CN108864081A - Fgfr4 inhibitor and its preparation and application - Google Patents

Abstract

The invention belongs to medicinal chemistry arts, and in particular to FGFR4 inhibitor, preparation method shown in a kind of Formula II, the purposes of the pharmaceutical composition containing the inhibitor and the inhibitor or pharmaceutical composition as tumor therapeutic agent.

Description

FGFR4 inhibitor and its preparation and application

Technical field

The invention belongs to medicinal chemistry arts, and in particular to a kind of novel FGFR4 inhibitor, the medicine containing the inhibitor The purposes of compositions and the inhibitor or pharmaceutical composition as tumor therapeutic agent.

Background technique

Receptor tyrosine kinase is due to the activation of its unconventionality expression or gene mutation, in tumor development, invasion transfer, medicine The links such as object resistance play key effect, it has also become the important target spot of anti-tumor drug research and development.Fibroblastic growth Factor acceptor (Fibroblast Growth Factor Receptors, FGFRs) is the important of receptor tyrosine kinase family Member mainly includes tetra- kinds of hypotypes of FGFR1, FGFR2, FGFR3 and FGFR4.Its ligand is fibroblast growth factor (Fibroblast Growth Factors,FGFs).These receptors by with FGFs and heparan sulfate proteoglycan (Heparan-SulfateProteoglycans, HSPGs) forms ternary complex, and then causes a series of signal transduction, It participates in adjusting the intracorporal a variety of physiology of biology, pathologic process.

Amino acid sequence between FGFR family member (FGFR1, FGFR2, FGFR3 and FGFR4) be it is highly conserved, Ligand affinity and Tissue distribution etc. performance are different.Due to gene magnification, mutation, fusion or ligand induction etc., Each member's sustained activation of FGFR induces tumor cell proliferation, invasion, migration, promotes angiogenesis, tumour is promoted to send out Exhibition.FGFRs high expression and abnormal activation in kinds of tumors, it is closely related with the poor prognosis of tumour patient, such as non-small cell Lung cancer, breast cancer, gastric cancer, bladder cancer, carcinoma of endometrium, prostate cancer, cervical carcinoma, colon cancer, the cancer of the esophagus, cutin mother cell Tumor, myeloma, rhabdomyosarcoma etc..Fibroblast growth factor receptor 4 (FGFR4) is fibroblast growth factor acceptor Member in family is encoded by FGFR4 gene, and FGFR4 genome structure contains 18 exons.At with FGFR1 inhibitor Observe dystopy mineralising in the rat body managed, be shown in soft tissue have improperly calcium phosphorus precipitation (Brown, AP etc. (2005), Toxicol.Pathol, the 449-455 pages).This shows selective inhibition FGFR4 to avoid certain toxicity be desirable.It grinds Study carefully discovery, FGFR4 is the receptor that FGF19 (physiologic ligand of FGFR4) uniquely shows specificity, and FGF19 overexpression can cause FGF19-FGFR4 Pathway Activation, so as to cause cancers such as certain sarcomas, clear-cell carcinoma, breast cancer and liver cancer.For with FGF19 The tumour of gene magnification, FGFR4 inhibitor for treating are effective.It is observed in the rat body with FGFR1 inhibitor for treating different Position mineralising, it is characterized in that have in soft tissue improperly calcium phosphorus precipitation (Brown, AP etc. (2005), Toxicol.Pathol, the 449-455 pages).This shows selective inhibition FGFR4, without inhibiting other hypotypes such as FGFR1 of FGFR to can avoid drug Certain toxic side effects.Currently, a series of FGFR4 inhibitor are disclosed, including WO2015/108992, WO2015/059668, Compound disclosed in WO2015/061572 etc..But still needing to exploitation has more preferable drug effect, and toxicity is smaller, selectivity higherization Close object.

Summary of the invention

In a first aspect, the present invention provides a kind of fibroblast growth factor acceptor inhibitor or its medicine with general formula I Acceptable salt, isomers, solvate, crystallization or prodrug are learned, such compound shows good FGFR inhibitory activity, especially The activity of the inhibition FGFR4 of its selectivity,

Wherein：

Bullet is the part that covalent bond can be formed with nucleopilic reagent；

X, G is each independently selected from CH and N；

R₁、R₂It is each independently selected from H, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, ammonia Base, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl acyl alkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein The alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, hydroxy alkyl, alkoxyalkyl, Aminoalkyl, alkyl acyl alkyl, naphthenic base, heterocycle, aryl and heteroaryl are optionally selected by one or more each independently From the substituent group institute of alkyl, halogen, halogenated alkyl, halogenated alkoxy, hydroxyl, nitro, amino, carboxyl, hydroxy alkyl, alkoxy Replace；Or

R₁And R₂Nitrogen-atoms connected to them is formed together saturated or unsaturated single heterocycle, spiro heterocyclic radical, thick miscellaneous Ring group or bridge heterocycle, wherein single heterocycle, spiro heterocyclic radical, condensed hetero ring base or the bridge heterocycle are optionally by one or more It is a selected from halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, Hydroxy alkyl, alkoxyalkyl, alkyl acyl, alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle substituent group It is replaced；

R₃、R₄、R₅It is each independently selected from halogen, alkyl, naphthenic base, halogenated alkyl, alkoxy, halogenated alkoxy, nitre Base, cyano, hydroxyl, amino, carboxyl, alkyl acyl alkyl, hydroxy alkyl, alkoxy, aminoalkyl, aryl, heteroaryl and miscellaneous Naphthenic base, wherein n is selected from 0,1 and 2, and p is selected from 0,1 and 2 and q and is selected from 0,1,2,3,4 and 5；

R₆The alkyl selected from H and optionally replaced；Or R₆The amino being connect jointly with adjacent aromatic ring or heteroaromatic with them It is formed together 8-12 circle heterocyclic ring base；With

R₇The alkyl selected from H and optionally replaced.

In some embodiments of the present invention, according to compounds of formula I or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, wherein R₁、R₂H, C each independently_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6 Alkoxy, nitro, cyano, hydroxyl, amino, hydroxyl C_1-6Alkyl, alkoxy C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkyl acyl C_1-6Alkyl, C_3-8Naphthenic base, C_3-8Heterocycle, aryl and heteroaryl, wherein the alkyl, halogenated alkyl, alkoxy, alkyl halide Oxygroup, nitro, cyano, hydroxyl, amino, carboxyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl acyl alkyl, cycloalkanes Base, heterocycle, aryl and heteroaryl are optionally selected from C by one or more each independently_1-6Alkyl, halogen, halogenated C_1-6Alkyl, Halogenated C_1-6Alkoxy, hydroxyl, nitro, amino, hydroxyl C_1-6Alkyl, C_1-6Replaced the substituent group of alkoxy.Of the invention one In a little embodiments, according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, Wherein R₁、R₂It is each independently selected from C_1-3Alkyl, amino C_1-3Alkyl, C_1-3Alkyl amino C_1-3Alkyl.In a specific implementation In scheme, according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, wherein R₁ For methyl, R₂For dimethyl aminoethyl.

In other embodiments, it is closed according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvent Object, crystallization or prodrug, wherein R₁And R₂Nitrogen-atoms connected to them is formed together saturated or unsaturated 3-12 unit monocycle nitrogen Heterocyclylalkyl, monocycle diazacyclo alkyl, monocycle nitrogen oxacycloalkyl, azaspiro alkyl, diaza spiro naphthenic base, nitrogen oxa- Spiro cycloalkyl group, azepine condensed ring alkyl, diaza cycloalkyl, nitrogen oxa- cycloalkyl, aza-bridged-ring alkyl, diaza bridged ring alkane Base and nitrogen oxa- bridge ring alkyl, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkane Base, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8It is miscellaneous Replaced the substituent group of ring group.

In other embodiments, it is closed according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvent Object, crystallization or prodrug, wherein R₁And R₂Nitrogen-atoms connected to them is formed together saturated or unsaturated aza-bridged-ring alkane Base, diaza bridge ring alkyl and nitrogen oxa- bridge ring alkyl, wherein these groups are optionally selected from halogen, C by one or more_1-6 Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkane Base, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

In other embodiments, it is closed according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvent Object, crystallization or prodrug, wherein R₆Selected from H and alkyl, wherein the alkyl is optionally selected from halogen, alkyl, halogenated alkyl, alcoxyl Base, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, The substituent group substitution of alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle.

In other embodiments, it is closed according to compounds of formula I or its pharmaceutically acceptable salt, isomers, solvent Object, crystallization or prodrug, wherein R₇Selected from H and alkyl, wherein the alkyl is optionally selected from halogen, alkyl, halogenated alkyl, alcoxyl Base, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, The substituent group substitution of alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle.

In other preferred embodiments of the invention, according to compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, formula of I have structure shown in following general formula II,

Wherein bullet, X, G, R₃、R₄、R₅、R₆、R₇, n, p, q definition as described in general formula I；

Ring A is Azacyclyl, wherein the Azacyclyl optionally further by one or more selected from halogen, alkyl, Halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxy Alkyl, alkyl acyl, alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle substituent group replaced.

In other preferred embodiments of the invention, according to general formula II compound represented or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, the nitrogen list heterocycle that middle ring A is 3 yuan -8 yuan；It is further preferably 5- or 6-membered nitrogen Single heterocycle；The non-limiting example of ring A includes substituted or unsubstituted pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyrrole It mutters base or tetrahydrofuran base.

In other preferred embodiments of the invention, according to general formula II compound represented or its can pharmaceutically connect Salt, isomers, solvate, crystallization or the prodrug received, middle ring A be 7 yuan to 15 yuan nitrogen multiring heterocyclics, more preferably 7 yuan It is further preferably miscellaneous for 7 yuan to 12 yuan nitrogen list spiro heterocyclic radicals and nitrogen bridge to 15 yuan of nitrogen spiro heterocyclic radicals, nitrogen condensed hetero ring base and nitrogen bridge heterocycle Ring group, wherein the nitrogen multiring heterocyclic, nitrogen spiro heterocyclic radical, nitrogen condensed hetero ring base or nitrogen bridge heterocycle are optionally one or more Selected from halogen, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxylic Base, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, virtue Base, heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

In other preferred embodiments of the invention, according to general formula II compound represented or its can pharmaceutically connect Salt, isomers, solvate, crystallization or the prodrug received, middle ring A are selected from 7 yuan to 15 yuan aza-bridged-ring alkyl, diaza bridged rings Alkyl and nitrogen oxa- bridge ring alkyl, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkane Base, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8It is miscellaneous Replaced the substituent group of ring group.

In other preferred embodiments of the invention, according to general formula II compound represented or its can pharmaceutically connect Salt, isomers, solvate, crystallization or the prodrug received, middle ring A are selected from 7 yuan to 12 yuan aza-bridged-ring alkyl, diaza bridged rings Alkyl and nitrogen oxa- bridge ring alkyl, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkane Base, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8It is miscellaneous Replaced the substituent group of ring group.

In other preferred embodiments of the invention, according to general formula II compound represented or its can pharmaceutically connect Salt, isomers, solvate, crystallization or the prodrug received, middle ring A are selected from 7 yuan to 12 yuan aza-bridged-ring alkyl, diaza bridged rings Alkyl and nitrogen oxa- bridge ring alkyl, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkane Base, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8It is miscellaneous Replaced the substituent group of ring group.

In some embodiments of the present invention, according to formula above II compound represented or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, middle ring A are selected from following bridge heterocycle：

Wherein these groups are optionally Halogen, C are selected from by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl Base, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, 3-8 member aryl, 3-8 unit's heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

In some embodiments of the present invention, according to formula above II compound represented or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, middle ring A are selected from following bridge heterocycle：

Wherein these groups are optionally by one It is a or multiple selected from halogen, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, Amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6 Alkyl, 3-8 member aryl, 3-8 unit's heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

In other preferred embodiments of the invention, it can be connect according to general formula I or compounds of formula II or its pharmacy Salt, isomers, solvate, crystallization or the prodrug received, shown in general formula I or general formula II have following general formula III shown in Structure：

Wherein：Bullet, X, G, R₃、R₄、R₅、R₆、R₇, n, p, q definition as described in general formula I；

M and d is each independently selected from 1,2,3 and 4；

Ring B is selected from naphthenic base and heterocycle, wherein the naphthenic base and heterocycle is optionally selected from by one or more Halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxyl alkane Base, alkoxyalkyl, alkyl acyl, alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle substituent group replaced.

In other preferred embodiments of the invention, it can be connect according to general formula III compound represented or its pharmacy Salt, isomers, solvate, crystallization or the prodrug received, middle ring B are selected from 3-8 member naphthenic base and heterocycle, it is preferable that ring B choosing From C_3-8Naphthenic base, C_3-8Azacycloalkyl, C_3-8Oxacycloalkyl, C_3-8Nitrogen oxacycloalkyl and C_3-8Sulfur heterocyclic alkyl base, wherein this A little groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, Nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl Base, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.In some realities It applies in scheme, the non-limiting example of ring B includes cyclopenta, cyclohexyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyrrole It mutters base or tetrahydrofuran base, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6 Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Replaced the substituent group of alkyl.

In some specific embodiments of the invention, according to general formula III compound represented or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein

GroupIt is selected from Wherein these groups are optionally selected from halogen, C by one or more_1-6Alkane Base, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, Hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Replaced the substituent group of alkyl.

In other preferred embodiments of the invention, according to chemical combination shown in general formula I, general formula II or general formula III Object or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, wherein bullet is selected from following group：

Wherein R_a、R_b、R_cIt is each independently selected from H, alkyl, naphthenic base, cyano, wherein the alkyl or cycloalkyl is optional By one it is multiple selected from halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, The group substitution of aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl alkyl, Xa are selected from halogen and triflate； Preferably, R_a、R_b、R_cIt is each independently selected from H, C_1-6Alkyl, C_3-8Naphthenic base, cyano, wherein the alkyl or cycloalkyl is optional It is multiple selected from halogen, C by one_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl Base, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, alkoxy C_1-6Alkyl, C_1-6Alkyl acyl C_1-6The group of alkyl takes Generation.

In other preferred embodiments of the invention, according to chemical combination shown in general formula I, general formula II or general formula III Object or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, wherein bullet is selected from acryloyl group, metering system Acyl group and propargyl acyl group.

In other preferred embodiments of the invention, according to general formula I, general formula II or general formula III compound represented Or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, wherein each R³、R⁴It is each independently selected from C_1-6Alkane Base, C_1-6Alkoxy；Preferably C_1-3Alkyl, C_1-3Alkoxy；Be more preferably selected from methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, wherein n is selected from 0,1 and 2 and p and is selected from 0,1 and 2.

In other preferred embodiments, according to general formula I, general formula II or general formula III compound represented or its medicine Acceptable salt, isomers, solvate, crystallization or prodrug are learned, wherein R₅Selected from halogen, C_1-6Alkoxy；It is preferably selected from halogen Element, C_1-3Alkoxy；R⁴Non-limiting example include fluorine, chlorine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, wherein q is selected From 0,1,2,3,4 and 5；In some specific embodiments, each R₅Selected from fluorine, chlorine, methoxyl group, ethyoxyl, propoxyl group, isopropyl Oxygroup, q 4.

In other preferred embodiments, according to general formula I, general formula II or general formula III compound represented or its medicine Acceptable salt, isomers, solvate, crystallization or prodrug are learned, wherein R₆Selected from for H and C_1-6Alkyl.

In other preferred embodiments, according to general formula I, general formula II or general formula III compound represented or its medicine Acceptable salt, isomers, solvate, crystallization or prodrug are learned, wherein R₇Selected from H and C_1-6Alkyl, preferably C_1-3Alkyl, more It is preferably selected from methyl, ethyl and isopropyl.

In some embodiments, according to general formula I, general formula II or general formula III compound represented or its is pharmaceutically acceptable Salt, isomers, solvate, crystallization or prodrug, wherein：

G is selected from CH and N；

X is selected from CH and N；

R₃Selected from C_1-3Alkoxy and C_1-3Alkyl, n 1；

P is 0；

R₅Selected from halogen and C_1-3Alkoxy, q 4；

R₆Selected from for H and C_1-6Alkyl；

R₇Selected from for H and C_1-6Alkyl.

In other preferred embodiments, according to general formula I, general formula II or general formula III compound represented or its medicine Acceptable salt, isomers, solvate, crystallization or prodrug are learned, wherein the salt is preferably phosphate, sulfate, hydrochloric acid Salt, hydrobromate, citrate, maleate, malonate, mandelate, succinate, fumarate, acetate, lactic acid Salt, nitrate, sulfonate, tosilate, malate or mesylate, more preferably mesylate.

In some specific embodiments of the invention, the general formula I, general formula II or general formula III compound represented Or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug non-limiting example include：

Second aspect, the present invention provide the preparation method of compounds of formula I, and this approach includes the following steps：

(1), formula i compound obtains formula iii compound by palladium mediated coupling reaction with formula ii compound；

(2), the nitro in the aromatic ring of formula iii compound or heteroaromatic is reduced to amino, obtains formula iv compound；

(3), formula iv compound and bullet-LG2 obtain compound of formula I by amide coupling reaction；

Wherein bullet, X, G, R₁、R₂、R₃、R₄、R₅、R₆、R₇, n, p, q have such as the definition in general formula I；

LG1, LG2 represent leaving group, can be the same or different, preferably halogen or sulfonyloxy, more preferably Cl,Br,I；

M can be-B (OR₁₁)₂,-Sn (alkyl) or-Zn- halogen-, wherein R₁₁For H or alkyl, preferably methyl.

Fragrant level-one amine, which is made, in nitro compound reduction can be used conventional reduction reaction, and common reagent has metal to add Acid, metal iron, zinc or tin, sour hydrochloric acid, sulfuric acid or acetic acid etc.；

Nitro can also be restored with catalytic hydrogenation, custom catalysts have Ni, Pt, Pd etc., and reaction is in neutral conditions It carries out.

In compound of Formula I provided by the invention or its pharmaceutically acceptable salt, isomers, solvate, crystallization or preceding On the basis of the preparation method of medicine, those skilled in the art select conventional raw material that general formula II or general formula III chemical combination can be obtained Object or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug.

In some embodiments, the present invention provides the preparation method of compounds of formula II of the invention, this method packet Include following steps：

(1), 1 compound of formula obtains 3 compound of formula by palladium mediated coupling reaction with 2 compound of formula；

(2), the nitro in the aromatic ring of 3 compound of formula or heteroaromatic is reduced to amino, obtains 4 compound of formula；

(3), 4 compound of formula and bullet-LG2 obtain Formula II compound by amide coupling reaction；

Its middle ring A, bullet, X, G, R₃、R₄、R₅、R₆、R₇, n, p, q have such as the definition in general formula II；

LG1, LG2 represent leaving group, can be the same or different, preferably halogen or sulfonyloxy, more preferably Cl,Br,I；

M can be-B (OR₁₁)₂,-Sn (alkyl) or-Zn- halogen-, wherein R₁₁For H or alkyl, preferably methyl.

Fragrant level-one amine, which is made, in nitro compound reduction can be used conventional reduction reaction, and common reagent has metal to add Acid, metal iron, zinc or tin, sour hydrochloric acid, sulfuric acid or acetic acid etc.；

Nitro can also be restored with catalytic hydrogenation, custom catalysts have Ni, Pt, Pd etc., and reaction is in neutral conditions It carries out.

The third aspect, the present invention provide pharmaceutical composition, and it includes change shown in general formula I of the present invention, general formula II or general formula III Close object or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.

Compound shown in general formula I, general formula II or general formula III or its pharmaceutically acceptable salt, isomers, solvent can be closed Object, crystallization or prodrug and pharmaceutically acceptable carrier are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral. Medication includes, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be with It is applied by any approach, such as by being transfused or injecting, passes through transepithelial or mucocutaneous (such as oral mucosa or rectum Deng) absorb approach application.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid agent Type, specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can pass through Methods known in the art preparation, and include the conventional use of carrier of field of pharmaceutical preparations.

Fourth aspect, compound shown in present invention offer general formula I, general formula II or general formula III or its pharmaceutically acceptable salt, It the method for isomers, solvate, crystallization or prodrug or medicine composite for curing of the invention and/or pre- preventing tumor and is preparing It treats and/or prevents the application in tumour medicine, including easily send out crowd or tumor patient application general formula I of the present invention to tumour, lead to Formula II or general formula III compound represented, isomers, solvate, crystallization or prodrug include general formula I of the present invention, general formula The pharmaceutical composition of compound shown in II or general formula III, isomers, solvate, crystallization or prodrug, tumour hair is effectively reduced Raw rate extends tumor patient life.

The present invention provides compound shown in general formula I, general formula II or general formula III or its pharmaceutically acceptable salt, isomers, molten The disease that object, crystallization or prodrug are closed in agent or pharmaceutical composition of the invention is used to treat and/or prevent to be mediated by FGFR-4 or FGF19 The method of disease or illness and in preparation treatment and/or prevent by the drug of FGFR-4 or the FGF19 disease mediated or illness Application, it is characterised in that individual in FGFR-4 or FGF19 overexpression, FGFR4 or FGF19 amplification.It is preferred real at one It applies in scheme, one kind having compound shown in general formula I, general formula II or general formula III or its pharmaceutically acceptable salt, isomers, molten Agent close the method for object, crystallization or prodrug or medicine composite for curing of the invention and/or pre- preventing tumor and in preparation treatment and/or Prevent the application in tumour medicine, wherein the tumour is mediated by FGFR4.In a preferred embodiment, one kind has Compound shown in general formula I, general formula II or general formula III or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug Or medicine composite for curing and/or pre- preventing tumor of the invention method and preparation treatment and/or prevention tumour medicine in Using wherein the tumour is selected from liver cancer, rhabdomyosarcoma, pernicious adenocarcinoma of lung, glioblastoma, esophageal squamous cell carcinoma, evil Property Peripheral Nerve Sheath Tumours, breast cancer, prostate cancer, oophoroma, gastric cancer, cancer of pancreas, colon cancer and clear-cell carcinoma.It is excellent at one In the embodiment of choosing, one kind having compound or its pharmaceutically acceptable salt, isomery shown in general formula I, general formula II or general formula III It the method for body, solvate, crystallization or prodrug or medicine composite for curing of the invention and/or pre- preventing tumor and is treated in preparation And/or the application in prevention tumour medicine, wherein the tumour is selected from a preferred embodiment, one kind having general formula I, compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug shown in general formula II or general formula III or this The method and the application in preparation treatment and/or prevention tumour medicine of the medicine composite for curing of invention and/or pre- preventing tumor, Wherein the tumour is selected from breast cancer, oophoroma, lung cancer, liver cancer and sarcoma.In a specific embodiment, the liver cancer For hepatocellular carcinoma.The reduction of FGF19 level can promote bile acid biosynthesis, therefore the compound for reducing FGF19 level can be used for controlling Treat hyperlipidemia.In a specific embodiment, the present invention provide compound shown in general formula I, general formula II or general formula III or Its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug or medicine composite for curing of the invention and/or prevention The method of hyperlipidemia and the application in the drug of preparation treatment and/or prevention hyperlipidemia.

Term explanation：

Unless otherwise defined, all technical and scientific terms used herein has and common skill of the art The normally understood identical meaning of art personnel.

" isomers " of the invention includes the cis-trans-isomer of cis or trans configuration, also includes the mapping that chiral carbon generates Isomers and diastereoisomer.

It is pharmaceutically acceptable that " pharmaceutically acceptable salt " of the invention refers to that compound of the present invention is formed with acid Salt, the acid can be selected from：Phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, Fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, methanesulfonic acid etc..

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

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

" prodrug " of the invention refer under the physiological condition of organism, due to reacting and conversion cost with enzyme, gastric acid etc. The compound of invention is converted to the compound of the present invention by the oxidation of enzyme, reduction, hydrolysis etc. and/or by gastric acid etc. Hydrolysis etc. is converted to the compound of the compound of the present invention.

" pharmaceutical composition " of the invention refer to comprising any compound as described herein, including isomers, prodrug, Solvate, the protection form of pharmaceutically acceptable salt or its chemistry and one or more pharmaceutically acceptable carriers it is mixed Close object.

" bullet " of the invention is the part that covalent bond is formed with nucleopilic reagent, and the covalent bond is the bullet in inhibitor It is formed between the cysteine ??acid residue of FGFR4.The bullet includes but is not limited to alkyl halide, sulfonic acid alkyl ester, heteroaryl Halide, epoxides, halogen acetamide, maleimide, sulphonic acid ester, alpha-beta beta-unsaturated ketone, alpha-beta beta-unsaturated esters, ethylene Base sulfone, propargyl acyl group, acryloyl group.The structure of exemplary bullet is as follows：

Wherein Xa represents leaving group, can be halogen or activated hydroxylic moiety (such as triflate)；R_a、 R_b、R_cIt is each independently selected from H, optional substituted or unsubstituted alkyl, optional substituted or unsubstituted naphthenic base, cyano Deng wherein the substituent group is selected from one or more halogens, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyanogen Base, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl alkyl.

" naphthenic base " of the invention refers to the unsaturated monocycle of saturation or part or polycyclic substituent group comprising 3-20 carbon Atom, preferably 4-13 carbon atom.The non-limiting example of monocycle alkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentene Base, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopenta, cyclohexyl. Multi-ring alkyl includes the naphthenic base of loop coil, condensed ring and bridged ring.

" spiro cycloalkyl group " of the invention refers to 5-20 member, and the polycyclic group of a carbon atom (claiming spiro-atom) is shared between monocycle Group, spiro cycloalkyl group can contain one or more double bonds, preferably 5-14 member, more preferably 7-10 member.According between ring and ring Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl groups or more spiro cycloalkyl groups by the number of shared spiro-atom, preferably single spiral shell Naphthenic base or double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan lists Spiro cycloalkyl group.The non-limiting example of loop coil includes

" cycloalkyl " of the invention refers to 5-20 member, other rings in each ring and system in system are shared to be adjoined The polycyclic alkyl group of a pair of of carbon atom, wherein one or more rings can be containing one or more double bonds, and preferably 6-14 is first, More preferably 7-10 member, can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl according to a group cyclic number, preferably double Ring or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl.The non-limiting example of cycloalkyl is：

" bridge ring alkyl " of the invention refers to 5 to 20 yuan, and any two ring shares two carbon atoms being not directly connected Full carbon polycyclic moiety, these can contain one or more double bonds.Preferably 6-14 member, more preferably 7-10 member.According to composition The number of ring can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic naphthene base, preferably bicyclic, tricyclic or Fourth Ring, more preferably bicyclic Or tricyclic.The non-limiting example of bridge ring alkyl includes

Naphthenic base of the invention can be substituted or unsubstituted, and when substituted, substituent group can make any It is substituted on tie point, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitre Base, azido, alkyl, alkenyl, alkynyl group, naphthenic base, heterocycle, heterocycle oxygroup, heterocyclylamino group, heterocyclic thio, Aryl, aryloxy, artyl sulfo, heteroaryl, heteroaryl oxygroup.

" heterocycle " of the invention refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3-20 A annular atom, wherein one or more annular atoms are selected from N, O and S (O)_e(wherein e be 0 to 2 integer) hetero atom, remaining ring Atom is carbon.Wherein heterocycle preferably includes 3-12 annular atom, wherein containing 1-4 hetero atom；More preferably heterocycle packet Containing 5-11 annular atom, wherein 1-2 are hetero atoms.

" Heterocyclylalkyl " of the invention refers to saturation or unsaturation, non-aromatic monocyclic, condensed ring, loop coil or bridged ring, contains There is 3-20 carbon atom and containing hetero atom such as N, O or S to substitute one or more C atoms.The example of Heterocyclylalkyl includes Tetrahydrofuran base, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazine Base, indolinyl, iso-dihydro-indole-group, morpholinyl, thio-morpholinyl, high morpholinyl, homopiperidinyl, high piperazine base, high-sulfur For morpholinyl, thio-morpholinyl-S- oxide, thio-morpholinyl-S, S- dioxide, pyranose, THP trtrahydropyranyl, tetrahydro thiophene Pheno base, high thio-morpholinyl-S, S- dioxide, oxazolidine radical, pyrazoline base, pyrrolin base, dihydro pyrazine base, dihydro Pyridyl group, dihydro-pyrimidin base, dihydrofuryl, dihydro pyranyl, tetrahydro-thienyl-S- oxide, tetrahydro-thienyl-S, S- bis- Oxide, high thio-morpholinyl-S- oxide, 2- oxa- -5- azabicyclo [2.2.1] heptane, 8- oxa- -3- azabicyclo [3.2.1] octane, 3,8- diazabicyclo [3.2.1] octane, 2,5- diazabicyclo [2.2.1] heptane, 3,8- diaza are double Ring [3.2.1] octane, 3,9- diazabicyclo [4.2.1] nonane and 2,6- diazabicyclo [3.2.2] nonane.

" spiro heterocyclic radical " refers to 5-20 member, and the polycyclic heterocyclic group of an atom (spiro-atom) is shared between monocycle, wherein One or more annular atoms are selected from N, O and S (O)_e(wherein e be 0 to 2 integer) hetero atom, remaining annular atom is carbon, and spiral shell is miscellaneous Naphthenic base can contain one or more double bonds, preferably 6-14 member, more preferably 7-12 member.When containing one or more nitrogen-atoms Spiro heterocyclic radical, referred to as " nitrogen spiro heterocyclic radical ".Spiro cycloalkyl group is divided into single spiral shell according to the number for sharing spiro-atom between ring and ring Heterocycle, double spiro heterocyclic radicals or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical or double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 Member/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical includes

" condensed hetero ring base " of the invention refers to 5-20 member, other rings in each ring and system in system are shared to be adjoined The polycyclic heterocyclic group of a pair of of atom, wherein one or more rings can be containing one or more double bonds, wherein one or more Annular atom is selected from N, O or S (O)_e(wherein e be 0 to 2 integer) hetero atom, remaining annular atom be carbon.Preferably 6-14 member, More preferably 7-12 member.When the condensed hetero ring base containing one or more nitrogen-atoms, referred to as " nitrogen condensed hetero ring base ".According to group cyclic Number can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 Member/5 yuan or 5 yuan/6 membered bicyclic alkyl.The non-limiting example of fused ring heterocycle base includes

" bridge heterocycle " of the invention refers to 5-14 member, and any two ring shares the polycyclic of two atoms being not directly connected Heterocyclic group, these can be selected from N, O or S (O) containing one or more double bonds, wherein one or more annular atoms_e(wherein e 0 to 2 integer) hetero atom, remaining annular atom be carbon.Preferably 6-14 member, more preferably 7-12 member.When containing one or The bridge heterocycle of multiple nitrogen-atoms, referred to as " nitrogen bridge heterocycle ".Bicyclic, tricyclic, Fourth Ring can be divided into according to a group cyclic number Or polycyclic bridged ring base, preferably bicyclic, tricyclic or Fourth Ring, the non-limiting example of bridged ring heterocycle include

These bridges Heterocycle is optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, Nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl Base, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

Heterocycle can be substituted or unsubstituted, and when substituted, substituent group can be in any workable connection It is substituted on point, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, nitrine Base, alkyl, alkenyl, alkynyl group, naphthenic base, heterocycle, heterocycle oxygroup, heterocyclylamino group, heterocyclic thio, aryl, virtue Base oxygroup, artyl sulfo, heteroaryl, heteroaryl oxygroup.

Of the inventionRefer to the heterocycle containing one or more nitrogen-atoms, referred to as " Azacyclyl ".Institute Stating heterocycle can also be containing other one or more hetero atom, such as O or S (O)_e(wherein e be 0 to 2 integer).As ring A When for single heterocycle, the present invention is referred to as " nitrogen list heterocycle "；When ring A is more heterocycles, the present invention is referred to as " the more heterocycles of nitrogen Base "；Successively column push away, and when ring A is single spiro heterocyclic radical, the present invention is referred to as " nitrogen list spiro heterocyclic radical ".

" aryl " of the invention, which refers to, may include monocycle or the multi-fused rings such as aromatic series of two rings or the aromatic rings of tricyclic, A part of wherein at least condensed ring forms the aromatic series of conjugation, contains 5 to 50 carbon atoms, and preferably from about 6 to about 14 Carbon atom.Suitable aryl includes but is not limited to phenyl, naphthalene, xenyl, anthryl, tetralyl, fluorenyl, indanyl, sub- connection Phenyl and acenaphthenyl.

Aryl can be substituted or unsubstituted, and when substituted, substituent group can be in any workable tie point It is upper to be substituted, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, Alkyl, alkenyl, alkynyl group, naphthenic base, heterocycle, heterocycle oxygroup, heterocyclylamino group, heterocyclic thio, aryl, aryl oxide Base, artyl sulfo, heteroaryl, heteroaryl oxygroup.

" heteroaryl " of the invention refers at least one carbon atom quilt of aromatic monocyclic or multi-fused rings such as two rings or tricyclic The aromatic radical of hetero atom substitution, the hetero atom are O, S, N.Suitable heteroaryl includes but is not limited to imidazole radicals, benzene And imidazole radicals, imidazopyridyl, quinazoline ketone group, pyrrole radicals, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl, Thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl etc..

Heteroaryl can be substituted or unsubstituted, and when substituted, substituent group can be in any workable connection It is substituted on point, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, nitrine Base, alkyl, alkenyl, alkynyl group, naphthenic base, heterocycle, heterocycle oxygroup, heterocyclylamino group, heterocyclic thio, aryl, virtue Base oxygroup, artyl sulfo, heteroaryl, heteroaryl oxygroup.

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

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

" alkyl " of the invention refers to linear or branched saturated hydrocarbon base, preferably C_1-8Alkyl, more preferable C_1-6Alkyl.Alkane The non-limiting example of base include base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl fourth Base, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2, 2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- Dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2, 3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- Dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethyl penta Base.

Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be in any workable tie point It is upper to be substituted, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, Alkyl, alkenyl, alkynyl group, naphthenic base, heterocycle, heterocycle oxygroup, heterocyclylamino group, heterocyclic thio, aryl, aryl oxide Base, artyl sulfo, heteroaryl, heteroaryl oxygroup.

" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen atom.

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

" halogenated alkoxy " of the invention refers to the alkoxy at least replaced by a halogen, preferably at least by a halogen The C that element replaces_1-6Alkoxy, the C more preferably at least replaced by a halogen_1-3Alkoxy, suitable halogenated C_1-3Alcoxyl Base is chloromethane epoxide, fluorine methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy；Two chloroethoxies, Difluoroethoxy, tri-chloroethoxy base, trifluoro ethoxy.

" nitro " of the invention refers to-NO₂。

" cyano " of the invention refers to-CN.

" hydroxyl " of the invention refers to-OH.

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

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

" amino " of the invention refers to-NH₂,-NH- (alkyl) or-N (alkyl) (alkyl).

" aminoalkyl " of the invention refers to NH₂Alkyl-, (alkyl) NH- alkyl-or (alkyl) (alkyl) N- alkyl-.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.

" hydrogen ", " carbon " in the compounds of this invention include its all isotope.Isotope is understood to include with identical Atomicity but there is those of different quality number atom, such as the isotope of hydrogen includes tritium and deuterium, the isotope of carbon includes¹³C With¹⁴C。

Specific embodiment

It further describes with reference to embodiments, explain the present invention, but these embodiments are not meant as the limitation present invention Range.Material used in the following embodiment is commercially available unless otherwise specified.

Embodiment 1：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (4- methylpiperazine-1-yl) phenyl) acrylamide preparation

Step 1：The preparation of 3,5- dimethoxyphenylacetic acid methyl esters

3,5- dimethoxyphenylacetic acid (20g, 100mmol), DMF (0.15mL) and methanol are added in single neck bottle (300mL) is slowly added to thionyl chloride (22mL, 300mmol) at room temperature, is stirred overnight at room temperature.TLC(EA：PE=1:1) it shows Fully reacting.Vacuum rotary steam removes solvent, and residue is neutralized through sodium bicarbonate aqueous solution, ethyl acetate (250 × 3mL) extraction, Organic phase is dried over anhydrous sodium sulfate, is concentrated, and obtains yellow oil 23g, yield 100%.ESI-MS m/z:211.2[M+H]⁺.

Step 2：The preparation of the chloro- 4- ethylamino ethyl nicotinate of 6-

4,6- dichloro-nicotinic acid ethyl ester (25g, 100mmol), DIPEA (25.8g, 200mmol) and second are added in single neck bottle Ethamine alcoholic solution (5.4g, 120mmol) is added at room temperature in nitrile (200mL), and 70 DEG C are stirred overnight.TLC(EA：PE=1:2) it shows Fully reacting.Vacuum rotary steam removes solvent, adds water 300mL, ethyl acetate (250 × 3mL) extraction, organic phase is through anhydrous sodium sulfate Dry, concentration, obtains yellow oil 20g, yield 90%.ESI-MS m/z：229.2[M+H]⁺.

Step 3：The preparation of the chloro- 4- ethylamino nicotinic alcohol of 6-

The chloro- 4- ethylamino ethyl nicotinate (20g, 90mmol) of 6- and THF (200mL) are added in single neck bottle, delays at room temperature It is slow that LiAlH is added₄(8g, 200mmol), is stirred at room temperature 3h.TLC(EA：PE=1:2) fully reacting is shown.Sodium hydroxide is water-soluble Liquid (1N, 20mL) is quenched, filtering, and in filtrate plus water 300mL, ethyl acetate (250 × 3mL) extract, and organic phase is through anhydrous slufuric acid Sodium is dry, is concentrated, and obtains yellow oil 20g, yield 100%.ESI-MS m/z：187.2[M+H]⁺.

Step 4：The preparation of the chloro- 4- ethylamino cigarette aldehyde of 6-

Be added in single neck bottle the chloro- 4- ethylamino nicotinic alcohol (15g, 80mmol) of 6-, manganese dioxide (104g, 1196mmol) and DCM (300mL), is stirred overnight at room temperature.TLC(EA：PE=1:2) fully reacting is shown.Filtering, DCM (100 × 3mL) washing, filter Liquid concentration, obtains yellow oil 15g, yield 100%.ESI-MS m/z:185.2[M+H]⁺.

Step 5：The preparation of -2 (1H) -one of the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- ethyl -1,6- naphthyridines

The chloro- 4- ethylamino cigarette aldehyde (10g, 54.3mmol) of 6-, 3,5- dimethoxyphenylacetic acid methyl esters are added in single neck bottle (11.55g, 55mmol), potassium carbonate (13.8g, 100mmol) and DMF (30mL), argon gas protection, 105 DEG C are stirred 3 hours.LC- MS shows fully reacting.Filtering, ethyl acetate (50 × 3mL) wash, and water 100mL, ethyl acetate (150 × 3mL) are added in filtrate Extraction, organic phase are dried over anhydrous sodium sulfate, are concentrated, and obtain brown oil 12g, are directly used in and react in next step, yield 64%. ESI-MS m/z:345.1[M+H]⁺.

Step 6：The system of -2 (1H) -one of the chloro- 3- of 7- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines It is standby

In single neck bottle be added the chloro- 3- of 7- (3,5- Dimethoxyphenyl)-ethyl -1,6- naphthyridines -2 (1H) -one (10g, 28mmol) and acetonitrile (300mmol), sulfonic acid chloride (4.8mL, 60mmol) is added dropwise under ice bath, continues stirring 1 hour.LC-MS is shown Fully reacting.Filtering, filter cake are washed with acetonitrile (20 × 2mL), obtain white solid 10g, are directly used in and are reacted in next step, yield 84%.ESI-MS m/z:413.1[M+H]⁺.

Step 7：The preparation of 1- (the bromo- 2- nitrobenzophenone of 4-) -4- methyl piperazine

Be added in single neck bottle the bromo- 2- nitrobenzene (2.2g, 10mmol) of the fluoro- 1- of 4-, methyl piperazine (1.2g, 12mmol), DIPEA (2.6g, 20mmol) and THF (30mmol), 70 DEG C of stirring 1h.LC-MS shows fully reacting.Rotary evaporation is concentrated to give Huang Color grease 3g, yield 100%.ESI-MS m/z:300.0[M+H]⁺.

Step 8：1- methyl -4- (2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) benzene Base) piperazine preparation

1- (the bromo- 2- nitrobenzophenone of 4-) -4- methyl piperazine (3g, 10mmol), connection boric acid pinacol are added in single neck bottle Ester (5g, 20mmol), potassium acetate (3g, 30mmol), two (triphenylphosphines) close palladium chloride (0.7g, 1mmol) and Isosorbide-5-Nitrae-dioxy six Ring (30mL), argon gas protection, 80 DEG C are stirred overnight.LC-MS shows fully reacting.Remove solvent, residue through silica gel column chromatography, Obtain yellow oil 2g.ESI-MS m/z:348.2[M+H]⁺.

Step 9：3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -7- (4- (4- methylpiperazine-1-yl) -3- Nitrobenzophenone) -1,6- naphthyridines -2 (1H) -one preparation

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- ethyl -1,6- naphthyridines -2 (1H) -one (1g, 2.4mmol), 1- methyl -4- (2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine Piperazine (0.84g, 2.4mmol), tetrakis triphenylphosphine palladium (277mg, 0.24mmol), sodium carbonate (5g, 4.8mmol), Isosorbide-5-Nitrae-dioxy Six rings (40mL) and water (10mL) are set in a round bottom flask, and argon gas displaces the air in system, 80 DEG C of reaction 5h, end of reaction Afterwards, Isosorbide-5-Nitrae-dioxane therein is evaporated off, column chromatographs to obtain yellow solid 440mg, yield 46%.ESI-MS m/z:598.1[M+ H]⁺.

Step 10：7- (3- amino -4- (4- methylpiperazine-1-yl) phenyl) -3- (chloro- 3,5- dimethoxy benzene of 2,6- bis- Base) -1- ethyl -1,6- naphthyridines -2 (1H) -one preparation

By 3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -7- (4- (4- methylpiperazine-1-yl) -3- nitro Phenyl) -1,6- naphthyridines -2 (1H) -one (440mg, 0.6mmol) is dissolved in ethyl alcohol (10ml), be added ammonium chloride (168mg, 3mmol), iron powder (200mg, 3.6mmol), H₂After O (2ml), 80 DEG C of reaction 1h.After the reaction was completed, it is filtered to remove insoluble matter, is received Collect filtrate, DCM extraction, saturation NaCl solution washing, DCM layers dry, anhydrous Na₂SO₄Dry, revolving obtains yellow solid 400mg, Yield 89.5%.ESI-MS m/z:568.1[M+H]⁺.

Step 11：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (4- methylpiperazine-1-yl) phenyl) acrylamide preparation

3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -7- (4- (4- methyl piperazine-is added in single neck bottle 1- yl) -3- nitrobenzophenone) -1,6- naphthyridines -2 (1H) -one (400mg, 0.7mmol), DIPEA (1mL) and anhydrous THF (20mL) is added with stirring acryloyl chloride (50 μ l, 0.7mmol) at -10 DEG C, continues to stir 20min.LC-MS display has been reacted Entirely.0.1mL water essence is added to go out, methylene chloride extraction, column chromatographs to obtain faint yellow solid 200mg, yield 52.4%.¹H-NMR (500MHz,CDCl₃):δ1.45(s,3H),2.44(s,3H),2.68(m,4H),3.02(t,4H),3.98(s,6H),4.48 (q,2H),5.85(d,1H),6.38(d,1H),6.48(d,1H),6.67(s,1H),7.36(d,1H),7.66(s,1H),7.72 (s,1H),7.91(dd,1H),8.69(s,1H),8.88(s,1H),9.16(s,1H).ESI-MS m/z:622.1[M+H]⁺.

Embodiment 2：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- isopropyl -2- oxo -1,2- dihydro - 1,6- naphthyridines -7- base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) acrylamide preparation

Step 1：The preparation of 6- chloro- 4- (isopropylamino) ethyl nicotinate

4,6- dichloro-nicotinic acid ethyl ester (10g, 45.45mmol) is dissolved in 100mL acetonitrile, addition DIPEA (6.2g, 47.73mmol), isopropylamine (2.82g, 47.73mmol) is slowly added dropwise at -5 DEG C, 70 DEG C are stirred overnight, and are added in reaction solution A large amount of water, ethyl acetate extraction is dry, is spin-dried for obtaining title compound.ESI-MS m/z:243[M+H]⁺

Step 2：The preparation of (6- chloro- 4- (isopropylamino) pyridin-3-yl) methanol

6- chloro- 4- (isopropylamino) ethyl nicotinate (10g, 41.32mmol) is dissolved in 100ml tetrahydrofuran, room temperature Under be slowly added to LiAlH₄(3.14g, 82.64mmol), is stirred at room temperature 3h, is quenched instead with sodium hydrate aqueous solution (1N, 16mL) It answers, filters, filtrate is extracted with ethyl acetate, and it is dry, it is spin-dried for obtaining title compound.ESI-MS m/z:201[M+H]⁺.

Step 3：The preparation of 6- chloro- 4- (isopropylamino) cigarette aldehyde

(6- chloro- 4- (isopropylamino) pyridin-3-yl) methanol (8g, 40mmol) is dissolved in 20mL methylene chloride, room It is slowly added to manganese dioxide (34.78g, 400mmol) under temperature, is stirred overnight at room temperature, filters, is spin-dried for obtaining title compound.ESI- MS m/z:199[M+H]⁺

Step 4：The preparation of -2 (1H) -one of the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- isopropyl -1,6- naphthyridines

By 6- chloro- 4- (isopropylamino) cigarette aldehyde (2g, 10.1mmol), 2- (3,5- Dimethoxyphenyl) methyl acetate (4.24g, 20.2mmol) and potassium carbonate (4.18g, 30.3mmol) are dissolved in 10mL DMF, argon gas protection, are reacted at 110 DEG C 7h dilutes reaction solution with saturated sodium chloride solution, ethyl acetate extraction, dry, is spin-dried for obtaining title compound.ESI-MS m/ z:359[M+H]⁺

Step 5：- 2 (1H) -one of the chloro- 3- of 7- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- isopropyl -1,6- naphthyridines Preparation

- 2 (1H) -one (358mg, 1mmol) of the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- isopropyl -1,6- naphthyridines is dissolved in In 10mLTHF, sulfonic acid chloride (400ul) is added dropwise under ice bath, 30min is stirred at room temperature, reaction solution is quenched with saturated sodium bicarbonate solution It goes out, ethyl acetate extraction is dry, is spin-dried for obtaining title compound.ESI-MS m/z:427[M+H]⁺

Step 6：The preparation of 1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -4- ethyl piperazidine

The fluoro- 2- methoxyl group -5- nitrobenzene (1.3g) of the bromo- 4- of 1- is dissolved in 10mL 1- ethyl piperazidine, is stirred at 70 DEG C Reaction solution is diluted with water by 2h, ethyl acetate extraction, dry, is spin-dried for obtaining title compound.ESI-MS m/z:344[M+H]⁺.

Step 7：1- ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxa boron heterocycle Pentane -2- base) phenyl) piperazine preparation

By 1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -4- ethyl piperazidine (1g, 2.92mmol), connection boric acid pinacol ester (0.811g, 3.21mmol), [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (0.214g, 0.292mmol) and acetic acid Potassium (0.858g, 8.76mmol) sequentially adds 10mL1, in 4- dioxane, argon gas protection, and 95 DEG C of reaction 2h, by reaction solution mistake Filter, filtrate are washed with saturation NaCl solution, ethyl acetate extraction, dry, are spin-dried for obtaining title compound.ESI-MS m/z:391[M +H]⁺.

Step 8：3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -7- (4- (4- ethyl piperazidine -1- base) -2- methoxyl group - 5- nitrobenzophenone) -1- isopropyl -1,6- naphthyridines -2 (1H) -one preparation

By 1- ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) phenyl) piperazine (700mg), the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- isopropyl -1,6- naphthyridines -2 (1H) -one (300mg), two (triphenylphosphine) palladium chlorides (25mg), potassium carbonate (290mg) sequentially add 15mL1,4- dioxy six In ring and 8mL water, argon gas protection, back flow reaction 2h filters reaction solution, and filtrate is washed with saturation NaCl solution, ethyl acetate Extraction, it is dry, it is spin-dried for obtaining title compound.ESI-MS m/z:656[M+H]⁺

Step 9：N- (5- (dihydro -1 3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- isopropyl -2- oxo -1,2-, 6- naphthyridines -7- base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) acrylamide preparation

Preparation method is similar to 1 step 10 of embodiment, 11.¹H-NMR(400MHz,CDCl₃):δ1.23(t,3H),1.71 (d,6H),2.63(q,2H),2.78(s,4H),3.08-3.14(m,5H),3.91(s,3H),3.98(s,6H),5.79(d, 1H),6.28-6.34(m,1H),6.43(d,1H),6.66(s,1H),6.91(s,1H),7.65(s,1H),8.08(s,1H), 8.28(s,1H),8.86(s,1H),8.96(s,1H).ESI-MSm/z:680.3[M+H]⁺.

Embodiment 3：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7-

Base) -2- (- 4- ethyl piperazidine -1- base) -6- methoxypyridine -3- base) acrylamide preparation

Step 1：The preparation of the bromo- 6- methoxyl group -3- nitropyridine -2- amine of 5-

6- methoxyl group -3- nitropyridine -2- amine (7.8g, 46mmol) is dissolved in 150mL DMF, N- bromo succinyl is added Imines (NBS) (9g, 51mmol), is stirred at room temperature 1 hour, and saturation NaCl solution is added, and ethyl acetate extracts dry column and chromatographs Title compound.ESI-MS m/z:248.0[M+H]⁺.

Step 2：The preparation of the fluoro- 2- methoxyl group -5- nitropyridine of the bromo- 6- of 3-

The pyridine that the bromo- 6- methoxyl group -3- nitropyridine -2- amine (1.85g, 7.5mmol) of 5- is dissolved in 30mL hydrogen fluoride is molten Liquid is cooled to -78 DEG C, is added portionwise sodium nitrite (570mg, 8.25mmol), rises to 0 DEG C of stirring 30min after stirring 30min, Then 60 DEG C of stirring 30min are risen to, ice water is quenched, and 1N sodium hydrate aqueous solution neutralizes, and mark is dried to obtain in ethyl acetate extraction Inscribe compound.ESI-MS m/z：250.9[M+H]⁺.

Step 3：The preparation of 1- (the bromo- 6- methoxyl group -3- nitropyridine -2- base of 5-) -4- ethyl piperazidine

The fluoro- 2- methoxyl group -5- nitropyridine (1.6g) of the bromo- 6- of 3- is dissolved in 5mL n-ethylpiperazine, 90 DEG C of heating stirrings 1 Hour, saturation NaCl solution is added, ethyl acetate extraction is dry to be spin-dried for up to title compound.ESI-MS m/z：345.1[M+ H]⁺.

Step 4：1- ethyl -4- (6- methoxyl group -3- nitro -5- (4,4,5,5- tetramethyl -1,3,2- dioxa boron heterocycle Pentane -2- base) pyridine -2- base) piperazine preparation

1- (the bromo- 6- methoxyl group -3- nitropyridine -2- base of 5-) -4- ethyl piperazidine (1.3g) is dissolved in 20mL 1,4- dioxy Connection boric acid pinacol ester (1.9g), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (0.25g) and vinegar is added in six rings Sour potassium (1.11g), nitrogen protection, 100 DEG C heating stirring 3 hours, filtering, be spin-dried for, ethyl acetate dissolution, saturation NaCl solution wash It washs, is spin-dried for, petroleum ether is spin-dried for up to title compound.ESI-MS m/z:393.3[M+H]⁺.

Step 5：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- (- 4- ethyl piperazidine -1- base) -6- methoxypyridine -3- base) acrylamide preparation

Preparation method is similar to 1 step 9 of embodiment, 10,11, the difference is that by the raw material 1- methyl -4- (2- in step 9 Nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with the gained of above-mentioned steps 4 Object 1- ethyl -4- (6- methoxyl group -3- nitro -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) pyrrole Pyridine -2- base) piperazine.¹H-NMR(400MHz,DMSO-d6):δ 1.04 (t, 3H), 1.32 (t, 3H), 2.34 (q, 2H), 2.46- 2.61 (m, 4H), 3.37-3.46 (m, 4H), 3.94 (s, 6H), 4.00 (s, 3H), 4.29 (q, 2H), 5.77 (d, 1H), 6.25 (d, 1H), 6.44-6.52 (m, 1H), 7.02 (s, 1H), 8.01 (s, 1H), 8.18 (s, 1H), 8.50 (s, 1H), 8.95 (s, 1H), 9.56 (s, 1H) .ESI-MS m/z:667.4[M+H]⁺.

Embodiment 4：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (4- ethyl piperazidine -1- base) phenyl) acrylamide preparation

Preparation method similar embodiment 1, the difference is that the raw material methyl piperazine in step 7 is replaced with 1- ethyl piperazidine.

¹H-NMR(400MHZ.CDCl₃):δ1.19(t,3H),1.47(t,3H),2.55(q,2H),2.62-2.80(m, 4H),3.03(t,4H),3.98(s,6H),4.47(q,2H),5.84(d,1H),6.32-6.38(m,1H),6.45(d,1H), 6.67(s,1H),7.35(d,1H),7.66(s,1H),7.71(s,1H),7.90(d,1H),8.71(s,1H),8.88(s,1H), 9.16(s,1H).ESI-MSm/z:636.2[M+H]⁺

Embodiment 5：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (- 4- ethyl -3,5- lupetazin -1- base) -4- methoxyphenyl) acrylamide preparation

Step 1：The preparation of (3S, 5R) -1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -3,5- lupetazin

In the method for 1 step 7 of embodiment, with the fluoro- 2- methoxyl group -5- nitrobenzene of the bromo- 4- of 1- and cis- 2,6-dimethyl-piperizine For raw material, synthesising title compound.ESI-MS m/z:344.0[M+H]⁺.

Step 2：The preparation of (3R, 5S) -1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -3,5- lupetazin

The fluoro- 2- methoxyl group -5- nitrobenzene (1g) of the bromo- 4- of 1- is dissolved in 10mL N-Methyl pyrrolidone, is added cis- 2,6- Lupetazin (1.38g), 100 DEG C heating stirring 2 hours, reaction solution is poured into 100mL saturated salt solution, ethyl acetate extraction It takes, merges organic phase, saturated common salt water washing dries to obtain 1.3g title compound.ESI-MS m/z:344.0[M+H]⁺.

Step 3：The system of (2S, 6R) -4- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -1- ethyl -2,6- lupetazin It is standby

(3S, 5R) -1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -3,5- dimethyl piperazine is added in the mono- neck bottle of 100mL Piperazine (1g, 3mmol), iodoethane (1g, 6mmol), potassium carbonate (1.2g, 9mmol) and DMF (10mL).Argon gas protection, is stirred at room temperature 3h.LC-MS shows fully reacting.DCM extraction, saturation NaCl solution washing, DCM layers dry, anhydrous Na₂SO₄Dry, revolving obtains Yellow oil 800mg, yield 89.5%.ESI-MS m/z:372.0[M+H]⁺.

Step 4：(2S, 6R) -1- ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxy Heterocycle pentaborane -2- base) phenyl) -2,6- lupetazin preparation

Step 8 that the preparation method is the same as that of Example 1, the difference is that raw material 1- (the bromo- 2- nitrobenzophenone of 4-) -4- methyl piperazine is replaced Change 3 gains of above-mentioned steps (2S, 6R) -4- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -1- ethyl -2,6- dimethyl piperazine into Piperazine, synthesising title compound.ESI-MS m/z:350.2[M+H]⁺.

Step 5：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- (- 4- ethyl -3,5- lupetazin -1- base) -4- methoxyphenyl) acrylamide preparation

1 step 9 of preparation method similar embodiment, 10,11, unlike by raw material 1- methyl -4- (2- nitro -4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with 4 gains of above-mentioned steps (2S, 6R) -1- Ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) -2, 6- lupetazin.¹H-NMR(500MHz,DMSO-d₆):δ1.03(t,3H),1.19(d,6H),1.44(t,3H),2.70(m, 2H),2.87-2.94(m,4H),3.03(dd,2H),3.90(s,3H),3.98(s,6H),4.42(q,2H),5.79(d,1H), 6.38(d,1H),6.44(d,1H),6.67(s,1H),6.86(s,1H),7.71(s,1H),7.84(s,1H),8.33(s,1H), 8.89(s,1H),8.96(s,1H).ESI-MS m/z:694.2[M+H]⁺.

Embodiment 6：N- (2- (4- Acetylpiperazine -1- base) -5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- Ethyl-2-oxo -1,2- dihydro -1,6- naphthyridines -7- base) -4- methoxyphenyl) acrylamide preparation

Step 1:1- (4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) phenyl) piperazine -1- base) and ethyl ketone preparation

Preparation method is similar to 2 step 6 of embodiment, 7, and the 1- ethyl piperazidine in step 6 is replaced with 1- Acetylpiperazine.

Step 2：N- (2- (4- Acetylpiperazine -1- base) -5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- second Base -2- oxo -1,2- dihydro -1,6- naphthyridines -7- base) -4- methoxyphenyl) acrylamide preparation

Preparation method be similar to 1 step 9 of embodiment, 10,11, unlike by raw material 1- methyl -4- (2- nitro -4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with 1 gains 1- (4- (5- of above-mentioned steps Methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine -1- base) second Ketone.¹H-NMR(500MHz,DMSO-d₆):δ1.30(t,3H),2.07(s,3H),2.95(m,4H),3.67(t,4H),3.96(s, 9H),4.31(dd,2H),5.76(d,1H),6.26(d,1H),6.68(m,1H),6.91(s,1H,ArH),7.02(s,1H), 8.02(s,1H),8.04(s,1H),8.45(s,1H),8.98(s,1H),9.22(s,1H).ESI-MS m/z:680.2[M+H ]⁺.

Embodiment 7：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (3- fluoropyrrolidine -1- base) -4- methoxyphenyl) acrylamide preparation

Step 1：The fluoro- 1- of 3- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes - 2- yl) phenyl) pyrrolidines preparation

Preparation method is similar to 2 step 6 of embodiment, 7, the difference is that the 1- ethyl piperazidine in step 6 is replaced with 3- fluorine Pyrrolidines.ESI-MSm/z:366[M+H]⁺

Step 2：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- (3- fluoropyrrolidine -1- base) -4- methoxyphenyl) acrylamide preparation

Preparation method be similar to 1 step 9 of embodiment, 10,11, unlike by raw material 1- methyl -4- (2- nitro -4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with the 1 fluoro- 1- of gains 3- of above-mentioned steps (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) pyrrolidines.¹H- NMR(400MHz,CDCl₃):δ1.42(t,3H),2.26-2.31(m,2H),3.23-3.35(m,1H),3.48-3.55(m, 4H),3.91(s,3H),3.95(s,6H),4.40(q,2H),5.74(d,1H),6.28(d,1H),6.38-6.43(m,1H), 6.61(s,1H),6.64(s,1H),7.63(s,1H),7.66(s,1H),7.87(s,1H),8.40(s,1H),8.83(s,1H) .ESI-MSm/z:641.2[M+H]⁺

Embodiment 8：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) acrylamide preparation

Preparation method be similar to 1 step 9 of embodiment, 10,11, unlike by raw material 1- methyl -4- (2- nitro -4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with 2 step 7 gains 1- second of embodiment Base -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine Piperazine.¹H-NMR(400MHz,DMSO-d₆):δ9.13(s,1H),8.97(s,1H),8.35(s,1H),8.04-8.02(m,2H), 7.02(s,1H),6.88(s,1H),6.66-6.60(m,1H),6.23(d,1H),5.74(d,1H),4.32-4.31(m,2H), 3.98(s,6H),3.94(s,3H),2.99(m,4H),2.61(m,4H),2.44-2.42(m,2H),1.30(t,3H),1.05 (t,3H).ESI-MS m/z:666.2[M+H]⁺

Embodiment 9：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) dihydro-1-1- ethyl-2-oxo-1,2-, 6- naphthyridines -7- base) -4- methoxyl group -2- (8- oxa- -2- azaspiro [4.5] decyl- 2- yl) phenyl) acrylamide preparation

Step 1：The preparation of 2- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -8- oxa- -2- azaspiro [4.5] decane

8- oxa- -2- azaspiro [4.5] (1.07g) and the fluoro- 2- methoxyl group -5- nitrobenzene (1mg) of the bromo- 4- of 1- are dissolved in 14mLN in dinethylformamide, is added potassium carbonate (2.78g), and 100 DEG C of stirring 2.5h, LCMS detections after the reaction was completed, add Enter massive laundering and go n,N-Dimethylformamide, ethyl acetate extraction, liquid separation drying, is spin-dried for ethyl acetate layer, obtains title compound Object.ESI-MS m/z:371[M+H]⁺

Step 2：2- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) Phenyl) -8- oxa- -2- azaspiro [4.5] decane preparation

By 2- made from step 1 (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -8- oxa- -2- azaspiro [4.5] decane (1.38g), connection boric acid pinacol ester (2.37g), [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (273.6mg) and Potassium acetate (1.10g) sequentially adds 15mL1, and in 4- dioxane, the lower 90 DEG C of reactions 12h of ar gas environment filters reaction solution, filter Liquid is washed with saturated sodium chloride solution, ethyl acetate extraction, dry, is spin-dried for obtaining title compound.ESI-MS m/z:418[M+H ]⁺

Step 3：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -4- methoxyl group -2- (8- oxa- -2- azaspiro [4.5] decyl- 2- yl) phenyl) acrylamide preparation

Preparation method be similar to 1 step 9 of embodiment, 10,11, unlike by raw material 1- methyl -4- (2- nitro -4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replaces with 3 gains 2- (5- first of above-mentioned steps Oxygroup -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) -8- oxa- -2- azaspiro [4.5] decane.¹H-NMR(400MHz,DMSO-d₆):δ1.31(t,3H),1.48-1.61(m,4H),1.81(t,2H,),3.29 (s,2H),3.44(t,2H),3.52-3.69(m,4H),3.98(s,9H),4.29(q,2H),5.71(d,1H),6.23(d, 1H),6.43-6.48(m,2H),7.01(s,1H),7.85(s,1H),7.96(s,1H),8.07(s,1H),8.89(s,1H), 9.50(s,1H).ESI-MS m/z：693.2[M+H]⁺.

Embodiment 10：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines -7- base) -2- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -4- methoxyphenyl) acrylamide Preparation

Step 1：7- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2,7- diaza spiro [4.4] nonane -2- carboxylic acid tert-butyl ester Preparation

The fluoro- 2- methoxyl group -5- nitrobenzene (700mg) of the bromo- 4- of 1- is dissolved in 8mLN- methyl pyrrolidone, 2,7- bis- is added Azaspiro [4.4] nonane -2- carboxylic acid tert-butyl ester (765mg), 100 DEG C heating stirring 2 hours, by reaction solution pour into 100mL saturation In saline solution, ethyl acetate extraction merges organic phase, and saturated common salt water washing dries to obtain 1.1g title compound.ESI- MS m/z:456.1[M+H]⁺

Step 2：The preparation of (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2,7- diaza spiro [4.4] nonane

By 7- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2,7- diaza spiro [4.4] nonane -2- carboxylic acid tert-butyl ester (1.1g) is dissolved in 20mL methylene chloride, is added trifluoroacetic acid (11g), is stirred at room temperature 2 hours, by reaction solution saturated sodium bicarbonate Aqueous solution neutralizes, and methylene chloride extraction merges organic phase, dries to obtain 800mg title compound.ESI-MS m/z:356.1 [M+H]⁺

Step 3：The preparation of 2- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -7- ethyl -2,7- diaza spiro [4.4] nonane

It is anhydrous that (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2,7- diaza spiro [4.4] nonane (600mg) is dissolved in 10mL N,N-Dimethylformamide, -10 DEG C are added with stirring 60%NaH (82mg), and iodoethane is added dropwise after continuing stirring 1 hour, and (176 is micro- Rise), saturated salt solution is added after 30min and is quenched, 550mg title compound is dried to obtain in ethyl acetate extraction.ESI-MS m/ z:384.1[M+H]⁺

Step 4：2- ethyl -7- (5- methoxyl group -2- nitro -4- (penta boron of 4,4,5,5- tetramethyl -1,3,2- dioxane Alkane -2- base) phenyl) -2,7- diaza spiro [4.4] nonane preparation

2- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -7- ethyl -2,7- diaza spiro [4.4] nonane (500mg) is molten In 20mL Isosorbide-5-Nitrae-dioxane, connection boric acid pinacol ester (440mg), [1,1'- bis- (diphenylphosphino) ferrocene] dichloro is added Change palladium (100mg) and potassium acetate (400mg), nitrogen protection, 100 DEG C of heating stirrings are stayed overnight, and column chromatographs to obtain 380mg title compound Object.ESI-MS m/z:432.3[M+H]⁺

Step 5：3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -7- (4- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -2- methoxyl group -5- nitrobenzophenone) -1,6- naphthyridines -2 (1H) -one preparation

By -2 (1H) -one of the chloro- 3- of compound 7- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines (181mg) is dissolved in 10mL Isosorbide-5-Nitrae-dioxane, and 4 gained compound 2- ethyl -7- (5- methoxyl group-of above-mentioned steps is added in 3mL water 2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) -2,7- diaza spiro [4.4] nonyl Alkane (380mg), four triphenyl phosphorus palladiums (102mg), sodium carbonate (140mg), nitrogen protection, 100 DEG C heating stirring 1 hour, filtering, It is spin-dried for, column chromatographs to obtain 190mg title compound.ESI-MS m/z:682.2[M+H]⁺

Step 6：7- (5- amino -4- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -2- methoxyphenyl) - The preparation of -2 (1H) -one of 3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines

By 3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -7- (4- (7- ethyl -2,7- diaza spiro [4.4] Nonane -2- base) -2- methoxyl group -5- nitrobenzophenone) -1,6- naphthyridines -2 (1H) -one (190mg) is dissolved in 20mL methanol, it is added 10% Palladium carbon (30mg), lead to hydrogen, 30 DEG C heating stirring 3 hours, be filtered to remove palladium carbon, be spin-dried for obtaining 120mg title compound.ESI-MS m/z:652.3[M+H]⁺.

Step 7：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -4- methoxyphenyl) acrylamide preparation

By 7- (5- amino -4- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -2- methoxyphenyl) -3- (2, The chloro- 3,5- Dimethoxyphenyl of 6- bis-) -1- ethyl -1,6- naphthyridines -2 (1H) -one (120mg) be dissolved in 10mL methylene chloride, be added Diisopropyl ethyl amine (96mg), -5 DEG C of stirrings are lower to instill acryloyl chloride (22 μ L), stirs 30 minutes, saturated sodium bicarbonate is added Aqueous solution, methylene chloride extraction merge organic phase, and drying is spin-dried for preparative separation and obtains title compound.¹H-NMR(400MHZ, DMSO-d₆):δ1.00(t,3H),1.28(t,3H),1.72-1.88(m,4H),2.35-2.67(m,4H),3.26-3.45(m, 4H),3.27(q,2H),3.96-3.97(m,9H),4.27(q,2H),5.72(dd,1H),6.21(dd,1H),6.40-6.48 (m,2H),7.01(s,1H),7.84(s,1H),7.97(s,1H),8.07(s,1H),8.89(s,1H),9.51(s,1H).ESI- MS m/z:706.3[M+H]⁺

Embodiment 11：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines -7- base) -2- ((3R, 5S) -3,5- lupetidine -1- base) -4- methoxyphenyl) acrylamide

Step 1：The preparation of (3R, 5S) -1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -3,5- lupetazin

The fluoro- 2- methoxyl group -5- nitrobenzene (1g) of the bromo- 4- of 1- is dissolved in 10mL N-Methyl pyrrolidone, is added cis- 2,6- Lupetazin (1.38g), 100 DEG C heating stirring 2 hours, reaction solution is poured into 100mL saturated salt solution, ethyl acetate extraction It takes, merges organic phase, saturated common salt water washing dries to obtain 1.3g title compound.ESI-MS m/z:344.1[M+H]⁺.

Step 2：(2R, 6S) -4- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-)-tertiary fourth of 2,6-dimethyl-piperizine -1- carboxylic acid The preparation of ester

(3R, 5S) -1- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -3,5- lupetazin (600mg) is dissolved in 20mL Methylene chloride is added 1N NaOH (3.5mL), lower addition di-tert-butyl dicarbonate (420mg) is stirred at room temperature, is stirred overnight, with two Chloromethanes extraction, it is dry, it is spin-dried for, column chromatographs to obtain 800mg title compound.ESI-MS m/z:444.1[M+H]⁺.

Step 3：(2R, 6S) -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxo bora ring penta Alkane -2- base) phenyl)-lupetidine -1- carboxylic acid tert-butyl ester preparation

By (2R, 6S) -4- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2,6- lupetazin -1- t-butyl formate (750mg) is dissolved in 20mL Isosorbide-5-Nitrae-dioxane, is added connection boric acid pinacol ester (471mg), [1,1'- bis- (diphenylphosphinos) two Luxuriant iron] palladium chloride (110mg), potassium acetate (496mg), nitrogen protection, 100 DEG C of heating stirrings are overnight, and column chromatographs to obtain 531mg mark Inscribe compound.ESI-MS m/z:492.2[M+H]⁺.

Step 4：(2R, 6S) -4- (4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- Dihydro -1,6- naphthyridines -4- base) -7- base) -5- methoxyl group -2- nitrobenzophenone) -2,6- lupetazin -1- carboxylic acid tert-butyl ester Preparation

By -2 (1H) -one of the chloro- 3- of compound 7- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines (531mg) is dissolved in 10mL Isosorbide-5-Nitrae-dioxane and 3mL water, and above-mentioned steps 3 gained compound (2R, 6S) -4- (5- first is added Oxygroup -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl)-lupetidine - 1- carboxylic acid tert-butyl ester (950mg), four triphenyl phosphorus palladiums (300mg) and sodium carbonate (410mg), nitrogen protection, 100 DEG C of heating stirrings It 1 hour, filters, be spin-dried for, column chromatography, obtaining 500mg title compound.ESI-MS m/z:742.2[M+H]⁺.

Step 5：(2R, 6S) -4- (2- amino -4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -2- oxygen Generation -1,2- dihydro -1,6- naphthyridines -7- base) -5- methoxyphenyl) and -2,6- lupetazin -1- carboxylic acid tert-butyl ester preparation

By (2R, 6S) -4- (4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines -4- base) -7- base) -5- methoxyl group -2- nitrobenzophenone) -2,6- lupetazin -1- carboxylic acid tert-butyl ester (450mg) Be dissolved in 20mL methanol, be added 10% palladium carbon (70mg), lead to hydrogen, 30 DEG C heating stirring 3 hours, be filtered to remove palladium carbon, be spin-dried for 340mg title compound.ESI-MS m/z:712.2[M+H]⁺.

Step 6：(2R, 6S) -4- (2- acrylamido -4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- second Base -2- oxo -1,2- dihydro -1,6- naphthyridines -7- base) -5- methoxyphenyl) -2,6- lupetazin -1- carboxylic acid tert-butyl ester Preparation

By (2R, 6S)-4- (2- amino-4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) ethyl-2-oxo-1-1-, 2- dihydro -1,6- naphthyridines -7- base) -5- methoxyphenyl) -2,6- lupetazin -1- carboxylic acid tert-butyl ester (290mg) is dissolved in 10mL methylene chloride is added diisopropyl ethyl amine (213mg), and -5 DEG C of stirrings are lower to instill allyl acyl chlorides (47 microlitres), stirring 30 minutes, saturated sodium bicarbonate aqueous solution is added, methylene chloride extraction merges organic phase, and drying is spin-dried for preparative separation and obtains 300mg Title compound.ESI-MS m/z:766.3[M+H]⁺.

Step 7：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- ((3R, 5S) -3,5- lupetazin -1- base) -4- methoxyphenyl) acrylamide preparation

By (2R, 6S) -4- (2- acrylamido -4- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -2- Oxo -1,2- dihydro -1,6- naphthyridines -7- base) -5- methoxyphenyl) -2,6- lupetazin -1- t-butyl formate (300mg) It is dissolved in 20mL methylene chloride, is added trifluoroacetic acid (1.4g), is stirred at room temperature 2 hours, saturated sodium bicarbonate aqueous solution, dichloro is added Methane extraction, it is dry, it is spin-dried for being prepared into 20mg.¹H-NMR(400MHZ,DMSO-d₆):0.97(d,6H),1.28(t,3H), 2.25-2.33(m,2H),3.00(d,4H),3.92(s,3H),3.95(s,6H),4.30(q,2H),5.75(d,1H),6.25 (d,1H,),6.51-6.59(m,1H),6.8(s,1H),6.98(s,1H),7.99(s,1H),8.02(s,1H),8.27(s, 1H),8.96(s,1H),9.12(s,1H).ESI-MS m/z:666.1[M+H]⁺.

Embodiment 12：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -2- oxygen -1,2- dihydroxy - 1,6- (naphthlypyridine -7- alkenyl) -2 (4- ethyl piperazidine -1- alkenyl) -4- methoxyphenyl)-butyl -2- alkynyl amide

Step 1：7- (5- amino -4- (4- ethyl piperazidine -1- base) -2- methoxyphenyl) -3- (chloro- 3,5- bis- of 2,6- bis- Methoxyphenyl) -1- ethyl -1,6- naphthyridines 2 (1H) -one preparation

Preparation method be similar to 1 step 9 of embodiment, 10, unlike by raw material 1- methyl -4- (2- nitro -4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) piperazine replace with implementation 2 in step 7 gains.ESI-MS m/z:642.2[M+H]⁺.

Step 2：The preparation of 2- alkynyl butyl chloride

2- tetrolic acid (100g, 1.20mol) is added in 3000mL three-necked bottle, addition 1.98L methylene chloride, 30mL N, Oxalyl chloride (151.2g, 1.20mol) is added dropwise after -5 DEG C of stirring 10min in dinethylformamide, after continuing -5 DEG C of stirring 20min, It moves to spare after reacting at room temperature 1.5h.

Step 3：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro -1,6- Naphthyridines -7- base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl)-butyl -2- alkynyl amide preparation

(2,6 2 is chloro- by -3- by 7- (5- amino -4- (4- ethyl piperazidine -1- base) -2- methoxyphenyl) prepared by step 1 3,5- Dimethoxyphenyls) -1- ethyl -1,6- naphthyridines -2 (1H) -one (300mg) is dissolved in N-Methyl pyrrolidone, delays under ice bath It is slow that 2- alkynyl butyl chloride (0.8mL) is added dropwise, 2h is stirred, saturated sodium carbonate solution is added and is quenched, methylene chloride extraction is spin-dried for, makes Back-up from.¹H-NMR(400MHz,DMSO-d₆):δ 1.05 (t, 3H), 1.29 (t, 3H), 2.06 (s, 3H), 2.39 (q, 2H), 2.57 (t, 4H), 2.99 (t, 4H), 3.93 (s, 3H), 3.98 (s, 6H), 4.30 (q, 2H), 6.86 (s, 1H), 7.02 (s, 1H), 8.01 (s, 1H), 8.02 (s, 1H), 8.12 (s, 1H), 8.97 (s, 1H), 9.41 (s, 1H) .ESI-MS m/z：678.3[M+H ]⁺.

Embodiment 13：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines -7- base) -4- methoxyl group -2- (8- oxa- -2- azaspiro [4.5] decane -2- base) phenyl) butyl- 2- alkynyl amide system It is standby

Preparation method be similar to embodiment 12, unlike by raw material 1- ethyl -4- (5- methoxyl group -2- nitro -4- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine is substituted for obtained by above-described embodiment 9 step 2 Object.¹H-NMR(400MHz,DMSO-d₆):δ1.30(t,3H),1.56(t,4H),1.84(t,2H),2.03(s,3H),3.31(s, 2H),3.48(t,2H),3.58-3.68(m,4H),3.95(s,9H),4.30(q,2H),6.36(s,1H,),7.01(s,1H), 7.74(s,1H),7.97(s,1H),8.04(s,1H),8.89(s,1H),8.93(s,1H).ESI-MS m/z:705.3[M+H ]⁺.

Embodiment 14：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine [2,3-d] pyrimidine -2-base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide Preparation

Step 1：The preparation of 4- ethylamino -2- (methyl mercapto)-pyrimidine -5- Ethyl formate

The chloro- 2- of 4- (methyl mercapto)-pyrimidine -5- Ethyl formate (23.2g, 100mmol), second is added in the mono- neck bottle of 500ml Amine methanol solution (30g, 200mmol) and tetrahydrofuran (200mL).It is stirred at room temperature 1 hour.TLC(PE：EA=20:1) display is anti- It should be complete.Vacuum rotary steam removes solvent, and unsaturated carbonate hydrogen is added in residue and receives aqueous solution to PH=7.Ethyl acetate (200 × It 3ml) extracts, for organic phase through saturated common salt water washing, anhydrous sodium sulfate is dry, and concentration obtains yellow oil 25g.Yield 100%.ESI-MS m/z：242.1[M+H]⁺.

Step 2：The preparation of 4- ethylamino -2- (methyl mercapto)-pyrimidine -5- ethyl alcohol

In the mono- neck bottle of 500ml be added 4- ethylamino -2- (methyl mercapto)-pyrimidine -5- Ethyl formate (25g, 100mmol) and Tetrahydrofuran (200mL).It is slowly added to LAH (7.6g, 200mmol) at room temperature.Continue stirring 1 hour at room temperature.TLC(PE：EA =2:1) fully reacting is shown.In reaction system slowly, sequentially add water (7.6g), 15% sodium hydrate aqueous solution (23g), water (7.6g) and anhydrous sodium sulfate (100g).After stirring 0.5 hour at room temperature, filtering.Filter cake is washed through ethyl acetate (100 × 3ml) It washs, filtrate is concentrated to give yellow solid 14g.Yield：75%.ESI-MS m/z：200.1[M+H]⁺.

Step 3：The preparation of 4- ethylamino -2- (methyl mercapto) pyrimidine -5-formaldehyde

4- ethylamino -2- (methyl mercapto) pyrimidine -5- ethyl alcohol (14g, 70mmol), titanium dioxide are added in the mono- neck bottle of 500ml Manganese (33g, 375mmol) and methylene chloride (300mL).It is stirred overnight at room temperature.TLC(PE：EA=2:1) fully reacting is shown.It crosses Filter, filter cake are washed through methylene chloride (100 × 3mL), and filtrate is concentrated to give yellow solid 12.5g.Yield：90%.ESI-MS m/z: 198.1[M+H]⁺.

Step 4：6- (3,5- Dimethoxyphenyl) -8- ethyl -2- (methyl mercapto) pyridine [2,3-d] pyrimidine -7 (8H) -one Preparation

4- ethylamino -2- (methyl mercapto) pyrimidine -5-formaldehyde (12g, 60mmol), 3,5- bis- are added in the mono- neck bottle of 250mL Methoxyphenylacetate (12.6g, 60mmol), potassium carbonate (16.5g, 120mmol) and DMF (40mL).It is heated to 110 DEG C instead It answers 3 hours.TLC(PE：EA=2:1) fully reacting is shown.After reaction system is cooled to room temperature, add water 500mL, ethyl acetate (200 × 3mL) extraction, water (200 × 3mL) and saturated salt solution (200mL) washing.Organic phase is dried over anhydrous sodium sulfate, is dense Contract to obtain yellow solid 16g, yield:74.5%.ESI-MS m/z:358.1[M+H]⁺.

Step 5：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (methyl mercapto) pyridine [2,3-d] pyrimidine - The preparation of 7 (8H) -one

6- (3,5- Dimethoxyphenyl) -8- ethyl -2- (methyl mercapto) pyridine [2,3-d] is added in the mono- neck bottle of 250mL Pyrimidine -7 (8H) -one (7g, 20mmol) and tetrahydrofuran (200mL).Be slowly added dropwise under ice bath sulfonic acid chloride (4.85mL, 60mmol).Drop finishes after five minutes, continues stirring 1 hour.LC-MS shows fully reacting.Water 1mL essence is added to go out reaction, vacuum rotary steam Remove solvent.Acetonitrile (100mL) is added in residue, filtering, acetonitrile (10 × 3mL) washing obtains yellow solid 5.5g, yield： 64.7%.ESI-MS m/z:426.0[M+H]⁺.

Step 6：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (methylsulfonyl) pyridine [2,3-d] pyrimidine - The preparation of 7 (8H) -one

6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (methyl mercapto) pyrrole is added in the mono- neck bottle of 250mL Pyridine [2,3-d] pyrimidine -7 (8H) -one (5g, 11.7mmol) and methylene chloride (150mL), are added metachloroperbenzoic acid at room temperature (4g, 23.4mmol) is stirred at room temperature 1 hour.TLC(PE：EA=1:2) fully reacting is shown.Saturated carbon is added in reaction system Sour hydrogen receives aqueous solution 200mL, adds water 100mL, methylene chloride (200 × 3mL) extraction, organic phase is dried over anhydrous sodium sulfate, dense Contracting, obtains yellow solid 3.2g, yield：69.8%.ESI-MS m/z:458.0[M+H]⁺.

Step 7：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2 hydroxy pyrimidine [2,3-d] pyrimidine -7 The preparation of (8H) -one

6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (methylsulfonyl) pyrrole is added in the mono- neck bottle of 100mL It is water-soluble that potassium hydroxide is added in pyridine [2,3-d] pyrimidine -7 (8H) -one (2.5g, 5.46mmol) and tetrahydrofuran (20mL) at room temperature Liquid (1.5g, 27mmol are dissolved in 20mL water) stirs 3 hours at room temperature.TLC(EA：PE=2:1) fully reacting is shown.Decompression Revolving removes solvent, and concentrated hydrochloric acid is added in reaction system and adjusts PH to 2, filtering, acetonitrile (2 × 2mL) washing obtains yellow solid 1.8g, yield：83.2%.ESI-MS m/z:396.0[M+H]⁺.

Step 8：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- chloropyridine [2,3-d] pyrimidine -7 (8H) - The preparation of ketone

In the mono- neck bottle of 100mL be added 6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2 hydroxy pyrimidine [2, 3-d] pyrimidine -7 (8H) -one (1.8g, 4.5mmol) and acetonitrile (10mL), phosphorus oxychloride (10mL) is added at room temperature, is heated to 90 DEG C, it reacts 3 hours.TLC(EA：PE=1:1) fully reacting is shown.Vacuum rotary steam removes solvent, and water is added in residue (5mL) is filtered, and acetonitrile (1 × 2mL) washes twice, and obtains yellow solid 2.0g, yield：100%.ESI-MS m/z:414.0[M+ H]⁺.

Step 9：N¹(5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- Base) phenyl)-N¹, N², N²The preparation of trimethylethyl -1,2- diamines

Preparation method is similar to step 6 in embodiment 2,7, unlike the 1- ethyl piperazidine in raw material replaced with into N, N, N '-trimethyl ethylenediamine.ESI-MS m/z:380.2[M+H]⁺.

Step 10：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -2- (4- ((2- (dimethylamino) ethyl) (ammonia Base) -2- methoxyl group -5- nitrobenzophenone) -8- ethyl) and pyridine [2,3-d] pyrimidine -7 (8H) -one preparation

6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- chloropyridine [2,3- is added in the mono- neck bottle of 100mL D] pyrimidine -7 (8H) -one (500mg, 1.2mmol), potassium carbonate (414mg, 3.0mmol), bis-triphenylphosphipalladium palladium dichloride (35.6mg, 0.05mmol), N¹(5- methoxyl group -2- nitro 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- Base) phenyl)-N¹, N², N²Trimethylethane -1,2- diamines (570mg, 1.5mmol), water (5mL) and dioxane (20mL), Argon gas protection, 80 DEG C are reacted 2 hours.LC-MS shows fully reacting.After reaction system is cooled to room temperature, add in reaction system Enter water 100mL, ethyl acetate (200 × 3mL) extraction, organic phase is washed through saturated salt solution (100 × 3mL), is concentrated, and yellow is obtained Solid 400mg, yield：52.8%.ESI-MS m/z:631.1[M+H]⁺.

Step 11：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -2- (4- ((2- (dimethylamino) ethyl) (ammonia Base) -2- methoxyl group -5- aminocarbonyl phenyl) -8- ethyl) and pyridine [2,3-d] pyrimidine -7 (8H) -one preparation

6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -2- (4- ((2- (dimethylamino is added in the mono- neck bottle of 100mL Base) ethyl) (amino) -2- methoxyl group -5- nitrobenzophenone) -8- ethyl) pyridine [2,3-d] pyrimidine -7 (8H) -one (400mg, 0.63mmol), stannous chloride (414mg, 3.0mmol) and ethyl alcohol (20mL), 80 DEG C are reacted 2 hours.LC-MS display has been reacted Entirely.Vacuum rotary steam removes solvent, and unsaturated carbonate hydrogen is added in residue and receives aqueous solution 100mL, ethyl acetate (200 × 3mL) extraction It takes, organic phase is concentrated, obtains yellow solid 300mg, yield：79.3%.

ESI-MS m/z:601.1[M+H]⁺.

Step 12：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydropyridine [2,3-d] pyrimidine -2-base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide Preparation

6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -2- (4- ((2- (dimethylamino is added in the mono- neck bottle of 100mL Base) ethyl) (amino) -2- methoxyl group -5- aminocarbonyl phenyl) -8- ethyl) pyridine [2,3-d] pyrimidine -7 (8H) -one (300mg, 0.5mmol), DIPEA (129mg, 1.0mmol) and anhydrous tetrahydro furan (20mL).Acryloyl chloride (40 μ are slowly added dropwise at -10 DEG C L, 0.5mmol are dissolved in 0.5mL tetrahydrofuran), drop finishes, and continues to stir 10min.LC-MS shows fully reacting.Vacuum rotary steam Remove solvent, prep-HPLC (CH₃CN/H₂O, 0.1%TEA), obtain yellow solid 30mg, yield：9.2%.¹H-NMR (400MHz,CDCl₃)：δ10.08(s,1H),9.13(s,1H),8.96(s,1H),7.63(s,1H),6.91(s,1H),6.65 (s,1H),6.46-6.42(d,1H),6.37-6.30(m,1H),5.71-5.69(d,1H),4.68-4.62(m,2H),3.96 (s,6H),3.90(s,3H),2.95(m,2H),2.80(s,3H),2.48(m,2H),2.32(s,6H),1.45-1.38(m, 3H).ESI-MSm/z:655.2[M+H]⁺

Embodiment 15：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) acrylamide preparation

Step 1：The preparation of 2- chloro- 4- (ethylamino) pyrimidine -5- Ethyl formate

The chloro- 5- pyrimidinecarboxylic acid ethyl ester (10g) of 2,4- bis- is dissolved in 100mLTHF, n,N-diisopropylethylamine is added (11.76g) is slowly added dropwise ethamine alcoholic solution (8.2g) at -5 DEG C, is stirred overnight at room temperature, a large amount of water, second will be added in reaction solution Acetoacetic ester extraction, it is dry, it is spin-dried for obtaining title compound.ESI-MS m/z:230[M+H]⁺

Step 2：The preparation of (2- chloro- 4- (ethylamino) pyrimidine -5- base) methanol

2- chloro- 4- (ethylamino) pyrimidine -5- Ethyl formate (2g) is dissolved in 20mL tetrahydrofuran, is slowly added at room temperature Enter LiAlH₄(0.736g), is stirred at room temperature 3h, with water (1mL) and sodium hydrate aqueous solution (2N, 1mL) quenching reaction, filters, filter Liquid is extracted with ethyl acetate, dry, is spin-dried for obtaining title compound.ESI-MS m/z:188[M+H]⁺

Step 3：The preparation of 2- chloro- 4- (ethylamino) pyrimidine -5-formaldehyde

(2- chloro- 4- (ethylamino) pyrimidine -5- base) methanol (1g) is dissolved in 20mL methylene chloride, is slowly added at room temperature Enter manganese dioxide (7g), be stirred overnight at room temperature, filters, be spin-dried for obtaining title compound.ESI-MS m/z:186[M+H]⁺

Step 4：The system of the chloro- 6- of 2- (3,5- Dimethoxyphenyl) -8- ethylpyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one It is standby

By 2- chloro- 4- (ethylamino) pyrimidine -5-formaldehyde (0.5g) and 2- (3,5- Dimethoxyphenyl) methyl acetate (0.681g) is dissolved in 10mL n,N-Dimethylformamide, reacts 2h at 100 DEG C, and reaction solution saturated sodium chloride solution is dilute It releases, ethyl acetate extraction is dry, is spin-dried for obtaining title compound.ESI-MS m/z:346[M+H]⁺

Step 5：6- (3,5- Dimethoxyphenyl) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- methoxyl group -5- Nitrobenzophenone) pyrido [2,3-d] pyrimidine -7 (8H) -one preparation

By 2 step 7 gained compound 1- ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl-of embodiment 1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine (476mg), above-mentioned steps 4 gains 2- chloro- 6- (3,5- diformazan Phenyl) -8- ethylpyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one (350mg), [bis- (diphenylphosphino) ferrocene of 1,1'-] Palladium chloride (74mg) and potassium acetate (298mg) sequentially add 15mL1, and in 4- dioxane and 8mL water, back flow reaction 2h will Reaction solution filtering, filtrate are washed with saturated sodium chloride solution, ethyl acetate extraction, dry, are spin-dried for obtaining title compound.ESI-MS m/z:575[M+H]⁺

Step 6：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- Methoxyl group -5- nitrobenzophenone) pyrido [2,3-d] pyrimidine -7 (8H) -one preparation

By 6- (3,5- Dimethoxyphenyl) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- methoxyl group -5- nitro Phenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (220mg) is dissolved in 10mL acetonitrile, sulfonic acid chloride (62ul) is added dropwise under ice bath, 30min is stirred at room temperature, reaction solution is quenched with saturated sodium bicarbonate solution, ethyl acetate extraction is dry, is spin-dried for obtaining title compound Object.ESI-MS m/z:643[M+H]⁺

Step 7：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- Methoxyl group -5- aminophenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one preparation

By 6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- methoxy Base -5- nitrobenzophenone) pyrido [2,3-d] pyrimidine -7 (8H) -one (200mg) is dissolved in 10mL methanol, it is added palladium carbon (70mg), Hydrogen is put on, 1h is stirred at room temperature, reaction solution is filtered, filtrate is spin-dried for obtaining title compound.ESI-MS m/z:613[M+H]⁺

Step 8：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydropyridine And [2,3-d] pyrimidine -2-base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) acrylamide preparation

By 6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (4- (4- ethyl piperazidine -1- base) -2- methoxy Base -5- aminophenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (200mg) is dissolved in 10mL tetrahydrofuran, N, N- bis- is added Wopropyl ethyl amine (212mg) is added dropwise acryloyl chloride (39ul) under ice bath, 30min is stirred at room temperature, by reaction solution unsaturated carbonate hydrogen Sodium solution is quenched, ethyl acetate extraction, dry, is spin-dried for, is prepared into title compound.¹H-NMR(400MHz,DMSO-d₆):δ 1.05(t,3H),1.29(t,3H),2.42(q,2H),2.59(s,4H),3.00(s,4H),3.89(s,3H),3.98(s,6H), 4.44(q,2H),5.73(d,1H),6.24(d,1H),6.63(q,1H),6.86(s,1H),7.03(s,1H),8.04(s,1H), 8.29(s,1H),9.18(s,1H),9.17(s,1H).ESI-MSm/z:667.2[M+H]⁺

Embodiment 16：N- [5- [6- (the chloro- 3,5- dimethoxy-benzene of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro-pyrrole Pyridine simultaneously [2,3-d] piperazine -1- base] -2- (4- thyl-piperazin -1- base)-phenyl]-acrylamide preparation

Preparation method is similar to 14 step 5 of embodiment, 6,7,8, the difference is that by the chemical combination of raw material in 14 step 5 of embodiment Object 1- ethyl -4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) benzene Base) piperazine replaces with 1 step 8 gains 1- methyl -4- (2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxy of embodiment Heterocycle pentaborane -2- base) phenyl) piperazine.¹H-NMR(400MHZ,CDCl₃):δ1.46(t,3H),1.62(s,4H),2.41(s, 3H),2.65(s,4H),3.96(s,6H),4.70(q,2H),5.82(dd,1H),6.33(dd,1H),6.47(dd,1H),6.65 (s,1H),7.31(d,1H),7.60(dd,1H),8.31(m,1H),8.56(d,1H),8.94(d,1H),9.63(s,1H) .ESI-MS m/z:623.3[M+H]⁺

Embodiment 17：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] piperazine -2- base) -2- (4- ethyl piperazidine -1- base)-phenyl] acrylamide preparation

Step 1：1- ethyl -4- (2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) benzene Base) piperazine preparation

Preparation method is similar to 1 step 7 of embodiment, 8, the difference is that the raw material methyl piperazine in 1 step 7 of embodiment is replaced It is changed to 1- ethyl piperazidine.ESI-MS m/z:360.2[M+H]⁺

Step 2：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydropyridine And [2,3-d] piperazine -2- base) -2- (4- ethyl piperazidine -1- base)-phenyl] acrylamide

Preparation method is similar to embodiment 15, the difference is that by the compound 1- ethyl -4- of raw material in 15 step 5 of embodiment The replacement of (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine At (2- nitro -4- (penta boron of 4,4,5,5- tetramethyl -1,3,2- dioxane of compound 1- ethyl -4- made from above-mentioned steps 1 Alkane -2- base) phenyl) piperazine.¹H-NMR(400MHZ,CDCl₃):δ1.11-1.21(m,3H),1.47(s,3H),2.54(q,2H), 2.62(s,2H),2.73(d,2H),3.03(t,4H),3.96(s,6H),4.70(q,2H),5.79-5.87(m,1H),6.33 (dd,1H),6.47(d,1H),6.65(s,1H),7.32(d,1H),7.62(s,1H),8.31(dd,1H),8.56(d,1H), 8.94(d,1H),9.63(s,1H).ESI-MS m/z:637.2[M+H]⁺

Embodiment 18：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -2- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) Methacrylamide preparation

Preparation method is similar to embodiment 15, the difference is that the raw material propylene acyl chlorides in 15 step 8 of embodiment is substituted for Methacrylic chloride.¹H-NMR(400MHz,CDCl₃):δ1.11(t,3H),1.35(t,3H),2.05(s,3H),2.48(m, 2H),2.54-2.80(m,4H),2.93-3.05(s,4H),3.81(s,3H),3.89(s,6H),4.56(q,2H),5.41(d, 1H),5.84(d,1H),6.57(s,1H),6.85(s,1H),7.56(s,1H),8.64(s,1H),8.89(s,1H),8.96(s, 1H).ESI-MSm/z:681.3[M+H]⁺

Embodiment 19：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -2- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base) -4- methoxyphenyl) third The preparation of acrylamide

Preparation method is similar to embodiment 5, the difference is that (2,6- bis- is chloro- by the chloro- 3- of raw material compound 7- in step 4 3,5- Dimethoxyphenyl) -1- ethyl -1,6- naphthyridines -2 (1H) -one replace with 14 step 8 gained compound 6- of embodiment (2, The chloro- 3,5- Dimethoxyphenyl of 6- bis-) -8- ethyl -2- chloropyridine [2,3-d] pyrimidine -7 (8H) -one.¹H-NMR(400MHz, DMSO-d₆):δ0.92(t,3H),1.03(d,6H),1.29(t,3H),2.48-2.53(m,2H,),2.84-2.87(m,4H), 3.08-3.11(m,2H),3.89(s,3H),3.98(s,6H),4.45(q,2H),5.79(d,1H),6.38(d,1H),6.59- 6.66(m,1H),6.79(s,1H),7.03(s,1H),8.03(s,1H),8.27(s,1H),9.17(s,2H).ESI-MSm/z: 695.3[M+H]⁺

Embodiment 20：N- (2- (2- oxa- -5- azabicyclo [2.2.1] heptane -5- base) -5- (6- (the chloro- 3,5- of 2,6- bis- Dimethoxyphenyl) -8- ethyl -7- oxo -7,8- dihydro pyrido [2,3-d] pyrimidine -2-base) -4- methoxyphenyl) propylene The preparation of amide

Step 1：The preparation of 5- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2- oxa- -5- azabicyclo [2.2.1] heptane

The fluoro- 2- methoxyl group -5- nitrobenzene (800mg, 3.23mmol) of the bromo- 4- of 1-, 2- oxa--are added in the mono- neck bottle of 50mL The hydrochloride (658mg, 4.84mm) of 5- azabicyclo [2.2.1] heptane, potassium carbonate (1.4g, 9.69mmol), 20mL N, N- bis- Methylformamide, 90 DEG C of stirring 2h.TLC(EA：PE=1:2) fully reacting is shown.Add water 100mL, ethyl acetate (50 × 3mL) Extraction, organic phase are dried over anhydrous sodium sulfate, are concentrated, and obtain title compound.ESI-MS m/z:329.09[M+H]⁺.

Step 2：5- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) Phenyl) -2- oxa- -5- azabicyclo [2.2.1] heptane preparation

5- (the bromo- 5- methoxyl group -2- nitrobenzophenone of 4-) -2- oxa- -5- azabicyclo is added in the mono- neck bottle of 100mL [2.2.1] heptane (1.1g, 3.35mmol), connection pinacol borate (1.69g, 6.7mmol), [1,1'- bis- (diphenylphosphinos) Ferrocene] palladium chloride (0.22g, 0.34mmol), potassium acetate (0.99g, 10mmol) and 20mL Isosorbide-5-Nitrae-dioxane, nitrogen Protection, 100 DEG C of heating stirrings are stayed overnight, and filtering is spin-dried for, and ethyl acetate dissolution, saturated common salt water washing, anhydrous sodium sulfate is dry, It is spin-dried for obtaining title compound.ESI-MS m/z:377.14[M+H]⁺.

Step 3：N- (2- (2- oxa- -5- azabicyclo [2.2.1] heptane -5- base) -5- (6- (the chloro- 3,5- bis- of 2,6- bis- Methoxyphenyl) -8- ethyl -7- oxo -7,8- dihydro pyrido [2,3-d] pyrimidine -2-base) -4- methoxyphenyl) acryloyl The preparation of amine

Preparation method is similar to embodiment 15, the difference is that by the compound 1- ethyl -4- (5- methoxyl group -2- in step 5 Nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) piperazine replace with above-mentioned steps 2 be made Compound 5- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) - 2- oxa- -5- azabicyclo [2.2.1] heptane.¹H-NMR(400MHz,DMSO-d₆):δ1.24(t,3H),1.83-1.95(m, 2H),2.97-2.99(m,1H),3.57-3.59(m,1H),3.79-3.84(m,2H),3.93(s,3H),4.01(s,6H), 4.41(q,2H),4.56(d,2H),5.61(s,1H),5.73(d,1H),6.20(d,1H),6.39(t,1H),6.94(s,1H), 7.74(s,1H),7.92(s,1H),9.06(s,1H),9.59(s,1H).ESI-MS m/z:652.2[M+H]⁺

Embodiment 21：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -2- (3,3- difluoropyrrolidin -1- base) -4- methoxyphenyl) acrylamide preparation

Step 1：The fluoro- 1- of 3,3- bis- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxane penta Borine -2- base) phenyl) pyrrolidines preparation

Synthetic method is with 20 steps 1 and 2 of embodiment, the difference is that by the raw material 2- oxa- -5- azabicyclo in step 1 The hydrochloride of [2.2.1] heptane is substituted for the hydrochloride of 3,3- difluoropyrrolidin.ESI-MS m/z:385.2[M+H]⁺

Step 2：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydropyridine And [2,3-d] pyrimidine -2-base) -2- (3,3- difluoropyrrolidin -1- base) -4- methoxyphenyl) acrylamide preparation

Preparation method is similar to embodiment 15, the difference is that by the compound 1- ethyl -4- (5- methoxyl group -2- in step 5 Nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine replaces with 1 institute of above-mentioned steps Obtain the fluoro- 1- of object 3,3- bis- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) Phenyl) pyrrolidines.¹H-NMR(400MHz,DMSO-d₆):δ1.29(t,3H),2.00(t,2H),3.63(t,2H),3.79(t, 2H),3.92(s,3H),3.98(s,6H),4.45(q,2H),5.74(d,1H),6.24(d,1H),6.49(t,1H),7.03(s, 1H),7.74(s,1H),7.86(s,1H),7.99(s,1H),9.12(s,1H),9.60(s,1H),ESI-MS m/z:660.19 [M+H]⁺

Embodiment 22：N- (2- (4- Acetylpiperazine -1- base) -5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- Ethyl -7- oxo -7,8- dihydro pyrido [d] pyrimidine -2-base) -4- methoxyphenyl) acrylamide

Preparation method is similar to embodiment 15, the difference is that by raw material compound 1- ethyl -4- (the 5- methoxy in step 5 Base -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) phenyl) piperazine replaces with embodiment 6 step 1 gains 1- (4- (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) phenyl) piperazine -1- base) title compound is prepared in ethyl ketone.¹H-NMR(400MHz,DMSO-d₆):δ1.29(s,3H), 2.07(s,3H),2.95-2.98(m,4H),3.67(t,4H),3.75(s,3H),3.90(s,6H),4.44(q,2H),5.76 (d,1H),6.26(d,1H),6.64-6.71(m,1H),6.89(s,1H),7.04(s,1H),8.04(s,1H),8.40(s, 1H),9.19(s,1H),9.23(s,1H),ESI-MS m/z:681.1[M+H]⁺

Embodiment 23：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (2- oxa- -7- azaspiro [3.5] nonane -7- base) phenyl) acrylamide Preparation

Synthetic method is with 20 steps 1 and 2 of embodiment, the difference is that by the raw material 2- oxa- -5- azabicyclo in step 1 The hydrochloride of [2.2.1] heptane is substituted for the oxalates of 2- oxa- -7- azaspiro [3.5] nonane.¹H-NMR(400MHz,DMSO- d₆):δ1.28(t,3H),2.01(t,4H),2.87(t,4H),3.87(s,3H),3.98(s,6H),4.39(s,4H),4.44 (q,2H),5.74(d,1H),6.24(d,1H),6.62(t,1H),6.84(s,1H),7.04(s,1H),8.03(s,1H),8.35 (s,1H),9.11(s,1H),9.18(s,1H),ESI-MS m/z:680.2[M+H]⁺

Embodiment 24：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (7- oxa- -2- azaspiro [3.5] nonane -2- base) phenyl) acrylamide Preparation

Synthetic method is with 20 steps 1 and 2 of embodiment, the difference is that by the raw material 2- oxa- -5- azabicyclo in step 1 The hydrochloride of [2.2.1] heptane is substituted for the oxalate of 7- oxa- -2- azaspiro [3.5] nonane¹H-NMR(400MHz, DMSO-d₆):δ1.29(t,3H),1.74(t,4H),3.55(t,4H),3.79(s,4H),3.88(s,3H),3.98(s,6H), 4.44(q,2H),5.72(d,1H),6.15(s,1H),6.24(d,1H),6.41-6.47(m,1H),7.02(s,1H),7.80 (s,1H),7.96(s,1H),9.08(s,1H),9.40(s,1H),ESI-MS m/z:680.2[M+H]⁺

Embodiment 25：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (3- methoxypyrrolidin -1- base) phenyl) acrylamide preparation

Synthetic method is with 20 steps 1 and 2 of embodiment, the difference is that by the raw material 2- oxa- -5- azabicyclo in step 1 The hydrochloride of [2.2.1] heptane is substituted for the hydrochloride of 3- methoxymethyl-pyrrolidin.¹H-NMR(400MHz,DMSO-d₆):δ1.29 (t,3H),1.93-2.03(m,2H),3.25(s,3H),3.39(d,2H),3.48-3.61(m,2H),3.90(s,3H),3.97 (s,6H),4.02-4.05(m,1H),4.46(m,2H),5.74(d,1H),6.24(m,1H),6.38(m,1H),6.44(s, 1H),7.02(s,1H),7.83(s,1H),7.96(s,1H),9.08(s,1H),9.57(s,1H).ESI-MS m/z:654.2[M +H]⁺

Embodiment 26:N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (1- oxa- -8- azaspiro [4.5] decane -8- base) phenyl) acrylamide Preparation

Synthetic method is with 20 steps 1 and 2 of embodiment, the difference is that by the raw material 2- oxa- -5- azabicyclo in step 1 The hydrochloride of [2.2.1] heptane is substituted for 1- oxa- -8- azaspiro [4.5] decane.¹H-NMR(400MHz,CDCl₃):δ1.26 (t,3H),1.43(t,4H),1.78-1.88(m,4H),2.87-2.91(m,2H),3.08-3.13(m,2H),3.89(s,3H), 3.93(m,2H),3.96(s,6H),4.63(q,2H),5.75(d,1H),6.30(d,1H),6.37-6.41(m,1H),6.65 (s,1H),6.90(s,1H),7.63(s,1H),8.31(s,1H),8.96(s,1H),9.00(s,1H).ESI-MSm/z:694.2 [M+H]⁺.

Embodiment 27:N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (8- oxa- -2- azaspiro [4.5] decane -2- base) phenyl) butyl- 2- alkynes The preparation of amide

Step 1：6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (2- methoxyl group -5- nitro -4- (8- oxygen Miscellaneous -2- azaspiro [4.5] decane -2- base) phenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one preparation

14 steps 1 and 2 of preparation method similar embodiment, 3,4,5,6,7,8,9,10, the difference is that by the raw material in step 10 N¹(5- methoxyl group -2- nitro 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) phenyl)-N¹, N², N²- three Methyl ethane -1,2- diamines replace with compound 2- that 9 step 2 of embodiment is prepared (5- methoxyl group -2- nitro -4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) -8- oxa- -2- azaspiro [4.5] decane.ESI-MS m/ z:670.2[M+H]⁺

Step 2：2- (5- amino -2- methoxyl group -4- (8- oxa- -2- azaspiro [4.5] decane -2- base) phenyl) -6- (2, The chloro- 3,5- Dimethoxyphenyl of 6- bis-) -8- ethylpyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one preparation

By 6- made from step 1 (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -2- (2- methoxyl group -5- nitro - 4- (8- oxa- -2- azaspiro [4.5] decane -2- base) phenyl) pyrido [2,3-d] pyrimidine -7 (8H) -one (140mg) is dissolved in second Alcohol (9mL) and water (3mL) are added reduced iron powder (90.9mg), ammonium chloride (86.8mg), and LCMS is detected after the reaction was completed, revolving Ethyl alcohol is removed, saturated sodium bicarbonate aqueous solution is added and is adjusted to neutrality, EA extraction is dry, is spin-dried for obtaining title compound.ESI-MS m/z:640.2[M+H]⁺

Step 3：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydropyridine And [2,3-d] pyrimidine -2-base) -4- methoxyl group -2- (8- oxa- -2- azaspiro [4.5] decane -2- base) phenyl) butyl- 2- alkynes acyl The preparation of amine

By (5- amino -2- methoxyl group -4- (8- oxa- -2- azaspiro [4.5] decane -2- base) benzene of 2- made from step 2 Base) simultaneously [2,3-d] pyrimidine -7 (8H) -one (70mg) is dissolved in -8- ethylpyridine -6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) In 2mLN- methyl pyrrolidone, N is added, N- diisopropyl ethyl amine (54.6mg), 0 DEG C is added with stirring 2- alkynyl butyl chloride (0.3mol/mL, 1mL), the reaction was continued 0.5 hour, and reaction solution is quenched with saturated sodium bicarbonate aqueous solution, ethyl acetate extraction It takes, it is dry, it is spin-dried for, preparative separation obtains title compound.¹H-NMR(400MHz,CDCl₃):δ1.26(m,3H),1.41(m,4H), 1.92(t,2H),2.02(s,3H),3.25(s,2H),3.47(t,2H),3.72(m,4H),3.94(s,3H),3.96(s,6H), 4.61(q,2H),6.48(s,1H),6.64(s,1H),7.32(s,1H),7.59(s,1H),8.22(s,1H),8.91(s,1H) .ESI-MS m/z:706.2[M+H]⁺

Embodiment 28：N- (5- (6- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -8- ethyl -7- oxo -7,8- dihydro pyrrole Pyridine simultaneously [2,3-d] pyrimidine -2-base) -2- (7- ethyl -2,7- diaza spiro [4.4] nonane -2- base) -4- methoxyphenyl) propylene The preparation of amide

Preparation method is similar to embodiment 14, the difference is that by the raw material compound N in step 10¹(5- methoxyl group -2- Nitro 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) phenyl)-N¹, N², N²Trimethylethane -1,2- two Amine is 10 step 4 gains 2- ethyl -7- of embodiment (5- methoxyl group -2- nitro -4- (4,4,5,5- tetramethyl -1,3,2- dioxy Heterocycle pentaborane -2- base) phenyl) -2,7- diaza spiro [4.4] nonane.

¹H-NMR(400MHz,DMSO-d₆):δ1.03(t,3H),1.29(t,3H),1.74-1.90(m,4H),2.50- 2.67(m,4H),3.26-3.45(m,4H),3.44(q,2H),3.89(s,3H),3.97(s,6H),4.46(q,2H),5.70 (d,1H),6.19(d,1H),6.22(m,1H),6.23-6.47(m,1H),7.02(s,1H),7.82(s,1H),7.96(s, 1H),9.07(s,1H),9.52(s,1H).

ESI-MS m/z:707.2[M+H]⁺

Embodiment 29：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines base -7- base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide preparation

The preparation method is the same as that of Example 1, the difference is that raw material N methyl piperazine is replaced with N, N, N'- trimethyl ethylenediamine system Obtain title compound.¹H-NMR(500MHz,CDCl₃-d₆):δ1.46(s,3H),1.73(s,6H),2.41(t,2H),2.80(s, 3H),2.94(t,2H),3.98(s,6H),4.49(dd,2H),5.79(d,1H),6.46(m,1H),6.52(d,1H),6.67 (s,1H,ArH),7.39(d,1H,ArH),7.68(s,1H,ArH),7.72(s,1H,ArH),7.87(d,1H,ArH),8.88 (s,1H,ArH),9.27(s,1H,ArH),10.34(s,1H,NH).ESI-MS m/z:624.2[M+H]⁺.

Embodiment 30：N- (5- (3- (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl-2-oxo -1,2- dihydro - 1,6- naphthyridines -7- base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide preparation

Preparation method is with embodiment 6, the difference is that raw material Acetylpiperazine is substituted for N, N, N '-trimethyl ethylenediamine.¹H-NMR (400MHz, CDCl₃)：δ10.13(s,1H),9.00(s,1H),8.87(s,1H),7.82(s,1H),7.76(s,1H), 6.90(s,1H),6.65(s,1H),6.42-6.42(m,1H),6.35-6.28(m,1H),5.71-5.68(m,1H),4.42- 4.14(m,2H),3.96(s,6H),3.91(s,3H),2.94(s,2H),2.79(s,3H),2.39(s,2H),2.79(s,6H), 1.42(t,3H).ESI-MS m/z:654.2[M+H]⁺.

Using different raw materials according to synthetic method the synthetic example 31-53, embodiment 31- of 1-30 of the embodiment of the present invention 53 characterization parameter is as shown in table 1：

Table 1：

Embodiment 49：N- (2- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -5- (3- (the chloro- 3,5- bis- of 2,6- bis- Methoxyphenyl) -1- ethyl-2-oxo -1,2- dihydro -1,6- benzodiazine -7- base) -4- methoxyphenyl) butyl- 2- alkynes acyl The preparation of amine

Step 1：7- (4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -2- methoxyl group -5- nitrobenzophenone) -3- The preparation of -2 (1H) -one of (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- ethyl -1,6- naphthyridines -2 (1H) -one (170mg, It 0.41mmol) is dissolved in 3.4mL Isosorbide-5-Nitrae-dioxane and 0.85mL water, addition 5- (5- methoxyl group -2- nitro -4- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) -2- oxa- -5- azabicyclo [2.2.1] heptane (170mg, 0.45mmol), four triphenyl phosphorus palladium (47.7mg, 0.04mmol), sodium carbonate (143mg, 1.36mmol), argon gas protection, 100 DEG C After heating stirring 2 hours, reaction is completed.Cooling is stood overnight, and yellow solid is obtained by filtration in next day, and after being dissolved in methylene chloride, Washing filters after ethyl acetate mashing is added after being spin-dried for, obtains title compound.ESI-MS m/z:627.26[M+H]⁺.

Step 2：7- (5- amino -4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -2- methoxyphenyl) -3- The preparation of -2 (1H) -one of (the chloro- 3,5- Dimethoxyphenyl of 2,6- bis-) -1- ethyl -1,6- naphthyridines

By 7- (4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -2- methoxyl group -5- nitrobenzophenone) -3- (2,6- Two chloro- 3,5- Dimethoxyphenyls) -1- ethyl -1,6- naphthyridines -2 (1H) -one (124.2mg, 0.198mmol) is dissolved in 2.48mL In ethyl alcohol and 0.62mL water, iron powder (111mg, 1.98mmol) and ammonium chloride (105mg, 1.98mmol) is added, flows back at 100 DEG C React 2h.After the reaction was completed, it is cooling to place room temperature, saturated sodium bicarbonate aqueous solution is added into reaction solution and neutralizes, is then added 20ml methylene chloride, filtering filter to obtain title compound after ethyl acetate mashing is added after taking organic layer is dry to be spin-dried for.ESI-MS m/z:597.20[M+H]⁺.

Step 3：N- (2- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -5- (3- (chloro- 3,5- diformazan of 2,6- bis- Phenyl) -1- ethyl-2-oxo -1,2- dihydro -1,6- benzodiazine -7- base) -4- methoxyphenyl) butyl- 2- alkynyl amide Preparation

By 7- (5- amino -4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) -2- methoxyphenyl) -3- (2,6- Two chloro- 3,5- Dimethoxyphenyls) -1- ethyl -1,6- naphthyridines -2 (1H) -one (94.5mg, 0.158mmol) is dissolved in 1.6mL bis- Chloromethanes is added diisopropyl ethyl amine (61.5mg, 0.476mmol), and -5 DEG C of stirrings are lower to instill 2- alkynyl butyl chloride 0.4mL (0.6mol/L, 0.238mmol) is stirred 15 minutes, and 20mL saturated sodium bicarbonate aqueous solution is added, and methylene chloride extraction merges Organic phase, dry rotation dry chromatography obtain title compound.¹H-NMR(400MHz,DMSO-d₆):δ1.30(t,3H),1.87(s, 2H),2.02(s,3H),3.05(d,1H),3.65(d,1H),3.80(d,1H),3.91(d,1H),3.95(s,3H),3.97(s, 6H),4.30(q,2H),4.61(s,1H),4.65(s,1H),6.42(s,1H),7.01(s,1H),7.74(s,1H),7.97(s, 1H),8.04(s,1H),8.91(s,1H),9.86(s,1H).ESI-MS m/z:663.2[M+H]⁺.

Comparative example 1 and comparative example 2

Referring to the method preparation described in patent application WO2015/4108992 about Compound Numbers 19 and 27 The compound of comparative example 1 (compound A) and comparative example 2 (compound B), and pass through hydrogen spectrum and Mass Spectrometric Identification.

Comparative example 3

Compound name is N- ((3S, 4S) -3- ((6- (2,6-dichloro-3,5-dimethoxyphenyl) Quinazolin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide (BLU-554), reference The synthetic method preparation of 40 compound of Compound in WO2015/061572, and pass through hydrogen spectrum and Mass Spectrometric Identification.

Using the method for following experimental example 1,2 and 3 test compound A, compound B and compound C to FGFR4 kinases and The inhibitory activity of FGFR1 kinases, to the inhibitory activity of human hepatoma cell strain Hep3B cell and HUH-7 cell, and in mouse Pharmacokinetic Characteristics.Experimental result shows, compound A, compound B, compound C are to FGFR4 kinases and FGFR1 kinases Selectivity is significantly lower than the compound of the present invention, obvious to the inhibitory activity of human hepatoma cell strain Hep3B cell and HUH-7 cell It is weaker than the compound of the present invention and half-life period and AUC is also worse than the compound of the present invention.

The evaluation of 1 vitro kinase activity of experimental example

1 experimental material

FGFR1 is purchased from Carna, cat. no 08-133；

FGFR4 is purchased from Carna, cat. no 08-136；

P22peptide is purchased from GL Biochem, cat. no 112393；

Staurosporine9 is purchased from Sigma, cat. no S4400-1MG；

2 experimental methods

1) prepare 1 × kinases basis buffer and stop buffer

A.1 × kinases basis buffer：20mM HEPES, 7.5 pH, 0.01%Triton X-100,10mM MgCl₂, 2mM DTT。

B. stop buffer：100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating Reagent#3, 50mM EDTA。

2) prepare compound

A. the compound of the embodiment of the present invention and the 10mM deposit of reference compound A, compound B, compound C are prepared Liquid.

B. prepare 50 × compound solution：The compound and reference compound of the above embodiment of the present invention since 500 μM, It is successively diluted for 3 times with DMSO, totally 10 concentration.

C. 100 μ L 100%DMSO are respectively added in 2 empty holes of 96 orifice plate of same as no compound and without sharp Enzyme control.Marking this 96 orifice plate is to carry out source plate.

D. prepare intermediate plate：10 μ L compounds are always shifted in source plate into 96 new orifice plates, as intermediate plate；In centre 90 μ 1 × kinase buffer liquids of L are added in the every hole of plate；Oscillation mixes 10min.

3) preparing experiment plate：From 96 hole intermediate plates, 5 μ L are shifted into 384 orifice plates in every hole, 2 multiple holes.

4) kinase reaction

A. prepare 2.5 × kinase solution：Kinases is added separately in 1 × basis buffer.

B. prepare 2.5 × polypeptide solution：The polypeptide of FAM label and ATP are added in 1 × basis buffer.

C. 5 μ L compounds (10%DMSO) have been contained in experimental plate.

D. 2.5 × kinase solution of transfer is into experimental plate：Add 10 2.5 × kinase solutions of μ L to each hole of 384 hole experimental plates In.

E. it is incubated at room temperature 10min.

F. 2.5 × polypeptide solution of transfer is into experimental plate：Add 10 2.5 × polypeptide solutions of μ L to each hole of 384 hole experimental plates In.

G. kinase reaction and termination：The regular hour is incubated under the conditions of 28 DEG C；25 μ L stop buffers are added to terminate instead It answers.

5) Caliper instrument readings：Data are read on Caliper instrument.

6) matched curve

A. conversion Value Data is obtained from Caliper program.

B. conversion values are converted into inhibiting rate.

Inhibiting rate %=(maximum conversion value-practical conversion values)/(maximum conversion value-minimum conversion values) × 100, wherein " maximum conversion value " representative has DMSO Vehicle controls of the kinases without compound, and " minimum conversion values " are represented without kinases without compound pair According to.

C. IC is calculated using Xlfit excel add-in 4.3.1 data processing software₅₀Value.Calculation formula：Y= Bottom+(Top–Bottom)/(1+LogIC₅₀/ X) × HillSlope), the results are shown in Table 2：

Table 2

The experimental results showed that the compound of the present invention has strong inhibitory activity to FGFR4 kinases, to FGFR1 kinases Inhibitory activity is low, is substantially better than reference compound to the selectivity of FGFR4 kinases and FGFR1 kinases.Therefore, chemical combination of the invention Object is kinase inhibitor of the selectivity for the active advantage of FGFR4, can be used for treating disease relevant to FGFR4 kinases, And side effect caused by may be decreased because of the inhibition to FGFR1 kinases.

2 cell growth inhibition assay of experimental example

1 experimental material

1.1 compound：The experiment is carried out using the compound of the embodiment of the present invention, compound A, compound C.

1.2 cell：Hep3B cell, HUH-7 cell, are provided by Shanghai Yaoming Kangde New Medicine Development Co., Ltd.

1.3 reagent：FBS, DMEM, culture medium are purchased from GIBCO company；CellTiter Glo is purchased from Promega company.

1.4 instrument Tecan D300e fast liquid shifters；Biotek fluorescence detector

2 experimental methods

All compounds are stored in -20 DEG C of refrigerators after being dissolved in DMSO.

Day-1：By 3X10³Cell is added in 96 holes the density of a cells/well, every 100 μ l of hole；

The culture medium of every 100 μ l of hole is added in blank control；The PBS of 100 μ l is added in remaining edge hole that do not test；

Day 0：Compound is set and is loaded program, and uses Tecan D300e automatic sample；The starting for testing compound is dense Degree is 10 μM, 3 times of dilutions, 9 concentration, multiple holes；Positive reference Staurosporine initial concentration is 1 μM, and 3 times of dilutions, 9 dense Degree, multiple holes；

Day 3:It will test 96 orifice plate equilibrium at room temperature 30 minutes；Compound dissolubility and cellular is observed before CTG is added State；50 μ l CellTiter Glo reagents are added in every hole, detect signal with BioTec (Luminescence) after ten minutes.

The analysis of 3 data：

XL-fit software analysis data (supplier：ID Business Solution Ltd., version：XL fit 5.0)

Calculation formula：R (%)={ 1-RLU_Compound-RLU_Blank}/{RLU_Control-RLU_Blank} × 100%

It the results are shown in Table 3：

Table 3

"-" expression is not surveyed

Experimental result shows that the human hepatoma cell strain HePB and HuH-7 that the compound of the present invention expands FGFR4DNA are thin The proliferation of born of the same parents has extraordinary inhibitory activity, and the activity of part of compounds is much better than reference compound, is effective FGFR4 choosing Selecting property inhibitor.

3 drug metabolism of experimental example experiment

1 experimental material

1.1 compound

The experiment is carried out using compound and reference compound A, the compound B and compound C of the embodiment of the present invention.Mouthful Medication composition formula is 10% ethyl alcohol, and 10%solutol, 0.5mg/ml clear solution, vein medicine is made in 80% physiological saline solution Composition formula is 2% ethyl alcohol, and 2%solutol, 0.1mg/ml clear solution is made in 96% physiological saline.

1.2 animal

Male BALB/c mouse, every group each 3, weight 18-22, Shanghai western Poole-Bi Kai experimental animal Co., Ltd mentions For.The environment laundering period that 2~4 days are given before test mice experiment, fasting 8-12h before being administered are administered water supply after 2h, give after 4h Food.

1.3 reagent

Methanol (chromatographically pure)：The production of Spectrum company；Acetonitrile (chromatographically pure)：The production of Spectrum company；

Remaining reagent is that commercially available analysis is pure.

1.4 instrument

The triple level four bars LC-MS instrument of American AB company API4500 type are furnished with electric spray ion source (ESI), LC-30AD Double pump；SIL-30AC autosampler；CTO-30AC column oven；DGU-20A3R degasser；AnalystQSA01.01 chromatography work It stands；Milli-Q Superpure water machine (Millipore Inc)；QilinbeierVortex-5 oscillator；HITACHI CF16RⅩ II table-type high-speed refrigerated centrifuge.

2 experimental methods

1) mouse fasting but 0 moment blank plasma can be taken after free water 12 hours；

2) mouse 3 in step 1) are taken, stomach-filling (intragastric administration, I.G.) give this hair The compound and reference compound 10mg/kg of bright embodiment；Vein (I.V.) give the embodiment of the present invention compound and Reference compound 1mg/kg；

3) 5min, 15min, 30min, 1h, 2h, 4h, 8h, 10h after stomach-filling are set from eyeground vein clump continuous blood sampling for 24 hours In the EP pipe that heparin is distributed with, upper plasma is taken after 8000rpm/min centrifugation 5min, -20 DEG C freeze, to LC-MS/MS points Analysis；

4) it according to the resulting blood concentration-time data of step 3), is asked using WinNonlin software and calculates pharmacokinetics ginseng Number, the results are shown in Table 4.

Table 4

Experiment shows that mouse is apparently higher than reference compound, half-life period to the oral absorption exposed amount of the compounds of this invention It is longer than reference compound, it is ensured that there is the effective blood drug concentrations of longer time in Mice Body for compound.

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

Claims (10)

1. a kind of general formula II compound represented or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,

Wherein：

Bullet is the part that covalent bond can be formed with nucleopilic reagent；

X, G is each independently selected from CH and N；

Ring A is selected from Azacyclyl, and the Azacyclyl is optionally selected from halogen, alkyl, halogenated alkyl, alcoxyl by one or more Base, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkyl acyl, Alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle substituent group replaced；

Each R₃、R₄、R₅Be each independently selected from halogen, alkyl, naphthenic base, halogenated alkyl, alkoxy, halogenated alkoxy, nitro, Cyano, hydroxyl, amino, carboxyl, alkyl acyl alkyl, hydroxy alkyl, alkoxy, aminoalkyl, aryl, heteroaryl and heterocycle alkane Base, wherein n is selected from 0,1 and 2, and p is selected from 0,1 and 2 and q and is selected from 0,1,2,3,4 and 5；

R₆The alkyl selected from H and optionally replaced；Or R₆With adjacent aromatic ring or heteroaromatic together with the amino that they are connected jointly Form 8-12 circle heterocyclic ring base；With

R₇The alkyl selected from H and optionally replaced.

2. compounds of formula II according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, Crystallization or prodrug, middle ring A be selected from 7 yuan to 15 yuan nitrogen bridge heterocycles, optionally by one or more selected from halogen, alkyl, Halogenated alkyl, alkoxy, halogenated alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, aminoalkyl, hydroxy alkyl, alkoxy Alkyl, alkyl acyl, alkyl acyl alkyl, aryl, heteroaryl, naphthenic base and heterocycle substituent group replaced.

3. compounds of formula II according to claim 2 or its pharmaceutically acceptable salt, isomers, solvate, Crystallization or prodrug, middle ring A are selected from 7 yuan to 12 yuan nitrogen bridge heterocycles, are optionally selected from halogen, C by one or more_1-6Alkane Base, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, Hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Ring Alkyl and C_3-8Replaced the substituent group of heterocycle.

4. compounds of formula II according to claim 3 or its pharmaceutically acceptable salt, isomers, solvate, Crystallization or prodrug, middle ring A are selected from following bridge heterocycle：

It is optionally selected by one or more From halogen, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, Amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, Heteroaryl, C_3-8Naphthenic base and C_3-8Replaced the substituent group of heterocycle.

5. compounds of formula II according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, Crystallization or prodrug, wherein the general formula II has the structure of following general formula III：

Wherein bullet, X, G, R₃、R₄、R₅、R₆、R₇, the definition of n, p, q it is as described in claim 1；

M and d is each independently selected from 1,2,3 and 4；

Ring B is selected from C_3-8Naphthenic base, C_3-8Azacycloalkyl, C_3-8Oxacycloalkyl, C_3-8Nitrogen oxacycloalkyl and C_3-8Sulfur heterocyclic alkyl Base, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6It is alkoxy, halogenated C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, aryl, heteroaryl, C_3-8Naphthenic base and C_3-8The substituent group of heterocycle is taken Generation；

Preferably, ring B is selected from cyclopenta, cyclohexyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyranose and tetrahydro furan It mutters base, wherein these groups are optionally selected from halogen, C by one or more_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, halogen For C_1-6Alkoxy, nitro, cyano, hydroxyl, amino, carboxyl, amino C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkane Base, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Replaced the substituent group of alkyl.

6. compounds of formula II according to claim 1 or its pharmaceutically acceptable salt, isomers, solvate, knot Brilliant or prodrug, wherein the compound is selected from：

7. a kind of compounds of formula II according to claim 1 or its pharmaceutically acceptable salt, isomers, molten of preparing The preparation method of object, crystallization or prodrug is closed in agent, the described method comprises the following steps：

(1), 1 compound of formula obtains 3 compound of formula by palladium mediated coupling reaction with 2 compound of formula；

(2), the nitro in the aromatic ring of 3 compound of formula or heteroaromatic is reduced to amino, obtains 4 compound of formula；

(3), 4 compound of formula and bullet-LG2 obtain Formula II compound by amide coupling reaction；

Its middle ring A, bullet, X, G, R₃、R₄、R₅、R₆、R₇, the definition of n, p, q it is as described in claim 1；

LG1, LG2 represent leaving group, can be the same or different, preferably halogen or sulfonyloxy；

M can be-B (OR₁₁)₂,-Sn (alkyl) or-Zn- halogen-, wherein R₁₁For H or alkyl, preferably methyl.

8. a kind of pharmaceutical composition, it includes described in any item compounds of claim 1-6 or its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.

9. compound according to claim 1-6 or composition according to claim 8 are used in preparation Application in prevention and/or tumor, it is preferable that the tumour is kinase mediated by FGFR4.

10. application according to claim 9, wherein the tumour is selected from liver cancer, breast cancer, oophoroma, lung cancer and meat Tumor.