WO2023011610A1

WO2023011610A1 - Benzodioxane compound, preparation method therefor and application thereof

Info

Publication number: WO2023011610A1
Application number: PCT/CN2022/110398
Authority: WO
Inventors: 邓贤明; 黄伟; 吴振华; 云彩红; 张建明; 黄鑫
Original assignee: 南京红云生物科技有限公司
Priority date: 2021-08-06
Filing date: 2022-08-05
Publication date: 2023-02-09
Also published as: TW202321228A; CN117794923A

Abstract

Provided are a benzodioxane compound, a preparation method therefor and an application thereof. Specifically, the present invention relates to a compound having EGFR inhibitory activity, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and a use of these compounds in the preparation of a drug for preventing and/or treating EGFR kinase-mediated cancer and other diseases.

Description

Benzodioxane compounds, their preparation method and application

technical field

The invention relates to the field of medicinal chemistry, in particular to benzodioxane compounds, their preparation method and application.

Background technique

In recent years, the morbidity and mortality of cancer have shown a gradual upward trend, seriously threatening human life and health. In order to improve the living conditions of cancer patients, scientific researchers have carried out extensive and in-depth research on the pathogenesis of cancer, targeting at the key proteins in the growth and proliferation of cancer cells, using small molecule compounds for selective intervention, and developed a series of Targeted drugs with high efficacy and few side effects have benefited a large number of patients. Studies have shown that at least 10% of patients with non-small cell lung cancer have epidermal growth factor receptor (EGFR) mutations (Nature Reviews Cancer, 2007, 7, 169-181), the most common of which is exon 19 deletion (19Del) or Point mutation in exon 20 (L858R). These mutations lead to enhanced kinase activity and downstream signaling pathways of EGFR, leading to tumorigenesis. Small-molecule inhibitors targeting EGFR block the combination of EGFR and adenosine triphosphate (ATP), thereby inhibiting EGFR activation and downstream signaling pathways, causing tumor cell growth, proliferation, and metastasis stagnation, leading to cell death, and achieving Effective control of EGFR-mediated tumors.

However, after the clinical use of EGFR inhibitors, drug resistance will soon appear. The main way is that the pathogenic EGFR further undergoes point mutations, resulting in the inability of small molecules to effectively bind to it, and the inhibitory effect decreases or even disappears, such as the most common The T790M mutation. In response to this situation, researchers have found a new generation of inhibitors that can effectively combine with drug-resistant EGFR through structural optimization, so as to overcome the problem of drug resistance. For the resistance of the first-generation inhibitors gefitinib or erlotinib, the second-generation inhibitor afatinib can effectively overcome the T790M mutation by forming a covalent bond with the 797-position cysteine residue of EGFR. The third-generation inhibitor osimertinib is also a covalent inhibitor, and because of its weak activity against wild-type EGFR, it reduces the toxic and side effects of the second-generation drugs. However, drug resistance will still appear after osimertinib treatment (Nature Medicine, 2015, 21, 560-562), the main mechanism is that the 797 cysteine residue of EGFR is mutated to a serine residue (C797S), resulting in cysteine The covalent bond between the sulfhydryl group of the amino acid residue and the inhibitor disappears, and the interaction between the two is greatly weakened, resulting in drug resistance. Currently, there is no marketed drug that can overcome C797S.

Therefore, it is of great significance and clinical value to develop fourth-generation EGFR inhibitors that can overcome the C797S mutation.

Contents of the invention

After extensive and in-depth research, the inventors of the present application have designed and synthesized a series of small molecular compounds with novel structures, which have a good inhibitory effect on various mutants of EGFR kinase commonly seen in clinical practice, including mutants containing C797S.

The present invention provides compounds as shown below:

Or a stereoisomer of the above compound, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate.

The definitions of substituents and symbols are described in detail below.

One object of the present invention is to provide a class of compounds with the activity of inhibiting EGFR kinase, their stereoisomers, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates.

Another object of the present invention is to provide the preparation method of the above compound.

Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

Another object of the present invention is to provide the use of the above compound and the pharmaceutical composition comprising the above compound in the preparation of medicaments for the prevention and/or treatment of EGFR kinase-mediated cancer or other diseases.

Another object of the present invention is to provide a method of treating cancer comprising administering to a subject an effective amount of a compound or composition of the present invention.

Detailed description of the invention

Various specific embodiments, modes, and examples are described herein, including exemplary embodiments and definitions used in order to understand the invention as claimed. While the following detailed description presents specific preferred embodiments, those skilled in the art will appreciate that these embodiments are exemplary only and that the invention may be practiced otherwise. For purposes of determining infringement, the scope of the invention will be to any one or more of the appended claims, including their equivalents, and those elements or limitations equivalent to those stated.

The present invention is achieved through the following technical solutions.

In a first aspect of the present invention, the present invention provides compounds of the following general formula (A):

or a stereoisomer of said compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

in:

R ¹ is selected from

1)

Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are each independently selected from the following, and Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) 2-N,N-Dimethylaminoethoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morphine Linylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N,N-dimethylaminopropoxy, 3-N,N-diethylaminopropyl Oxygen, 3-N,N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3-(N-acetylpiperazinyl)propoxy, 3- Morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidylpropoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, Phenylmethoxy, monohalogen substituted phenylmethoxy, gem dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy,

(4) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(5) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(6) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(8) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(9) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(10) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(11) Aminomethylene, N,N-dimethylaminomethylene, N,N-diethylaminomethylene, 4-methyl-1-piperazinemethylene, 4-ethyl- 1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1-piperazine methylene Methyl, 4-(2-N,N-Dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N,N-dimethylamino)- 1-Piperidine-1-methylene, 4-hydroxypiperidin-1-methylene, tetrahydropyrrole-1-methylene, 3-(N,N-dimethylamino)-1-tetrahydropyrromethene radical, benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(12) Carbamoyl, methylcarbamoyl, N,N-dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylamine Aminoacetyl, cyclohexylcarbamoyl, aminoacetyl, methylaminoacetyl, 2-(N,N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, Cyclobutylaminoacetyl, cyclopentylaminoacetyl, cyclohexylaminoacetyl,

Tetrahydropyrrole-1-formyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,

Morpholinyl-4-formyl, Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,

Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1 -Formyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N,N-diethylaminoethyl)piperazine-1-formyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-formyl,

(13) Hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, n-butoxyformyl, isobutoxyformyl, tert-butoxy formyl,

(14) Hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylamine Sulfonyl, cyclohexylaminosulfonyl,

Tetrahydropyrrole-1-sulfonyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,

Morpholinyl-4-sulfonyl, thiomorpholinyl-4-sulfonyl, 2 6-dimethylmorpholinyl-4-sulfonyl,

Piperidinyl-1-sulfonyl, 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,

N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl)piperazine-1 -sulfonyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N,N-diethylaminoethyl)piperazine-1-sulfonyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-sulfonyl,

(15) Carbamoylamino, methylcarbamoylamino, ethylcarbamido, propylcarbamoyl, isopropylcarbamido, cyclopropylcarbamido, cyclobutylcarbamido, cyclo Amylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-diethylpiperidinyl-1-carboxylamino, tetrahydropyrrolyl-1-carboxylamino, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxylamino, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxylamino, N-methylpiperazinyl-1-carboxylamino, N-ethylpiperazinyl-1-carboxylamino, N-acetyl Basepiperazinyl-1-carboxamido, N-tert-butoxycarbonylpiperazinyl-1-carboxamido, N-(2-hydroxyethyl)piperazinyl-1-carboxamido, N-(2 -cyanoethyl)piperazinyl-1-carboxamido, N-(2-N,N-dimethylaminoethyl)piperazinyl-1-carboxamido, N-(2-N,N -Diethylaminoethyl)piperazinyl-1-carboxamido, N-(3-hydroxypropyl)piperazinyl-1-carboxamido, N-(3-N,N-dimethylpropyl Base) piperazinyl-1-carboxamido, N-(3-N,N-diethylpropyl)piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3,5 -Dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazinyl)piperidinyl- 1-formylamino, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl)piperidinyl-1- Formylamino, N-(N-methyl-4-piperidinyl)piperazinyl-1-formylamino,

(16)

2)

Wherein Y ² , Y ³ , Y ⁴ , Y ⁵ are the same as defined in 1), and Y ² , Y ³ , Y ⁴ , Y ⁵ are not hydrogen at the same time;

3)

Wherein Y ¹ , Y ³ , Y ⁴ , Y ⁵ are the same as defined in 1), and Y ¹ , Y ³ , Y ⁴ , Y ⁵ are not hydrogen at the same time;

4)

Wherein Y ¹ , Y ² , Y ⁴ , Y ⁵ are as defined in 1), and Y ¹ , Y ² , Y ⁴ , Y ⁵ are not hydrogen at the same time;

5)

Wherein Y ¹ , Y ³ , Y ⁵ are the same as defined in 1), and Y ¹ , Y ³ , Y ⁵ are not hydrogen at the same time;

^R2 is selected from:

1)

Wherein, Z ¹ and Z ² are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl group, and ^Z2 is not hydrogen;

2)

Wherein, Z ^is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing Alkyl, C3-C8 heteroatom-containing cycloalkyl;

3)

Wherein, Z ⁴ and Z ⁵ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, or, Z ⁴ , Z ⁵ together with N form a substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms, the substituents are selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl;

R ³ and R ⁴ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 cycloalkyl (for example, cyclopropyl) , C2-C6 alkenyl;

Alternatively, R ³ , R ⁴ and the carbon atoms attached to them together form a 5-membered ring containing one N, O or S atom.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(4) Piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl Azinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethyl Aminopropyl)piperazinyl, N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-( N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl , 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N- Isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl Azinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl Acylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(16)

2)

3)

4)

5)

^R2 is selected from:

1)

2)

3)

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(3) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(4) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(5) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(10) Benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(11) piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperidinyl Azinyl) piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)

Wherein Y ¹ , Y ³ , Y ⁴ , Y ⁵ are the same as defined in 1), and Y ¹ , Y ³ , Y ⁴ , Y ⁵ are not hydrogen at the same time.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(3) Piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl Azinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethyl Aminopropyl)piperazinyl, N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-( N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl , 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N- Isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl Azinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl Acylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(12)

2)

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl , N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl Base) piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N- Ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N ,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino,

(11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4 -(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

(12)

2)

Wherein Y ¹ , Y ³ , Y ⁴ , and Y ⁵ are each independently selected from the following, and Y ¹ , Y ³ , Y ⁴ , and Y ⁵ are not hydrogen at the same time:

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N-dimethylamino)ethylamino, N -isopropyl-N-(2-N,N-dimethylamino)ethylamino.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4 -piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(nitrogen Hetidine-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidine-3 -yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl,

(12)

2)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- )piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine,

(3) piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, 4-(azacyclic Butane-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(7) 4-N,N-Dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-) piperidinyl,

(8) N-methyl-4-piperidinyl,

(9) 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N,N-dimethylaminoethylamino, N-methyl-N-(2- N,N-dimethylamino)ethylamino,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) 4-N,N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine,

(3) N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, 4-(azetidin-3-yl) piperazinyl, 4-(N -Methyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(8) N-methyl-4-piperidinyl,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) 4-N,N-Dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl.

In some embodiments, Z ¹ and Z ² are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z ² is not for hydrogen.

In some embodiments, Z ¹ , Z ² are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z ² is not hydrogen.

In some embodiments, Z ¹ , Z ² are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z ² is not hydrogen.

In some embodiments, Z ^is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from methyl, ethyl, isopropyl, cyclopropyl.

In some embodiments, Z ⁴ , Z ⁵ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z ⁴ , ^Z5 is not simultaneously hydrogen.

In some embodiments, Z ⁴ and Z ⁵ are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z ⁴ and Z ⁵ are not hydrogen at the same time.

In some embodiments, Z ⁴ and Z ⁵ are each independently selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl, and Z ⁴ and Z ⁵ are not hydrogen at the same time.

In some embodiments, R ³ and R ⁴ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen Alkyl, C1-C6 fluorinated alkyl, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl.

In some embodiments, R ³ and R ⁴ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing Alkyl, C2-C6 alkenyl.

In some embodiments, R ³ , R ⁴ are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoro Methyl, vinyl, 1-methyl-vinyl.

In some embodiments, R ³ , R ⁴ , together with the carbon atoms to which they are attached, form

In a second aspect of the present invention, the present invention provides compounds represented by the following formula I:

in:

R ¹ is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(16)

2)

3)

4)

5)

Z ^is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

^Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

^R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1 -C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl;

R ⁴ is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl;

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(16)

2)

3)

4)

5)

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(12)

2)

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(12)

2)

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(3) Piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl Base, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperazinyl Pyridyl) piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N -Ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl,

(12)

2)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(4) N-methyl-N-(2-N, N-dimethylamino) ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ethylamino, N -isopropyl-N-(2-N,N-dimethylamino)ethylamino.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(12)

2)

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy,

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(8) N-methyl-4-piperidinyl,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) 4-N,N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino.

In some embodiments, ^R is selected from

1)

(1) hydrogen, fluorine,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(8) N-methyl-4-piperidinyl,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) 4-N,N-Dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl.

In some embodiments, ^R is selected from

1)

in:

Y ^is selected from hydrogen, fluorine, methoxy, trifluoromethoxy,

Y ^is selected from hydrogen, fluorine,

^Y3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2-hydroxyl) ethylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N -Methyl-N-(2-N,N-dimethylamino)ethylamino, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methyl-4-piperidinyl , piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl- Azetidin-3-yl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1 -formyl,

Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl ^, cyclopropylmethylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,

Y ⁵ is hydrogen,

And Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are not hydrogen at the same time;

Preferably,

As a whole, selected from:

2)

in:

Y ^is selected from hydrogen, methoxy,

^Y3 is selected from 4-(N-methylpiperazin-1-)piperidinyl, 4-N,N-dimethylaminopiperidinyl, N-methyl-N-(2-N,N-di Methylamino) ethylamino;

Y ^is selected from hydrogen, methyl, ethyl;

Y is ^selected from hydrogen;

Preferably,

As a whole, selected from:

In some embodiments, ^R is selected from

1)

in:

Y ^is selected from hydrogen, fluorine, methoxy, trifluoromethoxy,

Y ^is selected from hydrogen, fluorine,

^Y3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2-hydroxyl) ethylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N -Methyl-N-(2-N,N-dimethylamino)ethylamino, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methylpiperazinyl, N- (N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(azetidin-3-yl ) piperazinyl, 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

Y ⁵ is hydrogen,

And Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are not hydrogen at the same time;

Preferably,

As a whole, selected from:

2)

in:

Y ^is selected from hydrogen, methoxy;

^Y3 is selected from 4-(N-methylpiperazin-1-)piperidinyl, 4-N,N-dimethylaminopiperidinyl;

Y ^is selected from hydrogen, methyl, ethyl;

Y is ^selected from hydrogen;

Preferably,

As a whole, selected from:

In some embodiments, Z ^is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from hydrogen, methyl, ethyl, cyclopropyl.

In some embodiments, Z ² is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from methyl, ethyl, isopropyl, cyclopropyl.

In some embodiments, R ^is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C2-C6 Alkenyl.

In some embodiments, ^R is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1-Methyl-vinyl.

In some embodiments, R ⁴ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, ^R4 is hydrogen.

In a third aspect of the present invention, the present invention provides compounds represented by the following formula II:

in:

R ¹ is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(4) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(5) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base;

2)

3)

4)

5)

^R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl;

R ⁴ is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl.

In some embodiments, R ^is

Wherein, Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are each independently selected from the following, and Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are not hydrogen at the same time:

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4 -piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl,

(4) 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl.

In some embodiments, R ^is

Hydrogen, C1-C6 alkyl, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methylpiperazinyl -1-)piperidinyl.

In some embodiments, R ^is

in:

Y ^is selected from hydrogen, methoxy,

^Y2 is hydrogen,

Y ^is selected from N-methylpiperazinyl, 4-(N-methylpiperazin-1-)piperidinyl, N-(N-methyl-4-piperidinyl)piperazinyl,

Y ⁴ is ethyl,

^Y5 is hydrogen.

In some embodiments, ^R is selected from

In some embodiments, Z ^is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from methyl, ethyl, isopropyl, cyclopropyl.

In some embodiments, R ^is selected from fluoro, chloro, bromo, iodo, C2-C6 alkenyl.

In some embodiments, ^R is selected from bromo, vinyl.

In some embodiments, R ⁴ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, ^R4 is hydrogen.

In the fourth aspect of the present invention, the present invention provides the compound shown in the following formula III:

in:

R ¹ is selected from

1)

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

2)

3)

4)

5)

Z ⁴ and Z ⁵ are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z ⁴ and Z ⁵ are not hydrogen at the same time ;

In some embodiments, R ^is

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4 -piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl.

In some embodiments, R ^is

Hydrogen, C1-C6 alkyl, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl.

In some embodiments, R ^is

in:

Y ^is selected from hydrogen, methoxy,

^Y2 is hydrogen,

Y ^is selected from N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl,

Y ⁴ is ethyl,

^Y5 is hydrogen.

In some embodiments, ^R is selected from

In some embodiments, Z ^is selected from hydrogen, C1-C6 alkyl, preferably hydrogen; Z ^is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

In some embodiments, Z ^is selected from hydrogen and ^Z is selected from methyl, ethyl, isopropyl, cyclopropyl.

In some embodiments, ^R is selected from bromo, vinyl.

In some embodiments, R ⁴ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, ^R4 is hydrogen.

Unless otherwise specified, the above-mentioned groups and substituents have ordinary meanings in the field of medicinal chemistry.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

The term "C1-C6 alkyl" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.

The term "C1-C3 alkyl" refers to any linear or branched chain group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

The term "deuterated alkyl" refers to a group formed after one or more hydrogen atoms in any of the above-mentioned alkyl groups (such as C1-C6 alkyl, C1-C3 alkyl, etc.) are replaced by deuterium atoms, for example, deuterated The alkyl group may be deuterated methyl, deuterated ethyl, deuterated n-propyl or deuterated isopropyl and the like. Specifically, for example, the deuteromethyl group may be monodeuteromethyl group, dideuteromethyl group or trideuteromethyl group.

The term "oxyalkyl group" refers to a group in which the alkyl skeleton is substituted by one or more alkoxy groups, for example, methoxyethyl, methoxyethoxymethyl and the like.

For example, a C1-C6 oxyalkyl group refers to a group in which the C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy base methyl etc. Similarly, a C1-C3 oxyalkyl group refers to a group in which a C1-C3 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups.

The term "C2-C6 alkenyl" refers to any straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl Base etc.

The term "C3-C8 cycloalkyl" refers to a 3-8-membered monocyclic hydrocarbon having a saturated ring, and the C3-C8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "C3-C6 cycloalkyl" refers to a 3-6-membered monocyclic hydrocarbon having a saturated ring, and the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "cyano" refers to a -CN residue.

The term "nitro" refers to a _-NO2 group.

The term "heteroatom" refers to N, O or S.

The terms "alkoxy", "cyclyloxy" and derivatives thereof refer to any of the above-mentioned alkyl (such as C1-C6 alkyl, C1-C3 alkyl, etc.), cycloalkyl (such as C3-C6 cycloalkane group), which is attached to the rest of the molecule through an oxygen atom (-O-).

The term "heteroaryl" refers to an aromatic heterocycle, usually a 5-, 6-, 7-, 8-membered heterocycle having 1 to 3 heteroatoms selected from N, O or S; heteroaryl The base ring can optionally be further fused or attached to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of said heteroaryl groups are e.g. pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaxazolyl, pyrrolyl, benzene Base-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuryl, benzothienyl, benzo1,3-dioxolane (benzodioxol), isoindolinyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3- Dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The term "heterocyclyl" (also "heterocycloalkyl") refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings in which one or more carbon atoms Replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc.

For example, "6-membered heterocyclyl" refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 6-membered heterocyclic groups are, for example, pyran, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl, and the like.

"5-membered heterocyclyl" refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 5-membered heterocyclic groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.

The term "optionally substituted heterocyclic group" refers to the above-mentioned "heterocyclic group" replaced by one or more "C1-C6 alkyl", "C1-C3 alkyl", "C3-C6 cycloalkyl", etc. replace.

"Fluorine-containing alkyl group" refers to a group in which the above-mentioned alkyl skeleton (such as C1-C6 alkyl group) is replaced by one or more fluorine groups, such as monofluoromethyl, difluoroethyl, trifluoromethyl wait.

The term "C1-C6 fluorine-containing alkyl group" refers to a group in which the above-mentioned C1-C6 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl wait.

Similarly, the term "C1-C3 fluorine-containing alkyl group" refers to a group in which the C1-C3 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl Base etc.

The term "fluorine-containing alkoxy" refers to any of the above-mentioned fluorine-containing alkyl groups (such as C1-C6 fluorine-containing alkyl groups, C1-C3 fluorine-containing alkyl groups, etc.) which are connected to the rest of the molecule through an oxygen atom (-O-) Moieties, such as trifluoromethoxy,

etc.

The term "C1-C6 heteroatom-containing alkyl group" refers to a group in which one or more carbon atoms in the C1-C6 alkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur, for example,

wait.

The term "C3-C8 heteroatom-containing cycloalkyl" refers to a group in which one or more carbon atoms in the C3-C8 cycloalkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur, For example, pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl and the like.

The term "sulfonyl" refers to and -S(=O) _2- .

The term "C1-C6 alkylsulfonyl" refers to -S(=O) ₂ -C1-C6 alkyl, such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and the like.

From all the foregoing descriptions, it will be apparent to those skilled in the art that any group whose name is a compound name, such as "fluorine-containing oxyalkyl", shall refer to the moiety from which it is conventionally derived, such as from a fluorinated group Substituted oxyalkyl groups wherein alkyl is as defined above. Similarly, there is also "fluorinated alkoxy". As another example, "arylamino" shall mean a moiety conventionally derived therefrom, for example constructed from an amino group substituted with an aryl group, wherein aryl is as defined above. Similarly, the meaning of "heteroarylamino" can be understood. Similarly, "hydroxysulfonyl", "aminosulfonyl" and the like are to be understood.

Likewise, arbitrary terms such as alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxyformyl, etc. compound group, wherein the alkyl, alkoxy, etc. moieties are as defined above.

The term "R ³ and R ⁴ are each independently selected from" means that the groups represented by R ³ and R ⁴ may be the same or different, and there is no restriction on each other. For example, R ³ and R ⁴ are each independently selected from hydrogen or methyl, which means that R ³ is selected from hydrogen or methyl, and R ⁴ is selected from hydrogen or methyl. Other similar definitions can be understood with reference to the foregoing.

According to the present invention and unless otherwise provided, any of the above-mentioned groups may optionally be substituted at any free position thereof by one or more groups, for example by 1-6 groups independently selected from: Halogen atom, nitro, oxo (=O), cyano, C1-C6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkylamino, Hydroxyheterocyclyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, heterocyclyl-alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, Alkyl-aryl, Alkyl-heteroaryl, Alkyl-heterocyclyl, Alkyl-cycloalkyl, Alkyl-aryl-alkyl, Alkyl-heteroaryl-alkyl, Alkyl-hetero Cyclo-Alkyl, Alkyl-Cycloalkyl-Alkyl, Alkyl-Heterocyclyl-Heterocyclyl, Heterocyclyl-Heterocyclyl, Heterocyclyl-Alkyl-Heterocyclyl, Heterocyclyl- Alkylamino, Alkyl-Heterocyclyl-Alkyl-Amino, Hydroxy, Alkoxy, Aryloxy, Heterocyclyloxy, Alkyl-Heterocyclyloxy, Methylenedioxy, Alkylcarbonyl Oxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclic oxycarbonyl, amino, ureido, alkylamino, amino-alkylamino, dialkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, arylamino, arylalkyl Alkylamino, diarylamino, heterocyclylamino, alkyl-heterocyclylamino, alkyl-heterocyclylcarbonyl, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkyl Base-heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonylamino-alkylamino, alkane Oxycarbonylheterocyclyl-alkylamino, alkoxy-aryl-alkyl, hydroxyamino-carbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino , formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aromatic Aminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate.

Furthermore, each of the above-mentioned substituents may be further substituted by one or more of the above-mentioned groups, if appropriate.

The term "oxygen-containing substituted or unsubstituted five-seven-membered ring" or "nitrogen-containing substituted or unsubstituted five-seven-membered ring" refers to 5-, 6- or 7-membered saturated or partially unsaturated carbon A ring in which one or more carbon atoms are replaced by oxygen or nitrogen. Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.

The term "substituted or unsubstituted five-seven-membered ring" refers to a 5-, 6- or 7-membered saturated or partially unsaturated carbocyclic ring. Non-limiting examples are, for example, cyclopentane, cyclohexane, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene (cyclohexa-1,3-diene, cyclohexa-1,4 -diene), etc.

The term "substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms" refers to a 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic ring, one or 2 carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.

For formula (A)

The compounds shown, the terms "R ³ , R ⁴ together with the carbon atoms to which they are attached, form

It refers to, the structural formula of the compound shown in formula (A) is

dotted double bond

Indicates the position where the heterocyclic ring formed by R ³ , R ⁴ and the carbon atoms connected to them is fused with the parent nucleus. In addition, formula (I)

Definitions of similar terms in the compounds shown are explained and understood with reference to the foregoing.

As used herein, unless otherwise stated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are inactive in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).

As used herein, examples of the term "pharmaceutically acceptable salts of compounds of formula (A), (I), (II) or (III)" are organic salts formed from organic acids that form pharmaceutically acceptable anions. Acid addition salts, including but not limited to formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α-ketoglutarate, α-glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkylsulfonate is methanesulfonate or ethylsulfonate; The arylsulfonate is benzenesulfonate or p-toluenesulfonate. Suitable inorganic salts may also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, and carbonate, sulfate or phosphate salts, and the like.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid to furnish a pharmaceutically acceptable anion.

The term "treating" as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.

According to a specific technical scheme of the present invention, the compound, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, wherein the compound is the following example One of the compounds described in.

In another aspect, the present invention provides a pharmaceutical composition, which comprises the compound described in any of the above technical schemes, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate material, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the pharmaceutical composition further comprises EGFR mAb.

In some embodiments, the EGFR mAb is cetuximab or a biosimilar thereof.

The term "biological analogue" refers to an antibody product whose sequence is identical to that of cetuximab, and whose physical and chemical properties, biological activity, clinical safety and efficacy are also consistent with those of cetuximab.

Methods for preparing various pharmaceutical compositions containing certain amounts of active ingredients are known, or will be apparent to those skilled in the art in light of this disclosure. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating suitable pharmaceutical excipients, carriers, diluents and the like.

The pharmaceutical formulations of the present invention are manufactured in known ways, including conventional mixing, dissolving or lyophilization methods. The compounds of the invention can be formulated into pharmaceutical compositions and administered to a patient by various routes suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).

Thus, the compounds of the present invention may be administered systemically, eg, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft-shell gelatin capsules, which can be compressed into tablets. For oral therapeutic administration, the active compound may be combined with one or more excipients and presented in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, discs, etc. use. Such compositions and preparations should contain at least 0.1% of active compound. The proportion of such compositions and preparations may of course vary and may comprise from about 1% to about 99% by weight of a given unit dosage form. In such therapeutically useful compositions, the amount of active compound is such that an effective dosage level will be obtained.

Tablets, troches, pills, capsules, etc. may also contain: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, Potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, oil of wintergreen, or cherry flavor. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar or the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propylparaben as a preservative, a dye and flavoring such as cherry flavor or orange flavor. Of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. Additionally, the active compounds can be incorporated into sustained release formulations and devices.

The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Aqueous solutions of the active compound, or a salt thereof, can be prepared, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may comprise sterile aqueous solutions or dispersions containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solutions or dispersions. elixirs or sterile powders. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, nontoxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, such as sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption (eg, aluminum monostearate and gelatin).

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional required ingredient present in a previously sterile-filtered solution. .

Useful solid carriers include comminuted solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like). Useful liquid carriers include water, ethanol or glycol or water-ethanol/glycol mixtures, in which the compounds of this invention can be dissolved or dispersed in effective amounts, optionally with the aid of nontoxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.

Thickening agents (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) can also be used with liquid carriers to form spreadable pastes, gels, and ointments , soap, etc., directly on the user's skin.

The therapeutic requirement of the compound or its active salt or derivative depends not only on the particular salt chosen, but also on the mode of administration, the nature of the disease to be treated and the age and condition of the patient, and ultimately on the attending physician or clinician decision.

The formulations described above can be presented in unit dosage form, which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies. The unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets. The amount of a unit dose of active ingredient may be varied or adjusted from about 0.1 to about 1000 milligrams or more depending on the particular treatment involved.

In addition, it also includes the application of various new drug dosage forms such as emulsion liposomes, microspheres and nanospheres, such as the use of particle dispersion systems including polymeric micelles, nanoemulsions, submicroemulsions and microemulsions. Drugs prepared from microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles).

On the other hand, the present invention also provides the preparation method of the compound described in any of the above technical schemes, comprising the following steps:

Reaction conditions:

(a) Nucleophilic substitution reactions under acidic or basic conditions;

(b) a coupling reaction catalyzed by metal palladium, or a nucleophilic substitution reaction under acidic conditions, or a nucleophilic substitution reaction under basic conditions;

(c) a coupling reaction catalyzed by metal palladium, or a coupling reaction catalyzed by metal copper;

in:

The metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride , Three (dibenzylideneacetone) dipalladium;

The basic conditions refer to the conditions under which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride;

The acidic conditions refer to the conditions under which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid;

X represents halogen, and R ³ -Y represents the boronic acid corresponding to R ³ (ie

), borate (ie

), tin reagent (such as n-tributyltin reagent that is

) or alkyne reagents (such as trimethylsilylacetylene ie

);

The definitions of R ¹ , R ² , R ³ and R ⁴ are detailed in the previous description.

On the other hand, the present invention also provides stereoisomers, prodrugs, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds described in any of the above technical schemes, and medicaments containing the compounds Use of the composition in preparing medicines for preventing and/or treating EGFR kinase-mediated cancer and other diseases, especially in preparing medicines for preventing and/or treating lung cancer (preferably non-small cell lung cancer) , especially in the preparation of drugs for the prevention and/or treatment of EGFR kinase 19Del, L858R, T790M, C797S or their combination mutant lung cancer (preferably non-small cell lung cancer), most preferably in the preparation of drugs for the prevention and/or Drugs for the treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer) use.

On the other hand, the present invention also provides a method for preventing and/or treating EGFR kinase-mediated cancer and other diseases, which comprises administering a preventive and/or therapeutically effective amount of the above-mentioned compound or its stereoisomer to a subject in need , its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above pharmaceutical composition.

In some embodiments, the method is for the prevention and/or treatment of lung cancer (preferably non-small cell lung cancer).

In some embodiments, the method is used to prevent and/or treat EGFR kinase 19Del, L858R, T790M, C797S or combinations thereof mutant lung cancer (preferably non-small cell lung cancer).

In some embodiments, the method is used to prevent and/or treat EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/ C797S triple mutation lung cancer (preferably non-small cell lung cancer).

On the other hand, the present invention also provides the above-mentioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition, which is used for preventing and / or treatment of EGFR kinase-mediated cancer and other diseases, preferably for the prevention and / or treatment of lung cancer (preferably non-small cell lung cancer), more preferably for the prevention and / or treatment of EGFR kinase 19Del, L858R, T790M, C797S or its Combined mutation lung cancer (preferably non-small cell lung cancer), most preferably for the prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation Or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).

In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal is a human.

In the present invention, "effective amount" refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dosage and time. A "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount in which any toxic or detrimental consequences are outweighed by the therapeutically beneficial effects of the substance/molecule. A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect. Usually, but not necessarily, the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease. In the case of cancer, the therapeutically effective amount of the drug reduces the number of cancer cells; reduces tumor volume; inhibits (i.e. slows down to some extent, preferably stops) the infiltration of cancer cells into surrounding organs; inhibits (i.e. slows down to some extent, preferably stops) ) tumor metastasis; inhibition of tumor growth to a certain extent; and/or alleviation of one or more symptoms associated with cancer to a certain extent.

Experimental part

For the examples referred to below, the compounds of the invention were synthesized using the methods described herein or other methods well known in the art.

General purification and analysis methods:

Thin-layer chromatography was performed on silica gel GF254 pre-coated plates (Qingdao Ocean Chemical Factory). Column chromatographic separation over silica gel (300-400 mesh, Huangwu Silica Gel Development Reagent Factory, Zhifu District, Yantai City) under medium pressure or by using ISCO Combiflash Rf200 rapid purification system with prepacked silica gel cartridges (ISCO or Welch) for column chromatography Chromatographic separation. The composition was visualized by UV light (wavelength 254nm) and by iodine vapor. When necessary, compounds were purified by preparative HPLC on a Waters Symmetry C18 (19 x 50mm, 5μm) column or on a Waters X Terra RP 18 (30 x 150mm, 5μm) column using a Waters Preparative 996 Waters PDA detector. Type HPLC 600 and Micromass mod.ZMD single quadruple mass spectrometry (electrospray ionization, positive ion mode) detection. Method 1: Phase A: 0.1% TFA/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: 10 to 90% B for 8 minutes, maintain 90% B for 2 minutes; flow rate 20mL/min. Method 2: Phase A: 0.05% NH4OH/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: 10 to 100% B for 8 minutes, 100% B for 2 minutes; flow rate 20mL/min.

¹ H-NMR spectra were recorded on a Bruker Avance 600 nuclear magnetic resonance spectrometer at 600 MHz. Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hz. The tetramethylsilane signal was used as reference (δ = 0 ppm). The following abbreviations are used for peak splitting: s = single; br.s. = broad signal; d = double; t = triple; m = multiple; dd = double double.

Electrospray (ESI) mass spectra were obtained with a Finnigan LCQ ion trap.

Unless otherwise stated, all final compounds were homogeneous (not less than 95% pure) as determined by high performance liquid chromatography (HPLC). HPLC-UV-MS analysis for evaluating compound purity was performed by combining ion trap MS equipment with HPLC system SSP4000 (Thermo Separation Products) equipped with autosampler LC Pal (CTC Analytics) and UV6000LP diode array Detector (UV detection 215-400nm). Equipment control, data acquisition and processing were performed with Xcalibur 1.2 software (Finnigan). HPLC chromatography was performed at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 μm). Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10, mobile phase B ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; gradient from 0 to 100% B was run for 7 minutes, then held at 100% B for 2 minutes before rebalancing.

Reagent purification was carried out with reference to Purification of Laboratory Chemicals (Perrin, D.D., Armarego, W.L.F. and Perrins Eds, D.R.; Pergamon Press: Oxford, 1980). Petroleum ether is a 60-90°C fraction, and ethyl acetate, methanol, and methylene chloride are all analytically pure.

Detailed ways

Compounds can be divided into three main categories:

Some raw materials and intermediates involved in the synthesis process are described as follows:

1.

From 1-(2-fluoro-5-nitrophenyl)ethanone (cas: 79110-05-7, Bi De, Shanghai) and N-methylpiperazine (cas: 109-01-3, Anaiji , Shanghai) responded to

Reduction of ketone carbonyl and nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

Morpholine (cas: 110-91-8, Aladdin, Shanghai), N-methyl-2-hydroxyethylamine (cas: 109-83-1, Anaiji, Shanghai), ethanolamine (cas: 141-43 -5, Aladdin, Shanghai), N,N-dimethylethylenediamine (cas: 108-00-9, Bi De, Shanghai), N,N,N'-trimethylethylenediamine (cas: 142-25-6, Biide, Shanghai), 2-oxa-6-azaspiro[3.3]heptane (cas: 174-78-7, Biide, Shanghai), 2-methyl-2,6 -Diazaspiro[3.3]heptane (cas: 1203567-11-6, Bi De, Shanghai), 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Ai Kang, Jiangsu), tert-butyl piperazine-1-carboxylate (cas: 57260-71-6, Bi De, Shanghai).

2.

By the reaction of 3-bromo-4-fluoronitrobenzene (cas: 701-45-1, Bi De, Shanghai) and N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai) to

Then react with cyclopropylboronic acid (cas: 411235-57-9, Bi De, Shanghai) to obtain

Reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

2-nitro-4-bromo-5-fluoroanisole (cas: 1352244-77-9, Bi De, Shanghai), morpholine (cas: 110-91-8, Aladdin, Shanghai), 1-methano Base-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Ai Kang, Jiangsu), 1-methyl-1H-pyrazole-4-boronic acid (cas: 847818-55-7, Biide, Shanghai), imidazole (cas: 288-32-4, Anaiji, Shanghai), pyrazole (cas: 288-13-1, Biide, Shanghai).

3.

Obtained by the reaction of 2-fluoro-5-nitrotoluene (cas: 455-88-9, Bi De, Shanghai) and N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai)

Reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (cas: 314298-13-0, Bi De, Shanghai), 2,3,4-trifluoronitrobenzene (cas: 771 -69-7, Bi De, Shanghai), 3,4,5-trifluoronitrobenzene (cas: 66684-58-0, Bi De, Shanghai), , 5-fluoro-2-nitroanisole ( cas: 448-19-1, Bi De, Shanghai), p-fluoronitrobenzene (cas: 350-46-9, Bi De, Shanghai), 2-fluoro-5-nitropyridine (cas: 456-24- 6, Bi De, Shanghai),

Morpholine (cas: 110-91-8, Aladdin, Shanghai), 3-N,N-Dimethylaminopyrrolidine (cas: 64021-83-6, TCI, Shanghai), 4-Dimethylaminopiperidine (cas: 50533-97-6, Shaoyuan, Shanghai), 1-methyl-4-(4-piperidinyl) piperazine (cas: 53617-36-0, Aikang, Jiangsu), 4-hydroxypiperazine Pyridine (cas: 5382-16-1, Anaiji, Shanghai).

4.

2-Fluoro-4-hydroxyacetophenone (cas: 98619-07-9, Bi De, Shanghai) was reduced to 3-fluoro-4-ethylphenol by palladium carbon and hydrogen, and then nitrated to obtain 3-fluoro-4 -Ethyl-6-nitrophenol, further reacted with iodomethane (cas: 74-88-4, West Asia reagent, Shandong) to obtain 3-fluoro-4-ethyl-6-nitroanisole, and then reacted with N -Methylpiperazine (cas: 109-01-3, Anaiji, Shanghai) was reacted to

The final reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

3-N,N-dimethylaminopyrrolidine (cas: 64021-83-6, TCI, Shanghai), 4-dimethylaminopiperidine (cas: 50533-97-6, Shaoyuan, Shanghai), ethanolamine ( cas: 141-43-5, Aladdin, Shanghai), N,N-Dimethylethylenediamine (cas: 108-00-9, Bi De, Shanghai), N,N,N'-trimethylethylenediamine Diamine (cas: 142-25-6, Biide, Shanghai), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (cas: 205059-24-1, Biide, Shanghai) , 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu), 1-(1-methylpiperidin-4-yl)piperazine (cas : 23995-88-2, Bailingwei, Shanghai), 1-(1-methylazetidin-3-yl) piperazine (cas: 864350-81-2, Bailingwei, Shanghai), 2-methyl- 2,7-Diazaspiro[3.5]nonane dihydrochloride (cas: 1610028-42-6, Bide, Shanghai), 2-methyl-2,6-diazaspiro[3.3]heptane Oxalate (cas: 1527515-86-1, Ai Kang, Jiangsu) 2-oxa-6-azaspiro[3.3]heptane oxalate (cas: 1159599-99-1, Bi De, Shanghai), tert-butyl piperazine-1-carboxylate (cas: 57260-71-6, Bi De, Shanghai).

5.

From tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (cas: 203661-69-2, Bi De, Shanghai) and dimethylamine (cas: 124-40-3, Aladdin, Shanghai) Responses get

After removing the tert-butoxycarbonyl group, react with 3-fluoro-4-ethyl-6-nitroanisole in (4) to obtain

Reduction of nitro derived.

6.

From 1-bromo-2-methyl-4-methoxy-5-nitrobenzene (cas: 89978-56-3, Jiuding Chemical, Shanghai) to 2-bromo-4-nitro-5-methanol Oxybenzoic acid, and then condensed with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to obtain

Further coupled with potassium ethylene trifluoroborate (cas: 13682-77-4, Bi De, Shanghai) to obtain

obtained by restoration.

7.

From 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (cas: 1352244-77-9, Bi De, Shanghai) and 1-methyl-4-(4-piperidinyl)piper Oxyzine (cas: 53617-36-0, Aikang, Jiangsu) was reacted to obtain

Then coupled with isopropenylboronic acid pinacol ester (cas: 126726-62-3, Bi De, Shanghai) to obtain

further restored.

8.

Nitrate 2-fluoro-4-methoxybenzaldehyde (cas: 331-64-6) to obtain 2-fluoro-4-methoxy-5-nitrobenzaldehyde, and then reduce it to obtain 2-fluoro-4-methoxybenzaldehyde Oxy-5-nitrobenzyl alcohol, further brominated to 2-fluoro-4-methoxy-5-nitrobenzyl bromide, and then with cyclopropylboronic acid (cas: 411235-57-9, Bi De, Shanghai) respond well

Then react with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to obtain

The final reduction of nitro derived.

Change cyclopropylboronic acid to phenylboronic acid (cas: 98-80-6, Anaiji, Shanghai), and obtain

9.

From nitration of 1-bromo-2-fluoro-4-trifluoromethoxybenzene (cas: 168971-68-4, Bi De, Shanghai) to obtain 2-trifluoromethoxy-4-fluoro-5 bromonitrobenzene , and then react with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to obtain

Obtained by debromination and reduction of nitro;

The above bromide is further reacted with vinyl pinacol borate (cas: 75927-49-0, Bi De, Shanghai) to obtain

Then reduce the nitro group to get

Simultaneous reduction of nitro group and double bond to obtain

10.

2-methoxy-3-nitro-6-chloropyridine was obtained by reacting 2,6-dichloro-3-nitropyridine with sodium methoxide (cas: 124-41-4, Anaiji, Shanghai), and then React with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to get

Reduction of amino derived.

From 2,6-dichloro-3-nitro-5-picoline obtained by a similar method.

It can be obtained by reacting with liquid bromine (cas: 7726-95-6, Sinopharm Group, Shanghai)

Then react with vinyl pinacol borate (cas: 75927-49-0, Bi De, Shanghai) to get

Then reduce the nitro group and the double bond to get

11.

Obtained by the reaction of m-bromonitrobenzene (cas: 585-79-5, Aladdin, Shanghai) and 4-pyridineboronic acid (cas: 1692-15-5, Shuya, Shanghai)

Further react with iodomethane (cas: 74-88-4, West Asia reagent, Shandong) to obtain

Finally, it can be obtained by reducing the nitro group and the pyridine ring.

From 4-bromo-2-nitroanisole (cas: 33696-00-3, Bi De, Shanghai) obtained by a similar method.

12.

Obtained by the reaction of m-bromonitrobenzene (cas: 585-79-5, Anaiji, Shanghai) and 4-hydroxypiperidine (cas: 5382-16-1, Anaiji, Shanghai)

It is obtained by reducing the nitro group;

The following intermediates were obtained in a similar manner:

The raw materials involved are:

N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai), 4-bromo-2-nitroanisole (cas: 33696-00-3, Shuya, Shanghai).

13. 2,4-dichloro-5-bromopyrimidine (cas: 36082-50-5, Bi De, Shanghai).

14. 2,4,5-Trichloropyrimidine (cas: 5750-76-5, Anaiji, Shanghai).

15. 2,4-dichloro-5-methylpyrimidine (cas: 1780-31-0, Bi De, Shanghai).

16. 2,4-Dichloropyrimidine (cas: 3934-20-1, Bide, Shanghai)

17. 2,4-dichloro-5-fluoropyrimidine (cas: 2927-71-7, Bi De, Shanghai).

18. 2,4-dichloro-5-trifluoromethylpyrimidine (cas: 3932-97-6, Bi De, Shanghai).

19. 2,4-Dichloro-5-ethylpyrimidine (cas: 34171-40-9, Bide, Shanghai)

20. 2,4-dichloro-5-isopropylpyrimidine (cas: 514843-12-0, Biide, Shanghai)

21. 2,4-dichloro-5-methoxypyrimidine (cas: 19646-07-2, Bi De, Shanghai).

22. 2,4-Dichloro-5-ethylpyrimidine (cas: 34171-40-9, Biide, Shanghai)

23. 2,4-dichloro-5-cyanopyrimidine (cas: 3177-24-0, Bi De, Shanghai).

24. 2,4-dichloro-5-nitropyrimidine (cas: 49845-33-2, Aikang, Shanghai).

25. 2,4-dichloro-7-(2-trimethylsilethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, derived from 2,4-dichloro-7H-pyrrolo [2,3-d]pyrimidine (cas: 90213-66-4, Shuya, Shanghai) and 2-(trimethylsilyl)ethoxymethyl chloride (CAS: 76513-69-4, Yifei, Shanghai ) reaction.

26.

From 2-methoxy-5-nitrophenol (cas: 636-93-1, Bi De, Shanghai) and 1,3-dichloro-5,5-dimethylhydantoin (cas: 118-52- 5, Bi De, Shanghai) reaction to obtain 2-chloro-6-methoxyl-3-nitrophenol, remove the methyl group to obtain 3-chloro-4-nitro-1,2-benzenediol, and then form Sulphonylethylamine (obtained by the reaction of methylsulfonyl chloride (cas: 124-63-0, West Asia reagent, Shandong) and ethylamine (cas: 75-04-7, Aladdin, Shanghai))

Then react with 1,2-dibromoethane (cas: 106-93-4, Aladdin, Shanghai) to get

Reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

Cyclopropylamine (cas: 765-30-0, Anaiji, Shanghai), Methanesulfonylmethylamine (cas: 1184-85-6, Bi De, Shanghai), Methylsulfonamide (cas: 3144- 09-0, Bide, Shanghai), methylamine (cas: 74-89-5, Anaiji, Shanghai), ethylsulfonyl chloride (cas: 594-44-5, Anaiji, Shanghai), isopropyl Sulfonyl chloride (cas: 10147-37-2, TCI, Shanghai), cyclopropylsulfonyl chloride (cas: 139631-62-2, Anaiji, Shanghai).

27.

From 2-methoxy-5-nitrophenol (cas: 636-93-1, Bi De, Shanghai) and N-bromosuccinimide (cas: 128-08-5, Bi De, Shanghai) React to get 2-bromo-6-methoxy-3-nitrophenol, demethylate to get 3-bromo-4-nitro-1,2-benzenediol, and then react with 1,2-dibromoethane (cas: 106-93-4, Aladdin, Shanghai) responded

Further react with sodium methanesulfinate (cas: 20277-69-4, Bi De, Shanghai) to obtain

Reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

Sodium ethyl sulfinate (cas: 20035-08-9, Aladdin, Shanghai), sodium isopropyl sulfinate (cas: 4160-19-4, Bi De, Shanghai), sodium cyclopropyl sulfinate (cas: 910209-21-1, Bi De, Shanghai).

28.

from (27)

Reaction with benzylthiol (cas: 100-53-8, Aladdin, Shanghai) to get

Reoxidized to get

Then react with methylamine (cas: 74-89-5, Anaiji, Shanghai) to convert to

The final reduction of nitro derived.

The following intermediates were obtained in a similar manner:

The raw materials involved are:

Ethylamine (cas: 75-04-7, Aladdin, Shanghai), Isopropylamine (cas: 75-31-0, Anaiji, Shanghai), Cyclopropylamine (cas: 765-30-0, Anaji, Shanghai)

29. Vinyl boronic acid pinacol ester (cas: 75927-49-0, Bi De, Shanghai).

30. Isopropenyl borate pinacol ester (cas: 126726-62-3, Bi De, Shanghai).

31.

Obtained by the reaction of 3-fluoro-4-ethyl-6-nitroanisole in (4) with tert-butyl piperazine-1-carboxylate (cas: 57260-71-6, Bide, Shanghai)

Then remove the tert-butoxycarbonyl group, and further react with deuterated methyl iodide (cas: 865-50-9, Aladdin, Shanghai) to obtain

The final reduction of nitro derived.

32.

From 1-(2-fluoro-5-nitrophenyl)ethanone (cas: 79110-05-7, Bi De, Shanghai) and piperazine-1-carboxylate tert-butyl ester (cas: 57260-71-6 , Bi De, Shanghai) the reaction gets

Reduction of nitro and carbonyl derived.

33.

From 2-nitro-4-methyl-5-chlorophenol (cas: 100278-74-8, Bi De, Shanghai) and iodomethane (cas: 74-88-4, West Asia reagent, Shandong) reaction to obtain 2- Nitro-4-methyl-5-chloroanisole, then reacted with 4-pyridineboronic acid (cas: 1692-15-5, Shuya, Shanghai) to obtain

Finally, it can be obtained by reduction of nitro group and pyridine ring.

34.

Obtained by the reaction of 2,6-dichloro-3-nitropyridine (cas: 16013-85-7, Bi De, Shanghai) and trifluoroethanol (cas: 75-89-8, Aladdin, Shanghai)

Further react with N,N,N'-trimethylethylenediamine (cas: 142-25-6, Bi De, Shanghai) to get

Then react with liquid bromine (cas: 7726-95-6, Sinopharm Group, Shanghai) to obtain

And then react with vinyl pinacol borate (cas: 75927-49-0, Bi De, Shanghai) to get

Finally, it can be obtained by reduction of double bond and nitro group.

The implementation of the present invention will be described in detail below through specific examples, but they should not be construed as limiting the present invention in any case.

Synthesis of compounds I-1 and I-79:

The first step: Dissolve compound 1 (200mg, 0.77mmol) in DMF (2mL), add NaH (60% content, dispersed in liquid paraffin, 62mg, 1.54mmol) in batches at 0°C, and add 2 , 4-dichloro-5-bromopyrimidine (194mg, 0.85mmol), reacted for 1 hour from heating, and TLC and LCMS detected that the reaction was complete. After adding 100 mL of water, solids were precipitated, filtered, and drained to obtain compound 2 (281 mg), which was directly used in the next step.

Step 2: Compound 2 (45mg, 0.1mmol), Compound 3 (22mg, 0.1mmol) and methanesulfonic acid (19μL, 0.3mmol) were heated in t-BuOH (2mL) at 100°C for 4h, TLC and LCMS detected that the reaction was complete . After cooling, the reaction mixture was concentrated, purified by silica gel column (eluted with dichloromethane/methanol), and then purified by preparative HPLC (with water and methanol containing 0.35% trifluoroacetic acid as mobile phase) to obtain compound I-1 ( 51 mg).

The third step: Compound I-1 (0.051mmol, 32mg), vinylboronic acid pinacol ester (0.102mmol, 17μL), PdCl ₂ (dppf)·CH ₂ Cl ₂ (0.0051mmol, 4.1mg), Na ₂ CO ₃ (0.20mmol, 22mg) was dispersed in 1,4-dioxane (1mL) and water (0.5mL), and the reaction system was heated at 100°C for 4h after nitrogen replacement. TLC and LC-MS detect that the reaction is complete, and the reaction system is diluted with 50 mL of water and extracted with DCM. After the organic phase is concentrated, the silica gel column is purified (eluted with dichloromethane/methanol), and then subjected to preparative HPLC (with 0.35% trifluoro Acetic acid (water and methanol as mobile phase) was purified to obtain compound I-79 (15.7 mg).

Synthesis of Compound I-220:

The first step: compound 4 is the same as compound 2 prepared from compound 1 and 2,4-dichloro-7-(2-trimethylsilethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine obtained by the method.

The second step: compound 4 (54.1mg, 0.1mmol), compound 5 (23.5mg, 0.1mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (7.2mg, 0.015mmol) , Tris(dibenzylideneacetone) dipalladium (9.2mg, 0.01mmol) and potassium carbonate (41.4mg, 0.3mmol) were dispersed in t-BuOH (2mL), and the reaction system was preheated to 100 It was heated and stirred in an oil bath at ℃, and after 6 hours, it was detected by TLC and LCMS that the reaction was complete. After cooling, it was diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was concentrated, and purified by silica gel column (eluted with dichloromethane/methanol) to obtain compound 6 (55.7 mg).

Step 3: Compound 6 (35mg, 0.047mmol) was stirred in TFA/DCM (1/2mL) at room temperature for 2 hours, TLC and LCMS detected that the reaction was complete, concentrated, the residue was dissolved in methanol (2mL), and 25% ammonia water was added (1 mL), after 4 hours at room temperature, LCMS detected that the reaction was complete. Dilute with dichloromethane (50mL), wash once with saturated brine (30mL), separate the layers, dry the organic phase over anhydrous Na ₂ SO ₄ , filter, concentrate and purify on a silica gel column (eluted with dichloromethane/methanol ), and purified by preparative HPLC (water and methanol containing 0.35% trifluoroacetic acid as mobile phase) to obtain compound 1-220 (13.5 mg).

The rest of the compounds were obtained by similar methods.

The following table lists specific compounds and structural identification data:

Synthesis of compounds II-1, II-13:

Step 1: Compound 8 (334 mg) can be obtained from compound 7 (250 mg, 1.09 mmol) and 2,4-dichloro-5-bromopyrimidine (274 mg, 1.2 mmol) by the same method as compound 2.

Synthesis of Compound II-1: Compound 8 (42mg, 0.1mmol) and Compound 3 (22mg, 0.1mmol) were synthesized by the same method as Compound I-1 (43mg).

Synthesis of compound II-13: Compound II-1 (0.05mmol, 30mg) and vinylboronic acid pinacol ester (0.1mmol, 17μL) were prepared by the same method as compound I-79 (12.8mg).

Synthesis of III-1 and III-13:

Step 1: Dissolve compound 9 (300mg, 1.23mmol), cesium fluoride (19mg, 0.12mmol), cesium carbonate (802mg, 2.46mmol) in DMF (3mL), add 2,4-dichloro - 5-bromopyrimidine (308 mg, 1.35 mmol), reacted for 5 hours by heating up, and the reaction was completed by TLC and LCMS. After adding 100 mL of water, solids were precipitated, filtered, and dried to obtain compound 10 (418 mg), which was directly used in the next step.

Synthesis of compound III-1: obtained from compound 10 (44 mg, 0.1 mmol) and compound 3 (22 mg, 0.1 mmol) by the same method as compound I-1 (51 mg).

Synthesis of compound III-13: Compound III-1 (0.05 mmol, 31 mg) and vinylboronic acid pinacol ester (0.1 mmol, 17 μL) were obtained by the same method as compound I-79 (12.8 mg).

Biological activity test.

Growth inhibitory activity of compounds against kinase-stabilized cell lines.

The activity of compounds against various mutants of the kinase EGFR was assessed by their inhibition of the growth of the kinase-stabilized BaF ₃ cell line. The specific test method is as follows:

1) Medium: DMEM (Dulbecco's modified eagle medium) or RPMI1640 (containing 10% fetal bovine serum, 100 μg/mL ampicillin, 100 μg/mL streptomycin).

2) Reagent: MTS reaction solution (containing 2 mg/mL of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt); 100 μg/mL of PES (phenazine methosulfate).

3) Compound test: the cells were inserted into a 96-well culture plate, the volume of the cell solution was 90 μL, and then 10 μL of compounds of various gradient concentrations were added, with the highest concentration being 10 μM, which were successively diluted by 1/3, and a total of 8 concentration points were set. The system contains 0.1% DMSO (dimethyl sulfoxide). The mixed compound cell plate was placed in a cell culture incubator (37°C; 5% CO ₂ ) for 48 hours, and then 20 μL of MTS reaction solution was added, mixed and placed in a cell culture incubator (37°C; 5% CO ₂ ) Incubate for 1-4 h; use a microplate reader (VARIOSKAN FLASH, Thermo) to measure the OD value at a wavelength of 490 nm. Two parallel experiments were set up for each group of experiments, with the final concentration of 0.1% DMSO as the negative control, and the culture medium without cells and compounds as the blank control. The cell growth inhibition rate was calculated by the following formula:

Inhibition rate%=1-(OD experimental group-OD blank group)/(OD negative group-OD blank group)*100%

4) Calculation of IC ₅₀ value: According to the measured cell inhibition rate, the half-inhibitory concentration of the compound acting on the cells was calculated using GradPad Prism 5 software.

The following table lists the growth inhibitory activity of compounds against kinase-stabilized cell lines:

Note: ++++ represents IC ₅₀ ≤50nM; +++ represents 50nM<IC ₅₀ ≤500nM; ++ represents 500nM<IC ₅₀ ≤2500nM; ND represents not determined.

The rest of the compounds also have excellent inhibitory activity on the growth of the above-mentioned kinase stably transfected cell lines.

Claims

Compounds of the following general formula (A):

or a stereoisomer of said compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

in:

R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) 2-N,N-Dimethylaminoethoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morphine Linylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N,N-dimethylaminopropoxy, 3-N,N-diethylaminopropyl Oxygen, 3-N,N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3-(N-acetylpiperazinyl)propoxy, 3- Morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidylpropoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, Phenylmethoxy, monohalogen substituted phenylmethoxy, gem dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy,

(4) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(5) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(6) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(8) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(9) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(10) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(11) Aminomethylene, N,N-dimethylaminomethylene, N,N-diethylaminomethylene, 4-methyl-1-piperazinemethylene, 4-ethyl- 1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1-piperazine methylene Methyl, 4-(2-N,N-Dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N,N-dimethylamino)- 1-Piperidine-1-methylene, 4-hydroxypiperidin-1-methylene, tetrahydropyrrole-1-methylene, 3-(N,N-dimethylamino)-1-tetrahydropyrromethene radical, benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(12) Carbamoyl, methylcarbamoyl, N,N-dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylamine Aminoacetyl, cyclohexylcarbamoyl, aminoacetyl, methylaminoacetyl, 2-(N,N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, Cyclobutylaminoacetyl, cyclopentylaminoacetyl, cyclohexylaminoacetyl,

Tetrahydropyrrole-1-formyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,

Morpholinyl-4-formyl, Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,

Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1 -Formyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N,N-diethylaminoethyl)piperazine-1-formyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-formyl,

(13) Hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, n-butoxyformyl, isobutoxyformyl, tert-butoxy formyl,

(14) Hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylamine Sulfonyl, cyclohexylaminosulfonyl,

Tetrahydropyrrole-1-sulfonyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,

Morpholinyl-4-sulfonyl, thiomorpholinyl-4-sulfonyl, 2 6-dimethylmorpholinyl-4-sulfonyl,

Piperidinyl-1-sulfonyl, 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,

N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl)piperazine-1 -sulfonyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N,N-diethylaminoethyl)piperazine-1-sulfonyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-sulfonyl,

(15) Carbamoylamino, methylcarbamoylamino, ethylcarbamido, propylcarbamoyl, isopropylcarbamido, cyclopropylcarbamido, cyclobutylcarbamido, cyclo Amylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-diethylpiperidinyl-1-carboxylamino, tetrahydropyrrolyl-1-carboxylamino, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxylamino, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxylamino, N-methylpiperazinyl-1-carboxylamino, N-ethylpiperazinyl-1-carboxylamino, N-acetyl Basepiperazinyl-1-carboxamido, N-tert-butoxycarbonylpiperazinyl-1-carboxamido, N-(2-hydroxyethyl)piperazinyl-1-carboxamido, N-(2 -cyanoethyl)piperazinyl-1-carboxamido, N-(2-N,N-dimethylaminoethyl)piperazinyl-1-carboxamido, N-(2-N,N -Diethylaminoethyl)piperazinyl-1-carboxamido, N-(3-hydroxypropyl)piperazinyl-1-carboxamido, N-(3-N,N-dimethylpropyl Base) piperazinyl-1-carboxamido, N-(3-N,N-diethylpropyl)piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3,5 -Dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazinyl)piperidinyl- 1-formylamino, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl)piperidinyl-1- Formylamino, N-(N-methyl-4-piperidinyl)piperazinyl-1-formylamino,

(16)

2)
Wherein Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

3)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

4)
Wherein Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;

5)
Wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time;

Preferably, R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(4) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(5) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(10) Benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(11) piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperidinyl Azinyl) piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl) piperidinyl-1-formyl,

N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1 -Formyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N,N-diethylaminoethyl)piperazine-1-formyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

More preferably, R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl , N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl Base) piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N- Ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(5) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N ,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino,

(10) Benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4 -(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N-dimethylamino)ethylamino, N -Isopropyl-N-(2-N,N-dimethylamino)ethylamino;

Most preferably, R is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl,

(3) piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, 4-(azacyclic Butane-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(7) 4-N,N-Dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-) piperidinyl,

(8) N-methyl-4-piperidinyl,

(9) 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N,N-dimethylaminoethylamino, N-methyl-N-(2- N,N-dimethylamino)ethylamino,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) 4-N,N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino;

R2 is selected from:

1)
Wherein, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl group, and Z2 is not hydrogen;

Preferably, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 2 is not hydrogen;

More preferably, Z 1 and Z 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 2 is not hydrogen;

Most preferably, Z 1 , Z 2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 2 is not hydrogen;

2)
Wherein, Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing Alkyl, C3-C8 heteroatom-containing cycloalkyl;

Preferably, Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

More preferably, Z 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl;

Most preferably, Z is selected from methyl, ethyl, isopropyl, cyclopropyl;

3)
Wherein, Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms, the substituents are selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl;

Preferably, Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 and Z 5 are not at the same time hydrogen;

More preferably, Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time;

Most preferably, Z 4 and Z 5 are each independently selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl, and Z 4 and Z 5 are not hydrogen at the same time;

R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 cycloalkyl (for example, cyclopropyl) , C2-C6 alkenyl;

Alternatively, R 3 , R 4 and the carbon atoms connected to them together form a 5-membered ring containing one N, O or S atom;

Preferably, R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl;

More preferably, R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl , C2-C6 alkenyl;

Most preferably, R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl , vinyl, 1-methyl-vinyl;

Or preferably, R 3 , R 4 and the carbon atoms connected to them together form

Or more preferably, R 3 , R 4 and the carbon atoms connected to them together form
The compound according to claim 1, which is the following:

or a stereoisomer of said compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

in:

R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) 2-N,N-Dimethylaminoethoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morphine Linylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N,N-dimethylaminopropoxy, 3-N,N-diethylaminopropyl Oxygen, 3-N,N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3-(N-acetylpiperazinyl)propoxy, 3- Morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidylpropoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, Phenylmethoxy, monohalogen substituted phenylmethoxy, gem dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy,

(4) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(5) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(6) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(8) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(9) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(10) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(11) Aminomethylene, N,N-dimethylaminomethylene, N,N-diethylaminomethylene, 4-methyl-1-piperazinemethylene, 4-ethyl- 1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1-piperazine methylene Methyl, 4-(2-N,N-Dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N,N-dimethylamino)- 1-Piperidine-1-methylene, 4-hydroxypiperidin-1-methylene, tetrahydropyrrole-1-methylene, 3-(N,N-dimethylamino)-1-tetrahydropyrromethene radical, benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(12) Carbamoyl, methylcarbamoyl, N,N-dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylamine Aminoacetyl, cyclohexylcarbamoyl, aminoacetyl, methylaminoacetyl, 2-(N,N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, Cyclobutylaminoacetyl, cyclopentylaminoacetyl, cyclohexylaminoacetyl,

Tetrahydropyrrole-1-formyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,

Morpholinyl-4-formyl, Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,

Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1 -Formyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N,N-diethylaminoethyl)piperazine-1-formyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-formyl,

(13) Hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, n-butoxyformyl, isobutoxyformyl, tert-butoxy formyl,

(14) Hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylamine Sulfonyl, cyclohexylaminosulfonyl,

Tetrahydropyrrole-1-sulfonyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,

Morpholinyl-4-sulfonyl, thiomorpholinyl-4-sulfonyl, 2 6-dimethylmorpholinyl-4-sulfonyl,

Piperidinyl-1-sulfonyl, 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,

N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl)piperazine-1 -sulfonyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N,N-diethylaminoethyl)piperazine-1-sulfonyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-sulfonyl,

(15) Carbamoylamino, methylcarbamoylamino, ethylcarbamido, propylcarbamoyl, isopropylcarbamido, cyclopropylcarbamido, cyclobutylcarbamido, cyclo Amylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-diethylpiperidinyl-1-carboxylamino, tetrahydropyrrolyl-1-carboxylamino, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxylamino, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxylamino, N-methylpiperazinyl-1-carboxylamino, N-ethylpiperazinyl-1-carboxylamino, N-acetyl Basepiperazinyl-1-carboxamido, N-tert-butoxycarbonylpiperazinyl-1-carboxamido, N-(2-hydroxyethyl)piperazinyl-1-carboxamido, N-(2 -cyanoethyl)piperazinyl-1-carboxamido, N-(2-N,N-dimethylaminoethyl)piperazinyl-1-carboxamido, N-(2-N,N -Diethylaminoethyl)piperazinyl-1-carboxamido, N-(3-hydroxypropyl)piperazinyl-1-carboxamido, N-(3-N,N-dimethylpropyl Base) piperazinyl-1-carboxamido, N-(3-N,N-diethylpropyl)piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3,5 -Dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazinyl)piperidinyl- 1-formylamino, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl)piperidinyl-1- Formylamino, N-(N-methyl-4-piperidinyl)piperazinyl-1-formylamino,

(16)

2)
Wherein Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

3)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

4)
Wherein Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;

5)
Wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time;

Preferably, R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propylpiperazinyl Base, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deutero-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl ) piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl, N-(2- Cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethylaminopropyl)piperazinyl , N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperazinyl Pyridyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl -azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidinyl Alkyl-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl, N-cyclopropyl Formylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-ring Propylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(4) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(5) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiper Azinyl)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propyl Basepiperidin-4-amino, N-isopropylpiperidin-4-amino,

(10) Benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(11) piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperidinyl Azinyl) piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl) piperidinyl-1-formyl,

N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1 -Formyl, N-(2-N,N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N,N-diethylaminoethyl)piperazine-1-formyl Acyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

More preferably, R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl Base, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperazinyl Pyridyl) piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N -Ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl,

(5) Tetrahydropyrrolyl, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 3-(N,N-diethylamino)tetrahydropyrrolyl, 3-(N,N-di isopropylamino) tetrahydropyrrolyl,

(6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl,

(7) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl,

(9) Amino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2 -N,N-Dimethylaminoethylamino, N-methyl-N-(2-N,N-dimethylamino)ethylamino, N-ethyl-N-(2-N,N- Dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino, 3-N,N-dimethylaminopropylamino, 3-N ,N-diethylaminopropylamino, 3-N,N-diisopropylaminopropylamino,

(10) Benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene,

(11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4 -(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) hydrogen, fluorine, chlorine, bromine, iodine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N, N-dimethylamino) ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ethylamino, N -Isopropyl-N-(2-N,N-dimethylamino)ethylamino;

Further preferably, R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl,

(3) piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, 4-(azacyclic Butane-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl,

(4) Morpholinyl,

(5) 3-(N,N-dimethylamino)tetrahydropyrrolyl,

(6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl,

(7) 4-N,N-Dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-) piperidinyl,

(8) N-methyl-4-piperidinyl,

(9) 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N,N-dimethylaminoethylamino, N-methyl-N-(2- N,N-dimethylamino)ethylamino,

(10) benzyl, cyclopropylmethylene,

(11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl,

(12)

2)
Wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkoxy,

(3) 4-N,N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl,

(4) N-methyl-N-(2-N,N-dimethylamino)ethylamino;

Most preferably, R is selected from

1)
in:

Y is selected from hydrogen, fluorine, methoxy, trifluoromethoxy,

Y is selected from hydrogen, fluorine,

Y3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2-hydroxyl) ethylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N -Methyl-N-(2-N,N-dimethylamino)ethylamino, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methyl-4-piperidinyl , piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl- Azetidin-3-yl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1 -formyl,

Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl , cyclopropylmethylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,

Y 5 is hydrogen,

And Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time;

Preferably,
As a whole, selected from:

2)
in:

Y is selected from hydrogen, methoxy,

Y3 is selected from 4-(N-methylpiperazin-1-)piperidinyl, 4-N,N-dimethylaminopiperidinyl, N-methyl-N-(2-N,N-di Methylamino) ethylamino;

Y is selected from hydrogen, methyl, ethyl;

Y is selected from hydrogen;

Preferably,
As a whole, selected from:

Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

Preferably, Z is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

More preferably, Z is selected from hydrogen, methyl, ethyl, cyclopropyl;

Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

Preferably, Z 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl;

More preferably, Z is selected from methyl, ethyl, isopropyl, cyclopropyl;

R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1 -C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl;

Preferably, R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C2-C6 alkenyl;

More preferably, R is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1- Methyl-vinyl;

R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl;

Preferably, R 4 is selected from hydrogen, C1-C6 alkyl;

More preferably, R4 is hydrogen;

Alternatively, R 3 , R 4 and the carbon atoms connected to them together form a 5-membered ring containing one N, O or S atom;

Preferably, R 3 , R 4 and the carbon atoms connected to them together form

More preferably, R 3 , R 4 and the carbon atoms connected to them together form
The compound according to claim 1, which is the following:

or a stereoisomer of said compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

in:

R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl Azinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethyl Aminopropyl)piperazinyl, N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-( N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl , 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N- Isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl Azinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl Acylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(4) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(5) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base;

2)
Wherein Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

3)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

4)
Wherein Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;

5)
Wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time;

Preferably, R1 is
Wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4 -piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl,

(4) 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl;

More preferably, R1 is
Wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

Hydrogen, C1-C6 alkyl, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methylpiperazinyl -1-) piperidinyl;

Further preferably, R 1 is
in:

Y is selected from hydrogen, methoxy,

Y2 is hydrogen,

Y is selected from N-methylpiperazinyl, 4-(N-methylpiperazin-1-)piperidinyl, N-(N-methyl-4-piperidinyl)piperazinyl,

Y 4 is ethyl,

Y is hydrogen ;

Most preferably, R is selected from

Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

Preferably, Z 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl;

More preferably, Z is selected from methyl, ethyl, isopropyl, cyclopropyl;

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl;

Preferably, R is selected from fluorine, chlorine, bromine, iodine, C2-C6 alkenyl;

More preferably, R is selected from bromo, vinyl;

R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl;

Preferably, R 4 is selected from hydrogen, C1-C6 alkyl;

More preferably, R4 is hydrogen.
The compound according to claim 1, which is the following:

or a stereoisomer of said compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

in:

R 1 is selected from

1)
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:

(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2- C6 alkenyl,

(3) Piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N,N-dimethylaminoethyl)piperazinyl, N-(2-N,N-diethylaminoethyl)piperazinyl Azinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N,N-dimethyl Aminopropyl)piperazinyl, N-(3-N,N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-( N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl , 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N- Isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-propionylpiperazinyl, N-isobutyrylpiperazinyl Azinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl Acylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl,

(4) piperidinyl, 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl )piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N,N-dimethylpropyl)piperazin-1-)piperidinyl, 4-(N -(3-N,N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-dimethyl Aminotetrahydropyrrol-1-)piperidinyl, 4-(3-N,N-diethylaminotetrahydropyrrol-1-)piperidinyl,

(5) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4 -piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2 -N,N-Dimethylaminoethyl)-4-piperidinyl, N-(2-N,N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl Base)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N,N-dimethylaminopropyl)-4-piperidinyl, N- (3-N,N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl base;

2)
Wherein Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

3)
Wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time;

4)
Wherein Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;

5)
Wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time;

Preferably, R1 is
Wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

(1) Hydrogen,

(2) C1-C6 alkyl, C1-C6 alkoxy,

(3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4 -piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl;

More preferably, R1 is
Wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:

Hydrogen, C1-C6 alkyl, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl;

Further preferably, R 1 is
in:

Y is selected from hydrogen, methoxy,

Y2 is hydrogen,

Y is selected from N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl,

Y 4 is ethyl,

Y is hydrogen ;

Most preferably, R is selected from

Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time ;

Preferably, Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time;

More preferably, Z is selected from hydrogen, C1-C6 alkyl, preferably hydrogen; Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl;

Most preferably, Z is selected from hydrogen, Z is selected from methyl, ethyl, isopropyl, cyclopropyl;

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl;

Preferably, R is selected from fluorine, chlorine, bromine, iodine, C2-C6 alkenyl;

More preferably, R is selected from bromo, vinyl;

R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl;

Preferably, R 4 is selected from hydrogen, C1-C6 alkyl;

More preferably, R4 is hydrogen.
The compound according to any one of claims 1-4, selected from the following:

Or a stereoisomer of the above compound, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate.
The method for the compound described in any one of 1-5 in the preparation claim, comprises the following steps:

Reaction conditions:

(a) Nucleophilic substitution reactions under acidic or basic conditions;

(b) a coupling reaction catalyzed by metal palladium, or a nucleophilic substitution reaction under acidic conditions, or a nucleophilic substitution reaction under basic conditions;

(c) a coupling reaction catalyzed by metal palladium, or a coupling reaction catalyzed by metal copper;

in:

The metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride , Three (dibenzylideneacetone) dipalladium;

The basic conditions refer to the conditions under which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride;

The acidic conditions refer to the conditions under which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid;

X represents halogen, and R 3 -Y represents the boronic acid corresponding to R 3 (ie
), borate (ie
), tin reagent (such as n-tributyltin reagent that is
) or alkyne reagents (such as trimethylsilylacetylene ie
);

R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-4.
A pharmaceutical composition comprising a compound according to any one of claims 1-5 or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and optionally a pharmaceutical acceptable excipients;

Preferably, the pharmaceutical composition further comprises EGFR monoclonal antibody;

Preferably, the EGFR monoclonal antibody is cetuximab or a biosimilar thereof.
The compound of any one of claims 1-5 or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the pharmaceutical composition described in claim 7 in Use in the preparation of medicines for preventing and/or treating EGFR kinase-mediated cancer and other diseases, especially the preparation of medicines for preventing and/or treating lung cancer (preferably non-small cell lung cancer), especially Use in the preparation of medicines for preventing and/or treating EGFR kinase 19Del, L858R, T790M, C797S or their combination mutant lung cancer (preferably non-small cell lung cancer), most preferably in the preparation of EGFR kinase for preventing and/or treating EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).
A method for the prevention and/or treatment of EGFR kinase-mediated cancer and other diseases, comprising administering to a subject in need a preventive and/or therapeutically effective amount of the compound of any one of claims 1-5 or a stereoisomer thereof , its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the pharmaceutical composition described in claim 7;

Preferably, the method is used to prevent and/or treat lung cancer (preferably non-small cell lung cancer);

More preferably, the method is used to prevent and/or treat EGFR kinase 19Del, L858R, T790M, C797S or a combination thereof mutant lung cancer (preferably non-small cell lung cancer);

Most preferably, the method is used to prevent and/or treat EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation Mutant lung cancer (preferably non-small cell lung cancer).
The compound of any one of claims 1-5 or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the pharmaceutical composition described in claim 7, It is used for the prevention and/or treatment of cancer and other diseases mediated by EGFR kinases, preferably for the prevention and/or treatment of lung cancer (preferably non-small cell lung cancer), more preferably for the prevention and/or treatment of EGFR kinases 19Del, L858R, T790M, C797S or their combination mutant lung cancer (preferably non-small cell lung cancer), most preferably for the prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/ T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).