CN109575045B

CN109575045B - Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof

Info

Publication number: CN109575045B
Application number: CN201710907030.4A
Authority: CN
Inventors: 邓贤明; 张保锭; 刘双; 董超; 孙细欢; 黄晓星; 邓舟; 李云展; 鲁岳; 李莉; 胡志钰
Original assignee: Nanjing Hongyun Bio Tech Co ltd
Current assignee: Xiamen University
Priority date: 2017-09-28
Filing date: 2017-09-28
Publication date: 2021-02-12
Anticipated expiration: 2037-09-28
Also published as: TWI780077B; CN109575045A; TW201915004A

Abstract

The invention relates to a thienopyrimidine compound, a preparation method thereof, a medicinal composition and application thereof. In particular to a compound with ALK and/or c-Met selective inhibitory activity, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compounds in preparing medicaments for preventing or treating diseases related to gradual-change lymphoma kinase in organisms, and application in preparing medicaments for preventing or treating diseases related to angiogenesis or cancer metastasis, especially application in preparing medicaments for preventing or treating tumor growth and metastasis.

Description

Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a compound with ALK and/or c-Met selective inhibitory activity, a preparation method thereof, a pharmaceutical composition containing the compound, application of the compound in preparing medicaments for preventing or treating diseases related to in vivo gradual-change lymphoma kinase, application in preparing medicaments for preventing or treating diseases related to angiogenesis or cancer metastasis, and especially application in preparing medicaments for preventing or treating tumor growth and metastasis.

Background

Progressive lymphoma enzyme (ALK) is a receptor tyrosine kinase, belonging to the insulin receptor superfamily. The protein structure is sequentially an extracellular receptor domain, a transmembrane region and an intracellular tyrosine kinase domain from the N end to the C end. The normal ALK protein is mainly expressed in the central nervous system and the peripheral nervous system, and the expression level of the ALK gene in a human body shows a descending trend along with the development degree of a brain, and particularly the ALK gene is rarely expressed in a mature brain tissue. The ALK expression is not found in other systems, particularly hematopoiesis systems, and the ALK expression and distribution are proved to have certain regionality.

Normally, the human ALK gene can code a 1602 amino acid, 200kDa type I transmembrane protein ALK, but the gene is usually in a dormant state. When fused to other genes, the ALK gene can be a very potent oncogene. The genes which can be fused with ALK gene which are discovered at present are nucleophosmin gene (NPM, anaplastic large cell lymphoma ALCL), echinoderm microtubule-associated protein-like 4 gene (EML4, non-small cell lung cancer NSCLC), tropomyosin 3 gene (TPM3, inflammatory myofibroblastic tumor IMT) and the like (nat. Rev. cancer,2008,8, 11-23.; nat. Rev. cancer,2013,13, 685-700.; Expert Opin. Ther. Pat, 2014.24(4): p.417-42.).

In non-small cell lung cancer, the fusion is mainly carried out with an EML4 gene, and the incidence rate of the fusion gene (EML4-ALK) in NSCLC is 4-7%. With the ongoing molecular biological research into non-small cell lung cancer (NSCLC), personalized therapies based on molecular markers (biomarker) have moved from the laboratory to the clinic and have made greater clinical progress in the treatment of patients with advanced non-small cell lung cancer. This means that in addition to traditional histopathological classification of NSCLC, molecular phenotypes can be classified according to the different expression levels of different molecular markers for a particular patient. NSCLC patients undergo relevant molecular marker detection prior to receiving treatment. Clinically, doctors can carry out targeted treatment according to the tumor molecular phenotype characteristics, thereby improving the treatment effect. Under such circumstances, research and development of new drugs using a driving gene closely related to tumorigenesis and tumor development or a protein encoded by the driving gene as a target has become a hot spot in research of antitumor drugs.

Currently, the U.S. food and drug administration has approved the marketing of the small molecule inhibitor CrizotinInib (J.Thorac.Oncol.,2010.5(12): p.2044-6.) developed by the company Pfizer, Ceritinib (J.Med.Chem.,2013.56(14): p.5675-90.) developed by the company Novartis, Alectoib (Cancer Lett.,2014.351(2): p.215-21.) developed by the company Chugai (Pfizer). However, clinical studies have shown that some patients have developed resistance to Crozotinib, and that the bioavailability of Crozotinib is yet to be improved. Ceritinib can be directed to patients who are partially resistant or intolerant to Crizotiib. Therefore, there is a great need in clinical practice for alternative compounds to these which have improved potency and resistance.

Disclosure of Invention

The inventor of the invention designs and synthesizes a series of polysubstituted thienopyrimidine (thiophene [3,2-d ] pyrimidine) derivatives which have novel structures, high safety and high activity on various tyrosine kinases (EGFR, PDGFR, c-Met and the like), especially on ALK, through extensive and intensive research in order to search for new ALK inhibitors, and researches the antitumor activity of the novel derivatives.

A compound of the general formula:

wherein the definitions of the substituents and symbols are explained in detail below.

An object of the present invention is to provide a class of compounds having ALK and/or c-Met selective inhibitory activity and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof;

another object of the present invention is to provide a process for the preparation of the above compound;

it is another object of the present invention to provide a pharmaceutical composition comprising the above compound;

another object of the present invention is to provide the use of the above-mentioned compound for the preparation of a medicament for preventing or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, and the like, associated with the enzyme, in vivo, of gradual degeneration lymphoma, and for the preparation of a medicament for preventing or treating diseases associated with angiogenesis or cancer metastasis, particularly for the preparation of a medicament for preventing or treating tumor growth and metastasis.

Description of the drawings

FIG. 1 depicts that compound IB-1 significantly inhibited tumor growth in the EML4-ALK (G1202R) -Ba/F3 nude mouse xenograft tumor model. A) The compound IB-1 is orally taken at the dose of 60mg/kg (1 time/day) and 40mg/kg (2 times/day, bid) respectively, and is continuously taken for 10 days, so that the tumor growth is obviously inhibited; B) in the administration process, the weight average of the mouse bodies of the administration group does not obviously change, which shows that the administration group has better tolerance to the medicament and IB-1 has no obvious toxic or side effect.

FIG. 2 depicts that compound IB-1 significantly inhibited tumor growth in a non-small cell lung carcinoma H3122 cell nude mouse xenograft tumor model. A) The compound IB-1 is orally taken at the dose of 30mg/kg (1 time/day) and 50mg/kg (1 time/day) respectively, and the tumor growth is obviously inhibited after the compound IB-1 is continuously taken for 18 days; B) in the administration process, the weight average of the mouse bodies of the administration group does not obviously change, which shows that the administration group has better tolerance to the medicament and IB-1 has no obvious toxic or side effect.

Detailed Description

The invention is realized by the following technical scheme.

In a first aspect, the present invention provides a compound represented by the following general formula I, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein: r' is hydrogen, chlorine or bromine;

R₁selected from:

1) C1-C6 alkyl, 2-N, N-dimethylaminoethyl, 2-hydroxyethyl, 2-N, N-diethylaminoethyl, 2-N, N-diisopropylaminoethyl, 2-morpholinoethyl, 2- (4-methylpiperazinyl) ethyl, 3-N, N-dimethylaminopropyl, 3-N, N-diethylaminopropyl, 3-N, N-diisopropylaminopropyl, 3-morpholinopropyl, 3- (4-methylpiperazinyl) propylyl, C3-C6 cycloalkyl, 4-N, N-dimethylaminocyclohexyl, 4-N, N-diethylaminocyclohexyl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, n-isopropyl-4-piperidinyl, 1, 3-dimethyl-5-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-5-isoxazolinyl, 1- (N-methyl-4-piperidinyl) -4-pyrazolyl, 1- (N-tert-butoxycarbonyl-4-piperidinyl) -4-pyrazolyl;

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each is independentThe land is selected from:

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

(2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, N-methyl-4-piperidyl,

(3) n, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, 2-N, N-dimethylaminoethylamino, 2-morpholinoethylamino, 2- (4-methylpiperazinyl) ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3- (4-methylpiperazinyl) propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-isopropylpiperidin-4-amino,

(4)2-N, N-dimethylaminoethoxy, 2-N, N-diethylaminoethoxy, 2-N, N-diisopropylaminoethoxy, 2- (4-methylpiperazinyl) ethoxy, 2- (4-acetylpiperazinyl) ethoxy, 2-morpholinoethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethylaminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3- (4-methylpiperazinyl) propoxy, 3- (4-acetylpiperazinyl) propoxy, 3-morpholinopropoxy, 3-thiomorpholinylpropoxy, 3-piperidinylpropoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, phenylmethoxy, mono-halogen substituted phenylmethoxy, gem-dihalo substituted phenylmethoxy, hetero-dihalo substituted phenylmethoxy,

(5) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, morpholinyl, 3, 5-dimethylmorpholinyl, thiepinyl, tetrahydropyrrolyl, 3-N, N-dimethylaminotetrahydropyrrolyl, 3-N, N-diethylaminotetrahydropyrrolyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl, 4-methanesulfonylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (2-cyanoethyl) piperazinyl, 4- (3-hydroxypropyl) piperazinyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl, 4- (2-N, N-diethylaminoethyl) piperazinyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl, 4- (3-N, N-diethylaminopropyl) piperazinyl, 2-oxo-piperazin-4-yl, imidazolyl, 4-methylimidazolyl,

(6)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (2-cyanoethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, n-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminodetrahydropyrrolyl) piperidinyl, 4- (N-methyl-4-piperidinyl) piperazinyl, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(7) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-dimethylaminostyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazin-1-ylsulfonyl, 4-acetylpiperazin-1-ylsulfonyl, 4-tert-butoxycarbonylpiperazin-1-ylsulfonyl, 4- (2-hydroxyethyl) piperazin-1-ylsulfonyl, 4- (2-cyanoethyl) piperazin-1-ylsulfonyl, 4- (2-N, N-dimethylaminoethyl) piperazin-1-ylsulfonyl, 4- (2-N, N-diethylethyl) piperazin-1-ylsulfonyl, 4- (3-hydroxypropyl) piperazin-1-ylsulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazin-1-ylsulfonyl, 4- (3-N, N-diethylaminopropyl) piperazin-1-ylsulfonyl, morpholin-1-ylsulfonyl, 3, 5-dimethylmorpholin-1-ylsulfonyl, 4- (tetrahydropyrrolyl) piperidin-1-ylsulfonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-ethylpiperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-acetyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazin-1-ylsulfonyl,

(8) Hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, 4- (tetrahydropyrrolyl) piperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-carbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-ethylpiperazinyl-1-carbonyl, 4-acetylpiperazinyl-1-carbonyl, 4-tert-butoxycarbonylpiperazinyl-1-carbonyl, 4- (2-hydroxyethyl) piperazinyl-1-carbonyl, 4- (2-cyanoethyl) piperazinyl-1-carbonyl, 4- (2-N, N-dimethylaminoethyl) piperazin-1-ylcarbonyl, 4- (2-N, N-diethylaminoethyl) piperazin-1-ylcarbonyl, 4- (3-hydroxypropyl) piperazin-1-ylcarbonyl, 4- (3-N, N-dimethylaminopropyl) piperazin-1-ylcarbonyl, 4- (3-N, n-diethylaminopropyl) piperazin-1-ylcarbonyl, morpholinyl-1-carbonyl, 3, 5-dimethylmorpholinyl-1-carbonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4- (4-ethyl-1-piperazinyl) piperidinyl-1-carbonyl, 4- (4-acetyl-piperazin-1-yl) piperidinyl-1-carbonyl, 4- (N-methyl-4-piperidinyl) piperazin-1-ylcarbonyl,

(9) Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,

(10) carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclopentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carboxamido, 3-N, N-diethylaminotetrahydropyrrolyl-1-carboxamido, 4-methylpiperazin-1-ylcarboxamido, 4-ethylpiperazin-1-ylcarboxamido, 4-acetylpiperazin-1-ylcarboxamido, 4-tert-butoxycarbonylpiperazin-1-ylcarboxamido, 4- (2-hydroxyethyl) piperazin-1-ylcarboxamido, 4- (2-cyanoethyl) piperazin-1-ylcarboxamido, 4- (2-N, N-dimethylaminoethyl) piperazin-1-ylcarboxamido, 4- (2-N, N-diethylaminoethyl) piperazin-1-ylcarboxamido, 4- (3-hydroxypropyl) piperazin-1-ylcarboxamido, 4- (3-N, N-dimethylaminopropyl) piperazin-1-ylcarboxamido, 4- (3-N, N-diethylaminopropyl) piperazin-1-ylcarboxamide, morpholin-1-ylcarboxamide, 3, 5-dimethylmorpholin-1-ylcarboxamide, 4- (tetrahydropyrrolyl) piperidin-1-ylcarboxamide, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarboxamide, 4- (4-ethylpiperazin-1-yl) piperidin-1-ylcarboxamide, 4- (4-acetyl-piperazin-1-yl) piperidin-1-ylcarboxamide, 4- (N-methyl-4-piperidinyl) piperazin-1-ylcarboxamide; or

(11) Aminoacetamido, 2-dimethylaminoacetamido, N-tert-butoxycarbonylacetamido, N-acetylaminoacetamido, acrylamido, cyclopropylamido, chloroacetamido, piperidinoacetamido, 4-hydroxypiperidinoacetamido, 4-N, N-dimethylaminepiperidinoacetamido, 4-N, N-diethylaminopiperidinoacetamido, tetrahydropyrroloacetamido, 3-N, N-dimethylaminetetrahydropyrroloacetamido, 3-N, N-diethylaminotetrahydropyrroloacetamido, 4-methylpiperazinoacetamido, 4-ethylpiperazinoacetamido, 4-acetylpiperazinoacetamido, 4-tert-butoxycarbonylpiperazinoacetamido, 4- (2-hydroxyethyl) piperazinylacetamino, 4- (2-cyanoethyl) piperazinylacetamino, 4- (2-N, N-dimethylaminoethyl) piperazinylacetamino, 4- (2-N, N-diethylaminoethyl) piperazinylacetamino, 4- (3-hydroxypropyl) piperazinylacetamino, 4- (3-N, N-dimethylaminopropyl) piperazinylacetamino, 4- (3-N, N-diethylaminopropyl) piperazinylacetamino, morpholinoacetamino, 3, 5-dimethylmorpholinoacetamino, 4- (4-methyl-piperazin-1-yl) piperidinylacetamino, 4- (4-ethyl-1-piperazinylacetamino), 4- (4-acetyl-1-piperazinyl) piperidinyl acetamido, N- (N-methyl-4-piperidinyl) piperazinyl acetamido, 4- (tetrahydropyrrole-1-yl) piperidinyl acetamido; 2-methylaminoacetamido, 2- (1-methylethyl) aminoacetamido; n-benzyloxycarbonyl-2-methylaminoacetamido;

(12)Z₂And Z₃Or Z₃And Z₄Forming an oxygen-containing substituted or unsubstituted five-or six-membered ring; the substituents may be selected from the group consisting of₁The same above-mentioned substituents as mentioned above,

(13)Z₂and Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-or six-membered ring; the substituents may be selected from the group consisting of₁The same above-mentioned substituents as mentioned above,

3)

wherein Z₂，Z₃，Z₄，Z₅The same as defined in 2) above;

4)

wherein Z₁，Z₃，Z₄，Z₅The same as defined in 2) above;

a is a direct bond or methylene;

x is NH, S or O;

R₂selected from:

1) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl;

2)

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

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

(2) methylthio, ethylthio, isopropylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, dimethylaminosulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl, diethylphosphinionyl, diisopropylphosphinionyl,

3)

Wherein Y is an NH, S or O atom,

A₆，A₇，A₈，A₉，A₁₀，A₁₁each independently selected from:

(2) methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl;

4)

wherein A is₁₂Selected from:

(2) methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl;

Y₂,Y₃,Y₄selected from the following combinations:

Y₂is N, Y₃Is N-A₁₃，Y₄Is CH or N;

Y₂is N, Y₃Is C-A₁₃，Y₄Is N, O or S;

Y₂Is O or S, Y₃Is N-A₁₃，Y₄Is CH;

Y₂is O or S, Y₃Is C-A₁₃，Y₄Is N; and

Y₂is C, Y₃Is N-A₁₃，Y₄Is O or S;

Y₂is C, Y₃Is N-A₁₃，Y₄Is N;

wherein A is₁₃Is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl;

5) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, morpholinyl, 3, 5-dimethylmorpholinyl, thiepinyl, tetrahydropyrrolyl, 3-N, N-dimethylaminotetrahydropyrrolyl, 3-N, N-diethylaminotetrahydropyrrolyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl, 4-methanesulfonylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (2-cyanoethyl) piperazinyl, 4- (3-hydroxypropyl) piperazinyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl, 4- (2-N, N-diethylaminoethyl) piperazinyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl, 4- (3-N, N-diethylaminopropyl) piperazinyl.

In some embodiments, R' is hydrogen.

In some embodiments, wherein R₁Selected from:

1) C1-C6 alkyl, 2-N, N-dimethylaminoethyl, 2-hydroxyethyl, 2-N, N-diethylaminoethyl, 2-N, N-diisopropylaminoethyl, 2-morpholinoethyl, 2- (4-methylpiperazinyl) ethyl, C3-C6 cycloalkyl, 4-N, N-dimethylaminocyclohexyl, 4-N, N-diethylaminocyclohexyl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, 1, 3-dimethyl-5-pyrazolyl, 1- (N-methyl-4-piperidinyl) -4-pyrazolyl;

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(3) n, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, 2-N, N-dimethylaminoethylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 3- (4-methylpiperazino) propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino,

(4)2-N, N-dimethylaminoethoxy, 2-N, N-diethylaminoethoxy, 2-N, N-diisopropylaminoethoxy, 2- (4-methylpiperazinyl) ethoxy, 2- (4-acetylpiperazinyl) ethoxy, 2-morpholinoethoxy, 2-thiomorpholinoethoxy, 2-piperidinoethoxy, 3-N, N-diisopropylaminopropoxy, 3- (4-acetylpiperazinyl) propoxy, 3-morpholinopropoxy, 3-thiomorpholinylpropoxy, 3-piperidinylpropoxy, pyridin-2-ylmethoxy, phenylmethoxy, mono-halo-substituted phenylmethoxy, gem-dihalo-substituted phenylmethoxy,

(5) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, morpholinyl, 3, 5-dimethylmorpholinyl, thiepinyl, tetrahydropyrrolyl, 3-N, N-dimethylaminotetrahydropyrrolyl, 3-N, N-diethylaminotetrahydropyrrolyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (3-N, N-diethylaminopropyl) piperazinyl, 2-oxo-piperazin-4-yl, imidazolyl, 4-methylimidazolyl,

(6)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (3-N, n-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (3-N, N-dimethylaminotetrahydropyrrolyl) piperidinyl, 4- (N-methyl-4-piperidinyl) piperazinyl, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(7) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 3-N, N-dimethylpyrrolidin-1-ylsulfonyl, 3-N, N-diethylaminopyrrolidin-1-ylsulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazin-1-ylsulfonyl, 4-acetylpiperazin-1-ylsulfonyl, 4-tert-butoxycarbonylpiperazinyl-1-sulfonyl, N- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazin-1-ylsulfonyl, 4- (3-hydroxypropyl) piperazin-1-ylsulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazin-1-ylsulfonyl, 4- (3-N, N-diethylaminopropyl) piperazin-1-ylsulfonyl, 4- (4-acetylpiperazin-1-yl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazin-1-ylsulfonyl,

(8) Hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 4- (2-N, N-dimethylaminoethyl) piperazin-1-ylcarbonyl, 4- (2-N, N-diethylaminoethyl) piperazin-1-ylcarbonyl, 4- (3-N, N-diethylaminopropyl) piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, 3, 5-dimethylmorpholin-1-ylcarbonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4- (4-acetyl-1-piperazinyl) piperidin-1-ylcarbonyl, 4- (N-methyl-4-piperidinyl) piperazin-1-ylcarbonyl,

(9) methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,

(10) carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, 4-acetylpiperazin-1-ylcarboxamido, 4- (2-hydroxyethyl) piperazin-1-ylcarboxamido, 4- (2-cyanoethyl) piperazin-1-ylcarboxamido, 4- (2-N, N-dimethylaminoethyl) piperazin-1-ylcarboxamido, 4- (3-N, N-dimethylaminopropyl) piperazin-1-ylcarboxamide, 4- (3-N, N-diethylaminopropyl) piperazin-1-ylcarboxamide, morpholin-1-ylcarboxamide, 4- (4-acetylpiperazin-1-yl) piperidin-1-ylcarboxamide, 4- (N-methyl-4-piperidinyl) piperazin-1-ylcarboxamide; or

(11) Aminoacetamido, N-tert-butoxycarbonylacetamido, N-acetylaminoacetamido, acrylamido, cyclopropylamido, chloroacetamido, piperidinylacetamido, 4-hydroxypiperidinylacetamido, 4-N, N-dimethylaminepiperidinylacetamido, 4-N, N-diethylaminopiperidinylacetamido, 3-N, N-dimethylaminotetrahydropyrrolylacetamido, N-ethylpiperazinylacetamido, 4-acetylpiperazinylacetamido, 4-tert-butoxycarbonylpiperazinylacetamido, 4- (2-cyanoethyl) piperazinylacetamido, N- (2-N, N-dimethylaminoethyl) piperazinylacetamido, 4- (2-N, n-diethylaminoethyl) piperazinylacetamino, 4- (3-N, N-dimethylaminopropyl) piperazinylacetamino, 4- (3-N, N-diethylaminopropyl) piperazinylacetamino, 4- (4-methyl-piperazin-1-yl) piperidinylacetamino, 4- (4-ethyl-1-piperazinyl) piperidinylacetamino, 4- (4-acetyl-1-piperazinyl) piperidinylacetamino, N-benzyloxycarbonyl-2 methylaminoacetamido;

3)

wherein Z₂，Z₃，Z₄，Z₅The same as defined in 2) above;

4)

wherein Z₁，Z₃，Z₄，Z₅The same as defined in 2) above.

In some embodiments, R₁Selected from:

1)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(4)2-N, N-dimethylaminoethoxy, 2-N, N-diethylaminoethoxy, 2-N, N-diisopropylaminoethoxy, 2- (4-methylpiperazino) ethoxy, 2- (4-acetylpiperazinyl) ethoxy, 2-morpholinoethoxy, 2-thiomorpholinoethoxy, 2-piperidinoethoxy, 3-N, N-diisopropylaminopropoxy, 3- (4-acetylpiperazinyl) propoxy, 3-morpholinopropoxy, 3-thiomorpholinylpropoxy, 3-piperidinylpropoxy, pyridin-2-ylmethoxy, phenylmethoxy, monohalo-substituted phenylmethoxy,

(6)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidyl group, 4- (3-N, n-dimethylaminotetrahydropyrrolyl) piperidinyl, 4- (N-methyl-4-piperidinyl) piperazinyl, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(7) Hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazino-1-sulfonyl, 4-acetylpiperazinyl-1-sulfonyl, 4-tert-butoxycarbonylpiperazinyl-1-sulfonyl, 4- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazinyl-1-sulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-sulfonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-sulfonyl,

(8) hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carbonyl, 4- (2-N, N-diethylaminoethyl) piperazinyl-1-carbonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carbonyl, morpholinyl-1-carbonyl, 3, 5-dimethylmorpholinyl-1-carbonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carbonyl,

(10) carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, 4-acetylpiperazinyl-1-carboxamido, 4- (2-hydroxyethyl) piperazinyl-1-carboxamido, 4- (2-cyanoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carboxamido, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carboxamido, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 4- (4-acetyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carboxamido; or

(11) Aminoacetamido, N-tert-butoxycarbonylacetamido, N-acetylaminoacetamido, acrylamido, cyclopropylamido, chloroacetamido, piperidinylacetamido, 4-hydroxypiperidinylacetamido, 4-N, N-dimethylaminopiperidinylacetamido, 4-N, N-diethylaminopiperidinylacetamido, 3-N, N-dimethylaminotetrahydropyrrolylacetamido, 4-ethylpiperazinylacetamido, 4-acetylpiperazinylacetamido, 4-tert-butoxycarbonylpiperazinylacetamido, 4- (2-cyanoethyl) piperazinylacetamido, 4- (2-N, N-dimethylaminoethyl) piperazinylacetamido, 4- (2-N, n-diethylaminoethyl) piperazinylacetamino, 4- (3-N, N-dimethylaminopropyl) piperazinylacetamino, 4- (3-N, N-diethylaminopropyl) piperazinylacetamino, 4- (4-methyl-piperazin-1-yl) piperidinylacetamino, 4- (4-ethyl-1-piperazinyl) piperidinylacetamino, 4- (4-acetyl-1-piperazinyl) piperidinylacetamino, N-benzyloxycarbonyl-2 methylaminoacetamido;

2)

wherein Z₂，Z₃，Z₄，Z₅The same as defined in 2) above;

3)

wherein Z₁，Z₃，Z₄，Z₅The same as defined in 2) above.

In some embodiments, a is a direct bond.

In some embodiments, a is methylene.

In some embodiments, R₂Selected from:

1) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl;

2)

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

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

(2) methylthio, ethylthio, isopropylthio, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, dimethylaminosulfonyl, methylsulfonylamino, methoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, cyclobutylaminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, dimethylphosphinoyl, diethylphosphinioyl, diisopropylphosphinioyl,

3)

Wherein Y is an NH, S or O atom,

A₆，A₇，A₈，A₉，A₁₀，A₁₁each independently selected from:

(2) methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopentylaminocarbonyl;

4)

wherein A is₁₂Selected from:

(2) methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclobutylaminocarbonyl, methylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl;

Y₂,Y₃,Y₄selected from the following combinations:

Y₂is N, Y₃Is N-A₁₃，Y₄Is CH or N;

Y₂is O or S, Y₃Is C-A₁₃，Y₄Is N; and

Y₂is C, Y₃Is N-A₁₃，Y₄Is O or S;

Y₂is C, Y₃Is N-A₁₃，Y₄Is N;

5) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, morpholinyl, 3, 5-dimethylmorpholinyl, 3-N, N-dimethylaminodetrahydropyrrolyl, 3-N, N-diethylaminotetrahydropyrrolyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4- (2-N, N-diethylaminoethyl) piperazinyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl, 4- (3-N, N-diethylaminopropyl) piperazinyl.

In some embodiments, R₂Selected from:

1)

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) the concentration of hydrogen, fluorine, chlorine,

2)

wherein Y is an NH, S or O atom,

A₆，A₇，A₈，A₉，A₁₀，A₁₁each independently selected from:

3)

wherein A is₁₂Selected from:

Y₂,Y₃,Y₄Selected from the following combinations:

Y₂is N, Y₃Is N-A₁₃，Y₄Is CH or N;

Y₂is O or S, Y₃Is C-A₁₃，Y₄Is N; and

Y₂is C, Y₃Is N-A₁₃，Y₄Is O or S;

Y₂is C, Y₃Is N-A₁₃，Y₄Is N;

wherein A is₁₃Hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl.

In some embodiments, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, and the organic acid salt is a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α -ketoglutarate, trifluoroacetate, α -glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkyl sulfonate is a methyl sulfonate or an ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.

In a second aspect, the present invention provides a compound having the structure of formula V, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof:

wherein: w is oxo, thioxo, or hydrogen;

n is 0, or 1;

R₃，R₄，R₅each independently selected from:

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

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

R₆selected from:

(1) hydrogen, C1-C6 alkyl, acetyl, propionyl, n-butyryl, isobutyryl,

(2) aminoacetyl group, 2-N, N-dimethylacetoyl group, 2-N, N-diethylacetoyl group, 2-N, N-diisopropylacetyl group, piperidineacetyl group, 4-hydroxypiperidinoacetyl group, 4-N, N-dimethylaminopiperidinoacetyl group, 4-N, N-diethylaminopiperidineacetyl group, tetrahydropyrroleacetyl group, 3-N, N-dimethylaminodetrahydropyrroleacetyl group, 3-N, N-diethylaminotetrahydropyrroleacetyl group, 4-methylpiperazineacetyl group, 4-ethylpiperazineacetyl group, 4-acetylpiperazineacetyl group, 4- (2-hydroxyethyl) piperazineacetyl group, 4- (2-cyanoethyl) piperazinylacetyl, 4- (2-N, N-dimethylaminoethyl) piperazinylacetyl, 4- (2-N, N-diethylaminoethyl) piperazinylacetyl, 4- (3-hydroxypropyl) piperazinylacetyl, 4- (3-N, N-dimethylaminopropyl) piperazinylacetyl, 4- (3-N, N-diethylaminopropyl) piperazinylacetyl, morpholinoacetyl, 3, 5-dimethylmorpholinoacetyl, 4- (4-methyl-piperazin-1-yl) piperidinylacetyl, 4- (4-ethyl-1-piperazinylacetyl), 4- (4-acetyl-1-piperazinylacetyl) piperidinylacetyl, 4- (N-methyl-4-piperidinyl) piperazinylacetyl;

A，X，R₂The definition is the same as that in the technical scheme.

In some embodiments, W is oxo.

In some embodiments, n ═ 1.

In some embodiments, n ═ 0.

In some embodiments, R₃，R₄，R₅Each independently selected from:

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

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

In some embodiments, R₆Selected from:

(1) hydrogen, C1-C6 alkyl, acetyl, propionyl,

(2) aminoacetyl group, 2-N, N-dimethylacetyl group, 2-N, N-diethylacetyl group, 2-N, N-diisopropylacetyl group, piperidinylacetyl group, 4-hydroxypiperidinylacetyl group, 4-N, N-dimethylaminopiperidinylacetyl group, 4-N, N-diethylaminopiperidinylacetyl group, tetrahydropyrrolylacetyl group, 4-acetylpiperazinylacetyl group, 4-tert-butoxycarbonylpiperazinylacetyl group, 4- (2-hydroxyethyl) piperazinylacetyl group, 4- (2-cyanoethyl) piperazinylacetyl group, 4- (2-N, N-dimethylaminoethyl) piperazinylacetyl group, 4- (2-N, N-diethylaminoethyl) piperazinylacetyl group, morpholinylacetyl, 3, 5-dimethylmorpholinylacetyl, 4- (4-methyl-piperazin-1-yl) piperidinylacetyl, 4- (4-ethyl-1-piperazinyl) piperidinylacetyl.

In a third aspect, the present invention provides a compound represented by the following general formula IA, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(3) piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

(4) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(5) N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, 2-N, N-dimethylaminoethylamino, 2-morpholinoethylamino, 2- (4-methylpiperazinyl) ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3- (4-methylpiperazinyl) propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-isopropylpiperidin-4-amino,

(6)2-N, N-dimethylaminoethoxy, 2-N, N-diethylaminoethoxy, 2-N, N-diisopropylaminoethoxy, 2- (4-methylpiperazinyl) ethoxy, 2- (4-acetylpiperazinyl) ethoxy, 2-morpholinoethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethylaminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3- (4-methylpiperazinyl) propoxy, 3- (4-acetylpiperazinyl) propoxy, 3-morpholinopropoxy, 3-thiomorpholinylpropoxy, 3-piperidinylpropoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, phenylmethoxy, mono-halogen substituted phenylmethoxy, gem-dihalo substituted phenylmethoxy, hetero-dihalo substituted phenylmethoxy,

(7) Hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-dimethylaminostyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazino-1-sulfonyl, 4-acetylpiperazinyl-1-sulfonyl, 4-t-butoxycarbonylpiperazinyl-1-sulfonyl, 4- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-diethylethyl) piperazinyl-1-sulfonyl, 4- (3-hydroxypropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-sulfonyl, morpholinyl-1-sulfonyl, 3, 5-dimethylmorpholinyl-1-sulfonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-ethyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (4-acetyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-sulfonyl,

(8) Hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-carbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-ethylpiperazinyl-1-carbonyl, 4-acetylpiperazinyl-1-carbonyl, 4-tert-butoxycarbonylpiperazinyl-1-carbonyl, 4- (2-hydroxyethyl) piperazinyl-1-carbonyl, 4- (2-cyanoethyl) piperazinyl-1-carbonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carbonyl, 4- (2-N, N-diethylaminoethyl) piperazinyl-1-carbonyl, 4- (3-hydroxypropyl) piperazinyl-1-carbonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carbonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carbonyl, morpholinyl-1-carbonyl, 3, 5-dimethylmorpholinyl-1-carbonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4- (4-ethyl-1-piperazinyl) piperidinyl-1-carbonyl, 4- (4-acetyl-1-piperazinyl) piperidinyl-1-carbonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, N-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,

(9) Carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclopentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carboxamido, 3-N, N-diethylaminotetrahydropyrrolyl-1-carboxamido, 4-methylpiperazinyl-1-carboxamido, 4-ethylpiperazino-1-carboxamido, 4-acetylpiperazinyl-1-carboxamido, 4-t-butoxycarbonylpiperazinyl-1-carboxamido, 4- (2-hydroxyethyl) piperazinyl-1-carboxamido, 4- (2-cyanoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-diethylaminoethyl) piperazinyl-1-carboxamido, 4- (3-hydroxypropyl) piperazinyl-1-carboxamido, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carboxamido, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3, 5-dimethylmorpholinyl-1-carboxamido, 4- (4-methyl-piperazin-1-yl) piperidinyl-1-carboxamido, 4- (4-ethyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (4-acetyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carboxamido; or

(10)Z₂And Z₃Or Z₃And Z₄Form a nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring, the substituents being selected from the group consisting of₁The same above-mentioned substituents;

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(2) methylthio, ethylthio, isopropylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl, diethylphosphinioyl, diisopropylphosphinioyl.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(4) piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl,

(5)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (2-cyanoethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, n-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

(6) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl, or

(7)Z₂And Z₃Or Z₃And Z₄Form a nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring, the substituents being selected from the group consisting of₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group is a group selected from the group consisting of,

(3) the free radical of the methoxy group,

(4) n-methyl-4-piperidyl,

(5) 4-methyl piperazine group, and a salt thereof,

(6)4- (4-methylpiperazino) piperidinyl group,

(7)4- (tetrahydropyrrole-1-yl) piperidinyl, or

(8)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

1)

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₂and Z₄One of the two is hydrogen and the other is methyl;

Z₃selected from: n-methyl-4-piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from: (1) hydrogen, (2) methanesulfonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is methylsulfonyl; a. the₂，A₃，A₄Are both hydrogen.

In a fourth aspect, the present invention provides a compound represented by the following general formula IB, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

2)

whereinZ₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(4) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl, 2-oxo-piperazin-4-yl,

(5) morpholinyl, 3, 5-dimethylmorpholinyl, thiepinyl,

(6) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazinyl-1-sulfonyl, 4-acetylpiperazinyl-1-sulfonyl, 4- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-diethylethyl) piperazinyl-1-sulfonyl, 4- (3-hydroxypropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-sulfonyl, morpholinyl-1-sulfonyl, 3, 5-dimethylmorpholinyl-1-sulfonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-ethyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-sulfonyl,

(7)4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-ethylpiperazino-1-carbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-carbonyl, 4- (2-hydroxyethyl) piperazine 3-N, N-diethylaminotetrahydropyrrolyl-1-carbonyl, yl-1-carbonyl, 4- (3-hydroxypropyl) piperazinyl-1-carbonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carbonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carbonyl, morpholinyl-1-carbonyl, hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, 3, 5-dimethylmorpholinyl-1-carbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,

(8) pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, phenylmethoxy, mono-halogen substituted phenylmethoxy, or

(9)Z₂And Z₃Or Z₃And Z₄Form a nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring, the substituents being selected from the group consisting of₁The same above-mentioned substituents;

3)

wherein Z₂，Z₃，Z₄，Z₅The same as defined in 2) above; 4)

wherein Z₁，Z₃，Z₄，Z₅The same as defined in 2) above;

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

1)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(4) n-methyl-4-piperidyl group, 4-hydroxypiperidinyl group, 4- (4-methylpiperazinyl) piperidyl group, 4- (tetrahydropyrrolyl) piperidyl group, 4-N, N-dimethylaminopiperidinyl group, 4-N, N-diethylaminopiperidyl group, 4-N, N-diisopropylaminopiperidinyl group,

(5) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl, 4-methanesulfonylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (2-cyanoethyl) piperazinyl, 4- (3-hydroxypropyl) piperazinyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl, 4- (2-N, N-diethylaminoethyl) piperazinyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl, 4- (3-N, N-diethylaminopropyl) piperazinyl, 2-oxo-piperazin-4-yl

(6) Morpholinyl, 3, 5-dimethylmorpholinyl,

(7) 4-hydroxypiperidin-1-ylsulfonyl, 4-methylpiperazin-1-ylsulfonyl, hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-dimethylaminostetrahydropyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-ethylpiperazinyl-1-sulfonyl group,

(8)4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, piperidinyl-1-carbonyl, 4-hydroxypiperidinyl-1-carbonyl, 4-N, N-dimethylaminopiperidinyl-1-carbonyl, 4-N, N-diethylaminopiperidinyl-1-carbonyl, tetrahydropyrrolyl-1-carbonyl, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carbonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-carbonyl, 4- (3-hydroxypropyl) piperazinyl-1-carbonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carbonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carbonyl, morpholinyl-1-carbonyl,

(9) Pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, phenylmethoxy, mono-halo-substituted phenylmethoxy, or

2)

wherein Z₂，Z₃，Z₄，Z₅The same as defined in 2) above;

3)

wherein Z₁，Z₃，Z₄，Z₅The same as defined in 2) above.

In some embodiments, R1 is selected from:

1)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group is a group selected from the group consisting of,

(3) methoxy group, ethoxy group, isopropoxy group,

(4) n-methyl-4-piperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, 4-dimethylamino-piperidinyl,

(5) 4-methylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl,

(6) a morpholino group in a group of amino acids,

(7) 4-hydroxypiperidin-1-ylsulfonyl, 4-methylpiperazin-1-ylsulfonyl,

(8)4- (4-methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl,

(9) a pyridin-2-ylmethoxy group which is,

(10) 2-dimethylamino-acetamido-group, which is a compound of the formula,

(11)–F，

(12)Z₂and Z₃Or Z₃And Z₄Form a

2)

Wherein Z₂，Z₃，Z₄，Z₅Each independently selected from: morpholinyl, 4-methylpiperazinyl, 4-hydroxypiperidinyl;

3)

Wherein Z₁，Z₃，Z₄，Z₅Each independently selected from: morpholinyl, 4-hydroxypiperidinyl.

In some embodiments, R1 is selected from:

1)

wherein Z₁And Z₅One of the two is hydrogen and the other is selected from: methoxy, ethoxy, isopropoxy;

Z₂and Z₄One of the two is hydrogen and the other is methyl, 2-dimethylaminoacetamido,

Z₃selected from: n-methyl-4-piperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrroln-1-yl) piperidinyl, 4-methylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl, morpholinyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4- (4-Methyl-piperazin-1-yl) piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, pyridin-2-ylmethoxy, 4-dimethylamino-piperidinyl, -F; or

Z₂And Z₃Or Z₃And Z₄Form a

2)

Wherein Z₃Selected from: morpholinyl, 4-methylpiperazinyl, 4-hydroxypiperidinyl; z₁、Z₂And Z₄Are all hydrogen;

3)

wherein Z₃Selected from: morpholinyl, 4-hydroxypiperidinyl; z₁、Z₂And Z₄Are both hydrogen.

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from: (1) hydrogen, (2) isopropylsulfonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylsulfonyl; a. the ₂，A₃，A₄Are both hydrogen.

In a fifth aspect, the present invention provides a compound represented by the following general formula IO, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(3) Piperidinyl, N-methyl-4-piperidinyl, 4-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(2) methylthio, ethylthio, isopropylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl, diethylphosphinioyl, diisopropylphosphinioyl.

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(4) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl or

(5)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-or oxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently optionally selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) C1-C6 alkoxy

(3)4- (4-methylpiperazin-1-yl) piperidinyl, 4-methylpiperazinyl, 4-dimethylamino-piperidinyl,

(4)Z₂and Z₃May form a nitrogen-containing substituted or unsubstituted five-membered ring

In some embodiments, R1 is selected from:

wherein the content of the first and second substances,

Z₁is methoxy, and Z₃Selected from: 4-dimethylamino-piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, the remainder being hydrogen; or

Z₃And Z₄Form a

And Z is₁Methoxy radical and the rest is hydrogen.

In some embodiments, R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen; (2) tert-butylsulfonyl group.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is tert-butylsulfonyl; a. the₂，A₃，A₄Are both hydrogen.

In a sixth aspect, the present invention provides a compound represented by the following general formula IC, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(4) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl, or

(9) Carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclopentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carboxamido, 3-N, N-diethylaminotetrahydropyrrolyl-1-carboxamido, 4-methylpiperazinyl-1-carboxamido, 4-ethylpiperazino-1-carboxamido, 4-acetylpiperazinyl-1-carboxamido, 4-t-butoxycarbonylpiperazinyl-1-carboxamido, 4- (2-hydroxyethyl) piperazinyl-1-carboxamido, 4- (2-cyanoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-diethylaminoethyl) piperazinyl-1-carboxamido, 4- (3-hydroxypropyl) piperazinyl-1-carboxamido, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carboxamido, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3, 5-dimethylmorpholinyl-1-carboxamido, 4- (4-methyl-piperazin-1-yl) piperidinyl-1-carboxamido, 4- (4-ethyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (4-acetyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carboxamido

(10)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-or oxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from₁The same above-mentioned substituents;

r2 is selected from: 1)

wherein Y is an NH, S or O atom,

A₆，A₇，A₈，A₉，A₁₀，A₁₁each independently selected from:

2)

wherein A is₁₂Selected from:

Y₂,Y₃,Y₄The combination is as follows:

Y₂is C, Y₃Is N-A₁₃，Y₄Is N, or

Y₂Is N, Y₃Is N-A₁₃，Y₄Is CH or N;

wherein A is₁₃Is hydrogen, C1-C6 alkyl.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) 4-hydroxypiperidinyl, piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl,

(5)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (2-cyanoethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, n-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl, or

(6)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-or oxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the free radical of the methoxy group,

(3) a 4-hydroxypiperidinyl group, a salt thereof,

(4) 4-methyl piperazine group, and a salt thereof,

(5)4- (4-methylpiperazino) piperidinyl, or

(6)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two being hydrogen and the other being methoxy, Z₄Is hydrogen;

Z₃selected from: 4-hydroxypiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, or

Z₂And Z₃Form a

In some embodiments, R2 is selected from:

wherein A is₁₂Selected from:

(1) hydrogen, methyl, fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro,

Y₂,Y₃,Y₄The combination is as follows:

Y₂is C, Y₃Is N-A₁₃，Y₄Is N, or

Y₂Is N, Y₃Is N-A₁₃，Y₄Is CH or N;

wherein A is₁₃Is hydrogen, C1-C6 alkyl.

In some embodiments, R2 is selected from:

wherein A is₁₂Selected from:

(1) the hydrogen, the methyl group,

(2) an isopropylsulfonyl group;

Y₂,Y₃,Y₄the combination is as follows:

Y₂is C, Y₃Is N-A₁₃，Y₄The content of the N is N,

wherein A is₁₃Is hydrogen, C1-C6 alkyl.

In some embodiments, R2 is selected from:

wherein A is₁₂Selected from the group consisting of isopropylsulfonyl;

Y₂,Y₃,Y₄the combination is as follows: y is₂Is C, Y₃Is N-A₁₃，Y₄Is N, wherein A₁₃Is methyl.

In a seventh aspect, the present invention provides a compound represented by the following general formula ID, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(4) piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl

(6) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl or

(7)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-or oxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group is a group selected from the group consisting of,

(3) a methoxy group and an isopropoxy group,

(4) n-methyl-4-piperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl,

(5) 4-methylpiperazinyl, or

(6)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₂And Z₄One of the two is hydrogen and the other is methyl,

Z₁and Z₅One of the two is hydrogen and the other is selected from: a methoxy group and an isopropoxy group,

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen; (2) a methoxycarbonyl group.

In some embodiments, R2 is selected from:

wherein A is₂And A₄One of the two is hydrogen and the other is methoxycarbonyl; a. the₁，A₃，A₅Are both hydrogen.

In an eighth aspect, the present invention provides a compound represented by the following general formula IE, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(9) Carbamoylamino, methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclopentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N, N-dimethylaminopiperidinyl-1-carboxamido, 4-N, N-diethylaminopiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N, N-dimethylaminotetrahydropyrrolyl-1-carboxamido, 3-N, N-diethylaminotetrahydropyrrolyl-1-carboxamido, 4-methylpiperazinyl-1-carboxamido, 4-ethylpiperazino-1-carboxamido, 4-acetylpiperazinyl-1-carboxamido, 4-t-butoxycarbonylpiperazinyl-1-carboxamido, 4- (2-hydroxyethyl) piperazinyl-1-carboxamido, 4- (2-cyanoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-carboxamido, 4- (2-N, N-diethylaminoethyl) piperazinyl-1-carboxamido, 4- (3-hydroxypropyl) piperazinyl-1-carboxamido, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-carboxamido, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-carboxamido, morpholinyl-1-carboxamido, 3, 5-dimethylmorpholinyl-1-carboxamido, 4- (4-methyl-piperazin-1-yl) piperidinyl-1-carboxamido, 4- (4-ethyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (4-acetyl-1-piperazinyl) piperidinyl-1-carboxamido, 4- (N-methyl-4-piperidinyl) piperazinyl-1-carboxamido;

R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(2) methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(6) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl.

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) methyl, methoxy, ethoxy, isopropoxy,

(3) n-methyl-4-piperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl,

(4) 4-methylpiperazinyl.

In some embodiments, R1 is selected from:

Z₂and Z₄One of the two is hydrogen and the other is methyl;

Z₃selected from: n-methyl-4-piperidyl, 4-hydroxypiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidyl, 4- (tetrahydropyrrole-1-yl) piperidyl.

In some embodiments, R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) methoxycarbonyl.

In some embodiments, R2 is selected from

Wherein A is₁And A₅One of the two is hydrogen and the other is methoxycarbonyl; a. the₂，A₃，A₄Are both hydrogen.

In a ninth aspect, the present invention provides a compound represented by the following general formula IF, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(3) Piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (N-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl

(4) Piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl, or

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) The free radical of the methoxy group,

(3) 4-methyl piperazine group, and a salt thereof,

(4)4- (4-methylpiperazino) piperidinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy; z₄Is hydrogen;

Z₃selected from: 4-methylpiperazino, 4- (4-methylpiperazino) piperidinyl, or

Z₂And Z₃Form a

In some embodiments, R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) fluorine, (3) methylaminocarbonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is selected from: fluoro, methylaminocarbonyl; and A is₂And A₄One of the two is hydrogen and the other is selected from: fluoro, methylaminocarbonyl; a. the₃Is hydrogen.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is methylaminocarbonyl; and A is₂And A₄One of the two is hydrogen and the other is fluorine; a. the₃Is hydrogen.

In a tenth aspect, the present invention provides a compound represented by the following general formula IG, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

1) propylaminoethyl, 2-morpholinoethyl, 2- (4-methylpiperazinyl) ethyl, 3-N, N-dimethylaminopropyl, 3-N, N-diethylaminopropyl, 3-N, N-diisopropylaminopropyl, 3-morpholinopropyl, 3- (4-methylpiperazinyl) propylyl, C3-C6 cycloalkyl, 4-N, N-dimethylaminocyclohexyl, 4-N, N-diethylaminocyclohexyl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, 1, 3-dimethyl-5-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-5-isoxazolinyl, 1- (N-methyl-4-piperidinyl) -4-pyrazolyl, 1- (N-tert-butoxycarbonyl-4-piperidinyl) -4-pyrazolyl;

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(6) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(7) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-dimethylaminostyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazino-1-sulfonyl, 4-acetylpiperazinyl-1-sulfonyl, 4-t-butoxycarbonylpiperazinyl-1-sulfonyl, 4- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-diethylethyl) piperazinyl-1-sulfonyl, 4- (3-hydroxypropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-sulfonyl, morpholinyl-1-sulfonyl, 3, 5-dimethylmorpholinyl-1-sulfonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-ethyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (4-acetyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-sulfonyl, or

(8)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-or oxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group, the methoxy group,

(4) aminosulfonyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₂and Z₄One of the two is hydrogen and the other is methyl;

Z₃selected from: n-methyl-4-piperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, aminosulfonyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) methylsulfonylamino.

In some embodiments, R2 is selected from:

wherein A is₂And A₄One of the two is hydrogen and the other is methylsulfonylamino; a. the₁，A₃，A₅Are both hydrogen.

In an eleventh aspect, the present invention provides a compound represented by the following general formula IH, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

1) propylaminoethyl, 2-morpholinylethyl, 2- (4-4-methylpiperazinyl) ethyl, 3-N, N-dimethylaminopropyl, 3-N, N-diethylaminopropyl, 3-N, N-diisopropylaminopropyl, 3-morpholinylpropyl, 3- (4-methylpiperazinyl) propylyl, C3-C6 cycloalkyl, 4-N, N-dimethylaminocyclohexyl, 4-N, N-diethylaminocyclohexyl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, 1, 3-dimethyl-5-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-5-isoxazolinyl, 1- (N-methyl-4-piperidinyl) -4-pyrazolyl, 1- (N-tert-butoxycarbonyl-4-piperidinyl) -4-pyrazolyl;

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from: 2)

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) piperidinyl, N-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl

(4)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (2-cyanoethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, n-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

(5) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl,

(6) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, piperidin-1-ylsulfonyl, 4-hydroxypiperidin-1-ylsulfonyl, 4-N, N-dimethylaminopiperidin-1-ylsulfonyl, 4-N, N-diethylaminopiperidin-1-ylsulfonyl, tetrahydropyrrolyl-1-sulfonyl, 3-N, N-dimethylaminostyrrolyl-1-sulfonyl, 3-N, N-diethylaminotetrahydropyrrolyl-1-sulfonyl, 4-methylpiperazin-1-ylsulfonyl, 4-ethylpiperazino-1-sulfonyl, 4-acetylpiperazinyl-1-sulfonyl, 4-t-butoxycarbonylpiperazinyl-1-sulfonyl, 4- (2-hydroxyethyl) piperazinyl-1-sulfonyl, 4- (2-cyanoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-dimethylaminoethyl) piperazinyl-1-sulfonyl, 4- (2-N, N-diethylethyl) piperazinyl-1-sulfonyl, 4- (3-hydroxypropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-dimethylaminopropyl) piperazinyl-1-sulfonyl, 4- (3-N, N-diethylaminopropyl) piperazinyl-1-sulfonyl, morpholinyl-1-sulfonyl, 3, 5-dimethylmorpholinyl-1-sulfonyl, 4- (4-methyl-piperazin-1-yl) piperidin-1-ylsulfonyl, 4- (4-ethyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (4-acetyl-1-piperazinyl) piperidin-1-ylsulfonyl, 4- (N-methyl-4-piperidinyl) piperazinyl-1-sulfonyl, or

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the free radical of the methoxy group,

(4) 4-methyl piperazine group, and a salt thereof,

(5) aminosulfonyl, or

(6)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

Z₃selected from: n-methyl-4-piperidinyl, 4-hydroxypiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, aminosulfonyl, or

Z₂And Z₃Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a methylsulfonylamino group.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is methylsulfonylamino; a. the₂，A₃，A₄Are both hydrogen.

In a twelfth aspect, the present invention provides a compound represented by the following general formula II, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) methyl, methoxy, ethoxy, isopropoxy;

(3) n-methyl-4-piperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, 4-hydroxypiperidinyl;

(4) 4-methylpiperazinyl.

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two is hydrogen, and the other is selected from methoxy, ethoxy and isopropoxy;

Z₂and Z₄One of the two is hydrogen and the other is methyl;

Z₃selected from: n-methyl-4-piperidinyl, 4-methylpiperazinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl.

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from: (1) hydrogen; (2) a methylaminocarbonyl group.

In some embodiments, R2 is selected from

Wherein A is₁And A₅One of the two is hydrogen and the other is methylaminocarbonyl; a. the₂，A₃，A₄Are both hydrogen.

In a thirteenth aspect, the present invention provides a compound represented by the following general formula IPQ, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(2) methylthio, ethylthio, isopropylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl, diethylphosphinioyl, diisopropylphosphinioyl.

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

In some embodiments, R1 is selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (4-methylpiperazino) piperidinyl, 4-methylpiperazino, 4-dimethylamino-piperidinyl.

In some embodiments, R1 is selected from:

wherein the content of the first and second substances,

Z₃And Z₄Form a

And Z is₁Methoxy radical and the rest is hydrogen.

In some embodiments, R2 is selected from:

Wherein A is₁，A₂，A₃，A₄，A₅Each independently optionally selected from:

(1) hydrogen, (2) isopropylaminocarbonyl, dimethylaminocarbonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylaminocarbonyl or dimethylaminocarbonyl; a. the₂，A₃，A₄Are both hydrogen.

In a fourteenth aspect, the present invention provides a compound represented by the following general formula IJ, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group, the methoxy group,

(3) n-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl,

(4) 4-methylpiperazinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two being hydrogen and the other being methoxy, Z₂And Z₄One of the two is hydrogen and the other is methyl,

Z₃selected from: n-methyl-4-piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) isopropylsulfinyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylsulfinyl; a. the₂，A₃，A₄Are both hydrogen.

In a fifteenth aspect, the present invention provides a compound represented by the following general formula IK, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) C1-C6 alkoxy

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group, the methoxy group,

(3) 4-methyl piperazine group, and a salt thereof,

(4) n-methyl-4-piperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrroln-1-yl) piperidinyl, 4-N, N-dimethylaminopiperidinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from

Wherein Z₂And Z₄One of the two being hydrogen and the other being methyl, Z₁And Z₅One of the two is hydrogen and the other is methoxy,

Z₃selected from: n-methyl-4-piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrol-1-yl) piperidinyl, 4-N, N-dimethylaminopiperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) dimethylphosphinyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is dimethylphosphinyl; a. the₂，A₃，A₄Are both hydrogen.

In a sixteenth aspect, the present invention provides a compound represented by the following general formula IRS, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

Wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

(3) piperidinyl, N-methyl-4-piperidinyl, 4-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl, 4- (tetrahydropyrrolyl-1-yl) piperidinyl

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) piperidinyl, N-methyl-4-piperidinyl, 4-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (4-acetylpiperazinyl) piperidinyl, 4- (4-tert-butoxycarbonylpiperazinyl) piperidinyl, 4- (4-methanesulfonylpiperazinyl) piperidinyl, 4- (4- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (4- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (4- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (2-N, N-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl, 4- (tetrahydropyrrolyl-1-yl) piperidinyl;

In some embodiments, R1 is selected from

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (tetrahydropyrrole-1-yl) piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4-dimethylamino-piperidinyl;

(4)Z₂and Z₃May form nitrogen-containing substitutions or non-substitutionsFive-membered ring of the generation

In some embodiments, R1 is selected from:

wherein

Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-dimethylamino-piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

(1) hydrogen; (2) diisopropylphosphinic acid, diethylphosphinic acid.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is diisopropylphosphinic or diethylphosphinic; a. the₂，A₃，A₄Are both hydrogen.

In a seventeenth aspect, the present invention provides a compound represented by the following general formula IL, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein A is methylene; x is NH;

r1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(4)4- (4-methylpiperazino) piperidyl group, 4- (4-ethylpiperazino) piperidyl group, 4- (4-isopropylpiperazinyl) piperidyl group, 4- (4-acetylpiperazinyl) piperidyl group, 4- (4-tert-butoxycarbonylpiperazinyl) piperidyl group, 4- (4-methanesulfonylpiperazinyl) piperidyl group, 4- (4- (2-hydroxyethyl) piperazinyl) piperidyl group, 4- (4- (2-cyanoethyl) piperazinyl) piperidyl group, 4- (4- (3-hydroxypropyl) piperazinyl) piperidyl group, 4- (4- (2-N, N-dimethylaminoethyl) piperazinyl) piperidyl group, 4- (4- (2-N, n-diethylaminoethyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-dimethylaminopropyl) piperazinyl) piperidinyl, 4- (4- (3-N, N-diethylaminopropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, 4- (3-N, N-dimethylaminostetrahydropyrrolyl) piperidinyl,

(5) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl, or

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the free radical of the methoxy group,

(3) 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl,

(4) 4-methylpiperazinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

Z₂And Z₃Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) methanesulfonyl.

In some embodiments, R2 is selected from:

In an eighteenth aspect, the present invention provides a compound represented by the following general formula IM, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein A is methylene; x is NH;

r1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) C1-C6 alkoxy

(5) 4-methylpiperazino group, 4-ethylpiperazino group, 4-isopropylpiperazinyl group, 4-acetylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-methanesulfonylpiperazinyl group, 4- (2-hydroxyethyl) piperazinyl group, 4- (2-cyanoethyl) piperazinyl group, 4- (3-hydroxypropyl) piperazinyl group, 4- (2-N, N-dimethylaminoethyl) piperazinyl group, 4- (2-N, N-diethylaminoethyl) piperazinyl group, 4- (3-N, N-dimethylaminopropyl) piperazinyl group, 4- (3-N, N-diethylaminopropyl) piperazinyl group, 4- (N-methyl-4-piperidinyl) piperazinyl group, 4- (N-ethyl-4-piperidinyl) piperazinyl or

(6)Z₂And Z₃Or Z₃And Z₄Form nitrogen orOxygen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the free radical of the methoxy group,

(3) 4-hydroxypiperidinyl, 4- (4-methylpiperazinyl) piperidinyl,

(4) 4-methylpiperazinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

Z₂And Z₃Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) isopropylsulfonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylsulfonyl; a. the₂，A₃，A₄Are both hydrogen.

In a nineteenth aspect, the present invention provides a compound represented by the following general formula IT, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein A is methylene; x is O;

r1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R1 is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

In some embodiments, R1 is selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) 4-methylpiperazino, 4- (4-methylpiperazino) piperidinyl, morpholinyl, 4-dimethylamino-piperidinyl,

In some embodiments, R1 is selected from:

wherein

Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-dimethylamino-piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4-methylpiperazinyl or morpholinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

(1) hydrogen

(2) An isopropylsulfonyl group.

In some embodiments, R2 is selected from:

IN a twentieth aspect, the present invention provides a compound represented by the following general formula IN, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each of which isIndependently selected from:

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) a C1-C6 alkoxy group,

(8)Z₂And Z₃Or Z₃And Z₄Form a nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring, the substituents being selected from the group consisting of₁The same substituents as described above.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) the methyl group, the methoxy group,

(3) 4-hydroxypiperidinyl, 4-methylpiperazinyl, N-methyl-4-piperidinyl,

(4)4- (4-methylpiperazino) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, aminosulfonyl, or

(5)Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₂and Z₄One of the two is hydrogen and the other is methyl,

Z₃selected from: 4-hydroxypiperidinyl, 4-methylpiperazinyl, N-methyl-4-piperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrole-1-yl) piperidinyl, aminosulfonyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

In some embodiments, R2 is selected from:

wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(1) hydrogen, (2) methoxycarbonyl.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen, and the other is methoxycarbonyl; a. the₂，A₃，A₄Are both hydrogen.

In a twenty-first aspect, the present invention provides a compound represented by the following general formula IU, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein R1 is selected from:

2)

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

r2 is selected from

Wherein A is₁，A₂，A₃，A₄，A₅Each independently selected from:

(2) methylthio, ethylthio, isopropylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, dimethylaminosulfonyl, methylsulfonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dimethylphosphinoyl, diethylphosphinionyl, diisopropylphosphinionyl.

In some embodiments, R1 is selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

In some embodiments, R1 is selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (4-methylpiperazino) piperidinyl, 4-methylpiperazinyl,

In some embodiments, R1 is selected from:

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-methylpiperazino, 4- (4-methylpiperazino) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

In some embodiments, R2 is selected from:

(1) hydrogen

(2) A dimethylaminosulfonyl group.

In some embodiments, R2 is selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is dimethylaminosulfonyl; a. the₂，A₃，A₄Are both hydrogen.

Unless otherwise specified, the above groups and substituents have the ordinary meaning in the field of pharmaceutical chemistry.

The term "C1-C6-containing oxyalkyl group" means a group in which the C1-C6 alkyl skeleton is substituted with one or more C1-C6 alkoxy groups, and examples thereof include methoxyethyl and methoxyethoxymethyl.

The term "C₁-C₆Alkyl "refers to any straight or branched chain group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, and the like.

The term "C₂-C₆Alkenyl "means any straight or branched chain group containing 2 to 6 carbon atoms and containing at least one alkenyl group, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, and the like.

The term "C₂-C₆Alkynyl "refers to any straight or branched chain group containing 2 to 6 carbon atoms and at least one alkynyl group, such as ethynyl, 2-propynyl, 4-pentynyl, and the like.

According to the present invention and unless otherwise provided, any of the above groups may be optionally substituted in any of its free positions by one or more groups, for example 1 to 6 groups, independently selected from halogen atoms, nitro groups, oxo (═ O), cyano groups, C₁-C₆Alkyl, polyfluorinated alkoxy, alkenyl, alkyneAlkyl, hydroxyalkyl, hydroxyalkylamino, hydroxyheterocyclyl, aryl-alkyl, heteroaryl-alkyl, heterocyclyl-alkyl, C ₃-C₇Cycloalkyl, cycloalkyl-alkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-aryl-alkyl, alkyl-heteroaryl-alkyl, alkyl-heterocyclyl-alkyl, alkyl-cycloalkyl-alkyl, alkyl-heterocyclyl, heterocyclyl-alkyl-heterocyclyl, heterocyclyl-alkylamino, alkyl-heterocyclyl-alkyl-amino, hydroxy, alkoxy, aryloxy, heterocyclyloxy, alkyl-heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, arylcarbonyloxy, cycloalkylcarbonyl, alkylheterocyclylcarbonyloxy, alkylheterocyclylcarbonyl-alkyl, alkylheterocyclylalkyl-alkyl, heterocyclylalkylamino, alkylheterocyclylalkylamino, carbonyl-alkoxy-carbonyl, aryl, Cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, amino-alkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, arylamino, arylalkylamino, diarylamino, heterocyclylamino, alkyl-heterocyclylcarbonyl, carbonylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkyl-heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino-alkylamino, alkoxycarbonylheterocyclyl-alkylamino, alkoxy-aryl-alkyl, hydroxyamino-carbonyl, alkoxyimino, ureido, alkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, dialkylamino-alkylcarbonylamino, alkylamino, heterocyclylcarbonylamino, alkylcarbonylamino, alkylamino, dialkylamino, ureido, alkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, Alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate.

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

In this respect, the term "halogen atom" refers to a fluorine, chlorine, bromine or iodine atom.

The term "cyano" refers to the residue — CN.

The term "nitro" refers to-NO₂A group.

The terms "alkoxy", "cyclyloxy", "aryloxy", "heterocyclyloxy" and derivatives thereof refer to any of the above C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, aryl or heterocyclyl, which are attached to the remainder of the molecule through an oxygen atom (-O-).

The term "aryl" refers to a mono-, di-or poly-carbocyclic hydrocarbon having 1 to 2 ring systems optionally further fused or connected to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic", wherein the term "aromatic" refers to a completely conjugated pi-electron bond system. The aryl ring may optionally be further fused or attached to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of said aryl groups are phenyl, alpha-or beta-naphthyl.

The term "heteroaryl" refers to an aromatic heterocyclic ring, typically a 5-to 8-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O or S; heteroaryl rings may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaoxazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, 1,2, 3-triazolyl, 1-phenyl-1, 2, 3-triazolyl, 2, 3-indolinyl, 2, 3-dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, benzopyranyl, 2, 3-dihydrobenzoxazinyl, 2, 3-dihydroquinoxalinyl, and the like.

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

The term "nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring" refers to a 5-or 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen. The nitrogen-or oxygen-containing substituted or unsubstituted five-or six-membered ring is selected from pyrrolidine, pyrroline, pyrrole, imidazoline, imidazolidine, imidazole, pyrazolidine, pyrazoline, pyrazole, dihydrofuran, tetrahydrofuran, furan, 1, 3-dioxolane, oxazole, dihydrooxazole; pyridine, pyrazine, pyrimidine, pyridazine, pyran, piperidine, piperazine, morpholine, and the like.

From all the above descriptions, it is obvious to the person skilled in the art that any group whose name is a composite name, such as "arylamino", shall mean a moiety conventionally derived therefrom, such as for example constructed from an amino group substituted by an aryl group, wherein aryl is as defined above.

Likewise, any term such as alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like includes groups wherein alkyl, alkoxy, aryl, C₃-C₇The cycloalkyl and heterocyclyl moieties are as defined above.

As used herein, unless otherwise specified, 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 active in a form in which they do not react. Prodrugs can generally be prepared using well known methods, such as those described in 1Burger's Medicinal Chemistry and Drug Discovery (1995)172-178,949-982 (edited by Man E.Wolff, 5 th edition).

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 provide 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 preventing the disease or its symptoms, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

According to a specific embodiment of the present invention, the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound is one of the compounds described in the following examples.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound according to any one of the above technical schemes, a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Methods of preparing various pharmaceutical compositions containing certain amounts of active ingredients are known or will be apparent to those skilled in the art in view of this disclosure. Methods of preparing the Pharmaceutical compositions include the incorporation of suitable Pharmaceutical excipients, carriers, diluents, etc., as described in Remington's Pharmaceutical Sciences, Martin, E.W., ed., Mack Publishing Company,19th ed. (1995).

The pharmaceutical formulations of the present invention are manufactured in a known manner, including conventional mixing, dissolving or lyophilizing processes. The compounds of the invention may be formulated into pharmaceutical compositions and administered to the patient by a variety of routes appropriate for the selected 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, e.g., orally, in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules and may be compressed into tablets. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The proportions of such compositions and formulations can, of course, vary and can range 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 is obtained.

Tablets, troches, pills, capsules and the like may also contain: binders, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a 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 and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained release formulations and sustained release devices.

The active compounds may also be administered intravenously or intraperitoneally by infusion or injection. An aqueous solution of the active compound or salt thereof may be prepared, optionally mixed with a non-toxic surfactant. Dispersants in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils may also be prepared. 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 include sterile aqueous solutions or dispersions or sterile powders of the active ingredient, optionally encapsulated in liposomes, containing ready-to-use preparations of injectable or infusible solutions or dispersions suitable for sterility. In all cases, the final dosage form must be sterile, liquid 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 (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required 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, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption of the agent (e.g., aluminum monostearate and gelatin).

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various 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 ingredients present in previously sterile-filtered solutions.

Useful solid carriers include finely divided solids (e.g., talc, clay, microcrystalline cellulose, silicon dioxide, alumina, and the like). Useful liquid carriers include water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixtures in which the compounds of the present invention may be dissolved or dispersed in effective amounts, optionally with the aid of non-toxic surfactants. Adjuvants (such as fragrances) and additional antimicrobial agents may be added to optimize the properties for a given use.

Thickeners (e.g., synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified inorganic materials) can also be used with liquid carriers to form coatable pastes, gels, ointments, soaps, etc., for direct application to the skin of the user.

The therapeutically required amount of the compound or its active salt or derivative will depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician or clinician.

The formulations may be presented in unit dosage form comprising physically discrete units of a unit dose suitable for administration to the human or other mammalian body. The unit dosage form may be a capsule or tablet, or a plurality of capsules or tablets. The amount of unit dose of the active ingredient may be varied or adjusted from about 0.1 to about 1000 mg or more depending upon the particular treatment involved.

In addition, the application of various new pharmaceutical forms such as milk fat masses, microspheres and nanospheres is also included, such as medicaments prepared using microparticle dispersions including polymeric micelles (polymeric micelles), nanoemulsions (nanoemulsions), submicroemulsions (microcapsules), microspheres (microspheres), liposomes (lipomes) and niosomes (also known as nonionic surfactant vesicles).

In another aspect, the present invention further provides a method for preparing a compound according to any one of the above technical schemes, comprising the following steps:

X ═ Cl or Br

The starting materials for this reaction are commercially available.

R'＝H,Cl,Br

Reaction conditions are as follows: (a) substitution reaction under basic conditions (such as diisopropylethylamine, triethylamine, potassium carbonate, etc.) or acidic conditions (trifluoroacetic acid, hydrochloric acid, etc.); (b) acidic conditions (trifluoroacetic acid, hydrochloric acid, etc.) or palladium catalyzed amination.

In another aspect, the present invention further provides a use of the compound, the stereoisomer, the prodrug, the pharmaceutically acceptable salt, or the pharmaceutically acceptable solvate of the compound according to any one of the above technical schemes in preparation of a medicament for preventing and treating tumors. Preferably, the tumor is any one of large cell lymphoma, inflammatory myofibroblastoma, non-small cell lung cancer, neuroblastoma, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma; more preferably, wherein the tumor is a large cell, progressive lymphoma, inflammatory myofibroblastoma, non-small cell lung cancer, or neuroblastoma.

Detailed Description

The embodiments of the present invention are described in detail below by way of specific examples, but they should not be construed as limiting the invention in any way.

Universal purification and analysis methods

Thin layer chromatography was performed on silica gel GF254 pre-coated plates (Qingdao oceanic chemical plant). Column chromatography over silica gel (300-400 mesh, Shintai yellow silica gel development reagent factory) at medium pressure or by using an ISCO Combiflash Rf200 Rapid purification System with pre-loaded silica gel cartridges (ISCO or Welch). The components passing UV light

And development by iodine vapor. When necessary, the compounds were purified by preparative HPLC prep on a Waters Symmetry C18(19X 50mm,5 μm) column or a Waters X Terra RP 18(30X 150mm,5 μm) column using a device equipped with 996Waters PDA for detectionWaters preparative HPLC 600 and Micromass mod. zmd single quadrupole mass spectrometry (electrospray ionization, cation mode) from the apparatus. The method comprises the following steps: phase A0.1% TFA/MeOH 95/5; phase B MeOH/H₂And O95/5. Gradient: performing the treatment for 10-90% B for 8min, and maintaining for 90% B for 2 min; the flow rate was 20 mL/min. The method 2 comprises the following steps: phase A0.05% NH₄OH/MeOH 95/5; phase B MeOH/H₂And O95/5. Gradient: 10-100% B for 8min, and keeping 100% B for 2 min. The flow rate was 20 mL/min.

Will be provided with¹H-NMR spectra in DMSO-d₆Or CDCl₃Via a Bruker Avance 600 spectrometer operating at 600MHz (for¹H) was recorded. Residual solvent signal was used as reference

Chemical shift

Reported in parts per million (ppm) and coupling constants (J) in Hz. The following abbreviations are used for peak splitting, s is mono; br.s. ═ wide signal; d is bis; t is three; m is multiple; dd is bis-bis.

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

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

Reagent Purification is described in the paper of Purification of Laboratory Chemicals (Perrin, D.D., Armarego, W.L.F. and Perrin Eds, D.R.; Pergamon Press: Oxford, 1980). The petroleum ether is 60-90 deg.C fraction, and the ethyl acetate, methanol and dichloromethane are analytically pure.

The compounds with the general formula are prepared by several kinds of synthesis.

General formula of compound I

Example 1

Synthesis general formula of compound IA

Preparation of Compound 3

Compound 2(200mg, 1.17mmol) was dissolved in N, N-dimethylformamide (4mL), sodium hydride (93.6mg, 2.34mmol) was added under ice bath conditions and stirred for 5-10min, then compound 1(240.0mg, 1.17mmol) was added and stirred at room temperature for 1.0h (TLC follow-up) and the reaction was stopped. To the system was added ice water to quench sodium hydride, ethyl acetate was added and the solution was separated, and the organic phase was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 5/1) to give compound 3 (solid, 270.0mg, yield 79.5%) which was used directly in the next reaction.

MS(ESI)m/z:340[M+H]⁺.

Preparation of Compound IA

The method A comprises the following steps:

dissolving the compound 3(30.0mg, 0.09mmol) and the arylamine (0.072mmol) in 1mL of tert-butyl alcohol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (7.7mg, 0.016mmol), tris (dibenzylideneacetone) dipalladium (9.9mg, 0.011mmol) and potassium carbonate (37mg, 0.27mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the arylamine reaction is complete (LC-MS and TLC tracking), and stopping the reaction. Adding methanol and dichloromethane to the reaction solution, filtering the system, concentrating, and performing silica gel column chromatography (dichloromethane/methanol) to obtain compound IA.

The method B comprises the following steps:

dissolving the compound 3(30.0mg, 0.09mmol) and the arylamine (0.072mmol) in 1mL of tert-butyl alcohol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (7.7mg, 0.016mmol), tris (dibenzylideneacetone) dipalladium (9.9mg, 0.011mmol) and potassium carbonate (37mg, 0.27mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the arylamine reaction is complete (LC-MS and TLC tracking), and stopping the reaction. Methanol and dichloromethane were added to the reaction solution, the system was filtered, concentrated and purified by reverse phase preparative HPLC (using an aqueous solution containing 0.35% trifluoroacetic acid and methanol as mobile phases) and concentrated in vacuo to give compound IA.

Compounds IB and IC can be synthesized using similar methods.

The following table lists specific compounds and structural identification data.

TABLE 1 Structure and characterization of Compounds IA-IC

Example 2

Synthetic general formula of compound ID

Preparation of Compound 5

Compound 1(205mg, 1.00mmol) and compound 4(151mg, 1.00mmol) were dissolved in 5mL of t-butanol, and 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (56mg, 0.12mmol), tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol), and potassium carbonate (415mg, 3.00mmol) were added to the solution, and the resulting reaction solution was placed in an oil bath preheated to 110 ℃ under nitrogen protection and heated with stirring until compound 1 was completely reacted (LC-MS and TLC follow-up). Methanol and dichloromethane were added to the reaction solution, the system was filtered, the filtrate was concentrated and diluted with dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated and subjected to silica gel column chromatography (dichloromethane/ammonia methanol ═ 10/1) to obtain compound 5 (white solid, 293.5mg, yield 92.0%) which was used directly in the next reaction.

MS(ESI)m/z:320[M+H]⁺

Preparation of Compound ID

The method A comprises the following steps:

dissolving a compound 5(31.8mg, 0.10mmol) and arylamine (0.09mmol) in 1mL of tert-butanol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (0.018mmol), tris (dibenzylideneacetone) dipalladium (0.012mmol) and potassium carbonate (0.30mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the compound 5 completely reacts (LC-MS and TLC tracking), and stopping the reaction. Methanol and dichloromethane were added to the reaction solution, and the system was filtered, concentrated and subjected to silica gel column chromatography (dichloromethane/methanol) to obtain compound ID.

The method B comprises the following steps:

dissolving a compound 5(31.8mg, 0.10mmol) and arylamine (0.09mmol) in 1mL of tert-butanol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (0.018mmol), tris (dibenzylideneacetone) dipalladium (0.012mmol) and potassium carbonate (0.30mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the compound 5 completely reacts (LC-MS and TLC tracking), and stopping the reaction. Methanol and dichloromethane were added to the reaction solution, the system was filtered, concentrated and purified by reverse phase preparative HPLC (using an aqueous solution containing 0.35% trifluoroacetic acid and methanol as mobile phases), and concentrated in vacuo to give compound ID.

Compounds IE, IF, IG, IH, II, IJ, IK can all be synthesized using similar methods.

TABLE 2 Compound ID-IK Structure and characterization

Example 3

Synthesis of compound IL

Preparation of Compound 7

Compound 6(185.2mg, 1.0mmol) and triethylamine (0.418mL, 3.0mmol) were dissolved in N, N-dimethylformamide (1.5mL), and the mixture was stirred at room temperature for 10min, then added dropwise to a solution of compound 1(205.0mg, 1.0mmol) in N, N-dimethylformamide (1.5mL), and stirred at room temperature overnight (TLC tracing) to stop the reaction. Ethyl acetate was added to the system, water was extracted, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate-2/1) to obtain compound 7 (solid, 120.0mg, yield 33.9%) which was used directly in the next reaction.

MS(ESI)m/z:354[M+H]⁺

Preparation of Compound IL

The method A comprises the following steps:

dissolving a compound 7(35.3mg, 0.10mmol) and arylamine (0.09mmol) in 1mL of tert-butanol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (0.018mmol), tris (dibenzylideneacetone) dipalladium (0.012mmol) and potassium carbonate (0.30mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the compound 7 completely reacts (LC-MS and TLC tracking), and stopping the reaction. Adding methanol and dichloromethane into the reaction solution, filtering the system, concentrating, and performing silica gel column chromatography (dichloromethane/methanol) to obtain compound IL.

The method B comprises the following steps:

dissolving a compound 7(35.3mg, 0.10mmol) and arylamine (0.09mmol) in 1mL of tert-butanol, adding 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (0.018mmol), tris (dibenzylideneacetone) dipalladium (0.012mmol) and potassium carbonate (0.30mmol) into the solution, placing the obtained reaction solution in an oil bath preheated to 110 ℃ under the protection of nitrogen, heating and stirring until the compound 7 completely reacts (LC-MS and TLC tracking), and stopping the reaction. Methanol and dichloromethane were added to the reaction solution, the system was filtered, concentrated and purified by reverse phase preparative HPLC (using an aqueous solution containing 0.35% trifluoroacetic acid and methanol as mobile phases), and concentrated in vacuo to give compound IL.

Compound IM can be synthesized using similar methods.

TABLE 3 Structure and characterization of the Compound IL-IM

Example 4

Synthetic general formula of compound IN

Preparation of Compound 9

Compound 1(500mg, 2.44mmol) and compound 8(0.09mmol) were dissolved in 20mL of t-butanol, and 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (135mg, 0.17mmol), tris (dibenzylideneacetone) dipalladium (90mg, 0.06mmol), and potassium carbonate (1.01g, 3.0mmol) were added to the solution, and the resulting reaction solution was heated and stirred in an oil bath preheated to 45 ℃ under nitrogen protection until the reaction of compound 1 was completed (LC-MS and TLC tracing), and then the reaction was stopped. The system was filtered and washed with methanol, and the filtrate was concentrated and subjected to silica gel column chromatography (dichloromethane/amine methanol ═ 5/1) to give compound 9 (yellow solid, 540mg, yield 65.7%) which was used in the next reaction.

MS(ESI)m/z:337[M+H]⁺

Preparation of Compound IN

Compound 9(50mg, 0.15mmol) and aromatic amine (0.13mmol) were dissolved in 1mL of t-butanol, and trifluoroacetic acid (35. mu.L, 0.45mmol) was added to the solution. The reaction solution is put in an oil bath preheated to 110 ℃ and heated and stirred until the arylamine reaction is complete (LC-MS and TLC tracking). The reaction was stopped, concentrated, purified by reverse phase preparative HPLC (using 0.35% trifluoroacetic acid IN water and methanol as mobile phase) and concentrated IN vacuo to give compound IN.

TABLE 4 Structure and characterization of Compound IN

Example 5

Compound IO

Compound IO was synthesized using a similar method to IA.

TABLE 5 Compound IO Structure and characterization

Example 6

Compounds IP, IQ

Compounds IP and IQ were synthesized in a similar manner as IA.

TABLE 6 Compound IP, IQ Structure and characterization

Example 7

Compounds IR, IS

Compounds IR and IS were synthesized using a method analogous to IA.

TABLE 7 Structure and characterization of Compounds IR and IS

Example 8

Compound IT

Compound IT was synthesized using a similar method to IA.

TABLE 8 Compound IT Structure and characterization

Example 9

Compound IU

Compound IU was synthesized using a similar method to IA.

TABLE 9 Structure and characterization of Compound IU

Test examples

And (3) biological activity test:

growth inhibitory Activity of Compounds on kinase Stable cell lines

The activity of compounds on the kinase ALK was evaluated by their inhibition of the growth of the kinase stable cell lines EML4-ALK-BaF3, EML4-ALK (L1196M) -BaF3, NPM-ALK-BaF3, and wild-type BaF3 (proc. natl. acad. sci. u s.a., 2006,103,3153-8.). The growth of kinase-stable cell lines EML4-ALK-BaF3, EML4-ALK (L1196M) -BaF3 and NPM-ALK-BaF3 depends on the kinase activity, and if the compound can inhibit the activity of the kinase ALK itself or the activity of ALK signal channel, the compound can inhibit the growth of stable BaF3 cells. While the cell growth of wild-type BaF3 is independent of the activity of ALK and ALK signaling pathways, the broad spectrum toxicity of wild-type BaF3 cells can be assessed by determining the effect of the compound on their growth. Therefore, the compounds are stable to wild type BaF3 and kinase and have IC between EML4-ALK-BaF3, EML4-ALK (L1196M) -BaF3 and NPM-ALK-BaF3₅₀A larger ratio of (A) indicates better targeting.

The specific test method is as follows:

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

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

3) Compound testing: kinase-stabilized cells (EML4-ALK-BaF3, or EML4-ALK (L1196M) -BaF3 or NPM-ALK-BaF3) (2X 10⁴One/well) was inoculated into a 96-well plate, the volume of the cell fluid was 90. mu.L, and then 10. mu.L of each compound was added at a gradient concentration (the maximum concentration was 10. mu.M, and the compounds were sequentially diluted in 1/3 stages to set 8 concentration points in total, and 0.1% DMSO (dimethylsulfoxide) was contained in the system). The cell plate of the mixed compound was placed in a cell incubator (37 ℃ C.; 5% CO)₂) Culturing for 48h, and culturingAdding 20 μ L of MTS reaction solution, mixing, and placing in cell culture box (37 deg.C; 5% CO)₂) Incubating for 1-4 hr; OD at 490nm was measured using a microplate reader (VARIOSKAN FLASH, Thermo). Three replicates of each set of experiments were set up with a final concentration of 0.1% DMSO as negative control and medium without cells and compounds as blank control. The cell growth inhibition rate was calculated by the following formula:

The cell inhibition rate is 1- (OD experimental group-OD blank group)/(OD negative group-OD blank group)% 100%

4)IC₅₀And (3) value calculation: the half inhibitory concentration of the compound on cell growth was calculated using GradPad Prism 5 software based on the measured inhibition of cell growth.

TABLE 10 growth inhibitory Activity of the Compound I series on kinase-Stable cell lines

Values represent the inhibition of cell growth at a compound concentration of 3.3 μ M, Crizotinib (Crizotinib) was used as a positive control, and ND means not determined.

TABLE 11 growth inhibitory Activity of Compound IB-1 against BaF3 cells that are stable to other ALK point mutations (IC)₅₀/nM)

Growth inhibitory Activity of Compounds on tumor cells

If the tumor cells to be tested are suspension cells, the measurement is carried out by referring to the method of (1) above.

If the tested tumor cells are adherent cells, 1000-10000 cells/well are added into a 96-well culture plate, and the compound is added after incubation until the cells are adherent. The other steps were carried out by referring to the method (1) above.

The compound IB-1 has good inhibitory activity on lung cancer cell strains H3122 positive by kinase ALK and gradual change large cell lymphoma Karpas-299. As can be seen from the activity data, the compound with better activity has better targeting selectivity.

TABLE 12 growth inhibitory Activity of Compound IB-1 on tumor cells and BaF3 cells

Crizotinib (Crizotinib) was used as positive control, ND means not determined.

Evaluation of in vivo drug efficacy

1. Compound IB-1 significantly inhibited tumor growth in EML4-ALK (G1202R) -Ba/F3 nude mouse xenograft tumor model (FIG. 1)

The test animal is selected from BALB/c (nu/nu) nude mice, the male and female animals are half each, the age of 4-6 weeks, the body weight is about 18 +/-2 g, the animals are fed in SPF level environment, and the animals are strictly aseptically operated. The experimental animals are adapted to the experimental environment 1 week in advance, and freely take food and drink water, and the circadian rhythm is kept for 12 h.

EML4-ALK (G1202R) -Ba/F3 cells used in the experiment are cultured by adding 10% fetal calf serum into PRMI-1640 culture solution, placing the cells at 37 ℃ and 5% CO₂An incubator environment.

Establishing a tumor nude mouse subcutaneous transplantation model by a cell inoculation method: filtering to collect cells in logarithmic growth phase, centrifuging, washing with PBS, resuspending into single cell suspension with PRMI-1640 culture solutionEach nude mouse is 1 × 10⁶Cell volume of 200. mu.L. The cell suspension was injected subcutaneously near the right anterior axilla of nude mice using a 1mL syringe (4.5 gauge needle). When the tumor of the tumor-bearing mice grows to a measurable size, the tumor volume is measured and calculated every day, and the tumor volume reaches 150mm³The mice were randomly divided into groups of 8 mice each, three groups, and the administration was started on the day. The administration component is IB-160 mg/kg (1 time/day), 40mg/kg (2 times/day, bid), oral administration, continuous administration for 10 days, and the negative control group is administered with equal amount of solvent. During the test period, the animal body weight and the tumor size were measured every day, the state of the mice was observed and recorded every day, the mice were sacrificed under anesthesia with 5% chloral hydrate 6 hours after the last administration, the tumors were taken out, weighed and photographed and recorded. The formula for tumor volume (TumorVolume, TV) is: TV 1/2 × a × b ²Wherein a and b represent the major diameter and the minor diameter of the tumor, respectively.

As shown in FIG. 1, compound IB-1 significantly inhibited tumor growth in the EML4-ALK (G1202R) -Ba/F3 nude mouse xenograft tumor model. A) The compound IB-1 is orally taken at the dose of 60mg/kg (1 time/day) and 40mg/kg (2 times/day, bid) respectively, and is continuously taken for 10 days, so that the tumor growth is obviously inhibited; B) in the administration process, the weight average of the mouse bodies of the administration group does not obviously change, which shows that the administration group has better tolerance to the medicament and IB-1 has no obvious toxic or side effect.

2. Compound IB-1 significantly inhibited tumor growth in H3122 tumor cell nude mouse xenograft tumor model (FIG. 2)

The test animal is a BALB/c (nu/nu) nude mouse, half of a male and a female, 4-6 weeks old, about 18 +/-2 g of body weight, fed in an SPF (specific pathogen free) environment and subjected to strict aseptic operation. The experimental animals are adapted to the experimental environment 1 week in advance, and freely take food and drink water, and the circadian rhythm is kept for 12 h.

NCI-H3122 cells used in the experiment are cultured with PRMI-1640 culture medium and 10% fetal calf serum, and the cells are placed at 37 deg.C and 5% CO₂An incubator environment.

Establishing a tumor nude mouse subcutaneous transplantation model by a cell inoculation method: filtering to collect cells in logarithmic growth phase, centrifuging, washing with PBS, resuspending into single cell suspension with PRMI-1640 culture medium, and adding into nude mice at a ratio of 5 × 10 ⁶Cell volume of 200. mu.L. Using a 1mL syringe(4.5 gauge needle) cell suspension was injected subcutaneously near the right anterior axilla of nude mice. When the tumor of the tumor-bearing mice grows to a measurable size, the tumor volume is measured and calculated every day, and the tumor volume reaches 150mm³The mice were randomly divided into groups of 5 mice each, four groups, and the administration was started on the day of the division. The administration components are IB-130 mg/kg (1 time/day) and 50mg/kg (1 time/day), the positive control group is administered with Crizotinib 50mg/kg (1 time/day), the negative control group is administered with solvent in equal amount, and the administration is continued for 18 days. Animal body weight and tumor size were measured at intervals during the test period, the status of the mice was observed and recorded daily, the mice were sacrificed under anesthesia with 5% chloral hydrate 6 hours after the last administration, tumors were taken, weighed and photographed and recorded. The Tumor Volume (Tumor Volume, TV) is calculated as: TV 1/2 × a × b²Wherein a and b represent the major diameter and the minor diameter of the tumor, respectively.

As shown in FIG. 2, compound IB-1 significantly inhibited tumor growth in a non-small cell lung carcinoma H3122 cell nude mouse xenograft tumor model. A) The compound IB-1 is orally taken at the dose of 30mg/kg (1 time/day) and 50mg/kg (1 time/day) respectively, and the tumor growth is obviously inhibited after the compound IB-1 is continuously taken for 18 days; B) in the administration process, the weight average of the mouse bodies of the administration group does not obviously change, which shows that the administration group has better tolerance to the medicament and IB-1 has no obvious toxic or side effect.

What has been described above are merely some embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the inventive concept thereof, and these changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A compound of the following general formula I:

wherein the content of the first and second substances,

r' is hydrogen, chlorine or bromine;

R₁selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(3)4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, morpholinyl, 3, 5-dimethylmorpholinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl,

(4)4- (4-methylpiperazino) piperidinyl, 4- (4-ethylpiperazino) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl,

(5) carbamoylamino, methylaminocarboxamido, ethylaminocarboxamido, propylcarbamoylamino, isopropylaminocarboxamido;

(6) aminoacetamido, 2-dimethylaminoacetamido, N-tert-butoxycarbonylacetamido, N-acetylaminoacetamido, acrylamido, chloroacetamido; 2-methylaminoacetamido, 2- (1-methylethyl) aminoacetamido;

(7)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring; the substituents may be selected from the group consisting of₁The same above substituents, the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline;

a is a direct bond or methylene;

x is NH, S or O;

R₂selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylsulfonyl, tert-butylsulfonyl, dimethylaminosulfonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylphosphono or diisopropylphosphono; a. the₂，A₃，A₄Are all hydrogen；

And excluding the following specific compounds:

or a pharmaceutically acceptable salt of the above compound,

wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a bicarbonate and a carbonate, a sulfate or a phosphate, and the organic acid salt is a formate, an acetate, a propionate, a benzoate, a maleate, a fumarate, a succinate, a tartrate, a citrate, an ascorbate, an alpha-ketoglutarate, a trifluoroacetate, an alpha-glycerophosphate, an alkylsulfonate or an arylsulfonate.

2. The compound according to claim 1, wherein R' is hydrogen.

3. A compound according to claim 1, wherein R₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) hydrogen, fluorine, chlorine, bromine,

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

(4)4- (4-methylpiperazino) piperidinyl, 4- (4-ethylpiperazino) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl,

(6) aminoacetamido, N-tert-butoxycarbonylacetamido, N-acetylaminoacetamido, acrylamido, chloroacetamido;

(7)Z₂and Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring; the substituents may be selected from the group consisting of₁The same above-mentioned substituents, and the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline.

4. The compound according to claim 1, wherein a is a direct bond.

5. The compound according to claim 1, wherein a is methylene.

6. The compound according to claim 1, wherein the alkyl sulfonate is a methyl sulfonate or an ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.

7. A compound according to claim 1, of formula IB:

wherein R is₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(3)4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl,

(4) 4-methylpiperazinyl group, 4-ethylpiperazinyl group, 4-isopropylpiperazinyl group,

(5) morpholinyl, 3, 5-dimethylmorpholinyl,

(6) 2-dimethylamino-acetamido-group, which is a compound of the formula,

(7)Z₂and Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same above substituents, the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline;

R₂selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylsulfonyl; a. the₂，A₃，A₄Are all hydrogen;

and excluding the following specific compounds:

or a pharmaceutically acceptable salt of the above compound.

8. A compound according to claim 7, wherein R₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkyl group,

(3) A C1-C6 alkoxy group,

(4)4- (4-methylpiperazinyl) piperidyl, 4- (tetrahydropyrrolyl) piperidyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidyl, 4-N, N-diisopropylaminopiperidinyl,

(5) 4-methylpiperazinyl group, 4-ethylpiperazinyl group, 4-isopropylpiperazinyl group,

(6) morpholinyl, 3, 5-dimethylmorpholinyl,

(7)Z₂and Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same above-mentioned substituents, and the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline.

9. A compound according to claim 7, wherein R₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2)4-N, N-dimethylaminopiperidinyl,

(3) 2-dimethylamino-acetamido-group, which is a compound of the formula,

(4)F。

10. a compound according to claim 7, wherein R₁Selected from:

wherein Z₂And Z₄One of the two is hydrogen and the other is selected from: 2-dimethylamino-acetamido-group, which is a compound of the formula,

Z₃selected from: 4-N, N-dimethylaminopiperidinyl, F.

11. A compound according to claim 1, of formula IO:

R₁selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(3)4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, (4) 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl,

(5) Carbamoylamino, methylaminocarboxamido, ethylaminocarboxamido, propylcarbamoylamino, isopropylaminocarboxamido; or

(6)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same above substituents, the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline;

R₂selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is tert-butylsulfonyl; a. the₂，A₃，A₄Are all hydrogen;

or a pharmaceutically acceptable salt of the above compound.

12. A compound according to claim 11, wherein R₁Is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(4) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, or

(5)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same above-mentioned substituents, and the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline.

13. A compound according to claim 11, wherein R₁Selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) C1-C6 alkoxy

(3)4- (4-methylpiperazino) piperidinyl, 4-methylpiperazino, 4-N, N-dimethylaminopiperidinyl,

14. A compound according to claim 11, wherein R₁Selected from:

wherein the content of the first and second substances,

Z₁is methoxy, and Z₃Selected from: 4-N, N-dimethylaminopiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, the remainder being hydrogen; or

Z₃And Z₄Form a

And Z is₁Methoxy radical and the rest is hydrogen.

15. A compound according to claim 1 of the formula IPQ:

R₁selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

R₂selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is isopropylaminocarbonyl or dimethylaminocarbonyl; a. the₂，A₃，A₄Are all hydrogen;

or a pharmaceutically acceptable salt of the above compound.

16. The compound according to claim 15, wherein R₁Is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(4) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, or

17. The compound according to claim 15, wherein R₁Selected from:

(1) The presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (4-methylpiperazino) piperidinyl, 4-methylpiperazino, 4-N, N-dimethylaminopiperidinyl.

18. The compound according to claim 15, wherein R₁Selected from:

wherein

Z₃And Z₄Form a

And Z is₁Methoxy radical and the rest is hydrogen.

19. A compound according to claim 1, of the formula IRS:

wherein R is₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(6)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of ₁The same above substituents, the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline;

R₂selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is diisopropylphosphinic or diethylphosphinic; a. the₂，A₃，A₄Are all hydrogen;

or a pharmaceutically acceptable salt of the above compound.

20. The compound according to claim 19, wherein R₁Is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (4-ethylpiperazinyl) piperidinyl, 4- (4-isopropylpiperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl;

(4) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, or

21. The compound according to claim 19, wherein R₁Is selected from

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (tetrahydropyrrolyl) piperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4-N, N-dimethylaminopiperidinyl;

22. The compound according to claim 19, wherein R₁Selected from:

wherein

Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-N, N-dimethylaminopiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

23. The compound according to claim 1, of the formula IT:

wherein A is methylene; x is O;

R₁selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

(6) morpholinyl; or

(7)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of ₁The same above substituents, the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline;

R₂selected from:

or a pharmaceutically acceptable salt of the above compound.

24. The compound according to claim 23, wherein R₁Is selected from

Wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(4) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, or

25. The compound according to claim 23, wherein R₁Selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3) 4-methylpiperazino, 4- (4-methylpiperazino) piperidinyl, morpholinyl, 4-N, N-dimethylaminopiperidinyl.

26. The compound according to claim 23, wherein R₁Selected from:

wherein the content of the first and second substances,

Z₁and Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-N, N-dimethylaminopiperidinyl, 4-methylpiperazinyl, 4- (4-methylpiperazinyl) piperidinyl, 4-methylpiperazinyl or morpholinyl.

27. A compound according to claim 1, of formula IU:

wherein R is₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

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

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

R₂Selected from:

wherein A is₁And A₅One of the two is hydrogen and the other is dimethylaminosulfonyl; a. the₂，A₃，A₄Are all hydrogen;

or a pharmaceutically acceptable salt of the above compound.

28. The compound according to claim 27, wherein R₁Selected from:

wherein Z₁，Z₂，Z₃，Z₄，Z₅Each independently selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl,

(5) 4-methylpiperazino, 4-ethylpiperazino, 4-isopropylpiperazinyl, or

(6)Z₂And Z₃Or Z₃And Z₄Forming a nitrogen-containing substituted or unsubstituted five-membered ring, the substituents being selected from the group consisting of₁The same above-mentioned substituents, and the nitrogen-containing substituted or unsubstituted five-membered ring is selected from pyrroline.

29. The compound according to claim 27, wherein R₁Selected from:

(1) the presence of hydrogen in the presence of hydrogen,

(2) a C1-C6 alkoxy group,

(3)4- (4-methylpiperazino) piperidinyl, 4-methylpiperazinyl,

30. The compound according to claim 27, wherein R ₁Selected from:

wherein Z₁And Z₅One of the two is hydrogen and the other is methoxy;

Z₃selected from: 4-methylpiperazino, 4- (4-methylpiperazino) piperidinyl, or

Z₂And Z₃Or Z₃And Z₄Form a

31. The compound according to any of claims 7-30, wherein said pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein said inorganic acid salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate and said organic acid salt is a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α -ketoglutarate, trifluoroacetate, α -glycerophosphate, alkylsulfonate or arylsulfonate.

32. The compound according to claim 31, said alkylsulfonate being a methylsulfonate or an ethylsulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.

33. A compound selected from the following:

or a pharmaceutically acceptable salt of the above compound.

34. A process for the preparation of a compound according to any one of claims 1 to 33, comprising the steps of:

1)

the starting materials for this reaction are commercially available;

2)

Reaction conditions are as follows: (a) substitution under basic or acidic conditions; (b) acidic conditions or palladium catalyzed amination.

35. The process according to claim 34, wherein the basic conditions are diisopropylethylamine, triethylamine or potassium carbonate.

36. The process according to claim 34, wherein the acidic conditions are trifluoroacetic acid or hydrochloric acid.

37. A pharmaceutical composition comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition according to claim 37, further comprising a pharmaceutically acceptable excipient.

39. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 37-38, in the manufacture of a medicament for: preventing or treating diseases associated with abnormal cell proliferation, morphological changes and hyperkinesia associated with gradual change lymphoma enzyme in vivo, and preventing or treating diseases associated with angiogenesis or cancer metastasis.

40. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 37-38, in the manufacture of a medicament for: can be used for preventing or treating tumor growth and metastasis.

41. The use according to claim 40, wherein the tumor is any one of a large-cell lymphoma, inflammatory myofibroblastoma, non-small cell lung cancer, neuroblastoma, small cell lung cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma.

42. The use of claim 41, wherein the non-small cell lung cancer is lung adenocarcinoma.

43. The use of claim 40, wherein the tumor is a large cell, progressive lymphoma, inflammatory myofibroblastoma, non-small cell lung cancer, or neuroblastoma.