CN103570731A

CN103570731A - Pyrimidotricyclic compounds or pyrimidotetracyclic compounds, pharmaceutical composition and applications thereof

Info

Publication number: CN103570731A
Application number: CN201210266329.3A
Authority: CN
Inventors: 丁克; 徐田锋; 常少华; 张连文; 罗金凤; 徐石林; 肖宜平; 涂正超
Original assignee: Guangzhou Institute of Biomedicine and Health of CAS
Current assignee: Guangzhou Institute of Biomedicine and Health of CAS
Priority date: 2012-07-30
Filing date: 2012-07-30
Publication date: 2014-02-12
Anticipated expiration: 2032-07-30
Also published as: CN103570731B

Abstract

The invention discloses pyrimidotricyclic compounds or pyrimidotetracyclic compounds having a structure represented by the formula (I), (II) or (III), pharmaceutically-acceptable salts, stereoisomers, or prodrug molecules. The compounds can inhibit various tumor cells, and especially, the compounds can selectively act on lung cancer cells of EGFR L858R/T790 and EGFR E745 A750/T790M. Compared to wild type cancer cells, the IC50 of the compounds is 10 times, 100 times or even 1000 times higher. The compounds are a novel protein kinase inhibitor, which can overcome the drug resistance of EGFR-TKI and has selectivity.

Description

Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds and medicinal compositions and application

Technical field

The invention belongs to chemical field of medicaments, relate to particularly a kind of Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds and medicinal compositions and application.

Background technology

No matter worldwide or in China, take the chronic disease (Non Communicable Diseases (NCD) in other words) that malignant tumour (cancer), cardiovascular disorder and diabetes etc. are representative, but becoming main long-term threat.In May, 2008, the 19， World Health Organization just explicitly pointed out in the report of its up-to-date announcement, and Non Communicable Diseases (NCD) is becoming the mankind the most fatal " killer ".Wherein, cancer is ranked first place.2004, the whole world had 7,400,000 people to die from cancer, and wherein, the situation of China is more severe.The Third National cause of the death retrospective survey of announcing in by the end of April, 2008 shows, Chinese urban and rural residents's cancer mortality has increased most probably in the past in 30 years more than; Wherein in every four to five dead Chinese, just there is a people to die from cancer.China dies from the total population of cancer every year, approaches 2,000,000 people.In recent years, though the hope that the discovery of various treatment approach and medicine brings cancer patients, the drawback of conventional treatment, side effect is large, result for the treatment of is not good, tumor prognosis recurrence, and the phenomenons such as transfer solve this class bottleneck effect in the urgent need to new treatment technology.International medical community is regarded the Individual Chemotherapy on molecule parting basis and targeted therapy as break through current lung cancer therapy bottleneck hope place.

Tumour molecular targeted therapy is based on the closely-related key molecule of tumor growth being passed through to a kind of methods for the treatment of of chemistry or biological means selective killing tumour cell.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of traditional chemotherapy, radiotherapy, reduces postoperative recurrence.With Gleevec (STI571) (Novartis, 2001), Gefitinib (ZD1839) (AstraZeneca, 2003), Erlotinib (OSI774) (Genentech and OSIP, 2004), BAY 43-9006 tosilate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and Dasatinib (BMS-354825) (Bristol-Myers Squibb, 2006) for the targeted drug of representative be that chemotherapy of tumors has been started a New Times.Neoplasm targeted therapy has obtained developing rapidly in recent years.The appearance of neoplasm targeted therapy forms impact to traditional administration idea and pattern, for example, and because the little targeted drug of toxic side effect often cannot reach dose-limiting toxicity and maximum tolerated dose in I clinical trial phase; During with target therapeutic agent without reaching satisfactory effect with maximum tolerated dose.Neoplasm targeted therapy is focus and the development trend of oncotherapy.

Protein tyrosine kinase (PTKs) is the phenolic hydroxyl group generation phosphorylation of a class on can the tyrosine residues of the multiple key protein of catalysis, and then the protease of the function of mobilizing function albumen system.In 520 multiple protein kinases in human body nearly half be Tyrosylprotein kinase (PTKs).They have occupied very consequence in intracellular signal transduction pathway, are regulating a series of physiology processes such as cell growth in vivo, differentiation, death.Protein tyrosine kinase functional disorder can cause a series of diseases in organism.Research shows, proto-oncogene more than half is all relevant to protein tyrosine kinase with the activation of oncogene.The unconventionality expression of protein tyrosine kinase can cause cell proliferation adjusting to get muddled, and then causes tumour to occur.In addition, the unconventionality expression of Tyrosylprotein kinase also with invasion and attack and the transfer of tumour, tumor neovasculature generation, the chemotherapy resistance of tumour is closely related.The Tyrosylprotein kinase of take becomes as target spot carries out antitumor drug research and development the emphasis that the research of an international focus ，Ye Shi various countries drug development mechanism drops into.

EGF-R ELISA (EGFR), a kind of receptor tyrosine protein kinase, has regulated and controled the increment of cell, survival, adhesion, migration and differentiation.EGFR is overactivity or continuous activation in kinds of tumor cells, such as lung cancer, and mammary cancer, prostate cancer etc.EGFR is that a kind of transmembrane protein ，Qi family has four kinds of hypotype: EGFR-1 (being called as afterwards EGFR, Erb-B1 or Her-1), HER-2 (Erb-B2, or neu), HER-3 (Erb-B3), and HER-4 (Erb-B4).Wherein the abnormal activation of EGFR and Erb-B2 the conversion of tumour with increase in play critical effect.The method that the activation of blocking-up EGFR and Erb-B2 has been taken as the leading factor by clinical verification is carried out targeting therapy on tumor cell.Take lung cancer as example, and EGFR has expression in 50% NSCLC case, and its expression is not good relevant to prognosis.These two factors become EGFR and family member thereof to carry out the main candidate of targeted therapy.The micromolecular inhibitor of two kinds of targeting EGFRs, Gefitinib and Tarceva, the quick approval that has obtained U.S. FDA is used for the treatment of advanced NSCLC patient, and these patients have lost reaction to conventional chemotherapy.

Early stage clinical data shows, 10% NSCLC patient responds to Gefitinib and Tarceva.This significant clinical efficacy is found in specific patient colony, comprises the East Asia Region women of non-smoking and shows as the gland cancer patient of bronchovesicular histological type.The analysis of molecular level shows, as a rule, the patient that medicine is responded on coding EGFR gene with specific sudden change.The disappearance of 747th～750 amino acids of the 19th exon accounts for 45% of sudden change, and 10% sudden change is at the 18th and the 20th exon in addition.The sudden change of EGFR kinase domain highly activates kinases, makes the existence of tumour cell have dependency to mutant kinase.Existing multinomial Prospective Clinical studies confirm that, the positive NSCLC patient of EGFR activation sudden change is significantly higher than EGFR wild-type NSCLC patient to the reactivity of EGFR-TKI, and Progression free survival (PFS) phase and total existence (OS) phase be significant prolongation also.However, the PFS of most of EGFR sudden change positive patient is no more than 12～14 months, resistance has been occurred TKI to.The another study hotspot that the mechanism of acquired resistance and clinical countermeasure thereof become targeted therapy field.

Targeting EGFR inhibitor resistance mechanism can be divided into two classes: medicament-resistant mutation and bypass activated pathway.Resistance mechanism 1:T790M sudden change is a point mutation in EGFR 20 exons, is one of resistance mechanism of comparatively approving at present.T790M causes the mechanism of TKI resistance still to imperfectly understand.Initial studies show that, T790M may change the crystalline structure of kinases district adenosine triphosphate (ATP) binding pocket, the combination in sealing LiaoTKIYu kinases district.Current research demonstration, it is stronger than simple L858R to the avidity of ATP that L858R merges T790M sudden change, and TKI is ATP competitiveness kinase inhibitor, therefore cause TKIYu kinases district combination rate to reduce.About one of dispute of T790M, be that this sudden change is after TKI treatment, produce or originally just exist, after TKI treatment is selected, be just found.At first, T790M only treats in failed NSCLC patient's sample and is found at TKI, but in the sample without any treatment, be also found subsequently, therefore think at present, this sudden change is also present in the tumor tissues without TKI treatment, but be detected in a few cell clone, because these cell clones are to the resistivity of TKI and be selected after treatment.The medicament-resistant mutation similar to T790M also has D761Y, L747S and T854A etc., and these sudden changes are referred to as " non-T790M secondary mutation ", and its total incidence is lower than 5%.Resistance mechanism 2:MET amplification is the another EGFR-TKI acquired resistance mechanism of finding for 2007.MET is a kind of cross-film tyrosine kinase receptor.The EGFR of TKI acquired resistance is being suddenlyd change in positive NSCLC patient, and approximately 20% has wild-type MET gene amplification, and major part increases without MET before treatment.MET associating ErbB family member, walks around the signal path that EGFR activation downstream AKT mediates, and promotes growth of tumour cell, suppresses its apoptosis.In experiment, by RNA perturbation technique, suppress MET signal path in vitro, can recover the susceptibility of resistance person to Gefitinib.Suppress EGFR and MET simultaneously, can overcome the TKI resistance of MET amplification mediation.Other are and some acceptor and MET effect are similar.Nearest external TKI resistance models show, type-1 insulin like growth factor acceptor (IGF-1R) also can be walked around EGFR, activates its downstream signal path, but due to technical reason, is difficult to carry out IGF-1R activation and detects in patient's sample.The resistance mechanism that these walk around EGFR, activate its downstream signal path is referred to as " bypass activated pathway ".To the EGFR sudden change positive patient of TKI resistance, approximately 30%～40% both without secondary mutation, and also, without MET amplification, these patients' resistance mechanism is also in exploration.

For resistance, the strategy adopting is clinically: strategy 1, continues to use EGFR-TKI, the cross-reference of Gefitinib and Tarceva.In a word, after TKI progress, continue to use TKI seemingly to have certain benefit, but benefit degree is very limited.Strategy 2, development of new EGFR-TKI.Preclinical study shows, EGFR irreversible inhibitor can suppress T790M in vitro, after this, a lot of EGFR irreversible inhibitors are developed out, be called " two generation EGFR-TKI ", from preclinical study, move towards gradually clinical at present, study more have neratinib, XL647, BIBW 2992 and PF-00299804.Neratinib is general ErbB(EGFR, ErbB2 and ErbB3) irreversible TKI.Based on I phase result of study, carrying out at present clinical study, inquire in the NSCLC patient of progress after Gefitinib or Tarceva treatment, neratinib(240mg/d) whether can overcome the TKI resistance that T790M sudden change or MET amplification cause.But some preclinical studies have shown unfavorable result, a kind of cell strain PC-9 of EGFR 19 Exon deletion, when being exposed to neratinib, has produced T790M sudden change; In mouse L858R-T790M tumor model, alone neratinib does not make Tumor response.Therefore whether neratinib does not effectively still learn T790M sudden change person.XL647 energy irreversible inhibition EGFR, HER2, VEGF R2 (VEGFR-2) and EphB4, in L858R-T790M catastrophic model, can suppress tumor growth.2008, an II phase clinical study about XL647 tentatively shows, in the treatment of 34 routine Gefitinib or Tarceva, alleviate after surpassing 3 months and occur in progression of disease or the NSCLC patient with T790M sudden change, with XL647(300mg/d) treatment after, 1 routine partial rcsponse only, this patient's non-smoking, 19 Exon deletion, suddenly change without T790M in blood plasma; And T790M suddenly change positive patient none alleviate, most of in 2 months progress.BIBW 2992 is irreversible TKI of EGFR and ErbB2.In the clinical study of II phase, BIBW 2992 has made 19 Exon deletion, and alleviating appears in L858R, L861Q and G719S/S768I sudden change patient.After BIBW 2,992 three line treatment chemotherapy failure, Gefitinib or a Tarceva benefit, the clinical study of progress NSCLC is carried out.BIBW 2992 contrast placebos, the random II b/ III phase clinical study that three line treatment Gefitinib or Tarceva are treated failed NSCLC is also underway.These researchs will contribute to determine that can BIBW 2992 bring benefit to Gefitinib or Tarceva resistance patient.PF-00299804 is general ErbB TKI inhibitor.In the clinical study of I phase, there is disease alleviation in 1 routine T790M sudden change positive.PF-00299804(45mg/d) the II phase clinical study that treatment KRAS wild-type, chemotherapy and Tarceva are treated failed NSCLC patient is carried out.Strategy 3, for other target treatments.Because " bypass activated pathway " plays a significant role in EGFR-TKI resistance, for the targeted drug of these bypasses, continue to bring out.MET-TKI may play a role in the patient with MET amplification.Preclinical study demonstration, EGFR-TKI combines with MET-TKI, positive and effective with the cell strain of MET amplification to EGFR sudden change, but both independent uses are all invalid.An important problem is, approximately half patient with MET amplification has T790M sudden change simultaneously, therefore MET-TKI may need to combine with T790M inhibitor.XL184 is a kind of novel TKI, and MET, VEGFR-2 and RET are had to restraining effect.Other MET inhibitor, as ARQ197, PF-2341066, SGX523 etc., also have relevant clinical research carrying out.PF-2341066 is a kind of selectivity c-MET and ALK receptor tyrosine kinase inhibitors, has shown good tumour control effect, especially to ALK-EML4 fusion gene positive patient in the clinical study of I phase.II/III phase clinical study about PF-2341066 is carried out, and it becomes a new focus in targeted therapy field already.For other possible bypass activated pathway, some medicines, as also in process in the correlative study of IGF-1R inhibitor, inhibitor of heat shock protein 90 etc.

In a word, current EGFR-TKI still can not solve the caused clinical pressure of drug resistance, and mostly existing medicine be to take the reversible or irreversible inhibitor of EGFR that quinazoline or quinoline amine are basic parent nucleus, its toxic side effect that poor selectivity of wild-type cell is brought is also inevitable.Therefore, in the urgent need to novel type, the compound of especially novel skeleton solves resistance, the problems such as poor selectivity.

Summary of the invention

Based on this, the object of this invention is to provide a kind of Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds.

Concrete technical scheme is as follows:

There is formula I, Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs of (II) or (III) structure:

N=1-3 wherein

R ₁certainly optional:

1）H；

2) C ₁-C ₅alkyl;

3) C ₃-C ₆cycloalkyl;

4) C ₁-C ₅containing fluoroalkyl;

5) (CH ₂) _nx, n=0-6, X is hydroxyl, amino, C ₁-C ₆heteroatom containing alkyl, C ₃-C ₇heterocyclic radical; a ₁, A ₂, A ₃, A ₄, A ₅certainly optional: halogen, cyano group, nitro, hydroxyl, amino, C ₁～C ₆alkyl, C ₃-C ₆cycloalkyl, C ₁-C ₆containing fluoroalkyl, C ₁-C ₆heteroatom containing alkyl, C ₁-C ₇the ester that heterocyclic radical and abovementioned alkyl form, acid amides, sulfone, sulfoxide, urea;

R ₂certainly optional:

1）H；

2) C ₁-C ₅alkyl;

3) C ₃-C ₆cycloalkyl;

4) C ₁-C ₅containing fluoroalkyl;

5) aryl;

6) heterocyclic radical;

R ₃certainly optional:

1）H；

2) halogen;

3) amino, hydroxyl, cyano group, nitro;

4) C ₁-C ₅alkyl;

5) C ₃-C ₆cycloalkyl;

6) aryl;

W is certainly optional: CH ₂, CH ₂cH ₂, O, S, NH, NR; R is alkyl or aryl;

R ₄certainly optional:

1）H;

2) halogen;

3) C ₁-C ₅alkyl;

4) C ₃-C ₆cycloalkyl;

5) aryl;

The above cycloalkyl, aryl can be optionally by 0,1, and 2 or 3 optionally from R ₅substituting group replace;

R ₅certainly optional:

1）H；

2) halogen;

3) C ₁-C ₃alkyl;

4) C ₃-C ₆cycloalkyl;

5) C ₁-C ₃alkoxyl group;

6) C ₁-C ₃containing fluoroalkyl;

7) heterocyclic radical;

8) C ₀-C ₃alkylidenyl-heterocyclic base;

9) phenyl.

In some embodiment, Kui Linpyrimido quinoline three encircles or Kui Linpyrimido quinoline tetracyclic compound or its pharmacy acceptable salt or steric isomer or its prodrugs therein, and it has formula IV, V, and VI structure:

N=1-3 wherein

R ₁certainly optional:

1), 4-N, N-lupetidine base, 1-methyl-4-(piperazine-4-replaces) and piperidyl, imidazolyl, 6-(4-methylpiperazine-1-replaces)-3-substituted pyridinyl related heterocycles,

a ₁, A ₂, A ₃, A ₄, A ₅certainly optional: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy, trifluoromethyl, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, 2-Pyrrolidine base oxethyl, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, imidazoles, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone, 1-methyl-4-piperazine-2-ketone, and the ester of above-mentioned group formation, acid amides, sulfone, sulfoxide, urea,

R ₆, R ₇, R ₈, R ₉certainly optional:

H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy;

R ₁₀, R ₁₁certainly optional:

R ₁₂certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) phenyl;

5) N, N-dimethylamino, N, N-diethylamino, N methyl piperazine base; morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, 4-N; N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, and 4-(4-methylpiperazine-1-replaces) methyl.

In some embodiment, Kui Linpyrimido quinoline three encircles or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or its prodrugs therein, and it has formula VII, VIII, and IX structure:

N=1～3 wherein

A ₁, A ₂, A ₃, A ₄, A ₅certainly optional:

H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, the neo-pentyl branched paraffin of being correlated with, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy is relevant containing oxygen alkane, the trifluoromethyl fluorine-containing alkane of being correlated with, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, 2-Pyrrolidine base oxethyl related heterocycles alkoxyl group, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone, 1-methyl-4-piperazine-2-ketone,

R ₆, R ₇, R ₈, R ₉certainly optional:

H, fluorine, chlorine, bromine, iodine;

R ₁₃, R ₁₄certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) phenyl;

5) N, N-dimethylaminomethyl, N, N-diethylamino methyl.

Therein in some embodiment, A wherein ₁, A ₂, A ₄, A ₅be selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, A ₃be selected from N, N-methyl amino ethoxy, N, N-methylamino propoxy-, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, 2-Pyrrolidine base oxethyl related heterocycles alkoxyl group, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone.

Therein in some embodiment, R wherein ₆, R ₇, R ₈, R ₉be selected from H, fluorine; R ₁₃, R ₁₄for hydrogen.

In some embodiment, Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs are selected from therein:

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-(4-(dimethylamino)-1-piperazine)-2 p-methoxy-phenyls) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide

N-(3-(2-((2-methoxyl group-4-morpholinyl phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-sulphur coffee quinoline phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(1-pyrryl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

(R)-N-(3-(2-((4-(3-(dimethylamino)-1-pyrrolidyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

(S)-N-(3-(2-((4-(3-(dimethylamino)-1-pyrrolidyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-(4-methyl isophthalic acid-piperazinyl)-piperidino) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-(2-(dimethylamino) oxyethyl group)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(2-morpholine oxyethyl group) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also) replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(2-methoxy ethoxy) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-fluorophenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-morpholine base phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(5-oxo-2-((4-sulphur coffee quinoline base phenyl) amino)-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((4-(1-methyl-4-piperidyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-oxyethyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-isopropoxy-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((3-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((1-methyl-4-piperazinyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

The fluoro-3-(2-((2-methoxyl group-4-(4-of N-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-8,9-dihydro-5 hydrogen-bis-Kui Linpyrimido quinoline [1,2-a:4 ', 5 '-d] pyrimidine-11(7 hydrogen)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8,9,10-tetrahydropyrimidine also [4 ', 5 ': 4,5] Kui Linpyrimido quinoline [1,2-a] [1,3] diaza-12(5 hydrogen)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-imidazole is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-oxyethyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replace) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-morpholine base phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((4-(dimethylamino)-piperidino)-2-p-methoxy-phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replace) phenyl) acrylamide;

(E)-N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) but-2-enamides;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl)-3 rare acid amides in methyl fourth-2;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) cinnamide;

(E)-4-(dimethylin)-N-(3-(2-((4-fluorophenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) the rare acid amides of fourth-2-;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) propionic acid amide;

10-(3-aminophenyl)-2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-5(10 hydrogen also)-one

Another object of the present invention is to provide a kind of medicinal compositions for the treatment of tumour.

Concrete technical scheme is as follows:

Treat a medicinal compositions for tumour, it is comprised of Kui Linpyrimido quinoline three ring described in claim 1-4 any one or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs and pharmaceutically acceptable carrier.

Another object of the present invention is to provide the application of a kind of above-claimed cpd in the medicine of preparation treatment tumour.

Concrete technical scheme is as follows:

Above-mentioned Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds and pharmacy acceptable salt thereof or steric isomer or the application of its prodrugs in the medicine of preparation treatment tumour.

In some embodiment, described tumour is any in nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histocyte lymphatic cancer, nasopharyngeal carcinoma therein.

In chemicals of the present invention, allow the combination of substituting group and variable, as long as this combination makes stability of compounds.The line that puts loop systems from substituting group under represents that the key of indication can be connected on any annular atoms that can replace.If loop systems is many rings, it means that this key is only connected on any suitable carbon atom of adjacent loops. be appreciated that those of ordinary skills can select the substituting group of the compounds of this invention and substitution pattern and provide chemically stable and can from the raw material that can easily obtain, be easy to synthetic compound by the method for art technology and following proposition.If being exceeded a group, substituting group self replaces, should understand these groups can be in identical carbon atoms or on different carbon atom, as long as make Stability Analysis of Structures. and phrase " is optionally replaced by one or more substituting groups " and is considered to " optionally by least one substituting group, be replaced " quite with phrase and preferred in the case embodiment will have 0-3 substituting group.

Term used herein " alkyl " and " alkylidene group " mean to comprise saturated fatty alkyl side chain and straight chain with particular carbon atom number.For example, " C ₁-C ₅alkyl " in " C ₁-C ₅" definition comprise the group with 1,2,3,4 or 5 carbon atom of arranging with straight or branched.For example, " C ₁-C ₅alkyl " specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group.Term " cycloalkyl " refers to have the monocycle saturated fatty alkyl of particular carbon atom number.For example " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.

Term used " heterocycle " or " heterocyclic radical " refer to and contain 1-4 heteroatomic 5 yuan of-6 yuan of aromaticity or nonaro-maticity heterocycle that is selected from O, N and S herein, and comprise bicyclic radicals." heterocyclic radical " comprises heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further embodiment includes but not limited to: imidazolyl, indyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl (oxetanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4-alkyl dioxin, pyrrolidyl, glyoxalidine base, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.

In one embodiment, heterocycle is selected from imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidone, 2-Pyrrolidone, thienyl, oxazolyl, triazol radical, isoxazolyl.

As understood by one of ordinary skill in the art, " halogen " used (" halo ") or " halogen " mean to comprise chlorine, fluorine, bromine and iodine herein.

Unless otherwise defined, alkyl, cycloalkyl, aryl and heterocyclic radical substituting group can be unsubstituted or replacement.For example, (C ₁-C ₆) alkyl can replace by one, substituting group that two or three are selected from OH, halogen, alkoxyl group, dialkyl amido or heterocyclic radical such as morpholinyl, piperidyl etc.

The free form that the present invention includes formula I-IX compound, also comprises its pharmacy acceptable salt and steric isomer.The protonated salt that some specific exemplary compounds are aminated compounds herein.Term " free form " refers to the aminated compounds with salt-independent shape.The pharmaceutically-acceptable salts being included not only comprises the exemplary salt of specific compound described herein, also comprises the typical pharmacy acceptable salt of all formula I-IX compound free forms.Can use technical point known in the art from the free form of described compound specific salts.For example, can by the alkali dilute aqueous soln with suitable, for example NaOH dilute aqueous soln, salt of wormwood dilute aqueous soln, weak ammonia and sodium bicarbonate dilute aqueous soln be processed this salt free form are regenerated.Free form some physical properties for example in polar solvent in solubleness with its separately salt form more or less distinguish, but for invention this hydrochlorate of object and alkali salt aspect other pharmacy with its free form is suitable separately.

Can be by conventional chemical method from the synthetic pharmacy acceptable salt of the present invention of the compounds of this invention that contains basic moiety or acidic moiety.Conventionally, by ion-exchange chromatography or the inorganic or organic acid by free alkali and stoichiometric quantity or excessive required salt form, in the combination of appropriate solvent or multi-solvents, react the salt of preparing basic cpd.Similarly, by the inorganic or organic bases reaction with suitable, form the salt of acidic cpd.

Therefore, the pharmacy acceptable salt of the compounds of this invention comprises by alkaline the compounds of this invention and conventional the non-toxic salt inorganic or the compounds of this invention that organic acid reaction forms.For example, conventional non-toxic salt comprises the salt that derives from mineral acid such as hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc., also comprises from organic acid such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, flutters the salt of the preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2 one acetoxyl group one phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.

If the compounds of this invention is acid, suitable " pharmacy acceptable salt " refers to comprise salt prepared by mineral alkali and organic bases by pharmaceutically acceptable nontoxic alkali. the salt that derives from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Particularly preferably ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali comprises primary amine, the salt of secondary amine and tertiary amine, the amine replacing comprises naturally occurring replacement amine, cyclic amine and deacidite be arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, monoethanolamine, thanomin, quadrol, N mono-ethyl morpholine, N mono-ethyl piperidine, glucosamine, glucosamine, Histidine, hydroxocobalamin, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.

Berg etc., " Pharmaceutical Salts, " J.Pharm.Sci. ' 1977:66:1-19 has been described in more detail the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt.

Due to the acidic moiety of deprotonation in compound under physiological condition for example carboxyl can be negatively charged ion, and this with electric charge then can by inside with cationic protonated or alkylating basic moiety for example the former quantum balancing of quaternary nitrogen offset, so should notice that the compounds of this invention is potential inner salt or zwitter-ion.

The present invention relates to there is formula I, Kui Linpyrimido quinoline three ring or the Kui Linpyrimido quinoline Fourth Ring compounds of II or III constitutional features, can suppress kinds of tumor cells, especially can selectively acting in EGFR L858R/T790M and EGFR E745_A750/T790M lung carcinoma cell.Contrast wild-type cancer cells, the IC of this compounds ₅₀want high 10 times, 100 times of order of magnitude difference of 1000 times even.This compounds be a class novelty can overcome existing EGFR-TKI resistance and there is optionally kinases inhibitor.

Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds and the pharmacy acceptable salts thereof that the present invention relates to, can effectively suppress the growth of kinds of tumor cells, and to EGFR, other protease-producing restraining effect of Her family, can be used for preparing antitumor drug, and can overcome existing medicine Gefitinib, the resistance that Tarceva etc. bring out.As understood by those skilled in the art, related compound and the pharmacologically acceptable salts thereof of the application can be used for the transition proliferative disease such as the preparation treatment mankind and other mammiferous tumour.

Embodiment

Except standard method known or illustration in experimental arrangement in the literature, can adopt the reaction as shown in following scheme to prepare the compounds of this invention.Following illustrative approach is for the object of explanation rather than is confined to listed compound or any specific substituting group.The substituting group number showing in scheme must not meet number used in claim, and for clarity sake, shows that monosubstituted base is connected under the definition of formula hereinbefore to allow on the compound of multi-substituent.

Scheme

As formula I-IX compound as described in inventing, those skilled in the art can be according to prior art and the general knowledge possessing, and can be that starting raw material passes through 6 steps reactions by the chloro-5-pyrimidinecarboxylic acid of 2,4-bis-ethyl ester synthetic.

Drug metabolite and prodrug

The compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug that can change in vivo the structure of the related compound of the application and pharmacologically acceptable salts thereof into, be also contained in the application's claim.

Drug combination

Formula I-IX compound can or improve the other medicines coupling of similar symptom to known treatment.During Combined Preparation, originally the administering mode & dosage of medicine remains unchanged, and simultaneously or take subsequently formula I-IX compound.When formula I-IX compound and other one or more medicines are taken simultaneously, preferably use contains the medicinal compositions of one or more known drugs and formula I compound simultaneously.Drug combination is also included within the overlapping time period and takes formula I-IX compound and other one or more known drugs.When formula I-IX compound and other one or more medicines carry out drug combination, the dosage when dosage of formula I-IX compound or known drug may be than their independent medications is lower.

Medicine or the activeconstituents that can carry out drug combination with formula I-IX compound comprise but are not limited to:

Estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, medicine and the cell death inducer at the interference cell cycle outpost of the tax office, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT inhibitor, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody etc.

Medicine or the activeconstituents that can carry out drug combination with formula I-IX compound comprise but are not limited to: rIL-2, clinic effect of alendronate, Interferon, rabbit, Ah Qu Nuoying, allopurinol, epidermal growth factor, Palonosetron hydrochloride, altretamine, amino glutethimide, amifostine, amrubicin, SN-11841, anastrozole, dolasetron, aranesp, arglabin, white arsenic, Arnold is new, U-18496, azathioprine, bacille Calmette-Guerin vaccine or tice bacille Calmette-Guerin vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, thyrocalcitonin, A Laizuo monoclonal antibody injection, capecitabine, carboplatin, Kang Shi get, cefesone, celmoleukin, daunorubicin, Chlorambucil, cis-platinum, CldAdo, CldAdo, chlorine is bent phosphoric acid, endoxan, arabinose born of the same parents former times, Dacarbazine, dactinomycin, daunorubicin liposome, dexamethasone, Wymesone, Estradiol Valerate, denileukin diftitox, Di Bomei, deslorelin, ground La Zuosheng, stilboestrol, Fluconazole, docetaxel, doxifluridine, Zorubicin, dronabinol, admire-166-chitosan complexes, eligard, rasburicase, epirubicin hydrochloride, aprepitant, pidorubicin, Epoetin Alfa, erythropoietin, eptalatin, Ergamisole, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinylestradiol, amifostine, hydroxyl phosphoric acid, Etopophos, etoposide, fadrozole, tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replaces, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, flutamide, formestane, 1-β-D-R furanose born of the same parents thialdine-5 '-stearyl phosphoric acid ester, fotemustine, fulvestrant, gamma-globulin, gemcitabine, WAY-CMA 676, imatinib mesylate, Gliadel, goserelin, Graniseeron Hydrochloride, histrelin, new with U.S., hydrocortisone, erythro-hydroxyl nonyl VITAMIN B4, hydroxyurea, replace not monoclonal antibody of smooth different shellfish, idarubicin, ifosfamide, interferon alpha, interferon-' alpha ' 2, interferon α-2 A, interferon α-2 B, Interferon α-nl, Alferon N, interferon beta, interferon-gamma-la, interleukin II, intron A, Iressa, Rinotecan, Kytril, sulfuric acid lentinan, letrozole, formyl tetrahydrofolic acid, Leuprolide, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, mustargen, mecobalamin, medroxyprogesterone acetate, Magace, melphalan, esterified estriol, 6-coloured glaze base purine, mesna, methotrexate, amino-laevulic acid methyl esters, miltefosine, Minomycin, ametycin, mitotane, rice holder green onion quinone, Win-24540, citric acid Evacet, S 254, Pegylation filgrastim, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Sostatin, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, pegaspargase, Pai Luoxin, pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin the soft star that compares, Plicamycin, porfimer sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa navel, epoetin, Raltitrexed, Libiee, etidronic acid rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Sostatin, sargramostim, semustine, sizofiran, sobuzoxane, bluff sodium prednisolone, Paphos acid, stem-cell therapy, streptozocin, Metastron, levothyroxine sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, taxotere, Ro 23-6019, Temozolomide, teniposide, testosterone propionate, Synrotabs, Tioguanine, thio-tepa, thyrotropic hormone, tiludronic acid, topotecan, toremifene, tositumomab, Herceptin, Treosulfan, tretinoin, Rheumatrex tablet, trimethylammonium melamine, trimetrexate, acetic acid triptorelin, triptorelin pamoate, Youfuding, uridine, valrubicin, vesnarinone, vinealeucoblastine(VLB), vincristine(VCR), vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, Zudan, taxol protein stabilization formulations, acolbifene, Interferon, rabbit r-lb, affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, Atamestane, atrasentan, BAY 43-9006, Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, crisnatol, cyproterone acetate, Decitabine, DN-101, Zorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, histamine dihydrochloric acid, histrelin hydrogel implant, holmium-166DOTMP, Ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanretide, Lasofoxifene, libra, lonafamib, Miproxifene, minot is bent acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, Ao Limosen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, QS-21, overstate the West, R-1549, raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, docosahexenoic acid taxol, extrasin alpha l, loud, high-pitched sound azoles furan woods, tipifarnib, Win-59075, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanib, Visudyne, Vinflunine, Z-100 and azoles come unicorn acid or their combination.

The present invention will be further described for following examples, but this embodiment is not for limiting the scope of the invention.

Embodiment 1

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-yl) phenyl) acrylamide (XTF-01)

Step 1.4-(3-t-butoxycarbonyl amino aniline)-2-chloropyrimide-5-ethyl-carbonate (1)

By 2, the chloro-5-pyrimidinecarboxylic acid of 4-bis-ethyl ester (22.1g, 100mmol, 1.0eq), N-Boc mphenylenediamine (20.8g, 1.0eq), under DIPEA (17.4ml, 1.0eq) room temperature, add successively in 500ml acetonitrile, be heated to return stirring reaction 2 hours, stop heating and treat that system temperature is down to room temperature, solid is separated out, and filtration under diminished pressure obtains white solid 35.3g (90%).

¹H?NMR(400MHz,CDCl ₃)δ10.44(s,1H,),8.81(s,1H),7.79(s,1H),7.36(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7.18(d,J＝8.0Hz,1H),6.55(s,1H),4.44(q,J＝7.2Hz,2H),1.52(s,9H),1.42(t,J＝7.2Hz,3H).

Step 2.4-(3-t-butoxycarbonyl amino aniline) the chloro-5-pyrimidinecarboxylic acid of-2-(2)

By compound 1(3,92g, 10mmol) add in 20ml THF, under room temperature, add 15ml 1N NaOH(15mmol, 1.5eq), be heated to 40 ℃ of stirring reactions 3 hours, stop heating the system for the treatment of and be down to room temperature, decompression steams THF, in system, add 15ml 1N HCl, separate out solid, filtration under diminished pressure, vacuum-drying obtains white solid 3.57g(98%).

¹H?NMR(400Hz,DMSO-d ₆)δ10.55(s,1H),9.46(s,1H),8.76(s,1H),7.67(t,J＝2.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),7.23(t,J＝6.0Hz,1H),1.48(s,9H)

Step 3.(3-(2-((3-hydrogen-[1,2,3] triazole also [4,5-b] pyridine-3-replaces) oxygen base)-5-oxygen-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) t-butyl carbamate

By compound 2(91.2mg, 0.178mmol, 1.0eq), HATU (190.11mg, 2.0eq), DIPEA (0.131mL, 3.0eq) add in 5mlDCM, 30 ℃ of stirrings added 2-first sulfydryl-4 after 0.5 hour, and 5-dihydro-1 hydrogen-imidazoles (31.94mg, 1.1eq) continues to stir 24 hours.Add 5mL H ₂o extracting and separating obtains organic phase, anhydrous Na ₂sO ₄dry, column chromatography obtains white solid 75mg (58%).

¹H?NMR(400MHz,DMSO-d ₆)δ9.44(s,1H),8.84(s,1H),8.68(dd,J=1.2,4.4Hz,1H),8.55(dd,J＝0.8,4.0Hz,1H),7.55(dd,J＝4.4,8.0Hz,1H),7.37(s,1H),7.23(d,J＝8.4Hz,1H)7.09(t.J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),3.97(t,J＝8.8Hz,2H),3.71(t,J＝8.8Hz,2H),1.50(s,9H).LCMS(ESI):m/z?515.1[M+H] ⁺

Step 4.(3-(2-((2-methoxyl group-4-4(4-methyl isophthalic acid-piperazinyl) phenyl) amino) 5-oxo-7,8-glyoxalidine is [1,2-a] pyrimidine-10-(5 hydrogen also)-replace) phenyl) t-butyl carbamate (4)

By compound 3-1(257mg, 0.5mmol, 1.0eq), 2-methoxyl group-4-(4-methylpiperazine-1-replaces) aniline (110.6mg, 1.0eq), K ₂cO ₃(207.3mg, 3.0eq), the 8ml trimethyl carbinol adds in 25mL tube sealing, is heated to 100 ℃ of stirring reactions 5 hours.Stop heating and be down to room temperature, decompression steams solvent, adds DCM and H ₂the organic phase of O extracting and separating, saturated NaCl solution washing organic phase once, obtains organic phase anhydrous Na ₂sO ₄dry.Decompression steams solvent, obtains solid and is directly used in next step reaction.

Step 5.10-(3-aminophenyl)-2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-7,8-glyoxalidine also [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-5(10 hydrogen)-one (XTF-42) LCMS (ESI): m/z 500.0[M+H] ⁺

Step 4 is obtained to product and add in 2mL DCM, add 2mL TFA stirred overnight at room temperature, decompression steams solvent, in system, slowly drips saturated NaHCO ₃solution is greater than 7 to pH, and filtration under diminished pressure obtains solid, and column chromatography obtains yellow solid 174.8mg (two step productive rates 70%).

Step 6N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-01)

By compound 5(100mg, 0.2mmol, 1.0eq) add in 5mlDCM, drip DIPEA(0.034ml, 1.0eq), under 0 ℃ of stirring, in system, slowly drip acrylate chloride (0.032ml, 2.0eq), dropwise and rise to room temperature continuation stirring 2 hours.In system, add 10mL normal hexane to separate out solid, filtration under diminished pressure obtains filter cake, and column chromatography for separation obtains yellow solid 71,9mg (65%).

¹H?NMR(400MHz,DMSO-d ₆)δ10.35(s,1H),8.16(brs,1H),8.36(brs,1H),7.82(brs,1H),7.70(s,1H),7.46(t,J＝8.0Hz,1H),7.20(d,J＝8.8Hz,1H),7.11(d,J＝8.0Hz,1H)6.50(brs,1H),6.47(dd,J＝10.0,16.8Hz,1H),6.28(dd,J＝2.0,16.8Hz,1H),5.94(brs,1H),5.78(dd,J＝2.0,10.0Hz,1H),3,97(t,J＝8.4Hz,2H),3.58-3.82(m,5H),3.04(m,4H),2.26(s,3H).LCMS(ESI):m/z?554.0[M+H] ⁺

Embodiment 2

N-(3-(2-((4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-02)

Synthetic method is as embodiment 1

¹H?NMR(400MHz,Acetic-d ₄)δ9.00(s,1H),8.13(d,J＝7.6Hz,1H),7.96(s,1H),7.62(t,J＝8.0Hz,1H),7.28-7.34(m,2H),6.71(s,1H),6.46-6.48(m,1H),6.26(brs,1H),5.84(dd,J＝3.6,8.0Hz,1H),4.43(t,J＝9.2Hz,2H),4.09(t,J＝9.2Hz,2H),3.84(m,5H),3.74(m,2H),3.18-3.24(m,4H),2.21(s,3H).LCMS(ESI):m/z?582.2[M+H] ⁺

Embodiment 3

N-3-(2-((4-(4-(dimethylamino)-1-piperazine)-2 p-methoxy-phenyls) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-03)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,Acetic-d ₄)δ9.03(s,1H),8.14(s,1H),8.03(d,J＝7.2Hz,1H),7.64(t,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),7.33(d,J＝7.6Hz,1H),7.01(s,1H),6.60-6.50(m,2H),6.46(d,J＝16.4Hz,1H),5.84(d,J＝10.8Hz,1H),4.45(t,J＝8.8Hz,2H),4.11(t,J＝8.8Hz,2H),3.87(s,3H),3.81(m,2H),3.70(m,1H),3.29(t,J＝11.2Hz,2H),2.93(s,6H),2.40-2.15(m,4H).LCMS(ESI):m/z?582.2[M+H] ⁺

Embodiment 4

N-(3-(2-((2-methoxyl group-4-morpholinyl phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-04)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.34(s,1H),8.61(brs,1H),8.37(brs,1H),7.81(brs,1H),7.70(s,1H),7.46(t,J＝8.0Hz,1H),7.21(d,J＝8.8Hz,1H),7.12(d,J＝7.6Hz,1H),6.52(s,1H),6.47(dd,J＝10.0,16.0Hz,1H),6.27(d,J＝16.8Hz,1H),5.95(brs,1H),5.78(d,J＝10.8Hz,1H),3,96(m,2H),3.74(m,9H),2.99(m,4H).LCMS(ESI):m/z?540.9[M+H] ⁺

Embodiment 5

N-(3-(2-((2-methoxyl group-4-sulphur coffee quinoline phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-05)

Synthetic method is as embodiment 1.

1H?NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.61(brs,1H),8.41(brs,1H),7.82(brs,1H),7.70(s,1H),7.46(t,J=8.0Hz,1H),7.20(d,J=8.8Hz,1H),7.11(d,J=8.0Hz,1H),6.48(s,1H),6.47(dd,J=10.0,17.2Hz,1H),6.29(dd,J1=2.0,17.2Hz,1H),5.95(brs,1H),5.78(dd,J=2.0,10.0Hz,1H),3.97(t,J=8.4Hz,2H),3.74-3.69(m,5H),2.66(m,4H).LCMS(ESI):m/z?557.0[M+H]+

Embodiment 6

N-(3-(2-((2-methoxyl group-4-(1-pyrryl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-06)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,Acetic-d ₄)δ8.98(s,1H),8.10(d,J＝8.0Hz,1H),8.04(s,1H),7.62(t,J＝8.0Hz,1H),7.32-7.29(m,2H),6.54(s,1H),6.52-6.41(m,2H),5.82(dd,J＝1.6,9.6Hz,1H),4.44(t,J＝8.8Hz,2H),4.10(t,J＝8.8Hz,2H),3.84(s,3H),3.84(m,4H),2.08(m,4H).LCMS(ESI):m/z525.2[M+H] ⁺

Embodiment 7

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-07)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.35(s,1H),8.61(s,1H),8.35(s,1H),7.84(s,1H),7.70(s,1H),7.46(t,J＝8.0Hz,1H),7.18(d,J＝9.2Hz,1H),7.11(d,J＝7.6Hz,1H),6.48(s,1H),6.47(dd,J＝10.0,16.8Hz,1H),6.28(dd,J＝2.0,16.8Hz,1H),5.78(dd,J＝2.0,10.0Hz,1H),3.96(t,J＝8.8Hz,2H),3.80-3.63(m,5H)2.99(m,4H),1.58(m,4H)1.51(m,2H).LCMS(ESI):m/z?539.1[M+H] ⁺

Embodiment 8

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-08)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.45(s,1H),10.34(s,1H),8.61(brs,1H),8.42(brs,1H),7.87(s,1H),7.70(s,1H),7.46(t,J＝8.0Hz,1H),7.15-7.09(m,2H),6.52(dd,J ₁=10.0,16.8Hz,1H),6.19-6.25(m,2H),7.58(d,J＝10.0Hz,1H),3.97(t,J＝8.4Hz,2H),3.75(m,7H),3.45(m,2H),3.09(m,2H),2.79(s,3H),2.16(m,2H).LCMS(ESI):m/z?568.2[M+H] ⁺

Embodiment 9

(R)-N-(3-(2-((4-(3-(dimethylamino)-1-pyrrolidyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen)-replace) phenyl) acrylamide (XTF-09)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.33(s,1H),8.60(s,1H),8.32(s,1H),7.84(s,1H),7.68(s,1H),7.44(t,J＝8.0Hz,1H),7.14-7.08(m,2H),6.47(dd,J＝2.0,16.8Hz,1H),6.28-6.24(m,1H),6.06(s,1H),5.78(d,J＝10.0Hz,1H),3.96(t,J＝8.8Hz,2H),3.74(m,5H),3.25(m,2H),3.15(m,1H),2.94(m,1H),2.76(m,1H),2.21(s,6H),2.12(m,1H),1.77(m,1H).LCMS(ESI):m/z?568.2[M+H] ⁺

Embodiment 10

(S)-N-(3-(2-((4-(3-(dimethylamino)-1-pyrrolidyl)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen)-replace) phenyl) acrylamide (XTF-10)

Synthetic method is as embodiment 1.

LCMS(ESI):m/z?568.2[M+H] ⁺

Embodiment 11

N-(3-(2-((2-methoxyl group-4-(4-(4-methyl isophthalic acid-piperazinyl)-piperidino) phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen)-replace) phenyl) acrylamide (XTF-11)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,Acetic-d ₄)δ9.02(s,1H),8.10(s,1H),8.05(d,J＝6.4Hz,1H),7.63(t,J＝8.0Hz,1H),7.63(t,J＝8.0Hz,1H),7.40(d,J＝8.8Hz,1H),7.33(d,J＝7.6Hz,1H),6.93(s,1H),6.56-6.42(m,2H),5.84(d,J＝11.2Hz,1H),4.45(t,J＝9.2Hz,2H),4.11(t,J＝9.2Hz,1H),3.85(s,3H),3.78(m,10H),3.56(m,1H),3.11(t,11.6Hz，2H),2.96(s,3H),2.36(m,2H),2.19(m,2H).LCMS(ESI):m/z?637.2[M+H] ⁺

Embodiment 12

N-(3-(2-((4-(2-(dimethylamino) oxyethyl group)-2-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-12)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.35(s,1H),8.62(brs,1H),8.44(brs,1H),7.76(brs,1H),7.72(s,1H)7.46(t,J＝8.0Hz,1H),7.25(d,J＝8.8Hz,1H),7.12(d,J＝8.0Hz,1H),6.52(s,1H),6.48(dd,J ₁=10.0,16.8Hz,1H),6.28(dd,J ₁=2.0,16,8Hz,1H),5.78(dd,J ₁=2.0,10.0Hz,1H),3.99-3.95(m,4H),3.77-3.69(m,5H),2.68-2.56(m,2H),2.24(s,6H).LCMS(ESI):m/z?543.2[M+H] ⁺

Embodiment 13

N-(3-(2-((2-methoxyl group-4-(2-morpholine oxyethyl group) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-13)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.34(s,1H),8.62(brs,1H),8.44(brs,1H),7.77(brs,1H),7.71(s,1H),7.46(t,J＝8.0Hz,1H),7.24(d,J＝8.8Hz,1H),7.12(d,J＝8.0Hz,1H),6.52(s,1H),6.47(dd,J＝10.0,16.8Hz,1H),6.28(d?d,J ₁=1.6,16.8Hz,1H),5.98(brs,1H),5,78(m,1H),3.97(t,J＝8.4Hz,2H),3.76(m,5H),3.58(t,J＝4.4Hz,4H),2.64(t,J＝5.6Hz,2H),2.46(m,4H).LCMS(ESI):m/z585.2[M+H] ⁺

Embodiment 14

N-(3-(2-((2-methoxyl group-4-(2-methoxy ethoxy) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-14)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.34(s,1H),8.62(brs,1H),8.45(brs,1H),7.76-7.70(m,2H),7.46(t,J＝8.0Hz,1H),7.24(d,J＝8.8Hz,1H),7.12(d,J＝8.0Hz,1H),6.53(s,1H),6.47(dd,J ₁=10.0,16.8Hz,1H),6.28(dd,J ₁=1.6,16.8Hz,1H),5.95(brs,1H),5.78(d,J＝10.0Hz,1H),4.03-3.94(m,4H),3.74-3.69(m,5H),3.62(t,J＝4.4Hz,2H),3.30(s,3H).LCMS(ESI):m/z?530.1[M+H] ⁺

Embodiment 15

N-(3-(2-((4-p-methoxy-phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-15)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.39(s,1H),10.07(s,1H),8.66(s,1H),7.79(s,1H),7.51(t,J＝8.0Hz,1H),7.21(d,J＝7.2Hz,2H),7.15(d,J＝8.4Hz,1H),6.53(m,2H),6.47(dd,J ₁=10.0,16.8Hz,1H),6.27(d,J＝16.8Hz,1H),5.78(d,J＝10.0Hz,1H),3.98(t,J＝8.8Hz,2H),3.72(t,J=8.4Hz,2H),3.63(s,3H).LCMS(ESI):m/z?456.1[M+H] ⁺

Embodiment 16

N-(3-(2-((4-fluorophenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-16)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.37(s,1H),10.24(brs,1H),8.70(s,1H),7.82(s,1H),7.76(d,J＝8.0Hz,1H),7.52(t,J＝8.4Hz,1H),7.31(brs,2H),7.16(d,J=7.6Hz,1H),6.78(brs,2H),6.46(dd,J ₁=2.0,16.8Hz,1H),6.27(dd,J ₁=2.0，16.8Hz,1H),5.78(dd,J ₁=2.0,10.0Hz,1H),3.98(t,J＝8.8Hz,2H),3.73(t,J＝8.8Hz,2H).LCMS(ESI):m/z?444.1[M+H] ⁺。

Embodiment 17

N-(3-(2-((4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-17)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.38(s,1H),10.00(s,1H),8.64(s,1H),7.90(d,J＝7.2Hz,1H),7.71(s,1H),7.50(t,J＝8.0Hz,1H),7.15-7.13(m,3H),6.53(d,J＝8.4Hz,2H),6.47(dd,J＝10,16.8Hz,1H),6.27(dd,J＝2.0,16.8Hz,1H),5.78(dd,J＝2.0,10.0Hz,1H),3.97(t,J＝8.8Hz,2H),3.72(t,J＝8.0Hz,2H),2.95(m,4H),2.41(m,4H),2.21(s,3H).LCMS(ESI):m/z?524.0[M+H] ⁺

Embodiment 18

N-(3-(2-((4-morpholine base phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-18)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.49(s,1H),10.01(s,1H),8.64(s,1H),7.73(brs,1H),7.50(s,1H),7.17-7.12(m,3H),6.54-6.52(m,2H),6.50(dd,J ₁=10.0,17.2Hz,1H),6.27-6.22(m,1H),5.77-5.74(m,1H),3.97(t,J＝9.2Hz,2H),3.71(m,6H),2.93(m,4H).LCMS(ESI):m/z?511.2[M+H] ⁺

Embodiment 19

N-(3-(5-oxo-2-((4-sulphur coffee quinoline base phenyl) amino)-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-19)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.43(s,1H),10.01(s.1H),8.64(s,1H),7.91(d,J＝7.6Hz,1H),7.72(s,1H),7.50(t,J＝8.0,1H),7.14(m,3H),6.53(m,2H),6.48(dd,J ₁=10.0,17.2Hz,1H),6.28(m,1H),5.78(d,J＝11.2Hz,1H),3.97(t,J＝8.8Hz,2H),3,74(t,J＝8.8Hz,2H),2.62(m,4H).LCMS(ESI):m/z?527.1[M+H] ⁺

Embodiment 20

N-(3-(2-((4-(1-methyl-4-piperidyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-20)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,Acetic-d ₄)δ9.01(s,1H),8.42(s,1H),7.98(d,J＝8.0Hz,1H),7.64(t,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,2H),7.00(d,J＝8.0Hz,2H),6.70(dd,J＝10.4,16.8Hz,1H),6.43(d,J＝16.8Hz,1H),5.82(d,J＝10.4Hz,1H),4.48(t,J＝8.8Hz,2H),4.15-4.11(m,2H),3.72(m,2H),3.08(t,J＝8.4Hz,2H),2.93(s,3H),2.76(m,1H),2.22-2.16(m,2H),1.96-1.87(m,2H).LCMS(ESI):m/z?523.2[M+H] ⁺

Embodiment 21

N-(3-(2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-21)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.31(s,1H),9.09(brs,1H),8.62(brs,1H),7.71(m,2H),7.40(brs,1H),7.05(brs,2H),6.70-6.58(m,2H),6.48(dd,J＝10.0,16.8Hz,1H),6.29(dd,J＝2.0,17.2Hz,1H),5.79(dd,J＝2.0,10.0Hz,1H),3.95(t,J＝8.8Hz,2H),3.71(t,J＝8.8Hz,2H),2.99(m,4H),2.41(m,4H),2.21(s,3H),2.05(s,3H).LCMS(ESI):m/z?538.2[M+H] ⁺

Embodiment 22

N-(3-(2-((2-oxyethyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-22)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.36(s,1H),8.62(s,1H),8.25(brs,1H),7.83(brs,1H),7.70(s,1H),7.47(t,J＝8.4Hz,1H),7.22(d,J＝8.8Hz,1H),7.12(d,J＝8.4Hz,1H),6.50(s,1H),6.47(dd,J ₁=10.0,17.2Hz,1H),6.28(dd,J＝2.0,16.8Hz,1H),5.78(dd,J ₁=2.0,10.0Hz,1H),4.03-3.95(m,4H),3.71(t,J＝8.4Hz,2H),3.15(m,4H),2.26(s,3H),1.38-1.18(m,3H).LCMS(ESI):m/z?568.2[M+H] ⁺

Embodiment 23

N-(3-(2-((2-isopropoxy-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-23)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.36(s,1H),8.62(s,1H),8.12(brs,1H),7.85(brs,1H),7.72(s,1H),7.48(t,J＝8.0Hz,1H),7.26(d,J＝9.2Hz,1H),7.14(d,J＝8.8Hz,1H),6.52(d,J＝2.0Hz,1H),6.47(dd,J＝10.0,16.8Hz,1H),6.27(dd,J＝2.0,16.8Hz,1H),5.93(brs,1H),5.78(dd,J＝2.0,10.0Hz,1H),4.67-4.54(m,1H),3.97(t,J＝9.2Hz,2H),3.72(t,J＝9.2Hz,2H),3.08-2.89(m,4H),2.44-2.35(m,4H),2.20(s,3H),1.29(s,6H).LCMS(ESI):m/z?582.2[M+H] ⁺

Embodiment 24

N-(3-(2-((3-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-24)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.37(s,1H),9.97(brs,1H),8.67(s,1H),7.85(brs,1H),7.72(s,1H),7.48(t,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),6.92-6.86(m,2H),6.47-6.40(m,2H),6.28(dd,J ₁=2.0Hz,J ₂=16.8Hz,1H),5.78-5.75(m,1H),3.97(t,J＝8.8Hz,2H),3,71(t,J＝8.8Hz,2H),3.55(s,3H),2.86(m,4H),2,58(m,4H),2.32(s,3H).LCMS(ESI):m/z?554.1[M+H] ⁺

Embodiment 25

N-(3-(2-((1-methyl-4-piperazinyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-25)

Synthetic method is as embodiment 1.

LCMS(ESI):m/z?447.1[M+H] ⁺

Embodiment 26

The fluoro-3-(2-((2-methoxyl group-4-(4-of N-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) acrylamide (XTF-26)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,Acetic-d ₄)δ8.96(s,1H),8.08-8.01(m,2H),7.39(t,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),6.57(s,1H),6.51-6.41(m,2H),6.22(d,J＝8.8Hz,1H),5.83(dd,J ₁=3.2Hz,J ₂=8.0H,1H),4.40(t,J＝8.8Hz,2H),4.09(t,J＝7.6Hz,2H),3.82(s,3H),3.73(m,4H),3.21(m,4H),2.95(s,3H).LCMS(ESI):m/z?572.1[M+H] ⁺

Embodiment 27

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-8,9-dihydro-5 hydrogen-bis-Kui Linpyrimido quinoline [1,2-a:4 ', 5 '-d] pyrimidine-11(7 hydrogen)-replace) phenyl) acrylamide (XTF-27)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.30(s,1H),8.65(s,1H),8.21(s,1H),7.53(s,1H),7.44(t,J＝8.0Hz,1H),7.16(d,J＝8.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.50(s,1H),6.46(dd,J＝10.0,16.8Hz,1H),6.27(dd,J＝2.0,16.8Hz,1H),5.93(brs,1H),5.77(dd,J＝2.0,10.4Hz,1H),3.86(s,2H),3.75(s,3H),3.03(m,4H),2.26(s,3H),1.79(m,2H).LCMS(ESI):m/z?568.0[M+H] ⁺

Embodiment 28

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8,9,10-tetrahydropyrimidine also [4 ', 5 ': 4,5] Kui Linpyrimido quinoline [1,2-a] [1,3] diaza-12(5 hydrogen)-replace) phenyl) acrylamide (XTF-28)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.29(s,1H),8.61(s,1H),8.18(brs,1H),7.85(brs,1H),7.49(s,1H),7.42(t,J＝8.0Hz,1H),7.16(d,J＝8.8Hz,1H),6.98(d,J＝8.4Hz,1H),6.49(s,1H),6.46(dd,J ₁=10.0,17.2Hz,1H),6.27(dd,J＝2.0,17.2Hz,1H),5.77(dd,J＝2.0,10.0Hz,1H),4.08(m,2H),3.75(s,3H),3,54(m,2H),3.01(m,4H),2.42(m,2H),2.21(s,3H),1.89-1.84(m,4H).LCMS(ESI):m/z?582.1[M+H] ⁺

Embodiment 29

N-(3-(2-((2-methoxyl group-4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-imidazole is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replacement) phenyl) acrylamide (XTF-29)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.41(s,1H)9.07(brs,1H),8.71(brs,1H),7.90(brs,1H),7.82(s,1H),7.74(s,1H),7.53(t,J＝8.0Hz,1H),7.35(d,J＝7.2Hz,1H),7.23(d,J＝8.0Hz,1H),7.07(s,1H),6.56(s,1H),6.49(dd,J ₁=10.0,16.8Hz,1H),6.28(d,J＝16.8Hz,1H),5.79(d,J＝10.0Hz,1H),3.77(s,3H),3.07(m,4H),2.32(m,4H).LCMS(ESI):m/z?552.0[M+H] ⁺

Embodiment 30

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide (XTF-30)

(3-(2-((3 hydrogen-[1,2,3] triazole also [4,5-b] pyridine-3-replaces) oxygen base)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replace) phenyl) t-butyl carbamate (3-5)

By compound 2(364mg, 1mmol, 1.0eq), HATU (760.4mg, 2.0eq), DIPEA (0.522ml, 3.0eq) add in 10mLDCM, 30 ℃ of stirrings add 2-Chlorobenzimidazole (152.5mg, 1.0eq) to continue to stir 24 hours after 0.5 hour.The solid generating in filtration under diminished pressure reaction, uses 5mL DCM, 2ml methyl alcohol, 5mL H ₂o is washing leaching cake successively, obtains faint yellow solid 270mg (48%).

¹H?NMR(400MHz,DMSO-d ₆)δ9.80(s,1H),9.60(s,1H),8.74(d,J＝3.6Hz,1H),8.41(d,J＝7.6Hz,1H)7.98(s,1H)7.83(d,J＝8.0Hz,1H),7.81-7.66(m,3H),7.58(dd,J ₁=4.4,8.4Hz,1H),7.50-7.42(m,2H),7.30-7.29(m,1H),1.43(s,9H).LCMS(ESI):m/z?564.1[M+H] ⁺

(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] pyrimidine [4,5-d] pyrimidine-12(5 hydrogen)-replace) phenyl) t-butyl carbamate (4-5)

By compound 3-5(323.8mg, 0.5mmol, 1.0eq), 2-methoxyl group-4-(4-methylpiperazine-1-replaces) aniline (110.6mg, 1.0eq), K ₂cO ₃(207.3mg, 3.0eq), the 8mL trimethyl carbinol adds in 25mL tube sealing, is heated to 110 ℃ of stirring reactions 24 hours.Stop heating and be down to room temperature, decompression steams solvent, adds DCM and H ₂the organic phase of O extracting and separating, saturated NaCl solution washing organic phase once, obtains organic phase anhydrous Na ₂sO ₄dry.Decompression steams solvent, obtains solid and is directly used in next step reaction.

Other steps are with embodiment 1

¹H?NMR(400MHz,Acetic-d ₄)δ9.11(s,1H),8.46(d,J＝6.8Hz,1H),8.44(d,J＝3.2Hz,1H),8.21(s,1H),7.82(s,1H),7.65(t,J＝8.0Hz,1H),7.61(d,J＝6.8Hz,1H),7.44-7.38(m,2H),7.36(d,J＝8.0Hz,1H),6.57(s,1H),6.48-6.46(m,2H),6.21(d,J＝8.8Hz,1H),5.83(dd,J ₁=4.0,7.6Hz,1H),3.85(s,3H),3.70(m,4H),3.20(m,4H),2.95(s,3H).LCMS(ESI):m/z?602.1[M+H] ⁺

Embodiment 31

N-(3-(2-((2-oxyethyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide (XTF-31)

Synthetic method is as embodiment 30.

¹H?NMR(400MHz,DMSO-d ₆)δ10.44(s,1H),9.09(s,1H),8.61(s,1H),8.35(d,J＝7.2Hz,1H),7.97(d,J＝8.0Hz,1H),7.89(s,1H),7.60-7.56(m,2H),7.40-7.34(m,3H),7.29-7.27(m,1H),6.51(s,1H),6.49(dd,J ₁=10.0Hz,J ₂=17.2Hz,1H),6.29(dd,J ₁=1.6,16.8Hz,1H),6.00(brs,1H),5.79(d?d,J＝1.6,10.0Hz,1H),4.06(q,J＝6.4Hz,2H),3.03(m,4H),2.43(m,4H),2.22(s,3H),1.33(s,3H).LCMS(ESI):m/z?616.3[M+H] ⁺

Embodiment 32

N-(3-(2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide (XTF-32)

Synthetic method is as embodiment 30.

LCMS(ESI):m/z?586.2[M+H] ⁺

Embodiment 33

N-(3-(2-((4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replace) phenyl) acrylamide (XTF-33)

Synthetic method is as embodiment 30.

¹H?NMR(400MHz,DMSO-d ₆)δ10.47(s,1H),9.10(s,1H),8.36(d,J＝7.6Hz,1H),8.03(d,J＝7.6Hz,1H),7.90(s,1H),7.60(t,J＝8.0Hz,1H),7.58(d,J＝7.6Hz,1H),7.39-7.36(m,1H),7.34-7.30(m,2H),7.27(d,J＝8.4Hz,1H),6.59(d,J＝8.4Hz,2H),6.47(dd,J ₁=10.0,16.8Hz,1H),6.29(d,J＝16.8Hz,1H),5.79(d,J＝10.0Hz,1H),2.99(m,4H),2.42(m,4H),2.22(s,3H).LCMS(ESI):m/z?572.1[M+H] ⁺

Embodiment 34

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide (XTF-34)

Synthetic method is as embodiment 30.

¹H?NMR(400MHz,DMSO-d ₆)δ10.43(s,1H),9.08-9.01(m,1H),8.73(s,1H),8.33(s,1H),7.97(s,1H),7.57(t,J＝8.0Hz,2H),7.38-7.28(m,4H),6.49-6.43(m,2H),6.29(d,J＝17.2H,1H),6.01(brs,1H),5.79(d,J＝10.0Hz,1H),3.77(s,3H),3.03(m,4H),1.60-1.53(m,6H).LCMS(ESI):m/z587.2[M+H] ⁺

Embodiment 35

N-(3-(2-((2-methoxyl group-4-morpholine base phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-replacement) phenyl) acrylamide (XTF-35)

Synthetic method is as embodiment 30.

¹H?NMR(400MHz,DMSO-d ₆)δ10.43(s,1H),9.09(m,1H),8.76(s,1H),8.33(m,1H),7.96(d,J＝8.4Hz,1H),7.88(s,1H),7.57(t,J＝8.0Hz,2H),7.40-7.26(m,4H),6.54(s,1H),6.49(dd,J＝10.4,16.8Hz,1H),6.29(dd,J＝2.0,16.8Hz,1H),6.02(brs,1H),5.79(dd,J＝2.0,10.0Hz,1H),3.78-3.72(m,7H),3.01(m,4H).LCMS(ESI):m/z?588.9[M+H] ⁺

Embodiment 36

N-(3-(2-((4-(dimethylamino)-piperidino)-2-p-methoxy-phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-12(5 hydrogen)-yl) phenyl) acrylamide (XTF-36)

Synthetic method is as embodiment 30.

¹H?NMR(400MHz,DMSO-d ₆)δ10.54(s,1H),9.09-9.00(m,1H),8.77(s,1H),8.35(d,J＝5.6Hz,1H),8.01(d,J＝5.6Hz,1H),7.86(s,1H),7.59-7.55(m,2H),7.38-7.26(m,4H),6.54-6.47(m,2H),6.30(d,J＝17.2Hz,1H),6.04(brs,1H),5.80(d,J＝11.6Hz,1H),3.78-3.72(m,5H),3.11(m,1H),2.66-2.61(m,8H),2.05-2.02(m,2H),1.67(m,2H).LCMS(ESI):m/z?630.4[M+H] ⁺

Embodiment 37

(E)-N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) but-2-enamides (XTF-37)

Synthetic method is as embodiment 1.

¹H?NMR(400Hz,DMSO-d ₆)δ10.14(s,1H),8.61(brs,1H),8.34(brs,1H),7.79(brs,1H),7.69(s,1H),7.43(t,J＝8.0Hz,1H),7.20(d,J＝7.2Hz,1H),7.08(d,J＝8.0Hz,1H),6.84-6.75(m,1H),6.50(s,1H),6.14(d,J＝15.2Hz,1H),5.95(brs,1H),3.96(t,J＝8.8Hz,2H),3.74-3.71(m,5H),3.03(m,4H),2.43(m,4H),2.22(s,3H),1.87(d,J＝6.8Hz,3H).LCMS(ESI):m/z?568.2[M+H] ⁺

Embodiment 38

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl)-3 rare acid amides in methyl fourth-2 (XTF-38)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.03(s,1H),8.60(brs,1H),8.35(brs,1H),7.72(m,2H),7.41(t,J＝8.0Hz,1H),7.20(d,J＝8.8Hz,1H),7.05(d,J＝8.0Hz,1H),6.50(s,1H),5.95(brs,1H),5.87(s,1H),3.96(t,J＝8.8Hz,2H),3.74(m,5H),3.04(m,4H),2.43(m,4H),2.21(s,3H),2.14(s,3H),1.86(s,3H).LCMS(ESI):m/z?582.1[M+H] ⁺

Embodiment 39

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) cinnamide (XTF-39)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.42(s,1H),8.62(brs,1H),8.35(brs,1H),7.87(brs,1H),7.74(s,1H),7.63-7.57(m,2H),7.49-7.39(m,4H),7.23(dJ＝8.8Hz,1H),7.12(d,J＝8.0Hz,1H),6.86(d,J＝15.6Hz,1H),6.48(s,1H),5.98(brs,1H),3.97(t,J＝8.4Hz,2H),3.74(m,5H),3.00(m,4H),2.36(m,4H),2.16(s,3H).LCMS(ESI):m/z?630.1[M+H] ⁺

Embodiment 40

(E)-4-(dimethylin)-N-(3-(2-((4-fluorophenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) the rare acid amides of fourth-2-(XTF-40)

Synthetic method is as embodiment 1.

¹H?NMR(400MHz,DMSO-d ₆)δ10.28(s,1H),10.21(brs,1H),8.69(s,1H),7.82(s,1H),7.73(d,J＝8.8Hz,1H),7.50(t,J＝8.0Hz,1H),7.31brs,2H),7.14(d,J＝8.0Hz,1H),6.76-6.69(m,3H),6.29(d,J＝15.6Hz,1H),3.98(t,J＝8.8Hz,2H),3.73(t,J＝8.8Hz,2H),3.10(d,J＝4.8Hz,2H),2.17(s,6H).LCMS(ESI):m/z?501.1[M+H] ⁺

Embodiment 41

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-10(5 hydrogen also)-replace) phenyl) propionic acid amide (XTF-41)

Synthetic method is as embodiment 1.

¹H?NMR(400Hz,DMSO-d ₆)δ10.05(s,1H),8.60(brs,1H),8.38(brs,1H),7.70(brs,1H),7.64(s,1H),7.42(t,J＝8.0Hz,1H),7.19(d,J＝8.8Hz,1H),7.06(d,J＝8.0Hz,1H),6.51(s,1H),5.94(brs,1H),3.96(t,J＝8.8Hz,2H),3,74-3.70(m,5H),3.04(m,4H),2.43(m,4H),2.34(q,J＝8.0Hz,2H),2.22(s,3H),1.06(t,J＝8.0Hz,3H).LCMS(ESI):m/z?556.2[M+H] ⁺

Embodiment 42

Kui Linpyrimido quinoline three rings or the Kui Linpyrimido quinoline Fourth Ring compounds kinases EC to EGFR wild-type and EGFR-T790M sudden change ₅₀test

Kinase activity detects: application Z '-LYTE ^tMtechnology (adopt that fluorescence detects, enzyme coupling form, take phosphorylation and non-phosphorylating polypeptide are basis to the sensitivity differences of proteolysis cutting), adopts FRET (fluorescence resonance energy transfer) (FRET) principle, uses Z ' LYTE ^tMfRET peptide class substrate, second order reaction detection compound is to kinase activity.(invitrogen, Z '-LYTE ^tMkINASE ASSAY KIT – TYR 2PEPTIDE, PV3191) by EGFR-T790M kinases (invitrogen, PV4803) after stepwise dilution, add FRET peptide, ATP, then add different concns compound, after reaction 1h, add locus specificity proteolytic enzyme, identify and cut unphosphorylated FRET peptide, reaction 1h, use 400nm excitation wavelength, detect 445nm and 520nm and absorb.

Emission Ratio = \frac{Coumarin Emission (445 nm)}{Fluorescein Emission (520 nm)}

% Phosphorylation = 1 - \frac{(Emission Ratio x F 100 %) - C 100 %}{(C 0 % - C 100 %) + [Emission Ratio x (F 100 % - F 0 %)]}

Show that inhibiting rate becomes positive correlation with drug level, make kinase activity and concentration relationship curve, calculate IC ₅₀value.

Institute's compound number of classifying as and corresponding kinase activity result in table 1.

Table 1 compound kinase activity

In the competitive assay of Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds and ATP, owing to existing with protein cysteine site, form irreversible Michael reaction, so it is active that five kinds of kinases are all embodied to higher inhibition.In conjunction with experimental data and compound structure feature, we can find out that substituted acryl is that active institute must structure, formula VII, VIII, substituted radical A in IX ₁, A ₂, A ₃, A ₄, A ₅, R ₆, R ₇, R ₈, R ₉less to activity influence, all there is good activity, but R ₁₃, R ₁₄while being hydrogen, active effect is best, active decline during for alkyl or aromatic substituent group.

Embodiment 43

The cell tests of EGFR activity

The impact of MTT detection compound on cell proliferation: 1500/every hole, HCC827(lung carcinoma cell, EGFR E746-A750deletion), H1975 (lung carcinoma cell, EGFR L858R & T790M) spread 96 orifice plates, after 24h, by the different concns compound treatment (DMSO final concentration 1 ‰, parallel control 3-5) of DMSO preparation, after 72h, add MTT (tetrazolium bromide, 5mg/ml, 10ul/ hole), 37 degree are hatched 4h.Suck supernatant, add DMSO150ul, fully, after vibration, detect OD570, use GraphPad Prism 4Demo software processes.Found that, Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds are processed and can obviously be reduced the absorption of above-mentioned cell to MTT, illustrate that Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds can significantly suppress H1975 (L858R/T790), the increment of HCC827 (DEL746-750) two class cells, inhibiting rate becomes positive correlation with drug level.According to Kui Linpyrimido quinoline three ring or the growth-inhibiting effects of Kui Linpyrimido quinoline Fourth Ring compounds to these cells, we calculate its half-inhibition concentration (IC ₅₀) value describes as table 2.

Table 2 compound cytoactive

The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims

1. there is formula I, Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs of (II) or (III) structure:

N=1～3 wherein

R ₁certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) C ₁～C ₅containing fluoroalkyl;

5) (CH ₂) _nx, n=0～6, X is hydroxyl, amino, C ₁～C ₆heteroatom containing alkyl, C ₃～C ₇heterocyclic radical;

a ₁, A ₂, A ₃, A ₄, A ₅certainly optional: halogen, cyano group, nitro, hydroxyl, amino, C ₁～C ₆alkyl, C ₃～C ₆cycloalkyl, C ₁～C ₆containing fluoroalkyl, C ₁～C ₆heteroatom containing alkyl, C ₁～C ₇the ester that heterocyclic radical and abovementioned alkyl form, acid amides, sulfone, sulfoxide, urea;

R ₂certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) C ₁～C ₅containing fluoroalkyl;

5) aryl;

6) heterocyclic radical;

R ₃certainly optional:

1）H；

2) halogen;

3) amino, hydroxyl, cyano group, nitro;

4) C ₁～C ₅alkyl;

5) C ₃～C ₆cycloalkyl;

6) aryl;

R ₄certainly optional:

1）H;

2) halogen;

3) C ₁～C ₅alkyl;

4) C ₃～C ₆cycloalkyl;

5) aryl;

R ₅certainly optional:

1）H；

2) halogen;

3) C ₁～C ₃alkyl;

4) C ₃～C ₆cycloalkyl;

5) C ₁～C ₃alkoxyl group;

6) C ₁～C ₃containing fluoroalkyl;

7) heterocyclic radical;

8) C ₀～C ₃alkylidenyl-heterocyclic base;

9) phenyl.

2. Kui Linpyrimido quinoline three according to claim 1 encircles or Kui Linpyrimido quinoline tetracyclic compound or its pharmacy acceptable salt or steric isomer or its prodrugs, and it has formula IV, V, and VI structure:

N=1～3 wherein

R ₁certainly optional:

a ₁, A ₂, A ₃, A ₄, A ₅certainly optional: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, the neo-pentyl branched paraffin of being correlated with, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy and containing oxygen alkane, trifluoromethyl and fluorine-containing alkane, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, imidazoles, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone, and the ester of above-mentioned group formation, acid amides, sulfone, sulfoxide, urea,

R ₆, R ₇, R ₈, R ₉certainly optional:

R ₁₀, R ₁₁certainly optional:

R ₁₂certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) phenyl;

3. Kui Linpyrimido quinoline three according to claim 2 encircles or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or its prodrugs, and it has formula VII, VIII, and IX structure:

N=1～3 wherein

A ₁, A ₂, A ₃, A ₄, A ₅certainly optional:

H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, the neo-pentyl branched paraffin of being correlated with, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy and containing oxygen alkane, trifluoromethyl and fluorine-containing alkane, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, 2-Pyrrolidine base oxethyl related heterocycles alkoxyl group, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone,

R ₆, R ₇, R ₈, R ₉certainly optional:

H, fluorine, chlorine, bromine, iodine;

R ₁₃, R ₁₄certainly optional:

1）H；

2) C ₁～C ₅alkyl;

3) C ₃～C ₆cycloalkyl;

4) phenyl;

5) N, N-dimethylaminomethyl, N, N-diethylamino methyl.

4. according to Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs described in claim 1-3 any one, it is characterized in that, wherein A ₁, A ₂, A ₄, A ₅be selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, A ₃be selected from N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methylpiperazine base) oxyethyl group, 2-(N-ethanoyl piperazinyl) oxyethyl group, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl oxyethyl group, 2-Pyrrolidine base oxethyl related heterocycles alkoxyl group, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, Pyrrolidine, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-ethanoyl piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methylpiperazine-1-replaces) methyl, 1-methyl piperidine-4-is amino, 4-piperazine-2-ketone.

5. Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs according to claim 4, is characterized in that, wherein R ₆, R ₇, R ₈, R ₉be selected from H, fluorine; R ₁₃, R ₁₄for hydrogen.

6. according to Kui Linpyrimido quinoline three ring or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs described in claim 1-3 any one, it is characterized in that, described compound is selected from:

10-(3-aminophenyl)-2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-7,8-glyoxalidine is [1,2-a] Kui Linpyrimido quinoline [4,5-d] pyrimidine-5(10 hydrogen also)-one.

7. treat a medicinal compositions for tumour, it is comprised of Kui Linpyrimido quinoline three ring described in claim 1-6 any one or Kui Linpyrimido quinoline Fourth Ring compounds or its pharmacy acceptable salt or steric isomer or its prodrugs and pharmaceutically acceptable carrier.

8. claim 1-6 any one Kui Linpyrimido quinoline three rings or Kui Linpyrimido quinoline Fourth Ring compounds and pharmacy acceptable salt thereof or steric isomer or the application of its prodrugs in the medicine of preparation treatment tumour.

9. application according to claim 8, is characterized in that: described tumour is any in nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histocyte lymphatic cancer, nasopharyngeal carcinoma.