CN108137544A

CN108137544A - For inhibiting the amino-metadiazine compound of protein tyrosine kinase activity

Info

Publication number: CN108137544A
Application number: CN201680061348.9A
Authority: CN
Inventors: 王义汉; 李焕银
Original assignee: Shenzhen Targetrx Inc
Current assignee: Shenzhen Targetrx Inc
Priority date: 2015-12-10
Filing date: 2016-11-24
Publication date: 2018-06-08
Anticipated expiration: 2036-11-24
Also published as: CN108137544B; WO2017097113A1

Abstract

The present invention relates to the inhibited amino-metadiazine compound of protein tyrosine kinase activity and be related to their preparation and use.Specifically, the amino-metadiazine compound shown in disclosure of the invention formula (I) and the pharmaceutical composition containing the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations.The compounds of this invention is diseases related available for treating and/or preventing protein tyrosine kinase, such as cell proliferation disorders, cancer, immunity disease.

Description

For inhibiting the amino-metadiazine compound of protein tyrosine kinase activity

Technical field

The invention belongs to field of medicaments.In particular it relates to which the amino-metadiazine compound inhibited to protein tyrosine kinase activity, includes their pharmaceutical composition and their preparation method and purposes.More particularly, the present invention relate to treat the amino-metadiazine compound for having related disorders (such as tumour and related disease) with the imbalance of protein tyrosine kinase (such as, but not limited to EGFR (including HER), ALK, PDGFR) metabolic pathway and its pharmaceutical composition and application method.

Background technique

Protein tyrosine kinase (protein tyrosine kinase, it PTK is) that γ-phosphoric acid is transferred to the kinases on protein-tyrosine residue on a kind of catalysis ATP, it can be catalyzed the tyrosine residue phosphorylation of a variety of substrate protein white matters, played a significant role in cell growth, proliferation, differentiation.Because protein tyrosine kinase has profound influence to cell, their activity is by height adjustment.Kinases is by phosphorylation (sometimes through autophosphorylation), opens or closes by combining activator protein, inhibit albumen or small molecule, or by controlling their positioning in cell.The dysfunction for being currently known kinase activity is related with a variety of diseases, and the dysfunction is caused by gene unconventionality or environmental factor.Some serious pathological states (including cancer and chronic inflammation) are related with Intracellular signals stimulation, and since kinases energetically transmits signal, their inhibition provides strong inhibition or the control cascade approach of signal transduction.

Whether there is according to protein tyrosine kinase can be divided into non-receptor type and membrane receptor type in cell-membrane receptor.Nonreceptor tyrosine kinase (non-receptor tyrosine kinase, nrRTK) is using Src as representative, and in addition there are Yes, Fyn, Lck, Fgr, Lyn, Fps/Fes and Ab1 etc..Receptor tyrosine kinase (receptortyrosinekinase, RTK) different according to their structure, 9 seed types can be divided into, it is wherein more typical to have following 4 seed type: EGF-R ELISA (EGFR) family, Insulin Receptor Family, PDGF/MCSF/SCF receptor family and fibroblast growth factor acceptor (FGFR) family.

EGF-R ELISA (the EGFR of the mankind；ErbB-1；HER1) be ErbB receptor family member, ErbB receptor family is four kinds of closely related receptor tyrosine kinase EGFR (ErbB-1), HER2/c-NEU (ErbB-2), the subfamily of HER 3 (ErbB-3) and HER 4 (ErbB-4).EGFR is the cell surface receptor of extracellular protein ligand epidermal growth factor family (EGF family) member.It influences EGFR expression or active mutation may cause cancer.It is reported that EGFR is in de-synchronization state in most of solid tumors such as lung cancer, breast cancer and brain tumor.It is estimated that 30% epithelioma is related with the mutation of EGFR or family member, amplification or imbalance.

Receptor tyrosine kinase inhibitors (protein receptor tyrosine kinase inhibitor, it RTKI is) inhibitor of receptor tyrosine kinase, inhibitor is usually small molecule compound, pass through the inhibition to receptor tyrosine kinase activity (reversible or irreversible), intracellular region activation signals after cell surface receptor and ligand binding are blocked, so that signal be inhibited to go to the final biological effect of access.

In recent years, receptor tyrosine kinase inhibitors research field attracts tremendous attention.First generation receptor tyrosine kinase inhibitors are single target spot tyrosine kinase inhibitor, such as Gefitinib, Tarceva drug.Gefitinib is EGFR tyrosine kinase inhibitor, is mainly used for non-small cell lung cancer (NSCLC), is up to 80% or more to the effective percentage of tyrosine kinase gene code area mutant tumours.Tarceva is EGFR tyrosine kinase inhibitor, which is 10% or so to the effective percentage of non-small cell lung cancer patients with recurrent.

However, becoming main clinical problem to the acquired resistance of Gefitinib or Tarceva after treatment a period of time.Research confirms that one that generates drug resistance is primarily due to T790M mutation, is " entrance guard " of EGFR.Then, it has developed for T790M's Second generation receptor tyrosine kinase inhibitors, such as Afatinib are the irreversible inhibitor of EGFR and show advantage in clinical test.Although these inhibitor effectively inhibit T790M to be mutated, also inhibits Wild type EGFR (WT EGFR) simultaneously, produce serious side effect, which has limited clinical applications.

The third generation and subsequent EGFR inhibitor include the compounds such as AZD9291 and CO-1686, can not retroactive inhibition EGFR, and still have higher effective percentage to the patient that T790M medicament-resistant mutation occurs, but there is also inhibiting effect to Wild type EGFR.

Therefore, it is necessary to further research and develop new EGFR inhibitor, effectively T790M can not only be inhibited to be mutated, and T790M is mutated with highly selective for wild type.

Summary of the invention

The present invention provides a new class of EGFR inhibitors, with better pharmacodynamics/pharmacokinetics performance, and it is higher to the selectivity of T790M mutation, L858R mutation and the bis- mutation of L858R/T790M.

Therefore, on the one hand, the present invention provides following formula (I) compounds:

Wherein,

R₁Independently selected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy；

R₂Independently selected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy；

Linker L is selected from

1) C, N, O or S atom, as long as valence link allows；Wherein C and N can be optionally by R^aReplace；

2)C_1-6Alkylidene, C_2-6Alkenylene, C_2-6Alkynylene, C_3-10Sub- carbocylic radical, 3 to 10 yuan of sub- heterocycles, C_6-14Arlydene or C_5-10Inferior heteroaryl；Wherein the group is optionally by one or more R^aReplace；

3)-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-,-N (R^b) C (=O) O- ,-N (R^b) C (=O) N (R^b)-、-N(R^b) S (=O)-,-N (R^b) S (=O)₂,-OC (=O)-,-OC (=O) N (R^b- OS)-, (=O)-,-OS (=O)₂,-S (=O)-,-S (=O)₂,-S (=O)₂O- or-S (=O)₂N(R^b)-；

R^aSelected from H, halogen ,-CN ,-NO₂, oxo base, C_1-6Alkyl, C_1-6Halogenated alkyl or C_1-6Alkoxy；

R^bSelected from H, C_1-6Alkyl or C_1-6Halogenated alkyl；

X is selected from C or N atom, as long as valence link allows；

Ring A is selected from C_3-6Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl；

R₃Selected from halogen ,-CN ,-NO₂、-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c)、-N(R^c)(R^c)、-N(R^c) C (=O) R^c、-N(R^c) C (=O) OR^c、-N(R^c) C (=O) N (R^c)(R^c)、-N(R^c) S (=O) R^c、-N(R^c) S (=O) N (R^c)(R^c)、-N(R^c) S (=O)₂R^c、-N(R^c) S (=O)₂N(R^c)(R^c)、-OR^c,-OC (=O) R^c,-OC (=O) OR^c,-OC (=O) N (R^c)(R^c) ,-S (=O) R^c,-S (=O) OR^c,-S (=O) N (R^c)(R^c) ,-S (=O)₂R^c,-S (=O)₂OR^c,-S (=O)₂N(R^c)(R^c) ,-SC (=O) R^c,-SC (=O) OR^cOr-SC (=O) N (R^c)(R^c), as long as chemistry allows；

R^cSelected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl；The wherein C_3-10Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl is also optionally by C_1-6Alkyl, C_1-6Halogenated alkyl or-C (=O) C_1-6Alkyl replaces；

M is 0,1 or 2；

N is 1,2 or 3；

P represents singly-bound or double bond, as long as chemical valence allows；

Q represents singly-bound or double bond, as long as chemical valence allows；

R₄、R₅And R₆Independently selected from H, halogen ,-CN, C_1-6Alkyl or C_1-6Halogenated alkyl；

W is selected from N, O or S atom, and wherein N can be optionally by R^aReplace；

On condition that X is C atom when m is 0；

Or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations.

On the other hand, the present invention provides the pharmaceutical compositions containing the compounds of this invention and pharmaceutically acceptable excipient.In a particular embodiment, the compounds of this invention is provided in described pharmaceutical composition with effective quantity.In a particular embodiment, the compounds of this invention is provided with therapeutically effective amount.In a particular embodiment, the compounds of this invention is provided with prevention effective dose.

On the other hand, the present invention provides the pharmaceutical composition containing the compounds of this invention and pharmaceutically acceptable excipient, also contain other therapeutic agents.

On the other hand, the present invention provides the kits comprising the compounds of this invention, its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations and other therapeutic agents and pharmaceutically acceptable carrier, adjuvant or mediator.

On the other hand, the present invention provides treated in needing its subject cancer caused by EGFR (including EGFR be mutated caused by cancer, such as, with T790M mutation, L858R mutation and the bis- mutation of L858R/T790M cancer) associated disease method, which comprises give a effective amount of the compounds of this invention of subject.In a particular embodiment, cancer caused by the EGFR is selected from: 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 lymph cancer, nasopharyngeal carcinoma etc..In a particular embodiment, oral, subcutaneous, intravenously or intramuscularly interior that the compound is administered.In a particular embodiment, compound described in long term administration.

By subsequent specific embodiment, embodiment and claim, other objects and advantages of the present invention will be apparent to those skilled in the art.

Definition

Chemistry definition

It is described in more detail below the definition of specific functional group and the technical terms of chemistry.

When listing numberical range, set includes each value and the subrange in the range.Such as " C_1-6Alkyl " includes C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6Alkyl.

It should be understood that any part defined below can be replaced by many substituent groups when being described herein, and define accordingly be listed below they in the range of, including this substitution part.Unless otherwise noted, term " substitution " is such as defined below.

“C_1-6Alkyl " refers to the linear chain or branched chain saturated hydrocarbons group with 1 to 6 carbon atom, herein also referred to as " low alkyl group ".In some embodiments, C_1-4Alkyl is particularly preferred.The example of the alkyl includes but is not limited to: methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), normal-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), isobutyl group (C₄), n-pentyl (C₅), 3- amyl (C₅), amyl (C₅), neopentyl (C₅), 3- methyl -2- butyl (C₅), tertiary pentyl (C₅) and n-hexyl (C₆).Unless otherwise noted, each of alkyl is independently optionally substituted, that is, unsubstituted (" unsubstituted alkyl ") or be substituted by one or more substituents (" substituted alkyl ")；For example, 1 to 5 substituent group, 1 to 3 substituent group or 1 substituent group.In some embodiments, alkyl is unsubstituted C_1-6Alkyl is (for example,-CH₃).In some embodiments, alkyl is the C replaced_1-6Alkyl.

“C_2-6Alkenyl " refers to the linear chain or branched chain hydrocarbyl group with 2 to 6 carbon atoms and one or more carbon-to-carbon double bonds (for example, 1,2 or 3 carbon-to-carbon double bond).One or more carbon-to-carbon double bonds can be at internal (for example, in 2- cyclobutenyl) or end (for example, in 1- cyclobutenyl).In some embodiments, C_2-4Alkenyl is particularly preferred.The example of the alkenyl includes but is not limited to: vinyl (C₂), 1- acrylic (C₃), 2- acrylic (C₃), 1- cyclobutenyl (C₄), 2- cyclobutenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), etc..Unless otherwise noted, each of alkenyl is independently optionally substituted, that is, unsubstituted (" unsubstituted alkenyl ") or be substituted by one or more substituents (" substituted alkenyl ")；For example, 1 to 5 substituent group, 1 to 3 substituent group or 1 substituent group.In some embodiments, alkenyl is unsubstituted C_2-6Alkenyl.In some embodiments, alkenyl is the C replaced_2-6Alkenyl.

“C_2-6Alkynyl " refer to 2 to 6 carbon atoms, one or more three key of carbon-to-carbon (such as; 1,2 or 3 three key of carbon-to-carbon) and optionally one or more carbon-to-carbon double bonds (for example, 1,2 or 3 carbon-to-carbon double bond) linear chain or branched chain hydrocarbyl group.In some embodiments, C_2-4Alkynyl is particularly preferred.In some embodiments, alkynyl does not contain any double bond.One or more three keys of carbon can be in internal (for example, in 2- butynyl) or end (for example, in 1- butynyl).The example of the alkynyl includes but is not limited to: acetenyl (C₂), 1- propinyl (C₃), 2-propynyl (C₃), 1- butynyl (C₄), 2- butynyl (C₄), pentynyl (C₅), hexin base (C₆), etc..Unless otherwise noted, each of alkynyl is independently optionally substituted, that is, unsubstituted (" unsubstituted alkynyl ") or be substituted by one or more substituents (" substituted alkynyl ")；For example, 1 to 5 substituent group, 1 to 3 substituent group or 1 substituent group.In some embodiments, alkynyl is unsubstituted C_2-6Alkynyl.In some embodiments, alkynyl is the C replaced_2-6Alkynyl.

" alkylidene " used herein, " alkenylene " and " alkynylene " refers respectively to the bilvalent radical of abovementioned alkyl, alkenyl and alkynyl.When specific " alkylidene ", " alkenylene " and " alkynylene " provides the range or number of carbon, it should be understood that the range or number refer to range or number of the carbon in linear bivalent carbochain." alkylidene ", " alkenylene " and " alkynylene " can be replaced or unsubstituted by one or more substituent groups described herein.

“C_1-6Alkylidene ", which refers to, removes C_1-6One hydrogen of alkyl and the alkylidene for forming divalent, and can be substituted or unsubstituted alkylidene.In some embodiments, C_1-4Alkylidene is particularly preferred.The unsubstituted alkylidene includes but is not limited to: methylene (- CH₂), ethylidene (- CH₂CH₂), propylidene (- CH₂CH₂CH₂), butylidene (- CH₂CH₂CH₂CH₂), pentylidene (- CH₂CH₂CH₂CH₂CH₂), hexylidene (- CH₂CH₂CH₂CH₂CH₂CH₂), etc..The alkylidene illustratively replaced, for example, the alkylidene replaced by one or more alkyl (methyl), including but not limited to: substituted methylene (- CH (CH₃)-、-C(CH₃)₂), replace ethylidene (- CH (CH₃)CH₂-、-CH₂CH(CH₃)-、-C(CH₃)₂CH₂-、-CH₂C(CH₃)_2-), replace propylidene (- CH (CH₃)CH₂CH₂-、-CH₂CH(CH₃)CH₂-、-CH₂CH₂CH(CH₃)-、-C(CH₃)₂CH₂CH₂-、-CH₂C(CH₃)₂CH₂-、-CH₂CH₂C(CH₃)₂), etc..

“C_2-6Alkenylene ", which refers to, removes C_2-6One hydrogen of alkenyl and the alkenylene for forming divalent, and can be substituted or unsubstituted sub- alkene Base.In some embodiments, C_2-4Alkenylene is particularly preferred.The illustrative unsubstituted alkenylene includes but is not limited to: ethenylidene (- CH=CH-) and allylidene are (for example,-CH=CHCH₂-、-CH₂- CH=CH-).The alkenylene illustratively replaced, for example, the alkenylene replaced by one or more alkyl (methyl), including but not limited to: substituted ethylidene (- C (CH₃)=CH- ,-CH=C (CH₃) -), the allylidene (- C (CH replaced₃)=CHCH₂,-CH=C (CH₃)CH₂,-CH=CHCH (CH₃)-,-CH=CHC (CH₃)₂-、-CH(CH₃)-CH=CH- ,-C (CH₃)₂- CH=CH- ,-CH₂-C(CH₃)=CH- ,-CH₂- CH=C (CH₃) -), etc..

“C_2-6Alkynylene ", which refers to, removes C_2-6One hydrogen of alkynyl and the alkynylene for forming divalent, and can be substituted or unsubstituted alkynylene.In some embodiments, C_2-4Alkynylene is particularly preferred.The illustrative alkynylene includes but is not limited to: ethynylene (- C=C-), substituted or unsubstituted sub- propinyl (- C=CCH₂), etc..

“C_1-6Alkoxy " refers to group-OR, wherein R is substituted or unsubstituted C_1-6Alkyl.In some embodiments, C_1-4Alkoxy is particularly preferred.The specific alkoxy includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy and 1,2- dimethyl butyrate oxygroup.

" halogenated " or " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).In some embodiments, halogen group is F, Cl or Br.In some embodiments, halogen group is F or Cl.In some embodiments, halogen group is F.

Therefore, " C_1-6Halogenated alkyl " and " C_1-6Halogenated alkoxy " refers to above-mentioned " C_1-6Alkyl " and " C_1-6Alkoxy " is replaced by one or more halogen groups.In some embodiments, C_1-4Halogenated alkyl is particularly preferred, more preferable C_1-2Halogenated alkyl.In some embodiments, C_1-4Halogenated alkoxy is particularly preferred, more preferable C_1-2Halogenated alkoxy.The illustrative halogenated alkyl includes but is not limited to :-CF₃、-CH₂F、-CHF₂、-CHFCH₂F、-CH₂CHF₂、-CF₂CF₃、-CCl₃、-CH₂Cl、-CHCl₂, 2,2,2- tri- fluoro- 1,1- dimethyl-ethyIs, etc..The illustrative halogenated alkoxy includes but is not limited to :-OCH₂F、-OCHF₂、-OCF₃, etc..

“C_3-10Carbocylic radical " refers to the non-aromatic ring hydrocarbyl group with 3 to 10 ring carbon atoms and zero heteroatoms.In some embodiments, C_3-6Carbocylic radical is particularly preferred, more preferable C_5-6Carbocylic radical.Carbocylic radical further includes wherein above-mentioned carbocyclic ring basic ring and one or more aryl or heteroaryl-condensed ring system, and wherein on carbocyclic ring basic ring, and in such a case, the number of carbon continues to indicate the number of the carbon in carbocylic radical system tie point.The illustrative carbocylic radical includes but is not limited to: cyclopropyl (C₃), cyclopropanyl (C₃), cyclobutyl (C₄), cyclobutane base (C₄), cyclopenta (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl group (C₆), cyclohexadiene base (C₆), suberyl (C₇), cycloheptenyl (C₇), cycloheptadiene base (C₇), cycloheptatriene base (C₇), cyclooctyl (C₈), cyclo-octene base (C₈), two rings [2.2.1] heptyl (C₇), two rings [2.2.2] octyl (C₈), cyclononyl (C₉), cyclonoene base (C₉), cyclodecyl (C₁₀), cyclodecene base (C₁₀), octahydro -1H- indenyl (C₉), decahydro naphthalene (C₁₀), spiral shell [4.5] decyl (C₁₀), etc..Unless otherwise noted, each of carbocylic radical independently is and optionally replaces, that is, unsubstituted (" unsubstituted carbocylic radical ") or be substituted by one or more substituents (" substituted carbocylic radical ").In some embodiments, carbocylic radical is unsubstituted C_3-10Carbocylic radical.In some embodiments, carbocylic radical is the C replaced_3-10Carbocylic radical.

" 3 to 10 circle heterocyclic ring base " or the group for referring to 3 to 10 yuan of non-aromatic ring systems with ring carbon atom and 1 to 4 ring hetero atom, wherein each hetero atom is independently selected from nitrogen, oxygen, sulphur, boron, phosphorus and silicon.In the heterocycle comprising one or more nitrogen-atoms, as long as chemical valence allows, tie point can be carbon or nitrogen-atoms.In some embodiments, 3 to 6 circle heterocyclic ring bases are particularly preferred, are 3 to 6 yuan of non-aromatic ring systems with ring carbon atom and 1 to 3 ring hetero atom；More preferable 5 to 6 circle heterocyclic ring base is 5 to 6 yuan of non-aromatic ring systems with ring carbon atom and 1 to 3 ring hetero atom.Unless otherwise noted, each of heterocycle independently is and optionally replaces, that is, unsubstituted (" unsubstituted heterocycle ") or be substituted by one or more substituents (" substituted heterocycle ").In some embodiments, Heterocycle is unsubstituted 3-10 circle heterocyclic ring base.In some embodiments, heterocycle is the 3-10 circle heterocyclic ring base replaced.Heterocycle further includes wherein above-mentioned heterocyclic ring and the condensed ring system of one or more carbocylic radicals, and wherein tie point is on carbocyclic ring basic ring or in which above-mentioned heterocyclic ring and one or more aryl or heteroaryl-condensed ring system, and wherein tie point is on heterocyclic ring；And in this case, the number of ring members continues to indicate the number in heterocyclyl ring system ring members.Illustratively include but is not limited to comprising a heteroatomic 3 circle heterocyclic ring base: aziridine base, oxirane base, thiirane base (thiorenyl).Illustratively include but is not limited to containing a heteroatomic 4 circle heterocyclic ring base: azetidinyl, oxetanyl and Thietane base.Illustratively include but is not limited to containing a heteroatomic 5 circle heterocyclic ring base: tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, pyrrolidinyl, pyrrolin base and pyrrole radicals -2,5- diketone.Illustratively include but is not limited to comprising two heteroatomic 5 circle heterocyclic ring bases: dioxolane base, oxathiolane base (oxasulfuranyl), dithiolane base (disulfuranyl) and oxazolidine -2- ketone.Illustratively include but is not limited to comprising three heteroatomic 5 circle heterocyclic ring bases: triazoline base, oxadiazoline base and Thiadiazoline base.Illustratively include but is not limited to comprising a heteroatomic 6 circle heterocyclic ring base: piperidyl, THP trtrahydropyranyl, dihydropyridine base and thia cyclohexyl (thianyl).Illustratively include but is not limited to comprising two heteroatomic 6 circle heterocyclic ring bases: piperazinyl, morpholinyl, dithian base, dioxanes base.Illustratively include but is not limited to comprising three heteroatomic 6 circle heterocyclic ring bases: Hexahydrotriazine base (triazinanyl).Illustratively include but is not limited to containing a heteroatomic 7 circle heterocyclic ring base: nitrogen heterocyclic heptyl, oxepane alkyl and thia cycloheptyl alkyl.Illustratively include but is not limited to comprising a heteroatomic 8 circle heterocyclic ring base: Azacyclooctane base, oxocane base and thia cyclooctane base.Illustratively and C₆5 condensed circle heterocyclic ring bases of aryl rings (being also referred to as 5,6- bicyclic heterocyclic radical herein) include but is not limited to: indolinyl, iso-dihydro-indole-group, dihydro benzo furyl, dihydrobenzo thienyl, benzoxazoles quinoline ketone group, etc..Illustratively and C₆The condensed 6 circle heterocyclic ring bases (also referring to 6,6- bicyclic heterocyclic radical herein) of aryl rings include but is not limited to: tetrahydric quinoline group, tetrahydro isoquinolyl, etc..

“C_6-14Aryl " refers to the group of monocycle or polycyclic (for example, bicyclic or tricyclic) 4n+2 aromatic ring system (for example, having 6,10 or 14 pi-electrons shared with annular arrangement) with 6-14 ring carbon atom and zero heteroatoms.In some embodiments, there are six ring carbon atom (" C for aryl tool₆Aryl "；For example, phenyl).In some embodiments, aryl has ten ring carbon atom (" C₁₀Aryl "；For example, naphthalene, for example, 1- naphthalene and 2- naphthalene).In some embodiments, aryl has 14 ring carbon atom (" C₁₄Aryl "；For example, anthryl).In some embodiments, C_6-10Aryl is particularly preferred, more preferable C₆Aryl.Aryl further includes the loop system that wherein above-mentioned aryl rings and one or more carbocylic radicals or heterocycle condense, and tie point, in the aryl rings, in this case, the number of carbon atom continues to indicate the carbon atom number in the aryl loop system.Unless otherwise noted, each of aryl is independently optionally substituted, that is, unsubstituted (" unsubstituted aryl ") or be substituted by one or more substituents (" substituted aryl ").In some embodiments, aryl is unsubstituted C_6-14Aryl.In some embodiments, aryl is the C replaced_6-14Aryl.

“C_5-10Heteroaryl " refer to 5-10 unit monocycle with ring carbon atom and 1-4 ring hetero atom or bicyclic 4n+2 aromatic ring system (such as; there are 6 or 10 pi-electrons shared with annular arrangement) group, wherein each hetero atom is independently selected from nitrogen, oxygen and sulphur.In the heteroaryl containing one or more nitrogen-atoms, as long as chemical valence allows, tie point can be carbon or nitrogen-atoms.Heteroaryl bicyclic system may include one or more hetero atoms in one or two ring.Heteroaryl further includes the loop system that wherein above-mentioned heteroaryl ring and one or more carbocylic radicals or heterocycle condense, and tie point, on the heteroaryl ring, in this case, the number of carbon atom continues to indicate the carbon atom number in the heteroaryl ring-member.In some embodiments, C_5-6Heteroaryl be it is particularly preferred, for ring carbon atom and 1-4 ring hetero atom 5-6 unit monocycle or bicyclic 4n+2 aromatic ring system.Unless otherwise noted, each of heteroaryl is independently optionally substituted, that is, unsubstituted (" unsubstituted heteroaryl ") or be substituted by one or more substituents (" substituted heteroaryl ").In some embodiment party In case, heteroaryl is unsubstituted 5-10 unit's heteroaryl.In some embodiments, heteroaryl is the 5-10 unit's heteroaryl replaced.Illustratively include but is not limited to containing heteroatomic 5 unit's heteroaryl: pyrrole radicals, furyl and thienyl.Illustrative heteroatomic 5 unit's heteroaryl containing there are two includes but is not limited to: imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.Illustrative heteroatomic 5 unit's heteroaryl containing there are three includes but is not limited to: triazolyl, oxadiazoles base and thiadiazolyl group.Illustrative heteroatomic 5 unit's heteroaryl containing there are four includes but is not limited to: tetrazole radical.Illustratively include but is not limited to containing heteroatomic 6 unit's heteroaryl: pyridyl group.Illustrative heteroatomic 6 unit's heteroaryl containing there are two includes but is not limited to: pyridazinyl, pyrimidine radicals and pyrazinyl.There are three illustratively containing or four heteroatomic 6 unit's heteroaryls are respectively included but are not limited to: triazine radical and tetrazine base.Illustratively include but is not limited to containing heteroatomic 7 unit's heteroaryl: azepine cycloheptatriene base, oxepin base and thia cycloheptatriene base.Illustrative 5,6- bicyclic heteroaryl includes but is not limited to: indyl, isoindolyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuranyl, benzisoxa furyl, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzoxadiazole base, benzothiazolyl, benzisothia oxazolyl, diazosulfide base, indenes piperazine base and purine radicals.Illustrative 6,6- bicyclic heteroaryl includes but is not limited to: naphthyridines base, quinolyl, isoquinolyl, scolds Lin Ji, quinoxalinyl, phthalazinyl and quinazolyl at pteridine radicals.

" sub- carbocylic radical " used herein, " sub- heterocycle ", " arlydene " and " inferior heteroaryl " refers respectively to the bilvalent radical of above-mentioned carbocylic radical, heterocycle, aryl and heteroaryl, removes a hydrogen atom in any possible position by the group and obtains bilvalent radical." sub- carbocylic radical ", " sub- heterocycle ", " arlydene " and " inferior heteroaryl " can be replaced or unsubstituted by one or more substituent groups described herein.Illustrative unsubstituted " sub- carbocylic radical ", " sub- heterocycle ", " arlydene " and " inferior heteroaryl " includes but is not limited to following group:

Wherein, Z indicates O, N or S atom.

" oxo base " refers to=O.

Other definition

Term " pharmaceutically acceptable salt " refers to, in reliable medical judgment scope, is suitble to contact without excessive toxicity, irritation, allergy etc. with the tissue of people and lower animal, and those of matches salt with reasonable benefit/hazard ratio.Pharmaceutically acceptable salt is well known in the art.For example, the pharmaceutically acceptable salt that Berge et al. is described in detail in J.Pharmaceutical Sciences (1977) 66:1-19.The pharmaceutically acceptable salt of the compounds of this invention includes the salt derived from suitable inorganic and organic bronsted lowry acids and bases bronsted lowry.The example of pharmaceutically acceptable non-toxic acid addition salts is the salt that amino and inorganic acid are formed, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or the salt formed with organic acid, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or use this field The salt that the method used is formed, for example, ion-exchange process.Other pharmaceutically acceptable salts include: hexanedioic acid salt, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, citrate, cipionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluconate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salt, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectinic acid salt, persulfate, 3- phenpropionate, phosphate, picrate, it is special Valerate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, tosilate, undecanoate, valerate, etc..Pharmaceutically acceptable salt derived from suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.Representative alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium salts, etc..If applicable, further pharmaceutically acceptable salt includes nontoxic ammonium salt, quaternary ammonium salt and the amine cation formed using counter ion, counter ion such as halogen ion, hydroxyl, carboxylate radical, sulfate radical, phosphate radical, nitrate anion, loweralkyl sulfonate and arylsulphonate.

" subject " of administration includes but is not limited to: people is (i.e., the sex of any age group, for example, pediatric subject (for example, baby, children and adolescents) or Adult human subjects (such as, young adult, middle aged adult or old adult)) and/or inhuman animal, for example, mammal, such as, primate (for example, machin, rhesus macaque), ox, pig, horse, sheep, goat, rodent, cat and/or dog.In some embodiments, subject is people.In some embodiments, subject is non-human animal.Term " people ", " patient " and " subject " used interchangeably herein.

" disease ", " obstacle " and " illness " uses interchangeably herein.

Unless otherwise mentioned, otherwise, terms used herein " treatment " include that subject suffers from the effect occurred when disease specific, obstruction and illness, it reduces disease, the severity of obstruction and illness, or postpone or slow down the development (" therapeutic treatment ") of disease, obstruction and illness, it further include that subject starts with the effect (" prophylactic treatment ") occurred before disease specific, obstruction and illness.

In general, " effective quantity " of compound refers to the quantity for being enough to cause target organism to react.As understood by those skilled in the art, the effective quantity of the compounds of this invention can change according to following factors: for example, the pharmacokinetics of biological interest, compound, the disease treated, the age health condition and symptom of mode of administration and subject.Effective quantity includes treatment and prevention property therapeutically effective amount.

Unless otherwise noted, " therapeutically effective amount " of compound used herein is to be enough to provide the quantity for the treatment of benefit during treating disease, obstruction and illness, or one or more symptoms related with disease, obstruction and illness is made to postpone or minimize.The therapeutically effective amount of compound refer to be used alone or with other therapies associated with therapeutic agent quantity, it provides treatment benefit during treating disease, obstruction and illness.Term " therapeutically effective amount " may include the quantity for improving the therapeutic efficacy of overall therapeutic, the symptom for reducing or avoiding disease or illness or the cause of disease or the other therapeutic agents of enhancing.

Unless otherwise mentioned, otherwise, " prevention effective dose " of compound used herein is the quantity for being enough to prevent disease, the quantity of obstruction and illness, or be enough to prevent the quantity of one or more symptoms related with disease, obstruction and illness, or preventing disease, obstruction and illness recurrence.The prevention effective dose of compound refer to be used alone or with other medicaments associated with therapeutic agent quantity, it provided during prevent disease, obstruction and illness prevents benefit.Term " prevention effective dose " may include the quantity for improving the quantity totally prevented, or enhancing the prevention efficiency of other prevention medicaments.

" combination " and relational language, which refer to, is administered either simultaneously or sequentially therapeutic agent of the invention.It for example, the unit dosage forms that the compounds of this invention can be separated with another therapeutic agent are administered either simultaneously or sequentially, or together with another therapeutic agent is in that single unit dosage forms are administered simultaneously.

" cancer caused by EGFR " refers to the cancer characterized by the unsuitable high expression of EGFR gene or characterized by changing the EGFR genetic mutation of bioactivity of EGFR nucleic acid molecules or polypeptide.Cancer caused by EGFR may alternatively appear in any tissue (including brain, blood, connective tissue, liver, mouth, muscle, spleen, stomach, testis and tracheae).Cancer caused by EGFR includes but is not limited to 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 lymph cancer, nasopharyngeal carcinoma.

" EGFR mutation " or " EGFR mutant " include one or more missings, displacement or addition in the amino acid or nucleotide sequence of EGFR albumen or EGFR coded sequence.EGFR mutation can also include one or more missings, displacement or addition or its segment, as long as the mutant retains relative to Wild type EGFR or increase tyrosine kinase activity.In specific EGFR mutation, kinases or phosphorylation activity can increase or decrease (for example, at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100%) relative to Wild type EGFR.Illustrative EGFR mutation includes but is not limited to T790M mutation, L858R mutation and the bis- mutation of L858R/T790M.

Specific embodiment

Compound

Herein, " the compounds of this invention " refers to formula below (I) compound-formula (VI) compound (including various subset, such as formula (VIf) compound and formula (VIf-1) compound), its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations.

In one embodiment, the present invention relates to formula (I) compounds:

Wherein,

Linker L is selected from

R^bSelected from H, C_1-6Alkyl or C_1-6Halogenated alkyl；

X is selected from C or N atom, as long as valence link allows；

M is 0,1 or 2；

N is 1,2 or 3；

P represents singly-bound or double bond, as long as chemical valence allows；

Q represents singly-bound or double bond, as long as chemical valence allows；

On condition that X is C atom when m is 0；

Preferably, in this embodiment, R₁Independently selected from halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy.It is highly preferred that R₁Independently selected from halogen, C_1-6Alkoxy or C_1-6Halogenated alkoxy.It is highly preferred that R₁For C_1-6Alkoxy, such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy and 1,2- dimethyl butyrate oxygroup.It is highly preferred that R₁For C_1-4Alkoxy, such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy and sec-butoxy.It is highly preferred that R₁For halogen, such as Cl or Br.It is highly preferred that R₁For Cl or methoxyl group.Most preferably, R₁For methoxyl group.

Preferably, in this embodiment, R₂Independently selected from halogen, C_1-6Alkyl or C_1-6Halogenated alkyl.It is highly preferred that R₂For C_1-6Halogenated alkyl.It is highly preferred that R₂For C_1-4Halogenated alkyl.It is highly preferred that R₂For C_1-2Halogenated alkyl, such as-CF₃、-CH₂F、-CHF₂、-CHFCH₂F、-CH₂CHF₂、-CF₂CF₃、-CCl₃、-CH₂Cl and-CHCl₂.Most preferably, R₂For-CF₃。

Preferably, in this embodiment, L is selected from: 1) C, N or O atom；It is optionally by R^aReplace；2)C_1-6Alkylidene, C_3-10Sub- carbocylic radical, 3 to 10 yuan of sub- heterocycles, C_6-14Arlydene or C_5-10Inferior heteroaryl, it is highly preferred that C_1-6Alkylidene, C_3-10Sub- carbocylic radical or 3 to 10 yuan of sub- heterocycles, it is highly preferred that 3 to 10 yuan of sub- heterocycles, it is highly preferred that 3 to 6 yuan of sub- heterocycles, it is highly preferred that 5 to 6 yuan of sub- heterocycles；It is optionally by R^aReplace；3)-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-,-N (R^b) S (=O)₂,-OC (=O)-,-OS (=O)-,-OS (=O)₂,-S (=O)-or-S (=O)₂, it is highly preferred that-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-or-OC (=O)-, it is highly preferred that-C (=O)-,-C (=O) O- or-OC (=O)-, most preferably ,-C (=O)-.

Preferably, in this embodiment, R^aSelected from H, halogen ,-CN, oxo base, C_1-6Alkyl or C_1-6Halogenated alkyl.It is highly preferred that R^aSelected from H, halogen or oxo base.Most preferably, R^aFor H.

Preferably, in this embodiment, R^bSelected from H or C_1-6Alkyl.It is highly preferred that R^bSelected from H or C_1-4Alkyl.

Preferably, in this embodiment, ring A is selected from C_3-6Carbocylic radical or 3 to 10 circle heterocyclic ring bases.It is highly preferred that ring A is selected from C_5-6Carbocylic radical or 3 to 6 circle heterocyclic ring bases.Most preferably, ring A is 5 to 6 circle heterocyclic ring bases.

Preferably, in this embodiment, R3 is selected from halogen ,-CN ,-NO₂、-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c)、-N(R^c)(R^c)、-N(R^c) C (=O) R^c、-N(R^c) S (=O) R^c、-N(R^c) S (=O)₂R^c、-OR^c,-OC (=O) R^cOr-S (=O)₂R^cAs long as chemistry allows.It is highly preferred that R₃Selected from-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c) or-S (=O)₂R^cAs long as chemistry allows.

Preferably, in this embodiment, R^cSelected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, 3 to 10 circle heterocyclic ring bases.It is highly preferred that R^cSelected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, 5 to 6 circle heterocyclic ring bases.In a preferred embodiment, R^cIn heterocycle optionally by C_1-6Alkyl, C_1-6Halogenated alkyl or-C (=O) C_1-6Alkyl replaces.In a preferred embodiment, R^cIn heterocycle optionally by-C (=O) C_1-6Alkyl replaces.

Preferably, in this embodiment, m is 0 or 1.In a preferred embodiment, 0 m.In a further preferred embodiment, 1 m.

Preferably, in this embodiment, n is 1 or 2.It is highly preferred that n is 1.

Preferably, in this embodiment, p and q represent singly-bound.In a preferred embodiment, p represents singly-bound and q represents double bond.In a further preferred embodiment, p represents double bond and q represents singly-bound.

Preferably, in this embodiment, R₄、R₅And R₆Independently selected from H, halogen ,-CN, C_1-6Alkyl.It is highly preferred that R₄、R₅And R₆It is H.

Preferably, in this embodiment, W is selected from N or O atom.

In another embodiment, the present invention relates to formula (IIa)-(IIe) compounds:

Wherein, Y is selected from C, N, O or S atom, R₁-R₆, X, W, A, n and q it is as hereinbefore defined.

In another embodiment, the present invention relates to formula (IIIa)-(IIIf) compounds:

Wherein, Y is selected from C, N, O or S atom, R₁-R₆、R^a, X, W, A, n, p and q it is as hereinbefore defined.

In another embodiment, the present invention relates to formula (IVa)-(IVo) compounds:

In another embodiment, the present invention relates to formula (Va)-(Vo) compounds:

Wherein, Y is selected from C, N, O or S atom, o 0,1,2 or 3, R₁-R₆、R^a, X, W, A, n and q it is as hereinbefore defined.

In another embodiment, the present invention relates to formula (VIa)-(VIf) compounds:

Wherein, Y is selected from C, N, O or S atom, R₁-R₆, W, A, n and q it is as hereinbefore defined.

In a more particular embodiment, the present invention relates to following formula: compounds:

Wherein, R₁For Cl or methoxyl group, W is-O- or-NH-, R₃It is as hereinbefore defined with n.

The compounds of this invention may include one or more asymmetric centers, and therefore may exist multiple stereoisomers form, for example, enantiomter and/or diastereomeric form.Such as, the compounds of this invention can be individual enantiomter, diastereoisomer or geometric isomer (such as cis and trans isomer), or can be for the form of the mixture of stereoisomer, the mixture including racemic mixture and rich in one or more stereoisomers.Isomers can be separated from mixture by methods known to those skilled in the art, which comprises the formation and crystallization of chiral high pressure liquid chromatography (HPLC) and chiral salt；Or preferred isomers can be prepared by asymmetric syntheses.

The present invention also includes all suitable isotopic variations of the compounds of this invention.The definition of the isotopic variations of the compounds of this invention is replaced by wherein at least one atom with the different atom of the atomic mass being generally found in same atoms number but atomic mass and nature.Example of isotopes that can be incorporated into the compounds of the invention includes the isotope of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as is respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²p、³⁵S and³⁶Cl.Some isotopic variations of the compounds of this invention, such as wherein mix radioactive isotope such as³H or¹⁴Those of C can be used for drug and/or substrate tissue distribution research.It is tritiated (i.e.³H) and carbon-14 (i.e.¹⁴C) isotope is particularly preferred because its is easily prepared and detectability.In addition, with isotope (such as deuterium, i.e.,²H some treatment advantages as obtained from bigger metabolic stability can be provided by) replacing, such as increased Half-life in vivo or the dosage of reduction need, and therefore can be in some cases preferred.The isotopic variations of the compounds of this invention can usually be prepared by the following procedure: conventional program for example by illustrative method or by preparing described in Examples below, uses the appropriate isotopic variations of suitable agent.

The present inventor is after study, it is surprised to find that, deuterated diaminopyrimidine compounds and its pharmaceutically acceptable salt of the invention are compared with not deuterated compound, with equivalent or superior pharmacokinetics and/or pharmacodynamics performance, therefore it is suitable as inhibiting the compound of EGFR kinases, and then the drug of more applicable preparation treating cancer and EGFR kinase-associated conditions.

The compounds of this invention or its pharmaceutically acceptable salt can be amorphous or crystal form.In addition, the compounds of this invention can exist with one or more crystal forms.Therefore, the present invention includes all amorphous or crystal form of the compounds of this invention within its scope.

It will be understood by those skilled in the art that many organic compounds can form compound with solvent, reacts in the solvent or precipitate or crystallize out from the solvent.These compounds are known as " solvate ".When solvent is water, compound is known as " hydrate ".Present invention encompasses all solvates of the compounds of this invention.

In addition, prodrug is also included in context of the invention.The term as used herein " prodrug " refers to the compound for being transformed into its active form with medical effect for example, by hydrolyzing in blood in vivo.Pharmaceutically acceptable prodrug is described in T.Higuchi and V.Stella, Prodrugs as Novel Delivery Systems, the Vol.14 of A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 and D.Fleisher, S.Ramon and H.Barbra " Improved ora L drug delivery:solubility limitations overcome by the use of prodrugs "; (1996) 19 (2) 115-130 of Advanced Drug Deliver yReviews, every is incorporated herein by reference.

Prodrug is the carrier of any covalent bonding, when giving this prodrug to patient, discharges formula (I) compound in vivo.Prodrug is usually prepared by modification functional group, modification is so that the modification can be carried out routine operation or in vivo by way of cracking generation parent compound.Prodrug includes, for example, the wherein the compounds of this invention of hydroxyl, amine or sulfydryl and any group bonding can crack to form hydroxyl, amine or sulfydryl when being given patient.Therefore, the representative example of prodrug includes but is not limited to acetic acid esters, formic acid esters and the benzoate derivatives of the alcohol of formula (I) compound, sulfydryl and amine functional group.In addition, ester, such as methyl esters, ethyl ester etc. can be used in the case where carboxylic acid (- COOH).Ester itself can be it is active and/or can be in body under the conditions of hydrolyze.It is suitable pharmaceutically acceptable internal Hydrolyzable ester group includes being easy to decompose in human body and discharge those of parent acid or its salt group.

Pharmaceutical composition, preparation and kit

On the other hand, the present invention provides pharmaceutical compositions, and it includes the compounds of this invention (also known as " active component ") and pharmaceutically acceptable excipient.In some embodiments, described pharmaceutical composition includes a effective amount of active component.In some embodiments, described pharmaceutical composition includes the active component of therapeutically effective amount.In some embodiments, described pharmaceutical composition includes the active component of prevention effective dose.

Refer to the non-toxic carriers that will not destroy the pharmacological activity for the compound deployed together, adjuvant or mediator for pharmaceutically acceptable excipient of the invention.It can be used for the pharmaceutically acceptable carrier in the present composition, adjuvant or mediator include but is not limited to ion-exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin (such as human serum albumin), buffer substance (such as phosphate), glycine, sorbic acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, substance based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

The invention also includes kit (for example, drug packages).Provided kit may include the compounds of this invention, other therapeutic agents, and the first and second containers (for example, bottle, ampoule bottle, bottle, syringe and/or dispersible packaging or other suitable containers) containing the compounds of this invention, other therapeutic agents.In some embodiments, the kit provided can also optionally include third container, contain the pharmaceutical excipient for dilute or suspend the compounds of this invention and/or other therapeutic agents.In some embodiments, the compounds of this invention in the first container and second container is provided and other therapeutic agents combine to form a unit dosage forms.

Following example of formulations explanation can representative pharmaceutical composition prepared in accordance with the present invention.However, the present invention is not limited to agents compositions.

Illustrative preparation 1- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 0.3-30mg tablet in tablet press machine (each tablet contains 0.1-10mg reactive compound).

Illustrative preparation 2- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 30-90mg tablet in tablet press machine (each tablet contains 10-30mg reactive compound).

Illustrative preparation 3- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 90-150mg tablet in tablet press machine (each tablet contains 30-50mg reactive compound).

Illustrative preparation 4- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 150-240mg tablet in tablet press machine (each tablet contains 50-80mg reactive compound).

Illustrative preparation 5- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 240-270mg tablet in tablet press machine (each tablet contains 80-90mg reactive compound).

Illustrative preparation 6- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 270-450mg tablet in tablet press machine (each tablet contains 90-150mg reactive compound).

Illustrative preparation 7- tablet: the compounds of this invention of dry powder form can be mixed with dry gel adhesive with about 1: 2 weight ratio.Less amount of magnesium stearate is added as lubricant.So that the mixture is shaped to 450-900mg tablet in tablet press machine (each tablet contains 150-300mg reactive compound).

Illustrative preparation 8- capsule: the compounds of this invention of dry powder form can be mixed with starch diluent with about 1: 1 weight ratio.The mixture is filled into 250mg capsule (each capsule contains 125mg reactive compound).

Illustrative preparation 9- liquid: the compounds of this invention (125mg) can be mixed with sucrose (1.75g) and xanthan gum (4mg), and obtained mixture can be blended, pass through No.10 sieve mesh U.S. sieve, then it is mixed with the aqueous solution of previously prepared microcrystalline cellulose and sodium carboxymethylcellulose (11: 89,50mg).Sodium benzoate (10mg), flavoring agent and colorant are diluted with water, and are added under stiring.It is then possible to which sufficient water is added, the total volume of 5mL is obtained.

Illustrative preparation 10- injection: the compounds of this invention can be dissolved or suspended in the aqueous medium of buffering Sterile Saline injectable, reaches the concentration of about 5mg/mL.

Administration

Pharmaceutical composition provided by the invention can be administered by many approach, including but not limited to: oral administration, inhalation, local administration, rectally, nasal-cavity administration, oral administration, vagina administration, passes through implant administration or other administration modes at parenteral administration.For example, parenteral administration used herein include subcutaneous administration, intradermal administration, intravenous administration, intramuscular adminstration, intra-articular administration, intraarterial delivery, synovial membrane intracavitary administration, administration in breastbone, in meninges administration, intralesional administration and encephalic injection or infusion techn.

In general, giving a effective amount of compound provided in this article.According to related situation, administration route including the illness, selection treated, the compound actually given, age, weight and the response of individual patient, the severity of patient symptom, etc. can be determined the amount for the compound actually given by doctor.

When for when preventing illness of the present invention, giving in the subject's compound provided in this article formed among the illness danger, will be typically based on the suggestion of doctor and being administered under doctor's supervision, dosage level is as described above.Subject among the danger for forming specific illness generally includes the subject with the family history of the illness, or determines subject especially those of sensitive to the formation illness by genetic test or screening.

Pharmaceutical composition provided in this article (" long term administration ") can also be given for a long time.Long term administration refers to gives compound or its pharmaceutical composition in a long time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years etc., or can indefinitely be administered continuously, for example, the remaining years of subject.In some embodiments, long term administration is intended to provide the constant level of the compound in blood in a long time, for example, in therapeutic window.

Various medications can be used, further deliver pharmaceutical composition of the invention.For example, in some embodiments, it can be with inject administration pharmaceutical composition, for example, in order to improve the concentration of compound in blood to effective level.Bolus dose is determined by the target systemic levels of the active component of body, such as, intramuscular or subcutaneous bolus dose makes active component slow release, and be directly delivered to the injecting of vein (such as, pass through IV intravenous drip) it can more rapidly deliver, so that the concentration of active component in blood is quickly increased to effectively It is horizontal.In other embodiments, pharmaceutical composition can be given in the form of continuous infusion, for example, by IV intravenous drip, to provide the active component of Css in subject's body.In addition, in other embodiments, the pharmaceutical composition of bolus dose can be given first, then continuous infusion.

Orally administered composition can be using bulk liquids solution or suspension or bulk powder form.However, more generally, for the ease of the administration of accurately dosage, providing the composition in a unit.Term " unit dosage forms " refers to the physical discrete unit for being suitable as the dosage unit of human patients and other mammals, and each unit includes predetermined quantity, active material and suitable pharmaceutical excipient suitable for therapeutic effect required for generating.Typical unit dosage form includes the prefilled of liquid composition, the ampoule or syringe, or pill, tablet, capsule in solid composite that measure in advance etc..In such a composition, the compound is usually less component (about 0.1 to about 50 weight %, or preferably from about 1 to about 40 weight %), and remainder is the various carriers or excipient and processing aid useful for form of medication needed for being formed.

For oral dose, representative scheme is daily one to five oral doses, especially two to four oral doses, typically three oral doses.Using these dosage mode of administration, each dosage provides about 0.01 to about 20mg/kg the compounds of this invention, and preferred dosage respectively provides about 0.1 to about 10mg/kg, especially about 1 to about 5mg/kg.

In order to provide the blood level similar with injection dosage is used, or than using the lower blood level of injection dosage, generally select transdermal dosage compositions, quantity is about 0.01 to about 20% weight, preferably approximately 0.1 to about 20% weight, preferably approximately 0.1 to about 10% weight, and more preferably from about 0.5 to about 15% weight.

From about 1 to about 120 hour, especially 24 to 96 hours, range of the injection dosage level at about 0.1mg/kg/ hours at least 10mg/kg/ hours.In order to obtain enough steady state levels, about 0.1mg/kg can also be given and injected to the preloading of about 10mg/kg or more.For 40 to 80kg human patients, maximum accumulated dose was no more than about 2g/ days.

Liquid form suitable for oral administration may include suitable aqueous or nonaqueous carrier and buffer, suspending agent and dispersing agent, colorant, flavoring agent, etc..Solid form may include, for example, any following component, or the compound with similarity: adhesive, for example, microcrystalline cellulose, bassora gum or gelatin；Excipient, for example, starch or lactose, disintegrating agent, for example, alginic acid, Primogel or cornstarch；Lubricant, for example, magnesium stearate；Glidant, for example, colloidal silicon dioxide；Sweetener, for example, sucrose or saccharin；Or flavoring agent, for example, peppermint, gaultherolin or orange flavoring.

The composition of injectable will be typically based on the Sterile Saline of injectable or the excipient of phosphate buffered saline (PBS) or other injectables as known in the art.As previously mentioned, in such a composition, reactive compound is typically less component, often about 0.05 to 10% weight, remainder is the excipient etc. of injectable.

Transdermal composition is typically formulated as to topical ointments or cream containing active component.When being formulated as ointment, active component is typically combined with paraffin or ointment bases miscible with water.Alternatively, active component can be formulated as cream together with such as oil-in-water type cream base.This preparation capable of permeating skin is it is well known in the art that and generally including other components of the stable Cutaneous permeation for promoting active component or preparation.All this known preparation capable of permeating skin and component include in range provided by the invention.

The compounds of this invention can also be given by transcutaneous device.Therefore, reservoir (reservoir) or porous film type or the patch of many kinds of solids matrix can be used to realize for percutaneous dosing.

Above-mentioned component for the oral composition given, inject or administered locally to is only representative.Other materials and processing technology etc. are set forth in Remington ' s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, In the 8th part of Pennsylvania, it is incorporated by reference the document herein.

The compounds of this invention can also be given with sustained release form, or give from sustained release administration system.The description of representative sustained release materials can be found in Remington ' s Pharmaceutical Sciences.

The invention further relates to the pharmaceutically acceptable preparations of the compounds of this invention.In one embodiment, the preparation includes water.In another embodiment, the preparation includes cyclodextrine derivatives.The most common cyclodextrin is respectively by 6,7 and 8 α -1; α -, β-and the gamma-cyclodextrin of the glucose unit composition of 4- connection; it optionally includes one or more substituent groups in the saccharide part of connection comprising but be not limited to: methylation, hydroxy alkylated, acylation and sulfoalkyl ether replaces.In some embodiments, the cyclodextrin is sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also referred to as Captisol.See, e.g., U.S.5,376,645.In some embodiments, the preparation includes six propyl-beta-cyclodextrins (for example, in water, 10-50%).

Combination

The compounds of this invention or combinations thereof object can with other therapeutic agent combination medicine-feedings, to treat the disease.The example of known treatment agent includes but is not limited to A Deli mycin (Adriamycin), dexamethasone (dexamethasone), vincristine (vincristine), cyclophosphamide (cyclophosphamide), fluorouracil (fluorouracil), topotecan (topotecan), taxol (taxol), interferon, platinum derivatives, taxane (taxane) (such as Paclitaxel (paclitaxel)), vinca alkaloids (such as vincaleukoblastinum (vinblastine)), anthracycline (anthracycline) (such as Doxorubicin (doxombicin)), epipodophyllotoxin (e Pipodophyllotoxin) (such as Etoposide (etoposide)), cis-platinum (cisplatin), mTOR inhibitors (such as rapamycin (rapamycin)), methotrexate (MTX) (methotrexate), actinomycin D (actinomycin D), aplysiatoxin 10 (dolastatin 10), colchicin (colchicine), emetine (emetine), Trimetrexate (trimetrexate), metoprine (metoprine), cyclosporin (cyclosporine), daunomycin (daunorubicin), Teniposide (tenipos Ide), anphotericin (amphotericin), alkylating agent (such as Chlorambucil (chlorambucil)), 5 FU 5 fluorouracil, camptothecine (camptothecin), cis-platinum, flagyl (metronidazole) and Gleevec^TM.In other embodiments, the compounds of this invention is with such as Arastin (Avastin) or dimension gram for than (VECTIBIX) biological agent combination medicine-feeding.

In some embodiments, the compounds of this invention or combinations thereof object can be administered with selected from any one of following or more than one antiproliferative or chemotherapeutic combination: abarelix (abarelix), Aldesleukin (aldesleukin), alemtuzumab (alemtuzumab), alitretinoin (alitretinoin), allopurinol (allopurinol), hemel (altretamine), Amifostine (amifostine), Anastrozole (anastrozole), arsenic trioxide, asparaginase, azacitidine (azacitidine), BCG Live, bevacizumab (bevacuzimab), fluorouracil , Bei Seluoting (bexarotene), bleomycin (bleomycin), bortezomib (bortezomib), busulfan (busulfan), clausterone (calusterone), capecitabine (capecitabine), camptothecine, carboplatin (carboplatin), Carmustine (carmustine), 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-l-yl (celecoxib), Cetuximab (cetuximab), Chlorambucil (chlorambucil), Cladribine (cladribine), clofarabine (clofarabine), cyclophosphamide, cytarabine (cytarabine), actinomycin D, it reaches Bei Boting α (darbepoetin alfa), daunomycin, denileukin (denileukin), dexrazoxane (dexrazoxane), Docetaxel (docetaxel), Doxorubicin, doxorubicin hydrochloride, dromostanolone propionate (dromostanolone propionate), epirubicin (epirubicin), Yi Baiting α (epoetin alfa), Erlotinib (erlotinib), Estramustine (estramustine), etoposide phosphate, Etoposide, Exemestane (exemestane), Filgrastim (filgrastim), floxuridine (floxurid Ine), fludarabine (fludarabine), fulvestrant (fulvestrant), Gefitinib, gemcitabine (gemcitabine), lucky trastuzumab (gemtuzumab), goserelin acetate (goserelin acetate), acetic acid Histrelin (histrelin Acetate), hydroxycarbamide (hydroxyurea), ibritumomab tiuxetan (ibritumomab), Ida mycin (idarubicin), ifosfamide (ifosfamide), imatinib mesylate (imatinib mesylate), Intederon Alpha-2a, Interferon Alpha-2b, Irinotecan (irinotecan), lenalidomide (lenalidomide), Letrozole (letrozole), formyl tetrahydrofolic acid (leucovorin), acetic acid leuproside (leuprolide acetate), levamisol (levamisole), lomustine (lomustine), acetic acid first Ground progesterone (megestrol acetate), melphalan (melphalan), mercaptopurine (mercaptopurine), 6-MP, mesna (mesna), methotrexate (MTX), psoralen (methoxsalen), mitomycin C (mitomycin C), mitotane (mitotane), mitoxantrone (mitoxantrone), nandrolone (nandrolone), nelarabine (nelarabine), nofetumomab (nofetumomab), oprelvekin (oprelvekin), oxaliplatin (oxaliplatin), Paclitaxel, Pa Lifuming (palifer Min), Pamidronate (pamidronate), Pegademase (pegademase), Pegaspargase (pegaspargase), glycation Filgrastim (pegfilgrastim), pemetrexed disodium (pemetrexed disodium), spray department statin (pentostatin), pipobroman (pipobroman), plicamycin (plicamycin), Porfimer Sodium (porfimer sodium), procarbazine (procarbazine), quinacrine (quinacrine), rasburicase (rasburicase), Rituximab (rituximab), Sargramostim (sargramostim), Sorafenib (sorafenib), streptozotocin (streptozocin), maleic acid Sutent (sunitinib maleate), talcum, tamoxifen (tamoxifen), Temozolomide (temozolomide), Teniposide, VM-26, Testolactone (testolactone), thioguanine (thioguanine), 6-TG, thiotepa (thiotepa), topotecan, Toremifene (toremifene), tositumomab (tosimmomab), Herceptin (trastuzumab), vitamin A acid (tretin Oin), ATRA, uracil mastard (uracil mustard), cut down it is soft than star (valrubicin), vincaleukoblastinum, vincristine (vincristine), vinorelbine (vinorelbine), zoledronate (zoledronate) or zoledronic acid (zoledronic acid).

The other examples for the therapeutic agent that the compounds of this invention can also combine include but is not limited to: the therapeutic agent of Alzheimer's disease (Alzheimer ' s Disease) are used for, as Doneppezil Hydrochloride (donepezil hydrochloride) and Leix replace bright (rivastigmine)；For the therapeutic agent of Parkinson's disease (Parkinson ' s Disease), such as L-DOPA/ carbidopa (carbidopa), Entacapone (entacapone), ropinirole (ropinrole), Pramipexole (pramipexole), bromocriptine (bromocriptine), pergolide (pergolide), artane (trihexephendyl) and amantadine (amantadine)；For multiple sclerosis (Multiple Sclerosis；MS therapeutic agent), such as beta interferon, grammer acetate (glatiramer acetate) and mitoxantrone；For the therapeutic agent of asthma, such as albuterol (albuterol) and montelukast；For schizoid therapeutic agent, such as Zyprexa (zyprexa), Li Sibi appropriate (risperdal), Seroquel (seroquel) and haloperidol (haloperidol)；Antiphlogistic, such as corticosteroid, TNF blocking agent, IL-1RA, imuran (azathioprine), cyclophosphamide and salicylazosulfapyridine (sulfasalazine)；Immunomodulator and immunosuppressor, such as cyclosporine (cyclosporin), tacrolimus (tacrolimus), rapamycin, mycophenolate mofetil (mycophenolate mofetil), interferon, corticosteroid, cyclophosphamide, imuran and salicylazosulfapyridine；Neurotrophic factor, such as acetylcholinesterase inhibitor, MAO inhibitor, interferon, anticonvulsant, ion channel blocking agent, Riluzole (riluzole) and anti-parkinson agent；For the therapeutic agent of cardiovascular disease, such as Beta receptor blockers, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, diuretics, nitrate, calcium ion channel blockor and Statins (statin)；For the therapeutic agent of hepatopathy, such as corticosteroid, cholestyramine (cholestyramine), interferon and antivirotic；For the therapeutic agent of blood disorder, such as corticosteroid, anti-leukocythemia agent and growth factor；And the therapeutic agent for immune deficiency illness, such as gamma Globulin.

Those other activating agents can separately be administered with the composition containing the compounds of this invention, a part as multiple dosage regimen.Alternatively, those activating agents can be a part of single formulation, it is mixed together in single composition with the compounds of this invention.If a part administration as multiple dosage regimen, two kinds of activating agents can simultaneously, successively or be spaced each other a period of time (being usually spaced each other within 5 hours) and provide.

Treatment

The present invention provides a kind of method for inhibiting protein tyrosine kinase (such as EGFR kinases) or the methods for treating disease (such as cancer, cell proliferation disorders, inflammation, infection, immunity disease, organ transplant, viral disease, cardiovascular disease or metabolic disease), it is comprising steps of give snibject's the compounds of this invention in need for the treatment of, or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations, or administration pharmaceutical composition of the present invention.

The compounds of this invention can be used for cancer caused by treating EGFR.Especially, the compound can be used for treating cancer caused by the EGFR of expression EGFR mutant and for treating cancer caused by the EGFR refractory to RTKI therapy (for example, Tarceva or Gefitinib).

The compounds of this invention is the inhibitor of at least one mutant of EGFR and is therefore suitable for the relevant one or more kinds of illnesss of activity for the treatment of with one or more EGFR mutant (such as deletion mutation, Activating mutations, resistant mutation or combinations thereof, specific example include T790M mutation, L858R mutation and the bis- mutation of L858R/T790M).Therefore, in a particular embodiment, the present invention provides a kind of method for treating the illness that mutation EGFR is mediated, it includes the compounds of this invention is administered to patient in need, or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations, or the step of pharmaceutical composition of the present invention is administered.

The medicable cancer of the compounds of this invention includes but is not limited to: the excess proliferative diseases such as non-small cell lung cancer (NSCLS), 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 lymph cancer, nasopharyngeal carcinoma.In addition, the compounds of this invention can also be used for the maintenance effect for playing prevention cancer return in the patient for needing such treatment.

The effective quantity of the compounds of this invention is usually 0.01mg to 50mg compound/kilogram of patient weight, preferably 0.1mg to 25mg compound/kilogram of patient weight, with single or multiple administrations in average daily dose.In general, the patient that the compounds of this invention can have this treatment to need to this is administered with the daily dose range of every patient about 1mg to about 3500mg, preferably 10mg to 1000mg.For example, the daily dose of every patient can be 10,20,30,40,50,60,70,80,90,100,150,200,250,300,350,400,500,600,700,800,900 or 1000mg.It can be administered once or repeatedly daily, weekly (or interval a couple of days) or with intermittent schedule.For example, can be on the basis of weekly (such as on every Mondays), it is one or many to be given once daily the compound, erratically or continues several weeks, such as 4-10 weeks.Alternatively, can daily administration take several days (such as 2-10 days), then the compound is not administered within several days (such as 1-30 days), erratically repeats the circulation or repeat given number, such as 4-10 recycles.For example, the compounds of this invention can daily administration continue 5 days, then be interrupted 9 days, then daily administration continues 5 days again, then be interrupted 9 days, and so on, erratically repeat the circulation or altogether repeat 4-10 times.

When RTKI (for example, Tarceva or Gefitinib) and the compounds of this invention are applied in combination, each ingredient of the combination treatment can be with the dosage level and administration of their monotherapies.For example, Tarceva, for treating NSCLC, with daily 150mg oral administration, for cancer of pancreas, with daily 100mg oral administration.In another example, Gefitinib is for treatment NSCLC with daily 250mg oral administration.

Preferably, when RTKI (for example, Tarceva or Gefitinib) is applied in combination with the compounds of this invention, the dosage level of one or two kinds of ingredients is reduced compared to when being used alone.

Embodiment

Following embodiment is provided to provide the complete disclosure and explanation that how to carry out, prepare and assess claimed method and compound herein for those skilled in the art, it is intended to which only example is of the invention rather than invention scope that limitation inventor thinks.

Synthetic method

The compounds of this invention can be prepared according to conventional method in that art, and using suitable reagent, raw material and purification process well known by persons skilled in the art.

Scheme 1

Scheme 1 instantiates the preparation of intermediate.Specifically; the intermediate can be prepared by following steps: 2 that 5- is replaced; (its commercially available acquisition of 4- dichloro pyrimidine; or obtained by known raw material through reaction well known in the art) be coupled under typical coupling condition with the aniline replaced of the 3- through protecting; deprotection base; then intermediate and substituted acrylic acid or derivatives thereof (such as acryloyl chloride) is coupled, obtains intermediate.

Scheme 2

Scheme 2 instantiates several preparations of another intermediate.Specifically, the intermediate can be prepared by following steps: for the 4- halogen nitrobenzene (its commercially available acquisition, or obtained by known raw material through reaction well known in the art) that 2- is replaced through coupling reaction, reduction reaction obtains intermediate；Or the 4- nitrobenzoic acid (ester) for replacing 3- obtains intermediate through reduction, halogenation, coupling, reduction.

Scheme 3

Scheme 3 instantiates the preparation of formula (I) compound.Specifically, it can be made by intermediate prepared by scheme 1 and scheme 2 through coupling reaction.

The preparation method of formula (I) compound of the present invention is described more particularly below, but these specific methods do not form any restrictions to the present invention.Various synthetic methods describing in the present specification or known in the art can also optionally be combined and are easily made by the compounds of this invention, and such combination can be easy to carry out by those skilled in the art in the invention.

In general, each reaction carries out usually in atent solvent at (such as 0 DEG C~100 DEG C, preferably 0 DEG C~80 DEG C) of room temperature to reflux temperature in preparation.Reaction time is usually -60 hours 0.1 hour, preferably 0.5-24 hours.

Embodiment 1

N- (3- ((2- ((4- (1- acetyl piperidine -4- base) oxygroup) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propylene Amide

Step 1:

4- hydroxy piperidine -1- t-butyl formate (4.70g, 23.3mmol), the fluoro- 2- methoxy nitrobenzene (2g, 11.6mmol) of 4-, tetrabutylammonium bromide (0.754g, 2.34mmol) and potassium hydroxide aqueous solution are stirred overnight in toluene in 60 DEG C.So that reaction mixture is restored to room temperature, is extracted after being diluted with water with ethyl acetate.Yellow oil product 4- (3- methoxyl group -4-nitrophenoxy) piperidines -1- t-butyl formate (3.73g, 91% yield) is obtained using column chromatography purifies and separates after the organic phase of collection is dry.¹HNMR (300MHz, CDCl₃) (δ/ppm): 8.01 (d, J=9.6Hz, 1H), 6.56-6.49 (m, 2H), 4.61-4.57 (m, 1H), 3.96 (s, 3H), 3.75-3.67 (m, 2H), 3.44-3.36 (m, 2H), 2.01-1.94 (m, 2H), 1.84-1.76 (m, 2H), 1.45 (s, 9H).LC-MS (APCI): m/z=353.2 (M+1)⁺, purity: 97.6%.

Step 2:

By 4- (3- methoxyl group -4-nitrophenoxy) piperidines -1- t-butyl formate (0.5g, 1.42mmol) be added to equipped with ethyl alcohol (15mL), water (5mL) mixture three-neck flask in, then it is continuously added to iron powder (0.48g, 8.51mmol) and ammonium chloride (38mg, 0.71mmol) and stir 1h, after low pressure revolving removes ethyl alcohol, water is added, and it is extracted with dichloromethane, collect organic phase, it is spin-dried for obtaining light brown oil product 4- (4- amino -3- Difluoro-phenoxy) piperidines -1- t-butyl formate (0.25g, yield 56.7%).LC-MS (APCI): m/z=323.2 (M+1)⁺, purity: 90.5%.

Step 3:

To equipped with magnetic agitation, N₂Ball, n-butanol (9mL) is added in the 50mL there-necked flask of thermometer, ice-water bath is cooling, temperature is no more than 5 DEG C in keeping, 3- aminophenyl is added) t-butyl carbamate (0.96g, 4.6mmol), it is slowly added dropwise into 2, the chloro- 5- trifluoromethyl pyrimidine (1.0g of 4- bis-, 4.6mmol), then N, N- diisopropyl ethyl amine (0.67g, 5.5mmol) it is slowly dropped into reaction solution, it finishes, mixed liquor ice-water bath stirs 1h, 4h is stirred under room temperature, the a large amount of white solids filtering generated, n-butanol (2mL) washing, it drains, 50 DEG C are dried in vacuo to obtain white solid 1.4g, yield 78.3%.¹H NMR (400MHz, DMSO-d6) (δ/ppm): 9.53 (s, 1H), 9.46 (s, 1H), 8.57 (s, 1H), 7.58 (s, 1H), 7.28-7.26 (m, 2H), 7.04-7.01 (m, 1H), 1.48 (s, 9H), LC-MS (APCI): m/z=389.1 (M+1)⁺, purity: 97%.

Step 4:

Methylene chloride (15mL) is added in 100mL three-necked flask, it is added with stirring (3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (1.0g, 2.57mmol), ice-water bath is cooling, it is added dropwise to trifluoracetic acid (3mL), remove ice bath, N₂Stirring at normal temperature reacts 1h under atmosphere.Methylene chloride (50mL) is added again, is added dropwise to triethylamine (5.6mL, 40.4mmol) under ice salt bath is cooling and neutralizes trifluoracetic acid, mixture is cooled to -10 DEG C, it is slowly added dropwise under nitrogen atmosphere into acryloyl chloride (0.27g, 3mmol), insulated and stirred 5min.H is added₂O (100mL) quenching reaction, separate organic layer, successively use water (100mL x 2), 0.5M HCl (aq., 15mL), saturated sodium bicarbonate water liquid (15mL) washs, and anhydrous sodium sulfate dries, filters, filtrate concentration, residue crosses silicagel column, and (petroleum ether: ethyl acetate=3: 1) 100-200 mesh obtains title compound 0.6g, two step yields 68.1%.¹HNMR (300MHz, DMSO-d6) δ (ppm): 10.25 (s, 1H), 9.59 (s, 1H), 8.59 (s, 1H), 7.80-1.79 (m, 1H), (7.51 d, J=7.8Hz, 1H), (7.36 t, J=7.8Hz, 1H), (7.14 d, J=7.8Hz, 1H), 6.50-6.41 (m, 1H), 6.30-6.23 (m, 1H), 5.77 (dd, J=9.3Hz, 2.1Hz, 1H) .LC-MS (APCI): m/z=343.1 (M+1)⁺, purity: 98%.

Step 5:

N- (3- (the chloro- 5- trifluoromethyl pyrimidine -4- base amino of 2-) phenyl) acrylamide (0.21g, 0.62mmol) and trifluoroacetic acid (three drops) are added Into Isosorbide-5-Nitrae-dioxane solution of 4- (4- amino -3- Difluoro-phenoxy) piperidines -1- t-butyl formate (0.2g, 0.62mmol), it is added to 60 DEG C, stirs 3h.After reacting liquid temperature is cooled to room temperature, 3 drop triethylamines, vacuum distillation are added, crude product separates to obtain white solid product (240mg, yield 61.3%) through column chromatography (PE: EA=4: 1).¹HNMR (300MHz, DMSO-d₆) (δ/ppm): 10.15 (s, 1H), 8.69 (br s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.75 (br s, 1H), 7.53-7.48 (m, 2H), 7.25 (t, J=7.5Hz, 1H), 7.16-7.15 (m, 1H), 6.58 (d, J=2.4Hz, 1H), 6.49-6.40 (m, 1H), 8.29-8.22 (m, 2H), 5.76 (dd, J=9.9Hz, 2.4Hz, 1H), 4.46-4.44 (m, 1H), 3.75 (s, 3H), 3.67-3.62 (m, 3H), 3.30-3.18 (m, 2H ), 1.85-1.83 (m, 2H), 1.50-1.45 (m, 2H), 1.41 (s, 9H).LC-MS (APCI): m/z=629.2 (M+1)⁺, purity: 95.6%.

Step 6:

Trifluoroacetic acid (2mL) is added in methylene chloride (15mL) solution of 4- (4- (4- (3- acrylamide phenylamino) -5- trifluoromethyl pyrimidine -2- base amino) -3- methoxyphenoxy) piperidines -1- t-butyl formate (200mg), stirs 2h.It is spin-dried for, is directly used in next step.

Step 7:

By triethylamine (60mg, 0.6mmol) it is added to N- (3- (2- (2- methoxyl group -4- (piperidin-4-yl oxygroup) phenylamino) -5- trifluoromethyl pyrimidine -4- base amino) phenyl) acrylamide (0.1g, in methylene chloride (10mL) solution 0.19mmol), it is cooled to 0 DEG C, Ac is added in a nitrogen atmosphere₂O (25mg, 0.25mmol), water is added after stirring 10min, it is extracted with dichloromethane, it is spin-dried for after anhydrous sodium sulfate is dry, cross column and obtain white solid product N- (3- ((2- ((4- (1- acetyl piperidine -4- base) oxygroup) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (60mg, yield 55%).¹H NMR (300MHz, DMSO-d₆) (δ/ppm): 10.16 (s, 1H), 8.67 (br s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.75 (br s, 1H), 7.52-7.48 (m, 2H), 7.25 (t, J=8.4Hz, 1H), 7.16 (br s, 1H), 8.59 (d, J=2.7Hz, 1H), 6.49-6.40 (m, 1H), 6.29-6.22 (m, 2H), 6.76 (dd, J=9.9Hz, 2.4Hz, 1H), 4.51-4.49 (m, 1H), 3.84-3.81 (m, 1H), 3.77 (s, 3H), 3.66-3.63 (m, 1H), 3.30-3.23 (m, 2H), 2.02 (s, 3H), 1.86-1.81 (m, 2H), 1.58-1.55 (m, 2H).LC-MS (APCI): m/z=571.2 (M+1)⁺, purity: 97.5%.

Embodiment 2

N- (3- ((2- ((4- (1- acetyl piperidine -4- base) amino) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propylene Amide

Step 1:

Synthesis step is identical as 1 step 1 of embodiment, obtains product 4- (3- methoxyl group -4- nitro-phenylamino) piperidines -1- t-butyl formate (0.96g, yield: 93.6%).LC-MS (APCI): m/z=352 (M+1)⁺, purity: 95.1%.

Step 2:

Synthesis step is identical as 1 step 2 of embodiment, and obtaining navy blue oil product 4- (4- amino -3- Methoxyphenylamino) piperidines -1- t-butyl formate, (yield: 91%) 0.19g, is directly used in next step.

Step 3:

Synthesis step is identical as 1 step 3 of embodiment, obtain white solid product 4- ((4- ((4- (3- acrylamide phenylamino) -5- trifluoromethyl pyrimidine -2- base) amino -3- methoxyphenyl) amino) piperidines -1- t-butyl formate (89mg, yield: 54.6%).

Step 4:

Synthesis step is identical as 1 step 4 of embodiment, obtain product N- (3- (2- (2- methoxyl group -4- (piperidin-4-yl amino) phenyl) amino) -5- trifluoromethyl pyrimidine -2- base) amino) phenyl) acrylamide, it is directly used in next step.

Step 5:

Synthesis step is identical as 1 step 5 of embodiment, obtain product N- (3- ((2- ((4- (1- acetyl piperidine -4- base) amino) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (48mg, yield: 60.3%).¹H NMR (300MHz, DMSO-d₆) (δ/ppm): 10.25 (s, 1H), 8.45 (br s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.65 (br s, 1H), 7.52-7.49 (m, 1H), 7.26-7.22 (m, 3H), 6.54-6.45 (m, 1H), 6.29-6.22 (m, 2H), 6.05-6.90 (m, 1H), 5.77-5.74 (m, 1H), 5.40-5.37 (m, 1H), 4.22-4.18 (m, 1H), 3.78-3.82 (m, 1H), 3.68 (s, 3H), 3.24-3.15 (m, 1H), 2.86-2.79 (m, 1H ), 2.00 (s, 3H), 1.93-1.85 (m, 2H), 1.30-1.25 (m, 3H).LC-MS (APCI): m/z=570.1 (M+1)⁺, purity: 95.6%.

Embodiment 3

N- (3- ((2- ((4- (1- acetyl group -1,2,3,6- tetrahydropyridine -4- bases) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) Phenyl) acrylamide

Step 1:

By PdCl₂(dppf)₂(422mg, 0.052mmol) is added to the bromo- 2- methoxy nitrobenzene (2.0g, 8.62mmol) of 4-, 4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- base) -1,2,5,6- tetrahydropyridine -1- t-butyl formates and K₂CO₃In Isosorbide-5-Nitrae-dioxane (40mL) solution of (3.57g, 19.38mmol), it is heated to 90 DEG C in a nitrogen atmosphere and stirs 14h.It is poured into water (150mL) to be extracted with methylene chloride (50mL x 3) afterwards, be spin-dried for, cross column and obtain yellow solid product 4- (3- methoxyl group -4- nitrobenzophenone) -1,2,5,6- tetrahydropyridine -1- t-butyl formate (1.6g, yields: 56%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 7.87 (d, J=9Hz, 1H), 7.03-7.00 (m, 2H), 6.19 (s, 1H), 4.13 (t, J=3Hz, 2H), 3.99 (s, 3H), (3.67 t, J=6Hz, 2H), 1.53 (s, 9H).LC-MS (APCI): m/z=335.2 (M+1)⁺, purity: 94.6%.

Step 2:

Concrete operation step does not have to separation, obtains product 4- (3- methoxyl group -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridines: LC-MS (APCI): m/z=235.3 (M+1) with the step 4 of embodiment 1⁺, purity: 93.4%.

Step 3:

By triethylamine (181.4mg, 1.79mmol) and acetic anhydride (91.5mg, 896 μm of ol) it is added in the reaction mixture of previous step, 30min is stirred at room temperature, is spin-dried for, crosses column (DCM: MeOH=40: 1~20: 1) and obtains yellow oil product 1- (4- (3- methoxyl group -4- nitrobenzophenone) -1,2,5,6- tetrahydropyridine -1- bases) ethyl ketone (150mg, yield: 90.9%).¹HNMR (300MHz, CDCl₃) (δ/ppm): 7.89 (d, J=8.7Hz, 1H), 7.05-7.00 (m, 2H), 6.25-6.16 (m, 1H), 4.32-4.18 (m, 2H), 4.00 (s, 3H), 3.88-3.69 (m, 2H), 2.64-2.62 (m, 2H).LC-MS (APCI): m/z=277.3 (M+1)⁺, purity: 98.9%.

Step 4:

1N HCL aqueous solution (3 drop) is added to 1- (4- (3- methoxyl group -4- nitrobenzophenone) -1,2,5,6- tetrahydropyridine -1- base) ethyl ketone (150mg, 542.9 μm of ol) and iron powder (182mg, in ethyl alcohol (10mL) solution 3.26mmol), flow back 2h at 95 DEG C, the brown oil being spin-dried for, is dissolved in methylene chloride, washed once with water, salt water, collect the yellow black oil product 1- (4- (3- methoxyl group -4- aminophenyl) -1 that organic phase is spin-dried for, 2,5,6- tetrahydropyridine -1- bases) ethyl ketone.LC-MS (APCI): m/z=247.2 (M+1)⁺, purity: 94.6%.

Step 5:

Trifluoroacetic acid (three drops) is added to 1- (4- (3- methoxyl group -4- aminophenyl) -1, 2, 5, 6- tetrahydropyridine -1- base) ethyl ketone (133mg, 540 μm of ol) and N- (3- ((the chloro- 5- trifluoromethyl pyrimidine -4- base of 2-) amino) phenyl) acrylamide (185mg, 540 μm of ol) 1, in 4- dioxane (5mL) solution, after stirring 2h at 60 DEG C, triethylamine is added dropwise to be adjusted to neutrality, after methylene chloride extraction, it was spin-dried for column (DCM: MeOH=40: 1), obtain white solid product N- (3- ((2- ((4- (1- acetyl group -1, 2, 3, 6- tetrahydropyridine -4- base) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl ) amino) phenyl) acrylamide (90mg, yield: 30.2%).¹HNMR (300MHz, CDCl₃) (δ/ppm): 8.32 (s, 1H), 8.18 (s, 1H), 7.89-7.79 (m, 2H), 7.64-7.51 (m, 2H), 7.38-7.34 (m, 1H), 7.24-7.20 (m, 1H), 6.90-6.75 (m, 3H), 6.43 (d, J=7.5Hz, 1H), 6.22-6.15 (m, 1H), 6.01-5.94 (d, J=18Hz, 1H), 5.75 (d, J=6.3Hz, 1H), 4.23-4.11 (m, 2H), 3.90 (s, 3H), 3.80 (t, J=3.2Hz, 1H), 3.64 (t, J=3.2Hz, 1H), 2.5 2 (d, J=13.5Hz, 2H), 2.17-2.14 (m, 3H).LC-MS (APCI): m/z=553.3 (M+1)⁺, purity: 97.8%.

Embodiment 4

N- (3- ((2- ((4- (1- acetyl piperidine -4- base) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide

Step 1:

Under atmosphere of hydrogen, Pd/C (9mg) is added to 1- (4- (3- methoxyl group -4- aminophenyl) -1,2,5,6- tetrahydropyridine -1- bases) ethyl ketone (90mg, 365 μm of ol) ethyl alcohol (10mL) solution in, 2h is stirred at room temperature, filtering, is spin-dried for obtaining yellow oil product 1- (4- (3- methoxyl group -4- aminophenyl) piperidin-1-yl) ethyl ketone (90mg, 99.2%).LC-MS (APCI): m/z=249.4 (M+1)⁺, purity: 95.1%.

Step 2:

Synthesis step is identical as 3 step 5 of embodiment, obtain white solid product N- (3- ((2- ((4- (1- acetyl piperidine -4- base) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (60mg, yield: 29.8%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 8.32 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.89 (m, 1H), 7.76-7.71 (m, 2H), 7.55 (br s, 1H), 7.39-7.28 (m, 2H), 6.91 (s, 1H), 6.69 (d, J=2.4Hz, 1H), 6.61 (d, J=7.5Hz, 1H), 6.50-6.44 (m, 1H), 6.30-6.21 (dd, J=16.8Hz, 10.2Hz, 1H), 5.80-5.76 (dd, J=10.2Hz, 1.5Hz, 1H), 4.81-4.76 (m, 1H), 3.96-3.87 (m, 4H ), 3.21-3.11 (m, 1H), 2.72-2.58 (m, 2H), 2.14 (s, 3H), 1.92-1.83 (m, 2H), 1.66-1.56 (m, 2H).LC-MS (APCI): m/z=555.4 (M+1)⁺, purity: 95.5%.

Embodiment 5

N- (3- ((2- ((2- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl amino) -5- trifluoromethyl) pyrimidine-4-yl) amino) phenyl) Acrylamide

Step 1:

By the fluoro- 2- methoxy nitrobenzene (1.0g, 5.84mmol) of 4-, 1- methyl -4- (4- piperidyl) piperazine (0.9g, 7.0mmol), K₂CO₃(2.0g, 14.6mmol) is sequentially added into a three-neck flask equipped with 4mL DMF, is heated to 80 DEG C, is stirred overnight.Reaction solution is cooled to room temperature, it is diluted with water, ethyl acetate extraction was spin-dried for column after anhydrous sodium sulfate is dry, obtain yellow solid product 1- (1- (3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl) -4- methyl piperazine (1.0g, yield: 51.1%).¹HNMR (300MHz, CDCl₃) (δ/ppm): 8.01 (d, J=9.3Hz, 1H), 6.43 (dd, J=9.6Hz, 2.7Hz, 1H), 6.31 (d, J=2.4Hz, 1H), 3.98-3.94 (m, 2H), 3.87 (s, 3H), 3.03-2.94 (m, 2H), 2.65-2.62 (m, 4H), 2.54-2.46 (m, 5H), 2.32 (s, 3H), 2.01-1.96 (m, 2H), 1.65-1.60 (m, 2H), LC-MS (APCI): m/z=335.2 (M+1)+；Purity: 95.0%.

Step 2:

By 1- (1- (3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl) -4- methyl piperazine (0.2g, 0.59mmol) it is added into the three-neck flask equipped with ethyl alcohol (6mL) and water (2mL) mixed liquor, then iron powder (0.2g is added again, 3.58mmol), ammonium chloride (16mg, 0.29mmol), flow back 2h, after reaction solution is cooled to room temperature, it is spin-dried for ethyl alcohol, the NaHCO of saturation is added₃(aq., 5mL), it is extracted with dichloromethane, merges organic phase and is spin-dried for after being dried with anhydrous sodium sulfate, obtain light brown oil product 2- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidines -1- aniline (180mg, yield: 100%).LC-MS (APCI): m/z=305 (M+1)⁺, purity: 90.3%.

Step 3:

Synthesis step is identical as 3 step 5 of embodiment, obtains white solid product (40mg, yield: 11.1%).¹H NMR (300MHz, DMSO-d₆) (δ/ppm): 10.25 (s, 1H), 8.45 (br s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.65 (br s, 1H), 7.52-7.49 (m, 1H), 7.26-7.22 (m, 3H), 6.54-6.45 (m, 1H), 6.29-6.22 (m, 2H), 6.05-6.90 (m, 1H), 5.77-5.74 (m, 1H), 3.77-3.72 (m, 2H), 2.82-2.61 (m, 11H), 2.48-2.34 (m, 3H), 2.03 (s, 3H), 1.91-1.85 (m, 2H), 1.59-1.52 (m, 2 H).LC-MS (APCI): m/z=611.1 (M+1)⁺, purity: 94.5%.

Embodiment 6

N- (3- ((2- ((2- methoxyl group -4- (4- morpholino piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl Amine

Step 1:

By the fluoro- 2- methoxy nitrobenzene (0.5g, 2.92mmol) of 4-, 4- piperidyl morpholine (0.6g, 3.5mmol), K₂CO₃(0.54g, 3.8mmol) is sequentially added into a three-neck flask equipped with 3mL DMF, is stirred overnight at room temperature under nitrogen atmosphere.Cold water (50mL) dilution, filtering obtain yellow solid product 4- (1- (3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl) morpholine (0.5g, yield 53%) after dry.LC-MS (APCI): m/z=322.2 (M+1)⁺, purity: 96.3%.

Step 2:

Synthesis step is identical as 5 step 2 of embodiment, obtains yellow solid product (0.12g, yield 67%).LC-MS (APCI): m/z=292.1 (M+1)⁺, purity: 98%.

Step 3:

Synthesis step is identical as 3 step 5 of embodiment, obtains brown solid (120mg, yield 67%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 8.29 (s, 1H), 7.97 (d, J=8.4Hz, 1H), 7.88 (s, 1H), 7.49-7.53 (m, 2H), 7.33 (t, J=8.7Hz, 1H), 7.16-7.19 (br, 1H), 6.87 (s, 1H), 6.48-6.52 (m, 2H), 6.37-6.42 (m, 2H), 6.26 (q, J=10.2Hz, 1H), 5.77 (d, J=10.8Hz, 1H), 3.86 (s, 3H), 3.77 (s, 4H), 3.64 (d, J=15.6Hz, 2H), 2.69 (d, J=16Hz, 2H), 2.62 (s, 4H), 2.33 (t, J=7.8Hz, 1H), 1.96 (d, J=6.3Hz, 4H).LC-MS (APCI): m/z=598.3 (M+1)⁺, purity: 97%.

Embodiment 7

N- (3- ((2- ((4- (4- acetylpiperazine -1- carbonyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl Amine

Step 1:

At 0 DEG C, the dichloromethane solution (2.8ml, 5.6mmol) of oxalyl chloride is added dropwise in tetrahydrofuran (14ml) solution of -4 nitrobenzoic acid of 3- methoxyl group (1.0g, 5.1mmol), few drops of DMF are added.Reaction mixture stirs 4h in nitrogen atmosphere at such a temperature, is restored to room temperature, is spin-dried for obtaining yellow product 1.2g, is dissolved in the dry methylene chloride of 5mL.1- Acetylpiperazine (0.85g will be housed, two neck flasks of dichloromethane solution (15mL) 6.6mmol) are cooled to 0 DEG C, by triethylamine (1mL, it 7.7mmol) is added in the mixed liquor, the resulting dichloromethane solution of previous step is slowly added dropwise into the reaction solution, stir 30min, water (20mL) is added to be quenched, it is extracted with methylene chloride (15mL x 2), collect organic phase, after anhydrous sodium sulfate drying, it was spin-dried for column and obtains product N-1- (4- (3- methoxyl group -4- nitro benzoyl) Acetylpiperazine (1.1g, 70.2% yield).LC-MS (APCI): m/z=308.1 (M+1)+, purity: 95.1%.

Step 2:

Synthesis step is identical as 1 step 2 of embodiment, obtains yellow solid product N-1- (4- (4- amino -3- methoxybenzoyl base) Acetylpiperazine (0.13g, yield: 72%).LC-MS (APCI): m/z=278.2 (M+1)+, purity: 98.3%.

Step 3:

Synthesis step is identical as 3 step 5 of embodiment, obtain brown solid N- (3- ((2- ((4- (4- acetylpiperazine -1- carbonyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (110mg, yield 43%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 10.23 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.86 (t, J=8.1Hz, 2H), 7.54 (d, J=8.4Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 7.15 (d, J=1.2Hz, 1H), 7.02 (d, J=1.8Hz, 1H), 6.65 (d, J=6Hz, 1H), 6.43 (dd, J=17.1Hz, 9.9Hz, 1H), 6.34 (dd, J=17.1Hz, 1.8Hz, 1H), 5.76 (s, 1H), 3.78 (s, 3H), 3.24 (s, 3H), 2.0 4 (d, J=6Hz, 4H), 1.23-1.34 (m, 4H).LC-MS (APCI): m/z=584.2 (M+1)+, purity: 97.6%.

Embodiment 8

N- (3- ((2- (4- (1- acetyl piperidine -4- methylene) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl Amine

Step 1:

Under nitrogen atmosphere, 3- methoxyl group -4- nitrobenzoic acid (0.48g, 1.66mmol), methanol (5mL), sulfuric acid (3mL) are sequentially added into single neck flask, flow back 2h.Add water (30mL) to dilute, continuously adds methylene chloride (30mL) stirring 5min, be extracted with dichloromethane, collect organic phase, after anhydrous sodium sulfate drying, be spin-dried for column and obtain yellow oil product (0.32g, yield 91%).LC-MS (APCI): m/z=212 (M+1)⁺, purity: 95.3%.

Step 2:

Under nitrogen atmosphere, 3- methoxyl group -4- nitrobenzene methyl, tetrahydrofuran are sequentially added into the mono- neck flask of 50mL, is cooled to 0 DEG C, LiAlH is added₄(0.16g) stirs 30min, and Disodium sulfate decahydrate dilution is added, and extraction was spin-dried for column and obtains brown oil product (3- methoxyl group -4- nitrobenzophenone) methanol (2.5g, yield 81%).LC-MS (APCI): m/z=184.1 (M+1)⁺, purity: 98.1%.

Step 3:

Under nitrogen atmosphere, by (3- methoxyl group -4- nitrobenzophenone) methanol (0.5g, 2.73mmol), methylene chloride (20mL) sequentially adds in the mono- neck flask of 25mL of a stirring, it is cooled to 0 DEG C, it is slowly added to phosphorus tribromide (960mg, 3.55mmol), 3h is stirred at room temperature.Water (30mL) and methylene chloride (30mL) dilution are added in the reactive mixture, stir 5min, organic phase is collected after being extracted with dichloromethane, it is washed with water, column was spin-dried for after anhydrous sodium sulfate is dry, obtain yellow oil product 4- bromomethyl -2- methoxy nitrobenzene (0.37g, yield 55%).LC-MS (APCI): m/z=246.1 (M+1)⁺, purity: 94.8%.

Step 4:

By 4- bromomethyl -2- methoxy nitrobenzene (100mg, 0.4mmol) and triethyl phosphite (68mg, 0.4mmol) it is added into the mono- neck flask of 100mL, it is heated to 160 DEG C, and be cooled to room temperature after stirring 4h at such a temperature, 1h is stirred in ice-water bath, and filtrate is collected by filtration and is spin-dried for obtaining yellow oil product 123mg, LC-MS (APCI): m/z=304 (M+1)+, purity: 96.6%.

Step 5:

In 0 DEG C, under nitrogen atmosphere, successively by NaH (1.52g, 15mmol), MsCl (1.5g, it 13mmol) is added to one and 3- methoxyl group -4- nitrophenylphosphate diethylester (3g is housed, in methylene chloride (60mL) solution 10mmol), 1h is stirred at room temperature, water (60mL) and methylene chloride (50mL) is added to be quenched, separate organic phase, successively with water (60mL), 0.5M HCl (aq., 20mL), saturation NaHCO₃It is molten Liquid (20mL) washing is spin-dried for after anhydrous sodium sulfate is dry, obtains pale solid product N-4- (3- methoxyl group -4- nitro benzylidene) piperidine acid tert-butyl ester (1.5g, yield 43%).¹HNMR (300MHz, CDCl₃) (δ/ppm): 7.87 (d, J=8.4Hz, 1H), 6.85-6.88 (m, 2H), 6.37 (s, 1H), 3.97 (s, 3H), 3.55 (t, J=7.8Hz, 2H), 3.45 (t, J=7.8Hz, 2H), 2.45 (t, J=7.8Hz, 2H), 2.15 (t, J=7.8Hz, 2H), 1.51 (s, 9H).LC-MS (APCI): m/z=349 (M+1)⁺, purity: 98.4%.

Step 6:

It is synthesis step and 3 step 2 of embodiment, 3 identical, obtain white solid product N- (4- (3- methoxyl group -4- nitro benzylidene) Acetylpiperidin (0.66g, yield 79%).LC-MS (APCI): m/z=291.2 (M+1)⁺, purity: 98.6%.

Step 7:

By N- (4- (3- methoxyl group -4- amino benzylidene) Acetylpiperidin (0.2g, 0.69mmol), iron powder (0.21g, 3.75mmol), NH₄Cl (33mg; in the mixed liquor for 0.62mmol) sequentially adding the ethyl alcohol (10mL) and water (2mL) into stirring; flow back 2h; ethyl alcohol is screwed out after being cooled to room temperature; water (20mL) and methylene chloride is added to extract; obtain yellow solid product N- (4- (3- methoxyl group -4- nitro benzylidene) Acetylpiperidin (0.13g, yield 73%).LC-MS (APCI): m/z=261.3 (M+1)⁺, purity: 93.6%.

Step 8:

Synthesis step is identical as 3 step 5 of embodiment, obtain white solid product N- (3- ((2- ((4- (1- acetyl piperidine -4- methylene) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (90mg, yield 38%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 8.32 (s, 1H), 7.78 (d, J=5.7Hz, 1H), 7.36 (q, J=6.6Hz, 1H), 6.89-6.92 (m, 2H), 6.62-6.72 (m, 4H), 6.43-6.49 (m, 2H), 6.34 (m, 2H), 5.79 (d, J=10.2Hz, 2H), 3.89 (d, J=4.8Hz, 3H), 3.41-3.69 (m, 4H), 2.53 (q, J=6.9Hz, 2H), 2.39 (m, 2H), 2.16 (d, J=4.5Hz, 3H).LC-MS (APCI): m/z=567.3 (M+1)⁺, purity: 97.1%.

Embodiment 9

N- (3- ((2- (4- (1- acetyl piperidine -4- methyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide

Step 1:

Synthesis step is identical as 4 step 1 of embodiment, obtains brown oil product 1- (4- (4- amino -3- methoxy-benzyl) piperidin-1-yl) ethyl ketone (90mg, yield 90%).LC-MS (APCI): m/z=263.2 (M+1)⁺, purity: 94.6%.

Step 2:

Synthesis step is identical as 3 step 5 of embodiment, obtain white solid product N- (3- ((2- (4- (1- acetyl piperidine -4- methyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (85mg, yield 37%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 8.33 (s, 1H), 8.09 (d, J=9Hz, 1H), 7.90 (s, 1H), 7.36 (d, J=18Hz, 2H), 7.49-7.54 (br, 2H), 7.31-7.39 (m, 2H), 6.91 (s, 2H), 6.64 (s, 1H), 6.57 (d, J=6.9Hz, 1H), 6.50 (d, J=1.5Hz, 1H), 6.44 (d, J=1.8Hz, 1H), 6.21-6.30 (m, 1H), 5.79 (d, J=10.2Hz, 2H), 5.79 (dd, J=9.9Hz, 1.2Hz, 1H), 4.59 (d, J=13.5Hz, 1H), 3.88 (s, 3H), 3.76-3.80 (m, 2H), 2.94-3.03 (m, 2H), 2.43-2.51 (m, 4H), 2.39 (m, 2H), 2.09 (s, 3H), 2.53 (q, J=6.9Hz, 2H), 1.27-1.32 (m, 2H).LC-MS (APCI): m/z=569.4 (M+1)+, purity: 94.6%.

Embodiment 10

N- (3- ((2- ((4- (4- acetylpiperazine -1- base) methyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propylene Amide

Step 1:

Synthesis step is identical as 1 step 2 of embodiment, obtains yellow solid product (0.12g, yield 68%).LC-MS (APCI): m/z=322.2 (M+1)⁺, purity: 95.6%.

Step 2:

Synthesis step is identical as 1 step 3 of embodiment, obtains brown solid (110mg, yield 43%), LC-MS (APCI): m/z=628.3 (M+1)⁺, purity: 97.6%.

Step 3:

Under nitrogen protection; the dichloromethane solution of 4- (4- ((4- ((3- acrylamide phenyl) amino) -5- trifluoromethyl pyrimidine -2- base) amino) -3- methoxyphenyl)-methyl piperazine -1- t-butyl formate is cooled to 0 DEG C; trifluoroacetic acid is added dropwise; 3h is stirred at room temperature; methylene chloride is added; it is cooling under ice salt bath; triethylamine is added to neutralize; chloroacetic chloride is slowly added dropwise; water quenching is added to go out; organic phase is separated, successively with water (100mL x2), 0.5M HCl (aq., 15mL), saturation NaHCO₃Solution (15mL) washing, column, which was spin-dried for, after anhydrous sodium sulfate is dry obtains white solid product N- (3- ((2- ((4- (4- acetylpiperazine -1- base) methyl) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (85mg, yield 47%).¹H NMR (300MHz, CDCl₃) (δ/ppm): 8.30 (s, 1H), 8.06 (d, J=7.8Hz, 1H), 7.91-7.96 (m, 3H), 7.43 (d, J=0.6Hz, 1H), 7.91-7.96 (m, 3H), 7.30-7.36 (m, 2H), 6.89 (dd, J=16.5Hz, 1.5Hz, 2H), 6.69 (d, J=6.6Hz, 1H), 6.21-6.41 (m, 2H), 5.76 (dd, J=9.9Hz, 1.5Hz, 1H), 3.87 (s, 3H), 3.64 (t, J=4.2Hz, 2H), 3.45-3.53 (m, 4H), 2.43-2.50 (m, 4H), 1.25 (s, 3H).LC-MS (APCI): m/z=570.1 (M+1)⁺, purity: 96.6%.

Biology test

(1) kinase inhibitory activity

Reagent and consumptive material:

WT EGFR (Cama, catalog number (Cat.No.) 08-115), EGFR [L858R/T790M] (Cama, catalog number (Cat.No.) 08-510), ATP (Sigma, catalog number (Cat.No.) A7699-1G), DMSO (Sigma, catalog number (Cat.No.) D2650), 96 orifice plate (Coming, catalog number (Cat.No.) 3365), 384 orifice plate (Greiner, catalog number (Cat.No.) 784076), HTRF Kinase TK kit (Cisbio, catalog number (Cat.No.) 62TK0PEJ), Tarceva (Selleckchem, catalog number (Cat.No.) S7787), EGFR [d746-750] (Life Technologies, catalog number (Cat.No.) PV6178) , 5x kinase buffer liquid A (Life Technologies, catalog number (Cat.No.) PV3186), kinases tracer 199 (Life Technologies, catalog number (Cat.No.) PV5830),Eu-anti-GST antibody (Life Technologies, catalog number (Cat.No.) PV5594).

Specific experiment method:

Compound is prepared: test-compound being dissolved in DMSO and is made into 20mM mother liquor.Then, 3 times of the constant gradient dilutions in DMSO, dilute ten times.Dosing Shi Zaiyong buffer dilutes 10 times.

EGFR and EGFR [L858R/T790M] kinase assay: in 5x kinase buffer liquid A, the compound for the various concentration that EGFR or EGFR [L858R/T790M] kinases and beforehand dilution are prepared is mixed 10 minutes, each concentration duplicate hole.Corresponding substrate and ATP, room is added Temperature reaction 20 minutes (be provided with yin and yang attribute control: feminine gender is blank control, and the positive is Tarceva).Detection reagent (reagent in HTRF Kinase TK kit) is added in end of reaction, after incubation at room temperature 30 minutes, it is detected by Evnvision microplate reader, measure the enzyme activity in the presence of the compounds of this invention of each concentration, and calculate the inhibitory activity of the compounds on enzyme activities of various concentration, later according to quadruplex parameters, it is fitted according to inhibitory activity of 5.0 software of Graphpad to enzyme activity under various concentration compound, calculates IC₅₀Value.

The result of kinase inhibitory activity in embodiment is summarized in as in the following table 1.

Table 1

(2) cytotoxicity experiment

The compounds of this invention is had detected to the external antiproliferative activity of 3 plants of tumour cells of in vitro culture using MTS method.The experimental results showed that the compounds of this invention is inhibited to the in-vitro multiplication of the cancer cell of in vitro culture；It is wherein stronger than the inhibiting effect of the in-vitro multiplication of skin cancer cell to the inhibiting effect of the in-vitro multiplication of lung carcinoma cell.

Cell line:

Skin cancer cell A431 (is purchased from Unite States Standard biology product collecting center (ATCC))；Lung carcinoma cell NCI-H1975 (being purchased from Unite States Standard biology product collecting center (ATCC)) and HCC827 (being purchased from Unite States Standard biology product collecting center (ATCC))；With the RPMI1640 culture medium culture for containing 10% fetal calf serum, 100U/ml penicillin, 100 μ g/ml streptomysins.

Reagent and consumptive material:

RPMI-1640 (GIBCO, catalog number (Cat.No.) A10491-01)；Fetal calf serum (GIBCO, catalog number (Cat.No.) 10099141)；0.25% trypsase-EDTA (GIBCO, catalog number (Cat.No.) 25200)；Pen .- Strep, liquid (GIBCO, catalog number (Cat.No.) 15140-122)；DMSO (Sigma, catalog number (Cat.No.) D2650)；MTS test kit (Promega, catalog number (Cat.No.) G3581), 96 orifice plates (Coming, catalog number (Cat.No.) 3365).

Specific experiment method:

Compound is prepared: test-compound is dissolved in DMSO and is made into 20mM mother liquor, -20 DEG C of preservations.It is diluted with 3 times of DMSO constant gradient, dilutes 10 times.4 times of dosing Shi Zaiyong cell culture medium.

The detection of MTS cell viability: 0.25% trypsase-EDTA digests logarithmic growth phase cell, 150 μ l are inoculated in 96 orifice plates by the density optimized, the compound that culture medium dilutes 4 times is added after 24 hours, 50 holes μ l/ (are typically chosen ten concentration: 100,33.3,11.1,3.70,1.23,0.412,0.137,0.0457,0.0152,0.00508 μM).Using be added same volume 0.5%DMSO hole as control.After cell continues culture 72 hours, MTS detects cell viability.

Concrete operations: attached cell discards culture medium, and the mixed liquor for containing 20 μ L MTS and 100 μ l culture mediums is added in every hole.It is put into after incubator continues culture 1-4 hours and detects OD490, using OD650 value as reference.With GraphPad Prism software development amount effect curve and calculate IC₅₀。

The result of the inhibiting effect of the in-vitro multiplication to cancer cell in embodiment is summarized in the following table 2.

Table 2

Claims

Formula (I) compound

Wherein,

R₁Independently selected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy；

R₂Independently selected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy；

Linker L is selected from

1) C, N, O or S atom, as long as valence link allows；Wherein C and N can be optionally by R^aReplace；

2)C_1-6Alkylidene, C_2-6Alkenylene, C_2-6Alkynylene, C_3-10Sub- carbocylic radical, 3 to 10 yuan of sub- heterocycles, C_6-14Arlydene or C_5-10Inferior heteroaryl；Wherein the group is optionally by one or more R^aReplace；

3)-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-,-N (R^b) C (=O) O- ,-N (R^b) C (=O) N (R^b)-、-N(R^b) S (=O)-,-N (R^b) S (=O)₂,-OC (=O)-,-OC (=O) N (R^b- OS)-, (=O)-,-OS (=O)₂,-S (=O)-,-S (=O)₂,-S (=O)₂O- or-S (=O)₂N(R^b)-；

R^aSelected from H, halogen ,-CN ,-NO₂, oxo base, C_1-6Alkyl, C_1-6Halogenated alkyl or C_1-6Alkoxy；

R^bSelected from H, C_1-6Alkyl or C_1-6Halogenated alkyl；

X is selected from C or N atom, as long as valence link allows；

Ring A is selected from C_3-6Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl；

R₃Selected from halogen ,-CN ,-NO₂、-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c)、-N(R^c)(R^c)、-N(R^c) C (=O) R^c、-N(R^c) C (=O) OR^c、-N(R^c) C (=O) N (R^c)(R^c)、-N(R^c) S (=O) R^c、-N(R^c) S (=O) N (R^c)(R^c)、-N(R^c) S (=O)₂R^c、-N(R^c) S (=O)₂N(R^c)(R^c)、-OR^c,-OC (=O) R^c,-OC (=O) OR^c,-OC (=O) N (R^c)(R^c) ,-S (=O) R^c,-S (=O) OR^c,-S (=O) N (R^c)(R^c) ,-S (=O)₂R^c,-S (=O)₂OR^c,-S (=O)₂N(R^c)(R^c) ,-SC (=O) R^c,-SC (=O) OR^cOr-SC (=O) N (R^c)(R^c), as long as chemistry allows；

R^cSelected from H, halogen ,-CN ,-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl；The wherein C_3-10Carbocylic radical, 3 to 10 circle heterocyclic ring bases, C_6-14Aryl or C_5-10Heteroaryl is also optionally by C_1-6Alkyl, C_1-6Halogenated alkyl or-C (=O) C_1-6Alkyl replaces；

M is 0,1 or 2；

N is 1,2 or 3；

P represents singly-bound or double bond, as long as chemical valence allows；

Q represents singly-bound or double bond, as long as chemical valence allows；

R₄、R₅And R₆Independently selected from H, halogen ,-CN, C_1-6Alkyl or C_1-6Halogenated alkyl；

W is selected from N, O or S atom, and wherein N can be optionally by R^aReplace；

On condition that X is C atom when m is 0；

Or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations.
The compound of claim 1, wherein R₁For halogen ,-CN, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Halogenated alkoxy, R₂For halogen ,-CN, C_1-6Alkyl or C_1-6Halogenated alkyl, W are-O- or-NH- and R₄、R₅And R₆It is H.
The compound of claims 1 or 2, wherein R₁For Cl or methoxyl group, R₂For CF₃, W is-O- or-NH- and R₄、R₅And R₆It is H.
The compound of any one of claim 1-3, wherein L is selected from:

1) C, N or O atom；It is optionally by R^aReplace；

2)C_1-6Alkylidene, C_3-10Sub- carbocylic radical, 3 to 10 yuan of sub- heterocycles, C_6-14Arlydene or C_5-10Inferior heteroaryl；Preferably, C_1-6Alkylidene, C_3-10Sub- carbocylic radical or 3 to 10 yuan of sub- heterocycles；It is optionally by R^aReplace；

3)-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-,-N (R^b) S (=O)₂,-OC (=O)-,-OS (=O)-,-OS (=O)₂,-S (=O)-or-S (=O)₂-；Preferably ,-C (=O)-,-C (=O) O- ,-C (=O) N (R^b)-、-N(R^b) C (=O)-or-OC (=O)-.
The compound of any one of claim 1-4, wherein L is selected from:

1) C, N or O atom；It is optionally by R^aReplace；

2) 3 to 10 yuan of sub- heterocycles；Preferably, 3 to 6 yuan of sub- heterocycles；It is highly preferred that 5 to 6 yuan of sub- heterocycles；It is optionally by R^aReplace；

3)-C (=O)-,-C (=O) O- or-OC (=O)-；Preferably ,-C (=O)-.
The compound of claim 1 is selected from following formula: compound:

Wherein o is 0,1,2 or 3, R₁-R₆、R^a, any one of X, W, A, n, p and q such as claim 1-5 defined.
The compound of claim 6 is selected from following formula: compound:

Wherein R₁-R₆、R^a, any one of X, W, A, n and q such as claim 1-5 defined.
The compound of claim 1 is selected from following formula: compound:

Wherein Y is selected from C, N, O or S atom, o 0,1,2 or 3, R₁-R₆、R^a, any one of X, W, n, p and q such as claim 1-5 defined.
The compound of claim 1 is selected from following formula: compound:

Wherein Y is selected from C, N, O or S atom, o 0,1,2 or 3, R₁-R₆、R^a, any one of W, n and q such as claim 1-5 defined.
The compound of claim 1 is selected from following formula: compound:

Wherein R₁For Cl or methoxyl group, W is-O- or-NH-, R₃It is as defined in claim 1 with n.
The compound of any one of claim 1-10, wherein

R₃Selected from halogen ,-CN ,-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c)、-N(R^c)(R^c) ,-S (=O) R^cOr-S (=O)₂R^cAs long as chemistry allows；

R^cSelected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, 3 to 10 circle heterocyclic ring bases；Wherein 3 to the 10 circle heterocyclic ring base is optionally by C_1-6Alkyl, C_1-6Halogenated alkyl or-C (=O) C_1-6Alkyl replaces.
The compound of claim 11, wherein

R₃Selected from-R^c,-C (=O) R^c,-C (=O) OR^c,-C (=O) N (R^c)(R^c) or-S (=O)₂R^c；

R^cSelected from H, C_1-6Alkyl, C_1-6Halogenated alkyl or 5 to 6 circle heterocyclic ring bases；Wherein 5 to the 6 circle heterocyclic ring base is optionally by-C (=O) C_1-6Alkyl replaces.
The compound of claim 12, wherein R₃Selected from H, Me ,-C (=O) Me ,-C (=O) CF₃,-C (=O) OH ,-C (=O) N (Me) (Me) ,-C (=O) N (Et) (Et) ,-C (=O) OtBu ,-S (=O)₂Me or Isosorbide-5-Nitrae-perperidylidene, wherein the Isosorbide-5-Nitrae-perperidylidene is replaced by-C (=O) Me.
The compound of claim 1 is selected from following compound:
Pharmaceutical composition, the compound containing any one of claim 1-14 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations and pharmaceutically acceptable excipient.
The pharmaceutical composition of claim 15 also contains other therapeutic agents.
Kit comprising

The first container, wherein the compound containing any one of claim 1-14 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations；With

Optionally, second container, wherein containing other therapeutic agents；With

Optionally, third container, wherein containing the pharmaceutical excipient for dilute or the suspend compound and/or other therapeutic agents.
The compound of any one of claim 1-14 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations are preparing the purposes in the drug for treating cancer caused by EGFR.
A method for the treatment of cancer caused by EGFR in subject, the method includes the pharmaceutical compositions of compound or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations or any one of claim 15-16 to any one of snibject's claim 1-14.
The purposes of claim 18 or 19 method, wherein cancer caused by the EGFR is selected from: 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 lymph cancer, nasopharyngeal carcinoma.
The purposes or method of claim 20, wherein cancer caused by the EGFR is the T790M mutation, L858R mutation and the bis- mutation of L858R/T790M of non-small cell lung cancer.
The compound of any one of claim 1-14 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations, or the pharmaceutical composition of any one of claim 15-16, it is used for cancer caused by treating EGFR.
The compound of any one of claim 1-14 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variations, or the pharmaceutical composition of any one of claim 15-16, it is used to treat the T790M mutation, L858R mutation and the bis- mutation of L858R/T790M of non-small cell lung cancer.