CN110305161A - 2- amino-metadiazine compound and its application - Google Patents

Abstract

The present invention relates to a kind of 2- amino-metadiazine compound and its applications, and the structure of 2- amino-metadiazine compound is as shown in I.Such compound can effectively inhibit EGFR protein kinase drug resistant mutants (such as EGFR^T790MAnd EGFR^T790M/C797S) activity, and existing third generation selectivity EGFR can be overcome^T790MThe clinical drug-resistant of the tumour patients such as micromolecular inhibitor Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) etc. the non-small cell lung cancer of inductions.

Description

2- amino-metadiazine compound and its application

Technical field

The present invention relates to chemical medicines, more particularly to a kind of 2- amino-metadiazine compound and its application.

Background technique

Tumor cells targeted therapy be based on to the closely related key molecule of tumour growth by chemistry or biology learn to do A kind for the treatment of method of section selective killing tumour cell.The characteristics of targeted therapy are as follows: specificity is high, and selectivity is strong, and poison is secondary to be made With relatively gently；When use in conjunction, it can reinforce the curative effect of classic chemotherapy, radiotherapy, reduce postoperative recurrence.With Gleevec (STI571) (Novartis, 2001), Gefitinib (ZD1839) (AstraZeneca, 2003), Erlotinib (OSI774) (Genentech and OSIP, 2004), Sorafenib tosilate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and Dasatinib (BMS-354825) (Bristol- Myers Squibb, 2006) it is that the targeted drug represented has started a new era as chemotherapy of tumors.Neoplasm targeted therapy exists It is rapidly developed in a few years.Going out for neoplasm targeted therapy constitutes impact, example to convenient administration idea and mode Such as, because the small targeted drug of toxic side effect is often unable to reach dose-limiting toxicity and maximum tolerance agent in Phase I clinical trial Amount；With when target therapeutic agent without with maximum tolerated dose can reach satisfactory effect.Neoplasm targeted therapy is oncotherapy Hot spot and development trend.

EGF-R ELISA (EGFR), a kind of receptor tyrosine protein kinase have regulated and controled the proliferation of cell, survival, Adhesion, migration and differentiation.EGFR overactivity or continuous activation in kinds of tumor cells, such as lung cancer, breast cancer, prostate Cancer etc..There are EGFR overexpressions for about 62% Patients with Non-small-cell Lung, can significantly improve part to the inhibition of EGFR and suffer from The life cycle of person.Also, EGFR micromolecular inhibitor the drug Gefitinib and Erlotinib of listing in 2003~2004 years, It is used for the treatment of advanced Non-small cell lung, having further clarified EGFR is the Effective target site for treating non-small cell lung cancer.

First generation EGFR micromolecular inhibitor obtains significant clinical efficacy in the patient for carrying EGFR sensitizing mutation, Extend their life cycle.But benefit patient after using drug 10~12 months, most of patient can generate drug resistance.Its In, the drug resistance patient (carrying EGFR sensitizing mutation) more than 50% is that bis- mutation of T790M have occurred due to EGFR to generate drug resistance. Compared to the EGFR of L858R sensitizing mutation, the EGFR of L858R/T790M bis- times mutation is stronger to the affinity of ATP, and first generation medicine Object is ATP competitive inhibitor, therefore leads to Drug-resistant.Although second generation EGFR irreversible inhibitor is in preclinical study It obtains preferable as a result, but to Wild type EGFR (EGFR^WT) lack selectivity, there is larger toxicity.FDA approval in 2013 Although EGFR irreversible inhibitor Gilotrif is to the advanced stage for carrying activity EGFR mutation (L858R, del E746-A750) Patient NSCLC is effective, but at clinical maximum tolerated dose (MTD), can not still solve clinical caused by EGFRT790M mutation Drug resistance.The third generation overcomes EGFR^T790MDrug resistant irreversible inhibitor Osimertinib (AZD9291) is obtained in November, 2015 It obtains U.S. FDA and accelerates approval listing (Cancer discovery 2014,4 (9), 1046-1061), can clinically have Effect treatment EGF-R ELISA (EGFR) T790M is mutated or to the drug resistant Advanced Non-Small Cell lung of other EGFR inhibitors Cancer patient.Although Osimertinib clinically treat EGFRT790M mutation non-small cell lung cancer achieve it is biggish at Function, but is there is the phenomenon that drug resistance (Nature Medicine after treatment in 9~14 months again in part benefited patient 2015,21(6),560-2).It has been investigated that up to 40% drug resistance patient is resulted in due to (EGFR) C797S point mutation Osimertinib drug resistance.Further Mechanism Study shows that the point mutation of (EGFR) C797S turns 797 cysteines Become serine, causes Osimertinib that can not form covalent bond with target protein, finally cause drug resistance.It is clinical at present still to lack It is weary to be directed to the effective EGFR inhibitor of new mutation (C797S) independent medication.Therefore, there is an urgent need to new types, highly selective EGFR inhibitor is come the problems such as solving drug resistance caused by (EGFR) C797S point mutation.

Summary of the invention

Based on this, the present invention provides a kind of 2- amino-metadiazine compound, such compound can effectively inhibit EGFR Protein kinase drug resistant mutants (such as EGFR^T790MAnd EGFR^T790M/C797S) activity.

Specific technical solution is as follows:

2- amino-metadiazine compound or its pharmaceutically acceptable salt or its solid with structure shown in Formulas I are different Structure body or its prodrugs:

In formula:

D, E, F, W, X, Y, Z are separately selected from: CH or N；

R¹And R²It is separately selected from: H, halogen, cyano, trifluoromethyl, nitro, substituted or unsubstituted C₁-C₆Alkane Base, substituted or unsubstituted C₃-C₆Naphthenic base, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkanes Oxygroup；

R³It is selected from: hydrogen, halogen, cyano, trifluoromethyl, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃- C₆Naphthenic base, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyloxy；

R⁴It is selected from: substituted or unsubstituted pyrazolyl ,-(CH₂)_mNR⁶R⁷、-(CH₂)_mOCR⁵R⁶R⁷、-(CH₂)_mCR⁵R⁶R⁷；

Wherein, m is selected from: 0,1,2,3 or 4；

R⁵It is selected from: hydrogen or C₁-C₃Alkyl；

R⁶And R⁷It is separately selected from: hydrogen, substituted or unsubstituted C₁-C₆Alkyl or R⁶、R⁷With the N or C being connected It is formed together substituted or unsubstituted containing heteroatomic monocycle or condensed ring.

In wherein some embodiments, R⁴It is selected from: R⁸Substituted pyrazolyl ,-(CH₂)_mNR⁶R⁷、-(CH₂)_mOCR⁵R⁶R⁷、 - (CH₂)_mCR⁵R⁶R⁷；Wherein, m is selected from: 0,1,2,3 or 4；

R⁵It is selected from: hydrogen or C₁-C₃Alkyl；

R⁶And R⁷It is separately selected from: hydrogen, R⁸Substituted C₁-C₆Alkyl or R⁶、R⁷It is formed together with the N or C being connected R⁸What is replaced contains n heteroatomic 3-8 unit monocycles or R⁶、R⁷R is formed together with the N or C being connected⁸What is replaced contains n miscellaneous originals 8-12 member condensed ring, loop coil or bridged ring, the n of son are selected from: 1,2 or 3, hetero atom is selected from: O, N, S；

R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, halogen, hydroxyl, amino, C₁-C₃Alkyl ,-C (=O) NHR⁹Replace C₁-C₃The C that alkyl, hydroxyl replace₁-C₃Alkyl, C₃-C₆The C that naphthenic base replaces₁-C₃Alkyl, C₃-C₈The C that heterocycle replaces₁-C₃Alkane Base, C₁-C₃Alkoxy ,-NHR⁹、-N(R⁹)₂,-C (=O) R⁹；R⁹For C₁-C₃Alkyl.

In wherein some embodiments, R⁴It is selected from :-(CH₂)_mNR⁶R⁷；M is selected from: 0 or 1；

R⁶And R⁷It is separately selected from: hydrogen, R⁸Substituted C₁-C₆Alkyl or R⁶、R⁷R is formed together with the N being connected⁸ What is replaced contains n heteroatomic 3-8 unit monocycles or R⁶、R⁷R is formed together with the N being connected⁸What is replaced contains n heteroatomic 8- 12 yuan of condensed ring, loop coil or bridged ring, wherein n is selected from: 1,2 or 3, hetero atom is selected from: O, N, S；

R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, halogen, hydroxyl, amino, C₁-C₃Alkyl, C₁-C₃Alkoxy ,- NHR⁹、 -N(R⁹)₂,-C (=O) R⁹；R⁹For C₁-C₃Alkyl.

In wherein some embodiments, R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, C₁-C₃Alkyl ,-NHR⁹、-N (R⁹)₂； R⁹For C₁-C₃Alkyl.

In wherein some embodiments, R⁴It is selected from:

In wherein some embodiments, F is selected from: CH or N；D, E, W, X, Y, Z are CH.

In wherein some embodiments, R¹And R²It is separately selected from: H, halogen, cyano, trifluoromethyl, nitro, C₁- C₆Alkyl, C₃-C₆Naphthenic base, C₁-C₆Alkoxy, C₃-C₆The C that cycloalkyloxy, halogen replace₁-C₆The C that alkyl, halogen replace₁-C₆ Alkoxy.

In wherein some embodiments, R¹It is selected from: halogen, methyl, cyano, trifluoromethyl, difluoromethyl, methoxyl group, ring Propyl, trifluoromethoxy.

In wherein some embodiments, R²It is selected from: halogen, C₁-C₆Alkyl, fluorine-substituted C₁-C₆Alkyl, C₃-C₆Naphthenic base, Fluorine-substituted C₃-C₆Naphthenic base, C₁-C₆Alkoxy, fluorine-substituted C₁-C₆Alkoxy.

In wherein some embodiments, R²It is selected from: fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, trifluoromethyl, difluoro first Base, trifluoromethoxy, cyclopropyl, isopropyl, n-propyl.

In wherein some embodiments, R³It is selected from: hydrogen, halogen, cyano, trifluoromethyl, nitro, C₁-C₆Alkyl, C₃-C₆Ring Alkyl, C₁-C₆Alkoxy, C₃-C₆The C that cycloalkyloxy, halogen replace₁-C₆The C that alkyl, halogen replace₁-C₆Alkoxy.

In wherein some embodiments, R³Be selected from: hydrogen, fluorine, chlorine, methyl, ethyl, cyano, trifluoromethyl, difluoromethyl, Methoxyl group, cyclopropyl, trifluoromethoxy.

In wherein some embodiments, the 2- amino-metadiazine compound is selected from:

(((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- trifluoromethyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- aminomethyl phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3aR, 6aS) -5- methyl hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) Phenyl) amino) pyrimidine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methyl-1,4- phenodiazine heptane -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(((the chloro- 2- of 5- ((3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (9- methyl -3,9- phenodiazine spiral shell [5.5] hendecane -3- base) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(((the chloro- 2- of 5- ((3- methyl -4- (7- methyl -2,7- phenodiazine spiral shell [3.5] nonane -2- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(S)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(R)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- ((2- (dimethylamino) ethyl) (methyl) amino) -6- picoline -2- base) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3R, 5S) -3,4,5- tri methyl piperazine -1- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((1- (2- (diethylamino) ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (oxetanes -3- base) piperazine -1- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- (piperazine -1- ylmethyl) pyridine -2- base) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphorus；

(2- ((the chloro- 2- of 5- ((3- methoxyl group -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- ethyl piperazidine -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((2- ((the bromo- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) -5- chlorine pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((2- ((the bromo- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- chlorine pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((6- methyl -5- (4- methylpiperazine-1-yl) pyridine 2- yl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((5- chlorine 2- ((3- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl Phosphorous oxide；

(2- ((the chloro- 2- of 5- ((4- (4- (dimethylamino) piperidin-1-yl) -3- aminomethyl phenyl) amino) pyrimidine 4- yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- methylpiperazine-1-yl) -3- trifluoromethyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the fluoro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- morpholino phenyl of 3-) amino) pyrimidine-4-yl) amino) phenyl) dimethyl Phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- base) Phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

1- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) benzene Base) piperazine -1- base) ethyl -1- ketone；

2- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) benzene Base) piperazine -1- base)-N- methylacetamide；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (2- ethoxy) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- hydroxy piperidine -1- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) heterocyclic butane -1- base) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (cyclopropyl alkyl methyl) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- Base) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- morpholinyl piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methyl-1,4- diaza heptane -1- base) piperidin-1-yl) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (piperidin-1-yl) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(((2- ((4- (4- (azetidine -1- ylmethyl) piperidin-1-yl) -3- chlorphenyl) amino) -5- chlorine is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((2- ((4- ([bis- piperidines of 1,4'-] -1'- base) -3- chlorphenyl) amino) -5- chlorine pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- chlorine 4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methylpyrrolidin- 3- yl) oxygroup) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methyl piperidine -4- base) oxygroup) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (1- (piperidin-4-yl) -1H- pyrazoles -4- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the bromo- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -4- ((2- (solutions of dimethyl phosphoryl Base) phenyl) amino) pyrimidine -5- formonitrile HCN；

(((the chloro- 2- of 5- ((3- cyclopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(((the chloro- 2- of 5- ((3- difluoromethyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- ethyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(((the chloro- 2- of 5- ((3- isopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- propyl phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridin-3-yl) dimethyl phosphorus；

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridin-4-yl) dimethyl phosphorus；

(4- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -3- Base) amino) pyridin-4-yl) dimethyl phosphorus；

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridine -2- base) dimethyl phosphorus.

The present invention also provides 2- amino-metadiazine compound or its pharmaceutically acceptable salt or its alloisomerisms The application of body or its prodrugs.

Specific technical solution is as follows:

Above-mentioned 2- amino-metadiazine compound or its pharmaceutically acceptable salt or its stereoisomer or its Prodrugs are preparing the application in mutant egf R inhibitor.

Above-mentioned 2- amino-metadiazine compound or its pharmaceutically acceptable salt or its stereoisomer or its Application of the prodrugs in the drug for preparing anti-curing oncoma.

In wherein some embodiments, the tumour is the malignant tumour of EGFR genetic mutation.

In wherein some embodiments, the tumour is EGFR^{L858R/T790M/C797S}The malignant tumour of mutation.

In wherein some embodiments, the tumour are as follows: non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, Cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, leukaemia, histiocytic leaching Bar cancer, nasopharyngeal carcinoma, head and neck neoplasm, colon and rectum carcinoma or glioma.

The present invention also provides a kind of pharmaceutical compositions of anti-curing oncoma.

Specific technical solution is as follows:

A kind of pharmaceutical composition of anti-curing oncoma, including active constituent and pharmaceutically acceptable carrier, the activity Ingredient include above-mentioned 2- amino-metadiazine compound or its pharmaceutically acceptable salt or its stereoisomer or Its prodrugs.

2- amino-metadiazine compound or its pharmaceutically acceptable salt of the invention or its stereoisomer or Its prodrugs can generate inhibiting effect to EGFR family protein enzyme, so as to inhibit the growth of kinds of tumor cells.It is right Than wild type cancer cell, the compound of the present invention is to saltant type cancer cell selectivity with higher.The compound of the present invention is outstanding It can effectively inhibit EGFR protein kinase drug resistant mutants (such as EGFR^T790MAnd EGFR^T790M/C797S) activity, can select Property acts on EGFR^L858R/T790M、EGFR^DelE745_A750And EGFR^{L858R/T790MC797S}Lung carcinoma cell can overcome existing third Generation selectivity EGFR^T790MMicromolecular inhibitor Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) clinical drug-resistant of the tumour patients such as non-small cell lung cancer of inductions such as.

The compound of the present invention can be used for preparing anti-tumor drug, and existing drug Gefitinib, Lip river in distress can be overcome to replace The drug resistance of the inductions such as Buddhist nun, especially Osimertinib (AZD9291), which is that one kind is novel, can overcome existing EGFR tyrosine Kinase inhibitor it is drug resistant and have selectivity and good medicine for property kinases inhibitor, can be used for treating the mankind and its The excess proliferative diseases such as the tumour of its mammal.

Detailed description of the invention

Fig. 1 is part of compounds of the invention to containing EGFR^{L858R/T790M/C797S}The BaF3EGFR of mutation^{L858R/T790M/C797S} The inhibiting effect test result of kinases in vehicles cells.

Fig. 2 is part of compounds of the invention to containing EGFR^{19D/T790M/C797S}The BaF3EGFR of mutation^{19D/T790M/C797S}Tool The inhibiting effect test result of kinases in cell.

Specific embodiment

In compound of the present invention, as any variable (such as R⁶、R⁷Deng) occur more than in any component it is primary, then Its definition occurred every time is independently of other definition occurred every time.Equally, the combination for allowing substituent group and variable, as long as this Combination stablizes compound.The line for being divided into loop system from substituent group indicates that signified key may be connected to any annular atom that can replace On.If loop system be it is polycyclic, it means that this key is connected only on any carbon atom appropriate of adjacent loops.It is appreciated that this Field those of ordinary skill may be selected the substituent group of the compounds of this invention and replace form and provide chemically stable and can lead to The compound that the method for crossing art technology and following proposition is readily synthesized from readily available raw material.If substituent group is certainly Body is exceeded a group and replaces, it should be understood that these groups can be in identical carbon atoms or on different carbon atoms, as long as making structure Stablize.Phrase " being replaced by substituent group selected from the group below " is considered with phrase " being replaced by least one substituent group " quite, and Preferred embodiment will have 1-4 substituent group in the case of this.

Terms used herein " alkyl " mean include have particular carbon atom number branch and straight chain saturated fat Alkyl.For example, " C₁-C₆" C in alkyl "₁-C₆" definition include with linear chain or branched chain arrangement have 1,2,3,4,5 or 6 carbon The group of atom.For example, " C₁-C₆Alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, isobutyl Base, amyl, hexyl.Term " naphthenic base " refers to the monocycle saturated fat alkyl with particular carbon atom number.Such as " naphthenic base " Including cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl etc..Term " alkoxy " refers to the group with-O- alkyl structure, as- OCH₃、 -OCH₂CH₃、-OCH₂CH₂CH₃、-O-CH₂CH(CH₃)₂、-OCH₂CH₂CH₂CH₃、-O-CH(CH₃)₂Deng.

As will be appreciated by a person skilled in the art, " halogen " used herein (" halo ") or " halogen " mean chlorine, fluorine, bromine And iodine.

The present invention provides a kind of compound of formula I, pharmaceutically acceptable salt or its stereoisomer or its prodrugs,

Wherein, R¹、R²、R³、R⁴It is as defined above with D, E, F, W, X, Y, Z.

The present invention includes the free form of compound of formula I, also includes its pharmaceutically acceptable salt and stereoisomer.This Some specific exemplary compounds are the salt of the protonation of aminated compounds in text.Term " free form " refers to salt-independent shape Aminated compounds.The pharmaceutically-acceptable salts being included not only include the exemplary salt of specific compound described herein, Typical pharmaceutically acceptable salt including all compound of formula I free forms.Techniques known in the art can be used to separate institute State the free form of compound specific salts.For example, can be by with alkali dilute aqueous solution appropriate such as NaOH dilute aqueous solution, potassium carbonate Dilute aqueous solution, weak aqua ammonia and sodium bicarbonate dilute aqueous solution, which handle the salt, regenerates free form.Free form is certain physical Matter for example in polar solvent respectively more or less distinguish with its in solubility by salt form, but is this hydrochlorate of purpose of invention And respectively free form is suitable with its in terms of other pharmacy for alkali salt.

It can be synthesized by conventional chemical processes from the compounds of this invention containing alkaline part or acidic moiety of the invention Pharmaceutically acceptable salt.In general, by ion-exchange chromatography or passing through free alkali and stoichiometric amount or excessive required salt The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of form prepares the salt of alkali compounds.Similar, The salt of acid compound is formed by reacting with appropriate inorganic or organic base.

Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkaline the compounds of this invention and inorganic or have Machine acid reacts the conventional non-toxic salts for the compounds of this invention to be formed.For example, conventional nontoxic salts include deriving from inorganic acid such as salt The salt of acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc. also includes from organic acid such as acetic acid, propionic acid, succinic acid, second Alkyd, 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, p-aminobenzene sulfonic acid, one benzoic acid of 2- acetoxyl group, fumaric acid, toluenesulfonic acid, methanesulfonic acid, The salt of the preparations such as ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.

If the compounds of this invention be it is acid, " pharmaceutically acceptable salt " appropriate refers to by pharmaceutically acceptable Nontoxic alkali include inorganic base and organic base preparation salt derive from inorganic base salt include aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali includes the salt of primary amine, secondary amine and tertiary amine, substituted Amine include naturally occurring substitution amine, cyclic amine and deacidite for example arginine, glycine betaine, caffeine, choline, N, N'- dibenzyl-ethylenediamin, diethylamine, 2- DEAE diethylaminoethanol, 2-dimethylaminoethanol, ethylaminoethanol, ethanol amine, second Diamines, N-ethylmorpholine, N-ethylpiperidine, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, Methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, triethylamine, trimethylamine, Tripropyl amine (TPA), tromethamine etc..

Berg etc., " Pharmaceutical Salts " J.Pharm.Sci. ' 1977:66:1-19 are described in more detail The preparation of the literary pharmaceutically acceptable salt and other typical pharmaceutically acceptable salts.

Since the acidic moiety such as carboxyl of deprotonation in compound in physiological conditions can be anion, and it is this The charge having then can be by the internal protonated or alkylated alkaline part such as quaternary nitrogen atom with cation Balance is offset, it is noted that the compounds of this invention is potential inner salt or amphoteric ion.

Except known in the literature or in addition to the standard method of illustration, can be used in following specific embodiment in experimental arrangement The reaction that listed scheme is shown prepares the compounds of this invention.Therefore, following illustrative approach is the purpose to illustrate rather than office It is limited to listed compound or any specific substituent group.The substituent group number shown in scheme not necessarily meets in claim Number used, and for clarity, showing monosubstituted base to be connected under the hereinbefore definition of Formulas I allows to have multi-substituent On compound.

Compound and its pharmaceutically acceptable salt provided by the invention with Formulas I structure can be used for treating people or other The transition such as mammal tumor proliferative diseases or symptom.In particular for treating or controlling non-small cell lung cancer, cellule lung It is cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, white The transition proliferative diseases such as blood disease, histiocytic lymph cancer, nasopharyngeal carcinoma, head and neck neoplasm, colon and rectum carcinoma, glioma.

Drug metabolite and prodrug: the metabolite of compound and its pharmaceutically acceptable salt according to the present invention, And the prodrug of the structure of compound according to the present invention and its pharmaceutically acceptable salt can be changed into vivo, also include In claims hereof.

Pharmaceutical composition: the present invention also provides a kind of pharmaceutical compositions, it includes the activity within the scope of safe and effective amount Ingredient and pharmaceutically acceptable carrier." active constituent " of the present invention refers to compound of formula I of the present invention.

" active constituent " of the present invention and pharmaceutical composition can be used as EGFR protease inhibitors.In another preference In, it is used to prepare prevention and/or treats the drug of tumour.

" safe and effective amount " refers to: the amount of active constituent is enough to be obviously improved the state of an illness, and is unlikely to generate serious pair Effect.In general, pharmaceutical composition contains 1-2000mg active constituent/agent, more preferably, contain 10-200mg active constituent/agent.Compared with Goodly, it is described it is " one " be a tablet.

" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity.

In " compatibility " referred to herein as composition each component energy and active constituent of the invention and they between mutually Blending, and significantly reduce the drug effect of active constituent.

Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl Sodium cellulosate, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, plant Oily (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsification Agent (such as tween), wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, Apirogen water etc..

In another preferred example, formula Compound I can be acted on macromolecular compound or macromolecule by nonbonding Form compound.In another preferred example, formula Compound I can also pass through chemical bond and macromolecular chemical combination as small molecule Object or macromolecule are connected.The macromolecular compound can be large biological molecule such as high glycan, albumen, nucleic acid, polypeptide etc..

The method of application of active constituent or pharmaceutical composition of the invention is not particularly limited, representative method of application packet Include (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) etc..

Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.

In these solid dosage forms, active constituent is mixed at least one conventional inert excipients (or carrier), such as lemon Sour sodium or Dicalcium Phosphate, or mixed with following compositions:

(a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；

(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arab Glue；

(c) moisturizer, for example, glycerol；

(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；

(e) retarding solvent, such as paraffin；

(f) absorbsion accelerator, for example, quaternary ammonium compound；

(g) wetting agent, such as cetanol and glycerin monostearate；

(h) adsorbent, for example, kaolin；With

(i) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate, or Its mixture.In capsule, tablet and pill, dosage form also may include buffer.

Coating and shell material preparation also can be used in the solid dosage forms, such as casing and other materials well known in the art.It May include opacifying agent, also, in this composition active constituent release can in a delayed fashion it is in the digestive tract certain It is discharged in a part.The example of adoptable embedding component is polymeric material and wax material.

Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. Other than active constituent, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, solubilising Agent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide And oil, the especially mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweetener, rectify Taste agent and fragrance.

Other than active constituent, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene mountain The pure and mild Isosorbide Dinitrate of pears, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..

Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.

The compounds of this invention can be administered alone, or be administered in combination with other treatment drug (such as antidiabetic drug).

It is that the compounds of this invention of safe and effective amount is applied to mammal in need for the treatment of when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000mg, preferably 20~500mg.Certainly, specific dosage is also contemplated that administration route, patient health situation etc. Factor, within the scope of these are all skilled practitioners technical ability.

Drug combination: compound of formula I can be combined to the known other medicines for treating or improving similar symptom.Combine to When medicine, originally the administration mode of drug and dosage are remained unchanged, and subsequently or simultaneously take compound of formula I.When compound of formula I with Other one or more drugs are simultaneously, it is preferable to use simultaneously containing one or more of known drugs and compound of formula I when taking Pharmaceutical composition.The period that drug combination is also included within overlapping takes compound of formula I and other one or more of known drugs. When Formulas I compound and other one or more of drugs carry out drug combination, the dosage of compound of formula I or known drug may Dosage when than their independent medications is lower.

The drug of drug combination can be carried out with compound of formula I or active constituent includes but is not limited to:

Estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cell suppression Preparation, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase Inhibitor, angiogenesis inhibitors, cell Proliferation and survival signaling inhibitor interfere the drug of cell cycle chechpoint and cell to wither Die inducer, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine egg White inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, Topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family egg White inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT inhibitor, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF are anti- Body, EGF antibody etc..

In one embodiment, the drug of drug combination can be carried out with compound of formula I or active constituent includes but not Limitation are as follows: Aldesleukin, alendronic acid, interferon, Ah Qu Nuoying, Allopurinol, allopurinol sodium, palonosetron hydrochloride, Hemel, amino glutethimide, Amifostine, Amrubicin, amphidine, arimidex, Dolasetron, aranesp, Arglabin, arsenic trioxide, A Nuoxin, U-18496, imuran, BCG vaccine or tice BCG vaccine, bestatin, acetic acid times Ta meter Song, betamethasone sodium phosphate preparation, bexarotene, Bleomycin Sulphate, broxuridine, bortezomib, busulfan, drop calcium Element, A Laizuo monoclonal antibody injection, capecitabine, carboplatin, Kang Shi get, cefesone, Celmoleukin, daunorubicin, benzenebutanoic acid Mustargen, cis-platinum, Cladribine, Cladribine, chlorine bend phosphoric acid, cyclophosphamide, arabinose born of the same parents' former times, Dacarbazine, actinomycin D, soft Erythromycin liposome, dexamethasone, dexamethasone phosphate, Estradiol Valerate, denileukin diftitox, Di Bomei, Deslorelin, La Zuosheng, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, adriamycin, Dronabinol, -166- chitosan of admiring are compound Object, eligard, rasburicase, epirubicin hydrochloride, aprepitant, Epi-ADM, Epoetin Alfa, erythropoietin(EPO), according to Platinum, Ergamisole, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinyloestradiol, Amifostine, hydroxyl phosphoric acid, it is all finish Again, etoposide, Fadrozole, tamoxifen preparation, Filgrastim, Tamsulosin, Fei Leisi are replaced, floxuridine, Fluconazole, fluorine reach Draw shore, 5- fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, Flutamide, formestane, 1- β-D- Ah Sugared furanose born of the same parents thialdine -5 '-stearoyl phosphate, Fotemustine, fulvestrant, gamma globulin, gemcitabine, lucky appropriate list Anti-, imatinib mesylate, Gliadel, Goserelin, Graniseeron Hydrochloride, Histrelin, He Meixin, Hydrocortisone, erythro-hydroxynonyl adenine, replace smooth different shellfish Mo Dankang, idarubicin, ifosfamide, interference at hydroxycarbamide Plain α, interferon-' alpha ' 2, interferon α-2 A, interferon α-2 B, Interferon α-nl, Alferon N, interferon beta, interferon gamma- La, interleukin 2, intron A, Iressa, Irinotecan, Kytril, sulfuric acid lentinan, Letrozole, Calcium Folinate-SF leaf Acid, Leuprorelin, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, Levothyroxine Preparation of sodium, lomustine, Lonidamine, Dronabinol, mustargen, Mecobalamin, medroxyprogesterone acetate, megestrol acetate, beauty Method logical sequence, esterified estriol, 6- coloured glaze base purine, mesna, amethopterin, amino-laevulic acid methyl esters, Miltefosine, happiness are mould Element, mitomycin C, mitotane, rice support green onion quinone, Trilostane, citric acid Evacet, Nedaplatin, Pegylation are non- Geseting, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11- β, Octreotide, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, prednisone sodium phosphate system Agent, Pegaspargase, PEG-IFN alpha-2a, Pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin it is soft than star, plicamycin, porphines nurse Sodium, prednimustine, Prednisolone Steaglate, prednisone, premarin, the third kappa navel, epoetin, thunder are for song Plug, Libiee, Etidronic Acid rhenium -186, Mabthera, Redoxon-A, Romurtide, Salagen, Octreotide, Sha Mo Department's pavilion, sizofiran, Sobuzoxane, bluffs sodium methylprednisolone, Paphos acid, stem-cell therapy, streptozotocin, strontium chloride-at Semustine 89, levoid, tamoxifen, tansulosin, Ta Suonaming, tastolactone, taxotere, teceleukin, replace Muzolimine, Teniposide, testosterone propionate, methyltestosterone, thioguanine, thio-tepa, thyrotropic hormone, Tiludronic Acid, topology are replaced Health, Toremifene, tositumomab, Herceptin, Treosulfan, Tretinoin, methopterin tablet, trimethyl melamine, front three Qu Sha, acetic acid Triptorelin, triptorelin pamoate, excellent fudding, uridine, valrubicin, Vesnarinone, vincaleukoblastinum, Changchun New alkali, Vindesine, vinorelbine, virulizin, dextropine imine, Zinostatin stimalamer, ondansetron, Taxol-protein are steady Customization agent, acolbifene, interferon r-lb, affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, atamestane, Atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, crisnatol, cyclopropyl Progesterone acetate, Decitabine, DN-101, adriamycin-MTC, dSLIM, dutasteride, edotecarin, Eflornithine, according to Health, Suwei A amine, histamine dihydrochloric acid, Histrelin hydrogel implant, holmium -166DOTMP, ibandronic acid, interferon are replaced in happiness γ, introne-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanreotide, lasofoxifene, libra, Lonafamib, Miproxifene, minot bend acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, new It cuts down and takes charge of he, Nola Qu Te, oblimersen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, QS- 21, overstate the West, R-1549, Raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, Docosahexaenoic acid taxol, extrasin alpha l, loud, high-pitched sound azoles furan woods, tipifarnib, Tirapazamine, TLK-286, Toremifene, Trans- MID-lo7R, valspodar, Vapreotide, vatalanib, Verteporfin, vinflunine, Z-100 and azoles come unicorn acid or it Combination.

The invention has the beneficial effects that:

(1) a kind of 2- amino-metadiazine compound of structure novel is provided.

(2) such compound can effectively inhibit the effect of EGFR protein kinase drug resistant mutants, can be used for preparing anti-swollen Tumor medicine.

(3) such compound can overcome existing drug Gefitinib, Tarceva especially Osimertinib (AZD9291) etc. the drug resistance of inductions has selectivity to Wild type EGFR, has good pharmacokinetic property.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and Number is calculated by weight.

Unless otherwise defined, all professional and scientific terms as used herein and meaning familiar to those skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong The preferred implement methods and materials are for illustrative purposes only.

Embodiment 1

(((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- trifluoromethyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus (LS2-31)

Synthetic route is as follows:

The preparation of step 1. (2- aminophenyl) dimethyl phosphorus (2)

By adjacent Iodoaniline (1,5.06g, 23mmol), dimethyl phosphorus (2.20g, 27.2mmol), palladium acetate (0.26g, 1.2 mmol), the bis- diphenylphosphine -9,9- xanthphos (0.67g, 1.2mmol) of 4,5- and potassium phosphate (5.40g, It 25.4mmol) is dissolved in 50 milliliters of n,N-Dimethylformamide solvents, argon gas protection, overnight in 120 degrees Celsius of reactions.To anti- Should completely, decompression is spin-dried for most of solvent, three times with methylene chloride/water extraction, merges organic layer, organic layer saturated salt solution It washes, then is spin-dried for after being dried with anhydrous sodium sulfate, obtain solid 3.2g, yield 82% through column chromatography for separation.

¹H NMR(400MHz,DMSO-d₆)δ7.26-7.13(m,2H),6.68-6.61(m,1H),6.59-6.52(m, 1H), 6.14 (s, 2H), 1.64 (d, J=13.2Hz, 6H)

MS(ESI):m/z 170[M+H]⁺.

The preparation of step 2. (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphorus (3)

By 2,4,5- trichloropyrimidine (2.70g, 14.6mmol), (2- aminophenyl) dimethyl phosphorus (2,2.47g, 14.6mmol), potassium carbonate (2.42g, 17.5mmol), tetra-n-butyl ammonium sulfate (0.5g, 1.46mmol) are dissolved in 20 milliliters of N, N- In solvent dimethylformamide, overnight in 65 degrees Celsius of reactions.It three times with methylene chloride/water extraction is associated with to fully reacting Machine layer, organic layer are washed with saturated common salt, then are spin-dried for after being dried with anhydrous sodium sulfate, obtain solid 3.8g through column chromatography for separation, are received Rate 84%.

¹H NMR(400MHz,DMSO-d₆) δ 11.83 (s, 1H), 8.46 (s, 1H), 8.43 (dd, J=8.3Hz, 4.2Hz, 1H), 7.71-7.56(m,2H),7.31-7.21(m,1H),1.83(s,3H),1.80(s,3H).

MS(ESI):m/z 316[M+H]⁺.

The preparation of step 3.1- methyl -4- (1- (4- nitro -2- benzotrifluoride) piperidin-4-yl) piperazine (5)

By 2- fluoro-5-nitro trifluor toluene (0.5g, 2.4mmol), 1- methyl -4- (piperidin-4-yl) piperazine hydrochloride (0.64g, 2.87 mmol), potassium carbonate (0.67g, 4.8mmol) are dissolved in 15 milliliters of acetonitrile solvents, are heated to 80 degrees Celsius instead It should stay overnight.Three times with methylene chloride/water extraction merge organic layer, organic layer is washed with saturated common salt, then is used to fully reacting It is spin-dried for after anhydrous sodium sulfate is dry, obtains solid 0.84g, yield 93% through column chromatography for separation.

¹H NMR(400MHz,DMSO-d₆) δ 8.41-8.32 (m, 2H), 7.49 (d, J=8.7Hz, 1H), 3.35 (s, 2H), 2.93 (s, 2H), 2.53-2.17 (m, 9H), 2.14 (s, 3H), 1.87 (d, J=11.4Hz, 2H), 1.62-1.44 (m, 2H)

MS(ESI):m/z 373[M+H]⁺.

The preparation of step 4.4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- (trifluoromethyl) aniline (6)

To the first of 1- methyl -4- (1- (4- nitro -2- benzotrifluoride) piperidin-4-yl) piperazine (5,0.84g, 2.23mmol) 10% palladium carbon of catalytic amount is added in alcohol, tetrahydrofuran mixed solvent (each 10 milliliters), reacts at room temperature 3 hours under an atmosphere of hydrogen. To fully reacting, suction filtered through kieselguhr is spin-dried for, and obtains solid 0.72g, yield 95% through column chromatography for separation.

¹H NMR(400MHz,DMSO-d₆) δ 7.19 (d, J=8.5Hz, 1H), 6.80 (d, J=2.6Hz, 1H), 6.78- (6.69 m, 1H), 5.31 (s, 2H), 2.81 (d, J=11.3Hz, 2H), 2.64 (t, J=10.8Hz, 2H), 2.55-2.40 (m, 4H), 2.40-2.16 (m, 5H), 2.14 (s, 3H), 1.76 (d, J=11.0Hz, 2H), 1.52-1.41 (m, 2H)

MS(ESI):m/z 343[M+H]⁺.

Step 5. (2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- trifluoromethyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus (LS2-31) preparation

Into 15 milliliters of tube sealings be added (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphorus (3, 0.1g, 0.32 mmol), 4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- (trifluoromethyl) aniline (6,0.1g, 0.29mmol), the ethanol solution and 3 milliliters of glycol monoethyl ethers of 0.3 milliliter of 2.5M HCl, is heated to 120 degrees Celsius and reacted Night.To fully reacting, after being spin-dried for most of solvent, three times with methylene chloride/water extraction, merge organic layer, organic layer saturation Salt washing, then be spin-dried for after being dried with anhydrous sodium sulfate, solid 0.12g, yield 71% are obtained through column chromatography for separation.

¹H NMR(400MHz,CDCl₃)δ10.96(s,1H),8.53(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.10 (s, 1H), 7.75 (d, J=2.5Hz, 1H), 7.67 (dd, J₁=8.6Hz, J₂=2.4Hz, 1H), 7.45 (t, J=7.9Hz, 1H), 7.33-7.27 (m, 2H), 7.16-7.08 (m, 1H), 6.96 (s, 1H), 3.07 (d, J=11.4Hz, 2H), 2.86- 2.31(m,11H), 2.30(s,3H),1.98-1.87(m,2H),1.85(s,3H),1.82(s,3H),1.78-1.70(m, 2H).

MS(ESI):m/z 622[M+H]⁺.

Embodiment 2

(2- ((the chloro- 2- of 5- ((5- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus (LS2-39)

Synthetic method is referring to embodiment 1, yield 67%.

¹H NMR(400MHz,CDCl₃) δ 8.45-8.35 (m, 1H), 8.18 (d, J=2.5Hz, 1H), 8.08 (s, 1H), 7.84 (d, J=2.5Hz, 1H), 7.62 (ddd, J₁=14.1Hz, J₂=7.7Hz, J₃=1.4Hz, 1H), 7.54 (t, J= 7.9Hz, 1H), 7.32-7.20 (m, 1H), 3.39 (d, J=12.4Hz, 2H), 3.09-2.65 (m, 9H), 2.64-2.32 (m, 5H),2.22(s,3H), 2.08-1.93(m,2H),1.87(s,3H),1.83(s,3H),1.76-1.65(m,2H).

MS(ESI):m/z 569[M+H]⁺.

Embodiment 3

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus (LS2-40)

Synthetic method is referring to embodiment 1, yield 58%.

¹H NMR(400MHz,CDCl₃)δ10.94(s,1H),8.58(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.08 (s, 1H), 7.76 (d, J=2.5Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 7.33-7.28 (m, 1H), 7.21 (dd, J₁= 8.6Hz,J₂=2.5Hz, 1H), 7.16-7.08 (m, 1H), 6.98 (d, J=8.7Hz, 1H), 6.84 (s, 1H), 3.40 (d, J =11.7Hz, 2H), 2.84-2.46 (m, 9H), 2.46-2.37 (s, 1H), 2.33 (s, 3H), 2.05-1.89 (m, 3H), 1.84 (d, J=13.1Hz, 6H), 1.81-1.73 (m, 2H)

MS(ESI):m/z 588[M+H]⁺.

Embodiment 4

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus (LS2-43)

Synthetic method is referring to embodiment 1, yield 61%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.62(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.44 (t, J=7.9Hz, 1H), 7.36-7.27 (m, 3H), 7.14-7.05 (m, 1H), 6.96 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 3.14 (d, J=11.9Hz, 2H), 2.86-2.38 (m, 10H), 2.37-2.29 (m, 4H), 2.27 (s, 3H), 2.00-1.90 (m, 2H), 1.83 (d, J=13.1Hz, 6H), 1.78-1.69 (m, 2H)

MS(ESI):m/z 568[M+H]⁺.

Embodiment 5

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus (LS2-71)

Synthetic method is referring to embodiment 1, yield 53%.

¹H NMR(400MHz,CDCl₃)δ10.90(s,1H),8.62(dd,J₁=8.0Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.48-7.39 (m, 1H), 7.37-7.26 (m, 3H), 7.15-7.06 (m, 1H), 7.01 (d, J=8.4Hz, 1H), 6.87 (s, 1H), 2.93 (t, J=4.7Hz, 4H), 2.78-2.44 (m, 4H), 2.37 (s, 3H), 2.28 (s, 3H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 485[M+H]⁺.

Embodiment 6

(2- ((the chloro- 2- of 5- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- aminomethyl phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus (LS2-73)

Synthetic method is referring to embodiment 1, yield 68%.

¹H NMR(400MHz,CDCl₃)δ10.88(s,1H),8.61(dd,J₁=8.0Hz, J₂=4.2Hz, 1H), 8.06 (s, 1H), 7.44 (t, J=7.6Hz, 1H), 7.38-7.20 (m, 3H), 7.18-7.05 (m, 2H), 7.01 (d, J=8.4Hz, 1H), 3.10 (t, J=6.8Hz, 2H), 2.73-2.53 (m, 5H), 2.37 (s, 6H), 2.26 (s, 3H), 1.82 (d, J= 12.4Hz,6H).

MS(ESI):m/z 487[M+H]⁺.

Embodiment 7

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3aR, 6aS) -5- methyl hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) Phenyl) amino) pyrimidine -4- base) amino) phenyl) dimethyl phosphorus (LS2-75)

Synthetic method is referring to embodiment 1, yield 56%.

¹H NMR(400MHz,CDCl₃)δ10.90(s,1H),8.63(dd,J₁=8.0Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.48-7.42 (m, 1H), 7.35-7.27 (m, 3H), 7.16-7.06 (m, 1H), 6.94 (d, J=8.4Hz, 1H), 6.77 (s, 1H), 3.13-2.78 (m, 8H), 2.45-2.22 (m, 8H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 511[M+H]⁺.

Embodiment 8

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methyl-1,4- phenodiazine heptane -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus (LS2-77)

Synthetic method is referring to embodiment 1, yield 47%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.63(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H),7.48-7.39(m,1H),7.33-7.26(m,3H),7.13-7.06(m,1H),7.07-6.98(m,1H),6.88 (s,1H), 3.23-3.10(m,4H),2.82-2.70(m,4H),2.43(s,3H),2.29(s,3H),2.02-1.95(m, 2H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 499[M+H]⁺.

Embodiment 9

(((the chloro- 2- of 5- ((3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus (LS2-80)

Synthetic method is referring to embodiment 1, yield 66%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.61(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.41 (t, J=7.8Hz, 1H), 7.32-7.22 (m, 1H), 7.13-6.96 (m, 4H), 6.87 (d, J=8.5Hz, 1H), 3.74 (s, 3H), 3.51 (t, J=16.4Hz, 2H), 2.73-2.35 (m, 10H), 2.33-2.08 (m, 5H), 1.90- 1.76(m,9H).

MS(ESI):m/z 584[M+H]⁺.

Embodiment 10

(2- ((the chloro- 2- of 5- ((4- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus (LS2-83)

Synthetic method is referring to embodiment 1, yield 68%.

MS(ESI):m/z 569[M+H]⁺.

Embodiment 11

(2- ((the chloro- 2- of 5- ((3- methyl -4- (9- methyl -3,9- phenodiazine spiral shell [5.5] hendecane -3- base) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus (LS2-86)

Synthetic method is referring to embodiment 1, yield 52%.

¹H NMR(400MHz,CDCl₃)δ10.88(s,1H),8.63(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.44 (t, J=7.8Hz, 1H), 7.35-7.21 (m, 3H), 7.15-7.06 (m, 1H), 6.98 (d, J=8.2Hz, 1H), 6.87 (s, 1H), 2.81 (t, J=5.2Hz, 4H), 2.52-2.36 (m, 4H), 2.27 (d, J=15.6Hz, 6H), 1.98-1.77(m,10H), 1.70-1.60(m,4H).

MS(ESI):m/z 553[M+H]⁺.

Embodiment 12

(((the chloro- 2- of 5- ((3- methyl -4- (7- methyl -2,7- phenodiazine spiral shell [3.5] nonane -2- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus (LS2-94)

Synthetic method is referring to embodiment 1, yield 60%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.64(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.04 (d, J=5.1Hz, 1H), 7.48-7.40 (m, 1H), 7.32-7.22 (m, 2H), 7.18 (dd, J₁=8.5Hz, J₂=2.4Hz, 1H),7.11 (td,J₁=7.5Hz, J₂=1.3Hz, 1H), 6.80 (s, 1H), 6.50 (d, J=8.4Hz, 1H), 3.99-3.76 (m, 5H), 3.52 (d, J=20.0Hz, 4H), 2.51-2.38 (m, 2H), 2.19 (s, 3H), 2.07-1.86 (m, 4H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 526[M+H]⁺.

Embodiment 13

(S)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus (LS2-95)

Synthetic method is referring to embodiment 1, yield 48%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.62(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.44 (t, J=7.2Hz, 1H), 7.36-7.21 (m, 3H), 7.14-7.04 (m, 1H), 6.99 (d, J=8.5Hz, 1H), 6.86 (s, 1H), 3.04-2.82 (m, 4H), 2.61-2.43 (m, 2H), 2.41-2.24 (m, 7H), 1.83 (d, J= 13.2Hz, 6H), 1.11 (d, J=6.4Hz, 3H)

MS(ESI):m/z 499[M+H]⁺.

Embodiment 14

(R)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus (LS2-96)

Synthetic method is referring to embodiment 1, yield 51%.

¹H NMR(400MHz,CDCl₃)δ10.90(s,1H),8.62(dd,J₁=8.2Hz, J₂=4.2Hz, 1H), 8.07 (s, 1H), 7.48-7.40 (m, 1H), 7.36-7.22 (m, 3H), 7.15-7.05 (m, 1H), 6.99 (d, J=8.4Hz, 1H), 6.83 (s, 1H), 3.06-2.80 (m, 4H), 2.60-2.42 (m, 2H), 2.42-2.16 (m, 7H), 1.83 (d, J=13.2Hz, 6H), 1.11 (d, J=6.4 Hz, 3H)

MS(ESI):m/z 499[M+H]⁺.

Embodiment 15

(2- ((the chloro- 2- of 5- ((5- ((2- (dimethylamino) ethyl) (methyl) amino) -6- picoline -2- base) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus (LS2-97)

Synthetic method is referring to embodiment 1, yield 55%.

¹H NMR(400MHz,CDCl₃) δ 10.99 (s, 1H), 8.61-8.46 (m, 1H), 8.02 (s, 1H), 7.53 (d, J= 8.8 Hz,1H),7.33-7.25(m,1H),7.21(dd,J₁=14.4Hz, J₂=7.6Hz, 1H), 7.03 (t, J=6.8Hz, 1H), 6.37 (s, 1H), 6.35 (s, 1H), 3.78-3.65 (m, 2H), 3.07 (s, 3H), 2.53 (t, J=7.2Hz, 2H), 2.35 (s, 3H), 2.33 (s, 6H), 1.82 (d, J=13.2Hz, 6H)

MS(ESI):m/z 488[M+H]⁺.

Embodiment 16

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3R, 5S) -3,4,5- tri methyl piperazine -1- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus (LS2-99)

Synthetic method is referring to embodiment 1, yield 46%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.62(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.48-7.40 (m, 1H), 7.36-7.23 (m, 3H), 7.17-7.04 (m, 1H), 6.96 (d, J=8.4Hz, 1H), 6.84(s,1H), 2.92(dd,J₁=8.7Hz, J₂=2.4Hz, 2H), 2.58 (t, J=10.4Hz, 2H), 2.49-2.38 (m, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.83 (d, J=13.2Hz, 6H), 1.14 (d, J=6.0Hz, 6H)

MS(ESI):m/z 513[M+H]⁺.

Embodiment 17

(2- ((the chloro- 2- of 5- ((1- (2- (diethylamino) ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus (LS2-100)

Synthetic method is referring to embodiment 1, yield 69%.

¹H NMR(400MHz,CDCl₃)δ10.81(s,1H),8.54(dd,J₁=7.6Hz, J₂=4.0Hz, 1H), 8.08 (s, 1H),7.76(s,1H),7.57-7.45(m,2H),7.34-7.27(m,1H),7.15-7.07(m,1H),6.66(s, 1H), 4.12 (t, J=6.8Hz, 2H), 2.87 (t, J=7.2Hz, 2H), 2.54 (q, J=7.2Hz, 4H), 1.83 (d, J= 13.2Hz, 6H), 0.99 (t, J=7.2Hz, 6H)

MS(ESI):m/z 462[M+H]⁺.

Embodiment 18

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (oxetanes -3- base) piperazine -1- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus (LS2-87)

Synthetic method is referring to embodiment 1, yield 40%.

¹H NMR(400MHz,CDCl₃)δ10.90(s,1H),8.61(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.44 (t, J=7.2Hz, 1H), 7.36 (dd, J₁=8.4Hz, J₂=2.4Hz, 1H), 7.33-7.22 (m, 2H), 7.18-7.05 (m,1H),6.98-6.87(m,2H),4.19(m,1H),4.00-3.83(m,2H),3.00-2.79(m,8H), 2.68 (s, 2H), 2.26 (s, 3H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 527[M+H]⁺.

Embodiment 19

(2- ((the chloro- 2- of 5- ((5- (piperazine -1- ylmethyl) pyridine -2- base) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphorus (LS2-101)

Synthetic method is referring to embodiment 1, yield 53%.

¹H NMR(400MHz,CDCl₃)δ10.74(s,1H),8.56(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.01 (s, 1H), 7.96 (d, J=2.0Hz, 1H), 7.54-7.41 (m, 2H), 7.32-7.21 (m, 2H), 7.13-7.02 (m, 1H), 6.50 (d, J=8.4Hz, 1H), 4.48 (s, 2H), 3.74 (t, J=5.2Hz, 4H), 2.47 (t, J=5.2Hz, 4H), 1.82 (d, J=13.2Hz, 6H)

MS(ESI):m/z 472[M+H]⁺.

Embodiment 20

(2- ((the chloro- 2- of 5- ((3- methoxyl group -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus (LS2-102)

Synthetic method is referring to embodiment 1, yield 66%.

¹H NMR(400MHz,CDCl₃)δ10.88(s,1H),8.60(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.06 (s, 1H), 7.39 (t, J=7.6Hz, 1H), 7.29-7.18 (m, 2H), 7.12-6.99 (m, 3H), 6.92-6.82 (m, 1H), 3.74 (s, 3H), 3.29-2.79 (m, 4H), 2.76-2.47 (m, 4H), 2.35 (s, 3H), 1.81 (d, J=13.2Hz, 6H)

MS(ESI):m/z 501[M+H]⁺.

Embodiment 21

(2- ((the chloro- 2- of 5- ((4- (4- ethyl piperazidine -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus (LS2-104)

Synthetic method is referring to embodiment 1, yield 70%.

¹H NMR(400MHz,CDCl₃)δ10.91(s,1H),8.63(dd,J₁=8.0Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H),7.46-7.40(m,1H),7.35(dd,J₁=8.4Hz, J₂=2.4Hz, 1H), 7.29 (d, J=2.9Hz, 1H), 7.28-7.22 (m, 1H), 7.15-7.05 (m, 1H), 7.01 (d, J=8.4Hz, 1H), 6.82 (s, 1H), 2.95 (t, J= 4.8Hz, 4H), 2.76-2.52 (m, 4H), 2.50 (q, J=7.2Hz, 2H), 2.29 (s, 3H), 1.83 (d, J=13.2Hz, 6H), 1.14 (t, J=7.2 Hz, 3H)

MS(ESI):m/z 499[M+H]⁺.

Embodiment 22

(2- ((2- ((the bromo- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) -5- chlorine pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus (LS2-106)

Synthetic method is referring to embodiment 1, yield 60%.

¹H NMR(400MHz,CDCl₃)δ10.85(s,1H),8.54(dd,J₁=8.0Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.87 (d, J=2.8Hz, 1H), 7.60-7.49 (m, 1H), 7.33 (dd, J₁=8.8Hz, J₂=2.4Hz, 1H), 7.31-7.23 (m,1H),7.17-7.07(m,1H),7.06-6.98(m,2H),3.04(s,4H),2.62(s,4H),2.37 (s, 3H), 1.83 (d, J=13.2Hz, 6H)

MS(ESI):m/z 549[M+H]⁺.

Embodiment 23

(2- ((2- ((the bromo- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- chlorine pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus (LS2-108)

Synthetic method is referring to embodiment 1, yield 55%.

¹H NMR(400MHz,CDCl₃)δ10.95(s,1H),8.58(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.08 (s, 1H), 7.89 (d, J=2.8Hz, 1H), 7.60-7.51 (m, 1H), 7.35-7.24 (m, 2H), 7.16-7.09 (m, 1H), 6.98 (d, J=8.4Hz, 1H), 6.85 (s, 1H), 3.37 (d, J=11.6Hz, 2H), 2.81-2.33 (m, 11H), 2.30 (s, 3H),1.98-1.88(m, 2H),1.87-1.73(m,8H).

MS(ESI):m/z 632[M+H]⁺.

Embodiment 24

(2- ((the chloro- 2- of 5- ((6- methyl -5- (4- methylpiperazine-1-yl) pyridine 2- yl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 486[M+H]⁺.

Embodiment 25

(2- ((5- chlorine 2- ((3- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl Phosphorous oxide

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 470[M+H]⁺.

Embodiment 26

(2- ((the chloro- 2- of 5- ((4- (4- (dimethylamino) piperidin-1-yl) -3- aminomethyl phenyl) amino) pyrimidine 4- yl) ammonia Base) phenyl) dimethyl phosphorus (LS2-116)

Synthetic method is referring to embodiment 1, yield 70%.

¹H NMR(400MHz,CDCl₃)δ10.89(s,1H),8.62(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.44 (t, J=8.4Hz, 1H), 7.34-7.22 (m, 3H), 7.14-7.07 (m, 1H), 6.99-6.90 (m, 2H), 3.15 (d, J=12.4Hz, 2H), 2.65 (t, J=10.4Hz, 2H), 2.49-2.44 (m, 1H), 2.42 (s, 6H), 2.27 (s, 3H), 2.04-1.91 (m, 2H), 1.83 (d, J=13.2Hz, 6H), 1.79-1.67 (m, 2H).

MS(ESI):m/z 513[M+H]⁺.

Embodiment 27

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus (LS2-114)

Synthetic method is referring to embodiment 1, yield 69%.

¹H NMR(400MHz,CDCl₃)δ10.92(s,1H),8.56(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.07 (s, 1H), 7.74 (d, J=2.8Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.33-7.18 (m, 3H), 7.15-7.06 (m, 1H), 7.00 (d, J=8.4Hz, 1H), 3.05 (s, 4H), 2.63 (s, 4H), 2.37 (s, 3H), 1.83 (d, J=13.2Hz, 6H)。

MS(ESI):m/z 505[M+H]⁺。

Embodiment 28

(2- ((the chloro- 2- of 5- ((4- (4- methylpiperazine-1-yl) -3- trifluoromethyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus (LS2-113)

Synthetic method is referring to embodiment 1, yield 73%.

¹H NMR(400MHz,CDCl₃)δ10.96(s,1H),8.52(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.11 (s, 1H), 7.77-7.69 (m, 2H), 7.45 (t, J=7.2Hz, 1H), 7.35 (d, J=9.6Hz, 1H), 7.32-7.25 (m, 1H), 7.16-7.09 (m, 1H), 7.05 (s, 1H), 2.94 (t, J=4.8Hz, 4H), 2.57 (s, 4H), 2.36 (s, 3H), 1.84 (d, J=13.2 Hz, 6H).

MS(ESI):m/z 539[M+H]⁺。

Embodiment 29

(2- ((the chloro- 2- of 5- ((the fluoro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus (LS2-70)

Synthetic method is referring to embodiment 1, yield 71%.

¹H NMR(400MHz,CDCl₃)δ10.90(s,1H),8.55(dd,J₁=8.4Hz, J₂=4.4Hz, 1H), 8.09 (s, 1H),7.58(dd,J₁=14.8Hz, J₂=2.8Hz, 1H), 7.52 (d, J=8.4Hz, 1H), 7.35-7.27 (m, 1H), 7.19-7.09 (m, 1H), 7.05-6.99 (m, 1H), 6.95 (s, 1H), 6.90 (t, J=8.8Hz, 1H), 3.14 (s, 4H), 2.72 (s, 4H), 2.43 (s, 3H), 1.83 (d, J=12.8Hz, 6H)

MS(ESI):m/z 489[M+H]⁺.

Embodiment 30

(2- ((the chloro- 2- of 5- ((the chloro- 4- morpholino phenyl of 3-) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 492[M+H]⁺.

Embodiment 31

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- base) Phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 517[M+H]⁺.

Embodiment 32

1- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) benzene Base) piperazine -1- base) ethyl -1- ketone

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 533[M+H]⁺.

Embodiment 33

2- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) benzene Base) piperazine -1- base)-N- methylacetamide

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 562[M+H]⁺.

Embodiment 34

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (2- ethoxy) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 535[M+H]⁺.

Embodiment 35

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 533[M+H]⁺.

Embodiment 36

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- hydroxy piperidine -1- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 506[M+H]⁺.

Embodiment 37

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 533[M+H]⁺.

Embodiment 38

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 519[M+H]⁺.

Embodiment 39

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) heterocyclic butane -1- base) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 505[M+H]⁺.

Embodiment 40

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 493[M+H]⁺.

Embodiment 41

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (cyclopropyl alkyl methyl) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 545[M+H]⁺.

Embodiment 42

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- Base) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 600[M+H]⁺.

Embodiment 43

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- morpholinyl piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 575[M+H]⁺.

Embodiment 44

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methyl-1,4- diaza heptane -1- base) piperidin-1-yl) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 602[M+H]⁺.

Embodiment 45

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (piperidin-1-yl) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 559[M+H]⁺.

Embodiment 46

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 559[M+H]⁺.

Embodiment 47

(((2- ((4- (4- (azetidine -1- ylmethyl) piperidin-1-yl) -3- chlorphenyl) amino) -5- chlorine is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 559[M+H]⁺.

Embodiment 48

(2- ((2- ((4- ([bis- piperidines of 1,4'-] -1'- base) -3- chlorphenyl) amino) -5- chlorine pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 573[M+H]⁺.

Embodiment 49

(2- ((the chloro- 2- of 5- ((3- chlorine 4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 534[M+H]⁺.

Embodiment 50

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methylpyrrolidin- 3- yl) oxygroup) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 506[M+H]⁺.

Embodiment 51

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methyl piperidine -4- base) oxygroup) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 520[M+H]⁺.

Embodiment 52

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (1- (piperidin-4-yl) -1H- pyrazoles -4- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 556[M+H]⁺.

Embodiment 53

(2- ((2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 622[M+H]⁺.

Embodiment 54

(2- ((the bromo- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 632[M+H]⁺.

Embodiment 55

2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -4- ((2- (solutions of dimethyl phosphoryl Base) phenyl) amino) pyrimidine -5- formonitrile HCN

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 579[M+H]⁺.

Embodiment 56

(((the chloro- 2- of 5- ((3- cyclopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 594[M+H]⁺.

Embodiment 57

(2- ((the chloro- 2- of 5- ((3- (difluoromethyl) -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 604[M+H]⁺.

Embodiment 58

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 638[M+H]⁺.

Embodiment 59

(2- ((the chloro- 2- of 5- ((3- ethyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 582[M+H]⁺.

Embodiment 60

(((the chloro- 2- of 5- ((3- isopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 596[M+H]⁺.

Embodiment 61

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- propyl phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 596[M+H]⁺.

Embodiment 62

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridin-3-yl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 589[M+H]⁺.

Embodiment 63

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridin-4-yl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 589[M+H]⁺.

Embodiment 64

(4- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -3- Base) amino) pyridin-4-yl) dimethyl phosphorus

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 589[M+H]⁺.

Embodiment 65

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) pyridine -2- base) dimethyl phosphorus.

Synthetic method is referring to embodiment 1.

MS(ESI):m/z 589[M+H]⁺.

Embodiment 66

2- amino-metadiazine compound tests the activity suppression of Wild type EGFR and mutability EGFR kinases:

EGFR (WT) is wild-type egf receptor, and EGFR (T790M) is with the 790th amino acids by Soviet Union's ammonia For acid mutation at the EGF-R ELISA of methionine, EGFR (L858R) is to be mutated with the 858th amino acids by leucine At arginic EGF-R ELISA, EGFR (L861Q) is to be mutated into glutamy by leucine with the 861st amino acids The EGF-R ELISA of amine, EGFR (L858R/T790M) are to be mutated into glutamy by leucine with the 858th amino acids Amine, the 790th amino acids are mutated into the EGF-R ELISA of the double mutation of methionine by threonine.EGFR (L858R/ T790M/C797S) to be mutated into glutamine by leucine with the 858th amino acids, the 790th amino acids are dashed forward by threonine Become methionine, the 797th EGF-R ELISA by three mutation that cysteine mutation is serine.

With enzyme linked immunosorbent assay (Enzyme-Linked Immunosorbent Assay, ELISA) detection compound pair The inhibiting effect of kinase activity.EGFR^WTAnd EGFR^T790M/L858RKinases is purchased from Eurofins company, EGFR^{T790M/L858R/C797SR}Swash Enzyme is purchased from BPS Bioscience company.Steps are as follows for major experimental: enzyme reaction substrate Poly (Glu, Tyr)_4:1With no potassium ion PBS (10mM sodium phosphate buffer, 150mM NaCl, pH 7.2-7.4) be diluted to 20 μ g/mL, 37 DEG C of reaction 12-16h packets By ELISA Plate.Every hole, which is added, uses reaction buffer (50mM HEPES pH 7.4,50mM MgCl₂,0.5mM MnCl₂,0.2 mM Na₃VO₄, 1mM DTT) and diluted ATP (5 μM of final concentration) solution, untested compound or solvent control is added, then kinase promoter Reaction, 37 DEG C of shaking tables react 1h.T-PBS board-washing three times, is added antibody PY99 in 37 DEG C of shaking tables and reacts 0.5h.T-PBS board-washing Afterwards, the IgG of the sheep anti mouse of horseradish peroxidase-labeled is added, 37 DEG C of shaking tables react 0.5h.Again after board-washing, 2mg/mL is added OPD developing solution, 25 DEG C are protected from light 1-10min.2M H is added₂SO₄Reaction is terminated, is declined orifice plate microplate reader with wavelengthtunable SPECTRA MAX 190 is detected, and uses wavelength for 492nm.IC₅₀Value is analyzed to obtain by suppression curve.

Be classified as compound number (corresponding with the compound number in above-described embodiment 1- embodiment 65) and change in table 1 Object is closed to the testing result of each kinase inhibiting activity.

Inhibitory activity result of 1 compound of table to kinases

Embodiment 67

Compound expresses EGFR to height^{L858R/T790M/C797S}BaF3 vehicles cells strain point of impact on target inhibiting effect experiment:

Using Western Blot method detection compound to EGFR in vehicles cells^{L858R/T790M/C797S}Inhibitory activity. By exogenous high expression EGFR^{L858R/T790M/C797S}BaF3 vehicles cells be inoculated in 6 orifice plates, adhere-wall culture is overnight, uses no blood instead Clear culture solution continues culture for 24 hours.Then, the compound effects 2h of various concentration is added, EGFR growth factor (50 is then added Ng/mL it) acts on 10 minutes.Cell is cleaned with the PBS of pre-cooling, and in triplicate, remove remnants PBS, cracked with SDS lysate thin Born of the same parents collect lysate using Western Blot method detection compound to EGFR in cell^{L858R/T790M/C797S}Inhibitory activity. P-EGFR (Tyr1068) antibody, EGFR antibody used etc. are tested, it is public purchased from Cell Signaling Technologies Department.

Be classified as compound number (corresponding with the compound number in above-described embodiment 1- embodiment 65) and change in table 2 Object is closed to the testing result of each vehicles cells strain proliferation inhibition activity.

The inhibitory activity result of 2 compound on intracellular of table proliferation

Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.

The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (19)

1. 2- amino-metadiazine compound or its pharmaceutically acceptable salt or its alloisomerism with structure shown in Formulas I Body or its prodrugs:

In formula:

D, E, F, W, X, Y, Z are separately selected from: CH or N；

R¹And R²It is separately selected from: H, halogen, cyano, trifluoromethyl, nitro, substituted or unsubstituted C₁-C₆Alkyl, substitution Or unsubstituted C₃-C₆Naphthenic base, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyloxy；

R³It is selected from: hydrogen, halogen, cyano, trifluoromethyl, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Ring Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyloxy；

R⁴It is selected from: substituted or unsubstituted pyrazolyl ,-(CH₂)_mNR⁶R⁷、-(CH₂)_mOCR⁵R⁶R⁷、-(CH₂)_mCR⁵R⁶R⁷；

Wherein, m is selected from: 0,1,2,3 or 4；

R⁵It is selected from: hydrogen or C₁-C₃Alkyl；

R⁶And R⁷It is separately selected from: hydrogen, substituted or unsubstituted C₁-C₆Alkyl or R⁶、R⁷With mono- similar shape of N or C being connected Contain heteroatomic monocycle or condensed ring at substituted or unsubstituted.

2. 2- amino-metadiazine compound according to claim 1 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that

R⁴It is selected from: R⁸Substituted pyrazolyl ,-(CH₂)_mNR⁶R⁷、-(CH₂)_mOCR⁵R⁶R⁷、-(CH₂)_mCR⁵R⁶R⁷；Wherein,

M is selected from: 0,1,2,3 or 4；

R⁵It is selected from: hydrogen or C₁-C₃Alkyl；

R⁶And R⁷It is separately selected from: hydrogen, R⁸Substituted C₁-C₆Alkyl or R⁶、R⁷R is formed together with the N or C being connected⁸It takes In generation, contains n heteroatomic 3-8 unit monocycles or R⁶、R⁷R is formed together with the N or C being connected⁸What is replaced is heteroatomic containing n 8-12 member condensed ring, loop coil or bridged ring, n are selected from: 1,2 or 3, hetero atom is selected from: O, N, S；

R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, halogen, hydroxyl, amino, C₁-C₃Alkyl ,-C (=O) NHR⁹Substituted C₁-C₃ The C that alkyl, hydroxyl replace₁-C₃Alkyl, C₃-C₆The C that naphthenic base replaces₁-C₃Alkyl, C₃-C₈The C that heterocycle replaces₁-C₃Alkyl, C₁-C₃Alkoxy ,-NHR⁹、-N(R⁹)₂,-C (=O) R⁹；R⁹For C₁-C₃Alkyl.

3. 2- amino-metadiazine compound according to claim 2 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that R⁴It is selected from :-(CH₂)_mNR⁶R⁷；M is selected from: 0 or 1；

R⁶And R⁷It is separately selected from: hydrogen, R⁸Substituted C₁-C₆Alkyl or R⁶、R⁷R is formed together with the N being connected⁸Replace Containing n heteroatomic 3-8 unit monocycles or R⁶、R⁷R is formed together with the N being connected⁸What is replaced is thick containing n heteroatomic 8-12 members Ring, loop coil or bridged ring, wherein n is selected from: 1,2 or 3, hetero atom is selected from: O, N, S；

R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, halogen, hydroxyl, amino, C₁-C₃Alkyl, C₁-C₃Alkoxy ,-NHR⁹、-N (R⁹)₂,-C (=O) R⁹；R⁹For C₁-C₃Alkyl.

4. 2- amino-metadiazine compound according to claim 3 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that R⁸It is selected from: H, R⁹Substituted 4-8 circle heterocyclic ring base, C₁-C₃Alkyl ,-NHR⁹、-N (R⁹)₂；R⁹For C₁-C₃Alkyl.

5. 2- amino-metadiazine compound according to claim 2 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that R⁴It is selected from:

6. 2- amino-metadiazine compound according to claim 1-5 or its pharmaceutically acceptable salt or Its stereoisomer or its prodrugs, which is characterized in that F is selected from: CH or N；D, E, W, X, Y, Z are CH.

7. 2- amino-metadiazine compound according to claim 1-5 or its pharmaceutically acceptable salt or Its stereoisomer or its prodrugs, which is characterized in that R¹And R²It is separately selected from: H, halogen, cyano, fluoroform Base, nitro, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₁-C₆Alkoxy, C₃-C₆The C that cycloalkyloxy, halogen replace₁-C₆Alkyl, halogen Substituted C₁-C₆Alkoxy.

8. 2- amino-metadiazine compound according to claim 7 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that R¹Be selected from: halogen, methyl, cyano, trifluoromethyl, difluoromethyl, methoxyl group, Cyclopropyl, trifluoromethoxy.

9. 2- amino-metadiazine compound according to claim 7 or its pharmaceutically acceptable salt or its solid are different Structure body or its prodrugs, which is characterized in that R²It is selected from: halogen, C₁-C₆Alkyl, fluorine-substituted C₁-C₆Alkyl, C₃-C₆Cycloalkanes Base, fluorine-substituted C₃-C₆Naphthenic base, C₁-C₆Alkoxy, fluorine-substituted C₁-C₆Alkoxy.

10. 2- amino-metadiazine compound according to claim 7 or its pharmaceutically acceptable salt or its solid Isomers or its prodrugs, which is characterized in that R²It is selected from: fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, trifluoromethyl, two Methyl fluoride, trifluoromethoxy, cyclopropyl, isopropyl, n-propyl.

11. 2- amino-metadiazine compound according to claim 1-5 or its pharmaceutically acceptable salt or Its stereoisomer of person or its prodrugs, which is characterized in that R³It is selected from: hydrogen, halogen, cyano, trifluoromethyl, nitro, C₁- C₆Alkyl, C₃-C₆Naphthenic base, C₁-C₆Alkoxy, C₃-C₆The C that cycloalkyloxy, halogen replace₁-C₆The C that alkyl, halogen replace₁-C₆ Alkoxy.

12. 2- amino-metadiazine compound according to claim 11 or its pharmaceutically acceptable salt or its solid Isomers or its prodrugs, which is characterized in that R³It is selected from: hydrogen, fluorine, chlorine, methyl, ethyl, cyano, trifluoromethyl, difluoro Methyl, methoxyl group, cyclopropyl, trifluoromethoxy.

13. 2- amino-metadiazine compound according to claim 1 or its pharmaceutically acceptable salt or its solid Isomers or its prodrugs, which is characterized in that the 2- amino-metadiazine compound is selected from:

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- trifluoromethyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphorus；

(2- ((the chloro- 2- of 5- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3aR, 6aS) -5- methyl hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) benzene Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- methyl-1,4- phenodiazine heptane -1- base) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- methyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (9- methyl -3,9- phenodiazine spiral shell [5.5] hendecane -3- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (7- methyl -2,7- phenodiazine spiral shell [3.5] nonane -2- base) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(S)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(R)-(2- ((the chloro- 2- of 5- ((4- (3,4- lupetazin -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- ((2- (dimethylamino) ethyl) (methyl) amino) -6- picoline -2- base) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- ((3R, 5S) -3,4,5- tri methyl piperazine -1- base) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((1- (2- (diethylamino) ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- methyl -4- (4- (oxetanes -3- base) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((5- (piperazine -1- ylmethyl) pyridine -2- base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl Phosphorous oxide；

(2- ((the chloro- 2- of 5- ((3- methoxyl group -4- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- ethyl piperazidine -1- base) -3- aminomethyl phenyl) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphorus；

(2- ((2- ((the bromo- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) -5- chlorine pyrimidine-4-yl) amino) phenyl) diformazan Base phosphorous oxide；

(2- ((2- ((the bromo- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- chlorine pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((6- methyl -5- (4- methylpiperazine-1-yl) pyridine 2- yl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((5- chlorine 2- ((3- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl Phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- (dimethylamino) piperidin-1-yl) -3- aminomethyl phenyl) amino) pyrimidine 4- yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) diformazan Base phosphorous oxide；

(2- ((the chloro- 2- of 5- ((4- (4- methylpiperazine-1-yl) -3- trifluoromethyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the fluoro- 4- of 3- (4- methylpiperazine-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) diformazan Base phosphorous oxide；

(2- ((the chloro- 2- of 5- ((the chloro- 4- morpholino phenyl of 3-) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- base) phenyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

1- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) phenyl) piperazine Piperazine -1- base) ethyl -1- ketone；

2- (4- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) phenyl) piperazine Piperazine -1- base)-N- methylacetamide；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (2- ethoxy) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- hydroxy piperidine -1- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) diformazan Base phosphorous oxide；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (dimethylamino) heterocyclic butane -1- base) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (methyl (2- (methylamino) ethyl) amino) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (cyclopropyl alkyl methyl) piperazine -1- base) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- ((1S, 4S) -5- methyl -2,5- diazabicylo [2.2.1] heptane -2- base) piperazine Pyridine -1- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- morpholinyl piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methyl-1,4- diaza heptane -1- base) piperidin-1-yl) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (3- (piperidin-1-yl) pyrrolidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) Phenyl) dimethyl phosphorus；

(2- ((2- ((4- (4- (azetidine -1- ylmethyl) piperidin-1-yl) -3- chlorphenyl) amino) -5- chlorine pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((2- ((4- ([bis- piperidines of 1,4'-] -1'- base) -3- chlorphenyl) amino) -5- chlorine pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- chlorine 4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) amino) pyrimidine-4-yl) amino) phenyl) Dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methylpyrrolidin- 3- yl) oxygroup) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- ((1- methyl piperidine -4- base) oxygroup) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (1- (piperidin-4-yl) -1H- pyrazoles -4- base) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

(((2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the bromo- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) dimethyl phosphorus；

2- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) -4- ((2- (solutions of dimethyl phosphoryl base) Phenyl) amino) pyrimidine -5- formonitrile HCN；

(2- ((the chloro- 2- of 5- ((3- cyclopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- difluoromethyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphorus；

(((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- ethyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((3- isopropyl -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -3- propyl phenyl) amino) pyrimidine-4-yl) Amino) phenyl) dimethyl phosphorus；

(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) pyridin-3-yl) dimethyl phosphorus；

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) pyridin-4-yl) dimethyl phosphorus；

(4- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-3-yl) ammonia Base) pyridin-4-yl) dimethyl phosphorus；

(3- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ammonia Base) pyridine -2- base) dimethyl phosphorus.

14. the described in any item 2- amino-metadiazine compounds of claim 1-13 or its pharmaceutically acceptable salt or its Stereoisomer or its prodrugs are preparing the application in mutant egf R inhibitor.

15. the described in any item 2- amino-metadiazine compounds of claim 1-13 or its pharmaceutically acceptable salt or its The application of stereoisomer or its prodrugs in the drug for preparing anti-curing oncoma.

16. application according to claim 15, which is characterized in that the tumour is the malignant tumour of EGFR genetic mutation.

17. application according to claim 16, which is characterized in that the tumour is EGFR^{L858R/T790M/C797S}The evil of mutation Property tumour.

18. application according to claim 16, which is characterized in that the tumour are as follows: non-small cell lung cancer, cellule lung It is cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, white Blood disease, histiocytic lymph cancer, nasopharyngeal carcinoma, head and neck neoplasm, colon and rectum carcinoma or glioma.

19. a kind of pharmaceutical composition of anti-curing oncoma, which is characterized in that including active constituent and pharmaceutically acceptable load Body, the active constituent includes the described in any item 2- amino-metadiazine compounds of claim 1-13 or it pharmaceutically may be used The salt of receiving or its stereoisomer or its prodrugs.