CN103570731B - Pyrimido three encircles or pyrimido Fourth Ring compounds and Pharmaceutical composition and application - Google Patents

Abstract

The invention discloses one and have formula (I), the pyrimido three of (II) or (III) structure encircles or pyrimido Fourth Ring compounds or its pharmaceutically acceptable salt or stereoisomer or its prodrugs. This compound 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 cell, it is high 10 times that the IC50 of this compounds wants, 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.

Description

Pyrimido three encircles or pyrimido Fourth Ring compounds and Pharmaceutical composition and application

Technical field

The invention belongs to chemical field of medicaments, relate to particularly that a kind of pyrimido three encircles or pyrimido Fourth Ring compounds andIts Pharmaceutical composition and application.

Background technology

No matter worldwide or in China, taking malignant tumour (cancer), angiocardiopathy and diabetes etc. asThe chronic disease (NCD in other words) of representative, is but becoming main long-term threat. On May 19th, 2008, generationBoundary's health organization just explicitly points out in the report of its up-to-date announcement, and it is the most fatal that NCD is becoming the mankind" 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 tightHigh. In by the end of April, 2008 announce Third National cause of the death retrospective survey show, Chinese urban and rural residents's cancer mortality is in the pastMore than having increased most probably in 30 years; Wherein in every four to five dead Chinese, just there is a people to die from cancer. China is annualDie from the total population of cancer, approach 2,000,000 people. In recent years, though the discovery of various treatment approach and medicine to cancerThe hope that patient brings, but the drawback of conventional therapy, side effect is large, and result for the treatment of is not good, tumor prognosis recurrence, transfers etc. are existingResemble in the urgent need to new treatment technology and solve this class bottleneck effect. International medical community is by the individuation on molecule parting basisTreatment and targeted therapy are regarded the hope place of breaking through current lung cancer therapy bottleneck as.

Tumour molecular targeted therapy is based on the closely-related key molecule of tumor growth is learned to do by chemistry or biologyA kind of methods for the treatment of of section selective killing tumour cell. The feature of targeted therapy is: specificity is high, selectively strong, and poison is secondary to be doneWith lighter; When use in conjunction, the curative effect that it can strengthen traditional chemotherapy, radiotherapy, reduces postoperative recurrence. With Gleevec(STI571) (Novartis, 2001), Gefitinib (ZD1839) (AstraZeneca, 2003), Erlotinib (OSI774)(GenentechandOSIP, 2004), BAY 43-9006 tosilate (Bay43-9006) (BayerandOnyx,2005), sunitinib malate (SU11248) (Pfizer, 2006) and Dasatinib (BMS-354825) (Bristol-MyersSquibb, 2006) for the targeted drug of representative is that chemotherapy of tumors has been started a New Times. Neoplasm targeted therapy is shortIn short several years, obtain developing rapidly. The appearance of neoplasm targeted therapy forms impact to traditional administration idea and pattern, for example,Because the little targeted drug of toxic and 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 the heat of oncotherapyPoint and development trend.

Protein tyrosine kinase (PTKs) is the phenol hydroxyl of a class on can the tyrosine residue of the multiple key protein of catalysisBase generation phosphorylation, and then the protease of the function of mobilizing function albumen system. About in 520 multiple protein kinases in human bodyHaving half is EGFR-TK (PTKs). They have occupied very consequence in intracellular signal transduction pathway, adjustSaving a series of physiology processes such as cell growth in vivo, differentiation, death. Protein tyrosine kinase functional disturbance can cause biologyA series of diseases in body. Research shows, proto-oncogene more than half and the activation of oncogene all with protein tyrosine kinaseRelevant. The unconventionality expression of protein tyrosine kinase can cause cell proliferation adjusting to get muddled, and then causes tumour to occur. ThisOutward, the unconventionality expression of EGFR-TK also with invasion and attack and the transfer of tumour, tumor neovasculature generation, the anti-medicine of chemotherapy of tumourProperty is closely related. Carry out antineoplastic research and development taking EGFR-TK as target spot and become an international focus, Ye Shi various countriesThe emphasis that the research of 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 breast cancer, prostateCancer etc. EGFR is a kind of transmembrane protein, and its family has four kinds of hypotype: EGFR-1 (to be 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 EGFR and Erb-B2's is abnormal aliveChange the conversion of tumour with increase in play critical effect. The activation of blocking-up EGFR and Erb-B2 has been main by clinical verificationThe method of leading is carried out targeting therapy on tumor cell. Taking lung cancer as example, EGFR has expression in 50% NSCLC case, and its tableReach 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 ofAdvanced NSCLC patient, these patients have lost reaction to conventional chemotherapy.

Early stage clinical data shows, 10% NSCLC patient responds to Gefitinib and Tarceva. This remarkableClinical efficacy be found in specific patient colony, comprise the East Asia Region women of non-smoking and show as bronchovesicular venereal diseaseThe gland cancer patient of reason type. The analysis of molecular level shows, as a rule, the patient that medicine is responded is at coding EGFROn gene with specific sudden change. The disappearance of 747th～750 amino acids of the 19th extron accounts for 45% of sudden change, also has10% sudden change is at the 18th and the 20th extron. The sudden change of EGFR kinase domain highly activates kinases, makes tumour cellExistence has dependence to mutant kinase. Existing multinomial Prospective Clinical studies confirm that, the NSCLC trouble that EGFR activation sudden change is positivePerson is significantly higher than EGFR wild type NSCLC patient to the reactivity of EGFR-TKI, Progression free survival (PFS) phase and total existence (OS)Phase is significant prolongation also. However, the PFS of most of EGFR sudden change positive patient is no more than 12～14 months, TKI is sent outGive birth to resistance. The mechanism of acquired resistance and clinical countermeasure thereof become the another study hotspot in 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 EGFR20 extron, is one of resistance mechanism of comparatively approving at present. T790M causesThe mechanism of TKI resistance still imperfectly understands. Initial studies show that, T790M may change kinases district adenosine triphosphate (ATP)The crystal structure of binding pocket, the combination of having sealed TKI and kinases district. Current research demonstration, it is right that L858R merges T790M sudden changeThe affinity of ATP is stronger than simple L858R, and TKI is ATP competitiveness inhibitors of kinases, therefore cause TKI to fall with the kinases district rate of being combinedLow. That this sudden change is after TKI treatment, produce or originally just exist, select through TKI treatment about one of dispute of T790MJust be found afterwards. At first, T790M only treats in failed NSCLC patient's sample and is found at TKI, but subsequently without anyIn the sample for the treatment of, be also found, therefore think at present, this sudden change is also present in the tumor tissues without TKI treatment, but rarely seenIn a few cell clone, be selected after treatment due to the repellence of these cell clones to TKI. Similar to T790MMedicament-resistant mutation also have D761Y, L747S and T854A etc., these sudden changes are referred to as " non-T790M secondary mutation ", its total incidenceLower than 5%. Resistance mechanism 2:MET amplification is the another EGFR-TKI acquired resistance mechanism of finding for 2007. MET be a kind of acrossFilm tyrosine kinase receptor. The EGFR of TKI acquired resistance is suddenlyd change in positive NSCLC patient, approximately 20% has wild type METGene magnification, and major part increases without MET before treatment. MET associating ErbB family member, walks around EGFR activation downstream AKT and is situated betweenThe signal path of leading, promotes growth of tumour cell, suppresses its apoptosis. In experiment, suppress MET by RNA perturbation technique in vitroSignal path, can recover the sensitiveness of resistance person to Gefitinib. Suppress EGFR and MET simultaneously, can overcome MET amplification mediationTKI resistance. Other are and some acceptor and MET effect are similar. Nearest external TKI resistance models show, insulin-like growth factorSon 1 acceptor (IGF-1R) also can be walked around EGFR, activates its downstream signal path, but due to technical reason, is difficult to the sample patientIn carry out IGF-1R activation and detect. The resistance mechanism that these walk around EGFR, activate its downstream signal path is referred to as that " bypass activatesApproach ". To the EGFR sudden change positive patient of TKI resistance, approximately 30%～40% both without secondary mutation, also without MET amplification, these troublePerson's resistance mechanism is also in exploration.

For drug resistance, the strategy adopting is clinically: strategy 1, continue to use EGFR-TKI, and Gefitinib and E Luo replaceBuddhist nun's cross-reference. 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 demonstration, EGFR irreversible inhibitor can suppress T790M in vitro, after this, a lotEGFR irreversible inhibitor is developed out, is called " two generation EGFR-TKI ", moves towards gradually clinical from preclinical study at present,Study more have neratinib, XL647, BIBW2992 and PF-00299804. Neratinib be general ErbB (EGFR,ErbB2 and ErbB3) irreversible TKI. Based on I phase result of study, carrying out at present clinical research, inquire at Gefitinib orAfter Tarceva treatment, in the NSCLC patient of progress, whether neratinib (240mg/d) can overcome T790M sudden change or MET expandsIncrease the TKI resistance causing. But some preclinical studies have shown unfavorable result, a kind of cell line of EGFR19 Exon deletionPC-9, in the time being exposed to neratinib, has produced T790M sudden change; In mouse L858R-T790M tumor model, aloneNeratinib does not make Tumor response. Therefore whether neratinib does not effectively still learn T790M sudden change person. XL647 can be irreversibleSuppress EGFR, HER2, VEGF R2 (VEGFR-2) and EphB4, in L858R-T790M catastrophic model,Can suppress tumor growth. 2008, an II phase clinical research about XL647 tentatively showed, in 34 routine Gefitinib or strategic pointsLip river is treated to alleviate to exceed after 3 months for Buddhist nun and is occurred, in PD or the NSCLC patient with T790M sudden change, to use XL647(300mg/d) after treatment, only 1 routine partial rcsponse, this patient's non-smoking, 19 Exon deletion, suddenly change without T790M in blood plasma; AndT790M suddenly change positive patient none alleviate, most of in 2 months progress. BIBW2992 be EGFR and ErbB2 can notContrary TKI. In the clinical research of II phase, BIBW2992 has made 19 Exon deletion, L858R, L861Q and G719S/S768I sudden changeAlleviating appears in patient. Progress NSCLC after BIBW2992 tri-line treatment chemotherapy failure, Gefitinib or a Tarceva benefitClinical research carry out. BIBW2992 contrasts placebo, and three line treatment Gefitinibs or Tarceva are treated unsuccessfullyThe random II b/ III phase clinical research of NSCLC is also underway. These researchs will contribute to determine that can BIBW2992 to lucky non-Bring benefit for Buddhist nun or Tarceva resistance patient. PF-00299804 is general ErbBTKI inhibitor. In the clinical research of I phase,There is disease alleviation in 1 routine T790M sudden change positive. PF-00299804 (45mg/d) treatment KRAS wild type, chemotherapy and E Luo replaceBuddhist nun treats failed NSCLC patient's II phase clinical research and carries out. Strategy 3, for other target treatments. Because " bypass swashsThe approach of living " in EGFR-TKI resistance, play a significant role, continue to bring out for the targeted drug of these bypasses. MET-TKI canCan in the patient with MET amplification, play a role. Preclinical study demonstration, EGFR-TKI combines with MET-TKI, prominent to EGFRBecome positive and effective with the cell line of MET amplification, but both independent uses are all invalid. An important problem is, about halfThe patient with MET amplification has T790M sudden change simultaneously, therefore MET-TKI may need to combine with T790M inhibitor. XL184 isA kind of novel TKI, has inhibitory action to MET, VEGFR-2 and RET. Other MET inhibitor, as ARQ197, PF-2341066,SGX523 etc., also have relevant clinical research carrying out. PF-2341066 is a kind of selective c-MET and ALK receptor tyrosine kinaseEnzyme inhibitor has been shown good tumour control effect in the clinical research of I phase, especially to the ALK-EML4 fusion positivePatient. II/III phase clinical research about PF-2341066 is carried out, and it becomes a new heat in targeted therapy field alreadyPoint. For other possible bypass activated pathway, some medicines, as IGF-1R inhibitor, inhibitor of heat shock protein 90 etc.Correlative study is also in process.

In a word, current EGFR-TKI still can not solve the caused clinical pressure of drug resistance, and existing medicineMostly thing is the reversible or irreversible inhibitor of the EGFR taking quinazoline or quinoline amine as basic parent nucleus, and it is to wild-type cellThe toxic and side effect that poor selectivity is brought is also inevitable. Therefore, in the urgent need to newtype, the change of especially novel skeletonThe problems such as compound solves drug resistance, poor selectivity.

Summary of the invention

Based on this, the object of this invention is to provide that a kind of pyrimido three encircles or pyrimido Fourth Ring compounds.

Concrete technical scheme is as follows:

There is formula (I), the pyrimido three of (II) or (III) structure encircle or pyrimido Fourth Ring compounds or its pharmaceuticallyAcceptable salt or stereoisomer or its prodrugs:

Wherein n=1-3

R₁Certainly optional:

1)H；

2)C₁-C₅Alkyl;

3)C₃-C₆Cycloalkyl;

4)C₁-C₅Containing fluoroalkyl;

5)(CH₂)_nX, n=0-6, X is hydroxyl, amino, C₁-C₆Heteroatom containing alkyl, C₃-C₇Heterocyclic radical;

6)A₁,A₂,A₃,A₄,A₅Certainly optional: halogen, cyano group, nitro, hydroxyl, amino, C₁～C₆Alkyl,C₃-C₆Cycloalkyl, C₁-C₆Containing fluoroalkyl, C₁-C₆Heteroatom containing alkyl, C₁-C₇The ester that heterocyclic radical and abovementioned alkyl form, acylAmine, sulfone, sulfoxide, urea;

R₂Certainly optional:

1)H；

2)C₁-C₅Alkyl;

3)C₃-C₆Cycloalkyl;

4)C₁-C₅Containing fluoroalkyl;

5) aryl;

6) heterocyclic radical;

R₃Certainly optional:

1)H；

2) halogen;

3) amino, hydroxyl, cyano group, nitro;

4)C₁-C₅Alkyl;

5)C₃-C₆Cycloalkyl;

6) aryl;

7)

W is certainly optional: CH₂,CH₂CH₂, O, S, NH, NR; R is alkyl or aryl;

R₄Certainly optional:

1)H；

2) halogen;

3)C₁-C₅Alkyl;

4)C₃-C₆Cycloalkyl;

5) aryl;

The above cycloalkyl, aryl can be optionally by 0,1, and 2 or 3 optionally from R₅Substituting group replace;

R₅Certainly optional:

1)H；

2) halogen;

3)C₁-C₃Alkyl;

4)C₃-C₆Cycloalkyl;

5)C₁-C₃Alkoxyl;

6)C₁-C₃Containing fluoroalkyl;

7) heterocyclic radical;

8)C₀-C₃Alkylidenyl-heterocyclic base;

9) phenyl.

In some embodiment, pyrimido three encircles or pyrimido tetracyclic compound or its pharmaceutically acceptable salt thereinOr stereoisomer or its prodrugs, it has formula IV, V, and VI structure:

Wherein n=1-3

R₁Certainly optional:

1), 4-N, N-lupetidine base, 1-methyl-4-(piperazine-4-replaces) piperidyl, imidazole radicals, 6-(4-methyl piperazinePiperazine-1-replaces)-3-substituted pyridinyl related heterocycles;

2)A₁,A₂,A₃,A₄,A₅Certainly optional: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-pro-pyl, isopropylBase, normal-butyl, isobutyl group, the tert-butyl group; N-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy,Methoxy ethoxy, ethoxy ethoxy, trifluoromethyl, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy,2-(N methyl piperazine base) ethyoxyl, 2-(N-acetyl group piperazinyl) ethyoxyl, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base secondOxygen base, 2-piperidyl ethyoxyl, 2-nafoxidine base oxethyl, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, tetrahydrochysenePyrroles, imidazoles, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-acetyl group piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methyl piperazine-1-replaces) methyl, 1-methyl piperidine-4-amino, 4-piperazine-2-ketone, 1-methyl-4-Piperazine-2-ketone, and the ester of above-mentioned group formation, acid amides, sulfone, sulfoxide, urea;

R₆,R₇,R₈,R₉Certainly optional:

H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, isopropoxy;

R₁₀,R₁₁Certainly optional:

R₁₂Certainly optional:

1)H；

2)C₁～C₅Alkyl;

3)C₃～C₆Cycloalkyl;

4) phenyl;

5) N, N-dimethylamino, N, N-diethylamino, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, fourHydrogen

Pyrroles, 4-N, N-lupetidine, 4-acetyl group piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-firstBase

Piperazine-1-replaces) methyl.

Therein in some embodiment, pyrimido three encircles or pyrimido Fourth Ring compounds or it is pharmaceutically acceptableSalt or its prodrugs, it has formula VII, VIII, IX structure:

Wherein n=1～3

A₁,A₂,A₃,A₄,A₅Certainly optional:

H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group; N-pentyl, differentAmyl group, the neopentyl branched paraffin of being correlated with, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, methoxy ethoxy, ethyoxyl secondOxygen base is relevant containing oxygen alkane, the trifluoromethyl fluorine-containing alkane of being correlated with, N, N-dimethylamino ethoxy, N, N-dimethylamino the third oxygenBase, 2-(N methyl piperazine base) ethyoxyl, 2-(N-acetyl group piperazinyl) ethyoxyl, 2-morpholine base oxethyl, 2-sulphur coffee quinolineBase oxethyl, 2-piperidyl ethyoxyl, 2-nafoxidine base oxethyl related heterocycles alkoxyl, N methyl piperazine base, morpholineBase, sulphur coffee quinoline, piperidines, nafoxidine, 3-N, N-dimethyl tetrahydro pyrroles, 4-N, N-lupetidine, 4-acetyl group piperazine, 1-Methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methyl piperazine-1-replaces) methyl, 1-methyl piperidine-4-amino, 4-piperazine-2-ketone, 1-methyl-4-piperazine-2-ketone;

R₆,R₇,R₈,R₉Certainly optional:

H, fluorine, chlorine, bromine, iodine;

R₁₃,R₁₄Certainly optional:

1)H；

2)C₁～C₅Alkyl;

3)C₃～C₆Cycloalkyl;

4) phenyl;

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

Therein in some embodiment, wherein A₁,A₂,A₄,A₅Be selected from hydrogen, methyl, ethyl, methoxyl group, ethyoxyl; A₃Be selected fromN, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N methyl piperazine base) ethyoxyl, 2-(N-acetyl groupPiperazinyl) ethyoxyl, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidyl ethyoxyl, 2-nafoxidine base secondOxygen base related heterocycles alkoxyl, N methyl piperazine base, morpholine base, sulphur coffee quinoline, piperidines, nafoxidine, 3-N, N-dimethyl fourHydrogen pyrroles, 4-N, N-lupetidine, 4-acetyl group piperazine, 1-methyl-4-(piperazine-4-replaces) piperidines, 4-(4-methyl piperazinePiperazine-1-replaces) methyl, 1-methyl piperidine-4-amino, 4-piperazine-2-ketone.

Therein in some embodiment, wherein R₆,R₇,R₈,R₉Be selected from H, fluorine; R₁₃，R₁₄For hydrogen.

Therein in some embodiment, pyrimido three encircles or pyrimido Fourth Ring compounds or it is pharmaceutically acceptableSalt or stereoisomer or its prodrugs are selected from:

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide;

N-(3-(2-((4-(4-(dimethylamino)-1-piperidines)-2 methoxyphenyls) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide

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

((2-((2-methoxyl group-4-sulphur coffee quinoline phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] is phonetic for 3-for N-Also [4,5-d] pyrimidine-10 (5 hydrogen) of pyridine-replacement) phenyl) acrylamide;

((2-((2-methoxyl group-4-(1-nafoxidine base) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo-7, also [1,2-of 8-glyoxalidineA] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide;

(R)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxygenGeneration-7, also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 8-glyoxalidine-replacement) phenyl) acrylamide;

(S)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxygenGeneration-7, also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 8-glyoxalidine-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-(4-methyl isophthalic acid-piperazinyl)-1-piperidyl) phenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide;

N-(3-(2-((4-(2-(dimethylamino) ethyoxyl)-2-methoxyphenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide;

((2-((2-methoxyl group-4-(2-morpholine ethyoxyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) replace) phenyl) acrylamide;

((2-((2-methoxyl group-4-(2-methoxy ethoxy) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((2-((4-methoxyphenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] pyrimido [4,5-also for 3-for N-D] pyrimidine-10 (5 hydrogen)-replace) phenyl) acrylamide;

((2-((4-fluorophenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] pyrimido [4,5-d] is phonetic for 3-for N-Pyridine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

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

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

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

((2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-ethyoxyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-isopropoxy-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide;

N-(3-(2-((3-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(the fluoro-3-of 4-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-dihydroImidazo [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8,9,10-tetrahydrochysenePyrimido [4', 5':4,5] pyrimidos [1,2-a] [1,3] diaza-12 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-methyl isophthalic acid-piperazinyl) phenyl) amino) also [1,2-a] pyrimidine of-5-oxo-imidazoleAnd [4,5-d] pyrimidine-10 (5 hydrogen)-replace) phenyl) acrylamide;

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

N-(3-(2-((2-ethyoxyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazolesAnd [1,2-a] pyrimido [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] pyrimido [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]Pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-A] pyrimido [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]Pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((4-(dimethylamino)-1-piperidyl)-2-methoxyphenyl) amino)-5-oxo benzo [4,5] miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen) of azoles-replacement) phenyl) acrylamide;

(E)-N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) but-2-enamides;

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

((2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) cinnamamide;

(E) ((2-((4-fluorophenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] also for 3-for-4-(dimethylamino)-N-Pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) 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-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) propionamide;

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

Another object of the present invention is to provide a kind of Pharmaceutical composition for the treatment of tumour.

Concrete technical scheme is as follows:

Treat a Pharmaceutical composition for tumour, it is encircled or pyrimidine by the pyrimido three described in claim 1-4 any oneAnd Fourth Ring compounds or its pharmaceutically acceptable salt or stereoisomer or its prodrugs and pharmaceutically acceptable yearBody composition.

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 pyrimido three encircle or pyrimido Fourth Ring compounds and pharmaceutically acceptable salt thereof or stereoisomer orThe application of its prodrugs in the medicine of preparation treatment tumour.

In some embodiment, described tumour is non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, pancreas thereinGland cancer, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, GISTs, leukaemia, histocyte lymphAny in cancer, nasopharyngeal carcinoma.

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

Term used herein " alkyl " and " alkylidene " mean to comprise have particular carbon atom number side chain and straight chainSaturated fat alkyl. For example, " C₁-C₅Alkyl " in " C₁-C₅" definition comprise arrange with straight or branched have 1,2,3,The group of 4 or 5 carbon atoms. For example, " C₁-C₅Alkyl " specifically comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, uncleButyl, isobutyl group, amyl group. Term " cycloalkyl " refers to have the monocycle saturated fat alkyl of particular carbon atom number. For example " cycloalkanesBase " comprise cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopenta, cyclohexyl etc.

Term used " heterocycle " or " heterocyclic radical " refer to and contain individual heteroatomic 5 yuan-6 of being selected from O, N and S of 1-4 hereinUnit's armaticity or nonaro-maticity heterocycle, and comprise bicyclic radicals. " heterocyclic radical " comprises heteroaryl, also comprises its dihydro and tetrahydrochyseneChange analog. " heterocyclic radical " further embodiment includes but not limited to: imidazole radicals, indyl, isothiazolyl, isoxazolyl,Oxadiazolyl, oxazolyl, oxetanyl (oxetanyl), pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, phoneticPyridine base, pyrrole radicals, quinoxalinyl, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4-alkyl dioxin, pyrrolesAlkyl, 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 tetrazole radical, thiodiazoline base, thiazolineBase, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxidationThing. The connection of heterocyclic substituent can realize by carbon atom or by hetero atom.

In one embodiment, heterocycle be selected from imidazole radicals, pyridine radicals, 1-pyrrolidones, 2-piperidones, 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 hereinChlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl and heterocyclic radical substituting group can be unsubstituted or replacement. ExampleAs, (C₁-C₆) alkyl can by one, two or three are selected from such as morpholine of OH, halogen, alkoxyl, dialkyl amido or heterocyclic radicalThe substituting group of base, piperidyl etc. replaces.

The free form that the present invention includes formula I-IX compound, also comprises its pharmaceutically acceptable salt and alloisomerismBody. The protonated salt that some specific exemplary compounds are aminated compounds herein. Term " free form " refer toThe aminated compounds of salt-independent shape. The pharmaceutically-acceptable salts being included not only comprises the example of specific compound described hereinProperty salt, also comprises the typical pharmaceutically acceptable salt of all formula I-IX compound free forms. Can use known in the artTechnical point is from the free form of described compound specific salts. For example, can pass through with the suitable rare water of for example NaOH of alkali dilute aqueous solutionSolution, potash dilute aqueous solution, weak aqua ammonia and sodium acid carbonate dilute aqueous solution are processed this salt and are made free form regeneration. Free form existsSome physical property for example in polar solvent in solubility with its separately salt form more or less distinguish, but for invention orderThis hydrochlorate and alkali salt aspect other pharmacy with its free form is suitable separately.

Can be synthetic of the present invention from the compounds of this invention that contains basic moiety or acidic moiety by conventional chemical methodPharmaceutically acceptable salt. Conventionally, by ion-exchange chromatography or by free alkali and stoichiometric amount or excessive required saltInorganic or the organic acid of form reacts the salt of preparing alkali compounds in the combination of appropriate solvent or multi-solvents. Similarly,By reacting with suitable inorganic or organic base the salt that forms acid compound.

Therefore, the pharmaceutically acceptable salt of the compounds of this invention comprises by alkaline the compounds of this invention and inorganic or haveThe conventional nontoxic salts of the compounds of this invention that machine acid reaction forms. For example, conventional nontoxic salts comprises and derives from such as salt of inorganic acidThe salt of acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc., also comprises from organic acid for example acetic acid, propionic acid, butanedioic acid, secondAlkyd, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid,Glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2 one acetoxyl group one benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid,The salt of the preparation such as ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.

If the compounds of this invention is acid, suitable " pharmaceutically acceptable salt " refers to by pharmaceutically acceptableNontoxic alkali comprise salt prepared by inorganic base and organic base. the salt that derives from inorganic base comprises aluminium salt, ammonium salt, calcium salt, mantoquita, ironSalt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc. Particularly preferably ammonium salt, calcium salt, magnesium salts, sylviteAnd sodium salt. Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali comprises the salt of primary amine, secondary amine and tertiary amine, replacementAmine comprise naturally occurring replacement amine, cyclic amine and deacidite for example arginine, betaine, caffeine, choline,N, N'-dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, ethylaminoethanol, ethanolAmine, ethylenediamine, N mono-ethyl morpholine, N mono-ethyl piperidine, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine,Lysine, methyl glucoside amine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, triethylamine,Trimethylamine, tripropyl amine (TPA), tromethamine etc.

Berg etc., " PharmaceuticalSalts, " J.Pharm.Sci. ' 1977:66:1-19 has been described in more detailThe preparation of pharmaceutically acceptable salt mentioned above and other typical pharmaceutically acceptable salt.

Because for example carboxyl of acidic moiety of deprotonation in compound under physiological condition can be anion, and thisWith electric charge then can be by inside with cationic protonated or for example quaternary nitrogen atom of alkylating basic moietyBalance is offset, so should notice that the compounds of this invention is potential inner salt or amphion.

The present invention relates to have general formula I, the pyrimido three of II or III architectural feature encircles or pyrimido Fourth Ring compounds, canTo suppress kinds of tumor cells, especially can selectively acting in EGFRL858R/T790M and EGFRE745_A750/T790M lung carcinoma cell. Contrast wild type cancer cell, the IC of this compounds₅₀Want high 10 times, 100 times of quantity of 1000 times evenLevel difference. This compounds be a class novelty can overcome existing EGFR-TKI resistance and there is optionally protein kinaseInhibitor.

The pyrimido three the present invention relates to encircles or pyrimido Fourth Ring compounds and pharmaceutically acceptable salt thereof, Ke YiyouEffect suppresses the growth of kinds of tumor cells, and to EGFR, other protease-producing strain inhibitory action of Her family, can be used for preparation anti-Tumour medicine, and can overcome existing medicine Gefitinib, the resistance that Tarceva etc. bring out. As those skilled in the art manageSeparate, the acceptable salt of the compound that the application is related and pharmacy thereof can be used for the preparation treatment mankind and other is mammiferousThe transition proliferative diseases such as tumour.

Detailed description of the invention

Except standard method known or illustration in experimental arrangement in the literature, can adopt as shown in following schemeReaction prepare the compounds of this invention. Following illustrative approach is for the object of explanation instead of is confined to listed compound or appointsWhat specific substituting group. The substituting group number showing in scheme must not meet number used in claim, and is clearChu Qijian, 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 according to prior art and possess normalKnow, can be that initiation material passes through 6 steps reactions by the chloro-5-pyrimidinecarboxylic acid of 2,4-bis-ethyl ester synthetic.

Drug metabolite and prodrug

The metabolite of the compound that the application is related and the acceptable salt of pharmacy thereof, and can change in vivoThe prodrug of the structure of the compound that the application is related and the acceptable salt of pharmacy thereof, is also contained in the application's claimIn.

Drug combination

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

Medicine or the active component 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/cell press downPreparation, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptaseMedicine and the cell at inhibitor, AI, cell proliferation and survival signaling inhibitor, the interference cell cycle outpost of the tax office witherThe derivant of dying, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine eggWhite inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, opens upFlutter isomerase inhibitors, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family proteinInhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKTInhibitor, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF antibody,EGF antibody etc.

Medicine or the active component that can carry out drug combination with formula I-IX compound comprise but are not limited to: Ah Di is white to be situated betweenElement, alendronic acid, interferon, Ah Qu Nuoying, Allopurinol, allopurinol sodium, palonosetron hydrochloride, hemel, amino latticeRumi spy, Amifostine, Amrubicin, SN-11841, arimidex, Dolasetron, aranesp, arglabin, arsenic trioxide,Arnold is new, U-18496, imuran, BCG vaccine or tice BCG vaccine, bestatin, betamethasone acetate, betamethasone phosphoric acidPreparation of sodium, bexarotene, Bleomycin Sulphate, broxuridine, bortezomib, busulfan, calcitonin, the injection of A Laizuo monoclonal antibodyAgent, capecitabine, carboplatin, Kang Shi get, cefesone, Celmoleukin, daunorubicin, Chlorambucil, cis-platinum, carat are bentShore, Cladribine, chlorine bend phosphoric acid, endoxan, arabinose born of the same parents former times, Dacarbazine, actinomycin D, daunorubicin liposome, fill inMeter Song, dexamethasone phosphate, Estradiol Valerate, denileukin diftitox, Di Bomei, Deslorelin, La Zuosheng, diethylstilbestrol, largeHold up health, docetaxel, doxifluridine, adriamycin, Dronabinol, by the emperor himself-166-chitosan complexes, eligard, granny rag to standEnzyme, epirubicin hydrochloride, aprepitant, Epi-ADM, Epoetin Alfa, erythropoietin(EPO), eptalatin, Ergamisole, femaleTwo alcohol formulations, 17-β-estradiol, estramustine phosphate sodium, ethinyloestradiol, Amifostine, hydroxyl phosphoric acid, Etopophos, etoposide, method are stubbornAzoles, TAM preparation, Filgrastim, Tamsulosin, Fei Leisi are for, floxuridine, Fluconazole, fludarabine, 5-fluorodeoxyglucose urinePyrimidine nucleoside monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, Flutamide, formestane, 1-β-D-R furanose born of the same parents thialdine-She replaces 5 '-stearoyl phosphate, Fotemustine, fulvestrant, gamma globulin, gemcitabine, WAY-CMA 676, methanesulfonic acid by horseBuddhist nun, Gliadel, Goserelin, Graniseeron Hydrochloride, Histrelin and U.S. new, hydrocortisone, redType-hydroxyl nonyl adenine, hydroxycarbamide, for not monoclonal antibody, idarubicin, ifosfamide, interferon-' alpha ', interferon-' alpha ' of smooth different shellfish2, interferon α-2 A, interferon α-2 B, Interferon α-nl, Alferon N, interferon beta, interferon gamma-la, interleukins-2, intron A, Iressa, Irinotecan, Kytril, sulfuric acid lentinan, Letrozole, formyl tetrahydrofolic acid, Leuprorelin, brightThe third nafarelin acetate salt, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, Luo MosiSpit of fland, Lonidamine, Dronabinol, mustargen, Mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterification are female swashsElement, 6-coloured glaze base purine, mesna, amethopterin, amino-laevulic acid methyl esters, Miltefosine, minocycline, mitomycin C, riceTuo Tan, rice holder green onion quinone, Trilostane, citric acid Evacet, Nedaplatin, Pegylation Filgrastim, Ao PuruibaiElement, neupogen, Nilutamide, TAM, NSC-631570, recombination human interleukins-11-β, Octreotide, hydrochloric acid Austria are situated betweenRed Shillong, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, Pegaspargase, groupLuo Xin, Pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin soft than star, plicamycin, Porfimer Sodium, prednimustine,Prednisolone Steaglate, metacortandracin, doubly U.S. power, the third kappa navel, epoetin, Raltitrexed, Libiee, according to for phosphineAcid rhenium-186, Mabthera, Redoxon-A, Romurtide, Salagen, Octreotide, sargramostim, Semustine,Sizofiran, Sobuzoxane, bluff sodium methylprednisolone, Paphos acid, stem-cell therapy, streptozotocin, Metastron, levothyrocineSodium, TAM, YM-617, Ta Suonaming, tastolactone, taxotere, teceleukin, Temozolomide, Teniposide,Testosterone propionate, methyltestosterone, thioguanine, thio-tepa, thyrotropic hormone, Tiludronic Acid, TPT, Toremifene, TosiNot monoclonal antibody, Herceptin, Treosulfan, Tretinoin, methopterin tablet, trimethyl melamine, Trimetrexate, acetic acid Qu PuruiWoods, triptorelin pamoate, UFT, uridine, valrubicin, Vesnarinone, vincaleukoblastinum, vincristine, Vindesine, lengthSpring Rui Bin, virulizin, ADR-529, Zinostatin stimalamer, ondansetron, taxol protein stabilization formulations,Acolbifene, interferon r-lb, affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, atamestane, A QushengSmooth, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, crisnatol, cyproterone vinegarAcid esters, Decitabine, DN-101, adriamycin-MTC, dSLIM, dutasteride, edotecarin, Eflornithine, replace according to happinessHealth, Suwei A amine, histamine dihydrochloric acid, Histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, inContaining son-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib,Miproxifene, minot are bent acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, Neovastat, promiseDraw Qu Te, Ao Limosen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, QS-21, overstate westOcean, R-1549, Raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, 22Carbon acid taxol, extrasin alpha l, loud, high-pitched sound azoles furan woods, tipifarnib, Tirapazamine, TLK-286, Toremifene, transMID-lo7R, valspodar, Vapreotide, vatalanib, Verteporfin, vinflunine, Z-100 and azoles come unicorn acid or theyCombination.

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

Embodiment 1

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

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

By chloro-2,4-bis-5-pyrimidinecarboxylic acid ethyl ester (22.1g, 100mmol, 1.0eq), N-Boc m-phenylene diamine (MPD) (20.8g,1.0eq), under DIPEA (17.4ml, 1.0eq) room temperature, add successively in 500ml acetonitrile, be heated to 2 of return stirring reactions littleTime, stopping 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%).

¹HNMR(400MHz,CDCl₃)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)

Compound 1 (3,92g, 10mmol) is added in 20mlTHF, under room temperature, add 15ml1NNaOH (15mmol,1.5eq), be heated to 40 DEG C of stirring reactions 3 hours, stop heating the system for the treatment of and be down to room temperature, decompression steams THF, in system, addsEnter 15ml1NHCl, separate out solid, filtration under diminished pressure, vacuum drying obtains white solid 3.57g (98%).

¹HNMR(400Hz,DMSO-d₆)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-((also [4,5-b] pyridine of 3-hydrogen-[1,2,3] triazole-3-replaces) oxygen base)-5-oxygen-7,8-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of glyoxalidine-replacement) 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 DEG C of stirrings added 2-first sulfydryl-4 after 0.5 hour, 5-dihydro-1 hydrogen-imidazoles (31.94mg,1.1eq) continue to stir 24 hours. Add 5mLH₂O extract and separate obtains organic phase, anhydrous Na₂SO₄Dry, column chromatography obtains white solidBody 75mg (58%).

¹HNMR(400MHz,DMSO-d₆)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/z515.1[M+H]⁺

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

By compound 3-1 (257mg, 0.5mmol, 1.0eq), 2-methoxyl group-4-(4-methyl piperazine-1-replaces) aniline(110.6mg,1.0eq),K₂CO₃(207.3mg, 3.0eq), the 8ml tert-butyl alcohol adds in 25mL tube sealing, is heated to 100 DEG C and stirs anti-Answer 5 hours. Stop heating and be down to room temperature, decompression steams solvent, adds DCM and H₂The organic phase of O extract and separate, saturated NaCl is moltenLiquid washing organic phase once, obtains organic phase anhydrous Na₂SO₄Dry. Decompression steams solvent, obtains solid and is directly used in that next step is anti-Should.

Step 5.10-(3-aminophenyl)-2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-7,8-glyoxalidine is [1,2-a] pyrimido [4,5-d] pyrimidine-5 (10 hydrogen)-one (XTF-42) LCMS (ESI) also: m/z500.0[M+H]⁺

Step 4 is obtained to product and add in 2mLDCM, add 2mLTFA stirred overnight at room temperature, decompression steams solvent, pastIn system, slowly drip saturated NaHCO₃Solution 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-bis-Hydrogen imidazo [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-01)

Compound 5 (100mg, 0.2mmol, 1.0eq) is added in 5mlDCM, drip DIPEA (0.034ml, 1.0eq), 0Under DEG C stirring, in system, slowly drip acryloyl chloride (0.032ml, 2.0eq), dropwise and rise to room temperature and continue to stir 2 littleTime. In system, add 10mL n-hexane to separate out solid, filtration under diminished pressure obtains filter cake, and column chromatography for separation obtains yellow solid 71,9mg(65％).

¹HNMR(400MHz,DMSO-d₆)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/z554.0[M+H]⁺

Embodiment 2

N-(3-(2-((4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide (XTF-02)

Synthetic method is as embodiment 1

¹HNMR(400MHz,Acetic-d₄)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/z582.2[M+H]⁺

Embodiment 3

N-(3-(2-((4-(4-(dimethylamino)-1-piperidines)-2 methoxyphenyls) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide (XTF-03)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,Acetic-d₄)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/z582.2[M+H]⁺

Embodiment 4

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z540.9[M+H]⁺

Embodiment 5

((2-((2-methoxyl group-4-sulphur coffee quinoline phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] is phonetic for 3-for N-Also [4,5-d] pyrimidine-10 (5 hydrogen) of pyridine-replacement) phenyl) acrylamide (XTF-05)

Synthetic method is as embodiment 1.

1HNMR(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/z557.0[M+H]+

Embodiment 6

((2-((2-methoxyl group-4-(1-nafoxidine base) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-06)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,Acetic-d₄)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, also [1,2-of 8-glyoxalidineA] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-07)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z539.1[M+H]⁺

Embodiment 8

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide (XTF-08)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z568.2[M+H]⁺

Embodiment 9

(R)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxygenGeneration-7, also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 8-glyoxalidine-replacement) phenyl) acrylamide (XTF-09)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z568.2[M+H]⁺

Embodiment 10

(S)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxygenGeneration-7, also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 8-glyoxalidine-replacement) phenyl) acrylamide (XTF-10)

Synthetic method is as embodiment 1.

LCMS(ESI):m/z568.2[M+H]⁺

Embodiment 11

N-(3-(2-((2-methoxyl group-4-(4-(4-methyl isophthalic acid-piperazinyl)-1-piperidyl) phenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide (XTF-11)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,Acetic-d₄)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/z637.2[M+H]⁺

Embodiment 12

N-(3-(2-((4-(2-(dimethylamino) ethyoxyl)-2-methoxyphenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide (XTF-12)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝10.0,16.8Hz,1H),6.28(dd,J₁＝2.0,16,8Hz,1H),5.78(dd,J₁＝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/z543.2[M+H]⁺

Embodiment 13

((2-((2-methoxyl group-4-(2-morpholine ethyoxyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-13)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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(dd,J₁＝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

((2-((2-methoxyl group-4-(2-methoxy ethoxy) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-14)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝10.0,16.8Hz,1H),6.28(dd,J₁＝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/z530.1[M+H]⁺

Embodiment 15

((2-((4-methoxyphenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] pyrimido [4,5-also for 3-for N-D] pyrimidine-10 (5 hydrogen)-replace) phenyl) acrylamide (XTF-15)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z456.1[M+H]⁺

Embodiment 16

((2-((4-fluorophenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] pyrimido [4,5-d] is phonetic for 3-for N-Pyridine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-16)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝2.0,16.8Hz,1H),6.27(dd,J₁＝2.0，16.8Hz,1H),5.78(dd,J₁＝2.0,10.0Hz,1H),3.98(t,J＝8.8Hz,2H),3.73(t,J＝8.8Hz,2H).LCMS(ESI):m/z444.1[M+H]⁺

Embodiment 17

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z524.0[M+H]⁺

Embodiment 18

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z511.2[M+H]⁺

Embodiment 19

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z527.1[M+H]⁺

Embodiment 20

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,Acetic-d₄)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/z523.2[M+H]⁺

Embodiment 21

((2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-21)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z538.2[M+H]⁺

Embodiment 22

N-(3-(2-((2-ethyoxyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-22)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝10.0,17.2Hz,1H),6.28(dd,J＝2.0,16.8Hz,1H),5.78(dd,J₁＝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/z568.2[M+H]⁺

Embodiment 23

N-(3-(2-((2-isopropoxy-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) acrylamide (XTF-23)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z582.2[M+H]⁺

Embodiment 24

N-(3-(2-((3-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-24)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝2.0Hz,J₂＝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/z554.1[M+H]⁺

Embodiment 25

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

Synthetic method is as embodiment 1.

LCMS(ESI):m/z447.1[M+H]⁺

Embodiment 26

N-(the fluoro-3-of 4-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-dihydroImidazo [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-26)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,Acetic-d₄)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,J₁＝3.2Hz,J₂＝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/z572.1[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-Two pyrimidos [1,2-a:4', 5'-d] pyrimidine-11 (7 hydrogen)-replacement) phenyl) acrylamide (XTF-27)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z568.0[M+H]⁺

Embodiment 28

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8,9,10-tetrahydrochysenePyrimido [4', 5':4,5] pyrimidos [1,2-a] [1,3] diaza-12 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-28)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z582.1[M+H]⁺

Embodiment 29

N-(3-(2-((2-methoxyl group-4-methyl isophthalic acid-piperazinyl) phenyl) amino) also [1,2-a] pyrimidine of-5-oxo-imidazoleAnd [4,5-d] pyrimidine-10 (5 hydrogen)-replace) phenyl) acrylamide (XTF-29)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z552.0[M+H]⁺

Embodiment 30

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

(3-(2-((also [4,5-b] pyridine of 3 hydrogen-[1,2,3] triazole-3-replaces) oxygen base)-5-oxo benzo [4,5] miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen) of azoles-replacement) 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 DEG C of stirrings add 2-Chlorobenzimidazole (152.5mg, 1.0eq) continuation stirring 24 little after 0.5 hourTime. The solid generating in filtration under diminished pressure reaction, with 5mLDCM, 2ml methyl alcohol, 5mLH₂O is washing leaching cake successively, obtains pale yellow colored solidBody 270mg (48%).

¹HNMR(400MHz,DMSO-d₆)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,J₁＝4.4,8.4Hz,1H),7.50-7.42(m,2H),7.30-7.29(m,1H),1.43(s,9H).LCMS(ESI):m/z564.1[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)-replacement) phenyl) t-butyl carbamate (4-5)

By compound 3-5 (323.8mg, 0.5mmol, 1.0eq), 2-methoxyl group-4-(4-methyl piperazine-1-replaces) aniline(110.6mg,1.0eq),K₂CO₃(207.3mg, 3.0eq), the 8mL tert-butyl alcohol adds in 25mL tube sealing, is heated to 110 DEG C and stirs anti-Answer 24 hours. Stop heating and be down to room temperature, decompression steams solvent, adds DCM and H₂The organic phase of O extract and separate, saturated NaClSolution washing organic phase once, obtains organic phase anhydrous Na₂SO₄Dry. Decompression steams solvent, obtains solid and is directly used in next stepReaction.

Other steps are with embodiment 1

¹HNMR(400MHz,Acetic-d₄)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,J₁＝4.0,7.6Hz,1H),3.85(s,3H),3.70(m,4H),3.20(m,4H),2.95(s,3H).LCMS(ESI):m/z602.1[M+H]⁺

Embodiment 31

N-(3-(2-((2-ethyoxyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo benzo [4,5] imidazolesAnd [1,2-a] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-31)

Synthetic method is as embodiment 30.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝10.0Hz,J₂＝17.2Hz,1H),6.29(dd,J₁＝1.6,16.8Hz,1H),6.00(brs,1H),5.79(dd,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/z616.3[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] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-32)

Synthetic method is as embodiment 30.

LCMS(ESI):m/z586.2[M+H]⁺

Embodiment 33

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

Synthetic method is as embodiment 30.

¹HNMR(400MHz,DMSO-d₆)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,J₁＝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/z572.1[M+H]⁺

Embodiment 34

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

Synthetic method is as embodiment 30.

¹HNMR(400MHz,DMSO-d₆)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]Pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide (XTF-35)

Synthetic method is as embodiment 30.

¹HNMR(400MHz,DMSO-d₆)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/z588.9[M+H]⁺

Embodiment 36

N-(3-(2-((4-(dimethylamino)-1-piperidyl)-2-methoxyphenyl) amino)-5-oxo benzo [4,5] miaowAzoles is [1,2-a] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-yl also) phenyl) acrylamide (XTF-36)

Synthetic method is as embodiment 30.

¹HNMR(400MHz,DMSO-d₆)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/z630.4[M+H]⁺

Embodiment 37

(E)-N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-dihydro miaowAlso [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of azoles-replacement) phenyl) but-2-enamides (XTF-37)

Synthetic method is as embodiment 1.

¹HNMR(400Hz,DMSO-d₆)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/z568.2[M+H]⁺

Embodiment 38

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

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z582.1[M+H]⁺

Embodiment 39

((2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5 oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) cinnamamide (XTF-39)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z630.1[M+H]⁺

Embodiment 40

(E) ((2-((4-fluorophenyl) amino)-5 oxo-7,8-glyoxalidine is [1,2-a] also for 3-for-4-(dimethylamino)-N-Pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) the rare acid amides of fourth-2-(XTF-40)

Synthetic method is as embodiment 1.

¹HNMR(400MHz,DMSO-d₆)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/z501.1[M+H]⁺

Embodiment 41

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) propionamide (XTF-41)

Synthetic method is as embodiment 1.

¹HNMR(400Hz,DMSO-d₆)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/z556.2[M+H]⁺

Embodiment 42

Pyrimido three encircles or the kinases EC of pyrimido Fourth Ring compounds to EGFR wild type and EGFR-T790M sudden change₅₀SurveyExamination

Kinase activity detects: application Z '-LYTE^TMTechnology (adopt that fluorescence detects, enzyme coupling form, with phosphorylation andNon-phosphorylating polypeptide is basis to the sensitivity differences of proteolysis cutting), adopt FRET (FRET) principle,Use Z ' LYTE^TMFRET peptide class substrate, second order reaction detection compound is to kinase activity. (invitrogen, Z '-LYTE^TMKINASEASSAYKIT – TYR2PEPTIDE, PV3191) by EGFR-T790M kinases (invitrogen,PV4803) after stepwise dilution, add FRET peptide, ATP, then add variable concentrations compound, after reaction 1h, add locus specificityProtease, identifies and cuts unphosphorylated FRET peptide, and reaction 1h, uses 400nm excitation wavelength, detects 445nm and 520nm and inhalesReceive.

$EmissionRatio=\frac{CoumarinE\mathrm{mi}ssiom\left(445nm\right)}{FluoresceinEmission\left(520nm\right)}$

$\%Phosphorylation=1-\frac{\left(EmissionRatioxF100\%\right)-C100\%}{\left(C0\%-C100\%\right)+\[EmissionRatiox\left(F100\%-F0\%\right)\]}$

Show that inhibiting rate becomes positive correlation with drug concentration, make kinase activity and concentration relationship curve, calculate IC₅₀Value.

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

Table 1 compound kinase activity

Pyrimido three encircle or the competitive assay of pyrimido Fourth Ring compounds and ATP in, owing to existing and albumen half Guang ammoniaAcid site forms irreversible Michael addition reaction, so five kinds of kinases are all embodied to higher inhibition activity. In conjunction with experimentWe can find out that substituted acryl is for the necessary structure of active institute data and compound structure feature, formula VII, and VIII, gets in IXFor group A₁,A₂,A₃,A₄,A₅,R₆,R₇,R₈,R₉Less to activity influence, all there is good activity, but R₁₃,R₁₄While being hydrogen, liveProperty effect 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, EGFRE746-A750deletion), H1975 (lung carcinoma cell, EGFRL858R&T790M) spreads 96 orifice plates, after 24h, by the difference of DMSO preparationConcentration compound treatment (DMSO final concentration 1 ‰, parallel control 3-5), adds MTT (tetrazolium bromide, 5mg/ml, 10ul/ after 72hHole), 37 degree are hatched 4h. Suck supernatant, add DMSO150ul, fully, after vibration, detect OD570, use GraphPadPrismThe processing of 4Demo software. Found that, pyrimido three encircles or the compounds processing of pyrimido Fourth Ring can obviously reduce above-mentioned cellTo the absorption of MTT, illustrate that pyrimido three encircles or pyrimido 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 concentration. Encircle or phonetic according to pyrimido threeThe growth inhibition effect to these cells of pyridine Fourth Ring compounds, we calculate its half-inhibition concentration (IC₅₀) be worth as table 2Institute is described.

Table 2 compound cytoactive

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

Claims (6)

1. pyrimido three encircles or pyrimido Fourth Ring compounds or its pharmaceutically acceptable salt, it is characterized in that, it hasFormula VII, VIII, IX structure:

Wherein n=1～3;

A₁,A₂,A₄,A₅Be selected from hydrogen, methyl, ethyl, methoxyl group, ethyoxyl, isopropoxy; A₃Be selected from fluorine, chlorine, bromine, iodine, methoxyBase, ethyoxyl, methoxy ethoxy, N, N-dimethylamino ethoxy, N, N-dimethylamino propoxy, 2-(N-methyl piperazinePiperazine base) ethyoxyl, 2-(N-acetyl group piperazinyl) ethyoxyl, 2-morpholine base oxethyl, 2-sulphur coffee quinoline base oxethyl, 2-piperidinesBase oxethyl, 2-nafoxidine base oxethyl, N methyl piperazine base, morpholine base, sulphur coffee quinoline base, piperidyl, nafoxidine base,3-N, N-dimethyl tetrahydro pyrrole radicals, 4-N, N-lupetidine base, 4-acetyl group piperazinyl, (piperazine-4-gets 1-methyl-4-Generation) piperidyl, 4-(4-methyl piperazine-1-replaces) methyl, 1-methyl piperidine-4-amino, 4-piperazine-2-ketone group;

R₆,R₇,R₈,R₉Certainly optional:

H, fluorine, chlorine, bromine, iodine;

R₁₃,R₁₄Certainly optional:

1)H。

2. pyrimido three according to claim 1 encircles or pyrimido Fourth Ring compounds or it is pharmaceutically acceptableSalt, is characterized in that, wherein R₆,R₇,R₈,R₉Be selected from H, fluorine; R₁₃，R₁₄For hydrogen.

3. pyrimido three encircles or pyrimido Fourth Ring compounds or its pharmaceutically acceptable salt, it is characterized in that, it is selected from:

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

((2-((4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((2-((4-(4-(dimethylamino)-1-piperidines)-2 methoxyphenyls) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

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

N-(3-(2-((2-methoxyl group-4-(1-nafoxidine base) phenyl) amino)-5-oxo-7, also [1,2-of 8-glyoxalidineA] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] is phonetic for 3-for N-Also [4,5-d] pyrimidine-10 (5 hydrogen) of pyridine-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) phenyl) amino)-5-oxo-7,8-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of glyoxalidine-replacement) phenyl) acrylamide;

(R)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide;

(S)-N-(3-(2-((4-(3-(dimethylamino)-1-nafoxidine alkyl)-2-methoxyphenyl) amino)-5-oxo-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of 7,8-glyoxalidine-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-(4-methyl isophthalic acid-piperazinyl)-1-piperidyl) phenyl) amino)-5-oxo-7,8-Also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) of glyoxalidine-replacement) phenyl) acrylamide;

((2-((4-(2-(dimethylamino) ethyoxyl)-2-methoxyphenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(2-morpholine ethyoxyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen) replacement) phenyl) acrylamide;

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

((2-((4-methoxyphenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] pyrimido [4,5-d] is phonetic for 3-for N-Pyridine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

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

((2-((4-morpholine base phenyl) amino)-5-oxo-7,8-glyoxalidine is [1,2-a] pyrimido [4,5-d] also for 3-for N-Pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((5-oxo-2-((4-sulphur coffee quinoline base phenyl) amino)-7,8-glyoxalidine is [1,2-a] pyrimido [4,5-d] also for 3-for N-Pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

N-(3-(2-((2-methyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7, also [1,2-of 8-glyoxalidineA] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-ethyoxyl-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((2-((2-isopropoxy-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidine also for 3-for N-[1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

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

N-(the fluoro-3-of 4-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8-glyoxalidineAnd [1,2-a] pyrimido [4,5-d] pyrimidine-10 (5 hydrogen)-replacement) phenyl) acrylamide;

((2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-8, hydrogen-bis-are phonetic in 9-dihydro-5 for 3-for N-Pyridine also [1,2-a:4', 5'-d] pyrimidine-11 (7 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl) amino)-5-oxo-7,8,9,10-tetrahydropyrimidineAnd [4', 5':4,5] pyrimidos [1,2-a] [1,3] diaza-12 (5 hydrogen)-replacement) phenyl) acrylamide;

N-(3-(2-((2-methoxyl group-4-methyl isophthalic acid-piperazinyl) phenyl) amino) also [1,2-a] pyrimido of-5-oxo-imidazole[4,5-d] pyrimidine-10 (5 hydrogen)-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] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide;

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

((2-((2-methoxyl group-4-(1-piperidyl) phenyl) amino)-5-oxo benzo [4,5] imidazo [1,2-a] is phonetic for 3-for N-Also [4,5-d] pyrimidine-12 (5 hydrogen) of pyridine-replacement) phenyl) acrylamide;

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

N-(3-(2-((4-(dimethylamino)-1-piperidyl)-2-methoxyphenyl) amino)-5-oxo benzo [4,5] imidazo[1,2-a] pyrimido [4,5-d] pyrimidine-12 (5 hydrogen)-replacement) phenyl) acrylamide.

4. treat a Pharmaceutical composition for tumour, it is encircled or pyrimido by the pyrimido three described in claim 1-3 any oneFourth Ring compounds or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier composition.

Claim 1-3 any one pyrimido three encircle or pyrimido Fourth Ring compounds and pharmaceutically acceptable salt thereof in systemApplication in the medicine of standby treatment tumour.

6. application according to claim 5, is characterized in that: described tumour is non-small cell lung cancer, ED-SCLC, lung glandCancer, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cell carcinoma, GISTs, leukaemia, histocyteAny in lymph cancer, nasopharyngeal carcinoma.