CN105218561A - Annelated pyrimidines ring derivatives, its preparation method and application - Google Patents
Annelated pyrimidines ring derivatives, its preparation method and application Download PDFInfo
- Publication number
- CN105218561A CN105218561A CN201410289021.XA CN201410289021A CN105218561A CN 105218561 A CN105218561 A CN 105218561A CN 201410289021 A CN201410289021 A CN 201410289021A CN 105218561 A CN105218561 A CN 105218561A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- amido
- halo
- dimethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 C*1*ICC1 Chemical compound C*1*ICC1 0.000 description 4
- URXMNCPUNDMODG-UHFFFAOYSA-N CC(C)(C(N1c2cc(N)ccc2)=O)Oc2c1nc(Nc(ccc(OCCN(C)C)c1)c1OC)nc2 Chemical compound CC(C)(C(N1c2cc(N)ccc2)=O)Oc2c1nc(Nc(ccc(OCCN(C)C)c1)c1OC)nc2 URXMNCPUNDMODG-UHFFFAOYSA-N 0.000 description 1
- RTEGXKDYKDAMAX-UHFFFAOYSA-N CC(C)(C(N1c2cc([N+]([O-])=O)ccc2)=O)Oc2c1nc(Nc(ccc(OCCN(C)C)c1)c1OC)nc2 Chemical compound CC(C)(C(N1c2cc([N+]([O-])=O)ccc2)=O)Oc2c1nc(Nc(ccc(OCCN(C)C)c1)c1OC)nc2 RTEGXKDYKDAMAX-UHFFFAOYSA-N 0.000 description 1
- RSZSNZTVVJOBKJ-UHFFFAOYSA-N CC(C)(C(N1c2cccc(N)c2)=O)Oc2c1nc(Nc(ccc(N(C)CCN(C)C(C)=O)n1)c1OCC(F)(F)F)nc2 Chemical compound CC(C)(C(N1c2cccc(N)c2)=O)Oc2c1nc(Nc(ccc(N(C)CCN(C)C(C)=O)n1)c1OCC(F)(F)F)nc2 RSZSNZTVVJOBKJ-UHFFFAOYSA-N 0.000 description 1
- YTPQOJARYSUPMQ-UHFFFAOYSA-N CC(C)(C1=O)Oc2cnc(Nc(ccc(NC(CCN(C)C)=O)c3)c3OC)nc2N1c1cc([N+]([O-])=O)ccc1 Chemical compound CC(C)(C1=O)Oc2cnc(Nc(ccc(NC(CCN(C)C)=O)c3)c3OC)nc2N1c1cc([N+]([O-])=O)ccc1 YTPQOJARYSUPMQ-UHFFFAOYSA-N 0.000 description 1
- PBUDJKXIOFPJPJ-UHFFFAOYSA-N CC(C)(C1=O)Oc2cnc(Nc3ccc(NC(CN(C)C)=O)nc3OC)nc2N1c1cc(N)ccc1 Chemical compound CC(C)(C1=O)Oc2cnc(Nc3ccc(NC(CN(C)C)=O)nc3OC)nc2N1c1cc(N)ccc1 PBUDJKXIOFPJPJ-UHFFFAOYSA-N 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N CCOc(c(NC(/C=C/CN(C)C)=O)cc1c2Nc(cc3Cl)ccc3F)cc1ncc2C#N Chemical compound CCOc(c(NC(/C=C/CN(C)C)=O)cc1c2Nc(cc3Cl)ccc3F)cc1ncc2C#N WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- AIUJDAOMGSZVAV-UHFFFAOYSA-N CN(C)C(CN(C)c(cc1)nc(OCC(F)(F)F)c1[N+]([O-])=O)=O Chemical compound CN(C)C(CN(C)c(cc1)nc(OCC(F)(F)F)c1[N+]([O-])=O)=O AIUJDAOMGSZVAV-UHFFFAOYSA-N 0.000 description 1
- DECRTUBGVZAOSH-UHFFFAOYSA-N CN(CCN1CCCC1)c(cc1)nc(OC)c1[N+]([O-])=O Chemical compound CN(CCN1CCCC1)c(cc1)nc(OC)c1[N+]([O-])=O DECRTUBGVZAOSH-UHFFFAOYSA-N 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N COc(c(NC(/C=C/CN1CCCCC1)=O)c1)cc2c1c(Nc(cc1Cl)ccc1F)ncn2 Chemical compound COc(c(NC(/C=C/CN1CCCCC1)=O)c1)cc2c1c(Nc(cc1Cl)ccc1F)ncn2 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
Abstract
The invention discloses a class as formula (I) the annelated pyrimidines ring derivatives of tyrosine kinase inhibitor and pharmacy acceptable salt, wherein R
1, R
2, R
3, R
4, R
5, A and B as in specification sheets define.The invention also discloses the preparation method of these compounds, comprise the pharmaceutical composition of described compound and pharmaceutically-acceptable salts thereof, and the application in the medicine for the treatment of disease mediate by the EGFR of some mutant forms and the disease mediated by the EGFR of some mutant forms for the preparation for the treatment of of described compound and pharmaceutically-acceptable salts thereof.
Description
Technical field
The present invention relates to a class as the annelated pyrimidines ring derivatives of tyrosine kinase inhibitor and pharmacy acceptable salt thereof, and this derivative and EGF-R ELISA (EGFR) (such as 19 exons disappearance activated mutant bodies, L858R activated mutant body and the T790M drug-resistant type mutant) inhibitor of pharmacy acceptable salt as some mutant forms thereof and the application of carcinostatic agent.The invention still further relates to its preparation method, and comprise the pharmaceutical composition of described annelated pyrimidines ring derivatives and pharmaceutically-acceptable salts thereof, and relate to the method utilizing described derivative and pharmaceutically-acceptable salts thereof to treat the disease mediated by the EGFR of some mutant forms.
Background technology
Cancer is considered to the disease of Cellular Signaling Transduction Mediated system or signal transduction mechanism.The most commonly encountered diseases of cancer is because being a series of defect, and described defect can be the defect (when it suddenlys change) of protein, or the defect of adjustment to the amount of intracellular protein, thus makes protein excessively produce or produce deficiency.The sudden change (this sudden change is passed the signal along in cell by Tyrosylprotein kinase usually) of cell surface receptor can cause kinases to be activated under the condition lacking part, and transmits in fact and non-existent signal.Or many receptor tyrosine kinases can, in cell surface overexpression, cause responding by force the mistake of weak signal.
Lung cancer is the first cause causing cancer mortality in industrial country.According to cell performance under the microscope, lung cancer is divided into nonsmall-cell lung cancer and small cell lung cancer two kinds of main Types, and nonsmall-cell lung cancer (NSCLC) accounts for 80%.In China, annual new lung cancer of sending out, more than 600,000 people, on average every 30 seconds, just has 1 people to die from lung cancer.Chemotherapy can provide the help of humidity in survival rate, but toxicity is too large, therefore relates to the therapeutical agent of tumor growth in the urgent need to specific target.
EGF-R ELISA (EGFR) is identified as vital driving factors in Growth of Cells and birth process.Epidermal Growth Factor Receptor Family is made up of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.EGF-R ELISA is relevant with the disease process of most of cancer, as lung cancer, colorectal carcinoma, mammary cancer etc.The overexpression of EGFR and sudden change have been the Major Risk Factors of the bad mammary cancer of prognosis by being unequivocally established.In addition, confirm that all four members of this receptor family all can be polymerized to heterodimer with other members of this family, form intracellular signaling mixture, if there is more than one member overexpression in malignant tumour in this family, just can cause the intracellular signaling effect of working in coordination with.
EGFR belongs to protein tyrosine kinase (PTK) family, and protein tyrosine kinase is phosphate group is transferred to the tyrosine residues being positioned at protein substrate by class enzyme from ATP catalysis.Protein tyrosine kinase works in normal cell growth.The overexpression of EGFR or sudden change, cause acceptor to be activated under the condition lacking part, make some albumen generation phosphorylation, create fissional signal.Therefore, EGFR, by the effect of self Tyrosylprotein kinase, result in the excessive amplification of weak signal, causes the excessive increment of cell.
Specific PTK inhibitors as potential anti-cancer therapeutic agent receives much concern.The Typical Representative of the EGFR reversible inhibitor gone on the market at present comprises Gefitinib (Gefitinib, commodity are called Iressa, developed by ASTRAZENECAUKLtd.), erlotinib (Erlotinib, commodity are called Tarceva, by Genentech, and OSIPharmaceuticals Inc., Inc develops), lapatinibditosylate (Lapatinib, commodity are called Tykerb, developed by GlaxoSmithKline), suppress EGFR wild-type and activated form sudden change (such as 19 exon disappearance activated mutants, or L858R activated mutant), its structure is as follows, be respectively used to the treatment of NSCLC and mammary cancer.Clinical study proves that Gefitinib, erlotinib have good therapeutic action to the NSCLC patient that 19 exon disappearances or L858R point mutation occur EGFR.But their limitation is that patient produces resistance (Kobayashi, M. etc., N.Engl.J.Med., 352:786-792,2005) after acceptance treatment, makes the further application clinically of this type of inhibitor be restricted.Research shows, after the Gefitinib of 50%, erlotinib treatment, secondary sudden change (T790M) relevant (PaoW. etc., PlosMed., 2:1-11,2005) occurs the EGFR that results from of resistance, and reversible inhibitor loses curative effect.
T790M is positioned at the entrance of EGFR and ATP binding pocket, and the size of its side chain directly affects the binding ability of EGFR and ATP.T790M sudden change spatially hinders the effect of EGFR inhibitor and ATP-binding site, increase EGFR to the avidity of ATP, thus make cell produce resistance (Cai-HongYun etc., Proc.Natl.Acad.Sci.U.S.A. to EGFR inhibitor, 105:2070-2075,2008)
Compared with irreversible EGFR inhibitor, irreversible EGFR inhibitor has very outstanding advantage.Irreversible EGFR inhibitor can suppress EGFR for a long time, is only subject to the restriction that acceptor combines the normal speed of (also referred to as replying) again.Studies have found that, irreversible EGFR inhibitor is by reversal of the Michael addition and EGFR cysteine residue (Cys797) covalent attachment, irreversible EGFR inhibitor and ATP-binding site are expanded, thus T790M can be overcome to a certain extent to suddenly change the resistance (LiD etc. caused, Oncogene, 27:4702-4711,2008).The irreversible EGFR inhibitor of having gone on the market at present has BIBW-2992 (Afatinib, BoehringerIngelheim develops), HKI-272 (Neratinib is comprised what grind, Wyeth develop), EKB-569 (Pelitinib, Wyeth develop), PF00299804 (Dacomitinib, Pfizer develops) etc., its structure is as follows.
But, this kind of irreversible EGFR inhibitor that can suppress EGFRT790M, also very large to the restraining effect of Wild type EGFR, bring larger toxic side effect, as diarrhoea, fash, nauseating, apocleisis, faint (Besse, B. Eur.J.CancerSuppl. is waited, 6,64, abstr.203,2008, Janne, P.A. etc., J.Clin.Oncol., 25:3936-3944, 2007), although therefore according to the literature, clinical front BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) display, there is significant anti-tumor activity, the activity of EGFR and EGFRT790M can be suppressed, but because the generation of these untoward reactions in clinical course, ultimately limit its clinical administration dosage and effective blood drug concentration, BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) is made to fail to obtain the progress (KatakamiN attracted people's attention overcoming in T790M medicament-resistant mutation, AtagiS, GotoK, etal. [J] .JournalofClinicalOncology, 2013, 31 (27): 3335-3341.,
pA, BossDS, CamidgeDR, etal. [J] .ClinicalCancerResearch, 2011,17 (5): 1131-1139., LandiL, CappuzzoF. [J] .TranslationalLungCancerResearch, 2013,2 (1): 40-49.).
Above-mentioned listing or be quinazoline compounds in the reversible or irreversible EGFR inhibitor major structural types of grinding, the quinazoline ditosylate salt EGFR inhibitor reported at present is the ATP competitive inhibitor of Wild type EGFR, nonspecific action, in EGFRT790M, causes the generation of some side reactions thus.2009, researchist reported the irreversible EGFR inhibitor of specific effect in EGFRT790M of a class miazines, and structure is as follows.Compared with existing aniline quinazoline EGFR inhibitor, the inhibit activities of this type of pyrimidine compound to EGFRT790M improves 30-100 doubly, 100 times of (WenjunZhou etc. are reduced to the inhibit activities of Wild type EGFR, Nature, 462:1070-1074,, but such pyrimidine compound of later stage does not enter clinical study 2009).
Disclose another serial pyrimidines in the international monopoly WO2012061299A of AvilaTherapeutics application, structural formula is as follows, and wherein representational compound is CO1686.According to the literature, CO1686 can suddenly change in the sudden change of EGFR activated form and T790M drug-resistant type by selectively acting, and to the more weak (WalterAO of Wild type EGFR restraining effect, SjinRTT, HaringsmaHJ, etal. [J] .Cancerdiscovery, 2013,3 (12): 1404-1415.).Current preparation enters clinical II stage phase.
Also disclose a series of pyrimidines in the international monopoly WO2013014448A of ASTRAZENECAAB application, structural formula is as follows, and wherein representational compound is AZD9291, is in I phase clinical stage at present.
For overcome clinical in the toxic side effect problem of common EGFR resistance mutation (such as T790M sudden change) and existing EGFR inhibitor, the micromolecular inhibitor that namely exploitation more shows relatively low suppression to Wild type EGFR to the higher suppression of the EGFR display of some activated mutant body and drug-resistant type mutant forms be simultaneously current antineoplastic field in the urgent need to.The present inventor is in the process of research EGFR inhibitor, surprisingly find a class annelated pyrimidines ring derivatives, inhibit activities to Wild type EGFR is significantly higher than to the inhibit activities that EGFR activated form suddenlys change (as 19 exons disappearance activated mutant or L858R activated mutants) and T790M drug-resistant type suddenlys change, energy specific effect is in EGFRT790M, have good selectivity, and toxic side effect is lower.Expect and be expected to the curative effect that this type of inhibitor will have overcome drug resistance problems and toxic side effect problem, there is good DEVELOPMENT PROSPECT.
Summary of the invention
The invention provides a kind of as shown in the formula (I) compound, or its pharmacy acceptable salt:
In formula:
Ring A is aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl ,-OR
7,-C (O) R
7,-C (O) NR
7r
7' ,-NR
7r
7', halogen ,-NO
2; Or R
1, R
2cyclization forms cycloalkyl or Heterocyclylalkyl together be connected carbon atom;
Each R
3be halogen, C independently
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
1-C
4alkyl ,-OR
6,-C (O) R
7,-C (O) NR
7r
7' ,-OR
7,-NR
7r
7' ,-CN or-NO
2;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SOR
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein work as R
4for
time, its amide nitrogen atom is participated in formation ring A directly as heteroatoms and is obtained heteroaryl or Heterocyclylalkyl;
R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' ,-(CH
2)
qnR
7c (O) R
7,-(CH
2)
qc (O) R
7or-(CH
2)
qc (O) NR
7r
7';
R
7and R
7' be separately hydrogen, C
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 4;
N is the integer of 1 ~ 5;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
The invention provides general formula (I) compound, it can suppress one or more EGFR activated forms or drug-resistant type sudden change, such as L858R activated mutant body, 19 exon disappearance activated mutant bodies, T790M drug-resistant type mutant.Advantageously, this compound can be used for the cancer therapy existing therapy based on EGFR inhibitor having been produced to resistance patient to a certain degree.
The invention provides formula (I) compound, it shows the suppression higher than Wild type EGFR to the EGFR of activation or drug-resistant type mutant forms.Owing to suppressing relevant toxicity to reduce to Wild type EGFR, thus expect that this compound is more suitable for being used as therapeutical agent, be particularly useful for the treatment of cancer.
Present invention also offers the preparation method of formula (I) compound.
The present invention also provides pharmaceutical composition, and it contains the invention described above general formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or thinner.
The present invention also provides general formula of the present invention (I) compound or its pharmacy acceptable salt the treatment Mammals especially mankind by the application in EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type.
The present invention also provides general formula of the present invention (I) compound or its pharmacy acceptable salt in the application of the preparation treatment Mammals especially mankind by the medicine of EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type.
The present invention also provides a kind of and treats Mammals especially the mankind are by the method for EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type, and described method comprises to be used formula (I) compound or its pharmacy acceptable salt to patient or comprise treatment formula (I) compound of significant quantity and the pharmaceutical composition of drug acceptable carrier, vehicle or thinner.
The present invention also provides a kind of method optionally suppressing EGFR activated form in biological sample or in patient or drug-resistant type sudden change compared to Wild type EGFR (WTEGFR), and described method comprises makes biological sample contact or to patient's administration formula (I) compound or its pharmacy acceptable salt or its pharmaceutical composition.
Cancer mentioned by the present invention, can be selected from lung cancer, ovarian cancer, cervical cancer, mammary cancer, cancer of the stomach, colorectal carcinoma, carcinoma of the pancreas, glioma, glioblastoma multiforme, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, hepatocellular carcinoma, gastrointestinal stromal knurl (GIST), thyroid carcinoma, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia (AML), multiple myeloma, mesothelioma.
In a preferred embodiment of the invention, described formula (I) compound or its pharmacy acceptable salt, R in formula
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl or-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Wherein, R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl.
In a preferred embodiment of the invention, described formula (I) compound or its pharmacy acceptable salt, each R described in formula
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl), NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SOR
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Described R
4for
wherein work as R
4for
time, its amide nitrogen atom is participated in formation ring A directly as heteroatoms and is obtained heteroaryl or Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' ,-(CH
2)
qnR
7c (O) R
7,-(CH
2)
qc (O) R
7or-(CH
2)
qc (O) NR
7r
7';
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In a preferred embodiment of the invention, provide formula (Ia) compound or its pharmacy acceptable salt,
Wherein, ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl or-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 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 heteroaryl is selected from pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl-, indyl, pseudoindoyl or 1,2,3,4-tetrahydro isoquinolyl.
In a preferred embodiment of formula (Ia) compound, ring B heteroaryl is pyridyl.
In a preferred embodiment of formula (Ia) compound, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom.
In a preferred embodiment of formula (Ia) compound, each R
3be halogen or C independently
1-C
4alkyl.
In a preferred embodiment of formula (Ia) compound, R
4for
wherein, R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl.
In a preferred embodiment of formula (Ia) compound, R
4for
wherein, R
7for hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl.
In a preferred embodiment of formula (Ia) compound, each R
5be halogen ,-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7azetidine base ,-O (CH that substituting group replaces
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace piperazinyl, piperidyl or pyrrolidyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In another preferred embodiment of the present invention, provide formula (Ia-1) compound or its pharmacy acceptable salt,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In a preferred embodiment of formula (Ia-1) compound, R
1, R
2be C independently of one another
1-C
4alkyl, is more preferably-CH
3.
In a preferred embodiment of formula (Ia-1) compound, m is 0.
In a preferred embodiment of formula (Ia-1) compound, R
4for
wherein, R
7for hydrogen.
In a preferred embodiment of formula (Ia-1) compound, each R
5be-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6or-NR
6r
7, or do not replace or be selected from C by 1
1-C
4alkyl or-C (O) R
7substituting group replace piperazinyl;
Wherein, R
6for-(CH
2)
qnR
7r
7';
R
7and R
7' be separately hydrogen or C
1-C
4alkyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 2;
P is the integer of 0 ~ 2.
In a more preferred of formula (Ia-1) compound, each R
5be-OR independently
7or-OR
6, wherein, R
6for-(CH
2)
qnR
7r
7'; R
7and R
7' be separately C
1-C
4alkyl;
N is 2; Q is the integer of 0 ~ 2; P is the integer of 0 ~ 2.
In another preferred embodiment of the present invention, provide formula (Ia-2) compound or its pharmacy acceptable salt,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7sO
2r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-O (CH that substituting group replaces
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In a preferred embodiment of formula (Ia-2) compound, R
1, R
2be C independently of one another
1-C
4alkyl, is more preferably-CH
3.
In a preferred embodiment of formula (Ia-2) compound, m is 0.
In a preferred embodiment of formula (Ia-2) compound, R
4for
wherein, R
7for hydrogen.
In a preferred embodiment of formula (Ia-2) compound, each R
5be-OR independently
7,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-by 1 halo C
1-C
4azetidine base ,-O (CH that alkyl replaces
2)
qsO
2r
7, or be selected from C by 1
1-C
4alkyl ,-NR
7r
7' or-C (O) R
7substituting group replace piperazinyl, piperidyl or pyrrolidyl;
Wherein R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form pyrrolidyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 3;
P is the integer of 0 ~ 3.
In a more preferred of formula (Ia-2) compound, each R
5be-OR independently
7or-NR
6r
7, or be selected from C by 1
1-C
4alkyl ,-NR
7r
7' or-C (O) R
7substituting group replace piperazinyl or piperidyl;
Wherein R
6for-(CH
2)
qoR
7or-(CH
2)
qnR
7c (O) R
7; R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl; N is 2; Q is the integer of 0 ~ 2; P is the integer of 0 ~ 2.
In a preferred embodiment of the invention, provide formula (Ib) compound or its pharmacy acceptable salt,
Wherein, ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl ,-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-SO
2r
6r
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 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 heteroaryl is selected from pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl-, indyl, pseudoindoyl or 1,2,3,4-tetrahydro isoquinolyl.
In a preferred embodiment of formula (Ia) compound, ring B heteroaryl is pyridyl.
In a preferred embodiment of formula (Ib) compound, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom.
In a preferred embodiment of formula (Ib) compound, each R
3be halogen or C independently
1-C
4alkyl.
In a preferred embodiment of formula (Ib) compound, each R
5be halogen ,-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace piperazinyl or piperidyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In another preferred embodiment of the present invention, provide formula (Ib-1) compound or its pharmacy acceptable salt,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7sO
2r
7,-NR
7(CH
2)
pc (O) R
6or-NR
6r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
In a preferred embodiment of formula (Ib-1) compound, R
1, R
2be C independently of one another
1-C
4alkyl, is more preferably-CH
3.
In a preferred embodiment of formula (Ib-2) compound, m is 0.
In a preferred embodiment of formula (Ib-1) compound, each R
5be-OR independently
7or-NR
6r
7, wherein, R
6for-(CH
2)
qnR
7r
7'; R
7and R
7' be separately C
1-C
4alkyl or halo C
1-C
4alkyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 2.
In the present invention, as the compound represented by formula (I) or its pharmacy acceptable salt, can specifically mention:
2-[4-(4-methylpiperazine-1-yl)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[4-(4-Acetylpiperazine-1-base)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-Acetylpiperazine-1-base)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin) acetamido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{6-[(2-(N-methyl vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(2-hydroxyethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-dimethylamino piperidine-1-base)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-trifluoro ethoxy-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(4-dimethylamino piperidine-1-base) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[4-Acetylpiperazine-1-base] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[4-methylpiperazine-1-yl] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[1-(2-fluoro ethyl) azetidine-3-amido] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(R)-8-(1-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(S)-8-(1-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-sec.-propyl oxygen base-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[3-(dimethylin) propionamido-]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(R)-2-[2-methoxyl group-6-(3-dimethylin pyrrolidin-1-yl) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one.
The present invention also provides the method for preparation formula (I) compound, and it comprises the following steps:
Wherein, ring A, ring B, R
1, R
2, R
3, R
4, R
5, m with n be identical with the definition in above-mentioned general formula (I) compound.
With 2, 4-dichloro-5-methoxy pyrimidine is starting raw material, compound (a) is obtained with ammonia generation ammonolysis reaction, compound (a) obtains compound (b) through boron tribromide demethylation, there is cyclization with halo acid esters (g) again and obtain compound (c), compound (c) and compound (h) carry out Suzuki linked reaction (Suzukireaction) and obtain compound (d), there is substitution reaction and obtain compound (e) in compound (d) and amine (i), the nitro of reducing compound (e) obtains compound (f), amino and the suitable carboxylic acid halides generation amidate action of compound (f) obtain compound (I).
The preparation method of formula of the present invention (I) compound, wherein there is cyclization and obtain compound (c) in compound (b) and halo acid esters (g) in the presence of base, and described alkali comprises salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammoniacal liquor, methylamine, ethamine, triethylamine etc.; It is ordinary method that the nitro of reducing compound (e) obtains method of reducing in the step of compound (f), such as palladium carbon/hydrogen reducing, PtO
2/ hydrogen reducing, iron powder reducing; The carboxylic acid halides that the amino of compound (f) and suitable carboxylic acid halides generation amidate action obtain using in the step of compound (I) comprises acyl chlorides, acylbromide.
In the present invention, halogen refers to fluorine, chlorine, bromine, iodine etc., preferred fluorine, chlorine, bromine.
C
1-C
4alkyl refers to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl; Preferable methyl, ethyl, propyl group, sec.-propyl or butyl, more preferably methyl.
Halo C
1-C
4alkyl refers to by one or more halogen, the C as defined herein of preferably one to five halogen atom replacement
1-C
4alkyl, includes but not limited to chloro-2 fluoro ethyls of trifluoromethyl, trifluoroethyl, difluoromethyl, 1-etc.
Thiazolinyl refers to the unit price base that hydrocarbyl group derives, C
2-C
6thiazolinyl refers to containing 2 to 6 carbon atoms and at least contains the thiazolinyl of a carbon-to-carbon double bond, includes but not limited to, vinyl, propenyl, butenyl, 2-methyl-2-butene, 2-methyl-2-amylene and similar group.
Alkynyl refers to the unit price base that hydrocarbyl group derives, C
2-C
6alkynyl refers to containing 2 to 6 carbon atoms and at least contains the alkynyl of a carbon-to-carbon triple bond, includes but not limited to, ethynyl, proyl, ethyl acetylene base, 2-butyne base and similar group.
Cycloalkyl refers to by monocycle or many ring fillings or the derivative unit price base of part unsaturated aliphatics carbocyclic ring ring compound, C
3~ C
8-cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclooctene base, cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, and C
9~ C
12-include but not limited to dicyclo [2.2.1] heptyl and dicyclo [2.2.1] octyl group etc.
Heterocyclylalkyl refers to monovalent monocyclic group that is saturated or part is undersaturated (but non-aromatic) three to eight annular atomses, preferably 4 ~ 7 rings, or monovalence fused bicyclic group that is saturated or part is undersaturated (but non-aromatic) five to ten two annular atomses, preferably 7 ~ 10 rings, wherein 1 to 4 ring hetero atom is independently selected from O, S, N, and all the other annular atomses are carbon.Described Heterocyclylalkyl includes but not limited to azetidine base, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, THP trtrahydropyranyl, pyrazolidyl, pyrazolinyl, imidazolinyl, imidazolidyl, [1, 3] dioxolane (dioxolane), dihydropyridine base, tetrahydro pyridyl, hexahydropyridine base, oxazolinyl, oxazolidinyl, isoxazole alkyl, thiazolinyl, thiazolidyl, thiazolidine base, different thiazolidine base, octahydro indyl, octahydro pseudoindoyl, tetrahydrofuran base etc., preferred azetidine base, oxetanyl, pyrrolidyl, piperidyl, morpholinyl or piperazinyl.
Aryl refers to aromatic ring alkyl, there is one or more aromatic nucleus, the carbon-loop system of condensed ring or non-condensed ring, comprise, but be not limited to phenyl, naphthyl, tetralyl, dihydro indenyl (indanyl), indenyl (indenyl) and similar group, preferred carbonatoms is 6 to 14, is more preferably the aryl of 6 to 10, as phenyl and naphthyl, more preferably phenyl.
Heteroaryl refers to heteroatomic 5 to the 6 yuan of bicyclic heteroaryls or itself that are selected from N, S or O containing 1 to 4 and the thick dicyclic heteroaryl of phenyl ring, and it can be fractional saturation.Described heteroaryl includes but not limited to furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzofuryl, benzothienyl, diazosulfide base, benzothiazolyl, benzimidazolyl-, indyl, pseudoindoyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, 1, 2, 3, 4-tetrahydro isoquinolyl, preferred pyrazolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, benzimidazolyl-, indyl, pseudoindoyl or 1, 2, 3, 4-tetrahydro isoquinolyl.
Should be appreciated that, cycloalkyl described herein, Heterocyclylalkyl and similar group thereof can be substituted further.Said replacement include but not limited to C
1-C
4alkyl, halo C
1-C
4alkyl, halogen ,-OH ,-OC
1-C
4alkyl ,-NO
2,-NH
2,-N (C
1-C
4alkyl)
2,-CN ,-C (O)-C
1-C
4alkyl ,-C (O)-NH
2,-C (O)-NH-C
1-C
4alkyl ,-NH-C (O)-C
1-C
4alkyl.
The present invention is contained (I) compound pharmaceutically acceptable salt also.Term " pharmacy acceptable salt " refers to acid salt or the base addition salt of the compounds of this invention of relative nontoxic.Described acid salt is the salt that formula (I) compound and suitable mineral acid or organic acid are formed, these salt can be prepared in the last isolation andpurification process of compound, or available mistake makes the formula of purifying (I) compound carry out reacting preparing with its free alkali form and suitable organic acid or mineral acid.Representative acid salt comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, sulphite, acetate, oxalate, valerate, oleate, palmitate, stearate, month silicate, borate, benzoate, lactic acid salt, phosphoric acid salt, hydrophosphate, carbonate, supercarbonate, toluylate, Citrate trianion, maleate, fumarate, succinate, tartrate, benzoate, mesylate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc.Described base addition salt is the salt that formula (I) compound and suitable mineral alkali or organic bases are formed, comprise the salt such as formed with basic metal, alkaline-earth metal, quaternary ammonium cation, such as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, tetramethyl-quaternary ammonium salt, tetraethyl-quaternary ammonium salt etc.; Amine salt, comprises and ammonia (NH
3), primary amine, secondary amine or tertiary amine formed salt, as methylamine salt, dimethylamine salt, front three amine salt, triethylamine salt, ethylamine salt etc.
Compound of the present invention or its pharmacy acceptable salt can deliver medicine to Mammals and comprise people, can administration in oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical (pulvis, ointment or drops) or knurl.
The dosage of the compounds of this invention can be approximately 0.05-50mg/kg body weight/day, such as 0.1-45mg/kg body weight/day, 0.5-35mg/kg body weight/day.
The compounds of this invention or its pharmacy acceptable salt can be formulated as the solid dosage for oral administration, include, but are not limited to capsule, tablet, pill, powder and granule etc.In these solid dosages, formula (I) compound mixes with at least one conventional inert excipients (or carrier) as activeconstituents, such as with Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (1) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid etc.; (2) tackiness agent, such as Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic etc.; (3) wetting Agent for Printing Inks, such as, glycerine etc.; (4) disintegrating agent, such as agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate etc.; (5) retarding solvent, such as paraffin etc.; (6) accelerator is absorbed, such as, quaternary ammonium compound etc.; (7) wetting agent, such as hexadecanol and glyceryl monostearate etc.; (8) sorbent material, such as, kaolin etc.; (9) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate etc., or its mixture.Also buffer reagent can be comprised in capsule, tablet and pill.
Described solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and shell material such as enteric coating and other materials well known in the art to carry out dressing or microencapsulation.They can comprise opacifying agent, and in this composition, the release of activeconstituents can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.If desired, activeconstituents also can form microencapsulation form with one or more in above-mentioned vehicle.
The compounds of this invention or its pharmacy acceptable salt can be formulated as the liquid dosage form for oral administration, include, but are not limited to pharmaceutically acceptable emulsion, solution, suspension, syrup and tincture etc.Except as except formula (I) compound of activeconstituents or its pharmacy acceptable salt, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water and other solvents, solubilizing agent and emulsifying agent, such as, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oils, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame wet goods or these materials.Except these inert diluents, liquid dosage form of the present invention also can comprise conven-tional adjuvants, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices etc.
Described suspension agent comprises, such as, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and anhydro sorbitol only, the mixture of Microcrystalline Cellulose, aluminum methylate and agar etc. or these materials.
The compounds of this invention or its pharmacy acceptable salt can be formulated as the formulation for parenteral injection, comprise, but be not limited to physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The compounds of this invention or its pharmacy acceptable salt also can be formulated as the formulation for topical, comprise as ointment, powder, suppository, drops, propellant and inhalation etc.As formula (I) compound of activeconstituents or its pharmacy acceptable salt aseptically with physiologically acceptable carrier and optional sanitas, buffer reagent, or the propelling agent that may need if desired is mixed together.
The present invention also provides pharmaceutical composition, and it contains formula (I) compound or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable carrier, vehicle or thinner.When pharmaceutical compositions, normally by formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or mixing diluents.The content of its formula of (I) compound or its pharmacy 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.
Preparation method the described present composition can be formulated as traditional drug formulations routinely.Such as tablet, pill, capsule, powder, granule, emulsion agent, mixed floating agent, dispersion liquid, solution, syrup, elixir, ointment, drops, suppository, inhalation, propellant etc.
Compound of the present invention or its pharmacy acceptable salt can be individually dosed, or with other pharmaceutically acceptable therapeutic agent administrations, particularly with other antitumor combination.Described therapeutical agent includes but not limited to: act on the drugs against tumor medicine of DNA chemical structure as cis-platinum, affect the antitumor drug of Nucleotide synthesis as methotrexate (MTX), 5 FU 5 fluorouracil (5FU) etc., affect the antitumor drug of transcribed nucleic acid as Zorubicin, pidorubicin, aclacinomycin, Plicamycin etc., act on the antitumor drug of tubulin synthesis as taxol, vinorelbine etc., arimedex is as aminoglutethimide, Lan Telong, letrozole, auspicious Ningde etc., cell-signaling pathways inhibitor is as epidermal growth factor receptor inhibitor imatinib (Imatinib), Gefitinib (Gefitinib), erlotinib (Erlotinib) etc.Each composition to be combined can give simultaneously or sequentially, gives with unitary agent form or with the form without preparation.Described combination not only comprises the combination of the compounds of this invention and other promoting agents a kind of, and comprises the combination of the compounds of this invention and two or more other promoting agents.
By to activated form sudden change i.e. 19 exon absence type activated mutant tumour cells if HCC827 cell, drug-resistant type tumour cell are as the external increment inhibition test of H1975 and Wild type EGFR human skin cancer cells A431, prove that the compounds of this invention has good increment restraining effect to activated mutant or drug-resistant type mutated tumor cell, but relative is more weak to the increment restraining effect of Wild type EGFR cancer cells, and selectivity is good.The compounds of this invention can be used as the medicine for the treatment of disease or the patient's condition, the particularly tumour such as cancer mediated by EGFR activated form or drug-resistant type mutant activity.Described cancer includes but not limited to, such as lung cancer, ovarian cancer, cervical cancer, mammary cancer, cancer of the stomach, colorectal carcinoma, carcinoma of the pancreas, glioma, glioblastoma multiforme, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, hepatocellular carcinoma, gastrointestinal stromal knurl (GIST), thyroid carcinoma, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia (AML), multiple myeloma, mesothelioma, especially the tumor type sporting methionine(Met) (EGFRT790M) for EGF-R ELISA 790 Threonines has better application.For example, the compounds of this invention can be used as and is used for the treatment of the medicine of non-small cell carcinoma (EGFRT790M).Can be used for overcoming the drug resistance problems caused by EGFRT790M after applying Gefitinib, erlotinib clinically.And because suppressing relevant toxicity to reduce to Wild type EGFR, expection the compounds of this invention is to be applied to the toxic side effect produced in the middle of the process of Therapeutic cancer relatively little.
The drug effect using conventional procedures of the compounds of this invention anticancer propagation measures, a kind of preferred evaluation method is Sulforhodamine B (SulforhodamIneB, SRB) protein staining method, calculates the inhibiting rate of medicine to cancer cell multiplication by the change measuring the absorbance value that drug effect produces after cancer cells.
Inhibiting rate (%)=[(blank OD-dosing OD)/blank OD] × 100%
Blank OD: the OD value referring to the hole of the cell not having drug effect normal growth.
Dosing OD: the OD value referring to the hole of the cell adding compound effects to be screened.
Half inhibitor concentration (IC
50) value employing GraphPad company PrIsm software 5.0 version, four parameter fitness methods calculate.Each experiment repetition 3 times, obtains the average IC of 3 experiments
50value is the final index of rejection ability.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustrating the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise number and per-cent are respectively weight part and weight percent.
Embodiment
I. the compounds of this invention prepares embodiment
Embodiment 1:2-[4-(4-methylpiperazine-1-yl)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-methoxyl group-4-(4-methylpiperazine-1-yl) oil of mirbane
The fluoro-2-Nitroanisole (0.51g) of 5-is dissolved in methyl-sulphoxide 20ml, adds N methyl piperazine (1.3ml), salt of wormwood (1.25g) successively, is warming up to 90 DEG C of reactions.Stirring reaction 0.5 hour stopped reaction.Pour in frozen water compound 100ml under being stirred by reaction solution, yellow needles is separated out, and suction filtration, dries, and obtains yellow solid 0.71g.MSm/z：252.2(M+1).
The synthesis of step 2:2-methoxyl group-4-(4-methylpiperazine-1-yl) aniline
1-(3-methoxyl group-4-nitrophenyl)-4-methylpiperazine (250mg) is dissolved in ethanol, adds appropriate palladium carbon, stirring reaction 1 hour under nitrogen atmosphere.By reaction solution suction filtration removing palladium carbon, evaporated under reduced pressure, obtains red-purple oily matter (211mg).MSm/z：222.3(M+1).
The synthesis of step 3:2-chloro-5-methoxyl pyrimidine-4-amine
2,4-dichloro-5-methoxy pyrimidine (100g) is dissolved in methyl alcohol, logical ammonia stirring reaction 24 hours under room temperature.Reaction solution evaporated under reduced pressure, obtains white solid, and add petrol ether/ethyl acetate (10: 1) making beating 3-5 time, suction filtration, obtains white solid 61g.MSm/z：160.0(M+1).
The synthesis of step 4:4-amino-2-chloropyrimide-5-alcohol
2-chloro-5-methoxyl pyrimidine-4-amine (25g) is dissolved in methylene dichloride 200ml, ice bath, slowly drips boron tribromide (75ml), drip off and rise to room temperature under nitrogen protection, is slowly heated to 50 DEG C of stirring reactions and spends the night.Cooling, slowly join 2L containing in ice cube methyl alcohol, limit edged stirs.Add salt of wormwood and adjust pH to 12, extraction into ethyl acetate, water layer dilute hydrochloric acid adjusts pH to 3, extraction into ethyl acetate, and dry, evaporated under reduced pressure, obtains white solid 47.6g.MSm/z：146.0(M+1).
Chloro-6,6-dimethyl-6H-pyrimidines [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one of step 5:2-
4-amino-2-chloropyrimide-5-alcohol (48g) is added in acetonitrile 300ml, stirring at room temperature, add salt of wormwood (72g), 2-isobutyl bromide methyl esters (180g).Be warming up to 60 DEG C, stirring reaction 48 hours.Stopped reaction, is poured into water reaction solution, extraction into ethyl acetate, saturated common salt water washing, and dry, evaporate to dryness, obtains crude solid, and sherwood oil is pulled an oar, and filters, obtains white solid 38g.MSm/z：214.0(M+1).
1HNMR(400MHz，CDCl
3)δ8.14(s，1H)，1.59(s，6H).
[the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one of chloro-6, the 6-dimethyl-8-(3-nitrophenyl) of step 6:2--6H-pyrimidine [5,4-b]
By chloro-for 2-6,6-dimethyl-6H-pyrimidines [5,4-b], [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one (8g), neutralized verdigris (3.4g) join in dry methylene chloride 50ml.Add DIPEA (6.5ml), activated molecular sieve (8g), stirring at room temperature, add 3-nitrobenzene boronic acid (4g), stirred overnight at room temperature.Stopped reaction, adds diatomite filtration, petrol ether/ethyl acetate (10: 1) flush cake repeatedly.Filtrate is with saturated common salt water washing, and dry organic phase, evaporate to dryness, obtains crude solid.Add sherwood oil making beating, filter, obtain Tan solid 7.2g.MSm/z：335.0(M+1).
1HNMR(400MHz，CDCl
3)δ8.37(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 group-4-(4-methylpiperazine-1-yl) phenyl] is amino } [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one of-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b]
2-chloro-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (1.35g), 2-methoxyl group-4-(4-methylpiperazine-1-yl) aniline (1.2g) add in sec-butyl alcohol 5ml, trifluoroacetic acid adjusts pH to 4, is warming up to back flow reaction 3 hours.TLC thin-layer chromatography (methylene chloride/methanol=10: 1) be separated to obtain yellow oil 0.6g.MSm/z：520.2(M+1).
Step 8:8-(3-aminophenyl)-2-{ [2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] is amino } [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one of-6,6-dimethyl-6H-pyrimidines [5,4-b]
2-{ [2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] is amino }-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (100mg) are dissolved in methylene dichloride, add trifluoracetic acid, palladium carbon is appropriate, stirring reaction 2 hours under nitrogen atmosphere.Reacting liquid filtering removing palladium carbon, evaporated under reduced pressure, obtains colorless oil 80mg.MSm/z：490.2(M+1).
The synthesis of step 9:2-[4-(4-methylpiperazine-1-yl)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
8-(3-aminophenyl)-2-{ [2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl] is amino }-6,6-dimethyl-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (20mg) are dissolved in methylene dichloride 3ml, triethylamine (8mg), acrylate chloride (4mg) is added, stirring reaction 0.5 hour under ice bath.TLC thin-layer chromatography (methylene chloride/methanol=10: 1) be separated to obtain yellow oil 8mg.MSm/z：544.3(M+1).
1HNMR(400MHz，CDCl
3)δ8.04(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-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of the chloro-3-nitro of step 1:6--2-(2,2,2-trifluoro ethoxy) pyridine
2,6-dichloro-3-nitropyridine (3g), trifluoroethanol (1.58g) join in 20ml tetrahydrofuran (THF), add sodium hydrogen (altogether 0.41g) in batches, add stirring reaction 2 hours under ice bath.Reaction solution is poured into water, extraction into ethyl acetate, and organic phase is with clear water, saturated common salt water washing, dry, evaporated under reduced pressure, yellow oil 3.4g.MSm/z：257.0(M+1).
The synthesis of step 2:6-(4-methylpiperazine-1-yl)-3-nitro-2-(2,2,2-trifluoro ethoxy) pyridine
The chloro-3-nitro of 6--2-(2,2,2-trifluoro ethoxy) pyridine (0.3g) is dissolved in 3ml ethanol, adds methylpiperazine (0.49g) under stirring, is warming up to 50 DEG C of reactions 2 hours.Stopped reaction, adds clear water, extraction into ethyl acetate, and dry, evaporate to dryness, obtains yellow solid 140mg.MSm/z：321.3(M+1).
The synthesis of step 3:6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridine-3-amine
1-methyl-4-(5-nitro-6-(2,2,2-trifluoro ethoxy) pyridine-2-base) piperazine (140mg) is dissolved in methyl alcohol 4ml, adds appropriate palladium carbon, stirring reaction 1 hour under nitrogen atmosphere.Suction filtration, evaporate to dryness, obtains lavender oily matter 103mg.MSm/z：291.1(M+1).
Step 4:6,6-dimethyl-2-{ [6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl] amino-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
2-chloro-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (100mg), 6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridine-3-amine (79mg) joins in sec-butyl alcohol 2ml, and trifluoracetic acid adjusts pH to 3-4, heating reflux reaction 3 hours.TLC thin-layer chromatography (methylene chloride/methanol=10: 1) be separated to obtain yellow oil 50mg.MSm/z：589.2(M+1).
Step 5:6,6-dimethyl-8-(3-aminophenyl)-2-{ [6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl] amino-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
6,6-dimethyl-2-{ [6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl] amino-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (20mg) are dissolved in methylene dichloride, add appropriate palladium carbon, stirring reaction 3 hours under nitrogen atmosphere.Suction filtration, evaporate to dryness, obtains colorless oil 15mg.MSm/z：559.2(M+1).
Step 6:2-[6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
6,6-dimethyl-8-(3-aminophenyl)-2-{ [6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl] amino-6H-pyrimidine [5,4-b] [1,4] Bing oxazine-7 (8H)-one (75mg) are dissolved in methylene dichloride 3ml, add acrylate chloride (12.1mg), triethylamine (16.3mg), stirring at room temperature 3 hours under ice bath.TLC thin-layer chromatography (methylene chloride/methanol=10: 1) be separated to obtain yellow oil 10mg.MSm/z：613.2(M+1).
1HNMR(400MHz，CDCl
3)δ8.05(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-base)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-methoxyl group-4-(piperazine-1-base) oil of mirbane
Prepare according to embodiment 1 step 2 method.MSm/z：238.1(M+1).
The synthesis of step 2:2-methoxyl group-4-(4-Acetylpiperazine-1-base) oil of mirbane
2-methoxyl group-4-(piperazine-1-base) oil of mirbane (1.4g) is dissolved in methylene dichloride 25ml, adds triethylamine (0.89g), drips Acetyl Chloride 98Min. (0.6ml) under ice bath, drip off stirring reaction 2 hours.Add water cancellation, extraction into ethyl acetate, and organic layer washs with clear water, and dry, evaporated under reduced pressure, obtains yellow solid 1.2g.MSm/z：280.1(M+1).
The synthesis of step 3:2-methoxyl group-4-(4-Acetylpiperazine-1-base) aniline
Prepare according to embodiment 1 step 2 method.MSm/z：238.1(M+1).
Step 4:2-[4-(4-ethanoyl-piperazine-1-base)-2-anisole amido]-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] the synthesis of oxazine-7 (8H)-one
Prepare according to embodiment 1 step 7 method.MSm/z：548.2(M+1).
Step 4:2-[4-(4-Acetylpiperazine-1-base)-2-anisole amido]-6,6-dimethyl-8-(3-aminocarbonyl phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] the synthesis of oxazine-7 (8H)-one
Prepare according to embodiment 1 step 8 method.MSm/z：518.2(M+1).
Step 5:2-[4-(4-Acetylpiperazine-1-base)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] the synthesis of oxazine-7 (8H)-one
Prepare according to embodiment 1 step 9 method.MSm/z：572.3(M+1).
1HNMR(400MHz，CDCl
3)δ8.06(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-base)-2-(2; 2; 2-trifluoro ethoxy) pyridin-3-yl amido]-6; 6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5; 4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
According to each step method preparation of embodiment 2.MSm/z：641.2(M+1).
1HNMR(400MHz，CDCl
3)δ8.06(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) is amino }-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
According to each step method preparation of embodiment 1.MSm/z：546.3(M+1).
Embodiment 6:2-{6-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Step 1:N, N, N ' synthesis of-trimethylammonium-N '-(5-nitro-6-(2,2,2-trifluoro ethoxy) pyridine-2-base) ethane-1,2-diamines
Prepare according to embodiment 2 step 2 method.MSm/z：323.1(M+1).
1HNMR(400MHz，CDCl
3)δ8.30(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).
The synthesis of step 2:N '-(2-(dimethylamino) ethyl)-N '-methyl-6-(2,2,2-trifluoro ethoxy) pyridine-2,5-diamines
Prepare according to embodiment 2 step 3 method.MSm/z：293.2(M+1).
Step 3:2-{6-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 4 method.MSm/z：591.2(M+1).
1HNMR(400MHz，CDCl
3)δ8.36(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) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 5 method.MSm/z：561.2(M+1).
Step 5:2-{6-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 6 method.MSm/z：615.3(M+1).
1HNMR(400MHz，DMSO)δ8.05(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-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6; 6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5; 4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
The synthesis of the chloro-2-of step 1:6-[3-(methylthio group) propoxy-]-3-nitropyridine
2,6-dichloro-3-nitropyridine (0.96g), 3 methylthiol propyl alcohol (0.53g) join in 12ml tetrahydrofuran (THF), add sodium hydrogen (0.2g) under ice bath, add stirring reaction 1 hour.Reaction solution is poured into water, extraction into ethyl acetate, and organic phase is with clear water, saturated common salt water washing, dry, evaporated under reduced pressure, yellow oil 1.15g.
The synthesis of step 2:6-(4-methylpiperazine-1-yl)-2-[3-(methylthio group) propoxy-]-3-nitropyridine
The chloro-2-of 6-[3-(methylthio group) propoxy-]-3-nitropyridine (0.26g) is dissolved in 3ml ethanol, adds methylpiperazine (0.2g) under stirring, is warming up to 50 DEG C of reactions 2 hours.Stopped reaction, adds clear water, extraction into ethyl acetate, and dry, evaporate to dryness, obtains yellow oil 330mg.MSm/z：327.2(M+1).
The synthesis of step 3:6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridine-3-amine
6-(4-methylpiperazine-1-yl)-2-[3-(methylthio group) propoxy-]-3-nitropyridine (0.28g) is dissolved in 5ml ethanol, two equivalent ammonium persulfate-sodium bisulfate (Oxone) aqueous solution are dripped under ice bath, drip off stirring 10 minutes, remove ice bath, add iron powder (0.96g), saturated ammonium chloride solution (3ml), stirring reaction 2 hours.Extraction into ethyl acetate, clear water, saturated common salt water washing, dry, evaporated under reduced pressure, obtains tan solid 250mg.MSm/z：329.1(M+1).
Step 4:2-{6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6; 6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5; 4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 4 method.MSm/z：627.1(M+1).
Step 5:2-{6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6; 6-dimethyl-8-(3-aminocarbonyl phenyl)-6H-pyrimidine [5; 4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 5 method.MSm/z：597.3(M+1).
Step 6:2-{6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6; 6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5; 4-b] [the synthesis of Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one
Prepare according to embodiment 2 step 6 method.MSm/z：651.3(M+1).
1HNMR(400MHz，CDCl
3)δ8.05(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 ethyl) (methyl) amido ethyl] methylamino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
According to each step method preparation of embodiment 6.MSm/z：647.2(M+1).
1HNMR(400MHz，CDCl
3)δ8.06(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 ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
According to each step method preparation of embodiment 6.MSm/z：579.3(M+1).
1HNMR(400MHz，DMSO)δ10.44(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-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(3-methoxyl group-4-nitrophenoxy)-N, N-dimethyl amine
2-methoxyl group-4-fluoronitrobenzene (3.4g; 20mmol) be dissolved in 50mL tetrahydrofuran (THF), under room temperature, add the sodium hydrogen (1.2g, 30mmol) of 60%; gas in displacement bottle; under nitrogen protection, at reaction solution being cooled to 5 DEG C, drip containing N; N-dimethylethanolamine (2.2mL; tetrahydrofuran solution (20mL) 22mmol), dropwises, rises to room temperature reaction and spend the night.In reaction solution, add 4mL shrend to go out reaction, remove most of solvent under reduced pressure, use 100mL extraction into ethyl acetate.Organic layer washed with water 3 times, anhydrous sodium sulfate drying, filters, and filtrate concentrates, and is separated (ethyl acetate), obtains 2.2g product with silicagel column.Yield is 46%.MSm/z：241.3。
1HNMR(400MHz，CDCl
3)δ7.91(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)。
The synthesis of step 2:2-(3-methoxyl group-4-amino-benzene oxygen)-N, N-dimethyl amine
2-(3-methoxyl group-4-nitrophenoxy)-N, N-dimethyl amine (1.02g, 4.25mmol) is dissolved in 15mL ethanol, and under nitrogen protection, add palladium carbon (95mg), pass into hydrogen, room temperature reaction spends the night.Stop pass into hydrogen, by reacting liquid filtering, filter cake ethanol rinse, filtrate reduced in volume obtains 900mg black liquor, not purified be directly used in next step reaction.
Step 3:2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
By 2-(3-methoxyl group-4-amino-benzene oxygen)-N; N-dimethyl amine (700mg, 3.33mmol) is dissolved in 10mL2-amylalcohol, adds trifluoroacetic acid (0.22mL under room temperature; 2.96mmol); under nitrogen protection, add chloro-6, the 6-dimethyl-8-(3-nitrophenyl) of 2--6H-pyrimidine [5; 4-b] [1; 4] oxazine-7 (8H)-one, 120 DEG C are reacted 3 hours, and 100 DEG C of reactions are spent the night.React complete, by reaction solution concentrating under reduced pressure, (methylene dichloride: methane=100: 0-40: 1) obtains 500mg product in silicagel column separation.Yield is 30%.MSm/z：509.3。
1HNMR(400MHz，CDCl
3)δ8.39(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＝3.4Hz，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-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
By 2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [1,4] oxazine-7 (8H)-one (500mg, 0.98mmol) be dissolved in 3mL ethanol and 1mL water, add iron powder (190mg, 3.39mmol) and ammonium chloride (40mg, 0.75mmol), 80 DEG C are reacted 1 hour.Filter, filter cake ethanol rinse, evaporated under reduced pressure solvent, adds 100mL methylene dichloride, uses 50mL saturated solution of sodium bicarbonate, 50mL water washing successively.Dichloromethane layer anhydrous sodium sulfate drying, filter, evaporated under reduced pressure obtains 330mg solid.Yield is 70%.MSm/z：479.2。
Step 5:2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
By 2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [1,4] oxazine-7 (8H)-one (50mg, 0.105mmol) be dissolved in 2mL methylene dichloride, ice-water bath cools, and adds acrylate chloride (8.5 μ L, 0.105mmol).React 1 hour under room temperature, remove solvent under reduced pressure, (methylene dichloride: methyl alcohol=5: 1) obtains 28mg product to prepare plate separation and purification.Yield is 50%.MSm/z：533.3。
1HNMR(400MHz，CDCl
3)δ9.25(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＝4.9Hz，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-(dimethylin) acetamido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-dimethylamino-N-[3-methoxyl group-4-(the two tert-butoxycarbonylamino of N, N-)] ethanamide
2-dimethylin acetic acid (0.43g is added in 100mL single port bottle, 4.14mmol), 20mLN, N-N,N-DIMETHYLACETAMIDE, diisopropyl ethyl amine (1.15g, 8.87mmol) with 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (1.8g, 4.73mmol), stirred at ambient temperature 15 minutes, adds 3-methoxyl group-4-[N, N-(two tert-butoxycarbonyl) amido] aniline (1.0g, 2.96mmol), stirring 1 hour is continued under room temperature.In reaction solution, add 150mL ethyl acetate, use water (100mL × 2) and saturated brine (100mL) washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.With silicagel column separation, (methylene dichloride: methyl alcohol=10: 1) obtains 0.7g product to residue.Yield is 56%.MSm/z：424。
The synthesis of step 2:2-dimethylamino-N-(3-methoxyl group-4-is amino) ethanamide
2-dimethylamino-N-[3-methoxyl group-4-(the two tert-butoxycarbonylamino of N, N-)] ethanamide (0.6g, 1.4mmol) is added, 5mL methylene dichloride and 5mL trifluoroacetic acid, stirred at ambient temperature 4 hours in 50mL single port bottle.By reaction solution evaporated under reduced pressure, residue is dissolved in 100mL methylene dichloride, and use 80mL saturated sodium bicarbonate and the water washing of 80mL saturated common salt successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains 0.24g tan solid, static after fixing.Yield is 76%.MSm/z：224。
1HNMR(400MHz，CDCl
3)δ8.93(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-(dimethylin) acetamido]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
2-chloro-6 is added in 25mL single port bottle, 6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5, 4-b] [1, 4] oxazine-7 (8H)-one (150mg, 0.45mmol), 2-dimethylamino-N-(3-methoxyl group-4-is amino) ethanamide (120mg, 0.54mmol), three (dibenzalacetone) two palladium (25mg, 0.03mmol), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (31mg, 0.054mmol), potassiumphosphate (190mg, 0.90mmol) with under the nitrogen protection of 6mL dioxane, 100 DEG C of reactions are spent the night.Diatomite drainage, filtrate decompression evaporate to dryness, (methylene dichloride: methyl alcohol=10: 1) obtains 120mg product to prepare plate separation.Yield is 51%.MSm/z：522。
Step 4:2-{4-[2-(dimethylin) acetamido]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 4 of embodiment 10.Yield is 71%.MSm/z：492。
Step 5:2-{4-[2-(dimethylin) acetamido]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 30%.MSm/z：546。
1HNMR(400MHz，DMSO-d6)δ10.45(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-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy-3-nitropyridine
By 2-trifluoro ethoxy-3-nitro-6-chloropyridine (256mg, 1mmol) be dissolved in 2mL Virahol, add N, N-dimethyl-2-(methylamino) ethanamide (348mg, 3mmol), reacts 1 hour under room temperature, solid is had to separate out in reaction solution, raw material is not exhausted, and adds 0.5mL diisopropyl ethyl amine in reaction solution, continues reaction 1.5 hours.Filter, filter cake washed with isopropyl alcohol, obtains 257mg yellow solid.Yield is 76%.MSm/z：337.1。
1HNMR(400MHz，CDCl
3)δ8.32(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)。
The synthesis of step 2:6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy-3-amido pyridine
6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy-3-nitropyridine (250mg, 0.74mmol) is suspended in 6mL methyl alcohol, adds 20mg platinum dioxide, pass into hydrogen, stirred at ambient temperature 1 hour.Filter, filtrate reduced in volume, silicagel column is separated (ethyl acetate), obtains 220mg product.Yield is 97%.MSm/z：307.2。
1HNMR(400MHz，CDCl
3)δ7.03(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-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
To 6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy-3-amido pyridine (92mg, 0.3mmol), 2-chloro-6, 6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5, 4-b] [1, 4] oxazine-7 (8H)-one (150mg, 0.45mmol) with potassiumphosphate (175mg, 2mL dioxane is added in mixture 0.825mmol), three (dibenzalacetone) two palladium (17mg, 0.018mmol) He 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (21mg, 0.036mmol), under nitrogen protection, 90 DEG C of reactions are spent the night.Diatomite drainage, filtrate decompression evaporate to dryness, (methylene dichloride: methyl alcohol=20: 1) obtains 85mg product to prepare plate separation.Yield is 47%.MSm/z：605.2。
1HNMR(400MHz，CDCl
3)δ8.39-8.35(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-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-aminocarbonyl phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is identical with the step 2 of embodiment 12.Yield is 82%.MSm/z：575.2。
Step 5:2-[6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 28%.MSm/z：629.3。
1HNMR(400MHz，CDCl
3)δ8.64(s，1H)，8.03(s，1H)，7.65-7.51(m，3H)，7.37(t，J＝8.0Hz，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 vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
Step 1:N-methyl-N-{2-[methyl (5-nitro-6-trifluoro ethoxy pyridine-2-base) amido] ethyl } synthesis of ethanamide
The synthesis of this compound is with the step 1 of embodiment 12.
Step 2:N-methyl-N-{2-[methyl (5-amino-6-trifluoro ethoxy pyridine-2-base) amido] ethyl } synthesis of ethanamide
The synthesis of this compound is with the step 2 of embodiment 12.
Step 3:2-{6-[(2-(N-methyl vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 58%.MSm/z：619。
Step 4:2-{6-[(2-(N-methyl vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 88%.MSm/z：589。
Step 5:2-{6-[(2-(N-methyl vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 44%.MSm/z：643。
1HNMR(400MHz，DMSO-d6)δ10.41(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-hydroxyethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-trifluoro ethoxy-3-nitro-6-(2-hydroxyethyl methylamino) pyridine
In 2-trifluoro ethoxy-3-nitro-6-chloropyridine (456mg, 1.78mmol), add 2-methyl aminoethanol (2mL, 25mmol), react 1 hour under room temperature.In reaction solution, add 30mL water, separate out yellow solid.Filter, filter cake washes with water, dries.Thick product silicagel column is separated, and obtains 410mg solid.Yield is 79%.MSm/z：296.1。
1HNMR(400MHz，CDCl
3)δ8.30(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)。
The synthesis of step 2:2-trifluoro ethoxy-3-amido-6-(2-hydroxyethyl methylamino) pyridine
The synthesis of this compound is identical with the step 4 of embodiment 10.Yield is 96%.MSm/z：266.3。
1HNMR(400MHz，CDCl
3)δ7.00(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-hydroxyethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is identical with the step 3 of embodiment 11.Yield is 11%.MSm/z：588.3。
1HNMR(400MHz，CDCl
3)δ8.05(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-base)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-trifluoro ethoxy-3-nitro-6-(4-dimethylamino piperidine-1-base) pyridine
2-trifluoro ethoxy-3-nitro-6-chloropyridine (256mg, 1mmol) be dissolved in 2mL methylene dichloride, add 4-dimethylamino piperidine (140mg, 1.1mmol), react 2 hours under room temperature, raw material unreacted is complete, reacts 10 minutes under adding 4-dimethylamino piperidine (0.5mL, 3.55mmol) room temperature.30mL water is added, 100mL extraction into ethyl acetate in reaction solution.Organic layer washed with water twice, anhydrous sodium sulfate drying, filter, evaporated under reduced pressure obtains 298mg product.Yield is 86%.
1HNMR(400MHz，DMSO)δ8.23(d，J＝9.3Hz，1H)，6.65(d，J＝9.3Hz，1H)，5.09(q，J＝9.0Hz，2H)，4.47(brs，2H)，3.07(t，J＝12.0Hz，2H)，2.63(brs，1H)，2.28(s，6H)，1.91(d，J＝12.2Hz，2H)，1.42(qd，J＝12.3，3.6Hz，2H)。
MSm/z：349.2。
The synthesis of step 2:2-trifluoro ethoxy-3-amino-6-(4-dimethylamino piperidine-1-base) pyridine
The synthesis of this compound is identical with the step 4 of embodiment 10.Yield is 74%.
Step 3:2-[6-(4-dimethylamino piperidine-1-base)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is identical with the step 3 of embodiment 11.
1HNMR(400MHz，CDCl
3)δ9.05(s，1H)，8.06(s，1H)，7.88-7.78(m，2H)，7.69(d，J＝8.6Hz，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 ethoxy-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(dimethylin)-N-(5-nitro-6-trifluoro ethoxy pyridine-2-base) ethanamide
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 72%.MSm/z：323。
1HNMR(400MHz，CDCl
3)δ9.76(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)。
The synthesis of step 2:2-(dimethylin)-N-(5-amino-6-trifluoro ethoxy pyridine-2-base) ethanamide
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 88%.MSm/z：293。
Step 3:2-[2-trifluoro ethoxy-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 46%.MSm/z：615。
1HNMR(400MHz，CDCl
3)δ9.23(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 group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-methoxyl group-3-nitro-6-(2-dimethylin-2-oxoethyl methylamino-) pyridine
The synthesis of this compound is with the step 1 of embodiment 12.Yield is 62%.MSm/z：291.1。
1HNMR(400MHz，CDCl
3)δ8.30(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)。
The synthesis of step 2:2-methoxyl group-3-amido-6-(2-dimethylin-2-oxoethyl methylamino-) pyridine
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 90%.
Step 3:2-[2-methoxyl group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 38%.MSm/z：537.2。
Step 4:2-[2-methoxyl group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-aminocarbonyl phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 87%.
Step 5:2-[2-methoxyl group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 19%.MSm/z：561.2。
1HNMR(400MHz，CDCl
3)δ8.38(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 group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(dimethylin)-N-(5-nitro-6-methoxypyridine-2-base) ethanamide
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 49%.MSm/z：255。
1HNMR(400MHz，CDCl
3)δ9.72(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)。
The synthesis of step 2:2-(dimethylin)-N-(5-amino-6-methoxypyridine-2-base) ethanamide
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 99%.MSm/z：225。
Step 3:2-[2-methoxyl group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 43%.MSm/z：523。
Step 4:2-[2-methoxyl group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5, the 4-b] [synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 71%.MSm/z：493。
Step 5:2-[2-methoxyl group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 54%.MSm/z：547。
1HNMR(400MHz，CDCl
3)δ9.20(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 group-6-(4-dimethylamino piperidine-1-base) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-methoxyl group-3-nitro-6-(4-dimethylamino piperidine-1-base) pyridine
2-methoxyl group-3-nitro-6-chloropyridine (376mg, 2mmol) is dissolved in 4mL Virahol, adds 4-dimethylamino piperidine (0.56mL, 4mmol), reacts 4 hours, have solid to separate out in reaction solution under room temperature.Filter, filter cake Virahol drip washing, dry, obtain 300mg product.Yield is 54%.MSm/z：281.4。
The synthesis of step 2:2-methoxyl group-3-amino-6-(4-dimethylamino piperidine-1-base) pyridine
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 75%.MSm/z：251.2。
Step 3:2-[2-methoxyl group-6-(4-dimethylamino piperidine-1-base) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 9%.MSm/z：573.4。
1HNMR(400MHz，CDCl
3)δ8.47(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 group-6-[4-Acetylpiperazine-1-base] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(4-Acetylpiperazine-1-base)-5-nitro-6-methoxypyridine
The synthesis of this compound is with the step 1 of embodiment 12.
The synthesis of step 2:2-(4-Acetylpiperazine-1-base)-5-amido-6-methoxypyridine
The synthesis of this compound is with the step 2 of embodiment 12.
Step 3:2-{2-methoxyl group-6-[4-Acetylpiperazine-1-base] pyridin-3-yl amido } [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one of-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b]
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 22%.MSm/z：573。
1HNMR(400MHz，CDCl
3)δ8.06(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 group-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:6-methoxy-. N-methyl-5-nitro-N-[2-(pyrrolidin-1-yl) ethyl]-pyridine-2-amine
The synthesis of this compound is with the step 1 of embodiment 12.
Step 2:6-methoxyl group-H
2-methyl H
2the synthesis of-[2-(pyrrolidin-1-yl) ethyl] pyridine-2,5-diamines
The synthesis of this compound is with the step 2 of embodiment 12.
Step 3:2-{2-methoxyl group-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 22%.MSm/z：573。
1HNMR(400MHz，CDCl
3)δ9.85(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(brs，2H)，3.21(t，J＝6.6Hz，2H)，3.01(s，3H)，2.84(brs，2H)，2.21(brs，2H)，2.09(brs，2H)，1.63(s，6H)。
Embodiment 22:2-{2-methoxyl group-6-[4-methylpiperazine-1-yl] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(4-methylpiperazine-1-yl)-5-nitro-6-methoxypyridine
The synthesis of this compound is with the step 1 of embodiment 12.
The synthesis of step 2:2-(4-methylpiperazine-1-yl)-5-amido-6-methoxypyridine
The synthesis of this compound is with the step 2 of embodiment 12.
Step 3:2-{2-methoxyl group-6-[4-methylpiperazine-1-yl] pyridin-3-yl amido } [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one of-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b]
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 26%.MSm/z：545。
1HNMR(400MHz，CDCl
3)δ8.27(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(brs，4H)，2.83(brs，4H)，2.54(s，3H)，1.62(s，6H)。
Embodiment 23:2-{2-methoxyl group-6-[1-(2-fluoro ethyl) azetidine-3-amido] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(N-tertbutyloxycarbonyl azetidin ring-3-amido)-5-nitro-6-methoxypyridine
By 2-methoxyl group-3-nitro-6-chloropyridine (1.32g, 7.02mmol) be dissolved in 1mL methyl-sulphoxide, add 3-amino-1-tertbutyloxycarbonyl azetidine (2.4g, 13.95mmol) with diisopropyl ethyl amine (2.5mL, 14.34mmol), 100 DEG C are reacted 2 hours, are cooled to room temperature.Add 50mL water, 50mL extraction into ethyl acetate.Organic layer washed with water, anhydrous sodium sulfate drying, filters, filtrate decompression evaporate to dryness.(methylene dichloride: ethyl acetate=100: 0-5: 1) obtains 2.2g product in thick product silicagel column separation.Yield is 97%.
1HNMR(400MHz，CDCl
3)δ8.24(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)。
The synthesis of step 2:2-(azetidin ring-3-amido)-5-nitro-6-methoxypyridine two (trifluoroacetic acid) salt
2-(N-tertbutyloxycarbonyl azetidin ring-3-amido)-5-nitro-6-methoxypyridine (2.2g, 6.8mmol) is dissolved in 20mL methylene dichloride, 10mL trifluoroacetic acid, reacts 1 hour under room temperature.Remove solvent under reduced pressure, in residue, add q. s. toluene, again evaporated under reduced pressure, obtain yellow crude, be directly used in next step reaction.MSm/z：225.2。
The synthesis of step 3:2-[N-(2-fluoro ethyl) azetidin ring-3-amido]-5-nitro-6-methoxypyridine
To 2-(azetidin ring-3-amido)-5-nitro-6-methoxypyridine two (trifluoroacetic acid) salt (400mg, 10mL acetonitrile is added 1.883mmol), cesium carbonate (860mg, 2.65mmol), the bromo-1-fluoroethane of 2-(59 μ L, 0.795mmol), 50 DEG C of reactions are spent the night.10mL water is added, 20mL extraction into ethyl acetate in reaction solution.Organic layer washed with water twice, anhydrous sodium sulfate drying, filters, filtrate decompression evaporate to dryness, and (ethyl acetate: methyl alcohol=20: 1) obtains 40mg product to prepare plate separation.Yield is 8%.MSm/z：271.1。
The synthesis of step 4:2-[N-(2-fluoro ethyl) azetidin ring-3-amido]-5-amino-6-methoxypyridine
The synthesis of this compound is identical with the step 2 of embodiment 12.Yield is 100%.
Step 5:2-{2-methoxyl group-6-[1-(2-fluoro ethyl) azetidine-3-amido] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 11%.MSm/z：563.3。
1HNMR(400MHz，CDCl
3)δ8.37(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-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6; 6-dimethyl-6H-pyrimidine [5; 4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthetic method of this compound is with embodiment 1.
1HNMR(400MHz，CDCl
3)δ7.99(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-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6; 6-dimethyl-6H-pyrimidine [5; 4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthetic method of this compound is with embodiment 1.
1HNMR(400MHz，CDCl3)δ7.99(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-sec.-propyl oxygen base-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthetic method of this compound is with embodiment 21.
1HNMR(400MHz，CDCl
3)δ9.86(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(brs，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-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:2-(dimethylin)-N-methyl-N-(3-methoxyl group-4-nitrophenyl) ethanamide
N-methyl-3-methoxyl group-4-N-methyl-p-nitroaniline (600mg is added in 100mL single port bottle, 3.3mmol) and 25mLN, dinethylformamide, ice-water bath is cooled to 5 DEG C, adds the sodium hydrogen (1.32g, 33mmol) of 60%, stir after 10 minutes, add 2-dimethylaminoacetyl chloride (1.2g, 9.9mmol), continue stirring 2 hours.150mL ethyl acetate is added in reaction solution, water (120mL × 2), saturated nacl aqueous solution (120mL) is used to wash successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, silicagel column is separated (methylene dichloride: methyl alcohol=10: 1), obtain 220mg product, yield is 25%.MSm/z：268。
The synthesis of step 2:2-(dimethylin)-N-methyl-N-(3-methoxyl group-4-aminophenyl) ethanamide
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 92%.MSm/z：238。
Step 3:2-{4-[2-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 74%.MSm/z：536。
Step 4:2-{4-[2-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 79%.MSm/z：506。
Step 5:2-{4-[2-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [the synthesis of Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 34%.MSm/z：560。
1HNMR(400MHz，DMSO-d6)δ10.58(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-(dimethylin) propionamido-]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of step 1:3-dimethylin-N-[3-methoxyl group-4-(the two tert-butoxycarbonylamino of N, N-) phenyl] propionic acid amide
The synthesis of this compound is with the step 1 of embodiment 11.Yield is 29%.MSm/z：438。
The synthesis of step 2:3-dimethylin-N-(3-methoxyl group-4-aminophenyl) propionic acid amide
The synthesis of this compound is with the step 2 of embodiment 11.Yield is 86%.MSm/z：238。
Step 3:2-{4-[3-(dimethylin) propionamido-]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-nitrophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 3 of embodiment 11.Yield is 51%.MSm/z：536。
Step 4:2-{4-[3-(dimethylin) propionamido-]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-aminophenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 2 of embodiment 12.Yield is 79%.MSm/z：506。
Step 5:2-{4-[3-(dimethylin) propionamido-]-2-anisole amido } synthesis of-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with the step 5 of embodiment 10.Yield is 24%.MSm/z：560。
1HNMR(400MHz，CDCl
3)δ9.82(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 group-6-(3-dimethylin pyrrolidin-1-yl) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one
The synthesis of this compound is with embodiment 19.
1HNMR(400MHz，CDCl
3)δ8.74(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 human skin cancer cells (A431, Wild type EGFR), human lung carcinoma cell (HCC827, EGFR19 exon absence type activated mutant), human lung carcinoma cell (sudden change of H1975, EGFRL858R/T790M drug-resistant type) inhibited proliferation
Get the cell being in logarithmic phase and be seeded in 96 orifice plates that (cell concn is 5000/hole; Cell suspension 180 μ l/ hole), 37 DEG C, 5%CO
2cultivate and make cell attachment in 24 hours.Each compound is dissolved in DMSO the storage liquid being mixed with 10mM in advance, in another 96 orifice plate, be diluted to 10 times of object concentration again with perfect medium when detecting, then in 96 orifice plates of inoculating cell, add compound 20 μ l/ hole, namely arrive object concentration.Each concentration establishes 3 multiple holes, and establishes blank.Continue at 37 DEG C, 5%CO
2middle continuation cultivation 72 hours.Stop cultivating, every hole adds 50% trichoroacetic acid(TCA) and the TCA (final concentration 10%) of 50 μ l precoolings (4 DEG C), is placed on 4 DEG C and fixes 1 hour, with purified water washing at least 5 times, and seasoning or 60 DEG C of oven dryings in air.With Sulforhodamine B and SRB of the purified water preparation 4mg/ml containing 1% glacial acetic acid, every hole adds 100 μ l, and room temperature dyeing 1H, abandons supernatant, with 1% glacial acetic acid washing at least 5 removing non-specific bindings, and dried for standby.Every hole adds the Tris-HCl solubilize of the 10mM of 150 μ l, surveys OD value at 510nm wavelength place, and carries out data preparation calculating inhibiting rate.The results are shown in Table 1:
Table 1
| HCC827 | H1975 | A431 | |
| Embodiment 1 compound | A | A | B |
| Embodiment 2 compound | A | A | D |
| Embodiment 3 compound | A | C | D |
| Embodiment 4 compound | A | A | D |
| Embodiment 5 compound | A | A | C |
| Embodiment 6 compound | A | A | C |
| Embodiment 7 compound | B | C | D |
| Embodiment 8 compound | A | A | B |
| Embodiment 9 compound | A | B | B |
| Embodiment 10 compound | A | A | D |
| Embodiment 11 compound | A | A | C |
| Embodiment 12 compound | A | B | D |
| Embodiment 13 compound | A | A | D |
| Embodiment 14 compound | A | A | D |
| Embodiment 15 compound | A | A | D |
| Embodiment 16 compound | A | C | D |
| Embodiment 17 compound | A | C | D |
| Embodiment 18 compound | A | C | D |
| Embodiment 19 compound | A | A | C |
| Embodiment 20 compound | A | A | D |
| Embodiment 21 compound | A | A | C |
| Embodiment 22 compound | A | A | C |
| Embodiment 23 compound | A | B | D |
| Embodiment 24 compound | B | C | D |
| Embodiment 25 compound | B | C | D |
| Embodiment 26 compound | B | C | D |
| Embodiment 27 compound | A | B | D |
| Embodiment 28 compound | B | B | D |
| Embodiment 29 compound | A | B | D |
A represents that IC50 is 1-100nM; B represents that IC50 is 100-500nM;
C represents that IC50 is 500-1000nM; D represents that IC50 is 1000-10000nM
Test result shows: the compounds of this invention is to human lung carcinoma cell (HCC827, EGFR19 exon absence type activated mutant), human lung carcinoma cell (H1975, EGFRL858R/T790M drug-resistant type suddenlys change) there is good inhibited proliferation, to human skin cancer cells (A431, Wild type EGFR) increment restraining effect relatively weak, selectivity is good.
The all documents mentioned in this article are merged in the application all by reference.What should indicate in addition is, after the above-mentioned disclosure of having read the application, those skilled in the art can without the need to deviating from the spirit and scope of the present invention, various modification, change or amendment are made to the present invention, but these versions equally all should fall within the scope described in the application's appended claims.
Claims (25)
1. a formula I, or its pharmacy acceptable salt,
In formula:
Ring A is aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl ,-OR
7,-C (O) R
7,-C (O) NR
7r
7' ,-NR
7r
7', halogen ,-NO
2; Or R
1, R
2cyclization forms cycloalkyl or Heterocyclylalkyl together be connected carbon atom;
Each R
3be halogen, C independently
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
1-C
4alkyl ,-OR
6,-C (O) R
7,-C (O) NR
7r
7' ,-OR
7,-NR
7r
7' ,-CN or-NO
2;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SOR
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Wherein work as R
4for
time, its amide nitrogen atom is participated in formation ring A directly as heteroatoms and is obtained heteroaryl or Heterocyclylalkyl;
R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' ,-(CH
2)
qnR
7c (O) R
7,-(CH
2)
qc (O) R
7or-(CH
2)
qc (O) NR
7r
7';
R
7and R
7' be separately hydrogen, C
1-C
4alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 4;
N is the integer of 1 ~ 5;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl or-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Wherein, R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that described each R
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl), NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SOR
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Described R
4for
wherein work as R
4for
time, its amide nitrogen atom is participated in formation ring A directly as heteroatoms and is obtained heteroaryl or Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' ,-(CH
2)
qnR
7c (O) R
7,-(CH
2)
qc (O) R
7or-(CH
2)
qc (O) NR
7r
7';
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
4. the compound as described in any one of claims 1 to 3 or its pharmacy acceptable salt, is characterized in that described compound is formula (Ia) compound,
Wherein, ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl or-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-SO that substituting group replaces
2r
6r
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
5. compound as claimed in claim 4 or its pharmacy acceptable salt, it is characterized in that described ring B aryl is phenyl, described ring B heteroaryl is selected from pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl-, indyl, pseudoindoyl or 1,2,3,4-tetrahydro isoquinolyl.
6. compound as claimed in claim 4 or its pharmacy acceptable salt, is characterized in that described R
4for
Wherein, R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl.
7. compound as claimed in claim 4 or its pharmacy acceptable salt, is characterized in that each R
5be halogen ,-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7azetidine base ,-O (CH that substituting group replaces
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace piperazinyl, piperidyl or pyrrolidyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
8. compound as claimed in claim 4 or its pharmacy acceptable salt, is characterized in that described compound is formula (Ia-1) compound,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
9. compound as claimed in claim 8 or its pharmacy acceptable salt, is characterized in that each R
5be-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6or-NR
6r
7, or do not replace or be selected from C by 1
1-C
4alkyl or-C (O) R
7substituting group replace piperazinyl;
Wherein, R
6for-(CH
2)
qnR
7r
7';
R
7and R
7' be separately hydrogen or C
1-C
4alkyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 2;
P is the integer of 0 ~ 2.
10. compound as claimed in claim 4 or its pharmacy acceptable salt, is characterized in that described compound is formula (Ia-2) compound,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7sO
2r
7,-NR
7-do not replace or be selected from R by 1 ~ 2
7heterocyclylalkyl ,-O (CH that substituting group replaces
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
R
4for
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
11. compound as claimed in claim 10 or its pharmacy acceptable salts, is characterized in that each R
5be-OR independently
7,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-NR
7-by 1 halo C
1-C
4azetidine base ,-O (CH that alkyl replaces
2)
qsO
2r
7, or be selected from C by 1
1-C
4alkyl ,-NR
7r
7' or-C (O) R
7substituting group replace piperazinyl, piperidyl or pyrrolidyl;
Wherein R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form pyrrolidyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 3;
P is the integer of 0 ~ 3.
12. compounds as described in claim 8 or 10 or its pharmacy acceptable salt, is characterized in that described R
4for
wherein, R
7for hydrogen.
13. compounds as described in any one of claims 1 to 3 or its pharmacy acceptable salt, is characterized in that described compound is formula (Ib) compound,
Wherein, ring B is aryl or heteroaryl;
R
1, R
2be selected from C independently of one another
1-C
4alkyl, C
2-C
6alkynyl ,-CN, halo C
1-C
4alkyl ,-C (O) NR
7r
7', or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen, C independently
1-C
4alkyl, halo C
1-C
4alkyl or-OR
7;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-C (O) R
6,-C (O) R
7,-COOR
7,-C (O) NR
7r
7' ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-SO
2r
6r
7,-SO
2nR
7r
7' ,-NR
7sO
2r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
14. compound as claimed in claim 13 or its pharmacy acceptable salts, it is characterized in that described ring B aryl is phenyl, described ring B heteroaryl is selected from pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl-, indyl, pseudoindoyl or 1,2,3,4-tetrahydro isoquinolyl.
15. compound as claimed in claim 13 or its pharmacy acceptable salts, is characterized in that each R
5be halogen ,-OR independently
7,-OR
6,-NR
7(CH
2)
pc (O) R
6,-NR
6r
7,-O (CH
2)
qsO
2r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-c
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace piperazinyl or piperidyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form piperidyl or pyrrolidyl;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
16. compound as claimed in claim 13 or its pharmacy acceptable salts, is characterized in that described compound is formula (Ib-1) compound,
Wherein, R
1, R
2be selected from C independently of one another
1-C
4alkyl, or R
1, R
2cyclization forms cyclopropane base, tetramethylene base or oxetanyl together be connected carbon atom,
Each R
3be halogen or C independently
1-C
4alkyl;
Each R
5be halogen ,-CN ,-NO independently
2, C
1-C
4alkyl, halo C
1-C
4alkyl ,-OR
7,-OR
6,-NHR
7,-NR
7-(C
1-C
4alkyl) ,-NR
7-(halo C
1-C
4alkyl) ,-NR
7sO
2r
7,-NR
7(CH
2)
pc (O) R
6or-NR
6r
7, or do not replace or be selected from halogen, C by 1 ~ 3
1-C
4alkyl, halo C
1-C
4alkyl ,-(CH
2)
qoH ,-NR
7r
7' ,-OR
7or-C (O) R
7substituting group replace Heterocyclylalkyl;
Wherein, R
6for-(CH
2)
qoR
7,-(CH
2)
qnR
7r
7' or-(CH
2)
qnR
7c (O) R
7;
R
7and R
7' be separately hydrogen, C
1-C
4alkyl or halo C
1-C
4alkyl, or R
7, R
7' together be connected nitrogen-atoms cyclization form Heterocyclylalkyl;
M is the integer of 0 ~ 3;
N is the integer of 1 ~ 3;
Q is the integer of 0 ~ 4;
P is the integer of 0 ~ 4.
17. compound as claimed in claim 16 or its pharmacy acceptable salts, is characterized in that described each R
5be-OR independently
7or-NR
6r
7,
Wherein, R
6for-(CH
2)
qnR
7r
7';
R
7and R
7' be separately C
1-C
4alkyl or halo C
1-C
4alkyl;
N is the integer of 1 ~ 2;
Q is the integer of 0 ~ 2.
18. compounds as described in claim 8 or 10 or 16 or its pharmacy acceptable salt, is characterized in that R
1, R
2be selected from C independently of one another
1-C
4alkyl, and m is 0.
19. compound as claimed in claim 1 or its pharmacy acceptable salts, it is selected from:
2-[4-(4-methylpiperazine-1-yl)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[4-(4-Acetylpiperazine-1-base)-2-anisole amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-Acetylpiperazine-1-base)-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-{ [2-(dimethyl amido) ethyl] (methyl) is amino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-(4-methylpiperazine-1-yl)-2-[3-(methyl sulphonyl) propoxy-] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] Bing oxazine-7 (8H)-one;
2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-(2,2,2-trifluoro ethoxy) pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin) oxyethyl group]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin) acetamido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(2-dimethylin-2-oxoethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{6-[(2-(N-methyl vinyl amido) ethyl dimethylamine base)]-2-trifluoro ethoxy pyridine-3-base amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(2-hydroxyethyl methylamino-)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[6-(4-dimethylamino piperidine-1-base)-2-trifluoro ethoxy pyridine-3-base amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-trifluoro ethoxy-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(2-dimethylin-2-oxoethyl methylamino-) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(2-dimethylaminoacetyl amido) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-[2-methoxyl group-6-(4-dimethylamino piperidine-1-base) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[4-Acetylpiperazine-1-base] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[4-methylpiperazine-1-yl] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-methoxyl group-6-[1-(2-fluoro ethyl) azetidine-3-amido] pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(R)-8-(1-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(S)-8-(1-acryl pyrrolidin-3-yl) 2-{6-{ [2-(2-fluoro ethyl) (methyl) amido ethyl] methylamino }-2-methoxypyridine-3-base amido }-6,6-dimethyl-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{2-sec.-propyl oxygen base-6-{ methyl [2-(pyrrolidin-1-yl) ethyl] amido } pyridin-3-yl amido }-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[2-(dimethylin)-N-methyl vinyl amido]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
2-{4-[3-(dimethylin) propionamido-]-2-anisole amido }-6,6-dimethyl-8-(3-acrylamide phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one;
(R)-2-[2-methoxyl group-6-(3-dimethylin pyrrolidin-1-yl) pyridin-3-yl amido]-6,6-dimethyl-8-(3-acrylamido phenyl)-6H-pyrimidine [5,4-b] [Isosorbide-5-Nitrae] oxazine-7 (8H)-one.
20. methods preparing formula (I) compound as claimed in claim 1, it comprises the following steps,
Wherein, ring A, ring B, R
1, R
2, R
3, R
4, R
5, m and n as claimed in claim 1,
With 2, 4-dichloro-5-methoxy pyrimidine is starting raw material, compound (a) is obtained with ammonia generation ammonolysis reaction, compound (a) obtains compound (b) through boron tribromide demethylation, there is cyclization with halo acid esters (g) again and obtain compound (c), compound (c) and compound (h) carry out Suzuki linked reaction (Suzukireaction) and obtain compound (d), there is substitution reaction and obtain compound (e) in compound (d) and amine (i), the nitro of reducing compound (e) obtains compound (f), amino and the suitable carboxylic acid halides generation amidate action of compound (f) obtain compound (I).
21. 1 kinds of pharmaceutical compositions, comprise formula (I) compound or its pharmacy acceptable salt and drug acceptable carrier, vehicle or thinner.
Compound described in 22. any one of claim 1 ~ 19 is in the application of the preparation treatment Mammals especially mankind by the medicine of EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type.
Compound described in 23. any one of claim 1 ~ 19 the treatment Mammals especially mankind by the application in EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type.
Treat Mammals especially the mankind are by the method for EGFR activated form or mutant mediated disease, the particularly cancer of drug-resistant type for 24. 1 kinds, described method comprises to be used formula (I) compound or its pharmacy acceptable salt to patient or comprises treatment formula (I) compound of significant quantity and the pharmaceutical composition of drug acceptable carrier, vehicle or thinner.
25. 1 kinds are optionally suppressed the methods of EGFR activated form in biological sample or in patient or drug-resistant type sudden change compared to Wild type EGFR (WTEGFR), and described method comprises makes biological sample contact or to patient's administration formula (I) compound or its pharmacy acceptable salt or its pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410289021.XA CN105218561B (en) | 2014-06-25 | 2014-06-25 | Annelated pyrimidines ring derivatives, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410289021.XA CN105218561B (en) | 2014-06-25 | 2014-06-25 | Annelated pyrimidines ring derivatives, preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105218561A true CN105218561A (en) | 2016-01-06 |
| CN105218561B CN105218561B (en) | 2018-10-30 |
Family
ID=54987893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410289021.XA Active CN105218561B (en) | 2014-06-25 | 2014-06-25 | Annelated pyrimidines ring derivatives, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105218561B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017144025A1 (en) * | 2016-02-26 | 2017-08-31 | 华东理工大学 | Pyrimido[4,5-d][1,3]oxazin-2-one derivative serving as egfr inhibitor, and application thereof |
| WO2017177837A1 (en) * | 2016-04-11 | 2017-10-19 | 上海勋和医药科技有限公司 | Heterocyclic-substituted pyridinopyrimidinone derivative as cdk inhibitor and use thereof |
| CN110294721A (en) * | 2019-07-22 | 2019-10-01 | 安庆缘启医药科技有限公司 | The synthesis technology of 1- acetyl group -4- [3- (methyl oxygroup) -4- nitrobenzophenone] piperazine |
| WO2022116943A1 (en) * | 2020-12-02 | 2022-06-09 | 上海瑛派药业有限公司 | Substituted fused bicyclic compound as kinase inhibitor and use thereof |
| CN115160340A (en) * | 2022-06-07 | 2022-10-11 | 四川大学华西医院 | Small molecule compound with ACK1 inhibitory activity and application thereof |
| WO2023245611A1 (en) * | 2022-06-24 | 2023-12-28 | 四川大学华西医院 | Small molecule compound with ttk inhibitory activity, preparation method therefor, and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3549627A (en) * | 1968-04-05 | 1970-12-22 | American Home Prod | 2,6-disubstituted-4h-pyrimido(5,4-d)(1,3)oxazin-4-0nes |
| CN1147205A (en) * | 1994-03-04 | 1997-04-09 | 伊莱利利公司 | Antithrombotic agents |
| CN1753897A (en) * | 2002-11-22 | 2006-03-29 | 日本烟草产业株式会社 | Fused bicyclic nitrogen-containing heterocycles |
| CN101668756A (en) * | 2007-05-04 | 2010-03-10 | 百时美施贵宝公司 | [6,6] and [6,7]-bicyclic gpr119 g protein-coupled receptor agonists |
| WO2011062885A1 (en) * | 2009-11-23 | 2011-05-26 | Schering Corporation | Fused bicyclic pyrimidine derivatives and methods of use thereof |
-
2014
- 2014-06-25 CN CN201410289021.XA patent/CN105218561B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3549627A (en) * | 1968-04-05 | 1970-12-22 | American Home Prod | 2,6-disubstituted-4h-pyrimido(5,4-d)(1,3)oxazin-4-0nes |
| CN1147205A (en) * | 1994-03-04 | 1997-04-09 | 伊莱利利公司 | Antithrombotic agents |
| CN1753897A (en) * | 2002-11-22 | 2006-03-29 | 日本烟草产业株式会社 | Fused bicyclic nitrogen-containing heterocycles |
| CN101668756A (en) * | 2007-05-04 | 2010-03-10 | 百时美施贵宝公司 | [6,6] and [6,7]-bicyclic gpr119 g protein-coupled receptor agonists |
| WO2011062885A1 (en) * | 2009-11-23 | 2011-05-26 | Schering Corporation | Fused bicyclic pyrimidine derivatives and methods of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| ITO, ISOO等: "Synthesis of compounds related to antitumor agents. III. On the additions of acyl halide, dialkyl acetylenedicarboxylate and N-substituted maleimides to 2,4-diamino-5-hydroxy-6-methylpyrimidine", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII: "Nitrogen- and sulfur-containing heterocycles. XXIV. Synthesis ofpyrimido[5,4-b][1,4]oxazin-7-ones", 《KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017144025A1 (en) * | 2016-02-26 | 2017-08-31 | 华东理工大学 | Pyrimido[4,5-d][1,3]oxazin-2-one derivative serving as egfr inhibitor, and application thereof |
| WO2017177837A1 (en) * | 2016-04-11 | 2017-10-19 | 上海勋和医药科技有限公司 | Heterocyclic-substituted pyridinopyrimidinone derivative as cdk inhibitor and use thereof |
| CN107286180A (en) * | 2016-04-11 | 2017-10-24 | 上海勋和医药科技有限公司 | Miscellaneous generation Pyridopyrimidinone derivatives are used as CDK inhibitor and its application |
| JP2019510822A (en) * | 2016-04-11 | 2019-04-18 | シャンハイ シュンフェァ ファーマシューティカル テクノロジー カンパニー リミテッドＳｈａｎｇｈａｉ Ｘｕｎｈｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． | Heterocyclic substituted pyridinopyrimidinone derivatives as CDK inhibitors and uses thereof |
| CN107286180B (en) * | 2016-04-11 | 2019-07-02 | 上海勋和医药科技有限公司 | Miscellaneous generation Pyridopyrimidinone derivatives are as CDK inhibitor and its application |
| CN110294721A (en) * | 2019-07-22 | 2019-10-01 | 安庆缘启医药科技有限公司 | The synthesis technology of 1- acetyl group -4- [3- (methyl oxygroup) -4- nitrobenzophenone] piperazine |
| WO2022116943A1 (en) * | 2020-12-02 | 2022-06-09 | 上海瑛派药业有限公司 | Substituted fused bicyclic compound as kinase inhibitor and use thereof |
| CN115160340A (en) * | 2022-06-07 | 2022-10-11 | 四川大学华西医院 | Small molecule compound with ACK1 inhibitory activity and application thereof |
| CN115160340B (en) * | 2022-06-07 | 2023-07-21 | 四川大学华西医院 | Small molecular compound with ACK1 inhibition activity and application thereof |
| WO2023245611A1 (en) * | 2022-06-24 | 2023-12-28 | 四川大学华西医院 | Small molecule compound with ttk inhibitory activity, preparation method therefor, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105218561B (en) | 2018-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105315259B (en) | Pyridine amine pyrimidine derivates, its preparation method and application | |
| EP3246328B1 (en) | Quinazoline heterocyclic compound as egfr kinase inhibitor, and preparation and application thereof | |
| JP6709786B2 (en) | Substituted 2-aminopyrimidine derivatives as EGFR modulators | |
| ES2927980T3 (en) | KRas G12C inhibitors | |
| KR101610005B1 (en) | Purin derivatives for use in the treatment of FAB-related diseases | |
| CN102666541B (en) | Be used for the treatment of the particularly purine of virus infection or the derivative of deazapurine | |
| CN105218561A (en) | Annelated pyrimidines ring derivatives, its preparation method and application | |
| AU2005230388B2 (en) | Use of 9H-purine-2,6-diamine derivatives in the treatment of proliferative diseases and novel 9H-purine-2,6-diamine derivatives | |
| EP3345906B1 (en) | 2-arylamino pyridine, pyridine or triazine derivative, preparation method and use thereof | |
| CN109627239B (en) | Inhibitors of fibroblast growth factor receptors | |
| TW200902531A (en) | Imidazolopyrimidine analogs and their use as PI3 kinase and mTOR inhibitors | |
| EP3312180B1 (en) | Use of pteridinone derivative serving as egfr inhibitor | |
| TW201429954A (en) | Inhibitors of the fibroblast growth factor receptor | |
| TWI496783B (en) | Quinolylpyrrolopyrimidine condensed cyclic compounds or salts | |
| JP2008543888A (en) | Pyrido (3,2-d) pyrimidine and pharmaceutical compositions useful for treating hepatitis C | |
| KR20090129434A (en) | Pyrimidine-2,4-diamine derivatives and their use as jak2 kinase inhibitors | |
| CN101679426A (en) | 9-(pyrazol-3-yl)-9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidaz0[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer | |
| NZ555462A (en) | Cancer treatment method | |
| CN112638897B (en) | EGFR kinase inhibitor and preparation method and application thereof | |
| US20220363648A1 (en) | Glucose Uptake Inhibitors | |
| CN102812010A (en) | Quinazoline derivatives, preparation methods and uses thereof | |
| ES2709003T3 (en) | 5- (pyridin-2-yl-amino) -pyrazine-2-carbonitrile compounds and their therapeutic use | |
| JP2010510990A (en) | How to treat cancer | |
| CN106916112B (en) | Pyrimidine derivative, preparation method and medical application thereof | |
| CN111362924B (en) | Deuterated pyrimidine derivatives and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: SHANGHAI ALLIST PHARMACEUTICALS, Inc. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 201203 floor 5, building 1, No. 1118, Halley Road, No. 1227, zhangheng Road, Shanghai pilot Free Trade Zone Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: No. 268 Lingxiaohua Road, Zhoupu Town, Pudong New Area, Shanghai, 201318 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 5 / F, building 1, 1118 Harley Road, 1227 zhangheng Road, Shanghai pilot Free Trade Zone, 201203 Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |