Macrocyclic heterocyclic compounds as egfr inhibitors and uses thereof

Abstract

The present application belongs to the field of medicinal chemistry, and relates to a kind of macrocyclic heterocyclic compounds as EGFR inhibitor and application thereof, specifically, the present application provides the compound shown in formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, their preparation method and the pharmaceutical composition containing these compounds and the purposes of these compounds or compositions for treating EGFR-mediated diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and particularly relates to a macrocyclic heterocyclic compound or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof as an EGFR inhibitor, a preparation method thereof, and a pharmaceutical composition containing the compound and the use of the compound or the composition for treating EGFR-mediated diseases. BACKGROUND

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. EGFR belongs to one of the ErbB receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR is also known as HER1, ErbB1, and mutation or overexpression generally triggers tumors. EGFR is a glycoprotein belonging to the tyrosine kinase type receptor, which penetrates the cell membrane, and has a molecular weight of 170 KDa.

[0003] EGFR is related to the proliferation of tumor cells, angiogenesis, tumor invasion, metastasis and inhibition of apoptosis, and studies have shown that there is high expression or abnormal expression of EGFR in solid tumors such as glioma, renal cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer, etc. About 30% to 40% of Asian NSCLC patients carry EGFR mutations at the time of diagnosis.

[0004] Common mutations of EGFR can be divided into two categories, one is a drug-sensitive mutation, that is, after mutation, an anti-tumor targeted drug can be used, for example, 19 exon deletion, 21 exon L858R mutation; the other is a drug-resistant mutation, that is, after mutation, a certain anti-tumor targeted drug is resistant, for example, 20 exon T790M mutation, 20 exon C797S mutation. AZD9291 (Osimertinib) is an oral small molecule third-generation EGFR-TKI, which is the first lung cancer drug targeting EGFR T790M mutation, but some patients who benefit from the drug have developed drug resistance after 9-14 months of treatment. Research has found that up to 40% of drug-resistant patients have developed osimertinib resistance due to EGFR_C797S point mutation. Further mechanism studies have shown that the point mutation of EGFR_C797S changes the cysteine at position 797 to serine, which prevents osimertinib from forming a covalent bond with the target protein, and C797S is an important reason for the emergence of resistance to the third-generation drug osimertinib. At present, there is still a lack of effective EGFR inhibitors for the new mutation (C797S) alone in clinical use, and therefore it is necessary to develop a new generation of EGFR inhibitors targeting C797S mutation. SUMMARY

[0005] An object of the present application is to provide a class of compounds having EGFR inhibiting activity represented by the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug,

[0006]

[0007] wherein,

[0008] Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, said aryl, heteroaryl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo;

[0009] Cy is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl and heteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl and heteroaryl being optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo;

[0010] L is selected from a chemical bond, -S-, -O-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2- and wherein R 4 , R 5 are each independently selected from hydrogen, halo, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

[0011] R 1 is selected from hydrogen, halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;

[0012] R 2selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylacyl, aminoacyl, alkylaminoacyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, heterocyclyl, aryl, and heteroaryl, said groups being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

[0013] R 3 each is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; m is 1, 2, or 3; and

[0014] when Cy is piperazinyl, L is -CH2-, and R1is -CH2OH, then ring A is not pyridinyl.

[0015] It is another object of the present application to provide a method of preparing a compound of general formula (I) of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.

[0016] It is still another object of the present application to provide a composition comprising a compound of general formula (I) of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof and a pharmaceutically acceptable carrier, and a composition comprising a compound of general formula (I) of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof and another drug or drugs.

[0017] It is still another object of the present application to provide a method of treating an EGFR-mediated disease with a compound of general formula (I) of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and the use of a compound of general formula (I) of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof for the manufacture of a medicament for treating an EGFR-mediated disease.

[0018] In order to achieve the above objects, the present application provides the following technical solutions:

[0019] In a first aspect, the present application provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

[0020]

[0021] wherein,

[0022] Ring A is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, said aryl, heteroaryl, cycloalkyl, and heterocyclyl being optionally substituted with one or more radicals selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

[0023] Cy is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclyl and heteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclyl and heteroaryl being optionally substituted with one or more radicals selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

[0024] L is selected from a bond, -S-, -O-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2-, and wherein R 4 , R 5 are each independently selected from hydrogen, halo, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

[0025] R 1 is selected from hydrogen, halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, and dialkylamino;

[0026] R 2selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylacyl, aminoacyl, alkylaminoacyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, heterocyclyl, aryl, and heteroaryl, said groups being optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

[0027] R 3 each is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; m is 1, 2, or 3; and

[0028] when Cy is piperazinyl, L is -CH2-, ring A is not pyridinyl.

[0029] In some preferred embodiments, the compounds of the application are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein:

[0030] R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, nitro, carboxy, cyano, amino, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl and dialkylamino; 1-6 alkylamino;

[0031] Further preferably, R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C

[0032] R 1 selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, haloC 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C

[0033] In some preferred embodiments, the compounds of the application are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein:

[0034] R 2 selected from C 1-6 alkyl, C 3-12 alkyl, C 2-6 alkyl, C 2-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 6-12 aryl and 5-12 membered heteroaryl, said groups being optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6alkylaminoacyl, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halo-C 1-6 alkylacyl, hydroxy-C 1-6 alkylacyl, C 3-12 cycloalkylacyl, 3- to 12-membered heterocyclylacyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl and oxo groups;

[0035] Further preferably, R 2 selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl, di-C 1-3 alkylsulfonyl, aminosulfonyl, C 1-3 alkylaminosulfonyl, 3- to 8-membered heterocyclyl, C 6-8 aryl and 5- to 6-membered heteroaryl, which groups are optionally substituted by one or more radicals selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, hydroxy-C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halo-C 1-6 alkylacyl, hydroxy-C 1-6 alkylacyl, C 3-12 cycloalkylacyl, 3- to 12-membered heterocyclylacyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl and oxo groups.

[0036] Still further preferably, R 2methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, isopropynyl, methoxy, ethoxy, propoxy, isopropoxy, methylacyl, ethylacyl, propylacyl, isopropylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoacyl, isopropylaminoacyl, butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, said groups being optionally substituted with one or more groups selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, oxo groups.

[0037] In some preferred embodiments, the compounds of the application are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein:

[0038] R 3 each is independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, nitro, carboxyl, cyano, amino, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, diC 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-6 alkylacyl, hydroxyC 1-6 alkylacyl, C 3-12 cycloalkylacyl, 3-12 membered heterocyclylacyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo groups;

[0039] Further preferably, R 6 each is independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3alkyl, haloC 1-3 alkoxy, nitro, carboxy, cyano, amino, monoC 1-3 alkylamino, C 1-3 alkylcarbonylamino, C 1-3 alkylcarbonyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-3 alkylcarbonyl, hydroxyC 1-3 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, 3-8 membered heterocyclylcarbonyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups;

[0040] More preferably still, R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxacyclopropyl, azacyclopropyl, oxacyclobutyl, azacyclobutyl and oxo groups.

[0041] In some preferred embodiments, the compounds of the application are compounds of general formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:

[0042] Ring A is selected from C 6-16 aryl, 5-16 membered heteroaryl, C 3-16 cycloalkyl and 3-16 membered heterocyclyl, said C 6-16 aryl, 5-16 membered heteroaryl, C 3-16 cycloalkyl and 3-16 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, nitro, carboxy, cyano, amino, monoC 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, diC 1-6 alkylamino, C 2-10 alkenyl, C2-10 alkynyl, haloC 1-6 alkylacyl, hydroxyC 1-6 alkylacyl, C 3-12 cycloalkylacyl, 3-12 membered heterocyclylacyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl and oxo groups;

[0043] Further preferably, ring A is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl, said C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, nitro, carboxy, cyano, amino, monoC 1-3 alkylamino, C 1-3 alkylacylamino, C 1-3 alkylacyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-3 alkylacyl, hydroxyC 1-3 alkylacyl, C 3-8 cycloalkylacyl, 3-8 membered heterocyclylacyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups;

[0044] Still further preferably, ring A is selected from C 6-10 aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heteroaryl, C 3-10 cycloalkyl and 9-10 membered bicyclic heterocyclyl, said C 6-10 aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heteroaryl, C 3-10 cycloalkyl and 9-10 membered bicyclic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3alkylsulfonyl, aminocarbonyl, C 1-3 alkylamino, C 1-3 alkylcarbonylamino, C 1-3 alkylcarbonyl, C 1-3 alkylsulfonyl, aminocarbonyl, C 1-3 alkylamino, C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-3 alkylcarbonyl, hydroxyC 1-3 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, 3-8 membered heterocyclylcarbonyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups.

[0045] In some preferred embodiments, the compounds of general formula (I) or its isomers, pharmaceutically acceptable salts, solvates, crystalline or prodrugs according to the present application, wherein ring A is selected from phenyl, pyridyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azacyclyl and 3-6 membered heterocyclyl and 5-6 membered heteroaryl, said groups are optionally substituted with one or more groups selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl and oxo groups.

[0046] In some embodiments, the compound according to Formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein ring A is selected from phenyl, pyridyl, 5-6 membered heteroaryl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyridopyrazolyl, pyrimidopyrazolyl, pyrimidimidazolyl, pyrimidtriazolyl, pyridotriazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered heterocyclyl and 3-6 membered heterocyclyl and 5-6 membered heteroaryl, is optionally substituted with one or more groups selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl and oxo groups.

[0047] In some preferred embodiments, the compound of the present application is a compound of Formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

[0048] Cy is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl and 5-12 membered heteroaryl, said C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl and 5-12 membered heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, nitro, carboxy, cyano, amino, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, bisC 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-6 alkylacyl, hydroxyC 1-6 alkylacyl, C 3-12cycloalkylcarbonyl, 3-12 membered heterocyclylcarbonyl, C 3-12 substituted with one or more groups selected from halo, hydroxy, C

[0049] Further preferably, Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered heterocyclyl, and 4-8 membered heterocyclyl fused with 5-8 membered heteroaryl, said Cy being optionally substituted with one or more groups selected from halo, hydroxy, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, and 3-10 membered heterocyclyl fused with 5-10 membered heteroaryl, said C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, and 3-10 membered heterocyclyl fused with 5-10 membered heteroaryl, said C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, nitro, carboxy, cyano, amino, monoC 1-3 alkylamino, C 1-3 alkylcarbonylamino, C 1-3 alkylcarbonyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, diC 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-3 alkylcarbonyl, hydroxyC 1-3 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, 3-8 membered heterocyclylcarbonyl, C 3-8 substituted with one or more groups selected from halo, hydroxy, C

[0050] Further preferably, Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered heterocyclyl, and 4-8 membered heterocyclyl fused with 5-8 membered heteroaryl, said Cy being optionally substituted with one or more groups selected from halo, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, nitro, carboxy, cyano, amino, monoC 1-3 alkylamino, C 1-3alkylcarbonyl, C 1-3 alkylcarbonyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, bisC 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-3 alkylcarbonyl, hydroxyC 1-3 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, 3-8 membered heterocyclylcarbonyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups.

[0051] In some specific embodiments, the compounds of general formula (I) according to the application or its isomers, pharmaceutically acceptable salts, solvates, crystalline or prodrugs, wherein Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered nitrogen heterocyclyl and 4-8 membered nitrogen heterocyclyl and 5-8 membered heteroaryl, which is optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, oxo groups.

[0052] In some preferred embodiments, the compounds of general formula (I) according to the application or its isomers, pharmaceutically acceptable salts, solvates, crystalline or prodrugs, wherein:

[0053] L is selected from a chemical bond, -S-, -O-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2- and wherein R 4 , R 5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 2-10 alkenyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl and C 1-6 alkoxy;

[0054] Further preferably, L is selected from a chemical bond, -S-, -O-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2- and wherein R 4 , R 5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C2-6 alkenyl, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl and C 1-3 alkoxy;

[0055] More preferably still, L is selected from the group consisting of a bond, -S-, -0-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2-, and wherein R 4 , R 5 each independently is selected from the group consisting of hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, vinyl, propenyl, isopropenyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy;

[0056] In some preferred embodiments, the present application provides a compound represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein the general formula (I) has the following general formula (II),

[0057]

[0058] wherein R 1 , R 2 , R 3 , m, Cy, and L have the definitions described above for the general formula (I);

[0059] R 6 each independently is selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; and

[0060] n is 1, 2, 3, or 4.

[0061] In some preferred embodiments, the present application provides a compound represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein the general formula (I) has the following general formula (IIa),

[0062]

[0063] wherein R 1 , R 2 , R 3 , R6 , m, n, Cy and L have the definitions described above for general formula (II).

[0064] In some preferred embodiments, the present application provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein general formula (I) has the structure of the following general formula (III),

[0065]

[0066] wherein R 1 , R 2 , R 3 , R 6 , m, n, Cy and L have the definitions described above for general formula (II).

[0067] In some preferred embodiments, the present application provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein general formula (I) has the structure of the following general formula (IV),

[0068]

[0069] wherein R 1 , R 2 , R 3 , R 6 , m, n, Cy and L have the definitions described above for general formula (II).

[0070] In some preferred embodiments, the present application provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein general formula (I) has the structure of the following general formula (V),

[0071]

[0072] wherein R 1 , R 2 , R 3 , R 6 , m, n, Cy and L have the definitions described above for general formula (II).

[0073] In some preferred embodiments, the present application provides a compound represented by general formula (II), general formula (IIa), general formula (III), general formula (IV) or general formula (V) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein

[0074] R 6 each independently is selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, hydroxy-C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono-C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 alkylaminoacyl, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halogen-C 1-6 alkylcarbonyl, hydroxy-C 1-6 alkylcarbonyl, C 3-12 cycloalkylcarbonyl, 3- to 12-membered heterocyclylcarbonyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl and oxo;

[0075] Further preferably, R 6 each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-3 alkyl, halogen-C 1-3 alkyl, hydroxy-C 1-3 alkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, hydroxy-C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono-C 1-3 alkylamino, C 1-3 alkylcarbonylamino, C 1-3 alkylcarbonyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 alkylaminoacyl, di-C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, halogen-C 1-3 alkylcarbonyl, hydroxy-C 1-3 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, 3- to 8-membered heterocyclylcarbonyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 8-membered aryl, 5- to 8-membered heteroaryl and oxo;

[0076] Still further preferably, R 6each independently is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, and oxo groups.

[0077] In some preferred embodiments, the compound according to the application of general formula (I), general formula (II), general formula (Ila), general formula (III), general formula (IV), or general formula (V), or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein L is selected from a chemical bond, -S-, -0-, -N-, -CH2-, -CH2CH2-, -C(O)-, -S(O)-, -S(O)2-,

[0078] In some preferred embodiments, the compound according to the application of general formula (I), general formula (II), general formula (Ila), general formula (III), general formula (IV), or general formula (V), or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein Cy-L- is selected from

[0079] In some embodiments, the present application provides a compound represented by general formula (I), or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, wherein general formula (I) has the following structure of general formula (VI),

[0080]

[0081] wherein R 1 , R 2 , R 6 , n, L have the definitions described above for general formula (I), and ring B is selected from 3-12 membered azacycloalkyl, 3-12 membered diazacycloalkyl, 3-12 membered azacyclyl, 3-12 membered diazacyclyl, 5-12 membered azaheteroaryl, R 7 each independently is selected from halogen, hydroxyl, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, o is 0, 1, 2, 3, 4, 5, or 6; or two R 7with the atom to which they are attached form a 3-12 membered azacycloalkyl, 3-12 membered diazacycloalkyl, 3-12 membered azacycloalkyl, 3-12 membered diazacycloalkyl, 5-12 membered azaheteroaryl, 3-12 membered oxacycloalkyl, 3-12 membered dioxacycloalkyl, 3-12 membered oxacycloalkyl, 3-12 membered dioxacycloalkyl, or 5-12 membered oxaheteroaryl, optionally substituted with a group selected from halogen, hydroxyl, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

[0082] In some embodiments, the compound according to Formula (VI) or isomers, pharmaceutically acceptable salts, solvates, crystals, or prodrugs thereof, according to the present application, wherein ring B is selected from 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 5-12 membered azaheteroaryl, R 7 each is independently selected from halogen, hydroxyl, carboxyl, cyano, amino, C 2-6 alkenyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl, C 6-12 aryl, C 5-12 heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, o is 0, 1, 2, 3, or 4; or two R 7 with the atom to which they are attached form a 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 5-12 membered azaheteroaryl, 3-8 membered oxacycloalkyl, 3-8 membered dioxacycloalkyl, 3-8 membered oxacycloalkyl, 3-8 membered dioxacycloalkyl, or 5-12 membered oxaheteroaryl, optionally substituted with a group selected from halogen, hydroxyl, carboxyl, cyano, amino, C 2-6 alkenyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl, C 6-12 aryl, C 5-12heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl groups.

[0083] In some embodiments, the compound according to the present application is represented by Formula (VI) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystalline form or a prodrug thereof, wherein ring B is selected from 3-8 membered nitrogen heterocycloalkyl, 3-8 membered diazaheterocycloalkyl, 3-8 membered nitrogen heterocyclyl, 3-8 membered diazaheterocyclyl, 5-12 membered nitrogen heteroaryl, R 7 each independently selected from halogen, hydroxy, carboxy, cyano, amino, C 2-6 alkenyl, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, monoC 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl, C 6-12 aryl, C 5-12 heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, o is 0, 1, 2, 3 or 4; or two R 7 form, together with the atom to which they are attached, a 3-8 membered nitrogen heterocycloalkyl, 3-8 membered diazaheterocycloalkyl, 3-8 membered nitrogen heterocyclyl, 3-8 membered diazaheterocyclyl, 5-12 membered nitrogen heteroaryl, 3-8 membered oxaheterocycloalkyl, 3-8 membered dioxaheterocycloalkyl, 3-8 membered oxaheterocyclyl, 3-8 membered dioxaheterocyclyl or 5-12 membered oxaheteroaryl, optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, oxo groups.

[0084] In some embodiments, the compound according to the present application is represented by Formula (VI) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystalline form or a prodrug thereof, wherein ring B is selected from and R 7one or more groups selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, oxo groups, o is 0, 1, 2, 3, or 4; or two R 7 one or more groups selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, oxo groups, o is 0, 1, 2, 3, or 4; or two R

[0085] The present application provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:

[0086]

[0087]

[0088]

[0089] In another aspect, the present application provides a method for preparing the compounds of general formula (I) of the present application, comprising:

[0090]

[0091] 1) the compound of formula (3) can be prepared by reacting the compound of formula (1) and the compound of formula (2),

[0092] 2) the compound of formula (4) can be prepared by reacting the compound of formula (3),

[0093] 3) the compound of formula (6) can be prepared by reacting the compound of formula (4) and the compound of formula (5) or a salt thereof,

[0094] 4) the compound of formula (7) can be prepared by reduction reaction of the compound of formula (6),

[0095] 5) the compound of formula (8) can be prepared by reacting the compound of formula (7),

[0096] 6) The compound of formula (9) can be prepared by hydrolysis reaction of the compound of formula (8),

[0097] 7) The compound of formula (10) can be prepared by reaction of the compound of formula (9),

[0098] 8) The compound of formula (I) can be prepared by reaction of the compound of formula (10).

[0099] wherein R 1 , R 2 , R 3 , m, Cy and L have the definitions described in general formula (I); X is a leaving group, preferably selected from halogen, further preferably selected from bromine; the compound of formula (2) and the compound of formula (5) or salts thereof are commercially available compounds or can be synthesized using other techniques conventional to those skilled in the art.

[0100] In a third aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.

[0101] In some embodiments, the present application provides a compound of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof and a pharmaceutical composition comprising a compound of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof for use in the treatment of a disease mediated by EGFR.

[0102] In some embodiments, the present application provides a pharmaceutical composition comprising a compound of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof and a pharmaceutically acceptable carrier.

[0103] A compound of the present application or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to produce a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The preparation can be administered by any route, for example, by infusion or bolus injection, by a route through the epithelial or skin membranes (for example, the oral mucosa or rectum, etc.). The administration can be systemic or local. Examples of preparations for oral administration include solid or liquid dosage forms, in particular, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art, and contains carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0104] In a fourth aspect, the present application provides the use of a compound of Formula (I), (II) or (III) of the present application, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for treating an EGFR-mediated disease, and for the manufacture of a medicament for treating an EGFR-mediated disease.

[0105] In some preferred embodiments, the present application provides the use of a compound of Formula (I), (II) or (III) of the present application, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for treating an EGFR-mediated disease, and for the manufacture of a medicament for treating an EGFR-mediated disease, wherein the EGFR-mediated disease includes, but is not limited to, a cancer, a proliferative disease, a metabolic disease or a hematological disease. In some embodiments, the EGFR-mediated disease of the present application is a cancer.

[0106] In some preferred embodiments, the present application provides the use of a compound of Formula (I), (II) or (III) of the present application, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for treating an EGFR-mediated disease, and for the manufacture of a medicament for treating an EGFR-mediated disease, wherein the EGFR-mediated disease includes, but is not limited to, a cancer, a proliferative disease, a metabolic disease or a hematological disease. In some embodiments, the EGFR-mediated disease of the present application is a cancer.

[0107] The compounds of the present application have specific tyrosine kinase inhibitory activity against mutant drug-resistant EGFR, such as del19, T790M, C797S, L858R mutant drug-resistant EGFR, as a mutant drug-resistant EGFR-specific tyrosine kinase inhibitor, and have a good preventive and / or therapeutic effect on diseases mediated by drug-resistant mutant EGFR, such as cancer, proliferative disease, metabolic disease or hematological disease, etc. In some embodiments, the mutant drug-resistant EGFR is Del19 / T790M / C797S or L858R / T790M / C797S triple mutation. In other embodiments, the mutant drug-resistant EGFR is del19 / T790M, L858R / T790M, L858R or del19 primary or secondary mutation.

[0108] Definitions

[0109] Unless otherwise indicated, the terms used in the specification and claims are intended to have the meanings ascribed to them below in the Dictionary.

[0110] "Hydrogen", "carbon", "oxygen" in the compounds of the present application include all isotopes thereof. Isotopes are atoms of the same element, but having different numbers of neutrons in their nuclei. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 12 C, 13 C and 14 C, isotopes of oxygen include 16 O and 18 O, etc.

[0111] An "isomer" of the present application refers to molecules having the same atomic constituents and connectivity, but different three-dimensional arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L, or R, S are used to denote the absolute configuration of the molecule. The prefixes D and L or (+) and (-) are employed to designate the sign of rotation of the plane-polarized light by the compound, (-) or L meaning that the compound is levorotatory. A particular stereoisomer can be designated by (R) or (S). The chemical structures of these stereoisomers are identical, but their orientations in three-dimensional space are mirror images of one another. A particular stereoisomer can be referred to as an enantiomer when it is not a racemic mixture. A mixture of enantiomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can result from chemical or physical processes such as racemization. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric forms lacking optical activity.

[0112] Depending on the choice of starting materials and methods, the compounds of the present application can be synthesized as one of the possible isomers or as a mixture of them, such as, for example, as a racemate or as a non-racemic mixture (depending on the number of asymmetric carbon atoms present). The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0113] Any mixture of stereoisomers can be separated into their individual components by conventional techniques, such as HPLC or fractional crystallization. Purification of the separated components can be effected by conversion to a salt, or to a mixture of salts, or to a mixture of two or more different salts.

[0114] "Halogen" or "halogen atom" of the present application refers to fluorine, chlorine, bromine, iodine. "Halo" or "halogenated" of the present application refers to substitution with fluorine, chlorine, bromine, or iodine.

[0115] "Alkyl" of the application refers to straight-chained or branched saturated aliphatic groups, preferably straight-chained or branched groups containing 1 to 6 carbon atoms, further preferably straight-chained or branched groups containing 1 to 3 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0116] -C(O)- of the application refers to "carbonyl".

[0117] -S(O)2- of the application refers to "sulfonyl".

[0118] "Haloalkyl" of the application refers to an alkyl group substituted with at least one halogen.

[0119] "Hydroxyalkyl" of the application refers to an alkyl group substituted with at least one hydroxyl group.

[0120] "Alkoxy" of the application refers to -O-alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0121] "Cycloalkyl" of the application refers to cyclic saturated hydrocarbon groups. Suitable cycloalkyl groups can be substituted or unsubstituted monocyclic, bicyclic, or tricyclic saturated hydrocarbon groups having 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0122] "Heterocyclyl" of the application refers to a group of a 3- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heterocyclyl groups can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system (e.g., a bicyclic ring system (also referred to as "bicyclic heterocyclyl")) and can be saturated or can be partially unsaturated. Suitable heterocyclyl groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Each instance of heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0123] The "aryl" of the present application refers to an aromatic system which can comprise a monocyclic or a fused polycyclic ring, preferably an aromatic system comprising a monocyclic or a fused bicyclic ring, containing 6 to 12 carbon atoms, preferably containing about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, fluorenyl, indanyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0124] The "heteroaryl" of the present application refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, preferably consisting of 5 to 12 atoms (5-12 membered heteroaryl), further preferably consisting of 5 to 10 atoms (5-10 membered heteroaryl), the heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidimidazolyl, and the like. The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0125] The "pharmaceutically acceptable salt" of the present application refers to a salt of the compound of the present application, which is safe and effective when used in a mammal, and which has an appropriate biological activity.

[0126] The "solvate" of the present application refers to a complex formed by the combination of a solute (e.g., an active compound, a salt of an active compound) and a solvent (e.g., water). The solvent refers to a solvent known or readily determined by one skilled in the art. If it is water, the solvate is often referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or a salt thereof in an alternative amount, and the like.

[0127] The in vivo action of the compound of formula (I) can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As described above, the in vivo action of the compound of formula (I) can also be exerted via metabolism of a precursor compound ("prodrug"). The "prodrug" of the present application refers to a compound which is converted into the compound of the present application under physiological conditions in a living body, i.e., a compound which is converted into the compound of the present application by oxidation, reduction, hydrolysis, etc. of an enzyme, a gastric acid, etc., and / or a compound which is converted into the compound of the present application by a hydrolysis reaction, etc. of a gastric acid, etc.

[0128] The "crystal" of the present application means a solid whose internal structure is regularly repeated by atoms (or groups thereof) in three dimensions, unlike an amorphous solid which does not have such a regular internal structure.

[0129] The "pharmaceutical composition" of the present application means a mixture comprising any one of the compounds of the present application, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and / or another or more drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used to prepare a medicament for the treatment and / or prevention of a disease mediated by one or more kinases.

[0130] The "pharmaceutically acceptable carrier" of the present application means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, etc. isotonic agents, thickening agents or emulsifiers, preservatives, solid binders, lubricants, etc. Except for any conventional carrier medium which is incompatible with the compound of the present application. Some examples of the pharmaceutically acceptable carrier can include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, and cellulose and cellulose acetate; malt, gelatin, etc.

[0131] The "excipient" of the present application means an inert substance added to the pharmaceutical composition to further facilitate the administration of the compound. The excipient can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol.

[0132] The "EGFR WT" of the present application is wide type EGFR, i.e. wild type EGFR. The "EGFR (del19 / T790M / C797S)" of the present application is del19 / T790M / C797S mutant EGFR. DETAILED DESCRIPTION

[0133] The present application will be further described in detail with reference to the following examples, but the present application is not limited to these examples. The materials used in the following examples are commercially available unless otherwise specified.

[0134] Example 1 (R,E)-2 6 -Fluoro-1 1 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -Dihydro-1 1 H,5 1H-11-oxa-4-aza-5(2, 1)-benzo[d]imidazol-l(4, 5)-pyrazol-2(l, 3)- benzocycloundecan-3-one

[0135]

[0136] Step 1 Preparation of 2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,2- dihydro-3H-pyrazol-3-one

[0137]

[0138] Weigh 1-methyl-lH-pyrazol-5-ol (20.0 g, 204.1 mmol) and potassium carbonate (K2CO3, 60.3 g, 437.0 mmol) into a 1 L three-necked flask, dissolve in 500 mL acetonitrile, stir at room temperature for 30 min. Slowly drop 2-(trimethylsilyl)ethoxymethyl chloride (60 mL) into the mixture, stir overnight. After the reaction is complete, filter under reduced pressure. Dissolve the crude product in 180 mL hot methyl tert-butyl ether, then add 600 mL n-hexane. Cool, filter to obtain white solid product. ESI-MS m / z: 229.3 [M+H] + .

[0139] Step 2 Preparation of 4-iodo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,2- dihydro-3H-pyrazol-3-one

[0140]

[0141] Weigh the starting material 2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,2- dihydro-3H-pyrazol-3-one (12.0 g, 52.3 mmol) into a 250 mL reaction flask, dissolve in 150 mL acetonitrile, cool to 0°C. Add N-iodosuccinimide (11.5 g, 86.1 mmol) to the mixture. After stirring for 2 h, gradually warm the reaction to room temperature, react for 1 h. Remove the solvent under reduced pressure, and dissolve the crude product in 200 mL dichloromethane. Wash the organic layer with saturated sodium bicarbonate solution (100 mL) and water (2 x 100 mL). Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow solid. Use directly in the next step. ESI-MS m / z: 355.1 [M+H] + .

[0142] Step 3 Preparation of methyl 4-fluoro-3-(2-methyl-3-oxo-l-((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-pyrazol-4-yl)benzoate

[0143]

[0144] Charge 2-fluoro-5-(methoxycarbonyl)benzeneboronic acid (5 g, 25.3 mmol), 4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (8.96 g, 25.3 mmol), tris(dibenzylideneacetone)dipalladium (394 mg, 0.430 mmol) in a 200 mL reaction flask, dissolved in toluene / water (200 mL; 3:1), then added cesium carbonate (20.6, 63.2 mmol), n-butyl bis(1-adamantyl)phosphine (454 mg, 1.265 mmol), argon protection, 50 °C reaction overnight. After the reaction was complete, filtered, extracted with ethyl acetate, washed with water, combined the organic phase, dried, concentrated, and purified by column chromatography to give the title product. ESI-MS m / z: 381.2 [M+H] + .

[0145] Step 4 Preparation of methyl 4-fluoro-3-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)benzoate

[0146]

[0147] Charge methyl 4-fluoro-3-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)benzoate (8.5 g, 22.37 mmol) in 50 mL of ethanol, add 4M hydrochloric acid / dioxane solution (100 mL), argon protection, stir at room temperature overnight, concentrate, purify to give the title product. ESI-MS m / z: 251.2 [M+H] + .

[0148] Step 5 Preparation of (R)-(+)-citronellic acid

[0149]

[0150] Dissolve R-(+)-pulegone (50.0 g, 328.4 mmol) in 4 mol / L hydrogen chloride in 1,4-dioxane solution (164.2 mL, 656.8 mmol), stir at 30 °C overnight, after the reaction is complete, add the reaction system to 2 mol / L potassium hydroxide solution (350.0 mL) dropwise, and stir at room temperature for 3 h, then adjust the pH of the reaction system to 1 with 2.5 mol / L dilute hydrochloric acid, extract the aqueous phase with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to give the title compound. ESI-MS m / z: 169.2 [M-H] - .

[0151] Step 6. Preparation of (R)-(2,6-dimethylhept-5-en-1-yl) tert-butyl carbamate

[0152]

[0153] (R)-(+)-citronellic acid (12.0 g, 70.5 mmol), triethylamine (14.3 g, 141.0 mmol) were dissolved in toluene (75 mL), stirred at 50 °C, then diphenyl phosphorazide (23.3 g, 84.6 mmol) was added slowly, the temperature was raised to 70 °C and stirred for 4 h, tert-pentanol (28.0 g, 317.3 mmol) was added, the temperature was raised to 120 °C and stirred overnight, after the reaction was completed, the reaction system was cooled to room temperature, water was added to quench the reaction, ethyl acetate was used for extraction, anhydrous sodium sulfate was used for drying, and column chromatography was used for purification to obtain the title compound. ESI-MS m / z: 256.2 [M+H] + .

[0154] Step 7. Preparation of (R)-(5-hydroxy-2-methylpentyl) tert-butyl carbamate

[0155]

[0156] (R)-(2,6-dimethylhept-5-en-1-yl) tert-butyl carbamate (9.5 g, 37.2 mmol) was dissolved in methanol (95 mL), pre-cooled at -78 °C, ozone was passed into the reaction system, after the raw material was completely reacted, argon was passed into the reaction system for 15 min, sodium borohydride (2.8 g, 74.4 mmol) was added, the temperature was slowly raised to room temperature, and stirred overnight, after the reaction was completed, saturated aqueous solution of ammonium chloride was added to quench the reaction, most of the methanol was removed by rotary evaporation, ethyl acetate was used for extraction, anhydrous sodium sulfate was used for drying, and column chromatography was used for purification to obtain the title compound. ESI-MS m / z: 232.2 [M+H] + .

[0157] Step 8. Preparation of (R)-5-amino-4-methylpentan-1-ol hydrochloride

[0158]

[0159] (R)-(5-hydroxy-2-methylpentyl) tert-butyl carbamate (5.1 g, 22.0 mmol) was dissolved in methyl tert-butyl ether (38 mL), 4 mol / L hydrogen chloride solution in 1,4-dioxane (33.0 mL, 132.0 mmol) was added at room temperature, and stirred at room temperature overnight, after the reaction was completed, it was dried by rotary evaporation to obtain the title compound. ESI-MS m / z: 118.1 [M+H-HCl] + .

[0160] Step 9. Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol

[0161]

[0162] (R)-5-amino-4-methylpentan-1-ol hydrochloride (1.3 g, 8.5 mmol), and potassium carbonate (3.3 g, 23.9 mmol) were added into N,N-dimethylformamide (20 mL) and stirred at room temperature overnight. After the reaction was completed, water was added for dilution, and ethyl acetate was extracted. After drying over anhydrous sodium sulfate, the title compound was obtained by concentration. ESI-MS m / z: 317.1 [M+H] + .

[0163] Step 10. Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate

[0164]

[0165] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (2.9 g, 9.2 mmol) was dissolved in dichloromethane (25 mL), and triethylamine (1.4 g, 13.8 mmol) was added. Methanesulfonyl chloride (1.3 g, 11.0 mmol) was added under ice bath, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water was added for quenching. After drying over anhydrous sodium sulfate, the title compound was obtained by concentration. ESI-MS m / z: 395.0 [M+H] + .

[0166] Step 11. Preparation of methyl (R)-3-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-4-fluorobenzoate

[0167]

[0168] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 4.3 mmol), potassium carbonate (1.5 g, 10.9 mmol), and methyl 4-fluoro-3-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)benzoate (1.1 g, 4.4 mmol) were weighed into a 100 mL reaction flask, dissolved in 20 mL of N,N-dimethylformamide, and protected by argon. The mixture was heated at 60°C in an oil bath overnight. After the reaction was completed, water was added for dilution, and ethyl acetate was extracted. After drying over anhydrous sodium sulfate, the title compound was obtained by concentration. ESI-MS m / z: 549.4 [M+H] + .

[0169] Step 12 Preparation of (R)-3-(5-((5-(((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-4-fluorobenzoic acid ethyl ester

[0170]

[0171] (R)-3-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)-4-fluorobenzoic acid ethyl ester (2.36 g, 4.296 mmol), iron powder (2.63 g, 42.96 mmol), ammonium chloride (2.28 g, 42.96 mmol) were weighed into a reaction flask, dissolved in 10 ml and 50 ml of ethanol, and argon was protected, heated in an oil bath at 75 °C for 1.5 h until the reaction was complete. Filtered with diatomite, rotary evaporated. Diluted with water, extracted with dichloromethane, concentrated to obtain the target compound. ESI-MS m / z: 519.42 [M+H] + .

[0172] Step 13 Preparation of (R)-3-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)- 4-methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-4-fluorobenzoic acid methyl ester

[0173]

[0174] (R)-3-(5-((5-(((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)-4-fluorobenzoic acid ethyl ester (2.2 g, 4.1 mmol), cyanogen bromide (0.5 g, 4.9 mmol) were weighed into a 100 mL single-necked flask, dissolved in 4.4 mL of tert-butyl alcohol and 22 mL of dichloromethane, and argon was protected, stirred at room temperature for 10 h. After the reaction was completed, saturated sodium bicarbonate solution was quenched, extracted with dichloromethane, and concentrated to obtain the target compound. ESI-MS m / z: 544.43 [M+H] + .

[0175] Step 14 Preparation of (R)-3-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)- 4-methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-4-fluorobenzoic acid

[0176]

[0177] Methyl (R)-3-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4- methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-4-fluorobenzoate (2.1 g, 3.86 mmol), sodium hydroxide (0.62 g, 15.43 mmol) and 36 mL of water were added into 36 mL of tetrahydrofuran, which was protected by argon and stirred at room temperature for 1 h. After the reaction was completed, the tetrahydrofuran was evaporated by rotary evaporation, the pH was adjusted to 5 with 1 mol / L HCl, a large amount of solid appeared, and the solid was filtered and dried to obtain the target compound. ESI-MS m / z: 530.40 [M+H] + .

[0178] Step 15 (R,E)-5 6 -bromo-2 6 -fluoro-1 1 ,7-dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(4,5)-pyrazol-2(1,3)-benzocycloundecan-3-one

[0179]

[0180] (R)-3-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1- methyl-1H-pyrazol-4-yl)-4-fluorobenzoic acid (1.88 g, 3.54 mmol) was weighed into a reaction bottle, dissolved in 40 mL of dichloromethane, and then 2 mL of triethylamine was added. The reaction was protected by nitrogen and stirred at 0°C for 30 min. 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.37 g, 4.25 mmol) was added in batches, and after the addition was completed, the reaction was stirred at room temperature for 30 min. After the reaction was completed, a small amount of water was added for dilution, dichloromethane was used for extraction, and the target product was obtained after concentration. ESI-MS m / z: 512.38 [M+H] + .

[0181] Step 16 (R,E)-2 6 -fluoro-1 1 ,7-dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(4,5)-pyrazol-2(1,3)-benzocycloundecan-5 6 -formaldehyde

[0182]

[0183] Change (R,E)-5 6 -Br-2 6 -Fluorine-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(4,5)-pyrazole-2(1,3)-benzocycloundecane-3-one (0.26 g, 0.51 mmol), sodium formate (0.35 g, 5.1 mmol), and n-butyl-di(1-adamantyl)phosphine (0.043 g, 0.15 mmol) were added to a reaction flask and dissolved in 20 ml of anhydrous dichloromethane. Palladium acetate (0.02 g, 0.1 mmol) was added. 0.1 ml of formic acid and 0.24 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 1 h under argon protection. Triethylamine (0.26 g, 2.54 mmol) was added, and the reaction was carried out at 108-110°C for 5 h. The mixture was concentrated to obtain the title product. ESI-MS m / z: 462.2 [M+H] + .

[0184] Step 17 (R, E)-2 6 -Fluorine-1 1 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5-(4-methylpiperazin-1-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(4,5)-pyrazole-2(1,3)-benzocycloundecane-3-one

[0185]

[0186] Weigh (R,E)-2 6 -Fluorine-1 1 ,7-dimethyl-3-oxo-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(4,5)-pyrazole-2(1,3)-benzocycloundecane-5-(2,1)-dihydro-1-nitro-2-nitro-1 ...2-nitro-1-nitro-2-nitro-1-nitro- 6- Formaldehyde (0.14 g, 0.303 mmol), N-methylpiperazine (0.259 g, 2.59 mmol), glacial acetic acid (0.110 g, 1.83 mmol) were dissolved in a reaction vial with 10 mL of dichloromethane, argon protection, stirring at room temperature for 30 min, then sodium triacetoxyborohydride (0.206 g, 0.97 mmol) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, saturated sodium bicarbonate solution was added for neutralization, dichloromethane was extracted, dried over anhydrous sodium sulfate, and concentrated to obtain the title crude product. ESI-MS m / z: 546.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.90 (d, J = 7.3 Hz, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.47 (s, 2H), 7.33 (d, J = 10.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.38 (s, 1H), 4.20 (d, J = 12.7 Hz, 1H), 4.05 (s, 1H), 3.93 - 3.83 (m, 1H), 3.73 (d, J = 13.9 Hz, 4H), 3.58 (s, 2H), 2.77 (s, 1H), 2.46 - 2.40 (m, 3H), 2.28 (s, 3H), 2.19 (s, 1H), 1.47 (s, 2H), 1.22 (s, 4H), 0.80 (d, J = 5.8 Hz, 4H).

[0187] Example 2 (R,E)-2 6 - Fluoro-1 1 ,7- dimethyl-5 6 - ((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5 2 ,5 3 - dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(4,5)-pyrazol-2(1,3)- benzocycloundecan-3-one

[0188]

[0189] This synthetic route is the same as Example 1, except that N-methylpiperazine is replaced by 1-(oxetan-3-yl)piperazine hydrochloride, to obtain the title product. ESI-MS m / z: 588.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.90 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 5.2 Hz, 2H), 7.35 - 7.27 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 4.51 (t, J = 6.2 Hz, 2H), 4.40 (s, 2H), 4.20 (d, J = 12.7 Hz, 1H), 4.05 (s, 1H), 3.92 - 3.83 (m, 1H), 3.75 (s, 3H), 3.57 (s, 2H), 2.77 (s, 1H), 2.41 (s, 3H), 2.10-2.35 (m, 5H), 1.92 (s, 3H), 1.46 (d, J = 8.6 Hz, 1H), 1.23 (s, 2H), 0.80 (d, J = 6.1 Hz, 3H).

[0190] Example 3 (R,E)-2 5 ,2 6 -((4-methylpiperazin-1-yl)methyl)-5 1 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(4,5)-pyrazol-2(1,3)- benzocycloundecan-3-one

[0191]

[0192] The synthetic route was the same as Example 1, except that (2-fluoro-5- (methoxycarbonyl)phenyl)boronic acid was replaced by (2,3-difluoro-5- (methoxycarbonyl)phenyl)boronic acid to produce the title product. ESI-MS m / z: 564.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.70 (d, J = 4.6 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.68 (m, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.15 (d, J = 7.7 Hz, 1H), 4.37 (s, 1H), 4.19 (d, J = 12.9 Hz, 1H), 4.05 (s, 1H), 3.97 - 3.83 (m, 1H), 3.76 (s, 3H), 3.54 (s, 2H), 2.74 (s, 1H), 2.36 (s, 2H), 2.35 (s, 2H), 2.18 (s, 1H), 2.15 (s, 3H), 1.92 (s, 2H), 1.46 (s, 1H), 1.34 (s, 1H), 1.25 (s, 1H), 1.23 (s, 2H), 0.79 (d, J = 5.3 Hz, 3H).

[0193] Example 4 (R,E)-5 6 -((4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)- pyrazolocycloundecan-3-one

[0194]

[0195] Step 1 Preparation of 2-(5-hydroxy-l-methyl-lH-pyrazol-4-yl)-6-isonicotinic acid methyl ester hydrochloride

[0196]

[0197] Methyl 2-chloro-6-methylisonicotinate (25.0 g, 134.7 mmol), 1-methyl-5- hydroxypyrazole (17.2 g, 175.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (4.9 g, 175.1 mmol) and sodium carbonate (28.6 g, 269.4 mmol) were added to anisole (600 mL) and heated to 130 °C under argon protection with stirring for 12 h. After the reaction was completed, the reaction system was cooled to room temperature and filtered with diatomite. To the filtrate was added 4 mol / L hydrogen chloride solution in 1,4-dioxane (67.5 mL, 270.0 mmol) and stirred at room temperature for 1 h. The filtrate was concentrated to give the title compound. ESI-MS m / z: 248.1 [M+H-HCI]+ .

[0198] Step 2 Preparation of (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester

[0199]

[0200] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (3.1 g, 7.8 mmol), 2-(5-hydroxy-l-methyl-lH-pyrazol-4-yl)-6-isonicotinic acid methyl ester hydrochloride (2.2 g, 7.8 mmol) and potassium carbonate (3.2 g, 23.4 mmol) were added into N,N-dimethylformamide (25 mL), stirred at 60 °C overnight, after the reaction was completed, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, purified by column chromatography to give the title compound. ESI-MS m / z: 546.1 [M+H] + .

[0201] Step 3 Preparation of (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester

[0202]

[0203] (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-l-methyl- lH-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester (3.4 g, 6.2 mmol) was added into ethanol (30 mL), 6 mL of water was added, then iron powder (3.4 g, 62.3 mmol) and ammonium chloride (3.3 g, 62.3 mmol) were added, stirred at 75 °C for 2 h, after the reaction was completed, filtered, concentrated, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 516.2 [M+H] + .

[0204] Step 4 Preparation of (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)- 4-methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester

[0205]

[0206] Methyl (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (3.2 g, 6.2 mmol) was dissolved in dichloromethane (30 mL), added tert-butanol (6 mL) and cyanogen bromide (0.79 g, 7.5 mmol), stirred at 40 °C overnight, after the reaction was completed, saturated aqueous sodium bicarbonate solution was added to quench the reaction, the organic layer was separated after drying with anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 541.1 [M+H] + .

[0207] Step 5 Preparation of (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid

[0208]

[0209] Methyl (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (3.2 g, 5.9 mmol) was dissolved in tetrahydrofuran (30 mL), added 1 mol / L aqueous sodium hydroxide solution (30 mL), stirred at room temperature for 2 h, after the reaction was completed, the tetrahydrofuran was removed by rotary evaporation, adjusted to weakly acidic with 4 mol / L dilute hydrochloric acid, filtered, vacuum dried to give the title compound. ESI-MS m / z: 527.1 [M+H] + .

[0210] Step 6 Preparation of (R,E)-5 6 -bromo-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridine-l(4,5)-pyrazole cycloundecan-3-one

[0211]

[0212] (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1- methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (2.6 g, 4.9 mmol) was dissolved in dichloromethane (60 mL), triethylamine (2.0 g, 19.6 mmol) and 2-(1H-benzotriazole-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (1.9 g, 5.9 mmol) were added, stirred at room temperature for 3 h, after the reaction was completed, the reaction system was washed with water three times, the organic phase was dried over anhydrous sodium sulfate, column chromatography purification, the title compound was obtained. ESI-MS m / z: 509.1 [M+H] + .

[0213] Step 7 (R,E)-1 1 ,2 6 ,7-Trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-5 6 -formaldehyde

[0214]

[0215] Palladium acetate (0.013 g, 0.059 mmol), n-butyl bis(1-adamantyl)phosphine (0.042 g, 0.118 mmol) and sodium formate (0.667 g, 9.81 mmol) were placed in a reaction bottle, replaced with argon three times, (R,E)-5 6 -bromo-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-3-one (0.500 g, 0.982 mmol) in N,N-dimethylformamide (10 mL) and a mixture of formic acid (0.148 mL) and acetic anhydride (0.371 mL) were stirred at 30 °C for 1 h, triethylamine (0.497 g, 4.91 mmol) was added, and stirring was continued at 110 °C for 3 h, after the reaction was completed, diluted with ethyl acetate, washed with water three times, the organic phase was dried over anhydrous sodium sulfate, column chromatography purification, the title compound was obtained. ESI-MS m / z: 459.2 [M+H] + .

[0216] Step 8 (R,E)-5 6 -((4-fluoro-4-(hydroxymethyl)piperidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-l l-oxa-4-aza-5(2,l)-benzo[d]imidazol-2(2,4)-pyridine-l(4,5)- pyrazolo cyclo undecan-3-one

[0217]

[0218] This product synthesis was carried out using (R,E)-l 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-l l-oxa-4-aza-5(2,l)-benzo[d]imidazol-2(2,4)-pyridine-l(4,5)- pyrazolo cyclo undecan-5 6 formaldehyde, 4-fluoro-4-piperidinemethanol hydrochloride as starting material, following the procedure of Example 1, step 17, afforded the title product. ESI-MS m / z: 576.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.43 (s, 1H), 7.93 (s, 1H), 7.51-7.57 (m, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 5.31 (s, 1H), 4.93 (s, 1H), 4.35 (s, 1H), 4.21 (s, 1H), 3.95-3.98 (m, 2H), 3.73 (s, 2H), 3.57 (s, 8H), 2.78 (s, 3H), 2.21 (s, 2H), 1.91 (s, 2H), 1.64-1.68 (m, 2H), 1.48 (s, 1H), 1.23 (s, 3H), 0.81 (s, 2H).

[0219] Example 5 (R,2 7 Z,5 2 (E)-l 1 ,7-dimethyl-5 6 -((4-methylpiperazin-l-yl)methyl)-5 2 ,5 3 -dihydro-l 1 H,51 H-11-oxa-4-aza-2(8,6),5(2,1)-d i im idazo [1,2-a] pyridine-1(4,5)-pyrazolocycloundecan-3-one

[0220]

[0221] Preparation of Step 1 methyl 8-(5-hydroxy-l-methyl-lH-pyrazol-4-yl)imidazo[l,2- a]pyridine-6-carboxylate hydrochloride

[0222]

[0223] Methyl 8-bromoimidazo[l,2-a]pyridine-6-carboxylate (5 g, 19.6 mmol), l-methyl-5- hydroxypyrazole (5.76 g, 58.8 mmol), [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride (573 mg, 0.784 mmol) and sodium carbonate (6.3 g, 58.8 mmol) were added into a 250 mL single-neck flask, 100 mL of anhydrous benzene was added, and the reaction was stirred at 130 °C for 12 h under argon protection. After the reaction was completed, the reaction system was cooled to room temperature, and filtered with diatomite. The pH value of the filtrate was adjusted to about 5 by adding 4 mol / L hydrogen chloride solution in 1,4-dioxane, and stirred at room temperature for 1 h. The title compound was obtained by filtration. ESI-MS m / z: 273.2 [M+H-HCI] + .

[0224] Preparation of Step 2 (R)-(+)-citronellic acid

[0225]

[0226] R-(+)-p-menthene (50.0 g, 328.4 mmol) was dissolved in 4 mol / L hydrogen chloride solution in 1,4-dioxane (164.2 mL, 656.8 mmol), and stirred at 30 °C overnight. After the reaction was completed, the reaction system was added dropwise into 2 mol / L potassium hydroxide solution (350.0 mL), and stirred at room temperature for 3 h. The pH value of the reaction system was adjusted to 1 by 2.5 mol / L dilute hydrochloric acid, and the aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound. ESI-MS m / z: 169.2 [M-H] - .

[0227] Preparation of Step 3 tert-Butyl (R)-(2,6-dimethylhept-5-en-l-yl)carbamate

[0228]

[0229] (R)-(+)-citronellic acid (12.0 g, 70.5 mmol), triethylamine (14.3 g, 141.0 mmol) were dissolved in toluene (75 mL), stirred at 50 °C, then diphenyl phosphorazide (23.3 g, 84.6 mmol) was added slowly, the temperature was raised to 70 °C and stirred for 4 h, tert-pentanol (28.0 g, 317.3 mmol) was added, the temperature was raised to 120 °C and stirred overnight, after the reaction was completed, the reaction system was cooled to room temperature, water was added to quench the reaction, ethyl acetate was used for extraction, anhydrous sodium sulfate was used for drying, and column chromatography was used for purification to obtain the title compound. ESI-MS m / z: 256.2 [M+H] + .

[0230] Step 4 Preparation of tert-pentyl (R)-(5-hydroxy-2-methylpentyl)carbamate

[0231]

[0232] (R)-(2,6-dimethylhept-5-en-1-yl)carbamic acid tert-pentyl ester (9.5 g, 37.2 mmol) was dissolved in methanol (95 mL), pre-cooled at -78 °C, ozone was passed into the reaction system, after the raw material was completely reacted, argon was passed into the reaction system for 15 min, sodium borohydride (2.8 g, 74.4 mmol) was added, the temperature was slowly raised to room temperature, and stirred overnight, after the reaction was completed, saturated aqueous solution of ammonium chloride was added to quench the reaction, most of the methanol was removed by rotary evaporation, ethyl acetate was used for extraction, anhydrous sodium sulfate was used for drying, and column chromatography was used for purification to obtain the title compound. ESI-MS m / z: 232.2 [M+H] + .

[0233] Step 5 Preparation of (R)-5-amino-4-methylpentan-1-ol hydrochloride

[0234]

[0235] (R)-(5-hydroxy-2-methylpentyl)carbamic acid tert-pentyl ester (5.1 g, 22.0 mmol) was dissolved in methyl tert-butyl ether (38 mL), 4 mol / L hydrogen chloride solution in 1,4-dioxane (33.0 mL, 132.0 mmol) was added at room temperature, and stirred at room temperature overnight, after the reaction was completed, it was dried by rotary evaporation to obtain the title compound. ESI-MS m / z: 118.1 [M+H-HCl] + .

[0236] Step 6 Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol

[0237]

[0238] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (2.9 g, 9.2 mmol) was dissolved in dichloromethane (25 mL), triethylamine (1.4 g, 13.8 mmol) was added, under ice bath, methanesulfonyl chloride (1.3 g, 11.0 mmol) was added, stirred at room temperature for 2 h, after the reaction was completed, quenched with water, the organic phase was dried over anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 395.0 [M+H] + .

[0239] Step 7 Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate

[0240]

[0241] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (2.9 g, 9.2 mmol) was dissolved in dichloromethane (25 mL), triethylamine (1.4 g, 13.8 mmol) was added, under ice bath, methanesulfonyl chloride (1.3 g, 11.0 mmol) was added, stirred at room temperature for 2 h, after the reaction was completed, quenched with water, the organic phase was dried over anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 395.0 [M+H] + .

[0242] Step 8 Preparation of (R)-8-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester

[0243]

[0244] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (3.0 g, 7.6 mmol), 8-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]-pyridine-6-carboxylic acid methyl ester hydrochloride (2.3 g, 7.6 mmol) and potassium carbonate (2.6 g, 19 mmol) were added to a 100 mL reaction bottle, 30 mL of N,N-dimethylformamide was dissolved, stirred at 60°C overnight, after the reaction was completed, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, purified by column chromatography to give the title compound. ESI-MS m / z: 571.2 [M+H] + .

[0245] Step 9. Preparation of methyl (R)-8-(5-((5-((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-6-carboxylate

[0246]

[0247] Methyl (R)-8-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-6-carboxylate (1.0 g, 1.7 mmol) was added to a 100 mL reaction flask, dissolved in 20 mL of ethanol and 4 mL of water, iron powder (0.95 g, 17.2 mmol), ammonium chloride (0.91 g, 17.2 mmol) were added, stirred at 75 °C for 2 h, after the reaction was completed, filtered, concentrated, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 541.2 [M+H] + .

[0248] Step 10. Preparation of (R)-8-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester

[0249]

[0250] Methyl (R)-8-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-6-carboxylate (0.76 g, 1.4 mmol) was weighed into a reaction flask, dissolved in 10 mL of dichloromethane, tert-butanol (2 mL) and cyanogen bromide (0.22 g, 2.1 mmol) were added, stirred at room temperature overnight, after the reaction was completed, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated to give the title compound. ESI-MS m / z: 566.2 [M+H] + .

[0251] Step 11. Preparation of (R)-8-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-6-carboxylic acid

[0252]

[0253] (R)-8-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (0.87 g, 1.53 mmol) was weighed into a reaction flask and dissolved in tetrahydrofuran (15 mL). 1.3 mol / L aqueous sodium hydroxide solution (15 mL) was added and stirred at room temperature for 2 h. After the reaction, the mixture was concentrated under reduced pressure, the pH was adjusted to weak acidity with 4 mol / L dilute hydrochloric acid, the mixture was filtered, and vacuum dried to obtain the title compound. ESI-MS m / z: 552.2 [M+H] + .

[0254] Step 12 (R, 2 7 Z,5 2 E)-5 6 -Br-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0255]

[0256] (R)-8-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-6-carboxylic acid (0.85 g, 1.5 mmol) was weighed into a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (0.93 g, 9.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.98 g, 3.06 mmol) were added and stirred at room temperature for 1 h. After the reaction, the mixture was washed three times with water, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain the title compound. ESI-MS m / z: 534.2 [M+H] + .

[0257] Step 13 (R, 2 7 Z,5 2 E)-1 1 ,7-dimethyl-3-oxo-5 2 ,5 3 -Dihydro-1 1 H,5 1H- 11 -oxa-4-aza-2(8,6),5(2,1)-d iimidazo [1,2-a]pyridine- 1 (4,5)-pyrazolacycloundecan-5 6 - Preparation of formaldehyde

[0258]

[0259] Palladium acetate (0.036 g, 0.164 mmol), n-butyl bis(1-adamantyl)phosphine (0.088 g, 0.246 mmol), sodium formate (0.558 g, 8.2 mmol), (R,2 7 Z,5 2 E)-5 6 - Bromo-1 1 ,7- dimethyl-5 2 ,5 3 - Dihydro-1 1 H,5 1 H- 11 -oxa-4-aza-2(8,6),5(2,1)-d iimidazo [1,2-a]pyridine- 1 (4,5)-pyrazolacycloundecan-5 + .

[0260] Step 14 (R,2 7 Z,5 2 E)-1 1 ,7- dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 - Dihydro-1 1 H,5 1 H- 11 -oxa-4-aza-2(8,6),5(2,1)-d iimidazo [1,2-a]pyridine- 1 (4,5)-pyrazolacycloundecan-5

[0261]

[0262] (R,2 7 Z,5 2 E)-1 1 ,7- dimethyl-3-oxo-5 2 ,53 - dihydro-1 1 H, 5 1 H- 11 -oxa-4-aza-2(8,6),5(2,1)- diimidazo[1,2-a]pyridine-1 (4,5)-pyrazole cycloundecan-5 6 - formaldehyde (0.06 g, 0.124 mmol) was dissolved in 100 mL reaction bottle, 5 ml dichloromethane, 1-methylpiperazine (0.087 g, 0.87 mmol), glacial acetic acid (0.07 g, 1.13 mmol) and sodium triacetoxyborohydride (0.074 g, 0.35 mmol) were added in turn, stirred at room temperature overnight, after the reaction was completed, saturated aqueous sodium bicarbonate solution was used to quench the reaction, dichloromethane was added to dilute, washed with water three times, the organic phase was dried over anhydrous sodium sulfate, column chromatography purification, the title compound was obtained. ESI-MS m / z: 568.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.08 (s, 1H), 8.85 (s, 1H), 8.61 (s, 1H), 8.17 (s, 1H), 7.68 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.0 Hz, 1H), 4.49 (d, J = 12.8 Hz, 1H), 4.24 (d, J = 12.5 Hz, 1H), 4.03 (s, 1H), 3.97 - 3.87 (m, 1H), 3.77 (s, 3H), 3.67 (s, 2H), 3.07 (d, J = 7.3 Hz, 2H), 2.87 (s, 2H), 2.62 (s, 2H), 2.24 (s, 2H), 1.97 (s, 2H), 1.49 (d, J = 7.8 Hz, 1H), 1.32 (d, J = 14.8 Hz, 1H), 1.23 (s, 3H), 1.19 (d, J = 7.0 Hz, 1H), 0.83 (d, J = 5.5 Hz, 3H).

[0263] Example 6: (R,2 7 Z, 5 2 E)-5 6 -((4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methyl)-1 1 ,7-dimethyl-5 2 ,5 3 - dihydro-1 1 H, 5 1 H- 11 -oxa-4-aza-2(8,6),5(2,1)- diimidazo[1,2-a]pyridine-1 (4,5)-pyrazole cycloundecan-5

[0264]

[0265] Replace methylpiperazine with 4-fluoropiperidinemethanol hydrochloride and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 601.30 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),9.09(s,1H),8.85(s,1H),8.61(s,1H),8.18(s,1H),7.94(s,1H),7.6 8(s,1H),7.58(s,1H),7.42(s,1H),5.32(s,1H),5.18(s,1H),4.47(s,2H),4.28(d,J=11.8Hz,1H),4.04(s,1 H),3.84(s,1H),3.77(s,2H),3.69–3.56(m,1H),3.45(s,1H),3.08(s,3H),2.86(s,1H),2.24(s,1H),1.98(s ,2H),1.48(s,1H),1.32(d,J=15.1Hz,1H),1.23(s,2H),1.21(s,1H),1.19(s,1H),1.17(s,1H),0.85(s,3H).

[0266] Example 7 (R, 2 7 Z,5 2 E)-1 1 ,7-dimethyl-5 6 -((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-(4- ... 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazoloundecan-3-one

[0267]

[0268] Replace methylpiperazine with 1-(3-oxetanyl)piperazine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 610.30 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.67(s,1H),7.51 (d,J=5.0Hz,2H),7.19(s,1H),4.52(d,J=6.3Hz,2H),4.41(s,2H),4.24(d,J=12.5Hz,1H),4.03(s,1H),3.98– 3.86(m,1H),3.77(s,3H),3.61(d,J=16.0Hz,2H),3.08(d,J=5.1Hz,2H),2.86(s,2H),2.27-2.30(m,4H),1.9 7(s,2H),1.49(d,J=9.1Hz,1H),1.39–1.28(m,1H),1.23(s,2H),1.18(t,J=7.2Hz,1H),0.82(d,J=5.7Hz,3H).

[0269] Example 8 (R, 2 7 Z,5 2 E)-1 1 ,7-dimethyl-5 6 -(morpholinomethyl)-5-(morpholinomethyl)- 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0270]

[0271] Replace methylpiperazine with morpholine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 555.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.67(s, 1H),7.50(d,J=7.8Hz,2H),7.18(d,J=7.8Hz,1H),4.48(s,1H),4.23(d,J=13.0Hz,1H),4.03(s,1H), 3.99–3.90(m,1H),3.77(s,3H),3.59(s,2H),3.57(s,2H),2.86(s,1H),2.38(s,2H),2.23(s,1H),2 .06–1.90(m,2H),1.49(d,J=9.6Hz,1H),1.32(d,J=15.0Hz,2H),1.23(s,2H),0.83(t,J=8.9Hz,3H).

[0272] Example 9 (R, 2 7 Z,5 2 E)-5 6 -((4-ethylpiperazin-1-yl)methyl)-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0273]

[0274] Replace methylpiperazine with ethylpiperazine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 582.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.16(s,1H),7.67(s,1H),7.49(d ,J=5.4Hz,2H),7.16(d,J=8.1Hz,1H),4.47(s,1H),4.23(d,J=12.5Hz,1H),4.03(s,1H),3.98–3.86(m,1H),3.7 7(s,2H),3.61–3.50(m,2H),2.85(s,2H),2.38(s,2H),2.30(dd,J=14.3,7.2Hz,2H),2.25–2.11(m,2H),1.99(d ,J=17.1Hz,2H),1.49(d,J=9.4Hz,2H),1.34(s,1H),1.23(s,3H),0.97(t,J=7.0Hz,3H),0.83(t,J=9.0Hz,3H).

[0275] Example 10 (R, 2 7 Z,5 2 E)-5 6 -((4-cyclopropylpiperazin-1-yl)methyl)-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0276]

[0277] Replace methylpiperazine with cyclopropylpiperazine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 594.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),9.08(s,1H),8.86(s,1H),8.61(s,1H),8.18(s,1H),7.68(s,1H) ,7.52(s,1H),7.20(s,1H),6.65(s,1H),5.33(s,1H),4.48(s,1H),4.23(s,2H),4.03(s,1H),3.92(s,1 H),3.78(s,3H),3.54(s,2H),3.08(s,1H),2.86(s,1H),2.40–2.31(m,1H),2.25(s,1H),1.98(s,2H),1 .54-1.48(m,2H),1.34(s,1H),1.24(s,3H),1.20–1.14(m,1H),0.83(s,2H),0.41(s,2H),0.29(s,2H).

[0278] Example 11 (R, 2 7 Z,5 2 E)-5 6 -((4-acetylpiperazin-1-yl)methyl)-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0279]

[0280] Replace methylpiperazine with acetylpiperazine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 596.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.72(s,1H),9.08(s,1H),8.87(d,J=10.2Hz,1H),8.61(s,1H),8.18(s,1H) ,7.68(s,1H),7.61–7.47(m,2H),7.19(d,J=8.1Hz,1H),4.48(s,1H),4.22(d,J=12.1Hz,1H),4.02(s ,1H),3.98–3.88(m,1H),3.77(s,3H),3.60(s,2H),3.43(s,2H),3.22(s,1H),2.87(s,2H),2.38(s,2 H),2.33(s,2H),2.23(s,1H),1.98(s,3H),1.49(d,J=8.9Hz,1H),1.23(s,2H),0.83(t,J=8.3Hz,3H).

[0281] Example 12 (R, 2 7 Z,5 2 E)-5 6 -((4-isopropylpiperazin-1-yl)methyl)-1 1 ,7-dimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-oxa-4-aza-2(8,6),5(2,1)-diimidazo[1,2-a]pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0282]

[0283] Replace methylpiperazine with isopropylpiperazine and proceed according to step 14 of Example 5 to obtain the title compound. ESI-MS m / z: 596.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.08 (s, 1H), 8.86 (s, 1H), 8.62 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.30 - 7.12 (m, 1H), 6.69 (s, 1H), 4.48 (s, 1H), 4.22 (d, J = 13.0 Hz, 1H), 4.03 (s, 1H), 3.98 - 3.89 (m, 1H), 3.77 (s, 3H), 3.55 (s, 2H), 3.20 (s, 1H), 2.86 (s, 1H), 2.67 (s, 1H), 2.59 (s, 2H), 2.37-2.39 (m, 2H), 2.23 (s, 1H), 2.04 - 1.88 (m, 2H), 1.46 (d, J = 6.1 Hz, 1H), 1.34 (s, 1H), 1.23 (s, 6H), 0.95 (d, J = 5.4 Hz, 2H), 0.89 - 0.76 (m, 3H).

[0284] Examples 13-25 were synthesized according to the synthetic procedure of Examples 1-12 using different starting materials. The characterization parameters of Examples 13-25 are shown in Table 1:

[0285] Table 1:

[0286]

[0287]

[0288]

[0289] Comparative Example 1

[0290] The compound represented by the following formula (Compound A) was prepared according to the method disclosed in BI-4020 in Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors J. Med. Chem. 2019, 62, 22, 10272-10293, and identified by hydrogen spectrum and mass spectrum,

[0291]

[0292] Evaluation of in vitro cell activity of the compound of Experimental Example 1

[0293] 1. Experimental materials

[0294] Test compounds: the compounds of the application prepared in the above examples and compound A prepared in the comparative example, each of which was formulated into a 10 mM stock solution with DMSO, and finally diluted into 10 concentrations for testing, the final concentration of the compounds in the HCC3255 (L858R) cell experiment was 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.038 nM; the final concentration of the compounds in the HCC827 (del19) cell experiment was 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.457 nM, 0.152 nM; the final concentration of the compounds in the PC-9 (del19 / T790M / C797S) cell experiment was 2000 nM, 666.66 nM, 222.22 nM, 74.07 nM, 24.69 nM, 8.23 nM, 2.74 nM, 0.91 nM, 0.30 nM; the final concentration of the compounds in the NCI-H1975 (L858R / T790M) cell experiment was 25000 nM, 6250 nM, 1563 nM, 390.6 nM, 97.66 nM, 24.41 nM, 6.10 nM, 1.53 nM, 0.38 nM.

[0295] HCC3255 (L858R) cells were provided by Kanglong Huazheng (Beijing) New Drug Technology Co., Ltd. PC-9 (del19 / T790M / C797S), HCC827 (del19) cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. NCI-H1975 (L858R / T790M) cells were purchased from ATCC.

[0296] Reagents: epidermal growth factor (EGF) was purchased from the United States invitrogen company, the goods number is PHG0311; CellTiter-Glo Luminescent Cell Viability Assay was purchased from the United States Promega company, the goods number is G7573; Brigatinib was purchased from the United States Selleck company, the goods number is S8229; CCK-8 proliferation inhibition detection kit was purchased from the United States KeyGEN company, the goods number is KGA317-2.

[0297] 2. Experimental method

[0298] 2.1 Cell culture and subculture

[0299] (1) All cells were cultured according to the recommended method of ATCC, and the cells were in the exponential growth phase for the experiment.

[0300] (2) Cell culture medium:

[0301] HCC3255 (L858R) cells: 1640 media, 10% FBS, 1% pen-strep, 1% GlutaMax.

[0302] HCC827 (del19) cells: 1640 media, 10% FBS, 1% pen-strep.

[0303] PC-9 (del19 / T790M / C797S) cells: 1640 media, 10% FBS, 1% pen-strep, 2 ug / ml puromycin.

[0304] NCI-H1975 (L858R / T790M) cells: 1640 media, 10% FBS, 1% pen-strep.

[0305] (3) Cell culture conditions: 37 °C, 5% CO2, 95% air

[0306] (4) Change media or passage cells every 2-3 days depending on cell growth.

[0307] 2.2 Cell plating

[0308] HCC3255 (L858R) cells: Removed from cell culture flask and resuspended with fresh media. 30 pL of cell resuspension was plated into a 384 well culture plate, 800 cells / well.

[0309] HCC827 (del19) cells: Removed from cell culture flask and resuspended with fresh media. 100 pL of cell resuspension was plated into a 96 well culture plate, 5000 cells / well.

[0310] PC-9 (del19 / T790M / C797S) cells: Removed from cell culture flask and resuspended with fresh media. 100 pL of cell resuspension was plated into a 96 well culture plate, 2000 cells / well.

[0311] NCI-H1975 (L858R / T790M) cells: Removed from cell culture flask and resuspended with fresh media. 100 pL of cell resuspension was plated into a 96 well culture plate, 1000 cells / well.

[0312] 2.3 Dosing

[0313] HCC3255(L858R) cells: On the basis of the original culture medium (30 μL), 30 nL of different concentrations of drugs were added to the drug administration group, 30 nL of 10 mM Brigatinib was added to the PC group (positive control group), 30 nL of DMSO was added to the DMSO group, two duplicate wells were set for each concentration group, and they were placed in a 5% CO2 incubator for culture for 3 days. The compounds were prepared as follows: 1-2 mg of the compound was weighed in advance, and a 10 mM stock solution was prepared using DMSO. The drug was diluted with DMSO, and the drug concentration was diluted in a 1:3 gradient to 10 concentration gradients starting from 10 mM as the highest concentration, and the final concentration of the drug was: 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.038 nM.

[0314] HCC827(del19) cells: On the basis of the original old culture medium (100 μL), 100 μL of culture medium (1640 + 10% FBS + 1% penicillin streptomycin) containing different concentrations (2x) of drugs was added to the drug administration group, 100 μL of culture medium (1640 + 10% FBS + 1% penicillin streptomycin) was added to the blank group (without cells), 100 μL of DMSO-containing culture medium was added to the DMSO group, two duplicate wells were set for each concentration group, and they were placed in a 5% CO2 incubator for culture for 3 days. The compounds were prepared as follows: 1-2 mg of the compound was weighed in advance, and a 20 mM stock solution was prepared using DMSO. The drug was diluted with DMSO, and the drug concentration was diluted in a 1:2 gradient to 9 concentration gradients starting from 2000 nM as the highest concentration, and the final concentration of the drug was: 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.457 nM, 0.152 nM.

[0315] PC-9 (del19 / T790M / C797S) cells: To the original culture medium (100 μL), the drug group was treated with 100 μL of culture medium (1640 + 10% FBS + 1% penicillin-streptomycin + 2 μg / ml puromycin) containing varying concentrations (2×). The blank group (no cells) was treated with 100 μL of culture medium (1640 + 10% FBS + 1% penicillin-streptomycin + 2 μg / ml puromycin). The DMSO group was treated with 100 μL of DMSO-containing culture medium. Two replicate wells were set up for each concentration group and cultured in a 5% CO2 incubator for 3 days. Compounds were prepared as follows: 1-2 mg of compound was weighed in advance and prepared into a 20 mM stock solution in DMSO. The drug was diluted with DMSO, starting at 2000 nM and diluted in 1:2 gradient to 9 concentration gradients. The final concentrations were: 2000 nM, 666.67 nM, 222.22 nM, 74.07 nM, 24.67 nM, 8.23 ​​nM, 2.74 nM, 0.914 nM, and 0.305 nM.

[0316] NCI-H1975 (L858R / T790M) cells: In addition to the original culture medium (100 μL), the drug group was treated with 100 μL of culture medium (1640 + 10% FBS + 1% penicillin-streptomycin) containing different concentrations (2×). The blank group (no cells) was treated with 100 μL of culture medium (1640 + 10% FBS + 1% penicillin-streptomycin). The DMSO group was treated with 100 μL of DMSO-containing culture medium. Two replicate wells were set for each concentration group and cultured in a 5% CO2 incubator for 3 days. Compounds were prepared as follows: 1-2 mg of compound was weighed in advance and prepared into a 20 mM stock solution in DMSO. The drug was diluted with DMSO, starting at 2500nM and diluted in 1:3 gradient to 9 concentration gradients. The final concentrations were: 25000nM, 6250nM, 1563nM, 390.6nM, 97.66nM, 24.41nM, 6.10nM, 1.53nM, and 0.38nM.

[0317] 2.4 Detection

[0318] HCC3255(L858R) cells: After 3 days of drug treatment, CellTiter-Glo Luminescent Cell Viabillity Assay was taken out 30 min in advance and equilibrated to room temperature. Then 30 μL of Celltiter-Glo reagent was added to PC wells, dosing wells and DMSO wells, and shaken. After 30 min of incubation at 37°C in the dark with 5% CO2, the luminescent signal was detected. According to the LUM value, the inhibition rate of each well relative to the solvent control well was calculated: Inhibition (%) = 100- (LUM 给药孔 - LUM PC孔 ) / (LUM DMSO孔 - LUM PC孔 )*100. According to different drug concentrations and their corresponding inhibition rates, IC 50 curve drawing was performed using GraghPad 5.0 software, data was analyzed, and the final IC 50 value was obtained. The experimental results are shown in Table 2.

[0319] PC-9(del19 / T790M / C797S), HCC827(del19) cells: After 72 h of drug treatment, the culture medium in the wells was aspirated and dried as much as possible, 100 μL of complete medium to which CCK-8 had been added (CCK-8: medium = 1:10) was added, and the 96-well plate was placed in the incubator for a certain period of time. Then the 96-well plate was taken out of the incubator, equilibrated at room temperature for 5 min, and placed in a multifunctional plate reader to detect the absorbance (OD value) at 450 nm, and the cell proliferation inhibition rate was calculated. The calculation formula was Inhibition (%) = 100- (OD 实验孔 - OD 空白孔 ) / (OD DMSO孔 - OD 空白孔 )*100, according to different drug concentrations and their corresponding inhibition rates, IC 50 curve drawing was performed using GraghPad 5.0 software, data was analyzed, and the final IC 50 value was obtained. The experimental results are shown in Table 2.

[0320] NCI-H1975(L858R / T790M) cells: After 7 days of drug treatment, the culture medium in the wells was aspirated and dried as much as possible, 100 μL of complete medium to which CCK-8 had been added (CCK-8: medium = 1:10) was added, and the 96-well plate was placed in the incubator for a certain period of time. Then the 96-well plate was taken out of the incubator, equilibrated at room temperature for 5 min, and placed in a multifunctional plate reader to detect the absorbance (OD value) at 450 nm, and the cell proliferation inhibition rate was calculated. The calculation formula was Inhibition (%) = 100- (OD 实验孔 - OD空白孔 ) / (OD DMSO孔 -OD 空白孔 )*100, according to different drug concentrations and the corresponding inhibition rates, IC 50 values were obtained by using GraghPad 5.0 software for curve drawing, data analysis, and final IC 50 values. The experimental results are shown in Table 2.

[0321] 3. Experimental results

[0322] Table 2

[0323]

[0324]

[0325] “-” means not tested

[0326] From the above experimental results, it can be seen that the compound of the present application has good inhibitory activity on tumor cells of EGFR del19 / T790M / C797S mutation, L858R / T790M mutation, L858R mutation, and del19 mutation.

[0327] Although the present application has been described in detail above, those skilled in the art understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application. The scope of the present application is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating EGFR-mediated diseases.

4. The use according to claim 3, wherein the disease is a tumor disease.

5. The method of claim 4, wherein the disease is breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic system cancer, lymphoma, medulloblastoma, medulloblastoma, rectal adenocarcinoma, colon cancer, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, head and neck squamous cell carcinoma, brain cancer, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma, thyroid cancer, multiple myeloma or renal cell carcinoma.

6. The use according to claim 4, wherein the disease is bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, hepatocellular carcinoma, mantle cell lymphoma or triple-negative breast cancer.

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