CN106995435B

CN106995435B - 2- (2,4,5- substituted anilines) pyrimidine derivatives

Info

Publication number: CN106995435B
Application number: CN201610045757.1A
Authority: CN
Inventors: 焦玉奇
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-01-22
Filing date: 2016-01-22
Publication date: 2018-06-08
Anticipated expiration: 2036-01-22
Also published as: CN106995435A; CN108530429A; CN108530429B; CN108610331A

Abstract

2 (2,4,5 substituted aniline) pyrimidine derivatives.Disclose formula (I) compound represented or its pharmaceutically acceptable salt, formula (I) compound represented or the method for its pharmaceutically acceptable salt are prepared, contains formula (I) compound represented or pharmaceutical composition and formula (I) compound represented of its pharmaceutically acceptable salt or the purposes of its pharmaceutically acceptable salt：Wherein R₁To R₆As defined in this Application.

Description

2- (2,4,5- substituted anilines) pyrimidine derivatives

Field

The application relates generally to medicinal chemistry art.Specifically, this application involves the inhibition of EGFR and/or EGFR mutant Agent.

Background

EGFR (Epidermal Growth Factor Receptor) is EGF-R ELISA (HER) family member One of.The family includes HER1 (ErbB1, EGFR), HER2 (ErbB2, neu), HER3 (ErbB3) and HER4 (ErbB4).HER Family plays important adjustment effect in cellular physiological processes.EGFR is epidermal growth factor (EGF) cell Proliferation and signal The receptor of conduction, mutation or overexpression can generally cause tumour.EGFR is a kind of glycoprotein, belong to tyrosine kinase type by Body, cell membrane perforation, molecular weight 170KDa.EGFR is located at cell membrane surface, by being activated with ligand binding, including EGF and TGF α(Transforming GrowthFactorα).After activation, EGFR is converted into dimer by monomer, although also evidence suggests, There is also dimers before activation.EGFR is also possible to polymerize to activate, such as ErbB2/ with other members of ErbB receptor family HER2/neu。

It summarizes

On the one hand, this application involves formula (I) compound represented and its pharmaceutically acceptable salt：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

On the other hand, this application involves the methods for preparing formula (I) compound represented or its pharmaceutically acceptable salt：

Wherein, the method includes：

Formula (II) compound represented and acryloyl chloride are carried out that formula (I) compound represented is obtained by the reaction：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

In another aspect, this application involves pharmaceutical composition, it includes formula (I) compound represented or its is pharmaceutically acceptable Salt and drug acceptable carrier：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

Another aspect, this application involves formula (I) compound represented or its pharmaceutically acceptable salt preparing for inhibiting Purposes in the drug of EGF-R ELISA (Her)：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

On the other hand, this application involves formula (I) compound represented or its pharmaceutically acceptable salt preparing for treating Purposes in the drug of cancer and/or tumour：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

Other aspects, this application involves treatment tumour and/or the method for cancer, including to the individual for needing the method It gives formula (I) compound represented of therapeutically effective amount or its pharmaceutically acceptable salt or gives including for therapeutically effective amount Formula (I) compound represented or the pharmaceutical composition of its pharmaceutically acceptable salt and pharmaceutically acceptable carrier,

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

It is described in detail

In the following description, it is comprehensively managed including certain concrete details with providing each disclosed embodiment Solution.However, those skilled in the relevant art are not, it will be recognized that use one or more of these concrete details, and use other Embodiment is still realized in the case of method, component, material etc..

Unless required otherwise in the application, in the whole instruction and appended claims, word " including (comprise) " and its English variant should be interpreted that opening for example " including (comprises) " and " including (comprising) " Formula, the meaning that includes formula, i.e., " include but not limited to ".

" embodiment " mentioned in entire this specification, " embodiment ", " in another embodiment " or " at certain In a little embodiments " mean an at least embodiment include with described in the embodiment it is relevant with specific reference to element, Structure or feature.Therefore, throughout the specification different location occur phrase " in one embodiment " or " in embodiment In " or " in another embodiment " or " in certain embodiments " same embodiment need not be all referred to.In addition, specifically Element, structure or feature can combine in one or more embodiments in any suitable manner.

It should be appreciated that the article " one " for the singulative used in present specification and appended claims (correspond to English " a ", " an " and " the ") includes the object of plural number, unless it is other in text it is manifestly intended that.Thus, for example it carries The reaction including " catalyst " arrived includes a kind of catalyst or two or more catalyst.It is also understood that term "or" is led to The meaning of Chang Yiqi including "and/or" and use, unless in text in addition it is manifestly intended that.

Definition

Unless otherwise opposite explanation, otherwise following term used in specification and appended is with following The meaning：

Term as used herein " isotope " is meant with identical proton number, the difference of the identity element of different neutron populations Nucleic.

Term as used herein " abundance " means the atomicity hundred accounted in native element of a certain isotope belonging to it Divide ratio.

Term as used herein " isotope natural abundance " or " natural abundance " mean some day present in nature The atomicity percentage that various isotopes account in the native element in right element.Such as the isotope natural abundance of hydrogen：¹H= 99.985%,²H=0.015%.The isotope natural abundance of oxygen：¹⁶O=99.76%,¹⁷O=0.04%,¹⁸O=0.20%.

Term as used herein " isotope enrichment index " means that the abundance of a certain isotope and the isotope are naturally rich The ratio between degree.For example, the D-atom that isotope enrichment index is 6000 means the D-atom that abundance is 90%.

Term as used herein " hydrogen " (" H ") is meant by with isotope natural abundance¹H (99.985%) and²H (0.015%) hydrogen of composition.

Term as used herein " deuterium " (" D " and " d ") means the isotope of hydrogen (H), and there are one protons in D-atom core With a neutron, isotope natural abundance is 0.015%.“d_x-y" mean the substitution carried out with x to y D-atom.For example, Methoxyl group-d₃Mean CD₃O-。

The salt of salt and alkali addition of the term as used herein " pharmaceutically acceptable salt " including sour addition.

Term as used herein " pharmaceutically acceptable acid-addition salts " refers to keep the biological effectiveness and property of free alkali The salt of matter will not be undesirable biologically or in other aspects, and it is formed with inorganic acids or organic acid. The example that can be used in the illustrative inorganic acids of the application includes but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid Deng.Can be used in the illustrative organic acid of the application example include but not limited to acetic acid, 2,2- dichloroacetic acid, oneself two Acid, alginic acid, ascorbic acid, asparatate, benzene sulfonic acid, benzoic acid, 4- acetaminobenzoic acids, camphoric acid, camphor -10- Sulfonic acid, capric acid, caproic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane -1,2- Disulfonic acid, ethane sulfonic acid, 2- hydroxyethanesulfonic acids, formic acid, fumaric acid, galactosaccharic acid, gentianic acid, glucoheptonic acid, Portugal Saccharic acid, glucuronic acid, glutamic acid, glutaric acid, 2- oxos-glutaric acid, phosphoglycerol, glycolic, hippuric acid, isobutyric acid, lactic acid, Lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, phenylglycolic acid, Loprazolam, glactaric acid, two sulphurs of naphthalene -1,5- Acid, naphthalene-2-sulfonic acid, 1- hydroxy-2-naphthoic acids, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, Jiao Gu Propylhomoserin, pyruvic acid, salicylic acid, 4-ASA, decanedioic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, to toluene sulphur Acid, trifluoracetic acid, undecenoic acid etc..

Term as used herein " pharmaceutically acceptable base addition salts " refers to keep the biological effectiveness and property of free acid The salt of matter will not be undesirable biologically or in other aspects.These salt in free acid by adding inorganic base Or organic base and prepare.Can be used in the illustrative salt derived from inorganic base of the application example include but not limited to sodium, Potassium, lithium, ammonium, calcium, magnesium, iron, diction, copper, manganese, aluminium salt etc..In certain embodiments, inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. The example that can be used in the illustrative salt derived from organic base of the application includes but not limited to following salt：Primary, secondary and tertiary Amine, substitution amine, cyclic amine and deacidite including naturally replacing amine, such as ammonia, isopropylamine, front three Amine, diethylamine, triethylamine, tripropyl amine (TPA), diethanol amine, ethanol amine, dimethylethanolamine, 2-dimethylaminoethanol, 2- diethylaminos Base ethyl alcohol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, Hai Baming, choline, glycine betaine, benzene Second benzylamine, benzyl star, ethylenediamine, gucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, Piperidines, N-ethylpiperidine, polyamino resin etc..In certain embodiments, organic base is isopropylamine, diethylamine, ethanol amine, front three Amine, dicyclohexylamine, choline and caffeine.

Term as used herein " pharmaceutical composition " refers to what is usually received in compound and this field in the application For transmitting bioactive compound to the preparation of the medium of mammal such as people.The medium includes all using for it Pharmaceutically acceptable carrier.Pharmaceutical composition is conducive to administration of the compound to organism.There are a variety of methods in the art Compound is administered, includes but not limited to oral medication, drug administration by injection, aerosol drug delivery, parenteral administration and office Portion is administered.By compound and such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, to benzene methanesulfonic acid, water The inorganic acids such as poplar acid or organic acid reaction can also obtain pharmaceutical composition.

Term as used herein " carrier " is defined as the compound for being conducive to introducing compound into cell or tissue.Such as Dimethyl sulfoxide (DMSO) is typically used as carrier, this is because it is easy to introduce certain organic compounds the cell or group of organism In knitting.

Term as used herein " tumour (tumour) " means body under the effect of the various tumorigenesis factors, and local organization is thin The neoformation (neogrowth) that born of the same parents' hyperplasia is formed.According to neoplastic cell characteristics and the harmfulness degree to body, and will Tumour is divided into two major class of benign tumour and malignant tumour.

Term as used herein " cancer (cancer) " means the general name of malignant tumour.

Term as used herein " therapeutically effective amount " refers to when to mammal, when preferably the mankind being administered, the application's Compound is enough effectively to treat (being defined as below) mammal, the preferably amount of the tumour of the mankind and/or cancer.According to chemical combination Object, morbid state and its seriousness and the age of mammal to be treated form the compound of the application of " therapeutically effective amount " Amount will be different, but those skilled in the art can according to usage determine this Shen according to the knowledge and the disclosure of its own The amount of compound please

The mammal with relevant disease or illness is covered in the term as used herein " treatment " or " treatment ", preferably Treatment-related disease or morbid state in the mankind, and including：

(i) prevent disease or morbid state occurs in mammals, especially when the mammal is susceptible in the disease Diseased state, but when being not yet diagnosed with this morbid state；

(ii) inhibit disease or morbid state, that is, prevent its generation；Or

(iii) alleviate disease or morbid state, even if disease or morbid state subside.

As used herein, term " disease " and " morbid state " can be exchanged with each other use or can be It is different, because special disease or morbid state may there is no known virulence factors (therefore cannot use teiology solution Release), therefore it is not acknowledged as disease, and is considered undesirable morbid state or illness, and wherein clinician has been It is identified go out more or less particular series symptom.

During the entire course for the treatment of, vivo medicine-feeding can with single-dose, accomplished continuously or intermittently administration (such as the agent with segmentation Amount is by suitable doses at intervals) in a manner of carry out.The method for measuring most effective administering mode and dosage is art technology Well known to personnel, and change with treatment preparation used, the purpose treated, the target cell treated and individual treated Become.Can be with single or multiple doses can be administered, dosage level and pattern are selected by attending physician.

Specific embodiment

In the art, modifying that the influence to pharmaceutical activity and the influence to drug metabolism characteristic have due to deuterium can not be pre- The property surveyed, so the technical staff belonging to this field would generally query or even abandon deuterium modification as feasible drug design strategies Idea.

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

In certain embodiments, R₁Selected from-CH₂D、-CHD₂Or-CD₃。

In certain embodiments, R₂Selected from-CH₂D、-CHD₂Or-CD₃。

In certain embodiments, R₃Selected from-CHD- or-CD₂-。

In certain embodiments, R₄Selected from-CHD- or-CD₂-。

In certain embodiments, R₅Selected from-CH₂D、-CHD₂Or-CD₃。

In certain embodiments, R₆Selected from-CH₂D、-CHD₂Or-CD₃。

In certain embodiments, R₁For-CD₃。

In certain embodiments, R₂For-CD₃。

In certain embodiments, R₃For-CD₂-。

In certain embodiments, R₄For-CD₂-。

In certain embodiments, R₅Or R₆For-CD₃。

In certain embodiments, R₅And R₆It is-CD₃。

In certain embodiments, R₁For-CD₃, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CD₃, and R₆For- CH₃。

In certain embodiments, R₁For-CD₃, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CD₃, and R₆For- CD₃。

In certain embodiments, R₁For-CD₃, R₂For-CD₃, R₃For-CD₂, R₄For-CD₂, R₅For-CD₃, and R₆For- CD₃。

In certain embodiments, R₁For-CH₃, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CH₂D, and R₆ For-CH₃。

In certain embodiments, R₁For-CH₃, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CHD₂, and R₆ For-CH₃。

In certain embodiments, R₁For-CH₂D, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CD₃, and R₆ For-CH₃。

In certain embodiments, R₁For-CHD₂, R₂For-CH₃, R₃For-CH₂, R₄For-CH₂, R₅For-CD₃, and R₆ For-CH₃。

In certain embodiments, R₁For-CD₃, R₂For-CH₃, R₃For-CHD-, R₄For-CH₂, R₅For-CD₃, and R₆ For-CH₃。

In certain embodiments, R₁For-CD₃, R₂For-CH₃, R₃For-CH₂, R₄For-CHD-, R₅For-CD₃, and R₆ For-CH₃。

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 200, i.e., as substitution The abundance of the D-atom of base is 3%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 400, i.e., as substitution The abundance of the D-atom of base is 6%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 666.67, that is, is used as and takes The abundance of the D-atom of Dai Ji is 10%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 1000, i.e., as substitution The abundance of the D-atom of base is 15%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 2000, i.e., as substitution The abundance of the D-atom of base is 30%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 3333.33, i.e. conduct The abundance of the D-atom of substituent group is 50%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 4000, i.e., as substitution The abundance of the D-atom of base is 60%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 5000, i.e., as substitution The abundance of the D-atom of base is 75%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6000, i.e., as substitution The abundance of the D-atom of base is 90%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6333.33, i.e. conduct The abundance of the D-atom of substituent group is 95%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6466.67, i.e. conduct The abundance of the D-atom of substituent group is 97%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6533.33, i.e. conduct The abundance of the D-atom of substituent group is 98%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6566.67, i.e. conduct The abundance of the D-atom of substituent group is 98.5%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6600, i.e., as substitution The abundance of the D-atom of base is 99%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6633.33, i.e. conduct The abundance of the D-atom of substituent group is 99.5%.

In certain embodiments, as the D-atom of substituent group, isotope enrichment index is 6660, i.e., as substitution The abundance of the D-atom of base is 99.9%.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 60%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 75%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 90%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 95%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 97%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 98%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 98.5%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 99%, and other isotopes have its natural abundance.

In certain embodiments, in formula (I) compound represented and its pharmaceutically acceptable salt, the deuterium as substituent group The abundance of atom is at least 99.5%, and other isotopes have its natural abundance.

In certain embodiments, formula (I) compound represented is selected from：

N- (2- { 2- [methyl (methyl-d₃) amino] ethyl-methylamino -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides；

N- (2- [(methyl-the d of 2- bis-₃) amino-ethyl-methylamino] { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides；

N- (2- [2- dimethylaminoethyls-methylamino] -4- (methoxyl group-d₃) -5- [4- (1-H- indol-3-yls) pyrimidine - 2- yls] amino } phenyl) propyl- 2- acrylamides；

N- (2- [2- dimethylaminoethyls-(methyl-d₃) amino] { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides；

N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -1,1-] -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides；And

N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -2,2-] -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides.

In some aspects, the compound of the application has improved pharmacodynamic profiles.

In some aspects, the compound of the application has EGF-R ELISA inhibitory activity.

In some aspects, the compound of the application has improved pharmacokinetic properties.

In some aspects, the compound of the application has improved internal metabolic characteristic.

In some aspects, the compound of the application has improved in-vivo tumour inhibitory activity.

In some aspects, the compound of the application has improved safety.

In some aspects, the compound of the application has improved tolerance.

In certain embodiments, the compound of the application especially following compounds：

Wherein, the method includes：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

In certain embodiments, formula (II) compound represented carries out reacting in the presence of a strong base with acryloyl chloride To formula (I) compound represented.

The example that can be used in the illustrative highly basic of the application includes but not limited to sodium hydroxide, potassium hydroxide, methanol Sodium, sodium ethoxide, potassium ethoxide and sodium tert-butoxide.

In certain embodiments, formula (II) compound represented carries out instead in the presence of a polar solvent with acryloyl chloride It should obtain formula (I) compound represented.

Can be used in the illustrative polar solvent of the application example include but not limited to water, formamide, trifluoroacetic acid, Dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, N,N-dimethylformamide (DMF), hexamethyl phosphoramide, methanol, ethyl alcohol, acetic acid, isopropyl Alcohol, pyridine, tetramethylethylenediamine, acetone, triethylamine, n-butanol, dioxane and tetrahydrofuran (THF).

In another aspect, this application involves pharmaceutical composition, it includes formula (I) compound represented of therapeutically effective amount or its Pharmaceutically acceptable salt and drug acceptable carrier：

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

Can be used in illustrative " the pharmaceutically acceptable carrier " of the application example include but not limited to it is any by state Family's medicine administrative organ is approved as being acceptable for the adjuvant of people or domestic animal, carrier, excipient, glidant, sweetener, dilution It is agent, preservative, dyestuff/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, molten Agent or emulsifier.

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

In certain embodiments, EGF-R ELISA (Her) is EGFR (Her1).

In certain embodiments, EGFR (Her1) is wild type.

In certain embodiments, EGFR (Her1) is mutant.

In certain embodiments, EGFR (Her1) is single mutant or double-mutant.

In certain embodiments, formula (I) compound represented and its pharmaceutically acceptable salt are mutated L858R EGFR Body, T790M EGFR mutant and Exon19 missing activated mutant bodies have inhibitory activity.

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

Due to the application formula (I) compound represented and its pharmaceutically acceptable salt to L858R EGFR mutant, T790M EGFR mutant and Exon19 missing activated mutant bodies have inhibitory activity, can be used for being situated between by EGFR mutant activities The disease led or the treatment of disease-states such as cancer.

In certain embodiments, formula (I) compound represented of the application and its pharmaceutically acceptable salt are used to treat By L858R EGFR mutant and/or the missing activated mutant body mediation of T790M EGFR mutant and/or Exon19 disease or The treatment of disease-states such as cancer.

In certain embodiments, cancer is selected from oophoroma, cervical carcinoma, colorectal cancer, breast cancer, cancer of pancreas, colloid Knurl, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver are thin Born of the same parents' cancer, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, Anaplastic large cell lymph Knurl, acute myelocytic leukemia (AML), Huppert's disease, melanoma and celiothelioma.

In certain embodiments, lung cancer is selected from Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC).

Wherein：

R₁The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₂The methyl replaced selected from methyl or by 1 to 3 D-atom；

R₃The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₄The methylene replaced selected from methylene or by 1 to 2 D-atom；

R₅The methyl replaced selected from methyl or by 1 to 3 D-atom；And

R₆The methyl replaced selected from methyl or by 1 to 3 D-atom；

Condition is R₁To R₆In at least contain there are one D-atom.

In certain embodiments, individual is mammal.

In certain embodiments, individual is the mankind.

In certain embodiments, to need the individual for treating tumour and/or cancer give formula (I) compound represented or The unit dose of its pharmaceutically acceptable salt is 0.1mg-1000mg.

In certain embodiments, to need the individual for treating tumour and/or cancer give formula (I) compound represented or The unit dose of its pharmaceutically acceptable salt is 1mg-1000mg.

Embodiment

Although any those skilled in the art can prepare the compound of the application according to general technology disclosed above, But for convenience, other places in this specification provide the synthetic technology of more detailed the application compound.In addition, this It all reagents and reaction condition used in the known synthesis of field technology personnel and can be obtained by common merchandise resources. For example, the various reagents including deuterated reagent used in embodiment all can be from Sigma-Aldrich Company Ltd is bought.Various cell lines used in embodiment all can be for example thin from the American Type Culture Collection committee of the Chinese Academy of Sciences Born of the same parents buy in library.

Unless otherwise indicated,¹HNMR be using deuterated dimethyl sulfoxide under 400 or 500MHz frequencies in about 20-30 DEG C Lower measure.It is abridged using standard NMR：S=is unimodal；D=is bimodal；Bimodal bimodal of dd=；T=triplets；Q=quartets；P= Quintet；M=multiplets；Br=broadbands.

Prepare embodiment

Intermediate 1

N¹(2- [methyl (methyl-d₃) amino] ethyl) -5- methoxyl groups-N¹Methyl-N⁴[4- (1-H- indol-3-yls) Pyrimidine -2-base] benzene -1,2,4- triamines

By N '-(2- [methyl (methyl-d₃) amino] ethyl) -2- methoxyl groups-N '-methyl-N- [4- (1-H- indoles -3- Base) pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines (intermediate 6,44g), iron (31g) and NH₄Cl (1.9g) is in ethyl alcohol Mixture in (120mL) and water (40mL) is heated to reflux 3.5 hours.By using the ion exchange chromatography of SCX columns to this Crude mixture is purified.It is eluted, is concentrated in vacuo from column with methanol-ammonia, obtain ecru title compound (90%).m/ z:434

Intermediate 2

N1- (2- [two (methyl-d₃) amino] ethyl) [4- (1-H- indol-3-yls) is phonetic by -5- methoxyl group-N1- methyl-N4- Pyridine -2- bases] benzene -1,2,4- triamines

By N '-(2- [two (methyl-d₃) amino] ethyl) -2- methoxyl groups-N '-methyl-N- [4- (1-H- indol-3-yls) Pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines (intermediate 7,44g), iron (31g) and NH₄Cl (1.9g) in ethyl alcohol (120mL) and Mixture in water (40mL) is heated to reflux 3.5 hours.By using SCX columns ion exchange chromatography to the crude mixture into Row purifying.It is eluted, is concentrated in vacuo from column with methanol-ammonia, obtain ecru title compound (95%).m/z:437

Intermediate 3

N¹(2- dimethyl aminoethyls) -5- (methoxyl group-d₃)-N¹Methyl-N⁴[4- (1-H- indol-3-yls) pyrimidine- 2- yls] benzene -1,2,4- triamines

By N '-(2- dimethyl aminoethyls) -2- (methoxyl group-d₃) [4- (1-H- indol-3-yls) is phonetic by-N '-methyl-N- Pyridine -2- bases] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines (intermediate 8,44g), iron (31g) and NH₄Cl (1.9g) is in ethyl alcohol (120mL) and water Mixture in (40mL) is heated to reflux 3.5 hours.The crude mixture is carried out by using the ion exchange chromatography of SCX columns Purifying.It is eluted, is concentrated in vacuo from column with methanol-ammonia, obtain ecru title compound (86%).m/z:434

Intermediate 4

N¹(two deuterated ethyls of 2- dimethylaminos -1,1-) -5- methoxyl groups-N¹Methyl-N⁴[4- (1-1-H- indoles -3- Base) pyrimidine -2-base] benzene -1,2,4- triamines

By N '-(two deuterated ethyls of 2- dimethylaminos -1,1-) -2- methoxyl groups-N '-methyl-N- [4- (1-H- indoles -3- Base) pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines (intermediate 9,220mg, 0.46mmol), iron (155mg, 2.78mmol) and NH₄Mixtures of the Cl (17.32mg, 0.32mmol) in ethyl alcohol (12mL) and water (4mL) is heated to reflux 2 hours.By using The ion exchange chromatography of SCX columns purifies the crude mixture.Desired product is eluted from column with 7M methanol-ammonia, it will Appropriate fraction merges, and is concentrated in vacuo on silica gel.It is purified using FCC, used in CH₂Cl₂In 0-5% 7N first Alcohol-ammonia is eluted, and obtains the title compound (175mg, 85%) as ecru foam.m/z:433

Intermediate 5

N1- (two deuterated ethyls of 2- dimethylaminos -2,2-) -5- methoxyl group-N1- methyl-N4- [4- (1-H- indol-3-yls) Pyrimidine -2-base] benzene -1,2,4- triamines

By N '-(the deuterated ethyls of 2- dimethylaminos -2,2-) -2- methoxyl groups-N '-methyl-N- [4- (1-H- indol-3-yls) Pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines (intermediate 10,220mg, 0.46mmol), iron (155mg, 2.78mmol) and Mixtures of the NH4Cl (17.32mg, 0.32mmol) in ethyl alcohol (12mL) and water (4mL) is heated to reflux 2 hours.By using The ion exchange chromatography of SCX columns purifies the crude mixture.Desired product is eluted from column with 7M methanol-ammonia, it will Appropriate fraction merges, and is concentrated in vacuo on silica gel.It is purified using FCC, the 7N first of the 0-5% in CH2Cl2 Alcohol-ammonia is eluted, and obtains the title compound (175mg, 85%) as ecru foam.m/z:433

Intermediate 6

N '-(2- [methyl (methyl-d₃) amino] ethyl) -2- methoxyl groups-N '-methyl-N- [4- (1-H- indol-3-yls) Pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines

In 500mL there-necked flasks, 190mL DMA, 16.9g N, N '-dimethyl-N '-(methyl-d are added in₃)-ethane, 23.1g DIPEA after being stirred at room temperature 30 minutes, adds in 47g N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1-H- indoles -3- Base) pyrimidine -2- amine (intermediate 11), this solid-liquid suspension object is then warming up to 85 DEG C and is reacted 2-3 hours, TLC and mass-directed preparative After the reaction was complete, filter while hot.300mL acetonitriles (the acetonitrile amount including washing filter cake) are added in filtrate, are cooled to 5 DEG C or so Afterwards, it has a large amount of red products at this time to be precipitated, filtering in 50 DEG C of decompression dryings, obtains 51g products, yield 90%, without pure Change, be directly used in the next step.m/z:464

Intermediate 7

N '-(2- [two (methyl-d3) amino] ethyl) [4- (1-H- indol-3-yls) is phonetic by -2- methoxyl groups-N '-methyl-N- Pyridine -2- bases] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines

In 500mL there-necked flasks, 190mL DMA, 16.9g N- methyl-N ', N '-(methyl-d are added in₃)-ethane, 23.1g DIPEA after being stirred at room temperature 30 minutes, adds in 47g N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1-H- indoles -3- Base) pyrimidine -2- amine (intermediate 11), this solid-liquid suspension object is then warming up to 85 DEG C and is reacted 2-3 hours, TLC and mass-directed preparative After the reaction was complete, filter while hot.300mL acetonitriles (the acetonitrile amount including washing filter cake) are added in filtrate, are cooled to 5 DEG C or so Afterwards, it has a large amount of red products at this time to be precipitated, filtering in 50 DEG C of decompression dryings, obtains 51g products, yield 90%, without pure Change, be directly used in the next step.m/z:467

Intermediate 8

N '-(2- dimethylamino-ethyls) -2- (methoxyl group-d3)-N '-methyl-N- [4- (1-H- indol-3-yls) pyrimidine - 2- yls] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines

In 500mL there-necked flasks, 190mL DMA, 16.9g N, N ', N '-Trimethylethane, 23.1g DIPEA, in room are added in After temperature stirring 30 minutes, 47g N- (the fluoro- 2- of 4- (methoxyl group-d are added in₃) -5- nitrobenzophenones) -4- (1-H- indol-3-yls) is phonetic Then this solid-liquid suspension object is warming up to 85 DEG C and reacted 2-3 hours by pyridine -2- amine (intermediate 12), TLC and mass-directed preparative have reacted Quan Hou is filtered while hot.300mL acetonitriles (the acetonitrile amount including washing filter cake) are added in filtrate, after being cooled to 5 DEG C or so, at this time It has a large amount of red products to be precipitated, filtering, in 50 DEG C of decompression dryings, obtains 51g products, yield 90% without purifying, is directly used In the next step.m/z:464

Intermediate 9

N '-(the deuterated ethyl of 2- dimethylaminos -1,1-) -2- methoxyl groups-N '-methyl-N- [4- (1- methyl indol -3- bases) Pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines

By N¹,N¹,N²Bis- deuterated ethane -1,2- diamines (80mg, 0.79mmol) of trimethyl -2,2- is added to N-, and (4- is fluoro- 2- methoxyl group -5- nitrobenzophenones) -4- (1-H- indol-3-yls) pyrimidine -2- amine (intermediate 11,350mg, 0.79mmol) and Suspension of the DIPEA (0.342mL, 1.97mmol) in 2,2,2- trifluoroethanols (5mL).By the mixture in microwave in It is heated 1 hour at 140 DEG C.The reaction mixture of cooling is purified by using the ion exchange chromatography of SCX columns.With 7M first Alcohol-ammonia elutes desired product from column, and appropriate fraction is merged, is concentrated in vacuo on silica gel.It is carried out using FCC pure Change, used in CH₂Cl₂In 0-4%7N methanol-ammonia eluted, obtain as orange solids title compound (230mg, 62%).m/z:463

Intermediate 10

N '-(the deuterated ethyls of 2- dimethylaminos -2,2-) -2- methoxyl groups-N '-methyl-N- [4- (1- methyl indol -3- bases) Pyrimidine -2-base] -5- nitrobenzenes-Isosorbide-5-Nitrae-diamines

By N¹,N¹,N²Bis- deuterated ethane -1,2- diamines (80mg, 0.79mmol) of trimethyl -1,1- is added to N-, and (4- is fluoro- 2- methoxyl group -5- nitrobenzophenones) -4- (1-H- indol-3-yls) pyrimidine -2- amine (intermediate 11,350mg, 0.79mmol) and Suspension of the DIPEA (0.342mL, 1.97mmol) in 2,2,2- trifluoroethanols (5mL).By the mixture in microwave in It is heated 1 hour at 140 DEG C.The reaction mixture of cooling is purified by using the ion exchange chromatography of SCX columns.With 7M first Alcohol-ammonia elutes desired product from column, and appropriate fraction is merged, is concentrated in vacuo on silica gel.It is carried out using FCC pure Change, used in CH₂Cl₂In 0-4%7N methanol-ammonia eluted, obtain as orange solids title compound (230mg, 62%).m/z:463

Intermediate 11

N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1-H- indol-3-yls) pyrimidine -2- amine

By p-methyl benzenesulfonic acid hydrate (22.73g, 119.5mmol) be disposably added to 3- (2- chlorine pyrimidine-4-yl)- 1-H- indoles (intermediate 13,24.27g, 99.58mmol) and the fluoro- 2- methoxyl groups -5- nitroanilines of 4- (intermediate 14, 18.54g, 99.58mmol) in mixture in 2- amylalcohols (500mL).It is small that gained mixture is stirred at 105 DEG C to 2.5 When.It is then cooled to room temperature.Gained sediment is collected by filtration, is cleaned, is dried under vacuum with 2- amylalcohols (50mL), obtains Some desired products as yellow solid.Filtrate is cooled down, gained sediment is collected by filtration, it is clear with 2- amylalcohols (10mL) It washes.This two batches product is merged, uses CH₃CN is ground, and obtains solid, the solid is collected by filtration, is dried under vacuum, Obtain the title compound (37.4g, 95%) as yellow solid.m/z:379

Intermediate 12

N- (the fluoro- 2- of 4- (methoxyl group-d₃) -5- nitrobenzophenones) -4- (1-H- indol-3-yls) pyrimidine -2- amine

By p-methyl benzenesulfonic acid hydrate (22.73g, 119.5mmol) be disposably added to 3- (2- chlorine pyrimidine-4-yl)- 1-H- indoles (intermediate 13,24.27g, 99.58mmol) and the fluoro- 2- of 4- (methoxyl group-d₃) -5- nitroanilines (intermediate 15, 18.54g, 99.58mmol) in mixture in 2- amylalcohols (500mL).It is small that gained mixture is stirred at 105 DEG C to 2.5 When.It is then cooled to room temperature.Gained sediment is collected by filtration, is cleaned, is dried under vacuum with 2- amylalcohols (50mL), obtains Some desired products as yellow solid.Filtrate is cooled down, gained sediment is collected by filtration, it is clear with 2- amylalcohols (10mL) It washes.This two batches product is merged, uses CH₃CN is ground, and obtains solid, the solid is collected by filtration, is dried under vacuum, Obtain the title compound (37.4g, 95%) as yellow solid.m/z:382

Intermediate 13

3- (2- chlorine pyrimidine-4-yl) -1H- indoles

In N at 0 DEG C within the time of 10 minutes₂In atmosphere, by CH₃MgBr (3M, in ether, 22.68mL, It is molten 68.03mmol) to be added dropwise to stirring of the 1-H- indoles (7.97g, 68.03mmol) in 1,2- dichloroethanes (250mL) In liquid.Acquired solution is stirred 15 minutes, then disposably adds 2,4- dichloro pyrimidines (15.00g, 100.69mmol).It allows Acquired solution is warming up to room temperature, is stirred for 16 hours.By adding CH₃Reaction is quenched in OH (25mL), then by the mixture into Row is concentrated in vacuo, it is made to be adsorbed onto on silica gel.It is purified using FCC, used in CH₂Cl₂In 0-20% CH₃OH is washed It is de-, obtain the title compound (7.17g, 46%) as yellow solid.m/z:229

Intermediate 14

The fluoro- 2- methoxyl groups -5- nitroanilines of 4-

The fluoro- 2- aminoanisoles (2.4g, 17.00mmol) of 4- are added batch-wise to the dense H cooled down in ice water bath₂SO₄ In (15mL), kept the temperature at during addition less than 15 DEG C.By the mixture stirring until all formed solids all It has dissolved.KNO is added batch-wise₃(0.815mL, 17.00mmol) is less than 10 DEG C to keep the temperature at.The mixture is stirred It mixes overnight, is subsequently poured into ice/water.The dense NH4OH of the mixture is alkalized.Obtained solid is filtered out, is then dissolved in CH₂Cl₂, wash with water, dry (Na₂SO₄), in evaporated onto silica gel.It is purified using FCC, with 50-0% in CH₂Cl₂In Heptane is eluted, and is obtained as yellow crystalline solid title compound (2.450g, 77%).m/z:186

Intermediate 15

The fluoro- 2- of 4- (methoxyl group-d₃) -5- nitroanilines

By the fluoro- 2- of 4- (methoxyl group-d₃) aniline (2.4g, 17.00mmol) be added batch-wise cooled down in ice water bath it is dense H₂SO₄In (15mL), kept the temperature at during addition less than 15 DEG C.By mixture stirring until all formed is consolidated Body has all dissolved.KNO is added batch-wise₃(0.815mL, 17.00mmol) is less than 10 DEG C to keep the temperature at.This is mixed Object is stirred overnight, and is subsequently poured into ice/water.The dense NH4OH of the mixture is alkalized.Obtained solid is filtered out, is then dissolved in CH₂Cl₂, wash with water, dry (Na₂SO₄), in evaporated onto silica gel.It is purified using FCC, with 50-0% in CH₂Cl₂In Heptane is eluted, and is obtained as yellow crystalline solid title compound (2.450g, 77%).m/z:189

Embodiment 1

N- (2- { 2- [methyl (methyl-d₃) amino] ethyl-methylamino -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides

To N under condition of ice bath¹(2- [methyl (methyl-d₃) amino] ethyl) -5- methoxyl groups-N¹Methyl-N⁴-[4-(1- H- indol-3-yls) pyrimidine -2-base] benzene -1,2,4- triamines (intermediate 1,20g) addition in THF (200mL) and water (20mL) 6.9g sodium hydroxide.Acryloyl chloride 4.05g is added in agitated solution, is stirred at room temperature 30 minutes, by the mixture at room temperature Stirring 1 hour.TLC is detected after reaction, and reaction solution adds in 200mL water and 20mL ammonium hydroxide, and solid is precipitated, filtering.Collect institute Solid is obtained, is washed with water, it is 8 hours dry at 50 DEG C, obtain title compound (yield 86%).

¹HNMR:2.23(3H,s),2.28(2H,t),2.71(3H,s),2.89(2H,t),3.88(3H,s),5.75(1H, dd),6.25(1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d), 7.90(1H,s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺488

N- (2- { 2- [methyl (methyl-d₃) amino] ethyl-methylamino -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamide mesylates

N- (2- { 2- [methyl (methyl-the d that upper step is obtained₃) amino] ethyl-methylamino -4- methoxyl group -5- { [4- (1-H- indol-3-yls) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides 20.5g (1.0eq) is added to 500mL there-necked flasks In, 120mL ethyl alcohol and 80mL ethyl acetate are dissolved in, at room temperature dropwise addition 4.1g methanesulfonic acids (1.05eq)+40mL ethyl acetate, about 1 Hour drip off, drip off after temperature 1.5-2 hour, be then slowly cooled to room temperature, filtering, filter cake with ethyl acetate/ Ethanol solution (2:1, v/v) it after washing 1 time, filters, drying obtains 18.0g products, yield 83%.

Embodiment 2

N- (2- { (methyl-the d of 2- bis-₃) amino-ethyl-methylamino { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides

To N under condition of ice bath¹(2- [two (methyl-d₃) amino] ethyl) -5- methoxyl groups-N¹Methyl-N⁴-[4-(1-H- Indol-3-yl) pyrimidine -2-base] benzene -1,2,4- triamines (intermediate 2,20g) addition in THF (200mL) and water (20mL) 6.9g sodium hydroxide.Acryloyl chloride 4.05g is added in agitated solution, 30min is stirred at room temperature, which is stirred at room temperature It mixes 1 hour.TLC is detected after reaction, and reaction solution adds in 200mL water and 20mL ammonium hydroxide, and solid is precipitated, filtering.Collect gained Solid washes with water, 8 hours dry at 50 DEG C, obtains title compound (yield 88%).

¹HNMR:2.28(2H,t),2.71(3H,s),2.89(2H,t),3.88(3H,s),5.75(1H,dd),6.25 (1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d),7.90(1H, s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺491

N- (2- { (methyl-the d of 2- bis-₃) amino-ethyl-methylamino { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamide mesylates

N- (2- { (methyl-the d of 2- bis- that upper step is obtained₃) amino-ethyl-methylamino -4- methoxyl groups -5- { [4- (1-H- Indol-3-yl) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides 20.5g (1.0eq) is added in 500mL there-necked flasks, is dissolved in 4.1g methanesulfonic acids (1.05eq)+40mL ethyl acetate is added dropwise in 120mL ethyl alcohol and 80mL ethyl acetate at room temperature, drips within about 1 hour It is complete, it drips off after temperature 1.5-2 hours, is then slowly cooled to room temperature, filter, filter cake is molten with ethyl acetate/ethyl alcohol Liquid (2:1, v/v) it after washing 1 time, filters, drying obtains yellow solid, yield 85%.

Embodiment 3

N- (2- [2- dimethylaminoethyls-methylamino] -4- (methoxyl group-d₃) -5- [4- (1-H- indol-3-yls) pyrimidine - 2- yls] amino } phenyl) propyl- 2- acrylamides

To N under condition of ice bath¹(2- dimethyl aminoethyls) -5- (methoxyl group-d₃)-N¹Methyl-N⁴-[4-(1-H- Indol-3-yl) pyrimidine -2-base] benzene -1,2,4- triamines (intermediate 3,20g) addition in THF (200mL) and water (20mL) 6.9g sodium hydroxide.Acryloyl chloride 4.05g is added in agitated solution, 30min is stirred at room temperature, which is stirred at room temperature It mixes 1 hour.TLC is detected after reaction, and reaction solution adds in 200mL water and 20mL ammonium hydroxide, and solid is precipitated, filtering.Collect gained Solid washes with water, 8 hours dry at 50 DEG C, obtains title compound (yield 85%).

¹HNMR:2.23(6H,s),2.28(2H,t),2.71(3H,s),2.89(2H,t),5.75(1H,dd),6.25 (1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d),7.90(1H, s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺488

N- (2- { 2- dimethylaminoethyls-methylamino } -4- (methoxyl group-d₃) -5- [4- (1-H- indol-3-yls) pyrimidine - 2- yls] amino } phenyl) propyl- 2- acrylamide mesylates

N- (2- { 2- dimethylaminoethyls-methylamino } -4- (methoxyl group-d that upper step is obtained₃) -5- { [4- (1-H- Yin Diindyl -3- bases) pyrimidine -2-base] amino } phenyl) -2- acrylamides 20.5g (1.0eq) is added in 500mL there-necked flasks, is dissolved in 4.1g methanesulfonic acids (1.05eq)+40mL ethyl acetate is added dropwise in 120mL ethyl alcohol and 80mL ethyl acetate at room temperature, drips within about 1 hour It is complete, it drips off after temperature 1.5-2 hours, is then slowly cooled to room temperature, filter, filter cake is molten with ethyl acetate/ethyl alcohol Liquid (2:1, v/v) it after washing 1 time, filters, drying obtains yellow solid, yield 88%.

Embodiment 4

N- (2- { 2- dimethylaminoethyls-(methyl-d₃) amino { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides

Preparation method and N- (2- { 2- dimethylaminoethyls-methylamino } -4- (methoxyl group-d₃) -5- [4- (1-H- indoles - 3- yls) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides are identical, use N¹(2- dimethyl aminoethyls) -5- (methoxies Base)-N¹(methyl-d₃)-N⁴[4- (1-H- indol-3-yls) pyrimidine -2-base] benzene -1,2,4- triamines replace N¹(2- dimethyl Amino-ethyl) -5- (methoxyl group-d₃)-N¹Methyl-N⁴[4- (1-H- indol-3-yls) pyrimidine -2-base] benzene -1,2,4- triamines, Yield 70%.

¹HNMR:2.23(6H,s),2.28(2H,t),2.89(2H,t),3.88(3H,s),5.75(1H,dd),6.25 (1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d),7.90(1H, s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺488

N- (2- { 2- dimethylaminoethyls-(methyl-d₃) amino { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamide mesylates

Preparation method and N- (2- { 2- dimethylaminoethyls-methylamino } -4- (methoxyl group-d₃) -5- [4- (1-H- indoles - 3- yls) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamide mesylates are identical, yellow solid, yield 79%.

Embodiment 5

N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -1,1-] -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides

To N under condition of ice bath¹(two deuterated ethyls of 2- dimethylaminos -1,1-) -5- methoxyl groups-N¹Methyl-N⁴-[4-(1- 1-H- indol-3-yls) pyrimidine -2-base] benzene -1,2,4- triamines (intermediate 4,10g, 21.32mmol) are in THF (95mL) and water Chlorpromazine chloride (3.28g, 25.59mmol) is added in agitated solution in (9.5mL).The mixture is stirred 15 at room temperature Minute, then add NaOH (3.48g, 85.28mmol).Gained mixture is heated to 65 DEG C and is maintained 10 hours.Then will The mixture is cooled to room temperature, adds CH₃OH (40mL) and water (70mL).Gained mixture is stirred overnight.It is received by filtering Collect obtained solid, cleaned with water (25mL), it is 12 hours dry at 50 DEG C, obtain title compound (7.0g, 94%).

¹HNMR:2.23(6H,s),2.28(2H,t),2.71(3H,s),3.88(3H,s),5.75(1H,dd),6.25 (1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d),7.90(1H, s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺487

To N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -1,1-] -4- methoxyl groups -5- { [4- (1- at 50 DEG C H- indol-3-yls) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides (4.44g, 9.11mmol) are in acetone (45.5mL) and water Methanesulfonic acid (0.893g, the 9.11mmol) solution of addition in acetone (4.55mL) in agitated solution in (4.55mL).It will Gained mixture stirs 1.5 hours.Obtained solid is collected by filtration, is dried in vacuum overnight at 80 DEG C, obtains solid form Title salt (4.9g, 94%).

Embodiment 6

N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -2,2-] -4- methoxyl groups -5- { [4- (1-H- indoles -3- Base) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides

To N under condition of ice bath¹(two deuterated ethyls of 2- dimethylaminos -2,2-) -5- methoxyl groups-N¹Methyl-N⁴-[4-(1- H- indol-3-yls) pyrimidine -2-base] benzene -1,2,4- triamines (intermediate 5,10g, 21.32mmol) are in THF (95mL) and water Chlorpromazine chloride (3.28g, 25.59mmol) is added in agitated solution in (9.5mL).The mixture is stirred 15 at room temperature Minute, then add NaOH (3.48g, 85.28mmol).Gained mixture is heated to 65 DEG C and is maintained 10 hours.Then will The mixture is cooled to room temperature, adds CH₃OH (40mL) and water (70mL).Gained mixture is stirred overnight.It is received by filtering Collect obtained solid, cleaned with water (25mL), it is 12 hours dry at 50 DEG C, obtain title compound (7.0g, 94%).

¹HNMR:2.23(6H,s),2.71(3H,s),2.89(2H,t),3.88(3H,s),5.75(1H,dd),6.25 (1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d),7.90(1H, s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺487

To N- (2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -2,2-] -4- methoxyl groups -5- { [4- (1- at 50 DEG C H- indol-3-yls) pyrimidine -2-base] amino } phenyl } propyl- 2- acrylamides (4.44g, 9.11mmol) are in acetone (45.5mL) and water Methanesulfonic acid (0.893g, the 9.11mmol) solution of addition in acetone (4.55mL) in agitated solution in (4.55mL).It will Gained mixture stirs 1.5 hours.Obtained solid is collected by filtration, is dried in vacuum overnight at 80 DEG C, obtains solid form Title salt (4.9g, 94%).

Embodiment 7

N- (2- [2- dimethylaminoethyls-methylamino] -5- { [4- (1H- indol-3-yls) pyrimidine -2-base] amino } -4- first Phenyl) propyl- 2- acrylamides

By acryloyl chloride, (0.584mL, 1M are in CH₂Cl₂In, 0.58mmol) solution be added dropwise to N¹(2- diformazan ammonia Base ethyl)-N⁴[4- (1H- indol-3-yls) pyrimidine -2-base] -5- methoxyl groups-N¹Methylbenzene -1,2,4- triamines (252mg, 0.58mmol) in CH₂Cl₂In solution in (10mL), then the mixture is stirred 1 hour at -5 DEG C.Then this is mixed Object CH₂Cl₂(100mL) dilutes, by acquired solution saturation NaHCO₃(25mL), water (25mL) and then use saturated brine (25mL) is cleaned, and is then concentrated in vacuo.It is purified using FCC, used in CH₂Cl₂In 0-30%CH₃OH is eluted, and is obtained The title compound (76mg, 27%) of white solid.

¹HNMR:2.23(6H,s),2.28(2H,t),2.71(3H,s),2.89(2H,t),3.88(3H,s),5.75(1H, dd),6.25(1H,dd),6.46(1H,dd),7.03(1H,s),7.12(1H,t),7.21-7.28(2H,m),7.55(1H,d), 7.90(1H,s),8.24(1H,d),8.35(1H,d),8.65(1H,s),9.15(1H,s),10.24(1H,s)

m/z:ES⁺MH⁺485

Biological examples

Embodiment 1

By Calu 3 (WT), Calu6 (WT), NCI-H1975 (T790M/L858R) and PC9 (Ex19del) PC9VanR (Ex19del/T 790M) cell line is seeded on 384 orifice plates, (is depended on cell line) per 500-1000, hole cell, is added per hole Enter the RPMI culture mediums that 70 μ L contain 10% fetal calf serum, 2mM L-Glutamines and 1% penicillin/streptomycin.Simultaneously with every The form of a cell line duplicate rows prepares the culture plate of the 0th day.Cell is at 37 DEG C, 5%CO₂Under it is adherent overnight.Next day uses Echo Liquid Handler add in the test compound of titration into assay plate, and treated cell is at 37 DEG C, 5%CO₂Under incubate again It educates 72 hours.For each compound by 11 dose point reaction assays, maximum concentration is 10 μM, 1:3 dilutions.It is parallel with administration assay plate The 0th day culture plate handled using Sytox Green and saponin(e, and measure the viable count in each hole.It is handled by compound Culture plate be incubated 72 hours after, the Sytox green of 2 μM of 5 μ L are added in per hole, and it is small that culture plate is incubated at room temperature 1 When.Fluorecyte number per hole is measured with Acumen.The saponin(e of 10 μ L 0.25% is added in per hole, culture plate is incubated at room temperature It educates overnight.Fluorecyte sum in per hole is read on Acumen.It is living thin that the calculating of dead cell number is subtracted from total number of cells Born of the same parents' number.The data that each compound obtains are inputted into suitable software package to perform curve fitting analysis.Pass through meter based on this data It calculates and obtains the compound concentration needed for 50% effect to determine IC₅₀Value.

Table 1 the results show that the compound of embodiment 1-6 and the compound (control group) of embodiment 7 to expressing wild type The Proliferation Ability of the cell line of EGFR and the cell line of expression mutant egf R (Ex19del, L858R and/or T790M EGFR) Effect is suitable.

Table 1 tests inhibiting effect of the compound to one group of NSCLC cell line proliferation of expression saltant type or Wild type EGFR (IC₅₀μM)

Embodiment 2

It raises 8 men's health volunteers and carries out single-dose pharmacokinetics comparative study.Subject is randomly divided into 2 Group, the compound (control group) of embodiment 7 and other 4 subjects of the compound component of embodiment 1-6.After 7 days cleaning phases again Other embodiment compound is tested in grouping.After subject's fasting 10 hours, feed in morning next day unified standard is opened after the meal Begin to take orally and give tested material, dosage is that (this dosage is about animal acute toxicity dosage 1/50 to 0.4mg/kg, therefore to subject There is no potential toxic side effect).During entire research, subject needs 9 time points in setting (before administration, 30 after administration 1,2,3,6,12,24,48,72 hour after minute, administration) acquisition blood sample, for measuring the drug concentration in blood plasma.It is adopted each Sampling point acquires about 5mL venous wholes and puts in dry heparin or EDTA test tubes respectively, 4 DEG C place 2 hours after carry out 4 DEG C centrifugation (6000rpm, 10min) detaches serum, and in serum transfers to sample cryopreservation tube, -20 DEG C of refrigerators are preserved to measure.Using reverse phase height Effect liquid phase chromatogram (HPLC) plus Turbo IonTandem mass spectrum (MS/MS) detection method is measured, this detection of empirical tests The lower limit of quantitation (LLOQ) of method is 0.025ng/mL, and the linear determination upper limit is 25ng/mL, and withinrun precision is arrived 1.5% Between 10.7%, betweenrun precision is 3.0% to 6.8%, and accuracy is accurate between batch between 96.0% to 108.0% in batch Spend is 97.6% to 105.0%.Using Watson LIMS v.7.3.0.01 (Thermo Scientific Inc.) software meters Blood concentration is calculated, medicine is analyzed for parameter using the non-compartment model of WinNonLin v5.2.1 (Pharsight Inc.) software (main pharmacokinetic parameters for area under the drug-time curve value AUC0-t and eliminate half-life period t1/2 in present study).

Result of study is as shown in table 2 below, AUC0-t and the compound (control of embodiment 7 of the compound of embodiment 1-6 Close object) compared to 46-84% is increased, t1/2 increases 54-88% compared with control compound.

2 health volunteer's single-dose medicine of table is for comparative study result

Embodiment 3

Experimental method：Nude mouse (Balb/c nude mouses, 6-8 week old, 20-22g) inoculates Human cell line H1975 (L858R/T790M), treat tumour growth to 100-300mm³Afterwards, animal is randomly divided into 5 groups, wherein given the test agent every group 8, Solvent group 12, female.Respectively 3 compound 2.5 of embodiment 1-6,5,10mg/kg/d dosage groups, the change of embodiment 7 Close object 5mg/kg/d dosage groups and solvent control group.More than each group continuous gavage is given 21 days totally.2-3 knurl is surveyed in experiment weekly Volume claims knurl weight.Gross tumor volume (TV), relative tumour volume (RTV), inhibition rate of tumor growth (TGI), tumor proliferation rate (T/ C) formula is as follows：

TV=1/2a × b2 (wherein a and b represent the major diameter and minor axis of tumour respectively)

RTV=TVDt/TVD0

Relative tumor proliferation rate (T/C%)=RTV treatment groups/RTV control group × 100%

Inhibition rate of tumor growth (TGI%)=100% × (1- (TVDt (treatment group)-TVD0 (treatment group))/(TVDt is (right According to group)-TVD0 (control group)))

Experimental result：The compound of embodiment 1-6 significantly inhibits the growth of human lung cancer H1975 Nude Mices, leads Cause some animals tumor regression.The compound of embodiment 7 is also effective in cure to H1975.Under Isodose, the change of embodiment 1-6 The effect of closing object is substantially better than the compound of embodiment 7, about increases 19-43%.Tumor-bearing mice can be preferably to more than compound Tolerance.

The effect of compound of 3 embodiment 1-7 of table is to human cell line's H1975 Nude Mices

Cited all patents, patent application publication, patent application and non-patent publications in this specification, with it It is incorporated by herein incorporated by reference.

Although specific embodiments of the present invention are described herein for illustrative purposes from being appreciated that above, But various amendments can be carried out under without departing from spirit and scope of the invention.Therefore, the scope of the present invention should be only by appended The restriction of claim.

Claims

1. compound as follows or its pharmaceutically acceptable salt：

N- (2- { 2- [methyl (methyl-d₃) amino] ethyl-methylamino { [4- (1-H- indol-3-yls) is phonetic by -4- methoxyl groups -5- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides；

N- (2- [(methyl-the d of 2- bis-₃) amino-ethyl-methylamino] -4- methoxyl groups -5- { [4- (1-H- indol-3-yls) pyrimidine -2- Base] amino } phenyl) propyl- 2- acrylamides；

N- (2- [2- dimethylaminoethyls-methylamino] -4- (methoxyl group-d₃) -5- { [4- (1-H- indol-3-yls) pyrimidine -2-base] Amino } phenyl) propyl- 2- acrylamides；

N- (2- [2- dimethylaminoethyls-(methyl-d₃) amino] -4- methoxyl groups -5- { [4- (1-H- indol-3-yls) pyrimidine -2- Base] amino } phenyl) propyl- 2- acrylamides；

({ [4- (1-H- indol-3-yls) is phonetic by 2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -1,1-] -4- methoxyl groups -5- by N- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides；And

({ [4- (1-H- indol-3-yls) is phonetic by 2- [two deuterated ethyl-methylaminos of 2- dimethylaminos -2,2-] -4- methoxyl groups -5- by N- Pyridine -2- bases] amino } phenyl) propyl- 2- acrylamides.

2. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is methylsulphur Hydrochlorate.

3. pharmaceutical composition, it includes the compound described in claims 1 or 2 of therapeutically effective amount or its pharmaceutically acceptable salt And drug acceptable carrier.

4. compound or its pharmaceutically acceptable salt described in claims 1 or 2 are preparing for inhibiting epidermal growth factor receptor Purposes in the drug of body (Her).

5. purposes as claimed in claim 4, wherein the EGF-R ELISA (Her) is EGFR (Her1).

6. purposes as claimed in claim 5, wherein the EGFR (Her1) is wild type or mutant.

7. purposes as claimed in claim 6, wherein the mutant is single mutant or double-mutant.

8. the compound or its pharmaceutically acceptable salt described in claims 1 or 2 are in the drug for treating tumour is prepared Purposes.

9. purposes as claimed in claim 8, wherein the tumour is non-small cell lung cancer.