CN117247394A

CN117247394A - Nitrogen-containing heterocyclic compounds as PDE4B inhibitors

Info

Publication number: CN117247394A
Application number: CN202310724354.XA
Authority: CN
Inventors: 张学军; 李金平; 贾一民; 刘礼飞; 杨俊�; 李莉娥
Original assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2022-06-16
Filing date: 2023-06-16
Publication date: 2023-12-19
Also published as: TW202413371A; WO2023241683A1

Abstract

本发明提出了PDE4B抑制剂及其用途，具体地，本发明提出了式(Ⅱ)所示的含氮杂环类化合物、或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药及其制备方法，以及在制备用于治疗PDE4B相关疾病的药物中的用途。 The present invention proposes PDE4B inhibitors and their uses. Specifically, the present invention proposes nitrogen-containing heterocyclic compounds represented by formula (II), or their tautomers, stereoisomers, hydrates, and solvates. , pharmaceutically acceptable salts or prodrugs and preparation methods thereof, and their use in preparing drugs for treating PDE4B-related diseases.

Description

Nitrogen-containing heterocyclic compounds as PDE4B inhibitors

技术领域Technical Field

本发明属于医药化学领域，具体地，本发明涉及PDE4B抑制剂及其用途，更具体地，本发明涉及式(II)所示的含氮杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药及其制备方法，以及在制备用于治疗与PDE4B相关疾病药物中的用途。The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to PDE4B inhibitors and uses thereof. More specifically, the present invention relates to nitrogen-containing heterocyclic compounds represented by formula (II), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and preparation methods thereof, as well as uses thereof in the preparation of drugs for treating diseases related to PDE4B.

背景技术Background Art

cAMP是细胞中的关键第二信使。已知cAMP的浓度增加可抑制各种类型的炎症和免疫细胞中的促发炎反应，包括淋巴细胞、单核球细胞、巨噬细胞、嗜中性白血球、嗜酸性白血球、嗜碱性白血球和肺部上皮细胞等。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全称为磷酸二酯酶，是包括11个家族(PDE1～PDE11)的超级酶家族，可以催化第二信使cAMP和/或cGMP水解，对细胞代谢发挥重要作用。在该家族中，cAMP专一性酶为磷酸二酯酶4(phosphodiesterase 4，PDE4)，其在炎症和免疫细胞中普遍存在。依据不同的基因编码，PDE4家族可以分为4个亚型(PDE4A、B、C、D)。其中，PDE4A、PDE4B和PDE4D在炎症细胞(如B细胞、T细胞和中性粒细胞等)中有较强的表达。PDE stands for phosphodiesterase, which is a super enzyme family that includes 11 families (PDE1 to PDE11). It can catalyze the hydrolysis of the second messenger 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. Based on 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会使cAMP的浓度下降，而使得其抑制各种类型的炎症和免疫细胞中的促发炎反应的效果降低，导致发炎性及过敏性疾病容易发生。目前已知PDE4活性的提高与某些发炎性及过敏性疾病有关，例如哮喘、慢性支气管炎、肺气肿、异位性皮肤炎、荨麻疹、过敏性鼻炎、过敏性结膜炎、干癣、类风湿性关节炎、慢性阻塞性肺病(COPD)、急性呼吸窘迫症候群和多发性硬化症等。抑制PDE4酶，导致cAMP水平的升高，从而调节TNFα水平，达到治疗疾病目的。PDE4 will reduce the concentration of cAMP, which reduces its effectiveness in inhibiting various types of inflammation and pro-inflammatory reactions 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, psoriasis, 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抑制剂的临床研究受到副作用的限制，包括恶心和呕吐，这些副作用被认为是由抑制PDE4D亚型引起的。同样，副作用也限制了第二代PDE4抑制剂cilomilast和roflumilast的治疗指数。PDE4B亚型的选择性抑制可能提供一种实现疗效的方法，同时可能减轻这些不良事件。鉴于此，本发明在现有技术基础上设计了系列化合物，以提供结构新颖、药效更好、生物利用度高、成药性强的PDE4B抑制剂，用于有效治疗PDE4B相关的疾病、病症。Clinical studies of PDE4 inhibitors are limited by side effects, including nausea and vomiting, which are believed to be caused by the inhibition of the PDE4D subtype. Similarly, side effects also limit the therapeutic index of the second-generation PDE4 inhibitors cilomilast and roflumilast. Selective inhibition of the PDE4B subtype may provide a method 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.

发明内容Summary of the invention

本发明的第一方面，本发明提出了一种化合物，其为式(Ⅱ)所示的化合物，或者式(Ⅱ)所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，In the first aspect of the present invention, the present invention provides 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),

其中，表示为单键或不存在；in, Represented as a single bond or absent;

X¹和X²分别独立地为CH或N，并且X¹和X²至少有一个为N； ^X1 and ^X2 are each independently CH or N, and at least one of ^X1 and ^X2 is N;

X⁴和X⁵分别独立地为CH或N，并且X¹和X²至少有一个为N； ^X4 and ^X5 are each independently CH or N, and at least one of ^X1 and ^X2 is N;

每个R^1a、R^1b、R^1c和R^1d分别各自独立地为H、卤素、OH、CN、NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氨基、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；Each of R ^1a , R ^1b , R ^1c and R ^1d is 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 _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 _1-6 alkyl, -C(=O)-NH-C _1-6 alkyl and -NH-C(=O)-OC _1-6 alkyl are each independently optionally substituted by 1, 2 or 3 R ^a ;

或者，R^1a、R^1b和它们所连接的碳原子一起形成环A，所述环A为任选地被1、2或3个R^b取代的C_3-8环烷基；Alternatively, R ^1a , R ^1b and the carbon atom to which they are attached together form a ring A, said ring A being a C _3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R ^b ;

或者，R^1b、R^1c和它们所连接的碳原子一起形成环B，所述环B为6-8元杂环烷基或6-8元杂环烯基，所述6-8元杂环烷基和6-8元杂环烯基分别独立地任选地被1、2或3个R^c取代；Alternatively, R ^1b , R ^1c and the carbon atom to which they are attached together form ring B, and the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, and the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are each independently optionally substituted by 1, 2 or 3 R ^c ;

或者，R^1c、R^1d和它们所连接的碳原子一起形成环C，所述环C为任选地被1、2或3个R^d取代的C_3-8环烷基；Alternatively, R ^1c , R ^1d and the carbon atom to which they are attached together form a ring C, said ring C being a C _3-8 cycloalkyl optionally substituted by 1, 2 or 3 R ^d ;

每个R^a各自独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基、C_3-6环烷基或4-6元杂环烷基，其中所述C_1-3烷基、C_1-3烷氧基、C_3-6环烷基和4-6元杂环烷基分别独立地任选地被1、2或3个R取代；each ^Ra is independently halogen, OH, CN, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R;

每个R^b、R^c和R^d分别各自独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基或C_1-3烷氨基，其中所述C_1-3烷基、C_1-3烷氧基和C_1-3烷氨基分别独立地任选地被1、2或3个R取代；Each R ^b , R ^c and R ^d is 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 optionally substituted by 1, 2 or 3 R;

每个R各自独立地为卤素、OH、CN或NH₂；Each R is independently halogen, OH, CN or NH ₂ ;

n为0、1或2；n is 0, 1 or 2;

m为1或2；m is 1 or 2;

环W为3-10元杂环烷基、3-10元杂环烯基或3-10元环烷基；Ring W is 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or 3-10 membered cycloalkyl;

R²为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、C_1-6烷基、C_3-8环烷基、C_1-6氘代烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_3-8卤代环烷基、C_1-6烷基羟基、C_1-6烷基羰基、C_1-6烷氧基、C_1-6卤代烷氧基、3～10元杂环烷基；所述C_1-6烷基、C_3-8环烷基、C_1-6氘代烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_3-8卤代环烷基、C_1-6烷基羟基、C_1-6烷基羰基、C_1-6烷氧基和C_1-6卤代烷氧基任选地被一个或多个R^e取代，当取代基R^e为多个时，所述R^e相同或不同； ^R2 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C3-8 cycloalkyl, _C1-6 deuterated alkyl, C2-6 alkenyl, _C2-6 alkynyl, C1-6 haloalkyl, _C3-8 halocycloalkyl, _C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _3-10 membered heterocycloalkyl; the _C1-6 alkyl, _C3-8 cycloalkyl, _C1-6 _deuterated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C3-8 halocycloalkyl _, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy and _C1-6 haloalkoxy are optionally substituted by one or more ^Re , when the substituent R When ^e is multiple, the ^Re are the same or different;

每个R^e分别各自独立地为卤素、羟基、氨基、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卤代烷基、C_1-6烷基羟基、C_1-6烷基羰基、C_1-6烷氧基或C_1-6卤代烷氧基。Each ^Re is independently halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C1-6 _deuterated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, C1-6 alkylhydroxy, _C1-6 alkylcarbonyl, _C1-6 alkoxy or _C1-6 haloalkoxy.

根据本发明的实施例，上述化合物还可以进一步包括如下技术特征的至少之一：According to an embodiment of the present invention, the above compound may further include at least one of the following technical features:

在本发明一任选实施方案中，表示为单键或不存在；X¹和X²分别独立地为CH或N，并且X¹和X²至少有一个为N；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为CH或N； ^X3 is CH or N;

R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；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 _1-6 alkyl, -C(=O)-NH-C _1-6 alkyl and -NH-C(=O)-OC _1-6 alkyl are each independently optionally substituted by 1, 2 or 3 R ^a ;

或者，R^1c、R^1d和它们所连接的碳原子一起形成环C，所述环C为任选地被1、2或3个R^d取代的C_3-6环烷基；Alternatively, R ^1c , R ^1d and the carbon atom to which they are attached together form a ring C, said ring C being a C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^d ;

各R^a独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基、C_3-6环烷基或4-6元杂环烷基，其中所述C_1-3烷基、C_1-3烷氧基、C_3-6环烷基和4-6元杂环烷基分别独立地任选地被1、2或3个R取代；each ^Ra is independently halogen, OH, CN, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R;

各R^b、R^c和R^d分别独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基或C_1-3烷氨基，其中所述C_1-3烷基、C_1-3烷氧基和C_1-3烷氨基分别独立地任选地被1、2或3个R取代；each R ^b , R ^c and R ^d is 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 optionally substituted by 1, 2 or 3 R;

R独立地为卤素、OH、CN或NH₂；R is independently halogen, OH, CN or NH ₂ ;

n为0、1或2；n is 0, 1 or 2;

m为1或2；m is 1 or 2;

每个R^e分别各自独立地为卤素、羟基、氨基、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卤代烷基、C_1-6烷基羟基、C_1-6烷基羰基、C_1-6烷氧基或C_1-6卤代烷氧基。。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 haloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy or _C1-6 haloalkoxy.

在本发明一任选实施方案中，为单键、n为1、m为1、且n为1时，X¹为N、X²为N、R^1a为H、R^1b为H、R^1c为H和R^1d为H不同时存在。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.

在本发明一任选实施方案中，当表示为单键、且n为1，X¹、X²、X⁴和X⁵均为N时，R^1a、R^1b、R^1c和R^1d不能同时为H。In an optional embodiment of the present invention, when When it represents 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.

在本发明一任选实施方案中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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烷氧基分别独立地任选地被1、2或3个R^a取代，R^a如本发明所定义。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 optionally substituted by 1, 2 or 3 ^Ra , and ^{Ra is} as defined in the present invention.

在本发明一任选实施方案中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、CH₃、CH₂CH₃、-OCH₃或-OCH₂CH₃，其中，所述CH₃、CH₂CH₃、-OCH₃或-OCH₂CH₃分别独立地任选地被1、2或3个R^a取代，R^a如本发明所定义。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 optionally substituted by 1, 2 or 3 ^Ra , and ^Ra is as defined in the present invention.

在本发明一任选实施方案中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、CH₃、CH₂F、CHF₂、CF₃、CH₂CH₂F、CH₂CHF₂、CH₂CF₃、-OCH₂F、-O CHF₂、-OCF₃、-OCH₂CH₂F、-OCH₂CHF₂、-OCH₂CF₃。In an optional embodiment of the present invention, 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 , —O CHF ₂ , —OCF ₃ , —OCH ₂ CH ₂ F , —OCH ₂ CHF ₂ , —OCH ₂ CF ₃ .

在本发明一任选实施方案中，各R^a独立地为F、Cl、Br、I、OH、CN、NH₂或环丙基。In an optional embodiment of the present invention, each ^Ra is independently F, Cl, Br, I, OH, CN, _NH2 or cyclopropyl.

在本发明一任选实施方案中，环A为任选地被1、2或3个R^b取代的C_3-6环烷基，R^b如本发明所定义。In an optional embodiment of the present invention, Ring A is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^b , R ^b is as defined herein.

在本发明一任选实施方案中，环A为 In an optional embodiment of the present invention, Ring A is

在本发明一任选实施方案中，环B为任选地被1、2或3个R^c取代的6-7元杂环烯基，R^c如本发明所定义。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 , R ^c being as defined herein.

在本发明一任选实施方案中，环B为6元杂环烯基。In an optional embodiment of the present invention, Ring B is a 6-membered heterocycloalkenyl.

在本发明一任选实施方案中，环B为 In an optional embodiment of the present invention, Ring B is

在本发明一任选实施方案中，当R^1b、R^1c和它们所连接的碳原子一起形成环B时，且n为1或2。In an optional 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.

需要说明的是，当R^1b、R^1c和它们所连接的碳原子一起形成环B时，R^1b和R^1c可参与成环也可不参与成环。例如，当R^1b和/或R^1c参与成环时，表示不存在时，结构单元为表示为单键时，为当R^1b和R^1c不参与成环时，为 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 bond, for When R ^1b and R ^1c do not participate in ring formation, for

在本发明一任选实施方案中，当R^1b、R^1c和它们所连接的碳原子一起形成环B时，n为2，此时环B为 In an optional embodiment of the present invention, 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

在本发明一任选实施方案中，环C为任选地被1、2或3个R^d取代的C_3-6环烷基，R^d如本发明所定义。In an optional embodiment of the present invention, Ring C is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^d , R ^d being as defined herein.

在本发明一任选实施方案中，环C为 In an optional embodiment of the present invention, ring C is

在本发明一任选实施方案中，各R^b、R^c和R^d分别独立地为卤素、OH、CN、NH₂或CH₃。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 .

在本发明一任选实施方案中，R²为F、Cl、CH₃或被1个或多个R^e取代的CH₃。In an optional embodiment of the present invention, R ² is F, Cl, CH ₃ or CH ₃ substituted by one or more ^Re .

在本发明一任选实施方案中，R²为Cl。In an optional embodiment of the present invention, ^R2 is Cl.

在本发明一任选实施方案中，R^e为F或Cl。In an optional embodiment of the present invention, ^Re is F or Cl.

在本发明一任选实施方案中，为单键，结构单元为或者In an optional embodiment of the present invention, is a single bond, a structural unit for or

为不存在，结构单元为其中，R^1a、R^1b、R^1c、R^1d、n和m如本发明前述所定义。 If it 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.

在本发明一任选实施方案中，中，n为1或2，R^1a、R^1b、R^1c、R^1d和m如本发明前述所定义。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.

在本发明一任选实施方案中，中，n为0或1，R^1a、R^1b、R^1c、R^1d和m如本发明前述所定义。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.

在本发明一任选实施方案中，结构单元为R^1a、R^1b、R^1c和R^1d如本发明所定义。In an optional embodiment of the present invention, the structural unit for R ^1a , R ^1b , R ^1c and R ^1d are as defined herein.

在本发明一任选实施方案中，结构单元为 R^1a、R^1b、R^1c和R^1d如本发明所定义。In an optional embodiment of the present invention, the structural unit for R ^1a , R ^1b , R ^1c and R ^1d are as defined herein.

在本发明一任选实施方案中，结构单元为其中，R^1a、R^1b、R^1c和R^1d如本发明前述所定义。In an optional embodiment of the present invention, the structural unit for wherein R ^1a , R ^1b , R ^1c and R ^1d are as defined above in the present invention.

在本发明一任选实施方案中，结构单元为 In an optional embodiment of the present invention, the structural unit for

在本发明一任选实施方案中，环W为4-7元杂环烷基。In an optional embodiment of the present invention, ring W is a 4-7 membered heterocycloalkyl group.

在本发明一任选实施方案中，环W为4-7元含氮杂环烷基。In an optional embodiment of the present invention, ring W is a 4-7 membered nitrogen-containing heterocycloalkyl group.

在本发明一任选实施方案中，环W为其中，X³为CH或N；h、g分别各自独立地为0、1或2；p、q分别各自独立地为1或2。In an optional embodiment of the present invention, ring W is wherein ^X3 is CH or N; h and g are each independently 0, 1 or 2; and p and q are each independently 1 or 2.

在本发明一任选实施方案中，h为1，g为1。In an optional embodiment of the present invention, h is 1 and g is 1.

在本发明一任选实施方案中，h为0，g为1。In an optional embodiment of the present invention, h is 0 and g is 1.

在本发明一任选实施方案中，h为1，g为0。In an optional embodiment of the present invention, h is 1 and g is zero.

在本发明一任选实施方案中，h为0，g为0。In an optional embodiment of the present invention, h is 0 and g is 0.

在本发明一任选实施方案中，X³为CH。In an optional embodiment of the present invention, X ³ is CH.

在本发明一任选实施方案中，X³为N。In an optional embodiment of the present invention, ^X3 is N.

在本发明一任选实施方案中，p为1，q为1。In an optional embodiment of the present invention, p is 1 and q is 1.

在本发明一任选实施方案中，环W为氮杂环丁基、吡咯烷基、哌啶基或2-氮杂螺[3.3]庚烷基。In an optional embodiment of the present invention, ring W is azetidinyl, pyrrolidinyl, piperidinyl or 2-azaspiro[3.3]heptanyl.

在本发明一任选实施方案中，环W为 In an optional embodiment of the present invention, ring W is

在本发明一任选实施方案中，X¹和X²均为N。In an optional embodiment of the present invention, ^X1 and ^X2 are both N.

在本发明一任选实施方案中，X¹为CH，X²为N。In an optional embodiment of the present invention, ^X1 is CH and ^X2 is N.

在本发明一任选实施方案中，X⁴和X⁵均为N。In an optional embodiment of the present invention, ^X4 and ^X5 are both N.

在本发明一任选实施方案中，R²为F、Cl、CH₃或被1个或多个R^e取代的CH₃其中，R^e如本发明前述所定义。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.

在本发明一任选实施方案中，m为1。In an optional embodiment of the present invention, m is 1.

在本发明一任选实施方案中，m为2。In an optional embodiment of the present invention, m is 2.

在本发明一任选实施方案中，式(Ⅱ)化合物具有结构式(ⅠIⅠa)或(ⅠIⅠb)：In an optional embodiment of the present invention, the compound of formula (II) has the structural formula (IIIa) or (IIIb):

其中，X³为CH或N；h、g分别各自独立地为0、1或2；p、q分别各自独立地为1或2，R^1a、R^1b、R^1c、R^1d、n、m、X¹、X²、X⁴和X⁵如本发明前述所定义。wherein ^X3 is CH or N; h and g are each independently 0, 1 or 2; p and q are each independently 1 or 2; ^R1a , R1b, ^R1c ^, ^R1d , n, m, ^X1 , ^X2 , ^X4 and ^X5 are as defined above in the present invention.

在本发明一任选实施方案中，式(II)所示化合物具有结构式(ⅠIⅠa3)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIa3):

其中，R^1a、R^1b、R^1c、R^1d、n、m、X¹、X²、X³、X⁴、X⁵、h、g、p和q如本发明前述所定义。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.

在本发明一任选实施方案中，式(II)所示化合物具有结构式(ⅠIⅠa4)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIa4):

在本发明一任选实施方案中，式(II)所示化合物具有结构式(IIⅠb2)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IIIb2):

在本发明一任选实施方案中，式(Ⅱ)化合物具有结构(Ⅰ)，In an optional embodiment of the present invention, the compound of formula (II) has structure (I),

其中，in,

表示为单键或不存在； Represented as a single bond or absent;

X³为CH或N； ^X3 is CH or N;

n为0、1或2。n is 0, 1 or 2.

在本发明一任选实施方案中，本发明化合物具有结构(Ia)：In an optional embodiment of the present invention, the compound of the present invention has structure (Ia):

其中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；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 _1-6 alkyl, -C(=O)-NH-C _1-6 alkyl and -NH-C(=O)-OC _1-6 alkyl are each independently optionally substituted by 1, 2 or 3 R ^a ;

或者，R^1c、R^1d和它们所连接的碳原子一起形成环C，所述环C为任选地被1、2或3个R^d取代的C_3-6环烷基。Alternatively, R ^1c , R ^1d and the carbon atom to which they are attached together form a ring C, which is a C _3-6 cycloalkyl group optionally substituted with 1, 2 or 3 R ^d .

在本发明一任选实施方案中，式(Ⅰ)化合物具有结构(Ia1)：In an optional embodiment of the present invention, the compound of formula (I) has the structure (Ia1):

在本发明一任选实施方案中，式(Ⅰ)化合物具有结构(Ia)：In an optional embodiment of the present invention, the compound of formula (I) has structure (Ia):

其中，R^1a、R^1b和它们所连接的碳原子一起形成环A，所述环A为任选地被1、2或3个R^b取代的C_3-8环烷基，R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；wherein 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 , 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 R _a , -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 optionally substituted by 1, 2 or 3 R ^a ;

或者，R^1c、R^1d和它们所连接的碳原子一起形成环C，所述环C为任选地被1、2或3个R^d取代的C_3-6环烷基，R^1a和R^1b分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代。Alternatively, 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 group optionally substituted by 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 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 _R _a and -S(═O) ₂ -C _1-6 _alkyl _are each independently optionally substituted with 1, 2 or 3 R ^a .

其中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代，且X¹为N时，R^1a、R^1b、R^1c和R^1d不能同时为H。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, _C1-6alkyl -C(=O)-NH- _C1-6alkyl and -NH-C(=O) _-OC1-6alkyl are each independently optionally substituted by 1, 2 or 3 R ^a , and when X ¹ is N, R ^1a , R ^1b , R ^1c and R ^1d cannot be H at the same time.

在本发明一任选实施方案中，式(Ⅱ)所示化合物具有结构式(IV)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (IV):

其中，式(IV)中，X¹为N、X²为N、R^1a为H、R^1b为H、R^1c为H和R^1d为H不同时存在；R^1a、R^1b、R^1c、R^1d、n、m、X¹、X²、X⁴、X⁵和R²如本发明前述所定义。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.

在本发明一任选实施方案中，式(Ⅱ)所示化合物具有结构式(V)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (V):

R^1a、R^1b、R^1c、R^1d、n、m、X¹、X²、X⁴、X⁵和R²如本发明前述所定义。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.

在本发明一任选实施方案中，式(Ⅱ)所示化合物具有结构式式(VI)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (VI):

在本发明一任选实施方案中，式(VI)中，n为0或1。In an optional embodiment of the present invention, in formula (VI), n is 0 or 1.

在本发明一任选实施方案中，式(VI)中，n为0。In an optional embodiment of the present invention, in formula (VI), n is 0.

在本发明一任选实施方案中，本发明化合物具有结构式(Ⅱ-A)：In an optional embodiment of the present invention, the compound of the present invention has the structural formula (II-A):

其中，各R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；m、X¹和环W如本发明所定义。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 _{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 herein.

在本发明一任选实施方案中，本发明化合物具有结构(Ⅱ-A1):In an optional embodiment of the present invention, the compound of the present invention has the structure (II-A1):

其中，各R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代；m为1或2；h、g分别地为0、1或2；p、q分别地为1或2。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 _C1-6alkyl , -C(=O)-NH- _C1-6alkyl and -NH-C(=O) _-OC1-6alkyl are each independently optionally substituted with 1, 2 or 3 ^Ra ; m is 1 or 2; h, g is 0, 1 or 2, respectively; p, q is 1 or 2, respectively.

在本发明一任选实施方案中，本发明化合物具有结构(Ⅱ-A2):In an optional embodiment of the present invention, the compound of the present invention has the structure (II-A2):

在本发明一任选实施方案中，本发明化合物具有结构(Ib)：In an optional embodiment of the present invention, the compound of the present invention has structure (Ib):

其中，各R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代。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, _{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 ^a .

在本发明一任选实施方案中，本发明化合物具有结构(Ib1)：In an optional embodiment of the present invention, the compound of the present invention has structure (Ib1):

在本发明一任选实施方案中，本发明化合物具有结构(Ic)：In an optional embodiment of the present invention, the compound of the present invention has structure (Ic):

其中，n为0、1或2；Where n is 0, 1 or 2;

R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代。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 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 ^a .

在本发明一任选实施方案中，本发明化合物具有结构(Ic1)：In an optional embodiment of the present invention, the compound of the present invention has the structure (Ic1):

其中，n为0、1或2；Where n is 0, 1 or 2;

在本发明一任选实施方案中，本发明化合物具有结构(Id)：In an optional embodiment of the present invention, the compound of the present invention has structure (Id):

其中，R^1a、R^1b、R^1c和R^1d分别独立地为H、卤素、OH、CN、NH₂、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a取代。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, _{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 ^a .

在本发明一任选实施方案中，本发明化合物具有结构(Id1)：In an optional embodiment of the present invention, the compound of the present invention has the structure (Id1):

在本发明一任选实施方案中，式(II)所示化合物具有结构式(Vd)或(Ve)：In an optional embodiment of the present invention, the compound represented by formula (II) has the structural formula (Vd) or (Ve):

在本发明一任选实施方案中，式(Ⅱ)或式(Ⅰ)所述化合物选自下列任一化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：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:

本发明的第二方面，本发明提出了一种中间体化合物，其为式(VⅡ)所示的化合物，或者式(VⅡ)所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，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),

X¹'和X²'分别独立地为CH或N，并且X¹'和X²'至少有一个为N；X ¹ ' and X ² ' are each independently CH or N, and at least one of X ¹ ' and X ² ' is N;

每个R^1a'、R^1b'、R^1c'和R^1d'分别各自独立地为H、卤素、OH、CN、NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氨基、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NH₂、C_1-6烷基、C_1-6烷氨基、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烷基分别独立地任选地被1、2或3个R^a'取代；Each of R ^1a ', R ^1b ', R ^1c ' and R ^1d ' is 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 _1-6 alkoxy, -SC _1-6 alkyl, -S(＝O)-C _1-6 alkyl, -S(＝O) ₂ -C 1-6 alkyl R _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 optionally substituted by 1, 2 or 3 R ^a ′;

或者，R^1a'、R^1b'和它们所连接的碳原子一起形成环A'，所述环A'为任选地被1、2或3个R^b'取代的C_3-8环烷基；Alternatively, 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 ';

或者，R^1b'、R^1c'和它们所连接的碳原子一起形成环B'，所述环B'为6-8元杂环烷基或6-8元杂环烯基，所述6-8元杂环烷基和6-8元杂环烯基分别独立地任选地被1、2或3个R^c'取代；Alternatively, R ^1b ', R ^1c ' and the carbon atom 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, and the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are each independently optionally substituted by 1, 2 or 3 R ^c ';

或者，R^1c'、R^1d'和它们所连接的碳原子一起形成环C'，所述环C'为任选地被1、2或3个R^d'取代的C_3-8环烷基；Alternatively, 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 _3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R ^d ';

每个R^a'各自独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基、C_3-6环烷基或4-6元杂环烷基，其中所述C_1-3烷基、C_1-3烷氧基、C_3-6环烷基和4-6元杂环烷基分别独立地任选地被1、2或3个R'取代；each ^Ra ' is independently halogen, OH, CN, _NH2 , _C1-3 alkyl, C1-3 alkoxy, _C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein said _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl and _4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R';

每个R^b'、R^c'和R^d'分别各自独立地为卤素、OH、CN、NH₂、C_1-3烷基、C_1-3烷氧基或C_1-3烷氨基，其中所述C_1-3烷基、C_1-3烷氧基和C_1-3烷氨基分别独立地任选地被1、2或3个R'取代；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';

每个R'各自独立地为卤素、OH、CN或NH₂；Each R' is independently halogen, OH, CN or _NH2 ;

n'为0、1或2；n' is 0, 1 or 2;

m'为0、1或2；m' is 0, 1 or 2;

R^x为卤素。 ^Rx is halogen.

在本发明一任选实施方案中，中间体化合物的特征在于，X¹和X²均为N。In an optional embodiment of the present invention, the intermediate compound is characterized in that ^X1 and ^X2 are both N.

在本发明一任选实施方案中，中间体化合物的特征在于，X¹为CH，X²为N。In an optional embodiment of the present invention, the intermediate compound is characterized in that ^X1 is CH and ^X2 is N.

在本发明一任选实施方案中，中间体化合物的特征在于，每个R^1a'、R^1b'、R^1c'和R^1d'分别各自独立地为H、卤素、OH、CN、NH₂、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烷氧基分别独立地任选地被1、2或3个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 optionally substituted by 1, 2 or 3 ^Ra '.

在本发明一任选实施方案中，中间体化合物的特征在于，每个R^1a'、R^1b'、R^1c'和R^1d'分别各自独立地为H、卤素、OH、CN、NH₂、CH₃、CH₂CH₃、-OCH₃或-OCH₂CH₃，其中，所述CH₃、CH₂CH₃、-OCH₃或-OCH₂CH₃分别独立地任选地被1、2或3个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 optionally substituted by 1, 2 or 3 ^Ra '.

在本发明一任选实施方案中，中间体化合物的特征在于，每个R^1a'、R^1b'、R^1c'和R^1d'分别各自独立地为H、卤素、OH、CN、NH₂、CH₃、CH₂F、CHF₂、CF₃、CH₂CH₂F、CH₂CHF₂、CH₂CF₃、-OCH₂F、-OCHF₂、-OCF₃、-OCH₂CH₂F、-OCH₂CHF₂、-OCH₂CF₃。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 ′ 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 .

在本发明一任选实施方案中，中间体化合物的特征在于，每个R^a'各自独立地为F、Cl、Br、I、OH、CN、NH₂或环丙基。In an optional embodiment of the present invention, the intermediate compound is characterized in that each ^Ra ' is independently F, Cl, Br, I, OH, CN, _NH2 or cyclopropyl.

在本发明一任选实施方案中，中间体化合物的特征在于，环A'为任选地被1、2或3个R^b'取代的C_3-6环烷基。In an optional embodiment of the invention, the intermediate compounds are characterized in that Ring A' is _C3-6 cycloalkyl optionally substituted by 1, 2 or 3 ^Rb '.

在本发明一任选实施方案中，中间体化合物的特征在于，当R^1b'、R^1c'和它们所连接的碳原子一起形成环B'时，n'为2，此时环B'为 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 the ring B' is

在本发明一任选实施方案中，中间体化合物的特征在于，环C'为任选地被1、2或3个R^b'取代的C_3-6环烷基。In an optional embodiment of the invention, the intermediate compounds are characterized in that ring C' is _C3-6 cycloalkyl optionally substituted by 1, 2 or 3 ^Rb '.

在本发明一任选实施方案中，中间体化合物的特征在于，每个R^b'、R^c'和R^d'分别各自独立地为卤素、OH、CN、NH₂或CH₃。In an optional embodiment of the present invention, the intermediate compound is characterized in that each R ^b ′, R ^c ′ and R ^d ′ are each independently halogen, OH, CN, NH ₂ or CH ₃ .

在本发明一任选实施方案中，中间体化合物的特征在于，环A'为 In an optional embodiment of the invention, the intermediate compound is characterized in that ring A' is

在本发明一任选实施方案中，中间体化合物的特征在于，环C'为在本发明一任选实施方案中，中间体化合物的特征在于，结构单元为 In an optional embodiment of the invention, the intermediate compound is characterized in that ring C' is In an optional embodiment of the invention, the intermediate compound is characterized in that the structural unit for

在本发明一任选实施方案中，中间体化合物的特征在于，中，n为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.

在本发明一任选实施方案中，中间体化合物的特征在于，中，n为0或1。In an optional embodiment of the present invention, the intermediate compound is characterized in that In this example, n is 0 or 1.

在本发明一任选实施方案中，中间体化合物的特征在于，结构单元为 In an optional embodiment of the invention, the intermediate compound is characterized in that the structural unit for

在本发明一任选实施方案中，中间体化合物的特征在于，结构单元为In an optional embodiment of the invention, the intermediate compound is characterized in that the structural unit for

在本发明一任选实施方案中，中间体化合物的特征在于，R^x为Cl。In an optional embodiment of the present invention, the intermediate compound is characterized in that R ^x is Cl.

在本发明一任选实施方案中，中间体化合物的特征在于，m'为0、1或2。In an optional embodiment of the present invention, the intermediate compound is characterized in that m' is 0, 1 or 2.

在本发明一任选实施方案中，中间体化合物的特征在于，m'为0。In an optional embodiment of the present invention, the intermediate compound is characterized in that m' is zero.

在本发明一任选实施方案中，中间体化合物的特征在于，m'为1。In an optional embodiment of the present invention, the intermediate compound is characterized in that m' is 1.

在本发明一任选实施方案中，中间体化合物的特征在于，m'为2。In an optional embodiment of the present invention, the intermediate compound is characterized in that m' is 2.

在本发明一任选实施方案中，式(VⅡ)化合物具有结构式(VⅠⅠa)：In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIIa):

在本发明一任选实施方案中，式(VⅡ)化合物具有结构式(VⅠⅠb)或式(VⅠⅠc)：In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIIb) or formula (VIIIc):

其中，m'和R^x如本发明前述所定义。wherein m' and ^Rx are as defined above in the present invention.

在本发明一任选实施方案中，式(VⅡ)化合物具有结构式(VⅠⅠd)或式(VⅠⅠe)：In an optional embodiment of the present invention, the compound of formula (VII) has the structural formula (VIIId) or formula (VIIIe):

在本发明一任选实施方案中，式(VⅡ)化合物选自下列任一化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：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:

本发明的第三方面，本发明提出了一种药物组合物，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.

在本发明一任选实施方案中，上述药物组合物进一步包括药学上可接受的载体或赋形剂。In an optional embodiment of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

本发明的第四方面，本发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药物组合物在制备用于治疗或预防PDE4B相关疾病的药物中的用途。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.

在本发明一任选实施方案中，上述PDE4B相关疾病包括选自下列的至少之一：治疗呼吸道疾病、胃肠疾病、炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应以及与平滑肌收缩性相关的疾病。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.

在本发明一任选实施方案中，上述PDE4B相关疾病包括选自下列的至少之一：哮喘、慢性支气管炎、特发性肺纤维化、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。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.

术语和定义Terms and Definitions

除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。Those skilled in the art will appreciate that, according to the conventions used in the art, 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.

除非另有规定，术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。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 the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

除非另有规定，术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of the compounds of the present invention.

除非另有规定，术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。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 the administration of a compound to an organism.

除非另有规定，术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。Unless otherwise specified, the terms “comprise” or “include” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

除非另有规定，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples 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 pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.

除非另有规定，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。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 solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino 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 amino group, respectively.

除非另有规定，术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes cis-trans isomers, enantiomers, diastereomers and conformational isomers.

依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of raw 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 a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent 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 for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called 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 olefins, 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 the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。When the bonds to the chiral carbon in the formula of the present invention are depicted 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 graphic 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)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的色谱柱上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, 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 a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolution acid that is an optically active salified 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, malic 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 α-methyl-benzylamine (e.g., S and R forms or diastereomeric pure forms), 2-phenylglycinol, norephedrine, 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., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configurations can also be used to obtain any enantiomer or diastereomer of the compounds described in the present invention through stereo organic synthesis.

除非另有规定，术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in two positions in a molecule. 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 a mixture of compounds. The position of equilibrium depends on the chemical characteristics 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.

除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。例如：表示为中的其中一种构型，而则表示为剩下的另一种构型。Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter. For example: Expressed as One of the configurations, and It represents the remaining configuration.

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(²H)，氚(³H)，碘-125(¹²⁵I)或C-14(¹⁴C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, 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 oral dosage forms of the present invention, an "effective amount" of an active substance in a 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 skilled in the art based on routine experiments.

除非另有规定，术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。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 substituted compound 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.

除非另有规定，术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。Unless otherwise specified, the terms "optional" or "optionally" mean 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 it does not.

除非另有规定，术语“C_1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。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、C₆和C₅烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C_1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。Unless otherwise specified, the term "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl 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, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C _1-6 alkyl 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.

除非另有规定，术语“C_1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C_1-3烷基包括C_1-2和C_2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C_1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C _1-3 alkyl" is used to represent a straight 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.

在单独或作为其他取代基一部分时，术语“卤代”可与术语“卤素取代”互换使用。The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

除非另有规定，“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基。Unless otherwise specified, "haloalkyl" or "halogen-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

除非另有规定，“C_2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C_2-6烯基包括C_2-4、C_2-3、C₄、C₃和C₂烯基等；其可以是一价、二价或者多价。C_2-6烯基的实施例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。Unless otherwise specified, "C _2-6 alkenyl" is used to represent a straight 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 C _2-6 alkenyl includes C _2-4 , C _2-3 , C ₄ , C ₃ and C ₂ alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C _2-6 alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

除非另有规定，“C_2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C_2-6炔基包括C_2-4、C_2-3、C₄、C₃和C₂炔基等。其可以是一价、二价或者多价。C_2-6炔基的实施例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。Unless otherwise specified, "C _2-6 alkynyl" is used to represent a straight or branched hydrocarbon 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 group includes C _2-4 , C _2-3 , C ₄ , C ₃ and C ₂ alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C _2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

除非另有规定，术语“C_1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。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、C₆、C₅、C₄和C₃烷氧基等。C_1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-6 alkoxy 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, etc. Examples of C _1-6 alkoxy 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, isopentyl and neopentyl), hexyl and the like.

除非另有规定，术语“C_1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C_1-3烷氧基包括C_1-2、C_2-3、C₃和C₂烷氧基等。C_1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C _1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-3 alkoxy includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy, etc. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

除非另有规定，术语“C_3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C_3-8环烷基包括C_3-6、C_3-5、C_4-8、C_4-6、C_4-5、C_5-8或C_5-6环烷基等；其可以是一价、二价或者多价。C_3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。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, fused 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.

除非另有规定，术语“C_3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C_3-6环烷基包括C_3-5、C_4-5和C_5-6环烷基等；其可以是一价、二价或者多价。C_3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, the term "C _3-6 cycloalkyl" means 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.

除非另有规定，C_n-n+m或C_n-C_n+m包括n至n+m个碳的任何一种具体情况，例如C_1-12包括C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、和C₁₂，也包括n至n+m中的任何一个范围，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元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。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. _9-12, etc.; similarly, n-membered to n+m-membered means that the number of atoms in 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.

除非另有规定，术语“6-8元杂环烷基”本身或者与其他术语联合分别表示由6至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“6-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。例如6-8元杂环烷基包括但不限于6元、7元、8元。6-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基。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 may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected 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, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

除非另有规定，术语“6-8元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由6至8个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“6-8元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述6-8元杂环烯基包括6元、7元和8元杂环烯基等。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, 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 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 ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "6-8 membered heterocycloalkenyl", heteroatoms may occupy the position where the heterocycloalkenyl is connected to the rest of the molecule. The 6-8 membered heterocycloalkenyl includes 6-membered, 7-membered and 8-membered heterocycloalkenyl, etc.

除非另有规定，术语“卤代基”或“卤素”为氟、氯、溴和碘。Unless otherwise specified, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless otherwise clearly indicated, 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. In more detail, 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.

除非另有规定，术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。Unless otherwise specified, the term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

除非另有规定，术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。Unless otherwise specified, the term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and 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 does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing 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) Alleviating disease: e.g., alleviating a 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.

本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, i.e. arresting its development;

(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.

有益效果Beneficial Effects

根据本发明的实施例，本发明至少具有如下技术效果至少之一：According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

(1)本发明提供了结构新颖、药代动力学性质优良、药效或成药性好的PDE4B抑制剂，可以用于有效治疗PDE4B相关的疾病、病症；(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 conditions;

(2)相对于PDE4D型受体，本发明化合物对PDE4B型受体的抑制活性更为显著，具有更好的PDE4B选择性，能显著改善因PDE4D型受体抑制导致的胃肠道副作用如呕吐等；(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)本发明化合物有着优良的人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；(3) The compounds of the present invention have excellent human PBMC secretion TNFα inhibitory activity, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and have good anti-inflammatory effects;

(4)本发明化合物表现出优良的血浆暴露、半衰期和生物利用度，有优良的药代动力学性质，成药前景良好。(4) The compounds of the present invention exhibit excellent plasma exposure, half-life and bioavailability, have excellent pharmacokinetic properties and have good prospects for drug development.

具体实施方式DETAILED DESCRIPTION

以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。The present invention is further described below in conjunction with specific examples. 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 examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art 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.

中间体A1的合成路线如下：The synthetic route of intermediate A1 is as follows:

第一步：(1-氨基环丁基)甲醇(A1)的合成Step 1: Synthesis of (1-aminocyclobutyl)methanol (A1)

将室温下将1-氨基环丁甲酸(15g，130.3mmol)溶解于四氢呋喃(300Ml)中，在0℃、氩气保护并且搅拌条件下滴加氢化铝锂(2.5M四氢呋喃溶液，104mL，260mmol)。滴加完毕将反应液缓慢升至室温并且氩气保护下搅拌16h。冰浴下用十水合硫酸钠固体淬灭反应后再用无水硫酸钠干燥，过滤。滤饼用乙酸乙酯淋洗。合并后的滤液在室温下浓缩得(1-氨基环丁基)甲醇(12g，产率90％)。Dissolve 1-aminocyclobutanecarboxylic acid (15 g, 130.3 mmol) in tetrahydrofuran (300 mL) at room temperature, and add lithium aluminum hydride (2.5 M tetrahydrofuran solution, 104 mL, 260 mmol) dropwise at 0°C, under argon protection and stirring. After the addition is complete, slowly warm the reaction solution to room temperature and stir for 16 hours under argon protection. Quench the reaction with sodium sulfate decahydrate solid in an ice bath, dry with anhydrous sodium sulfate, and filter. Rinse the filter cake with ethyl acetate. The combined filtrate is concentrated at room temperature to obtain (1-aminocyclobutyl)methanol (12 g, yield 90%).

中间体A2的合成路线如下：The synthetic route of intermediate A2 is as follows:

第一步：哌啶-4-甲脒(A2-2)的合成Step 1: Synthesis of piperidine-4-carboxamidine (A2-2)

将在4M HCl的1,4-二氧六环(45ml,3eq,180mmo1)加至烧瓶中。将该溶液冷却至0℃，并在约30分钟内加入4-氰基哌啶(6.6g,60mmol)，然后加入甲醇(6mL,180mmol,3eq)，同时保持该温度低于10℃(反应放热)。将上述混合物在室温搅拌6-8小时，将该混合物冷却至5℃，并加在25wt％NaOMe(甲醇溶液)(32g,100mmol,2eq)，同时保持温度低于15℃，然后将该反应液搅拌1小时。将7Ν在甲醇中的氨水(13mL,1.5eq,90mmol)加至上述混合物，并在标准室温搅拌8小时。将该混合物减压浓缩至约50ml的体积，得到粗制的中间体A2-2的溶液，使用不需分离。1,4-Dioxane (45 ml, 3 eq, 180 mmol) in 4 M 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 maintaining 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 25 wt% NaOMe (methanol solution) (32 g, 100 mmol, 2 eq) was added while maintaining the temperature below 15°C, and the reaction was stirred for 1 hour. 7N ammonia in methanol (13 mL, 1.5 eq, 90 mmol) was added to the mixture and stirred at standard room temperature for 8 hours. The mixture was concentrated under reduced pressure to a volume of about 50 ml to give a crude solution of intermediate A2-2, which was used without isolation.

第二步：5-氯-2-(哌啶-4-基)嘧啶(中间体A2)的合成Step 2: Synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (Intermediate A2)

将中间体A2-2的上述溶液冷却至约20℃，并加入25wt％NaOMe(甲醇溶液)(33g,150mmol)。然后将该化合物搅拌30分钟。在标准室温，经约30分钟分两批将化合物D(＝(Z)-N-(2-氯-3-(二甲氨基)亚烯丙基)-N-甲基甲烷-六氟磷酸铵(17g,51mmol)加至上述混合物，并在室温搅拌3小时。将该混合物减压浓缩，将反应混合物用水稀释，然后用乙酸乙酯萃取，合并有机层，用饱和食盐水洗涤有机相，硫酸钠干燥，浓缩得到粗品，用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝20:1-10:1，梯度洗脱)得4-(5-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯(中间体A2)(9g，产率75％)。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. The compound was then stirred for 30 minutes. At standard room temperature, 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, 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, the organic phases were 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)piperazine-1-carboxylic acid tert-butyl ester (intermediate A2) (9 g, yield 75%).

实施例1：目标化合物1-P1&P2的制备Example 1: Preparation of target compounds 1-P1 & P2

(S)&(R)-2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)-甲醇(目标化合物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)

目标化合物1-P1&P2的合成路线如下：The synthetic route of the target compound 1-P1&P2 is as follows:

第一步：甲基-3-氧亚基四氢-2H-噻喃-2-甲酸基酯(1-2)的合成Step 1: Synthesis of methyl-3-oxyylidenetetrahydro-2H-thiopyran-2-carboxylate (1-2)

将甲基4-(2-甲氧基-2-氧亚基-乙基)巯基丁酯(1-1)(3.00g,14.5mmol)溶解在甲苯(50mL)中，加入甲醇钠(942mg,17.4mmol)，升至105℃反应3小时。将反应液倒入冷的的12N浓盐酸中(10mL)中，再用乙酸乙酯(90mL)萃取3次，合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩得到黄色油状产物甲基-3-氧亚基四氢-2H-噻喃-2-甲酸基酯(1-2)(2.70g,直接用于下一步)。LC-MS,M/Z(ESI):175.0(M+H).Dissolve methyl 4-(2-methoxy-2-oxyylidene-ethyl) mercaptobutyl ester (1-1) (3.00 g, 14.5 mmol) in toluene (50 mL), add sodium methoxide (942 mg, 17.4 mmol), and heat to 105 ° C for 3 hours. Pour the reaction solution into cold 12N concentrated hydrochloric acid (10 mL), extract with ethyl acetate (90 mL) three times, combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate 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)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-酚(1-3)的合成Step 2: Synthesis of 2-(methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-4-ol (1-3)

将氢氧化钾(1.21g,21.5mmol)溶于无水甲醇(40mL)中，加入甲基-3-氧亚基四氢-2H-噻喃-2-甲酸基酯(1-2)(2.50g,14.3mmol)和2-甲基-2-异硫代脲硫酸盐(2.00g,7.17mmol)，25℃反应16小时。将反应液倒入冰水(40mL)和冰醋酸(2mL)中，过滤收集析出沉淀物，得到2-(甲硫基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-酚(1-3)(3.00g,直接用于下一步)。LC-MS,M/Z(ESI):215.0(M+H).Potassium hydroxide (1.21 g, 21.5 mmol) was dissolved in anhydrous methanol (40 mL), and methyl-3-oxyylidenetetrahydro-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]pyrimidine-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：7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-2,4-二酚(1-4)的合成Step 3: Synthesis of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (1-4)

将2-(甲硫基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-酚(1-3)(4.00g,18.6mmol)溶解在水(20mL)和冰醋酸(40mL)中，升温至105℃，反应60小时。将反应液冷却后过滤收集析出固体，干燥，得到产物7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-2,4-二酚(1-4)(5.00g,直接用于下一步)。LC-MS,M/Z(ESI):185.0(M+H).2-(Methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine-4-ol (1-3) (4.00 g, 18.6 mmol) was dissolved in water (20 mL) and glacial acetic acid (40 mL), heated to 105°C, and reacted for 60 hours. After the reaction solution was cooled, the precipitated solid was collected by filtration and dried 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶(1-5)的合成Step 4: Synthesis of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (1-5)

将7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-2,4-二酚(1-4)(4.00g,21.7mmol)和N,N-二甲基苯胺(657mg,5.43mmol,688μL)溶解在三氯氧磷(16.6g,108mmol,10.0mL)中，氮气置换，在90℃下反应3小时。将反应液浓用二氯甲烷(100mL)稀释，小心倒入水(100mL)中淬灭，二氯甲烷(300mL)萃取三次，饱和食盐水(150mL)洗涤，无水硫酸钠干燥，浓缩拌样,硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1/0-10/1)得到化合物2,4-二氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶(1-5)(700mg,产率13.6％)。LC-MS,M/Z(ESI):220.9(M+H)。¹H NMR(400MHz,DMSO-d₆)δ＝3.12-3.22(m,2H),2.94(m,2H),2.05-2.18(m,2H).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 dichloromethane (100 mL), carefully poured into water (100 mL) to quench, extracted with dichloromethane (300 mL) three times, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated and mixed, and separated and purified by silica gel column (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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(1-6)的合成Step 5: Synthesis of (1-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (1-6)

将2,4-二氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶(1-5)(600mg,2.52mmol)和(1-氨基环丁基)甲醇(304mg,3.03mmol)溶解在乙腈(20mL)中，加入三乙胺(1.28g,12.6mmol,1.76mL)。80℃反应10小时。将反应液用水(40mL)稀释，乙酸乙酯(120mL)萃取三次，饱和食盐水洗涤(40mL)，无水硫酸钠干燥，浓缩，硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10/1)得到化合物(1-((2-氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(1-6)(700mg,产率77.6％)。LC-MS,M/Z(ESI):286.0(M+H).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) were dissolved in acetonitrile (20 mL), and triethylamine (1.28 g, 12.6 mmol, 1.76 mL) was added. The mixture was reacted 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 separated and purified on a silica gel plate (dichloromethane: methanol (V/V) = 10/1) to obtain the 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-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(1-7)的合成Step 6: Synthesis of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7)

将(1-((2-氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(1-6)(700mg,1.96mmol)、S-(-)-1,1'-联-2-萘酚(56.1mg,195μmol)溶解在二氯甲烷(10mL)中，再加入四异丙氧化钛(27.8mg,97.9μmol,28.9μL)和水(5.31mg,1.96mmol,35.3μL)，加完后置换氮气，20℃反应1小时。再加入过氧叔丁醇(264mg,2.06mmol,281μL,70％purity)，25℃反应1.5小时。将反应液用10％亚硫酸钠水溶液(10mL)淬灭，二氯甲烷(90mL)萃取三次，合并有机相用水(50mL)洗涤，无水硫酸钠干燥，浓缩，硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10/1)得到化合物2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(1-7)(300mg,产率45.7％)。LC-MS,M/Z(ESI):302.2(M+H).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), replace nitrogen after addition, 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), the combined organic phases were washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified on a silica gel plate (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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)-甲醇(化合物1)的合成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)

将2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(1-7)(200mg,596μmol)溶解在1,4-二氧六环(30mL)中，加入5-氯-2-(4-哌啶基)嘧啶(167mg,715μmol)和N,N-二异丙基乙胺(385mg,2.98mmol,519μL)。80℃下反应3小时。将反应液浓缩,加入饱和碳酸氢钠溶液(30mL)，乙酸乙酯(90mL)萃取三次,饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩，硅胶板分离纯化(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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)-甲醇(化合物1)(250mg,，产率86.0％)。LC-MS,M/Z(ESI):463.4(M+H).2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (1-7) (200 mg, 596 μmol) was dissolved in 1,4-dioxane (30 mL), and 5-chloro-2-(4-piperidinyl)pyrimidine (167 mg, 715 μmol) and N,N-diisopropylethylamine (385 mg, 2.98 mmol, 519 μL) were added. The mixture was reacted 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 separated and purified on a silica gel plate (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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)-甲醇(目标化合物1-P1&P2)的合成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)

将外消旋体化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)-甲醇(化合物1)(250mg,513μmol)通过正相高效液相色谱法进行手性分离，分离方法为(色谱柱：DAICEL CHIRALPAKAD(250mm*30mm,10μm)；流动相：A＝二氧化碳，B＝氨水(0.1％)+乙醇；梯度：50％-50％，7分钟)，化合物(S)or(R)-2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(目标化合物1-P1，保留时间1.387min)(90.0mg,产率37.9％yield)，LC-MS,M/Z(ESI):463.4(M+H)。¹H NMR(400MHz,DMSO-d₆)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).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 high performance liquid chromatography (chromatographic column: DAICEL CHIRALPAKAD (250mm*30mm, 10μm); mobile phase: A=carbon dioxide, B=ammonia water (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 1.387min) (90.0mg, yield 37.9% yield), LC-MS, M/Z(ESI):463.4(M+H). ¹ H NMR (400MHz, 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-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(目标化合物1-P2，保留时间1.739min)(130mg,产率54.7％yield)。LC-MS,M/Z(ESI):463.4(M+H)。¹H NMR(400MHz,DMSO-d₆)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).(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%). LC-MS, M/Z (ESI): 463.4 (M+H). ¹ H NMR (400MHz, 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).

实施例2：目标化合物8-P1和8-P2的制备：Example 2: Preparation of target compounds 8-P1 and 8-P2:

(R)or(S)-2-(6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物8-P1&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 compound 8-P1 & 8-P2)

目标化合物8-P1&8-P2的合成路线:Synthesis route of target compound 8-P1 & 8-P2:

第一步：6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚-5-烯-2-羧酸叔丁酯的合成Step 1: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate

将6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2-氮杂螺[3.3]庚-5-烯-2-羧酸叔丁酯(4.0g,12.45mmol)和5-氯-2-碘嘧啶(3.59g,14.94mmol)溶解在1,4二氧六环(60mL)和水(12mL)中，加入碳酸钾(4.3g,31.13mmol)和1,1-双(二苯基磷)二茂铁氯化钯(903mg,1.24mmol)，在氮气保护下90℃反应5小时。将反应液加水(100mL)稀释，然后用乙酸乙酯(200mL)萃取三次，用饱和食盐水(100mL)洗涤有机相，用无水硫酸钠干燥，过滤，浓缩，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-5:1)纯化得到化合物6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚-5-烯-2-羧酸叔丁酯(1.3g,收率34％)。Dissolve tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (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 separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1:0-5:1) to obtain compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (1.3 g, yield 34%).

第二步：6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成Step 2: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate

将原料6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚-5-烯-2-羧酸叔丁酯(1.3g，4.22mmol)和Rh(PPh₃)₃Cl(338.45mg，0.844mmol)溶在甲醇(20mL)中，置换氢气并升温至50℃搅拌反应12小时。反应完毕后，将反应液浓缩得到粗品，经层析柱分离纯化(二氯甲烷：甲醇(V/V)＝10:1)，得6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(1.2g，产率91.7％)。LC-MS,M/Z(ESI):309.98(M+1).The raw materials 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl 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°C for stirring and reaction for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1) to obtain 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl 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-氮杂螺[3.3]庚烷的合成Step 3: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane

将原料6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(700mg，2.26mmol)溶在二氯甲烷(10mL)中，加入三氟乙酸(3mL)，反应液在室温下搅拌2小时。反应完毕后浓缩旋干得到粗品，经层析柱分离纯化(二氯甲烷：甲醇(V/V)＝10:1)，得6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷(440mg，产率92.8％)。LC-MS,M/Z(ESI):210.99(M+1).The raw material 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl 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 dried to obtain a crude product, which was separated and purified by chromatography (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-氮杂螺[3.3]庚烷-2-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物8-P1&8-P2)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)

将原料6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷(41.69mg，0.198mmol)和(R)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AA)(50mg，0.165mmol)和N,N-二异丙基乙胺(64.24mg，0.497mmol)溶于1,4-二氧六环(2mL)中，将反应加热至100℃反应10小时。反应完毕后用二氯甲烷稀释反应液并用层析柱分离纯化(二氯甲烷：甲醇(V/V)＝10:1)，浓缩过柱液，然后通过反相高效液相色谱制备纯化，(色谱柱:SYMC-Triart Prep C187μm 30mm×40cm)；流动相：A＝0.1％氨水，B＝乙腈；梯度：1％-35％，6.7分钟)得到化合物(R)-2-(6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-基)-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫吡喃并[3,2-d]嘧啶5-氧化物(8-P1)(23mg，产率29％)。LC-MS,M/Z(ESI):475.29(M+1).¹H NMR(600MHz,cdcl3)δ8.62(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).The raw 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 was completed, the reaction solution was diluted with dichloromethane and separated and purified by a chromatography column (dichloromethane: methanol (V/V) = 10:1), the column liquid was concentrated, 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 mg, yield 29%). LC-MS, M/Z(ESI):475.29(M+1). ¹ H NMR(600MHz,cdcl3)δ8.62(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).

将原料6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷(41.69mg，0.198mmol)和(S)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AB)(50mg，0.165mmol)和N,N-二异丙基乙胺(64.24mg，0.497mmol)溶于1,4-二氧六环(2mL)中，将反应加热至100℃反应10小时。反应完毕后用二氯甲烷稀释反应液并用层析柱分离纯化(二氯甲烷：甲醇(V/V)＝10:1)，浓缩过柱液，然后通过反相高效液相色谱制备纯化，(色谱柱:SYMC-Triart Prep C187μm 30mm×40cm)；流动相：A＝0.1％氨水，B＝乙腈；梯度：1％-35％，6.7分钟)得到化合物(S)-2-(6-(5-氯嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-基)-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫吡喃并[3,2-d]嘧啶5-氧化物(8-P2)(24mg，产率30％)LC-MS,M/Z(ESI):475.29(M+1).¹H NMR(600MHz,cdcl3)δ8.62(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).The raw 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 was completed, the reaction solution was diluted with dichloromethane and separated and purified by a chromatography column (dichloromethane: methanol (V/V) = 10:1), the column liquid was concentrated, and then purified by reverse phase high performance liquid chromatography (chromatographic column: SYMC-Triart Prep C187μm 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(600MHz,cdcl3)δ8.62(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,4 H),2.56–2.50(m,1H),2.38–2.31(m,2H),2.21–2.04(m,4H),1.95(ddd,2H).

实施例3：目标化合物9的制备Example 3: Preparation of target compound 9

2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5,5-二氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物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)

目标化合物9的合成路线如下所示：The synthetic route of target compound 9 is as follows:

第一步：2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5,5-二氧化(9-2)的合成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)

将(1-((2-氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(1-6)(20.0mg,62.9μmol)、S-(-)-1,1'-联-2-萘酚(1.80mg,6.30μmol)溶解在二氯甲烷(5mL)中，再加入四异丙氧化钛(895μg,3.15μmol,0.929μL)和水(1.13mg,62.9μmol,1.13μL)，加完后置换氮气，20℃反应1小时。再加入过氧叔丁醇(5.96mg,66.1μmol,5M,13.2μL)，25℃反应1.5小时。将反应液用10％亚硫酸钠水溶液(10mL)淬灭，二氯甲烷(30mL)萃取三次，合并有机相用水(20mL)洗涤，无水硫酸钠干燥，浓缩，硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10/1)得到黄色固体化合物2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5,5-二氧化(9-2)(25.0mg,产率95.0％)。LC-MS,M/Z(ESI):318.2(M+H)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), replace nitrogen after addition, and react at 20°C for 1 hour. Then add tert-butyl peroxide (5.96 mg, 66.1 μmol, 5M, 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), the combined organic phases were washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified on a silica gel plate (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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(化合物9)的合成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)

将2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5,5-二氧化(9-2)(20.0mg,62.9μmol)溶解在1,4-二氧六环(10mL)中，加入5-氯-2-(4-哌啶基)嘧啶(12.4mg,62.9μmol)和N,N-二异丙基乙胺(40.6mg,314μmol,54.8μL)。100℃下反应3小时。将反应液浓缩,加入饱和碳酸氢钠溶液(10mL)，乙酸乙酯(30mL)萃取三次,饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩，通过反相高效液相色谱法分离纯化(色谱柱：YMC-Actus Triart C18150*30mm*7μm；流动相：A＝水+FA(0.05％))，B＝乙腈；梯度：33％-63％，10分钟)，得化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5,5-二氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(化合物9)(18.0mg,，产率56.8％)。LC-MS,M/Z(ESI):479.2(M+H)。¹H NMR(400MHz,DMSO-d₆)δ＝8.86(s,2H),6.68(s,1H),4.95(brm,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).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, ethyl acetate (30 mL) was extracted three times, saturated brine (20 mL) was washed, dried over anhydrous sodium sulfate, concentrated, and separated and purified by reverse phase high performance liquid chromatography (chromatographic column: YMC-Actus Triart C18150*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 (400MHz, DMSO-d ₆ ) δ = 8.86 (s, 2H), 6.68 (s, 1H), 4.95 (brm, 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), 2.2 6-2.36(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).

实施例4：目标化合物10-P1-A&10-P1-B&10-P2-A&10-P2-B的制备Example 4: Preparation of target compounds 10-P1-A & 10-P1-B & 10-P2-A & 10-P2-B

(S)&(R)-2-((S)&(R)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(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)

目标化合物10-P1-A&10-P1-B&10-P2-A&10-P2-B的合成路线如下所示：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：叔-丁基3-(5-氯嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸基酯(10-2)的合成Step 1: Synthesis of tert-butyl 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10-2)

将叔-丁基3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,5-二氢吡咯-1-甲酸基酯(10-1)(13.0g,44.0mmol)和5-氯-2-碘嘧啶(10.0g,41.8mmol)溶解在1,4-二氧己环(200mL)和水(40mL)中，再将碳酸钾(18.2g,132mmol)和[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(3.22g,4.40mmol)加入反应液中。缓慢升温至90℃，反应2个小时。将反应液硅藻土过滤，浓缩，拌样。硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50/1-10/1)得到黄色固体产物叔-丁基3-(5-氯嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸基酯(10-2)(11.0g,产率88.6％)。Dissolve tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 mix. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) = 50/1-10/1) to obtain 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：叔-丁基3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3)的合成Step 2: Synthesis of tert-butyl 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylate (10-3)

将叔-丁基3-(5-氯嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸基酯(10-2)(9.34g,33.1mmol)溶于无水甲醇(200mL)中，在惰性气体保护下加入三(三苯基膦)氯化铑(I)(3.07g,3.32mmol)氩气置换，通入氢气在50℃，50Psi条件下反应24小时。将反应液浓缩拌样,硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1/0-5/1)褐色固体产物叔-丁基3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3)(9.41g,产率99.7％)Tert-butyl 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10-2) (9.34 g, 33.1 mmol) was dissolved in anhydrous methanol (200 mL), and tri(triphenylphosphine)rhodium chloride (I) (3.07 g, 3.32 mmol) was added under the protection of inert gas, and argon was replaced. Hydrogen was introduced and reacted at 50°C, 50 Psi for 24 hours. The reaction solution was concentrated and mixed, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain brown solid product 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)嘧啶盐酸盐(10-4)的合成Step 3: Synthesis of 5-chloro-2-(pyrrolidin-3-yl)pyrimidine hydrochloride (10-4)

将叔-丁基3-(5-氯嘧啶-2-基)吡咯烷-1-甲酸基酯(10-3)(4.00g,18.6mmol)溶解在无水二氧六环(30mL)中，缓慢将二氧六环盐酸汽(4mol/L,6mL)滴加至反应液中，25℃反应1小时。将反应液浓缩得褐色固体产物5-氯-2-(吡咯烷-3-基)嘧啶盐酸盐(10-4)(3.08g,产率96.9％)。Tert-butyl 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylate (10-3) (4.00 g, 18.6 mmol) was dissolved in anhydrous dioxane (30 mL), and dioxane hydrochloric acid vapor (4 mol/L, 6 mL) was slowly added dropwise to the reaction solution, and the reaction was carried out at 25°C for 1 hour. The reaction solution was concentrated 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P1)的合成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)

将5-氯-2-(吡咯烷-3-基)嘧啶盐酸盐(10-4)(77.2mg,347μmol)和(R)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(100mg,331μmol)溶解在无水二氧六环(10.0mL)中，氮气置换，在90℃下反应3小时。将反应液浓用饱和的氯化铵溶液(30mL)稀释，乙酸乙酯(120mL)萃取四次，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。硅胶板分离纯化(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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P1)(110mg,产率72.7％).LC-MS,M/Z(ESI):449.2(M+H)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 plate 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P1-A&10-P1-B)的合成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)

将外消旋体(5R)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(110mg,240μmol)(10-P1)通过正相高效液相色谱法进行手性分离，分离方法为(色谱柱：DAICEL CHIRALPAK IG(250mm*30mm,10μm)；流动相：A＝二氧化碳-乙腈，B＝异丙醇+氨水(0.1％)；B＝55％等梯度洗脱，6.6分钟)浓缩，得到(R)-2-((S)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P1-A，保留时间：1.337min)(30mg,收率27.6％)。LC-MS,M/Z(ESI):449.2(M+H)。¹H NMR(400MHz,DMSO-d₆)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).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 high performance liquid chromatography (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) concentrated to obtain (R)-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-P1-A, retention time: 1.337min) (30mg, yield 27.6%). LC-MS, M/Z (ESI): 449.2 (M+H). ¹ H NMR (400MHz, 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P1-B，保留时间：1.683min)(30mg,收率27.6％)。LC-MS,M/Z(ESI):449.2(M+H)。¹H NMR(400MHz,DMSO-d₆)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).(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 (400MHz, 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P2)的合成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)

将5-氯-2-(吡咯烷-3-基)嘧啶盐酸盐(10-4)(77.2mg,347μmol)和(R)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(100mg,331μmol)溶解在无水二氧六环(10.0mL)中，氮气置换，在90℃下反应3小时。将反应液浓用饱和的氯化铵溶液(30mL)稀释，乙酸乙酯(120mL)萃取四次，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。硅胶板分离纯化(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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P2)(110mg,产率72.7％)。LC-MS,M/Z(ESI):449.2(M+H).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 plate 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P2-A&10-P2-B)的合成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)

将外消旋体(5S)-2-(3-(5-氯嘧啶-2-基)吡咯烷-1-基)-45-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(110mg,240μmol)(10-P2)通过正相高效液相色谱法进行手性分离，分离方法为(色谱柱：DAICEL CHIRALPAK IG(250mm*30mm,10μm)；流动相：A＝二氧化碳-乙腈，B＝异丙醇+氨水(0.1％)；B＝55％等梯度洗脱，6.6分钟)浓缩，得到(S)-2-((S)-3-(5-氯嘧啶-2-基)吡咯烷-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P2-A,保留时间：1.589min)(35.0mg,收率31.8％)。LC-MS,M/Z(ESI):449.3(M+H)。1H NMR(400MHz,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).The racemic (5S)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-4-(5-oxy-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 high performance liquid chromatography (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) concentrated 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: 1.589min) (35.0mg, yield 31.8%). LC-MS, M/Z (ESI): 449.3 (M+H). 1H NMR(400MHz,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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(10-P2-B,保留时间：2.074min)(45.0mg,收率40.9％)。(10-P2-B):LC-MS,M/Z(ESI):449.3(M+H)。1H NMR(400MHz,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).(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(400MHz,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),3.02-3.0 9(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),1.70-1.8 4(m,2H).

实施例5：目标化合物11-P1&11-P2的制备Example 5: Preparation of target compounds 11-P1 & 11-P2

(R)or(S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物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)

目标化合物11-P1&11-P2的合成路线如下所示：The synthetic routes of target compounds 11-P1 & 11-P2 are as follows:

第一步：中间体(R)or(S)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AA)的合成Step 1: Synthesis of intermediate (R)or(S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (AA)

将外消旋体化合物2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(1-7)(1.00g,3.31mmol)通过正相高效液相色谱法进行手性分离，分离方法为(色谱柱：DAICEL CHIRALPAK IC(250mm*30mm,10um；流动相：A＝二氧化碳，B＝氨水(0.1％)+乙醇；梯度：50％-50％，25分钟)，浓缩旋干，得到化合物(R)or(S)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AA，保留时间：1.423min)(480mg,产率45.8％)，LC-MS,M/Z(ESI):302.1(M+H).¹HNMR(400MHz,DMSO-d₆)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)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 chirally separated by normal phase high performance liquid chromatography (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 spin-dried 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: 1.423min) (480mg, yield 45.8%), LC-MS, M/Z(ESI):302.1(M+H). ¹ HNMR(400MHz,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-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AB，保留时间：1.794min)(540mg,产率51.3％)。LC-MS,M/Z(ESI):302.1(M+H).¹H NMR(400MHz,DMSO-d₆)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).(R)or(S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxidation (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：叔-丁基3-(5-氯嘧啶-2-基)吖丁啶-1-甲酸基酯(11-2)的合成Step 2: Synthesis of tert-butyl 3-(5-chloropyrimidin-2-yl)azetidine-1-carboxylate (11-2)

将锌粉(3.46g,52.9mmol)和1,2-二溴乙烷(663mg,3.53mmol,266μL)加入到无水四氢呋喃(200mL)中，置换氮气三次，加热到66℃回流1小时。冷却至25℃，用注射器加入三甲基氯硅烷(383mg,3.53mmol,448μL)，25℃搅拌1小时。加入3-碘吖丁啶-1-甲酸基酯(10.0g,35.3mmol)的四氢呋喃(20mL)溶液，加热至60℃搅拌1小时，然后冷却至25℃。加入5-氯-2-碘-嘧啶(9.93g,41.3mmol)和四(三苯基膦)钯(3.98g,3.44mmol)，置换氮气三次，加热到60℃回流1小时,冷却至25℃搅拌8小时。将反应液用硅藻土过滤,浓缩拌样。使用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1/0-5/1)得到黄色固体产物叔-丁基3-(5-氯嘧啶-2-基)吖丁啶-1-甲酸基酯(11-2)(2.00g,产率16.2％)。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), nitrogen was replaced three times, and the mixture was heated to 66°C and refluxed for 1 hour. After cooling to 25°C, trimethylsilyl chloride (383 mg, 3.53 mmol, 448 μL) was added with a syringe and 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 cooled to 25°C. 5-chloro-2-iodo-pyrimidine (9.93 g, 41.3 mmol) and tetrakis(triphenylphosphine)palladium (3.98 g, 3.44 mmol) were added, nitrogen was replaced three times, the mixture was heated to 60°C and refluxed for 1 hour, and then cooled to 25°C and stirred for 8 hours. The reaction solution was filtered through diatomaceous earth, concentrated and mixed. The yellow solid product tert-butyl 3-(5-chloropyrimidin-2-yl)azetidine-1-carboxylate (11-2) (2.00 g, yield 16.2%) was obtained by separation and purification using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1).

第三步：2-(吖丁啶-3-基)-5-氯嘧啶(11-3)的合成Step 3: Synthesis of 2-(azetidine-3-yl)-5-chloropyrimidine (11-3)

将叔-丁基(2R)-4-(5-氯嘧啶-2-基)-2-甲基哌啶-1-甲酸基酯(11-2)(800mg,2.97mmol)溶解在二氯甲烷(10mL)和三氟乙酸(3mL)中，在25℃反应1小时。将反应液体浓缩拌样,硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝1/0-10/1)，得到黄色固体化合物2-(吖丁啶-3-基)-5-氯嘧啶(11-3)(1.20g,产率95.6％)。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 mixed, and separated and purified by silica gel column (dichloromethane: methanol (V/V) = 1/0-10/1) to obtain a yellow solid compound 2-(azetidine-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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(11-P1)的合成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)

将到2-(吖丁啶-3-基)-5-氯嘧啶(3)(85.3mg,189μmol)和(R)or(S)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AA)(50.0mg,158μmol)溶解在1,4-二氧己环(10mL)中，加入N,N-二异丙基乙胺(102mg,790μmol,137μL)，然后缓慢升至90℃，反应3小时。将反应液倒加入饱和碳酸氢钠溶液(30mL)，用乙酸乙酯(30mL)萃取3次，饱和食盐水(30mL)洗涤，硫酸钠干燥，浓缩，通过反相高效液相色谱法进行分离(色谱柱：Waters Xbridge 150*25mm*5μm；流动相：A＝水+氨水(0.1％)，B＝乙腈；梯度：13％-43％，8分钟)得到(R)or(S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(11-P1，保留时间：1.286min)(40.0mg，产率58.4％)。LC-MS,M/Z:435.2(M+H).¹H NMR(400MHz,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).2-(Azetidine-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: 1.286 min) (40.0 mg, yield 58.4%). LC-MS, M/Z: 435.2 (M+H). ¹ H NMR (400MHz, 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-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(11-P2)的合成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)

将到2-(吖丁啶-3-基)-5-氯嘧啶(11-3)(85.3mg,189μmol)和(R)or(S)-2-氯-4-((1-(羟甲基)环丁基)氨基)-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶5-氧化(AB)(50.0mg,158μmol)溶解在1,4-二氧己环(10mL)中，加入N,N-二异丙基乙胺(102mg,790μmol,137μL)，然后缓慢升至90℃，反应3小时。将反应液倒加入饱和碳酸氢钠溶液(30ml)，用乙酸乙酯(30mL)萃取3次，饱和食盐水(30ml)洗涤，硫酸钠干燥，浓缩，通过反相高效液相色谱法进行分离(色谱柱：Waters Xbridge 150*25mm*5μm；流动相：A＝水+氨水(0.1％)，B＝乙腈；梯度：13％-43％，8分钟)得到(R)or(S)-2-(3-(5-氯嘧啶-2-基)吖丁啶-1-基)-5-氧化-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(11-P2，保留时间：1.263min)(40.0mg，产率58.4％)。LC-MS,M/Z:435.2(M+H).¹H NMR(400MHz,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).2-(Azetidine-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 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*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, yield 58.4%). LC-MS, M/Z: 435.2 (M+H). ¹ H NMR (400MHz, 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).

实施例6：目标化合物3的制备Example 6: Preparation of target compound 3

2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物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)

目标化合物3的合成路线如下所示：The synthetic route of target compound 3 is as follows:

第一步：甲基3-((2-甲氧基-2-氧亚基乙基)硫代)丁酯(3-2)的合成Step 1: Synthesis of methyl 3-((2-methoxy-2-oxyylideneethyl)thio)butyl ester (3-2)

将甲基2-巯基醋酸盐(3-1)(9.80g,92.3mmol,8.38mL)和哌啶(235mg,2.77mmol,273uL)冷却至0℃,逐滴加入甲基(E)-丁-2-烯酯(11.1g,111mmol,11.8mL)，30分钟后分两批次加入哌啶(157mg,1.85mmol,182uL)，20℃反应11.5小时。将反应液倒入甲基叔丁基醚(100mL)和1N稀盐酸(100mL)中，再用乙酸乙酯(300mL)萃取3次，合并有机相用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，浓缩得到黄色油状产物甲基3-((2-甲氧基-2-氧亚基乙基)硫代)丁酯(3-2)(20.0g,收率98.7％)。Methyl 2-mercaptoacetate (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, methyl (E)-but-2-enyl ester (11.1 g, 111 mmol, 11.8 mL) was added dropwise, and piperidine (157 mg, 1.85 mmol, 182 uL) was added in two batches after 30 minutes, and the mixture was reacted at 20°C for 11.5 hours. The reaction solution was poured into methyl tert-butyl ether (100 mL) and 1N dilute hydrochloric acid (100 mL), and then extracted with ethyl acetate (300 mL) for 3 times. The organic phases were combined, 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-氧亚基四氢噻吩-2-甲酸基酯(3-3)的合成Step 2: Synthesis of methyl 5-methyl-3-oxyylidenetetrahydrothiophene-2-carboxylate (3-3)

将甲基3-((2-甲氧基-2-氧亚基乙基)硫代)丁酯(3-2)(5.01g,23.0mmol)溶解在甲苯(110mL)中，加入甲醇钠(1.50g,27.6mmol)，升至105℃反应3小时。将反应液倒入冷的的12N浓盐酸中(10mL)中,再用乙酸乙酯(90mL)萃取3次，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩拌样,硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1/0-5/1)得到黄色油状产物甲基5-甲基-3-氧亚基四氢噻吩-2-甲酸基酯(3-3)(3.00g,收率74.6％)。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 reaction for 3 hours. The reaction solution was poured into cold 12N concentrated hydrochloric acid (10 mL), and then extracted with ethyl acetate (90 mL) for 3 times. The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated and mixed, and separated and purified on a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain a yellow oily product, methyl 5-methyl-3-oxyylidenetetrahydrothiophene-2-carboxylate (3-3) (3.00 g, yield 74.6%).

第三步：6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-2,4-二酚(3-4)的合成Step 3: Synthesis of 6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (3-4)

将甲基5-甲基-3-氧亚基四氢噻吩-2-甲酸基酯(3-3)(1.90g,10.9mmol)溶于无水乙醇(20mL)中，加入尿素(654mg,10.9mmol)和甲醇钠(2.95g,54.5mmol)，80℃反应15小时。将反应液倒入冰水(40mL)和冰醋酸(2mL)中，过滤收集析出沉淀物，得到白色固体6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-2,4-二酚(3-4)(3.00g,直接用于下一步)。Methyl 5-methyl-3-oxyylidene tetrahydrothiophene-2-carboxylate (3-3) (1.90 g, 10.9 mmol) was dissolved in anhydrous ethanol (20 mL), urea (654 mg, 10.9 mmol) and sodium methoxide (2.95 g, 54.5 mmol) were added, and the mixture was reacted at 80°C for 15 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 a 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-6,7-二氢噻吩并[3,2-d]嘧啶(3-5)的合成Step 4: Synthesis of 2,4-dichloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine (3-5)

将6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-2,4-二酚(3-4)(300mg,1.42mmol)和N,N-二甲基苯胺(171mg,1.42mmol,179μL)溶解在三氯氧磷(1.09g,7.08mmol,660μL)中，氮气置换，在90℃下反应3小时。将反应液浓用二氯甲烷(10mL)稀释，小心倒入水(100mL)中淬灭，二氯甲烷(90mL)萃取三次，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，浓缩拌样，硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1/0-10/1)得到黄色固体化合物2,4-二氯-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶(3-5)(250mg,产率71.8％)。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 three times with dichloromethane (90 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated and mixed, and separated and purified on a silica gel column (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-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(3-6)的合成Step 5: Synthesis of (1-((2-chloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3-6)

将2,4-二氯-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶(3-5)(200mg,814μmol)和(1-氨基环丁基)甲醇盐酸盐(134mg,976μmol)溶解在乙腈(10mL)中，加入三乙胺(411mg,4.07mmol,566μL)。80℃反应10小时。将反应液用水(40mL)稀释，乙酸乙酯(120mL)萃取三次，饱和食盐水洗涤(50mL)，无水硫酸钠干燥，浓缩，硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5/1-1/1)得到黄色固体化合物(1-((2-氯-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(3-6)(150mg,产率60.3％)。2,4-Dichloro-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine (3-5) (200 mg, 814 μmol) and (1-aminocyclobutyl)methanol hydrochloride (134 mg, 976 μmol) were dissolved in acetonitrile (10 mL), and triethylamine (411 mg, 4.07 mmol, 566 μL) was added. The mixture was reacted 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 separated and purified by silica gel column (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-(羟甲基)环丁基)氨基)-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶5-氧化(3-7)的合成Step 6: Synthesis of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6-methyl-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (3-7)

将(1-((2-氯-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇(3-6)(125mg,433μmol)和S-(-)-1,1'-联-2-萘酚(2.40mg,43.3μmol)溶解在二氯甲烷(10mL)中，再加入四异丙氧化钛(6.15mg,21.6μmol,6.39μL)和水(7.80mg,433μmol,7.80μL)，加完后置换氮气，20℃反应1小时。再加入过氧叔丁醇(58.5mg,454μmol,62.2μL,70％纯度)，25℃反应1.5小时。将反应液用10％亚硫酸钠水溶液(10mL)淬灭，二氯甲烷(90mL)萃取三次，合并有机相用水(50mL)洗涤，无水硫酸钠干燥，浓缩，硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10/1)得到黄色固体化合物2-氯-4-((1-(羟甲基)环丁基)氨基)-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶5-氧化(3-7)(90.0mg,产率67.6％)。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, react at 20°C for 1 hour. Then add tert-butyl peroxide (58.5 mg, 454 μmol, 62.2 μL, 70% purity) and react at 25°C for 1.5 hours. The reaction solution was quenched with 10% aqueous sodium sulfite 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 separated and purified on a silica gel plate (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-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物3)的合成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)

将2-氯-4-((1-(羟甲基)环丁基)氨基)-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶5-氧化(3-7)(80.0mg,260μmol)溶解在1,4-二氧六环(10mL)中，加入5-氯-2-(4-哌啶基)嘧啶(77.1mg,390μmol)和N,N-二异丙基乙胺(100mg,780μmol,135μL)。80℃下反应3小时。将反应液浓缩,加入饱和碳酸氢钠溶液(20mL)，乙酸乙酯(60mL)萃取三次,饱和食盐水(40mL)洗涤，无水硫酸钠干燥，浓缩，通过反相高效液相色谱法分离纯化(色谱柱：Waters Xbridge150*25mm*5um；流动相：A＝水+氨水(0.05％))，B＝乙腈；梯度：20％-50％，15分钟)，得到产物化合物2-(4-(5-氯嘧啶-2-基)哌啶-1-基)-5-氧化-6-甲基-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)-环丁基)-甲醇(目标化合物3)(80.0mg,，产率66.4％)。LC-MS,M/Z(ESI):463.2(M+H)。¹H NMR(400MHz,DMSO-d₆)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)。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) was dissolved in 1,4-dioxane (10 mL), and 5-chloro-2-(4-piperidinyl)pyrimidine (77.1 mg, 390 μmol) and N,N-diisopropylethylamine (100 mg, 780 μmol, 135 μL) were added. The mixture was reacted at 80°C for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (60 mL) was extracted three times, saturated brine (40 mL) was washed, dried over anhydrous sodium sulfate, concentrated, and separated and purified by reverse 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-oxidized-6-methyl-6,7-dihydrothieno[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 (400MHz, 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的制备参照本发明实施例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的结构式、LC-MS和核磁表征结果如下表所示：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 formulas, LC-MS and NMR characterization results of Compound 2, Compound 4, Compound 5, Compound 6 and Compound 7 are shown in the following table:

生物测试Biological Testing

测试方案1：PDE4B和PDE4D酶活试验Test plan 1: PDE4B and PDE4D enzyme activity test

本发明提供的化合物对PDE4B和PDE4D的抑制活性可以利用PDE-GloPhosphodiesterase Assay Kit(promega，V1361)进行检测。简单来说，首先将待检测化合物在DMSO溶剂中配制成10mM的浓储液，随后以试剂盒提供的Reaction buffer稀释十倍。在冰上操作，用Reaction buffer将PDE4B酶(Enzo Life Sciences，BML-SE522-0020)稀释至浓度为1ng/μL，PDE4D酶(Enzo Life Sciences，BMLSE523-0020)稀释至浓度为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，室温震荡孵育5分钟，随后加入2.5μL/孔cAMP(2μM in Reactionbuffer)，继续室温震荡孵育20分钟，加入2.5μL/孔1×Termination Buffer，随后加入2.5μL/孔1×Detection Buffer，继续室温震荡20分钟。最后加入10μL/孔1×Kinase-Glo，室温震荡孵育10分钟，以PheraStar仪器检测生物发光。实验结果输入GraphPadPrism软件，经拟合计算得到各化合物的IC₅₀，具体参见表1。实验结果表明，本发明化合物可作为PDE4B的选择性抑制剂。The inhibitory activity of the compounds provided by the present invention on PDE4B and PDE4D can be detected using PDE-GloPhosphodiesterase Assay Kit (promega, V1361). In short, the compound to be tested is first prepared into a 10mM concentrated stock solution in DMSO solvent, and then diluted ten times with the reaction buffer provided by the kit. The operation is carried out on ice, and 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 for 5 minutes, and then 2.5 μL/well cAMP (2 μM in Reaction buffer) was added, and incubated at room temperature for 20 minutes, and 2.5 μL/well 1×Termination Buffer was added, followed by 2.5 μL/well 1×Detection Buffer, and continued to be shaken at room temperature for 20 minutes. Finally, 10 μL/well 1×Kinase-Glo was added, incubated at room temperature for 10 minutes, and bioluminescence was detected by PheraStar instrument. The experimental results were input into GraphPadPrism 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.

表1Table 1

化合物编号Compound No. PDE4BIC₅₀(nM)PDE4BIC ₅₀ (nM) PDE4DIC₅₀(nM)PDE4DIC ₅₀ (nM) 化合物1-P1Compound 1-P1 27.4527.45 111.9111.9 化合物8-P1Compound 8-P1 38.1938.19 111.30111.30 化合物10-P2-ACompound 10-P2-A 52.4152.41 162.10162.10 化合物10-P2-BCompound 10-P2-B 31.2631.26 91.4491.44 化合物11-P2Compound 11-P2 27.9927.99 72.0072.00

测试列2：LPS诱导人PBMC分泌TNFα模型试验Test column 2: LPS-induced TNFα secretion model test in human PBMC

PBMC提取过程：获取新鲜人外周浓缩血，吸取1单位人外周浓缩血(浓缩自200cc外周血)，定量加入0.9％生理盐水至总体积为120ml，混匀。取50ml离心管，分别加入15mlLymphoprepTM，手持离心管，约斜45°，吸取30ml稀释后的浓缩血，小心而缓慢地贴壁加入，使稀释血液重叠于分层液上，避免将稀释血液混入分离液或冲破分离液液面。LymphoprepTM与稀释血液的比例为1:2。将离心管配平放置入水平离心机(eppendorf，5810R)，在20℃、800×g条件下离心20min，升速设为1，降速设为0。小心取出离心管。直接将巴氏吸管深入白膜层，吸取PBMC。加3倍体积0.9％生理盐水或PBS(不含钙镁)，轻轻吹打混匀。混匀后在20℃、250×g条件下离心10min，去除细胞悬液中留存的血小板，去上清液，将细胞沉淀以20ml PBS悬起，台盼蓝染色计数。PBMC extraction process: Get fresh human peripheral concentrated blood, draw 1 unit of human peripheral concentrated blood (concentrated from 200cc peripheral blood), quantitatively add 0.9% saline to a total volume of 120ml, and mix. Take a 50ml centrifuge tube, add 15ml LymphoprepTM respectively, hold the centrifuge tube, tilt it at 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 LymphoprepTM to diluted blood is 1:2. Level the centrifuge tube and place it in a horizontal centrifuge (eppendorf, 5810R), centrifuge at 20℃, 800×g for 20min, set the speed of increase to 1, and the speed of decrease to 0. Carefully remove the centrifuge tube. Directly insert the Pasteur pipette into the buffy coat layer to draw PBMC. Add 3 times the volume of 0.9% saline or PBS (without calcium and magnesium), and gently blow and mix. After mixing, centrifuge at 20°C and 250×g for 10 min to remove platelets remaining in the cell suspension, remove the supernatant, suspend the cell pellet in 20 ml PBS, and count by trypan blue staining.

PBMC筛选过程：将步骤1取得的PBMC离心，去除PBS，然后用完全培养基(RPMI1640+10％FBS+1％P/S)重悬计数。按照5×10⁴/孔，100μL/孔接入细胞。将待筛选的化合物配制成终浓度的4×，按照50μL/孔加入到细胞中，提前预孵育30min。同时设定对照孔，不加化合物(即为对照组)。LPS的刺激终浓度为10ng/ml，稀释成4倍溶液，按照50μl/孔加入到细胞中。同时设定对照孔，不加LPS孔。继续孵育细胞，在24h时收集10％上清进行检测。收集的上清按照Invitrogen公司的Human TNFα试剂盒检测(REF：88-7346-88)。按照上述方法测定本发明提供的化合物对LPS诱导人PBMC分泌TNFα的抑制活性，结果参见表2。PBMC screening process: centrifuge the PBMC obtained in step 1, remove PBS, and then resuspend and count with complete medium (RPMI1640+10% FBS+1% P/S). Inoculate cells at 5×10 ⁴ /well and 100μL/well. Prepare the compound to be screened to a final concentration of 4×, add it to the cells at 50μL/well, and pre-incubate for 30min in advance. At the same time, set up control wells without adding compounds (i.e., the 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 is detected 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 TNFα secretion by human PBMC is determined according to the above method, and the results are shown in Table 2.

表2：测试化合物对LPS诱导人PBMC分泌TNFα的抑制活性结果Table 2: Inhibitory activity of test compounds on LPS-induced secretion of TNFα by human PBMC

化合物编号Compound No. TNFα分泌IC₅₀(nM)TNFα Secretion IC ₅₀ (nM) 化合物1-P1Compound 1-P1 69.7069.70

实验结果表明，本发明化合物有着优良的人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。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.

测试例3：小鼠药代动力学试验Test Example 3: Pharmacokinetics test in mice

小鼠药代动力学试验，采用雄性ICR小鼠，体重为20-25g/只，禁食过夜。取3只小鼠，采用本发明的化合物口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时分别采血。血液样品在6800×g、2-8℃条件下离心6分钟，收集血浆，于-20℃保存。分别取各时间点血浆，加入3-5倍量含内标的乙腈溶液，涡旋混合1分钟，在13000转/分钟、4℃条件下离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析，结果参见表3。Mouse pharmacokinetic test, using male ICR mice, weighing 20-25g/mouse, fasting overnight. Take 3 mice, and use the compound of the present invention to orally administer 10mg/kg. Blood was collected before administration and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. The blood sample was centrifuged at 6800×g and 2-8℃ for 6 minutes, and the plasma was collected and stored at -20℃. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing internal standard, vortex mix for 1 minute, centrifuge at 13000 rpm and 4℃ for 10 minutes, take the supernatant, add 3 times the amount of water and mix, and take an appropriate amount of the mixed solution for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model, and the results are shown in Table 3.

表3：小鼠的药代动力学试验结果Table 3: Pharmacokinetic test results in mice

实验结果表明，本发明化合物在小鼠中表现出优良的血浆暴露，有优良的药代动力学性质。The experimental results show that the compound of the present invention exhibits excellent plasma exposure in mice and has excellent pharmacokinetic properties.

测试例4：大鼠药代动力学试验Test Example 4: Pharmacokinetics test in rats

大鼠药代动力学试验，采用雄性SD小鼠，体重为200-250g/只，禁食过夜。取3只大鼠，采用本发明的化合物口服灌胃给药10mg/kg。在给药前和在给药后5、15、30分钟以及1、2、4、8、24小时分别采血。采血0.2mL置于含标记的EDTA-2K抗凝管中。上下轻柔颠倒使抗凝剂(EDTA-2K)与血液充分混合后，立即置于湿冰中，并于采血后1小时之内离心分离血浆，离心条件设置为4℃、6800×g、6分钟。离心后分离得到的血浆装于标记好的EP管中，并尽快存放于超低温冰箱内，直至样品分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析，结果参见表4。The pharmacokinetic test in rats was conducted using male SD mice weighing 200-250 g/mouse and fasted overnight. Three rats 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 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 the anticoagulant (EDTA-2K) and the blood to mix thoroughly, it was immediately placed in wet ice and centrifuged within 1 hour after blood collection to separate plasma. 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 by non-compartmental model using WinNonlin 7.0 software, and the results are shown in Table 4.

表4：大鼠的药代动力学试验结果Table 4: Pharmacokinetic test results in rats

实验结果表明，本发明化合物在大鼠中表现出优良的血浆暴露，有优良的药代动力学性质。The experimental results show that the compound of the present invention exhibits excellent plasma exposure in rats and has excellent pharmacokinetic properties.

测试例5：Beagle犬药代动力学试验Test Example 5: Beagle dog pharmacokinetic study

Beagle犬药代动力学试验，采用雄性Beagle犬，体重为7-12kg/只，禁食过夜。取3只Beagle犬，采用本发明的化合物口服灌胃给药10mg/kg。在给药前和在给药后5、15、30分钟以及1、2、4、8、24小时分别采血。血液样品在2200×g、2-8℃条件下离心6分钟，收集血浆，于-20℃保存。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析，结果参见表5。Beagle dog pharmacokinetic test, using male Beagle dogs, weighing 7-12kg/dog, fasted overnight. Take 3 Beagle dogs, and use the compound of the present invention to be orally administered by gavage at 10 mg/kg. Blood was collected before administration and at 5, 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. The blood samples were centrifuged at 2200×g and 2-8℃ for 6 minutes, and the plasma was collected and stored at -20℃. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software, and the results are shown in Table 5.

表5：Beagle犬的药代动力学试验结果Table 5: Pharmacokinetic test results in Beagle dogs

实验结果表明，本发明化合物在Beagle犬表现出优良的血浆暴露，有优良的药代动力学性质。The experimental results show that the compound of the present invention exhibits excellent plasma exposure in Beagle dogs and has excellent pharmacokinetic properties.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. 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 refer 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 a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. 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),

in, Represented as a single bond or absent;

^X1 and ^X2 are each independently CH or N, and at least one of ^X1 and ^X2 is N;

^X4 and ^X5 are each independently CH or N, and at least one of ^X1 and ^X2 is N;

Each of R ^1a , R ^1b , R ^1c and R ^1d is 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 _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 _1-6 alkyl, -C(=O)-NH-C _1-6 alkyl and -NH-C(=O)-OC _1-6 alkyl are each independently optionally substituted by 1, 2 or 3 R ^a ;

Alternatively, R ^1a , R ^1b and the carbon atom to which they are attached together form a ring A, said ring A being a C _3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R ^b ;

Alternatively, R ^1b , R ^1c and the carbon atom to which they are attached together form ring B, and the ring B is a 6-8 membered heterocycloalkyl or a 6-8 membered heterocycloalkenyl, and the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are each independently optionally substituted by 1, 2 or 3 R ^c ;

Alternatively, R ^1c , R ^1d and the carbon atom to which they are attached together form a ring C, said ring C being a C _3-8 cycloalkyl optionally substituted by 1, 2 or 3 R ^d ;

each ^Ra is independently halogen, OH, CN, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said _C1-3 alkyl, _C1-3 alkoxy, _C3-6 cycloalkyl, and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R;

Each R ^b , R ^c and R ^d is 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 optionally substituted by 1, 2 or 3 R;

Each 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;

^R2 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C3-8 cycloalkyl, _C1-6 deuterated alkyl, C2-6 alkenyl, _C2-6 alkynyl, C1-6 haloalkyl, _C3-8 halocycloalkyl, _C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _3-10 membered heterocycloalkyl; the _C1-6 alkyl, _C3-8 cycloalkyl, _C1-6 _deuterated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C3-8 halocycloalkyl _, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy and _C1-6 haloalkoxy are optionally substituted by one or more ^Re , when the substituent R When ^e is multiple, the ^Re are the same or different;

Each ^Re is independently halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C1-6 _deuterated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, C1-6 alkylhydroxy, _C1-6 alkylcarbonyl, _C1-6 alkoxy or _C1-6 haloalkoxy.

2. The compound according to claim 1, 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 optionally substituted by 1, 2 or 3 ^Ra ;

or, each R ^1a , R ^1b , R ^1c and R ^1d is each 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 is each independently optionally substituted by 1, ² or 3 Ra;

or, each R ^1a , R ^1b , R ^1c and R ^1d is 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 ;

Alternatively, each ^Ra is independently F, Cl, Br, I, OH, CN, _NH2 or cyclopropyl;

Alternatively, Ring A is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^b ;

Alternatively, 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

Alternatively, Ring C is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^b ;

Alternatively, each R ^b , R ^c and R ^d are each independently halogen, OH, CN, NH ₂ or CH ₃ ;

Alternatively, ring A is

Alternatively, ring C is

3. The compound according to claim 1, characterized in that the structural unit for

Further preferably, In, n is 1 or 2;

Further preferably, In, n is 0 or 1;

Further preferably, the structural unit for

Further preferably, the structural unit for Further preferably, the structural unit for

4. The compound according to claim 1, characterized in that ^X1 and ^X2 are both N;

Alternatively, ^X1 is CH, ^X2 is N;

Alternatively, ^X4 and ^X5 are both N;

Alternatively, R ² is F, Cl, CH _3, or CH ₃ substituted by one or more ^Re ;

Alternatively, ^Re is F or Cl;

Alternatively, R ² is Cl;

Or, m is 1;

Alternatively, m is 2.

5. The compound according to claim 1, characterized in that ring W is a 4-7 membered heterocycloalkyl group;

Further preferably, ring W is a 4-7 membered nitrogen-containing heterocycloalkyl group;

Further preferably, ring W is

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, h is 1, 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, g is 0;

Further preferably, X ³ is CH;

Further preferably, X ³ is N;

Further preferably, p is 1, q is 1;

Further preferably, ring W is azetidinyl, pyrrolidinyl, piperidinyl or 2-azaspiro[3.3]heptyl;

Further preferably, ring W is

6. The compound according to any one of claims 1 to 5, characterized in that the compound of formula (II) has the structural formula (IIIa) or (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):

7. The compound according to any one of claims 1 to 5, characterized in that the compound of formula (II) has the structural formula (I):

Wherein, X ³ is CH or N;

Further preferably, the compound of formula (II) has the structural formula (Ia) or (Ia1):

8. The compound according to any one of claims 1 to 5, characterized in that the compound represented by formula (II) has structural formula (IV), (V) or (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):

9. The compound according to claim 8, characterized in that the compound of formula (II) has the structural formula (Ib), (Ib1), (II-A1) or (II-A2):

h, g are 0, 1 or 2 respectively;

p and q are 1 or 2 respectively.

10. The compound according to claim 8, characterized in that the compound of formula (II) has the structural formula (Ic) or (Ic1):

11. The compound according to claim 8, characterized in that the compound of formula (II) has structural formula (Id) or (Id1):

12. The compound according to any one of claims 1 to 5, characterized in that the compound represented by formula (II) has the structural formula (Vd) or (Ve):

13. The compound according to claim 1, characterized in that it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

14. The compound according to claim 1, characterized in that it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

15. 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),

in, Represented as a single bond or absent;

X ^1' and X ^2' are each 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' is 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 _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 _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 ^' ;

Alternatively, 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' ;

Alternatively, R ^1b' , R ^1c' and the carbon atom 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, and the 6-8 membered heterocycloalkyl and the 6-8 membered heterocycloalkenyl are each independently optionally substituted by 1, 2 or 3 R ^c' ;

Alternatively, 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 _3-8 cycloalkyl group optionally substituted by 1, 2 or 3 R ^d' ;

each ^Ra' is independently halogen, OH, CN, _NH2 , _C1-3 alkyl, C1-3 alkoxy, _C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein said _C1-3 alkyl, _C1-3 alkoxy, _C3-6 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' is 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 optionally substituted by 1, 2 or 3 R';

Each R' is independently halogen, OH, CN or _NH2 ;

n' is 0, 1 or 2;

m' is 0, 1 or 2;

^Rx is halogen.

16. The intermediate compound according to claim 15, characterized in that ^X1 and ^X2 are both N;

Alternatively, ^X1 is CH, ^X2 is N;

Alternatively, each of R ^1a' , R ^1b' , R ^1c' and R ^1d' is 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 optionally substituted by 1, 2 or 3 R ^a ';

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 ′ is 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 ;

Alternatively, each ^Ra ' is independently F, Cl, Br, I, OH, CN, _NH2 or cyclopropyl;

Alternatively, Ring A' is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^b ';

Alternatively, 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

Alternatively, Ring C' is C _3-6 cycloalkyl optionally substituted by 1, 2 or 3 R ^b ';

Alternatively, each R ^b ', R ^c ' and R ^d ' are each independently halogen, OH, CN, NH ₂ or CH ₃ ;

Alternatively, ring A' is

Alternatively, ring C' is

Alternatively, the structural unit for

Further preferably, In, n is 1 or 2;

Further preferably, In, n is 0 or 1;

Further preferably, the structural unit for

Alternatively, R ^x is Cl;

Alternatively, m' is 1 or 2;

Further preferably, m' is 1;

More preferably, m' is 2.

17. The intermediate compound according to claim 15 or 16, characterized in that the compound of formula (VII) has the structural formula (VIIIa):

Further preferably, the compound of formula (VII) has the structural formula (VIIIb) or formula (VIIIc):

Further preferably, the compound of formula (VII) has the structural formula (VIIId) or formula (VIIIe):

18. The intermediate compound according to claim 15, characterized in that it is selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

19. A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 14.

20. The pharmaceutical composition according to claim 19, further comprising a pharmaceutically acceptable carrier or excipient.

21. Use of the compound according to any one of claims 1 to 14 or the pharmaceutical composition according to any one of claims 19 to 20 in the preparation of a medicament for treating or preventing a PDE4B-related disease.

22. The use according to claim 21, characterized in that the PDE4B-related disease comprises at least one selected from the following:

Treat respiratory diseases, gastrointestinal diseases, and inflammatory diseases;

More preferably, the respiratory diseases include asthma, chronic bronchitis, idiopathic pulmonary fibrosis, chronic obstructive pneumonia, allergic rhinitis, and adult respiratory distress syndrome;

Alternatively, the gastrointestinal disease includes ulcerative colitis, Crohn's disease, overactive bladder;

Alternatively, the inflammatory disease includes atopic dermatitis, psoriasis, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis.