CN116265447A - 一种抗甲型流感病毒化合物的制备及其用途 - Google Patents
一种抗甲型流感病毒化合物的制备及其用途 Download PDFInfo
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- CN116265447A CN116265447A CN202111555431.0A CN202111555431A CN116265447A CN 116265447 A CN116265447 A CN 116265447A CN 202111555431 A CN202111555431 A CN 202111555431A CN 116265447 A CN116265447 A CN 116265447A
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Abstract
本发明提供了一种抗甲型流感病毒化合物的制备及其用途，具体地，本发明提供了一种如下式I所示的化合物，或其药学上可接受的盐。本发明首次发现该类化合物具有抗甲型流感病毒活性，且提供了一种一步实现其合成的方法，原子效益高，步骤经济，原料易得。
Description
技术领域
本发明涉及药物领域，具体涉及了一种羟肟大环内酰胺类化合物的应用及其制备方法。
背景技术
流行性感冒(Influenza)，是由流感病毒(Influenza viruses,IVs)感染引起的，可引起急性呼吸道感染，主要是口、咽、支气管甚至肺部的不适，特征是突发高热、咽痛、咳嗽、流涕和肌肉关节痛等，严重的将导致死亡。世界卫生组织在2018年底的统计结果显示，每年仅因季节性流感引起的呼吸道疾病，就会造成全球范围内29万到65万人死亡。历史上四次大规模流感的爆发，每年的季节性流感和新型流感的突发与流行，提示着流感病毒对人类健康有持续性的威胁。
流感病毒属于正黏病毒科(Orthomyxoviridae)，是一种高突变率、高致病性的RNA病毒。流感病毒根据核蛋白和基质蛋白抗原决定簇的不同，可划分为甲(A)、乙(B)、丙(C)和丁(D)四个亚型。其中，甲型流感病毒抗原性易发生变异，多次引起世界性大流行。虽然疫苗接种仍然是用于控制流感感染的主要预防策略，但疫苗开发周期长且难以应对快速变异的突变体，因此，抗流感药物的开发仍然是本领域亟待解决的问题。
发明内容
本发明的目的是提供一类抗甲型流感病毒化合物及其制备方法和用途。
本发明的第一方面，提供了一种如下式I所示的化合物，或其药学上可接受的盐：
其中，
Ar选自下组：苯基、萘基、联苯基、5-7元杂芳基；
R1、R2和R3各自独立地选自下组：氢、卤素、氰基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基；或-CHR3-不存在；
Linker具有如下式所示的结构：
-L1-(L2)m-L3-；
其中，m为1、2、3、4、5或6；
L1选自下组：化学键、-O-、-CO-、-CONH-、-CH2-、或-SO2-；
L2选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基、取代或未取代的C1-C6亚烷基(优选为C1-C4亚烷基)、-O-、-CO-、-NH-、取代或未取代的C2-C6亚烯基(优选为C2-C4亚烯基，更优选为C2-C3亚烯基)；
L3选自下组：-O-、-CO-、-CONH-、-CH2-、或-SO2-；
其中，所述的任一“取代”是指基团上的一个或多个(优选为1、2、3或4个)氢原子被选自下组的取代基所取代：卤素、-CN、卤代C1-C4烷基(如-CF3)、羟基、氨基、甲磺酰基、-NH-C6-C10芳基、-NH-5-12元杂芳基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C10芳基、C6-C10芳基-C1-C4烷基-、C6-C10芳基-C1-C4烷氧基-、C1-C4烷硫基、5-12元杂芳基、C2-C4酯基、或氨基酸残基(即，天然氨基酸缩合过程中失去一分子水从而形成的基团)；
所述的杂环基和杂芳基的杂环上各自独立地具有1-3个(优选为1、2或3个)选自N、O和S的杂原子。
在另一优选例中，R1为未取代或具有1-3个(优选为1、2或3个)取代的C6-C20芳基(如苯基、萘基)。
在另一优选例中，R1为具有1-3个(优选为1、2或3个)取代或未取代的C6-C20芳基(如苯基、萘基)，所述的取代基为卤素、-CN、卤代C1-C4烷基(如-CF3)、氰基、羟基、氨基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C12芳基、C6-C12芳基-C1-C4烷基-、C6-C12芳基-C1-C4烷氧基-、C1-C4烷硫基、5-12元杂芳基、C2-C4酯基、或氨基酸残基。
在另一优选例中，所述的R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基；其中，所述的取代指基团上的一个或多个H原子被选自下组的取代基取代：卤素、-CN、卤代C1-C4烷基(如-CF3)、羟基、氨基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C12芳基、或5-12元杂芳基。
在另一优选例中，所述的R2选自下组：氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C4酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基。
在另一优选例中，所述的R2选自下组：氢、卤素、取代或未取代的C1-C4烷基、取代或未取代的C2-C4酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基。
在另一优选例中，R2选自下组：氢、-CF3、甲基、取代或未取代的苯基、-COOMe。
在另一优选例中，所述的R3选自下组：氢、取代或未取代的C1-C10烷基，或-CHR3-不存在。
在另一优选例中，所述的式I化合物具有如下式II所示的结构：
在另一优选例中，R1为具有1-3个(优选为1或2个)取代或未取代的C6-C20芳基(如苯基、萘基)，所述的取代基为卤素、F、Br、-CF3、氰基、羟基、氨基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C12芳基、C6-C12芳基-C1-C4烷基-、C6-C12芳基-C1-C4烷氧基-、C1-C4烷硫基、5-12元杂芳基、C2-C4酯基、
在另一优选例中，所述的Linker为选自下组的结构：
在另一优选例中，所述的式I化合物选自下组：
本发明的第二方面，提供了如本发明第一方面所述的式I化合物的制备方法，所述的方法包括步骤(1)、(2)或(3)：
(1)在催化剂、银盐和第一碱试剂的作用下，式C1化合物与式C2化合物经碳氢键活性反应，生成式I化合物；
(2)在催化剂、银盐和第一碱试剂的作用下，式C3化合物与式C4化合物经碳氢键活性反应，生成式I化合物；其中，R3为H；
(3)在催化剂、银盐和第一碱试剂的作用下，式C3化合物与式C4化合物经碳氢键活性反应，生成式I化合物；其中，-CHR3-不存在；
在另一优选例中，所述的步骤(1)中，所述的催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体([Cp*RhCl2]2)。
在另一优选例中，所述的步骤(1)中，所述的银盐为六氟锑酸银(AgSbF6)。
在另一优选例中，所述的步骤(1)中，所述的第一碱试剂选自下组：碳酸钠、碳酸钾、碳酸铯，碳酸银或其组合。
在另一优选例中，所述的步骤(1)中，所述的第一碱试剂为碳酸银。
在另一优选例中，所述的步骤(1)中，所述的反应在无溶剂和第一溶剂中进行。
在另一优选例中，所述的第一溶剂选自下组：甲醇、四氢呋喃、二氧六环、氯仿、二氯甲烷、1,2-二氯乙烷、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜或者六甲基磷酰三胺，或其组合。
在另一优选例中，所述的步骤(1)中，所述反应的温度为20-100℃，较佳地40-100℃，更佳地60-90℃。
在另一优选例中，所述的步骤(1)中，所述反应的时间为6-36h，较佳地8-24h，更佳地16-24h，最佳地20-24h。
在另一优选例中，所述的步骤(1)中，所述的式C1化合物与所述的银盐的摩尔比为1:0.05-2，较佳地1:0.05-1，更佳地1：0.1-0.5。
在另一优选例中，所述的步骤(1)中，所述的银盐与所述第一碱试剂的摩尔比为1：0.5-10。
在另一优选例中，所述的步骤(1)中，所述的银盐与所述催化剂的摩尔比为0.5-20:1，较佳地1-15:1，更佳地1-10:1，更佳地2-6：1。
在另一优选例中，所述的步骤(1)中，所述的催化剂与所述第一碱试剂的摩尔比为1：2-40。
在另一优选例中，所述的步骤(1)中，所述的式C1化合物与所述的式C1化合物的摩尔比为1：1-5，较佳地1：1-3，更佳地1：1-2。
本发明的第三方面，提供了一种药物组合物，所述的组合物包含：(a)如本发明第一方面所述的式I化合物，或其异构体，或其药学上可接受的盐；和(b)药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物的用途，其用于制备药物组合物，且所述的药物组合物用于治疗或预防甲型流感病毒导致的疾病或病症。
在另一优选例中，所述的疾病或病症为甲型流感，或甲型流感病毒致细胞病变效应(CPE)(细胞圆形、变性、脱落)。
在另一优选例中，所述的药物组合物还用于提高细胞存活率。
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。限于篇幅，在此不再一一累述。
附图说明
附图1化合物抗甲型流感病毒活性。
附图2化合物改善甲型流感病毒致细胞病变效应(CPE)。
具体实施方式
本发明人经过长期而深入的研究，意外开发了一种式I化合物，或其异构体，或其药学上可接受的盐，所述的式I化合物具有抗甲型流感病毒活性。此外，本申请还提供一种式I化合物，或其异构体，或其药学上可接受的盐以及式I化合物，或其异构体，或其药学上可接受的盐的制备方法，所述的式I化合物，或其异构体，或其药学上可接受的盐的制备方法为铑催化碳氢键活化反应，对于式I化合物的制备方法，首次一步实现了多取代式I类化合物，具有原子效益高，步骤经济，原料易得等特点，在此之前，利用其他方法均无法简便快速地得到式I化合物。在此基础上，发明人完成了本发明。
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-C10烷基”是指具有1至10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“C1-C7烷氧基”是指具有1至7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“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“C2-C6亚烯基”是指C2-C6烯基失去一个氢原子形成的二价基团。
在本发明中，术语“C3-C8环烷基”是指在环上具有3至8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、和环辛基等。术语“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“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。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-C10芳基”具有类似的含义。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的，除非特别说明，优选的杂芳基是5-12元的杂芳基，更优选为5-7元杂芳基。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基、C1-10磺酰基等。
具有抗甲型流感病毒活性的大环内酰胺类化合物
本发明中，提供了一类羟肟大环内酰胺类化合物，其为一类15到24元环的以内酰胺作为连接的化合物，核心结构是通过不同的羟肟前体与多样性的五元环噁唑酮化合物，经铑催化碳氢键活化制备而成。经测试，这一类化合物具有优异的抗甲型流感病毒活性。
本发明中，示例性的大环内酰胺化合物具有如下式所示的结构：
其中，
Ar选自下组：苯基、萘基、联苯基、5-7元的杂芳基；
R1、R2和R3各自独立地选自下组：氢、卤素、氰基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基；或-CHR3-不存在；
Linker具有如下式所示的结构：
-L1-(L2)m-L3-；
其中，m为1、2、3、4、5或6；
L1选自下组：化学键、-O-、-CO-、-CONH-、-CH2-、或-SO2-；
L2选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基、取代或未取代的C1-C6亚烷基(优选为C1-C4亚烷基)、-O-、-CO-、-NH-、取代或未取代的C2-C6亚烯基(优选为C2-C4亚烯基，更优选为C2-C3亚烯基)；
L3选自下组：-O-、-CO-、-CONH-、-CH2-、或-SO2-；
其中，所述的任一“取代”是指基团上的一个或多个(优选为1、2、3或4个)氢原子被选自下组的取代基所取代：卤素、-CN、卤代C1-C4烷基(如-CF3)、羟基、氨基、甲磺酰基、-NH-C6-C10芳基、-NH-5-12元杂芳基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C10芳基、C6-C10芳基-C1-C4烷基-、C6-C10芳基-C1-C4烷氧基-、C1-C4烷硫基、5-12元杂芳基、C2-C4酯基、或氨基酸残基(即，天然氨基酸缩合过程中失去一分子水从而形成的基团)；
所述的杂环基和杂芳基的杂环上各自独立地具有1-3个(优选为1、2或3个)选自N、O和S的杂原子。
药物组合物和施用方法
由于本发明化合物具有优异的抗甲型流感病毒活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与甲型流感病毒感染相关的疾病，特别是甲型流感，。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物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1-3000(活性剂量范围3-30mg/kg)mg本发明化合物/剂，更佳地，含有10-2000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”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化合物以及它们之间相互掺和，而不明显降低化合物的药效。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
)、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。
本发明化合物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)、和局部给药。
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。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
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。除了活性化合物外，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。
除了活性化合物外，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。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
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6～600mg。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。
与现有技术相比，本发明的主要优点包括：
本发明所发现的羟肟大环内酰胺类化合物，或其异构体，或其药学上可接受的盐，具有抗甲型流感病毒活性。此外，本申请还提供这类化合物，或其异构体，或其药学上可接受的盐的制备方法，首次一步实现了多取代羟肟大环内酰胺类化合物，具有原子效益高，步骤经济，原料易得等特点，在此之前，利用其他方法均无法快速地得到羟肟大环内酰胺类化合物。此类结构的抗甲型流感病毒活性是首次报道，属于源头创新，具有重要的学术意义和应用前景。
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，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
化合物的1H-NMR光谱数据测量使用Varian Mercury-400MHz或Varian Mercury-500MHz核磁共振，质谱EI-MS用Finnigan MAT 95质谱仪，ESI-MS使用Finnigan LCQ Deca质谱仪测定。快速柱层析在硅胶H(10-40μM)上进行。试剂纯化参照Purification oflaboratory Chemicals；D.D.Perrin；W.L.F.Armarego and D.R.Perrin Eds.,PergamonPress:Oxiford,1980。
如未作特别说明，本发明所采用的试剂和方法等为本领域熟知的试剂和方法。
实施例1
反应条件：
实验方法：在空气氛围中，向含有螺旋盖的螺纹耐压管中依次加入大环内酰胺化合物前体1’(0.2mmol,2.0当量)、二噁唑酮1”(0.1mmol,1.0当量)、[Cp*RhCl2]2(0.005mmol,5mol％)、AgSbF6(0.02mmol,20mol％)及Ag2CO3(0.02mmol,20mol％)，随后立即加入10mL二氯乙烷溶液并充分混匀。将反应体系在80℃下搅拌24小时。TLC监测反应完全后，将反应体系冷却至室温，用硅藻土过滤金属及其他固态杂质，随后旋转蒸发除去溶剂。最后利用柱层析分离纯化得到目标产物1。白色固体，反应产率为46％。
1H NMR(500MHz,Chloroform-d)δ7.68(d,J＝7.9Hz,1H),7.51(td,J＝7.6,1.5Hz,1H),7.46–7.39(m,3H),7.35(td,J＝7.7,1.5Hz,2H),7.08(ddd,J＝8.2,2.7,0.9Hz,1H),6.32(t,J＝6.2Hz,1H),5.00–4.81(m,1H),4.25(dt,J＝11.5,4.6Hz,1H),4.15–4.03(m,1H),3.76(s,3H),3.63(dd,J＝13.1,4.7Hz,1H),3.39(dd,J＝13.5,6.8Hz,1H),3.31(dd,J＝13.2,10.9Hz,1H),2.99(dd,J＝13.6,5.6Hz,1H),2.74(dt,J＝13.0,8.5Hz,1H),2.07(ddd,J＝12.6,7.4,4.2Hz,1H),1.71–1.59(m,4H),1.10(s,3H),0.99(s,3H).
13C NMR(126MHz,Chloroform-d)δ196.81,168.43,163.83,158.56,137.32,136.50,133.03,130.74,130.07,128.94,128.42,127.04,126.56(q,J＝280.7Hz),121.63,121.36,113.39,66.99,61.41,47.65,42.58(q,J＝28.2Hz),41.17,40.41,27.72,25.04,24.75,23.38,23.06.
19F NMR(471MHz,Chloroform-d)δ-68.05(d,J＝8.9Hz).
HRMS(ESI)calcd.for C27H30F3N2O4[M-H]-:503.2163,found:503.2150.
实施例2
化合物的合成方法参见化合物1，白色固体，产率45％。
1H NMR(500MHz,Chloroform-d)δ7.55(d,J＝8.0Hz,1H),7.45(dt,J＝7.7,1.2Hz,1H),7.42–7.40(m,1H),7.35(t,J＝7.9Hz,1H),7.33–7.30(m,1H),7.22(d,J＝1.9Hz,1H),7.08(ddd,J＝8.2,2.7,0.9Hz,1H),6.23(t,J＝6.1Hz,1H),4.96–4.77(m,1H),4.26(dt,J＝11.5,4.5Hz,1H),4.07(ddd,J＝11.9,7.2,5.3Hz,1H),3.78(s,3H),3.64(dd,J＝13.0,4.7Hz,1H),3.39(dd,J＝13.5,7.1Hz,1H),3.26(dd,J＝13.1,11.0Hz,1H),2.97–2.89(m,1H),2.75(dt,J＝12.8,8.4Hz,1H),2.35(s,3H),2.07(ddd,J＝12.9,7.3,4.0Hz,1H),1.70–1.60(m,4H),1.10(s,3H),0.98(s,3H).
13C NMR(126MHz,Chloroform-d)δ196.98,168.46,163.78,158.52,138.35,137.20,136.51,131.48,130.08,129.82,128.80,127.62,126.60(q,J＝280.4Hz),121.63,121.41,113.32,66.92,61.40,47.50,42.33(q,J＝28.2Hz),41.14,40.50,27.70,25.03,24.75,23.42,23.07,21.09.
19F NMR(471MHz,Chloroform-d)δ-68.28(d,J＝9.0Hz).
HRMS(ESI)calcd.for[M-H]-C28H32F3N2O4:517.2320,found:517.2308.
实施例3
化合物的合成方法参见化合物1，白色固体，产率42％。
1H NMR(500MHz,Chloroform-d)δ7.63(dd,J＝8.5,2.1Hz,1H),7.56(d,J＝2.1Hz,1H),7.55–7.52(m,1H),7.45–7.43(m,1H),7.39–7.35(m,2H),7.09(ddd,J＝8.1,2.6,0.9Hz,1H),6.32(t,J＝6.0Hz,1H),4.87(ddt,J＝11.4,9.1,4.1Hz,1H),4.27(d,J＝11.8Hz,1H),4.09(d,J＝6.0Hz,1H),3.81(s,3H),3.79–3.74(m,1H),3.68(dd,J＝13.3,4.3Hz,1H),3.36(dd,J＝13.5,7.0Hz,1H),3.21(dd,J＝13.2,11.4Hz,1H),2.85(dd,J＝13.5,5.3Hz,1H),2.82–2.73(m,1H),2.06(ddd,J＝12.9,7.0,4.0Hz,1H),1.71–1.56(m,3H),1.10(s,3H),1.00(s,3H).
13C NMR(126MHz,Chloroform-d)δ196.50,166.73,163.69,158.51,139.21,136.29,133.75,131.92,130.59,130.18,130.04,126.23(q,J＝280.6Hz),122.49,122.20,121.39,112.80,66.94,61.63,47.68,42.24(q,J＝28.5Hz),41.01,40.09,27.59,25.28,24.72,23.44,23.13.
19F NMR(471MHz,Chloroform-d)δ-68.35(d,J＝8.4Hz).
HRMS(ESI)calcd.for[M-H]-C27H29BrF3N2O4:581.1268,found:581.1261.
实施例4
化合物的合成方法参见化合物1，白色固体，产率43％。
1H NMR(500MHz,Chloroform-d)δ7.45(dt,J＝7.5,1.2Hz,2H),7.40(dd,J＝2.7,1.5Hz,1H),7.34(t,J＝7.9Hz,1H),7.31(d,J＝7.8Hz,1H),7.15–7.12(m,1H),7.07(ddd,J＝8.2,2.6,0.9Hz,1H),6.25(t,J＝6.2Hz,1H),5.05–4.83(m,1H),4.25(dt,J＝11.4,4.6Hz,1H),4.07(ddd,J＝11.8,7.3,5.0Hz,1H),3.77(s,3H),3.63(dd,J＝13.0,4.8Hz,1H),3.37(dd,J＝13.5,6.8Hz,1H),3.29(dd,J＝13.1,10.8Hz,1H),2.97(dd,J＝13.5,5.6Hz,1H),2.74(dt,J＝13.0,8.5Hz,1H),2.42(s,3H),2.06(ddd,J＝12.4,7.4,4.1Hz,1H),1.78–1.58(m,4H),1.09(s,3H),0.97(s,3H).
13C NMR(151MHz,Chloroform-d)δ196.51,167.95,163.34,158.04,140.48,136.02,133.92,132.50,129.56,129.09,128.64,126.56,126.13(q,J＝280.8Hz),121.19,120.93,112.83,66.48,60.95,47.09,41.85(q,J＝27.9Hz),40.69,39.95,27.19,24.58,24.24,22.90,22.58,21.11.
19F NMR(471MHz,Chloroform-d)δ-68.02(d,J＝9.4Hz).
HRMS(ESI)calcd.for[M-H]-C28H32F3N2O4:517.2320,found:517.2309.
实施例5
化合物的合成方法参见化合物1，白色固体，产率42％。
1H NMR(500MHz,Chloroform-d)δ7.67(d,J＝1.5Hz,1H),7.43(dd,J＝2.6,1.6Hz,1H),7.41(dt,J＝7.7,1.2Hz,1H),7.34–7.28(m,2H),7.05(ddd,J＝8.2,2.7,0.9Hz,1H),6.22(t,J＝6.2Hz,1H),4.96(tt,J＝9.6,4.7Hz,1H),4.22(dt,J＝11.1,4.7Hz,1H),4.08(dt,J＝11.4,5.8Hz,1H),3.78(s,3H),3.54(dd,J＝13.1,5.3Hz,1H),3.45–3.35(m,2H),3.11(dd,J＝13.5,6.1Hz,1H),2.73(dt,J＝16.8,6.2Hz,1H),2.08(ddd,J＝12.6,7.7,4.1Hz,1H),1.74–1.62(m,4H),1.35(s,9H),1.10(s,3H),1.02(s,3H).
13C NMR(126MHz,Chloroform-d)δ197.01,168.42,163.77,158.61,153.98,136.74,134.18,132.95,129.88,126.78,126.71(q,J＝280.8Hz),126.18,125.14,121.26,121.07,113.91,67.20,61.42,47.56,42.63(q,J＝27.4Hz),41.33,40.58,34.94,31.08,27.87,24.90,24.81,23.34,23.10.
19F NMR(471MHz,Chloroform-d)δ-67.79(d,J＝9.1Hz).
HRMS(ESI)calcd.for[M-H]-C31H38F3N2O4:559.2789,found:559.2780.
实施例6
化合物的合成方法参见化合物1，白色固体，产率32％。
1H NMR(500MHz,Chloroform-d)δ7.90(s,1H),7.61(dd,J＝8.1,1.8Hz,1H),7.54(d,J＝8.1Hz,1H),7.42(dt,J＝7.7,1.2Hz,1H),7.38(dd,J＝2.7,1.5Hz,1H),7.34(t,J＝7.9Hz,1H),7.09(ddd,J＝8.2,2.7,0.9Hz,1H),6.42(t,J＝6.2Hz,1H),5.07–4.82(m,1H),4.23(dt,J＝11.9,4.8Hz,1H),4.09(dt,J＝12.1,6.0Hz,1H),3.76(s,3H),3.67(dd,J＝13.6,4.1Hz,1H),3.39(dd,J＝13.5,6.2Hz,1H),3.32(dd,J＝13.6,11.3Hz,1H),3.09(dd,J＝13.5,6.1Hz,1H),2.80–2.62(m,1H),2.17–1.99(m,1H),1.76–1.51(m,4H),1.11(s,3H),1.01(s,3H).
13C NMR(151MHz,Chloroform-d)δ195.69,166.75,163.49,158.08,140.42,135.78,133.89,132.14(q,J＝32.8Hz),129.68,127.59(q,J＝280.1Hz),127.06,125.37,124.88(q,J＝3.6Hz),122.90(q,J＝272.9Hz),121.95,120.86,112.20,66.64,61.01,47.32,42.01(q,J＝28.4Hz),40.67,39.20,27.13,24.78,24.25,22.75,22.73.
19F NMR(471MHz,Chloroform-d)δ-62.99,-68.21(d,J＝8.9Hz).
HRMS(ESI)calcd.for[M-H]-C28H29F6N2O4:571.2037,found:571.2023.
实施例7
化合物的合成方法参见化合物1，白色固体，产率40％。
1H NMR(500MHz,Chloroform-d)δ7.69(d,J＝7.9Hz,1H),7.51(dd,J＝7.6,1.4Hz,1H),7.49–7.45(m,1H),7.43(dd,J＝7.8,1.4Hz,1H),7.37(d,J＝2.0Hz,1H),7.33(td,J＝7.5,1.2Hz,1H),6.85(d,J＝8.4Hz,1H),6.46(t,J＝6.1Hz,1H),4.98(ddt,J＝12.5,9.3,4.6Hz,1H),4.41–4.28(m,1H),4.16(dt,J＝9.8,6.1Hz,1H),3.93(s,3H),3.75(s,3H),3.68(dd,J＝13.1,2.9Hz,1H),3.31(dd,J＝13.4,6.1Hz,1H),3.19(t,J＝12.8Hz,1H),3.00(dd,J＝13.4,6.2Hz,1H),2.88–2.74(m,1H),2.07–1.95(m,1H),1.60(d,J＝5.6Hz,4H),1.09(s,3H),0.98(s,3H).
13C NMR(126MHz,Chloroform-d)δ195.16,168.36,163.81,154.26,147.22,137.74,133.03,130.57,128.88,128.39,128.34,127.06,126.69(q,J＝280.6Hz),123.53,112.16,110.46,67.56,61.43,56.14,47.74,42.49(q,J＝28.2Hz),41.07,39.12,27.08,25.66,24.36,23.29,23.18.
19F NMR(471MHz,Chloroform-d)δ-68.63(d,J＝9.4Hz).
HRMS(ESI)calcd.for[M-H]-C28H32F3N2O5:533.2269,found:533.2256.
实施例8
化合物的合成方法参见化合物1，白色固体，产率31％。
1H NMR(500MHz,Chloroform-d)δ7.68(d,J＝7.9Hz,1H),7.47(td,J＝7.7,1.5Hz,1H),7.43–7.39(m,2H),7.36(dd,J＝7.7,1.4Hz,1H),7.31(t,J＝7.9Hz,1H),7.27(d,J＝1.1Hz,1H),7.26–7.23(m,2H),7.22–7.16(m,1H),7.13–7.09(m,2H),7.05(ddd,J＝8.2,2.6,1.0Hz,1H),6.30(t,J＝6.2Hz,1H),4.92(ddd,J＝10.7,9.0,4.5Hz,1H),4.24(dt,J＝11.4,4.7Hz,1H),4.08(ddd,J＝11.9,7.3,4.5Hz,1H),3.98(t,J＝6.5Hz,2H),3.60(dd,J＝13.2,4.5Hz,1H),3.42–3.28(m,2H),3.02(dd,J＝13.5,5.7Hz,1H),2.82–2.73(m,1H),2.62(td,J＝7.5,3.2Hz,2H),2.15–2.07(m,1H),1.96–1.84(m,2H),1.75–1.67(m,4H),1.11(s,3H),1.02(s,3H).
13C NMR(126MHz,Chloroform-d)δ196.76,168.39,163.70,158.55,141.71,137.34,136.53,133.09,130.71,130.04,128.92,128.39,126.97,126.59(q,J＝280.8Hz),125.87,121.66,121.33,113.21,72.89,67.00,47.71,42.52(q,J＝28.4,27.8Hz),41.28,40.29,32.27,30.75,27.88,25.11,24.82,23.45,23.19.
19F NMR(471MHz,Chloroform-d)δ-68.14(d,J＝9.3Hz).
HRMS(ESI)calcd.for[M-H]-C35H38F3N2O4:607.2789,found:607.2778.
实施例9
化合物的合成方法参见化合物1，白色固体，产率47％。
1H NMR(500MHz,Chloroform-d)δ8.12(s,1H),7.93(s,1H),7.90(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.61–7.51(m,2H),7.47(d,J＝7.6Hz,1H),7.42(t,J＝2.0Hz,1H),7.33(t,J＝7.9Hz,1H),7.06(dd,J＝8.2,2.6Hz,1H),6.46(t,J＝6.2Hz,1H),5.02(ddt,J＝14.4,9.4,4.6Hz,1H),4.21(dt,J＝11.5,4.5Hz,1H),4.07(ddd,J＝11.8,7.4,4.8Hz,1H),3.79(s,3H),3.73(dd,J＝13.4,4.9Hz,1H),3.51–3.39(m,2H),3.05(dd,J＝13.4,5.6Hz,1H),2.75(dt,J＝12.7,8.1Hz,1H),2.09(ddd,J＝12.2,7.5,3.6Hz,1H),1.72–1.58(m,4H),1.16(s,3H),1.04(s,3H).
13C NMR(151MHz,Chloroform-d)δ196.41,168.20,163.42,158.06,136.07,134.51,133.28,131.55,129.60,129.57,128.43,127.69,127.41,127.36,126.94,126.58,126.27(q,J＝280.3Hz),121.02,120.84,113.02,66.53,61.01,47.16,41.96(q,J＝27.8Hz),40.80,40.74,27.24,24.63,24.37,22.89,22.63.
19F NMR(471MHz,Chloroform-d)δ-68.01(d,J＝9.6Hz).
HRMS(ESI)calcd.for[M-H]-C31H32F3N2O4:553.2320,found:553.2307.
实施例10
化合物的合成方法参见化合物1，白色固体，产率41％。
1H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.79–7.70(m,1H),7.51(dd,J＝7.5,1.5Hz,1H),7.46(d,J＝7.8Hz,1H),7.41–7.34(m,2H),7.33–7.27(m,2H),7.16–7.11(m,1H),4.90(ddd,J＝11.8,9.6,2.6Hz,1H),4.67(d,J＝14.7Hz,1H),4.46(d,J＝14.7Hz,1H),3.93(dd,J＝13.2,9.4Hz,1H),3.77(s,3H),3.75–3.67(m,1H),3.61(dd,J＝18.4,2.5Hz,1H),3.54–3.34(m,3H),2.53(td,J＝12.2,3.8Hz,1H),2.02(ddt,J＝12.5,8.2,4.5Hz,1H),1.89(td,J＝12.2,4.5Hz,1H),1.82–1.72(m,1H),1.58(qt,J＝12.4,4.1Hz,1H),1.45(ddt,J＝15.6,9.2,3.0Hz,1H),1.36(s,3H),1.15(s,3H).
13C NMR(126MHz,Chloroform-d)δ194.36,169.37,165.07,140.38,140.07,135.93,133.85,130.98,129.79,128.37,127.94,127.54,127.41,127.06(q,J＝280.2Hz),126.49,125.55,70.45,70.21,61.50,47.21,42.17,40.15(q,J＝27.6Hz),39.45,30.96,26.69,25.79,25.72,22.22.
19F NMR(471MHz,Chloroform-d)δ-68.34(d,J＝9.6Hz).
HRMS(ESI)calcd.for[M-H]-C28H32F3N2O4:517.2320,found:517.2306.
实施例11
化合物的合成方法参见化合物1，白色固体，产率41％。
1H NMR(500MHz,Chloroform-d)δ8.61(t,J＝1.9Hz,1H),8.15(dt,J＝7.8,1.3Hz,1H),7.97(dt,J＝7.9,1.4Hz,1H),7.60–7.49(m,2H),7.46(dd,J＝7.7,1.5Hz,1H),7.40(td,J＝7.7,1.5Hz,1H),7.31(td,J＝7.6,1.2Hz,1H),6.57(dd,J＝9.3,3.6Hz,1H),5.31(td,J＝10.1,3.4Hz,1H),4.51(dt,J＝10.7,3.3Hz,1H),4.07(td,J＝10.5,3.5Hz,1H),3.85(dd,J＝13.4,9.1Hz,1H),3.81(s,3H),3.65–3.51(m,2H),3.45(dd,J＝13.4,3.6Hz,1H),2.60(td,J＝11.6,5.9Hz,1H),2.06–1.97(m,1H),1.94–1.81(m,3H),1.79–1.69(m,1H),1.43(s,3H),1.16(s,3H).
13C NMR(126MHz,Chloroform-d)δ194.28,168.97,165.19,164.89,138.75,135.79,134.50,133.55,131.46,131.34,130.57,130.28,128.98,128.44,128.10,127.35,127.10(q,J＝279.5Hz),64.71,61.52,47.04,42.05,39.97(q,J＝27.6Hz),39.96,29.23,26.20,25.48,23.47,21.98.
19F NMR(471MHz,Chloroform-d)δ-67.82(d,J＝9.4Hz).
HRMS(ESI)calcd.for[M-H]-C28H30F3N2O5:531.2112,found:531.2097.
实施例12
化合物的合成方法参见化合物1，白色固体，产率37％。
1H NMR(500MHz,Chloroform-d)δ8.20(d,J＝2.0Hz,1H),7.86(dd,J＝7.8,1.8Hz,2H),7.56–7.47(m,3H),7.40(td,J＝7.6,1.5Hz,1H),7.33(td,J＝7.8,1.8Hz,2H),7.28(t,J＝2.1Hz,1H),7.20(dd,J＝7.7,1.3Hz,1H),7.02(dd,J＝7.7,4.6Hz,1H),6.91(dd,J＝8.1,2.5Hz,1H),4.99(pd,J＝9.8,9.1,2.8Hz,1H),4.22(t,J＝6.5Hz,2H),3.89–3.76(m,2H),3.70(s,3H),3.58(dd,J＝17.6,3.5Hz,1H),3.48(dd,J＝13.4,4.6Hz,1H),2.56–2.39(m,1H),2.33(ddd,J＝12.4,10.5,4.3Hz,1H),1.83(dhept,J＝11.8,7.7,6.1Hz,3H),1.73–1.59(m,1H),1.32(s,3H),1.19(s,3H).
13C NMR(126MHz,Chloroform-d)δ195.63,169.20,164.52,159.28,141.00,140.58,139.22,136.34,133.10,131.43,130.13,130.04,129.16,128.22,127.83,127.76,126.90,126.86(q,J＝280.3Hz),126.66,118.84,117.09,112.50,68.03,61.36,47.52,41.66,40.58(q,J＝27.6Hz),39.61,29.29,26.25,24.71,23.41,23.28.
19F NMR(471MHz,Chloroform-d)δ-68.28(d,J＝9.7Hz).
HRMS(ESI)calcd.for[M-H]-C33H34F3N2O4:579.2476,found:579.24762.
实施例13
化合物的合成方法参见化合物1，白色固体，产率33％。
1H NMR(500MHz,Chloroform-d)δ8.54(d,J＝1.4Hz,1H),7.80(d,J＝1.4Hz,1H),7.76(t,J＝2.1Hz,1H),7.54(d,J＝7.9Hz,1H),7.48(td,J＝7.6,1.6Hz,1H),7.44(dd,J＝7.6,1.5Hz,1H),7.38(td,J＝7.4,1.3Hz,1H),7.31(t,J＝7.9Hz,1H),7.21(ddd,J＝7.7,1.7,0.9Hz,1H),6.83(ddd,J＝8.1,2.5,0.9Hz,1H),6.03(dd,J＝9.6,3.5Hz,1H),5.10–4.93(m,1H),4.33–4.19(m,1H),4.13–3.99(m,2H),3.88(s,3H),3.65–3.54(m,1H),3.30(dd,J＝13.5,11.4Hz,1H),2.91–2.79(m,1H),2.66–2.47(m,2H),1.92–1.84(m,2H),1.80(dt,J＝11.9,4.9Hz,1H),1.74–1.65(m,1H),1.21(s,3H),1.14(s,3H).
13C NMR(126MHz,Chloroform-d)δ190.19,169.17,164.16,159.37,143.36,143.25,137.66,135.87,132.94,130.74,129.74,128.87,128.82,128.59,127.18,126.27(q,J＝280.2Hz),118.03,115.34,111.93,68.37,61.43,47.55,43.10(q,J＝27.7Hz),41.80,41.69,28.72,26.48,24.83,24.22,23.18.
19F NMR(471MHz,Chloroform-d)δ-67.15(d,J＝9.2Hz).
HRMS(ESI)calcd.for[M-H]-C31H32F3N2O4S:585.2040,found:585.2034.
实施例14
化合物的合成方法参见化合物1，白色固体，产率26％。
1H NMR(500MHz,Chloroform-d)δ7.91(d,J＝1.7Hz,1H),7.84(dt,J＝7.7,1.4Hz,1H),7.66(dt,J＝8.0,1.3Hz,1H),7.57–7.54(m,1H),7.52(dt,J＝7.2,3.1Hz,1H),7.48(t,J＝7.7Hz,1H),7.35(d,J＝3.5Hz,3H),7.10(t,J＝8.2Hz,1H),6.53(ddd,J＝8.3,2.4,0.9Hz,1H),6.43(ddd,J＝8.1,2.4,0.9Hz,1H),6.37(t,J＝2.3Hz,1H),5.30–5.03(m,2H),4.77(ddq,J＝19.0,9.4,4.6,4.0Hz,1H),3.92–3.76(m,4H),3.65(s,3H),3.61(dd,J＝18.2,4.1Hz,1H),3.52(dd,J＝13.5,5.1Hz,1H),2.29(td,J＝12.1,5.2Hz,1H),2.17–2.07(m,1H),1.73(td,J＝6.7,3.0Hz,2H),1.61–1.50(m,2H),1.23(s,3H),1.17(s,3H).
13C NMR(126MHz,Chloroform-d)δ195.86,169.10,164.28,159.99,158.96,139.45,138.73,136.05,132.87,131.20,130.02,129.88,129.29,128.71,128.45,127.77,126.89,126.71,126.50(q,J＝280.5Hz),109.40,107.66,101.86,69.59,67.18,61.20,47.44,41.87,40.59(q,J＝28.1Hz),38.75,28.96,25.41,24.16,23.52,22.97.
19F NMR(471MHz,Chloroform-d)δ-69.00(d,J＝8.3Hz).
HRMS(ESI)calcd.for[M-H]-C34H36F3N2O5:609.2582,found:609.2576.
实施例15
化合物的合成方法参见化合物1，白色固体，产率33％。
1H NMR(500MHz,Chloroform-d)δ7.56–7.49(m,2H),7.48–7.43(m,2H),7.41–7.34(m,5H),7.33–7.27(m,2H),7.21–7.14(m,2H),5.19(s,2H),4.75(ddd,J＝11.3,9.2,3.3Hz,1H),4.55–4.41(m,2H),3.80–3.72(m,2H),3.69(s,3H),3.57–3.49(m,2H),3.34(t,J＝6.2Hz,2H),2.23(dq,J＝11.7,5.7Hz,1H),2.17–2.00(m,1H),1.63–1.56(m,2H),1.52–1.44(m,2H),1.19(s,3H),1.15(s,3H).
13C NMR(126MHz,Chloroform-d)δ195.37,169.11,164.17,158.67,139.56,139.03,137.18,136.81,131.24,129.80,128.64,128.55,128.36,127.26,126.77,126.56(q,J＝279.6Hz),126.31,126.05,121.47,121.00,114.24,72.55,69.85,69.32,61.26,47.38,41.63,40.63(q,J＝27.7Hz),38.68,30.32,26.05,24.44,23.57,23.13.
19F NMR(471MHz,Chloroform-d)δ-68.99(d,J＝8.3Hz).
HRMS(ESI)calcd.for[M-H]-C35H38F3N2O5:623.2738,found:623.2733.
实施例16
反应条件：
实验方法：在空气氛围中，向含有螺旋盖的螺纹耐压管中依次加入大环内酰胺化合物前体16’(0.2mmol,2.0当量)、二噁唑酮16”(0.1mmol,1.0当量)、[Cp*RhCl2]2(0.005mmol,5mol％)、AgSbF6(0.02mmol,20mol％)及AgOAc(0.02mmol,20mol％)，随后立即加入10mL二氯甲烷溶液并充分混匀。将反应体系在80℃下搅拌24小时。TLC监测反应完全后，将反应体系冷却至室温，用硅藻土过滤金属及其他固态杂质，随后旋转蒸发除去溶剂。最后利用柱层析分离纯化得到分化产物16，反应产率为26％。
1H NMR(500MHz,Chloroform-d)δ7.39–7.30(m,2H),7.26–7.18(m,2H),6.46(q,J＝1.7Hz,1H),5.97(t,J＝5.3Hz,1H),5.68(q,J＝1.2Hz,1H),3.91–3.86(m,2H),3.85(s,2H),3.75(s,3H),3.57(d,J＝5.8Hz,2H),2.37(t,J＝6.8Hz,2H),1.52(dt,J＝10.0,6.8Hz,2H),1.45(tt,J＝8.0,2.9Hz,2H),1.25(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.89,167.07,163.38,138.44,136.70,136.64,129.93,129.27,128.12,126.38,126.36,65.10,61.24,48.07,42.11,35.63,27.63,25.33,23.95,23.69.
HRMS[ESI]calcd.for[M+H]+C21H29N2O4:373.2122,found:373.2128.
实施例17
化合物的合成方法参见化合物16，白色固体，产率28％。
1H NMR(500MHz,Chloroform-d)δ7.15(d,J＝1.9Hz,1H),7.13(dd,J＝7.8,1.8Hz,1H),7.08(d,J＝7.9Hz,1H),6.44(q,J＝1.8Hz,1H),5.94(t,J＝5.5Hz,1H),5.65(q,J＝1.3Hz,1H),3.95–3.86(m,2H),3.79(d,J＝1.2Hz,2H),3.76(s,3H),3.56(d,J＝5.8Hz,2H),2.37(t,J＝6.8Hz,2H),2.33(s,3H),1.58–1.42(m,4H),1.25(s,6H).
13C NMR(126MHz,Chloroform-d)δ170.08,167.15,163.45,138.60,136.57,136.06,133.38,130.63,129.05,128.07,127.01,65.05,61.24,48.04,42.06,35.19,27.68,25.31,23.99,23.67,20.90.
HRMS[ESI]calcd.for[M+H]+C22H31N2O4:387.2278,found:387.2277.
实施例18
化合物的合成方法参见化合物16，白色固体，产率30％。
1H NMR(500MHz,Chloroform-d)δ7.52(dd,J＝8.1,1.7Hz,1H),7.48(d,J＝8.0Hz,1H),7.44(d,J＝1.7Hz,1H),6.55(q,J＝1.6Hz,1H),6.04(t,J＝6.0Hz,1H),5.75(q,J＝1.3Hz,1H),3.95–3.89(m,2H),3.86(s,2H),3.75(s,3H),3.59(d,J＝5.9Hz,2H),2.39(t,J＝6.7Hz,2H),1.58–1.46(m,2H),1.47–1.40(m,2H),1.25(s,6H).
13C NMR(126MHz,Chloroform-d)δ168.57,166.46,163.24,139.95,137.93,137.27,131.95(q,J＝32.38),130.57,126.88,124.83(q,J＝3.84),123.66(q,J＝272.49),123.56(q,J＝3.93),122.57,120.40,65.23,61.29,47.97,42.26,35.59,27.53,25.36,23.83,23.70.
HRMS[ESI]calcd.for[M+H]+C22H28F3N2O4:441.1996,found:441.2003.
实施例19
化合物的合成方法参见化合物16，白色固体，产率30％。
1H NMR(500MHz,Chloroform-d)δ7.56–7.50(m,2H),7.48–7.39(m,5H),7.39–7.33(m,1H),6.49(q,J＝1.8Hz,1H),6.02(t,J＝5.7Hz,1H),5.72(q,J＝1.3Hz,1H),3.95–3.86(m,4H),3.76(s,3H),3.59(d,J＝5.7Hz,2H),2.38(t,J＝6.8Hz,2H),1.58–1.43(m,4H),1.26(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.75,167.02,163.40,142.77,140.18,138.40,137.24,135.46,129.47,128.85,127.82,127.19,126.92,126.88,125.12,65.17,61.27,48.14,42.11,35.67,27.70,25.36,24.01,23.74.
HRMS[ESI]calcd.for[M-H]-C27H31N2O4:447.2289,found:447.2274.
实施例20
化合物的合成方法参见化合物16，白色固体，产率31％。
1H NMR(500MHz,Chloroform-d)δ7.44(dd,J＝7.7,1.3Hz,1H),7.19–7.09(m,2H),6.51(d,J＝1.6Hz,1H),5.85(t,J＝6.0Hz,1H),5.67(d,J＝1.4Hz,1H),3.94(t,J＝4.8Hz,2H),3.77(s,3H),3.75(s,2H),3.65(d,J＝5.9Hz,2H),1.69–1.52(m,4H),1.33-1.24(m,8H).
13C NMR(126MHz,Chloroform-d)δ167.62,166.70,162.91,138.28,138.17,137.29,130.88,130.31,130.13,126.22,119.70,65.13,61.27,47.63,41.85,36.02,27.48,25.30(m),23.66,23.60.
HRMS[ESI]calcd.for[M-H]-C21H26BrN2O4:449.1081,found:449.1074.
实施例21
化合物的合成方法参见化合物16，白色固体，产率36％。
1H NMR(500MHz,Chloroform-d)δ7.89–7.80(m,2H),7.78–7.71(m,1H),7.61(s,1H),7.49(tt,J＝6.9,5.3Hz,2H),6.55(d,J＝1.7Hz,1H),6.15(t,J＝5.8Hz,1H),5.77(d,J＝1.7Hz,1H),3.95(s,2H),3.87–3.81(m,2H),3.71(s,3H),3.63(d,J＝5.8Hz,2H),2.38(t,J＝6.9Hz,2H),1.52(dt,J＝10.1,6.8Hz,2H),1.44–1.35(m,2H),1.28(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.89,167.15,163.36,138.35,135.74,133.90,133.77,131.38,129.32,127.77,127.68,127.20,126.88,126.26,125.94,65.08,61.25,48.05,42.38,35.72,27.50,25.48,23.90,23.75.
HRMS[ESI]calcd.for[M+H]+C25H31N2O4:423.2278,found:423.2289.
实施例22
化合物的合成方法参见化合物16，白色固体，产率32％。
1H NMR(500MHz,Chloroform-d)δ7.24–7.20(m,2H),7.15(dd,J＝8.3,1.6Hz,1H),7.11(d,J＝7.9Hz,1H),6.88(t,J＝2.0Hz,1H),6.84–6.77(m,2H),6.49(t,J＝6.4Hz,1H),6.32(q,J＝1.2Hz,1H),5.47(d,J＝1.6Hz,1H),5.13(s,2H),4.09(t,J＝5.7Hz,2H),3.83(s,2H),3.74(s,3H),3.50(d,J＝6.4Hz,2H),2.33(s,3H),2.28–2.20(m,2H),1.75(q,J＝6.1Hz,2H),1.69–1.59(m,2H),1.09(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.81,166.55,164.22,159.04,139.63,137.70,137.10,136.35,133.13,130.56,130.52,129.39,127.96,127.48,119.97,115.38,114.00,67.19,65.84,61.33,47.13,41.86,35.03,28.89,25.30,23.79,22.63,20.96.
HRMS[ESI]calcd.for[M+H]+C29H37N2O5:493.2697,found:493.2703.
实施例23
化合物的合成方法参见化合物16，白色固体，产率33％。
1H NMR(500MHz,Chloroform-d)δ7.30(d,J＝1.9Hz,1H),7.15(dt,J＝7.9,1.4Hz,1H),7.04(d,J＝7.9Hz,1H),6.63(s,1H),6.34(q,J＝1.3Hz,1H),5.33(q,J＝1.7Hz,1H),4.32–4.15(m,2H),3.74(d,J＝1.6Hz,2H),3.71(s,3H),3.56(d,J＝5.9Hz,2H),2.35(s,3H),2.26(t,J＝6.8Hz,2H),1.65(dd,J＝6.5,4.7Hz,2H),1.60–1.52(m,2H),1.42–1.32(m,2H),1.15(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.94,166.74,164.07,139.77,137.78,136.55,131.36,130.41,129.88,128.65,127.58,64.01,61.26,47.52,41.60,35.11,28.32,26.12,25.88,25.30,24.74,20.95.
HRMS[ESI]calcd.for[M+H]+C23H33N2O4:401.2435,found:401.2431.
实施例24
化合物的合成方法参见化合物16，白色固体，产率31％。
1H NMR(500MHz,Chloroform-d)δ7.63–7.54(m,2H),7.54–7.51(m,1H),7.50(d,J＝2.0Hz,1H),7.47–7.41(m,2H),7.27(d,J＝8.0Hz,1H),6.50(d,J＝1.7Hz,1H),6.05(t,J＝5.9Hz,1H),5.71(q,J＝1.2Hz,1H),3.96–3.88(m,2H),3.85(s,2H),3.73(s,3H),3.61(d,J＝5.9Hz,2H),2.39(t,J＝6.7Hz,2H),1.57–1.52(m,2H),1.51–1.42(m,2H),1.26(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.67,167.00,163.38,138.84,138.15,137.45,135.94,132.05,129.58,128.75,128.58,128.25,124.77,121.95,65.17,61.30,47.97,42.30,35.45,27.55,25.41,23.88,23.67.
HRMS[ESI]calcd.for[M+H]+C27H32BrN2O4:527.1540,found:527.1544.
实施例25
反应条件：
实验方法：
第一步：取干燥的反应瓶，将化合物24(1mmol,1当量)、Pd(dppf)Cl2(15mol％)、B2Pin2(2.0当量)、KOAc(3.0当量)溶解于1,4-二氧六环溶液中。充分置换氮气后将反应体系密封，于90℃下反应2～3小时。反应结束后经柱层析纯化，得到苯基硼酸酯24’。
第二步：取干燥的反应瓶，将化合物24’(1mmol,1当量)、6-氯代-2-(甲磺酰基)-N-苯基嘧啶-4-氨基(化合物24”，1.3当量)、Pd(PPh3)4(10mol％)和碳酸钠(3.0当量)溶解于1,4-二氧六环与水的混合溶液(v/v＝10/1)中。充分置换氮气后将反应体系封闭，与90℃下反应过夜。反应结束后经柱层析纯化，得到产物25。
产物25为白色固体，两步产率为68％。
1H NMR(500MHz,Chloroform-d)δ8.08–7.91(m,2H),7.71–7.63(m,2H),7.60(d,J＝2.0Hz,1H),7.56(dd,J＝8.2,2.2Hz,2H),7.47(t,J＝7.8Hz,2H),7.42(d,J＝7.9Hz,2H),7.29(dd,J＝7.8,4.8Hz,2H),7.18(s,1H),6.50(d,J＝1.7Hz,1H),6.10(t,J＝5.9Hz,1H),5.71(d,J＝1.7Hz,1H),3.93(t,J＝5.0Hz,2H),3.86(s,2H),3.72(s,3H),3.62(d,J＝5.9Hz,2H),3.42(s,3H),2.39(t,J＝6.6Hz,2H),1.64–1.56(m,2H),1.56–1.43(m,2H),1.26(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.73,166.97,166.05,163.99,163.38,162.70,142.73,138.14,138.09,137.49,137.06,136.37,134.78,129.89,129.65,128.85,128.47,127.78,127.37,126.18,124.95,123.01,65.19,61.31,48.02,42.32,38.95,35.50,27.56,25.42,23.89,23.67.
HRMS[ESI]Calcd for[M+H]+C38H42N5O6S:696.2850,Found:696.2847.
实施例26
反应条件：
实验方法：在空气氛围中，向含有螺旋盖的螺纹耐压管中依次加入大环内酰胺化合物前体26’(0.2mmol,2.0当量)、二噁唑酮26”(0.1mmol,1.0当量)、[Cp*RhCl2]2(0.005mmol,5mol％)、AgSbF6(0.02mmol,20mol％)及AgOAc(0.04mmol,40mol％)，随后立即加入5mL四氯乙烷溶液并充分混匀。将反应体系在80℃下搅拌24小时。TLC监测反应完全后，将反应体系冷却至室温，用硅藻土过滤金属及其他固态杂质，随后旋转蒸发除去溶剂。最后利用柱层析分离纯化得到目标产物26。白色固体，反应产率为30％。
1H NMR(500MHz,Chloroform-d)δ7.83(d,J＝16.0Hz,1H),7.47(d,J＝7.8Hz,1H),7.40(td,J＝8.0,5.5Hz,1H),7.25–7.24(m,1H),7.14(t,J＝8.6Hz,1H),6.91(d,J＝2.5Hz,1H),6.83(dd,J＝8.3,2.5Hz,1H),6.47(dd,J＝15.9,0.9Hz,1H),6.47(dd,J＝15.9,0.9Hz,1H),6.36(t,J＝6.6Hz,1H),5.23(s,2H),4.11(t,J＝5.5Hz,2H),3.72(s,3H),3.61(d,J＝6.5Hz,2H),2.42–2.00(m,2H),1.75(p,J＝6.1Hz,2H),1.66(q,J＝7.1Hz,2H),1.04(s,6H).
13C NMR(126MHz,Chloroform-d)δ165.56,164.63,163.79,159.05(d,J＝247.5Hz),140.89(d,J＝2.5Hz),138.01,134.98(d,J＝3.4Hz),130.87(d,J＝8.4Hz),129.41,122.42(d,J＝3.1Hz),121.69,120.05,117.10(d,J＝22.5Hz),116.04,112.88,66.01,65.59,61.45,47.04,41.70,28.48,25.03,23.54,21.40.
HRMS[ESI]Calcd for[M+H]+C27H32FN2O5:483.2290,Found:483.2302.
实施例27
化合物的合成方法参见化合物16，白色固体，产率33％。
1H NMR(500MHz,Chloroform-d)δ7.20(s,1H),7.13(d,J＝8.0Hz,1H),7.09(d,J＝7.9Hz,1H),6.43(d,J＝1.6Hz,1H),6.22(dd,J＝9.4,4.0Hz,1H),5.67(s,1H),4.00(d,J＝16.2Hz,1H),3.97–3.86(m,2H),3.82–3.78(m,1H),3.77(s,3H),3.66(d,J＝16.2Hz,1H),3.29(td,J＝13.1,12.5,4.0Hz,1H),2.84(td,J＝11.6,4.4Hz,1H),2.74(dqd,J＝11.1,6.9,4.0Hz,1H),2.33(s,3H),1.90(dt,J＝12.5,4.7Hz,1H),1.61–1.41(m,3H),1.37–1.22(m,1H),1.14(d,J＝6.9Hz,3H).
13C NMR(126MHz,Chloroform-d)δ169.73,167.09,162.07,138.71,135.88,135.59,134.69,130.90,128.74,128.22,127.25,64.73,61.25,41.80,38.07,35.35,27.77,25.92,23.05,20.90,17.81.
HRMS[ESI]calcd.for[M+H]+C21H29N2O4:373.2122,found:373.2124.
实施例28
化合物的合成方法参见化合物16，白色固体，产率22％。
1H NMR(500MHz,Chloroform-d)δ7.52(t,J＝5.6Hz,2H),7.45(s,1H),6.55(t,J＝1.2Hz,1H),6.30(dd,J＝9.2,3.8Hz,1H),5.78(s,1H),4.07(d,J＝16.4Hz,1H),4.03–3.91(m,2H),3.83–3.76(m,1H),3.76(s,3H),3.72(d,J＝16.4Hz,1H),3.31(td,J＝13.3,12.5,3.8Hz,1H),2.91–2.79(m,1H),2.80–2.64(m,1H),1.91(dt,J＝12.5,4.4Hz,1H),1.56–1.45(m,3H),1.31–1.20(m,1H),1.15(d,J＝6.8Hz,3H).
13C NMR(126MHz,Chloroform-d)δ168.23,166.37,161.82,139.17,138.94,137.36,132.16(d,J＝32.8Hz),130.32,127.06,124.98(d,J＝3.7Hz),123.64(d,J＝272.6Hz),123.43(d,J＝3.8Hz),64.87,61.31,41.72,37.98,35.69,27.72,25.76,23.06,17.74.
HRMS[ESI]calcd.for[M+H]+C21H26F3N2O4:427.1839,found:427.1845.
实施例29
化合物的合成方法参见化合物16，白色固体，产率36％。
1H NMR(500MHz,Chloroform-d)δ7.92(s,1H),7.84(d,J＝7.7Hz,1H),7.75(d,J＝7.8Hz,1H),7.61(s,1H),7.49(ddd,J＝13.4,7.6,3.9Hz,2H),6.60–6.50(m,1H),6.48–6.34(m,1H),5.78(s,1H),4.11(d,J＝16.3Hz,1H),4.02(ddd,J＝13.1,9.2,4.0Hz,1H),3.93(td,J＝11.1,1.8Hz,1H),3.85(d,J＝16.4Hz,1H),3.73(s,3H),3.73–3.69(m,1H),3.44–3.19(m,1H),2.85(td,J＝11.9,4.6Hz,1H),2.76(dqd,J＝11.0,6.9,3.8Hz,1H),1.89(dt,J＝12.5,4.8Hz,1H),1.58–1.39(m,3H),1.29–1.19(m,1H),1.16(d,J＝6.9Hz,3H).
13C NMR(126MHz,Chloroform-d)δ169.57,167.05,161.92,138.50,134.80,134.77,133.91,131.28,129.00,127.79,127.65,127.34,127.05,126.41,126.25,64.74,61.26,41.69,38.14,35.80,27.69,25.88,23.10,17.81.
HRMS[ESI]calcd.for[M+H]+C24H29N2O4:409.2122,found:409.2123.
实施例30
化合物的合成方法参见化合物16，白色固体，产率29％。
1H NMR(500MHz,Chloroform-d)δ7.36(dd,J＝8.1,5.7Hz,1H),6.99–6.82(m,2H),6.50(d,J＝1.6Hz,1H),5.96(t,J＝4.9Hz,1H),5.71(d,J＝1.5Hz,1H),4.01–3.87(m,2H),3.83(s,2H),3.75(s,3H),3.55(d,J＝5.8Hz,2H),2.38(t,J＝6.7Hz,2H),1.58–1.39(m,4H),1.24(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.03,166.69,163.52(d,J＝249.6Hz).163.33,140.16(d,J＝7.4Hz),137.80,132.81(d,J＝3.2Hz),129.99,128.30(d,J＝8.6Hz),115.29(d,J＝22.6Hz),113.35(d,J＝21.8Hz),65.26,61.27,48.10,42.17,35.64,27.59,25.37,23.93,23.74.
HRMS[ESI]Calcd for[M+H]+C21H28FN2O4:391.2028,Found:391.2037.
实施例31
化合物的合成方法参见化合物16，白色固体，产率35％。
1H NMR(500MHz,Chloroform-d)δ7.23–7.15(m,1H),7.13–7.04(m,1H),6.35(d,J＝1.2Hz,1H),6.01(t,J＝5.8Hz,1H),5.60(t,J＝1.4Hz,1H),4.13(t,J＝5.1Hz,2H),3.91(d,J＝1.7Hz,2H),3.74(s,3H),3.49(d,J＝5.8Hz,2H),2.33(t,J＝6.5Hz,2H),1.65–1.54(m,4H),1.19(s,6H).
13C NMR(126MHz,Chloroform-d)δ167.85(d,J＝1.74Hz),166.25,163.57,151.33(d,J＝252.0Hz),149.77(d,J＝249.7Hz),137.20,134.06(d,J＝3.7Hz),128.28,126.96(d,J＝12.5Hz),123.33(dd,J＝7.1,4.4Hz),115.47(d,J＝17.6Hz),64.54,61.31,48.12,41.51,29.74,28.24,25.05,24.33,22.86.
HRMS[ESI]Calcd for[M+H]+C21H27F2N2O4:409.1933,Found:409.1936.
实施例32
化合物的合成方法参见化合物16，白色固体，产率30％。
1H NMR(500MHz,Chloroform-d)δ7.92(dd,J＝7.9,1.7Hz,1H),7.84(d,J＝1.6Hz,1H),7.44(d,J＝7.9Hz,1H),6.55(d,J＝1.6Hz,1H),6.04(t,J＝5.9Hz,1H),5.77(q,J＝1.3Hz,1H),3.90(s,3H),3.89(d,J＝5.5Hz,2H),3.85(s,2H),3.74(s,3H),3.58(d,J＝5.9Hz,2H),2.38(t,J＝6.8Hz,2H),1.52(dp,J＝9.9,4.6,3.1Hz,2H),1.47–1.39(m,2H),1.25(s,6H).
13C NMR(126MHz,Chloroform-d)δ169.02,166.72,166.42,163.25,140.65,137.46,137.23,131.48,130.42,129.07,127.87,126.55,65.17,61.27,52.37,47.95,42.24,35.59,27.51,25.35,23.83,23.71.
HRMS[ESI]Calcd for[M+H]+C23H31N2O6:431.2177,Found:431.2180.
实施例33
化合物的合成方法参见化合物16，白色固体，产率27％。
1H NMR(500MHz,Chloroform-d)δ7.91(dd,J＝7.9,1.7Hz,1H),7.85(s,1H),7.47(d,J＝7.9Hz,1H),6.54(d,J＝1.5Hz,1H),6.31(dd,J＝9.0,3.8Hz,1H),5.78(s,1H),4.09–4.02(m,1H),4.00–3.96(m,1H),3.95–3.92(m,1H),3.90(s,3H),3.80–3.77(m,1H),3.75(s,3H),3.72(d,J＝16.3Hz,1H),3.30(ddd,J＝13.2,11.3,3.8Hz,1H),2.85(td,J＝11.8,4.4Hz,1H),2.73(ddt,J＝11.2,7.0,3.5Hz,1H),1.90(dt,J＝12.6,4.5Hz,1H),1.52–1.39(m,3H),1.30–1.18(m,1H),1.15(d,J＝6.9Hz,3H).
13C NMR(126MHz,Chloroform-d)δ168.64,166.62,166.39,161.86,139.65,138.45,137.59,131.68,130.11,129.23,127.73,126.72,64.80,61.28,52.36,41.70,38.00,35.70,27.70,25.77,23.06,17.74.
HRMS[ESI]Calcd for[M+H]+C22H29N2O6:417.2020,Found:417.2009.
实施例34
化合物的合成方法参见化合物16，白色固体，产率46％。
1H NMR(500MHz,Chloroform-d)δ7.41(dd,J＝8.2,5.7Hz,1H),6.91(td,J＝8.1,4.0Hz,2H),6.50(d,J＝1.5Hz,1H),6.24(dd,J＝9.5,4.0Hz,1H),5.72(d,J＝1.6Hz,1H),4.08(d,J＝16.3Hz,1H),3.97(td,J＝11.0,1.6Hz,1H),3.91(td,J＝9.0,4.5Hz,1H),3.79(dt,J＝11.3,3.7Hz,1H),3.76(s,3H),3.67(d,J＝16.4Hz,1H),3.27(ddd,J＝13.2,11.4,3.9Hz,1H),2.93–2.80(m,1H),2.74(ddp,J＝10.0,7.0,3.5,3.0Hz,1H),1.89(dt,J＝12.5,4.5Hz,1H),1.59–1.38(m,2H),1.26(qt,J＝9.9,2.8Hz,1H),1.14(d,J＝6.9Hz,3H).
13C NMR(126MHz,Chloroform-d)δ168.66,166.58,163.71(d,J＝249.9Hz),161.96,141.51(d,J＝7.6Hz),137.95,131.86(d,J＝2.8Hz),129.63,128.61(d,J＝8.7Hz),115.48(d,J＝22.4Hz),113.18(d,J＝21.7Hz),64.90,61.26,41.83,37.98,35.77,27.73,25.91,23.12,17.76.
HRMS[ESI]Calcd for[M+H]+C20H26FN2O4:377.1871,Found:377.1871.
实施例35
化合物的合成方法参见化合物16，白色固体，产率36％。
1H NMR(500MHz,Chloroform-d)δ7.19–7.10(m,1H),7.10–6.90(m,1H),6.32(s,1H),6.37–6.27(m,1H),5.75(d,J＝1.8Hz,1H),4.16–3.99(m,3H),3.91(d,J＝15.8Hz,1H),3.85–3.76(m,1H),3.76(s,3H),3.34–3.24(m,1H),2.83–2.75(m,1H),2.74–2.63(m,1H),2.01(dt,J＝13.5,5.4Hz,1H),1.65–1.51(m,3H),1.44–1.35(m,1H),1.13(d,J＝7.0Hz,3H).
13C NMR(126MHz,Chloroform-d)δ167.53,166.27,162.11,151.58(d,J＝252.4Hz),151.47(d,J＝252.1Hz),137.02,133.46(d,J＝3.1Hz),128.76,128.32(d,J＝11.7Hz),122.70(dd,J＝6.9,4.6Hz),115.05(d,J＝17.4Hz),63.91,61.37,42.06,37.68,29.60,25.36,21.83,17.45.
HRMS[ESI]Calcd for[M+H]+C20H25F2N2O4:395.1777,Found:395.1777.
实施例36
化合物的合成方法参见化合物16，白色固体，产率32％。
1H NMR(500MHz,Chloroform-d)δ7.25(d,J＝7.9Hz,1H),7.03(dd,J＝7.8,1.7Hz,1H),6.99(s,1H),6.46(d,J＝1.7Hz,1H),5.96–5.88(m,1H),5.68(d,J＝1.7Hz,1H),3.93–3.86(m,2H),3.83(s,2H),3.75(s,3H),3.54(d,J＝5.6Hz,2H),2.36(t,J＝6.8Hz,2H),2.30(s,3H),1.55–1.48(m,2H),1.48–1.41(m,2H),1.24(s,6H).
13C NMR(101MHz,Chloroform-d)δ170.03,167.16,163.37,139.96,138.55,136.63,133.84,129.15,128.83,126.99,126.38,65.12,61.22,48.16,41.98,35.44,27.73,25.31,24.03,23.72,21.40.
HRMS[ESI]calcd.for[M+H]+C22H31N2O4:387.2278,found:387.2275.
实施例37
化合物的合成方法参见化合物16，白色固体，产率40％。
1H NMR(500MHz,Chloroform-d)δ7.31–7.27(m,1H),7.14(td,J＝9.3,7.7Hz,1H),6.50(s,1H),6.31(s,1H),5.30–5.10(m,1H),4.38–4.26(m,2H),3.82(q,J＝1.9Hz,2H),3.70(s,3H),3.53(d,J＝6.0Hz,2H),2.24(t,J＝7.0Hz,2H),1.77–1.68(m,2H),1.54(dd,J＝10.6,6.8Hz,3H),1.43–1.36(m,2H),1.12(s,6H).
13C NMR(126MHz,Chloroform-d)δ167.69(d,J＝1.8Hz),165.97,164.18,151.11(dd,J＝250.7,12.4Hz),149.02(dd,J＝248.6,11.6Hz),137.68,135.39–135.23(m),126.40,124.81(d,J＝13.4Hz),124.44(dd,J＝6.8,4.5Hz),116.09(d,J＝17.4Hz),64.26,61.30,47.70,41.55,29.17,28.01,26.41,25.86,25.69,24.56.
HRMS[ESI]Calcd for[M+H]+C22H29F2N2O4:423.2090,Found:423.2095.
实施例38
化合物的合成方法参见化合物16，白色固体，产率37％。
1H NMR(500MHz,Chloroform-d)δ7.95(dd,J＝8.0,1.7Hz,1H),7.84(d,J＝1.6Hz,1H),7.54(d,J＝8.0Hz,1H),6.81(s,1H),6.40(q,J＝1.1Hz,1H),5.43(q,J＝1.5Hz,1H),4.25–4.17(m,2H),3.91(s,3H),3.82(s,2H),3.70(s,3H),3.57(d,J＝5.8Hz,2H),2.27(t,J＝6.7Hz,2H),1.63(dt,J＝11.7,6.2Hz,2H),1.37–1.29(m,1H),1.16(s,6H).
13C NMR(126MHz,Chloroform-d)δ168.86,166.47,164.00,141.91,138.89,135.31,131.13,130.85,128.35,128.19,127.98,63.94,61.23,52.29,47.65,41.58,35.50,28.45,25.87,25.79,25.13,24.79.
HRMS[ESI]Calcd for[M+H]+C24H33N2O6:445.2333,Found:445.2342.
药理实施例1抗甲型流感病毒活性
MDCK细胞(ATCC,CCL-34)接种于96孔培养板，接种密度为每孔10000个细胞。置37℃，5％CO2培养箱培养24小时后，加入不同浓度的化合物孵育1小时后，加入甲型流感病毒H1N1 A/Puerto Rico/8/34(A/PR/8/34)(0.025TCID50)，共培养3天。设病毒对照、细胞对照和样品组。培养3天后，提取上清液中的病毒RNA，并通过基于探针的一步实时PCR方法进行定量，以合成RNA寡糖稀释液作为标准，以实现病毒RNA的绝对定量，并计算化合物的EC50(半数抑制浓度)。同时，MTT法测定化合物的体外细胞毒性。简言之，在化合物与MDCK细胞共培养3天后，将每个孔中的MDCK细胞与100μl MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2-四唑溴胺)试剂(最终浓度2.5mg/mL)孵育2小时。然后，用含10％十二烷基硫酸钠(SDS)和50％N，N-二甲基甲酰胺(pH 7.2)裂解液裂解细胞。通过读取570nm处的吸光度，测量与活细胞数成正比的甲赞含量，计算化合物的CC50(半数致死浓度)。
药理实施例2甲型流感病毒病毒细胞病变效应(CPE)测定
MDCK细胞接种于6孔培养板，接种密度为每孔600000个细胞。置37℃，5％CO2培养箱培养24小时后，加入最终浓度为20μM的化合物孵育1小时后，加入甲型流感病毒H1N1(2.5TCID50)，共培养3天。设病毒对照、细胞对照和样品组。3天后，使用显微镜观察细胞活力和形态。结果显示化合物很好的改善了甲型流感病毒致细胞病变效应(CPE)(细胞圆形、变性、脱落)，并提高了细胞存活率。
药理实施例1和2的实验结果如下表1中所述。
表1化合物抗甲型流感病毒活性
注：CC50为样品药物对MDCK细胞的生长的影响，50％致死浓度。
EC50为样品对H1N1 RNA拷贝的抑制达50％时的浓度。
SI为样品的生物活性选择系数。SI值>2为有效，且越大越好。
NA：没有活性；-：无法计算
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 (11)
1.一种如下式I所示的化合物，或其药学上可接受的盐：
其中，
Ar选自下组：苯基、萘基、联苯基、5-7元杂芳基；
R1、R2和R3各自独立地选自下组：氢、卤素、氰基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基；或-CHR3-不存在；
Linker具有如下式所示的结构：
-L1-(L2)m-L3-；
其中，m为1、2、3、4、5或6；
L1选自下组：化学键、-O-、-CO-、-CONH-、-CH2-、或-SO2-；
L2选自下组：取代或未取代的苯基、取代或未取代的5-7元杂芳基、取代或未取代的5-7元杂环基、取代或未取代的C1-C6亚烷基(优选为C1-C4亚烷基)、-O-、-CO-、-NH-、取代或未取代的C2-C6亚烯基(优选为C2-C4亚烯基，更优选为C2-C3亚烯基)；
L3选自下组：-O-、-CO-、-CONH-、-CH2-、或-SO2-；
其中，所述的任一“取代”是指基团上的一个或多个(优选为1、2、3或4个)氢原子被选自下组的取代基所取代：卤素、-CN、卤代C1-C4烷基(如-CF3)、羟基、氨基、甲磺酰基、-NH-C6-C10芳基、-NH-5-12元杂芳基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C10芳基、C6-C10芳基-C1-C4烷基-、C6-C10芳基-C1-C4烷氧基-、C1-C4烷硫基、5-12元杂芳基、C2-C4酯基、或氨基酸残基(即，天然氨基酸缩合过程中失去一分子水从而形成的基团)；
所述的杂环基和杂芳基的杂环上各自独立地具有1-3个(优选为1、2或3个)选自N、O和S的杂原子。
2.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基；其中，所述的取代指基团上的一个或多个H原子被选自下组的取代基取代：卤素、-CN、卤代C1-C4烷基(如-CF3)、羟基、氨基、C1-C4烷基、C3-C8环烷基、C1-C7烷氧基、C6-C12芳基、或5-12元杂芳基。
3.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R2选自下组：氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C4酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基。
4.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R2选自下组：氢、卤素、取代或未取代的C1-C4烷基、取代或未取代的C2-C4酯基、取代或未取代的C6-C10芳基、或取代或未取代的5-15元杂芳基。
5.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R3选自下组：氢、取代或未取代的C1-C10烷基，或-CHR3-不存在。
6.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的式I化合物具有如下式II所示的结构：
7.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的Linker为选自下组的结构：
8.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的式I化合物选自下组：
9.如权利要求1所述的式I化合物的制备方法，其特征在于，所述的方法包括步骤(1)、(2)或(3)：
(1)在催化剂、银盐和第一碱试剂的作用下，式C1化合物与式C2化合物经碳氢键活性反应，生成式I化合物；
(2)在催化剂、银盐和第一碱试剂的作用下，式C3化合物与式C4化合物经碳氢键活性反应，生成式I化合物；其中，R3为H；
(3)在催化剂、银盐和第一碱试剂的作用下，式C3化合物与式C4化合物经碳氢键活性反应，生成式I化合物；其中，-CHR3-不存在；
10.一种药物组合物，其特征在于，所述的组合物包含：(a)如权利要求1-8任一所述的式I化合物，或其异构体，或其药学上可接受的盐；和(b)药学上可接受的载体。
11.如权利要求1所述的化合物的用途，其特征在于，所述的化合物用于制备药物组合物，且所述的药物组合物用于治疗或预防甲型流感病毒导致的疾病或病症。
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