 43N-cyclopropyl-4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-imidazole carboxamide

The compound prepared with embodiment 28 and cyclopropylamine are for raw material, and the method with embodiment 32 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

Embodiment 44 ((2S)-1-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methyl) pyrroles-2-base) methyl alcohol (B-85)

Step the 14-((synthesis of 4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formaldehyde

Take the compound of 200mg embodiment 22 preparation in 50ml single port bottle, add ethyl acetate/DMSO mixing solutions 14mL (4:3) to dissolve, under stirring at room temperature, add 480mg o-iodobenzoic acid (IBX), 85 DEG C of reaction 15min, after reaction terminates, add 20ml water, extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated common salt water washing, drying, filter, column chromatography purification obtains title compound.

ESI-MS(m/z):351[M+H] ⁺。

Step 2:((2S)-1-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methyl) pyrroles-2-base) synthesis of methyl alcohol (B-85)

Take the compound of 120mg step 1 preparation in 50ml single port bottle, add 10mL toluene/ethanol mixed solvent (volume ratio 16:3) to dissolve, add 52mgD-dried meat ammonia alcohol, 110 DEG C of reaction 6h, after reaction terminates, be cooled to room temperature, add 218mg sodium triacetoxy borohydride, stirring at room temperature 2h, after reaction terminates, directly add 1ml water, preparative column chromatography obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methyl) ethanamide (B-86)

Take the compound of 200mg embodiment 41 preparation in 50ml there-necked flask, add 10ml anhydrous methylene chloride to dissolve, after 0-5 DEG C of stirring 10min, drip the dichloromethane solution that 5ml is dissolved with 80mg Acetyl Chloride 98Min., 0-5 DEG C of reaction 1h, after reaction terminates, add 20ml water, dichloromethane extraction (3 × 20mL), dry, filter, be spin-dried for, column chromatography purification obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) methyl) Toluidrin (B-87)

The compound prepared with embodiment 41 and methylsulfonyl chloride are for raw material, and the method with embodiment 45 obtains title compound.

¹H NMR(500M Hz,DMSO-d ₆)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] ⁺。

Embodiment 471-(4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6,7-dihydro-5H-penta rings also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-base) ethanol (B-88)

Take compound the 4-((4-((the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base)-6 of 40mg embodiment 44 step 1 preparation, 7-dihydro-5H-penta ring also [3,4] pyrrolo-[2,1-f] [1,2,4] triazine-6-formaldehyde is in 25ml single port bottle, adds the anhydrous THF of 8ml and dissolves, at-50 DEG C, drip the CH of 1 equivalent ₃mgCl, drips and finishes, react 30min at-50 DEG C, after reaction terminates, adds NH ₄cl cancellation, extraction into ethyl acetate, dry, filter, be spin-dried for, column chromatography purification obtains 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] ⁺。

Experimental example 1 Compound ira vitro enzymic activity of the present invention is evaluated

1 experiment material

1.1 compound

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

1.2 reagent

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

Fibroblast growth factor acceptor 1(Fibroblast growth factor receptor1, FGFR1), purchased from Japanese Carna Biosciences company;

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 company of the U.S.;

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

1 × kinase buffer liquid (50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl ₂, 2mM DTT), prepared before use;

Stop buffer (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 company of the U.S..

2 experimental techniques

1) get in compound solution 10 μ l to 96 orifice plate of each concentration, add 90 μ l1 × kinase buffer liquid; Set up DMSO control group simultaneously and without enzyme control group alive, all only contain 10 μ l DMSO and 90 μ l1 × kinase buffer liquid.Each group at room temperature mixes 10min, then distinguishes in transferase 45 μ l to 384 orifice plate;

2) kinases VEGFR2 or FGFR1 is dissolved in 1 × kinase buffer liquid, is mixed with 2.5 × kinase solution, then shift 10 μ l2.5 × kinase solution to above-mentioned containing in 384 orifice plates of each concentration compound; DMSO control group adds 10 μ l2.5 × kinase solution; 10 μ l are added not containing kinase whose 1 × kinase buffer liquid without enzyme control group alive.Incubated at room temperature 10min;

3) polypeptide marked by FAM and ATP are dissolved in 1 × kinase buffer liquid, are mixed with 2.5 × substrate solution, then shift in 10 μ l2.5 × substrate solutions to above-mentioned 384 orifice plates, hatch 1hr for 28 DEG C;

4) 25 μ l stop buffer termination 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 is I%=(Max-Conversion)/(Max-Min) × 100, wherein Max is the transformation efficiency of DMSO control group, Min is the transformation efficiency without enzyme control group alive, and Conversion is the transformation efficiency of compound treatment group.Data are through XLfit process, and matching obtains IC ₅₀.IC ₅₀value represents and does not add compared with compound treatment group, compound concentration corresponding when compound suppresses 50% enzyme activity.IC ₅₀the results are shown in Table 1.

Table 1

As can be seen from above experimental result, compound of the present invention has good inhibit activities to VEGFR2 or FGFR1.

Although be below described in detail the present invention, it will be appreciated by those skilled in the art that and can carry out various amendment and change to the present invention under prerequisite without departing from the spirit and scope of the present invention.Interest field of the present invention is not limited to done detailed description above, and should belong to claims.

Claims

1. the compound of general formula I or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug,

Wherein:

X is selected from O, S, N (R ₄), C _1-3alkylidene group;

R ₄be selected from hydrogen, alkyl;

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

2. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:

X is selected from O, S, N (R ₄), CH ₂;

R ₄be selected from hydrogen, C _1-6alkyl;

N is selected from 1,2 and 3.

3. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of claim 1 or 2, wherein ring A is selected from the carbocyclic ring containing 4-8 carbon atom, be preferably the carbocyclic ring containing 5-7 carbon atom, carbocyclic ring more preferably containing 5-6 carbon atom, is further preferably pentamethylene base, cyclopentenyl, cyclohexyl, cyclohexenyl.

4. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of claim 1 or 2, wherein ring A is selected from containing 1-2 heteroatomic quaternary, five yuan, hexa-atomic, seven yuan or eight yuan of heterocycles, be preferably containing 1-2 heteroatomic five yuan, hexa-atomic or seven membered heterocyclic, more preferably containing 1-2 heteroatomic five yuan or hexa-member heterocycle, be further preferably tetrahydrofuran (THF) cyclic group, Pyrrolidine cyclic group, tetrahydropyrans cyclic group, piperidyl.

5. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of any one of claim 1-4, wherein:

6. the compound according to any one of claim 2-5 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:

X is selected from N (R ₄), O, described R ₄be selected from hydrogen, C _1-6alkyl; Be preferably N (R ₄), O, described R ₄be selected from hydrogen, C _1-3alkyl; More preferably NH, O.

7. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein said compound is be selected from following compound:

8. prepare the intermediate of the compound described in any one of claim 1 to 7 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug:

9. a pharmaceutical composition, it comprises compound described in any one of claim 1 to 7 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.

10. the compound described in any one of claim 1-7 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug or the application of pharmaceutical composition according to claim 9 in the medicine for the preparation for the treatment of or prophylaxis of tumours.