WO2022007841A1

WO2022007841A1 - Egfr inhibitor, preparation method therefor, and pharmaceutical application thereof

Info

Publication number: WO2022007841A1
Application number: PCT/CN2021/104977
Authority: WO
Inventors: 张鸣鸣; 赵保卫; 喻红平; 陈椎; 徐耀昌
Original assignee: 上海和誉生物医药科技有限公司
Priority date: 2020-07-09
Filing date: 2021-07-07
Publication date: 2022-01-13
Also published as: CN116096372A; CN116096372B

Abstract

Disclosed are an EGFR inhibitor, a preparation method therefor, and a pharmaceutical application thereof, in particular relating to an EGFR inhibitor having the structure of formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use of same as an EGFR inhibitor, and a use of same in the preparation of drugs for the treatment and/or prevention of cancers, tumours, or metastatic diseases at least partially related to the insertion, deletion, or other mutation of EGFR exon 20, in particular the use of same in the preparation of drugs for the treatment and/or prevention of hyperproliferative diseases and induced cell death disorders. Each substituent of formula (I) has the same definition as in the description.

Description

A kind of EGFR inhibitor, its preparation method and its application in pharmacy

technical field

The invention belongs to the field of drug synthesis, and in particular relates to an EGFR inhibitor, a preparation method and pharmaceutical application thereof.

Background technique

Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%. Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multi-target therapy has been successfully developed and clinically validated. Inhibitors targeting EGFR can significantly improve the progression-free survival of adenocarcinoma in NSCLC, and its acquired resistance mutations can be targeted by third-generation EGFR inhibitors.

Although classical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M) can be inhibited by existing drugs, insertional mutations in exon 20 (Exon 20) also lead to structural EGFR signaling activated and were insensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR. These mutations were mutually exclusive with other known oncogene driver mutations and were enriched in adenocarcinomas in women, non-smokers, Asian populations, and patients with non-small cell lung cancer. In addition to NSCLC, EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the EGFR family.

Multiple retrospective analyses have shown that currently available first-, second-, and third-generation EGFR inhibitors have limited efficacy against exon 20 insertion mutations, with the exception of the A763-Y764insFQEA mutation. The irreversible inhibitor Poziotinib and the EGFR/MET bispecific antibody Amivantamab are in clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in patients with EGFR exon 20 non-small cell lung cancer. However, due to their limited selectivity for EGFR wild-type, adverse effects in clinical use are unavoidable and may lead to dose-limiting toxicity. At the same time, it has been clinically shown that there may be insufficient exposure to existing compounds. Therefore, there is an urgent need for small-molecule inhibitors with higher exposure and/or high selectivity for EGFR exon 20 insertion mutations for these patients.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide an EGFR inhibitor, its preparation method and pharmaceutical application. The series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation, and have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation. EGFR wild-type has high selectivity and can be widely used in the preparation of drugs for the treatment and/or prevention of cancers, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertions, deletions or other mutations, especially for the treatment of hyperproliferative disease and cell death-inducing disorders, thus promising the development of a new generation of EGFR inhibitors.

The first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:

in,

X is CH or N;

Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CR ₁ or N;

R _{1 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _{1- 10} alkyl, hydroxy substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heterocyclic Aryl, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R _{_{8) -C (O) R 7}} ;

R ₂ and R ₃ are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C( O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N( R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ , independently optionally further modified by one or more Selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered _{heteroaryl, = O, -SF 5, -S} (O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -C(=NR ₈ )R ₇ , -N (R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents;

R _4a and R _4b are each independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, -C(O)OR ₆ , -C(O)R ₇ and -C(O)NR ₈ R ₉ ;

Each R _{5 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl radicals, 5-10-membered heteroaryl groups, and -NR ₈ R ₉ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C _1-10 alkyl, C _{1- 10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6-10 substituted by the substituents of aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₈ R ₉ ;

Each R ₆ is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl group, and 5-10-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₈ R ₉ substituents;

Each R _{7 is} selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl , C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₈ R ₉ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _1-10 Alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryl substituted by the substituents of oxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₈ R ₉ ;

Each R ₈ and R _{9 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, C _6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _{1 -10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6- Substitution of _10- aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _{1-10 alkanoyl} base substituted;

Alternatively, R ₈ and R ₉ together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or 4-10-membered heteroaryl group, which is either is further selected by one or more selected from deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _{6 -10} aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and Substituents of C _1-10 alkanoyl groups are substituted;

n is 0, 1, 2, 3, or 4; and

Each r is independently 0, 1, or 2.

As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, R ₂ and R ₃ are each independently selected from hydrogen, deuterium, halogen, cyano, Nitro, azido, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O )OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ ;

wherein R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and r are as described for the compound of formula (I).

As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, R _{1 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, C _1-4 Alkyl, halogen-substituted C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, - S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ ) R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ ;

As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, each R _{5 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkane group, C _2-4 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl and -NR ₈ R ₉ , the above-mentioned groups independently optionally further selected by one or more of the group consisting of deuterium, halogen, hydroxy, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkane Oxy, 3-8-membered heterocyclyl, 3-8-membered heterocyclyloxy, C _6-8 aryl, C _6-10- aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy substituted with the substituent of _{-NR 8} R _9;

Each R ₆ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-8 aryl group, and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5 -8-membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₈ R ₉ substituents;

Each R _{7 is} selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl , C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR ₈ R ₉ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 Alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryl substituted by the substituents of oxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR ₈ R ₉ ;

Each of R ₈ and R _{9 is} independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3 -8-membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _{3 -8} cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 substituted by substituents of heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl;

Alternatively, R ₈ and R ₉ are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C _1-4 alkyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3 -8-membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, Substituents of mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl groups.

As a further preferred solution, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (II):

in,

X is CH or N;

Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently CR ₁ or N;

R _{1 is} selected from hydrogen, deuterium, hydroxy, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ ;

Each R _{3 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, halo-substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O )R ₇ ;

R _4a and R _4b are each independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, halo-substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl and -C(O)R ₇ ;

Each R ₅ is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-8 aryl radicals, 5-8 membered heteroaryl groups and -NR ₈ R ₉ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C _1-4 alkyl, C _{1- 4} alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 substituted by the substituents of aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR ₈ R ₉ ;

Alternatively, R ₈ and R ₉ are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C _1-4 alkyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3 -8-membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, substituted by the substituents of mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _{1-4 alkanoyl;}

n is 0, 1, 2, 3, or 4; and

Each r is independently 0, 1, or 2.

As a further preferred solution, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, the compound of formula (I) is the compound of formula (III) as follows:

in,

X is CH or N;

Y ₂ and Y ₄ are each independently CR ₁ or N;

Each R _{1 is} independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo-substituted C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl base, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ and -C(=NR ₈ )R ₇ ;

R _4a and R _4b are each independently selected from hydrogen, deuterium, C _1-4 alkyl, halo-substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl and -C( O)R ₇ ;

As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, R _4a and R _4b are each independently selected from hydrogen, deuterium, methyl, Ethyl, propyl, isopropyl, cyclopropyl, _{-CHF 2} , -CF ₃ , -CHD ₂ , -CD ₃ and -C(O)R ₇ ; wherein R _{7 is} as described for the compound of formula (I) ;

Preferably, R _4a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, _{_{cyclopropyl, -CHF 2, -CF 3, -CHD}} 2 , and -CD _3; R _4b is selected from hydrogen, Deuterium and -C(O)R ₇ ; wherein R _{7 is} as described for compounds of formula (I).

As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, each R _{1 is} independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, oxetanyl, C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ and -C(= NR ₈ )R ₇ ;

As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, each R _{5 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkane group, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and -NR ₈ R ₉ independently optionally further selected from one or more Substituted by substituents of deuterium, halogen, hydroxyl, oxo, C _1-4 alkyl and C _{1-4 alkoxy;}

Each R _{6 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, the above groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, hydroxy, oxo, cyano, C _1-4 alkyl and C _1-4 alkoxy;

Each R _{7 is} selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy group, phenyl, and -NR ₈ R ₉ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, hydroxy, cyano, C _1-4 alkyl and C _1-4 alkoxy substituted by the substituent of the base;

Each R ₈ and R _{9 is} independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _3-8 cycloalkyl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclo Propylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl;

Alternatively, R ₈ and R ₉ together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group optionally further substituted by one or more members selected from the group consisting of deuterium, fluorine, chlorine, hydroxy , C _1-4 alkyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, phenyl, amino, mono-C _{1 -4} alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl substituents.

As the most preferred solution, the compounds of formula (I), their stereoisomers, prodrugs or their pharmaceutically acceptable salts include but are not limited to the following compounds:

The second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt, comprising the following steps:

wherein X, Y ₁ , Y ₂ , Y ₃ , Y ₄ , R ₂ , R ₃ , R _4a , R _4b and n are as described for the compound of formula (I).

A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention also relates to the compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof in the preparation of treatment and/or prophylaxis at least partially associated with EGFR exon 20 insertions, deletions or other mutations Use in the medicament of cancer, tumor or metastatic disease.

The present invention also relates to compounds of formula (I), their stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, in the preparation of the prevention and/or treatment of tumors, cancers and or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in medicines. The present invention also relates to the aforementioned compounds of formula (I), their stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, in the preparation of the prevention and/or treatment of lung cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations, Colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, stomach cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, Use in endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, paranasal sinus inverted papilloma or paranasal sinus squamous cell carcinoma associated with sinus inverted papilloma.

The present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the treatment and/or prophylaxis of insertions, deletions or other mutations at least partially associated with EGFR exon 20 Use in associated cancer, tumor or metastatic disease.

The present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of tumors, cancers and or metastatic disease.

The present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the treatment and/or prophylaxis of insertions, deletions or other mutations at least partially associated with EGFR exon 20 Related lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal Use for tract tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, naso-inverted papilloma or naso-sinus-associated squamous cell carcinoma.

The present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of preventing and/or treating tumors, cancers and or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I) , its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof.

The present invention also relates to a treatment and/or prophylaxis of lung, colon, pancreatic, head and neck, breast, ovarian, uterine, gastric, non-small cell carcinomas associated at least in part with EGFR exon 20 insertions, deletions or other mutations Cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus inversion A method of paranasal papilloma or paranasal inversion papilloma-associated squamous cell carcinoma of the paranasal sinuses, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), its stereoisomers, pro- medicine or a pharmaceutically acceptable salt thereof.

detailed description

After extensive and in-depth research, the inventors of the present application have developed for the first time an EGFR inhibitor with the structure of the following formula (I). Drugs for cancers, tumors or metastatic diseases associated with exon 20 insertions, deletions or other mutations, especially for hyperproliferative diseases and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.

DETAILED DESCRIPTION: Unless stated to the contrary or specifically stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C _1-10 alkyl" refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups, "C _1-4 alkyl" refers to straight-chain alkyl groups including 1 to 4 carbon atoms and Contains branched alkyl groups.

Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C _3-12 cycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, "C _3-8 cycloalkyl" refers to cycloalkyl groups including 3 to 8 carbon atoms Atom cycloalkyl, "C _3-6 cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, including but not limited to:

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.

Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) _{heteroatoms of r} (wherein r is an integer of 0, 1, 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, preferably including 3 to 12 or 3 to Heterocyclyl groups of 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl" refers to a ring group containing 3 to 6 ring atoms, and "4-8 membered heterocyclyl" refers to a group containing 4 to 6 ring atoms A ring group of 8 ring atoms, "3-8 membered heterocyclyl" refers to a ring group containing 3 to 8 ring atoms, "4-10 membered heterocyclyl" refers to a ring group containing 4 to 10 ring atoms, "3-12 membered heterocyclyl" refers to a ring group containing 3 to 12 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) _r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings. Spiroheterocyclyl groups include, but are not limited to:

"Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) _r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:

"Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:

Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, "C _6-10 aryl" refers to all-carbon aryl groups containing 6-10 carbons, "C _6-8 aryl" refers to a full carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

"Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, 5-6 membered heteroaryl means containing 5-6 ring atoms The heteroaromatic system of Not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

"Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, Halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 Alkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ ) R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons For example, C _2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons, and C _2-4 alkenyl refers to a straight or branched alkenyl containing 2-4 carbons . Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

"Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons, For example, C _2-10 alkynyl group refers to a straight chain containing 2-10 carbon atoms or branched alkynyl group, C _2-4 alkynyl group refers to a straight chain containing 2-4 carbons or a branched alkynyl group. Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ )R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Alkoxy" refers to -O-alkyl, where alkyl is as defined above, eg, "C _1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, "C _1-4 "Alkoxy" refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

"Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, Halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 Alkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-10 -membered aryl, 5-10-membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ ) R ₇ , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R ₇ substituents.

"Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, "C _3-12 cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C _3-8 cycloalkoxy" refers to a cycloalkyloxy group containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

"Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium , halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _{1- 10} alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ ) Substituents substituted by _{R 7} , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R _{7 .}

"Heterocyclyloxy" refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.

"Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium , halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _{1- 10} alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₅ , -OR ₆ , -C(O)OR ₆ , -C(O)R ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -P(O)R ₈ R ₉ , -C(=NR ₈ ) Substituents substituted by _{R 7} , -N(R ₈ )-C(=NR ₉ )R ₇ , -C(O)NR ₈ R ₉ and -N(R ₈ )-C(O)R _{7 .}

"C _1-10 alkanoyl" refers to the _{monovalent atomic group remaining after C 1-10} alkyl acid removes the hydroxyl group, usually also expressed as "C _0-9 alkyl-C(O)-", for example, "C ₁ alkyl -C (O) - "means acetyl;" C ₂ alkyl group -C (O) - "refers propionyl;" C ₃ alkyl -C (O) - "refers to butyryl or isobutyryl Acyl.

"Halo-substituted C _1-10 alkyl" refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl (-CHF ₂ ), dichloromethyl (-CHCl ₂ ), dibromomethyl (-CHBr ₂ ), trifluoromethyl (-CF ₃ ), trichloromethyl (-CCl ₃ ), tribromomethyl (-CBr ₃ ) etc.

"Halo-substituted C _1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"Deuterium-substituted _C1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to a deuterated methyl (-CH ₂ D), two deuterium methyl (-CHD _2), trideuteromethyl (-CD ₃₎ and the like.

"Deuterium substituted C _1-10 alkoxy" refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy and the like.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted . For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.

"Stereoisomer", its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, if the compound of the present invention contains a double bond, if not specified, it can be understood as containing E and/or Z form. Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations. In the present invention, the "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configuration isomers and conformation isomers unless otherwise specified, preferably S configuration type.

"Pharmaceutically acceptable salts" in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The present invention will be further described in detail and completely below in conjunction with the examples, but the present invention is by no means limited, and the present invention is not limited to the contents of the examples.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), internal standard For tetramethylsilane (TMS).

An Agilent 6120 mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm~0.20mm, and the specifications used for TLC separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

One, the preparation of specific embodiment

Example 1a and Example 1b: (S)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrole Iso[2,1-a]isoquinolin-5-yl)acrylamide and (R)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[ Preparation of 5',4':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)acrylamide

The first step: the synthesis of 2-(2-bromophenyl) oxa propane

Dissolve o-bromobenzaldehyde (55.5g, 0.3mol) and trimethylsulfonium iodide (71g, 0.34mol) in DMF (200 mL), add potassium hydroxide (33.6g, 0.6mol) and stir at room temperature for 1 After hours, LCMS showed that the reaction was complete, the reaction solution was extracted with saturated aqueous NaHCO ₃ solution (500 mL), ethyl acetate (500 mL), and the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain the crude product 2-(2-bromophenyl)oxapropane (60 g, yield 96%), which was directly used in the next reaction without further purification.

The second step: synthesis of tert-butyl (1-(2-bromophenyl)-2-hydroxyethyl) carbamate

2-(2-Bromophenyl)oxapropane (60 g, 0.3 mol) was dissolved in acetonitrile (500 mL), and concentrated sulfuric acid (59 g, 0.6 mol) was slowly added dropwise. The reaction was stirred at room temperature for 8 hours, water (300 mL) was added, and the reaction was stirred at 50° C. for an additional 16 hours. LCMS showed the reaction was complete. Ethyl acetate (200 mL) was added to the reaction solution, water (200 mL) was layered, the organic phase was discarded, and the pH of the aqueous phase was adjusted to 9-10 with 6M NaOH. _{Boc 2} O (122 g, 0.56 mol) was added to the aqueous solution, the reaction was stirred at room temperature for 2 hours, the resulting mixture was filtered, the filter cake was washed with water (100 mL) and methyl tert-butyl ether (3*20 mL), the filter cake was collected and dried tert-Butyl(1-(2-bromophenyl)-2-hydroxyethyl)carbamate (25.5 g, 29% yield) was obtained. ESI-MS: 260[M-56] ⁺ .

The third step: tert-butyl (1-(2-bromophenyl)-2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl) Synthesis of Carbamate

4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17.8 mmol), tert-butyl (1-(2-bromophenyl)-2-hydroxyethyl) Carbamate (4.7 g, 14.9 mmol), triphenylphosphine (7.8 g, 29.8 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), the reaction was stirred under nitrogen for 10 minutes, and DEAD (5.2 g, 29.8 mmol) was added. mmol), the reaction was stirred under nitrogen protection at 24 ° C for 16 hours, LCMS showed that the reaction was complete, and the reaction solution was concentrated to obtain crude tert-butyl (1-(2-bromophenyl)-2-(4-chloro-5-iodo- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)carbamate (9.0 g, 99% yield). ESI-MS: 577[M+H] ⁺ . The reaction was used directly for the next reaction.

The fourth step: tert-butyl (1-(2-bromophenyl)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl) Synthesis of Carbamate

tert-Butyl(1-(2-bromophenyl)-2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)carbamic acid The ester (9.0 g, 17.8 mmol) was dissolved in tetrahydrofuran (200 mL) and water (50 mL), and concentrated ammonia (50 mL) was added. The reaction was stirred at 100°C for 16 hours in a sealed tube, LCMS showed that the reaction was complete, the resulting mixture was filtered, the filter cake was washed with methyl tert-butyl ether (2*30 mL), and the filter cake was collected to obtain tert-butyl (1-(2- bromophenyl)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)carbamate (6.45 g, 65% yield). ESI-MS: 558[M+H] ⁺ .

The fifth step: tert-butyl(1-(2-bromophenyl)-2-(4-amino-5-(quinoline-3)-7H-pyrrolo[2,3-d]pyrimidine-7- Synthesis of ethyl)ethyl)carbamate

tert-butyl(1-(2-bromophenyl)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)carbamic acid Ester (4.3 g, 7.7 mmol), quinoline-3-boronic acid (2.0 g, 11.56 mmol), Pd(dppf)Cl ₂ (281 mg, 0.38 mmol), sodium carbonate (2.5 g, 23.12 mmol) in dioxane In a ring (200 mL) and water (20 mL), the reaction was stirred under nitrogen protection at 60°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was added with water (100 mL) and concentrated to about (150 mL), the resulting mixture was filtered, and the filter cake was washed with ethyl acetate. Ester (2*20mL) was washed, and the filter cake was collected to obtain tert-butyl(1-(2-bromophenyl)-2-(4-amino-5-(quinoline-3)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)ethyl)carbamate (3.91 g, 90% yield). ESI-MS: 559[M+H] ⁺ .

The sixth step: (11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline Synthesis of tert-butyl lin-5-yl)carbamate

tert-Butyl(1-(2-bromophenyl)-2-(4-amino-5-(quinoline-3)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane base) carbamate (2.1 g, 3.76 mmol), Pd ₂ (dba) ₃ (340 mg, 0.37 mmol), tricyclohexylphosphine (208 mg, 0.74 mmol), sodium hydroxide (752 mg, 18.8 mmol) in dichloromethane oxygen six ring (100 mL) and water (20 mL), and the reaction was stirred under nitrogen at 110 ℃ 16 h, LCMS showed the reaction was complete, the reaction was concentrated to dryness and the residue was washed with saturated aqueous NaHCO ₃ (100 mL) and dichloromethane (100 mL ) layered extraction, the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was separated by flash silica gel column chromatography [0～40% EA:PE, EA phase contained 20% EtOH] to obtain (11-amino-12-(quinolin-3-yl)-5,6-di Hydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)carbamate tert-butyl ester (1.42 g, 79% yield). ESI-MS: 479[M+H] ⁺ .

Step 7: 12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline-5,11 -Synthesis of diamines

(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline-5 -yl) tert-butyl carbamate (1.42 g, 2.97 mmol) was dissolved in a 4M hydrogen chloride dioxane solution (30 mL), the reaction was stirred at 24 ° C for 1 hour, LCMS showed that the reaction was complete, the reaction solution was concentrated to dryness, the remaining The compound was washed with methyl tert-butyl ether (3*30 mL) to give 12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2 ,1-a]isoquinoline-5,11-diamine (1.01 g, 90% yield). ESI-MS: 379[M+H] ⁺ .

Step 8: N-(11-Amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a] Synthesis of isoquinolin-5-yl)acrylamide

12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline-5,11-diamine (600 mg, 1.59 mmol), triethylamine (1 mL) was dissolved in dichloromethane (10 mL), acryloyl chloride (171 mg, 1.9 mmol) was slowly added dropwise at 0 °C, the reaction was stirred at 0 ~ 24 °C for 1 hour, LCMS It showed that the reaction was complete, the reaction was quenched with saturated aqueous NaHCO ₃ (10 mL), the reaction solution was concentrated to dryness, and the residue was separated by a flash reverse-phase silica gel column [0-40% MeCN:H ₂ O] to give N-(11- Amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)propene amide (203 mg, 28% yield). ESI-MS: 433[M+H] ⁺ .

The ninth step: (S)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2, 1-a]Isoquinolin-5-yl)acrylamide and (R)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4 Synthesis of ':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)acrylamide

N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline -5-yl)acrylamide (203 mg, 0.20 mmol) was isolated by chiral resolution:

(1a) (S)-N-(11-Amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1 -a]Isoquinolin-5-yl)acrylamide (28.2 mg, 14% recovery by resolution).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.89(d,J=2.2Hz,1H),8.49(d,J=2.5Hz,1H),8.06(dd,J=5.6,2.3Hz,2H) ,7.95(d,J＝8.2Hz,1H),7.79(ddd,J＝8.5,6.9,1.5Hz,1H),7.63(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz, 1H), 7.18(t, J=7.5Hz, 1H), 6.94(tt, J=7.8, 1.8Hz, 1H), 6.88-6.79(m, 1H), 6.26-6.10(m, 2H), 5.58(dd , J=9.5, 2.6Hz, 1H), 5.43 (t, J=4.2Hz, 1H), 4.45 (s, 2H), 4.18 (d, J=12.9Hz, 1H). ESI-MS: 433[M+H] ⁺ .

(1b) (R)-N-(11-Amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1 -a]Isoquinolin-5-yl)acrylamide (14.3 mg, 7% recovery from resolution).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.90(d,J=2.2Hz,1H),8.50(d,J=2.4Hz,1H),8.12-8.02(m,2H),7.96(d, J=8.0Hz,1H),7.79(ddd,J=8.5,6.8,1.4Hz,1H),7.63(t,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),7.18( t, J=7.6Hz, 1H), 6.95 (t, J=7.7Hz, 1H), 6.85 (d, J=7.9Hz, 1H), 6.32–6.09 (m, 2H), 5.58 (dd, J=9.5 , 2.6Hz, 1H), 5.44 (t, J=4.2Hz, 1H), 4.45 (s, 2H), 4.19 (d, J=13.2Hz, 1H). ESI-MS: 433[M+H] ⁺ .

Examples 2a～38b can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Examples 1, 1a and 1b:

Example 39: N-(11-Amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2, Preparation of 1-a]isoquinolin-5-yl)-N-methacrylamide

The first step: the synthesis of 2-bromo-1-(2-bromo-4-fluorophenyl) ethane-1-one

1-(2-Bromo-4-fluorophenyl)ethan-1-one (6.2 g, 28.4 mmol) was dissolved in acetic acid (20 mL) and tribromopyridine (9.3 g, 29.1 mmol) was added. The reaction was stirred at 70°C for 2 hours. Water (60 mL) was added to the reaction, followed by extraction with methyl tert-butyl ether (30 mL*2). The organic phases were combined and washed with saturated aqueous sodium bicarbonate solution (30 mL*3). The organic phase was dried and concentrated to obtain crude 2-bromo-1-(2-bromo-4-fluorophenyl)ethan-1-one, which was directly used in the next reaction.

Step 2: 1-(2-Bromo-4-fluorophenyl)-2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1 -Synthesis of ketones

The crude 2-bromo-1-(2-bromo-4-fluorophenyl)ethan-1-one was dissolved in acetonitrile (40 mL), and 4-chloro-5-iodo-7H-pyrrolo[2,3- d] Pyrimidine (7.9 g, 28.4 mmol) and potassium carbonate (3.9 g, 28.3 mmol). The reaction solution was reacted at 60°C for 1 hour. Water (100 mL) was added and extracted with ethyl acetate (40 mL*3). The organic phases were combined and concentrated to give 1-(2-bromo-4-fluorophenyl)-2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane The crude product of -1-one was directly used in the next reaction. ESI-MS 493.9 [M+H] ⁺ .

The third step: 2-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl)ethane-1 -Synthesis of ketones

1-(2-Bromo-4-fluorophenyl)-2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-one The crude product was dissolved in tetrahydrofuran (50 mL), ammonia water (20 mL) was added, and the reaction was carried out at 100° C. in a sealed pot for 16 hours. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated using a normal phase column [methanol:dichloromethane=0%-10%] to obtain 2-(4-amino-5-iodo-7H-pyrrolo[2] ,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl)ethan-1-one (2.2 g, overall yield over three steps: 16%). ESI-MS: 475.0 [M+H] ⁺ .

Step 4: 2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluoro Synthesis of Phenyl)Ethan-1-one

2-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl)ethan-1-one ( 2.2g, 4.7mmol) was dissolved in a mixed solvent of dioxane (30mL) and water (6mL), quinolin-3-ylboronic acid (1.2g, 6.8mmol), potassium carbonate (2.1g, 14.9mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.22 g, 0.27 mmol). The reaction solution was reacted under nitrogen protection at 60°C for 18 hours. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated using a normal phase column [methanol:dichloromethane=0%-5%] to obtain 2-(4-amino-5-(quinolin-3-yl) Crude -7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl)ethan-1-one (0.63 g). ESI-MS: 476.0 [M+H] ⁺ .

The fifth step: 7-(2-(2-Bromo-4-fluorophenyl)-2-(methylimino)ethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2 Synthesis of ,3-d]pyrimidin-4-amine

2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl) The crude ethane-1-one (0.63 g, 1.3 mmol) was dissolved in dichloromethane (30 mL), titanium tetraisopropoxide (3.7 g, 12.9 mmol), methylamine hydrochloride (0.97 g, 14.3 mmol) and trimethylamine were added. Ethylamine (3 mL, 40.6 mmol). The reaction solution was reacted at 50°C for 1 hour. Water (100 mL) was added to the reaction solution, filtered, the filtrate was recovered, and the organic phase was separated and concentrated to obtain 7-(2-(2-bromo-4-fluorophenyl)-2-(methylimino)ethyl)- The crude 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.78 g) was used directly in the next reaction. ESI-MS: 489.0 [M+H] ⁺ .

The sixth step: 7-(2-(2-Bromo-4-fluorophenyl)-2-(methylamino)ethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2, Synthesis of 3-d]pyrimidin-4-amine

7-(2-(2-Bromo-4-fluorophenyl)-2-(methylimino)ethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d] The crude pyrimidin-4-amine (0.78 g) was dissolved in a mixed solvent of N,N-dimethylformamide (12 mL) and acetic acid (3 mL), and sodium cyanoborohydride (0.64 g, 10.2 mmol) was added. The reaction solution was reacted at room temperature for 30 minutes. Water (80 mL) was added to the reaction solution, the pH of the reaction solution was adjusted to 9 or more using sodium hydroxide, and 7-(2-(2-bromo-4-fluorophenyl)-2-(methylamino) was obtained by separation )ethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine solution was used directly in the next reaction. ESI-MS: 491.0 [M+H] ⁺ .

The seventh step: tert-butyl (2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo Synthesis of -4-fluorophenyl)ethylcarbamate methyl ester

To the reaction solution in the previous step was added dichloromethane (10 mL) and di-tert-butyl dicarbonate (4 mL, 19.3 mmol). The reaction solution was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated using a normal phase column [methanol:dichloromethane=0%-4%] to obtain tert-butyl (2-(4-amino-5- Crude methyl (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4-fluorophenyl)ethylcarbamate (0.26g) ).ESI-MS: 591.2[M+H] ⁺ .

The eighth step: tert-butyl (11-amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimidine[5',4':4,5]pyrrolo[2, Synthesis of 1-a]isoquinoline-5-carbamic acid (methyl) ester

tert-Butyl(2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo-4- Crude methyl fluorophenyl)ethylcarbamate (0.26g, 0.4mmol) was dissolved in a mixed solvent of dioxane (8mL) and water (1mL), added with palladium acetate (0.03g, 0.1mmol), tricyclohexyl Phosphine (0.07 g, 0.26 mM) and sodium hydroxide (0.05 g, 1.3 mmol). The reaction solution was reacted under nitrogen protection at 100° C. for 3.5 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate ( 20mL*3) extraction. Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain tert-butyl (11-amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydrogen The crude pyrimidine[5',4':4,5]pyrrolo[2,1-a]isoquinoline-5-carbamic acid (methyl) ester was directly used in the next reaction. ESI-MS511.2 [M +H] ⁺ .

Step 9: 2-fluoro--N ⁵ - methyl-12- (quinolin-3-yl) -5,6-dihydro-pyrimido [5 ', 4': 4,5] pyrrolo [2,1 Synthesis of -a]isoquinoline-5,11-diamine

tert-Butyl(11-amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimidine[5',4':4,5]pyrrolo[2,1-a ] The crude product of isoquinoline-5-carbamic acid (methyl) ester was dissolved in dioxane (20 mL), and a solution of 4M hydrogen chloride in dioxane (20 mL) was added. The reaction was stirred at room temperature for 2 hours. Concentrated after the separation using reverse phase column separation [acetonitrile: water = 10% -15%] to give 2-fluoro -N ⁵ - methyl-12- (quinolin-3-yl) -5,6-dihydro-pyrimido [5 ',4':4,5]pyrrolo[2,1-a]isoquinoline-5,11-diamine (8.4 mg, overall yield in six steps: 4%). ESI-MS: 411.0 [M +H] ⁺ .

Step 10: N-(11-Amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2, Synthesis of 1-a]isoquinolin-5-yl)-N-methacrylamide

2-Fluoro -N ⁵ - methyl-12- (quinolin-3-yl) -5,6-dihydro-pyrimido [5 ', 4': 4,5] pyrrolo [2,1-a] Isoquinoline-5,11-diamine (8.4 mg, 0.02 mmol) was dissolved in dichloromethane (5 mL), N,N-diisopropylethylamine (0.5 mL, 3.0 mM) and acryloyl chloride (2.9 mg, 0.03 mmol). The reaction solution was reacted at room temperature for 1 hour. The reaction solution was concentrated and separated by high performance liquid chromatography to obtain N-(11-amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4': 4,5]pyrrolo[2,1-a]isoquinolin-5-yl)-N-methacrylamide (1.7 mg, 19%). ESI-MS: 465.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.98(s, 1H), 8.62(s, 1H), 8.48(s, 1H), 8.20(d, J=8.5Hz, 1H), 8.12(d, J=8.1Hz, 1H), 7.92(t, J=7.7Hz, 1H), 7.75(t, J=7.5Hz, 1H), 7.38(s, 1H), 7.20(dd, J=9.9, 7.4Hz, 1H), 6.86(s, 1H), 6.50(dd, J=10.3, 2.5Hz, 1H), 6.25(d, J=16.7Hz, 1H), 6.09(s, 1H), 5.80(d, J=10.5 Hz, 1H), 4.60 (s, 2H), 2.83 (s, 3H).

N-(11-Amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a ]Isoquinolin-5-yl)-N-methacrylamide chiral resolution to obtain (S)-N-(11-amino-2-fluoro-12-(quinolin-3-yl)-5,6 -Dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)-N-methacrylamide (39a) and (R)-N- (11-Amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquino olin-5-yl)-N-methacrylamide (39b).

Embodiments 40a-45b can be prepared with reference to all or part of the synthetic methods of Examples 39, 39a and 39b to select corresponding raw materials:

The NMR data of the compounds prepared in the above examples are as follows:

Biological Test Evaluation

1. Cell proliferation experiment

(1) Reagents and consumables

Fetal bovine serum FBS (GBICO, Cat#10099-141);

Luminescence cell viability detection kit (Promega, Cat#G7572); black transparent flat-bottom 96-well plate, (

Cat#3603).

(2) Instruments

SpectraMax Multi-label Microplate Detector MD, 2104-0010A;

CO2 incubator, Thermo Scientific 3100 series;

Biological Safety Cabinet, Thermo Scientific, 1300 Series Type A2;

Inverted microscope, Olympus, CKX41SF;

Siemens refrigerator KK25E76TI.

(3) Cell lines and culture conditions

No.No.	细胞系cell line	细胞培养基cell culture medium	细胞密度Cell density
11	A431A431	DMEM+15％FBSDMEM+15%FBS	50005000
22	Ba/F3EGFR-D770-N771ins_SVDBa/F3EGFR-D770-N771ins_SVD	RPMI1640+10％FBSRPMI1640+10%FBS	30003000
33	Ba/F3EGFR-V769-D770ins_ASVBa/F3EGFR-V769-D770ins_ASV	RPMI1640+10％FBSRPMI1640+10%FBS	30003000

(4) Experimental steps

1. Cell culture and inoculation:

(1) Harvest cells in logarithmic growth phase and count the cells using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability was above 90%.

(2) Adjust the cell concentration to achieve the desired final density; add 90 μL of the cell suspension to a 96-well plate.

(3) The cells were at 37 [deg.] C in 96 well plates, incubated overnight at 5% CO ₂ and 95% humidity.

2. T0 benchmark data:

(1) Add 10 μL of PBS to each well of the T0 plate containing cells.

(2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

(3) Add an equal volume of CTG solution to each well.

(4) Shake for 5 minutes on an orbital shaker to lyse cells.

(5) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.

(6) Read the T0 fluorescence signal value.

3. Compound dilution and addition

(1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10 mM stock solution.

(2) Prepare a 1000-fold, 3.16-fold diluted compound solution.

(3) Dilute the 1000× diluted compound solution 100 times with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μM, 9 concentrations, diluted 3.16 times, and add 10 μL to each well inoculated with a 96-well plate drug solution, seeded with cells. Three replicate wells were set up for each compound concentration and the final concentration of DMSO was 0.1%.

(4) The cells were placed in a drug-filled 96-well plate at a temperature of 37°C, 5% CO ₂ and 95% humidity, and cultured for 72 hours, followed by CTG analysis.

4. Fluorescence signal reading

(1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

(2) Add an equal volume of CTG solution to each well.

(3) Shake for 5 minutes on an orbital shaker to lyse cells.

(4) The cell plate was left at room temperature for 20 minutes to stabilize the fluorescent signal.

(5) Read the fluorescence value.

5. Data processing

Use GraphPad Prism 7.0 software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-response curve, and calculate the IC ₅₀ value (unit: nM) accordingly. The specific experimental results are shown in Table 1:

Cell survival rate (%)=(Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control)×100%.

Table 1: Biological Test Results

Judging from the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutations at the cellular level, and have certain selectivity for EGFR WT.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure 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

Compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:

in,

X is CH or N;

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 1 or N;

R 1 is selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1- 10 alkyl, hydroxy substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heterocyclic Aryl, -SF 5 , -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -OC(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(=NR 8 )R 7 , -N(R 8 )-C(=NR 9 )R 7 , -C(O)NR 8 R 9 and -N(R 8) -C (O) R 7 ;

R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O) r R 5 , -OR 6 , -C( O)OR 6 , -C(O)R 7 , -OC(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(=NR 8 )R 7 , -N( R 8 )-C(=NR 9 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O)R 7 , independently optionally further modified by one or more Selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, = O, -SF 5, -S (O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -OC(O)R 7 , -NR 8 R 9 , -C(=NR 8 )R 7 , -N (R 8 )-C(=NR 9 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O)R 7 substituents;

R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, -C(O)OR 6 , -C(O)R 7 and -C(O)NR 8 R 9 ;

Each R 5 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl radicals, 5-10-membered heteroaryl groups, and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 substituted by the substituents of aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 ;

Each R 6 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl group, and 5-10-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 substituents;

Each R 7 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl , C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryl substituted by the substituents of oxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 ;

Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- Substitution of 10- aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl base substituted;

Alternatively, R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or 4-10-membered heteroaryl group, which is either is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6 -10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of C 1-10 alkanoyl groups are substituted;

n is 0, 1, 2, 3, or 4; and

Each r is independently 0, 1, or 2.
The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyanide base, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 5 , -OR 6 , -C (O)OR 6 , -C(O)R 7 , -OC(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(=NR 8 )R 7 , -N (R 8 )-C(=NR 9 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O)R 7 ;

wherein R 5 , R 6 , R 7 , R 8 , R 9 and r are as defined in claim 1 .
The compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt according to claim 1, wherein R 1 is selected from hydrogen, deuterium, hydroxyl, halogen, cyano, C 1 -4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl , -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(= NR 8 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O)R 7 ;

wherein R 5 , R 6 , R 7 , R 8 , R 9 and r are as defined in claim 1 .
The compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt according to claim 1, wherein,

Each R 5 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl radicals, 5-8 membered heteroaryl groups and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1- 4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-10 substituted by the substituents of aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 ;

Each R 6 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl group, and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5 -8-membered heteroaryl, 5-8 membered heteroaryloxy and -NR 8 R 9 substituents;

Each R 7 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryl substituted by the substituents of oxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 ;

Each of R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3 -8-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3 -8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 substituted by substituents of heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;

Alternatively, R 8 and R 9 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3 -8-membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, Substituents of mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups.
The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the following compound of formula (II):

in,

X is CH or N;

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 1 or N;

R 1 is selected from hydrogen, deuterium, hydroxy, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(=NR 8 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O)R 7 ;

Each R 3 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -OC(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 , -C(=NR 8 )R 7 , -N(R 8 )-C(=NR 9 )R 7 , -C(O)NR 8 R 9 and -N(R 8 )-C(O )R 7 ;

R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl and -C(O)R 7 ;

Each R 5 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl radicals, 5-8 membered heteroaryl groups and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1- 4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 substituted by the substituents of aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 ;

Each R 6 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl group, and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5 -8-membered heteroaryl, 5-8 membered heteroaryloxy and -NR 8 R 9 substituents;

Each R 7 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryl substituted by the substituents of oxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 ;

Each of R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3 -8-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3 -8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 substituted by substituents of heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;

Alternatively, R 8 and R 9 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3 -8-membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, substituted by the substituents of mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;

n is 0, 1, 2, 3, or 4; and

Each r is independently 0, 1, or 2.
The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the following compound of formula (III):

in,

X is CH or N;

Y 2 and Y 4 are each independently CR 1 or N;

Each R 1 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl base, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 and -C(=NR 8 )R 7 ;

R 4a and R 4b are each independently selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and -C( O)R 7 ;

wherein R 5 , R 6 , R 7 , R 8 , R 9 and r are as defined in claim 1 .
The compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt according to claim 6, wherein,

R 4a and R 4b are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2, -CF 3, -CHD 2, -CD 3 and -C ( O) R 7; wherein R 7 6 as defined in claim 1;

Preferably, R 4a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2, -CF 3, -CHD 2 , and -CD 3; R 4b is selected from hydrogen, Deuterium and -C(O)R 7 ; wherein R 7 is as defined in claim 6.
The compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt according to claim 6, wherein,

Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, oxetanyl, C 1-4 alkyl, halo-substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, -S(O) r R 5 , -OR 6 , -C(O)OR 6 , -C(O)R 7 , -NR 8 R 9 , -P(O)R 8 R 9 and -C(=NR 8 )R 7 ;

wherein R 5 , R 6 , R 7 , R 8 , R 9 and r are as defined in claim 6 .
The compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt according to claim 6, wherein,

Each R 5 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and -NR 8 R 9 , the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl and C 1-4 alkoxy;

Each R 6 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, the above groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, hydroxy, oxo, cyano, C 1-4 alkyl and C 1-4 alkoxy;

Each R 7 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy group, phenyl, and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, hydroxy, cyano, C 1-4 alkyl and C 1-4 alkoxy substituted by the substituent of the base;

Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclo Propylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;

Alternatively, R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group optionally further substituted by one or more members selected from the group consisting of deuterium, fluorine, chlorine, hydroxy , C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, amino, mono-C 1 -4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1-9, characterized in that, it is selected from the following compounds:
A preparation method of the compound of formula (I) according to claim 1, its stereoisomer, prodrug or its pharmaceutically acceptable salt, is characterized in that, comprises the steps:

wherein X, Y 1 , Y 2 , Y 3 , Y 4 , R 2 , R 3 , R 4a , R 4b and n are as defined in claim 1 .
A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-10, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A compound of formula (I) according to any one of claims 1-10, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, in the manufacture of a therapeutic and/or prophylactic at least partial insertion with EGFR exon 20 Use in the medicament of cancer, tumor or metastatic disease associated with , deletion or other mutation.
A compound of formula (I) according to any one of claims 1-10, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof in the manufacture of a prophylactic and/or therapeutic disorder caused by hyperproliferation and induction of cell death Use in the medicament of tumor, cancer and/or metastatic disease.
The compound of formula (I) according to any one of claims 1-10, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof in the manufacture of prophylactic and/or therapeutic and EGFR exon 20 insertions, deletions or other mutations associated with lung, colon, pancreatic, head and neck, breast, ovarian, uterine, gastric, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphoma, head and neck tumors, thoracic Neoplasms, gastrointestinal neoplasms, endocrine neoplasms, breast and other gynecological neoplasms, urological neoplasms, skin neoplasms, sarcomas, naso-inverted papilloma or nasosinus-associated squamous cell carcinoma use in medicines.
A compound of formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of insertions with EGFR exon 20 , deletion or other mutation-associated lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer , thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous Use of cell carcinoma.