Aza fused ring compound, preparation method thereof and application of aza fused ring compound in medicine

Abstract

The invention relates to aza fused ring compounds, a preparation method thereof and application of the aza fused ring compounds in medicine. Specifically, the invention relates to an aza-fused ring compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a phosphodiesterase (PDEs) inhibitor, especially application of the compound in preparation of drugs for treating and / or preventing PDE4 enzyme mediated diseases or symptoms. # imgabs0 #

Description

Aza-fused ring compound, preparation method thereof and application thereof in medicine

[0001] This disclosure claims priority to the Chinese patent application filed with the Patent Office of China on September 29, 2022, with the invention name “Azo-fused ring compounds, preparation methods thereof and their application in medicine” and application number 202211201376.X. The entire contents of the above application are incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure relates to the field of medicine and relates to an aza-fused ring compound, a method for preparing the same, and its use in medicine. Specifically, the present disclosure relates to an aza-fused ring compound represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use as a phosphodiesterase (PDE) inhibitor, particularly in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by the PDE4 enzyme. Background Art

[0003] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading them and thereby terminating the biochemical effects transmitted by these second messengers. cAMP and cGMP play a crucial role in regulating cellular activity. The regulation of their concentrations is primarily determined by the balance between synthesis by adenylate cyclase and hydrolysis by phosphodiesterases (PDEs). PDEs are widely distributed throughout the human body, and their physiological effects span multiple research areas.

[0004] Among the 11 phosphodiesterases currently identified, PDE4, PDE7, and PDE8 are cAMP selective. The PDE4 family includes four subtypes (PDE4A, B, C, and D) with more than 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). The above four subtypes are differentially expressed in different tissues and cell types, such as PDE4B, which is mainly expressed in monocytes and neutrophils, but not in cortical cells and epithelial cells, while PDE4D is expressed in the lungs, cortex, cerebellum, and T cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs, 16(1), 2007, 109-124). PDE4B is mainly expressed in the presence of PDE4 enzymes that hydrolyze cAMP, and the substrate apparent K of cAMP is m1-5 μM. PDE4 is the most important regulator of cAMP expressed in immune cells and inflammatory cells such as neutrophils, macrophages and T-lymphocytes. Since cAMP is a key second messenger in regulating inflammatory responses, PDE4 has been found to regulate the inflammatory response of inflammatory cells by regulating proinflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF and LTB4. Therefore, inhibiting PDE4 has become an attractive target for treating inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, inflammatory bowel diseases such as Crohn's disease, etc. (MD Houslay et al, Drug Discovery Today, 2005, 10 (22), 1503-1519). Since PDE activity is elevated in patients with atopic dermatitis (AD), inhibiting PDE4 also seems to be a feasible treatment for AD (Journal of Investigative Dermatology, 1986, 87 (3), 372-376).

[0005] Published related patent applications include WO2009053268A1, WO2009050242A2, WO2009050236A1, CN101827852B, CN101163706A, CN101426505A, CN102875556B, CN103497201A, CN103889970B, and CN108299400B.

[0006] Summary of the Invention

[0007] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008] in:

[0009] Ring A is selected from heteroaryl, aryl, heterocyclyl and cycloalkyl;

[0010] L is -(CR 4a R 4b ) p (CR 5a R 5b ) q -;

[0011] Z is selected from -S-, -S(O)-, -S(O)2- and -O-;

[0012] R 1 and R 2are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from a deuterium atom, an alkyl group, a halogen, an oxo group, a haloalkyl group, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 、-C(O)NR d3 R d4 、-S(O)2NR d3 R d4 、-(CH2) v1 NR d5 C(O)R e1 、-(CH2) v1 NR d5 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 substituted by one or more substituents selected from R, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0013] R 3 Selected from hydrogen atom, deuterium atom, alkyl group, alkenyl group, alkynyl group, halogen, cyano group, alkylcyano group, oxo group, -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 wherein the alkyl, alkenyl and alkynyl groups are each independently selected from deuterium atoms, halogen, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0014] Ring B is selected from heteroaryl, aryl, heterocyclyl and cycloalkyl;

[0015] Each R b are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, an alkylcyano group, an oxo group, an alkyl group, a haloalkyl group, -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;

[0016] R 4 、R 4a 、R 4b 、R 5 、R 5a and R 5b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a halogen, an alkenyl group, an alkynyl group, a cyano group, an alkylcyano group, a hydroxyalkyl group, a haloalkyl group, -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 5bTogether with the carbon atoms to which they are attached, they form an oxo group;

[0017] R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a halogen, a cyano group, an alkylcyano group, a haloalkyl group, a hydroxyalkyl group, -OR c3 、-(CH2) u2 NR d6 R d7 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] Each R a are the same or different and are each independently selected from a deuterium atom, an alkyl group, a halogen, an oxo group, an alkenyl group, an alkynyl group, a cyano group, an alkylcyano group, a hydroxyalkyl group, a haloalkyl group, -OR c3 、-(CH2) u2 NR d6 R d7 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R is selected from cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from deuterium atoms, halogen, oxo, alkyl, haloalkyl, -OR c1 , cyano, alkyl cyano, -(CH2) u1 NR d1 R d2 , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R c1 、R c2 、R c3 and R c4 are the same or different at each occurrence and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from a deuterium atom, a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an alkylcyano group, -(CH2) u1 NR d1 Rd2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 、R d9 and R d10 is the same or different at each occurrence and is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0022] 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, they form a heterocyclic group, wherein the heterocyclic group is independently optionally substituted by one or more substituents selected from the group consisting of a deuterium atom, a halogen, an oxo group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an alkylcyano group, an amino group, an alkylamino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0023] 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 each independently selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium atoms, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH2) u1 NR d1 R d2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] m is 0, 1, 2, or 3;

[0025] n is 0, 1, 2, 3, 4, 5 or 6;

[0026] p is 0, 1, or 2;

[0027] q is 0, 1, or 2;

[0028] r is 0, 1, or 2;

[0029] s is 1 or 2;

[0030] t is 0, 1, or 2;

[0031] u is 0, 1, 2, or 3;

[0032] u1 is 0, 1, 2, or 3;

[0033] u2 is 0, 1, 2, or 3;

[0034] v1 is 0, 1, 2, or 3;

[0035] v2 is 0, 1, 2, or 3;

[0036] w1 is 0, 1, 2, or 3; and

[0037] w2 is 0, 1, 2, or 3.

[0038] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: s is 1 or 2; preferably, s is 1.

[0039] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 3 for Ring B, R b and n are as defined in the general formula (I).

[0040] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z is selected from -S-, -S(O)- and -S(O)2-; preferably, Z is -S(O)- or -S(O)2-; more preferably, Z is -S(O)-.

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, 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, R6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, 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, R 6 、R 7 、R 8 and R 9 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; most preferably, R 6 、R 7 、R 8 and R 9 All are hydrogen atoms.

[0042] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0043] in:

[0044] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , n and m are as defined in the general formula (I).

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or the general formula (II-2) or a pharmaceutically acceptable salt thereof:

[0046] in:

[0047] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , n and m are as defined in the general formula (I).

[0048] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein: L is -(CR 4a R 4b) p (CR 5a R 5b ) q -, p is 1 or 2, q is 0, 1 or 2, R 4a 、R 4b 、R 5a and R 5b As defined in formula (I); preferably, L is -(CR 4a R 4b ) p (CR 5a R 5b ) q -, p is 1, q is 0 or 1, R 4a 、R 4b 、R 5a and R 5b As defined in general formula (I).

[0049] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0050] in:

[0051] 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 the general formula (I).

[0052] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof:

[0053] in:

[0054] 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 the general formula (I).

[0055] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:

[0056] in:

[0057] 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 the general formula (I).

[0058] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:

[0059] in:

[0060] 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 the general formula (I).

[0061] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein: ring A is selected from a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 8-membered heterocyclyl and a 3- to 8-membered cycloalkyl; preferably, ring A is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl; more preferably, ring A is a 5- to 6-membered heteroaryl or a phenyl.

[0062] In some embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts 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; preferably, ring B is selected from 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered heterocyclyl and 3- to 6-membered cycloalkyl.

[0063] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2 or 3; and each R b are the same or different and are each independently selected from 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 R b Selected from 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 Alkoxy.

[0064] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2 or 3; and each R a are the same or different and are each independently selected from 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.

[0065] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein: Selected from R 3 、R a and m are as defined in the general formula (I).

[0066] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, 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 said 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 heterocyclic group are each independently optionally selected from deuterium atoms, C 1-6 Alkyl, halogen, oxo, haloC 1-6 Alkyl, -OR c1 , 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 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R c1 、Rc2 、R d1 to R d5 、R e1 to R e4 , R, u, u1, v1, w1 and r are as defined in formula (I); preferably, R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, 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 the C 1-6 Alkyl, 5 to 10 membered heteroaryl, 6 to 10 membered aryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group are each independently optionally selected from deuterium atoms, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, -(CH2) u1 NR d1 R d2 、-(CH2) w1 C(O)OR c2 、-(CH2) u R, 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; R c2 、R d1 、R d2 , R, u, u1 and w1 are as defined in the general formula (I); more preferably, R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, C 1-6 alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; wherein the C 1-6 Alkyl, 5 to 6 membered heteroaryl, phenyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group are each independently optionally selected from deuterium atoms, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 、-(CH2) u R and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R c2 , R, u and w1 are as defined in formula (I); most preferably, R 1 and R 2 One of them is a hydrogen atom, and the other is selected from a deuterium atom, C 1-6alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; wherein the C 1-6 Alkyl, 5 to 6 membered heteroaryl, phenyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group are each independently optionally selected from deuterium atoms, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 、-(CH2) u R and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R c2 , R, u and w1 are as defined in the general formula (I).

[0067] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 One of them is a hydrogen atom, and the other is selected from C 1-6 alkyl, 5- to 6-membered heteroaryl, phenyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; wherein the C 1-6 Alkyl, 5 to 6 membered heteroaryl, phenyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, amino, -(CH2) w1 C(O)OR c2 , and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R c2 A hydrogen atom or C 1-6 Alkyl; w1 is 0 or 1; preferably, R 1 and R 2 One of them is a hydrogen atom, and the other is a phenyl group or a 3- to 6-membered cycloalkyl group; wherein the phenyl group or the 3- to 6-membered cycloalkyl group are each independently optionally selected from halogen, -(CH2) w1 C(O)OR c2 and hydroxy C 1-6 The alkyl group is substituted by one or more substituents; R c2 A hydrogen atom or C 1-6 Alkyl; w1 is 0 or 1; most preferably, R 1 and R 2 One of them is a hydrogen atom, and the other is selected from

[0068] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 4 、R 4a 、R 4b and R 5 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, nitro, amino, hydroxy 1-6 Alkyl, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy; preferably, R 4 、R 4a 、R 4b and R 5 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; More preferably, R 4 、R 4a 、R 4b and R 5 All are hydrogen atoms.

[0069] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, nitro, amino, hydroxy 1-6 Alkyl, haloalkyl and haloC 1-6 Alkoxy; preferably, R 5a and R 5b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; More preferably, R 5a and R 5b All are hydrogen atoms.

[0070] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R c1 、R c2 、R c3 and R c4 are the same or different at each occurrence and are independently selected from hydrogen atoms, deuterium atoms, 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 said C 1-6 Alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium atoms, 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 The alkyl group is substituted with one or more substituents; preferably, R c1 、R c2 、R c3 and R c4 are the same or different at each occurrence and are independently selected from hydrogen atoms, deuterium atoms, C 1-6 Alkyl and hydroxy C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally selected from deuterium atoms, halogens, 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 The alkyl group is substituted by one or more substituents;

[0071] 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 atoms, deuterium atoms, C1-6 Alkyl, halogenated C 1-6 Alkyl and hydroxy C 1-6 alkyl.

[0072] 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 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.

[0073] Table A Typical compounds of the present disclosure include, but are not limited to:

[0074] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0075] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0076] The compound represented by the general formula (IA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0077] in:

[0078] X is a halogen, preferably Cl;

[0079] Ring A, L, Z, R a 、R 1 to R 9 , m and s are as defined in the general formula (I).

[0080] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0081] The compound represented by general formula (IIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or a salt thereof to obtain the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0082] in:

[0083] X is a halogen, preferably Cl;

[0084] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II).

[0085] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a salt thereof, the method comprising the following steps:

[0086] The compound represented by the general formula (IIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-1B) or a salt thereof to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0087] X is a halogen, preferably Cl;

[0088] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II-1).

[0089] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0090] The compound represented by general formula (IIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-2B) or a salt thereof to obtain the compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0091] X is a halogen, preferably Cl;

[0092] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II-2).

[0093] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0094] The compound represented by general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or a salt thereof to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0095] X is a halogen, preferably Cl;

[0096] 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 the general formula (III).

[0097] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0098] The compound represented by the general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-1B) or a salt thereof to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0099] X is a halogen, preferably Cl;

[0100] 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 the general formula (III-1).

[0101] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0102] The compound represented by general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-2B) or a salt thereof to obtain the compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0103] X is a halogen, preferably Cl;

[0104] 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 the general formula (III-2).

[0105] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0106] The compound represented by general formula (IVA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0107] X is a halogen, preferably Cl;

[0108] 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 the general formula (IV).

[0109] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0110] The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-1B) or a salt thereof to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0111] X is a halogen, preferably Cl;

[0112] 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 the general formula (IV-1).

[0113] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0114] The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-2B) or a salt thereof to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0115] X is a halogen, preferably Cl;

[0116] 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 the general formula (IV-2).

[0117] Another aspect of the present disclosure relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of the present disclosure represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0118] The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in 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.

[0119] The present disclosure further relates to the use of compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by PDEs enzymes, preferably in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by PDE4 enzymes, more preferably in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by PDE4B enzymes.

[0120] The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in 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 disease or condition mediated by a PDEs enzyme, preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by a PDE4 enzyme, more preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by a PDE4B enzyme, wherein the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer and peripheral or central nervous system diseases.

[0121] The present disclosure further relates to a method for inhibiting PDEs enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the present disclosure further relates to a method for inhibiting PDE4 enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A , a compound shown in 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; more preferably, the present disclosure further relates to a method for inhibiting PDE4B enzyme, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in 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.

[0122] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by PDEs enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by PDE4 enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof; Compounds represented by 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 comprising the same; more preferably, the present disclosure further relates to a method for treating and / or preventing diseases or conditions mediated by PDE4B enzyme, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by 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 comprising the same.

[0123] The present disclosure relates to a method for treating and / or preventing a disease or condition mediated by PDEs enzymes, preferably a method for treating and / or preventing a disease or condition mediated by PDE4 enzymes, and more preferably a method for treating and / or preventing a disease or condition mediated by PDE4B enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0124] The present disclosure further relates to a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug.

[0125] The present disclosure further relates to a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a PDEs enzyme inhibitor; preferably, it is used as a PDE4 enzyme inhibitor; more preferably, it is used as a PDE4B enzyme inhibitor.

[0126] The present disclosure further relates to a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing diseases or conditions mediated by PDEs enzymes; preferably, for use in treating and / or preventing diseases or conditions mediated by PDE4 enzymes; more preferably, for use in treating and / or preventing diseases or conditions mediated by PDE4B enzymes.

[0127] The present disclosure further relates to a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing diseases or conditions mediated by PDEs enzymes, preferably for treating and / or preventing diseases or conditions mediated by PDE4 enzymes, more preferably for treating and / or preventing diseases or conditions mediated by PDE4B enzymes; wherein the diseases or conditions are selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancers and peripheral or central nervous system diseases.

[0128] Preferably, the respiratory and lung diseases of the present disclosure are selected from respiratory and lung diseases associated with increased mucus production, obstructive lung 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.

[0129] Preferably, the gastrointestinal disease of the present disclosure is selected from Crohn's disease, ulcerative colitis and Crohn's disease.

[0130] Preferably, the inflammatory disease of the present disclosure is selected from proliferative and inflammatory skin diseases, arthritis diseases and eye inflammatory diseases; wherein the inflammatory skin disease is preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, hair loss, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, skin photoaging, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, eczematous hand dermatitis and psoriasis; the arthritis disease is preferably selected from rheumatoid arthritis, psoriatic arthritis and spondyloarthritis; the eye inflammatory disease is preferably glaucoma or dry eye syndrome; wherein the contact dermatitis includes irritant contact dermatitis and allergic contact dermatitis; the psoriasis includes psoriasis vulgaris and inverse psoriasis; the SAPHO syndrome includes synovitis, acne, impetigo, bone hypertrophy and osteitis.

[0131] Preferably, the peripheral or central nervous system disease described in the present disclosure 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, mental retardation, cerebrovascular disease, depression, schizophrenia, stroke, neurological disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment caused by lack of sleep, intellectual and developmental disabilities and multiple sclerosis.

[0132] Preferably, the cancer of the present disclosure 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, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor and myeloma.

[0133] In certain embodiments, the unit dose of the pharmaceutical composition described herein is 0.001 mg-1000 mg.

[0134] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a compound of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), or Table A, or a pharmaceutical composition comprising the same, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a compound of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), or Table A, or a pharmaceutical composition comprising the same. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a compound of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the pharmaceutical composition contains 1%-99% of a compound of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the pharmaceutical composition contains 2%-98% of a compound of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0135] In certain embodiments, the pharmaceutical compositions of the present disclosure contain 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent, or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 1%-99% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 2%-98% of a pharmaceutically acceptable carrier, diluent, or excipient.

[0136] The compounds of the present disclosure represented by Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can be administered into a living organism via any route of administration. The routes of administration may include oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or topical or systemic transdermal administration.

[0137] The compounds of the present disclosure represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can be formulated into single doses containing the active compounds of the present disclosure and carriers, excipients, etc., and the dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms can contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonicity adjusters, and anti-adherents.

[0138] Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins published in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press published in 2005, and thus can be easily prepared by those skilled in the art.

[0139] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0140] Terminology

[0141] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0142] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group 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 alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group 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-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0143] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0144] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0145] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0146] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0147] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., a monocyclic cycloalkyl) or a polycyclic ring system (i.e., a 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., a 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), or preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group).

[0148] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0149] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0150] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 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 spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, 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 group. Non-limiting examples include:

[0151] Its connection point can be at any position;

[0152] wait.

[0153] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 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 fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, 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 bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0154] Its connection point can be at any position;

[0155] wait.

[0156] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 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 preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0157] Its connection point can be at any position.

[0158] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0159] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, 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 heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0160] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0161] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0162] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain 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 (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 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 spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0163] wait.

[0164] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 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 fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0165] wait.

[0166] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 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 heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0167] wait.

[0168] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0169] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group), more preferably an aromatic group having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include: wait.

[0170] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0171] 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) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -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).

[0172] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0173] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2,4]triazolo[1,5-a]pyridinyl. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0174] wait.

[0175] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0176] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0177] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the 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, etc.

[0178] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0179] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0180] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0181] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0182] The term "hydroxy" refers to -OH.

[0183] The term "amino" refers to -NH2.

[0184] The term "cyano" refers to -CN.

[0185] The term "nitro" refers to -NO2.

[0186] The term "oxo" or "oxo" refers to "=0".

[0187] The term "carbonyl" refers to C=O.

[0188] The term "carboxy" refers to -C(O)OH.

[0189] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0190] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" includes all isomeric forms including enantiomers, diastereomers and geometric isomers including cis-trans isomers. Therefore, the single stereochemical isomers of the compounds designed in the present disclosure or their enantiomers, diastereomers, or geometric isomers (or cis-trans isomers) and their mixtures all fall within the scope of the present disclosure. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereomers is usually completed by chromatography.

[0191] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0192] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by 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 and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, 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., preferably deuterium.

[0193] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0194] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0195] "Substitution" 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 by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0196] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0197] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately 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 acids and organic acids.

[0198] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0199] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0200] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0201] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0202] Synthesis method of the disclosed compound

[0203] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0204] Option 1

[0205] The method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0206] The compound represented by general formula (IA) or its salt and the compound represented by general formula (IB) or its salt undergo nucleophilic substitution reaction under microwave conditions to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

[0207] in:

[0208] X is a halogen, preferably Cl;

[0209] Ring A, L, Z, R a 、R 1 to R 9 , m and s are as defined in the general formula (I).

[0210] Option 2

[0211] The method for preparing the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0212] The compound represented by general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or its salt under microwave conditions to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0213] in:

[0214] X is a halogen, preferably Cl;

[0215] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II).

[0216] Option 3

[0217] The method for preparing the compound represented by the general formula (II-1) or a salt thereof disclosed herein comprises the following steps:

[0218] The compound represented by general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-1B) or its salt under microwave conditions to obtain the compound represented by general formula (II-1) or its pharmaceutically acceptable salt;

[0219] X is a halogen, preferably Cl;

[0220] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II-1).

[0221] Option 4

[0222] The method for preparing the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0223] The compound represented by general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-2B) or its salt under microwave conditions to obtain the compound represented by general formula (II-2) or its pharmaceutically acceptable salt;

[0224] X is a halogen, preferably Cl;

[0225] Ring A, Ring B, L, R a 、R b 、R 1 、R 2 、R 4 、R 5 , m and n are as defined in the general formula (II-2).

[0226] Plan 5

[0227] The method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0228] The compound represented by general formula (IIIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or its salt under microwave conditions to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0229] X is a halogen, preferably Cl;

[0230] 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 the general formula (III).

[0231] Plan 6

[0232] The method for preparing the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0233] The compound represented by general formula (IIIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-1B) or its salt under microwave conditions to obtain the compound represented by general formula (III-1) or its pharmaceutically acceptable salt;

[0234] X is a halogen, preferably Cl;

[0235] 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 the general formula (III-1).

[0236] Plan 7

[0237] The method for preparing the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0238] The compound represented by general formula (IIIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (II-2B) or its salt under microwave conditions to obtain the compound represented by general formula (III-2) or its pharmaceutically acceptable salt;

[0239] X is a halogen, preferably Cl;

[0240] 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 the general formula (III-2).

[0241] Plan 8

[0242] The method for preparing the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0243] The compound represented by general formula (IVA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (IIB) or its salt under microwave conditions to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0244] X is a halogen, preferably Cl;

[0245] 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 the general formula (IV).

[0246] Plan 9

[0247] The method for preparing the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0248] The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-1B) or a salt thereof under microwave conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0249] X is a halogen, preferably Cl;

[0250] Ring A, Ring B, R a 、R b 、R 1 、R 2 、R 4 、R 5 、R4a 、R 4b 、R 5a 、R 5b , m and n are as defined in the general formula (IV-1).

[0251] Plan 10

[0252] The method for preparing the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0253] The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (II-2B) or a salt thereof under microwave conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0254] X is a halogen, preferably Cl;

[0255] 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 the general formula (IV-2).

[0256] The reagents providing the alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, 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 or 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; preferably, the reagent providing the alkaline conditions is N,N-diisopropylethylamine.

[0257] The reaction in the above steps 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

[0258] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0259] Example

[0260] Compound structures are obtained using a Varian 400 MHz NMR spectrometer, typically using CDCl₃ and DMSO-d₆ as solvents. Chemical shifts are reported in ppm. Peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.

[0261] The LC-MS instrument used was a Waters ACQUITY Arc equipped with a QDa Detector. The mass spectrometer (MS) used an ESI source and only indicated the molecular weight M of the parent molecule, usually reporting [M+H]. + The injection volume was determined by the sample concentration; the flow rate was 0.8 mL / min; HPLC peaks 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).

[0262] Chiral HPLC analysis was performed using a SHIMADZU LC-30AD SFC high performance liquid chromatograph.

[0263] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0264] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0265] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0266] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0267] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0268] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0269] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0270] Microwave reactions were performed using a Biotage microwave reactor.

[0271] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0272] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0273] The reaction progress in the examples 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 included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0274] The abbreviations used in this disclosure are as follows:

[0275] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0276] HOBT: 1-Hydroxybenzotriazole

[0277] TEA: triethylamine

[0278] DCM: dichloromethane

[0279] DMF: N,N-dimethylformamide

[0280] DMF-DMA: N,N-dimethylformamide dimethyl acetal

[0281] LHMDS: lithium bis(trimethylsilyl)amide

[0282] TMSI: Iodotrimethylsilane

[0283] THF: Tetrahydrofuran

[0284] Example 1

[0285] (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

[0286] first step

[0287] (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol 1b

[0288] 2,4-Dichloro-6,7-dihydrothiophene[3,2-d]1a (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, the solvent was concentrated under reduced pressure. Water (100 mL) was then added and the mixture was extracted with dichloromethane (200 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title product 1b (15.2 g).

[0289] Step 2

[0290] (R)-2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 1c

[0291] Under nitrogen protection, compound 1b (15.2 g, 58.1 mmol), S-1,1'-bi-2-naphthol (1.66 g, 5.81 mmol), tetraisopropoxytitanium (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. Subsequently, tert-butyl peroxide (5.75 g, 63.9 mmol) was added and the reaction solution was heated to 40°C and stirred for 5 hours. After completion of the reaction, the solid was filtered out and purified by methanol slurrying to obtain the title product 1c (16.7 g, ee value: 97.4%).

[0292] Step 3

[0293] 4-Chloro-N-(4-hydroxypyridin-3-yl)benzamide 1f

[0294] Under nitrogen, 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. A solution of 4-chlorobenzoyl chloride 1e (3.3 g, 19.1 mmol) in dichloromethane (5 mL) was then slowly added dropwise. The mixture was stirred at room temperature for two hours, filtered, and the filter cake was washed with water and dried to give the title product 1f (2.5 g).

[0295] Step 4

[0296] 2-(4-Chlorophenyl)oxazolo[4,5-c]pyridine 1g

[0297] To a solution of hexachloroethane (4.7 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature were added triphenylphosphine (6.7 g, 24.3 mmol) and triethylamine (6.5 g, 64.8 mmol). The mixture was stirred at room temperature for 10 minutes, then compound 1f (2 g, 8.1 mmol) was added portionwise 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 flash column chromatography to obtain 1 g (1.3 g) of the title product.

[0298] Step 5

[0299] 2-(4-Chlorophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 1h

[0300] 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 solution was concentrated to obtain the title product 1h (1.1 g).

[0301] Step 6

[0302] 2-(4-Chlorophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 1i

[0303] Under ice, sodium borohydride (225 mg, 5.9 mmol) was added portionwise to a solution of compound 1h (1.1 g, 2.9 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated to dryness with methanol and extracted with ethyl acetate (30 mL x 3). The combined organic phases were 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 flash column chromatography to obtain the title product 1i (700 mg, 21.7% yield).

[0304] Step 7

[0305] 2-(4-Chlorophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 1j

[0306] To a dichloroethane solution (8 mL) of compound 1i (400 mg, 1.6 mmol) at zero degrees Celsius was added 1-chloroethyl chloroformate (343.5 mg, 2.4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 2 hours, then the mixture was cooled to room temperature and concentrated to dryness. Methanol (6 mL) was added to the mixture and stirring continued for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 1j (350 mg).

[0307] Step 8

[0308] (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

[0309] To a solution of compound 1j (50 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 1 (20 mg, yield: 21.7%).

[0310] 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).

[0311] MS m / z(ESI):486[M+1].

[0312] Example 2

[0313] (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

[0314] first step

[0315] 4-Fluoro-N-(4-hydroxypyridin-3-yl)benzamide 2b

[0316] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridine-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0°C in an ice bath. A solution of 4-fluorobenzoyl chloride 2a (3.0 g, 19.1 mmol) in dichloromethane (5 mL) was then slowly added dropwise. After stirring at room temperature for two hours, 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 a crude product. The crude product was purified by flash column chromatography to obtain the title product 2b (3.7 g).

[0317] Step 2

[0318] 2-(4-Fluorophenyl)oxazolo[4,5-c]pyridine 2c

[0319] To a solution of hexachloroethane (5.1 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature were added triphenylphosphine (6.8 g, 25.8 mmol) and triethylamine (6.9 g, 68.8 mmol). The mixture was stirred at room temperature for 10 minutes, then compound 2b (2.0 g, 8.6 mmol) was added portionwise 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 flash column chromatography to obtain the title product 2c (1.2 g).

[0320] Step 3

[0321] 2-(4-Fluorophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 2d

[0322] 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. The mixture was stirred at room temperature for 5 h, and the reaction solution was concentrated to give the title product 2d (1.1 g).

[0323] Step 4

[0324] 2-(4-Fluorophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 2e

[0325] Under ice, sodium borohydride (230 mg, 6.2 mmol) was added portionwise to a solution of compound 2d (1.1 g, 3.1 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (20 mL). The mixture was concentrated to dryness and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography to afford the title compound 2e (930 mg).

[0326] Step 5

[0327] 2-(4-Fluorophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 2f

[0328] At zero degrees Celsius, 1-chloroethyl chloroformate (370 mg, 2.6 mmol) was added to a dichloroethane solution (8 mL) of compound 2e (400 mg, 1.7 mmol) under a nitrogen atmosphere. The reaction solution was stirred at 80°C for 2 hours, then the mixture was cooled to room temperature and concentrated to dryness. Methanol (6 mL) was added to the mixture and stirring continued for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 2f (380 mg).

[0329] Step 6

[0330] (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

[0331] To a solution of compound 2f (45 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 2 (25 mg, yield: 28.1%).

[0332] 1H 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).

[0333] MS m / z(ESI):470[M+1].

[0334] Example 3

[0335] (R)-4-(5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-ylbenzonitrile 3

[0336] first step

[0337] 4-Cyano-N-(4-hydroxypyridin-3-yl)benzamide 3b

[0338] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridine-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 two hours, 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 flash column chromatography to obtain the title product 3b (2.8 g).

[0339] Step 2

[0340] 4-(Oxazolo[4,5-c]pyridin-2-yl)benzonitrile 3c

[0341] To a solution of hexachloroethane (5.1 g, 20.2 mmol) in dichloromethane (30 mL) at room temperature were added triphenylphosphine (6.8 g, 25.8 mmol) and triethylamine (6.9 g, 68.8 mmol). The mixture was stirred at room temperature for 10 minutes, then compound 3b (2.0 g, 8.6 mmol) was added portionwise 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 flash column chromatography to obtain the title product 3c (1.1 g).

[0342] Step 3

[0343] 2-(4-Cyanophenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 3d

[0344] 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. The mixture was stirred at room temperature for 5 h, and the reaction solution was concentrated to give the title product 3d (1.0 g).

[0345] Step 4

[0346] 2-(4-Cyanophenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 3e

[0347] Under ice, sodium borohydride (200 mg, 5.5 mmol) was added portionwise to a solution of compound 3d (1.0 g, 2.8 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 3 hours and quenched with water (20 mL). The mixture was concentrated to dryness with methanol and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography to afford the title product 3e (200 mg).

[0348] Step 5

[0349] 2-(4-Cyanophenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 3f

[0350] At zero degrees Celsius, 1-chloroethyl chloroformate (250 mg, 1.8 mmol) was added to a dichloroethane solution (8 mL) of compound 3e (200 mg, 0.9 mmol) under a nitrogen atmosphere. The reaction solution was stirred at 80°C for 2 hours, then the mixture was cooled to room temperature and concentrated to dryness. Methanol (6 mL) was added to the mixture and stirring continued for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 3f (180 mg).

[0351] Step 6

[0352] (R)-4-(5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-ylbenzonitrile 3

[0353] To a solution of compound 3f (47 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 3 (20 mg, yield: 22.2%).

[0354] 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).

[0355] MS m / z(ESI):477[M+1].

[0356] Example 4

[0357] (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

[0358] first step

[0359] 3-(2-Methoxyethoxy)benzoyl chloride 4b

[0360] Under nitrogen, 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. A solution of oxalyl chloride (771 mg, 6.1 mmol) in dichloromethane (3 mL) was then slowly added dropwise. After stirring at room temperature for two hours, the mixture was concentrated to afford the title product 4b (1.1 g).

[0361] Step 2

[0362] N-(4-Hydroxypyridin-3-yl)-3-(2-methoxyethoxy)benzamide 4c

[0363] Compound 4b (1.1 g, 5.1 mmol) was prepared according to the method of the third step of Example 1 to give the title product 4c (700 mg).

[0364] Step 3

[0365] 2-(3-(2-methoxyethoxy)phenyl)oxazolo[4,5-c]pyridine 4d

[0366] At room temperature, compound 4c (700 mg, 2.4 mmol) was prepared according to the method of step 4 of Example 1 to give the title product 4d (600 mg).

[0367] Step 4

[0368] 2-(3-(2-methoxyethoxy)phenyl)-5-methyloxazolo[4,5-c]pyridin-5-ium 4e

[0369] At room temperature, compound 4d (600 mg, 2.2 mmol) was prepared according to the method of step 5 of Example 1 to give the title product 4e (900 mg).

[0370] Step 5

[0371] 2-(3-(2-methoxyethoxy)phenyl)-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 4f

[0372] At zero degrees, compound 4e (900 mg, 2.2 mmol) was prepared according to the method of step 6 of Example 1 to obtain the title product 4f (500 mg).

[0373] Step 6

[0374] 2-(3-(2-methoxyethoxy)phenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 4g

[0375] At room temperature, compound 4E (500 mg, 1.7 mmol) was prepared according to the method of step 7 of Example 1 to obtain the title product 4 g (400 mg).

[0376] Step 7

[0377] (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

[0378] 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 obtain the title product 4 (20 mg, yield: 23.8%).

[0379] 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).

[0380] MS m / z(ESI):526[M+1].

[0381] Example 5

[0382] (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

[0383] first step

[0384] N-(4-Hydroxypyridin-3-yl)cyclohexanecarboxamide 5b

[0385] Under nitrogen protection, triethylamine (2.75 g, 27.3 mmol) was added to a solution of 3-aminopyridine-4-ol 1d (2.0 g, 18.2 mmol) in dichloromethane (30 mL). The mixture was cooled to 0°C in an ice bath. A solution of cyclohexanecarbonyl chloride 5a (2.8 g, 19.1 mmol) in dichloromethane (5 mL) was then slowly added dropwise. After stirring at room temperature for two hours, 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 flash column chromatography to obtain the title product 5b (2.8 g).

[0386] Step 2

[0387] 2-Cyclohexyloxazolo[4,5-c]pyridine 5c

[0388] To a solution of hexachloroethane (5.4 g, 22.5 mmol) in dichloromethane (30 mL) was added triphenylphosphine (7.2 g, 7.3 mmol) and triethylamine (7.4 g, 72.8 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes, and then compound 5b (2.0 g, 9.1 mmol) was added portionwise 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 give the crude product. The crude product was purified by flash column chromatography to give the title product 5c (0.8 g).

[0389] Step 3

[0390] 2-Cyclohexyl-5-methyloxazolo[4,5-c]pyridin-5-ium 5d

[0391] 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. The mixture was stirred at room temperature for 5 h, and the reaction solution was concentrated to give the title product 5d (0.9 g).

[0392] Step 4

[0393] 2-Cyclohexyl-5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 5e

[0394] Under ice, sodium borohydride (190 mg, 5.2 mmol) was added portionwise to a solution of compound 5d (0.9 g, 2.6 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 3 hours and quenched with water (20 mL). The mixture was concentrated to dryness with methanol and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography to afford the title product 5e (700 mg).

[0395] Step 5

[0396] 2-Cyclohexyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine 5f

[0397] At zero degrees Celsius, 1-chloroethyl chloroformate (910 mg, 6.4 mmol) was added to a dichloroethane solution (8 mL) of compound 5e (700 mg, 3.2 mmol) under a nitrogen atmosphere. The reaction solution was stirred at 80°C for 2 hours, then the mixture was cooled to room temperature and concentrated to dryness. Methanol (6 mL) was added to the mixture and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 5f (280 mg).

[0398] Step 6

[0399] (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

[0400] To a solution of compound 5f (44 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 5 (16 mg, yield: 18.4%).

[0401] 1H 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).

[0402] MS m / z(ESI):458[M+1].

[0403] Example 6

[0404] (R)-2-(2-(4-chlorophenyl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 6

[0405] first step

[0406] 4-Chloro-N-(4-chloropyridin-3-yl)benzamide 6b

[0407] 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 two hours, 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 a crude product. The crude product was purified by flash column chromatography to obtain the title product 6b (2.1 g).

[0408] Step 2

[0409] 2-(4-Chlorophenyl)thiazo[4,5-c]pyridine 6c

[0410] To a solution of Lawesson's reagent (2.1 g, 5.3 mmol) in xylene (50 mL) was added compound 6b (2.0 g, 7.5 mmol) at room temperature, and the mixture was heated to 120°C and stirred for 5 hours. The solvent was removed by rotary evaporation, and sodium hypochlorite solution was added, followed by extraction 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 flash column chromatography to obtain the title product 6c (1.1 g).

[0411] Step 3

[0412] 2-(4-Chlorophenyl)-5-methylthiazolo[4,5-c]pyridin-5-ium 6d

[0413] 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. The mixture was stirred at room temperature for 5 h, and the reaction solution was concentrated to give the title product 6d (1.2 g).

[0414] Step 4

[0415] 2-(4-Chlorophenyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine 6e

[0416] Under ice, sodium borohydride (230 mg, 6.2 mmol) was added portionwise to a solution of compound 6d (1.2 g, 3.1 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 3 hours and quenched with water (20 mL). The mixture was concentrated to dryness with methanol and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography to afford the title product 6e (800 mg).

[0417] Step 5

[0418] 2-(4-Chlorophenyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine 6f

[0419] At zero degrees Celsius, 1-chloroethyl chloroformate (860 mg, 6.0 mmol) was added to a dichloroethane solution (12 mL) of compound 6e (800 mg, 3.0 mmol) under a nitrogen atmosphere. The reaction solution was stirred at 80°C for 2 hours, then the mixture was cooled to room temperature and concentrated to dryness. Methanol (6 mL) was added to the mixture and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 6f (350 mg).

[0420] Step 6

[0421] (R)-2-(2-(4-chlorophenyl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 6

[0422] To a solution of compound 6f (53 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 6 (16 mg, yield: 16.8%).

[0423] 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).

[0424] MS m / z(ESI):503[M+1].

[0425] Example 7

[0426] (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

[0427] first step

[0428] tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate 7b

[0429] 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. A solution of 4-chlorobenzoyl chloride (0.57 g, 3.3 mmol) in dichloromethane (3 mL) was then slowly added dropwise. After stirring at room temperature for two hours, 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 give a crude product. The crude product was purified by flash column chromatography to give the title product 7b (0.56 g).

[0430] Step 2

[0431] Tert-butyl 3-(4-chlorobenzamide)-4-oxopyrrolidine-1-carboxylate 7c

[0432] To a solution of compound 7b (0.56 g, 1.6 mmol) in dichloromethane (50 mL) at 0°C was added Dess-Martin periodinane (1.4 g, 3.3 mmol). After stirring at room temperature for two hours, the mixture was 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 flash column chromatography to obtain the title product 7c (0.41 g).

[0433] Step 3

[0434] tert-Butyl 2-(4-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate 7d

[0435] To a solution of hexachloroethane (0.71 g, 3.0 mmol) in dichloromethane (30 mL) at room temperature were added triphenylphosphine (0.94 g, 3.6 mmol) and triethylamine (0.97 g, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, then compound 7c (0.41 g, 1.2 mmol) was added portionwise 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 flash column chromatography to obtain the title product 7d (0.19 g).

[0436] Step 4

[0437] 2-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole hydrochloride 7e

[0438] Compound 7d (0.19 g, 3.1 mmol) was stirred in a 1,4-dioxane hydrochloride solution (5 mL) at room temperature for 1 hour, and then concentrated to dryness to obtain the title product 7e (150 mg).

[0439] Step 5

[0440] (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

[0441] To a solution of compound 7e (54 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 7 (11 mg, yield: 12.3%).

[0442] 1 H 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),2.89-2.96(m,1H),2.34-2.48(m,2H),2.21-2.30(m,2H),1.76-1.89(m,2H).

[0443] MS m / z(ESI):472[M+1].

[0444] Example 8

[0445] (R)-2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 8

[0446] first step

[0447] Ethyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8b

[0448] 2,4-Dichloro-6,7-dihydrothiophene[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, the solvent was removed by rotary evaporation, followed by addition of water (30 mL) and extraction with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash column chromatography to yield the title product 8b (800 mg).

[0449] Step 2

[0450] (R)-ethyl 2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8c

[0451] At room temperature, compound 8b (800 mg, 2.3 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 8c (500 mg).

[0452] Step 3

[0453] (R)-ethyl 2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 8d

[0454] 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 obtain the title product 8d (60 mg).

[0455] Step 4

[0456] (R)-2-(4-((2-(2-(4-chlorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 8

[0457] To a solution of compound 8d (60 mg, 0.11 mmol) in methanol (6 mL) / water (2 mL) was added sodium hydroxide (18 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After concentration to dryness, the mixture was spin-dried with methanol. Dilute hydrochloric acid (2 M) was added to adjust the pH to 2-3, and the mixture was filtered. The filter cake was washed with ethyl acetate and dried to afford the title product 8 (30 mg, 50.8% yield).

[0458] 1 H 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).

[0459] MS m / z(ESI):536[M+1].

[0460] Example 9

[0461] (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

[0462] first step

[0463] tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 9b

[0464] Under nitrogen, tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate 9a (1.0 g, 3.2 mmol), pinacol diboron (0.9 g, 3.5 mmol), potassium acetate (0.47 mg, 4.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (250 mg, 0.3 mmol) were mixed in a 1,4-dioxane solution (15 mL). The reaction mixture was stirred at 90°C for 3 hours. After completion, the solvent was removed by rotary evaporation, followed by addition of water (30 mL) and extraction with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the crude title product 9b (1.2 g).

[0465] Step 2

[0466] tert-Butyl 6-(5-chloropyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 9c

[0467] Under nitrogen, 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]palladium dichloride dichloromethane complex (81 mg, 0.1 mmol) were mixed in a 1,4-dioxane (15 mL) / water (3 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed 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 flash column chromatography to obtain the title product 9c (300 mg).

[0468] Step 3

[0469] 6-(5-chloropyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 9d

[0470] To a dichloromethane solution of compound 9c (300 mg, 0.87 mmol) was added a 1,4-dioxane hydrochloride solution (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated to dryness to give the title product 9d (330 mg).

[0471] Step 4

[0472] (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

[0473] 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 obtain the title product 9 (22 mg, yield: 27.8%).

[0474] 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).

[0475] MS m / z(ESI):497[M+1].

[0476] Example 10

[0477] (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

[0478] first step

[0479] tert-Butyl 6-(4-fluoropiperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 10a

[0480] Under nitrogen, 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'-bisdiphenylphosphine (206 mg, 0.32 mmol) were mixed in a toluene solution (15 mL). The reaction mixture was stirred at 110°C for 6 hours. After completion of the reaction, the solvent was removed by rotary evaporation, followed by addition of water (30 mL) and extraction with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to afford the title product 10a (400 mg).

[0481] Step 2

[0482] 6-(4-Fluoropiperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 10b

[0483] To a dichloromethane solution of compound 10a (400 mg, 1.2 mmol) was added a 1,4-dioxane hydrochloride solution (4 M, 2 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated to dryness to obtain the title product 10b (300 mg).

[0484] Step 3

[0485] (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

[0486] 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 product 10 (22 mg, yield: 28.2%).

[0487] 1 H 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).

[0488] MS m / z(ESI):486[M+1].

[0489] Example 11

[0490] (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

[0491] first step

[0492] tert-Butyl 3-(4-fluorobenzoyl)-4-oxopiperidine-1-carboxylate 11b

[0493] 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 solution was stirred at this temperature for 30 min. Subsequently, a solution of 4-fluorobenzoyl chloride (1.7 g, 10.0 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at this temperature for 3 h. Saturated ammonium chloride (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and concentrated under reduced pressure to give the title product, crude product 11b (3 g).

[0494] Step 2

[0495] tert-Butyl 3-(4-fluorophenyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 11c

[0496] Compound 11b (3 g, 9.3 mmol) and hydrazine hydrate (0.75 g, 18.7 mmol, 80% in H2O) were dissolved in ethanol (30 mL) and reacted at 80°C for 3 h. The reaction solution was cooled to room temperature and the ethanol was concentrated. Water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title product 11c (400 mg).

[0497] Step 3

[0498] 3-(4-Fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride 11d

[0499] To a dichloromethane solution of compound 11c (400 mg, 1.2 mmol) was added a 1,4-dioxane hydrochloride solution (4 M, 2 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated to dryness to obtain the title product 11d (450 mg).

[0500] Step 4

[0501] (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

[0502] 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 product 11 (10 mg, yield: 11.9%).

[0503] 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).

[0504] MS m / z(ESI):469[M+1].

[0505] Example 12

[0506] (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

[0507] first step

[0508] tert-Butyl 3-((dimethylamino)methyl)-4-oxopiperidine-1-carboxylate 12a

[0509] Under nitrogen, 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, added to a saturated ammonium chloride solution (40 mL), and extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to give the title product 12a (2.2 g).

[0510] Step 2

[0511] tert-Butyl 1-phenyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 12c

[0512] Compound 12a (2.1 g, 9.3 mmol) was dissolved in methanol (100 mL) and water (50 mL), followed by the addition of sodium bicarbonate (0.53 g, 5.0 mmol) and phenylhydrazine hydrochloride 12b (1.43 g, 9.9 mmol), and finally acetic acid (1 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was then neutralized with saturated sodium bicarbonate solution and concentrated to dryness with methanol. The mixture was then extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 12c (1.3 g).

[0513] Step 3

[0514] 1-Phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride 12d

[0515] To a dichloromethane solution of compound 12c (200 mg, 1.2 mmol) was added a 1,4-dioxane hydrochloride solution (4 M, 2 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated to dryness to obtain the title product 12d (250 mg).

[0516] Step 4

[0517] (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

[0518] 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 product 12 (20 mg, yield: 24.7%).

[0519] 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).

[0520] MS m / z(ESI):451[M+1].

[0521] Example 13

[0522] (R)-2-(2-(4-fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 13

[0523] first step

[0524] tert-Butyl 2-(4-fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate 13c

[0525] At room temperature, tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate 13a (1.0 g, 3.6 mmol) and 4-fluorobenzosulfamide 13b (0.56 g, 3.6 mmol) were mixed in an isopropanol solution (20 mL). The mixture was stirred at 60°C for 5 hours and then filtered. The filter cake was washed with isopropanol and dried to give the title product 13c (0.54 g).

[0526] Step 2

[0527] 2-(4-Fluorophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride 13d

[0528] Compound 13c (0.54 g, 1.6 mmol) was stirred in a 1,4-dioxane hydrochloride solution (8 mL) at room temperature for 1 hour, and then concentrated to dryness to obtain the title product 13d (0.48 g).

[0529] Step 3

[0530] (R)-2-(2-(4-fluorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 13

[0531] To a solution of compound 13d (57 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 13 (30 mg, yield: 32.6%).

[0532] 1 H 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).

[0533] MS m / z(ESI):486[M+1].

[0534] Example 14

[0535] (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

[0536] first step

[0537] tert-Butyl 2-(pyridin-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate 14b

[0538] At room temperature, 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 an isopropanol solution (20 mL). The mixture was stirred at 60°C for 5 hours and then filtered. The filter cake was washed with isopropanol and dried to give the title product 14b (0.9 g).

[0539] Step 2

[0540] 2-(Pyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride 14c

[0541] Compound 14b (0.9 g, 2.8 mmol) was stirred in a 1,4-dioxane hydrochloride solution (8 mL) at room temperature for 1 hour, and then concentrated to dryness to obtain the title product 14c (0.8 g).

[0542] Step 3

[0543] (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

[0544] To a solution of compound 14c (53 mg, 0.21 mmol) and compound 1c (55 mg, 0.19 mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (108 mg, 0.84 mmol). The reaction mixture was stirred at 120°C under microwave conditions for 40 min. 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. The crude product was purified by flash column chromatography to obtain the title product 14 (35 mg, yield: 39.3%).

[0545] 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).

[0546] MS m / z(ESI):469[M+1].

[0547] Example 15

[0548] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-phenyl-7,8-dihydropyrimidin[4,3-d]pyrimidin-6(5H)-yl)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 15

[0549] first step

[0550] tert-Butyl 2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 15b

[0551] Under nitrogen, 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 x 2). The organic phases were combined and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography to give the title product 15b (700 mg).

[0552] Step 2

[0553] 2-Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride 15c

[0554] To a dichloromethane solution of compound 15b (300 mg, 0.96 mmol) was added a 1,4-dioxane hydrochloride solution (4 M, 2 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated to dryness to obtain the title product 15c (350 mg).

[0555] Step 3

[0556] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(2-phenyl-7,8-dihydropyrimidin[4,3-d]pyrimidin-6(5H)-yl)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 15

[0557] 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 product 15 (20 mg, yield: 24.1%).

[0558] 1H 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).

[0559] MS m / z(ESI):463[M+1].

[0560] Example 16

[0561] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16

[0562] first step

[0563] 3-(((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16b

[0564] 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 the first step of Example 1 to obtain the title product 16b (1.1 g).

[0565] Step 2

[0566] (R)-3-(((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16c

[0567] Under nitrogen protection, compound 16b (1.10 g, 3.41 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 16c (0.8 g).

[0568] Step 3

[0569] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one 16

[0570] 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 obtain the title product 16 (3 mg, yield: 6%).

[0571] 1 H NMR (400MHz, DMSO-d6) δppm 11.55(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).

[0572] MS m / z(ESI):521[M+1].

[0573] Example 17

[0574] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17

[0575] first step

[0576] tert-Butyl (6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)methylcarbamate 17b

[0577] Under ice, 2-(6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)acetonitrile 17a (0.5 g, 2.5 mmol), nickel 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 then added and stirred for 2 hours. Subsequently, sodium borohydride (0.19 g, 5.0 mmol) was added and the temperature was raised to 25°C and stirred for 14 hours. After completion of the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain the title product 17b (0.1 g).

[0578] Step 2

[0579] 3-(Aminomethyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one hydrochloride 17c

[0580] Compound 17b (0.1 g, 0.3 mmol) was stirred in a 1,4-dioxane hydrochloride solution (4 M, 3 mL) at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to give the title product 17c (80 mg).

[0581] Step 3

[0582] 3-(((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17d

[0583] 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 the first step of Example 1 to obtain the title product 17d (20 mg).

[0584] Step 4

[0585] (R)-3-(((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17e

[0586] Under nitrogen protection, compound 17d (20 mg, 0.05 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 17e (15 mg).

[0587] Step 5

[0588] (R)-3-(((2-(2-(4-fluorophenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one 17

[0589] 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 obtain the title product 17 (2 mg, yield: 9%).

[0590] 1 H NMR (400MHz, DMSO-d6) δppm 8.03 (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).

[0591] MS m / z(ESI):575[M+1].

[0592] Example 18

[0593] (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

[0594] first step

[0595] tert-Butyl (2-methoxy-4,6-dimethylpyridin-3-yl)methylcarbamate 18b

[0596] Under ice-cooling, 2-(2-methoxy-4,6-dimethylpyridin-3-yl)acetonitrile 18a (0.5 g, 3.08 mmol) was prepared according to the method of the first step of Example 17 to obtain the title product 18b (0.2 g).

[0597] Step 2

[0598] (2-Methoxy-4,6-dimethylpyridin-3-yl)methylamine hydrochloride 18c

[0599] At room temperature, compound 18b (0.2 g, 0.75 mmol) was prepared according to the method of the second step of Example 17 to obtain the title product 18c (15 mg).

[0600] Step 3

[0601] 2-Chloro-N-((2-methoxy-4,6-dimethyl-1,2-dihydropyridin-3-yl)methyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine 18d

[0602] Compound 1a (0.15 g, 0.75 mmol) and (2-methoxy-4,6-dimethylpyridin-3-yl)methanamine hydrochloride 18c (0.15 g, 0.75 mmol) were prepared according to the method of the first step of Example 1 to obtain the title product 18d (0.23 g).

[0603] Step 4

[0604] (R)-2-chloro-4-(((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 18e

[0605] Under nitrogen protection, compound 18d (0.23 g, 0.68 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 18e (0.23 g).

[0606] Step 5

[0607] (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

[0608] 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 obtain the title product 18 (5 mg, yield: 9%).

[0609] 1H NMR (400MHz, DMSO-d6) δppm 8.03 (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).

[0610] MS m / z(ESI):535[M+1].

[0611] Example 19

[0612] (R)-4-(Benzo[d]oxazol-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

[0613] first step

[0614] N-(2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)benzo[d]oxazol-6-amine 19b

[0615] 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 of the first step of Example 1 to give the title product 19b (0.72 g).

[0616] Step 2

[0617] (R)-4-(Benzo[d]oxazol-6-amino)-2-chloro-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide 19c

[0618] Under nitrogen protection, compound 19b (0.72 g, 2.36 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 19c (0.58 g)

[0619] Step 3

[0620] (R)-4-(Benzo[d]oxazol-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

[0621] 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 obtain the title product 19 (12 mg, yield: 12%).

[0622] 1 H NMR (400MHz, DMSO-d6) δppm 9.93 (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).

[0623] MS m / z(ESI):502[M+1].

[0624] Example 20

[0625] (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

[0626] first step

[0627] (1s,4s)-4-((2-chloro-6,7-dihydrothiophen[3,2-d]pyrimidin-4-yl)amino)cyclohexan-1-ol 20b

[0628] Compound 1a (300 mg, 1.45 mmol) and compound 20a (167 mg, 1.45 mmol) were prepared according to the method of the first step of Example 1 to obtain the title product 20b (300 mg).

[0629] Step 2

[0630] (R)-2-Chloro-4-(((1s,4S)-4-hydroxycyclohexyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 20c

[0631] Under nitrogen protection, compound 20b (200 mg, 0.70 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 20c (150 mg).

[0632] Step 3

[0633] (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

[0634] 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 obtain the title product 20 (12 mg, yield: 12%).

[0635] 1 H NMR (400MHz, DMSO-d6) δppm 8.02(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).

[0636] MS m / z(ESI):484[M+1].

[0637] Example 21

[0638] (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

[0639] first step

[0640] Benzyl 4-(4-chlorobenzamido)-3-hydroxypiperidine-1-carboxylate 21c

[0641] 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 hour. Compound 21a (500 mg, 2.00 mmol) and TEA (404 mg, 4.00 mmol) were then added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 3), washed with saturated NaHCO3 solution, dried over sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title product 21c (700 mg).

[0642] Step 2

[0643] Benzyl 4-(4-chlorobenzamido)-3-oxopiperidine-1-carboxylate 21d

[0644] Compound 21c (400 mg, 1.03 mmol) was dissolved in dichloromethane. Dess-martin (1309 mg, 3.09 mmol) was added at 0°C under nitrogen protection, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, water (10 mL) was added to the mixture to quench the reaction. The mixture was extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The title product 21d (350 mg) was purified by flash chromatography.

[0645] Step 3

[0646] Benzyl 2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4]pyridine-5(4H)-carboxylate 21e

[0647] Compound 21d (300 mg, 0.77 mmol) was dissolved in phosphorus oxychloride (10 mL) and stirred at 100° C. for 3 hours. After completion of the reaction, most of the solvent was removed by spin drying, and ice water was added to quench the reaction. The product was extracted with DCM (20 mL x 3), washed with saturated NaHCO solution, dried over sodium sulfate, and spin dried to give a crude product. The title product 21e (150 mg) was purified by flash chromatography.

[0648] Step 4

[0649] 2-(4-Chlorophenyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine 21f

[0650] Compound 21e (100 mg, 0.27 mmol) was dissolved in acetonitrile and TMSI (163 mg, 0.81 mmol) was added at 0°C under nitrogen protection. The mixture was stirred at 25°C for 18 h. After the reaction, water (5 mL) was added to the mixture to quench the reaction. The mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The title product 21f (50 mg) was purified by flash chromatography.

[0651] Step 5

[0652] (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

[0653] 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 obtain the title product 21 (10 mg, yield: 11%).

[0654] 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).

[0655] MS m / z(ESI):486[M+1].

[0656] Example 22

[0657] (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

[0658] first step

[0659] tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 22b

[0660] Under nitrogen, compound 22a (1 g, 3.2 mmol), pinacol diboronate (1.1 g, 4.2 mmol), potassium acetate (0.41 g, 4.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (150 mg, 0.2 mmol) were mixed in a 1,4-dioxane solution (15 mL). The reaction mixture was stirred at 90°C for 3 hours. After completion, the solvent was removed by concentration under reduced pressure. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the crude title product 22b (1.2 g).

[0661] Step 2

[0662] tert-Butyl 6-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 22d

[0663] Under nitrogen, compound 22b (1.2 g, 3.3 mmol) and compound 22c (349 mg, 2.2 mmol), potassium carbonate (455 mg, 3.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (146 mg, 0.2 mmol) were mixed in a 1,4-dioxane (10 mL) / water (2 mL) solution. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain the title product 22d (0.97 g).

[0664] Step 3

[0665] 6-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline 22e

[0666] To a solution of compound 22d (0.97 g, 3.1 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (4 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated to dryness to give the title product 22e (654 mg).

[0667] Step 4

[0668] 2-Chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine 22g

[0669] 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 the first step of Example 1 to obtain the title product 22g (180 mg).

[0670] Step 5

[0671] (R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 22h

[0672] At room temperature, compound 22g (180 mg, 0.66 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 22h (150 mg).

[0673] Step 6

[0674] (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

[0675] Compound 22e (80 mg, 0.37 mmol) and compound 22h (106 mg, 0.37 mmol) were prepared according to the eighth step of Example 1 under microwave conditions at 120°C to give the title product 22 (27 mg, yield: 15%).

[0676] 1 H NMR(400MHz,DMSO-d6)δppm 8.89(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,1H),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).

[0677] MS m / z(ESI):463.55[M+1]

[0678] Example 23

[0679] (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

[0680] first step

[0681] 4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide 23b

[0682] 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 the first step of Example 1 to obtain the title product 23b (180 mg).

[0683] Step 2

[0684] (R)-4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide 23c

[0685] At room temperature, compound 23b (180 mg, 0.56 mmol) was prepared according to the method of the second step of Example 1 to obtain the title product 23c (150 mg).

[0686] Step 3

[0687] (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

[0688] 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 obtain the title product 23 (15 mg, yield: 33%).

[0689] 1 H NMR (400MHz, DMSO-d6) δppm 8.92 (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).

[0690] MS m / z(ESI):511[M+1].

[0691] Example 24

[0692] (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

[0693] first step

[0694] (3-((2-Chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol 24b

[0695] 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 the first step of Example 1 to obtain the title product 24b (180 mg).

[0696] Step 2

[0697] (R)-2-Chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 24c

[0698] At room temperature, compound 24b (180 mg, 0.64 mmol) was prepared according to the method of the second step of Example 1 to give the title product 24c (140 mg).

[0699] Step 3

[0700] (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

[0701] 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 obtain the title product 24 (15 mg, yield: 32%).

[0702] 1H NMR(400MHz,DMSO-d6)δppm 8.92(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).

[0703] MS m / z(ESI):475[M+1].

[0704] Example 25

[0705] 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 25

[0706] first step

[0707] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide 25b

[0708] 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 m-chloroperbenzoic acid (2.57 g, 14.94 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to obtain the title product 25b (0.85 g).

[0709] Step 2

[0710] Ethyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 25d

[0711] 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, the solvent was concentrated under reduced pressure, followed by addition of water (20 mL) and extraction with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash column chromatography to afford the title product 25d (100 mg).

[0712] Step 3

[0713] Ethyl 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate 25f

[0714] 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 tube was placed in a microwave reactor and reacted at 120°C for 1 hour. After completion of the reaction, the solvent was concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to yield the title product 25f (60 mg).

[0715] Step 4

[0716] 2-(4-((2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-5,5-dioxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid 25

[0717] Compound 25f (60 mg, 0.12 mmol) and lithium hydroxide (15 mg, 0.36 mmol) were dissolved in a mixture of THF / MeOH / H₂O (3 mL / 1 mL / 1 mL) at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The pH was then adjusted to 2-3 with dilute hydrochloric acid and extracted with dichloromethane (20 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford the title product 25 (20 mg, 36% yield).

[0718] 1H NMR (400MHz, DMSO-d6) δppm 12.37 (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)

[0719] MS m / z(ESI):471[M+1].

[0720] Example 26

[0721] 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxido-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid 26

[0722] first step

[0723] Ethyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate 26b

[0724] 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 the second step of Example 25 to obtain the title product 26b (180 mg)

[0725] Step 2

[0726] Ethyl 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxido-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate 26d

[0727] Compound 26c (58 mg, 0.43 mmol) and compound 26b (180 mg, 0.43 mmol) were prepared according to the method of the third step of Example 25 to obtain the title product 26d (120 mg).

[0728] Step 3

[0729] 2-(4-((2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,5-dioxido-7,8-dihydro-6-hydrothiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid 26

[0730] At room temperature, compound 26d (60 mg, 0.12 mmol) was prepared according to the method of step 4 of Example 25 to give the title product 26 (20 mg, yield 36%).

[0731] 1 H NMR(400MHz,DMSO-d6)δppm 8.74(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).

[0732] MS m / z(ESI):483[M+1]

[0733] Biological evaluation

[0734] Test Example 1: Inhibitory effect of the disclosed compounds on PDE4 enzyme

[0735] PDE4 enzyme can hydrolyze cAMP to produce AMP. We used a synthetic PDE4 enzyme inhibitor to act on PDE4 enzyme and substrate cAMP for a period of time, and then used AMP-Glo TM The assay is performed using an assay kit. This assay is divided into two steps: first, converting the AMP produced by the reaction into ADP, and second, converting ADP into ATP. ATP binds to the reagent and emits fluorescence, which is then detected using an Echo 550. The fluorescence value is plotted to calculate the IC value of the PDE4 enzyme inhibitor. 50 The specific contents are as follows:

[0736] 1.1 Reagents and Instruments

[0737] 1.1.1 Reagents

[0738] 1.1.2 Instruments

[0739] 1.2 Experimental steps

[0740] 1.2.1 Compound preparation and handling

[0741] a) Preparation of compound DMSO stock solution: All compounds were dissolved in DMSO to a concentration of 10 mM.

[0742] Prepare solution.

[0743] b) Compound Storage: All compounds dissolved in DMSO were stored in a desiccator at room temperature for short-term storage.

[0744] 1.2.2 Preparation of working stock solution

[0745] a) The positive control AKEX0834 (compound of Example 2 in WO2013026797A1) was diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0746] b) The test compound was serially diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0747] c) Prepare 200X positive control (1 mM AKEX0834) and 200X solvent control (100% DMSO) Centrifuge the compound plate at 1000 rpm for 1 minute.

[0748] 1.2.3 Compound Screening

[0749] a) Use the Echo 550 to transfer 20 nL of compound dilution to each well of the assay plate.

[0750] b) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute.

[0751] c) Prepare 2X PDE4B2 or PDE4D2 in chilled PDE assay buffer.

[0752] d) Add 2 μL of 2X PDE4B2 or PDE4D2 to individual wells of the assay plate (prepared in step b).

[0753] e) Seal the assay plate and equilibrate at room temperature for 10 minutes.

[0754] f) Prepare 2X Cyclic-3',5'-AMP in PDE assay buffer.

[0755] g) Start the reaction by adding 2 μL of 2X Cyclic-3',5'-AMP (prepared in step f) to each well of the assay plate (prepared in step e). Incubate at room temperature for 60 minutes.

[0756] h) Add 4 μL of AMP-Glo ​​Reagent I and incubate at room temperature for 60 minutes.

[0757] i) Add 8 μL of AMP detection solution and incubate at room temperature for 60 minutes.

[0758] j) Read the RLU signal on an Envision 2105 plate reader.

[0759] 1.3 Data Analysis

[0760] The calculation formula is as follows:

[0761] % inhibition rate = {1-(average RLU of compound-average RLU of positive control of the whole plate) / (average RLU of negative control of the whole plate-average RLU of positive control of the whole plate)}

[0762] IC was calculated by fitting the % inhibition values ​​and the logarithm of compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 8.0. 50 .

[0763] Table 1 Inhibitory effect of the disclosed compounds on PDE4 enzyme

[0764] Conclusion: The disclosed compounds have a significant inhibitory effect on PDE4 enzyme.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from heteroaryl, aryl, heterocyclyl and cycloalkyl; L is -(CR 4a R 4b ) p (CR 5a R 5b ) q -; Z is selected from -S-, -S(O)-, -S(O)2- and -O-; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from a deuterium atom, an alkyl group, a halogen, an oxo group, a haloalkyl group, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 、-C(O)NR d3 R d4 、-S(O)2NR d3 R d4 、-(CH2) v1 NR d5 C(O)R e1 、-(CH2) v1 NR d5 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 substituted by one or more substituents selected from R, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 3 Selected from hydrogen atom, deuterium atom, alkyl group, alkenyl group, alkynyl group, halogen, cyano group, alkylcyano group, oxo group, -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 wherein the alkyl, alkenyl and alkynyl groups are each independently selected from deuterium atoms, halogen, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 , 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 are each independently selected from a deuterium atom, a halogen, a cyano group, an alkylcyano group, an oxo group, an alkyl group, a haloalkyl group, -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 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a halogen, an alkenyl group, an alkynyl group, a cyano group, an alkylcyano group, a hydroxyalkyl group, a haloalkyl group, -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 Together with the carbon atoms to which they are attached, they form an oxo group; R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a halogen, a cyano group, an alkylcyano group, a haloalkyl group, a hydroxyalkyl group, -OR c3 、-(CH2) u2 NR d6 R d7 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, haloalkyl, -OR c1 , cyano, -(CH2) u1 NR d1 R d2 , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R a are the same or different and are each independently selected from a deuterium atom, an alkyl group, a halogen, an oxo group, an alkenyl group, an alkynyl group, a cyano group, an alkylcyano group, a hydroxyalkyl group, a haloalkyl group, -OR c3 、-(CH2) u2 NR d6 R d7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R is selected from cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from deuterium atoms, halogen, oxo, alkyl, haloalkyl, -OR c1 , cyano, alkyl cyano, -(CH2) u1 NR d1 R d2 , 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 each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from a deuterium atom, a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an alkylcyano group, -(CH2) u1 NR d1 R d2 , 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 is the same or different at each occurrence and is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; 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, they form a heterocyclic group, wherein the heterocyclic group is independently optionally substituted by one or more substituents selected from the group consisting of a deuterium atom, a halogen, an oxo group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an alkylcyano group, an amino group, an alkylamino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; 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 each independently selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium atoms, halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, alkylcyano, -(CH2) u1 NR d1 R d2 , 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.

2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 3 for Ring B, R b and n as defined in claim 1.

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

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

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

6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof: in: 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.

7. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof: in: 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.

8. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof: in: 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 claim 1.

9. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 8, which is a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof: in: 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 claim 1.

10. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, 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; preferably, ring A is 5- to 6-membered heteroaryl or phenyl.

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

12. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: n is 0, 1, 2 or 3; and each R b are the same or different and are each independently selected from deuterium atoms, halogens, 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 Alkoxy.

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

14. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, 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 the C 1-6 Alkyl, 5 to 10 membered heteroaryl, 6 to 10 membered aryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group are each independently optionally selected from deuterium atoms, halogen, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, -(CH2) u1 NR d1 R d2 、-(CH2) w1 C(O)OR c2 、-(CH2) u R, 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; R c2 、R d1 、R d2 , R, u, u1 and w1 are as defined in claim 1.

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

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

17. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is selected from the following compounds:

18. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is selected from the following compounds:

19. A compound selected from the group consisting of:

20. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound represented by the general formula (IA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; in: X is a halogen, preferably Cl; Ring A, L, Z, R a 、R 1 to R 9 , m and s are as defined in claim 1.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of 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 the compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the 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 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 disease or condition mediated by PDEs enzymes, preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4 enzymes, more preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4B enzymes.

24. The use according to claim 23, wherein the disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer and peripheral or central nervous system diseases.

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

26. The use according to claim 24, wherein the gastrointestinal disease is selected from Crohn's disease, ulcerative colitis and Crohn's disease.

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

28. The method of claim 24, wherein the peripheral or central nervous system disease is selected from the group consisting of Alzheimer's disease, age-associated memory impairment (AAMI), age-related cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, depression, schizophrenia, stroke, neurological disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumors, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities, and multiple sclerosis.

29. The method of claim 24, wherein 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, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric cancer, urothelial carcinoma, ureteral cancer, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

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