CN115433207A - Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and relates to macrocyclic heterocyclic compounds serving as EGFR inhibitors and application thereof, in particular to compounds shown in a formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, a preparation method thereof, pharmaceutical compositions containing the compounds, and application of the compounds or the compositions in treating EGFR-mediated diseases.

Description

Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to macrocyclic heterocyclic compounds serving as EGFR inhibitors or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, a preparation method thereof, pharmaceutical compositions containing the compounds, and application of the compounds or the compositions 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 will generally trigger tumors. EGFR is a glycoprotein belonging to tyrosine kinase type receptor, and has a penetrating cell membrane and a molecular weight of 170KDa.

EGFR is related to the proliferation of tumor cells, angiogenesis, tumor invasion, metastasis and apoptosis inhibition, and research shows 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 post-resistant to certain anti-tumor 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 oxcetinic 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 failure of covalent binding of axitinib to the target protein, and C797S is an important reason for the development of drug 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 directed 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,

wherein the content of the first and second substances,

ring a is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, said aryl, heteroaryl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;

cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclylheteroaryls optionally substituted with one or more groups selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;

l is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

R ¹ selected 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;

R ² selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkanoyl, aminoacyl, alkylaminoacyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, heterocyclyl, aryl, and heteroaryl, said groups optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamido, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxoSubstituted by groups;

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

when Cy is piperazinyl, L is-CH ₂ -when ring a is not pyridyl.

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 formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention, and the use of the compound of 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,

wherein the content of the first and second substances,

ring a is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, said aryl, heteroaryl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;

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-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

R ¹ selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoylA group, an aminoacyl group, an alkylaminoacyl group, and a dialkylamino group;

R ² a group selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkanoyl, aminoacyl, alkylaminoacyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, heterocyclyl, aryl, and heteroaryl, said group optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo;

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

when Cy is piperazinyl, L is-CH ₂ -when ring a is not pyridyl.

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:

R ¹ selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylamino radicalAcyl and di-C _1-6 An alkylamino group;

further preferably, R ¹ Selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl and di-C _1-3 An alkylamino group;

even more preferably, R ¹ Selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl and di-C _1-3 An 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:

R ² is selected from C _1-6 Alkyl radical, C _3-12 Cycloalkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl radical, C _1-6 Alkylsulfonyl, aminosulfonyl, C _1-6 Alkylaminosulfonyl, 3-12 membered heterocyclic group, C _6-12 Aryl and 5-12 membered heteroaryl, said groups optionally substituted by one or more groups selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

further preferably, R ² Is selected from C _1-3 Alkyl radical, C _3-6 Cycloalkyl, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-3 Alkoxy radical, C _1-3 Alkyl acyl, amino acyl, C _1-3 Alkylaminoacyl radical, C _1-3 Alkylsulfonyl, aminosulfonyl, C _1-3 Alkylaminosulfonyl, 3-8 membered heterocyclic group, C _6-8 Aryl and 5-6 membered heteroaryl, said groups being optionally substituted by one or more groups selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.

Even more preferably, R ² Selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, isopropynyl, methoxy, ethoxy, propoxy, isopropoxy, methylacyl, ethylacoyl, propylacyl, isopropylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoacyl, isopropylaminoacylPropylaminoyl, butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, which are optionally substituted with one or more groups selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl, oxo 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:

R ³ each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

further preferably, R ⁶ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylamino radicalAcyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;

even more preferably, R ⁶ Each independently selected from the group consisting of hydrogen, 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, and oxo.

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

ring A is selected from C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl, said C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

further preferably, ring A is selected from C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl, said C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;

even more preferably, ring A is selected from C _6-10 Aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heteroaryl, C _3-10 Cycloalkyl and 9-10 membered bicyclic heterocyclyl, said C _6-10 Aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heteroaryl, C _3-10 Cycloalkyl and 9-10 membered bicyclic heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl radical, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.

In some preferred embodiments, the compound of general formula (I) according to the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein ring a is selected from the group consisting of phenyl, pyridyl, 5-6 membered heteroaryl, 5-6 membered heteroarylo-5-6 membered heteroaryl, phenyl-5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azaheterocyclyl and 3-6 membered heterocyclo-5-6 membered heteroaryl, said group being optionally substituted by one or more groups 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 and oxo groups.

In some specific embodiments, a compound of formula (I) 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 phenyl, pyridyl, 5-6 membered heteroaryl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyridopyrazolyl, pyrimidopyrazolyl, pyrimidotriazolyl, pyridotriazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azaheterocyclyl and 3-6 membered azaheterocyclo and 5-6 membered heteroaryl, said groups being 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 and oxo groups.

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

cy is selected from C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

further preferably, cy is selected from C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C _6-10 Aryl, 5-10 membered heteroaryl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 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, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.

In some specific embodiments, the compound of 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, oxetanyl, aziridinyl, oxetanyl, azetidinyl, oxogroup.

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

l is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C _2-10 Alkenyl radical, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl and C _1-6 An alkoxy group;

it is further preferred that the first and second liquid crystal compositions, L is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C _2-6 Alkenyl radical, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl and C _1-3 An alkoxy group;

it is still further preferred that the first and second substrates are, L is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, ethenyl, propenyl, isopropenyl, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy and propoxy.

In some embodiments, the present invention provides compounds of formula (I), or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula (I) has the structure of formula (Ia),

wherein R is ¹ 、R ² 、R ³ M, cy and L have the definitions described above for formula (I);

x, Q and Y are independently selected from N, C and CH;

ring B is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, said aryl, heteroaryl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;

represents a single or double bond;

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

n is 1,2, 3 or 4.

The compound shown in the general formula (Ia) or the isomer, the pharmaceutically acceptable salt and the solution thereofAn agent, crystal or prodrug, in some embodiments, when

When represents a single bond, X, Q and Y are all CH; in some embodiments, when

When represents a single bond, X and Y are CH, and Q is N; in some embodiments, when

When represents a single bond, X and Q are CH, Y is N; in some embodiments, when

When represents a single bond, Q and Y are CH, and X is N; in some embodiments, when

When represents a single bond, X and Y are N, and Q is CH; in some embodiments, when

When represents a single bond, X and Q are N, and Y is CH; in some embodiments, when

When represents a single bond, Q and Y are N, and X is CH; in some embodiments, when

When represents a single bond, X is CH, Q is N, and Y is C; in some embodiments, when

When represents a single bond, X is CH, Q is C, and Y is N; in some embodiments, when

When represents a double bond, X is CH, Q is C, Y isC; in some embodiments, when

When the double bond is represented, X is N, Q is C, and Y is C.

In some embodiments, ring B is selected from C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl, said C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

preferably, ring B is selected from C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl, said C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;

preferably, ring B is selected from C _6-10 Aryl, 5-6 membered heteroaryl, C _3-10 Cycloalkyl and C _4-10 Heterocyclyl, optionally substituted by one or more groups selected from halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl radical, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;

preferably, ring B is selected from phenyl, pyridyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-10 membered azaheterocyclyl and 3-6 membered heterocyclyl, said groups being optionally substituted by 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 and oxo groups;

preferably, the first and second liquid crystal display panels are,

selected from benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolylIsothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyridopyrazolyl, pyrimidopyrazolyl, pyrimidoimidazoimidazolyl, pyrimidoiizoxazolyl, pyridotriazolyl, 3-6 membered azaheterocyclyl and 5-6 membered heteroaryl, said groups being 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 and oxo groups.

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 the general formula (I) has the following general formula (II),

wherein R is ¹ 、R ² 、R ³ M, cy and L have the definitions given above for formula (I);

R ⁶ each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamido, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; and

n is 1,2, 3 or 4.

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 the general formula (I) has the structure of the following general formula (III),

wherein R is ¹ 、R ² 、R ³ 、R ⁶ M, n, cy and L have the definitions given above for formula (II).

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 the general formula (I) has the following general formula (IV),

wherein R is ¹ 、R ² 、R ³ 、R ⁶ M, n, cy and L have the definitions described above for formula (II).

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 (V),

wherein R is ¹ 、R ² 、R ³ 、R ⁶ M, n, cy and L have the definitions described above for formula (II).

In some preferred embodiments, the present invention provides a compound of formula (Ia), (II), (III), (IV) or (V) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein

R ⁶ Each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radicalHydroxy group C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;

further preferably, R ⁶ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy C _1-3 Alkyl radical, C _1-3 Alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-3 Alkylamino radical, C _1-3 Alkylacylamino group, C _1-3 Alkyl acyl radical, C _1-3 Alkylsulfonyl, aminoacyl, C _1-3 Alkylaminoacyl, di-C _1-3 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-3 Alkyl acyl, hydroxy C _1-3 Alkyl acyl, C _3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;

even more preferably, R ⁶ Each independently selected from the group consisting of hydrogen, 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, and oxo.

In some preferred embodiments, the compound of formula (I), formula (Ia), formula (II), formula (III), formula (IV) or formula (V) according to the invention or an isomer, a pharmaceutically acceptable salt thereofA solvate, crystal or prodrug thereof, wherein L is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -、

In some preferred embodiments, the compound of formula (I), formula (Ia), formula (II), formula (III), formula (IV) or formula (V) 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

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 (VI),

wherein R is ¹ 、R ² 、R ⁶ N, L have the meanings given above for the general formula (I), ring B 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, R ⁷ Each 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,o is 0, 1,2, 3,4, 5 or 6; or two R ⁷ Together 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 (VI) according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Ring B 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, R ⁷ Each independently selected from halogen, hydroxy, carboxy, cyano, amino, C _2-6 Alkenyl radical, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl radical, C _6-12 Aryl radical, C _5-12 Heteroaryl, C _3-8 Cycloalkyl, C _3-8 Heterocycloalkyl, o is 0, 1,2, 3 or 4; or two R ⁷ Together 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 selected from halogen, hydroxy, carboxy, cyano, amino, C _2-6 Alkenyl radical, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl radical, C _6-12 Aryl radical, C _5-12 Heteroaryl group, C _3-8 Cycloalkyl and C _3-8 Heterocycloalkyl group.

In some embodiments, a compound according to the present invention having formula (VI) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Ring B 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, R ⁷ Each independently selected from halogen, hydroxy, carboxy, cyano, amino, C _2-6 Alkenyl radical, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl radical, C _6-12 Aryl radical, C _5-12 Heteroaryl, C _3-8 Cycloalkyl radical, C _3-8 Heterocycloalkyl, o is 0, 1,2, 3 or 4; or two R ⁷ Together 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 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 (VI) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein ring B is selected from the group consisting of

R ⁷ Each independently selected fromFluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, methoxy, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl, oxo, and o is 0, 1,2, 3, or 4; or two R ⁷ Together 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 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, oxacyclopropyl, azacyclopropyl, oxetanyl, azetidinyl, oxoyl.

The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:

in another aspect, the present invention provides a process for the preparation of a compound of formula (I) according to the invention, comprising:

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) may 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) or a salt thereof,

4) The compound of formula (7) can be prepared by reduction of the compound of formula (6),

5) The compound of formula (8) may be prepared by reacting a compound of formula (7),

6) The compound of formula (9) may be prepared by hydrolysis of a compound of formula (8),

7) The compound of formula (10) may be prepared by reacting a compound of formula (9),

8) The compounds of formula (I) may be prepared by reacting compounds of formula (10).

Wherein R is ¹ 、R ² 、R ³ M, cy and L have the meanings given in formula (I); x is a leaving group, preferably selected from halogen, further preferably selected from bromine; the compounds of formula (2) and compounds of formula (5) or salts thereof are commercially available compounds or may 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 EGFR-mediated diseases.

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), (Ia), (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), (Ia), (II), or (III) of the present invention, or an isomer, a pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof, or a pharmaceutical composition comprising the same, for use in a method of treating an EGFR-mediated disease, including but 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), (Ia), (II) or (III) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or 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 manufacture 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 carcinoma, prostate cancer, head and neck squamous cell carcinoma, brain cancer, hepatocellular cancer, melanoma, oligodendroglioma, glioblastoma, testicular cancer, clear cell carcinoma of the ovary, serous cystadenocarcinoma of the ovary, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple negative breast cancer.

The compound has specific tyrosine kinase inhibition activity on mutant drug-resistant EGFR (epidermal growth factor receptor), such as del19, T790M, C797S and L858R mutant drug-resistant EGFR, and has good prevention and/or treatment effects on diseases mediated by the drug-resistant mutant EGFR, such as cancers, proliferative diseases, metabolic diseases, 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, 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.

The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include 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 include ¹² C、 ¹³ C and ¹⁴ c, isotopes of oxygen including ¹⁶ O and ¹⁸ o, 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 denote 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 prefix (+) 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 mixture of enantiomers of 50. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, 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 term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine. "halo" as used herein means substituted by fluorine, chlorine, bromine or iodine.

"alkyl" in the present invention means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain or branched-chain group having 1 to 6 carbon atoms, further preferably a straight-chain or branched-chain 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.

The term-C (O) -in the present invention means a "carbonyl group".

Of the invention-S (O) ₂ -means "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, as valency permits. 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. <xnotran> , , , , , , , , , , </xnotran>

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" 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), and more preferably composed of 5 to 10 atoms (5-10 membered heteroaryl), and the heteroatom is O, S or 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 effects of the compounds of formula (I) may also be exerted via precursor compound ("prodrug") metabolism. 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 'EGFR (del 19/T790M/C797S)' of the invention is the del19/T790M/C797S mutated EGFR, and the 'EGFR (L858R/T790M)' of the invention is the L858R/T790M 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 1B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - ((dimethylamino) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Pyridin-1 (4, 5) -pyrazoloundundecan-3-ones

Step 1 preparation of methyl 8- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-6-carboxylate hydrochloride

Reacting 8-bromoimidazo [1,2-a ]]Pyridine-6-carboxylic acid methyl ester (5g, 19.6mmol), 1-methyl-5-hydroxypyrazole (5.76g, 58.8mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (573mg, 0.784mmol) and sodium carbonate (6.3g, 58.8mmol) were charged into a 250mL one-neck flask, dissolved with 100mL anisole, and stirred under argon at 130 ℃ for 12 hours. After the reaction, the reaction system was cooled to room temperature and filtered through celite, and 4 mol/L1, 4-dioxane solution of hydrogen chloride was added to the filtrate to adjust the pH to about 5, and the mixture was stirred at room temperature for 1 hour and filtered to obtain the title compound. ESI-MS m/z:273.2[ 2 ] M + H-HCl] ⁺ _。

Step 2 preparation of (R) - (+) -citronellaic acid

R- (+) -pulegone (50.0g, 328.4mmol) was dissolved in a 4 mol/L1, 4-dioxane solution of hydrogen chloride (164.2mL, 656.8mmol) and stirred at 30 ℃ overnight, after the reaction was completed, the reaction system was added dropwise to a 2mol/L potassium hydroxide solution (350.0 mL) and stirred at room temperature for 3 hours, the reaction system pH 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 of 169.2[ m-H ]] ^- _。

Step 3 preparation of tert-amyl (R) - (2, 6-dimethylhept-5-en-1-yl) carbamate

Dissolving (R) - (+) -citronellic acid (12.0 g,70.5 mmol) and triethylamine (14.3 g,141.0 mmol) in toluene (75 mL), moving to 50 ℃ and stirring, then slowly adding diphenyl azide phosphate (23.3 g,84.6 mmol), heating to 70 ℃ and stirring for 4h, adding tertiary amyl alcohol (28.0 g,317.3 mmol), 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[ 2 ], [ M ] +H] ⁺ 。

Step 4 preparation of tert-amyl (R) - (5-hydroxy-2-methylpentyl) carbamate

Dissolving (R) - (2, 6-dimethylhept-5-en-1-yl) carbamic acid tert-amyl ester (9.5g, 37.2mmol) in methanol (95 mL), placing at-78 ℃ for precooling, introducing ozone into a reaction system, introducing argon into the reaction system for 15min after the raw materials are reacted, adding sodium borohydride (2.8g, 74.4mmol), slowly heating to room temperature, stirring overnight, after the reaction is finished, adding a saturated aqueous solution of ammonium chloride for quenching reaction, performing 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[ 2 ] M + H] ⁺ 。

Step 5 preparation of (R) -5-amino-4-methylpentyl-1-ol hydrochloride

Tert-amyl (R) - (5-hydroxy-2-methylpentyl) carbamate (5.1g, 22.0 mmol) was dissolved in methyl tert-butyl ether (38 mL), a solution of 4mol/L hydrogen chloride in 1, 4-dioxane (33.0 mL,132.0 mmol) was added thereto at room temperature, and the mixture was stirred at room temperature overnight, after completion of the reaction, and then, it was dried by spinning to obtain the titled compound. ESI-MS m/z 118.1[ 2 ] M + H-HCl] ⁺ 。

Step 6 preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentan-1-ol

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 (20 mL), 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[ 2 ], [ M ] +H] ⁺ 。

Step 7 preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate

(R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentan-1-ol (2.9g, 9.2mmol) was dissolved in dichloromethane (25 mL), 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[ 2 ] M + H] ⁺ 。

Step 8 preparation of methyl (R) -8- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-6-carboxylate

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

Step 9 preparation of methyl (R) -8- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-6-carboxylate

Reacting (R) -8- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (1.0g, 1.7mmol) was charged in a 100mL reaction flask and the reaction flask was charged with 2Dissolving in 0mL ethanol and 4mL water, adding iron powder (0.95g, 17.2mmol) and ammonium chloride (0.91g, 17.2mmol), stirring at 75 deg.C for 2h, filtering after the reaction is finished, concentrating, diluting with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, and concentrating to obtain the title compound. ESI-MS m/z 541.2[ 2 ], [ M + H ]] ⁺ 。

Step 10 preparation of methyl (R) -8- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-6-carboxylate

Weighing (R) -8- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (0.76g, 1.4 mmol) was dissolved in 10mL of dichloromethane in a reaction flask, t-butanol (2 mL) and cyanogen bromide (0.22g, 2.1 mmol) were added, stirring was carried out at room temperature overnight, after completion of the reaction, a saturated aqueous sodium bicarbonate solution was added to quench the reaction, dichloromethane was added for extraction, anhydrous sodium sulfate was added for drying, and concentration was carried out to give the title compound. ESI-MS m/z of 566.2[ deg. ] M + H] ⁺ 。

Step 11 preparation of (R) -8- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-6-carboxylic acid

Weighing (R) -8- (5- ((5- (2-amino-6-bromo-1H-benzo [ d)]Imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (0.87g, 1.53mmol) is dissolved in tetrahydrofuran (15 mL) in a reaction flask, 1.3mol/L sodium hydroxide aqueous solution (15 mL) is added, the mixture is stirred for 2h at room temperature, after the reaction is finished, the mixture is concentrated under reduced pressure, 4mol/L diluted hydrochloric acid is used for adjusting the pH value to weak acidity, and the title compound is obtained after filtration and vacuum drying. ESI-MS m/z:552.2[ deg. ] M + H] ⁺ 。

Step 12 (R, 2) ⁷ Z,5 ² E)-5 ⁶ -bromo-1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

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

Step 13 (R, 2) ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Pyridine-1 (4, 5) -pyrazoloundecane-5 ⁶ Preparation of formaldehyde

Palladium acetate (0.036g, 0.164mmol), n-butyldi (1-adamantyl) phosphine (0.088g, 0.246mmol), sodium formate (0.558g, 8.2mmol), (R, 2) ⁷ Z,5 ² E)-5 ⁶ -bromo-1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Dissolving pyridine-1 (4, 5) -pyrazoloundecan-3-one (0.437g, 0.82mmol) in N, N-dimethylformamide (16 mL) in a reaction bottle, adding a mixed solution of formic acid (0.155 mL) and acetic anhydride (0.387 mL), stirring at 30 ℃ for 1h under the protection of argon, adding triethylamine (0.570g, 4.1mmol), reacting at 110 ℃ for 3h, diluting with ethyl acetate after the reaction is finished, and diluting with waterWashing for three times, drying the organic phase by anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound. ESI-MS m/z of 484.2[ 2 ] M + H] ⁺ .

Step 14 (R, 2) ⁷ Z,5 ² E)-5 ⁶ - ((dimethylamino) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

Weighing (R, 2) ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Pyridine-1 (4, 5) -pyrazoloundecane-5 ⁶ Formaldehyde (0.06g, 0.124mmol) was dissolved in 5mL dichloromethane in a 100mL reaction flask, dimethylamine (0.022g, 0.50mmol), glacial acetic acid (0.07g, 1.13mmol) and sodium triacetoxyborohydride (0.074g, 0.35mmol) were sequentially stirred at room temperature overnight, after completion of the reaction, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate, diluted with dichloromethane, washed with water three times, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. ESI-MS m/z:513.3[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.72(s,1H),9.08(s,1H),8.85(s,1H),8.61(s,1H),8.16(d,J＝12.6Hz,1H),7.68(s,1H),7.59–7.45(m,2H),7.18(d,J＝7.8Hz,1H),4.47(s,1H),4.23(d,J＝13.1Hz,1H),4.03(s,1H),3.95(d,J＝11.6Hz,1H),3.77(s,3H),2.23(s,6H),2.02–1.94(m,2H),1.49(d,J＝9.2Hz,2H),1.34(d,J＝5.3Hz,1H),1.24(s,2H),0.82(d,J＝6.3Hz,3H).

Example 2B: (R, 2) ⁷ Z,5 ² E)-5 ⁶ - (((S) -3, 4-dimethylpiperidin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

The title compound was obtained by substituting dimethylamine with (S) -1, 2-dimethylpiperazine and performing the procedure in step 14 of example 1B. ESI-MS m/z of 582.30[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.73(s,1H),9.08(s,1H),8.86(s,1H),8.62(s,1H),8.18(s,1H),7.68(s,1H),7.52(s,2H),7.18(d,J＝8.2Hz,1H),4.49(s,1H),4.25(d,J＝13.0Hz,1H),4.03(s,1H),3.98–3.89(m,2H),3.78(s,3H),3.60(s,2H),3.51(s,3H),2.85(s,2H),2.23(dd,J＝29.9,16.4Hz,2H),1.99(d,J＝7.5Hz,2H),1.48(s,2H),1.34(s,2H),1.24(s,3H),1.05(s,1H),0.87–0.79(m,3H).

Example 3B (R, 2) ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-5 ⁶ - ((4-methyl-3-oxapiperazin-1-yl) methyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-one

The title compound was obtained by substituting dimethylamine with 1-methylpiperazino-2-one and performing the procedure in step 14 of example 1B. ESI-MS m/z of 582.30[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.72(s,1H),9.08(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.68(s,1H),7.58–7.49(m,2H),7.19(d,J＝8.0Hz,1H),4.48(s,1H),4.22(d,J＝12.0Hz,1H),4.03(s,1H),4.00–3.91(m,1H),3.77(s,3H),3.64(s,2H),3.00(s,2H),2.82(s,3H),2.64(d,J＝3.4Hz,2H),2.23(s,1H),1.98(d,J＝10.2Hz,2H),1.49(d,J＝9.4Hz,2H),1.23(s,2H),0.82(d,J＝6.3Hz,3H).

Example 4B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - (((R) -3, 4-dimethylpiperidin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

The title compound was obtained by substituting dimethylamine with (R) -1, 2-dimethylpiperazine and performing the procedure in step 14 of example 1B. ESI-MS m/z:582.3[ 2 ], [ M + H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.71(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.67(s,1H),7.50(d,J＝5.8Hz,2H),7.20–7.14(m,1H),4.47(s,1H),4.38(s,1H),4.23(d,J＝12.1Hz,1H),4.03(d,J＝7.0Hz,1H),3.77(s,3H),3.57(d,J＝5.5Hz,2H),3.17(s,3H),2.71(s,2H),2.33(s,2H),2.26–2.18(m,3H),1.34(s,2H),1.23(s,3H),1.01(s,3H),0.83(d,J＝2.9Hz,3H).

Example 5B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - (((S) -2, 4-dimethylpiperidin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

The title compound was obtained by substituting dimethylamine with (S) -1, 3-dimethylpiperidine and performing the procedure in step 14 of example 1B. ESI-MS m/z:582.3[ 2 ], [ M + H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.72(s,1H),9.08(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.68(s,1H),7.51(d,J＝7.0Hz,2H),7.19(s,1H),4.47(s,1H),4.24(d,J＝12.3Hz,1H),4.03(s,1H),3.95–3.86(m,1H),3.77(s,3H),3.07(d,J＝6.8Hz,2H),2.86(s,2H),2.72(s,2H),2.56(s,2H),2.25(d,J＝7.3Hz,1H),2.21–2.13(m,1H),1.97(t,J＝12.7Hz,2H),1.48(s,2H),1.23(s,3H),1.19(s,3H),0.83(d,J＝6.2Hz,3H).

Example 6B (R, 2) ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-5 ⁶ - (piperazin-1-ylmethyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -bisImidazo [1,2-a ]]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

Replacing dimethylamine with 1-formic acid tert-butyl ester piperazine, and carrying out the operation according to the step 14 of the embodiment 1B to obtain a crude product, and stirring the crude product for 1 hour by using 2M hydrochloric acid/dioxane; purification gives the title compound. ESI-MS m/z 554.3[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.67(s,1H),7.50(d,J＝7.8Hz,2H),7.17(d,J＝8.2Hz,1H),4.47(s,1H),4.23(d,J＝12.5Hz,1H),4.03(s,1H),3.98–3.89(m,1H),3.77(s,3H),3.55(s,2H),3.51(s,1H),2.85(s,2H),2.77(s,2H),2.36(s,2H),2.23(s,2H),2.02–1.93(m,2H),1.49(d,J＝9.5Hz,1H),1.23(s,2H),0.85(s,1H),0.82(d,J＝6.3Hz,3H).

Example 7B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - ((4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Pyridin-1 (4, 5) -pyrazoloundundecan-3-ones

The title compound was obtained by substituting dimethylamine with 4- (trifluoromethyl) piperidin-4-ol, and purifying by the procedure of example 1B, step 14. ESI-MS m/z:637.3[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.06(d,J＝17.6Hz,1H),8.82(d,J＝28.1Hz,1H),8.59(d,J＝20.7Hz,1H),8.15(d,J＝18.2Hz,1H),7.68(s,1H),7.56(d,J＝29.5Hz,2H),7.26–7.12(m,1H),5.74(s,1H),4.48(s,1H),4.24(d,J＝10.3Hz,1H),4.03(s,1H),3.94(s,1H),3.77(s,2H),3.60(s,3H),3.12–3.04(m,1H),2.86(s,1H),2.67(s,1H),2.26(dd,J＝41.5,17.5Hz,2H),1.98(d,J＝7.2Hz,2H),1.76(s,2H),1.65(s,1H),1.49(d,J＝8.9Hz,1H),1.20(dd,J＝17.3,10.0Hz,3H),0.83(s,3H).

Examples8B:(R,2 ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-5 ⁶ - (1-methyl-1H-pyrazol-4-yl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoline cycloundecan-3-ones

Step 1 (R, 2) ⁷ Z,5 ² Z)-5 ⁶ -bromo-1 ¹ 7-dimethyl-5 ³ - ((2- (trimethylsilyl) ethoxy) methyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoline cycloundecan-3-ones

Will be (R, 2) ⁷ Z,5 ² E)-5 ⁶ -bromo-1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazole- [1,2-a]-pyridine-1 (4, 5) -pyrazoloundecan-3-one (0.4g, 0.75mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), and after 2h reaction, sodium hydride (0.04g, 0.9mmol) was added at 0 deg.C, 2- (trimethylsilyl) ethoxymethyl chloride (0.17mL, 0.97mmol) was added dropwise and reacted at room temperature for 1h. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, washing is carried out for three times, an organic phase is dried by anhydrous sodium sulfate, and column chromatography purification is carried out to obtain the title compound. ESI-MS m/z of 664.2[ 2 ] M + H] ⁺ .

Step 2 (R, 2) ⁷ Z,5 ² Z)-1 ¹ 7-dimethyl-5 ⁶ - (1-methyl-1H-pyrazol-4-yl) -5 ³ - ((2- (trimethylsilyl) ethoxy) methyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

Will be (R, 2) ⁷ Z,5 ² Z)-5 ⁶ -bromo-1 ¹ 7-dimethyl-5 ³ - ((2- (trimethylsilyl) ethoxy) methyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Pyridine-1 (4, 5) -pyrazoline cycloundecan-3-one (0.05g, 0.075mmol) was dissolved in 10ml of N, N-dimethylformamide, and then 0.05mL of water, 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -1H-pyrazole (0.015g, 0.075mmol), palladium acetate (0.005g, 0.0125mmol), potassium phosphate (0.05g, 0.125mmol), n-butyl (di-adamantylphosphine) (0.025g, 0.0075mmol) were sequentially added, and reacted at 125 ℃ for 16 hours. After the reaction was complete, the title compound was obtained by filtration over celite, extraction with ethyl acetate, washing with water three times, drying the organic phase over anhydrous sodium sulfate and concentration. ESI-MS m/z:666.3[ 2 ], [ M + H ]] ⁺ .

Step 3 (R, 2) ⁷ Z,5 ² E)-1 ¹ 7-dimethyl-5 ⁶ - (1-methyl-1H-pyrazol-4-yl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoline cycloundecan-3-ones

Will be (R, 2) ⁷ Z,5 ² Z)-1 ¹ 7-dimethyl-5 ⁶ - (1-methyl-1H-pyrazol-4-yl) -5 ³ - ((2- (trimethylsilyl) ethoxy) methyl) -5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Pyridine-1 (4, 5) -pyrazoloundecan-3-one (0.05g, 0.075mmol) was dissolved in 5mL dichloromethane, and 2mL dioxane hydrochloride solution (4M) was further charged and reacted at room temperature overnight. After the reaction, adjusting the pH of saturated sodium bicarbonate aqueous solution to about 5, extracting with ethyl acetate, washing with water for three times, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain the titleA compound is provided. ESI-MS m/z:536.3 2[ 2 ], [ M + H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.68(s,1H),9.08(s,1H),8.85(s,1H),8.62(s,1H),8.17(s,1H),7.94(d,J＝9.3Hz,2H),7.82(d,J＝9.8Hz,1H),7.68(s,1H),7.51(d,J＝8.2Hz,1H),7.44(d,J＝8.0Hz,1H),4.49(s,1H),4.37(d,J＝7.1Hz,1H),3.89(s,1H),3.78(s,1H),2.89(s,3H),2.73(s,3H),1.40(s,1H),1.24(s,4H),0.85(d,J＝6.0Hz,3H).

Example 9B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - ((3- (dimethylamino) azetidin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1,2-a ]]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

The title compound was obtained by substituting dimethylamine with 3-dimethylaminoazetidine and purifying it as in example 1B, step 14. ESI-MS m/z 568.3[ 2 ] M + H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.70(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.68(s,1H),7.56–7.46(m,2H),7.16(d,J＝8.1Hz,1H),4.47(s,1H),4.23(d,J＝12.4Hz,2H),4.03(s,2H),3.98–3.87(m,2H),3.77(s,3H),2.99(s,2H),2.89(s,2H),2.06(s,6H),1.97(s,1H),1.55–1.45(m,2H),1.34(s,2H),0.83(d,J＝6.1Hz,3H).

Example 10B (R, 2) ⁷ Z,5 ² E)-5 ⁶ - ((4- (2, 2-difluoroethyl) piperazin-1-yl) methyl) -1 ¹ 7-dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-2 (8, 6), 5 (2, 1) -diimidazo [1, 2-a)]Preparation of pyridin-1 (4, 5) -pyrazoloundecan-3-ones

Dimethylamine was replaced with 1- (2, 2-difluoroethyl) piperazine and purified as in step 14 of example 1BThe title compound. ESI-MS m/z of 618.3[ 2 ], [ M + H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.67(s,1H),9.07(s,1H),8.85(s,1H),8.61(s,1H),8.17(s,1H),7.67(s,1H),7.49(d,J＝4.1Hz,2H),7.16(d,J＝8.2Hz,1H),6.12(t,J＝55.8Hz,1H),4.48(s,1H),4.22(d,J＝12.1Hz,1H),4.02(s,1H),3.98–3.88(m,1H),3.77(s,3H),3.56(s,2H),2.73(dd,J＝15.6,3.8Hz,2H),2.54(s,2H),2.40(s,4H),2.23(s,2H),1.96(t,J＝10.1Hz,2H),1.53–1.45(m,1H),1.17(s,2H),0.81(d,J＝6.3Hz,3H).

Examples 11B-22B were synthesized according to the synthesis method of examples 1B-10B of the present invention using different starting materials, and the characterization parameters of examples 11B-22B are shown in Table 1B:

table 1B:

experimental example 1 evaluation of cell Activity of Compound in vitro

1. Experimental Material

Test compounds: the compounds of the invention prepared in the above examples, each compound was prepared in DMSO as a 10mM stock solution, and tested by final dilution at 10 concentrations, with the compounds tested in PC-9 (del 19/T790M/C797S) cells at 2000nM, 666.66nM, 222.22nM, 74.07nM, 24.69nM, 8.23nM, 2.74nM, 0.91nM, 0.30nM; NCI-H1975 (L858R/T790M) cell experiments showed final concentrations of 25000nM, 6250nM, 1563nM, 390.6nM, 97.66nM, 24.41nM, 6.10nM, 1.53nM, 0.38nM of compound.

PC-9 (del 19/T790M/C797S) cells were purchased from Beijing Bai Biotech, inc. of Nanjing. NCI-H1975 (L858R/T790M) cells were purchased from ATCC.

Reagent: epidermal Growth Factor (EGF) available from Invitrogen, USA under the reference PHG0311; cellTiter-Glo Luminescent Cell vitality Assay, available from Promega, USA under the product number G7573; brigatinib, available from Selleck, USA under the trade designation S8229; the CCK-8 proliferation inhibition detection kit is purchased from KeygEN company in the United states, and has the product number of KGA317-2.

2. Experimental method

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:

PC-9 (del 19/T790M/C797S) cells: 1640 medium, 10% FBS,1% streptomycin, 2ug/ml puromycin.

NCI-H1975 (L858R/T790M) cells: 1640 medium, 10% FBS,1% streptomycin.

(3) Cell culture conditions: 37 ℃ and 5% of CO ₂ 95% air

(4) The culture medium is changed or passaged every 2-3 days according to the growth condition of the cells.

2.2 cell plating

PC-9 (del 19/T790M/C797S) cells: removed from the cell culture flask and resuspended in fresh medium. 100 μ L of cell resuspension was inoculated in 96-well culture plates at 2X10 ³ Individual cells/well.

NCI-H1975 (L858R/T790M) cells: removed from the cell culture flask and resuspended in fresh medium. 100 μ L of cell resuspension was inoculated into 96-well culture plates at 1X10 ³ Individual cells/well.

2.3 administration of drugs

PC-9 (del 19/T790M/C797S) cells: cells on the basis of the original old medium (100. Mu.L), 100. Mu.L of medium containing different concentrations of drugs (2X) (1640 +10% FBS +1% streptomycin lividans + 2. Mu.g/ml puromycin) was added to the administration group, 100. Mu.L of medium (1640 +10% FBS +1% streptomycin lividans +2ug/ml puromycin) was added to the blank group (no cells), 100. Mu.L of medium containing DMSO was added to the DMSO group, two duplicate wells were set for each concentration group, and 5 CO was put in successively ₂ The incubator was used for 3 days. The compounds were formulated as follows: weighing in advanceCompound 1-2mg, formulated in 20mM stock solution using DMSO. Drugs were diluted with DMSO starting at maximum concentration of 2000nM to 9 concentration gradients in sequence with 1: 2000nM, 666.67nM, 222.22nM, 74.07nM, 24.67nM, 8.23nM, 2.74nM, 0.914nM, 0.305nM.

NCI-H1975 (L858R/T790M) cells: cells on the basis of the original old medium (100. Mu.L), 100. Mu.L of medium containing drugs at different concentrations (2X) (1640 +10% FBS +1% streptomycin) was added to the dosing group, 100. Mu.L of medium (1640 +10% FBS +1% streptomycin) was added to the blank group (no cells), 100. Mu.L of medium (1640 +10% FBS +1% streptomycin) was added to the DMSO group, two duplicate wells were set for each concentration group, and 5% CO was put on ₂ The incubator is used for 3 days. The compounds were formulated as follows: compounds 1-2mg were weighed in advance and made up in 20mM stock solution using DMSO. Drugs were diluted with DMSO starting at 2500nM maximum concentration, sequentially diluted to 9 concentration gradients in 1: 25000nM, 6250nM, 1563nM, 390.6nM, 97.66nM, 24.41nM, 6.10nM, 1.53nM, 0.38nM.

2.4 detection

NCI-H1975 (L858R/T790M) cells: after 7 days of drug treatment, the medium in the wells was aspirated away, and the wells were drained as much as possible, 100. Mu.L of complete medium to which CCK-8 had been added (CCK-8: medium =1 10) was added, and after continuing to be placed in an incubator and cultured for a certain time, the 96-well plate was taken out from the incubator, allowed to stand at room temperature for 5min for equilibration, placed in a multifunctional plate reader, and the absorbance (OD value) at 450nm was measured, and the cell proliferation inhibition rate was calculated. The formula is Inhibition (%) =100- (OD) _{Experiment hole} -OD _{Blank hole} )/(OD _{DMSO hole} -OD _{Blank hole} ) 100, IC based on different drug concentrations and their corresponding inhibition rates, using GraghPad 5.0 software ₅₀ Drawing a curve, analyzing data to obtain a final IC ₅₀ Values, experimental results are shown in table 2B.

PC-9 (del 19/T790M/C797S): after 72 hours of drug treatment, the medium in the wells was aspirated off, and the wells were drained as much as possible, 100. Mu.L of complete medium to which CCK-8 had been added (CCK-8: medium =1 10) was added, and after continuing to be placed in the incubator for a certain time, the 96-well plate was taken out from the incubator, and placed at room temperatureAnd (4) balancing for 5min, placing in a multifunctional plate reader, detecting the absorbance (OD value) at 450nm, and calculating the cell proliferation inhibition rate. The formula is Inhibition (%) =100- (OD) _{Experiment hole} -OD _{Blank hole} )/(OD _{DMSO hole} -OD _{Blank hole} ) 100, IC using GraghPad 5.0 software according to different drug concentrations and their corresponding inhibition rates ₅₀ Drawing a curve, analyzing the data to obtain a final IC ₅₀ Values, experimental results are shown in table 2B.

3. Results of the experiment

TABLE 2B

"-" indicates no test

As can be seen from the experimental results, the compound of the invention shows good inhibitory activity on EGFR del19/T790M/C797S mutant and L858R/T790M mutant tumor cells.

Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

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,

wherein the content of the first and second substances,

ring a is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, said aryl, heteroaryl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;

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-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy;

R ¹ selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylamino;

R ² selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkanoyl,Aminoacyl, alkylaminoacyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, heterocyclyl, aryl, and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkanoyl, hydroxyalkanoyl, cycloalkylacyl, heterocyclanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;

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

when Cy is piperazinyl and L is-CH ₂ -when ring a is not pyridyl.

2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein ring a is selected from C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl, said C _6-16 Aryl, 5-16 membered heteroaryl, C _3-16 Cycloalkyl and 3-16 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo; and

cy is selected from C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C _6-12 Aryl, 5-12 membered heteroaryl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.

3. The compound of claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein L is selected from the group consisting of a bond, -S-, -O-, -N-, -CH ₂ -、-CH ₂ CH ₂ 、-C(O)-、-S(O)-、-S(O) ₂ -and

wherein R is ⁴ 、R ⁵ Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C _2-10 Alkenyl radical, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl and C _1-6 An alkoxy group.

4. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ¹ Selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl and di-C _1-6 An alkylamino 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 R ² Is selected from C _1-6 Alkyl radical, C _3-12 Cycloalkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Alkyl acyl, amino acyl, C _1-6 Alkylaminoacyl radical, C _1-6 Alkylsulfonyl, aminosulfonyl, C _1-6 Alkylaminosulfonyl, 3-12 membered heterocyclic group, C _6-12 Aryl and 5-12 membered heteroaryl, said groups being optionally substituted by one or more groups selected from halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl radical, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo; r is ³ Each independently selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 Alkylamino radical, C _1-6 Alkylacylamino group, C _1-6 Alkyl acyl, C _1-6 Alkylsulfonyl, aminoacyl, C _1-6 Alkylaminoacyl, di-C _1-6 Alkylamino radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo C _1-6 Alkyl acyl, hydroxy C _1-6 Alkyl acyl radical, C _3-12 Cycloalkylacyl, 3-12 membered heterocycloyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.

6. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the general formula (I) has the following structure of the general formula (Ia),

wherein R is ¹ 、R ² 、R ³ M, cy and L have the definitions given above for formula (I);

x, Q and Y are independently selected from N, C and CH;

ring B is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;

represents a single or double bond;

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

n is 1,2, 3 or 4.

7. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the general formula (I) has the following general formula (II),

wherein R is ¹ 、R ² 、R ³ M, cy and L have the meanings indicated for general formula (I) in claims 1 to 6;

R ⁶ each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamido, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; and

n is 1,2, 3 or 4.

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:

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 1-8, or an isomer, a pharmaceutically acceptable salt, solvate, crystal or 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 ovarian cell cancer, serous cystic ovarian cancer, thyroid cancer, multiple myeloma, renal cell cancer, mantle cell lymphoma, or triple negative breast cancer.