CN105218561B

CN105218561B - Annelated pyrimidines ring derivatives, preparation method and application

Info

Publication number: CN105218561B
Application number: CN201410289021.XA
Authority: CN
Inventors: 罗会兵; 吴勇; 周华勇
Original assignee: Shanghai Allist Pharmaceuticals Inc
Current assignee: Shanghai Allist Medicine Polytron Technologies Inc
Priority date: 2014-06-25
Filing date: 2014-06-25
Publication date: 2018-10-30
Anticipated expiration: 2034-06-25
Also published as: CN105218561A

Abstract

The invention discloses a kind of formula (I) annelated pyrimidines ring derivatives and its pharmaceutically acceptable salt as tyrosine kinase inhibitor, wherein R₁、R₂、R₃、R₄、R₅, A and B be defined as in the description.The invention also discloses the preparation methods of these compounds, including the application in terms of the drug of disease and the disease for being used to prepare EGFR mediations of the treatment by certain mutant forms that the pharmaceutical composition and the compound and its pharmaceutically-acceptable salts of the compound and its pharmaceutically-acceptable salts are mediated in the EGFR treated by certain mutant forms.

Description

Annelated pyrimidines ring derivatives, preparation method and application

Technical field

The present invention relates to a kind of annelated pyrimidines ring derivatives as tyrosine kinase inhibitor and its pharmaceutically acceptable EGF-R ELISA as certain mutant forms of salt and the derivative and its pharmaceutically acceptable salt (EGFR) (such as 19 exons missing activated mutant body, L858R activated mutants body and T790M drug-resistant types mutant) inhibits The application of agent and anticancer agent.The invention further relates to preparation methods, and include the annelated pyrimidines ring derivatives and its pharmacy The pharmaceutical composition of upper acceptable salt, and relate to the use of the derivative and its pharmaceutically-acceptable salts treatment by certain mutation The method for the disease that the EGFR of form is mediated.

Background technology

Cancer is considered as Cellular Signaling Transduction Mediated system or the disease of signal transduction mechanism.The most commonly encountered diseases of cancer are because being A series of defect, the defect can be the defects (when it is mutated) of protein, or to the amount of intracellular protein Adjusting defect, to make protein excessively generate or generate deficiency.(mutation is usually logical for the mutation of cell surface receptor Tyrosine kinase is crossed to pass the signal along into the cell) kinases can be caused to be activated under conditions of lacking ligand, and transmit the fact On not existing signal.Alternatively, many receptor tyrosine kinases can be over-expressed in cell surface, cause to weak signal Too strong response.

Lung cancer is to lead to the first cause of cancer mortality in industrial country.According to the performance of cell under the microscope, lung cancer It is divided into two kinds of main Types of non-small cell lung cancer and Small Cell Lung Cancer, non-small cell lung cancer (NSCLC) accounts for 80%.In China, Annual new hair lung cancer is more than 600,000 people, average every 30 seconds, just has 1 people to die of lung cancer.Chemotherapy is in terms of survival rate The help of humidity can be provided, but toxicity is too big, therefore there is an urgent need to the therapeutic agents that the targeting of specificity is related to tumour growth.

EGF-R ELISA (EGFR) is identified as the vital driving in cell growth and birth process Factor.Epidermal Growth Factor Receptor Family is by EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4 groups At.EGF-R ELISA is related with most of disease process of cancer, such as lung cancer, colon cancer, breast cancer.EGFR's It is the Major Risk Factors of the bad breast cancer of prognosis that overexpression and mutation are unequivocally established.Furthermore, it has been established that this receptor All four members of family can be polymerized to heterodimer with other members of the family, form signal transduction compound, If over-expressed in malignant tumour there are one above member in the family, the signal transduction effect of collaboration can be caused.

EGFR belongs to protein tyrosine kinase (PTK) family, and protein tyrosine kinase is that one kind urges phosphate group from ATP Change the enzyme for being transferred to the tyrosine residue positioned at protein substrate.Protein tyrosine kinase works in normal cell growth. The overexpression or mutation of EGFR causes receptor to be activated under conditions of lacking ligand, makes certain albumen that phosphorylation occur, Produce fissional signal.Therefore, EGFR results in excessively putting for weak signal by the effect of itself tyrosine kinase Greatly, the excessive increment of cell is caused.

Specific PTK inhibitors as potential anti-cancer therapeutic agent are concerned.The EGFR listed at present can The Typical Representative of inverse property inhibitor includes Gefitinib (Gefitinib, trade name Iressa, by ASTRAZENECAUK Ltd. develop), Erlotinib (Erlotinib, trade name Tarceva, by Genentech, Inc. and OSI Pharmaceuticals, Inc develop), Lapatinib (Lapatinib, trade name Tykerb, by GlaxoSmithKline Exploitation), inhibit EGFR wild types and activated form mutation (such as 19 exons missing activated mutant or L858R activation it is prominent Become), structure is as follows, is respectively used to the treatment of NSCLC and breast cancer.Clinical research proves Gefitinib, Erlotinib pair 19 exons missing or the NSCLC patient of L858R point mutation, which occur, for EGFR good therapeutic effect.However, their office Limit be patient receive treat after generate drug resistance (Kobayashi, M. etc., N.Engl.J.Med., 352：786-792, 2005) so that the further application of such inhibitor clinically is restricted.Studies have shown that 50% Gefitinib, angstrom Sieve for after Buddhist nun's treatment drug resistance result from EGFR occur secondary mutation (T790M) correlation (Pao W. etc., Plos Med., 2： 1-11,2005), reversible inhibitor loses curative effect.

T790M is located at the entrance of EGFR and ATP binding pockets, and the size of side chain directly affects the combination of EGFR and ATP Ability.T790M mutation spatially hinder the effect of EGFR inhibitor and ATP-binding site, increase EGFR to the affine of ATP Power, to make cell to EGFR inhibitor generate drug resistance (Cai-Hong Yun etc., Proc.Natl.Acad.Sci. U.S.A., 105：2070-2075,2008)

Compared with irreversible EGFR inhibitor, irreversible EGFR inhibitor has the advantages that very prominent.Irreversible EGFR Inhibitor can inhibit EGFR for a long time, and only the normal speed by receptor in conjunction with (also referred to as replying) is limited.There is research It was found that irreversible EGFR inhibitor can covalently be tied by reversal of the Michael addition and EGFR cysteines residue (Cys797) It closes, irreversible EGFR inhibitor is made to expand with ATP-binding site, caused by overcoming T790M to be mutated to a certain extent Drug resistance (Li D etc., Oncogene, 27：4702-4711,2008).The irreversible EGFR inhibitor listed at present has BIBW-2992 (Afatinib, Boehringer Ingelheim exploitation), grind include HKI-272 (Neratinib, Wyeth is developed), EKB-569 (Pelitinib, Wyeth develop), PF00299804 (Dacomitinib, Pfizer are developed) Deng structure is as follows.

However, this kind of irreversible EGFR inhibitor that can inhibit EGFR T790M, to the inhibiting effect of Wild type EGFR Also very big, larger toxic side effect is brought, such as diarrhea, fash, nausea, apocleisis, faint (Besse, B. etc. Eur.J.Cancer Suppl., 6,64, abstr.203,2008；Janne, P.A. etc., J.Clin.Oncol., 25：3936- 3944,2007), thus while according to the literature, in preclinical BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) display has significant antitumor activity, can inhibit the activity of EGFR and EGFR T790M, but in clinic In the process because the generation of these adverse reactions, ultimately limits its clinical administration dosage and effective blood drug concentration so that BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) fails to obtain order in terms of overcoming T790M medicament-resistant mutations Progress (Katakami N, Atagi S, Goto K, et al. [J] the .Journal of Clinical that people attractes attention Oncology, 2013,31 (27)：3335-3341.；P A, Boss D S, Camidge D R, et al. [J] .Clinical Cancer Research, 2011,17 (5)：1131-1139.；Landi L, Cappuzzo F. [J] .Translational Lung Cancer Research, 2013,2 (1)：40-49.).

Above-mentioned listing is quinazoline compounds, mesh in the reversible or irreversible EGFR inhibitor major structural types ground The preceding quinazoline ditosylate salt EGFR inhibitor reported is the ATP competitive inhibitors of Wild type EGFR, nonspecific action in Thus EGFR T790M lead to the generation of some side reactions.2009, the specificity that researcher reports a kind of miazines was made For the irreversible EGFR inhibitor of EGFR T790M, structure is as follows.With existing aniline quinazoline EGFR inhibitor phase Than such pyrimidine compound improves 30-100 times to the inhibitory activity of EGFR T790M, to the inhibitory activity of Wild type EGFR Reduce 100 times (Wenjun Zhou etc., Nature, 462：1070-1074,2009), but such pyrimidine compound of later stage is not Into clinical research.

Another serial miazines is disclosed in the international monopoly WO2012061299A of Avila Therapeutics applications Object is closed, structural formula is as follows, wherein representative compound is CO1686.According to the literature, CO1686 can selectively acting in EGFR activated forms are mutated and the mutation of T790M drug-resistant types, and to weaker (Walter A O, the Sjin R of Wild type EGFR inhibiting effect T T, Haringsma H J, et al. [J] .Cancer discovery, 2013,3 (12)：1404-1415.).Prepare at present Into clinical stage II phases.

A series of pyrimidines are also disclosed that in the international monopoly WO2013014448A of ASTRAZENECAAB applications, Structural formula is as follows, wherein representative compound is AZD9291, is in I phase clinical stages at present.

To overcome the poison of EGFR resistance mutations common in clinic (such as T790M mutation) and existing EGFR inhibitor Side-effect problem is developed and more shows higher inhibition to the EGFR of certain activated mutant bodies and drug-resistant type mutant forms Show that the micromolecular inhibitor of relatively low inhibition has been that the urgent of current antineoplastic field is essential to Wild type EGFR simultaneously It wants.The present inventor is surprisingly found that a kind of annelated pyrimidines ring derivatives, to EGFR during studying EGFR inhibitor The inhibition of activated form mutation (such as 19 exons lack activated mutant or L858R activated mutants) and the mutation of T790M drug-resistant types Activity is significantly higher than the inhibitory activity to Wild type EGFR, and energy specific effect has good selectivity in EGFR T790M, And toxic side effect is relatively low.It is expected that the curative effect that such inhibitor will have, is expected to that drug resistance problems and toxic side effect is overcome to ask Topic has good development prospect.

Invention content

The present invention provides a kind of such as following formula (I) compound or its pharmaceutically acceptable salt：

In formula：

Ring A is aryl, heteroaryl, naphthenic base or Heterocyclylalkyl；

Ring B is aryl or heteroaryl；

R₁、R₂It is each independently selected from C₁-C₄Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl ,-CN, halogenated C₁-C₄Alkyl ,-OR₇、 -C(O)R₇、-C(O)NR₇R₇′、-NR₇R₇', halogen ,-NO₂；Or R₁、R₂Naphthenic base is formed with cyclization together be connected carbon atom Or Heterocyclylalkyl；

Each R₃It independently is halogen, C₁-C₄Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, halogenated C₁-C₄Alkyl ,-OR₆、-C (O)R₇、 -C(O)NR₇R₇′、-OR₇、-NR₇R₇' ,-CN or-NO₂；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, halogenated C₁-C₄Alkane Base ,-C (O) R₆、-C(O)R₇、-COOR₇、-C(O)NR₇R₇′、-OR₇、-OR₆、-NHR₇、-NR₇-(C₁-C₄Alkyl) ,-NR₇(halogen For C₁-C₄Alkyl) ,-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 be selected from R₇Substituent group replaces miscellaneous Naphthenic base ,-SO₂R₆R₇、-SOR₇、-SO₂NR₇R₇′、-NR₇SO₂R₇、-O(CH₂)_qSO₂R₇It is unsubstituted or by 1~3 be selected from halogen Element, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution heterocycle alkane Base；

R₄For

Wherein work as R₄For When, amide nitrogen atom forms ring A as hetero atom directly participation and obtains heteroaryl or Heterocyclylalkyl；

R₆For-(CH₂)_qOR₇、-(CH₂)_qNR₇R₇′、-(CH₂)_qNR₇C(O)R₇、-(CH₂)_qC(O)R₇Or-(CH₂)_qC(O) NR₇R₇′；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl or halogenated C₁-C₄Alkyl or R₇、 R₇' together be connected nitrogen-atoms cyclization formed Heterocyclylalkyl；

The integer that m is 0~4；

The integer that n is 1~5；

The integer that q is 0~4；

The integer that p is 0~4.

The present invention, which provides, leads to formula (I) compound, one or more EGFR activated forms or drug-resistant type can be inhibited to be mutated, example Such as L858R activated mutants body, 19 exons missing activated mutant body, T790M drug-resistant type mutant.Advantageously, this chemical combination Object can be used for having generated the existing therapy based on EGFR inhibitor the treatment of cancer of a degree of drug resistance patient.

The present invention provides formula (I) compound, is shown to the EGFR of activation or drug-resistant type mutant forms and compares wild type The higher inhibition of EGFR.Due to inhibiting relevant toxicity to reduce with Wild type EGFR, thus expected this compound is more suitable for using Make therapeutic agent, is particularly suitable for the treatment of cancer.

The present invention also provides the preparation methods of formula (I) compound.

The present invention also provides pharmaceutical compositions, it contains, and aforementioned present invention leads to formula (I) compound or its is pharmaceutically acceptable Salt and pharmaceutically acceptable carrier, excipient or diluent.

The present invention also provides the logical formula (I) compounds of the present invention or its pharmaceutically acceptable salt to treat mammal especially The mankind are by the application in terms of EGFR activated forms or drug-resistant type mutant mediated disease, particularly cancer.

The present invention also provides the logical formula (I) compounds of the present invention or its pharmaceutically acceptable salt to prepare treatment mammal Especially the mankind by the mutant mediated disease of EGFR activated forms or drug-resistant type, particularly cancer drug application.

To treat the mammal especially mankind mutant mediated by EGFR activated forms or drug-resistant type the present invention also provides a kind of The method of disease, particularly cancer, the method includes to patient apply formula (I) compound or its pharmaceutically acceptable salt, Or the pharmaceutical composition of formula (I) compound and drug acceptable carrier, excipient or diluent including therapeutically effective amount.

The present invention also provides one kind selectively to inhibit in biological sample or patient compared to Wild type EGFR (WT EGFR) In EGFR activated forms or drug-resistant type mutation method, the method includes so that biological sample is contacted or to patient's administration formula (I) Compound or its pharmaceutically acceptable salt or its pharmaceutical composition.

Cancer mentioned by the present invention can be selected from lung cancer, oophoroma, cervical carcinoma, breast cancer, gastric cancer, colorectal cancer, pancreas Gland cancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, liver are thin Born of the same parents' cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, Acute myelocytic leukemia (AML), Huppert's disease, celiothelioma.

In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula R₁、 R₂It is each independently selected from C₁-C₄Alkyl, C₂-C₆Alkynyl ,-CN, halogenated C₁-C₄Alkyl or-C (O) NR₇R₇' or R₁、R₂With Cyclization forms cyclopropane base, cyclobutane base or oxetanyl to the carbon atom being connected together,

Wherein, R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' with the nitrogen that is connected Cyclization forms Heterocyclylalkyl to atom together.

In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula Each R₃It independently is halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl or-OR₇；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-C (O) R₆、-C(O)R₇、 - COOR₇、-C(O)NR₇R₇′、-OR₇、-OR₆、-NHR₇、-NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl), NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 be selected from R₇The Heterocyclylalkyl ,-SO of substituent group substitution₂R₆R₇、-SOR₇、- SO₂NR₇R₇′、-NR₇SO₂R₇、-O(CH₂)_qSO₂R₇It is unsubstituted or by 1~3 selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄ Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

The R₄For Wherein work as R₄ForWhen, amide nitrogen atom directly participates in being formed as hetero atom Ring A obtains heteroaryl or Heterocyclylalkyl；

Wherein, R₆For-(CH₂)_qOR₇、-(CH₂)_qNR₇R₇′、-(CH₂)_qNR₇C(O)R₇、-(CH₂)_qC(O)R₇Or-(CH₂)_qC (O)NR₇R₇′；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' with the nitrogen-atoms that is connected Cyclization forms Heterocyclylalkyl together；

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of the invention, formula (Ia) compound or its pharmaceutically acceptable salt are provided,

Wherein, ring B is aryl or heteroaryl；

R₁、R₂It is each independently selected from C₁-C₄Alkyl, C₂-C₆Alkynyl ,-CN, halogenated C₁-C₄Alkyl or-C (O) NR₇R₇', Or R₁、R₂Cyclopropane base, cyclobutane base or oxetanyl are formed with cyclization together be connected carbon atom,

Each R₃It independently is halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl or-OR₇；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-C (O) R₆、-C(O)R₇、 - COOR₇、-C(O)NR₇R₇′、-OR₇、-OR₆、-NHR₇、-NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl) ,-NR₇ (CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 be selected from R₇The Heterocyclylalkyl ,-SO of substituent group substitution₂R₆R₇、- SO₂NR₇R₇′、-NR₇SO₂R₇、-O(CH₂)_qSO₂R₇It is unsubstituted or by 1~3 selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkane Base ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

R₄For

Wherein, R₆For-(CH₂)_qOR₇、-(CH₂)_qNR₇R₇' or-(CH₂)_qNR₇C(O)R₇；

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of formula (Ia) compound, ring B aryl is phenyl or naphthyl.

In a preferred embodiment of formula (Ia) compound, ring B aryl is phenyl.

In a preferred embodiment of formula (Ia) compound, ring B heteroaryls be selected from pyrazolyl, pyridyl group, Pyrimidine radicals, pyrazinyl, benzimidazolyl, indyl, isoindolyl or 1,2,3,4- tetrahydro isoquinolyls.

In a preferred embodiment of formula (Ia) compound, ring B heteroaryls are pyridyl group.

In a preferred embodiment of formula (Ia) compound, R₁、R₂It is each independently selected from C₁-C₄Alkyl, Or R₁、R₂Cyclopropane base, cyclobutane base or oxetanyl are formed with cyclization together be connected carbon atom.

In a preferred embodiment of formula (Ia) compound, each R₃It independently is halogen or C₁-C₄Alkane Base.

In a preferred embodiment of formula (Ia) compound, R₄ForWherein, R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkane Base or R₇、R₇' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidinyl.

In a preferred embodiment of formula (Ia) compound, R₄ForWherein, R₇For hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl.

In a preferred embodiment of formula (Ia) compound, each R₅It independently is halogen ,-OR₇、-OR₆、 -NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 be selected from R₇The azete piperidinyl of substituent group substitution ,-O (CH₂)_qSO₂R₇It is unsubstituted or by 1~3 selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、 - NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution piperazinyl, piperidyl or pyrrolidinyl；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' with the nitrogen-atoms that is connected Cyclization forms piperidyl or pyrrolidinyl together；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In another preferred embodiment of the present invention, formula (Ia-1) compound is provided or its is pharmaceutically acceptable Salt,

Wherein, R₁、R₂It is each independently selected from C₁-C₄Alkyl or R₁、R₂Ring is formed with cyclization together be connected carbon atom Propyl, cyclobutane base or oxetanyl,

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-OR₇、-OR₆、-NHR₇、 - NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl) ,-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇SO₂R₇、-O(CH₂)_qSO₂R₇It is unsubstituted or by 1~3 selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、 -NR₇R₇′、-OR₇ Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

R₄For

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of formula (Ia-1) compound, R₁、R₂It is each independently C₁-C₄Alkyl, More preferably-CH₃。

In a preferred embodiment of formula (Ia-1) compound, m 0.

In a preferred embodiment of formula (Ia-1) compound, R₄ForWherein, R₇For Hydrogen.

In a preferred embodiment of formula (Ia-1) compound, each R₅It independently is-OR₇、-OR₆、 - NR₇(CH₂)_PC(O)R₆Or-NR₆R₇It is unsubstituted or by 1 be selected from C₁-C₄Alkyl or-C (O) R₇Substituent group substitution piperazine Base；

Wherein, R₆For-(CH₂)_qNR₇R₇′；

R₇And R₇' it is separately hydrogen or C₁-C₄Alkyl；

The integer that n is 1~2；

The integer that q is 0~2；

The integer that p is 0~2.

In a more preferred of formula (Ia-1) compound, each R₅It independently is-OR₇Or-OR₆, Wherein, R₆For-(CH₂)_qNR₇R₇′；R₇And R₇' it is separately C₁-C₄Alkyl；

N is 2；The integer that q is 0~2；The integer that p is 0~2.

In another preferred embodiment of the present invention, formula (Ia-2) compound is provided or its is pharmaceutically acceptable Salt,

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-OR₇、-OR₆、-NHR₇、 - NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl) ,-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇SO₂R₇、-NR₇It does not take In generation, is selected from R by 1~2₇Heterocyclylalkyl, the-O (CH of substituent group substitution₂)_qSO₂R₇It is unsubstituted or by 1~3 be selected from halogen Element, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution heterocycle alkane Base；

R₄For

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of formula (Ia-2) compound, R₁、R₂It is each independently C₁-C₄Alkyl, More preferably-CH₃。

In a preferred embodiment of formula (Ia-2) compound, m 0.

In a preferred embodiment of formula (Ia-2) compound, R₄ForWherein, R₇For Hydrogen.

In a preferred embodiment of formula (Ia-2) compound, each R₅It independently is-OR₇、 -NR₇ (CH₂)_PC(O)R₆、-NR₆R₇、-NR₇By 1 halogenated C₁-C₄Alkyl-substituted azete piperidinyl ,-O (CH₂)_qSO₂R₇, or by 1 Selected from C₁-C₄Alkyl ,-NR₇R₇' or-C (O) R₇Substituent group substitution piperazinyl, piperidyl or pyrrolidinyl；

Wherein R₆For-(CH₂)_qOR₇、-(CH₂)_qNR₇R₇' or-(CH₂)_qNR₇C(O)R₇；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' with the nitrogen-atoms that is connected Cyclization forms pyrrolidinyl together；

The integer that n is 1~2；

The integer that q is 0~3；

The integer that p is 0~3.

In a more preferred of formula (Ia-2) compound, each R₅It independently is-OR₇Or- NR₆R₇Or it is selected from C by 1₁-C₄Alkyl ,-NR₇R₇' or-C (O) R₇Substituent group substitution piperazinyl or piperidyl；

Wherein R₆For-(CH₂)_qOR₇Or-(CH₂)_qNR₇C(O)R₇；R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogen For C₁-C₄Alkyl；N is 2；The integer that q is 0~2；The integer that p is 0~2.

In a preferred embodiment of the invention, formula (Ib) compound or its pharmaceutically acceptable salt are provided,

Wherein, ring B is aryl or heteroaryl；

R₁、R₂It is each independently selected from C₁-C₄Alkyl, C₂-C₆Alkynyl ,-CN, halogenated C₁-C₄Alkyl ,-C (O) NR₇R₇', or R₁、R₂Cyclopropane base, cyclobutane base or oxetanyl are formed with cyclization together be connected carbon atom,

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-C (O) R₆、-C(O)R₇、 - COOR₇、-C(O)NR₇R₇′、-OR₇、-OR₆、-NHR₇、-NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl) ,-NR₇ (CH₂)_PC(O)R₆、-NR₆R₇、-SO₂R₆R₇、-SO₂NR₇R₇′、-NR₇SO₂R7、-O(CH₂)_qSO₂R₇Or it is unsubstituted or by 1~3 Selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution it is miscellaneous Naphthenic base；

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of formula (Ia) compound, ring B aryl is phenyl.

In a preferred embodiment of formula (Ib) compound, R₁、R₂It is each independently selected from C₁-C₄Alkyl, Or R₁、R₂Cyclopropane base, cyclobutane base or oxetanyl are formed with cyclization together be connected carbon atom.

In a preferred embodiment of formula (Ib) compound, each R₃It independently is halogen or C₁-C₄Alkane Base.

In a preferred embodiment of formula (Ib) compound, each R₅It independently is halogen ,-OR₇、-OR₆、 -NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-O(CH₂)_qSO₂R₇It is unsubstituted or by 1~3 selected from halogen, C₁-C₄It is alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group substitution piperazinyl or piperidyl；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In another preferred embodiment of the present invention, formula (Ib-1) compound is provided or its is pharmaceutically acceptable Salt,

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is halogen ,-CN ,-NO₂、C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-OR₇、-OR₆、-NHR₇、 - NR₇-(C₁-C₄Alkyl) ,-NR₇(halogenated C₁-C₄Alkyl) ,-NR₇SO₂R₇、-NR₇(CH₂)_PC(O)R₆Or-NR₆R₇Or it is unsubstituted or By 1~3 selected from halogen, C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-(CH₂)_qOH、-NR₇R₇′、-OR₇Or-C (O) R₇Substituent group Substituted Heterocyclylalkyl；

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

In a preferred embodiment of formula (Ib-1) compound, R₁、R₂It is each independently C₁-C₄Alkyl, More preferably-CH₃。

In a preferred embodiment of formula (Ib-2) compound, m 0.

In a preferred embodiment of formula (Ib-1) compound, each R₅It independently is-OR₇Or-NR₆R₇, Wherein, R₆For-(CH₂)_qNR₇R₇′；R₇And R₇' it is separately C₁-C₄Alkyl or halogenated C₁-C₄Alkyl；

The integer that n is 1~2；

The integer that q is 0~2.

In the present invention, it as the compound or its pharmaceutically acceptable salt represented by formula (I), can specifically refer to：

2- [4- (4- methylpiperazine-1-yls) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acrylamido benzene Base) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6,6- dimethyl - 8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [4- (4- Acetylpiperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acrylamido benzene Base) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- Acetylpiperazine -1- bases) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amine Base } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amido } -6,6- bis- Methyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- (2,2,2- trifluoro ethoxy) pyridine -3- Base amido } -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- methoxypyridine -3- bases amido } -6,6- Dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamidos Phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamides Base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- bis- Methyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- bases amido } -6,6- Dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (2- ethoxys methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl -8- (3- propylene Amidophenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- dimethylamino piperidine -1- bases) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- trifluoro ethoxies -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- (3- Acrylamide phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6,6- dimethyl - 8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- (3- propylene Amide phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (4- dimethylamino piperidine -1- bases) pyridin-3-yl amido] -6,6- dimethyl -8- (3- third Acrylamide base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [4- Acetylpiperazine -1- bases] pyridin-3-yl amido } -6,6- dimethyl -8- (3- propylene Amidophenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [4- methylpiperazine-1-yls] pyridin-3-yl amido } -6,6- dimethyl -8- (3- acryloyls Aminocarbonyl phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [1- (2- fluoro ethyls) azetidine -3- amidos] pyridin-3-yl amido } -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(R) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamines Base } -2- methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(S) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamines Base } -2- methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- isopropyl oxygroups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } -6,6- Dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- third Acrylamide phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamides Phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(R) -2- [2- methoxyl groups -6- (3- dimethylamino pyrrolidin-1-yl) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one.

The present invention also provides the methods for preparing formula (I) compound, it includes the following steps：

Wherein, ring A, ring B, R₁、R₂、R₃、R₄、R₅, m and n it is identical as the definition in above-mentioned logical formula (I) compound.

With 2,4- dichloro-5-methoxy pyrimidines for starting material, ammonolysis reaction occurs with ammonia and obtains compound (a), changes It closes object (a) and obtains compound (b) through Boron tribromide demethylation, then cyclization occurs with halogenated acid esters (g) and obtains compound (c), change Close object (c) and carry out Suzuki coupling reaction (Suzuki reaction) with compound (h) and obtain compound (d), compound (d) with Amine (i) occurs substitution reaction and obtains compound (e), and the nitro of reducing compound (e) obtains compound (f), compound (f) Amino occurs amidation process with carboxylic acid halides appropriate and obtains compound (I).

The presence of the preparation method of formula (I) compound of the present invention, wherein compound (b) and halogenated acid esters (g) in alkali Lower generation cyclization obtains compound (c), the alkali include potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, Potassium hydroxide, ammonium hydroxide, methylamine, ethamine, triethylamine etc.；In the step of nitro of reducing compound (e) obtains compound (f) also Original method is conventional method, such as palladium carbon/hydrogen reducing, PtO₂/ hydrogen reducing, iron powder reducing；The amino of compound (f) with The carboxylic acid halides that carboxylic acid halides appropriate occurs to use in the step of amidation process obtains compound (I) includes acyl chlorides, acylbromide.

In the present invention, halogen refers to fluorine, chlorine, bromine, iodine etc., preferably fluorine, chlorine, bromine.

C₁-C₄Alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl or tertiary butyl；It is preferred that first Base, ethyl, propyl, isopropyl or butyl, more preferable methyl.

Halogenated C₁-C₄Alkyl refer to by one or more halogens, preferably one to five halogen atom substitution it is as defined herein C₁-C₄Alkyl, including but not limited to trifluoromethyl, trifluoroethyl, difluoromethyl, chloro- 2 fluoro ethyls of 1- etc..

Alkenyl refers to the monovalent radical that hydrocarbyl group derives, C₂-C₆Alkenyl refers to containing containing 2 to 6 carbon atoms and at least one The alkenyl of a carbon-to-carbon double bond, including but not limited to, vinyl, acrylic, cyclobutenyl, 2- methyl-2-butenes, 2- methyl -2- Amylene and similar group.

Alkynyl refers to the monovalent radical that hydrocarbyl group derives, C₂-C₆Alkynyl refers to containing containing 2 to 6 carbon atoms and at least one The alkynyl of a carbon-carbon triple bond, including but not limited to, acetenyl, propinyl, 1- butynyls, 2- butynyls and similar group.

Naphthenic base refers to derived from the unsaturated aliphatic carbocyclic ring cyclic compound of monocycle or more ring fillings or part Monovalent radical, C₃~C₈Naphthenic base includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, ring Octenyl, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl and C₉~C₁₂Include but not limited to Bicyclic [2.2.1] heptyl and bicyclic [2.2.1] octyl etc..

Heterocyclylalkyl refers to the monovalent monocyclic base of saturation or part undersaturated (but non-aromatic) three to eight annular atoms Group, preferably 4~7 membered rings, or saturation or the monovalence of part undersaturated (but non-aromatic) five to 12 annular atoms condensed two Cyclic group, preferably 7~10 membered rings, wherein 1 to 4 ring hetero atom, independently selected from O, S, N, remaining annular atom is carbon.It is described miscellaneous Naphthenic base includes but not limited to azete piperidinyl, oxetanyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydrochysene pyrrole Mutter base, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, [1,3] dioxolanes (dioxolane), dihydropyridine base, Tetrahydro pyridyl, hexahydropyridine Ji, oxazolinyl, oxazolidine radical, isoxazole alkyls, thiazolinyl, thiazolidinyl, tetrahydrochysene thiophene Oxazolyl, different tetrahydro-thiazoles base, octahydro indyl, octahydro isoindolyl, tetrahydrofuran base etc., preferably azete piperidinyl, oxa- ring fourth Alkyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl.

Aryl refers to aromatic ring alkyl, has the carbon-loop system of one or more aromatic rings, condensed ring or non-condensed ring, including, But it is not limited to phenyl, naphthalene, tetralyl, dihydro indenyl (indanyl), indenyl (indenyl) and similar group, preferably carbon Atomicity is 6 to 14, more preferably 6 to 10 aryl, such as phenyl and naphthalene, more preferable phenyl.

Heteroaryl refers to heteroatomic 5 to the 6 unit monocycle heteroaryl for being selected from N, S or O containing 1 to 4 or it is thick with phenyl ring Made of dicyclic heteroaryl, it can be fractional saturation.The heteroaryl includes but not limited to furyl, thienyl, pyrrole Cough up base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyls, triazolyl, tetrazole radical, thiadiazolyl group, pyrrole Piperidinyl, pyrimidine radicals, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, diazosulfide base, benzothiazolyl, benzo Imidazole radicals, indyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, 1,2,3,4- tetrahydro isoquinolyls, It is preferred that pyrazolyl, pyridyl group, pyrimidine radicals, imidazole radicals, pyrazinyl, benzimidazolyl, indyl, isoindolyl or 1,2,3,4- Tetrahydro isoquinolyl.

It will be appreciated that naphthenic base described herein, Heterocyclylalkyl and its similar group can be further substituted.Substitution described herein It include but are not limited to C₁-C₄Alkyl, halogenated C₁-C₄Alkyl, halogen ,-OH ,-OC₁-C₄Alkyl ,-NO₂、-NH₂、-N(C₁-C₄ Alkyl)₂、-CN、-C(O)-C₁-C₄Alkyl ,-C (O)-NH₂、-C(O)-NH-C₁-C₄Alkyl ,-NH-C (O)-C₁-C₄Alkyl.

The present invention also includes formula (I) compound pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " refers to The acid-addition salts or base addition salts of the compounds of this invention of relative nontoxic.The acid-addition salts be formula (I) compound of the present invention and The salt that suitable inorganic acid or organic acid are formed, these salt can be prepared in the last separation of compound and purification process, or Person used can be such that formula (I) compound of purifying is reacted with suitable organic acid or inorganic acid with its free alkali form to make It is standby.Representative acid-addition salts include hydrobromate, hydrochloride, sulfate, disulfate, sulphite, acetate, oxalates, Valerate, oleate, palmitate, stearate, moon silicate, borate, benzoate, lactate, phosphate, phosphoric acid Hydrogen salt, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, tartaric acid Salt, benzoate, mesylate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc..The alkali Addition salts are the salt that formula (I) compound is formed with suitable inorganic base or organic base, including for example golden with alkali metal, alkaline earth Belong to, the salt that quaternary ammonium cation is formed, such as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, tetramethyl based quaternary ammonium salt, tetrem based quaternary ammonium salt Deng；Amine salt, including with ammonia (NH₃), the salt that is formed of primary amine, secondary amine or tertiary amine, such as methylamine salt, dimethylamine salt, front three amine salt, three Ethylamine salt, ethylamine salt etc..

It includes people that the compound of the present invention or its pharmaceutically acceptable salt, which can deliver medicine to mammal, can be taken orally, directly Administration in intestines, parenteral (intravenous, intramuscular or subcutaneous), local administration (pulvis, ointment or drops) or tumor.

The dosage of the compounds of this invention can be about 0.05-50mg/kg body weight/days, such as 0.1-45mg/kg bodies Weight/day, 0.5-35mg/kg body weight/days.

The compounds of this invention or its pharmaceutically acceptable salt may be formulated for the solid dosage forms of oral medication, packet Include, but be not limited to capsule, tablet, pill, powder and granule etc..In these solid dosage forms, formula (I) chemical combination of the present invention Object is mixed as active constituent at least one conventional inert excipients (or carrier), for example, with sodium citrate or Dicalcium Phosphate, Or it is mixed with following compositions：(1) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid etc.； (2) adhesive, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum etc.；(3) Moisturizer, for example, glycerine etc.；(4) disintegrant, for example, it is agar, calcium carbonate, potato starch or tapioca, alginic acid, certain Composition silicate and sodium carbonate etc.；(5) retarding solvent, such as paraffin etc.；(6) absorbsion accelerator, for example, quaternary ammonium compound etc.； (7) wetting agent, such as cetanol and glycerin monostearate etc.；(8) adsorbent, for example, kaolin etc.；(9) lubricant, Or mixtures thereof for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate etc.,.Capsule, It also may include buffer in tablet and pill.

Coating and shell material such as enteric can be used in the solid dosage forms such as tablet, sugar-pill, capsule, pill and granule Clothing and other materials well known in the art are coated or microencapsulation.They may include opacifying agent, also, this composition The release of middle active constituent can discharge in certain part in the digestive tract in a delayed fashion.Adoptable embedding component Example is polymeric material and wax material.When necessary, active constituent also can be micro- with one or more formation in above-mentioned excipient Capsule form.

The compounds of this invention or its pharmaceutically acceptable salt may be formulated for the liquid dosage form of oral medication, packet Include, but be not limited to pharmaceutically acceptable lotion, solution, suspension, syrup and tincture etc..In addition to the formula as active constituent (I) outside compound or its pharmaceutically acceptable salt, liquid dosage form may include the inert diluent routinely used in this field, Such as water and other solvents, solubilizer and emulsifier, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3- Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame The mixture etc. of oil etc. or these substances.Other than these inert diluents, fluid present invention dosage form also may include conventional help Agent, such as wetting agent, emulsifier and suspending agent, sweetener, corrigent and fragrance.

The suspending agent includes, for example, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and anhydro sorbitol only, The mixture of microcrystalline cellulose, aluminium methoxide and agar etc. or these substances.

The compounds of this invention or its pharmaceutically acceptable salt may be formulated for the dosage form of parenteral injection, including, But it is not limited to physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or lotion, and for again molten Solution at sterile Injectable solution or dispersion liquid aseptic powdery.Suitable carrier, diluent, solvent or excipient include water, Ethyl alcohol, polyalcohol and its suitable mixture.

The compounds of this invention or its pharmaceutically acceptable salt can also be formulated as the dosage form for local administration, including such as Ointment, powder, suppository, drops, propellant and inhalant etc..As the formula (I) compound of the present invention of active constituent or its medicine On acceptable salt aseptically with physiologically acceptable carrier and optional preservative, buffer, or when necessary The propellant that may be needed is mixed together.

The present invention also provides pharmaceutical compositions, it contains formula (I) compound of the present invention or its pharmaceutically acceptable salt is made For active constituent and pharmaceutically acceptable carrier, excipient or diluent.When preparing pharmaceutical composition, typically it incite somebody to action this Invention formula (I) compound or its pharmaceutically acceptable salt are mixed with pharmaceutically acceptable carrier, excipient or diluent.Its Formula of (I) compound or the content of its pharmaceutically acceptable salt can be 0.01-1000mg, such as 0.05-800mg, 0.1-500mg, 0.01-300mg, 0.01-200mg, 0.05-150mg, 0.05-50mg etc..

Routinely preparation method the present composition can be formulated as traditional drug formulations.Such as tablet, pill, Capsule, powder, granule, emulsion agent, mixed floating agent, dispersion liquid, solution, syrup, elixir, ointment, drops, bolt Agent, inhalant, propellant etc..

Compound of the present invention or its pharmaceutically acceptable salt can be administered alone, or pharmaceutically may be used with other The therapeutic agent of receiving is administered, especially with other antitumor combinations.The therapeutic agent includes but not limited to：Effect In the drugs against tumor medicine such as cis-platinum of DNA chemical constitutions, influence nucleotide synthesis antitumor drug such as methotrexate (MTX) (MTX), 5 FU 5 fluorouracil (5FU) etc. influences antitumor drug such as adriamycin, Epi-ADM, aclacinomycin, the radiance of transcribed nucleic acid Mycin etc. acts on the antitumor drug such as taxol, vinorelbine etc. of tubulin synthesis, arimedex such as ammonia Rumi is special, Lactel is grand, Letrozole, auspicious Ningde etc., her horse of cell-signaling pathways inhibitor such as epidermal growth factor receptor inhibitor For Buddhist nun (Imatinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib) etc..Each ingredient to be combined can be same When or sequence give, give in the form of single formulation or in the form of without preparation.The combination includes not only the present inventionization Object and a kind of combination of other activating agents are closed, and includes the compounds of this invention and two or more other activating agents Combination.

By being 19 exon deletion form activated mutant tumour cell such as HCC827 cells, drug-resistant types to activated form mutation The external increment of tumour cell such as H1975 and Wild type EGFR application on human skin cancer cell A431 inhibit experiment, it was demonstrated that of the present inventionization Close object has good increment inhibiting effect to activated mutant or drug-resistant type mutated tumor cell, but opposite to wild type The increment inhibiting effect of EGFR cancer cells is weaker, and selectivity is good.The compounds of this invention can be used as treatment by EGFR activated forms or resistance to The drug of disease or the patient's condition, particularly tumour such as cancer that Types of Medicine mutant activity mediates.The cancer includes but unlimited In, for example, lung cancer, oophoroma, cervical carcinoma, breast cancer, gastric cancer, colorectal cancer, cancer of pancreas, glioma, glioblastoma, Melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), It is thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia (AML), more Hair property myeloma, celiothelioma, methionine (EGFR T790M) is sported particularly with 790 threonines of EGF-R ELISA Tumor type have better application.For example, the compounds of this invention can be used as and for treating non-small cell carcinoma (EGFR T790M drug).It can be used for overcoming clinically using the drug resistance caused by EGFR T790M after Gefitinib, Erlotinib Problem.And because inhibiting relevant toxicity to reduce with Wild type EGFR, it is contemplated that the compounds of this invention is in the mistake applied to treating cancer The toxic side effect that Cheng Dangzhong is generated is relatively small.

The compounds of this invention inhibits the drug effect of cancer cell multiplication that can be measured with conventional method, and a kind of preferred evaluation method is Sulforhodamine B (SulforhodamIne B, SRB) protein staining method, produced by measuring drug effect after cancer cell The variation of absorbance value calculate inhibiting rate of the drug to cancer cell multiplication.

Inhibiting rate (%)=[(blank control OD- dosing OD)/blank control OD] × 100%

Blank control OD：Refer to the OD values in the hole of the cell of no drug effect normal growth.

Dosing OD：Refer to the OD values in the hole for the cell that compound effects to be screened are added.

Half inhibitor concentration (IC₅₀) value use 5.0 version of GraphPad companies PrIsm softwares, four parameter fitness methods It calculates.Each experiment is repeated 3 times, and finds out the average IC of 3 experiments₅₀Value is the final index of rejection ability.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are only used for illustrating this It invents rather than limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal Rule condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages are respectively parts by weight And weight percent.

Specific implementation mode

I. the compounds of this invention prepares embodiment

Embodiment 1：2- [4- (4- methylpiperazine-1-yls) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acryloyls Aminocarbonyl phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- methoxyl groups -4- (4- methylpiperazine-1-yls) nitrobenzene

The fluoro- 2- Nitroanisoles (0.51g) of 5- are dissolved in dimethyl sulfoxide 20ml, sequentially add N methyl piperazine (1.3ml), Potassium carbonate (1.25g) is warming up to 90 DEG C of reactions.It is stirred to react 0.5 hour and stops reaction.Reaction solution is stirred down and pours into ice water In compound 100ml, yellow needles are precipitated, and filter, dry, obtain yellow solid 0.71g.MS m/z：252.2(M+1).

Step 2：The synthesis of 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline

1- (3- methoxyl group -4- nitrobenzophenones) -4- methyl piperazines (250mg) are dissolved in ethyl alcohol, add appropriate palladium carbon, nitrogen atmosphere Under be stirred to react 1 hour.Reaction solution is filtered and removes palladium carbon, evaporated under reduced pressure obtains aubergine grease (211mg).MS m/z： 222.3(M+1).

Step 3：The synthesis of 2- chloro-5-methoxyl pyrimidine -4- amine

2,4- dichloro-5-methoxy pyrimidines (100g) are dissolved in methanol, are led to ammonia at room temperature and are stirred to react 24 hours.Reaction Liquid evaporated under reduced pressure obtains white solid, and petrol ether/ethyl acetate (10: 1) is added and is beaten 3-5 times, filters, obtains white solid 61g. MS m/z：160.0(M+1).

Step 4：The synthesis of 4- amino -2- chlorine pyrimidine -5- alcohol

2- chloro-5-methoxyl pyrimidine -4- amine (25g) is dissolved in dichloromethane 200ml, ice bath, is slowly dripped under nitrogen protection Add Boron tribromide (75ml), drip off and be warmed to room temperature, is heated slowly to 50 DEG C and is stirred to react overnight.It is cooling, it is slowly added into 2L and contains It is stirring while adding in ice cube methanol.Potassium carbonate tune pH to 12, ethyl acetate extraction, water layer dilute hydrochloric acid tune pH to 3, acetic acid is added Ethyl ester extracts, dry, and evaporated under reduced pressure obtains white solid 47.6g.MS m/z：146.0(M+1).

Step 5：[the synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines of chloro- 6, the 6- dimethyl -6H- pyrimidines [5,4-b] of 2-

4- amino -2- chlorine pyrimidine -5- alcohol (48g) is added in acetonitrile 300ml, is stirred at room temperature, potassium carbonate (72g) is added, 2- isobutyl bromides methyl esters (180g).60 DEG C are warming up to, is stirred to react 48 hours.Stop reaction, reaction solution is poured into water, second Acetoacetic ester extracts, saturated common salt water washing, dry, is evaporated, and obtains crude solid, petroleum ether mashing, and filtering obtains white solid 38g.MS m/z：214.0(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.14 (s, 1H), 1.59 (s, 6H)

Step 6：2- chloro- 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] Bing oxazines -7 (8H) - The synthesis of ketone

By chloro- 6, the 6- dimethyl -6H- pyrimidines [5,4-b] of 2- [- 7 (8H) -one (8g) of Isosorbide-5-Nitrae] Bing oxazines, copper acetate (3.4g) It is added in dry methylene chloride 50ml.N,N-diisopropylethylamine (6.5ml) is added, activated molecular sieve (8g), room temperature is stirred It mixes, 3- nitrobenzene boronic acids (4g) is added, are stirred overnight at room temperature.Stop reaction, adds diatomite to filter, petrol ether/ethyl acetate (10: 1) rinse filter cake repeatedly.Filtrate is evaporated with saturated common salt water washing, dry organic phase, is obtained crude solid.Add petroleum ether Mashing, filtering, obtains Tan solid 7.2g.MS m/z：335.0(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.37 (d, J=8.3Hz, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.73 (t, J=8.1Hz, 1H), 7.58 (d, J=8.2Hz, 1H), 1.69 (s, 6H)

Step 7：2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -6,6- dimethyl -8- (3- nitros Phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

2- chloro- 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines (1.35g), 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (1.2g) are added in sec-butyl alcohol 5ml, and trifluoroacetic acid tune pH is extremely 4, it is warming up to back flow reaction 3 hours.TLC thin-layer chromatographies (methylene chloride/methanol=10: 1) detach to obtain yellow oil 0.6g. MS m/z： 520.2(M+1).

Step 8：8- (3- aminophenyls) -2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -6,6- Dimethyl -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -6,6- dimethyl -8- (3- nitrobenzophenones) - 6H- pyrimidines [5,4-b] [- 7 (8H) -one (100mg) of Isosorbide-5-Nitrae] Bing oxazines is dissolved in dichloromethane, adds trifluoracetic acid, appropriate palladium carbon, It is stirred to react under nitrogen atmosphere 2 hours.Reaction solution is filtered to remove palladium carbon, and evaporated under reduced pressure obtains colorless oil 80mg.MS m/z： 490.2(M+1).

Step 9：2- [4- (4- methylpiperazine-1-yls) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acrylamides Base phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

8- (3- aminophenyls) -2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -6,6- dimethyl - [- 7 (8H) -one (20mg) of Isosorbide-5-Nitrae] Bing oxazines is dissolved in dichloromethane 3ml 6H- pyrimidines [5,4-b], and triethylamine is added under ice bath (8mg), acryloyl chloride (4mg), is stirred to react 0.5 hour.TLC thin-layer chromatographies (methylene chloride/methanol=10: 1) detach yellow Color grease 8mg.MS m/z：544.3(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.04 (s, 1H), 7.83 (d, J=7.1Hz, 1H), 7.71 (br, 1H), 7.54 (s, 1H), 7.51 (t, J=7.8Hz, 2H), 7.03 (d, J=7.7Hz, 1H), 6.41 (d, J=9.7Hz, 2H), 6.25 (m, 1H), 6.18 (d, J=8.7Hz, 1H), 5.75 (d, J=10.1Hz, 1H), 3.80 (s, 3H), 3.14 (br, 4H), 2.72 (br, 4H), 2.45 (s, 3H), 1.63 (s, 6H)

Embodiment 2：2- [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6, 6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 6- chloro- 3- nitros -2- (2,2,2- trifluoro ethoxy) pyridine

2,6- dichloro-3-nitropyridines (3g), trifluoroethanol (1.58g) are added in 20ml tetrahydrofurans, lower point of ice bath It criticizes and sodium hydrogen (total 0.41g) is added, add and be stirred to react 2 hours.Reaction solution is poured into water, and ethyl acetate extraction, organic phase is with clear Water, saturated common salt water washing, dry, evaporated under reduced pressure, yellow oil 3.4g.MS m/z：257.0(M+1).

Step 2：The synthesis of 6- (4- methylpiperazine-1-yls) -3- nitros -2- (2,2,2- trifluoro ethoxy) pyridine

6- chloro- 3- nitros -2- (2,2,2- trifluoro ethoxy) pyridines (0.3g) are dissolved in 3ml ethyl alcohol, are added with stirring first Base piperazine (0.49g) is warming up to 50 DEG C and reacts 2 hours.Stopping reaction, clear water is added, ethyl acetate extraction is dry, is evaporated, Obtain yellow solid 140mg.MS m/z：321.3(M+1).

Step 3：The synthesis of 6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridine -3- amine

1- methyl -4- (5- nitros -6- (2,2,2- trifluoro ethoxy) pyridine -2- bases) piperazine (140mg) is dissolved in methanol 4ml In, appropriate palladium carbon is added, is stirred to react under nitrogen atmosphere 1 hour.It filters, is evaporated, obtains lavender grease 103mg.MS m/z： 291.1(M+1).

Step 4：6,6- dimethyl -2- { [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridine -3- Base] amino } [the synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines of -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

2- chloro- 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines (100mg), 6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridine -3- amine (79mg) are added to sec-butyl alcohol In 2ml, trifluoracetic acid tune pH to 3-4, heating reflux reaction 3 hours.TLC thin-layer chromatographies (methylene chloride/methanol=10: 1) divide From yellow oil 50mg.MS m/z：589.2(M+1).

Step 5：6,6- dimethyl -8- (3- aminophenyls) -2- { [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoros Ethyoxyl) pyridin-3-yl] amino } -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

6,6- dimethyl -2- { [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl] ammonia Base } [- 7 (8H) -one (20mg) of Isosorbide-5-Nitrae] Bing oxazines is dissolved in dichloromethane -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b], is added Enter appropriate palladium carbon, is stirred to react under nitrogen atmosphere 3 hours.It filters, is evaporated, obtains colorless oil 15mg.MS m/z：559.2(M+ 1).

Step 6：2- [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6,6- Dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

6,6- dimethyl -8- (3- aminophenyls) -2- { [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoroethoxies Base) pyridine -3- bases] amino } [- 7 (8H) -one (75mg) of Isosorbide-5-Nitrae] Bing oxazines is dissolved in dichloromethane 3ml to -6H- pyrimidines [5,4-b] In, acryloyl chloride (12.1mg), triethylamine (16.3mg) are added under ice bath, is stirred at room temperature 3 hours.TLC thin-layer chromatography (dichloromethanes Alkane/methanol=10: 1) yellow oil 10mg is detached to obtain.MS m/z：613.2(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 7.87 (d, J=8.4Hz, 1H), 7.68 (d, J=8.2Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.45 (s, 1H), 7.03 (d, J=7.2Hz, 1H), 6.42 (d, J=16.7Hz, 1H), 6.22 (dd, J=16.9,10.3Hz, 1H), 5.92 (d, J=8.6Hz, 1H), 5.80 (d, J=8.6Hz, 1H), 4.69 (q, J =8.5Hz, 2H), 3.42 (br, 4H), 2.62 (br, 4H), 2.41 (s, 3H), 1.63 (s, 6H)

Embodiment 3：2- [4- (4- Acetylpiperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- propylene Amidophenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- methoxyl groups -4- (piperazine -1- bases) nitrobenzene

It is prepared according to 1 step 2 method of embodiment.MS m/z：238.1(M+1).

Step 2：The synthesis of 2- methoxyl groups -4- (4- Acetylpiperazine -1- bases) nitrobenzene

2- methoxyl groups -4- (piperazine -1- bases) nitrobenzene (1.4g) is dissolved in dichloromethane 25ml, adds triethylamine (0.89g), Chloroacetic chloride (0.6ml) is added dropwise under ice bath, drips off and is stirred to react 2 hours.Water quenching is added to go out, ethyl acetate extraction, organic layer is with clear water Washing, dry, evaporated under reduced pressure obtains yellow solid 1.2g.MS m/z：280.1(M+1).

Step 3：The synthesis of 2- methoxyl groups -4- (4- Acetylpiperazine -1- bases) aniline

It is prepared according to 1 step 2 method of embodiment.MS m/z：238.1(M+1).

Step 4：2- [4- (4- acetyl group-piperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- nitros Phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 1 step 7 method of embodiment.MS m/z：548.2(M+1).

Step 4：2- [4- (4- Acetylpiperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- amido benzene Base) -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 1 step 8 method of embodiment.MS m/z：518.2(M+1).

Step 5：2- [4- (4- Acetylpiperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acryloyls Aminocarbonyl phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 1 step 9 method of embodiment.MS m/z：572.3(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.90 (d, J=8.1Hz, 1H), 7.55 (s, 1H), 7.52 (t, J=8.1Hz, 1H), 7.43 (s, 1H), 7.04 (d, J=8.0Hz, 1H), 6.44 (s, 1H), 6.41 (d, J=16.8Hz, 1H), 6.18 (m, 2H), 5.76 (d, J=11.3Hz, 1H), 3.81 (s, 3H), 3.74 (br, 2H), 3.59 (br, 2H), 3.01 (br, 4H), 2.14 (s, 3H), 1.63 (s, 6H)

Embodiment 4：2- [6- (4- Acetylpiperazine -1- bases) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] - 6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

It is prepared according to 2 each step method of embodiment.MS m/z：641.2(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.83 (d, J=8.3Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.48 (t, J=8.1Hz, 1H), 7.43 (s, 1H), 7.00 (d, J=7.9Hz, 1H), 6.40 (d, J=16.8Hz, 1H), 6.17 (dd, J=16.8,10.2Hz, 1H), 5.92 (d, J=8.7Hz, 1H), 5.75 (d, J=10.3Hz, 1H), 4.70 (q, J =8.5Hz, 2H), 3.69 (br, 2H), 3.55 (br, 2H), 3.38 (br, 2H), 3.30 (br, 2H), 2.13 (s, 3H), 1.63 (s, 6H)

Embodiment 5：2- { 4- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- methoxybenzenes amido } -6,6- bis- Methyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 1 each step method of embodiment.MS m/z：546.3(M+1).

Embodiment 6：2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyrroles Pyridine -3- bases amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] Bing oxazines -7 (8H) -one

Step 1：N, N, N '-trimethyl-N '-(5- nitros -6- (2,2,2- trifluoro ethoxy) pyridine -2- bases) ethane -1, The synthesis of 2- diamines

It is prepared according to 2 step 2 method of embodiment.MS m/z：323.1(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.30 (d, J=9.1Hz, 1H), 6.19 (d, J=9.1Hz, 1H), 4.88 (q, J =8.3Hz, 2H), 3.72 (br, 2H), 3.19 (s, 3H), 2.54 (m, 2H), 2.32 (s, 6H)

Step 2：N '-(2- (dimethylamino) ethyl)-N '-methyl -6- (2,2,2- trifluoro ethoxy) pyridine -2,5- bis- The synthesis of amine

It is prepared according to 2 step 3 method of embodiment.MS m/z：293.2(M+1).

Step 3：2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyridines - 3- bases amido } -6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 2 step 4 method of embodiment.MS m/z：591.2(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.36 (d, J=8.3Hz, 1H), 8.15 (s, 1H), 7.73 (t, J=8.1Hz, 1H), 7.63 (d, J=7.8Hz, 1H), 7.56 (br, 1H), 6.87 (br, 1H), 5.74 (d, J=8.0Hz, 1H), 4.75 (q, J =8.4Hz, 2H), 3.93 (br, 2H), 3.18 (br, 2H), 2.97 (s, 3H), 2.86 (s, 6H), 1.66 (s, 6H)

Step 4：2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyridines - 3- bases amido } -6,6- dimethyl -8- (3- aminophenyls) -6H- pyrimidines [5,4-b] [synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

It is prepared according to 2 step 5 method of embodiment.MS m/z：561.2(M+1).

Step 5：2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyridines - 3- bases amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines Synthesis

It is prepared according to 2 step 6 method of embodiment.MS m/z：615.3(M+1).

¹H NMR (400MHz, DMSO) δ 8.05 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 7.59 (s, 1H), 7.44 (t, J=8.0Hz, 1H), 7.38 (d, J=8.5Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 6.43 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=16.9,1.9Hz, 1H), 5.90 (d, J=8.3Hz, 1H), 5.77 (dd, J=10.1,1.9Hz, 1H), 4.83 (q, J=9.1Hz, 2H), 3.53 (br, 2H), 2.91 (s, 3H), 2.42 (br, 2H), 2.23 (s, 6H), 1.54 (s, 6H).

Embodiment 7：2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amine Base } -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines

Step 1：The synthesis of the chloro- 2- of 6- [3- (methyl mercapto) propoxyl group] -3- nitropyridines

2,6- dichloro-3-nitropyridines (0.96g), 3 methylthiol propyl alcohol (0.53g) are added in 12ml tetrahydrofurans, ice Bath is lower to be added sodium hydrogen (0.2g), adds and is stirred to react 1 hour.Reaction solution is poured into water, and ethyl acetate extraction, organic phase is with clear Water, saturated common salt water washing, dry, evaporated under reduced pressure, yellow oil 1.15g.

Step 2：The synthesis of 6- (4- methylpiperazine-1-yls) -2- [3- (methyl mercapto) propoxyl group] -3- nitropyridines

The chloro- 2- of 6- [3- (methyl mercapto) propoxyl group] -3- nitropyridines (0.26g) are dissolved in 3ml ethyl alcohol, are added with stirring first Base piperazine (0.2g) is warming up to 50 DEG C and reacts 2 hours.Stopping reaction, clear water is added, ethyl acetate extraction is dry, is evaporated, Obtain yellow oil 330mg.MS m/z：327.2(M+1).

Step 3：The synthesis of 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridine -3- amine

6- (4- methylpiperazine-1-yls) -2- [3- (methyl mercapto) propoxyl group] -3- nitropyridines (0.28g) are dissolved in 5ml ethyl alcohol In, two equivalent ammonium persulfate-sodium bisulfate (Oxone) aqueous solutions are added dropwise under ice bath, drips off stirring 10 minutes, removes ice bath, add Enter iron powder (0.96g), saturated ammonium chloride solution (3ml) is stirred to react 2 hours.Ethyl acetate extracts, clear water, saturated common salt Water washing, dry, evaporated under reduced pressure obtains tan solid 250mg.MS m/z：329.1(M+1).

Step 4：2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amido } - [the synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines of 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

It is prepared according to 2 step 4 method of embodiment.MS m/z：627.1(M+1).

Step 5：2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amido } - [the synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines of 6,6- dimethyl -8- (3- aminocarbonyl phenyls) -6H- pyrimidines [5,4-b]

It is prepared according to 2 step 5 method of embodiment.MS m/z：597.3(M+1).

Step 6：2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amido } - [the synthesis of -7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines of 6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b]

It is prepared according to 2 step 6 method of embodiment.MS m/z：651.3(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 7.83 (d, J=8.3Hz, 1H), 7.70 (br, 1H), 7.49 (m, 2H), 7.00 (d, J=8.0Hz, 1H), 6.41 (d, J=16.3Hz, 1H), 6.19 (dd, J=16.3,10.3Hz, 1H), 5.91 (d, J=8.1Hz, 1H), 5.74 (d, J=10.3Hz, 1H), 4.37 (t, J=6.1Hz, 2H), 3.67 (br, 4H), 3.16 (br, 4H), 3.15 (t, J=8.1Hz, 2H), 2.93 (s, 3H), 2.43 (s, 3H), 2.28 (m, 2H), 1.63 (s, 6H)

Embodiment 8：2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- (2,2,2- trifluoroethoxies Base) pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

It is prepared according to 6 each step method of embodiment.MS m/z：647.2(M+1).

¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.79 (d, J=8.2Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.57 (s, 1H), 7.50 (t, J=8.1Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.44 (dd, J=16.8, 1.1Hz, 1H), 6.22 (dd, J=16.8,10.2Hz, 1H), 5.78 (m, 2H), 4.73 (q, J=8.6Hz, 2H), 4.61 (t, J =4.9Hz, 1H), 4.49 (t, J=4.9Hz, 1H), 3.57 (m, 2H), 2.96 (s, 3H), 2.81 (t, J=4.9Hz, 1H), 2.74 (t, J=4.9Hz, 1H), 2.61 (m, 2H), 2.40 (s, 3H), 1.65 (s, 6H)

Embodiment 9：2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- methoxypyridine -3- base amine Base } -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

It is prepared according to 6 each step method of embodiment.MS m/z：579.3(M+1).

¹H NMR (400MHz, DMSO) δ 10.44 (s, 1H), 9.81 (br, 1H), 8.13 (s, 1H), 7.78 (d, J= 8.3Hz, 1H), 7.69 (s, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.07 (d, J= 7.6Hz, 1H), 6.49 (dd, J=17.0,10.0Hz, 1H), 6.28 (dd, J=16.9,1.6Hz, 1H), 5.94 (br, 1H), 5.79 (d, J=11.8Hz, 1H), 4.93 (t, J=4.0Hz, 1H), 4.81 (t, J=4.0Hz, 1H), 3.87 (t, J= 6.0Hz, 2H), 3.82 (s, 3H), 3.60 (m, 2H), 3.40 (m, 2H), 2.93 (s, 3H), 2.92 (s, 2H), 2.51 (s, 3H), 1.59 (s, 6H)

Embodiment 10：2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- third Acrylamide base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：2- (3- methoxyl groups -4-nitrophenoxy)-N, the synthesis of N- dimethyl amines

2- methoxyl group -4- fluoronitrobenzenes (3.4g, 20mmol) are dissolved in 50mL tetrahydrofurans, and 60% sodium is added at room temperature Hydrogen (1.2g, 30mmol) replaces gas in bottle, and under nitrogen protection, reaction solution is cooled at 5 DEG C, is added dropwise and contains N, N- diformazans The tetrahydrofuran solution (20mL) of ethylethanolamine (2.2mL, 22mmol), is added dropwise, and is warmed to room temperature reaction overnight.To reaction 4mL water quenchings are added in liquid to go out reaction, remove most of solvent under reduced pressure, with the extraction of 100mL ethyl acetate.Organic layer is washed with water 3 Secondary, anhydrous sodium sulfate drying is filtered, and filtrate concentration with silica gel post separation (ethyl acetate), obtains 2.2g products.Yield is 46%.MS m/z：241.3.

¹H NMR (400MHz, CDCl₃) δ 7.91 (dd, J=9.1,5.0Hz, 1H), 6.55 (d, J=2.4Hz, 1H), 6.47 (dd, J=9.1,2.4Hz, 1H), 4.09 (t, J=5.5Hz, 2H), 3.88 (s, 3H), 2.70 (t, J=5.5Hz, 2H), 2.29 (s, 6H).

Step 2：2- (3- methoxyl group -4- amino-benzene oxygens)-N, the synthesis of N- dimethyl amines

By 2- (3- methoxyl groups -4-nitrophenoxy)-N, N- dimethyl amines (1.02g, 4.25mmol) are dissolved in 15mL second Under nitrogen protection, palladium carbon (95mg) is added in alcohol, is passed through hydrogen, room temperature reaction is overnight.Stopping is passed through hydrogen, by reaction solution mistake Filter, filter cake ethanol rinse, filtrate decompression are concentrated to give 900mg black liquors, and not purified be directly used in is reacted in next step.

Step 3：2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- nitros Phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

By 2- (3- methoxyl group -4- amino-benzene oxygens)-N, N- dimethyl amines (700mg, 3.33mmol) are dissolved in 10mL2- Trifluoroacetic acid (0.22mL, 2.96mmol) is added in amylalcohol at room temperature, and under nitrogen protection, chloro- 6, the 6- dimethyl -8- of 2- are added [Isosorbide-5-Nitrae] oxazines -7 (8H) -one, 120 DEG C are reacted 3 hours (3- nitrobenzophenones) -6H- pyrimidines [5,4-b], and 100 DEG C of reactions are overnight.Instead It should finish, reaction solution is concentrated under reduced pressure, silica gel post separation (dichloromethane: methane=100: 0-40: 1), obtains 500mg products. Yield is 30%.MS m/z：509.3.

¹H NMR (400MHz, CDCl₃) δ 8.39 (ddd, J=8.2,2.1,1.0Hz, 1H), 8.21 (t, J=2.0Hz, 1H), 8.11 (s, 1H), 7.75 (t, J=8.1Hz, 1H), 7.69-7.64 (m, 1H), 7.44 (d, J=8.7Hz, 1H), 7.29 (d, J=3.4 Hz, 1H), 6.48 (d, J=2.6Hz, 1H), 6.06 (dd, J=8.8,2.0Hz, 1H), 4.16 (t, J= 5.3Hz, 2H), 3.81 (s, 3H), 3.00 (t, J=5.3Hz, 2H), 2.58 (s, 6H), 1.67 (s, 6H).

Step 4：2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- amino Phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

By 2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- nitrobenzenes Base) [Isosorbide-5-Nitrae] oxazines -7 (8H) -one (500mg, 0.98mmol) is dissolved in 3mL ethyl alcohol and 1mL water to -6H- pyrimidines [5,4-b], is added Iron powder (190 mg, 3.39mmol) and ammonium chloride (40mg, 0.75mmol), 80 DEG C are reacted 1 hour.Filtering, filter cake are drenched with ethyl alcohol It washes, evaporated under reduced pressure solvent, 100mL dichloromethane is added, use 50mL saturated solution of sodium bicarbonate, 50mL water washings successively.Two Chloromethanes layer is dried with anhydrous sodium sulfate, and filtering, evaporated under reduced pressure obtains 330mg solids.Yield is 70%.MS m/z： 479.2.

Step 5：2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- propylene Amidophenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

By 2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- aminobenzenes Base) [Isosorbide-5-Nitrae] oxazines -7 (8H) -one (50mg, 0.105mmol) is dissolved in 2mL dichloromethane to -6H- pyrimidines [5,4-b], and ice-water bath is cold But, acryloyl chloride (8.5 μ L, 0.105mmol) is added.It reacts 1 hour at room temperature, removes solvent under reduced pressure, prepare plate and isolate and purify (dichloromethane: methanol=5: 1), obtain 28mg products.Yield is 50%.MS m/z：533.3.

¹H NMR (400MHz, CDCl₃) δ 9.25 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.46 (t, J=8.1Hz, 2H), 7.33 (s, 1H), 7.00 (d, J=7.7Hz, 1H), 6.52 (dd, J=16.9, 10.0Hz, 1H), 6.44-6.35 (m, 2H), 6.17 (dd, J=9.0,2.5Hz, 1H), 5.68 (dd, J=10.1,1.4Hz, 1H), 4.30 (t, J=4.9 Hz, 2H), 3.78 (s, 3H), 3.16 (t, J=4.9Hz, 2H), 2.71 (s, 6H), 1.65 (s, 6H)。

Embodiment 11：2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- Acrylamido phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- dimethylaminos-N- [3- methoxyl groups -4- (the bis- tert-butoxycarbonylaminos of N, N-)] acetamide

2- dimethylamino acetic acid (0.43g, 4.14mmol), 20mLN, N- dimethylacetamides are added into 100mL single port bottles Amine, diisopropyl ethyl amine (1.15g, 8.87mmol) and 2- (7- azos benzotriazole)-N, N, N ', N '-tetramethylureas six Fluorophosphoric acid ester (1.8g, 4.73mmol) stirs 15 minutes at room temperature, and 3- methoxyl groups -4- [N, N- (double tert-butoxy carbonyls are added Base) amido] aniline (1.0g, 2.96mmol), continues stirring 1 hour at room temperature.150mL ethyl acetate is added into reaction solution, It is washed successively with water (100mL × 2) and saturated brine (100mL), anhydrous sodium sulfate drying is concentrated under reduced pressure.Residue silica gel Post separation (dichloromethane: methanol=10: 1), obtains 0.7g products.Yield is 56%.MS m/z：424.

Step 2：The synthesis of 2- dimethylaminos-N- (3- methoxyl group -4- amino) acetamide

2- dimethylaminos-N- [3- methoxyl groups -4- (the bis- tert-butoxycarbonylaminos of N, N-)] second is added into 50mL single port bottles Amide (0.6 g, 1.4mmol), 5mL dichloromethane and 5mL trifluoroacetic acids stir 4 hours at room temperature.Reaction solution is depressurized and is steamed Dry, residue is dissolved in 100mL dichloromethane, uses 80mL saturated sodium bicarbonates and 80mL saturated common salt water washings successively, anhydrous Sodium sulphate is dried, and is concentrated under reduced pressure, and is obtained 0.24g tan solids, is cured after static.Yield is 76%.MS m/z：224.

¹H NMR (400MHz, CDCl₃) δ 8.93 (s, 1H), 7.37 (d, J=2.2Hz, 1H), 6.81 (dd, J=8.3, 2.2Hz, 1H), 6.67 (d, J=8.3Hz, 1H), 3.88 (s, 3H), 3.07 (s, 2H), 2.39 (s, 6H).

Step 3：2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- nitre Base phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

2- chloro- 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] are added into 25mL single port bottles Oxazine -7 (8H)-ketone (150mg, 0.45mmol), 2- dimethylaminos-N- (3- methoxyl group -4- amino) acetamide (120mg, 0.54mmol), tris(dibenzylideneacetone) dipalladium (25mg, 0.03mmol), 4,5- bis- diphenylphosphine -9,9- dimethyl oxa-s Anthracene (31mg, 0.054 mmol), under potassium phosphate (190mg, 0.90mmol) and 6mL dioxane nitrogen protections, 100 DEG C were reacted Night.Diatomite drainage, filtrate decompression are evaporated, and are prepared plate separation and (dichloromethane: methanol=10: 1), are obtained 120mg products.It receives Rate is 51%. MS m/z：522.

Step 4：2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- ammonia Base phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 4 of the synthesis of the compound with embodiment 10.Yield is 71%.MS m/z：492.

Step 5：2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- third Acrylamide phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 30%.MS m/z：546.

¹H NMR (400MHz, DMSO-d6) δ 10.45 (s, 1H), 9.83 (s, 1H), 8.18 (s, 1H), 7.81 (d, J= 8.2Hz, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 7.55-7.47 (m, 2H), 7.38 (d, J=2.0Hz, 1H), 7.10 (d, J =8.8Hz, 1H), 6.81 (d, J=8.7Hz, 1H), 6.47 (dd, J=16.9,10.2Hz, 1H), 6.26 (dd, J=16.9, 1.8Hz, 1H), 5.77 (dd, J=10.2,1.8Hz, 1H), 3.77 (s, 3H), 3.35 (s, 2H), 2.44 (s, 6H), 1.58 (s, 6H)。

Embodiment 12：2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- base amine Base] -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy -3- nitropyridines

2- trifluoro ethoxy -3- nitro -6- chloropyridines (256mg, 1mmol) are dissolved in 2mL isopropanols, N, N- diformazans is added Base -2- (methylamino) acetamide (348mg, 3mmol) reacts 1 hour, has solid precipitation, raw material not to disappear in reaction solution at room temperature Consumption finishes, and 0.5mL diisopropyl ethyl amines is added into reaction solution, the reaction was continued 1.5 hours.Filtering, filter cake are washed with isopropanol It washs, obtains 257mg yellow solids.Yield is 76%.MS m/z：337.1.

¹H NMR (400MHz, CDCl₃) δ 8.32 (d, J=9.1Hz, 1H), 6.27 (s, 1H), 4.79 (q, J=7.9Hz, 2H), 4.43 (s, 2H), 3.24 (s, 3H), 3.09 (s, 3H), 3.01 (s, 3H).

Step 2：The synthesis of 6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy -3- amido pyridines

By 6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy -3- nitropyridines (250mg, It 0.74mmol) is suspended in 6mL methanol, 20mg platinum dioxides are added, are passed through hydrogen, is stirred 1 hour at room temperature.Filtering, filtrate subtract Pressure concentration, silica gel post separation (ethyl acetate) obtain 220mg products.Yield is 97%.MS m/z：307.2.

¹H NMR (400MHz, CDCl₃) δ 7.03 (d, J=8.2Hz, 1H), 6.12 (d, J=8.3Hz, 1H), 4.69 (q, J =8.6Hz, 2H), 4.29 (s, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 2.97 (s, 3H).

Step 3：2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] - [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of 6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

To 6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy -3- amidos pyridine (92mg, 0.3mmol), chloro- 6, the 6- dimethyl -8- of 2- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one 2mL dioxane, three (two benzal are added in the mixture of (150mg, 0.45mmol) and potassium phosphate (175mg, 0.825mmol) Benzylacetone) two palladiums (17 mg, 0.018mmol) and 4, bis- diphenylphosphine -9, the 9- xanthphos of 5- (21mg, 0.036mmol), under nitrogen protection, 90 DEG C of reactions are overnight.Diatomite drainage, filtrate decompression are evaporated, and prepare plate separation (dichloromethane Alkane: methanol=20: 1), 85mg product is obtained.Yield is 47%.MS m/z：605.2.

¹H NMR (400MHz, CDCl₃) δ 8.39-8.35 (m, 1H), 8.21 (t, J=2.0Hz, 1H), 8.10 (s, 1H), 7.73 (t, J=8.1Hz, 1H), 7.63 (d, J=8.7Hz, 1H), 7.61-7.55 (m, 1H), 6.77 (s, 1H), 5.80 (d, J =8.5Hz, 1H), 4.65 (q, J=8.6Hz, 2H), 4.28 (s, 2H), 3.07 (s, 3H), 3.06 (s, 3H), 2.98 (s, 3H), 1.68 (s, 6H).

Step 4：2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] - [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of 6,6- dimethyl -8- (3- aminocarbonyl phenyls) -6H- pyrimidines [5,4-b]

The synthesis of the compound is identical as the step 2 of embodiment 12.Yield is 82%.MS m/z：575.2.

Step 5：2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] - 6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 28%.MS m/z：629.3.

¹H NMR (400MHz, CDCl₃) δ 8.64 (s, 1H), 8.03 (s, 1H), 7.65-7.51 (m, 3H), 7.37 (t, J= 8.0 Hz, 1H), 6.94 (d, J=7.7Hz, 1H), 6.87 (s, 1H), 6.34 (d, J=16.8Hz, 1H), 6.17 (dd, J= 16.8,10.2Hz, 1H), 5.81 (d, J=8.6Hz, 1H), 5.63 (d, J=10.2Hz, 1H), 4.56 (q, J=8.6Hz, 2H), 4.25 (s, 2H), 3.06 (s, 3H), 3.00 (s, 3H), 2.97 (s, 3H), 1.63 (s, 6H).

Embodiment 13：2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- bases Amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：N- methyl-N- { 2- [methyl (5- nitro -6- trifluoro ethoxy pyridine -2- bases) amido] ethyl } acetamide Synthesis

Step 1 of the synthesis of the compound with embodiment 12.

Step 2：N- methyl-N- { 2- [methyl (5- amino -6- trifluoro ethoxy pyridine -2- bases) amido] ethyl } acetamide Synthesis

Step 2 of the synthesis of the compound with embodiment 12.

Step 3：2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- base amine Base } -6,6- dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 3 of the synthesis of the compound with embodiment 11.Yield is 58%.MS m/z：619.

Step 4：2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- base amine Base } -6,6- dimethyl -8- (3- aminophenyls) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 2 of the synthesis of the compound with embodiment 12.Yield is 88%.MS m/z：589.

Step 5：2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- base amine Base } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 44%.MS m/z：643.

¹H NMR (400MHz, DMSO-d6) δ 10.41 (s, 1H), 8.08 (d, J=3.6Hz, 2H), 7.75 (t, J= 7.2Hz, 1H), 7.65 (s, 1H), 7.54-7.34 (m, 2H), 7.01 (d, J=7.3Hz, 1H), 6.46 (dd, J=16.9, 10.1Hz, 1H), 6.26 (d, J=16.5Hz, 1H), 5.96-5.89 (m, 1H), 5.77 (d, J=10.1Hz, 1H), 4.91- 4.79 (m, 2H), 3.61 (d, J=6.0Hz, 2H), 3.39 (d, J=6.6Hz, 2H), 2.88 (s, 6H), 1.88 (s, 3H), 1.56 (s, 6H).

Embodiment 14：2- [6- (2- ethoxys methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl - 8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- trifluoro ethoxy -3- nitros -6- (2- ethoxys methylamino) pyridine

To be added in 2- trifluoro ethoxy -3- nitro -6- chloropyridines (456mg, 1.78mmol) 2- methyl aminoethanols (2mL, 25mmol), it reacts 1 hour at room temperature.30mL water is added into reaction solution, yellow solid is precipitated.Filtering, filter cake are washed with water, Drying.Crude product silica gel post separation, obtains 410mg solids.Yield is 79%.MS m/z：296.1.

¹H NMR (400MHz, CDCl₃) δ 8.30 (d, J=9.1Hz, 1H), 6.25 (d, J=9.1Hz, 1H), 4.85 (q, J =8.3Hz, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.25 (s, 3H).

Step 2：The synthesis of 2- trifluoro ethoxy -3- amidos -6- (2- ethoxys methylamino) pyridine

The synthesis of the compound is identical as the step 4 of embodiment 10.Yield is 96%.MS m/z：266.3.

¹H NMR (400MHz, CDCl₃) δ 7.00 (d, J=8.3Hz, 1H), 6.08 (d, J=8.3Hz, 1H), 4.72 (q, J =8.6Hz, 2H), 3.81 (t, J=5.4Hz, 2H), 3.61 (t, J=5.4Hz, 2H), 2.99 (s, 3H).

Step 3：2- [6- (2- ethoxys methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b]

The synthesis of the compound is identical as the step 3 of embodiment 11.Yield is 11%.MS m/z：588.3.

¹H NMR (400MHz, CDCl₃) δ 8.05 (d, J=6.9Hz, 1H), 7.92 (d, J=7.7Hz, 1H), 7.87 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 7.49 (t, J=8.1Hz, 1H), 7.27 (s, 1H), 7.00 (d, J=8.4Hz, 2H), 6.42 (d, J=16.8Hz, 1H), 6.24-6.15 (m, 1H), 5.88-5.71 (m, 2H), 4.67 (q, J=8.6Hz, 2H), 3.75 (t, J=6.0Hz, 2H), 3.54 (t, J=6.0Hz, 2H), 3.51 (s, 1H), 3.01 (d, J=8.5Hz, 3H), 1.65 (s, 6H).

Embodiment 15：2- [6- (4- dimethylamino piperidine -1- bases) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- bis- Methyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- trifluoro ethoxy -3- nitros -6- (4- dimethylamino piperidine -1- bases) pyridine

2- trifluoro ethoxy -3- nitro -6- chloropyridines (256mg, 1mmol) are dissolved in 2mL dichloromethane, and 4- diformazan ammonia is added Phenylpiperidines (140mg, 1.1mmol) react 2 hours at room temperature, and raw material unreacted is complete, adds 4- dimethylamino piperidines (0.5 ML, 3.55mmol) it reacts 10 minutes at room temperature.30mL water, the extraction of 100mL ethyl acetate are added into reaction solution.Organic layer is used Water washing twice, filter, and evaporated under reduced pressure obtains 298mg products by anhydrous sodium sulfate drying.Yield is 86%.

¹H NMR (400MHz, DMSO) δ 8.23 (d, J=9.3Hz, 1H), 6.65 (d, J=9.3Hz, 1H), 5.09 (q, J =9.0Hz, 2H), 4.47 (br s, 2H), 3.07 (t, J=12.0Hz, 2H), 2.63 (br s, 1H), 2.28 (s, 6H), 1.91 (d, J=12.2Hz, 2H), 1.42 (qd, J=12.3,3.6Hz, 2H).

MS m/z：349.2.

Step 2：The synthesis of 2- trifluoro ethoxy -3- amino -6- (4- dimethylamino piperidine -1- bases) pyridine

The synthesis of the compound is identical as the step 4 of embodiment 10.Yield is 74%.

Step 3：2- [6- (4- dimethylamino piperidine -1- bases) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

The synthesis of the compound is identical as the step 3 of embodiment 11.

¹H NMR (400MHz, CDCl₃) δ 9.05 (s, 1H), 8.06 (s, 1H), 7.88-7.78 (m, 2H), 7.69 (d, J= 8.6 Hz, 1H), 7.47 (t, J=7.9Hz, 1H), 7.00 (d, J=11.3Hz, 2H), 6.49 (dd, J=16.8,9.6Hz, 1H), 6.41 (d, J=16.6Hz, 1H), 5.96 (d, J=8.7Hz, 1H), 5.74 (d, J=9.7Hz, 1H), 4.69 (q, J= 8.5Hz, 2H), 4.25 (d, J=12.7Hz, 2H), 3.23-3.17 (m, 1H), 2.79-2.64 (m, 8H), 2.17 (d, J= 11.0Hz, 2H), 1.78- 1.58 (m, 8H).

Embodiment 16：2- [2- trifluoro ethoxies -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- bis- Methyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (dimethylamino)-N- (5- nitro -6- trifluoro ethoxy pyridine -2- bases) acetamide

Step 3 of the synthesis of the compound with embodiment 11.Yield is 72%.MS m/z：323.

¹H NMR (400MHz, CDCl₃) δ 9.76 (s, 1H), 8.48 (d, J=8.8Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 4.90 (q, J=8.2Hz, 2H), 3.17 (s, 2H), 2.44 (s, 6H).

Step 2：The synthesis of 2- (dimethylamino)-N- (5- amino -6- trifluoro ethoxy pyridine -2- bases) acetamide

Step 2 of the synthesis of the compound with embodiment 12.Yield is 88%.MS m/z：293.

Step 3：2- [2- trifluoro ethoxies -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- diformazans Base -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 3 of the synthesis of the compound with embodiment 11.Yield is 46%.MS m/z：615.

¹H NMR (400MHz, CDCl₃) δ 9.23 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.84 (d, J=8.6Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.26 (s, 1H), 7.02 (d, J=7.4Hz, 1H), 6.38 (dd, J=16.9,1.3Hz, 1H), 6.26 (dd, J=16.9, 10.1Hz, 1H), 5.71 (dd, J=10.1,1.3Hz, 1H), 4.75 (q, J=8.4Hz, 2H), 3.13 (s, 2H), 2.42 (s, 6H), 1.68 (s, 6H).

Embodiment 17：2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6, 6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- methoxyl group -3- nitros -6- (2- dimethylamino -2- oxoethyls methylamino) pyridine

Step 1 of the synthesis of the compound with embodiment 12.Yield is 62%.MS m/z：291.1.

¹H NMR (400MHz, CDCl₃) δ 8.30 (d, J=9.1Hz, 1H), 6.18 (s, 1H), 4.49 (s, 2H), 4.00 (s, 3H), 3.25 (s, 3H), 3.09 (s, 3H), 3.01 (s, 3H).

Step 2：The synthesis of 2- methoxyl group -3- amidos -6- (2- dimethylamino -2- oxoethyls methylamino) pyridine

Step 2 of the synthesis of the compound with embodiment 12.Yield is 90%.

Step 3：2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6,6- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of dimethyl -8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

Step 3 of the synthesis of the compound with embodiment 11.Yield is 38%.MS m/z：537.2.

Step 4：2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6,6- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of dimethyl -8- (3- aminocarbonyl phenyls) -6H- pyrimidines [5,4-b]

Step 2 of the synthesis of the compound with embodiment 12.Yield is 87%.

Step 5：2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6,6- Dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 19%.MS m/z：561.2.

¹H NMR (400MHz, CDCl₃) δ 8.38 (s, 1H), 8.02 (s, 1H), 7.69 (d, J=7.9Hz, 1H), 7.54 (d, J=9.0Hz, 2H), 7.43 (t, J=8.0Hz, 1H), 7.01-6.91 (m, 2H), 6.39 (d, J=16.7Hz, 1H), 6.24 (dd, J=16.9,10.1Hz, 1H), 5.74 (d, J=8.5Hz, 1H), 5.69 (d, J=10.1Hz, 1H), 4.33 (s, 2H), 3.79 (s, 3H), 3.07 (s, 3H), 3.01 (s, 3H), 2.98 (s, 3H), 1.64 (s, 6H).

Embodiment 18：2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl - 8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (dimethylamino)-N- (5- nitro -6- methoxypyridine -2- bases) acetamide

Step 3 of the synthesis of the compound with embodiment 11.Yield is 49%.MS m/z：255.

¹H NMR (400MHz, CDCl₃) δ 9.72 (s, 1H), 8.43 (d, J=8.8Hz, 1H), 7.95 (d, J=8.8Hz, 1H), 4.11 (s, 3H), 3.17 (s, 2H), 2.44 (s, 6H).

Step 2：The synthesis of 2- (dimethylamino)-N- (5- amino -6- methoxypyridine -2- bases) acetamide

Step 2 of the synthesis of the compound with embodiment 12.Yield is 99%.MS m/z：225.

Step 3：2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

Step 3 of the synthesis of the compound with embodiment 11.Yield is 43%.MS m/z：523.

Step 4：2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- aminophenyls) -6H- pyrimidines [5,4-b]

Step 2 of the synthesis of the compound with embodiment 12.Yield is 71%.MS m/z：493.

Step 5：2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- acrylamides phenyl) -6H- pyrimidines [5,4-b]

Step 5 of the synthesis of the compound with embodiment 10.Yield is 54%.MS m/z：547.

¹H NMR (400MHz, CDCl₃) δ 9.20 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.76 (d, J=8.3Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.37-7.32 (m, 3H), 7.03 (d, J=7.5Hz, 1H), 6.38 (dd, J=16.9,1.3Hz, 1H), 6.27 (dd, J=16.9,10.0Hz, 1H), 5.71 (dd, J=10.0,1.3Hz, 1H), 3.93 (s, 3H), 3.15 (s, 2H), 2.43 (s, 6H), 1.67 (s, 6H).

Embodiment 19：2- [2- methoxyl groups -6- (4- dimethylamino piperidine -1- bases) pyridin-3-yl amido] -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- methoxyl group -3- nitros -6- (4- dimethylamino piperidine -1- bases) pyridine

2- methoxyl group -3- nitro -6- chloropyridines (376mg, 2mmol) are dissolved in 4mL isopropanols, and 4- dimethylamino piperidines are added (0.56mL, 4mmol) reacts 4 hours, there is solid precipitation in reaction solution at room temperature.Filtering, filter cake are eluted with isopropanol, are dried It is dry, obtain 300mg products.Yield is 54%.MS m/z：281.4.

Step 2：The synthesis of 2- methoxyl group -3- amino -6- (4- dimethylamino piperidine -1- bases) pyridine

Step 2 of the synthesis of the compound with embodiment 12.Yield is 75%.MS m/z：251.2.

Step 3：2- [2- methoxyl groups -6- (4- dimethylamino piperidine -1- bases) pyridin-3-yl amido] -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b]

Step 3 of the synthesis of the compound with embodiment 11.Yield is 9%.MS m/z：573.4.

¹H NMR (400MHz, CDCl₃) δ 8.47 (s, 1H), 8.05 (s, 1H), 7.90-7.80 (m, 1H), 7.72-7.59 (m, 2H), 7.48 (t, J=8.0Hz, 1H), 7.10 (s, 1H), 7.01 (d, J=7.7Hz, 1H), 6.42 (d, J=16.6Hz, 1H), 6.31 (dd, J=16.6,10.0Hz, 1H), 5.86 (d, J=8.4Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 4.22 (d, J=12.8Hz, 2H), 3.88 (s, 3H), 2.82-2.75 (m, 1H), 2.71-2.62 (m, 2H), 2.50 (s, 6H), 2.00 (d, J=11.8Hz, 2H), 1.69-1.53 (m, 8H).

Embodiment 20：2- { 2- methoxyl groups -6- [4- Acetylpiperazine -1- bases] pyridin-3-yl amido } -6,6- dimethyl - 8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (4- Acetylpiperazine -1- bases) -5- nitro -6- methoxypyridines

Step 1 of the synthesis of the compound with embodiment 12.

Step 2：The synthesis of 2- (4- Acetylpiperazine -1- bases) -5- amido -6- methoxypyridines

Step 2 of the synthesis of the compound with embodiment 12.

Step 3：2- { 2- methoxyl groups -6- [4- Acetylpiperazine -1- bases] pyridin-3-yl amido } -6,6- dimethyl -8- [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b]

Step 3 of the synthesis of the compound with embodiment 11.Yield is 22%.MS m/z：573.

¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.71 (d, J=6.6Hz, 1H), 7.53-7.46 (m, 2H), 7.17 (s, 1H), 7.02 (d, J=7.9Hz, 1H), 6.42 (dd, J=16.9, 1.2Hz, 1H), 6.19 (dd, J=16.9,10.2Hz, 1H), 5.86 (d, J=8.6Hz, 1H), 5.76 (dd, J=10.2, 1.2Hz, 1H), 3.90 (s, 3H), 3.75-3.69 (m, 2H), 3.60-3.54 (m, 2H), 3.45-3.39 (m, 2H), 3.37- 3.31 (m, 2H), 2.15 (s, 3H), 1.65 (s, 6H).

Embodiment 21：2- { 2- methoxyl groups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } - 6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 6- methoxy-. N-methyl -5- nitros-N- [2- (pyrrolidin-1-yl) ethyl]-pyridine -2- amine

Step 1 of the synthesis of the compound with embodiment 12.

Step 2：6- methoxyl groups-H²Methyl H²The synthesis of [2- (pyrrolidin-1-yl) ethyl] pyridine -2,5- diamines

Step 2 of the synthesis of the compound with embodiment 12.

Step 3：2- { 2- methoxyl groups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } -6, 6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

¹H NMR (400MHz, CDCl₃) δ 9.85 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=8.2Hz, 1H), 7.54 (d, J=8.5Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.19 (s, 1H), 6.94 (d, J=7.7Hz, 1H), 6.67 (dd, J=16.9,10.2Hz, 1H), 6.39 (dd, J=16.9,1.5Hz, 1H), 5.89 (d, J=8.6Hz, 1H), 5.66 (dd, J=10.2,1.5Hz, 1H), 3.86 (s, 5H), 3.80 (br s, 2H), 3.21 (t, J=6.6Hz, 2H), 3.01 (s, 3H), 2.84 (br s, 2H), 2.21 (br s, 2H), 2.09 (br s, 2H), 1.63 (s, 6H).

Embodiment 22：2- { 2- methoxyl groups -6- [4- methylpiperazine-1-yls] pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (4- methylpiperazine-1-yls) -5- nitro -6- methoxypyridines

Step 1 of the synthesis of the compound with embodiment 12.

Step 2：The synthesis of 2- (4- methylpiperazine-1-yls) -5- amido -6- methoxypyridines

Step 2 of the synthesis of the compound with embodiment 12.

Step 3：2- { 2- methoxyl groups -6- [4- methylpiperazine-1-yls] pyridin-3-yl amido } -6,6- dimethyl -8- (3- Acrylamido phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 3 of the synthesis of the compound with embodiment 11.Yield is 26%.MS m/z：545.

¹H NMR (400MHz, CDCl₃) δ 8.27 (s, 1H), 8.03 (s, 1H), 7.82 (d, J=8.5Hz, 1H), 7.73- 7.56 (m, 2H), 7.46 (t, J=8.1Hz, 1H), 7.10 (s, 1H), 6.99 (d, J=7.9Hz, 1H), 6.44-6.25 (m, 2H), 5.85 (d, J=8.6Hz, 1H), 5.72 (dd, J=9.7,1.8Hz, 1H), 3.86 (s, 3H), 3.57 (br s, 4H), 2.83 (br s, 4H), 2.54 (s, 3H), 1.62 (s, 6H).

Embodiment 23：2- { 2- methoxyl groups -6- [1- (2- fluoro ethyls) azetidine -3- amidos] pyridin-3-yl amido } - 6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (N- tertbutyloxycarbonyl azetidin ring -3- amidos) -5- nitro -6- methoxypyridines

2- methoxyl group -3- nitro -6- chloropyridines (1.32g, 7.02mmol) are dissolved in 1mL dimethyl sulfoxides, 3- amino-is added 1- tertbutyloxycarbonyls azetidine (2.4g, 13.95mmol) and diisopropyl ethyl amine (2.5mL, 14.34mmol), 100 DEG C reaction 2 hours, be cooled to room temperature.50mL water, the extraction of 50mL ethyl acetate is added.Organic layer is washed with water, anhydrous slufuric acid Sodium is dried, and filtering, filtrate decompression is evaporated.Crude product (dichloromethane: ethyl acetate=100: 0-5: 1), is obtained with silica gel post separation To 2.2g products.Yield is 97%.

¹H NMR (400MHz, CDCl₃) δ 8.24 (d, J=8.9Hz, 1H), 6.07 (d, J=8.9Hz, 1H), 6.03 (d, J =5.3Hz, 1H), 4.68 (t, J=10.0Hz, 1H), 4.38-4.30 (m, 2H), 4.04 (s, 3H), 3.90 (dd, J=9.3, 5.1Hz, 2H), 1.46 (s, 9H).

Step 2：The synthesis of two (trifluoroacetic acid) salt of 2- (azetidin ring -3- amidos) -5- nitro -6- methoxypyridines

By 2- (N- tertbutyloxycarbonyl azetidin ring -3- amidos) -5- nitro -6- methoxypyridines (2.2g, 6.8mmol) It is dissolved in 20mL dichloromethane, 10mL trifluoroacetic acids react 1 hour at room temperature.It removes solvent under reduced pressure, is added into residue suitable Toluene is measured, evaporated under reduced pressure, obtains yellow crude again, is directly used in and reacts in next step.MS m/z：225.2.

Step 3：The synthesis of 2- [N- (2- fluoro ethyls) azetidin ring -3- amidos] -5- nitro -6- methoxypyridines

To two (trifluoroacetic acid) salt of 2- (azetidin ring -3- amidos) -5- nitro -6- methoxypyridines (400mg, Addition 10mL acetonitriles in 1.883mmol), cesium carbonate (860mg, 2.65mmol), the bromo- 1- fluoroethanes of 2- (59 μ L, 0.795mmol), 50 DEG C of reactions are stayed overnight.10mL water, the extraction of 20mL ethyl acetate are added into reaction solution.Organic layer is washed with water Twice, anhydrous sodium sulfate is dried, and filtering, filtrate decompression is evaporated, and is prepared plate separation and (ethyl acetate: methanol=20: 1), is obtained 40mg products.Yield is 8%.MS m/z：271.1.

Step 4：The synthesis of 2- [N- (2- fluoro ethyls) azetidin ring -3- amidos] -5- amino -6- methoxypyridines

The synthesis of the compound is identical as the step 2 of embodiment 12.Yield is 100%.

Step 5：2- { 2- methoxyl groups -6- [1- (2- fluoro ethyls) azetidine -3- amidos] pyridin-3-yl amido } -6, 6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 3 of the synthesis of the compound with embodiment 11.Yield is 11%.MS m/z：563.3.

¹H NMR (400MHz, CDCl₃) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.68 (d, J=7.9Hz, 1H), 7.56 (d, J=8.2Hz, 1H), 7.45 (t, J=8.0Hz, 1H), 7.00 (d, J=6.4Hz, 2H), 6.41 (d, J= 2.8Hz, 1H), 5.74 (dd, J=8.9,2.6Hz, 1H), 5.66 (d, J=8.4Hz, 1H), 4.73-4.68 (m, 1H), 4.62- 4.57 (m, 1H), 4.57-4.48 (m, 1H), 4.12 (t, J=7.6Hz, 2H), 3.82 (s, 3H), 3.48-3.44 (m, 2H), 3.15-3.13 (m, 1H), 3.08-3.06 (m, 1H), 1.65 (s, 6H).

Embodiment 24：(R) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amido second Base] methylamino } -2- methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) - Ketone

The synthetic method of the compound is the same as embodiment 1.

¹H NMR (400MHz, CDCl₃) δ 7.99 (d, J=4.8Hz, 1H), 6.82 (d, J=3.8Hz, 1H), 6.58-6.41 (m, 1H), 6.40-6.34 (m, 1H), 5.99 (d, J=8.4Hz, 1H), 5.77-5.59 (m, 2H), 4.71-4.47 (m, 1H), 4.59-5.56 (m, 1H), 4.19 (t, J=9.2Hz, 1H), 3.97-3.91 (m, 5H), 3.77 (d, J=8.6Hz, 2H), 3.65 (dd, J=17.8,8.3Hz, 1H), 3.53 (dd, J=18.8,10.6Hz, 1H), 3.01 (d, J=7.2Hz, 3H), 2.97- 2.93 (m, 1H), 2.92-2.86 (m, 1H), 2.84-2.75 (m, 2H), 2.52 (d, J=7.9Hz, 3H), 2.28-2.14 (m, 1H), 2.11- 2.00 (m, 1H), 1.53-1.50 (m, 6H).

Embodiment 25：(S) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amido second Base] methylamino } -2- methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) - Ketone

The synthetic method of the compound is the same as embodiment 1.

¹H NMR (400MHz, CDCl3) δ 7.99 (d, J=4.9Hz, 1H), 6.81 (d, J=5.3Hz, 1H), 6.57- 6.42 (m, 1H), 6.40-6.34 (m, 1H), 5.99 (d, J=8.5Hz, 1H), 5.78-5.60 (m, 2H), 4.68-4.63 (m, 1H), 4.57-4.51 (m, 1H), 4.20 (t, J=9.2Hz, 1H), 4.02-3.87 (m, 5H), 3.79-3.73 (m, 2H), 3.70-3.62 (m, 1H), 3.58-3.50 (m, 1H), 3.03 (d, J=6.9Hz, 3H), 2.97-2.70 (m, 4H), 2.52- 2.44 (m, 3H), 2.27-2.22 (m, 1H), 2.12-2.03 (m, 1H), 1.56-1.49 (m, 6H).

Embodiment 26：2- { 2- isopropyl oxygroups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amine Base } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

The synthetic method of the compound is the same as embodiment 21.

¹H NMR (400MHz, CDCl₃) δ 9.86 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.60 (d, J=8.4Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 7.15 (s, 1H), 6.98 (d, J=7.3Hz, 1H), 6.55 (dd, J=16.8,10.0Hz, 1H), 6.41 (d, J=16.7Hz, 1H), 5.78 (d, J=7.6Hz, 1H), 5.69 (d, J =10.0Hz, 1H), 5.26-5.20 (m, 1H), 3.80 (t, J=6.5Hz, 2H), 3.27 (br s, 4H), 3.18 (t, J= 6.9Hz, 2H), 2.99 (s, 3H), 2.12-2.10 (m, 4H), 1.66 (s, 6H), 1.32 (s, 3H), 1.31 (s, 3H).

Embodiment 27：2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- diformazans Base -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The synthesis of 2- (dimethylamino)-N- methyl-N- (3- methoxyl group -4- nitrobenzophenones) acetamide

N- methyl -3- methoxyl group -4- nitroanilines (600mg, 3.3mmol) and 25mLN are added into 100mL single port bottles, Dinethylformamide, ice-water bath are cooled to 5 DEG C, and 60% sodium hydrogen (1.32g, 33mmol) is added, and stirring after ten minutes, adds Enter 2- dimethylaminoacetyl chlorides (1.2g, 9.9mmol), continues stirring 2 hours.150mL ethyl acetate is added into reaction solution, It is washed successively with water (120mL × 2), saturated nacl aqueous solution (120mL), anhydrous sodium sulfate drying is concentrated under reduced pressure, silicagel column Separation (dichloromethane: methanol=10: 1), obtains 220mg products, yield 25%.MS m/z：268.

Step 2：The synthesis of 2- (dimethylamino)-N- methyl-N- (3- methoxyl group -4- aminophenyls) acetamide

Step 2 of the synthesis of the compound with embodiment 12.Yield is 92%.MS m/z：238.

Step 3：2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- dimethyl - [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of 8- (3- nitrobenzophenones) -6H- pyrimidines [5,4-b]

Step 3 of the synthesis of the compound with embodiment 11.Yield is 74%.MS m/z：536.

Step 4：2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- dimethyl - [the synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one of 8- (3- aminophenyls) -6H- pyrimidines [5,4-b]

Step 2 of the synthesis of the compound with embodiment 12.Yield is 79%.MS m/z：506.

Step 5：2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- dimethyl - 8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 34%.MS m/z：560.

¹H NMR (400MHz, DMSO-d6) δ 10.58 (s, 1H), 8.23 (s, 1H), 7.85-7.79 (m, 2H), 7.74 (s, 1H), 7.63 (d, J=8.5Hz, 1H), 7.53 (t, J=8.0Hz, 1H), 7.12-7.08 (m, 1H), 6.97 (s, 1H), 6.50 (dd, J=17.0,10.1Hz, 2H), 6.25 (dt, J=4.4,2.6Hz, 1H), 5.76 (dd, J=10.1,2.0Hz, 1H), 3.84 (s, 3H), 3.41 (s, 2H), 3.13 (s, 3H), 2.49 (s, 6H), 1.60 (s, 6H).

Embodiment 28：2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- Acrylamide phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 1：The conjunction of 3- dimethylamino-N- [3- methoxyl groups -4- (the bis- tert-butoxycarbonylaminos of N, N-) phenyl] propionamide At

Step 1 of the synthesis of the compound with embodiment 11.Yield is 29%.MS m/z：438.

Step 2：The synthesis of 3- dimethylamino-N- (3- methoxyl group -4- aminophenyls) propionamide

Step 2 of the synthesis of the compound with embodiment 11.Yield is 86%.MS m/z：238.

Step 3：2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- nitre Base phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 3 of the synthesis of the compound with embodiment 11.Yield is 51%.MS m/z：536.

Step 4：2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- ammonia Base phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5：2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- third Acrylamide phenyl) -6H- pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazines -7 (8H) -one

Step 5 of the synthesis of the compound with embodiment 10.Yield is 24%.MS m/z：560.

¹H NMR (400MHz, CDCl₃) δ 9.82 (s, 1H), 9.26 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.61 (d, J=7.6Hz, 1H), 7.46-7.45 (m, 2H), 7.42-7.37 (m, 2H), 6.94 (d, J=7.1Hz, 1H), 6.59 (d, J =7.5Hz, 1H), 6.49 (dd, J=16.9,10.1Hz, 1H), 6.34 (d, J=16.7Hz, 1H), 5.63 (d, J= 11.0Hz, 1H), 3.74 (s, 3H), 3.30 (t, J=6.2Hz, 2H), 2.95 (d, J=6.2Hz, 2H), 2.73 (s, 6H), 1.62 (s, 6H).

Embodiment 29：(R) -2- [2- methoxyl groups -6- (3- dimethylamino pyrrolidin-1-yl) pyridin-3-yl amido] -6,6- Dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one

The synthesis of the compound is the same as embodiment 19.

¹H NMR (400MHz, CDCl₃) δ 8.74 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.54 (d, J=7.4Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 6.96 (d, J=4.0Hz, 2H), 6.45-6.35 (m, 2H), 5.69 (dd, J=8.1,3.6Hz, 1H), 5.55 (d, J=8.5Hz, 1H), 3.84 (s, 3H), 3.68-3.61 (m, 3H), 3.51-3.45 (m, 1H), 3.39-3.32 (m, 1H), 2.63 (s, 6H), 2.34-2.19 (m, 2H), 1.62 (s, 6H).

II. the compounds of this invention active testing embodiment

Testing example 1：The compounds of this invention is to application on human skin cancer cell (A431, Wild type EGFR), human lung carcinoma cell (HCC827, EGFR19 exon deletion form activated mutant), human lung carcinoma cell (H1975, EGFR L858R/T790M drug resistances Type is mutated) inhibited proliferation

Taking the cell inoculation in exponential phase, (cell concentration is 5000/hole in 96 orifice plates；180 μ of cell suspension The holes l/), 37 DEG C, 5%CO₂Culture keeps cell adherent in 24 hours.Each compound is dissolved in DMSO and is configured to 10mM's in advance Storing liquid is diluted to 10 times of purpose concentration when detection with complete medium in another 96 orifice plate again, then thin in inoculation 20 holes μ l/ of compound are added in 96 orifice plates of born of the same parents, that is, reach purpose concentration.Each concentration sets 3 multiple holes, and sets blank control. Continue in 37 DEG C, 5%CO₂In continue culture 72 hours.Culture is terminated, 50% 3 chloroethene of 50 μ l precoolings (4 DEG C) is added per hole Acid is TCA (final concentration 10%), is placed on 4 DEG C and fixes 1 hour, with purifying water washing at least 5 times, spontaneously dried in air or 60 DEG C of oven dryings.100 μ are added per hole by Sulforhodamine B, that is, SRB that 4mg/ml is prepared with the purified water containing 1% glacial acetic acid L, room temperature dye 1H, abandon supernatant, and at least 5 times removing non-specific bindings, dried for standby are washed with 1% glacial acetic acid.It is added per hole The Tris-HCl solution of the 10mM of 150 μ l dissolves, and OD values are surveyed at 510nm wavelength, and carries out data preparation and calculate inhibiting rate. It the results are shown in Table 1：

Table 1

	HCC827	H1975	A431
				1 compound of embodiment	A	A	B
2 compound of embodiment	A	A	D
				3 compound of embodiment	A	C	D
4 compound of embodiment	A	A	D
				5 compound of embodiment	A	A	C
6 compound of embodiment	A	A	C
				7 compound of embodiment	B	C	D
8 compound of embodiment	A	A	B
				9 compound of embodiment	A	B	B

10 compound of embodiment	A	A	D
				11 compound of embodiment	A	A	C
12 compound of embodiment	A	B	D
				13 compound of embodiment	A	A	D
14 compound of embodiment	A	A	D
				15 compound of embodiment	A	A	D
16 compound of embodiment	A	C	D
				17 compound of embodiment	A	C	D
18 compound of embodiment	A	C	D
				19 compound of embodiment	A	A	C
20 compound of embodiment	A	A	D
				21 compound of embodiment	A	A	C
22 compound of embodiment	A	A	C
				23 compound of embodiment	A	B	D
24 compound of embodiment	B	C	D
				25 compound of embodiment	B	C	D
26 compound of embodiment	B	C	D
				27 compound of embodiment	A	B	D
28 compound of embodiment	B	B	D
				29 compound of embodiment	A	B	D

A indicates that IC50 is 1-100nM；B indicates that IC50 is 100-500nM；

C indicates that IC50 is 500-1000nM；D indicates that IC50 is 1000-10000nM

Test result shows：To human lung carcinoma cell, (HCC827, EGFR19 exon deletion form activate the compounds of this invention Mutation), human lung carcinoma cell (mutation of H1975, EGFR L858R/T790M drug-resistant types) with good inhibited proliferation, it is right The increment inhibiting effect of application on human skin cancer cell (A431, Wild type EGFR) is relatively weak, and selectivity is good.

Referenced herein all documents are incorporated by reference in the application.Additionally it is noted that, readding After having read the above disclosure of the application, those skilled in the art may not need away from the spirit and scope of the present invention, right The present invention makes various modifications, change or modification, but these versions equally should all fall within the application the appended claims Recorded range.

Claims

1. a kind of compound of formula I or its pharmaceutically acceptable salt,

In formula：

Ring A is phenyl or pyrrolidinyl；

Ring B is phenyl or pyridyl group；

R₁、R₂It is each independently selected from C₁-C₄Alkyl；

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is C₁-C₄Alkyl ,-OR₇、-OR₆、-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 It is a to be selected from R₇Heterocyclylalkyl, the-O (CH of substituent group substitution₂)_qSO₂R₇It is unsubstituted or by 1~3 be selected from C₁-C₄It is alkyl, halogenated C₁-C₄Alkyl ,-N (CH₃)₂、-OR₇Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

R₄ForWherein work as R₄ForWhen, amide nitrogen atom is as miscellaneous Atom directly participation forms ring A and obtains pyrrolidinyl；

R₆For-(CH₂)_qOR₇、-(CH₂)_qNR₇R₇' or-(CH₂)_qNR₇C(O)R₇；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' together be connected nitrogen-atoms Cyclization forms azete and stings base, pyrrolidinyl or piperidyl；

The integer that m is 0~3；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4；

Wherein, the Heterocyclylalkyl is 4~7 unit monocycle groups, the ring hetero atom for being selected from O, S, N containing 1 to 4.

2. compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that the compound is formula (Ia) compound,

Wherein, ring B is phenyl or pyridyl group；

R₁、R₂It is each independently selected from C₁-C₄Alkyl；

Each R₃It independently is halogen or C₁-C₄Alkyl；

R₄For

M is 0；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4；

Wherein, the Heterocyclylalkyl is that azete stings base, oxetanyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl.

3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that the R₄ForWherein, R₇For hydrogen or C₁-C₄Alkyl.

4. compound as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that each R₅Independently be- OR₇、-OR₆、-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or by 1~2 be selected from R₇The azetidine of substituent group substitution Base ,-O (CH₂)_qSO₂R₇It is unsubstituted or by 1~3 be selected from C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,-N (CH₃)₂、-OR₇Or-C (O)R₇Substituent group substitution piperazinyl, piperidyl or pyrrolidinyl；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' together be connected nitrogen-atoms Cyclization forms piperidyl or pyrrolidinyl；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4.

5. compound as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that the compound is formula (Ia-1) compound,

Wherein, R₁、R₂It is each independently selected from C₁-C₄Alkyl；

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is-OR₇、-OR₆、-NR₇(CH₂)_PC(O)R₆、-NR₆R₇It is unsubstituted or by 1~3 be selected from C₁-C₄Alkane Base, halogenated C₁-C₄Alkyl ,-N (CH₃)₂、-OR₇Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

R₄For

M is 0；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4；

6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, it is characterised in that each R₅Independently be- OR₇、-OR₆、-NR₇(CH₂)_PC(O)R₆Or-NR₆R₇It is unsubstituted or by 1 be selected from C₁-C₄Alkyl or-C (O) R₇Substituent group take The piperazinyl in generation；

Wherein, R₆For-(CH₂)_qNR₇R₇′；

R₇And R₇' it is separately hydrogen or C₁-C₄Alkyl；

The integer that n is 1~2；

The integer that q is 0~2；

The integer that p is 0~2.

7. compound as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that the compound is formula (Ia-2) compound,

Wherein, R₁、R₂It is each independently selected from C₁-C₄Alkyl；

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is-OR₇、-OR₆、-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇It is unsubstituted or taken selected from R7 by 1~2 Heterocyclylalkyl ,-O (CH for base substitution₂)_qSO₂R₇It is unsubstituted or by 1~3 be selected from C₁-C₄Alkyl, halogenated C₁-C₄Alkyl ,- N(CH₃)₂、-OR₇Or-C (O) R₇Substituent group substitution Heterocyclylalkyl；

R₄For

M is 0；

The integer that n is 1~3；

The integer that q is 0~4；

The integer that p is 0~4；

8. compound as claimed in claim 7 or its pharmaceutically acceptable salt, it is characterised in that each R₅Independently be- OR₇、-NR₇(CH₂)_PC(O)R₆、-NR₆R₇、-NR₇By 1 halogenated C₁-C₄Alkyl-substituted azete piperidinyl ,-O (CH₂)_qSO₂R₇, or It is selected from C by 1₁-C₄Alkyl ,-N (CH₃)₂Or-C (O) R₇Substituent group substitution piperazinyl, piperidyl or pyrrolidinyl；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl or R₇、R₇' together be connected nitrogen-atoms Cyclization forms pyrrolidinyl；

The integer that n is 1~2；

The integer that q is 0~3；

The integer that p is 0~3.

9. compound as described in claim 5 or 7 or its pharmaceutically acceptable salt, it is characterised in that the R₄ForWherein, R₇For hydrogen.

10. compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that the compound is formula (Ib-1) compound,

Wherein, R₁、R₂It is each independently selected from C₁-C₄Alkyl；

Each R₃It independently is halogen or C₁-C₄Alkyl；

Each R₅It independently is-OR₇Or-NR₆R₇；

Wherein, R₆For-(CH₂)_qNR₇R₇′；

R₇And R₇' it is separately hydrogen, C₁-C₄Alkyl or halogenated C₁-C₄Alkyl；

M is 0；

The integer that n is 1~2；

The integer that q is 0~2.

11. compound or its pharmaceutically acceptable salt, it is selected from：

2- [4- (4- methylpiperazine-1-yls) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) - 6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- methylpiperazine-1-yls) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [4- (4- Acetylpiperazine -1- bases) -2- methoxybenzenes amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) - 6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- Acetylpiperazine -1- bases) -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- third Acrylamide base phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- { [2- (dimethyl amido) ethyl] (methyl) amino } -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amido } - 6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- (4- methylpiperazine-1-yls) -2- [3- (methyl sulphonyl) propoxyl group] pyridin-3-yl amido } -6,6- dimethyl - 8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [- 7 (8H) -one of Isosorbide-5-Nitrae] Bing oxazines；

2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- (2,2,2- trifluoro ethoxy) pyridin-3-yl amine Base } -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- methoxypyridine -3- bases amido } -6,6- diformazans Base -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino) ethyoxyl] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamido benzene Base) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino) acetamido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamido benzene Base) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (2- dimethylamino -2- oxoethyls methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl - 8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 6- [(2- (N- methyl vinyls amido) ethyl dimethylamine base)] -2- trifluoro ethoxy pyridine -3- bases amido } -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (2- ethoxys methylamino) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl -8- (3- acrylamides Base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [6- (4- dimethylamino piperidine -1- bases) -2- trifluoro ethoxy pyridine -3- bases amido] -6,6- dimethyl -8- (3- third Acrylamide base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- trifluoro ethoxies -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- (3- propylene Amide phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (2- dimethylamino -2- oxoethyls methylamino) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acrylamides phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (2- dimethylaminoacetyls amido) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acrylamides Phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- [2- methoxyl groups -6- (4- dimethylamino piperidine -1- bases) pyridin-3-yl amido] -6,6- dimethyl -8- (3- acryloyls Aminocarbonyl phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [4- Acetylpiperazine -1- bases] pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamides Base phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [4- methylpiperazine-1-yls] pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamidos Phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- methoxyl groups -6- [1- (2- fluoro ethyls) azetidine -3- amidos] pyridin-3-yl amido } -6,6- dimethyl -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(R) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- Methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(S) -8- (1- acryloyl groups pyrrolidin-3-yl) 2- { 6- { [2- (2- fluoro ethyls) (methyl) amidos ethyl] methylamino } -2- Methoxypyridine -3- bases amido } -6,6- dimethyl -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 2- isopropyl oxygroups -6- { methyl [2- (pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido } -6,6- diformazans Base -8- (3- acrylamidos phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [2- (dimethylamino)-N- methyl vinyls amido] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acryloyls Amine phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

2- { 4- [3- (dimethylamino) propionamido-] -2- methoxybenzenes amido } -6,6- dimethyl -8- (3- acrylamide benzene Base) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one；

(R) -2- [2- methoxyl groups -6- (3- dimethylamino pyrrolidin-1-yl) pyridin-3-yl amido] -6,6- dimethyl -8- (3- Acrylamido phenyl) -6H- pyrimidines [5,4-b] [Isosorbide-5-Nitrae] oxazines -7 (8H) -one.

12. the method for preparing formula as described in claim 1 (I) compound comprising following steps,

Wherein, ring A, ring B, R₁、R₂、R₃、R₄、R₅, m and n it is as described in claim 1,

With 2,4- dichloro-5-methoxy pyrimidines for starting material, ammonolysis reaction occurs with ammonia and obtains compound (a), compound (a) compound (b) is obtained through Boron tribromide demethylation, then cyclization occurs with halogenated acid esters (g) and obtains compound (c), compound (c) Suzuki coupling reaction is carried out with compound (h) and obtains compound (d), and compound (d) occurs substitution reaction with amine (i) and obtains The nitro of compound (e), reducing compound (e) obtains compound (f), and with carboxylic acid halides appropriate acyl occurs for the amino of compound (f) Aminating reaction obtains compound (I).

13. a kind of pharmaceutical composition, including any one of claim 1~11 formula (I) compound or its is pharmaceutically acceptable Salt and drug acceptable carrier, excipient or diluent.

14. claim 1~11 any one of them compound is preparing treatment mammal by EGFR activated forms or drug-resistant type Application in the drug of mutant mediated disease.

15. application as claimed in claim 14, the disease is cancer.

16. application as claimed in claim 14, the mammal is the mankind.