CN103374000A - Pyrimido diazepine compound as well as pharmaceutical composition and application thereof - Google Patents

Abstract

The invention discloses a 5,8-dioxo-pyrimido[4,5-e][1,4]diazepine compound of a structural formula (1) or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof. The 5,8-dioxo-pyrimido[4,5-e][1,4]diazepine compound has the effects of effectively inhibiting the growth of various tumor cells and the generation of the EGFR (epidermal growth factor receptor), can be used for preparing anticancer medicaments and can overcome the resistance of the existing medicaments including the gefitinib, the erlotinib and the like.

Description

Kui Linpyrimido quinoline Diazepines and medicinal compositions thereof and application

Technical field

The invention belongs to chemical field of medicaments, particularly relate to Kui Linpyrimido quinoline Diazepines and medicinal compositions thereof and application.

Background technology

No matter worldwide or in China, the chronic disease (in other words Non Communicable Diseases (NCD)) take malignant tumour (cancer), cardiovascular disorder and diabetes etc. as representative is all becoming main long-term threat.On May 19th, 2008, the World Health Organization just explicitly points out in the report of its up-to-date announcement, and Non Communicable Diseases (NCD) is becoming human the most fatal " killer ".Wherein, cancer is ranked the first place.2004, the whole world had 7,400,000 people to die from cancer, and wherein, the situation of China is then more severe.The Third National cause of the death retrospective survey of announcing in by the end of April, 2008 shows, the cancer mortality of Chinese urban and rural residents has increased most probably in the past in 30 years more than; Wherein just there is a people to die from cancer among the Chinese of per four to five death.China dies from the total population of cancer every year, near 2,000,000 people.In recent years, although the discovery of various treatment approach and medicine has brought hope to the cancer patients, the drawback of conventional treatment, side effect is large, result for the treatment of is not good, the 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 the molecule parting basis and targeted therapy as break through present lung cancer therapy bottleneck hope place.

The tumour molecular targeted therapy is based on a kind of methods for the treatment of of the closely-related key molecule of tumor growth by chemistry or biological means selective killing tumour cell.The characteristics of targeted therapy are: 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) be that chemotherapy of tumors has been started a New Times for the targeted drug of representative.Neoplasm targeted therapy has obtained developing rapidly in recent years.The appearance of neoplasm targeted therapy consists of impact to traditional administration idea and pattern, for example, and because the little targeted drug of toxic side effect often can't reach dose-limiting toxicity and maximum tolerated dose in the I clinical trial phase; Need not during with target therapeutic agent can reach 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 the 520 multiple protein kinases in the human body nearly half be Tyrosylprotein kinase (PTKs).They have occupied very consequence in intracellular signal transduction pathway, regulating a series of physiology processes such as cell growth in vivo, differentiation, death.The protein tyrosine kinase functional disorder can cause a series of diseases in the organism.Studies show that proto-oncogene more than half is all relevant with protein tyrosine kinase with the activation of oncogene.The unconventionality expression of protein tyrosine kinase can cause the 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.Carrying out the antitumor drug research and development take Tyrosylprotein kinase as target spot and become an international focus, also is the emphasis that the research of various countries drug development mechanism drops into.

EGF-R ELISA (EGFR), a kind of receptor tyrosine protein kinase has been regulated and control propagation, survival, adhesion, migration and the differentiation of cell.EGFR is overactivity or continuous activation in kinds of tumor cells, such as lung cancer, and mammary cancer, prostate cancer etc.EGFR is a kind of transmembrane protein, and there are 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) in its family.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 come the targeting therapy on tumor cell.Take lung cancer as example, EGFR has expression in 50% NSCLC (non-small-sized sexual cell lung cancer) case, and its expression is not good relevant with prognosis.These two factors are so that EGFR and family member thereof become the main candidate of carrying out 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 the advanced NSCLC patient, and these patients have lost reaction to conventional chemotherapy.

Early stage clinical data shows that 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 venereal disease reason type.The analysis showed that of molecular level, as a rule, the patient that medicine is responded on coding EGFR gene with specific sudden change.The disappearance of the 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, so that the existence of tumour cell has dependency to mutant kinase.Existing multinomial Prospective Clinical studies confirm that, the NSCLC patient of the EGFR activation sudden change positive is significantly higher than EGFR wild-type NSCLC patient to the reactivity of EGFR-TKI (EGFR-tyrosine kinase inhibitor), 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, namely resistance has been occured TKI.The another study hotspot that the mechanism of acquired resistance and clinical countermeasure thereof become the 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 of having sealed TKI and kinases district.Current research shows that it is stronger than simple L858R to the avidity of ATP that L858R merges the T790M sudden change, and TKI is ATP competitiveness kinase inhibitor, so cause TKI and kinases district combination rate to reduce.That this sudden change is to produce after the TKI treatment or originally just existing, just be found after the TKI treatment is selected about one of dispute of T790M.At first, T790M only treats in failed NSCLC patient's sample at TKI and is found, but in the sample without any treatment, also be found subsequently, so think at present, this sudden change also is present in the tumor tissues for the treatment of without TKI, 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 in 2007.MET is a kind of cross-film tyrosine kinase receptor.In the EGFR to the TKI acquired resistance suddenlyd change positive NSCLC patient, about 20% had 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 in vitro, suppress the MET signal path by the RNA perturbation technique, can recover resistance person to the susceptibility of Gefitinib.Suppress simultaneously EGFR and MET, 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 because technical reason is difficult to carry out IGF-1R activation detection 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, about 30%～40% both without secondary mutation, and also without the MET amplification, these patients' resistance mechanism is also in exploration.

For resistance, the strategy that adopts clinically is: strategy 1---continue to use EGFR-TKI, the cross-reference of Gefitinib and Tarceva.In a word, continue to use TKI that certain benefit is arranged after the TKI progress, but the benefit degree is very limited.Strategy 2---development of new EGFR-TKI.Preclinical study shows, the EGFR irreversible inhibitor can be at vitro inhibition T790M, after this, a lot of EGFR irreversible inhibitors are developed out, be called " two generation EGFR-TKI ", move towards gradually clinical from preclinical study at present, study more have neratinib, XL647, BIBW 2992 and PF-00299804.Neratinib is the irreversible TKI of general ErbB (EGFR, ErbB2 and ErbB3).Based on I phase result of study, carrying out at present clinical study, inquire among the NSCLC patient of progress after Gefitinib or Tarceva treatment, whether neratinib (240mg/d) can overcome the TKI resistance that T790M suddenlys change or the MET amplification causes.But some preclinical studies have shown unfavorable result, and a kind of cell strain PC-9 of EGFR 19 Exon deletion has produced the T790M sudden change when being exposed to neratinib; In mouse L858R-T790M tumor model, alone neratinib does not make Tumor response.So whether neratinib does not effectively still learn T790M sudden change person.XL647 energy irreversible inhibition EGFR, HER2, VEGF R2 (VEGFR-2) and EphB4 in the L858R-T790M catastrophic model, can suppress tumor growth.2008, II phase clinical study about XL647 tentatively shows, the treatment of 34 routine Gefitinib or Tarceva alleviate surpass 3 months after among diseases progress or the NSCLC patient with the T790M sudden change, after XL647 (300mg/d) treatment, 1 routine partial rcsponse only, this patient's non-smoking, 19 Exon deletion are suddenlyd change without T790M in the blood plasma; And positive none alleviation of patient of T790M sudden change, major part is progress in 2 months.BIBW 2992 is irreversible TKI of EGFR and ErbB2.In II phase clinical study, BIBW 2992 has made 19 Exon deletion, and alleviating appears in L858R, L861Q and G719S/S768I sudden change patient.The clinical study of progress NSCLC was carried out after the failure of BIBW 2,992 three a lines treatment chemotherapy, Gefitinib or Tarceva benefited.BIBW 2992 contrast placebos, the at random IIb/III phase clinical study that three lines treatment Gefitinib or Tarceva are treated failed NSCLC is also underway.These researchs will help to determine that can BIBW 2992 bring benefit to Gefitinib or Tarceva resistance patient.PF-00299804 is general ErbB TKI inhibitor.In I phase clinical study, 1 routine T790M sudden change positive disease occurs and alleviates.PF-00299804 (45mg/d) treatment KRAS wild-type, chemotherapy and Tarceva are treated failed NSCLC patient's II phase clinical study and are carried out.Strategy 3---for other target treatments.Because " bypass activated pathway " play a significant role in the EGFR-TKI resistance, continue to bring out for the targeted drug of these bypasses.MET-TKI may play a role in the patient with the MET amplification.The preclinical study demonstration, EGFR-TKI and MET-TKI unite, and be positive and effective with the cell strain of MET amplification to the EGFR sudden change, but both independent uses are all invalid.An important problem is that the patient who makes an appointment with half to have the MET amplification has the T790M sudden change simultaneously, so MET-TKI may need to unite with the T790M inhibitor.XL184 is a kind of novel TKI, and MET, VEGFR-2 and RET are had restraining effect.Other MET inhibitor such 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 showed preferably tumour control effect in I phase clinical study, especially to ALK-EML4 fusion gene positive patient.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, also in process such as the correlative study of IGF-1R inhibitor, inhibitor of heat shock protein 90 etc.

In a word, present EGFR-TKI still can not solve the caused clinical pressure of drug resistance, and existing medicine be mostly take quinazoline or quinoline amine as the EGFR of basic parent nucleus reversible or irreversible inhibitor, its toxic side effect that poor selectivity of wild-type cell is brought also is 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

The purpose of this invention is to provide a kind of new Kui Linpyrimido quinoline diaza table compounds.

Concrete technical scheme is as follows:

Have 5 of formula (I) structure, 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs:

Wherein, Y is certainly optional: CH or N;

N is optional to be 0 or 1;

R ₁Certainly optional:

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) (CH ₂) _mX, m=0～6, X is hydroxyl, amino, C ₁～C ₆Heteroatom containing alkyl, C ₃～C ₆Contain the heteroatomic ring alkyl;

6) A ₁, A ₂, A ₃, A ₄, A ₅Certainly optional:

a)H；

B) halogen;

C) cyano group;

D) nitro;

E) hydroxyl;

F) amino;

G) C ₁～C ₆Alkyl;

H) C ₃～C ₆Cycloalkyl;

I) C ₁～C ₆Contain fluoroalkyl;

J) C ₁～C ₆Heteroatom containing alkyl;

K) C ₃～C ₇Contain the heteroatomic ring alkyl;

L) ester of abovementioned alkyl formation, acid amides, sulfone, sulfoxide, urea;

Above-mentioned heteroatoms is selected from N, O, S;

R ₂Certainly optional:

When n elects 0 as

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) aryl;

6) C ₁～C ₅Contain the aryl substituted alkyl;

7) contain the heteroatomic ring alkyl;

When n elects 1 as

1) C ₁～C ₅Alkyl;

2) C ₁～C ₅Contain fluoroalkyl;

Above-mentioned heteroatoms is selected from N, O, S;

R ₃Certainly optional:

When n elects 0 as

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) aryl;

6) C ₁～C ₅Contain the aryl substituted alkyl;

7) contain the heteroatomic ring alkyl;

When n elects 1 as

1) C ₁～C ₅Alkyl;

2) C ₁～C ₅Contain fluoroalkyl;

Above-mentioned heteroatoms is selected from N, O, S;

R ₄Certainly optional:

1)H；

2) halogen;

3) amino, hydroxyl, cyano group, nitro;

4) C ₁～C ₅Alkyl;

5) C ₃～C ₆Cycloalkyl;

6) aryl;

7)

W is certainly optional: CH ₂, CH ₂CH ₂, O, S, NH, NR, wherein R is C ₁～C ₅Alkyl or aryl;

R ₅Certainly optional:

a)H；

B) halogen;

C) C ₁～C ₅Alkyl;

D) C ₃～C ₆Cycloalkyl;

E) aryl;

The above cycloalkyl, aryl can be chosen wantonly by 0,1, and 2 or 3 optional from R ₆Substituting group replace;

R ₆Certainly optional:

a)H；

B) halogen;

C) C ₁～C ₃Alkyl;

D) C ₃～C ₆Cycloalkyl;

E) C ₁～C ₃Alkoxyl group;

F) C ₁～C ₃Contain fluoroalkyl;

G) contain the heteroatomic ring alkyl;

H) C ₀～C ₃The alkylidenyl-heterocyclic base;

I) phenyl;

Described M is the single replacement of place aromatic ring 2,4,5 or 6 sites or polysubstituted functional group, and is certainly optional:

1) hydrogen;

2) halogen;

3) cyano group;

4) nitro;

5) hydroxyl;

6) amino;

7) C ₁～C ₆Alkyl;

8) C ₃～C ₆Cycloalkyl;

9) C ₁～C ₆Contain fluoroalkyl;

10) C ₁～C ₆Heteroatom containing alkyl;

11) C ₁～C ₇Contain the heteroatomic ring alkyl;

12) ester of abovementioned alkyl formation, acid amides, sulfone, sulfoxide, urea;

Above-mentioned heteroatoms is O, N or S.

Therein among some embodiment, described 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (II) structure:

R ₂, R ₃, R ₄, n, M as claimed in claim 1;

Described R ₁Be selected from:

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

3) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

4) (CH ₂) _mX, m=0～6, X is hydroxyl, amino, methoxyl group, oxyethyl group, methoxy ethoxy, the relevant oxyalkyl that contains of ethoxy ethoxy, the first sulfydryl, N, N-dimethyl, N methyl piperazine base, the morpholine base, sulphur coffee quinoline base, piperidyl, the Pyrrolidine base, 4-N, N-lupetidine base, 1-methyl-4-(piperazine-4-replaces) piperidyl, imidazolyl, 6-(4-methylpiperazine-1-replaces)-3-substituted pyridinyl;

5)

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

a)H；

B) fluorine, chlorine, bromine, iodine;

C) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

D) methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy;

E) trifluoromethyl;

F) N, N-dimethylamino ethoxy, N, the N-dimethylamino propoxy, 2-(N methyl piperazine 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, imidazoles, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, the 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;

G) ester of above-mentioned group formation, acid amides, sulfone, inferior maple, urea;

Above-mentioned heteroatoms is O, N or S.

Therein among some embodiment, described 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (III) structure:

R ₁, R ₂, R ₃, n, M as claimed in claim 2;

Described R ₇, R ₈Certainly optional:

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

3) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

4) phenyl;

5)

W is certainly optional: CH ₂, CH ₂CH ₂, O, S, NH, NR, wherein R is methyl, ethyl, phenyl;

R ₅Be selected from:

a)H；

B) fluorine, chlorine, bromine, iodine;

C) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl;

D) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

E) phenyl, the single replacement or polysubstituted phenyl.

Therein among some embodiment, described 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (IV) structure:

R ₂Certainly optional:

When n elects 0 as

1)H；

2) methyl, ethyl;

3) phenyl;

4) benzyl;

When n elects 1 as

1)-CH ₂-，-C ₂H ₄-；

R ₃Certainly optional:

When n elects 0 as

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl;

3) phenyl;

4) benzyl, 4-luorobenzyl, 4-chlorobenzyl, 4-methoxy-benzyl;

When n elects 1 as

1)-CH ₂-，-C ₂H ₄-。

Therein among some embodiment, described 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs is characterized in that, described compound is selected from:

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,10-dioxo-8,9,9a, 10-tetrahydrochysene-5H-Kui Linpyrimido quinoline [4,5-e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza table-11 (7H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,11-dioxo-7,8,9,10,10a, 11-hexahydropyrrolo also [1,2-a] Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-12 (5H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6,7-dimethyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-sec.-propyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-isobutyl--2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-6-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-7-(4-methoxy-benzyl)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-(4-chlorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-(4-luorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(6-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide.

Another purpose of the present invention provides a kind of medicinal compositions for the treatment of tumour.

Concrete technical scheme is as follows:

A kind of medicinal compositions for the treatment of tumour, it is by above-mentioned 5, and 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs and pharmaceutically acceptable carrier form.

Another purpose of the present invention provides a kind of application of above-claimed cpd.

Concrete technical scheme is as follows:

Described 5, the application in the medicine of preparation treatment tumour of 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines and pharmacy acceptable salt thereof or steric isomer or its prodrugs.

Among 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, the nasopharyngeal carcinoma therein.

The Kui Linpyrimido quinoline diaza table compounds of (I) constitutional features that the present invention relates to have general formula can suppress kinds of tumor cells, especially can selectively acting in EGFR ^L858R/T790MAnd EGFR ^{Del E745_A750}Lung carcinoma cell.Contrast wild-type cancer cells, the IC of this compounds ₅₀Want high 10 times order of magnitude difference.This compounds be the existing EGFR-TKI resistance of can overcoming of a class novelty and have an optionally kinases inhibitor.

The present invention relates to 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [1,4] Diazepines and pharmacy acceptable salt thereof, growth that can the establishment kinds of tumor cells, and to EGFR protease-producing restraining effect, can be used for preparing antitumor drug, and can overcome existing medicine Gefitinib, the resistance that Tarceva etc. bring out.As skilled in the art to understand, 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.

Description of drawings

Fig. 1-4 is EGFR ^WTKinases EC50 test result;

Fig. 5-8 is EGFR ^T790MKinases EC50 test result;

Fig. 9-12 is EGFR ^L858RKinases EC50 test result;

Figure 13-16 is EGFR ^L861QKinases EC50 test result;

Figure 17-20 is EGFR ^T790/L858RKinases EC50 test result;

Figure 21-25 is that compound is to lung carcinoma cell and normal liver cell's MTT experimental result;

Figure 26 is that compound S L05 and SL13 are on the result that affects of EGFR tyrosine phosphorylation.

Embodiment

In the chemicals of the present invention, as any variable (R for example ₁, R etc.) in any component, occur surpassing once, then its each definition that occurs is independent of other each definition that occurs.Equally, 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 only is 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 method that can be by art technology and following proposition from the easy synthetic compound of the raw material that can obtain easily.Replace if substituting group self is exceeded a group, should understand these groups can be on the identical carbon atoms or on the different carbon atom, as long as make Stability Analysis of Structures.Phrase " optional replaced by one or more substituting groups " be considered to phrase " optional replaced by at least one substituting group " quite 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 comprise 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.

Used term " heterocycle " or " heterocyclic radical " refer to 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 " therefore comprises above mentioned heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further embodiment includes but not limited to: imidazolyl, indyl, isothiazolyl isoxazolyl oxadiazolyl oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, 1, the 4-alkyl dioxin, pyrrolidyl, the glyoxalidine base, the dihydro-isoxazole base, dihydro isothiazolyl Er Qing oxadiazolyl dihydro-oxazole base, the dihydro pyrazinyl, the pyrazoline base, the dihydropyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydro tetrazyl, the thiodiazoline base, dihydro-thiazolyl, the dihydro-thiophene base, the dihydro triazolyl, the dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.

As understood by one of ordinary skill in the art, used " halogen " (" halo ") or " halogen " mean to comprise fluorine, chlorine, 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 present invention includes the free form of formula I-IV compound, also comprise its pharmacy acceptable salt and steric isomer.Some specific exemplary compounds are the protonated salt of aminated compounds herein.Term " free form " refers to the aminated compounds with salt-independent shape.The pharmaceutically-acceptable salts that is included not only comprises the exemplary salt of specific compound described herein, also comprises the typical pharmacy acceptable salt of all formula I-IV compound free forms.Can use technical point known in the art from the free form of described compound specific salts.For example, can be by for example NaOH dilute aqueous soln, salt of wormwood dilute aqueous soln, weak ammonia and sodium bicarbonate dilute aqueous soln are processed this salt and made free form regeneration with suitable alkali dilute aqueous soln.Free form some physical properties for example in polar solvent on the solubleness with its separately salt form more or less distinguish, but for the invention this hydrochlorate of purpose and alkali salt aspect other pharmacy with its free form is suitable separately.

Can be by the 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.Usually, by ion-exchange chromatography or in the combination of appropriate solvent or multi-solvents, react the salt of preparation basic cpd by the inorganic or organic acid of free alkali and stoichiometric quantity or excessive required salt form.Similarly, by reacting the salt that forms acidic cpd with suitable inorganic or organic bases.

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, pounces on 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-acetoxyl group-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, then suitable " pharmacy acceptable salt " refers to comprise by pharmaceutically acceptable nontoxic alkali the salt of mineral alkali and organic bases preparation. 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 that replaces 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 one ethyl morpholine, N one ethyl piperidine, glucosamine, glucosamine, Histidine, hydroxocobalamin, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, the croak smack one's lips, the 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 more detailed description the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt.

Since under physiological condition in the compound acidic moiety of deprotonation 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, be potential inner salt or zwitter-ion so should note the compounds of this invention.

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

Scheme

As formula I-IV compound as described in inventing, it is synthetic to be that starting raw material passes through 9 step reactions by 4-chloro-2-first mercaptopyrimidine-5-ethyl-carbonate.

In one embodiment, the application provides compound and transition proliferative disease or the symptoms such as pharmacologically acceptable salts treatment people or other mammal tumor that a kind of utilization has formula I-IV.

In one embodiment, designed compound and the pharmacologically acceptable salts thereof of the application can be used for the treatment of or control the transition proliferative disease such as 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.

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 are also contained in the application's the claim.

Drug combination

Formula I-IV compound can or improve the other medicines coupling of similar symptom to known treatment.During Combined Preparation, originally the administering mode of medicine and dosage remain unchanged, and simultaneously or take subsequently formula I-IV compound.When formula I-IV compound and other one or more medicines were taken simultaneously, preferred use contained 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-IV compound and other one or more known drugs.When formula I-IV compound and other one or more medicines carried out drug combination, the dosage the when dosage of formula I-IV compound or known drug may be than their independent medications was lower.

Can carry out the medicine of drug combination or activeconstituents with formula I-IV compound comprises but is not limited to:

Estrogenic agents; androgen receptor modifier; the retinoid-like receptor modulators; cytotoxin/cytostatics; antiproliferative; protein transferase inhibitor; the HMG-CoA reductase inhibitor; the 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; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the Histone deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor, the Bcl-2 family protein inhibitor; the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin retarding agent; interferon-' alpha '; IL-12; cox 2 inhibitor; p53; the p53 activator; VEGF antibody; EGF antibody etc.

In one embodiment, can carry out the medicine of drug combination or activeconstituents with formula I-IV compound comprises but is not limited to: rIL-2, clinic effect of alendronate, Interferon, rabbit, Ah Qu Nuoying, allopurinol, epidermal growth factor, the 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 Shide, 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-the 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, the tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replaces, floxuridine, fluconazole, fludarabine, the 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, the sulfuric acid lentinan, letrozole, formyl tetrahydrofolic acid, Leuprolide, leuprolide acetate, L-tetramisole, the 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, the amino-laevulic acid methyl esters, miltefosine, Minomycin, ametycin, mitotane, rice holder green onion quinone, Win-24540, the citric acid Evacet, S 254, the Pegylation filgrastim, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Sostatin, Ondansetron Hydrochloride, the dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, pegaspargase, Pai Luoxin, pentostatin, Picibanil, the hydrochloric acid pilocarpine, adjoin the gentle star that compares, Plicamycin, porfimer sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa navel, the epoetin, Raltitrexed, Libiee, etidronic acid rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Sostatin, sargramostim, semustine, sizofiran, sobuzoxane, bluff the 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, the Rheumatrex tablet, the trimethylammonium melamine, trimetrexate, the acetic acid triptorelin, triptorelin pamoate, Youfuding, uridine, valrubicin, vesnarinone, vinealeucoblastine(VLB), vincristine(VCR), vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, Zudan, the 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, the dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, histamine dihydrochloric acid, the histrelin hydrogel implant, holmium-166 DOTMP, 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-154, raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, the 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 restriction protection scope of the present invention.

Embodiment 1

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL02)

(N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide)

Step 1.4-(3-t-butoxycarbonyl amino aniline)-2-first mercaptopyrimidine-5-carboxylic acid, ethyl ester (1)

(ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylate)

4-chloro-2-first mercaptopyrimidine-5-ethyl-carbonate (12.63g, 54.27mmol), N-Boc mphenylenediamine (11.29g, 54.27mmol), K ₂CO ₃(15g, 108.54mmol) is dissolved in the 200ml dry DMF, under the argon shield, is heated to 80 ℃, and stirring is spent the night.Be cooled to room temperature, stir the lower 500ml of adding frozen water, a large amount of solids are separated out.Filtration under diminished pressure, vacuum-drying get white solid 21.3g (97%).

MS(ESI)m/z 405.0[M+H] ⁺.

¹H NMR(400MHz，CDCl ₃)δ10.41(s，1H)，8.77(s，1H)，7.92(s，1H)，7.34(d，J＝8.8Hz，1H)，7.25(t，J＝8.0Hz，1H)，7.17(dd，J＝0.8，8.8Hz，1H)，6.49(s，1H)，4.38(q，J＝7.2Hz，2H)2.56(s，3H)，1.52(s，9H)，1.41(t，J＝7.2Hz，3H)。

Step 2.4-(3-t-butoxycarbonyl amino aniline)-2-first mercaptopyrimidine-5-carboxylic acid (2)

(4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylic acid)

4-(3-t-butoxycarbonyl amino aniline)-2-first mercaptopyrimidine-5-carboxylic acid, ethyl ester (1) (7g, 17.33mmol) be dissolved in 200mL tetrahydrofuran (THF) and the 100mL water, add lithium hydroxide monohydrate (1.46g, 34.66mmol), stirred overnight at room temperature.Rotary evaporation is removed most of solvent, and surplus solution is regulated PH to 2 with the 1M hydrochloric acid soln, and a large amount of white solids are separated out, decompress filter, and with 100mL water washing filter cake, vacuum-drying gets white solid 6.39g (98%).

MS(ESI)m/z 377.0[M+H] ⁺。

¹H NMR(400MHz，DMSO)δ13.76(br，1H)，10.56(s，1H)，9.45(s，1H)，8.72(s，1H)，7.90(s，1H)，7.38(d，J＝9.2Hz，1H)，7.27(t，J＝8.0Hz，1H)，7.15(d，J＝8.0Hz，1H)，2.53(s，3H)，1.50(s，9H)。

Step 3.2-(4-(3-tertbutyloxycarbonyl aniline)-N-methyl-2-first mercaptopyrimidine-5-formyl radical) amino acid methyl ester (3)

(methyl 2-(4-(3-(tert-butoxycarbonylamino)phenylamino)-N-methyl-2-(methylthio)pyrimidine-5-carboxamido)acetate)

4-(3-t-butoxycarbonyl amino aniline)-2-first mercaptopyrimidine-5-carboxylic acid (2) (4.5g; 11.97mmol) be dissolved in the 200mL anhydrous methylene chloride; in the argon shield; under 0 ℃ of ice bath; slowly drip oxalyl chloride (1.5mL; 17.96mmol), add subsequently the dry DMF (500 μ L) of catalytic amount.Stirring at room 4 as a child, rotary evaporation goes out desolventizing, obtains yellow solid.Then this yellow solid is dissolved in the 200mL anhydrous methylene chloride; in the argon shield; under 0 ℃ of ice bath; add the sarcosine methyl esters (2.51g that has been dissolved in the 20mL anhydrous methylene chloride; 17.96mmol) solution, then slowly drip DIPEA (8.3mL, 47.88mmol); reaction solution is back to room temperature, and stirring is spent the night.After raw material reaction is complete, add 10%NaHCO ₃The aqueous solution with dichloromethane extraction twice, merges organic phase, with saturated common salt water washing one time, organic phase anhydrous Na ₂SO ₄Drying, then filtration is spin-dried for, and column chromatography for separation gets solid 4.68g (84.8%).

MS(ESI)m/z 462.1[M+H] ⁺。

¹H NMR(400MHz，CDCl ₃)δ8.88(s，1H)，8.19(s，1H)，7.94(s，1H)，7.34(d，J＝8.0Hz，1H)，7.24(t，J＝8.0Hz，1H)，7.25(dd，J＝1.2，8.0Hz，1H)，6.48(s，1H)，4.25(s，2H)，3.83(s，3H)，3.16(s，3H)，2.56(s，3H)，1.51(s，9H)。

Step 4.2-(4-(3-tertbutyloxycarbonyl aniline)-N-methyl-2-first mercaptopyrimidine-5-formyl radical) amino acid (4)

(2-(4-(3-(tert-butoxycarbonylamino)phenylamino)-N-methyl-2-(methylthio)pyrimidine-5-carboxa mido)acetic acid)

2-(4-(3-tertbutyloxycarbonyl aniline)-N-methyl-2-first mercaptopyrimidine-5-formyl radical) amino acid methyl ester (3) (4.98g; 10.78mmol) be dissolved in 100mL tetrahydrofuran (THF) and the 50mL water; add lithium hydroxide monohydrate (0.91g; 21.56mmol), stirred overnight at room temperature.Rotary evaporation is removed most of solvent, and surplus solution is regulated PH to 2 with the 1M hydrochloric acid soln, and a large amount of white solids are separated out, decompress filter, and with 50mL water washing filter cake, vacuum-drying gets white solid 4.37g (90%).

MS(ESI)m/z 448.0[M+H] ⁺。

¹H NMR(400MHz，DMSO)δ13.19(br，1H)，9.38(s，1H)，8.92(s，1H)，8.17(s，1H)，7.95(s，1H)，7.22-7.19(m，2H)，7.08(d，J＝6.8Hz，1H)，4.19(s，2H)，3.02(s，3H)，2.46(s，3H)，1.47(s，9H)。

Step 5. tertiary butyl-3-(6-methyl-2-first sulfydryl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl urethan (5)

(tert-butyl 3-(6-methyl-2-(methylthio)-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenylcarbamate)

2-(4-(3-tertbutyloxycarbonyl aniline)-N-methyl-2-first mercaptopyrimidine-5-formyl radical) amino acid (4) (6.85g; 15.3mmol) be dissolved in the 1L anhydrous methylene chloride; add HATU (17.5g under 0 ℃ of ice bath in batches; 45.9mmol) and DIEA (8mL; 45.9mmol); be back to room temperature, stirred 24 hours.After having reacted, add 10%NaHCO ₃The aqueous solution, dichloromethane extraction twice merges organic phase, with saturated common salt water washing one time, anhydrous Na ₂SO ₄Drying, filtration is spin-dried for, and column chromatography for separation gets solid 5.25g (80%).

MS(ESI)m/z 430.1[M+H] ⁺。

¹H NMR(400MHz，CDCl ₃)δ8.98(s，1H)，7.46(s，1H)，7.33(t，J＝8.4Hz，1H)，7.24(d，J＝8.4Hz，1H)，6.83(d，J＝7.6Hz，1H)，6.65(s，1H)，4.12(s，2H)，3.31(s.3H)，2.13(s，3H)，1.49(s，9H)。

Step 6. tertiary butyl-3-(6-methyl-2-methylsulfonyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl urethan (6)

(tert-butyl 3-(6-methyl-2-(methylsulfonyl)-5，8-dioxo-7，8-dihydro-5H-pyrimido [4，5-e][1，4]diazepin-9(6H)-yl)phenylcarbamate)

The tertiary butyl-3-(6-methyl-2-first sulfydryl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl urethan (5) (4.59g, 10.7mmol) be dissolved in the 50mL anhydrous methylene chloride, under 0 ℃ of ice bath, slowly add metachloroperbenzoic acid (6.52g, 32.1mmol), be back to room temperature, stirred 4 hours.Add the methylene dichloride dilute reaction solution, use 50%Na ₂S ₂O ₃/ NaHCO ₃Aqueous solution cancellation reaction.Organic phase saturated common salt water washing twice, anhydrous Na ₂SO ₄Drying, filtration is spin-dried for, and gets solid 4.44g (90%) with ethyl acetate and sherwood oil mixed solution recrystallization.

¹H NMR(400MHz，CDCl ₃)δ9.39(s，1H)，7.56(s，1H)，7.37(t，J＝8.0Hz，1H)，7.19(dd，J＝1.2，8.0Hz，1H)，6.85(dd，J＝1.2，8.0Hz，1H)，6.62(s，1H)，4.18(s，2H)，3.36(s，3H)，2.99(s，3H)，1.49(s，9H)。

Step 7. tertiary butyl-3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl urethan (7)

(tert-butyl 3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenylcarbamate)

The tertiary butyl-3-(6-methyl-2-methylsulfonyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [1,4] diaza table-9 (6H)-replacement) phenyl urethan (6) (1g, 2.17mmol) adding is equipped with in the envelope bottle of 10mL sec-butyl alcohol, adds successively 2-methoxyl group-4-(4-methylpiperazine-1-replaces) aniline (529mg, 2.39mmol) and TFA (177 μ L, 2.39mmol).Be heated to 110 ℃, stirred 18 hours.Be cooled to room temperature, pour 10%NaHCO into ₃In the aqueous solution, dichloromethane extraction twice merges organic phase, saturated common salt water washing twice, anhydrous Na ₂SO ₄Drying, filtration is spin-dried for, the solid 0.88g (67%) of column chromatography for separation.

MS(ESI)m/z 603.2[M+H] ⁺。

¹H NMR(400MHz，CDCl ₃)δ8.91(s，1H)，7.82(s，1H)，7.49(s，1H)，7.42(t，J＝8.0Hz，1H)，7.32(s，1H)，7.07(d，J＝6.8Hz，1H)，6.89(d，J＝7.6Hz，1H)，6.64(s，1H)，6.42(s，1H)，6.10(s，1H)，4.12(s，2H)，3.81(s，3H)，3.28(s，3H)，3.12(t，J＝4.8Hz，4H)，2.57(t，J＝4.8Hz，4H)，2.35(s，3H)，1.48(s，9H)。

Step 8.9-(3-aminophenyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenylamino)-6-methyl-6,7-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-5,8 (9H)-diketone (8)

(9-(3-aminophenyl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-6，7-dihydro-5H-pyrimido[4，5-e][1，4]diazepine-5，8(9H)-dione)

The tertiary butyl-3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [1,4] diaza table-9 (6H)-replacement) phenyl urethan (7) (687mg, 1.14mmol) is dissolved in the 5mL methylene dichloride, adds TFA (0.85mL, 11.4mmol), stirring at room 4h.Reaction is diluted with methylene dichloride, uses saturated NaHCO ₃Solution is regulated PH to 9, and dichloromethane extraction twice merges organic phase, 10%NaHCO ₃Solution washing twice, saturated common salt water washing twice, anhydrous Na ₂SO ₄Drying, filtration is spin-dried for, the solid 487mg (85%) of column chromatography for separation

Step 9.N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8 dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL02)

(N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide)

9-(3-aminophenyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenylamino)-6-methyl-6,7-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [1,4] diaza table-5,8 (9H)-diketone (8) (428mg, 0.85mmol) is dissolved in the 10mL anhydrous methylene chloride, add DIEA (221 μ L under 0 ℃ of ice bath, 1.28mmol), slowly add acrylate chloride (105 μ L, 1.28mmol).Be back to stirring at room 4 hours.After having reacted, add 10%NaHCO ₃The aqueous solution, dichloromethane extraction twice merges organic phase, with saturated common salt water washing one time, anhydrous Na ₂SO ₄Drying, filtration is spin-dried for, and column chromatography for separation gets solid 388mg (82%)

¹H NMR(400MHz，CDCl ₃)δ8.90(s，1H)，7.98(s，2H)，7.74(s，1H)，7.45(t，J＝8.0Hz，1H)，7.40(s，1H)，7.00-6.91(m，2H)，6.43-6.39(m，2H)，6.31-6.25(m，1H)，6.08(d，J＝8.0Hz，1H)，5.74(dd，J＝1.2，10.0Hz，1H)，4.06(s，2H)，3.81(s，3H)，3.26(s，3H)，3.18(t，J＝4.4Hz，4H)，2.71(s，4H)，2.46(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ167.70，165.16，163.33，162.97，159.35，158.47，148.89，147.78，139.21，139.16，130.99，130.22，128.12，124.29，120.22，120.08，119.83，119.57，109.46，107.53，99.35，55.60，55.07，53.65，49.47，46.07，35.96。

HRMS(ESI)Calcd for[M+H] ⁺＝557.2619，found：[M+H] ⁺＝557.2621。

Embodiment 2

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,10-dioxo-8,9,9a, 10-tetrahydrochysene-5H-Kui Linpyrimido quinoline [4,5-e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza table-11 (7H)-replacement) phenyl) acrylamide (SL01)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5，10-dioxo-8，9，9a，10-tetrahydro-5H-pyrimido[4，5-e]pyrrolo[1，2-a][1，4]diazepin-11(7H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.95(s，1H)，7.91(s，1H)，7.78(s，1H)，7.73(s，1H)，7.44(t，J＝7.6Hz，1H)，7.38(s，1H)，7.00(s，1H)，6.93(d，J＝7.2Hz，1H)，6.42-6.38(m，2H)，6.22-6.16(m，1H)，6.09(s，1H)，5.74(d，J＝10.0Hz，1H)，4.34(d，J＝5.2Hz，1H)，3.80(s，3H)，3.77(s，1H)，3.67-3.65(m，1H)，3.12(br，4H)，2.79(s，1H)，2.60(br，4H)，2.38(s，3H)，2.14-2.05(m，3H)。

¹³C NMR(125MHz，CDCl ₃)δ169.16，163.27，162.40，159.46，158.28，148.79，147.51，140.23，139.17，131.05，130.10，127.96，124.35，120.46，120.31，119.64，119.53，113.04，110.43，107.76，99.61，58.04，55.60，55.02，49.42，47.00，45.92，26.95，23.81。

HRMS(ESI)Calcd for[M+H] ⁺＝583.2776，found：[M+H] ⁺＝583.2773。

Embodiment 3

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,11-dioxo-7,8,9,10,10a, 11-hexahydropyrrolo also [1,2-a] Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-12 (5H)-replacement) phenyl) acrylamide (SL09)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5，11-dioxo-7，8，9，10，10a，11-hexahydr opyrido[1，2-a]pyrimido[4，5-e][1，4]diazepin-12(5H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.87(s，1H)，7.97(s，1H)，7.90(s，1H)，7.77(s，1H)，7.43(t，J＝8.0Hz，1H)，7.40(s，1H)，7.08(s，1H)，6.92(d，J＝7.6Hz，1H)，6.40-6.36(m，2H)，6.27-6.20(m 1H)，6.09(s，1H)，5.72(d，J＝10.8Hz，1H)，4.50-4.47(m，1H)，4.43-4.40(m，1H)，3.79(s，3H)，3.15(br，4H)，3.06-2.99(m，1H)，2.67(br，4H)，2.42(s，3H)，2.27(s，1H)，1.95-1.90(m，1H)，1.83-1.62(m，4H)。

¹³C NMR(125MHz，CDCl ₃)δ169.68，166.07，163.26，162.49，159.44，158.26，148.78，147.61，139.42，139.06，131.02，130.05，127.95，124.47，120.39，120.33，119.70，119.47，110.55，107.69，99.55，55.60，55.02，52.63，49.51，46.01，39.88，23.27，22.84，18.83。

HRMS(ESI)Calcd for[M+H] ⁺＝597.2932，found：[M+H] ⁺＝597.2929。

Embodiment 4

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6,7-dimethyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL07)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6，7-dimethyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.89(s，1H)，8.04(s，1H)，7.88(s，1H)，7.77(s，1H)，7.47-7.41(m，2H)，7.06(s，1H)，6.92(d，J＝7.6，1H)，6.41-6.23(m，3H)，6.15-6.06(m，1H)，5.72(dd，J＝1.2，10.0Hz，1H)，4.45(dd，J＝6.8，13.6Hz，1H)，3.80(s，3H)，3.17(br，4H)，3.10(s，3H)，2.72(br，4H)，2.45(s，3H)，1.57(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ169.25，165.99，163.45，162.65，159.50，158.16，148.85，147.17，139.61，139.30，134.60，131.13，129.99，127.92，124.25，120.94，120.40，119.69，110.35，108.11，100.08，55.61，54.69，52.47，49.12，45.36，28.37，12.65。

HRMS(ESI)Calcd for[M+H] ⁺＝571.2776，found：[M+H] ⁺＝571.2770。

Embodiment 5

N-(3-(7-sec.-propyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL03)

N-(3-(7-isopropyl-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ8.97(s)and 8.92(s)(together 1H)，8.04-7.96(m)and 7.80(s)(together 3H)，7.51-7.33(m，2H)，7.04(d，J＝6.8Hz)and 6.91(d，J＝6.8Hz)(together 2H)，6.41-6.35(m，2H)，6.20-6.06(m，2H)，5.73-5.70(m，1H)，3.82(s，1H)，3.80(s，3H)，3.45(s，0.70H)and 3.33(s，2.30H)，3.10(br，4H)，2.59(br，4H)，2.37(s，3H)，2.13-2.05(m，1H)，1.07-0.96(m，6H)。

¹³C NMR(125MHz，CDCl ₃)δ169.45，163.60，163.28，162.62，162.42，157.16，148.77，147.49，140.26，139.57，131.08，130.24，130.12，127.87，124.47，120.42，120.19，119.71，119.39，107.73，99.52，74.31，55.61，54.99，49.39，45.93，39.73，28.76，20.12，19.96，19.48，19.28。

HRMS(ESI)Calcd for[M+H] ⁺＝599.3089，found：[M+H] ⁺＝599.3087。

Embodiment 6

N-(3-(7-isobutyl--2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL04)

N-(3-(7-isobutyl-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ8.92(s)and 8.90(s)(together 1H)，7.92-7.79(m，3H)，7.49-7.42(m，1H)，7.36(s，1H)，7.05-6.91(m，2H)，6.41-6.37(m，2H)，6.26-6.19(m，1H)，6.10(s，1H)，5.73(d，J＝10.4Hz，1H)，4.32(t，J＝7.6Hz，0.3H)and 4.27(t，J＝7.6Hz，0.7H)，3.80(s，3H)，3.32(s)and 3.08(s)(together 3H)，3.14(br，4H)，2.66(br，4H)，2.41(s，3H)，2.07-1.61(m，3H)，0.96-0.91(m，3H)。

¹³C NMR(125MHz，CDCl ₃)δ169.82，168.67，166.38，163.81，163.35，162.76，162.60，158.31，148.86，147.38，139.58，139.26，131.10，130.05，127.90，124.38，120.57，120.27，119.80，107.92，99.81，55.62，55.25，54.88，49.30，45.71，38.83，38.59，35.42，28.84，25.69，25.18，22.59，22.32。

HRMS(ESI)Calcd for[M+H] ⁺＝613.3245，found：[M+H] ⁺＝613.3237。

Embodiment 7

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL11)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7-phenyl-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.67(s，1H)，8.48(s.1H)，7.97(d，J＝6.4Hz，1H)，7.63(s，1H)，7.56(s，1H)，7.47(t，J＝7.6Hz，1H)，7.24(d，J＝7.2Hz，2H)，7.18(d，J＝6.8Hz，3H)，6.98(d，J＝7.6Hz，1H)，6.87(s，1H)，6.39-6.37(m，2H)，6.32(s，1H)，6.10(s，1H)，5.73-5.70(m，1H)，5.57(s，1H)，3.73(s，3H)，3.52(s，3H)，3.23(br，4H)，2.85(br，4H)，2.54(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ168.99，165.02，163.67，162.41，158.81，156.75，148.66，146.52，139.84，139.61，133.36，131.27，130.05，129.18，128.41，127.89，124.12，121.37，120.36，119.78，119.36，108.41，100.30，69.08，55.57，54.44，48.70，44.86，29.66。

HRMS(ESI)Calcd for[M+H] ⁺＝633.2932，found：[M+H] ⁺＝633.2927。

Embodiment 8

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-6-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL10)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5，8-dioxo-6-phenyl-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.96(s，1H)，8.07(s，1H)，7.94(s，1H)，7.82(s，1H)，7.48-7.46(m，3H)，7.41(t，J＝8.0Hz，2H)，7.31-7.27(m，2H)，6.96(d，J＝7.2Hz，2H)，6.40-6.36(m，2H)，6.19-6.06(m，2H)，5.70(d，J＝10.8Hz，1H)，4.44(s，2H)，3.83(s，3H)，3.09(br，4H)，2.56(br，4H)，2.36(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ168.30，164.26，163.31，159.35，158.37，148.87，147.86，141.72，139.33，138.96，131.01，130.30，129.27，127.95，127.30，125.35，124.05，120.18，119.95，119.86，119.60，109.75，107.47，99.21，55.62，55.07，54.54，49.33，46.10。

HRMS(ESI)Calcd for[M+H] ⁺＝619.2776，found：[M+H] ⁺＝619.2770。

Embodiment 9

N-(3-(7-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL05)

N-(3-(7-benzyl-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ9.04(s)and 8.89(s)(together 1H)，7.92-7.75(m，3H)，7.43-7.39(m，1H)，7.35-7.27(m，3H)，7.25-7.09(m，3H)，6.96(s，1H)，6.86-6.81(m，1H)，6.40-6.35(m，2H)，6.16-6.04(m，2H)，5.70(d，J＝10.4Hz，1H)，4.61-4.58(m，0.64H)and 4.51(t，J＝8.4Hz，0.36H)，3.81(s)and 3.78(s)(together 3H)，3.63-3.52(m)，3.26-3.21(m)and 3.04(br)(together 2H)，3.14(s)and 2.98(s)(together 3H)，3.12-3.06(m，4H)，2.60-2.55(m，4H)，2.37-2.35(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ168.88，167.96，166.06，163.64，163.21，162.98，162.69，158.23，139.05，136.06，135.15，130.96，130.17，129.08，128.98，128.89，128.09，127.59，127.17，124.53，120.07，107.65，107.53，99.48，68.88，58.25，55.63，55.58，55.07，49.54，46.11，38.82，35.41，32.87，29.06。

HRMS(ESI)Calcd for[M+H] ⁺＝647.3089，found：[M+H] ⁺＝647.3079。

Embodiment 10

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-7-(4-methoxy-benzyl)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL08)

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-7-(4-methoxybenzyl)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ9.04(s)and 8.99(s)(together 1H)，8.08-7.75(m，3H)，7.43(t，J＝8.0Hz，1H)，7.34-7.24(m，2H)，7.16(d，J＝8.4Hz，1H)，7.03-6.82(m，4H)，6.41-6.37(m，2H)，6.30-6.21(m，1H)，6.10-6.06(m，1H)，5.73(d，J＝9.6Hz，1H)，4.53-4.45(m，1H)，3.84-3.78(m，6H)，3.55-3.46(m)，3.24-3.22(m)and 2.99(s)(together 2H)，3.21-3.18(m，4H)，3.15(s)and 3.01(s)(together 3H)，2.76-2.72(m，4H)，2.53-2.46(m，3H)。

¹³C NMR(125MHz，CDCl ₃)δ170.00，168.09，166.05，163.64，163.37，163.00，162.69，158.99，158.65，158.19，148.95，147.16，139.40，131.10，130.13，130.04，127.95，126.96，124.37，120.10，119.81，114.53，114.32，108.26，108.09，100.19，100.07，68.99，58.50，55.65，55.60，55.28，54.71，49.08，45.38，38.81，34.56，32.02，29.05。

HRMS(ESI)Calcd for[M+H] ⁺＝677.3194，found：[M+H] ⁺＝677.3190。

Embodiment 11

N-(3-(7-(4-chlorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL12)

N-(3-(7-(4-chlorobenzyl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ9.03(s)and 8.89(s)(together 1H)，7.96-7.87(m，2H)，7.59(s，1H)，7.45-7.43(m，1H)，7.32(d，J＝8.4Hz，1H)，7.25-7.16(m，3H)，7.05(d，J＝8.0Hz，1H)，6.96(s，1H)，6.88-6.82(m，1H)，6.43-6.37(m，2H)，6.22-6.15(m，1H)，6.10-6.03(m，1H)，5.75(d，J＝10.8Hz，1H)，4.53-4.47(m，1H)，3.82(s)and 3.78(s)(together 3H)，3.58-3.53(m)，3.20-3.19(m)and 3.05(br)(together 2H)，3.15(s)and 3.03(s)(together 3H)，3.09(br，4H)，2.58(br，4H)，2.39(s)and 2.37(s)(together 3H)。

³C NMR(125MHz，CDCl ₃)δ168.57，167.84，166.00，163.57，163.30，162.97，162.69，159.53，159.35，158.13，157.24，148.91，147.64，139.33，134.52，133.63，133.59，133.03，130.97，130.55，130.33，130.15，129.31，129.00，128.01，124.31，120.17，119.88，119.59，107.75，107.61，99.63，68.63，58.20，55.58，54.93，49.37，45.87，38.83，34.81，32.34，29.05。

HRMS(ESI)Calcd for[M+H] ⁺＝681.2699，found：[M+H] ⁺＝681.2692。

Embodiment 12

N-(3-(7-(4-luorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL13)

N-(3-(7-(4-fluorobenzyl)-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-6-methyl-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃，a mixture of rotamers)δ9.04(s)and 8.89(s)(together 1H)，7.93-7.66(m，3H)，7.44(s，1H)，7.36-6.93(m，6H)，6.87-6.81(m，1H)，6.42(s)and 6.38(s)(together 2H)，6.20(d，J＝10.0Hz)and 6.16(d，J＝10.0Hz)(together 1H)，6.10-6.03(m，1H)，5.74(d，J＝10.4Hz，1H)，4.53-4.45(m，1H)，3.82(s)and 3.78(s)(together 3H)，3.58-3.52(m)，3.21-3.17(m)and3.05-3.02(m)(together 2H)，3.15(s)and 3.01(s)(together 3H)，3.10(br，4H)，2.63-2.58(br，4H)，2.40(s)and 2.37(s)(together 3H)。

¹³C NMR(125MHz，CDCl ₃)δ167.88，166.02，163.58，163.30，162.88，162.68，160.92，158.15，148.92，147.69，139.37，131.73，131.70，130.97，130.79，130.72，130.58，130.52，130.13，128.03，124.36，120.17，119.97，119.85，119.63，116.18，116.01，115.83，115.66，107.81，107.66，99.64，68.89，58.38，55.63，55.58，54.96，49.41，45.91，38.81，34.61，32.16，29.04。

HRMS(ESI)Calcd for[M+H] ⁺＝665.2995，found：[M+H] ⁺＝665.2982。

Embodiment 13

N-(3-(6-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide (SL06)

N-(3-(6-benzyl-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-5，8-dioxo-7，8-dihydro-5H-pyrimido[4，5-e][1，4]diazepin-9(6H)-yl)phenyl)acrylamide

Synthetic method such as embodiment 1.

¹H NMR(400MHz，CDCl ₃)δ8.97(s，1H)，7.96(s，1H)，7.77(d，J＝13.2Hz，2H)，7.44(t，J＝8.0Hz，1H)，7.36-7.30(m，6H)，7.01-6.96(m，1H)，6.90(d，J＝7.6Hz，1H)，6.41-6.37(m，2H)，6.19-6.10(m，1H)，6.07(d，J＝6.4Hz，1H)，5.72(dd，J＝1.2，6.4Hz，1H)，4.84(s，2H)，4.00(s，2H)，3.81(s，3H)，3.12(t，J＝4.8Hz，4H)，2.60(t，J＝4.8Hz，4H)，2.38(s，3H)。

¹³C NMR(125MHz，CDCl ₃)δ167.77，165.23，163.22，159.34，158.51，148.86，147.59，139.19，135.90，131.07，130.19，128.90，128.39，128.10，127.95，124.09，120.27，119.85，119.62，109.31，107.71，99.54，55.61，54.99，51.44，51.09，49.34，45.89。

HRMS(ESI)Calcd for[M+H] ⁺＝633.2932，found：[M+H] ⁺＝633.2929。

Embodiment 14

5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines is to EGFR wild-type and EGFR-T790M mutant kinases EC ₅₀Test

Kinase activity detects: use Z '-LYTE ^TMTechnology (adopt that fluorescence detects, enzyme coupling form, take phosphorylation and non-phosphorylating polypeptide to the sensitivity differences of proteolysis cutting as the basis) adopts FRET (fluorescence resonance energy transfer) (FRET) principle, uses Z '-LYTE ^TMFRET peptide class substrate, the second order reaction detection compound is to kinase activity.(invitrogen, Z '-LYTE ^TMKINASE ASSAY KIT-TYR 2 PEPTIDE, PV3191) with EGFR-T790M kinases (invitrogen, PV4803) add the FRET peptide behind the stepwise dilution, ATP adds the different concns compound again, behind the reaction 1h, add locus specificity proteolytic enzyme, identify and cut unphosphorylated FRET peptide, reaction 1h, use the 400nm excitation wavelength, detect 445nm and 520nm and absorb.Draw inhibiting rate and become positive correlation with drug level, make kinase activity and concentration relationship curve, calculate IC ₅₀Value the results are shown in Table 1.

Table 1 compound number and corresponding kinase activity result.

At 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [1,4] in the competitive assay of Diazepines and ATP, part of compounds (for example, SL05, SL13 etc.) shows stronger inhibition active (seeing Fig. 1-2 0) to EGFR kinases (comprising the T790M mutant).

Can find according to the compound structure activity relationship among the embodiment 1-13, in 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines, R ₂, R ₃When substituting group was non-five-ring, it is active that compound all shows certain inhibition.

Embodiment 15

5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines is to the cancer cells IC of EGFR high expression level ₅₀The impact of test MTT detection compound on cell proliferation: 1500/every hole, H1975 (lung carcinoma cell, EGFR ^L858R/T790M), HCC827 (lung carcinoma cell, EGFR ^{Del E746-A750}), A431 (people's epidermal carcinoma, EGFR high expression level), A549 (lung carcinoma cell, EGFR high expression level), HL7702 (normal liver cell), spread 96 orifice plates, behind the 24h, with the different concns compound treatment (DMSO final concentration 1 ‰, parallel control 3-5) of DMSO preparation, add MTT (tetrazolium bromide behind the 72h, 5mg/ml, the 10ul/ hole), 37 degree are hatched 4h.Suck supernatant, add DMSO 150ul, fully after the vibration, detect OD570, use GraphPad Prism 4 Demo software processes.

Found that (see Table 2 and Figure 21-25), through 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines processes and can obviously reduce above-mentioned cancer cells to the absorption of MTT, illustrates 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines can significantly suppress the propagation of above-mentioned cancer cells, especially suppresses H1975 (EGFR ^L858R/T790), HCC827 (EGFR ^{Del E746-A750}) propagation of two class cells, inhibiting rate becomes positive correlation with drug level.According to the growth-inhibiting effect of 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines to these cells, we calculate its half-inhibition concentration IC ₅₀The value such as table 2 description.(compound used therefor is respectively the prepared compound of embodiment 1-13, represents with the embodiment label in table 2).

The impact of table 2MTT detection compound on cell proliferation

Can find that by Figure 21-24 inhibiting rate curve to wild-type cancer cells A431, A549 shows lower inhibiting rate to 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines when lower concentration.In addition, because this compounds shows stronger inhibition activity to the EGFR kinases, still, the vital role that EGFR also brings into play in the normal human tissue cell.Therefore, it is active to the inhibition of HL7702 (normal liver cell) that we have tested this compounds, in order to investigate the toxicity of this compounds.By Figure 25 inhibiting rate curve, we can find that 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines is to its IC ₅₀Be worth generally larger, explanation is lower to Normocellular toxicity, prove absolutely 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [1,4] the Diazepines selectively acting is in for the simple point mutation of Gefitinib (Iressa) resistance or the lung carcinoma cell of multipoint mutation, and lower to wild-type lung carcinoma cell and normal cell toxicity, this optionally treatment advantage has very large clinical application meaning.

Embodiment 16

5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines is on the impact of H1975 cell EGFR tyrosine phosphorylation

Use conventional Western Blot (immunoblotting), it comprises four steps: sample preparation; Electrophoretic separation; The film of albumen shifts; Immuning hybridization and colour developing (Protein Detection).

Sample preparation

1. culturing cell or drug treating;

2. abandon substratum, use 1X PBS rinsing cell 2 times, remove residual to the greatest extent substratum;

3. add 1X SDS sample buffer (6-well plate, 100 μ l/w or 75cm ²Plate, 500-1000 μ l/ bottle), scrape cell, transfer to the Ep pipe;

4. sheared DNA in ultrasonic 10～15 seconds to lower sample viscosity;

5. boil sample 5minutes;

6. centrifugal 12000g, 5min gets supernatant;

7. electrophoretic separation: loading 15 μ l～20 μ l to the SDS-PAGE glue (electrophoresis of 10cm * 10cm).(with reference to the SDS-PAGE electrophoresis method)

Transferring film

1. glue is dipped in balance 10min in the transfering buffering liquid;

2. according to 6 of the big or small clip film of glue and filter paper, put into transfering buffering liquid balance 10min.Pvdf membrane need soak saturated 3-5 second with pure methyl alcohol;

3. sandwich is shifted in assembling: sponge → 3 metafiltration paper → glue → films → 3 metafiltration paper → sponges, every layer put well after, with the test tube bubble of rushing;

4. transfer groove is placed ice bath, put into sandwich (black side is to black side), add transfering buffering liquid, plug electrode, 100V, 1h (electric current is about 0.3A).Transferring film is cut off the electricity supply after finishing, and takes out Hybond membrane.

Immuning hybridization and colour developing

1. wash film 5min with 25ml TBS, room temperature is shaken;

2. put film 1h in 25ml sealing damping fluid, room temperature is shaken;

3.15ml TBS/T washes (5min/T) 6 times;

4. add suitable dilution primary antibodie, incubated at room 1-2h or 4 ℃ spend the night;

5.15ml TBS/T washes (5min/T) 6 times;

6. add two of suitable dilution alkaline phosphatase (AP) or horseradish peroxidase (HRP) mark and resist, incubated at room 1h slowly shakes;

7.15ml TBS/T washes (5min/T) 3 times;

8.15ml TBS washes 1 time;

9. carry out the albumen compressing tablet with ECL;

10. develop.

Can find that by Figure 26 in 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines, compound S L05 and SL13 can significantly cause the retardance of EGFR phosphorylation.

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 claim of the present invention.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 (8)

1. have 5 of formula (I) structure, 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs:

Wherein, Y is certainly optional: CH or N;

N is optional to be 0 or 1;

R ₁Certainly optional:

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) (CH ₂) _mX, m=0～6, X is hydroxyl, amino, C ₁～C ₆Heteroatom containing alkyl, C ₃～C ₆Contain the heteroatomic ring alkyl;

6)

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

a)H；

B) halogen;

C) cyano group;

D) nitro;

E) hydroxyl;

F) amino;

G) C ₁～C ₆Alkyl;

H) C ₃～C ₆Cycloalkyl;

I) C ₁～C ₆Contain fluoroalkyl;

J) C ₁～C ₆Heteroatom containing alkyl;

K) C ₃～C ₇Contain the heteroatomic ring alkyl;

L) ester of abovementioned alkyl formation, acid amides, sulfone, sulfoxide, urea;

Above-mentioned heteroatoms is selected from N, O, S;

R ₂Certainly optional:

When n elects 0 as

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) aryl;

6) C ₁～C ₅Contain the aryl substituted alkyl;

7) contain the heteroatomic ring alkyl;

When n elects 1 as

1) C ₁～C ₅Alkyl;

2) C ₁～C ₅Contain fluoroalkyl;

Above-mentioned heteroatoms is selected from N, O, S;

R ₃Certainly optional:

When n elects 0 as

1)H；

2) C ₁～C ₅Alkyl;

3) C ₃～C ₆Cycloalkyl;

4) C ₁～C ₅Contain fluoroalkyl;

5) aryl;

6) C ₁～C ₅Contain the aryl substituted alkyl;

7) contain the heteroatomic ring alkyl;

When n elects 1 as

1) C ₁～C ₅Alkyl;

2) C ₁～C ₅Contain fluoroalkyl;

Above-mentioned heteroatoms is selected from N, O, S;

R ₄Certainly optional:

1)H；

2) halogen;

3) amino, hydroxyl, cyano group, nitro;

4) C ₁～C ₅Alkyl;

5) C ₃～C ₆Cycloalkyl;

6) aryl;

7)

W is certainly optional: CH ₂, CH ₂CH ₂, O, S, NH, NR, wherein R is C ₁～C ₅Alkyl or aryl;

R ₅Certainly optional:

a)H；

B) halogen;

C) C ₁～C ₅Alkyl;

D) C ₃～C ₆Cycloalkyl;

E) aryl;

The above cycloalkyl, aryl can be chosen wantonly by 0,1, and 2 or 3 optional from R ₆Substituting group replace;

R ₆Certainly optional:

a)H；

B) halogen;

C) C ₁～C ₃Alkyl;

D) C ₃～C ₆Cycloalkyl;

E) C ₁～C ₃Alkoxyl group;

F) C ₁～C ₃Contain fluoroalkyl;

G) contain the heteroatomic ring alkyl;

H) C ₀～C ₃The alkylidenyl-heterocyclic base;

I) phenyl;

Described M is the single replacement of place aromatic ring 2,4,5 or 6 sites or polysubstituted functional group, and is certainly optional:

1) hydrogen;

2) halogen;

3) cyano group;

4) nitro;

5) hydroxyl;

6) amino;

7) C ₁～C ₆Alkyl;

8) C ₃～C ₆Cycloalkyl;

9) C ₁～C ₆Contain fluoroalkyl;

10) C ₁～C ₆Heteroatom containing alkyl;

11) C ₁～C ₇Contain the heteroatomic ring alkyl;

12) ester of abovementioned alkyl formation, acid amides, sulfone, sulfoxide, urea;

Above-mentioned heteroatoms is O, N or S.

2. according to claim 15,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (II) structure:

R ₂, R ₃, R ₄, n, M as claimed in claim 1;

Described R ₁Be selected from:

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

3) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

4) (CH ₂) _mX, m=0～6, X is hydroxyl, amino, methoxyl group, oxyethyl group, methoxy ethoxy, the relevant oxyalkyl that contains of ethoxy ethoxy, the first sulfydryl, N, N-dimethyl, N methyl piperazine base, the morpholine base, sulphur coffee quinoline base, piperidyl, the Pyrrolidine base, 4-N, N-lupetidine base, 1-methyl-4-(piperazine-4-replaces) piperidyl, imidazolyl, 6-(4-methylpiperazine-1-replaces)-3-substituted pyridinyl;

5)

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

a)H；

B) fluorine, chlorine, bromine, iodine;

C) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

D) methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methoxy ethoxy, ethoxy ethoxy;

E) trifluoromethyl;

F) N, N-dimethylamino ethoxy, N, the N-dimethylamino propoxy, 2-(N methyl piperazine 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, imidazoles, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, the 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;

G) ester of above-mentioned group formation, acid amides, sulfone, inferior maple, urea;

Above-mentioned heteroatoms is O, N or S.

3. according to claim 25,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (III) structure:

R ₁, R ₂, R ₃, n, M as claimed in claim 2;

Described R ₇, R ₈Certainly optional:

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; N-pentyl, isopentyl, neo-pentyl;

3) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

4) phenyl;

5)

W is certainly optional: CH ₂, CH ₂CH ₂, O, S, NH, NR, wherein R is methyl, ethyl, phenyl;

R ₅Be selected from:

a)H；

B) fluorine, chlorine, bromine, iodine;

C) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl;

D) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

E) phenyl, the single replacement or polysubstituted phenyl.

4. according to claim 35,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or its prodrugs, it has formula (IV) structure:

R ₂Certainly optional:

When n elects 0 as

1)H；

2) methyl, ethyl;

3) phenyl;

4) benzyl;

When n elects 1 as

1)-CH ₂-，-C ₂H ₄-；

R ₃Certainly optional:

When n elects 0 as

1)H；

2) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl;

3) phenyl;

4) benzyl, 4-luorobenzyl, 4-chlorobenzyl, 4-methoxy-benzyl;

When n elects 1 as

1)-CH ₂-，-C ₂H ₄-。

5. each is described 5 according to claim 1-4, and 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs is characterized in that, described compound is selected from:

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,10-dioxo-8,9,9a, 10-tetrahydrochysene-5H-Kui Linpyrimido quinoline [4,5-e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza table-11 (7H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,11-dioxo-7,8,9,10,10a, 11-hexahydropyrrolo also [1,2-a] Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-12 (5H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6,7-dimethyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-sec.-propyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-isobutyl--2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-6-phenyl-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-7-(4-methoxy-benzyl)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-(4-chlorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(7-(4-luorobenzyl)-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-6-methyl-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide;

N-(3-(6-benzyl-2-(2-methoxyl group-4-(4-methylpiperazine-1-replaces) phenylamino)-5,8-dioxo-7,8-dihydro-5H-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] diaza table-9 (6H)-replacement) phenyl) acrylamide.

6. medicinal compositions for the treatment of tumour, its by claim 1-5 each described 5,8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines or its pharmacy acceptable salt or steric isomer or its prodrugs and pharmaceutically acceptable carrier form.

7. each is described 5 for claim 1-5, the application in the medicine of preparation treatment tumour of 8-dioxo-Kui Linpyrimido quinoline [4,5-e] [Isosorbide-5-Nitrae] Diazepines and pharmacy acceptable salt thereof or steric isomer or its prodrugs.

8. application according to claim 7 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, the nasopharyngeal carcinoma.

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