阅读说明：本技术 甲氧基取代苯基酰胺类氨基嘧啶衍生物的应用 (Application of methoxy-substituted phenylamide aminopyrimidine derivative ) 是由 黄军海 王彩月 谭绍英 吕志良 李明 胡锦 于 2019-02-28 设计创作，主要内容包括：本发明公开了一种甲氧基取代苯基酰胺类氨基嘧啶衍生物的应用。本发明的如式I所示的化合物或其药学上可接受的盐,可用于制备EGFR抑制剂。本发明如式I所示的化合物或其药学上可接受的盐,对EGFR有抑制作用,对正常细胞毒性较小,具有较高的成药前景。<Image he="642" wi="544" file="DDA0001981863350000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses an application of methoxy-substituted phenylamide aminopyrimidine derivatives. The compound shown in the formula I or the pharmaceutically acceptable salt thereof can be used for preparing an EGFR inhibitor. The compound shown as the formula I or the pharmaceutically acceptable salt thereof has an inhibitory effect on EGFR, has small toxicity on normal cells, and has high patent medicineAnd (4) foreground.)

1. The application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing an EGFR inhibitor is as follows:

wherein R is

R¹Is C_1～10Alkyl, halogen substituted C_1～10Alkyl radical, C_3～10Cycloalkyl radical, C_6～30Aryl radical, R^1-1Substituted C_6～30Aryl, 3-to 30-membered heteroaryl or

said halogen substituted C_1～10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;

each R^1-1Independently of one another, halogen, C_1～10Alkyl radical, C_1～10Alkoxy or

the R is^1-1-1aAnd R^1-1-1bIndependently is C_1～4An alkyl group;

R²is C_6～30Aryl or R^2-1Substituted C_6～30An aryl group;

each R^2-1Independently of one another, halogen, C_1～10Alkyl or C_1～10An alkoxy group; the R is^2-1Is 1 or more; when said R is^2-1When there are plural, R is^2-1The same or different.

2. Use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a mesylate, esylate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate or phosphate salt, preferably a mesylate salt;

in the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10C in alkyl_1～10Alkyl is C_1～6Alkyl, preferably C_1～3An alkyl group; more preferably methyl, ethyl, n-propyl or isopropyl, and still more preferably ethyl;

in the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10Halogen in the alkyl is F, Cl, Br or I, preferably Cl;

in the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10The number of halogen substitution in the alkyl group is 1 or more, preferably 1;

in the compound shown in the formula I, when the halogen is substituted C_1～10When the alkyl group has a chiral center, the halogen is substituted C_1～10The spatial configuration of the alkyl is R type;

in the compound shown in the formula I, when R is¹Is C_3～10When a cycloalkyl group is present, C is_3～10Cycloalkyl being C_3～6Cycloalkyl, further preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, further preferably cyclopropyl;

in the compound shown in the formula I, when R is¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1Substituted C_6～30C in aryl_6～30Aryl is C_6～20Aryl, preferably C_6～14Aryl, more preferably phenyl, naphthyl, phenanthryl or anthryl, and still more preferably phenyl;

in the compound shown in the formula I, when R is¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1The number of (a) is 1,2 or 3;

in the compound shown in the formula I, when R is¹In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group is a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group;

in the compound shown in the formula I, when R is¹In the case of 3-30-membered heteroaryl, the heteroatom in the 3-30-membered heteroaryl is N and/or O, preferably N;

in the compound shown in the formula I, when R is¹In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group is 1 or 2, preferably 1;

in the compound shown in the formula I, when R is^1-1When halogen, the halogen may be F, Cl, Br or I, preferably F, Cl or Br;

in the compound shown in the formula I, when R is^1-1Is C_1～10At alkoxy, the C_1～10Alkoxy is C_1～6Alkoxy, preferably C_1～3Alkoxy, more preferably methoxy or ethoxyN-propoxy or isopropoxy, more preferably methoxy;

in the compound shown in the formula I, when R is^1-1-1aAnd R^1-1-1bIndependently is C_1～4When alkyl, said C_1～4Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;

in the compound shown in the formula I, when R is²Is R^2-1Substituted C_6～30When aryl is said to R^2-1Substituted C_6～30C in aryl_6～30Aryl is C_6～20Aryl, preferably C_6～14Aryl, more preferably phenyl, naphthyl, phenanthryl or anthryl, and still more preferably phenyl;

in the compound shown in the formula I, when R is^2-1Is C_1～10When alkyl, said C_1～10Alkyl is C_1～6Alkyl, preferably C_1～3An alkyl group.

3. The use of claim 1, wherein in the compound of formula I, when R isWhen R is in the above-mentioned range¹Is halogen substituted C_1～10Alkyl radical, C_3～10Cycloalkyl radical, R^1-1Substituted C_6～30Aryl, 3-to 30-membered heteroaryl orPreferably halogen-substituted C_1～10An alkyl group;

in the compound shown in the formula I, when R isWhen R is²Is R^2-1Substituted C_6～30And (4) an aryl group.

4. The method of claim 3Characterized in that in the compound shown in the formula I, when R is

In the compound shown in the formula I, when R is

5. The use of claim 1, wherein in the compound of formula I, when R isR¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10Alkyl chloride substituted C_1～3Alkyl, more preferablyFurther preferred is

In the compound shown in the formula I, when R isR¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1Substituted C_6～30Aryl is "substituted by 1,2 or 3Halogen or

In the compound shown in the formula I, when R is

in the compound shown in the formula I, when R isR²Is R^2-1Substituted C_6～30When aryl is said to R^2-1Is C_1～10An alkyl group.

6. The use according to claim 1, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is any one of the following compounds:

7. the application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a medicament; the medicament is used for preventing and/or treating diseases related to EGFR mediation; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is as described in any one of claims 1-6.

8. The use according to claim 7, wherein the medicament is for the prevention and/or treatment of diseases associated with EGFR mutation-mediated diseases.

9. The use of claim 8, wherein the disease is ovarian cancer, cervical cancer, colorectal cancer, breast cancer, membranous adenocarcinoma, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, or mesothelioma; preferably lung cancer, and more preferably non-small cell lung cancer.

10. A pharmaceutical composition, which comprises a compound shown as a formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound shown as the formula I or the pharmaceutically acceptable salt thereof is as claimed in any one of claims 1 to 6.

Technical Field

The invention relates to application of methoxyl substituted phenylamide aminopyrimidine derivatives.

Background

Specific cysteine (Cys797) residues exist near openings of ATP binding domains of EGFR receptor family, and cysteine residues at similar positions exist only in 11 kinases such as EGFR, HER2, HER4, Jak3, Blk, Lkb1, 95Bmx, Btk, Itk, Tec and Txk. The specific cysteine residue, unlike the glutamate or serine residues of other kinases, is nucleophilic and can undergo a michael addition reaction with an electrophilic michael acceptor group. The introduction of an electrophilic michael acceptor group into the inhibitor to react with nucleophilic Cys797 through michael addition irreversibly prevents the binding of the kinase to ATP, thus realizing irreversible selective inhibition of EGFR kinase and improving the action strength of the inhibitor.

Currently, EGFR inhibitors and the mainstream drugs developed by the EGFR inhibitors are designed based on the above mechanisms, such as the second generation EGFR inhibitor afatinib, the structural formula of which is shown in the specificationAlso for example, the third generation EGFR inhibits oxitinib, which has the structural formula

However, second generation EGFR inhibitors have a deficiency in that they lack selectivity for EGFR mutant T790M and wild-type EGFR kinase. On the basis, the developed third-generation EGFR inhibitor oxitinib has good selectivity on T790M mutant and wild-type EGFR kinase. Therefore, the third generation EGFR inhibitor ocitiniHas received a lot of attention after coming into the market.

However, the allyl structure of the EGFR inhibitor also has the defect of certain toxicity to wild-type EGFR kinase, and the defect of drug resistance brought by the single main bond functional group is inevitable.

Disclosure of Invention

The invention aims to solve the technical problem of overcoming the defects that the existing EGFR inhibitor has certain toxicity and drug resistance to wild EGFR kinase in the prior art, and provides the application of the methoxy-substituted phenylamide aminopyrimidine derivative. The inhibitor has an inhibiting effect on EGFR, has small toxicity on normal cells, and has good selectivity on EGFR mutant strains.

The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof, and an application of the compound in preparation of an EGFR inhibitor:

wherein R is

R¹Is C_1～10Alkyl, halogen substituted C_1～10Alkyl radical, C_3～10Cycloalkyl radical, C_6～30Aryl radical, R^1-1Substituted C_6～30Aryl, 3-to 30-membered heteroaryl orThe heteroatoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the heteroatoms is 1,2 or 3; when the number of the hetero atoms is plural, the species of the hetero atoms are the same or different;

said halogen substituted C_1～10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;

each R^1-1Independently of one another, halogen, C_1～10Alkyl radical, C_1～10Alkoxy or

The R is^1-11,2, 3 or 4; when said R is^1-1When plural, R is^1-1The same or different;

the R is^1-1-1aAnd R^1-1-1bIndependently is C_1～4An alkyl group;

R²is C_6～30Aryl or R^2-1Substituted C_6～30An aryl group;

each R^2-1Independently of one another, halogen, C_1～10Alkyl or C_1～10An alkoxy group; the R is^2-1Is 1 or more; when said R is^2-1When there are plural, R is^2-1The same or different.

Wherein, the pharmaceutically acceptable salt of the compound shown in formula I can be a salt which is conventional in the field, preferably a methanesulfonate, ethanesulfonate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, preferably a methanesulfonate.

In the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10C in alkyl_1～10The alkyl group may be C_1～6Alkyl, preferably C_1～3An alkyl group. Said C is_1～3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably ethyl.

In the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10The halogen in the alkyl group may be F, Cl, Br or I, preferably Cl.

In the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10Halogen substitution in alkyl groupsThe number of (A) may be1 or more, preferably 1.

In the compound shown in the formula I, when the halogen is substituted C_1～10When the alkyl group has a chiral center, the halogen is substituted C_1～10The steric configuration of the alkyl group may be R-type.

In the compound shown in the formula I, when R is¹Is halogen substituted C_1～10When alkyl, said halogen being substituted by C_1～10Alkyl chloride substituted C_1～3Alkyl, more preferablyFurther preferred is

In the compound shown in the formula I, when R is¹Is C_3～10When a cycloalkyl group is present, C is_3～10Cycloalkyl radicals may be C_3～6A cycloalkyl group. Said C is_3～6Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

In the compound shown in the formula I, when R is¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1Substituted C_6～30C in aryl_6～30Aryl may be C_6～20Aryl, preferably C_6～14And (4) an aryl group. Said C is_6～14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.

In the compound shown in the formula I, when R is¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1The number of (a) may be1, 2 or 3.

In the compound shown in the formula I, when R is¹Is R^1-1Substituted C_6～30When aryl is said to R^1-1Substituted C_6～30Aryl may be "substituted by 1,2 or 3 times", halogen or

"substituted phenyl radical, further preferred

In the compound shown in the formula I, when R is¹In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group.

In the compound shown in the formula I, when R is¹In the case of a 3-to 30-membered heteroaryl group, the heteroatom in the 3-to 30-membered heteroaryl group may be N and/or O, preferably N.

In the compound shown in the formula I, when R is¹In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group may be1 or 2, preferably 1.

In the compound shown in the formula I, when R is¹In the case of the 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "3-to 10-membered heteroaryl group in which the number of hetero atoms is 1 or 2", preferably a "3-to 6-membered heteroaryl group in which the number of hetero atoms is 1", and more preferably a pyrrolyl group.

In the compound shown in the formula I, when R is^1-1When halogen, the halogen may be F, Cl, Br or I, preferably F, Cl or Br.

In the compound shown in the formula I, when R is^1-1Is C_1～10At alkoxy, the C_1～10Alkoxy may be C_1～6Alkoxy, preferably C_1～3An alkoxy group. Said C is_1～3The alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, with methoxy being preferred.

In the compound shown in the formula I, when R is^1-1-1aAnd R^1-1-1bIndependently is C_1～4When alkyl, said C_1～4The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In the compound shown in the formula I, when R is²Is R^2-1Substituted C_6～30When aryl is said to R^2-1Substituted byC_6～30C in aryl_6～30Aryl may be C_6～20Aryl, preferably C_6～14And (4) an aryl group. Said C is_6～14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.

In the compound shown in the formula I, when R is^2-1Is C_1～10When alkyl, said C_1～10The alkyl group may be C_1～6Alkyl, preferably C_1～3An alkyl group. Said C is_1～3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.

In one embodiment, in the application, in the compound shown as the formula I, R is

In one embodiment, in the application, in the compound shown in the formula I, when R isWhen R is in the above-mentioned range¹Is halogen substituted C_1～10Alkyl radical, C_3～10Cycloalkyl radical, R^1-1Substituted C_6～30Aryl, 3-to 30-membered heteroaryl or

In one embodiment, in the application, in the compound shown in the formula I, when R isWhen R is in the above-mentioned range¹Is halogen substituted C_1～10An alkyl group.

In a certain embodiment, in the application, in the compound shown in the formula I, when R isR¹Is R^1-1Substituted C_6～30When aryl is said each R^1-1Independently of one another, halogen, C_1～10Alkyl or

In a certain embodiment, in the application, in the compound shown in the formula I, when R is

When R is in the above-mentioned range²Is R^2-1Substituted C_6～30And (4) an aryl group.

In a certain embodiment, in the application, in the compound shown in the formula I, when R isR²Is R^2-1Substituted C_6～30When aryl is said each R^2-1Is C_1～10An alkyl group.

In one embodiment, in the application, in the compound shown as the formula I, R is¹Is halogen substituted C_1～10Alkyl radical, C_3～10Cycloalkyl radical, R^1-1Substituted C_6～30Aryl, 3-to 30-membered heteroaryl orR²Is R^2-1Substituted C_6～30And (4) an aryl group.

In one embodiment, in the application, in the compound shown as the formula I, R is¹Is halogen substituted C_1～10An alkyl group; r²Is R^2-1Substituted C_6～30And (4) an aryl group.

In the application, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably any one of the following compounds:

the application can also further comprise a preparation method of the pharmaceutically acceptable salt of the compound shown as the formula I, which is a method 1, a method 2 or a method 3:

the method comprises the following steps: the method comprises the following steps of carrying out condensation reaction of a compound shown in a formula II and a compound shown in a formula III in an organic solvent under the action of a condensing agent and an alkaline reagent to obtain a compound shown in a formula I;

the method 2 comprises the following steps: the method comprises the following steps of carrying out acylation reaction on a compound shown in a formula II and a compound shown in a formula IV in an organic solvent in the presence of an acid binding agent to obtain a compound shown in a formula I;

the method 3 comprises the following steps: the method comprises the following steps of reacting a compound shown as a formula I with acid in a solvent to obtain a salt of the compound shown as the formula I;

wherein R in the method 1, the method 2 and the method 3 is the same as the above.

In method 1, the conditions and operation of the condensation reaction may be those conventional in the art.

In method 1, the condensing agent may be a condensing agent conventional in this reaction in the art, preferably 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC) or Carbonyldiimidazole (CDI), such as HATU.

In the method 1, the molar ratio of the condensing agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 2.0, for example 1.5.

In method 1, the basic reagent may be a reagent conventional in the art, preferably Triethylamine (TEA) and/or N, N-Diethylisopropylamine (DIEA), such as TEA.

In the method 1, the molar ratio of the alkaline agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 5.0, for example 3.0.

In the method 1, the molar ratio of the compound III to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.

In the method 1, the organic solvent may be an organic solvent that is conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.

In the process 1, the compound III may be

In method 1, the condensation reaction may be at a temperature conventional in the art for such reactions, preferably 10-40 deg.C, for example 25 deg.C.

In method 1, the progress of the condensation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 3 to 10 hours, for example 5 hours.

In the method 1, after the condensation reaction is finished, the method may further include a post-treatment step: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In method 2, the conditions and operation of the acylation reaction may be those conventional in the art for such reactions.

In the method 2, the acid-binding agent can be a reagent conventional in the art, and is preferably an organic weak base. The weak organic base may be one or more of pyridine, Triethylamine (TEA) and N, N-Diethylisopropylamine (DIEA), such as TEA.

In the method 2, the molar ratio of the acid-binding agent to the compound II may be a molar ratio conventional in this reaction in the art, and is preferably 1.0-5.0, for example 2.0.

In the method 2, the molar ratio of the compound IV to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.

In method 2, the organic solvent may be an organic solvent conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.

In method 2, the compound IV can be

In method 2, the temperature of the acylation reaction may be a temperature conventional in the art for such reactions, preferably 0 to 40 ℃, e.g. 25 ℃.

In method 2, the progress of the acylation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 1 to 5 hours, for example, 1 hour.

After the condensation reaction is finished, the method can further comprise the following post-treatment steps: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In the method 3, the salt of the compound shown in the formula I can be prepared according to the conventional method and conditions of salt forming reaction in the field.

In method 3, the acid may be an organic acid or an inorganic acid capable of salt formation, which is conventional in the art. The organic acid can be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, and preferably methanesulfonic acid. The inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

In the method 3, the molar ratio of the acid to the compound represented by the formula I may be1 to 3, for example, 1.

In method 3, the solvent may be a ketone solvent, such as acetone.

In the method 3, the reaction temperature may be 10 to 60 ℃, for example, 50 ℃.

The invention also provides the application of the compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to EGFR mediation.

In the above application, preferably, the medicament is used for preventing and/or treating diseases related to EGFR mutation mediation.

Wherein the disease can be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, membrane adenocarcinoma, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma, melanoma, or mesothelioma; preferably lung cancer, and more preferably non-small cell lung cancer.

The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula I or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition can also consist of the compound shown as the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In the present invention, the pharmaceutically acceptable carrier may be a carrier conventional in the art, including one or more of a lubricant, a binder, a filler and a disintegrant. The lubricant is selected from one or more of magnesium stearate, aerosil, silicon dioxide and talcum powder; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, starch and crospovidone; the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and methyl cellulose; the filler is selected from one or more of lactose, pregelatinized starch and microcrystalline cellulose.

In the present invention, the amount of the pharmaceutically acceptable carrier is not particularly limited as long as it meets the requirements of a formulation which is conventional in the art.

In the invention, the pharmaceutical composition can be prepared into various dosage forms, such as tablets, capsules, pills, powder, emulsion, granules, suppositories, injections and the like.

In the present invention, the term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to occur in a subject who may be exposed to a disease causing agent or predisposing disease prior to the onset of the disease).

In the invention: the term "R-S configuration" is the term used to designate the R-S system nomenclature in the nomenclature of chiral C. The specific nomenclature of the R-S system is as follows: when a, b, c, d attached to the central carbon atom are different groups, the molecule is chiral. Assuming that the four substituents in the molecule are arranged in the CIP order rule in the order a > b > c > d, if the smallest d group is placed at the position furthest from the viewer, the other three groups are viewed in a-b-c precedence order, with a → b → c being observed in a clockwise direction, the configuration of this carbon center is defined as R (latin recatus); otherwise, S (Latin Sinister) is identified.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and raw materials used in the invention are commercially available, wherein S-2-chloropropionic acid is purchased from Annaiji (batch number: BE170142), the purity is 98%, and the specific rotation degree is-13.5 degrees; r-2-chloropropionic acid was purchased from Annaiji (batch No.: EE040098) and had a purity of 98% and a specific rotation of +13.4 °.

The positive progress effects of the invention are as follows: the methoxy-substituted phenylamide aminopyrimidine derivative has low toxicity to normal cells and good selectivity and activity to EGFR mutant strains.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.