Macrocyclic compounds as EGFR inhibitors and their applications

Abstract

The present invention belongs to the field of medicinal chemistry and relates to a class of macrocyclic compounds used as EGFR inhibitors and their applications. Specifically, the present invention provides compounds represented by formula (I) or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating EGFR-mediated diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to macrocyclic compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as EGFR inhibitors, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating EGFR-mediated diseases. Background Art

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. EGFR belongs to 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 and ErbB1. Mutations or overexpression generally cause tumors. EGFR is a glycoprotein, a tyrosine kinase receptor, which penetrates the cell membrane and has a molecular weight of 170KDa.

[0003] EGFR is associated with the proliferation, angiogenesis, invasion, metastasis and inhibition of apoptosis of tumor cells. Studies have shown that EGFR is highly expressed or abnormally expressed in solid tumors such as glial cells, renal cancer, lung cancer, prostate cancer, pancreatic cancer, and breast cancer. Currently, about 30% to 40% of Asian NSCLC patients carry EGFR mutations when diagnosed.

[0004] Common mutations of EGFR can be divided into two categories. One is drug-sensitive mutations, that is, anti-tumor targeted drugs can be used after mutation, such as exon 19 deletion and exon 21 L858R mutation; the other is drug-resistant mutations, that is, resistance to certain anti-tumor targeted drugs after mutation, such as exon 20 T790M mutation and exon 20 C797S mutation. AZD9291 (osimertinib) is an oral small molecule third-generation EGFR-TKI and the first lung cancer drug targeting EGFR T790M mutation, but some benefited patients developed drug resistance after 9 to 14 months of treatment. Studies have found that up to 40% of drug-resistant patients are resistant to osimertinib due to EGFR_C797S point mutations. Further mechanism studies have shown that the point mutation of EGFR_C797S converts cysteine ​​at position 797 to serine, resulting in the inability of osimertinib to form a covalent bond with the target protein. C797S is an important cause of resistance to the third-generation drug osimertinib. Currently, there is a lack of EGFR inhibitors that are effective against the new mutation (C797S) alone in clinical practice, so there is a need to develop a new generation of EGFR inhibitors targeting C797S mutations. Summary of the invention

[0005] One object of the present invention is to provide a class of compounds having EGFR inhibitory activity represented by general formula (I) or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs,

[0006]

[0007] in,

[0008] Cy is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl-heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl-heteroaryl are optionally substituted with one or more groups selected from halogen, hydroxy, 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;

[0009] L is selected from a chemical bond, -S-, -O-, -CH2-, -CH2CH2, -C(O)-, -S(O)-, -S(O)2-, Where R 4 , R 5 independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

[0010] R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, and dialkylamino; and

[0011] R 2 , R 3 Independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and cycloalkyl.

[0012] Another object of the present invention is to provide a method for preparing the compound of general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.

[0013] Another object of the present invention is to provide a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, as well as a composition comprising a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another one or more drugs.

[0014] Another object of the present invention is to provide a method for treating EGFR-mediated diseases using the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, as well as the use of the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs in the preparation of drugs for treating EGFR-mediated diseases.

[0015] In view of the above-mentioned invention object, the present invention provides the following technical solutions:

[0016] In a first aspect, the present invention provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

[0017]

[0018] in,

[0019] Cy is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl-heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclyl-heteroaryl are optionally substituted with one or more groups selected from halogen, hydroxy, 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;

[0020] L is selected from a chemical bond, -S-, -O-, -CH2-, -CH2CH2, -C(O)-, -S(O)-, -S(O)2-, Where R 4 , R 5 independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

[0021] R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, and dialkylamino; and

[0022] R 2 , R 3 Independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and cycloalkyl.

[0023] In some preferred embodiments, the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

[0024] 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, the 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 are optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, 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 Alkyl acyl, hydroxyl C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, 3-12 membered heterocyclic acyl, C 3-12 radical substitution with cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl and oxo;

[0025] Further preferably, Cy is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclyl and 5-10 membered heteroaryl, the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, C1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxyl C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, 3-8 membered heterocyclic acyl, C 3-8 Substitution by cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo;

[0026] More preferably, 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, wherein Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered heterocyclyl and 4-8 membered heterocyclyl and 5-8 membered heteroaryl, and is optionally substituted by one or more selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxyl C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, 3-8 membered heterocyclic acyl, C 3-8 The alkyl radicals are substituted with cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl and oxo.

[0027] In some specific embodiments, according to the compound of general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azacyclyl and 4-8 membered azacyclyl 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, oxirane, aziridine, oxetanyl, azetidinyl and oxo groups.

[0028] In some preferred embodiments, the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

[0029] R 1 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 Alkylamino;

[0030] More preferably, R 1 Selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino;

[0031] More preferably, R 1 is selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino.

[0032] In some preferred embodiments, the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

[0033] R 2 , R 3 are independently selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, single C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and C 3-6 Cycloalkyl;

[0034] More preferably, R 2 , R 3 independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, amino, methyl, ethyl, propyl, halo 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, single C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and C 3-6 Cycloalkyl.

[0035] In some preferred embodiments, the present invention 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 (II),

[0036]

[0037] Among them, R 1 , R 3, Cy, and L have the definitions given above in the general formula (I).

[0038] In some preferred embodiments, according to the compound of general formula (I) or general formula (II) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein L is selected from a chemical bond, -CH2-, -CH2CH2, -C(O)-, -S(O)2-,

[0039] In some embodiments, according to the compound of the general formula (I) or general formula (II) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein Cy is selected from It is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, 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 Alkyl acyl, hydroxyl C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, 3-12 membered heterocyclic acyl, C 3-12 The cycloalkyl group may be substituted with a 3- to 12-membered heterocyclic group, a 6- to 12-membered aryl group, a 5- to 12-membered heteroaryl group, and an oxo group.

[0040] In some preferred embodiments, according to the compound of general formula (I) or general formula (II) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein Cy-L is selected from

[0041] In some embodiments, the present invention 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),

[0042]

[0043] Where R 1 , R 2 , R 3 , L has the definition as described in the above general formula (I), Ring A is selected from 3-12-membered azacycloalkyl, 3-12-membered diazacycloalkyl, 3-12-membered azacyclyl, 3-12-membered diazacyclyl, 5-12-membered azaaryl, R 6 Each R is independently selected from halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, n is 1, 2, 3, 4, 5 or 6; or two R 6 Together with the atoms to which they are attached they form a 3-12 membered azacycloalkyl, a 3-12 membered diazacycloalkyl, a 3-12 membered azacyclyl, a 3-12 membered diazacyclyl, a 5-12 membered azaaryl, a 3-12 membered oxacycloalkyl, a 3-12 membered dioxacycloalkyl, a 3-12 membered oxacyclyl, a 3-12 membered dioxacyclyl or a 5-12 membered oxaaryl, which is optionally substituted with a group selected from halogen, hydroxy, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

[0044] In some embodiments, according to the compound represented by formula (III) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azacyclyl, 3-8 membered diazacyclyl, 5-12 membered azaaryl, R 6 Each independently selected from halogen, hydroxyl, carboxyl, cyano, amino, C 2-6 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, single C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 heterocycloalkyl, n is 2, 3 or 4; or two R 6Together with the atoms to which they are attached, they form a 3-8-membered azacycloalkyl, a 3-8-membered diazacycloalkyl, a 3-8-membered azacyclyl, a 3-8-membered diazacyclyl, a 5-12-membered azaaryl, a 3-8-membered oxacycloalkyl, a 3-8-membered dioxacycloalkyl, a 3-8-membered oxacyclyl, a 3-8-membered dioxacyclyl or a 5-12-membered oxaaryl, which is optionally selected from halogen, hydroxy, carboxyl, cyano, amino, C 2-6 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, single C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl and C 3-8 The alkylene group is substituted with a heterocycloalkyl group.

[0045] In some embodiments, according to the compound represented by formula (III) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azacyclyl, 3-8 membered diazacyclyl, 5-12 membered azaaryl, R 6 Each independently selected from halogen, hydroxyl, carboxyl, cyano, amino, C 2-6 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, single C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 heterocycloalkyl, n is 2, 3 or 4; or two R 6Together with the atoms to which they are attached, they form a 3-8 membered azacycloalkyl, a 3-8 membered diazacycloalkyl, a 3-8 membered azacyclyl, a 3-8 membered diazacyclyl, a 5-12 membered azaaryl, a 3-8 membered oxacycloalkyl, a 3-8 membered dioxacycloalkyl, a 3-8 membered oxacyclyl, a 3-8 membered dioxacyclyl or a 5-12 membered oxaaryl, which is optionally substituted with one or more groups selected from fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxacyclopropyl, aziridine, oxetanyl, azetidinyl, and oxo groups.

[0046] In some embodiments, according to the compound represented by formula (III) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein ring A is selected from R 6 Each R is independently selected from 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, oxirane, aziridine, oxetanyl, azetidinyl, oxo, and n is 2, 3 or 4; or two R 6 Together with the atoms to which they are attached, they form a 3-8 membered azacycloalkyl, a 3-8 membered diazacycloalkyl, a 3-8 membered azacyclyl, a 3-8 membered diazacyclyl, a 5-12 membered azaaryl, a 3-8 membered oxacycloalkyl, a 3-8 membered dioxacycloalkyl, a 3-8 membered oxacyclyl, a 3-8 membered dioxacyclyl or a 5-12 membered oxaaryl, which is optionally substituted with one or more groups selected from fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxacyclopropyl, aziridine, oxetanyl, azetidinyl, and oxo groups.

[0047] The present invention provides the following specific compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs:

[0048]

[0049]

[0050] In another aspect, the present invention provides a method for preparing a compound of the general formula (I) of the present invention, comprising:

[0051]

[0052] 1) The compound of formula 3 can be prepared by reacting the compound of formula 1 with the compound of formula 2,

[0053] 2) The compound of formula 4 can be prepared by reacting the compound of formula 3,

[0054] 3) The compound of formula 6 can be prepared by reacting the compound of formula 4 with the compound of formula 5,

[0055] 4) The compound of formula 7 can be prepared by reducing the compound of formula 6,

[0056] 5) The compound of formula 8 can be prepared by reacting the compound of formula 7,

[0057] 6) The compound of formula 9 can be prepared by hydrolysis of the compound of formula 8,

[0058] 7) The compound of formula 10 can be prepared by reacting the compound of formula 9,

[0059] 8) The compound of formula (I) can be prepared by reacting the compound of formula 10.

[0060] Among them, R 1 , R 2 , R 3 , Cy, and L have the definitions given in the general formula (I). The compounds of formula (2) and formula (5) are commercially available compounds or can be synthesized by other technical means commonly used by those skilled in the art.

[0061] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof.

[0062] In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the compound or pharmaceutical composition is used to treat an EGFR-mediated disease.

[0063] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.

[0064] The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, suitable for oral or parenteral administration. The method of administration includes, but is not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The preparation can be administered by any route, such as by infusion or push injection, by the route of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art, and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0065] In a fourth aspect, the present invention provides a method for treating EGFR-mediated diseases using a compound represented by formula (I), (II) or (III) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same, as well as use of the compound in the preparation of a drug for treating EGFR-mediated diseases.

[0066] In some preferred embodiments, the present invention provides a method for treating EGFR-mediated diseases and a use of a compound represented by formula (I), (II) or (III) of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same in the preparation of a drug for treating EGFR-mediated diseases, wherein the EGFR-mediated diseases include but are not limited to: cancer, proliferative diseases, metabolic diseases or blood diseases. In some embodiments, the EGFR-mediated disease of the present invention is cancer.

[0067] In some preferred embodiments, the present invention provides a compound represented by general formula (I), (II) or (III) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition comprising the same for use in a method for treating EGFR-mediated diseases and in the preparation of a medicament for treating EGFR-mediated diseases, wherein the EGFR-mediated diseases include but are not limited to: breast cancer, esophageal cancer, bladder cancer, lung cancer (e.g., bronchial cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, 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, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple-negative breast cancer.

[0068] The compounds of the present invention have specific tyrosine kinase inhibitory activity against mutant drug-resistant EGFR, such as del19, T790M, C797S, and L858R mutant drug-resistant EGFR. As a specific tyrosine kinase inhibitor of mutant drug-resistant EGFR, it has a good preventive and / or therapeutic effect on diseases mediated by drug-resistant mutant EGFR, such as cancer, proliferative diseases, metabolic diseases, or blood diseases. In some embodiments, the mutant drug-resistant EGFR is a triple mutation of Del19 / T790M / C797S or L858R / T790M / C797S. In other embodiments, the mutant drug-resistant EGFR is a primary or secondary mutation of del19 / T790M, L858R / T790M, L858R, or del19.

[0069] Definition of terms

[0070] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0071] The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium and deuterium, and isotopes of carbon include 12 C. 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc.

[0072] The "isomer" of the present invention refers to a molecule with the same atomic composition and connection mode, but different three-dimensional spatial arrangement, 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, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefix D, L or (+), (-) is used to name the sign of rotation of plane polarized light of the compound, (-) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed. The chemical structure of these stereoisomers is the same, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0073] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0074] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0075] The "halogen" of the present invention refers to fluorine, chlorine, bromine, and iodine. The "halogenated" of the present invention refers to substitution with fluorine, chlorine, bromine, or iodine.

[0076] The "alkyl" of the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group containing 1 to 6 carbon atoms, and further preferably a straight or branched group containing 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

[0077] The -C(O)- group of the present invention refers to a "carbonyl group".

[0078] The -S(O)2- group of the present invention means a "sulfonyl group".

[0079] The "haloalkyl group" of the present invention refers to an alkyl group substituted with at least one halogen.

[0080] The "hydroxyalkyl group" of the present invention refers to an alkyl group substituted with at least one hydroxy group.

[0081] The "alkoxy" of the present invention refers to -O-alkyl. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

[0082] The "cycloalkyl" of the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0083] "Heterocyclyl" of the present invention refers to a group of a 3- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, each of which 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 long as the valence permits. The heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system (also known as a "bicyclic heterocyclyl")) and can be saturated or partially unsaturated. Suitable heterocyclyl groups include, but are not limited to, piperidinyl, azetidinyl, aziridine, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Each example of heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

[0084] The "aryl" of the present invention refers to an aromatic system that may contain a monocyclic or fused polycyclic ring, preferably a monocyclic or 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, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any usable point of attachment.

[0085] The "heteroaryl" of the present invention refers to an aromatic group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-12 atoms (5-12-membered heteroaryl), and more preferably composed of 5-10 atoms (5-10-membered heteroaryl), wherein the heteroatom is O, S, or N. The heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, etc. The heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

[0086] The "pharmaceutically acceptable salt" of the present invention refers to the salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity.

[0087] The "solvate" of the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense. The solvent refers to a solvent known to or easily determined by a person skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative thereof.

[0088] The in vivo effects of the compounds of formula (I) may be partially exerted by one or more metabolites formed in the human or animal body after the compound of formula (I) is administered. As described above, the in vivo effects of the compounds of formula (I) may also be exerted via the metabolism of precursor compounds ("prodrugs"). "Prodrugs" of the present invention refer to compounds that are converted into compounds of the present invention under physiological conditions in an organism due to reactions with enzymes, gastric acid, etc., i.e., compounds that are converted into compounds of the present invention by oxidation, reduction, hydrolysis, etc. of enzymes and / or compounds that are converted into compounds of the present invention by hydrolysis reactions of gastric acid, etc.

[0089] The term "crystalline" in the present invention refers to a solid whose internal structure is formed by regularly repeating constituent atoms (or groups thereof) in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure.

[0090] The "pharmaceutical composition" of the present invention refers to a mixture comprising any one of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and / or one or more other 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 drug for the treatment and / or prevention of a disease mediated by one or more kinases.

[0091] The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that 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, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention. Some examples of pharmaceutically acceptable carriers 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 carboxymethylcellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.

[0092] The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

[0093] The "EGFR WT" of the present invention is wide type EGFR, i.e., wild-type EGFR. The "EGFR (del19 / T790M / C797S)" of the present invention is del19 / T790M / C797S mutated EGFR. DETAILED DESCRIPTION

[0094] The present invention is further described in detail below in conjunction with the examples, but the present invention is not limited to these examples. The materials used in the following examples are commercially available unless otherwise specified.

[0095] Example 1 (R, E)-5 6 -(4-cyclopropylpiperazine-1-carbonyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0096]

[0097] Step 1 Preparation of 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-isonicotinic acid methyl ester hydrochloride

[0098]

[0099] Add 2-chloro-6-methylisonicotinic acid methyl ester (25.0g, 134.7mmol), 1-methyl-5-hydroxypyrazole (17.2g, 175.1mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (4.9g, 6.7mmol) and sodium carbonate (28.6g, 269.4mmol) to anisole (600mL), and heat and stir at 130℃ for 12h under argon protection. After the reaction, the reaction system was cooled to room temperature and filtered with diatomaceous earth. A 4mol / L hydrogen chloride solution in 1,4-dioxane (67.5mL, 270.0mmol) was added to the filtrate, and stirred at room temperature for 1h, concentrated and filtered to obtain the title compound. ESI-MS m / z: 248.1[M+H-HCl] + .

[0100] Step 2 Preparation of (R)-(+)-3,7-dimethyl-6-octenoic acid

[0101]

[0102] Dissolve (R)-(+)-5-methyl-2-(prop-2-ylidene)cyclohexanone (50.0 g, 328.4 mmol) in 4 mol / L hydrogen chloride 1,4-dioxane solution (164.2 mL, 656.8 mmol), stir overnight at 30°C, add 2 mol / L potassium hydroxide solution (350.0 mL) dropwise to the reaction system after the reaction is complete, and stir at room temperature for 3 h. 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 obtain the title compound. ESI-MSm / z: 169.2 [MH] - .

[0103] Step 3 Preparation of tert-amyl (R)-(2,6-dimethylhept-5-en-1-yl)carbamate

[0104]

[0105] Dissolve (R)-(+)-3,7-dimethyl-6-octenoic acid (12.0 g, 70.5 mmol) and triethylamine (14.3 g, 141.0 mmol) in toluene (75 mL), move to 50°C and stir, then slowly add diphenylphosphoryl azide (23.3 g, 84.6 mmol), heat to 70°C and stir for 4 h, add tert-amyl alcohol (28.0 g, 317.3 mmol), heat to 120°C and stir overnight, after the reaction is completed, cool the reaction system to room temperature, add water to quench the reaction, extract with ethyl acetate, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound. ESI-MS m / z: 256.2 [M+H] + .

[0106] Step 4 Preparation of tert-amyl (R)-(5-hydroxy-2-methylpentyl)carbamate

[0107]

[0108] Dissolve (R)-(2,6-dimethylhept-5-en-1-yl)carbamic acid tert-amyl ester (9.5 g, 37.2 mmol) in methanol (95 mL), pre-cool at -78 °C, pass ozone into the reaction system, pass argon into the reaction system for 15 min after the reaction of the raw materials, add sodium borohydride (2.8 g, 74.4 mmol), slowly warm to room temperature, and stir overnight. After the reaction is completed, add a saturated aqueous solution of ammonium chloride to quench the reaction, rotary evaporate most of the methanol, extract with ethyl acetate, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound. ESI-MS m / z: 232.2 [M+H] + .

[0109] Step 5 Preparation of (R)-5-amino-4-methylpentyl-1-ol hydrochloride

[0110]

[0111] Dissolve (R)-(5-hydroxy-2-methylpentyl)carbamic acid tert-amyl ester (5.1 g, 22.0 mmol) in methyl tert-butyl ether (38 mL), add 4 mol / L hydrogen chloride 1,4-dioxane solution (33.0 mL, 132.0 mmol) at room temperature, stir overnight at room temperature, and after the reaction is completed, spin dry to obtain the title compound. ESI-MS m / z: 118.1 [M+H-HCl] + .

[0112] Step 6 Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol

[0113]

[0114] 2-Fluoro-4-bromonitrobenzene (1.7 g, 7.7 mmol), (R)-5-amino-4-methylpentyl-1-ol hydrochloride (1.3 g, 8.5 mmol) and potassium carbonate (3.3 g, 23.9 mmol) were added to N,N-dimethylformamide (20 mL) and stirred at room temperature overnight. After the reaction was completed, water was added for dilution, ethyl acetate was extracted, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound. ESI-MS m / z: 317.1 [M+H] + .

[0115] Step 7 Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate

[0116]

[0117] Dissolve (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (2.9 g, 9.2 mmol) in dichloromethane (25 mL), add triethylamine (1.4 g, 13.8 mmol), add methanesulfonyl chloride (1.3 g, 11.0 mmol) in an ice bath, stir at room temperature for 2 h, after the reaction is completed, add water to quench, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain the title compound. ESI-MSm / z: 395.0 [M+H] + .

[0118] Step 8 Preparation of (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0119]

[0120] (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (3.1 g, 7.8 mmol), 2-(5-hydroxy-1-methyl-1H-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 to N,N-dimethylformamide (25 mL) and stirred at 60°C overnight. After the reaction was completed, water was added for dilution, ethyl acetate was extracted, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound. ESI-MS m / z: 546.1 [M+H] + .

[0121] Step 9 Preparation of (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0122]

[0123] Add (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester (3.4 g, 6.2 mmol) to ethanol (30 mL), add 6 mL of water, then add iron powder (3.4 g, 62.3 mmol) and ammonium chloride (3.3 g, 62.3 mmol), stir at 75 ° C for 2 h, after the reaction is completed, filter, concentrate, dilute with water, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound. ESI-MS m / z: 516.2 [M+H] + .

[0124] Step 10 Preparation of (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-isonicotinic acid methyl ester

[0125]

[0126] Dissolve (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester (3.2 g, 6.2 mmol) in dichloromethane (30 mL), add tert-butyl alcohol (6 mL) and cyanogen bromide (0.79 g, 7.5 mmol), stir overnight at 40°C, after the reaction is completed, add saturated sodium bicarbonate aqueous solution to quench the reaction, separate the organic layer, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound. ESI-MS m / z: 541.1 [M+H] + .

[0127] Step 11 Preparation of (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

[0128]

[0129] Dissolve (R)-2-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-isonicotinic acid methyl ester (3.2 g, 5.9 mmol) in tetrahydrofuran (30 mL), add 1 mol / L sodium hydroxide aqueous solution (30 mL), stir at room temperature for 2 h, after the reaction is completed, concentrate and rotary evaporate tetrahydrofuran, adjust pH to weak acidity with 4 mol / L dilute hydrochloric acid, filter, and vacuum dry to obtain the title compound. ESI-MS m / z: 527.1[M+H] + .

[0130] Step 12 (R, E)-5 6 -Bromo-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0131]

[0132] (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), and triethylamine (2.0 g, 19.6 mmol) and 2-(1H-benzotriazol L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.9 g, 5.9 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, the reaction system was washed three times with water, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound. ESI-MS m / z: 509.1[M+H] + .

[0133] Step 13 (R, E)-1 1 ,2 6 ,7-Trimethyl-3-oxo-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxo-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)pyrazolocyclopentane-5-nitropropane 6 - Preparation of carboxylic acids

[0134]

[0135] Palladium acetate (0.011 g, 0.047 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 g, 0.047 mmol) were placed in a reaction flask, the argon atmosphere was replaced three times, formic acid (0.254 g, 5.5 mmol) and ((R,E)-5 6 -Bromo-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 -Dihydro-1 1 H, 5 1 A solution of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one (0.400 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added with dicyclohexylcarbodiimide (0.033 g, 0.16 mmol) and triethylamine (0.160 g, 1.58 mmol), and stirred at 100°C for 3 h. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography to obtain the title compound. ESI-MS m / z: 475.2[M+H] + .

[0136] Step 14 (R, E)-56 -(4-cyclopropylpiperazine-1-carbonyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0137]

[0138] (R,E)-1 1 ,2 6 ,7-Trimethyl-3-oxo-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxo-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)pyrazolocyclopentane-5-nitropropane 6 -carboxylic acid (0.085 g, 0.179 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.036 g, 0.358 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.035 g, 0.179 mmol), 1-hydroxybenzotriazole (0.024 g, 0.179 mmol) and 1-cyclopropylpiperazine (0.022 g, 0.179 mmol) were added in sequence. The mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound. 1H NMR (400MHz, CDCl3) δ8.44(s,1H),8.12(s,1H),7.62(s,1H),7.37(s,1H),7.31(d,J=8.1Hz,1H),7.24( s,1H),4.43(dd,J=13.0,8.4Hz,1H),4.33(d,J=13.2Hz,1H),3.90–3.83(m,1H),3.79–3.63(m,6H),3.2 7–3.16(m,2H),2.86–2.76(m,1H),2.64–2.48(m,6H),2.34–2.27(m,1H),2.19(s,3H),1.96–1.85(m,1H ),1.74–1.67(m,1H),1.63(s,1H),1.54–1.43(m,1H),1.20(t,J=7.2Hz,1H),0.49–0.36(m,4H).ESI-MS m / z:583.3[M+H] + .

[0139] Example 2 (R, E)-5 6 -(3-Hydroxy-3-methylazetidine-1-carbonyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0140]

[0141] The preparation method is the same as that of Example 1, except that the raw material 1-cyclopropylpiperazine is replaced by 3-methyl-3-acridinol hydrochloride to obtain the title compound. 1H NMR (400MHz, CDCl3) δ8.42(s,1H),8.12(s,1H),7.65(d,J=21.1Hz,2H),7.43(d,J=7.7Hz,1 H),7.30(d,J=6.4Hz,1H),4.47–4.38(m,1H),4.34(d,J=12.2Hz,2H),4.19(s,3H),3.90–3. 81(m,1H),3.81–3.66(m,4H),2.87–2.73(m,1H),2.60(s,3H),2.29–2.18(m,1H),2.14–2.0 3(m,1H),1.97–1.87(m,1H),1.82–1.74(m,1H),1.59(s,3H),0.89(d,J=5.0Hz,3H).ESI-MS m / z:544.3[M+H] + .

[0142] Example 3 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -((((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0143]

[0144] Step 1(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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-5 6 -Preparation of formaldehyde

[0145]

[0146] Palladium acetate (0.013 g, 0.059 mmol), n-butyl di(1-adamantyl) phosphine (0.042 g, 0.118 mmol) and sodium formate (0.667 g, 9.81 mmol) were placed in a reaction flask, the argon atmosphere was replaced three times, and (R,E)-56 -Bromo-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 A solution of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-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, it was diluted with ethyl acetate, washed with water three times, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain the title compound. ESI-MS m / z: 459.2[M+H] + .

[0147] Step 2 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -((((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0148]

[0149] (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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-5 6-Formaldehyde (0.080 g, 0.175 mmol) and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride (0.070 g, 0.350 mmol) were dissolved in dichloromethane (10 mL), and triethylamine (0.071 g, 0.70 mmol), glacial acetic acid (0.106 g, 1.75 mmol) and sodium triacetoxyborohydride (0.112 g, 0.525 mmol) were added in sequence. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and dichloromethane was added to dilute the mixture. The mixture was washed with water three times, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain the title compound. 1 H NMR(400MHz, CDCl3)δ8.65(s,1H),8.48(s,1H),8.15(s,1H),7.66(s,1H),7.31–7.27(m,1 H),7.24–7.20(m,1H),4.53–4.42(m,1H),4.36(d,J=12.9Hz,1H),3.94–3.85(m,1H),3.79 (s,3H),3.74–3.59(m,3H),3.48(s,2H),2.88–2.73(m,3H),2.70–2.59(m,5H),2.55(s,3H ),2.32–2.22(m,1H),2.15–1.92(m,6H),1.58–1.47(m,1H),0.91(d,J=6.3Hz,3H).ESI-MS m / z:569.3[M+H] + .

[0150] Example 4 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(((6-methyl-2,6-diazaspiro[3.3]hept-2-yl)methyl)-5-(((6-methyl-2,6-diazaspiro[3.3]hept-2-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,2)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0151]

[0152] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 2-methyl-2,6-diazaspiro[3.3]heptane hydrochloride to obtain the title compound. 1HNMR(400MHz, CDCl3)δ8.47(d,J=4.3Hz,2H),8.15(s,1H),7.65(s,1H),7.24(s,1H),7.1 0(d,J=7.8Hz,1H),4.50–4.43(m,1H),4.34(d,J=13.0Hz,1H),3.92–3.85(m,1H),3.82–3 .65(m,10H),3.44(s,4H),2.90–2.78(m,1H),2.64(s,3H),2.54(s,3H),2.31–2.20(m,1H ),2.17–2.08(m,1H),2.00–1.88(m,1H),1.57–1.46(m,1H),0.90(d,J=6.0Hz,3H).ESI-MS m / z:555.3[M+H] + .

[0153] Example 5 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)methyl)-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)methyl)- 2 ,5 3 -Dihydrogen 1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0154]

[0155] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide to obtain the title compound. 1H NMR (400MHz, CDCl3) δ8.41(s,1H),8.09(s,1H),7.59(s,1H),7.19(s,2H),7.15(d,J=6.9Hz,1H),4.45–4.35( m,1H),4.28(d,J=12.9Hz,1H),3.81(d,J=13.3Hz,2H),3.74(d,J=14.4Hz,4H),3.66(d,J=12.2Hz,1H),3.29( s,2H),3.02(d,J=8.4Hz,1H),2.79(d,J=7.4Hz,2H),2.64(d,J=11.6Hz,1H),2.57(s,3H),2.41(s,3H),2.20( d,J=6.8Hz,1H),2.04(s,1H),1.92(dd,J=22.9,5.7Hz,3H),1.76(s,2H),0.82(s,3H).ESI-MSm / z:555.3[M+H] + .

[0156] Example 6 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -((2-methyl-2,7-diazaspiro[3.5]nonyl-7-yl)methyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonyl-7-yl)methyl) 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0157]

[0158] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride to obtain the title compound. 1HNMR(400MHz, CDCl3)δ8.48(s,1H),8.16(s,1H),7.66(s,1H),7.29(s,2H),7.17(d,J=7.9Hz, 1H),4.52–4.42(m,1H),4.35(d,J=13.1Hz,1H),3.93–3.85(m,1H),3.79(s,3H),3.75–3.69(m, 1H),3.55(q,J=13.7Hz,2H),3.10(s,4H),2.90–2.79(m,1H),2.64(s,3H),2.39(s,3H),2.37– 2.26(m,4H),2.19–2.08(m,2H),2.01–1.90(m,2H),1.79(s,4H),0.91(d,J=6.2Hz,3H).ESI-MS m / z:583.3[M+H] + .

[0159] Example 7 (R, E)-5 6 -(2-Fluoro-5-(4-methylpiperazin-1-yl)phenyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0160]

[0161] Step 1 Preparation of 1-(3-bromo-4-fluorophenyl)-4-methylpiperazine

[0162]

[0163] 3-Bromo-4-fluoroaniline (2.0 g, 10.5 mmol), di(2-chloroethyl)methylamine hydrochloride (2.0 g, 10.5 mmol) and sodium carbonate (3.9 g, 36.8 mmol) were placed in a bottle, protected by argon, and isopropanol (190 mL) was added. The mixture was stirred overnight at 100°C. After the reaction was completed, the mixture was filtered, dried by spin drying, and purified by column chromatography to obtain the title compound. ESI-MS m / z: 273.0 [M+H] + .

[0164] Step 2 Preparation of (2-fluoro-5-(4-methylpiperazin-1-yl)phenyl)boronic acid

[0165]

[0166] Dissolve 1-(3-bromo-4-fluorophenyl)-4-methylpiperazine (1.0 g, 3.7 mmol) in anhydrous tetrahydrofuran (10 mL), precool at -78 ° C under argon protection, add 2.5 mol / L tetrahydrofuran solution of n-butyl lithium (2.2 mL), stir for 20 min, add triisopropyl borate (1.1 g, 5.6 mmol), stir at -78 ° C for 1 h, after the reaction is completed, add saturated aqueous ammonium chloride to quench the reaction, concentrate, extract with dichloromethane / isopropanol (V1:V2=3:1), dry with anhydrous sodium sulfate, and concentrate to obtain the title compound. ESI-MS m / z: 239.1 [M+H] + .

[0167] Step 3(R,E)-5 6 -(2-Fluoro-5-(4-methylpiperazin-1-yl)phenyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0168]

[0169] (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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one (0.100 g, 0.197 mmol), (2-fluoro-5-(4-methylpiperazin-1-yl)phenyl)boric acid (0.094 g, 0.394 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.015 g, 0.020 mmol) and sodium carbonate (0.084 g, 0.788 mmol) were added to N,N-dimethylformamide (10 mL), and water (2 mL) was added. Under argon protection, the mixture was heated and stirred at 120°C for 6 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water three times. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain the title compound. 1H NMR (400MHz, CDCl3) δ8.50(s,1H),8.16(s,1H),7.68(s,1H),7.46(s,1H),7.41(s,2H),7.10(t,J=9.4 Hz,1H),7.02–6.97(m,1H),6.94–6.88(m,1H),4.53–4.44(m,1H),4.39(d,J=14.1Hz,1H),3.94–3.86( m,1H),3.83–3.72(m,4H),3.21(s,4H),2.91–2.82(m,1H),2.65(s,3H),2.61(s,4H),2.37(s,3H),2.3 1–2.24(m,1H),2.18–2.10(m,1H),2.00–1.91(m,1H),1.53–1.47(m,1H),0.93(d,J=6.3Hz,3H).ESI-MS m / z:623.3[M+H] + .

[0170] Example 8 (R, E)-5 6 -(((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0171]

[0172] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 4-(trifluoromethyl)piperidin-4-ol to obtain the title compound. ESI-MS m / z: 612.3 [M+H] + . 1H NMR(400MHz,DMSO)δ12.56(s,1H),8.43(s,1H),7.93(s,1H),7.57(s,1H),7.54–7 .42(m,2H),7.18(d,J=7.8Hz,1H),5.26(s,1H),4.60(s,2H),4.36(s,1H),4.19(s ,1H),4.01(s,1H),3.96–3.82(m,1H),3.74(s,3H),2.82(s,1H),2.56(s,3H),2.2 2(s,1H),1.98(t,J=22.8Hz,3H),1.46(s,2H),1.24(s,4H),0.83(d,J=6.3Hz,5H).

[0173] Example 9 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -((4-(oxetane-3-yl)piperazin-1-yl)methyl)-5-(4-(oxetane-3-yl)piperazin-1-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H, 5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0174]

[0175] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 1-(3-oxacyclobutyl)piperazine to obtain the title compound. ESI-MS m / z: 585.3 [M+H] +.1H NMR (400MHz, DMSO) δ12.71(s,1H),8.43(s,1H),7.93(s,1H),7.70–7.30(m,3H),7.17(d,J=7.9Hz,1H) ,4.54(dd,J=22.4,16.2Hz,2H),4.38(d,J=18.5Hz,2H),4.20(d,J=13.1Hz,1H),3.95(dd,J=26.5,14. 3Hz,2H),3.74(s,3H),3.55(d,J=26.7Hz,2H),3.39(s,3H),2.56(s,2H),2.42(s,3H),2.26(s,3H),2. 03–1.90(m,2H),1.46(s,1H),1.34(s,1H),1.24(s,2H),1.18(d,J=6.4Hz,1H),0.82(t,J=11.1Hz,3H).

[0176] Example 10(E)-5 6 -((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-1 1 ,2 6 -Dimethyl-5- 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0177]

[0178] The preparation method is the same as that of Examples 1 and 3, except that the raw material (R)-5-amino-4-methylpentyl-1-ol hydrochloride is replaced with 5-amino-1-pentanol to obtain the title compound. ESI-MS m / z: 598.3 [M+H] +.1H NMR(400MHz,DMSO)δ12.60(s,1H),8.41(s,1H),8.32(s,1H),7.92(s,1H),7.57(s ,1H),7.56–7.43(m,1H),7.19(d,J=7.9Hz,1H),5.32(s,1H),4.21(s,3H),3.73(s ,2H),3.58(s,2H),2.69(d,J=11.7Hz,2H),2.56(s,2H),2.33–2.18(m,2H),2.02( d,J=32.6Hz,3H),1.80(s,2H),1.65(t,J=16.2Hz,3H),1.23(s,4H),0.85(s,1H).

[0179] Example 11 (R, E)-5 6 -((3-hydroxy-3-(trifluoromethyl)-azetidin-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0180]

[0181] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 3-(trifluoromethyl)azetidin-3-ol hydrochloride to obtain the title compound. ESI-MS m / z: 584.3 [M+H]+. 1 H NMR (400MHz, DMSO) δ12.72(s,1H),8.42(s,1H),8.18(s,1H),7.93(s,1H),7.53(d,J=31 .3Hz,2H),7.15(d,J=7.2Hz,1H),5.76(s,1H),4.35(s,1H),4.19(d,J=12.3Hz,1H),3.95 (d,J=26.6Hz,3H),3.73(s,3H),3.53(d,J=8.1Hz,2H),3.21(d,J=6.9Hz,2H),2.78(s,1 H),2.55(s,3H),2.20(s,1H),2.10–1.78(m,2H),1.45(s,1H),1.22(s,1H),0.81(s,3H).

[0182] Example 12 (R, E)-5 6 -((7,8-dihydro-1,6-naphthyridin-6(5H)-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0183]

[0184] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride to obtain the title compound. ESI-MS m / z: 577.3 [M+H]+. 1 H NMR (400MHz, DMSO) δ12.71(s,1H),8.39(d,J=19.9Hz,1H),8.33(s,1H),8.18(s,1H),7.92(s,1H),7.57( s,1H),7.51(d,J=7.1Hz,1H),7.42(d,J=6.5Hz,1H),7.24(d,J=7.1Hz,1H),7.13(s,1H),4.35(s,1H),4. 18(d,J=12.3Hz,1H),4.03–3.88(m,3H),3.78(s,2H),3.72(s,2H),3.61(s,2H),2.87(d,J=23.4Hz,2H), 2.73(d,J=43.5Hz,3H),2.51(s,3H),2.19(s,1H),2.03–1.82(m,2H),1.44(s,1H),0.80(d,J=4.2Hz,3H).

[0185] Example 13 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-5-nitropropene 2 ,5 3 -Dihydro-1 1 H, 5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0186]

[0187] Weigh (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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one (120 mg; 0.2358 mmol); 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (53 mg, 0.3536 mmol) were dissolved in a 25 ml three-necked flask with 6 mL of N,N-dimethylformamide, and triphenylphosphine (4 mg, 0.0142 mmol); palladium acetate (2 mg, 0.0071 mmol) were weighed; the reaction was carried out at 110°C overnight under argon protection. After the reaction was complete, 20 ml of water was added and the mixture was extracted with ethyl acetate to obtain the title product. ESI-MS m / z: 595.3[M+H] + . 1H NMR(400MHz,DMSO)δ12.84(s,1H),8.42(s,1H),7.93(s,1H),7.73(s,1H),7.5 7(s,2H),7.28(d,J=7.8Hz,1H),4.35(s,1H),4.10(dd,J=36.8,19.1Hz,2H),3 .74(s,3H),2.85–2.71(m,3H),2.56(s,3H),2.29(d,J=24.5Hz,5H),2.04–1.8 6(m,3H),1.43(s,3H),1.33(d,J=15.6Hz,2H),1.24(s,6H),0.89–0.78(m,4H).

[0188] Example 14 (R, E)-5 6 -((3S,4R)-4-amino-3-methyl-1-oxa-8-azaspiro[4.5]dec-8-yl)methyl)-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0189]

[0190] The preparation method is the same as the preparation method of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by (R)-2-methyl-N-((3S,4R)-3-methyl-1-oxo-8-azaspiro[4.5]dec-4-yl)propane-2-sulfenamide to obtain the title compound 1 H NMR (400MHz, DMSO) δ8.43(s,1H),7.93(s,1H),7.57(s,1H),7.41(dd,J=53.6,7.2Hz,2H),7.17(d,J=7.8Hz,1H),4.36 (s,1H),4.20(d,J=12.7Hz,1H),4.03(d,J=23.0Hz,2H),3.96–3.86(m,1H),3.73(s,3H),3.62(d,J=8.1Hz,1H),3.55( s,2H),2.99(s,1H),2.87–2.67(m,2H),2.56(s,3H),2.17(dd,J=18.5,10.8Hz,2H),1.97(dd,J=24.2,14.9Hz,3H),1. 65(dd,J=24.2,10.3Hz,2H),1.49(d,J=27.5Hz,3H),1.23(s,6H),1.10(d,J=5.6Hz,2H),0.81(d,J=5.2Hz,3H).ESI-MS m / z:613.4[M+H] + .

[0191] Example 15 (R, E)-5 6 -(((1R,5R)-1,4-diazabicyclo[3.2.1]octan-4-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]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0192]

[0193] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by (1R,5R)-1,4-diazabicyclo[3.2.1]octane dihydrochloride to obtain the title compound. 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),8.16(s,1H),7.66(s,1H),7.30(d,J=6.9Hz,2H),7.18(d,J=7.9Hz,1H),4.48(dd,J =13.1,8.3Hz,1H),4.37(d,J=13.3Hz,1H),3.93–3.87(m,1H),3.79(s,3H),3.73(d,J=13.1Hz,1H),3.61–3.52(m,2H) ,3.32(s,1H),3.24–3.15(m,2H),3.12(d,J=10.9Hz,1H),2.92–2.77(m,4H),2.71–2.67(m,1H),2.64(s,3H),2.47–2. 38(m,1H),2.32–2.23(m,1H),2.18–2.08(m,2H),2.03–1.91(m,2H),1.69–1.63(m,1H),0.91(d,J=6.4Hz,3H).ESI-MS m / z:555.3[M+H] + .

[0194] Example 16 (R, E)-1 1 ,2 6 ,7-Trimethyl-5 6 -((3-methyl-3,6-diazabicyclo[3.1.1]heptyl-6-yl)methyl)-5-(3-methyl-3,6-diazabicyclo[3.1.1]heptyl-6-yl)methyl)- 2 ,5 3 -Dihydro-1 1 H, 5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole-2-(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one

[0195]

[0196] The preparation method is the same as that of Example 3, except that the raw material 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride is replaced by 3-methyl-3,6-diazabicyclo[3.1.1]heptane dihydrochloride to obtain the title compound. 1H NMR(400MHz, CDCl3)δ8.48(s,1H),8.15(s,1H),7.65(s,1H),7.30–7.25(m,2H),7.2 2(d,J=7.7Hz,1H),4.51–4.42(m,1H),4.35(d,J=13.0Hz,1H),3.95–3.85(m,2H),3. 85–3.64(m,7H),3.27–2.96(m,4H),2.89–2.70(m,2H),2.64(s,3H),2.57(s,3H),2. 30–2.21(m,1H),2.18–2.07(m,2H),2.00–1.90(m,2H),0.93(d,J=5.9Hz,3H).ESI-MS m / z:555.3[M+H] + .

[0197] Experimental Example 1 Evaluation of compound in vitro cell activity

[0198] 1. Experimental Materials

[0199] Test compounds: The compounds of the present invention prepared in the above examples were formulated into 10 mM stock solution with DMSO and finally diluted to 10 concentrations for detection. The final concentrations of the compounds in the BaF3 (EGFR del19 / T790M / C797S) cell experiment were 1000 nM, 250 nM, 62.5 nM, 15.63 nM, 3.91 nM, 0.977 nM, 0.244 nM, 0.0610 nM, 0.0153 nM, and 0.00382 nM. The final concentrations of the compounds in the BaF3 (EGFR WT) cell experiment were 50000 nM, 12500 nM, 3125 nM, 781.25 nM, 195.31 nM, 48.83 nM, 12.21 nM, 3.05 nM, 0.76 nM, and 0.19 nM.

[0200] BaF3 (EGFR del19 / T790M / C797S) cells and BaF3 (EGFR WT) cells were provided by Pharmaron (Beijing) Pharmaceutical Technology Co., Ltd.

[0201] Epidermal growth factor (EGF), catalog number is invitrogen PHG0311; CellTiter-Glo Luminescent Cell Viability Assay, catalog number is Promega G7573; Brigatinib, catalog number is Selleck S8229.

[0202] 2. Experimental Methods

[0203] 2.1 Cell culture and passaging

[0204] (1) All cells were cultured according to the method recommended by ATCC, and the experiments were performed in the exponential growth phase.

[0205] (2) Cell culture medium: 1640 medium, 10% FBS, 1% penicillin-streptomycin, 1% GlutaMax, 10 ng / mL EGF.

[0206] (3) Cell culture conditions: 37°C, 5% CO2, 95% air

[0207] (4) Depending on the growth of the cells, the culture medium should be changed every 2-3 days or the cells should be subcultured.

[0208] 2.2 Cell plating

[0209] Remove the cells from the cell culture flask and resuspend them in fresh culture medium. Inoculate 30 μL of the cell resuspension into a 384-well culture plate at 700 cells / well.

[0210] 2.3 Administration

[0211] BaF3 (EGFR del19 / T790M / C797S) cells: On the basis of the original culture medium (30μL), 30nL of drugs of different concentrations were added to the drug administration group, 30nL of 10mM Brigatinib was added to the positive control (PC) group, and 30nLDMSO was added to the DMSO group. Two replicate wells were set for each concentration group and cultured in a 5% CO2 incubator for 3 days. The compound was prepared as follows: 1-2mg of the compound was weighed in advance and prepared into a 10mM stock solution using DMSO. Use DMSO to dilute the drug. The drug concentration starts at 1 mM and is diluted in a 1:3 gradient to 10 concentration gradients: 1000000 nM, 250000 nM, 62500 nM, 15625 nM, 3906.25 nM, 9760.563 nM, 244.14 nM, 61.03 nM, 15.26 nM, and 3.81 nM.

[0212] BaF3 (EGFR WT) cells: On the basis of the original culture medium (30 μL), 150 nL of drugs of different concentrations were added to the cells. 150 nL of 10 mM Brigatinib was added to the positive control (PC) group, and 150 nL of DMSO was added to the DMSO group. Two replicate wells were set for each concentration group and cultured in a 5% CO2 incubator for 3 days. The compound was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 10 mM stock solution using DMSO. The drug was diluted with DMSO, with the drug concentration starting at 10 mM as the highest concentration, and diluted to 10 concentration gradients in a 1:3 gradient: 10000000 nM, 2500000 nM, 625000 nM, 156250 nM, 39062.5 nM, 9765.63 nM, 2441.41 nM, 610.35 nM, 152.59 nM, 38.15 nM.

[0213] 2.4 Detection

[0214] After 3 days of drug treatment, the BaF3 (EGFR del19 / T790M / C797S) cells and BaF3 (EGFR WT) cells were taken out of the CellTiter-Glo Luminescent Cell Viabillity Assay 30 minutes in advance and equilibrated to room temperature. Then 30 μL of Celltiter-Glo reagent was added to the positive control (PC) well, the drug-dosing well, and the DMSO well, and the cells were shaken. After incubation for 30 minutes at 5% CO2 and 37°C in the dark, 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 溶剂对照孔 -LUM PC孔 )*100. According to different drug concentrations and their corresponding inhibition rates, IC was analyzed using GraphicPad 5.0 software. 50 Draw curves, analyze data, and obtain final IC 50 The experimental results are shown in Table 1.

[0215] 3. Experimental results

[0216] Table 1

[0217]

[0218] “-” means not detected.

[0219] From the above experimental results, it can be seen that the compounds of the present invention exhibit good inhibitory activity against EGFR mutant BaF3 cells, while the inhibitory activity against EGFR wild-type BaF3 cells is weak, indicating that the compounds of the present invention have excellent selectivity and are very promising as therapeutic agents for EGFR mutant non-small cell lung cancer.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, in, Cy-L is selected from R 1 Selected from C 1-6 Alkyl; and R 2 is hydrogen; R 3 Selected from C 1-3 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

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

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

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

6. The method according to claim 5, wherein the tumor 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.

7. The use according to claim 5, wherein the tumor disease is bronchial 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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