Substituted dihydrothienopyrimidine compounds, methods for producing the same, and uses

Abstract

The present invention relates to substituted dihydrothienopyrimidine compounds, methods for producing the same, and uses thereof, and belongs to the field of biopharmaceuticals. Specifically, the present invention relates to a compound represented by general formula (I), a method for producing the same, a pharmaceutical composition containing the compound, and its use in the manufacture of drugs for treating inflammatory diseases, autoimmune diseases, metabolic diseases, neurological diseases and related diseases, where each substituent in general formula (I) is as defined in the specification. [Formula 1] TIFF2026514091000183.tif40169

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2023103934873, filed on April 13, 2023, and to Chinese Patent Application No. 2024103199932, filed on March 20, 2024. This application incorporates all the contents of the above Chinese Patent Application. This invention belongs to the field of biopharmaceuticals and specifically relates to substituted dihydrothienopyrimidine compounds, methods for producing the same, and uses thereof. [Background technology]

[0002] PDE4 is the most broad-spectrum member of the PDE family, which includes 11 members from PDE1 to PDE11, each differing in expression site and the range of substrates they catalyze. PDE4 is highly expressed in cells involved in various physiological processes in the brain, kidney, smooth muscle, heart, and endothelial cells, and is also expressed in hematopoietic cells. PDE4 is responsible for selectively catalyzing the hydrolysis of cAMP in different organs and cells, and plays a crucial role in cAMP-mediated signaling pathways such as cAMP / PKA / CREB and EPAC / Rap1 and ERK / BCL-6 signaling pathways.

[0003] The PDE4 gene family comprises four subtypes, PDE4A-D, and each PDE4 subtype gene can express 3-11 proteins, generating at least 25 different PDE4 subtypes. PDE4 subtypes and allotypes exhibit different cell type-specific and tissue type-specific intracellular distributions, which contribute to their specific effects in cellular function. Different PDE4 subtypes and allotypes can regulate spatially distinct cAMP signaling cascades. PDE4 enzymes are expressed in inflammatory cells such as T cells, B cells, eosinophils, neutrophils, airway epithelial cells, and endothelial cells, and they specifically hydrolyze the 3',5' phosphodiester bond of cAMP to produce 5'-adenosine monophosphate (5'-AMP), which can further regulate the production of pro-inflammatory and anti-inflammatory cytokines. PDE4 inhibitors inhibit the hydrolysis of cAMP, effectively increasing cAMP levels and activating protein kinase A (PKA), thereby inhibiting signaling pathways such as NFκB and NFAT, reducing the release of downstream cytokines and chemokines, and suppressing inflammation. These factors regulate the expression of inflammatory media such as IL-2, IL-4, IL-6, IL-31, and TNF-α, and further modulate inflammatory responses in cells such as T cells and Th2 cells, including neutrophil degranulation, chemotaxis, and adhesion to endothelial cells. In addition to T cells and Th2 cells, PDE4 inhibition can inhibit inflammatory responses in macrophages, dendritic cells (DCs), Th1 and Th17 cells, and interfere with the expression type and function of B cells. Therefore, PDE4 targets are widely applied in the development of drugs for various inflammatory diseases, including respiratory diseases (chronic obstructive pulmonary disease, asthma), various skin diseases (psoriasis, atopic dermatitis, etc.), and immune system diseases (systemic lupus erythematosus, rheumatoid arthritis, etc.). They are also used in the development of drugs for diseases such as cognitive and emotional disorders, fragile X syndrome, autoimmune diseases, and tumors.

[0004] According to literature reports, PDE4B is a major inflammatory factor, PDE4D is highly associated with side effects, PDE4D is expressed in many tissues of the human body, the brain is the main site of PDE4D expression, and many related studies have been conducted. The main side effect of PDE4 inhibitors is vomiting, and PDE4D is present in the extracorporeal posterior region, nucleus tractus solitarius, and locus coeruleus, all of which are associated with the vomiting effect of PDE4 inhibition. Clearly, selective inhibitors are needed to maintain therapeutic effect while ensuring safety.

[0005] Many PDE4 inhibitors have been published and disclosed, including WO2006 / 1111549, WO2007 / 118793, US20070259846, WO2009 / 050236, WO2009 / 050242, and WO2009 / 052268, WO2009 / 050248, WO2013 / 026797 (all from Boehringer Ingelheim International), WO2019 / 057806, WO2019 / 11577, WO2019 / 115775, and WO2019 / 115776 (all from Leo Pharma, A / S), all of which 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) discloses a bicyclic heteroaryl compound referred to as a PDE4 inhibitor.

[0006] Currently, further development is needed to find new PDE4 inhibitors with a more favorable treatment window and fewer side effects.

[0007] The object of the present invention is to provide novel substituted dihydrothienopyrimidine compounds. The present invention relates to PDE4 inhibitors and can be used as therapeutic agents for PDE4-mediated diseases, which include chronic obstructive pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, idiopathic pulmonary fibrosis, neurological disorders, cognitive and emotional disorders, fragile X syndrome, other inflammatory allergic diseases and autoimmune diseases, lung injury and tumors.

[0008] The compounds of the present invention can have high oral bioavailability, solubility, and absorption / metabolic stability. They also have high safety, making them more tolerable than other PDE4 inhibitors. Like other PDE4 inhibitors, the compounds of the present invention have a certain selectivity for PDE4D and can have an improved window for side effects such as nausea and vomiting, allowing them to be administered in higher doses to achieve greater medical efficacy. [Overview of the project]

[0009] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] During the ceremony, S* represents a chiral sulfur atom, and its configuration is either R configuration or S configuration. W is selected from N, CH, or C. Ring A is a monocyclic or bicyclic group, and the monocyclic group is a 5-8 membered heteroaryl or C 6-10 Selected from aryls, the bicyclic group is selected from 5-6 member heteroaryl condensation 5-6 member heteroaryl, 5-6 member heteroarylphenyl, 5-6 member cycloalkylphenyl, 5-6 member cycloalkyl condensation 5-6 member heteroaryl, 5-6 member heterocyclylphenyl, 5-6 member heterocyclyl condensation 5-6 member heteroaryl, benzo 5-6 member heterocyclyl, or benzo 5-6 member heteroaryl. R1 is hydrogen or C 1-6 Selected from alkyl groups, R2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Selected from aryl or 5-10 member heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10Aryl and 5- to 10-membered heteroaryl are optionally further substituted with one or more groups selected from deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-substituted C 1-6 alkyl, R 2.1 substituted C 1-6 alkyl, C 1-6 alkyl-substituted 5- to 6-membered heteroaryl, C 1-6 alkyl-substituted 3- to 6-membered heterocyclyl, -C(O)-R 2.1 , -S(O)2-R 2.2 , -C(O)O-R 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 and are optionally further substituted with one or more groups selected from deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, C Alternatively, R1 and R2 are linked to form a 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, and the 3- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one or more groups selected from hydrogen, deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, and are optionally further substituted with one or more groups selected from deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, C R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, 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- to 6-membered heterocyclyl, Alternatively, any one of the R3 is linked to a carbon atom on the ring to form C 3-8Forming cycloalkyl or 3-8 membered heterocyclines, R4 is hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl deuterated, 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 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl deuterated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyls, 3-6 membered heterocyclines, 7-9 membered heterocyclines, and 5-8 membered heteroaryls may optionally be further enriched with deuterium, halogens, cyano, hydroxyl, oxo, or 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 It may be substituted with one or more groups of cycloalkyl or 3-6 membered heterocyclyl groups. R5 is hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl deuterated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, -C(O)-R 5.1 , -S(O)2-R 5.2 , -C(O)O-R 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 selected from, or, R4 and R5 are linked to form a 5- to 6-membered heteroaryl or C 6-10 aryl, and the 5- to 6-membered heteroaryl and C 6-10 aryl may optionally be further substituted with one or more groups of deuterium, halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C<00****090>alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 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 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxy, 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- to 6-membered heterocyclyl, m and n are each independently selected from 1, 2 or 3, [[ID=****0]] p is selected from 1 or 2. <****00622>

[0010] In preferred embodiments of the present invention, the above compounds are further represented by formulas (II-A), (II-B), (II-C), or (II-D). [ka]

[0011] 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, a 6-membered heteroaryl, or phenyl, and preferably the ring A is selected from thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0012] In a preferred embodiment of the present invention, the above-mentioned ring A is a bicyclic group, and the bicyclic group is selected from a 5-membered heteroaryl condensed 6-membered heteroaryl, a 5-membered heteroarylphenyl, a 6-membered cycloalkylphenyl, a 6-membered heterocyclylphenyl, a benzo-5-membered heterocyclyl, a benzo-5-membered heteroaryl, a 6-membered heteroaryl condensed 5-membered heteroaryl, a 6-membered heterocyclyl condensed 6-membered heteroaryl, or a 6-membered heteroarylphenyl. Preferably, ring A is pyrazolopyrimidinyl, imidazophenyl, imidazopyridyl, pyrazolopyridyl, cyclohexylphenyl, oxanylphenyl, benzodioxazolyl, [ka] Benzoxazolyl, [ka] Selected from oxanylpyridyl, pyridonephenyl, pyridopyrazolyl, benzopyrazolyl, thienophenyl, or pyridophenyl.

[0013] In some embodiments of the present invention, the above [ka] teeth, [ka] Selected from.

[0014] In preferred embodiments of the present invention, the compounds described in the present invention are further represented by formula (III-A) or formula (III-B). [ka]

[0015] In a preferred embodiment of the present invention, formula (III-A) of the present invention is further represented by formula (IV), [ka] In the formula, ring B is C 3-6 The components are cycloalkyl, 3-6 member heterocyclyl, 7-9 member heterocyclyl, phenyl, or 5-6 member heteroaryl, and R 4a These are, independently, deuterium, halogen, amino, hydroxy, cyano, carboxy, and 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 Selected from cycloalkyl or 3- to 6-membered heterocyclyl, where y is 0, 1, or 2.

[0016] In a preferred embodiment of the present invention, the above-mentioned ring B is C 3-6 The components are cycloalkyl, 3-6 member heterocyclyl, 7-9 member heterocyclyl, phenyl, or 5-6 member heteroaryl, and R 4a These are, independently, deuterium, halogen, amino, hydroxy, cyano, carboxy, oxo, and C. 1-3Alkyl, 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 Selected from cycloalkyl or 3- to 6-membered heterocyclyl, where y is 0, 1, or 2.

[0017] In preferred embodiments of the present invention, the above ring B is cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, azilidinil, azetidinil, pyrrolidinil, triazolyl, piperidinil, morpholinil, piperazinil, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, [ka] Selected from.

[0018] In a preferred embodiment of the present invention, R1 is selected from hydrogen, and R2 is C 1-3 Alkyl, C 3-6 Selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl may optionally be further enriched with deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, or C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 member heterocyclyl, 5-6 member heteroaryl, 5-6 member heteroaryl substituted C 1-6 Alkyl, R 2.1 substitution C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 member heteroaryl, C 1-6 Alkyl-substituted 3-6 member heterocyclyl, -C(O)-R 2.1 -S(O)2-R 2.2 , -C(O)OR2.1 -C(O)NR 2.3 R 2.4 , -SR 2.5 -SOR 2.2 , -OR 2.5 or -NR 2.3 R 2.4 It is substituted with one or more of the following groups.

[0019] In a preferred embodiment of the present invention, the above R 4a Each of these is independently selected from deuterium, fluorine, chlorine, amino, hydroxy, cyano, carboxy, oxo, methyl, ethyl, -CH2OCH3, -N(CH3)2, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, or hydroxyethyl.

[0020] In a preferred embodiment of the present invention, the above R 2.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 Each of these is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, carboxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, -C(O)NH2, cyclopropyl, cyclobutyl, cyclopentyl, oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, or tetrahydrofuranyl.

[0021] In a preferred embodiment of the present invention, R2 is C 1-3 Alkyl, C 3-6 Selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl may optionally be further enriched with deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, or C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, 3-6 member heterocyclyl, 5-6 member heteroaryl, 5-6 member heteroaryl substituted C 1-6 Alkyl, R 2.1 substitution C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6 member heteroaryl, C 1-6 Alkyl-substituted 3-6 member heterocyclyl, -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 It is substituted with one or more of the following groups.

[0022] In a preferred embodiment of the present invention, R1 is hydrogen or C 1-6 Selected from alkyl groups, Alternatively, R2 is as shown in equation (III), [ka] During the ceremony, R6 is selected from hydroxy, cyano, amino, or halogen. R7 and R 7’ These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl, the C 1-6 Alkyl can optionally contain deuterium, halogen, amino, hydroxy, cyano, oxo, or 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 -NR2.3 R 2.4 It is substituted with one or more of the following groups: Preferably, R7 and R 7’ Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. Alternatively, R2 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxanil, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanil, azetidinil, thietanil, tetrahydropyranil, tetrahydrofuranil, tetrahydrothiopyranil, pyrrolidinil, tetrahydropyrrolidinil, tetrahydrothienyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, azepanil, oxapiroheptanil, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinil, or naphthyl, and the aforementioned methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxanil, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl , oxetanyl, azetidinyl, thietanyl, tetrahydropyranil, tetrahydrofuranil, tetrahydrothiopyranil, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinil, thiomorpholinil, azepanil, oxapiroheptanil, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl and naphthyl may optionally be further deuterium, fluorine, chlorine, bromine, amino, hydroxy, thiol, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hydroxymethyl, hydroxyethyl, cyclopropyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, oxylanil, oxetanyl, aziridinyl, 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 -NR2.3 R 2.4 It may be substituted with one or more of the following groups: Alternatively, R3 can be independently hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl deuterated, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Alternatively, R4 can be hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or 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 Selected from cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C 3-6 Cycloalkyls, 3-6 membered heterocyclines, 7-9 membered heterocyclines, phenyls, and 5-6 membered heteroaryls may optionally be further enriched with deuterium, halogens, aminos, nitros, cyanos, hydroxys, oxos, or 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 It may be substituted with one or more substituents from the haloalkyl group. Alternatively, R5 can be hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or C. 1-3Alkyl, 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 Selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl may optionally be further enriched with deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 It may be substituted with one or more substituents from the haloalkyl group. The aforementioned 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 These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, and C. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -C(O)NH2, C 3-6 Selected from cycloalkyl or 3-6 membered heterocyclyl, Preferably, the R 2.1 , R 2.2 , R 2.3 , R2.4 , 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 of these is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, carboxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF3, -CHF2, -CH2F, methoxy, ethoxy, propoxy, -C(O)NH2, cyclopropyl, cyclobutyl, cyclopentyl, oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, or tetrahydrofuranyl.

[0023] In a preferred embodiment of the present invention, R4 is hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Selected from haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, azilidinil, azetidinil, pyrrolidinil, triazolyl, piperidinil, morpholinil, piperazinil, thiazolyl, imidazolyl, or pyrazolyl, the C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxyranyl, oxetanyl, azilidinyl, 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.

[0024] In preferred embodiments of the present invention, R4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxylanil, oxetanil, aziridinyl, azetidinyl, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe, -CO2Me, [ka] Selected from, 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, oxylanyl, oxetanyl, azilidinyl, azetidinyl, -NH-(CH2)2-OH, -CF3, -CHF2, -CH2F, -NMe2, -SO2Me, -SO2Et, -CONH2, -CONHMe, or -CO2Me.

[0025] In a preferred embodiment of the present invention, the above formulas (II-A), (II-B), (II-C), and (II-D) [ka] Each is independent of the others. [ka] Selected from, Alternatively, in formulas (II-A), (II-B), (II-C), and (II-D) above [ka] Each is independent of the others. [ka] Selected from.

[0026] In a preferred embodiment of the present invention, R1 is hydrogen, C 1-3 Selected from alkyl groups, Alternatively, R2 is [ka] -(CH2)2OH, [ka] Selected from the basis of, Alternatively, R3 may be 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, cyclopentyl, oxyranil, oxetanil, aziridinil, azetidinil, tetrahydropyrrolyl, tetrahydrofuranil, -CH2OH, -CF3, -CHF2, -CH2F, or -CD3.

[0027] In a preferred embodiment of the present invention, the compound described in the present invention is [ka] TIFF2026514091000020.tif236169 TIFF2026514091000021.tif242169 TIFF2026514091000022.tif237169 TIFF2026514091000023.tif252169 TIFF2026514091000024.tif255168 TIFF2026514091000025.tif251169 TIFF2026514091000026.tif190169 It is selected from compounds with the following structure.

[0028] The present invention further provides preferred solutions for pharmaceutical compositions comprising a therapeutically effective amount of any of the above compounds or compounds of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0029] The present invention further relates to the use of any of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the manufacture of PDE4 inhibitor drugs.

[0030] The present invention further relates to the use of any of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the manufacture of drugs for treating or preventing inflammatory diseases, autoimmune diseases, metabolic diseases and neurological diseases and related diseases. [Modes for carrying out the invention]

[0031] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0032] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched 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. In the present invention, methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred.

[0033] The term "alkenyl" refers to the alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyls may be substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0034] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where a 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, etc. Polycyclic cycloalkyls include spirocyclic, fused, and crosslinked cyclic cycloalkyls, and non-limiting examples include [ka] This includes, among others.

[0035] The cycloalkyl ring may be condensed with an aryl, heteroaryl, or heterocycloalkyl ring, where the ring bonded to the parent structure is cycloalkyl, preferably a 5-6 membered cycloalkylphenyl or a 5-6 membered cycloalkyl condensed 5-6 membered heteroaryl. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl.

[0036] The cycloalkyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylic acid esters.

[0037] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents containing 3 to 20 ring atoms, one or more of which are nitrogen, oxygen, C(O), S(O)(=NH), or S(O). mThe heteroatoms are selected from (where m is an integer from 0 to 2), but do not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 12 ring atoms, and most preferably 3 to 6 ring atoms, where the number of heteroatoms is 1 or 2. Non-limiting examples of monocyclic heterocyclils include oxetanil, thietanil, azetidinil, tetrahydropyranil, azepanil, pyrrolidinil, imidazolidinil, tetrahydrofuranil, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinil, pyrrolidinil, piperazinil, morpholinil, thiomorpholinil, homopiperazinil, pyranil, pyridonil, etc. Preferably, oxetanil, thietanil, azetidinil, tetrahydrofuranil, tetrahydropyranil, 1-imino-1-oxothiopyran, azepanil, pyrrolidinil, piperidinil and piperazinil. Polycyclic heterocyclils include spiro-ring, fused-ring and cross-linked-ring heterocyclils, non-limiting examples of which include [ka] The heterocyclyl may be substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from hydrogen, alkyl, hydroxyalkyl, amino, imino, cyano, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0038] The heterocyclyl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylic acid esters.

[0039] The heterocyclyl can be condensed with a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl, preferably a 5-6 membered heterocyclylphenyl or a 5-6 membered heterocyclyl condensed 5-6 membered heteroaryl, for example. [ka] That is the case.

[0040] The term "aryl" refers to a 6-14 membered monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent carbon atom pairs) having a conjugated π-electron system, preferably 6-10 membered, such as phenyl and naphthyl. More preferably phenyl.

[0041] The aforementioned aryl ring can be condensed to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, preferably a benzo 5-6 membered heterocyclyl or a benzo 5-6 membered heteroaryl, for example, [ka] That is the case.

[0042] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylic acid esters.

[0043] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably a 5-8 member monocyclic heteroaryl or a 7-14 member bicyclic heteroaryl, more preferably a 5-member monocyclic heteroaryl, a 6-member monocyclic heteroaryl, an 8-member bicyclic heteroaryl, a 9-member bicyclic heteroaryl, or a 10-member bicyclic heteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, piperazinyl, pyridoimidazolyl, pyridadinyl These include doimidazolyl, preferably pyridoimidazolyl, pyridoimidazolyl, benzothiazolyl, thiazolothienyl, imidazothiazolyl, thienothiazolyl, thiazolothiazolyl, thiazolotriazolyl, pyrazolothiazolyl, thiazolopyarzolyl, imidazothienyl, indolyl, quinazolinyl, benzoisoxazolyl, benzoxazinyl, triazolopyridyl, benzofuranil, isobenzofuranil, thiadiazolyl, tetrazolyl, triazolothiadiazolyl, or oxadiazolyl.

[0044] The heteroaryl ring can condense with a heteroaryl, heterocyclyl, or cycloalkyl ring to form a condensed ring, where the ring bonded to the parent structure is a heteroaryl ring, preferably a 5-6 membered heteroaryl condensation, a 5-6 membered heteroaryl, or a 5-6 membered heteroarylphenyl, for example, [ka] That is the case.

[0045] The heteroaryl may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylic acid esters.

[0046] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylic acid esters.

[0047] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above. Non-limiting examples include trifluoromethyl and difluoromethyl.

[0048] "Haloalkoxy" refers to an alkoxy compound substituted with one or more halogens, where alkoxy is defined as described above.

[0049] "Hydroxyalkyl" refers to an alkyl group substituted with hydroxyl, where alkyl is defined as above. Non-restrictive examples include -C(CH3)2(OH).

[0050] The different phrases such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C", etc. all represent the same meaning, that is, X can be any one or more of A, B, and C.

[0051] In the present invention

Chemical formula

[0052] The "*" on the substituent of the present invention or

Chemical formula

[0053] Any hydrogen described in the present invention can be substituted with its isotope deuterium, and any hydrogen in the compounds of the examples according to the present invention can be substituted with deuterium atoms.

[0054] "Optional" or "optionally" means that the event or circumstance described subsequently may occur, but does not necessarily occur, and the description includes the cases of occurrence or non-occurrence of the event or circumstance. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may be present, but does not necessarily be present, and the description includes the cases where heterocyclyl is substituted with alkyl and where heterocyclyl is not substituted with alkyl.

[0055] "Substitution" refers to the substitution of one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, with a corresponding number of substituents that are independent of each other. Of course, substituents exist only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without excessive effort (by experiment or theory). For example, amino or hydroxyl compounds with free hydrogen may have unstable bonds with carbon atoms that have unsaturated (e.g., olefinic) bonds.

[0056] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and to enhance the absorption of the active ingredient in order to exert biological activity.

[0057] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective in vivo in mammals and possesses the relevant biological activity.

[0058] The present invention will be described in detail below with reference to examples, but this does not mean that the present invention is disadvantageously limited. The compounds of the present invention can be produced by a variety of synthetic methods familiar to those skilled in the art, and these include, but are not limited to, the specific embodiments listed below, embodiments formed in combination with other chemical synthesis methods, and equivalent substitution forms and preferred embodiments familiar to those skilled in the art. All reagents used in the present invention are commercially available or produced by reference to the prior art. Except for the reagents, the names of all compounds are generated by ChemDrew 20.0.

[0059] General method The compounds of the present invention can be produced by the following non-limiting general methods and examples.

[0060] Plan 1 The synthesis of a compound of general formula (I), where R1, R2, R3, R4, and R5 are as defined above. [ka]

[0061] As shown in Plan 1, compound A of the general formula can be prepared by reacting commercially available 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with the amine of formula R1R2NH. Typical reaction conditions involve heating a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine and a suitable amine in a suitable protic or polar aprotic solvent at a temperature from room temperature to the boiling point of the solvent in the presence of an added organic or inorganic base. The amine R1R2NH can be obtained commercially or can be 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 and the amine of formula R1R2NH with DMF at 120°C in the presence of DIPEA, as shown in Preparation Example 1.

[0062] Furthermore, compound A of the general formula may be produced by reacting 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with a suitable 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.

[0063] As shown in Plan 1, sulfoxide compounds of compound B of the general formula can be produced by reacting compound A of the general formula with a suitable oxidizing agent in a suitable solvent, optionally in the presence of a chiral catalyst. For example, a DCM / aqueous solution of compound A of the general formula is t The oxidation may also be carried out using BuOOH at 0°C to room temperature in the presence of Ti(OiPr)4 and (S)-(-)-1,1'-bi(2-naphthol).

[0064] The sulfoxide compound of the compound B of the general formula may be produced in the form of a single enantiomer, or may be produced in the form of an enantiomer mixture and then separated by a method known to those skilled in the art. Alternatively, it may be preferable to carry out subsequent reactions on the compound in the form of an enantiomer mixture and separate the enantiomers at a later stage.

[0065] As shown in Scheme 1, the compound (I) of the general formula can be produced by reacting the compound B of the general formula with an amine of the compound C of the general formula (obtained as a commercial product or easily synthesized by a method known to those skilled in the art).

[0066] Typical reaction conditions include heating a solution of the compound B of the general formula and an appropriate amine of the compound C of the general formula in an appropriate protic or polar aprotic solvent from room temperature to the boiling point of the solvent under the presence of an added organic or inorganic base. For example, dissolve the compound B of the general formula in DMSO and react it with the amine of the compound C of the general formula in the presence of DIPEA.

[0067] Alternatively, the compound (I) of the general formula may be produced by reacting the compound B of the general formula with an amine of the compound C of the general formula in an appropriate solvent or solvent mixture such as 1,4-dioxane in the presence of a palladium catalyst and an appropriate inorganic or organic base, such as potassium tert-butoxide, potassium carbonate, cesium carbonate, etc.

[0068] Production Examples and Examples The following examples are illustrative descriptions of the present invention and do not limit the present invention in any way. Unless otherwise specified, all fractions are by weight, and the temperature is in degrees Celsius. The pressure is atmospheric pressure or near atmospheric pressure. All data are measured by Agilent (Agilent6120 and / or 1100). Except for the synthesized intermediates, all reagents used in the present invention are obtained as commercial products. Except for the reagents, the names of all compounds are generated by ChemDrew20.0.

[0069] The following abbreviations are used. (Boc)2O: Ditert-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: Enantiomer excess, NCS: N-Chlorosuccinimide, Rochelle's salt: potassium sodium tartrate tetrahydrate, PE: petroleum ether, Pd(dppf)2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, Pd2(dba)3: trisdibenzylideneacetone dipalladium, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, PMB: p-methoxybenzyl cyanide, PPh3: triphenylphosphine, Pin2B2: bispinacolatodiborone, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TsOH: 4-toluenesulfonic acid, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, Burgess reagent: N-(triethylammonium sulfonyl)carbamate methyl.

[0070] Manufacturing Example 1: (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(I01) [ka] 1)(1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methanol(I01-b) At room temperature, (1-aminocyclobutyl)methanol hydrochloride (15 g, 110.00 mmol, 1 eq) and triethylamine (80 ml, 550.00 mmol, 5 eq) were successively added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (I01-a, 22.6 g, 110 mmol, 1 eq) in acetonitrile (200 mL). The temperature was raised to 65-70°C and stirred for 12 hours. Then, water (1.2 L) was gradually added over 20 minutes, and the mixture was cooled to 25°C over 2 hours. The mixture was stirred for another 12 hours, filtered, and the filtered cake was successively washed with a 2:1 mixture of water and acetonitrile (400 mL) and water (200 mL). The resulting solid was vacuum-dried at 50°C for 12 hours to obtain I01-b (15 g, 50.5%). LCMS: 272.15[M+H] + .

[0071] 2)(R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(I01) At room temperature, (S)-(-)-1,1'-bis-2-naphthol (4.4g, 15.20mmol, 0.2eq) and Ti(O) are added in order to a 50mL solution of IO1-b (10.36g, 38mmol) of dichloromethane. 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 batch. The reaction mixture became homogeneous, and the reaction temperature rose to approximately 40°C. The mixture was allowed to cool naturally to room temperature, and stirred for 1.5 hours, then filtered. The filtered cake was washed with isopropyl acetate (243 mL x 2) and air-dried to obtain IO1 (6.2 g, 56.5%). LCMS: 288.25 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 3.89 (d, J=2.0 Hz, 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, 2.1 Hz, 4H), 1.97 - 1.77 (m, 2H).

[0072] Example 1 Synthesis of Compound 1 [ka] 1) N-benzyl-N-(3-cyanopropyl)glycine ethyl ester (1-a) At room temperature, 4-bromobutyronitrile (4.59 g, 31.04 mmol, 1.2 eq) and K2CO3 (10.72 g, 77.61 mmol, 3.0 eq) were added to a 50 mL solution of benzylglycine ethyl ester (5.01 g, 25.87 mmol, 1.0 eq) in acetonitrile. The mixture was stirred at 80°C for 16 hours, then cooled to room temperature, and water (150 mL) was added. Extraction with ethyl acetate (100 mL x 3), drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (PE:siRNA=5:1) yielded a yellow oily product 1-a (4.61 g, 68.5%). LCMS: 261.20 [M+H] + .

[0073] 2) N-(tert-butyloxycarbonyl)-N-(3-cyanopropyl)glycine ethyl ester (1-b) At room temperature, 10% Pd / C (0.4g) was added to a solution of 1-a (4g, 15.38 mmol, 1.0eq) and Boc2O (6.71g, 30.77 mmol, 2.0eq) in EtOH (100mL). After hydrogen absorption at room temperature for 16 hours, the solid was removed by filtration, the solution was concentrated, and purified by column chromatography (petroleum ether / SiO1 = 3:1) to obtain a colorless oily product 1-b (3.66g, 88.1%). LCMS: 271.20 [M+H] + .

[0074] 3) 4-Cyano-3-piperidone-1-carboxylate tert-butyl(1-c) At 0°C, t-BuOK (8.5 g, 75.5 mmol) was added to a solution of 1-b (17 g, 62.9 mmol) in toluene (100 mL). After stirring at room temperature for 30 minutes, saturated NH4Cl (200 mL) and n-hexane (200 mL) were added. Subsequently, HCl (2N) was added until the pH reached 6. Extraction with ethyl acetate (200 mL x 2), drying over anhydrous Na2SO4, filtration, and concentration were performed to obtain the yellow oily product 1-c (13 g). This crude product was used directly in the next step without purification. LCMS: 225.15 [M+H] + .

[0075] 4) 3-amino-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl(1-d) 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. Depositphotos (250 mL) was added, and the mixture was washed sequentially with saturated Na₂CO₃ (100 mL) and brine (100 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 20:1) to obtain a white solid product 1-d (10 g, 72%). LCMS: 239.15 [M+H] + .

[0076] 5) 3-Chloro-9,10-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidine-8(7H)-carboxylate tert-butyl(1-e) At room temperature, 150 mg, 0.63 mmol, 1 eq of 1-d was added to a 4 mL solution of AcOH, 2-chloromalonaldehyde (66 mg, 0.63 mmol, 1 eq) was added, and the mixture was stirred for 16 hours. Then, a saturated NaHCO3 (40 mL) solution was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The solution was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA = 1:1) to obtain the yellow solid product 1-e (80 mg, 41.2%). LCMS: 309.10 [M+H] + .

[0077] 6) 3-Chloro-7,8,9,10-tetrahydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidine(1-f) At 0°C, 1 mL of TFA was added to a solution of 1-e (80 mg, 0.26 mmol, 1 eq) in DCM (3 mL). After stirring at room temperature for 1 hour, the mixture was concentrated to obtain the yellow solid product 1-f (55 mg, 99%). This crude product was used directly in the next step without purification. LC-MS: 209.25 [M+H] + .

[0078] 7)(R)-2-(3-chloro-9,10-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidine-8(7H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(1) At room temperature, DIEPA (168 mg, 1.3 mmol, 5.0 eq) was added to solutions 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). After stirring overnight at 70°C, the solution was concentrated. Purification by pre-TLC (SiO2, DCM / MeOH = 10 / 1) yielded a white solid product 1 (67.3 mg, 56%). LCMS: 460.25 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.3 Hz, 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 = 13.5 Hz, 2H), 2.99 - 2.89 (m, 1H), 2.81 (s, 3H), 2.31 (dd, J = 21.2, 10.5 Hz, 2H), 2.18 (s, 2H), 1.85 - 1.69 (m, 2H).

[0079] The following compounds were synthesized using a similar method. [Table 1]

[0080] Example 2 Synthesis of Compounds 5 and 6 [ka] 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) At room temperature, NaOH (15 g, 0.38 mol, 27.0 eq) and water (15 mL) were added to a 100 mL three-necked flask, and the mixture was stirred until the solution became clear. Subsequently, (6-chloro-1H-benzo[d]imidazole-2-yl)methylamine hydrochloride (2.63 g, 14.32 mmol, 1.0 eq) and tetrabutylammonium bromide (185 mg, 0.57 mmol, 0.04 eq) were added in order. After stirring for 1 hour, a 50 mL LDMF solution of 1,2-dibromoethane (5.38 g, 28.64 mmol, 2.0 eq) was added dropwise. After stirring for a further 4 hours, the solid was removed by filtration, and the filtrate was concentrated. The mixture of 5-a and 5-b (1.25 g, 50.4%) was purified by column chromatography (DCM:MeOH:aqueous ammonia = 50:1:0.05~40:1:0.05) to obtain a white solid product. LCMS: 208.10 [M+H] + .

[0081] 2)(R)-2-(8-chloro-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-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]pyrazine-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(6) At room temperature, DIEPA (55 mg, 0.42 mmol, 3 eq) was added to solutions 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). 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 purification by SFC yielded white solid products 5 (7.94 mg, 12.4%) and 6 (5.36 mg, 8.42%). LCMS: 459.10 [M+H] + . 5-a: 1H NMR (400MHz, methanol-d4)δ 7.58(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). 5-b: 1 H NMR (400MHz, methanol-d4)δ 7.58(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).

[0082] Example 3 Synthesis of Compound 7 [ka] 1) 7-Chloro-3-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridine-2-carboxylate methyl(7-a) A solution of 4-chloropyridine-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 = 50:1:0.05~40:1:0.05) yielded product 7-a (800 mg, 20.2%) as a yellow solid. LCMS: 283.13 [M+H] + .

[0083] 2) 2-(7-chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-yl)ethane-1-ol(7-b) At 0°C, 7-a (500 mg, 1.77 mmol, 1.0 eq) was dissolved in CH2Cl2 (10 mL), to which 1 M DIBAL-H (10.8 mL, 10.8 mmol, 6.0 eq) in CH2Cl2 was added dropwise. After stirring for 2 hours, Rochelle's salt solution (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 (DCM:MeOH:aqueous ammonia = 50:1:0.05~40:1:0.05) to obtain the yellow oily product 7-b (220 mg, 54.8%). LCMS: 227.05 [M+H] + .

[0084] 3) 2-(2-(azidomethyl)-7-chloroimidazo[1,2-a]pyridine-3-yl)diphenylethyl phosphate(7-c) At 0°C, DPPA (487 mg, 1.77 mmol, 2.0 eq) was added to a THF (5 mL) solution of 7-b (200 mg, 0.88 mmol, 1.0 eq) and DBU (269 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). The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (n-hexane / siRNA = 2:1) to obtain a yellow oily product 7-c (170 mg, yield 40%). LCMS: 484.10 [M+H] + .

[0085] 4) 8-Chloro-1,2,3,4-tetrahydroimidazo[1,2-a:4,5-c']dipyridine(7-d) 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) were stirred at 60°C for 4 hours. The mixture was cooled to room temperature and concentrated. Purification by pre-HPLC (5%-95% H2O / ACN with 0.1% TFA) yielded a colorless oily product, 7-d (30 mg, 69%). LC-MS: 208.10 [M+H] + .

[0086] 5)(R)-2-(8-chloro-3,4-dihydroimidazo[1,2-a:4,5-c']dipyridine-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(7) At room temperature, DIEPA (50 mg, 0.39 mmol, 3.0 eq) and water (0.5 mL) were added 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). After stirring overnight at 65 °C, the solution was concentrated. Purification by pre-HPLC (5%-95% H2O / ACN with 0.1% TFA) yielded product 7 (33.5 mg, 38.4%) as a white solid. LCMS: 459.10 [M+H] + . 1 H NMR 1H NMR (400MHz, methanol-d4)δ 8.62 - 8.58(m, 1H), 8.04 - 8.01 (m, 1H), 7.52 (dd, J = 7.2, 2.0 Hz, 1H), 5.14 (s, 2H), 4.33 (s, 2H), 3.94 (q, J = 11.4 Hz, 2H), 3.58 (dd, J = 17.2, 8.5 Hz, 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, 8.7 Hz, 2H).

[0087] Example 4 Synthesis of Compound 8 [ka] 1) 7-Chloroimidazo[1,2-a]pyridine-2,3-dicarboxylate diethyl(8-c) At room temperature, 2-chloro-3-oxalacetate diethyl (8-b, 8.65 g, 38.89 mmol, 0.5 eq) was added to a solution of 4-chloropyridine-2-amine (8-a, 10 g, 77.78 mmol, 1 eq) in ethanol (100 mL). The mixture was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, the solution was concentrated. Purification by column chromatography (PE:siRNA=5:1) yielded the white solid product 8-c (7.67 g, 33.2%). LCMS: 297.05 [M+H] + .

[0088] 2) 7-Chloro-2-formylimidazo[1,2-a]pyridine-3-carboxylate ethyl(8-d) Under -78°C and nitrogen protection, DIBAL-H (20.00 mL, 29.93 mmol, 1.2 eq) was added dropwise to a solution of 8-c (7.4 g, 24.94 mmol, 1 eq) in dry THF (100 mL) and stirred for 2 hours. Then, a saturated Rochelle's salt solution (100 mL aqueous solution) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the white solid product 8-d (4.5 g, 71.4%). LCMS: 253.00 [M+H] + .

[0089] 2) 7-Chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate ethyl(8-e) At room temperature, NaBH4 (336.87 mg, 8.91 mmol, 0.5 eq) was added in batches to a solution of 8-d (4.5 g, 17.81 mmol, 1 eq) in MeOH (50 mL), stirred for 2 hours, then 2 M H2SO4 (15 mL) was added. Extraction was performed with dichloromethane (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to obtain the white solid product 8-e (4.2 g, 92.6%). LCMS: 255.00 [M+H] + .

[0090] 4) 7-Chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate ethyl(8-g) At room temperature, 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) were added to a solution of 8-e (4.2 g, 16.50 mmol, 1 eq) in CHCl3 (100 mL). The mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the solution was concentrated and purified by column chromatography (PE:Â=5:1) to obtain 8-g (4.8 g, 85.9%) of the yellow oil product. LCMS: 339.15 [M+H] + .

[0091] 5) (7-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine-3-yl)methanol(8-h) At 0°C and under nitrogen protection, 8-g (4.8g, 14.17 mmol, 1eq) of 8-g in Et2O (150mL) was mixed with LAH (6.00mL, 14.17 mmol, 1eq) and stirred for 1 hour. Then, water (2.4mL) and 15% NaOH (0.6mL) solution were added. The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH=50:1) to obtain the white solid product 8-h (1.6g, 38.1%). LCMS: 297.20 [M+H] + .

[0092] 6)3-(azidomethyl)-7-chloro-2-((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine(8-i) Under 0°C and nitrogen protection, DPPA (1.93 g, 7.00 mmol, 1.3 eq) and DBU (1.07 g, 7.00 mmol, 1.3 eq) were added to a 20 mL solution of 8-h (1.6 g, 5.39 mmol, 1 eq) in THF. The mixture was heated to room temperature and stirred for 16 hours. The reaction solution was then used directly in the next step. LCMS: 322.20 [M+H] +.

[0093] 7)(7-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)imidazo[1,2-a]pyridine-3-yl)methyl)carbamate tert-butyl(8-j) 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 the mixture was stirred for 4 hours. After cooling to room temperature, 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:SiO=1:1) to obtain the white solid product 8-j (1 g, 81.3%). LCMS: 396.20 [M+H] + .

[0094] 8) (7-chloro-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-yl)methyl)carbamate tert-butyl(8-k) The 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. After cooling to room temperature, 4 M NaOH was added until the pH reached 7-8, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to obtain the white solid product 8-k (520 mg, 66%). LCMS: 312.00 [M+H] + .

[0095] 9) (2-(bromomethyl)-7-chloroimidazo[1,2-a]pyridine-3-yl)methyl)carbamate tert-butyl(8-l) At room temperature, CBr4 (562.00 mg, 1.69 mmol, 1.2 eq) and PPh3 (444.00 mg, 1.69 mmol, 1.2 eq) were added sequentially to a 10 mL solution of 8-k (440 mg, 1.41 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 20:1) yielded a white solid product 8-l (340 mg, 64.3%). LCMS: 374.10 [M+H] + .

[0096] 10) 6-Chloro-1,3-dihydro-2H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridine-2-carboxylate tert-butyl(8-m) At room temperature, 8-l (290 mg, 1.06 mmol, 1 eq) of NaH (64.00 mg, 1.58 mmol, 1.5 eq) was added to DMSO (60 mL) solution. The mixture was heated to 90°C and stirred for 10 minutes. After cooling to room temperature, water (60 mL) was added. The solution was extracted with ethyl acetate (60 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by pre-TLC (SiO₂, PE:Â=1:1) yielded a white solid product 8-m (13 mg, 5.9%). LCMS: 294.25 [M+H] + .

[0097] 11) 6-chloro-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridine(8-n) At room temperature, 1 mL of TFA was added to a solution of 8-m (17 mg, 0.04 mmol, 1 eq) in DCM (4 mL). After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 8-n (9 mg, 80.35%). This crude product was used directly in the next step without purification. LC-MS: 194.20 [M+H] + .

[0098] 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) At room temperature, DIEPA (20 mg, 0.15 mmol, 3 eq) was added to 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). After stirring at 65 °C for 3 hours, the mixture was cooled to room temperature and concentrated. Purification by Prep-HPLC (ACN / H2O with 0.1% TFA) yielded product 8 (10.9 mg, 52.6%) as a white solid. LCMS: 445.15 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.61 (dd, J = 48.6, 7.2 Hz, 1H), 7.83 (dd, J = 11.5, 2.2 Hz, 1H), 7.15 (ddd, J = 7.1, 5.1, 2.2 Hz, 1H), 4.89 (s, 2H), 4.71 (d, J = 20.0 Hz, 2H), 3.80 (s, 2H), 3.49 (m, J = 17.7, 16.4, 8.3 Hz, 2H), 3.28 - 2.88 (m, 4H), 2.36 - 2.20 (m, 4H), 1.78 (dd, J = 18.9, 10.0 Hz, 2H).

[0099] Example 5 Synthesis of Compound 9 [ka] 1) 4-(tetrahydro-2H-pyran-2-yl)oxy) 2-butin-1-ol (9-b) At room temperature, 3,4-dihydro-2H-pyran (8-f, 28.4g, 336.86 mmol, 1eq) and PPTS (8.5g, 33.69 mmol, 0.1eq) were added to a 300 mL DCM solution of 2-butyne-1,4-diol (9-a, 29 g, 336.86 mmol, 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:siRNA = 2:1) to obtain a yellow oily product 9-b (26 g, 45.4%). 1 H NMR (400 MHz, DMSO- d6) δ 5.16 (t, J = 5.4 Hz, 1H), 4.70 (d, J = 3.7 Hz, 1H), 4.25 - 4.10 (m, 2H), 4.06 (d, J = 4.9 Hz, 2H), 3.67 (ddd, J = 11.5, 8.8, 3.1 Hz, 1H), 3.41 (dd, J = 10.6, 5.3 Hz, 1H), 1.68 - 1.56 (m, 2H), 1.48 - 1.38 (m, 4H).

[0100] 2) 4-(tetrahydro-2H-pyran-2-yl)oxy)-2-butynal(9-c) At 0°C, Dess-Martin (97.00 g, 229.13 mmol, 1.5 eq) was added to a solution of 9-b (26 g, 152.75 mmol, 1 eq) in DCM (300 mL). After stirring at room temperature for 2 hours, water (300 mL) was added. Extraction was performed with dichloromethane (300 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA = 10:1) to obtain a yellow oily product 9-c (21.9 g, 85.2%). 1H NMR (400 MHz, DMSO- d6) δ 9.21 (s, 1H), 4.72 (s, 1H), 4.53 - 4.40 (m, 2H), 3.74 - 3.65 (m, 1H), 3.44 (d, J = 11.6 Hz, 1H), 1.64 (dd, J = 11.8, 3.8 Hz, 2H), 1.47 (d, J = 10.3 Hz, 4H).

[0101] 3) Amino-3-chloropyridine-1-ium(9-f) At 0°C, O-(2,4-dinitrophenyl)hydroxylamine (9-e, 19.30 g, 96.88 mmol, 1.1 eq) was added to a solution of 3-chloropyridine (9-d, 10 g, 88.07 mmol, 1 eq) in DCM (300 mL). After stirring at room temperature for 16 hours, the mixture was concentrated to obtain product 9-f (crude, 22.4 g, 81.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ 9.02 (s, 1H), 8.70 (d, J = 6.4 Hz, 1H), 8.58 (s, 2H), 8.55 (d, J = 3.2 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.4, 6.3 Hz, 1H), 7.76 (dd, J = 9.8, 3.2 Hz, 1H), 6.30 (d, J = 9.8 Hz, 1H).

[0102] 4) 6-Chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(9-g) At 0°C, 9-f (27.2 g, 86.81 mmol, 1 eq) was dissolved in DMF (300 mL) and then 9-c (21.9 g, 130.21 mmol, 1.5 eq) and K2CO3 (15.60 g, 112.85 mmol, 1.3 eq) were added 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:siRNA = 10:1) to obtain the yellow solid product 9-g (1.5 g, 5.9%). LCMS: 295.20 [M+H] + .

[0103] 5)(E)-6-chloro-3-(2-nitrovinyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine(9-h) The compounds 9-g (1.7g, 5.77 mmol, 1 eq) and NH4OAc (223.00 mg, 2.88 mmol, 0.5 eq) in MeNO2 (20 mL) were stirred at 100°C for 2 hours. After cooling to room temperature, saturated NaHCO3 (20 mL) solution was added. Extraction with ethyl acetate (30 mL x 3), drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (DCM: siRNA=20:1) yielded the yellow solid product 9-h (1.2g, 61.6%). LCMS: 338.15 [M+H] + .

[0104] 6)2-(6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-amine(9-i) At 0°C, LAH (5.68 mL, 14.20 mmol, 4 eq) was added dropwise to a solution of 9-h (1.2 g, 3.55 mmol, 1 eq) in THF (20 mL). After stirring at room temperature for 4 hours, saturated Rochelle's salt solution (30 mL) was added. Extraction was performed with ethyl acetate (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (DCM: Â=20:1) to obtain a yellow oily product 9-i (900 mg, 81.8%). LCMS: 310.05 [M+H] + .

[0105] 7)(2-(6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-yl)ethyl)carbamate tert-butyl(9-j) At room temperature, Boc2O (676.3 mg, 3.10 mmol, 1.2 eq) was added to a solution of 9-i (800 mg, 2.58 mmol, 1 eq) in THF (10 mL). After stirring for 16 hours, saturated NaHCO3 solution (20 mL) was added. Extraction was performed with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:Â=3:1) to obtain a yellow oily product 9-j (270 mg, 25.5%). LCMS: 410.30 [M+H] + .

[0106] 8) (2-(6-chloro-2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-yl)ethyl) tert-butyl(9-k) carbamate At room temperature, 250 mg (0.61 mmol, 1 eq) of 9-j in 4 mL of 1,4-dioxane was mixed with 2 mL of 1 N HCl and stirred for 2 hours. Then, 1 N NaOH was added until the pH reached 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:Â=1:1) to obtain the yellow solid product 9-k (150 mg, 75.5%). LCMS: 326.25 [M+H] + .

[0107] 9)(2-(2-(bromomethyl)-6-chloropyrazolo[1,5-a]pyridine-3-yl)ethyl) tert-butyl(9-l) carbamate At room temperature, CBr4 (245 mg, 0.74 mmol, 1.5 eq) and PPh3 (168 mg, 0.64 mmol, 1.3 eq) were added sequentially to a 9k (160 mg, 0.49 mmol, 1 eq) solution in DCM (4 mL). After half a hour, saturated NaHCO3 aqueous solution (10 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA = 2:1) to obtain a white solid product 9-l (110 mg, 57.6%). LCMS: 388.10 [M+H] + .

[0108] 10) 7-Chloro-3,4-dihydropyrazolo[1,5-a:3,4-c']dipyridine-2(1H)-carboxylate tert-butyl(9-m) At room temperature, NaH (16 mg, 0.39 mmol, 1.5 eq) was added to a 15 mL solution of 9-l (100 mg, 0.26 mmol, 1 eq) in DMF, and the mixture was stirred for 16 hours. Water (20 mL) was then added. Extraction was performed with ethyl acetate (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by pre-TLC (SiO₂, PE:Â=4:1) to obtain the white solid product 9-m (73 mg, 92.2%). LCMS: 308.15 [M+H] + .

[0109] 11) 7-Chloro-1,2,3,4-tetrahydropyrazolo[1,5-a:3,4-c']dipyridine(9-n) At room temperature, 9-m (70 mg, 0.23 mmol, 1 eq) in a solution of 1,4-dioxane (4 mL) was mixed with 4 M HCl / 1,4-dioxane (4 mL) and stirred for 16 hours. The mixture was concentrated to obtain the white solid product 9-n (40 mg, 84.7%). The crude product was used directly in the next step without purification. LCMS: 208.20 [M+H] + .

[0110] 12)(R)-2-(7-chloro-3,4-dihydropyrazolo[1,5-a:3,4-c']dipyridine-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(9) At room temperature, DIEPA (65.91 mg, 0.51 mmol, 3 eq) was added to solutions 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). After stirring at 65 °C for 3 hours, the solution was concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 15:1) yielded product 9 (62.1 mg, 80.6%) as a white solid. LCMS: 459.25 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.89 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.20 (dd, J = 9.5, 1.8 Hz, 1H), 5.01 (s, 2H), 4.06 (t, J = 3.72 (d, J = 2.7 Hz, 2H), 3.45 (d, J = 8.7 Hz, 1H), 3.24 - 3.18 (m, 1H), 3.03 (d, J = 7.9 Hz, 1H), 2.88 (d, J = 6.4 Hz, 1H), 2.80 (s, 2H), 2.31 (q, J = 10.3 Hz, 2H), 2.21 - 2.16 (m, 2H), 1.76 (t, J = 8.0 Hz, 2H).

[0111] The following compounds were synthesized by a similar method. [Table 2]

[0112] Example 6 Synthesis of Compound 11 [ka] 1) 8-Chloro-1,2,3,4,5,6-Hexahydrobenzo[f]isoquinoline(11-b) At room temperature, formaldehyde (100.84 mg, 3.39 mmol, 6.0 eq) was added 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). The mixture was stirred at 70°C for 1 hour, then NH4Cl (89.82 mg, 1.68 mmol, 3.0 equiv.) was added, and the mixture was stirred at 70°C for 2 hours. The mixture was cooled to room temperature, and a saturated NaHCO3 (100 mL) solution was added. Extraction with ethyl acetate (20 mL x 2), drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (PE:siRNA = 1:1) yielded the yellow solid product 11-b (40 mg, 32.5%). LCMS: 220.10 [M+H] + .

[0113] 2)(R)-2-(8-chloro-1,4,5,6-tetrahydrobenzo[f]isoquinoline-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(11) At room temperature, 11-b (40 mg, 0.19 mmol, 0.9 equiv.) and DIEPA (269.48 mg, 2.09 mmol, 10 equiv.) were added to a solution of I01 (60 mg, 0.21 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by column chromatography (PE:SiO=1:1) yielded a white solid product 11 (20.7 mg, 20.9%). LCMS: 471.25[M+H] + . 1H NMR δ 7.26 - 6.99 (m, 3H), 4.24 (s, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.71 (s, 2H), 3.45 (s, 1H), 3.28 - 3.16 (m, 1H), 3.02 (d, J = 10.5 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.75 (t, J = 7.9 Hz, 2H), 2.63 (s, 1H), 2.36 - 2.27 (m, 3H), 2.17 (s, 4H), 1.76 (s, 2H).

[0114] The following compounds were synthesized by a similar method. [Table 3]

[0115] Example 7 Synthesis of Compound 12 [ka] 1) 7-Chloro-4-methyl-1,2-dihydronaphthalene(11-a) At 0°C, 6-chloro-3,4-dihydronaphthalene-1(2H)-one (5 g, 27.8 mmol, 1.0 eq) was added dropwise to a solution of THF (15 mL) and diethyl ether (35 mL) with MeMgBr (9.27 mL, 3 M, 27.8 mmol, 1.0 eq). After stirring for 2 hours, a saturated NH4Cl (50 mL) solution was added. Extraction was performed with ethyl acetate (50 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:SiO=5:1) to obtain product 11-a (2.2 g, 44.5%) as a yellow solid. LCMS: 179.10 [M+H] + .

[0116] 2) 3-benzyl-8-chloro-1,2,3,4,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline(12-a) At room temperature, formaldehyde (3.06 g, 33.58 mmol, 6.0 equiv.) was added to a solution of 11-a (1.0 g, 5.60 mmol, 1.0 equiv.) in acetic acid (40 ml). The mixture was heated to 70 °C and stirred for 2 hours. Then, BnNH₂ (3 g, 5.0 equiv.) was added, and the mixture was stirred at 70 °C for 12 hours. After cooling to room temperature, a saturated NaHCO₃ (100 mL) solution was added. The mixture was extracted with ethyl acetate (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:siRNA = 1:1) to obtain the yellow solid product 12-a (200 mg, 11.5%). LCMS: 312.15[M+H] + .

[0117] 3) 8-Chloro-1,2,3,4,4a,5,6,10b-Octahydrobenzo[f]isoquinoline(12-b) At 0°C, 1-chloroethyl chloroformate (110.03 mg, 0.77 mmol, 2.0 equiv.) was added dropwise to a solution of 12-a (120 mg, 0.38 mmol, 1.0 equiv.) in 1,2-DCE (2 ml). After stirring at room temperature for 1 hour, the mixture was concentrated until dry, and then MeOH (10 ml) was added. After stirring at 65°C for 12 hours, the mixture was cooled to room temperature, and saturated NaHCO3 (20 mL) solution was added. Extraction was performed with ethyl acetate (20 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA = 1:1) to obtain the yellow solid product 12-b (60 mg, 70.3%). LCMS: 222.10 [M+H] + .

[0118] 4)(R)-2-((4aS,10bS)-8-chloro-1,4,4a,5,6,10-hexahydrobenzo[f]isoquinoline-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(12) At room temperature, 12-b (46.23 mg, 0.21 mmol, 1.0 equiv.) and DIEPA (269.48 mg, 2.09 mmol, 10 equiv.) were added to a solution of I01 (60 mg, 0.21 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 12 hours and then concentrated. Purification by column chromatography (PE:SiO=1:1) yielded a white solid product 12 (60 mg, 60.8%). LCMS: 473.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.20 (q, J = 19.7, 16.5 Hz, 3H), 5.89 (s, 1H), 3.66 (d, J = 19.0 Hz, 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, 7.4 Hz, 2H), 2.68 - 2.54 (m, 4H), 2.34 - 2.23 (m, 2H), 2.12 (s, 4H), 1.72 (s, 2H).

[0119] Example 8 Synthesis of Compounds 13 and 14 [ka] 1) 4-Chloro-2-(methoxymethoxy)benzaldehyde (13-a) At 0°C, chloro-(methoxy)methane (5.14g, 63.87mmol, 1.0equiv.) and triethylamine (32.31g, 319.35mmol, 5.0equiv.) were sequentially added dropwise to a 100ml solution of 4-chloro-2-hydroxybenzaldehyde (10g, 63.87mmol, 1.0equiv.) in dichloromethane. After stirring at room temperature for 1 hour, H2O (150mL) was added. Extraction with dichloromethane (300mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA=10:1) to obtain a yellow oily product 13-a (7.02g, 54.6%). LCMS: 201.05 [M+H] + .

[0120] 2)(E)-3-(4-chloro-2-(methoxymethoxy)phenyl)ethyl acrylate (13-b) At 0°C, a solution of triethylphosphonoacetate (7.02 g, 34.89 mmol, 1.0 equiv.) in THF (100 ml) was batch-added with NaH (837.40 mg, 34.89 mmol, 1 equiv.), followed by stirring for 30 minutes. Then, a solution of 13-a (7.82 g, 34.89 mmol, 1.0 equiv.) in THF (15 mL) was added dropwise. After stirring at 0°C for 1 hour, a saturated NH4Cl (100 ml) solution was added. Extraction with ethyl acetate (200 mL x 3), drying over anhydrous Na2SO4, filtration, concentration, and purification by column chromatography (PE:SiO=10:1) yielded the yellow oily product 13-b (8 g, 84.7%). LCMS: 271.20 [M+H] + .

[0121] 3)(3S,4R)-1-benzyl-4-(4-chloro-2-(methoxymethoxy)phenyl)-2,6-dipiperidone-3-carboxylate ethyl(13-c) At room temperature, NaH (177.30 mg, 7.39 mmol, 2.0 equiv.) was added 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). After stirring at 70 °C for 1 hour, the mixture was cooled to room temperature, and a saturated NH4Cl (30 mL) solution was added. Extraction was performed with ethyl acetate (35 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:HCl = 1:1) to obtain the yellow solid product 13-c (600 mg, 36.4%). LCMS: 446.25 [M+H] + .

[0122] 4) ((3S,4R)-1-benzyl-4-(4-chloro-2-(methoxymethoxy)phenyl)piperidine-3-yl)methanol(13-d) At room temperature, BH3 (10.54 ml, 10.54 mmol, 10 equiv.) was added dropwise to a solution of 13-c (470 mg, 1.05 mmol, 1.0 eq.) in THF (20 ml). The THF was stirred at 70°C for 3 hours, then cooled to 0°C. MeOH (30 mL) was added dropwise, and the mixture was stirred at 60°C for 3 hours. After cooling to room temperature, Depositphotos (100 mL) was added, followed by washing with saturated brine (35 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE: Depositphotos = 1:1) to obtain the yellow solid product 13-d (220 mg, 55.5%). LCMS: 376.25 [M+H] + .

[0123] 5) 2-((3S,4R)-1-benzyl-3-(hydroxymethyl)piperidine-4-yl)-5-chlorophenol(13-e) At room temperature, TFA (1 ml, 8.77 mmol, 14.98 equiv.) was added to a solution of 13-d (220 mg, 0.59 mmol, 1.0 equiv.) in DCM (3 ml), and the mixture was stirred for 3 hours. The solution was then concentrated, and toluene (30 mL) and saturated NaHCO3 (30 mL) were added. Extraction was performed with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:toluene = 1:1) to obtain the yellow solid product 13-e (190 mg, 97.8%). LCMS: 332.20 [M+H] + .

[0124] 6) (4aS,10bR)-3-benzyl-8-chloro-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine(13-f) At 0°C, PPh3 (829.93 mg, 3.16 mmol, 5.0 eq.) and DIAD (639.83 mg, 3.16 mmol, 5.0 equiv.) were sequentially added to a 10 ml THF (10 ml) solution of 13-e (210 mg, 0.63 mmol, 1.0 equiv.). After stirring at room temperature for 16 hours, the solution was concentrated, HCl (30 mL) was added, and the mixture was washed sequentially with water (30 mL x 2) and brine (30 mL). The solution was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:HCl = 3:1) to obtain the yellow solid product 13-f (80 mg, 40.3%). LCMS: 314.20 [M+H] + .

[0125] 7) (4aS,10bR)-8-chloro-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine(13-g) At 0°C, 1-chloroethyl chloroformate (72.89 mg, 0.51 mmol, 2.0 equiv.) was added dropwise to a solution of 13-f (80 mg, 0.25 mmol, 1.0 equiv.) in 1,2-DCE (3 ml). After stirring at room temperature for 1 hour, the mixture was concentrated, then 10 ml of MeOH was added, the mixture was stirred overnight, and a saturated NaHCO3 (10 mL) solution 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:siRNA = 1:1) to obtain a yellow solid product of 13-g (30 mg, 52.6%). LCMS: 224.20 [M+H] + .

[0126] 8)(R)-2-((4aS,10bR)-8-chloro-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-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]pyridine-3(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(14) At room temperature, DIEPA (134.74 mg, 1.04 mmol, 10 equiv.) was added to a solution of I01 (30 mg, 0.13 mmol, 1.3 equiv.) and 13-g (30 mg, 0.13 mmol, 1.3 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 12 hours and then concentrated. Purification by column chromatography (PE:SiO=1:1) and further purification by SFC yielded white solid products 13 (17.2 mg, 36.0%) and 14 (15.4 mg, 32.0%). LCMS: 475.10 [M+H] + . 13: 1H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 8.2, 2.2 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 4.26 (s, 1H), 3.88 (t, J = 11.1 Hz, 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 = 11.2 Hz, 1H), 2.39 - 2.23 (m, 4H), 2.15 (s, 2H), 1.82 - 1.68 (m, 2H), 1.57 (s, 1H). 14: 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 8.3, 2.2 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4.82 (t, J = 5.5 Hz, 1H), 4.73 (s, 1H), 4.25 (d, J = 10.1 Hz, 1H), 3.88 (t, J = 11.0 Hz, 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).

[0127] Example 9 Synthesis of Compound 18 (R)-2-(6-chloro-3,4-dihydroisoquinoline-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide [ka] At room temperature, DIEPA (65.91 mg, 0.51 mmol, 3 eq) was added to a solution of IO1 (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). After stirring at 65 °C for 3 hours, the solution was concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 15:1) yielded product 18 (50.4 mg, 86.8%) as a white solid. LCMS: 419.30 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 7.26 (s, 1H), 7.23 (d, J = 1.3 Hz, 2H), 4.81 (s, 2H), 3.89 (d, J = 5.9 Hz, 2H), 3.71 (d, J = 1.8 Hz, 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).

[0128] The following compounds were synthesized by a similar method. [Table 4] JPEG2026514091000049.jpg238169 JPEG2026514091000050.jpg238169 JPEG2026514091000051.jpg238169 JPEG2026514091000052.jpg238169 TIFF2026514091000053.tif216169 TIFF2026514091000054.tif239169 TIFF2026514091000055.tif216169 TIFF2026514091000056.tif216169 TIFF2026514091000057.tif238169 TIFF2026514091000058.tif221169

[0129] Example 10 Synthesis of Compounds 28 and 29 [ka] 1) N-(3-chlorophenethyl)acetamide(28-b) At 0°C, 2-(3-chlorophenyl)ethane-1-amine (28-a, 5 g, 32.258 mmol, 1 eq) was added dropwise to a 30 mL solution of anhydrous DCM (DCM) to which TEA (4.88 g, 48.387 mmol, 1.5 eq) and acetyl chloride (3.8 g, 48.387 mmol, 1.5 eq) were successively added. After stirring at room temperature for 1 hour, water (30 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the yellow oily product 28-b (5.6 g, 88.1%). LCMS: 198.05 [M+H] + .

[0130] 2) 6-Chloro-1-methyl-3,4-dihydroisoquinoline(28-c) At room temperature, 28-b (1.1 g, 5.584 mmol, 1 eq) was added to POCl3 (10 mL) solution. After stirring at 120 °C for 18 hours, the mixture was cooled to room temperature, the reaction solution was poured into ice water (100 mL), and then the pH was adjusted to 8 with 12N NaOH. Extraction was performed with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain product 28-c (1 g, 100%). LCMS: 180.05 [M+H] + .

[0131] 3) 6-Chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline(28-d) At 0°C, NaBH4 (1.05 g, 27.64 mmol, 2 eqs) was added in batches to a solution of 28-c (2.48 g, 13.85 mmol, 1 eq) in MeOH (20 mL). After stirring at room temperature for 2 hours, HCl (1 N) was added, and then the pH was adjusted to 8 with NaOH (1 N). Extraction was performed with dichloromethane (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain product 28-d (1.04 g, 41%). LCMS: 182.05 [M+H] + .

[0132] 4)(R)-2-((S)-6-chloro-1-methyl-3,4-dihydroisoquinoline-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-dihydroisoquinoline-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(29) At room temperature, 8-d (83.2 mg, 0.460 mmol, 1.1 eq) and DIEPA (161.8 mg, 1.254 mmol, 3 eq) were added sequentially to a THF / H2O (4 mL:1 mL) solution of I01 (120 mg, 0.418 mmol, 1 eq). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by pre-HPLC (5%-95% ACN:H2O with 0.1% TFA) and further separation by SFC yielded white solid products 28 (44.9 mg, 24.9%) and 29 (35.1 mg, 19.4%). LCMS: 433.25 [M+H] + . 28_ 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 20.0 Hz, 3H), 3.70 (s, 2H), 3.42 (dd, J = 16.9, 8.3 Hz, 2H), 3.16 (s, 1H), 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). 29_ 1 H NMR (400 MHz, DMSO- d6)) δ 7.28 (d, J = 25.6 Hz, 3H), 3.83 - 3.66 (m, 2H), 3.22 (dt, J = 15.6, 8.5 Hz, 1H), 2.97 (dd, J = 17.1, 8.0 Hz, 1H), 2.91 - 2.73 (m, 4H), 2.44 - 2.26 (m, 3H), 2.14 (d, J = 48.7 Hz, 2H), 1.80 (d, J = 8.0 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H), 1.24 (m, 1H)

[0133] Example 11 Synthesis of Compound 38 [ka] 1) 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate tert-butyl(38-b) At room temperature, 4,5,6,7-tetrahydro-3H-imidazo[4,5-C]pyridine dihydrochloride (100 mg, 0.51 mmol, 1 eq) was added to a 5 mL solution of DCM, followed by 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 obtain a yellow oily product 38-b (100 mg, 55.2%). LCMS: 224.30 [M+H] + .

[0134] 2) 3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate tert-butyl(38-c) At room temperature, K2CO3 (129.00 mg, 0.93 mmol, 3 eqs) and MeI (45.00 mg, 0.31 mmol, 1 eq) were sequentially added to a solution of 38-b (70 mg, 0.31 mmol, 1 eq) in DMF (4 mL). After stirring for 2 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a yellow, oily product 38-c (45 mg, 60.5%). This crude product was used directly in the next step without purification. LCMS: 238.35 [M+H] + .

[0135] 3) 3-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine(38-d) At room temperature, 1 mL of TFA was added to a 4 mL solution of 38-c (45 mg, 0.19 mmol, 1 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 38-d (22 mg, 84.6%). This crude product was used directly in the next step without purification. LC-MS: 138.35 [M+H] + .

[0136] 4)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide(38) At room temperature, DIEPA (55.00 mg, 0.42 mmol, 3 eq) was added to solutions 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). After stirring at 65 °C for 3 hours, the solution was concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 15:1) yielded product 38 (20.7 mg, 38.2%) as a white solid. LCMS: 389.15 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.89 (d, J = 14.2 Hz, 1H), 7.65 (s, 1H), 4.85 (s, 1H), 4.01 (s, 2H), 3.77 (s, 2H), 3.69 (d, J = 4.2 Hz, 5H), 3.29 (dt, J = 79.2, 7.5 Hz, 2H), 2.96 - 2.81 (m, 2H), 2.71 (s, 2H), 2.24 (d, J = 43.0 Hz, 4H), 1.80 - 1.70 (m, 2H).

[0137] Example 12 Synthesis of Compound 39 [ka] 1) 2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate tert-butyl(39-c) A solution of cyclopropanecarbothioamide (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. Extraction was performed with ethyl acetate (10 mL x 3), dried over anhydrous sodium 2SO4, filtered, and concentrated. Purification by pre-TLC (SiO2, PE:siRNA = 3:1) yielded product 39-c (56 mg, 27.8%) as a white solid. LC-MS: 281.10 [M+H] + .

[0138] 2) 2-Cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(39-d) At room temperature, 1 mL of TFA was added to a 4 mL solution of 39-c (56 mg, 0.20 mmol, 1 eq) in DCM. After stirring for 2 hours, the mixture was concentrated to obtain a yellow, oily product 39-d (30 mg, 83.3%). This crude product was used directly in the next step without purification. LC-MS: 181.25 [M+H] + .

[0139] 3)(R)-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(39) At room temperature, DIEPA (67.37 mg, 0.51 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 39 (69.7 mg, 92.9%) as a white solid. LCMS: 432.15 [M+H] + . 1H NMR (400 MHz, DMSO- d6) δ 4.87 (m, 4H), 4.00 (t, J = 5.8 Hz, 2H), 3.69 (s, 2H), 3.51 - 3.38 (m, 1H), 3.27 - 3.14 (m, 1H), 3.06 - 2.85 (m, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.31 - 2.15 (m, 5H), 1.75 (m, J = 8.9 Hz, 2H), 1.03 (m, J = 8.2, 3.3 Hz, 2H), 0.88 - 0.82 (m, 2H).

[0140] Example 13 Synthesis of Compound 44 [ka] 1) 8-Chloro-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(44-c) At room temperature and under nitrogen protection, 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate tert-butyl (44-a, 200 mg, 0.52 mmol, 1 eq) and 2-bromo-5-chloroaniline (44-b, 108 mg, 0.52 mmol, 1 eq) were dissolved in THF (4 mL), to which Na₂CO₃ (132 mg, 1.58 mmol, 3 eq), Pd(dppf)Cl₂ (36 mg, 0.05 mmol, 0.1 eq), and water (1 mL) were added in order. After heating under reflux for 6 hours, the mixture was cooled to room temperature, and the solid was removed by filtration. The solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The product 44-c (50 mg, 28.7%) was purified by column chromatography (PE:EA, 15:1-5:1) to obtain a yellow solid. LCMS: 335.15 [M+H] + .

[0141] 2) 8-Chloro-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-5(1H)-one(44-d) At room temperature, 1 mL of TFA was added to a 2 mL solution of 44-c (50 mg, 0.15 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded a white solid product 44-d (35 mg, 99.4%). LC-MS: 235.10 [M+H] + .

[0142] 3)(R)-8-chloro-3-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-5(1H)-one(44) At room temperature, 44-d (35 mg, 0.15 mmol, 1.2 eq) and I01 (36 mg, 0.12 mmol, 1 eq) were dissolved in THF (4 mL), to which DIEPA (48 mg, 0.38 mmol, 3 eq) and water (1 mL) were added. After stirring at 65 °C for 3 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded a white solid product 44 (35.7 mg, 48.9%). LCMS: 486.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.6, 2.2 Hz, 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, 8.0 Hz, 1H), 2.91 (d, J = 21.6 Hz, 3H), 2.41 - 2.25 (m, 3H), 2.19 (s, 2H), 1.77 (d, J = 22.0 Hz, 2H).

[0143] The following compounds were synthesized by a similar method. [Table 5]

[0144] Example 14 Synthesis of Compound 45 [ka] 1) 8-Chloro-6-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(45-a) At 0°C, NaH (10 mg, 0.02 mmol, 0.1 eq) was added to a solution of 44-c (50 mg, 0.14 mmol, 1 eq) in DMF (4 mL), and 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, 15:1-3:1) yielded the yellow solid product 45-a (45 mg, 91.8%). LCMS: 349.15 [M+H] + .

[0145] 2) 8-Chloro-6-methyl-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-5(1H)-one(45-b) At room temperature, 1 mL of TFA was added to a 2 mL solution of 45-a (36 mg, 0.11 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded the white solid product 45-b (25.7 mg, 89.3%). LC-MS: 249.10 [M+H] + .

[0146] 3)(R)-8-chloro-3-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-6-methyl-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-5(1H)-one(45) At room temperature, DIEPA (31 mg, 0.30 mmol, 3 eq) and water (1 mL) were added 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). After stirring at 65 °C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 45 (19.7 mg, 39.4%) as a white solid. LCMS: 500.25 [M+H] + . 1 1H NMR (399 MHz, DMSO-d 6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.6, 2.0 Hz, 1H), 4.65 (s, 2H), 4.03 (s, 2H), 3.82 - 3.67 (m, 4H), 3.46 (dt, J = 15.9, 7.8 Hz, 2H), 3.20 (dd, J = 14.0, 8.0 Hz, 1H), 3.04 - 2.85 (m, 4H), 2.46 - 2.27 (m, 4H), 2.18 (s, 2H), 1.79 (dd, J = 19.6, 10.3 Hz, 2H).

[0147] Example 15 Synthesis of Compound 48 [ka] 1) 1,2,3,4-Tetrahydroisoquinoline-6,7-diol (48-a) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.01 g, 10.36 mmol, 1.0 eq) was mixed in HBr (22.5 mL, 40% in H2O) and CH3COOH (100 mL) and stirred at 120°C for 8 hours. The mixture was cooled to room temperature and concentrated. Purification by column chromatography (100% siRNA) yielded product 48-a (2.21 g, 86.3%) as a white solid. LCMS: 166.10 [M+H] + .

[0148] 6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl(48-b) At room temperature, triethylamine (4.52 g, 44.72 mmol, 5.0 eq) was added to a 30 mL DCM solution of 48-a (2.21 g, 8.94 mmol, 1.0 eq) and Boc2O (1.95 g, 8.94 mmol, 1.0 eq). After stirring at room temperature for 16 hours, the solution was concentrated. Purification by column chromatography (siRNA / hexane = 50:50) yielded the white solid product 48-b (1.81 g, 75.89%). LCMS: 210.15 [M-56+H] + .

[0149] 5) 2-Thioxo-7,8-dihydro-[1,3]dioxo[4,5-g]isoquinoline-6(5H)-carboxylate tert-butyl(48-c) At 0°C, thiophosgene (0.57 mL, 7.55 mmol, 2.0 eq) was added dropwise 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). After stirring at room temperature for 16 hours, the solution was concentrated. Purification by column chromatography (Âxy / hexane = 50:50) yielded the white solid product 48-c (870 mg, 75.1%). LCMS: 251.90 [M-56+H] + .

[0150] 2,2-Difluoro-7,8-dihydro-[1,3]dioxacyclo[4,5-g]isoquinoline-6(5H)-carboxylate tert-butyl(48-d) At -40°C, pyridine hydrogen fluoride (70% wt HF, 643 mg, 6.51 mmol, 10 eq) was added to a solution of 48-c (200 mg, 0.65 mmol, 1.0 eq) in DCM (4 mL). Then, N-iodosuccinimide (438 mg, 1.95 mmol, 3.0 eq) was added in batches. The reaction mixture was raised to 0°C within 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). It was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (Â / hexane = 3:1) yielded the white solid product 48-d (60 mg, 29.4%). LCMS: 258.05 [M-56+H] + .

[0151] 6) 2,2-difluoro-5,6,7,8-tetrahydro-[1,3]dioxacyclo[4,5-g]isoquinoline(48-e) At room temperature, 0.25 mL of TFA was added dropwise to a 1 mL solution of 48-d (20 mg, 0.064 mmol, 1.0 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain the white solid product 48-e (20 mg, 95.7%). This crude product was used directly in the next step without purification. LC-MS: 214.10 [M+H] + .

[0152] 7)(R)-2-(2,2-difluoro-7,8-dihydro-[1,3]dioxacyclo[4,5-g]isoquinoline-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(48) At room temperature, DIEPA (24 mg, 0.18 mmol, 3.0 eq) and water (0.25 mL) were added to a THF (1 mL) solution of 48-e (20 mg, 0.061 mmol, 1.0 eq) and I01 (16 mg, 0.055 mmol, 0.9 eq). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded a white solid product 48 (18.06 mg, 63.8%). LCMS: 465.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (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, 8.3 Hz, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.88 (d, J = 6.8 Hz, 1H), 2.83 (s, 2H), 2.34 - 2.18 (m, 4H), 1.82 - 1.69 (m, 2H).

[0153] Example 16 Synthesis of Compound 49 [ka] 1) 2,2,2-trifluoro-1-(7-hydroxy-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one(49-a) 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one (50-e, 500 mg, 1.65 mol, 1.0 eq) was dissolved in DCM (5 mL) and TfOH (5 mL) and stirred at 70°C for 1 hour, then concentrated. 100 mL of  (amethyst) 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 ( / hexane = 1:1) yielded the white solid product 49-a (420 mg, 88%). LCMS: 291.05 [M+H] +.

[0154] 2) 1-(6-amino-7-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one(49-b) At room temperature, Pd / C (10% wt., 40 mg) was added to a solution of 49-a (400 mg, 1.37 mol, 1.0 eq) in EtOH (100 mL). After hydrogen absorption at room temperature for 16 hours, the solid was removed by filtration, and the solution was concentrated to obtain the white solid product 49-b (290 mg, 80.8%). LC-MS: 261.10 [M+H] + .

[0155] 3) 1-(7,8-dihydrooxazolo[4,5-g]isoquinoline-6(5H)-yl)-2,2,2-trifluoroethane-1-one(49-c) At room temperature, triethyl orthoformate (680.4 mg, 4.59 mol, 6.0 eq) and TsOH (4 mg, 0.076 mmol, 0.1 eq) were added to a solution of 49-b (200 mg, 0.76 mmol, 1.0 eq) in EtOH (10 mL). After stirring at 80 °C for 2 hours, the mixture was cooled to 0 °C and H2O (50 mL) was added. The solution was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (siRNA / hexane = 1:1) yielded the white solid product 49-c (180 mg, 86.6%). LCMS: 271.10 [M+H] + .

[0156] 4) 5,6,7,8-Tetrahydrooxazolo[4,5-g]isoquinoline(49-d) At room temperature, K2CO3 (46 mg, 0.33 mmol, 3.0 eq) was added to a solution of 49-c (30 mg, 0.11 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL). After stirring at 90 °C for 2 hours, the mixture was cooled to room temperature, saturated NaHCO3 (30 mL) solution was added, and the solution was extracted with ethyl acetate (15 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (petroleum ether:ethyl acetate = 1:3) yielded the white solid product 49-d (19 mg, 98.2%). LCMS: 175.10 [M+H] + .

[0157] 5)(R)-2-(7,8-dihydrooxazolo[4,5-g]isoquinoline-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(49) At room temperature, DIEPA (92.88 mg, 0.72 mmol, 3 eq) was added 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). After heating under reflux for 48 hours, the solution was concentrated. Purification by pre-TLC (SiO2, dichloromethane:methanol = 15:1) yielded product 49 (2.24 mg, 2.2%) as a white solid. LCMS: 416.20 [M+H] + . 1 H NMR (400MHz, methanol-d4)δ 8.41(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 = 9.4 Hz, 4H), 1.92 (s, 2H).

[0158] Example 17 Synthesis of Compound 50 [ka] 1) Methyl (4-methoxyphenethyl)carbamate (50-a) At -40°C, 2-(4-methoxyphenyl)ethane-1-amine (30 g, 0.2 mol, 1 eq) was added to a 400 mL solution of DCM with K2CO3 (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 NaHCO3 (300 mL) solution was added. The solution was extracted with DCM (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:Â at 10:1 to 1:1) yielded product 50-a (72.2 g) as a white solid. LCMS: 210.15 [M+H] + .

[0159] 2) 6-Methoxy-3,4-dihydroisoquinoline-1(2H)-one(50-b) A solution of 50a (10 g, 0.04 mol, 1.0 eq) in PPA (60 mL) was stirred at 120 °C for 1 hour, then cooled to room temperature. A saturated Na₂CO₃ (300 mL) solution was slowly added, and the mixture was extracted with ethyl acetate (150 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. The solution was purified by column chromatography (PE:Â at 10:1 to 3:1) to obtain the white solid product 50-b (2.0 g, 23.6%). LCMS: 178.10 [M+H] + .

[0160] 3) 6-Methoxy-1,2,3,4-tetrahydroisoquinoline(50-c) At -40°C, LiAlH4 (0.39 g, 10.16 mmol, 1.2 eq) was added to a solution of 50-b (1.5 g, 8.47 mmol, 1 eq) in THF (10 mL). After stirring at 70°C for 2 hours, the mixture was cooled to room temperature and H2O (30 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:siRNA 10:1~3:1) yielded the white solid product 50-c (1 g, 72.4%). LCMS: 164.10 [M+H] + .

[0161] 4) 2,2,2-trifluoro-1-(7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one(50-d) At 0°C, TEA (5.1g, 24.29 mmol, 3.0eq) and TFAA (5.1g, 24.29 mmol, 1.2eq) were added sequentially to a 40mL solution of 50-c (3.3g, 20.24 mmol, 1.0eq) in dimethyl chlorine (DCM). After stirring at room temperature for 3 hours, water (100mL) was added. Extraction was performed with DCM (50mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, PE:siRNA=10:1) yielded the white solid product 50-d (3.5g, 66.7%). LCMS: 260.10 [M+H] + .

[0162] 5) 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one(50-e) At 0°C, 217 mg (3.44 mmol, 1.1 eq) of 50-d (810 mg, 3.1 mmol, 1.0 eq) was added dropwise to a 10 mL TFA solution, and the mixture was stirred for 3 hours. Then, a 100 mL saturated NaHCO3 solution 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:HCl = 1:1) yielded the yellow solid product 50-e (720 mg, 75.7%). LCMS: 305.10 [M+H] + .

[0163] 6) 7-Methoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline(50-f) At room temperature, 30 mg (0.1 mmol, 1.0 eq) of 50-e was dissolved in 4 mL of EtOH and 1 mL of H2O, to which 14 mg (0.3 mmol, 3.0 eq) of K2CO3 was added. After stirring at 90°C for 2 hours, the mixture was cooled to room temperature, and 20 mL of H2O was added. The solution was extracted with ethyl acetate (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (PE:Â=1:3) yielded a yellow solid product, 50-f (16 mg, 77.8%). LCMS: 209.10 [M+H] + .

[0164] 7)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(7-methoxy-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(50) At room temperature, DIEPA (92.88 mg, 0.72 mmol, 3.0 eq) was added 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). The solution was heated under reflux for 48 hours and concentrated. Purification by pre-TLC (SiO2, dichloromethane:methanol = 15:1) yielded product 50 (20.33 mg, 18.2%) as a white solid. LCMS: 460.25 [M+H] + . 1 H NMR (400MHz, methanol-d4)δ 7.65(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, 8.1 Hz, 1H), 3.35 (d, J = 13.9 Hz, 1H), 3.29 (s, 2H), 3.10 (s, 2H), 2.85 (s, 2H), 2.32 (s, 4H), 1.90 (s, 2H).

[0165] Example 18 Synthesis of Compound 51 [ka] 1) 6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(51-a) At room temperature, CDI (180 mg, 3.0 mmol, 3.0 eq) was added to a solution of 49-b (160 mg, 1.0 mol, 1.0 eq) in THF (5 mL), and the mixture was stirred for 2 hours. H2O (30 mL) was then added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:Â 15:1-5:1) yielded the white solid product 51-a (140 mg, 79.2%). LCMS: 287.10 [M+H] + .

[0166] 2) 5,6,7,8-Tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(51-b) At room temperature, K2CO3 (46 mg, 0.33 mmol, 3.0 eq) was added to a solution of 51-b (30 mg, 0.11 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL). After stirring at 90 °C for 2 hours, the mixture was cooled to room temperature and H2O (30 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (PE:Â=1:1) yielded a white solid product 51-b (19 mg, 98.2%). LCMS: 191.10 [M+H]+.

[0167] 3)(R)-6-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(51) At room temperature, DIPEA (92.88 mg, 0.72 mmol, 3.0 eq) was added 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). After heating under reflux for 48 hours, the solution was concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 15:1) yielded product 51 (45.41 mg, 39.2%) as a white solid. LCMS: 442.05 [M+H] + ¹H NMR (400 MHz, methanol-d4) δ values: 7.04 (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).

[0168] Example 19 Synthesis of Compound 53 [ka] 1) 2-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine(53-b) At room temperature, liquid bromine (63.1 mg, 0.39 mmol, 1.1 eq.) was added to a solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrogen chloride (50 mg, 0.36 mmol, 1 eq.) in HOAc (2 mL). After stirring for 1.5 hours, the mixture was filtered, washed with ethanol (10 mL x 3), and dried to obtain product 53-b (50 mg, 63%) as a yellow solid. LCMS: [M+H + ] = 218.10

[0169] 2)(R)-2-(2-bromo-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(53) At room temperature, DIEPA (40.4 mg, 0.31 mmol, 3 eq) was added to THF (2 mL) / H2O (0.5 mL) solutions of I01 (30 mg, 0.10 mmol, 1 eq) and 53-b (34.1 mg, 0.15 mmol, 1.5 equiv.). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (ACN / H2O with 0.1% TFA) yielded product 53 (27.84 mg, 42%) as a white solid. LCMS: [M+2] + = 470.45. 1 HNMR: 1 H NMR (399 MHz, DMSO-d6) δ 7.77 (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).

[0170] Example 20 Synthesis of Compound 54 [ka] 1) 2,3-dibromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine(54-a) At room temperature, liquid bromine (126.2 mg, 0.79 mmol, 2.2 equiv.) was added to a solution of 3-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (500 mg, 3.59 mmol, 1 eq) in HOAc (20 mL). The mixture was stirred at 80 °C for 16 hours and then cooled to room temperature. The solution was filtered, and the filter cake was washed with ethanol (20 mL x 3). The filtrate was concentrated to obtain product 54-a (1.0 g, 93%) as a yellow solid. The crude product was used directly in the next step without purification. LCMS: [M+H] + = 297.75

[0171] 2) 3-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine(54-b) At room temperature, zinc powder (110 mg, 1.7 mmol, 5 equiv.) was added to a solution of 54-a (100 mg, 0.33 mmol, 1 equiv.) in HOAc (2 mL) and H2O (2 mL). The mixture was stirred at 60 °C for 16 hours and then cooled to room temperature. The solid was removed by filtration and washed with ethyl acetate (15 mL). Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). It was dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (DCM:MeOH = 10:1) yielded a yellow, oily product 54-b (20 mg, 27%). LCMS: [M+H] + = 219.90.

[0172] 3)(R)-2-(3-bromo-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(54) At room temperature, DIPEA (32.3 mg, 0.25 mmol, 3 equiv.) was added 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). After stirring at 65 °C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 54 (37.2 mg, 95%) as a white solid. LCMS: [M+1] + = 470.80. 1 1H NMR: 1 H NMR (399 MHz, DMSO-d6) δ 7.73 (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).

[0173] Example 21 Synthesis of Compound 56 [ka] 1) 2-iodo-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate tert-butyl(56-b) At -20°C, 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate tert-butyl (56-a, 200 mg, 0.84 mmol, 1 eq) was dissolved in THF (5 mL), to which N-iodosuccinimide (376 mg, 1.67 mmol, 2 eq) was added. After stirring for 2 hours, water (10 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA 15:1~3:1) yielded a yellow oily product 56-b (100 mg, 32.8%). LCMS: 366.10 [M+H] + .

[0174] 2) 2-iodo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(56-c) At room temperature, 1 mL of TFA was added to a solution of 56-b (100 mg, 0.27 mmol, 1 eq) in DCM (4 mL). After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 56-c (50 mg, 68.9%). This crude product was used directly in the next step without purification. LC-MS: 266.15 [M+H] + .

[0175] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-iodo-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-6,7-dihydrothieno[2,2-d]pyrimidine 5-oxide(56) At room temperature, DIEPA (67.37 mg, 0.51 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 56 (16.5 mg, 18.4%) as a white solid. LCMS: 517.20 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 7.76 (s, 1H), 7.15 (s, 1H), 4.72 (s, 2H), 3.98 (s, 2H), 3.69 (t, J = 2.1 Hz, 2H), 3.41 (dd, J = 17.2, 8.3 Hz, 1H), 3.18 (dd, J = 14.4, 7.6 Hz, 1H), 2.96 (dd, J = 17.2, 8.0 Hz, 1H), 2.86 (dd, J = 13.5, 7.1 Hz, 1H), 2.76 (s, 2H), 2.33 - 2.23 (m, 2H), 2.17 (m, 2H), 1.78 - 1.68 (m, 2H).

[0176] Example 22 Synthesis of Compound 57 [ka] 1) 2,3-dibromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(57-a) At 0°C, liquid bromine (267.10 mg, 1.6713 mmol, 2.0 eq) was added dropwise to a solution of 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate tert-butyl (56-a, 200 mg, 0.8357 mmol, 1.0 eq) in CHCl3 (5 mL). After stirring at 60°C for 3 hours, the mixture was cooled to room temperature and water (20 mL) was added. Extraction was performed using DCM (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, PE:Â=1:1) yielded product 57-a (180 mg, 87.6%) as a yellow solid. LCMS: 296.05 [M+H] + .

[0177] 2) 3-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(57-b) At room temperature, Zn (66.05 mg, 1.0101 mmol, 2.0 eq) and TFA (172.76 mg, 1.5151 mmol, 3.0 eq) were added sequentially to a solution of 57-a (150.00 mg, 0.5051 mmol, 1.0 eq) in HOAc (2 mL) and H2O (2 mL). The mixture was stirred at 60°C for 16 hours and then cooled to room temperature. Water (20 mL) was added. The solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Pre-TLC (SiO2, PE:Â=1:1) (PE:EA 15:1~3:1) yielded the yellow solid product 57-b (80 mg, 67%). LCMS: 218.10 [M+H] + .

[0178] 3)(R)-2-(3-bromo-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[2,2-d]pyrimidine 5-oxide(57) At room temperature, DIPEA (107.70 mg, 0.8333 mmol, 3.0 eq) was added to a THF / H2O (4 mL:1 mL) solution of I01 (80 mg, 0.2777 mmol, 1.0 eq) and 57-b (90.83 mg, 0.4166 mmol, 1.5 eq). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 57 (28.5 mg, 60.3%) as a white solid. LCMS: 469.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (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, 7.8 Hz, 1H), 3.20 (dt, J = 15.1, 8.1 Hz, 1H), 2.98 (dd, J = 17.3, 8.2 Hz, 2H), 2.87 (dd, J = 13.7, 7.2 Hz, 3H), 2.83 (s, 2H), 2.47 (d, J = 9.9 Hz, 1H), 2.36- 2.17 (m, 2H), 1.74 (m, 2H).

[0179] Example 23 Synthesis of Compound 60 [ka] 5-Cyanoizoindoline-2-carboxylate tert-butyl(60-b) At room temperature, Zn(CN)2 (158 mg, 1.34 mmol, 2 eq) and Pd(PPh3)4 (155 mg, 0.13 mmol, 0.2 eq) were sequentially added to a solution of 5-bromoisoindoline-2-carboxylate tert-butyl (60-a, 200 mg, 0.67 mmol, 1 eq) in DMF (5 mL). After stirring at 80°C for 3 hours, the mixture was cooled to room temperature and water (10 mL) was added. The solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (SiO2, PE:Â=10:1) yielded the white solid product 60-b (80 mg, 48.82%). LCMS: 245.25 [M+H] + .

[0180] 2) Isoindoline-5-carbonitrili(60-c) At room temperature, 1 mL of TFA was added to a 4 mL solution of 60-b (80 mg, 0.33 mmol, 1 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 60-c (40.00 mg, 84.7%). This crude product was used directly in the next step without purification. LC-MS: 145.30 [M+H] + .

[0181] 3)(R)-2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carbonitrile(60) At room temperature, DIEPA (55 mg, 0.42 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 60 (47.5 mg, 86.3%) as a white solid. LCMS: 396.30 [M+H] + . 1H NMR (400 MHz, DMSO- d6) δ 8.10 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (m, J = 17.8, 7.9 Hz, 1H), 4.84 (t, J = 12.5 Hz, 4H), 3.77 (s, 2H), 3.56 - 3.46 (m, 1H), 3.26 (dt, J = 13.6, 8.2 Hz, 1H), 3.08 (d, J = 16.2 Hz, 1H), 2.93 (dd, J = 13.8, 7.2Hz, 1H), 2.36 - 2.20 (m, 4H), 1.82 - 1.70 (m, 2H).

[0182] Example 24 Synthesis of Compound 64 [ka] 1) 2-(azetidine-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate tert-butyl(64a) At room temperature, 2-bromo-6,7-dihydrothiazolo[5,4]pyridine-5(4H)-carboxylate tert-butyl (500 mg, 1.57 mmol, 1.0 eq) and azetidine (179.3 mg, 3.14 mmol, 2.0 eq) were dissolved in tert-butanol (5 mL), to which Na₂CO₃ (499.3 mg, 4.71 mmol, 3.0 eq) was added. After stirring under reflux 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 Na₂SO₄, filtered, and concentrated. Purification by pre-TLC (SiO₂, PE:siRNA = 3:1) yielded product 64-a (280 mg, 76.2%) as a white solid. LCMS: 296.15 [M+H] + .

[0183] 2) 2-(azetidine-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(64-b) At room temperature, 1 mL of TFA was added to a 4 mL solution of 64-a (200 mg, 0.6770 mmol, 1.0 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain the white solid product 64-b (150.5 mg, 80.5%). LC-MS: 196.10 [M+H] + .

[0184] 3)(R)-2-(2-(azetidine-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7dihydrothieno[3,2-d]pyrimidine 5-oxide(64) At room temperature, DIPEA (107.70 mg, 0.8333 mmol, 3.0 eq) was added to a THF / H2O (4 mL:1 mL) solution of I01 (80.00 mg, 0.2777 mmol, 1.0 eq) and 64-b (81.67 mg, 0.4166 mmol, 1.5 eq). The mixture was stirred at 65°C for 4 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 64 (30.8 mg, 76.5%) as a white solid. LCMS: 447.30 [M+H] + . 1 H NMR (400MHz, methanol-d4)δ 4.33(t, J=7.7 Hz, 4H), 4.12 (s, 2H), 3.96 - 3.86 (t, 3H), 3.60 (dt, J = 16.9, 8.0 Hz, 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).

[0185] Example 25 Synthesis of Compound 65 [ka] 1) 6-(thiazole-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl(65-b) At room temperature, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (65-a, 50 mg, 0.14 mmol, 1 eq), 2-bromothiazole (22.8 mg, 0.14 mmol, 1 eq), and Cs2CO3 (136 mg, 0.42 mmol, 3 eq) were dissolved in H2O (1 mL) / 1,4-dioxane (4 mL) and Pd(dppf)Cl2 (10.00 mg, 0.02 mmol, 0.1 eq) was added. After stirring at 100 °C for 16 hours, the mixture was cooled to room temperature, the solid was removed by filtration, and water (20 mL) was added. The solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product 65-b (40 mg, 90.9%) was purified by column chromatography (PE:EA ratio 10:1-4:1) to obtain a yellow solid. LCMS: 317.15 [M+H] + .

[0186] 2) 2-(1,2,3,4-tetrahydroisoquinoline-6-yl)thiazole(65-c) At room temperature, 1 mL of TFA was added to a 2 mL solution of 65-b (40 mg, 0.13 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded a white solid product 65-c (25 mg, 89.3%). LC-MS: 217.10 [M+H] + .

[0187] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(thiazole-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(65) At room temperature, DIEPA (50 mg, 0.39 mmol, 3 eq) and water (1 mL) were added 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). The mixture was stirred at 65°C for 3 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded a white solid product 65 (34.6 mg, 55.7%). LCMS: 468.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 3.2 Hz, 1H), 7.78 - 7.72 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 4.88 (s, 3H), 3.95 (t, J = 6.0 Hz, 2H), 3.73 (d, J = 2.1 Hz, 2H), 3.45 (d, J = 8.5 Hz, 1H), 3.26 - 3.16 (m, 1H), 3.05 (s, 1H), 2.92 (d, J = 6.3 Hz, 4H), 2.39 - 2.26 (m, 2H), 2.21 (s, 2H), 1.84 - 1.70 (m, 2H).

[0188] Example 26 Synthesis of Compound 66 [ka] 1) 6-Cyclopropyl-3,4-Dihydroisoquinoline-2(1H)-carboxylate tert-butyl(66-b) At room temperature, a mixture of 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (66-a, 500 mg, 1.60 mmol, 1 eq), cyclopropylboronic 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) was mixed with 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 removed by filtration, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product 66-b (200 mg, 45.6%) was purified by column chromatography (PE:EA ratio 15:1-5:1) to obtain a yellow solid. LCMS: 274.38 [M+H] + .

[0189] 2) 6-Cyclopropyl-1,2,3,4-Tetrahydroisoquinoline(66-c) At room temperature, 1 mL of TFA was added to a 2 mL solution of 66-b (200 mg, 0.73 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded the white solid product 66-c (100 mg, 78.74%). LC-MS: 174.26 [M+H] + .

[0190] 3)(R)-2-(6-cyclopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(66) At room temperature, DIEPA (112.00 mg, 0.93 mmol, 3.0 eq) and water (1 mL) were added 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded a white solid product 66 (69.9 mg, 35.9%). LCMS: 425.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.87 (dd, J = 10.5, 2.4 Hz, 2H), 4.76 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.72 (s, 2H), 3.49 (dd, J = 17.1, 8.3 Hz, 1H), 3.24 (dt, J = 13.4, 8.2 Hz, 1H), 3.08 (dd, J = 17.5, 8.1 Hz, 1H), 2.92 (dd, J = 13.8, 7.1 Hz, 1H), 2.80 (d, J = 6.1 Hz, 2H), 2.37 - 2.24 (m, 2H), 2.21 (d, J = 11.7 Hz, 2H), 1.85 - 1.69 (m, 3H), 0.86 (dt, J = 8.5, 3.1 Hz, 2H), 0.64 - 0.54 (m, 2H).

[0191] Example 27 Synthesis of Compound 68 [ka] 1) Methyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(68-a) At room temperature, Cs2CO3 (114 mg, 0.84 mmol, 3.0 eq) and CH3I (1 mL) were added to a solution of 51-a (80 mg, 0.28 mol, 1.0 eq) in DMF (5 mL). After stirring at 50 °C for 2 hours, the mixture was cooled to room temperature and H2O (30 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:Â=5:1) yielded the white solid product 68-a (60 mg, 71.2%). LCMS: 301.10 [M+H] + .

[0192] 2) 1-Methyl-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(68-b) At room temperature, K2CO3 (41 mg, 0.3 mmol, 3.0 eq) was added to a solution of 68-a (30 mg, 0.1 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL). After stirring at 90 °C for 2 hours, the mixture was cooled to room temperature and H2O (30 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (PE:Â=1:1) yielded the white solid product 68-b (19 mg, 92.9%). LCMS: 205.10 [M+H]+.

[0193] 3)(R)-6-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-1-methyl-5,6,7,8-tetrahydrooxazolo[4,5-g]isoquinoline-2(1H)-one(68) At room temperature, DIPEA (92.88 mg, 0.72 mmol, 3.0 eq) was added to a 5 mL IPA solution of 68-b (50.00 mg, 0.24 mmol, 1.0 eq) and I01 (70.0 mg, 0.24 mmol, 1.0 eq). After 48 hours, the solution was heated under reflux and then concentrated. Purification by pre-TLC (SiO2, DCM:MeOH = 15:1) yielded the white solid product 68 (44.2 mg, 39.6%). LCMS: 456.50 [M+H] +. 1 H NMR (400MHz, methanol-d4)δ 7.13(s, 1H), 7.04 (s, 1H), 3.95 (d, J = 14.5 Hz, 4H), 3.71 (s, 1H), 3.48 (s, 1H), 3.36 (s, 3H), 3.32 (dd, J = 8.4, 1.6 Hz, 1H), 3.28 (s, 2H), 3.17 (ddd, J = 13.9, 7.4, 1.6 Hz, 1H), 3.04 (d, J = 6.6 Hz, 2H), 2.36 (s, 4H), 1.92 (s, 2H).

[0194] Example 28 Synthesis of Compound 69 [ka] 1) 4-((4-fluorophenyl)thio)-3-acetateethyl(69-a) At 0°C, triethylamine (12 g, 117.18 mmol, 1.5 eq) was added dropwise to a 400 mL solution of 4-fluorothiophenol (10 g, 78.12 mmol, 1.0 eq) and 4-chloro-3-acetoethyl acetate (13 g, 78.12 mmol) in dimethylcellulose (DCM). After stirring for 2 hours, the mixture was injected into 300 mL of water. Extraction was performed with 3 x 200 mL DCM solutions, dried over anhydrous sodium 2SO4, filtered, and concentrated. Purification by column chromatography (hexane / siRNA = 10:1) yielded a yellow, oily product 69-a (18 g, 90%). LCMS: 257.10 [M+H] + .

[0195] 2) 2-(5-fluorobenzo[b]thiophen-3-yl)ethyl acetate (69-b) At 100°C, a solution of 69-a (5 g, 19.51 mmol, 1.0 eq) in toluene (5 mL) was added to a solution of PPA (21.6 g) in toluene (20 mL). After stirring for 16 hours, the mixture was cooled to room temperature, poured into ice water (100 mL), and the pH was adjusted to pH-8 by adding K2CO3. The solution was extracted with ethyl acetate (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:siRNA=10:1) yielded the yellow oily product 69-b (2.21 g, 47.5%). LCMS: 239.10 [M+H] + .

[0196] 3) 2-(5-fluorobenzo[b]thiophen-3-yl)acetamide(69-c) At room temperature, a solution of 69-b (2.21 g, 9.27 mmol, 1.0 eq) and ammonia in MeOH (7 M, 40 mL, 278 mmol) was stirred for 3 days and then concentrated. Purification by column chromatography (DCM / MeOH = 10:1) yielded the white solid product 69-c (1.4 g, 72.1%). LCMS: 210.05 [M+H] + .

[0197] 4) 2-(5-fluorobenzo[b]thiophen-3-yl)ethane-1-amine(69-d) At room temperature, 1 M borane / Me2S complex in THF (5.64 mL, 5.64 mmol, 2.5 eq) was added dropwise to a solution of 69-c (500 mg, 2.26 mmol, 1.0 eq) in THF (10 mL). The mixture was stirred at 50 °C for 16 hours, then cooled to 0 °C. Methanol (20 mL) was slowly added dropwise, followed by reflux for 3 hours. The mixture was cooled to room temperature and concentrated. 2N NaOH (15 mL) was added, and the solution was extracted with ethyl acetate (100 mL x 3). It was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (DCM / MeOH = 20:1) yielded a colorless oily product, 69-d (130 mg, 27.8%). LCMS: 196.10 [M+H] + .

[0198] 2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate (69-e) At 0°C, ethyl chloroformate (61 mg, 0.56 mmol, 1.1 eq) was added dropwise 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). 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). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (hexane / ethyl acetate = 10:1) yielded a colorless oily product 69-e (109 mg, 79.6%). LCMS: 268.10 [M+H] + .

[0199] 8) 6-Fluoro-3,4-dihydrobenzo[4,5]thieno[2,3-c]pyridine-2(1H)-ethyl(69-f)carboxylate 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) were refluxed at 115°C for 2 hours. The mixture was cooled to room temperature and concentrated. Purification by pre-TLC (hexane / ethyl acetate = 10:1) yielded a colorless oily product, 69-f (70 mg, 67%). LC-MS: 280.10 [M+H] + .

[0200] 9) 6-Fluoro-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine(69-g) At room temperature, NaOH (36 mg, 0.89 mmol, 5.0 eq) was added to a solution of 69-f (50 mg, 0.18 mmol, 1.0 eq) in methanol (2 mL) and water (0.5 mL). The mixture was stirred at 80°C for 16 hours, cooled to room temperature, and concentrated. Purification by pre-HPLC (5%-95% water / 0.1% TFA in ACN) yielded a white solid product, 69-g (20 mg, 18.3%). LCMS: 208.10 [M+H] + .

[0201] 10)(R)-2-(6-fluoro-3,4-dihydrobenzo[4,5]thieno[2,3-c]pyridine-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(69) At room temperature, DIEPA (37 mg, 0.29 mmol, 3.0 eq) and water (0.25 mL) were added 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). The mixture was stirred at 65°C for 16 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded a yellow solid product 69 (37.24 mg, 83.8%). LC-MS: 459.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J = 8.8, 4.9 Hz, 1H), 7.48 (dd, J = 9.9, 2.5 Hz, 1H), 7.17 (td, J = 8.9, 2.5 Hz, 1H), 5.03 (s, 2H), 4.10 (s, 3H), 3.72 (s, 2H), 3.43 (dt, J = 17.1, 8.1 Hz, 1H), 3.19 (dt, J = 15.1, 8.3 Hz, 1H), 3.00 - 2.91 (m, 1H), 2.89 - 2.84 (m, 1H), 2.81 (s, 2H), 2.32 (d, J = 24.7 Hz, 2H), 2.24 - 2.17 (m, 2H), 1.78 (d, J = 9.0 Hz, 2H).

[0202] Example 29 Synthesis of Compound 70 [ka] 1) (S)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylic acid (70-a) At room temperature, paraformaldehyde (1052.2 mg, 35.04 mmol, 6.0 equiv.) was added to a 30 ml HOAc solution of thiophene-2-yl-L-alanine (1 g, 5.84 mmol, 1.0 equiv.). The mixture was stirred at 70°C for 2 hours, cooled to room temperature, and saturated NaHCO3 (20 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (DCM / MeOH = 20:1) yielded a colorless solid product 70-a (300 mg, 28%). LCMS: 184.05 [M+H] + .

[0203] 3) Methyl(S)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylate(70-b) At 0°C, SOCl2 (194.8 mg, 1.64 mmol, 3 equiv.) was added to a solution of 70-a (100 mg, 0.55 mmol, 1 equiv.) in MeOH (2 ml). The mixture was stirred at 60°C for 5 hours and concentrated to obtain the yellow solid product 70-b (100 mg, 92.9%). This crude product was used directly in the next step without purification. LCMS: 198.05 [M+H] + .

[0204] 4) (S)-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-yl)methanol(70-c) At 0°C, LiAlH4 (0.052 ml, 1.52 mmol, 3.0 equiv.) was added to a solution of 70-b (100 mg, 0.51 mmol, 1.0 equiv.) in THF (2 mL), and the mixture was stirred for 5 hours. Water (2 mL) was then added and the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded the yellow solid product 70-c (40 mg, 0.24 mmol, 46.6%). LCMS: 170.10 [M+H] + .

[0205] 5)(R)-2-((S)-6-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(70) At room temperature, DIEPA (89.82 mg, 0.70 mmol, 20 equiv.) was added to solutions 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). After stirring at 65°C for 12 hours, the solution was concentrated. Purification by pre-TLC (MeOH:DCM=1:10) (0.1% TFA in ACN / H2O) yielded product 70 (2.30 mg, 17.16%) as a white solid. LCMS: 421.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.24 (m, 2H), 6.90 (d, J = 5.0 Hz, 1H), 5.32 (d, J = 18.0 Hz, 1H), 5.20 (s, 1H), 4.80 (s, 2H), 4.07 (d, J = 17.3 Hz, 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).

[0206] Example 30 Synthesis of Compound 71 [ka] 1) 5-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-ol(71-b) 1-benzyl-4-piperidone-3-carboxylate methyl hydrochloride (71-a, 2 g, 6.72 mmol, 1 eq) and methylhydrazine sulfate (4.85 g, 33.58 mmol, 5 eq) were stirred in EtOH (20 mL) at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded the yellow oily product 71-b (1.8 g, 91.5%). LC-MS: 244.30 [M+H] + .

[0207] 2) 5-benzyl-3-chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(71-c) 71-b (1.8 g, 7.39 mmol, 1 eq) was dissolved in POCl3 (20 mL) and then stirred at 150°C for 3 hours. The mixture was cooled to room temperature and concentrated. 50 mL of 1N NaOH (aqueous solution) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). It was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (DCM:MeOH=20:1) yielded a yellow, oily product 71-c (110 mg, 5.7%). LCMS: 262.25 [M+H] + .

[0208] 3) 3-Chloro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(71-d) At 0°C, 1-chloroethyl chloroformate (120 mg, 0.84 mmol, 2 eqs) was added to a solution of 71-c (110 mg, 0.42 mmol, 1 eq) in DCM (5 mL). After stirring at room temperature for 2 hours, the mixture was concentrated. Then, MeOH (5 mL) was added. After stirring at 65°C for 16 hours, the mixture was concentrated to obtain the yellow solid product 71-d (50 mg, 69.3%). This crude product was used directly in the next step without purification. LCMS: 172.25 [M+H] + .

[0209] 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) At room temperature, DIEPA (66 mg, 0.51 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 71 (41.9 mg, 57%) as a yellow solid. LCMS: 423.20 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 4.64 (s, 2H), 3.96 (d, J = 7.0 Hz, 2H), 3.69 (s, 3H), 3.66 (s, 2H), 3.42 (dt, J = 16.5, 7.7 Hz, 2H), 3.26 - 3.08 (m, 2H), 2.99 - 2.84 (m, 2H), 2.61 (m, J = 6.0 Hz, 2H), 2.35 - 2.24 (m, 2H), 2.14 (m, 2H), 1.75 (q, J = 9.1 Hz, 2H).

[0210] Example 31 Synthesis of Compound 72 [ka] 1) 8-Chloro-5-((trifluoromethyl)sulfonyl)oxy)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(72-a) At 0°C, pyridine (1169.50 mg, 14.79 mmol, 15 equiv.) and Tf2O (834.29 mg, 2.96 mmol, 3 equiv.) were sequentially added to a 10 ml DCM solution of 44-c (330 mg, 0.99 mmol, 1 equiv.). After stirring at room temperature for 16 hours, a saturated NH4Cl solution (20 mL) was added. Extraction was performed using 3 x 20 mL DCM solutions, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:siRNA 20:1-5:1) yielded the yellow solid product 72-a (300 mg, 65.2%). LCMS: 467.10 [M+H] + .

[0211] 2) 8-Chloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(72-b) At room temperature, 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.) were sequentially added to a solution of 72-a (40 mg, 0.086 mmol, 1 equiv.) in THF (2 ml). After stirring at 50°C for 5 hours, the solid was removed by filtration. The filtrate was concentrated and purified by column chromatography (PE:SiO 20:1-5:1) to obtain the yellow solid product 72-b (20 mg, 73.2%). LCMS: 319.15 [M+H] + .

[0212] 3) 8-Chloro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyrizine(72-c) At 0°C, TFA (0.5 ml, 5.10 mmol, 65.04 equiv.) was added to a solution of 72-b (25 mg, 0.078 mmol, 1 equiv.) in DCM (1.5 ml). After stirring for 1 hour, the mixture was concentrated to obtain the white solid product 72-c (69.8 mg, 81.8%). This crude product was used directly in the next step without purification. LCMS: 219.10 [M+H] + .

[0213] 4)(R)-2-(8-chloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(72) At room temperature, DIEPA (67.37 mg, 0.52 mmol, 10 equiv.) was added to solutions 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). After stirring at 65°C for 12 hours, the solution was concentrated. Purification by pre-TLC (MeOH:DCM = 1:10) yielded product 72 (10 mg, 40.8%) as a yellow solid. LCMS: 470.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 8.80 (s, 1H), 8.10 - 7.99 (m, 2H), 7.63 (dd, J = 9.0, 2.3 Hz, 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 = 6.0 Hz, 2H), 2.94 (dd, J = 17.0, 8.3 Hz, 1H), 2.84 (dd, J = 13.8, 7.3 Hz, 1H), 2.30 (s, 1H), 2.21 (s, 2H), 1.84 - 1.72 (m, 2H).

[0214] Example 32 Synthesis of Compound 73 [ka] 1) 5,8-dichloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(73-a) A 1.5 ml 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-pentaoxacyclopentadecane (141.54 mg, 0.64 mmol, 10 equiv.) in DMF (1.5 ml) was stirred in a sealed tube at 100°C for 2 hours. The mixture was cooled to room temperature and concentrated. Purification by pre-TLC (PE:SiO=1:1) yielded the yellow solid product 73-a (15 mg, 66.1%). LCMS: 353.10 [M+H] + .

[0215] 2) 5,8-dichloro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyrizine(73-b) At 0°C, TFA (0.50 ml) was added to a solution of 73-a (15 mg, 0.042 mmol, 1 equiv.) in DCM (1.5 ml). After stirring for 1 hour, the mixture was concentrated to obtain the yellow solid product 72-b (69.8 mg, 81.8%). This crude product was used directly in the next step without purification. LCMS: 253.05 [M+H] + .

[0216] 3)(R)-2-(5,8-dichloro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(73) At room temperature, 73-b (10.00 mg, 0.040 mmol, 0.8 equiv.) and DIEPA (67.37 mg, 0.52 mmol, 10 equiv.) were added to a solution of I01 (15 mg, 0.052 mmol, 1 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 12 hours and then concentrated. Purification by pre-TLC (MeOH:DCM = 1:10) yielded the white solid product 73 (8 mg, 30.4%). LCMS: 504.20 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 9.0, 2.2 Hz, 1H), 7.48 (s, 1H), 4.98 (s, 2H), 4.81 (s, 1H), 4.11 (s, 2H), 3.74 (s, 2H), 3.49 - 3.37 (m, 1H), 3.23 (s, 3H), 3.00 - 2.90 (m, 1H), 2.85 (dd, J = 13.6, 7.2 Hz, 1H), 2.34 (dd, J = 21.4, 11.1 Hz, 2H), 2.20 (s, 2H), 1.85 - 1.72 (m, 2H).

[0217] Example 33 Synthesis of Compound 74 [ka] 1) 8-Chloro-5-(methylamino)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate tert-butyl(74-a) 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 in order. After stirring at 100°C for 2 hours, the mixture was cooled to room temperature and concentrated. Purification by pre-TLC (PE:SiO=1:1) yielded the yellow solid product 74-a (25 mg, 83.9%). LCMS: 348.15 [M+H] + .

[0218] 2) 8-Chloro-N-methyl-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine-5-amine(74-b) At 0°C, 0.5 ml of TFA was added to a 1.5 ml solution of 74-a (25 mg, 0.072 mmol, 1 equiv.) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain the white solid product 74-b (17.2 mg, 97.2%). This crude product was used directly in the next step without purification. LCMS: 248.10 [M+H] + .

[0219] 3)(R)-2-(8-chloro-5-(methylamino)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(74) At room temperature, 74-b (17.22 mg, 0.070 mmol, 1.0 equiv.) and DIEPA (89.83 mg, 0.70 mmol, 10 equiv.) were added to a solution of I01 (20 mg, 0.070 mmol, 1.0 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 12 hours and then concentrated. Purification by pre-TLC (MeOH:DCM = 1:10) yielded the white solid product 74 (10 mg, 28.8%). LCMS: 499.25 [M+H] + . 1H NMR (399 MHz, DMSO-d6) δ 7.70 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 7.18 - 7.10 (m, 1H), 6.75 (s, 1H), 4.80 (d, J = 20.1 Hz, 1H), 4.69 (d, J = 17.3 Hz, 1H), 4.16 - 4.07 (m, 1H), 4.01 (s, 1H), 3.74 (s, 2H), 3.40 (dt, J = 16.3, 7.8 Hz, 1H), 3.26 (s, 1H), 3.17 (dt, J = 15.4, 8.3 Hz, 1H), 3.01 - 2.90 (m, 5H), 2.83 (dd, J = 13.6, 7.2 Hz, 1H), 2.31 (d, J = 14.3 Hz, 2H), 2.20 (s, 2H), 1.79 (s, 2H).

[0220] Example 34 Synthesis of Compound 76 [ka] 1) 6-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl(76-b) At room temperature, XPhos-Pd-G3 (28.00 mg, 0.03 mmol, 0.1 eq) was added to a mixture of 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (76-a, 100 mg, 0.32 mmol, 1 eq), methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (66.7 mg, 0.32 mmol, 1 eq), and Cs2CO3 (312 mg, 0.96 mmol, 3 eq) in H2O (1 mL) / 1,4-dioxane (4 mL). After stirring at 120 °C for 16 hours, the mixture was cooled to room temperature, the solid was removed by filtration, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography (PE:EA ratio 10:1-4:1) to obtain product 76-b (80 mg, 79.62%) as a yellow solid. LCMS: 314.20 [M+H] + .

[0221] 2) 6-(1-methyl-1H-pyrazole-5-yl)-1,2,3,4-tetrahydroisoquinoline(76-c) At room temperature, 1 mL of TFA was added to a 2 mL solution of 76-b (80 mg, 0.26 mmol, 1 eq) in DCM. After stirring for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded the white solid product 76-c (69.8 mg, 81.8%). LC-MS: 214.15 [M+H] + .

[0222] 3)(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(76) At room temperature, DIEPA (127.70 mg, 0.99 mmol, 3.0 eq) and water (1 mL) were added 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 76 (65.7 mg, 42.8%) as a yellow solid. LCMS: 465.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ7.42 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 4.8 Hz, 3H), 6.33 (d, J = 1.9 Hz, 1H), 4.89 (s, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 2H), 3.51 (dt, J = 16.5, 7.7 Hz, 1H), 3.26 (dt, J = 15.0, 8.2 Hz, 1H), 3.09 (dd, J = 17.6, 8.2 Hz, 1H), 2.93 (d, J = 6.3 Hz, 3H), 2.38 - 2.14 (m, 4H), 1.85 - 1.70 (m, 2H).

[0223] The following compounds were synthesized using a similar method. [Table 6]

[0224] Example 35 Synthesis of Compound 80 [ka] 1) 6-(2-oxoxazolidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl(80-a) At room temperature, 2-oxazolidinone (112 mg, 1.28 mmol, 2 eq), Pd2(dba)3 (59 mg, 0.06 mmol, 0.1 eq), Xantphos (37 mg, 0.06 mmol, 0.1 eq), and Cs2CO3 (1.30 g, 3.84 mmol, 6 eq) were added sequentially to a solution of 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (76-a, 200 mg, 0.64 mmol, 1 eq) in 1,4-dioxane (20 mL). The mixture was stirred at 110 °C for 16 hours, then cooled to room temperature. The solid was removed by filtration, and water (20 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by pre-TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain a white solid product 80-a (200 mg, 98.1%). LCMS: 319.15 [M+H] + .

[0225] 2) 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl(80-b) At room temperature, a solution of 80-a (200 mg, 0.63 mmol, 1 eq) in 4 M HCl / 1,4-dioxane (4 mL) was stirred for 1 hour. The solution was concentrated to obtain the yellow solid product 80-b (120 mg, 87.5%). This crude product was used directly in the next step without purification. LC-MS: 219.15 [M+H] + .

[0226] 3)(R)-3-(2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxazolidine-2-one(80) At room temperature, DIEPA (55.00 mg, 0.42 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 80 (64 mg, 98%) as a yellow solid. LCMS: 470.25 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 7.40 (dd, J = 8.4, 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 4.80 (s, 2H), 4.39 (dd, J = 9.1, 6.9 Hz, 2H), 4.00 (dd, J = 9.0, 7.0 Hz, 2H), 3.90 (t, J = 5.9 Hz, 2H), 3.76 - 3.68 (m, 2H), 3.46 (dd, J = 16.9, 8.2 Hz, 1H), 3.21 (dd, J = 15.0, 7.1 Hz, 1H), 3.03 (dd, J = 17.4, 8.1 Hz, 1H), 2.87 (dt, J = 19.7, 6.3 Hz, 3H), 2.35 - 2.16 (m, 4H), 1.77 (m, J = 8.8 Hz, 2H).

[0227] Example 36 Synthesis of Compound 104 [ka] 1) Synthesis of compound 104a At room temperature, 2.00 g, 10.04 mmol, 1 eq of 4-oxopiperidine-1-carboxylate tert-butyl was added to a 2 mL solution of DMF. N,N-dimethylformamide dimethyl acetal (1.20 g, 10.04 mmol, 1 eq) was added. The mixture was stirred at 80°C for 24 hours, then cooled to room temperature. The solid was removed by filtration, and water (20 mL) was added. Extraction with ethyl acetate (30 mL x 2) was performed, dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:EA 15:1-3:1) yielded product 104a (1.56 g, 61.11%) as a yellow solid. LCMS: 255.15 [M+H] + .

[0228] 2) Synthesis of compound 104b At room temperature, 2-methylpyrazole-3-amine (595.72 mg, 6.13 mmol, 1 equiv.) was added to a solution of 104a (1.56 g, 6.13 mmol, 1 eq) in acetic acid (50 mL). The mixture was stirred at 100°C for 24 hours, then cooled to room temperature and concentrated. Purification by pre-HPLC (5%-95% ACN:H2O with 0.1% TFA) yielded the white solid product 104b (750.00 mg, 42.40%). LC-MS: 289.15 [M+H] + .

[0229] 3) Synthesis of compound 104c At room temperature, 1 mL of TFA was added to a 2 mL solution of 10⁴b (200.00 mg, 0.69 mmol, 1 eq) in DCM. After stirring at room temperature for 1 hour, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H₂O) yielded a white solid product 10⁴c (50.00 mg, 38.29%). LC-MS: 189.22 [M+H] + .

[0230] 4) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methyl-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (104) At room temperature, N,N-diisopropylethylamine (80.84 mg, 0.63 mmol, 3 eq) and water (1 mL) were added to a THF (4 mL) solution of 104c (43.72 mg, 0.21 mmol, 1 eq) and I01 (60.00 mg, 0.21 mmol, 1 eq). After stirring at 65°C for 16 hours, the solution was concentrated. Purification by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O) yielded compound 104 (51.00 mg, 53.06%). LCMS: 440.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.04 (s, 1H), 4.98 (s, 2H), 4.00 (d, J = 15.0 Hz, 6H), 3.74 (s, 2H), 3.47 (dd, J = 17.0, 8.2 Hz, 1H), 3.26 - 3.19 (m, 1H), 3.12 (s, 2H), 3.09 - 3.02 (m, 1H), 2.90 (dd, J = 13.5, 7.1 Hz, 1H), 2.38 - 2.17 (m, 5H), 1.82 - 1.75 (m, 2H).

[0231] The following compounds were synthesized using a similar method. [Table 7]

[0232] Example 37 Synthesis of Compound 113 [ka] 1) Synthesis of compound 113a Under nitrogen protection at 0°C, chloro-(methoxy)methane (6.6g, 81.30 mmol, 1.0 equiv.) and triethylamine (41.05g, 406.5 mmol, 5.0 equiv.) were added sequentially to a 100ml solution of compound 113h (10g, 81.30 mmol, 1.0 equiv.) in dimethyl chloride (DCM). After stirring at 0°C for 1 hour, water (150mL) was added. Extraction was performed with DCM (200mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:siRNA=10:1) yielded the yellow oily product 113a (7.02g, 42.03 mmol, 51.73%). LCMS: 168.05 [M+H] + .

[0233] 2) Synthesis of compound 113b Under nitrogen protection at 0°C, NaH (1.7g, 42.03 mmol, 1 equiv.) was added in batches to a solution of 2-(diethoxyphosphoryl)ethyl acetate (10g, 81.30 mmol, 1.0 equiv.) in THF (100ml). After stirring at 0°C for 30 minutes, a solution of 113a (9.4g, 42.03 mmol, 1.0 equiv.) in THF (15ml) was added dropwise. After stirring at 0°C for 1 hour, saturated NH4Cl aqueous solution (100mL) was added. Extraction with SiO2 (150mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:SiO2 = 10:1) yielded the yellow oily product 113b (8g, 33.75 mmol, 80.29%). LCMS: 238.10 [M+H] + .

[0234] 3) Synthesis of compound 113c At room temperature, NaH (336.8 mg, 8.42 mmol, 2.0 equiv.) was added 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). After stirring at 70 °C for 1 hour, the mixture was cooled to room temperature, saturated NH4Cl (30 mL) was added, and the solution was extracted with HCl (35 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:HCl = 1:1) yielded the yellow solid product 113c (600 mg, 1.45 mmol, 34.52%). LCMS: 413.15 [M+H] + .

[0235] 4) Synthesis of compound 113d At room temperature, borane (11.44 ml, 11.44 mmol, 10 equiv.) was added dropwise to a solution of 113c (470 mg, 1.14 mmol, 1.0 eq.) in THF (20 mL). The mixture was stirred at 70°C for 3 hours, then cooled to 0°C. The reaction was slowly quenched with methanol (30 mL), followed by stirring at 60°C for 3 hours. The mixture was then cooled to room temperature, and water (50 mL) was added. Extraction was performed with HCl (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:HCl = 1:1) yielded the yellow solid product 113d (100 mg, 0.29 mmol, 25.64%). LCMS: 343.20 [M+H] + .

[0236] 5) Synthesis of compound 113e At room temperature, TFA (1 ml, 9.58 mmol, 14.98 equiv.) was added to a solution of 113d ((220 mg, 0.64 mmol, 1.0 equiv.)) in DCM (3 mL). After stirring for 3 hours, the solution was concentrated. Depositphotos (30 mL) and saturated NaHCO3 (20 mL) were added. Extraction with Depositphotos (30 mL x 3), drying over anhydrous Na2SO4, filtration, and concentration were obtained. Purification by column chromatography (PE: Depositphotos = 1:1) yielded the yellow solid product 113e (190 mg, 0.63 mmol, 98.43%). LCMS: 299.17 [M+H] + .

[0237] 6) Synthesis of compound 113f Under nitrogen protection at 0°C, PPh3 (917 mg, 3.5 mmol, 5.0 eq.) and DIAD (707 mg, 3.5 mmol, 5.0 equiv.) were sequentially added to a 10 mL THF solution of 113e (210 mg, 0.70 mmol, 1.0 equiv.). After stirring at room temperature for 16 hours, toluene (30 mL), water (30 mL x 2), and saturated brine (30 mL) were added. Extraction with toluene (30 mL x 3), drying over anhydrous sodium 2SO4, filtration, and concentration were performed. Purification by column chromatography (PE:toluene = 3:1) yielded the yellow solid product 113f (80 mg, 0.28 mmol, 40.00%). LCMS: 281.16 [M+H] + .

[0238] 7) Synthesis of 113g of compound Under nitrogen protection at 0°C, ACE-Cl (73.89 mg, 0.56 mmol, 2.0 equiv.) was added to a 1,2-DCE (3 mL) solution of 113 f (80 mg, 0.28 mmol, 1.0 equiv.). After stirring at room temperature for 1 hour, the mixture was concentrated. MeOH (10 mL) was added, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, saturated NaHCO3 (10 mL) was added, and the mixture was extracted with Depositphotos (20 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE: Depositphotos = 1:1) yielded 113 g (30 mg, 0.15 mmol, 53.6%) of the yellow solid product. LCMS: 191.10 [M+H] + .

[0239] 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']dipyridine-8(7H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(113) At room temperature, DIEA (438.6 mg, 3.4 mmol, 10 equiv.) was added to solutions 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). The mixture was stirred at 65°C for 12 hours and then cooled to room temperature. Water (10 mL) was added, and the mixture was extracted with SiO2 (20 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (MeOH:DCM = 1:10) to obtain a mixed product. Further purification by SFC yielded compound 113 (42.69 mg, 0.096 mmol, 28.45%). LCMS: 442.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.99 (m, 2H), 7.37 (s, 1H), 7.18 (d, J = 4.9 Hz, 1H), 4.85 (s, 1H), 4.83 - 4.70 (m, 2H), 4.30 (s, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.69 (d, J = 5.7 Hz, 2H), 3.36 (dd, J = 16.6, 7.9 Hz, 1H), 3.16 (d, J = 13.8 Hz, 1H), 2.90 (ddd, J = 30.1, 23.8, 12.8 Hz, 4H), 2.79 (d, J = 2.9 Hz, 1H), 2.62 (d, J = 12.3 Hz, 1H), 2.40 (d, J = 12.5 Hz, 1H), 2.29 (dd, J = 24.6, 11.2 Hz, 2H), 2.15 (s, 2H), 1.82 - 1.69 (m, 2H), 1.64 (s, 1H).

[0240] The following compounds were synthesized using a similar method. [Table 8]

[0241] Example 38 Synthesis of Compound 114 [ka] 1) Synthesis of compound 114a At room temperature, 3-bromo-5-chloro-2-iodopyridine (2 g, 6.28 mmol, 1.0 eq) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)ethyl acrylate (1.42 g, 6.28 mmol, 1.0 eq) were dissolved in THF (20 mL) and K2CO3 (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) were added in order. The mixture was heated under nitrogen for 6 hours under reflux. After cooling to room temperature, the solid was removed by filtration, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography (PE:EA ratio 15:1-5:1) to obtain a white solid product 114a (1.7 g, 6.89 mmol, 93.34%). LCMS: 290.54 [M+H] + .

[0242] 2) Synthesis of compound 114b At room temperature, 114a (2 g, 6.89 mmol, 1.0 equiv.) was mixed with THF (30 ml), ethyl 3-(benzylamino)-3-oxopropanoate (1.52 g, 6.89 mmol, 1.0 eq.), and NaH (551.2 mg, 13.78 mmol, 2.0 equiv.). The mixture was heated to 70°C and stirred for 1 hour. After cooling to room temperature, saturated NH4Cl (30 mL) was added, and the mixture was extracted with SiO4 (30 mL x 3). It was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:SiO4 = 1:1) yielded the yellow solid product 114b (2 g, 4.30 mmol, 62.40%). LCMS: 465.01 [M+H] + .

[0243] 3) Synthesis of compound 114c Under nitrogen protection at 0°C, borane (4.3 ml, 43.0 mmol, 10 equiv.) was added dropwise to a solution of 114b (2 g, 4.30 mmol, 1.0 eq.) in anhydrous THF (20 ml, 100.0%), and the mixture was heated to 80°C and stirred for 3 hours. The mixture was cooled to 0°C, MeOH (30 mL) was carefully added, and the mixture was stirred at 60°C for 3 hours. Water (30 mL) was added, and the mixture was extracted with RINKAN (30 mL x 3). The solution was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:RINKAN = 1:1) yielded the yellow solid product 114c (200 mg, 0.50 mmol, 11.7%). LCMS: 395.05 [M+H] + .

[0244] 4) Synthesis of compound 114d Under nitrogen protection at 0°C, NaH (38.3 mg, 1.0 mmol, 2.0 equiv. 60% wt) was added to a 30 ml THF solution of 114c (200 mg, 0.50 mmol, 1.0 equiv.). After stirring at 70°C for 1 hour, the mixture was cooled to 0°C, a 30 mL saturated NH4Cl solution was added, and the mixture was extracted with  (35 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:Â=1:1) yielded the yellow solid product 114d (100 mg, 0.31 mmol, 63.69%). LCMS: 315.15 [M+H] + .

[0245] 5) Synthesis of compound 114e Under nitrogen protection at 0°C, ACE-Cl (87.2 mg, 0.61 mmol, 2.0 equiv.) was added dropwise to a solution of 114d (100 mg, 0.31 mmol, 1.0 equiv.) in 1,2-DCE (3 ml). The mixture was stirred at room temperature for 1 hour, concentrated, and then MeOH (10 ml) was added. The mixture was heated under reflux for 12 hours and cooled to room temperature. Saturated NaHCO3 (10 mL) was added, and the solution was extracted with siRNA (20 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:siRNA = 1:1) yielded the yellow solid product 114e (60 mg, 0.26 mmol, 83.87%). LCMS: 225.10 [M+H] + .

[0246] 6) Synthesis of (R)-2-((6aS,10aR)-3-chloro-6a,9,10,10-tetrahydro-6H-pyran[3,2-b:5,4-c']dipyridine-8(7H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(114) At room temperature, DIEA (438.6 mg, 3.4 mmol, 10 equiv.) was added to solutions 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). The mixture was stirred at 65°C for 12 hours, cooled to room temperature, water (20 mL) was added, and the solution was extracted with SiO2 (20 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:SiO = 1:1) yielded compound 114 (15.59 mg, 0.032 mmol, 16.4%). LCMS: 476.00 [M+H] + . 1H NMR(399MHz, methanol-d4)δ 8.03(d, J=2.2 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 4.35 (dd, J = 10.6, 3.8 Hz, 1H), 4.03 - 3.87 (m, 4H), 3.55 (dd, J = 17.3, 8.6 Hz, 1H), 3.41 - 3.32 (m, 1H), 3.12 - 3.00 (m, 4H), 2.89 - 2.84 (m, 1H), 2.71 (d, J = 11.8 Hz, 1H), 2.63 (d, J = 11.4 Hz, 1H), 2.39 - 2.30 (m, 4H), 1.93 - 1.84 (m, 2H), 1.41 - 1.32 (m, 2H).

[0247] The following compounds were synthesized using a similar method. [Table 9]

[0248] Example 39 Synthesis of Compound 118 [ka] 1) Synthesis of compound 118a Under nitrogen protection at 0°C, 4-bromo-1H-indazole (10 g, 51.28 mmol, 1.0 equiv.) was dissolved in 100 ml of DCM, to which SEMCl (8.54 g, 51.28 mmol, 1.0 equiv.) and triethylamine (25.89 g, 256.40 mmol, 5.0 equiv.) were sequentially added dropwise. The mixture was stirred at room temperature for 1 hour, water (150 mL) was added, and the solution was extracted with 2 x 300 mL of DCM. The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE:HCl=10:1) yielded a yellow, oily product 118a (7.02 g, 21.46 mmol, 41.86%). LCMS: 327.29 [M+H] + .

[0249] 2) Synthesis of compound 118b At room temperature, 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) were added to a 20 mL NMP solution of 118a (2 g, 6.11 mmol, 1 eq) and acrylamide (434.25 mg, 6.11 mmol, 1 eq). The mixture was expanded at 130 °C for 18 hours, cooled to room temperature, and the solid was removed by filtration. Water (20 mL) was added, and the mixture was extracted with EtOAC (30 mL x 2). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography (PE:EA ratio 15:1-5:1) to obtain product 118b (1.7 g, 5.36 mmol, 87.8%) as a yellow solid. LCMS: 318.15 [M+H] + .

[0250] 3) Synthesis of compound 118c At room temperature, NaBH4 (119.87 mg, 3.15 mmol, 1.0 eq.) and NiCl2 (40.3 mg, 0.31 mmol, 0.1 equiv.) were added to a 30 ml MeOH solution of 118b (1 g, 3.15 mmol, 1.0 equiv.). After stirring for 1 hour, a 30 ml saturated NH4Cl solution was added, and the mixture was extracted with EtOAC (35 ml x 2). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:SiO=1:1) yielded the yellow solid product 118c (1 g, 3.12 mmol, 99.20%). LCMS: 320.17 [M+H] + .

[0251] 4) Synthesis of compound 118d At room temperature, NaClO (1 ml, 4.38 mmol, 3 equiv.) and NaOH (175.2 mg, 4.38 mmol, 3 eq.) were added to a solution of 1,4-dioxane (2 ml, 80.0%) and H2O (1 ml, 20.0%) in 118c (470 mg, 1.46 mmol, 1.0 eq.). 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:SiO=1:1) yielded the yellow solid product 118d (220 mg, 0.75 mmol, 51.78%). LCMS: 292.18 [M+H] + .

[0252] 5) Synthesis of compound 118e Under nitrogen protection at 0°C, ClC(O)OCH3 (105.75 mg, 1.12 mmol, 1.5 equiv.) and triethylamine (378.75 mg, 3.75 mmol, 5.0 equiv.) were sequentially added to a 5 ml solution of 118d (220 mg, 0.75 mmol, 1.0 equiv.) in DCM. After stirring at room temperature for 1 hour, water (150 mL) was added, and the mixture was extracted with DCM (300 mL x 2). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:Â=10:1) yielded the yellow oily product 118e (200 mg, 0.57 mmol, 76.00%). LCMS: 350.18 [M+H] + .

[0253] 6) Synthesis of compound 118f At room temperature, (CH2O)n (153.9 mg, 1.71 mmol, 3.0 eq.) and TsOH (9.80 mg, 0.057 mmol, 0.1 equiv.) were sequentially added to a 10 ml Tol solution of 118e (200 mg, 0.57 mmol, 1.0 equiv.). The mixture was stirred at 110°C for 16 hours, then cooled to room temperature and concentrated. SiO (30 mL), water (30 mL x 2), and saturated brine (30 mL) were added. Extraction with EtOAC (30 mL x 3), drying over anhydrous Na2SO4, filtration, and concentration were performed. Purification by column chromatography (PE:SiO = 1:1) yielded the yellow solid product 118f (100 mg, 0.43 mmol, 75.62%). LCMS: 232.10 [M+H] + .

[0254] 7) Synthesis of 118 g of compound Under nitrogen protection at 0°C, KOH (48.16 mg, 0.86 mmol, 2.0 equiv.) was added to a solution of 118 f (100 mg, 0.43 mmol, 1.0 equiv.) in EtOH (4 ml) and H2O (1 ml). The mixture was heated under reflux for 12 hours and cooled to room temperature. SiO (30 mL) was added, and the solutions were 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) yielded 118 g (60 mg, 0.34 mmol, 80.65%) of the yellow solid product. LCMS: 174.10 [M+H] + .

[0255] 8) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3,6,8,9-tetrahydro-7H-pyrazolo[4,3-f]isoquinoline-7-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(118) At room temperature, DIEA (890.1 mg, 6.9 mmol, 10 equiv.) was added to solutions of I01 (200 mg, 0.69 mmol, 1.0 equiv.) and 118 g (155.18 mg, 0.89 mmol, 1.3 equiv.) in THF (3 ml) and H2O (0.6 ml). The mixture was stirred at 65°C for 12 hours, cooled to room temperature, and water (20 mL) solution was added. Extraction was performed with EtOAC (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (MeOH:DCM = 1:10) yielded compound 118 (54.48 mg, 12.84 mmol, yield 18.62%). LCMS: 425.10 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.03(s, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 4.98 (s, 2H), 4.16 (d, J = 5.5 Hz, 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 = 8.6 Hz, 2H).

[0256] Example 40 Synthesis of Compound 135 [ka] 1) Synthesis of compound 135a At room temperature, 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) were added sequentially to a 1,4-dioxane (5 mL) solution of 135c (100.00 mg, 0.37 mmol, 1 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the solid was removed by filtration, and water (15 mL) was added. The solution was extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) yielded a yellow, oily product 135a (45.00 mg, 0.14 mmol, 39.98%). LCMS: 304.19 [M+H] + .

[0257] 2) Synthesis of compound 135b At room temperature, 1 mL of TFA was added to a 4 mL solution of 135a (45.00 mg, 0.14 mmol, 1 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 135b (20.00 mg, 0.098 mmol, 70.02%). This crude product was used directly in the next step without purification. LC-MS: 204.14 [M+H] + .

[0258] 3) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyrrolidine-1-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(135) At room temperature, N,N-diisopropylethylamine (85.14 mg, 0.66 mmol, 3.0 eq) was added to a THF (5 mL) solution of 135b (44.66 mg, 0.22 mmol, 1 eq) and I01 (64.00 mg, 0.22 mmol, 1 eq). The mixture was stirred at 80°C for 4 hours and then concentrated. Compound 135 (37.05 mg) was obtained by pre-HPLC (0.1% TFA in 5%-95% ACN:H2O). LCMS: 455.22[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 9.3 Hz, 1H), 7.65 (s, 1H), 6.93 (d, J = 9.3 Hz, 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 = 13.8 Hz, 1H), 2.99 - 2.85 (m, 4H), 2.26 (d, J = 40.1 Hz, 4H), 1.97 (d, J = 6.7 Hz, 4H), 1.81 - 1.70 (m, 2H).

[0259] Example 41 Synthesis of Compound 169 [ka] 1) Synthesis of compound 169a At room temperature, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate tert-butyl (500.00 mg, 1.69 mmol, 1 eq) was dissolved in DCM (4 mL) and TFA (1 mL) was added. After stirring for 1 hour, the mixture was concentrated to obtain a colorless oily product 169a (180.00 mg, 1.59 mmol, 95.25%). This crude product was used directly in the next step without purification. LCMS: 196.2 [M+H] + .

[0260] 2) Synthesis of compound 169b At room temperature, 169a (180 mg, 1.59 mmol, 1.0 eq) and 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (495.39 mg, 1.59 mmol, 1.0 eq) were dissolved in THF (10 mL) and K2CO3 (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) were added in sequence. The mixture was heated under reflux for 6 hours, cooled to room temperature, the solid was removed by filtration, and water (20 mL) was added. The solution was extracted with RINKAN (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography (MeOH:DCM = 1:10) to obtain product 169b (200 mg, 0.66 mmol, 41.92%) as a yellow solid. LCMS: 301.18 [M+H] + .

[0261] 3) Synthesis of compound 169c At room temperature, HCHO (19.8 mg, 0.66 mmol, 1.0 eq.) and AcOH (3.96 mg, 0.066 mmol, 0.1 equiv.) were sequentially added to a 3 ml solution of 169b (200 mg, 0.66 mmol, 1.0 equiv.) in anhydrous DCE. The mixture was then stirred for 1 hour, cooled to 0°C, and NaBH4 (50.16 mg, 1.32 mmol, 2.0 equiv.) was added in batches. After stirring at room temperature for 2 hours, a 30 mL solution of saturated NH4Cl was added, and the mixture was extracted with Depositphotos (35 mL x 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (PE: Depositphotos = 1:1) yielded the yellow solid product 169c (200 mg, 0.63 mmol, 96.50%). LCMS: 315.20 [M+H] + .

[0262] 4) Synthesis of compound 169d At room temperature, 1 mL of TFA was added to a 4 mL solution of 169c (200.00 mg, 0.63 mmol, 1 eq) in DCM. After stirring at room temperature for 1 hour, the mixture was concentrated to obtain a yellow, oily product 169d (100.00 mg, yield 74.17%). The crude product was used directly in the next step without purification. LC-MS: 215.15 [M+H] + .

[0263] 5) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(1-methyl-2,5-dihydro-1H-pyrrole-3-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(169) At room temperature, DIEA (812.70 mg, 6.30 mmol, 10 equiv.) was added to THF (3 ml) and H2O (0.6 ml) of I01 (181.44 mg, 0.63 mmol, 1.0 equiv.) and 169d (30 mg, 0.63 mmol, 1.0 equiv.). After stirring at 65°C for 12 hours, the mixture was cooled to room temperature and water (20 mL) was added. Extraction was performed with RINKAN (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-HPLC (5%~95% ACN:H2O with 0.1% TFA) yielded compound 169 (22.18 mg, 36.0%). LCMS: 466.10 [M+H] + . 1H NMR (400MHz, methanol-d4)δ 7.25(d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 4.05 - 3.89 (m, 4H), 3.82 (d, J = 4.3 Hz, 2H), 3.64 (s, 2H), 3.56 (dt, J = 16.9, 8.1 Hz, 1H), 3.36 (dd, J = 14.3, 8.4 Hz, 1H), 3.29 (d, J = 1.7 Hz, 2H), 3.13 - 2.99 (m, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.55 (s, 3H), 2.40 - 2.27 (m, 4H), 1.91 (q, J = 9.1 Hz, 2H).

[0264] Example 42 Synthesis of Compound 180 [ka] 1) Synthesis of compound 180a At room temperature, 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (100.00 mg, 0.43 mmol, 1 eq) was dissolved in DCM (5 mL) and Boc2O (94.86 mg, 0.43 mmol, 1 eq) and TEA (131.94 mg, 1.30 mmol, 3 eq) were added sequentially. After stirring for 2 hours, water (10 mL) was added. Extraction was performed with DCM (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a yellow oily product 180a (crude, 100.00 mg, 69.92%). LCMS: 330.20 [M+H] + .

[0265] 2) Synthesis of compound 180b At room temperature, 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) were added sequentially to a 1,4-dioxane (5 mL) solution of 180a (100.00 mg, 0.30 mmol, 1 eq). After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the solid was removed by filtration, and water (20 mL) was added. The solution was extracted with  (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain a yellow, oily product 180b (45.00 mg, 46.21%). LCMS: 321.20 [M+H] + .

[0266] 3) Synthesis of compound 180c At room temperature, 1 mL of TFA was added to a 4 mL solution of 180b (45.00 mg, 0.14 mmol, 1 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product 180c (20.00 mg, 64.66%). This crude product was used directly in the next step without purification. LC-MS: 221.15 [M+H] + .

[0267] 4) Synthesis of (R)-2-(5-fluoro-6-(pyrrolidine-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(180) At room temperature, DIEA (35.20 mg, 0.24 mmol, 3 eq) was added to solutions of I01 (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). After stirring at 65°C for 3 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded compound 180 (2.17 mg, 5.06%). LCMS: 472.10 [M+H]+ . 1 H NMR (400MHz, methanol-d4)δ 6.85(d, J=8.5 Hz, 1H), 6.69 (t, J = 8.6 Hz, 1H), 4.00 - 3.91 (m, 4H), 3.60 (d, J = 7.6 Hz, 1H), 3.33 (s, 6H), 3.23 - 3.05 (m, 4H), 2.87 (s, 3H), 2.37 (dd, J = 12.3, 8.4 Hz, 4H), 1.94 (d, J = 6.8 Hz, 6H).

[0268] Example 43 Synthesis of Compound 181 [ka] 1) Synthesis of compound 181a Under nitrogen protection at 0°C, 6-bromo-7-fluoroisoquinoline (200.00 mg, 0.88 mmol, 1 eq) was dissolved in HOAc (4 mL) and NaBH4 (66.94 mg, 1.77 mmol, 2 eqs) was added. The mixture was stirred at room temperature for 3 hours, then saturated Rochelle's reagent (20 mL) was added. Extraction was performed with ₹ (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a yellow oily product 181a (150 mg, 73.68%). LCMS: 231.95 [M+H] + .

[0269] 2) Synthesis of compound 181b At room temperature, Boc2O (214.00 mg, 0.98 mmol, 1.5 eq) and TEA (198.00 mg, 1.95 mmol, 3 eq) were added sequentially to a 5 mL solution of 181a (150.00 mg, 0.65 mmol, 1 eq) in DCM. After stirring for 3 hours, water (10 mL) was added. Extraction was performed with DCM (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a yellowish oily product 181b (crude, 160.00 mg, 74.32%). LCMS: 331.95 [M+H] + .

[0270] 3) Synthesis of compound 181c At room temperature, 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) were added sequentially to a 1,4-dioxane (5 mL) solution of 181b (160.00 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 solution was extracted with siRNA (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification by pre-TLC (SiO2, petroleum ether:ethyl acetate = 3:1) yielded a yellow, oily product 181c (50.00 mg, yield 32.49%). LCMS: 321.10 [M+H] + .

[0271] 4) Synthesis of compound 181d At room temperature, 1 mL of TFA was added to a 4 mL solution of 181c (50.00 mg, 0.16 mmol, 1 eq) in DCM. After stirring for 1 hour, the mixture was concentrated to obtain a yellow, oily product, 181d (30.00 mg, 87.28%). This crude product was used directly in the next step without purification. LC-MS: 221.20 [M+H] + .

[0272] 5) Synthesis of (R)-2-(7-fluoro-6-(pyrrolidine-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(181) At room temperature, DIEA (53.00 mg, 0.41 mmol, 3 eq) was added to solutions of I01 (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). After stirring at 65°C for 16 hours, the solution was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded compound 181 (33.89 mg, 52.77%). LCMS: 472.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.91 (d, J = 14.3 Hz, 1H), 6.51 (d, J = 9.1 Hz, 1H), 4.69 (s, 2H), 3.72 (s, 2H), 3.85 (d, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.53 - 3.42 (m, 2H), 3.23 (s, 6H), 3.03 (d, J = 16.3 Hz, 1H), 2.89 (dd, J = 13.7, 7.3 Hz, 1H), 2.74 (s, 2H), 2.32 - 2.18 (m, 4H), 1.85 (d, J = 6.0 Hz, 4H), 1.76 (dd, J = 11.6, 7.1 Hz, 2H).

[0273] The following compounds were synthesized using a similar method. [Table 10]

[0274] Example 44 Synthesis of Compound 184 [ka] 1) Synthesis of compound 184a At room temperature, tert-butyl 3-oxopiperidine-1-carboxylate (1.50 g, 7.53 mmol, 1 eq) and 1-methyl-3,5-dinitropyridine-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. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded product 184a (90 mg, 6.0%) as a yellow solid. LCMS: 280.25 [M+H] + .

[0275] 2) Synthesis of compound 184b At room temperature, Pd / C (10%, 6 mg) was added to a solution of 184a (60.00 mg, 0.21 mmol, 1 eq) in MeOH (4 mL), and the mixture was deoxygenated three times. Hydrogen absorption was performed at room temperature using a balloon for 1 hour, the solid was removed by filtration, and the mixture was concentrated to obtain the yellow solid product 184b (40.00 mg, 74.69%). LCMS: 250.15 [M+H] + .

[0276] 3) Synthesis of compound 184c At room temperature, 1,4-dibromobutane (51.96 mg, 0.24 mmol, 1.5 eq) and DIPEA (61.92 mg, 0.48 mmol, 3.0 eq) were added to a solution of 184b (40.00 mg, 0.16 mmol, 1 eq) in DMF (3 mL). After stirring at 100 °C for 16 hours, the mixture was cooled to room temperature and water (10 mL) was added. The solution was extracted with RINKAN (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by pre-TLC (SiO₂, petroleum ether:ethyl acetate = 3:1) yielded a yellow oily product 184c (10.00 mg, 20.54%). LCMS: 304.15 [M+H] + .

[0277] 4) Synthesis of compound 184d At room temperature, 13.00 mg (0.04 mmol, 1 eq) of 184c in a 2 mL solution of DCM was mixed with 0.5 mL of TFA and stirred for 1 hour. The mixture was then concentrated to obtain a yellow, oily product, 184d (8.00 mg, 91.84%). This crude product was used directly in the next step without purification. LC-MS: 204.20 [M+H] + .

[0278] 5) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(pyrrolidine-1-yl)-5,8-dihydro-1,7-naphthyridine-7(6H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(184) At room temperature, DIEA (16.00 mg, 0.12 mmol, 3 eq) was added to solutions 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). After stirring at 65°C for 16 hours, the mixture was concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded compound 184 (4.65 mg, 26.00%). LCMS: 455.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 2.7 Hz, 1H), 7.35 (s, 1H), 4.84 (t, J = 5.7 Hz, 1H), 4.73 (s, 1H), 3.92 (s, 2H), 3.72 (t, J = 4.1 Hz, 2H), 3.40 (d, J = 8.7 Hz, 2H), 3.18 (d, J = 6.6 Hz, 6H), 2.94 - 2.82 (m, 2H), 2.76 (s, 2H), 2.32 (dd, J = 21.0, 10.5 Hz, 2H), 2.19 - 2.12 (m, 2H), 1.91 (t, J = 3.3 Hz, 4H), 1.76 (q, J = 9.1 Hz, 2H).

[0279] Example 45 Synthesis of Compound 218 [ka] 1) Synthesis of compound 218a At room temperature, ethyl glyoxylate (9.2 g, 46.22 mmol, 1.1 eq) was added to a solution of pyridine-3,4-diamine (5.00 g, 42.02 mmol, 1 eq) in ethanol (75 mL). The mixture was stirred at room temperature for 30 minutes, then stirred at 90 °C for 18 hours. After cooling to room temperature, the mixture was filtered, washed with ethanol, and dried to obtain product 218a (3.1 g, 50.16%) as a yellow solid. This crude product was used directly in the next step without purification. LC-MS: 148.45 [M+H] + .

[0280] 2) Synthesis of compound 218b Under nitrogen protection, a solution of 218a (1.00 g, 6.80 mmol, 1 eq) in POCl3 (10 mL) was stirred at 100 °C for 24 hours. After cooling to room temperature, the blackish-white solid product 218b (1.00 g, 89.29%) was concentrated. The crude product was used directly in the next reaction without purification. LC-MS: 166.05 [M+H] + .

[0281] 3) Synthesis of compound 218c At room temperature, DIPEA (1.56 g, 12.12 mmol, 2 eqs) and pyrrolidine (860.60 mg, 12.12 mmol, 2 eqs) were added to a solution of 218b (1.00 g, 6.06 mmol, 1 eq) in DMF (20 mL). 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:siRNA=1:1) yielded the yellow solid product 218c (130 mg, 10.74%). LCMS: 201.15 [M+H] + .

[0282] 4) Synthesis of compound 218d At room temperature, benzyl bromide (114.48 mg, 0.67 mmol, 1.03 eq) was added to a 5 mL solution of 218°C (130.00 mg, 0.65 mmol, 1 eq) of acetonitrile. The mixture was stirred at 80°C for 2 hours, cooled to room temperature, filtered, and dried to obtain 6-benzyl-2-(pyrrolidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (120 mg). 6-benzyl-2-(pyrrolidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (120 mg) was dissolved in 5 mL of acetonitrile, and sodium borohydride (123.5 mg, 3.35 mmol, 5 eq) was added at 0°C. The mixture was continued to stir at 0°C for 2 hours, and a saturated NaHCO3 (10 mL) solution was added. Extraction was performed with toluene (10 mL x 3), dried over anhydrous sodium 2SO4, filtered, and concentrated. Purification by column chromatography (PE:toluene = 1:1) yielded a yellow solid product 218d (50 mg, 26.16%). LCMS: 295.15 [M+H] + .

[0283] 5) Synthesis of compound 218e At room temperature, a solution of 218d (50.00 mg, 0.17 mmol, 1 eq) and 10% Pd / C (20 mg) in ethanol (2 mL) was hydrogenated overnight under balloon. The solid was removed by filtration, and the solution was concentrated to obtain the yellow solid product 218e (30 mg, 86.45%). LC-MS: 205.15 [M+H] + .

[0284] 6) Synthesis of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyrrolidine-1-yl)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide(218) At room temperature, 2 mL of THF (2 mL) solution of 218e (30 mg, 0.15 mmol, 1 eq) and I01 (42.35 mg, 0.15 mmol, 1 eq) was mixed with DIPEA (37.94 mg, 0.29 mmol, 2 eq) and water (1 mL). The mixture was stirred at 80°C for 4 hours and then concentrated. Purification by Prep-HPLC (0.1% TFA in ACN / H2O) yielded compound 218 (11.26 mg, 16.80%). LC-MS: 456.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.80 (s, 1H), 5.05 (s, 1H), 4.77 (s, 2H), 4.03 (t, J = 6.0 Hz, 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, 8.0 Hz, 1H), 2.93 (dd, J = 13.6, 7.2 Hz, 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).

[0285] The following compounds were synthesized by referring to the manufacturing methods of Examples 1 to 45. [Table 11] TIFF2026514091000102.tif238169 TIFF2026514091000103.tif238169 TIFF2026514091000104.tif221169 TIFF2026514091000105.tif238169 TIFF2026514091000106.tif238169 TIFF2026514091000107.tif240169 TIFF2026514091000108.tif221169 TIFF2026514091000109.tif238169 TIFF2026514091000110.tif238169 TIFF2026514091000111.tif238169 TIFF2026514091000112.tif238169 TIFF2026514091000113.tif238169 TIFF2026514091000114.tif238169 TIFF2026514091000115.tif227169 TIFF2026514091000116.tif227169 TIFF2026514091000117.tif238169 TIFF2026514091000118.tif238169 TIFF2026514091000119.tif238169 TIFF2026514091000120.tif222169 TIFF2026514091000121.tif238169 TIFF2026514091000122.tif221169 TIFF2026514091000123.tif221169 TIFF2026514091000124.tif238169 TIFF2026514091000125.tif238169 TIFF2026514091000126.tif238169 TIFF2026514091000127.tif238169 TIFF2026514091000128.tif238169 TIFF2026514091000129.tif238169 TIFF2026514091000130.tif238169 TIFF2026514091000131.tif232169 TIFF2026514091000132.tif232169 TIFF2026514091000133.tif238169 TIFF2026514091000134.tif216169 TIFF2026514091000135.tif238169 TIFF2026514091000136.tif238169 TIFF2026514091000137.tif238169 TIFF2026514091000138.tif238169 TIFF2026514091000139.tif238169 TIFF2026514091000140.tif238169 TIFF2026514091000141.tif238169 TIFF2026514091000142.tif238169 TIFF2026514091000143.tif238169 TIFF2026514091000144.tif232169 TIFF2026514091000145.tif238169 TIFF2026514091000146.tif238169 TIFF2026514091000147.tif232169 TIFF2026514091000148.tif238169 TIFF2026514091000149.tif82169

[0286] Example 46: In vitro activity test A. PDE4B2 enzyme experiment and PDE4D2 enzyme experiment All compounds were prepared as 10 mM or 20 mM stock solutions with DMSO. The compounds to be tested were gradient diluted 3-fold with DMSO. 20 nL of the compound or DMSO control was transferred to each well of a 384-well plate using an Echo550 instrument. The plates were sealed with film and centrifuged for 1 minute. A 2x enzyme solution was prepared in assay buffer, and 2 μL of the 2x enzyme solution was added to each well and equilibrated at room temperature for 10 minutes. A 2x Cyclic-3',5'-AMP substrate solution was prepared in assay buffer, and 2 μL of the 2x substrate solution was added to each well and incubated at room temperature for 60 minutes. 4 μL of AMP-glo reagent was added and incubated at room temperature for 60 minutes. 8 μL of AMP detection solution was added and incubated at room temperature for 60 minutes. The RLU value was read using an Envision2105 plate reader, and the RLU value represents the concentration of the product AMP. Inhibition rate % = (1 - (RLU) 陽性対照 -RLU 化合物 ) / (RLU 陽性対照 -RLU 陰性対照 ))*100, and then using Graphpad 8.0 software, Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) with IC 50 The value was calculated.

[0287] The experimental results are shown in Tables 1 and 2. [Table 12] TIFF2026514091000151.tif206169 [Table 13]

[0288] Based on the above data, the compounds of the present invention have high inhibitory activity against the PDE4B2 enzyme.

[0289] B. PDE4B2 cell experiment All compounds were dissolved in 10 mM or 20 mM stock solutions with DMSO. The compounds to be tested were gradient diluted 3-fold with DMSO. First, 20 nL of Foskolin (10 mM) was transferred to each well of a 384-cell culture plate using an Echo instrument. 40 nL of the compound or DMSO control was transferred to each well of a 384-well plate using an Echo 550 instrument. Flpin-293-PDE4B2 cells were digested, resuspended in experimental buffer, and inoculated into a 384-cell culture plate with an inoculation density of 20,000 cells / well and an inoculation volume of 20 μl / well. Incubated at 37°C for 30 minutes. Eu-cAMP tracer and Ulight-anti-cAMP were freeze-thawed and diluted in lysis buffer. 10 μl of Eu-cAMP tracer was added to the experimental well, followed by 10 μl of Ulight-anti-cAMP. The reaction plate was centrifuged at room temperature with 200g for 30s, then allowed to stand at 25°C for 1 hour, after which data was collected using Envision. %Inhibition = 100 - (Signal compound - SignalAve positive control) / (SignalAve negative control - SignalAve positive control) × 100. Next, using Graphpad 8.0 software, Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC) 50 -X)*HillSlope)) with IC 50 The value was calculated.

[0290] The experimental results are shown in Tables 3 and 4. [Table 14] [Table 15] TIFF2026514091000155.tif239169 TIFF2026514091000156.tif239169 TIFF2026514091000157.tif239169 TIFF2026514091000158.tif67169

[0291] Based on the above data, the compounds of the present invention have high inhibitory activity against PDE4B2 cells.

[0292] Example 47: LPS-induced PBMC TNFα-releasing cell experiment Human PBMCs were purchased from TPCS, catalog number PB025C-W. PBMCs were inoculated into 96-well plates, all compounds were dissolved in 10 mM stock solution with DMSO, positive and test compounds were 3-fold diluted with DMSO, further diluted in culture medium, and added to the 96-well plates to achieve a maximum concentration of 3000 nM or 1000 nM in the test wells. LPS was purchased from Sigma (catalog number L2880), diluted in culture medium, and added to the 96-well plates. The cell well plates were incubated at 37°C in a 5% CO2 incubator for 24 hours, centrifuged, and the supernatant was collected and detected using the Elisa kit (the kit was purchased from R&D, catalog number VAL105). OD450 data were collected using an Envision instrument. %Inhibition = 100 - (Signal compound - SignalAve positive control) / (SignalAve negative control - SignalAve positive control) × 100. Next, using Graphpad 8.0 software, IC was calculated as Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)). 50 The value was calculated.

[0293] Experiments have shown that the compound of the present invention has excellent TNFα inhibitory activity in human PBMC secretion, can more effectively suppress the secretion of the inflammatory factor TNFα in human PBMCs, and has a high anti-inflammatory effect.

[0294] The embodiments of this patent are provided for illustrative purposes only and are not limiting. Those skilled in the art will readily recognize that substantially similar effects can be obtained by changing or modifying various non-essential parameters.

[0295] Although the technical solutions of the present invention have been described in detail and illustrated, those skilled in the art should understand that these are merely illustrative descriptions, and that modifications to the above embodiments or the adoption of equivalent substitutions will be obvious to those skilled in the art, and that all such modifications or improvements made without departing from the spirit of the invention shall be included within the scope of the claims of the present invention.

Claims

1. Equation (I) 【Chemistry 1】 A compound represented by, its stereoisomer, or a pharmaceutically acceptable salt thereof, During the ceremony, S* represents a chiral sulfur atom, and its configuration is either R configuration or S configuration. W is selected from N, CH, or C. Ring A is a monocyclic or bicyclic group, and the monocyclic group is a 5-8 membered heteroaryl or C ６－１０ Selected from aryl, the bicyclic group is selected from 5-6 member heteroaryl condensation 5-6 member heteroaryl, 5-6 member heteroarylphenyl, 5-6 member cycloalkylphenyl, 5-6 member cycloalkyl condensation 5-6 member heteroaryl, 5-6 member heterocyclylphenyl, 5-6 member heterocyclyl condensation 5-6 member heteroaryl, benzo 5-6 member heterocyclyl, or benzo 5-6 member heteroaryl. R １ is hydrogen or C １－６ Selected from alkyl groups, R ２ is selected from C １－６ alkyl, C ３－８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, and the C １－６ alkyl, C ３－８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl may optionally further be substituted with one or more groups selected from deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, C １－６ alkyl, C １－６ hydroxyalkyl, C １－６ alkoxy, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-substituted C １－６ alkyl, R ２．１ substituted C １－６ alkyl, C １－６ alkyl-substituted 5- to 6-membered heteroaryl, C １－６ alkyl-substituted 3- to 6-membered heterocyclyl, -C(O)-R ２．１ 、-S(O) ２ -R ２．２ 、-C(O)O-R 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 and is substituted with one or more of these groups, Or, R １ and R ２ These are linked together to form a 3-6 membered heterocycline or a 5-6 membered heteroaryl, and the 3-6 membered heterocycline and 5-6 membered heteroaryl may optionally be further composed of hydrogen, deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, or C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C ３－６ Substituted with one or more cycloalkyl or 3- to 6-membered heterocyclyl groups, R ３ These are, independently, hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and C. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl deuterated, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, any of the R ３ It is linked to a carbon atom on the ring C ３－８ Forming a cycloalkyl or 3-8 membered heterocycline, R ４ These are hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and C. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl deuterated, 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)O-R 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 Selected from, the C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl deuterated, 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 may optionally be further enriched with deuterium, halogen, cyano, hydroxy, oxo, or 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 It may be substituted with one or more groups of cycloalkyl or 3- to 6-membered heterocyclyl groups. R ５ is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, 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- to 6-membered heterocyclyl, -C(O)-R ５．１ , -S(O) ２ -R ５．２ , -C(O)O-R 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 and is selected from or R ４ and R ５ are linked to form a 5- or 6-membered heteroaryl or C ６－１０ aryl, and the 5- or 6-membered heteroaryl and C ６－１０ aryl may optionally be further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, oxo, C １－６ alkyl, C １－６ hydroxyalkyl, C １－６ alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocyclyl 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 These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, and C. １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Alkoxy, -C(O)NH ２ , C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, m and n are each independently selected from 1, 2, or 3. p is selected from 1 or 2, a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, a stereoisomer thereof, 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). 【Chemistry 2】

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic group, the monocyclic group is selected from a five-membered heteroaryl, a six-membered heteroaryl, or phenyl, and preferably, ring A is selected from thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

4. Ring A is a bicyclic group, and the bicyclic group is selected from a 5-membered heteroaryl condensed 6-membered heteroaryl, a 5-membered heteroarylphenyl, a 6-membered cycloalkylphenyl, a 6-membered heterocyclylphenyl, a benzo-5-membered heterocyclyl, a benzo-5-membered heteroaryl, a 6-membered heteroaryl condensed 5-membered heteroaryl, a 6-membered heterocyclyl condensed 6-membered heteroaryl, or a 6-membered heteroarylphenyl. Preferably, ring A is pyrazolopyrimidinyl, imidazophenyl, imidazopyridyl, pyrazolopyridyl, cyclohexylphenyl, oxanylphenyl, benzodioxazolyl, 【Transformation 3】 Benzoxazolyl, 【Chemistry 4】 A compound according to claim 1 or 2, characterized by being selected from oxanylpyridyl, pyridonephenyl, pyridopyrazolyl, benzopyrazolyl, thienophenyl, or pyridophenyl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

6. The above formula (III-A) is further shown in formula (IV), 【Transformation 6】 In the formula, ring B is C ３－６ The components are cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and R ４ａ These are, independently, deuterium, halogen, amino, hydroxy, cyano, carboxy, oxo, and C. １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Alkoxyalkyl, -N(CH ３ ) ２ , -C(O)NH ２ , C ３－６ A compound according to claim 5, characterized in that it is selected from cycloalkyl or 3- to 6-membered heterocycline, and y is 0, 1, or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. The aforementioned ring B is cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, azilidinil, azetidinil, pyrrolidinil, triazolyl, piperidinil, morpholinil, piperazinil, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 【Transformation 7】 A compound according to claim 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

8. The aforementioned R １ R is selected from hydrogen, ２ C １－３ Alkyl, C ３－６ Selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C １－３ Alkyl, C ３－６ Cycloalkyl, 3-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl may optionally be further enriched with deuterium, halogen, amino, nitro, oxo, cyano, hydroxy, or C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, 3-6 member heterocyclyl, 5-6 member heteroaryl, 5-6 member heteroaryl substituted C １－６ Alkyl, R ２．１ Substitution C １－６ Alkyl, C １－６ Alkyl-substituted 5-6 member heteroaryl, C １－６ Alkyl-substituted 3-6 member heterocyclyl, -C(O)-R ２．１ , -S(O) ２ -R ２．２ , -C(O)O-R 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 A compound according to any one of claims 5 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more of the groups.

9. The aforementioned R ４ａ These are, independently, deuterium, fluorine, chlorine, amino, hydroxy, cyano, carboxy, oxo, methyl, ethyl, and -CH₂, respectively. ２ OCH ３ , -N(CH ３ ) ２ The compound according to claim 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from methoxy, ethoxy, trifluoromethyl, hydroxymethyl, or hydroxyethyl.

10. R １ is hydrogen or C １－６ Selected from alkyl groups, Or, R ２ This is as shown in equation (III), 【Transformation 8】 During the ceremony, R ６ is selected from hydroxy, cyano, amino, or halogen, R ７ and R ７’ These are hydrogen and C, respectively, independently. １－６ Selected from alkyl, the C １－６ Alkyl can optionally further contain deuterium, halogen, amino, hydroxy, cyano, oxo, or 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)O-R 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 It is substituted with one or more of the following groups: Preferably, R ７ and R ７’ Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. Or, R ２ This is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxanyl, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanyl, azetidinyl, thietanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxapiroheptanyl, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinyl, or naphthyl, and the aforementioned methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , oxanil, cycloheptyl, phenyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, oxetanil, azetidinil, thietanil, tetrahydropyranil, tetrahydrofuranil, tetrahydrothiopyranil, pyrrolidinil, tetrahydropyrrolidinil, tetrahydrothienyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, azepanil, oxapiroheptanil, benzopyridyl, pyridopyridyl, benzimidazolyl, benzopyrimidinil and naphthyl may optionally be further deuterium, fluorine, chlorine, bromine, amino, hydroxy, thiol, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, -CF ３ ,-CHF ２ ien-CH ２ F, Methoxy, Ethoxy, Propoxy, Oxylanil, Oxetanil, Azilidinil, Azetidinil, - (CH ２ ) ２ CN, -C(O)-R ２．１ , -S(O) ２ -R ２．２ , -C(O)O-R 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 It may be substituted with one or more of the following groups: Or, R ３ These are, independently, hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkyl deuterated, C １－３ Hydroxyalkyl, C １－３ Alkoxy, C ３－６ Selected from cycloalkyl or 3-6 membered heterocyclyl, Or, R ４ These are hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and 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)O-R 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 Selected from cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C ３－６ Cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl may optionally be further enriched with deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or 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 It may be substituted with one or more substituents from the haloalkyl group. Or, R ５ These are hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and 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)O-R 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 Selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C ３－６ Cycloalkyl, 3-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl may optionally be further composed of deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, or C １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Alkoxy or C １－３ It may be substituted with one or more substituents from the haloalkyl group. The aforementioned 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 These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, and C. １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkyl, C １－３ Alkoxy, -C(O)NH ２ , C ３－８ Selected from cycloalkyl or 3- to 8-membered heterocyclyl, 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 These are, independently, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, carboxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, -CF ３ ,-CHF ２ ien-CH ２ F, Methoxy, Ethoxy, Propoxy, -C(O)NH ２ A compound according to any one of claims 1 to 6, characterized by being selected from cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, azilidinil, azetidinil, tetrahydropyrrolyl, or tetrahydrofuranil, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. The aforementioned R ４ These are hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, oxo, and C. １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Alkoxy, C １－３ Selected from haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, azilidinil, azetidinil, pyrrolidinil, triazolyl, piperidinil, morpholinil, piperazinil, thiazolyl, imidazolyl, or pyrazolyl, the C １－３ Alkyl, C １－３ Hydroxyalkyl, C １－３ Alkoxy, C １－３ Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, aziridinil, azetidinil, pyrrolidinil, triazolyl, piperidinil, morpholinil, piperazinil, thiazolyl, imidazolyl, and pyrazolyl may optionally contain deuterium, halogen, amino, nitro, cyano, hydroxy, fluorine, chlorine, oxo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, trifluoroethyl, -CH ２ OCH ３ or -N(CH ３ ) ２ A compound according to any one of claims 1 to 5 or 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from the above.

12. The aforementioned R ４ This includes hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxylanil, oxetanil, aziridinyl, azetidinyl, -CF ３ ,-CHF ２ ien-CH ２ F, -NMe ２ , -SO ２ Me, -SO ２ Et, -CONH ２ , -CONHMe, -CO ２ Me, 【Chemistry 9】 Selected from, Or, R ５ Hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, amino, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxylanil, oxetanil, aziridinyl, azetidinyl, -NH-(CH ２ ) ２ -OH, -CF ３ ,-CHF ２ ien-CH ２ F, -NMe ２ , -SO ２ Me, -SO ２ Et, -CONH ２ , -CONHMe or -CO ２ A compound according to any one of claims 1 to 5, 8, or 10, characterized by being selected from Me, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. In the above formulas (II-A), (II-B), (II-C), and (II-D) 【Chemistry 10】 Each is independent of the others. 【Chemistry 11】 Selected from, Alternatively, in formulas (II-A), (II-B), (II-C), and (II-D) 【Chemistry 12】 Each is independent of the others. 【Chemistry 13】 A compound according to any one of claims 1 to 4 or 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

14. The aforementioned R １ is hydrogen, C １－３ Selected from alkyl groups, Or, the R ２ teeth, 【Chemistry 14】 -(CH ２ ) ２ OH、 【Chemistry 15】 Selected from the basis of, Or, the R ３ These are, independently, hydrogen, deuterium, fluorine, chlorine, bromine, cyano, oxo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, and -CF. ３ ,-CHF ２ ien-CH ２ F, cyclopropyl, cyclobutyl, cyclopentyl, oxyranil, oxetanil, aziridinil, azetidinil, tetrahydropyrrolyl, tetrahydrofuranil, -CH ２ OH, -CF ３ ,-CHF ２ ien-CH ２ F or -CD ３ A compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

15. The aforementioned compound, 【Chemistry 16】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to any one of claims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from compounds having the structure of the above.

16. A pharmaceutical composition comprising a therapeutically effective amount 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 a compound according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a PDE4 inhibitor drug.

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

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