TW202413371A - Nitrogen-containing heterocyclic compounds as pde4b inhibitors - Google Patents

Nitrogen-containing heterocyclic compounds as pde4b inhibitors Download PDF

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TW202413371A
TW202413371A TW112122671A TW112122671A TW202413371A TW 202413371 A TW202413371 A TW 202413371A TW 112122671 A TW112122671 A TW 112122671A TW 112122671 A TW112122671 A TW 112122671A TW 202413371 A TW202413371 A TW 202413371A
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alkyl
independently
compound
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alkoxy
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TW112122671A
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張學軍
李金平
賈壹民
劉禮飛
俊 楊
李莉娥
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大陸商武漢人福創新藥物研發中心有限公司
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Abstract

The present invention provides PDE4B inhibitors and use thereof. Specifically, the present invention provides nitrogen-containing heterocyclic compounds represented by formula (Ⅱ), tautomeric form, stereoisomers, hydrates, solvates, pharmaceutically acceptable salt or prodrug and preparation method thereof, as well as the use in the preparation of medicines for treating diseases related to PDE4B.

Description

作為PDE4B抑制劑的含氮雜環類化合物Nitrogen-containing heterocyclic compounds as PDE4B inhibitors

本發明屬於醫藥化學領域，具體地，本發明涉及PDE4B抑制劑及其用途，更具體地，本發明涉及式（Ⅱ）所示的含氮雜環類化合物、其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥及其製備方法，以及在製備用於治療與PDE4B相關疾病藥物中的用途。The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to a PDE4B inhibitor and its use. More specifically, the present invention relates to a nitrogen-containing heterocyclic compound represented by formula (II), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and preparation methods thereof, as well as its use in the preparation of drugs for treating diseases related to PDE4B.

cAMP是細胞中的關鍵第二信使。已知cAMP的濃度增加可抑制各種類型的炎症和免疫細胞中的促發炎反應，包括淋巴細胞、單核球細胞、巨噬細胞、嗜中性白血球、嗜酸性白血球、嗜鹼性白血球和肺部上皮細胞等。cAMP is a key second messenger in cells. Increased concentrations of cAMP are known to inhibit pro-inflammatory responses in various types of inflammatory and immune cells, including lymphocytes, monocytes, macrophages, neutrophils, eosinophils, basophils, and lung epithelial cells.

PDE全稱為磷酸二酯酶，是包括11個家族(PDE1~PDE11)的超級酶家族，可以催化第二信使cAMP和/或cGMP水解，對細胞代謝發揮重要作用。在該家族中，cAMP 專一性酶為磷酸二酯酶4(phosphodiesterase 4，PDE4)，其在炎症和免疫細胞中普遍存在。依據不同的基因編碼，PDE4家族可以分為4個亞型(PDE4A、B、C、D)。其中，PDE4A、PDE4B和PDE4D在炎症細胞(如B細胞、T細胞和中性粒細胞等)中有較強的表達。PDE stands for phosphodiesterase, which is a super enzyme family including 11 families (PDE1~PDE11). It can catalyze the hydrolysis of second messengers cAMP and/or cGMP and play an important role in cell metabolism. In this family, the cAMP-specific enzyme is phosphodiesterase 4 (PDE4), which is commonly found in inflammatory and immune cells. According to different gene codes, the PDE4 family can be divided into 4 subtypes (PDE4A, B, C, D). Among them, PDE4A, PDE4B and PDE4D are strongly expressed in inflammatory cells (such as B cells, T cells and neutrophils).

PDE4會使cAMP的濃度下降， 而使得其抑制各種類型的炎症和免疫細胞中的促發炎反應的效果降低，導致發炎性及過敏性疾病容易發生。目前已知PDE4活性的提高與某些發炎性及過敏性疾病有關，例如哮喘、慢性支氣管炎、肺氣腫、異位性皮膚炎、蕁麻疹、過敏性鼻炎、過敏性結膜炎、乾癬、類風濕性關節炎、慢性阻塞性肺病(COPD)、急性呼吸窘迫症候群和多發性硬化症等。抑制PDE4酶，導致cAMP水平的升高，從而調節TNFα水平，達到治療疾病目的。PDE4 will reduce the concentration of cAMP, which reduces its ability to inhibit various types of inflammation and pro-inflammatory responses in immune cells, making inflammatory and allergic diseases more likely to occur. It is currently known that increased PDE4 activity is associated with certain inflammatory and allergic diseases, such as asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, tinea, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome and multiple sclerosis. Inhibiting the PDE4 enzyme leads to an increase in cAMP levels, thereby regulating TNFα levels to achieve the purpose of treating diseases.

PDE4抑制劑的臨床研究受到副作用的限制，包括噁心和嘔吐，這些副作用被認為是由抑制PDE4D亞型引起的。同樣，副作用也限制了第二代PDE4抑制劑 cilomilast 和 roflumilast 的治療指數。PDE4B 亞型的選擇性抑制可能提供一種實現療效的方法，同時可能減輕這些不良事件。鑒於此，本發明在現有技術基礎上設計了系列化合物，以提供結構新穎、藥效更好、生物利用度高、成藥性強的PDE4B抑制劑，用於有效治療PDE4B相關的疾病、病症。Clinical studies of PDE4 inhibitors have been limited by side effects, including nausea and vomiting, which are believed to be caused by inhibition of the PDE4D subtype. Similarly, side effects have limited the therapeutic index of the second-generation PDE4 inhibitors cilomilast and roflumilast. Selective inhibition of the PDE4B subtype may provide a way to achieve therapeutic efficacy while potentially alleviating these adverse events. In view of this, the present invention designs a series of compounds based on the prior art to provide PDE4B inhibitors with novel structures, better efficacy, high bioavailability, and strong drugability for the effective treatment of PDE4B-related diseases and conditions.

本發明的第一方面，本發明提出了一種化合物，其為式（Ⅱ）所示的化合物，或者式（Ⅱ）所示化合物的互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥， （Ⅱ）， 其中， 表示為單鍵或不存在； X 1和X 2分別獨立地為CH或N，並且X 1和X 2至少有一個為N； X 4和X 5分別獨立地為CH或N，並且X 1和X 2至少有一個為N； 每個R 1a、R 1b、R 1c和R 1d分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1b、R 1c和它們所連接的碳原子一起形成環B，所述環B為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-8環烷基； 每個R a各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R取代； 每個R b、R c和R d分別各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R取代； 每個R各自獨立地為鹵素、OH、CN或NH 2； n為0、1或2； m為1或2； 環W為3-10元雜環烷基、3-10元雜環烯基或3-10元環烷基； R 2為H、鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基、C 1-6鹵代烷氧基、3~10元雜環烷基；所述C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基和C 1-6鹵代烷氧基任選地被一個或多個R e取代，當取代基R e為多個時，所述R e相同或不同； 每個 R e分別各自獨立地為鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基或C 1-6鹵代烷氧基。 In a first aspect of the present invention, a compound is provided, which is a compound represented by formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II). (II), where represents a single bond or does not exist; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; X4 and X5 are independently CH or N, and at least one of X1 and X2 is N; each of R1a , R1b , R1c and R1d is independently H, halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylamino, C1-6 alkoxy , -SC1-6 alkyl, -S(=O) -C1-6 alkyl, -S(=O) 2 - C1-6 alkyl, -C(=O) -C1-6 alkyl, -C(=O)-NH -C1-6 alkyl or -NH-C(=O) -OC1-6 alkyl, wherein the NH2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 R a ; or, R 1a , R 1b and the carbon atom to which they are attached together form a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1b , R R 1c and the carbon atoms to which they are attached form a ring B, wherein the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c ; or, R 1c , R 1d and the carbon atoms to which they are attached form a ring C, wherein the ring C is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R d ; each Ra is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are each independently and optionally substituted by 1, 2 or 3 R; each R b , R c and R d are each independently and optionally substituted by 1, 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1, 2 or 3 R; n is 0, 1 or 2; m is 1 or 2; ring W is 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or 3-10 membered cycloalkyl; R 2 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino. C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl , C 1-6 deuterated alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy and C 1-6 halogenated alkoxy are optionally substituted by one or more Re , when the substituent R When e is multiple, the Re is the same or different; each Re is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy or C1-6 halogenated alkoxy.

根據本發明的實施例，上述化合物還可以進一步包括如下技術特徵的至少之一：According to an embodiment of the present invention, the above compound may further include at least one of the following technical features:

在本發明一任選實施方案中， 表示為單鍵或不存在；X 1和X 2分別獨立地為CH或N，並且X 1和X 2至少有一個為N； X 3為CH或N； X 4和X 5分別獨立地為CH或N，並且X 1和X 2至少有一個為N； R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1b、R 1c和它們所連接的碳原子一起形成環B，所述環B為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基； 各R a獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R取代； 各R b、R c和R d分別獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R取代； R獨立地為鹵素、OH、CN或NH 2； n為0、1或2； m為1或2； 環W為3-10元雜環烷基、3-10元雜環烯基或3-10元環烷基； R 2為H、鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基、C 1-6鹵代烷氧基、3~10元雜環烷基；所述C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基和C 1-6鹵代烷氧基任選地被一個或多個R e取代，當取代基R e為多個時，所述R e相同或不同； 每個 R e分別各自獨立地為鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基或C 1-6鹵代烷氧基。 In an optional embodiment of the present invention, represents a single bond or does not exist; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; X3 is CH or N; X4 and X5 are independently CH or N, and at least one of X1 and X2 is N; R1a , R1b , R1c and R1d are independently H, halogen, OH, CN, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C1-6 alkoxy, -SC1-6 alkyl, -S(=O) -C1-6 alkyl, -S(=O) 2 - C1-6 alkyl, -C(=O) -C1-6 alkyl, -C(=O) -NH-C1-6 alkyl or -NH-C(=O) -OC1-6 alkyl, wherein the NH R 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 R a ; or, R 1a , R 1b and the carbon atom to which they are attached together form a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1b , R R 1c and the carbon atoms to which they are attached together form a ring B, wherein the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c ; or, R 1c , R 1d and the carbon atoms to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R d ; each Ra is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are independently and optionally substituted by 1, 2 or 3 R; each R b , R c and R d are independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are independently and optionally substituted by 1, 2 or 3 R; R is independently halogen, OH, CN or NH 2 ; n is 0, 1 or 2; m is 1 or 2; Ring W is 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or 3-10 membered cycloalkyl; R 2 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl , C 1-6 deuterated alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy and C 1-6 halogenated alkoxy are optionally substituted by one or more Re , when the substituent R When e is multiple, the Re is the same or different; each Re is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy or C1-6 halogenated alkoxy.

在本發明一任選實施方案中， 為單鍵、n為1、m為1、且n為1時，X 1為N、X 2為N、R 1a為H、R 1b為H、R 1c為H和R 1d為H不同時存在。 In an optional embodiment of the present invention, is a single bond, n is 1, m is 1, and when n is 1, X1 is N, X2 is N, R1a is H, R1b is H, R1c is H, and R1d is H do not exist at the same time.

在本發明一任選實施方案中，當 表示為單鍵、且n為1，X 1、X 2、X 4和X 5均為N時，R 1a、R 1b、R 1c和R 1d不能同時為H。 In an optional embodiment of the present invention, when When it is represented by a single bond, n is 1, and X 1 , X 2 , X 4 and X 5 are all N, R 1a , R 1b , R 1c and R 1d cannot be H at the same time.

在本發明一任選實施方案中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-3烷基或C 1-3烷氧基，其中，所述C 1-3烷基和C 1-3烷氧基分別獨立地任選地被1、2或3個R a取代，R a如本發明所定義。 In an optional embodiment of the present invention, R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are independently and optionally substituted by 1, 2 or 3 Ra , and Ra is as defined in the present invention.

在本發明一任選實施方案中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3，其中，所述CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3分別獨立地任選地被1、2或3個R a取代，R a如本發明所定義。 In an optional embodiment of the present invention, R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 , wherein said CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 are independently and optionally substituted by 1, 2 or 3 Ras , and Ra is as defined in the present invention.

在本發明一任選實施方案中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CHF 2、-OCH 2CF 3。 In an optional embodiment of the present invention, R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , -OCH 2 F , -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F , -OCH 2 CHF 2 , -OCH 2 CF 3 .

在本發明一任選實施方案中，各R a獨立地為F、Cl、Br、I、OH、CN、NH 2或環丙基。 In an optional embodiment of the present invention, each Ra is independently F, Cl, Br, I, OH, CN, NH2 or cyclopropyl.

在本發明一任選實施方案中，環A為任選地被1、2或3個R b取代的C 3-6環烷基，R b如本發明所定義。 In an optional embodiment of the present invention, Ring A is a C 3-6 cycloalkyl group optionally substituted by 1, 2 or 3 R b , and R b is as defined in the present invention.

在本發明一任選實施方案中，環A為 。 In an optional embodiment of the present invention, Ring A is .

在本發明一任選實施方案中，環B為任選地被1、2或3個R c取代的6-7元雜環烯基，R c如本發明所定義。 In an optional embodiment of the present invention, Ring B is a 6-7 membered heterocycloalkenyl group optionally substituted by 1, 2 or 3 R c , and R c is as defined in the present invention.

在本發明一任選實施方案中，環B為6元雜環烯基。In an alternative embodiment of the present invention, Ring B is a 6-membered heterocycloalkenyl group.

在本發明一任選實施方案中，環B為 或 。 In an optional embodiment of the present invention, ring B is or .

在本發明一任選實施方案中，環B為 。 In an optional embodiment of the present invention, ring B is .

在本發明一任選實施方案中，當R 1b、R 1c和它們所連接的碳原子一起形成環B時，且n為1或2。 In an alternative embodiment of the present invention, when R 1b , R 1c and the carbon atom to which they are attached together form Ring B, and n is 1 or 2.

需要說明的是，當R 1b、R 1c和它們所連接的碳原子一起形成環B時，R 1b和R 1c可參與成環也可不參與成環。例如，當R 1b和/或R 1c參與成環時， 表示不存在時，結構單元 為 ， 表示為單鍵時， 為 ；當R 1b和R 1c不參與成環時， 為 。 It should be noted that when R 1b , R 1c and the carbon atom to which they are connected together form ring B, R 1b and R 1c may or may not participate in the ring formation. For example, when R 1b and/or R 1c participate in the ring formation, When it does not exist, the structural unit for , When expressed as a single key, for ; When R 1b and R 1c do not participate in ring formation, for .

在本發明一任選實施方案中，當R 1b、R 1c和它們所連接的碳原子一起形成環B時，n為2，此時環B為 或 。 In an optional embodiment of the present invention, when R 1b , R 1c and the carbon atom to which they are attached together form a ring B, n is 2, and the ring B is or .

在本發明一任選實施方案中，當R 1b、R 1c和它們所連接的碳原子一起形成環B時，n為2，此時環B為 。 In an optional embodiment of the present invention, when R 1b , R 1c and the carbon atom to which they are attached together form a ring B, n is 2, and the ring B is .

在本發明一任選實施方案中，環C為任選地被1、2或3個R d取代的C 3-6環烷基，R d如本發明所定義。 In an optional embodiment of the present invention, Ring C is a C 3-6 cycloalkyl group optionally substituted with 1, 2 or 3 R d , wherein R d is as defined in the present invention.

在本發明一任選實施方案中，環C為 。 In an optional embodiment of the present invention, ring C is .

在本發明一任選實施方案中，各R b、R c和R d分別獨立地為鹵素、OH、CN、NH 2或CH 3。 In an optional embodiment of the present invention, each of R b , R c and R d is independently halogen, OH, CN, NH 2 or CH 3 .

在本發明一任選實施方案中，R 2為F、Cl、CH 3或被1個或多個R e取代的CH 3。 In an optional embodiment of the present invention, R 2 is F, Cl, CH 3 or CH 3 substituted by one or more Re .

在本發明一任選實施方案中，R 2為Cl。 In an optional embodiment of the present invention, R2 is Cl.

在本發明一任選實施方案中，R e為F或Cl。 In an optional embodiment of the present invention, Re is F or Cl.

在本發明一任選實施方案中， 為單鍵，結構單元 為 ；或者 為不存在，結構單元 為 ；其中，R 1a、R 1b、R 1c、R 1d、n和m如本發明前述所定義。 In an optional embodiment of the present invention, For a single key, structural unit for ;or does not exist, the structural unit for wherein R 1a , R 1b , R 1c , R 1d , n and m are as defined above in the present invention.

在本發明一任選實施方案中， 中，n為1或2，R 1a、R 1b、R 1c、R 1d和m如本發明前述所定義。 In an optional embodiment of the present invention, wherein n is 1 or 2, and R 1a , R 1b , R 1c , R 1d and m are as defined above in the present invention.

在本發明一任選實施方案中， 中，n為0或1，R 1a、R 1b、R 1c、R 1d和m如本發明前述所定義。 In an optional embodiment of the present invention, wherein n is 0 or 1, and R 1a , R 1b , R 1c , R 1d and m are as defined above in the present invention.

在本發明一任選實施方案中，結構單元 為 或 ，R 1a、R 1b、R 1c和R 1d如本發明所定義。 In an optional embodiment of the present invention, the structural unit for or , R 1a , R 1b , R 1c and R 1d are as defined in the present invention.

在本發明一任選實施方案中，結構單元 為 、 或 ，R 1a、R 1b、R 1c和R 1d如本發明所定義。 In an optional embodiment of the present invention, the structural unit for , or , R 1a , R 1b , R 1c and R 1d are as defined in the present invention.

在本發明一任選實施方案中，結構單元 為 、 、 或 ，其中，R 1a、R 1b、R 1c和R 1d如本發明前述所定義。 In an optional embodiment of the present invention, the structural unit for , , or , wherein R 1a , R 1b , R 1c and R 1d are as defined above in the present invention.

在本發明一任選實施方案中，結構單元 為 、 、 、 、 、 、 或 。 In an optional embodiment of the present invention, the structural unit for , , , , , , or .

在本發明一任選實施方案中，結構單元 為 、 或 ，R 1a、R 1b、R 1c和R 1d如本發明所定義。 In an optional embodiment of the present invention, the structural unit for , or , R 1a , R 1b , R 1c and R 1d are as defined in the present invention.

在本發明一任選實施方案中，環W為4-7元雜環烷基。In an optional embodiment of the present invention, ring W is a 4-7 membered heterocycloalkyl group.

在本發明一任選實施方案中，環W為4-7元含氮雜環烷基。In an optional embodiment of the present invention, ring W is a 4-7 membered nitrogen-containing heterocycloalkyl group.

在本發明一任選實施方案中，環W為 或 ，其中，X 3為CH或N；h、g分別各自獨立地為0、1或2；p、q分別各自獨立地為1或2。 In an optional embodiment of the present invention, ring W is or , wherein X 3 is CH or N; h and g are each independently 0, 1 or 2; p and q are each independently 1 or 2.

在本發明一任選實施方案中，h為1，g為1。In an optional embodiment of the present invention, h is 1 and g is 1.

在本發明一任選實施方案中，h為0，g為1。In an optional embodiment of the present invention, h is 0 and g is 1.

在本發明一任選實施方案中，h為1，g為0。In an optional embodiment of the present invention, h is 1 and g is 0.

在本發明一任選實施方案中，h為0，g為0。In an optional embodiment of the present invention, h is 0 and g is 0.

在本發明一任選實施方案中，X 3為CH。 In an optional embodiment of the present invention, X3 is CH.

在本發明一任選實施方案中，X 3為N。 In an optional embodiment of the present invention, X3 is N.

在本發明一任選實施方案中，p為1，q為1。In an optional embodiment of the present invention, p is 1 and q is 1.

在本發明一任選實施方案中，環W為氮雜環丁基、吡咯烷基、哌啶基或2-氮雜螺[3.3]庚烷基。In an alternative embodiment of the present invention, ring W is azacyclobutyl, pyrrolidinyl, piperidinyl or 2-azaspiro[3.3]heptyl.

在本發明一任選實施方案中，環W為 、 、 或 。 In an optional embodiment of the present invention, ring W is , , or .

在本發明一任選實施方案中，X 1和X 2均為N。 In an optional embodiment of the present invention, X1 and X2 are both N.

在本發明一任選實施方案中，X 1為CH，X 2為N。 In an alternative embodiment of the present invention, X1 is CH and X2 is N.

在本發明一任選實施方案中，X 4和X 5均為N。 In an optional embodiment of the present invention, X4 and X5 are both N.

在本發明一任選實施方案中，R 2為F、Cl、CH 3或被1個或多個R e取代的CH 3其中，R e如本發明前述所定義。 In an optional embodiment of the present invention, R 2 is F, Cl, CH 3 or CH 3 substituted by one or more Re , wherein Re is as defined above in the present invention.

在本發明一任選實施方案中，R e為F或Cl。 In an optional embodiment of the present invention, Re is F or Cl.

在本發明一任選實施方案中，R 2為Cl。 In an optional embodiment of the present invention, R2 is Cl.

在本發明一任選實施方案中，m為1。In an optional embodiment of the present invention, m is 1.

在本發明一任選實施方案中，m為2。In an optional embodiment of the present invention, m is 2.

在本發明一任選實施方案中，式（Ⅱ）化合物具有結構式（IIIa）或（IIIb）： （IIIa）； （IIIb）； 其中，X 3為CH或N；h、g分別各自獨立地為0、1或2；p、q分別各自獨立地為1或2，R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 4和X 5如本發明前述所定義。 In an optional embodiment of the present invention, the compound of formula (II) has the structural formula (IIIa) or (IIIb): (IIIa); (IIIb); wherein X 3 is CH or N; h and g are each independently 0, 1 or 2; p and q are each independently 1 or 2; R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 4 and X 5 are as defined above in the present invention.

在本發明一任選實施方案中，式（II）所示化合物具有結構式（IIIa3）： （IIIa3）， 其中，R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 3、X 4、X 5、h、g、p和q如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIa3): (IIIa3), wherein R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 3 , X 4 , X 5 , h, g, p and q are as defined above in the present invention.

在本發明一任選實施方案中，式（II）所示化合物具有結構式（IIIa4）： （IIIa4）， 其中，R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 3、X 4、X 5、h、g、p和q如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIa4): (IIIa4), wherein R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 3 , X 4 , X 5 , h, g, p and q are as defined above in the present invention.

在本發明一任選實施方案中，式（II）所示化合物具有結構式（IIIb2）： （IIIb2）； 其中，R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 3、X 4、X 5、h、g、p和q如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIb2): (IIIb2); wherein R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 3 , X 4 , X 5 , h, g, p and q are as defined above in the present invention.

在本發明一任選實施方案中，式（Ⅱ）化合物具有結構（Ⅰ）， （Ⅰ）， 其中， 表示為單鍵或不存在； X 1和X 2分別獨立地為CH或N，並且X 1和X 2至少有一個為N； X 3為CH或N； X 4和X 5分別獨立地為CH或N，並且X 1和X 2至少有一個為N； R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1b、R 1c和它們所連接的碳原子一起形成環B，所述環B為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基； 各R a獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R取代； 各R b、R c和R d分別獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R取代； R獨立地為鹵素、OH、CN或NH 2； n為0、1或2。 In an optional embodiment of the present invention, the compound of formula (II) has structure (I), (I), where represents a single bond or does not exist; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; X3 is CH or N; X4 and X5 are independently CH or N, and at least one of X1 and X2 is N; R1a , R1b , R1c and R1d are independently H, halogen, OH, CN, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C1-6 alkoxy, -SC1-6 alkyl, -S(=O) -C1-6 alkyl, -S(=O) 2 - C1-6 alkyl, -C(=O) -C1-6 alkyl, -C(=O) -NH-C1-6 alkyl or -NH-C(=O) -OC1-6 alkyl, wherein the NH R 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 R a ; or, R 1a , R 1b and the carbon atom to which they are attached together form a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1b , R R 1c and the carbon atoms to which they are attached together form a ring B, wherein the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c ; or, R 1c , R 1d and the carbon atoms to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R d ; each Ra is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R; each R b , R c and R d are each independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R; R is each independently halogen, OH, CN or NH 2 ; n is 0, 1 or 2.

在本發明一任選實施方案中，本發明化合物具有結構(Ia)： (Ia)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基。 In an optional embodiment of the present invention, the compound of the present invention has structure (Ia): (Ia), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, R 1a , R 1b , and the carbon atom to which they are attached form together a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1c , R 1d , and the carbon atom to which they are attached form together a ring C, and the ring C is a C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R d .

在本發明一任選實施方案中，式（Ⅰ）化合物具有結構(Ia1)： (Ia1)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基。 In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia1): (Ia1), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl R 1a , R 1b , and the carbon atom to which they are attached form together a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1c , R 1d , and the carbon atom to which they are attached form together a ring C, and the ring C is a C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R d .

在本發明一任選實施方案中，式（Ⅰ）化合物具有結構(Ia)： (Ia)， 其中，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基，R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基，R 1a和R 1b分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia): (Ia), wherein R 1a , R 1b and the carbon atom to which they are attached together form a ring A, wherein the ring A is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b , and R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl , -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl. wherein R 1c , R 1d and the carbon atom to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R d , and R 1a and R 1b are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH -C(=O)-OC 1-6 alkyl are each independently and optionally substituted with 1, 2 or 3 Ra; or, R 1c , R 1d and the carbon atom to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R d , and R 1a and R 1b are each independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl-C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 Ra .

在本發明一任選實施方案中，式（Ⅰ）化合物具有結構(Ia1)： (Ia1)， 其中，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基，R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-6環烷基，R 1a和R 1b分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia1): (Ia1), wherein R 1a , R 1b and the carbon atom to which they are attached together form a ring A, wherein the ring A is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b , and R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC wherein R 1c , R 1d and the carbon atom to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R d , and R 1a and R 1b are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH -C(=O)-OC 1-6 alkyl are each independently and optionally substituted with 1, 2 or 3 Ra; or, R 1c , R 1d and the carbon atom to which they are attached together form a ring C, wherein the ring C is a C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R d , and R 1a and R 1b are each independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 Ra .

在本發明一任選實施方案中，式（Ⅰ）化合物具有結構(Ia)： (Ia)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代，且X 1為N時，R 1a、R 1b、R 1c和R 1d不能同時為H。 In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia): (Ia), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl , -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH -C 1-6 alkyl or -NH -C(=O)-OC 1-6 alkyl wherein R 1a , R 1b , R 1c and R 1d are not H at the same time; wherein R 1a , R 1b , R 1c and R 1d are independently and optionally substituted by 1, 2 or 3 R 1a , R 1b , R 1c and R 1d are not H at the same time; and wherein R 1a , R 1b , R 1c and R 1d are not H at the same time;

在本發明一任選實施方案中，式（Ⅰ）化合物具有結構(Ia1)： (Ia1)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代，且X 1為N時，R 1a、R 1b、R 1c和R 1d不能同時為H。 In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia1): (Ia1), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl , -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH -C 1-6 alkyl or -NH -C(=O)-OC 1-6 alkyl wherein R 1a , R 1b , R 1c and R 1d are not H at the same time; wherein R 1a , R 1b , R 1c and R 1d are independently and optionally substituted by 1, 2 or 3 R 1a , R 1b , R 1c and R 1d are not H at the same time; and wherein R 1a , R 1b , R 1c and R 1d are not H at the same time;

在本發明一任選實施方案中，式（Ⅱ）所示化合物具有結構式（IV）： （IV）； 其中，式（IV）中，X 1為N、X 2為N、R 1a為H、R 1b為H、R 1c為H和R 1d為H不同時存在；R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 4、X 5和R 2如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IV): (IV); wherein, in formula (IV), X1 is N, X2 is N, R1a is H, R1b is H, R1c is H and R1d is H do not exist at the same time; R1a , R1b , R1c , R1d , n, m, X1 , X2 , X4 , X5 and R2 are as defined above in the present invention.

在本發明一任選實施方案中，式（Ⅱ）所示化合物具有結構式（V）： （V）， R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 4、X 5和R 2如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (V): (V), R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 4 , X 5 and R 2 are as defined above in the present invention.

在本發明一任選實施方案中，式（Ⅱ）所示化合物具有結構式式（VI）： （VI）； R 1a、R 1b、R 1c、R 1d、n、m、X 1、X 2、X 4、X 5和R 2如本發明前述所定義。 In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (VI): (VI); R 1a , R 1b , R 1c , R 1d , n, m, X 1 , X 2 , X 4 , X 5 and R 2 are as defined above in the present invention.

在本發明一任選實施方案中，式（VI）中，n為0或1。In an optional embodiment of the present invention, in formula (VI), n is 0 or 1.

在本發明一任選實施方案中，式（VI）中，n為0。In an optional embodiment of the present invention, in formula (VI), n is 0.

在本發明一任選實施方案中，本發明化合物具有結構式(Ⅱ- A)： (Ⅱ- A) 其中，各R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代；m、X 1和環W如本發明所定義。 In an optional embodiment of the present invention, the compound of the present invention has the structural formula (II-A): (II-A) wherein each of R 1a , R 1b , R 1c and R 1d is independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, wherein R 1-6 alkyl, —C(═O)—NH—C 1-6 alkyl and —NH—C(═O)—OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 R 1-6 alkyl; m, X 1 and ring W are as defined in the present invention.

在本發明一任選實施方案中，本發明化合物具有結構(Ⅱ- A1): (Ⅱ- A1) 其中，各R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代；m為1或2；h、g分別地為0、1或2；p、q分別地為1或2。 In an optional embodiment of the present invention, the compound of the present invention has the structure (II-A1): (II-A1) wherein each of R 1a , R 1b , R 1c and R 1d is independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl wherein the -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra ; m is 1 or 2; h, g are each 0, 1 or 2; p, q are each 1 or 2.

在本發明一任選實施方案中，本發明化合物具有結構(Ⅱ- A2): (Ⅱ- A2) 其中，各R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代；m為1或2；h、g分別地為0、1或2；p、q分別地為1或2。 In an optional embodiment of the present invention, the compound of the present invention has the structure (II-A2): (II-A2) wherein each of R 1a , R 1b , R 1c and R 1d is independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl wherein the -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra ; m is 1 or 2; h, g are each 0, 1 or 2; p, q are each 1 or 2.

在本發明一任選實施方案中，本發明化合物具有結構(Ib)： (Ib)， 其中，各R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Ib): (Ib), wherein each of R 1a , R 1b , R 1c and R 1d is independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl In the invention, -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra .

在本發明一任選實施方案中，本發明化合物具有結構(Ib1)： (Ib1)， 其中，各R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Ib1): (Ib1), wherein each of R 1a , R 1b , R 1c and R 1d is independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl In the invention, -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra .

在本發明一任選實施方案中，本發明化合物具有結構(Ic)： (Ic)， 其中，n為0、1或2； R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Ic): (Ic), wherein n is 0, 1 or 2; R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C In the invention, R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a , R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1 , 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a .

在本發明一任選實施方案中，本發明化合物具有結構(Ic1)： (Ic1)， 其中，n為0、1或2； R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Ic1): (Ic1), wherein n is 0, 1 or 2; R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C In the invention, R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a , R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1 , 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a, R a is preferably substituted with 1, 2 or 3 R a .

在本發明一任選實施方案中，本發明化合物具有結構(Id)： (Id)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Id): (Id), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl , -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH -C 1-6 alkyl or -NH -C(=O)-OC 1-6 alkyl In the invention, -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra .

在本發明一任選實施方案中，本發明化合物具有結構(Id1)： (Id1)， 其中，R 1a、R 1b、R 1c和R 1d分別獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6烷基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代。 In an optional embodiment of the present invention, the compound of the present invention has structure (Id1): (Id1), wherein R 1a , R 1b , R 1c and R 1d are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl , -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C(=O)-C 1-6 alkyl, -C(=O) -NH -C 1-6 alkyl or -NH -C(=O)-OC 1-6 alkyl In the invention, -C(=O)-NH-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are each independently optionally substituted with 1, 2 or 3 Ra .

在本發明一任選實施方案中，式（II）所示化合物具有結構式（Vd）或（Ve）： （Vd）、 （Ve）。 In an optional embodiment of the present invention, the compound represented by formula (II) has a structural formula (Vd) or (Ve): (Vd), (Ve).

在本發明一任選實施方案中，式（Ⅱ）或式（Ⅰ）所述化合物選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 、 、 、 、 、 、 、 、 、 或 。 In an optional embodiment of the present invention, the compound of formula (II) or formula (I) is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: , , , , , , , , , or .

在本發明一任選實施方案中，式（Ⅱ）或式（Ⅰ）所述化合物選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 、 、 、 、 、 、 、 、 或 。 In an optional embodiment of the present invention, the compound of formula (II) or formula (I) is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: , , , , , , , , or .

本發明的第二方面，本發明提出了一種中間體化合物，其為式（VⅡ）所示的化合物，或者式（VⅡ）所示化合物的互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥， （VⅡ）， 其中， 表示為單鍵或不存在； X 1'和X 2'分別獨立地為CH或N，並且X 1'和X 2'至少有一個為N； 每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a'取代； 或者，R 1a'、R 1b'和它們所連接的碳原子一起形成環A'，所述環A'為任選地被1、2或3個R b'取代的C 3-8環烷基； 或者，R 1b'、R 1c'和它們所連接的碳原子一起形成環B'，所述環B'為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c'取代； 或者，R 1c'、R 1d'和它們所連接的碳原子一起形成環C'，所述環C'為任選地被1、2或3個R d'取代的C 3-8環烷基； 每個R a'各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R'取代； 每個R b'、R c'和R d'分別各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R'取代； 每個R'各自獨立地為鹵素、OH、CN或NH 2； n'為0、1或2； m'為0、1或2； R x為鹵素。 In a second aspect of the present invention, the present invention provides an intermediate compound, which is a compound represented by formula (VII), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (VII), (VⅡ), where: represents a single bond or does not exist; X 1 'and X 2 'are independently CH or N, and at least one of X 1 'and X 2 'is N; each of R 1a ', R 1b ', R 1c 'and R 1d 'are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl R 1a ' , R 1b ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; or, R 1b ', R 1c ', R 1d ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; or, R 1b ', R 1c ', R 1d ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; R ' and the carbon atoms to which they are attached form a ring B', wherein the ring B' is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c '; or, R 1c ', R 1d ' and the carbon atoms to which they are attached form a ring C', wherein the ring C' is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R d '; each Ra ' is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R'; each R b ', R c ' and R d ' are each independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R'; each R' is each independently halogen, OH, CN or NH 2 ; n' is 0, 1 or 2; m' is 0, 1 or 2; R x is halogen.

在本發明一任選實施方案中，中間體化合物的特徵在於，X 1和X 2均為N。 In an alternative embodiment of the invention, the intermediate compound is characterized in that X1 and X2 are both N.

在本發明一任選實施方案中，中間體化合物的特徵在於，X 1為CH，X 2為N。 In an alternative embodiment of the invention, the intermediate compound is characterized in that X1 is CH and X2 is N.

在本發明一任選實施方案中，中間體化合物的特徵在於，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-3烷基或C 1-3烷氧基，其中，所述C 1-3烷基和C 1-3烷氧基分別獨立地任選地被1、2或3個R a'取代。 In an optional embodiment of the present invention, the intermediate compound is characterized in that each R 1a ', R 1b ', R 1c ' and R 1d ' are each independently H, halogen, OH, CN, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are each independently and optionally substituted by 1, 2 or 3 Ra '.

在本發明一任選實施方案中，中間體化合物的特徵在於，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3，其中，所述CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3分別獨立地任選地被1、2或3個R a'取代。 In an optional embodiment of the present invention, the intermediate compound is characterized in that each R 1a ', R 1b ', R 1c ' and R 1d ' are each independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 , wherein the CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 are each independently and optionally substituted by 1, 2 or 3 Ra '.

在本發明一任選實施方案中，中間體化合物的特徵在於，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CHF 2、-OCH 2CF 3。 In an optional embodiment of the present invention, the intermediate compound is characterized in that each of R 1a ', R 1b ', R 1c ' and R 1d ' is independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 .

在本發明一任選實施方案中，中間體化合物的特徵在於，每個R a'各自獨立地為F、Cl、Br、I、OH、CN、NH 2或環丙基。 In an alternative embodiment of the invention, the intermediate compound is characterized in that each Ra ' is independently F, Cl, Br, I, OH, CN, NH2 or cyclopropyl.

在本發明一任選實施方案中，中間體化合物的特徵在於，環A'為任選地被1、2或3個R b'取代的C 3-6環烷基。 In an alternative embodiment of the invention, the intermediate compound is characterized in that ring A' is C3-6 cycloalkyl optionally substituted by 1, 2 or 3 Rb '.

在本發明一任選實施方案中，中間體化合物的特徵在於，當R 1b'、R 1c'和它們所連接的碳原子一起形成環B'時，n'為2，此時環B'為 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that when R 1b ', R 1c ' and the carbon atom to which they are attached together form a ring B', n' is 2, and in this case, the ring B' is or .

在本發明一任選實施方案中，中間體化合物的特徵在於，環C'為任選地被1、2或3個R b'取代的C 3-6環烷基。 In an alternative embodiment of the invention, the intermediate compound is characterized in that the ring C' is a C3-6 cycloalkyl optionally substituted by 1, 2 or 3 Rb '.

在本發明一任選實施方案中，中間體化合物的特徵在於，每個R b'、R c'和R d'分別各自獨立地為鹵素、OH、CN、NH 2或CH 3。 In an alternative embodiment of the present invention, the intermediate compound is characterized in that each of R b ′, R c ′ and R d ′ is independently halogen, OH, CN, NH 2 or CH 3 .

在本發明一任選實施方案中，中間體化合物的特徵在於，環A'為 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that ring A' is .

在本發明一任選實施方案中，中間體化合物的特徵在於，環C'為 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that ring C' is .

在本發明一任選實施方案中，中間體化合物的特徵在於，結構單元 為 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that the structural unit for or .

在本發明一任選實施方案中，中間體化合物的特徵在於， 中，n為1或2。 In an optional embodiment of the present invention, the intermediate compound is characterized in that: In this example, n is 1 or 2.

在本發明一任選實施方案中，中間體化合物的特徵在於， 中，n為0或1。 In an optional embodiment of the present invention, the intermediate compound is characterized in that: , n is 0 or 1.

在本發明一任選實施方案中，中間體化合物的特徵在於，結構單元 為 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that the structural unit for or .

在本發明一任選實施方案中，中間體化合物的特徵在於，結構單元 為 、 、 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that the structural unit for , , or .

在本發明一任選實施方案中，中間體化合物的特徵在於，結構單元 為 、 、 、 、 、 、 、 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that the structural unit for , , , , , , , or .

在本發明一任選實施方案中，中間體化合物的特徵在於，結構單元 為 、 、 、 或 。 In an optional embodiment of the present invention, the intermediate compound is characterized in that the structural unit for , , , or .

在本發明一任選實施方案中，中間體化合物的特徵在於，R x為Cl。 In an alternative embodiment of the invention, the intermediate compound is characterized in that R x is Cl.

在本發明一任選實施方案中，中間體化合物的特徵在於，m'為0、1或2。In an alternative embodiment of the invention, the intermediate compound is characterized in that m' is 0, 1 or 2.

在本發明一任選實施方案中，中間體化合物的特徵在於，m'為0。In an alternative embodiment of the invention, the intermediate compound is characterized in that m' is 0.

在本發明一任選實施方案中，中間體化合物的特徵在於，m'為1。In an alternative embodiment of the invention, the intermediate compound is characterized in that m' is 1.

在本發明一任選實施方案中，中間體化合物的特徵在於，m'為2。In an optional embodiment of the present invention, the intermediate compound is characterized in that m' is 2.

在本發明一任選實施方案中，式（VⅡ）化合物具有結構式（VⅠⅠa）： （VⅡa）。 In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIIa): (VⅡa).

在本發明一任選實施方案中，式（VⅡ）化合物具有結構式（VⅠⅠb）或式（VⅠⅠc）： （VⅡb）、 （VⅡc）。 In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIIb) or formula (VIIIc): (VⅡb), (VⅡc).

在本發明一任選實施方案中，式（VⅡ）化合物具有結構式（VⅠⅠd）或式（VⅠⅠe）： （VⅡd）、 （VⅡe）。 In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIId) or formula (VIIIe): (VⅡd), (VⅡe).

在本發明一任選實施方案中，式（VⅡ）化合物選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 。 In an optional embodiment of the present invention, the compound of formula (VII) is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: .

本發明的第三方面，本發明提出了一種藥物組合物，包含上述第二方面所述的化合物。In the third aspect of the present invention, a pharmaceutical composition is provided, comprising the compound described in the second aspect.

在本發明一任選實施方案中，上述藥物組合物進一步包括藥學上可接受的載體或賦形劑。In an optional embodiment of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

本發明的第四方面，本發明提出了上述第二方面所述的化合物或上述第三方面所述的藥物組合物在製備用於治療或預防PDE4B相關疾病的藥物中的用途。In a fourth aspect of the present invention, the present invention proposes use of the compound described in the second aspect or the pharmaceutical composition described in the third aspect in the preparation of a drug for treating or preventing PDE4B-related diseases.

在本發明一任選實施方案中，上述PDE4B相關疾病包括選自下列的至少之一：治療呼吸道疾病、胃腸疾病、炎性疾病、變應性疾病、自身免疫性疾病、移植排斥反應以及與平滑肌收縮性相關的疾病。In an optional embodiment of the present invention, the above-mentioned PDE4B-related diseases include at least one selected from the following: treatment of respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and diseases related to smooth muscle contractility.

在本發明一任選實施方案中，上述PDE4B相關疾病包括選自下列的至少之一：哮喘、慢性支氣管炎、特發性肺纖維化、慢性阻塞性肺炎、變應性鼻炎、成人呼吸窘迫症候群、特發性皮炎、銀屑病、蕁麻疹、類風濕性關節炎、骨關節炎、痛風性關節炎或脊椎炎、潰瘍性結腸炎、克隆氏症、膀胱過度活動症。 術語和定義 In an optional embodiment of the present invention, the above-mentioned PDE4B-related diseases include at least one selected from the following: asthma, chronic bronchitis, idiopathic pulmonary fibrosis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome, atopic dermatitis, psoriasis, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn's disease, overactive bladder. Terms and Definitions

除非另有說明，用於本發明申請，包括本申請說明書和發明申請專利範圍中記載的術語和定義如下。Unless otherwise stated, the terms and definitions used in this invention, including this application specification and the scope of the invention, are as follows.

本發明所屬技術領域具有通常知識者可以理解，根據本領域中使用的慣例，在本申請的結構式中， 用於描繪化學鍵，所述化學鍵為部分或取代基與核心結構或骨架結構相連的點。 A person skilled in the art to which the present invention belongs can understand that, according to the common practice used in the field, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

除非另有規定，術語「藥學上可接受的」，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

除非另有規定，術語「藥學上可接受的鹽」是指藥學上可接受的無毒酸或鹼的鹽，包括無機酸和鹼、有機酸和鹼的鹽。Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

除了藥學可接受的鹽外，本發明還考慮其他鹽。它們可以在化合物純化中或在製備其它藥學上可接受的鹽中充當中間體或可用於本發明化合物的鑒別、表徵或純化。In addition to pharmaceutically acceptable salts, other salts are contemplated in the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.

除非另有規定，術語「藥物組合物」表示一種或多種文本所述化合物或其生理學/藥學上可接受的鹽或前體藥物與其它化學組分的混合物，其它組分例如生理學/藥學上可接受的載體和賦形劑。藥物組合物的目的是促進化合物對生物體的給藥。Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

除非另有規定，術語「包含」或「包括」為開放式表達，即包括本發明所指明的內容，但並不排除其他方面的內容。Unless otherwise specified, the term “comprise” or “include” is an open expression, which includes the contents specified in the present invention but does not exclude other contents.

除非另有規定，術語「輔料」是指可藥用惰性成分。術語「賦形劑」的種類實例非限制性地包括粘合劑、崩解劑、潤滑劑、助流劑、穩定劑、填充劑和稀釋劑等。賦形劑能增強藥物製劑的操作特性，即通過增加流動性和/或粘著性使製劑更適於直接壓縮。Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the types of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a drug formulation, i.e., make the formulation more suitable for direct compression by increasing flowability and/or adhesion.

除非另有規定，術語「前藥」是指可以在生理條件下或者通過溶劑解轉化為具有生物活性的本發明化合物。本發明的前藥通過修飾在該化合物中的功能基團來製備，該修飾可以按常規的操作或者在體內被除去，而得到母體化合物。前藥包括本發明化合物中的一個羥基或者胺基連接到任何基團上所形成的化合物，當本發明化合物的前藥被施予哺乳動物個體時，前藥被割裂而分別形成游離的羥基、游離的胺基。Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvent decomposition. The prodrug of the present invention is prepared by modifying the functional group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl or amine group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amine group, respectively.

除非另有規定，術語「立體異構體」是指由分子中原子在空間上排列方式不同所產生的異構體，包括順反異構體、對映異構體、非對應異構體和構象異構體。Unless otherwise specified, the term "stereoisomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

依據原料和方法的選擇，本發明化合物可以以可能的異構體中的一個或它們的混合物的形式存在，例如作為純旋光異構體，或作為異構體混合物，如作為外消旋和非對映異構體混合物，這取決於不對稱碳原子的數量。當描述具有光學活性的化合物時，使用前綴D和L或R和S來表示就分子中的手性中心(或多個手性中心)而言分子的絕對構型。前綴D和L或(+)和(–)是用於指定化合物所致平面偏振光旋轉的符號，其中(–)或L表示化合物是左旋的。前綴為(+)或D的化合物是右旋的。就給定的化學結構而言，除了這些立體異構體互為鏡像外，這些立體異構體是相同的。具體的立體異構體也可稱為對映異構體，並且所述異構體的混合物通常稱作對映異構體的混合物。對映異構體的50:50混合物稱為外消旋混合物或外消旋體，當在化學反應或方法中沒有立體選擇性或立體特異性時，可出現所述外消旋混合物或外消旋體。烯烴、C＝N雙鍵等的許多幾何異構體也可以存在於本文所述的化合物中，且所有這種穩定的異構體在本發明中均被考慮。當本文所描述化合物含有烯雙鍵時，除非另外說明，否則，這種雙鍵包括E和Z幾何異構體。如果化合物中含有二取代的環烷基，環烷基的取代基可能為順式或反式(cis-或trans-)構型。Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When a compound described herein contains an olefinic double bond, such double bonds include both E and Z geometric isomers unless otherwise stated. If the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis- or trans- configuration.

當將本發明式中與手性碳的鍵描寫直成線時，應當理解為，手性碳的(R)和(S)兩種構型和由此產生的其對映體純的化合物和混合物兩者包括在該通式範圍內。本文中消旋體或者對映體純的化合物的圖示法來自Maehr，J.Chem.Ed.1985，62:114-120。除非另有說明，用楔形鍵和虛線鍵表示一個立體中心的絕對構型。When the bonds to the chiral carbon in the formula of the present invention are drawn as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The schematic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

旋光性的(R)-或(S)-異構體可使用手性合成子或手性製劑製備，或使用常規技術拆分。含有不對稱取代的碳原子的本發明化合物能夠以旋光活性形式或外消旋形式分離。化合物的外消旋混合物的拆分可以通過本領域已知的許多方法中的任一種來進行。示例性方法包括使用手性拆分酸的分級重結晶，該手性拆分酸是旋光活性的成鹽有機酸。用於分級重結晶方法的適合的拆分劑例如是旋光活性酸，例如酒石酸、二乙醯基酒石酸、二苯甲醯基酒石酸、扁桃酸、蘋果酸、乳酸或各種旋光活性樟腦磺酸如β-樟腦磺酸的D和L形式。適合於分級結晶方法的其它的拆分劑包括立體異構純形式的α-甲基-苄胺(例如，S和R形式或者非對映異構純形式)、2-苯基甘氨醇、降麻黃鹼、麻黃鹼、N-甲基麻黃鹼、環己基乙胺、1，2-二胺基環己烷等。外消旋混合物的拆分還可以通過在填充有旋光活性拆分劑(例如，二硝基苯甲醯基苯基甘氨酸)的色譜柱上洗脫來進行。可以採用高效液相色譜(HPLC)法也可以採用超臨界流體色譜法(SFC)進行。具體方法的選擇以及洗脫條件、色譜柱的選擇可以由本發明所屬技術領域具有通常知識者根據化合物的結構以及試驗結果選擇。進一步的，還可以使用已知構型的光學純的起始原料或試劑，通過立體有機合成，獲得本發明所描述化合物的任何對映體或非對映體。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salifying organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, apple acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norphedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzylphenylglycine). High performance liquid chromatography (HPLC) can be used, and supercritical fluid chromatography (SFC) can also be used. The selection of specific methods and elution conditions and the selection of chromatographic columns can be selected by those of ordinary skill in the art to which the present invention belongs according to the structure of the compound and test results. Furthermore, any enantiomer or diastereomer of the compounds described in the present invention can be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

除非另有規定，術語「互變異構體」是指因分子中某一原子在兩個位置迅速移動而產生的官能團異構體。本發明化合物可表現出互變異構現象。互變異構的化合物可以存在兩種或多種可相互轉化的種類。質子移變互變異構體來自兩個原子之間共價鍵合的氫原子的遷移。互變異構體一般以平衡形式存在，嘗試分離單一互變異構體時通常產生一種混合物，其理化性質與化合物的混合物是一致的。平衡的位置取決於分子內的化學特性。例如，在很多脂族醛和酮如乙醛中，酮型佔優勢；而在酚中，烯醇型佔優勢。本發明包含化合物的所有互變異構形式。Unless otherwise specified, the term "tautomer" refers to functional group isomers that arise from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant, while in phenols, the enol form is predominant. The present invention includes all tautomeric forms of the compounds.

除非另有說明，用楔形實線鍵（ ）和楔形虛線鍵（ ）表示一個立體中心的絕對構型，用直形實線鍵（ ）和直形虛線鍵（ ）表示立體中心的相對構型。例如： 表示為 、 中的其中一種構型，而 則表示為剩下的另一種構型。 Unless otherwise noted, use a solid wedge key ( ) and the Dashed Wedge Key ( ) represents the absolute configuration of a stereocenter, with a straight solid line key ( ) and the straight dashed line key ( ) represents the relative configuration of the stereocenter. For example: Represented as , One of the configurations, and is represented by the remaining configuration.

本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

針對藥物或藥理學活性劑而言，術語「有效量」或「治療有效量」是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。對於本發明中的口服劑型，組合物中一種活性物質的「有效量」是指與該組合物中另一種活性物質聯用時為了達到預期效果所需要的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本發明所屬技術領域具有通常知識者根據常規試驗確定。With respect to drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person having ordinary knowledge in the technical field to which the present invention belongs based on routine experiments.

除非另有規定，術語「活性成分」、「治療劑」、「活性物質」或「活性劑」是指一種化學實體，它可以有效地治療目標紊亂、疾病或病症。Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" mean a chemical entity that is effective in treating a target disorder, disease, or condition.

除非另有規定，術語「被取代的」是指特定原子上的任意一個或多個氫原子被取代基取代，包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為酮基(即=O)時，意味著兩個氫原子被取代。酮取代不會發生在芳香基上。Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

除非另有規定，術語「任選」或「任選地」指的是隨後描述的事件或狀況可能但不是必需出現的，並且該描述包括其中所述事件或狀況發生的情況以及所述事件或狀況不發生的情況。Unless otherwise specified, the term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.

除非另有規定，術語「C 1-6烷基」用於表示直鏈或支鏈的由1至6個碳原子組成的飽和碳氫基團。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一價(如甲基)、二價(如亞甲基)或者多價(如次甲基)。C 1-6烷基的實例包括但不限於甲基(Me)、乙基(Et)、丙基(包括n-丙基和異丙基)、丁基(包括n-丁基，異丁基，s-丁基和t-丁基)、戊基(包括n-戊基，異戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to represent a linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-6 alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

除非另有規定，術語「C 1-3烷基」用於表示直鏈或支鏈的由1至3個碳原子組成的飽和碳氫基團。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一價(如甲基)、二價(如亞甲基)或者多價(如次甲基)。C 1-3烷基的實例包括但不限於甲基(Me)、乙基(Et)、丙基(包括n-丙基和異丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to represent a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-3 alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

在單獨或作為其他取代基一部分時，術語「鹵代」可與術語「鹵素取代」互換使用。The term "halogenated" when used alone or as part of another substituent is used interchangeably with the term "halogen-substituted".

除非另有規定，「鹵代烷基」或「鹵素取代的烷基」指包括具有特定數目的碳原子、被一或多個鹵素取代的支鏈和直鏈的飽和脂族烴基。Unless otherwise specified, "haloalkyl" or "halogen-substituted alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chains having the specified number of carbon atoms, substituted with one or more halogens.

除非另有規定，「C 2-6烯基」用於表示直鏈或支鏈的包含至少一個碳-碳雙鍵的由2至6個碳原子組成的碳氫基團，碳-碳雙鍵可以位於該基團的任何位置上。所述C 2-6烯基包括C 2-4、C 2-3、C 4、C 3和C 2烯基等；其可以是一價、二價或者多價。C 2-6烯基的實施例包括但不限於乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁間二烯基、戊間二烯基、己間二烯基等。 Unless otherwise specified, " C2-6 alkenyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C2-6 alkenyl group includes C2-4 , C2-3 , C4 , C3 and C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C2-6 alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

除非另有規定，「C 2-6炔基」用於表示直鏈或支鏈的包含至少一個碳-碳三鍵的由2至6個碳原子組成的碳氫基團，碳-碳三鍵可以位於該基團的任何位置上。所述C 2-6炔基包括C 2-4、C 2-3、C 4、C 3和C 2炔基等。其可以是一價、二價或者多價。C 2-6炔基的實施例包括但不限於乙炔基、丙炔基、丁炔基、戊炔基等。 Unless otherwise specified, "C 2-6 alkynyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C 2-6 alkynyl includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl, etc. It may be monovalent, divalent or polyvalent. Examples of C 2-6 alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

除非另有規定，術語「C 1-6烷氧基」表示通過一個氧原子連接到分子的其餘部分的那些包含1至6個碳原子的烷基基團。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(包括正丙氧基和異丙氧基)、丁氧基(包括n-丁氧基、異丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、異戊氧基和新戊氧基)、己氧基等。 Unless otherwise specified, the term "C 1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. Examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

除非另有規定，術語「C 1-3烷氧基」表示通過一個氧原子連接到分子的其餘部分的那些包含1至3個碳原子的烷基基團。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(包括正丙氧基和異丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

除非另有規定，術語「C 3-8環烷基」表示由3至8個碳原子組成的飽和環狀碳氫基團，其包括單環和雙環體系，其中雙環體系包括螺環、並環和橋環。所述C 3-8環烷基包括C 3-6、C 3-5、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6環烷基等；其可以是一價、二價或者多價。C 3-8環烷基的實例包括，但不限於，環丙基、環丁基、環戊基、環己基、環庚基、降冰片烷基、[2.2.2]二環辛烷等。 Unless otherwise specified, the term "C 3-8 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, paracyclic and bridged rings. The C 3-8 cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, etc.

除非另有規定，術語「C 3-6環烷基」表示由3至6個碳原子組成的飽和環狀碳氫基團，其為單環和雙環體系，所述C 3-6環烷基包括C 3-5、C 4-5和C 5-6環烷基等；其可以是一價、二價或者多價。C 3-6環烷基的實例包括，但不限於，環丙基、環丁基、環戊基、環己基等。 Unless otherwise specified, the term "C 3-6 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

除非另有規定，C n-n+m或C n-C n+m包括n至n+m個碳的任何一種具體情況，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一個範圍，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示環上原子數為n至n+m個，例如3-12元環包括3元環、4元環、5元環、6元環、7元環、8元環、9元環、10元環、11元環、和12元環，也包括n至n+m中的任何一個範圍，例如3-12元環包括3-6元環、3-9元環、5-6元環、5-7元環、6-7元環、6-8元環、和6-10元環等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 . Similarly , n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

除非另有規定，術語「6-8元雜環烷基」本身或者與其他術語聯合分別表示由6至8個環原子組成的飽和環狀基團，其1、2、3或4個環原子為獨立選自O、S和N的雜原子，其餘為碳原子，其中氮原子任選地被季銨化，氮和硫雜原子可任選被氧化(即NO和S(O)p，p是1或2)。其包括單環和雙環體系，其中雙環體系包括螺環、並環和橋環。此外，就該「6-8元雜環烷基」而言，雜原子可以佔據雜環烷基與分子其餘部分的連接位置。例如6-8元雜環烷基包括但不限於6元、7元、8元。6-8元雜環烷基的實例包括但不限於氮雜環丁基、氧雜環丁基、硫雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌𠯤基(包括1-哌𠯤基和2-哌𠯤基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二㗁烷基、二噻烷基、異㗁唑烷基、異噻唑烷基、1,2-㗁𠯤基、1,2-噻𠯤基、六氫嗒𠯤基。Unless otherwise specified, the term "6-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 6 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", the heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. For example, 6-8 membered heterocycloalkyl includes but is not limited to 6-membered, 7-membered, and 8-membered. Examples of 6-8 membered heterocycloalkyl groups include, but are not limited to, azacyclobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl, The invention also includes but is not limited to: piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperidine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxazolidinyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazolidinyl, 1,2-thiazolyl, and hexahydropyridine.

除非另有規定，術語「6-8元雜環烯基」本身或者與其他術語聯合分別表示包含至少一個碳-碳雙鍵的由6至8個環原子組成的部分不飽和的環狀基團，其1、2、3或4個環原子為獨立選自O、S和N的雜原子，其餘為碳原子，其中氮原子任選地被季銨化，碳、氮和硫雜原子可任選被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括單環和雙環體系，其中雙環體系包括螺環、並環和橋環，此體系的任意環都是非芳香性的。此外，就該「6-8元雜環烯基」而言，雜原子可以佔據雜環烯基與分子其餘部分的連接位置。所述6-8元雜環烯基包括6元、7元和8元雜環烯基等。Unless otherwise specified, the term "6-8 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 6 to 8 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may be optionally oxidized (i.e. C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings, and any ring of this system is non-aromatic. In addition, for the "6-8 membered heterocycloalkenyl", a hetero atom may occupy the connection position between the heterocycloalkenyl and the rest of the molecule. The 6-8 membered heterocycloalkenyl includes 6-membered, 7-membered and 8-membered heterocycloalkenyl.

除非另有規定，術語「鹵代基」或「鹵素」為氟、氯、溴和碘。Unless otherwise specified, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

另外，需要說明的是，除非以其他方式明確指出，在本發明中所採用的描述方式「……獨立地」應作廣義理解，是指所描述的各個個體之間是相互獨立的，可以獨立地為相同或不同的具體基團。更詳細地，描述方式「……獨立地」既可以是指在不同基團中，相同符合之間所表達的具體選項之間互相不影響，也可以表示在相同的基團中，相同符號之間所表達的具體選項之間互相不影響。In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. More specifically, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

除非另有規定，術語「患者」是指包括哺乳動物在內的任何動物，優選小鼠、大鼠、其它齧齒類動物、兔、狗、貓、豬、牛、羊、馬或靈長類動物，最優選人。Unless otherwise specified, the term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.

除非另有規定，術語「治療有效量」是指研究人員、獸醫、醫師或其它臨床醫師正在組織、系統、動物、個體或人中尋找的引起生物學或醫學反應的活性化合物或藥物的量，它包括以下一項或多項：(1)預防疾病：例如在易感染疾病、紊亂或病症但尚未經歷或出現疾病病理或症狀的個體中預防疾病、紊亂或病症。(2)抑制疾病：例如在正經歷或出現疾病、紊亂或病症的病理或症狀的個體中抑制疾病、紊亂或病症(即阻止病理和/或症狀的進一步發展)。(3)緩解疾病：例如在正經歷或出現疾病、紊亂或病症的病理或症狀的個體中緩解疾病、紊亂或病症(即逆轉病理和/或症狀)。Unless otherwise specified, the term "therapeutically effective amount" means the amount of an active compound or drug that will elicit the biological or medicinal response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, which includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting the disease, disorder or condition (i.e., arresting further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Relieving disease: e.g., alleviating the disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

本文所用的術語「治療」和其它類似的同義詞包括以下含義： (i)預防疾病或病症在哺乳動物中出現，特別是當這類哺乳動物易患有該疾病或病症，但尚未被診斷為已患有該疾病或病症時； (ii)抑制疾病或病症，即遏制其發展； (iii)緩解疾病或病症，即，使該疾病或病症的狀態消退；或者 (iv)減輕該疾病或病症所造成的症狀。 有益效果 As used herein, the term "treat" and other similar synonyms include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e., curbing its development; (iii) alleviating the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition. Beneficial Effects

根據本發明的實施例，本發明至少具有如下技術效果至少之一： （1）本發明提供了結構新穎、藥代動力學性質優良、藥效或成藥性好的PDE4B抑制劑，可以用於有效治療PDE4B相關的疾病、病症； （2）相對於PDE4D型受體，本發明化合物對PDE4B型受體的抑制活性更為顯著，具有更好的PDE4B選擇性，能顯著改善因PDE4D型受體抑制導致的胃腸道副作用如嘔吐等； （3）本發明化合物有著優良的人PBMC分泌TNFα抑制活性，能更好地抑制人PBMC中炎症因子TNFα的分泌，具有良好的抗炎效果； （4）本發明化合物表現出優良的血漿暴露、半衰期和生物利用度，有優良的藥代動力學性質，成藥前景良好。 According to the embodiments of the present invention, the present invention has at least one of the following technical effects: (1) The present invention provides a PDE4B inhibitor with novel structure, excellent pharmacokinetic properties, good efficacy or drugability, which can be used to effectively treat PDE4B-related diseases and symptoms; (2) Compared with PDE4D receptors, the compounds of the present invention have more significant inhibitory activity on PDE4B receptors, have better PDE4B selectivity, and can significantly improve gastrointestinal side effects such as vomiting caused by PDE4D receptor inhibition; (3) The compounds of the present invention have excellent human PBMC secretion of TNFα inhibitory activity, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and have good anti-inflammatory effects; (4) The compounds of the present invention show excellent plasma exposure, half-life and bioavailability, have excellent pharmacokinetic properties, and have good prospects for drug development.

以下結合具體實施例，進一步說明本發明。需理解，以下的描述僅為本發明的最優選實施方式，而不應當被認為是對於本發明保護範圍的限制。在充分理解本發明的基礎上，下列實施例中未注明具體條件的實驗方法，通常按照常規條件，或按照製造廠商所建議的條件，本發明所屬技術領域具有通常知識者可以對本發明的技術方案作出非本質的改動，這樣的改動應當被視為包括於本發明的保護範圍之中的。The present invention is further described below in conjunction with specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of a full understanding of the present invention, the experimental methods in the following embodiments that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. A person with ordinary knowledge in the technical field to which the present invention belongs may make non-essential changes to the technical solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

中間體A1的合成路線如下： The synthetic route of intermediate A1 is as follows:

第一步：(1-胺基環丁基)甲醇(A1)的合成 將室溫下將1‑胺基環丁甲酸(15 g，130.3 mmol)溶解於四氫呋喃(300 Ml)中，在0℃、氬氣保護並且攪拌條件下滴加氫化鋁鋰(2.5 M四氫呋喃溶液，104 mL，260 mmol)。滴加完畢將反應液緩慢升至室溫並且氬氣保護下攪拌16 h。冰浴下用十水合硫酸鈉固體淬滅反應後再用無水硫酸鈉乾燥，過濾。濾餅用乙酸乙酯淋洗。合併後的濾液在室溫下濃縮得(1-胺基環丁基)甲醇(12 g，產率90％)。 Step 1: Synthesis of (1-aminocyclobutyl)methanol (A1) Dissolve 1-aminocyclobutanecarboxylic acid (15 g, 130.3 mmol) in tetrahydrofuran (300 mL) at room temperature, and add lithium aluminum hydroxide (2.5 M tetrahydrofuran solution, 104 mL, 260 mmol) dropwise at 0°C, under argon protection and stirring. After the addition, slowly raise the reaction solution to room temperature and stir under argon protection for 16 h. Quench the reaction with solid sodium sulfate decahydrate under ice bath, dry with anhydrous sodium sulfate, and filter. Rinse the filter cake with ethyl acetate. Concentrate the combined filtrate at room temperature to obtain (1-aminocyclobutyl)methanol (12 g, yield 90%).

中間體A2的合成路線如下： The synthetic route of intermediate A2 is as follows:

第一步：哌啶-4-甲脒(A2-2)的合成 將在4M HCl 的1,4-二氧六環(45 ml, 3 eq, 180 mmo1)加至燒瓶中。將該溶液冷卻至0℃，並在約30分鐘內加入4-氰基哌啶(6.6 g, 60 mmol)，然後加入甲醇(6 mL, 180 mmol, 3 eq)，同時保持該溫度低於10℃ (反應放熱)。將上述混合物在室溫攪拌6-8小時，將該混合物冷卻至5℃，並加在25wt% NaOMe (甲醇溶液)(32 g, 100 mmol, 2 eq)， 同時保持溫度低於15℃，然後將該反應液攪拌1小時。將7 Ν在甲醇中的氨水(13 mL, 1.5 eq, 90 mmol)加至上述混合物， 並在標準室溫攪拌8小時。將該混合物減壓濃縮至約50ml的體積，得到粗制的中間體A2-2的溶液，使用不需分離。 Step 1: Synthesis of piperidine-4-carboxamidine (A2-2) 1,4-Dioxane (45 ml, 3 eq, 180 mmol) in 4M HCl was added to the flask. The solution was cooled to 0°C and 4-cyanopiperidine (6.6 g, 60 mmol) was added over about 30 minutes, followed by methanol (6 mL, 180 mmol, 3 eq) while keeping the temperature below 10°C (reaction exothermic). The mixture was stirred at room temperature for 6-8 hours, the mixture was cooled to 5°C and 25wt% NaOMe (methanol solution) (32 g, 100 mmol, 2 eq) was added while keeping the temperature below 15°C, and the reaction was stirred for 1 hour. 7 N aqueous ammonia in methanol (13 mL, 1.5 eq, 90 mmol) was added to the above mixture and stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure to a volume of about 50 ml to obtain a solution of crude intermediate A2-2, which was used without isolation.

第二步：5-氯-2-(哌啶-4-基)嘧啶（中間體A2）的合成 將中間體A2-2的上述溶液冷卻至約20℃，並加入25wt% NaOMe (甲醇溶液) (33 g, 150 mmol)。然後將該化合物攪拌30分鐘。在標準室溫，經約30分鐘分兩批將化合物D (= (Z) -N- (2-氯-3-(二甲胺基)亞烯丙基)-N-甲基甲烷-六氟磷酸銨(17 g, 51 mmol)加至上述混合物，並在室溫攪拌3小時。將該混合物減壓濃縮，將反應混合物用水稀釋，然後用乙酸乙酯萃取，合併有機層，用飽和食鹽水洗滌有機相，硫酸鈉乾燥，濃縮得到粗品，用矽膠柱分離純化(二氯甲烷:甲醇(V/V)=20:1-10:1，梯度洗脫)得4-(5-氯嘧啶-2-基)哌𠯤-1-羧酸三級丁酯(中間體A2) (9 g，產率75%)。 Step 2: Synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (Intermediate A2) The above solution of intermediate A2-2 was cooled to about 20°C, and 25 wt% NaOMe (methanol solution) (33 g, 150 mmol) was added, and the mixture was stirred for 30 minutes. Compound D (= (Z) -N- (2-chloro-3-(dimethylamino)allylidene) -N-methylmethane-ammonium hexafluorophosphate (17 g, 51 mmol) was added to the above mixture in two batches over about 30 minutes at standard room temperature, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the reaction mixture was diluted with water, and then extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column (dichloromethane: methanol (V/V) = 20:1-10:1, gradient elution) to obtain 4-(5-chloropyrimidin-2-yl)piperidin-1-carboxylic acid tributyl ester (intermediate A2) (9 g, yield 75%).

實施例1：目標化合物1-P1&P2的製備 (S)&(R)- 2-(4-(5-氯嘧啶-2-基)哌啶-1-基) -5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基) 環丁基)-甲醇(目標化合物1-P1&P2) 目標化合物1-P1&P2的合成路線如下： Example 1: Preparation of target compound 1-P1 & P2 (S & (R)- 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (target compound 1-P1 & P2) The synthetic route of the target compound 1-P1&P2 is as follows:

第一步：甲基-3-氧亞基四氫-2H-噻喃-2-甲酸基酯(1-2)的合成 將甲基4-(2-甲氧基-2-氧亞基-乙基)巰基丁酯(1-1) (3.00 g, 14.5 mmol)溶解在甲苯（50 mL）中，加入甲醇鈉(942 mg, 17.4 mmol)，升至105 ℃反應3小時。將反應液倒入冷的12 N 濃鹽酸中(10 mL)中，再用乙酸乙酯(90 mL)萃取3次，合併有機相用飽和食鹽水(50 mL)洗滌，無水硫酸鈉乾燥，濃縮得到黃色油狀產物甲基-3-氧亞基四氫-2H-噻喃-2-甲酸基酯(1-2) (2.70 g, 直接用於下一步)。LC-MS, M/Z (ESI): 175.0 (M+H). Step 1: Synthesis of methyl-3-oxyylidene tetrahydro-2H-thiopyran-2-carboxylate (1-2) Methyl 4-(2-methoxy-2-oxyylidene-ethyl)butyl ester (1-1) (3.00 g, 14.5 mmol) was dissolved in toluene (50 mL), sodium methanolate (942 mg, 17.4 mmol) was added, and the temperature was raised to 105 °C for 3 hours. The reaction solution was poured into cold 12 N concentrated hydrochloric acid (10 mL), and then extracted with ethyl acetate (90 mL) three times. The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily product, methyl-3-oxyylidene tetrahydro-2H-thiopyran-2-carboxylate (1-2) (2.70 g, used directly in the next step). LC-MS, M/Z (ESI): 175.0 (M+H).

第二步：2-(甲硫基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-酚(1-3)的合成 將氫氧化鉀(1.21 g, 21.5 mmol)溶於無水甲醇(40 mL)中，加入甲基-3-氧亞基四氫-2H-噻喃-2-甲酸基酯(1-2) (2.50 g, 14.3 mmol)和2-甲基-2-異硫代脲硫酸鹽(2.00 g, 7.17 mmol)，25℃反應16小時。將反應液倒入冰水(40 mL)和冰醋酸(2 mL)中，過濾收集析出沉澱物，得到2-(甲硫基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-酚(1-3)(3.00 g, 直接用於下一步)。LC-MS, M/Z (ESI): 215.0 (M+H). Step 2: Synthesis of 2-(methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-4-ol (1-3) Potassium hydroxide (1.21 g, 21.5 mmol) was dissolved in anhydrous methanol (40 mL), and methyl-3-oxyylidene tetrahydro-2H-thiopyran-2-carboxylate (1-2) (2.50 g, 14.3 mmol) and 2-methyl-2-isothiourea sulfate (2.00 g, 7.17 mmol) were added, and the mixture was reacted at 25°C for 16 hours. The reaction solution was poured into ice water (40 mL) and glacial acetic acid (2 mL), and the precipitate was collected by filtration to obtain 2-(methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (1-3) (3.00 g, used directly in the next step). LC-MS, M/Z (ESI): 215.0 (M+H).

第三步：7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-2,4-二酚(1-4)的合成 將2-(甲硫基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-酚(1-3) (4.00 g, 18.6 mmol)溶解在水(20 mL)和冰醋酸(40 mL)中，升溫至105 ℃，反應60小時。將反應液冷卻後過濾收集析出固體，乾燥，得到產物7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-2,4-二酚(1-4) (5.00 g, 直接用於下一步)。LC-MS, M/Z (ESI): 185.0 (M+H). Step 3: Synthesis of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (1-4) Dissolve 2-(Methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-4-ol (1-3) (4.00 g, 18.6 mmol) in water (20 mL) and glacial acetic acid (40 mL), heat to 105 °C, and react for 60 hours. After cooling the reaction solution, filter and collect the precipitated solid, and dry it to obtain the product 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (1-4) (5.00 g, used directly in the next step). LC-MS, M/Z (ESI): 185.0 (M+H).

第四步：2,4-二氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶(1-5)的合成 將7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-2,4-二酚(1-4) (4.00 g, 21.7 mmol) 和N,N-二甲基苯胺(657 mg, 5.43 mmol, 688 μL)溶解在三氯氧磷（16.6 g, 108 mmol, 10.0 mL）中，氮氣置換，在90℃下反應3小時。將反應液用濃二氯甲烷(100 mL)稀釋，小心倒入水(100 mL)中淬滅，二氯甲烷(300 mL)萃取三次，飽和食鹽水(150 mL)洗滌，無水硫酸鈉乾燥，濃縮拌樣, 矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=1/0-10/1)得到化合物2,4-二氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶(1-5) (700 mg, 產率13.6 %)。LC-MS, M/Z (ESI): 220.9 (M+H)。 1H NMR (400 MHz, DMSO- d 6) δ =3.12-3.22 (m, 2H), 2.94 (m, 2H), 2.05-2.18 (m, 2H). Step 4: Synthesis of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (1-5) 7,8-Dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (1-4) (4.00 g, 21.7 mmol) and N,N-dimethylaniline (657 mg, 5.43 mmol, 688 μL) were dissolved in phosphorus oxychloride (16.6 g, 108 mmol, 10.0 mL), replaced with nitrogen, and reacted at 90°C for 3 hours. The reaction solution was diluted with concentrated dichloromethane (100 mL), carefully poured into water (100 mL) for quenching, extracted with dichloromethane (300 mL) three times, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated and stirred, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) to obtain compound 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (1-5) (700 mg, yield 13.6 %). LC-MS, M/Z (ESI): 220.9 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ =3.12-3.22 (m, 2H), 2.94 (m, 2H), 2.05-2.18 (m, 2H).

第五步：(1-((2-氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇（1-6）的合成 將2,4-二氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶(1-5) (600 mg, 2.52 mmol)和(1-胺基環丁基)甲醇 (304 mg, 3.03 mmol)溶解在乙腈(20 mL)中，加入三乙胺(1.28 g, 12.6 mmol, 1.76 mL )。80℃反應10小時。將反應液用水(40 mL)稀釋，乙酸乙酯(120 mL)萃取三次，飽和食鹽水洗滌(40 mL)，無水硫酸鈉乾燥，濃縮，矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到化合物 (1-((2-氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇(1-6) (700 mg, 產率77.6%)。LC-MS, M/Z (ESI): 286.0 (M+H). Step 5: Synthesis of (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (1-6) Dissolve 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (1-5) (600 mg, 2.52 mmol) and (1-aminocyclobutyl)methanol (304 mg, 3.03 mmol) in acetonitrile (20 mL), add triethylamine (1.28 g, 12.6 mmol, 1.76 mL), and react at 80°C for 10 hours. The reaction solution was diluted with water (40 mL), extracted three times with ethyl acetate (120 mL), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel separation (dichloromethane:methanol (V/V) = 10/1) to obtain compound (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (1-6) (700 mg, yield 77.6%). LC-MS, M/Z (ESI): 286.0 (M+H).

第六步： 2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶5-氧化（1-7）的合成 將(1-((2-氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇(1-6) (700 mg, 1.96 mmol) 、S-(-)-1,1'-聯-2-萘酚(56.1 mg, 195 μmol)溶解在二氯甲烷（10 mL)中，再加入四異丙氧化鈦(27.8 mg, 97.9 μmol, 28.9 μL)和水(5.31 mg, 1.96 mmol, 35.3 μL)，加完後置換氮氣，20℃反應1小時。再加入過氧三級丁醇(264 mg, 2.06 mmol, 281 μL, 70% purity)，25℃反應1.5小時。將反應液用10%亞硫酸鈉水溶液(10 mL)淬滅，二氯甲烷(90 mL)萃取三次，合併有機相用水(50 mL)洗滌，無水硫酸鈉乾燥，濃縮，矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到化合物2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(1-7) (300 mg, 產率45.7%)。LC-MS, M/Z (ESI): 302.2 (M+H). Step 6: Synthesis of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7) Dissolve (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (1-6) (700 mg, 1.96 mmol) and S-(-)-1,1'-bi-2-naphthol (56.1 mg, 195 μmol) in dichloromethane (10 mL), then add titanium tetraisopropoxide (27.8 mg, 97.9 μmol, 28.9 μL) and water (5.31 mg, 1.96 mmol, 35.3 μL). After the addition, replace nitrogen and react at 20°C for 1 hour. Then add tert-butyl peroxide (264 mg, 2.06 mmol, 281 μL, 70% purity) and react at 25°C for 1.5 hours. The reaction solution was quenched with 10% sodium sulfite aqueous solution (10 mL), extracted three times with dichloromethane (90 mL), and the combined organic phases were washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel separation (dichloromethane: methanol (V/V) = 10/1) to obtain compound 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7) (300 mg, yield 45.7%). LC-MS, M/Z (ESI): 302.2 (M+H).

第七步：2-(4-(5-氯嘧啶-2-基)哌啶-1-基) -5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基) 環丁基)-甲醇(化合物1)的合成 將2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(1-7) (200 mg, 596 μmol) 溶解在1,4-二氧六環(30 mL)中，加入5-氯-2-(4-哌啶基)嘧啶(167 mg, 715 μmol)和N,N-二異丙基乙胺(385 mg, 2.98 mmol, 519 μL)。80℃下反應3小時。將反應液濃縮, 加入飽和碳酸氫鈉溶液(30 mL)，乙酸乙酯(90 mL)萃取三次, 飽和食鹽水(50 mL)洗滌，無水硫酸鈉乾燥，濃縮，矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基) -5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基) 環丁基)-甲醇(化合物1) (250 mg,，產率86.0%)。LC-MS, M/Z (ESI): 463.4 (M+H). Step 7: Synthesis of 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compound 1) Dissolve 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7) (200 mg, 596 μmol) in 1,4-dioxane (30 mL), add 5-chloro-2-(4-piperidinyl)pyrimidine (167 mg, 715 μmol) and N,N-diisopropylethylamine (385 mg, 2.98 mmol, 519 μL), and react at 80°C for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution (30 mL) was added, and ethyl acetate (90 mL) was used for extraction three times, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel separation (dichloromethane: methanol (V/V) = 10/1) to obtain compound 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compound 1) (250 mg, yield 86.0%). LC-MS, M/Z (ESI): 463.4 (M+H).

第八步：(S)&(R)- 2-(4-(5-氯嘧啶-2-基)哌啶-1-基) -5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基) 環丁基)-甲醇(目標化合物1-P1&P2)的合成 將外消旋體化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基) -5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基) 環丁基)-甲醇(化合物1) (250 mg, 513 μmol)通過正相高效液相色譜法進行手性分離，分離方法為(色譜柱：DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流動相：A = 二氧化碳，B = 氨水(0.1%)+乙醇；梯度：50% - 50%，7分鐘），化合物(S) or (R)- 2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化 (目標化合物1-P1，保留時間1.387 min) (90.0 mg, 產率37.9% yield)，LC-MS, M/Z (ESI): 463.4 (M+H)。 1H NMR (400 MHz, DMSO- d 6) δ = 8.86 (s, 2H), 6.50 (s, 1H), 4.90 (m, 1H), 4.67 (br d, 2H), 3.69 (br d, 2H), 3.13-3.22 (m, 1H), 2.98-3.10 (m, 3H), 2.86-2.95 (m, 1H), 2.59-2.71 (m, 2H), 2.30-2.39 (m, 3H), 2.13 (br d, 2H), 1.95 (br d, 3H), 1.72-1.83 (m, 2H), 1.56-1.68 (m, 2H). (S) or (R)- 2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化 (目標化合物1-P2，保留時間1.739 min) (130 mg, 產率54.7% yield)。LC-MS, M/Z (ESI): 463.4 (M+H)。 1H NMR (400 MHz, DMSO- d 6) δ =8.86 (s, 2H), 6.50 (s, 1H), 4.90 (br m, 1H), 4.64-4.72 (m, 2H), 3.70 (br d, 2H), 3.15-3.20 (m, 1H), 3.00-3.08 (m, 3H), 2.91 (br s, 1H), 2.65 (br d, 2H), 2.31-2.40 (m, 3H), 2.13 (br s, 2H), 1.95 (br d, 3H), 1.73-1.82 (m, 2H), 1.58-1.66 (m, 2H). Step 8: Synthesis of (S) & (R)- 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (target compound 1-P1 & P2) The racemic compound 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compound 1) (250 mg, 513 μmol) was chirally separated by normal phase HPLC (chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), compound (S) or (R)- 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxidation (target compound 1-P1, retention time 1.387 min) (90.0 mg, yield 37.9% yield), LC-MS, M/Z (ESI): 463.4 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.86 (s, 2H), 6.50 (s, 1H), 4.90 (m, 1H), 4.67 (br d, 2H), 3.69 (br d, 2H), 3.13-3.22 (m, 1H), 2.98-3.10 (m, 3H), 2.86-2.95 (m, 1H), 2.59-2.71 (m, 2H), 2.30-2.39 (m, 3H), 2.13 (br d, 2H), 1.95 (br d, 3H), 1.72-1.83 (m, 2H), 1.56-1.68 (m, 2H). (S) or (R)- 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxidation (target compound 1-P2, retention time 1.739 min) (130 mg, yield 54.7% yield). LC-MS, M/Z (ESI): 463.4 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ =8.86 (s, 2H), 6.50 (s, 1H), 4.90 (br m, 1H), 4.64-4.72 (m, 2H), 3.70 (br d, 2H), 3.15-3.20 (m, 1H), 3.00-3.08 (m, 3H), 2.91 (br s, 1H), 2.65 (br d, 2H), 2.31-2.40 (m, 3H), 2.13 (br s, 2H), 1.95 (br d, 3H), 1.73-1.82 (m, 2H), 1.58-1.66 (m, 2H).

實施例2：目標化合物8-P1和8-P2的製備： (R) or (S)-2-（6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-基）-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇（目標化合物8-P1&8-P2） 目標化合物8-P1&8-P2的合成路線: Example 2: Preparation of target compounds 8-P1 and 8-P2: (R) or (S)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (target compounds 8-P1 & 8-P2) Synthesis route of target compounds 8-P1 & 8-P2:

第一步：6-(5-氯嘧啶-2-基)-2-氮雜螺[3.3]庚-5-烯-2-羧酸三級丁酯的合成 將6-（4,4,5,5-四甲基-1,3,2-二㗁硼戊環-2-基）-2-氮雜螺[3.3]庚-5-烯-2-羧酸三級丁酯 (4.0 g, 12.45 mmol)和 5-氯-2-碘嘧啶(3.59 g, 14.94 mmol)溶解在1,4二氧六環（60 mL）和水(12 mL)中，加入碳酸鉀(4.3 g, 31.13 mmol)和1,1-雙(二苯基磷)二茂鐵氯化鈀(903 mg, 1.24 mmol)，在氮氣保護下90℃反應5小時。將反應液加水(100 mL)稀釋，然後用乙酸乙酯（200 mL）萃取三次，用飽和食鹽水（100 mL）洗滌有機相，用無水硫酸鈉乾燥，過濾，濃縮，用矽膠柱分離純化(石油醚:乙酸乙酯（V/V）=1:0- 5:1)純化得到化合物6-(5-氯嘧啶-2-基)-2-氮雜螺[3.3]庚-5-烯-2-羧酸三級丁酯（1.3 g, 收率34%）。 Step 1: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester Dissolve 6-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tributyl ester (4.0 g, 12.45 mmol) and 5-chloro-2-iodopyrimidine (3.59 g, 14.94 mmol) in 1,4-dioxane (60 mL) and water (12 mL), add potassium carbonate (4.3 g, 31.13 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (903 mg, 1.24 mmol), and react at 90°C for 5 hours under nitrogen protection. The reaction solution was diluted with water (100 mL), then extracted three times with ethyl acetate (200 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1:0-5:1) to obtain the compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tributyl ester (1.3 g, yield 34%).

第二步：6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-羧酸三級丁酯的合成 將原料6-(5-氯嘧啶-2-基)-2-氮雜螺[3.3]庚-5-烯-2-羧酸三級丁酯（1.3 g，4.22 mmol）和Rh(PPh 3) 3Cl（338.45 mg，0.844 mmol）溶在甲醇（20 mL）中，置換氫氣並升溫至50 ℃攪拌反應12小時。反應完畢後，將反應液濃縮得到粗品，經層析柱分離純化（二氯甲烷：甲醇（V/V）=10:1），得6-(5-氯嘧啶-2-基)-2-氮雜螺[3.3]庚烷-2-羧酸三級丁酯（1.2 g，產率91.7%）。LC-MS, M/Z (ESI): 309.98 (M+1). Step 2: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester The raw material 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tributyl ester (1.3 g, 4.22 mmol) and Rh(PPh 3 ) 3 Cl (338.45 mg, 0.844 mmol) were dissolved in methanol (20 mL), the hydrogen was replaced and the temperature was raised to 50 ℃ for stirring and reaction for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tributyl ester (1.2 g, yield 91.7%). LC-MS, M/Z (ESI): 309.98 (M+1).

第三步：6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷的合成 將原料6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-羧酸三級丁酯（700 mg，2.26 mmol）溶在二氯甲烷（10 mL）中，加入三氟乙酸（3 mL），反應液在室溫下攪拌2小時。反應完畢後濃縮旋乾得到粗品，經層析柱分離純化（二氯甲烷：甲醇（V/V）=10:1），得6-(5-氯嘧啶-2-基)-2-氮雜螺[3.3]庚烷（440 mg，產率92.8%）。LC-MS, M/Z (ESI): 210.99 (M+1). Step 3: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane The raw material 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tributyl ester (700 mg, 2.26 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was concentrated and vortexed to obtain a crude product, which was purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (440 mg, yield 92.8%). LC-MS, M/Z (ESI): 210.99 (M+1).

第四步：(R) or (S)-2-（6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-基）-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇（目標化合物8-P1&8-P2） 將原料6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷（41.69 mg，0.198 mmol）和(R) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(AA)（50 mg，0.165 mmol）和N,N-二異丙基乙胺（64.24 mg，0.497 mmol）溶於1,4-二氧六環（2 mL）中，將反應加熱至100 ℃反應10小時。反應完畢後用二氯甲烷稀釋反應液並用層析柱分離純化（二氯甲烷：甲醇（V/V）=10:1），濃縮過柱液，然後通過反相高效液相色譜製備純化，（色譜柱: SYMC-Triart Prep C18 7μm 30mm×40cm）；流動相：A = 0.1%氨水，B = 乙腈；梯度：1% - 35%，6.7分鐘）得到化合物（R）-2-（6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-基）-4-（（1-（羥甲基）環丁基）胺基）-7,8-二氫-6H-硫吡喃並[3,2-d]嘧啶5-氧化物（8-P1）（23 mg，產率29%）。LC-MS, M/Z (ESI): 475.29 (M+1). 1H NMR (600 MHz, cdcl3) δ 8.62 (s, 2H), 8.10 – 8.01 (m, 1H), 6.41 (s, 1H), 4.27 – 4.04 (m, 4H), 3.90 – 3.82 (m, 2H), 3.69 – 3.63 (m, 1H), 3.21 (dd, 2H), 2.93 – 2.83 (m, 2H), 2.72 – 2.49 (m, 6H), 2.34 (s, 2H), 2.17 – 2.06 (m, 2H), 1.93 (ddt, 2H). 將原料6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷（41.69 mg，0.198 mmol）和 (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(AB)（50 mg，0.165 mmol）和N,N-二異丙基乙胺（64.24 mg，0.497 mmol）溶於1,4-二氧六環（2 mL）中，將反應加熱至100 ℃反應10小時。反應完畢後用二氯甲烷稀釋反應液並用層析柱分離純化（二氯甲烷：甲醇（V/V）=10:1），濃縮過柱液，然後通過反相高效液相色譜製備純化，（色譜柱: SYMC-Triart Prep C18 7μm 30mm×40cm）；流動相：A = 0.1%氨水，B = 乙腈；梯度：1% - 35%，6.7分鐘）得到化合物（S）-2-（6-（5-氯嘧啶-2-基）-2-氮雜螺[3.3]庚烷-2-基）-4-（（1-（羥甲基）環丁基）胺基）-7,8-二氫-6H-硫吡喃並[3,2-d]嘧啶5-氧化物（8-P2）（24 mg，產率30%）LC-MS, M/Z (ESI): 475.29 (M+1). 1H NMR (600 MHz, cdcl3) δ 8.62 (s, 2H), 8.03 (s, 1H), 6.41 (s, 1H), 4.16 (d, 4H), 3.86 (s, 2H), 3.69 – 3.63 (m, 1H), 3.21 (dd, 1H), 2.89 (ddd, 2H), 2.66 – 2.59 (m, 4H), 2.56 – 2.50 (m, 1H), 2.38 – 2.31 (m, 2H), 2.21 – 2.04 (m, 4H), 1.95 (ddd, 2H). Step 4: (R) or (S)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (target compound 8-P1 & 8-P2) The starting materials 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (41.69 mg, 0.198 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AA) (50 mg, 0.165 mmol) and N,N-diisopropylethylamine (64.24 mg, 0.497 mmol) were dissolved in 1,4-dioxane (2 mL) and the reaction was heated to 100 °C for 10 hours. After the reaction, the reaction solution was diluted with dichloromethane and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1), concentrated and passed through the column, and then purified by reverse phase high performance liquid chromatography (chromatographic column: SYMC-Triart Prep C18 7μm 30mm×40cm); mobile phase: A = 0.1% ammonia water, B = acetonitrile; gradient: 1% - 35%, 6.7 minutes) to obtain compound (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (8-P1) (23 3H-4H-1,3-deg.-1H-4,3-deg.-1H-5,3-deg.-2H-1 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3 - deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 3H-1,3-deg.-1H-5 The starting materials 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (41.69 mg, 0.198 mmol) and (S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AB) (50 mg, 0.165 mmol) and N,N-diisopropylethylamine (64.24 mg, 0.497 mmol) were dissolved in 1,4-dioxane (2 mL) and the reaction was heated to 100 °C for 10 hours. After the reaction, the reaction solution was diluted with dichloromethane and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1), concentrated and passed through the column, and then purified by reverse phase high performance liquid chromatography (chromatographic column: SYMC-Triart Prep C18 7μm 30mm×40cm); mobile phase: A = 0.1% ammonia water, B = acetonitrile; gradient: 1% - 35%, 6.7 minutes) to obtain compound (S)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (8-P2) (24 mg, yield 30%) LC-MS, M/Z (ESI): 475.29 (M+1). 1 H NMR (600 MHz, cdcl3) δ 8.62 (s, 2H), 8.03 (s, 1H), 6.41 (s, 1H), 4.16 (d, 4H), 3.86 (s, 2H), 3.69 – 3.63 (m, 1H), 3.21 (dd, 1H), 2.89 (ddd, 2H), 2.66 – 2.59 (m, 4H), 2.56 – 2.50 (m, 1H), 2.38 – 2.31 (m, 2H), 2.21 – 2.04 (m, 4H), 1.95 (ddd, 2H).

實施例3：目標化合物9的製備 2-(4-(5-氯嘧啶-2-基)哌啶-1-基)- 5,5-二氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(目標化合物9) 目標化合物9的合成路線如下所示： Example 3: Preparation of Target Compound 9 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (Target Compound 9) The synthetic route of target compound 9 is as follows:

第一步：2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5,5-二氧化（9-2）的合成 將(1-((2-氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇(1-6) (20.0 mg, 62.9 μmol) 、S-(-)-1,1'-聯-2-萘酚(1.80 mg, 6.30 μmol)溶解在二氯甲烷（5 mL)中，再加入四異丙氧化鈦(895 μg, 3.15 μmol, 0.929 μL)和水(1.13 mg, 62.9 μmol, 1.13 μL)，加完後置換氮氣，20℃反應1小時。再加入過氧三級丁醇(5.96 mg, 66.1 μmol, 5 M, 13.2 μL)，25℃反應1.5小時。將反應液用10%亞硫酸鈉水溶液(10 mL)淬滅，二氯甲烷(30 mL)萃取三次，合併有機相用水(20 mL)洗滌，無水硫酸鈉乾燥，濃縮，矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到黃色固體化合物2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5,5-二氧化(9-2) (25.0 mg, 產率95.0%)。LC-MS, M/Z (ESI): 318.2 (M+H) Step 1: Synthesis of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (9-2) Dissolve (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (1-6) (20.0 mg, 62.9 μmol) and S-(-)-1,1'-bi-2-naphthol (1.80 mg, 6.30 μmol) in dichloromethane (5 mL), then add titanium tetraisopropoxide (895 μg, 3.15 μmol, 0.929 μL) and water (1.13 mg, 62.9 μmol, 1.13 μL). After the addition, replace nitrogen and react at 20°C for 1 hour. Then add tert-butyl peroxide (5.96 mg, 66.1 μmol, 5 M, 13.2 μL) and react at 25°C for 1.5 hours. The reaction solution was quenched with 10% sodium sulfite aqueous solution (10 mL), extracted three times with dichloromethane (30 mL), and the combined organic phases were washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel separation (dichloromethane: methanol (V/V) = 10/1) to obtain a yellow solid compound 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (9-2) (25.0 mg, yield 95.0%). LC-MS, M/Z (ESI): 318.2 (M+H)

第二步：2-(4-(5-氯嘧啶-2-基)哌啶-1-基)- 5,5-二氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(化合物9)的合成 將2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5,5-二氧化(9-2) (20.0 mg, 62.9 μmol) 溶解在1,4-二氧六環(10 mL)中，加入5-氯-2-(4-哌啶基)嘧啶(12.4 mg, 62.9 μmol)和N,N-二異丙基乙胺(40.6 mg, 314 μmol, 54.8 μL)。100℃下反應3小時。將反應液濃縮, 加入飽和碳酸氫鈉溶液(10 mL)，乙酸乙酯(30 mL)萃取三次, 飽和食鹽水(20 mL)洗滌，無水硫酸鈉乾燥，濃縮，通過反相高效液相色譜法分離純化（色譜柱：YMC-Actus Triart C18 150*30mm*7μm；流動相：A = 水+FA(0.05%)），B = 乙腈；梯度：33% - 63%，10分鐘），得化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基)- 5,5-二氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (化合物9) (18.0 mg,，產率56.8%)。LC-MS, M/Z (ESI): 479.2 (M+H)。 1H NMR (400 MHz, DMSO- d 6) δ = 8.86 (s, 2H), 6.68 (s, 1H), 4.95 (br m, 1H), 4.66 (br d, 2H), 3.68 (br d, 2H), 3.39-3.45 (m, 3H), 3.19 (br m, 2H), 3.05 (br m, 2H), 2.26-2.36 (m, 2H), 2.17-2.24 (m, 2H), 2.12 (br s, 2H), 1.97 (br d, 2H), 1.73-1.85 (m, 2H), 1.62 (br m, 2H). Step 2: Synthesis of 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (Compound 9) 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (9-2) (20.0 mg, 62.9 μmol) was dissolved in 1,4-dioxane (10 mL), and 5-chloro-2-(4-piperidinyl)pyrimidine (12.4 mg, 62.9 μmol) and N,N-diisopropylethylamine (40.6 mg, 314 μmol, 54.8 μL) were added. The mixture was reacted at 100°C for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution (10 mL) was added, and ethyl acetate (30 mL) was used for extraction three times, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by reversed-phase high performance liquid chromatography (chromatographic column: YMC-Actus Triart C18 150*30mm*7μm; mobile phase: A = water + FA (0.05%), B = acetonitrile; gradient: 33% - 63%, 10 minutes) to obtain compound 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (Compound 9) (18.0 mg, yield 56.8%). LC-MS, M/Z (ESI): 479.2 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.86 (s, 2H), 6.68 (s, 1H), 4.95 (br m, 1H), 4.66 (br d, 2H), 3.68 (br d, 2H), 3.39-3.45 (m, 3H), 3.19 (br m, 2H), 3.05 (br m, 2H), 2.26-2.36 (m, 2H), 2.17-2.24 (m, 2H), 2.12 (br s, 2H), 1.97 (br d, 2H), 1.73-1.85 (m, 2H), 1.62 (br m, 2H).

實施例4：目標化合物10-P1-A&10-P1-B&10-P2-A&10-P2-B的製備 (S)&(R)-2-((S) &(R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 （10--P1-A&10-P1-B&10-P2-A&10-P2-B) 目標化合物10-P1-A&10-P1-B&10-P2-A&10-P2-B的合成路線如下所示： Example 4: Preparation of target compound 10-P1-A & 10-P1-B & 10-P2-A & 10-P2-B (S & (R)-2-((S) & (R)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10--P1-A & 10-P1-B & 10-P2-A & 10-P2-B) The synthetic routes of the target compounds 10-P1-A & 10-P1-B & 10-P2-A & 10-P2-B are as follows:

第一步：三級-丁基 3-(5-氯嘧啶-2-基)-2,5-二氫-1H-吡咯-1-甲酸基酯(10-2)的合成 將三級-丁基 3-(4,4,5,5-四甲基-1,3,2-二㗁硼戊環-2-基)-2,5-二氫吡咯-1-甲酸基酯(10-1) (13.0 g, 44.0 mmol)和5-氯-2-碘嘧啶(10.0 g, 41.8 mmol)溶解在1,4-二氧己環(200 mL)和水(40 mL)中，再將碳酸鉀(18.2 g, 132 mmol)和[1,1'-二(二苯基膦基)二茂鐵]二氯鈀(II)( 3.22 g, 4.40 mmol)加入反應液中。緩慢升溫至90 ℃，反應2個小時。將反應液矽藻土過濾，濃縮，拌樣。矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=50/1-10/1)得到黃色固體產物三級-丁基 3-(5-氯嘧啶-2-基)-2,5-二氫-1H-吡咯-1-甲酸基酯(10-2) (11.0 g , 產率 88.6%)。 Step 1: Synthesis of tertiary butyl 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10-2) Dissolve tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-2,5-dihydropyrrole-1-carboxylate (10-1) (13.0 g, 44.0 mmol) and 5-chloro-2-iodopyrimidine (10.0 g, 41.8 mmol) in 1,4-dioxane (200 mL) and water (40 mL), then add potassium carbonate (18.2 g, 132 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (3.22 g, 4.40 mmol) to the reaction solution. Slowly raise the temperature to 90 °C and react for 2 hours. Filter the reaction solution through diatomaceous earth, concentrate, and stir. Silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) = 50/1-10/1) gave a yellow solid product, tert-butyl 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10-2) (11.0 g, yield 88.6%).

第二步：三級-丁基 3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3)的合成 將三級-丁基 3-(5-氯嘧啶-2-基)-2,5-二氫-1H-吡咯-1-甲酸基酯(10-2) (9.34 g, 33.1 mmol)溶於無水甲醇(200 mL)中，在惰性氣體保護下加入三(三苯基膦)氯化銠(I) (3.07 g, 3.32 mmol) 氬氣置換，通入氫氣在50 ℃，50 Psi條件下反應24小時。將反應液濃縮拌樣, 矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=1/0-5/1) 褐色固體產物三級-丁基 3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3) (9.41 g, 產率99.7 %) Step 2: Synthesis of tertiary butyl 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylate (10-3) Dissolve tert-butyl 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10-2) (9.34 g, 33.1 mmol) in anhydrous methanol (200 mL). Add tris(triphenylphosphine)rhodium(I) chloride (3.07 g, 3.32 mmol) under inert gas protection. Replace with hydrogen and introduce hydrogen at 50 °C, 50 Psi for 24 hours. The reaction solution was concentrated and stirred, and then separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1). The brown solid product was tert-butyl 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylate (10-3) (9.41 g, yield 99.7%).

第三步：5-氯-2-(吡咯烷-3-基)嘧啶鹽酸鹽(10-4)的合成 將三級-丁基 3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3) (4.00 g, 18.6 mmol)溶解在無水二氧六環(30 mL)中，緩慢將二氧六環鹽酸氣(4 mol/L, 6 mL)滴加至反應液中，25℃反應1小時。將反應液濃縮得褐色固體產物5-氯-2-(吡咯烷-3-基)嘧啶鹽酸鹽(10-4) (3.08 g, 產率96.9%)。 Step 3: Synthesis of 5-chloro-2-(pyrrolidin-3-yl)pyrimidine hydrochloride (10-4) Dissolve tert-butyl 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylate (10-3) (4.00 g, 18.6 mmol) in anhydrous dioxane (30 mL), slowly add dioxane hydrochloric acid gas (4 mol/L, 6 mL) dropwise to the reaction solution, and react at 25°C for 1 hour. Concentrate the reaction solution to obtain a brown solid product, 5-chloro-2-(pyrrolidin-3-yl)pyrimidine hydrochloride (10-4) (3.08 g, yield 96.9%).

第四步：(5R)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (10-P1)的合成 將5-氯-2-(吡咯烷-3-基)嘧啶鹽酸鹽(10-4) (77.2 mg, 347 μmol) 和(R)-2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化 (100 mg, 331 μmol)溶解在無水二氧六環(10.0 mL)中，氮氣置換，在90℃下反應3小時。將反應液濃用飽和的氯化銨溶液(30 mL)稀釋，乙酸乙酯(120 mL)萃取四次，飽和食鹽水(100 mL)洗滌，無水硫酸鈉乾燥，濃縮。矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到化合物(5R)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P1) (110 mg, 產率72.7 %).LC-MS, M/Z (ESI): 449.2 (M+H) Step 4: Synthesis of (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P1) 5-Chloro-2-(pyrrolidin-3-yl)pyrimidine hydrochloride (10-4) (77.2 mg, 347 μmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (100 mg, 331 μmol) were dissolved in anhydrous dioxane (10.0 mL), replaced with nitrogen, and reacted at 90°C for 3 hours. The reaction solution was diluted with saturated ammonium chloride solution (30 mL), extracted four times with ethyl acetate (120 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Silica gel separation and purification (dichloromethane: methanol (V/V) = 10/1) gave compound (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P1) (110 mg, yield 72.7 %). LC-MS, M/Z (ESI): 449.2 (M+H)

第五步：(R)-2-((S&R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P1-A&10-P1-B)的合成 將外消旋體(5R)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(110 mg, 240 μmol )(10-P1)通過正相高效液相色譜法進行手性分離，分離方法為(色譜柱：DAICEL CHIRALPAK IG (250mm*30mm,10μm)；流動相：A = 二氧化碳-乙腈，B =異丙醇+氨水(0.1%)；B=55%等梯度洗脫，6.6分鐘）濃縮，得到 (R)-2-((S)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P1-A，保留時間：1.337 min) (30 mg, 收率27.6%)。LC-MS, M/Z (ESI): 449.2 (M+H)。 1H NMR (400 MHz, DMSO-d 6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.91 (br s, 1H), 3.87-4.02 (m, 1H), 3.48-3.81 (m, 6H), 3.02-3.10 (m, 1H), 2.84-2.94 (m, 1H), 2.62-2.68 (m, 1H), 2.56 (br s, 1H), 2.39 (br d, 4H), 2.18-2.26 (m, 1H), 2.11 (br d, 2H), 1.91-1.99 (m, 1H), 1.68-1.85 (m, 2H). (R)-2-((R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P1-B，保留時間：1.683 min) (30 mg, 收率27.6% )。LC-MS, M/Z (ESI): 449.2 (M+H)。 1H NMR (400 MHz , DMSO-d 6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.99 (br s, 1H), 3.89-4.01 (m, 1H), 3.77 (s, 2H), 3.70 (br s, 2H), 3.60-3.67 (m, 1H), 3.50-3.60 (m, 1H), 3.06 (br m, 1H), 2.84-2.94 (m, 1H), 2.63-2.68 (m, 1H), 2.58 (br d, 1H), 2.31-2.44 (m, 4H), 2.18-2.27 (m, 1H), 2.10 (br s, 2H), 1.96 (br d, 1H), 1.71 (br s, 2H). Step 5: Synthesis of (R)-2-((S&R)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P1-A&10-P1-B) The racemic (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (110 mg, 240 μmol) (10-P1) was chirally separated by normal phase HPLC (chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A = carbon dioxide-acetonitrile, B = isopropanol + ammonia (0.1%); B = 55% isocratic elution, 6.6 minutes) to give (R)-2-((S)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)- 5-Oxidation-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (10-P1-A, retention time: 1.337 min) (30 mg, yield 27.6%). LC-MS, M/Z (ESI): 449.2 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.91 (br s, 1H), 3.87-4.02 (m, 1H), 3.48-3.81 (m, 6H), 3.02-3.10 (m, 1H), 2.84-2.94 (m, 1H), 2.62-2.68 (m, 1H), 2.56 (br s, 1H), 2.39 (br d, 4H), 2.18-2.26 (m, 1H), 2.11 (br d, 2H), 1.91-1.99 (m, 1H), 1.68-1.85 (m, 2H). (R)-2-((R)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P1-B, retention time: 1.683 min) (30 mg, yield 27.6%). LC-MS, M/Z (ESI): 449.2 (M+H). 1 H NMR (400 MHz , DMSO-d 6 ) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.99 (br s, 1H), 3.89-4.01 (m, 1H), 3.77 (s, 2H), 3.70 (br s, 2H), 3.60-3.67 (m, 1H), 3.50-3.60 (m, 1H), 3.06 (br m, 1H), 2.84-2.94 (m, 1H), 2.63-2.68 (m, 1H), 2.58 (br d, 1H), 2.31-2.44 (m, 4H), 2.18-2.27 (m, 1H), 2.10 (br s, 2H), 1.96 (br d, 1H), 1.71 (br s, 2H).

第四步：(5S)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P2)的合成 將5-氯-2-(吡咯烷-3-基)嘧啶鹽酸鹽(10-4) (77.2 mg, 347 μmol) 和(R)-2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化 (100 mg, 331 μmol)溶解在無水二氧六環(10.0 mL)中，氮氣置換，在90℃下反應3小時。將反應液用飽和的氯化銨溶液(30 mL)稀釋，乙酸乙酯(120 mL)萃取四次，飽和食鹽水(100 mL)洗滌，無水硫酸鈉乾燥，濃縮。矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到化合物(5S)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P2) (110 mg, 產率72.7 %)。LC-MS, M/Z (ESI): 449.2 (M+H). Step 4: Synthesis of (5S)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P2) 5-Chloro-2-(pyrrolidin-3-yl)pyrimidine hydrochloride (10-4) (77.2 mg, 347 μmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (100 mg, 331 μmol) were dissolved in anhydrous dioxane (10.0 mL), replaced with nitrogen, and reacted at 90°C for 3 hours. The reaction solution was diluted with saturated ammonium chloride solution (30 mL), extracted four times with ethyl acetate (120 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Silica gel separation and purification (dichloromethane: methanol (V/V) = 10/1) gave compound (5S)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P2) (110 mg, yield 72.7 %). LC-MS, M/Z (ESI): 449.2 (M+H).

第五步：(S)-2-((S&R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P2-A&10-P2-B)的合成 將外消旋體(5S)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)-4 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(110 mg, 240 μmol )(10-P2)通過正相高效液相色譜法進行手性分離，分離方法為(色譜柱：DAICEL CHIRALPAK IG (250mm*30mm,10μm)；流動相：A = 二氧化碳-乙腈，B =異丙醇+氨水(0.1%)；B=55%等梯度洗脫，6.6分鐘）濃縮，得到 (S)-2-((S)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P2-A, 保留時間：1.589 min) (35.0 mg, 收率31.8% )。LC-MS, M/Z (ESI): 449.3 (M+H)。1H NMR (400 MHz , DMSO-d6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.92 (br s, 1H), 3.93 (br s, 1H), 3.77 (br d, 2H), 3.70 (br s, 2H), 3.59-3.66 (m, 1H), 3.50-3.59 (m, 1H), 3.00-3.11 (m, 1H), 2.84-2.94 (m, 1H), 2.62-2.68 (m, 1H), 2.53-2.60 (m, 1H), 2.31-2.46 (m, 4H), 2.16-2.26 (m, 1H), 2.10 (br s, 2H), 1.91-1.98 (m, 1H), 1.66-1.87 (m, 2H). (S)-2-((R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)- 5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(10-P2-B, 保留時間：2.074 min) (45.0 mg, 收率40.9%)。(10-P2-B):LC-MS, M/Z (ESI): 449.3 (M+H)。1H NMR (400 MHz , DMSO-d6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.94 (br d, 1H), 3.87-4.03 (m, 1H), 3.72-3.83 (m, 2H), 3.67-3.71 (m, 2H), 3.57 (br s, 2H), 3.02-3.09 (m, 1H), 2.84-2.94 (m, 1H), 2.61-2.69 (m, 1H), 2.56 (br m, 1H), 2.31-2.47 (m, 4H), 2.18-2.25 (m, 1H), 2.05-2.14 (m, 2H), 1.90-1.98 (m, 1H), 1.70-1.84 (m, 2H). Step 5: Synthesis of (S)-2-((S&R)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P2-A&10-P2-B) The racemic (5S)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-4-(5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (110 mg, 240 μmol) (10-P2) was chirally separated by normal phase HPLC (chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm,10μm); mobile phase: A = carbon dioxide-acetonitrile, B = = isopropanol + ammonia water (0.1%); B = 55% isocratic elution, 6.6 minutes) to obtain (S)-2-((S)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P2-A, retention time: 1.589 min) (35.0 mg, yield 31.8%). LC-MS, M/Z (ESI): 449.3 (M+H). 1H NMR (400 MHz , DMSO-d6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.92 (br s, 1H), 3.93 (br s, 1H), 3.77 (br d, 2H), 3.70 (br s, 2H), 3.59-3.66 (m, 1H), 3.50-3.59 (m, 1H), 3.00-3.11 (m, 1H), 2.84-2.94 (m, 1H), 2.62-2.68 (m, 1H), 2.53-2.60 (m, 1H), 2.31-2.46 (m, 4H), 2.16-2.26 (m, 1H), 2.10 (br s, 2H), 1.91-1.98 (m, 1H), 1.66-1.87 (m, 2H). (S)-2-((R)-3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (10-P2-B, retention time: 2.074 min) (45.0 mg, yield 40.9%). (10-P2-B): LC-MS, M/Z (ESI): 449.3 (M+H). 1H NMR (400 MHz , DMSO-d6) δ: 8.90 (s, 2H), 6.46 (s, 1H), 4.94 (br d, 1H), 3.87-4.03 (m, 1H), 3.72-3.83 (m, 2H), 3.67-3.71 (m, 2H), 3.57 (br s, 2H), 3.02-3.09 (m, 1H), 2.84-2.94 (m, 1H), 2.61-2.69 (m, 1H), 2.56 (br m, 1H), 2.31-2.47 (m, 4H), 2.18-2.25 (m, 1H), 2.05-2.14 (m, 2H), 1.90-1.98 (m, 1H), 1.70-1.84 (m, 2H).

實施例5：目標化合物11-P1&11-P2的製備 (R) or (S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇（目標化合物11-P1&11-P2） 目標化合物11-P1&11-P2的合成路線如下所示： Example 5: Preparation of target compound 11-P1 & 11-P2 (R) or (S)-2-(3-(5-chloropyrimidin-2-yl)azetidine-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (target compound 11-P1 & 11-P2) The synthetic routes of target compounds 11-P1 & 11-P2 are as follows:

第一步：中間體(R) or (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(AA)的合成 將外消旋體化合物2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(1-7) (1.00 g, 3.31 mmol)通過正相高效液相色譜法進行手性分離，分離方法為（色譜柱：DAICEL CHIRALPAK IC(250mm*30mm,10um；流動相：A = 二氧化碳，B = 氨水(0.1%)+乙醇；梯度：50% - 50%，25分鐘），濃縮旋乾，得到化合物(R) or (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶5-氧化(AA，保留時間：1.423 min) (480 mg, 產率45.8%)，LC-MS, M/Z (ESI) : 302.1 (M+H). 1H NMR (400 MHz, DMSO- d 6) δ = 7.61 (br d, 1H), 4.93 (br s, 1H), 3.68 (s, 2H), 3.01-3.25 (m, 2H), 2.62-2.85 (m, 2H), 2.11-2.38 (m, 5H), 1.99-2.06 (m, 1H), 1.66-1.91 (m, 2H) (R) or (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶5-氧化(AB，保留時間：1.794 min) (540 mg, 產率51.3%)。LC-MS, M/Z (ESI) : 302.1 (M+H). 1H NMR (400 MHz, DMSO- d 6) δ = 7.61 (br s, 1H), 4.95 (br d, 1H), 3.68 (s, 2H), 3.02-3.24 (m, 2H), 2.61-2.86 (m, 2H), 2.13-2.35 (m, 5H), 2.02 (m, 1H), 1.68-1.87 (m, 2H). Step 1: Synthesis of the intermediate (R) or (S) -2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AA) The racemic compound 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7) (1.00 g, 3.31 mmol) was subjected to chiral separation by normal phase HPLC (chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10um; mobile phase: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 25 minutes), concentrated and vortexed to obtain compound (R) or (S) -2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AA, retention time: 1.423 min) (480 mg, yield 45.8%), LC-MS, M/Z (ESI): 302.1 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.61 (br d, 1H), 4.93 (br s, 1H), 3.68 (s, 2H), 3.01-3.25 (m, 2H), 2.62-2.85 (m, 2H), 2.11-2.38 (m, 5H), 1.99-2.06 (m, 1H), 1.66-1.91 (m, 2H) (R) or (S) -2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AB, retention time: 1.794 min) (540 mg, yield 51.3%). LC-MS, M/Z (ESI) : 302.1 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.61 (br s, 1H), 4.95 (br d, 1H), 3.68 (s, 2H), 3.02-3.24 (m, 2H), 2.61-2.86 (m, 2H), 2.13-2.35 (m, 5H), 2.02 (m, 1H), 1.68-1.87 (m, 2H).

第二步：三級-丁基 3-(5-氯嘧啶-2-基)吖丁啶-1-甲酸基酯(11-2)的合成 將鋅粉(3.46 g, 52.9 mmol)和1,2-二溴乙烷(663 mg, 3.53 mmol, 266 μL)加入到無水四氫呋喃(200 mL) 中，置換氮氣三次，加熱到66℃回流1小時。冷卻至25℃，用注射器加入三甲基氯矽烷(383 mg, 3.53 mmol, 448 μL)， 25℃攪拌1小時。加入3-碘吖丁啶-1-甲酸基酯(10.0 g, 35.3 mmol)的四氫呋喃(20 mL) 溶液，加熱至60℃攪拌1小時，然後冷卻至25℃。加入5-氯-2-碘-嘧啶(9.93 g, 41.3 mmol)和四(三苯基膦)鈀(3.98 g, 3.44 mmol)， 置換氮氣三次，加熱到60℃回流1小時, 冷卻至25℃攪拌8小時。將反應液用矽藻土過濾,濃縮拌樣。使用矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=1/0-5/1)得到黃色固體產物三級-丁基 3-(5-氯嘧啶-2-基)吖丁啶-1-甲酸基酯(11-2)(2.00 g, 產率16.2 %)。 Step 2: Synthesis of tertiary butyl 3-(5-chloropyrimidin-2-yl)azetidine-1-carboxylate (11-2) Zinc powder (3.46 g, 52.9 mmol) and 1,2-dibromoethane (663 mg, 3.53 mmol, 266 μL) were added to anhydrous tetrahydrofuran (200 mL), the atmosphere was replaced with nitrogen three times, and the mixture was heated to 66°C and refluxed for 1 hour. The mixture was cooled to 25°C, trimethylsilyl chloride (383 mg, 3.53 mmol, 448 μL) was added with a syringe, and the mixture was stirred at 25°C for 1 hour. A solution of 3-iodoazetidine-1-carboxylate (10.0 g, 35.3 mmol) in tetrahydrofuran (20 mL) was added, the mixture was heated to 60°C and stirred for 1 hour, and then the mixture was cooled to 25°C. Add 5-chloro-2-iodo-pyrimidine (9.93 g, 41.3 mmol) and tetrakis(triphenylphosphine)palladium (3.98 g, 3.44 mmol), replace nitrogen three times, heat to 60°C and reflux for 1 hour, cool to 25°C and stir for 8 hours. Filter the reaction solution with diatomaceous earth, concentrate and stir. Use silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain a yellow solid product tertiary-butyl 3-(5-chloropyrimidin-2-yl)azetidine-1-carboxylate (11-2) (2.00 g, yield 16.2%).

第三步：2-(吖丁啶-3-基)-5-氯嘧啶(11-3)的合成 將三級-丁基 (2R)-4-(5-氯嘧啶-2-基)-2-甲基哌啶-1-甲酸基酯(11-2)( 800 mg, 2.97 mmol)溶解在二氯甲烷(10 mL)和三氟乙酸(3 mL)中，在25 ℃反應1小時。將反應液體濃縮拌樣, 矽膠柱分離純化(二氯甲烷:甲醇(V/V)=1/0-10/1)，得到黃色固體化合物2-(吖丁啶-3-基)-5-氯嘧啶(11-3) (1.20 g, 產率95.6 %)。 Step 3: Synthesis of 2-(azetidine-3-yl)-5-chloropyrimidine (11-3) Tert-butyl (2R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (11-2) (800 mg, 2.97 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 25 °C for 1 hour. The reaction liquid was concentrated and stirred, and then separated and purified by silica gel column (dichloromethane: methanol (V/V) = 1/0-10/1) to obtain a yellow solid compound 2-(azetidin-3-yl)-5-chloropyrimidine (11-3) (1.20 g, yield 95.6 %).

第四步：(R) or (S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (11-P1)的合成 將到2-(吖丁啶-3-基)-5-氯嘧啶(3)( 85.3 mg, 189 μmol)和(R) or (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(AA) (50.0 mg, 158 μmol)溶解在1,4-二氧己環(10 mL)中，加入N,N-二異丙基乙胺(102 mg, 790 μmol, 137 μL)，然後緩慢升至90℃，反應3小時。將反應液倒加入飽和碳酸氫鈉溶液(30 mL)，用乙酸乙酯(30 mL)萃取3次，飽和食鹽水(30 mL)洗滌，硫酸鈉乾燥，濃縮，通過反相高效液相色譜法進行分離（色譜柱：Waters Xbridge 150*25mm* 5μm；流動相：A = 水+氨水(0.1%)，B = 乙腈；梯度：13% -43%，8分鐘）得到 (R) or (S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (11-P1，保留時間：1.286min) (40.0 mg，產率58.4 %)。LC-MS, M/Z : 435.2 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ= 8.68 (s, 2H), 6.04-6.52 (m, 1H), 4.99-5.54 (m, 1H), 4.28-4.67 (m, 4H), 4.04-4.24 (m, 1H), 3.86 (br s, 2H), 3.21 (br m, 1H), 2.75-3.05 (m, 2H), 2.41-2.74 (m, 2H), 2.28-2.40 (m, 2H), 2.04-2.24 (m, 3H), 1.79-2.03 (m, 2H). Step 4: Synthesis of (R) or (S)-2-(3-(5-chloropyrimidin-2-yl)azetidine-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (11-P1) 2-(Azetidin-3-yl)-5-chloropyrimidine (3) (85.3 mg, 189 μmol) and (R) or (S) -2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AA) (50.0 mg, 158 μmol) were dissolved in 1,4-dioxane (10 mL), N,N-diisopropylethylamine (102 mg, 790 μmol, 137 μL) was added, and then the temperature was slowly raised to 90°C and reacted for 3 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (30 mL), extracted three times with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over sodium sulfate, concentrated, and separated by reverse phase high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: A = water + ammonia water (0.1%), B = acetonitrile; gradient: 13%-43%, 8 minutes) to obtain (R) or (S)-2-(3-(5-chloropyrimidin-2-yl)azetidine-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (11-P1, retention time: 1.286min) (40.0 mg, 58.4 % yield). LC-MS, M/Z : 435.2 (M+H). 1 H NMR (400 MHz, CHLOROFORM-d) δ= 8.68 (s, 2H), 6.04-6.52 (m, 1H), 4.99-5.54 (m, 1H), 4.28-4.67 (m, 4H), 4.04-4.24 (m, 1H), 3.86 (br s, 2H), 3.21 (br m, 1H), 2.75-3.05 (m, 2H), 2.41-2.74 (m, 2H), 2.28-2.40 (m, 2H), 2.04-2.24 (m, 3H), 1.79-2.03 (m, 2H).

第五步：(R) or (S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (11-P2)的合成 將到2-(吖丁啶-3-基)-5-氯嘧啶(11-3)( 85.3 mg, 189 μmol)和(R) or (S) -2-氯-4-((1-(羥甲基)環丁基)胺基)-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶 5-氧化(AB) (50.0 mg, 158 μmol)溶解在1,4-二氧己環(10 mL)中，加入N,N-二異丙基乙胺(102 mg, 790 μmol, 137 μL)，然後緩慢升至90℃，反應3小時。將反應液倒加入飽和碳酸氫鈉溶液(30ml)，用乙酸乙酯(30 mL)萃取3次，飽和食鹽水(30ml)洗滌，硫酸鈉乾燥，濃縮，通過反相高效液相色譜法進行分離（色譜柱：Waters Xbridge 150*25mm* 5μm；流動相：A = 水+氨水(0.1%)，B = 乙腈；梯度：13% -43%，8分鐘）得到 (R) or (S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(11-P2，保留時間：1.263min) (40.0 mg，產率58.4 %)。LC-MS, M/Z : 435.2 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ= 8.68 (s, 2H), 6.24 (br s, 1H), 5.29 (br d, 1H), 4.30-4.66 (m, 4H), 4.08-4.24 (m, 1H), 3.86 (br s, 2H), 3.21 (br m, 1H), 2.78-3.01 (m, 2H), 2.46-2.67 (m, 2H), 2.29-2.41 (m, 2H), 2.04-2.24 (m, 3H), 1.79-2.02 (m, 2H). Step 5: Synthesis of (R) or (S)-2-(3-(5-chloropyrimidin-2-yl)azetidine-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (11-P2) 2-(Azetidin-3-yl)-5-chloropyrimidine (11-3) (85.3 mg, 189 μmol) and (R) or (S) -2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AB) (50.0 mg, 158 μmol) were dissolved in 1,4-dioxane (10 mL), N,N-diisopropylethylamine (102 mg, 790 μmol, 137 μL) was added, and then the temperature was slowly raised to 90°C and reacted for 3 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (30 ml), extracted with ethyl acetate (30 mL) three times, washed with saturated brine (30 ml), dried over sodium sulfate, concentrated, and separated by reversed-phase high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25 mm* 5 μm; mobile phase: A = water + ammonia water (0.1%), B = acetonitrile; gradient: 13% -43%, 8 minutes) to obtain (R) or (S)-2-(3-(5-chloropyrimidin-2-yl)azetidine-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (11-P2, retention time: 1.263 min) (40.0 mg, 58.4 % yield). LC-MS, M/Z : 435.2 (M+H). 1 H NMR (400 MHz, CHLOROFORM-d) δ= 8.68 (s, 2H), 6.24 (br s, 1H), 5.29 (br d, 1H), 4.30-4.66 (m, 4H), 4.08-4.24 (m, 1H), 3.86 (br s, 2H), 3.21 (br m, 1H), 2.78-3.01 (m, 2H), 2.46-2.67 (m, 2H), 2.29-2.41 (m, 2H), 2.04-2.24 (m, 3H), 1.79-2.02 (m, 2H).

實施例6：目標化合物3的製備 2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇 (目標化合物3) 目標化合物3的合成路線如下所示： Example 6: Preparation of Target Compound 3 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (Target Compound 3) The synthetic route of target compound 3 is as follows:

第一步：甲基 3-((2-甲氧基-2-氧亞基乙基)硫代)丁酯(3-2)的合成 將甲基 2-巰基醋酸鹽(3-1) (9.80 g, 92.3 mmol, 8.38 mL)和哌啶(235 mg, 2.77 mmol, 273 uL)冷卻至0 ℃,逐滴加入甲基 (E)-丁-2-烯酯(11.1 g, 111 mmol, 11.8 mL)，30分鐘後分兩批次加入哌啶(157 mg, 1.85 mmol, 182 uL)，20 ℃反應11.5小時。將反應液倒入甲基三級丁基醚 (100 mL) 和1 N 稀鹽酸(100 mL)中，再用乙酸乙酯(300 mL)萃取3次，合併有機相用飽和食鹽水(300 mL)洗滌，無水硫酸鈉乾燥，濃縮得到黃色油狀產物甲基 3-((2-甲氧基-2-氧亞基乙基)硫代)丁酯(3-2) (20.0 g, 收率98.7%)。 Step 1: Synthesis of methyl 3-((2-methoxy-2-oxyylideneethyl)thio)butyl ester (3-2) Methyl 2-butyl acetate (3-1) (9.80 g, 92.3 mmol, 8.38 mL) and piperidine (235 mg, 2.77 mmol, 273 uL) were cooled to 0 °C, and methyl (E)-but-2-enyl ester (11.1 g, 111 mmol, 11.8 mL) was added dropwise. After 30 minutes, piperidine (157 mg, 1.85 mmol, 182 uL) was added in two batches. The reaction was continued at 20 °C for 11.5 hours. The reaction solution was poured into methyl tertiary butyl ether (100 mL) and 1 N dilute hydrochloric acid (100 mL), and then extracted with ethyl acetate (300 mL) three times. The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily product, methyl 3-((2-methoxy-2-oxyylideneethyl)thio)butyl ester (3-2) (20.0 g, yield 98.7%).

第二步：甲基 5-甲基-3-氧亞基四氫噻吩-2-甲酸基酯(3-3)的合成 將甲基 3-((2-甲氧基-2-氧亞基乙基)硫代)丁酯(3-2) (5.01 g, 23.0 mmol)溶解在甲苯（110 mL）中，加入甲醇鈉(1.50 g, 27.6 mmol)，升至105 ℃反應3小時。將反應液倒入冷的12 N 濃鹽酸中(10 mL)中,再用乙酸乙酯(90 mL)萃取3次，合併有機相用飽和食鹽水(100 mL)洗滌，無水硫酸鈉乾燥，濃縮拌樣, 矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=1/0-5/1)得到黃色油狀產物甲基 5-甲基-3-氧亞基四氫噻吩-2-甲酸基酯(3-3) (3.00 g, 收率74.6%)。 Step 2: Synthesis of methyl 5-methyl-3-oxyylidene tetrahydrothiophene-2-carboxylate (3-3) Methyl 3-((2-methoxy-2-oxyylideneethyl)thio)butyl ester (3-2) (5.01 g, 23.0 mmol) was dissolved in toluene (110 mL), sodium methoxide (1.50 g, 27.6 mmol) was added, and the temperature was raised to 105 °C for 3 hours. The reaction solution was poured into cold 12 N concentrated hydrochloric acid (10 mL), and then extracted with ethyl acetate (90 mL) three times. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated and stirred, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain a yellow oily product methyl 5-methyl-3-oxyylidene tetrahydrothiophene-2-carboxylate (3-3) (3.00 g, yield 74.6%).

第三步：6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-2,4-二酚(3-4)的合成 將甲基 5-甲基-3-氧亞基四氫噻吩-2-甲酸基酯(3-3) (1.90 g, 10.9 mmol)溶於無水乙醇(20 mL)中，加入尿素 (654 mg, 10.9 mmol)和甲醇鈉(2.95 g, 54.5 mmol)，80℃反應15小時。將反應液倒入冰水(40 mL)和冰醋酸(2 mL)中，過濾收集析出沉澱物，得到白色固體6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-2,4-二酚(3-4)(3.00 g, 直接用於下一步)。 Step 3: Synthesis of 6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (3-4) Dissolve methyl 5-methyl-3-oxyylidene tetrahydrothiophene-2-carboxylate (3-3) (1.90 g, 10.9 mmol) in anhydrous ethanol (20 mL), add urea (654 mg, 10.9 mmol) and sodium methoxide (2.95 g, 54.5 mmol), and react at 80°C for 15 hours. Pour the reaction solution into ice water (40 mL) and glacial acetic acid (2 mL), and collect the precipitate by filtration to obtain white solid 6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (3-4) (3.00 g, used directly in the next step).

第四步：2,4-二氯-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶(3-5)的合成 將6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-2,4-二酚(3-4) (300 mg, 1.42 mmol) 和N,N-二甲基苯胺(171 mg, 1.42 mmol, 179 μL)溶解在三氯氧磷（1.09 g, 7.08 mmol, 660 μL）中，氮氣置換，在90℃下反應3小時。將反應液濃用二氯甲烷(10 mL)稀釋，小心倒入水(100 mL)中淬滅，二氯甲烷(90 mL)萃取三次，飽和食鹽水(30 mL)洗滌，無水硫酸鈉乾燥，濃縮拌樣，矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=1/0-10/1)得到黃色固體化合物2,4-二氯-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶(3-5) (250 mg, 產率71.8 %)。 Step 4: Synthesis of 2,4-dichloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine (3-5) 6-Methyl-6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (3-4) (300 mg, 1.42 mmol) and N,N-dimethylaniline (171 mg, 1.42 mmol, 179 μL) were dissolved in phosphorus oxychloride (1.09 g, 7.08 mmol, 660 μL), replaced with nitrogen, and reacted at 90°C for 3 hours. The reaction solution was diluted with dichloromethane (10 mL), carefully poured into water (100 mL) for quenching, extracted with dichloromethane (90 mL) three times, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated and stirred, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) to obtain a yellow solid compound 2,4-dichloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine (3-5) (250 mg, yield 71.8 %).

第五步：(1-((2-氯-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇（3-6）的合成 將2,4-二氯-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶(3-5)(200 mg, 814 μmol)和(1-胺基環丁基)甲醇鹽酸鹽(134 mg, 976 μmol)溶解在乙腈(10 mL)中，加入三乙胺(411 mg, 4.07 mmol, 566 μL )。80℃反應10小時。將反應液用水(40 mL)稀釋，乙酸乙酯(120 mL)萃取三次，飽和食鹽水洗滌(50 mL)，無水硫酸鈉乾燥，濃縮，矽膠柱分離純化(石油醚:乙酸乙酯(V/V)=5/1-1/1)得到黃色固體化合物 (1-((2-氯-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇(3-6) (150 mg, 產率60.3%)。 Step 5: Synthesis of (1-((2-chloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3-6) Dissolve 2,4-dichloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine (3-5) (200 mg, 814 μmol) and (1-aminocyclobutyl)methoxide hydrochloride (134 mg, 976 μmol) in acetonitrile (10 mL), add triethylamine (411 mg, 4.07 mmol, 566 μL), and react at 80°C for 10 hours. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (120 mL) three times, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (petroleum ether:ethyl acetate (V/V) = 5/1-1/1) to obtain a yellow solid compound (1-((2-chloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3-6) (150 mg, yield 60.3%).

第六步：2-氯-4-((1-(羥甲基)環丁基)胺基)-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶 5-氧化（3-7）的合成 將(1-((2-氯-7,8-二氫-6H-硫代吡喃並[3,2-d]嘧啶-4-基)胺基)環丁基)甲醇(3-6) (125 mg, 433 μmol)和S-(-)-1,1'-聯-2-萘酚(2.40 mg, 43.3 μmol)溶解在二氯甲烷（10 mL)中，再加入四異丙氧化鈦(6.15 mg, 21.6 μmol, 6.39 μL)和水(7.80 mg, 433 μmol, 7.80 μL)，加完後置換氮氣，20℃反應1小時。再加入過氧三級丁醇(58.5 mg, 454 μmol, 62.2 μL, 70% 純度)，25℃反應1.5小時。將反應液用10%亞硫酸鈉水溶液(10 mL)淬滅，二氯甲烷(90 mL)萃取三次，合併有機相用水(50 mL)洗滌，無水硫酸鈉乾燥，濃縮，矽膠板分離純化(二氯甲烷:甲醇(V/V)=10/1)得到黃色固體化合物2-氯-4-((1-(羥甲基)環丁基)胺基)-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶 5-氧化(3-7) (90.0 mg, 產率67.6%)。 Step 6: Synthesis of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (3-7) Dissolve (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3-6) (125 mg, 433 μmol) and S-(-)-1,1'-bi-2-naphthol (2.40 mg, 43.3 μmol) in dichloromethane (10 mL), add titanium tetraisopropoxide (6.15 mg, 21.6 μmol, 6.39 μL) and water (7.80 mg, 433 μmol, 7.80 μL), replace nitrogen after addition, and react at 20℃ for 1 hour. Then add tert-butyl peroxide (58.5 mg, 454 μmol, 62.2 μL, 70% purity) and react at 25℃ for 1.5 hours. The reaction solution was quenched with 10% sodium sulfite aqueous solution (10 mL), extracted three times with dichloromethane (90 mL), and the combined organic phases were washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel separation (dichloromethane: methanol (V/V) = 10/1) to obtain a yellow solid compound 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (3-7) (90.0 mg, yield 67.6%).

第七步：2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(目標化合物3)的合成 將2-氯-4-((1-(羥甲基)環丁基)胺基)-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶 5-氧化(3-7) (80.0 mg, 260 μmol) 溶解在1,4-二氧六環(10 mL)中，加入5-氯-2-(4-哌啶基)嘧啶(77.1 mg, 390 μmol)和N,N-二異丙基乙胺(100 mg, 780 μmol, 135 μL)。80℃下反應3小時。將反應液濃縮, 加入飽和碳酸氫鈉溶液(20 mL)，乙酸乙酯(60 mL)萃取三次, 飽和食鹽水(40 mL)洗滌，無水硫酸鈉乾燥，濃縮，通過反相高效液相色譜法分離純化（色譜柱：Waters Xbridge 150*25mm* 5um；流動相：A = 水+氨水(0.05%)），B = 乙腈；梯度：20% - 50%，15分鐘），得到產物化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-6-甲基-6,7-二氫噻吩並[3,2-d]嘧啶-4-基)胺基)-環丁基)-甲醇(目標化合物3) (80.0 mg,，產率66.4%)。LC-MS, M/Z (ESI): 463.2(M+H)。 1H NMR (400 MHz, DMSO- d 6) δ = 8.76-9.00 (m, 2H), 7.17-7.70 (m, 1H), 4.87 (br s, 1H), 4.53-4.79 (m, 2H), 3.72 (br d, 2H), 3.58 (m, 1H), 3.14-3.25 (m, 2H), 3.05 (br m, 2H), 2.86-2.99 (m, 1H), 2.26-2.36 (m, 2H), 2.10-2.21 (m, 2H), 1.91-2.02 (m, 2H), 1.55-1.84 (m, 4H), 1.13-1.33 (m, 3H)。 化合物2、化合物4、化合物5、化合物6和化合物7的製備參照本發明實施例6的化合物3的合成。化合物2、化合物4、化合物5、化合物6和化合物7的結構式、LC-MS和核磁表徵結果如下表所示： 結構 LC-MS和核磁表徵 2 LC-MS, M/Z (ESI): 463.1 (M+1). 1H NMR (400 MHz, DMSO- d 6) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.10-3.04 (m, 8H), 1.66-1.90 (m, 10H), 1.27（d, 3H）. 4 LC-MS, M/Z (ESI): 475.1 (M+1). 1H NMR (400 MHz, DMSO- d 6) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.78-3.24 (m, 4H), 2.70-2.75 (m, 3H), 1.74-2.08 (m, 10H), 0.80-1.05 (m, 4H). 5 LC-MS, M/Z (ESI): 475.1 (M+1). 1H NMR (400 MHz, DMSO- d 6) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.78-3.24 (m, 4H), 2.70-2.75 (m, 3H), 1.74-2.08 (m, 10H), 1.05-1.25 (m, 2H)，0.80-1.00 (m, 2H). 6 LC-MS, M/Z (ESI): 437.1 (M+1). 1H NMR (400 MHz, DMSO- d 6) δ = 8.30 (s, 2H), 7.93 (s, 1H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 3.05-3.14 (m, 4H), 2.81-3.00 (m, 1H), 2.70-2.95 (m, 3H), 2.50 (s, 2H), 1.74-2.08 (m, 4H), 1.60-1.70 (m, 4H). 7 LC-MS, M/Z (ESI): 448.1 (M+1). 1H NMR (400 MHz, CDCl 3) δ 8.21 (s, 2H), 6.22 (s, 1H), 5.95 (s, 1H), 5.34 (s, 1H), 4.80 (d, 2H), 3.87 (d, 2H), 3.72 – 3.53 (m, 2H), 3.23 – 3.09 (m, 2H), 3.01 – 2.89 (m, 3H), 2.35 – 2.18 (m, 4H), 1.96 (ddd, 4H), 1.76 (ddd, 2H). Step 7: Synthesis of 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (target compound 3) Dissolve 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (3-7) (80.0 mg, 260 μmol) in 1,4-dioxane (10 mL), add 5-chloro-2-(4-piperidinyl)pyrimidine (77.1 mg, 390 μmol) and N,N-diisopropylethylamine (100 mg, 780 μmol, 135 μL), and react at 80°C for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (60 mL) was used for extraction three times, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by reversed-phase high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm* 5um; mobile phase: A = water + ammonia water (0.05%), B = acetonitrile; gradient: 20% - 50%, 15 minutes), to obtain the product compound 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-6-methyl-6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino)-cyclobutyl)-methanol (target compound 3) (80.0 mg, yield 66.4%). LC-MS, M/Z (ESI): 463.2 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.76-9.00 (m, 2H), 7.17-7.70 (m, 1H), 4.87 (br s, 1H), 4.53-4.79 (m, 2H), 3.72 (br d, 2H), 3.58 (m, 1H), 3.14-3.25 (m, 2H), 3.05 (br m, 2H), 2.86-2.99 (m, 1H), 2.26-2.36 (m, 2H), 2.10-2.21 (m, 2H), 1.91-2.02 (m, 2H), 1.55-1.84 (m, 4H), 1.13-1.33 (m, 3H). The preparation of compound 2, compound 4, compound 5, compound 6 and compound 7 refers to the synthesis of compound 3 in Example 6 of the present invention. The structural formula, LC-MS and NMR characterization results of compound 2, compound 4, compound 5, compound 6 and compound 7 are shown in the following table: Structure LC-MS and NMR characterization 2 LC-MS, M/Z (ESI): 463.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.10-3.04 (m, 8H), 1.66-1.90 (m, 10H), 1.27（d, 3H）. 4 LC-MS, M/Z (ESI): 475.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.78-3.24 (m, 4H), 2.70-2.75 (m, 3H), 1.74-2.08 (m, 10H), 0.80-1.05 (m, 4H). 5 LC-MS, M/Z (ESI): 475.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.30 (s, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 2.78-3.24 (m, 4H), 2.70-2.75 (m, 3H), 1.74-2.08 (m, 10H), 1.05-1.25 (m, 2H), 0.80-1.00 (m, 2H). 6 LC-MS, M/Z (ESI): 437.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.30 (s, 2H), 7.93 (s, 1H), 5.61 (s, 1H), 4.87 (s, 1H), 3.50 (d, 2H), 3.05-3.14 (m, 4H), 2.81-3.00 (m, 1H), 2.70-2.95 (m, 3H), 2.50 (s, 2H), 1.74-2.08 (m, 4H), 1.60-1.70 (m, 4H). 7 LC-MS, M/Z (ESI): 448.1 (M+1). 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 2H), 6.22 (s, 1H), 5.95 (s, 1H), 5.34 (s, 1H), 4.80 (d, 2H), 3.87 (d, 2H), 3.72 – 3.53 (m, 2H), 3.23 – 3.09 (m, 2H), 3.01 – 2.89 (m, 3H), 2.35 – 2.18 (m, 4H), 1.96 (ddd, 4H), 1.76 (ddd, 2H).

生物測試 測試方案1：PDE4B和PDE4D酶活試驗 本發明提供的化合物對PDE4B和PDE4D的抑制活性可以利用PDE-Glo Phosphodiesterase Assay Kit(promega，V1361)進行檢測。簡單來說，首先將待檢測化合物在DMSO溶劑中配製成10mM的濃儲液，隨後以試劑盒提供的Reaction buffer稀釋十倍。在冰上操作，用Reaction buffer將PDE4B酶(Enzo Life Sciences，BML-SE522-0020)稀釋至濃度為1ng/μL，PDE4D酶(Enzo Life Sciences，BMLSE523-0020)稀釋至濃度為4ng/μL。在384孔板(Corning，CLS3707)的孔中加入1.5μLPDE4B或PDE4D工作液和1μL化合物工作液，室溫震盪孵育5分鐘，隨後加入2.5μL/孔cAMP(2μM in Reaction buffer)，繼續室溫震盪孵育20分鐘，加入2.5μL/孔1× Termination Buffer，隨後加入2.5μL/孔1× Detection Buffer，繼續室溫震盪20分鐘。最後加入10μL/孔1×Kinase-Glo，室溫震盪孵育10分鐘，以PheraStar儀器檢測生物發光。實驗結果輸入GraphPad Prism軟體，經擬合計算得到各化合物的IC 50，具體參見表1。實驗結果表明，本發明化合物可作為PDE4B的選擇性抑制劑。 表1 化合物編號 PDE4B IC 50(nM) PDE4D IC 50(nM) 化合物1-P1 27.45 111.9 化合物8-P1 38.19 111.30 化合物10-P2-A 52.41 162.10 化合物10-P2-B 31.26 91.44 化合物11-P2 27.99 72.00 Biological test protocol 1: PDE4B and PDE4D enzyme activity test The inhibitory activity of the compounds provided by the present invention on PDE4B and PDE4D can be detected using PDE-Glo Phosphodiesterase Assay Kit (promega, V1361). Briefly, the compound to be tested is first prepared into a 10mM concentrated stock solution in DMSO solvent, and then diluted tenfold with the reaction buffer provided in the kit. Operating on ice, the PDE4B enzyme (Enzo Life Sciences, BML-SE522-0020) is diluted to a concentration of 1ng/μL, and the PDE4D enzyme (Enzo Life Sciences, BMLSE523-0020) is diluted to a concentration of 4ng/μL with reaction buffer. 1.5 μL PDE4B or PDE4D working solution and 1 μL compound working solution were added to the wells of a 384-well plate (Corning, CLS3707), incubated at room temperature with shaking for 5 minutes, then 2.5 μL/well cAMP (2 μM in Reaction buffer) was added, incubated at room temperature with shaking for 20 minutes, 2.5 μL/well 1× Termination Buffer was added, then 2.5 μL/well 1× Detection Buffer was added, and incubated at room temperature with shaking for 20 minutes. Finally, 10 μL/well 1× Kinase-Glo was added, incubated at room temperature with shaking for 10 minutes, and bioluminescence was detected with a PheraStar instrument. The experimental results were input into GraphPad Prism software, and the IC 50 of each compound was obtained by fitting calculation, as shown in Table 1. The experimental results show that the compounds of the present invention can be used as selective inhibitors of PDE4B. Table 1 Compound No. PDE4B IC 50 (nM) PDE4D IC 50 (nM) Compound 1-P1 27.45 111.9 Compound 8-P1 38.19 111.30 Compound 10-P2-A 52.41 162.10 Compound 10-P2-B 31.26 91.44 Compound 11-P2 27.99 72.00

測試列2：LPS誘導人PBMC分泌TNFα模型試驗 PBMC提取過程：獲取新鮮人外周濃縮血，吸取1單位人外周濃縮血(濃縮自200cc外周血)，定量加入0.9％生理鹽水至總體積為120ml，混勻。取50ml離心管，分別加入15ml Lymphoprep TM，手持離心管，約斜45°，吸取30ml稀釋後的濃縮血，小心而緩慢地貼壁加入，使稀釋血液重疊於分層液上，避免將稀釋血液混入分離液或衝破分離液液面。Lymphoprep TM與稀釋血液的比例為1:2。將離心管配平放置入水平離心機(eppendorf，5810R)，在20℃、800×g條件下離心20min，升速設為1，降速設為0。小心取出離心管。直接將巴氏吸管深入白膜層，吸取PBMC。加3倍體積0.9％生理鹽水或PBS(不含鈣鎂)，輕輕吹打混勻。混勻後在20℃、250×g條件下離心10min，去除細胞懸液中留存的血小板，去上清液，將細胞沉澱以20ml PBS懸起，台盼藍染色計數。 PBMC篩選過程：將步驟1取得的PBMC離心，去除PBS，然後用完全培養基(RPMI1640+10％FBS+1％P/S)重懸計數。按照5× 10 4/孔，100μL/孔接入細胞。將待篩選的化合物配製成終濃度的4×，按照50μL/孔加入到細胞中，提前預孵育30min。同時設定對照孔，不加化合物（即為對照組）。LPS的刺激終濃度為10ng/ml，稀釋成4倍溶液，按照50μl/孔加入到細胞中。同時設定對照孔，不加LPS孔。繼續孵育細胞，在24h時收集10％上清進行檢測。收集的上清按照Invitrogen公司的Human TNFα試劑盒檢測(REF：88-7346-88)。按照上述方法測定本發明提供的化合物對LPS誘導人PBMC分泌TNFα的抑制活性，結果參見表2。 表2：測試化合物對LPS誘導人PBMC分泌TNFα的抑制活性結果 化合物編號 TNFα分泌IC 50(nM) 化合物1-P1 69.70 實驗結果表明，本發明化合物有著優良的人PBMC分泌TNFα抑制活性，能更好地抑制人PBMC中炎症因子TNFα的分泌，具有良好的抗炎效果。 Test row 2: LPS-induced human PBMC secretion TNFα model test PBMC extraction process: obtain fresh human peripheral concentrated blood, draw 1 unit of human peripheral concentrated blood (concentrated from 200cc peripheral blood), quantitatively add 0.9% physiological saline to a total volume of 120ml, and mix. Take a 50ml centrifuge tube, add 15ml Lymphoprep TM respectively, hold the centrifuge tube, tilt it about 45°, draw 30ml of diluted concentrated blood, carefully and slowly add it to the wall, so that the diluted blood overlaps on the layering liquid, avoid mixing the diluted blood into the separation liquid or breaking the separation liquid surface. The ratio of Lymphoprep TM to diluted blood is 1:2. Place the centrifuge tube in a horizontal centrifuge (eppendorf, 5810R) and centrifuge at 20°C and 800×g for 20 min. Set the speed increase to 1 and the speed decrease to 0. Carefully remove the centrifuge tube. Directly insert the Pasteur pipette into the buffy coat layer to absorb PBMC. Add 3 times the volume of 0.9% saline or PBS (calcium-free and magnesium-free) and gently pipette to mix. After mixing, centrifuge at 20°C and 250×g for 10 min, remove the platelets retained in the cell suspension, remove the supernatant, suspend the cell pellet in 20 ml PBS, and count with trypan blue staining. PBMC screening process: Centrifuge the PBMC obtained in step 1, remove PBS, and then resuspend and count with complete culture medium (RPMI1640+10% FBS+1% P/S). Inoculate cells at 5× 10 4 /well and 100μL/well. Prepare the compounds to be screened to a final concentration of 4×, add them to the cells at 50μL/well, and pre-incubate for 30 minutes in advance. At the same time, set up control wells without adding compounds (i.e., control group). The final concentration of LPS stimulation is 10ng/ml, which is diluted into a 4-fold solution and added to the cells at 50μl/well. At the same time, set up control wells without adding LPS. Continue to incubate the cells and collect 10% of the supernatant for detection at 24h. The collected supernatant was tested according to the Human TNFα kit of Invitrogen (REF: 88-7346-88). The inhibitory activity of the compounds provided by the present invention on LPS-induced human PBMC secretion of TNFα was determined according to the above method. The results are shown in Table 2. Table 2: Inhibitory activity results of the test compounds on LPS-induced human PBMC secretion of TNFα Compound No. TNFα Secretion IC 50 (nM) Compound 1-P1 69.70 The experimental results show that the compound of the present invention has excellent human PBMC secretion TNFα inhibitory activity, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and has a good anti-inflammatory effect.

測試例3：小鼠藥代動力學試驗 小鼠藥代動力學試驗，採用雄性ICR小鼠，體重為20-25g/只，禁食過夜。取3只小鼠，採用本發明的化合物口服灌胃給藥10mg/kg。在給藥前和在給藥後15、30分鐘以及1、2、4、8、24小時分別採血。血液樣品在6800×g、2-8℃條件下離心6分鐘，收集血漿，於-20℃保存。分別取各時間點血漿，加入3-5倍量含內標的乙腈溶液，渦旋混合1分鐘，在13000轉/分鐘、4℃條件下離心10分鐘，取上清液加入3倍量水混合，取適量混合液進行LC-MS/MS分析。主要藥代動力學參數用WinNonlin 7 .0軟體非房室模型分析，結果參見表3。 表3：小鼠的藥代動力學試驗結果 測試化合物 小鼠藥代動力學參數（口服灌胃給藥） C max(ng/mL) T max(hr) AUC o-t(h*ng/mL) T 1/2（h） 化合物1-P1 3330 0.25 9993 2.92 實驗結果表明，本發明化合物在小鼠中表現出優良的血漿暴露，有優良的藥代動力學性質。 Test Example 3: Mouse Pharmacokinetic Test For the mouse pharmacokinetic test, male ICR mice with a body weight of 20-25g/mouse were fasted overnight. Three mice were taken and the compound of the present invention was orally administered by gavage at 10 mg/kg. Blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. The blood samples were centrifuged at 6800×g and 2-8°C for 6 minutes, and the plasma was collected and stored at -20°C. The plasma was taken at each time point, 3-5 times the amount of acetonitrile solution containing the internal standard was added, vortexed for 1 minute, centrifuged at 13000 rpm and 4°C for 10 minutes, the supernatant was added with 3 times the amount of water and mixed, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model using WinNonlin 7.0 software. The results are shown in Table 3. Table 3: Pharmacokinetic test results in mice Test compound Pharmacokinetic parameters in mice (oral gavage) C max (ng/mL) Tmax (hr) AUCot (h*ng/mL) T 1/2 (h) Compound 1-P1 3330 0.25 9993 2.92 The experimental results show that the compound of the present invention exhibits excellent plasma exposure in mice and has excellent pharmacokinetic properties.

測試例4：大鼠藥代動力學試驗 大鼠藥代動力學試驗，採用雄性SD小鼠，體重為200-250g/只，禁食過夜。取3只大鼠，採用本發明的化合物口服灌胃給藥10mg/kg。在給藥前和在給藥後5、15、30分鐘以及1、2、4、8、24小時分別採血。採血0.2 mL置於含標記的EDTA-2K抗凝管中。上下輕柔顛倒使抗凝劑（EDTA-2K）與血液充分混合後，立即置於濕冰中，並於採血後1小時之內離心分離血漿，離心條件設置為4℃、6800 ×g、6分鐘。離心後分離得到的血漿裝於標記好的EP管中，並儘快存放於超低溫冰箱內，直至樣品分析。主要藥代動力學參數用WinNonlin 7 .0軟體非房室模型分析，結果參見表4。 表4：大鼠的藥代動力學試驗結果 測試化合物 大鼠藥代動力學參數（口服灌胃給藥） C max(ng/mL) T max(hr) AUC o-t(h*ng/mL) T 1/2（h） 化合物1-P1 1780 2 10969 13.1 實驗結果表明，本發明化合物在大鼠中表現出優良的血漿暴露，有優良的藥代動力學性質。 Test Example 4: Pharmacokinetics Test in Rats Male SD mice weighing 200-250 g/mouse were fasted overnight. Three rats were orally gavaged with the compound of the present invention at 10 mg/kg. Blood was collected before and 5, 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. 0.2 mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. After gently inverting up and down to fully mix the anticoagulant (EDTA-2K) and blood, it was immediately placed in wet ice and centrifuged to separate the plasma within 1 hour after blood collection. The centrifugation conditions were set to 4°C, 6800 × g, and 6 minutes. The plasma separated after centrifugation was placed in a labeled EP tube and stored in an ultra-low temperature refrigerator as soon as possible until the sample was analyzed. The main pharmacokinetic parameters were analyzed using the non-compartmental model using WinNonlin 7.0 software. The results are shown in Table 4. Table 4: Pharmacokinetic test results in rats Test compound Pharmacokinetic parameters in rats (oral gavage) C max (ng/mL) Tmax (hr) AUCot (h*ng/mL) T 1/2 (h) Compound 1-P1 1780 2 10969 13.1 The experimental results show that the compound of the present invention exhibits excellent plasma exposure in rats and has excellent pharmacokinetic properties.

測試例5：Beagle犬藥代動力學試驗 Beagle犬藥代動力學試驗，採用雄性Beagle犬，體重為7-12kg/只，禁食過夜。取3只Beagle犬，採用本發明的化合物口服灌胃給藥10mg/kg。在給藥前和在給藥後5、15、30分鐘以及1、2、4、8、24小時分別採血。血液樣品在2200 ×g、2-8℃條件下離心6分鐘，收集血漿，於-20℃保存。主要藥代動力學參數用WinNonlin 7 .0軟體非房室模型分析，結果參見表5。 表5： Beagle犬的藥代動力學試驗結果 測試化合物 Beagle犬藥代動力學參數（口服灌胃給藥） C max(ng/mL) T max(hr) AUC o-t(h*ng/mL) T 1/2（h） 化合物1-P1 2095 1.0 9435 10.7 實驗結果表明，本發明化合物在Beagle犬表現出優良的血漿暴露，有優良的藥代動力學性質。 Test Example 5: Beagle Dog Pharmacokinetic Test Beagle dog pharmacokinetic test, male Beagle dogs with a body weight of 7-12 kg/dog were fasted overnight. Three Beagle dogs were orally gavaged with the compound of the present invention at 10 mg/kg. Blood was collected before and at 5, 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. The blood samples were centrifuged at 2200 × g and 2-8°C for 6 minutes, and the plasma was collected and stored at -20°C. The main pharmacokinetic parameters were analyzed using the non-compartmental model using WinNonlin 7.0 software. The results are shown in Table 5. Table 5: Results of the pharmacokinetic test in Beagle dogs Test compound Pharmacokinetic parameters of Beagle dogs (oral gavage) C max (ng/mL) Tmax (hr) AUCot (h*ng/mL) T 1/2 (h) Compound 1-P1 2095 1.0 9435 10.7 The experimental results show that the compound of the present invention exhibits excellent plasma exposure in Beagle dogs and has excellent pharmacokinetic properties.

在本說明書的描述中，參考術語「一個實施例」、「一些實施例」、 「示例」、「具體示例」、或「一些示例」等的描述意指結合該實施例或示例描述的具體特徵、結構、材料或者特點包含於本發明的至少一個實施例或示例中。在本說明書中，對上述術語的示意性表述不必須針對的是相同的實施例或示例。而且，描述的具體特徵、結構、材料或者特點可以在任一個或多個實施例或示例中以合適的方式結合。此外，在不相互矛盾的情況下，本發明所屬技術領域具有通常知識者可以將本說明書中描述的不同實施例或示例以及不同實施例或示例的特徵進行結合和組合。In the description of this specification, reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily need to be directed to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in an appropriate manner. In addition, to the extent that there is no contradiction, a person having ordinary knowledge in the technical field to which the present invention belongs may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples.

儘管上面已經示出和描述了本發明的實施例，可以理解的是，上述實施例是示例性的，不能理解為對本發明的限制，本發明所屬技術領域具有通常知識者在本發明的範圍內可以對上述實施例進行變化、修改、替換和變型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations of the present invention. A person having ordinary knowledge in the technical field to which the present invention belongs can change, modify, replace and modify the above embodiments within the scope of the present invention.

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無without

Claims (22)

一種化合物，其為式（Ⅱ）所示的化合物，或者式（Ⅱ）所示化合物的互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥， （Ⅱ）， 其中， 表示為單鍵或不存在； X 1和X 2分別獨立地為CH或N，並且X 1和X 2至少有一個為N； X 4和X 5分別獨立地為CH或N，並且X 1和X 2至少有一個為N； 每個R 1a、R 1b、R 1c和R 1d分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a取代； 或者，R 1a、R 1b和它們所連接的碳原子一起形成環A，所述環A為任選地被1、2或3個R b取代的C 3-8環烷基； 或者，R 1b、R 1c和它們所連接的碳原子一起形成環B，所述環B為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c取代； 或者，R 1c、R 1d和它們所連接的碳原子一起形成環C，所述環C為任選地被1、2或3個R d取代的C 3-8環烷基； 每個R a各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R取代； 每個R b、R c和R d分別各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R取代； 每個R各自獨立地為鹵素、OH、CN或NH 2； n為0、1或2； m為1或2； 環W為3-10元雜環烷基、3-10元雜環烯基或3-10元環烷基； R 2為H、鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基、C 1-6鹵代烷氧基、3~10元雜環烷基；所述C 1-6烷基、C 3-8環烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 3-8鹵代環烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基和C 1-6鹵代烷氧基任選地被一個或多個R e取代，當取代基R e為多個時，所述R e相同或不同； 每個 R e分別各自獨立地為鹵素、羥基、胺基、硝基、氰基、羰基、氧代、羧基、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6鹵代烷基、C 1-6烷基羥基、C 1-6烷基羰基、C 1-6烷氧基或C 1-6鹵代烷氧基。 A compound, which is a compound represented by formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II), (II), where represents a single bond or does not exist; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; X4 and X5 are independently CH or N, and at least one of X1 and X2 is N; each of R1a , R1b , R1c and R1d is independently H, halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylamino, C1-6 alkoxy , -SC1-6 alkyl, -S(=O) -C1-6 alkyl, -S(=O) 2 - C1-6 alkyl, -C(=O) -C1-6 alkyl, -C(=O)-NH -C1-6 alkyl or -NH-C(=O) -OC1-6 alkyl, wherein the NH2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl and -NH-C(=O)-OC 1-6 alkyl are independently and optionally substituted by 1, 2 or 3 R a ; or, R 1a , R 1b and the carbon atom to which they are attached together form a ring A, and the ring A is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R b ; or, R 1b , R R 1c and the carbon atoms to which they are attached form a ring B, wherein the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c ; or, R 1c , R 1d and the carbon atoms to which they are attached form a ring C, wherein the ring C is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R d ; each Ra is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are each independently and optionally substituted by 1, 2 or 3 R; each R b , R c and R d are each independently and optionally substituted by 1, 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1 , 2 or 3 R; each R is each independently and optionally substituted by 1, 2 or 3 R; n is 0, 1 or 2; m is 1 or 2; ring W is 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or 3-10 membered cycloalkyl; R 2 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino. C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl , C 1-6 deuterated alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy and C 1-6 halogenated alkoxy are optionally substituted by one or more Re , when the substituent R When e is multiple, the Re is the same or different; each Re is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy or C1-6 halogenated alkoxy. 如請求項1所述的化合物，其中每個R 1a、R 1b、R 1c和R 1d分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-3烷基或C 1-3烷氧基，其中，所述C 1-3烷基和C 1-3烷氧基分別獨立地任選地被1、2或3個R a取代； 或者，每個R 1a、R 1b、R 1c和R 1d分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3，其中，所述CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3分別獨立地任選地被1、2或3個R a取代； 或者，每個R 1a、R 1b、R 1c和R 1d分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CHF 2、-OCH 2CF 3； 或者，每個R a各自獨立地為F、Cl、Br、I、OH、CN、NH 2或環丙基； 或者，環A為任選地被1、2或3個R b取代的C 3-6環烷基； 或者，當R 1b、R 1c和它們所連接的碳原子一起形成環B時，n為2，此時環B為 或 ； 或者，環C為任選地被1、2或3個R b取代的C 3-6環烷基； 或者，每個R b、R c和R d分別各自獨立地為鹵素、OH、CN、NH 2或CH 3； 或者，環A為 ； 或者，環C為 。 The compound of claim 1, wherein each R 1a , R 1b , R 1c and R 1d are each independently H, halogen, OH, CN, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 Ra ; or, each R 1a , R 1b , R 1c and R 1d are each independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 , wherein the CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 are each independently optionally substituted by 1, 2 or 3 Ra ; or, each R 1a , R 1b , R 1c and R 1d are each independently H, halogen, OH , CN, NH 2 , CH 3 , CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 R 1c and R 1d are each independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 ; or, each Ra is each independently F, Cl, Br, I, OH, CN, NH 2 or cyclopropyl; or, Ring A is a C 3-6 cycloalkyl group optionally substituted by 1, 2 or 3 R b ; or, when R 1b , R 1c and the carbon atom to which they are attached together form Ring B, n is 2, and Ring B is or ; or, Ring C is a C 3-6 cycloalkyl group optionally substituted by 1, 2 or 3 R b ; or, each of R b , R c and R d is independently a halogen, OH, CN, NH 2 or CH 3 ; or, Ring A is ; Alternatively, ring C is . 如請求項1所述的化合物，其中結構單元 為 或 ； 進一步地優選， 中，n為1或2； 進一步地優選， 中，n為0或1； 進一步地優選，結構單元 為 或 ； 進一步地優選，結構單元 為 、 、 或 ； 進一步地優選，結構單元 為 、 、 、 、 、 、 或 。 The compound as claimed in claim 1, wherein the structural unit for or ; Further preferred, , n is 1 or 2; further preferably, In the embodiment, n is 0 or 1; preferably, the structural unit for or ; Further preferably, the structural unit for , , or ; Further preferably, the structural unit for , , , , , , or . 如請求項1所述的化合物，其中X 1和X 2均為N； 或者，X 1為CH，X 2為N； 或者，X 4和X 5均為N； 或者，R 2為F、Cl、CH 3或被1個或多個R e取代的CH 3； 或者，R e為F或Cl； 或者，R 2為Cl； 或者，m為1； 或者，m為2。 The compound as described in claim 1, wherein X1 and X2 are both N; or, X1 is CH, X2 is N; or, X4 and X5 are both N; or, R2 is F, Cl, CH3 or CH3 substituted by one or more Re ; or, Re is F or Cl; or, R2 is Cl; or, m is 1; or, m is 2. 如請求項1所述的化合物，其中環W為4-7元雜環烷基； 進一步地優選，環W為4-7元含氮雜環烷基； 進一步地優選，環W為 或 ； 其中，X 3為CH或N； h、g分別各自獨立地為0、1或2； p、q分別各自獨立地為1或2； 進一步地優選，h為1，g為1； 進一步地優選，h為0，g為1； 進一步地優選，h為1，g為0； 進一步地優選，h為0，g為0； 進一步地優選，X 3為CH； 進一步地優選，X 3為N； 進一步地優選，p為1，q為1； 進一步地優選，環W為氮雜環丁基、吡咯烷基、哌啶基或2-氮雜螺[3.3]庚烷基； 進一步地優選，環W為 、 、 或 。 The compound as claimed in claim 1, wherein ring W is a 4-7 membered heterocycloalkyl group; more preferably, ring W is a 4-7 membered nitrogen-containing heterocycloalkyl group; more preferably, ring W is or ; wherein X 3 is CH or N; h, g are each independently 0, 1 or 2; p, q are each independently 1 or 2; further preferably, h is 1 and g is 1; further preferably, h is 0 and g is 1; further preferably, h is 1 and g is 0; further preferably, h is 0 and g is 0; further preferably, X 3 is CH; further preferably, X 3 is N; further preferably, p is 1 and q is 1; further preferably, ring W is azacyclobutyl, pyrrolidinyl, piperidinyl or 2-azaspiro[3.3]heptyl; further preferably, ring W is , , or . 如請求項1~5任一項所述的化合物，其中式（Ⅱ）化合物具有結構式（IIIa）或（IIIb）： （IIIa）； （IIIb）； 其中，X 3為CH或N； h、g分別各自獨立地為0、1或2； p、q分別各自獨立地為1或2； 進一步地優選，式（II）所示化合物具有結構式（IIIa3）、（IIIa4）或（IIⅠb2）： （IIIa3）， （IIIa4）， （IIIb2）。 The compound as described in any one of claims 1 to 5, wherein the compound of formula (II) has the structural formula (IIIa) or (IIIb): (IIIa); (IIIb); wherein X 3 is CH or N; h and g are each independently 0, 1 or 2; p and q are each independently 1 or 2; further preferably, the compound represented by formula (II) has the structural formula (IIIa3), (IIIa4) or (IIIb2): (IIIa3), (IIIa4), (IIIb2). 如請求項1~5任一項所述的化合物，其中式（Ⅱ）化合物具有結構式（Ⅰ）： （Ⅰ）， 其中，X 3為CH或N； 進一步地優選，式（Ⅱ）化合物具有結構式(Ia)或(Ia1)： (Ia)， (Ia1)。 The compound as described in any one of claims 1 to 5, wherein the compound of formula (II) has the structural formula (I): (I), wherein X 3 is CH or N; Further preferably, the compound of formula (II) has the structural formula (Ia) or (Ia1): (Ia), (Ia1). 如請求項1~5任一項所述的化合物，其中式（II）所示化合物具有結構式（IV）、（V）或（VI）： （IV）， （V）， （VI）； 式（IV）中，X 1為N、X 2為N、R 1a為H、R 1b為H、R 1c為H和R 1d為H不同時存在； 進一步地優選，式（VI）中，n為0或1； 進一步地優選，式（VI）中，n為0； 進一步地優選，式（Ⅱ）化合物具有結構式(Ⅱ-A)： (Ⅱ-A)。 The compound as described in any one of claims 1 to 5, wherein the compound represented by formula (II) has a structural formula (IV), (V) or (VI): (IV), (V), (VI); In formula (IV), X1 is N, X2 is N, R1a is H, R1b is H, R1c is H and R1d is H do not exist at the same time; Further preferably, in formula (VI), n is 0 or 1; Further preferably, in formula (VI), n is 0; Further preferably, the compound of formula (II) has the structural formula (II-A): (Ⅱ-A). 如請求項8所述的化合物，其中式（Ⅱ）化合物具有結構式(Ib)、(Ib1)、(Ⅱ-A1)或(Ⅱ-A2)： (Ib)， (Ib1) (Ⅱ- A1)， (Ⅱ- A2)， h、g分別地為0、1或2； p、q分別地為1或2。 The compound as claimed in claim 8, wherein the compound of formula (II) has the structural formula (Ib), (Ib1), (II-A1) or (II-A2): (Ib), (Ib1) (Ⅱ- A1), (Ⅱ- A2), h, g are 0, 1 or 2 respectively; p, q are 1 or 2 respectively. 如請求項8所述的化合物，其中式（Ⅱ）化合物具有結構式(Ic)或(Ic1)： (Ic)， (Ic1)。 The compound as claimed in claim 8, wherein the compound of formula (II) has the structural formula (Ic) or (Ic1): (Ic), (Ic1). 如請求項8所述的化合物，其中式（Ⅱ）化合物具有結構式(Id)或(Id1)： (Id)， (Id1)。 The compound as claimed in claim 8, wherein the compound of formula (II) has the structural formula (Id) or (Id1): (Id), (Id1). 如請求項1~5任一項所述的化合物，其中式（II）所示化合物具有結構式（Vd）或（Ve）： （Vd）、 （Ve）。 The compound as described in any one of claims 1 to 5, wherein the compound represented by formula (II) has a structural formula (Vd) or (Ve): (Vd), (Ve). 如請求項1所述的化合物，其中選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 、 、 、 、 、 、 、 、 、 或 。 The compound as described in claim 1, wherein it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: , , , , , , , , , or . 如請求項1所述的化合物，其中選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 、 、 、 、 、 、 、 、 或 。 The compound as described in claim 1, wherein it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: , , , , , , , , or . 一種中間體化合物，其為式（VⅡ）所示的化合物，或者式（VⅡ）所示化合物的互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥， （VⅡ）， 其中， 表示為單鍵或不存在； X 1'和X 2'分別獨立地為CH或N，並且X 1'和X 2'至少有一個為N； 每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基或-NH-C(=O)-O-C 1-6烷基，其中，所述NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基、-S-C 1-6烷基、-S(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-C(=O)-C 1-6烷基、-C(=O)-NH-C 1-6烷基和-NH-C(=O)-O-C 1-6烷基分別獨立地任選地被1、2或3個R a'取代； 或者，R 1a'、R 1b'和它們所連接的碳原子一起形成環A'，所述環A'為任選地被1、2或3個R b'取代的C 3-8環烷基； 或者，R 1b'、R 1c'和它們所連接的碳原子一起形成環B'，所述環B'為6-8元雜環烷基或6-8元雜環烯基，所述6-8元雜環烷基和6-8元雜環烯基分別獨立地任選地被1、2或3個R c'取代； 或者，R 1c'、R 1d'和它們所連接的碳原子一起形成環C'，所述環C'為任選地被1、2或3個R d'取代的C 3-8環烷基； 每個R a'各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或4-6元雜環烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和4-6元雜環烷基分別獨立地任選地被1、2或3個R'取代； 每個R b'、R c'和R d'分別各自獨立地為鹵素、OH、CN、NH 2、C 1-3烷基、C 1-3烷氧基或C 1-3烷胺基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷胺基分別獨立地任選地被1、2或3個R'取代； 每個R'各自獨立地為鹵素、OH、CN或NH 2； n'為0、1或2； m'為0、1或2； R x為鹵素。 An intermediate compound, which is a compound represented by formula (VII), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (VII), (VⅡ), where: represents a single bond or does not exist; X 1 'and X 2 'are independently CH or N, and at least one of X 1 'and X 2 'is N; each of R 1a ', R 1b ', R 1c 'and R 1d 'are independently H, halogen, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl, wherein the NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkoxy, -SC 1-6 alkyl, -S(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl or -NH-C(=O)-OC 1-6 alkyl R 1a ' , R 1b ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; or, R 1b ', R 1c ', R 1d ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; or, R 1b ', R 1c ', R 1d ' and the carbon atom to which they are attached together form a ring A', and the ring A' is a C 3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; R ' and the carbon atoms to which they are attached form a ring B', wherein the ring B' is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, wherein the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are independently and optionally substituted by 1, 2 or 3 R c '; or, R 1c ', R 1d ' and the carbon atoms to which they are attached form a ring C', wherein the ring C' is a C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R d '; each Ra ' is independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl 3-6 membered cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R'; each R b ', R c ' and R d ' are each independently halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R'; each R' is each independently halogen, OH, CN or NH 2 ; n' is 0, 1 or 2; m' is 0, 1 or 2; R x is halogen. 如請求項15所述的中間體化合物，其中X 1和X 2均為N； 或者，X 1為CH，X 2為N； 或者，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、C 1-3烷基或C 1-3烷氧基，其中，所述C 1-3烷基和C 1-3烷氧基分別獨立地任選地被1、2或3個R a'取代； 或者，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3，其中，所述CH 3、CH 2CH 3、-OCH 3或-OCH 2CH 3分別獨立地任選地被1、2或3個R a'取代； 或者，每個R 1a'、R 1b'、R 1c'和R 1d'分別各自獨立地為H、鹵素、OH、CN、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CHF 2、-OCH 2CF 3； 或者，每個R a'各自獨立地為F、Cl、Br、I、OH、CN、NH 2或環丙基； 或者，環A'為任選地被1、2或3個R b'取代的C 3-6環烷基； 或者，當R 1b'、R 1c'和它們所連接的碳原子一起形成環B'時，n'為2，此時環B'為 或 ； 或者，環C'為任選地被1、2或3個R b'取代的C 3-6環烷基； 或者，每個R b'、R c'和R d'分別各自獨立地為鹵素、OH、CN、NH 2或CH 3； 或者，環A'為 ； 或者，環C'為 ； 或者，結構單元 為 或 ； 進一步地優選， 中，n為1或2； 進一步地優選， 中，n為0或1； 進一步地優選，結構單元 為 或 ； 進一步地優選，結構單元 為 、 、 或 ； 進一步地優選，結構單元 為 、 、 、 、 、 、 、 或 ； 進一步地優選，結構單元 為 、 、 、 或 ； 或者，R x為Cl； 或者，m'為1或2； 進一步地優選，m'為1； 進一步地優選，m'為2。 The intermediate compound as described in claim 15, wherein X1 and X2 are both N; or, X1 is CH, and X2 is N; or, each of R1a ', R1b ', R1c ' and R1d ' is each independently H, halogen, OH, CN, NH2 , C1-3 alkyl or C1-3 alkoxy, wherein the C1-3 alkyl and C1-3 alkoxy are each independently and optionally substituted by 1, 2 or 3 Ra '; or, each of R1a ', R1b ', R1c ' and R1d ' is each independently H, halogen, OH, CN, NH2 , CH3 , CH2CH3 , -OCH3 or -OCH2CH3 , wherein the CH3 , CH2CH3 , -OCH 3 or -OCH 2 CH 3 are each independently optionally substituted by 1, 2 or 3 Ra '; or, each R 1a ', R 1b ', R 1c ' and R 1d ' are each independently H, halogen, OH, CN, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 ; or, each Ra ' is each independently F, Cl, Br, I, OH, CN, NH 2 or cyclopropyl; or, Ring A' is C optionally substituted by 1, 2 or 3 R b ' 3-6 cycloalkyl; or, when R 1b ', R 1c ' and the carbon atom to which they are attached together form a ring B', n' is 2, in which case the ring B' is or ; or, Ring C' is a C 3-6 cycloalkyl group optionally substituted by 1, 2 or 3 R b '; or, each of R b ', R c ' and R d ' is independently a halogen, OH, CN, NH 2 or CH 3 ; or, Ring A' is ; Alternatively, ring C' is ; or, structural unit for or ; Further preferred, , n is 1 or 2; further preferably, In the embodiment, n is 0 or 1; preferably, the structural unit for or ; Further preferably, the structural unit for , , or ; Further preferably, the structural unit for , , , , , , , or ; Further preferably, the structural unit for , , , or ; or, R x is Cl; or, m' is 1 or 2; further preferably, m' is 1; further preferably, m' is 2. 如請求項15或16所述的中間體化合物，其中式（VⅡ）化合物具有結構式（VⅠⅠa）： （VⅡa）； 進一步地優選，式（VⅡ）化合物具有結構式（VⅠⅠb）或式（VⅠⅠc）： （VⅡb）、 （VⅡc）； 進一步地優選，式（VⅡ）化合物具有結構式（VⅠⅠd）或式（VⅠⅠe）： （VⅡd）、 （VⅡe）。 The intermediate compound as described in claim 15 or 16, wherein the compound of formula (VII) has the structural formula (VIIIa): (VⅡa); Further preferably, the compound of formula (VⅡ) has the structural formula (VⅠⅠb) or formula (VⅠⅠc): (VⅡb), (VⅡc); Further preferably, the compound of formula (VⅡ) has the structural formula (VⅠⅠd) or formula (VⅠⅠe): (VⅡd), (VⅡe). 如請求項15所述的中間體化合物，其中選自下列任一化合物或其互變異構體、立體異構體、水合物、溶劑化物、藥學上可接受的鹽或前藥： 、 、 、 或 。 The intermediate compound as described in claim 15, wherein it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: , , , or . 一種藥物組合物，包含請求項1~14中任一項所述的化合物或依據請求項18所述的方法製備的所述化合物。A pharmaceutical composition comprising the compound of any one of claims 1 to 14 or the compound prepared according to the method of claim 18. 如請求項19所述的藥物組合物，進一步包括藥學上可接受的載體或賦形劑。The pharmaceutical composition as described in claim 19 further comprises a pharmaceutically acceptable carrier or formulation. 一種如請求項1~14中任一項所述的化合物或請求項19~20任一項所述的藥物組合物在製備用於治療或預防PDE4B相關疾病的藥物中的用途。Use of the compound of any one of claims 1 to 14 or the pharmaceutical composition of any one of claims 19 to 20 in the preparation of a medicament for treating or preventing a PDE4B-related disease. 如請求項21所述的用途，其中所述PDE4B相關疾病包括選自下列的至少之一： 治療呼吸道疾病、胃腸疾病、炎性疾病； 進一步優選為，所述呼吸道疾病包括哮喘、慢性支氣管炎、特發性肺纖維化、慢性阻塞性肺炎、變應性鼻炎、成人呼吸窘迫症候群； 或者，所述胃腸疾病包括潰瘍性結腸炎、克隆氏症、膀胱過度活動症； 或者，所述炎性疾病包括特發性皮炎、銀屑病、蕁麻疹、類風濕性關節炎、骨關節炎、痛風性關節炎、脊椎炎。 The use as described in claim 21, wherein the PDE4B-related diseases include at least one selected from the following: Treatment of respiratory diseases, gastrointestinal diseases, inflammatory diseases; Further preferably, the respiratory diseases include asthma, chronic bronchitis, idiopathic pulmonary fibrosis, chronic obstructive pneumonia, allergic rhinitis, and adult respiratory distress syndrome; Or, the gastrointestinal diseases include ulcerative colitis, Crohn's disease, and overactive bladder; Or, the inflammatory diseases include idiopathic dermatitis, psoriasis, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis, and spondylitis.
TW112122671A 2022-06-16 2023-06-16 Nitrogen-containing heterocyclic compounds as pde4b inhibitors TW202413371A (en)

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