CN103183674B - One class fused heterocyclic derivative and its application - Google Patents

One class fused heterocyclic derivative and its application Download PDF

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CN103183674B
CN103183674B CN201110460766.4A CN201110460766A CN103183674B CN 103183674 B CN103183674 B CN 103183674B CN 201110460766 A CN201110460766 A CN 201110460766A CN 103183674 B CN103183674 B CN 103183674B
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heteroaryl
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CN103183674A (en
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黄伟
丛欣
叶军
赵兴俄
王佳
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Hainan Simcere Pharmaceutical Co ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

The present invention relates to a class fused heterocyclic derivative and its application, it has formula (I) structure.Compound of the structure as shown in formula (I) of the present invention has good inhibiting effect to a variety of kinase activities, and its half-inhibition concentration to kinases such as c Met, KDR, c kit is universal 10‑7mol.L‑1Below.Meanwhile, the compound with formula (I) structure prepared in the embodiment of the present invention is inhibited to the propagation of kinds of tumor cells.In addition, the invention further relates to the preparation method of the intermediate of such compound and intermediate.

Description

One class fused heterocyclic derivative and its application
Technical field
The present invention relates to biomedicine field, a more particularly to class have formula (I) structure fused heterocyclic derivative and its Prepare the application in tyrosine kinase inhibitor or serine-threonine kinase inhibitor.The invention further relates to such compound Intermediate and intermediate preparation method.
Background technology
Extracellular various signals are delivered to cell interior by signal transduction as a kind of integrated regulation mechanism of cell, are made thin Born of the same parents respond, and realize the processes such as propagation, differentiation, apoptosis.Protein kinase (PKs) has important work in this course With.PKs can be divided into EGFR-TK (PTKs) and serine/threonine kinase (STKs), and PTKs can make the junket ammonia on protein Sour residue phosphorylation, STKs can make the serine/threonine residue phosphorylation on protein, and they turn in the signal of normal cell Lead in mechanism and play an important roll.
Go deep into the research of molecular biology, on a molecular scale for cell signalling, regulation growth factor Function and regulation and control oncogene are the effective ways for suppressing cell propagation and treatment tumour.The approach can weaken spectral artifacts The effect of passage, prevents the growth of tumour, while can also promote death of neoplastic cells.Find there is half proto-oncogene in egg so far All there is tyrosine structure on white coding, they participate in cell signalling by phosphorylation and dephosphorylation, while in tumour In generating process, cancer cell can be changed into by normal cell by becoming the EGFR-TK of XOR overexpression, while promoting tumour The growth and mitosis of cell.Because EGFR-TK and serine-threonine kinase are in the neoplastic transformation process of cell In there is important effect, and have with the generation and development of tumour and directly or indirectly contact, therefore by tyrosine-kinase enzyme level The treatment that agent or serine-threonine kinase inhibitor are applied to tumour is especially suitable.
7-naphthyridine derivatives have extensive bioactivity, have important application in field of medicaments.In recent years, many naphthyridines Micromolecular compound as kinases inhibitor, is widely used in a variety of diseases related to abnormal kinase activity for the treatment of Disease, such as tumour, psoriasis, hepatic sclerosis, diabetes, angiogenesis, ophthalmology disease, rheumatoid arthritis and other inflammation diseases Disease, immunological diseases, angiocardiopathy such as artery sclerosis and a variety of nephrosis.Wherein, 2,7- naphthyridine types compound (WO0192256, WO0242264), 1,5- naphthyridine types compound (WO2006106046), 1,6- naphthyridine types compound (WO2007060028, WO2010037249, WO2010088177), 2,6- naphthyridine types compound (WO2008122614), heterocyclic fused naphthyridine type chemical combination Thing (WO2009148887, WO2009148916), 2,7- naphthyridones compound (WO2008109613, WO2009097287), 1,8- naphthyridones compound (WO2010002779) etc. is used to EGFR-TK and/or serine-threonine kinase suppresses Agent.But a class condensed hetero ring 7-naphthyridine derivatives are used to treat EGFR-TK and/or serine-threonine kinase inhibitor yet there are no Report.
The content of the invention
It is an object of the invention to provide the fused heterocyclic derivative shown in a kind of logical formula (I) or its is pharmaceutically acceptable Salt：
Wherein,
A is selected from C5-C10Heteroaryl or C6-C10Aryl, wherein the heteroaryl, aryl are optional further one or more Selected from hydrogen, C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10Heteroaryl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl, halogen, halo C1-C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10Alkoxy, C6-C10 Aryloxy group, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O) R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11Or-OC (=O) R9Substituent replaced；
B is selected from-O- ,-NR7-、-S-、-SO-、-SO2- or-CR12R13-；
X and W is independently selected from C or N；
M is 0,1,2,3 or 4；
R1Selected from hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, hydroxyl, C1- C10Alkoxy ,-OC (=O) R9,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-NR7R8Or-NR7C (=O) R8, wherein C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkoxy is optional further by one or many It is individual to be selected from C1-C10Alkyl, C1-C10The substituent of alkoxy or halogen is replaced；
R2And R3Independently selected from hydrogen, halogen, C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10It is miscellaneous Aryl, halo C1-C10Alkyl, hydroxyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C6-C10Aryloxy group, cyano group, nitro ,-OC (=O) R9、-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S(O)2R10 Or-S (O)2NR7R8, wherein C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10Heteroaryl, halo C1-C10 Alkyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C6-C10Aryloxy group is optional to be further selected from C by one or more1-C10Alkane Base, C1-C10The substituent of alkoxy or halogen is replaced；
R4Selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 To 8 yuan of heteroalicyclyls ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan Full carbon monocyclic cycloalkyl, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6- C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2) nR11,-OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R5Selected from hydrogen, C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl, C5- C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, hydroxyl, cyano group or carboxylic acid Substituent replaced；
R6Selected from hydrogen, C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl or C5-C10It is miscellaneous Fragrant C1-C10Alkyl, wherein C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, The substituent of hydroxyl, cyano group or carboxylic acid is replaced；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl, C5-C10Heteroaryl Base, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl, C5-C10Heteroaryl is optional further by one It is individual or multiple selected from C1-C10Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
While R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein 5 to 8 circle heterocycles are included There are one or more N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, Halogen, C6-C10Aryl, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxyl, cyano group, C1-C10Alkoxy, amino C1-C10Alkyl Or the substituent of carboxylic acid is replaced；
R9Selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl or C5-C10 Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl Base, amino, the substituent of cyano group or carboxylic acid are replaced；
R10Selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, halogen For C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkane Epoxide, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R11Selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl or-NR7R8, wherein C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10 Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R12And R13Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl or C5-C10It is miscellaneous Aryl, wherein C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl, C5-C10Heteroaryl is optional further by one Or it is multiple selected from C1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substitution of cyano group or carboxylic acid Base is replaced；
N is 1,2,3 or 4.
Further, in compound or its pharmaceutically acceptable salt of the structure that the present invention is provided as shown in formula (I),
A in the present invention may be selected from C5-C10Heteroaryl or C6-C10Aryl, wherein the heteroaryl, aryl are optional further Hydrogen, C are selected from by one or more1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10Heteroaryl, C6-C10Virtue Base C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl, halogen, halo C1-C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10 Alkoxy, C6-C10Aryloxy group, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11Or-OC (=O) R9Substituent replaced；
A is further selected from C5-C10Heteroaryl or C6-C10Aryl, wherein the heteroaryl, aryl are optional further by one It is individual or multiple selected from hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (=O) R9Substituent Replaced；
A yet further may be selected from six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic virtue Ring or hexa-atomic and hexa-atomic aromatic ring yl, wherein six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic virtue Ring or hexa-atomic and hexa-atomic aromatic ring yl are optional further by one or more selected from hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8、- C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl Base ,-O (CH2)nR11Or-OC (=O) R9Substituent replaced；
A yet further may be selected from six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic virtue Ring or hexa-atomic and hexa-atomic aromatic ring yl, wherein six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic virtue Ring or hexa-atomic and hexa-atomic aromatic ring yl are optional further by one or more selected from hydrogen, halogen, amino ,-CONH2, cyano group, C1-C4Alkane Epoxide or-O (CH2)nR11Substituent replaced；
A further may be selected from pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl, wherein The pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl is optional is further selected from by one or more Hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10 Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (=O) R9Substituent replaced；
A further may be selected from pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl, wherein The pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl is optional is further selected from by one or more Hydrogen, halogen, amino ,-CONH2, cyano group, C1-C4Alkoxy or-O (CH2)nR11Substituent replaced；
A is more preferably selected from following group：
Wherein, RaAnd RbIndependently selected from hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, Amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (=O) R9 Substituent replaced；
A is most preferably selected from following group：
Wherein, RaAnd RbIndependently selected from hydrogen, halogen, amino ,-CONH2, cyano group, C1-C4Alkoxy or-O (CH2)nR11。
B in the present invention is further selected from-O- ,-S- ,-NH- or-CH2-；B is most preferably-O-.
W in the present invention is further selected from C.
X in the present invention is further selected from C or N.
M in the present invention is further 0 or 1.
R in the present invention1、R2And R3Further independently selected from hydrogen or halogen.Work as R1Most preferably in phenyl ring during for halogen 3 upper (being counted using the phenyl ring site being connected with-NH- groups as 1).
R in the present invention4It is further selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan Full carbon monocyclic cycloalkyl, 5 to 8 yuan of heteroalicyclyls ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5- C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkane Base, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10 Aryloxy group ,-O (CH2)nR11,-OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R4It yet further may be selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, wherein C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Aryl, C5-C10 Heteroaryl ,-C (=O) R9,-C (=O) OR9Substituent replaced；
R4More preferably it is preferably hydrogen, C1-C4Alkyl, pi-allyl, benzyl or-CH2COOEt。
R in the present invention5It further may be selected from hydrogen.
R in the present invention6It further may be selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine Base, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, Pyrazinyl, imidazole radicals are optional to be further selected from halogen, trihalomethyl or C by one or more1-C10The substituent of alkoxy is taken Generation；
R6It yet further may be selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, Pyrimidine radicals, pyrazinyl, imidazole radicals, wherein, C1-C10It is alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, phonetic Piperidinyl, pyrazinyl, imidazole radicals are optional to be further selected from halogen, trihalomethyl or C by one or more1-C10The substitution of alkoxy Base is replaced；
R6Further can be hydrogen, phenyl or 2- thienyls, wherein, phenyl is optional further by one or more halogen Element, trihalomethyl or C1-C4Alkoxy replaces；
R6Most preferably H, phenyl, p-fluorophenyl, a fluorophenyl, o-fluorophenyl, p-methoxyphenyl, to trifluoromethyl Phenyl.
R in the present invention7And R8Further can be independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, Phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 First full carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals it is optional enter One step is selected from C by one or more1-C10Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced； While R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein in 5 to 8 circle heterocycles containing one or Multiple N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, halogen, benzene Base, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl, cyano group, C1-C10Alkoxy, amino C1-C10The substituent of alkyl or carboxylic acid is replaced；
R7And R8Yet further can be independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thiophenes Fen base, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon lists Ring cycloalkyl, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals are optional further by one It is individual or multiple selected from C1-C10Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；While R7With R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein in 5 to 8 circle heterocycles containing one or more N, O, It is optional on S hetero atoms, and 5 to 8 circle heterocycles to be further selected from C by one or more1-C10Alkyl, halogen, phenyl, thienyl, Furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl, cyano group, C1-C10Alcoxyl Base, amino C1-C10The substituent of alkyl or carboxylic acid is replaced.
R in the present invention9It further may be selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10 Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen Element, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R9It further may be selected from C1-C10It is alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, phonetic Piperidinyl, pyrazinyl or imidazole radicals.
R in the present invention10It further may be selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10It is miscellaneous Aryl, wherein C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional further one or more Selected from C1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are taken Generation.
R in the present invention11It further may be selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5- C10Heteroaryl or-NR7R8, wherein C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional further C is selected from by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, cyano group or carboxylic acid Substituent replaced；
R11It yet further may be selected from C1-C10Alkoxy, C6-C10Aryloxy group, hydroxyl or-NR7R8；
R11Further preferably it is C1-C4Alkoxy, N methyl piperazine subbase, morpholino base, piperidino, pyrroles Alkyl or-N (C2H5)2。
N in the present invention can be further 1,2,3 or 4.
N is preferably 2 or 3.
It is more excellent that the structure that the present invention is provided has in the compound or its pharmaceutically acceptable salt as shown in formula (I) That selects is combined as：
A is selected from following group：
Wherein, RaAnd RbIndependently selected from hydrogen, halogen, amino ,-CONH2, cyano group, C1-C4Alkoxy or-O (CH2)nR11。
B is selected from-O-；
W is selected from C；
X is selected from C or N；
M is 0 or 1；
R1、R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, C1-C4Alkyl, pi-allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen；
R6Selected from hydrogen, phenyl or 2- thienyls, wherein, phenyl is optional further by one or more halogens, trihalomethyl Or C1-C4Alkoxy replaces；
R11Selected from C1-C4Alkoxy, N methyl piperazine subbase, morpholino base, piperidino, pyrrolidinyl or-N (C2H5)2；
N is 2 or 3.
Wave in group of the present invention represents the tie point with other groups (such as B).
" optional further by ... group replaces " in the present invention refers to that each group indicated above can be with " quilt ... group replaces ", can not also " quilt ... group replaces ".
Compound preferred compound shown in the logical formula (I) of the present invention includes, but are not limited to：
Or its pharmaceutically acceptable salt.
Further, the present invention includes the compound shown in logical formula (II), and the compound is the logical formula (I) compound of synthesis Intermediate：
Wherein,
R2And R3Independently selected from hydrogen, halogen, C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10It is miscellaneous Aryl, halo C1-C10Alkyl, hydroxyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C6-C10Aryloxy group, cyano group, nitro ,-OC (=O) R9、-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S(O)2R10 Or-S (O)2NR7R8, wherein C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10Heteroaryl, halo C1-C10 Alkyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C6-C10Aryloxy group is optional to be further selected from C by one or more1-C10Alkane Base, C1-C10The substituent of alkoxy or halogen is replaced；
R4Selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 To 8 yuan of heteroalicyclyls ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan Full carbon monocyclic cycloalkyl, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6- C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2) nR11,-OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R5Selected from hydrogen, C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl, C5- C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, hydroxyl, cyano group or carboxylic acid Substituent replaced；
R6Selected from hydrogen, C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl or C5-C10It is miscellaneous Fragrant C1-C10Alkyl, wherein C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, The substituent of hydroxyl, cyano group or carboxylic acid is replaced；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl, C5-C10Heteroaryl Base, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, C6-C10Aryl, C5-C10Heteroaryl is optional further by one It is individual or multiple selected from C1-C10Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
While R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein 5 to 8 circle heterocycles are included There are one or more N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, Halogen, C6-C10Aryl, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxyl, cyano group, C1-C10Alkoxy, amino C1-C10Alkyl Or the substituent of carboxylic acid is replaced；
R9Selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl or C5-C10 Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl Base, amino, the substituent of cyano group or carboxylic acid are replaced；
R10Selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, halogen For C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkane Epoxide, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R11Selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl or-NR7R8, wherein C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10 Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
N is 1,2,3 or 4.
Further, in compound of the structure that the present invention is provided as shown in formula (II), wherein,
R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 To 8 yuan of heteroalicyclyls ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan Full carbon monocyclic cycloalkyl, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6- C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2) nR11,-OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R5Selected from hydrogen；
R6Selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazine Base, imidazole radicals, wherein, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals it is optional enter one Step is selected from halogen, trihalomethyl or C by one or more1-C10The substituent of alkoxy is replaced；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thienyl, furyl, Pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, benzene Base, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals are optional to be further selected from by one or more C1-C10Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
While R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein 5 to 8 circle heterocycles are included There are one or more N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, Halogen, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl Base, cyano group, C1-C10Alkoxy, amino C1-C10The substituent of alkyl or carboxylic acid is replaced；
R9Selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl or C5-C10 Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl Base, amino, the substituent of cyano group or carboxylic acid are replaced；
R10Selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, halogen For C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkane Epoxide, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R11Selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl or-NR7R8, wherein C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10 Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
N is 1,2,3 or 4.
As a preferred embodiment, wherein,
R4Selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, wherein C1-C10Alkyl, 3 to 8 yuan of full carbon are monocyclic Cycloalkyl is optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9Substituent replaced；
R6Selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazine Base, imidazole radicals, wherein, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, Imidazole radicals is optional to be further selected from halogen, trihalomethyl or C by one or more1-C10The substituent of alkoxy is replaced；
R9Selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl or Imidazole radicals.
Further, in compound of the structure that the present invention is provided as shown in formula (II),
R2And R3Preferably hydrogen or halogen；
R4Preferably hydrogen, C1-C4Alkyl, pi-allyl, benzyl or-CH2COOEt；
R5Preferably hydrogen；
R6Preferably hydrogen, phenyl or 2- thienyls, wherein, phenyl is optional further by one or more halogens, three halogen first Base or methoxy substitution.
The preferred compound of compound shown in the logical formula (II) of the present invention includes, but are not limited to：
It is to be related to the method for preparing compound shown in intermediate (II) in another aspect of the present invention, it is characterised in that should Method comprises the following steps：
(1) reaction under alkali effect obtains compound c to compound a with compound b；
(2) compound c and aminopyridines d is in protonic solvent, under acid catalysis, and reaction obtains compound e；
(3) compound e reactions under diphenyl ether effect obtain general formula compound (II)；
Wherein, R2、R3、R4、R5And R6Such as logical formula (I) of definition define.
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
(1) ethyl acetate class compound a is with compound b in the presence of alkali, and reaction temperature is -15 DEG C to 50 DEG C, reaction Time is 2 hours to 48 hours, obtains compound (c).
The reaction is carried out in the presence of an inorganic base, and wherein alkali includes sodium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, In a preferred embodiment of the present invention, the alkali is preferably sodium hydride.
The reaction temperature is generally -15 DEG C to 50 DEG C, preferably 0 DEG C to 30 DEG C.
The reaction time of the reaction is 2 hours to 48 hours, and the time preferably is 5 hours to 24 hours.
(2) compound c and aminopyridines d are in protonic solvent, under acid catalysis, reaction temperature be 60 DEG C extremely 100 DEG C, the reaction time is 2 hours to 20 hours, obtains compound e.
The reaction is carried out in protonic solvent, including isopropanol, ethanol, methanol, in the preferred embodiment of the invention In, the solvent is preferably ethanol.
The reaction is carried out under acid catalysis, wherein acid includes hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid or acetic acid, in this hair In bright preferred embodiment, the acid is preferably concentrated hydrochloric acid.
The reaction temperature is generally 60 DEG C to 100 DEG C, preferably 60 DEG C to 85 DEG C.
The reaction time of the reaction is 2 hours to 20 hours, and the time preferably is 5 hours to 10 hours.
(3) compound e is in diphenyl ether, and reaction temperature is 90 DEG C to 258 DEG C, and the reaction time is 30 minutes to 10 hours, Reaction obtains general formula compound (II).
The reaction temperature is generally 90 DEG C to 258 DEG C, preferably 160 DEG C to 258 DEG C,
The reaction time of the reaction is 30 minutes to 10 hours, and the time preferably is 30 minutes to 5 hours.
Prepared in addition, compound (III) of the present invention is referred to the existing document report in this area.Such as CN201110027560；Borzilleri, Robert M.et al, Journal of Medicinal Chemistry, 2009, 52：1251；WO2008058229；Mannion, M.et al, Bioorganic ＆ Medicinal Chemistry Letters, 2009,19：6552；WO2009127417；US20080004273；WO2007146824；Zhao, Ailing et Al, Bioorganic ＆Medicinal Chemistry, 2011,19：3906 and the pertinent literature cited in them.This hair It is prepared by the method that bright involved compound (II) is referred to this area similar information report, such as WO2010083444 with And the pertinent literature cited in them.
The invention further relates to a kind of Pharmaceutical composition, free form or pharmaceutical acceptable salt comprising therapeutically effective amount it is logical Formula compound (I) is used as active component；One or more medicinal carrier substances and/or diluent.It can also be carried including the present invention The general formula compound (I) and pharmaceutically acceptable carrier, excipient or diluent of confession.
The invention further relates to a kind of Pharmaceutical composition of combination, free form or pharmaceutical acceptable salt comprising effective dose General formula compound (I)；One or more medicinal carrier substances and/or diluent.
Fused heterocyclic derivative, pharmaceutical composition shown in logical formula (I) of the present invention can be applied to prepare treatment through egg In terms of the disease medicament of white kinases intermediary.It is characterized in that the protein kinase includes c-Met, KDR or c-kit.
Preferably, the protein kinase related disorder is selected from the related disease of receptor tyrosine kinase, non-acceptor junket ammonia The related disease of acid kinase or the related disease of serine-threonine kinase.
Preferably, the protein kinase related disorder is selected from HGF, vascular endothelial growth factor receptor The related disease of the related disease of the disease of correlation, stem cell factor receptor, EGF-R ELISA, platelet derived growth The related disease of the related disease of factor acceptor, IGF-1 or the related disease of tire liver kinases.
Preferably, the protein kinase related disorder is selected from diabetes, excess proliferative disease, angiogenesis, inflammatory Disease, immunity disease or angiocardiopathy.
Preferably, the protein kinase related disorder (or proliferative diseases) is selected from colorectal cancer, carcinoma of urinary bladder, mammary gland Cancer, liver cancer, lung cancer, cancer of pancreas, human primary gastrointestinal cancers, leukaemia, oophoroma, head and neck cancer, prostate cancer, kidney, nasopharyngeal carcinoma, collagen Cytoma, squamous cell carcinoma, astrocyte cancer, Kaposi's sarcoma, melanoma, glioma, genitourinary cancer or bone Marrow proliferative disorder.
In order to examine the compound that the present invention is provided for the exposure level of protein kinase, surveyed using biochemistry level enzymatic activity The various compounds that examination, the test of cellular level enzymatic activity, suppression proliferative activity o f tumor are tested to determine the present invention are to one kind Or a variety of PK activity and exposure level., can be in the same way for any kinases using well known method in technique The similar experiment of design.
In the test of biochemistry level enzymatic activity, using the activity of HTRF technology for detection EGFR-TKs, when HTRF is a kind of Between resolved fluorescent resonance ability transfer techniques, can be carried out according to known specification or literature method, referring to Kolb etc., “Tyrosine kinase assays adapted to homogenous time-resolved fluorescence” .Drug .3 volumes of Discovery Today magazines：pp 333-342.HTRF (homogeneous phase time discrimination fluorescence) is homogeneous for detecting A kind of most common method of determinand in system, this technology combines FRET (FRET) and time resolution Technology (TR), has been widely used in the different phase of the medicament research and development based on cell experiment and biochemical test.According to HTRF The measuring principle of method, after incubation reaction, Avidin mark is added by pure enzyme Met together with biotinylated substrate and ATP The antibody of the Eu marks of XL-665 and identification substrate phosphorylation, after substrate is by Met phosphorylations, the antibody of Eu marks is to know The not other Phosphorylated products, the XL665 marked with Avidin forms time-resolved FRET (FRET), and not by The substrate of phosphorylation due to can not the identification of times antibody and FRET signals can not be formed, believed by the fluorescence for determining 665nm and 620nm Number difference determines determinand under various concentrations to EGFR-TKs such as c-Met, Flt-3, VEGFR-2, PDGFR- β, c-Kit Inhibitory activity.Thus, active function of the compounds of this invention to the biochemistry level of above-mentioned EGFR-TK can be determined using this method, Method well known in the art is utilized simultaneously, can use similar assay method to other protein kinases.
In the test of cellular level enzymatic activity, enzyme linked immunosorbent assay (ELISA) (ELISA) can be for examining and determine junket ammonia The presence of kinase activity.ELISA can be carried out in accordance with known methods, such as Voller, 1980, " Enzyme-linked Immunosorbent Assay Determine " (Enzyme-Linkd Immunosorbent Assay), see what Rose and Friedman write《Clinical immunization is learned to do Volume》(Manual of Clinical Immunology), second edition, pp 359-371, American Society of Microbiology publishes, Washington Special zone.The tyrosine-kinase enzymatic ATP such as c-Met, Flt-3, VEGFR-2, PDGFR- β, c-Kit and biotin mark mark substrate The phosphorylation reaction of peptide, inhibitory enzyme activity will suppress this reaction.According to ELISA method measuring principle, anti-Met antibody is coated on On solid phase carrier, to capture the Met total proteins in cell pyrolysis liquid；Then with anti-tyrosine phosphorylation antibody labeling Met albumen The middle part for occurring phosphorylation；The antibody of horseradish peroxidase (HRP) mark is added, is allowed to and anti-tyrosine phosphorylation antibody With reference to；It is eventually adding HRP substrate TMB colour developings.Met in cell is detected by determining the absorbance at 450nM absorbing wavelengths Receptor autophosphorylation level, so as to determine determinand under various concentrations to c-Met, Flt-3, VEGFR-2, PDGFR- β, c- The inhibitory activity of the EGFR-TKs such as Kit.Thus, the compounds of this invention can be determined to above-mentioned EGFR-TK cell using this method The active function of level, while using method well known in the art, similar assay method can be used to other protein kinases.
In proliferative activity o f tumor test is suppressed, determine routinely using blue (MTT) method of bromination tetrazole.Living cells Succinate dehydrogenase in mitochondria can make bromination 3- (4,5- dimethylthiazole -2)-nitrogen of 2,5- diphenyl four of exogenous yellow Azoles (MTT) is reduced to the bluish violet crystal Jia Za (Formazan) of slightly solubility, and is deposited in cell, and dead cell is without this work( Can, dimethyl sulfoxide (DMSO) (DMSO) can dissolve the purple crystal thing Jia Za in cell, with enzyme-linked immunosorbent assay instrument at 570nm wavelength Its absorbance value is determined, living cells quantity can be reflected indirectly.Thus Jia Za growing amount is under normal conditions with viable count into just Than that can deduce the number of living cells according to OD values, understand Drug inhibition or kill the ability of cell.The assay method can be used In determining different the compounds of this invention to the rejection ability of one or more cancer cell multiplications, side well known in the art is utilized Method, can use similar assay method to any cancer cell.
The compound of structure prepared by the present invention as shown in formula (I) has good inhibiting effect to a variety of kinase activities, Its half-inhibition concentration (IC to kinases such as c-Met, KDR, c-kit50) universal 10-7Below mol/L.Meanwhile, the present invention is real Apply the compound with Formulas I structure prepared in example inhibited to the propagation of kinds of tumor cells, wherein most Compound suppresses the effect of tumor cell proliferation significantly, its IC5010-5Below mol/L.There is this to deduce, the present invention has formula (I) The compound of structure can be applied to prepare the medicine of protein kinase related disorder in treatment organism.
Detailed description of the invention
Unless stated to the contrary, it is following that there are following implications with term in the specification and in the claims.
Alkyl " refers to the aliphatic hydrocarbon group of saturation.Include the straight or branched group of 1 to 20 carbon atom.Preferably comprise 1 to The median size alkyl of 10 carbon atoms, such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group, the tert-butyl group, amyl group Deng.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl Base or the tert-butyl group etc..Alkyl can be substituted or unsubstituted, and when substituted, group preferably is：Halogen, C2-C6Alkene Base, C6-C10Aryl, C5-C10Heteroaryl, halo C1-C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10Alkoxy, C6-C10 Aryloxy group ,-NR7R8、-NR7C (=O) R8,-C (=O) OR9Or-OC (=O) R9。
" cycloalkyl " refers to monocyclic 3 to 8 yuan of full carbon, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan thick and rings or polycyclic thick and ring is (" thick With " ring means each ring in system and shared a pair of the carbon atoms adjoined of other rings in system) group, one of them or Multiple rings have the electronic systems that are fully connected, the example (being not limited to) of cycloalkyl is cyclopropane, cyclobutane, pentamethylene, Cyclopentene, hexamethylene, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.Cycloalkyl is commutable and is substitution.When When substituted, substituent be preferably it is one or more each be selected from following group, including：C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, halogen, 5 to 8 yuan of heteroalicyclyls, hydroxyl, sulfydryl, C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkane mercapto Base, C6-C10Aromatic thiohydroxy, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) NR7R8,-C (=O) R9,-C (=O) OR9、- S(O)R10、-S(O)2R10、-S(O)2NR7R8Or-OC (=O) R9。
" aryl " represent 6 to 14 carbon atoms full carbon is monocyclic or fused polycycle group, the pi-electron system with total conjugated System." aryl " includes：
Hexa-atomic carbon aromatic rings, e.g., benzene；
Bicyclic, wherein at least one ring is carbon aromatic rings, e.g., naphthalene, indenes and 1,2,3,4- tetrahydroquinolines；And
Three rings, wherein at least one ring is carbon aromatic rings, e.g., fluorenes.
For example, aryl is included containing hexa-atomic carbon aromatic rings and a hexa-member heterocycle, this heterocycle includes one or more choosings From the hetero atom of nitrogen, oxygen and sulphur, condition is tie point on carbon aromatic rings.But, aryl does not include, not by any mode yet It is overlapping with the heterocyclic aryl defined separately below.Therefore, define herein, if one or more carbon aromatic rings and a heteroaryl perfume (or spice) Ring and ring, resulting loop system is heteroaryl, rather than aryl.The non-limiting examples of aryl have phenyl, naphthyl.Aryl Can be substituted or unsubstituted.When substituted, group preferably is：Hydrogen, C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynes Base, C6-C10Aryl, C5-C10Heteroaryl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl, halogen, halo C1- C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11Or- OC (=O) R9。
" heteroaryl " represents the monocyclic or fused ring group of 5 to 14 annular atoms, contains one, two, three or four Ring hetero atom selected from N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated.Heteroaryl is referred to：
The mononuclear aromatics of 5-8 members, containing one or more hetero atoms selected from N, O and S, such as 1-4 hetero atom, in some realities Apply in scheme, 1-3 hetero atom, other atoms are carbon atoms on ring；
The double ring arene of 8-12 members, containing one or more hetero atoms selected from N, O and S, such as 1-4 hetero atom, at some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings；And
The thrcylic aromatic hydrocarbon of 11-14 members, containing one or more hetero atoms selected from N, O and S, such as 1-4 hetero atom, at some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings.
For example, heteroaryl includes the cycloalkyl of the miscellaneous aromatic rings of a 5-6 member and a 5-6 member.For such bicyclic And the heteroaryl got up, only one of which ring contains one or more hetero atoms, and connection site is on miscellaneous aromatic rings.
When the sulphur atom on heteroaryl and oxygen atom sum are more than 1, these hetero atoms will not be adjacent one by one.In some realities Apply in scheme, the sum of sulphur atom and oxygen atom in heteroaryl is no more than 2.In some embodiments, sulphur atom and oxygen are former Sum of the son in heteroaryl is no more than 1.
The example of heteroaryl, includes but is not limited to, pyrroles, furans, thiophene, imidazoles, oxazoles, thiazole, pyrazoles, pyrimidine, pyrrole Pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzimidazole, indoline, indolone, quinoline, isoquinolin, quinoline Oxazoline, thienopyridine, Thienopyrimidine etc..The preferred embodiment of such group is thiophene, pyridine, quinoline, quinazoline, thiophene And pyrimidine.One or all hydrogen atom in heteroaryl can be replaced by following groups：C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynes Base, C6-C10Aryl, C5-C10Heteroaryl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl, halogen, halo C1- C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11Or- OC (=O) R9。
" heteroalicyclyl " represents monocyclic or thick and cyclic group, has 5 to 9 annular atoms in ring, wherein one or two Annular atom is to be selected from N, O or S (O)pThe hetero atom of (wherein p is 0 to 2 integer), remaining annular atom is C.These rings can have There is one or more double bond, but these rings do not have the pi-electron system of total conjugated.Unsubstituted heteroalicyclyl it is non-limiting Example has pyrrolidinyl, piperidino, Piperazino, morpholino base, thiomorpholine for base, homopiperazino etc..Heteroalicyclyl Can be substituted or unsubstituted.When substituted, substituent is preferably one or more, more preferably one, two Or three, and then one or two is more preferably, independently selected from following group, including：Hydrogen, hydroxyl, C1-C10Alkyl, C6-C10 Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan of heteroalicyclyls ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan of heteroalicyclyls are further by one It is individual or multiple selected from C1-C10Alkyl, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl Base, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2)nR11,-OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent Replaced.
Piperazino refers to the group with following chemical constitution.
Morpholino base refers to the group with following chemical constitution.
Piperidino refers to the group with following chemical constitution.
Pyrrolidinyl refers to the group with following chemical constitution.
" alkenyl " represents the straight or branched alkyl with one or more double bonds.Typically C2-C6Alkenyl, such as ethene Base, pi-allyl, cyclobutenyl, butadienyl, pentenyl or hexenyl.
" alkynyl " represents the straight or branched alkyl with one or more three keys.Typically C2-C6Alkynyl, such as acetylene Base, propinyl, butynyl.
" alkoxy " expression-O- (unsubstituted alkyl) and-O (unsubstituted cycloalkyl).Representational example include but It is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" aryloxy group " expression-O- aryl and-O- heteroaryls.Representative example include but is not limited to phenoxy group, pyridine epoxide, Furans epoxide, thiophene oxy, 2-pyrimidinyl oxy, pyrazine epoxide etc. and its derivative.
" aralkyl " expression alkyl, low alkyl group preferably as defined above, it is substituted as described above for aryl groups, example Such as-CH2Phenyl ,-(CH2)2Phenyl ,-(CH2)3Phenyl, CH3CH(CH3)CH2Phenyl and its derivative.
" heteroarylalkyl " expression alkyl, low alkyl group preferably as defined above, it is replaced by heteroaryl as described above, Such as-CH2Pyridine radicals ,-(CH2)2Pyrimidine radicals ,-(CH2)3Imidazole radicals etc. and its derivative.
" hydroxyl " expression-OH groups.
" sulfydryl " expression-SH groups.
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine or chlorine.
" haloalkyl " expression alkyl, low alkyl group preferably as defined above, it is by one or more identical or different Halogen atom substitution, such as-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3Deng.
" trihalomethyl " expression-CX3Group, wherein X are halogens as defined above.
" cyano group " expression-CN groups.
" amino " expression-NH2Group.
" nitro " expression-NO2Group.
The event or situation that are meant that subsequent descriptions of so-called " optionally " will not may also may occur, and should Description, which includes things or situation, will not may also occur, and the description includes things or situation occurs and do not occur two The situation of kind.
In some embodiments, one in specified atom or group is referred to " by one or more substituent groups " It is individual, two, three or four hydrogen atoms identical or different group that is designated to select in the group of scope respectively replaces.
" pharmaceutically acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of property.This kind of salt Including：
(1) obtained, inorganic acid bag by the reaction of the free alkali and inorganic acid or organic acid of parent compound into salt with acid Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc. are included, organic acid includes acetic acid, propionic acid, propylene Acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, adjacent benzene Dioctyl phthalate, methanesulfonic acid, ethyl sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, breast Acid, mandelic acid, butanedioic acid or malonic acid etc..
(2) it is present in the acid proton in parent compound to be replaced or given birth to organic base ligand compound by metal ion Into salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example monoethanolamine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten Agent compound, hydrate or prodrug and other chemical composition, such as pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition Be to promote process of the administration to animal.
" pharmaceutical carrier " refers to not causing obvious excitant to organism and does not disturb the biology of given compound Non-active ingredient in the pharmaceutical composition of activity and property, such as, but not limited to：Calcium carbonate, calcium phosphate, various sugar are (such as newborn Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric Thing, gel, water, polyethylene glycol, propane diols, ethylene glycol, castor oil or rilanit special or many ethoxy aluminium castor oil, sesame Oil, corn oil, peanut oil etc..
In foregoing pharmaceutical composition, in addition to including pharmaceutically acceptable carrier, medicine (agent) is additionally may included in Upper conventional assistant agent, for example：Antibacterial agent, antifungal agent, antimicrobial, preservative, toner, solubilizer, thickener, table Face activating agent, complexing agent, protein, amino acid, fat, carbohydrate, vitamin, mineral matter, trace element, sweetener, pigment, perfume (or spice) Essence or their combination etc..
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the model of the present invention Enclose.
Embodiment 1：The preparation of compound 1
(Z) preparation of-ethyl -3- hydroxyl -2- bezene acrylic acids
28g ethyl phenylacetates and 230mL Ethyl formates are placed in 1L three-necked bottles, ice bath.20gNaH is weighed, is slowly added to Into three-necked bottle, there are a large amount of gases to emerge, add about 30 minutes time.Add and stop reaction after rear stirring at normal temperature 5h, will react Liquid is added in suitable quantity of water, and regulation PH is acidity, and organic layer is extracted with appropriate ethyl acetate, is merged, and is dried, and rotation is gone organic molten Agent, obtains oil product 32g.
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- bezene acrylic acids
Ethyl -3- hydroxyl -2- bezene acrylic acids (19g, 1eq), the chloro- 4-aminopyridines of 2- are added into reaction bulb (12.7g, 1eq), ethanol (300mL), concentrated hydrochloric acid (0.5mL) is well mixed and is warming up to 85 DEG C and react 5 hours, stops reaction, Ethanol is removed under reduced pressure, residue column chromatography for separation obtains ethyl -3- ((2- chloropyridine -4- bases) amino) -2- bezene acrylic acids (19.3g)。
The preparation of chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one of 5-
Ethyl -3- ((2- chloropyridine -4- bases) amino) -2- bezene acrylic acids (10g, 1eq), hexichol is added into reaction bulb Ether (80mL) mixing is warming up to 258 DEG C of reaction half an hour with after, stops reaction, is cooled at 50-60 DEG C and pours into 500mL oil In ether, chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one (2.0g) of 5- are obtained after filtering the solid separated out, solid chromatography post separation.
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- phenyl -1,6- naphthyridines -4 The preparation of (1H) -one
Chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one (50mg, 1eq) of 5-, 4- ((6,7- dimethoxies are added into reaction bulb Base quinazoline -4- bases) oxygen) -3- fluoroanilines (61.5mg, 1eq), concentrated hydrochloric acid (1 drop), electromagnetism is stirred after isopropanol (65mL) mixing Mix, be warming up to 50 DEG C and react 3 hours, filter out insoluble matter, filter cake obtains 5- ((4- after being dried in vacuo after being washed with isopropanol ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) -4 (1H) -one (38mg) of amino -3- phenyl -1,6- naphthyridines.
1H-NMR (400M, DMSO-d6) δ 13.59 (s, 1H), 12.88 (s, 1H), 8.57 (s, 1H), 8.32-8.35 (m, 1H), 8.15 (s, 1H), 8.07-8.08 (d, 1H), 7.68-7.70 (d, 2H), 7.58 (s, 1H), 7.44-7.46 (m, 1H), (s, the 6H) ppm of 7.35-7.41 (m, 1H), 7.28-7.30 (m, 1H), 3.99.
Embodiment 2：The preparation of compound 2
The chloro- 4- of 3- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acyls The preparation of amine pyridine
Chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one (150mg, 1eq) of 5-, 4- (4- amino -2- fluorine are added into reaction bulb Phenoxy group) the chloro- 2- acid amides pyridines (162mg, 1eq) of -3-, concentrated hydrochloric acid (3 drop), electromagnetic agitation after isopropanol (130mL) mixing, liter Warm to 50 DEG C are reacted 3 hours, filter out insoluble matter, filter cake obtains the chloro- 4- of 3- after being dried in vacuo after being washed with isopropanol, and (2- is fluoro- 4- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridine (68mg).5-((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- phenyl -1,6- naphthyridines -4 (1H) -one preparation
At room temperature to the chloro- 4- of 3- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridine (65mg, 1eq), acetonitrile (35mL), ethyl acetate (35mL) adds trifluoro vinegar in the solution of water (7mL) Sour iodobenzene (98mg, 2eq), takes out inflated with nitrogen, and the lower reaction of nitrogen protection 2 hours puts plate and reacts complete, stops reaction, add water (20mL), saturated sodium bicarbonate (15mL), ethyl acetate (20mL*5) extraction merges organic phase, anhydrous sodium sulfate drying is taken out Filter, concentration, crude product silica gel column chromatography obtains 5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- Phenyl -1,6- naphthyridines -4 (1H) -one (31mg).MS：[M-H]+=472.4.
1H-NMR (400M, DMSO-d6) δ 13.61 (s, 1H), 12.55 (s, 1H), 8.34-8.37 (d, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.74-7.75 (d, 1H), 7.68-7.69 (d, 2H), 7.38-7.44 (m, 2H), 7.23-7.30 (m, 2H), 6.34 (s, 2H), 5.94-6.03 (m, 3H) ppm.
Embodiment 3：The preparation of compound 3
The preparation of 4- (4- amino -2- fluorobenzene oxygen) iodo- 2- picolinamides of -3-
The iodo- 4- Chloro-2-Pyridyles acid amides (281mg, 1.0eq) of 3-, the fluoro- 4- amino-phenols of 2- are added into reaction bulb (127mg, 1.0eq), potassium tert-butoxide (145.6mg, 1.3eq), dry DMF (25mL) is heated to 90 DEG C and reacted 4 hours, puts plate Reaction is complete, stops reaction, solvent is recovered under reduced pressure, crude residue silica gel column chromatography obtains 4- (4- amino -2- fluorobenzene) -3- Iodo- 2- picolinamides (300mg).
4- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) iodo- 2- acyls of -3- The preparation of amine pyridine
Into 100mL round-bottomed flask add add 4- (4- amino -2- fluorobenzene oxygen) iodo- 2- picolinamides of -3- (580mg, 1.0eq), the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (426mg, 1eq), isopropanol 100mL, concentrated hydrochloric acid 0.1mL, is heated to 50 DEG C and reacts 6 hours, stop reaction, solid is filtered out, after solid is washed with 30mL isopropanol It is dried in vacuo 4- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) the phenoxy group) -3- that weighs to obtain Iodo- 2- acid amides pyridine 200mg.
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- phenyl -1,6- naphthyridines -4 (1H) The preparation of ketone
4- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthalenes are added into 100ml round-bottomed flask at room temperature Pyridine -5- bases) amino) phenoxy group) the iodo- 2- acid amides pyridines (100mg, 1eq) of -3-, acetonitrile (18mL), ethyl acetate (18mL), water Iodobenzene acetate (125mg, 2eq) is added into reaction after (9mL), stirring 5min, inflated with nitrogen is taken out, nitrogen protection is lower to react 1 hour, Point plate reaction is complete, stops reaction, add water (20mL), ethyl acetate (20mL*5) extraction, merges organic phase, and anhydrous sodium sulfate is done Dry, suction filtration, concentration, crude product silica gel column chromatography obtains 5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) ammonia Base) -3- phenyl -1,6- naphthyridines -4 (1H) ketone (61.5mg).MS：[M+H]+=566.1.
1H-NMR (400M, DMSO-d6) δ 13.2 (s, 1H), 12.4 (s, 1H), 8.34-8.25 (d, 1H), 8.20-8.10 (m, 2H), 7.70-7.60 (m, 2H), 7.40-7.50 (m, 4H), 7.30-7.41 (t, 1H), 7.20-7.29 (t, 1H), 6.80- 6.91 (d, 2H), 6.15-6.20 (s, 2H), 5.74-5.85 (d, H) ppm.
Embodiment 4：The preparation of compound 4
(Z) preparation of-ethyl -2- (4- fluorophenyls)-acrolactic acid ester
2- (4- fluorophenyls) ethyl acetate (17.2g, 1eq), Ethyl formate (84mL, 15eq), ice are added into reaction bulb Under the conditions of bath, sodium hydride (22.6g, 6eq) is slowly added to, is reacted 16 hours, point plate reaction terminates, and stops reaction, adds appropriate Water, pH is to acidity for regulation, is extracted with ethyl acetate, and merges organic phase, and anhydrous sodium sulfate drying, vacuum distillation obtains grease (Z)-ethyl -2- (4- fluorophenyls)-acrolactic acid ester (10.0g).
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- fluorophenyls) acrylate
(Z)-ethyl -2- (4- fluorophenyls)-acrolactic acid ester (10.0g, 1eq), the chloro- 4- of 2- is added into reaction bulb Aminopyridine (7.3g, 1.2eq), ethanol (100mL), concentrated hydrochloric acid (0.3mL) is well mixed and to be warming up to 60 DEG C of reactions 10 small When, stop reaction, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2- chloropyridine -4- bases) ammonia Base) -2- (4- fluorophenyls) acrylate (5.9g).
The preparation of the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- fluorophenyls) acrylate is added into reaction bulb (5.9g, 1eq), diphenyl ether (40mL) mixing is warming up to 160 DEG C with after and reacted 5 hours, stops reaction, is cooled to 50-60 DEG C Under pour into 400mL petroleum ethers, filtering separate out solid, solid chromatography post separation after obtain the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthalenes Pyridine -4 (1H) -one (700mg).
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridines preparation
The chloro- 4- of 3- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- in preparation method be the same as Example 2 Base) amino) phenoxy group) and -2- acid amides pyridines synthesis, difference is chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one of 5- The chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one is changed to, the reaction time is 5 hours.
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 2 The synthesis of phenyl -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitraes - Dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) and -2- acid amides pyridines be changed to the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) - 4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridines, the reaction time is 2 hours.MS：[M+H]+ =493.1.
1H-NMR (400M, DMSO-d6) δ 13.14 (s, 1H), 12.41 (s, 1H), 8.31-8.35 (d, 1H), 8.17-8.18 (d, 2H), 7.70-7.76 (m, 3H), 7.45-7.47 (m, 1H), 723-7.29 (m, 3H), 6.85-6.87 (d, 1H), 6.35 (s, 2H), 5.94-5.95 (d, 1H) ppm.
Embodiment 5：The preparation of compound 5
4- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -3- The preparation of iodo- 2- acid amides pyridine
Into 100mL round-bottomed flask add add 4- (4- amino -2- fluorobenzene oxygen) iodo- 2- picolinamides of -3- (373mg, 1.0eq), the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (275mg, 1eq), isopropanol 65mL, concentrated hydrochloric acid 0.1mL, It is heated to 50 DEG C to react 7 hours, stops reaction, filter out solid, vacuum is done after solid is washed with 30mL isopropanol Dry 4- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) the phenoxy group) -3- that weighs to obtain Iodo- 2- acid amides pyridine 213mg.
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
4- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydros-are added into 100mL round-bottomed flask at room temperature 1,6- naphthyridines -5- bases) amino) phenoxy group) the iodo- 2- acid amides pyridines (100mg, 1eq) of -3-, acetonitrile (18mL), ethyl acetate Iodobenzene acetate (128mg, 2eq) is added into reaction after (18mL), water (9mL), stirring 5min, inflated with nitrogen is taken out, under nitrogen protection Reaction 1 hour, point plate reaction is complete, stops reaction, add water (20mL), ethyl acetate (20mL*5) extraction, merges organic phase, nothing Aqueous sodium persulfate is dried, suction filtration, and concentration, crude product silica gel column chromatography obtains 5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- Fluorophenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (57.1mg).MS：[M+H]+=583.03.
1H-NMR (400M, DMSO-d6) δ 13.15 (s, 1H), 12.42 (s, 1H), 8.32-8.34 (m, 1H), 8.20- 8.10 (m, 2H), 7.70-7.60 (m, 3H), 7.40-7.50 (m, 1H), 7.22-7.27 (m, 3H), 6.80-6.91 (d, 1H), 6.15-6.20 (s, 2H), 5.74-5.85 (d, 1H) ppm.
Embodiment 6：The preparation of compound 6
The chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorine Phenoxy group) -2- acid amides pyridines preparation
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- are added into reaction bulb Base) amino) phenoxy group) -2- acid amides pyridine (50mg, 1eq), bromoethane (15mg, 1.5eq), potassium carbonate (19mg, 1.5eq), Electromagnetic agitation after DMF (30mL) mixing, is warming up to 90 DEG C and reacts 3 hours, column chromatography for separation obtains the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) -2- acid amides pyridine (45mg).
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- ethyls -3- (4- fluorophenyls) - The preparation of 1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 2 The synthesis of phenyl -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (the fluoro- 4- of 2- ((4- oxygen -3- phenyl-Isosorbide-5-Nitraes - Dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) and -2- acid amides pyridines be changed to the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) - 4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) -2- acid amides pyridines, the reaction time is 2 hours.MS： [M+H]+=520.1.
1H-NMR (400M, DMSO-d6) δ 13.49 (s, 1H), 8.34-8.37 (d, 2H), 8.29-8.30 (d, 1H), 7.73- 7.77 (m, 3H), 7.62-7.64 (d, 2H), 7.46-7.48 (d, 1H), 7.26-7.32 (m, 3H), 7.06-7.08 (d, 1H), 6.43 (s, 2H), 5.94-5.96 (d, 1H) ppm.
Embodiment 7：The preparation of compound 7
5- ((the fluoro- 4- of 3- ((7- methoxy quinoline -4- bases) oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
Chloro- 4- fluorophenyls -1,6- naphthyridines -4 (1H) -one (50mg, 1eq) of 5-, 4- ((7- methoxyl groups are added into reaction bulb Quinolyl-4) oxygen) -3- fluoroanilines (52mg, 1eq), concentrated hydrochloric acid (1 drop), electromagnetic agitation after isopropanol (25mL) mixing, heating Reacted 4 hours to 40 DEG C, filter out insoluble matter, filter cake obtains 5- ((fluoro- the 4- ((7- of 3- after being dried in vacuo after being washed with isopropanol Methoxy quinoline -4- bases) oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (18mg).
1H-NMR (400M, DMSO-d6) δ 13.30 (s, 1H), 13.06 (s, 1H), 9.02-9.04 (d, 1H), 8.53-8.55 (d, 1H), 8.32.-8.36 (d, 1H), 8.27-8.29 (d, 1H), 8.11-8.13 (d, 1H), 7.71-7.76 (m, 3H), 7.59- (s, the 3H) ppm of 7.67 (m, 3H), 7.27-7.32 (m, 2H), 7.20-7.26 (d, 1H), 7.02-7.04 (d, 1H), 4.05.
Embodiment 8：The preparation of compound 8
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -1- methyl -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) ammonia Base) phenoxy group) -2- acid amides pyridines preparation
In preparation method be the same as Example 6 the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1, 6- naphthyridines -5- bases) amino) -2- fluorophenoxies) and -2- acid amides pyridines synthesis, difference is bromoethane being changed to iodine first Alkane, the reaction time is 2 hours.
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) -1- methyl - The preparation of 1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- in preparation method be the same as Example 6 The synthesis of ethyl -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) to be changed to 3- chloro- for -2- acid amides pyridines 4- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -1- methyl -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acyls Amine pyridine, the reaction time is 2 hours.MS：[M+H]+=506.0.
1H-NMR (400M, DMSO-d6) δ 13.27 (s, 1H), 8.21-8.25 (m, 2H), 7.67 (s, 1H), 7.54 (s, 1H), 7.45-7.46 (m, 2H), 7.35-7.37 (d, 1H), 7.04-7.11 (m, 3H), 6.54-6.56 (d, 1H), 6.09-6.11 (d, 1H), 5.74 (s, 2H), 5.27-5.29 (d, 2H) ppm.
Embodiment 9：The preparation of compound 9
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- (4- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) ammonia in preparation method be the same as Example 1 The synthesis of (1H) -one of base -3- phenyl -1,6- naphthyridines -4, difference is chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one of 5- It is changed to the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one.MS：[M+H]+=554.1.
1H-NMR (400M, DMSO-d6) δ 13.37 (s, 1H), 13.07 (s, 1H), 8.64 (s, 1H), 8.29-8.31 (d, 1H), 8.10-8.13 (d, 1H), 8.04-8.06 (d, 1H), 7.73-7.76 (m, 2H), 7.61 (s, 1H), 7.49-7.58 (m, 2H), (s, the 6H) ppm of 7.45 (s, 1H), 7.27-7.31 (m, 2H), 7.00-7.01 (m, 2H), 4.01.
Embodiment 10：The preparation of compound 10
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -1- ethyls -3- (4- fluorobenzene Base) -1,6- naphthyridines -4 (1H) -one preparation
In preparation method be the same as Example 6 the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1, 6- naphthyridines -5- bases) amino) -2- fluorophenoxies) and -2- acid amides pyridines synthesis, difference is the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridines are changed to 5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one. MS：[M+H]+=582.1.
1H-NMR (400M, DMSO-d6) δ 13.47 (s, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 8.29-8.35 (m, 3H), 7.74-7.78 (m, 1H), 7.59 (s, 1H), 7.48-7.51 (d, 1H), 7.39-7.44 (m, 2H), 7.27-7.31 (m, 2H), 7.06-7.07 (d, 1H), 4.35 (m, 2H), 4.00 (s, 6H), 1.38-1.41 (d, 3H) ppm.
Embodiment 11：The preparation of compound 11
5- ((4- ((2- amino -3- iodo-pyridin -4- bases) oxygen) -3- fluorophenyls) amino) -1- ethyls -3- (4- fluorobenzene Base) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorobenzene is added into 50mL round-bottomed flask at room temperature Base) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (58mg, 1eq), DMF (15mL), bromine second The lower reaction of 90 DEG C of nitrogen protections of heating 2 hours after alkane (214mg, 2eq), potassium carbonate (414mg, 3eqL), stirring 5min, point plate is anti- Should be complete, stop reaction, decompression removes DMF, and add water (20mL), stirring separates out solid, suction filtration is dried, crude product silica gel column chromatography 5- ((4- ((2- amino -3- iodo-pyridin -4- bases) oxygen) -3- fluorophenyls) amino) -1- ethyls -3- (4- fluorophenyls) -1 is obtained, 6- naphthyridines -4 (1H) -one (51mg).MS：[M+H]+=512.0.
1H-NMR (400M, DMSO-d6) δ 13.1 (s, 1H), 12.4 (s, 1H), 8.34 (d, 1H), 8.20-8.10 (m, 2H), 7.70-7.60 (m, 2H), 7.40-7.50 (m, 4H), 7.30-7.41 (t, 1H), 7.22-7.27 (t, 2H), 6.80-6.91 (d, 2H), 6.15-6.20 (ds, 2H), 5.74-5.85 (d, H) ppm, 4.31-4.37 (dd, 2H), 1.31-1.47 (t, 2H).
Embodiment 12：The preparation of compound 12
1- ethyls -5- ((the fluoro- 4- of 3- ((7- methoxy quinoline -4- bases) oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- The preparation of naphthyridines -4 (1H) -one
5- ((the fluoro- 4- of 3- ((7- methoxy quinoline -4- bases) oxygen) phenyl) ammonia is added into 50mL round-bottomed flask at room temperature Base) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (52.2mg, 1eq), DMF (25mL), bromoethane The lower reaction of 90 DEG C of nitrogen protections of heating 2 hours, point plate reaction after (214mg, 2eq), potassium carbonate (414mg, 3eqL), stirring 5min Completely, reaction is stopped, decompression removes DMF, and add water (20mL), stirring separates out solid, suction filtration is dried, and crude product silica gel column chromatography is obtained To 1- ethyls -5- ((the fluoro- 4- of 3- ((7- methoxy quinoline -4- bases) oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (43mg).MS：[M+H] +=550.1.
1H-NMR (400M, DMSO-d6) δ 13.5 (s, 1H), 8.62-8.64 (d, 1H), 8.31-8.44 (m, 2H), 8.30-8.32 (d, 1H), 8.25-8.27 (d, 1H), 7.74-7.78 (m, 2H), 7.55-7.56 (d, 1H), 7.42-7.46 (m, 2H), 7.27-7.33 (m 3H), 7.08-7.09 (d, 1H), 6.51-6.52 (d, 1H), 4.31-4.37 (dd, 2H), 1.31- 1.47 (t, 2H).
Embodiment 13：The preparation of compound 13
1- pi-allyls -5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen -3- fluorophenyls) amino) -3- (4- fluorophenyls) - The preparation of 1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorobenzene is added into 50mLl round-bottomed flask at room temperature Base) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (582mg, 1eq), DMF (25mL), alkene The lower reaction of 90 DEG C of nitrogen protections of heating 2 hours, point after propyl bromide (238mg, 2eq), potassium carbonate (414mg, 3eqL), stirring 5min Plate reaction is complete, stops reaction, and decompression removes DMF, and add water (20mL), and stirring separates out solid, and suction filtration is dried, crude product silicagel column Chromatography obtain 1- pi-allyls -5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen -3- fluorophenyls) amino) -3- (4- fluorophenyls) - 1,6- naphthyridines -4 (1H) -one (57.0mg).MS：[M+H]+=623.0.
1H-NMR (400M, DMSO-d6) δ 13.42 (s, 1H), 8.32-8.36 (m, 2H), 7.71-7.74 (m, 3H), 7.45-7.48 (d, 1H), 7.25-7.31 (m, 3H), 6.95-6.97 (d, 2H), 6.24 (s, 2H), 6.00-6.11 (m, 1H), 5.80-5.82 (d, 2H), 5.17-5.32 (m, 2H), 4.95-4.97 (d, 2H).
Embodiment 14：The preparation of compound 14
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- benzyls -3- (4- fluorophenyls) - The preparation of 1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorobenzene is added into 50ml round-bottomed flask at room temperature Base) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (58.2mg, 1eq), DMF (25mL), benzyl The lower reaction of 90 DEG C of nitrogen protections of heating 2 hours after bromine (338mg, 2eq), potassium carbonate (414mg, 3eq), stirring 5min, point plate is anti- Should be complete, stop reaction, decompression removes DMF, and add water (20mL), stirring separates out solid, suction filtration is dried, crude product silica gel column chromatography Obtain 5- ((4- ((2- amino -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- benzyls -3- (4- fluorophenyls) -1,6- Naphthyridines -4 (1H) -one (78.3mg).MS：[M+H]+=673.0.
1H-NMR (400M, DMSO-d6) δ 13.42 (s, 1H), 8.61 (s, 1H), 8.30-8.34 (d, 1H), 8.18-8.20 (d, 1H), 7.76-7.79 (m, 3H), 7.74-7.79 (d, 1H), 7.27-7.49 (m, 8H), 6.89-6.90 (d, 1H), 6.38 (s, 2H), 5.91-5.92 (d, 1H), 5.59 (s, 2H), 4.95-4.97 (d, 2H).
Embodiment 15：The preparation of compound 15
Ethyl -2- (5- ((4- ((2- amido -3- iodine pyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) - (the 4H)-yl of 4- oxygen -1,6- naphthyridines -1) ethyl acetate preparation
5- ((4- ((2- amino -3- iodo-pyridin -4- bases) oxygen) -3- fluorophenyls) ammonia in preparation method be the same as Example 11 Base) -1- ethyls -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is bromoethane being changed to chloroethene Acetoacetic ester, the reaction time is 3 hours.MS：[M+H]+=669.0.
1H-NMR (400M, DMSO-d6) δ 13.10 (s, 1H), 8.22-8.28 (m, 2H), 7.78-7.80 (d, 1H), 7.55-7.99 (m, 3H), 7.40-7.42 (d, 1H), 7.11-7.19 (m, 3H), 6.38-6.40 (d, 1H), 5.95-5.97 (d, 1H), 5.22 (s, 2H), 4.77 (s, 2H), 4.31-4.36 (dd, 2H), 3.47-3.53 (m, 1H), 1.33-1.36 (t, 3H).
Embodiment 16：The preparation of compound 16
4- (4- ((1- benzyls -3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorobenzene oxygen Base) the chloro- 2- acid amides pyridines of -3- preparation
In preparation method be the same as Example 6 the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1, 6- naphthyridines -5- bases) amino) -2- fluorophenoxies) and -2- acid amides pyridines synthesis, difference is bromoethane being changed to benzyl chloride, Reaction time is 2 hours.
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- benzyls -3- (4- fluorophenyls) - 1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- in preparation method be the same as Example 6 The synthesis of ethyl -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) -2- acid amides pyridines are changed to 4- (4- ((1- benzyls -3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) the chloro- 2- acyls of -3- Amine pyridine, the reaction time is 2 hours.MS：[M+H]+=583.1.
1H-NMR (400M, DMSO-d6) δ 13.42 (s, 1H), 8.61 (s, 1H), 8.30-8.34 (d, 1H), 8.18-8.20 (d, 1H), 7.76-7.79 (m, 3H), 7.74-7.79 (d, 1H), 7.27-7.49 (m, 8H), 6.89-6.90 (d, 1H), 6.38 (s, 2H), 5.91-5.92 (d, 1H), 5.59 (s, 2H), 4.95-4.97 (d, 2H) ppm.
Embodiment 17：The preparation of compound 17
Ethyl -2- (5- ((4- ((2- formoxyl -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorobenzene Base) -1 (4H)-yl of -4- oxygen -1,6- naphthyridines) ethyl acetate preparation
In preparation method be the same as Example 6 the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1, 6- naphthyridines -5- bases) amino) -2- fluorophenoxies) and -2- acid amides pyridines synthesis, difference is bromoethane being changed to monoxone Ethyl ester, the reaction time is 2 hours.
Ethyl -2- (5- ((4- ((2- amido -3- chloropyridine -4- bases) epoxide) -3- fluorophenyls) amino) -3- (4- fluorobenzene Base) -1 (4H)-yl of -4- oxygen -1,6- naphthyridines) ethyl acetate preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -1- in preparation method be the same as Example 6 The synthesis of ethyl -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (4- ((1- ethyls 3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) -2- fluorophenoxies) and -2- acid amides pyridines be changed to ethyl - 2- (5- ((4- ((2- formoxyl -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) -4- oxygen -1,6- naphthalenes Pyridine -1 (4H)-yl) ethyl acetate, the reaction time is 2 hours.MS：[M+H]+=578.0.
1H-NMR (400M, DMSO-d6) δ 13.32 (s, 1H), 8.36 (s, 1H), 8.32-8.36 (d, 1H), 8.26-8.27 (d, 1H), 7.70-7.76 (m, 3H), 7.47-7.50 (d, 1H), 7.28-7.33 (m, 3H), 6.84-6.86 (d, 1H), 6.44 (s, 2H), 5.94-5.96 (d, 1H), 5.27 (s, 2H), 4.19-4.24 (m, 2H), 1.23-1.26 (m, 6H) ppm.
Embodiment 18：The preparation of compound 18
5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines are added into 100mL round-bottomed flask (314mg, 1.0eq), the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (274mg, 1eq), isopropanol 100mL, dense salt Sour 0.1mL, is heated to 70 DEG C and reacts 4 hours, stop reaction, filter out solid, solid is washed with 30mL isopropanol 5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorobenzene of weighing to obtain is dried in vacuo afterwards Base)-(1H) -one of 1,6- naphthyridines -4 300mg.MS：[M+H]+=552.1.
1H-NMR (400M, DMSO-d6) δ 13.51 (s, 1H), 12.89 (s, 1H), 8.26-8.27 (d, 1H), 8.20- 8.21 (d, 1H), 7.60-7.76 (m, 4H), 7.68-7.70 (d, 1H), 7.26-7.31 (t, 2H), 7.02-7.03 (d, 1H), 6.76-6.77 (d, 1H), 6.56 (s, 2H), 3.94 (s, 3H), 3.73 (s, 3H).
Embodiment 19：The preparation of compound 19
The preparation of 7- (benzyloxy) -4- (the fluoro- 4-nitrophenoxys of 2-) -6- methoxy quinolines
Into reaction bulb add 7- benzyloxy -6- methoxy quinoline -4- alcohol (0.84g, 1eq), cesium carbonate (6.5g, 10eq), DMF (50mL), acetonitrile (50mL), react 1 hour, the fluoro- 4- nitrobenzene of 1,2- bis- are then added into system at room temperature (0.48g, 1.5eq), is heated to 40 DEG C and reacts 6 hours, stops reaction, and decompression is removed after solvent, and dry method crosses post, obtains 7- (benzyls Epoxide) -4- (the fluoro- 4-nitrophenoxys of 2-) -6- methoxy quinolines 0.75g.
The preparation of 4- (4- amino -2- fluorophenoxies) -6- methoxy quinoline -7- alcohol
Into reaction bulb add 7- (benzyloxy) -4- (the fluoro- 4-nitrophenoxys of 2-) -6- methoxy quinolines (0.75g, 1eq), methanol (50mL), Pd-C (0.1g), in room temperature reaction 2 hours under hydrogen effect, stop reaction, are filtered to remove insoluble 4- (4- amino -2- fluorophenoxies) -6- methoxy quinoline -7- alcohol 0.5g is obtained after thing, concentration.
The preparation of the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) oxygen) aniline
4- (4- amino -2- fluorophenoxies) -6- methoxy quinoline -7- alcohol (500mg, 1eq), 4- are added into reaction bulb (3- chloropropyls) morpholine (817mg, 3eq), potassium carbonate (690mg, 3eq), DMF (75mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) oxygen) aniline 213.5mg。
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) oxygen) phenyl) amino) -3- (4- fluorine Phenyl) -1,6- naphthyridines -4 (1H) -one preparation
The fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinoline -4- are added into 100mL round-bottomed flask Base) oxygen) aniline (213.5mg, 1.0eq), the chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (137mg, 1eq), isopropyl Alcohol 50mL, concentrated hydrochloric acid 0.05mL, are heated to 90 DEG C and react 3 hours, stop reaction, filter out solid, solid 15mL Isopropanol washing after vacuum drying weigh to obtain 5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) Oxygen) phenyl) amino) -3- (4- fluorophenyls)-(1H) -one of 1,6- naphthyridines -4 189mg.MS：[M+H]+=665.2.
1H-NMR (400M, CDCl3) δ 13.33 (s, 1H), 12.18 (s, 1H), 8.50-8.54 (d, 1H), 8.21-8.22 (d, 1H), 7.84-7.85 (d, 1H), 7.82 (s, 1H), 7.57-7.63 (m, 4H), 7.31-7.35 (t, 1H), 7.14-7.18 (t, 2H), 6.90-6.92 (d, 1H), 6.39-6.44 (t, 2H), 3.94-3.97 (m, 6H), 3.71 (s, 3H), 2.50-2.56 (m, 6H), 2.02-2.05 (m, 2H).
Embodiment 20：The preparation of compound 20
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridines preparation
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) in preparation method be the same as Example 19 Oxygen) phenyl) amino) and -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is fluoro- the 4- ((6- of 3- Methoxyl group -7- (3- morpholines propoxyl group) quinolyl-4) oxygen) aniline is changed to 4- (4- amino -2- fluorophenoxies) chloro- 2- acid amides of -3- Pyridine, the reaction time is 3.5 hours.MS：[M+H]+=519.0.
1H-NMR (400M, DMSO-d6) δ 13.22 (s, 1H), 12.47 (s, 1H), 8.40-8.44 (dd, 1H), 8.34- 8.35 (d, 1H), 8.19-8.20 (d, 2H), 8.07 (s, 2H), 7.71-7.76 (m, 3H), 7.52-7.54 (d, 1H), 7.36- 7.40 (t, 1H), 7.25-7.29 (t, 2H), 36.85-6.89 (dd, 2H).
Embodiment 21：The preparation of compound 21
The preparation of (4- (7- benzyloxy -6- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines
The chloro- 6- methoxyquinazoline hydrochlorides (11.5g, 1eq) of 7- benzyloxies -4-, 4- amino -2- fluorophenols are added into reaction bulb (5.3g, 1.1eq), potassium tert-butoxide (5.1g, 1.2eq), DMF (250mL), are heated to 80 DEG C and react 2 hours, stop reaction, subtract Pressure is removed after solvent, and dry method crosses post, obtains (4- (7- benzyloxy -6- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines 8.1g。
The preparation of 4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol
(4- (7- (benzyloxy) -6- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines are added into reaction bulb (3.91g, 1eq), methanol (240mL), Pd-C (0.4g), react 6 hours in 0 DEG C under hydrogen effect, stop reaction, cross and filter out Insoluble matter is removed, post is crossed after concentration and obtains 4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol 2.3g.
The preparation of the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrroles -1- bases) propoxyl group) quinazoline -4- bases) oxygen) aniline
4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol (50mg, 1eq), 1- are added into reaction bulb (3- chloropropyls) pyrrolidines (73.5mg, 3eq), potassium carbonate (68mg, 3eq), DMF (10mL), are heated to 80 DEG C and react 2 hours, Stop reaction, filter, be concentrated to give the fluoro- 4- of crude product 3- ((6- methoxyl groups -7- (3- (pyrroles -1- bases) propoxyl group) quinazoline -4- Base) oxygen) aniline 38mg.
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrroles -1- bases) propoxyl group) quinazoline -4- bases) oxygen) benzene) amine) -3- The preparation of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) in preparation method be the same as Example 19 Oxygen) phenyl) amino) and -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is fluoro- the 4- ((6- of 3- Methoxyl group -7- (3- morpholines propoxyl group) quinolyl-4) oxygen) aniline is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrroles -1- Base) propoxyl group) quinazoline -4- bases) oxygen) aniline, the reaction time is 5 hours.MS：[M+H]+=650.3.
1H-NMR (400M, DMSO-d6) δ 13.30 (s, 1H), 8.39-8.42 (d, 1H), 8.28 (s, 1H), 8.20-8.23 (t, 2H), 7.72-7.75 (t, 2H), 7.54-7.55 (t, 3H), 7.25-7.29 (t, 3H), 6.96-6.97 (d, 1H), 4.26- 4.29 (t, 2H), 3.92 (s, 3H), 3.17-3.22 (t, 6H), 2.21-2.25 (t, 2H), 1.93 (s, 4H).
Embodiment 22：The preparation of compound 22
The preparation of (4- (6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines
The chloro- 7- methoxyquinazoline hydrochlorides (10.0g, 1eq) of 6- benzyloxies -4-, 4- amino -2- fluorophenols are added into reaction bulb (4.65g, 11eq), potassium tert-butoxide (4.5g, 1.2eq), DMF (500mL), are heated to 55 DEG C and react 3 hours, stop reaction, subtract Pressure is removed after solvent, and dry method crosses post, obtains (4- (6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines 7g.
The preparation of 4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol
Into reaction bulb add (4- (6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) -3- fluoroanilines (3.0g, 1eq), methanol (150mL), Pd-C (0.6g), react 6 hours in 0 DEG C under hydrogen effect, stop reaction, be filtered to remove insoluble Thing, crosses post and obtains 4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol 1.6g after concentration.
The preparation of the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (pyrroles -1- bases) propoxyl group) quinazoline -4- bases) oxygen) aniline
4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 1- are added into reaction bulb (3- chloropropyls) pyrrolidines (294mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, Stop reaction, filter, be concentrated to give the fluoro- 4- of crude product 3- ((7- methoxyl groups -6- (3- (pyrroles -1- bases) propoxyl group) quinazoline -4- Base) oxygen) aniline 123mg.
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (2- methoxyethoxies) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline, and the reaction time is 6 hours (1753-23-15).MS：[M-H]+=596.1.
1H-NMR (400M, DMSO-d6) δ 13.43 (s, 1H), 13.26 (s, 1H), 8.69 (s, 1H), 8.31-8.32 (d, 1H), 8.01-8.07 (m, 2H), 7.74-7.77 (m, 2H), 7.65 (s, 1H), 7.56-7.60 (m, 2H), 7.48-7.52 (m, 2H), 7.28-7.32 (t, 2H), 7.05-7.07 (m, 1H), 4.34-4.37 (m, 2H), 4.03-4.05 (m, 5H), 3.35 (s, 3H)ppm。
Embodiment 23：The preparation of compound 23
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (pyrrolidin-1-yl) propoxyl group) quinazoline -4- bases) oxygen) phenyl) ammonia Base) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (pyrrolidin-1-yl) propoxyl group) quinazoline -4- bases) oxygen) aniline, Reaction time is 5 hours.MS：[M+H]+=651.2, [M-H]+=649.2.
1H-NMR (400M, DMSO-d6) δ 13.36 (s, 1H), 13.16 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 8.27-8.29 (m, 1H), 8.11-8.14 (m, 1H), 8.06-8.08 (d, 1H), 7.73-7.77 (m, 2H), 7.64 (s, 1H), 7.48-7.53 (m, 2H), 7.27-7.31 (t, 2H), 7.03-7.04 (d, 1H), 4.32-4.35 (m, 2H), 4.03 (s, 3H), 3.01-3.30 (m, 6H), 1.89-2.27 (m, 6H) ppm.
Embodiment 24：The preparation of compound 24
4- ((6- (3- lignocaines) propoxyl group) -7- methoxyquinazoline hydrochloride -4- bases) oxygen) -3- fluoroanilines preparation
4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 3- are added into reaction bulb Chloro- N, N- diethyl propane base -1- amine (298mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C instead Answer 2 hours, stop reaction, filter, be concentrated to give crude product 4- ((6- (3- lignocaines) propoxyl group) -7- methoxyquinazoline hydrochlorides -4- Base) oxygen) -3- fluoroanilines 128mg.
5- ((4- ((6- (3- lignocaines) propoxyl group) -7- methoxyquinazoline hydrochloride -4- bases) oxygen) -3- fluorophenyls) amino) - The preparation of 3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to 4- ((6- (3- lignocaines) propoxyl group) -7- methoxyquinazoline hydrochloride -4- bases) oxygen) -3- fluoroanilines, reaction Time is 6 hours.MS：[M+H]+=653.3, [M-H]+=651.3.
1H-NMR (400M, DMSO-d6) δ 13.31 (s, 1H), 12.94 (s, 1H), 10.21 (s, 1H), 8.64 (s, 1H), 8.26-8.27 (m, 1H), 8.18-8.21 (d, 1H), 8.10-8.12 (d, 1H), 7.73-7.77 (m, 2H), 7.65 (s, 1H), 7.47-7.53 (m, 2H), 7.27-7.33 (m, 2H), 6.98-6.99 (d, 1H), 4.34-4.35 (m, 2H), 3.82 (s, 3H), 3.15-3.27 (m, 6H), 2.23-2.27 (m, 2H), 1.26-1.27 (m, 6H) ppm.
Embodiment 25：The preparation of compound 25
The preparation of the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (base of piperidines -1) propoxyl group) quinazoline -4- bases) oxygen) aniline is to anti- Answer and 4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 1- (3- chloropropyls) piperazine are added in bottle Pyridine (322mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop reaction, filter, It is concentrated to give the fluoro- 4- of crude product 3- ((7- methoxyl groups -6- (3- (base of piperidines -1) propoxyl group) quinazoline -4- bases) oxygen) aniline 220mg.
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (base of piperidines -1) propoxyl group) quinazoline -4- bases) oxygen) phenyl) ammonia Base) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (base of piperidines -1) propoxyl group) quinazoline -4- bases) oxygen) aniline, reaction Time is 5 hours.MS：[M+H]+=665.3, [M-H]+=663.2.
1H-NMR (400M, DMSO-d6) δ 13.18 (s, 1H), 12.84 (s, 1H), 10.86 (s, 1H), 8.59 (s, 1H), 8.32-8.36 (m, 1H), 8.18-8.20 (d, 1H), 7.72-7.76 (m, 2H), 7.62 (s, 1H), 7.49-7.52 (m, 1H), 7.38-7.43 (m, 2H), 7.25-7.29 (t, 2H), 6.95-6.97 (d, 1H), 4.27-4.30 (m, 2H), 4.02 (s, 3H), 2.82-2.97 (m, 6H), 2.21-2.24 (m, 2H), 1.71-1.73 (m, 4H), 1.49-1.51 (m, 2H) ppm.
Embodiment 26：The preparation of compound 26
The system of the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (base of 4- methyl piperazines -1) propoxyl group) quinazoline -4- bases) oxygen) aniline It is standby
4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 1- are added into reaction bulb (3- chloropropyls) -4- methyl piperazines (352mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C of reactions 2 Hour, stop reaction, filter, be concentrated to give the fluoro- 4- of crude product 3- ((7- methoxyl groups -6- (3- (base of 4- methyl piperazines -1) propoxyl group) Quinazoline -4- bases) oxygen) aniline 140mg.
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (4- methylpiperazine-1-yls) propoxyl group) quinazoline -4- bases) oxygen) benzene Base) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- (4- methylpiperazine-1-yls) propoxyl group) quinazoline -4- bases) oxygen) benzene Amine, the reaction time is 2 hours.MS：[M+H]+=680.3, [M-H]+=678.3.
1H-NMR (400M, DMSO-d6) δ 13.29 (s, 1H), 12.98 (s, 1H), 12.00 (s, 1H), 8.63 (s, 1H), 8.24-8.25 (m, 2H), 8.11-8.12 (d, 1H), 7.73-7.76 (m, 2H), 7.64 (s, 1H), 7.47-7.50 (m, 2H), 7.27-7.31 (m, 2H), 6.99-7.00 (d, 1H), 4.33-4.36 (m, 2H), 4.04 (s, 3H), 3.36-3.48 (m, 10H), 2.85 (s, 3H), 2.09-2.11 (m, 2H) ppm.
Embodiment 27：The preparation of compound 27
The preparation of the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) epoxide) aniline
4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 4- are added into reaction bulb (3- chloropropyls) morpholine (326mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) epoxide) benzene Amine 136mg.
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline, and the reaction time is 2 hours.MS：[M+H]+=667.3.
1H-NMR (400M, DMSO-d6) δ 13.31 (s, 1H), 12.93 (s, 1H), 10.86 (s, 1H), 8.64 (s, 1H), 8.26-8.27 (d, 1H), 8.18-8.21 (d, 1H), 8.10-8.12 (d, 1H), 7.73-7.77 (m, 2H), 7.65 (s, 1H), 7.48-7.51 (m, 2H), 7.27-7.31 (t, 2H), 6.98-7.00 (d, 1H), 4.34-4.35 (m, 2H), 4.21 (s, 3H), 3.79-3.85 (m, 2H), 3.50-3.53 (m, 2H), 3.14-3.16 (m, 2H), 3.09-3.11 (m, 2H), 2.31-2.34 (m, 2H), 1.04-1.06 (m, 2H) ppm.
Embodiment 28：The preparation of compound 28
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrrolidin-1-yl) propoxyl group) quinazoline -4- bases) oxygen) phenyl) ammonia Base) -3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrrolidin-1-yl) propoxyl group) quinazoline -4- bases) oxygen) aniline, Reaction time is 5 hours (1753-28-13).MS：[M-H]+=649.2.
1H-NMR (400M, DMSO-d6) δ 13.30 (s, 1H), 13.16 (s, 1H), 10.79 (s, 1H), 8.63 (s, 1H), 8.19-8.26 (m, 2H), 8.11-8.12 (d, 1H), 7.73-7.77 (m, 2H), 7.63 (s, 1H), 7.47-7.51 (m, 2H), 7.27-7.31 (t, 2H), 7.00-7.01 (d, 1H), 4.34-4.37 (m, 2H), 4.02-4.05 (m, 2H), 3.84 (s, 3H), 3.59-3.61 (m, 2H), 3.31-3.33 (m, 2H), 2.28-2.32 (m, 2H), 1.90-1.93 (m, 4H) ppm.
Embodiment 29：The preparation of compound 29
The preparation of the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline
4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol (200mg, 1eq), 4- are added into reaction bulb (3- chloropropyls) morpholine (326mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline 125mg。
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline, and the reaction time is 6 hours.MS：[M-H]+=665.2.
1H-NMR (400M, DMSO-d6) δ 13.30 (s, 1H), 12.91 (s, 1H), 10.90 (s, 1H), 8.63 (s, 1H), 8.25-8.27 (d, 1H), 8.18-8.22 (d, 1H), 8.10-8.12 (d, 1H), 7.73-7.77 (m, 2H), 7.63 (s, 1H), 7.48-7.53 (m, 2H), 7.27-7.31 (m, 2H), 6.97-7.00 (d, 1H), 4.34-4.37 (m, 2H), 3.98-4.02 (m, 7H), 3.11-3.33 (m, 6H), 2.30-2.32 (m, 2H) ppm.
Embodiment 30：The preparation of compound 30
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) aniline, and the reaction time is 4 hours.MS：[M+H]+= 536.2, [M-H]+=534.1.
1H-NMR (400M, DMSO-d6) δ 13.22 (s, 1H), 12.58 (s, 1H), 8.27 (s, 1H), 8.15-8.18 (m, 2H), 8.03-8.05 (d, 2H), 7.73-7.76 (m, 2H), 7.53 (s, 1H), 7.45-7.47 (d, 2H), 7.23-7.29 (m, 3H), 6.88-6.90 (d, 1H), 3.93 (s, 6H) ppm.
Embodiment 31：The preparation of compound 31
The preparation of the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline
4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol (200mg, 1eq), 1- are added into reaction bulb Chloro- 2- Ethyl Methyl Ethers (188mg, 3eq), potassium carbonate (183mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((6- methoxyl groups -7- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline 134mg。
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- methoxyethoxies) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline, and the reaction time is 4.5 hour.MS：[M+H]+=598.2.
1H-NMR (400M, DMSO-d6) δ 13.17 (s, 1H), 12.57 (s, 1H), 8.58 (s, 1H), 8.32-8.36 (dd, 1H), 8.19-8.20 (m, 2H), 7.72-7.76 (m, 2H), 7.60 (s, 1H), 7.49-7.51 (m, 1H), 7.39-7.44 (m, 2H), 7.25-7.30 (m, 2H), 6.89-6.91 (d, 1H), 4.34-4.36 (m, 2H), 4.11 (s, 3H), 4.01-4.02 (m, 2H), 3.18 (s, 3H) ppm.
Embodiment 32：The preparation of compound 32
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) phenyl) amino) -3- phenyl -1,6- naphthyridines -4 (1H) - The preparation of ketone
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) ammonia in preparation method be the same as Example 1 Base) -3- phenyl -1,6- naphthyridines -4 (1H) -one synthesis, difference is 4- ((6,7- dimethoxyquinazoline -4- bases) Oxygen) -3- fluoroanilines are changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) aniline, and the reaction time is 4 hours.MS：[M+H]+ =518.2.
1H-NMR (400M, DMSO-d6) δ 13.51 (s, 2H), 8.73 (s, 1H), 8.33-8.35 (d, 1H), 7.89-7.90 (d, 1H), 7.70-7.75 (m, 4H), 7.62 (s, 1H), 7.45-7.52 (m, 5H), 7.40-7.42 (m, 1H), 7.06-7.08 (d, 1H), 4.02 (s, 6H) ppm.
Embodiment 33：The preparation of compound 33
The preparation of 4- ((6,7- bis- (2- methoxyethoxies) quinazoline -4- bases) oxygen) -3- fluoroanilines
Into DMF (10mL) solution of 4- amino -2- fluorophenols (200mg, 2eq) add 60% sodium hydride (94.5mg, 3eq), stir 10 minutes at room temperature, 4- chloro- 6,7- bis- (2- methoxy ethoxies) quinazoline is slowly added into system DMF (15mL) solution of (492mg, 1eq), reacts 2 hours at room temperature after dripping, and stops reaction, and concentration, post excessively obtain 4- ((6,7- bis- (2- methoxyethoxies) quinazoline -4- bases) oxygen) -3- fluoroanilines 200mg.
5- ((4- ((6,7- bis- (2- methoxyethoxies) quinazoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- fluorobenzene Base) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to 4- ((6,7- bis- (2- methoxyethoxies) quinazoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 5 small When.MS：[M+H]+=642.3.
1H-NMR (400M, DMSO-d6) δ 13.40 (s, 1H), 13.16 (s, 1H), 8.67 (s, 1H), 8.30-8.31 (d, 1H), 8.03-8.10 (m, 2H), 7.74-7.77 (m, 2H), 7.66 (s, 1H), 7.49-7.52 (m, 3H), 7.28-7.32 (t, 2H), 7.03-7.04 (d, 1H), 4.37 (s, 6H), 3.77-3.80 (m, 8H) ppm.
Embodiment 34：The preparation of compound 34
The preparation of 4- ((6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) aniline
Added into reaction bulb 6- benzyloxies -4- chloro- 7- methoxyquinazoline hydrochlorides (5g, 1eq), PAP (2.0g, 1.1eq), potassium tert-butoxide (2.2g, 1.2eq), DMF (250mL), are heated to 55 DEG C and react 3 hours, stop reaction, and decompression is removed After solvent, dry method crosses post, obtains 4- ((6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) aniline 3.7g.
The preparation of 4- (4- amino-benzene oxygens) -7- methoxyquinazoline hydrochloride -6- alcohol
4- ((6- benzyloxy -7- methoxyquinazoline hydrochloride -4- bases) epoxide) aniline (3.0g, 1eq), first are added into reaction bulb Alcohol (160mL), Pd-C (0.7g), react 6 hours in 0 DEG C under hydrogen effect, stop reaction, be filtered to remove insoluble matter, concentrate Post is crossed afterwards obtains 4- (4- amino-benzene oxygens) -7- methoxyquinazoline hydrochloride -6- alcohol 1.5g.
The preparation of 4- ((7- methoxyl groups -6- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline
4- (4- amino-benzene oxygens) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), the chloro- 2- of 1- are added into reaction bulb Ethyl Methyl Ether (200mg, 3eq), potassium carbonate (293mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop anti- Should, filter, be concentrated to give crude product 4- ((7- methoxyl groups -6- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline 120mg.
3- (4- fluorophenyls) -5- ((4- ((7- methoxyl groups -6- (methoxyethoxy) quinazoline -4- bases) oxygen) phenyl) ammonia Base) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to 4- ((7- methoxyl groups -6- (2- methoxyethoxies) quinazoline -4- bases) oxygen) aniline, and the reaction time is 5.5 small When.MS：[M-H]+=577.9.
1H-NMR (400M, DMSO-d6) δ 13.56 (s, 1H), 13.46 (s, 1H), 8.74 (s, 1H), 8.34-8.35 (d, 1H), 7.90-7.91 (d, 1H), 7.73-7.77 (m, 4H), 7.66 (s, 1H), 7.49-7.52 (m, 3H), 7.28-7.33 (m, 2H), 7.09-7.10 (d, 1H), 4.34-4.36 (m, 2H), 3.76-3.79 (m, 8H) ppm.
Embodiment 35：The preparation of compound 35
5- ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) phenyl) amino) -3- (4- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline, and the reaction time is 4 hours.MS：[M-H]+= 497.8.
1H-NMR (400M, DMSO-d6) δ 13.32 (s, 1H), 12.88 (s, 1H), 8.76 (s, 1H), 8.54-8.55 (d, 1H), 8.27-8.28 (d, 1H), 8.18-8.21 (d, 1H), 8.09-8.10 (d, 1H), 7.73-7.77 (m, 3H), 7.49-7.58 (m, 2H), 7.27-7.32 (t, 2H), 6.97-6.98 (d, 1H) ppm.
Embodiment 36：The preparation of compound 36
(Z)-ethyl -3- hydroxyls -2- (4- methoxyl groups) preparation of acrylate
Addition 2- (4- methoxyphenyls) ethyl acetate (28.3g, 1eq) into reaction bulb, Ethyl formate (129.9mL, 15eq), under condition of ice bath, sodium hydride (34.9g, 6eq) is slowly added to, is reacted 8 hours, point plate reaction terminates, and stops reaction, plus Enter suitable quantity of water, pH is to acidity for regulation, is extracted with ethyl acetate, and merges organic phase, and anhydrous sodium sulfate drying, vacuum distillation obtains oil Shape thing (Z)-ethyl -3- hydroxyls -2- (4- methoxyl groups) acrylate (29.5g).
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- methoxyl groups) acrylate
(Z)-ethyl -3- hydroxyls -2- (4- methoxyl groups) acrylate (29.5g, 1eq), the chloro- 4- of 2- are added into reaction bulb Aminopyridine (11g, 1eq), ethanol (260mL), concentrated hydrochloric acid (0.4mL) is well mixed and is warming up to 70 DEG C and react 5 hours, stops Only react, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- methoxyl groups) acrylate (19.3g).
The preparation of the chloro- 3- of 5- (4- methoxyphenyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- methoxyl groups) acrylate is added into reaction bulb (10g, 1eq), diphenyl ether (80mL) mixing is warming up to 200 DEG C of reaction half an hour with after, stops reaction, is cooled to 50-60 DEG C Under pour into 500mL petroleum ethers, filter separate out solid, solid chromatography post separation after obtain the chloro- 3- of 5- (4- methoxyphenyls)- 1,6- naphthyridines -4 (1H) -one (1.0g).
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- anisyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridines preparation
The chloro- 3- of 5- (4- methoxyphenyls) -1,6- naphthyridines -4 (1H) -one (50mg, 1eq), 4- (4- are added into reaction bulb Amino -2- fluorophenoxies) the chloro- 2- acid amides pyridines (78mg, 1eq) of -3-, concentrated hydrochloric acid (1 drop), electromagnetism after isopropanol (65mL) mixing Stirring, is warming up to 60 DEG C and reacts 3 hours, filters out insoluble matter, and filter cake obtains the chloro- 4- of 3- after being dried in vacuo after being washed with isopropanol (the fluoro- 4- of 2- ((3- (4- anisyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridines (76mg)。
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- anisyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
At room temperature to the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (4- anisyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) Amino) phenoxy group) -2- acid amides pyridine (85mg, 1eq), acetonitrile (35mL), ethyl acetate (35mL), in the solution of water (7mL) plus Enter trifluoracetic acid iodobenzene (137mg, 2eq), take out inflated with nitrogen, the lower reaction of nitrogen protection 2 hours puts plate and reacts complete, stops reaction, Add water (20mL), saturated sodium bicarbonate (15mL), ethyl acetate (20mL*5) extraction, merging organic phase, anhydrous sodium sulfate drying, Suction filtration, concentration, crude product silica gel column chromatography obtain 5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) - 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one (31mg).MS：[M-H]+=502.1.
1H-NMR (400M, DMSO-d6) δ 13.25 (s, 1H), 12.38 (s, 1H), 8.35-8.39 (dd, 1H), 8.17- 8.18 (d, 1H), 8.13 (s, 1H), 7..76-7.77 (d, 1H), 7.62-7.64 (d, 2H), 7.46-7.48 (d, 1H), 7.27- 7.32 (dd, 1H), 7.00-7.02 (d, 2H), 6.86-6.88 (d, 1H), 6.40 (s, 2H), 5.95-5.97 (d, 1H), 3.81 (s, 3H) ppm.
Embodiment 37：The preparation of compound 37
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- (4- anisyls) -1,6- The preparation of naphthyridines -4 (1H) -one
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 36- The synthesis of 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- Chloropyridine -2- amino is changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 4 hours.MS： [M+H]+=566.3.
1H-NMR (400M, DMSO-d6) δ 13.21 (s, 1H), 12.58 (s, 1H), 8.66-8.68 (d, 1H), 8.26-8.27 (d, 1H), 7.98-8.00 (m, 2H), 7.65-7.67 (d, 2H), 7.60-7.62 (m, 2H), 7.50-7.52 (d, 1H), 7.46- (s, the 3H) ppm of 7.47 (m, 2H), 7.02-7.06 (m, 2H), 4.01 (s, 6H), 3.82.
Embodiment 38：The preparation of compound 38
5- ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) phenyl) amino) -3- (4- methoxyphenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 36- The synthesis of 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- Chloropyridine -2- amino is changed to the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline, and the reaction time is 4 hours.MS：[M- 2H]+=511.0.
1H-NMR (400M, DMSO-d6) δ 13.47 (s, 1H), 12.96 (s, 1H), 8.77 (s, 1H), 8.54-8.56 (d, 1H), 8.22-8.24 (d, 1H), 8.11-8.12 (d, 1H), 8.02-8.04 (d, 1H), 7.73-7.75 (d, 1H), 7.64-7.67 (d, 2H), 7.51-7.53 (m, 1H), 7.49-7.50 (m, 1H), 6.99-7.04 (m, 3H), 3.82 (s, 3H) ppm.
Embodiment 39：The preparation of compound 39
5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- anisyls) -1,6- The preparation of naphthyridines -4 (1H) -one
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 36- The synthesis of 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- Chloropyridine -2- amino is changed to 4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 4 hours.MS： [M-H]+=563.2.
1H-NMR (400M, DMSO-d6) δ 13.61 (s, 1H), 12.82 (s, 1H), 8.46-8.49 (d, 1H), 8.38-8.40 (d, 1H), 8.17-8.22 (dd, 2H), 7.64-7.75 (m, 5H), 7.01-7.03 (m, 3H), 6.78-6.80 (d, 1H), 6.59 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H) ppm.
Embodiment 40：The preparation of compound 40
(Z) preparation of-ethyl -2- (3- fluorophenyls)-acrolactic acid ester
2- (3- fluorophenyls) ethyl acetate (14.3g, 1eq), Ethyl formate (70mL, 15eq), ice are added into reaction bulb Under the conditions of bath, sodium hydride (18.8g, 6eq) is slowly added to, is reacted 16 hours, point plate reaction terminates, and stops reaction, adds appropriate Water, pH is to acidity for regulation, is extracted with ethyl acetate, and merges organic phase, and anhydrous sodium sulfate drying, vacuum distillation obtains grease (Z)-ethyl -2- (3- fluorophenyls)-acrolactic acid ester (10.0g).
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (3- fluorophenyls) acrylate
(Z)-ethyl -2- (3- fluorophenyls)-acrolactic acid ester (10.0g, 1eq), the chloro- 4- of 2- is added into reaction bulb Aminopyridine (7.3g, 1.2eq), ethanol (100mL), concentrated hydrochloric acid (0.3mL) is well mixed and to be warming up to 60 DEG C of reactions 10 small When, stop reaction, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2- chloropyridine -4- bases) ammonia Base) -2- (3- fluorophenyls) acrylate (7.1g).
The preparation of the chloro- 3- of 5- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (3- fluorophenyls) acrylate is added into reaction bulb (7.1g, 1eq), diphenyl ether (50mL) mixing is warming up to 160 DEG C with after and reacted 5 hours, stops reaction, is cooled to 50-60 DEG C Under pour into 500mL petroleum ethers, filtering separate out solid, solid chromatography post separation after obtain the chloro- 3- of 5- (3- fluorophenyls) -1,6- naphthalenes Pyridine -4 (1H) -one (900mg).
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (3- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridines preparation
The chloro- 3- of 5- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (74mg, 1eq), 4- (4- ammonia are added into reaction bulb Base -2- fluorophenoxies) the chloro- 2- acid amides pyridines (72mg, 1eq) of -3-, concentrated hydrochloric acid (1 drop), electromagnetism is stirred after isopropanol (30mL) mixing Mix, be warming up to 65 DEG C and react 4 hours, filter out insoluble matter, filter cake obtains the chloro- 4- of 3- after being dried in vacuo after being washed with isopropanol (the fluoro- 4- of 2- ((3- (3- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridines (50mg)。
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- (3- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
At room temperature to the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (3- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) ammonia Base) phenoxy group) -2- acid amides pyridine (50mg, 1eq), acetonitrile (5mL), ethyl acetate (5mL), in the solution of water (1.25mL) plus Enter trifluoracetic acid iodobenzene (75mg, 2eq), take out inflated with nitrogen, the lower reaction of nitrogen protection 2 hours puts plate and reacts complete, stops reaction, Add water (20mL), saturated sodium bicarbonate (15mL), ethyl acetate (20mL*5) extraction, merging organic phase, anhydrous sodium sulfate drying, Suction filtration, concentration, crude product silica gel column chromatography obtain 5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) - 3- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (40mg).MS：[M+H]+=492.1, [M-H]+=490.1.
1H-NMR (400M, DMSO-d6) δ 13.11 (s, 1H), 12.17 (s, 1H), 8.29-8.36 (m, 3H), 8.04-8.06 (m, 2H), 7.76 (s, 1H), 7.49-7.57 (m, 5H), 7.37-7.42 (t, 1H), 7.21-7.23 (m, 1H), 6.85-6.86 (d, 1H) ppm.
Embodiment 41：The preparation of compound 41
(Z)-ethyl -3- hydroxyls -2- (2- fluorophenyls) preparation of acrylate
2- (2- fluorophenyls) ethyl acetate (20.0g, 1eq), Ethyl formate (140mL, 15eq), ice are added into reaction bulb Under the conditions of bath, sodium hydride (16.0g, 6eq) is slowly added to, is reacted 8 hours, point plate reaction terminates, and stops reaction, adds appropriate Water, pH is to acidity for regulation, is extracted with ethyl acetate, and merges organic phase, and anhydrous sodium sulfate drying, vacuum distillation obtains grease (Z)-ethyl -3- hydroxyls -2- (2- fluorophenyls) acrylate (10.0g).
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (2- fluorophenyls) acrylate
(Z)-ethyl -3- hydroxyls -2- (2- fluorophenyls) acrylate (10.0g, 1eq), the chloro- 4- of 2- are added into reaction bulb Aminopyridine (7.3g, 1.2eq), ethanol (100mL), concentrated hydrochloric acid (0.3mL) is well mixed and to be warming up to 70 DEG C of reactions 10 small When, stop reaction, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2- chloropyridine -4- bases) ammonia Base) -2- (2- fluorophenyls) acrylate (7.1g).
The preparation of the chloro- 3- of 5- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (2- fluorophenyls) acrylate is added into reaction bulb (7.1g, 1eq), diphenyl ether (50mL) mixing is warming up to 200 DEG C with after and reacted 1 hour, stops reaction, is cooled to 50-60 DEG C Under pour into 500mL petroleum ethers, filtering separate out solid, solid chromatography post separation after obtain the chloro- 3- of 5- (2- fluorophenyls) -1,6- naphthalenes Pyridine -4 (1H) -one (900mg).
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) amino) -3- (2- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
The chloro- 3- of 5- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (30mg, 1eq), 4- ((6,7- are added into reaction bulb Dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines (35mg, 1eq), concentrated hydrochloric acid (1 drop), electromagnetism after isopropanol (20mL) mixing Stirring, is warming up to 60 DEG C and reacts 4 hours, separates out faint yellow solid, filtering, and filter cake is obtained after being dried in vacuo after being washed with isopropanol 5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) amino) -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (25mg).MS：[M+H]+=554.2.
1H-NMR (400M, DMSO-d6) δ 13.13 (s, 1H), 12.69 (s, 1H), 8.60 (s, 1H), 8.19-8.21 (m, 2H), 8.13-8.15 (m, 1H), 7.59 (s, 1H), 7.42-7.49 (m, 5H), 7.26-7.31 (m, 2H), 6.92-6.93 (d, 1H), 4.01 (s, 6H) ppm.
Embodiment 42：The preparation of compound 42
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) amino) -3- (3- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 40- The synthesis of 3- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine Pyridine -2- amino is changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 5 hours.MS：[M +H]+=554.2, [M-H]+=552.1.
1H-NMR (400M, DMSO-d6) δ 13.29 (s, 1H), 13.01 (s, 1H), 8.45 (s, 1H), 8.35-8.36 (m, 1H), 8.09-8.14 (m, 2H), 7.60-7.63 (m, 2H), 7.56 (s, 1H), 7.51-7.52 (m, 3H), 7.45 (s, 1H), (s, the 6H) ppm of 7.19-7.24 (m, 1H), 7.00-7.01 (d, 1H), 4.01.
Embodiment 43：The preparation of compound 43
5- ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) phenyl) amino) -3- (3- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino -3- in preparation method be the same as Example 40 The synthesis of (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline.MS：[M+H]+=500.2, [M-H]+= 498.1.
1H-NMR (400M, DMSO-d6) δ 13.30 (s, 1H), 13.07 (s, 1H), 8.76 (s, 1H), 8.53-8.54 (d, 1H), 8.34-8.35 (d, 1H), 8.13-8.16 (d, 1H), 8.07-8.08 (m, 1H), 7.72-7.74 (d, 1H), 7.46-7.61 (m, 5H), 7.19-7.23 (m, 1H), 7.00-7.02 (d, 1H) ppm.
Embodiment 44：The preparation of compound 44
The preparation of the fluoro- 4- of 3- ((7- methoxyl groups -6- (2- morpholines ethyoxyl) quinazoline -4- bases) epoxide) aniline
4- (4- amino -2- fluorophenoxies) -7- methoxyquinazoline hydrochloride -6- alcohol (200mg, 1eq), 4- are added into reaction bulb (2- chloroethyls) morpholine (298mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((7- methoxyl groups -6- (2- morpholines ethyoxyl) quinazoline -4- bases) epoxide) benzene Amine 136mg.
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (2- morpholines ethyoxyl) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (2- morpholines ethyoxyl) quinazoline -4- bases) oxygen) aniline, and the reaction time is 6 hours.MS：[M-H]+=650.8.
1H-NMR (400M, DMSO-d6) δ 13.35 (s, 1H), 13.08 (s, 1H), 11.56 (s, 1H), 8.67 (s, 1H), 8.27-8.29 (d, 1H), 8.14-8.17 (d, 1H), 8.08-8.09 (d, 1H), 7.74-7.77 (m, 3H), 7.50-7.53 (m, 2H), 7.27-7.32 (t, 2H), 7.01-7.03 (d, 1H), 4.71-4.73 (m, 2H), 4.39 (s, 3H), 3.89-3.99 (m, 4H), 3.26-3.31 (m, 6H) ppm.
Embodiment 45：The preparation of compound 45
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (2- fluorophenyls) -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) benzene oxygen Base) -2- acid amides pyridines preparation
The chloro- 4- of 3- (the fluoro- 4- of 2- ((3- phenyl -4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- in preparation method be the same as Example 2 Base) amino) phenoxy group) and -2- acid amides pyridines synthesis, difference is chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one of 5- The chloro- 3- of 5- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one is changed to, the reaction time is 3 hours.
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) chloro- 3- of -8- (2- fluorophenyls) -1, The preparation of 6- naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 2 The synthesis of phenyl -1,6- naphthyridines -4 (1H) -one, difference is the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- phenyl -4- oxygen-Isosorbide-5-Nitraes - Dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) and -2- acid amides pyridines be changed to the chloro- 4- of 3- (the fluoro- 4- of 2- ((3- (2- fluorophenyls) - 4- oxygen-Isosorbide-5-Nitrae-dihydro -1,6- naphthyridines -5- bases) amino) phenoxy group) -2- acid amides pyridines, the reaction time is 2 hours.MS：[M+H]+ =526.1.
1H-NMR (400M, DMSO-d6) δ 13.02 (s, 1H), 12.18 (s, 1H), 8.37 (s, 1H), 8.23-8.27 (dd, 1H), 8.01 (s, 1H), 7.75-7.76 (d, 1H), 7.45-7.53 (m, 3H), 7.27-7.32 (m, 3H), 6.39 (s, 2H), (5.94-5.95 d, 1H) ppm.
Embodiment 46：The preparation of compound 46
5- ((2- chloropyridine -4- bases) amino) methyl) -2,2- dimethyl-1,3-dioxane -4,6- diketone preparation
The chloro- 4-aminopyridines of 2- (5.0g, 1eq), 2,2- dimethyl-1,3-dioxanes -4,6- are added into reaction bulb Diketone (5.6g, 1eq), triethyl orthoformate (50mL) electromagnetic agitation is warming up to 150 DEG C and reacted 3 hours, now reacts after mixing Liquid is in kermesinus, is cooled to and filters out solid at room temperature, solid petroleum ether is dried in vacuo to obtain 5- ((2- chloropyridines -4- Base) amino) methyl) -2,2- dimethyl-1,3-dioxanes -4,6- diketone (6.7g).
The preparation of chloro- 1,6- naphthyridines -4 (1H) -one of 5-
5- ((2- chloropyridine -4- bases) amino) methyl is added into reaction bulb) -2,2- dimethyl-1,3-dioxane -4, 6- diketone (5.0g, 1eq), diphenyl ether (40mL) electromagnetic agitation is warming up to 220 DEG C and reacted 30 minutes after mixing, now reaction solution In furvous, reaction solution is cooled to be poured into 300mL petroleum ethers at room temperature, and stirring separates out solid, filters out solid, solid silicone Column chromatography obtains chloro- 1,6- naphthyridines -4 (1H) -one (0.4g) of 5-.
5- (the systems of (4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino -1,6- naphthyridines -4 (1H) -one It is standby
Addition chloro- 1,6- naphthyridines -4 (1H) -one (50mg, 1eq) of 5- into reaction bulb, 4- ((6,7- dimethoxy-quinolines - 4- yls) oxygen) -3- fluoroanilines (44mg, 1eq), concentrated hydrochloric acid (1 drop), electromagnetic agitation after isopropanol (35mL) is mixed is warming up to 50 DEG C Reaction 4 hours, filters out insoluble matter, and filter cake obtains 5- ((4- ((6,7- dimethoxy quinolines after being dried in vacuo after being washed with isopropanol Quinoline -4- bases) oxygen) -3- fluorophenyls) amino -1,6- naphthyridines -4 (1H) -one (15mg).MS：[M+H]+=459.1, [M-H]+= 457.0.
1H-NMR (400M, DMSO-d6) δ 13.43 (s, 1H), 12.78 (s, 1H), 8.50-8.52 (d, 1H), 8.41-8.44 (d, 1H), 8.14-8.16 (d, 1H), 8.03-8.06 (m, 1H), 7.76-7.81 (t, 1H), 7.64-7.67 (d, 2H), 6.97- (s, the 3H) ppm of 7.03 (m, 2H), 6.65 (s, 1H), 6.34-6.36 (d, 1H), 3.96 (s, 3H), 3.78.
Embodiment 47：The preparation of compound 47
5- be ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -1,6- naphthyridines -4 (1H) -one Prepare
5- in preparation method be the same as Example 46 ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino - The synthesis of 1,6- naphthyridines -4 (1H) -one, difference is 4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines It is changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines.MS：[M-H]+=458.1.
1H-NMR (400M, DMSO-d6) δ 13.21 (s, 1H), 12.58-12.59 (m, 1H), 8.61-8.63 (d, 1H), 8.15-8.17 (d, 1H), 8.04-8.08 (m, 2H), 7.61 (s, 1H), 7.45-7.52 (m, 3H), 6.91-6.93 (d, 1H), 6.35-6.36 (d, 1H), 4.01 (s, 6H) ppm.
Embodiment 48：The preparation of compound 48
The preparation of the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- morpholines ethyoxyl) quinazoline -4- bases) epoxide) aniline
4- (4- amino -2- fluorophenoxies) -6- methoxyquinazoline hydrochloride -7- alcohol (200mg, 1eq), 4- are added into reaction bulb (2- chloroethyls) morpholine (298mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL), are heated to 80 DEG C and react 2 hours, stop Only react, filter, be concentrated to give the fluoro- 4- of crude product 3- ((6- methoxyl groups -7- (2- morpholines ethyoxyl) quinazoline -4- bases) epoxide) benzene Amine 120mg.
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- morpholines ethyoxyl) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (2- morpholines ethyoxyl) quinazoline -4- bases) oxygen) aniline, and the reaction time is 7 hours.MS：[M+H]+=653.3, [M-H]+=650.8.
1H-NMR (400M, DMSO-d6) δ 13.35 (s, 1H), 13.09 (s, 1H), 11.56 (s, 1H), 8.66 (s, 1H), 8.27-8.28 (d, 1H), 8.18-8.22 (d, 1H), 8.07-8.09 (d, 1H), 7.73-7.77 (m, 2H), 7.66 (s, 1H), 7.52-7.56 (m, 2H), 7.27-7.31 (t, 2H), 7.02-7.03 (d, 1H), 4.73-4.76 (m, 2H), 4.00 (m, 5H), 3.59-3.71 (m, 6H), 3.27-3.30 (m, 2H) ppm.
Embodiment 49：The preparation of compound 49
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Anisyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 36- The synthesis of 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- Chloropyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) epoxide) aniline.MS： [M+H]+=679.3.
1H-NMR (400M, DMSO-d6) δ 13.38 (s, 1H), 12.79 (s, 1H), 10.66 (s, 1H), 8.62 (s, 1H), 8.18-8.19 (d, 2H), 8.07-8.08 (d, 1H), 7.63-7.65 (m, 3H), 7.46-7.50 (m, 2H), 7.00-7.02 (d, 2H), 6.94-6.96 (d, 1H), 4.34 (s, 2H), 4.31-4.33 (s, 6H), 3.49-3.52 (m, 3H), 3.28-3.33 (m, 3H), 3.10-3.15 (m, 2H), 2.29-2.32 (m, 2H), 1.03-1.05 (m, 2H) ppm.
Embodiment 50：The preparation of compound 50
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (4- Anisyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 36- The synthesis of 3- (4- anisyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- Chloropyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) epoxide) aniline.MS： [M+2H]+=680.4
1H-NMR (400M, DMSO-d6) δ 13.38 (s, 1H), 12.79 (s, 1H), 8.57 (s, 1H), 8.31-8.35 (m, 1H), 8.16-8.17 (d, 1H), 8.11 (s, 1H), 7.62-7.64 (d, 2H), 7.59 (s, 1H), 7.48-7.50 (d, 1H), 7.38-7.42 (m, 2H), 6.99-7.01 (d, 2H), 6.89-6.90 (d, 1H), 4.26-4.27 (m, 2H), 3.99-4.00 (m, 3H), 3.80-3.81 (m, 3H), 3.60-3.61 (m, 4H), 2.50 (s, 6H), 1.08-1.23 (m, 2H) ppm.
Embodiment 51：The preparation of compound 51
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -1,6- The preparation of naphthyridines -4 (1H) -one
Added into 100mL round-bottomed flask 3- fluoro- 4- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline - 4- yls) oxygen) aniline (427mg, 1.0eq), chloro- 1,6- naphthyridines -4 (1H) -one (186mg, 1eq) of 5-, isopropanol 100mL, dense salt Sour 0.1mL, is heated to 60 DEG C and reacts 6 hours, stop reaction, filter out solid, solid is washed with 30mL isopropanol 5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) ammonia of weighing to obtain is dried in vacuo afterwards Base)-(1H) -one of 1,6- naphthyridines -4 318mg.MS：[M+H]+=572.2.
1H-NMR (400M, DMSO-d6) δ 13.17 (s, 1H), 12.60 (s, 1H), 10.82 (s, 1H), 8.62 (s, 1H), 8.16-8.19 (d, 1H), 8.08 (s, 1H), 8.01-8.03 (d, 1H), 7.46-7.48 (d, 1H), 6.89-6.91 (d, 1H), 6.31-6.33 (s, 1H), 4.30-4.34 (t, 2H), 4.02 (s, 3H), 3.97-4.01 (m, 3H), 3.75-3.78 (t, 2H), 3.20-3.33 (m, 3H), 3.09-3.02 (m, 2H), 2.28-2.32 (m, 2H).
Embodiment 52：The preparation of compound 52
The chloro- 3- of 5- (4- fluorophenyls) -1- methyl isophthalic acids, the preparation of 6- naphthyridines -4 (1H) -one
The chloro- 3- of 5- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one is added into 50mL round-bottomed flask at room temperature (274mg, 1eq), DMF (25mL), iodomethane (284mg, 2eq), potassium carbonate (414mg, 3eq), stirring Heat up the lower reaction of 70 DEG C of nitrogen protections 2 hours after 5min, and point plate reaction is complete, stops reaction, and decompression removes DMF, added water (20mL), stirring separates out solid, and suction filtration is dried, and crude product silica gel column chromatography obtains the chloro- 3- of 5- (4- fluorophenyls) -1- methyl isophthalic acids, 6- Naphthyridines -4 (1H) -one (178.3mg).
5- ((5- ((6,7- dimethoxyquinazoline -4- bases) oxygen) pyridine -2- bases) amino) -3- (4- fluorophenyls) -1- first The preparation of base -1,6- naphthyridines -4 (1H) -one
Addition 5- chloro- 3- (4- fluorophenyls) -1- methyl isophthalic acids into reaction bulb, 6- naphthyridines -4 (1H) -one (144mg, 1.0eq), 5- ((6,7- dimethoxyquinazoline -4- bases) oxygen) pyridine -2- amine (150mg, 1.0eq), three (dibenzalacetones) Two palladiums (57.9mg, 0.2eq), 1,2- double (diphenylphosphine) propane (91.5mg, 0.2eq), sodium tert-butoxide (12.74mg, 1.3eq) With Isosorbide-5-Nitrae-dioxane (100mL), inflated with nitrogen being taken out three times, being reacted 8 hours in 90 DEG C, point plate reaction is complete, is cooled to room temperature, takes out Filter, concentration, crude product silica gel column chromatography (to 3.5/1 of PE/EA 6/1) obtains 5- ((5- ((6,7- dimethoxyquinazoline -4- Base) oxygen) pyridine -2- bases) amino) -3- (4- fluorophenyls) -1- methyl isophthalic acids, (1H) -one of 6- naphthyridines -4 84mg.MS：[M+H]+= 550.1.
1H-NMR (400M, DMSO-d6) δ 13.62 (s, 1H), 8.79-8.81 (d, 1H), 8.57 (s, 1H), 8.33-8.35 (m, 3H), 7.83-7.86 (dd, 1H), 7.73-7.76 (t, 2H), 7.60 (s, 1H), 7.40 (s, 1H), 7.25-7.30 (t, 2H), 7.02-7.03 (d, 1H).
Embodiment 53：The preparation of compound 53
5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) 3- fluorophenyls) amino) -3- (3- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 40- The synthesis of 3- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine Pyridine -2- amino is changed to 4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 4 hours.MS：[M+ H]+=553.2.
1H-NMR (400M, DMSO-d6) δ 13.47 (s, 1H), 12.98 (s, 1H), 8.46-8.50 (m, 2H), 8.33-8.35 (d, 1H), 8.20-8.22 (d, 1H), 7.71-7.77 (m, 2H), 7.69 (s, 1H), 7.63-7.66 (m, 1H), 7.55-7.57 (m, 1H), 7.46-7.52 (m, 1H), 7.17-7.22 (m, 1H), 7.04-7.05 (d, 1H), 6.89-6.91 (d, 1H), 6.60 (s, 1H), 3.75 (s, 6H) ppm.
Embodiment 54：The preparation of compound 54
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (3- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 40- The synthesis of 3- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine Pyridine -2- amino is changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline, reaction time For 7 hours.MS：[M+H]+=667.2.
1H-NMR (400M, DMSO-d6) δ 13.29 (s, 1H), 13.05 (s, 1H), 10.91 (s, 1H), 8.67 (s, 1H), 8.35-8.36 (d, 1H), 8.18-8.22 (d, 1H), 8.12-8.14 (d, 1H), 7.63-7.67 (m, 6H), 7.22-7.24 (m, 1H), 7.02-7.03 (m, 1H), 4.36-4.38 (m, 2H), 4.00-4.05 (m, 6H), 3.52-3.55 (m, 2H), 3.32 (s, 3H), 3.12-3.15 (m, 2H), 2.34-2.36 (m, 2H) ppm.
Embodiment 55：The preparation of compound 55
5- ((the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (3- Fluorophenyl) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((2- amino-3- chloropyridine-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 40- The synthesis of 3- (3- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine Pyridine -2- amino is changed to the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) aniline, reaction time For 7 hours.MS：[M+H]+=667.2.
1H-NMR (400M, DMSO-d6) δ 13.27 (s, 1H), 13.07 (s, 1H), 11.04 (s, 1H), 8.64 (s, 1H), 8.33-8.34 (d, 1H), 8.14-8.18 (d, 1H), 8.09-8.10 (d, 1H), 7.46-7.63 (m, 6H), 7.18-7.23 (m, 1H), 7.00-7.02 (d, 1H), 4.35-4.36 (m, 2H), 3.98-4.02 (m, 6H), 3.81 (s, 3H), 3.28-3.32 (m, 2H), 3.08-3.16 (m, 2H), 2.34-2.38 (m, 2H) ppm.
Embodiment 56：The preparation of compound 56
5- ((5- ((6,7- dimethoxyquinazoline -4- bases) oxygen) pyridine -2- bases) amino) -3- (4- fluorophenyls) -1,6- The preparation of naphthyridines -4 (1H) -one
5- ((4- ((2- amino -3- chloropyridine -4- bases) oxygen) -3- fluorophenyls) amino) -3- in preparation method be the same as Example 4 The synthesis of (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- (4- amino -2- fluorophenoxies) -3- chlorine pyrroles Pyridine -2- amino is changed to 5- ((6,7- dimethoxyquinazoline -4- bases) oxygen)-PA, and the reaction time is 4 hours.MS：[M +H]+=537.2.
1H-NMR (400M, DMSO-d6) δ 13.37 (s, 1H), 12.91 (s, 1H), 8..80-8.01 (d, 1H), 8.58 (s, 1H), 8.32-8.33 (m, 1H), 8.21-8.23 (d, 1H), 8.18-8.19 (m, 1H), 7.83-7.85 (m, 1H), 7.73-7.77 (m, 2H), 7.61 (s, 1H), 7.41 (s, 1H), 7.24-7.28 (m, 2H), 7.02-7.04 (d, 1H), 3.99 (s, 6H) ppm.
Embodiment 57：The preparation of compound 57
(E) preparation of-ethyl -3- hydroxyl -2- thiophene acrylate
The synthesis of (Z)-ethyl -3- hydroxyl -2- bezene acrylic acids in preparation method be the same as Example 1, difference be by Ethyl phenylacetate is changed to thiophene acetic acid ethyl ester, and the reaction time is 16 hours.
(E) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- thiophene acrylate
The synthesis of (Z)-ethyl -3- hydroxyl -2- acrylate in preparation method be the same as Example 1, difference is benzene Ethyl acetate is changed to thiophene acetic acid ethyl ester, and the reaction time is 9 hours.
The preparation of the chloro- 3- of 5- (thiophene -2- bases) -1,6- naphthyridines -4 (1H) -one
The synthesis of (Z)-ethyl -3- hydroxyl -2- acrylate in preparation method be the same as Example 1, difference is benzene Ethyl acetate is changed to thiophene acetic acid ethyl ester, and reaction temperature is 180 DEG C, and the reaction time is 2 hours.
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- (thiophene -2- bases) -1,6- The preparation of naphthyridines -4 (1H) -one
5- in preparation method be the same as Example 1 ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino - The synthesis of 3- phenyl -1,6- naphthyridines -4 (1H) -one, difference is to change chloro- 3- phenyl -1,6- naphthyridines -4 (1H) -one of 5- For the chloro- 3- of 5- (thiophene -2- bases) -1,6- naphthyridines -4 (1H) -one, the reaction time is 4 hours.MS：[M+H]+=542.9.
1H-NMR (400M, DMSO-d6) δ 13.28 (s, 1H), 13.10 (s, 1H), 8.81-8.82 (d, 1H), 8.67 (s, 1H), 8.11-8.14 (d, 1H), 8.04-8.05 (d, 1H), 7.79-7.80 (m, 1H), 7.62 (s, 1H), 7.52-7.60 (m, 3H), (s, the 6H) ppm of 7.45 (s, 1H), 7.16-7.18 (m, 1H), 7.05-7.06 (d, 1H), 4.02.
Embodiment 58：The preparation of compound 58
5- ((the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) phenyl) amino) -3- (thiophenes Fen -2- bases) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) ammonia in preparation method be the same as Example 57 The synthesis of base -3- (thiophene -2- bases) -1,6- naphthyridines -4 (1H) -one, difference is 4- ((6,7- dimethoxy quinoline azoles Quinoline -4- bases) oxygen) -3- fluoroanilines are changed to the fluoro- 4- of 3- ((7- methoxyl groups -6- (3- morpholines propoxyl group) quinazoline -4- bases) oxygen) benzene Amine, the reaction time is 3 hours.MS：[M+H]+=667.3.
1H-NMR (400M, DMSO-d6) δ 13.26 (s, 1H), 13.14 (s, 1H), 10.83 (s, 1H), 8.80 (s, 1H), 8.79 (s, 1H), 8.17-8.20 (d, 1H), 8.07-8.09 (d, 1H), 7.78-7.79 (d, 1H), 7.54-7.57 (m, 3H), 7.48 (s, 1H), 7.16-7.17 (t, 1H), 7.05-7.06 (d, 1H), 4.34 (m, 2H), 4.03 (s, 3H), 3.98 (m, 2H), 3.79-3.85 (m, 2H), 3.14-3.16 (m, 2H), 2.12-2.14 (m, 2H), 3.09-3.11 (m, 2H), 2.33 (m, 2H) ppm。
Embodiment 59：The preparation of compound 59
5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (2- fluorophenyls) -1,6- naphthalenes The preparation of pyridine -4 (1H) -one
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) ammonia in preparation method be the same as Example 41 Base) -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is 4- ((6,7- dimethoxy quinoline azoles Quinoline -4- bases) oxygen) -3- fluoroanilines are changed to 4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 5 small When.MS：[M+H]+=553.2.
1H-NMR (400M, DMSO-d6) δ 13.31 (s, 1H), 12.54 (s, 1H), 8.46-8.50 (dd, 1H), 8.25- 8.27 (d, 1H), 8.19 (s, 1H), 7.86-7.88 (d, 1H), 7.58-7.63 (m, 3H), 7.47-7.49 (m, 2H), 7.26- 7.31 (m, 2H), 6.94-6.95 (d, 1H), 6.33 (s, 1H), 6.11-6.12 (d, 1H), 3.86 (s, 3H), 3.63 (s, 3H) ppm。
Embodiment 60：The preparation of compound 60
5- ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) phenyl) amino) -3- (2- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) ammonia in preparation method be the same as Example 41 Base) -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is 4- ((6,7- dimethoxy quinoline azoles Quinoline -4- bases) oxygen) -3- fluoroanilines are changed to the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline, and the reaction time is 45 minutes. MS：[M+H]+=500.1.
1H-NMR (400M, DMSO-d6) δ 13.13 (s, 1H), 12.68 (s, 1H), 8.74 (s, 1H), 8.52-8.53 (d, 1H), 8.19-8.25 (m, 2H), 8.14-8.16 (d, 1H), 7.71-7.72 (d, 1H), 7.44-7.51 (m, 4H), 7.27-7.31 (m, 2H), 6.92-6.93 (d, 1H) ppm.
Embodiment 61：The preparation of compound 61
(Z)-ethyl -3- hydroxyls -2- (4- trifluoromethyls) preparation of acrylate
Addition 2- (4- trifluoromethyls) ethyl acetate (10.0g, 1eq) into reaction bulb, Ethyl formate (35mL, 10eq), under condition of ice bath, sodium hydride (12.8g, 10eq) is slowly added to, is reacted 18 hours, point plate reaction terminates, and stops reaction, Suitable quantity of water is added, pH is to acidity for regulation, is extracted with ethyl acetate, and merges organic phase, and anhydrous sodium sulfate drying, vacuum distillation is obtained Grease (Z)-ethyl -3- hydroxyls -2- (4- trifluoromethyls) acrylate (11.0g).
(Z) preparation of-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- trifluoromethyls) acrylate
(Z)-ethyl -3- hydroxyls -2- (4- trifluoromethyls) acrylate (11.0g, 1eq) is added into reaction bulb, The chloro- 4-aminopyridines of 2- (5.5g, 1eq), ethanol (200mL), concentrated hydrochloric acid (0.3mL) is well mixed and is warming up to 70 DEG C of reactions 5 Hour, stop reaction, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2- chloropyridine -4- bases) ammonia Base) -2- (4- trifluoromethyls) acrylate (6.5g).
The preparation of the chloro- 3- of 5- (4- trifluoromethyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2- chloropyridine -4- bases) amino) -2- (4- trifluoromethyls) propylene is added into reaction bulb Acid esters (6.5g, 1eq), diphenyl ether (50mL) mixing is warming up to 220 DEG C of reaction half an hour with after, stops reaction, is cooled to 50- Poured at 60 DEG C in 500mL petroleum ethers, filtering obtains 5- chloro- 3- (4- trifluoromethylbenzenes after separating out solid, solid chromatography post separation Base) -1,6- naphthyridines -4 (1H) -one (1.0g).
5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- trifluoromethyls) - The preparation of 1,6- naphthyridines -4 (1H) -one
The chloro- 3- of 5- (4- trifluoromethyls) -1,6- naphthyridines -4 (1H) -one (68mg, 1eq), 4- are added into reaction bulb ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluoroanilines (40mg, 1eq), concentrated hydrochloric acid (1 drop), after isopropanol (20mL) mixing Electromagnetic agitation, is warming up to 60 DEG C and reacts 3 hours, faint yellow solid, filtering is separated out, after filter cake is dried in vacuo after being washed with isopropanol Obtain 5- ((4- ((6,7- dimethoxy-quinoline -4- bases) oxygen) -3- fluorophenyls) amino) -3- (4- trifluoromethyls) -1,6- Naphthyridines -4 (1H) -one (25mg).MS：[M-H]+=603.3.
1H-NMR (400M, DMSO-d6) δ 13.37 (s, 1H), 12.73-12.75 (d, 1H), 8.50-8.53 (d, 1H), 8.35-8.36 (d, 1H), 8.25-8.27 (d, 1H), 8.11-8.13 (d, 1H), 7.93--7.95 (dd, 2H), 7.79-7.81 (dd, 2H), 7.65-7.66 (m, 2H), 7.61 (s, 1H), 6.98-6.99 (s, 1H), 6.40-6.43 (m, 2H), 3.90 (s, 3H), 3.68 (s, 3H) ppm.
Embodiment 62：The preparation of compound 62
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluorophenyls) amino -3- (4- trifluoromethyls) - The preparation of 1,6- naphthyridines -4 (1H) -one
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) ammonia in preparation method be the same as Example 61 Base) -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference be by 4- ((6,7- dimethoxy-quinolines - 4- yls) oxygen) -3- fluoroanilines are changed to 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines, and the reaction time is 4 small When.MS：[M+H]+=604.2.
1H-NMR (400M, DMSO-d6) δ 13.18 (s, 1H), 12.84 (s, 1H), 8.18 (s, 1H), 8.35-8.37 (d, 1H), 8.21-8.24 (d, 1H), 8.14-8.16 (d, 1H), 7.94-7.96 (dd, 2H), 7.80-7.82 (dd, 2H), 7.60 (s, 1H), (s, the 3H) ppm of 7.45-7.51 (m, 2H), 7.429 (s, 1H), 6.94-6.96 (s, 1H), 3.99 (s, 3H), 4.01.
Embodiment 63：The preparation of compound 63
5- ((the fluoro- 4- of 3- (thiophene [2,3-d] pyrimidine-4-yl oxygen) phenyl) amino) -3- (4- trifluoromethyls) -1,6- The preparation of naphthyridines -4 (1H) -one
5- ((4- ((6,7- dimethoxy-quinoline-4- bases) oxygen)-3- fluorophenyls) amino) in preparation method be the same as Example 61- The synthesis of 3- (4- trifluoromethyls) -1,6- naphthyridines -4 (1H) -one, difference is 4- ((6,7- dimethoxy quinolines Quinoline -4- bases) oxygen) -3- fluoroanilines are changed to the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline, and the reaction time is 45 Minute.MS：[M+H]+=550.1.
1H-NMR (400M, DMSO-d6) δ 13.16 (s, 1H), 12.71 (s, 1H), 8.76 (s, 1H), 8.53-8.54 (d, 1H), 8.35-8.36 (d, 1H), 8.28-8.31 (m, 2H), 8.19-8.20 (d, 1H), 7.95-7.97 (dd, 2H), 7.80- 7.82 (dd, 2H), 7.50-7.51 (m, 2H), 6.93-6.94 (d, 1H) ppm.
Embodiment 64：The preparation of compound 64
The preparation of 5- ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine -4- oxygen) phenyl) amino) -1,6- naphthyridines -4 (1H) -one
Into 100mL round-bottomed flask add add 3- fluoro- 4- (thiophene [3,2-d] pyrimidine-4-yl oxygen) aniline (261mg, 1.0eq), chloro- 1,6- naphthyridines -4 (1H) -one (186mg, 1eq) of 5-, isopropanol 100mL, concentrated hydrochloric acid 0.1mL, are heated to 60 DEG C are reacted 4 hours, stop reaction, filter out solid, and solid is dried in vacuo the 5- that weighs to obtain after being washed with 30mL isopropanol ((the fluoro- 4- of 3- (thiophene [3,2-d] pyrimidine -4- oxygen) phenyl) amino)-(1H) -one of 1,6- naphthyridines -4 221mg.MS：[M+H]+= 406.1.
1H-NMR (400M, DMSO-d6) δ 13.27 (s, 1H), 12.76 (s, 1H), 8.76 (s, 1H), 8.54-8.55 (d, 1H), 8.02-8.12 (m, 3H), 7.73-7.74 (d, 1H), 7.57-7.61 (t, 1H), 7.45-7.48 (dd, 1H), 6.95- 6.96 (d, 1H), 6.37-6.39 (d, 1H) ppm.
Embodiment 65：The preparation of compound 65
5- ((the fluoro- 4- of 3- ((7- methoxy quinoline -4- bases) oxygen) phenyl) amino -3- (2- fluorophenyls) -1,6- naphthyridines -4 The preparation of (1H) -one
Chloro- 2- fluorophenyls -1,6- naphthyridines -4 (1H) -one (36.2mg, 1eq) of 5-, 4- ((7- methoxies are added into reaction bulb Base quinolyl-4) oxygen) -3- fluoroanilines (37.5mg, 1eq), concentrated hydrochloric acid (1 drop), electromagnetic agitation after isopropanol (20mL) mixing, It is warming up to 60 DEG C to react 3 hours, filters out insoluble matter, filter cake obtains 5- ((the fluoro- 4- of 3- after being dried in vacuo after being washed with isopropanol ((7- methoxy quinoline -4- bases) oxygen) phenyl) amino -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one (21mg).MS：[M+ H]+=523.2.
1H-NMR (400M, DMSO-d6) δ 13.21 (s, 1H), 12.73 (s, 1H), 8.98-9.00 (d, 1H), 8.52-8.55 (d, 1H), 8.42-8.46 (d, 1H), 8.19-8.21 (d, 1H), 7.58-7.64 (m, 4H), 7.47-7.49 (m, 2H), 7.27- (s, the 3H) ppm of 7.31 (m, 2H), 7.06-7.08 (d, 1H), 6.96-6.97 (d, 1H), 7.02-7.04 (d, 1H), 4.04.
Embodiment 66：The preparation of compound 66
5- ((4- ((6,7- bis- (2- methoxy ethoxies) quinazoline -4- bases) oxygen) 3- fluorophenyls) amino) -3- (2- fluorobenzene Base) -1,6- naphthyridines -4 (1H) -one preparation
5- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) 3- fluorophenyls) ammonia in preparation method be the same as Example 41 Base) -3- (2- fluorophenyls) -1,6- naphthyridines -4 (1H) -one synthesis, difference is 4- ((6,7- dimethoxy quinoline azoles Quinoline -4- bases) oxygen) -3- fluoroanilines are changed to 4- ((6,7- bis- (2- methoxy ethoxies) quinazoline -4- bases) oxygen) -3- fluoroanilines, instead It is 7 hours between seasonable.MS：[M+H]+=642.3.
1H-NMR (400M, DMSO-d6) δ 1311 (s, 1H), 12.65 (s, 1H), 8.59 (s, 1H), 8.19-8.20 (m, 2H), 8.15-8.16 (m, 1H), 7.63 (d, 1H), 7.45-7.49 (m, 5H), 7.26-7.30 (m, 2H), 6.91-6.93 (d, 1H), (s, the 6H) ppm of 4.32-4.38 (m, 4H), 3.76-3.77 (m, 4H), 3.23.
Embodiment 67：The preparation of compound 67
(Z) preparation of-ethyl -3- ((2,6- dichloropyridine -4- bases) amino) -2- (4- fluorophenyls) acrylate
(Z)-ethyl -2- (4- fluorophenyls)-acrolactic acid ester (15g, 1eq) is added into reaction bulb, 2,6- bis- is chloro- 4-aminopyridine (11.6g, 1eq), ethanol (250mL), concentrated hydrochloric acid (0.5mL) is well mixed and to be warming up to 80 DEG C of reactions 5 small When, stop reaction, ethanol is removed under reduced pressure, residue column chromatography for separation obtains (Z)-ethyl -3- ((2,6- dichloropyridine -4- bases) Amino) -2- (4- fluorophenyls) acrylate (22.8g).
The preparation of 5,7- bis- chloro- 3- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one
(Z)-ethyl -3- ((2,6- dichloropyridine -4- bases) amino) -2- (4- fluorophenyls) acrylic acid is added into reaction bulb Ester (10g, 1eq), diphenyl ether (80mL) mixing is warming up to 250 DEG C of reaction half an hour with after, stops reaction, is cooled to 50-60 Poured at DEG C in 500mL petroleum ethers, chloro- 3- (the 4- fluorobenzene of 5,7- bis- is obtained after filtering the solid separated out, solid chromatography post separation Base) -1,6- naphthyridines -4 (1H) -one (2.35g).
5,7- bis- chloro- 3- (4- fluorophenyls) -1- methyl isophthalic acids, the preparation of 6- naphthyridines -4 (1H) -one
The chloro- 3- of 5,7- bis- (4- fluorophenyls) -1,6- naphthyridines -4 (1H) -one is added into 50mL round-bottomed flask at room temperature (307mg, 1eq), DMF (25mL), iodomethane (284mg, 2eq), potassium carbonate (414mg, 3eqL), stirring Heat up the lower reaction of 70 DEG C of nitrogen protections 2 hours after 5min, and point plate reaction is complete, stops reaction, and decompression removes DMF, added water (20mL), stirring separate out solid, suction filtration, dry, crude product silica gel column chromatography obtain 5,7- bis- chloro- 3- (4- fluorophenyls) -1- methyl - 1,6- naphthyridines -4 (1H) -one (330mg).
The chloro- 5- of 7- ((4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines) -3- (4- fluorophenyls) -1- first Base -1,6- naphthyridines -4 (1H) -one
Add 5,7- bis- chloro- 3- (4- fluorophenyls) -1- methyl isophthalic acids into reaction bulb, 6- naphthyridines -4 (1H) -one (322mg, 1.0eq), 4- ((6,7- dimethoxyquinazoline -4- bases) oxygen) -3- fluoroanilines (315mg, 1.0eq), three (dibenzalacetones) Two palladiums (57.9mg, 0.2eq), 1,2- double (diphenylphosphine) propane (91.5mg, 0.2eq), sodium tert-butoxide (12.74mg, 1.3eq) With Isosorbide-5-Nitrae-dioxane (100mL), inflated with nitrogen being taken out three times, being reacted 8 hours in 80 DEG C, point plate reaction is complete, is cooled to room temperature, takes out Filter, concentration, crude product silica gel column chromatography (PE/EA 6/1to 3.5/1) obtain the chloro- 5- of 7- ((4- ((6,7- dimethoxyquinazolines- 4- yls) oxygen) -3- fluoroanilines) -3- (4- fluorophenyls) -1- methyl isophthalic acids, (1H) -one of 6- naphthyridines -4 221mg.MS：[M+H]+= 602.2.
1H-NMR (400M, DMSO-d6) δ 13.54 (s, 1H), 8.59 (s, 1H), 8.33 (s, 1H), 8.14-8.17 (d, 1H), 7.72-7.75 (m, 2H), 7.60 (s, 1H), 7.42-7.52 (m, 3H), 7.27-7.31 (t, 2H), 7.06 (s, 6H), 3.87 (s, 3H) ppm.
Embodiment 68：External biochemistry level suppresses protein kinase (PK) activity experiment
Materials and methods：C-Met, Flt-3, VEGFR-2, PDGFR- β and c-Kit kinases, from Invitrogen； HTRF KinEASE；TK kit (Cisbio companies)；384 orifice plates (Greiner companies)；ATP (sigma companies), MgCl2 (sigma) company；PHERAstar FS multi-function microplate readers (BMG companies)；Low speed centrifuge (StaiteXiangyi companies)； Insulating box (Binder companies).The positive drug of selection is BMS777607, and structure is as follows：
Compound dissolves and preserved：Test-compound is configured to 0.5-10mmol/L mother liquor depending on dissolubility with DMSO, - 20 DEG C of preservations after packing；
The preparation of compound working solutions：The compound of packing is taken out from refrigerator before test, it is diluted to 50 with pure DMSO × Required concentration；Then with deionized water by diluted chemical compound to 4 × required concentration；
1.33 × Enzymatic buffer preparation：5 × Enzymatic buffer are derived from into HTRF kit) spend Ionized water is diluted to 1.33 ×, and add the corresponding composition of 1.33 × final concentration：1.33mmol/LDTT and 1.33mmol/ LMgCl2；
The preparation of kinases working solution：Met is diluted to 2 with 1.33 × Enzymatic buffer × required final concentration 0.2ng/μL；
The preparation of substrate working solution：Substrate-biotin (is derived from 1.33 × Enzymatic buffer HTRF kit) and ATP (10mM) be diluted to 4 × mixed liquor of required final concentration；
Detect the preparation of working solution：With HTRF detection buffer by 16.67 μm of ol/L Streptavidin- XL665 is diluted to 4 × required final concentration, then mixed with isometric Antibody-Cryptate and (derive from HTRF kit)。
Enzyme reaction step：4 μ L μ l kinases working solution is added into each hole of the microwell plate of low volume 384, while adding 4 μ L 1.33 × Enzymatic buffer are used as negative control (Negative)；2 μ l compound working solutions are added to hole, together When add the 2 μ L 8%DMSO aqueous solution as pulverised compound concentrations control (i.e. positive control, Positive)；In 25 DEG C (or 30 DEG C) it is incubated 5-10min；Xiang Kongzhong adds 2 μ L substrates working solutions and starts enzyme reaction, in 25 DEG C of (or 30 DEG C) oscillating reactions 15- 60min。
HTRF reagent detecting steps：8 μ L detection working solution terminating reaction is added to hole；25 DEG C of reaction 1h；
The reading of HTRF signals：Signal is detected using PHERAstar FS readings, instrument relative set is as follows：
Optic module
Integration delay(lag time)50μs
Integration time 400μs
Number of flashes 200
The initial data read for every hole, ratio=665nm/620nm；
The calculating of inhibiting rate：
IC50The calculating of value：Using the logarithm of compound concentration as abscissa, inhibiting rate is ordinate, in GraphPad In Prism 5, fit non-linear curve：Log (inhibitor) vs.response--Variable slope, obtain enzyme activity suppression Testing compound concentration when rate processed is 50% is IC50。
Experimental result：C-Met kinase activity half-inhibition concentrations (IC50nM)
The present invention provides structure half-inhibition concentration (IC of the compound to c-Met kinase activities shown in formula I50) it is shown in Table 1：
Half-inhibition concentration (IC of the compound of table 1 to c-Met kinase activities50)
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ + +++
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ +++ ++ ++ + + +
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity +++ +++ +++ +++ +++ ++ + +++ +++ +++
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity ++ + + +++ ++ +++ ++ +++ +++ +++
Compound 61 62 63 64 65 66 67 BMS777607
Activity intensity + +++ +++ + +++ +++ +++
+++ represent IC50＜ 500nM；++ represent IC50Scope is 500-5000nM；+ represent IC50Scope is 5000nM-50 μ M；- represent not test
Half-inhibition concentration (IC of the compound of table 2 to KDR kinase activities50)
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ ++ +++ - +++ ++
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity - - - - - - ++ - - -
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity - +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ +++ +++ +++ + +++
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity +++ +++ +++ +++ +++ +++ + +++ +++ +++
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity +++ ++ + +++ + +++ +++ +++ +++ +++
Compound 61 62 63 64 65 66 67 BMS777607
Activity intensity + +++ +++ ++ +++ ++ - +++
+++ represent IC50＜ 500nM；++ represent IC50Scope is 500-5000nM；+ represent IC50Scope is 5000nM-50 μ M；- represent not test
Half-inhibition concentration (IC of the compound of table 3 to c-Kit kinase activities50)
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ ++ +++ - +++ -
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity - - - - - - - - - -
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity - +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ +++ +++ +++ ++ +++
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity +++ +++ +++ +++ +++ +++ + +++ +++ +++
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity ++ +++ + +++ + +++ +++ +++ +++ +++
Compound 61 62 63 64 65 66 67 BMS777607
Activity intensity + +++ +++ ++ +++ +++ - +++
+++ represent IC50＜ 500nM；++ represent IC50Scope is 500-5000nM；+ represent IC50Scope is 5000nM-50 μ M；- represent not test
Experimental result：Inhibitory activity and positive drug of the part of compounds of the present invention to c-Met kinases biochemistry levels Quite, the inhibitory activity to VEGR-2 kinases and the biochemistry level of c-kit kinases is significantly better than positive drug to BMS777607 BMS777607。
Embodiment：69：Cell in vitro level suppresses protein kinase (PK) activity experiment
Materials and methods：BGC823 cell line MKN-45 etc. derives from Chinese Academy of Sciences's Shanghai cell bank；1640 culture mediums (GIBCO companies)；Hyclone (GIBCO companies)；24 porocyte culture plates (Costar companies)；96 hole water white transparency height are affine Power ELISA Plate (Costar companies)；HGF (R＆D System companies)；Cell pyrolysis liquid (green skies company)；c-Met capture Antibody (R＆D System companies)；(Upstate is public by Anti-phosphotyrosine antibody, clone 4G10 Department)；HRP labeled goat-anti-mouse antibody (company of Zhong Shan Golden Bridge)；TMB (Pierce companies)；Enzyme mark is examined Survey instrument (Tecan companies, Infinite M200)；Multifunctional plate washing machine (Bio-Rad companies)
Compound is configured：Positive drug and each test-compound are configured to 10mM mother liquor, -20 DEG C of preservations with DMSO.
Met antibody is coated with：C-met antibodies are diluted to 2 μ g/mL, added with every μ L of hole 100 amount in ELISA Plate, 4 DEG C of bags Stayed overnight (16-18h).PBST (PBS/0.05%Tween20, pH 7.4) is washed 3 times；Add confining liquid (5%BSA/PBS) per hole 200 μ l, 37 DEG C of closing 2h；PBST is washed 3 times；Capture c-Met albumen：80~90% degrees of fusion are inoculated with 24 porocyte culture plates MKN-45 cells, after 8-10h cell attachments, change the culture medium of serum-free 1640, overnight starvation；With the culture medium of serum-free 1640 The compound of gradient dilution；Culture medium in 24 orifice plates is sucked, 180 μ L/ holes compound concentration gradient dilutions are rapidly joined, and will The cell of compound effects is incubated 1h in incubator；HGF is configured to 800ng/mL solution with the culture medium of serum-free 1640, Add 20 μ l per hole in 24 orifice plates, 5-8min are stimulated at 37 DEG C after slight mixing；Culture medium supernatant in 24 orifice plates quickly is sucked, per hole Plus 240 μ l RIPA lysates；Add 100 μ l cell pyrolysis liquids in ELISA Plate after closure per hole, 37 DEG C of 100rpm shake 2h； PBST is washed 3 times；
Phosphotyrosine detection：Primary antibody is incubated：Add 100 μ mouse source Anti-phosphotyrosine per hole Antibody, Clone 4G10 (dilutions of 0.5%BSA/PBS (W/V) 1: 2000), 37 DEG C of 100rpm shake 1-1.5h；PBST is washed Wash 3 times；Secondary antibody is incubated：Add 100 μ l HRP goat anti mouse IgG (1: 3000 times of 0.5%BSA/PBS (W/V) per hole Dilution), 37 DEG C of 100rpm shake 1h；PBST is washed 6 times；Tmb substrate develops the color：Add 10%L TMB substrate, room temperature per hole 2-10min is reflected in darkroom；After after substrate to appropriate color, 50 μ L2M H are added per hole2SO4；ELIASA 450nm absorbing wavelengths Place determines light absorption value.
Experiment sets two control groups, negative control group：The SCR-1 of 10-5mol/L high concentrations is added, HGF stimulations are not added with；Sun Property control group：Any medicine is not added with, only adds HGF to stimulate；
The average value of all administration groups and control group is calculated, inhibiting rate is calculated as follows：
IC50The calculating of value：Using the logarithm of compound concentration as abscissa, inhibiting rate is ordinate, in GraphPad In Prism 5, fit non-linear curve：Log (inhibitor) vs.response--Variable slope, obtain enzyme activity suppression Testing compound concentration when rate processed is 50% is IC50。
Experimental result：Part of compounds of the present invention is to c-Met kinases cellular level activity and positive drug BMS777607 phases As the half-inhibition concentration scope (IC of part of compounds50) 2 are shown in Table,
Half-inhibition concentration scope (IC of the compound of table 2 to c-Met kinases cellular level activity50)
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ +++ ++ +++ +++ -
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity - - - - - - - +++ + ++
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity + +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ - - - - - -
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity - - - - - - - - - -
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity - - - - - - - - - -
Compound 61 62 63 64 65 66 67 BMS777607
Activity intensity - - - - - - - +++
+++ represent IC501 μM of ＜；++ represent IC50Scope is 1-10 μM；+ represent IC50Scope is 10 μM -100 μM；- represent Do not test
Embodiment 70：The compound that the present invention is provided suppresses the assay method (mtt assay) of tumor cell proliferation
Reagent and instrument：
The culture mediums of RPMI 1640 (RPMI 1640+12% calf serum+HERES 3.5g/L+NaHCO32.2g/L+ it is blue or green Mycin 0.13g/L+ streptomysin 0.15g/L)；
The culture mediums of RPMI 1640 (RPMI 1640+12% hyclone+HERES 3.5g/L+NaHCO α32.2g/L+ it is blue or green Mycin 0.13g/L+ streptomysin 0.15g/L)；
DMEM in high glucose culture medium (DMEM+10% calf serum+HEPES 3.5g/L+NaHCO32.2g/L+ penicillin 0.13g/L+ streptomysin 0.15g/L)；
DMEM in high glucose culture medium (DMEM+12% hyclone+HERES 3.5g/L+NaHCO32.2g/L+ penicillin 0.13g/L+ streptomysin 0.15g/L)；
MC COYS 5-A culture mediums (DMEM+12% hyclone+HERES 3.5g/L+NaHCO32.2g/L+ penicillin 0.13g/L+ streptomysin 0.15g/L)；
Trypsase；MTT (U.S.'s Amresco Products)；ELIASA (TECAN infinite M200)
BGC823 cell line (BGC)；Non-small cell lung carcinoma (A549)；Human leukemia cell line (K562)；Human pancreas JEG-3 (PANC-1)；Human small cell lung carcinoma (NCI-H446)；RPMI of the listed JEG-3 containing 12% calf serum 1640 culture mediums, in 37 DEG C, 5%CO2Incubator in cultivate；
Human pancreas cancer cell strain (BXPC-3)；Human bladder cancer cell's strain (T24)；12% hyclone of listed JEG-3 The culture mediums of RPMI 1640, in 37 DEG C, 5%CO2Incubator in cultivate；
Human hepatoma cell strain (HEPG2)；Breast cancer lines (MCF-7)；12% calf serum of listed JEG-3 DMEM in high glucose culture medium, in 37 DEG C, 5%CO2Incubator in cultivate；
Human colon adenocarcinoma cell's strain (CACO-2), with the DMEM in high glucose culture medium of 12% hyclone, in 37 DEG C, 5%CO2 Incubator in cultivate；
Human colon cancer cell strain (HT29)；Human colon cancer cell strain (HCT116)；Human oophoroma cell line (SK-OV-3)； The MC COYS 5-A culture mediums of 12% hyclone of listed JEG-3, in 37 DEG C, 5%CO2Incubator in cultivate.
Inoculation：Take in exponential phase of growth, one bottle of cell in good condition, add appropriate tryptic digestive juice, digestion Attached cell is come off, cell suspension be made into RPMI1640 (or DMEM or 5A) nutrient solution containing 12% calf serum, count, And cell density adjustment is diluted to 1.67 × 104/ mL takes cell suspension inoculation on 96 orifice plates, and 180 μ L/ holes are (thin containing tumour The hole of born of the same parents 3000/).
Culture：Culture plate is transferred to constant temperature CO2In incubator, in 37 DEG C, 5%CO2And culture 24 is small under the conditions of saturated humidity When.
Primary dcreening operation：Testing compound is first configured to 0.1M concentration with DMSO, remakes 3 dilution factors, and for primary dcreening operation, concentration is successively For 10-5mol/L、10-6Mol/L and 10-7mol/L.Testing compound is added, 20 μ L/ holes are cultivated 72 hours.Every group sets 3 and puts down Row hole, and be repeated 3 times, 96 orifice plates are determined per hole light absorption value, and record result calculates inhibitory rate of cell growth, takes three average values.
Dyeing：MTT is added in 96 orifice plates (attached cell), 20 μ L/ holes, be placed in incubator and be incubated 4 hours, hole is abandoned in suction Interior supernatant, adds the μ L/ holes of DMSO 100, puts and is shaken 5 minutes on plate shaker.MTT is added in 96 orifice plates (suspension cell), 20 μ L/ holes, are placed in incubator and are incubated 4 hours, add the μ L/ holes of 20%SDS 50, are placed in incubator overnight.
Determine：ELIASA sets wavelength as 570nm, and reference wavelength is 630nm, determines 96 orifice plates per hole light absorption value, record As a result and inhibitory rate of cell growth is calculated, to judge the antitumor activity of test medicine.
Secondary screening：It is 10 in primary dcreening operation concentration-5During mol/L, the compound of 3 cell inhibitory rate >=50% is used for secondary screening, will 0.1mol/L remakes 10 dilution factors, and concentration is followed successively by 10-5mol/L、0.5×10-5mol/L、10-6mol/L、0.8×10- 6mol/L、0.6×10-6mol/L、0.4×10-6mol/L、0.2×10-6mol/L、10-7mol/L、0.8×10-7Mol/L and 0.4 ×10-7mol/L.Test-compound is added, 20 μ L/ holes are cultivated 48 hours.Same every group sets 3 parallel holes, and is repeated 3 times, and According to prescreening method, 96 orifice plates are determined per hole light absorption value, are recorded result and are calculated inhibitory rate of cell growth.
Inhibitory rate of cell growth and IC50Calculating：
Simultaneously according to the growth inhibition ratio of each concentration, use with the logarithm of compound concentration with Logit linear regressions, obtain The testing compound concentration suppressed when growth rate is 50% is IC50, take three average values.
Result of the test：The compound with Formulas I structure prepared in the embodiment of the present invention 1 to 67 is to kinds of tumor cells Breed inhibited, statistical analysis, effect is notable (P ＜ 0.05), its IC5010-5Below mol/L.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (21)

1. compound or its pharmaceutically acceptable salt of the structure as shown in formula (I)：
Wherein,
A is selected from C5-C10Heteroaryl or C6-C10Aryl, is further selected from wherein the heteroaryl, aryl are optional by one or more Hydrogen, C1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10Aryl, C5-C10Heteroaryl, C6-C10Aryl C1-C10Alkyl, C5- C10Heteroaryl C1-C10Alkyl, halogen, halo C1-C10Alkyl, 5 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C10Alkoxy, C6-C10Virtue Epoxide, cyano group, nitro ,-NR7R8、-NR7C (=O) R8,-C (=O) R9,-C (=O) OR9,-C (=O) NR7R8、-S(O)R10、-S (O)2R10、-S(O)2NR7R8、-O(CH2)nR11Or-OC (=O) R9Substituent replaced；
B is selected from-O- ,-S- ,-NH- or-CH2-；
W is selected from C；
X is selected from C or N；
M is 0 or 1；
R1、R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan Heteroalicyclyl ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon lists Ring cycloalkyl, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Virtue Base, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2)nR11、- OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R5Selected from hydrogen；
R6Selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, miaow Oxazolyl, wherein, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals it is optional further by It is one or more to be selected from halogen, trihalomethyl or C1-C10The substituent of alkoxy is replaced；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thienyl, furyl, pyridines Base, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thiophenes Fen base, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals are optional to be further selected from C by one or more1-C10 Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
Or R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein containing one in 5 to 8 circle heterocycles Individual or multiple N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, halogen, Phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl, cyanogen Base, C1-C10Alkoxy, amino C1-C10The substituent of alkyl or carboxylic acid is replaced；
R9Selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl Base is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, ammonia The substituent of base, cyano group or carboxylic acid is replaced；
R10Selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alcoxyl Base, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R11Selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl or-NR7R8, wherein C1-C10 Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
N is 1,2,3 or 4.
2. compound according to claim 1 or its pharmaceutically acceptable salt,
Wherein,
A is selected from C5-C10Heteroaryl or C6-C10Aryl, is further selected from wherein the heteroaryl, aryl are optional by one or more Hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10 Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (=O) R9Substituent replaced；
B is selected from-O- ,-S- ,-NH- or-CH2-；
W is selected from C；
X is selected from C or N；
M is 0 or 1；
R1、R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, wherein C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls It is optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9Substituent replaced；
R5Selected from hydrogen；
R6Selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, miaow Oxazolyl, wherein, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazoles Base is optional to be further selected from halogen, trihalomethyl or C by one or more1-C10The substituent of alkoxy is replaced；
R9Selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl or imidazoles Base；
R11Selected from C1-C10Alkoxy, C6-C10Aryloxy group, hydroxyl or-NR7R8；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thienyl, furyl, pyridines Base, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thiophenes Fen base, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals are optional to be further selected from C by one or more1-C10 Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
Or R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein containing one in 5 to 8 circle heterocycles Individual or multiple N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, halogen, Phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl, cyanogen Base, C1-C10Alkoxy, amino C1-C10The substituent of alkyl or carboxylic acid is replaced；
N is 1,2,3 or 4.
3. compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that：
A is selected from six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring or hexa-atomic and hexa-atomic virtue Ring group, wherein six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring or hexa-atomic and hexa-atomic virtue Ring group is optional to be further selected from hydrogen, halogen ,-C (=O) NH by one or more2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or- OC (=O) R9Substituent replaced；
B is selected from-O-.
4. compound according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that：
A is selected from pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl, wherein the pyridine radicals, thieno Pyrimidine radicals, quinazolyl, quinolyl, naphthyl or phenyl are optional further by one or more selected from hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyano group, amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Virtue Epoxide, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (=O) R9Substituent replaced；
B is selected from-O-.
5. compound according to claim 4 or its pharmaceutically acceptable salt, it is characterised in that：
A is selected from following group：
Wherein, RaAnd RbIndependently selected from hydrogen, halogen ,-C (=O) NH2,-C (=O) NHR8,-C (=O) R9,-C (=O) OR9, cyanogen Base, amino ,-NHC (=O) R8、C1-C10Alkoxy, C6-C10Aryloxy group, C1-C10Alkyl, hydroxyl ,-O (CH2)nR11Or-OC (= O)R9Substituent；
B is selected from-O-.
6. compound according to claim 1 or its pharmaceutically acceptable salt,
Wherein,
A is selected from six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring or hexa-atomic and hexa-atomic virtue Ring group, wherein six membered heteroaryl, five yuan and six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring or hexa-atomic and hexa-atomic virtue Ring group is optional to be further selected from hydrogen, halogen, amino ,-CONH by one or more2, cyano group, C1-C4Alkoxy or-O (CH2)nR11 Substituent replaced；
B is selected from-O-；
W is selected from C；
X is selected from C or N；
M is 0 or 1；
R1、R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, C1-C4Alkyl, pi-allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen；
R6Selected from hydrogen, phenyl or 2- thienyls, wherein, phenyl is optional further by one or more halogens, trihalomethyl or C1- C4Alkoxy replaces；
R11Selected from C1-C4Alkoxy, N methyl piperazine subbase, morpholino base, piperidino, pyrrolidinyl or-N (C2H5)2；
N is 2 or 3.
7. compound according to claim 6 or its pharmaceutically acceptable salt, it is characterised in that：
A is selected from pyridine radicals, Thienopyrimidine base, quinazolyl, quinolyl, naphthyl or phenyl, wherein the pyridine radicals, thieno Pyrimidine radicals, quinazolyl, quinolyl, naphthyl or phenyl it is optional further by it is one or more selected from hydrogen, halogen, amino ,-C (= O)NH2, cyano group, C1-C4Alkoxy or-O (CH2)nR11Substituent replaced.
8. compound according to claim 6 or its pharmaceutically acceptable salt, it is characterised in that：
A is selected from following group：
Wherein, RaAnd RbIndependently selected from hydrogen, halogen, amino ,-CONH2, cyano group, C1-C4Alkoxy or-O (CH2)nR11。
9. compound or its pharmaceutically acceptable salt, wherein described compound is selected from：
10. the compound shown in logical formula (II), the compound is synthesis logical formula (I) compound as claimed in claim 1 Intermediate：
Wherein, R2、R3、R4And R5Definition as defined in claim 1；
R6Selected from C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl or C5-C10Heteroaryl C1-C10Alkane Base, wherein C6-C10Aryl, C5-C10Heteroaryl, C1-C10Alkyl, C6-C10Aryl C1-C10Alkyl, C5-C10Heteroaryl C1-C10Alkyl It is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, cyano group Or the substituent of carboxylic acid is replaced.
11. compound according to claim 10, wherein,
R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, hydroxyl, C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan Heteroalicyclyl ,-C (=O) R9Or-S (O)2R10, wherein C1-C10Alkyl, C6-C10Aryl, C5-C10Heteroaryl, 3 to 8 yuan of full carbon lists Ring cycloalkyl, 5 to 8 yuan of heteroalicyclyls are optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Virtue Base, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9, hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group ,-O (CH2)nR11、- OC (=O) R10、-NR7R8Or-NR7C (=O) R8Substituent replaced；
R5Selected from hydrogen；
R6Selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazoles Base, wherein, phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals optionally by one or It is multiple to be selected from halogen, trihalomethyl or C1-C10The substituent of alkoxy is replaced；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thienyl, furyl, pyridines Base, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, wherein the C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, phenyl, thiophenes Fen base, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals are optional to be further selected from C by one or more1-C10 Alkyl, hydroxyl, amino, cyano group, C1-C10The substituent of alkoxy or carboxylic acid is replaced；
Or R7And R85 to 8 circle heterocycles bases are formed together with the nitrogen-atoms that they are connected, wherein containing one in 5 to 8 circle heterocycles Individual or multiple N, O, S hetero atoms, and it is optional further by one or more selected from C in 5 to 8 circle heterocycles1-C10Alkyl, halogen, Phenyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, halo C1-C10Alkyl, hydroxyl, cyanogen Base, C1-C10Alkoxy, amino C1-C10The substituent of alkyl or carboxylic acid is replaced；
R9Selected from C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl Base is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, ammonia The substituent of base, cyano group or carboxylic acid is replaced；
R10Selected from C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl, wherein C1-C10Alkyl, halo C1-C10Alkyl, C6-C10Aryl or C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alcoxyl Base, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
R11Selected from hydroxyl, C1-C10Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl or-NR7R8, wherein C1-C10 Alkoxy, C6-C10Aryloxy group, C6-C10Aryl, C5-C10Heteroaryl is optional to be further selected from C by one or more1-C10Alkyl, C1-C10Alkoxy, halogen, halo C1-C10Alkyl, hydroxyl, amino, the substituent of cyano group or carboxylic acid are replaced；
N is 1,2,3 or 4.
12. compound according to claim 11, it is characterised in that：
R4Selected from hydrogen, C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, wherein C1-C10Alkyl, 3 to 8 yuan of full carbon monocyclic cycloalkyls It is optional to be further selected from C by one or more1-C10Alkyl, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl ,-C (=O) R9,-C (=O) OR9Substituent replaced；
R6Selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazoles Base, wherein, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals Optionally halogen, trihalomethyl or C are selected from by one or more1-C10The substituent of alkoxy is replaced；
R9Selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl or imidazoles Base.
13. compound according to claim 10, wherein,
R2And R3Independently selected from hydrogen or halogen；
R4Selected from hydrogen, C1-C4Alkyl, pi-allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen；
R6Selected from phenyl or 2- thienyls, wherein, phenyl is optionally taken by one or more halogens, trihalomethyl or methoxyl group Generation.
14. compound according to claim 10, wherein described compound is selected from：
15. prepare the method for logical formula (II) compound according to claim 10, it is characterised in that this method includes following Step：
(1) reaction under alkali effect obtains compound c to compound a with compound b；
(2) compound c and aminopyridines d is in protonic solvent, under acid catalysis, and reaction obtains compound e；
(3) compound e reactions under diphenyl ether effect obtain general formula compound (II)；
Wherein, R2、R3、R4、R5And R6Definition as defined in claim 1.
16. synthetic method according to claim 15, wherein,
Alkali described in step (1) is inorganic base, selected from sodium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, reaction temperature For -15 DEG C to 50 DEG C, the reaction time is 2 hours to 48 hours；
Protonic solvent described in step (2) be isopropanol, ethanol or methanol, it is described acid for hydrochloric acid, sulfuric acid, phosphoric acid, to toluene Sulfonic acid or acetic acid, reaction temperature are 60 DEG C to 100 DEG C, and the reaction time is 2 hours to 20 hours；
Reaction dissolvent is diphenyl ether in step (3), and reaction temperature is 90 DEG C to 258 DEG C；Reaction time is 30 minutes to 10 hours.
17. synthetic method according to claim 16, wherein,
Alkali described in step (1) is sodium hydride, and reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 5 hours to 24 hours；
Solvent described in step (2) is ethanol, and the acid is concentrated hydrochloric acid, and reaction temperature is 60 DEG C to 85 DEG C, and the reaction time is 5 small Up to 10 hours；
Reaction dissolvent is diphenyl ether in step (3), and reaction temperature is 160 DEG C to 258 DEG C；Reaction time is 30 minutes to 5 hours.
18. the power of a kind of pharmaceutical composition, free form of the pharmaceutical composition comprising therapeutically effective amount or pharmaceutical acceptable salt Compound defined in any one during profit requires 1 to 9；One or more medicinal carrier substances and/or diluent.
19. a kind of compound prepare treatment the disease medicament through protein kinase intermediary in terms of application, the compound be to Give the compound of any one in the claim 1 to 9 of Case treatment effective dose.
20. application according to claim 19, it is characterised in that the relevant disease of the protein kinase be selected from c-Met, Disease related KDR or c-kit.
21. application according to claim 20, it is characterised in that the disease is selected from colorectal cancer, carcinoma of urinary bladder, mammary gland Cancer, liver cancer, lung cancer, cancer of pancreas, human primary gastrointestinal cancers, leukaemia, oophoroma, head and neck cancer, prostate cancer, kidney, nasopharyngeal carcinoma, collagen Cytoma, squamous cell carcinoma, astrocyte cancer, Kaposi's sarcoma, melanoma, glioma, genitourinary cancer or bone Marrow proliferative disorder.
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