CN113527335A - Macrocyclic compound as EGFR inhibitor and application thereof - Google Patents

Macrocyclic compound as EGFR inhibitor and application thereof Download PDF

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Publication number
CN113527335A
CN113527335A CN202110397805.4A CN202110397805A CN113527335A CN 113527335 A CN113527335 A CN 113527335A CN 202110397805 A CN202110397805 A CN 202110397805A CN 113527335 A CN113527335 A CN 113527335A
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alkyl
hydroxy
membered
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cancer
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王海
王小伟
王亚洲
赵立文
于澍嘉
梁程
韦艺丹
李雪
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention belongs to the field of medicinal chemistry, and relates to macrocyclic compounds serving as EGFR inhibitors and application thereof, in particular to compounds shown as a formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, and the macrocyclic compoundsProcesses for their preparation, pharmaceutical compositions containing them and the use of these compounds or compositions for the treatment of EGFR mediated diseases.

Description

Macrocyclic compound as EGFR inhibitor and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to macrocyclic compound serving as an EGFR inhibitor or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds or the composition in treating EGFR mediated diseases.
Background
EGFR (epidermal Growth Factor receptor) is a receptor for cell proliferation and signaling of Epidermal Growth Factor (EGF). 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, ErbB1, and mutation or overexpression typically causes tumors. EGFR is a glycoprotein belonging to tyrosine kinase type receptor, and has a penetrating cell membrane and a molecular weight of 170 KDa.
EGFR is related to the proliferation, angiogenesis, tumor invasion, metastasis and apoptosis inhibition of tumor cells, and researches show that high expression or abnormal expression of EGFR exists in solid tumors such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and the like. Currently about 30% to 40% of asian NSCLC patients carry EGFR mutations at the time of diagnosis.
Common mutations of EGFR can be classified into two broad categories, one is drug-sensitive mutation, i.e., after mutation, an anti-tumor targeting drug can be used, such as 19 exon deletion, 21 exon L858R mutation; another class are drug-resistant mutations, i.e., mutations that are resistant to certain antitumor targeted drugs, such as the 20 exon T790M mutation, the 20 exon C797S mutation. AZD9291 (oxitinib) is an oral small molecule third-generation EGFR-TKI, is the first lung cancer drug aiming at EGFR T790M mutation, but a part of beneficial patients have drug resistance after being treated for 9-14 months. It was found that up to 40% of resistant patients caused oxitinib resistance due to EGFR _ C797S point mutation. Further mechanistic studies indicate that point mutation of EGFR _ C797S converts cysteine at position 797 to serine, resulting in no covalent binding of axitinib to the target protein, and C797S is an important reason for the development of resistance of the third-generation drug axitinib. Currently, there is no clinically effective EGFR inhibitor against the new mutation (C797S) administered alone, and therefore there is a need to develop a new generation of EGFR inhibitors against mutations involving C797S.
Disclosure of Invention
An object of the present invention is to provide a compound having an EGFR inhibitory activity represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure BDA0003019219690000021
wherein the content of the first and second substances,
cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocycloheteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;
l is selected from the group consisting of a bond, -S-, -O-, -CH2-、-CH2CH2、-C(O)-、-S(O)-、-S(O)2-、
Figure BDA0003019219690000022
Wherein R is4、R5Independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;
R1selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylaminoamino; and
R2、R3independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and cycloalkyl.
It is another object of the present invention to provide a method for preparing the compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.
It is a further object of the present invention to provide a composition comprising a compound of formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, and a composition comprising a compound of formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another drug or drugs.
It is still another object of the present invention to provide a method for treating EGFR-mediated diseases by using the compound of the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention, and the use of the compound of the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention for the preparation of a medicament for treating EGFR-mediated diseases.
Aiming at the above purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound represented by the general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure BDA0003019219690000031
wherein the content of the first and second substances,
cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocycloheteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;
l is selected from the group consisting of a bond, -S-, -O-, -CH2-、-CH2CH2、-C(O)-、-S(O)-、-S(O)2-、
Figure BDA0003019219690000032
Wherein R is4、R5Independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;
R1selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylaminoamino; and
R2、R3independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, alkenyl, alkylHaloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl and cycloalkyl.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
cy is selected from C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6Alkyl acyl radical, C3-12Cycloalkylacyl, 3-12 membered heterocycloyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;
further preferably, Cy is selected from C6-10Aryl, 5-10 membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C6-10Aryl, 5-10 membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkylacyl, 3-8 membered heterocycloyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;
still further preferably, Cy is selected from the group consisting of phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azaheterocyclyl and 4-8 membered azaheterocyclyl and 5-8 membered heteroaryl, said Cy is selected from the group consisting of phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered heterocyclyl and 4-8 membered heterocyclyloxy and 5-8 membered heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkylacyl, 3-8 membered heterocycloyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.
In some specific embodiments, the compound of general formula (I) according to 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 azaheterocyclyl and 4-8 membered azaheterocyclyl and 5-8 membered heteroaryl, 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, oxacyclopropyl, aziridinyl, oxetanyl, azetidinyl, oxogroup.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R1selected from hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl and di-C1-6An alkylamino group;
further preferably, R1Selected from hydrogen, halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl and di-C1-3An alkylamino group;
even more preferably, R1Selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl and di-C1-3An alkylamino group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R2、R3independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl and C3-6A cycloalkyl group;
further preferably, R2、R3Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, amino, methyl, ethyl, propyl, halogenated C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl and C3-6A cycloalkyl group.
In some preferred embodiments, the present invention 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 structure of the following general formula (II),
Figure BDA0003019219690000051
wherein R is1、R3Cy and L have the meanings given above for the general formula (I).
In some preferred embodiments, the compound of formula (I) or formula (II) according to the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein L is selected from the group consisting of a chemical bond, -CH2-、-CH2CH2、-C(O)-、-S(O)2-、
Figure BDA0003019219690000052
In some embodiments, according toThe compound of the general formula (I) or the general formula (II) of the invention or the isomer, the pharmaceutically acceptable salt, the solvate, the crystal or the prodrug thereof, wherein Cy is selected from
Figure BDA0003019219690000053
Figure BDA0003019219690000054
Figure BDA0003019219690000055
Optionally substituted by one or more groups selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6Alkyl acyl radical, C3-12Cycloalkylacyl, 3-12 membered heterocycloyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.
In some preferred embodiments, the compound of formula (I) or formula (II) according to the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein Cy-L is selected from the group consisting of
Figure BDA0003019219690000056
Figure BDA0003019219690000057
Figure BDA0003019219690000061
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 the general formula (I) has the structure of the following general formula (III),
Figure BDA0003019219690000062
wherein R is1、R2、R3L has the meaning described above for the general formula (I), ring A is selected from the group consisting of 3-12 membered azacycloalkyl, 3-12 membered diazacycloalkyl, 3-12 membered azaheterocyclyl, 3-12 membered diazacyclo, 5-12 membered azaaryl, R6Each independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, n is 1,2, 3, 4,5, or 6; or two R6Together with the atoms to which they are attached form a 3-12 membered azacycloalkyl, 3-12 membered diazacycloalkyl, 3-12 membered azaheterocyclyl, 3-12 membered diazacycloalkyl, 5-12 membered azaaryl, 3-12 membered oxacycloalkyl, 3-12 membered dioxacycloalkyl, 3-12 membered oxacyclyl, 3-12 membered dioxaheterocyclyl, or 5-12 membered oxaaryl, optionally substituted with a group selected from halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
In some embodiments, a compound of formula (III) according to the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein Ring A is selected from the group consisting of 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azaheterocyclyl, 3-8 membered diazacyclo, 5-12 membered azaaryl, R6Each independently selected from halogen, hydroxy, carboxy, cyano, amino, C2-6Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkyl acylAmino radical, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl radical, C6-12Aryl radical, C5-12Heteroaryl group, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, n is 2, 3 or 4; or two R6Together with the atoms to which they are attached form a 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azaheterocyclyl, 3-8 membered diazacycloalkyl, 5-12 membered azaaryl, 3-8 membered oxacycloalkyl, 3-8 membered dioxacycloalkyl, 3-8 membered oxacyclyl, 3-8 membered dioxaheterocyclyl or 5-12 membered oxaaryl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, cyano, amino, C2-6Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl radical, C6-12Aryl radical, C5-12Heteroaryl group, C3-8Cycloalkyl and C3-8Heterocycloalkyl group.
In some embodiments, a compound of formula (III) according to the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein Ring A is selected from the group consisting of 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azaheterocyclyl, 3-8 membered diazacyclo, 5-12 membered azaaryl, R6Each independently selected from halogen, hydroxy, carboxy, cyano, amino, C2-6Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl radical, C6-12Aryl radical, C5-12Heteroaryl group, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, n is 2, 3 or 4; or two R6Together with the atoms to which they are attached form a 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azaheterocyclyl, 3-8 membered diazacycloalkyl, 5-12 membered azaaryl, 3-8 membered oxacycloalkyl, 3-8 membered dioxacycloalkyl, 3-8 membered oxacycloalkylCyclyl, 3-8 membered dioxyheterocyclyl or 5-12 membered oxaaryl 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, oxacyclopropyl, aziridinyl, oxetanyl, azetidinyl, oxo.
In some embodiments, a compound according to the present invention having formula (III) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein ring a is selected from the group consisting of
Figure BDA0003019219690000071
R6Each independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxy, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl, oxo, and n is 2, 3 or 4; or two R6Together with the atoms to which they are attached form a 3-8 membered azacycloalkyl, 3-8 membered diazacycloalkyl, 3-8 membered azaheterocyclyl, 3-8 membered diazacycloalkyl, 5-12 membered azaaryl, 3-8 membered oxacycloalkyl, 3-8 membered dioxacycloalkyl, 3-8 membered oxacyclyl, 3-8 membered dioxaheterocyclyl or 5-12 membered oxaaryl, which 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, oxetanyl, aziridinyl, oxetanyl, azetidinyl, oxo.
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
Figure BDA0003019219690000081
Figure BDA0003019219690000091
in another aspect, the present invention provides a process for the preparation of a compound of formula (I) according to the invention, comprising:
Figure BDA0003019219690000092
1) the compound of formula 3 can be prepared by reacting a compound of formula 1 with a compound of formula 2,
2) the compound of formula 4 can be prepared by reacting a compound of formula 3,
3) the compound of formula 6 can be prepared by reacting a compound of formula 4 with a compound of formula 5,
4) the compound of formula 7 can be prepared by a reduction reaction of the compound of formula 6,
5) the compound of formula 8 can be prepared by reacting a compound of formula 7,
6) the compound of formula 9 can be prepared by hydrolysis of the compound of formula 8,
7) the compound of formula 10 can be prepared by reacting a compound of formula 9,
8) the compounds of formula (I) can be prepared by reacting compounds of formula 10.
Wherein R is1、R2、R3Cy and L have the meanings given in the general formula (I), and the compounds of the formula (2) and the compounds of the formula (5) are commercially available compounds or can be synthesized by other techniques customary to those skilled in the art.
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, solvate, crystal or prodrug thereof.
In some embodiments, the present invention provides a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for use in the treatment of an EGFR-mediated disease.
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.
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. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides 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, for use in a method of treating an EGFR-mediated disease and in the preparation of a medicament for treating an EGFR-mediated disease.
In some preferred embodiments, the present invention provides a compound of 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 of treating an EGFR-mediated disease and for use in the manufacture of a medicament for treating an EGFR-mediated disease, wherein the EGFR-mediated disease includes, but is not limited to: cancer, proliferative disease, metabolic disease, or hematological disease. In some embodiments, the EGFR-mediated disease of the present invention is cancer.
In some preferred embodiments, the present invention provides a compound of formula (I), (II) or (III) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same, for use in a method of treating an EGFR-mediated disease and for use in the preparation of a medicament for treating an EGFR-mediated disease, wherein the EGFR-mediated disease includes, but is 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 cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon cancer, stomach cancer, pancreatic cancer, liver cancer, adenoid cystic cancer, prostate cancer, head and neck squamous cell cancer, brain cancer, hepatocellular cancer, melanoma, oligodendroglioma, glioblastoma, testicular cancer, clear cell carcinoma of the ovary, serous cystic carcinoma of the ovary, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple negative breast cancer.
The compound has specific tyrosine kinase inhibiting activity on mutant drug-resistant EGFR (epidermal growth factor receptor), such as del19, T790M, C797S and L858R mutant drug-resistant EGFR, and has good preventing and/or treating effects on diseases mediated by the drug-resistant mutant EGFR, such as cancers, proliferative diseases, metabolic diseases or blood diseases, and the like as a mutant drug-resistant EGFR specific tyrosine kinase inhibitor. In some embodiments, the mutant drug-resistant EGFR is a Del19/T790M/C797S or L858R/T790M/C797S triple mutation. In other embodiments, the mutant drug-resistant EGFR is a del19/T790M, L858R/T790M, L858R, or del19 primary or secondary mutation.
Definition of terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
"Hydrogen", "carbon" and "oxygen" in the compounds of the invention "Including all isotopes thereof. Isotopes are 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 include12C、13C and14c, isotopes of oxygen including16O and18o, and the like.
"isomers" as used herein refers to molecules having the same atomic composition and attachment pattern but different three-dimensional spatial 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 form, i.e., they have the ability to rotate the plane of plane polarized light. In 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 prefixes D, L or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or L indicating that the compound is left-handed and the prefixes (+) or D indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" in the context of the present invention means substituted by fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
In the present invention, -C (O) -means a "carbonyl group".
Of the present invention-S (O)2-means a "sulfonyl".
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.
"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "cycloalkyl group" in the present invention means 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, cyclohexyl.
"heterocyclyl" in the present invention refers to a group of a 3-to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, wherein 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 may be a carbon or nitrogen atom, onlyThe valency will permit. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic ring system (also known as "bicyclic heterocyclyl") and can be saturated or can be partially unsaturated. Suitable heterocyclic groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroquinazolinyl, oxapiperazinyl, dihydroquinazolinyl, and dihydroquinazolinyl,
Figure BDA0003019219690000121
Figure BDA0003019219690000122
Figure BDA0003019219690000123
And the like. Each instance of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
"aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having from 6 to 12 carbon atoms, preferably from 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 available point of attachment.
The "heteroaryl group" in the present invention means an aryl group in which at least one carbon atom is replaced with a heteroatom, and is preferably composed of 5 to 12 atoms (5-12 membered heteroaryl group), and more preferably composed of 5 to 10 atoms (5-10 membered heteroaryl group), and the heteroatom is 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, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.
The in vivo effect of the compound of formula (I) may 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 mentioned above, the in vivo effect of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention refers to a compound which is converted into the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into the compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into the compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" in the present invention is a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, and is different from an amorphous solid having no such regular internal structure.
The term "pharmaceutical composition" as used herein is intended to encompass a mixture comprising any one of the compounds of the present invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form 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 compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
The "pharmaceutically acceptable carrier" of the present invention means 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, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable 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 acetate; malt, gelatin, and the like.
"excipient" in the context of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
The EGFR WT of the present invention is the wipe type EGFR, i.e., the wild type EGFR. The term "EGFR (del 19/T790M/C797S)" as used herein refers to a del19/T790M/C797S mutated EGFR.
Detailed Description
The present invention will be further illustrated in detail with reference to the following examples, but the present invention is not limited to these examples. The materials used in the following examples are all commercially available unless otherwise specified.
Example 1(R, E) -56- (4-cyclopropylpiperazine-1-carbonyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000141
Step preparation of 12- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-isonicotinic acid methyl ester hydrochloride
Figure BDA0003019219690000142
Methyl 2-chloro-6-methylisonicotinate (25.0g,134.7mmol), 1-methyl-5-hydroxypyrazole (17.2g,175.1mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (4.9g,6.7mmol) and sodium carbonate (28.6g,269.4mmol) were added to anisole (600mL) and stirred under argon at 130 ℃ for 12 h. After the reaction was completed, the reaction was cooled to room temperature and filtered through celite, and a 4mol/L solution of hydrogen chloride in 1, 4-dioxane (67.5mL,270.0mmol) was added to the filtrate, followed by stirring at room temperature for 1h, and concentration and filtration to give the title compound. ESI-MS M/z 248.1[ M + H-HCl ]]+。
Step 2 preparation of (R) - (+) -3, 7-dimethyl-6-octenoic acid
Figure BDA0003019219690000143
(R) - (+) -5-methyl-2- (prop-2-ylidene) cyclohexanone (50.0g,328.4mmol) was dissolved in 4mol/L hydrogen chloride in 1, 4-dioxane (164.2mL,656.8mmol) and stirred at 30 ℃ overnight, after completion of the reaction, the reaction system was added dropwise to 2mol/L potassium hydroxide solution (350.0mL) and stirred at room temperature for 3 hours, the pH of the reaction system was adjusted to 1 with 2.5mol/L dilute hydrochloric acid, and the aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 169.2[ M-H ]]-。
Step 3 preparation of tert-amyl (R) - (2, 6-dimethylhept-5-en-1-yl) carbamate
Figure BDA0003019219690000144
Is (R) - (+)) Dissolving-3, 7-dimethyl-6-octenoic acid (12.0g,70.5mmol) and triethylamine (14.3g,141.0mmol) in toluene (75mL), moving to 50 ℃ and stirring, then slowly adding diphenyl azido phosphate (23.3g,84.6mmol), heating to 70 ℃ and stirring for 4h, adding tert-amyl alcohol (28.0g,317.3mmol), heating to 120 ℃ and stirring overnight, after the reaction is finished, cooling the reaction system to room temperature, adding water to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 256.2[ M + H ]]+。
Step 4 preparation of tert-amyl (R) - (5-hydroxy-2-methylpentyl) carbamate
Figure BDA0003019219690000145
Dissolving (R) - (2, 6-dimethylhept-5-en-1-yl) carbamic acid tert-amyl ester (9.5g,37.2mmol) in methanol (95mL), placing at-78 ℃ for precooling, introducing ozone into a reaction system, introducing argon into the reaction system for 15min after raw materials react, adding sodium borohydride (2.8g,74.4mmol), slowly heating to room temperature, stirring overnight, adding a saturated aqueous solution of ammonium chloride to quench the reaction after the reaction is finished, carrying out rotary evaporation to obtain most of methanol, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 232.2[ M + H ]]+。
Step 5 preparation of (R) -5-amino-4-methylpentyl-1-ol hydrochloride
Figure BDA0003019219690000151
(R) - (5-hydroxy-2-methylpentyl) carbamic acid tert-amyl ester (5.1g,22.0mmol) is dissolved in methyl tert-butyl ether (38mL), a solution of 4mol/L hydrogen chloride in 1, 4-dioxane (33.0mL,132.0mmol) is added at room temperature, the mixture is stirred at room temperature overnight, and after the reaction is finished, the title compound is obtained by rotary drying. ESI-MS M/z 118.1[ M + H-HCl ]]+。
Step 6 preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpent-1-ol
Figure BDA0003019219690000152
2-fluoro-4-bromonitrobenzene (1.7g,7.7mmol), (R) -5-amino-4-methylpentyl-1-ol hydrochloride (1.3g,8.5mmol) and potassium carbonate (3.3g,23.9mmol) were added to N, N-dimethylformamide (20mL), stirred at room temperature overnight, after completion of the reaction, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 317.1[ M + H ]]+。
Step 7 preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate
Figure BDA0003019219690000153
(R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentan-1-ol (2.9g,9.2mmol) was dissolved in dichloromethane (25mL), triethylamine (1.4g,13.8mmol) was added, methanesulfonyl chloride (1.3g,11.0mmol) was added under ice bath, stirring was carried out at room temperature for 2h, after completion of the reaction, water was added for quenching, the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 395.0[ M + H ]]+.
Step 8 preparation of methyl (R) -2- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate
Figure BDA0003019219690000154
Adding (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate (3.1g,7.8mmol), 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-isonicotinic acid methyl ester hydrochloride (2.2g,7.8mmol) and potassium carbonate (3.2g,23.4mmol) into N, N-dimethylformamide (25mL), stirring at 60 ℃ overnight, after the reaction is finished, adding water for dilution, extracting with ethyl acetate, drying over anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 546.1[ M + H ]]+.
Step 9 preparation of methyl (R) -2- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate
Figure BDA0003019219690000161
Methyl (R) -2- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (3.4g,6.2mmol) was added to ethanol (30mL), 6mL of water was added, iron powder (3.4g,62.3mmol) and ammonium chloride (3.3g, 62.3mmol) were added, stirred at 75 ℃ for 2H, after the reaction was completed, filtered, concentrated, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give the title compound. ESI-MS M/z 516.2[ M + H ]]+.
Step 10 preparation of methyl (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-isonicotinate
Figure BDA0003019219690000162
Methyl (R) -2- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (3.2g,6.2mmol) was dissolved in dichloromethane (30mL), tert-butanol (6mL) and cyanogen bromide (0.79g,7.5mmol) were added, stirring was carried out overnight at 40 ℃, after completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to give the title compound. ESI-MS M/z 541.1[ M + H ]]+.
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
Figure BDA0003019219690000163
Reacting (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d)]Imidazol-1-yl) -4-methylpentyl) oxy) -1-methylDissolving methyl-1H-pyrazol-4-yl) -6-isonicotinate (3.2g,5.9mmol) in tetrahydrofuran (30mL), adding 1mol/L sodium hydroxide aqueous solution (30mL), stirring at room temperature for 2H, concentrating and rotationally evaporating the tetrahydrofuran after the reaction is finished, adjusting the pH to weak acidity by using 4mol/L dilute hydrochloric acid, filtering, and drying in vacuum to obtain the title compound. ESI-MS M/z 527.1[ M + H ]]+.
Step 12(R, E) -56-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000171
Reacting (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 (2.6g,4.9mmol) was dissolved in dichloromethane (60mL), triethylamine (2.0g,19.6mmol) and 2- (1H-benzotriazo L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (1.9g,5.9mmol) were added, the mixture was stirred at room temperature for 3 hours, after the reaction was completed, the reaction system was washed with water three times, the organic phase was dried over anhydrous sodium sulfate, and column chromatography was performed to purify the title compound. ESI-MS M/z 509.1[ M + H ]]+。
Step 13(R, E) -11,267-trimethyl-3-oxo-52,53-dihydro-11H,51H-11-oxo-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) pyrazolocyclopentane-56Preparation of carboxylic acids
Figure BDA0003019219690000172
Palladium acetate (0.011g,0.047mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.027g,0.047mmol) were placed in a reaction flask, argon was substituted three times, and formic acid (0.254g,5.5mmol) and ((R, E) -5-dimethylxanthene were added6-bromo-11,267-trimethyl-52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one (0.400g,0.79mmol) in N, N-dimethylformamide (10mL), dicyclohexylcarbodiimide (0.033g,0.16mmol) and triethylamine (0.160g,1.58mmol) were added and stirred at 100 ℃ for 3h, after the reaction was completed, filtration, concentration and column chromatography purification were carried out to obtain the title compound. ESI-MS M/z 475.2[ M + H ]]+.
Step 14(R, E) -56- (4-cyclopropylpiperazine-1-carbonyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000173
Mixing (R, E) -11,267-trimethyl-3-oxo-52,53-dihydro-11H,51H-11-oxo-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) pyrazolocyclopentane-56-carboxylic acid (0.085g,0.179mmol) was dissolved in dichloromethane (10mL), triethylamine (0.036g, 0.358mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.035g,0.179mmol), 1-hydroxybenzotriazole (0.024g,0.179mmol) and 1-cyclopropylpiperazine (0.022g,0.179mmol) were added sequentially, stirred overnight at room temperature, after the reaction was completed, diluted with dichloromethane and washed three times with water, dried over anhydrous sodium sulfate and purified by column chromatography to give 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),3.27–3.16(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]+.
Example 2(R, E) -56- (3-hydroxy-3-methylazetidine-1-carbonyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000181
Preparation method the title compound was obtained in the same manner as in example 1 except that 1-cyclopropylpiperazine was replaced with 3-methyl-3-acridinium alkoxide as a starting material.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,1H),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),2.14–2.03(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]+。
Example 3(R, E) -11,267-trimethyl-56- ((((1R,5S) -8-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000182
Step 1(R, E) -11,267-trimethyl-3-oxo-52,53-dihydro-11H,51H-11-oxa-4-aza 5(2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazolocycloundecane-56Preparation of formaldehyde
Figure BDA0003019219690000183
Palladium acetate (0.013g,0.059mmol), n-butyldi (1-adamantyl) phosphine (0.042 g)0.118mmol) and sodium formate (0.667g, 9.81mmol) were placed in a reaction flask, replaced with argon three times, and (R, E) -5 was added6-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one (0.500g,0.982mmol) in N, N-dimethylformamide (10mL) and a mixture of formic acid (0.148mL) and acetic anhydride (0.371mL) were stirred at 30 ℃ for 1h, triethylamine (0.497g,4.91mmol) was added, stirring was continued at 110 ℃ for 3h, after the reaction was completed, the mixture was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. ESI-MS M/z 459.2[ M + H ]]+.
Step 2(R, E) -11,267-trimethyl-56- ((((1R,5S) -8-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000191
Mixing (R, E) -11,267-trimethyl-3-oxo-52,53-dihydro-11H,51H-11-oxa-4-aza 5(2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazolocycloundecane-56Formaldehyde (0.080g,0.175mmol), 8-methyl-3, 8-diaza-bicyclo [3.2.1]Dissolving octane hydrochloride (0.070g,0.350mmol) in dichloromethane (10mL), sequentially adding triethylamine (0.071g,0.70mmol), glacial acetic acid (0.106g,1.75mmol) and sodium triacetoxyborohydride (0.112g,0.525mmol), stirring at room temperature overnight, after the reaction is finished, quenching the reaction by using saturated aqueous solution of sodium bicarbonate, adding dichloromethane for dilution, washing with water for three times, drying the organic phase by using anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound.1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.48(s,1H),8.15(s,1H),7.66(s,1H),7.31–7.27(m,1H),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]+.
Example 4(R, E) -11,267-trimethyl-56- (((6-methyl-2, 6-diazaspiro [ 3.3))]Hept-2-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,2) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000192
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by 2-methyl-2, 6-diazaspiro [3.3 ]]Heptane hydrochloride to yield the title compound.1H NMR(400MHz,CDCl3)δ8.47(d,J＝4.3Hz,2H),8.15(s,1H),7.65(s,1H),7.24(s,1H),7.10(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]+。
Example 5(R, E) -11,267-trimethyl-56- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -52,53-dihydro 11H,51H-11-oxa-4-aza 5(2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000201
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by (1S,4S) -2-methyl-2, 5-diazabicyclo [2.2.1]Heptane (Heptane)Dihydrobromide salt to give 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-MS m/z:555.3[M+H]+.
Example 6(R, E) -11,267-trimethyl-56- ((2-methyl-2, 7-diazaspiro [3.5 ]]Nonyl-7-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000202
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by 2-methyl-2, 7-diazaspiro [3.5 ]]Nonane dihydrochloride to give the title compound.1H NMR(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]+。
Example 7(R, E) -56- (2-fluoro-5- (4-methylpiperazin-1-yl) phenyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza 5(2,1) -benzo [ d]Imidazole 2(2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000203
Step 11- (3-bromo-4-fluorophenyl) -4-methylpiperazine preparation
Figure BDA0003019219690000211
Placing 3-bromo-4-fluoroaniline (2.0g,10.5mmol), bis (2-chloroethyl) methylamine hydrochloride (2.0g,10.5mmol) and sodium carbonate (3.9g,36.8mmol) in a bottle, adding isopropanol (190mL) under the protection of argon, stirring overnight at 100 ℃, after the reaction is finished, filtering, spin-drying and purifying by column chromatography to obtain the title compound. ESI-MS M/z 273.0[ M + H ]]+.
Step 2 preparation of (2-fluoro-5- (4-methylpiperazin-1-yl) phenyl) boronic acid
Figure BDA0003019219690000212
Dissolving 1- (3-bromo-4-fluorophenyl) -4-methylpiperazine (1.0g,3.7mmol) in anhydrous tetrahydrofuran (10mL), precooling at-78 ℃ under the protection of argon, adding a 2.5mol/L n-butyllithium tetrahydrofuran solution (2.2mL), stirring for 20min, adding triisopropyl borate (1.1g,5.6mmol), stirring at-78 ℃ for 1h, adding a saturated ammonium chloride aqueous solution after the reaction is finished, quenching the reaction, concentrating, and adding dichloromethane/isopropanol (V)1:V2Extraction 3:1), drying over anhydrous sodium sulfate and concentration gave the title compound. ESI-MS M/z 239.1[ M + H ]]+。
Step 3(R, E) -56- (2-fluoro-5- (4-methylpiperazin-1-yl) phenyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza 5(2,1) -benzo [ d]Preparation of imidazole 2(2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000213
Mixing (R, E) -56-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one (0.100g,0.197mmol), (2-fluoro-5- (4-methylpiperazin-1-yl) phenyl) boronic acid (0.094g,0.394mmol), (1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.015g,0.020mmol) and sodium carbonate (0.084g,0.788mmol) are added into N, N-dimethylformamide (10mL), water (2mL) is added, the mixture is heated and stirred at 120 ℃ for 6 hours under the protection of argon, after the reaction is finished, ethyl acetate is diluted and washed for three times, an organic phase is dried by anhydrous sodium sulfate, and column chromatography purification is carried out 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＝9.4Hz,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),2.31–2.24(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]+.
Example 8(R, E) -56- (((4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000221
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Octane hydrochloride was replaced with 4- (trifluoromethyl) piperidin-4-ol to afford 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),2.22(s,1H),1.98(t,J＝22.8Hz,3H),1.46(s,2H),1.24(s,4H),0.83(d,J＝6.3Hz,5H).
Example 9(R, E) -11,267-trimethyl-56- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) -52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000222
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Octane hydrochloride was replaced with 1- (3-oxetanyl) piperazine to give 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).
Example 10(E) -56- ((4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) methyl) -11,26-dimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000231
Preparation method the same as that of examples 1 and 3, except that the starting material (R) -5-amino-4-methylpentyl-1-ol hydrochloride was replaced with 5-amino-1-pentanol, was used to prepare 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).
Example 11(R, E) -56- ((3-hydroxy-3- (trifluoromethyl) -azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000232
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]The title compound was prepared by replacing octane hydrochloride with 3- (trifluoromethyl) azetidine-3-ol hydrochloride. ESI-MS M/z 584.3[ M + H ]]+.1H 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,1H),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).
Example 12(R, E) -56- ((7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000233
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Octane hydrochloride was replaced with 5,6,7, 8-tetrahydro-1, 6-naphthyridine dihydrochloride to give the title compound. ESI-MS M/z 577.3[ M + H ]]+.1H 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).
Example 13(R, E) -11,267-trimethyl-56- (3-methyl-3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) -52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000241
Weighing (R, E) -56-bromo-11,267-trimethyl-52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one (120 mg; 0.2358 mmol); 1-methyl-4- (2-methylbut-3-yn-2-yl) piperazine (53mg, 0.3536mmol) was dissolved in 6mL of N, N-dimethylformamide in a 25mL three-necked flask, and triphenylphosphine (4mg, 0.0142mmol) was weighed; palladium acetate (2mg, 0.0071 mmol); the reaction was carried out overnight at 110 ℃ under the protection of argon, and after completion of the reaction, 20ml of water was added and extracted with ethyl acetate to give 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),7.57(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),2.04–1.86(m,3H),1.43(s,3H),1.33(d,J＝15.6Hz,2H),1.24(s,6H),0.89–0.78(m,4H).
Example 14(R, E) -56- ((3S,4R) -4-amino-3-methyl-1-oxa-8-azaspiro [ 4.5)]Decan-8-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000242
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by (R) -2-methyl-N- ((3S,4R) -3-methyl-1-oxo-8-azaspiro [4.5 ]]Decan-4-yl) propane-2-sulfinamide to give the title compound1H 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]+。
Example 15(R, E) -56- (((1R,5R) -1, 4-diazabicyclo [ 3.2.1)]Octane-4-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003019219690000251
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by (1R,5R) -1, 4-diazabicyclo [3.2.1]Octane dihydrochloride to give the title compound.1H 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]+。
Example 16(R, E) -11,267-trimethyl-56- ((3-methyl-3, 6-diazabicyclo [ 3.1.1)]Heptyl-6-yl) methyl) -52,53-dihydro-11H，51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazole-2- (2,4) -pyridine-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003019219690000252
The preparation process is the same as that of example 3, except that the starting material, 8-methyl-3, 8-diaza-bicyclo [3.2.1 ] is used]Replacement of octane hydrochloride by 3-methyl-3, 6-diazabicyclo [3.1.1]Heptane dihydrochloride to yield 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),7.22(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]+。
Experimental example 1 evaluation of cell Activity of Compound in vitro
1. Experimental Material
Test compounds: the compounds of the present invention prepared in the above examples were prepared as 10mM stock solutions in DMSO and tested by final dilution to 10 concentrations, with the compounds tested in BaF3(EGFR del19/T790M/C797S) cells at 1000nM, 250nM, 62.5nM, 15.63nM, 3.91nM, 0.977nM, 0.244nM, 0.0610nM, 0.0153nM, 0.00382nM, and the compounds tested in BaF3(EGFR WT) cells at 50000nM, 12500nM, 3125nM, 781.25nM, 195.31nM, 48.83nM, 12.21nM, 3.05nM, 0.76nM, 0.19 nM.
BaF3(EGFR del19/T790M/C797S) cells and BaF3(EGFR WT) cells are provided by KANGLONGCHENGCHENGCHENGXIN technology GmbH (Beijing).
Epidermal Growth Factor (EGF), cat # invitrogen PHG 0311; CellTiter-Glo Luminescent Cell vitality Assay, Cat. Promega G7573; brigatinib, cat # Selleck S8229.
2. Experimental methods
2.1 cell culture and passage
(1) All cells were cultured according to the method recommended by ATCC, and the cells were subjected to the experiment in the exponential growth phase.
(2) Cell culture medium: 1640 medium, 10% FBS, 1% streptomycin, 1% GlutaMax, 10ng/mL EGF.
(3) Cell culture conditions: 37 ℃ and 5% CO295% air
(4) The culture medium is changed or subcultured every 2-3 days depending on the growth of the cells.
2.2 cell plating
The cells were removed from the cell culture flask and resuspended in fresh medium. 30 μ L of cell resuspension was plated in 384 well plates at 700 cells/well.
2.3 administration of drugs
BaF3(EGFR del19/T790M/C797S) cells: on the basis of original culture medium (30 mu L), 30nL of drugs with different concentrations are added into an administration group, 30nL of 10mM Brigatinib is added into a Positive Control (PC) group, 30nL of DMSO is added into a DMSO group, each concentration group is provided with two multiple holes, and 5% CO is continuously put into each hole2The incubator is used for 3 days. The compounds were formulated as follows: compounds 1-2mg were weighed in advance and made up in 10mM stock solution using DMSO. The drugs were diluted with DMSO starting at 1mM maximum concentration and sequentially diluted to 10 concentration gradients in a 1:3 gradient: 1000000nM, 250000nM, 62500nM, 15625nM, 3906.25nM, 9760.563nM, 244.14nM, 61.03nM, 15.26nM, 3.81 nM.
BaF3(EGFR WT) cells: on the basis of original culture medium (30 μ L), 150nL of different concentrations of drugs are added to cells, 150nL of 10mM Brigatinib is added to a Positive Control (PC) group, 150nL of DMSO is added to a DMSO group, each concentration group is provided with two multiple wells, and 5% CO is continuously added2The incubator is used for 3 days. The compounds were formulated as follows: compounds 1-2mg were weighed in advance and made up in 10mM stock solution using DMSO. Diluting the drug with DMSO, wherein the drug concentration is 10mM as the initial maximum concentration, and the ratio is 1:3The concentration is sequentially diluted to 10 concentration gradients: 10000000nM, 2500000nM, 625000nM, 156250nM, 39062.5nM, 9765.63nM, 2441.41nM, 610.35nM, 152.59nM, 38.15 nM.
2.4 detection
BaF3(EGFR del19/T790M/C797S) cells and BaF3(EGFR WT) cells after 3 days of drug treatment, CellTiter-Glo Luminescent Cell viability Assay was removed 30min in advance and allowed to equilibrate to room temperature. Then Positive Control (PC) wells, dosing wells and DMSO wells were added to 30. mu.L of Celltiter-Glo reagent and shaken. Continued at 5% CO2And incubating for 30min at 37 ℃ in a dark condition, and detecting a luminescent signal. From the LUM values, the inhibition ratio of each well relative to the solvent control well was calculated: increment (%) 100- (LUM)Medicine feeding hole–LUMPC hole)/(LUMSolvent control wells-LUMPC hole)*100. IC was performed using GraghPad 5.0 software according to the drug concentrations and their corresponding inhibition rates50Drawing a curve, analyzing data to obtain a final IC50The values, experimental results are shown in table 1.
3. Results of the experiment
TABLE 1
Figure BDA0003019219690000271
"-" indicates no detection.
As can be seen from the above experimental results, the compounds of the present invention exhibit good inhibitory activity against EGFR-mutated BaF3 cells, while having weak inhibitory activity against EGFR wild-type BaF3 cells, showing excellent selectivity of the compounds of the present invention, and are very promising as EGFR-mutated non-small cell lung cancer therapeutics.

Claims (10)

1. A compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure FDA0003019219680000011
wherein the content of the first and second substances,
cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocycloheteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;
l is selected from the group consisting of a bond, -S-, -O-, -CH2-、-CH2CH2、-C(O)-、-S(O)-、-S(O)2-、
Figure FDA0003019219680000012
Wherein R is4、R5Independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;
R1selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylaminoamino;
R2、R3independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and cycloalkyl, and
when R is1、R3Is methyl, R2Is hydrogen, L is-CH2When Cy is not
Figure FDA0003019219680000013
2. The compound of claim 1, or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein Cy is selected from C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6Alkyl acyl radical, C3-12Cycloalkylacyl, 3-12 membered heterocycloyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.
3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R1Selected from hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl and di-C1-6An alkylamino group.
4. A compound according to any one of claims 1 to 3 or an isomer thereofA body, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R2、R3Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl and C3-6A cycloalkyl group.
5. The compound according to any one of claims 1 to 4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein L is selected from the group consisting of a bond, -CH2-、-CH2CH2、-C(O)-、-S(O)2-、
Figure FDA0003019219680000021
6. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Cy is selected from the group consisting of
Figure FDA0003019219680000022
Figure FDA0003019219680000023
Optionally substituted by one or more groups selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6An alkyl acyl group,C3-12Cycloalkylacyl, 3-12 membered heterocycloyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.
7. The compound according to any one of claims 1 to 6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Cy-L is selected from the group consisting of
Figure FDA0003019219680000024
Figure FDA0003019219680000025
Figure FDA0003019219680000031
8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
Figure FDA0003019219680000032
Figure FDA0003019219680000041
9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound of any one of claims 1 to 8, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the treatment of an EGFR-mediated disease, preferably a neoplastic disease such as breast cancer, esophageal cancer, bladder cancer, lung cancer (e.g., bronchial cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon cancer, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic cancer, prostate cancer, head and neck squamous cell cancer, brain cancer, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, clear cell carcinoma of the ovary, serous cystic carcinoma of the ovary, thyroid cancer, Multiple myeloma, renal cell carcinoma, mantle cell lymphoma, or triple negative breast cancer.
CN202110397805.4A 2020-04-15 2021-04-14 Macrocyclic compound as EGFR inhibitor and application thereof Pending CN113527335A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022117051A1 (en) * 2020-12-03 2022-06-09 北京鞍石生物科技有限责任公司 Macrocyclic compound, preparation method therefor and use thereof
WO2022135432A1 (en) * 2020-12-23 2022-06-30 南京圣和药业股份有限公司 Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof
WO2022204544A1 (en) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Macrocyclic egfr inhibitors for the treatment of cancer
WO2022242712A1 (en) * 2021-05-21 2022-11-24 深圳市塔吉瑞生物医药有限公司 Substituted macrocyclic compound, composition comprising compound, and use thereof
WO2023001069A1 (en) * 2021-07-23 2023-01-26 南京明德新药研发有限公司 Macrocyclic amide compounds and application thereof
WO2023098730A1 (en) * 2021-11-30 2023-06-08 正大天晴药业集团股份有限公司 Compound containing cycloalkyl or haloalkyl
WO2024017358A1 (en) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Macrocyclic compound, pharmaceutical composition thereof, and use thereof
WO2024046221A1 (en) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Egfr inhibitors and uses thereof

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