Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

Abstract

The present invention relates to a compound represented by general formula I, or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof, which has high inhibitory activity and excellent selectivity on phosphodiesterase (PDEs), particularly on PDE4, and can be used in the preparation of a pharmaceutical composition. Meanwhile, the medicine effect, the solubility, the in-vitro / in-vivo pharmacokinetic property and the safety are excellent, and the clinical application prospect is high.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to a nitrogen-containing heterocyclic compound, its preparation method, and its use as an inhibitor of phosphodiesterases (PDEs). Background Technology

[0002] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading intracellular cAMP or cGMP and thus terminating the biochemical processes mediated by these second messengers. cAMP and cGMP play crucial regulatory roles in cellular activity, and their concentrations are primarily determined by the balance between the synthesis of adenylate cyclases and the hydrolytic activity of phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological functions are studied in multiple fields.

[0003] Of the 11 phosphodiesterases currently identified, PDE4, PDE7, and PDE8 are cAMP-selective. The PDE4 family comprises 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). These four subtypes are differentially expressed in different tissues and cell types. For example, PDE4B is mainly expressed in monocytes and neutrophils, but not in cortical and epithelial cells, while PDE4D is expressed in lung, 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 PDE4 enzyme that hydrolyzes cAMP, and the substrate of cAMP is expressed as K. mThe concentration is 1-5 μM. PDE4 is the most important regulator of cAMP expressed by immune cells and inflammatory cells such as neutrophils, macrophages, and T-lymphocytes. Since cAMP is a key second messenger in regulating the inflammatory response, PDE4 has been found to regulate the inflammatory response of inflammatory cells by modulating pro-inflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF, and LTB4. Therefore, inhibiting PDE4 has become an attractive target for the treatment of inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, and inflammatory bowel diseases such as Crohn's disease (MDHouslay et al., Drug Discovery Today, 2005, 10(22), 1503-1519). Since PDE activity is elevated in patients with atopic dermatitis (AD), inhibiting PDE4 also appears to be a feasible treatment for AD (Journal of Investigative Dermatology, 1986, 87(3), 372-376). However, clinical studies of marketed PDE4 inhibitors have revealed a high incidence of gastrointestinal adverse reactions such as nausea and vomiting in most drugs, limiting their clinical application. These adverse reactions are believed to be caused by inhibition of the PDE4D subtype. Therefore, there is an urgent need to develop highly selective PDE4B inhibitors with good activity, high safety, few side effects, and superior pharmacokinetic properties.

[0004] The disclosed related patent applications include WO2009053268A1, WO2009050242A2, WO2009050236A1, CN101827852B, CN101163706A, CN101426505A, CN102875556B, CN103497201A, CN103889970B, WO2023241683A1, WO2023241684A1, WO2023232135A1, WO2024032673A1, and CN108299400B, etc. Summary of the Invention

[0005] This disclosure provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] Z is selected from S, O, S (=O) (=NR) z ), SO and SO2;

[0009] R 1and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0010] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0011] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, -COR a -COOR a -CO-NR a R c -NR a -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0012] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0013] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6Alkoxy, cycloalkyl-(hydroxy-C1-6 alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6 Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0014] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0015] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0016] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0017] R 6 R 7 R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, halogen, and amino; wherein the C 1-6 The alkyl group is optionally replaced by one or more substituents selected from halogens and hydroxyl groups;

[0018] L is selected from direct bonds and -N(R) a )-R b -;

[0019] R b Selected from -(CH2) t -;

[0020] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0021] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0022] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0023] R 3 Selected from -MR 3.1 ;

[0024] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0025] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1 Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0026] t can be 0, 1, 2, or 3;

[0027] s is 1, 2, or 3;

[0028] k is 1, 2, 3 or 4;

[0029] n is an integer between 0 and 9.

[0030] The effects of the invention

[0031] The nitrogen-containing heterocyclic compounds disclosed herein exhibit high inhibitory activity and excellent selectivity against PDE4B, while also possessing superior efficacy, solubility, in vitro / in vivo pharmacokinetic properties, and safety, showing great promise for clinical application. Detailed Implementation

[0032] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below 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 pertains.

[0033] This disclosure provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof:

[0034]

[0035] in:

[0036] Z is selected from S, O, S (=O) (=NR) z ), SO and SO2;

[0037] R 1 and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0038] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0039] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, -COR a -COOR a -CO-NR a R c -NR a -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0040] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0041] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl-(hydroxy-C) 1-6 Alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0042] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0043] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0044] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0045] R 6 R 7 R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, halogen, and amino; wherein the C 1-6 The alkyl group is optionally replaced by one or more substituents selected from halogens and hydroxyl groups;

[0046] L is selected from direct bonds and -N(R) a )-R b -;

[0047] R b Selected from -(CH2) t -;

[0048] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0049] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0050] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0051] R 3 Selected from -MR 3.1 ;

[0052] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0053] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1 Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0054] t can be 0, 1, 2, or 3;

[0055] s is 1, 2, or 3;

[0056] k is 1, 2, 3 or 4;

[0057] n is an integer between 0 and 9.

[0058] In some implementations, Z is selected from S, O, SO and SO2.

[0059] In some implementations, Z is selected from SO.

[0060] In some implementations, the R 6Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen, and amino.

[0061] In some implementations, the R 6 Selected from hydrogen, deuterium, hydroxyl, halogen and amino.

[0062] In some implementations, the R 6 Selected from hydrogen, deuterium, and halogens.

[0063] In some implementations, the R 6 Selected from hydrogen.

[0064] In some implementations, the R 7 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen, and amino.

[0065] In some implementations, the R 7 Selected from hydrogen, deuterium, hydroxyl, halogen and amino.

[0066] In some implementations, the R 7 Selected from hydrogen, deuterium, and halogens.

[0067] In some implementations, the R 7 Selected from hydrogen.

[0068] In some implementations, the R 8 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen, and amino.

[0069] In some implementations, the R 8 Selected from hydrogen, deuterium, hydroxyl, halogen and amino.

[0070] In some implementations, the R 8 Selected from hydrogen, deuterium, and halogens.

[0071] In some implementations, the R 8 Selected from hydrogen.

[0072] In some implementations, the R 9 Selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, halogen, and amino.

[0073] In some implementations, the R 9 Selected from hydrogen, deuterium, hydroxyl, halogen and amino.

[0074] In some implementations, the R 9 Selected from hydrogen, deuterium, and halogens.

[0075] In some implementations, the R 9Selected from hydrogen.

[0076] In some implementations, the R 1 Selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 .

[0077] In some implementations, the R occurs each time it appears. 2.1 Each is independently selected from halogens, hydroxyl groups, and hydroxyl-C. 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0078] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0079] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H and methyl.

[0080] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Together with the carbon atoms they are linked to, they form cyclopropane or cyclobutane, which may be optionally substituted with fluorine or hydroxyl groups.

[0081] In some implementations, the R 1 Selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyisobutyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetyl, and other compounds.

[0082] In some implementations, the R 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 .

[0083] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3Halogenated alkyl groups and C 1-3 Alkyl group.

[0084] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each of them is independently selected from H.

[0085] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, they form unsubstituted or substituted 4-8 membered heterocyclic groups.

[0086] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, which are either substituted or substituted.

[0087] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N or O, which are either substituted or replaced.

[0088] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms substituted or substituted piperidinyl, morpholino, and tetrahydropyrroleyl groups.

[0089] In some implementations, the R 2.1 Selected from halogens, hydroxyl groups, C 1-3 Alkyl groups and Het.

[0090] In some implementations, the Het is selected from C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0091] In some implementations, the Het is selected from C 3-5 cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0092] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, pyrrole, pyrazolyl, triazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.

[0093] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, thiophene, thiazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl.

[0094] In some implementations, the Het is optionally selected from one or more R... Het The group is substituted.

[0095] In some implementations, the Het is selected from... Where v is 0, 1 or 2.

[0096] In some implementations, the R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -(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 and -S(O)2-R a .

[0097] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, and -(CH2). t -COOR a and -S(O)2-R a .

[0098] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, -COOR a and -S(O)2-R a .

[0099] In some implementations, the R a Selected from hydrogen, amino and C 1-3 alkyl.

[0100] In some implementations, the R a Selected from hydrogen, amino, and methyl.

[0101] In some embodiments, ring A is selected from C. 6-10 Aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclic.

[0102] In some embodiments, ring A is selected from C. 6-10 The aryl group, a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 4-8 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or a 5-12 membered spooled, bridged or fused ring, wherein the 4-8 membered monoheterocyclic group or the 5-12 membered spooled, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0103] In some embodiments, ring A is selected from phenyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrroloyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrroloalkyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0104] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and so on.

[0105] In some implementations, M is selected from direct bond, -O-, C. 1-6 Alkylene, -NR a -、-NR a -CO-, -CO-, -COO- and -CO-NH-.

[0106] In some embodiments, M is selected from direct bonds, -NH-, -NH-CO-, -N(CH3)-CO-, -O-, and C. 1-4 Alkylene.

[0107] In some implementations, M is selected from direct bonds, -O-, and -CH2-.

[0108] In some implementations, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0109] In some implementations, the R 3.1 Selected from H, C 1-3Alkyl, C 1-3 Halogenated alkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0110] In some implementations, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridinyl, pyridinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacyclobutane, pyrazolone, and tetrahydrofuranyl.

[0111] In some implementations, the R 3.1 It is selected from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl.

[0112] In some implementations, the R 3.1 Optionally, it is selected from one or more oxygen, C 1-6 Alkyl, halogen, C 1-6 The alkyl halogroup is substituted by a substituent.

[0113] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0114] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, and chlorine.

[0115] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, and C. 1-6 Alkyl groups, halogens, and -(CH2) t -CN.

[0116] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN.

[0117] In some implementations, the R 4 Each occurrence is independently selected from hydrogen and fluorine.

[0118] In some implementations, t is 0, 1, or 2.

[0119] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0120] This disclosure provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative thereof, and a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula (II):

[0121]

[0122] in:

[0123] R 1 and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0124] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0125] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, -COR a -COOR a -CO-NR a R c -NR a -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0126] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0127] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl-(hydroxy-C) 1-6 Alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6 Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0128] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0129] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0130] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0131] L is selected from direct bonds and -N(R) a )-R b -;

[0132] R b Selected from -(CH2) t -;

[0133] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0134] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0135] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0136] R 3 Selected from -MR 3.1 ;

[0137] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0138] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1 Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0139] t can be 0, 1, 2, or 3;

[0140] k is 1, 2, 3 or 4;

[0141] n is an integer between 0 and 9.

[0142] In some implementations, the R 1 Selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 .

[0143] In some implementations, the R occurs each time it appears. 2.1 Each is independently selected from halogens, hydroxyl groups, and hydroxyl-C. 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0144] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0145] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H and methyl.

[0146] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Together with the carbon atoms they are linked to, they form cyclopropane or cyclobutane, which may be optionally substituted with fluorine or hydroxyl groups.

[0147] In some implementations, the R 1 Selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyisobutyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetyl, and other compounds.

[0148] In some implementations, the R 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 .

[0149] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0150] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each of them is independently selected from H.

[0151] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, they form unsubstituted or substituted 4-8 membered heterocyclic groups.

[0152] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, which are either substituted or substituted.

[0153] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N or O, which are either substituted or replaced.

[0154] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms substituted or substituted piperidinyl, morpholino, and tetrahydropyrroleyl groups.

[0155] In some implementations, the R 2.1 Selected from halogens, hydroxyl groups, and hydroxyl-C 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0156] In some implementations, the Het is selected from C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0157] In some implementations, the Het is selected from C 3-5 cycloalkyl, C6-10 Aryl, 4-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0158] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, pyrrole, pyrazolyl, triazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.

[0159] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, thiophene, thiazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl.

[0160] In some implementations, the Het is optionally selected from one or more R... Het The group is substituted.

[0161] In some implementations, the Het is selected from... Where v is 0, 1 or 2.

[0162] In some implementations, the R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -(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 and -S(O)2-R a .

[0163] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, and -(CH2). t -COOR a and -S(O)2-R a .

[0164] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, -COOR a and -S(O)2-R a .

[0165] In some implementations, the R a Selected from hydrogen, amino and C 1-3 alkyl.

[0166] In some implementations, the R a Selected from hydrogen, amino, and methyl.

[0167] In some embodiments, ring A is selected from C. 6-10 Aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclic.

[0168] In some embodiments, ring A is selected from C. 6-10 The aryl group, a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 4-8 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or a 5-12 membered spooled, bridged or fused ring, wherein the 4-8 membered monoheterocyclic group or the 5-12 membered spooled, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0169] In some embodiments, ring A is selected from phenyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrroloyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrroloalkyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0170] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and so on.

[0171] In some implementations, M is selected from direct bond, -O-, C. 1-6 Alkylene, -NR a -、-NR a -CO-, -CO-, -COO- and -CO-NH-.

[0172] In some embodiments, M is selected from direct bonds, -NH-, -NH-CO-, -N(CH3)-CO-, -O-, and C. 1-4 Alkylene.

[0173] In some implementations, M is selected from direct bonds, -O-, and -CH2-.

[0174] In some implementations, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10Aryl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0175] In some implementations, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0176] In some implementations, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridinyl, pyridinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacyclobutane, pyrazolone, and tetrahydrofuranyl.

[0177] In some implementations, the R 3.1 It is selected from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl.

[0178] In some implementations, the R 3.1 Optionally, it is selected from one or more oxygen, C 1-6 Alkyl, halogen, C 1-6 The alkyl halogroup is substituted by a substituent.

[0179] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0180] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, and chlorine.

[0181] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, and C. 1-6 Alkyl groups, halogens, and -(CH2) t -CN.

[0182] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN.

[0183] In some implementations, the R 4 Each occurrence is independently selected from hydrogen and fluorine.

[0184] In some implementations, t is 0, 1, or 2.

[0185] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0186] This disclosure provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative thereof, and a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula (III):

[0187]

[0188] in:

[0189] R 1 and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0190] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0191] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, -COR a -COOR a -CO-NR a Rc -NR a -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0192] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0193] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl-(hydroxy-C) 1-6 Alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6 Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0194] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0195] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C3-6 cycloalkyl;

[0196] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0197] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0198] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0199] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0200] R 3 Selected from -MR 3.1 ;

[0201] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0202] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1 Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0203] t can be 0, 1, 2, or 3;

[0204] k is 1, 2, 3 or 4;

[0205] n is an integer between 0 and 9.

[0206] In some implementations, the R 1 Selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 .

[0207] In some implementations, the R occurs each time it appears. 2.1 Each is independently selected from halogens, hydroxyl groups, and hydroxyl-C. 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0208] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0209] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H and methyl.

[0210] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Together with the carbon atoms they are linked to, they form cyclopropane or cyclobutane, which may be optionally substituted with fluorine or hydroxyl groups.

[0211] In some implementations, the R 1 Selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyisobutyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetyl, and other compounds.

[0212] In some implementations, the R 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 .

[0213] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0214] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each of them is independently selected from H.

[0215] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, they form unsubstituted or substituted 4-8 membered heterocyclic groups.

[0216] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, which are either substituted or substituted.

[0217] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N or O, which are either substituted or replaced.

[0218] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms substituted or substituted piperidinyl, morpholino, and tetrahydropyrroleyl groups.

[0219] In some implementations, the R 2.1 Selected from halogens, hydroxyl groups, C 1-3 Alkyl groups and Het.

[0220] In some implementations, the Het is selected from C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0221] In some implementations, the Het is selected from C 3-5 cycloalkyl, C 6-10Aryl, 4-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0222] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, pyrrole, pyrazolyl, triazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.

[0223] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, thiophene, thiazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl.

[0224] In some implementations, the Het is optionally selected from one or more R... Het The group is substituted.

[0225] In some implementations, the Het is selected from... Where v is 0, 1 or 2.

[0226] In some implementations, the R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -(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 and -S(O)2-R a .

[0227] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, and -(CH2). t -COOR a and -S(O)2-R a .

[0228] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, -COOR a and -S(O)2-R a .

[0229] In some implementations, the Ra Selected from hydrogen, amino and C 1-3 alkyl.

[0230] In some implementations, the R a Selected from hydrogen, amino, and methyl.

[0231] In some embodiments, ring A is selected from C. 6-10 Aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclic.

[0232] In some embodiments, ring A is selected from C. 6-10 The aryl group, a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 4-8 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or a 5-12 membered spooled, bridged or fused ring, wherein the 4-8 membered monoheterocyclic group or the 5-12 membered spooled, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0233] In some embodiments, ring A is selected from phenyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrroloyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrroloalkyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0234] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and so on.

[0235] In some implementations, M is selected from direct bond, -O-, C. 1-6 Alkylene, -NR a -、-NR a -CO-, -CO-, -COO- and -CO-NH-.

[0236] In some embodiments, M is selected from direct bonds, -NH-, -NH-CO-, -N(CH3)-CO-, -O-, and C. 1-4 Alkylene.

[0237] In some implementations, M is selected from direct bonds, -O-, and -CH2-.

[0238] In some implementations, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10Aryl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0239] In some implementations, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0240] In some implementations, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridinyl, pyridinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacyclobutane, pyrazolone, and tetrahydrofuranyl.

[0241] In some implementations, the R 3.1 It is selected from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl.

[0242] In some implementations, the R 3.1 Optionally, it is selected from one or more oxygen, C 1-6 Alkyl, halogen, C 1-6 The alkyl halogroup is substituted by a substituent.

[0243] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0244] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, and chlorine.

[0245] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, and C. 1-6 Alkyl groups, halogens, and -(CH2) t -CN.

[0246] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN.

[0247] In some implementations, the R 4 Each occurrence is independently selected from hydrogen and fluorine.

[0248] In some implementations, t is 0, 1, or 2.

[0249] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0250] This disclosure provides a compound of formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotope derivative thereof, and a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula (IV):

[0251]

[0252] in:

[0253] R 1 and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0254] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0255] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl, -COR a -COOR a -CO-NR a R c -NRa -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0256] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0257] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl-(hydroxy-C) 1-6 Alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6 Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0258] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0259] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0260] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0261] L is selected from direct bonds and -N(R) a )-R b -;

[0262] R b Selected from -(CH2) t -;

[0263] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0264] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0265] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0266] R 3 Selected from -MR 3.1 ;

[0267] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0268] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1 Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0269] t can be 0, 1, 2, or 3;

[0270] k is 1, 2, 3 or 4;

[0271] n is an integer between 0 and 9.

[0272] In some implementations, the R 1 Selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 .

[0273] In some implementations, the R occurs each time it appears. 2.1 Each is independently selected from halogens, hydroxyl groups, and hydroxyl-C. 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0274] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0275] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H and methyl.

[0276] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Together with the carbon atoms they are linked to, they form cyclopropane or cyclobutane, which may be optionally substituted with fluorine or hydroxyl groups.

[0277] In some implementations, the R 1 Selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyisobutyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetyl, and other compounds.

[0278] In some implementations, the R 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 .

[0279] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0280] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each of them is independently selected from H.

[0281] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, they form unsubstituted or substituted 4-8 membered heterocyclic groups.

[0282] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, which are either substituted or substituted.

[0283] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N or O, which are either substituted or replaced.

[0284] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms substituted or substituted piperidinyl, morpholino, and tetrahydropyrroleyl groups.

[0285] In some implementations, the R 2.1 Selected from halogens, hydroxyl groups, C 1-3 Alkyl groups and Het.

[0286] In some implementations, the Het is selected from C 3-6 cycloalkyl, C 6-10Aryl, 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0287] In some implementations, the Het is selected from C 3-5 cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0288] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, pyrrole, pyrazolyl, triazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.

[0289] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, thiophene, thiazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl.

[0290] In some implementations, the Het is optionally selected from one or more R... Het The group is substituted.

[0291] In some implementations, the Het is selected from... Where v is 0, 1 or 2.

[0292] In some implementations, the R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -(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 and -S(O)2-R a .

[0293] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, and -(CH2). t -COOR a and -S(O)2-R a .

[0294] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, -COOR a and -S(O)2-R a .

[0295] In some implementations, the R a Selected from hydrogen, amino and C 1-3 alkyl.

[0296] In some implementations, the R a Selected from hydrogen, amino, and methyl.

[0297] In some embodiments, ring A is selected from C. 6-10 Aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclic.

[0298] In some embodiments, ring A is selected from C. 6-10 The aryl group, a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 4-8 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or a 5-12 membered spooled, bridged or fused ring, wherein the 4-8 membered monoheterocyclic group or the 5-12 membered spooled, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0299] In some embodiments, ring A is selected from phenyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrroloyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrroloalkyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0300] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and so on.

[0301] In some implementations, M is selected from direct bond, -O-, C. 1-6 Alkylene, -NR a -、-NR a -CO-, -CO-, -COO- and -CO-NH-.

[0302] In some embodiments, M is selected from direct bonds, -NH-, -NH-CO-, -N(CH3)-CO-, -O-, and C. 1-4 Alkylene.

[0303] In some implementations, M is selected from direct bonds, -O-, and -CH2-.

[0304] In some implementations, the R 3.1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0305] In some implementations, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0306] In some implementations, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridinyl, pyridinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacyclobutane, pyrazolone, and tetrahydrofuranyl.

[0307] In some implementations, the R 3.1 It is selected from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl.

[0308] In some implementations, the R 3.1 Optionally, it is selected from one or more oxygen, C 1-6 Alkyl, halogen, C 1-6 The alkyl halogroup is substituted by a substituent.

[0309] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0310] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, and chlorine.

[0311] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, and C. 1-6 Alkyl groups, halogens, and -(CH2) t -CN.

[0312] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN.

[0313] In some implementations, the R 4 Each occurrence is independently selected from hydrogen and fluorine.

[0314] In some implementations, t is 0, 1, or 2.

[0315] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0316] This disclosure provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative thereof, and a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula (V):

[0317]

[0318] in:

[0319] R 1 and R 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and R. 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 Or R 1 and R 2 Together with the nitrogen atom it is attached to, it forms an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substituted 4-10 membered heterocyclic group is bonded by at least one R 2.1 Group substitution;

[0320] Each time R appears, 2.2 and R 2.3 Each element is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy; or R 2.2 and R 2.3 Together with the carbon atoms they are bonded to, they can be formed by halogens, hydroxyl groups, or C atoms. 1-6 Alkyl-substituted C 3-6 cycloalkyl;

[0321] Each time R appears, 2.1 Each is independently selected from halogens, deuterium, hydroxyl groups, and C. 1-6 Haloalkyl, C 1-6Alkoxy, hydroxy-C 1-6 Alkyl, C 1-6 Alkyl, -COR a -COOR a -CO-NR a R c -NR a -CO-、-NR a -COOR a -O-(CH2) t -OR a and Het;

[0322] Het is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic;

[0323] The Het is optionally selected by one or more of R Het The group substitution, wherein the R Het Selected from halogen, oxo, hydroxyl, amino, C 3-8 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl-(hydroxy-C) 1-6 Alkyl), 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 -S(O)2-R a and optionally by one or more elements selected from hydroxyl, halogen, C 1-6 Alkoxy and C 3-8 Cycloalkyl-substituted C 1-6 Alkyl group, wherein the heteroaryl group is optionally surrounded by one or more C24 groups. 1-6 Halogenated alkyl substitution;

[0324] Each time it appears, R a Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0325] Each time it appears, R 2.4 and R 2.5 Each is independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkyl, amino, with at least one C 1-6 Alkyl-substituted amino groups; or R 2.4 and R 2.5 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0326] R z Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0327] Ring A is selected from C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 4-12 membered heterocyclic;

[0328] R 4 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxyl, halogen, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl, -CO-NR a R c -S(O)2-NR a R c C 1-6 Alkyl sulfone group, CN, and -(CH2) t -CN;

[0329] Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl;

[0330] R 3 Selected from -MR 3.1 ;

[0331] M is selected from direct bond, C 1-6 Alkylene, -O-, -NR a -、-NR a -CO-, -CO-, -COO-, -CO-NR a -and-NR a -CO-O-;

[0332] R 3.1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic, wherein R 3.1Optionally, it is selected from one or more of the following groups: oxo, deuterium, hydroxyl, halogen, amino, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl and C 3-8 Substituents of cycloalkyl groups;

[0333] t can be 0, 1, 2, or 3;

[0334] k is 1, 2, 3 or 4;

[0335] n is an integer between 0 and 9.

[0336] In some implementations, the R 1 Selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 .

[0337] In some implementations, the R occurs each time it appears. 2.1 Each is independently selected from halogens, hydroxyl groups, and hydroxyl-C. 1-6 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl groups and Het.

[0338] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0339] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H and methyl.

[0340] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Together with the carbon atoms they are linked to, they form cyclopropane or cyclobutane, which may be optionally substituted with fluorine or hydroxyl groups.

[0341] In some implementations, the R 1 Selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyisobutyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetyl, and other compounds.

[0342] In some implementations, the R 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 .

[0343] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each is independently selected from H, halogen, and C. 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl group.

[0344] In some implementations, the R occurs each time it appears. 2.2 and R 2.3 Each of them is independently selected from H.

[0345] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, they form unsubstituted or substituted 4-8 membered heterocyclic groups.

[0346] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, which are either substituted or substituted.

[0347] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N or O, which are either substituted or replaced.

[0348] In some implementations, the R 1 and R 2 Together with the nitrogen atom it is attached to, it forms substituted or substituted piperidinyl, morpholino, and tetrahydropyrroleyl groups.

[0349] In some implementations, the R 2.1 Selected from halogens, hydroxyl groups, C 1-3 Alkyl groups and Het.

[0350] In some implementations, the Het is selected from C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0351] In some implementations, the Het is selected from C 3-5 cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0352] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, pyrrole, pyrazolyl, triazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.

[0353] In some embodiments, the Het is selected from cyclopropyl, cyclobutyl, thiophene, thiazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl.

[0354] In some implementations, the Het is optionally selected from one or more R... Het The group is substituted.

[0355] In some implementations, the Het is selected from... Where v is 0, 1 or 2.

[0356] In some implementations, the R Het Selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -(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 and -S(O)2-R a .

[0357] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, and -(CH2). t -COOR a and -S(O)2-R a .

[0358] In some implementations, the R Het Selected from fluorine, chlorine, hydroxyl, methyl, -COORa and -S(O)2-R a .

[0359] In some implementations, the R a Selected from hydrogen, amino and C 1-3 alkyl.

[0360] In some implementations, the R a Selected from hydrogen, amino, and methyl.

[0361] In some embodiments, ring A is selected from C. 6-10 Aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclic.

[0362] In some embodiments, ring A is selected from C. 6-10 The aryl group, a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, a 4-8 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or a 5-12 membered spooled, bridged or fused ring, wherein the 4-8 membered monoheterocyclic group or the 5-12 membered spooled, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S.

[0363] In some embodiments, ring A is selected from phenyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrroloyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrroloalkyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0364] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and so on.

[0365] In some implementations, M is selected from direct bond, -O-, C. 1-6 Alkylene, -NR a -、-NR a -CO-, -CO-, -COO- and -CO-NH-.

[0366] In some embodiments, M is selected from direct bonds, -NH-, -NH-CO-, -N(CH3)-CO-, -O-, and C. 1-4 Alkylene.

[0367] In some implementations, M is selected from direct bonds, -O-, and -CH2-.

[0368] In some implementations, the R 3.1 Selected from H, C 1-6Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0369] In some implementations, the R 3.1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0370] In some implementations, the R 3.1 Selected from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridinyl, pyridinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacyclobutane, pyrazolone, and tetrahydrofuranyl.

[0371] In some implementations, the R 3.1 It is selected from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl.

[0372] In some implementations, the R 3.1 Optionally, it is selected from one or more oxygen, C 1-6 Alkyl, halogen, C 1-6 The alkyl halogroup is substituted by a substituent.

[0373] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0374] In some implementations, the R 3.1 Optionally substituted with one or more substituents selected from oxo, methyl, and chlorine.

[0375] In some implementations, the R 4 Each occurrence is independently selected from hydrogen, oxo, and C. 1-6 Alkyl groups, halogens, and -(CH2) t -CN.

[0376] In some implementations, the R 4Each occurrence is independently selected from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, -(CH2)-CN and -(CH2)2-CN.

[0377] In some implementations, the R 4 Each occurrence is independently selected from hydrogen and fluorine.

[0378] In some implementations, t is 0, 1, or 2.

[0379] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0380] In some embodiments, this disclosure provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0381]

[0382]

[0383]

[0384]

[0385] In some embodiments, this disclosure provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0386]

[0387]

[0388]

[0389]

[0390] This 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.

[0391] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0392] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0393] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0394] All compounds disclosed herein, as well as mixtures and compositions comprising compounds of the present invention, can be administered to a living organism via any route of administration. Routes of administration may include oral, intravenous, intramuscular, subcutaneous, rectal, vaginal, sublingual, nasal, oral, ophthalmic, or local or systemic transdermal administration.

[0395] All compounds disclosed herein, as well as mixtures and compositions containing compounds of the present invention, can be formulated into single doses containing the active compounds of the present invention, as well as carriers, excipients, etc. The dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalers, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain commonly used pharmaceutical ingredients, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonic adjusters, anti-adhesives, etc. In some embodiments, the single dose includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, etc. The compounds of the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, in doses of 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

[0396] Suitable formulations for the aforementioned dosage forms are available from publicly available sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Therefore, those skilled in the art can readily prepare them.

[0397] Depending on the nature and severity of the disease suffered by different individuals, the patient's age, sex, weight, route of administration, and other factors, different dosages can be selected. The dosage of the compound of the present invention can be from 0.01 to 500 mg / kg daily, preferably 1-100 mg / kg daily, and can be administered once or multiple times. Examples of daily dosages include, but are not limited to, 0.01-500 mg, 0.01-400 mg, 0.01-300 mg, 0.01-200 mg, 0.01-100 mg, 0.01-50 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-2 00mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-500mg, 5-400mg , 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5- 50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10- 40mg, 10-30mg, 10-20mg; 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-1 50mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg.

[0398] This 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 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.

[0399] This disclosure also provides the use of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of medicaments for treating and / or preventing PDEs enzyme-mediated diseases or conditions, preferably in the preparation of medicaments for treating and / or preventing PDE4 enzyme-mediated diseases or conditions, and more preferably in the preparation of medicaments for treating and / or preventing PDE4B enzyme-mediated diseases or conditions.

[0400] In some embodiments, the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0401] In some embodiments, 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, α1-antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension.

[0402] In some embodiments, the gastrointestinal disease is selected from segmental enteritis, ulcerative colitis, and Crohn's disease.

[0403] In some embodiments, the inflammatory disease is selected from proliferative and inflammatory skin diseases, arthritic diseases, and ocular inflammatory diseases; wherein the inflammatory skin diseases are preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, hair loss, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, photoaging of the skin, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, eczematous hand dermatitis, and psoriasis; the arthritic diseases are preferably selected from rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis; and the ocular inflammatory diseases are preferably glaucoma or dry eye syndrome.

[0404] In some embodiments, the peripheral or central nervous system disease is selected from Alzheimer's disease, age-related memory disorder (AAMI), age-related cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, intellectual disability, cerebrovascular disease, depression, schizophrenia, stroke, neurofunctional disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities, and multiple sclerosis.

[0405] In some embodiments, the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenoma, medullary carcinoma, bronchial 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, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0406] Terminology Explanation:

[0407] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0408] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0409] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkylene containing 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-), etc. The alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0410] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0411] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0412] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more 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 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0413] The term "spirocyclic ring" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocyclic alkyl groups are classified as monospirocyclic, bispirocyclic, or polyspirocyclic based on the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic alkyl groups being preferred. More preferably, they are 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic alkyl groups. Non-limiting examples of spirocyclic alkyl groups include:

[0414]

[0415] The term "fused ring" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0416]

[0417] The term "bridging ring" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging cycloalkyl groups include:

[0418]

[0419] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0420] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0421] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0422] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0423] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0424]

[0425] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings 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 optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0426]

[0427] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It 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 optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as 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:

[0428]

[0429] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0430] wait.

[0431] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0432] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0433]

[0434] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0435] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0436]

[0437]

[0438] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0439] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0440] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0441] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0442] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0443] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0444] The term "hydroxyl group" refers to -OH.

[0445] The term "amino" refers to -NH2.

[0446] The term "cyano" refers to -CN.

[0447] The term "nitro" refers to -NO2.

[0448] The term "oxo" or "oxo" refers to "=O".

[0449] The term "carbonyl" refers to C=O.

[0450] The term "carboxyl group" refers to -C(O)OH.

[0451] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, that are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0452] In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key It can be Or simultaneously include Two configurations. Bond Indicates a single configuration, for In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0453] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0454] The term "isotope derivative" refers to compounds whose structure differs only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 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 carbon atoms are replaced by C-isotopes are within the scope of this 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, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0455] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of the present invention with an organic or inorganic acid, 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 this 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; and organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 Alkyl)4 salt.

[0456] The term "solvent" refers to the physical combination of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical combination includes hydrogen bonds. In some cases, such as when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0457] The term "hydrate" refers to the case where the solvent in the aforementioned term "solvent" is water.

[0458] The term "prodrug" refers to a compound that can be converted in the body to produce an active drug substance under physiological conditions, such as through hydrolysis in the blood.

[0459] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0460] The terms involved in this invention have been defined above. Those skilled in the art can also understand the above terms in conjunction with the prior art. The following is a further description based on the content of this invention and the definition of the terms.

[0461] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts described in this disclosure, but these examples are not intended to limit the scope of this disclosure.

[0462] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0463] The following describes the general test conditions in the embodiments of the present invention:

[0464] First, the reactions in the examples are generally carried out under nitrogen protection.

[0465] Furthermore, the intermediates and final products were separated and purified using chromatographic columns, preparative chromatographic plates, and the ISCO rapid preparative chromatography system. The chromatographic columns were packed with silica gel (300-400 mesh), manufactured by Shanghai Titan Technology Co., Ltd., and the preparative chromatographic plates were manufactured by Yantai Jiangyou Silica Gel Development Co., Ltd. The ISCO system used columns with a particle size of 40-63 μm. It is manufactured by Changzhou Santai Technology Co., Ltd.

[0466] Furthermore, the LC-MS system used was a Waters ACQUITYArc equipped with a QDa Detector. A Waters XBridge C18 column (2.1 × 50 mm, 3.5 μm) was used. Mass spectrometry (MS) employed an ESI source, indicating only 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 peak values ​​were recorded and read using UV-Vis wavelengths at 220 nm and 254 nm. The mobile phase consisted of an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and an acetonitrile solution of 0.01% formic acid (mobile phase B). Gradient elution conditions are shown in Tables 1 and 2 below.

[0467] Table 1: Gradient elution conditions 1

[0468] Time (min) <![CDATA[A(H2O,0.01%HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.0-0.3 95-85 5-15 0.3-3.2 85-20 15-80 3.2-3.8 20-5 80-95 3.8-3.81 5-95 95-5 3.81-4.0 95 5

[0469] Table 2: Gradient elution conditions 2

[0470] Time (min) <![CDATA[A(H2O,0.01%HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.00-5.90 95-5 5-95 5.90-5.91 5-95 95-5 5.91-6.00 95 5

[0471] Furthermore, the NMR spectrum was used Varian 400MHz nuclear magnetic resonance spectrometerData is obtained using CDCl3 or DMSO-d6 as solvents, and chemical shifts are reported in ppm. The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz.

[0472] Example

[0473] Example 1

[0474] (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 1)

[0475]

[0476]

[0477] Step 1: Preparation of methyl 5-(bromomethyl)thiophene-3-carboxylate (compound 1b)

[0478] At room temperature, methyl 5-methylthiophene-3-carboxylate 1a (2 g, 12.8 mmol), N-bromosuccinimide (2.13 g, 15.4 mmol), and azobisisobutyronitrile (0.21 g, 1.3 mmol) were mixed in carbon tetrachloride (50 mL). The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the solvent was removed by vacuum concentration, followed by the addition of water (40 mL) and extraction with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain title compound 1b (2.6 g). Step 2: Preparation of methyl 5-((methylamino)methyl)thiophene-3-carboxylate (compound 1c)

[0479] Compound 1b (1 g, 4.3 mmol), methylamine hydrochloride (0.86 g, 12.8 mmol), and potassium carbonate (1.8 g, 12.8 mmol) were mixed in acetonitrile (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 1c (0.65 g).

[0480] Step 3: Preparation of methyl 5-(((2-chloro-6,7-dihydrothiopheneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid (compound 1e)

[0481] At room temperature, 2,4-dichloro-6,7-dihydrothiophene[3,2-d]1d (0.3 g, 1.5 mmol), methyl 5-((methylamino)methyl)thiophene-3-carboxylate 1c (0.50 g, 2.70 mmol), and N,N-diisopropylethylamine (1 g, 8.1 mmol) were mixed in ethanol (20 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 1e (0.75 g).

[0482] Step 4: Preparation of methyl 5-((2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylate (compound 1 g)

[0483] Under nitrogen protection, methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid ester 1e (0.25 g, 0.7 mmol), compound 1f (200 mg, 1.06 mmol), potassium carbonate (385 mg, 2.8 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (50 mg, 0.07 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 1 g (0.33 g).

[0484] Step 5: Preparation of (R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 1h)

[0485] At room temperature, 1 g (0.33 g, 0.71 mmol) of compound S-1,1'-bi-2-naphthol (61 mg, 0.21 mmol), tetraisopropoxytitanium (11 mg, 0.036 mmol), and water (13 mg, 0.71 mmol) were mixed in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Then, tert-butanol peroxide (0.12 g, 0.78 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 1h (0.22 g).

[0486] Step 6: Preparation of (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 1)

[0487] To a mixture of compound 1h (220 mg, 0.46 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (58 mg, 1.38 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (200 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 1 (110 mg, yield: 51.16%).

[0488] 1 H NMR(400MHz,DMSO-d6)δppm 8.64(d,J=8.10Hz,2H)8.32(s,1H)8.13-8.18(m,3H)7.56(s,1H)7.48(d,J=0.64Hz,1H)5.38(d,J=15 .38Hz,1H)5.23(d,J=15.29Hz,1H)3.72-3.83(m,1H)3.56(s,3H)3.39-3.49(m,2H)3.16-3.24(m,1H).

[0489] MS m / z(ESI): 467[M+1].

[0490] Example 2

[0491] (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 2)

[0492]

[0493] Step 1: Preparation of methyl 5-((ethylamino)methyl)thiophene-3-carboxylate (compound 2a)

[0494] Ethylamine (13 mL, 2 M in THF) was added to a tetrahydrofuran (10 mL) solution under ice bath conditions. Then, a tetrahydrofuran solution of compound 1b (1.00 g, 4.3 mmol) was slowly added dropwise, and the reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 2a (650 mg).

[0495] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid (compound 2b)

[0496] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (205 mg, 1.0 mmol), compound 2a (197 mg, 1.0 mmol), and triethylamine (303 mg, 3.0 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 2b (230 mg).

[0497] Step 3: Preparation of methyl thiophene-3-carboxylate ((R)-5-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylate (compound 2c)

[0498] Compound 2b (230 g, 0.62 mmol), S-1,1'-bi-2-naphthol (17.8 mg, 0.062 mmol), tetraisopropoxytitanium (17.8 mg, 0.062 mmol), and water (22 mg, 1.24 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (87 mg, 0.68 mmol) was added, and the reaction mixture was stirred for 2 hours at room temperature. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 2c (204 mg).

[0499] Step 4: Preparation of (R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid ethyl ester (compound 2d)

[0500] Under nitrogen protection, compound 2c (80.0 mg, 0.21 mmol), compound 1f (61.5 mg, 0.23 mmol), potassium carbonate (43.5 mg, 0.31 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (15.4 mg, 0.021 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 2d (68 mg).

[0501] Step 5: Preparation of (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 2)

[0502] To a mixture of compound 2d (68.00 mg, 0.14 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (28.9 mg, 0.69 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4–5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (40 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 2 (39 mg, yield: 59%).

[0503] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(m,2H),8.32(s,1H),8.14-8.19(m,2H),8.12(d,J=1.37Hz,1H),7.59(s,1H),7.48(s,1H),5.28( s,2H),3.95-4.05(m,1H),3.75-3.91(m,2H),3.40-3.49(m,2H),3.17-3.25(m,1H),1.28-1.33(m,3H).

[0504] MS m / z(ESI): 481.10 [M+1].

[0505] Example 3

[0506] (R)-2-chloro-5-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 3)

[0507]

[0508] Step 1: Preparation of methyl 2-chloro-5-methylthiophene-3-carboxylic acid (compound 3a)

[0509] At room temperature, methyl 2-methylthiazolyl-4-carboxylate 1a (2.0 g, 12.72 mmol) and N-chlorosuccinimide (2.72 g, 15.27 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 3a (2.4 g).

[0510] Step 2: Preparation of methyl 5-(bromomethyl)-2-chlorothiophene-3-carboxylic acid (compound 3b)

[0511] At room temperature, methyl 5-(bromomethyl)-2-chlorothiophene-3-carboxylic acid ester 3a (2.4 g, 12.72 mmol), N-bromosuccinimide (2.72 g, 15.27 mmol), and azobisisobutyronitrile (3.13 g, 19.09 mmol) were mixed in carbon tetrachloride (20 mL). The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 3b (2.0 g).

[0512] Step 3: Preparation of methyl 2-chloro-5-((methylamino)methyl)thiophene-3-carboxylic acid (compound 3c)

[0513] In an ice bath, methylamine hydrochloride (5.7 g, 84.72 mmol) and potassium carbonate (11.71 g, 84.72 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 3b (1.15 g, 4.24 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 3c (0.5 g).

[0514] Step 4: Preparation of 2-chloro-5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 3d)

[0515] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.22 g, 1.06 mmol), compound 3c (0.28 g, 1.27 mmol), and triethylamine (0.41 g, 3.19 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 3d (0.35 g).

[0516] Step 5: Preparation of (R)-2-chloro-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 3e)

[0517] Compound 3d (0.2 g, 0.51 mmol), S-1,1'-bi-2-naphthol (28.08 mg, 0.098 mmol), tetraisopropoxytitanium (13.94 mg, 0.049 mmol), and water (17.67 mg, 0.98 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (50 mg, 0.56 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 3e (0.1 g).

[0518] Step 6: Preparation of (R)-2-chloro-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 3f)

[0519] Under nitrogen protection, compound 3e (100 mg, 0.25 mmol), compound 1f (100 mg, 0.37 mmol), potassium carbonate (101.9 mg, 0.738 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (18 mg, 0.025 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 3f (20 mg).

[0520] Step 7: Preparation of (R)-2-chloro-5-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 3)

[0521] To a mixture of compound 3f (20 mg, 0.039 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (4.6 mg, 0.19 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (20 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 3 (10 mg, yield: 51.4%).

[0522] MS m / z(ESI): 500.91 [M+1].

[0523] Example 4

[0524] (R)-2-methyl-5-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 4)

[0525]

[0526] Step 1: Preparation of methyl 2-bromo-5-(bromomethyl)thiophene-3-carboxylate (compound 4b)

[0527] At room temperature, methyl 2-bromo-5-methylthiophene-3-carboxylate 4a (2.0 g, 8.6 mmol), N-bromosuccinimide (1.5 g, 8.6 mmol), and azobisisobutyronitrile (213 mg, 1.3 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 4b (2.5 g).

[0528] Step 2: Preparation of methyl 2-bromo-5-((methylamino)methyl)thiophene-3-carboxylate (compound 4c)

[0529] In an ice bath, methylamine hydrochloride (3.3 g, 48.2 mmol) and potassium carbonate (6.6 g, 48.2 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 4b (1.00 g, 3.2 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 4c (380 mg).

[0530] Step 3: Preparation of methyl 2-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-3-carboxylate (compound 4d)

[0531] Compound 4c (380 mg, 1.4 mmol), di-tert-butyl dicarbonate (379 mg, 1.7 mmol), and triethylamine (172 mg, 1.7 mmol) were mixed in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 4d (450 mg).

[0532] Step 4: Preparation of methyl 5-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-2-methylthiophene-3-carboxylate (compound 4e)

[0533] Under nitrogen protection, compound 4d (450 mg, 1.23 mmol), methylboric acid (97 mg, 1.61 mmol), potassium carbonate (255 mg, 1.84 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (88 mg, 0.12 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 90 °C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 4e (310 mg).

[0534] Step 5: Preparation of methyl 2-methyl-5-((methylamino)methyl)thiophene-3-carboxylate (compound 4f)

[0535] Hydrochloric acid (3 ml, 4 min dioxane) was added to a solution of compound 4e (310 mg, 1.1 mmol) in dichloromethane (5 ml) at room temperature. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain the title compound 4f (320 mg).

[0536] Step 6: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)-2-methylthiophene-3-carboxylate (compound 4g)

[0537] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (207 mg, 1.0 mmol), compound 4f (200 mg, 1.0 mmol), and triethylamine (410 mg, 3.2 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 4 g (180 mg).

[0538] Step 7: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)-2-methylthiophene-3-carboxylate (compound 4h)

[0539] At room temperature, 4 g (180 mg, 0.49 mmol) of compound S-1,1'-bi-2-naphthol (14.3 mg, 0.05 mmol), tetraisopropoxytitanium (14.3 mg, 0.05 mmol), and water (18 mg, 1.0 mmol) were mixed in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Then, tert-butanol peroxide (64 mg, 0.5 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 4h (170 mg).

[0540] Step 8: Preparation of (R)-2-methyl-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 4i)

[0541] Under nitrogen protection, compound 4h (80 mg, 0.21 mmol), compound 1f (58 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphine)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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 4i (50 mg).

[0542] Step 9: Preparation of (R)-2-methyl-5-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 4)

[0543] To a mixture of compound 4i (50 mg, 0.10 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (21 mg, 0.5 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 4 (34 mg, yield: 71%).

[0544] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(m,2H),8.32(s,1H),8.17(m,2H),7.48(s,1H),7.44(s,1H),5.25-5.34(m,1H),5.14-5. 21(m,1H),3.72-3.83(m,1H),3.53(s,3H),3.39-3.48(m,2H),3.16-3.24(m,1H),2.57(s,3H).

[0545] MS m / z(ESI): 481.10 [M+1].

[0546] Example 5

[0547] (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylic acid (compound 5)

[0548]

[0549] Step 1: Preparation of methyl 5-(bromomethyl)thiophene-2-carboxylate (compound 5b)

[0550] At room temperature, methyl 5-methylthiophene-2-carboxylate 5a (2.0 g, 12.7 mmol), N-bromosuccinimide (2.72 g, 15.3 mmol), and azobisisobutyronitrile (213 mg, 1.3 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 5b (2.6 g).

[0551] Step 2: Preparation of methyl 5-((methylamino)methyl)thiophene-2-carboxylate (compound 5c)

[0552] In an ice bath, methylamine hydrochloride (5.7 g, 84.7 mmol) and potassium carbonate (11.7 g, 84.7 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 5b (1.00 g, 4.2 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 5c (520 mg).

[0553] Step 3: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-2-carboxylate (compound 5d)

[0554] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (223 mg, 1.1 mmol), compound 5c (200 mg, 1.1 mmol), and triethylamine (410 mg, 3.2 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 5d (305 mg).

[0555] Step 4: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-2-carboxylate (compound 5e)

[0556] Compound 5d (305 mg, 0.86 mmol), S-1,1'-bi-2-naphthol (24.6 mg, 0.086 mmol), tetraisopropoxytitanium (24.6 mg, 0.086 mmol), and water (31 mg, 1.7 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (122 mg, 0.95 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 5e (270 mg).

[0557] Step 5: Preparation of (R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylate (compound 5f)

[0558] Under nitrogen protection, compound 5e (80 mg, 0.21 mmol), compound 1f (58 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphine)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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 5f (60 mg).

[0559] Step 6: Preparation of (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylic acid (compound 5)

[0560] To a mixture of compound 5f (60 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (26 mg, 0.62 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (200 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 5 (41 mg, yield: 71%).

[0561] 1 H NMR(400MHz,DMSO-d6)δppm 8.62(d,J=8.51Hz,2H),8.32(s,1H),8.16(d,J=8.51Hz,2H),7.54(d,J=3.48Hz,1H),7.48(s,1H),7.24(d,J=3. 66Hz,1H),5.42(d,J=15.47Hz,1H),5.24(d,J=15.56Hz,1H),3.72-3.83(m,1H),3.38-3.49(m,5H),3.20(s,3H).

[0562] MS m / z(ESI): 467.08 [M+1].

[0563] Example 6

[0564] (R)-2-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazol-4-carboxylic acid (compound 6)

[0565] Step 1: Preparation of methyl 2-(bromomethyl)thiazole-4-carboxylate (compound 6b)

[0566] At room temperature, methyl 2-methylthiazolium-4-carboxylate 6a (2.0 g, 12.72 mmol), N-bromosuccinimide (2.72 g, 15.27 mmol), and azobisisobutyronitrile (3.13 g, 19.09 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by vacuum concentration, followed by the addition of water (20 mL) and extraction with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 6b (2.6 g). Step 2: Preparation of methyl 2-((methylamino)methyl)thiazolium-4-carboxylic acid (compound 6c)

[0567] In an ice bath, methylamine hydrochloride (5.7 g, 84.72 mmol) and potassium carbonate (11.71 g, 84.72 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 6b (1.00 g, 4.24 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 6c (0.24 g).

[0568] Step 3: Preparation of methyl 2-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiazole-4-carboxylic acid (compound 6e)

[0569] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.22 g, 1.06 mmol), compound 6c (0.24 g, 1.27 mmol), and triethylamine (0.41 g, 3.19 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 6e (0.35 g).

[0570] Step 4: Preparation of (R)-2-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiazol-4-carboxylic acid methyl ester (compound 6f)

[0571] Compound 6e (0.35 g, 0.98 mmol), S-1,1'-bi-2-naphthol (28.08 mg, 0.098 mmol), tetraisopropoxytitanium (13.94 mg, 0.049 mmol), and water (17.67 mg, 0.98 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.15 g, 1.18 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 6f (0.28 g).

[0572] Step 5: Preparation of (R)-2-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazole-4-carboxylic acid methyl ester (compound 6h)

[0573] Under nitrogen protection, compound 6f (280.0 mg, 0.75 mmol), compound 1f (244.3 mg, 0.90 mmol), potassium carbonate (311.37 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (54.8 mg, 0.075 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 6h (220 mg).

[0574] Step 6: Preparation of (R)-2-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazol-4-carboxylic acid (compound 6)

[0575] To a mixture of compound 6h (220.00 mg, 0.46 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (76.68 mg, 1.83 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 6 (105 mg, yield: 49.29%).

[0576] 1 H NMR(400MHz,DMSO-d6)δppm 8.54(br d,J=8.06Hz,1H),8.28(s,1H),8.10(brd,J=8.15Hz,1H),7.74(s,1H),7.44(s,1H),5. 16-5.50(m,1H),5.12-5.48(m,1H),3.69-3.81(m,1H),3.60(s,3H),3.10-3.22(m,1H).

[0577] MS m / z(ESI): 468.08 [M+1].

[0578] Example 7

[0579] (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)isothiazol-3-carboxylic acid (compound 7)

[0580]

[0581]

[0582] Step 1: Preparation of methyl 5-(bromomethyl)isothiazol-3-carboxylic acid (compound 7b)

[0583] At room temperature, methyl 5-methylisothiazolium-3-carboxylate 7a (500 mg, 3.2 mmol), N-bromosuccinimide (620 g, 3.5 mmol), and azobisisobutyronitrile (49 mg, 0.3 mmol) were mixed in acetonitrile (10 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 7b (250 mg).

[0584] Step 2: Preparation of methyl 5-((methylamino)methyl)isothiazol-3-carboxylic acid (compound 7c)

[0585] In an ice bath, methylamine hydrochloride (1.36 g, 20 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 7b (250 mg, 1.1 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 7c (120 mg).

[0586] Step 3: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)isothiazol-3-carboxylic acid (compound 7d)

[0587] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (133 mg, 0.64 mmol), compound 7c (120 mg, 0.64 mmol), and triethylamine (194 mg, 1.92 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 7d (130 mg).

[0588] Step 4: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)isothiazol-3-carboxylic acid methyl ester (compound 7e)

[0589] Compound 7d (130 mg, 0.36 mmol), S-1,1'-bi-2-naphthol (10.4 mg, 0.036 mmol), tetraisopropoxytitanium (10.4 mg, 0.036 mmol), and water (13 mg, 0.72 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (51 mg, 0.40 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 7e (110 mg).

[0590] Step 5: Preparation of (R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)isothiazol-3-carboxylic acid methyl ester (compound 7f)

[0591] Under nitrogen protection, compound 7e (80 mg, 0.21 mmol), compound 1f (58 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 7f (53 mg).

[0592] Step 6: Preparation of (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)isothiazol-3-carboxylic acid (compound 7)

[0593] To a mixture of compound 7f (53 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (26 mg, 0.62 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with dichloromethane (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 7 (21 mg, yield: 41%).

[0594] 1 H NMR (400MHz, DMSO-d6) δppm 8.62(d,J=7.69Hz,2H),8.32(s,1H),8.16(d,J=7.97Hz,2H),7.69(s,1H),7.48(s,1H),5.47(d,J=15.38Hz,1H),5.27(br s,1H),3.69-3.88(m,2H),3.60(s,3H),3.18-3.24(m,2H).

[0595] MS m / z(ESI): 468.08 [M+1].

[0596] Example 8

[0597] (R)-2-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazol-5-carboxylic acid (compound 8)

[0598]

[0599] Step 1: Preparation of methyl 2-(bromomethyl)thiazole-5-carboxylate (compound 8b)

[0600] At room temperature, methyl 2-methylthiazolyl-5-carboxylate 8a (1.0 g, 6.36 mmol), N-bromosuccinimide (1.36 g, 7.63 mmol), and azobisisobutyronitrile (0.10 g, 0.64 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 8b (1.3 g).

[0601] Step 2: Preparation of methyl 2-((methylamino)methyl)thiazole-5-carboxylic acid (compound 8c)

[0602] In an ice bath, methylamine hydrochloride (3.7 g, 55.3 mmol) and potassium carbonate (3.8 g, 27.7 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 8b (1.3 g, 5.53 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 8c (0.34 g).

[0603] Step 3: Preparation of methyl 2-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiazole-5-carboxylic acid (compound 8e)

[0604] At room temperature, 2,4-dichloro-6,7-dihydrothiophene[3,2-d]1d (0.41 g, 2.0 mmol), compound 8c (0.34 g, 1.82 mmol), and N,N-diisopropylethylamine (0.71 g, 5.46 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 8e (0.50 g).

[0605] Step 4: Preparation of (R)-2-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiazole-5-carboxylic acid methyl ester (compound 8f)

[0606] Compound 8e (0.50 g, 1.40 mmol), S-1,1'-bi-2-naphthol (121 mg, 0.42 mmol), tetraisopropoxytitanium (20 mg, 0.07 mmol), and water (26 mg, 1.40 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.16 g, 1.54 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 8f (0.30 g).

[0607] Step 5: Preparation of (R)-2-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazole-5-carboxylic acid methyl ester (compound 8h)

[0608] Under nitrogen protection, compound 8f (60 mg, 0.16 mmol), compound 1f (61 mg, 0.32 mmol), potassium carbonate (66 mg, 0.48 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (12 mg, 0.016 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 8h (60 mg).

[0609] Step 6: Preparation of (R)-2-((methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiazol-5-carboxylic acid (compound 8)

[0610] To a mixture of compound 8h (60 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (16 mg, 0.36 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (200 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 8 (16 mg, yield: 27.59%).

[0611] 1 H NMR(400MHz,DMSO-d6)δppm 8.55(m,J=8.51Hz,2H)8.32(s,1H)8.28(s,1H)8.12-8.17(m,2H)7.48(s,1H)5.54(d,J=16.39Hz ,1H)5.38(d,J=16.39Hz,1H)3.75-3.85(m,1H)3.68(s,3H)3.39-3.49(m,3H)3.18-3.26(m,2H).

[0612] MS m / z(ESI): 468.08 [M+1].

[0613] Example 9

[0614] (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)isoxazole-3-carboxylic acid (compound 9)

[0615]

[0616] Step 1: Preparation of methyl 5-(bromomethyl)isoxazole-3-carboxylic acid (compound 9b)

[0617] At room temperature, methyl 5-methylisoxazole-3-carboxylate 9a (1.5 g, 10.6 mmol), N-bromosuccinimide (2.2 g, 12.7 mmol), and azobisisobutyronitrile (0.19 g, 1.1 mmol) were mixed in acetonitrile (20 mL). The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 9b (1.6 g).

[0618] Step 2: Preparation of methyl 5-((methylamino)methyl)isoxazole-3-carboxylic acid (compound 9c)

[0619] In an ice bath, methylamine hydrochloride (4.9 g, 73.1 mmol) and potassium carbonate (5.1 g, 36.6 mmol) were mixed in tetrahydrofuran (50 mL) and stirred in an ice bath for 2 hours. Then, a tetrahydrofuran solution of compound 9b (1.6 g, 7.31 mmol) was added, and the reaction mixture was stirred in an ice bath for 0.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 9c (0.23 g).

[0620] Step 3: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)isoxazole-3-carboxylic acid (compound 9e)

[0621] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.28 g, 1.36 mmol), compound 9c (0.23 g, 1.24 mmol), and N,N-diisopropylethylamine (0.48 g, 3.72 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 9e (0.40 g).

[0622] Step 4: Preparation of (R)-5-((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)isoxazole-3-carboxylic acid methyl ester (compound 9f)

[0623] Compound 9e (0.40 g, 1.18 mmol), S-1,1'-bi-2-naphthol (95 mg, 0.35 mmol), tetraisopropoxytitanium (17 mg, 0.059 mmol), and water (22 mg, 1.18 mmol) were mixed in dichloromethane (8 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.19 g, 1.30 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 9f (0.20 g).

[0624] Step 5: Preparation of (R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)isoxazole-3-carboxylic acid methyl ester (compound 9h)

[0625] Under nitrogen protection, compound 9f (60 mg, 0.16 mmol), compound 1f (48 mg, 0.25 mmol), potassium carbonate (71 mg, 0.51 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (12 mg, 0.017 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 9h (30 mg).

[0626] Step 6: Preparation of (R)-5-(methyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)isoxazole-3-carboxylic acid (compound 9)

[0627] To a mixture of compound 9h (30 mg, 0.065 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (8 mg, 0.19 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (200 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 9 (16 mg, yield: 54.61%).

[0628] 1 H NMR(400MHz, DMSO-d6)δppm 8.52(br d,J=8.24Hz,2H)8.32(s,1H)8.14(d,J=8.51Hz,2H)7.48(s,1H)3.76(br dd,J=15.88,7.64Hz,1H)3.53(br s,3H)3.39-3.44(m,2H)3.18-3.24(m,1H).

[0629] MS m / z(ESI): 452.10 [M+1].

[0630] Example 10

[0631] (R)-5-(((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 10)

[0632]

[0633] Step 1: Preparation of methyl 5-((2-hydroxyethyl)amino)methyl)thiophene-3-carboxylate (compound 10d)

[0634] Ethanolamine 10c (1.04 g, 17.1 mmol) and compound 1b (0.4 g, 1.71 mmol) were mixed in tetrahydrofuran (20 mL) under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 10d (0.33 g).

[0635] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(2-hydroxyethyl)amino)methyl)thiophene-3-carboxylate (compound 10f)

[0636] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.33 g, 1.59 mmol), compound 10d (0.31 g, 1.44 mmol), and N,N-diisopropylethylamine (0.56 g, 4.32 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 10f (0.21 g).

[0637] Step 3: Preparation of (R)-5-((2-chloro-5-oxy-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(2-hydroxyethyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 10g)

[0638] Compound 10f (0.21 g, 0.56 mmol), S-1,1'-bi-2-naphthol (48 mg, 0.17 mmol), tetraisopropoxytitanium (8 mg, 0.028 mmol), and water (10 mg, 0.56 mmol) were mixed in dichloromethane (8 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.092 g, 0.62 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 10 g (0.16 g).

[0639] Step 4: Preparation of (R)-5-((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 10i)

[0640] Under nitrogen protection, 10 g (60 mg, 0.15 mmol) of compound 1f (57 mg, 0.30 mmol), potassium carbonate (62 mg, 0.45 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (11 mg, 0.015 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 10i (80 mg).

[0641] Step 5: Preparation of ((R)-5-(((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 10)

[0642] To a mixture of compound 10i (80 mg, 0.16 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (20 mg, 0.48 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 10 (17 mg, yield: 21.85%).

[0643] 1 H NMR(400MHz,DMSO-d6)δppm 8.60-8.64(m,2H)8.32(s,1H)8.12-8.17(m,3H)7.54(s,1H)7.48(s,1H)5.78(s,1H)5.46(d,J=15.66H z,1H)5.24(d,J=15.93Hz,1H)3.75-3.91(m,3H)3.40-3.45(m,2H)3.18-3.24(m,3H)2.55-2.60(m,2H).

[0644] MS m / z(ESI): 497.09 [M+1].

[0645] Example 11

[0646] (R)-5-((cyclopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 11)

[0647]

[0648] Step 1: Preparation of methyl 5-((cyclopropylamino)methyl)thiophene-3-carboxylate (compound 11a)

[0649] Cyclopropylamine (1.2 g, 21 mmol) was dissolved in tetrahydrofuran (50 mL) under ice bath conditions. Then, a tetrahydrofuran solution of compound 1b (0.5 g, 2.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 11a (0.3 g).

[0650] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(cyclopropyl)amino)methyl)thiophene-3-carboxylic acid (compound 11b)

[0651] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.353 g, 1.70 mmol), compound 11a (0.30 g, 1.42 mmol), and triethylamine (0.43 g, 4.26 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 11b (0.37 g).

[0652] Step 3: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(cyclopropyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 11c)

[0653] Compound 11b (0.37 g, 0.98 mmol), S-1,1'-bi-2-naphthol (28.08 mg, 0.098 mmol), tetraisopropoxytitanium (13.94 mg, 0.049 mmol), and water (17.67 mg, 0.98 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.15 g, 1.18 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 11c (0.30 g).

[0654] Step 4: Preparation of (R)-5-((cyclopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 11d)

[0655] Under nitrogen protection, compound 11c (300 mg, 0.75 mmol), compound 1f (244.3 mg, 0.90 mmol), potassium carbonate (311.37 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (54.8 mg, 0.075 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 11d (230 mg).

[0656] Step 5: Preparation of (R)-5-((cyclopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 11)

[0657] To a mixture of compound 11d (230 mg, 0.46 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (76.68 mg, 1.83 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 11 (85 mg, yield: 35.8%).

[0658] 1 H NMR(400MHz,DMSO-d6)δppm 8.59(d,J=8.80Hz,2H),8.32(s,1H),8.15(d,J=8.04Hz,2H),8.10(d,J=1.44Hz,1H),7.44-7.49(m,2H),5.53(d,J=16.12Hz,1H),5.13 (d,J=16.12Hz,1H),3.69-3.85(m,1H),3.39-3.52(m,2H),3.08-3.19(m,2H),1.14-1.24(m,2H),1.07-1.13(m,1H),0.95-1.04(m,1H).

[0659] MS m / z(ESI): 492.98 [M+1].

[0660] Example 12

[0661] (R)-5-(isopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 12)

[0662]

[0663] Step 1: Preparation of methyl 5-(isopropylamino)methyl)thiophene-3-carboxylate (compound 12a)

[0664] Isopropylamine (1.26 g, 21.4 mmol) was added to a tetrahydrofuran (10 mL) solution under ice bath conditions, followed by the slow addition of a tetrahydrofuran solution of compound 1b (1.00 g, 4.3 mmol). The reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 12a (650 mg).

[0665] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(isopropyl)amino)methyl)thiophene-3-carboxylate (compound 12b)

[0666] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (205 mg, 1.0 mmol), compound 12a (211 mg, 1.0 mmol), and triethylamine (303 mg, 3.0 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 12b (200 mg).

[0667] Step 3: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(isopropyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 12c)

[0668] Compound 12b (200 g, 0.522 mmol), S-1,1'-bi-2-naphthol (14.9 mg, 0.052 mmol), tetraisopropoxytitanium (14.8 mg, 0.052 mmol), and water (19 mg, 1.04 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (87 mg, 0.68 mmol) was added, and the reaction mixture was stirred for 2 hours at room temperature. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 12c (180 mg).

[0669] Step 4: Preparation of (R)-5-((isopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 12d)

[0670] Under nitrogen protection, compound 12c (80.0 mg, 0.20 mmol), compound 1f (61.5 mg, 0.23 mmol), potassium carbonate (43.5 mg, 0.31 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (15.4 mg, 0.021 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 12d (34 mg).

[0671] Step 5: Preparation of (R)-5-(isopropyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 12)

[0672] To a mixture of compound 12d (34.00 mg, 0.067 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (14 mg, 0.33 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (40 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 12 (10 mg, yield: 30%).

[0673] Example 13

[0674] (R)-5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid (compound 13)

[0675]

[0676]

[0677] Step 1: Preparation of methyl 5-((propylamino)methyl)thiophene-3-carboxylate (compound 13a)

[0678] Under ice bath conditions, propylamine (1.2 g, 20 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of a tetrahydrofuran solution of compound 1b (0.5 g, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 13a (0.4 g).

[0679] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid (compound 13b)

[0680] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.466 g, 2.25 mmol), compound 13a (0.40 g, 1.87 mmol), and triethylamine (0.43 g, 4.26 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 13b (0.4 g).

[0681] Step 3: Preparation of (R)-5-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylate (compound 13c)

[0682] Compound 13b (0.37 g, 0.98 mmol), S-1,1'-bi-2-naphthol (28.08 mg, 0.098 mmol), tetraisopropoxytitanium (13.94 mg, 0.049 mmol), and water (17.67 mg, 0.98 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.15 g, 1.18 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 13c (0.32 g).

[0683] Step 4: Preparation of (R)-5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 13d)

[0684] Under nitrogen protection, compound 13c (300 mg, 0.75 mmol), compound 1f (244.3 mg, 0.90 mmol), potassium carbonate (311.37 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (54.8 mg, 0.075 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 13d (190 mg).

[0685] Step 5: Preparation of (R)-5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid (compound 13)

[0686] To a mixture of compound 13d (190 mg, 0.37 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (76.6 mg, 1.86 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 13 (80 mg, yield: 43.3%).

[0687] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(d,J=8.08Hz,2H),8.32(s,1H),8.16(d,J=8.80Hz,2H),8.11(s,1H),7.59(s,1H),7.48(s,1H),5.18-5.42(m,2H), 3.84-3.90(m,1H),3.71-3.81(m,2H),3.36-3.46(m,3H),3.18-3.25(m,1H),1.64-1.86(m,2H),0.97(t,J=7.32Hz,3H).

[0688] MS m / z(ESI): 495.10 [M+1].

[0689] Example 14

[0690] (R)-5-(methyl(2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 14)

[0691]

[0692] Step 1: Preparation of (R)-5-((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylate (compound 14f)

[0693] Compound 1e (0.36 g, 1.03 mmol), S-1,1'-bi-2-naphthol (88 mg, 3.09 mmol), tetraisopropoxytitanium (15 mg, 0.052 mmol), and water (18 mg, 1.03 mmol) were mixed in dichloromethane (8 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.17 g, 1.13 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 14f (0.31 g).

[0694] Step 2: Preparation of (R)-5-((2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 14h)

[0695] Under nitrogen protection, compound 14f (50 mg, 0.13 mmol), compound 14g (77 mg, 0.26 mmol), potassium carbonate (58 mg, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (10 mg, 0.013 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 14h (40 mg). Step 3: Preparation of (R)-5-(methyl(2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 14)

[0696] To a mixture of compound 14h (40 mg, 0.081 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (10 mg, 0.24 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 14 (15 mg, yield: 38.66%).

[0697] 1 H NMR(400MHz,DMSO-d6)δppm 8.56-8.60(m,3H)8.12-8.18(m,3H)7.55(s,1H)5.22(d,J=15.29Hz,1H)5.37(d,J=15.38Hz,1H) 3.98(s,3H)3.73-3.80(m,1H)3.56(s,3H)3.36-3.45(m,2H)3.31-3.32(m,3H)3.16-3.22(m,1H).

[0698] MS m / z(ESI): 481.11 [M+1].

[0699] Example 15

[0700] (R)-5-(methyl(2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 15)

[0701]

[0702] Step 1: Preparation of (R)-5-((2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 15h)

[0703] Under nitrogen protection, compound 14f (100 mg, 0.27 mmol), compound 15g (154 mg, 0.54 mmol), potassium carbonate (112 mg, 0.81 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (20 mg, 0.027 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 15h (100 mg).

[0704] Step 2: Preparation of (R)-5-(methyl(2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 15)

[0705] To a mixture of compound 15h (100 mg, 0.20 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (25 mg, 0.60 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 15 (6 mg, yield: 6.24%).

[0706] 1 H NMR(400MHz,DMSO-d6)δppm 8.69-8.73(m,2H)8.26-8.30(m,2H)8.14(d,J=1.37Hz,1H)7.57(s,1H)5.39(d,J=15.47Hz,1H)5.24(d,J=15 .38Hz,1H)3.76-3.84(m,1H)3.57(s,3H)3.40-3.46(m,3H)3.31-3.34(m,4H)3.20-3.25(m,1H)2.48(s,3H).

[0707] MS m / z(ESI): 482.09 [M+1].

[0708] Example 16

[0709] (R)-5-(methyl(2-(4-(5-methyloxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 16)

[0710]

[0711] Step 1: Preparation of 4-bromo-N-(prop-2-yn-1-yl)benzamide (compound 16c)

[0712] At room temperature, 4-bromobenzoic acid 16a (1.0 g, 5.0 mmol), compound 16b (276 mg, 5.0 mmol), and triethylamine (1.0 g, 10.0 mmol) were mixed in dichloromethane (20 mL). HATU (2.3 g, 6.0 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (40 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 16c (1.1 g).

[0713] Step 2: Preparation of 2-(4-bromophenyl)-5-methyloxazole (compound 16d)

[0714] Compound 16c (1 g, 4.2 mmol) and ferric chloride (686 mg, 4.2 mmol) were mixed in dichloroethane (20 mL) at room temperature. The reaction mixture was then stirred at 85 °C for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 16d (620 mg).

[0715] Step 3: Preparation of 5-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)oxazole (compound 16e)

[0716] Under nitrogen protection, compound 16d (400 mg, 1.7 mmol), pinacol diborate (474 ​​mg, 1.8 mmol), potassium acetate (333 mg, 3.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (146 mg, 0.2 mmol) were mixed in 8 mL of 1,4-dioxane solution. The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the solvent was removed by rotary evaporation, followed by the addition of water (30 mL) and extraction with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product, compound 16e (title product). This crude product (600 mg) was used directly in the next reaction without purification.

[0717] Step 4: Preparation of (R)-5-((2-(4-(5-methyloxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 16f)

[0718] Under nitrogen protection, compound 14f (82 mg, 0.22 mmol), compound 16e (80 mg, 0.22 mmol), potassium carbonate (55 mg, 0.40 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 16f (50 mg).

[0719] Step 5: Preparation of (R)-5-(methyl(2-(4-(5-methyloxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 16)

[0720] To a mixture of compound 16f (50 mg, 0.10 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (21 mg, 0.50 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (30 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 16 (23 mg, yield: 48%).

[0721] 1 H NMR(400MHz,DMSO-d6)δppm 8.62(d,J=8.51Hz,2H),8.09-8.14(m,3H),7.56(s,1H),7.09(d,J=1.10Hz,1H),5.37(d,J=15.38Hz,1H),5 .22(d,J=15.29Hz,1H),3.72-3.83(m,1H),3.56(s,3H),3.40-3.48(m,2H),3.18-3.23(m,1H),2.43(s,3H).

[0722] MS m / z(ESI): 481.10 [M+1].

[0723] Example 17

[0724] (R)-5-(methyl(2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thieno-3-carboxylic acid (compound 17)

[0725]

[0726]

[0727] Step 1: Preparation of 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1H-pyrazole (compound 17b)

[0728] Under nitrogen protection, 5-(4-bromophenyl)-3-methyl-1,2,4-oxadiazole 17a (0.5 g, 2.1 mmol), pinacol diborate (1.1 g, 4.2 mmol), potassium acetate (0.41 g, 4.2 mmol), and [1,1'-bis(diphenylphosphine)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 the reaction was complete, the solvent was removed by vacuum concentration. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under vacuum to give the title compound 17b (0.6 g, crude product).

[0729] Step 2: Preparation of (R)-5-((2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 17c)

[0730] Under nitrogen protection, compound 17b (60 mg, 0.2 mmol), compound 14f (75 mg, 0.2 mmol), potassium carbonate (55 mg, 0.4 mmol), and [1,1'-bis(diphenylphosphine)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. The organic phase was washed successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography to obtain the title compound 17c (50 mg, yield: 50.3%).

[0731] Step 3: Preparation of (R)-5-(methyl(2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 17)

[0732] To a mixture of compound 17c (50 mg, 0.10 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H₂O (20.8 mg, 0.51 mmol) in H₂O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4–5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 17 (30 mg, yield: 61.7%).

[0733] 1 H NMR(400MHz,DMSO-d6)δppm 8.51(d,J=8.08Hz,2H),8.13(s,1H),7.96(d,J=8.08Hz,2H),7.80(d,J=2.20Hz,1H),7.55(d,J=1.44Hz,1H),6.83(d,J=2.20Hz,1H), 5.36(d,J=15.36Hz,1H),5.21(d,J=15.36Hz,1H),3.94(s,3H),3.70-3.80(m,1H),3.55(s,3H),3.38-3.43(m,2H),3.12-3.22(m,1H).

[0734] MS m / z(ESI): 479.99 [M+1].

[0735] Example 18

[0736] ((R)-5-(((2-(2-fluoro-4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid (compound 18)

[0737] Step 1: Preparation of ((R)-5-((2-(2-fluoro-4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 18h)

[0738] Under nitrogen protection, compound 14f (50 mg, 0.15 mmol), compound 18g (75 mg, 0.26 mmol), potassium carbonate (58 mg, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (10 mg, 0.013 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 18h ​​(24 mg). Step 2: Preparation of ((R)-5-(((2-(2-fluoro-4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(methyl)amino)methyl)thiophene-3-carboxylic acid (compound 18)

[0739] To a mixture of compound 18h ​​(24 mg, 0.048 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (6 mg, 0.14 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 18 (1.5 mg, yield: 6.52%).

[0740] 1 H NMR(400MHz,DMSO-d6)δppm 8.47(dd,J=8.29,1.51Hz,1H)8.40(s,1H)8.37(s,1H)8.23(t,J=7.87Hz,1H)8.15(d,J=1.37Hz,1H)7.55-7.58(m,2H )5.24(d,J=15.29Hz,1H)5.40(d,J=15.38Hz,1H)3.76-3.82(m,1H)3.58(s,3H)3.40-3.48(m,3H)3.19-3.26(m,2H).

[0741] MS m / z(ESI): 485.06 [M+1].

[0742] Example 19

[0743] (R)-5-(((2-methoxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxide-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 23)

[0744]

[0745] Step 1: Preparation of 5-(((2-methoxyethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 23a)

[0746] Under ice bath conditions, 2-methoxyethylamine (1.2 g, 16 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of a tetrahydrofuran solution of compound 1b (0.4 g, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 23a (0.4 g).

[0747] Step 2: Preparation of methyl 5-(((2-chloro-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(2-methoxyethyl)amino)methyl)thiophene-3-carboxylic acid (compound 23b)

[0748] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.466 g, 2.25 mmol), compound 23a (0.40 g, 1.7 mmol), and triethylamine (0.43 g, 4.26 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 23b (0.4 g).

[0749] Step 3: Preparation of (R)-5-(((2-chloro-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)(2-methoxyethyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 23c)

[0750] Compound 23b (0.4 g, 0.1 mmol), S-1,1'-bi-2-naphthol (28.08 mg, 0.01 mmol), tetraisopropoxytitanium (13.94 mg, 0.05 mmol), and water (17.67 mg, 0.1 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.15 g, 1.2 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 23c (0.32 g).

[0751] Step 4: Preparation of (R)-5-(((2-methoxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 23d)

[0752] Under nitrogen protection, compound 23c (300 mg, 0.72 mmol), compound 1f (244.3 mg, 0.90 mmol), potassium carbonate (311.37 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (54.8 mg, 0.075 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 23d (190 mg).

[0753] Step 5: Preparation of (R)-5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid (compound 23)

[0754] Compound 23d (190 mg, 0.36 mmol) was added to a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) in LiOH-H2O (76.6 mg, 1.86 mmol) in H2O (1 mL), and the reaction mixture was stirred at 50 °C for 2 hours. After LCMS showed that the reaction was complete, 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography to give title compound 23 (80 mg, yield: 43.2%).

[0755] 1 H NMR(400MHz,DMSO-d6,25℃)δppm 8.61(d,J=8.79Hz,2H)8.32(s,1H)8.16(d,J=8.79Hz,2H)8.11(s,1H)7.52(s,1H)7.48(s,1H)5.41(d,J=15.38Hz ,1H)5.21(d,J=16.11Hz,1H)3.94-4.03(m,1H)3.70-3.75(m,2H)3.32(s,5H)3.16-3.25(m,3H)2.32-2.39(m,1H).

[0756] MS m / z(ESI): 511.1 [M+1].

[0757] Example 20

[0758] (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylic acid (compound 24)

[0759]

[0760] Step 1: Preparation of methyl 5-((ethylamino)methyl)thiophene-2-carboxylic acid ester (compound 24a)

[0761] Under ice bath conditions, ethylamine (17 mmol, 4 ml, 4 M in THF) solution was added dropwise to a tetrahydrofuran (10 ml) solution of compound 5b (1.00 g, 4.2 mmol). The mixture was stirred in an ice bath for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 24a (520 mg).

[0762] Step 2: Preparation of methyl 5-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-2-carboxylic acid ester (compound 24b)

[0763] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (223 mg, 1.1 mmol), compound 24a (200 mg, 1.1 mmol), and triethylamine (410 mg, 3.2 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 24b (305 mg).

[0764] Step 3: Preparation of methyl(R)-5-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-2-carboxylic acid ester (compound 24c)

[0765] Compound 24b (305 mg, 0.86 mmol), S-1,1'-bi-2-naphthol (24.6 mg, 0.086 mmol), tetraisopropoxytitanium (24.6 mg, 0.086 mmol), and water (31 mg, 1.7 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (122 mg, 0.95 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 24c (230 mg).

[0766] Step 4: Preparation of methyl(R)-5-((ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylic acid ester (compound 24d)

[0767] Under nitrogen protection, compound 24c (80 mg, 0.21 mmol), compound 1f (58 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphine)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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 24d (55 mg).

[0768] Step 5: Preparation of (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-2-carboxylic acid (compound 24)

[0769] A solution of LiOH-H2O (26 mg, 0.62 mmol) in H2O (1 mL) was added to a mixture of compound 24d (55 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), and the reaction mixture was stirred at 40 °C for 2 hours. After LCMS showed that the reaction was complete, 1 N HCl was added to adjust the pH to 4-5, the mixture was diluted with EA (50 mL), washed with brine (200 mL), dried, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography to give title compound 24 (34 mg).

[0770] 1 H NMR(400MHz,DMSO-d6)δppm 8.62(m,J=8.51Hz,2H),8.32(s,1H),8.16(m,J=8.51Hz,2H),7.61(d,J=3.66Hz,1H),7.48(s,1H),7.31(d,J=3.66H z,1H),5.32(s,2H),3.97-4.07(m,1H),3.76-3.91(m,2H),3.42-3.50(m,2H),3.17-3.26(m,1H),1.27-1.32(m,3H).

[0771] MS m / z(ESI): 481.11 [M+1].

[0772] Example 21

[0773] (R)-5-[(ethyl(2-[4-(4-methyloxazol-2-yl)phenyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 28)

[0774]

[0775] Step 1: Preparation of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)oxazole (compound 28b)

[0776] Under nitrogen protection, 2-(4-bromophenyl)-4-methyloxazole 28a (95 mg, 0.40 mmol), pinacol diborate (153 mg, 0.60 mmol), potassium acetate (117 mg, 1.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30 mg, 0.04 mmol) were mixed in a 1,4-dioxane solution (5 mL). The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the solvent was removed by vacuum concentration, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under vacuum to give the title compound 28b (0.15 g, crude product).

[0777] Step 2: Preparation of (R)-5-((ethyl(2-(4-(4-methyl-2-oxo-1,3-thiazolyl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 28c)

[0778] Under nitrogen protection, compound 28b (40 mg, 0.19 mmol), compound 2c (50 mg, 0.13 mmol), potassium carbonate (54 mg, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (10 mg, 0.013 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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 28c (50 mg, yield: 75.8%).

[0779] Step 3: Preparation of (R)-5-[(ethyl(2-[4-(4-methyloxazol-2-yl)phenyl]-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 28)

[0780] To a mixture of compound 28c (50 mg, 0.098 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H₂O (12 mg, 0.30 mmol) in H₂O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 4–5 by adding 1 N HCl. The mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated. The crude product was purified by rapid column chromatography to give title compound 28 (13 mg, yield: 27.08%).

[0781] 1 H NMR(400MHz,DMSO-d6)δppm 8.61(m,J=8.61Hz,2H)8.12(m,J=8.61Hz,2H)8.07(s,1H)8.01(d,J=1.28Hz,1H)7.57(s,1H)5.27(s,2H)3.97 -4.03(m,1H)3.75-3.90(m,2H)3.39-3.49(m,3H)3.18-3.24(m,2H)2.22(d,J=1.19Hz,3H)1.29-1.34(m,3H).

[0782] MS m / z(ESI): 495.11 [M+1].

[0783] Example 22

[0784] (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 29)

[0785]

[0786] Step 1: Preparation of methyl 5-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 29b)

[0787] At room temperature, 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 29a (210 mg, 1.0 mmol), compound 2a (197 mg, 1.0 mmol), and triethylamine (303 mg, 3.0 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 29b (230 mg).

[0788] Step 2: Preparation of methyl(R)-5-((2-chloro-5-oxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 29c)

[0789] Compound 29b (230 g, 0.62 mmol), S-1,1'-bi-2-naphthol (17.8 mg, 0.062 mmol), tetraisopropoxytitanium (17.8 mg, 0.062 mmol), and water (22 mg, 1.24 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (87 mg, 0.68 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 29c (204 mg).

[0790] Step 3: Preparation of methyl(R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid ester (compound 29d)

[0791] Under nitrogen protection, compound 29c (80.0 mg, 0.21 mmol), compound 1f (61.5 mg, 0.23 mmol), potassium carbonate (43.5 mg, 0.31 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (15.4 mg, 0.021 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 29d (55 mg).

[0792] Step 4: Preparation of (R)-5-(ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 29)

[0793] To a mixture of compound 29d (55 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (13 mg, 0.30 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LCMS showed that the reaction was complete. 1 N HCl was added to adjust the pH to 4-5, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 29 (30 mg).

[0794] 1 H NMR(400MHz,DMSO-d6)δppm 8.57(d,J=8.51Hz,2H),8.31(s,1H),8.10-8.16(m,3H),7.56-7.59(m,1H),7.47(s,1H),5.18(s,2H),3.94-4.03(m,1 H),3.59-3.74(m,1H),3.27-3.29(m,1H),2.98-3.21(m,3H),2.57-2.71(m,1H),2.09-2.11(m,1H),1.37-1.43(m,3H).

[0795] MS m / z(ESI): 495.10 [M+1].

[0796] Example 23

[0797] (R)-5-[(ethyl(2-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 30)

[0798]

[0799] Step 1: Preparation of 3-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)phenyl]-1H-1,2,4-triazole (compound 30b)

[0800] Under nitrogen protection, 1-(4-bromophenyl)-3-methyl-1H-1,2,4-triazole 30a (143 mg, 0.59 mmol), pinacol diborate (225 mg, 0.89 mmol), potassium acetate (183 mg, 1.77 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (43 mg, 0.059 mmol) were mixed in a 1,4-dioxane solution (6 mL). The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the solvent was removed by vacuum concentration, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under vacuum to give the title compound 30b (0.25 g, crude product).

[0801] Step 2: Preparation of (R)-5-[2-(2-(4-[3-methyl-1H-1,2,4-triazol-1-yl]phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)butyl]thiophene-3-carboxylate (compound 30c)

[0802] Under nitrogen protection, compound 30b (40 mg, 0.19 mmol), compound 2c (50 mg, 0.13 mmol), potassium carbonate (54 mg, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (10 mg, 0.013 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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 30c (30 mg, yield: 45.5%).

[0803] Step 3: Preparation of (R)-5-[(ethyl(2-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 30)

[0804] To a mixture of compound 30c (30 mg, 0.059 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (8 mg, 0.18 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LCMS showed that the reaction was complete. The pH was adjusted to 4-5 with 1 N HCl, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 30 (11 mg, yield: 37.93%).

[0805] 1 H NMR (400MHz, DMSO-d6) δppm 9.29 (s, 1H) 8.62 (m, J = 8.88Hz, 2H) 8.06 (s, 1H)

[0806] 8.01(m,J=8.79Hz,2H)7.56(s,1H)5.26(s,2H)3.96-4.02(m,1H)3.74-3.90(m,2H)3.18-3.23(m,2H)2.41(s,3H)1.28-1.33(m,3H).

[0807] MS m / z(ESI): 495.10 [M+1].

[0808] Example 24

[0809] (R)-5-[((cyclopropylmethyl)(2-[4-(oxazol-2-yl)phenyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 35)

[0810]

[0811] Step 1: Preparation of methyl 5-(((cyclopropylmethyl)amino)methyl)thiophene-3-carboxylate (compound 35a)

[0812] Cyclopropylamine (1.2 g, 21 mmol) was dissolved in tetrahydrofuran (50 mL) under ice bath conditions. Then, a tetrahydrofuran solution of compound 1b (0.5 g, 2.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 35a (0.3 g).

[0813] Step 2: Preparation of methyl 5-[((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(cyclopropylmethyl)amino)methyl]thiophene-3-carboxylate (compound 35b)

[0814] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.322 g, 1.56 mmol), compound 35a (0.32 g, 1.42 mmol), and triethylamine (0.43 g, 4.26 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and water (20 mL) was added. The mixture was then extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 35b (0.34 g).

[0815] Step 3: Preparation of (R)-5-[((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(cyclopropylmethyl)amino)methyl]thiophene-3-carboxylate (compound 35c)

[0816] Compound 35b (0.34 g, 0.86 mmol), S-1,1'-bi-2-naphthol (74 mg, 0.26 mmol), tetraisopropoxytitanium (13 mg, 0.043 mmol), and water (16 mg, 0.86 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (0.14 g, 0.95 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 35c (0.21 g).

[0817] Step 4: Preparation of (R)-5-[((cyclopropylmethyl)(2-[4-(oxazol-2-yl)phenyl]-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylate (compound 35d)

[0818] Under nitrogen protection, compound 35c (50 mg, 0.12 mmol), compound 1f (35 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (9 mg, 0.012 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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 35d (40 mg).

[0819] Step 5: Preparation of (R)-5-[((cyclopropylmethyl)(2-[4-(oxazol-2-yl)phenyl]-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 35)

[0820] To a mixture of compound 35d (40 mg, 0.077 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (10 mg, 0.23 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LCMS showed that the reaction was complete. The pH was adjusted to 4-5 with 1 N HCl, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 35 (11 mg, yield: 28.2%).

[0821] 1 H NMR(400MHz,DMSO-d6)δppm 8.62(m,J=8.61Hz,2H)8.32(s,1H)8.16(m,J=8.51Hz,2H)8.05(s,1H)7.53(s,1H)7.48(s,1H)5.39(d,J=15.84Hz,1H)5.26(d,J=15. 84Hz,1H)4.04(dd,J=15.38,5.68Hz,1H)3.75-3.82(m,1H)3.53-3.62(m,1H)3.38-3.48(m,3H)3.18-3.24(m,1H)0.41-0.60(m,4H).

[0822] MS m / z(ESI): 507.10 [M+1].

[0823] Example 25

[0824] (R)-5-((2-fluoroethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 39)

[0825]

[0826]

[0827] Step 1: Preparation of methyl 5-((2-fluoroethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 39a)

[0828] Fluoroethylamine (1.2 g, 21 mmol) was dissolved in tetrahydrofuran (50 mL) under ice bath conditions. Then, a tetrahydrofuran solution of compound 1b (0.5 g, 2.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 39a (0.3 g).

[0829] Step 2: Preparation of methyl 5-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(2-fluoroethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 39b)

[0830] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.322 g, 1.56 mmol), compound 39a (0.3 g, 1.4 mmol), and triethylamine (0.43 g, 4.26 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was completed, the solvent was removed by vacuum concentration, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 39b (120 mg).

[0831] Step 3: Preparation of methyl(R)-5-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(2-fluoroethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 39c)

[0832] Compound 39b (120 mg, 0.31 mmol), S-1,1'-bi-2-naphthol (8.6 mg, 0.03 mmol), tetraisopropoxytitanium (8.5 mg, 0.03 mmol), and water (6 mg, 0.31 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (44 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 39c (80 mg).

[0833] Step 4: Preparation of methyl(R)-5-((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(propyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 39d)

[0834] Under nitrogen protection, compound 39c (50 mg, 0.12 mmol), compound 1f (35 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (9 mg, 0.012 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 39d (40 mg).

[0835] Step 5: Preparation of (R)-5-((2-fluoroethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 39)

[0836] To a mixture of compound 39d (40 mg, 0.077 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (10 mg, 0.23 mmol) in H2O (1 mL) was added. The reaction mixture was stirred at 50 °C for 2 hours. LCMS showed that the reaction was complete. The pH was adjusted to 4-5 with 1 N HCl, and the mixture was diluted with EA (50 mL). The mixture was then washed with brine (20 mL), dried, and concentrated to obtain a crude product, which was purified by rapid column chromatography to give title compound 39 (12 mg).

[0837] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(m,J=8.51Hz,2H),8.33(s,1H),8.17(m,J=8.61Hz,2H),8.12(s,1H) ,7.55(s,1H),7.48(s,1H),5.45(d,J=15.93Hz,1H),5.22(d,J=15.75Hz,1 H),4.90(t,J=5.26Hz,1H),4.79(t,J=5.31Hz,1H),4.32-4.45(m,1H),4. 11-4.24(m,1H),3.76-3.86(m,1H),3.42-3.49(m,2H),3.18-3.26(m,1H).

[0838] MS m / z(ESI): 499.08 [M+1].

[0839] Example 26

[0840] (R)-5-(ethyl(2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 40)

[0841]

[0842] Step 1: Preparation of methyl(R)-5-(ethyl(2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid ester (compound 40a)

[0843] Under nitrogen protection, compound 2c (60 mg, 0.12 mmol), compound 17b (49 mg, 0.24 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (9 mg, 0.012 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. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 40a (60 mg).

[0844] Step 2: Preparation of (R)-5-(ethyl(2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 40)

[0845] To a mixture of compound 40a (60 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (15 mg, 0.33 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. LCMS showed that the reaction was complete. The pH was adjusted to 4-5 with 1 N HCl, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 40 (20 mg).

[0846] 1 H NMR(400MHz,DMSO-d6)δppm 8.51(m,J=8.42Hz,2H),8.12(d,J=1.19Hz,1H),7.96(m,J=8.42Hz,2H),7.80(d,J=2.20Hz,1H),7.58(s,1H),6.82(d,J=2.29Hz,1H ),5.26(s,2H),3.96-4.04(m,1H),3.93-3.96(m,3H),3.73-3.89(m,2H),3.39-3.47(m,2H),3.15-3.23(m,1H),1.27-1.32(m,3H).

[0847] MS m / z(ESI): 494.12 [M+1].

[0848] Example 27

[0849] (R)-5-[((2-hydroxyethyl)(2-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 41)

[0850] Step 1: Preparation of (R)-5-[((2-hydroxyethyl)(2-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid methyl ester (compound 41a)

[0851] Under nitrogen protection, 10 g (50 mg, 0.12 mmol) of compound 17b (49 mg, 0.24 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (9 mg, 0.012 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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 41a (60 mg). Step 2: Preparation of (R)-5-[((2-hydroxyethyl)(2-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl]thiophene-3-carboxylic acid (compound 41)

[0852] To a mixture of compound 41a (60 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (15 mg, 0.33 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, 1 N HCl was added to adjust the pH to 4-5, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 41 (14 mg, yield: 25.00%).

[0853] 1 H NMR(400MHz,DMSO-d6)δppm 8.50(d,J=8.42Hz,2H)8.10(s,1H)7.96(d,J=8.51Hz,2H)7.80(d,J=2.20Hz,1H)7.53 (s,1H)6.82(d,J=2.29Hz,1H)5.44(d,J=15.66Hz,1H)5.22(d,J=15.56Hz,1H)5.02(br s,1H)3.98-4.14(m,1H)3.94(s,3H)3.73-3.90(m,4H)3.39-3.47(m,3H)3.15-3.23(m,1H).

[0854] MS m / z(ESI): 510.12 [M+1].

[0855] Example 28

[0856] (R)-2-chloro-5-(((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 42)

[0857]

[0858] Step 1: Preparation of methyl 2-chloro-5-(((2-hydroxyethyl)amino)methyl)thiophene-3-carboxylate (compound 42b)

[0859] Ethanolamine 42a (0.96 g, 14.8 mmol) and compound 3b (0.4 g, 1.48 mmol) were mixed in tetrahydrofuran (20 mL) under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 42b (0.35 g).

[0860] Step 2: Preparation of methyl 2-chloro-5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(2-hydroxyethyl)amino)methyl)thiophene-3-carboxylate (compound 42c)

[0861] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.32 g, 1.54 mmol), compound 42b (0.35 g, 1.40 mmol), and N,N-diisopropylethylamine (0.54 g, 4.20 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 42c (0.25 g).

[0862] Step 3: Preparation of (R)-2-chloro-5-((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(2-hydroxyethyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 42d)

[0863] Compound 42c (0.235 g, 0.56 mmol), S-1,1'-bi-2-naphthol (48 mg, 0.17 mmol), tetraisopropoxytitanium (8 mg, 0.028 mmol), and water (10 mg, 0.56 mmol) were mixed in dichloromethane (8 mL) at room temperature. After stirring at room temperature for 1 hour, tert-butanol peroxide (0.092 g, 0.62 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 42d (0.18 g).

[0864] Step 4: Preparation of (R)-2-chloro-5-((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 42e)

[0865] Under nitrogen protection, compound 42d (65 mg, 0.15 mmol), compound 1f (57 mg, 0.30 mmol), potassium carbonate (62 mg, 0.45 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (11 mg, 0.015 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, and ethyl acetate (30 mL) was added. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 42e (87 mg).

[0866] Step 5: Preparation of (R)-2-chloro-5-(((2-hydroxyethyl)(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 42)

[0867] To a mixture of compound 42e (87 mg, 0.16 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (20 mg, 0.48 mmol) in H2O (1 mL) was added. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, 1 N HCl was added to adjust the pH to 4-5, the mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give compound 42 (25 mg, yield: 29.49%).

[0868] 1 H NMR (400MHz, DMSO-d6) δppm 8.58(d,J=8.80Hz,2H),8.29(s,1H),8.13(d,J=8.80Hz,2H),7.44(s,2H),5.25-5.32(m,1H),5.10-5.20(m,1H),4.99(br s,1H),3.95-4.08(m,1H),3.87(s,1H),3.72-3.78(m,2H),3.38(br d,J=2.93Hz,2H),3.16(s,1H).

[0869] MS m / z(ESI): 531.05 [M+1].

[0870] Example 29

[0871] (R)-2-chloro-5-((ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 43)

[0872]

[0873] Step 1: Preparation of methyl 2-chloro-5-((ethylamino)methyl)thiophene-3-carboxylic acid (compound 43a)

[0874] Ethylamine (13 mL, 2 M in THF) was added to a tetrahydrofuran (10 mL) solution under ice bath conditions. Then, a tetrahydrofuran solution of compound 3b (1.00 g, 3.7 mmol) was slowly added dropwise, and the reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 43a (0.5 g).

[0875] Step 2: Preparation of 2-chloro-5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid ester (compound 43b)

[0876] At room temperature, 2,4-dichloro-6,7-dihydrothiophene [3,2-d]1d (0.22 g, 1.06 mmol), compound 43a (0.3 g, 1.28 mmol), and triethylamine (0.41 g, 3.19 mmol) were mixed in ethanol (5 mL). The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum concentration, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography to obtain compound 43b (0.3 g).

[0877] Step 3: Preparation of (R)-2-chloro-5-(((2-chloro-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 43c)

[0878] Compound 43b (250 mg, 0.62 mmol), S-1,1'-bi-2-naphthol (17.8 mg, 0.062 mmol), tetraisopropoxytitanium (17.8 mg, 0.062 mmol), and water (22 mg, 1.24 mmol) were mixed in dichloromethane (5 mL) at room temperature and stirred for 1 hour. Then, tert-butanol peroxide (87 mg, 0.68 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 43c (200 mg).

[0879] Step 4: Preparation of (R)-2-chloro-5-(((2-chloro-5-oxy-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)(ethyl)amino)methyl)thiophene-3-carboxylic acid methyl ester (compound 43d)

[0880] Under nitrogen protection, compound 43c (105 mg, 0.25 mmol), compound 1f (100 mg, 0.37 mmol), potassium carbonate (101.9 mg, 0.738 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (18 mg, 0.025 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, and ethyl acetate (30 mL) was added. The organic phase was washed successively 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 rapid column chromatography to obtain the title compound 43d (55 mg).

[0881] Step 5: Preparation of (R)-2-chloro-5-((ethyl(2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieneno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 43)

[0882] To a mixture of compound 43d (25 mg, 0.047 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (9.9 mg, 0.24 mmol) in H2O (1 mL) was added. The reaction mixture was stirred at 40 °C for 2 hours. LCMS showed that the reaction was complete, and the pH was adjusted to 4-5 with 1 N HCl. The mixture was diluted with EA (20 mL), washed with brine (20 mL), dried, and concentrated to give a crude product, which was purified by rapid column chromatography to give title compound 43 (13 mg, yield: 53.4%).

[0883] 1 H NMR(400MHz,DMSO-d6)δppm 8.60(d,J=8.80Hz,2H),8.30(s,1H),8.15(d,J=8.80Hz,2H),7.52(s,1H),7.46(s,1 H),5.11-5.24(m,2H),3.70-4.01(m,4H),3.44-3.49(m,2H),1.29(t,J=6.96Hz,3H).

[0884] MS m / z(ESI): 515.06 [M+1].

[0885] Example 30

[0886] (R)-5-(ethyl(2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 44)

[0887]

[0888]

[0889] Step 1: Preparation of methyl(R)-5-(ethyl(2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid ester (compound 44a)

[0890] Under nitrogen protection, compound 2c (60 mg, 0.16 mmol), compound 14 g (49 mg, 0.24 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (9 mg, 0.012 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 successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain the title compound 44a (50 mg).

[0891] Step 2: Preparation of (R)-5-(ethyl(2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 44)

[0892] To a mixture of compound 44a (50 mg, 0.10 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), LiOH-H2O (15 mg, 0.33 mmol) in H2O (1 mL) was added, and the reaction mixture was stirred at 50 °C for 2 hours. After LCMS showed the reaction was complete, 1 N HCl was added to adjust the pH to 4-5. The mixture was diluted with EA (50 mL), washed with brine (20 mL), dried, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give title compound 44 (20 mg).

[0893] 1 H NMR(400MHz,DMSO-d6)δppm 8.55-8.61(m,3H),8.16(d,J=8.42Hz,2H),8.11(d,J=1.10Hz,1H),7.58(s,1H),5.27(s,2H),3 .985-4.04(m,4H),3.74-3.91(m,2H),3.39-3.48(m,2H),3.16-3.24(m,1H),1.27-1.32(m,3H).

[0894] MS m / z(ESI): 495.12 [M+1].

[0895] Biological evaluation

[0896] Test Example 1: Inhibitory effect of the disclosed compound on PDE4 enzyme

[0897] PDE4 enzyme can hydrolyze cAMP to produce AMP. We co-treated a synthetic PDE4 enzyme inhibitor with PDE4 enzyme and the substrate cAMP for a period of time, using AMP-Glo TM The assay kit is used for detection. The assay involves two steps: first, the AMP produced in the reaction is converted to ADP; second, ADP is converted to ATP. ATP binds to the reagent and emits fluorescence, which is detected using an Echo 550. The IC50 of the PDE4 enzyme inhibitor is calculated by plotting the fluorescence values. 50 The specific details are as follows:

[0898] 1.1 Reagents and Instruments

[0899] 1.1.1 Reagents

[0900]

[0901]

[0902] 1.1.2 Instruments

[0903]

[0904] 1.2 Experimental Procedure

[0905] 1.2.1 Compound preparation and treatment

[0906] a) Preparation of DMSO stock solutions for all compounds: All compounds were dissolved in DMSO to prepare stock solutions with a concentration of 10 mM.

[0907] b) Compound storage: All compounds dissolved in DMSO shall be stored in a desiccator at room temperature for a short period of time.

[0908] 1.2.2 Preparation of working stock solution

[0909] a) Positive control AKEX0834 (compound in Example 2 of WO2013026797A1) was serially diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0910] b) The test compound was serially diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0911] c) Prepare a 200X positive control (1 mM AKEX0834) and a 200X solvent control (100% DMSO). Centrifuge the compound plate at 1000 rpm for 1 minute.

[0912] 1.2.3 Compound Screening

[0913] a) Use an Echo 550 to transfer 20 nL of compound dilution to each well of the detection plate.

[0914] b) Seal the test plate and centrifuge the compound plate at 1000 rpm for 1 minute.

[0915] c) Prepare 2X PDE4B2 or PDE4D2 in frozen PDE assay buffer.

[0916] d) Add 2 μL of 2X PDE4B2 or PDE4D2 to a single well of the detection plate (prepared in step b).

[0917] e) Seal the test plate and equilibrate at room temperature for 10 minutes.

[0918] f) Prepare 2X Cyclic-3',5'-AMP in PDE detection buffer.

[0919] g) Initiate the reaction by adding 2 μL of 2X Cyclic-3',5'-AMP (prepared in step f) to each well of the detection plate (prepared in step e). Incubate at room temperature for 60 minutes.

[0920] h) Add 4 μL of AMP-Glo ​​Reagent I and incubate at room temperature for 60 minutes.

[0921] i) Add 8 μL of AMP detection solution and incubate at room temperature for 60 minutes.

[0922] j) Read the RLU signal on the Envision 2105 reader.

[0923] 1.3 Data Analysis

[0924] The calculation formula is as follows:

[0925] % Inhibition rate = {1 - (average RLU of the compound - average RLU of the positive control across the entire plate) / (average RLU of the negative control across the entire plate - average RLU of the positive control across the entire plate)}

[0926] IC was calculated by fitting the %inhibition value and the logarithm of the compound concentration to a nonlinear regression (dose response-variable slope) using Graphpad 8.0. 50 .

[0927] Table 1. Inhibitory effect of the disclosed compounds on PDE4 enzyme.

[0928]

[0929] Conclusion: The compound disclosed herein has a significant inhibitory effect on PDE4 enzyme.

[0930] Test Example 2: Pharmacokinetic Study of Compound Concentration in Mice Using LC-MS / MS

[0931] Test principle: The concentration of the target drug in plasma at different time points is determined using LC-MS / MS, and the pharmacokinetic curve of the target compound in vivo is plotted.

[0932] Test method:

[0933] Weigh an appropriate amount of the test compound, add 40% PEG400, vortex to dissolve, then add 10% Cremophor RH40, vortex to mix, then add 50% Water, vortex to mix, and obtain a 1.0 mg / mL dosage form.

[0934] The mice were male C57BL / 6J (JH Laboratory Animal Co., LTD). Three mice per group were administered 10 mg / kg PO, and blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Approximately 30 μL of blood sample was collected at each time point and placed in an anticoagulant tube containing EDTA-K2. The plasma was obtained by centrifugation within 30 minutes. Whole blood samples were placed on wet ice before centrifugation. Forty-two plasma samples were collected for each test substance. All collected plasma samples were stored on dry ice or in a freezer until analysis. Blood drug concentrations were determined using the Triplequadrupole MS system (SCIEX), including standard curve and quality control preparation and sample preparation.

[0935] Standard curve and quality control preparation: Dilute the working solution with ACN:H2O (1:1) and add 3 μL of the above standard curve and quality control working solution to 57 μL of blank plasma.

[0936] Sample preparation: Add 70 μL of internal standard solution (Propranolol, Tolbutamide, Glipizide, Osalmid, each 200 ng / mL in ACN) to 7 μL of plasma sample, mix well for 5 minutes, centrifuge at 4000 rpm for 10 minutes, take 50 μL of supernatant and transfer it to a fresh plate containing 200 μL for analysis.

[0937] Chromatographic conditions were optimized based on the mobile phase composition, elution gradient, flow rate, and retention time of each sample. The chromatographic column was a WatersAcquity UPLC HSS T31.8μm, 2.1x50 mm, and the injection volume was 2μL.

[0938] Mass spectrometry was performed using an electrospray ionization source. In positive ion detection mode, multichannel reaction monitoring (MRM) mode was selected for secondary mass spectrometry analysis.

[0939] Based on drug concentration-time data, pharmacokinetic parameters, including peak concentration C, were calculated using a non-compartmental model using WinNonlin 8.2 software. max Peak time T max Area under the drug-time curve (AUC) and elimination half-life (t) 1 / 2 The AUC is calculated using the linear trapezoidal rule (linear up log down).

[0940] The experimental results are as follows:

[0941]

[0942] The results showed that both Examples 1 and 2 had improved half-lives.

[0943] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound of general formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotopic derivative thereof, or pharmaceutically acceptable salt thereof: in: Z is selected from S, O, S(=0)(=N-R z ), SO and S02; R 1 and R 2 are the same or different and each is independently selected from the group consisting of hydrogen, deuterium, R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 ; or R 1 and R 2 together with the nitrogen atom to which they are both attached form an unsubstituted or substituted 4-10 membered heterocyclyl group, said substituted 4-10 membered heterocyclyl group being substituted with at least one R 2.1 group; R is, at each occurrence, independently selected from H, deuterium, halogen, C 2.2 R is, at each occurrence, independently selected from H, deuterium, halogen, C 2.3 R is, at each occurrence, independently selected from H, deuterium, halogen, C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; or R 2.2 and R 2.3 together with the carbon atom to which they are both attached form a C 1-6 cycloalkyl group optionally substituted with halogen, hydroxy or C 3-6 alkyl; R is, at each occurrence, selected from the group consisting of halogen, deuterium, hydroxyl, C 2.1 each independently selected from the group consisting of halogen, deuterium, hydroxyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, -COR a , -COOR a , -CO-NR a R c , -NR a -CO-, -NR a -COOR a , -O-(CH2) t -OR a and Het; Het is selected from C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl; said Het is optionally substituted with one or more groups selected from R Het Het selected from halogen, oxo, hydroxy, amino, C 3-8 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl-(hydroxy-C 1-6 alkyl), heterocyclyl, 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 , -S(O)2-R a and C 1-6 alkyl optionally substituted with one or more groups selected from hydroxy, halogen, C 3-8 alkoxy and C 1-6 cycloalkyl, said heteroaryl is optionally substituted with one or more C 1-6 haloalkyl groups;​ R is, at each occurrence, independently selected from the group consisting of hydrogen, halo, amino, and C1-C6alkyl; a each R is independently selected from the group consisting of hydrogen, amino, and C1-C6alkyl; 1-6 alkyl; each occurrence of R 2.4 and R 2.5 are each independently selected from H, halogen, hydroxyl, C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino, amino substituted with at least one C 1-6 alkyl; or R 2.4 and R 2.5 together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl; R z selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and hydroxy-C 1-6 alkyl; R 6 , R 7 , R 8 and R 9 are the same or different and each is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, halogen and amino; wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; L is selected from the group consisting of a direct bond and -N(R a )-R b -; R b selected from -(CH2) t -; Ring A is selected from C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 4-12 membered heterocyclyl; R 4 each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, -CO-NR a R c , -S(O)2-NR a R c , C 1-6 alkylsulfone, CN and -(CH2) t -CN; Each time it appears, R c Each is independently selected from hydrogen, amino, and C. 1-6 alkyl; R 3 selected from -M-R 3.1 ; M is selected from a direct bond, C 1-6 alkylene, -O-, -NR a -, -NR a -CO-, -CO-, -COO-, -CO-NR a - and -NR a -CO-O-; R 3.1 selected from hydrogen, deuterium, hydroxyl, halogen, amino, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, said R 3.1 optionally substituted with one or more substituents selected from oxo, deuterium, hydroxyl, halogen, amino, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl and C 3-8 cycloalkyl; t can be 0, 1, 2, or 3; s is 1, 2, or 3; k is 1, 2, 3 or 4; n is an integer between 0 and 9.

2. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof, characterized in that Z is selected from S, O, SO and SO2; preferably from SO.

3. The compound of general formula I according to claim 1 or 2, or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, characterized in that R 6 is selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkyl, halogen and amino; preferably from the group consisting of hydrogen, deuterium, hydroxyl, halogen and amino; more preferably from the group consisting of hydrogen, deuterium and halogen; most preferably from the group consisting of hydrogen; Preferably, said R 7 selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkyl, halogen and amino; preferably selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen and amino; more preferably selected from the group consisting of hydrogen, deuterium and halogen; most preferably selected from the group consisting of hydrogen; Preferably, said R 8 is selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkyl, halogen and amino; preferably from the group consisting of hydrogen, deuterium, hydroxyl, halogen and amino; more preferably from the group consisting of hydrogen, deuterium and halogen; most preferably from the group consisting of hydrogen; Preferably, said R 9 is selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkyl, halogen and amino; preferably from the group consisting of hydrogen, deuterium, hydroxyl, halogen and amino; more preferably from the group consisting of hydrogen, deuterium and halogen; most preferably from the group consisting of hydrogen.

4. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that the compound has the structure of formula (III): wherein Rings A, R 1 , R 2 , R 3 , R 4 and n are as defined in any one of claims 1 to 7.

5. The compound of Formula I according to any one of claims 1 or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, characterized in that R 1 is selected from R 2.1 and -(CR 2.2 R 2.3 ) k -R 2.1 ; R is, at each occurrence, independently selected from the group consisting of halogen, hydroxy, hydroxy-C 2.1 each independently selected from the group consisting of halogen, hydroxy, hydroxy-C 1-6 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and Het; R is, at each occurrence, independently selected from the group consisting of H, halogen, C 2.2 R is, at each occurrence, independently selected from the group consisting of H, halogen, C 2.3 alkyl, hydroxy-C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 haloalkyl and C 1-3 alkoxy, preferably from H and methyl; or in each occurrence, said R 2.2 and R 2.3 together with the carbon atom to which they are both attached form a cyclopropane or cyclobutane group optionally substituted with fluoro or hydroxy; Preferably, said R 1 is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-i-butyl, fluoroethyl, trifluoroethyl, cyclopropyl, oxetanyl, 6. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that R... 2 Selected from -(CR) 2.2 R 2.3 ) k -R 2.1 ; R is, at each occurrence, selected from the group consisting of H, halogen, C 2.2 R is, at each occurrence, selected from the group consisting of H, halogen, C 2.3 R is, at each occurrence, selected from the group consisting of H, halogen, C 1-3 alkyl, hydroxy-C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy, preferably from H.

7. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that R 1 and R 2 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4-8 membered heterocyclyl, preferably selected from the group consisting of substituted or unsubstituted 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S, preferably selected from the group consisting of substituted or unsubstituted 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently from each other selected from N or O, preferably selected from the group consisting of substituted or unsubstituted piperidinyl, morpholinyl and tetrahydropyrrolyl; Preferably, said R 2.1 selected from halogen, hydroxy, C 1-3 alkoxy and Het.

8. Compounds of general formula I according to claim 1, wherein Het is selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S; preferably from cyclopropyl, cyclobutyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and thiadiazolyl; most preferably from cyclopropyl, cyclobutyl, thienyl, thiazolyl, isothiazolyl, isoxazolyl and thiadiazolyl; said Het is optionally substituted by one or more groups selected from R 3-5 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S; preferably from cyclopropyl, cyclobutyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and thiadiazolyl; most preferably from cyclopropyl, cyclobutyl, thienyl, thiazolyl, isothiazolyl, isoxazolyl and thiadiazolyl; said Het is optionally substituted by one or more groups selected from R Het or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof.

9. The compound of general formula I as claimed in claim 1, wherein Het is selected from ###0009### or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof. wherein, v can be 0, 1, or 2.

10. Compounds of general formula I according to claim 8 or 9, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that R Het is selected from the group consisting of halogen, oxo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, -(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 and -S(O)2-R a ; preferably from the group consisting of fluorine, chlorine, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, hydroxymethyl, -(CH2) t -COOR a and -S(O)2-R a ; preferably from the group consisting of fluorine, chlorine, hydroxy, methyl, -COOR a and -S(O)2-R a ; Preferably, said R a selected from the group consisting of hydrogen, amino and C 1-3 alkyl; preferably selected from the group consisting of hydrogen, amino and methyl.

11. A compound of general formula I according to claim 1, wherein ring A is selected from C 6-10 aryl, 5-8 membered heteroaryl and 4-12 membered heterocyclyl; preferably from C 6-10 aryl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S, 4-8 membered mono-heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S, 5-12 membered spiro, bridged or fused ring, wherein the 4-8 membered mono-heterocyclyl, 5-12 membered spiro, bridged or fused ring contains 0, 1, 2, 3 or 4 heteroatoms independently from each other selected from N, O or S; more preferably from phenyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, most preferably from phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, 12. Compounds of general formula I according to claim 1, wherein M is selected from the group consisting of a direct bond, -0-, C 1-6 alkylene, -NR a -, -NR a -CO-, -CO-, -COO- and -CO-NH-; preferably from the group consisting of a direct bond, -NH-, -NH-CO-, -N(CH3)-CO-, -0- and C 1-4 alkylene; more preferably from the group consisting of a direct bond, -0- and -CH2-. or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof.

13. A compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that R 3.1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S and 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S; preferably from H, C 1-3 alkyl, C 1-3 haloalkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S and 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently from each other selected from N, O or S; more preferably from H, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolonyl and tetrahydrofuranyl; most preferably from phenyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrahydrofuranyl; said R 3.1 optionally substituted with one or more substituents selected from oxo, C 1-6 alkyl, halo, C 1-6 haloalkyl; preferably, said R 3.1 optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, difluoromethyl, and trifluoromethyl; more preferably, said R 3.1 optionally substituted with one or more substituents selected from oxo, methyl, and chloro.

14. The compound of general formula I as claimed in claim 1, wherein said R 4 each occurrence is independently selected from hydrogen, oxo, C 1-6 alkyl, halo, and -(CH2) t -CN; preferably from hydrogen, oxo, methyl, ethyl, propyl, isopropyl, fluoro, chloro, -(CH2)-CN, and -(CH2)2-CN; more preferably from hydrogen and fluoro; Preferably, t is 0, 1, or 2; Preferably, n is 0, 1, 2, 3, 4 or 5.

15. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound is any one of the following:

16. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound is any one of the following:

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 16 or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative and a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound of general formula I according to any one of claims 1 to 16, its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 17, in the preparation of a medicament for treating and / or preventing PDEs enzyme-mediated diseases or conditions, preferably in the preparation of a medicament for treating and / or preventing PDE4 enzyme-mediated diseases or conditions, more preferably in the preparation of a medicament for treating and / or preventing PDE4B enzyme-mediated diseases or conditions.

19. The use according to claim 18, wherein the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases; Preferably, the respiratory system and lung diseases are selected from respiratory system and lung diseases accompanied by increased mucus production, obstructive lung diseases and airway diseases, and more preferably from COPD, asthma, interstitial lung disease, pulmonary fibrosis (preferably idiopathic pulmonary fibrosis), α1 antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension. Preferably, the gastrointestinal disease is selected from segmental enteritis, ulcerative colitis, and Crohn's disease; Preferably, the inflammatory disease is selected from the group consisting of proliferative and inflammatory skin diseases, arthritic diseases and ocular inflammatory diseases; wherein the inflammatory skin diseases are preferably selected from the group consisting of atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rhinophyma, SAPHO syndrome, skin atrophy, skin photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, eczematous hand dermatitis and psoriasis; the arthritic diseases are preferably selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis; the ocular inflammatory diseases are preferably glaucoma or dry eye syndrome; Preferably, the peripheral or central nervous system disease is selected from the group consisting of 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, neurotic disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumors, apoplexy, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities and multiple sclerosis; Preferably, 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 carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' 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, renal cancer, nasopharyngeal carcinoma, gastric 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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