Dihydrothienopyrimidine compound as well as preparation method and application thereof

Abstract

Relates to a dihydrothienopyrimidine compound as well as a preparation method and application thereof, and belongs to the field of biological medicines. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound in preparation of drugs for treating inflammatory diseases, autoimmune diseases, metabolic diseases, nervous system diseases and related diseases.

Description

Dihydrothienopyrimidine compounds, preparation methods and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 2023103459757, filed on April 3, 2023, and Chinese Patent Application No. 2024102834497, filed on March 13, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a dihydrothienopyrimidine compound, a preparation method and application thereof. Background Art

[0003] PDE4 is the most widespread member of the PDE family, which consists of 11 members, from PDE1 to PDE11, each with distinct locations of expression and substrate catalysis. PDE4 is highly expressed in cells involved in various physiological processes in the brain, kidney, smooth muscle, heart, and endothelium, and is also expressed in cells of the blood system. PDE4 selectively catalyzes the hydrolysis of cAMP in various organs and cells, playing a crucial role in cAMP-mediated signaling pathways such as the cAMP / PKA / CREB, EPAC / Rap1, and ERK / BCL-6 pathways.

[0004] The PDE4 gene family consists of four isoforms, PDE4A-D. Each PDE4 isoform gene can express 3-11 proteins, resulting in at least 25 different PDE4 isoforms. PDE4 isoforms and isoforms exhibit distinct cell-type- and tissue-type-specific intracellular distributions, contributing to their specific roles in cellular function. Different PDE4 isoforms and isoforms can regulate spatially distinct cAMP signaling cascades. PDE4 is expressed in inflammatory cells such as T cells, B cells, eosinophils, neutrophils, airway epithelial cells, and endothelial cells. It specifically hydrolyzes the 3', 5' phosphodiester bond of cAMP to produce 5'-adenosine monophosphate (5'-AMP), thereby regulating the production of pro- and anti-inflammatory cytokines. PDE4 inhibitors inhibit cAMP hydrolysis, effectively increasing cAMP levels and activating protein kinase A (PKA), thereby inhibiting signaling pathways such as NFκB and NFAT, thereby reducing the release of downstream cytokines and chemokines, thereby suppressing inflammation. These factors control the expression of inflammatory mediators such as IL-2, IL-4, IL-6, IL-31, and TNF-α, which in turn regulate the inflammatory responses of T cells, Th2 cells, and other cells, such as neutrophil degranulation, chemotaxis, and adhesion to endothelial cells. In addition to T cells and Th2 cells, inhibiting PDE4 can suppress the inflammatory responses of macrophages, dendritic cells (DCs), Th1, and Th17 cells, and interfere with the phenotype and function of B cells. Therefore, PDE4 targets are widely used in the development of drugs for various inflammatory diseases, such as respiratory diseases (chronic obstructive pulmonary disease, asthma), various skin diseases (psoriasis, atopic dermatitis, etc.), and immune system diseases (systemic lupus erythematosus, rheumatoid arthritis, etc.). In addition, they are also used to develop drugs for diseases such as cognitive and affective disorders, fragile X syndrome, autoimmune diseases, and tumors.

[0005] According to literature, PDE4B is a major inflammatory factor, while PDE4D is more associated with side effects. PDE4D is expressed in multiple tissues throughout the body, with the brain being the primary region of expression. Numerous studies have examined this phenomenon, and vomiting is a major side effect of PDE4 inhibitors. PDE4D is present in the posterior compartment, nucleus tractus solitarius, and locus coeruleus in vitro, all of which are associated with the emetic effects of PDE4 inhibition. This suggests the need for selective inhibitors to ensure safety while maintaining therapeutic efficacy.

[0006] Many PDE4 inhibitors have been published and disclosed, WO2006 / 1111549, WO2007 / 118793, US20070259846, WO2009 / 050236, WO2009 / 050242, and WO2009 / 052268, WO2009 / 050248, WO2013 / 026797 (all Boehringer Ingelheim International), WO2019 / 057806, WO2019 / 11577, WO2019 / 115775, WO2019 / 115776 ((all Leo Pharma, A / S) disclose substituted dihydrothienopyrimidines for the treatment of respiratory or inflammatory diseases. These compounds are said to inhibit the PDE4 enzyme. WO2014 / 066659 (Tetra Discovery Partners) disclosed bicyclic heteroaryl compounds that are said to be PDE4 inhibitors.

[0007] There is still a need to continue to develop new PDE4 inhibitors with a more favorable therapeutic window and fewer side effects.

[0008] The present invention relates to a novel class of substituted dihydrothienopyrimidines. The present invention relates to PDE4 inhibitors, which can be used as therapeutic agents for diseases mediated by PDE4, including chronic obstructive pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, idiopathic pulmonary fibrosis, neurological diseases, cognitive and emotional disorders, fragile X syndrome, other inflammatory allergic diseases and autoimmune diseases, lung damage and tumors.

[0009] The compounds of the present invention may have good oral bioavailability, solubility, absorption, and metabolic stability. They also have a good safety profile, making them better tolerated than other PDE4 inhibitors. Compared to other PDE4 inhibitors, the compounds of the present invention have a certain selectivity for PDE4D and may have an improved window for nausea and vomiting side effects, thereby allowing them to be administered at higher multiples to achieve greater therapeutic effects.

[0010] Summary of the Invention

[0011] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0012] in:

[0013] represents a single bond or a double bond;

[0014] S* represents a chiral sulfur atom, and its configuration is R configuration or S configuration;

[0015] m is selected from 0, 1 or 2;

[0016] R 1 Selected from H or C 1-6 alkyl;

[0017] R 2 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups in;

[0018] Or, R 1 and R 2 The 3-12 membered heterocyclic group or 5-14 membered heteroaryl group is linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, wherein the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group are optionally further substituted by deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R2.4 is substituted by one or more groups in;

[0019] R 3 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 or -NR 3.3 R 3.4 , the amino group, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally deuterated, halogenated, amino, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 and -NR 3.3 R 3.4 is substituted by one or more groups in;

[0020] Or, when m=2, two R 3 Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted by deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 and -NR 3.3 R 3.4 is substituted by one or more groups in;

[0021] R 2.1 、R 2.2 、R 2.3 、R 2.4 、R 2.5 、R 3.1 、R 3.2 、R 3.3 、R 3.4 and R 3.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0022] R 4 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally deuterated, halogenated, hydroxylated, cyanoated, oxoated, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 C(O)-R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2) n9 NR 4.3 R 4.4 is substituted by one or more groups in;

[0023] R 4.1 、R 4.2 、R 4.3 、R 4.4 and R 4.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in the alkoxy group;

[0024] n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from 0, 1, 2, 3 or 4.

[0025] In a preferred embodiment of the present invention, the compound of the present invention is further represented by formula (II-A) or formula (II-B):

[0026] In one embodiment of the present invention, the compounds of formula (II-A) and formula (II-B) described above are further represented by formula (III-A) and (III-B):

[0027] In a preferred embodiment of the present invention, the above R 2 Selected from C 1-6 Alkyl, 3-7 membered monocyclic heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 6-14 Aryl, 5-7 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl, the C 1-6 Alkyl, 3-7 membered monocyclic heterocyclic group, C 3-7Monocyclic cycloalkyl, C 6-14 Aryl, 5-7 membered monocyclic heteroaryl and 9-10 membered bicyclic heteroaryl, optionally further substituted by deuterium, halogen, oxo, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、 -S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups.

[0028] In a preferred embodiment of the present invention, the above R 2 Selected from C 1-6 Alkyl, the C 1-6 Alkyl, optionally further substituted with a 5-6 membered heteroaryl.

[0029] In a preferred embodiment of the present invention, the R 2 is selected from 5-membered heteroaryl, 6-membered heteroaryl, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocyclyl or 10-membered bicyclic heteroaryl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocyclyl and 10-membered bicyclic heteroaryl are optionally further substituted by deuterium, halogen, oxo, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3- 6-membered cycloalkyl, 3-6-membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups.

[0030] In a preferred embodiment of the present invention, the R 2 As shown in formula (III):

[0031] Among them, R 5 and R 5 ' are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups in;

[0032] Preferably, R 5 and R 5 'Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or butyl;

[0033] R 6 is selected from hydroxy, cyano, amino or halogen;

[0034] Alternatively, the R 2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl or naphthyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl or naphthyl alkyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiropanyl, benzopyridinyl, pyridopyridinyl, benzimidazolyl, benzopyrimidinyl and naphthyl, which may optionally be further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, oxirane, oxetanyl, azirane, azetidine, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups;

[0035] The R 2.1 、R 2.2 、R 2.3 、R 2.4 and R 2.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0036] Preferably, the R 2.1 、R 2.2 、R 2.3 、R 2.4 and R 2.5Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, nitromethyl, ethyl, propyl, isopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0037] In a preferred embodiment of the present invention, the above R 2 is selected from pyrazolyl, imidazolyl, triazolyl or tetrazolyl, wherein the pyrazolyl, imidazolyl, triazolyl and tetrazolyl are optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, CD3, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetane, azirane, azetidine, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups, the R 2.1 、R 2.2 、R 2.3 、R 2.4 and R 2.5 As defined above in the present invention.

[0038] In a preferred embodiment of the present invention, the above R 3 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 or -NR 3.3 R 3.4 , the amino group, C1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally deuterated, halogenated, amino, cyano, nitro, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.1 、-C(O)OR 3.1 、-C(O)NR 3.2 R 3.3 、-SR 3.1 、-SOR 3.1 、-OR 3.1 or -NR 3.2 R 3.3 is substituted by one or more groups in;

[0039] The R 3.1 、R 3.2 、R 3.3 、R 3.4 and R 3.5 Each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0040] Preferably, R 3 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -CHF2, -CH2F, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidine, tetrahydropyrrolyl, tetrahydrofuranyl, -CH2OH, -CH2OMe, -CH2NH2, -CH2NHMe, -CH2N(Me)2, -CF3, -CHF2, -CH2F, -CH2CN, -CO-NH2, -CO-NHMe, -CO-N(CH3)2, -SO2Me, -SO2Et, -COMe, -CD3 or -COOMe.

[0041] In a preferred embodiment of the present invention, the above R 4 Selected from C 6-10 Aryl, 5-7 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl, the C6-10 Aryl, 5-7 membered monocyclic heteroaryl and 9-10 membered bicyclic heteroaryl, optionally further substituted by deuterium, halogen, oxo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n1 C(O)-R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5 、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2) n9 NR 4.3 R 4.4 is substituted by one or more groups in;

[0042] Preferably, R 4phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, thiazolothiphenyl, imidazothiazolyl, imidazothiadiazolyl, thienothiazolyl, thiazolothiazolyl, thiazotriazolyl, tetrahydropyrrolophenyl, tetrahydropyrrolopyrimidinyl, pyrazolothiazolyl, thiazolopyrazolyl, imidazothiophenyl, isoindolyl, dihydrofuropyrimidinyl, dihydrothienopyrimidinyl, dihydropyrrolopyrimidinyl, indolyl, dihydroindolyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, benzisoxazolyl, dihydrobenzisoxazolyl , benzoxazolyl, dihydrobenzoxazinyl, dihydrobenzothiazolyl, triazolopyridinyl, dihydrotriazolopyridinyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, thiadiazolyl, tetrazolyl, triazolothiadiazolyl or oxadiazolyl, the phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, thiazolothiphenyl, imidazothiazolyl, imidazothiadiazolyl, thienothiazolyl, thiazolothiazolyl, thiazotriazolyl, tetrahydropyrrolophenyl, tetrahydropyrrolopyrimidinyl, pyrazolothiazolyl, thiazolopyrazolyl, imidazothiophenyl, isoindolyl, dihydrofuropyrimidinyl, dihydrothienopyrimidinyl, dihydropyrrolopyrimidinyl, indolyl, dihydroindolyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, benzisoxazolyl, dihydrobenzisoxazolyl, benzoxazolyl, dihydrobenzoxazinyl, dihydrobenzothiazolyl, triazolopyridinyl, dihydrotriazolopyridinyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, thiadiazolyl, tetrazolyl, triazolothiadiazolyl and oxadiazolyl, optionally deuterated, fluorinated, chlorinated, brominated, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, methyl-substituted pyrazolyl, imidazolyl, methyl-substituted imidazolyl, triazolyl, methyl-substituted triazolyl, tetrazolyl, methyl-substituted tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, furyl, thienyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R 4.1 、-S(O)-R 4.2 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SR 4.5 、-SOR 4.5 、-OR 4.5 or -NR 4.3R 4.4 is substituted by one or more groups in;

[0043] The R 4.1 、R 4.2 、R 4.3 、R 4.4 and R 4.5 Each independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0044] Preferably, R 4.1 、R 4.2 、R 4.3 、R 4.4 and R 4.5 Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0045] In a preferred embodiment of the present invention, the R 4 is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl or 10-membered bicyclic heteroaryl, wherein the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl and 10-membered bicyclic heteroaryl are optionally further substituted by deuterium, halogen, oxo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n1 C(O)-R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5 、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2)n9 NR 4.3 R 4.4 Preferably, the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl and 10-membered bicyclic heteroaryl are optionally further substituted by deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxa Cyclopropane, oxetanyl, aziridine, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, methyl-substituted pyrazolyl, imidazolyl, methyl-substituted imidazolyl, triazolyl, methyl-substituted triazolyl, tetrazolyl, methyl-substituted tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, furanyl, thienyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R 4.1 、-S(O)-R 4.2 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SR 4.5 、-SOR 4.5 、-OR 4.5 or -NR 4.3 R 4.4 is substituted by one or more groups; the R 4.1 、R 4.2 、R 4.3 、R 4.4 and R 4.5 As defined above in the present invention. In a preferred embodiment of the present invention, R 2 Selected from the following groups:

[0046] Alternatively, the R 4 Selected from the following groups:

[0047] In a preferred embodiment of the present invention, the above R 2 It can also be selected from the following groups:

[0048] In a preferred embodiment of the present invention, the compound of the present invention is selected from the following compounds:

[0049] The present invention also provides a preferred embodiment, which relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds or compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers or excipients.

[0050] The present invention further relates to the use of any of the aforementioned compounds, stereoisomers or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation of PDE4 inhibitor drugs.

[0051] The present invention further relates to the use of any of the aforementioned compounds, their stereoisomers or pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions in the preparation of drugs for treating or preventing inflammatory diseases, autoimmune diseases, metabolic diseases, nervous system diseases and related diseases.

[0052] Detailed Description of the Invention

[0053] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0054] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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, and various branched isomers thereof. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred in the present invention.

[0055] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0056] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, and non-limiting examples include wait.

[0057] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0058] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 12 ring atoms; and most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetane, thietanyl, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetane, thietanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminoylidene-1-oxothiopyran, azepanyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, non-limiting examples of which include The heterocyclic group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, hydroxyalkyl, amino, imino, cyano, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0059] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0060] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl.

[0061] The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, such as:

[0062] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0063] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5-8 membered monoheteroaryl or a 7-14 membered biheteroaryl group, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl, an 8-membered biheteroaryl, a 9-membered bicyclic heteroaryl or a 10-membered bicyclic heteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl, etc., preferably pyridoimidazolyl, pyrimidoimidazolyl, benzothiazolyl, thiazolothiphenyl, imidazothiazolyl, thienothiazolyl, thiazolothiazolyl, thiazotriazolyl, pyrazolothiazolyl, thiazolopyrazolyl, imidazothiophenyl, indolyl, quinazolinyl, benzisoxazolyl, benzoxazolyl, triazolopyridinyl, benzofuranyl, isobenzofuranyl, thiadiazolyl, tetrazolyl, triazolothiadiazolyl or oxadiazolyl.

[0064] The heteroaryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, such as:

[0065] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0066] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0067] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0068] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0069] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -C(CH3)2(OH).

[0070] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0071] In the present invention Indicates that the key does not exist;

[0072] The chiral carbon in the compounds of the present invention may be in either R or S configuration.

[0073] The "*" or "*" on the substituent of the present invention It indicates the position where the substituent is attached to the substituted site.

[0074] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atom in the example compounds of the present invention may also be replaced by a deuterium atom.

[0075] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0076] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0077] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0078] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0079] The present invention is described in detail below by way of examples, but this is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining these with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments are, but are not limited to, the examples of the present invention.

[0080] General Methods: The compounds of the present invention can be prepared according to the following non-limiting general methods and examples.

[0081] Scheme 1: Synthesis of compounds of formula (I), wherein R 1 ,R 2 ,R 3 ,R 4 As defined above:

[0082] As shown in Scheme 1, the general compound A can be prepared by reacting commercially available 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with a compound of formula R 1 R 2Typical reaction conditions include heating a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine and an appropriate amine in a suitable protic or polar aprotic solvent at a temperature ranging from room temperature to the boiling point of the solvent in the presence of an added organic or inorganic base. 1 R 2 NH is commercially available or readily synthesized by methods known to those skilled in the art. Suitable conditions include reacting 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with a compound of formula R 1 R 2 The NH amine was reacted in DMF in the presence of DIPEA at 120°C as exemplified in Preparation 1.

[0083] Alternatively, compound A can be prepared by reacting 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with an appropriate amine in a suitable solvent or solvent mixture such as 1,4-dioxane in the presence of a palladium catalyst and a suitable inorganic or organic base such as potassium tert-butoxide, potassium carbonate, or cesium carbonate.

[0084] As shown in Scheme 1, the sulfoxide compound of the general formula compound B can be prepared by reacting the general formula compound A with an appropriate oxidant in a suitable solvent, optionally in the presence of a chiral catalyst. For example, a DCM / water solution of the general formula compound A can be prepared by using t BuOOH was treated at 0°C to room temperature in the presence of Ti(OiPr)4 and (S)-(-)-1,1'-binaphthol for oxidation, as described in Preparation Example 1.

[0085] The sulfoxide compounds of the general formula compound B can be prepared in the form of a single enantiomer or in the form of a mixture of enantiomers and then separated by methods known to those skilled in the art. Alternatively, it may be preferred to subject the compound to the subsequent reaction in the form of a mixture of enantiomers and to separate the enantiomers at a later stage.

[0086] As shown in Scheme 1, compounds of formula (I) can be prepared by reacting compounds of formula B with amines of formula C (which are commercially available or readily synthesized by methods known to those skilled in the art).

[0087] Typical reaction conditions include heating a solution of compound B and an appropriate amine of compound C in a suitable protic or polar aprotic solvent at a temperature ranging from room temperature to the boiling point of the solvent in the presence of an added organic or inorganic base. For example, a DMSO solution of compound B is reacted with an amine of compound C in the presence of DIPEA.

[0088] Alternatively, the compound of formula (I) can also be prepared by reacting compound B with an amine of formula C in a suitable solvent or solvent mixture such as 1,4-dioxane in the presence of a palladium catalyst and a suitable inorganic or organic base such as potassium tert-butoxide, potassium carbonate, cesium carbonate.

[0089] Preparation Examples and Examples

[0090] The following examples are provided for illustrative purposes only and are not intended to limit the present invention in any way. Unless otherwise indicated, all parts are by weight and temperatures are in degrees Celsius. Pressure is at or near atmospheric pressure. All data were obtained using an Agilent 6120 and / or 1100. Except for synthetic intermediates, all reagents used in this invention were obtained from commercial sources. All compound names, except for those for reagents, were generated using ChemDrew 20.0.

[0091] The following abbreviations are used: ACN acetonitrile Boc tert-Butoxycarbonyl (Boc)2O tert-Butyl dicarbonate BH3 borane DCM dichloromethane DMF N,N-dimethylformamide DIEPA N,N-diisopropylethylamine EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EA ethyl acetate Et3N triethylamine HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU O-Benzotriazole-tetramethyluronium hexafluorophosphate HOAc acetic acid HOBt 1-Hydroxybenzotriazole ee Enantiomeric excess mL milliliters g grams mg milligrams ng nanograms mol moles mmol millimoles h hours MeOH methanol NaH sodium hydride NCS N-Chlorosuccinimide PE petroleum ether Pd(dppf)2Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium (Pd(PPh3)4), tetrakis(triphenylphosphine)palladium (PMB), p-methoxybenzylcyanide PPh3, triphenylphosphine (Pin2B2), pinacol borate (THF), tetrahydrofuran (TFA), trifluoroacetic acid (TsOH), 4-toluenesulfonic acid (Xphos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Burgess reagent), methyl N-(triethylammoniumsulfonyl)carbamate

[0092] Preparation Example 1: (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (I01)

[0093] 1)(1-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (I01-b)

[0094] To a solution of 2,4-dichloro-6,7-dihydrothiopheno[3,2-d]pyrimidine (I01-a, 22.60 g, 110.00 mmol) in acetonitrile (200.00 mL) at room temperature were added (1-aminocyclobutyl)methanol hydrochloride (15.00 g, 110.00 mmol) and triethylamine (80.00 mL, 550.00 mmol). The temperature was raised to 65-70°C and stirring continued for 12 hours. Then, water (1.20 L) was slowly added over 20 minutes and the mixture was allowed to cool to 25°C over 2 hours. Stirring was continued for 12 hours, the mixture was filtered, and the filter cake was washed sequentially with a 2:1 mixture of water and acetonitrile (400 mL) and water (200 mL). The resulting solid was dried under vacuum at 50°C for 12 hours to yield I01-b (15 g, 50.52%).

[0095] LCMS: 272.15 [M+H] + .

[0096] 2)(R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (I01)

[0097] To a dichloromethane solution (50.00 mL) of I01-b (10.36 g, 38.00 mmol) at room temperature were added (S)-(-)-1.1'-bis-2-naphthol (4.40 g, 15.20 mmol), Ti(O i To the reaction mixture was added 4-[(2 ... + found; 1 H NMR (400MHz, CD3OD) δ3.89(d,J=2.0Hz,2H),3.71–3.62(m,1H),3.51–3.41(m,1H),3.25–3.10(m,2H),2.30(tt,J=6.4,2.1Hz,4H),1.97–1.77(m,2H).

[0098] Example 1: Synthesis of Compound 1

[0099] 1)(2S)-4-cyano-2-methylpiperidine-1-carboxylic acid tert-butyl ester (1b)

[0100] A mixture of 1-a (2.01 g, 9.39 mmol) and p-toluenesulfonylmethyl isocyanide (2.43 g, 12.31 mmol) in 1,2-dimethoxyethane (20 mL) was cooled to -10°C. Potassium tert-butoxide (2.61 g, 23.33 mmol) was then added portionwise, maintaining the reaction temperature below 0°C. The mixture was allowed to warm to room temperature and stirred for 3 hours before being quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford the product 1-b (1.21 g, 57.6%) as a yellow solid. LCMS: 225.15 [M+H] + .

[0101] 2)(2S)-2-Methylpiperidin-4-carbamic acid methyl ester hydrochloride (1-c)

[0102] To a solution of 1-b (1.21 g, 5.41 mmol) in methanol (1.6 mL) at 0°C was added HCl solution (4N in 1,4-dioxane, 10 mL). After stirring for 3 hours, the mixture was allowed to warm to room temperature and stirred for another 16 hours. The crude product 1-c (1 g) was obtained by concentration. The crude product was used directly in the next reaction without purification. LCMS: 157.13 [M+H] + .

[0103] 3)(2S)-2-Methylpiperidine-4-carboxamidine (1-d)

[0104] To a solution of 1-c (1 g) in methanol (1.6 mL) was added a 7N methanolic ammonia solution (4 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated to afford product 1-d (900 mg). The crude product was used directly in the next reaction without purification. LCMS: 170.1 [M+H] + .

[0105] 4) 5-Chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine (1-e)

[0106] A mixture of 1-d (900 mg) and N-[(2Z)-2-chloro-3-(dimethylamino)-2-propenylidene]-N-methylmethanamine hexafluorophosphate (1.61 g, 5.42 mmol) in MeOH (10 mL) was cooled to -20°C and a solution of MeONa (861 mg, 15.93 mmol) in MeOH (5 mL) was added dropwise. After stirring for 1 hour, the mixture was warmed to room temperature and stirred for 3 hours. The product 1-e was concentrated and purified by reverse phase HPLC to give a yellow oil (60 mg, 4.4%). LCMS: 212.69 [M+H] + .

[0107] 5)(R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1)

[0108] To a solution of 1-e (40 mg, 0.19 mmol) and I01 (51 mg, 0.18 mmol) in THF (1 mL) at room temperature were added DIEPA (73 mg, 0.57 mmol) and water (0.25 mL). The mixture was heated to 65°C and stirred for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by reverse phase HPLC (0.1% TFA in ACN / H2O) to afford the product 1 as a white solid (6.68 mg, 7.7%).

[0109] LCMS: 463.25 [M+H] + .

[0110] 1 H NMR (400MHz, CD3OD) δ8.76(s,2H),5.47(s,1H),4.61(s,1H),4.40(d,J=5.9Hz,1H),3.91(d,J=4.3Hz,2H),3.67(d,J=21.7Hz,1H),3.45(s,1H) ,3.15(s,1H),2.38(s,2H),2.30(s,3H),2.19(dd,J=14.3,7.0Hz,2H),1.89(d,J=8.8Hz,2H),1.27(s,4H),1.07(d,J=6.6Hz,3H),0.88(s,1H).

[0111] Example 2: Synthesis of Compound 2

[0112] 1)(2S)-4-(5-chloropyrimidin-2-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (2-b)

[0113] To a solution of 5-chloro-2-iodopyrimidine 2-a (1.13 g, 4.70 mmol) in toluene (10 mL) at -78°C was added dropwise n-BuLi (1.96 mL, 2.5 M, 4.90 mmol). After stirring for 1 hour, a solution of (S)-tert-butyl 2-methyl-4-piperidone-1-carboxylate 1-a (1.00 g, 4.70 mmol) in toluene (5 mL) was added dropwise. Stirring was continued at -78°C for 2 hours, followed by addition of saturated NH4Cl (100 mL), and extraction with ethyl acetate (100 mL x 2). The organic phases were combined, dried over Na2SO4, and concentrated. Purification by column chromatography (PE:EA = 5:1) afforded the product 2-b as a yellow solid (964 mg, 62.60%). LCMS: 328.81 [M+H] + .

[0114] 2)(S)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2-c)

[0115] To a solution of 2-b (964 mg, 2.90 mmol) in pyridine (10 mL) at 0°C was added dropwise POCl3 (676.00 mg, 4.40 mmol). The mixture was allowed to warm to room temperature, stirred for 1 hour, and concentrated. Purification by column chromatography (PE:EA = 1:1) afforded the product 2-c (200 mg, 21.95%) as a yellow solid. LCMS: 310.79 [M+H] + .

[0116] 3)(S)-5-chloro-2-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (2-d)

[0117] To a solution of 2-c (200 mg, 0.61 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 2 hours, the mixture was concentrated to afford the yellow oily product 2-d (128 mg, 94.81%). LCMS: 210.1 [M+H] + .

[0118] 4)(R)-2-((S)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2)

[0119] To a solution of 2-d (128 mg, 0.61 mmol) and I01 (117 mg, 0.41 mmol) in acetonitrile (5 mL) was added KCO (283 mg, 2.05 mmol). The mixture was heated to 70°C and stirred overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over NaSO and concentrated. Pre-TLC (SiO, dichloromethane / methanol = 10 / 1) was performed to obtain 2 (48.77 mg, 26.22%) as a yellow solid. LCMS: 461.98 [M+H] + .

[0120] 1 H NMR (400MHz, CD3OD) δ8.74 (s, 2H), 7.24 (dd, J = 4.4, 2.3Hz, 1H), 5.16 (s, 1H), 3. 93(d,J=1.9Hz,2H),3.79(dt,J=17.8,7.4Hz,1H),3.52(dt,J=13.7,7.9Hz,1H), 3.40(ddd,J=17.7,8.6,1.6Hz,2H),3.25–3.18(m,1H),3.03–2.95(m,1H),2.62 (d,J=14.6Hz,1H),2.51–2.22(m,5H),1.97–1.87(m,2H),1.44(d,J=6.8Hz,3H).

[0121] According to the above method, the following compounds were synthesized:

[0122] Example 3: Synthesis of Compound 3

[0123] 1) Benzyl 4-(2-thioaminohydrazide-1-carbonyl)piperidine-1-carboxylate (3-b)

[0124] To a solution of N-methylimidazole (NMI, 9.4 g, 114.07 mmol) and N,N,N',N'-N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 12.8 g, 45.62 mmol, 1.2 eq) in acetonitrile (100 mL) at room temperature were added 3-a (10 g, 38.02 mmol, 1.0 eq) and hydrazinothioamide (4.2 g, 45.62 mmol, 1.2 eq). After stirring at room temperature for 16 hours, methanol was added, the mixture was filtered, and the mixture was further washed with methanol to obtain the product 3-b (8 g, 75.36%) as a white solid. LCMS: 337.13 [M+H] + .

[0125] 1) Benzyl 4-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (3-c)

[0126] At room temperature, 3-b (8 g, 23.80 mmol) was added to a 1 M NaOH solution (80 mL) and stirred at 50°C for 1 hour. The mixture was cooled to room temperature and neutralized to pH 5 with 1 M HCl. The mixture was extracted with dichloromethane (3 x 300 mL). The combined organic phases were dried over Na2SO4 and concentrated. Purification by column chromatography (DCM:MeOH / 55:1) afforded the product 3-c (6 g, 83.26%) as a white solid. LCMS: 319.12 [M+H] + .

[0127] 3) Benzyl 4-(thiazolo[3,2-b][1,2,4]triazol-2-yl)piperidine-1-carboxylate (3-d)

[0128] 2-Chloroacetaldehyde (75 mg, 0.94 mmol) was added dropwise to a solution of 3-c (250 mg, 0.79 mmol) in 1,4-dioxane (1 mL) at room temperature. The mixture was then refluxed at 120°C for 4 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (DCM:MeOH / 40:1) to afford the product 3-d (28 mg, 7.7%) as a light yellow solid. LCMS: 343.12 [M+H] + .

[0129] 4) 2-(Piperidin-4-yl)thiazolo[3,2-b][1,2,4]triazole (3-e)

[0130] At room temperature, trimethylsilyl iodide (780 mg, 3.9 mmol) was added dropwise to a solution of 3-d (890 mg, 2.61 mmol) in acetonitrile (10 mL). The mixture was heated to 70°C and stirred for 15 minutes. The mixture was cooled to room temperature and methanol was added. The product was concentrated and purified by column chromatography (DCM:MeOH / 30:1) to afford the product 3-e (608 mg, 95.36%) as a white solid. LCMS: 209.08 [M+H] + .

[0131] 5)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thiazolyl[3,2-b][1,2,4]triazol-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (3)

[0132] To a solution of 3-e (40 mg, 0.19 mmol) and I01 (51 mg, 0.18 mmol) in THF (1 mL) at room temperature were added DIEPA (73 mg, 0.57 mmol) and water (0.25 mL) in sequence. After stirring at 65°C for 3 hours, the mixture was cooled to room temperature, concentrated, and purified by HPLC (0.1% TFA in water / acetonitrile from 5% to 95%) to give the product 3 (6.68 mg, 7.7%) as a white solid. LCMS: 460.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.44(s,1H),4.46(s,2H),3.69(s,2H),3.46(d,J=12.1Hz,2H),3.22(s,4H) ,3.09–2.97(m,2H),2.89(s,1H),2.29–2.23(m,2H),2.16(d,J=7.4Hz,2H),2.01(d,J=12.7Hz,2H),1.64(s,4H).

[0133] Example 4: Synthesis of Compound 4

[0134] 1) Benzyl 4-(5-chlorothiazolyl[3,2-b][1,2,4]triazol-2-yl)piperidine-1-carboxylate (4-a)

[0135] To a solution of 3-d (800 mg, 2.3 mmol) in DMF (10 mL) at room temperature were added NCS (623 mg, 3.5 mmol) and AcOH (28 mg 0.4 mmol). The mixture was heated to 100°C and stirred for 16 hours. The mixture was cooled to room temperature, and H₂O (20 mL) was added. The mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined, dried over Na₂SO₄, and concentrated. Purification by column chromatography (DCM:MeOH / 50:1) afforded the product 4-a (370 mg, 37.6%) as a white solid. LCMS: 377.08 [M+H] + .

[0136] 2) 5-Chloro-2-(piperidin-4-yl)thiazolyl[3,2-b][1,2,4]triazole(4-b)

[0137] At room temperature, trimethylsilyl iodide (71.6 mg, 0.19 mmol) was added dropwise to a solution of 4-a (40 mg, 0.19 mmol) in acetonitrile (4 mL). The mixture was heated to 70°C and stirred for 15 minutes. The mixture was cooled to room temperature and methanol was added. The mixture was concentrated and purified by column chromatography (DCM:MeOH / 30:1) to afford the product 4-b (36.5 mg, 77%) as a white solid. LCMS: 243.04 [M+H] + .

[0138] 3)(R)-2-(4-(5-chlorothiazolyl[3,2-b][1,2,4]triazol-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (4)

[0139] To a solution of 4-b (20 mg, 0.19 mmol) and I01 (11 mg, 0.18 mmol) in THF (1 mL) at room temperature were added DIEPA (73 mg, 0.57 mmol) and water (0.25 mL) in sequence. After stirring at 65°C for 3 hours, the mixture was cooled to room temperature, concentrated, and purified by HPLC (0.1% TFA in water / acetonitrile from 5% to 95%) to give the product 4 (5.24 mg, 27.7%) as a white solid. LCMS: 494.10 [M+H] + .

[0140] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.33(s,1H),4.81(s,1H),4.56(d,J=13.0Hz,2H),3.69(s,2H),3.1 0(t,J=12.4Hz,4H),2.94–2.77(m,3H),2.30(s,2H),2.13(s,2H),1.99(s,2H),1.71(s,2H),1.62(s,2H).

[0141] Example 5: Synthesis of Compound 5

[0142] 1) 2-Bromothiophene[2,3-d]thiazole (5-b)

[0143] To a solution of 5-a (2.8 g, 17.92 mmol) in acetonitrile (50 mL) at room temperature were added t-BuNO2 (2.80 g, 26.88 mmol) and CuBr2 (4.0 g, 17.92 mmol) in sequence. The mixture was heated to 65°C and stirred for 1 hour. The mixture was cooled to room temperature, 6N HCl (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (100% petroleum ether) afforded the product 5-b (750 mg, 19.01%) as a yellow oil. LCMS: 220.11 [M+H] + .

[0144] 2) tert-Butyl 4-(thieno[2,3-d]thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5-c)

[0145] Under argon, 5-b (840.00 mg, 3.82 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.40 g, 4.58 mmol), 2N K2CO3 solution (5.80 mL, 11.46 mmol), and Pd(dppf)Cl2 (280.00 mg, 0.38 mmol) in 1,4-dioxane (10 mL) were stirred at 100°C for 16 hours. The mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (100% petroleum ether) afforded the product 5-c (350.00 mg, 28.45%) as a yellow solid. LCMS: 323.20 [M+H] + .

[0146] 3) tert-Butyl 4-(thieno[2,3-d]thiazol-2-yl)piperidine-1-carboxylate (5-d)

[0147] To a solution of 5-c (150 mg, 0.62 mmol) in EtOH (5 mL) at room temperature was added Pd / C (10%, 15 mg). After hydrogen absorption for 16 hours, the solid was filtered off and the product was concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 5:1) yielded the product 5-d (28 mg, 28.45%) as a yellow oil. LCMS: 325.15 [M+H] + .

[0148] 4) 2-(Piperidin-4-yl)thieno[2,3-d]thiazole (5-e)

[0149] To a solution of 5-d (60 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow oily product 5-e (30 mg, 73.17%). The crude product was used directly in the next reaction without purification. LCMS: 224.95 [M+H] + .

[0150] 5)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thieno[2,3-d]thiazol-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (5)

[0151] To a solution of 5-e (30 mg, 0.13 mmol) and I01 (39 mg, 0.13 mmol) in THF (4 mL) and H₂O (1 mL) at room temperature was added DIEPA (50.40 mg, 0.39 mmol). After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO₂, dichloromethane:methanol = 20:1) yielded the product 5 (28.75 mg, 44.60%) as a white solid.

[0152] LCMS: 476.25 [M+H] + .

[0153] 1 H NMR (400MHz, DMSO-d6) δ7.61(d,J=5.6Hz,1H),7.38(d,J=5.6Hz,1H),4.67(d,J=11.5Hz,2H),3.68(s,2H),3.39(dd,J=16.6,8.5Hz,2H),3.20 –3.14(m,1H),3.06(t,J=11.5Hz,2H),2.92–2.80(m,2H),2.32–2.25(m,2H),2.15–2.07(m,4H),1.73(d,J=8.9Hz,2H),1.62(d,J=9.7Hz,2H).

[0154] Example 6: Synthesis of Compound 6

[0155] 1) 2-(1,2,3,6-tetrahydropyridin-4-yl)thiophene[2,3-d]thiazole (6-a)

[0156] To a solution of 5-c (90 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow oily product 6-a (50 mg, 73.17%). The crude product was used directly in the next reaction without purification. LCMS: 222.95 [M+H] + .

[0157] 2)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thieno[2,3-d]thiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (6)

[0158] At room temperature, DIEPA (55 mg, 0.42 mmol) was added dropwise to a solution of 6-a (47 mg, 0.21 mmol) and I01 (40.00 mg, 0.14 mmol) in THF (4 mL) and H2O (1 mL). After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 20:1) yielded the product 6 (40.71 mg, 61.79%) as a white solid. LCMS: 474.05 [M+H] + .

[0159] 1 H NMR (400MHz, DMSO-d6) δ7.68(d,J=5.6Hz,1H),7.42(d,J=5.6Hz,1H),6.76( s,1H),4.49–4.32(m,2H),3.96(t,J=5.5Hz,2H),3.75–3.69(m,2H),3.40(d d,J=16.8,8.1Hz,1H),3.22–3.16(m,1H),2.98–2.82(m,2H),2.66(d,J=9.0 Hz,2H),2.33(dq,J=19.8,10.5,9.8Hz,4H),2.18(s,2H),1.81–1.70(m,2H).

[0160] Example 7: Synthesis of Compound 7

[0161] 1) tert-Butyl 4-(thieno[2,3-d]thiazol-2-yl)piperidine-1-carboxylate (5-d)

[0162] To a solution of 5-b (1 g, 4.52 mmol) in dry DMA (10 mL) at room temperature under argon was added CuI (173 mg, 0.91 mmol), Pd(dppf)Cl2·CH2Cl2 (732 mg, 0.91 mmol), and 1-(tert-butyloxycarbonyl)piperidin-4-yl)zinc(II) iodide (7-a, 10 mL, 5.43 mmol, 0.5 M) in sequence. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 10:1) afforded the product 5-d (140 mg, 9.49%) as a colorless oil. LCMS: 325.25 [M+H] + .

[0163] 2) tert-Butyl 4-(5-chlorothieno[2,3-d]thiazol-2-yl)piperidine-1-carboxylate (7-b)

[0164] To a solution of 5-d (120 mg, 0.37 mmol) in AcOH (6 mL) at room temperature was added NCS (75 mg, 0.56 mmol). After stirring for 16 hours, the mixture was heated to 80°C and stirred for another 2 hours. The mixture was cooled to room temperature, saturated Na2CO3 solution was added to pH 8, and extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 5:1) afforded the product 7-b as a colorless oil (60 mg, 45.45%). LCMS: 359.15 [M+H] + .

[0165] 3) 5-Chloro-2-(piperidin-4-yl)thieno[2,3-d]thiazole (7-c)

[0166] To a solution of 7-b (70 mg, 0.19 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow solid product 7-c (40.00 mg, 79.25%). The crude product was used directly in the next reaction without purification. LCMS: 259.15 [M+H] + .

[0167] 4)(R)-2-(4-(5-chlorothieno[2,3-d]thiazol-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (7)

[0168] To a solution of 7-c (40 mg, 0.17 mmol) and I01 (50 mg, 0.17 mmol) in THF (4 mL) and H₂O (1 mL) at room temperature was added DIEPA (65.90 mg, 0.51 mmol). After stirring at 65°C for 3 h, the mixture was concentrated. Pre-TLC (SiO₂, dichloromethane:methanol = 20:1) yielded the product 7 (52.91 mg, 67.11%) as a white solid. LCMS: 510.05 [M+H] + .

[0169] 1 H NMR (400MHz, DMSO-d6) δ7.55(s,1H),4.57(d,J=13.2Hz,2H),3.69(d,J=3.5Hz,2H),3.46(d,J=8.7Hz,2H),3.28–3.10(m, 5H), 3.03 (d, J = 9.6Hz, 1H), 2.91 (d, J = 6.9Hz, 1H), 2.30–2.23 (m, 2H), 2.14 (d, J = 8.4Hz, 4H), 1.72 (dd, J = 18.1, 9.2Hz, 4H).

[0170] Example 8: Synthesis of Compound 8

[0171] 1) 2,5-Dibromothiophene[2,3-d]thiazole (8-a)

[0172] To a solution of 5-a (2.8 g, 17.92 mmol) in acetonitrile (50 mL) at room temperature were added t-BuNO2 (2.80 g, 26.88 mmol) and CuBr2 (4.0 g, 17.92 mmol), sequentially. After stirring at 65°C for 1 hour, 6N HCl (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (100% petroleum ether) afforded the product 8-a (1.70 g, 31.72%) as a white solid.

[0173] 2) tert-Butyl 4-(5-bromothieno[2,3-d]thiazol-2-yl)piperidine-1-carboxylate (8-b)

[0174] To a solution of 8-a (1.00 g, 3.43 mmol) in DMA (10 mL) at room temperature were added CuI (128.00 mg, 0.67 mmol), Pd(dppf)Cl2·CH2Cl2 (542.00 mg, 0.67 mmol), and 1-(tert-butyloxycarbonyl)piperidin-4-yl)zinc(II) iodide (7-a, 8.00 mL, 4.01 mmol, 0.5 M) in sequence. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 10:1) afforded the product 8-b (150 mg, 6.54%) as a yellow solid. LCMS: 403.10 [M+H] + .

[0175] 3) 5-Bromo-2-(piperidin-4-yl)thieno[2,3-d]thiazole (8-c)

[0176] To a solution of 8-b (150 mg, 0.19 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow solid product 8-c (80 mg, 70.94%). The crude product was used directly in the next reaction without purification. LCMS: 303.05 [M+H] + .

[0177] 4)(R)-2-(4-(5-bromothieno[2,3-d]thiazol-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (8)

[0178] To a solution of 8-c (80 mg, 0.26 mmol) and I01 (50 mg, 0.17 mmol) in ACN (4 mL) was added KCO (71 mg, 0.51 mmol) at room temperature. After stirring for 3 hours, water (10 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with water, dried over NaSO, and concentrated. Prep-TLC (SiO, dichloromethane:methanol = 15:1) afforded the product 8 (39 mg, 26.71%) as a white solid. LCMS: 554.10 [M+H] + .

[0179] 1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.36(s,1H),4.65(s,1H),3.67(s,2H),3.42(s,2H),3.30(s,2 H),3.15(s,1H),3.05(s,2H),2.88(d,J=21.6Hz,2H),2.30(s,2H),2.10(s,4H),1.75–1.58(m,4H).

[0180] Example 9: Synthesis of Compound 9

[0181] 1) 2,5-di(furan-2-yl)thiazolo[5,4-d]thiazole (9-c)

[0182] A mixture of furan-2-carboxaldehyde (9-a, 10 g, 104.08 mmol) and dithioacetamide (9-b, 6.20 g, 52.04 mmol) was prepared in DMF (100 mL) and stirred at 130°C for 5 hours. The mixture was cooled to room temperature and filtered. The resulting solid was washed sequentially with ethanol, ether, and n-hexane. Further, the product 9-c (3.80 g, 13.31%) was recrystallized from chloroform to obtain a brown solid. LCMS: 275.10 [M+H] + .

[0183] 2) Thiazolo[5,4-d]thiazole-2,5-dicarboxylic acid (9-d)

[0184] To a stirred solution of 9-c (3.83 g, 13.96 mmol) in refluxing t-BuOH (130 mL) were added water (30 mL) and Aliquat 336 (1.70 g, 4.19 mmol) in that order. KMnO4 (25.40 g, 160.56 mmol) was then added portionwise, followed by an additional 70 mL of water. Stirring was continued for 16 hours, followed by filtration. The filter cake was then added to a solution of NaHSO3, stirred for 30 minutes, and filtered. The resulting white solid was washed with water and THF. The white solid was then taken up in water (200 mL), cooled to 0°C, and concentrated hydrochloric acid was added to adjust the pH to 0–1. After standing for half an hour, the mixture was filtered, washed with a small amount of ice water, and dried to yield the product 9-d (800 mg, 24.89%) as a white solid. LCMS: 231.00 [M+H]. + .

[0185] 3) Thiazolo[5,4-d]thiazole (9-e)

[0186] A solution of 9-d (800 mg, 3.47 mmol) in EtOH (10 mL) was stirred at 80°C for 48 hours. The mixture was cooled to room temperature and concentrated to give a yellow solid 9-e (400 mg, 80.97%). LCMS: 143.30 [M+H] + .

[0187] 4) 2-Bromothiazolo[5,4-d]thiazole (9-f)

[0188] To a solution of 9-e (400 mg, 2.81 mmol) in CCl₄ (10 mL) at room temperature were added pyridine (444.52 mg, 5.62 mmol) and liquid bromine (1.35 g, 8.43 mmol). The mixture was heated to 80°C and stirred for 4 hours. The mixture was cooled to room temperature and treated with saturated NaHSO₃ aq. (20 mL). Extraction was performed with dichloromethane (20 mL x 3). The combined organic phases were washed with water, dried over Na₂SO₄, and concentrated. Prep-TLC (SiO₂, petroleum ether:ethyl acetate = 5:1) afforded the product 9-f (150 mg, 24.15%) as a yellow solid. LCMS: 221.00 [M+H] + .

[0189] 5) tert-Butyl 4-(thiazolo[5,4-d]thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9-g)

[0190] To a solution of 9-f (220 mg, 0.99 mmol) in 1,4-dioxane (5 mL) at room temperature were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (306.12 mg, 0.99 mmol), 2N K2CO3 solution (aq. 1.50 mL, 2.97 mmol), and Pd(dppf)Cl2 (73 mg, 0.10 mmol). After stirring at 100°C for 16 hours, the mixture was cooled to room temperature, added with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 5:1) afforded the product 9-g (40 mg, 12.46%) as a yellow oil. LCMS: 324.15 [M+H] + .

[0191] 6) tert-Butyl 4-(thiazolo[5,4-d]thiazol-2-yl)piperidine-1-carboxylate (9-h)

[0192] To a solution of 9-h (50 mg, 0.15 mmol) in EtOH (4 mL) at room temperature was added Pd / C (10%, 5 mg). After 4 hours of hydrogen absorption, the solid was filtered and concentrated. Prep-TLC (SiO2, petroleum ether:ethyl acetate = 5:1) was used to obtain the product 9-h as a yellow oil (9 mg, 17.88%). LCMS: 326.15 [M+H] + .

[0193] 7) 4-(thiazolo[5,4-d]thiazol-2-yl)piperidine (9-i)

[0194] To a solution of 9-h (9 mg, 0.03 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow oily product 9-i (5 mg, 72.21%). The crude product was used directly in the next reaction without purification. LCMS: 226.15 [M+H] + .

[0195] 8)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thiazolo[5,4-d]thiazol-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (9)

[0196] To a solution of 9-i (5 mg, 0.02 mmol) and I01 (10.00 mg, 0.03 mmol) in THF (4 mL) and water (1 mL) was added DIEPA (9.00 mg, 0.07 mmol) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 15:1) yielded the product 9 (4.34 mg, 41.91%) as a white solid. LCMS: 477.00 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.04(s,1H),4.81(s,2H),3.92(d,J=17.4Hz,2H),3.50(d,J=26.5Hz,2H),3.35(d,J=13.9Hz,1H),3.12(d,J=12.0H z,2H),3.08–3.02(m,2H),2.30(d,J=8.0Hz,2H),2.17(s,2H),2.00(s,1H),1.93–1.87(m,2H),1.79(dd,J=12.5,3.8Hz,2H),1.58(s,1H).

[0197] Example 10: Synthesis of Compound 10

[0198] 1) 2-(1,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-d]thiazole (10-a)

[0199] To a solution of 9-g (10 mg, 0.03 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow oily product 10-a (6 mg, 86.95%). The crude product was used directly in the next reaction without purification. LCMS: 224.15 [M+H] + .

[0200] 2)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thiazolo[5,4-d]thiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (10)

[0201] To a solution of 10-a (6 mg, 0.03 mmol) and I01 (10 mg, 0.03 mmol) in THF (4 mL) and H2O (1 mL) at room temperature was added DIEPA (10.40 mg, 0.08 mmol). After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 15:1) yielded the product 10 (8.08 mg, 63.37%) as a yellow solid. LCMS: 475.00 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.06 (s, 1H), 6.80 (s, 1H), 4.48 (d, J = 3.4Hz, 2H), 4.06 (t, J = 5.7Hz, 2H), 3.95 (d, J = 7.5Hz ,2H),3.65(s,1H),3.43(d,J=14.0Hz,1H),3.16(s,2H),2.83(s,2H),2.39–2.33(m,4H),1.92(d,J=8.9Hz,2H).

[0202] Example 11: Synthesis of Compound 11

[0203] 1) Methyl 2-(1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (11-b)

[0204] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) in 1,4-dioxane (20 mL) and H₂O (4 mL) at room temperature was added methyl 2-chloropyrimidine-5-carboxylate (11-a, 1.14 g, 6.47 mmol), K₂CO₃ (1.80 g, 12.94 mmol), and Pd(dppf)Cl₂ (946.00 mg, 1.29 mmol). The mixture was stirred at 90°C under nitrogen for 16 hours. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water, dried over Na₂SO₄, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gave a white solid product 11-b (1.50 g, 72.81%). LCMS: 320.05 [M+H] + .

[0205] 2) 2-(1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (11-c)

[0206] To a solution of 11-b (1.50 g, 4.70 mmol) in THF (20 mL) and H2O (4 mL) at room temperature was added LiOH (225.13 mg, 9.40 mmol). After stirring for 2 hours, the mixture was concentrated to afford the yellow solid product 11-c (1.4 g, 97.62%). The crude product was used directly in the next reaction without purification. LCMS: 306.00 [M+H] + .

[0207] 3) tert-Butyl 4-(5-((2,2-dimethoxyethyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (11-d)

[0208] To a solution of 11-c (1.40 g, 4.58 mmol) in DMF (20 mL) at room temperature were added 2,2-dimethoxyethane-1-amine (481.00 mg, 4.58 mmol), DIEPA (1.77 g, 13.74 mmol), and HATU (2.61 g, 6.87 mmol). Stirring was continued for 4 hours, followed by addition of water (30 mL) and extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (dichloromethane:methanol = 20:1) afforded the product 11-d (1.50 g, 83.37%) as a yellow oil. LCMS: 393.10 [M+H] + .

[0209] 3) tert-Butyl 4-(5-(oxazol-2-yl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (11-e)

[0210] A solution of 11-d (300 mg, 0.76 mmol) in Eaton's reagent (4 mL) was stirred at 65°C for 2 hours at room temperature. The mixture was cooled to room temperature, and then Na2CO3 solution, THF (10 mL), Boc2O (166.88 mg, 0.76 mmol), and DMAP (9.28 mg, 0.08 mmol) were added. After stirring for 1 hour, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 20:1) yielded 11-e (15 mg, 5.97%) as a white solid. LCMS: 329.05 [M+H] + .

[0211] 4) 2-(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)oxazole (11-f)

[0212] To a solution of 11-e (15 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the yellow oily product 11-f (8.00 mg, 76.77%). The crude product was used directly in the next reaction without purification. LCMS: 229.25 [M+H] + .

[0213] 5)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(5-(oxazol-2-yl)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (11)

[0214] To a solution of 11-f (8 mg, 0.04 mmol) and I01 (10 mg, 0.04 mmol) in THF (4 mL) and H₂O (1 mL) at room temperature was added DIEPA (14 mg, 0.11 mmol). After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (ACN:0.1% TFA / H₂O from 5% to 95%) yielded the product 11 (4.59 mg, 27.32%) as a yellow solid. LCMS: 480.10 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.26(s,2H),8.33(s,1H),7.47(s,1H),7.39(s,1H),4.46(s,2H),3.95(t,J=5.6Hz,2H),3.72(s,2H),3.44–3.38(m,2H) ,3.19(dt,J=13.4,8.3Hz,2H),2.89(dt,J=27.1,7.6Hz,2H),2.67(s,2H),2.32(d,J=13.0Hz,2H),2.18(d,J=6.4Hz,2H),1.76(d,J=9.4Hz,2H).

[0215] The following compounds were synthesized using a similar method:

[0216] Example 12: Synthesis of Compound 17

[0217] 1) tert-Butyl 2-methyl (2R)-4-(5-chloropyrimidin-2-yl)-4-hydroxypiperidine-1,2-dicarboxylate (17-b)

[0218] To a solution of 2-a (1.0 g, 4.17 mmol) in anhydrous toluene (20 mL) at -78°C was added dropwise n-BuLi (1.67 mL, 4.17 mmol). After stirring for 1 hour, a toluene solution of 17-a (1.2 g, 4.58 mmol) (5 mL) was added. After stirring at -78°C for 3 hours, a saturated aqueous solution of NH4Cl was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Column chromatography gave the product 17-b (290.0 mg, 18%) as a yellow oil. LCMS: [M-56]+ = 315.90.

[0219] 2) tert-Butyl 2-methyl (R)-4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridine-1,2(2H)-dicarboxylate (17-c)

[0220] Phosphorus trichloride (1.5 mL) was added dropwise to a solution of 17-b (290 mg, 0.81 mmol) in pyridine (3 mL) at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. Water (15 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (PE:EA from 20:1 to 5:1) afforded the product 17-c (100 mg, 10.92%) as a yellow oil. LCMS: 354.10 [M+H] + .

[0221] 3)(R)-4-(5-chloropyrimidin-2-yl)-2-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (17-d)

[0222] To a solution of 17-c (50 mg, 0.14 mmol) in anhydrous THF (3 mL) at 0°C was added dropwise DIBAL-H (0.70 mL, 0.70 mmol). After stirring for 6 hours, saturated aqueous NH4Cl was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Pre-TLC (DCM:Me = 20:1) gave the product 17-d (30 mg, 65%) as a white solid. LCMS: 326.15 [M+H] + .

[0223] 4)(R)-(4-(5-chloropyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-2-yl)methanol (17-e)

[0224] To a solution of 17-d (30 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the product 17-e (20 mg, 96%) as a white solid. The crude product was used directly in the next reaction without purification. LCMS: 226.05 [M+H] + .

[0225] 5)(R)-2-((R)-4-(5-chloropyrimidin-2-yl)-2-(hydroxymethyl)-3,6-dihydropyridin-1(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (17)

[0226] To a solution of 17-e (20.0 mg, 0.09 mmol) and I01 (25.3 mg, 0.09 mmol) in THF (2 mL) / H₂O (0.5 mL) at room temperature was added DIPEA (34.3 mg, 0.27 mmol). After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (ACN:0.1% TFA in H₂O from 5% to 95%) was used to obtain the product 17 (2.70 mg, 6.3%) as a white solid. LCMS: 477.15 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.88(s,2H),7.24-7.34(t,1H),5.07-5.19(m,1H),3.63-3.72(m,4H ),3.37-3.44(m,2H),3.20-3.43(m,2H),2.80-2.91(m,4H),2.18-2.30(m,6H),1.77(s,2H).

[0227] Example 13: Synthesis of Compound 18

[0228] 1) tert-Butyl 4-(2-acetylhydrazine-1-carbonyl)piperidine-1-carboxylate (18-b)

[0229] To a solution of 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid 18-a (40 mg, 0.19 mmol) and acetohydrazide (40 mg, 0.19 mmol) in DMF (1 mL) at room temperature were added HATU (108 mg, 0.29 mmol) and DIPEA (123 mg, 0.95 mmol) in sequence. After stirring for 3 hours, water and 1N HCl were added to a pH of 5-6. The solid was collected by filtration, further washed with water, and dried under vacuum to afford the product 18-b as a white solid (43 mg, 77%). LCMS: 286.15 [M+H] + .

[0230] 2) tert-Butyl 4-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (18-c)

[0231] To a solution of 18-b (54.0 mg, 0.19 mmol) in toluene (2 mL) at room temperature was added Lawessons reagent (77.0 mg, 0.19 mmol, 0.1 eq). The mixture was then stirred at 120°C for 1 hour. The mixture was cooled to room temperature, concentrated, and added with dichloromethane (30 mL). The mixture was washed with water (25 mL x 2), dried over Na2SO4, and concentrated. Purification by column chromatography (DCM:Me = 20:1) afforded the solid product 18-c (24.4 mg, 45%). LCMS: 284.14 [M+H] + .

[0232] 4) 2-Methyl-5-(piperidin-4-yl)-1,3,4-thiadiazole (18-d)

[0233] To a solution of 18-c (66 mg, 0.22 mmol) in dichloromethane (2 mL) at room temperature was added 1 mL. After stirring for 1 hour, the mixture was concentrated and purified by Pre-HPLC (0.1% TFA in water / acetonitrile from 5% to 95%) to afford the product 18-d (40 mg, 90.91%) as a white solid. LCMS: 184.08 [M+H] + .

[0234] 5)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (18)

[0235] To a solution of 18-d (29.3 mg, 0.16 mmol) and I01 (46.1 mg, 0.16 mmol) in THF (4 mL) at room temperature were added DIEPA (60 mg, 0.48 mmol) and water (1 mL). After stirring at 65°C for 16 hours, the mixture was concentrated. Pre-TLC (ACN:0.1% TFA in H2O from 5% to 95%) yielded the product 18 (27.34 mg, 39.37%) as a white solid. LCMS: 435.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ4.51 (s, 2H), 3.69 (d, J = 3.6Hz, 2H), 3.48–3.41 (m, 4H), 3.22 (s, 2H), 3.14 (t, J = 12. 5Hz,2H),2.91(s,1H),2.64(s,3H),2.28(s,2H),2.20–2.13(m,2H),2.04(s,2H),1.70(s,2H),1.58(s,2H).

[0236] The following compounds were synthesized using a similar method:

[0237] Example 13: Synthesis of Compound 19

[0238] 1) Benzyl 4-(2-thioaminohydrazide-1-carbonyl)piperidine-1-carboxylate (19-b)

[0239] To a solution of 1-(benzyloxy)carbonyl)piperidine-4-carboxylic acid (19-a, 79 mg, 0.30 mmol) and thiocarbamoylhydrazide (27.3 mg, 0.30 mmol) in DMF (3 mL) at room temperature were added HATU (167.6 mg, 0.45 mmol) and DIPEA (194.0 mg, 1.50 mmol) in sequence. After stirring for 3 hours, water and 1N HCl were added to a pH of 5-6. The solid was collected by filtration, further washed with water, and dried under vacuum to afford the product 19-b as a white solid (77.4 mg, 76%). LCMS: 337.13 [M+H] + .

[0240] 2) Benzyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (19-c)

[0241] To a solution of 19-b (67.3 mg, 0.20 mmol) in toluene (5 mL) at room temperature was added methanesulfonic acid (2.0 mg, 0.02 mmol). After stirring at 90°C for 2 hours, the mixture was concentrated and saturated NaHCO₃ solution was added. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with water, dried over Na₂SO₄, and concentrated. Pre-TLC (DCM:Me = 20:1) afforded 19-c (22.3 mg, 36%) as a white solid. LCMS: 319.10 [M+H] + .

[0242] 3) Benzyl 4-(5-chloro-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (19-d)

[0243] To a solution of 19-c (100 mg, 0.31 mmol) in ACN (5 mL) at room temperature were added t-BuONO (0.074 mL, 0.62 mmol) and CuCl2 (50 mg, 0.37 mmol) in sequence. After stirring at 65°C for 1 hour, methanol was added and the mixture was concentrated. Pre-TLC (DCM:MeOH = 30:1) gave the solid product 19-d (44 mg, 42%). LCMS: 338.10 [M+H] + .

[0244] 4) 2-Bromo-5-(piperidin-4-yl)-1,3,4-thiadiazole (19-e)

[0245] To a solution of 19-d (50 mg, 0.15 mmol) in DCM (3 mL) was added HBr / HAc (37%, 3 mL) at 0°C. After stirring at room temperature for 1 hour, the mixture was concentrated and purified by Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) to afford the product 19-e (40 mg, 82%) as a yellow oil. LCMS: 248.14, 250.14 [M+H] + .

[0246] 5)(R)-2-(4-(5-bromo-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (19)

[0247] To a solution of 19-e (40.0 mg, 0.12 mmol) and I01 (34.6 mg, 0.12 mmol) in THF (2 mL) at room temperature were added DIPEA (46.4 mg, 0.36 mmol) and water (0.50 mL). After stirring at 65°C for 16 hours, the mixture was concentrated. Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) was used to give the product 19 (22.87 mg, 38.1%) as a white solid. LCMS: [M+1] + =501.20.

[0248] 1 H NMR (400MHz, CD3OD) δ4.83(s,2H),3.93(s,2H),3.53(s,2H),3.40–3.32(m,1H),3.02(s,4H),2.30(s,4H),2.14(s,2H),1.89(s,2H),1.71(s,2H).

[0249] Example 14: Synthesis of Compound 20

[0250] 1) 2-Bromoimidazo[2,1-b][1,3,4]thiadiazole (20-b)

[0251] A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (20 g, 0.11 mol) and 2-chloroacetaldehyde (10.50 g, 0.13 mol) in 1,4-dioxane (200 mL) was stirred at 120°C overnight. After cooling to room temperature, the mixture was washed with ethyl acetate (600 mL), water (200 mL), and saturated brine (200 mL). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) afforded the product 20-b as a yellow oil (426 mg, 1.88%). LCMS: 203.95 [M+H] + .

[0252] 2) tert-Butyl 4-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-1-carboxylate (20-c)

[0253] To a solution of 20-b (426 mg, 2.09 mmol) in DMA (35 mL) were added CuI (79.00 mg, 0.42 mmol), Pd(dppf)Cl2 (343.00 mg, 0.42 mmol), and ((1-(tert-butyloxycarbonyl)piperidin-4-yl)zinc(II) iodide) (5.00 mL, 2.51 mmol) in sequence at room temperature. The mixture was stirred at 80°C overnight. The solid was filtered off, ethyl acetate (100 mL) was added, and the mixture was washed with water (20 mL). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. The product 20-c (50 mg, 7.78%) was purified by column chromatography (PE:EA from 15:1 to 5:1) to afford a yellow oil. LCMS: 309.05 [M+H] + .

[0254] 3) 2-(Piperidin-4-yl)imidazo[2,1-b][1,3,4]thiadiazole (20-d)

[0255] To a solution of 20-c (50.00 mg, 0.16 mmol) in dichloromethane (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated and purified by Pre-TLC (DCM:MeOH = 10:1) to give the product 20-d (20 mg, 60.61%) as a white solid. LCMS: 209.28 [M+H] + .

[0256] 4)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-1-yl)

[0257] -6,7-Dihydrothieno[3,2-d]pyrimidine 5-oxide (20)

[0258] To a solution of 20-d (20 mg, 0.096 mmol) and I01 (28 mg, 0.096 mmol) in THF (4 mL) at room temperature were added DIEPA (37.00 mg, 0.29 mmol) and water (1 mL). The mixture was stirred at 65°C for 16 hours and then concentrated. Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) was used to obtain the product 20 (2 mg, 4.55%) as a white solid.

[0259] LCMS: 460.20 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.87(d,J=1.7Hz,1H),7.24(d,J=1.6Hz,1H), 4.62(s,1H),3.98–3.87(m,2H),3.59–3.51(m,1H),3.47–3.32(m,3H),3.12(d,J=12.1Hz,2H),3.09–3.02( m,2H),2.37–2.29(m,3H),2.17(d,J=12.8Hz,2H),1.92–1.82(m,2H),1.76(d,J=11.4Hz,2H),1.27(s,1H).

[0260] Example 15: Synthesis of Compound 21

[0261] 1) tert-Butyl 4-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (21-a)

[0262] To a solution of 20-b (50 mg, 0.25 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (76 mg, 0.25 mmol), and K2CO3 (102 mg, 0.74 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (18 mg, 0.03 mmol) at room temperature. The mixture was stirred at 100°C for 16 hours, the solid was filtered off, ethyl acetate (50 mL) was added, and the mixture was washed with water (20 mL). The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) afforded the product 21-a (56 mg, 74.67%) as a yellow oil. LCMS: 307.25 [M+H] + .

[0263] 2) 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b][1,3,4]thiadiazole (21-b)

[0264] To a solution of 21-a (56 mg, 0.18 mmol) in dichloromethane (2 mL) at room temperature was added 1 mL of TFA. After stirring for 1 hour, the mixture was concentrated and purified by Pre-TLC (DCM:MeOH = 10:1) to give the product 21-b (40 mg, 68.32%) as a white solid. LCMS: 207.10 [M+H] + .

[0265] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (21)

[0266] To a solution of 21-b (38 mg, 0.13 mmol) and I01 (40.00 mg, 0.13 mmol) in THF (4 mL) at room temperature were added DIEPA (50.00 mg, 0.39 mmol) and water (1 mL). After stirring at 65°C for 16 hours, the mixture was concentrated. Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) was used to give the product 21 (4.70 mg, 7.70%) as a white solid. LCMS: 458.20 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.16(d,J=1.7Hz,1H),7.33(d,J=1.7Hz,1H),6.79(d,J=3 .8Hz,1H),4.43(s,2H),3.96–3.92(m,4H),3.71(d,J=2.5Hz,2H),3.45(dd,J= 17.0,8.2Hz,1H),3.26–3.18(m,1H),3.00(dd,J=17.4,8.0Hz,1H),2.93–2.86 (m,1H),2.67–2.62(m,2H),2.32–2.26(m,2H),2.18(s,2H),1.79–1.69(m,2H).

[0267] Example 16: Synthesis of Compound 22

[0268] 1) 1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (22-b)

[0269] To a solution of butyl 4-methyl-3,6-dihydropyridine-1,4(2H)-dicarboxylate in water (1 mL) / THF (1 mL) / MeOH (2 mL) at room temperature was added LiOH (60 mg, 2.49 mmol). After stirring for 2 hours, 2N HCl was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, and concentrated to afford the product 22-b as a white solid (180 mg, 87.7%). The crude product was used directly in the next reaction without purification. LCMS: 226.12 [MH] - .

[0270] 2) tert-Butyl 4-(2-thioaminohydrazide-1-carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate (22-c)

[0271] To a solution of 22-b (180 mg, 0.79 mmol) and hydrazinemethylthioamide (89.18 mg, 0.98 mmol) in DMF (5 mL) at room temperature were added HATU (450.3 mg, 1.19 mmol) and DIPEA (645.0 mg, 3.95 mmol) in sequence. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, concentrated, and purified by column chromatography (DCM:MeOH from 50:1 to 10:1) to afford 22-c (160 mg, 60.3%) as a white solid. LCMS: 301.13 [M+H]+.

[0272] 3) tert-Butyl 4-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (22-d)

[0273] To a solution of 22-c (200 mg, 0.67 mmol) in water (10 mL) was added 1N NaOH solution at room temperature, followed by stirring at 50°C for 1 hour. The mixture was cooled to room temperature and neutralized with 1N HCl to pH 5. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with water, dried over Na2SO4, concentrated, and purified by column chromatography (DCM:MeOH from 50:1 to 10:1) to afford 22-d as a white solid (180 mg, 95%). LCMS: 283.15 [M+H] + .

[0274] 4) tert-Butyl 4-(5-((2-ethoxy)thio)-1H-1,2,4-triazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (22-e)

[0275] 2-Chloroacetaldehyde (59 mg, 0.76 mmol) was added dropwise to a solution of 22-d (180 mg, 0.63 mmol) in 1,4-dioxane (10 mL) at room temperature. The mixture was stirred at 120°C for 4 hours, cooled to room temperature, concentrated, and purified by column chromatography (DCM:MeOH / 40:1) to afford product 22-e (20 mg, 9.8%). LCMS: 325.13 [M+H] + .

[0276] 5) tert-Butyl 4-(thiazolo[3,2-b][1,2,4]triazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (22-f)

[0277] To a solution of 22-e (20 mg, 0.061 mmol) in 1,4-dioxane (5 mL) at room temperature was added methanesulfonic acid (2.0 mg, 0.02 mmol). After stirring at 100°C for 16 hours, the mixture was concentrated, and then saturated NaHCO₃ solution was added. Extraction with dichloromethane (30 mL x 3) was performed, and the combined organic phases were washed with water, dried over Na₂SO₄, and concentrated. Purification by Pre-TLC (dichloromethane / methanol = 20:1) afforded the product 22-f (16 mg, 85.7%) as a white solid. LCMS: 307.15 [M+H] + .

[0278] 6) 2-(1,2,3,6-tetrahydropyridin-4-yl)thiazolyl[3,2-b][1,2,4]triazole (22-g)

[0279] To a solution of 22-f (16 mg, 0.05 mmol, 1.0 eq) in DCM (1 mL) was added TFA (1 mL) at room temperature. After stirring for 3 hours, the mixture was concentrated and purified by Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) to afford the product 22-g (15.6 mg) as a white solid. LCMS: 207.10 [M+H] + .

[0280] 7)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(thiazolyl[3,2-b][1,2,4]triazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (22)

[0281] To a solution of 22-g (15.6 mg, 0.05 mmol) and I01 (14.4 mg, 0.05 mmol) in THF (1 mL) at room temperature were added DIPEA (19.4 mg, 0.15 mmol) and water (0.25 mL) in sequence. After stirring at 65°C for 4 hours, the mixture was concentrated. Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) purified the product 22 (6.68 mg, 29.2%) as a white solid. LCMS: [M+1]+ = 458.10 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.01(s,1H),7.31(s,1H),6.84(s,1H),4.45(s,2H),4.04(d,J=10.8Hz,2H), 4.00–3.90(m,2H),3.57(s,1H),3.40(s,1H),3.04(s,2H),2.69(s,2H),2.35(s,4H),1.94(s,2H).

[0282] Example 17: Synthesis of Compound 23

[0283] 1) tert-Butyl 4-(5-(thiazol-2-yl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (23-a)

[0284] To a solution of 2-c (100 mg, 0.32 mmol) in H2O (1 mL) / 1,4-dioxane (4 mL) at room temperature were added CS2CO3 (312 mg, 0.96 mmol), XPhos-Pd-G3 (28 mg, 0.03 mmol), and 2-(tributyltinyl)thiazole (122.00 mg, 0.32 mmol). After stirring at 70°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with water, dried over Na2SO4, concentrated, and purified by column chromatography (PE:EA from 15:1 to 5:1) to afford the product 23-a (66 mg, 67.35%) as a yellow solid. LCMS: 359.43 [M+H] + .

[0285] 2)(S)-2-(2-(2-methyl 1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)thiazole (23-b)

[0286] To a solution of 22-c (66 mg, 0.22 mmol) in dichloromethane (2 mL) was added TFA (1 mL) at room temperature. After stirring for 3 hours, the mixture was concentrated and purified by Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) to afford the product 23-b (40.00 mg, 90.91%) as a white solid. LCMS: 259.19 [M+H] + .

[0287] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((S)-2-methyl-4-(5-(thiazol-2-yl)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (23)

[0288] To a solution of 23-b (40 mg, 0.16 mmol) and I01 (45 mg, 0.16 mmol) in THF (4 mL) at room temperature were added DIEPA (60 mg, 0.48 mmol) and water (1 mL). After stirring at 65°C for 4 hours, the mixture was concentrated. Pre-HPLC (0.1% TFA in ACN / H2O from 5% to 95%) was used to give the product 23 (4.50 mg, 5.53%) as a white solid. LCMS: 510.30 [M+H] + ; 1 H NMR (400MHz, DMSO) δ9.27 (s, 2H), 8.02 (d, J = 3.2Hz, 1H), 7.93 (d, J = 3.2Hz, 1H) ,7.32(t,J=3.2Hz,1H),5.19(s,1H),4.82(s,1H),3.72(s,2H),3.42(d,J=9.6 Hz,1H),3.23–3.18(m,1H),3.15–2.95(m,3H),2.90–2.82(m,2H),2.33(dt,J= 28.6,11.4Hz,4H),2.19(s,2H),1.77(d,J=8.3Hz,2H),1.30(d,J=6.7Hz,3H).

[0289] The following compounds were synthesized using a similar method:

[0290] Example 18: Synthesis of Compound 102

[0291] 1) Synthesis of tert-butyl (S)-4-(5-(azetidin-1-yl)pyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (102a)

[0292] To a solution of 2c (50.00 mg, 0.19 mmol, 1 eq) in 1,4-dioxane (4 mL) was added azetidine (11.24 mg, 0.19 mmol, 1 eq), Pd2(dba)3 (18.03 mg, 0.01 mmol, 0.1 eq), Xantphos (22.78 mg, 0.03 mmol, 0.2 eq) and Cs2CO3 (150 mg, 0.46 mmol, 3 eq). The mixture was stirred at 110 ° C for 16 hours under a nitrogen atmosphere. LCMS detection reaction was complete. The mixture was quenched with water (20 mL), filtered and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a preparative thin-layer silica gel plate (SiO2, petroleum ether:ethyl acetate = 1:1) to give the title compound 102a (40.00 mg, 75.0% yield). LCMS: 331.21 [M+H] + .

[0293] 2) Synthesis of (S)-5-(azetidin-1-yl)-2-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine trifluoroacetate

[0294] To a solution of compound 102a (40.00 mg, 0.12 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated to afford compound 102b (28.50 mg, 71.7% yield) as a yellow oil, which was used directly in the next step without further purification. LCMS: 231.15 [M+H] + .

[0295] 3. Synthesis of (R)-2-((S)-4-(5-(azetidin-1-yl)pyrimidin-2-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (102)

[0296] To a solution of compound 102b (28.50 mg, 0.087 mmol, 1 eq) and intermediate I01 (25.01 mg, 0.087 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIPEA (33.67 mg, 0.26 mmol, 3 eq) at room temperature. After addition, the mixture was stirred at 65°C under a nitrogen atmosphere for 3 hours. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by Pre-HPLC (0.1% TFA in ACN / H₂O) to give the title compound 102 (4.75 mg, 11.35% yield). LCMS: 482.4 [M+H] + , 1 H NMR(400MHz, Methanol-d4)δ7.94(s,2H),6.85(d,J=4.0Hz,1H),4.05–3.87(m,7H),3.74–3.67(m,1H),3.46(s,1H),3.17(dd,J=14.9, 7.3Hz,2H),2.90(d,J=17.4Hz,1H),2.51–2.35(m,6H),2.34(s,1H),1.92(s,2H),1.39(d,J=6.7Hz,3H),1.28(dd,J=12.0,5.5Hz,4H).

[0297] The following compounds were synthesized using a similar method

[0298] Example 19: Synthesis of (R)-2-((S)-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (107)

[0299] 1) Synthesis of methyl 3-bromo-1-(2-bromoethyl)-1H-pyrazole-5-carboxylate (107b)

[0300] To a solution of 107a (900.00 mg, 4.39 mmol, 1 eq) in acetonitrile (20 mL) were added 1,2-dibromoethane (743.00 mg, 3.95 mmol, 0.9 eq) and K2CO3 (3.03 g, 21.95 mmol, 5 eq) at room temperature. The mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. LCMS confirmed the reaction was complete. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound 107b (490.00 mg, 35.77%). LCMS: 312.85 [M+H] + .

[0301] 2) Synthesis of (3-bromo-1-(2-bromoethyl)-1H-pyrazol-5-yl)methanol (107c)

[0302] At 0 ° C, under nitrogen protection, LiBH4 (2.10 mL, 4.25 mmol, 2.7 eq, 2 M) was added dropwise to a solution of compound 107b (490.00 mg, 1.58 mmol, 1 eq) in dry THF (10 mL). Stir at room temperature for 5 hours. LCMS detection showed that the reaction was complete. The mixture was quenched with saturated NH4Cl (aqueous solution 20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound 107c (440.00 mg, yield: 98.65%). LCMS: 284.85 [M+H] + .

[0303] 3) Synthesis of 2-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (107d)

[0304] To a solution of compound 107c (440.00 mg, 1.55 mmol, 1 eq) in DMF (5 mL) was added TEA (314.00 mg, 3.10 mmol, 2.0 eq) at room temperature. The mixture was then stirred at 100°C for 3 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to afford the title compound 107d (150.00 mg, 47.67% yield). LCMS: 203.00 [M+H] + .

[0305] 4) Synthesis of tert-butyl (S)-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (107e)

[0306] To a solution of compound 107d (100.00 mg, 0.49 mmol, 1 eq) in 1,4-dioxane (5 mL) and H2O (1 mL) was added (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (320.00 mg, 0.99 mmol, 2 eq), XPhos-Pd-G3 (42.00 mg, 0.05 mmol, 0.1 eq) and Cs2CO3 (479.00 mg, 1.47 mmol, 3.0 eq) at room temperature. The mixture was then stirred at 120 ° C for 2 hours. LCMS detection showed that the reaction was complete. Cooled to room temperature, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to give the title compound 107e (35.00 mg, 22.24% yield). LCMS: 320.15 [M+H] + .

[0307] 5) Synthesis of (S)-2-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (107f)

[0308] A solution of 107e (50.00 mg, 0.16 mmol, 1 eq) in HCl / dioxane (4 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated to afford the title compound 107f (25.00 mg, 72.82% yield), which was used directly in the next step without further purification. LCMS: 220.20 [M+H] + .

[0309] 6)(R)-2-((S)-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-

[0310] Synthesis of 4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (107)

[0311] To a solution of compound 107f (25.00 mg, 0.12 mmol, 1 eq) and intermediate I01 (34.00 mg, 0.12 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEA (47.00 mg, 0.36 mmol, 3 eq) at room temperature. The mixture was then stirred at 65°C for 16 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (SiO₂, dichloromethane:methanol = 10:1) to afford the title compound 107 (2.55 mg, 5.19% yield). LCMS: 471.10 [M+H] + . 1 H NMR(400 MHz, CD3OD) δ6.23(s,1H),6.19(s,1H),4.78(s,2H),4.56(s,2H),4.08(s,4H),3.95(s,1H),3.89(d,J=11.3Hz,1H),3.58–3. 51(m,1H),3.37–3.33(m,1H),3.14(s,1H),3.11–3.00(m,4H),2.35(dd,J=24.3,15.4Hz,6H),1.92–1.85(m,2H),1.29(s,3H).

[0312] The following compounds were synthesized using a similar method

[0313] Referring to the preparation methods of Examples 1 to 19, the following compounds were synthesized:

[0314] Example 20: In vitro activity test

[0315] A. PDE4B2 and PDE4D2 enzyme assays

[0316] All compounds were dissolved in DMSO to a 10mM or 20mM stock solution. The test compound was diluted 3-fold with DMSO. 20nL of compound or DMSO control was transferred to each well of a 384-well plate using an Echo 550 instrument. Seal the membrane and centrifuge for 1 minute. Prepare 2x enzyme solution with assay buffer, add 2uL of 2x enzyme solution to each well, and equilibrate at room temperature for 10 minutes. Prepare 2x Cyclic-3',5'-AMP substrate solution with assay buffer, add 2uL of 2x substrate solution to each well, incubate at room temperature for 60 minutes, add 4uL AMP-glo reagent, and incubate at room temperature for 60 minutes. Add 8ul AMP detection solution and incubate at room temperature for 60 minutes. Read the RLU value on the Envision 2105 plate reader. The RLU value represents the concentration of the product AMP. Inhibition rate % = (1-(RLU 阳性对照 -RLU 化合物 ) / (RLU 阳性对照 -RLU 阴性对照 ))*100, and then use Graphpad 8.0 software Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))Calculate IC 50 value.

[0317] The experimental results are shown in Table 1 and Table 2:

[0318] Table 1

[0319] Table 2

[0320] The above data show that the compounds of the present invention have strong inhibitory activity against PDE4B2 and PDE4D2 enzymes.

[0321] B. PDE4B2 cell experiments

[0322] All compounds were dissolved in DMSO to a 10 mM or 20 mM stock solution. Test compounds were serially diluted three-fold in DMSO. Foskolin (10 mM) was first transferred (20 nL) to each well of a 384-well cell culture plate using an Echo instrument. 40 nL of compound or DMSO control was then transferred to each well of a 384-well plate using an Echo 550 instrument. Flpin-293-PDE4B2 cells were digested, resuspended in assay buffer, and seeded into 384-well cell culture plates at a seeding density of 20,000 cells per well in a 20 μL seeding volume. Incubate at 37°C for 30 minutes. Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP and dilute in lysis buffer. Add 10 μL of Eu-cAMP tracer to the assay wells, followed by 10 μL of Ulight-anti-cAMP. The reaction plate was centrifuged at 200 g for 30 seconds at room temperature and allowed to stand at 25°C for 1 hour before data collection using Envision. % Inhibition = 100 - (Signal Compound - SignalAve Positive Control) / (SignalAve Negative Control - SignalAve Positive Control) × 100. Graphpad 8.0 software was then used to calculate the Y value: Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))Calculate IC 50 value.

[0323] The experimental results are shown in Tables 3 and 4.

[0324] Table 3

[0325] Table 4

[0326] The above data show that the compound of the present invention has strong inhibitory activity on PDE4B2 cells.

[0327] Example 21: LPS-induced PBMC TNFa release cell experiment

[0328] Human PBMCs were purchased from TPCS, Catalog No. PB025C-W. PBMCs were seeded into 96-well plates. All compounds were dissolved in DMSO to a 10 mM stock solution. Positive and test compounds were diluted 3-fold in DMSO, then diluted in culture medium and added to the 96-well plates, achieving a maximum compound concentration of 3000 nM or 1000 nM in the test wells. LPS was purchased from Sigma (Cat. No. L2880), diluted in culture medium, and added to the 96-well plates. The plates were incubated at 37°C in a 5% CO2 incubator for 24 hours. The supernatant was centrifuged and assayed using an ELISA kit (R&D, Catalog No. VAL105). OD450 data were collected on an Envision instrument. % Inhibition = 100 - (Signal Compound - SignalAve Positive Control) / (SignalAve Negative Control - SignalAve Positive Control) × 100. IC was then calculated using Graphpad 8.0 software: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)) 50 value.

[0329] The experimental results are shown in Table 5:

[0330] Table 5

[0331] The experimental results show that the compound of the present invention has excellent TNFα inhibitory activity under human PBMC secretion, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and has a good anti-inflammatory effect.

[0332] Example 22: Pharmacokinetics test in mice

[0333] Male ICR mice were fasted overnight. Six mice were weighed before dosing, and the dose was calculated based on body weight. Three mice were administered intravenously or orally via gavage. The compound vehicle consisted of 5% DMSO + 10% solutol + 85% saline. The compound was administered orally via gavage at 3 mg / kg, and via tail vein injection at 1 mg / kg. IV administration was repeated 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after dosing. PO administration was repeated 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing. Blood was collected from the jugular vein, approximately 0.03 mL per sample, anticoagulated with sodium heparin, and placed on ice. Blood samples were placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800 g, 6 minutes, 2-8°C). Plasma samples were stored at -80°C until analysis. Intraday accuracy assessment of quality control samples was performed simultaneously with sample analysis, with a requirement that over 66.7% of quality control samples have an accuracy between 80% and 120%. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 using plasma drug concentration data at different time points, providing parameters such as AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, along with their mean and standard deviations.

[0334] The experimental results are shown in Table 6:

[0335] Table 6

[0336] The experimental results show that the compound of the present invention has good bioavailability and excellent pharmacokinetic properties.

[0337] The examples of this patent are provided by way of illustration only and not limitation. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially similar results.

[0338] Although the technical solutions of the present invention have been described and listed in detail, it should be understood that these are merely examples for those skilled in the art. It is obvious to those skilled in the art to make modifications to the above embodiments or adopt equivalent alternatives. These modifications or improvements made without departing from the spirit of the present invention are within the scope of protection claimed by the present invention.

Claims

1. A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: represents a single bond or a double bond; S* represents a chiral sulfur atom, and its configuration is R configuration or S configuration; m is selected from 0, 1 or 2; R 1 Select from H or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups; Or, R 1 and R 2 The 3-12 membered heterocyclic group or the 5-14 membered heteroaryl group are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, wherein the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group are optionally further substituted by deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups; R 3 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 or -NR 3.3 R 3.4 , the amino group, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 and-NR 3.3 R 3.4 is substituted by one or more groups; Or, when m = 2, two R 3 Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 and-NR 3.3 R 3.4 is substituted by one or more groups; R 2.1 , R 2.2 , R 2.3 , R 2.4 , R 2.5 , R 3.1 , R 3.2 , R 3.3 , R 3.4 and R 3.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 4 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 C(O)- R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5 、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2) n9 NR 4.3 R 4.4 is substituted by one or more groups; R 4.1 , R 4.2 , R 4.3 , R 4.4 and R 4.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in the alkoxy group; n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by formula (II-A) or formula (II-B):

3. The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compounds of formula (II-A) and formula (II-B) are further represented by formula (III-A) and (III-B):

4. The compound according to claim 2 or 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 2 Selected from C 1-6 Alkyl, 3-7 membered monocyclic heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 6-14 aryl, 5-7 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, 3-7 membered monocyclic heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 6-14 aryl, 5-7 membered monocyclic heteroaryl and 9-10 membered bicyclic heteroaryl, optionally further substituted with deuterium, halogen, oxo, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups.

5. The compound according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 2 is selected from 5-membered heteroaryl, 6-membered heteroaryl, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocyclyl or 10-membered bicyclic heteroaryl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocyclyl and 10-membered bicyclic heteroaryl are optionally further substituted by deuterium, halogen, oxo, cyano, hydroxyl, C 1- 3 alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups in; said R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably, the R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, nitromethyl, ethyl, propyl, isopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

6. The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 2 is selected from pyrazolyl, imidazolyl, triazolyl or tetrazolyl, wherein the pyrazolyl, imidazolyl, triazolyl and tetrazolyl are optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, CD3, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetane, aziridine, azetidine, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups; said R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably, the R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, nitromethyl, ethyl, propyl, isopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

7. The compound according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 2 As shown in formula (III): Among them, R 5 and R 5 ' are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups; Preferably, R 5 and R 5 'Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or butyl; R 6 is selected from hydroxy, cyano, amino or halogen; Or, R 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl or naphthyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl , tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiropanyl, benzopyridinyl, pyridopyridinyl, benzimidazolyl, benzopyrimidinyl and naphthyl, which may be further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetanyl, azirane, azetidine, -C(O)-R 2.1 、-S(O)2-R 2.2 、-C(O)OR 2.1 、-C(O)NR 2.3 R 2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups; The R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; Preferably, the R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, nitromethyl, ethyl, propyl, isopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

8. The compound according to any one of claims 2 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 3 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.2 、-C(O)OR 3.1 、-C(O)NR 3.3 R 3.4 、-SOR 3.2 、-OR 3.5 、-SR 3.5 or -NR 3.3 R 3.4 , the amino group, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 3.1 、-S(O)2-R 3.1 、-C(O)OR 3.1 、-C(O)NR 3.2 R 3.3 、-SR 3.1 、-SOR 3.1 、-OR 3.1 or -NR 3.2 R 3.3 is substituted by one or more groups; The R 3.1 , R 3.2 , R 3.3 , R 3.4 and R 3.5 Each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R 3 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -CHF2, -CH2F, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidine, tetrahydropyrrolyl, tetrahydrofuranyl, -CH2OH, -CH2OMe, -CH2NH2, -CH2NHMe, -CH2N(Me)2, -CF3, -CHF2, -CH2F, -CH2CN, -CO-NH2, -CO-NHMe, -CO-N(CH3)2, -SO2Me, -SO2Et, -COMe, -CD3 or -COOMe.

9. The compound according to any one of claims 2 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 4 Selected from C 6-10 aryl, 5-7 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl, wherein the C 6-10 aryl, 5-7 membered monocyclic heteroaryl and 9-10 membered bicyclic heteroaryl, optionally further substituted by deuterium, halogen, oxo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n1 C(O)-R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5 、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2) n9 NR 4.3 R 4.4 is substituted by one or more groups; Preferably, R 4 phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, thiazolothiphenyl, imidazothiazolyl, imidazothiadiazolyl, thienothiazolyl, thiazolothiazole, thiazotriazolyl, tetrahydropyrrolophenyl, tetrahydropyrrolopyrimidinyl, pyrazolothiazolyl, thiazolopyrazolyl, imidazothienyl, isoindolyl, dihydrofuranopyrimidine yl, dihydrothienopyrimidinyl, dihydropyrrolopyrimidinyl, indolyl, dihydroindolyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, benzisoxazolyl, dihydrobenzisoxazolyl, benzoxazolyl, dihydrobenzoxazinyl, dihydrobenzothiazolyl, triazolopyridinyl, dihydrotriazolopyridinyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, thiadiazolyl, tetrazolyl, triazolopyridinyl, dihydrotriazolopyridinyl, oxadiazole or oxadiazole, the phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, thiazolothienyl, imidazothiazolyl, imidazothiadiazolyl, thienothiazolyl, thiazolothiazolyl, thiazolotriazolyl, tetrahydropyrrolophenyl, tetrahydropyrrolopyrimidinyl, pyrazolothiazolyl, thiazolopyrazolyl, imidazothienyl, isocyanate indolyl, dihydrofuranopyrimidinyl, dihydrothienopyrimidinyl, dihydropyrrolopyrimidinyl, indolyl, dihydroindolyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, benzisoxazolyl, dihydrobenzisoxazolyl, benzoxazolyl, dihydrobenzoxazininyl, dihydrobenzothiazolyl, triazolopyridinyl, dihydrotriazolopyridinyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl , thiazolyl, tetrazolyl, triazolothiazolyl and oxadiazolyl, optionally substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, methyl substituted pyrazolyl, imidazolyl, methyl substituted imidazolyl, triazolyl, methyl substituted triazolyl, tetrazolyl, methyl substituted tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, furanyl, thienyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R 4.1 、-S(O)-R 4.2 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SR 4.5 、-SOR 4.5 、-OR 4.5 or -NR 4.3 R 4.4 is substituted by one or more groups; The R 4.1 , R 4.2 , R 4.3 , R 4.4 and R 4.5 Each independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R 4.1 , R 4.2 , R 4.3 , R 4.4 and R 4.5 Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

10. The compound according to claim 2-8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 4 is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl or 10-membered bicyclic heteroaryl, wherein the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl and 10-membered bicyclic heteroaryl are optionally further substituted by deuterium, halogen, oxo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n1 C(O)-R 4.1 、-(CH2) n2 S(O)-R 4.2 、-(CH2) n3 S(O)2-R 4.2 、-(CH2) n4 C(O)OR 4.1 、-(CH2) n5 C(O)NR 4.3 R 4.4 、-(CH2) n6 SR 4.5 、-(CH2) n7 SOR 4.5 、-(CH2) n8 OR 4.5 or -(CH2) n9 NR 4.3 R 4.4 Preferably, the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl and 10-membered bicyclic heteroaryl are optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxa- Cyclopropane, oxetanyl, aziridine, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, methyl substituted pyrazolyl, imidazolyl, methyl substituted imidazolyl, triazolyl, methyl substituted triazolyl, tetrazolyl, methyl substituted tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, furanyl, thienyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R 4.1 、-S(O)-R 4.2 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SR 4.5 、-SOR 4.5 、-OR 4.5 or -NR 4.3 R 4.4 is substituted by one or more groups in 4.1 , R 4.2 , R 4.3 , R 4.4 and R 4.5 Each independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; preferably, R 4.1 , R 4.2 , R 4.3 , R 4.4 and R 4.5 Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, oxirane, oxetanyl, azirane, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

11. The compound according to any one of claims 2 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 2 Selected from the following groups: Or, R 4 Selected from the following groups:

12. The compound according to any one of claims 2 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

13. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

14. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a PDE4 inhibitor drug.

15. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the composition according to claim 13 in the preparation of a medicament for treating or preventing inflammatory diseases, autoimmune diseases, metabolic diseases, nervous system diseases and related diseases.