CN115611808A - 肠道病毒d68型的新型抑制剂、其制备方法和用途 - Google Patents
肠道病毒d68型的新型抑制剂、其制备方法和用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及式1和式2所示的喹啉衍生物类及其药学上可接受的盐，或其溶剂化物或其水合物，还涉及含有该化合物的药物组合物，制备该化合物的方法，以及该化合物用于制备预防和/或治疗由肠道病毒引起的疾病的药物中的应用。
Description
技术领域
本发明涉及式1和式2所示的喹啉衍生物类化合物及其药学上可接受的盐，其溶剂化物或其水合物，还涉及含有该化合物的药物组合物，制备该化合物的方法，以及该化合物用于预防和/或治疗由肠道病毒引起的疾病的药物中的应用。
背景技术
肠道病毒D68型(Enterovirus D68，EV-D68)是一种非脊髓灰质炎肠道病毒，属于小核糖核酸病毒科的肠道病毒属。EV-D68的感染主要引起呼吸道疾病，症状包括咳嗽、流鼻涕、发热、哮喘、呼吸困难和组织缺氧等，但也可能导致严重的细支气管炎或肺炎，偶尔会导致死亡，而且主要感染对象为婴幼儿和免疫功能低下的个体。EV-D68除引起严重的呼吸道疾病外，还会导致中枢神经系统疾病及急性迟缓性麻痹的发生，严重者导致四肢瘫痪。与其他肠道病毒不同，EV-D68主要通过呼吸道传播并结合在上呼吸道唾液酸受体，这种传播途径对大规模传播构成潜在威胁。2014年在美国爆发了由EV-D68引起的严重呼吸系统疾病，共有1153感染病例和数百万未经检测的较轻病例。同期，欧洲和许多国家亚洲相继报告出现EV-D68流行病。
尽管EV-D68的感染会导致严重疾病，且已经被认为是一种公共健康威胁，但目前还没有用于治疗EV-D68感染的抗病毒药物或预防EV-D68感染的疫苗。因此，迫切需要开发新结构的、特异性的抗病毒药物来更好地治疗EV-D68感染。
EV-D68是一种被衣壳蛋白包围无包膜病毒，衣壳蛋白是一种结构蛋白，由60个原聚体组成，这些原聚体包含表面的VP1、VP2和VP3以及内部VP4亚基。VP1蛋白底部含有一个小的疏水口袋，通常充满脂质部分或口袋因子，口袋因子通过填充衣壳蛋白VP1的疏水口袋，使得病毒的衣壳结构保持稳定。当病毒与受体结合后，“口袋因子”被排出，病毒表面的蛋白结构发生改变，随后病毒的RNA基因组释放，进入宿主细胞中进行后续的复制及翻译过程。衣壳蛋白抑制剂可以作为一种口袋因子竞争性结合的抑制剂，能进入VP1蛋白表面凹陷的峡谷，稳定病毒的衣壳结构，阻止病毒的RNA释放，以达到抗病毒增殖的作用。
发明内容
发明人根据VP1蛋白的结构特点，筛选了具有新型骨架结构的喹啉衍生物，并且评估了这些衍生物对EV-D68等肠道病毒的抑制活性。
特别地，本发明涉及一种结构新颖的喹啉衍生物类化合物，其药学上可接受的盐、其水合物或其溶剂合物，还涉及该化合物的合成方法及其在治疗肠道病毒中的应用。
本发明的技术方案如下：
本发明的第一方面提供了如式1所示的化合物、其药学上可接受的盐，其水合物或其溶剂合物，
其中：
R1选自C1-8烷基；
R2选自5-14元取代或者未取代的芳基、5-14元取代或者未取代的杂芳基。
在某些实施方案中，本发明所述式1化合物中，R1选自C1-8烷基。
在某些实施方案中，本发明所述式1化合物中，R1选自C1-6烷基。
在某些实施方案中，本发明所述式1化合物中，R1选自C1-3烷基。
在某些实施方案中，本发明所述式1化合物中，R1为乙基。
在某些实施方案中，本发明所述式1化合物中，R2选自5-14元芳基、5-14元杂芳基，所述5-14元芳基或5-14元杂芳基可以任选地被一个或者多个Ra取代，每个Ra各自独立地为氢、氨基、C1-4烷基、氨酰基。在某些实施方案中，所述5-14元芳基为5-10元芳基，例如苯基。在某些实施方案中，所述5-14元杂芳基为5-6元单杂芳基，所述5-6元单杂芳基含有1-2个杂原子，所述杂原子选自氮原子、氧原子、硫原子。
在某些实施方案中，R2为苯基或含1-2个氮原子的5-6元杂芳基(例如4H-吡唑基)，所述苯基可以任选地被一个或者多个Ra取代，每个Ra各自独立地选自氢、氨基、C1-4烷基、氨酰基。
在某些实施方案中，本发明所述式1化合物中，R1为乙基，R2为苯基，所述苯基可以任选地被一个或者多个Ra取代，每个Ra各自独立地选自氢、氨基、C1-4烷基(例如甲基、乙基、正丙基、异丙基或正丁基)、氨酰基。
在某些实施方案中，本发明所述式1化合物中，R1为乙基，R2为含1-2个氮原子的5-6元杂芳基，例如4H-吡唑基。
在某些实施方案中，本发明所述式1化合物中，R1为乙基，R2选自：
在某些实施方案中，本发明所述式1化合物选自：
本发明所述的式1化合物可根据需要采用常规的合成路线制备。
本发明的第二方面提供了如式2所示的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其包括：
其中：
R3为C1-12取代或者未取代的烷基；
R4选自5-14元取代或者未取代的芳基、5-14元取代或者未取代的杂芳基。
在某些实施方案中，本发明所述式2化合物中，R3选自C1-12烷基，所述C1-12烷基可以任选地被一个或者多个Rb取代，每个Rb各自独立地为氢或卤素。
在某些实施方案中，本发明所述式2化合物中，R3选自C1-6烷基，所述C1-6烷基可以任选地被一个或者多个Rb取代，每个Rb各自独立地为氢或卤素。
在某些实施方案中，本发明所述式2化合物中，R3选自C1-4烷基，所述C1-4烷基可以任选地被一个或者多个Rb取代，每个Rb各自独立地为氢、卤素(例如氟)。
在某些实施方案中，本发明所述式2化合物中，R3选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基。
在某些实施方案中，本发明所述式2化合物中，R4选自5-8元芳基、5-8元杂芳基，所述5-8元芳基或5-8元杂芳基可以任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、卤素、氨基、羟基、氰基、(C1-4烷基)2-N-、C1-8烷基、C1-3酰胺基，C1-6烷氧基、5-8元芳基、5-6元单杂环基。
在某些实施方案中，本发明所述式2化合物中，R4选自5-6元芳基、5-6元单杂芳基，所述5-6元芳基或5-6元单杂芳基可以任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、卤素、氨基、羟基、氰基、(C1-4烷基)2-N-、C1-8烷基、C1-3酰胺基、C1-6烷氧基、5-8元芳基、5-6元含N和/或O单杂环基。
在某些实施方案中，本发明所述式2化合物中，R4选自苯基、吡啶基，所述苯基或吡啶基可以任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、氟、氯、氨基、二甲氨基、C1-4烷基、乙酰氨基、C1-2烷氧基、羟基、苯基、氰基、吗啉基。
在某些实施方案中，本发明所述式2化合物中，R4选自：
在某些实施方案中，本发明所述式2化合物选自：
本发明的化合物中，当提及基团“取代或者未取代”，是指所述基团没有被取代或者被一个或多个(例如2、3或4个)相同或不同的取代基取代，所述取代基可以选自，例如苯基、卤素、羟基、氰基、氨基、氨酰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基。
本文中当提及“一个或多个”时，所述“多个”优选的是2、3或4个。
本发明的第三方面提供药物组合物，其包含至少一种本发明第一方面所述式1和/或第二方面所述式2化合物、其药学上可接受的盐，其水合物或其溶剂合物，任选地，还包括一种或多种药学上可接受的载体或赋形剂。本发明第一方面所述式1和/或第二方面所述式2化合物、其药学上可接受的盐，其水合物或其溶剂合物以治疗有效量(例如治疗由肠道病毒感染引起的疾病的有效量)存在。
本发明的第四方面提供第一方面所述式1和/或第二方面所述式2化合物、其药学上可接受的盐，其水合物或其溶剂合物或者本发明第三方面的药物组合物在制备药物中的用途，所述药物用于以下的一种或者多种：
1)预防或治疗肠道病毒感染或肠道病毒感染引起的疾病；
2)抑制肠道病毒在细胞(例如哺乳动物细胞)中的复制或繁殖。
在某些实施方案中，所述肠道病毒选自脊髓灰质炎病毒(Poliovirus，PV)、柯萨奇A病毒(Coxsackie A Virus，CV-A)、柯萨奇B病毒(Coxsackie B Virus，CV-B)、埃可病毒(Echovirus)、肠道病毒71型(Enterovirus 71，EV71)、肠道病毒D68型(Enterovirus D68，EV-D68)或其任意组合。
在某些实施方案中，所述肠道病毒选自EV-D68。
在某些实施方案中，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹、非特异性发热性疾病、肺炎、毛细支气管炎、脑炎和心肌炎、急性迟缓性脊髓炎或其任意组合。
在某些实施方案中，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹或其任意组合。
本发明的第五方面提供一种预防治疗肠道病毒感染或肠道病毒感染引起的疾病的方法，包括：向有需要的受试者施用有效量的本发明的第一方面所述式1和/或第二方面所述式2化合物、其药学上可接受的盐，其水合物或其溶剂合物或者本发明第三方面的药物组合物。
在某些实施方案中，所述肠道病毒选自脊髓灰质炎病毒(Poliovirus，PV)、柯萨奇A病毒(Coxsackie A Virus，CV-A)、柯萨奇B病毒(Coxsackie B Virus，CV-B)、埃可病毒(Echovirus)、肠道病毒71型(Enterovirus 71，EV71)、肠道病毒D68型(Enterovirus D68，EV-D68)或其任意组合。
在某些实施方案中，所述肠道病毒选自EV-D68。
在某些实施方案中，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹、非特异性发热性疾病、肺炎、毛细支气管炎、脑炎和心肌炎、急性迟缓性脊髓炎或其任意组合。
在某些实施方案中，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹或其任意组合。
本发明的第六方面提供一种抑制肠道病毒在细胞(例如哺乳动物细胞)中复制或繁殖的方法，其包括给予细胞(例如哺乳动物细胞)有效量的本发明的第一方面所述式1和/或第二方面所述式2化合物、其药学上可接受的盐，其水合物或其溶剂合物或者本发明第三方面的药物组合物。所述方法可以在体内或体外进行，例如可以在体外的细胞系中进行。所述方法可以用于治疗目的，也可用于非治疗目的(例如药物研究)。
在某些实施方案中，所述肠道病毒选自脊髓灰质炎病毒(Poliovirus，PV)、柯萨奇A病毒(Coxsackie A Virus，CV-A)、柯萨奇B病毒(Coxsackie B Virus，CV-B)、埃可病毒(Echovirus)、肠道病毒71型(Enterovirus 71，EV71)、肠道病毒D68型(Enterovirus D68，EV-D68)或其任意组合。
在某些实施方案中，所述肠道病毒选自EV-D68。
本发明的第七方面提供制备本发明的第二方面所述的式2所示化合物或其药学上可接受的盐，其水合物或其溶剂合物的方法。所述方法包括：以下述结构式6所示的中间体为原料，与R4-B(OH)2所示的硼酸衍生物反应，即得到本发明第二方面所述化合物、其药学上可接受的盐，其水合物或其溶剂合物，其反应通式如下：
其中，R3和R4如前所述。
在某些实施方案中，结构式6所示的中间体是由下述结构式5所示的中间体为原料，与(R3-CO)2O所示的酸酐反应制备得到，
其中，R3如前所述。
在某些实施方案中，结构式5所示中间体是由6-溴喹啉-3-甲腈与羟胺反应得到。
在本发明的某些实施方案中，式2所示化合物或其药学上可接受的盐，其水合物或其溶剂合物的制备方法的反应流程如下所示：
其中R3和R4如前所述。
定义
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
在本发明中，在某些实施方案中，本发明所述的受试者包括哺乳动物受试者，特别是人受试者，包括男性和女性受试者且包括新生儿、婴儿、少年、青少年、成人和老年受试者，并且包括各种种族和族裔，包括但不限于，白人、黑人、亚洲人、美洲印第安人和西班牙裔。
在本发明中，在某些实施方案中，本发明所述的哺乳动物包括牛科动物、马科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物、例如是人、猫、狗、猴或猪。
本发明化合物既可以其本身也可以其可药用盐的形式使用。式1和式2所示化合物的药学上可接受的盐包括与药学上可接受的无机酸或有机酸、或者与药学上可接受的无机碱或有机碱形成的盐。合适的酸加成盐的例子包括与盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸或鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N'-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺或普鲁卡因等形成的盐。用于制备本发明化合物的药学上可接受的盐的方法为本领域技术人员已知的。本文中涉及到本发明化合物时，包括式1或式2所示化合物及其药学上可接受的盐。
本发明中，溶剂合物是指式1或式2所示化合物或其药学上可接受的盐与有机溶剂分子缔合形成的物质，所述有机溶剂包括但不限于甲醇、乙醇、丙醇、乙腈等。式1或式2所示化合物或其药学上可接受的盐可以与水形成水合物。
本发明所述的药物组合物包含本发明所述的式1和式2所示化合物或其药学上可接受的盐，其水合物或其溶剂合物，还可以包含药学上可接受的载体和/或赋形剂。本发明的药物组合物可按本领域常规方法制备成各种剂型，包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等，经例如口服或非肠道等途径给药。
另外需要指出，本发明所述式1和式2所示化合物或其药学上可接受的盐，其水合物或其溶剂合物的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.001－1000mg/kg体重/天。
本发明所用术语“药学上可接受的”是指其描述的物质不但是受试者生理学上可接受,而且还可指在药学上有使用价值的物质。例如在描述“药学上可接受的盐”时，表示该盐其不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质。
本发明所用术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995)，包括但不限于粘合剂、稀释剂、填充剂、崩解剂、润湿剂、润滑剂、着色剂、调味剂、增溶剂、渗透压调节剂或其它常规添加剂。典型的药学上可接受的载体和/或赋形剂包括例如微晶纤维素、淀粉、交联聚维酮、聚维酮、聚乙烯吡咯烷酮、麦芽糖醇、柠檬酸、十二烷基磺酸钠或硬脂酸镁等。
本发明所用术语“有效量”是指能够有效实现预期目的的量。例如治疗疾病(例如病毒感染或由病毒感染引起的疾病)有效量是指，能够减轻或消除疾病状态或病症的量。测定这样的有效量在本领域技术人员的能力范围之内。
本发明所用术语“任选地”是指其描述的事件或情况发生或未发生。
本发明所用术语“C1-12烷基”是指具有1－12个碳原子的饱和的直链或支链一价烃基，其可包括其子基团例如C1-8烷基、C1-6烷基、C1-4烷基、C1-3烷基等。“C1-12烷基”的典型实例包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基、叔丁基，正戊基，叔戊基，新戊基，正己基等。
本文所用的术语“烷氧基”意指通过氧原子连接至母分子部分的如上文所定义的烷基。术语“C1-6烷氧基”是指具有指定数目碳原子的烷氧基，其可包括其子基团例如C1-6烷氧基、C1-4烷氧基、C1-2烷氧基等。“烷氧基”的典型实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。
本文所用的术语“酰胺基”意指通过氨基连接至母分子部分的酰基。术语“C1-3酰胺基”是指具有指定数目碳原子的酰基，其可包括其子基团例如C1-3烷氧基、C1-2烷氧基等。“酰胺基”的典型实例包括但不限于乙酰胺基、丙酰胺基等。
本文所用术语“C1-6卤代烷基”是指被卤素例如氟，氯，溴或碘单或多取代的如上文所定义的C1-6烷基。卤代C1-6烷基的代表性实例包括但不限于氯甲基、氯乙基、二氯乙基、三氟甲基、二氟甲基、单氟甲基等。
本文使用的术语“5-14元取代或未取代的芳基”是指具有一个单环或者两个或多个稠合环的含5-14个碳原子的不饱和芳族碳环基，并且该基团未被取代或者被取代。所述芳基例如具有5-10个碳原子。所述芳基的典型实例包括但不限于苯基、萘基和蒽基等。
本文所用的术语“5-14元取代或未取代的杂芳基”表示意指具有5-14个环成员的杂芳族环基团，包括单环杂芳族环和多环芳族环，并且该基团未被取代或者被取代。“5-14元杂芳基”中具有一个或两个或多个选自氧、硫或氮的杂原子，所述杂芳基上的碳原子、氮原子或硫原子任选地可以被氧代(oxo)。“5-14元杂芳基”的实例包括但不限于5-8元杂芳基、8-10元杂芳基、10-14元杂芳基，例如5-6元单杂芳基、8-10元或10-14元多杂芳基，例如5-6元含1-2个杂原子的单杂芳基，所述杂原子选自氮原子、氧原子或硫原子。本发明所用的术语“杂芳基”范围内还包括的是其中芳族环与一个或多个非芳族环(碳环或杂环)稠合的基团，其中连接基团或点位于芳族环或非芳族环上。“5-14元杂芳基”的典型实例包括但不限于呋喃基、咪唑基、三氮唑基、吲哚基、四氮唑基、吡啶基、恶二唑基、喋啶基、嘧啶基、三唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基等。
本文所用的术语“单杂环基”指的是至少一个(例如1、2或3个)环原子为杂原子(例如氮原子、氧原子或硫原子)的非芳香性的单环状基团。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。当含有多个杂原子时，所述杂原子可以相同或不同。
本发明的有益技术效果
1、本发明所述式1和式2化合物对例如EV-D68等肠道病毒具有较强的抑制活性。
2、本发明所述式1和式2化合物的体内毒性低。
具体实施方式
下面的具体实施例是本发明的优选实施方案，其不应理解为对本发明构成任何限制。
实施例1：
制备式1所示化合物中的1-1至1-9
化合物1-1
将6-溴喹啉-3-羧酸乙酯(1.0equiv)、4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷(1.3equiv)、PdCl2(dppf)(0.05equiv)和K2CO3(2equiv)溶解在DME/水＝5:1的溶剂中，混合物在氮气保护下，在120℃下微波反应40min。减压浓缩反应液，将剩余物经正己烷/乙酸乙酯柱层析纯化，得到白色固体，收率70％。1H NMR(600MHz,DMSO-d6)δ9.28(d,J＝2.2Hz,1H),9.02(dd,J＝2.2,0.8Hz,1H),8.48(d,J＝2.1Hz,1H),8.23(dd,J＝8.8,2.1Hz,1H),8.15(dd,J＝8.8,0.9Hz,1H),7.78–7.73(m,2H),7.37–7.32(m,2H),4.42(q,J＝7.1Hz,2H),2.61(dd,J＝8.3,6.9Hz,2H),1.68–1.59(m,2H),1.39(t,J＝7.1Hz,3H),0.92(t,J＝7.3Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.83,149.23,148.53,142.37,139.03,138.69,136.24,131.22,129.37,129.22,127.05,126.92,126.46,123.16,61.34,36.94,24.08,14.24,13.74.HRMS(ESI)calcd for C21H21NO2[M+H]+320.1651,found 320.1645.
化合物1-2
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率41.3％。1H NMR(600MHz,DMSO-d6)δ9.29(d,J＝2.2Hz,1H),9.05(d,J＝2.1Hz,1H),8.40(d,J＝2.0Hz,1H),8.18–8.10(m,2H),7.24(t,J＝7.8Hz,1H),7.10(t,J＝2.0Hz,2H),7.07(dt,J＝7.7,1.2Hz,1H),6.77–6.72(m,1H),4.42(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.85,149.24,148.59,147.46,139.83,139.76,138.77,131.33,129.86,129.32,126.88,126.55,123.20,116.31,114.95,113.63,61.35,14.25.HRMS(ESI)calcd for C18H16N2O2[M+H]+293.1290,found 293.1287
化合物1-3
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为2-(4-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率83％。1H NMR(600MHz,DMSO-d6)δ9.27(d,J＝2.2Hz,1H),8.99(d,J＝2.4Hz,1H),8.45(d,J＝2.2Hz,1H),8.19(dd,J＝8.7,2.2Hz,1H),8.13(d,J＝8.7Hz,1H),7.74(d,J＝7.9Hz,2H),7.38(d,J＝7.9Hz,2H),4.41(q,J＝7.1Hz,2H),2.94(m,J＝6.9Hz,1H),1.38(t,J＝7.1Hz,3H),1.24(d,J＝7.0Hz,6H).13C NMR(151MHz,DMSO-d6)δ164.83,149.24,148.58,139.07,138.69,136.41,131.27,129.38,127.18,126.92,126.49,123.16,61.35,33.23,23.88,14.25.HRMS(ESI)calcd for C21H21NO2[M+H]+320.1651,found 320.1646
化合物1-4
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为2-(4-丁基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率30％。1H NMR(600MHz,DMSO-d6)δ9.29(d,J＝2.1Hz,1H),9.03(d,J＝2.1Hz,1H),8.49(d,J＝2.1Hz,1H),8.23(dd,J＝8.7,2.2Hz,1H),8.15(d,J＝8.8Hz,1H),7.78–7.73(m,2H),7.37–7.32(m,2H),4.42(q,J＝7.1Hz,2H),2.64(t,J＝7.7Hz,2H),1.64–1.55(m,2H),1.39(t,J＝7.1Hz,3H),1.33(h,J＝7.4Hz,2H),0.91(t,J＝7.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.83,149.23,148.53,142.58,139.03,138.69,136.20,131.22,129.37,129.17,127.07,126.93,126.45,123.17,61.34,34.52,33.11,21.85,14.25,13.86.HRMS(ESI)calcd for C22H23NO2[M+H]+334.1807,found 334.1803.
化合物1-5
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼烷，得到白色固体，收率20％。1H NMR(600MHz,DMSO-d6)δ9.30(d,J＝2.1Hz,1H),9.04(d,J＝2.1Hz,1H),8.52(d,J＝2.1Hz,1H),8.25(dd,J＝8.7,2.2Hz,1H),8.17(d,J＝8.8Hz,1H),7.88–7.83(m,2H),7.55(t,J＝7.7Hz,2H),7.48–7.42(m,1H),4.42(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).13CNMR(151MHz,DMSO-d6)δ164.81,149.40,148.63,139.08,138.88,138.78,131.32,129.44,129.24,128.25,127.23,126.93,126.89,123.21,61.36,14.25.HRMS(ESI)calcd forC18H15NO2[M+H]+278.1181,found 278.1176.
化合物1-6
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率76％。1H NMR(600MHz,DMSO-d6)δ9.21(d,J＝2.1Hz,1H),8.94(d,J＝2.1Hz,1H),8.31(d,J＝2.2Hz,1H),8.15(dd,J＝8.8,2.2Hz,1H),8.06(d,J＝8.7Hz,1H),7.60–7.54(m,2H),6.73–6.69(m,2H),5.40(s,2H),4.40(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.93,149.26,148.37,148.00,139.64,138.26,130.69,129.09,127.83,127.13,125.67,124.08,123.00,114.37,61.26,14.24.HRMS(ESI)calcdfor C18H16N2O2[M+H]+293.1290,found 293.1288.
化合物1-7
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率67％。1H NMR(600MHz,DMSO-d6)δ9.30(d,J＝2.2Hz,1H),9.00(d,J＝2.0Hz,1H),8.23(d,J＝2.0Hz,1H),8.14(d,J＝8.7Hz,1H),7.97(dd,J＝8.7,2.0Hz,1H),7.15–7.08(m,2H),6.83(dd,J＝7.9,1.0Hz,1H),6.70(td,J＝7.4,1.2Hz,1H),5.05(s,2H),4.42(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.90,149.14,148.31,145.43,139.09,138.60,133.68,130.49,129.10,128.89,128.84,126.89,124.48,122.93,116.97,115.67,61.33,14.26.HRMS(ESI)calcd for C18H16N2O2[M+H]+293.1290,found 293.1287.
化合物1-8
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，得到黑色固体，收率10％。1H NMR(600MHz,DMSO-d6)δ13.12(s,1H),9.22(t,J＝1.6Hz,1H),8.88(d,J＝1.9Hz,1H),8.45–8.37(m,2H),8.21(dt,J＝8.7,1.6Hz,1H),8.12(s,1H),8.07(d,J＝8.7Hz,1H),4.41(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.84,148.39,148.06,137.86,136.84,132.32,130.67,129.26,127.13,126.53,123.71,123.11,120.26,61.29,14.22.HRMS(ESI)calcd for C15H13N3O2[M+H]+268.1086,found 268.1081.
化合物1-9
采用实施例1中化合物1-1的制备方法，将其中的4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酰胺，得到白色固体，收率51％。1H NMR(600MHz,DMSO-d6)δ9.32(d,J＝2.1Hz,1H),9.07(d,J＝2.1Hz,1H),8.67–8.57(m,1H),8.36–8.29(m,1H),8.19(d,J＝8.8Hz,1H),8.09(s,1H),8.05(d,J＝8.0Hz,2H),7.96(d,J＝7.9Hz,2H),7.45(s,1H),4.43(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ167.48,164.78,149.69,148.83,141.40,138.91,138.12,133.79,131.25,129.54,128.42,127.47,127.02,126.88,123.31,61.40,14.25.HRMS(ESI)calcd for C18H16N2O2[M+H]+321.1239,found 321.1234.
实施例2
中间体4
将二水合氯化亚锡(26.49g,117.39mmol)加入到5-溴-2-硝基苯甲醛(9.0g,39.13mmol)和乙醇(250mL)的溶液中并搅拌10min。加入3,3-二乙氧基丙酸乙酯(14.0g,97.83mmol)，加热回流5h。反应完成后，反应液过滤，固体用乙醇冲洗，干燥得黄色固体7.72g，收率85％。1H NMR(600MHz,DMSO-d6)δ9.20(d,J＝2.3Hz,1H),9.02(q,J＝2.0Hz,1H),8.38(q,J＝2.2Hz,1H),8.11–8.03(m,2H).13C NMR(151MHz,DMSO-d6)δ150.67,146.73,141.74,135.96,131.29,130.75,127.19,121.42,117.17,106.83.HRMS(ESI)calcd forC10H5BrN2[M+H]+232.9714,found 232.9704.
实施例3
中间体5
将中间体4(3.08g,13.3mmol)和50％羟胺水溶液(1.05g,16.0mmol)在乙醇(30mL)中加热回流4h。反应完成后，过滤反应混合物，滤饼用乙酸乙酯冲洗，干燥得白色固体3.2g，收率91％。1H NMR(600MHz,DMSO-d6)δ10.08(s,1H),9.23(d,J＝2.1Hz,1H),8.55(d,J＝2.2Hz,1H),8.25(d,J＝2.2Hz,1H),7.96(d,J＝8.9Hz,1H),7.88(dd,J＝8.9,2.2Hz,1H),6.12(s,2H).13C NMR(151MHz,DMSO-d6)δ148.96,148.80,146.08,132.91,131.16,131.00,130.31,128.52,127.22,120.09.HRMS(ESI)calcd for C10H8BrN3O[M+H]+265.9929,found265.9920.
实施例4
制备中间体6-1至6-9
化合物6-1
6-溴-N-羟基喹啉-3-羧肟酰胺(1equiv)和三氟乙酸酐(1.2equiv)加入吡啶中，将反应混合物加热回流3h后冷却至室温。将反应混合物倒入水中并加入1.0N HCl调节至pH＝4，然后用乙酸乙酯萃取，合并乙酸乙酯相并用无水硫酸钠干燥，减压浓缩，剩余物经柱层析纯化(正己烷/乙酸乙酯)，得到黄色固体，收率71％。1H NMR(600MHz,chloroform-d)δ9.57(d,J＝2.1Hz,1H),8.84–8.80(m,1H),8.12(d,J＝2.2Hz,1H),8.06(d,J＝8.9Hz,1H),7.91(dd,J＝8.9,2.2Hz,1H).13C NMR(151MHz,chloroform-d)δ167.21,166.38(q,J＝44.8Hz),148.22,148.10,135.21,134.99,131.38,130.64,128.20,122.01,119.20,115.88(q,J＝273.7Hz).19F NMR(565MHz,Chloroform-d)δ-65.19.HRMS(ESI)calcd for C12H5BrF3N3O[M+H]+343.9646,found 343.9642.
化合物6-2
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为乙酸酐，得到白色固体，收率57％。1H NMR(600MHz,chloroform-d)δ9.54(d,J＝2.1Hz,1H),8.73(d,J＝2.1Hz,1H),8.06(d,J＝2.1Hz,2H),8.03(d,J＝8.9Hz,1H),7.85(dd,J＝9.1,2.2Hz,1H),2.71(s,3H).13C NMR(151MHz,chloroform-d)δ177.19,166.29,148.69,147.56,134.44,134.07,131.19,130.46,128.46,121.52,121.05,12.44.HRMS(ESI)calcd for C12H8BrN3O[M+H]+289.9929,found 289.9921.
化合物6-3
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为丙酸酐，得到黄色固体，收率52％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.75(d,J＝2.0Hz,1H),8.07(d,J＝2.2Hz,1H),8.03(d,J＝8.9Hz,1H),7.85(dd,J＝8.9,2.2Hz,1H),3.03(q,J＝7.6Hz,2H),1.49(t,J＝7.6Hz,3H).13C NMR(151MHz,chloroform-d)δ181.40,166.16,148.74,147.52,134.40,134.12,131.18,130.48,128.48,121.49,121.21,20.37,10.81.HRMS(ESI)calcd for C13H10BrN3O[M+H]+304.0085,found 304.0079.
化合物6-4
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为丁酸酐，得到黄色固体，收率50％。1H NMR(600MHz,chloroform-d)δ9.57(d,J＝2.1Hz,1H),8.77(d,J＝2.5Hz,1H),8.11–8.03(m,2H),7.86(dd,J＝8.9,2.2Hz,1H),2.99(t,J＝7.5Hz,2H),1.96(h,J＝7.4Hz,2H),1.10(t,J＝7.4Hz,3H).13C NMR(151MHz,chloroform-d)δ180.61,166.14,148.70,147.43,134.49,134.24,131.13,130.50,128.53,121.57,121.26,28.49,20.20,13.66.HRMS(ESI)calcd for C14H12BrN3O[M+H]+318.0242,found 318.0233.
化合物6-5
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为异丁酸酐，得到黄色固体，收率60％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.76(d,J＝2.0Hz,1H),8.08(d,J＝2.2Hz,1H),8.03(d,J＝9.0Hz,1H),7.85(dd,J＝9.0,2.2Hz,1H),3.34(m,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,6H).13C NMR(151MHz,chloroform-d)δ184.61,166.05,148.79,147.51,134.35,134.13,131.19,130.47,128.49,121.46,121.30,27.61,20.20.HRMS(ESI)calcd for C14H12BrN3O[M+H]+318.0242,found 318.0236.
化合物6-6
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为戊酸酐，得到黄色固体，收率56％。1H NMR(600MHz,chloroform-d)δ9.56(d,J＝2.2Hz,1H),8.75(d,J＝2.1Hz,1H),8.07(d,J＝2.2Hz,2H),8.03(d,J＝8.9Hz,1H),7.85(dd,J＝9.0,2.2Hz,1H),3.01(t,J＝7.6Hz,2H),1.90(p,J＝7.5Hz,2H),1.50(h,J＝7.4Hz,2H),1.00(t,J＝7.4Hz,3H).13C NMR(151MHz,chloroform-d)δ180.73,166.13,148.77,147.54,134.35,134.06,131.19,130.45,128.46,121.45,121.19,28.62,26.34,22.18,13.56.HRMS(ESI)calcd forC15H14BrN3O[M+H]+332.0398,found 332.0393.
化合物6-7
采用实施例4中化合物6-1的制备方法，将其中的三氟乙酸酐改为特戊酸酐，得到黄色固体，收率40％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.76(d,J＝2.0Hz,1H),8.08(d,J＝2.2Hz,1H),8.03(d,J＝8.9Hz,1H),7.84(dd,J＝9.0,2.2Hz,1H),1.53(s,9H).13C NMR(151MHz,chloroform-d)δ186.95,165.98,148.84,147.50,134.29,134.13,131.20,130.47,128.49,121.42,121.39,33.77,28.42.HRMS(ESI)calcd forC15H14BrN3O[M+H]+332.0398,found 332.0390.
实施例5:
制备式2所示化合物中的2-1至2-42
化合物2-1
将化合物6-1(1.0equiv)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(1.3equiv)、PdCl2(dppf)(0.05equiv)和K2CO3(2equiv)溶解在DME/水＝5:1的溶剂中，混合物在氮气下通过微波条件，在120℃下反应40min。减压浓缩反应液，将剩余物经正己烷/乙酸乙酯柱层析纯化，得到黄色固体，收率58％。1H NMR(600MHz,DMSO-d6)δ9.35(d,J＝2.2Hz,1H),9.07(d,J＝2.1Hz,1H),8.37(d,J＝2.1Hz,1H),8.17(dd,J＝8.8,2.2Hz,1H),8.09(d,J＝8.8Hz,1H),7.60–7.55(m,2H),6.74–6.69(m,2H),5.42(s,2H).13C NMR(151MHz,DMSO-d6)δ167.13,165.28(q,J＝44.5,44.1Hz),149.33,147.63,146.39,139.98,135.96,130.53,129.24,127.85,127.47,125.58,123.78,118.25,115.87(q,J＝273.0Hz),114.36.19F NMR(565MHz,DMSO-d6)δ-64.65.HRMS(ESI)calcd for C18H11F3N4O[M+H]+357.0963,found 357.0958.
化合物2-2
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为6-2，得到黄色固体，收率29％。1H NMR(600MHz,DMSO-d6)δ9.31(d,J＝2.0Hz,1H),8.95(d,J＝2.0Hz,1H),8.30(d,J＝2.0Hz,1H),8.12(dd,J＝8.8,2.1Hz,1H),8.07(d,J＝8.8Hz,1H),7.60–7.55(m,2H),6.74–6.69(m,2H),5.41(s,2H),2.72(s,3H).13C NMR(151MHz,DMSO-d6)δ177.91,166.19,149.24,147.32,146.74,139.72,134.91,129.91,129.20,127.84,127.62,125.76,123.62,119.92,114.36,12.16.HRMS(ESI)calcd for C18H14N4O[M+H]+303.1246,found303.1241
化合物2-3
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，得到黄色固体，收率48％。1H NMR(600MHz,DMSO-d6)δ9.32(d,J＝2.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),8.13(dd,J＝8.8,2.0Hz,1H),8.07(d,J＝8.7Hz,1H),7.58(d,J＝8.1Hz,2H),6.71(d,J＝8.2Hz,2H),5.40(s,2H),3.07(q,J＝7.6Hz,2H),1.39(t,J＝7.5Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.67,166.08,149.24,147.32,146.74,139.72,134.93,129.90,129.19,127.83,127.63,125.77,123.66,119.97,114.36,19.73,10.53.HRMS(ESI)calcd for C19H16N4O[M+H]+317.1402,found 317.1396.
化合物2-4
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-4，得到黄色固体，收率48％。1H NMR(600MHz,DMSO-d6)δ9.31(d,J＝2.2Hz,1H),8.96(d,J＝2.3Hz,1H),8.32(d,J＝2.2Hz,1H),8.13(dd,J＝8.8,2.1Hz,1H),8.07(d,J＝8.7Hz,1H),7.58(d,J＝8.2Hz,2H),6.71(d,J＝8.2Hz,2H),5.40(s,2H),3.03(t,J＝7.4Hz,2H),1.85(h,J＝7.4Hz,2H),1.02(t,J＝7.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ180.70,166.08,149.24,147.32,146.74,139.71,134.94,129.89,129.19,127.83,127.62,125.77,123.65,119.95,114.35,27.69,19.60,13.48.HRMS(ESI)calcd for C20H18N4O[M+H]+331.1559,found331.1553.
化合物2-5
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-5，得到黄色固体，收率37％。1H NMR(600MHz,DMSO-d6)δ9.32(d,J＝2.1Hz,1H),8.97(d,J＝2.0Hz,1H),8.34(d,J＝2.4Hz,1H),8.13(dd,J＝8.8,2.1Hz,1H),8.07(d,J＝8.8Hz,1H),7.61–7.56(m,2H),6.74–6.68(m,2H),5.40(s,2H),3.41(m,J＝7.0Hz,1H),1.43(d,J＝7.0Hz,6H).13C NMR(151MHz,DMSO-d6)δ184.54,166.03,149.24,147.32,146.74,139.72,134.97,129.89,129.19,127.83,127.64,125.78,123.69,119.97,114.36,26.95,19.92.HRMS(ESI)calcd for C20H18N4O[M+H]+331.1559,found 331.1553.
化合物2-6
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-6，得到黄色固体，收率20％。1H NMR(600MHz,DMSO-d6)δ9.32(d,J＝2.1Hz,1H),8.96(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),8.13(dd,J＝8.8,2.1Hz,1H),8.07(d,J＝8.8Hz,1H),7.61–7.55(m,2H),6.74–6.68(m,2H),5.40(s,2H),3.05(t,J＝7.5Hz,2H),1.85–1.77(m,2H),1.47–1.38(m,2H),0.94(t,J＝7.3Hz,3H).13C NMR(151MHz,DMSO-d6)δ180.85,166.09,149.25,147.32,146.74,139.72,134.96,129.90,129.19,127.83,127.63,125.76,123.66,119.95,114.35,28.09,25.57,21.64,13.56.HRMS(ESI)calcd for C21H20N4O[M+H]+345.1715,found 345.1711.
化合物2-7
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-7，得到黄色固体，收率48％。1H NMR(600MHz,DMSO-d6)δ9.32(d,J＝2.2Hz,1H),8.96(d,J＝2.1Hz,1H),8.35(d,J＝2.3Hz,1H),8.13(dd,J＝8.7,2.1Hz,1H),8.07(d,J＝8.8Hz,1H),7.61–7.54(m,2H),6.74–6.67(m,2H),5.40(s,2H),1.49(s,9H).13C NMR(151MHz,DMSO-d6)δ186.68,166.01,149.24,147.33,146.74,139.72,134.99,129.88,129.19,127.83,127.63,125.78,123.71,119.97,114.36,33.49,28.05.HRMS(ESI)calcd for C21H20N4O[M+H]+345.1715,found 345.1710.
化合物2-8
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-8，得到黄色固体，收率12％。1H NMR(600MHz,DMSO-d6)δ9.39(t,J＝2.3Hz,1H),9.11(q,J＝2.4Hz,1H),8.49–8.43(m,2H),8.20(dt,J＝8.8,2.2Hz,1H),8.13(dd,J＝8.8,2.4Hz,1H),7.91(dt,J＝8.7,2.0Hz,1H),6.60(d,J＝8.6Hz,1H),6.27(s,2H).13C NMR(151MHz,DMSO-d6)δ167.08,165.32(q,J＝43.7Hz),159.77,147.80,146.75,146.59,137.53,136.06,135.68,130.25,129.48,127.43,124.10,122.33,118.39,115.87(q,J＝273.4Hz),108.21.19F NMR(565MHz,DMSO-d6)δ-64.64.HRMS(ESI)calcd for C17H10F3N5O[M+H]+358.0916,found358.0910.
化合物2-9
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-9，得到白色固体，收率35％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.25(d,J＝9.2Hz,1H),8.11(m,J＝4.8,2.1Hz,2H),7.67–7.62(m,2H),7.34(d,J＝7.8Hz,2H),2.72–2.68(m,2H),1.71–1.64(m,2H),1.46–1.38(m,2H),0.97(t,J＝7.4Hz,3H).13C NMR(151MHz,chloroform-d)δ167.53,166.24(q,J＝44.7Hz),148.61,147.48,143.27,140.78,136.84,136.36,131.62,129.88,129.23,127.42,127.28,125.82,118.66,115.94(q,J＝274.4Hz),35.33,33.60,22.41,13.97.19F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C22H18F3N3O[M+H]+398.1480,found 398.1475.
化合物2-10
采用实施例5中化合物2-1的制备方法，将其中的4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-(对甲苯基)-1,3,2-二氧硼烷，得到白色固体，收率25％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.24(d,J＝9.2Hz,1H),8.10(dt,J＝5.2,2.6Hz,2H),7.65–7.60(m,2H),7.34(d,J＝7.8Hz,2H),2.44(s,3H).13C NMR(151MHz,chloroform-d)δ167.54,166.23(q,J＝44.7Hz),148.69,147.55,140.71,138.22,136.68,136.29,131.54,129.95,129.86,127.40,127.28,125.80,118.66,115.94(q,J＝273.7Hz),21.17.19F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C19H12F3N3O[M+H]+356.1011,found 356.1005.
化合物2-11
采用实施例5中化合物2-1的制备方法，将其中的4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼烷，得到白色固体，收率54％。1H NMR(600MHz,chloroform-d)δ9.57(d,J＝2.2Hz,1H),8.97(d,J＝2.0Hz,1H),8.27(d,J＝8.6Hz,1H),8.15–8.09(m,2H),7.75–7.71(m,2H),7.53(t,J＝7.6Hz,2H),7.45(t,J＝7.4Hz,1H).13C NMR(151MHz,chloroform-d)δ167.49,166.26(q,J＝44.7Hz),148.71,147.68,140.83,139.59,136.41,131.64,129.99,129.15,128.23,127.47,127.38,126.23,118.73,115.94(q,J＝273.3Hz).19F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C18H10F3N3O[M+H]+342.0854,found 342.0849.
化合物2-12
采用实施例5中化合物2-1的制备方法，将其中的4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率45％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.24(d,J＝9.2Hz,1H),8.11(m,J＝4.6,2.1Hz,2H),7.69–7.64(m,2H),7.42–7.37(m,2H),3.01(h,J＝6.9Hz,1H),1.33(d,J＝6.9Hz,6H).13C NMR(151MHz,acetone-d6)δ168.41,166.58(q,J＝43.7Hz),149.75,149.60,148.10,140.98,137.74,136.86,131.80,130.67,128.28,128.05,127.91,126.85,119.64,116.99(d,J＝272.5Hz),34.45,24.12.19FNMR(565MHz,chloroform-d)δ-65.19.HRMS(ESI)calcd for C21H16F3N3O[M+H]+384.1324,found 384.1319.
化合物2-13
采用实施例5中化合物2-1的制备方法，将其中的4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-(叔丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率44％。1H NMR(600MHz,chloroform-d)δ9.56(d,J＝2.1Hz,1H),8.97(d,J＝2.1Hz,1H),8.26(d,J＝9.3Hz,1H),8.15–8.10(m,2H),7.71–7.65(m,2H),7.59–7.53(m,2H),1.40(s,9H).13C NMR(151MHz,chloroform-d)δ167.52,166.24(q,J＝44.7Hz),151.47,148.63,147.49,14 0.65,136.61,136.38,131.61,129.89,127.42,127.11,126.13,125.85,118.66,115.94(q,J＝273.7Hz),34.67,31.32.19F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C22H18F3N3O[M+H]+398.1480,found 398.1475.
化合物2-14
采用实施例5中化合物2-1的制备方法，将其中的4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-([1,1'-联苯]-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率29％。1H NMR(600MHz,chloroform-d)δ9.58(d,J＝2.1Hz,1H),8.99(d,J＝2.0Hz,1H),8.29(d,J＝8.5Hz,1H),8.20–8.15(m,2H),7.83–7.80(m,2H),7.76(d,J＝8.3Hz,2H),7.69–7.66(m,2H),7.49(t,J＝7.7Hz,2H),7.43–7.37(m,1H).13C NMR(151MHz,chloroform-d)δ167.49,166.26(q,J＝44.8Hz),148.76,147.70,141.12,140.31,140.29,138.38,136.39,131.47,130.07,128.91,127.84,127.81,127.65,127.43,127.08,126.06,118.78,115.94(q,J＝273.3Hz).19F NMR(565MHz,chloroform-d)δ-65.18.HRMS(ESI)calcdfor C24H14F3N3O[M+H]+418.1167,found 418.1162.
化合物2-15
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-胺，得到黄色固体，收率32％。1H NMR(600MHz,DMSO-d6)δ9.33(d,J＝2.2Hz,1H),8.96(d,J＝2.4Hz,1H),8.46(d,J＝2.5Hz,1H),8.36(d,J＝2.1Hz,1H),8.14(dd,J＝8.8,2.1Hz,1H),8.09(d,J＝8.7Hz,1H),7.90(dd,J＝8.6,2.6Hz,1H),6.60(d,J＝8.6Hz,1H),6.25(s,2H),2.73(s,3H).13C NMR(151MHz,DMSO-d6)δ177.94,166.14,159.70,147.47,147.07,146.52,137.24,135.70,134.96,129.61,129.42,127.56,123.94,122.48,120.02,108.20,12.16.HRMS(ESI)calcd for C17H13N5O[M+H]+304.1198,found 304.1191.
化合物2-16
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-丁基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率17％。1H NMR(600MHz,chloroform-d)δ9.53(d,J＝2.1Hz,1H),8.88(d,J＝1.9Hz,1H),8.22(d,J＝8.6Hz,1H),8.09–8.03(m,2H),7.67–7.61(m,2H),7.35–7.31(m,2H),2.72(s,3H),2.71–2.67(m,2H),1.70–1.63(m,2H),1.41(dt,J＝14.8,7.4Hz,2H),0.96(t,J＝7.4Hz,3H).13C NMR(151MHz,chloroform-d)δ177.03,166.67,148.24,148.07,143.04,140.33,137.12,135.38,130.84,129.78,129.16,127.63,127.29,125.73,120.50,35.32,33.60,22.40,13.97,12.45.HRMS(ESI)calcd for C22H21N3O[M+H]+344.1763,found 344.1757.
化合物2-17
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷，得到白色固体，收率11％。1H NMR(600MHz,chloroform-d)δ9.53(d,J＝2.1Hz,1H),8.88(d,J＝2.2Hz,1H),8.23(d,J＝8.6Hz,1H),8.10–8.04(m,2H),7.64(d,J＝8.0Hz,2H),7.33(d,J＝7.9Hz,2H),2.72(s,3H),2.67(t,J＝7.6Hz,2H),1.71(h,J＝7.4Hz,2H),1.00(t,J＝7.3Hz,3H).13C NMR(151MHz,chloroform-d)δ177.04,166.64,148.13,148.00,142.83,140.37,137.14,135.45,130.89,129.71,129.21,127.64,127.28,125.73,120.52,37.70,24.53,13.87,12.45.HRMS(ESI)calcd for C22H21N3O[M+H]+330.1606,found330.1601.
化合物2-18
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率10％。1H NMR(600MHz,chloroform-d)δ9.54(d,J＝2.0Hz,1H),8.88(d,J＝2.0Hz,1H),8.22(d,J＝8.6Hz,1H),8.09–8.03(m,2H),7.68–7.63(m,2H),7.35(d,J＝7.9Hz,2H),2.77–2.70(m,5H),1.31(t,J＝7.6Hz,3H).13C NMR(151MHz,chloroform-d)δ177.04,166.67,148.26,148.09,144.36,140.32,137.20,135.38,130.84,129.79,128.62,127.63,127.38,125.76,120.51,28.56,15.56,12.45.HRMS(ESI)calcdfor C20H17N3O[M+H]+316.1450,found 316.1442.
化合物2-19
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-(对甲苯基)-1,3,2-二氧硼烷，得到白色固体，44％。1H NMR(600MHz,chloroform-d)δ9.53(d,J＝2.0Hz,1H),8.87(d,J＝2.0Hz,1H),8.21(d,J＝8.5Hz,1H),8.08–8.02(m,2H),7.64–7.59(m,2H),7.32(d,J＝7.8Hz,2H),2.72(s,3H),2.43(s,3H).13C NMR(151MHz,acetone-d6)δ178.51,167.35,149.23,148.53,140.62,138.61,137.54,135.71,131.02,130.60,130.50,128.47,127.91,126.60,121.49,20.98,12.15.HRMS(ESI)calcd for C19H15N3O[M+H]+302.1293,found 302.1290.
化合物2-20
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼烷，得到白色固体，收率44％。1H NMR(600MHz,chloroform-d)δ9.54(d,J＝2.1Hz,1H),8.88(d,J＝2.4Hz,1H),8.24(d,J＝8.7Hz,1H),8.10–8.03(m,2H),7.74–7.69(m,2H),7.52(t,J＝7.7Hz,2H),7.46–7.40(m,1H),2.72(s,3H).13C NMR(151MHz,chloroform-d)δ177.05,166.61,148.27,148.21,140.36,139.83,135.44,130.86,129.84,129.06,128.04,127.58,127.45,126.11,120.57,12.44.HRMS(ESI)calcd for C18H13N3O[M+H]+288.1137,found 288.1131.
化合物2-21
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚，得到白色固体，收率24％。1H NMR(600MHz,DMSO-d6)δ9.72(s,1H),9.35(t,J＝1.5Hz,1H),8.99(d,J＝2.1Hz,1H),8.37(d,J＝2.0Hz,1H),8.17–8.08(m,2H),7.69(d,J＝8.4Hz,2H),6.96–6.90(m,2H),2.73(s,3H).13C NMR(151MHz,DMSO-d6)δ177.95,166.15,157.88,147.55,147.22,139.23,135.13,130.24,129.59,129.36,128.41,127.49,124.92,120.03,116.05,12.16.HRMS(ESI)calcd for C18H13N3O2[M+H]+304.1086,found304.1081.
化合物2-22
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-2，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率17％。1H NMR(600MHz,DMSO-d6)δ9.38(d,J＝2.1Hz,1H),9.04(d,J＝2.0Hz,1H),8.45(d,J＝2.0Hz,1H),8.20(dd,J＝8.7,2.2Hz,1H),8.15(d,J＝8.7Hz,1H),7.85–7.79(m,2H),7.14–7.08(m,2H),3.84(s,3H),2.74(s,3H).13C NMR(151MHz,DMSO-d6)δ178.00,166.14,159.56,147.68,147.42,138.86,135.25,131.21,130.33,129.44,128.41,127.48,125.40,120.09,114.70,55.36,12.17.HRMS(ESI)calcdfor C19H15N3O2[M+H]+318.1243,found 318.1237.
化合物2-23
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-胺，得到黄色固体，42％。1H NMR(600MHz,DMSO-d6)δ9.33(d,J＝2.2Hz,1H),8.96(d,J＝2.0Hz,1H),8.47(d,J＝2.5Hz,1H),8.38(d,J＝2.0Hz,1H),8.14(dd,J＝8.8,2.1Hz,1H),8.09(d,J＝8.8Hz,1H),7.90(dd,J＝8.7,2.6Hz,1H),6.60(d,J＝8.6Hz,1H),6.24(s,2H),3.07(q,J＝7.5Hz,2H),1.38(t,J＝7.5Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.68,166.01,159.70,147.46,147.05,146.55,137.23,135.66,134.97,129.56,129.41,127.56,123.95,122.49,120.05,108.17,19.72,10.51.HRMS(ESI)calcdfor C18H15N5O[M+H]+318.1355,found 318.1348
化合物2-24
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率34％。1H NMR(600MHz,DMSO-d6)δ9.39(d,J＝2.2Hz,1H),9.05(d,J＝2.1Hz,1H),8.38(d,J＝2.1Hz,1H),8.15(d,J＝8.7Hz,1H),8.09(dd,J＝8.7,2.1Hz,1H),7.18(t,J＝7.7Hz,1H),7.01(t,J＝2.0Hz,1H),6.96(dt,J＝7.7,1.2Hz,1H),6.67–6.62(m,1H),5.25(s,2H),3.08(q,J＝7.6Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.73,166.02,149.39,147.88,147.56,140.21,139.78,135.36,130.57,129.72,129.35,127.37,125.99,120.11,114.88,113.86,112.54,19.73,10.53.HRMS(ESI)calcd for C19H16N4O[M+H]+317.1402,found 317.1396
化合物2-25
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率35％。1H NMR(600MHz,DMSO-d6)δ9.41(d,J＝2.2Hz,1H),9.02(d,J＝2.1Hz,1H),8.23(d,J＝2.0Hz,1H),8.14(d,J＝8.6Hz,1H),7.94(dd,J＝8.6,2.0Hz,1H),7.15–7.08(m,2H),6.82(dd,J＝8.1,1.2Hz,1H),6.73–6.67(m,1H),5.01(s,2H),3.08(q,J＝7.6Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.75,166.05,147.63,147.51,145.53,139.20,135.27,132.87,130.47,129.19,128.86,128.40,127.40,124.53,119.91,116.86,115.58,19.73,10.54.HRMS(ESI)calcd for C19H16N4O[M+H]+317.1402,found 317.1397
化合物2-26
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-丁基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率38％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.0Hz,1H),8.90(d,J＝2.0Hz,1H),8.23(d,J＝8.7Hz,1H),8.11–8.04(m,2H),7.66–7.62(m,2H),7.33(d,J＝8.1Hz,2H),3.04(q,J＝7.6Hz,2H),2.72–2.66(m,2H),1.70–1.63(m,2H),1.51(t,J＝7.6Hz,2H),1.41(h,J＝7.4Hz,2H),0.96(t,J＝7.4Hz,3H).13C NMR(151MHz,acetone-d6)δ182.41,167.18,149.16,148.50,143.62,140.63,137.75,135.74,131.03,130.55,129.89,128.48,127.93,126.64,121.55,35.70,34.30,22.87,20.56,14.07,10.80.HRMS(ESI)calcd for C23H23N3O[M+H]+358.1919,found 358.1914
化合物2-27
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-(4-丙基苯基)-1,3,2-二氧硼烷，得到白色固体，收率44％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.2Hz,1H),8.90(d,J＝2.2Hz,1H),8.23(d,J＝8.7Hz,1H),8.11–8.04(m,2H),7.67–7.62(m,2H),7.35–7.31(m,2H),3.04(q,J＝7.6Hz,2H),2.70–2.64(m,2H),1.76–1.66(m,2H),1.51(t,J＝7.6Hz,3H),1.00(t,J＝7.4Hz,3H).13C NMR(151MHz,acetone-d6)δ182.42,167.19,149.21,148.53,143.40,140.63,137.81,135.72,131.02,130.59,129.94,128.48,127.92,126.65,121.56,38.09,25.16,20.55,13.94,10.80.HRMS(ESI)calcd for C22H21N3O[M+H]+344.1763,found 344.1758
化合物2-28
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率48％。1H NMR(600MHz,chloroform-d)δ9.55(d,J＝2.1Hz,1H),8.90(d,J＝2.4Hz,1H),8.23(d,J＝8.7Hz,1H),8.11–8.03(m,2H),7.65(d,J＝8.0Hz,2H),7.35(d,J＝7.9Hz,2H),3.04(q,J＝7.6Hz,2H),2.74(q,J＝7.6Hz,2H),1.51(t,J＝7.6Hz,2H),1.31(t,J＝7.6Hz,3H).13C NMR(151MHz,acetone-d6)δ182.41,167.18,149.18,148.51,145.02,140.63,137.78,135.73,131.03,130.56,129.33,128.47,128.01,126.64,121.54,28.95,20.55,15.88,10.80.HRMS(ESI)calcd for C21H19N3O[M+H]+330.1606,found 330.1601
化合物2-29
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-(对甲苯基)-1,3,2-二氧硼烷，得到白色固体，收率39％。1H NMR(600MHz,chloroform-d)δ9.54(d,J＝2.1Hz,1H),8.89(d,J＝1.9Hz,1H),8.22(d,J＝8.7Hz,1H),8.09–8.02(m,2H),7.64–7.60(m,2H),7.32(d,J＝7.8Hz,2H),3.04(q,J＝7.6Hz,2H),2.43(s,3H),1.50(t,J＝7.7Hz,3H).13C NMR(151MHz,methanol-d4)δ183.28,167.51,148.78,148.72,141.82,139.37,137.83,137.15,132.07,130.84,129.80,129.23,128.30,126.88,122.21,21.22,21.06,11.02.HRMS(ESI)calcd for C20H17N3O[M+H]+316.1450,found 316.1444
化合物2-30
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼烷，得到白色固体，收率35％。1H NMR(600MHz,chloroform-d)δ9.56(d,J＝2.1Hz,1H),8.91(d,J＝2.0Hz,1H),8.24(d,J＝8.7Hz,1H),8.12–8.04(m,2H),7.75–7.70(m,2H),7.52(t,J＝7.7Hz,2H),7.46–7.40(m,1H),3.04(q,J＝7.6Hz,2H),1.51(t,J＝7.6Hz,3H).13CNMR(151MHz,acetone-d6)δ182.40,167.15,149.29,148.70,140.62,140.44,135.76,131.05,130.65,129.83,128.76,128.41,128.06,127.06,121.58,20.55,10.79.HRMS(ESI)calcd for C19H15N3O[M+H]+302.1293,found 302.1289
化合物2-31
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚，得到白色固体，收率23％。1H NMR(600MHz,DMSO-d6)δ9.72(s,1H),9.36(d,J＝2.1Hz,1H),9.00(d,J＝2.2Hz,1H),8.40(d,J＝2.2Hz,1H),8.17–8.09(m,2H),7.73–7.65(m,2H),6.96–6.90(m,2H),3.07(q,J＝7.5Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.71,166.02,157.87,147.55,147.22,139.21,135.15,130.21,129.59,129.34,128.40,127.50,124.94,120.07,116.04,19.73,10.53.HRMS(ESI)calcdfor C19H15N3O2[M+H]+318.1243,found 318.1237
化合物2-32
采用实施例5中化合物2-1的制备方法，将其中化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率62％。1H NMR(600MHz,DMSO-d6)δ9.37(d,J＝2.0Hz,1H),9.02(d,J＝2.0Hz,1H),8.45(d,J＝2.1Hz,1H),8.18(dd,J＝8.7,2.0Hz,1H),8.13(d,J＝8.8Hz,1H),7.81(d,J＝8.6Hz,2H),7.13–7.08(m,2H),3.83(s,3H),3.07(q,J＝7.5Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.71,166.00,159.54,147.66,147.39,138.80,135.23,131.19,130.25,129.41,128.37,127.47,125.38,120.10,114.67,55.34,19.72,10.51.HRMS(ESI)calcd for C20H17N3O2[M+H]+332.1399,found 332.1394.
化合物2-33
采用实施例5中化合物2-1的制备方法，将其中4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉，得到黄色固体，收率16.7％。1H NMR(600MHz,DMSO-d6)δ9.41(d,J＝2.2Hz,1H),9.15(d,J＝2.1Hz,1H),8.50(d,J＝2.1Hz,1H),8.25(dd,J＝8.8,2.2Hz,1H),8.15(d,J＝8.7Hz,1H),7.78(d,J＝8.9Hz,2H),7.11(d,J＝8.9Hz,2H),3.84–3.69(m,4H),3.26–3.18(m,4H).13CNMR(151MHz,DMSO-d6)δ165.33,163.55(q,J＝43.6Hz),149.31,146.13,145.07,137.47,134.46,128.95,127.65,127.08,126.00,125.65,123.10,116.62,114.10(q,J＝273.4Hz),113.56,64.34,46.23.19F NMR(565MHz,DMSO-d6)δ-64.64.HRMS(ESI)calcd forC22H17F3N4O2[M+H]+427.1382,found 427.1376.
化合物2-34
采用实施例5中化合物2-1的制备方法，将其中4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率17.5％。1H NMR(600MHz,DMSO-d6)δ9.43(d,J＝2.2Hz,1H),9.15(d,J＝2.0Hz,1H),8.54(d,J＝2.1Hz,1H),8.23(dd,J＝8.7,2.2Hz,1H),8.18(d,J＝8.7Hz,1H),7.92–7.88(m,2H),7.41–7.36(m,2H).13CNMR(151MHz,DMSO-d6)δ167.02,165.34(q,J＝44.5,44.0Hz),162.42(d,J＝245.4Hz),148.18,147.49,138.36,136.46,135.30(d,J＝3.4Hz),131.13–131.00(m),129.60,129.30(d,J＝8.1Hz),127.18,126.58,118.52,116.12(d,J＝21.3Hz),115.86(q,J＝273.2Hz).19F NMR(565MHz,DMSO-d6)δ-64.66,-114.30.HRMS(ESI)calcd forC18H9F4N3O[M+H]+360.0760,found 360.0755.
化合物2-35
采用实施例5中化合物2-1的制备方法，将其中4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-氯苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率9.52％。1H NMR(600MHz,DMSO-d6)δ9.45(d,J＝2.2Hz,1H),9.18(d,J＝2.1Hz,1H),8.59(d,J＝2.2Hz,1H),8.25(dd,J＝8.8,2.2Hz,1H),8.20(d,J＝8.8Hz,1H),7.91–7.87(m,2H),7.64–7.60(m,2H).13C NMR(151MHz,DMSO-d6)δ166.30,165.33–163.76(m),147.63,146.96,137.35,136.93,135.84,132.60,130.23,129.00,128.54,128.29,126.48,126.10,117.88,115.17(d,J＝273.4Hz).19F NMR(565MHz,DMSO-d6)δ-64.65.HRMS(ESI)calcd forC18H9ClF3N3O[M+H]+376.0464,found 376.0459.
化合物2-36
采用实施例5中化合物2-1的制备方法，将其中4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺，得到黄色固体，收率13.6％。1H NMR(600MHz,DMSO-d6)δ9.39(d,J＝2.1Hz,1H),9.14(d,J＝2.3Hz,1H),8.46(d,J＝2.2Hz,1H),8.24(dd,J＝8.8,2.1Hz,1H),8.14(d,J＝8.8Hz,1H),7.78–7.72(m,2H),6.91–6.85(m,2H),2.99(s,6H).13C NMR(151MHz,DMSO-d6)δ166.95,165.13(q,J＝43.8Hz),150.26,147.56,146.37,139.40,135.91,130.41,129.16,127.54,127.33,125.59,123.95,118.16,115.70(q,J＝273.0,272.6Hz),112.56,29.82.19F NMR(565MHz,DMSO-d6)δ-64.63.HRMS(ESI)calcd for C20H15F3N4O[M+H]+385.1276,found385.1271.
化合物2-37
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率23.8％。1H NMR(600MHz,DMSO-d6)δ9.39(d,J＝2.1Hz,1H),9.04–9.00(m,1H),8.48(d,J＝2.0Hz,1H),8.20–8.12(m,2H),7.92–7.86(m,2H),7.41–7.34(m,2H),3.07(q,J＝7.5Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.73,165.94,163.18,161.55,147.82(d,J＝10.3Hz),138.07,135.44(d,J＝3.4Hz),135.37,130.39,129.54,129.27(d,J＝8.5Hz),127.33,126.40,120.20,116.06(d,J＝21.3Hz),19.72,10.51.19F NMR(565MHz,DMSO-d6)δ-114.44.HRMS(ESI)calcd forC19H14FN3O[M+H]+320.1199,found 320.1194.
化合物2-38
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酰胺，得到白色固体，收率21.7％。1H NMR(600MHz,DMSO-d6)δ10.12(s,1H),9.39(d,J＝2.1Hz,1H),9.03(d,J＝2.0Hz,1H),8.48(d,J＝2.0Hz,1H),8.20(dd,J＝8.8,2.1Hz,1H),8.15(d,J＝8.7Hz,1H),7.82(d,J＝8.7Hz,2H),7.76(d,J＝8.6Hz,2H),3.09(q,J＝7.5Hz,2H),2.10(s,3H),1.40(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.56,168.38,165.82,147.59,147.33,139.38,138.55,135.10,133.11,130.03,129.28,127.33,126.26,125.42,119.97,119.29,24.00,19.55,10.34.HRMS(ESI)calcdfor C21H18N4O2[M+H]+359.1508,found 359.1503.
化合物2-39
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉，得到白色固体，收率24％。1H NMR(600MHz,DMSO-d6)δ9.37(d,J＝2.1Hz,1H),9.04(d,J＝2.2Hz,1H),8.46(d,J＝2.1Hz,1H),8.20(dd,J＝8.8,2.2Hz,1H),8.13(d,J＝8.7Hz,1H),7.81–7.75(m,2H),7.14–7.08(m,2H),3.80–3.75(m,4H),3.24–3.19(m,4H),3.09(q,J＝7.6Hz,2H),1.40(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.56,165.87,150.84,147.40,146.98,138.80,134.99,129.89,129.18,128.86,127.57,127.40,124.55,119.90,115.15,65.93,47.85,19.55,10.35.HRMS(ESI)calcd forC23H22N4O2[M+H]+387.1821,found 387.1816.
化合物2-40
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，得到白色固体，收率26.1％。1H NMR(600MHz,DMSO-d6)δ9.33(d,J＝2.2Hz,1H),8.97(d,J＝2.0Hz,1H),8.39(d,J＝2.1Hz,1H),8.14(dd,J＝8.9,2.1Hz,1H),8.07(d,J＝8.7Hz,1H),7.75(d,J＝2.2Hz,1H),7.58(dd,J＝8.4,2.2Hz,1H),6.94(d,J＝8.4Hz,1H),5.66(s,2H),3.07(q,J＝7.5Hz,2H),1.39(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.68,166.01,147.50,147.11,144.98,138.18,135.07,129.76,129.31,127.53,127.49,127.24,126.52,124.40,120.06,117.81,115.83,19.72,10.51.HRMS(ESI)calcd for C19H15ClN4O[M+H]+351.1013,found 351.1007.
化合物2-41
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为2-(4-氯苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，得到白色固体，收率27.3％。1H NMR(600MHz,DMSO-d6)δ9.42(s,1H),9.07(s,1H),8.56(s,1H),8.20(q,J＝9.3,8.8Hz,2H),7.89(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),3.08(d,J＝8.9Hz,2H),1.40(d,J＝8.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.61,165.76,147.84,147.80,137.62,135.31,133.01,130.11,129.47,129.03,128.81,127.18,126.48,120.10,19.55,10.34.HRMS(ESI)calcd for C19H14ClN3O[M+H]+336.0904,found336.0898.
化合物2-42
采用实施例5中化合物2-1的制备方法，将其中的化合物6-1改为化合物6-3，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺改为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄腈，得到白色固体，收率27.9％。1H NMR(600MHz,DMSO-d6)δ9.45(d,J＝2.1Hz,1H),9.10(d,J＝2.0Hz,1H),8.67(d,J＝2.0Hz,1H),8.28(dd,J＝8.8,2.2Hz,1H),8.22(d,J＝8.7Hz,1H),8.11–8.06(m,2H),8.05–8.00(m,2H),3.09(q,J＝7.5Hz,2H),1.40(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ181.65,165.71,148.26,148.15,143.27,137.03,135.51,132.95,130.10,129.63,127.92,127.53,127.12,120.23,118.67,110.59,19.55,10.34.HRMS(ESI)calcd for C20H14N4O[M+H]+327.1246,found 327.1239.
实施例5：
体外抗肠道病毒活性实验
实验材料与试剂：
病毒株：肠道病毒D68型
细胞系：人横纹肌瘤细胞(RD)
实验试剂：DMEM高糖培养基，Gibco公司胎牛血清，Promega公司CellTiter-
化学发光细胞活力检测试剂，细胞生长液为含10％胎牛血清的DMEM高糖培养基，细胞维持液和病毒生长液均为2％胎牛血清的DMEM高糖培养基。
实验方法：
化合物抗EV-D68活性测定：根据待测化合物及阳性化合物的质量及分子量，将待测化合物和阳性化合物用DMSO溶解至100mM。将RD细胞按照1.5×105/mL浓度接种白壁透明底的96孔板，置入CO2孵箱，37℃培养24h。用细胞维持液稀释待测化合物，起始浓度为800μM，之后3倍稀释，10个梯度，将稀释好的化合物加入到96孔板，每孔50μL，随后加入100TCID50的EV-D68病毒稀释液，每孔50μL，3天后用CellTiter-
化学发光细胞活力检测试剂盒测定每孔的细胞活力值。
化合物对细胞毒性测定：将RD细胞按照1.5×105/mL的浓度接种白壁透明底的96孔板，用细胞维持液稀释待测化合物，起始浓度为400μM，之后3倍稀释，10个梯度，将稀释好的化合物加入到96孔板，每孔100μL，72h后用CellTiter-
化学发光细胞活力检测试剂盒测定每孔的细胞活力值。
式1和式2所示化合物的抗肠道病毒D68型(EV-D68)的活性和对RD细胞毒性测定结果分别如下表所示，其中，EC50代表半数有效浓度(50％effective concentration)，CC50代表半数毒性浓度(50％cytotoxic concentration)，SI代表选择指数(selection index)，SI＝CC50/EC50。
表1式1所示化合物抗EV-D68的活性及对RD细胞的毒性
表2式2所示化合物抗EV-D68的活性及对RD细胞的毒性
结果显示，本发明的式1和式2所示化合物如实施例制备的化合物1-1至1-9和化合物2-1至2-42对肠道病毒EV-D68具有抑制活性。
最后应当说明的是：以上实施例仅用以说明本发明的技术方案而非对其限制；尽管参照较佳实施例对本发明进行了详细的说明，所属领域的普通技术人员应当理解；依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换；而不脱离本发明技术方案的精神，其均应涵盖在本发明请求保护的技术方案范围当中。
Claims (11)
1.式1所示的化合物、其药学上可接受的盐，其水合物或其溶剂合物，
其中：
R1选自C1-8烷基；
R2选自5-14元取代或者未取代的芳基、5-14元取代或者未取代的杂芳基。
2.权利要求1所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，R1选自C1-8烷基；
优选地，R1选自C1-6烷基；
更优选的，R1选自C1-3烷基；
最优选地，R1为乙基。
3.权利要求1或2所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，
R2选自5-14元芳基、5-14元杂芳基，所述5-14元芳基或5-14元杂芳基任选地被一个或者多个Ra取代，每个Ra各自独立地为氢、氨基、C1-4烷基、氨酰基。
更优选地，R2为苯基或含1-2个氮原子的5-6元杂芳基(例如4H-吡唑基)，所述苯基任选地被一个或者多个Ra取代，每个Ra各自独立地选自氢、氨基、C1-4烷基、氨酰基；
最优选地，R2选自
4.权利要求1-3任一项所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，式1所示化合物选自以下：
5.式2所示的化合物、其药学上可接受的盐，其水合物或其溶剂合物，
其中：
R3为C1-12取代或者未取代的烷基；
R4选自5-14元取代或者未取代的芳基、5-14元取代或者未取代的杂芳基。
6.权利要求5所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，R3选自C1-12烷基，所述C1-12烷基任选地被一个或者多个Rb取代，每个Rb各自独立地为氢或卤素；
优选地，R3选自C1-6烷基，所述C1-6烷基任选地被一个或者多个Rb取代，每个Rb各自独立地为氢或卤素；
更优选地，R3选自C1-4烷基，所述C1-4烷基任选地被一个或者多个Rb取代，每个Rb各自独立地为氢或卤素(例如氟)。
最优选地，R3选自三氟甲基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
7.权利要求5或6的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，R4选自5-8元芳基、5-8元杂芳基，所述5-8元芳基或5-8元杂芳基任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、卤素、氨基、氰基、(C1-4烷基)2-N-、C1-8烷基、C1-3酰胺基，C1-6烷氧基、羟基、5-8元芳基、5-6元单杂环基；
优选地，R4选自5-6元芳基、5-6元单杂芳基，所述5-6元芳基或5-6元单杂芳基任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、卤素、氨基、氰基、C1-8烷基、C1-3酰胺基，(C1-4烷基)2-N-、C1-6烷氧基、羟基、5-8元芳基、5-6元含N和/或O单杂环基；
更优选地，R4选自苯基，吡啶基，所述苯基或吡啶基任选地被一个或者多个Rc取代，每个Rc各自独立地选自氢、氟、氯、氨基、氰基、二甲氨基、乙酰氨基、C1-4烷基、C1-2烷氧基、羟基、苯基、吗啉基；
最优选地，R4选自
8.权利要求5-7任一项所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，其中，式2所示化合物选自以下：
9.药物组合物，其包含权利要求1-8任一项所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物，任选地，还包含一种或多种药学上可接受的载体或赋形剂；
优选地，所述药物组合物的制剂形式为片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂。
10.制备权利要求5-8任一项所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物的方法，其包括：
以下述结构式6所示的中间体为原料，与R4-B(OH)2所示的硼酸衍生物反应，反应通式如下：
优选地，结构式6所示的中间体是由下述结构式5所示的中间体为原料，与(R3-CO)2O所示的酸酐反应制备得到，反应通式如下：
优选地，结构式5所示中间体是由6-溴喹啉-3-甲腈与羟胺反应得到。
优选地，权利要求5-8任一项所述的化合物由如下所示的反应通式制备得到：
其中，R3和R4如权利要求5-7任一项所限定。
11.权利要求1-8任一项所述的化合物、其药学上可接受的盐，其水合物或其溶剂合物或者权利要求9所述的药物组合在制备药物中的用途，所述药物用于以下的一种或多种：
1)预防或治疗肠道病毒感染或肠道病毒感染引起的疾病；
2)抑制肠道病毒在细胞(例如哺乳动物细胞)中的复制或繁殖；
优选地，所述肠道病毒选自脊髓灰质炎病毒(Poliovirus，PV)、柯萨奇A病毒(Coxsackie A Virus，CV-A)、柯萨奇B病毒(Coxsackie B Virus，CV-B)、埃可病毒(Echovirus)、肠道病毒71型(Enterovirus 71，EV71)、肠道病毒D68型(Enterovirus D68，EV-D68)或其任意组合；
优选地，所述肠道病毒选自EV-D68；
优选地，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹、非特异性发热性疾病、肺炎、毛细支气管炎、脑炎和心肌炎、急性迟缓性脊髓炎或其任意组合；
优选地，所述肠道病毒感染引起的疾病选自手足口病、呼吸系统感染、中枢神经系统疾病、急性迟缓性麻痹或其任意组合；
优选地，所述哺乳动物包括牛科动物、马科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，例如是人、猫、狗、猴或猪。
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