Aza fused ring compound as well as preparation method and application thereof

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof, the compound has very high inhibitory activity on phosphodiesterase (PDEs), particularly PDE4, has excellent drug effect, in-vitro / in-vivo pharmacokinetic property and safety, and can be used for preparing a medicine for preventing and treating PDE4. The clinical application prospect is high.

Description

Aza-fused ring compounds and their preparation methods and uses

[0001] This disclosure claims priority to a Chinese patent application filed with the Patent Office of China on September 25, 2023, with the invention name “Aza-fused ring compounds, preparation methods and uses thereof” and application number 202311240039.6. The entire contents of the above application are incorporated into this disclosure by reference. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to an aza-fused ring compound, a preparation method thereof, and use thereof as a phosphodiesterase (PDEs) inhibitor. Background Art

[0003] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading them and thereby terminating the biochemical effects transmitted by these second messengers. cAMP and cGMP play a crucial role in regulating cellular activity. The regulation of their concentrations is primarily determined by the balance between synthesis by adenylate cyclase and hydrolysis by phosphodiesterases (PDEs). PDEs are widely distributed throughout the human body, and their physiological effects span multiple research areas.

[0004] Among the 11 phosphodiesterases currently identified, PDE4, PDE7, and PDE8 are cAMP selective. The PDE4 family includes four subtypes (PDE4A, B, C, and D) with more than 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). The above four subtypes are differentially expressed in different tissues and cell types, such as PDE4B, which is mainly expressed in monocytes and neutrophils, but not in cortical cells and epithelial cells, while PDE4D is expressed in the lungs, cortex, cerebellum, and T cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs, 16(1), 2007, 109-124). PDE4B is mainly expressed in the presence of PDE4 enzymes that hydrolyze cAMP, and the substrate apparent K of cAMP is m1-5 μM. PDE4 is the most important regulator of cAMP expressed in immune cells and inflammatory cells such as neutrophils, macrophages and T-lymphocytes. Since cAMP is a key second messenger in regulating inflammatory responses, PDE4 has been found to regulate the inflammatory response of inflammatory cells by regulating proinflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF and LTB4. Therefore, inhibiting PDE4 has become an attractive target for treating inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, inflammatory bowel diseases such as Crohn's disease, etc. (MD Houslay et al, Drug Discovery Today, 2005, 10 (22), 1503-1519). Since PDE activity is elevated in patients with atopic dermatitis (AD), inhibiting PDE4 also seems to be a feasible treatment for AD (Journal of Investigative Dermatology, 1986, 87 (3), 372-376).

[0005] Published related patent applications include WO2009053268A1, WO2009050242A2, WO2009050236A1, CN101827852B, CN101163706A, CN101426505A, CN102875556B, CN103497201A, CN103889970B and CN108299400B, etc.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0008] in:

[0009] Z is selected from S, O, S(=O)(=NR z ), SO and SO2;

[0010] R 1 Selected from hydrogen and C 1-6 alkyl;

[0011] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0012] At each occurrence, the R 2.2and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0013] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0014] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0015] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0016] R a Selected from hydrogen and C 1-6 alkyl;

[0017] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0018] R z Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkyl hydroxyl groups;

[0019] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0020] R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino; wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0021] L is selected from a direct bond and -N(R a )R b -;

[0022] R b Selected from -(CH2) t -;

[0023] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0024] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0025] R 3Selected from-MR 3.1 ;

[0026] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0027] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0028] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0029] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0030] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0031] t is 0, 1, 2, or 3;

[0032] s is 1, 2, or 3;

[0033] k is 1, 2, 3, or 4;

[0034] n is an integer from 0 to 10.

[0035] Effects of the Invention

[0036] The present disclosure provides aza-fused ring compounds that exhibit high inhibitory activity against phosphodiesterases (PDEs), specifically PDE4, while also possessing excellent efficacy, in vitro and in vivo pharmacokinetic properties, and safety, suggesting promising clinical applications. Furthermore, the compounds exhibit preferential selectivity against the PDE4B subtype. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG1 shows the results of drug efficacy evaluation in a C57BL / 6J mouse emesis model. DETAILED DESCRIPTION

[0038] To make the technical solutions and beneficial effects of the present invention more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0039] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0040] in:

[0041] Z is selected from S, O, S(=O)(=NR z ), SO and SO2;

[0042] R 1 Selected from hydrogen and C 1-6 alkyl;

[0043] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0044] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0045] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0046] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0047] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0048] R a Selected from hydrogen and C 1-6 alkyl;

[0049] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0050] R z Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkyl hydroxyl groups;

[0051] R 2a and R 2bare independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0052] R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino; wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0053] L is selected from a direct bond and -N(R a )R b -;

[0054] R b Selected from -(CH2) t -;

[0055] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0056] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0057] R 3 Selected from-MR 3.1 ;

[0058] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0059] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0060] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0061] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0062] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0063] t is 0, 1, 2, or 3;

[0064] s is 1, 2, or 3;

[0065] k is 1, 2, 3, or 4;

[0066] n is an integer from 0 to 10.

[0067] In certain embodiments, Z is selected from S, O, SO, and SO2.

[0068] In certain embodiments, Z is selected from SO and SO2.

[0069] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino.

[0070] In certain embodiments, the R 6 is selected from hydrogen, deuterium, hydroxy, halogen and amino.

[0071] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0072] In certain embodiments, the R 6 Selected from hydrogen.

[0073] In certain embodiments, the R 7 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino.

[0074] In certain embodiments, the R 7 is selected from hydrogen, deuterium, hydroxy, halogen and amino.

[0075] In certain embodiments, the R 7 Selected from hydrogen, deuterium and halogen.

[0076] In certain embodiments, the R 7 Selected from hydrogen.

[0077] In certain embodiments, the R 8 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino.

[0078] In certain embodiments, the R 8 is selected from hydrogen, deuterium, hydroxy, halogen and amino.

[0079] In certain embodiments, the R 8 Selected from hydrogen, deuterium and halogen.

[0080] In certain embodiments, the R 8 Selected from hydrogen.

[0081] In certain embodiments, the R 9 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino.

[0082] In certain embodiments, the R 9 is selected from hydrogen, deuterium, hydroxy, halogen and amino.

[0083] In certain embodiments, the R 9 Selected from hydrogen, deuterium and halogen.

[0084] In certain embodiments, the R 9 Selected from hydrogen.

[0085] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0086] In certain embodiments, the ring A is selected from C 6-10Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0087] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0088] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0089] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0090] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0091] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0092] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0093] In certain embodiments, the R3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0094] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0095] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0096] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0097] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0098] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0099] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0100] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0101] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0102] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0103] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0104] In certain embodiments, the R 1 Selected from hydrogen.

[0105] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0106] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0107] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0108] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0109] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0110] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0111] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0112] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0113] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0114] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0115] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0116] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0117] In certain embodiments, the R a Selected from hydrogen.

[0118] In certain embodiments, t is 0, 1, or 2.

[0119] In certain embodiments, s is 1 or 2.

[0120] In certain embodiments, n is an integer from 0-5.

[0121] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0122] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (II):

[0123] in:

[0124] R 1 Selected from hydrogen and C 1-6 alkyl;

[0125] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 )k -R 2.1 ;

[0126] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0127] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0128] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0129] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0130] R a Selected from hydrogen and C 1-6 alkyl;

[0131] Every time R appears 2.4 and R 2.5are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0132] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0133] L is selected from a direct bond and -N(R a )R b -;

[0134] R b Selected from -(CH2) t -;

[0135] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0136] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0137] R 3 Selected from-MR 3.1 ;

[0138] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0139] R 3.1Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0140] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0141] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0142] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0143] t is 0, 1, 2, or 3;

[0144] k is 1, 2, 3, or 4;

[0145] n is an integer from 0 to 10.

[0146] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0147] In certain embodiments, the ring A is selected from C 6-10 Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0148] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0149] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0150] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0151] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0152] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0153] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0154] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0155] In certain embodiments, the R 3.1is selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0156] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0157] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0158] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0159] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0160] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0161] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0162] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0163] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0164] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0165] In certain embodiments, the R 1 Selected from hydrogen.

[0166] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0167] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0168] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0169] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0170] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0171] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0172] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0173] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0174] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0175] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0176] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0177] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0178] In certain embodiments, the R a Selected from hydrogen.

[0179] In certain embodiments, t is 0, 1, or 2.

[0180] In certain embodiments, n is an integer from 0-5.

[0181] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0182] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (III):

[0183] in:

[0184] R 1 Selected from hydrogen and C 1-6 alkyl;

[0185] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0186] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C3-6 Cycloalkyl;

[0187] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0188] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0189] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0190] R a Selected from hydrogen and C 1-6 alkyl;

[0191] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0192] R 2a and R 2bare independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0193] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0194] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0195] R 3 Selected from-MR 3.1 ;

[0196] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0197] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0198] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0199] R 3a With R 3.1and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0200] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0201] t is 0, 1, 2, or 3;

[0202] k is 1, 2, 3, or 4;

[0203] n is an integer from 0 to 10.

[0204] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0205] In certain embodiments, the ring A is selected from C 6-10 Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0206] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0207] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0208] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0209] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0210] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0211] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0212] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0213] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0214] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0215] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0216] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0217] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0218] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0219] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0220] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0221] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0222] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0223] In certain embodiments, the R 1 Selected from hydrogen.

[0224] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0225] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0226] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0227] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0228] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0229] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0230] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0231] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0232] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0233] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0234] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0235] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0236] In certain embodiments, the R a Selected from hydrogen.

[0237] In certain embodiments, t is 0, 1, or 2.

[0238] In certain embodiments, n is an integer from 0-5.

[0239] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0240] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (IV):

[0241] in:

[0242] R 1 Selected from hydrogen and C 1-6 alkyl;

[0243] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0244] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0245] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0246] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0247] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 )t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0248] R a Selected from hydrogen and C 1-6 alkyl;

[0249] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0250] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0251] R b Selected from -(CH2) t -;

[0252] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0253] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0254] R 3 Selected from-MR3.1 ;

[0255] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0256] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0257] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0258] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0259] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0260] t is 0, 1, 2, or 3;

[0261] k is 1, 2, 3, or 4;

[0262] n is an integer from 0 to 10.

[0263] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0264] In certain embodiments, the ring A is selected from C 6-10Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0265] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0266] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0267] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0268] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0269] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0270] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0271] In certain embodiments, the R3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0272] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0273] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0274] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0275] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0276] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0277] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0278] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0279] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0280] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0281] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0282] In certain embodiments, the R 1 Selected from hydrogen.

[0283] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0284] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0285] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0286] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0287] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0288] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0289] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0290] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0291] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0292] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0293] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0294] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0295] In certain embodiments, the R a Selected from hydrogen.

[0296] In certain embodiments, t is 0, 1, or 2.

[0297] In certain embodiments, n is an integer from 0-5.

[0298] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0299] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (III-1):

[0300] in:

[0301] X1, X2, X3 and X4 are each independently selected from N or CR 4 ;

[0302] R 1 Selected from hydrogen and C 1-6 alkyl;

[0303] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR2.2 R 2.3 ) k -R 2.1 ;

[0304] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0305] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0306] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0307] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0308] R a Selected from hydrogen and C 1-6 alkyl;

[0309] Every time R appears2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0310] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0311] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0312] R 3 Selected from-MR 3.1 ;

[0313] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0314] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0315] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0316] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0317] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0318] t is 0, 1, 2, or 3;

[0319] k is 1, 2, 3 or 4.

[0320] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0321] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0322] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0323] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0324] In certain embodiments, the R 3.1Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0325] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0326] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0327] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0328] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0329] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0330] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0331] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0332] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0333] In certain embodiments, the R1 Selected from hydrogen and C 1-3 alkyl.

[0334] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0335] In certain embodiments, the R 1 Selected from hydrogen.

[0336] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0337] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0338] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0339] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0340] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0341] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0342] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0343] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0344] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0345] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5)-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0346] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0347] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0348] In certain embodiments, the R a Selected from hydrogen.

[0349] In certain embodiments, t is 0, 1, or 2.

[0350] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula (III-1-1) or (III-1-2):

[0351] in:

[0352] R 1 Selected from hydrogen and C 1-6 alkyl;

[0353] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0354] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0355] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0356] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0357] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0358] R a Selected from hydrogen and C 1-6 alkyl;

[0359] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0360] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0361] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0362] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0363] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0364] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0365] R 3a With R 3.1 and the S connected to it via -(CH2)t - linked together to form a 4-8 membered heterocyclic group; or

[0366] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0367] t is 0, 1, 2, or 3;

[0368] k is 1, 2, 3 or 4.

[0369] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0370] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0371] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0372] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0373] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0374] In certain embodiments, the R 3.1Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0375] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole and pyrazolonyl;

[0376] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0377] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0378] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0379] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0380] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0381] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0382] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0383] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0384] In certain embodiments, the R 1 Selected from hydrogen.

[0385] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0386] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0387] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0388] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0389] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0390] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0391] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0392] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0393] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0394] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0395] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0396] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0397] In certain embodiments, the R a Selected from hydrogen.

[0398] In certain embodiments, t is 0, 1, or 2.

[0399] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (III-2):

[0400] in:

[0401] R 1 Selected from hydrogen and C 1-6 alkyl;

[0402] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0403] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0404] R 2.1 Selected from hydroxyl, -O-(CH2) t -ORa and Het;

[0405] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0406] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0407] R a Selected from hydrogen and C 1-6 alkyl;

[0408] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0409] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0410] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0411] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0412] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0413] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0414] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0415] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0416] t is 0, 1, 2, or 3;

[0417] k is 1, 2, 3 or 4.

[0418] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0419] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0420] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0421] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0422] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0423] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0424] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0425] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0426] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0427] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0428] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0429] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0430] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0431] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0432] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0433] In certain embodiments, the R 1 Selected from hydrogen.

[0434] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0435] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0436] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0437] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0438] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0439] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0440] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0441] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0442] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0443] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0444] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0445] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0446] In certain embodiments, the R a Selected from hydrogen.

[0447] In certain embodiments, t is 0, 1, or 2.

[0448] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (IV-1):

[0449] in:

[0450] m is 0, 1, or 2;

[0451] R 1 Selected from hydrogen and C 1-6 alkyl;

[0452] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0453] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0454] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0455] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0456] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R2.5) t -OR a、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0457] R a Selected from hydrogen and C 1-6 alkyl;

[0458] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0459] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0460] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0461] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0462] R 3 Selected from-MR 3.1 ;

[0463] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0464] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0465] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0466] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0467] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0468] t is 0, 1, 2, or 3;

[0469] k is 1, 2, 3, or 4;

[0470] n is an integer from 0 to 10.

[0471] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0472] In certain embodiments, the ring A is selected from C6-10 Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0473] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0474] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0475] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0476] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0477] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0478] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0479] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0480] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0481] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0482] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0483] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0484] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0485] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0486] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0487] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0488] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0489] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0490] In certain embodiments, the R 1 Selected from hydrogen.

[0491] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0492] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0493] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0494] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0495] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0496] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0497] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0498] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0499] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0500] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0501] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0502] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0503] In certain embodiments, the R a Selected from hydrogen.

[0504] In certain embodiments, t is 0, 1, or 2.

[0505] In certain embodiments, n is an integer from 0-5.

[0506] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0507] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (IV-1-1):

[0508] in:

[0509] Y1 and Y2 are each independently selected from N, CR 10 ;

[0510] R 10 Selected from absent, hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 1-6 haloalkyl, halogen and amino; or R10 With -(CH2) m - connected to form a 3-5 membered spiro ring;

[0511] m is 0, 1, or 2;

[0512] R 1 Selected from hydrogen and C 1-6 alkyl;

[0513] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0514] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0515] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0516] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0517] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2band optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0518] R a Selected from hydrogen and C 1-6 alkyl;

[0519] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0520] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0521] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0522] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0523] R 3.1Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0524] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0525] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0526] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0527] t is 0, 1, 2, or 3;

[0528] k is 1, 2, 3, or 4;

[0529] n is an integer from 0 to 10.

[0530] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0531] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0532] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0533] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0534] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0535] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0536] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0537] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0538] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0539] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0540] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0541] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0542] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0543] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0544] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0545] In certain embodiments, the R 1 Selected from hydrogen.

[0546] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0547] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0548] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0549] In certain embodiments, the Het is selected from C4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0550] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0551] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0552] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0553] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0554] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0555] In certain embodiments, the RHet Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0556] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0557] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0558] In certain embodiments, the R a Selected from hydrogen.

[0559] In certain embodiments, t is 0, 1, or 2.

[0560] In certain embodiments, n is an integer from 0-5.

[0561] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0562] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (V):

[0563] in:

[0564] R 1 Selected from hydrogen and C 1-6 alkyl;

[0565] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0566] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0567] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0568] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0569] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0570] R a Selected from hydrogen and C1-6 alkyl;

[0571] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0572] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0573] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0574] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0575] R 3 Selected from-MR 3.1 ;

[0576] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0577] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0578] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0579] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0580] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0581] t is 0, 1, 2, or 3;

[0582] k is 1, 2, 3, or 4;

[0583] n is an integer from 0 to 10.

[0584] In certain embodiments, the ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclyl.

[0585] In certain embodiments, the ring A is selected from C 6-10 Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic ring, wherein the 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0586] In certain embodiments, the ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl,

[0587] In certain embodiments, the ring A is selected from phenyl, pyridinyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl,

[0588] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0589] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0590] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0591] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0592] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0593] In certain embodiments, the R 3.1Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0594] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0595] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0596] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0597] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0598] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0599] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0600] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0601] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0602] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0603] In certain embodiments, the R 1 Selected from hydrogen.

[0604] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0605] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0606] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0607] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0608] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0609] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0610] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0611] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0612] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0613] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0614] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0615] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0616] In certain embodiments, the R a Selected from hydrogen.

[0617] In certain embodiments, t is 0, 1, or 2.

[0618] In certain embodiments, n is an integer from 0-5.

[0619] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0620] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (V-1):

[0621] in:

[0622] R 1 Selected from hydrogen and C 1-6 alkyl;

[0623] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0624] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0625] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0626] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0627] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0628] R a Selected from hydrogen and C 1-6 alkyl;

[0629] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0630] R2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0631] Ring A is selected from 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S and 4-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0632] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0633] R 3 Selected from-MR 3.1 ;

[0634] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0635] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0636] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6Alkyl, cycloalkyl, halogen and amino; or

[0637] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0638] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0639] t is 0, 1, 2, or 3;

[0640] k is 1, 2, 3, or 4;

[0641] n is an integer from 0 to 10.

[0642] In certain embodiments, the ring A is selected from a 4-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0643] In certain embodiments, the ring A is selected from a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N or O.

[0644] In certain embodiments, the ring A is selected from azetidinyl.

[0645] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0646] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0647] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0648] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0649] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0650] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0651] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0652] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0653] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0654] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0655] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0656] In certain embodiments, the R 4Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0657] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0658] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0659] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0660] In certain embodiments, the R 1 Selected from hydrogen.

[0661] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0662] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0663] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0664] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0665] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0666] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0667] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0668] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0669] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0670] In certain embodiments, the R HetSelected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0671] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0672] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0673] In certain embodiments, the R a Selected from hydrogen.

[0674] In certain embodiments, t is 0, 1, or 2.

[0675] In certain embodiments, n is an integer from 0-5.

[0676] In certain embodiments, n is 0, 1, 2, 3, 4, or 5.

[0677] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (V-1-1):

[0678] in:

[0679] R 1 Selected from hydrogen and C 1-6 alkyl;

[0680] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0681] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0682] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0683] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0684] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0685] R a Selected from hydrogen and C1-6 alkyl;

[0686] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0687] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0688] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN;

[0689] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0690] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 substituted with a substituent of the alkylhydroxy group;

[0691] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0692] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0693] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0694] t is 0, 1, 2, or 3;

[0695] k is 1, 2, 3 or 4.

[0696] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0697] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0698] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0699] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0700] In certain embodiments, the R 3.1 Selected from H, C 1-3Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0701] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0702] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0703] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0704] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0705] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0706] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN.

[0707] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN and -(CH2)2-CN.

[0708] In certain embodiments, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, fluoro and -(CH2)-CN.

[0709] In certain embodiments, the R 1 Selected from hydrogen and C1-3 alkyl.

[0710] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0711] In certain embodiments, the R 1 Selected from hydrogen.

[0712] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0713] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0714] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0715] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0716] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0717] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0718] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0719] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0720] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0721] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0722] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0723] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0724] In certain embodiments, the R a Selected from hydrogen.

[0725] In certain embodiments, t is 0, 1, or 2.

[0726] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (VI):

[0727] in:

[0728] R 1 Selected from hydrogen and C 1-6 alkyl;

[0729] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0730] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0731] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0732] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0733] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0734] R a Selected from hydrogen and C 1-6 alkyl;

[0735] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0736] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0737] R 3 Selected from-MR 3.1 ;

[0738] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0739] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0740] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0741] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0742] -N=S(O)R 3a -S and R in 4 Via -(CH2)t - linked together to form a 4-8 membered heterocyclic group;

[0743] Q is -(CR 5c R 5d ) u -;

[0744] R 5c and R 5d are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino;

[0745] Ring B is selected from 4-8 membered heterocyclic groups and 5-7 membered heteroaryl groups, wherein the 4-8 membered cycloalkyl groups and the 5-7 membered heteroaryl groups contain 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring B is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 substituted by alkyl, halogen and amino substituents;

[0746] Ring C is selected from 5-7 membered heteroaryl, wherein the 5-7 membered heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0747] u is 1, 2, or 3;

[0748] t is 0, 1, 2, or 3;

[0749] k is 1, 2, 3 or 4.

[0750] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0751] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0752] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0753] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0754] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0755] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0756] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0757] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0758] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0759] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0760] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0761] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0762] In certain embodiments, the R 1Selected from hydrogen.

[0763] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0764] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0765] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0766] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0767] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0768] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0769] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0770] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0771] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0772] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0773] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0774] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0775] In certain embodiments, the R a Selected from hydrogen.

[0776] In certain embodiments, the R 5c is selected from hydrogen, deuterium, halogen and amino.

[0777] In certain embodiments, the R 5c Selected from hydrogen.

[0778] In certain embodiments, the R 5d is selected from hydrogen, deuterium, halogen and amino.

[0779] In certain embodiments, the R 5d Selected from hydrogen.

[0780] In certain embodiments, the ring B is selected from 5-7 membered heterocyclyl and 5-7 membered heteroaryl, wherein the 5-7 membered cyclyl and 5-7 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or O; the ring B is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Substituted with alkyl, halogen and amino substituents

[0781] In certain embodiments, the ring C is selected from a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N or O.

[0782] In certain embodiments, the ring C is selected from pyridinyl.

[0783] In certain embodiments, t is 0, 1, or 2.

[0784] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula (VI-1):

[0785] in:

[0786] R 1 Selected from hydrogen and C 1-6 alkyl;

[0787] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0788] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0789] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0790] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0791] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COORa 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0792] R a Selected from hydrogen and C 1-6 alkyl;

[0793] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0794] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0795] R 3 Selected from-MR 3.1 ;

[0796] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0797] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0798] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0799] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0800] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0801] Ring B is selected from 4-8 membered heterocyclic groups and 5-7 membered heteroaryl groups, wherein the 4-8 membered cycloalkyl groups and the 5-7 membered heteroaryl groups contain 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring B is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 substituted by alkyl, halogen and amino substituents;

[0802] Ring C is selected from 5-7 membered heteroaryl, wherein the 5-7 membered heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0803] t is 0, 1, 2, or 3;

[0804] k is 1, 2, 3 or 4.

[0805] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0806] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a, -O- and C 1-4 Alkylene.

[0807] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0808] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0809] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0810] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0811] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0812] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0813] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0814] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0815] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0816] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0817] In certain embodiments, the R 1 Selected from hydrogen.

[0818] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0819] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0820] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0821] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0822] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0823] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0824] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0825] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0826] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0827] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0828] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0829] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0830] In certain embodiments, the R a Selected from hydrogen.

[0831] In certain embodiments, the ring B is selected from 5-7 membered heterocyclyl and 5-7 membered heteroaryl, wherein the 5-7 membered cyclyl and 5-7 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or O; the ring B is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 The alkyl, halogen and amino substituents are substituted.

[0832] In certain embodiments, the ring C is selected from a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N or O.

[0833] In certain embodiments, the ring C is selected from pyridinyl.

[0834] In certain embodiments, t is 0, 1, or 2.

[0835] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (VII):

[0836] in:

[0837] R 1 Selected from hydrogen and C 1-6 alkyl;

[0838] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0839] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0840] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0841] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0842] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0843] R a Selected from hydrogen and C 1-6 alkyl;

[0844] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0845] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0846] R 3 Selected from-MR 3.1 ;

[0847] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0848] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6substituted with a substituent of the alkylhydroxy group;

[0849] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0850] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0851] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0852] Ring D is selected from 4-6 membered heterocyclic groups and 4-6 membered heteroaryl groups, wherein the 4-6 membered cycloalkyl groups and 4-6 membered heteroaryl groups contain 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring D is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 substituted by alkyl, halogen and amino substituents;

[0853] Ring E is selected from 4-6 membered heterocyclyl and 4-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl and 4-6 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0854] t is 0, 1, 2, or 3;

[0855] k is 1, 2, 3 or 4.

[0856] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0857] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0858] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a, -O- and -CH2-.

[0859] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0860] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0861] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0862] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0863] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0864] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0865] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0866] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0867] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0868] In certain embodiments, the R 1 Selected from hydrogen.

[0869] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0870] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0871] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0872] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0873] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0874] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0875] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0876] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0877] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、 -N=S(O)R 2a R 2b .

[0878] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0879] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0880] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0881] In certain embodiments, the R a Selected from hydrogen.

[0882] In certain embodiments, the ring D is selected from 4-5 membered heterocyclyl and 4-5 membered heteroaryl, wherein the 4-5 membered cyclyl and 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S; the ring D is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 The alkyl, halogen and amino substituents are substituted.

[0883] In certain embodiments, the ring E is selected from a 4-5 membered heterocyclyl and a 4-5 membered heteroaryl, wherein the 4-5 membered cyclyl and the 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S.

[0884] In certain embodiments, t is 0, 1, or 2.

[0885] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts, characterized by compounds having the structures of formula (VII-1), (VII-2), (VII-3) and (VII-4):

[0886] in:

[0887] R 1 Selected from hydrogen and C 1-6 alkyl;

[0888] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0889] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0890] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0891] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0892] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C1-6 Alkyl, the heteroaryl is optionally replaced by one or more C 1-6 haloalkyl substitution;

[0893] R a Selected from hydrogen and C 1-6 alkyl;

[0894] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0895] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0896] R 3 Selected from-MR 3.1 ;

[0897] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0898] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6substituted with a substituent of the alkylhydroxy group;

[0899] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0900] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0901] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0902] Ring D is selected from 4-6 membered heterocyclic groups and 4-6 membered heteroaryl groups, wherein the 4-6 membered cycloalkyl groups and 4-6 membered heteroaryl groups contain 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring D is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 substituted by alkyl, halogen and amino substituents;

[0903] Ring E is selected from 4-6 membered heterocyclyl and 4-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl and 4-6 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0904] t is 0, 1, 2, or 3;

[0905] k is 1, 2, 3 or 4.

[0906] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0907] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0908] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a, -O- and -CH2-.

[0909] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0910] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0911] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0912] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0913] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0914] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0915] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0916] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0917] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0918] In certain embodiments, the R 1 Selected from hydrogen.

[0919] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0920] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0921] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0922] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0923] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0924] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0925] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0926] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0927] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0928] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0929] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0930] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0931] In certain embodiments, the R a Selected from hydrogen.

[0932] In certain embodiments, the ring D is selected from 4-5 membered heterocyclyl and 4-5 membered heteroaryl, wherein the 4-5 membered cyclyl and 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S; the ring D is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 The alkyl, halogen and amino substituents are substituted.

[0933] In certain embodiments, the ring E is selected from a 4-5 membered heterocyclyl and a 4-5 membered heteroaryl, wherein the 4-5 membered cyclyl and the 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S.

[0934] In certain embodiments, t is 0, 1, or 2.

[0935] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has a structure of formula (VIII):

[0936] in:

[0937] R 1 Selected from hydrogen and C 1-6 alkyl;

[0938] R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ;

[0939] At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl;

[0940] R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het;

[0941] Het is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;

[0942] The Het is optionally replaced by one or more selected from R Het The group substituted, the R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally replaced by one or more C1-6 haloalkyl substitution;

[0943] R a Selected from hydrogen and C 1-6 alkyl;

[0944] Every time R appears 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0945] R 2a and R 2b are independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group;

[0946] R 3 Selected from-MR 3.1 ;

[0947] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -;

[0948] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, the R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted with a substituent of the alkylhydroxy group;

[0949] R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or

[0950] R 3a With R 3.1 and the S connected to it via -(CH2) t - linked together to form a 4-8 membered heterocyclic group; or

[0951] -N=S(O)R 3a -S and R in 4 Via -(CH2) t - linked together to form a 4-8 membered heterocyclic group;

[0952] Ring F is selected from C 6-10 Aryl and 4-6 membered heteroaryl, wherein the 4-6 membered heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0953] t is 0, 1, 2, or 3;

[0954] k is 1, 2, 3 or 4.

[0955] In certain embodiments, the M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-.

[0956] In certain embodiments, the M is selected from a direct bond, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene.

[0957] In certain embodiments, the M is selected from a direct bond, -N=S(O)R 3a , -O- and -CH2-.

[0958] In certain embodiments, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0959] In certain embodiments, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0960] In certain embodiments, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl.

[0961] In certain embodiments, the R 3.1 is selected from H, methyl, trifluoromethyl, phenyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, and pyrazolonyl;

[0962] In certain embodiments, the R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0963] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl and trifluoromethyl.

[0964] In certain embodiments, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

[0965] In certain embodiments, the R 1 Selected from hydrogen and C 1-3 alkyl.

[0966] In certain embodiments, the R 1 is selected from hydrogen and methyl.

[0967] In certain embodiments, the R 1 Selected from hydrogen.

[0968] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k-R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0969] In certain embodiments, the R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

[0970] In certain embodiments, the Het is selected from C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0971] In certain embodiments, the Het is selected from C 4-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0972] In certain embodiments, the Het is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0973] In certain embodiments, the Het is selected from cyclobutyl, cyclohexyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, and the heterocycle in the benzoheterocyclyl is selected from a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0974] In certain embodiments, the Het is optionally replaced by one or more selected from R Het The group is substituted.

[0975] In certain embodiments, the Het is selected from Where v is 0, 1, or 2.

[0976] In certain embodiments, the R Het Selected from halogen, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylhydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b .

[0977] In certain embodiments, the R Het Selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a .

[0978] In certain embodiments, the R Het Selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

[0979] In certain embodiments, the R a Selected from hydrogen and C 1-3 alkyl.

[0980] In certain embodiments, the R a Selected from hydrogen.

[0981] In certain embodiments, the ring F is selected from phenyl and a 4-5 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S.

[0982] In certain embodiments, the ring F is selected from phenyl, oxazolyl, thiazolyl, thienyl.

[0983] In certain embodiments, t is 0, 1, or 2.

[0984] In certain embodiments, the present disclosure provides a compound or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0985] In certain embodiments, the present disclosure provides a compound or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0986] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0987] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0988] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of the aforementioned compound, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound.

[0989] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent, or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent, or excipient.

[0990] All compounds disclosed herein, as well as mixtures and compositions comprising the compounds of the present invention, may be administered to a living organism via any route of administration. Routes of administration may include oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, and topical or systemic transdermal administration.

[0991] All compounds disclosed herein, as well as mixtures and compositions containing the compounds of the present invention, can be formulated into single doses containing the active compounds of the present invention as well as carriers, excipients, and the like, and the dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, and the like. These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonicity adjusters, and anti-adherents.

[0992] Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005. Therefore, those skilled in the art can easily prepare them.

[0993] Different dosages can be selected based on the nature and intensity of the disease suffered by different individuals, the patient's age, gender, weight, route of administration and other factors. The dosage of the compound of the present invention can be 0.01 to 500 mg / kg per day, preferably 1-100 mg / kg per day, and can be administered in single or multiple doses.

[0994] The present disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of a drug for inhibiting PDEs enzymes, preferably in the preparation of a drug for inhibiting PDE4 enzymes, and more preferably in the preparation of a drug for inhibiting PDE4B enzymes.

[0995] The present disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDEs enzymes, preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4 enzymes, and more preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4B enzymes.

[0996] In certain embodiments, the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0997] In certain embodiments, the respiratory and pulmonary diseases are selected from respiratory and pulmonary diseases associated with increased mucus production, obstructive lung diseases and airway diseases, preferably selected from COPD, asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension.

[0998] In certain embodiments, the gastrointestinal disease is selected from Crohn's disease, ulcerative colitis, and Crohn's disease.

[0999] In certain embodiments, the inflammatory disease is selected from proliferative and inflammatory skin diseases, arthritic diseases and inflammatory diseases of the eye; wherein the inflammatory skin disease is preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, skin photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, eczematous hand dermatitis and psoriasis; the arthritic disease is preferably selected from rheumatoid arthritis, psoriatic arthritis and spondyloarthritis; the inflammatory disease of the eye is preferably glaucoma or dry eye syndrome.

[1000] In certain embodiments, the peripheral or central nervous system disease is selected from Alzheimer's disease, age-associated memory impairment (AAMI), age-related cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, depression, schizophrenia, stroke, neurological disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment caused by lack of sleep, intellectual and developmental disabilities and multiple sclerosis.

[1001] In certain embodiments, the cancer is selected from the group consisting of leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric cancer, urothelial carcinoma, ureteral cancer, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[1002] Explanation of terms:

[1003] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[1004] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[1005] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

[1006] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[1007] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[1008] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[1009] The term " spiroalkyl " refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between the monocycle, which can contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[1010] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of composition ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic alkyl.Non-limiting examples of fused cycloalkyl include:

[1011] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[1012] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[1013] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[1014] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, are preferably one or more of the following groups independently selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[1015] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclyls.

[1016] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between the monocycles, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably a 3 / 5 member, 3 / 6 member, 4 / 4 member, 4 / 5 member, 4 / 6 member, 5 / 5 member or a 5 / 6 member monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[1017] The term "fused heterocyclic radical" refers to 5 to 20 yuan, and each ring in the system shares a polycyclic heterocyclic group of a pair of atoms adjacent to other rings in the system, and one or more rings can contain one or more double bonds, wherein one or more annular atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulphur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining annular atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radicals, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radicals. The limiting examples of fused heterocyclic radicals include:

[1018] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[1019] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[1020] wait.

[1021] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[1022] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[1023] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[1024] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) members, more preferably 5 or 6, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryls as described above fused to aryl, heterocyclyl, or cycloalkyl rings, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[1025] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[1026] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[1027] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[1028] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[1029] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[1030] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[1031] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[1032] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[1033] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[1034] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[1035] The term "hydroxy" refers to -OH.

[1036] The term "amino" refers to -NH2.

[1037] The term "cyano" refers to -CN.

[1038] The term "nitro" refers to -NO2.

[1039] The term "oxo" or "oxo" refers to "=0".

[1040] The term "carbonyl" refers to C=O.

[1041] The term "carboxy" refers to -C(O)OH.

[1042] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art will be able to determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[1043] In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e., the bond Can be or include both Two configurations. Represents a single configuration, In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[1044] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[1045] The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure disclosed herein with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a deuterium atom (C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetics, or receptor studies. The various deuterated forms of the compounds disclosed herein refer to compounds in which each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated compounds, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[1046] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in the pharmaceutical salts described by SM Berge in J. Pharmaceutical Sciences (Volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts refer to salts formed by the compounds of the present invention with organic or inorganic acids, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 Alkyl) 4 salt.

[1047] The term "solvate" refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[1048] The term "hydrate" refers to the case where the solvent in the above-mentioned term "solvate" is water.

[1049] The term "prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example, by hydrolysis in the blood, to yield the active prodrug.

[1050] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[1051] The above definitions are given for the terms involved in the present invention. Those skilled in the art can also understand the above terms in combination with the existing technology. The following is a further description based on the content of the present invention and the definitions of the terms.

[1052] The preparation of the compounds and pharmaceutically acceptable salts disclosed herein is further described below with reference to examples, but these examples are not intended to limit the scope of the disclosure.

[1053] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[1054] The following describes the general experimental conditions in the embodiments of the present invention:

[1055] First, the reactions in the examples are generally carried out under nitrogen protection.

[1056] Furthermore, the intermediates and final products were separated and purified by chromatographic columns, preparative chromatographic plates, and ISCO rapid preparative chromatography systems. The chromatographic columns were filled with silica gel (300-400 mesh) produced by Shanghai Titan Technology Co., Ltd., the preparative chromatographic plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd., and the chromatographic columns used by ISCO (particle size 40-63 μm, ) is produced by Changzhou Santai Technology Co., Ltd.

[1057] Furthermore, the LC-MS instrument used was a Waters ACQUITY Arc equipped with a QDa Detector. A Waters XBridge C18 column (2.1×50 mm, 3.5 μm) was used. The mass spectrometer (MS) employed an ESI source and only indicates the molecular weight M of the parent molecule, typically reporting [M+H]. + The injection volume was determined by the sample concentration; the flow rate was 1.2 mL / min; HPLC peaks were recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). Gradient elution conditions are shown in Tables 1 and 2 below:

[1058] Table 1: Gradient elution conditions 1

[1059] Table 2: Gradient elution conditions 2

[1060] NMR spectra were obtained using a Varian 400 MHz nuclear magnetic resonance spectrometer, typically using CDCl₃ and DMSO-d₆ as solvents. Chemical shifts are reported in ppm. Peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.

[1061] Example

[1062] Example 1

[1063] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (Compound 1)

[1064] Step 1: Preparation of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (Compound 1b)

[1065] 2,4-Dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (Compound 1a) (1.5 g, 7.3 mmol), 1-aminocyclobutylmethylamine hydrochloride (1.1 g, 8.0 mmol), and triethylamine (2.2 g, 21.8 mmol) were mixed in ethanol (20 mL) at room temperature. The reaction mixture was stirred at 85°C for 8 hours. After completion, the solvent was concentrated under reduced pressure. Water (20 mL) was then added and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 1b (1.5 g).

[1066] Step 2: Preparation of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 1c)

[1067] Compound 1b (1.5 g, 5.8 mmol), S-1,1'-bi-2-naphthol (0.17 g, 0.58 mmol), tetraisopropoxytitanium (0.08 g, 2.9 mmol), and water (0.11 g, 5.8 mmol) were mixed in dichloromethane (20 mL) at room temperature and stirred for 1 hour. Tert-butyl peroxide (0.58 g, 6.4 mmol) was then added and the reaction mixture was stirred for 5 hours. After completion of the reaction, water (30 mL) was added and the mixture was extracted with dichloromethane (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 1c (1.7 g).

[1068] Step 3: Preparation of 5-(4-bromophenyl)-3-methyl-1,2,4-oxadiazole (Compound 1f)

[1069] 4-Bromobenzamide 1d (1.0 g, 5.0 mmol) was mixed with 1,1-dimethoxy-N,N-dimethylethane-1-amine 1e (8 mL) at room temperature. The reaction mixture was stirred at 125°C for 2 hours. After completion, the mixture was cooled to 25°C and concentrated under reduced pressure to remove the solvent, yielding a yellow solid. Hydroxylamine hydrochloride (0.41 g, 6.0 mmol) was mixed with sodium hydroxide solution (1N, 7 mL) and then added. 1,4-dioxane (7 mL) and acetic acid (9 mL) were then added. The mixture was stirred at 25°C for 0.5 hour, then heated to 90°C and stirred for 3 hours. After completion, the mixture was cooled to 25°C, saturated potassium carbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (40 mL). The organic phase was washed with saturated brine, and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phases were concentrated under reduced pressure to yield the crude product. The crude product was purified by flash column chromatography to yield the title compound 1f (0.5 g).

[1070] Step 4: Preparation of 3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazole (Compound 1g)

[1071] Under nitrogen, 5-(4-bromophenyl)-3-methyl-1,2,4-oxadiazole 1f (0.5 g, 2.1 mmol), pinacol diboronate (1.1 g, 4.2 mmol), potassium acetate (0.41 g, 4.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (150 mg, 0.2 mmol) were mixed in a 1,4-dioxane solution (15 mL). The reaction mixture was stirred at 90°C for 3 hours. After completion, the solvent was removed by concentration under reduced pressure. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield 1 g (0.6 g, crude product) of the title compound.

[1072] Step 5: Preparation of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (Compound 1)

[1073] Under nitrogen, compound 1g (60 mg, 0.2 mmol), compound 1c (60 mg, 0.2 mmol), potassium carbonate (60 mg, 0.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15 mg, 0.02 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 1 (10 mg, yield: 12%).

[1074] 1 H NMR(400MHz,DMSO-d6)δppm 8.54(m,J=8.42Hz,2H),8.24(m,J=8.42Hz,2H),8.19(s,1H),4.96(t,J=5.49Hz,1H),3.82-3.91(m,2H),3.65-3.74(m,1H) ,3.41-3.47(m,1H),3.24-3.32(m,1H),3.08(dt,J=7.78,5.77Hz,1H),2.47(s,3H),2.35-2.46(m,4H),1.83-1.94(m,2H).

[1075] MS m / z(ESI):412[M+1].

[1076] Example 2

[1077] (R)-2-(4-(oxazol-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2)

[1078] Step 1: Preparation of 2-chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Compound 2a)

[1079] At room temperature, compound 1a (1.5 g, 7.3 mmol) and tetrahydro-2H-pyran-4-amine (0.81 g, 8.0 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 2a (1.5 g).

[1080] Step 2: Preparation of (R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2b)

[1081] Under nitrogen protection, compound 2a (1.5 g) was prepared according to the method of the second step in Example 1 to obtain the title compound 2b (1.2 g).

[1082] Step 3: Preparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (Compound 2d)

[1083] Under nitrogen protection, 2-(4-bromophenyl)oxazole 2c (0.2 g, 1.0 mmol) was prepared according to the method of step 4 of Example 1 to obtain the title compound 2d (0.2 g).

[1084] Step 4: Preparation of (R)-2-(4-(oxazol-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2)

[1085] Under nitrogen protection, compound 2d (38 mg, 0.14 mmol) and compound 2b (40 mg, 0.14 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 2 (11 mg, yield: 20%).

[1086] 1 H NMR(400MHz,DMSO-d6)δppm 8.55(m,J=8.42Hz,2H),8.33(s,1H),8.25(d,J=7.42Hz,1H),8.16(m,J=8.42Hz,2H),7.49(s,1H),4.54(s,1H),3.93-4.02(m,2H),3 .65-3.78(m,1H),3.39-3.56(m,3H),3.26-3.34(m,1H),3.10(dd,J=13.23,6.82Hz,1H),1.91(d,J=12.45Hz,2H),1.68-1.82(m,2H).

[1087] MS m / z(ESI):397[M+1].

[1088] Example 3

[1089] (R)-4-(((1s,3S)-3-(hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3)

[1090] Step 1: Preparation of ((1s,3s)-3-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (Compound 3a)

[1091] At room temperature, compound 1a (0.4 g, 2.0 mmol) and ((1s, 3s)-3-aminocyclobutyl)methanol hydrochloride (0.3 g, 2.0 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 3a (0.39 g).

[1092] Step 2: Preparation of (R)-2-chloro-4-(((1s,3S)-3-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3b)

[1093] Under nitrogen protection, compound 3a (0.39 g, 1.44 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 3b (0.19 g).

[1094] Step 3: Preparation of (R)-4-(((1s,3S)-3-(hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3)

[1095] Under nitrogen protection, compound 3b (60 mg, 0.21 mmol) and compound 2d (57 mg, 0.21 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 3 (40 mg, yield: 49%).

[1096] 1 H NMR(400MHz,DMSO-d6)δppm 8.51-8.58(m,3H),8.32(s,1H),8.15(d,J=8.51Hz,2H),7.48(s,1H),4.68(d,J=6.78Hz,1H),3.65-3.74(m,2H),3.38-3 .49(m,3H),3.24-3.33(m,1H),3.09(dd,J=13.32,6.91Hz,1H),2.40-2.49(m,2H),2.15-2.27(m,1H),1.90-2.01(m,2H).

[1097] MS m / z(ESI):397[M+1].

[1098] Example 4

[1099] (R)-4-((1-(Hydroxymethyl)cyclopropyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 4)

[1100] Step 1: Preparation of (1-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclopropyl)methanol (Compound 4a)

[1101] Compound 1a (0.2 g, 1.0 mmol), (1-aminocyclopropyl)methanol (90 mg, 1.0 mmol), and triethylamine (0.4 g, 3.0 mmol) were mixed in ethanol (10 mL) at room temperature. The reaction mixture was stirred at 85°C for 8 hours. After completion, the solvent was concentrated under reduced pressure. Water (10 mL) was then added and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 4a (0.11 g).

[1102] Step 2: Preparation of (R)-2-chloro-4-((1-(hydroxymethyl)cyclopropyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 4b)

[1103] Compound 4a (0.11 g, 0.43 mmol), S-1,1'-bi-2-naphthol (12 mg, 0.04 mmol), tetraisopropoxytitanium (63 mg, 0.22 mmol), and water (8 mg, 0.43 mmol) were mixed in dichloromethane (10 mL) at room temperature and stirred for 1 hour. Tert-butyl peroxide (60 mg, 0.47 mmol) was then added and the reaction mixture was stirred for 5 hours. After completion of the reaction, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 4b (70 mg).

[1104] Step 3: Preparation of (R)-4-((1-(hydroxymethyl)cyclopropyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 4)

[1105] Under nitrogen, compound 4b (40 mg, 0.14 mmol), compound 2d (38 mg, 0.14 mmol), potassium carbonate (39 mg, 0.28 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15 mg, 0.02 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 4 (6 mg, yield: 11%).

[1106] 1 H NMR(400MHz,DMSO-d6)δppm 8.54-8.60(m,3H),8.32(s,1H),8.16(d,J=8.61Hz,2H),7.48(s,1H),4.82(t,J=5.68Hz,1H),3.65-3.81(m,3H),3.25-3.33(m,2H),3.09(br dd,J=12.82,6.77Hz,1H),0.93-1.02(m,2H),0.84-0.91(m,2H).

[1107] MS m / z(ESI):383[M+1].

[1108] Example 5

[1109] (R)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 5)

[1110] Step 1: Preparation of (1s,4s)-4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclohexane-1-ol (Compound 5a)

[1111] At room temperature, compound 1a (0.2 g, 1.0 mmol) and ((1s, 4s)-4-aminocyclohexane-1-ol (115 mg, 1.0 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 5a (0.14 g).

[1112] Step 2: Preparation of (R)-2-chloro-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 5b)

[1113] Under nitrogen protection, compound 5a (0.14 g, 0.5 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 5b (0.12 g).

[1114] Step 3: Preparation of (R)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 5)

[1115] Under nitrogen protection, compound 5b (90 mg, 0.3 mmol) and compound 1g (86 mg, 0.3 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 5 (18 mg, yield: 14%).

[1116] 1 H NMR(400MHz,DMSO-d6)δppm 8.59(d,J=8.42Hz,2H),8.19-8.28(m,3H),4.43(d,J=2.47Hz,1H),4.26(s,1H),3.87(s,1H),3.64-3.76(m,1H),3.40-3.47(m,1H),3 .25-3.32(m,1H),3.09(dd,J=12.77,7.55Hz,1H),2.46-2.50(m,3H),1.85-2.02(m,2H),1.77(d,J=11.81Hz,2H),1.61-1.73(m,4H).

[1117] MS m / z(ESI):426[M+1].

[1118] Example 6

[1119] (R)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 6)

[1120] Step 1: Preparation of (3S,4R)-4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)tetrahydrofuran-3-ol (Compound 6a)

[1121] At room temperature, compound 1a (0.2 g, 1.0 mmol) and ((3S,4R)-4-aminotetrahydrofuran-3-ol (0.1 g, 1.0 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 6a (0.22 g).

[1122] Step 2: Preparation of (R)-2-chloro-4-(((3R,4S)-4-hydroxytetrahydrofuran-3-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 6b)

[1123] Under nitrogen protection, compound 6a (0.22 g, 0.80 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 6b (90 mg).

[1124] Step 3: Preparation of (R)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 6)

[1125] Under nitrogen protection, compound 6b (60 mg, 0.21 mmol) and compound 2d (57 mg, 0.21 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 6 (7 mg, yield: 9%).

[1126] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.58(m,J=8.42Hz,2H),8.48(d,J=6.41Hz,1H),8.32(s,1H),8.15(m,2H),7. 48(s,1H),5.36(d,J=3.94Hz,1H),4.67(s,1H),4.45(s,1H),4.23(t,J=7.14 Hz,1H),4.01(dd,J=9.25,5.04Hz,1H),3.68-3.77(m,2H),3.62(dd,J=9.25, 2.56Hz, 1H), 3.43 (dt, J=13.69, 8.31Hz, 2H), 3.11 (dd, J=13.32, 7.00Hz, 1H).

[1127] MS m / z(ESI):399[M+1].

[1128] Example 7

[1129] (R)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 7)

[1130] Step 1: Preparation of (1r,4R)-4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclohexane-1-ol (Compound 7a)

[1131] At room temperature, compound 1a (0.2 g, 1.0 mmol) and ((1r, 4r)-4-aminocyclohexane-1-ol (115 mg, 1.0 mmol) were prepared according to the first step of Example 1 to give the title compound 7a (0.13 g).

[1132] Step 2: Preparation of (R)-2-chloro-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 7b)

[1133] Under nitrogen protection, compound 7a (0.13 g, 0.46 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 7b (0.1 g).

[1134] Step 3: Preparation of (R)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 7)

[1135] Under nitrogen protection, compound 7b (30 mg, 0.1 mmol) and (4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)boronic acid 7c (21 mg, 0.1 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 7 (15 mg, yield: 36%).

[1136] 1H NMR (400MHz, DMSO-d6) δppm 8.57 (d, J=8.42Hz, 2H), 8.15 (d, J=8.42Hz, 3H), 4.64(s,1H),4.25(s,1H),3.65-3.75(m,1H),3.43(dt,J=13.69,8.22Hz,2H),3.20-3.32(m,1H), 3.08(dd,J=12.91,6.87Hz,1H),2.64(s,3H),1.94(s,4H),1.44-1.59(m,2H),1.34-1.44(m,2H).

[1137] MS m / z(ESI):426[M+1].

[1138] Example 8

[1139] (R)-2-(6-(4-chlorophenoxy)pyridin-3-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 8)

[1140] Step 1: Preparation of 5-bromo-2-(4-chlorophenoxy)pyridine (Compound 8c)

[1141] 5-Bromo-2-fluoropyridine 8a (1.0 g, 5.1 mmol), 4-chlorophenol 8b (0.65 g, 5.1 mmol), and potassium carbonate (1.4 g, 10.2 mmol) were mixed in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 90°C for 5 hours. After completion, water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 8c (1.4 g).

[1142] Step 2: Preparation of 2-(4-chlorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 8d)

[1143] Under nitrogen, compound 8c (0.3 g, 1.0 mmol), pinacol diboronate (0.5 g, 2.0 mmol), potassium acetate (0.2 g, 2.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (75 mg, 0.1 mmol) were mixed in a 1,4-dioxane solution (8 mL). The reaction mixture was stirred at 90°C for 3 hours. After completion, the solvent was removed by concentration under reduced pressure. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the title compound 8d (0.2 g, crude product).

[1144] Step 3: Preparation of (R)-2-(6-(4-chlorophenoxy)pyridin-3-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 8)

[1145] Under nitrogen, compound 8d (60 mg, 0.24 mmol), compound 1c (69 mg, 0.24 mmol), potassium carbonate (66 mg, 0.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15 mg, 0.02 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 8 (5 mg, yield: 4%).

[1146] 1 H NMR(400MHz,DMSO-d6)δppm 9.02(d,J=1.92Hz,1H),8.67(dd,J=8.65,2.33Hz,1H),8.18(s,1H),7.51-7.55(m,2H),7.26-7.32(m,2H),7.22(d,J=8.61Hz,1H),4.95(t,J= 5.77Hz,1H),3.81(d,J=5.86Hz,2H),3.62-3.71(m,1H),3.37-3.43(m,1H),3.32- 3.34(m,1H),3.24(td,J=8.61,6.68Hz,1H),2.31-2.51(m,4H),1.79-1.89(m,2H).

[1147] MS m / z(ESI):457[M+1].

[1148] Example 9

[1149] (R)-2-(4-((2-(3-fluoro-4-methoxyphenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenoxy)acetic acid (Compound 9)

[1150] Step 1: Preparation of methyl 2-(4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)phenoxy)acetate (Compound 9b)

[1151] At room temperature, compound 1a (0.2 g, 1.0 mmol) and methyl 2-(4-aminophenoxy)acetate 9a (0.18 g, 1.0 mmol) were prepared according to the first step of Example 1 to give the title compound 9b (0.17 g).

[1152] Step 2: Preparation of (R)-methyl 2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenoxy)acetate (Compound 9c)

[1153] Under nitrogen protection, compound 9b (0.17 g, 0.50 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 9c (80 mg).

[1154] Step 3: Preparation of (R)-2-(4-((2-(3-fluoro-4-methoxyphenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenoxy)acetic acid (Compound 9)

[1155] Under nitrogen protection, compound 9c (80 mg, 0.22 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid 9d (38 mg, 0.22 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 9 (8 mg, yield: 8%).

[1156] 1 H NMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.11-8.18(m,1H),7.98-8.03(m,1H),7.59(d,J=8.88Hz,2H),7.33(t,J=8.74Hz,1H),7.00(d,J= 8.97Hz,2H),4.71(s,2H),3.94(s,3H),3.68-3.78(m,1H),3.42-3.53(m,2H),3.12(dd,J=13.64,6.23Hz,1H).

[1157] MS m / z(ESI):444[M+1].

[1158] Example 10

[1159] (R)-4-((Tetrahydro-2H-pyran-4-yl)amino)-2-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 10)

[1160] Step 1: Preparation of (R)-tert-butyl 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (Compound 10c)

[1161] 2,3-Difluoro-5-(trifluoromethyl)pyridine 10a (1.0 g, 5.5 mmol), (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate 10b (1.3 g, 6.0 mmol), and N,N-diisopropylethylamine (0.9 g, 6.6 mmol) were mixed in dimethyl sulfoxide (20 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 10c (1.55 g).

[1162] Step 2: Preparation of tert-butyl (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate (Compound 10d)

[1163] (R)-tert-Butyl 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate 10c (0.4 g, 1.0 mmol) and potassium tert-butoxide (0.34 g, 3.0 mmol) were mixed in tert-butanol (15 mL) at room temperature. The reaction mixture was stirred at 80°C for 2 hours. After completion, the solvent was concentrated under reduced pressure. Water (30 mL) was then added and the mixture was extracted with dichloromethane (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 10d (0.3 g).

[1164] Step 3: Preparation of 2,2,2-trifluoro-1-((6aR)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-8l4-pyrazino[4,3-d]pyrido[3,2-b][1,4]oxazin-8-yl)ethan-1-one (Compound 10e)

[1165] Trifluoroacetic acid (1 mL) was added to a solution of compound 10d (0.3 g, 0.83 mmol) in dichloromethane (8 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated to dryness to give the title compound 10e (0.28 g).

[1166] Step 4: Preparation of (R)-4-((tetrahydro-2H-pyran-4-yl)amino)-2-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 10)

[1167] To a solution of compound 2b (29 mg, 0.1 mmol) and compound 10e (26 mg, 0.1 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (40 mg, 0.3 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 50 min. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 10 (11 mg, yield: 20%).

[1168] 1 H NMR(400MHz,DMSO-d6)δppm 8.09-8.12(m,1H),7.72(d,J=7.51Hz,1H),7.32(d,J=2.01Hz,1H),4.81(d,J=12.54Hz,2H),4.49-4.63(m,2H),4.25( d,J=6.68Hz,1H),4.08(dd,J=11.22,8.10Hz,1H),3.88-3.96(m,2H),3.36-3.62(m,5H),2.89-3.12(m,4H),2.83(t,J =12.08Hz,1H),1.81(d,J=11.17Hz,2H),1.58-1.72(m,2H).

[1169] MS m / z(ESI):511[M+1].

[1170] Example 11

[1171] (R)-4-((tetrahydro-2H-pyran-4-yl)amino)-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 11)

[1172] Step 1: Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 11c)

[1173] Under ice, ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate 11a (1.0 g, 3.9 mmol) and potassium tert-butoxide (0.5 g, 4.3 mmol) were mixed in N,N-dimethylformamide (20 mL). After stirring for 1 hour, tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 11b (1.0 g, 4.3 mmol) was added. The temperature was raised to 25°C and stirred for 2 hours. After completion of the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 11c (1.2 g).

[1174] Step 2: Preparation of ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride (Compound 11d)

[1175] Compound 11c (1.2 g, 3.0 mmol) was stirred in a 1,4-dioxane hydrochloride solution (4 M, 10 mL) at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the title compound 11d (0.88 g).

[1176] Step 3: Preparation of 3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 11e)

[1177] Under nitrogen, ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride 11d (0.88 g, 2.6 mmol) and potassium carbonate (1.8 g, 13.0 mmol) were mixed in methanol (20 mL) and stirred at 25°C for 18 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, followed by addition of water (100 mL). The mixture was filtered, and the filter cake was washed with water (100 mL x 3) and dried to afford the title compound 11e (0.6 g).

[1178] Step 4: Preparation of 3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (Compound 11f)

[1179] 3-(Trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one 11e (0.6 g, 2.4 mmol) was mixed with methyl tert-butyl ether (10 mL), followed by the addition of lithium aluminum hydride (0.18 g, 4.7 mmol) and stirring at 55°C for 2 hours. After completion of the reaction, the mixture was cooled to 25°C, and water (100 mL) was added. The mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 11f (0.33 g).

[1180] Step 5: Preparation of (R)-4-((tetrahydro-2H-pyran-4-yl)amino)-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 11)

[1181] Compound 2b (29 mg, 0.1 mmol) and compound 11f (24 mg, 0.1 mmol) were prepared according to the method of step 4 of Example 10 to give the title compound 11 (11 mg, yield: 22%).

[1182] 1 H NMR(400MHz,DMSO-d6)δppm 8.57(s,1H),8.38(s,1H),7.86(d,J=7.32Hz,1H),6.61(s,1H),5.25(s,2H),4.35(s,4H),3.90-3.98(m,2H),3. 44-3.57(m,3H),3.27(dt,J=13.69,8.35Hz,1H),2.91-3.09(m,2H),1.83(d,J=12.08Hz,2H),1.61-1.74(m,2H).

[1183] MS m / z(ESI):493[M+1].

[1184] Example 12

[1185] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 12)

[1186] Step 1: Preparation of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 12)

[1187] Under nitrogen, compound 1c (40 mg, 0.14 mmol), compound 2d (38 mg, 0.14 mmol), potassium carbonate (39 mg, 0.28 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15 mg, 0.02 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 12 (6 mg, yield: 11%).

[1188] 1 H NMR (400MHz, DMSO-d6) δppm 8.49 (d, J=8.33Hz, 2H), 8.31 (s, 1H), 8.12-8.16 (m, 3H),7.47(s,1H),4.95(t,J=5.68Hz,1H),3.84-3.91(m,2H),3.64-3.74(m,1H),3.37-3 .46(m,1H),3.23-3.31(m,1H),3.03-3.10(m,1H),2.34-2.50(m,4H),1.83-1.93(m,2H).

[1189] MS m / z(ESI):397[M+1].

[1190] Example 13

[1191] (R)-2-(6-(piperidin-1-yl)pyridin-3-yl)-4-(thiazol-5-ylmethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 13)

[1192] Step 1: Preparation of 2-chloro-N-(thiazol-5-ylmethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Compound 13a)

[1193] At room temperature, compound 1a (200 mg, 0.965 mmol) and thiazol-5-ylmethylamine hydrochloride (132 mg, 1.16 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 13a (155 mg).

[1194] Step 2: Preparation of (R)-2-chloro-4-((thiazol-5-ylmethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 13b)

[1195] Under nitrogen protection, compound 13a (155 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 13b (125 mg).

[1196] Step 3: Preparation of (R)-2-(6-(piperidin-1-yl)pyridin-3-yl)-4-(thiazol-5-ylmethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 13)

[1197] Under nitrogen protection, compound 13b (80 mg, 0.266 mmol) and 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (92 mg, 0.319 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 13 (45.3 mg, yield: 39.8%).

[1198] 1 H NMR(400MHz,DMSO-d6)δppm 1.58(d,J=3.75Hz,4H)1.66(d,J=4.67Hz,2H)3.00-3.07(m,1H)3.18-3.35(m,2H)3.39-3.48(m,1H)3.60-3.71(m,5H)4.94(d,J=5.7 7Hz, 2H) 6.92 (d, J = 9.16Hz, 1H) 7.90 (s, 1H) 8.42 (dd, J = 9.06, 2.38Hz, 1H) 8.82 (t, J = 5.73Hz, 1H) 8.94 (s, 1H) 9.15 (d, J = 2.20Hz, 1H).

[1199] MS m / z(ESI):427[M+1].

[1200] Example 14

[1201] (R)-4-(((1r,3R)-3-hydroxycyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 14)

[1202] Step 1: Preparation of (1r,3r)-3-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-ol (Compound 14a)

[1203] At room temperature, compound 1a (200 mg, 0.97 mmol) and (1r,3r)-3-aminocyclobutane-1-ol (126 mg, 1.45 mmol) were prepared according to the first step of Example 1 to give the title compound 14a (150 mg).

[1204] Step 2: Preparation of (R)-2-chloro-4-(((1r,3R)-3-hydroxycyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 14b)

[1205] Under nitrogen protection, compound 14a (150 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 14b (120 mg).

[1206] Step 3: Preparation of (R)-4-(((1r,3R)-3-hydroxycyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 14)

[1207] Under nitrogen protection, compound 14b (50 mg, 0.18 mmol) and compound 2d (65 mg, 0.24 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 14 (14 mg, yield: 20%).

[1208] 1 H NMR (400MHz, DMSO-d6) δppm 8.53(d,J=8.51Hz,2H),8.32(s,1H),8.16(d,J=8.51Hz,2H),7.48(s,1H),5.13(d,J=5.04Hz,1H),4.86(br s,1H),4.35-4.41(m,1H),3.64-3.78(m,1H),3.39-3.47(m,1H),3.25-3.33(m,1H),3.09(m,1H),2.40-2.49(m,2H),2.28-2.37(m,2H).

[1209] MS m / z(ESI):397[M+1].

[1210] Example 15

[1211] (S)-1-Methyl-5-(((R)-2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)piperidin-2-one (Compound 15)

[1212] Step 1: Preparation of (S)-5-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)-1-methylpiperidin-2-one (Compound 15a)

[1213] At room temperature, compound 1a (250 mg, 1.21 mmol) and (S)-5-amino-1-methylpiperidin-2-one dihydrochloride (242 mg, 1.21 mmol) were prepared according to the first step of Example 1 to give the title compound 15a (140 mg).

[1214] Step 2: Preparation of (S)-5-((R)-2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1-methylpiperidin-2-one (Compound 15b)

[1215] Under nitrogen protection, compound 15a (140 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 15b (110 mg).

[1216] Step 3: Preparation of (S)-1-methyl-5-(((R)-2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)piperidin-2-one (Compound 15)

[1217] Under nitrogen protection, compound 15b (25 mg, 0.079 mmol) and compound 2d (23 mg, 0.119 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 15 (9.1 mg, yield: 27%).

[1218] 1H NMR(400MHz, DMSO-d6)δppm 2.01-2.13(m,2H)2.36-2.49(m,2H)2.87(d,J=6.04Hz,3H)3.11(br dd,J=13.46,6.77Hz,1H)3.25-3.32(m,1H)3.39-3.50(m,2H)3.55-3.78(m,2H)4.85(br s,1H)7.48(s,1H)8.15(m,J=8.42Hz,2H)8.32(s,1H)8.44(t,J=6.36Hz,1H)8.57(m,J=8.33Hz,2H).

[1219] MS m / z(ESI):424[M+1].

[1220] Example 16

[1221] (R)-3-((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (Compound 16)

[1222] Step 1: Preparation of methyl 3-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (Compound 16a)

[1223] Compound 1a (200 mg, 0.97 mmol) and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (204 mg, 1.45 mmol) were prepared according to the first step of Example 1 to give the title compound 16a (180 mg).

[1224] Step 2: Preparation of (R)-3-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (Compound 16b)

[1225] Under nitrogen protection, compound 16a (180 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 16b (130 mg).

[1226] Step 3: Preparation of (R)-3-((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (Compound 16c)

[1227] Under nitrogen protection, compound 16b (100 mg, 0.18 mmol) and compound 2d (65 mg, 0.24 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 16c (50 mg).

[1228] Step 4: Preparation of (R)-3-((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (Compound 16)

[1229] Compound 16c (50 mg, 0.11 mmol) and lithium hydroxide (19 mg, 0.44 mmol) were dissolved in a mixture of THF / MeOH / H₂O (3 mL / 1 mL / 1 mL) at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The pH was then adjusted to 2-3 with dilute hydrochloric acid and extracted with dichloromethane (20 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 16 (10 mg, 21% yield).

[1230] 1 H NMR(400MHz,DMSO-d6)δppm 9.05(s,1H),8.53(m,2H),8.32(s,1H),8.19(m,2H),7.48(s,1H),3.67- 3.76(m,1H),3.43(m,2H),3.30(m,1H),3.09(m,1H),2.48-2.51(m,6H).

[1231] MS m / z(ESI):423[M+1].

[1232] Example 17

[1233] (R)-4-((3-(Hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 17)

[1234] Step 1: Preparation of (3-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (Compound 17a)

[1235] Compound 1a (200 mg, 0.97 mmol) and (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (164 mg, 1.45 mmol) were prepared according to the first step of Example 1 to give the title compound 17a (120 mg).

[1236] Step 2: Preparation of (R)-2-chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 17b)

[1237] Under nitrogen protection, compound 17a (120 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 17b (80 mg).

[1238] Step 3: Preparation of (R)-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 17)

[1239] Under nitrogen protection, compound 17b (50 mg, 0.17 mmol) and compound 2d (65 mg, 0.24 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 17 (11 mg, yield: 16%).

[1240] 1 H NMR(400MHz,DMSO-d6)δppm 8.95(s,1H),8.54(d,J=8.42Hz,2H),8.32(s,1H),8.17(d,J=8.42Hz,2H),7.48(s,1H),4.62(t,J=5.58Hz, 1H),3.65-3.76(m,1H),3.53-3.64(m,2H),3.39-3.46(m,1H),3.26-3.33(m,1H),3.08(m,1H),2.15(s,6H).

[1241] MS m / z(ESI):409[M+1].

[1242] Example 18

[1243] (R)-4-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 18)

[1244] Step 1: Preparation of ((1r,3r)-3-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (Compound 18a)

[1245] Compound 1a (0.4 g, 2.0 mmol) and ((1r, 3r)-3-aminocyclobutyl)methanol hydrochloride (0.3 g, 2.0 mmol) were prepared according to the first step of Example 1 to give the title compound 18a (200 mg).

[1246] Step 2: Preparation of (R)-2-chloro-4-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 18b)

[1247] Under nitrogen protection, compound 18a (200 mg, 0.74 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 18b (180 mg).

[1248] Step 3: Preparation of (R)-4-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 18)

[1249] Under nitrogen protection, compound 18b (50 mg, 0.17 mmol) and compound 2d (65 mg, 0.24 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 18 (20 mg, yield: 29%).

[1250] 1 H NMR(400MHz,DMSO-d6)δppm 8.59(d,J=4.94Hz,1H),8.53(m,2H),8.32(s,1H),8.15(m,2H),7.48(s,1H),4.82(d,J=6.96Hz,2H),3.6 5-3.76(m,1H),3.57(d,J=5.95Hz,2H),3.43(m,1H),3.25-3.34(m,1H),3.09(m,1H),2.21-2.41(m,5H).

[1251] MS m / z(ESI):397[M+1].

[1252] Example 19

[1253] (R)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 19)

[1254] Step 1: Preparation of (R)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 19)

[1255] Under nitrogen protection, compounds 7b (30 mg, 0.1 mmol) and 2d (40 mg, 0.15 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 19 (9 mg, yield: 22%).

[1256] 1 H NMR (400MHz, DMSO-d6) δppm 8.53(m,2H),8.32(s,1H),8.16(m,2H),8.09(br d,J=6.96Hz,1H),7.48(s,1H),4.63(d,J=4.30Hz,1H),4.25(br s,1H),3.64-3.74(m,1H),3.39-3.48(m,2H),3.23-3.30(m,1H),3.08(m,1H),1.94(br s,4H),1.36-1.61(m,4H).

[1257] MS m / z(ESI):411[M+1].

[1258] Example 20

[1259] (R)-1-(2-((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one (Compound 20)

[1260] Step 1: Preparation of tert-butyl (2-(2-oxopyridin-1(2H)yl)ethyl)carbamate (Compound 20c)

[1261] Pyridin-2(1H)-one 20a (1 g, 10.5 mmol), tert-butyl (2-chloroethyl)carbamate (1.9 g, 10.5 mmol), and cesium carbonate (4.1 g, 12.6 mmol) were mixed in ethanol (20 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 hours. After completion, the solvent was concentrated under reduced pressure. Water (20 mL) was then added and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 20c (600 mg).

[1262] Step 2: Preparation of 1-(2-aminoethyl)pyridin-2(1H)-one hydrochloride (Compound 20d)

[1263] To a solution of compound 20c (600 mg, 2.5 mmol) in dichloromethane (5 mL) was added a solution of 1,4-dioxane hydrochloride (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the title compound 20d (650 mg).

[1264] Step 3: Preparation of 1-(2-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one (Compound 20e)

[1265] Compound 1a (400 mg, 1.9 mmol) and compound 20d (361 mg, 2.1 mmol) were prepared according to the first step of Example 1 to give the title compound 20e (300 mg).

[1266] Step 4: Preparation of (R)-1-(2-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one (Compound 20f)

[1267] Under nitrogen protection, compound 20e (300 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 20f (245 mg).

[1268] Step 5: Preparation of (R)-1-(2-((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one (Compound 20)

[1269] Under nitrogen protection, compound 20f (50 mg, 0.15 mmol) and compound 2d (65 mg, 0.24 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 20 (12 mg, yield: 18%).

[1270] 1H NMR (400MHz, DMSO-d6) δppm 8.53 (m, 2H), 8.40 (t, J = 5.72Hz, 1H), 8.33 (s, 1H), 8.13 (m, 2H), 7.51 (br d,J=6.77Hz,1H),7.49(s,1H),7.29(t,J=7.13Hz,1H),6.31(d,J=8.97Hz,1H),6.08(t,J=6.64Hz,1H),4. 17-4.23(m,2H),3.89-4.05(m,2H),3.70(m,1H),3.44-3.55(m,1H),3.25-3.33(m,1H),3.06-3.12(m,1H).

[1271] MS m / z(ESI):434[M+1].

[1272] Example 21

[1273] (R)-2-(4-(oxazol-2-yl)phenyl)-4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 21)

[1274] Step 1: Preparation of 2-chloro-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Compound 21a)

[1275] Compound 1a (200 mg, 0.97 mmol) and (2-(trifluoromethyl)pyridin-3-yl)methanamine (204 mg, 1.16 mmol) were prepared according to the method of the first step of Example 1 to give the title compound 21a (170 mg).

[1276] Step 2: Preparation of (R)-2-chloro-4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 21b)

[1277] Under nitrogen protection, compound 20a (170 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 21b (130 mg).

[1278] Step 3: Preparation of (R)-2-(4-(oxazol-2-yl)phenyl)-4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 21)

[1279] Under nitrogen protection, compound 21b (50 mg, 0.14 mmol) and compound 2d (49 mg, 0.18 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 21 (14 mg, yield: 21%).

[1280] 1 H NMR(400MHz,DMSO-d6)δppm 9.05(t,J=5.54Hz,1H),8.65(d,J=4.30Hz,1H),8.34(m,2H),8.30(s,1H),8.05(m,2H),7.98(d,J=7.97Hz,1H),7.71(m ,1H),7.46(s,1H),5.03(d,J=5.13Hz,2H),3.70-3.79(m,1H),3.50-3.59(m,1H),3.29-3.34(m,1H),3.11-3.18(m,1H).

[1281] MS m / z(ESI):372[M+1].

[1282] Example 22

[1283] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 22)

[1284] Step 1: Preparation of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 22)

[1285] Under nitrogen protection, compound 1c (50 mg, 0.17 mmol) and compound 7c (49 mg, 0.21 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 22 (14 mg, yield: 21%).

[1286] 1H NMR(400MHz,DMSO-d6)δppm 8.53(m,2H),8.18(s,1H),8.14(m,2H),4.96(t,J=5.72Hz,1H),3.83-3.91(m,2H),3.70(m,1H),3.36- 3.46(m,1H),3.24-3.33(m,1H),3.05-3.12(m,1H),2.64(s,3H),2.34-2.50(m,4H),1.83-1.94(m,2H).

[1287] MS m / z(ESI):412[M+1].

[1288] Example 23

[1289] (R)-4-((4-((1-oxidotetrahydro-1,6-thiophen-1-ylidene)amino)phenyl)amino)-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 23)

[1290] Step 1: Preparation of N-(4-nitrophenyl)tetrahydro-1H-114-thiophene-1-imine (Compound 23b)

[1291] Under nitrogen, compound 23a (5 g, 36.2 mmol) and tetrahydrothiophene (3.2 g, 36.2 mmol) were dissolved in 60 mL of dichloromethane at -40°C. N-chlorosuccinimide (4.84 g, 36.2 mmol) was added dropwise and allowed to react for 1 hour. After the reaction was complete, the mixture was quenched with pure water and extracted with dichloromethane (50 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate and spin-dried to afford crude compound 23b (2 g) as a yellow solid.

[1292] Step 2: Preparation of 1-((4-nitrophenyl)imino)tetrahydro-1H-116-thiophene-1-oxide (Compound 23c)

[1293] Dissolve compound 23b (1.9 g, 8.5 mmol) in 45 mL of ethanol and potassium carbonate (2.93 g, 21.2 mmol) in 5.5 mL of water. Mix the two and stir at room temperature. Dissolve m-chloroperbenzoic acid (2.93 g, 17 mmol) in 4.5 mL of ethanol and slowly add dropwise to the reaction mixture. Allow to react for 1 hour under these conditions. After the reaction is complete, quench with pure water and extract with dichloromethane (30 mL x 3). Collect the organic phase, dry over anhydrous sodium sulfate, and spin-dry. The crude product is purified by flash column chromatography to yield the title compound 23c.

[1294] Step 3: Preparation of 1-((4-aminophenyl)imino)tetrahydro-1H-116-thiophene-1-oxide (Compound 23d)

[1295] Compound 23c (480 mg, 2.0 mmol) was dissolved in ethanol, and 10% palladium on carbon (48 mg) was added. The hydrogen was replaced three times, and the mixture was reacted at room temperature for 30 minutes. The mixture was filtered through celite and the filtrate was dried to give the title compound 23d (250 mg).

[1296] Step 4: Preparation of 1-((4-((2-chloro-6,7-dihydrothiophen[3,2-d]pyrimidin-4-yl)amino)phenyl)imino)tetrahydro-1H-16-thiophene-1-oxide (Compound 23e)

[1297] Compound 1a (200 mg, 1.0 mmol) and compound 23d (203 mg, 1.0 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 23e (80 mg).

[1298] Step 5: Preparation of (R)-2-chloro-4-((4-((1-oxidotetrahydro-116-thiophen-1-ylidene)amino)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 23f)

[1299] Under nitrogen protection, compound 23e (80 mg, 0.21 mmol) was prepared according to the method of the second step of Example 1 to obtain the title compound 23f (45 mg).

[1300] Step 6: Preparation of (R)-4-((4-((1-oxytetrahydro-116-thiophen-1-ylidene)amino)phenyl)amino)-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 23)

[1301] Under nitrogen protection, compound 23f (45 mg, 0.11 mmol) and compound 23g (30 mg, 0.15 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 23 (18 mg, yield: 31%).

[1302] 1H NMR(400MHz,DMSO)δ9.77(s,1H),8.98(d,J=2.4Hz,1H),8.27(dd,J=9.2,2.4Hz,1H),7 .53(d,J=8.8Hz,2H),6.97–6.93(m,2H),6.90(d,J=9.2Hz,1H),3.65(t,J=5.4Hz,5H), 3.37(dd,J=13.6,5.6Hz,3H),3.30–3.21(m,4H),3.06(dd,J=13.6,5.8Hz,1H),2.22(dd,J=1 3.2, 6.4Hz, 3H), 2.13 (dd, J = 13.8, 6.8Hz, 3H), 1.64 (d, J = 5.0Hz, 2H), 1.55 (d, J = 3.6Hz, 5H). MS m / z(ESI):523[M+1].

[1303] Example 24

[1304] (R)-6-((5-oxido-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 24)

[1305] Step 1: Preparation of 6-amino-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 24b)

[1306] Compound 24a (1 g, 4.08 mmol) and palladium on carbon (100 mg) were dissolved in methanol and stirred at 25°C for 1 h under a hydrogen atmosphere (80 psi). After the reaction, the palladium on carbon was removed by filtration through celite, and the organic phase was dried over anhydrous sodium sulfate and dried to give the title compound 24b (300 mg).

[1307] Step 2: Preparation of 6-((2-chloro-6,7-dihydrothiophen[3,2-d]pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 24c)

[1308] Under nitrogen protection, compound 24b (300 mg) was prepared according to the method of the first step of Example 1 to obtain the title compound 24c (210 mg).

[1309] Step 3: Preparation of (R)-6-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 24d)

[1310] Under nitrogen protection, compound 24c (120 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 24d (100 mg).

[1311] Step 4: Preparation of (R)-6-((5-oxido-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 24)

[1312] Under nitrogen protection, compound 24d (50 mg, 0.14 mmol) and compound 23g (49 mg, 0.18 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 24 (11 mg, yield: 16%).

[1313] 1 H NMR (400MHz, DMSO) δ10.27 (s, 1H), 9.00 (d, J = 2.4Hz, 1H), 8.28 (m, 1H), 8.15 (s, 1H), 8.02 (m, 1H), 7.59-7.57 (m, 1H) ,6.85-6.83(m,1H),3.65-3.55(m,7H),3.45-3.35(m,4H),3.15-3.10(m,1H),1.65-1.63(m,2H),1.58-1.54(m,4H).

[1314] MS m / z(ESI):496[M+1].

[1315] Example 25

[1316] (R)-2-(4-((5-oxido-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 25)

[1317] Step 1: Preparation of ethyl 2-(4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 25b)

[1318] Under nitrogen protection, compound 1a (200 mg, 0.97 mmol) and compound 25a (174 mg, 0.97 mmol) were prepared according to the method of the first step of Example 1 to obtain the title compound 25b (150 mg).

[1319] Step 2: Preparation of (R)-ethyl 2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 25c)

[1320] Under nitrogen protection, compound 25b (150 mg) was prepared according to the method of the second step of Example 1 to obtain the title compound 25c (130 mg).

[1321] Step 3: Preparation of (R)-ethyl 2-(4-((5-oxido-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 25d)

[1322] Under nitrogen protection, compound 25c (130 mg, 0.36 mmol) and compound 23g (88 mg, 0.43 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 25d (70 mg).

[1323] Step 4: Preparation of (R)-2-(4-((5-oxido-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 25)

[1324] Under nitrogen protection, compound 25d (70 mg, 0.14 mmol) was prepared according to the method of step 4 of Example 16 to obtain the title compound 25 (25 mg, yield 37%).

[1325] MS m / z(ESI):492[M+1].

[1326] Example 26

[1327] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 26)

[1328] Step 1: Preparation of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(piperidin-1-yl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 26)

[1329] Under nitrogen, compound 23g (96.15 mg, 0.33 mmol), compound 1c (80 mg, 0.28 mmol), potassium carbonate (115.27 mg, 0.84 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (20.47 mg, 0.03 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain the title compound 26 (20 mg, yield: 17.4%).

[1330] 1 H NMR(400MHz,DMSO-d6)δppm 9.00(1H,d,J=2.20Hz),8.29(1H,dd,J=9.06,2.38Hz),7.87(1H,s),6.88(1H,d,J=9.16Hz),4.92(1H,t,J=5.72Hz),3.80(2H,br d,J=5.76Hz),3.68-3.55(5H,m),3.38-3.34(1H,m),3.32-3.28(1H,m),3.20-3.12(1H ,m),2.99(1H,dt,J=7.71,5.80Hz),2.44-2.25(4H,m),1.90-1.76(2H,m),1.64(2H,br d,J=4.68Hz),1.59-1.51(4H,m).

[1331] MS m / z(ESI):414[M+1].

[1332] Example 27

[1333] (S)-5-(((R)-2-(6-(4-chlorophenoxy)pyridin-3-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1-methylpiperidin-2-one (Compound 27)

[1334] Step 1: Preparation of (S)-5-((R)-2-(6-(4-chlorophenoxy)pyridin-3-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1-methylpiperidin-2-one (Compound 27)

[1335] Under nitrogen protection, compound 15b (25 mg, 0.079 mmol) and compound 8d (40 mg, 0.119 mmol) were prepared according to the method of step 5 of Example 1 to obtain the title compound 27 (7.7 mg, yield: 20%).

[1336] 1 H NMR(400MHz,DMSO-d6)δppm 2.03(dd,J=14.88,9.11Hz,2H)2.33-2.50(m,2H)2.84(d,J=5.86Hz,3H)3.09(dd,J= 13.82,6.41Hz,1H)3.25-3.33(m,2H)3.39-3.47(m,1H)3.56(dt,J=12.11,6.26Hz,1 H)3.64-3.76(m,1H)4.84(s,1H)7.21(d,J=8.61Hz,1H)7.26-7.31(m,2H)7.51-7.55 (m, 2H) 8.44 (t, J = 6.50Hz, 1H) 8.75 (dd, J = 8.61, 2.01Hz, 1H) 9.13 (d, J = 2.29Hz, 1H).

[1337] MS m / z(ESI):484[M+1].

[1338] Example 28

[1339] 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinolin-2(1H)-one (Compound 28)

[1340] Step 1: Preparation of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 28b)

[1341] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 28a (1.1 g, 4.98 mmol) was dissolved in dichloromethane (25 mL) at room temperature, and m-chloroperbenzoic acid (2.57 g, 14.94 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by flash column chromatography to obtain the title compound 28b (0.85 g).

[1342] Step 2: Preparation of 7-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinolin-2(1H)-one (Compound 28c)

[1343] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 28b (100 mg, 0.4 mmol), 7-amino-3,4-dihydroquinolin-2(1H)-one (88 mg, 0.54 mmol), and N,N-diisopropylethylamine (0.24 mL, 1.35 mmol) were mixed in ethanol (10 mL) at room temperature. The reaction mixture was stirred at 100°C for 12 hours. After completion, the solvent was concentrated under reduced pressure, followed by addition of water (20 mL) and extraction with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash column chromatography to afford the title compound 28c (100 mg).

[1344] Step 3: Preparation of 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinolin-2(1H)-one (Compound 28)

[1345] At room temperature, a microwave reaction tube was added with 7-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinolin-2(1H)-one 28c (20 mg, 0.05 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (16 mg, 0.075 mmol), N,N-diisopropylethylamine (0.37 uL, 0.2 mmol), and dioxane (3 mL). The tube was placed in a microwave reactor and reacted at 120°C for 1 hour. After completion of the reaction, the solvent was concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to afford the title compound 28 (5 mg, yield, 18.5%).

[1346] 1 H NMR(400MHz,DMSO-d6)δppm 10.15(s,1H),8.57(s,1H),7.46–7.41(m,4H),7.31–7.30(m,1H),7.11–7.09(m,1H),7.03–7.00(m,1H),4. 50(s,1H),4.09–3.94(m,3H),3.59–3.56(m,2H),2.83–2.78(m,4H),2.44–2.40(m,2H),2.30–2.24(m,2H).

[1347] MS m / z(ESI):510[M+1].

[1348] Example 29

[1349] 6-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-methylquinazolin-4(3H)-one (Compound 29)

[1350] Step 1: Preparation of 6-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-methylquinazolin-4(3H)-one (Compound 29a)

[1351] At room temperature, compound 28b (0.1 g, 0.39 mmol) and 6-amino-3-methylquinazolin-4(3H)-one (69 mg, 0.39 mmol) were prepared according to the second step of Example 28 to give the title compound 29a (75 mg).

[1352] Step 2: Preparation of 6-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-methylquinazolin-4(3H)-one (Compound 29)

[1353] Compound 29a (20 mg, 0.051 mmol) and 3-(4-chlorophenoxy)azetidine hydrochloride (17 mg, 0.077 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 29 (14.4 mg, yield, 52.3%).

[1354] 1 H NMR (400MHz, DMSO-d6) δppm 2.32 (m, 2H), 2.86 (t, J = 6.45Hz, 2H), 3.51-3.55 (m, 3H), 3.59-3.66 (m, 2H), 4.06 (br s, 1H), 4.13 (br s, 1H), 4.61 (br s,2H),5.16-5.23(m,1H),6.94-6.98(m,2H),7.37-7.42(m,2H),7.66(d,J=8.79Hz,1 H), 7.88 (dd, J = 8.79, 2.66 Hz, 1H), 8.33 (s, 1H), 8.83 (d, J = 2.56 Hz, 1H), 8.94 (s, 1H).

[1355] MS m / z(ESI):539[M+1].

[1356] Example 30

[1357] 7-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (Compound 30)

[1358] Step 1: Preparation of 7-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (Compound 30b)

[1359] 4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 30a (0.1 g, 0.4 mmol), 7-amino-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (0.054 g, 0.3 mmol) and N,N-diisopropylethylamine (0.16 g, 1.2 mmol) were prepared according to the method of the second step of Example 28 to obtain the title compound 30b (0.12 g).

[1360] Step 2: Preparation of 7-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (Compound 30)

[1361] Compound 30b (25 mg, 0.063 mmol), 3-(4-chlorophenoxy)azetidine hydrochloride (28 mg, 0.13 mmol) and N,N-diisopropylethylamine (25 mg, 0.19 mmol) were prepared according to the method of the third step of Example 28 to give the title compound 30 (25 mg, yield: 75%).

[1362] 1H NMR(400MHz, DMSO-d6)δppm 8.64(s,1H)7.61(s,1H)7.51(dd,J=8.24,2.01Hz,1H)7.37-7.41(m,2H)7.19(d,J=8.33Hz,1H)6.93-6.97(m,2H)5.16(br d,J=3.48Hz,1H)4.51-4.59(m,4H)4.04(br d,J=5.77Hz,2H)3.58-3.63(m,2H)3.51(s,2H)2.98(s,3H)2.83(t,J=6.41Hz,2H)2.30(quin,J=6.25Hz,2H).

[1363] MS m / z(ESI):540[M+1].

[1364] Example 31

[1365] 5-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-1-methylpyridin-2(1H)-one (Compound 31)

[1366] Step 1: Preparation of 5-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-1-methylpyridin-2(1H)-one (Compound 31b)

[1367] 4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 31a (0.2 g, 0.79 mmol), 5-amino-1-methylpyridin-2(1H)-one hydrochloride (0.13 g, 0.79 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.37 mmol) were prepared according to the second step of Example 28 to give the title compound 31b (0.15 g).

[1368] Step 2: Preparation of 5-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-1-methylpyridin-2(1H)-one (Compound 31)

[1369] Compound 31b (20 mg, 0.059 mmol), 3-(4-chlorophenoxy)azetidine hydrochloride (26 mg, 0.12 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 31 (16 mg, yield: 57%).

[1370] 1 H NMR(400MHz,DMSO-d6)δppm 8.25(s,1H),7.98(d,J=2.84Hz,1H),7.57(dd,J=9.66,2.88Hz,1H),7.36-7.40 (m,2H),6.90-6.94(m,2H),6.37(d,J=9.61Hz,1H),5.07-5.13(m,1H),4.48(br s,2H),3.98(br s,2H),3.52-3.58(m,2H),3.43(s,3H),2.80(t,J=6.36Hz,2H),2.24-2.36(m,2H).

[1371] MS m / z(ESI):488[M+1].

[1372] Example 32

[1373] 7-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 32)

[1374] Step 1: Preparation of 7-((2-chloro-5,5-dioxide-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 32b)

[1375] 4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 32a (0.2 g, 0.79 mmol), 7-aminoisoquinolin-1-ol (0.13 g, 0.79 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.37 mmol) were prepared according to the method of the second step of Example 28 to obtain the title compound 32b (0.16 g).

[1376] Step 2: Preparation of 7-((2-(3-(4-chlorophenoxy)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 32)

[1377] Compound 32b (15 mg, 0.040 mmol), 3-(4-chlorophenoxy)azetidine hydrochloride (17 mg, 0.080 mmol) and N,N-diisopropylethylamine (15 mg, 0.12 mmol) were prepared according to the method of the third step of Example 28 to give the title compound 32 (2.6 mg, yield: 12%).

[1378] 1 H NMR(400MHz,DMSO-d6)δppm 11.86(s,1H),8.88(s,1H),7.85-7.90(m,2H),7.64(d,J=8.51Hz,1H),7.39-7.44(m,2H),7.20(dd, J=8.61,2.01Hz,1H),6.94-6.99(m,2H),6.41(dd,J=9.43,1.74Hz,1H),5.15-5.21(m,1H),4.32(br s,1H),4.07(br s,1H),3.60-3.66(m,2H),3.38-3.38(m,1H),2.85(t,J=6.41Hz,2H),2.28-2.34(m,2H).

[1379] MS m / z(ESI):524[M+1].

[1380] Example 33

[1381] 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinazolin-2(1H)-one (Compound 33)

[1382] Step 1: Preparation of 2-(aminomethyl)-5-nitroaniline (Compound 33b)

[1383] 2-Amino-4-nitrobenzonitrile 33a (1 g, 6.13 mmol) and borane-tetrahydrofuran (24.53 mL, 24.53 mmol) were mixed in tetrahydrofuran (30 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 hours. Upon completion, the reaction was quenched with aqueous hydrogen chloride solution, followed by addition of water (200 mL) and extraction with dichloromethane (80 mL x 2). The organic phases were combined and concentrated under reduced pressure to afford the crude product 33b (1.1 g).

[1384] Step 2: Preparation of 7-nitro-3,4-dihydroquinazolin-2(1H)-one (Compound 33c)

[1385] 2-(Aminomethyl)-5-nitroaniline 33b (1 g, 5.99 mmol), N,N'-carbonyldiimidazole (0.96 g, 23.94 mmol), and sodium hydride (1.45 g, 8.98 mmol) were mixed in tetrahydrofuran (30 mL) at 0°C. The reaction mixture was stirred at 80°C for 5 hours. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride. Water (200 mL) was then added and the mixture was extracted with dichloromethane (80 mL x 3). The organic phases were combined and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash column chromatography to afford the title compound 33c (0.3 g).

[1386] Step 3: Preparation of 7-amino-3,4-dihydroquinazolin-2(1H)-one (Compound 33d)

[1387] 7-Nitro-3,4-dihydroquinazolin-2(1H)-one 33c (0.1 g, 0.52 mmol), ammonium chloride (0.083 g, 1.55 mmol), and iron powder (0.058 g, 1.04 mmol) were mixed in methanol (8 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at 90°C for 2 hours. After completion, the solvent was concentrated under reduced pressure. Water (20 mL) was then added and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 33d (0.06 g).

[1388] Step 4: Preparation of 7-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinazolin-2(1H)-one (Compound 33f)

[1389] 4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 33e (0.08 g, 0.32 mmol), 7-amino-3,4-dihydroquinazolin-2(1H)-one (0.04 g, 0.25 mmol) and N,N-diisopropylethylamine (0.13 g, 0.98 mmol) were prepared according to the method of the second step of Example 28 to obtain the title compound 33f (0.06 g).

[1390] Step 5: Preparation of 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3,4-dihydroquinazolin-2(1H)-one (Compound 33)

[1391] Compound 33f (15 mg, 0.040 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (16 mg, 0.080 mmol) and N,N-diisopropylethylamine (15 mg, 0.12 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 33 (9.1 mg, yield: 45%).

[1392] 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),8.59(s,1H),7.43-7.50(m,4H),7.25(d,J=1.92Hz,1H),7.04(d,J=8.24Hz,1H),6.98(dd,J=8.19,1.97 Hz,1H),6.83(s,1H),4.29(s,2H),3.96-4.01(m,1H),3.58-3.63(m,2H),2.83(t,J=6.36Hz,2H),2.27-2.33(m,2H).

[1393] MS m / z(ESI):511[M+1].

[1394] Example 34

[1395] 5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2(1H)-one (Compound 34)

[1396] Step 1: Preparation of 5-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2(1H)-one (Compound 34a)

[1397] Compound 28b (100 mg, 0.4 mmol) and 5-aminopyridin-2(1H)-one (52 mg, 0.48 mmol) were prepared according to the method of the second step of Example 28 to give the title compound 34a (40 mg).

[1398] Step 2: Preparation of 5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2(1H)-one (Compound 34)

[1399] Compound 34a (10 mg, 0.03 mmol) and 3-(4-chlorophenyl)azetidine hydrochloride (16 mg, 0.080 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 34 (9.4 mg, yield, 67.1%).

[1400] 1 H NMR(400MHz,DMSO-d6)δppm 11.37(brs,1H),8.22(s,1H),7.71–7.70(m,1H),7.55–7.52(m,1H),7.43–7.39(m,4H),6.30–6.28(m ,1H),4.39–4.38(m,2H),3.97–3.92(m,3H),3.53–3.50(m,2H),2.79–2.76(m,2H),2.28–2.22(m,2H).

[1401] MS m / z(ESI):458[M+1].

[1402] Example 35

[1403] 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 35)

[1404] Step 1: Preparation of 7-((2-chloro-5,5-dioxide-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 35a)

[1405] At room temperature, compound 28b (0.1 g, 0.39 mmol) and 7-aminoquinolin-2(1H)-one (63 mg, 0.39 mmol) were prepared according to the method of the second step of Example 28 to give the title compound 35a (16 mg).

[1406] Step 2: Preparation of 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinolin-2(1H)-one (Compound 35)

[1407] At room temperature, compound 35a (16 mg, 0.042 mmol) and 3-(4-chlorophenyl)-azetidine hydrochloride (10 mg, 0.05 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 35 (4.2 mg, yield, 19.4%).

[1408] 1 H NMR (400MHz, DMSO-d6) δppm 2.23-2.33(m,2H),2.81(t,J=6.41Hz,2H),3.55-3.63(m,2H),3.93-4.11(m,2H),4.20(br s,1H),4.50(br s,1H),4.60(br s,1H),6.35(dd,J=9.48,1.60Hz,1H),7.17(dd,J=8.47,1.97Hz,1H),7.40-7.4 8(m,4H),7.57(d,J=8.01Hz,1H),7.78-7.89(m,2H),8.84(s,1H),11.78(s,1H).

[1409] MS m / z(ESI):508[M+1].

[1410] Example 36

[1411] 6-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinazolin-4(3H)-one (Compound 36)

[1412] Step 1: Preparation of 6-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinazolin-4(3H)-one (Compound 36a)

[1413] Compound 28b (100 mg, 0.4 mmol) and 6-aminoquinazolin-4(3H)-one (76 mg, 0.48 mmol) were prepared according to the method of the second step of Example 28 to give the title compound 36a (32 mg).

[1414] Step 2: Preparation of 6-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)quinazolin-4(3H)-one (Compound 36)

[1415] Compound 36a (16 mg, 0.04 mmol) was prepared according to the method of the third step of Example 28 to give the title compound 36 (7.3 mg, yield, 33.8%).

[1416] 1 H NMR(400MHz,DMSO-d6)δppm 12.14(s,1H),8.90(s,1H),8.75–8.74(m,1H),8.01–8.00(m,1H),7.89–7.86(m,1H),7.63–7.61(m,1H),7.46–7.41(m,4H),4.52(brs,2H), 4.07–3.98(m,3H),3.61–3.58(m,2H),2.85–2.82(m,2H),2.32–2.26(m,2H).

[1417] MS m / z(ESI):509[M+1].

[1418] Example 37

[1419] 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)isoquinolin-1(2H)-one (Compound 37)

[1420] Step 1: Preparation of 7-((2-chloro-5,5-dioxide-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)isoquinolin-1(2H)-one (Compound 37b)

[1421] 4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 28b (0.2 g, 0.79 mmol), 7-aminoisoquinolin-1-ol (0.13 g, 0.79 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.37 mmol) were prepared according to the second step of Example 28 to give the title compound 37b (0.16 g).

[1422] Step 2: Preparation of 7-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)isoquinolin-1(2H)-one (Compound 37)

[1423] Compound 37b (10 mg, 0.027 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (8 mg, 0.040 mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) were prepared according to the method of the third step of Example 28 to obtain the title compound 37 (2.2 mg, yield: 16%).

[1424] 1 H NMR(400MHz,DMSO-d6)δppm 11.15(d,J=4.85Hz,1H),8.88(s,1H),8.80(d,J=2.29Hz,1H),7.83(d,J=8.73Hz,1H),7.65(d,J=8.61Hz,1H),7.43-7.50(m,4H),7 .11(t,J=6.28Hz,1H),6.54(d,J=6.87Hz,1H),4.00-4.12(m,3H),3.61-3.65(m,2H),2.86(t,J=6.41Hz,2H),2.70(s,1H),2.33(br dd,J=12.68,6.45Hz,2H).

[1425] MS m / z(ESI):508[M+1].

[1426] Example 38

[1427] 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 38)

[1428] Step 1: Preparation of ethyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (Compound 38b)

[1429] Under nitrogen protection, compound 28b (200 mg, 0.79 mmol) and compound 38a (156 mg, 0.79 mmol) were prepared according to the method of the second step of Example 28 to obtain the title compound 38b (180 mg).

[1430] Step 2: Preparation of ethyl 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxido-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (Compound 38d)

[1431] Compound 38c (72 mg, 0.43 mmol) and compound 38b (180 mg, 0.43 mmol) were prepared according to the method of the third step of Example 28 to give the title compound 38d (120 mg).

[1432] Step 3: Preparation of 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxido-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 38)

[1433] At room temperature, compound 38d (60 mg, 0.11 mmol) was prepared according to the fourth step of Example 16 to give the title compound 38 (20 mg, yield 36%).

[1434] 1 H NMR (400MHz, DMSO-d6) δppm 12.44(br s,1H),8.76(s,1H),7.78-7.85(m,1H),7.42-7.51(m,4H),7.27-7.32(m,2H),4.53(br t,J=7.74Hz,2H),3.96-4.11(m,3H),3.56-3.67(m,4H),2.85(t,J=6.45Hz,2H),2.27-2.37(m,2H).

[1435] MS m / z(ESI):517[M+1].

[1436] Example 39

[1437] 2-(4-(((5,5-Dioxy-2-(3-phenylazetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 39)

[1438] Step 1: Preparation of ethyl 2-(4-(((5,5-dioxido-2-(3-phenylazetidin-1-yl)-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (Compound 39b)

[1439] Compound 38b (50 mg, 0.12 mmol) and compound 39a (16 mg, 0.12 mmol) were prepared according to the method of the third step of Example 28 to give the title compound 39b (40 mg).

[1440] Step 2: Preparation of 2-(4-(((5,5-dioxy-2-(3-phenylazetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 39)

[1441] At room temperature, compound 39b (40 mg, 0.08 mmol) was prepared according to the method of step 4 of Example 16 to give the title compound 39 (20 mg, yield 52%).

[1442] 1 H NMR (400MHz, DMSO-d6) δppm 12.48 (br s, 1H), 8.80 (s, 1H), 7.86 (d, J = 12.91Hz, 1H), 7.41-7.52 (m, 4H), 7.31-7.37 (m, 3H), 4.59 (br t,J=8.51Hz,2H),4.01-4.18(m,3H),3.61-3.69(m,4H),2.90(t,J=6.36Hz,2H),2.32-2.41(m,2H).

[1443] MS m / z(ESI):483[M+1].

[1444] Example 40

[1445] (R)-2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 40)

[1446] Step 1: Preparation of tert-butyl (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)(methyl)carbamate (Compound 40c)

[1447] Compound 40a (500 mg, 2.34 mmol), compound 40b (343 mg, 2.34 mmol), and potassium carbonate (414 mg, 3.0 mmol) were mixed in DMF (10 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 40c (800 mg).

[1448] Step 2: Preparation of 1-(5-chloropyrimidin-2-yl)-N-methylpiperidin-4-amine (Compound 40d)

[1449] To a solution of compound 40c (800 mg, 2.45 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then concentrated to dryness to give the title compound 40d (700 mg).

[1450] Step 3: Preparation of (R)-2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-4-(((1r,4R)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 40)

[1451] Compound 40d (36 mg, 0.16 mmol) and compound 7b (50 mg, 0.13 mmol) were prepared according to the method of step 4 of Example 10 to obtain the title compound 40 (11 mg, yield 13%).

[1452] 1 H NMR (400MHz, DMSO-d6) δppm 8.44(s,2H),7.42(br s,1H),4.80(br s,2H),4.55(d,J=4.39Hz,1H),3.93(br s,1H),3.39-3.48(m,2H),3.18-3.26(m,1H),2.84-3.05(m,8H),1.82-1.92(m,4H),1.68-1.74(m,4H),1.31-1.51(m,4H).

[1453] MS m / z(ESI):492[M+1].

[1454] Example 41

[1455] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 41)

[1456] Step 1: Preparation of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 41)

[1457] To a solution of compound 1c (50 mg, 0.17 mmol) and compound 10e (92.63 mg, 0.26 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (67.74 mg, 0.52 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 41 (20 mg, yield: 22.72%).

[1458] 1 H NMR (400MHz, DMSO-d6) δppm 8.07 (1H, s), 7.50 (1H, s), 7.29 (1H, d, J = 1.83Hz), 4.71 (2H, br s), 4.55 (1H, br d, J = 12.82Hz), 4.46 (1H, br d,J=8.61Hz),4.04(1H,dd,J=11.12,8.29Hz),3.72(2H,s),3.38-3.59(3H,m),3.18-3.27(1H,m) ,3.02-3.09(1H,m),2.78-2.99(4H,m),2.17-2.40(4H,m),1.72-1.85(2H,m),1.21-1.34(1H,m).

[1459] MS m / z(ESI):511.54[M+1].

[1460] Example 42

[1461] 2-(4-(((5,5-dioxy-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 42)

[1462] Step 1: Preparation of ethyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 42c)

[1463] At room temperature, 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 42a (0.50 g, 2.26 mmol), ethyl 2-(4-aminophenyl)acetate 42b (0.45 g, 2.49 mmol), and diisopropylethylamine (0.88 g, 6.78 mmol) were mixed in ethanol (8 mL). The reaction mixture was stirred at 90°C for 5 hours. After completion, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title compound 42c (0.62 g).

[1464] Step 2: Preparation of ethyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 42d)

[1465] Ethyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 42c (620.00 mg, 1.70 mmol) and m-CPBA (1.18 g, 6.82 mmol) were dissolved in DCM (8 mL), and the mixture was warmed to 35° C. and stirred for 5 hours. The reaction mixture was poured into an aqueous solution of NaSO and NaHCO and extracted with EA (50 mL). The organic phase was concentrated and purified by silica gel column (DCM:MeOH=10:1) to give the title compound 42d (0.55 g) as a yellow solid.

[1466] Step 3: Preparation of ethyl 2-(4-(((5,5-dioxy-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 42e)

[1467] To a solution of compound 42d (50 mg, 0.13 mmol) and compound 11f (45.70 mg, 0.19 mmol) in 1,4-dioxane (3 mL) was added diisopropylethylamine (48.97 mg, 0.38 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title compound 42e (50 mg, yield: 66.7%).

[1468] Step 4: Preparation of 2-(4-(((5,5-dioxy-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 42)

[1469] To a mixture of ethyl 2-(4-(((5,5-dioxy-2-(3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 42e (50.00 mg, 0.083 mmol) in THF (2 mL) were added LiOH-H2O (13.97 mg, 0.332 mmol) and H2O (1 mL), and the mixture was stirred at 50°C for 2 hours. After the reaction, the reaction solvent was dried, 5 mL of water was added, and the mixture was extracted with EA (20 mL). The combined organic phases were concentrated and evaporated to dryness, and then purified by silica gel column chromatography to give the title compound 42 (8 mg, 16.78%).

[1470] 1 H NMR (400MHz, DMSO-d6) δppm 8.64(1H,s),8.55(1H,s),8.35(1H,s),7.54(2H,d,J=8.42Hz),7.32(2H,br d,J=8.24Hz),6.60(1H,s),5.18(2H,br s),4.34(2H,br s),4.26(2H,br s),3.61-3.56(6H,m),2.86(2H,br t,J=6.32Hz),2.35-2.25(2H,m).

[1471] MS m / z(ESI):573[M+1].

[1472] Example 43

[1473] (R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 43)

[1474] Step 1: Preparation of (S)-tert-butyl 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (Compound 43c)

[1475] Compounds 43a (1.0 g, 4.6 mmol) and 43b (0.84 g, 4.6 mmol) were prepared according to the first step of Example 10 to give the title compound 43c (430 mg).

[1476] Step 2: Preparation of tert-butyl (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate (Compound 43d)

[1477] Compound 43c (430 mg) was prepared according t...

Claims

1. A compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts: in: Z is selected from S, O, S(=O)(=NR z ), SO and SO2; R 1 Selected from hydrogen and C 1-6 alkyl; R 2 Selected from hydrogen, deuterium, R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl and C 1-6 Alkoxy, or R 2.2 and R 2.3 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl; R 2.1 Selected from hydroxyl, -O-(CH2) t -OR a and Het; Het is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl; The Het is optionally replaced by one or more selected from R Het The group substituted, said R Het Selected from halogen, oxo, hydroxy, amino, C 3-8 Cycloalkyl, C 1-6 Alkoxy, cycloalkyl-C 1-6 Alkylhydroxyl, heterocyclic, heteroaryl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b and optionally one or more selected from hydroxy, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl substituted C 1-6 Alkyl, the heteroaryl is optionally substituted by one or more C 1-6 Haloalkyl substitution; R a Selected from hydrogen and C 1-6 alkyl; Each time it appears, R 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, amino, at least one C 1-6 Alkyl-substituted amino; or R 2.4 and R 2.5 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl; R z Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkyl hydroxyl; R 2a and R 2b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen and amino, or R 2a and R 2b are linked together via S to form a 4-8 membered heterocyclic group; R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino; wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and hydroxy; L is selected from a direct bond and -N(R a )R b -; R b Selected from -(CH2) t -; Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl; R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylhydroxyl, CN and -(CH2) t -CN; R 3 Selected from -MR 3.1 ; M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -、-NR a -CO-O- and -N=S(O)R 3a -; R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, wherein R 3.1 Optionally, one or more selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl group is substituted by a substituent; R 3a Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, cycloalkyl, halogen and amino; or R 3a With R 3.1 and the S connected to it via -(CH2) t - are linked together to form a 4-8 membered heterocyclic group; or -N=S(O)R 3a -S and R in 4 Via -(CH2) t - are linked together to form a 4-8 membered heterocyclic group; t is 0, 1, 2, or 3; s is 1, 2, or 3; k is 1, 2, 3 or 4; n is an integer from 0 to 10.

2. The compound of formula I according to claim 1 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that Z is selected from S, O, SO and SO2; preferably SO and SO2.

3. The compound of formula I according to claim 1 or 2, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 6 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino; preferably selected from hydrogen, deuterium, hydroxyl, halogen and amino; more preferably selected from hydrogen, deuterium and halogen; most preferably selected from hydrogen.

4. The compound of formula I according to any one of claims 1 to 3 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 7 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino; preferably selected from hydrogen, deuterium, hydroxyl, halogen and amino; more preferably selected from hydrogen, deuterium and halogen; most preferably selected from hydrogen.

5. The compound of formula I according to any one of claims 1 to 4 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 8 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino; preferably selected from hydrogen, deuterium, hydroxyl, halogen and amino; more preferably selected from hydrogen, deuterium and halogen; most preferably selected from hydrogen.

6. The compound of formula I according to any one of claims 1 to 5 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 9 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen and amino; preferably selected from hydrogen, deuterium, hydroxyl, halogen and amino; more preferably selected from hydrogen, deuterium and halogen; most preferably selected from hydrogen.

7. A compound of formula I according to any one of claims 1 to 6 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (II): in, Ring A, L, R 1 , R 2 , R 3 , R 4 and n is as defined in any one of claims 1-6.

8. A compound of the general formula I according to any one of claims 1 to 7 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (III): in, Ring A, R 1 , R 2 , R 3 , R 4 and n is as defined in any one of claims 1-7.

9. The compound of general formula I according to any one of claims 1 to 7 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having a structure of formula (IV): in, Ring A, R 1 , R 2 , R 3 , R 4 , R a , R b and n is as defined in any one of claims 1-7.

10. The compound of formula I according to any one of claims 1 to 9 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the ring A is selected from C 6-10 Aryl, 5-14 membered heteroaryl and 3-20 membered heterocyclic group; preferably selected from C 6-10 Aryl, 5-12 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-12 membered benzoheterocycle, 10-20 membered spiro, bridged or fused tricyclic, wherein, The 10-20 membered spiro, bridged or fused tricyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; more preferably selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, adamantyl, azetidinyl, norbornyl, benzisothiazolyl, benzothiazolyl, benzothienyl, pyridin-2(1H)onyl, Most preferably, it is selected from phenyl, pyridyl, piperazinyl, thienyl, piperidinyl, azetidinyl, pyridin-2(1H)onyl, 11. The compound of formula I according to claim 8 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (III-1): in, X1, X2, X3 and X4 are each independently selected from N or CR 4 ; R 1 , R 2 , R 3 and R 4 As defined in claim 8.

12. The compound of general formula I according to claim 11 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, characterized in that it has a compound with the structure of formula (III-1-1) or (III-1-2): in, R 1 , R 2 , R 3.1 , R 4 And M as defined in claim 11.

13. The compound of formula I according to claim 8 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (III-2): in, R 1 , R 2 , R 3.1 , R 4 And M as defined in claim 8.

14. The compound of general formula I according to claim 9 or 10, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having the structure of formula (IV-1): in, m is 0, 1 or 2; Ring A, R 1 , R 2 , R 3 , R 4 , R a and n is as defined in claim 9 or 10.

15. The compound of general formula I according to claim 14 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having the structure of formula (IV-1-1): in, Y1 and Y2 are each independently selected from N, CR 10 ; R 10 Selected from absent, hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, C 1-6 haloalkyl, halogen and amino; or R 10 With -(CH2) m - connected to form a 3-5 membered spiro ring; R 1 , R 2 , R 4 , M, R 3.1 , R a , n and m are as defined in claim 14.

16. A compound of formula I according to any one of claims 1 to 6 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (V): in, Ring A, R 1 , R 2 , R 3 , R 4 and n is as defined in any one of claims 1-6.

17. The compound of formula I according to claim 16 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (V-1): in, R 1 , R 2 , R 3 , R 4 and n as defined in claim 16; Ring A is selected from 5-12 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S and 4-10 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably 4-10 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; more preferably 4-10 membered heterocyclic groups containing 1 or 2 heteroatoms independently selected from N or O heteroatom; most preferably selected from azetidinyl.

18. The compound of formula I according to claim 17 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (V-1-1): in, R 1 , R 2 , M, R 3.1 and R 4 As defined in claim 17.

19. A compound of formula I according to any one of claims 1 to 6 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (VI): in, Q is -(CR 5c R 5d ) u -, u is 1, 2, or 3; R 5c and R 5d are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino; preferably selected from hydrogen, deuterium, halogen and amino; more preferably selected from hydrogen; Ring B is selected from 4-8 membered heterocyclyl and 5-7 membered heteroaryl, wherein the 4-8 membered cycloalkyl and 5-7 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably 5-7 membered heterocyclyl and 5-7 membered heteroaryl, wherein the 5-7 membered cycloalkyl and 5-7 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or O; Ring B is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino substituents; Ring C is selected from 5-7 membered heteroaryl, wherein the 5-7 membered heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1 or 2 heteroatoms independently selected from N or O; most preferably selected from pyridinyl; R 1 , R 2 and R 3 As defined in any one of claims 1 to 6.

20. The compound of formula I according to claim 19 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula (VI-1): in, Ring B, Ring C, R 1 , R 2 and R 3 As defined in claim 19.

21. A compound of formula I according to any one of claims 1 to 6 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a structure of formula (VII): in, Ring D is selected from 4-6 membered heterocyclyl and 4-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl and 4-6 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably selected from 4-5 membered heterocyclyl and 4-5 membered heteroaryl, wherein the 4-5 membered cyclyl and 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S; Ring D is optionally substituted with one or more selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl, halogen and amino substituents; Ring E is selected from 4-6 membered heterocyclyl and 4-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl and 4-6 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably selected from 4-5 membered heterocyclyl and 4-5 membered heteroaryl, wherein the 4-5 membered cycloalkyl and 4-5 membered heteroaryl contain 1 or 2 heteroatoms independently selected from N or S; R 1 , R 2 and R 3 As defined in any one of claims 1 to 6.

22. The compound of the general formula I according to claim 21 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, characterized in that the compound has the structure of formula (VII-1), (VII-2), (VII-3) or (VII-4): in, Ring D, Ring E, R 1 , R 2 and R 3 As defined in claim 21.

23. A compound of formula I according to any one of claims 1 to 6 or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula (VIII): in, Ring F is selected from C 6-10 Aryl and 4-6 membered heteroaryl, the 4-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably phenyl and 4-5 membered heteroaryl, the 4-5 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S; more preferably phenyl, oxazolyl, thiazolyl, thienyl; R 1 , R 2 and R 3 As defined in any one of claims 1 to 6.

24. The compound of formula I according to any one of claims 1 to 24, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that M is selected from a direct bond, -O-, C 1-6 Alkylene, -NR a -、-NR a -CO-, -N=S(O)R 3a , -CO-, -COO- and -CO-NH-; preferably selected from direct bonds, -NH-, -N(CH3)-, -NH-CO-, -N(CH3)-CO-, -N=S(O)R 3a , -O- and C 1-4 Alkylene; more preferably selected from direct bond, -N=S(O)R 3a , -O- and -CH2-.

25. The compound of formula I according to any one of claims 1 to 24, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably selected from H, C 1-3 Alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; more preferably selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl; most preferably selected from H, methyl, trifluoromethyl, phenyl, piperidyl, piperazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole and pyrazolonyl; The R 3.1 Optionally, one or more selected from oxo, C 1-6 Alkyl, halogen, C 1-6 Preferably, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl; More preferably, said R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, chloro and trifluoromethyl.

26. The compound of formula I according to any one of claims 1 to 18, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 4 Each occurrence is independently selected from hydrogen, oxo, C 1-6 Alkyl, halogen and -(CH2) t -CN; preferably selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN; more preferably selected from hydrogen, oxo, methyl, fluorine and -(CH2)-CN.

27. The compound of formula I according to any one of claims 1 to 26, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 1 Selected from hydrogen and C 1-3 Alkyl; preferably selected from hydrogen and methyl; more preferably selected from hydrogen.

28. The compound of formula I according to any one of claims 1 to 27, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 ; At each occurrence, the R 2.2 and R 2.3 are each independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkyl hydroxyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

29. The compound of formula I according to any one of claims 1 to 27, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 2 Selected from R 2.1 and-(CR 2.2 R 2.3 ) k -R 2.1 , at each occurrence, the R 2.2 and R 2.3 Together with the carbon atom to which they are commonly attached, they form a cyclopropane or cyclobutane group which is optionally substituted by fluorine.

30. The compound of formula I according to any one of claims 1 to 28, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the Het is selected from C 3-6 Cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; preferably selected from C 4-6 Cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; more preferably cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyrimidinyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, morpholinyl, azetidinyl, tetrahydrothiopyranyl and benzoheterocyclyl, wherein the heterocyclic ring in the benzoheterocyclyl is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S; most preferably selected from cyclobutyl, cyclohexyl, cyclopentyl, piperidinyl, tetrahydrofuran, tetrahydropyranyl, pyridinyl, dihydropyridinyl, phenyl, thiazolyl, pyrazolyl, morpholinyl, tetrahydrothiopyranyl and benzoheterocyclyl, wherein the heterocyclic ring in the benzoheterocyclyl is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S; wherein Het is optionally replaced by one or more selected from R Het The group is substituted.

31. The compound of formula I according to claim 30 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the Het is selected from in, v is 0, 1, or 2.

32. The compound of formula I according to any one of claims 1 to 31 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Alkyl hydroxyl, -(CR 2.4 R 2.5 ) t -OR a 、-(CR 2.4 R 2.5 ) t -COOR a 、-O-(CR 2.4 R 2.5 ) t -COOR a 、-N=S(O)R 2a R 2b ; preferably selected from fluorine, chlorine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl alcohol, -(CH2) t -COOR a 、-(CH2)-(CR 2.4 R 2.5 )-OR a 、-(CH2)-(CR 2.4 R 2.5 )-COOR a 、-(CR 2.4 R 2.5 )-COOR a and -O-(CH2)-COOR a ; preferably selected from fluorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, hydroxymethyl, -(CH2) t -COOR a 、-(CH2)-C(CH3)2-OR a 、-(CH(CH3))-COOR a 、-(C(CH3)2)-COOR a and -O-(CH2)-COOR a .

33. The compound of formula I according to any one of claims 1 to 32, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R a Selected from hydrogen and C 1-3 Alkyl; preferably selected from hydrogen.

34. A compound of formula I according to any one of claims 1 to 33 or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative or pharmaceutically acceptable salt thereof, characterized in that t is 0, 1, or 2; s is 1 or 2.

35. A compound of formula I according to any one of claims 1 to 33 or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative or pharmaceutically acceptable salt thereof, characterized in that n is an integer of 0 to 5.

36. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

37. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 37 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

39. Use of the compound represented by general formula (I) according to any one of claims 1 to 37 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the pharmaceutical composition according to claim 38 in the preparation of a medicament for inhibiting PDEs enzymes, preferably in the preparation of a medicament for inhibiting PDE4 enzymes, and more preferably in the preparation of a medicament for inhibiting PDE4B enzymes.

40. Use of a compound of formula (I) according to any one of claims 1 to 37 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or a pharmaceutical composition according to claim 38 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDEs enzymes, preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4 enzymes, more preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4B enzymes.

41. The use according to claim 40, wherein the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer and peripheral or central nervous system diseases.

42. Use according to claim 41, wherein the respiratory and lung diseases are selected from respiratory and lung diseases accompanied by increased mucus production, obstructive lung diseases and airway diseases, preferably selected from COPD, asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension.

43. The use according to claim 41, wherein the gastrointestinal disease is selected from Crohn's disease, ulcerative colitis and Crohn's disease.

44. The use according to claim 41, wherein the inflammatory disease is selected from the group consisting of proliferative and inflammatory skin diseases, arthritic diseases and inflammatory diseases of the eye; wherein the inflammatory skin disease is preferably selected from the group consisting of atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, skin photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, eczematous hand dermatitis and psoriasis; the arthritic disease is preferably selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis; the inflammatory disease of the eye is preferably glaucoma or dry eye syndrome.

45. The method of claim 41, wherein the peripheral or central nervous system disease is selected from Alzheimer's disease, age-related memory impairment (AAMI), age-related cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, depression, schizophrenia, stroke, neurological disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumors, stroke, cognitive impairment caused by lack of sleep, intellectual and developmental disabilities and multiple sclerosis.

46. ​​The method of claim 41, wherein the cancer is selected from the group consisting of leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor and myeloma.

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