CN108264511A

CN108264511A - Heterocyclic derivative and preparation method thereof and its purposes in medicine

Info

Publication number: CN108264511A
Application number: CN201710003456.7A
Authority: CN
Inventors: 陈磊; 关东亮; 白骅; 凌龙; 赵松锋
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd
Priority date: 2017-01-03
Filing date: 2017-01-03
Publication date: 2018-07-10
Anticipated expiration: 2037-01-03
Also published as: CN108264511B

Abstract

The present invention relates to a kind of new heterocyclic derivative, preparation method and pharmaceutical composition containing the derivative as well as therapeutic agent especially as the purposes of FGFR4 inhibitor.Preferred compounds of the invention has good inhibiting effect to FGFR4.

Description

Heterocyclic derivative and preparation method thereof and its purposes in medicine

Invention field

The present invention relates to a kind of new heterocyclic derivative, preparation method and pharmaceutical composition containing the derivative with And its as therapeutic agent especially as the purposes of FGFR4 inhibitor.

Background of invention

Fibroblast growth factor acceptor (FGFR) family be by four members (FGFR1, FGFR2, FGFR3 and FGFR4 it) forms, belongs to the kinases of receptor tyrosine kinase family, FGF, which is combined, leads to FGFR dimerizations, then for receptor certainly The activation of body phosphorylation and downstream signaling pathway.Receptor activation is enough to recover and activates participation such as cell growth, cell new old generation Thank to the specific downstream signal partner with the diversification process adjustment of cell survival.Therefore, for tumor cell proliferation, migration, Infiltration, vascularization, cell key many bioprocess in, FGF/FGFR signal paths have manifold effect effect.FGFR Four members of family are different from each other in terms of its ligand affinity and Tissue distribution.The genome structure of FGFR-4 genes contains 18 extrons.

Mankind FGF19 genes be located at 11q13.1, FGFR4 and its ligand FGF19 specific binding inhibit Apoptosis and NF-kB signals, and raise it is cell proliferation related because expression；It can be led in the cell that the activation of FGFR4 is handled in TNF-α The decline of Ikk 'beta ' activities is caused, with the NF-kB reductions being distributed in cell and weakens Apoptosis effect.Four kinds of FGFR genes There are expression, but maturation hepatic parenchymal cells (Hepatpcyte) only great expression FGFR4 in human liver.FGFR4 matches with it Body, which combines, can also have the metabolism of bile acid regulating and controlling effect, and cholesterol is a variety of to the balance that bile acid converts and body in body Normal physiological function has close relationship, and the destruction of this balance can cause a variety of diseases of body such as fatty liver and artery sclerosis etc. Cardiovascular and cerebrovascular disease, therefore FGFR4 and FGF19 interactions become the new target of the cholesterol-lowering drugs such as hyperlipidemia.

In recent years, more and more evidences show to have in a plurality of types of cancers FGFR1, FGFR2, FGFR3 and The gene magnification mutation of FGFR4.A large amount of evidence shows：FGFR1 is in breast cancer, lung cancer in non-cellule type and spongioblastoma In have gene mutation, there is the fusion protein as caused by gene transposition to be formed in acute myelogenous leukemia, in cancer of pancreas, bladder There is overexpression in cancer, prostate cancer, cancer of the esophagus；FGFR2 has gene mutation and amplification in gastric cancer, breast cancer and uterine cancer Phenomenon, while have overexpression in prostate cancer, cancer of the esophagus, oophoroma, cancer of pancreas, brain tumor, colorectal cancer；FGFR3 is multiple There is gene mutation in property myeloma and carcinoma of urinary bladder, have overexpression in oophoroma, lung cancer in non-cellule type, hepatocellular carcinoma； FGFR4 has mutation and overexpression in lung cancer, oophoroma, prostate cancer, liver cancer and cholangiocarcinoma etc., in thyroid cancer, ovary Also there are excessive expression (French et al.2012PLos ONE 7 (5) in cancer etc.：e367313；Sia et al.2013Gastroejterology 144：829-840).

A series of FGFR inhibitor patent is had been disclosed at present, but the patent of FGFR4 selective depressions is disclosed It is less, for the inhibitor of FGFR4 selectivity, there is advantage (Brown, AP the et al of small toxicity relative to FGFR inhibitor (2005), Toxocol.Pathol., 449-455), but at this stage for research of the FGFR4 inhibitor for tumours such as anti-liver cancer and anti-s It is far from being enough, it is still necessary to the FGFR4 inhibitor that research and development is new.

Invention content

It is an object of the present invention to disclose a new class of heterocyclic derivative and its salt pharmaceutically.

The present invention provides a kind of logical formula (I) compound represented or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt：

Wherein：

For singly-bound or double bond；Preferably singly-bound；

X is selected from N or CH；Preferably CH；

Ring A is selected from cycloalkyl, heterocycle, aryl or heteroaryl；

Each R¹It is each independently selected from hydrogen atom, alkyl, halogen, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl Base ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹, wherein the alkyl, alkoxy, cycloalkanes Base, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alcoxyl Base, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹ Substituent group replaced；

R²Ortho position is in-the NH- of ring A, selected from following group：

-NR⁶C(O)CR⁷=CHR⁸Or-NR⁶C(O)C≡CR⁷；

Each R³Be each independently selected from hydrogen atom, halogen, alkoxy, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, Heteroaryl ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹, wherein the alkoxy, alkyl, Cycloalkyl, heterocycle, aryl or heteroaryl optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, Alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkoxy ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O) NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；

(i)R⁴Selected from alkyl, wherein the further-NR of the alkyl^AR^BReplaced；

R^AAnd R^BHydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein the alkane Base, cycloalkyl, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkane Base, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O)NR¹³R¹⁴Or- NR¹³C(O)R¹⁴Substituent group replaced；Or

(ii)R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

R^CAnd R^DWith connecting R^CAnd R^DC atoms ring collectively forms 3~6 yuan of cycloalkyl together；

R^ESelected from alkyl；

Each R⁵Be each independently selected from hydrogen atom, halogen, alkoxy, oxo base, hydroxyl, cyano, alkyl, cycloalkyl, Heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl are optionally into one Step by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,- C(O)R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；Preferably oxo base；

Each R⁶Hydrogen atom or alkyl are each independently selected from, wherein the alkyl is optionally further one or more Selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkoxy ,-C (O)R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；

R⁷And R⁸Be each independently selected from hydrogen atom, alkyl or halogen, wherein the alkyl optionally further by one or It is multiple to be selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, haloalkoxy Base ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；

R⁹、R¹⁰And R¹¹Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein institute Alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are stated optionally further by one or more selected from hydroxyl, halogen, nitro, cyanogen Base, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O)NR¹³R¹⁴ Or-NR¹³C(O)R¹⁴Substituent group replaced；

Alternatively, R¹⁰And R¹¹With forming 4~8 circle heterocyclic ring bases together with the N atoms being connected, wherein in 4~8 circle heterocyclic rings Contain one or more N, O, S (O)_qAtom, and in 4~8 circle heterocyclic rings further by one or more selected from hydroxyl, halogen, Nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,=O ,-C (O) R¹²、-C(O)OR¹²、- NR¹³R¹⁴、-C(O)NR¹³R¹⁴Or-NR¹³C(O)R¹⁴Substituent group replaced；

R¹²、R¹³And R¹⁴Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein institute Alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are stated optionally further by one or more selected from hydroxyl, halogen, nitro, cyanogen Base, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；

M is 1,2,3 or 4；

N is 0,1 or 2；Preferably 1；

P is 0,1,2,3 or 4；

Q is 0,1 or 2；And

S is selected from 1,2,3 or 4.

The present invention preferred embodiment in, lead to formula (I) described in compound or its stereoisomer, tautomer or its Pharmaceutical salt, for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (II)：

Wherein：R¹~R⁴, m and p definition as described in logical formula (I).

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided In tautomeric or its pharmaceutical salt, each R¹It is each independently selected from halogen or alkoxy, preferably chlorine or methoxyl group.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided In tautomeric or its pharmaceutical salt, R²Selected from-NHC (O) CH=CH₂。

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, wherein each R³It is each independently selected from hydrogen atom.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, wherein each R³Heterocycle, preferably 3~8 circle heterocyclic ring bases are each independently selected from, it is more excellent 5~6 circle heterocyclic ring bases are selected as, wherein the heterocycle is optionally further by one or more selected from alkyl, alkoxy, cycloalkanes Base, heterocycle, aryl or heteroaryl substituent group replaced.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, wherein：

Each R³Alkyl is each independently selected from, the alkyl is further replaced by heterocycle, and preferably 3~8 yuan miscellaneous Ring group, more preferably 5~6 circle heterocyclic ring bases, wherein the heterocycle is optionally further by one or more selected from alkyl, alcoxyl Base, cycloalkyl, heterocycle, aryl or heteroaryl substituent group replaced.

Each R³It is each independently selected from-C (O) R⁹, R⁹Selected from heterocycle, preferably 3~8 circle heterocyclic ring bases, more preferably 5 ~6 circle heterocyclic ring bases, wherein the heterocycle is optionally further by one or more selected from alkyl, alkoxy, cycloalkyl, heterocycle The substituent group of base, aryl or heteroaryl is replaced.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, wherein each R³It is each independently selected from halogen, preferably F, Cl or Br, more preferably F Or Cl.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, middle ring A are selected from 4~8 circle heterocyclic ring bases, preferably tetrahydrofuran base or THP trtrahydropyranyl.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, middle ring A are selected from phenyl.

In the preferred embodiment of the present invention, logical formula (I) or compound described in (II) or its stereoisomer, mutually are provided Tautomeric or its pharmaceutical salt, wherein

R⁴Selected from-(CH₂)rNR^AR^B；

R is selected from 1,2,3 or 4；

R^AAnd R^BHydrogen atom or alkyl are each independently selected from, wherein the alkyl is optionally further one or more Hydroxyl,

The substituent group of halogen is replaced.

R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

S is selected from 1,2,3 or 4；

R^ESelected from alkyl.

R²Selected from-NHC (O) CH=CH₂；

Each R³It is each independently selected from hydrogen atom.

R²Selected from-NHC (O) CH=CH₂；

Each R³Heterocycle, preferably 3~8 circle heterocyclic ring bases, more preferably 5~6 circle heterocyclic ring bases are each independently selected from, Described in heterocycle optionally further by one or more be selected from alkyl, alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl The substituent group of base is replaced.

R²Selected from-NHC (O) CH=CH₂；

Each R³It being each independently selected from selected from alkyl, the alkyl is further replaced by heterocycle, and preferably 3~8 Circle heterocyclic ring base, more preferably 5~6 circle heterocyclic ring bases, wherein the heterocycle optionally further by one or more selected from alkyl, Alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl substituent group replaced.

R²Selected from-NHC (O) CH=CH₂；

R⁴Selected from-(CH₂)rNR^AR^B；

R is selected from 1,2,3 or 4；

R^AAnd R^BHydrogen atom or alkyl are each independently selected from, wherein the alkyl is optionally further one or more Substituent group selected from hydroxyl, halogen is replaced.

R²Selected from-NHC (O) CH=CH₂；

R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

S is selected from 1,2,3 or 4；

R^ESelected from alkyl.

The typical compound of the present invention includes, but are not limited to：

Or its stereoisomer, tautomer or its pharmaceutical salt.

Further, the present invention provides the compound or its stereoisomer, tautomer described in a kind of general formula (IA) Or its pharmaceutical salt,

Wherein：

R^aSelected from hydrogen atom or amino protecting group, the amino protecting group is preferably benzenesulfonyl, benzyloxycarbonyl group, formyl Base, trifluoroacetyl group and tert-butoxycarbonyl；More preferably benzenesulfonyl and tert-butoxycarbonyl；

R¹、R³~R⁵, X, m, n and p definition as described in logical formula (I).

Compound described in general formula (IA) includes but not limited to：

Or its stereoisomer, tautomer or its pharmaceutical salt.

Further, the present invention provides a kind of preparation method of logical formula (I) compound, and this method includes：

General formula (IA) compound and acetyl halide compound, preferably Y-C (O) CR⁷=CHR⁸Or Y-C (O) C ≡ CR⁷Reaction, obtains To general formula (IB) compound：

Wherein：

Y is halogen；

Work as R^aDuring for hydrogen atom, general formula (IB) compound is logical formula (I) compound；

Work as R^aDuring for amino protecting group, R is further sloughed^aLogical formula (I) compound is obtained,

Wherein：R¹~R⁵, X, m, n and p definition as described in logical formula (I).

Further, the present invention provides a kind of pharmaceutical composition, and the pharmaceutical composition contains the general formula of effective dose (I) or the compound described in (II) or its stereoisomer, tautomer or its pharmaceutical salt and pharmaceutical carrier, Excipient or combination thereof.

The present invention provides a kind of method for inhibiting FGFR4, and this method is included the receptor and logical formula (I) or (II) institute The compound stated or its stereoisomer, tautomer or its pharmaceutical salt are in contact with its pharmaceutical composition.

The present invention provide a kind of logical formula (I) or compound described in (II) or its stereoisomer, tautomer or its The purposes of pharmaceutical salt or its pharmaceutical composition in the drug for inhibiting FGFR4 is prepared.

The present invention provide a kind of logical formula (I) or compound described in (II) or its stereoisomer, tautomer or its The purposes of pharmaceutical salt or its pharmaceutical composition in the drug of disease for the treatment of FGFR4 transition expression is prepared.

The present invention provide a kind of logical formula (I) or compound described in (II) or its stereoisomer, tautomer or its The purposes of pharmaceutical salt or its pharmaceutical composition in the drug of disease for the treatment of FGF19 amplifications is prepared.

The present invention provide a kind of logical formula (I) or compound described in (II) or its stereoisomer, tautomer or its The purposes of pharmaceutical salt or its pharmaceutical composition in treating cancer drug is prepared, wherein the cancer is selected from non-small thin Born of the same parents' lung cancer, gastric cancer, Huppert's disease, liver cancer, cholangiocarcinoma, preferably liver cancer and cholangiocarcinoma.

Detailed description of the invention

Unless stated to the contrary, otherwise used part term defines such as the present invention in the specification and in the claims Under：

Refer to include C when " alkyl " is as a part for a group or a group₁-C₂₀Straight chain or the fat with branch Hydrocarbyl group.Preferably C₁-C₁₀Alkyl, more preferably C₁-C₆Alkyl.The embodiment of alkyl group includes but not limited to methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl Propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be taken In generation, is unsubstituted.

" cycloalkyl " refers to the carbocyclic ring of saturation or the monocyclic of fractional saturation, condensed ring, bridged ring and loop coil.Preferably C₃-C₁₂Ring Alkyl, more preferably C₃-C₈Cycloalkyl, most preferably C₃-C₆Cycloalkyl.The embodiment of monocyclic cycloalkyl includes but not limited to ring Propyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring are pungent Base etc., preferably cyclopropyl, cyclohexenyl group.

" spiro cycloalkyl group " refers to 5 to 18 yuan, two or more cyclic structures, and it is monocyclic between each other share a carbon original The polycyclic moiety of son (claiming spiro-atom), ring is interior containing one or more double bonds, but neither one ring has the pi-electron of total conjugated Aroma system.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to sharing the number of spiro-atom between ring and ring by loop coil Alkyl is divided into single spiral shell, double spiral shells or more spiro cycloalkyl groups, preferably single spiral shell and double spiro cycloalkyl groups, preferably 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan.The non-limiting example of " spiro cycloalkyl group " includes but not limited to：Spiral shell [4.5] decyl, spiral shell [4.4] nonyl Base, spiral shell [3.5] nonyl, spiral shell [2.4] heptyl.

" cycloalkyl " refers to 5 to 18 yuan, contains the complete of two or more cyclic structures public a pair of of carbon atom each other Carbon polycyclic moiety, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron of total conjugated Aroma system, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, four can be divided into according to the number of composition ring Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl." cycloalkyl " Non-limiting example include but not limited to：Two rings [3.1.0] hexyl, two rings [3.2.0] hept- 1- alkenyls, two rings [3.2.0] Heptyl, decahydronaphthalene naphthalene or ten tetrahydrochysene phenanthryl.

" bridge ring alkyl " refers to 5 to 18 yuan, containing two or more cyclic structures, shares two each other and is not connected directly The full carbon polycyclic moiety of carbon atom is connect, one or more rings can contain one or more double bonds, but neither one ring has had The aroma system of the pi-electron of full conjugate, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.Preferably 6 to 14 yuan, more preferably 7 To 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to the number of composition ring, preferably bicyclic, tricyclic or Bicyclic or tricyclic is more selected as at Fourth Ring.The non-limiting example of " bridge ring alkyl " includes but not limited to：(1s, 4s)-two ring [2.2.1] heptyl, two rings [3.2.1] octyl group, (1s, 5s)-two ring o [3.3.1] nonyl, two rings [2.2.2] octyl group, (1r, 5r)- Two rings [3.3.2] decyl.

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein being connected to one with precursor structure The ring risen is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be It is optionally substituted or unsubstituted.

" heterocycle ", " heterocycle " or " heterocycle " is used interchangeably in this application, all referring to non-aromatic heterocyclyl groups, The atom of middle one or more cyclization is hetero atom, such as oxygen, nitrogen, sulphur atom, including monocyclic, condensed ring, bridged ring and loop coil.It is preferred that With 5 to 7 unit monocycles or 7 to 10 yuan it is double-or tricyclic, can include and 1,2 or 3 the atom in nitrogen, oxygen and/or sulphur. The example of " heterocycle " includes but not limited to morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, 1,1- dioxo-thiomorpholinyl, Piperidyl, 1,2,3,6- tetrahydro pyridyl, 2- oxo-pipehdinyls, pyrrolidinyl, 2- oxo-pyrrolidines, piperazine -2- ketone, 8- Oxa- -3- aza-bicyclos [3.2.1] octyl group and piperazinyl.Heterocycle can be substituted or unsubstituted.

" spiro heterocyclic radical " refers to 5 to 18 yuan, two or more cyclic structures, and it is monocyclic between each other share an atom Polycyclic moiety, containing one or more double bonds in ring, but neither one ring has the aroma system of the pi-electron of total conjugated, Middle one or more annular atom is selected from nitrogen, oxygen or S (O)_qThe hetero atom of (wherein q from 0,1 or 2), remaining annular atom are carbon.It is preferred that It is 6 to 14 yuan, more preferably 7 to 10 yuan.It is miscellaneous that spiro heterocyclic radical is divided into single spiral shell by the number according to spiro-atom is shared between ring and ring Ring group, double spiro heterocyclic radicals or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 3 yuan/6 yuan, 4 yuan/ 4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.Wherein " a members/single spiro heterocyclic radical of b members " it is single to refer to a members The spiro heterocyclic radical of ring and b unit monocycles a public atom each other.The non-limiting example of " spiro heterocyclic radical " includes but not limited to： 1,7- dioxo spiro [4.5] decyl, 2- oxa- -7- azaspiros [4.4] nonyl, 7- oxaspiros [3.5] nonyl and 5- oxaspiros [2.4] heptyl.

" condensed hetero ring base " refers to the full carbon polycyclic moiety for sharing a pair of of atom each other containing two or more cyclic structures, One or more rings can contain one or more double bonds, but neither one ring has the aroma system of the pi-electron of total conjugated, Wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_qThe hetero atom of (wherein q is selected from 0,1 or 2), remaining annular atom are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to ring is formed can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic thick Heterocycle, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases.The non-limit of " condensed hetero ring base " Property embodiment processed includes but not limited to：Octahydro pyrrolo- [3,4-c] pyrrole radicals, octahydro -1H- isoindolyls, 3- azabicyclics [3.1.0] hexyl, octahydro benzo [b] [Isosorbide-5-Nitrae] bioxin (dioxine).

" bridge heterocycle " refers to 5 to 14 yuan, 5 to 18 yuan, containing two or more cyclic structures, shares two each other not The polycyclic moiety for the atom being connected directly, one or more rings can contain one or more double bonds, but neither one ring has There is the aroma system of the pi-electron of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_n(wherein n is selected from 0,1 Or 2) hetero atom, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can according to the number of composition ring To be divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle, preferably bicyclic, tricyclic or Fourth Ring, it is more selected as bicyclic or tricyclic. The non-limiting example of " condensed hetero ring base " includes but not limited to：2- azabicyclics [2.2.1] heptyl, 2- azabicyclics [2.2.2] octyl group and 2- azabicyclics [3.3.2] decyl.The heterocyclic ring can be condensed in aryl, heteroaryl or cycloalkyl On ring, wherein being heterocycle with the ring that precursor structure links together.Heterocycle can be optionally substituted or unsubstituted.

" aryl " refers to the carbocyclic aromatic system containing one or two rings, wherein the ring can be in a manner of condensed It links together.Term " aryl " including such as phenyl, naphthalene, tetralyl aromatic group.Preferred aryl groups are C₆-C₁₀Virtue Base, more preferable aryl are phenyl and naphthalene, most preferably phenyl.Aryl can be substituted or unsubstituted." aryl " can With heteroaryl, heterocycle or Cycloalkylfused, wherein it is aryl rings to link together with precursor structure, non-limiting example Including but not limited to：

" heteroaryl " refers to 5 to 6 unit monocycle of aromatic series or 9 to 10 membered bicyclics, can include 1 to 4 selected from nitrogen, oxygen And/or the atom in sulphur.The embodiment of " heteroaryl " includes but not limited to furyl, pyridyl group, 2- oxo -1,2- dihydropyridines Base, pyridazinyl, pyrimidine radicals, pyrazinyl, thienyl , isoxazolyl , oxazolyl , oxadiazolyls, imidazole radicals, pyrrole radicals, pyrazolyl, Triazolyl, tetrazole radical, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl group, benzodioxole group, benzimidazolyl, Indyl, isoindolyl, 1,3- dioxo-isoindolyl, quinolyl, indazolyl, benzisothia oxazolyl, benzoxazolyl and benzene Bing isoxazolyls.Heteroaryl can be substituted or unsubstituted.The heteroaryl ring can be condensed in aryl, heterocycle or cycloalkanes On basic ring, wherein being heteroaryl ring with the ring that precursor structure links together, non-limiting example includes but not limited to：

" alkoxy " refers to the group of (alkyl-O-).Wherein, alkyl is shown in related definition herein.C₁-C₆Alkoxy to be excellent First select.The example includes, but are not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Tert-butoxy etc..

" hydroxyl " refers to-OH groups.

" halogen " refers to fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.

" amino " refers to-NH₂。

" cyano " refers to-CN.

" nitro " refers to-NO₂。

" benzyl " refers to-CH₂Phenyl.

" carboxyl " refers to-C (O) OH.

" carboxylate " refers to-C (O) O (alkyl) or (cycloalkyl), and wherein alkyl, cycloalkyl is as defined above.

" oxo base " refers to=O.

" amino protecting group " refers in organic synthesis, in order to make-NH₂Or-NH- commonly uses certain examination from the destruction of reaction Agent is first protected, and is waited after the completion of reacting, then slough protecting group.Amino protecting group includes but not limited to tert-butoxycarbonyl, benzyl Oxygen carbonyl, formoxyl or trifluoroacetyl group.

" substituted " refers to one or more of group hydrogen atom, 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 technology personnel can determine and (pass through experiment or theoretical) may or impossible to take in the case where not paying excessive make great efforts Generation.

" substitution " or " substituted " described in this specification, as without particularly pointing out, each meant that group can be one or more Replace selected from following group：Alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, dredge base, hydroxyl, nitro, Cyano, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, Halogenated alkyl, hydroxyalkyl, carboxyl, carboxylate ,=O ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C (O)R¹¹,

Wherein, R⁹、R¹⁰And R¹¹Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, Described in alkyl, cycloalkyl, heterocycle, aryl or heteroaryl optionally further by one or more selected from hydroxyl, halogen, nitre Base, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O) NR¹³R¹⁴Or-NR¹³C(O)R¹⁴Substituent group replaced；

R¹²、R¹³And R¹⁴Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein institute Alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are stated optionally further by one or more selected from hydroxyl, halogen, nitro, cyanogen Base, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced.

" pharmaceutical salt " refers to that above compound can keep original bioactivity and be suitable for the certain of medical usage Salt.The amine salt that the pharmaceutical salt of compound represented by formula (I) can be metal salt and suitably acid is formed, metal salt Preferred as alkali, alkali salt, suitable acid include inorganic acid and organic acid, such as acetic acid, benzene sulfonic acid, benzoic acid, camphor Sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, Malaysia Acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-methyl benzenesulfonic acid etc..Particularly preferably hydrochloric acid, Hydrobromic acid, phosphoric acid and sulfuric acid, most preferably hydrochloride.

" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically pharmaceutical salt or Pro-drug and the mixture and the pharmaceutical carrier of other components such as physiology and excipient of other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, absorption and then performance bioactivity conducive to active constituent.

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention adopts the following technical scheme that：

The preparation method of compound or its salt described in the logical formula (I) of the present invention, includes the following steps：

General formula (Ia) compound is in condition existing for bis- diphenylphosphine -9, the 9- xanthphos of 4,5- and palladium catalyst Under, preferably three (dibenzalacetone) two palladium is reacted with general formula (Ib) compound in the presence of carbonate, obtains general formula (Ic) compound；By the R in general formula (Ic) compound^b- NH- carries out deprotection reaction, obtains general formula (IA) compound；General formula (IA) compound and acetyl halide compound, preferably Y-C (O) CR⁷=CHR⁸Or Y-C (O) C ≡ CR⁷Reaction obtains logical formula (I) chemical combination Object；

Wherein：

R^aSelected from hydrogen atom；

R^bSelected from amino protecting group, preferably benzenesulfonyl, benzyloxycarbonyl group, formoxyl, trifluoroacetyl group and tert-butoxy Carbonyl

Base；More preferably benzenesulfonyl and tert-butoxycarbonyl；

R^cSelected from halogen；

Y is selected from halogen；

R¹~R⁵, X, m, n and p definition as described in logical formula (I).

In the preferred embodiment of the present invention, the preparation method of the compound or its salt described in logical formula (I) includes the following steps：

General formula (Ia) compound is in condition existing for bis- diphenylphosphine -9, the 9- xanthphos of 4,5- and palladium catalyst Under, preferably three (dibenzalacetone) two palladium is reacted with general formula (Id) compound in the presence of carbonate, is led to Formula (Ie) compound；Amino in general formula (Ie) compound is protected, is preferably reacted with di-tert-butyl dicarbonate, obtains R^a General formula (If) compound of protection；The nitro of general formula (If) compound is further reduced into amino, obtains general formula (IA) chemical combination Object；General formula (IA) compound and acetyl halide compound, preferably Y-C (O) CR⁷=CHR⁸Or Y-C (O) C ≡ CR⁷Reaction, obtains general formula (IB) compound；General formula (IB) compound further sloughs amino protecting group R^aObtain logical formula (I) compound；

Wherein：

R^aSelected from amino protecting group, preferably benzenesulfonyl, benzyloxycarbonyl group, formoxyl, trifluoroacetyl group and tert-butoxy Carbonyl；More preferably benzenesulfonyl and tert-butoxycarbonyl；

R^cSelected from halogen；

Y is selected from halogen；

R¹~R⁵, X, m, n and p definition as described in logical formula (I).

Description of the drawings

Fig. 1 is the average tumor that 3 compound of embodiment inhibits human liver cancer Hep 3B Nude Mouse Models in test case 3 Volume change figure.

Fig. 2 is that 3 compound of embodiment inhibits relatively average to human liver cancer Hep 3B Nude Mouse Models in test case 3 Tumor Volume Changes figure.

Specific embodiment

With reference to embodiments for further describing the present invention, but these embodiments are not to limit the model of the present invention It encloses.

Embodiment

Embodiment gives the preparation of the representative compound represented by formula (I) and dependency structure appraising datum.It must say Bright, following embodiments are for illustrating rather than limitation of the present invention.¹H NMR spectras are with Bruker instruments (400MHz) is measured and is obtained, and chemical shift is represented with ppm.It uses tetramethylsilane internal standard (0.00ppm).¹The expression of H NMR Method：S=is unimodal, d=doublets, t=triplets, m=multiplets, what br=broadened, the doublet of dd=doublets, dt= The doublet of triplet.If coupling constant is provided, unit Hz.

Mass spectrum is to measure to obtain with LC/MS instrument, and Ionization mode can be ESI or APCI.

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。

Column chromatography is carrier generally using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.

In the examples below that, unless otherwise specified, all temperature are Celsius temperature, unless otherwise specified, various startings Raw materials and reagents come from commercially available or are synthesized according to known method, and marketable material and reagent are direct without further purification It uses, unless otherwise specified, commercially available producer includes but not limited to Aldrich Chemical Company, ABCR GmbH＆ Co.KG, Acros Organics, Guang Zan Chemical Industry Science Co., Ltd and Jing Yan Chemical Industry Science Co., Ltd etc. purchase.

CD₃OD：Deuterated methanol.

CDCl₃：Deuterochloroform.

DMSO-d₆：Deuterated dimethyl sulfoxide.

Argon atmospher refers to that reaction bulb connects the argon gas balloon of an about 1L volume.

Without specified otherwise in embodiment, the solution in reaction refers to aqueous solution.

Compound is purified, using silica gel column chromatography eluant, eluent system and thin-layered chromatography, wherein eluant, eluent system It is selected from：A：Petroleum ether and ethyl acetate system；B：Dichloromethane and methanol system；C：Dichloromethane：Ethyl acetate；Wherein solvent Volume ratio it is different and different according to the polarity of compound, a small amount of acidity or alkaline reagent progress condition can also be added in, such as Acetic acid or triethylamine etc..

Embodiment 1

N- (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) acrylamide

The first step

The chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) ethyl nicotinate

By 4,6- dichloro-nicotinic acid ethyl ester 1a (30.1g, 136.99mmol) and N¹, N¹Dimethylpropane -1,3- diamines 1b (18.95mL, 150.46mmol) is dissolved in 300mL tetrahydrofurans, and 60 DEG C are reacted 2 hours.Reaction solution is concentrated under reduced pressure, and what is obtained is residual Stay object silica gel column chromatography (eluant, eluent：A systems) purifying, obtain the chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) cigarette Acetoacetic ester 1c (22.84g, white solid), yield：58.5%.

MS m/z(ESI)：286.0[M+1]

Second step

(the chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) pyridin-3-yl) methanol

The chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) ethyl nicotinate 1c (16.5g, 57.74mmol) is dissolved in In 300mL tetrahydrofurans, it is cooled to 0 DEG C and adds in lithium aluminium hydride reduction (78.0mL, 77.39mmol), be then warmed to room temperature 10 points of reaction Clock.4mL water, 4mL sodium hydroxide solutions (20%) and 12mL water are sequentially added into reaction solution, adds in anhydrous sodium sulfate (20.0g) is stirred 1 hour, filtering, and filtrate decompression concentration obtains (the chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) pyrrole Pyridine -3- bases) methanol 1d (13.26g, faint yellow solid), yield：94.2%.

¹H NMR (400MHz, CDCl₃) δ 7.64 (s, 1H), 6.42 (s, 1H), 6.35 (s, 1H), 4.51 (s, 2H), 3.45 (s, 1H), 3.16 (d, J=4.7Hz, 2H), 2.34 (t, J=6.7Hz, 2H), 2.18 (s, 6H), 1.80-1.70 (m, 2H)

Third walks

The chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) nicotine aldehyde

By (the chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) pyridin-3-yl) methanol 1d (17.8g, 73.0mmol) It is dissolved in 600mL dichloromethane, adds in activated manganese dioxide (75.0g, 876mmol), reaction solution reacts at room temperature 18 hours.Reaction Liquid is filtered by diatomite, and filtrate decompression concentration obtains the chloro- 4- of crude product 6- ((3- (dimethylamino) propyl) amino) nicotine aldehyde 1e (14.52g, yellow liquid), yield：82.4%.

MS m/z(ESI)：241.9[M+1]

4th step

The chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one

By the chloro- 4- of 6- ((3- (dimethylamino) propyl) amino) nicotine aldehyde 1e (1.49g, 6.17mmol), 2- (3,5- bis- Methoxyphenyl) methyl acetate 1f (1.43g, 6.68mmol) and cesium carbonate (2.41g, 7.40mmol) be dissolved in 25mL N, N- bis- In methylformamide, 125 DEG C of microwave reactions 2 hours.30mL dichloromethane and 30mL water, water phase dichloro are added in into reaction solution Methane (30mL × 2) extracts, and merges organic phase, is washed with water (30mL × 3), is concentrated under reduced pressure, residue silica gel column chromatography (solvent：B systems) purifying, obtain the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1,6- (1H) -one of naphthyridines -2 1g (1.95g, yellow solid), yield：78.8%.

MS m/z(ESI)：401.9[M+1]

5th step

The chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one

By the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one 1g (2.91g, 7.77mmol) is dissolved in 200mL acetonitriles, is cooled to -20 DEG C of dropwise addition sulfonic acid chlorides (1.4mL, 17.3mmol) and is dissolved in In 40mL acetonitriles, react at room temperature 10 minutes.Reaction solution concentrates, and adds in 200mL dichloromethane, is adjusted with saturated sodium bicarbonate solution PH=8~9, layering, water phase are extracted with dichloromethane (100mL), merge organic phase, are concentrated under reduced pressure, are obtained the chloro- 3- (2,6- of 7- Two chloro- 3,5- Dimethoxyphenyls) and -1- (3- (dimethylamino) propyl)-(1H) -one of 1,6- naphthyridines -2 1h (3.22g, it is yellowish Color color solid), yield：88.2%.

MS m/z(ESI)：471.8[M+1]

6th step

(4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- Dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) t-butyl carbamate

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (200mg, 0.425mmol), (4- amido tetrahydrofuran -3- bases) t-butyl carbamate Bis- diphenylphosphine -9, the 9- xanthphos (49mg, 0.093mmol) of 1i (86mg, 0.425mmol), 4,5-, three (two benzal Benzylacetone) two palladiums (39mg, 0.0425mmol) and cesium carbonate (415mg, 1.270mmol) be dissolved in 15mL toluene, it is heated to 120 DEG C reaction 4 hours.Reaction solution is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：C systems) purifying, it obtains (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro -1, 6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) t-butyl carbamate 1j (95mg, faint yellow solid), yield：35.2%.

MS m/z(ESI)：635.8[M+1]

7th step

7- ((4- amido tetrahydrofuran -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (two Methylamino) propyl) -1,6- naphthyridines -2 (1H) -one

Will (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) t-butyl carbamate 1j (85mg, 0.133mmol) is dissolved in In 3mL dichloromethane, add 1mL trifluoroacetic acids, react at room temperature 4 hours.Reaction solution is concentrated under reduced pressure, and obtains crude product 7- ((4- amino four Hydrogen furans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthalenes (1H) -one of pyridine -2 1k (60mg, faint yellow solid), product directly carry out next step reaction without further purification.

MS m/z(ESI)：535.8[M+1]

8th step

By 7- ((4- amido tetrahydrofuran -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl)-(1H) the -one 1k of 1,6- naphthyridines -2 (60mg, 0.112mmol) is dissolved in 3mL dichloromethane, add in third Alkene acyl chlorides (9.30 μ L, 0.112mmol) reacts at room temperature 2 hours.Reaction solution is concentrated under reduced pressure, obtained residue silica gel thin-layer Chromatography (solvent：B systems) purifying, obtain N- (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (diformazans Base amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) acrylamide 1 (8mg, Faint yellow solid), yield：12.1%.

MS m/z(ESI)：589.9[M+1]

¹H NMR (400MHz, DMSO) δ 8.39 (s, 1H), 8.12 (d, J=7.9Hz, 1H), 7.66 (s, 1H), 6.96 (s, 1H), 6.91 (d, J=7.2Hz, 1H), 6.44 (s, 1H), 6.22 (dd, J=17.1,10.2Hz, 1H), 6.00 (dd, J= 17.1,1.9Hz, 1H), 5.52 (dd, J=10.2,1.9Hz, 1H), 4.65 (s, 2H), 4.15-4.06 (m, 3H), 4.02 (dd, J =8.7,6.3Hz, 1H), 3.94 (s, 6H), 3.72-3.61 (m, 2H), 2.32 (t, J=6.7Hz, 2H), 2.17 (d, J= 8.7Hz, 6H), 1.76 (d, J=7.2Hz, 2H)

Embodiment 2

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino -3- fluorophenyls) acrylamide

The first step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((fluoro- 6- nitros of 2- Phenyl) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) the fluoro- 6- nitroanilines 2a (94mg, 0.467mmol) of-(1H) the -one 1h of 1,6- naphthyridines -2 (200mg, 0.425mmol), 2-, 4, Bis- diphenylphosphine -9, the 9- xanthphos (49mg, 0.085mmol) of 5-, three (dibenzalacetone) two palladium (39mg, It 0.0425mmol) is dissolved in 10mL toluene with cesium carbonate (415mg, 1.270mmol), is heated to 120 DEG C and reacts 4 hours.Reaction Liquid is concentrated under reduced pressure, obtained residue silicon thin-layer chromatography (solvent：C systems) purifying, obtain 3- (2,6- bis- chloro- 3, 5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((the fluoro- 6- nitrobenzophenones of 2-) amino) -1,6- naphthyridines -2 (1H) -one 2b (199mg, yellow solid), yield：80.0%.

MS m/z(ESI)：589.8[M+1]

Second step

7- (tertbutyloxycarbonyl-(the fluoro- 6- nitrobenzophenones of 2-) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((the fluoro- 6- nitre of 2- Base phenyl) amino)-(1H) the -one 2b of 1,6- naphthyridines -2 (199mg, 0.337mmol) is dissolved in 6mL tetrahydrofurans, add in two carbonic acid Di tert butyl carbonate (146.9mg, 0.674mmol) and 4-dimethylaminopyridine (82.2mg, 0.674mmol) are warming up to 80 DEG C of reactions 2 Hour.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 7- (uncles Butoxy carbonyl-(the fluoro- 6- nitrobenzophenones of 2-) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylaminos Base) propyl)-(1H) -one of 1,6- naphthyridines -2 2c (230mg, faint yellow solid), yield：98.7%.

MS m/z(ESI)：690.2[M+1]

Third walks

7- ((2- amino -6- fluorophenyls) (tertbutyloxycarbonyl) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one

By 7- (tertbutyloxycarbonyl-(the fluoro- 6- nitrobenzophenones of 2-) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (3- (dimethylamino) propyl)-(1H) -one 2c of 1,6- naphthyridines -2 (230mg, 0.33mmol) is dissolved in 5mL methanol, is added in Raney's nickel (200mg) under hydrogen shield, reacts at room temperature 1 hour.Reaction solution filters, and filtrate decompression concentration obtains 7- ((2- ammonia Base -6- fluorophenyls) (tertbutyloxycarbonyl) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) Propyl)-(1H) -one of 1,6- naphthyridines -2 2d (150mg, pale solid), yield：68.2%.

MS m/z(ESI)：662.3[M+1]

4th step

N- (2- (tertbutyloxycarbonyls-(3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -3- fluorophenyls) acrylamide

By 7- ((2- amino -6- fluorophenyls) (tertbutyloxycarbonyl) amino) -3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl)-(1H) -one 2d of 1,6- naphthyridines -2 (100mg, 0.151mmol) is dissolved in 10mL dichloromethanes In alkane, n,N-diisopropylethylamine (78mg, 0.606mmol) and acryloyl chloride (25 μ L, 0.303mmol), room are added under ice bath Temperature reaction 12 hours.PH=8~9 are adjusted with saturated sodium bicarbonate solution, are extracted with dichloromethane (10mL), anhydrous sodium sulfate is done It is dry, it filters, is concentrated under reduced pressure, obtained residue silica gel column chromatography (solvent：B systems) purifying, obtain N- (2- (tertiary fourths Oxygen carbonyl-(3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) amino) -3- fluorophenyls) acrylamide 2e (55mg, pale solid), yield：51%.

MS m/z(ESI)：714.2[M+1]

5th step

By N- (2- (tertbutyloxycarbonyls-(3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -3- fluorophenyls) acrylamide 2e (55mg, 0.077mmol) is molten In 3mL dichloromethane, add 1mL trifluoroacetic acids, react at room temperature 12 hours.PH=8~9 are adjusted with saturated sodium bicarbonate solution, It is extracted with dichloromethane (10mL), anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, and obtained residue is chromatographed with silica gel thin sheet Method (solvent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylaminos Base) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino -3- fluorophenyls) (17mg, grey are solid for acrylamide 2 Body), yield：32.6%.

MS m/z(ESI)：613.8[M+1]

¹H NMR (400MHz, CDCl₃) δ 9.09 (s, 1H), 8.39 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.22 (d, J=8.0Hz, 1H), 6.97 (t, J=8.9Hz, 1H), 6.77 (s, 1H), 6.61 (s, 1H), 6.36 (d, J =5.4Hz, 2H), 5.70-5.62 (m, 1H), 4.24 (s, 2H), 3.93 (s, 6H), 3.00 (s, 2H), 2.67 (s, 6H), 2.22 (s, 2H)

Embodiment 3

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino -5- morpholino phenyls) acrylamide

The first step

N- (the bromo- 2- nitrobenzophenones of 4-) acetamide

The bromo- 2- nitroanilines 3a (30.3g, 138mmol) of 4- are dissolved in 240mL acetic acid, addition acetic anhydride (22.44g, 220.2mmol), 95 DEG C are heated to react 7.5 hours.Reaction solution, which is cooled to room temperature, to be poured into 600mL ice water, is used after ice dissolves Dichloromethane (90mL × 3) extracts, and solid 600mL dichloromethane dissolves, and merges organic phase, is dried with anhydrous sodium sulfate, mistake Filter, filtrate decompression are concentrated to give N- (the bromo- 2- nitrobenzophenones of 4-) acetamide 3b (35.4g, orange solids), yield：99.1%.

MS m/z(ESI)：258.8[M+1]

Second step

N- (4- morpholinyl -2- nitrobenzophenones) acetamide

Under argon gas protection, by N- (the bromo- 2- nitrobenzophenones of 4-) acetamide 3b (30.0g, 115.8mmol), morpholine 3c Bis- diphenylphosphine -9, the 9- xanthphos (6.7g, 11.58mmol) of (10.1g, 115.8mmol), 4,5-, three (dibenzylidenes Acetone) two palladiums (5.3g, 5.79mmol) and cesium carbonate (113g, 347.4mmol) be dissolved in 1000mL toluene, and 120 DEG C of reactions 4 are small When.Reaction solution is cooled to room temperature, and adds in 800mL dichloromethane and 500mL water, layering, and water phase is with dichloromethane (500mL × 3) Extraction merges organic phase, is washed with saturated salt solution (1000mL), and anhydrous sodium sulfate drying filters, is concentrated under reduced pressure, obtains Residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain N- (4- morpholinyl -2- nitrobenzophenones) acetamide 3d (22.0g, black solid), yield：73.3%.

MS m/z(ESI)：265.9[M+1]

Third walks

4- morpholinyl -2- nitroanilines

Will (N- (4- morpholinyl -2- nitrobenzophenones) acetamide 3d (6.00g, 25.4mmol) and sodium hydroxide (7.00g, The in the mixed solvent of 110mL second alcohol and water (V/V=15/7) 125mmol) is dissolved in, 90 DEG C are reacted 4 hours.Reaction solution decompression is dense Contracting adds in 100mL water and 100mL dichloromethane, layering, and organic phase is dried with anhydrous sodium sulfate, is filtered, and is concentrated under reduced pressure, is obtained Residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 4- morpholinyl -2- nitroanilines 3e (3.20g, black Solid), yield：64.0%.

¹H NMR (400MHz, CDCl₃) δ 7.58 (s, 1H), 7.19 (d, J=7.5Hz, 1H), 6.79 (d, J=9.0Hz, 1H), 5.89 (s, 2H), 3.98-3.70 (m, 4H), 3.23-2.97 (m, 4H)

4th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- morpholinyls -2- Nitrobenzophenone) amino) -1,6- naphthyridines -2 (1H) -one

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines - 2 (1H) -one 1h (2.20g, 4.67mmol), 4- morpholinyl -2- nitroanilines 3e (1.04g, 4.67mmol), the bis- diphenyl of 4,5- Phosphine -9,9- xanthphos (540mg, 0.933mmol), three (dibenzalacetone) two palladium (438mg, 0.478mmol) and Cesium carbonate (4.57g, 19.38mmol) is dissolved in 60mL toluene, and lower 120 DEG C of argon gas protection is reacted 4 hours.Reaction solution is cooled to room Temperature filters, and is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- Chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- morpholinyl -2- nitrobenzophenones) amino) -1, (1H) -one of 6- naphthyridines -2 3f (2.82g, red solid), yield：91.8%.

MS m/z(ESI)：656.8[M+1]

5th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- morpholinyl -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- morpholinyls - 2- nitrobenzophenones) amino)-(1H) the -one 3f of 1,6- naphthyridines -2 (2.820g, 4.26mmol) is dissolved in 40mL tetrahydrofurans, it adds in Di-tert-butyl dicarbonate (2.79g, 12.77mmol) and 4-dimethylaminopyridine (500mg, 4.26mmol) are warming up to 80 DEG C instead It answers 4 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydros -1,6- naphthyridines - 7- yls) (4- morpholinyl -2- nitrobenzophenones) t-butyl carbamate 3g (2.50g, yellow solid), yield：77.4%.

MS m/z(ESI)：756.8[M+1]

6th step

(2- amino -4- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (dimethylamino) Propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- morpholinyl -2- nitrobenzophenones) t-butyl carbamate 3g (1.58g, 2.08mmol) is dissolved in In 50mL methanol, Raney's nickel (1.50g) is added in, under hydrogen shield, is reacted at room temperature 0.5 hour.50mL bis- is added in into reaction solution Chloromethanes is filtered by diatomite, and filter cake, filtrate are washed with the mixed solvent of 30mL dichloromethane and methanol (V/V=10/1) It is concentrated under reduced pressure, obtains (2- amino -4- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (dimethyl Amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 3h (1.30g, faint yellow solid), Yield：86.3%.

MS m/z(ESI)：726.8[M+1]

7th step

(2- acrylamido -4- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (diformazans Base amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl)-(1-3- (dimethylaminos Base) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 3h (1.30g, 1.79mmol) is dissolved in In 15mL dichloromethane, add in n,N-diisopropylethylamine (923mg, 7.15mmol) and acryloyl chloride (286mg, 3.57mmol), 4-dimethylaminopyridine (44mg, 0.357mmol) is then added in, is reacted at room temperature 2 hours.Reaction solution saturated carbon Sour hydrogen sodium solution adjusts pH to 8~9, layering, and organic phase is dried with anhydrous sodium sulfate, is filtered, and is concentrated under reduced pressure, obtained residue With silica gel column chromatography (solvent：B systems) purifying, obtaining (2- acrylamido -4- morpholino phenyls), ((2,6- bis- is chloro- by 3- 3,5- Dimethoxyphenyls)-(1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino first Tert-butyl acrylate 3i (450mg, yellow solid), yield：37.1%.

MS m/z(ESI)：781.8[M+1]

8th step

By (2- acrylamido -4- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl)-(1-3- (two Methylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 3i (450mg, It 0.576mmol) is dissolved in 5mL dichloromethane, adds 2mL trifluoroacetic acids, react at room temperature 2 hours.Reaction solution is concentrated under reduced pressure, and adds in 10mL dichloromethane adjusts pH to 8~9, layering with saturated sodium bicarbonate solution, and organic phase is dried with anhydrous sodium sulfate, is filtered, It is concentrated under reduced pressure, obtained residue silica gel column chromatography (solvent：B systems) purifying, obtaining N-, ((((2,6- bis- is chloro- by 3- by 2- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino - 5- morpholino phenyls) acrylamide 3 (190mg, yellow solid), yield：48.5%.

MS m/z(ESI)：680.8[M+1]

¹H NMR (400MHz, DMSO) δ 9.68 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.72 (s, 1H), 7.46- 7.27 (m, 2H), 6.96 (s, 1H), 6.84 (d, J=8.9Hz, 1H), 6.49 (dd, J=16.9,10.4Hz, 1H), 6.41 (s, 1H), 6.23 (d, J=17.0Hz, 1H), 5.72 (d, J=11.6Hz, 1H), 4.02 (s, 2H), 3.94 (s, 6H), 3.75 (s, 4H), 3.10 (s, 4H), 2.25 (s, 2H), 2.09 (s, 6H), 1.67 (s, 2H)

Embodiment 4

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -5- ((4- ethyl piperazidine -1- bases) methyl) phenyl) acrylamide

The first step

The fluoro- 3- nitrobenzyl alcohols of 4-

Sodium borohydride (2.70g, 64.83mmol) is dissolved in 100mL tetrahydrofurans, 0 DEG C is cooled to, 4- is added portionwise Fluoro- 3- nitrobenzoic acids 4a (12.0g, 64.83mmol), 0 DEG C is reacted 1 hour.Then it is molten that boron trifluoride ether is added dropwise at 0 DEG C Liquid (6.55mL, 71.31mmol), reaction solution are warmed to room temperature reaction 3 hours.Into reaction solution add in 500mL ethyl acetate and 300mL water, layering, organic phase are washed with saturated nacl aqueous solution (500mL), anhydrous sodium sulfate drying, filtering, under filtrate decompression Concentration, obtain the fluoro- 3- nitrobenzyl alcohols 4b of 4- (11.0g, faint yellow solid), yield：99.1%.

MS m/z(ESI)：171.9[M+1]

Second step

The fluoro- 3- nitrobenzaldehydes of 4-

At 0 DEG C, the fluoro- 3- nitrobenzyl alcohols 4b (10.0g, 58.4mmol) of 4- are dissolved in 200mL dichloromethane, are added in 100-200 mesh silica gel (18.9g).Pyridine chlorochromate (18.9g, 87.7mmol) is slowly added under stirring.Room temperature reaction 3 hours. Reaction solution filters, filtrate decompression concentration, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain 4- Fluoro- 3- nitrobenzaldehydes 4c (10.3g, weak yellow liquid), product directly carry out next step reaction without further purification.

¹H NMR (400MHz, CDCl₃) δ 10.15-9.95 (m, 1H), 8.60 (dd, J=2.0,7.0Hz, 1H), 8.30- 8.11 (m, 1H), 7.52 (t, J=9.3Hz, 1H)

Third walks

4- amino -3- nitrobenzaldehydes

The fluoro- 3- nitrobenzaldehydes 4c (10.0g, 59.13mmol) of 4- are dissolved in 360mL tetrahydrofurans, add in 90mL ammonia Water reacts at room temperature 1 hour.Reaction solution, which is concentrated under reduced pressure, removes solvent, and filtering is washed with saturated nacl aqueous solution (200mL × 3), It is concentrated under reduced pressure, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude product 4- amino -3- nitrobenzaldehydes 4d (10.0g, yellow solid), product directly carry out next step reaction without further purification.

MS m/z(ESI)：166.9[M+1]

4th step

4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitroanilines

1- ethyl piperazidines 4e (4.11g, 36.0mmol) is dissolved in 90mL methanol, addition tetra isopropyl oxygen titanium (7.70g, 27.0mmol), it stirs 15 minutes.Then 4- amino -3- nitrobenzaldehydes 4d (4.50g, 27.0mmol) are added in and are dissolved in 30mL first The solution of alcohol reacts at room temperature 18 hours.Sodium borohydride (1.33g, 35.1mmol) is added, is reacted at room temperature 2 hours.To reaction solution Middle addition 100mL ethyl acetate filtering, filtrate decompression concentration add 50mL ethyl acetate, use saturated nacl aqueous solution (100mL) is washed, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B System) purifying, obtain 4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitroanilines 4f (2.40g, yellow solid), yield： 33.6%.

MS m/z(ESI)：265.0[M+1]

5th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- ((4- ethyl piperazines Piperazine -1- bases) methyl) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines - 2 (1H) -one 1h (1.00g, 2.12mmol), 4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitroanilines 4f (585mg, 2.34mmol), bis- diphenylphosphine -9, the 9- xanthphos (245mg, 0.424mmol) of 4,5-, three (dibenzalacetones) two Palladium (195mg, 0.212mmol) and cesium carbonate (2.08g, 6.37mmol) are dissolved in 20mL toluene, the lower 100 DEG C of reactions of argon gas protection 4 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, Obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- ((4- ethyl piperazidines - 1- yls) methyl) -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 4g (610mg, yellow solid), yield：42.1%.

MS m/z(ESI)：697.8[M+1]

6th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- ((4- ethyls Piperazine -1- bases) methyl) -2- nitrobenzophenones) amino)-(1H) the -one 4g of 1,6- naphthyridines -2 (600mg, 0.876mmol) is dissolved in 10mL In tetrahydrofuran, add in di-tert-butyl dicarbonate (407mg, 2.63mmol) and 4-dimethylaminopyridine (107mg, 0.876mmol), 80 DEG C are warming up to react 2.5 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) - 2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) (4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitrobenzophenones) carbamic acid Tert-butyl ester 4h (260mg, yellow solid), yield：37.9%.

MS m/z(ESI)：799.8[M+1]

7th step

(2- amino -4- ((4- ethyl piperazidine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- ((4- ethyl piperazidine -1- bases) methyl) -2- nitrobenzophenones) t-butyl carbamate 4h (260mg, 0.326mmol) is dissolved in 5mL methanol, addition Raney's nickel (500mg), under hydrogen shield, is reacted at room temperature 40 minutes.Instead Liquid is answered to be filtered by diatomite, filter cake is washed with the mixed solvent of dichloromethane and methanol (V/V=10/1) (100mL × 3), is filtered Liquid is concentrated under reduced pressure, and obtains (2- amino -4- ((4- ethyl piperazidine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxies Base phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 4i (180mg, faint yellow solid), yield：71.9%.

8th step

(2- acrylamidos -4- ((4- ethyl piperazidine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- ((4- ethyl piperazidine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 4i (180mg, 0.234mmol) is dissolved in 10mL dichloromethane, adds in n,N-diisopropylethylamine (121mg, 0.936mmol) and third Alkene acyl chlorides (42mg, 0.468mmol) reacts at room temperature 1.5 hours.Reaction solution adjusts pH to 8~9 with saturated sodium bicarbonate solution, 20mL dichloromethane and 10mL water, layering are added in, water phase is extracted (10mL × 2) with dichloromethane, is merged organic phase and is used, uses saturation Water salt water washing (20mL), anhydrous sodium sulfate drying, is filtered, and is concentrated under reduced pressure, is obtained crude product (2- acrylamidos -4- ((4- second Base piperazine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) - 2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 4j (192mg, yellow solid), product is straight without further purification Row is tapped into react in next step.MS m/z(ESI)：823.8[M+1]

9th step

By (2- acrylamidos -4- ((4- ethyl piperazidine -1- bases) methyl) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxies Base phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 4j (192mg, 0.233mmol) is dissolved in 4mL dichloromethane, adds 1.5mL trifluoroacetic acids, is reacted at room temperature 2 hours.Reaction solution decompression is dense Contracting continues to concentrate under reduced pressure, 10mL dichloros is added in obtained residue after residue dichloromethane (10ml × 3) dissolving Methane and 5mL water adjust pH to 9, layering with saturated sodium bicarbonate solution, and organic phase is dried with anhydrous sodium sulfate, is filtered, decompression Concentration, obtained residue silica gel thin sheet chromatography (solvent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3, 5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- ((4- ethyl piperazidine -1- bases) methyl) phenyl) acrylamide 4 (20mg, faint yellow solid), yield：11.9%.

MS m/z(ESI)：721.8[M+1]

¹H NMR (400MHz, CDCl₃) 69.33 (s, 1H), 8.39 (s, 1H), 8.38-8.35 (m, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 6.39 (d, J= 16.4Hz, 1H), 5.69 (d, J=10.5Hz, 1H), 4.24 (s, 2H), 3.93 (s, 6H), 3.58 (s, 2H), 3.08 (d, J= 7.3Hz, 6H), 2.84 (d, J=14.7Hz, 6H), 2.72 (s, 6H), 2.24 (s, 2H), 0.87 (s, 3H)

Embodiment 5

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (1- methyl-1 H- pyrazoles -4- bases) phenyl) acrylamide

The first step

4- (1- methyl-1 H- pyrazoles -4- bases) -2- nitroanilines

Under argon gas protection, by the bromo- 2- nitroanilines 5a (1.00g, 4.61mmol) of 4-, (1- methyl-1 H- pyrazoles -4- bases) Boric acid 5b (754mg, 5.99mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (388mg, 5.53mmol) and Cesium carbonate (4.50g, 13.8mmol) is dissolved in 20mL1, the mixed solvent (V/V/V=5/5/ of 4 dioxane, tetrahydrofuran and water 1) in, lower 80 DEG C of argon gas protection is reacted 4 hours.Reaction solution is cooled to room temperature, and adds in 100mL ethyl acetate, layering, water phase second Acetoacetic ester (100mL × 3) extracts, and merges organic phase, is washed, subtracted with water (200mL × 2) and saturated salt solution (300mL) successively Pressure concentration, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain 4- (1- methyl-1 H- pyrazoles -4- Base) -2- nitroanilines 5c (600mg, dark yellow solid), yield：60%.

MS m/z(ESI)：218.9[M+1]

Second step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (1- methyl - 1H- pyrazoles -4- bases) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (200mg, 0.425mmol), 4- (1- methyl-1 H- pyrazoles -4- bases) -2- nitroanilines 5c Bis- diphenylphosphine -9, the 9- xanthphos (49mg, 0.085mmol) of (102mg, 0.467mmol), 4,5-, three (dibenzylidenes Acetone) two palladiums (39mg, 0.043mmol) and cesium carbonate (415mg, 1.27mmol) be dissolved in 10mL toluene, argon gas protection lower 120 DEG C reaction 4 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B bodies System) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (1- first Base -1H- pyrazoles -4- bases) -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 5d (250mg, black solid), yield： 90.2%.

MS m/z(ESI)：651.8[M+1]

Third walks

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- (1- methyl-1 H- pyrazoles -4- bases) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (1- methyl - 1H- pyrazoles -4- bases) -2- nitrobenzophenones) amino)-(1H) the -one 5d of 1,6- naphthyridines -2 (250mg, 0.383mmol) is dissolved in 6mL tetra- In hydrogen furans, di-tert-butyl dicarbonate (250mg, 1.14mmol) and 4-dimethylaminopyridine (8.9mg, 0.073mmol) are added in, 80 DEG C are warming up to react 4 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) Purifying, obtains 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (1- methyl-1 H- pyrazoles -4- bases) -2- nitrobenzophenones) t-butyl carbamate 5e (280mg, Yellow solid), yield：97.2%.

MS m/z(ESI)：751.7[M+1]

4th step

(2- amino -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (1- methyl-1 H- pyrazoles -4- bases) -2- nitrobenzophenones) t-butyl carbamate 5e (220mg, It 0.292mmol) is dissolved in 5mL methanol, addition Raney's nickel (100mg), under hydrogen shield, reacts at room temperature 1 hour.Reaction solution passes through Diatomite filters, and washs filter cake with the mixed solvent of dichloromethane and methanol (V/V=10/1) (100mL × 3), filtrate decompression is dense Contracting, obtains crude product (2- amino -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 5f (140mg, faint yellow solid), yield：66.4%.MS m/z(ESI)：721.8[M+1]

5th step

(2- acrylamidos -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) - 1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 5f (140mg, It 0.193mmol) is dissolved in 5mL dichloromethane, adds in n,N-diisopropylethylamine (100mg, 0.774mmol) and acryloyl chloride (35mg, 0.387mmol) is reacted at room temperature 12 hours.Reaction solution saturated sodium bicarbonate solution adjusts pH to 8~9, layering, water Mutually there is dichloromethane to extract (10mL x2), merge organic phase and dried with anhydrous sodium sulfate, filtered, be concentrated under reduced pressure, obtain crude product (2- acrylamidos -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) and t-butyl carbamate 5g (150mg, it is light Yellow solid), product directly carries out next step reaction without further purification.

MS m/z(ESI)：776.2[M+1]

6th step

By (2- acrylamidos -4- (1- methyl-1 H- pyrazoles -4- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 5g (150mg, 0.193mmol) is dissolved in 3mL dichloromethane, adds 1mL trifluoroacetic acids, is reacted at room temperature 3 hours.Reaction solution decompression is dense Contracting continues to concentrate under reduced pressure, 10mL dichloros is added in obtained residue after residue dichloromethane (10ml × 3) dissolving Methane and 5mL water adjust pH to 8~9, layering with saturated sodium bicarbonate solution, and organic phase is dried with anhydrous sodium sulfate, is filtered, It is concentrated under reduced pressure, obtained residue silica gel thin sheet chromatography (solvent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- Chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) ammonia Base) -5- (1- methyl-1 H- pyrazoles -4- bases) phenyl) acrylamide 5 (26mg, greenish yellow solid), yield：20.0%.

MS m/z(ESI)：675.8[M+1]

¹H NMR (400MHz, CDCl₃) δ 9.22 (s, 1H), 8.38 (s, 1H), 8.11 (d, J=20.6Hz, 2H), 7.75 (s, 1H), 7.64 (s, 1H), 7.56 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.31 (d, J=8.3Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 6.46 (d, J=9.8Hz, 1H), 6.40 (d, J=16.8Hz, 1H), 5.69 (d, J=11.3Hz, 1H), 4.18 (s, 2H), 3.93 (s, 6H), 3.90 (s, 3H), 3.00 (s, 2H), 2.67 (s, 6H), 2.20 (s, 2H)

Embodiment 6

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- Dihydro -1,6- naphthyridines -7- bases) amino) -5- (4- ethyl piperazidine -1- bases) phenyl) acrylamide

The first step

N- (the bromo- 2- nitro-phenyls of 4-)-N- t-butoxycarbonyl amino t-butyl formates

The bromo- 2- nitroanilines 3a (7.50g, 34.56mmol) of 4- are dissolved in 90mL tetrahydrofurans, add in two dimethyl dicarbonates Butyl ester (15.08g, 69.12mmol) and 4-dimethylaminopyridine (200mg, 1.64mmol) are warming up to 80 DEG C and react 2 hours.Instead Answer liquid decompression is lower to concentrate, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain N- (the bromo- 2- nitre of 4- Base-phenyl)-N- t-butoxycarbonyl amino t-butyl formates 6a (12.6g, yellow solid), yield：87.4%.

MS m/z(ESI)：361.0[M+1-56]

Second step

N- tert-butoxycarbonyls-N- [4- (4- ethyl piperazidine -1- bases) -2- nitro-phenyls] t-butyl carbamate

By N- (the bromo- 2- nitro-phenyls of 4-)-N- t-butoxycarbonyl amino t-butyl formate 6a (5.40g, 12.94mmol), Bis- diphenylphosphine -9, the 9- xanthphos (3.00g, 5.18mmol) of 1- ethyl piperazidines 4e (2.22g, 2.00mmol), 4,5-, Three (dibenzalacetone) two palladium (2.37g, 2.59mmol) and cesium carbonate (8.43g, 25.88mmol) are dissolved in 70mL toluene, Under argon gas protection, 120 DEG C are reacted 4 hours.Reaction solution is cooled to room temperature, and is filtered, and is concentrated under reduced pressure, obtained residue silicagel column Chromatography (eluant, eluent：A systems) purifying, obtain N- tert-butoxycarbonyls-N- [4- (4- ethyl piperazidine -1- bases) -2- nitros-benzene Base] t-butyl carbamate 6b (2.56g, aubergine oily liquids), yield：43.9%.

MS m/z(ESI)：351.0[M+1-100]

Third walks

4- (4- ethyl piperazidine -1- bases) -2- nitroanilines

By N- tert-butoxycarbonyls-N- [4- (4- ethyl piperazidine -1- bases) -2- nitro-phenyls] t-butyl carbamate 6b (3.50g, 7.78mmol) is dissolved in 20mL dichloromethane, adds in 20mL trifluoroacetic acids, is reacted at room temperature 3 hours.Reaction solution depressurizes Concentration adds in saturated sodium bicarbonate solution and adjusts pH=7-8, extracted with dichloromethane (20mL × 3), merges organic phase, use water (30mL × 3) are washed, and are concentrated under reduced pressure, obtained residue silicon thin-layer chromatography (solvent：B systems) purifying, obtain 4- (4- ethyl piperazidine -1- bases) -2- nitroanilines 6c (1.81g, dark red solid), yield：92.8%.

MS m/z(ESI)：251.3[M+1]

4th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (4- ethyl piperazines Piperazine -1- bases) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (1.00g, 2.12mmol), 4- (4- ethyl piperazidine -1- bases) -2- nitroanilines 6c Bis- diphenylphosphine -9, the 9- xanthphos (246mg, 0.424mmol) of (585mg, 2.34mmol), 4,5-, three (dibenzylidenes Acetone) two palladiums (195mg, 0.212mmol) and cesium carbonate (2.08g, 6.37mmol) be dissolved in 40mL toluene, under argon gas protection 120 DEG C are reacted 4 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B System) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (4- Ethyl piperazidine -1- bases) -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 6d (679mg, black solid), yield： 46.8%.

MS m/z(ESI)：685.8[M+1]

5th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (4- ethyls Piperazine -1- bases) -2- nitrobenzophenones) amino)-(1H) the -one 6d of 1,6- naphthyridines -2 (670mg, 0.97mmol) is dissolved in 20mL tetrahydrochysene furans In muttering, di-tert-butyl dicarbonate (340.20mg, 1.47mmol) and 4-dimethylaminopyridine (119.6mg, 0.97mmol) are added in, Reflux 2 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, it obtains 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthalenes Pyridine -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) t-butyl carbamate 6e (560mg, yellow solid), production Rate：72.9%.

6th step

(2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) t-butyl carbamate 6e (560mg, It 0.713mmol) is dissolved in 20mL methanol, addition Raney's nickel (200mg), under hydrogen shield, reacts at room temperature 12 hours.Reaction solution mistake Filter, filtrate decompression concentration, obtains (2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 6f (480mg, gray solid), yield：89.2%.MS m/z(ESI)：754.8[M+1]

7th step

(2- acrylamidos -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 6f (300mg, It 0.397mmol) is dissolved in 10mL dichloromethane, adds in n,N-diisopropylethylamine (205mg, 1.59mmol) and acryloyl chloride (72mg, 0.795mmol) is reacted at room temperature 2 hours.5mL dichloromethane and 5mL water are added in into reaction solution, uses saturated carbon Sour hydrogen sodium solution adjusts pH to 8~9, layering, and organic phase is dried with anhydrous sodium sulfate, is filtered, and filtrate decompression concentration obtains crude product (2- acrylamidos -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (two Methylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) (321mg, yellow are solid by t-butyl carbamate 6g Body), product directly carries out next step reaction without further purification.

MS m/z(ESI)：808.3[M+1]

8th step

By (2- acrylamidos -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 6g (321mg, 0.398mmol) is dissolved in 4mL dichloromethane, adds 1.5mL trifluoroacetic acids, is reacted at room temperature 12 hours.Reaction solution is used full PH to 9, layering are adjusted with sodium bicarbonate solution, organic phase is concentrated under reduced pressure, and obtained residue analyses method (expansion with silica gel thin sheet Agent：B=10: 1) it purifies, obtains N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (4- ethyl piperazidine -1- bases) phenyl) acrylamide 6 (30mg, yellow solid), yield：10.7%.

MS m/z(ESI)：707.8[M+1]

Embodiment 7

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (morpholine -4- carbonyls) phenyl) acrylamide

The first step

(4- amino -3- nitrobenzophenones) (morpholinyl) ketone

By 4- amino -3- nitrobenzoic acids 7a (1.00g, 5.49mmol), morpholine 3c (960mg, 11.00mmol), 1- hydroxyls Base benzotriazole (741.89mg, 5.50mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.05g, 5.50mmol) and n,N-diisopropylethylamine (3.30g, 22.00mmol) are dissolved in 60mL n,N-Dimethylformamide In, it reacts at room temperature 3 hours.80mL dichloromethane and 50mL water, layering, organic phase water (50mL are added in into reaction solution × 3) it washs, is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain (4- amino -3- Nitrobenzophenone) (morpholinyl) ketone 7b (800mg, yellow solid), yield：72.5%.

MS m/z(ESI)：251.9[M+1]

Second step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine -4- carbonyls Base) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (500mg, 1.06mmol), (4- amino -3- nitrobenzophenones) (morpholinyl) ketone 7b Bis- diphenylphosphine -9, the 9- xanthphos (122mg, 0.212mmol) of (320mg, 1.27mmol), 4,5-, three (dibenzylidenes Acetone) two palladiums (97mg, 0.106mmol) and cesium carbonate (1.04g, 3.19mmol) be dissolved in 15mL toluene, argon gas protection lower 120 DEG C reaction 4 hours.Reaction solution is cooled to room temperature, and 20mL dichloromethane and 20mL water, layering, water phase are added in into reaction solution It is extracted with dichloromethane (20mL), merges organic pressure of subtracting each other and concentrate, obtained residue silica gel column chromatography (eluant, eluent：B bodies System) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine - 4- carbonyls) -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 7c (633mg, yellow solid), yield：87.0%.

MS m/z(ESI)：684.7[M+1]

Third walks

(3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (morpholine -4- carbonyls) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine -4- Carbonyl) -2- nitrobenzophenones) amino)-(1H) the -one 7c of 1,6- naphthyridines -2 (600mg, 0.877mmol) is dissolved in 10mL tetrahydrofurans In, di-tert-butyl dicarbonate (382mg, 1.75mmol) and 4-dimethylaminopyridine (32mg, 0.263mmol) are added in, is warming up to 80 DEG C are reacted 2 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, Obtain (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro -1, 6- naphthyridines -7- bases) (4- (morpholine -4- carbonyls) -2- nitrobenzophenones) t-butyl carbamate 7d (594mg, yellow solid), production Rate：86.5%.

MS m/z(ESI)：784.8[M+1]

4th step

(2- amino -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (diformazans Base amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (morpholine -4- carbonyls) -2- nitrobenzophenones) t-butyl carbamate 7d (594mg, It 0.785mmol) is dissolved in 10mL methanol, addition Raney's nickel (300mg), under hydrogen shield, reacts at room temperature 0.5 hour.To reaction Liquid is filtered by diatomite, washs filter cake with the mixed solvent of 30mL dichloromethane and methanol (V/V=10/1), filtrate decompression is dense Contracting, obtains (2- amino -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (diformazans Base amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 7e (550mg, yellow solid), Yield：96.3%.

MS m/z(ESI)：756.8[M+1]

5th step

(2- acryloyl groups -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (two Methylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 7e (550mg, It 0.728mmol) is dissolved in 15mL dichloromethane, adds in n,N-diisopropylethylamine (376mg, 2.91mmol) and acryloyl chloride (132mg, 1.46mmol) is reacted at room temperature 2 hours.20mL dichloromethane and 1mL water are added in into reaction solution, uses saturated carbon Sour hydrogen sodium solution adjusts pH to 8~9, layering, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, is obtained crude product (2- acryloyls Base -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) - 2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 7f (589mg, yellow solid), product is straight without further purification Row is tapped into react in next step.MS m/z(ESI)：809.8[M+1]

6th step

By (2- acryloyl groups -4- (morpholine -4- carbonyls) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 7f (589mg, It 0.728mmol) is dissolved in 8mL dichloromethane, adds 1.5mL trifluoroacetic acids, react at room temperature 2 hours.Reaction solution unsaturated carbonate hydrogen Sodium solution adjusts pH to 8~9, layering, and organic phase is dried with anhydrous sodium sulfate, is filtered, and is concentrated under reduced pressure, obtained residue silicon Gel column chromatography (solvent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (morpholine -4- carbonyls) phenyl) third Acrylamide 7 (130mg, yellow solid), yield：25.2%.

MS m/z(ESI)：708.8[M+1]

¹H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.93 (s, 1H), 8.56 (s, 1H), 7.84 (d, J=8.3Hz, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.26 (d, J=8.3Hz, 1H), 6.99 (s, 1H), 6.86 (s, 1H), 6.57 (dd, J =17.1,10.2Hz, 1H), 6.29 (d, J=16.9Hz, 1H), 5.78 (d, J=12.1Hz, 1H), 4.14 (s, 2H), 3.96 (s, 6H), 3.63 (s, 4H), 3.55 (s, 4H), 2.66 (s.2H) 2.28 (s, 6H), 1.83 (s, 2H)

Embodiment 8

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -4- morpholino phenyls) acrylamide

The first step

N- (the bromo- 2- nitro-phenyls of 5-)-N- t-butoxycarbonyl amino t-butyl formates

The bromo- 2- nitroanilines 8a (5.00g, 23.00mmol) of 5- are dissolved in 250mL tetrahydrofurans, add in two carbonic acid two The tert-butyl ester (8.30g, 69.00mmol) and 4-dimethylaminopyridine (1.60g, 12.00mmol) are warming up to 70 DEG C and react 2 hours. Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, obtain crude product N- (5- Bromo- 2- nitro-phenyls)-N- t-butoxycarbonyl amino t-butyl formates 8b (11.59g, white green solid), product is without further purification Directly carry out next step reaction.

MS m/z(ESI)：440.8[M+23]

Second step

N- tertbutyloxycarbonyls-N- (5- morpholinyl -2- nitro-phenyls) t-butyl carbamate

Argon gas protection under, by N- (the bromo- 2- nitro-phenyls of 5-)-N- t-butoxycarbonyl amino t-butyl formates 8b (2.00g, 4.78mmol), bis- diphenylphosphine -9, the 9- xanthphos of morpholine 3c (416mg, 4.78mmol), 4,5- (552mg, 0.956mmol), three (dibenzalacetone) two palladium (381mg, 0.478mmol) and cesium carbonate (4.67g, 14.34mmol) are dissolved in In 30mL toluene, 110 DEG C are reacted 4 hours.Reaction solution is filtered after being cooled to room temperature by diatomite, filter cake ethyl acetate (50mL × 3) are washed, filtrate decompression concentration, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, it obtains N- tertbutyloxycarbonyls-N- (5- morpholinyl -2- nitro-phenyls) t-butyl carbamate 8c (1.27g, yellow-brown solid), yield： 62.8%.

Third walks

5- morpholinyl -2- nitroanilines

By N- tertbutyloxycarbonyls-N- (5- morpholinyl -2- nitro-phenyls) t-butyl carbamate 8c (1.27g, It 3.00mmol) is dissolved in 12mL dichloromethane, adds in 4mL trifluoroacetic acids, react at room temperature 2 hours.20mL is added in into reaction solution Dichloromethane adjusts pH to 8~9, layering, organic phase washed with water (20mL × 3) and saturation food with saturated sodium bicarbonate solution Brine (20mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, the silica gel column chromatography (elution of obtained residue Agent：B systems) purifying, obtain 5- morpholinyl -2- nitroanilines 8d (410mg, yellow solid), yield：61.2%.

4th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((5- morpholinyls -2- Nitrobenzophenone) amino) -1,6- naphthyridines -2 (1H) -one

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines - 2 (1H) -one 1h (200mg, 0.895mmol), 5- morpholinyl -2- nitroanilines 8d (422mg, 0.895mmol), the bis- hexichol of 4,5- Base phosphine -9,9- xanthphos (51.8mg, 0.089mmol), three (dibenzalacetone) two palladium (41mg, 0.044mmol) It is dissolved in 30mL toluene, flows back 4 hours with cesium carbonate (438mg, 1.34mmol).Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, is obtained The residue arrived silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)- 1- (3- (dimethylamino) propyl) -7- ((5- morpholinyl -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 8e (260mg, red solid), yield：38.9%.

MS m/z(ESI)：656.8[M+1]

5th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (5- morpholinyl -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((5- morpholinyls - 2- nitrobenzophenones) amino)-(1H) the -one 8e of 1,6- naphthyridines -2 (260mg, 0.395mmol) is dissolved in 20mL tetrahydrofurans, it adds in Di-tert-butyl dicarbonate (86.3mg, 0.395mmol) and 4-dimethylaminopyridine (72.5mg, 0.593mmol) flow back 2 hours. Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- Chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) (5- Morpholinyl -2- nitrobenzophenones) t-butyl carbamate 8f (250mg, light yellow solid), yield：83.4%.

MS m/z(ESI)：756.8[M+I]

6th step

(2- amino -5- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (dimethylamino) Propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (5- morpholinyl -2- nitrobenzophenones) t-butyl carbamate 8f (240mg, 0.32mmol) is dissolved in In 20mL methanol, Raney's nickel (100mg) is added in, under hydrogen shield, is reacted at room temperature 12 hours.Reaction solution filters, and filtrate decompression is dense Contracting, obtains crude product (2- amino -5- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (dimethylaminos Base) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 8g (210mg, faint yellow solid), production Rate：91.1%.

MS m/z(ESI)：726.8[M+1]

7th step

(2- acrylamido -5- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1-3- (diformazans Base amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -5- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl)-(1-3- (dimethylaminos Base) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 8g (210.0mg, 0.288mmol), third Olefin(e) acid (31.2mg, 0.432mmol), triethylamine (58.4mg, 0.577mmol) and bis- (2- oxo -3- oxazolidinyls) secondary phosphinylidynes Chlorine (110.2mg, 0.432mmol) is dissolved in 20mL dichloromethane, is reacted at room temperature 12 hours.Reaction solution is concentrated under reduced pressure, and obtains Residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain (2- acrylamido -5- morpholino phenyls) (3- (2, Bis- chloro- 3,5- Dimethoxyphenyls of 6-)-(1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- Base) t-butyl carbamate 8h (81mg, light yellow solid), yield：35.9%.

MS m/z(ESI)：780.8[M+1]

8th step

By (2- acrylamido -5- morpholino phenyls) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl)-(1-3- (two Methylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 8h (81.00mg, It 0.103mmol) is dissolved in 3mL dichloromethane, adds 1mL trifluoroacetic acids, react at room temperature 2 hours.Reaction solution is concentrated under reduced pressure, and adds in 20mL dichloromethane, with saturated sodium bicarbonate solution adjust pH to 8~9, layering, organic phase washed with water (10mL × 3) and satisfy It is washed with saline solution (10mL), anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, and obtained residue analyses method (exhibition with silica gel thin sheet Open agent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -4- morpholino phenyls) (29mg, grey are solid for acrylamide 8 Body), yield：39.6%.

MS m/z(ESI)：680.8[M+1]

¹H NMR (400MHz, CDCl3) δ 9.153 (s, 1H), 8.405 (s, 2H), 7.662 (d, 1H), 7.517 (s, 1H), 7.248 (s, 1H), 6.868 (s, 1H), 6.745 (d, 1H), 6.624 (s, 1H), 6.302-6.453 (m, 2H), 5.630 (d, 1H), 4.18-4.23 (m, 2H), 3.936 (s, 6H), 3.79-3.83 (m, 4H), 3.06-3.14 (m, 6H), 2.729 (s, 6H), (2.19-2.29 m, 2H)

Embodiment 9

N- (5- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- ((3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) phenyl) acrylamide

The first step

4- (4- acetylaminohydroxyphenylarsonic acid 3- nitrobenzophenones) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester

Under argon gas protection, by N- (the bromo- 2- nitrobenzophenones of 4-) acetamide 3b (550mg, 2.12mmol), 4- (4,4,5,5- Tetramethyl -1,3,2- dioxy boron pentane -2- bases) -5,6 dihydro -2H- pyridine -1- carboxylic acid tert-butyl esters 9a (853mg, 2.76mmol), Tricyclohexyl phosphine (59mg, 0.212mmol), three (dibenzalacetone) two palladium (97mg, 0.106mmol) and cesium carbonate (2.08g, 6.37mmol) is dissolved in the mixed solvent (V/V=1/4) of 40mL water and Isosorbide-5-Nitrae-dioxane, and 80 DEG C are reacted 2 hours. Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, and adds in 50mL ethyl acetate and 20mL water, is layered, and organic phase saturated sodium-chloride is molten Liquid (20mL) washs, anhydrous sodium sulfate drying, filtering, is concentrated under filtrate decompression, obtained residue silica gel column chromatography (is washed De- agent：B systems) purifying, obtain 4- (4- acetylaminohydroxyphenylarsonic acid 3- nitrobenzophenones) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester 9b (644mg, yellow solid), yield：83.9%.

MS m/z(ESI)：383.9[M+23]

Second step

N- (2- nitros -4- (1,2,3,6- tetrahydropyridine -4- bases) phenyl) acetamide

By 4- (4- acetylaminohydroxyphenylarsonic acid 3- nitrobenzophenones) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester 9b (640mg, It 1.77mmol) is dissolved in 10mL dichloromethane, adds in 20mL trifluoroacetic acids.Room temperature reaction 1 hour.Reaction solution is dense under reduced pressure Contracting, obtained residue dichloromethane (10mL × 3) dissolving continue the residue unsaturated carbonate for concentrating, obtaining under reduced pressure Hydrogen sodium solution adjusts pH to 8~9, layering, and water phase extracts (10mL x3), organic phase saturated nacl aqueous solution with dichloromethane (20mL) is washed, and anhydrous sodium sulfate drying filters, is concentrated under reduced pressure, obtains crude product N- (2- nitros -4- (1,2,3,6- tetrahydrochysene pyrroles Pyridine -4- bases) phenyl) acetamide 9c (463mg, yellow solid), product directly progress next step reaction without further purification.

MS m/z(ESI)：261.9[M+1]

Third walks

N- (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) acetamide

N- (2- nitros -4- (1,2,3,6- tetrahydropyridine -4- bases) phenyl) acetamide 9c (355mg, 1.36mmol) is molten In 15mL dichloromethane, add in n,N-diisopropylethylamine (351mg, 2.72mmol) and chloroacetic chloride (117mg, 1.49mmol), it reacts at room temperature 5 minutes.Reaction solution adds in 20mL water, layering, and organic phase is washed with saturated nacl aqueous solution (20mL) It washs, anhydrous sodium sulfate drying filters, is concentrated under reduced pressure, obtains crude product N- (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- Base) -2- nitrobenzophenones) acetamide 9d (397mg, yellow solid), yield：96.5%.

MS m/z(ESI)：303.9[M+1]

4th step

1- (4- (4- amino -3- nitrobenzophenones) -5,6- dihydropyridines -1 (2H)-yl) ethyl ketone

By N- (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) acetamide 9d (440mg, It 1.45mmol) is dissolved in the mixed solvent (V/V=1/2) of 18mL water and ethyl alcohol with potassium hydroxide (407mg, 7.25mmol), 80 DEG C reaction 5 minutes.20mL water and 50mL dichloromethane, layering are added in into reaction solution, organic phase is concentrated under reduced pressure, and what is obtained is residual Stay object silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 1- (4- (4- amino -3- nitrobenzophenones) -5,6- dihydro pyrroles Pyridine -1 (2H)-yl) ethyl ketone 9e (235mg, red solid), yield：62.0%.

MS m/z(ESI)：261.9[M+1]

5th step

(2,6- bis- is chloro- by -3- by 7- ((4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) amino) 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines -2 (1H) -one

By the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -1,6- naphthyridines - 2 (1H) -one 1h (100mg, 0.212mmol), 1- (4- (4- amino -3- nitrobenzophenones) -5,6- dihydropyridines -1 (2H)-yl) second Bis- diphenylphosphine -9, the 9- xanthphos (25mg, 0.042mmol) of ketone 9e (61mg, 0.234mmol), 4,5-, three (two Asias Benzylacetone) two palladiums (20mg, 0.021mmol) and cesium carbonate (208mg, 0.637mmol) be dissolved in 5mL toluene, argon gas protection Lower 120 DEG C are reacted 4 hours.Reaction solution adds in 10mL water and 30mL dichloromethane, layering, and water phase is extracted with dichloromethane (20mL) It takes, merges organic phase, be concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 7- ((4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) amino) -3- (2,6- bis- chloro- 3,5- dimethoxies Base phenyl) -1- (3- (dimethylamino) propyl)-(1H) -one of 1,6- naphthyridines -2 9f (115mg, yellow solid), yield：77.7%.

MS m/z(ESI)：694.7[M+1]

6th step

(4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) (3- (2,6- bis- chloro- 3,5- diformazans Oxygroup benzene

Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) the tertiary fourth of carbamic acid Ester

By 7- ((4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) amino) -3- (2,6- bis- Chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl)-(1H) -one of 1,6- naphthyridines -2 9f (115mg, It 0.165mmol) is dissolved in 4mL tetrahydrofurans, adds in di-tert-butyl dicarbonate (108mg, 0.496mmol) and 4- dimethylamino pyrroles Pyridine (20mg, 0.165mmol) is warming up to 80 DEG C and reacts 2 hours.Reaction solution decompression is lower to be concentrated, obtained residue silicagel column Chromatography (eluant, eluent：B systems) purifying, it obtains (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthalenes Pyridine -7- bases) t-butyl carbamate 9g (140mg, yellow solid), product directly progress next step reaction without further purification.

MS m/z(ESI)：795.7[M+1]

7th step

(4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- aminophenyls) (3- (2,6- bis- chloro- 3,5- diformazans Phenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate By (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- nitrobenzophenones) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 9g (140mg, 0.176mmol) is dissolved in 8mL methanol, addition Raney's nickel (200mg), under hydrogen shield, is reacted at room temperature 30 minutes.To Reaction solution is filtered by diatomite, and filter cake is washed with the mixed solvent of dichloromethane and methanol (V/V=10/1) (10mL × 3), Filtrate decompression concentrates, and obtaining (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- aminophenyls), ((2,6- bis- is chloro- by 3- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino first Tert-butyl acrylate 9h (130mg, gray solid), yield：97%.

MS m/z(ESI)：767.8[M+1]

8th step

(4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- acrylamidos) (3- (2,6- bis- chloro- 3,5- bis- Methoxybenzene

By (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- aminophenyls) (3- (2,6- bis- chloro- 3,5- bis- Methoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) the tertiary fourth of carbamic acid Ester 9h (130mg, 0.169mmol) is dissolved in 5mL dichloromethane, add in n,N-diisopropylethylamine (88mg, 0.679mmol) and Acryloyl chloride (38mg, 0.424mmol) reacts at room temperature 0.5 hour.Reaction solution with saturated sodium bicarbonate solution adjust pH to 8~ 9, layering, organic phase is concentrated under reduced pressure, and obtains crude product (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- acrylamides Base) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydros -1,6- Naphthyridines -7- bases) t-butyl carbamate 9i (139mg, yellow solid), product directly progress next step reaction without further purification.

MS m/z(ESI)：819.8[M+1]

9th step

By (4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- acrylamidos) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) carbamic acid uncle Butyl ester 9i (139mg, 0.17mmol) is dissolved in 4mL dichloromethane, adds 1mL trifluoroacetic acids, is reacted at room temperature 12 hours.Reaction solution subtracts Pressure concentration, obtained residue dichloromethane (10mL × 3) dissolving continue the residue saturation for concentrating, obtaining under reduced pressure Sodium bicarbonate solution adjusts pH to 8~9, layering, and water phase extracts (10mL x3) organic phase with dichloromethane and is concentrated under reduced pressure, obtains The residue arrived silica gel thin sheet chromatography (solvent：B systems) purifying, obtain N- (5- (1- acetyl group -1,2,3,6- tetrahydrochysenes Pyridin-4-yl) -2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) phenyl) acrylamide 9 (10mg, yellow solid), yield：8.2%.

MS m/z(ESI)：721.8[M+1]

¹H NMR (400MHz, CDCl₃) δ 9.20 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.20 (s, 1H), 6.87 (s, 1H), 6.62 (s, 1H), 6.45 (s, 1H), 6.39 (d, J= 15.7Hz, 1H), 6.07 (d, J=24.6Hz, 1H), 5.69 (d, J=10.8Hz, 1H), 4.21 (s, 3H), 4.09 (s, 1H), 3.94 (s, 6H), 3.78 (s, 2H), 3.62 (s, 2H), 3.09 (s, 2H), 2.74 (s, 6H), 2.26 (s, 2H), 2.14 (d, J= 9.3Hz, 3H)

Embodiment 10

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (morpholinyl methyl) phenyl) acrylamide

The first step

4- (morpholinyl methyl) -2- nitroanilines

Under argon gas protection, 4- amino -3- nitrobenzaldehydes 4d (1.00g, 6.02mmol) are dissolved in 60mL methanol, are added in Morpholine 3c (1.04mL, 12.04mmol) and tetra isopropyl oxygen titanium (3.56mL, 12.04mmol), are stirred at room temperature 12 hours.Cooling To 0 DEG C, sodium borohydride (412mg, 10.84mmol) is added in, is warmed to room temperature reaction 2 hours.300mL saturations are added in into reaction solution Sodium carbonate liquor is extracted with ethyl acetate (200mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (200mL × 2) It washs, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：A systems) purifying, Obtain 4- (morpholinyl methyl) -2- nitroanilines 10a (1.00g, yellow oil), yield：70%.

MS m/z(ESI)：237.9[M+1]

Second step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholinyl As Base) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (500mg, 1.06mmol), 4- (morpholinyl methyl) -2- nitroanilines 10a (257mg, 1.08mmol), bis- diphenylphosphine -9, the 9- xanthphos (306mg, 0.53mmol) of 4,5-, three (dibenzalacetones) two Palladium (485mg, 0.53mmol) and cesium carbonate (1.03g, 3.18mmol) are dissolved in 10mL toluene, the lower 110 DEG C of reactions of argon gas protection 3.5 hour.Reaction solution is cooled to room temperature, and is extracted with ethyl acetate (100mL), organic phase water (100mL × 2) and saturation chlorination Sodium solution (100mL) washs, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) - 7- ((4- (morpholinyl methyl) -2- nitrobenzophenones) amino)-(1H) -one of 1,6- naphthyridines -2 10b (671mg, brown-red solid), production Rate：94%.

MS m/z(ESI)：670.8[M+1]

Third walks

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- (morpholinyl methyl) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholinyls Methyl) -2- nitrobenzophenones) amino)-(1H) the -one 10b of 1,6- naphthyridines -2 (671mg, 1.00mmol) is dissolved in 10mL tetrahydrofurans In, add in di-tert-butyl dicarbonate (436.5mg, 2.00mmol) and 4-dimethylaminopyridine (122mg, 1.00mmol), heating It is reacted 4 hours to 80 DEG C.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) it is pure Change, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- (morpholinyl methyl) -2- nitrobenzophenones) t-butyl carbamate 10c (380mg, white solid), production Rate：49.2%.

MS m/z(ESI)：771.8[M+1]

4th step

(2- amino -4- (4- (morpholinyl methyl) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (two Methylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (morpholinyl methyl) -2- nitrobenzophenones) t-butyl carbamate 10c (380mg, 0.49mmol) It is dissolved in the mixed solvent (V/V=1/1) of 10mL methanol and tetrahydrofuran, addition Raney's nickel (190mg), under hydrogen shield, room Temperature reaction 4 hours.Reaction solution filters, filtrate decompression concentration, obtained residue silica gel column chromatography (eluant, eluent：B systems) Purifying, obtains (2- amino -4- (4- (morpholinyl methyl) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 10d (260mg, white Solid), yield：71.2%.

MS m/z(ESI)：742.8[M+1]

5th step

(2- acrylamidos -4- (4- (morpholinyl methyl) benzene) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (4- (morpholinyl methyl) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 10d (200mg, It 0.27mmol) is dissolved in 8mL dichloromethane, adds in n,N-diisopropylethylamine (0.24mL, 1.35mmol) and acryloyl chloride (49mg, 0.54mmol) is reacted at room temperature 1 hour.Reaction adds in 100mL dichloromethane and saturated sodium bicarbonate solution (30mL), Layering, organic phase are washed with saturated nacl aqueous solution (100mL), and anhydrous sodium sulfate drying filters, is concentrated under reduced pressure, obtains crude product (2- acrylamidos -4- (4- (morpholinyl methyl) benzene) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethyl Amino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 10e (215mg, colorless oil), Product directly carries out next step reaction without purifying.

MS m/z(ESI)：796.8[M+1]

6th step

By (2- acrylamidos -4- (4- (morpholinyl methyl) benzene) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 10e (215mg, It 0.27mmol) is dissolved in 5mL dichloromethane, adds 2mL trifluoroacetic acids, react at room temperature 1 hour.Reaction solution is concentrated under reduced pressure, and adds in 100mL dichloromethane is washed with saturated sodium bicarbonate solution (100mL), and organic phase is dried with anhydrous sodium sulfate, is filtered, decompression Concentration, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (morpholinyl methyl) phenyl) acrylamide 10 (160mg, faint yellow solid), yield：85.1%.

MS m/z(ESI)：696.8[M+1]

¹H NMR (400MHz, DMSO-d₆) δ 9.89-9.78 (m, 1H), 8.66-8.58 (m, 1H), 8.55-8.45 (m, 1H), 7.76 (s, 1H), 7.68-7.52 (m, 2H), 7.14 (d, J=8.0Hz, 1H), 7.03-6.89 (m, 1H), 6.66 (s, 1H), 6.52 (dd, J=10.0,17.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.83-5.67 (m, 1H), 4.14-4.02 (m, 2H), 3.96 (s, 6H), 3.64-3.52 (m, 4H), 3.46 (s, 2H), 2.39 (br.s., 4H), 2.26 (br.s., 2H), 2.15-2.05 (m, 6H), 1.78-1.64 (m, 2H)

Embodiment 11

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (cis- -2,6- thebaines) phenyl) acrylamide

The first step

N- (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) acetamide

Under argon gas protection, by N- (the bromo- 2- nitrobenzophenones of 4-) acetamide 3b (1.00g, 3.86mmol), cis- -2,6- bis- Bis- diphenylphosphine -9, the 9- xanthphos (233mg, 0.386mmol) of methyl morpholine 11a (445mg, 3.86mmol), 4,5-, Three (dibenzalacetone) two palladium (177mg, 0.193mmol) and cesium carbonate (3.77g, 11.58mmol) are dissolved in 40mL toluene, 100 DEG C are reacted 4 hours.Reaction solution is concentrated under reduced pressure, and adds in 200mL ethyl acetate and 200mL water, layering, having literary or intellectual fame ethyl acetate (100mL x3) is extracted, and merges organic phase, is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：A systems) it is pure Change, obtain N- (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) acetamide 11b (950mg, Orange red solid), produce Rate：84%.

MS m/z(ESI)：293.9[M+1]

Second step

4- (cis- -2,6- thebaines) -2- nitroanilines

N- (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) acetamide 11b (950mg, 3.24mmol) is dissolved in In 4M hydrochloric acid, flow back 3 hours.100mL water is added in into reaction solution, pH value of solution is adjusted to 8~9 with saturated sodium bicarbonate solution, Organic phase is extracted with dichloromethane (100mL x3), is merged organic phase, is dried with anhydrous sodium sulfate, is filtered, and is concentrated under reduced pressure, is obtained Crude product 4- (cis- -2,6- thebaines) -2- nitroanilines 11c (883mg, brown-red solid), product are straight without purifying Row is tapped into react in next step.

MS m/z(ESI)：251.9[M+1]

Third walks

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (cis- -2,6- Thebaine) -2- nitrobenzophenones) amino) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base)-(1H) the -one 1h of 1,6- naphthyridines -2 (240mg, 0.51mmol), 4- (cis- -2,6- thebaines) -2- nitroanilines 11c Bis- diphenylphosphine -9, the 9- xanthphos (59mg, 0.101mmol) of (128mg, 0.51mmol), 4,5-, three (dibenzylidenes Acetone) two palladiums (47mg, 0.051mmol) and cesium carbonate (500mg, 1.53mmol) be dissolved in 10mL toluene, and 120 DEG C of reactions 4 are small When.20mL water and 30mL dichloromethane, layering are added in into reaction solution, water phase is extracted with dichloromethane, and merging is organic to subtract each other pressure Concentration, obtained residue silica gel column chromatography (eluant, eluent：Dichloromethane：Methanol system) purifying, obtain 3- (2,6- bis- Chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (cis- -2,6- thebaines) -2- nitre Base phenyl) amino)-(1H) -one of 1,6- naphthyridines -2 11d (288mg, red solid), yield：82.3%.

MS m/z(ESI)：684.8[M+1]

4th step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -7- ((4- (cis- -2, 6- thebaines) -2- nitrobenzophenones) amino)-(1H) the -one 11d of 1,6- naphthyridines -2 (288mg, 0.42mmol) is dissolved in 8mL tetra- In hydrogen furans, di-tert-butyl dicarbonate (218mg, 1.26mmol) and 4-dimethylaminopyridine (122mg, 0.42mmol) are added in, 80 DEG C are warming up to react 1 hour.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) Purifying, obtains 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) t-butyl carbamate 11e (320mg, Red solid), yield：97.0%.

MS m/z(ESI)：365.6[(M+1-100)/2+23]

5th step

(2- amino -4- (cis- -2,6- thebaines) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - (1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) propyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases) (4- (cis- -2,6- thebaines) -2- nitrobenzophenones) t-butyl carbamate 11e (320mg, It 0.41mmol) is dissolved in 10mL methanol, addition Raney's nickel (300mg), under hydrogen shield, reacts at room temperature 12 hours.To reaction solution Middle addition 50mL dichloromethane, is filtered by diatomite, is washed with the mixed solvent of 30mL dichloromethane and methanol (V/V=10/1) Filter cake is washed, filtrate decompression concentration obtains (2- amino -4- (cis- -2,6- thebaines) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl)-(1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) carbamic acid uncle Butyl ester 11f (300mg, yellow solid), yield：97.7%.

MS m/z(ESI)：754.8[M+1]

6th step

(2- acrylamidos -4- (cis- -2,6- thebaines) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base)-(1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (cis- -2,6- thebaine) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 11f (300mg, It 0.397mmol) is dissolved in 10mL dichloromethane, adds in n,N-diisopropylethylamine (205mg, 1.59mmol) and acryloyl chloride (90mg, 0.992mmol) is reacted at room temperature 0.5 hour.Reaction solution saturated sodium bicarbonate solution adjusts pH to 8~9, layering, water It is mutually extracted with dichloromethane (10mL x2), merges organic phase and dried with anhydrous sodium sulfate, filtered, be concentrated under reduced pressure, obtain crude product (2- acrylamidos -4- (cis- -2,6- thebaines) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)-(1- 3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 11g (321mg, it is yellow Color solid), product directly carries out next step reaction without purifying.

MS m/z(ESI)：405.0[M/2+1]

7th step

By (2- acrylamidos -4- (cis- -2,6- thebaine) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl)-(1-3- (dimethylamino) propyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 11g (321mg, 0.396mmol) is dissolved in 8mL dichloromethane, adds 2mL trifluoroacetic acids, is reacted at room temperature 1 hour.Reaction solution decompression is dense Contracting, obtained residue dichloromethane (10mL × 3) dissolving continue the residue unsaturated carbonate for concentrating, obtaining under reduced pressure Hydrogen sodium solution adjusts pH to 8~9, layering, and organic phase is concentrated under reduced pressure, the silica gel thin sheet chromatography (expansion of obtained residue Agent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (3- (dimethylamino) third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (cis- -2,6- thebaines) phenyl) acrylamide 11 (30mg, yellow solids), yield：10.8%.

MS m/z(ESI)：710.8[M+1]

¹H NMR (400MHz, CDCl₃) δ 8.38 (s, 1H), 8.34 (s, 1H), 7.91 (s, 1H), 7.50 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 6.73 (d, J=8.6Hz, 1H), 6.61 (s, 1H), 6.39 (d, J=16.9Hz, 1H), 6.27 (d, J=9.9Hz, 2H), 5.71 (d, J=10.4Hz, 1H), 4.11 (s, 2H), 3.93 (s, 6H), 3.79 (s, 2H), 3.52 (d, J= 11.3Hz, 2H), 2.46 (t, J=11.0Hz, 4H), 2.27 (s, 6H), 1.87 (s, 2H), 1.26 (s, 6H)

Embodiment 12

N- (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos - 1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) acrylamide

The first step

1- (methoxy) cyclopropylamine hydrochloride

2- methoxyacetonitriles 12a (19.5g, 27.4mmol) and tetra isopropyl oxygen titanium (90.68mL, 30.3mmol) are dissolved in In 300mL ether, -20 DEG C are cooled to, displacement argon gas three times, adds in ethylmagnesium bromide (73.1g, 54.9mmol), anti-at -20 DEG C It answers 0.5 hour.60mL water quenchings are added in reaction system to go out reaction, are filtered, filter cake are washed with 1000mL dichloromethane, into filtrate The ethyl acetate solution (100mL) of 4M hydrogen chloride is added in, filtrate decompression concentration obtains 1- (methoxy) cyclopropylamine hydrochloride 12b (17.0g, dark red solid), yield：45.1%.

¹H NMR (400MHz, CDCl3) δ 7.32 (d, J=23.5Hz, 3H), 3.50 (s, 2H), 3.45-3.39 (m, 3H), 1.30-1.14 (m, 2H), 0.77-0.69 (m, 2H)

Second step

(the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino)) ethyl nicotinate

By 4,6- dichloro-nicotinic acid ethyl ester 1a (20.0g, 90.8mmol), 1- (methoxy) cyclopropylamine hydrochloride 12b (14.0g, 101.7mmol) and n,N-diisopropylethylamine (23.4g, 181.6mmol) are dissolved in 200mL N, N- dimethyl formyls In amine, reaction solution is warming up to 90 DEG C and reacts 3 hours.500mL water and 500mL dichloromethane, layering, water phase are added in into reaction solution It is extracted with dichloromethane (200mL × 3), merges organic phase, be concentrated under reduced pressure, the silica gel column chromatography (elution of obtained residue Agent：A systems) purifying, obtain (the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino)) ethyl nicotinate 12c (11.5g, it is colourless Oily liquids), yield：46%.

MS m/z(ESI)：285.0[M+1]

Third walks

(the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) pyridin-3-yl) methanol

(the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino)) ethyl nicotinate 12c (11.0g, 38.61mmol) is molten In 200mL tetrahydrofurans, 5 DEG C are cooled to, adds in lithium aluminium hydride reduction (2.93g, 77.2mmol), is then reacted 30 minutes at 5 DEG C. 3mL water and 9mL sodium hydroxide solutions (20%) are sequentially added into reaction solution, adds in anhydrous sodium sulfate drying, filtering, filtrate subtracts Pressure concentration, obtain (the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) pyridin-3-yl) methanol 12d (8.2g, it is colourless solid Body), yield：83%.

¹H NMR (400MHz, CDCl3) δ 7.76 (s, 1H), 6.83 (s, 1H), 6.12 (s, 1H), 4.57 (s, 2H), 3.48 (s, 1H), 3.43 (s, 2H), 3.33 (d, J=5.5Hz, 3H), 0.98-0.81 (m, 4H)

4th step

(the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) nicotine aldehyde

By (the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) pyridin-3-yl) methanol 12d (8.2g, It 33.79mmol) is dissolved in 250mL dichloromethane, adds in activated manganese dioxide (35.25g, 405.44mmol), room temperature reaction 12 Hour.Reaction solution filters, and filtrate decompression concentration obtains crude product (the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) nicotine Aldehyde 12e (7.12g, gray solid), yield：85.8%.

MS m/z(ESI)：240.9[M+1]

5th step

The chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines -2 (1H) -one

By (the chloro- 4- of 6- ((1- (methoxy) cyclopropyl) amino) nicotine aldehyde 12e (0.90g, 4.15mmol) and 2- (3,5- Dimethoxyphenyl) methyl acetate 1f (873.45mg, 4.15mmol) is dissolved in 10mL n,N-Dimethylformamide, is delayed It is slow to add in hexamethyldisilazide lithium (834mg, 6.23mmol), it is stirred at room temperature 10 minutes, it is small then to rise to 80 DEG C of reactions 2 When.Reaction solution is cooled to room temperature, and is added in 200mL water quenchings and is gone out reaction, is extracted with dichloromethane (20mL × 3), merging organic phase, nothing Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, residue silica gel column chromatography (solvent：B systems) purifying, obtain 7- Chloro- 3- (3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl)-(1H) -one of 1,6- naphthyridines -2 12f (1.35g, Oily liquids), yield：90%.

MS m/z(ESI)：400.9[M+1]

6th step

The chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines - 2 (1H) -one

By the chloro- 3- of 7- (3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines -2 (1H) - Ketone 12f (1.35g, 3.37mmol) is dissolved in 20mL acetonitriles, and three times, reaction solution is cooled to 0 DEG C to argon gas substitution gas, adds in sulphonyl Chlorine (1.00g, 7.41mmol), 0 DEG C is reacted 30 minutes.Reaction solution concentrates, and adds in 10mL saturated sodium bicarbonate solutions, uses dichloromethane Alkane (20mL) extracts, and organic phase is concentrated under reduced pressure, residue silica gel column chromatography (solvent：B systems) purifying, it is chloro- to obtain 7- 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl)-(1H) -one of 1,6- naphthyridines -2 12g (1.2g, white powder), yield：75.9%.

MS m/z(ESI)：470.7[M+1]

7th step

(4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxo -1, 2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) t-butyl carbamate

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) rings third Base)-(1H) the -one 12g of 1,6- naphthyridines -2 (500mg, 1.06mmol), (4- amido tetrahydrofuran -3- bases) t-butyl carbamate Bis- diphenylphosphine -9, the 9- xanthphos (123.18mg, 0.213mmol) of 12h (236.8mg, 1.17mmol), 4,5-, three (dibenzalacetone) two palladium (97.47mg, 0.106mmol) and cesium carbonate (693.61mg, 2.13mmol) are dissolved in 20mL toluene In, it is heated to 120 DEG C and reacts 6 hours.Reaction solution is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B bodies System) purifying, obtain (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxygen Generation -1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) (198mg, rice white are solid by t-butyl carbamate 12i Body), yield：29.3%.

MS m/z(ESI)：634.8[M+1]

8th step

7- ((4- amido tetrahydrofuran -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (first Oxygroup methyl) cyclopropyl) -1,6- naphthyridines -2 (1H) -one

Will (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl) -2- oxos - 1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) t-butyl carbamate 12i (180mg, 0.283mmol) It is dissolved in 5mL dichloromethane, adds 5mL trifluoroacetic acids, react at room temperature 2 hours.Reaction solution is concentrated to dryness, adds in 10mL saturated carbons Sour hydrogen sodium solution and 10mL dichloromethane, layering, organic phase are concentrated under reduced pressure, and obtain crude product 7- ((4- amido tetrahydrofuran -3- bases) Amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines -2 (1H) - Ketone 12j (140mg, faint yellow solid), yield：92.3%.

MS m/z(ESI)：534.8[M+1]

9th step

By 7- ((4- amido tetrahydrofuran -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl)-(1H) the -one 12j of 1,6- naphthyridines -2 (150mg, 0.28mmol) and n,N-diisopropylethylamine (144.83mg, 1.12mmol) is dissolved in 10mL dichloromethane, adds in acryloyl chloride (25.36mg, 0.28mmol), room temperature reaction 2 hours.10mL saturated sodium bicarbonate solutions are added in into reaction solution, divides and goes water phase, organic phase is concentrated under reduced pressure, obtained residue With silica gel column chromatography (eluant, eluent：B systems) purifying, obtain N- (4- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrofuran -3- bases) propylene Amide 12 (53mg, white solid), yield：32.9%.

MS m/z(ESI)：588.8[M+1]

¹H NMR (400MHz, CDCl3) δ 8.27 (d, J=7.7Hz, 1H), 7.46 (d, J=2.4Hz, 1H), 6.95 (d, J =12.6Hz, 1H), 6.61 (s, 1H), 6.26 (dd, J=16.6,5.5Hz, 1H), 6.08 (dd, J=17.0,10.2Hz, 1H), 5.64 (dd, J=10.6,3.5Hz, 1H), 5.38 (d, J=61.3Hz, 1H), 4.71 (ddd, J=75.4,41.1,18.6Hz, 2H), 4.37-4.09 (m, 3H), 3.94 (d, J=3.5Hz, 6H), 3.87-3.72 (m, 2H), 3.29 (d, J=5.8Hz, 3H), 3.23 (dd, J=14.8,10.6Hz, 1H), 1.47-1.09 (m, 4H)

Embodiment 13

N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos - 1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (4- ethyl piperazidine -1- bases) phenyl) acrylamide

The first step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -7- ((4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) ammonia Base) -1- (1- (methoxy) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) rings third Base)-(1H) the -one 12g of 1,6- naphthyridines -2 (300mg, 0.639mmol), 4- (4- ethyl piperazidine -1- bases) -2- nitroanilines 6c Bis- diphenylphosphine -9, the 9- xanthphos (73.90mg, 0.128mmol) of (161.45mg, 0.645mmol), 4,5-, three (two BENZYLIDENE ACETONE) two palladiums (58.48mg, 0.064mmol) and cesium carbonate (417.17mg, 1.28mmol) be dissolved in 20mL toluene, Lower 120 DEG C of argon gas protection is reacted 4 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, obtain 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -7- ((4- (4- ethyl piperazidine -1- bases) - 2- nitrobenzophenones) amino) -1- (1- (methoxy)-(1H) -one of 1,6- naphthyridines -2 13a (377mg, brown-red solid), production Rate：86.5%.

MS m/z(ESI)：684.8[M+1]

Second step

3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos -1,2- bis- Hydrogen -1,6- naphthyridines -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -7- ((4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) ammonia Base) (1- (methoxy)-(1H) -one 13a of 1,6- naphthyridines -2 (322mg, 0.471mmol) is dissolved in 20mL tetrahydrofurans to -1- In, di-tert-butyl dicarbonate (205.61mg, 0.941mmol) and 4-dimethylaminopyridine (28.77mg, 0.235mmol) are added in, 75 DEG C are reacted 2 hours.Reaction solution decompression is lower to be concentrated, obtained residue silica gel column chromatography (eluant, eluent：B systems) purifying, 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos -1,2- dihydro -1 is obtained, 6- naphthyridines -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) (302mg, yellow are solid by t-butyl carbamate 13b Body), yield：81.8%.

MS m/z(ESI)：782.8[M+1]

Third walks

(2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos -1,2- Dihydro -1,6- naphthyridines -7- bases)-(4- (4- ethyl piperazidine -1- bases) -2- nitrobenzophenones) t-butyl carbamate 13b (300mg, It 0.383mmol) is dissolved in 20mL methanol, addition Raney's nickel (600mg), under atmosphere of hydrogen, reacts at room temperature 1 hour.Reaction solution mistake Filter, filtrate decompression concentration, obtains (2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 13c (288mg, orange/yellow solid), yield：100%.

MS m/z(ESI)：754.8[M+1]

4th step

(2- acrylamidos -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate

By (2- amino -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 13c (288mg, It 0.382mmol) is dissolved in 10mL dichloromethane, adds in n,N-diisopropylethylamine (148.15mg, 1.15mmol) and acryloyl Chlorine (69.17mg, 0.762mmol) reacts at room temperature 0.5 hour.10mL dichloromethane and 10mL saturated carbons are added in into reaction solution Sour hydrogen sodium solution divides and goes water phase, and organic phase is concentrated under reduced pressure, and obtains crude product (2- acrylamidos -4- (4- ethyl piperazidine -1- bases) Phenyl) (3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl) -2- oxos -1,2- dihydro - 1,6- naphthyridines -7- bases) t-butyl carbamate 13d (245mg, yellow solid), yield：79.3%.

MS m/z(ESI)：806.8[M+1]

5th step

By (2- acrylamidos -4- (4- ethyl piperazidine -1- bases) phenyl) (3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) t-butyl carbamate 13d (245mg, 0.303mmol) is dissolved in 5mL dichloromethane, adds in 5mL trifluoroacetic acids, is reacted at room temperature 1 hour.Reaction solution decompression is dense Contracting adds in 10mL saturated sodium bicarbonate solutions and 10mL dichloromethane, divides and goes water phase, and organic phase is concentrated under reduced pressure, obtained residual Object silica gel column chromatography (eluant, eluent：B systems) purifying, obtain N- (2- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls)- 1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) -5- (4- ethyl piperazidines -1- Base) phenyl) acrylamide 13 (177mg, faint yellow solid), yield：82.7%.

MS m/z(ESI)：706.8[M+1]

¹H NMR (400MHz, CDCl3) δ 8.35 (s, 1H), 8.15 (d, J=13.9Hz, 2H), 7.47 (s, 1H), 7.22 (d, J=8.6Hz, 1H), 6.81 (s, 1H), 6.73 (d, J=6.1Hz, 1H), 6.60 (s, 2H), 6.40 (d, J=16.8Hz, 1H), 6.24-6.10 (m, 1H), 5.73 (d, J=10.6Hz, 1H), 4.07 (d, J=10.7Hz, 1H), 3.93 (d, J= 3.4Hz, 6H), 3.38 (s, 4H), 3.10 (d, J=8.4Hz, 3H), 3.04 (d, J=10.8Hz, 1H), 2.74 (d, J= 58.4Hz, 6H), 1.43 (d, J=7.1Hz, 3H), 1.20-1.15 (m, 1H), 1.08 (s, 1H), 0.99 (d, J=6.2Hz, 1H), 0.86 (s, 1H)

Embodiment 14

N- ((3S, 4S) -3- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) rings third Base) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) tetrahydrochysene -2H- pyrans -4- bases) acrylamide

The first step

7- (((3S, 4S) -4- azido tetrahydrochysene -2H- pyrans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines -2 (1H) -one

Under argon gas protection, by the chloro- 3- of 7- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) rings third Base)-(1H) the -one 12g of 1,6- naphthyridines -2 (450.86mg, 1.12mmol), (3S, 4S) -4- azido tetrahydrochysene -2H- pyrans -3- amine Bis- diphenylphosphine -9, the 9- xanthphos of hydrochloride 14a (200mg, 1.12mmol), 4,5- (129.58mg, 0.224mmol), three (dibenzalacetone) two palladium (102.53mg, 0.11mmol) and potassium tert-butoxide (188.46mg, It 1.68mmol) is dissolved in 20mL toluene, flows back 2 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, obtained residue silicon Gel column chromatography (eluant, eluent：A systems) purifying, obtain 7- (((3S, 4S) -4- azido tetrahydrochysene -2H- pyrans -3- bases) amino) - 3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) -1- (1- (methoxy) cyclopropyl)-(1H) -one of 1,6- naphthyridines -2 14b (180mg, white solid), yield：31.6%.

MS m/z(ESI)：576.8[M+1]

Second step

7- (((3S, 4S) -4- amino tetrahydrochysene -2H- pyrans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- dimethoxy benzenes Base) -1- (1- (methoxy) cyclopropyl) -1,6- naphthyridines -2 (1H) -one

By 7- (((3S, 4S) -4- azido tetrahydrochysene -2H- pyrans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- dimethoxies Base phenyl) -1- (1- (methoxy) cyclopropyl)-(1H) -one 14b of 1,6- naphthyridines -2 (180mg, 0.313mmol) is dissolved in In 10mL methanol, Raney's nickel (30mg) is added in, under atmosphere of hydrogen, is reacted at room temperature 2 hours.Reaction solution filters, filtrate decompression concentration, Obtain 7- (((3S, 4S) -4- amino tetrahydrochysene -2H- pyrans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- Dimethoxyphenyls) - 1- (1- (methoxy) cyclopropyl)-(1H) -one of 1,6- naphthyridines -2 14c (152mg, white solid), yield：88.6%.

MS m/z(ESI)：548.8[M+1]

Third walks

By 7- (((3S, 4S) -4- amino tetrahydrochysene -2H- pyrans -3- bases) amino) -3- (2,6- bis- chloro- 3,5- dimethoxys Phenyl) -1- (1- (methoxy) cyclopropyl)-(1H) -one 14c of 1,6- naphthyridines -2 (152mg, 0.276mmol), acrylic acid (29.9mg, 0.415mmol), triethylamine (56mg, 0.553mmol) and 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne two are sub- Amine hydrochlorate (106.07mg, 0.553mmol) is dissolved in 5mL dichloromethane, is reacted at room temperature 2 hours.Reaction solution is concentrated under reduced pressure, and obtains The residue arrived thin plate chromatography method (solvent：A systems) purifying, obtain N- ((3S, 4S) -3- ((3- (2,6- bis- chloro- 3,5- Dimethoxyphenyl) -1- (1- (methoxy) cyclopropyl) -2- oxo -1,2- dihydro -1,6- naphthyridines -7- bases) amino) four Hydrogen -2H- pyrans -4- bases) acrylamide 14 (100mg, white solid), yield：59.8%.

MS m/z(ESI)：602.8[M+1]

¹H NMR (400MHz, CDCl3) δ 9.251-9.314 (m, 1H), 8.025 (s, 1H), 7.379 (s, 1H), 7.118- 7.210 (m, 2H), 6.217 (s, 1H), 6.283 (t, J=31.6Hz, 1H), 6.093-6.179 (m, 1H), 5.665 (t, J= 18.8Hz, 1H), 4.551-4.580 (m, 1H), 4.166-4.253 (dd, J=34.8Hz, 2H), 4.079-4.101 (m, 1H), 3.939-3.952 (m, 7H), 3.550-3.742 (m, 2H), 3.295 (d, J=37.2Hz, 3H), 3.059-3.152 (m, 1H), 2.301-2.324 (m, 1H), 1.782-1.808 (m, 1H), 1.345-1.434 (m, 2H), 1.069-1.108 (m, 2H)

Biological assessment

Test case 1, the compounds of this invention measure FGFR kinase activities

Following methods are used to measure preferred compound of the present invention under in vitro conditions to the kinases of recombination human source FGFR albumen The inhibition level of activity.This method uses Cisbio companiesKinEASE-TK tyrosine-kinase enzyme reagent kit (article No.s 62TK0PEB), which is based on time-resolved fluorescence resonance energy transfer (TF-FRET), by measuring FGFR albumen It is strong and weak to the inhibition of FGFR kinase activities that the phosphorylation degree of the biotinylated peptide substrate of mediation carrys out compound of reaction.In detail Experimental implementation can refer to kit specification.Recombination human source FGFR albumen is purchased from Cama bioscience (Japan, article No. difference For FGFR1 #08-133, FGFR2 #08-134, FGFR3 #08-135, FGFR4 #08-136).

Experiment flow is summarized as follows：Test-compound, which is initially dissolved in DMSO, is prepared as storage liquid, then with reagent The buffer solution provided in box carries out gradient dilution, the final concentration of test-compound in the reaction system ranging from 10 μM~0.1nM. The ATP Km values of each FGFR hypotypes of correspondence of a concentration of measured in advance of test atriphos (ATP) solution used are dense Degree.Reaction carries out in 384 hole microwell plates, compound and a certain amount of FGFR albumen is added in first into hole, and at room temperature It is incubated 5-30 minutes, then to addition ATP solution and biotinylated peptide substrate solution in reaction solution, and vibrates at room temperature It is incubated 50 minutes.There are the anti phosphotyrosine antibody of europium series elements compound and coupling to repair then to coupling is added in reaction The streptavidin of the allophycocyanin XL665 of decorationsization, and continue oscillation incubation at room temperature 1 hour.After incubation, in enzyme Instrument is marked to measure each hole in TF-FRET patterns in excitation wavelength as 304nm, launch wavelength is the fluorescence intensity of 620nM and 665nM Value.It is compared by the fluorescence intensity ratio with control group and calculates the percent inhibition of compound at various concentrations, and led to It crosses 5 softwares of GraphPad Prism and nonlinear regression analysis is carried out with compound concentration logarithm-inhibiting rate, obtain compound IC₅₀Value, is shown in Table 1.

1 preferred compound of the present invention of table is to the IC of FGFR inhibition of enzyme activity₅₀Data

As it can be seen from table 1 preferred compounds of the invention is preferable to the inhibiting effect of FGFR4, selectively it is better than FGFR1, FGFR2 and FGFR3.

N/A represents undetermined.

Test case 2, the compounds of this invention are to liver cancer cells Huh7 determinations of activity

Following methods are used to measure influence of the preferred compound of the present invention to tumor cell proliferation.By using Cell Counting Kit-8 kits (Dojindo, eastern Renhua subject skill) are measured.It is thin using liver cancer for FGFR4 hypotypes Born of the same parents Huh7 (is purchased from Shanghai Inst. of Life Science, CAS cell resource center), is cultivated according to corresponding conditions.

Experimental method is summarized as follows：Test-compound, which is initially dissolved in DMSO, is prepared as storage liquid, then with corresponding thin The culture medium of born of the same parents carries out gradient dilution, is configured to test sample, the final concentration range of compound is in 30 μM of -0.01nM.It will be in The tumour cell of exponential phase is seeded to suitable density in 96 porocyte culture plates, the overnight incubation under the conditions of corresponding Afterwards, continue to cultivate cell 72 hours after adding in test compound sample.After culture, the CCK- of appropriate volume is added in every hole 8 detection liquid, and be incubated at 37 DEG C 1~4 hour, the extinction number of degrees of each hole of sample under 450nM are then read in microplate reader Value.It is compared by the absorption values with control group and calculates compound in the percent inhibition of each concentration point, Zhi Hou Nonlinear regression analysis is carried out with compound concentration logarithm-inhibiting rate in 5 softwares of GraphPad Prism, obtains compound suppression The IC of cell Proliferation processed₅₀Value, is shown in Table 2.

2 preferred compound of the present invention of table is to the IC of liver cancer cells Huh7 activity suppressions₅₀Data

Embodiment is numbered	IC₅₀(nM)/Huh7
		2	11
3	11
		10	7.5
11	4.2
		12	28

From table 2 it can be seen that preferred compounds of the invention has notable Proliferation Ability to the liver cancer cells of FGFR4 exceptions Effect.

The suppression of test case 3, the compounds of this invention to human liver cancer cell Hep 3B Nude Mouse Model tumor growth in vivo Making is tested

1. experiment purpose

This test gives tested material to human liver cancer cell for evaluating continuous 18 days daily secondary (BID) intraperitoneal injection (IP) The inhibiting effect of Hep 3B Nude Mouse Model tumor growth in vivo.

2. tested material is prepared

2.1 blank solvent control group drug-delivery preparations are prepared

That prepares appropriate volume contains 5%DMSO, the preparation of 80 and 77% physiological saline of 10%PEG300,8%Tween As blank solvent control group drug-delivery preparation.

2.2 embodiment, 3 compound drug-delivery preparation is prepared

Appropriate 3 compound of embodiment is weighed, is fitted into vial；Appropriate volume DMSO is added in, vortex oscillation makes drug complete Fully dissolved adds PEG300, Tween-80 and physiological saline of appropriate volume, and vortex oscillation is uniform, makes DMSO: PEG300: Tween-80：Physiological saline ratio is 5: 10: 8: 77 (v/v/v/v), is configured to the drug-delivery preparation that effective concentration is 5mg/mL.

3. experimental animal

Female BAl BIc/c nude mouse (numbers of elements：16；Week old：5~7 weeks, quality certification number：11400700159209) purchased from north Capital experimental animal Technology Co., Ltd. of dimension tonneau China, raises in Suzhou Sheng Su new drug developments Co., Ltd SPF animal houses, temperature 20 ~25 DEG C, relative humidity 40%~70%, light and shade illuminates each 12 hours；Animal free water and feeding.It is normal to feed about 5 days Afterwards, through veterinary inspector, mouse can enter anthology experiment to sign in order.

4. tumor cell culture

In 5%CO₂, under 37 DEG C of condition of culture, Hep 3B cells carry out in the EMEM culture solutions containing 10% fetal calf serum Regular growth culture；With 0.25% pancreatin had digestive transfer culture；It is passed on according to cell growth status, passage ratio is 1: 3 to 1: 6。

5. animal inoculation pvaccination and grouping

It tests the 0th day, collects exponential phase Hep 3B cells, serum-free EMEM culture mediums are resuspended in after cell count In, adjustment cell concentration to 5 × 10⁷Cell/mL；Centrifuge tube is placed in ice chest；Cell suspension, note are drawn with 1mL syringes It is subcutaneous to be mapped to nude mice front right limb armpit, every 100 μ L (5 × 10 of animal inoculation pvaccination⁶Cell/only), establish Hep 3B transplanted tumor in nude mice Model.When being seeded to the 9th day, mean tumour volume reaches about 150mm³, select be in a good state of health and gross tumor volume similar in Mice with tumor 16 is divided into 2 groups using randomized blocks.

6. animal is administered and observation

Animal packet, 3 compound group of blank solvent control group and embodiment, every group 8, in the grouping same day (inoculation the 9th My god) start to be administered for the first time, administered volume 10mL/kg.1st group is blank solvent control group, and it is molten that blank is given in intraperitoneal injection Agent, 2 times a day (BID).2nd group is injected intraperitoneally gives given the test agent embodiment 3 compound respectively, dosage 50mg/kg (BID).Successive administration 26 days.

The formation situation of each group animal inoculation pvaccination region tumors is observed, experiment measures weekly 2 knurl footpaths after starting, calculate tumour Volume, while weigh the weight of animals and record.

Gross tumor volume (TV) calculation formula is as follows：

TV(mm³)=l × w²/2

Wherein, l represents tumour major diameter (mm)；W represents tumour minor axis (mm).

The calculation formula of relative tumour volume (RTV) is：

RTV=100 × TV_t/TV_initial

Wherein, TV_initialThe gross tumor volume measured when being administered for grouping；TV_tIt is swollen during to be measured each time during administration Knurl is accumulated.

The calculation formula of Relative tumor proliferation rate (%T/C) is：%T/C=100% × (RTV_T/RTV_C)

Wherein, RTV_TRepresent treatment group RTV；RTV_CRepresent blank solvent control group RTV.

The calculation formula of inhibition rate of tumor growth TGI (%) is：

TGI=100% × [1- (TV_t(T)-TV_initial(T))/(TV_t(C)-TV_initial(C))]

Wherein, TV_t(T)Represent the gross tumor volume that treatment group measures every time；TV_initial(T)Represent treatment group during grouping administration Gross tumor volume；TV_t(C)Represent the gross tumor volume that blank solvent control group measures every time；TV_initial(C)Represent blank during grouping administration The gross tumor volume of solvent control group.

The calculation formula of the weight of animals rate of descent is：The weight of animals rate of descent=100% × (BW_initial-BW_t)/ BW_initial

Wherein, BW_tRepresent the weight of animals measured every time during administration；BW_initialRepresent animal body during grouping administration Weight.

The calculation formula of knurl weight tumour inhibiting rate IR (%) is：IR (%)=100% × (W_C-W_T)/W_C

Wherein, W_CRepresent control group knurl weight；W_TRepresent treatment group's knurl weight.

7. result

Each group animal mean tumour volume and inhibition rate of tumor growth during table 1. is administered

The variation of each group animal mean tumour volume is as shown in Figure 1 during administration.

Each group animal relative mean tumor volumes and Relative tumor proliferation rate during table 2. is administered

Each group animal relative mean tumor volumes are as shown in Figure 2 during administration.

Each group animal knurl weight and knurl weight tumour inhibiting rate at the end of table 3. is tested

Note：In table 1~3, " * * " represents gross tumor volume compared with blank solvent control group, and there are pole significant difference (P ＜ 0.01)。

Each group the weight of animals and weight loss rate during table 4. is administered

Conclusion：By table 1~4 and Fig. 1~2 it is found that 3 compound of embodiment is under 50mg/kg dosage, to human liver cancer cell Hep 3B Nude Mouse Model tumour growths have obvious inhibiting effect.

Claims

1. a kind of logical formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutical salt：

Wherein：

For singly-bound or double bond；Preferably singly-bound；

X is selected from N or CH；Preferably CH；

Ring A is selected from cycloalkyl, heterocycle, aryl or heteroaryl；

Each R¹It is each independently selected from hydrogen atom, alkyl, halogen, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O)R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹, wherein the alkyl, alkoxy, cycloalkyl, miscellaneous Ring group, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, ring Alkyl, heterocycle, aryl, heteroaryl ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substitution Base is replaced；

R²Ortho position is in-the NH- of ring A, selected from following group：

-NR⁶C(O)CR⁷=CHR⁸Or-NR⁶C(O)C≡CR⁷；

Each R³It is each independently selected from hydrogen atom, halogen, alkoxy, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl Base ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹, wherein the alkoxy, alkyl, cycloalkanes Base, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alcoxyl Base, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkoxy ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹ Or-NR¹⁰C(O)R¹¹Substituent group replaced；

(i)R⁴Selected from alkyl, wherein the alkyl is further by-NR^AR^BReplaced；

R^AAnd R^BHydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein the alkyl, ring Alkyl, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkane Oxygroup, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O)NR¹³R¹⁴Or-NR¹³C(O) R¹⁴Substituent group replaced；Or

(ii)R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

R^ESelected from alkyl；

Each R⁵It is each independently selected from hydrogen atom, halogen, alkoxy, oxo base, hydroxyl, cyano, alkyl, cycloalkyl, heterocycle Base, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl optionally further by One or more is selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；R⁵Preferably oxo base；

Each R⁶Hydrogen atom or alkyl are each independently selected from, wherein the alkyl is optionally further selected from by one or more Hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkoxy ,-C (O) R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；

R⁷And R⁸Hydrogen atom, alkyl or halogen are each independently selected from, wherein the alkyl is optionally further one or more Selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, halogenated alkoxy ,-C (O)R⁹、-C(O)OR⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹Or-NR¹⁰C(O)R¹¹Substituent group replaced；

R⁹、R¹⁰And R¹¹Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein the alkane Base, cycloalkyl, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkane Base, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O)NR¹³R¹⁴Or- NR¹³C(O)R¹⁴Substituent group replaced；

Alternatively, R¹⁰And R¹¹With forming 4~8 circle heterocyclic ring bases together with the N atoms being connected, wherein containing one in 4~8 circle heterocyclic rings A or multiple N, O, S (O)_qAtom, and further by one or more selected from hydroxyl, halogen, nitro, cyanogen in 4~8 circle heterocyclic rings Base, alkyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,=O ,-C (O) R¹²、-C(O)OR¹²、-NR¹³R¹⁴、-C(O) NR¹³R¹⁴Or-NR¹³C(O)R¹⁴Substituent group replaced；

R¹²、R¹³And R¹⁴Hydrogen atom, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are each independently selected from, wherein the alkane Base, cycloalkyl, heterocycle, aryl or heteroaryl are optionally further by one or more selected from hydroxyl, halogen, nitro, cyano, alkane Base, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；

M is 1,2,3 or 4；

N is 0,1 or 2；Preferably 1；

P is 0,1,2,3 or 4；

Q is 0,1 or 2；And

S is selected from 1,2,3 or 4.

2. compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, are logical Compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (II)：

Wherein：R¹~R⁴, m, p definition as described in the appended claim 1.

3. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, In each R¹It is each independently selected from halogen or alkoxy, preferably chlorine or methoxyl group.

4. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, Middle R²For-NHC (O) CH=CH₂。

5. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, In：

Each R³It is each independently selected from hydrogen atom；Or

Each R³It is each independently selected from heterocycle, preferably 3~8 circle heterocyclic ring bases, more preferably 5~6 circle heterocyclic ring bases, wherein institute The heterocycle stated is optionally further by one or more selected from alkyl, alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl Substituent group is replaced；Or

Each R³Alkyl is each independently selected from, wherein the alkyl is further replaced by heterocycle, preferably 3~8 circle heterocyclic rings Base, more preferably 5~6 circle heterocyclic ring bases, wherein the heterocycle is optionally further by one or more selected from alkyl, alcoxyl Base, cycloalkyl, heterocycle, aryl or heteroaryl substituent group replaced；Or

Each R³It is each independently selected from-C (O) R⁹, wherein R⁹Selected from heterocycle, preferably 3~8 circle heterocyclic ring bases, more preferably 5 ~6 circle heterocyclic ring bases, wherein the heterocycle is optionally further by one or more selected from alkyl, alkoxy, cycloalkyl, heterocycle The substituent group of base, aryl or heteroaryl is replaced.

6. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, In each R³It is each independently selected from halogen, preferably F, Cl or Br, more preferably F or Cl.

7. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, Middle ring A is selected from 4~8 circle heterocyclic ring bases, preferably tetrahydrofuran base or THP trtrahydropyranyl.

8. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, Middle ring A is selected from phenyl.

9. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt, In：

R⁴Selected from-(CH₂)rNR^AR^B；

R is selected from 1,2,3 or 4；

R^AAnd R^BHydrogen atom or alkyl are each independently selected from, wherein the alkyl is optionally further selected from by one or more Hydroxyl, halogen substituent group replaced；Or

R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

S is selected from 1,2,3 or 4；

R^ESelected from alkyl.

10. compound according to claim 1 or 2 or its stereoisomer, tautomer or its pharmaceutical salt,

Wherein：

R²Selected from-NHC (O) CH=CH₂；

R⁴Selected from-(CH₂)rNR^AR^B；

R is selected from 1,2,3 or 4；

R²Selected from-NHC (O) CH=CH₂；

R⁴Selected from-CR^CR^D-(CH₂)s-OR^E；

S is selected from 1,2,3 or 4；

R^ESelected from alkyl.

11. compound according to claim 4 or its stereoisomer, tautomer or its pharmaceutical salt, wherein：

Each R³It is each independently selected from hydrogen atom；Or

12. compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, wherein The compound is selected from：

13. a kind of preparation method of formula according to claim 1 (I) compound, the method includes：

General formula (IA) compound and acetyl halide compound, preferably Y-C (O) CR⁷=CHR⁸Or Y-C (O) C ≡ CR⁷Reaction, is led to Formula (IB) compound；

Wherein：

R^aSelected from hydrogen atom or amino protecting group, the amino protecting group is preferably benzenesulfonyl, benzyloxycarbonyl group, formoxyl, trifluoro Acetyl group and tert-butoxycarbonyl；More preferably benzenesulfonyl and tert-butoxycarbonyl；

Y is halogen；

Wherein：R¹~R⁵, X, m, n and p definition as described in the appended claim 1.

14. a kind of general formula (IA) compound represented or its stereoisomer, tautomer or its pharmaceutical salt：

Wherein：

R¹、R³~R⁵, X, m, n and p definition as described in the appended claim 1.

15. compound according to claim 14 or its stereoisomer, tautomer or its pharmaceutical salt, wherein The compound is selected from：

16. a kind of pharmaceutical composition, the pharmaceutical composition contain effective dose according to any one of claim 1~12 The compound or its stereoisomer, tautomer or its pharmaceutical salt and pharmaceutical carrier, excipient or it Combination.

17. a kind of method for inhibiting FGFR4, including by the receptor and according to any one of claim 1~12 institute The compound stated or its stereoisomer, tautomer or its pharmaceutical salt or with medicine according to claim 16 Compositions are in contact.

18. compound or its stereoisomer, tautomer according to any one of claim 1~12 or its can medicine The purposes of salt or pharmaceutical composition according to claim 16 in the drug for inhibiting FGFR4 is prepared.

19. compound or its stereoisomer, tautomer according to any one of claim 1~12 or its can medicine Salt or pharmaceutical composition according to claim 16 are in the disease for preparing treatment FGF19 amplifications or FGFR4 transition expression Purposes in the drug of disease.

20. compound or its stereoisomer, tautomer according to any one of claim 1~12 or its can medicine The purposes of salt or pharmaceutical composition according to claim 16 in treating cancer drug is prepared, wherein described Cancer is selected from non-small cell lung cancer, gastric cancer, Huppert's disease, liver cancer, preferably cholangiocarcinoma, liver cancer and cholangiocarcinoma.