Nitrogen-containing fused heterocyclic compounds, their preparation process and their use in medicine

Abstract

The present disclosure relates to nitrogen-containing fused heterocyclic compounds, methods for their preparation, and their use in medicine. Specifically, the disclosure relates to nitrogen-containing fused heterocyclic compounds represented by general formula (I), methods for their preparation, and pharmaceutical compositions containing such compounds, as well as their use as inhibitors of phosphodiesterases (PDEs), particularly in the preparation of medicaments for treating and / or preventing PDE4 enzyme-mediated diseases or conditions. [Formula 1] TIFF2025534418000211.tif112150

Description

[Technical Field]

[0001] The present disclosure is in the field of medicine and relates to nitrogen-containing fused heterocyclic compounds, methods for their preparation, and their use in medicine. Specifically, the present disclosure relates to nitrogen-containing fused heterocyclic compounds represented by general formula (I), methods for their preparation, pharmaceutical compositions containing such compounds, and their use as phosphodiesterase (PDE) inhibitors, particularly in the preparation of medicaments for treating and / or preventing PDE4 enzyme-mediated diseases or conditions.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to Chinese Patent Application No. 202211201376.X, filed with the China Patent Office on September 29, 2022, entitled "Nitrogen-containing fused heterocyclic compounds, their preparation methods, and their use in medicine," the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Phosphodiesterases (PDEs) function to hydrolyze second messengers (cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate)) within cells, thereby terminating the biochemical actions mediated by these second messengers. cAMP and cGMP play important roles in regulating cellular activity. Regulation of their concentrations is primarily determined by the balance between their synthesis by adenylate cyclase and their hydrolysis by phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological roles have been studied in many fields.

[0004] Of the 11 currently identified phosphodiesterases, PDE4, PDE7, and PDE8 are cAMP-selective. The PDE4 family contains four isoforms (PDE4A, B, C, and D) with over 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). These four isoforms are differentially expressed in different tissues and cell types, such as PDE4B, which is primarily expressed in monocytes and neutrophils but not in cortical or epithelial cells, and PDE4D, which is expressed in the lung, cortex, cerebellum, and T cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs, 16(1), 2007, 109-124). PDE4B primarily hydrolyzes cAMP in the PDE4 enzyme, increasing the apparent K of the cAMP substrate. m PDE4 is the most important regulator of cAMP expression in immune and inflammatory cells, such as neutrophils, macrophages, and T lymphocytes. Because cAMP is a key second messenger in regulating inflammatory responses, PDE4 regulates the inflammatory response of inflammatory cells by regulating proinflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF, and LTB4. Therefore, inhibition of PDE4 has become an attractive target for the treatment of inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, and inflammatory bowel diseases such as Crohn's disease (MD Houslay et al., Drug Discovery Today, 2005, 10(22), 1503-1519). Since PDE activity is increased in patients with atopic dermatitis (AD), inhibition of PDE4 is also thought to be a viable treatment for AD (Journal of Investigative Dermatology, 1986, 87(3), 372-376).

[0005] Related patent applications disclosed include WO2009053268A1, WO2009050242A2, WO2009050236A1, CN101827852B, CN101163706A, CN101426505A, CN102875556B, CN103497201A, CN103889970B, CN108299400B, etc. Summary of the Invention

[0006] The object of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, [ka] where: Ring A is selected from heteroaryl, aryl, heterocyclyl, and cycloalkyl; L is -(CR 4a R 4b ) p (CR 5a R 5b ) q - and Z is selected from -S-, -S(O)-, -S(O)2- and -O-; R 1 and R 2 are the same or different and are independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, alkyl, halogen, oxo, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 , -C(O)NR d3 R d4 , -S(O)NR d3 R d4 , -(CH2) v1 NR d5 C(O)R e1 , -(CH2) v1 NRd5 S(O)2R e1 , -C(O)R e2 , -OC(O)R e3 , -S(O) r R e4 , -(CH2) w1 C(O)OR c2 , -(CH2) u optionally substituted with one or more substituents selected from R, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 3 represents a hydrogen atom, a deuterium atom, an alkyl, an alkenyl, an alkynyl, a halogen, a cyano, an alkylcyano, an oxo, or an -OR. c3 , -(CH2) u2 NR d6 R d7 , -C(O)NR d8 R d9 , -(CH2) v2 NR d10 C(O)R e5 , -C(O)R e6 , -OC(O)R e7 , -S(O) t R e8 , -(CH2) w2 C(O)OR c4 and [ka] wherein the alkyl, alkenyl and alkynyl are independently selected from deuterium atoms, halogen atoms, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 optionally substituted with one or more substituents selected from hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from heteroaryl, aryl, heterocyclyl, and cycloalkyl; Each R b are the same or different and independently represent a deuterium atom, a halogen atom, a cyano, an alkylcyano, an oxo, an alkyl, a haloalkyl, -OR c3 , -(CH2)u2 NR d6 R d7 , -C(O)NR d8 R d9 , -(CH2) v2 NR d10 C(O)R e5 , -C(O)R e6 , -OC(O)R e7 , -S(O) t R e8 , -(CH2) w2 C(O)OR c4 , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 4 , R 4a , R 4b , R 5 , R 5a and R 5b are the same or different and independently represent a hydrogen atom, a deuterium atom, an alkyl, a halogen, an alkenyl, an alkynyl, a cyano, an alkylcyano, a hydroxyalkyl, a haloalkyl, -OR c3 , -(CH2) u2 NR d6 R d7 , -C(O)NR d8 R d9 , -(CH2) v2 NR d10 C(O)R e5 , -C(O)R e6 , -OC(O)R e7 , -S(O) t R e8 , -(CH2) w2 C(O)OR c4 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R 4 and R 5 , R 4a and R 4b , R 5a and R 5b form an oxo group together with the carbon atom to which they are attached, R 6 , R 7 , R 8 and R 9are the same or different and independently represent a hydrogen atom, a deuterium atom, an alkyl, an alkenyl, an alkynyl, a halogen, a cyano, an alkylcyano, a haloalkyl, a hydroxyalkyl, -OR c3 , -(CH2) u2 NR d6 R d7 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from halogen, oxo, alkyl, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 optionally substituted with one or more substituents selected from hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R a are the same or different and independently represent a deuterium atom, an alkyl, a halogen, an oxo, an alkenyl, an alkynyl, a cyano, an alkylcyano, a hydroxyalkyl, a haloalkyl, -OR c3 , -(CH2) u2 NR d6 R d7 cycloalkyl, heterocyclyl, aryl, and heteroaryl; R is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently a deuterium atom, a halogen atom, an oxo group, an alkyl group, a haloalkyl group, -OR c1 , cyano, alkylcyano, -(CH2) u1 NR d1 R d2 optionally substituted with one or more substituents selected from hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R c1 , R c2 , R c3 and R c4are the same or different at each occurrence and are independently selected from hydrogen, deuterium, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH) u1 NR d1 R d2 optionally substituted with one or more substituents selected from hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 are the same or different at each occurrence and are independently selected from hydrogen, deuterium, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R d1 and R d2 , R d3 and R d4 , R d6 and R d7 and R d8 and R d9 together with the nitrogen atom to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium atoms, halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, alkylcyano, amino, alkylamino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R e1 , R e2 , R e3 , R e4 , R e5 , R e6, R e7 and R e8 are the same or different at each occurrence and are independently selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH) u1 NR d1 R d2 optionally substituted with one or more substituents selected from hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; s is 1 or 2, t is 0, 1, or 2; u is 0, 1, 2 or 3; u1 is 0, 1, 2 or 3, u2 is 0, 1, 2 or 3, v1 is 0, 1, 2 or 3, v2 is 0, 1, 2 or 3, w1 is 0, 1, 2 or 3; and w2 is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments of the present disclosure, s is 1 or 2, preferably 1, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments of the present disclosure, R 3 teeth, [ka] and rings B and R b and n is as defined in general formula (I), a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments of the present disclosure, Z is selected from -S-, -S(O)-, and -S(O)-, preferably -S(O)- or -S(O)-, more preferably -S(O)-, and is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments of the present disclosure, R 6 , R 7 , R 8 and R 9 are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl, preferably the same or different and independently of each other, a hydrogen atom, a deuterium atom, C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy and amino, more preferably the same or different, independently of each other, a hydrogen atom or C 1-6 and most preferably, all are hydrogen atoms, and the compound is represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments of the present disclosure, the compound is represented by general formula (II) or a pharmaceutically acceptable salt thereof: [ka] where: Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , n and m are as defined in general formula (I), and are a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments of the present disclosure, the compound is represented by general formula (II-1) or general formula (II-2), or a pharmaceutically acceptable salt thereof: [ka] or [ka] where: Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , n and m are as defined in general formula (I), and are a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments of the present disclosure, L is -(CR 4a R 4b ) p (CR 5a R 5b ) q -, p is 1 or 2, q is 0, 1 or 2, and R 4a , R 4b , R 5a and R 5b is as defined in general formula (I), and preferably L is -(CR 4a R 4b ) p (CR 5a R 5b )q -, p is 1, q is 0 or 1, and R 4a , R 4b , R 5a and R 5b is a compound represented by the above general formula (I), general formula (II), general formula (II-1) or general formula (II-2), or a pharmaceutically acceptable salt thereof, which is as defined in general formula (I).

[0014] In some embodiments of the present disclosure, the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof: [ka] where: Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , n and m are as defined in general formula (I), and are a compound represented by the above general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments of the present disclosure, the compound is represented by general formula (III-1) or general formula (III-2), or a pharmaceutically acceptable salt thereof: [ka] or [ka] where: Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b, n and m are as defined in general formula (I), a compound represented by the above general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments of the present disclosure, the compound is represented by general formula (IV) or a pharmaceutically acceptable salt thereof: [ka] where: Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , n and m are as defined in general formula (I), and are a compound represented by the above general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments of the present disclosure, a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof is [ka] or [ka] where: Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b, n and m are as defined in general formula (I), a compound represented by the above general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of the present disclosure, ring A is selected from 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl, preferably 5- to 10-membered heteroaryl or 6- to 10-membered aryl, more preferably 5- to 6-membered heteroaryl or phenyl, and is a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments of the present disclosure, ring B is selected from 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl, preferably selected from 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl, and is a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), or general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments of the present disclosure, n is 0, 1, 2, or 3, and each R b are the same or different and independently represent deuterium atoms, halogens, C 1-6 Alkyl, Cyano, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy, preferably n is 0 or 1, and Rb is a halogen, C 1-6 Alkyl, Cyano, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, C 1-6 Alkoxy-C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 The compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof, is selected from alkoxy.

[0021] In some embodiments of the present disclosure, m is 0, 1, 2, or 3, and each R a are the same or different and independently represent deuterium atoms, halogens, C 1-6 Alkyl, Cyano, C 1-6 Alkoxy, Amino, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy, preferably m is 0, and the compound is a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments of the present disclosure, [ka] teeth, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] Selected from R 3 , R a and m are as defined in general formula (I), a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments of the present disclosure, R 1 and R 2 are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently a deuterium atom, C 1-6 Alkyl, halogen, oxo, halogenated C 1-6 Alkyl, -ORc1 , nitro, cyano, -(CH2) u1 NR d1 R d2 , -C(O)NR d3 R d4 , -(CH2) v1 NR d5 C(O)R e1 , -C(O)R e2 , -OC(O)R e3 , -S(O) r R e4 , -(CH2) w1 C(O)OR c2 , -(CH2) u R, hydroxy C 1-6 optionally substituted with one or more substituents selected from alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R c1 , R c2 , R d1 ~R d5 , R e1 ~R e4 , R, u, u1, v1, w1 and r are as defined in general formula (I), preferably R 1 and R 2 are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 alkyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 1-6 Alkyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently selected from the group consisting of a deuterium atom, a halogen atom, an oxo atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, -(CH2) u1 NR d1 R d2 , -(CH2) w1 C(O)OR c2 , -(CH2) u R, hydroxy C 1-6optionally substituted with one or more substituents selected from alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R c2 , R d1 , R d2 , R, u, u1 and w1 are as defined in general formula (I), more preferably R 1 and R 2 are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, wherein C 1-6 Alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently selected from the group consisting of a deuterium atom, a halogen atom, an oxo atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 , -(CH2) u R and hydroxy C 1-6 optionally substituted with one or more substituents selected from alkyl, R c2 , R, u and w1 are as defined in general formula (I), most preferably R 1 and R 2 One of them is a hydrogen atom, and the other is a deuterium atom, C 1-6 alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, wherein C 1-6 Alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently selected from the group consisting of a deuterium atom, a halogen atom, an oxo atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 , -(CH2) u R and hydroxy C 1-6optionally substituted with one or more substituents selected from alkyl, R c2 , R, u and w1 are as defined in general formula (I), a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments of the present disclosure, R 1 and R 2 One of them is a hydrogen atom and the other is C 1-6 alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, wherein C 1-6 Alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are independently selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 , and hydroxy C 1-6 optionally substituted with one or more substituents selected from alkyl, R c2 is a hydrogen atom or C 1-6 alkyl, and w1 is 0 or 1, preferably R 1 and R 2 is a hydrogen atom and the other is phenyl or 3- to 6-membered cycloalkyl, wherein the phenyl or 3- to 6-membered cycloalkyl are each independently selected from halogen, —(CH2) w1 C(O)OR c2 and hydroxy C 1-6 optionally substituted with one or more substituents selected from alkyl, R c2 is a hydrogen atom or C 1-6 alkyl, w1 is 0 or 1, and most preferably R 1 and R 2 One of the is a hydrogen atom and the other is [ka] , [ka] and [ka] The compound is a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0025] In some embodiments of the present disclosure, R 4 , R 4a , R 4b and R 5 are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, nitro, amino, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl and halogenated C 1-6 alkoxy, preferably identical or different, independently of each other, a hydrogen atom or a C 1-6 and more preferably, all are hydrogen atoms.

[0026] In some embodiments of the present disclosure, R 5a and R 5b are the same or different and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, nitro, amino, hydroxy C1-6 Alkyl, haloalkyl and halogenated C 1-6 alkoxy, preferably identical or different, independently of each other, a hydrogen atom or a C 1-6 and alkyl, more preferably all hydrogen atoms, are compounds represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments of the present disclosure, R c1 , R c2 , R c3 and R c4 are the same or different in each occurrence and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, hydroxy C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein C 1-6 Alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are each independently selected from the group consisting of deuterium atom, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Cyano, C 1-6 Alkyl cyano, amino, C 1-6 Alkylamino, hydroxy and hydroxy C 1-6 alkyl, preferably the same or different at each occurrence and independently of each other, a hydrogen atom, a deuterium atom, C 1-6 Alkyl and Hydroxy C 1-6 alkyl, wherein C 1-6 Alkyl is a deuterium atom, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Cyano, C 1-6 Alkyl cyano, amino, C1-6 Alkylamino, hydroxy and hydroxy C 1-6 optionally substituted with one or more substituents selected from alkyl; R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 are the same or different in each occurrence and independently represent hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, halogenated C 1-6 Alkyl and Hydroxy C 1-6 alkyl, R e1 , R e2 , R e3 , R e4 , R e5 , R e6 , R e7 and R e8 are the same or different for each occurrence and are independent of each other. 1-6 Alkyl, hydroxy C 1-6 The compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof, is selected from alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl.

[0028] Table A: Exemplary compounds of the present disclosure include, but are not limited to: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0029] Table B Exemplary intermediate compounds of the present disclosure include, but are not limited to: [Table 7] [Table 8] [Table 9]

[0030] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] a compound represented by general formula (IA) or a salt thereof is subjected to a nucleophilic substitution reaction with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; where: X is a halogen, preferably Cl; Rings A, L, Z, R a , R 1 ~R 9 , m and s are as defined in general formula (I), or a process for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0031] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (IIA) or a salt thereof is subjected to a nucleophilic substitution reaction with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof; where: X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II), or a pharmaceutically acceptable salt thereof.

[0032] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II-1), or a salt thereof.

[0033] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II-2), or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] a compound represented by general formula (IIIA) or a salt thereof is subjected to a nucleophilic substitution reaction with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof; X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III), or a pharmaceutically acceptable salt thereof.

[0035] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III-1), or a pharmaceutically acceptable salt thereof.

[0036] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III-2), or a pharmaceutically acceptable salt thereof.

[0037] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (IVA) or a salt thereof is subjected to a nucleophilic substitution reaction with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof; X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV), or a pharmaceutically acceptable salt thereof.

[0038] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV-1), or a pharmaceutically acceptable salt thereof.

[0039] Another aspect of the present disclosure is a method for producing a fluororesin comprising the steps of: [ka] A compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction between a compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV-2), or a pharmaceutically acceptable salt thereof.

[0040] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0041] The present disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting PDEs enzymes, preferably in the preparation of a medicament for inhibiting PDE4 enzymes, more preferably in the preparation of a medicament for inhibiting PDE4B enzymes.

[0042] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a PDEs enzyme-mediated disease or condition, preferably in the preparation of a medicament for treating and / or preventing a PDE4 enzyme-mediated disease or condition, more preferably in the preparation of a medicament for treating and / or preventing a PDE4B enzyme-mediated disease or condition.

[0043] The present disclosure further relates to the use of a compound represented by the above general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a PDEs enzyme-mediated disease or condition, preferably in the preparation of a medicament for treating and / or preventing a PDE4 enzyme-mediated disease or condition, more preferably in the preparation of a medicament for treating and / or preventing a PDE4B enzyme-mediated disease or condition, wherein the disease or condition is selected from a respiratory disease, a pulmonary disease, a gastrointestinal disease, an inflammatory disease, cancer, a peripheral nervous system disease, or a central nervous system disease.

[0044] The present disclosure further relates to a method for inhibiting PDEs enzymes, comprising administering a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a patient in need thereof, and preferably, the present disclosure further relates to a method for inhibiting PDEs enzymes, comprising administering a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), More preferably, the present disclosure further relates to a method for inhibiting the PDE4 enzyme, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same,

[0045] The present disclosure further relates to a method for treating and / or preventing a PDEs enzyme-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A or a pharmaceutically acceptable salt thereof. More preferably, the present disclosure further relates to a method for treating and / or preventing a PDE4 enzyme-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0046] The present disclosure relates to a method for treating and / or preventing a PDEs enzyme-mediated disease or condition, preferably a method for treating and / or preventing a PDE4 enzyme-mediated disease or condition, more preferably a method for treating and / or preventing a PDE4B enzyme-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from a respiratory disease, a pulmonary disease, a gastrointestinal disease, an inflammatory disease, cancer, a peripheral nervous system disease, or a central nervous system disease.

[0047] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, or a pharmaceutical composition containing the same.

[0048] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a PDEs enzyme inhibitor, preferably a PDE4 enzyme inhibitor, more preferably a PDE4B enzyme inhibitor.

[0049] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a PDE enzyme-mediated disease or condition, preferably a PDE4 enzyme-mediated disease or condition, more preferably a PDE4B enzyme-mediated disease or condition.

[0050] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used to treat and / or prevent a PDEs enzyme-mediated disease or condition, preferably a PDE4 enzyme-mediated disease or condition, more preferably a PDE4B enzyme-mediated disease or condition, wherein the disease or condition is selected from a respiratory disease, a pulmonary disease, a gastrointestinal disease, an inflammatory disease, cancer, a peripheral nervous system disease, or a central nervous system disease.

[0051] Preferably, the respiratory and pulmonary diseases described in the present disclosure are selected from respiratory and pulmonary diseases associated with increased mucus, obstructive pulmonary diseases and airway diseases, preferably selected from COPD (chronic obstructive pulmonary disease), asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), alpha 1 antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension.

[0052] Preferably, the gastrointestinal disease according to the present disclosure is selected from tract enteritis, ulcerative colitis and Crohn's disease.

[0053] Preferably, the inflammatory disease according to the present disclosure is selected from proliferative and inflammatory skin diseases, articular inflammatory diseases and ocular inflammatory diseases, wherein said inflammatory skin diseases are preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, cutaneous photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, cutaneous pruritus, hand eczema and psoriasis, said articular inflammatory diseases are preferably selected from rheumatoid arthritis, psoriatic arthritis and spondyloarthritis, said ocular inflammatory disease is preferably glaucoma or dry eye syndrome, wherein said contact dermatitis includes irritant contact dermatitis and allergic contact dermatitis, said psoriasis includes psoriasis vulgaris and inverse psoriasis, and said SAPHO syndrome includes synovitis, acne, pustulosis, hyperostosis and osteitis.

[0054] Preferably, the peripheral nervous system disease or central nervous system disease described in the present disclosure is selected from Alzheimer's disease, age-associated memory impairment (AAMI), age-associated cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, intellectual disability, cerebrovascular disease, depression, schizophrenia, cerebral infarction, neurological dysfunction, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disability, and multiple sclerosis.

[0055] Preferably, the cancer according to the present disclosure is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, adenoid cystic carcinoma, medullary carcinoma, bronchogenic carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, renal cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0056] In certain embodiments, the unit dose of the pharmaceutical composition described herein is between 0.001 mg and 1000 mg.

[0057] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

[0058] In certain embodiments, the pharmaceutical compositions described herein contain 0.01% to 99.99% of a pharmaceutically acceptable carrier, diluent, or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions described herein contain 0.1% to 99.9% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions described herein contain 0.5% to 99.5% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions described herein contain 1% to 99% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions described herein contain 2% to 98% of a pharmaceutically acceptable carrier, diluent, or excipient.

[0059] The compounds of the present disclosure represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, can be administered to a living body by any administration route. The administration route may be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, ocular instillation, or local or systemic transdermal administration.

[0060] The compounds of the present disclosure represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, can be formulated as a single dose containing the active compound of the present disclosure, a carrier, an excipient, etc., and the dosage form can be a tablet, capsule, injection, infusion, granule, powder, suppository, pill, emulsion, paste, gel, dispersion, oral solution, inhalant, suspension, dry suspension, patch, detergent, etc. These dosage forms may contain ingredients commonly used in pharmaceutical formulations, such as diluents, absorbents, wetting agents, adhesives, disintegrants, colorants, pH adjusters, antioxidants, bacteriostats, osmotic pressure adjusters, and anti-adherents.

[0061] Suitable formulations of the various dosage forms mentioned above are readily available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005, and therefore can be easily prepared by those skilled in the art.

[0062] As is well known to those skilled in the art, the dosage of a pharmaceutical depends on various factors, including, but not limited to, the activity of the specific compound used, the patient's age, body weight, health condition, behavior, diet, administration time, administration mode, excretion rate, pharmaceutical combination, severity of disease, etc. Furthermore, the optimal treatment method, such as the treatment method, daily dose of the compound, and type of pharmaceutically acceptable salt, can be verified based on conventional treatment protocols.

[0063] Explanation of terms Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0064] The term "alkyl" refers to alkyl groups containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkyl group refers to a saturated straight or branched chain aliphatic hydrocarbon group having an alkyl group with 1 to 12 carbon atoms (i.e., C 1-12 alkyl) is preferred, and alkyl groups having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl may be substituted or unsubstituted, and if substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0065] The term “alkylene” refers to a divalent alkyl, where alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene includes alkylene having 1 to 12 carbon atoms (i.e., C 1-12 alkylene) is preferred, and alkylene having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene) is more preferred. Non-limiting examples include -CH-, -CH(CH)-, -C(CH)-, -CHCH-, -CH(CHCH)-, -CHCH(CH)-, -CHC(CH)-, -CHCHCH-, -CHCHCHCH-, and the like. Alkylene can be substituted or unsubstituted, and if substituted, can be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0066] The term "alkenyl" refers to an alkyl containing at least one carbon-carbon double bond in the molecule, where alkyl has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, as defined above (i.e., C 2-12 alkenyl). The alkenyl is an alkenyl having 2 to 6 carbon atoms (i.e., C 2-6Alkenyl) is preferred. Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl can be substituted or unsubstituted, and if substituted, can be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0067] The term "alkynyl" refers to an alkyl containing at least one carbon-carbon triple bond in the molecule, where alkyl has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, as defined above (i.e., C 2-12 The alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) is preferred. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and if substituted, can be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0068] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like. An alkoxy can be substituted or unsubstituted, and if substituted, can be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0069] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20-membered cycloalkyl). Preferably, the cycloalkyl has 3 to 12 ring atoms (i.e., 3-12-membered cycloalkyl), more preferably 3 to 8 ring atoms (i.e., 3-8-membered cycloalkyl), or more preferably 3 to 6 ring atoms (i.e., 3-6-membered cycloalkyl).

[0070] Said monocyclic cycloalkyls include, by way of non-limiting example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0071] The above polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls and bridged cycloalkyls.

[0072] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom (called a spiro atom) between rings which may contain one or more double bonds in the ring or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (wherein the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides, and the sulfur may optionally be replaced with oxygen, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and which contains at least one all-carbocyclic ring, provided that the point of attachment is on that all-carbocyclic ring having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20-membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl), and more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and multispirocycloalkyl (e.g., dispirocycloalkyl, etc.), and is preferably a monospirocycloalkyl or dispirocycloalkyl, and more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocycloalkyl. Non-limiting examples include: [ka] and the attachment points are [ka] It can be in any position such as

[0073] The term "fused cycloalkyl" refers to a polycyclic ring system in which a monocyclic cycloalkyl is fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl is fused to one or more heterocyclyls, aryls, or heteroaryls, sharing two adjacent carbon atoms between the rings, where the point of attachment is on a monocyclic cycloalkyl containing one or more double bonds in the ring and having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20-membered fused cycloalkyl). Preferably, the fused cycloalkyl has 6 to 14 ring atoms (i.e., a 6-14-membered fused cycloalkyl), and more preferably, has 7 to 10 ring atoms (i.e., a 7-10-membered fused cycloalkyl). The fused cycloalkyls mentioned above include bicyclic fused cycloalkyls and polycyclic fused cycloalkyls (e.g., tricyclic fused cycloalkyls, tetracyclic fused cycloalkyls, etc.), with bicyclic fused cycloalkyls or tricyclic fused cycloalkyls being preferred, and 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cycloalkyls being more preferred. Non-limiting examples include: [ka] and the attachment points are [ka] It can be in any position such as

[0074] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system containing one or more double bonds in the ring and sharing two carbon atoms that are not directly bonded between the rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5- to 20-membered bridged cycloalkyl). The bridged cycloalkyl is preferably a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl), and more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., a 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyls and polycyclic bridged cycloalkyls (e.g., tricyclic bridged cycloalkyls, tetracyclic bridged cycloalkyls, etc.), with bicyclic bridged cycloalkyls or tricyclic bridged cycloalkyls being preferred. Non-limiting examples include: [ka] and the attachment point can be at any position.

[0075] Cycloalkyl may be substituted or unsubstituted, and if substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0076] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur in the ring (wherein the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and the sulfur may optionally be replaced with oxygen, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS-, or -SS-) and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclyl is preferably a heterocyclyl having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclyl), more preferably a heterocyclyl having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclyl), even more preferably a heterocyclyl having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl), or preferably a heterocyclyl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl).

[0077] Said monocyclic heterocyclyl comprises, by way of non-limiting example, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0078] The polycyclic heterocyclyls mentioned above include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

[0079] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system that contains one or more double bonds in the ring and may have at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (wherein the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and the sulfur may optionally be replaced with oxygen, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS-, or -SS-), sharing one atom (called a spiro atom) between rings, and includes at least one monocyclic heterocyclyl, provided that the point of attachment is on the monocyclic heterocyclyl having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20-membered spiroheterocyclyl). The spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (ie, a 6- to 14-membered spiroheterocyclyl), and more preferably a spiroheterocyclyl having 7 to 10 ring atoms (ie, a 7- to 10-membered spiroheterocyclyl). The spiroheterocyclyl includes monospiroheterocyclyl and multispiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocyclyl. Non-limiting examples include: [ka] Includes:

[0080] The term "fused heterocyclyl" refers to a heterocyclic ring containing one or more double bonds and having at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur in the ring (wherein the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and the sulfur may optionally be replaced with oxygen, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS-, or -SS-), sharing two adjacent atoms between the rings.

[0023] It refers to a polycyclic heterocyclic ring system, which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyls, aryls, or heteroaryls, where the point of attachment is on a monocyclic heterocyclyl having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20-membered fused heterocyclyl). The fused heterocyclyl is preferably a fused heterocyclyl having 6 to 14 ring atoms (i.e., a 6-14-membered fused heterocyclyl), and more preferably a fused heterocyclyl having 7 to 10 ring atoms (i.e., a 7-10-membered fused heterocyclyl). The above-mentioned fused heterocyclyl includes bicyclic and polycyclic fused heterocyclyl (e.g., tricyclic fused heterocyclyl, tetracyclic fused heterocyclyl, etc.), with bicyclic fused heterocyclyl or tricyclic fused heterocyclyl being preferred, and 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclyl being more preferred. Non-limiting examples include: [ka] Includes:

[0081] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system containing one or more double bonds in the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (wherein the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and the sulfur may optionally be replaced with oxygen, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclyl) sharing two atoms that are not directly bonded between the rings. The above bridged heterocyclyl is preferably a bridged heterocyclyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl), and more preferably a bridged heterocyclyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclyl). Bridged heterocyclyls are divided into bicyclic and polycyclic (e.g., tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.) depending on the number of constituent rings, and bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl is preferred. Non-limiting examples include: [ka] Includes:

[0082] The heterocyclyl may be substituted or unsubstituted, and if substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0083] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) containing a conjugated π-electron system and having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6-14-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6-10-membered aryl), and more preferably an aryl having 8 to 10 ring atoms (i.e., 8-10-membered polycyclic aryl). An example of the monocyclic aryl is phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthracenyl, and phenanthryl. The polycyclic aryls mentioned above include phenyl fused to one or more heterocyclyls or cycloalkyls, or naphthyl fused to one or more heterocyclyls or cycloalkyls, where the point of attachment is on the phenyl or naphthyl, and in this case the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, including, but not limited to: [ka] [ka] [ka] [ka] [ka] [ka] Includes:

[0084] Aryl may be substituted or unsubstituted, and if substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0085] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) containing a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (which may optionally be oxidized, i.e., to form a nitrogen oxide, and which may optionally be replaced with oxygen, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS-, or -SS-) and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl), or preferably a heteroaryl having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic heteroaryl).

[0086] Non-limiting examples of the monocyclic heteroaryl include furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridinyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g., [ka] etc.), pyrazinyl, pyridazinyl, etc.

[0087] The above polycyclic heteroaryls include, by way of non-limiting example, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuryl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyridinyl, imidazopyridazinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc. The above polycyclic heteroaryls further include monocyclic heteroaryls fused with one or more aryls, where the point of attachment is on the aromatic ring, in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The above polycyclic heteroaryls further include monocyclic heteroaryls fused to one or more cycloalkyls or heterocyclyls, where the point of attachment is on the monocyclic heteroaromatic ring, in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes:

[0088] Heteroaryl may be substituted or unsubstituted, and if substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0089] The term "amino-protecting group" refers to an easily removable group introduced at an amino group to keep the amino group unchanged when other portions of the molecule undergo reaction. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (FmOC), allyloxycarbonyl (AllOC), trimethylsilylethoxycarbonyl (TeOC), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), tosyl (Tos), trifluoroacetyl (Tfa), triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0090] The term "hydroxy protecting group" refers to an easily removable group introduced to a hydroxy to block or protect the hydroxy from reacting with other functional groups in a compound. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

[0091] The term "haloalkyl" refers to an alkyl substituted with one or more halogens, where alkyl is defined above.

[0092] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0093] The term "hydroxyalkyl" refers to an alkyl substituted with one or more hydroxy groups, where alkyl is as defined above.

[0094] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] The term "hydroxy" refers to --OH.

[0096] The term "amino" refers to -NH2.

[0097] The term "cyano" refers to -CN.

[0098] The term "nitro" refers to -NO2.

[0099] The term "oxygen substituted" or "oxo" refers to "=O".

[0100] The term "carbonyl" refers to C=O.

[0101] The term "carboxy" refers to -C(O)OH.

[0102] The term "carboxylate group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are defined above.

[0103] The compounds of the present disclosure can exist in specific stereoisomeric forms. The term "stereoisomer" encompasses all isomeric forms, including enantiomers, diastereoisomers, and geometric isomers, including cis-trans isomers. Therefore, individual stereochemical isomers of the compounds designed in the present disclosure, or their enantiomers, diastereoisomers, or geometric isomers (or cis-trans isomers), and mixtures thereof, are within the scope of the present disclosure. An isomer of a specific compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the compound can be reacted with an appropriate optically active acid or base to form a diastereoisomeric salt, which can then be resolved into pure isomers by conventional methods known in the art. Separation of enantiomers from diastereoisomers is typically achieved by chromatography.

[0104] In the chemical structures of the compounds described in this disclosure, [ka] " bond indicates unspecified configuration, i.e., if chiral isomers are present in the chemical structure, " [ka] " Bond is " [ka] "or" [ka] " or " [ka] " and " [ka] " includes both configurations. The compounds of the present disclosure are made up of all suitable isotopic derivatives of the compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable isotopes and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, etc., for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., and preferably deuterium.

[0105] Compared with non-deuterated pharmaceuticals, deuterated pharmaceuticals have the advantages of reduced toxicity, improved drug stability, enhanced therapeutic effect, and extended biological half-life of drugs.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included in the scope of the present disclosure.Each available hydrogen atom linked to a carbon atom may be independently replaced with a deuterium atom, and the deuterium replacement may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced with at least one deuterium.

[0106] "Optionally" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and includes both the occurrence or non-occurrence of the event or circumstance. For example, "alkyl optionally substituted with halogen or cyano" includes cases where the alkyl is substituted with halogen or cyano and cases where the alkyl is not substituted with halogen or cyano.

[0107] "Substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group, are independently replaced with the corresponding number of substituents. Those skilled in the art can easily determine (experimentally or theoretically) possible or impossible substitutions. For example, an amino group or hydroxyl group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond, such as an alkene.

[0108] A "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or pharmaceutically acceptable salts thereof, together with other chemical components, such as pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body, contribute to the absorption of the active ingredient, and allow it to exert its biological activity.

[0109] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the desired biological activity. These salts are prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

[0110] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent means an amount of the pharmaceutical or active agent sufficient to achieve, or at least partially achieve, a desired effect. Determination of a therapeutically effective amount will vary from person to person and will depend not only on the particular active agent, but also on the age and general condition of the recipient, and the appropriate therapeutically effective amount in each individual case can be determined by one skilled in the art based on routine testing.

[0111] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, and that are effective for their intended use, having a reasonable benefit / risk ratio.

[0112] As used herein, the singular forms "a," "one," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0113] The term "about," when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter may vary within ±10%, and in some cases more preferably ±5%. As will be understood by those skilled in the art, when a parameter is not critical, the numerical value is generally given for purposes of illustration only and not limitation. Methods for synthesizing compounds of the present disclosure

[0114] In order to achieve the objectives of the present disclosure, the following technical means are adopted: Means 1

[0115] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; where: X is a halogen, preferably Cl; Rings A, L, Z, R a , R 1 ~R 9 , m and s are as defined in general formula (I). Means 2

[0116] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, where: X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II). Means 3

[0117] The present disclosure provides a method for preparing a compound represented by general formula (II-1) or a salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II-1). Means 4

[0118] The present disclosure provides a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, L, R a , R b , R 1 , R 2 , R 4 , R 5 , m and n are as defined in general formula (II-2). Means 5

[0119] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III). Means 6

[0120] The present disclosure provides a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III-1). Means 7

[0121] The present disclosure provides a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , m and n are as defined in general formula (III-2). Means 8

[0122] The present disclosure provides a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV). Means 9

[0123] The present disclosure provides a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (II-1B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV-1). means 10

[0124] The present disclosure provides a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (II-2B) or a salt thereof are subjected to a nucleophilic substitution reaction by microwave irradiation to obtain a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, X is a halogen, preferably Cl; Ring A, Ring B, R a , R b , R 1 , R 2 , R 4 , R 5 , R 4a , R 4b , R 5a , R 5b , m and n are as defined in general formula (IV-2).

[0125] In the above synthesis methods, the reagents that provide the basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide. The reagent for the basic conditions is preferably N,N-diisopropylethylamine.

[0126] The reaction in the above step is preferably carried out in a solvent, and the solvent used includes, but is not limited to, pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION

[0127] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. <Example>

[0128] Compound structures were determined using NMR spectra obtained on a Varian 400 MHz nuclear magnetic resonance spectrometer, often using CDCl3 and DMSO-d6 as solvents. Chemical shifts are reported in ppm. The various peaks are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and dd (double doublet). Coupling constants are expressed in Hz.

[0129] The LC-MS liquid chromatography mass spectrometer was a Waters ACQUITY Arc equipped with a QDa Detector. Mass spectrometry (MS) used an ESI ion source to reveal only the molecular weight M of the parent molecule, usually [M + H]. + The injection volume was determined by the sample concentration, the flow rate was 0.8 mL / min, and HPLC peak values ​​were recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B).

[0130] Chiral HPLC analysis was performed using a SHIMADZU LC-30AD SFC high performance liquid chromatograph.

[0131] The silica gel plates used for thin-layer chromatography were Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plate specifications for thin-layer chromatography (TLC) were 0.15mm to 0.2mm, while those for products separated and purified by thin-layer chromatography were 0.4mm to 0.5mm.

[0132] Silica gel column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0133] Known starting materials in this disclosure can be synthesized using or according to methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Technology (Shanghai) Co., Ltd. (Accela ChemBio Inc), Dari Chemical, etc.

[0134] In the examples, unless otherwise specified, the reactions can be carried out under an argon or nitrogen atmosphere.

[0135] By argon or nitrogen atmosphere is meant that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0136] By hydrogen atmosphere is meant that the reaction flask is connected to a hydrogen balloon with a volume of approximately 1 L.

[0137] The hydrogenation reaction was typically repeated three times by evacuating and filling with hydrogen.

[0138] Microwave reactions were carried out using a Biotage microwave synthesizer.

[0139] In the examples, unless otherwise specified, the term "solution" refers to an aqueous solution.

[0140] In the examples, the reaction temperature was room temperature, 20°C to 30°C, unless otherwise specified.

[0141] In the examples, the reaction process was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography comprised A: n-hexane / ethyl acetate system and B: dichloromethane / methanol system, and the volume ratio of the solvents was adjusted according to the polarity of the compound, and could also be adjusted by adding a small amount of a basic or acidic reagent such as triethylamine or acetic acid.

[0142] The abbreviations used in this disclosure are as follows: EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBT: 1-hydroxybenzotriazole TEA: Triethylamine DCM: dichloromethane DMF: N,N-dimethylformamide DMF-DMA: N,N-dimethylformamide dimethyl acetal LHMDS: lithium bis(trimethylsilyl)amide TMSI: iodotrimethylsilane THF: tetrahydrofuran [Example]

[0143] Example 1 (R)-2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 1 [ka] Step 1 (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol 1b

[0144] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]la (15.0 g, 72.8 mmol), 1-aminocyclobutylmethylamine hydrochloride (11.0 g, 80.1 mmol), and triethylamine (22.1 g, 218.4 mmol) were mixed in 1,4-dioxane (100 mL) at room temperature. The reaction mixture was stirred at 80 °C for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. Water (100 mL) was then added, and the mixture was extracted with dichloromethane (200 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 1b (15.2 g). Step 2 (R)-2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 1c

[0145] Under nitrogen protection, compound 1b (15.2 g, 58.1 mmol), S-1,1'-bi-2-naphthol (1.66 g, 5.81 mmol), titanium(IV) tetraisopropoxide (0.82 g, 2.9 mmol), and water (1.05 g, 58.1 mmol) were mixed in dichloromethane (100 mL) and stirred at room temperature for 1 hour. Then, tert-butyl hydroperoxide (5.75 g, 63.9 mmol) was added, and the reaction mixture was heated to 40°C and stirred for 5 hours. After the reaction was completed, the solid was filtered off, slurried in methanol, and purified to give the title compound 1c (16.7 g, ee value: 97.4%). Step 3 4-Chloro-N-(4-hydroxypyridin-3-yl)benzamide 1f

[0146] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridin-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0 °C in an ice bath. Then, a solution of 4-chlorobenzoyl chloride 1e (3.3 g, 19.1 mmol) in dichloromethane (5 mL) was slowly added dropwise. After stirring at room temperature for 2 hours, the mixture was filtered, and the filter cake was washed with water and dried to give the title compound 1f (2.5 g). Step 4 2-(4-chlorophenyl)oxazolo[4,5-c]pyridine 1g

[0147] Triphenylphosphine (6.7 g, 24.3 mmol) and triethylamine (6.5 g, 64.8 mmol) were added to a solution of hexachloroethane (4.7 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature. After stirring the mixture at room temperature for 10 minutes, compound 1f (2 g, 8.1 mmol) was added in batches and stirred at room temperature for 5 hours. The mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 1g (1.3 g). Step 5 2-(4-chlorophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 1h

[0148] To a solution of compound 1g (1.0 g, 4.3 mmol) in DMF (10 mL) was added iodomethane (0.9 g, 6.5 mmol) at room temperature. The mixture was stirred at room temperature for 5 h, and the reaction mixture was concentrated to give the title compound 1h (1.1 g). Step 6 2-(4-Chlorophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 1i

[0149] Sodium borohydride (225 mg, 5.9 mmol) was added batchwise to a solution of compound 1h (1.1 g, 2.9 mmol) in methanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated by centrifugal evaporation until the methanol was removed, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 1i (700 mg, 21.7% yield). Step 7 2-(4-Chlorophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 1j

[0150] At 0°C under a nitrogen atmosphere, 1-chloroethyl chloroformate (343.5 mg, 2.4 mmol) was added to a solution of compound 1i (400 mg, 1.6 mmol) in dichloroethane (8 mL). The reaction mixture was stirred at 80°C for 2 hours, and then the mixture was cooled to room temperature and concentrated to dryness. To the mixture was added a solution of methanol (6 mL), and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 1j (350 mg). Step 8 (R)-2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 1

[0151] To a 1,4-dioxane solution (4 mL) of compound 1j (50 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 1 (20 mg, yield: 21.7%).

[0152] 1 H NMR (400MHz, DMSO-d6): δ7.98(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),7.49(s,1H),4.87(t,J=8.0Hz,1H),4.79(br.s,2H),4.18(br.s,2H),3.78(d,J =4.0Hz,2H),3.43-3.51(m,1H),3.22-3.29(m,1H),2.96-3.02(m,2H),2.89 (t,J=7.6Hz,2H),2.31-2.44(m,2H),2.22-2.27(m,2H),1.78-1.86(m,2H).

[0153] MS m / z(ESI): 486[M+1]. Example 2

[0154] (R)-2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 2 [ka] Step 1 4-Fluoro-N-(4-hydroxypyridin-3-yl)benzamide 2b

[0155] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridin-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0 °C in an ice bath. Then, a solution of 4-fluorobenzoyl chloride 2a (3.0 g, 19.1 mmol) in dichloromethane (5 mL) was slowly added dropwise. After stirring at room temperature for 2 h, the mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 2b (3.7 g). Step 2 2-(4-Fluorophenyl)oxazolo[4,5-c]pyridine 2c

[0156] Triphenylphosphine (6.8 g, 25.8 mmol) and triethylamine (6.9 g, 68.8 mmol) were added to a solution of hexachloroethane (5.1 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature. After stirring the mixture at room temperature for 10 minutes, compound 2b (2.0 g, 8.6 mmol) was added in batches and stirred at room temperature for 5 hours. The mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 2c (1.2 g). Step 3 2-(4-Fluorophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 2d

[0157] To a solution of compound 2c (1.0 g, 4.7 mmol) in DMF (10 mL) was added iodomethane (1.0 g, 7.0 mmol) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to give the title compound 2d (1.1 g). Step 4 2-(4-Fluorophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 2e

[0158] Sodium borohydride (230 mg, 6.2 mmol) was added batchwise to a solution of compound 2d (1.1 g, 3.1 mmol) in methanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated by centrifugal evaporation until the methanol was removed, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 2e (930 mg), a yellow eluate. Step 5 2-(4-Fluorophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 2f

[0159] At 0°C under a nitrogen atmosphere, 1-chloroethyl chloroformate (370 mg, 2.6 mmol) was added to a solution of compound 2e (400 mg, 1.7 mmol) in dichloroethane (8 mL). The reaction mixture was stirred at 80°C for 2 hours, and then the mixture was cooled to room temperature and concentrated to dryness. To the mixture was added a solution of methanol (6 mL), and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 2f (380 mg). Step 6 (R)-2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 2

[0160] To a 1,4-dioxane solution (4 mL) of compound 2f (45 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 2 (25 mg, yield: 28.1%).

[0161] 1 H NMR(400MHz,DMSO-d6):δ8.03(dd,J=16.0,8.0Hz,2H),7.54(s,1H),7.39(t,J=8.0Hz,2H),4.89(t,J=4.0Hz,1H),4.79(br.s,2H),4.18(br.s,2H),3.7 8(d,J=4.0Hz,2H),3.42-3.53(m,1H),3.21-3.30(m,1H),2.95-3.04(m,1H) ,2.89(br.s,3H),2.30-2.43(m,2H),2.22-2.29(m,2H),1.76-1.89(m,2H).

[0162] MS m / z(ESI): 470 [M+1]. Example 3

[0163] (R)-4-(5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-ylbenzonitrile 3 [ka] [ka] Step 1 4-Cyano-N-(4-hydroxypyridin-3-yl)benzamide 3b

[0164] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridin-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0 °C in an ice bath. Then, a solution of 4-cyanobenzoyl chloride 3a (3.2 g, 19.1 mmol) in dichloromethane (5 mL) was slowly added dropwise. After stirring at room temperature for 2 h, the mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 3b (2.8 g). Step 2 4-(Oxazolo[4,5-c]pyridin-2-yl)benzonitrile 3c

[0165] Triphenylphosphine (6.8 g, 25.8 mmol) and triethylamine (6.9 g, 68.8 mmol) were added to a solution of hexachloroethane (5.1 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature. After stirring the mixture at room temperature for 10 minutes, compound 3b (2.0 g, 8.6 mmol) was added in batches and stirred at room temperature for 5 hours. The mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 3c (1.1 g). Step 3 2-(4-cyanophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 3d

[0166] To a solution of compound 3c (1.0 g, 4.5 mmol) in DMF (10 mL) was added iodomethane (0.97 g, 6.8 mmol) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to give the title compound 3d (1.0 g). Step 4 2-(4-cyanophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 3e

[0167] Sodium borohydride (200 mg, 5.5 mmol) was added batchwise to a solution of compound 3d (1.0 g, 2.8 mmol) in methanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated by centrifugal evaporation until the methanol was removed, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 3e (200 mg). Step 5 2-(4-cyanophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 3f

[0168] At 0°C under a nitrogen atmosphere, 1-chloroethyl chloroformate (250 mg, 1.8 mmol) was added to a solution of compound 3e (200 mg, 0.9 mmol) in dichloroethane (8 mL). The reaction mixture was stirred at 80°C for 2 hours, and then the mixture was cooled to room temperature and concentrated to dryness. To the mixture was added a solution of methanol (6 mL), and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 3f (180 mg). Step 6 (R)-4-(5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-ylbenzonitrile 3

[0169] To a 1,4-dioxane solution (4 mL) of compound 3f (47 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 3 (20 mg, yield: 22.2%).

[0170] 1 H NMR (400MHz, DMSO-d6): δ8.14(m,4H),7.61(d,J=8.0Hz,2H),7.54(s,1H),4.89(t,J=4.0Hz,1H),4.83(br.s,2H),4.19(br.s,2H),3.78(d,J=4. 0Hz,2H),3.43-3.53(m,1H),3.21-3.30(m,1H),2.96-3.04(m,1H),2.87 -2.95(m,3H),2.30-2.45(m,2H),2.20-2.29(m,2H),1.79-1.89(m,2H).

[0171] MS m / z(ESI): 477[M+1]. Example 4

[0172] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(3-(2-methoxyethoxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 4 [ka] [ka] Step 1 3-(2-Methoxyethoxy)benzoyl chloride 4b

[0173] Under nitrogen protection, DMF (37 mg, 0.5 mmol) was added to a solution of 3-(2-methoxyethoxy)benzoic acid 4a (1.0 g, 5.1 mmol) in dichloromethane (10 mL). The mixture was cooled to 0 °C in an ice bath. Then, a solution of oxalyl chloride (771 mg, 6.1 mmol) in dichloromethane (3 mL) was slowly added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated to give the title compound 4b (1.1 g). Step 2 N-(4-Hydroxypyridin-3-yl)-3-(2-methoxyethoxy)benzamide 4c

[0174] Compound 4b (1.1 g, 5.1 mmol) was prepared according to the method of Step 3 of Example 1 to give the title compound 4c (700 mg). Step 3 2-(3-(2-methoxyethoxy)phenyl)oxazolo[4,5-c]pyridine 4d

[0175] Compound 4c (700 mg, 2.4 mmol) was prepared according to the method of Step 4 of Example 1 at room temperature to give the title compound 4d (600 mg). Step 4 2-(3-(2-methoxyethoxy)phenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 4e

[0176] Compound 4d (600 mg, 2.2 mmol) was prepared according to the method of Step 5 of Example 1 at room temperature to give the title compound 4e (900 mg). Step 5 2-(3-(2-methoxyethoxy)phenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 4f

[0177] Compound 4e (900 mg, 2.2 mmol) was prepared according to the method of Step 6 of Example 1 at 0° C. to give the title compound 4f (500 mg). Step 6 2-(3-(2-methoxyethoxy)phenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 4g

[0178] Compound 4E (500 mg, 1.7 mmol) was prepared according to the method of Step 7 of Example 1 at room temperature to give the title compound 4g (400 mg). Step 7 (R)-4-(1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(3-(2-methoxyethoxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 4

[0179] Compound 4g (50 mg, 0.18 mmol) and compound 1c (47 mg, 0.16 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 4 (20 mg, yield: 23.8%).

[0180] 1 H NMR(400MHz,DMSO-d6):δ7.55(m,2H),7.45(m,2H),7.11(dd,J=2.0Hz,8.0Hz,1H ),4.90(t,J=5.6Hz,1H),4.78(br.s,2H),4.18-4.21(m,2H),3.78(d,J=5.2Hz,2 H),3.70(t,J=4.8Hz,2H),3.45-3.51(m,1H),3.22-3.35(m,4H),2.92-3.02(m,1 H),2.88-2.89(m,4H),2.31-2.38(m,2H),2.24-2.27(m,2H),1.80-1.84(m,2H).

[0181] MS m / z(ESI): 526 [M+1]. Example 5

[0182] (R)-2-(2-Cyclohexyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 5 [ka] [ka] Step 1 N-(4-hydroxypyridin-3-yl)cyclohexanecarboxamide 5b

[0183] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridin-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0 °C in an ice bath. Then, a solution of cyclohexanecarbonyl chloride 5a (2.8 g, 19.1 mmol) in dichloromethane (5 mL) was slowly added dropwise. After stirring at room temperature for 2 h, the mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 5b (2.8 g). Step 2 2-Cyclohexyloxazolo[4,5-c]pyridine 5c

[0184] Triphenylphosphine (7.2 g, 7.3 mmol) and triethylamine (7.4 g, 72.8 mmol) were added to a solution of hexachloroethane (5.4 g, 22.5 mmol) in dichloromethane (30 mL) at room temperature. After stirring the mixture at room temperature for 10 minutes, compound 5b (2.0 g, 9.1 mmol) was added in batches and stirred at room temperature for 5 hours. The mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 5c (0.8 g). Step 3 2-Cyclohexyl-5-methyloxazolo[4,5-c]pyridin-5-ium 5d

[0185] To a solution of compound 5c (0.8 g, 4.0 mmol) in DMF (10 mL) was added iodomethane (0.85 g, 6.0 mmol) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to give the title compound 5d (0.9 g). Step 4 2-Cyclohexyl-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 5e

[0186] Sodium borohydride (190 mg, 5.2 mmol) was added batchwise to a solution of compound 5d (0.9 g, 2.6 mmol) in methanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated by centrifugal evaporation until the methanol was removed, extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 5e (700 mg). Step 5 2-Cyclohexyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 5f

[0187] At 0°C under a nitrogen atmosphere, 1-chloroethyl chloroformate (910 mg, 6.4 mmol) was added to a solution of compound 5e (700 mg, 3.2 mmol) in dichloroethane (8 mL). The reaction mixture was stirred at 80°C for 2 hours, and then the mixture was cooled to room temperature and concentrated to dryness. To the mixture was added a solution of methanol (6 mL), and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 5f (280 mg). Step 6 (R)-2-(2-Cyclohexyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 5

[0188] To a 1,4-dioxane solution (4 mL) of compound 5f (44 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 5 (16 mg, yield: 18.4%).

[0189] 1 H NMR(400MHz,DMSO-d6):δ7.49(s,1H),4.88(t,J=8.0Hz,1H),4.66(s,2H), 4.11(s,2H),3.77(d,J=8.0Hz,2H),3.40-3.50(m,1H),3.19-3.29(m,1H),2 .78-3.01(m,2H),2.70-2.77(m,2H),2.28-2.44(m,2H),2.18-2.26(m,2H), 1.80-1.98(m,4H),1.62-1.70(m,1H)1.44-1.56(m,2H),1.22-1.43(m,4H).

[0190] MS m / z(ESI): 458 [M+1]. Example 6

[0191] (R)-2-(2-(4-chlorophenyl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 6 [ka] [ka] Step 1 4-Chloro-N-(4-chloropyridin-3-yl)benzamide 6b

[0192] Under nitrogen protection, a solution of 4-chloropyridin-3-amine 6a (2.0 g, 15.6 mmol) in dichloromethane (30 mL) was cooled to 0 °C in an ice bath. Then, a solution of 4-chlorobenzoyl chloride 1e (3.0 g, 17.2 mmol) in dichloromethane (5 mL) was slowly added dropwise. After stirring at room temperature for 2 h, the mixture was quenched with ammonium chloride solution and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 6b (2.1 g). Step 2 2-(4-Chlorophenyl)thiazolo[4,5-c]pyridine 6c

[0193] Compound 6b (2.0 g, 7.5 mmol) was added to a xylene solution (50 mL) of Lawesson's reagent (2.1 g, 5.3 mmol) at room temperature, and the mixture was heated to 120 °C and stirred for 5 hours. The solvent was removed by rotary evaporation, sodium hypochlorite solution was added, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 6c (1.1 g). Step 3 2-(4-chlorophenyl)-5-methylthiazolo[4,5-c]pyridin-5-ium 6d

[0194] To a solution of compound 6c (1.1 g, 4.2 mmol) in DMF (10 mL) was added iodomethane (0.9 g, 6.3 mmol) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to give the title compound 6d (1.2 g). Step 4 2-(4-Chlorophenyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine 6e

[0195] Sodium borohydride (230 mg, 6.2 mmol) was added batchwise to a solution of compound 6d (1.2 g, 3.1 mmol) in methanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated by centrifugal evaporation until the methanol was removed, extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 6e (800 mg). Step 5 2-(4-chlorophenyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine 6f

[0196] 1-Chloroethyl chloroformate (860 mg, 6.0 mmol) was added to a solution of compound 6e (800 mg, 3.0 mmol) in dichloroethane (12 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 2 hours, and then the mixture was cooled to room temperature and concentrated to dryness. A solution of methanol (6 mL) was added to the mixture, and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 6f (350 mg). Step 6 (R)-2-(2-(4-chlorophenyl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 6

[0197] To a 1,4-dioxane solution (4 mL) of compound 6f (53 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 6 (16 mg, yield: 16.8%).

[0198] 1 H NMR (400MHz, DMSO-d6): δ7.93(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.51(s,1H),4.98(br.s,2H),4.89(t,J=8.0Hz,1H),4.15(br.s,2H) ,3.78(d,J=4.0Hz,2H),3.43-3.52(m,1H),3.21-3.29(m,1H),2.86-3.05(m,4H),2.33-2.46(m,2H),2.20-2.29(m,2H),1.77-1.89(m,2H).

[0199] MS m / z(ESI): 503 [M+1]. Example 7

[0200] (R)-2-(2-(4-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 7 [ka] [ka] Step 1 tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate 7b

[0201] Under nitrogen protection, a solution of tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate 7a (0.6 g, 3.0 mmol) in dichloromethane (20 mL) was cooled to 0 °C in an ice bath. Then, a solution of 4-chlorobenzoyl chloride (0.57 g, 3.3 mmol) in dichloromethane (3 mL) was slowly added dropwise. After stirring at room temperature for 2 h, the mixture was quenched with ammonium chloride solution and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 7b (0.56 g). Step 2 tert-Butyl 3-(4-chlorobenzamido)-4-oxopyrrolidine-1-carboxylate 7c

[0202] At 0°C, Dess-Martin oxidant (1.4 g, 3.3 mmol) was added to a dichloromethane solution (50 mL) of compound 7b (0.56 g, 1.6 mmol). The mixture was stirred at room temperature for 2 hours, quenched with sodium thiosulfate solution, and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 7c (0.41 g). Step 3 tert-Butyl 2-(4-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate 7d

[0203] Triphenylphosphine (0.94 g, 3.6 mmol) and triethylamine (0.97 g, 9.6 mmol) were added to a solution of hexachloroethane (0.71 g, 3.0 mmol) in dichloromethane (30 mL) at room temperature. After stirring the mixture at room temperature for 10 minutes, compound 7c (0.41 g, 1.2 mmol) was added in batches and stirred at room temperature for 5 hours. The mixture was quenched with ammonium chloride solution and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 7d (0.19 g). Step 4 2-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole hydrochloride 7e

[0204] Compound 7d (0.19 g, 3.1 mmol) was stirred in 1,4-dioxane with hydrochloric acid (5 mL) at room temperature for 1 hour, and the solvent was concentrated by centrifugal evaporation to give the title compound 7e (150 mg). Step 5 (R)-2-(2-(4-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 7

[0205] To a 1,4-dioxane solution (4 mL) of compound 7e (54 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 7 (11 mg, yield: 12.3%).

[0206] 1H NMR(400MHz,DMSO-d6):δ8.00-8.05(m,2H),7.63-7.68(m,2H),7.51(s,1H),4.85-4.91(m,1H),4.74-4.81(m,2H),4.56-4.62(m,2H),3.79(d,J= 8.0Hz,2H),3.46-3.53(m,1H),3.23-3.32(m,1H),2.98-3.08(m,1H),2.8 9-2.96(m,1H),2.34-2.48(m,2H),2.21-2.30(m,2H),1.76-1.89(m,2H). MS m / z(ESI): 472 [M+1]. Example 8

[0207] (R)-2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 8 [ka] [ka] Step 1 Ethyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8b

[0208] 2,4-Dichloro-6,7-dihydrothieno[3,2-d] 8a (1.0 g, 4.9 mmol), ethyl 2-(4-aminophenyl)acetate (0.96 g, 5.4 mmol), and triethylamine (0.99 g, 9.8 mmol) were mixed in ethanol (15 mL) at room temperature. The reaction mixture was stirred at 80 °C for 5 hours. After completion of the reaction, the solvent was removed by rotary evaporation. Water (30 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 8b (800 mg). Step 2 Ethyl (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8c

[0209] Compound 8b (800 mg, 2.3 mmol) was prepared according to the method of Step 2 of Example 1 at room temperature to give the title compound 8c (500 mg). Step 3 Ethyl (R)-2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8d

[0210] Compound 8c (100 mg, 0.27 mmol) and compound 1j (66 mg, 0.24 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 8d (60 mg). Step 4 (R)-2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 8

[0211] Sodium hydroxide (18 mg, 0.44 mmol) was added to a solution of compound 8d (60 mg, 0.11 mmol) in methanol (6 mL) / water (2 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated by centrifugal evaporation until the methanol was removed. Dilute hydrochloric acid (2 M) was added to the reaction mixture to adjust the pH to 2-3, and the mixture was filtered. The filter cake was washed with ethyl acetate and dried to give the title compound 8 (30 mg, yield: 50.8%).

[0212] 1H NMR(400MHz,DMSO-d6):δ9.66(s,1H),7.97(d,J=8.4Hz,2H),7.61-7.65(m,4H),7.28(d,J=8.4Hz,2H),4.81(br. s,2H),4.21(br.s,2H),3.60(s,2H),3.55-3.57(m,1H),3.28-3.30(m,1H),2.99-3.14(m,2H),2.90-2.92(m,2H), MS m / z(ESI):536[M+1]. Example 9

[0213] (R)-2-(6-(5-chloropyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 9 [ka] [ka] Step 1 tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 9b

[0214] Under nitrogen protection, tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate 9a (1.0 g, 3.2 mmol), bis(pinacolato)diboron (0.9 g, 3.5 mmol), potassium acetate (0.47 mg, 4.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (250 mg, 0.3 mmol) were mixed in 1,4-dioxane (15 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the solvent was removed by rotary evaporation. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were concentrated under reduced pressure to give the crude title compound 9b (1.2 g). Step 2 tert-Butyl 6-(5-chloropyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 9c

[0215] Under nitrogen protection, compound 9a (500 mg, 1.4 mmol), 2-bromo-5-chloropyrimidine (322 mg, 1.7 mmol), potassium carbonate (309 mg, 2.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (81 mg, 0.1 mmol) were mixed in 1,4-dioxane (15 mL) / water (3 mL). The reaction mixture was stirred at 80 °C for 3 h. Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 9c (300 mg). Step 3 6-(5-chloropyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 9d

[0216] To a solution of compound 9c (300 mg, 0.87 mmol) in dichloromethane was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound 9d (330 mg). Step 4 (R)-2-(6-(5-chloropyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 9

[0217] Compound 9d (50 mg, 0.18 mmol) and compound 1c (47 mg, 0.16 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 9 (22 mg, yield: 27.8%).

[0218] 1H NMR(400MHz,DMSO-d6):δ9.01(s,2H),8.20(d,J=7.2Hz,2H),7.38-7.42(m,2H),4.98(br.s,2H),4.88(t,J=5.6Hz,2H),4.04(t,J=5.6Hz,2H) ),3.78(d,J=5.6Hz,2H),3.44-3.49(m,1H),3.22-3.26(m,1H),2.85-2.95(m,4H),2.36-2.41(m,2H),2.22-2.26(m,2H),1.80-1.87(m,2H).

[0219] MS m / z(ESI): 497[M+1]. Example 10

[0220] (R)-2-(6-(4-fluoropiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 10 [ka] [ka] Step 1 tert-Butyl 6-(4-fluoropiperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 10a

[0221] Under nitrogen protection, tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate 9a (1.0 g, 3.2 mmol), 4-fluoropiperidine hydrochloride (0.54 mg, 3.8 mmol), sodium tert-butoxide (0.70 g, 7.1 mmol), tris(dibenzylideneacetone)dipalladium (293 mg, 0.32 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (206 mg, 0.32 mmol) were mixed in toluene (15 mL). The reaction mixture was stirred at 110 °C for 6 h. After completion of the reaction, the solvent was removed by rotary evaporation. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 10a (400 mg). Step 2 6-(4-Fluoropiperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 10b

[0222] To a solution of compound 10a (400 mg, 1.2 mmol) in dichloromethane was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound 10b (300 mg). Step 3 (R)-2-(6-(4-fluoropiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 10

[0223] Compound 10b (50 mg, 0.18 mmol) and compound 1c (47 mg, 0.16 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 10 (22 mg, yield: 28.2%).

[0224] 1H NMR (400MHz, DMSO-d6): δ7.35(s,1H),7.06(d,J=7.6Hz,1H),6.85(dd,J=2.0Hz,8.0Hz,1H),6. 78(s,1H),4.90-4.93(m,2H),4.77-4.79(m,2H),3.94(br.s,2H),3.78(d,J=5.6Hz,2H),3.44- 3.49(m,1H),3.22-3.26(m,1H),3.09-3.15(m,1H),2.85-2.95(m,2H),2.81(t,J=5.6Hz,2H),2 .35-2.40(m,2H),2.22-2.33(m,2H),2.35-2.40(m,2H),1.90-2.08(m,2H),1.79-1.82(m,4H).

[0225] MS m / z(ESI): 486[M+1]. Example 11

[0226] (R)-2-(3-(4-fluorophenyl)-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 11 [ka] [ka] Step 1 tert-Butyl 3-(4-fluorobenzoyl)-4-oxopiperidine-1-carboxylate 11b

[0227] Under nitrogen protection, LHMDS (10 mL, 1 M) was slowly added dropwise to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10.0 mmol) in tetrahydrofuran (30 mL) while maintaining the temperature at -30 °C. The reaction mixture was stirred at this temperature for 30 min. Next, a solution of 4-fluorobenzoyl chloride (1.7 g, 10.0 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at this temperature for 3 h. The mixture was quenched by adding saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (40 mL × 2), and the combined organic phase was concentrated under reduced pressure to give the crude product 11b (3 g) of the title compound. Step 2 tert-Butyl 3-(4-fluorophenyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 11c

[0228] Compound 11b (3 g, 9.3 mmol) and hydrazine hydrate (0.75 g, 18.7 mmol, 80% in HO) were dissolved in ethanol (30 mL) and the reaction was carried out at 80 °C for 3 h. The reaction mixture was cooled to room temperature, and the majority of the ethanol was removed by concentration. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 11c (400 mg). Step 3 3-(4-Fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride 11d

[0229] To a solution of compound 11c (400 mg, 1.2 mmol) in dichloromethane was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound 11d (450 mg). Step 4 (R)-2-(3-(4-fluorophenyl)-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 11

[0230] Compound 11d (50 mg, 0.20 mmol) and compound 1c (51 mg, 0.18 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 11 (10 mg, yield: 11.9%).

[0231] 1 H NMR(400MHz,DMSO-d6):δ7.68-7.69(m,2H),7.36-7.43(m,2H),4.85-5.05(m,3H),4.1(br.s,2H),3.65-3.79(m,2H) ,3.44-3.49(m,1H),3.22-3.26(m,1H),2.77-2.96(m,4H),2.35-2.41(m,2H),2.22-2.33(m,2H),1.80-1.85(m,2H).

[0232] MS m / z(ESI): 469 [M+1]. Example 12

[0233] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(1-phenyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide 12 [ka] [ka] Step 1 tert-Butyl 3-((dimethylamino)methyl)-4-oxopiperidine-1-carboxylate 12a

[0234] Under nitrogen protection, DMF-DMA (1.2 g, 10.0 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate 11a (2.0 g, 10.0 mmol) in DMF (20 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was then concentrated, saturated ammonium chloride (40 mL) solution was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The combined organic phases were concentrated under reduced pressure to give the title compound 12a (2.2 g). Step 2 tert-Butyl 1-phenyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 12c

[0235] Compound 12a (2.1 g, 9.3 mmol) was dissolved in methanol (100 mL) and water (50 mL). Sodium bicarbonate (0.53 g, 5.0 mmol) and phenylhydrazine hydrochloride 12b (1.43 g, 9.9 mmol) were then added, followed by acetic acid (1 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was then neutralized with saturated sodium bicarbonate solution, concentrated by centrifugal evaporation until the methanol was removed, and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 12c (1.3 g). Step 3 1-Phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride 12d

[0236] To a solution of compound 12c (200 mg, 1.2 mmol) in dichloromethane was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound 12d (250 mg). Step 4 (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(1-phenyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide 12

[0237] Compound 12d (50 mg, 0.21 mmol) and compound 1c (51 mg, 0.18 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 12 (20 mg, yield: 24.7%).

[0238] 1 H NMR(400MHz,DMSO-d6):δ7.66(s,1H),7.60(d,J=7.6Hz,2H),7.53(t,J=8.0Hz, 2H),7.50(s,1H),7.40(d,J=7.6Hz,1H),4.89(t,J=5.6Hz,1H),4.82-4.85(m,2 H),4.06(br.s,2H),3.78(d,J=5.6Hz,2H),3.44-3.49(m,1H),3.22-3.27(m,1H ),2.90-3.00(m,4H),2.23-2.40(m,2H),2.22-2.26(m,2H),1.80-1.88(m,2H). MS m / z(ESI): 451 [M+1]. Example 13

[0239] (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 13 [ka] [ka] Step 1 tert-Butyl 2-(4-fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate 13c

[0240] tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate 13a (1.0 g, 3.6 mmol) and 4-fluorobenzosulfonamide 13b (0.56 g, 3.6 mmol) were mixed in an isopropanol solution (20 mL) at room temperature. The mixture was stirred at 60° C. for 5 hours, filtered, and the filter cake was washed with isopropanol and dried to give the title compound 13c (0.54 g). Step 2 2-(4-Fluorophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride 13d

[0241] Compound 13c (0.54 g, 1.6 mmol) was stirred in 1,4-dioxane with hydrochloric acid (8 mL) at room temperature for 1 hour, and the solvent was concentrated by centrifugal evaporation to give the title compound 13d (0.48 g). Step 3 (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 13

[0242] To a 1,4-dioxane solution (4 mL) of compound 13d (57 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 13 (30 mg, yield: 32.6%).

[0243] 1H NMR(400MHz,DMSO-d6):δ7.96(dd,J=8.0,2.0Hz,2H),7.56(s,1H),7.36(t,J=8.0Hz,2H),5.07(br.s,2H),4.89(t,J=4.0Hz,1H),4.14(br.s,2H) ),3.79(br,d,J=8.0Hz,2H),3.42-3.52(m,1H),3.20-3.29(m,1H),2.86 -3.04(m,4H),2.31-2.43(m,2H),2.21-2.29(m,2H),1.76-1.89(m,2H).

[0244] MS m / z(ESI): 486[M+1]. Example 14

[0245] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6,7-dihydroxythieno[3,2-d]pyrimidine 5-oxide 14 [ka] [ka] Step 1 tert-Butyl 2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate 14b

[0246] tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate 13a (1.0 g, 3.6 mmol) and pyridine-2-thioamide 14a (0.5 g, 3.6 mmol) were mixed in isopropanol (20 mL) at room temperature. The mixture was stirred at 60° C. for 5 hours, filtered, and the filter cake was washed with isopropanol and dried to give the title compound 14b (0.9 g). Step 2 2-(Pyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride 14c

[0247] Compound 14b (0.9 g, 2.8 mmol) was stirred in 1,4-dioxane with hydrochloric acid (8 mL) at room temperature for 1 hour, and the solvent was concentrated by centrifugal evaporation to give the title compound 14c (0.8 g). Step 3 (R)-4-(1-(hydroxymethyl)cyclobutyl)amino)-2-(2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6,7-dihydroxythieno[3,2-d]pyrimidine 5-oxide 14

[0248] To a 1,4-dioxane solution (4 mL) of compound 14c (53 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol), diisopropylethylamine (108 mg, 0.84 mmol) was added. The reaction mixture was stirred at 120 °C for 40 min using microwave irradiation. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 14 (35 mg, yield: 39.3%).

[0249] 1 H NMR(400MHz,DMSO-d6):δ8.63(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.96(t,J =8.0Hz,1H),7.54(s,1H),7.50(t,J=8.0Hz,1H),5.09(br.s,2H),4.89(t,J=8.0H z,1H),4.15(br.s,2H),3.77(d,J=4.0Hz,2H),3.41-3.51(m,1H),3.20-3.30(m, 1H), 2.87-3.04 (m, 4H), 2.31-2.44 (m, 2H), 2.20-2.29 (m, 2H), 1.76-1.89 (m, 2H).

[0250] MS m / z(ESI): 469 [M+1]. Example 15

[0251] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-phenyl-7,8-dihydropyrimido[4,3-d]pyrimidin-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 15 [ka] [ka] Step 1 tert-Butyl 2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 15b

[0252] Under nitrogen protection, compound 12a (1 g, 3.9 mmol), benzamidine hydrochloride 15a (0.67 g, 4.3 mmol), and triethylamine (0.98 g, 9.7 mmol) were dissolved in ethanol (15 mL), and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was concentrated, diluted with water (30 mL), and extracted with ethyl acetate (40 mL × 2). The combined organic phase was concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 15b (700 mg). Step 2 2-Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride 15c

[0253] To a solution of compound 15b (300 mg, 0.96 mmol) in dichloromethane was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound 15c (350 mg). Step 3 (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-phenyl-7,8-dihydropyrimido[4,3-d]pyrimidin-6(5H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 15

[0254] Compound 15c (50 mg, 0.20 mmol) and compound 1c (51 mg, 0.18 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 15 (20 mg, yield: 24.1%).

[0255] 1 H NMR(400MHz,DMSO-d6):δ8.82(s,1H),8.38-8.41(m,2H),7.51-7.54(m,4H),5.01(br.s,2H),4.89(t,J=5.6Hz,1H),4.16(t,J=5.6Hz,2H),4.06(b r.s,2H),3.79(d,J=5.6Hz,2H),3.44-3.49(m,1H),3.22-3.27(m,1H),2. 91-3.05(m,4H),2.37-2.40(m,2H),2.28-2.34(m,2H),1.79-1.85(m,2H).

[0256] MS m / z(ESI): 463 [M+1]. Example 16

[0257] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16 [ka] [ka] Step 1 3-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16b

[0258] Compound 1a (1.0 g, 5.0 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one 16a (0.75 g, 1.0 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 16b (1.1 g). Step 2 (R)-3-(((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16c

[0259] Under nitrogen protection, compound 16b (1.10 g, 3.41 mmol) was prepared according to the method of Step 2 of Example 1 to give the title compound 16c (0.8 g). Step 3 (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16

[0260] Compound 2f (20 mg, 0.1 mmol) and compound 16c (30 mg, 0.1 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 16 (3 mg, yield: 6%).

[0261] 1 H NMR(400MHz,DMSO-d6)δppm11.55(br s,1H),8.03(dd,J=8.74,5.45Hz,2H),7.61(br s,1H),7.39(t,J=8.88Hz,2H),5.88(s,1H),4.86(br s,2H),4.46-4.59(m,2H),4.26(br s,2H),3.37-3.53(m,1H),3.25-3.32(m,1H),2.94-3.06(m,1H),2.84-2.93(m,3H),2.19(s,3H),2.14(s,3H).

[0262] MS m / z(ESI): 521 [M+1]. Example 17

[0263] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17 [ka] [ka] Step 1 (6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)methylcarbamate tert-butyl 17b

[0264] In an ice bath, 2-(6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)acetonitrile 17a (0.5 g, 2.5 mmol), nickel(II) chloride (40 mg, 0.25 mmol), and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) were mixed in methanol (20 mL). Sodium borohydride (0.19 g, 5.0 mmol) was added and stirred for 2 hours. Sodium borohydride (0.19 g, 5.0 mmol) was then added and the mixture was heated to 25 ° C. and stirred for 14 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 17b (0.1 g). Step 2 3-(Aminomethyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one hydrochloride 17c

[0265] Compound 17b (0.1 g, 0.3 mmol) was stirred in a 1,4-dioxane hydrochloric acid solution (4 M, 3 mL) at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give the title compound 17c (80 mg). Step 3 3-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17d

[0266] Compound 1a (70 mg, 0.3 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one hydrochloride 17c (80 mg, 0.3 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 17d (20 mg). Step 4 (R)-3-(((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17e

[0267] Under nitrogen protection, compound 17d (20 mg, 0.05 mmol) was prepared according to the method of Step 2 of Example 1 to give the title compound 17e (15 mg). Step 5 (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17

[0268] Compound 2f (9 mg, 0.04 mmol) and compound 17e (15 mg, 0.04 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 17 (2 mg, yield: 9%).

[0269] 1H NMR(400MHz,DMSO-d6)δppm8.03(dd,J=8.79,5.40Hz,2H),7.68(br s,1H),7.39(t,J=8.88Hz,2H),6.32(s,1H),4.79-4.89(m,2H),4.55-4.66(m,2H),4.20-4.29(m,2H),3.43-3.52(m,2H),3.01(br dd,J=17.03,7.87Hz,1H),2.87-2.93(m,3H),2.29(s,3H).

[0270] MS m / z(ESI): 575 [M+1]. Example 18

[0271] (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 18 [ka] [ka] Step 1 (2-Methoxy-4,6-dimethylpyridin-3-yl)methylcarbamate tert-butyl 18b

[0272] In an ice bath, 2-(2-methoxy-4,6-dimethylpyridin-3-yl)acetonitrile 18a (0.5 g, 3.08 mmol) was prepared according to the method in Step 1 of Example 17 to give the title compound 18b (0.2 g). Step 2 (2-Methoxy-4,6-dimethylpyridin-3-yl)methylamine hydrochloride 18c

[0273] Compound 18b (0.2 g, 0.75 mmol) was prepared according to the method of Step 2 of Example 17 at room temperature to give the title compound 18c (15 mg). Step 3 2-Chloro-N-((2-methoxy-4,6-dimethyl-1,2-dihydropyridin-3-yl)methyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine 18d

[0274] Compound 1a (0.15 g, 0.75 mmol) and (2-methoxy-4,6-dimethylpyridin-3-yl)methylamine hydrochloride 18c (0.15 g, 0.75 mmol) were prepared according to the method in Step 1 of Example 1 to give the title compound 18d (0.23 g). Step 4 (R)-2-Chloro-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 18e

[0275] Under nitrogen protection, compound 18d (0.23 g, 0.68 mmol) was prepared according to the method of Step 2 of Example 1 to give the title compound 18e (0.23 g). Step 5 (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 18

[0276] Compound 2f (22 mg, 0.1 mmol) and compound 18e (35 mg, 0.1 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 18 (5 mg, yield: 9%).

[0277] 1H NMR(400MHz,DMSO-d6)δppm8.03(dd,J=8.79,5.40Hz,2H),7.85(br s,1H),7.40(t,J=8.83Hz,2H),6.69(s,1H),4.83(s,2H),4.70(dd,J=14.14,5.08Hz,1H),4.56(dd,J=14.14,4.53Hz,1H),4.23(br s,2H),3.85-3.93(m,3H),3.41-3.51(m,1H),3.27(dt,J=13.73,8.51Hz,1H),3.01(br dd,J=17.58,7.51Hz,1H),2.84-2.93(m,3H),2.35(s,3H),2.28(s,3H).

[0278] MS m / z(ESI): 535 [M+1]. Example 19

[0279] (R)-4-(Benzo[d]oxazole-6-amino)-2-(2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-7-dihydrothieno[3,2-d]pyrimidine 5-oxide 19 [ka] [ka] Step 1 N-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)benzo[d]oxazol-6-amine 19b

[0280] Compound 1a (1.0 g, 4.83 mmol) and benzo[d]oxazol-6-amine 19a (0.65 g, 4.83 mmol) were prepared according to the method in Step 1 of Example 1 to give the title compound 19b (0.72 g). Step 2 (R)-4-(Benzo[d]oxazole-6-amino)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 19c

[0281] Under nitrogen protection, compound 19b (0.72 g, 2.36 mmol) was prepared according to the method of Step 2 of Example 1 to give the title compound 19c (0.58 g). Step 3 (R)-4-(Benzo[d]oxazole-6-amino)-2-(2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-7-dihydrothieno[3,2-d]pyrimidine 5-oxide 19

[0282] Compound 14c (50 mg, 0.2 mmol) and compound 19c (63 mg, 0.2 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 19 (12 mg, yield: 12%).

[0283] 1 H NMR(400MHz,DMSO-d6)δppm9.93(s,1H),8.75(s,1H),8.65(d,J=4.30Hz,1H),8.18(br s,1H),8.10(d,J=7.87Hz,1H),7.96(td,J=7.71,1.60Hz,1H),7.81(d,J=8.61Hz,1H),7.69(br d,J=8.15Hz,1H),7.50(dd,J=6.91,5.36Hz,1H),5.13(br s,2H),4.18(br s,2H),3.54-3.65(m,1H),3.26-3.33(m,1H),3.15(br dd,J=16.80,8.01Hz,1H),2.95-3.07(m,3H).

[0284] MS m / z(ESI): 502 [M+1]. Example 20

[0285] (R)-2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 20 [ka] [ka] Step 1 (1s,4s)-4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclohexan-1-ol 20b

[0286] Compound 1a (300 mg, 1.45 mmol) and compound 20a (167 mg, 1.45 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 20b (300 mg). Step 2 (R)-2-Chloro-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 20c

[0287] Under nitrogen protection, compound 20b (200 mg, 0.70 mmol) was prepared according to the method of Step 2 of Example 1 to give the title compound 20c (150 mg). Step 3 (R)-2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 20

[0288] Compound 20c (30 mg, 0.1 mmol) and compound 2f (21 mg, 0.1 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 20 (12 mg, yield: 12%).

[0289] 1H NMR(400MHz,DMSO-d6)δppm8.02(m,2H),7.59(d,J=7.23Hz,1H),7.39(t,J=8.83Hz,2H),4.81(br s,2H),4.38(d,J=2.75Hz,1H),4.21(br s,2H),4.01(br s,1H),3.83(br s,1H),3.41-3.54(m,1H),3.24(m,1H),2.86-3.05(m,4H),1.77-1.90(m,2H),1.73(m,2H),1.51-1.68(m,4H).

[0290] MS m / z(ESI): 484 [M+1]. Example 21

[0291] (R)-2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 21 [ka] [ka] Step 1 Benzyl 4-(4-chlorobenzamido)-3-hydroxypiperidine-1-carboxylate 21c

[0292] Compound 21b (312 mg, 2.00 mmol), EDCI (766 mg, 4.00 mmol), and HOBT (540 mg, 4.00 mmol) were dissolved in dichloromethane (10 mL) and stirred at 25 °C for 1 h. Compound 21a (500 mg, 2.00 mmol) and TEA (404 mg, 4.00 mmol) were added and stirred at room temperature for 18 h. After the reaction was completed, the reaction was quenched by adding water, extracted with DCM (20 mL × 3), washed with saturated NaHCO3 solution, dried over sodium sulfate, and evaporated by centrifugal evaporation to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 21c (700 mg). Step 2 Benzyl 4-(4-chlorobenzamido)-3-oxopiperidine-1-carboxylate 21d

[0293] Compound 21c (400 mg, 1.03 mmol) was dissolved in dichloromethane, and Dess-martin (1309 mg, 3.09 mmol) was added under nitrogen protection at 0 °C. The mixture was stirred at room temperature for 18 h. After the reaction was completed, water (10 mL) was added to the mixture to quench the reaction, and the mixture was extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated by centrifugal evaporation to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 21d (350 mg). Step 3 2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4]pyridine-5(4H)-carboxylate benzyl 21e

[0294] Compound 21d (300 mg, 0.77 mmol) was dissolved in phosphorus oxychloride (10 mL) and stirred at 100 °C for 3 h. After the reaction was completed, most of the solvent was removed by centrifugal evaporation. The reaction was quenched by adding ice water, extracted with DCM (20 mL × 3), washed with saturated NaHCO3 solution, dried over sodium sulfate, and centrifuged to obtain the crude product. The product was purified by high-performance column chromatography to obtain the title compound 21e (150 mg). Step 4 2-(4-chlorophenyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine 21f

[0295] Compound 21e (100 mg, 0.27 mmol) was dissolved in acetonitrile, and TMSI (163 mg, 0.81 mmol) was added under nitrogen protection at 0 °C, followed by stirring at 25 °C for 18 h. After completion of the reaction, water (5 mL) was added to the mixture to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated by centrifugal evaporation to obtain the crude product, which was purified by high-performance column chromatography to obtain the title compound 21f (50 mg). Step 5 (R)-2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 21

[0296] Compound 1c (50 mg, 0.17 mmol) and compound 21f (49 mg, 0.21 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 21 (10 mg, yield: 11%).

[0297] 1 H NMR(400MHz,DMSO)δ7.97-7.95(d,J=8.4Hz,2H),7.60-7.57(m,3H),4.94(s,2H),4.88-4.86(m,1H),4.09(s,2H),3.75-3.74( d,J=5.2Hz,2H),3.41-3.39(m,1H),3.19-3.17(m,1H),2.85-2.84(m,2H),2.67(s,2H),2.22-2.21(m,4H),1.81-1.77(m,2H).

[0298] MS m / z(ESI): 486[M+1]. Example 22

[0299] (R)-2-(6-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide [ka] [ka] Step 1 tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 22b

[0300] Under nitrogen protection, compound 22a (1 g, 3.2 mmol), bis(pinacolato)diboron (1.1 g, 4.2 mmol), potassium acetate (0.41 g, 4.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (150 mg, 0.2 mmol) were mixed in 1,4-dioxane (15 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were concentrated under reduced pressure to give the crude product 22b (1.2 g). Step 2 tert-Butyl 6-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 22d

[0301] Under nitrogen protection, compound 22b (1.2 g, 3.3 mmol), compound 22c (349 mg, 2.2 mmol), potassium carbonate (455 mg, 3.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (146 mg, 0.2 mmol) were mixed in 1,4-dioxane (10 mL) / water (2 mL). The reaction mixture was stirred at 80 °C for 3 h. Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by high-performance column chromatography to give the title compound 22d (0.97 g). Step 3 6-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline 22e

[0302] To a solution of compound 22d (0.97 g, 3.1 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (4 mL), and the reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness to give the title compound 22e (654 mg). Step 4 2-chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine 22g

[0303] Under nitrogen protection, compound 1a (200 mg, 0.97 mmol) and compound 22f (101 mg, 0.97 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 22g (180 mg). Step 5 (R)-2-Chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 22h

[0304] Compound 22g (180 mg, 0.66 mmol) was prepared according to the method of Step 2 of Example 1 at room temperature to give the title compound 22h (150 mg). Step 6 (R)-2-(6-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 22

[0305] Compound 22e (80 mg, 0.37 mmol) and compound 22h (106 mg, 0.37 mmol) were prepared by microwave irradiation at 120° C. according to the method of step 8 of example 1 to give the title compound 22 (27 mg, yield: 15%).

[0306] 1 H NMR(400MHz,DMSO-d6)δppm8.89(d,J=4.85Hz,2H),8.21-8.24(m,2H),7.61(d,J=7.42Hz,1H),7.37-7.45(m,2H),4.97(s,2H),4.24-4.28(m,1 H),4.05(t,J=5.86Hz,2H),3.87-3.94(m,2H),3.40-3.50(m,3H),3.18 -3.27(m,1H),2.97-3.01(m,4H),1.78-1.84(m,2H),1.58-1.71(m,2H).

[0307] MS m / z (ESI): 463.55 [M+1] Example 23

[0308] (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 23 [ka] Step 1 4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide 23b

[0309] Under nitrogen protection, compound 1a (200 mg, 0.97 mmol) and compound 23a (145 mg, 0.97 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 23b (180 mg). Step 2 (R)-4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide 23c

[0310] Compound 23b (180 mg, 0.56 mmol) was prepared according to the method of Step 2 of Example 1 at room temperature to give the title compound 23c (150 mg). Step 3 (R)-2-(2-(4-Fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 23

[0311] Compound 23c (30 mg, 0.09 mmol) and compound 22e (19 mg, 0.09 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 23 (15 mg, yield: 33%).

[0312] 1 H NMR(400MHz,DMSO-d6)δppm8.92(d,J=4.85Hz,2H),8.22-8.30(m,2H),7.86(br d,J=7.42Hz,1H),7.46(br t,J=4.81Hz,2H),5.02(s,2H),4.39-4.54(m,1H),4.11(br t,J=5.40Hz,2H),3.42-3.54(m,3H),3.15-3.28(m,3H),2.89-3.08(m,4H),2.20(br s,4H).

[0313] MS m / z(ESI): 511 [M+1]. Example 24

[0314] (R)-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-2-(6-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 24 [ka] Step 1 (3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol 24b

[0315] Under nitrogen protection, compound 1a (200 mg, 0.97 mmol) and compound 24a (109 mg, 0.97 mmol) were prepared according to the method of Step 1 of Example 1 to give the title compound 24b (180 mg). Step 2 (R)-2-Chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 24c

[0316] Compound 24b (180 mg, 0.64 mmol) was prepared according to the method of Step 2 of Example 1 at room temperature to give the title compound 24c (140 mg). Step 3 (R)-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-2-(6-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 24

[0317] Compound 24c (30 mg, 0.1 mmol) and compound 22e (21 mg, 0.1 mmol) were prepared according to the method of Step 8 of Example 1 to give the title compound 24 (15 mg, yield: 32%).

[0318] 1H NMR(400MHz,DMSO-d6)δppm8.92(d,J=4.85Hz,2H),8.35(s,1H),8.26(s,1H),8.25(d,J=7.35Hz,1H),7.39-7.48(m,2H),5.02(s,2H) ,4.58(t,J=5.63Hz,1H),4.09(t,J=5.86Hz,2H),3.46-3.59(m,3H),3.19-3.27(m,1H),2.98-3.06(m,3H),2.90(m,1H),2.06(s,6H).

[0319] MS m / z(ESI): 475 [M+1]. Example 25

[0320] 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 25 [ka] [ka] Step 1 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 25b

[0321] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 25a (1.1 g, 4.98 mmol) was dissolved in dichloromethane (25 mL) at room temperature, and metachloroperbenzoic acid (2.57 g, 14.94 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, and the crude product was purified by high-performance column chromatography to give the title compound 25b (0.85 g). Step 2 Ethyl 2-(4-((2-chloro-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 25d

[0322] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 25b (100 mg, 0.4 mmol), compound 25c (88 mg, 0.54 mmol), and N,N-diisopropylethylamine (0.24 mL, 1.35 mmol) were mixed in ethanol (10 mL) at room temperature. The reaction mixture was stirred at 60 °C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. Water (20 mL) was then added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography to obtain the title compound 25d (100 mg). Step 3 Ethyl 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 25f

[0323] Compound 25d (100 mg, 0.25 mmol), compound 25e (35 mg, 0.25 mmol), N,N-diisopropylethylamine (65 mg, 0.5 mmol), and dioxane (3 mL) were added to a microwave reaction tube at room temperature. The microwave tube was placed in a microwave synthesizer and reacted at 120 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and the crude product was purified by high-performance column chromatography to obtain the title compound 25f (60 mg). Step 4 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 25

[0324] Compound 25f (60 mg, 0.12 mmol) and lithium hydroxide (15 mg, 0.36 mmol) were dissolved in a mixture of THF / MeOH / HO (3 mL / 1 mL / 1 mL) at room temperature. The reaction mixture was reacted at room temperature for 1 hour, then adjusted to pH 2-3 with dilute hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 2). The combined organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance column chromatography to give the title compound 25 (20 mg, 36% yield).

[0325] 1 H NMR(400MHz,DMSO-d6)δppm12.37(br s,1H),8.62(s,1H),7.55(m,2H),7.39(d,J=5.13Hz,1H),7.32(m,2H),6.98(br d,J=4.85Hz,1H),4.72-4.91(m,2H),4.05(br s,2H),3.55-3.65(m,4H),2.83-2.92(m,4H),2.28-2.36(m,2H)

[0326] MS m / z(ESI): 471 [M+1]. Example 26

[0327] 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxo-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid 26 [ka] [ka] Step 1 Ethyl 2-(4-((2-chloro-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate 26b

[0328] Under nitrogen protection, compound 25b (200 mg, 0.79 mmol) and compound 26a (156 mg, 0.79 mmol) were prepared according to the method of Step 2 of Example 25 to give the title compound 26b (180 mg). Step 2 Ethyl 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxo-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate 26d

[0329] Compound 26c (58 mg, 0.43 mmol) and compound 26b (180 mg, 0.43 mmol) were prepared according to the method of Step 3 of Example 25 to give the title compound 26d (120 mg). Step 3 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxo-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid 26

[0330] Compound 26d (60 mg, 0.12 mmol) was prepared according to the method of Step 4 of Example 25 at room temperature to give the title compound 26 (20 mg, 36% yield).

[0331] 1 H NMR(400MHz,DMSO-d6)δppm8.74(s,1H),7.73(br s,1H),7.37(t,J=8.05Hz,1H),7.20-7.32(m,5H),4.82-5.00(m,2H),3.9 3-4.07(m,2H),3.57-3.68(m,4H),2.85-2.95(m,4H),2.30-2.36(m,2H).

[0332] MS m / z(ESI):483[M+1]

[0333] Biological evaluation

[0334] Test Example 1: Inhibitory effect of the compounds of the present disclosure on PDE4 enzyme

[0335] PDE4 enzyme can hydrolyze cAMP to generate AMP. The synthesized PDE4 enzyme inhibitor acts in cooperation with PDE4 enzyme and the substrate cAMP for a certain period of time, resulting in the formation of AMP-Glo. TM The assay was performed using an assay kit. The measurement of the reagent was divided into two steps: converting the AMP produced by the reaction into ADP, and converting ADP into ATP. ATP binds to the reagent and emits fluorescence, and the fluorescence value was measured using an Echo550. A graph was created from the fluorescence value, and the IC value of the PDE4 enzyme inhibitor was calculated. 50 The specific details are as follows:

[0336] 1.1 Reagents and equipment

[0337] 1.1.1 Reagents [Table 10]

[0338] 1.1.2 Equipment [Table 11]

[0339] 1.2 Experimental procedure

[0340] 1.2.1 Compound preparation and processing a) Preparation of compound DMSO stock solutions: All compounds were dissolved in DMSO as stock solutions at a concentration of 10 mM. b) Compound storage: All compounds dissolved in DMSO were stored in a desiccator at room temperature for short periods of time.

[0341] 1.2.2 Preparation of working stock solution a) Positive control AKEX0834 (the compound of Example 2 in WO2013026797A1) was serially diluted in DMSO in a 3-fold gradient starting from 100 μM to give a total of 10 concentrations. b) Test compounds were serially diluted in 3-fold gradients starting from 100 μM in DMSO for a total of 10 concentrations. c) A 200X positive control (1 mM AKEX0834) and a 200X solvent control (100% DMSO) were set up. The compound plate was centrifuged at 1000 rpm for 1 minute.

[0342] 1.2.3 Compound screening a) 20 nL of compound dilutions were transferred to each well of the measurement plate using Echo550. b) The assay plate was sealed and the compound plate was centrifuged at 1000 rpm for 1 minute. c) 2X PDE4B2 or PDE4D2 was prepared in frozen PDE assay buffer. d) 2 μL of L2X PDE4B2 or PDE4D2 (prepared in step b) was added to a single well of the assay plate. e) The measurement plate was sealed and equilibrated at room temperature for 10 minutes. f) 2X cyclic-3',5'-AMP was prepared in PDE assay buffer. g) 2 μL of L2X Cyclic-3',5'-AMP (prepared in step f) was added to each well of the assay plate (prepared in step e) to initiate the reaction. The plate was incubated at room temperature for 60 minutes. h) 4 μL of AMP-Glo ​​Reagent I was added and incubated at room temperature for 60 minutes. i) 8 μL of AMP measurement solution was added, and the mixture was incubated at room temperature for 60 minutes. j) RLU signals were read on an Envision2105 plate reader.

[0343] 1.3 Data analysis

[0344] The calculation formula is as follows: Inhibition (%) = {1 - (mean RLU of compound - mean RLU of positive control across plate) / (mean RLU of negative control across plate - mean RLU of positive control across plate)} I C 50 was calculated using graphpad 8.0 by fitting the percent inhibition (%) to the logarithm of the compound concentration with a nonlinear regression (dose-response - variable slope).

[0345] Table 1: Inhibitory effect of PDE4 enzymes by compounds of the present disclosure [Table 12]

[0346] Conclusion: The compounds of the present disclosure have significant inhibitory effects on the PDE4 enzyme.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 where: Ring A is selected from heteroaryl, aryl, heterocyclyl, and cycloalkyl; L is -(CR ４ａ R ４ｂ ) ｐ (CR ５ａ R ５ｂ ) ｑ - and Z is -S-, -S(O)-, -S(O) ２ - and -O-; R １ and R ２ are the same or different and are independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, alkyl, halogen, oxo, haloalkyl, -OR ｃ１ , cyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ , -C(O)NR ｄ３ R ｄ４ , -S(O) ２ NR ｄ３ R ｄ４ , -(CH ２ ) ｖ１ NR ｄ５ C(O)R ｅ１ , -(CH ２ ) ｖ１ NR ｄ５ S (O) ２ R ｅ１ , -C(O)R ｅ２ , -OC(O)R ｅ３ , -S(O) ｒ R ｅ４ , -(CH ２ ) ｗ１ C(O)OR ｃ２ , -(CH ２ ) ｕ optionally substituted with one or more substituents selected from R, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ３ represents a hydrogen atom, a deuterium atom, an alkyl, an alkenyl, an alkynyl, a halogen, a cyano, an alkylcyano, an oxo, an -OR ｃ３ , -(CH ２ ) ｕ２ NR ｄ６ R ｄ７ , —C(O)NR ｄ８ R ｄ９ , -(CH ２ ) ｖ２ NR ｄ１０ C(O)R ｅ５ , -C(O)R ｅ６ , -OC(O)R ｅ７ , -S(O) ｔ R ｅ８ , -(CH ２ ) ｗ２ C(O)OR ｃ４ and 【Chemistry 2】 wherein said alkyl, alkenyl and alkynyl are independently selected from deuterium atoms, halogen, haloalkyl, -OR ｃ１ , cyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ optionally substituted with one or more substituents selected from hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from heteroaryl, aryl, heterocyclyl, and cycloalkyl; Each R ｂ are the same or different and independently represent a deuterium atom, a halogen atom, a cyano group, an alkylcyano group, an oxo group, an alkyl group, a haloalkyl group, -OR ｃ３ , -(CH ２ ) ｕ２ NR ｄ６ R ｄ７ , —C(O)NR ｄ８ R ｄ９ , -(CH ２ ) ｖ２ NR ｄ１０ C(O)R ｅ５ , -C(O)R ｅ６ , -OC(O)R ｅ７ , -S(O) ｔ R ｅ８ , -(CH ２ ) ｗ２ C(O)OR ｃ４ , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ４ , R ４ａ , R ４ｂ , R ５ , R ５ａ and R ５ｂ are the same or different and independently represent a hydrogen atom, a deuterium atom, an alkyl, a halogen, an alkenyl, an alkynyl, a cyano, an alkylcyano, a hydroxyalkyl, a haloalkyl, -OR ｃ３ , -(CH ２ ) ｕ２ NR ｄ６ R ｄ７ , —C(O)NR ｄ８ R ｄ９ , -(CH ２ ) ｖ２ NR ｄ１０ C(O)R ｅ５ , -C(O)R ｅ６ , -OC(O)R ｅ７ , -S(O) ｔ R ｅ８ , -(CH ２ ) ｗ２ C(O)OR ｃ４ , cycloalkyl, heterocyclyl, aryl and heteroaryl, or R ４ and R ５ , R ４ａ and R ４ｂ , R ５ａ and R ５ｂ form an oxo group together with the carbon atom to which they are attached, R ６ , R ７ , R ８ and R ９ are the same or different and independently represent a hydrogen atom, a deuterium atom, an alkyl, an alkenyl, an alkynyl, a halogen, a cyano, an alkylcyano, a haloalkyl, a hydroxyalkyl, -OR ｃ３ , -(CH ２ ) ｕ２ NR ｄ６ R ｄ７ , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, independently of one another, are optionally selected from halogen, oxo, alkyl, haloalkyl, -OR ｃ１ , cyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R ａ are the same or different and independently represent a deuterium atom, an alkyl, a halogen, an oxo, an alkenyl, an alkynyl, a cyano, an alkylcyano, a hydroxyalkyl, a haloalkyl, -OR ｃ３ , -(CH ２ ) ｕ２ NR ｄ６ R ｄ７ cycloalkyl, heterocyclyl, aryl, and heteroaryl; R is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently a deuterium atom, a halogen, an oxo, an alkyl, a haloalkyl, -OR ｃ１ , cyano, alkylcyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ optionally substituted with one or more substituents selected from hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ｃ１ , R ｃ２ , R ｃ３ and R ｃ４ are the same or different at each occurrence and are independently selected from hydrogen, deuterium, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ optionally substituted with one or more substituents selected from hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ , R ｄ５ , R ｄ６ , R ｄ７ , R ｄ８ , R ｄ９ and R ｄ１０ are the same or different at each occurrence and are independently selected from hydrogen, deuterium, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R ｄ１ and R ｄ２ , R ｄ３ and R ｄ４ , R ｄ６ and R ｄ７ and R ｄ８ and R ｄ９ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium atoms, halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, alkylcyano, amino, alkylamino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ｅ１ , R ｅ２ , R ｅ３ , R ｅ４ , R ｅ５ , R ｅ６ , R ｅ７ and R ｅ８ are the same or different at each occurrence and are independently selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently selected from deuterium, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ optionally substituted with one or more substituents selected from hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; s is 1 or 2; t is 0, 1 or 2; u is 0, 1, 2 or 3; u1 is 0, 1, 2 or 3; u2 is 0, 1, 2 or 3; v1 is 0, 1, 2 or 3; v2 is 0, 1, 2 or 3; w1 is 0, 1, 2 or 3; A compound or a pharmaceutically acceptable salt thereof, wherein w2 is 0, 1, 2 or 3.

2. R ３ teeth, 【Chemistry 3】 and ring B, R ｂ and n are as defined in claim 1, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

3. Z is -S-, -S(O)- and -S(O) ２ 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from -, preferably -S(O)-.

4. A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 where: Ring A, Ring B, L, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ 4. The compound of formula (I) according to any one of claims 1 to 3, wherein n and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

5. A compound represented by general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, 【Chemistry 5】 or 【Chemistry 6】 where: Ring A, Ring B, L, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ 5. The compound of formula (I) according to any one of claims 1 to 4, wherein n and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

6. A compound represented by general formula (III) or a pharmaceutically acceptable salt thereof: 【Chemistry 7】 where: Ring A, Ring B, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ , R ４ａ , R ４ｂ , n and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

7. A compound represented by general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, 【Chemistry 8】 or 【Chemistry 9】 where: Ring A, Ring B, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ , R ４ａ , R ４ｂ 7. The compound of formula (I) according to any one of claims 1 to 6, wherein n and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

8. A compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 where: Ring A, Ring B, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ 5. The compound of formula (I) according to any one of claims 1 to 4, wherein n and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

9. A compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 or 【Chemistry 12】 where: Ring A, Ring B, R ａ , R ｂ , R １ , R ２ , R ４ , R ５ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ 10. A compound of general formula (I) according to any one of claims 1 to 5 and 8, or a pharmaceutically acceptable salt thereof, wherein n and m are as defined in claim 1.

10. The compound represented by general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered heterocyclyl and 3- to 8-membered cycloalkyl, and is preferably 5- to 6-membered heteroaryl or phenyl.

11. The compound represented by general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl, and preferably selected from 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl.

12. n is 0, 1, 2, or 3; ｂ are the same or different and independently represent a deuterium atom, a halogen, C １-６ Alkyl, cyano, C １-６ Alkoxy, amino, C １-６ Alkylamino, C １-６ Alkoxy-C １-６ Alkoxy, halogenated C １-６ Alkyl and halogenated C １-６ 12. The compound represented by general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the alkoxy is selected from the group consisting of alkoxy, ...

13. 13. The compound represented by general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein m is 0.

14. R １ and R ２ are the same or different and independently represent a hydrogen atom, a deuterium atom, or C １-６ alkyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C １-６ Alkyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently selected from the group consisting of a deuterium atom, a halogen atom, an oxo atom, C １-６ Alkyl, halogenated C １-６ Alkyl, hydroxy, C １-６ Alkoxy, -(CH ２ ) ｕ１ NR ｄ１ R ｄ２ , -(CH ２ ) ｗ１ C(O)OR ｃ２ , -(CH ２ ) ｕ R, hydroxy C １-６ optionally substituted with one or more substituents selected from alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R ｃ２ , R ｄ１ , R ｄ２ 14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R, u, u1 and w1 are as defined in claim 1.

15. R ４ , R ４ａ , R ４ｂ and R ５ The compound represented by general formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein all of are hydrogen atoms.

16. R ５ａ and R ５ｂ The compound represented by general formula (I) according to any one of claims 1 to 5 and 8 to 15, or a pharmaceutically acceptable salt thereof, wherein all of are hydrogen atoms.

17. The following compounds: 【Chemistry 13】 、 【Chemistry 14】 、 【Chemistry 15】 、 【Chemistry 16】 、 【Chemistry 17】 、 【Chemistry 18】 、 【Chemistry 19】 、 【Chemistry 20】 、 【Chemical 21】 、 【Chemical 22】 、 【Chemical 23】 、 【Chemistry 24】 、 【Chemistry 25】 、 【Chemical 26】 、 【Chemical 27】 、 【Chemical formula 28】 and 【Chemical 29】 The compound represented by general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

18. The following compounds: 【Chemistry 30】 、 【Chemical 31】 、 【Chemical 32】 、 【Chemical 33】 、 【Chemical 34】 、 【Chemistry 35】 、 【Chemical 36】 、 【Chemical 37】 、 【Chemical 38】 、 【Chemical 39】 、 【Chemistry 40】 and 【Chemistry 41】 The compound represented by general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

19. 【Chemistry 42】 、 【Chemistry 43】 、 【Chemical 44】 、 【Chemistry 45】 、 【Chemistry 46】 、 【Chemistry 47】 、 【Chemistry 48】 、 【Chemistry 49】 、 【Chemistry 50】 、 【Chemistry 51】 、 【Chemistry 52】 、 【Chemistry 53】 、 【Chemical 54】 、 【Chemistry 55】 、 【Chemical 56】 、 【Chemical 57】 、 【Chemistry 58】 、 【Chemical 59】 、 【Chemistry 60】 、 【Hua 61】 、 【Hua 62】 、 【Chemistry 63】 、 【Hua 64】 、 【Chemistry 65】 、 【Hua 66】 、 【Chemical Formula 67】 and 【Chemistry 68】 A compound selected from:

20. The method includes the following steps: 【Chemical Formula 69】 a compound represented by general formula (IA) or a salt thereof is subjected to a nucleophilic substitution reaction with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; where: X is a halogen, preferably Cl; Rings A, L, Z, R ａ , R １ ~R ９ 10. A process for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that m, m and s are as defined in claim 1.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for inhibiting PDEs enzymes, preferably in the preparation of a medicament for inhibiting PDE4 enzymes, more preferably in the preparation of a medicament for inhibiting PDE4B enzymes.

23. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating and / or preventing a PDEs enzyme-mediated disease or condition, preferably for treating and / or preventing a PDE4 enzyme-mediated disease or condition, more preferably for treating and / or preventing a PDE4B enzyme-mediated disease or condition.

24. 24. The use according to claim 23, characterized in that the disease or condition is selected from a respiratory disease, a pulmonary disease, a gastrointestinal disease, an inflammatory disease, cancer, a peripheral nervous system disease or a central nervous system disease.

25. 25. The use according to claim 24, characterized in that the respiratory and pulmonary diseases are selected from respiratory and pulmonary diseases associated with increased mucus, obstructive pulmonary diseases and airway diseases, preferably COPD, asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, alpha-1 antitrypsin deficiency, chronic sinusitis, chronic bronchitis and pulmonary hypertension.

26. 25. The use according to claim 24, characterized in that the gastrointestinal disease is selected from tract enteritis, ulcerative colitis and Crohn's disease.

27. 25. The use according to claim 24, wherein the inflammatory disease is selected from proliferative and inflammatory skin diseases, articular inflammatory diseases and ocular inflammatory diseases, wherein the inflammatory skin diseases are preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, cutaneous photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, cutaneous pruritus, hand eczema and psoriasis, the articular inflammatory disease is preferably selected from rheumatoid arthritis, psoriatic arthritis and spondyloarthritis, and the ocular inflammatory disease is preferably glaucoma or dry eye syndrome.

28. 25. The use according to claim 24, wherein the peripheral nervous system disease or central nervous system disease is selected from Alzheimer's disease, age-associated memory impairment (AAMI), age-related cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, intellectual disability, cerebrovascular disease, depression, schizophrenia, cerebral infarction, neurological dysfunction, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disability, and multiple sclerosis.

29. 25. The use according to claim 24, characterized in that the cancer is selected from the group consisting of leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, adenoid cystic carcinoma, medullary carcinoma, bronchogenic carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, renal cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, childhood tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor and myeloma.

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