CN113248491B - 一类取代的吲哚脲衍生物、合成方法及其用途 - Google Patents
一类取代的吲哚脲衍生物、合成方法及其用途 Download PDFInfo
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- CN113248491B CN113248491B CN202010086875.3A CN202010086875A CN113248491B CN 113248491 B CN113248491 B CN 113248491B CN 202010086875 A CN202010086875 A CN 202010086875A CN 113248491 B CN113248491 B CN 113248491B
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Abstract
本发明公开了一类取代的吲哚脲衍生物、合成方法及其用途，结构如式I所示，式中，各取代基的定义如说明书中所述。本发明的化合物，能够用作cGAS‑STING通路靶向抑制剂，用于炎症性疾病和自身免疫性疾病的治疗。
Description
技术领域
本发明涉及生物医药领域，具体涉及一类取代的吲哚脲衍生物、合成方法及其用途。
背景技术
近年来研究证明，cGAS/STING信号通路在固有免疫过程中发挥重要作用。当DNA感受器cGAS(cyclic GMP-AMP synthase)感测到病原体DNA后诱导产生cGAMP(cyclic GMP-AMP)，引起干扰素基因刺激因子(stimulator of interferon genes,STING)的活化，招募TANK结合激酶1(TANK-binding kinase 1,TBK1)进而磷酸化干扰素调节因子3(Interferonregulatory Factor 3，IRF3)，诱导I型干扰素和细胞因子的产生，并通过一系列的级联反应，激活适应性免疫系统，活化T细胞从而发挥抗肿瘤免疫作用。固有免疫途径的异常激活与多种疾病的发生发展息息相关，其在分子机制方面的研究进展为靶向药物治疗策略带来希望。
cGAS-STING信号通路被一系列因素精密调控，这些因素包括蛋白质翻译后修饰(磷酸化，泛素化等)及小分子拮抗剂与激动剂等(例如合成小分子DMXAA与CMA)。通路处于异常激活或过度激活时，会引发炎症性疾病及自身免疫性疾病，如AGS综合征、系统性红斑狼疮(SLE)。由此可见，靶向抑制cGAS-STING通路可用于该类炎症性疾病及自身免疫性疾病的治疗。
目前，靶向抑制cGAS-STING通路的小分子化合物尚处于起步阶段。2018年SimoneM.Haag等人在《自然》上报道了一类硝基呋喃和吲哚类化合物(Nature 2018,559,269-273.)，这些化合物可与STING蛋白Cys91共价结合，阻断STING活化所诱导的棕榈酰化，进而阻断其在高尔基体组装成多聚体复合物，抑制下游信号通路传导。此外，该类抑制剂可以减少人和小鼠细胞中STING蛋白介导的炎性细胞因子的产生，减弱小鼠自身炎症疾病的病理特征。2019年，Lama L.等研究者在《自然·通讯》上发表了吲哚并哌啶系列化合物(Nat.Commun.2019,10,2261.)，该类化合物在人类骨髓来源的巨噬细胞(BMDM)能有效抑制cGAS。一系列科学研究结果证实，靶向抑制cGAS-STING通路小分子有望成为治疗自身免疫性疾病的最有潜力的策略之一。
近年来，随着诺华、施贵宝等各大知名制药企业纷纷投入靶向抑制cGAS-STING通路小分子抑制剂的研究中，该类化合物的研发进入白热化阶段。然而该类化合物由于起步较晚，结构类型缺乏多样化，大部分研究尚处于细胞活性验证阶段。基于此，急需研发更多的具有多样性结构的靶向抑制cGAS-STING通路的小分子化合物，用于验证该类抑制剂治疗自身免疫性疾病的靶点确定性和有效性。
发明内容
本发明的目的在于提供一种靶向抑制cGAS-STING通路的小分子化合物。
本发明的第一方面，提供一种通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，
式中，R1是苯环上的取代基，个数为1-4个，各R1独立地为H、卤素、羟基、氰基、氨基、硝基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-8元杂芳基；所述取代为单取代或多取代，各取代基独立为卤素、羟基或3-8元杂环基；
A、T、V、E各自独立为N或C；
n为0或1；
R2、R3、R4存在时，各自独立为H、卤素、羟基、氰基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C6烷基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、5-8元杂芳基；所述取代选自卤素、羟基；
或者R2、R3与T、V形成取代或未取代的5-6元芳环或取代或未取代的5-8元杂芳环，所述取代为单取代或多取代，各取代基独立为卤素、羟基、氰基、Ra取代的C1-C6烷基、Ra取代的C1-C6烷氧基、Ra取代的C2-C6烯基、Ra取代的C2-C6炔基、Ra取代的C1-C6烷基酰基、Ra取代的氨基酰基、Ra取代的C1-C6烷基酰胺基、Ra取代的C1-C6烷基氨基、Ra取代的3-8元杂环基、Ra取代的3-8元环烷基、Ra取代的5-8元杂芳基；
Ra选自H、卤素、羟基、C1-C4烷基、卤代C1-C4烷基、-C1-C4亚烷基-(3-6元环烷基)；
R5、R6、R7各自独立为H、卤素、羟基、氰基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基；取代基选自卤素、羟基。
在另一优选例中，所述化合物具有以下结构：
式中，R5、R6、R4和R7定义如前所述，
两R1相同或不同，各自独立地如前所述，
各Rb独立地为H、氟、氯、溴、羟基、氰基、Ra取代的C1-C4烷基、Ra取代的C1-C4烷氧基、Ra取代的C2-C4烯基、Ra取代的C2-C4炔基、Ra取代的C1-C4烷基酰基、Ra取代的氨基酰基、Ra取代的C1-C4烷基酰胺基、Ra取代的C1-C4烷基氨基、Ra取代的3-6元杂环基、Ra取代的3-6元环烷基、Ra取代的5-6元杂芳基；
Ra选自H、卤素、羟基、C1-C4烷基、卤代C1-C3烷基、-C1-C4亚烷基-(3-6元环烷基)。
在另一优选例中，所述化合物具有以下结构：
式中，R5、R6、R4和R7定义如前所述；两R1相同或不同，各自独立地如前所述。
在另一优选例中，各R1独立地为H、氟、氯、溴、羟基、氰基、氨基、硝基、取代或未取代C1-C4烷基、取代或未取代C2-C4烯基、取代或未取代C2-C4炔基、取代或未取代C1-C4烷氧基、取代或未取代C1-C4烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C4烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代3-6元杂环基、取代或未取代3-6元环烷基、取代或未取代5-6元杂芳基；所述取代为单取代、二取代、三取代或四取代，各取代基独立为氟、氯、溴、羟基、3-6元杂环基。
在另一优选例中，R5、R6、R7各自独立为H、卤素、羟基、氰基、取代或未取代C1-C4烷基、取代或未取代C2-C4烯基、取代或未取代C2-C4炔基、取代或未取代C1-C4烷氧基；取代基选自卤素、羟基。
在另一优选例中，R2、R3与T、V形成取代或未取代的苯环，所述取代为单取代、二取代或三取代，各取代基独立为氟、氯、溴、羟基、氰基、Ra取代的C1-C6烷基、Ra取代的C1-C4烷氧基、Ra取代的C2-C4烯基、Ra取代的C2-C4炔基、Ra取代的C1-C4烷基酰基、Ra取代的氨基酰基、Ra取代的C1-C6烷基酰胺基、Ra取代的C1-C4烷基氨基、Ra取代的3-6元杂环基、Ra取代的3-6元环烷基、Ra取代的5-6元杂芳基；
Ra为H、卤素、羟基、C1-C4烷基、卤代C1-C4烷基、-C1-C4亚烷基-(3-6元环烷基)。
在另一优选例中，所述化合物选自下组：
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明的第二方面，提供一种药物组合物，所述药物组合物包含第一方面所述的化合物或其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐；以及
药学上可接受的载体或赋形剂。
本发明提供新型的化合物，可以单独使用，或者将其与可药用的辅料(例如赋形剂、稀释剂等)混合，配制成口服给药的片剂、胶囊剂、颗粒剂或糖浆剂等。该药物组合物可以按照制药学上常规方法制得。
本发明的第三方面，提供第一方面所述的通式(I)所示的化合物或第二方面所述的药物组合物用途，用于制备cGAS-STING通路靶向抑制剂；
或用于预防和/或治疗炎症性疾病和自身免疫性疾病的药物。
在另一优选例中，所述炎症性疾病和自身免疫性疾病选自：Singleton-Merten综合征(SMS)、Aicardi-Goutières综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银屑病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
具体实施方式
本申请的发明人经过广泛而深入地研究，研发出一种取代的吲哚脲衍生物，能够用作cGAS-STING通路靶向抑制剂，用于炎症性疾病和自身免疫性疾病的治疗。在此基础上，完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C6”是指具有1、2、3、4、5或6个碳原子，“C1-C8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。“5-14元”是指具有5-14个环原子，依此类推。
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“烷氧基”表示-O-(C1-6烷基)基团。例如术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“炔基”是指含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中，术语“杂环烷基”表示包含至少一个环杂原子(例如N，O或S)的环状基团，例如四氢呋喃基、吡咯基、四氢吡啶基或吡咯烷基。
在本发明中，术语“芳基”表示包含一个或多个芳环的烃基部分。例如术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C12芳基”具有类似的含义。芳基的例子包括但不限于苯基(Ph)、萘基、芘基、蒽基和菲基。
除非另外说明，本文所述的烷基、烷氧基、环烷基、杂环基和芳基为取代的和未取代的基团。烷基、烷氧基、环烷基、杂环基和芳基上可能的取代基包括，但不限于：羟基、氨基、硝基、腈基、卤素、C1-C6烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C6烷氧基、芳基、杂芳基、杂芳氧基、C1-C10烷基氨基、C1-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。另一方面，环烷基、杂环烷基、杂环烯基、芳基和杂芳基也可互相稠合。
本发明中，所述取代为单取代或多取代，所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基，依此类推。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
在另一优选例中，“药学上可接受的盐”是指式I化合物同选自下组的酸形成的盐类：氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
药物组合物
本发明还提供了一种药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的式I化合物。
本发明所述的“活性成分”和药物组合物用于制备治疗炎症性疾病和自身免疫性疾病的药物。本发明所述的“活性成分”和药物组合物可用作cGAS-STING通路靶向抑制剂。
所述炎症性疾病和自身免疫性疾病选自：Singleton-Merten综合征(SMS)、Aicardi-Goutières综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银屑病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病等。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他治疗药物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1化合物的制备
1.化合物S1的合成
步骤1：将化合物1a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物1b。1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.31–8.22(m,1H),7.95(d,J＝2.8Hz,1H),7.46–7.41(m,1H),7.34–7.29(m,2H).
步骤2：将化合物1b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物1c。1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.62(d,J＝7.9Hz,1H),7.36(d,J＝8.2Hz,1H),7.29–7.25(m,2H),7.20(t,J＝7.5Hz,1H),7.05(d,J＝2.3Hz,1H).
步骤3：将化合物1d(1eq)悬浮于浓盐酸中，于0℃下逐滴加入亚硝酸钠(1.2eq)的水溶液，反应1小时后将反应液于0℃下缓慢滴加到氯化亚锡(2.2eq)的浓盐酸溶液中，有大量固体析出，约半小时后过滤，水洗滤饼，烘干得化合物1e。1H NMR(400MHz,DMSO)δ9.90(br,2H),8.22(s,1H),7.34(t,J＝8.2Hz,1H),7.19(d,J＝7.1Hz,1H),7.02(s,1H).
步骤4：将化合物1e(1eq)和4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物1f。1H NMR(400MHz,DMSO)δ11.47(s,1H),7.38(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),4.07(s,2H),3.24(t,J＝5.9Hz,2H),2.85(t,J＝5.1Hz,2H).
步骤5：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S1。1H NMR(400MHz,DMSO)δ11.49(s,1H),10.71(s,1H),8.33(s,1H),7.61(d,J＝7.8Hz,1H),7.42(d,J＝8.3Hz,1H),7.36(d,J＝2.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.19(d,J＝8.4Hz,1H),7.06(t,J＝7.7Hz,1H),6.95(t,J＝7.3Hz,1H),4.70(s,2H),3.87(t,J＝5.3Hz,2H),2.88(t,J＝5.6Hz,2H).
2.化合物S2的合成
步骤1：将化合物2a(1eq)溶于浓硫酸中，加入N-溴代丁二酰亚胺(1.2eq)，于65℃下反应约3小时。反应完全后，将反应液倾入冰水中，用乙酸乙酯萃取，盐洗，无水硫酸钠干燥，旋干后得化合物2b，直接用于下一步。
步骤2：将化合物2b(1eq)溶于70mL乙醇中，加入氯化铵(1.82eq)的0.33M水溶液和铁粉(10eq)，于60℃下反应约5小时。反应完全后，将反应液趁热过硅藻土，旋掉大部分溶剂，用乙酸乙酯萃取，盐洗，过柱纯化得化合物2c。1H NMR(400MHz,CDCl3)δ6.99(d,J＝2.2Hz,1H),6.81(d,J＝2.2Hz,1H),4.26(s,2H).
步骤3：将化合物2c(1eq)溶于浓盐酸中，于0℃下缓慢滴加亚硝酸钠(1.5eq)的水溶液，反应约1小时后，缓慢滴加氯化亚锡(2.5eq)的浓盐酸溶液并继续反应约2小时。反应结束后，过滤，滤饼用水洗而后用甲基叔丁基醚打浆，过滤，烘干得化合物2d，直接用于下一步。1H NMR(400MHz,DMSO)δ10.07(br,2H),8.57(s,1H),7.48(s,1H),7.28(s,1H).
步骤4：将化合物2d(1eq)和4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物2e。1H NMR(400MHz,DMSO)δ11.66(s,1H),7.35(s,1H),4.12(s,2H),2.98(t,J＝5.6Hz,2H),2.68(t,J＝5.6Hz,2H).
步骤5：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1e(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S2。1H NMR(400MHz,DMSO)δ11.84(s,1H),10.71(s,1H),8.45(s,1H),7.59(d,J＝8.0Hz,1H),7.43(s,1H),7.36(s,1H),7.30(d,J＝8.4Hz,1H),7.06(t,J＝7.4Hz,1H),6.95(t,J＝7.4Hz,1H),4.94(s,2H),3.85(t,J＝5.7Hz,2H),2.89(t,J＝5.3Hz,2H).
3.化合物S3的合成
步骤1：将化合物3a(1eq)溶于浓盐酸中，于0℃下缓慢滴加亚硝酸钠(1.5eq)的水溶液，反应约1小时后，缓慢滴加氯化亚锡(2.5eq)的浓盐酸溶液并继续反应约2小时。反应结束后，过滤，滤饼用水洗而后用甲基叔丁基醚打浆，过滤，烘干得化合物3b，直接用于下一步。
步骤2：将化合物3b(1eq)和4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物3c。
步骤3：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物3c(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S3。1H NMR(400MHz,DMSO)δ11.37(s,1H),10.73(s,1H),8.24(s,1H),7.62(d,J＝7.8Hz,1H),7.42(d,J＝8.3Hz,1H),7.36(d,J＝1.8Hz,1H),7.30(d,J＝7.9Hz,1H),7.19(d,J＝8.4Hz,1H),7.06(t,J＝7.7Hz,1H),6.95(t,J＝7.1Hz,1H),6.33(s,1H),4.66(s,2H),3.89(t,J＝5.4Hz,2H),2.86(t,J＝5.8Hz,2H).
4.化合物S4的合成
步骤1：将化合物4a(1eq)溶于浓盐酸中，于0℃下缓慢滴加亚硝酸钠(1.5eq)的水溶液，反应约1小时后，缓慢滴加氯化亚锡(2.5eq)的浓盐酸溶液并继续反应约2小时。反应结束后，过滤，滤饼用水洗而后用甲基叔丁基醚打浆，过滤，烘干得化合物4b，直接用于下一步。
步骤2：将化合物4b(1eq)和4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物4c。
步骤3：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物4c(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S4。1H NMR(400MHz,DMSO)δ11.39(s,1H),10.72(s,1H),8.24(s,1H),7.62(d,J＝7.8Hz,1H),7.42(d,J＝8.3Hz,1H),7.36(d,J＝1.8Hz,1H),7.30(d,J＝7.9Hz,1H),7.19(d,J＝8.3Hz,1H),7.11(t,J＝7.4Hz,1H),7.06(t,J＝7.7Hz,1H),6.95(t,J＝7.1Hz,1H),4.66(s,2H),3.89(t,J＝5.4Hz,2H),2.86(t,J＝5.8Hz,2H).
5.化合物S5的合成
步骤1：将化合物S2(1eq)和1-甲基吡唑-3-硼酸频哪醇酯(2eq)溶于1,4-二氧六环中，在氮气保护下加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.2eq)和醋酸钾(3eq)于100℃反应5小时。反应完全后，加水稀释，用乙酸乙酯萃取，过柱纯化得化合物S5。1H NMR(400MHz,DMSO)δ11.54(s,1H),10.67(s,1H),8.26(s,1H),7.80(d,J＝2.2Hz,1H),7.53(d,J＝8.0Hz,1H),7.31(d,J＝2.4Hz,1H),7.28(d,J＝8.1Hz,1H),7.22(s,1H),7.04(t,J＝7.0Hz,1H),6.94(t,J＝7.1Hz,1H),6.57(d,J＝2.2Hz,1H),4.57(s,2H),3.93(s,3H),3.85(t,J＝5.9Hz,2H),2.92(t,J＝5.1Hz,2H).
6.化合物S6的合成
步骤1：在氮气保护下，将化合物S2(1eq)，2-丙炔-1-醇(2eq)，四(三苯基膦)钯(0.05eq)，碘化亚铜(0.02eq)加入四氢吡咯中，升温至90℃回流反应3小时。反应完全后，加水稀释，用乙酸乙酯萃取，过柱纯化得化合物S6。1H NMR(400MHz,DMSO)δ11.82(s,1H),10.70(s,1H),8.43(s,1H),7.60(d,J＝7.9Hz,1H),7.40(s,1H),7.37(d,J＝2.3Hz,1H),7.31(d,J＝8.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.95(s,2H),4.53(s,2H),3.86(t,J＝5.2Hz,2H),2.89(t,J＝5.4Hz,2H).
7.化合物S7的合成
步骤1：将化合物S2(1eq)和1-环丙基甲基-4-硼酸频哪醇酯(2eq)溶于1,4-二氧六环中，在氮气保护下加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.2eq)和醋酸钾(3eq)于100℃反应4小时。反应完全后，加水稀释，用乙酸乙酯萃取，过柱纯化得化合物S7。1H NMR(400MHz,DMSO)δ11.42(s,1H),10.35(s,1H),8.33(s,1H),8.28(s,1H),7.96(s,1H),7.53(d,J＝7.9Hz,1H),7.49(s,1H),7.37(d,J＝2.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.16(t,J＝7.4Hz,1H),7.04(t,J＝7.5Hz,1H),4.78(s,2H),4.04(d,J＝12.5Hz,2H),3.94(t,J＝5.2Hz,2H),2.94(t,J＝5.4Hz,2H),1.51-1.48(m,1H),0.52-0.41(m,4H).
8.化合物S8的合成
步骤1：将化合物S2(1eq)和1-(2,2-二氟乙基)-4-(四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(2eq)溶于1,4-二氧六环中，在氮气保护下加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.2eq)和醋酸钾(3eq)于100℃反应4小时。反应完全后，加水稀释，用乙酸乙酯萃取，过柱纯化得化合物S8。
1H NMR(400MHz,DMSO)δ11.62(s,1H),10.55(s,1H),8.54(s,1H),8.33(s,1H),8.02(s,1H),7.51(d,J＝7.8Hz,1H),7.49(s,1H),7.38(d,J＝2.2Hz,1H),7.27(d,J＝8.0Hz,1H),7.18(t,J＝7.6Hz,1H),6.99(t,J＝7.4Hz,1H),6.08–5.76(m,1H),4.88(s,2H),4.32–4.27(m,2H),3.95(t,J＝5.3Hz,2H),2.93(t,J＝5.5Hz,2H).
9.化合物S9的合成
步骤1：将化合物1e(1eq)和2-甲基-4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，用乙酸乙酯萃取，过柱纯化，得化合物9a和9b。
步骤2：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物9a(1.2eq)，于室温下反应6小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S9。1H NMR(400MHz,DMSO)δ11.41(s,1H),10.67(s,1H),8.13(s,1H),7.63(d,J＝7.9Hz,1H),7.38(d,J＝8.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.27(d,J＝8.1Hz,1H),7.15(d,J＝8.3Hz,1H),7.11(t,J＝7.6Hz,1H),7.01(t,J＝7.4Hz,1H),4.71(s,2H),4.68–4.59(m,1H),2.97(d,J＝5.4Hz,2H),1.28(d,J＝6.4Hz,3H).
10.化合物S10的合成
步骤2：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物9b(1.2eq)，于室温下反应6小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S10。1HNMR(400MHz,DMSO)δ11.48(s,1H),10.72(s,1H),8.35(s,1H),7.60(d,J＝7.8Hz,1H),7.45(d,J＝8.2Hz,1H),7.39(d,J＝2.1Hz,1H),7.29(d,J＝8.0Hz,1H),7.21(d,J＝8.3Hz,1H),7.07(t,J＝7.6Hz,1H),6.98(t,J＝7.4Hz,1H),5.17–5.02(m,1H),4.02(t,J＝5.4Hz,2H),2.99(t,J＝5.7Hz,2H),1.62(d,J＝6.6Hz,3H).
11.化合物S11的合成
步骤1：将化合物1e(1eq)和3-氟-4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物11a。
步骤2：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物11a(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S11。1HNMR(400MHz,DMSO)δ11.29(s,1H),10.62(s,1H),8.03(s,1H),7.64(d,J＝7.7Hz,1H),7.41(d,J＝8.2Hz,1H),7.38(d,J＝2.0Hz,1H),7.29(d,J＝8.1Hz,1H),7.22(d,J＝8.5Hz,1H),7.10(t,J＝7.6Hz,1H),6.99(t,J＝7.1Hz,1H),5.23–5.16(m,1H),4.67(s,2H),4.15–4.09(m,2H).
12.化合物S12的合成
步骤1：将化合物1e(1eq)和3-氰基-4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物11a。
步骤2：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物12a(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S12。1HNMR(400MHz,DMSO)δ11.51(s,1H),10.78(s,1H),8.41(s,1H),7.63(d,J＝7.9Hz,1H),7.46(d,J＝8.5Hz,1H),7.41(d,J＝2.1Hz,1H),7.28(d,J＝8.1Hz,1H),7.22(d,J＝8.5Hz,1H),7.08(t,J＝7.6Hz,1H),6.97(t,J＝7.5Hz,1H),4.80(t,J＝5.8Hz,1H),4.73(s,2H),4.18(d,J＝5.5Hz,2H).
13.化合物S13的合成
步骤1：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物13a(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S13。1HNMR(400MHz,DMSO)δ10.78(s,1H),8.63(s,1H),7.62(d,J＝7.9Hz,1H),7.38(d,J＝2.0Hz,1H),7.32(d,J＝8.2Hz,1H),7.07(t,J＝7.3Hz,1H),6.97(t,J＝7.3Hz,1H),4.99(s,2H),4.25(t,J＝5.2Hz,2H),4.01(t,J＝5.2Hz,2H).
14.化合物S14的合成
步骤1：将化合物1e(1eq)和3-甲基-4-哌啶酮盐酸盐(1.5eq)溶于1,4-二氧六环溶液中，加入浓硫酸(21eq)，升温至115℃反应过夜。反应完全后，旋掉大部分有机溶剂，冰浴下逐滴加入4N氢氧化钠溶液调节pH至8左右。待固体充分析出后，过滤，将滤饼用甲基叔丁基醚打浆，过滤将固体烘干，得化合物14a。
步骤2：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物14a(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S14。1HNMR(400MHz,DMSO)δ11.38(s,1H),10.60(s,1H),8.22(s,1H),7.57(d,J＝7.6Hz,1H),7.39(d,J＝8.1Hz,1H),7.28(d,J＝2.1Hz,1H),7.26(d,J＝7.9Hz,1H),7.18(d,J＝8.3Hz,1H),7.07(t,J＝7.6Hz,1H),6.89(t,J＝7.4Hz,1H),4.66(s,2H),3.95(d,J＝5.3Hz,2H),3.12–2.98(m,1H),1.34(d,J＝6.2Hz,3H).
15.化合物S15的合成
步骤1：将化合物1c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物15a(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S15。1HNMR(400MHz,DMSO)δ10.72(s,1H),8.58(s,1H),7.63(d,J＝7.9Hz,1H),7.39(d,J＝2.0Hz,1H),7.34(d,J＝8.1Hz,1H),7.08(t,J＝7.2Hz,1H),6.96(t,J＝7.3Hz,1H),5.01(s,2H),4.76–4.69(m,1H),4.11(d,J＝5.5Hz,2H),1.49(d,J＝6.5Hz,3H).
16.化合物S16的合成
步骤1：将化合物16a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物16b。
步骤2：将化合物16b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物16c。
步骤3：将化合物16c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S16。1HNMR(400MHz,DMSO)δ11.55(s,1H),10.69(s,1H),8.42(s,1H),7.69–7.62(m,1H),7.45(d,J＝8.2Hz,1H),7.39(d,J＝2.1Hz,1H),7.35(d,J＝8.1Hz,1H),7.21(d,J＝8.3Hz,1H),7.17–7.12(m,1H),4.71(s,2H),3.86(t,J＝5.3Hz,2H),2.90(t,J＝5.5Hz,2H).
17.化合物S17的合成
步骤1：将化合物17a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物17b。
步骤2：将化合物17b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物17c。
步骤3：将化合物17c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S17。1HNMR(400MHz,DMSO)δ11.47(s,1H),10.77(s,1H),8.37(s,1H),7.61(dd,J＝8.6,5.7Hz,1H),7.41(d,J＝8.3Hz,1H),7.36(d,J＝2.3Hz,1H),7.19(d,J＝8.3Hz,1H),7.07(dd,J＝10.1,2.2Hz,1H),6.86–6.78(m,1H),4.69(s,2H),3.86(t,J＝5.4Hz,2H),2.88(t,J＝4.8Hz,2H).
18.化合物S18的合成
步骤1：将化合物18a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物18b。
步骤2：将化合物18b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物18c。
步骤3：将化合物18c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S18。1HNMR(400MHz,DMSO)δ11.48(s,1H),10.86(s,1H),8.41(s,1H),7.64(d,J＝8.5Hz,1H),7.42(s,1H),7.41(d,J＝4.7Hz,1H),7.35(d,J＝1.8Hz,1H),7.19(d,J＝8.4Hz,1H),6.97(dd,J＝8.5,1.9Hz,1H),4.69(s,2H),3.86(t,J＝5.5Hz,2H),2.88(t,J＝5.0Hz,2H).
19.化合物S19的合成
步骤1：将化合物19a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物19b。
步骤2：将化合物19b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物19c。
步骤3：将化合物19c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S19。1HNMR(400MHz,DMSO)δ11.19(s,1H),10.60(s,1H),8.03(s,1H),7.58(d,J＝7.9Hz,1H),7.41(d,J＝8.3Hz,1H),7.27(d,J＝8.1Hz,1H),7.16(d,J＝8.3Hz,1H),7.01(t,J＝7.5Hz,1H),6.85(t,J＝7.0Hz,1H),4.67(s,2H),3.84(t,J＝5.4Hz,2H),2.89(t,J＝5.5Hz,2H),2.38(s,3H).
20.化合物S20的合成
步骤1：将化合物20a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物20b。
步骤2：将化合物20b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物20c。
步骤3：将化合物20c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S20。1HNMR(400MHz,DMSO)δ11.48(s,1H),10.56(s,1H),8.25(s,1H),7.41(d,J＝8.4Hz,1H),7.33(d,J＝2.3Hz,1H),7.19(dd,J＝8.5,4.4Hz,2H),7.09(d,J＝2.2Hz,1H),6.71(dd,J＝8.8,2.3Hz,1H),4.70(s,2H),3.87(t,J＝5.4Hz,2H),3.74(s,3H),2.89(t,J＝4.6Hz,2H).
21.化合物S21的合成
步骤1：将化合物21a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物21b。
步骤2：将化合物21b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物21c。
步骤3：将化合物21c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S21。1HNMR(400MHz,DMSO)δ11.62(s,1H),10.79(s,1H),8.66(s,1H),7.75(d,J＝7.8Hz,1H),7.49–7.30(m,3H),7.26–7.03(m,2H),4.72(s,2H),3.89(t,J＝5.4Hz,2H),2.91(t,J＝5.6Hz,2H).
22.化合物S22的合成
步骤1：将化合物22a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物22b。
步骤2：将化合物22b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物22c。
步骤3：将化合物22c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。反应完全后，将反应液倾入水中，用乙酸乙酯萃取，过柱纯化得化合物S22。1HNMR(400MHz,DMSO)δ11.50(s,1H),10.67(s,1H),8.41(s,1H),7.44(d,J＝8.1Hz,1H),7.38(d,J＝2.1Hz,1H),7.26–7.21(m,2H),7.13(d,J＝2.2Hz,1H),6.96–6.92(m,1H),4.73(s,2H),3.85(t,J＝5.2Hz,2H),2.91(t,J＝5.3Hz,2H).
23.化合物S23的合成
步骤1：将化合物23a(1eq)溶于甲苯中，在氮气保护下加入三乙胺(1eq)，约15分钟后加入叠氮磷酸二苯酯(1.1eq)，在室温下搅拌过夜。待反应完全后，旋干溶剂，而后过柱纯化，得化合物23b。
步骤2：将化合物23b溶于甲苯中，在氮气保护下回流过夜。待反应完全后，旋干溶剂，抽干，得化合物23c。
步骤3：将化合物23c(1eq)溶于N,N-二甲基甲酰胺中，加入化合物1f(1.2eq)，于室温下反应5小时。1H NMR(400MHz,DMSO)δ11.48(s,1H),10.63(s,1H),8.38(s,1H),7.43(d,J＝8.2Hz,1H),7.36(d,J＝2.2Hz,1H),7.29–7.25(m,2H),7.19(d,J＝2.3Hz,1H),7.12–6.98(m,1H),4.73(s,2H),3.84(t,J＝5.3Hz,2H),2.88(t,J＝4.9Hz,2H).
实施例2
荧光素酶方法检测化合物对THP-1-Dual细胞中cGAMP刺激的STING信号通路活化的抑制作用
1)将处于对数生长期的THP-1-Dual(Invivogen)细胞按5*10^4个/孔种于96孔板中，加入不同浓度的化合物，培养箱内预孵育1h。DMSO组作为化合物的阴性对照。
2)细胞转染2.5μg/ml cGAMP(Invivogen)与Lipofectamine 2000(Invitrogen)复合物培养24h。
转染复合物配制方法：0.5μg cGAMP加入10μl Opti-MEM(Gibco)，0.5μlLipofectamine 2000加入10μl Opti-MEM，混合后，将20μl复合物加入96孔板中。
3)采用QUANTI-LucTM试剂(InvivoGen)检测荧光素酶活性。取20μl细胞培养上清加入96孔不透明白板中，再加入50μl QUANTI-LucTM试剂，多功能酶标仪进行读值(BioTek,Winooski,VT)。
相对荧光素酶活性计算方法：Lipofectamine 2000-作用的细胞作为阴性对照，Lipofectamine 2000:cGAMP复合物作用的细胞作为阳性对照，
相对荧光素酶活性＝(RLU sample-RLU negative control)/(RLU positivecontrol -RLU negative control)
RLU代表原始荧光素酶读值。
4)A:IC50＜5μM；B:5μM≤IC50＜10μM；C:≥10μM
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (8)
1.一种通式(I)所示的化合物或其药学上可接受的盐，
式中，两R1相同或不同，各R1独立地为H、卤素、取代或未取代C1-C6烷基或者取代或未取代C1-C6烷氧基；所述取代为单取代或多取代，各取代基独立为卤素；
R4为H或者取代或未取代C1-C6烷基；取代基选自卤素、羟基；
R5、R6、R7各自独立为H、卤素、羟基、氰基、取代或未取代C1-C6烷基、或者取代或未取代C1-C6烷氧基；取代基选自卤素、羟基；
各Rb独立地为H、氟、氯、溴、羟基、氰基、Ra取代的C1-C4烷基、Ra取代的C1-C4烷氧基、Ra取代的C2-C4烯基、Ra取代的C2-C4炔基、Ra取代的3-6元杂环基、Ra取代的3-6元环烷基或者Ra取代的5-6元杂芳基；
Ra选自H、卤素、羟基、C1-C4烷基、卤代C1-C3烷基、-C1-C4亚烷基-(3-6元环烷基)。
2.如权利要求1所述的化合物，其特征在于，
各Rb独立地为H、氟、氯、溴、Ra取代的C1-C4烷基、Ra取代的C2-C4炔基或者Ra取代的5元杂芳基；
Ra选自H、卤素、羟基、C1-C4烷基、卤代C1-C3烷基、-C1-C4亚烷基-(3-6元环烷基)。
3.如权利要求1或2所述的化合物，其特征在于，各R1独立地为H、氟、氯、溴、取代或未取代C1-C4烷基、或者取代或未取代C1-C4烷氧基；所述取代为单取代、二取代、三取代或四取代，各取代基独立为氟、氯或溴。
4.如权利要求1或2所述的化合物，其特征在于，R5、R6、R7各自独立为H、卤素、羟基、氰基、取代或未取代C1-C4烷基、或者取代或未取代C1-C4烷氧基；取代基选自卤素、羟基。
5.如权利要求1或2所述的化合物，其特征在于，所述化合物选自下组：
6.一种药物组合物，其特征在于，包含：
如权利要求1所述的通式(I)所示的化合物或其药学上可接受的盐；和
药学上可接受的载体。
7.如权利要求1所述的通式(I)所示的化合物或权利要求6所述的药物组合物用途，其特征在于，用于制备cGAS-STING通路靶向抑制剂；
或用于制备预防和/或治疗炎症性疾病和自身免疫性疾病的药物。
8.如权利要求7所述的用途，其特征在于，所述炎症性疾病和自身免疫性疾病选自：Singleton-Merten综合征(SMS)、Aicardi-Goutières综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银屑病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病。
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