WO2023046030A1

WO2023046030A1 - Egfr small-molecule inhibitor, pharmaceutical composition containing same, and use thereof

Info

Publication number: WO2023046030A1
Application number: PCT/CN2022/120630
Authority: WO
Inventors: 吕志俭; 钟利; 杨保成; 高安慧; 楼洋
Original assignee: 河南晟翔医药科技有限公司; 百极弘烨(南通)医药科技有限公司
Priority date: 2021-09-23
Filing date: 2022-09-22
Publication date: 2023-03-30

Abstract

An EGFR small-molecule inhibitor, a pharmaceutical composition containing same, and the use thereof. Specifically, provided is a compound as represented by formula I, and a stereoisomer thereof, optical isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof or solvate thereof. The compound can be used for preventing and/or treating EGFR-mediated related diseases, and particularly has a specific effect against the resistance to early related drugs caused by two mutations and three mutations.

Description

A kind of EGFR small molecule inhibitor, its pharmaceutical composition and its use

technical field

The invention relates to a small molecule inhibitor of EGFR, a pharmaceutical composition containing it and use thereof.

Background technique

Epidermal growth factor receptor (EGFR, also known as HER-1 or c-erbB-1) is a 170-kDa transmembrane glycoprotein composed of 1186 amino acids. EGFR is a member of the receptor tyrosine kinase c-erbB family, which regulates cell proliferation, survival, adhesion, migration and differentiation. EGFR consists of three parts: the extracellular receptor region; the transmembrane region; and the intracellular tyrosine kinase region. The confirmed ligands that can bind to EGFR include: epidermal growth factor (EGF), transforming growth factor ɑ (TGFɑ), two-way regulator, heparin-binding EGF, cytokines, etc. EGFR is overactivated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, and prostate cancer.

Due to the key role of EGFR in controlling cell proliferation, survival, and metabolism, interfering with its activity can block signal transduction, making EGFR an attractive molecular target for tumor-targeted therapy. Drugs targeting EGFR It has also become a hot spot in tumor treatment. At present, tumor molecular targeting drugs targeting EGFR are mainly divided into two categories according to their properties: one is a monoclonal antibody that directly acts on the extracellular receptor region; the other is a drug that interferes with the activity of intracellular EGFR tyrosine kinase. small molecule inhibitors. Monoclonal antibody drugs interact with the extramembrane ligand-binding domain of EGFR, so that endogenous ligands such as EGF cannot bind to EGFR, thereby preventing the signal from passing into cells; small molecule drugs interact with the catalytic domain of intracellular tyrosine kinase Binding, inhibiting its catalytic activity, thereby blocking cell proliferation signals.

At present, the EGFR-TKI small molecule inhibitors that have been marketed include the first-generation Iressa, Tarceva, and Conmana, the second-generation afatinib and dacomitinib, and the third-generation osimertinib. NSCLC patients benefited from EGFR-TKI therapy. However, in the course of treatment, drug-resistant mutations in tumors and resistance are inevitable problems. After treatment with first- and second-generation EGFR-TKIs, about 60% of patients will develop T790M drug-resistant mutations, resulting in the loss of therapeutic effect of first- and second-generation drugs. As a third-generation EGFR-TKI, osimertinib has very good inhibitory activity on T790M, thus bringing better therapeutic effect and survival benefits to patients. However, with the widespread use of the third-generation EGFR-TKI, the EGFR C797S triple mutation was generated, resulting in the inability of the third-generation inhibitors to covalently bind to protein kinases, making these inhibitors ineffective.

Therefore, there is an urgent need to develop a new generation of inhibitors to overcome drug-resistant mutations.

Contents of the invention

The object of the present invention is to provide a class of macrocyclic small molecule compounds with novel structure, which can be used as mutant EGFR inhibitors, for double mutations produced by T790M (such as L858R/T790M or T790M/C797S), and L858R/T790M/C797S , Del19/T790M/C797S and other triple mutations have excellent therapeutic effects, and have good selectivity for wild-type EGFR protein.

In the first aspect, the present invention provides a compound represented by formula I, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate,

In the formula,

R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, -NR ₆ R ₇ , -C(O)NR ₆ R ₇ , -N(R ₆ )SO _m R ₇ , -C(O)R' ₆ , -P(=O)R' ₆ R' ₇ , -S(O) _m NR ₆ R ₇ , -NR ₆ C (O)R ₇ , -C(O)OR ₆ , -OC(O)R ₆ , -S(O) _m' R' ₆ , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 Membered heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O-; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered Heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O- are optionally substituted by 1-3 R;

Alternatively, R ₁ , R ₂ and the atoms connected to them jointly form a C5-C6 cycloalkyl group, a 5-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group; wherein, the C5-C6 cycloalkane Base, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by 1-3 R;

X is N or CR _x , wherein, R _x is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, -NR ₆ R ₇ , -C(O)NR ₆ R ₇ , -N(R ₆ )SO _m R ₇ , -C(O)R' ₆ , -P(=O)R' ₆ R' ₇ , -S(O) _m NR ₆ R ₇ , -NR ₆ C(O)R ₇ , -C(O)OR ₆ , -OC(O)R ₆ , -S(O) _m' R' ₆ , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl are optionally substituted by 1-3 R;

Ring A is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are further optionally substituted by 1-3 R;

Ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are optionally substituted by 1-3 R;

R ₆ , R ₇ , R' ₆ and R' ₇ are each independently selected from the following group: H, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 ring Alkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl are optionally substituted by 1-3 R;

R is selected from: D, halogen, cyano, nitro, hydroxyl, -NR ₈ R ₉ , -C(O)NR ₈ R ₉ , -N(R ₈ )SO _m R ₉ , -C(O)R' ₈ , -P(=O)R' ₈ R' ₉ , -S(O) _m NR ₈ R ₉ , -NR ₈ C(O)R ₉ , -C(O)OR ₈ , -OC(O)R _8. -S(O) _m' R' ₈ , C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1- C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclic Base-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O-; wherein, the C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2 -C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O- are optionally replaced by 1-3 R'replace;

R'is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) ₂ , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl , 5-10 membered heteroaryl;

R ₈ , R ₉ , R' ₈ and R' ₉ are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C12 cycloalkane Base, 3-12 membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group, C3-C12 cycloalkyl C1-C6 alkyl, 3-12 membered heterocyclic group C1-C6 alkyl, C6 -C10 aryl C1-C6 alkyl, 5-10 membered heteroaryl C1-C6 alkyl;

In formula I, the group connecting ring A to the pyrazole ring

One or more of -CH ₂ - in is optionally replaced by -SO ₂ -;

n is 1, 2, 3, 4, 5, 6 or 7;

m and m' are each independently 0, 1 or 2.

In some technical solutions of the present invention, X is CH or N, preferably N.

In some technical solutions of the present invention, ring A is selected from: phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic; wherein, the phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic The group is further optionally substituted by 1-3 groups selected from the group consisting of halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl.

In some technical solutions of the present invention, ring A is selected from: phenyl, piperidinyl, tolyl; wherein, the phenyl is preferably

The piperidinyl is preferably

More preferably, the left side of the piperidine ring is connected to the N in the right-NH- in formula I; the tolyl group is preferably

More preferably, the left side of the benzene ring is connected to the N in -NH- on the right side of formula I.

In some technical solutions of the present invention, ring B is selected from: phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic; wherein, the phenyl, 5-6 membered heteroaryl, 6-membered heterocyclic The group is optionally substituted with 1-3 groups selected from the group consisting of D, halogen, cyano, nitro, hydroxyl, -NR ₈ R ₉ , -C(O)NR ₈ R ₉ , -N(R ₈ ) SO ₂ R ₉ , -C(O)R' ₈ , -P(=O)R' ₈ R' ₉ , -S(O) ₂ NR ₈ R ₉ , -NR ₈ C(O)R ₉ , -C(O)OR ₈ , -OC(O)R ₈ , -S(O) ₂ R' ₈ , C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Base, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-6 membered heteroaryl, C3-C6 Cycloalkyl-O-, 3-6 membered heterocyclic group-O-, C6-C10 aryl-O-, 5-6 membered heteroaryl-O-; wherein, the C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6 -C10 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C6-C10 aryl-O-, 5-6 membered heteroaryl -O- is optionally substituted by 1-3 R';

R'is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) ₂ , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5- 6-membered heteroaryl;

R ₈ , R ₉ , R' ₈ and R' ₉ are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C6 cycloalkane Base, 3-6 membered heterocyclic group, C6-C10 aryl group, 5-6 membered heteroaryl group, C3-C6 cycloalkyl C1-C6 alkyl group, 3-6 membered heterocyclic group C1-C6 alkyl group, C6 -C10 aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl.

In some technical solutions of the present invention, ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl or 5-10 membered heteroaryl; or, B ring is selected from: Phenyl, 5-6 membered heteroaryl or 6 membered heterocyclic group;

Wherein, H in each of the above groups is further substituted by 1, 2 or 3 R; R is selected from: -NR ₈ R ₉ ;

_R is selected from: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl or C1-C6 alkoxyl, and H in each of the above groups is optionally selected from 1 of the following group , 2 or 3 groups are substituted: D, halogen, cyano, nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) ₂ ;

_R9 is selected from: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl or C1-C6 alkoxyl, and H in each of the above groups is further selected from the following group 1, Substitution by 2 or 3 groups: D, halogen, cyano, nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) ₂ .

Wherein, the H in each of the above groups is further substituted by 1, 2 or 3 R; R is selected from: C1-C6 alkoxy, and the C1-C6 alkoxy is further substituted by a 3-7 membered heterocycle or 5-membered heterocyclic group, and the 3-7-membered heterocyclic group or 5-membered heterocyclic group is further substituted by oxo. R can for example be

In some technical solutions of the present invention, ring B is selected from: phenyl, substituted phenyl, pyridyl, substituted pyridyl, pyrimidyl, substituted pyrimidyl, piperidyl, substituted piperidyl, pyrazine Base, substituted pyrazinyl;

In ring B, the phenyl group is preferably

The pyridyl group is preferably

The pyrimidinyl group is preferably

The piperidinyl is preferably

More preferably, the N of the piperidine ring is connected to the pyrazole ring of formula I;

In Ring B, the substitution refers to being substituted by one or more groups selected from the following group: D, halogen, cyano, nitro, hydroxyl, amino, carboxyl, -COOCH ₃ , -COOCH ₂ CH ₃ , - OCOCH ₃ , -CONHCH ₃ , -NHCOCH ₃ , -CON(CH ₃ ) ₂ , -SO ₂ CH ₃ , -SOCH ₃ , -N(CH ₃ )SO ₂ CH ₃ , C1-C6 alkyl, halogenated C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 Aryl, 5-6 membered heteroaryl,

Among them, the halogen is preferably F or Cl; the C1-C6 alkyl is preferably methyl; the C1-C6 alkoxy is preferably methoxy; the halogenated C1-C6 alkoxy is preferably CF ₃ -O-; The 3-6 membered heterocyclic group is preferably morpholinyl, more preferably

In some technical solutions of the present invention, the substitution on ring B refers to substitution by one or more groups selected from the following groups:

In some technical solutions of the present invention,

selected from:

Wherein, R ₁₀ and R ₁₁ are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, Halogenated C1-C6 alkoxy;

R ₁ and R ₂ are as defined above.

In some technical solutions of the present invention, R ₁ is H or C1-C3 alkyl, preferably H or methyl.

In some technical solutions of the present invention, R _is selected from: H, F, Cl, Br, I, methyl, ethyl, vinyl, isopropenyl, isopropyl, cyclopropyl, ethynyl, propyne phenyl, halophenyl, trifluoromethyl; or, R and _R together with the atoms to which they are attached form substituted or unsubstituted thienyl _, thiazolyl, furyl, imidazolyl, pyrrolyl, pyryl Azolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, wherein the substitution refers to being substituted by one or more groups selected from the group: H, D, halogen, cyano, nitro, hydroxyl , C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy.

In some technical solutions of the present invention, R _is selected from: H, F, Cl, Br, I, methyl, phenyl, fluorophenyl, cyclopropyl, propynyl, vinyl, isopropenyl, Ethyl, isopropyl, trifluoromethyl, ethynyl; alternatively, R _and _R together with the atoms to which they are attached form thienyl, methylimidazolyl, pyrrolyl, methylthienyl, methylpyrrolyl, imidazolyl, methylthiazolyl, furyl, phenyl, pyridyl; wherein, the propynyl is preferably

The fluorophenyl group is preferably

In some technical solutions of the present invention, R ₃ is selected from: -P(O)(CH ₃ ) ₂ , -SO ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHSO ₂ CH ₃ , -N(CH ₃ )SO ₂ CH ₃ , -N(cyclopropyl)SO ₂ CH ₃ ,

In some technical solutions of the present invention, R ₄ is H.

In some technical solutions of the present invention, R ₅ is H.

In some technical solutions of the present invention, R is selected from: D, halogen, cyano, nitro, hydroxyl, -NR ₈ R ₉ , -C(O)NR ₈ R ₉ , -N(R ₈ )SO _m R ₉ , -C(O)R' ₈ , -P(=O)R' ₈ R' ₉ , -S(O) _m NR ₈ R ₉ , -NR ₈ C(O)R ₉ , -C(O) OR ₈ , -OC(O)R ₈ , -S(O) _m' R' ₈ , C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl- O-, 3-6 membered heterocyclic group-O-, C6-C10 aryl-O-, 5-6 membered heteroaryl-O-; wherein, the C1-C6 alkyl, halogenated C1-C6 alkane Base, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl , 5-6 membered heteroaryl, C3-C6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C6-C10 aryl-O-, 5-6 membered heteroaryl-O-any optionally replaced by 1-3 R';

In some technical solutions of the present invention, in formula I, the group that ring A is connected to the pyrazole ring

One of the -CH ₂ - is replaced by -SO ₂ -, the group is preferably

In some technical schemes of the present invention, the group that ring A is connected to the pyrazole ring

H in is optionally substituted by 1, 2, 3, 4 or more than 5 (including 5) R'; wherein R' is as defined above. Preferably, R' is selected from: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy, for example methyl.

for example can be

1, 2, or more than 3 (including 3) of -CH ₂ - are replaced by O or NH, and this group can be, for example,

In some technical solutions of the present invention, the compound has a structure shown in formula II,

In the formula,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X and n are as defined above.

In some technical schemes of the present invention, the compound has a structure shown in formula III,

In the formula,

The definition of each R ₁₂ is the same as the aforementioned R; preferably, the definition of each R ₁₂ is the same as the aforementioned substituent of the B ring.

p is 0, 1, 2, 3 or 4;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X and n are as defined above.

In some technical solutions of the present invention, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₂ , X, A and B are the groups corresponding to the specific compounds in the examples, and n and p are the groups in the examples The parameters corresponding to each specific compound in .

In some technical solutions of the present invention, the compound has a structure shown in formula IV:

in,

Q is selected from: N or CR ₁₄ ;

R ₁₃ , R ₁₄ and R ₁₅ are as defined above for R;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X and n are as defined above.

In some technical schemes of the present invention, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, A and B are the groups corresponding to each specific compound in the examples, and n is the group corresponding to each specific compound in the examples. corresponding parameters.

In some technical schemes of the present invention, the compound is selected from the following group:

In the second aspect, the present invention provides a pharmaceutical composition, comprising the compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate ; and a pharmaceutically acceptable carrier.

In some technical solutions of the present invention, a preparation method of a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the present invention, its stereoisomer, its optical isomer, its pharmaceutical The above acceptable salts, prodrugs or solvates thereof are mixed to form a pharmaceutical composition.

In some technical solutions of the present invention, the pharmaceutical composition further includes other therapeutic agents. Other therapeutic agents may be EGFR mAbs or MEK inhibitors.

Wherein, the EGFR monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, necituzumab, nimotuzumab, or a combination thereof.

Wherein, the MEK inhibitor is selected from the group consisting of selumetinib, trametinib, PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), or a combination thereof.

In the third aspect, the present invention provides the compound described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as in the second aspect Use of the pharmaceutical composition in the preparation of medicines for inhibiting EGFR kinase.

In some technical solutions of the present invention, the compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as described in the second aspect Use of the pharmaceutical composition in the preparation of medicines for EGFR-mediated diseases.

In some technical solutions of the present invention, the EGFR is mutant EGFR, preferably L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, or a combination thereof; more preferably L858R, T790M, C797S, Del19, Or a combination thereof; more preferably L858R/T790M double mutation, T790M/C797S double mutation, L858R/T790M/C797S triple mutation or Del19/T790M/C797S triple mutation.

In some technical solutions of the present invention, the drug for inhibiting EGFR kinase is a drug for treating cancer. Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal carcinoma tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, rectal cancer, glioma, or a combination thereof.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR L858R mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR Del19 mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR C797S mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR T790M mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR L858R/T790M mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR T790M/C797S mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR L858R/T790M/C797S mutation.

In some technical solutions of the present invention, the drug is used to treat lung cancer caused by EGFR Del19/T790M/C797S mutation.

In a fourth aspect, the present invention provides a method for treating cancer, which includes the step of: administering an effective amount of the compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutical An acceptable salt, a prodrug or a solvate thereof, or a pharmaceutical composition as described in the second aspect.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Detailed ways

Through extensive and in-depth research, the inventors have discovered for the first time a new macrocyclic EGFR inhibitor, which can be used to treat EGFR-mediated related diseases (such as cancer), especially for double and triple mutations. It is particularly useful for diseases (such as cancer) that are resistant to earlier-associated drugs. The present invention has been accomplished on this basis.

Herein, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprises" or "includes (comprising)" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of", or "consisting of".

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C ₁ -C ₆ alkyl represents a straight-chain or branched alkyl group having 1-6 (eg 1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert-butyl, etc.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. For example, C ₂ -C ₆ alkenyl refers to a linear or branched alkenyl group having 2-6 (eg 2, 3, 4, 5 or 6) carbon atoms, such as vinyl, allyl, 1-propene group, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C ₂ -C ₆ alkynyl refers to a straight-chain or branched alkynyl group having 2-6 (eg 2, 3, 4, 5 or 6) carbon atoms, such as ethynyl, propynyl, butynyl group, or similar groups.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C12 cycloalkyl" refers to a group having 3-12 (eg 3, 4, 5, 6, 7 , 8, 9, 10, 11 or 12) carbon atom cycloalkyl. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms such as bridged or spiro forms are also possible. The cycloalkyl group can also be fused to an aryl, heteroaryl, heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, such as

wait. Herein, cycloalkyl is intended to include substituted cycloalkyl groups.

As used herein, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1-6 carbon atoms (eg 1, 2, 3, 4, 5 or 6); it has Formula C1-C6 alkyl-O- or -C1-C5 alkyl-O-C1-C5 alkyl (eg, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -O-(CH ₂ ) ₂ CH _3. -CH ₂ CH ₂ -O-CH ₂ CH ₃ ) structure, preferably C1-C6 alkyl-O-, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy base, isobutoxy or tert-butoxy, etc.

As used herein, "heterocyclyl (heterocyclyl)" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O, and "3-12 membered heterocyclyl" refers to having 3-12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) atoms and wherein 1-3 (e.g. 1, 2 or 3) atoms are selected from Saturated or partially saturated cyclic radicals of heteroatoms of groups N, S and O. It may be monocyclic or bicyclic, for example bridged or spiro. The 3-12-membered heterocyclic group is preferably a 3-8-membered heterocyclic group, more preferably a 3-6-membered or 6-8-membered heterocyclic group. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like. The heterocyclyl may be fused to a heteroaryl, aryl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heterocyclyl such as

wait.

As used herein, "aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring, and "C6-C12 aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring and has 6 to 12 (such as 6, 7, 8 , 9, 10, 11 or 12) carbon atoms of the aromatic ring group, which may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is Aryl ring. Such as phenyl (ie six-membered aryl), naphthyl, etc., wherein the six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl (such as

) and six-membered aryl and 5-6-membered heterocyclic group (such as

wait). The C6-C12 aryl group is preferably a C6-C10 aryl group. Aryl groups can be optionally substituted or unsubstituted.

As used herein, "heteroaryl" refers to a cyclic aromatic group having 1-3 (eg 1, 2 or 3) atoms are heteroatoms selected from the group consisting of N, S and O, "5-12 membered heteroatoms "Aryl" means having 5-12 (e.g. 5, 6, 7, 8, 9, 10, 11 or 12) atoms and wherein 1-3 (e.g. 1, 2 or 3) atoms are selected from Cyclic aromatic radicals of heteroatoms of the groups N, S and O. It may be a single ring or a condensed ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamide, Formyl, formamide, carboxyl and carboxylate groups, etc.

As used herein, "halogen" refers to F, Cl, Br and I. More preferably, halogen is selected from F, Cl and Br.

Herein, "amino" refers to _-NH2 .

Herein, "carboxy" refers to -COOH.

Herein, "C1-C6 alkylamino" refers to C1-C6 alkyl NH ₂ , C1-C6 alkyl NH (C1-C6 alkyl) or C1-C6 alkyl-N (C1-C6 alkyl) ₂ , preferably C1-C6 alkylamino is CH ₂ NH ₂ , CH ₂ CH ₂ NH ₂ , CH ₂ CH 2 CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ CH ₂ _NHCH ₃ , CH ₂ CH ₂ CH ₂ NCH _3. CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ .

Herein, "C3-C12 cycloalkyl C1-C6 alkyl" refers to -C3-C12 cycloalkyl C1-C6 alkyl or C3-C12 cycloalkyl C1-C6 alkyl-, "3-12 membered hetero "Cycloyl C1-C6 alkyl", "C6-C10 aryl C1-C6 alkyl", "5-10 membered heteroaryl C1-C6 alkyl" have similar meanings.

Herein, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible.

Unless specifically stated as "substituted or unsubstituted", the groups described in the present invention can be substituted by substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl.

"Optionally" herein means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.

Herein, the term "plurality" independently refers to 2, 3, 4, 5 or more than 5 positive integers.

Unless otherwise specified, the structural formulas described herein are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers and geometric isomers (or conformers)): R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers or geometric isomers (or conformers) are within the scope of the present invention.

As used herein, the term "solvate" refers to a complex in which a compound represented by formula I coordinates with solvent molecules to form a specific ratio.

active ingredient

As used herein, "the compound of the present invention" refers to the compound represented by formula I, and also includes stereoisomers, pharmaceutically acceptable salts, prodrugs or solvates of the compound represented by formula I.

The compounds of the present invention may contain one or more chiral carbon atoms, and thus may arise in enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual optical isomers (i.e., enantiomers and diastereomers) include chiral synthesis from suitable optically pure precursors, or resolution of the exoisomers using, for example, chiral high performance liquid chromatography. Racemates (or racemates of salts or derivatives), see for example Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M. Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010; Fumiss et al.(eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

The invention also includes isotopically labeled compounds (ie, isotopically derivatives) equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs. Examples of isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. Isotopic derivatives of the compounds of the present invention are within the protection scope of the present invention. Herein, ³ H-labeled compounds and ¹⁴ C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) labeled compounds are relatively easy to prepare and detect, and are the first choice among isotopes. In addition, substitution of heavier isotopes such as deuterium, ie ² H, may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the schemes disclosed in the Examples.

Herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, and then separated by crystallization or chromatography. Separation by conventional means then gives the pure enantiomers.

As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. In general, the term "substituted" refers to replacing a hydrogen radical with a designated structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. Herein, eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence. Furthermore, this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are considered by the present invention to be therapeutically advantageous in the form of stable compounds. The term "stable" herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.

Metabolites of compounds shown in formula I and pharmaceutically acceptable salts thereof, and prodrugs that can be transformed into compounds shown in formula I and pharmaceutically acceptable salts thereof in vivo are also included in the protection scope of the present invention.

Compound preparation method

Methods for preparing compounds of formula I are described in the following schemes. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

Preferably, the preparation of the compounds of the present invention comprises the steps of:

In the formula, X' is halogen;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, n, A and B are as defined above;

s1) Compound I-1 is reacted in an inert solvent (such as tert-butanol) in the presence of a catalyst (p-toluenesulfonic acid) to obtain Compound I.

Preferably, the synthesis of the compound also includes the steps of:

P is an amino protecting group (such as Boc);

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, X', n, A and B are as defined above;

s'1) In the presence of a catalyst (such as cesium carbonate) in an inert solvent (such as DMF), compound I-4 is reacted with compound I-3 to obtain compound I-2;

s'2) In an inert solvent (such as DCM) under acidic conditions (such as TFA), compound I-2 is deprotected to obtain compound I-1.

In each of the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

Starting materials and intermediates are purchased from commercial sources or prepared by known procedures or using methods well known in the art.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent inhibitory activity of EGFR kinase, the pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and/or treat (stabilize, alleviate or cure) EGFR kinase related diseases (such as non-small cell Lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, rectal cancer, glioma or a combination thereof, etc.).

The pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound/dose of the present invention, more preferably 10-200 mg of the compound/dose of the present invention. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility" here means that each component in the pharmaceutical composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the compound of the invention is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, For example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) moisturizing (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; ( f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc , calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents, and the release of the compound of the invention in such pharmaceutical compositions may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The compounds of the present invention can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the compounds of the present invention, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol , 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the pharmaceutical compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the compounds of this invention, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances wait.

Pharmaceutical compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions . Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as EGFR inhibitors.

When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (such as EGFR inhibitors). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (such as EGFR inhibitors) can be used simultaneously, separately or sequentially with the compound of the present invention Prevention and/or treatment of diseases related to the activity or expression of EGFR kinase.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, The daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The main advantages of the present invention are:

1. The compound of the present invention has novel structure and excellent EGFR kinase inhibitory effect;

2. The compounds of the present invention can be used as EGFR kinase inhibitors, especially as mutant EGFR (especially double mutation or triple mutation, such as L858R/T790M, T790M/C797S, L858R/T790M/C797S, Del19/T790M/C797S, etc.) inhibitors.

Syntheses of the compounds of the present invention are shown in the Schemes, Methods and Examples below. Starting materials are commercially available or can be prepared according to methods known in the art or as described herein. The compounds of the present invention are illustrated by the specific examples shown below. However, these specific examples should not be construed as the only kinds of the invention. These examples further illustrate the preparation of compounds of the invention. Those skilled in the art will readily appreciate that known variations of conditions and procedures can be used to prepare these compounds.

Example

Herein, all temperatures are in °C unless otherwise stated.

Herein, all percentages are by volume unless otherwise indicated.

Here, the preparative PTLC (thin layer chromatography) was performed on 20 x 20 cm plates (500 micron thick silica gel); the silica gel chromatography was performed on a Biotage flash chromatography system.

Herein, ¹ H NMR (hydrogen spectrum) adopts Bruker AscendTM400 spectrometer, 400MHz, 298°K, and the chemical shift (ppm) of residual proton in deuterated reagent is given as a reference: the δ (chemical shift) of _CHCl is 7.26 ppm, the δ of CH ₃ OH or CH ₃ OD is 3.30 ppm, and the δ of DMSO-d6 is 32.50 ppm.

In this paper, in the LCMS (liquid chromatography mass spectrometry) test, the liquid chromatography adopts Agilent Technologies 1200 series or 6120 quadrupole spectrometer; for liquid chromatography, the mobile phase is acetonitrile (A) and water (B) and 0.01% Formic acid, eluent gradient: 6.0 min 5-95% A, 5.0 min 60-95% A, 5.0 min 80-100% A and 10 min 85-100% A, using SBC 18 50 mm x 4.6 mm x 2.7 µm capillary Column; mass spectrum (MS) was determined by electrospray ion mass spectrometry (ESI).

Herein, high performance liquid chromatography (HPLC)-mass spectrometry (MS) analysis conditions:

LC1 column: SB-C18 50mm×4.6mm×2.7μm;

Temperature: 50°C;

Eluent: 5:95 to 95:5 acetonitrile/water (the above ratio is volume ratio) + 0.01% formic acid, 6 minutes;

Flow rate: 1.5mL/min, inject 5μL;

Detection: PDA detector, 200-600nm;

MS: mass range 150-750 amu; positive ion electrospray ionization.

LC2 column: SB-C18 50mm×4.6mm×2.7μm;

Temperature: 50°C;

Eluent: 5:95 to 95:5 acetonitrile/water (the above ratio is volume ratio) + 0.05% TFA (trifluoroacetic acid) gradient, over 3.00 minutes;

Flow rate: 1.5mL/min, inject 5μL;

Detection: PDA detector, 200-600nm;

MS: mass range 150-750 amu; positive ion electrospray ionization.

LC3 column: SB-C18 50mm×4.6mm×2.7μm;

Temperature: 50°C;

Eluent: 10:90 to 98:2 acetonitrile/water (the above ratio is volume ratio) + 0.05% TFA gradient, over 3.75 minutes;

Flow rate: 1.0mL/min, inject 10μL;

Detection: PDA detector, 200-600nm;

MS: mass range 150-750 amu; positive ion electrospray ionization.

In this article, the meanings of each abbreviation are as follows:

Ms = methylsulfonyl; AcOH = acetic acid; Alk is alkyl; AR is aryl; Boc = tert-butoxycarbonyl; CH ₂ Cl ₂ = dichloromethane; DBU = 1,8-diazabicyclo[5.4.0 ] Undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; EA = ethyl acetate; Et=ethyl; EtOAc=ethyl acetate; EtOH=ethanol; HOAc=acetic acid; LiOH=lithium hydroxide; Me=methyl; MeCN=acetonitrile; MeOH=methanol; _MgSO4 =magnesium sulfate; NaCl=sodium chloride; NaOH=sodium hydroxide; _Na2SO4 =sodium _sulfate ; PE=petroleum ether; Ph=phenyl; PG=protecting group; TFA=trifluoroacetic acid; THF=tetrahydrofuran; Ts=p-toluenesulfonyl;

rt = room temperature; h = hours; min = minutes; bs = broad; s = singlet; d = doublet; dd = double doublet; t = triplet; m = multiplet.

intermediate

Preparation of intermediate M2

Add m-bromoaniline (10g, 58.1mmol, 1.0eq) and Boc anhydride (19g, 87.1mmol, 1.5eq) into a round bottom reaction flask, add 2M aqueous sodium hydroxide solution, and heat the reaction solution under reflux for 1 hour, TLC and LCMs detected that the reaction was complete, diluted the reaction solution with water, extracted three times by adding ethyl acetate, washed the organic phase with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product by silica gel column chromatography (PE:EA=20: 1) The product M1 (14 g, yield 88.5%) was isolated.

To the reaction flask was added intermediate bromine M1 (8.16g, 30.0mmol, 1.0eq), 1H-pyrazole-4-boronic acid (6.72g, 60.0mmol, 2.0eq), potassium carbonate (8.28g, 60.0mmol, 2.0eq ), dppf palladium dichloride (2.19g, 3.0mmol, 0.1eq), a mixed solution of 1,4-dioxane and water (150mL/30mL) was used as a solvent, and the reaction was heated under reflux overnight under nitrogen protection. The reaction solution was concentrated by filtration, diluted with water, extracted three times by adding ethyl acetate, the organic phase was washed with water and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, concentrated by filtration to obtain the crude product by silica gel column chromatography (PE:EA=2:1) to obtain Product M2 (3.2 g, 41.2% yield). LCMS: m/z=260[M+H] ^+.

Preparation of Intermediate M3

Intermediate M3 was prepared according to the method of intermediate M2, except that intermediate M1 was replaced by m-bromonitrobenzene (1.05g, 5.20mmol, 1.0eq) to obtain intermediate M3 (0.8g, yield 81.3%) ), as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ=10.66(s,1H),8.36(s,1H),8.10(d,J=8.2Hz,1H),7.97(s,2H),7.83(d,J= 7.7Hz,1H),7.56(t,J=8.0Hz,1H).LCMS:m/z=190[M+H] ^+.

Other intermediates used in the examples of the present application can be prepared using commercial reagents, reagents reported in literature or conventional methods in the art as raw materials, and prepared by referring to the methods of intermediates M2 and M3.

Example 1:

Step 1: Preparation of compound 1A

Dissolve ethyl 4-aminophenylacetate (40g, 225mmol, 1.0eq) and sodium bicarbonate (37.7g, 449mmol, 2.0eq) in a mixed solution (200mL: 600mL) of acetonitrile and water (1:3), and divide Iodine (57.05 g, 225 mmol, 1.0 eq) was added in batches, and the reaction solution was stirred at room temperature overnight. After the reaction is complete, add ethyl acetate to dilute, add saturated aqueous sodium bisulfite solution to quench, the organic phase is washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filter and concentrate to the crude product column chromatography (petroleum ether: acetic acid Ethyl ester=10:1) Compound 1A (40 g, yield 58.7%) was isolated. LCMS: m/z=306[M+H] ^+.

Step 2: Preparation of compound 1B

Compound 1A (40g, 131mmol, 1.0eq) was dissolved in anhydrous tetrahydrofuran (100mL), and 1N borane tetrahydrofuran (400mL) solution was added dropwise under ice bath, and the reaction solution was stirred and reacted at room temperature for 4 hours. The brown solution turned into a pale yellow solution. Add methanol to quench excess borane, dilute with water, extract three times with ethyl acetate, wash the organic phase with water and saturated sodium chloride respectively, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product 1B (32g, yield 92.8%) directly for the next step. LCMS: m/z=264[M+H] ^+.

Step 3: Preparation of Compound 1C

Compound 1B (21g, 79.8mmol, 1.0eq), dimethylphosphorus oxide (6.85g, 87.8mmol, 1.1eq), tripotassium phosphate (18.64, 87.8mmol, 1.1eq), palladium acetate (2.1g, 10% w) and Xantphos (4.2g, 20%w) were dissolved in anhydrous DMF (70mL), heated to 150°C for 6 hours under nitrogen protection, and reacted for 6 hours. =100:1-20:1) The product 1C (14.8 g, yield 86.7%) was obtained. ¹ H NMR (400MHz, DMSO) δ = 7.02 (d, J = 11.3Hz, 2H), 6.58 (dd, J = 8.0, 4.7Hz, 1H), 5.92 (s, 2H), 5.76 (s, 1H), 4.54(t, J=5.1Hz, 1H), 3.51(dd, J=12.2, 7.0Hz, 2H), 2.56(t, J=7.2Hz, 2H), 1.66(s, 3H), 1.62(s, 3H ).LCMS: m/z=214[M+H] ^+.

Step 4: Preparation of Compound 1D

Compound 1C (6.4g, 30.02mmol, 1.0eq), 2,4,5-trichloropyrimidine (8.26g, 45.02mmol, 1.5eq) and potassium carbonate (8.30g, 60.03mmol, 2.0eq) were added to NMF ( 50 mL), the reaction solution was heated to 60°C for overnight reaction. After the reaction was complete, the reaction solution was filtered, diluted with water, extracted three times with ethyl acetate, the organic phase was washed with water and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, silica gel column chromatography (DCM: MeOH =100:1-30:1) Separation gave product 1D (4.2 g, yield 38.8%). ¹ H NMR (400MHz, DMSO) δ=11.67(s,1H),8.42(s,1H),8.28(dd,J=8.8,4.4Hz,1H),7.48(dd,J=8.2,6.2Hz,2H ), 4.67(d, J=5.1Hz, 1H), 3.64(dd, J=11.9, 6.8Hz, 2H), 2.75(t, J=6.9Hz, 2H), 1.81(s, 3H), 1.78(s ,3H).LCMS: m/z=360[M+H] ^+.

Step 5: Preparation of compound 1E

Compound 1D (4.2g, 11.66mmol, 1.0eq) was dissolved in DCM (50mL), triethylamine (1.77g, 17.49mmol, 1.2eq) was added, and the reaction solution was stirred and added dropwise with MsCl (1.60g, 13.99mmol, 1.2eq), then the reaction solution was stirred at room temperature for 1.5 hours, diluted with water after the reaction was complete, added DCM for extraction three times, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Crude product (4.3 g, yield 84.1%). LCMS: m/z=438[M+H] ^+.

Step 6: Preparation of compound 1F

Compound 1E (3.0g, 6.85mmol, 1.0eq), intermediate M2 (1.78g, 6.85mmol, 1.0eq) and cesium carbonate (3.35g, 10.27mmol, 1.5eq) were added to the reaction flask, and the solvent anhydrous DMF (30mL), the reaction solution was heated to 75°C overnight. After the reaction was complete, dilute with water, add ethyl acetate to extract three times, wash the organic phase with water and saturated sodium chloride respectively, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, silica gel column chromatography (DCM:MeOH=100:1-30:1 ) to obtain compound 1F (2.3 g, yield 63.2%). LCMS: m/z=601[M+H] ^+.

Step 7: Preparation of Compound 1G

Compound 1F (30mg, 0.05mmol, 1.0eq) was dissolved in DCM (5.0mL), trifluoroacetic acid (1.0mL) was added, and the reaction solution was stirred and reacted at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain crude compound 1G , used directly in the next step. LCMS: m/z=501[M+H] ^+.

Step 8: Preparation of compound 1

Add p-toluenesulfonic acid hydrate (30mg, 0.15mmol, 3.0eq) and tert-butanol (2.0mL) to the crude compound 1G as a solvent, and heat the reaction solution under reflux for 4 hours. After the reaction is complete, add sodium bicarbonate aqueous solution, dichloromethane Extracted three times, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated by Prep-HPLC to obtain the product compound 1 (20 mg, yield 86%). ¹ H NMR (400MHz, CDCl ₃ )δ=10.19(s,1H),8.32(s,1H),8.09(s,1H),7.72(s,1H),7.68(dd,J=8.3,4.2Hz, 1H), 7.28(d, J=8.1Hz, 1H), 7.23(d, J=15.8Hz, 1H), 7.08(d, J=7.6Hz, 1H), 6.71(d, J=8.0Hz, 1H) ,6.33(s,1H),6.12(d,J=8.4Hz,1H),4.75(dd,J=10.3,3.1Hz,1H),3.83(dd,J=13.5,7.4Hz,1H),3.05– 2.97(m, 2H), 1.93(d, J=13.2Hz, 3H), 1.81(d, J=13.0Hz, 3H): LCMS: m/z=465[M+H] ^+.

Example 2

Compounds 36 and 38:

Step 1: Preparation of compound 36A

4-(4-Aminophenyl)butyric acid (2.0g, 11.16mmol, 1.0eq) was dissolved in methanol (20mL), and thionyl chloride (3.0mL) was added dropwise in an ice-water bath, and the reaction solution was heated at room temperature The reaction was stirred overnight. After the reaction was complete, the reaction solution was concentrated, added saturated aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product 36A (2.4 g) as light yellow solid. LCMS: m/z=194[M+H] ^+.

Step 2: Preparation of compound 36B

Compound 36B was prepared according to the same method as compound 1A in Example 1, except that compound 4-aminophenylacetic acid ethyl ester was replaced by compound 36A to obtain compound 36B (2.2 g, yield 61.8%) as a black oil. LCMS: m/z=320[M+H] ^+.

Step 3: Preparation of compound 36C

Compound 36C was prepared according to the same method as compound 1B in Example 1, except that compound 1A was replaced by compound 36B to obtain compound 36C (2.0 g, yield 99.7%) as a colorless oil. LCMS: m/z=292[M+H] ^+.

Step 4: Preparation of compound 36D

Compound 36D was prepared according to the same method as compound 1C in Example 1, replacing compound 1B with compound 36C to obtain compound 36D (1.5 g, yield 90.5%) as a light-colored oil. LCMS: m/z=242[M+H] ^+.

Step 5: Preparation of compound 36E

Compound 36E was prepared according to the same method as compound 1D in Example 1, except that compound 1C and 2,4,5-trichloropyrimidine were replaced by compound 36D (520mg, 2.16mmol, 1.0eq) and 5-bromo- 2,4-dichloropyrimidine to obtain compound 36E (0.42 g, yield 45.0%) as a white solid. LCMS: m/z=432[M+H] ^+.

Step 6: Preparation of compound 36F

Compound 36F was prepared according to the same method as compound 1E in Example 1, except that compound 1D was replaced by compound 36E to obtain compound 36F (0.5 g, yield 99%) as a white solid. LCMS: m/z=510[M+H] ^+.

Step 7: Preparation of compound 36G

Compound 36G was prepared according to the same method as compound 1F in Example 1, except that compound 1E was replaced by compound 36F (150 mg, 0.29 mmol, 1.0 eq), and intermediate M2 was replaced by intermediate M3 to obtain compound 36G (160 mg, Yield: 91.4%) as a colorless oil. LCMS: m/z=603[M+H] ^+.

Step 8: Preparation of Compound 36H

Compound 36G (160mg, 0.26mmol, 1.0eq) was dissolved in ethanol (8.0mL), iron powder (148mg, 2.65mmol, 10.0eq) and ammonium chloride saturated aqueous solution (4.0mL) were added, and the reaction solution was heated to reflux for reaction 2 Hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude compound 36H, which was directly used in the next step. LCMS: m/z=573[M+H] ^+.

Preparation of compound 36

Compound 36 was prepared according to the method of compound 1 in Example 1, except that compound 1G was replaced by compound 36H to obtain compound 36 (40 mg, yield 28.1%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ=8.52(dd,J=8.6,4.4Hz,1H),8.09(s,1H),7.95(s,1H),7.80(s,1H),7.37(s, 2H), 7.21(d, J=3.5Hz, 1H), 7.08(d, J=14.3Hz, 1H), 6.99(s, 1H), 6.85(d, J=8.6Hz, 1H), 4.13(d, J=5.1Hz, 2H), 2.65(s, 2H), 1.95(s, 3H), 1.92(s, 3H), 1.61(d, J=21.8Hz, 4H): LCMS: m/z=537[M +H] ^+.

Preparation of Compound 38

Add compound 36 (36 mg, 0.067 mmol, 1.0 eq), trimethylboroxane (0.2 mL), potassium carbonate (19 mg, 0.134 mmol, 2.0 eq), dppf palladium dichloride (20 mg) to the reaction vial , a mixed solution of 1,4-dioxane and water (2.0mL/0.2mL), heated under reflux under the protection of nitrogen to react overnight. The reaction solution was concentrated by filtration, diluted with water, extracted three times by adding ethyl acetate, the organic phase was washed with water and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, concentrated by filtration to obtain a crude product, which was prepared and separated by Prep-HPLC to obtain the product compound 38 (10 mg , the yield is 31.6%). ¹ H NMR (400MHz,MeOD)δ=8.44(dd,J=8.6,4.4Hz,1H),8.19(s,1H),7.87(s,1H),7.82(s,1H),7.43(dt,J =16.2,7.9Hz,3H),7.21(s,1H),7.01(d,J=8.0Hz,1H),6.83(d,J=8.5Hz,1H),4.17–4.04(m,2H),2.68 (s,2H), 2.26(s,3H), 1.96(s,3H), 1.93(s,3H), 1.68(s,2H), 1.49(s,2H): LCMS: m/z=473[M +H] ^+.

Example compounds 2-35, 37, and 39-128 were prepared by referring to the method of Example 1 or Example 2, and the example compounds 1-128 of the present invention are summarized in Table 1 below:

Table 1

Effect Example 1: Evaluation of EGFR Kinase Activity Inhibition

experimental method:

Compounds (10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM) were incubated with purified EGFR-WT, EGFR-L858R/T790M, EGFR-Del19/T790M/C797S or EGFR-L858R/T790M/C797S The buffer solution was added to the 384 reaction plate (ProxiPlate-384Plus, PerkinElmer). After incubating at room temperature for half an hour, the substrate buffer solution was added to start the reaction. After one hour of room temperature incubation, XL665 and antibody were added to continue incubation for one hour, and finally the fluorescent signal was detected with Envision The ratio of 665nm to 620nm. At the same time, a blank control group without enzyme, a solvent control group with DMSO instead of compounds, and a positive control group (AZD-9291, BI-4020) were set up. The final volume of the reaction was 10 μL, and the specific reaction system was 2% DMSO, 0.04ng/μL EGFR, 1 μM TK-s, 2 μM ATP, 5 mM MgCl ₂ , 1 mM DTT, 1×kinase buffer (kinase buffer). The experimental results are shown in Table 2.

The test data are divided into the following categories: A: IC ₅₀ <10nM; B: IC ₅₀ =11-100nM; C: IC ₅₀ =101-1000nM; D: IC ₅₀ =1001-10000nM; E: IC ₅₀ >10000nM. In Table 2, "-" means not tested.

Table 2

Experimental results show that: the compound of the present invention has excellent inhibitory activity on mutant EGFR, especially the double mutation and triple mutation, can overcome drug resistance to early related drugs, and is expected to be further developed as a compound for the preparation of EGFR (L858R/T790M , L858R/T790M/C797S, Del19/T790M/C797S, etc.) kinase activity or drugs for the treatment of EGFR (L858R/T790M, L858R/T790M/C797S, Del19/T790M/C797S, etc.) related diseases.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

The compound represented by formula I, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate,

In the formula,

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, -NR 6 R 7 , -C(O)NR 6 R 7 , -N(R 6 )SO m R 7 , -C(O)R' 6 , -P(=O)R' 6 R' 7 , -S(O) m NR 6 R 7 , -NR 6 C (O)R 7 , -C(O)OR 6 , -OC(O)R 6 , -S(O) m' R' 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 Membered heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O-; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered Heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O- are optionally substituted by 1-3 R;

Alternatively, R 1 , R 2 and the atoms connected to them jointly form a C5-C6 cycloalkyl group, a 5-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group; wherein, the C5-C6 cycloalkane Base, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by 1-3 R;

X is N or CR x , wherein, R x is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, -NR 6 R 7 , -C(O)NR 6 R 7 , -N(R 6 )SO m R 7 , -C(O)R' 6 , -P(=O)R' 6 R' 7 , -S(O) m NR 6 R 7 , -NR 6 C(O)R 7 , -C(O)OR 6 , -OC(O)R 6 , -S(O) m' R' 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl are optionally substituted by 1-3 R;

Ring A is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are further optionally substituted by 1-3 R;

Ring B is selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C3-C12 cycloalkyl, 3-12 membered heteroaryl Cyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group are optionally substituted by 1-3 R;

R 6 , R 7 , R' 6 and R' 7 are each independently selected from the following group: H, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 ring Alkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl are optionally substituted by 1-3 R;

R is selected from: D, halogen, cyano, nitro, hydroxyl, -NR 8 R 9 , -C(O)NR 8 R 9 , -N(R 8 )SO m R 9 , -C(O)R' 8 , -P(=O)R' 8 R' 9 , -S(O) m NR 8 R 9 , -NR 8 C(O)R 9 , -C(O)OR 8 , -OC(O)R 8. -S(O) m' R' 8 , C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1- C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclic Base-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O-; wherein, the C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2 -C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O-, 5-10 membered heteroaryl-O- are optionally replaced by 1-3 R'replace;

R'is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl , 5-10 membered heteroaryl;

R 8 , R 9 , R' 8 and R' 9 are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C12 cycloalkane Base, 3-12 membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group, C3-C12 cycloalkyl C1-C6 alkyl, 3-12 membered heterocyclic group C1-C6 alkyl, C6 -C10 aryl C1-C6 alkyl, 5-10 membered heteroaryl C1-C6 alkyl;

In formula I, the group connecting ring A to the pyrazole ring
One or more of -CH 2 - in is optionally replaced by -SO 2 -;

n is 1, 2, 3, 4, 5, 6 or 7;

m and m' are each independently 0, 1 or 2.
The compound as claimed in claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, A ring is selected from: phenyl, 5 -6-membered heteroaryl, 6-membered heterocyclic group; wherein, the phenyl, 5-6-membered heteroaryl, and 6-membered heterocyclic group are further optionally replaced by 1-3 groups selected from the following group Substitution: halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl;

In particular, ring A is selected from: phenyl, piperidinyl, tolyl; wherein, the phenyl is preferably

The piperidinyl is preferably
More preferably, the left side of the piperidine ring is connected to the N in the right-NH- in formula I; the tolyl group is preferably
More preferably, the left side of the benzene ring is connected to the N in -NH- on the right side of formula I.
The compound as claimed in claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, B ring is selected from: phenyl, 5 -6-membered heteroaryl, 6-membered heterocyclic group; wherein, the phenyl, 5-6-membered heteroaryl, and 6-membered heterocyclic group are optionally substituted by 1-3 groups selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, NR 8 R 9 , -C(O)NR 8 R 9 , -N(R 8 )SO 2 R 9 , -C(O)R' 8 , -P( =O)R' 8 R' 9 , -S(O) 2 NR 8 R 9 , -NR 8 C(O)R 9 , -C(O)OR 8 , -OC(O)R 8 , -S( O) 2 R' 8 , C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C6 -C10 aryl-O-, 5-6 membered heteroaryl-O-; wherein, the C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl -O-, 3-6 membered heterocyclyl-O-, C6-C10 aryl-O-, 5-6 membered heteroaryl-O- are optionally substituted by 1-3 R';

R'is selected from: D, halogen, cyano, nitro, hydroxyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl; wherein, the substitution refers to being substituted by 1-3 groups selected from the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5- 6-membered heteroaryl;

R 8 , R 9 , R' 8 and R' 9 are each independently selected from the following group: H, D, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C6 cycloalkane Base, 3-6 membered heterocyclic group, C6-C10 aryl group, 5-6 membered heteroaryl group, C3-C6 cycloalkyl C1-C6 alkyl group, 3-6 membered heterocyclic group C1-C6 alkyl group, C6 -C10 aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl;

In particular, ring B is selected from the group consisting of: phenyl, substituted phenyl, pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, piperidinyl, substituted piperidinyl, pyrazinyl, substituted pyrazine base;

In ring B, the phenyl group is preferably
The pyridyl group is preferably
The pyrimidyl group is preferably
The piperidinyl is preferably
More preferably, the N of the piperidine ring is connected to the pyrazole ring of formula I;

In Ring B, the substitution refers to being substituted by one or more groups selected from the following group: D, halogen, cyano, nitro, hydroxyl, amino, carboxyl, -COOCH 3 , -COOCH 2 CH 3 , - OCOCH 3 , -CONHCH 3 , -NHCOCH 3 , -CON(CH 3 ) 2 , -SO 2 CH 3 , -SOCH 3 , -N(CH 3 )SO 2 CH 3 , C1-C6 alkyl, halogenated C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 Aryl, 5-6 membered heteroaryl,

Among them, the halogen is preferably F or Cl; the C1-C6 alkyl is preferably methyl; the C1-C6 alkoxy is preferably methoxy; the halogenated C1-C6 alkoxy is preferably CF 3 -O-; The 3-6 membered heterocyclic group is preferably morpholinyl, more preferably
The compound according to any one of claims 1-3, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that,
selected from:

Wherein, R 10 and R 11 are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, Halogenated C1-C6 alkoxy;

And/or, R 1 is H or C1-C3 alkyl, preferably H or methyl;

And/or, R is selected from: H, F, Cl, Br, I, methyl, ethyl, vinyl, isopropenyl, isopropyl, cyclopropyl, ethynyl, propynyl, phenyl, Halophenyl, trifluoromethyl ; or R and R together with the atoms to which they are attached form substituted or unsubstituted thienyl, thiazolyl, furyl, imidazolyl, pyrrolyl, pyrazolyl, phenyl, Pyridyl, pyrimidyl, pyrazinyl, wherein, the substitution refers to being substituted by one or more groups selected from the group: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; in particular, R2 is selected from: H, F, Cl, Br, I, methyl, phenyl, fluorine substituted phenyl, cyclopropyl, propynyl, vinyl, isopropenyl, ethyl, isopropyl, trifluoromethyl, ethynyl; or, R 1 , R 2 and the atoms attached to them together form thiophene Base, methylimidazolyl, pyrrolyl, methylthienyl, methylpyrrolyl, imidazolyl, methylthiazolyl, furyl, phenyl, pyridyl; wherein, the propynyl is preferably
The fluorophenyl group is preferably

And/or, R 3 is selected from: -P(O)(CH 3 ) 2 , -SO 2 CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHSO 2 CH 3 , -N (CH 3 )SO 2 CH 3 , -N(cyclopropyl)SO 2 CH 3 ,

And/or, R 4 is H;

And/or, R 5 is H;

And/or, in formula I, the group that ring A is connected to the pyrazole ring
One of the -CH 2 - is replaced by -SO 2 -, the group is preferably
The compound according to claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, the compound has the formula II structure,

In the formula,

R 1 , R 2 , R 3 , R 4 , R 5 , X, B and n are as defined in claim 1.
The compound as claimed in claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, the compound has the formula III structure,

In the formula,

The definition of each R 12 is the same as R in claim 1; preferably, the definition of each R 12 is the same as the substituent on the B ring in claim 3;

p is 0, 1, 2, 3 or 4;

R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined in claim 1.
The compound according to claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, the compound has the formula IV structure:

in,

Q is selected from: N or CR 14 ;

The definitions of R 13 , R 14 and R 15 are the same as R in claim 1;

R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined in claim 1.
The compound as claimed in claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, B ring is selected from: phenyl, 5 -6-membered heteroaryl or 6-membered heterocyclic group; wherein, H in each of the above groups is further substituted by 1, 2 or 3 R; R is selected from: -NR 8 R 9 ; R 8 is selected from: C1 -C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxy or C1-C6 alkoxy, the H in each of the above groups is optionally selected from 1, 2 or 3 groups in the following group Substitution: D, halogen, cyano, nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 ; R 9 is selected from: C1-C6 alkyl, C1-C6 alkane Amylamino, C1-C6 alkylhydroxy or C1-C6 alkoxy, and H in each of the above groups is further substituted by 1, 2 or 3 groups selected from the group: D, halogen, cyano, Nitro, hydroxyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 ;

Alternatively, ring B is selected from: phenyl, 5-6 membered heteroaryl or 6 membered heterocyclic group; wherein, H in each of the above groups is further substituted by 1, 2 or 3 R; R is selected from: C1 -C6 alkoxy, and the C1-C6 alkoxy is further substituted by a 3-7-membered heterocyclic group or a 5-membered heterocyclic group, and the 3-7-membered heterocyclic group or a 5-membered heterocyclic group is further substituted By oxo; R for example can be

Alternatively, substitution on ring B refers to substitution by one or more groups selected from the following groups:

Alternatively, the group that ring A is connected to the pyrazole ring
H in is optionally substituted by 1, 2, 3, 4 or more than 5 R'; wherein, the definition of R' is as described in claim 1; preferably, R' is selected from: D , halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylhydroxy, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy, such as methyl;
for example can be

Alternatively, the group that ring A is connected to the pyrazole ring
1, 2 or more of -CH 2 - in is replaced by O or NH, and this group can be, for example,
The compound as claimed in claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, is characterized in that, said compound is selected from the following group:
A pharmaceutical composition comprising the compound according to any one of claims 1-9 or claim 11, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or a solvate thereof; and a pharmaceutically acceptable carrier.
The compound as described in any one of claims 1-9, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as described in claim 10 Use of the pharmaceutical composition in the preparation of a medicament for inhibiting EGFR kinase;

In particular, the EGFR is a mutant EGFR, preferably L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, or a combination thereof; more preferably L858R, T790M, C797S, Del19, or a combination thereof; further more Preferably L858R/T790M double mutation, T790M/C797S double mutation, L858R/T790M/C797S triple mutation or Del19/T790M/C797S triple mutation;

In particular, the drug for inhibiting EGFR kinase is a drug for treating cancer;

Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal carcinoma tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, rectal cancer, glioma, or a combination thereof;

More preferably, the drug is used to treat lung cancer caused by EGFR L858R mutation;

Alternatively, the drug is used for the treatment of lung cancer caused by EGFR Del19 mutation;

Alternatively, the drug is used to treat lung cancer caused by EGFR C797S mutation;

Alternatively, the drug is used to treat lung cancer caused by EGFR T790M mutation;

Alternatively, the drug is used for the treatment of lung cancer caused by EGFR L858R/T790M mutation;

Alternatively, the drug is used for the treatment of lung cancer caused by EGFR T790M/C797S mutation;

Alternatively, the drug is used for the treatment of lung cancer caused by EGFR L858R/T790M/C797S mutation;

Alternatively, the drug is used to treat lung cancer caused by EGFR Del19/T790M/C797S mutation.