Substituted dihydrothienopyrimidine compound as well as preparation method and application thereof

Abstract

The invention relates to a substituted 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 as shown in a general formula (I), a preparation method thereof, 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, and substituents in the general formula (I) are as defined in the specification.

Description

Substituted dihydrothienopyrimidine compounds, preparation methods and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 2023103934873, filed on April 13, 2023, and Chinese Patent Application No. 2024103199932, filed on March 20, 2024. The entire text of the above-mentioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a substituted 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 aims to provide a novel class of substituted dihydrothienopyrimidine compounds. 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] S* represents a chiral sulfur atom, and its configuration is R configuration or S configuration;

[0014] W is selected from N, CH or C;

[0015] Ring A is a monocyclic group or a bicyclic group, wherein the monocyclic group is selected from 5-8 membered heteroaryl or C 6-10 Aryl, the bicyclic group is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroarylphenyl, 5-6 membered cycloalkylphenyl, 5-6 membered cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocyclylphenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, benzo 5-6 membered heterocyclyl or benzo 5-6 membered heteroaryl;

[0016] R1 is selected from hydrogen or C 1-6 alkyl;

[0017] R2 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted C 1-6 Alkyl, R 2.1 Substituted C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 membered heteroaryl, C 1-6 Alkyl-substituted 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] Alternatively, R1 and R2 are linked to form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally further substituted with deuterium, deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic groups;

[0019] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0020] Alternatively, any one of R3 is linked to a carbon atom on the ring to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0021] R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, 5-8 membered heteroaryl, -C(O)-R 4.1 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SOR 4.2 、-OR 4.5 、-SR 4.5 or -NR 4.3 R 4.4 , the C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered heterocyclic group and 5-8 membered heteroaryl, which may be further substituted with deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, -NR 4.3 R 4.4 、C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic groups;

[0022] R5 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 5.1 、-S(O)2-R 5.2 、-C(O)OR 5.1 、-C(O)NR 5.3 R 5.4 、-SOR 5.2 、-OR 5.5 、-SR 5.5 or -NR 5.3 R 5.4 ;

[0023] Alternatively, R4 and R5 are linked to form a 5-6 membered heteroaryl or C 6-10 Aryl, the 5-6 membered heteroaryl and C 6-10 Aryl, optionally further substituted with deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic groups;

[0024] R 2.1 、R 2.2 、R 2.3 、R 2.4 、R 2.5 、R 4.1 、R 4.2 、R 4.3 、R 4.4 、R 4.5 、R 5.1 、R 5.2 、R 5.3 、R 5.4 and R 5.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0025] m and n are each independently selected from 1, 2 or 3;

[0026] p is selected from 1 or 2.

[0027] In a preferred embodiment of the present invention, the compound described above is further represented by formula (II-A), formula (II-B), formula (II-C) or formula (II-D):

[0028] In a preferred embodiment of the present invention, the ring A is a monocyclic group, and the monocyclic group is selected from a 5-membered heteroaryl group, a 6-membered heteroaryl group or a phenyl group; preferably, the ring A is selected from a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a phenyl group, a pyrazolyl group, a thienyl group, a furanyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group.

[0029] In a preferred embodiment of the present invention, the ring A is a bicyclic group, and the bicyclic group is selected from a 5-membered heteroaryl and 6-membered heteroaryl group, a 5-membered heteroarylphenyl group, a 6-membered cycloalkylphenyl group, a 6-membered heterocyclylphenyl group, a benzo 5-membered heterocyclyl group, a benzo 5-membered heteroaryl group, a 6-membered heteroaryl and 5-membered heteroaryl group, a 6-membered heterocyclyl and 6-membered heteroaryl group, or a 6-membered heteroarylphenyl group;

[0030] Preferably, ring A is selected from pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, pyrazolopyridinyl, cyclohexylphenyl, oxacyclohexylphenyl, benzodioxazolyl, Benzoxazolyl, oxacyclohexylpyridinyl, pyridonophenyl, pyridopyrazolyl, benzopyrazolyl, thienophenyl or pyridophenyl.

[0031] In some embodiments of the present invention, the above-mentioned Selected from

[0032] In a preferred embodiment of the present invention, the compound of the present invention is further represented by formula (III-A) or formula (III-B):

[0033] In a preferred embodiment of the present invention, the formula (III-A) of the present invention is further represented by formula (IV):

[0034] Among them: Ring B is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R 4a Each independently selected from deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1- 3 alkoxyalkyl, -N(CH3)2, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; y is 0, 1 or 2.

[0035] In a preferred embodiment of the present invention, the ring B is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R 4a Each independently selected from deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkoxyalkyl, -N(CH3)2, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; y is 0, 1 or 2.

[0036] In a preferred embodiment of the present invention, the ring B described above is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,

[0037] In a preferred embodiment of the present invention, the above R1 is selected from hydrogen; the R2 is selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted C 1-6 Alkyl, R 2.1 Substituted C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 membered heteroaryl, C 1-6 Alkyl-substituted 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.

[0038] In a preferred embodiment of the present invention, the above-mentioned R 4a Each is independently selected from deuterium, fluorine, chlorine, amino, hydroxy, cyano, carboxyl, oxo, methyl, ethyl, -CH2OCH3, -N(CH3)2, methoxy, ethoxy, trifluoromethyl, hydroxymethyl or hydroxyethyl.

[0039] In a preferred embodiment of the present invention, the above-mentioned 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, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, -C(O)NH2, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0040] In a preferred embodiment of the present invention, R2 is selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted C 1-6 Alkyl, R 2.1 Substituted C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 membered heteroaryl, C 1-6 Alkyl-substituted 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 R2.4 、-SR 2.5 、-SOR 2.2 、-OR 2.5 or -NR 2.3 R 2.4 is substituted by one or more groups.

[0041] In a preferred embodiment of the present invention, R1 is selected from hydrogen or C 1-6 alkyl;

[0042] Alternatively, R2 is represented by formula (III):

[0043] in,

[0044] R6 is selected from hydroxy, cyano, amino or halogen;

[0045] R7 and R 7’ 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;

[0046] Preferably, R7 and R 7’ each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or butyl;

[0047] Alternatively, R2 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl or naphthyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, 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, hydroxymethyl, hydroxyethyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxirane, oxetanyl, aziridine, azetidinyl, -(CH2)2CN, -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;

[0048] Alternatively, R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0049] Alternatively, R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Haloalkyl, -C(O)-R 4.1、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SOR 4.2 、-OR 4.5 、-SR 4.5 、-NR 4.3 R 4.4 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, which may be further substituted with deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, -NR 4.3 R 4.4 、C 1-3 Alkoxy C 1-3 Alkyl or C 1-3 substituted by one or more substituents in a haloalkyl group;

[0050] Alternatively, R5 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Haloalkyl, -C(O)-R 5.1 、-S(O)2-R 5.2 、-C(O)OR 5.1 、-C(O)NR 5.3 R 5.4 、-SOR 5.2 、-OR 5.5 、-SR 5.5 、-NR 5.3 R 5.4 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, which may be further substituted with deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 substituted by one or more substituents in a haloalkyl group;

[0051] The R 2.1 、R 2.2、R 2.3 、R 2.4 、R 2.5 、R 4.1 、R 4.2 、R 4.3 、R 4.4 、R 4.5 、R 5.1 、R 5.2 、R 5.3 、R 5.4 and R 5.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0052] Preferably, the R 2.1 、R 2.2 、R 2.3 、R 2.4 、R 2.5 、R 4.1 、R 4.2 、R 4.3 、R 4.4 、R 4.5 、R 5.1 、R 5.2 、R 5.3 、R 5.4 and R 5.5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, -C(O)NH2, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0053] In a preferred embodiment of the present invention, R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl or pyrazolyl, wherein C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl and pyrazolyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, nitro, cyano, hydroxy, fluorine, chlorine, oxo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, trifluoroethyl, -CH2OCH3 or -N(CH3)2.

[0054] In a preferred embodiment of the present invention, R4 described above is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxyl, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidinyl, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe, -CO2Me,

[0055] Alternatively, R5 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidinyl, -NH-(CH2)2-OH, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe or -CO2Me.

[0056] In a preferred embodiment of the present invention, the above-mentioned formula (II-A), formula (II-B), formula (II-C) and formula (II-D) Each independently selected

[0057] Alternatively, the formula (II-A), formula (II-B), formula (II-C) and formula (II-D) Each independently selected

[0058] In a preferred embodiment of the present invention, R1 is selected from hydrogen, C 1-3 alkyl;

[0059] Alternatively, the R2 is selected from the following groups:

[0060] Alternatively, each of the R3 groups is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -CHF2, -CH2F, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetane, azirane, azetidine, tetrahydropyrrolyl, tetrahydrofuranyl, -CH2OH, -CF3, -CHF2, -CH2F or -CD3.

[0061] In a preferred embodiment of the present invention, the compound of the present invention is selected from the compounds with the following structures:

[0062] 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.

[0063] 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.

[0064] 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.

[0065] Detailed Description of the Invention

[0066] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0067] 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.

[0068] 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.

[0069] 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, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 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.

[0070] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, preferably a 5-6 membered cycloalkylphenyl, a 5-6 membered cycloalkyl and a 5-6 membered heteroaryl; non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0071] The cycloalkyl 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.

[0072] 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-, and the remaining ring atoms are 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 6 ring atoms, of which the number of heteroatoms is 1 or 2. Non-limiting examples of monocyclic heterocyclic groups include oxetane, thietanyl, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, pyridonyl, etc., preferably oxetane, thietanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminoylidene-1-oxothiopyran, azepanyl, pyrrolidinyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups, non-limiting examples 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.

[0073] 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.

[0074] The heterocyclic group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl, preferably a 5-6 membered heterocyclic phenyl group, a 5-6 membered heterocyclic phenyl group, a 5-6 membered heterocyclic phenyl group, a 5-6 membered heteroaryl group, such as:

[0075] 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.

[0076] The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, preferably a benzo 5-6 membered heterocyclyl or a benzo 5-6 membered heteroaryl; for example:

[0077] 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.

[0078] 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.

[0079] The heteroaryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring to form a fused ring, wherein the ring connected to the parent structure is a heteroaryl ring, preferably a 5-6 membered heteroaryl fused 5-6 membered heteroaryl, or a 5-6 membered heteroaryl phenyl ring; for example:

[0080] 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.

[0081] 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.

[0082] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0083] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0084] "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).

[0085] 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.

[0086] In the present invention Indicates that the key does not exist;

[0087] The chiral carbon in the compounds of the present invention may be in either R or S configuration.

[0088] The "*" or "*" on the substituent of the present invention It indicates the position where the substituent is attached to the substituted site.

[0089] 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.

[0090] "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.

[0091] "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.

[0092] 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.

[0093] "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

[0094] The present invention is described in detail below by way of examples, but this does not necessarily limit the present invention. 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 them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, preferred embodiments but not limited to the examples of the present invention. All reagents used in the present invention were obtained from commercial channels or prepared with reference to prior art. The names of all compounds except reagents were generated by ChemDrew 20.0.

[0095] General Methods: The compounds of the present invention can be prepared according to the following non-limiting general methods and examples.

[0096] Scheme 1: Synthesis of compounds of formula (I), wherein R1, R2, R3, R4, and R5 are as defined above:

[0097] As shown in Scheme 1, compound A of formula can be prepared by reacting commercially available 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with an amine of formula R1R2NH. Typical reaction conditions include heating a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine and the appropriate amine in a suitable protic or polar aprotic solvent in the presence of an added organic or inorganic base at a temperature ranging from room temperature to the boiling point of the solvent. Amines R1R2NH are 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 an amine of formula R1R2NH in DMF in the presence of DIPEA at 120°C, as exemplified in Preparation 1.

[0098] 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.

[0099] 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 with Ti(OiPr)4 and (S)-(-)-1,1'-binaphthol for oxidation at 0℃~room temperature.

[0100] 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.

[0101] 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 easily synthesized by methods known to those skilled in the art).

[0102] 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.

[0103] 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.

[0104] Preparation Examples and Examples

[0105] 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.

[0106] The following abbreviations are used:

[0107] (Boc)2O: tert-butyl dicarbonate; BH3: borane; 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; NCS: N-chlorosuccinimide; Rochelle's salt: potassium sodium tartrate tetrahydrate; PE: petroleum ether; Pd(dppf)2Cl2: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium; Pd2(dba)3: trisdibenzylideneacetone 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.

[0108] Preparation Example 1: (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (I01)

[0109] 1)(1-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (I01-b)

[0110] To a solution of 2,4-dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (I01-a, 22.6 g, 110 mmol, 1 eq) in acetonitrile (200 mL) at room temperature were added (1-aminocyclobutyl)methanol hydrochloride (15 g, 110.00 mmol, 1 eq) and triethylamine (80 mL, 550.00 mmol, 5 eq). The temperature was raised to 65-70°C and stirring continued for 12 hours. Then, water (1.2 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 with a 2:1 mixture of water and acetonitrile (400 mL) and then water (200 mL). The resulting solid was dried under vacuum at 50°C for 12 hours to afford I01-b (15 g, 50.5%). LCMS: 272.15 [M+H]. + .

[0111] 2)(R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (I01)

[0112] At room temperature, to a dichloromethane solution (50 mL) of I01-b (10.36 g, 38 mmol) were added (S)-(-)-1.1'-bis-2-naphthol (4.4 g, 15.20 mmol, 0.2 eq), Ti(O i Pr)4 (540 mg, 1.90 mmol, 0.05 eq) and water (8 mL) were added. After stirring for 1 hour, tert-butyl hydroperoxide (70% in water, 3.79 g, 42 mmol, 1.1 eq) was added in one portion. The reaction mixture became homogeneous and the reaction temperature rose to approximately 40°C. The mixture was allowed to cool to room temperature, stirred for 1.5 hours, and filtered. The filter cake was washed with isopropyl acetate (243 mL x 2) and air-dried to yield I01 (6.2 g, 56.5%). LCMS: 288.25 [M+H] + . 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).

[0113] Example 1: Synthesis of Compound 1

[0114] 1) N-Benzyl-N-(3-cyanopropyl)glycine ethyl ester (1-a)

[0115] To a solution of benzylglycine ethyl ester (5.01 g, 25.87 mmol, 1.0 eq) in acetonitrile (50 mL) at room temperature were added 4-bromobutyronitrile (4.59 g, 31.04 mmol, 1.2 eq) and K2CO3 (10.72 g, 77.61 mmol, 3.0 eq). After stirring at 80°C for 16 hours, the mixture was cooled to room temperature and water (150 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to afford the product 1-a (4.61 g, 68.5%) as a yellow oil. LCMS: 261.20 [M+H] + .

[0116] 2) N-(tert-Butyloxycarbonyl)-N-(3-cyanopropyl)glycine ethyl ester (1-b)

[0117] To a solution of 1-a (4 g, 15.38 mmol, 1.0 eq) and Boc2O (6.71 g, 30.77 mmol, 2.0 eq) in EtOH (100 mL) at room temperature was added 10% Pd / C (0.4 g). After hydrogen absorption at room temperature for 16 hours, the solid was filtered off, the mixture was concentrated, and purified by column chromatography (petroleum ether / EtOAc = 3:1) to afford the product 1-b (3.66 g, 88.1%) as a colorless oil. LCMS: 271.20 [M+H] + .

[0118] 3) tert-Butyl 4-cyano-3-piperidone-1-carboxylate (1-c)

[0119] To a solution of 1-b (17 g, 62.9 mmol) in toluene (100 mL) at 0°C was added t-BuOK (8.5 g, 75.5 mmol). After stirring at room temperature for 30 minutes, saturated NH4Cl (200 mL) and n-hexane (200 mL) were added. HCl (2N) was then added to raise the pH to 6. Extraction was performed with ethyl acetate (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 1-c (13 g) as a yellow oil. The crude product was used directly in the next reaction without purification. LCMS: 225.15 [M+H] + .

[0120] 4) tert-Butyl 3-amino-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1-d)

[0121] A mixture of 1-c (13 g, 57.9 mmol) and hydrazine hydrate (85%, 6.6 mL, 116 mmol) in EtOH (100 mL) was stirred at 60°C for 3 hours. The mixture was cooled to room temperature and concentrated. EtOAc (250 mL) was added and the mixture was washed sequentially with saturated Na2CO3 (100 mL) and brine (100 mL). Drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (DCM / MeOH = 20:1) gave the product 1-d (10 g, 72%) as a white solid. LCMS: 239.15 [M+H] + .

[0122] 5) tert-Butyl 3-chloro-9,10-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidine-8(7H)-carboxylate (1-e)

[0123] To a solution of 1-d (150 mg, 0.63 mmol, 1 eq) in AcOH (4 mL) at room temperature was added 2-chloromalealdehyde (66 mg, 0.63 mmol, 1 eq). After stirring for 16 hours, a saturated NaHCO₃ solution (40 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to give the product 1-e (80 mg, 41.2%) as a yellow solid. LCMS: 309.10 [M+H] + .

[0124] 6) 3-Chloro-7,8,9,10-tetrahydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidine (1-f)

[0125] To a solution of 1-e (80 mg, 0.26 mmol, 1 eq) in DCM (3 mL) at 0° was added TFA (1 mL). After stirring at room temperature for 1 hour, the mixture was concentrated to afford the product 1-f (55 mg, 99%) as a yellow solid. The crude product was used directly in the next reaction without purification. LCMS: 209.25 [M+H] + .

[0126] 7)(R)-2-(3-chloro-9,10-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-8(7H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1)

[0127] To a solution of I01 (66 mg, 0.26 mmol, 1 eq) and 1-f (55 mg, 0.26 mmol, 1.0 eq) in THF (2 mL) and H₂O (0.5 mL) was added DIEPA (168 mg, 1.3 mmol, 5.0 eq) at room temperature. The mixture was stirred at 70°C overnight and then concentrated. Pre-TLC (SiO₂, DCM / MeOH = 10 / 1) yielded the product 1 (67.3 mg, 56%) as a white solid. LCMS: 460.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.42(d,J=2.3Hz,1H),8.48(d,J=2.3Hz,1H),7.46(s,1H),5.03(s,2H),4.84(s,1H),4.07(s,2H),3.72 (s,2H),3.17(d,J=13.5Hz,2H),2.99–2.89(m,1H),2.81(s,3H),2.31(dd,J=21.2,10.5Hz,2H),2.18(s,2H),1.85–1.69(m,2H).

[0128] The following compounds were synthesized using a similar method

[0129] Example 2: Synthesis of Compounds 5 and 6

[0130] 1) 7-Chloro-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (5-a) and 8-chloro-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (5-b)

[0131] To a 100 mL three-necked flask at room temperature, add NaOH (15 g, 0.38 mol 27.0 eq) and water (15 mL) and stir until the solution becomes clear. Then, add (6-chloro-1H-benzo[d]imidazol-2-yl)methanamine hydrochloride (2.63 g, 14.32 mmol 1.0 eq) and tetrabutylammonium bromide (185 mg, 0.57 mmol 0.04 eq) in sequence. After stirring for 1 hour, a solution of 1,2-dibromoethane (5.38 g, 28.64 mmol 2.0 eq) in 50 mL of DMF is added dropwise. After stirring for another 4 hours, the solid is filtered off and the filtrate is concentrated. Purification by column chromatography (DCM:MeOH:aqueous ammonia = 50:1:0.05 to 40:1:0.05) affords a mixture of products 5-a and 5-b (1.25 g, 50.4%) as white solids. LCMS: 208.10 [M+H] + .

[0132] 2) (R)-2-(8-chloro-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (5) and (R)-2-(7-chloro-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (6)

[0133] To a solution of I01 (40 mg, 0.14 mmol, 1.0 eq) and 5-a / 5-b (34.5 mg, 0.17 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (55. mg, 0.42 mmol, 3 eq) at room temperature. After stirring at 65°C for 4 hours, the mixture was cooled to room temperature and concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) and further SFC purification afforded products 5 (7.94 mg, 12.4%) and 6 (5.36 mg, 8.42%) as white solids. LCMS: 459.10 [M+H] + .

[0134] 5-a: 1 H NMR(400MHz,Methanol-d4)δ7.58(s,1H),7.47(s,1H),7.27(s,1H),5.20(s,2H),4.59(s,2H) ,4.41(s,2H),4.24(s,2H),3.93(s,2H),3.57(s,2H),3.11(s,2H),2.34(s,2H),1.94(s,2H).

[0135] 5-b: 1 H NMR(400MHz,Methanol-d4)δ7.58(s,2H),7.47(s,1H),7.27(s,2H),5.20(s,2H),4.59 (s,2H),4.41(s,2H),4.24(s,2H),3.93(s,2H),3.11(s,2H),2.34(s,4H),1.94(s,2H).

[0136] Example 3: Synthesis of Compound 7

[0137] 1) 7-chloro-3-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester (7-a)

[0138] A solution of 4-chloropyridin-2-amine (1.8 g, 14.06 mmol, 1.0 eq) and dimethyl 3-bromo-2-oxoglutarate (4.6 g, 18.18 mmol, 1.3 eq) in ethanol (35 mL) was stirred at 100°C for 12 hours. The mixture was cooled to room temperature and concentrated. Purification by column chromatography (dichloromethane:methanol:aqueous ammonia = 50:1:0.05 to 40:1:0.05) afforded the product 7-a (800 mg, 20.2%) as a yellow solid. LCMS: 283.13 [M+H] + .

[0139] 2) 2-(7-chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl)ethan-1-ol (7-b)

[0140] To a solution of 7-a (500 mg, 1.77 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0°C was added 1M DIBAL-H in CH2Cl2 (10.8 mL, 10.8 mmol, 6.0 eq) dropwise. After stirring for 2 hours, a solution of Rochelle's salt (30 mL) was added. The mixture was extracted with dichloromethane (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH:aqueous ammonia = 50:1:0.05 to 40:1:0.05) to afford 7-b as a yellow oil (220 mg, 54.8%). LCMS: 227.05 [M+H] + .

[0141] 3) 2-(2-(azidomethyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)diphenylethyl phosphate (7-c)

[0142] To a solution of 7-b (200 mg, 0.88 mmol, 1.0 eq) and DBU (269 mg, 1.77 mmol, 2.0 eq) in THF (5 mL) at 0°C was added DPPA (487 mg, 1.77 mmol, 2.0 eq). After stirring at room temperature for 1 hour, ethyl acetate (50 mL) was added and the mixture was washed sequentially with water (50 mL x 2) and saturated brine (50 mL). Drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (n-hexane / EtOAc = 2:1) afforded the product 7-c (170 mg, 40% yield) as a yellow oil. LCMS: 484.10 [M+H] + .

[0143] 4) 8-Chloro-1,2,3,4-tetrahydroimidazo[1,2-a:4,5-c']bipyridine (7-d)

[0144] A mixture of 7-c (100 mg, 0.21 mmol, 1.0 eq) and PPh3 (66 mg, 0.25 mmol) in THF / H2O (2.2 mL, v1 / v2 = 10:1) was stirred at 60°C for 4 hours. The mixture was cooled to room temperature and concentrated. Pre-HPLC (0.1% TFA in H2O / ACN from 5% to 95%) gave the product 7-d (30 mg, 69%) as a colorless oil. LCMS: 208.10 [M+H] + .

[0145] 5)(R)-2-(8-chloro-3,4-dihydroimidazo[1,2-a:4,5-c']bipyridin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (7)

[0146] To a solution of 7-d (40 mg, 0.19 mmol, 1.5 eq) and I01 (37 mg, 0.13 mmol, 1.0 eq) in THF (2 mL) at room temperature were added DIEPA (50 mg, 0.39 mmol, 3.0 eq) and water (0.5 mL). After stirring at 65°C overnight, the mixture was concentrated. Pre-HPLC (0.1% TFA in H2O / ACN from 5% to 95%) was used to obtain the product 7 (33.5 mg, 38.4%) as a white solid. LCMS: 459.10 [M+H] + . 1 H NMR 1H NMR (400MHz, Methanol-d4) δ8.62–8.58(m,1H),8.04–8.01(m,1H),7.52(dd,J=7.2,2.0Hz,1H),5.14(s,2H),4.33(s,2H),3.94(q, J=11.4Hz,2H),3.58(dd,J=17.2,8.5Hz,1H),3.42–3.32(m,1H),3.16–3.01(m,5H),2.41–2.32(m,4H),1.92(q,J=10.0,8.7Hz,2H).

[0147] Example 4: Synthesis of Compound 8

[0148] 1) Diethyl 7-chloroimidazo[1,2-a]pyridine-2,3-dicarboxylate (8-c)

[0149] To a solution of 4-chloropyridin-2-amine (8-a, 10 g, 77.78 mmol, 1 eq) in ethanol (100 mL) was added diethyl 2-chloro-3-oxaloacetate (8-b, 8.65 g, 38.89 mmol, 0.5 eq) at room temperature. The mixture was heated to 100°C and stirred for 16 hours. The mixture was cooled to room temperature and concentrated. Purification by column chromatography (PE:EtOAc = 5:1) afforded the product 8-c (7.67 g, 33.2%) as a white solid. LCMS: 297.05 [M+H] + .

[0150] 2) Ethyl 7-chloro-2-formyl imidazo[1,2-a]pyridine-3-carboxylate (8-d)

[0151] To a solution of 8-c (7.4 g, 24.94 mmol, 1 eq) in dry THF (100 mL) at -78°C under nitrogen was added dropwise DIBAL-H (20.00 mL, 29.93 mmol, 1.2 eq). Stirring was continued for 2 hours, followed by the addition of a saturated Rochelle's salt solution (aq. 100 mL). The mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 8-d (4.5 g, 71.4%) as a white solid. LCMS: 253.00 [M+H] + .

[0152] 2) Ethyl 7-chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (8-e)

[0153] To a solution of 8-d (4.5 g, 17.81 mmol, 1 eq) in MeOH (50 mL) at room temperature was added NaBH4 (336.87 mg, 8.91 mmol, 0.5 eq) portionwise. After stirring for 2 hours, 2M H2SO4 (15 mL) was added. The mixture was extracted with dichloromethane (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give the product 8-e (4.2 g, 92.6%) as a white solid. LCMS: 255.00 [M+H] + .

[0154] 4) Ethyl 7-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (8-g)

[0155] To a solution of 8-e (4.2 g, 16.50 mmol, 1 eq) in CHCl₃ (100 mL) at room temperature were added 3,4-dihydro-2H-pyran (8-f, 7.00 g, 84.46 mmol, 5 eq) and In(OTf)₃ (434.00 mg, 0.83 mmol, 0.05 eq). The mixture was heated to 80°C and stirred for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to afford the product 8-g (4.8 g, 85.9%) as a yellow oil. LCMS: 339.15 [M+H] + .

[0156] 5)(7-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridin-3-yl)methanol (8-h)

[0157] To a solution of 8-g (4.8 g, 14.17 mmol, 1 eq) in Et2O (150 mL) at 0°C under nitrogen was added dropwise LAH (6.00 mL, 14.17 mmol, 1 eq). After stirring for 1 hour, water (2.4 mL) and 15% NaOH (0.6 mL) were added. The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 50:1) to afford the product 8-h as a white solid (1.6 g, 38.1%). LCMS: 297.20 [M+H] + .

[0158] 6) 3-(Azidomethyl)-7-chloro-2-((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine (8-i)

[0159] To a solution of 8-h (1.6 g, 5.39 mmol, 1 eq) in THF (20 mL) at 0°C under nitrogen was added dropwise DPPA (1.93 g, 7.00 mmol, 1.3 eq) and DBU (1.07 g, 7.00 mmol, 1.3 eq). The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was then used directly in the next reaction. LCMS: 322.20 [M+H] + .

[0160] tert-Butyl 7)(7-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridin-3-yl)methyl)carbamate (8-j)

[0161] At room temperature, PPh3 (2.12 g, 8.09 mmol, 1.5 eq) and water (20 mL) were added sequentially to the reaction mixture from the previous step. The temperature was raised to 60°C and stirring was continued for 4 hours. The mixture was cooled to room temperature, and Boc2O (2.40 g, 10.78 mmol, 2 eq) and DMAP (33.00 mg, 0.27 mmol, 0.05 eq) were added sequentially. After stirring for 12 hours, water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to obtain the product 8-j (1 g, 81.3%) as a white solid. LCMS: 396.20 [M+H] + .

[0162] tert-Butyl 8)(7-chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl)methyl)carbamate (8-k)

[0163] A suspension of 8-j (1 g, 2.52 mmol, 1 eq) in AcOH (10 mL) and H2O (10 mL) was stirred at 100°C for 1 hour. The mixture was cooled to room temperature, and 4 M NaOH was added to a pH of 7-8. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give 8-k (520 mg, 66%) as a white solid. LCMS: 312.00 [M+H] + .

[0164] tert-Butyl (9)(2-(bromomethyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)carbamate (8-1)

[0165] To a solution of 8-k (440 mg, 1.41 mmol, 1 eq) in DCM (10 mL) at room temperature were added CBr4 (562.00 mg, 1.69 mmol, 1.2 eq) and PPh3 (444.00 mg, 1.69 mmol, 1.2 eq). After stirring for 1 hour, the mixture was concentrated. Pre-TLC (SiO2, DCM:MeOH = 20:1) yielded the product 8-1 (340 mg, 64.3%) as a white solid. LCMS: 374.10 [M+H] + .

[0166] 10) tert-Butyl 6-chloro-1,3-dihydro-2H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridine-2-carboxylate (8-m)

[0167] To a solution of 8-1 (290 mg, 1.06 mmol, 1 eq) in DMSO (60 mL) at room temperature was added NaH (64.00 mg, 1.58 mmol, 1.5 eq). The mixture was heated to 90°C and stirred for 10 minutes. The mixture was cooled to room temperature and water (60 mL) was added. The mixture was extracted with ethyl acetate (60 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, PE:EtOAc = 1:1) afforded the product 8-m (13 mg, 5.9%) as a white solid. LCMS: 294.25 [M+H] + .

[0168] 11) 6-Chloro-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridine (8-n)

[0169] To a solution of 8-m (17 mg, 0.04 mmol, 1 eq) 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 8-n (9 mg, 80.35%). The crude product was used directly in the next reaction without purification. LCMS: 194.20 [M+H] + .

[0170] 12)(R)2-(6-chloro-1,3-dihydro-2H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (8)

[0171] To a mixture of 8-n (9 mg, 0.05 mmol, 1 eq) and I01 (13.38 mg, 0.05 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (20 mg, 0.15 mmol, 3 eq) at room temperature. After stirring at 65°C for 3 hours, the mixture was cooled to room temperature and concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 8 (10.9 mg, 52.6%) as a white solid. LCMS: 445.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.61(dd,J=48.6,7.2Hz,1H),7.83(dd,J=11.5,2.2Hz,1H),7.15(ddd,J=7.1,5.1,2.2Hz,1H),4.89(s,2H),4.71 (d,J=20.0Hz,2H),3.80(s,2H),3.49(m,J=17.7,16.4,8.3Hz,2H),3.28–2.88(m,4H),2.36–2.20(m,4H),1.78(dd,J=18.9,10.0Hz,2H).

[0172] Example 5: Synthesis of Compound 9

[0173] 1) 4-(tetrahydro-2H-pyran-2-yl)oxy)2-butyn-1-ol (9-b)

[0174] To a solution of 2-butyne-1,4-diol (9-a, 29 g, 336.86 mmol, 1 eq) in DCM (300 mL) at room temperature were added 3.4-dihydro-2H-pyran (8-f, 28.4 g, 336.86 mmol, 1 eq) and PPTS (8.5 g, 33.69 mmol, 0.1 eq). After stirring at 40°C for 16 hours, water (300 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 2:1) to afford the product 9-b (26 g, 45.4%) as a yellow oil. 1 H NMR(400MHz, DMSO-d6)δ5.16(t,J=5.4Hz,1H),4.70(d,J=3.7Hz,1H),4.25–4.10(m,2H),4.06(d,J=4.9Hz,2 H), 3.67 (ddd, J=11.5, 8.8, 3.1Hz, 1H), 3.41 (dd, J=10.6, 5.3Hz, 1H), 1.68–1.56 (m, 2H), 1.48–1.38 (m, 4H).

[0175] 2) 4-(tetrahydro-2H-pyran-2-yl)oxy)-2-butynal (9-c)

[0176] To a solution of 9-b (26 g, 152.75 mmol, 1 eq) in DCM (300 mL) at 0°C was added Dess-Martin (97.00 g, 229.13 mmol, 1.5 eq). After stirring at room temperature for 2 hours, water (300 mL) was added. The product was extracted with dichloromethane (300 mL x 3), dried over anhydrous NaSO, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 10:1) to afford 9-c (21.9 g, 85.2%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),4.72(s,1H),4.53–4.40(m,2H),3.74–3.65(m ,1H),3.44(d,J=11.6Hz,1H),1.64(dd,J=11.8,3.8Hz,2H),1.47(d,J=10.3Hz,4H).

[0177] 3)Amino-3-chloropyridin-1-ium (9-f)

[0178] To a solution of 3-chloropyridine (9-d, 10 g, 88.07 mmol, 1 eq) in DCM (300 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (9-e, 19.30 g, 96.88 mmol, 1.1 eq) at 0°C. After stirring at room temperature for 16 hours, the mixture was concentrated to afford the crude product 9-f (22.4 g, 81.4%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.70(d,J=6.4Hz,1H),8.58(s,2H),8.55(d,J=3.2Hz,1H),8.3 8(d,J=8.6Hz,1H),7.98(dd,J=8.4,6.3Hz,1H),7.76(dd,J=9.8,3.2Hz,1H),6.30(d,J=9.8Hz,1H).

[0179] 4) 6-Chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (9-g)

[0180] To a solution of 9-f (27.2 g, 86.81 mmol, 1 eq) in DMF (300 mL) at 0°C were added 9-c (21.9 g, 130.21 mmol, 1.5 eq) and K2CO3 (15.60 g, 112.85 mmol, 1.3 eq) in sequence. After stirring at room temperature for 16 hours, water (300 mL) was added and the mixture was extracted with ethyl acetate (300 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 10:1) to afford the product 9-g (1.5 g, 5.9%) as a yellow solid. LCMS: 295.20 [M+H] + .

[0181] 5)(E)-6-chloro-3-(2-nitrovinyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine (9-h)

[0182] A mixture of 9-g (1.7 g, 5.77 mmol, 1 eq) and NH4OAc (223.00 mg, 2.88 mmol, 0.5 eq) in MeNO2 (20 mL) was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, and saturated NaHCO3 (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:EtOAc = 20:1) to afford the product 9-h (1.2 g, 61.6%) as a yellow solid. LCMS: 338.15 [M+H] + .

[0183] 6) 2-(6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-3-yl)ethan-1-amine (9-i)

[0184] To a solution of 9-h (1.2 g, 3.55 mmol, 1 eq) in THF (20 mL) at 0°C was added dropwise LAH (5.68 mL, 14.20 mmol, 4 eq). After stirring at room temperature for 4 hours, a saturated Rochelle's salt solution (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:EtOAc = 20:1) to afford the product 9-i (900 mg, 81.8%) as a yellow oil. LCMS: 310.05 [M+H] + .

[0185] tert-Butyl 7)(2-(6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-3-yl)ethyl)carbamate (9-j)

[0186] To a solution of 9-i (800 mg, 2.58 mmol, 1 eq) in THF (10 mL) at room temperature was added Boc2O (676.3 mg, 3.10 mmol, 1.2 eq). After stirring for 16 hours, saturated NaHCO3 solution (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to afford 9-j (270 mg, 25.5%) as a yellow oil. LCMS: 410.30 [M+H] + .

[0187] tert-Butyl 8)(2-(6-chloro-2-(hydroxymethyl)pyrazolo[1,5-a]pyridin-3-yl)ethyl)carbamate (9-k)

[0188] To a solution of 9-j (250 mg, 0.61 mmol, 1 eq) in 1,4-dioxane (4 mL) at room temperature was added 1N HCl (2 mL). After stirring for 2 hours, 1N NaOH was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 9-k (150 mg, 75.5%) as a yellow solid. LCMS: 326.25 [M+H] + .

[0189] tert-Butyl 9)(2-(2-(bromomethyl)-6-chloropyrazolo[1,5-a]pyridin-3-yl)ethyl)carbamate (9-1)

[0190] To a solution of 9k (160 mg, 0.49 mmol, 1 eq) in DCM (4 mL) at room temperature were added CBr4 (245 mg, 0.74 mmol, 1.5 eq) and PPh3 (168 mg, 0.64 mmol, 1.3 eq) in sequence. After stirring for half an hour, saturated aqueous NaHCO3 (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 2:1) to afford the product 9-1 as a white solid (110 mg, 57.6%). LCMS: 388.10 [M+H] + .

[0191] 10) tert-Butyl 7-chloro-3,4-dihydropyrazolo[1,5-a:3,4-c']dipyridine-2(1H)-carboxylate (9-m)

[0192] To a solution of 9-1 (100 mg, 0.26 mmol, 1 eq) in DMF (15 mL) at room temperature was added NaH (16 mg, 0.39 mmol, 1.5 eq). Stirring was continued for 16 hours, followed by the addition of water (20 mL). Extraction was performed with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by Pre-TLC (SiO2, PE:EtOAc = 4:1) to afford the product 9-m (73 mg, 92.2%) as a white solid. LCMS: 308.15 [M+H] + .

[0193] 11) 7-Chloro-1,2,3,4-tetrahydropyrazolo[1,5-a:3,4-c']dipyridine (9-n)

[0194] To a solution of 9-m (70 mg, 0.23 mmol, 1 eq) in 1,4-dioxane (4 mL) was added dropwise 4M HCl / 1,4-dioxane (4 mL) at room temperature and stirring continued for 16 hours. Concentration afforded the product 9-n (40 mg, 84.7%) as a white solid. The crude product was used directly in the next reaction without purification. LCMS: 208.20 [M+H] + .

[0195] 12)(R)-2-(7-chloro-3,4-dihydropyrazolo[1,5-a:3,4-c']dipyridin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (9)

[0196] To a solution of I01 (50 mg, 0.17 mmol, 1 eq) and 9-n (43.3 mg, 0.21 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (65.91 mg, 0.51 mmol, 3 eq) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO₂, DCM:MeOH = 15:1) yielded the product 9 (62.1 mg, 80.6%) as a white solid. LCMS: 459.25 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.89(d,J=1.8Hz,1H),7.60(d,J=9.4Hz,1H),7.20(dd,J =9.5,1.8Hz,1H),5.01(s,2H),4.06(t,J=5.8Hz,4H),3.72(d,J=2.7Hz,2H),3.45 (d,J=8.7Hz,1H),3.24–3.18(m,1H),3.03(d,J=7.9Hz,1H),2.88(d,J=6.4Hz,1H ),2.80(s,2H),2.31(q,J=10.3Hz,2H),2.21–2.16(m,2H),1.76(t,J=8.0Hz,2H).

[0197] The following compounds were synthesized using a similar method:

[0198] Example 6: Synthesis of Compound 11

[0199] 1) 8-Chloro-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (11-b)

[0200] To a solution of 7-chloro-4-methyl-1,2-dihydronaphthalene (11-a, 100 mg, 0.56 mmol, 1.0 eq) in acetic acid (4 mL) was added formaldehyde (100.84 mg, 3.39 mmol, 6.0 eq) at room temperature. After stirring at 70°C for 1 hour, NH4Cl (89.82 mg, 1.68 mmol, 3.0 equiv.) was added and stirring continued at 70°C for 2 hours. The mixture was cooled to room temperature and saturated NaHCO3 solution (100 mL) was added. The product was extracted with ethyl acetate (20 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 11-b as a yellow solid (40 mg, 32.5%). LCMS: 220.10 [M+H] + .

[0201] 2)(R)-2-(8-chloro-1,4,5,6-tetrahydrobenzo[f]isoquinolin-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (11)

[0202] To a solution of 101 (60 mg, 0.21 mmol, 1 equiv.) in THF (3 ml) and H₂O (0.6 ml) at room temperature were added 11-b (40 mg, 0.19 mmol, 0.9 equiv.) and DIEPA (269.48 mg, 2.09 mmol, 10 equiv.). After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 11 (20.7 mg, 20.9%) as a white solid. LCMS: 471.25 [M+H] + . 1 H NMRδ7.26–6.99(m,3H),4.24(s,2H),3.95(t,J=5.9Hz,2H),3.71(s,2H),3.45(s,1H),3.28–3.16(m,1H),3.02(d,J =10.5Hz,1H),2.94–2.85(m,1H),2.75(t,J=7.9Hz,2H),2.63(s,1H),2.36–2.27(m,3H),2.17(s,4H),1.76(s,2H).

[0203] The following compounds were synthesized using a similar method

[0204] Example 7: Synthesis of Compound 12

[0205] 1)7-Chloro-4-methyl-1,2-dihydronaphthalene (11-a)

[0206] To a solution of 6-chloro-3,4-dihydronaphthalen-1(2H)-one (5 g, 27.8 mmol, 1.0 eq) in THF (15 mL) and ether (35 mL) at 0°C was added MeMgBr (9.27 mL, 3 M, 27.8 mmol, 1.0 eq) dropwise. After stirring for 2 hours, a saturated NH4Cl solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to afford the product 11-a as a yellow solid (2.2 g, 44.5%). LCMS: 179.10 [M+H] + .

[0207] 2) 3-Benzyl-8-chloro-1,2,3,4,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (12-a)

[0208] To a solution of 11-a (1.0 g, 5.60 mmol, 1.0 equiv.) in acetic acid (40 mL) at room temperature was added formaldehyde (3.06 g, 33.58 mmol, 6.0 equiv.). The mixture was heated to 70°C and stirred for 2 hours, followed by the addition of BnNH2 (3 g, 5.0 equiv.). Stirring was continued at 70°C for 12 hours, followed by cooling to room temperature and the addition of saturated NaHCO3 (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 12-a (200 mg, 11.5%) as a yellow solid. LCMS: 312.15 [M+H] + .

[0209] 3) 8-Chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (12-b)

[0210] To a solution of 12-a (120 mg, 0.38 mmol, 1.0 equiv.) in 1,2-DCE (2 mL) at 0°C was added dropwise 1-chloroethyl chloroformate (110.03 mg, 0.77 mmol, 2.0 equiv.). After stirring at room temperature for 1 hour, the mixture was concentrated to dryness, and MeOH (10 mL) was added. Stirring was continued at 65°C for 12 hours, the mixture was cooled to room temperature, and saturated NaHCO₃ (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 12-b (60 mg, 70.3%) as a yellow solid. LCMS: 222.10 [M+H] + .

[0211] 4)(R)-2-((4aS,10bS)-8-chloro-1,4,4a,5,6,10-hexahydrobenzo[f]isoquinolin-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (12)

[0212] To a solution of 101 (60 mg, 0.21 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml) at room temperature were added 12-b (46.23 mg, 0.21 mmol, 1.0 equiv.) and DIEPA (269.48 mg, 2.09 mmol, 10 equiv.). After stirring at 65°C for 12 hours, the mixture was concentrated. Purification by column chromatography (PE:EtOAc = 1:1) gave the product 12 (60 mg, 60.8%) as a white solid. LCMS: 473.10 [M+H] + .1 H NMR(400MHz, DMSO-d6)δ7.63(s,1H),7.20(q,J=19.7,16.5Hz,3H),5.89(s,1H),3.66(d,J=19.0Hz,4H),3.41–3.33(m,1H),3.31 (s,1H),3.16(s,1H),3.02(s,3H),2.82(dd,J=13.8,7.4Hz,2H),2.68–2.54(m,4H),2.34–2.23(m,2H),2.12(s,4H),1.72(s,2H).

[0213] Example 8: Synthesis of Compounds 13 and 14

[0214] 1) 4-Chloro-2-(methoxymethoxy)benzaldehyde (13-a)

[0215] To a solution of 4-chloro-2-hydroxybenzaldehyde (10 g, 63.87 mmol, 1.0 equiv.) in DCM (100 ml) at 0°C were added chloro-(methyloxy)methane (5.14 g, 63.87 mmol, 1.0 equiv.) and triethylamine (32.31 g, 319.35 mmol, 5.0 equiv.) dropwise. After stirring at room temperature for 1 hour, H₂O (150 mL) was added. The mixture was extracted with dichloromethane (300 mL x 2), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 10:1) to afford the product 13-a (7.02 g, 54.6%) as a yellow oil. LCMS: 201.05 [M+H] + .

[0216] 2)(E)-3-(4-chloro-2-(methoxymethoxy)phenyl)acrylate (13-b)

[0217] To a solution of triethylphosphonoacetate (7.02 g, 34.89 mmol, 1.0 equiv.) in THF (100 mL) at 0°C was added portionwise NaH (837.40 mg, 34.89 mmol, 1 equiv.). Stirring was continued for 30 minutes, followed by dropwise addition of a solution of 13-a (7.82 g, 34.89 mmol, 1.0 equiv.) in THF (15 mL). After stirring at 0°C for 1 hour, a saturated solution of NH4Cl (100 mL) was added. The product was extracted with ethyl acetate (200 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 10:1) to afford the product 13-b (8 g, 84.7%) as a yellow oil. LCMS: 271.20 [M+H] + .

[0218] 3)(3S,4R)-1-benzyl-4-(4-chloro-2-(methoxymethoxy)phenyl)-2,6-dipiperidone-3-carboxylic acid ethyl ester (13-c)

[0219] To a solution of 13-b (1 g, 3.69 mmol, 1.0 equiv.) and ethyl 3-(benzylamino)-3-oxopropanoate (817.31 mg, 3.69 mmol, 1.0 eq.) in THF (30 mL) was added NaH (177.30 mg, 7.39 mmol, 2.0 equiv.) at room temperature. After stirring at 70°C for 1 hour, the mixture was cooled to room temperature and saturated NH4Cl (30 mL) was added. The mixture was extracted with ethyl acetate (35 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 13-c (600 mg, 36.4%) as a yellow solid. LCMS: 446.25 [M+H] + .

[0220] 4)((3S,4R)-1-Benzyl-4-(4-chloro-2-(methoxymethoxy)phenyl)piperidin-3-yl)methanol (13-d)

[0221] To a solution of 13-c (470 mg, 1.05 mmol, 1.0 eq.) in THF (20 mL) was added dropwise BH₃ (10.54 mL, 10.54 mmol, 10 equiv.) at room temperature. After stirring at 70°C for 3 hours, the mixture was cooled to 0°C, and MeOH (30 mL) was added dropwise. The mixture was then stirred at 60°C for 3 hours. The mixture was cooled to room temperature, EtOAc (100 mL) was added, and the mixture was washed with saturated brine (35 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 13-d (220 mg, 55.5%) as a yellow solid. LCMS: 376.25 [M+H] + .

[0222] 5) 2-((3S,4R)-1-benzyl-3-(hydroxymethyl)piperidin-4-yl)-5-chlorophenol (13-e)

[0223] To a solution of 13-d (220 mg, 0.59 mmol, 1.0 equiv.) in DCM (3 mL) at room temperature was added TFA (1 mL, 8.77 mmol, 14.98 equiv.). After stirring for 3 hours, the mixture was concentrated, and EtOAc (30 mL) and saturated NaHCO₃ (30 mL) were added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 13-e (190 mg, 97.8%) as a yellow solid. LCMS: 332.20 [M+H] + .

[0224] 6)(4aS,10bR)-3-Benzyl-8-chloro-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (13-f)

[0225] To a solution of 13-e (210 mg, 0.63 mmol, 1.0 equiv.) in THF (10 mL) at 0°C were added PPh3 (829.93 mg, 3.16 mmol, 5.0 equiv.) and DIAD (639.83 mg, 3.16 mmol, 5.0 equiv.) sequentially. After stirring at room temperature for 16 hours, the mixture was concentrated, and EtOAc (30 mL) was added. The mixture was then washed dropwise with water (30 mL x 2) and brine (30 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to afford the product 13-f (80 mg, 40.3%) as a yellow solid. LCMS: 314.20 [M+H] + .

[0226] 7)(4aS,10bR)-8-chloro-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (13-g)

[0227] To a solution of 13-f (80 mg, 0.25 mmol, 1.0 equiv.) in 1,2-DCE (3 mL) at 0°C was added dropwise 1-chloroethyl chloroformate (72.89 mg, 0.51 mmol, 2.0 equiv.). After stirring at room temperature for 1 hour, the mixture was concentrated, followed by the addition of MeOH (10 mL). The mixture was stirred overnight, and then a saturated NaHCO₃ solution (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 1:1) to afford the product 13-g (30 mg, 52.6%) as a yellow solid. LCMS: 224.20 [M+H] + .

[0228] 8) (R)-2-((4aS,10bR)-8-chloro-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridin-3(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (13) and (R)-2-((4aR,10bS)-8-chloro-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridin-3(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (14)

[0229] To a solution of I01 (30 mg, 0.10 mmol, 1.0 equiv.) and 13-g (30 mg, 0.13 mmol, 1.3 equiv.) in THF (3 ml) and H2O (0.6 ml) was added DIEPA (134.74 mg, 1.04 mmol, 10 equiv.) at room temperature. After stirring at 65°C for 12 hours, the mixture was concentrated. Purification by column chromatography (PE:EtOAc = 1:1) and further SFC purification afforded white solids 13 (17.2 mg, 36.0%) and 14 (15.4 mg, 32.0%). LCMS: 475.10 [M+H] + .

[0230] 13: 1 H NMR (400MHz, DMSO-d6) δ7.37(s,1H),7.18(d,J=8.3Hz,1H),6.86(dd,J=8.2,2.2Hz,1H),6.78( d,J=2.2Hz,1H),4.84(s,1H),4.74(s,1H),4.26(s,1H),3.88(t,J=11.1Hz,1H),3.68(d,J=4.5 Hz,2H),3.44–3.33(m,1H),3.31(s,1H),3.22–3.11(m,1H),3.00–2.78(m,3H),2.70(s,1H) ),2.62(d,J=11.2Hz,1H),2.39–2.23(m,4H),2.15(s,2H),1.82–1.68(m,2H),1.57(s,1H).

[0231] 14: 1H NMR (400MHz, DMSO-d6) δ7.37(s,1H),7.18(d,J=8.3Hz,1H),6.86(dd,J=8.3,2.2Hz,1H),6.78(d,J =2.2Hz,1H),4.82(t,J=5.5Hz,1H),4.73(s,1H),4.25(d,J=10.1Hz,1H),3.88(t,J=11.0Hz,1H),3 .68(s,2H),3.44–3.32(m,1H),3.31(s,1H),3.22–3.10(m,1H),3.00–2.78(m,3H),2.70(t,J=11.4 Hz,1H),2.65–2.56(m,1H),2.40–2.21(m,4H),2.15(s,2H),1.82–1.68(m,2H),1.63–1.49(m,1H).

[0232] Example 9: Synthesis of Compound 18:

[0233] (R)-2-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0234] To a solution of I01 (40 mg, 0.14 mmol, 1 eq) and 6-chloro-1,2,3,4-tetrahydroisoquinoline (18-a, 28 mg, 0.17 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (65.91 mg, 0.51 mmol, 3 eq) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO₂, DCM:MeOH = 15:1) yielded the product 18 (50.4 mg, 86.8%) as a white solid. LCMS: 419.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.26(s,1H),7.23(d,J=1.3Hz,2H),4.81(s,2H),3.89(d,J=5.9Hz,2H),3.71(d,J=1.8Hz,2H),3.50 –3.43(m,1H),3.26–3.19(m,1H),3.05–2.99(m,1H),2.92–2.83(m,3H),2.38–2.25(m,2H),2.20(s,2H),1.81–1.71(m,2H).

[0235] The following compounds were synthesized using a similar method

[0236] Example 10: Synthesis of Compounds 28 and 29:

[0237] 1) N-(3-chlorophenethyl)acetamide (28-b)

[0238] To a solution of 2-(3-chlorophenyl)ethane-1-amine (28-a, 5 g, 32.258 mmol, 1 eq) in anhydrous DCM (30 mL) at 0°C, TEA (4.88 g, 48.387 mmol, 1.5 eq) and acetyl chloride (3.8 g, 48.387 mmol, 1.5 eq) were added dropwise in that order. After stirring at room temperature for 1 hour, water (30 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 28-b as a yellow oil (5.6 g, 88.1%). LCMS: 198.05 [M+H] + .

[0239] 2) 6-Chloro-1-methyl-3,4-dihydroisoquinoline (28-c)

[0240] 28-b (1.1 g, 5.584 mmol, 1 eq) was added to a POCl₃ (10 mL) solution at room temperature. After stirring at 120°C for 18 hours, the mixture was cooled to room temperature and poured into ice water (100 mL). The pH was then adjusted to -8 with 12N NaOH. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford product 28-c (1 g, 100%). LCMS: 180.05 [M+H] + .

[0241] 3) 6-Chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline (28-d)

[0242] To a solution of 28-c (2.48 g, 13.85 mmol, 1 eq) in MeOH (20 mL) at 0°C was added NaBH₄ (1.05 g, 27.64 mmol, 2 eq) portionwise. After stirring at room temperature for 2 hours, HCl (1 N) was added and the pH was adjusted to -8 with NaOH (1 N). The product was extracted with dichloromethane (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford product 28-d (1.04 g, 41%). LCMS: 182.05 [M+H] + .

[0243] 4)(R)-2-((S)-6-chloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (28); (R)-2-(((R)-6-chloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29)

[0244] To a solution of I01 (120 mg, 0.418 mmol, 1 eq) in THF / H₂O (4 mL:1 mL) at room temperature were added 8-d (83.2 mg, 0.460 mmol, 1.1 eq) and DIEPA (161.8 mg, 1.254 mmol, 3 eq). The mixture was stirred at 65°C for 3 hours and then concentrated. Pre-HPLC (ACN:0.1% TFA in H₂O from 5% to 95%) was used for purification. Further SFC separation afforded the following products: 28 (44.9 mg, 24.9%) and 29 (35.1 mg, 19.4%) as white solids. LCMS: 433.25 [M+H] + .

[0245] 28_ 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=20.0Hz,3H),3.70(s,2H),3.42(dd,J=16.9,8.3Hz,2H),3.16(s,1 H),2.96–2.75(m,4H),2.38–2.24(m,3H),2.17(s,2H),1.76(m,2H),1.38(s,3H),1.21–1.10(m,1H).

[0246] 29_ 1 H NMR(400MHz, DMSO-d6)) δ7.28(d,J=25.6Hz,3H),3.83–3.66(m,2H),3.22(dt,J=15.6,8.5Hz,1H),2.97(dd,J=17.1,8.0Hz,1 H),2.91–2.73(m,4H),2.44–2.26(m,3H),2.14(d,J=48.7Hz,2H),1.80(d,J=8.0Hz,2H),1.42(d,J=6.8Hz,3H),1.24(m,1H).

[0247] Example 11: Synthesis of Compound 38:

[0248] 1) tert-Butyl 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (38-b)

[0249] To a solution of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine dihydrochloride (100 mg, 0.51 mmol, 1 eq) in DCM (5 mL) at room temperature were added Boc2O (114 mg, 0.51 mmol, 1 eq) and TEA (155 mg, 1.53 mmol, 3 eq). After stirring for 2 hours, water (10 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 38-b as a yellow oil (100 mg, 55.2%). LCMS: 224.30 [M+H] + .

[0250] 2) tert-Butyl 3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (38-c)

[0251] To a DMF (4 mL) solution of 38-b (70 mg, 0.31 mmol, 1 eq) was added K2CO3 (129.00 mg, 0.93 mmol, 3 eq) and MeI (45.00 mg, 0.31 mmol, 1 eq) at room temperature. After stirring for 2 hours, water (10 mL) and ethyl acetate (10 mL x 10 mL) were added.

[0252] 3) Extraction, drying over anhydrous Na2SO4, filtration, and concentration gave the yellow oily product 38-c (45 mg, 60.5%). The crude product was used directly in the next reaction without purification. LCMS: 238.35 [M+H] + .

[0253] 3) 3-Methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (38-d)

[0254] To a solution of 38-c (45 mg, 0.19 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 38-d (22 mg, 84.6%) as a yellow oil. The crude product was used directly in the next step without purification. LCMS: 138.35 [M+H] + .

[0255] 4)(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (38)

[0256] To a solution of I01 (40 mg, 0.14 mmol, 1 eq) and 38-d (23.5 mg, 0.17 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (55.00 mg, 0.42 mmol, 3 eq) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Pre-TLC (SiO₂, DCM:MeOH = 15:1) yielded the product 38 (20.7 mg, 38.2%) as a white solid. LCMS: 389.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=14.2Hz,1H),7.65(s,1H),4.85(s,1H),4.01(s,2H),3.77(s,2H),3.69(d,J=4. 2Hz,5H),3.29(dt,J=79.2,7.5Hz,2H),2.96–2.81(m,2H),2.71(s,2H),2.24(d,J=43.0Hz,4H),1.80–1.70(m,2H).

[0257] Example 12: Synthesis of Compound 39:

[0258] 1) tert-Butyl 2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (39-c)

[0259] A solution of cyclopropanethiocarboamide (39-a, 219 mg, 2.16 mmol, 3 eq) and tert-butyl 3-bromo-4-piperidone-1-carboxylate (39-b, 200 mg, 0.72 mmol, 1 eq) in DMF (4 mL) was stirred at 100°C for 1.5 hours. The mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, PE:EtOAc = 3:1) gave the product 39-c (56 mg, 27.8%) as a white solid. LCMS: 281.10 [M+H] + .

[0260] 2) 2-Cyclopropyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (39-d)

[0261] To a solution of 39-c (56 mg, 0.20 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 39-d (30 mg, 83.3%) as a yellow oil. The crude product was used directly in the next step without purification. LCMS: 181.25 [M+H] + .

[0262] 3)(R)-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (39)

[0263] To a solution of I01 (50 mg, 0.17 mmol, 1 eq) and 39-d (30 mg, 0.17 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (67.37 mg, 0.51 mmol, 3 eq) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 39 (69.7 mg, 92.9%) as a white solid. LCMS: 432.15 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ4.87(m,4H),4.00(t,J=5.8Hz,2H),3.69(s,2H),3.51–3.38(m,1H),3.27–3.14(m,1H),3.06–2.8 5(m,2H),2.71(t,J=5.7Hz,2H),2.31–2.15(m,5H),1.75(m,J=8.9Hz,2H),1.03(m,J=8.2,3.3Hz,2H),0.88–0.82(m,2H).

[0264] Example 13: Synthesis of Compound 44:

[0265] 1) tert-Butyl 8-chloro-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (44-c)

[0266] To a solution of tert-butyl 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (44-a, 200 mg, 0.52 mmol, 1 eq) and 2-bromo-5-chloroaniline (44-b, 108 mg, 0.52 mmol, 1 eq) in THF (4 mL) at room temperature under nitrogen was added NaCO (132 mg, 1.58 mmol, 3 eq), Pd(dppf)Cl (36 mg, 0.05 mmol, 0.1 eq), and water (1 mL) in that order. After heating under reflux for 6 hours, the mixture was cooled to room temperature and the solid was filtered off. The product was extracted with ethyl acetate (10 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) gave the yellow solid product 44-c (50 mg, 28.7%). LCMS: 335.15 [M+H] + .

[0267] 2) 8-Chloro-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridin-5(1H)-one (44-d)

[0268] To a solution of 44-c (50 mg, 0.15 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 44-d (35 mg, 99.4%) as a white solid. LCMS: 235.10 [M+H] + .

[0269] 3)(R)-8-chloro-3-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridin-5(1H)-one (44)

[0270] To a solution of 44-d (35 mg, 0.15 mmol, 1.2 eq) and I01 (36 mg, 0.12 mmol, 1 eq) in THF (4 mL) at room temperature were added DIEPA (48 mg, 0.38 mmol, 3 eq) and water (1 mL). After stirring at 65°C for 3 hours, the mixture was concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) gave the product 44 (35.7 mg, 48.9%) as a white solid. LCMS: 486.05 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.7Hz,1H),7.33(d,J=2.2Hz,1H),7.23(dd,J=8.6,2.2Hz,1H),4.62(s,2H),4.02(s,4H),3.73(s,2H),3.52 –3.45(m,1H),3.27–3.18(m,1H),3.06(dd,J=17.4,8.0Hz,1H),2.91(d,J=21.6Hz,3H),2.41–2.25(m,3H),2.19(s,2H),1.77(d,J=22.0Hz,2H).

[0271] The following compounds were synthesized using a similar method

[0272] Example 14: Synthesis of Compound 45:

[0273] 1) tert-Butyl 8-chloro-6-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (45-a)

[0274] To a solution of 44-c (50 mg, 0.14 mmol, 1 eq) in DMF (4 mL) at 0°C was added NaH (10 mg, 0.02 mmol, 0.1 eq). After stirring for 30 minutes, iodomethane (7.12 mg, 0.30 mmol, 2 eq) was added dropwise. After stirring at room temperature for 2 hours, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 3:1) afforded the product 45-a (45 mg, 91.8%) as a yellow solid. LCMS: 349.15 [M+H] + .

[0275] 2) 8-Chloro-6-methyl-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridin-5(1H)-one (45-b)

[0276] To a solution of 45-a (36 mg, 0.11 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 45-b (25.7 mg, 89.3%) as a white solid. LCMS: 249.10 [M+H] + .

[0277] 3)(R)-8-chloro-3-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-6-methyl-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridin-5(1H)-one (45)

[0278] To a solution of 44-b (25.7 mg, 0.10 mmol, 1.5 eq) and I01 (20 mg, 0.07 mmol, 1 eq) in THF (4 mL) at room temperature were added DIEPA (31 mg, 0.30 mmol, 3 eq) and water (1 mL). After stirring at 65°C for 3 hours, the mixture was concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) gave the product 45 (19.7 mg, 39.4%) as a white solid. LCMS: 500.25 [M+H] + . 1 H NMR (399 MHz, DMSO-d 6) δ7.79(d,J=8.6Hz,1H),7.63(d,J=2.0Hz,1H),7.34(dd,J=8.6,2.0Hz,1H),4.65(s,2H),4.03(s,2H),3.82–3.67(m,4H),3.46(dt,J =15.9,7.8Hz,2H),3.20(dd,J=14.0,8.0Hz,1H),3.04–2.85(m,4H),2.46–2.27(m,4H),2.18(s,2H),1.79(dd,J=19.6,10.3Hz,2H).

[0279] Example 15: Synthesis of Compound 48

[0280] 1) 1,2,3,4-Tetrahydroisoquinoline-6,7-diol (48-a)

[0281] A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.01 g, 10.36 mmol, 1.0 eq) in HBr (22.5 mL, 40% in H2O) and CH3COOH (100 mL) was stirred at 120°C for 8 hours. The mixture was cooled to room temperature and concentrated. Purification by column chromatography (100% EtOAc) afforded the product 48-a as a white solid (2.21 g, 86.3%). LCMS: 166.10 [M+H] + .

[0282] 1. tert-Butyl 6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (48-b)

[0283] To a solution of 48-a (2.21 g, 8.94 mmol, 1.0 eq) and Boc2O (1.95 g, 8.94 mmol, 1.0 eq) in DCM (30 mL) was added triethylamine (4.52 g, 44.72 mmol, 5.0 eq) at room temperature. After stirring at room temperature for 16 hours, the mixture was concentrated. Purification by column chromatography (EtOAc / hexanes = 50:50) afforded the product 48-b (1.81 g, 75.89%) as a white solid. LCMS: 210.15 [M-56+H] + .

[0284] 5) tert-Butyl 2-thio-7,8-dihydro-[1,3]dioxo[4,5-g]isoquinoline-6(5H)-carboxylate (48-c)

[0285] To a solution of T48-b (1.01 g, 3.77 mmol, 1.0 eq) and DMAP (1.61 g, 13.21 mmol, 3.5 eq) in CH2Cl2 (200 mL) was added dropwise thiophosgene (0.57 mL, 7.55 mmol, 2.0 eq) at 0°C. After stirring at room temperature for 16 hours, the mixture was concentrated. Purification by column chromatography (EtOAc / hexanes = 50:50) afforded the product 48-c as a white solid (870 mg, 75.1%). LCMS: 251.90 [M-56+H] + .

[0286] 2. tert-Butyl 2,2-difluoro-7,8-dihydro-[1,3]dioxetane[4,5-g]isoquinoline-6(5H)-carboxylate (48-d)

[0287] To a solution of 48-c (200 mg, 0.65 mmol, 1.0 eq) in DCM (4 mL) at -40°C was added pyridine hydrofluoride (70% wt HF; 643 mg, 6.51 mmol, 10 eq). N-iodosuccinimide (438 mg, 1.95 mmol, 3.0 eq) was then added portionwise. The reaction mixture was allowed to warm to 0°C over 30 minutes. After stirring at room temperature for 30 minutes, a solution of NaHSO₃ (0.5 g) in water (3 mL) was added. After stirring for 15 minutes, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-TLC (EtOAc / hexanes = 3:1) afforded the product 48-d (60 mg, 29.4%) as a white solid. LCMS: 258.05 [M-56+H] + .

[0288] 6) 2,2-Difluoro-5,6,7,8-tetrahydro-[1,3]dioxacyclo[4,5-g]isoquinoline (48-e)

[0289] To a solution of 48-d (20 mg, 0.064 mmol, 1.0 eq) in DCM (1 mL) was added dropwise TFA (0.25 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the white solid product 48-e (20 mg, 95.7%). The crude product was used directly in the next reaction without purification. LCMS: 214.10 [M+H] + .

[0290] 7)(R)-2-(2,2-difluoro-7,8-dihydro-[1,3]dioxacyclo[4,5-g]isoquinolin-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (48)

[0291] To a solution of 48-e (20 mg, 0.061 mmol, 1.0 eq) and I01 (16 mg, 0.055 mmol, 0.9 eq) in THF (1 mL) was added DIEPA (24 mg, 0.18 mmol, 3.0 eq) and water (0.25 mL) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) afforded the product 48 (18.06 mg, 63.8%) as a white solid. LCMS: 465.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.32(s,1H),7.22(s,1H),4.82(s,2H),3.87(s,2H),3.71(s,2H),3.48–3.38(m,1H),3.19(dt, J=15.6,8.3Hz,1H),2.97(d,J=14.4Hz,1H),2.88(d,J=6.8Hz,1H),2.83(s,2H),2.34–2.18(m,4H),1.82–1.69(m,2H).

[0292] Example 16: Synthesis of Compound 49

[0293] 1) 2,2,2-Trifluoro-1-(7-hydroxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (49-a)

[0294] A solution of 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (50-e, 500 mg, 1.65 mol, 1.0 eq) in DCM (5 mL) and TfOH (5 mL) was stirred at 70°C for 1 hour and concentrated. EtOAc (100 mL) was added and the mixture was washed with saturated NaHCO₃ (100 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (EtOAc / hexanes = 1:1) gave the product 49-a (420 mg, 88%) as a white solid. LCMS: 291.05 [M+H] + .

[0295] 2) 1-(6-amino-7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (49-b)

[0296] To a solution of 49-a (400 mg, 1.37 mol, 1.0 eq) in EtOH (100 mL) at room temperature was added Pd / C (10% wt., 40 mg). After hydrogen absorption at room temperature for 16 hours, the solid was filtered off and concentrated to afford the product 49-b as a white solid (290 mg, 80.8%). LCMS: 261.10 [M+H] + .

[0297] 3) 1-(7,8-dihydrooxazolo[4,5-g]isoquinolin-6(5H)-yl)-2,2,2-trifluoroethane-1-one (49-c)

[0298] To a solution of 49-b (200 mg, 0.76 mmol, 1.0 eq) in EtOH (10 mL) at room temperature were added triethyl orthoformate (680.4 mg 4.59 mol 6.0 eq) and TsOH (4 mg 0.076 mmol 0.1 eq). After stirring at 80°C for 2 hours, the mixture was cooled to 0°C and H₂O (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (EtOAc / hexanes = 1:1) afforded the product 49-c (180 mg, 86.6%) as a white solid. LCMS: 271.10 [M+H] + .

[0299] 4) 5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline (49-d)

[0300] To a solution of 49-c (30 mg, 0.11 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL) at room temperature was added K2CO3 (46 mg, 0.33 mmol, 3.0 eq). After stirring at 90°C for 2 hours, the mixture was cooled to room temperature and saturated NaHCO3 (30 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (petroleum ether:ethyl acetate = 1:3) gave the product 49-d (19 mg, 98.2%) as a white solid. LCMS: 175.10 [M+H] + .

[0301] 5)(R)-2-(7,8-dihydrooxazolo[4,5-g]isoquinolin-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (49)

[0302] To a solution of 49-d (50.00 mg, 0.24 mmol, 1 eq) and I01 (70.0 mg, 0.24 mmol, 1 eq) in IPA (5 mL) was added DIEPA (92.88 mg, 0.72 mmol, 3 eq) at room temperature. After heating under reflux for 48 hours, the mixture was concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 15:1) was performed to give the product 49 (2.24 mg, 2.2%) as a white solid. LCMS: 416.20 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.41(s,1H),7.56(s,1H),7.53(s,1H),5.04(s,2H),3.99( s,4H),3.57(s,1H),3.38–3.32(m,1H),3.04(s,4H),2.35(d,J=9.4Hz,4H),1.92(s,2H).

[0303] Example 17: Synthesis of Compound 50

[0304] 1)(4-methoxyphenethyl)carbamic acid methyl ester (50-a)

[0305] To a solution of 2-(4-methoxyphenyl)ethane-1-amine (30 g, 0.2 mol, 1 eq) in DCM (400 mL) at -40°C was added KCO (82 g, 0.59 mol, 3.0 eq). After stirring for 1 hour, methyl chloroformate (18.8 g, 0.2 mol, 1.0 eq) was added dropwise. After stirring for another 2 hours, a saturated NaHCO solution (300 mL) was added. The mixture was extracted with DCM (300 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EtOAc from 10:1 to 1:1) afforded the product 50-a (72.2 g) as a white solid. LCMS: 210.15 [M+H] + .

[0306] 2) 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one (50-b)

[0307] A solution of 50a (10 g, 0.04 mol, 1.0 eq) in PPA (60 mL) was stirred at 120°C for 1 hour and then cooled to room temperature. Saturated Na2CO3 solution (300 mL) was slowly added, and the mixture was extracted with ethyl acetate (150 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc from 10:1 to 3:1) afforded the product 50-b (2.0 g, 23.6%) as a white solid. LCMS: 178.10 [M+H] + .

[0308] 3) 6-Methoxy-1,2,3,4-tetrahydroisoquinoline (50-c)

[0309] To a solution of 50-b (1.5 g, 8.47 mmol, 1 eq) in THF (10 mL) at -40°C was added LiAlH₄ (0.39 g, 10.16 mmol, 1.2 eq). After stirring at 70°C for 2 hours, the mixture was cooled to room temperature and H₂O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc from 10:1 to 3:1) afforded the product 50-c (1 g, 72.4%) as a white solid. LCMS: 164.10 [M+H] + .

[0310] 4) 2,2,2-Trifluoro-1-(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (50-d)

[0311] To a solution of 50-c (3.3 g, 20.24 mmol, 1.0 eq) in DCM (40 mL) at 0°C, TEA (5.1 g, 24.29 mmol, 3.0 eq) and TFAA (5.1 g, 24.29 mmol, 1.2 eq) were added sequentially. After stirring at room temperature for 3 hours, water (100 mL) was added. The product was extracted with DCM (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, PE:EtOAc = 10:1) gave the product 50-d (3.5 g, 66.7%) as a white solid. LCMS: 260.10 [M+H] + .

[0312] 5) 2,2,2-Trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (50-e)

[0313] To a solution of 50-d (810 mg, 3.1 mmol, 1.0 eq) in TFA (10 mL) at 0°C was added dropwise HNO₃ (217 mg, 3.44 mmol, 1.1 eq). After stirring for 3 hours, a saturated NaHCO₃ solution (100 mL) was added. Extraction was performed with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 50-e (720 mg, 75.7%) as a yellow solid. LCMS: 305.10 [M+H] + .

[0314] 6) 7-Methoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline (50-f)

[0315] To a solution of 50-e (30 mg, 0.1 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL) at room temperature was added K2CO3 (14 mg, 0.3 mmol, 3.0 eq). After stirring at 90°C for 2 hours, the mixture was cooled to room temperature and H2O (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (PE:EtOAc = 1:3) gave the product 50-f (16 mg, 77.8%) as a yellow solid. LCMS: 209.10 [M+H] + .

[0316] 7)(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50)

[0317] To a solution of 50-f (50.00 mg, 0.24 mmol, 1.0 eq) and I01 (70.0 mg, 0.24 mmol, 1.0 eq) in IPA (5 mL) was added DIEPA (92.88 mg, 0.72 mmol, 3.0 eq) at room temperature. After heating under reflux for 48 hours, the mixture was concentrated. Pre-TLC (SiO2, dichloromethane:methanol = 15:1) yielded the product 50 (20.33 mg, 18.2%) as a white solid. LCMS: 460.25 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.65(s,1H),7.10(s,1H),4.98(s,2H),4.06–3.99(m,2H),3.92(s,3H),3.57(dt, J=17.0,8.1Hz,1H),3.35(d,J=13.9Hz,1H),3.29(s,2H),3.10(s,2H),2.85(s,2H),2.32(s,4H),1.90(s,2H).

[0318] Example 18: Synthesis of Compound 51

[0319] 1) 6-(2,2,2-Trifluoroacetyl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (51-a)

[0320] To a solution of 49-b (160 mg, 1.0 mol, 1.0 eq) in THF (5 mL) at room temperature was added CDI (180 mg, 3.0 mmol, 3.0 eq). After stirring for 2 hours, H₂O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc from 15:1 to 5:1) afforded the product 51-a (140 mg, 79.2%) as a white solid. LCMS: 287.10 [M+H] + .

[0321] 2) 5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (51-b)

[0322] To a solution of 51-b (30 mg, 0.11 mmol, 1.0 eq) in EtOH (4 mL) and H₂O (1 mL) at room temperature was added K₂CO₃ (46 mg, 0.33 mmol, 3.0 eq). After stirring at 90°C for 2 hours, the mixture was cooled to room temperature and H₂O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-TLC (PE:EtOAc = 1:1) gave the product 51-b (19 mg, 98.2%) as a white solid. LCMS: 191.10 [M+H]⁺.

[0323] 3)(R)-6-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (51)

[0324] To a solution of 51-b (50.00 mg, 0.24 mmol, 1.0 eq) and I01 (70.0 mg, 0.24 mmol, 1 eq) in IPA (5 mL) was added DIPEA (92.88 mg, 0.72 mmol, 3.0 eq) at room temperature. After heating under reflux for 48 hours, the mixture was concentrated. Pre-TLC (SiO2, DCM:MeOH = 15:1) yielded the product 51 (45.41 mg, 39.2%) as a white solid. LCMS: 442.05 [M+H] + . H NMR (400MHz, Methanol-d4) δ7.04(s,1H),6.87(s,1H),3.92(s,4H),3.54(s,1H),3.36(s,1H),3.05(s,2H),2.88(s,2H), 2.33(s,4H),1.88(s,2H).

[0325] Example 19: Synthesis of Compound 53

[0326] 1) 2-Bromo-4,5,6,7-tetrahydrothiophene[2,3-c]pyridine (53-b)

[0327] To a solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride (50 mg, 0.36 mmol, 1 eq.) in HOAc (2 mL) was added liquid bromine (63.1 mg, 0.39 mmol, 1.1 eq.) at room temperature. After stirring for 1.5 hours, the mixture was filtered, washed with ethanol (10 mL x 3), and dried to give the product 53-b as a yellow solid (50 mg, 63%). LCMS: [M+H + ]=218.10

[0328] 2)(R)-2-(2-bromo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (53)

[0329] To a solution of I01 (30 mg, 0.10 mmol, 1 eq) and 53-b (34.1 mg, 0.15 mmol, 1.5 equiv.) in THF (2 mL) / H₂O (0.5 mL) was added DIEPA (40.4 mg, 0.31 mmol, 3 eq). The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) gave the product 53 (27.84 mg, 42%) as a white solid. LCMS: [M+2] + =470.45. 1 HNMR: 1 H NMR(399MHz,DMSO-d6)δ7.77(s,1H),6.94(s,1H),4.81(s,2H),3.93(s,3H),3.68(s,2H),3.43–3.39(m,1H) ,3.20-3.14(m,1H),2.99-2.94(m,1H),2.88-2.83(m,1H),2.61(s,2H)2.27-2.16(m,4H),1.75-1.71(m,2H).

[0330] Example 20: Synthesis of Compound 54

[0331] 1) 2,3-Dibromo-4,5,6,7-tetrahydrothiophene[2,3-c]pyridine (54-a)

[0332] To a solution of 3-bromo-4,5,6,7-tetrahydrothiophene[2,3-c]pyridine (500 mg, 3.59 mmol, 1 eq) in HOAc (20 mL) at room temperature was added liquid bromine (126.2 mg, 0.79 mmol, 2.2 equiv.). After stirring at 80°C for 16 hours, the mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethanol (20 mL x 3). The filtrate was concentrated to afford the product 54-a as a yellow solid (1.0 g, 93%). The crude product was used directly in the next reaction without purification. LCMS: [M+H] + =297.75

[0333] 2) 3-Bromo-4,5,6,7-tetrahydrothiophene[2,3-c]pyridine (54-b)

[0334] To a solution of 54-a (100 mg, 0.33 mmol, 1 equiv.) in HOAc (2 mL) and H2O (2 mL) at room temperature was added zinc powder (110 mg, 1.7 mmol, 5 equiv.). After stirring at 60°C for 16 hours, the mixture was cooled to room temperature. The solid was filtered off and washed with ethyl acetate (15 mL). Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (DCM:MeOH = 10:1) gave the product 54-b (20 mg, 27%) as a yellow oil. LCMS: [M+H] + =219.90.

[0335] 3)(R)-2-(3-bromo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (54)

[0336] To a solution of I01 (24 mg, 0.08 mmol, 1 equiv.) and 54-b (18.19 mg, 0.08 mmol, 1 equiv.) in THF (2 mL) / H₂O (0.5 mL) was added DIPEA (32.3 mg, 0.25 mmol, 3 equiv.) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 54 (37.2 mg, 95%) as a white solid. LCMS: [M+1] + =470.80. 1 H NMR: 1 H NMR (399MHz, DMSO-d6) δ7.73(s,1H),7.55(s,1H),4.93(s,2H),4.00(s,2H),3.70(s,2H),3.45–3. 4(m,1H),3.23–3.17(m,1H),2.98–2.83(m,2H),2.52(s,2H),2.29–2.18(m,4H),1.77–1.73(m,2H).

[0337] Example 21: Synthesis of Compound 56

[0338] 1) tert-Butyl 2-iodo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylate (56-b)

[0339] To a solution of tert-butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (56-a, 200 mg, 0.84 mmol, 1 eq) in THF (5 mL) at -20°C was added N-iodosuccinimide (376 mg, 1.67 mmol, 2 eq). After stirring for 2 hours, water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 3:1) afforded the product 56-b as a yellow oil (100 mg, 32.8%). LCMS: 366.10 [M+H] + .

[0340] 2) 2-iodo-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine (56-c)

[0341] To a solution of 56-b (100 mg, 0.27 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 56-c (50 mg, 68.9%) as a yellow oil. The crude product was used directly in the next reaction without purification. LCMS: 266.15 [M+H] + .

[0342] 3)(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(2-iodo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-6,7-dihydrothieno[2,2-d]pyrimidine 5-oxide (56)

[0343] To a solution of I01 (50 mg, 0.17 mmol, 1 eq) and 56-c (50 mg, 0.19 mmol, 1.1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (67.37 mg, 0.51 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Prep-HPLC (0.1% TFA in ACN / H₂O) gave the product 56 (16.5 mg, 18.4%) as a white solid. LCMS: 517.20 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.76(s,1H),7.15(s,1H),4.72(s,2H),3.98(s,2H),3.69(t,J=2.1Hz,2H),3.41(dd,J=17.2,8.3Hz,1H),3.18(dd,J= 14.4,7.6Hz,1H),2.96(dd,J=17.2,8.0Hz,1H),2.86(dd,J=13.5,7.1Hz,1H),2.76(s,2H),2.33–2.23(m,2H),2.17(m,2H),1.78–1.68(m,2H).

[0344] Example 22: Synthesis of Compound 57

[0345] 1) 2,3-Dibromo-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine (57-a)

[0346] To a solution of tert-butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (56-a, 200 mg, 0.8357 mmol, 1.0 eq) in CHCl₃ (5 mL) at 0°C was added dropwise bromine (267.10 mg, 1.6713 mmol, 2.0 eq). After stirring at 60°C for 3 hours, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with DCM (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-TLC (SiO₂, PE:EtOAc = 1:1) yielded the product 57-a as a yellow solid (180 mg, 87.6%). LCMS: 296.05 [M+H] + .

[0347] 2) 3-Bromo-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine (57-b)

[0348] To a solution of 57-a (150.00 mg, 0.5051 mmol, 1.0 eq) in HOAc (2 mL) and H₂O (2 mL) at room temperature were added Zn (66.05 mg, 1.0101 mmol, 2.0 eq) and TFA (172.76 mg, 1.5151 mmol, 3.0 eq) in sequence. After stirring at 60°C for 16 hours, the mixture was cooled to room temperature. Water (20 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-TLC (SiO₂, PE:EtOAc = 1:1) (PE:EA from 15:1 to 3:1) yielded the product 57-b (80 mg, 67%) as a yellow solid. LCMS: 218.10 [M+H]+ .

[0349] 3)(R)-2-(3-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[2,2-d]pyrimidine 5-oxide (57)

[0350] To a solution of I01 (80 mg, 0.2777 mmol, 1.0 eq) and 57-b (90.83 mg, 0.4166 mmol, 1.5 eq) in THF / H₂O (4 mL:1 mL) was added DIPEA (107.70 mg, 0.8333 mmol, 3.0 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 57 (28.5 mg, 60.3%) as a white solid. LCMS: 469.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.54(s,1H),4.65(m,2H),4.02(m,1H),3.75–3.68(m,3H),3.45(dt,J=16.5,7.8Hz,1H),3.20(dt,J=15. 1,8.1Hz,1H),2.98(dd,J=17.3,8.2Hz,2H),2.87(dd,J=13.7,7.2Hz,3H),2.83(s,2H),2.47(d,J=9.9Hz,1H),2.36–2.17(m,2H),1.74(m,2H).

[0351] Example 23: Synthesis of Compound 60

[0352] 3.5-Cyanoisoindoline-2-carboxylic acid tert-butyl ester (60-b)

[0353] To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (60-a, 200 mg, 0.67 mmol, 1 eq) in DMF (5 mL) at room temperature were added Zn(CN)2 (158 mg, 1.34 mmol, 2 eq) and Pd(PPh3)4 (155 mg, 0.13 mmol, 0.2 eq) in sequence. After stirring at 80°C for 3 hours, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC purification (SiO2, PE:EtOAc = 10:1) afforded the product 60-b as a white solid (80 mg, 48.82%). LCMS: 245.25 [M+H] + .

[0354] 2) Isoindoline-5-carbonitrile (60-c)

[0355] To a solution of 60-b (80 mg, 0.33 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 60-c (40.00 mg, 84.7%) as a yellow oil. The crude product was used directly in the next step without purification. LCMS: 145.30 [M+H] + .

[0356] 3)(R)-2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)isoindoline-5-carbonitrile (60)

[0357] To a solution of I01 (40 mg, 0.14 mmol, 1 eq) and 60-c (25 mg, 0.17 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (55 mg, 0.42 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 60 (47.5 mg, 86.3%) as a white solid. LCMS: 396.30 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.89(d,J=4.0Hz,1H),7.77(dd,J=7.9,1.5Hz,1H),7.60(m,J=17.8,7.9Hz,1H),4.84(t,J=12.5Hz,4H),3.77( s,2H),3.56–3.46(m,1H),3.26(dt,J=13.6,8.2Hz,1H),3.08(d,J=16.2Hz ,1H),2.93(dd,J=13.8,7.2Hz,1H),2.36–2.20(m,4H),1.82–1.70(m,2H).

[0358] Example 24: Synthesis of Compound 64

[0359] 1) tert-Butyl 2-(azetidin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (64-a)

[0360] To a solution of tert-butyl 2-bromo-6,7-dihydrothiazolyl[5,4]pyridine-5(4H)-carboxylate (500 mg, 1.57 mmol, 1.0 eq) and azetidine (179.3 mg, 3.14 mmol, 2.0 eq) in tert-butanol (5 mL) at room temperature was added NaCO (499.3 mg, 4.71 mmol, 3.0 eq). After stirring and refluxing for 16 hours, the mixture was cooled to room temperature and concentrated. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous NaSO, filtered, and concentrated. Pre-TLC purification (SiO, PE:EtOAc = 3:1) afforded the product 64-a as a white solid (280 mg, 76.2%). LCMS: 296.15 [M+H]. + .

[0361] 2) 2-(azetidin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (64-b)

[0362] To a solution of 64-a (200 mg, 0.6770 mmol, 1.0 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the product 64-b (150.5 mg, 80.5%) as a white solid. LCMS: 196.10 [M+H] + .

[0363] 3)(R)-2-(2-(azetidin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (64)

[0364] To a solution of I01 (80.00 mg, 0.2777 mmol, 1.0 eq) and 64-b (81.67 mg, 0.4166 mmol, 1.5 eq) in THF / H₂O (4 mL:1 mL) was added DIPEA (107.70 mg, 0.8333 mmol, 3.0 eq) at room temperature. After stirring at 65°C for 4 hours, the mixture was concentrated. Prep-HPLC (0.1% TFA in ACN / H₂O) purified the product 64 (30.8 mg, 76.5%) as a white solid. LCMS: 447.30 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ4.33(t,J=7.7Hz,4H),4.12(s,2H),3.96–3.86(t,3H),3.60(dt,J=16 .9,8.0Hz,3H),3.33(m,2H),3.15–3.07(m,3H),2.68-2.57(m,4H),2.31(m,3H),1.91-1.86(m,2H).

[0365] Example 25: Synthesis of Compound 65

[0366] 1) tert-Butyl 6-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (65-b)

[0367] To a solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (65-a, 50 mg, 0.14 mmol, 1 eq), 2-bromothiazole (22.8 mg, 0.14 mmol, 1 eq), and CsCO (136 mg, 0.42 mmol, 3 eq) in H2O (1 mL) / 1,4-dioxane (4 mL) at room temperature was added Pd(dppf)Cl2 (10.00 mg, 0.02 mmol, 0.1 eq). After stirring at 100°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 10:1 to 4:1) gave the yellow solid product 65-b (40 mg, 90.9%). LCMS: 317.15 [M+H] + .

[0368] 2) 2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazole (65-c)

[0369] To a solution of 65-b (40 mg, 0.13 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 65-c (25 mg, 89.3%) as a white solid. LCMS: 217.10 [M+H] + .

[0370] 3)(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(6-(thiazol-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (65)

[0371] To a solution of 65-c (28 mg, 0.13 mmol, 1 eq) and I01 (37 mg, 0.13 mmol, 1 eq) in THF (4 mL) was added DIEPA (50 mg, 0.39 mmol, 3 eq) and water (1 mL) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) afforded the product 65 (34.6 mg, 55.7%) as a white solid. LCMS: 468.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.87(d,J=3.2Hz,1H),7.78–7.72(m,3H),7.32(d,J=8.4Hz,1H),4.88(s,3H),3.95(t,J=6.0Hz,2H),3.73(d,J=2. 1Hz,2H),3.45(d,J=8.5Hz,1H),3.26–3.16(m,1H),3.05(s,1H),2.92(d,J=6.3Hz,4H),2.39–2.26(m,2H),2.21(s,2H),1.84–1.70(m,2H).

[0372] Example 26: Synthesis of Compound 66

[0373] 1) tert-Butyl 6-cyclopropyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (66-b)

[0374] To a mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (66-a, 500 mg, 1.60 mmol, 1 eq), cyclopropaneboronic acid (138 mg, 1.60 mmol, 1 eq), and Cs2CO3 (1.56 g, 4.80 mmol, 3 eq) in H2O (1 mL) / 1,4-dioxane (4 mL) at room temperature was added Pd(dppf)Cl2 (117 mg, 0.16 mmol, 0.1 eq). After stirring at 100°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) afforded the product 66-b as a yellow solid (200 mg, 45.6%). LCMS: 274.38 [M+H] + .

[0375] 2) 6-Cyclopropyl-1,2,3,4-tetrahydroisoquinoline (66-c)

[0376] To a solution of 66-b (200 mg, 0.73 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 66-c (100 mg, 78.74%) as a white solid. LCMS: 174.26 [M+H] + .

[0377] 3)(R)-2-(6-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (66)

[0378] To a solution of 66-c (127 mg, 0.46 mmol, 1.5 eq) and I01 (88.00 mg, 0.31 mmol, 1 eq) in THF (4 mL) was added DIEPA (112.00 mg, 0.93 mmol, 3.0 eq) and water (1 mL) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Prep-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 66 (69.9 mg, 35.9%) as a white solid. LCMS: 425.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.19 (s, 1H), 7.03 (d, J = 7.8Hz, 1H), 6.87 (dd, J = 10.5, 2.4Hz, 2H), 4.76 (s,2H),3.87(t,J=6.0Hz,2H),3.72(s,2H),3.49(dd,J=17.1,8.3Hz,1H),3.24(dt,J=13.4,8.2 Hz,1H),3.08(dd,J=17.5,8.1Hz,1H),2.92(dd,J=13.8,7.1Hz,1H),2.80(d,J=6.1Hz,2H),2.37–2.2 4(m,2H),2.21(d,J=11.7Hz,2H),1.85–1.69(m,3H),0.86(dt,J=8.5,3.1Hz,2H),0.64–0.54(m,2H).

[0379] Example 27: Synthesis of Compound 68

[0380] 1) Methyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (68-a)

[0381] To a solution of 51-a (80 mg, 0.28 mol, 1.0 eq) in DMF (5 mL) at room temperature were added Cs2CO3 (114 mg, 0.84 mmol, 3.0 eq) and CH3I (1 mL). After stirring at 50°C for 2 hours, the mixture was cooled to room temperature and H2O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 5:1) afforded the product 68-a (60 mg, 71.2%) as a white solid. LCMS: 301.10 [M+H] + .

[0382] 2) 1-Methyl-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (68-b)

[0383] To a solution of 68-a (30 mg, 0.1 mmol, 1.0 eq) in EtOH (4 mL) and H₂O (1 mL) at room temperature was added K₂CO₃ (41 mg, 0.3 mmol, 3.0 eq). After stirring at 90°C for 2 hours, the mixture was cooled to room temperature and H₂O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-TLC (PE:EtOAc = 1:1) gave the product 68-b (19 mg, 92.9%) as a white solid. LCMS: 205.10 [M+H]⁺.

[0384] 3)(R)-6-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1-methyl-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinolin-2(1H)-one (68)

[0385] To a solution of 68-b (50.00 mg, 0.24 mmol, 1.0 eq) and I01 (70.0 mg, 0.24 mmol, 1.0 eq) in IPA (5 mL) was added DIPEA (92.88 mg, 0.72 mmol, 3.0 eq) at room temperature. After heating under reflux for 48 hours, the mixture was concentrated. Pre-TLC (SiO2, DCM:MeOH = 15:1) yielded the product 68 (44.2 mg, 39.6%) as a white solid. LCMS: 456.50 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ7.13(s,1H),7.04(s,1H),3.95(d,J=14.5Hz,4H),3.71(s,1H),3.48(s,1H),3.36(s,3H),3.3 2(dd,J=8.4,1.6Hz,1H),3.28(s,2H),3.17(ddd,J=13.9,7.4,1.6Hz,1H),3.04(d,J=6.6Hz,2H),2.36(s,4H),1.92(s,2H).

[0386] Example 28: Synthesis of Compound 69

[0387] 1) Ethyl 4-((4-fluorophenyl)thio)-3-acetoacetate (69-a)

[0388] To a solution of 4-fluorobenzenethiol (10 g, 78.12 mmol, 1.0 eq) and ethyl 4-chloro-3-acetoacetate (13 g, 78.12 mmol) in DCM (400 mL) at 0°C was added triethylamine (12 g, 117.18 mmol, 1.5 eq) dropwise. Stirring was continued for 2 hours, and the mixture was poured into water (300 mL). Extraction was performed with DCM (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (hexanes / EtOAc = 10:1) afforded the product 69-a (18 g, 90%) as a yellow oil. LCMS: 257.10 [M+H] + .

[0389] 2) Ethyl 2-(5-fluorobenzo[b]thiophen-3-yl)acetate (69-b)

[0390] To a solution of PPA (21.6 g) in toluene (20 mL) at 100°C was added a solution of 69-a (5 g, 19.51 mmol, 1.0 eq) in toluene (5 mL). After stirring for 16 hours, the mixture was cooled to room temperature and poured into ice water (100 mL). KCO was added to adjust the pH to pH ~8. Extraction was performed with ethyl acetate (50 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 10:1) afforded the product 69-b (2.21 g, 47.5%) as a yellow oil. LCMS: 239.10 [M+H] + .

[0391] 3) 2-(5-Fluorobenzo[b]thiophen-3-yl)acetamide (69-c)

[0392] A solution of 69-b (2.21 g, 9.27 mmol, 1.0 eq) in ammonia in MeOH (7 M, 40 mL, 278 mmol) was stirred at room temperature for 3 days and then concentrated. Purification by column chromatography (DCM / MeOH = 10:1) gave the product 69-c (1.4 g, 72.1%) as a white solid. LCMS: 210.05 [M+H] + .

[0393] 4) 2-(5-Fluorobenzo[b]thiophen-3-yl)ethan-1-amine (69-d)

[0394] To a solution of 69-c (500 mg, 2.26 mmol, 1.0 eq) in THF (10 mL) at room temperature was added dropwise 1M borane / Me2S Complex in THF (5.64 mL, 5.64 mmol, 2.5 eq). After stirring at 50°C for 16 hours, the mixture was cooled to 0°C and slowly added dropwise with methanol (20 mL). The mixture was then refluxed for 3 hours. The mixture was cooled to room temperature and concentrated. 2N NaOH (15 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (DCM / MeOH = 20:1) afforded the product 69-d (130 mg, 27.8%) as a colorless oil. LCMS: 196.10 [M+H] + .

[0395] 4. Ethyl 2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate (69-e)

[0396] To a solution of 69-d (100 mg, 0.51 mmol, 1.0 eq) and Et3N (78 mg, 0.77 mmol, 1.5 eq) in DCM (3 mL) at 0°C was added ethyl chloroformate (61 mg, 0.56 mmol, 1.1 eq) dropwise. After stirring at room temperature for 2 hours, saturated NH4Cl (30 mL) was added, and the mixture was extracted with DCM (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (hexanes / ethyl acetate = 10:1) gave the product 69-e (109 mg, 79.6%) as a colorless oil. LCMS: 268.10 [M+H] + .

[0397] 8) Ethyl 6-fluoro-3,4-dihydrobenzo[4,5]thieno[2,3-c]pyridine-2(1H)-carboxylate (69-f)

[0398] A mixture of 69-e (100 mg, 0.39 mmol, 1.0 eq), paraformaldehyde (22 mg, 0.75 mmol, 2.0 eq), and p-toluenesulfonic acid monohydrate (4 mg, 0.019 mmol, 0.05 eq) in toluene (2 mL) was stirred and refluxed at 115°C for 2 hours. The mixture was cooled to room temperature and concentrated. Pre-TLC (hexanes / ethyl acetate = 10:1) gave the product 69-f (70 mg, 67%) as a colorless oil. LCMS: 280.10 [M+H] + .

[0399] 9) 6-Fluoro-1,2,3,4-tetrahydrobenzo[4,5]thiophene[2,3-c]pyridine (69-g)

[0400] To a solution of 69-f (50 mg, 0.18 mmol, 1.0 eq) in methanol (2 mL) and water (0.5 mL) was added NaOH (36 mg, 0.89 mmol, 5.0 eq) at room temperature. The mixture was stirred at 80°C for 16 hours, cooled to room temperature, and concentrated. Pre-HPLC (0.1% TFA in water / ACN from 5% to 95%) purified the product 69-g (20 mg, 18.3%) as a white solid. LCMS: 208.10 [M+H] + .

[0401] 10)(R)-2-(6-fluoro-3,4-dihydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (69)

[0402] To a solution of 69-g (20 mg, 0.097 mmol, 1.0 eq) and I01 (25 mg, 0.087 mmol, 0.9 eq) in THF (1 mL) at room temperature were added DIEPA (37 mg, 0.29 mmol, 3.0 eq) and water (0.25 mL). After stirring at 65°C for 16 hours, the mixture was concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) gave the product 69 (37.24 mg, 83.8%) as a yellow solid. LCMS: 459.35 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.93 (dd, J=8.8, 4.9Hz, 1H), 7.48 (dd, J=9.9, 2.5Hz, 1H), 7.17(td,J=8.9,2.5Hz,1H),5.03(s,2H),4.10(s,3H),3.72(s,2H),3.43(dt,J=1 7.1,8.1Hz,1H),3.19(dt,J=15.1,8.3Hz,1H),3.00–2.91(m,1H),2.89–2.84(m,1 H), 2.81 (s, 2H), 2.32 (d, J = 24.7Hz, 2H), 2.24–2.17 (m, 2H), 1.78 (d, J = 9.0Hz, 2H).

[0403] Example 29: Synthesis of Compound 70

[0404] 1)(S)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylic acid (70-a)

[0405] To a solution of thiophen-2-yl-L-alanine (1 g, 5.84 mmol, 1.0 equiv.) in HOAc (30 mL) at room temperature was added paraformaldehyde (1052.2 mg, 35.04 mmol, 6.0 equiv.). The mixture was stirred at 70°C for 2 hours, cooled to room temperature, and saturated NaHCO₃ (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (DCM / MeOH = 20:1) afforded the product 70-a as a colorless solid (300 mg, 28%). LCMS: 184.05 [M+H] + .

[0406] 3) Methyl (S)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylic acid (70-b)

[0407] To a solution of 70-a (100 mg, 0.55 mmol, 1 equiv.) in MeOH (2 ml) at 0°C was added SOCl2 (194.8 mg, 1.64 mmol, 3 equiv.). The mixture was stirred at 60°C for 5 hours and concentrated to afford the product 70-b (100 mg, 92.9%) as a yellow solid. The crude product was used directly in the next reaction without purification. LCMS: 198.05 [M+H] + .

[0408] 4)(S)-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-6-yl)methanol(70-c)

[0409] To a solution of 70-b (100 mg, 0.51 mmol, 1.0 equiv.) in THF (2 mL) at 0°C was added LiAlH₄ (0.052 ml, 1.52 mmol, 3.0 equiv.). Stirring was continued for 5 hours, followed by addition of water (2 mL) and concentration. Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 70-c (40 mg, 0.24 mmol, 46.6%) as a yellow solid. LCMS: 170.10 [M+H] + .

[0410] 5)(R)-2-((S)-6-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70)

[0411] To a solution of I01 (10 mg, 0.035 mmol, 1 equiv.) and 70-c (5.88 mg, 0.035 mmol, 1.0 equiv.) in THF (3 ml) and H₂O (0.6 ml) was added DIEPA (89.82 mg, 0.70 mmol, 20 equiv.) at room temperature. After stirring at 65°C for 12 hours, the mixture was concentrated. Pre-TLC (MeOH:DCM = 1:10) (0.1% TFA in ACN / H₂O) gave the product 70 (2.30 mg, 17.16%) as a white solid. LCMS: 421.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.39–7.24(m,2H),6.90(d,J=5.0Hz,1H),5.32(d,J=18.0Hz,1H),5.20(s,1H),4.80(s,2H),4.07(d,J=17.3Hz ,1H),3.71(s,2H),3.44–3.36(m,1H),3.26(s,2H),3.19(s,1H),3.02–2.79(m,4H),2.37–2.27(m,2H),2.16(s,2H),1.83–1.68(m,2H).

[0412] Example 30: Synthesis of Compound 71

[0413] 1) 5-Benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ol (71-b)

[0414] A mixture of methyl 1-benzyl-4-piperidone-3-carboxylate hydrochloride (71-a, 2 g, 6.72 mmol, 1 eq) and methylhydrazine sulfate (4.85 g, 33.58 mmol, 5 eq) in EtOH (20 mL) was stirred at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) gave the product 71-b as a yellow oil (1.8 g, 91.5%). LCMS: 244.30 [M+H] + .

[0415] 2) 5-Benzyl-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (71-c)

[0416] Dissolve 71-b (1.8 g, 7.39 mmol, 1 eq) in POCl₃ (20 mL) and stir at 150°C for 3 hours. Cool to room temperature and concentrate. Add 1N NaOH (aq. 50 mL) and extract with ethyl acetate (50 mL x 3). Dry over anhydrous Na₂SO₄, filter, and concentrate. Purify by column chromatography (DCM:MeOH = 20:1) to afford 71-c (110 mg, 5.7%) as a yellow oil. LCMS: 262.25 [M+H] + .

[0417] 3) 3-Chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (71-d)

[0418] To a solution of 71-c (110 mg, 0.42 mmol, 1 eq) in DCM (5 mL) at 0°C was added 1-chloroethyl chloroformate (120 mg, 0.84 mmol, 2 eq). After stirring at room temperature for 2 hours, the mixture was concentrated. MeOH (5 mL) was then added. After stirring at 65°C for 16 hours, the mixture was concentrated to afford the product 71-d (50 mg, 69.3%) as a yellow solid. The crude product was used directly in the next reaction without purification. LCMS: 172.25 [M+H] + .

[0419] 4)(R)-2-(3-chloro-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (71)

[0420] To a solution of I01 (50 mg, 0.17 mmol, 1 eq) and 71-d (45 mg, 0.26 mmol, 1.5 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (66 mg, 0.51 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 71 (41.9 mg, 57%) as a yellow solid. LCMS: 423.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ4.64(s,2H),3.96(d,J=7.0Hz,2H),3.69(s,3H),3.66(s,2H),3.42(dt,J=16.5,7.7Hz,2H), 3.26–3.08(m,2H),2.99–2.84(m,2H),2.61(m,J=6.0Hz,2H),2.35–2.24(m,2H),2.14(m,2H),1.75(q,J=9.1Hz,2H).

[0421] Example 31: Synthesis of Compound 72

[0422] 1) tert-Butyl 8-chloro-5-((trifluoromethyl)sulfonyl)oxy)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (72-a)

[0423] To a solution of 44-c (330 mg, 0.99 mmol, 1 equiv.) in DCM (10 mL) at 0°C were added pyridine (1169.50 mg, 14.79 mmol, 15 equiv.) and Tf2O (834.29 mg, 2.96 mmol, 3 equiv.) in sequence. After stirring at room temperature for 16 hours, saturated NH4Cl solution (20 mL) was added. The product was extracted with DCM (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc from 20:1 to 5:1) afforded the product 72-a (300 mg, 65.2%) as a yellow solid. LCMS: 467.10 [M+H] + .

[0424] 2) tert-Butyl 8-chloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (72-b)

[0425] To a solution of 72-a (40 mg, 0.086 mmol, 1 equiv.) in THF (2 ml) at room temperature were added pyridine (101.66 mg, 1.29 mmol, 15 equiv.), triethylsilane (149.44 mg, 1.29 mmol, 15 equiv.), and Pd(PPh3)4 (19.80 mg, 0.017 mmol, 0.2 equiv.). After stirring at 50°C for 5 hours, the solid was filtered off. The filtrate was concentrated and purified by column chromatography (PE:EtOAc from 20:1 to 5:1) to afford the product 72-b (20 mg, 73.2%) as a yellow solid. LCMS: 319.15 [M+H] + .

[0426] 3)8-Chloro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (72-c)

[0427] To a solution of 72-b (25 mg, 0.078 mmol, 1 equiv.) in DCM (1.5 ml) was added TFA (0.5 ml, 5.10 mmol, 65.04 equiv.) at 0°C. After stirring for 1 hour, the mixture was concentrated to afford the product 72-c (69.8 mg, 81.8%) as a white solid. The crude product was used directly in the next reaction without purification. LCMS: 219.10 [M+H] + .

[0428] 4)(R)-2-(8-chloro-1,4-dihydrobenzo[c][2,7]naphthyridin-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (72)

[0429] To a solution of I01 (15 mg, 0.052 mmol, 1 equiv.) and 72-c (11.40 mg, 0.052 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml) was added DIEPA (67.37 mg, 0.52 mmol, 10 equiv.) at room temperature. After stirring at 65°C for 12 hours, the mixture was concentrated. Pre-TLC (MeOH:DCM = 1:10) gave the product 72 (10 mg, 40.8%) as a yellow solid. LCMS: 470.05 [M+H] + . 1H NMR(400MHz, DMSO-d6)8.80(s,1H),8.10–7.99(m,2H),7.63(dd,J=9.0,2.3H z,1H),7.48(s,1H),5.03(s,2H),4.84(s,1H),4.11(s,2H),3.73(s,2H),3.46 –3.36(m,1H),3.28(s,2H),3.18(d,J=6.0Hz,2H),2.94(dd,J=17.0,8.3Hz,1H ),2.84(dd,J=13.8,7.3Hz,1H),2.30(s,1H),2.21(s,2H),1.84–1.72(m,2H).

[0430] Example 32: Synthesis of Compound 73

[0431] 1) tert-Butyl 5,8-dichloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (73-a)

[0432] A solution of 72-a (30 mg, 0.064 mmol, 1 equiv.), DIPEA (132.88 mg, 1.03 mmol, 16 equiv.), LiCl (54.48 mg, 1.29 mmol, 20 equiv.), and 1.4.7.10.13-pentaoxopentadecane (141.54 mg, 0.64 mmol, 10 equiv.) in DMF (1.5 ml) was sealed and stirred at 100°C for 2 hours. The mixture was cooled to room temperature and concentrated. Pre-TLC (PE:EtOAc = 1:1) gave the product 73-a (15 mg, 66.1%) as a yellow solid. LCMS: 353.10 [M+H] + .

[0433] 2) 5,8-Dichloro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (73-b)

[0434] To a solution of 73-a (15 mg, 0.042 mmol, 1 equiv.) in DCM (1.5 ml) was added TFA (0.50 ml) at 0°C. After stirring for 1 hour, the mixture was concentrated to afford the yellow solid product 72-b (69.8 mg, 81.8%). The crude product was used directly in the next reaction without purification. LCMS: 253.05 [M+H] + .

[0435] 3)(R)-2-(5,8-dichloro-1,4-dihydrobenzo[c][2,7]naphthyridin-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (73)

[0436] To a solution of I01 (15 mg, 0.052 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml) at room temperature were added 73-b (10.00 mg, 0.040 mmol, 0.8 equiv.) and DIEPA (67.37 mg, 0.52 mmol, 10 equiv.). The mixture was stirred at 65°C for 12 hours and then concentrated. Pre-TLC (MeOH:DCM = 1:10) gave the product 73 (8 mg, 30.4%) as a white solid. LCMS: 504.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=9.0Hz,1H),8.00(d,J=2.2Hz,1H),7.68(d d,J=9.0,2.2Hz,1H),7.48(s,1H),4.98(s,2H),4.81(s,1H),4.11(s,2H),3.7 4(s,2H),3.49–3.37(m,1H),3.23(s,3H),3.00–2.90(m,1H),2.85(dd,J=13. 6,7.2Hz,1H),2.34(dd,J=21.4,11.1Hz,2H),2.20(s,2H),1.85–1.72(m,2H).

[0437] Example 33: Synthesis of Compound 74

[0438] 1) tert-Butyl 8-chloro-5-(methylamino)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (74-a)

[0439] In a sealed tube, 73-a (40 mg, 0.086 mmol, 1 equiv.), MeNH2HCl (46.28 mg, 0.69 mmol, 8 equiv.), DIPEA (177.17 mg, 1.37 mmol, 16 equiv.), and DMF (2 mL) were added sequentially. After stirring at 100°C for 2 hours, the mixture was cooled to room temperature and concentrated. Pre-TLC (PE:EtOAc = 1:1) purification afforded the product 74-a (25 mg, 83.9%) as a yellow solid. LCMS: 348.15 [M+H] + .

[0440] 2) 8-Chloro-N-methyl-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-5-amine (74-b)

[0441] To a solution of 74-a (25 mg, 0.072 mmol, 1 equiv.) in DCM (1.5 ml) was added TFA (0.5 ml) at 0°C. After stirring for 1 hour, the mixture was concentrated to afford the product 74-b (17.2 mg, 97.2%) as a white solid. The crude product was used directly in the next reaction without purification. LCMS: 248.10 [M+H] + .

[0442] 3)(R)-2-(8-chloro-5-(methylamino)-1,4-dihydrobenzo[c][2,7]naphthyridin-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (74)

[0443] To a solution of I01 (20 mg, 0.070 mmol, 1.0 equiv.) in THF (3 ml) and H2O (0.6 ml) at room temperature were added 74-b (17.22 mg, 0.070 mmol, 1.0 equiv.) and DIEPA (89.83 mg, 0.70 mmol, 10 equiv.). After stirring at 65°C for 12 hours, the mixture was concentrated. Pre-TLC (MeOH:DCM = 1:10) gave the product 74 (10 mg, 28.8%) as a white solid. LCMS: 499.25 [M+H] + . 1 H NMR(399MHz,DMSO-d6)δ7.70(d,J=8.8Hz,1H),7.49(d,J=2.2Hz,1H),7.41 (s,1H),7.18–7.10(m,1H),6.75(s,1H),4.80(d,J=20.1Hz,1H),4.69(d,J= 17.3Hz,1H),4.16–4.07(m,1H),4.01(s,1H),3.74(s,2H),3.40(dt,J=16.3 ,7.8Hz,1H),3.26(s,1H),3.17(dt,J=15.4,8.3Hz,1H),3.01–2.90(m,5H), 2.83(dd,J=13.6,7.2Hz,1H),2.31(d,J=14.3Hz,2H),2.20(s,2H),1.79(s,2H).

[0444] Example 34: Synthesis of Compound 76

[0445] 1) tert-Butyl 6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (76-b)

[0446] To a mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (76-a, 100 mg, 0.32 mmol, 1 eq), methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66.7 mg, 0.32 mmol, 1 eq), and CsCO (312 mg, 0.96 mmol, 3 eq) in H2O (1 mL) / 1,4-dioxane (4 mL) at room temperature was added XPhos-Pd-G3 (28.00 mg, 0.03 mmol, 0.1 eq). After stirring at 120°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 10:1 to 4:1) gave the yellow solid product 76-b (80 mg, 79.62%). LCMS: 314.20 [M+H] + .

[0447] 2) 6-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (76-c)

[0448] To a solution of 76-b (80 mg, 0.26 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain the product 76-c (69.8 mg, 81.8%) as a white solid. LCMS: 214.15 [M+H] + .

[0449] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (76)

[0450] To a solution of 76-c (69.8 mg, 0.33 mmol, 1 eq) and I01 (94 mg, 0.33 mmol, 1 eq) in THF (4 mL) was added DIEPA (127.70 mg, 0.99 mmol, 3.0 eq) and water (1 mL) at room temperature. After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) afforded the product 76 (65.7 mg, 42.8%) as a yellow solid. LCMS: 465.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=1.9Hz,1H),7.33(d,J=4.8Hz,3H),6.33( d,J=1.9Hz,1H),4.89(s,2H),3.95(t,J=5.9Hz,2H),3.81(s,3H),3.74(s,2H ),3.51(dt,J=16.5,7.7Hz,1H),3.26(dt,J=15.0,8.2Hz,1H),3.09(dd,J=17 .6,8.2Hz,1H),2.93(d,J=6.3Hz,3H),2.38–2.14(m,4H),1.85–1.70(m,2H).

[0451] The following compounds were synthesized using a similar method

[0452] Example 35: Synthesis of Compound 80

[0453] 1) tert-Butyl 6-(2-oxooxazolidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (80-a)

[0454] To a solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (76-a, 200 mg, 0.64 mmol, 1 eq) in 1,4-dioxane (20 mL) at room temperature were added 2-oxazolidinone (112 mg, 1.28 mmol, 2 eq), Pd(dba) (59 mg, 0.06 mmol, 0.1 eq), Xantphos (37 mg, 0.06 mmol, 0.1 eq), and CsCO (1.30 g, 3.84 mmol, 6 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Pre-TLC purification (SiO2, petroleum ether:ethyl acetate = 1:1) gave the white solid product 80-a (200 mg, 98.1%). LCMS: 319.15 [M+H] + .

[0455] 2) tert-Butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (80-b)

[0456] A solution of 80-a (200 mg, 0.63 mmol, 1 eq) in 4M HCl / 1,4-dioxane (4 mL) was stirred at room temperature for 1 hour. The solution was concentrated to afford 80-b (120 mg, 87.5%) as a yellow solid. The crude product was used directly in the next reaction without purification. LCMS: 219.15 [M+H] + .

[0457] 3)(R)-3-(2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxazolidin-2-one (80)

[0458] To a solution of I01 (40 mg, 0.14 mmol, 1 eq) and 80-b (36.40 mg, 0.17 mmol, 1.2 eq) in THF (4 mL) and H₂O (1 mL) was added DIEPA (55.00 mg, 0.42 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded the product 80 (64 mg, 98%) as a yellow solid. LCMS: 470.25 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.40(dd,J=8.4,2.4Hz,1H),7.34(d,J=2.4Hz,1H),7.20(d,J=8.5Hz ,1H),4.80(s,2H),4.39(dd,J=9.1,6.9Hz,2H),4.00(dd,J=9.0,7.0Hz,2H),3.90(t,J=5.9Hz ,2H),3.76–3.68(m,2H),3.46(dd,J=16.9,8.2Hz,1H),3.21(dd,J=15.0,7.1Hz,1H),3.03(dd ,J=17.4,8.1Hz,1H),2.87(dt,J=19.7,6.3Hz,3H),2.35–2.16(m,4H),1.77(m,J=8.8Hz,2H).

[0459] Example 36: Synthesis of Compound 104

[0460] 1) Synthesis of Compound 104a

[0461] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.00 g, 10.04 mmol, 1 eq) in DMF (2 mL) at room temperature was added N,N-dimethylformamide dimethyl acetal (1.20 g, 10.04 mmol, 1 eq). After stirring at 80°C for 24 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 3:1) afforded the product 104a as a yellow solid (1.56 g, 61.11%). LCMS: 255.15 [M+H] + .

[0462] 2) Synthesis of Compound 104b

[0463] To a solution of 104a (1.56 g, 6.13 mmol, 1 eq) in acetic acid (50 mL) at room temperature was added 2-methylpyrazol-3-amine (595.72 mg, 6.13 mmol, 1 equiv.). After stirring at 100°C for 24 hours, the mixture was cooled to room temperature and concentrated. Pre-HPLC purification (ACN:0.1% TFA in H2O from 5% to 95%) afforded the product 104b as a white solid (750.00 mg, 42.40%). LCMS: 289.15 [M+H] + .

[0464] 3) Synthesis of Compound 104c

[0465] To a solution of 104b (200.00 mg, 0.69 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated. Pre-HPLC purification (ACN:0.1% TFA in H2O from 5% to 95%) afforded the product 104c (50.00 mg, 38.29%) as a white solid. LCMS: 189.22 [M+H] + .

[0466] 4. Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridin-7-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (104)

[0467] To a solution of 104c (43.72 mg, 0.21 mmol, 1 eq) and I01 (60.00 mg, 0.21 mmol, 1 eq) in THF (4 mL) was added N,N-diisopropylethylamine (80.84 mg, 0.63 mmol, 3 eq) and water (1 mL) at room temperature. After stirring at 65°C for 16 hours, the mixture was concentrated. Pre-HPLC purification (ACN:0.1% TFA in H2O from 5% to 95%) afforded compound 104 (51.00 mg, 53.06%). LCMS: 440.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),8.04(s,1H),4.98(s,2H),4.00(d,J=15.0Hz,6H),3.74(s,2H),3.47(dd,J=17.0,8.2Hz ,1H),3.26–3.19(m,1H),3.12(s,2H),3.09–3.02(m,1H),2.90(dd,J=13.5,7.1Hz,1H),2.38–2.17(m,5H),1.82–1.75(m,2H).

[0468] The following compounds were synthesized using a similar method

[0469] Example 37: Synthesis of Compound 113

[0470] 1) Synthesis of compound 113a

[0471] To a solution of compound 113h (10 g, 81.30 mmol, 1.0 equiv.) in DCM (100 mL) at 0°C under nitrogen was added chloro-(methyloxy)methane (6.6 g, 81.30 mmol, 1.0 equiv.) and triethylamine (41.05 g, 406.5 mmol, 5.0 equiv.) in sequence. After stirring at 0°C for 1 hour, water (150 mL) was added. The mixture was extracted with DCM (200 mL x 2), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 10:1) afforded the product 113a (7.02 g, 42.03 mmol, 51.73%) as a yellow oil. LCMS: 168.05 [M+H] + .

[0472] 2) Synthesis of compound 113b

[0473] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (10 g, 81.30 mmol, 1.0 equiv.) in THF (100 mL) at 0°C under nitrogen was added portionwise NaH (1.7 g, 42.03 mmol, 1 equiv.). After stirring at 0°C for 30 minutes, a solution of 113a (9.4 g, 42.03 mmol, 1.0 equiv.) in THF (15 mL) was added dropwise. After stirring at 0°C for 1 hour, saturated aqueous NH4Cl (100 mL) was added. The mixture was extracted with EtOAc (150 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 10:1) afforded 113b (8 g, 33.75 mmol, 80.29%) as a yellow oil. LCMS: 238.10 [M+H]. + .

[0474] 3) Synthesis of compound 113c

[0475] To a solution of 113b (1 g, 4.21 mmol, 1.0 equiv.) and ethyl 3-(benzylamino)-3-oxopropanoate (930.41 mg, 4.21 mmol, 1.0 eq.) in THF (30 mL) was added NaH (336.8 mg, 8.42 mmol, 2.0 equiv.) at room temperature. After stirring at 70°C for 1 hour, the mixture was cooled to room temperature, saturated NH4Cl (30 mL) was added, and the mixture was extracted with EtOAc (35 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 113c (600 mg, 1.45 mmol, 34.52%) as a yellow solid. LCMS: 413.15 [M+H] + .

[0476] 4) Synthesis of Compound 113d

[0477] To a solution of 113c (470 mg, 1.14 mmol, 1.0 eq.) in THF (20 mL) at room temperature was added dropwise borane (11.44 mL, 11.44 mmol, 10 equiv.). After stirring at 70°C for 3 hours, the mixture was cooled to 0°C and slowly quenched with methanol (30 mL). The mixture was then stirred at 60°C for 3 hours, cooled to room temperature, and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 113d (100 mg, 0.29 mmol, 25.64%) as a yellow solid. LCMS: 343.20 [M+H] + .

[0478] 5) Synthesis of Compound 113e

[0479] To a solution of 113d (220 mg, 0.64 mmol, 1.0 equiv.) in DCM (3 mL) was added TFA (1 ml, 9.58 mmol, 14.98 equiv.) at room temperature. Stirring was continued for 3 hours, then concentrated. EtOAc (30 mL) and saturated NaHCO₃ (20 mL) were added. The mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 113e (190 mg, 0.63 mmol, 98.43%) as a yellow solid. LCMS: 299.17 [M+H] + .

[0480] 6) Synthesis of Compound 113f

[0481] To a solution of 113e (210 mg, 0.70 mmol, 1.0 equiv.) in THF (10 mL) at 0°C under nitrogen was added PPh3 (917 mg, 3.5 mmol, 5.0 equiv.) and DIAD (707 mg, 3.5 mmol, 5.0 equiv.) sequentially. After stirring at room temperature for 16 hours, EtOAc (30 mL), water (30 mL x 2), and saturated brine (30 mL) were added. The mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 3:1) afforded the product 113f (80 mg, 0.28 mmol, 40.00%) as a yellow solid. LCMS: 281.16 [M+H] + .

[0482] 7) Synthesis of Compound 113g

[0483] To a solution of 113f (80 mg, 0.28 mmol, 1.0 equiv.) in 1,2-DCE (3 mL) at 0°C under nitrogen was added ACE-Cl (73.89 mg, 0.56 mmol, 2.0 equiv.). After stirring at room temperature for 1 hour, the mixture was concentrated. MeOH (10 mL) was added and the mixture was heated at reflux for 12 hours. The mixture was cooled to room temperature, saturated NaHCO₃ (10 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 113f (30 mg, 0.15 mmol, 53.6%) as a yellow solid. LCMS: 191.10 [M+H] + .

[0484] 8) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((6aR,10aS)-6a,9,10,10-tetrahydro-6H-pyrano[2,3-c:5,4-c']bipyridin-8(7H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (113)

[0485] To a solution of I01 (100 mg, 0.34 mmol, 1.0 equiv.) and 113 g (86.06 mg, 0.45 mmol, 1.3 equiv.) in THF (3 ml) and H₂O (0.6 ml) at room temperature was added DIEA (438.6 mg, 3.4 mmol, 10 equiv.). After stirring at 65°C for 12 hours, the mixture was cooled to room temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture was purified by column chromatography (MeOH:DCM = 1:10) to afford the product mixture. Further purification by SFC afforded compound 113 (42.69 mg, 0.096 mmol, 28.45%). LCMS: 442.30 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.05–7.99(m,2H),7.37(s,1H),7.18(d,J=4.9Hz,1H),4.85(s,1H),4.83–4.7 0(m,2H),4.30(s,1H),3.91(d,J=11.2Hz,1H),3.69(d,J=5.7Hz,2H),3.36(dd,J=16.6,7.9Hz,1H),3.1 6(d,J=13.8Hz,1H),2.90(ddd,J=30.1,23.8,12.8Hz,4H),2.79(d,J=2.9Hz,1H),2.62(d,J=12.3Hz,1H ),2.40(d,J=12.5Hz,1H),2.29(dd,J=24.6,11.2Hz,2H),2.15(s,2H),1.82–1.69(m,2H),1.64(s,1H).

[0486] The following compounds were synthesized using a similar method

[0487] Example 38: Synthesis of Compound 114

[0488] 1) Synthesis of compound 114a

[0489] To a solution of 3-bromo-5-chloro-2-iodopyridine (2 g, 6.28 mmol, 1.0 eq) and ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.42 g, 6.28 mmol, 1.0 eq) in THF (20 mL) at room temperature were added KCO (2.59 g, 18.84 mmol, 3.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (453.22 mg, 0.62 mmol, 0.1 eq), and water (5 mL). The mixture was heated to reflux under nitrogen for 6 h. The mixture was cooled to room temperature, the solid was filtered off, and the mixture was extracted with EtOAc (20 mL x 3). The mixture was dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) gave the product 114a as a white solid (1.7 g, 6.89 mmol, 93.34%). LCMS: 290.54 [M+H] + .

[0490] 2) Synthesis of compound 114b

[0491] To 114a (2 g, 6.89 mmol, 1.0 equiv.) in THF (30 ml) was added ethyl 3-(benzylamino)-3-oxopropanoate (1.52 g, 6.89 mmol, 1.0 equiv.) and NaH (551.2 mg, 13.78 mmol, 2.0 equiv.) at room temperature. The mixture was heated to 70°C and stirred for 1 hour. The mixture was cooled to room temperature, saturated NH4Cl (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 114b (2 g, 4.30 mmol, 62.40%) as a yellow solid. LCMS: 465.01 [M+H] + .

[0492] 3) Synthesis of compound 114c

[0493] To a solution of 114b (2 g, 4.30 mmol, 1.0 eq.) in anhydrous THF (20 mL, 100.0%) at 0°C under nitrogen was added dropwise borane (4.3 mL, 43.0 mmol, 10 equiv.) at 80°C and stirred for 3 hours. The mixture was cooled to 0°C, and MeOH (30 mL) was carefully added, followed by stirring at 60°C for 3 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 114c as a yellow solid (200 mg, 0.50 mmol, 11.7%). LCMS: 395.05 [M+H] + .

[0494] 4) Synthesis of Compound 114d

[0495] To a solution of 114c (200 mg, 0.50 mmol, 1.0 equiv.) in THF (30 mL) at 0°C under nitrogen was added NaH (38.3 mg, 1.0 mmol, 2.0 equiv. 60% wt). After stirring at 70°C for 1 hour, the mixture was cooled to 0°C and saturated NH4Cl (30 mL) was added. The mixture was extracted with EtOAc (35 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 114d (100 mg, 0.31 mmol, 63.69%) as a yellow solid. LCMS: 315.15 [M+H] + .

[0496] 5) Synthesis of Compound 114e

[0497] To a solution of 114d (100 mg, 0.31 mmol, 1.0 equiv.) in 1,2-DCE (3 mL) at 0°C under nitrogen was added dropwise ACE-Cl (87.2 mg, 0.61 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 1 hour, concentrated, and then MeOH (10 mL) was added. The mixture was heated at reflux for 12 hours and cooled to room temperature. Saturated NaHCO₃ (10 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 114e (60 mg, 0.26 mmol, 83.87%) as a yellow solid. LCMS: 225.10 [M+H] + .

[0498] Synthesis of 6)(R)-2-((6aS,10aR)-3-chloro-6a,9,10,10-tetrahydro-6H-pyrano[3,2-b:5,4-c']bipyridin-8(7H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (114)

[0499] To a solution of I01 (60 mg, 0.20 mmol, 1.0 equiv.) and 114e (60.93 mg, 0.27 mmol, 1.3 equiv.) in THF (3 ml) and H₂O (0.6 ml) at room temperature was added DIEA (438.6 mg, 3.4 mmol, 10 equiv.). The mixture was stirred at 65°C for 12 hours, cooled to room temperature, and extracted with water (20 mL) and EtOAc (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded compound 114 (15.59 mg, 0.032 mmol, 16.4%). LCMS: 476.00 [M+H] + . 1 H NMR(399MHz,Methanol-d4)δ8.03(d,J=2.2Hz,1H),7.22(d,J=2.2Hz,1H),4.35 (dd,J=10.6,3.8Hz,1H),4.03–3.87(m,4H),3.55(dd,J=17.3,8.6Hz,1H),3.41 –3.32(m,1H),3.12–3.00(m,4H),2.89–2.84(m,1H),2.71(d,J=11.8Hz,1H),2. 63(d,J=11.4Hz,1H),2.39–2.30(m,4H),1.93–1.84(m,2H),1.41–1.32(m,2H).

[0500] The following compounds were synthesized using a similar method

[0501] Example 39: Synthesis of Compound 118

[0502] 1) Synthesis of compound 118a

[0503] To a solution of 4-bromo-1H-indazole (10 g, 51.28 mmol, 1.0 equiv.) in DCM (100 mL) at 0°C under nitrogen was added SEMCl (8.54 g, 51.28 mmol, 1.0 equiv.) and triethylamine (25.89 g, 256.40 mmol, 5.0 equiv.) dropwise. The mixture was stirred at room temperature for 1 hour, then water (150 mL) was added and extracted with DCM (300 mL x 2). The mixture was dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 10:1) afforded the product 118a (7.02 g, 21.46 mmol, 41.86%) as a yellow oil. LCMS: 327.29 [M+H] + .

[0504] 2) Synthesis of compound 118b

[0505] To a solution of 118a (2 g, 6.11 mmol, 1 eq) and acrylamide (434.25 mg, 6.11 mmol, 1 eq) in NMP (20 mL) at room temperature were added DIPEA (2.36 g, 18.33 mmol, 3 eq), P(o-tolyl)3 (185.44 mg, 0.6 mmol, 0.1 eq), and Pd(AcO)2 (137.86 mg, 0.61 mmol, 0.1 eq). The mixture was stirred at 130°C for 18 hours, cooled to room temperature, and the solid was filtered. The mixture was then extracted with water (20 mL) and EtOAc (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA from 15:1 to 5:1) afforded the product 118b (1.7 g, 5.36 mmol, 87.8%) as a yellow solid. LCMS: 318.15 [M+H] + .

[0506] 3) Synthesis of compound 118c

[0507] To a solution of 118b (1 g, 3.15 mmol, 1.0 equiv.) in MeOH (30 mL) at room temperature were added NaBH4 (119.87 mg, 3.15 mmol, 1.0 equiv.) and NiCl2 (40.3 mg, 0.31 mmol, 0.1 equiv.). After stirring for 1 hour, saturated NH4Cl solution (30 mL) was added. The mixture was extracted with EtOAC (35 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 118c (1 g, 3.12 mmol, 99.20%) as a yellow solid. LCMS: 320.17 [M+H] + .

[0508] 4) Synthesis of Compound 118d

[0509] To a solution of 118c (470 mg, 1.46 mmol, 1.0 eq.) in 1.4-dioxance (2 ml, 80.0%) and H₂O (1 ml, 20.0%) were added NaClO (1 ml, 4.38 mmol, 3 equiv.) and NaOH (175.2 mg, 4.38 mmol, 3.0 eq.) at room temperature. The mixture was stirred at room temperature for 3 hours, extracted with EtOAC (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 118d (220 mg, 0.75 mmol, 51.78%) as a yellow solid. LCMS: 292.18 [M+H] + .

[0510] 5) Synthesis of Compound 118e

[0511] To a solution of 118d (220 mg, 0.75 mmol, 1.0 equiv.) in DCM (5 mL) at 0°C under nitrogen was added ClC(O)OCH3 (105.75 mg, 1.12 mmol, 1.5 equiv.) and triethylamine (378.75 mg, 3.75 mmol, 5.0 equiv.) in sequence. After stirring at room temperature for 1 hour, the mixture was added with water (150 mL) and extracted with DCM (300 mL x 2). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 10:1) afforded the product 118e (200 mg, 0.57 mmol, 76.00%) as a yellow oil. LCMS: 350.18 [M+H] + .

[0512] 6) Synthesis of Compound 118f

[0513] To a solution of 118e (200 mg, 0.57 mmol, 1.0 equiv.) in Tol (10 mL) at room temperature were added (CHO)n (153.9 mg, 1.71 mmol, 3.0 eq.) and TsOH (9.80 mg, 0.057 mmol, 0.1 equiv.). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature and concentrated. EtOAc (30 mL), water (30 mL x 2), and saturated brine (30 mL) were added. The mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 118f (100 mg, 0.43 mmol, 75.62%) as a yellow solid. LCMS: 232.10 [M+H] + .

[0514] 7) Synthesis of Compound 118g

[0515] To a solution of 118f (100 mg, 0.43 mmol, 1.0 equiv.) in EtOH (4 mL) and H₂O (1 mL) at 0°C under nitrogen was added KOH (48.16 mg, 0.86 mmol, 2.0 equiv.). The mixture was heated at reflux for 12 hours and then cooled to room temperature. EtOAc (30 mL) was added and washed with saturated NH₄Cl (30 mL x 2) and brine (30 mL), respectively. The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (DCM:MeOH = 10:1) afforded the product 118f (60 mg, 0.34 mmol, 80.65%) as a yellow solid. LCMS: 174.10 [M+H] + .

[0516] 8. Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinolin-7-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (118)

[0517] To a solution of I01 (200 mg, 0.69 mmol, 1.0 equiv.) and 118g (155.18 mg, 0.89 mmol, 1.3 equiv.) in THF (3 ml) and H₂O (0.6 ml) at room temperature was added DIEA (890.1 mg, 6.9 mmol, 10 equiv.). The mixture was stirred at 65°C for 12 hours, cooled to room temperature, and added with water (20 mL). The mixture was extracted with EtOAC (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (MeOH:DCM = 1:10) afforded compound 118 (54.48 mg, 12.84 mmol, 18.62% yield). LCMS: 425.10 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.03(s,1H),7.37(d,J=8.6Hz,1H),7.17(d,J=8.6Hz,1H),4.98(s,2H),4.16(d,J=5.5Hz,2H ),4.03–3.91(m,2H),3.64–3.52(m,1H),3.41–3.32(m,1H),3.13–3.04(m,4H),2.45–2.32(m,4H),1.92(d,J=8.6Hz,2H).

[0518] Example 40: Synthesis of Compound 135

[0519] 1) Synthesis of compound 135a

[0520] To a solution of 135c (100.00 mg, 0.37 mmol, 1 eq) in 1,4-dioxane (5 mL) at room temperature were added pyrrolidine (26.49 mg, 0.37 mmol, 1 eq), XPhos-Pd-G3 (31.3 mg, 0.037 mmol, 0.1 eq), Pd2(dba)3 (67.71 mg, 0.074 mmol, 0.2 eq), and Cs2CO3 (630.75 mg, 1.11 mmol, 3.0 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and water (15 mL) was added. The mixture was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) purification gave the yellow oily product 135a (45.00 mg, 0.14 mmol 39.98%). LCMS: 304.19 [M+H] + .

[0521] 2) Synthesis of compound 135b

[0522] To a solution of 135a (45.00 mg, 0.14 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 135b as a yellow oil (20.00 mg, 0.098 mmol, 70.02%). The crude product was used directly in the next step without purification. LCMS: 204.14 [M+H] + .

[0523] 3. Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyrrolidin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (135)

[0524] To a solution of 135b (44.66 mg, 0.22 mmol, 1.0 eq) and I01 (64.00 mg, 0.22 mmol, 1 eq) in THF (5 mL) was added N,N-diisopropylethylamine (85.14 mg, 0.66 mmol, 3.0 eq) at room temperature. The mixture was stirred at 80°C for 4 hours and concentrated. Pre-HPLC (ACN:0.1% TFA in H2O from 5% to 95%) was used to obtain compound 135 (37.05 mg). LCMS: 455.22 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.86(d,J=9.3Hz,1H),7.65(s,1H),6.93(d,J=9.3Hz,1H),4.71(s,2H),4.00(s,2H),3.71(s,2H),3.50( s,4H),3.39(s,1H),3.20(d,J=13.8Hz,1H),2.99–2.85(m,4H),2.26(d,J=40.1Hz,4H),1.97(d,J=6.7Hz,4H),1.81–1.70(m,2H).

[0525] Example 41: Synthesis of Compound 169

[0526] 1) Synthesis of compound 169a

[0527] To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (500.00 mg, 1.69 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the product 169a as a colorless oil (180.00 mg, 1.59 mmol, 95.25%). The crude product was used directly in the next step without purification. LCMS: 196.2 [M+H] + .

[0528] 2) Synthesis of compound 169b

[0529] To a solution of 169a (180 mg, 1.59 mmol, 1.0 eq) and tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (495.39 mg, 1.59 mmol, 1.0 eq) in THF (10 mL) at room temperature were added KCO (658.26 mg, 4.77 mmol, 3.0 eq), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (116.38 mg, 0.159 mmol, 0.1 eq), and water (5 mL). The mixture was heated at reflux for 6 h, cooled to room temperature, the solid was filtered off, and water (20 mL) was added. The mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. Purification by column chromatography (MeOH:DCM=1:10) gave the yellow solid product 169b (200 mg, 0.66 mmol, 41.92%). LCMS: 301.18 [M+H] + .

[0530] 3) Synthesis of compound 169c

[0531] To a solution of 169b (200 mg, 0.66 mmol, 1.0 equiv.) in anhydrous DCE (3 mL) at room temperature were added HCHO (19.8 mg, 0.66 mmol, 1.0 equiv.) and AcOH (3.96 mg, 0.066 mmol, 0.1 equiv.) in sequence. Stirring was continued for 1 hour, then cooled to 0°C and NaBH4 (50.16 mg, 1.32 mmol, 2.0 equiv.) was added portionwise. After stirring at room temperature for 2 hours, saturated NH4Cl (30 mL) was added, and the mixture was extracted with EtOAc (35 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 169c (200 mg, 0.63 mmol, 96.50%) as a yellow solid. LCMS: 315.20 [M+H] + .

[0532] 4) Synthesis of Compound 169d

[0533] To a solution of 169c (200.00 mg, 0.63 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to afford the product 169d (100.00 mg, 74.17% yield) as a yellow oil. The crude product was used directly in the next step without purification. LCMS: 215.15 [M+H] + .

[0534] 5. Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (169)

[0535] To a solution of I01 (181.44 mg, 0.63 mmol, 1.0 equiv.) and 169d (30 mg, 0.63 mmol, 1.0 equiv.) in THF (3 mL) and H₂O (0.6 mL) at room temperature was added DIEA (812.70 mg, 6.30 mmol, 10 equiv.). After stirring at 65°C for 12 hours, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Pre-HPLC purification (ACN:0.1% TFA in H₂O from 5% to 95%) afforded compound 169 (22.18 mg, 36.0%). LCMS: 466.10 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.25(d,J=8.0Hz,1H),7.19(s,1H),7.13(d,J=8.0Hz,1 H),6.17(s,1H),4.05–3.89(m,4H),3.82(d,J=4.3Hz,2H),3.64(s,2H),3.56(dt,J= 16.9,8.1Hz,1H),3.36(dd,J=14.3,8.4Hz,1H),3.29(d,J=1.7Hz,2H),3.13–2.99(m ,2H),2.87(t,J=5.9Hz,2H),2.55(s,3H),2.40–2.27(m,4H),1.91(q,J=9.1Hz,2H).

[0536] Example 42: Synthesis of Compound 180

[0537] 1) Synthesis of compound 180a

[0538] To a solution of 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (100.00 mg, 0.43 mmol, 1 eq) in DCM (5 mL) at room temperature were added Boc2O (94.86 mg, 0.43 mmol, 1 eq) and TEA (131.94 mg, 1.30 mmol, 3 eq). Stirring was continued for 2 hours, and then water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 180a as a yellow oil (crude, 100.00 mg, 69.92%). LCMS: 330.20 [M+H] + .

[0539] 2) Synthesis of compound 180b

[0540] To a solution of 180a (100.00 mg, 0.30 mmol, 1 eq) in 1,4-dioxane (5 mL) at room temperature were added pyrrolidine (21.61 mg, 0.30 mmol, 1 eq), XPhos-Pd-G3 (25.75 mg, 0.03 mmol, 0.1 eq), Pd2(dba)3 (55.62 mg, 0.06 mmol, 0.2 eq), and Cs2CO3 (296.32 mg, 0.91 mmol, 3.0 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the solid was filtered, and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) afforded the product 180b (45.00 mg, 46.21%) as a yellow oil. LCMS: 321.20 [M+H] + .

[0541] 3) Synthesis of compound 180c

[0542] To a solution of 180b (45.00 mg, 0.14 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. Stirring was continued for 1 hour, and the mixture was concentrated to afford 180c as a yellow oil (20.00 mg, 64.66%). The crude product was used directly in the next step without purification. LCMS: 221.15 [M+H] + .

[0543] 4. Synthesis of (R)-2-(5-fluoro-6-(pyrrolidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (180)

[0544] To a solution of 101 (26.15 mg, 0.09 mmol, 1 eq) and 180c (20.00 mg, 0.09 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEA (35.20 mg, 0.24 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded compound 180 (2.17 mg, 5.06%). LCMS: 472.10 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ6.85(d,J=8.5Hz,1H),6.69(t,J=8.6Hz,1H),4.00–3.91(m,4H),3.60(d,J=7. 6Hz,1H),3.33(s,6H),3.23–3.05(m,4H),2.87(s,3H),2.37(dd,J=12.3,8.4Hz,4H),1.94(d,J=6.8Hz,6H).

[0545] Example 43: Synthesis of Compound 181

[0546] 1) Synthesis of compound 181a

[0547] To a solution of 6-bromo-7-fluoroisoquinoline (200.00 mg, 0.88 mmol, 1 eq) in HOAc (4 mL) at 0°C under nitrogen was added NaBH₄ (66.94 mg, 1.77 mmol, 2 eq). After stirring at room temperature for 3 hours, saturated Rochelle's reagent (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product 181a as a yellow oil (150 mg, 73.68%). LCMS: 231.95 [M+H] + .

[0548] 2) Synthesis of compound 181b

[0549] To a solution of 181a (150.00 mg, 0.65 mmol, 1 eq) in DCM (5 mL) at room temperature were added Boc2O (214.00 mg, 0.98 mmol, 1.5 eq) and TEA (198.00 mg, 1.95 mmol, 3 eq). Stirring was continued for 3 hours, and then water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product 181b (crude, 160.00 mg, 74.32%) as a yellow oil. LCMS: 331.95 [M+H] + .

[0550] 3) Synthesis of compound 181c

[0551] To a solution of 181b (160.00 mg, 0.49 mmol, 1 eq) in 1,4-dioxane (5 mL) at room temperature were added pyrrolidine (35.00 mg, 0.49 mmol, 1 eq), XPhos-Pd-G3 (42.00 mg, 0.049 mmol, 0.1 eq), Pd2(dba)3 (45.00 mg, 0.049 mmol, 0.1 eq), and Cs2CO3 (473.00 mg, 1.46 mmol, 3.0 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) purification gave the yellow oily product 181c (50.00 mg, 32.49% yield). LCMS: 321.10 [M+H] + .

[0552] 4) Synthesis of Compound 181d

[0553] To a solution of 181c (50.00 mg, 0.16 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford the product 181d (30.00 mg, 87.28%) as a yellow oil. The crude product was used directly in the next step without purification. LCMS: 221.20 [M+H] + .

[0554] 5. Synthesis of (R)-2-(7-fluoro-6-(pyrrolidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (181)

[0555] To a solution of 101 (40.00 mg, 0.14 mmol, 1 eq) and 181d (30.00 mg, 0.14 mmol, 1 eq) in THF (4 mL) and H₂O (1 mL) was added DIEA (53.00 mg, 0.41 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 16 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H₂O) afforded compound 181 (33.89 mg, 52.77%). LCMS: 472.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ6.91(d,J=14.3Hz,1H),6.51(d,J=9.1Hz,1H),4.69 (s,2H),3.72(s,2H),3.85(d,J=5.7Hz,2H),3.72(s,2H),3.53–3.42(m,2H), 3.23(s,6H),3.03(d,J=16.3Hz,1H),2.89(dd,J=13.7,7.3Hz,1H),2.74(s, 2H),2.32–2.18(m,4H),1.85(d,J=6.0Hz,4H),1.76(dd,J=11.6,7.1Hz,2H).

[0556] The following compounds were synthesized using a similar method

[0557] Example 44: Synthesis of Compound 184

[0558] 1) Synthesis of compound 184a

[0559] At room temperature, tert-butyl 3-oxopiperidine-1-carboxylate (1.50 g, 7.53 mmol, 1 eq), 1-methyl-3,5-dinitropyridin-2(1H)-one (1.95 g, 9.79 mmol, 1.3 eq), and 7M NH3 / MeOH (15 mL) were placed in a sealed tube. After stirring at 90°C for 2 hours, the mixture was cooled to room temperature and concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) afforded the product 184a (90 mg, 6.0%) as a yellow solid. LCMS: 280.25 [M+H] + .

[0560] 2) Synthesis of compound 184b

[0561] To a solution of 184a (60.00 mg, 0.21 mmol, 1 eq) in MeOH (4 mL) at room temperature was added Pd / C (10%, 6 mg), followed by deoxygenation three times. Hydrogen was absorbed by balloon at room temperature for 1 hour, the solid was filtered off, and the product 184b was concentrated to a yellow solid (40.00 mg, 74.69%). LCMS: 250.15 [M+H] + .

[0562] 3) Synthesis of compound 184c

[0563] To a solution of 184b (40.00 mg, 0.16 mmol, 1 eq) in DMF (3 mL) at room temperature were added 1,4-dibromobutane (51.96 mg, 0.24 mmol, 1.5 eq) and DIPEA (61.92 mg, 0.48 mmol, 3.0 eq). After stirring at 100°C for 16 hours, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) afforded the product 184c (10.00 mg, 20.54%) as a yellow oil. LCMS: 304.15 [M+H] + .

[0564] 4) Synthesis of compound 184d

[0565] To a solution of 184c (13.00 mg, 0.04 mmol, 1 eq) 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 yellow oil 184d (8.00 mg, 91.84%). The crude product was used directly in the next reaction without purification. LCMS: 204.20 [M+H] + .

[0566] 5. Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(pyrrolidin-1-yl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (184)

[0567] To a solution of I01 (11.00 mg, 0.04 mmol, 1 eq) and 184d (8.00 mg, 0.04 mmol, 1 eq) in THF (2 mL) and H₂O (0.5 mL) was added DIEA (16.00 mg, 0.12 mmol, 3 eq) at room temperature. The mixture was stirred at 65°C for 16 hours and then concentrated. Prep-HPLC (0.1% TFA in ACN / H₂O) gave compound 184 (4.65 mg, 26.00%). LCMS: 455.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.7Hz,1H),7.35(s,1H),4.84(t,J=5.7H z,1H),4.73(s,1H),3.92(s,2H),3.72(t,J=4.1Hz,2H),3.40(d,J=8.7Hz,2H ),3.18(d,J=6.6Hz,6H),2.94–2.82(m,2H),2.76(s,2H),2.32(dd,J=21.0,1 0.5Hz, 2H), 2.19–2.12 (m, 2H), 1.91 (t, J = 3.3Hz, 4H), 1.76 (q, J = 9.1Hz, 2H).

[0568] Example 45: Synthesis of Compound 218

[0569] 1) Synthesis of compound 218a

[0570] To a solution of pyridine-3,4-diamine (5.00 g, 42.02 mmol, 1 eq) in ethanol (75 mL) was added ethyl glyoxylate (9.2 g, 46.22 mmol, 1.1 eq) at room temperature. The mixture was stirred at room temperature for 30 minutes and then at 90°C for 18 hours. The mixture was cooled to room temperature, filtered, washed with ethanol, and dried to afford the product 218a as a yellow solid (3.1 g, 50.16%). The crude product was used directly in the next step without purification. LCMS: 148.45 [M+H] + .

[0571] 2) Synthesis of compound 218b

[0572] Under nitrogen, a solution of 218a (1.00 g, 6.80 mmol, 1 eq) in POCl3 (10 mL) was stirred at 100°C for 24 hours. The mixture was cooled to room temperature and concentrated to afford a black-white solid, 218b (1.00 g, 89.29%). The crude product was used directly in the next step without purification. LCMS: 166.05 [M+H] + .

[0573] 3) Synthesis of compound 218c

[0574] To a solution of 218b (1.00 g, 6.06 mmol, 1 eq) in DMF (20 mL) at room temperature were added DIPEA (1.56 g, 12.12 mmol, 2 eq) and pyrrolidine (860.60 mg, 12.12 mmol, 2 eq). The mixture was stirred at 100°C for 1 hour. After cooling to room temperature, ethyl acetate (30 mL) was added and the mixture was washed with saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EtOAc = 1:1) afforded the product 218c as a yellow solid (130 mg, 10.74%). LCMS: 201.15 [M+H] + .

[0575] 4) Synthesis of Compound 218d

[0576] To a solution of 218c (130.00 mg, 0.65 mmol, 1 eq) in acetonitrile (5 mL) at room temperature was added benzyl bromide (114.48 mg, 0.67 mmol, 1.03 eq). The mixture was stirred at 80°C for 2 hours, cooled to room temperature, filtered, and dried to afford 6-benzyl-2-(pyrrolidin-1-yl)-6-(4-pyrido[3,4-b]pyrazine (120 mg). 6-Benzyl-2-(pyrrolidin-1-yl)-6-(4-pyrido[3,4-b]pyrazine (120 mg) was dissolved in acetonitrile (5 mL) and sodium borohydride (123.5 mg, 3.35 mmol, 5 eq) was added at 0°C. Stirring was continued at 0°C for 2 hours, and saturated NaHCO₃ solution (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EtOAc=1:1) gave the yellow solid product 218d (50 mg, 26.16%). LCMS: 295.15 [M+H] + .

[0577] 5) Synthesis of Compound 218e

[0578] A solution of 218d (50.00 mg, 0.17 mmol, 1 eq) and 10% Pd / C (20 mg) in ethanol (2 mL) was hydrogenated under a balloon overnight at room temperature. The solid was filtered and concentrated to afford the product 218e (30 mg, 86.45%) as a yellow solid. LCMS: 205.15 [M+H] + .

[0579] 6) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyrrolidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (218)

[0580] To a solution of 218e (30 mg, 0.15 mmol, 1 eq) and I01 (42.35 mg, 0.15 mmol, 1 eq) in THF (2 mL) at room temperature was added DIPEA (37.94 mg, 0.29 mmol, 2 eq) and water (1 mL). After stirring at 80°C for 4 hours, the mixture was concentrated. Prep-HPLC (0.1% TFA in ACN / H2O) gave compound 218 (11.26 mg, 16.80%). LCMS: 456.25 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.80(s,1H),5.05(s,1H),4.77(s,2H),4.03( t,J=6.0Hz,2H),3.80–3.69(m,2H),3.57–3.45(m,1H),3.44–3.34(m,4H),3.30–3. 20(m,1H),3.06(dd,J=17.2,8.0Hz,1H),2.93(dd,J=13.6,7.2Hz,1H),2.83–2.76( m,2H),2.40–2.25(m,2H),2.25–2.15(m,2H),1.97–1.88(m,4H),1.85–1.72(m,2H).

[0581] Referring to the preparation methods of Examples 1 to 45, the following compounds were synthesized:

[0582] Example 46: In vitro activity test

[0583] A. PDE4B2 enzyme test and PDE4D2 enzyme test

[0584] 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.

[0585] The experimental results are shown in Table 1 and Table 2:

[0586] Table 1

[0587] Table 2

[0588] The above data show that the compounds of the present invention have strong inhibitory activity on PDE4B2 enzyme.

[0589] B. PDE4B2 cell experiments

[0590] 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.

[0591] The experimental results are shown in Tables 3 and 4.

[0592] Table 3

[0593] Table 4

[0594] The above data show that the compound of the present invention has strong inhibitory activity on PDE4B2 cells.

[0595] Example 47: LPS-induced PBMC TNFa release cell experiment

[0596] 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.

[0597] Experiments have shown 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.

[0598] 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.

[0599] 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: S* represents a chiral sulfur atom, and its configuration is R configuration or S configuration; W is selected from N, CH or C; Ring A is a monocyclic group or a bicyclic group, wherein the monocyclic group is selected from a 5-8 membered heteroaryl group or a C 6-10 Aryl, the bicyclic group is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl phenyl, 5-6 membered cycloalkyl phenyl, 5-6 membered cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocyclyl phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, benzo 5-6 membered heterocyclyl or benzo 5-6 membered heteroaryl; R1 is selected from hydrogen or C 1-6 alkyl; R2 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted C 1-6 Alkyl, R 2.1 Substituted C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 membered heteroaryl, C 1-6 Alkyl-substituted 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; Alternatively, R1 and R2 are linked to form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally further substituted with deuterium, deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic group; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Alternatively, any one R3 is linked to a carbon atom on the ring to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, 5-8 membered heteroaryl, -C(O)-R 4.1 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SOR 4.2 、-OR 4.5 、-SR 4.5 or -NR 4.3 R 4.4 , the C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted with deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, -NR 4.3 R 4.4 , C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic group; R5 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)-R 5.1 、-S(O)2-R 5.2 、-C(O)OR 5.1 、-C(O)NR 5.3 R 5.4 、-SOR 5.2 、-OR 5.5 、-SR 5.5 or -NR 5.3 R 5.4 ; Alternatively, R4 and R5 are linked to form a 5-6 membered heteroaryl or C 6-10 Aryl, the 5-6 membered heteroaryl and C 6-10 Aryl, optionally further substituted with deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 substituted by one or more groups of cycloalkyl or 3-6 membered heterocyclic group; R 2.1 , R 2.2 , R 2.3 , R 2.4 , R 2.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 and R 5.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; m and n are each independently selected from 1, 2 or 3; p is selected from 1 or 2.

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), formula (II-B), formula (II-C) or formula (II-D):

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is a monocyclic group, and the monocyclic group is selected from a 5-membered heteroaryl group, a 6-membered heteroaryl group or a phenyl group; preferably, the ring A is selected from a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a phenyl group, a pyrazolyl group, a thienyl group, a furanyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group.

4. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is a bicyclic group, and the bicyclic group is selected from 5-membered heteroaryl and 6-membered heteroaryl, 5-membered heteroaryl phenyl, 6-membered cycloalkyl phenyl, 6-membered heterocyclyl phenyl, benzo 5-membered heterocyclyl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, 6-membered heterocyclyl and 6-membered heteroaryl, or 6-membered heteroaryl phenyl; Preferably, ring A is selected from pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, pyrazolopyridinyl, cyclohexylphenyl, Oxyheterocyclohexylphenyl, benzodioxazolyl, Benzoxazolyl, oxacyclohexylpyridinyl, pyridonophenyl, pyridopyrazolyl, benzopyrazolyl, thienophenyl or pyridophenyl.

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

6. The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The formula (III-A) is further shown in formula (IV): Among them: Ring B is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R 4a Each independently selected from deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkoxyalkyl, -N(CH3)2, -C(O)NH2, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; y is 0, 1 or 2.

7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 8. The compound according to any one of claims 5 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from hydrogen; the R2 is selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted C 1-6 Alkyl, R 2.1 Substituted C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 membered heteroaryl, C 1-6 Alkyl-substituted 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.

9. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R 4a Each is independently selected from deuterium, fluorine, chlorine, amino, hydroxy, cyano, carboxyl, oxo, methyl, ethyl, -CH2OCH3, -N(CH3)2, methoxy, ethoxy, trifluoromethyl, hydroxymethyl or hydroxyethyl.

10. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen or C 1-6 alkyl; Alternatively, R2 is as shown in formula (III): in, R6 is selected from hydroxy, cyano, amino or halogen; R7 and R 7’ 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, R7 and R 7’ Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or butyl; Alternatively, R2 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothiophenyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaspiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl or naphthyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclohexyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanyl, azepan ... cyclobutane, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyran, 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, azetidinyl, -(CH2)2CN, -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; Alternatively, R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Alternatively, R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Haloalkyl, -C(O)-R 4.1 、-S(O)2-R 4.2 、-C(O)OR 4.1 、-C(O)NR 4.3 R 4.4 、-SOR 4.2 、-OR 4.5 、-SR 4.5 、-NR 4.3 R 4.4 , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which may be further substituted with deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, -NR 4.3 R 4.4 , C 1-3 Alkoxy C 1-3 Alkyl or C 1-3 is substituted by one or more substituents in a haloalkyl group; Alternatively, R5 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Haloalkyl, -C(O)-R 5.1 、-S(O)2-R 5.2 、-C(O)OR 5.1 、-C(O)NR 5.3 R 5.4 、-SOR 5.2 、-OR 5.5 、-SR 5.5 、-NR 5.3 R 5.4 , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which may be further substituted with deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 is substituted by one or more substituents in a haloalkyl group; The R 2.1 , R 2.2 , R 2.3 , R 2.4 , R 2.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 and R 5.5 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1- 3 alkoxy, -C(O)NH2, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; Preferably, the R 2.1 , R 2.2 , R 2.3 , R 2.4 , R 2.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 and R 5.5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, -C(O)NH2, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, azirane, azetidine, tetrahydropyrrolyl or tetrahydrofuranyl.

11. The compound according to any one of claims 1 to 5 or 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl or pyrazolyl, wherein C 1-3 Alkyl, C 1- 3-Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, aziridine, azetidinyl, pyrrolidinyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl and pyrazolyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, nitro, cyano, hydroxy, fluorine, chlorine, oxo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, trifluoroethyl, -CH2OCH3 or -N(CH3)2.

12. The compound according to any one of claims 1 to 5, 8 or 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxyl, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxirane, oxetane, aziridine, azetidinyl, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe, -CO2Me, Alternatively, R5 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxyl, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidinyl, -NH-(CH2)2-OH, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe or -CO2Me.

13. The compound according to any one of claims 1 to 4 or 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: In the formula (II-A), formula (II-B), formula (II-C) and formula (II-D) Independently selected from Alternatively, in the formula (II-A), formula (II-B), formula (II-C) and formula (II-D), Independently selected from 14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from hydrogen, C 1-3 alkyl; Alternatively, the R2 is selected from the following groups: -(CH2)2OH、 Alternatively, each of the R3 groups is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -CHF2, -CH2F, cyclopropyl, cyclobutyl, cyclobutyl, oxirane, oxetanyl, aziridine, azetidine, tetrahydropyrrolyl, tetrahydrofuranyl, -CH2OH, -CF3, -CHF2, -CH2F or -CD3.

15. The compound according to any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

16. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

17. Use of the compound according to any one of claims 1 to 15, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a PDE4 inhibitor drug.

18. Use of the compound according to any one of claims 1 to 15, its stereoisomer or pharmaceutically acceptable salt thereof, or the composition according to claim 16 in the preparation of a medicament for treating or preventing inflammatory diseases, autoimmune diseases, metabolic diseases, nervous system diseases and related diseases.

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