CN116041230B - 一种nlrp3炎症小体抑制剂及其制备方法和应用 - Google Patents

一种nlrp3炎症小体抑制剂及其制备方法和应用 Download PDF

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CN116041230B
CN116041230B CN202310036113.6A CN202310036113A CN116041230B CN 116041230 B CN116041230 B CN 116041230B CN 202310036113 A CN202310036113 A CN 202310036113A CN 116041230 B CN116041230 B CN 116041230B
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compound
synthesis
nmr
dmso
acid
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CN116041230A (zh
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江余祺
李晓杨
黄超
秦冲
孙思敏
于启欣
徐文方
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Qingdao Haiji Biomedical Co ltd
Ocean University of China
Qingdao Marine Biomedical Research Institute Co Ltd
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Qingdao Haiji Biomedical Co ltd
Ocean University of China
Qingdao Marine Biomedical Research Institute Co Ltd
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Abstract

本发明公开了一种如通式（I）所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、溶剂合物、氘代物、或前药及其制备方法和应用。本发明提供的通式（I）化合物表现出了显著的抑制NLRP3炎症小体的活性，且部分化合物都在几百个纳摩尔，优于已报道的同类型的化合物格列本脲、JC124。此外，在体内抗炎实验中代表性化合物I‑41能显著抑制LPS诱导的小鼠急性腹膜炎中的IL‑1β的释放，而不影响另一炎症因子TNF‑α的释放，表明化合物能特异性的抑制NLRP3炎症小体，具有一定的选择性。

Description

一种NLRP3炎症小体抑制剂及其制备方法和应用
技术领域
本发明涉及化学合成药物技术领域，具体涉及一种含有2-氨基茚满母核的NLRP3炎症小体抑制剂及其制备方法和应用。
发明背景
炎症小体是负责激活炎症反应的胞内大分子蛋白复合体，它对机体免疫系统具有重要的调节作用。在目前发现的炎症小体中，NLRP3炎症小体是研究最多，最具代表性的。NLRP3炎症小体主要是由模式识别受体NOD样受体(NLRP3)、接头蛋白凋亡相关点样蛋白(ASC)和效应蛋白半胱氨酸天冬酶原-1(pro-caspase-1)组成的多聚蛋白复合物(ImmunolRev.2011,243,136-151)。NLRP3炎症小体的活化需要启动和激活两个步骤，启动步骤为信号通过刺激细胞表面的Toll样受体，激活NF-κB通路，使pro-IL-1β和NLRP3蛋白的表达量增加；激活步骤为在病原相关分子模式(PAMPs)、危险相关分子模式(DAMPs)的刺激下，NLRP3蛋白通过N端PYD与ASC的PYD结合，募集procaspase-1，组装成NLRP3炎症小体复合物。Procaspase-1裂解活化成caspase-1后，一方面促进促炎因子IL-1β、IL-18成熟和分泌，另一方面切割消皮素D(Gasdermin D)，介导细胞焦亡(细胞炎症性坏死)，引起炎性损伤(AdvImmunol.2020,145,55-93)。NLRP3蛋白能够识别多种病原及危险相关分子模式，包括病毒微生物、核酸、细菌分泌物、微生物细胞壁成分、ATP、尿酸晶体(MSU)、amyloidβ、胆固醇晶体等。正因为NLRP3识别的分子模式复杂多样，所以NLRP3炎症小体与多种疾病如冷吡啉相关周期性综合症(又称NLRP3相关自身炎症性疾病)、阿尔兹海默症、帕金森症、痛风、类风湿性关节炎、炎症性肠病、非典型肺炎、动脉粥样硬化、非酒精性脂肪性肝炎、多发性硬化和慢性阻塞性肺病、创伤性脑伤、心力衰竭、冠状动脉疾病、骨关节炎等的发生发展密切相关(NatRev Immunol.2017,17,208-214)。因此，NLRP3炎症小体有望作为治疗多种疾病的潜在靶点。
通过随机筛选，已发现了一些针对NLRP3炎症小体通路的小分子抑制剂。目前报道的大部分化合物都在微摩尔级别，活性有待进一步提高(Eur J Med Chem.2020,185,111822)。磺酰脲类化合物MCC950靶向于NLRP3蛋白中NACHT结构域的ATP酶结合位点，尽管MCC950抑制IL-1β产生的IC50为7.5nM，但其在类风湿性关节炎二期临床研究因存在肝毒性被终止(Nat Rev Drug Discov.2018,17,588-606)。因此，急需寻找结构多样、活性更高、安全性更高的NLRP3炎症小体抑制剂，为治疗NLRP3炎症小体相关疾病提供更优的策略。
发明内容
针对上述问题，本发明第一目的在于提供一种具有良好的治疗NLRP3相关疾病的活性，并表现出优异的NLRP3炎症小体抑制作用的抑制剂。
本发明的第二目的在于提供一种NLRP3炎症小体的抑制剂化合物的制备方法，该方法以价格低廉、易得的原料、较高的产率合成所需化合物，并且化合物的性质稳定。
本发明的第三目的在于提供上述化合物用于制备NLRP3炎症小体抑制剂及治疗NLRP3-相关疾病的用途。
为了研发潜在的NLRP3炎症小体抑制剂并用于治疗NLRP3-相关疾病，本发明在深入研究当前NLRP3炎症小体抑制不足的基础上，设计和成了一类母核为2-氨基茚满的NLRP3炎症小体抑制剂，并在体外实验中验证了这类化合物能够抑制NLRP3炎症小体的激活，从而可以治疗与NLRP3炎症小体相关的疾病，比如：神经性疾病及脑损伤，如阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤；炎症性疾病，如炎症性肠病、急性肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急，慢性胃炎、急，慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染休克；代谢性疾病，如痛风、非酒精性脂肪肝、II型糖尿病；心血管疾病，包括心衰、动脉粥样硬化；肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷吡啉相关周期性综合症和系统性红斑狼疮。
第一方面，本发明提供了一种NLRP3炎症小体抑制剂，其特征在于以2-氨基茚满为母核的磺酰胺类化合物，所述NLRP3炎症小体抑制剂是具有如通式(1)所示的化合物，或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、溶剂合物、氘代物、或前药：
其中，R1选自
R2选自H、
R3选自
其中，R4取代基可以是一个或多个且在环上的位置不定，选自卤素、甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、2-甲氧基乙氧基、N,N-2-甲基乙氧基、氰基、异丙基、三氟甲基；
其中，R5取代基为H、卤素、C1-C6取代的烷基、OH、CN、CF3、CHF2、NO2、 其中n＝0-6，X5为O、N或S；
其中，R6取代基为H、卤素、CF3、C1-C4取代的烷基；
其中，R7取代基是一个或多个且在环上的位置不定，选自H、卤素、C1-C4取代的烷基、OH、羟基取代的C1-C3烷基；
其中，R8取代基是一个或多个且在环上的位置不定，选自H、卤素、C1-C4取代的烷基、OH、OCH3、羟基取代的C1-C3烷基、
其中，R9取代基是一个或多个且在环上的位置不定，选自H、卤素、OH、OCH3、
其中，R10取代基为H、卤素、C1-C4取代的烷基、OH、OCH3、羟基取代的C1-C3烷基、
其中，R11取代基为H、Boc；
其中，X1取代基为O、S、NH；X2取代基为N、CH；X3取代基为O、S；X4取代基为O、CH2、NH。
在一些技术方案中，所述的R1优选为
进一步优选：R1为
最优选：R1为
在一些技术方案中，所述的R2选自H、
优选：R2为
进一步优选：R2为
优选：R5为其中n＝0-6，X5为O、N、S；
最优选：R5为
R6为H、卤素、CF3、C1-C4取代的烷基；
优选：R6为卤素(氟、氯、溴)、CF3；
进一步优选：R6为氯、氟；
在一些技术方案中，所述的R3选自
优选：R3为 其中X1取代基为O、S、NH；n＝0-3；R9取代基为可以是一个或多个且在环上的位置不定，选自H、卤素、OH、OCH3、/>R10取代基为H、卤素、C1-C4取代的烷基、OH、OCH3、羟基取代的C1-C3烷基、/>
进一步优选：R3为
其中X1取代基为O、S；n＝0-1；R10取代基为H、卤素、OCH3；
最优选：R3为其中X1取代基为O、S；R10取代基为H、OCH3；
在一些技术方案中，所述的R4取代基可以是一个或多个且在环上的位置不定，选自卤素、甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、2-甲氧基乙氧基、N,N-2-甲基乙氧基、氰基、异丙基、三氟甲基；
优选：R4取代基为卤素、甲氧基；
最优先：R4取代基为甲氧基。
在一些技术方案中，所述的X1取代基为O、S、NH；X2取代基为N、CH；X3取代基为O、S；X4取代基为O、CH2、NH。
优选的：X1取代基为O、S；X2取代基为N、CH；X3取代基为O、S；X4取代基为O、CH2。
在一些具体的技术方案中，所述的化合物结构式如下：
除非特别定义，本文中提供的化合物和盐还可以包含存在于中间体或最终化合物中的原子的所有同位素。同位素包括具有相同的原子序数但是具有不同的质量数的那些原子。
如本文中所使用的，“卤素”是指F、Cl、Br或I。在一些实施方案中，卤素为F、Cl或Br。在一些实施方案中，卤素为F。在一些实施方案中，卤素为Cl。在一些实施方案中，卤素为Br。在一些实施方案中，卤素为I。
在本文中使用短语“药学上可接受的”以指如下的那些化合物、材料、组合物和/或剂型，其在合理的医学判断的范围内，适合用于与人类和动物的组织接触而没有过度的毒性、刺激、过敏反应或者其它问题或并发症，与合理的获益/风险比相称。
其中药学上可接受的盐是指所公开的化合物的衍生物，其中通过将现有的酸或碱部分转化为其盐形式来修饰母体化合物。药学上可接受的盐的实例包括但不限于例如胺等碱性残基的无机酸盐或有机酸盐；和例如羧酸等酸性残基的碱金属盐或有机盐等。本申请的药学上可接受的盐包括例如由无毒的无机酸或有机酸形成的母体化合物的常规的无毒盐,主要包括无机酸盐如硫酸、硝酸、氢溴酸、磷酸、盐酸、硼酸、氨基磺酸等；或有机酸如乙酸、丙酸、丁酸、丙戊酸、樟脑酸、癸酸、己酸、辛酸、辛二酸、碳酸、肉桂酸、羟基乙酸、三氟乙酸、己二酸、丙酮酸、水杨酸、甲磺酸、海藻酸、2-羟基丙酸、2-氧代丙酸、硬脂酸、乳酸、柠檬酸、草酸、丙二酸、琥珀酸、焦谷氨酸、抗坏血酸、天冬氨酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、羟基马来酸、棕榈酸、肉桂酸、异丁酸、月桂酸、扁桃酸,、马来酸、富马酸、苹果酸、酒石酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、2-羟基-1,2,3-丙三酸、葡糖酸、葡萄糖醛酸、谷氨酸、戊二酸、甲酸、反丁烯二酸、粘酸、龙胆酸、乙基磺酸、苯甲磺酸、对甲苯磺酸、环己基亚磺酸、羟乙基磺酸、乙烷二磺酸、4-(笏甲氧羰基氨基)丁酸、二氯乙酸、1，2-乙烷二磺酸、樟脑-10-磺酸、2，4-二羟基苯甲酸、α-酮戊二酸、1-羟基-2-萘甲酸、对乙酰氨基苯甲酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸、全反式维甲酸。可以通过常规的化学方法从包含碱性或酸性部分的母体化合物合成本申请的药学上可接受的盐。通常，可以通过使这些化合物的游离酸或碱形式与化学计量量的适当的碱或酸在水中或在有机溶剂中或者在二者的混合物中反应来制备这样的盐；通常，非水性介质如醚、乙酸乙酯、醇类(例如，甲醇、乙醇、异丙醇或丁醇)或乙腈(MeCN)是优选的。
第二方面，本发明还提供了如上所述的通式(1)的化合物或其药学上可接受的盐的制备方法，包括以下步骤：
以化合物1为起始原料，先用三氟乙酰基保护氨基得到化合物2，进一步与氯磺酸反应得到中间体3；所述中间体3与氨基化合物反应得到化合物4，中间体4在碳酸钾的条件下将三氟乙酰基脱掉得到中间体5；中间体5与取代羧酸或者取代磺酰氯等化合物通过缩合反应得到目标化合物6(通式I化合物)；或者中间体5与取代苯甲醛经席夫碱还原生成仲胺后再与取代羧酸或取代磺酰氯等化合物缩合得到目标化合物6(通式I化合物)。
第三方面，本发明还提供了一种药物组合物，其包含如上所述的通式(I)所示的化合物或其光学异构体、或其药学上可接受的盐、溶剂合物、氘代物、或前药以及药学上可接受的稀释剂或载体。所述化合物或其光学异构体、或其药学上可接受的盐、溶剂合物、氘代物、或前药的含量为0.1-99.9wt％。
第四方面，本发明提供了如上所述的通式(I)的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、溶剂合物、氘代物、或前药在制备NLRP3炎症小体抑制剂中的用途。
第五方面，本发明还提供了如上所述的通式(I)的化合物或其光学异构体、非对映异构体、消旋体或其药学上可接受的盐、溶剂合物、氘代物、或前药在制备与NLRP3炎症小体异常活化相关的疾病的药物中的用途。
所述与NLRP3炎症小体异常活化相关疾病包括阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤、亨廷顿病等神经性疾病及脑损伤；炎症性肠病、急性肺炎、非典型肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急，慢性胃炎、急，慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染休克等炎症性疾病；痛风、非酒精性脂肪肝、II型糖尿病等代谢性疾病；心力衰竭、动脉粥样硬化、急性心肌梗塞、冠状动脉疾病等心血管疾病；肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷吡啉相关周期性综合症或系统性红斑狼疮。
本发明的有益效果：本发明的有益效果在于基于NLRP3炎症小体抑制剂的药物设计，为治疗NLRP3炎症小体异常活化相关疾病提供新的化学实体。
1、本发明在现有技术的基础上，针对现有NLRP3炎症小体抑制剂的不足，提供了一类母核为2-氨基茚满的全新骨架的NLRP3炎症小体抑制剂。
2、本发明中提供的化合物对NLRP3炎症小体都具有显著的抑制活性，且部分化合物的抑制IC50都在几百个纳摩尔，优于已报道的同类型的化合物格列本脲、JC124。同时代表性化合物I-40能显著的抑制LPS诱导的小鼠急性腹膜炎中的炎症因子IL-1β的生成，而对另一个炎症因子TNF-α无抑制作用，表明化合物I-41选择性抑制NLRP3炎症小体通路。同时I-41的抗炎活性与目前报道的活性最好的NLRP3炎症小体抑制剂MCC950相当。
附图说明
图1是化合物I-41(10mg/kg)及MCC950(10mg/kg)对LPS诱导的C57BL/6小鼠产生IL-1β(a)和TNF-α(b)的影响图。
图中，*P<0.05，**P<0.01，NS-无统计学意义。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
本发明的化合物可形成水合物或溶剂合物。本领域技术人员已知将化合物与水一起冻干时所形成的水合物或在溶液中与合适的有机溶剂浓缩时形成溶剂合物的方法。
本发明包含含有治疗量本发明化合物的药物，和一种或多种药学上可接受载体和/或赋形剂的药物组合物。载体包括如盐水，缓冲盐水，葡萄糖，水，甘油，乙醇和它们的结合物，下文更详细地论述。如果需要，该组合物还可以包含较小量的润湿剂或乳化剂，或pH缓冲剂。该组合物可以是液体，悬浮液，乳剂，片剂，丸剂，胶囊，持续释放制剂或粉末。该组合物可以用传统的黏合剂和载体如三酸甘油酯配制成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，纤维素和碳酸镁等等。视需要制剂而定，配制可以设计混合，制粒和压缩或溶解成分。在另一个途径中，该组合物可以配制成纳米颗粒和肠溶性的微丸。
使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖，石膏粉，蔗糖，滑石，凝胶，琼脂，果胶，阿拉伯胶，硬脂酸镁，硬脂酸等等。固体载体可以包括一种或多种可能同时作为增香剂，润滑剂，增溶剂，悬浮剂，填料，助流剂，压缩助剂，粘合剂或片剂-崩解剂的物质；它还可以是包封材料。在粉末中，载体为精细粉碎的固体，它与精细粉碎的活性成分的混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合，以需要的形状和大小压缩。粉末和片剂优选包含至多99％活性成分。合适的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，糖，乳糖，糊精，淀粉，凝胶，纤维素，甲基纤维素，羧甲基纤维素钠盐，聚乙烯吡咯烷酮烷酮，低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆，花生油，橄榄油，水等等。液体载体用于制备溶液，悬浮液，乳剂，糖浆，酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可接受的液体载体如水，有机溶剂，二者的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，增甜剂，增香剂，悬浮剂，增稠剂，颜料，粘度调节剂，稳定形或渗透压-调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠盐溶液)，醇(包括一元醇和多元醇，例如乙二醇)和它们的衍生物，和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来，例如，静脉内，肌内，腹膜内或皮下注射。注射时可单次推入或逐渐注入，如30分钟的静脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料，如单硬脂酸甘油酯或二硬脂酸甘油酯，还可包括蜡，乙基纤维素，羟丙基甲基纤维素，异丁烯酸甲酯等等。当制剂用于口服时，公认PHOSALPG-50(磷脂(phospholipid)与1,2-丙二醇浓缩，A.Nattermann&Cie.GmbH)中的0.01％吐温80用于其他化合物的可接受的口服制剂的配制，可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体，制剂可以为肠溶性胞衣片剂，被放入硬胶囊中肠溶性微丸或锭剂或糖锭形式。固体载体的量在很大程度上变化，但是优选从约25mg到约1.0g。如果使用液体载体，制剂可以为糖浆，乳剂，软胶囊，在安瓿或小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
各种释放系统是已知的并且可以用于化合物或其他各种制剂的给药，这些制剂包括片剂，胶囊，可注射的溶液，脂质体中的胶囊，微粒，微胶囊，等等。引入的方法包括但是不局限于皮肤的，皮内，肌内，腹膜内的，静脉内的，皮下的，鼻腔内的，肺的，硬膜外的，眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药，例如通过注入或快速浓注，通过上皮的或粘膜线路(例如，口腔粘膜，直肠和肠粘膜，等等)吸收或通过负载药物的支架以及可以于其他生物活性剂一起给药。可以全身或局部给药。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案，以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的试验材料均为本领域常规的试验材料，均可通过商业渠道购买得到。
本发明中通式(I)的化合物的制备如路线一、路线二或路线三所示，各取代基如发明内容部分所定义。
合成路线一：
a反应试剂和反应条件:(a)TFAA；(b)氯磺酸,DCM；(c)丙胺,K2CO3,DMF；(d)K2CO3,MeOH,H2O；(e)各种有机酸,EDCI,HOBT,TEA,DCM；(f)(5-氯-2-甲氧苯基)甲胺,硫代氯甲酸苯酯或4-硝基苯基氯甲酸酯，TEA,DCM。
合成路线二：
a反应试剂和反应条件:(a)1-溴丙烷,K2CO3,DMF；(b)乙酸,NaCNBH3,MeOH；(c)2-(噻吩-3-基)乙酸,EDCI,HOBT,TEA,DCM；(d)1-溴-2-甲氧乙烷,K2CO3,DMF；(e)乙酸,NaCNBH3,MeOH；(f)各种有机酸,EDCI,HOBT,TEA,DCM。
合成路线三：
a反应试剂和反应条件:(a)各种伯胺,TEA,DCM；(b)K2CO3,MeOH,H2O；(c)乙酸,NaCNBH3,MeOH；(d)各种有机酸,EDCI,HOBT,TEA,DCM；(e)各种有机酸,EDCI,HOBT,TEA,DCM。
下面通过具体的实施例对本发明进行详细说明，但这些例举性实施方式的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
路线一中化合物的制备：
实施例1:N-(2,3-二氢-1H-茚-2-基)-2,2,2-三氟乙酰胺(2)的合成：
将二氨基茚满盐酸盐(2g,，16.8mmol)置于100mL茄型瓶中，冰浴降温后，加入三氟乙酸酐(4.4mL，33.6mmol)，搅拌10min后，室温反应4-5h。TLC检测原料反应完全，将茄型瓶置于冰浴下降温后，加饱和碳酸氢钠猝灭，DCM萃取(10mL×3)，有机相用饱和食盐水洗涤1次，有机相用无水Na2SO4干燥。经柱色谱分离，得到化合物2，(2.5g，收率69.4％)，为透明油状物，直接用于下一步合成。1H NMR(400MHz,DMSO-d6)δ9.71(d,J＝6.9Hz,1H),7.23(d,J＝8.7Hz,2H),7.19-7.14(m,2H),4.55(d,J＝8.2Hz,1H),3.23(dd,J＝16.6,8.4Hz,2H),2.92(d,J＝9.7Hz,2H)。
实施例2:2-(2,2,2-三氟乙酰胺基)-2,3-二氢-1H-茚-5-磺酰氯(3)的合成
将化合物2(2.5g，11.6mmol)置于100mL茄型瓶中，加入20mL DCM，-10℃下降温，滴加氯磺酸(7.6mL，116mmol)搅5min后，室温反应1.5h。TLC检测原料反应完全，冰水猝灭，DCM萃取(10mL×3),饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后得到粗品化合物3(2.2g，收率61％)，直接用于下一步合成。ESI-MS m/z：284.85[M+H]+。
实施例3:2,2,2-三氟-N-(5-(正丙基磺酰基)-2,3-二氢-1H-茚-2-基)乙酰胺(4)的合成。
将正丙胺(0.36g，6.12mmol)置于100mL茄型瓶中，加入30mLDCM，冰浴降温后，加三乙胺(1.2mL，9.18mmol)再将化合物3(2g，6.12mmol)滴入反应液，室温反应1.5h。TLC检测原料反应完全，将反应液用1％的柠檬酸洗1次，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到化合物4(1.53g，收率73％)，用于下一步合成。1HNMR(400MHz,DMSO-d6)δ9.75(d,J＝7.0Hz,1H),7.63(s,1H),7.59(d,J＝9.1Hz,1H),7.49(d,J＝6.0Hz,1H),7.43(d,J＝7.9Hz,1H),4.60(p,J＝7.0Hz,1H),3.34-3.27(m,2H),3.02-2.94(m,2H),2.66(d,J＝6.8Hz,2H),1.38(h,J＝7.3Hz,2H),0.80(t,J＝7.5Hz,3H)。
实施例4:2-氨基正丙基-2,3-二氢-1H-茚-5-磺酰胺(5)的合成
将2,2,2-三氟-N-(5-(正丙基磺酰基)-2,3-二氢-1H-茚-2-基)乙酰胺(1.53g，4.37mmol)置于100mL茄型瓶中，加入20mL MeOH、5mL H2O，再将碳酸钾(1.8g，13.11mmol)室温反应过夜。TLC检测原料反应完全，蒸除有机溶剂后，EA萃取(10mL×3)，将有机相用饱和碳酸氢钠洗1次，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后得到粗产品化合物4(0.8g，收率73％)，直接用于下一步合成。1H NMR(400MHz,DMSO-d6)δ7.57(s,1H),7.53(d,J＝9.1Hz,1H),7.36(d,J＝7.8Hz,1H),3.74(d,J＝8.5Hz,1H),3.07(d,J＝14.2Hz,2H),2.69-2.58(m,4H),1.37(q,J＝7.4Hz,2H),0.83-0.77(m,3H)。
实施例5:5-氯-2-甲氧基-N-(5-(正丙基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-01)的合成。
将5-氯-2-甲氧基苯甲酸(150mg，0.804mmol)置于25mL茄形瓶中，加入4mL THF溶解，冰浴降温后依次加入三乙胺(106mg，1.045mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(199mg，1.045mmol)、1-羟基苯并三氮唑(HOBT)(141mg，1.045mmol)室温搅拌30min，再加入2-氨基正丙基-2,3-二氢-1H-茚-5-磺酰胺(265mg，1.045mmol)。室温反应过夜。TLC检测原料反应完全，将溶剂蒸除，EA萃取(10mL×3)，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经柱色谱分离，得到目标化合物I-01。(300mg，收率59％)。1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝7.1Hz,1H),7.63(s,1H),7.58(dd,J＝10.2,2.1Hz,2H),7.52–7.45(m,2H),7.43(d,J＝7.9Hz,1H),7.13(d,J＝8.9Hz,1H),4.72(h,J＝7.0Hz,1H),3.81(s,3H),3.37–3.25(m,2H),3.05–2.93(m,2H),2.66(q,J＝6.9Hz,2H),1.37(h,J＝7.3Hz,2H),0.79(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ164.39,156.00,146.63,142.96,139.40,131.65,129.56,126.19,125.51,125.45,124.65,122.97,114.51,56.71,50.87,44.82,41.76,39.31,39.23,22.86,11.62。
实施例6:5-氯-2-丙氧基-N-(5-(N-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-02)的合成。
将实施例5中5-氯-2-甲氧基苯甲酸替换成5-氯-2-丙氧基苯甲酸，其余与实施例5相同。收率63％。1H NMR(400MHz,)δ8.42(d,J＝7.2Hz,1H),7.66(d,J＝2.8Hz,2H),7.59(dd,J＝7.9,1.7Hz,1H),7.53–7.43(m,3H),7.11(d,J＝8.9Hz,1H),4.74(qd,J＝7.1,2.5Hz,1H),3.99–3.90(m,2H),3.31(t,J＝5.9Hz,2H),3.00–2.87(m,2H),2.72–2.61(m,2H),1.53(h,J＝7.3Hz,2H),1.37(p,J＝7.3Hz,2H),0.81(dt,J＝9.2,7.4Hz,6H).13C NMR(126MHz,DMSO-d6)δ163.92,155.56,146.47,142.83,139.52,131.98,129.85,125.60,125.58,125.32,124.77,123.14,115.37,70.92,51.04,44.81,39.56,22.88,22.23,11.61,10.80。
实施例7:5-氯-2-(2-甲氧基乙氧基)-N-(5-(N-丙基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-03)的合成。
将实施例5中5-氯-2-甲氧基苯甲酸替换成5-氯-2-甲氧基乙氧基苯甲酸，其余与实施例5相同，收率55％。1H NMR(400MHz,)δ8.48(d,J＝6.8Hz,1H),7.74(s,1H),7.65(s,1H),7.59(d,J＝8.0Hz,1H),7.50(t,J＝7.2Hz,2H),7.45(d,J＝7.9Hz,1H),7.18(d,J＝8.8Hz,1H),4.74(h,J＝6.6Hz,1H),4.19(s,2H),3.60(d,J＝4.4Hz,2H),3.40(d,J＝6.6Hz,2H),3.21(s,3H),2.94(dd,J＝15.4,6.5Hz,2H),2.66(q,J＝6.6Hz,2H),1.37(h,J＝7.0Hz,2H),0.79(t,J＝7.3Hz,3H).13C NMR(126MHz,DMSO-d6)δ163.66,155.48,146.46,142.80,139.51,132.29,130.18,130.15,125.57,125.54,125.30,124.90,124.86,123.06,115.99,70.26,68.60,58.46,50.89,44.81,39.53,39.44,22.87,11.60。
实施例8:5-氯-2-(2-(甲氨基)乙氧基)-N-(5-(N-丙基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-04)的合成。
将实施例5中5-氯-2-甲氧基苯甲酸替换成5-氯-2-(2-(甲氨基)乙氧基-苯甲酸，其余与实施例5相同，收率45％。1H NMR(500MHz,DMSO-d6)δ8.72(d,J＝6.9Hz,1H),7.72(s,1H),7.65(s,1H),7.59(d,J＝9.1Hz,1H),7.52(dd,J＝8.8,2.8Hz,1H),7.48(t,J＝5.9Hz,1H),7.44(d,J＝7.9Hz,1H),7.21(d,J＝8.9Hz,1H),4.76(dq,J＝13.8,6.5Hz,1H),4.22(s,2H),3.38(dd,J＝16.1,7.7Hz,2H),2.97(dd,J＝16.6,6.1Hz,2H),2.67(q,J＝6.9Hz,3H),1.37(dq,J＝14.6,7.3Hz,2H),1.24(d,J＝7.0Hz,2H),0.79(t,J＝7.4Hz,3H)。
实施例9:2,5-二氯-N-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-05)的合成。
将实施例5中5-氯-2-甲氧基苯甲酸替换为2,5-二氯苯甲酸，其余与实施例5相同。收率57％。1H NMR(400MHz,DMSO-d6)δ8.94–8.88(m,1H),7.64(s,1H),7.59(d,J＝8.0Hz,1H),7.55–7.47(m,4H),7.44(d,J＝7.9Hz,1H),4.74–4.63(m,1H),3.34–3.28(m,2H),3.03–2.91(m,2H),2.66(q,J＝6.6Hz,2H),1.37(p,J＝7.2Hz,2H),0.80(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ165.16,146.55,142.90,139.44,138.84,132.06,131.71,130.89,129.22,128.95,125.49,123.01,50.83,44.82,39.25,39.16,22.87,11.62。
实施例10:5-(3-氯苯基-3-羟基-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)吡啶酰胺(I-06)的合成。
与实施例5类似，收率64％。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.47(d,J＝8.0Hz,1H),8.45(s,1H),7.86(s,1H),7.74(s,2H),7.61(s,1H),7.55(t,J＝7.6Hz,1H),7.51(d,J＝5.0Hz,2H),7.46(t,J＝6.0Hz,1H),7.40(d,J＝7.9Hz,1H),4.81(h,J＝7.7Hz,1H),3.26–3.08(m,4H),2.64(q,J＝6.8Hz,2H),1.35(h,J＝8.5,7.9Hz,2H),0.77(t,J＝7.3Hz,3H).13C NMR(126MHz,DMSO-d6)δ168.85,157.71,146.48,142.84,139.77,139.44,138.45,138.38,134.42,131.41,130.96,129.29,127.50,126.53,125.52,125.42,123.93,122.93,50.56,44.83,38.68,38.60,22.90,22.87,11.63。
实施例11:5-(3-氯苯基)-3-丙氧基-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)吡啶酰胺(I-07)的合成。
与实施例5类似，收率53％。1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝7.0Hz,1H),8.44–8.40(m,1H),7.87(d,J＝2.3Hz,1H),7.79–7.69(m,2H),7.61(d,J＝4.3Hz,1H),7.55(dd,J＝8.0,2.0Hz,1H),7.53–7.44(m,3H),7.40(d,J＝7.9Hz,1H),4.69(h,J＝6.6Hz,1H),4.08(t,J＝6.3Hz,2H),3.26(d,J＝6.7Hz,2H),2.95(dd,J＝16.5,5.4Hz,2H),2.63(q,J＝6.7Hz,2H),1.66(h,J＝7.1Hz,2H),1.35(q,J＝7.4Hz,2H),0.93(t,J＝7.4Hz,3H),0.77(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ165.34,153.24,146.70,143.62,143.03,139.39,139.10,138.48,136.64,134.38,131.32,128.81,127.41,126.38,125.49,125.46,123.01,119.40,70.42,50.62,50.07,44.82,44.57,39.30,39.22,22.89,22.39,11.63,10.86。
实施例12:5-(3-氯苯基)-3-(2-甲氧基乙氧基)-N-(5-(正丙基磺酰基)-2,3-二氢-1H-茚-2-基)吡啶酰胺(I-08)的合成。
与实施例5类似，收率62％。1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝7.2Hz,1H),8.45(s,1H),7.88(s,1H),7.81(s,1H),7.73(d,J＝7.0Hz,1H),7.61(s,1H),7.58–7.43(m,4H),7.41(d,J＝8.0Hz,1H),4.75–4.66(m,1H),4.28(t,J＝4.4Hz,2H),3.63(t,J＝4.5Hz,2H),3.30–3.24(m,5H),2.95(dd,J＝16.6,5.7Hz,2H),2.63(q,J＝6.8Hz,2H),1.39–1.28(m,2H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ165.15,153.19,146.71,143.38,143.04,139.41,139.02,138.89,136.69,134.41,131.35,128.87,127.45,126.40,125.49,123.01,119.90,70.64,68.76,58.82,50.56,44.82,39.30,39.22,22.88,11.62。
实施例13:N-(5-(N-丙基磺酰基)-2,3-二氢-1H-吲哚-2-基)噻吩-2-磺酰胺(I-09)的合成。
与实施例5类似，收率64％。1H NMR(400MHz,DMSO-d6)δ8.29(d,J＝6.6Hz,1H),8.00–7.95(m,1H),7.65(d,J＝2.9Hz,1H),7.55(d,J＝8.7Hz,2H),7.47(t,J＝5.8Hz,1H),7.36(d,J＝7.7Hz,1H),7.22(t,J＝4.3Hz,1H),4.04(h,J＝6.3Hz,1H),3.10(ddd,J＝19.0,11.7,7.6Hz,2H),2.81(dt,J＝16.7,5.1Hz,2H),2.63(q,J＝6.7Hz,2H),1.37(dt,J＝14.3,7.2Hz,2H),0.78(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ145.79,142.39,142.16,139.51,133.16,132.23,128.27,125.58,125.35,122.83,54.61,44.79,39.51,39.40,22.86,11.61。
实施例14:5-氯-N-(5-(N-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)噻吩-2-磺酰胺(I-10)的合成。
与实施例5类似，收率72％。1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.58(s,1H),7.55(d,J＝4.4Hz,2H),7.47(t,J＝5.8Hz,1H),7.38(d,J＝7.9Hz,1H),7.30(d,J＝3.9Hz,1H),4.12–4.02(m,1H),3.15(dt,J＝16.8,8.3Hz,2H),2.83(dd,J＝15.8,4.7Hz,2H),2.64(q,J＝6.7Hz,2H),1.36(h,J＝7.0Hz,2H),0.78(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ145.70,142.08,140.84,139.54,134.95,132.08,128.51,125.59,125.36,122.86,54.61,44.81,44.79,39.52,39.41,22.87,11.61。
实施例15:5-溴-N-(5-(N-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)噻吩-2-磺酰胺(I-11)的合成。
与实施例5类似，收率68％。1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝6.3Hz,1H),7.58(s,1H),7.56(d,J＝8.2Hz,1H),7.51(d,J＝3.9Hz,1H),7.47(t,J＝5.9Hz,1H),7.40–7.36(m,2H),4.06(q,J＝6.8Hz,1H),3.14(dt,J＝16.7,8.4Hz,2H),2.83(dd,J＝16.1,5.0Hz,2H),2.63(q,J＝6.7Hz,2H),1.36(h,J＝7.0Hz,2H),0.78(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ145.71,143.43,139.57,139.53,132.83,131.89,125.58,125.37,122.86,118.74,54.61,44.81,44.79,39.53,39.42,22.87,11.61。
实施例16:2-(3-(5-氯-2-甲氧基苄基)硫脲基)-正丙基-2,3-二氢-1H茚-5-磺酰胺(I-13)的合成。
将(5-氯-2-甲氧基苯基)甲胺(241mg，1.16mmol)置于25mL茄形瓶中，加入8mL DCM溶解，冰浴降温后加入TEA(325mg，3.47mmol)，然后将邻苯基羰基氯代硫酸酯(200mg，1.16mmol)溶于2mL DCM滴入反应液，室温反应2h。TLC检测原料反应完全，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后得到粗品化合物直接用作下一步合成。(200mg，收率59.5％)。将上步制备的邻苯基(5-氯-2-甲氧基苯基)氨基硫酸酯(215mg，0.7mmol)置于25mL茄形瓶中，加入5mL DCM溶解，再加入TEA(92mg，0.73mmol)，再将2-氨基正丙基-2,3-二氢-1H-茚-5-磺酰胺(187mg，0.73mmol)，室温反应过夜。TLC检测原料反应完全，蒸除有机溶剂后，用饱和NaHCO3洗涤1次，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后,经柱色谱分离，得到目标化合物I-13。(180mg，收率55％)。1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.61(s,1H),7.55(d,J＝7.9Hz,1H),7.45(t,J＝5.9Hz,1H),7.41(d,J＝7.9Hz,1H),7.25(dd,J＝8.7,2.7Hz,1H),7.10(d,J＝2.6Hz,1H),6.97(d,J＝8.7Hz,1H),4.90(s,1H),4.56(s,2H),3.77(s,2H),3.27(dd,J＝7.2,3.3Hz,1H),2.85(dd,J＝16.8,5.1Hz,2H),2.62(q,J＝6.7Hz,2H),1.34(h,J＝7.2Hz,2H),0.76(t,J＝7.3Hz,3H).13C NMR(126MHz,DMSO-d6)δ155.90,146.55,142.89,139.46,129.59,127.94,125.55,125.53,124.31,123.06,112.69,56.21,44.82,22.89,11.60。
实施例17:2-(3-(5-氯-2-甲氧基苄基)脲基)-正丙基-2,3-二氢-1H-茚-5-磺酰胺(I-12)的合成。
与实施例16类似，收率54％。1H NMR(400MHz,DMSO-d6)δ7.59(s,1H),7.53(dd,J＝7.9,1.8Hz,1H),7.45(t,J＝5.9Hz,1H),7.39(d,J＝7.9Hz,1H),7.23(dd,J＝8.7,2.6Hz,1H),7.08(d,J＝2.7Hz,1H),6.94(d,J＝8.7Hz,1H),6.40(d,J＝7.2Hz,1H),6.14(t,J＝6.2Hz,1H),4.35(h,J＝6.4Hz,1H),4.10(d,J＝6.0Hz,2H),3.76(s,2H),3.17(ddd,J＝16.7,7.1,4.3Hz,2H),2.74(dd,J＝16.4,5.3Hz,2H),2.62(q,J＝6.7Hz,2H),1.34(h,J＝7.1Hz,2H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ158.10,155.84,146.86,143.18,139.35,131.19,127.64,127.47,125.50,125.44,124.37,123.01,112.60,56.15,51.46,44.82,44.52,38.19,22.89,11.62,11.55。
路线二中化合物的制备：
实施例18:N-(5-氯-2-丙氧基苄基)-N-(5-(5-丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(噻吩-3-基)乙酰胺(I-14)的合成。
a)、5-氯-2-(正丙氧基)苯甲醛(7)的合成。
将5-氯-2-羟基苯甲醛(1.2g，7.67mmol)置于100mL茄型瓶中，加8mL DMF溶解，加入碳酸钾(2.65g，19.2mmol)搅拌10min，再加入1-溴丙烷(1.40g，11.5mmol)，100℃下反应2-3h。TLC检测原料反应完全，向反应液中加入EA(5mL)，H2O洗涤8次，EA萃取(10mL×3)，将有机相用饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后得到粗产品化合物7(1.05g，收率88％)，直接用于下一步合成。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.69–7.60(m,3H),7.24(d,J＝9.1Hz,1H),4.05(t,J＝4.2Hz,2H),1.81–1.69(m,5H),0.96(s,3H)。
b)、5-氯-2-丙氧基苄基氨基-N-丙基-2，3-二氢茚-5-磺酰胺(8)的合成。
将2-氨基正丙基-2,3-二氢-1H-茚-5-磺酰胺(0.8g，3.15mmol)置于100mL茄型瓶中，加10mL MeOH溶解，再将5-氯-2-(正丙氧基)苯甲醛(0.624g，3.15mmol)加入反应液，室温反应1h，再加2d冰醋酸，室温反应1h，冰浴降温后滴加氰基硼氢化钠(0.99g，15.75mmol)室温反应2h。TLC检测原料反应完全，加冰水淬灭，将MeOH旋干，DCM萃取(10mL×3)，将有机相用饱和食盐水洗涤3次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到化合物8(0.9g，收率64％)，用于下一步合成。1H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.59(dd,J＝18.7,10.8Hz,3H),7.45(d,J＝7.9Hz,1H),7.42–7.32(m,1H),7.07(d,J＝8.9Hz,1H),4.48(s,1H),4.10–3.86(m,5H),3.17(d,J＝17.2Hz,2H),2.71–2.61(m,2H),1.78(q,J＝7.2Hz,2H),1.43–1.34(m,2H),1.05–0.97(m,3H),0.80(d,J＝7.1Hz,3H)。
c)、N-(5-氯-2-丙氧基苄基)-N-(5-(5-丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(噻吩-3-基)乙酰胺(I-14)的合成。
合成步骤：
将2-(噻吩-3-基)乙酸(0.036mg，0.25mmol)置于25mL茄型瓶中，加2mL DCM溶解，冰浴降温后依次加入三乙胺(0.033mg，0.33mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(0.063g，0.33mmol)、1-羟基苯并三氮唑(HOBT)(0.05g，0.33mmol)室温搅拌30min，再将5-氯-2-丙氧基苄基氨基-N-丙基-2，3-二氢茚-5-磺酰胺(144mg，0.33mmol)加入反应液，室温反应过夜。TLC检测原料反应完全，1mol/L HCl洗1次，饱和碳酸氢钠洗1次，饱和食盐水洗1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到目标化合物Ⅰ-14(80mg，收率55％)。1H NMR(400MHz,DMSO-d6)δ7.55–7.42(m,4H),7.38–7.28(m,2H),7.23–7.15(m,1H),7.08–7.01(m,1H),6.97–6.91(m,1H),6.87(d,J＝2.7Hz,1H),5.76(s,1H),4.53(s,1H),4.44–4.32(m,1H),4.03–3.99(m,1H),3.94(t,J＝6.4Hz,1H),3.85(t,J＝6.4Hz,1H),3.63(s,1H),3.10–2.94(m,3H),2.90–2.78(m,2H),2.65–2.58(m,2H),1.64(dq,J＝35.8,6.9Hz,2H),1.40–1.31(m,2H),0.95–0.74(m,6H).13C NMR(126MHz,DMSO-d6)δ171.30,171.20,162.73,155.17,154.56,146.48,145.73,142.77,142.08,139.51,139.23,136.01,135.70,129.34,128.98,128.93,128.69,128.49,127.50,127.01,126.63,126.38,126.35,125.50,125.30,125.22,124.62,124.46,122.93,122.76,122.69,113.78,113.37,70.07,69.82,58.21,56.55,45.34,44.78,36.59,36.53,36.22,36.03,35.97,35.73,31.22,22.85,22.36,22.30,11.60,10.82,10.74。
实施例19:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(噻吩-3-基)乙酰胺(I-15)的合成。
a)、5-氯-2-(2-甲氧基乙氧基)苯甲醛(9)的合成。
将5-氯-2-羟基苯甲醛(1.2g，7.67mmol)置于100mL茄型瓶中，加8mL DMF溶解，加入碳酸钾(2.65g，19.2mmol)搅拌10min，再加入1-溴-2-甲氧基乙烷(1.08mL，11.5mmol)，100℃下反应2-3h。TLC检测原料反应完全，向反应液中加入EA(5mL)，H2O洗涤8次，EA萃取(10mL×3)，将有机相用饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后得到粗产品化合物9(1.05g，收率64％)，直接用于下一步合成。1HNMR(500MHz,Chloroform-d)δ10.44(s,1H),7.77(d,J＝2.8Hz,1H),7.46(dd,J＝8.9,2.8Hz,1H),6.95(d,J＝8.9Hz,1H),4.24-4.20(m,2H),3.81-3.76(m,2H),3.44(s,3H)。
b)、2-(5-氯-2-(2-甲氧基乙氧基)苄基)-氨基)-正丙基-2,3-二氢-1H-茚-5-磺酰胺(10)的合成。
将2-氨基正丙基-2,3-二氢-1H-茚-5-磺酰胺(0.8g，3.15mmol)置于100mL茄型瓶中，加10mL MeOH溶解，再将5-氯-2-(2-甲氧基乙氧基)苯甲醛(0.67g，3.15mmol)加入反应液，室温反应1h，再加2滴冰醋酸，室温反应1h，冰浴降温后滴加氰基硼氢化钠(0.99g，15.75mmol)室温反应2h。TLC检测原料反应完全，加冰水淬灭，将MeOH旋干，DCM萃取(10mL×3)，将有机相用饱和食盐水洗涤3次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到化合物10(0.9g，收率64％)，用于下一步合成。1H NMR(500MHz,DMSO-d6)δ7.62(s,1H),7.58(dd,J＝7.8,1.7Hz,1H),7.46(t,J＝5.8Hz,1H),7.41(d,J＝8.4Hz,2H),7.31(dd,J＝8.8,2.7Hz,1H),7.04(d,J＝8.8Hz,1H),4.14(dd,J＝5.5,3.6Hz,2H),3.86(s,2H),3.73(t,J＝6.8Hz,1H),3.70-3.65(m,2H),3.23(dt,J＝16.8,7.1Hz,3H),3.06(q,J＝7.3Hz,2H),2.90(dt,J＝17.0,5.6Hz,2H),2.66(q,J＝6.8Hz,2H),1.37(h,J＝7.4Hz,2H),1.17(t,J＝7.3Hz,3H),0.79(t,J＝7.3Hz,3H)。
c)、N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(噻吩-3-基)乙酰胺(I-15)的合成。
将2-(噻吩-3-基)乙酸(0.036mg，0.25mmol)置于25mL茄型瓶中，加2mL DCM溶解，冰浴降温后依次加入三乙胺(0.033mg，0.33mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(0.063g，0.33mmol)、1-羟基苯并三氮唑(HOBT)(0.05g，0.33mmol)室温搅拌30min，在将2-(5-氯-2-(2-甲氧基乙氧基)苄基)-氨基)-正丙基-2,3-二氢-1H-茚-5-磺酰胺(150mg，0.33mmol)加入反应液，室温反应过夜。TLC检测原料反应完全，1mol/L HCl洗1次，饱和碳酸氢钠洗1次，饱和食盐水洗1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到I-15(80mg，收率55％)。1H NMR(400MHz,DMSO-d6)δ7.53–7.37(m,4H),7.31(dd,J＝9.6,5.7Hz,2H),7.21–7.14(m,1H),7.06–7.00(m,1H),6.96–6.92(m,1H),4.50(s,1H),4.43–4.29(m,1H),4.10(t,J＝4.5Hz,1H),4.00(dd,J＝9.4,5.6Hz,2H),3.64–3.55(m,1H),3.49(t,J＝4.6Hz,1H),3.14(d,J＝28.9Hz,3H),3.06–2.74(m,3H),2.58(q,J＝6.9Hz,2H),1.33(p,J＝7.2,6.7Hz,2H),0.74(t,J＝7.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ171.31,171.26,155.16,154.50,146.50,145.71,142.79,142.06,139.51,139.20,136.01,135.77,129.57,128.98,128.95,128.56,127.53,127.28,126.63,126.46,126.35,125.50,125.34,125.26,124.98,124.84,122.93,122.78,122.70,114.37,113.96,70.62,68.33,58.60,58.31,56.70,45.51,44.78,36.48,36.41,36.00,35.94,35.88,35.72,22.86,11.60。
实施例20:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)噻吩-2-甲酰胺(I-16)的合成。
合成路线与实施例19类似，产率52％。1H NMR(400MHz,DMSO-d6)δ7.78(d,J＝5.1Hz,1H),7.54(dd,J＝10.5,2.7Hz,2H),7.46(t,J＝5.9Hz,1H),7.44–7.39(m,1H),7.36(d,J＝7.9Hz,1H),7.33–7.29(m,1H),7.17(s,1H),7.10(t,J＝4.3Hz,1H),7.05(d,J＝8.7Hz,1H),5.08(s,1H),4.66(s,2H),4.09(t,J＝4.6Hz,2H),3.57–3.54(m,2H),3.33(s,2H),3.17(s,3H),3.16–3.10(m,2H),2.65–2.60(m,2H),1.36(q,J＝7.3Hz,2H),0.77(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ164.67,154.87,146.06,142.39,139.40,136.75,130.60,129.11,129.05,128.30,127.84,127.57,127.01,125.45,125.29,124.92,122.78,114.38,70.62,68.38,58.63,44.79,36.49,29.47,22.86,11.60。
实施例21:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)四氢呋喃-3-甲酰胺(I-17)的合成。
合成路线与实施例19类似，产率60％。1H NMR(400MHz,DMSO-d6)δ7.52(d,J＝10.6Hz,2H),7.44(t,J＝14.1Hz,1H),7.37–7.18(m,2H),7.05(d,J＝13.1Hz,1H),6.99–6.82(m,1H),5.01(dt,J＝107.3,8.8Hz,1H),4.45(d,J＝56.3Hz,2H),4.05(d,J＝35.7Hz,2H),3.81–3.61(m,4H),3.53(d,J＝32.8Hz,2H),3.25–3.07(m,5H),2.96(dt,J＝38.0,11.0Hz,3H),2.59(d,J＝7.8Hz,2H),2.21–1.86(m,2H),1.33(q,J＝7.7Hz,2H),0.76(d,J＝7.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ174.33,173.74,155.09,154.53,146.53,145.82,145.79,142.82,142.16,142.13,139.51,139.21,129.67,129.16,128.59,127.56,127.25,126.38,125.52,125.34,125.28,125.21,124.93,124.81,122.83,122.74,114.50,114.04,70.61,68.35,68.23,58.62,58.60,57.46,44.79,41.31,22.86,11.60。
实施例22:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(四氢呋喃-3-基)乙酰胺(I-18)的合成。
合成路线与实施例19类似，产率62％。1H NMR(400MHz,Chloroform-d)δ7.68–7.55(m,2H),7.22(dd,J＝8.7,2.4Hz,2H),6.99(dd,J＝43.4,2.6Hz,1H),6.77(dd,J＝25.6,8.7Hz,1H),4.61–4.36(m,3H),4.14–3.45(m,8H),3.34(d,J＝29.8Hz,4H),3.08(ddt,J＝44.6,16.5,8.7Hz,4H),2.95–2.64(m,4H),2.45–2.26(m,2H),1.66(s,2H),0.86(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ173.00,154.29,146.34,142.25,142.23,138.38,128.28,127.74,126.21,125.71,124.92,124.90,123.05,123.02,112.76,73.18,70.85,70.80,67.91,67.67,67.56,59.12,55.64,44.96,43.86,37.64,36.79,36.52,36.28,36.13,36.00,35.88,35.65,35.52,32.13,29.67,22.96,11.10。
实施例23:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)环己烷芳酰胺(I-19)的合成。
合成路线与实施例19类似，产率59％。1H NMR(400MHz,DMSO-d6)δ7.59–7.43(m,3H),7.40–7.30(m,1H),7.23(dd,J＝8.7,2.7Hz,1H),7.10–6.96(m,1H),6.83(d,J＝2.7Hz,1H),5.08(dt,J＝58.5,8.4Hz,1H),4.51–4.32(m,2H),4.09(dt,J＝34.7,4.5Hz,2H),3.57(dt,J＝27.4,4.6Hz,2H),3.18(d,J＝29.9Hz,5H),3.06–2.97(m,1H),2.92(ddd,J＝16.9,11.1,5.8Hz,2H),2.65–2.59(m,2H),1.84–1.53(m,6H),1.47–1.30(m,6H),0.78(td,J＝7.4,2.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ176.49,176.23,154.88,154.56,146.53,145.86,142.81,142.20,139.49,139.23,129.82,129.75,128.42,127.42,126.77,126.30,125.50,125.37,125.28,125.23,124.94,124.77,122.87,122.75,114.59,114.02,70.63,68.49,68.36,58.61,57.33,56.02,44.79,44.08,41.23,36.95,36.90,36.19,36.16,30.14,30.05,29.74,26.01,25.86,25.54,25.50,22.86,11.61,11.53。
实施例24:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)四氢-2H-吡喃-4-甲酰胺(I-20)的合成。
合成路线与实施例19类似，产率52％。1H NMR(400MHz,Chloroform-d)δ7.68–7.53(m,2H),7.24–7.11(m,2H),7.03(d,J＝2.6Hz,1H),6.89–6.71(m,1H),4.65–4.29(m,3H),4.12–3.86(m,4H),3.70–3.59(m,2H),3.51–3.21(m,5H),3.19–2.94(m,4H),2.87(q,J＝6.9Hz,2H),2.01(dq,J＝24.7,12.1,11.5Hz,2H),1.59–1.40(m,4H),0.86(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ175.80,154.17,146.46,142.35,138.37,128.33,128.25,126.29,125.71,124.88,123.01,112.88,109.99,70.80,68.01,67.05,59.10,55.61,44.98,43.40,38.85,36.51,36.18,29.29,29.26,22.98,11.09。
实施例25:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(四氢-2H-吡喃-4-基)乙酰胺(I-21)的合成。
合成路线与实施例19类似，产率61％。1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝9.3Hz,2H),7.24–7.11(m,1H),6.99(d,J＝40.3Hz,1H),6.76(dd,J＝26.1,8.7Hz,1H),4.44(d,J＝23.2Hz,2H),4.05(d,J＝25.5Hz,2H),4.00–3.88(m,2H),3.71–3.59(m,2H),3.50–3.39(m,2H),3.33(d,J＝28.7Hz,3H),3.13(dd,J＝16.4,8.4Hz,2H),3.00(dd,J＝16.4,8.4Hz,2H),2.86(q,J＝6.8Hz,2H),2.16(s,2H),1.67(d,J＝41.1Hz,4H),1.46(h,J＝7.1Hz,2H),0.85(t,J＝7.4Hz,3H)。
实施例26:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-5-氧代-N-(5-(N-丙基氨基磺酰基)-2，3-二氢-1H-茚-2-基)吡咯烷-2-甲酰胺(I-22)的合成。
合成路线与实施例19类似，产率58％。1H NMR(400MHz,DMSO-d6)δ7.97–7.62(m,1H),7.60–7.43(m,3H),7.41–7.05(m,2H),7.02–6.92(m,1H),5.11–4.80(m,1H),4.57–4.26(m,2H),4.21–4.02(m,2H),3.74–3.50(m,2H),3.32(s,2H),3.18(d,J＝33.9Hz,3H),3.09–2.85(m,2H),2.63(dt,J＝13.2,7.2Hz,2H),2.47(d,J＝6.8Hz,2H),2.19–1.85(m,2H),1.45–1.31(m,2H),0.78(t,J＝8.4Hz,3H)。
实施例27:2-((5-氯-2-(2-甲氧基乙氧基)苄基)(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)氨基甲酰基)乙酸苯酯(I-23)的合成。
合成路线与实施例19类似，产率54％。1H NMR(400MHz,)δ7.59–7.36(m,6H),7.35–7.25(m,3H),7.16(d,J＝2.7Hz,1H),7.03(d,J＝8.8Hz,1H),4.75(q,J＝7.6Hz,1H),4.53(p,J＝8.2Hz,1H),4.38(d,J＝18.2Hz,1H),4.11–3.94(m,2H),3.51(q,J＝6.1,5.3Hz,2H),3.41(s,2H),3.16(s,1H),3.13(s,3H),2.96–2.78(m,1H),2.61(dq,J＝20.7,7.1,6.7Hz,2H),2.33(d,J＝14.8Hz,3H),1.37–1.28(m,2H),0.76(t,J＝8.0Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.56,168.21,154.59,146.83,139.57,130.75,130.20,129.19,127.99,127.66,126.73,126.58,125.57,125.29,124.78,123.89,122.78,114.24,70.59,68.37,59.73,58.58,44.80,44.74,22.85,21.28,21.07,11.58。
实施例28:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-2-羟基-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-24)的合成。
合成路线与实施例19类似，产率52％。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.60–7.41(m,4H),7.37–6.85(m,6H),4.68–4.52(m,2H),4.21–3.98(m,2H),3.58(dd,J＝5.6,3.3Hz,2H),3.37–3.30(m,2H),3.19(s,3H),2.99(d,J＝8.8Hz,2H),2.68–2.52(m,2H),1.32(p,J＝7.2Hz,2H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.65,154.70,153.56,145.52,141.87,139.48,130.61,129.81,129.12,128.04,127.54,127.04,126.14,125.50,125.31,124.96,124.87,122.79,119.83,116.04,113.84,70.67,68.35,60.19,59.57,58.67,44.80,44.74,36.64,36.53,22.84,19.79,14.53,11.58。
实施例29:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(吡啶-3-基)噻唑-4-甲酰胺(I-25)的合成。
合成路线与实施例19类似，产率66％。1H NMR(400MHz,)δ8.66(dd,J＝26.6,4.7Hz,1H),8.39(d,J＝29.2Hz,2H),7.98(d,J＝23.5Hz,1H),7.63–7.16(m,8H),7.03(d,J＝8.8Hz,1H),4.69–4.56(m,1H),4.06(d,J＝14.1Hz,2H),3.53(d,J＝20.1Hz,2H),3.29–3.05(m,7H),2.73(s,2H),2.62(q,J＝7.6,6.7Hz,2H),1.34(dt,J＝13.5,7.7Hz,2H),0.80–0.71(m,3H).13CNMR(126MHz,DMSO-d6)δ164.67,164.37,163.62,162.75,154.72,151.63,147.39,147.25,146.45,145.80,142.74,142.14,139.48,139.27,134.29,133.99,131.13,129.86,128.03,127.87,126.78,125.88,125.29,124.78,124.55,122.78,114.09,70.57,68.38,68.23,59.54,58.58,57.88,55.33,46.97,44.78,40.80,37.00,36.23,35.99,31.22,22.85,11.59。
实施例30:4-(4-((5-氯-2-(2-甲氧基乙氧基)苄基)(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)氨甲酰基)苯基)哌嗪-1-羧酸叔丁酯(I-26)的合成。
合成路线与实施例19类似，产率49％。1H NMR(400MHz,Chloroform-d)δ7.58(dd,J＝10.1,2.2Hz,1H),7.41(d,J＝8.3Hz,1H),7.24–7.14(m,2H),6.87(s,1H),6.74(d,J＝8.7Hz,0H),4.65(s,1H),4.58(t,J＝6.2Hz,0H),4.01(dd,J＝5.6,3.7Hz,1H),3.66–3.59(m,1H),3.54(t,J＝5.2Hz,2H),3.30(d,J＝0.7Hz,1H),3.17(t,J＝5.2Hz,2H),3.15–3.02(m,0H),2.83(q,J＝6.8Hz,1H),1.53–1.41(m,6H),0.91–0.74(m,1H)。
实施例31:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-4-(哌嗪-1-基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯甲酰胺(I-27)的合成
合成路线与实施例19类似，产率63％。1H NMR(400MHz,Chloroform-d)δ7.59(d,J＝8.6Hz,2H),7.41(d,J＝8.1Hz,2H),7.24–7.13(m,3H),6.86(d,J＝8.1Hz,2H),6.75(d,J＝8.7Hz,1H),4.76(d,J＝91.9Hz,4H),4.02(dd,J＝5.5,3.8Hz,2H),3.67–3.57(m,2H),3.46(dd,J＝2.7,0.8Hz,2H),3.37–3.32(m,4H),3.30(d,J＝1.1Hz,3H),3.22–3.11(m,4H),2.83(t,J＝7.1Hz,3H),1.52–1.40(m,2H),0.84(t,3H)。
实施例32:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)苄基[d][1,3]二氧杂茂-5-羧酰胺(I-28)的合成。
合成路线与实施例19类似，产率64％。1H NMR(400MHz,DMSO-d6)δ7.51–7.46(m,2H),7.42(t,J＝5.9Hz,1H),7.32–7.22(m,2H),7.13(s,1H),7.04–6.93(m,4H),6.03(s,2H),4.49(s,2H),4.05–3.99(m,2H),3.54–3.48(m,2H),3.14(s,7H),2.77(d,J＝63.9Hz,1H),2.57(q,J＝6.8Hz,2H),1.31(h,J＝7.3Hz,2H),0.73(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ171.22,162.74,154.87,148.65,147.67,139.37,130.71,129.10,125.43,125.25,124.83,122.73,121.08,114.17,108.71,107.62,101.90,70.62,68.30,58.60,44.77,36.44,36.35,36.22,31.22,22.85,11.59。
实施例33:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)新戊酰胺(I-29)的合成。
合成路线与实施例19类似，产率58％。1H NMR(400MHz,DMSO-d6)δ7.54–7.42(m,3H),7.33(d,J＝7.9Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),7.00–6.90(m,1H),4.35(d,J＝26.6Hz,1H),4.00(s,2H),3.49(t,J＝4.7Hz,2H),3.24–3.04(m,5H),2.95(dd,J＝16.9,8.8Hz,2H),2.59(hept,J＝6.7Hz,2H),1.30(dt,J＝27.2,7.9Hz,11H),0.75(t,J＝7.3Hz,3H).13C NMR(126MHz,DMSO-d6)δ177.11,154.61,145.97,142.31,139.45,129.86,127.43,126.04,125.44,125.34,124.72,122.84,114.10,70.61,70.57,68.39,58.64,44.78,44.74,39.27,36.78,36.69,28.76,27.21,27.19,22.87,22.85,11.60。
实施例34:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-2,2,2-三氟-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)乙酰胺(I-30)的合成。
合成路线与实施例19类似，产率50％。1H NMR(400MHz,)δ7.56(d,J＝14.3Hz,2H),7.53–7.42(m,1H),7.39–7.27(m,2H),7.10–6.84(m,1H),4.71–4.45(m,2H),4.17–3.99(m,2H),3.63–3.46(m,2H),3.32–2.98(m,7H),2.66–2.57(m,2H),1.43–1.29(m,2H),0.78(td,J＝7.4,1.5Hz,3H).13C NMR(126MHz,Deuterium Oxide)δ131.36,130.49,128.06,127.89,127.52,127.02,125.00,116.55,116.46,72.72,70.59,70.42,61.33,59.92,46.96,44.11,42.65,42.48,42.31,42.14,41.98,41.81,41.64,39.03,25.04,13.77。
实施例35:2-溴-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)乙酰胺(I-31)的合成。
合成路线与实施例19类似，产率56％。1H NMR(400MHz,DMSO-d6)δ7.67–7.51(m,3H),7.50–7.26(m,3H),7.16–7.02(m,1H),4.55(d,J＝48.9Hz,3H),4.28–4.04(m,3H),3.63(d,J＝25.0Hz,2H),3.41(s,2H),3.21(s,3H),3.01(td,J＝15.8,8.1Hz,2H),2.68(q,J＝6.7Hz,2H),1.41(dd,J＝14.8,7.2Hz,3H),0.83(t,J＝7.5Hz,3H).13C NMR(126MHz,Chloroform-d)δ167.82,154.74,146.28,142.19,138.38,128.85,127.11,126.20,125.74,124.90,123.03,112.93,70.68,67.98,67.95,59.12,59.07,56.84,46.14,44.98,35.95,35.71,29.68,27.55,22.97,11.11。
实施例36:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)环丙烷甲酰胺(I-32)的合成。
合成路线与实施例19类似，产率55％。1H NMR(400MHz,DMSO-d6)δ7.53(d,J＝13.4Hz,2H),7.42(p,J＝5.6Hz,1H),7.37–7.15(m,2H),7.14–6.99(m,1H),6.99–6.83(m,1H),5.24(dt,J＝105.9,8.4Hz,1H),4.64(s,1H),4.44(d,J＝17.8Hz,1H),4.13–3.99(m,2H),3.62–3.45(m,2H),3.24–2.86(m,7H),2.60(q,J＝6.7Hz,2H),1.57(s,1H),1.33(q,J＝7.3Hz,2H),0.81–0.55(m,7H).13C NMR(126MHz,DMSO-d6)δ173.99,173.71,154.80,154.55,146.39,145.84,142.69,142.17,139.52,139.28,129.94,129.63,128.29,127.59,126.70,125.53,125.34,125.01,122.80,114.44,114.05,70.64,68.46,68.36,58.64,57.64,56.10,55.35,44.79,43.90,36.93,36.06,22.86,12.21,11.60,8.17,7.82。
实施例37:2-(N-(5-氯-2-(2-甲氧基乙氧基)苄基)环丙烷磺酰胺)-N-丙基-2,3-二氢-1H-茚-5-磺酰胺(I-33)的合成。
合成路线与实施例19类似，产率59％。1H NMR(400MHz,DMSO-d6)δ7.50(d,J＝6.6Hz,2H),7.45(d,J＝5.9Hz,1H),7.37(d,J＝2.6Hz,1H),7.31(d,J＝8.4Hz,1H),7.23(dd,J＝8.7,2.7Hz,1H),6.93(d,J＝8.8Hz,1H),4.79(p,J＝8.1Hz,1H),4.33(s,2H),4.00–3.92(m,2H),3.50–3.39(m,2H),3.18(dt,J＝17.0,8.4Hz,2H),3.10(s,3H),2.99–2.82(m,3H),2.58(td,J＝7.2,5.9Hz,2H),1.35–1.29(m,2H),1.06–0.96(m,4H),0.74(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ154.01,145.62,141.55,138.69,128.60,128.26,128.03,126.12,125.87,124.84,122.96,112.51,70.78,67.78,59.01,58.61,44.97,42.01,37.08,36.66,34.96,31.91,31.49,31.42,30.11,29.68,29.34,23.00,22.67,14.10,11.09,5.70。
实施例38:(E)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-4-(哌啶-1-基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丁-2-烯酰胺(I-34)的合成。
合成路线与实施例19类似，产率60％。1H NMR(400MHz,DMSO-d6)δ7.62–7.44(m,3H),7.41–7.20(m,2H),7.10–6.91(m,2H),6.75–6.55(m,1H),5.18(q,J＝8.3Hz,1H),4.54(d,J＝20.4Hz,2H),4.16–4.05(m,2H),3.64–3.51(m,2H),3.41–2.87(m,13H),2.63(q,J＝6.7Hz,2H),1.46–1.29(m,6H),0.78(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ167.04,154.14,146.37,142.29,138.42,128.20,128.13,126.61,126.15,125.76,124.93,124.82,123.05,112.71,109.99,70.83,68.00,59.41,59.13,55.51,54.50,54.05,44.98,43.50,42.73,36.33,36.06,29.68,27.32,25.12,23.48,22.97,14.10,12.27,11.10。
实施例39:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)辛那酰胺(I-35)的合成。
合成路线与实施例19类似，产率66％。1H NMR(400MHz,DMSO-d6)δ7.77–7.42(m,7H),7.42–7.17(m,6H),7.03(d,J＝26.7Hz,2H),5.24(d,J＝149.6Hz,1H),4.62(d,J＝68.2Hz,2H),4.07(s,2H),3.54(s,2H),3.09(d,J＝33.0Hz,7H),2.70–2.55(m,2H),1.43–1.27(m,2H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ167.02,166.85,155.00,154.62,146.54,145.91,142.83,142.62,142.48,142.25,139.52,139.26,135.52,132.69,132.67,131.68,131.60,130.09,129.71,129.28,129.22,129.18,129.15,128.65,128.52,128.39,127.68,127.30,126.82,125.53,124.87,122.88,119.44,118.99,114.50,114.10,70.66,68.41,64.60,58.61,57.65,56.72,44.80,37.04,36.19,31.74,31.59,29.44,29.14,22.87,18.79,13.88,11.61。
实施例40:(E)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-3-(4-羟基苯基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丙烯酰胺(I-36)的合成。
合成路线与实施例19类似，产率62％。1H NMR(400MHz,DMSO-d6)δ9.91–9.79(m,1H),7.70–7.13(m,9H),7.13–6.91(m,2H),6.80–6.61(m,2H),5.25(d,J＝122.8Hz,1H),4.60(d,J＝56.7Hz,2H),4.07(s,2H),3.65–3.50(m,2H),3.27–2.80(m,7H),2.71–2.51(m,2H),1.35(dd,J＝14.7,7.8Hz,2H),0.84–0.71(m,3H).13C NMR(126MHz,DMSO-d6)δ169.91,167.33,159.54,158.22,154.59,145.95,145.57,142.97,142.29,141.92,139.47,139.23,130.52,130.41,130.22,129.90,127.90,127.73,127.63,127.28,127.11,126.81,126.60,126.41,125.53,125.28,124.85,122.87,122.73,116.02,115.79,115.73,115.46,115.05,114.48,114.14,70.66,70.58,68.41,68.29,59.14,58.61,58.57,58.55,57.55,56.52,56.20,44.80,44.76,40.80,37.07,36.38,36.26,22.87,22.84,11.61,11.58。
实施例41:(E)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-3-(3,4-二羟基苯基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丙烯酰胺(I-37)的合成。
合成路线与实施例19类似，产率58％。1H NMR(400MHz,DMSO-d6)δ9.46(d,J＝16.4Hz,1H),8.97(d,J＝27.7Hz,1H),7.52(q,J＝11.1,9.2Hz,2H),7.48–7.40(m,1H),7.39–7.26(m,2H),7.25–7.09(m,2H),7.08–6.91(m,3H),6.90–6.79(m,1H),6.73–6.65(m,1H),5.47–5.05(m,1H),4.67–4.45(m,2H),4.07(d,J＝15.5Hz,2H),3.59–3.49(m,2H),3.24–3.06(m,5H),3.04–2.90(m,2H),2.63–2.56(m,2H),1.38–1.28(m,2H),0.75(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ167.04,154.14,146.37,142.29,138.42,128.20,128.13,126.61,126.15,125.76,124.93,124.82,123.05,112.71,109.99,70.83,68.00,59.41,59.13,55.51,54.50,54.05,44.98,43.50,42.73,36.33,36.06,29.68,27.32,25.12,23.48,22.97,14.10,12.27,11.10。
实施例42:(E)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-3-(4-羟基-3-甲氧苯基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丙烯酰胺(I-38)的合成。
合成路线与实施例19类似，产率56％。1H NMR(400MHz,DMSO-d6)δ9.45(d,J＝1.9Hz,1H),7.62–7.40(m,4H),7.40–7.19(m,3H),7.20–6.87(m,4H),6.74(d,J＝8.6Hz,1H),5.25(d,J＝140.6Hz,1H),4.69(s,1H),4.53(q,J＝17.4Hz,1H),4.06(s,2H),3.74(d,J＝16.7Hz,3H),3.54(s,2H),3.25–2.91(m,7H),2.66–2.56(m,2H),1.33(qd,J＝7.3,1.9Hz,2H),0.75(td,J＝7.4,2.0Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.83,167.33,154.96,154.60,149.05,148.21,147.78,146.56,145.94,143.46,143.17,142.85,142.29,139.53,139.23,133.62,129.92,128.45,127.87,127.62,127.29,127.03,126.82,125.54,125.42,125.30,124.92,124.85,123.04,122.91,122.75,122.47,121.51,115.96,115.15,114.58,114.07,112.80,112.12,70.65,70.61,68.40,68.35,59.19,58.61,57.42,56.62,56.29,56.15,56.00,55.81,44.80,44.76,44.13,40.82,37.11,36.24,22.87,11.61。
实施例43:(Z)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-3-(4-羟基苯基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丙烯酰胺(I-39)的合成。
合成路线与实施例19类似，产率53％。1H NMR(400MHz,DMSO-d6)δ9.86(d,J＝7.1Hz,1H),7.61–7.11(m,9H),7.09–6.93(m,2H),6.73(t,J＝9.1Hz,2H),5.47–4.98(m,1H),4.66(s,1H),4.53(d,J＝10.5Hz,1H),4.06(s,2H),3.55(s,2H),3.20–2.85(m,7H),2.60(p,J＝7.1Hz,2H),1.34(h,J＝8.7,8.0Hz,2H),0.76(t,J＝7.5Hz,3H).13C NMR(126MHz,DMSO-d6)δ169.91,169.87,167.33,159.55,158.22,154.90,154.59,146.53,145.95,145.57,142.98,142.29,141.92,139.48,139.23,133.39,133.26,130.52,130.47,130.41,130.22,129.90,129.45,128.56,128.42,127.90,127.62,127.28,127.11,126.86,126.59,126.40,125.53,125.37,125.28,124.89,124.85,122.88,122.78,122.73,121.49,121.29,116.02,115.80,115.73,115.46,115.06,114.48,114.14,114.06,70.66,70.60,70.58,68.40,68.29,68.27,59.14,58.61,58.55,57.55,56.53,56.20,44.80,44.76,44.07,40.80,37.08,36.38,36.24,35.49,35.38,29.46,22.87,22.84,11.61。
实施例44:(Z)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-3-(4-羟基-3-甲氧苯基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)丙烯酰胺(I-40)的合成。
合成路线与实施例19类似，产率52％。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.52(t,J＝20.4Hz,4H),7.40–7.18(m,3H),7.17–6.90(m,3H),6.81–6.65(m,1H),5.25(d,J＝141.8Hz,1H),4.76–4.43(m,2H),4.07(s,2H),3.74(d,J＝15.0Hz,3H),3.54(s,2H),3.14(q,J＝32.6,27.3Hz,8H),2.65–2.52(m,2H),1.41–1.25(m,2H),0.75(t,J＝7.8Hz,3H).13CNMR(126MHz,Chloroform-d)δ168.09,154.22,147.50,146.62,144.13,142.46,138.36,128.43,128.27,127.63,126.97,126.36,125.72,124.92,123.05,122.01,115.28,114.69,112.75,110.31,70.87,68.11,59.13,55.98,44.99,43.62,36.53,36.20,31.91,30.19,29.69,22.99,22.68,11.12。
实施例45:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)噻吩-2-甲酰胺(I-41)的合成。
合成路线与实施例19类似，产率64％。1H NMR(400MHz,DMSO-d6)δ9.62(d,J＝7.8Hz,1H),9.50–9.39(m,3H),9.36–9.27(m,2H),9.24(d,J＝7.9Hz,1H),9.25–9.14(m,1H),8.92(d,J＝8.8Hz,1H),5.98–5.92(m,2H),5.41(dd,J＝5.5,3.5Hz,2H),5.12–5.03(m,5H),5.01(s,3H),4.56–4.47(m,2H),3.24(h,J＝7.3Hz,2H),2.66(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ161.43,154.39,139.41,128.83,127.14,127.04,125.44,125.29,124.81,124.14,122.97,122.78,114.24,112.16,111.12,70.59,68.35,58.57,44.79,31.73,29.44,29.14,22.87,22.53,14.40,11.61。
实施例46:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-1H-吲哚-2-甲酰胺(I-42)的合成。
合成路线与实施例19类似，产率55％。1H NMR(400MHz,DMSO-d6)δ7.58–7.49(m,3H),7.44(t,J＝5.9Hz,1H),7.42–7.37(m,1H),7.34(d,J＝7.9Hz,1H),7.28(dd,J＝7.5,3.5Hz,1H),7.20–7.10(m,1H),7.01(ddd,J＝28.7,13.8,8.4Hz,2H),4.10–4.02(m,2H),3.70–3.61(m,1H),3.53–3.49(m,1H),3.31–3.23(m,3H),3.11(s,4H),2.60(qd,J＝7.1,4.9Hz,2H),1.37–1.28(m,2H),0.75(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ164.37,154.41,142.14,138.55,135.64,129.08,128.32,127.99,127.67,127.13,126.28,125.85,124.90,124.76,123.04,122.16,120.57,112.95,111.65,105.27,70.81,68.01,59.08,53.40,44.98,29.68,23.00,11.11。
实施例47:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)苄基[b]噻吩-2-甲酰胺(I-43)的合成。
合成路线与实施例19类似，产率56％。1H NMR(400MHz,DMSO-d6)δ7.53–7.37(m,4H),7.31(dd,J＝9.6,5.7Hz,2H),7.21–7.14(m,1H),7.06–7.00(m,1H),6.96–6.92(m,1H),4.50(s,1H),4.43–4.29(m,1H),4.10(t,J＝4.5Hz,1H),4.00(dd,J＝9.4,5.6Hz,2H),3.64–3.55(m,1H),3.49(t,J＝4.6Hz,1H),3.14(d,J＝28.9Hz,3H),3.06–2.74(m,3H),2.58(q,J＝6.9Hz,2H),1.33(p,J＝7.2,6.7Hz,2H),0.74(t,J＝7.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ161.43,154.39,139.41,128.83,127.14,127.04,125.44,125.29,124.81,124.14,122.97,122.78,114.24,112.16,111.12,70.59,68.35,58.57,44.79,31.73,29.44,29.14,22.87,14.40,11.61。
实施例48:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯并[b]噻吩-2-羧酰胺(I-44)的合成。
合成路线与实施例19类似，产率63％。1H NMR(400MHz,DMSO-d6)δ8.24–7.92(m,2H),7.55(d,J＝12.7Hz,4H),7.43(s,1H),7.35(t,J＝10.6Hz,1H),7.31–7.11(m,2H),7.00(d,J＝9.0Hz,1H),5.39(s,1H),4.73(d,J＝60.7Hz,1H),4.05(d,J＝19.2Hz,2H),3.54(s,2H),3.29–2.75(m,7H),2.62(s,2H),1.42–1.25(m,2H),0.76(s,3H).13C NMR(126MHz,DMSO-d6)δ165.90,164.87,162.06,161.45,155.55,154.65,152.90,146.43,145.77,142.74,142.12,139.59,139.26,135.90,135.82,128.74,128.65,128.48,128.01,127.44,127.39,127.09,126.64,125.57,125.42,125.32,125.23,124.93,124.89,124.73,124.64,122.93,122.89,122.75,114.23,70.63,70.51,68.44,68.17,58.89,58.63,58.54,58.46,55.36,51.79,50.66,47.26,44.81,42.05,36.84,36.82,35.91,35.84,22.88,12.01,11.61。
实施例49:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-5-氟-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-45)的合成。
合成路线与实施例19类似，产率66％。1H NMR(400MHz,DMSO-d6)δ7.73–7.60(m,1H),7.56–7.48(m,3H),7.43(t,J＝5.9Hz,1H),7.33(d,J＝7.8Hz,1H),7.29–7.21(m,3H),7.15(s,1H),7.01(d,J＝8.7Hz,1H),4.69(d,J＝65.5Hz,2H),4.04(dd,J＝5.4,3.8Hz,2H),3.49(t,J＝4.6Hz,2H),3.10(s,3H),2.60(q,J＝6.7Hz,2H),1.38–1.26(m,2H),0.75(t,3H).13C NMR(126MHz,Chloroform-d)δ161.67,160.38,158.46,154.37,150.88,150.44,128.81,128.23,128.02,127.67,127.59,127.32,126.09,125.80,124.90,123.04,114.89,114.68,112.84,112.80,112.72,111.94,107.63,107.43,70.79,68.01,59.05,44.98,31.90,30.18,29.67,29.63,29.34,22.97,22.67,19.17,14.10,11.11。
实施例50:5-氯-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-46)的合成。
合成路线与实施例19类似，产率59％。1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝2.2Hz,1H),7.72–7.60(m,1H),7.52(d,J＝4.1Hz,2H),7.50(d,J＝1.8Hz,1H),7.45–7.40(m,2H),7.33(d,J＝7.9Hz,1H),7.26(dd,J＝8.8,2.5Hz,1H),7.16(d,J＝9.7Hz,0H),7.00(d,J＝8.8Hz,1H),4.69(d,J＝62.9Hz,2H),4.15–3.98(m,2H),3.49(t,J＝4.6Hz,2H),3.10(s,7H),2.60(q,J＝6.8Hz,2H),1.48–1.27(m,2H),0.75(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ154.35,152.97,129.30,128.17,127.98,126.98,126.12,125.82,124.91,123.05,121.79,112.97,112.84,70.79,68.00,59.06,44.99,31.91,29.68,29.34,23.00,22.67,14.10,11.10。
实施例51:5-氯-N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-47)的合成。
合成路线与实施例19类似，产率66％。1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.75–7.31(m,8H),7.15(s,1H),7.01(d,J＝9.3Hz,1H),4.91–4.48(m,2H),4.04(s,2H),3.49(s,2H),3.15(d,J＝34.2Hz,10H),2.60(d,J＝6.9Hz,2H),1.33(q,J＝8.4,7.8Hz,2H),0.76(d,J＝8.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ161.03,153.23,139.41,129.61,129.41,128.64,125.45,125.35,125.28,124.82,122.78,116.31,114.23,110.39,70.58,68.33,58.57,55.34,44.79,31.73,31.59,30.27,29.44,29.14,22.87,22.54,11.60。
实施例52:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-5-甲氧-N-(5-(N-丙基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-48)的合成。
合成路线与实施例19类似，产率55％。1H NMR(400MHz,DMSO-d6)δ7.52(d,J＝13.1Hz,2H),7.48–7.39(m,2H),7.33(d,J＝7.8Hz,2H),7.26(d,J＝8.9Hz,1H),7.19(s,2H),7.00(t,J＝9.9Hz,2H),4.65(s,2H),4.05(s,2H),3.76(d,J＝11.3Hz,3H),3.50(s,2H),3.12(d,J＝11.8Hz,7H),2.60(q,J＝7.6Hz,2H),1.33(q,J＝7.4Hz,2H),0.79–0.71(m,3H).13C NMR(126MHz,Chloroform-d)δ161.67,160.38,158.46,154.37,150.88,128.02,127.67,127.59,127.32,126.09,125.80,124.90,123.04,114.89,114.68,112.84,112.80,112.72,107.63,107.43,70.79,68.01,59.05,44.98,31.90,29.67,29.34,22.97,22.67,14.10,11.11。
实施例53:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-5-羟基-N-(5-(N-丙基氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-49)的合成。
合成路线与实施例19类似，产率55％。1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.55–7.49(m,2H),7.42(t,J＝5.9Hz,2H),7.33(d,J＝7.9Hz,2H),7.26(dd,J＝8.7,2.6Hz,1H),7.12(d,J＝24.2Hz,1H),7.03–6.95(m,2H),6.83(dd,J＝8.9,2.5Hz,1H),4.65(s,2H),4.08–4.00(m,2H),3.53–3.47(m,2H),3.11(s,7H),2.60(td,J＝7.1,5.9Hz,2H),1.33(h,J＝7.4Hz,2H),0.75(t,J＝7.4Hz,3H)。
实施例54:2-(5-氯-2-(2-甲氧基乙氧基)苄基)(5-(N-丙基氨基磺酰基)-2，3-二氢-1H-茚-2-基氨基甲酰基)苯并呋喃-5-基特戊酸酯(I-50)的合成。
合成路线与实施例19类似，产率57％。1H NMR(400MHz,DMSO-d6)δ7.70–7.43(m,5H),7.36(d,J＝7.9Hz,1H),7.33–7.11(m,3H),7.04(d,J＝8.8Hz,1H),4.93–4.58(m,2H),4.10–4.03(m,2H),3.53(t,J＝4.6Hz,2H),3.13(s,6H),2.63(q,J＝6.7Hz,2H),1.39–1.34(m,2H),1.31(s,9H),0.78(t,J＝7.4Hz,3H)。
实施例55:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)-2-萘酰胺(I-51)的合成。
合成路线与实施例19类似，产率53％。1H NMR(400MHz,DMSO-d6)δ8.16–7.86(m,4H),7.69–7.13(m,9H),6.98(s,1H),4.78(d,J＝8.4Hz,1H),4.58(s,2H),4.01(s,2H),3.49(s,2H),3.11(s,7H),2.56(s,2H),1.30(s,2H),0.72(d,J＝9.1Hz,3H).13C NMR(126MHz,DMSO-d6)δ171.83,154.84,139.39,134.50,133.45,132.71,130.94,129.71,128.80,128.14,128.09,127.55,127.26,126.21,125.60,125.44,125.25,124.86,124.33,122.74,114.20,70.59,68.28,58.58,55.36,44.75,22.84,11.58。
实施例56:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)喹啉-2-甲酰胺(I-52)的合成。
合成路线与实施例19类似，产率63％。1H NMR(400MHz,DMSO-d6)δ9.30(d,J＝59.5Hz,1H),8.21–7.96(m,3H),7.82(d,J＝8.2Hz,1H),7.74(d,J＝8.3Hz,1H),7.58–7.37(m,3H),7.27(d,J＝9.9Hz,3H),6.95(dd,J＝53.6,8.6Hz,1H),4.95–4.74(m,1H),4.64(s,2H),3.99(d,J＝56.4Hz,2H),3.49(d,J＝44.6Hz,2H),3.24–2.89(m,7H),2.62(s,2H),1.30(p,J＝9.0,7.6Hz,2H),0.73(q,J＝8.8,7.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ170.13,154.72,152.21,148.57,145.63,141.98,139.44,135.84,131.70,129.22,129.02,128.63,128.18,127.84,127.66,126.58,125.46,125.27,124.92,122.77,120.48,114.17,70.65,68.43,59.71,58.65,55.35,44.74,36.69,36.61,22.84,11.58。
实施例57:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-1,6-萘甲酰胺(I-53)的合成。
合成路线与实施例19类似，产率57％。1H NMR(400MHz,DMSO-d6)δ9.45(dd,J＝25.5,0.9Hz,1H),8.84–8.58(m,2H),8.03–7.77(m,2H),7.61–7.53(m,1H),7.51–7.37(m,3H),7.35–7.28(m,2H),6.97(dd,J＝70.7,8.7Hz,1H),4.89(dt,J＝53.2,8.3Hz,1H),4.71–4.58(m,2H),4.13–4.07(m,1H),3.92–3.86(m,1H),3.59–3.53(m,1H),3.45–3.41(m,1H),3.32(d,J＝5.8Hz,1H),3.17(s,2H),3.08(s,1H),2.65–2.53(m,2H),1.45–1.22(m,2H),0.76(t,2H).13C NMR(126MHz,DMSO-d6)δ169.36,168.98,159.19,159.05,154.91,154.70,153.69,153.60,148.89,148.42,147.84,147.82,146.46,145.56,142.77,141.92,139.46,139.29,138.36,137.90,128.92,128.79,128.57,128.39,128.01,126.73,125.46,125.36,125.26,124.97,124.63,123.51,123.24,122.79,122.74,122.26,122.24,122.13,121.76,114.23,114.04,70.63,70.43,68.43,67.98,59.61,58.65,58.47,57.44,46.56,44.81,44.72,36.69,36.63,36.22,36.01,35.93,22.87,22.82,11.61,11.56。
实施例58:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-7-磺酰胺(I-54)的合成。
合成路线与实施例19类似，产率70％。1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝37.1Hz,1H),7.80–7.71(m,1H),7.52–7.42(m,4H),7.35(d,J＝2.7Hz,1H),7.30–7.24(m,2H),6.94(dd,J＝8.9,1.6Hz,1H),4.97(td,J＝8.1,3.6Hz,1H),4.89(d,J＝16.8Hz,2H),4.31(d,J＝3.8Hz,2H),3.96(dd,J＝6.1,3.2Hz,2H),3.86(td,J＝6.0,2.6Hz,2H),3.46(ddd,J＝6.3,3.2,1.9Hz,2H),3.12(d,J＝3.4Hz,3H),3.08–2.95(m,4H),2.72(dq,J＝15.9,7.7Hz,2H),2.59(td,J＝7.1,5.9Hz,2H),1.34(h,J＝7.3Hz,2H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ154.56,154.53,145.33,145.28,141.72,141.67,140.25,139.77,139.49,139.47,138.19,138.06,134.06,133.81,130.27,130.16,129.30,129.27,129.23,128.30,128.28,128.24,126.05,125.95,125.69,125.67,125.47,125.39,125.20,124.75,122.69,114.10,70.50,68.19,58.70,58.50,58.48,45.41,44.75,41.96,41.91,41.48,36.24,36.14,36.06,35.93,29.12,27.66,22.84,11.58。
实施例59:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(5-正丙基磺酰基)-2,3-二氢-1H-茚-2-基)-1,2,3,4-四氢异喹啉-7-磺酰胺(I-55)的合成。
将I-54(120mg，0.161mmol)置于20mL茄形瓶中，加入3mL MeOH、1mL H2O溶解，加入K2CO3室温反应2h。TLC检测原料反应完全，将MeOH蒸除，EA萃取(10mL×3)，饱和食盐水洗涤1次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经柱色谱分离，得到目标化合物Ⅰ-55(60mg，收率58％)。1H NMR(400MHz,DMSO-d6)δ7.66–7.53(m,1H),7.52–7.40(m,3H),7.40–7.23(m,5H),6.95(d,J＝8.7Hz,1H),4.94(p,J＝8.0Hz,1H),4.29(s,2H),3.99–3.88(m,4H),3.46(dd,J＝5.5,3.7Hz,2H),3.13(s,3H),2.99(dt,J＝17.8,7.0Hz,4H),2.81–2.68(m,4H),2.59(q,J＝6.7Hz,2H),1.34(h,J＝7.3Hz,2H),0.77(t,J＝7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ154.52,145.32,141.70,139.46,138.59,136.87,130.64,129.46,129.44,128.24,128.22,125.46,125.33,125.20,124.77,124.60,122.68,114.09,70.50,68.20,58.63,58.52,48.02,44.75,43.21,41.88,36.19,36.03,29.27,22.84,11.58。
路线三中化合物的制备：
实施例60:N-(5-氯-2-(2-(二甲氨基)乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-56)的合成。
I-56的合成路线与实施例19类似，将5-氯-2-(2-甲氧基乙氧基)苯甲醛用5-氯-2-(2-(二甲氨基)乙氧基)苯甲醛替代。收率55％。1H NMR(400MHz,Chloroform-d)δ7.72(t,J＝6.0Hz,1H),7.63(d,J＝7.6Hz,2H),7.51(s,1H),7.47(d,J＝8.4Hz,1H),7.41–7.37(m,2H),7.31–7.27(m,1H),7.21–7.16(m,2H),6.83–6.76(m,1H),4.76(s,1H),4.60(d,J＝6.0Hz,2H),4.37–4.20(m,2H),3.38(s,2H),3.22(d,J＝5.6Hz,2H),3.18(s,2H),2.83(s,6H),2.66(s,2H),1.59–1.43(m,2H),0.84(t,J＝7.2Hz,3H)。
实施例61:N-(5-氯-2-(2-(二甲氨基)乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-57)的合成。
I-57的合成路线与实施例19类似，将5-氯-2-(2-甲氧基乙氧基)苯甲醛用5-氯-2-(2-(二甲氨基)乙氧基)苯甲醛替代。收率65％。1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝7.2Hz,1H),7.60–7.52(m,3H),7.48(t,J＝6.0Hz,1H),7.45–7.30(m,5H),7.11(d,J＝8.8Hz,1H),5.42(s,1H),4.70(s,2H),4.29(t,J＝12.4Hz,2H),3.38–3.27(m,2H),3.25–3.08(m,2H),2.63(q,J＝6.8Hz,2H),1.64(t,J＝19.6Hz,3H),1.41 -1.31(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例62:N-(5-氯-2-(2-(二甲氨基)乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-58)的合成。
I-58的合成路线与实施例19类似，将5-氯-2-(2-甲氧基乙氧基)苯甲醛用5-氟-2-(2-(二甲氨基)乙氧基)苯甲醛替代。收率45％。1H NMR(400MHz,DMSO-d6)δ7.74(d,J＝7.2Hz,1H),7.65–7.46(m,5H),7.46–7.24(m,3H),7.10(d,J＝5.6Hz,2H),5.39(s,1H),4.69(s,2H),4.27(t,J＝12.4Hz,2H),3.35–3.28(m,2H),3.25–3.14(m,2H),2.63(q,J＝6.8Hz,2H),1.65(t,J＝19.6Hz,3H),1.40 -1.31(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例63:N-(5-氟-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙基氨基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-59)的合成。
I-59的合成路线与实施例19类似，将5-氯-2-(2-甲氧基乙氧基)苯甲醛用5-氟-2-(2-甲氧基乙氧基)苯甲醛替代。收率55％。1H NMR(400MHz,DMSO-d6)δ7.71(d,J＝7.7Hz,1H),7.52(d,J＝12.5Hz,3H),7.34(ddd,J＝30.2,20.7,9.4Hz,5H),7.00(t,J＝13.9Hz,3H),4.69(s,2H),4.09–3.97(m,2H),3.50(s,2H),3.13(d,J＝19.2Hz,7H),2.65–2.54(m,2H),1.32(tt,J＝15.1,7.3Hz,2H),0.81–0.71(m,3H).13C NMR(126MHz,DMSO-d6)δ161.46,157.86,155.98,154.38,139.42,128.88,128.82,127.14,127.01,125.44,125.28,124.13,122.95,122.78,113.99,113.93,112.15,111.00,70.70,68.61,58.56,55.35,44.79,22.86,11.60。
实施例64:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙酰基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-60)的合成。
a)、中间体2，2，2-三氟-N-(5-氨基磺酰基-2，3-二氢-1H-茚-2-基)乙酰胺的合成
合成步骤：将化合物3(1g，3.06mmol)置于50mL茄形瓶中，加入DCM(15mL)溶解，冰浴降温后，再将一水合氨(1.18mL，30.6mmol)滴入反应液，室温反应2-3h。TLC检测原料反应完全，DCM萃取(10mL×3)，有机相用饱和食盐水洗涤1次，有机相用无水Na2SO4干燥。真空旋干后，得到化合物中间体，收率89％，直接投下一步。ESI-MS m/z:309.09[M+H]+
b)中间体N-(2-(2，2，2-三氟乙酰氨基)-2，3-二氢-1H-茚-5-基磺酰基)丙酰胺的合成
合成步骤：将正丙酸(142mg，1.91mmol)和N,N'-羰基二咪唑(310mg，1.91mmol)置于50mL茄形瓶中，加入四氢呋喃(20mL)溶解，N2保护，70℃回流1h。将反应液放至室温后，加入2，2，2-三氟-N-(5-氨基磺酰基-2，3-二氢-1H-茚-2-基)乙酰胺(453mg，1.47)和2，2，2-三氟-N-(5-氨基磺酰基-2，3-二氢-1H-茚-2-基)乙酰胺(560mg，3.68mg)，室温反应过夜。TLC检测原料反应完全，将溶剂旋干后，DCM萃取(10mL×3)，有机相用饱和食盐水洗涤1次，有机相用无水Na2SO4干燥。真空旋干后，经柱色谱分析得到化合物中间体，收率69％。1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),9.76(s,1H),7.80–7.67(m,2H),7.52–7.38(m,1H),4.61(d,J＝4.8Hz,1H),3.31(d,J＝12.0Hz,2H),3.05–2.15(m,2H),2.32–2.15(m,2H),0.89(t,J＝8.0Hz,3H)。
c)、中间体N-(2-(5-氯-2-(2-甲氧基乙氧基)苄基)氨基)-2，3-二氢-1H-茚-5-基)磺酰基丙酰胺的合成
合成步骤：将N-(2-氨基-2，3-二氢-1H-茚-5-基)磺酰基)丙酰胺(0.8g，3.15mmol)置于100mL茄型瓶中，加10mL MeOH溶解，再将5-氯-2-(2-甲氧基乙氧基)苯甲醛(0.67g，3.15mmol)加入反应液，室温反应1h，再加2d冰醋酸，室温反应1h，冰浴降温后滴加氰基硼氢化钠(0.99g，15.75mmol)室温反应2h。TLC检测原料反应完全，加冰水淬灭，将MeOH旋干，DCM萃取(10mL×3)，将有机相用饱和食盐水洗涤3次，有机相用无水Na2SO4干燥，蒸除有机溶剂后，经色谱柱分离得到中间体(0.9g，收率64％)，用于下一步合成。1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.73–7.63(m,2H),7.47–7.26(m,4H),7.08–7.03(m,1H),4.22–4.10(m,2H),3.89(d,J＝7.2Hz,2H),3.83–3.73(m,1H),3.73–3.66(m,2H),3.22–2.18(m,2H),3.33–3.04(m,3H),3.01–2.86(m,2H),2.21–2.10(m,2H),,0.86(t,J＝7.2,3H)。
d)、N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-丙酰基磺酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-60)的合成。
合成步骤：合成路线与实施例19类似，收率48％。1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),7.75–7.62(m,3H),7.55(t,J＝8.4Hz,1H),7.46–7.23(m,5H),7.15(d,J＝10.5Hz,1H),7.00(d,J＝8.8Hz,1H),4.70(d,J＝74.2Hz,2H),4.08–3.99(m,2H),3.49(s,2H),3.09(s,7H),2.21–2.11(m,2H),0.87–0.77(m,3H).13C NMR(126MHz,DMSO-d6)δ172.54,161.44,154.40,138.27,128.78,127.14,127.05,126.58,125.22,124.85,124.81,124.14,123.67,122.98,114.22,112.18,111.15,70.59,70.55,68.34,58.57,55.36,29.09,29.06,8.68。
实施例65:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N，N-二丁基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-61)的合成。
合成步骤同路线一。
a)、中间体N-(5-(N，N-二丁基氨基磺酰基)-2，3-二氢-1H-茚-2-基)-2，2，2-三氟乙酰胺的合成
合成步骤：合成步骤与实施例19合成方法类似，收率62.3％。1H NMR(400MHz,DMSO-d6)δ9.74(d,J＝6.8Hz,1H),7.64(s,1H),7.59(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),4.61(m,1H),3.38–3.27(m,2H),3.06–3.00(m,4H),3.01–2.94(m,2H),1.43(m,4H),1.27–1.18(m,4H),0.85(t,J＝7.2Hz,6H)。
b)、中间体N，N-二丁基-2-(5-氯-2-(2-甲氧基乙氧基)苄基)氨基)-2，3-二氢-1H-茚-5-磺酰胺的合成
合成步骤：合成步骤与实施例19合成方法类似，收率70％。1H NMR(400MHz,DMSO-d6)δ7.73–7.57(m,2H),7.55–7.45(m,2H),7.42(dd,J＝8.8,2.4Hz,1H),7.13(d,J＝8.8Hz,1H),7.23–7.15(m,2H),4.06(s,2H),4.00(s,1H),3.77–3.66(m,2H),7.45–7.37(m,2H),3.33–3.27(m,4H),3.15–3.04(m,2H),3.06–3.00(m,3H),1.48–1.37(m,4H),1.28–1.18(m,4H),0.85(t,J＝7.2Hz,6H)。
c)、N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N，N-二丁基氨基甲酰基)-2,3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-61)的合成。
合成步骤与实施例64合成方法类似，收率50％。1H NMR(400MHz,DMSO-d6)δ7.75–7.48(m,4H),7.36(dd,J＝17.5,8.1Hz,3H),7.31–7.05(m,3H),6.95(dd,J＝46.4,8.8Hz,1H),4.69(d,J＝71.3Hz,1H),4.11–3.96(m,2H),3.63–3.40(m,3H),3.29–3.02(m,7H),2.99–2.88(m,4H),1.38(p,J＝7.8Hz,4H),1.19(q,J＝7.5Hz,4H),0.84–0.76(m,6H).13CNMR(126MHz,DMSO-d6)δ161.44,155.69,154.39,138.03,130.64,129.51,128.82,127.73,127.14,127.05,125.83,125.44,124.83,124.51,124.15,123.16,122.98,114.25,113.84,112.16,111.13,70.80,70.60,68.36,68.16,58.71,58.58,48.30,31.06,30.86,19.75,19.62,14.01,13.98,13.87。
实施例66::N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(1，2，3，5，6，7-六氢-s-茚酸-4-基)氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-62)的合成。
合成路线与实施例65类似，产率57％。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.71(d,J＝7.8Hz,1H),7.66–7.45(m,1H),7.43–7.35(m,2H),7.34–7.08(m,6H),7.01(d,J＝8.8Hz,1H),6.95–6.86(m,1H),4.92–4.39(m,2H),4.05(s,2H),3.63–3.56(m,1H),3.50(s,2H),3.09(d,J＝18.3Hz,7H),2.66(d,J＝8.8Hz,4H),2.32(d,J＝7.2Hz,4H),1.70(d,J＝10.4Hz,4H).13C NMR(126MHz,DMSO-d6)δ161.43,154.38,143.83,140.83,128.77,128.76,127.32,127.12,127.06,126.68,125.50,125.27,124.83,124.17,122.97,122.82,119.71,114.25,113.55,112.14,111.11,70.79,70.60,68.34,68.20,58.78,58.61,57.83,32.95,30.68,29.46,25.71。
实施例67::2-溴-N-(5-(N-丙基氨基磺酰基)-2，3-二氢-1H-茚-2-基)-N-(4-三氟甲基)苄基)乙酰胺(I-63)的合成。
合成路线与实施例65类似，产率56％。1H NMR(400MHz,DMSO-d6)δ7.80–7.57(m,4H),7.57–7.36(m,7H),7.31(dd,J＝14.9,7.7Hz,2H),4.84(s,2H),3.31–3.05(m,4H),2.60(q,J＝6.6Hz,2H),1.39–1.25(m,2H),0.74(t,J＝7.4Hz,3H)。
实施例68:N-(5-(N-丙基氨基磺酰基)-2，3-二氢-1H-茚-2-基)-N-(4-(三氟甲基)苄基)苯并呋喃-2-甲酰胺(I-64)的合成。
合成路线与实施例65类似，产率61％。1H NMR(400MHz,DMSO-d6)δ7.68(dd,J＝34.2,8.1Hz,1H),7.56–7.51(m,1H),7.49–7.41(m,0H),7.33(dd,J＝10.6,8.1Hz,1H),5.08–4.78(m,1H),4.66(t,J＝3.3Hz,1H),4.40(d,J＝2.5Hz,1H),3.25–2.90(m,2H),2.65–2.56(m,1H),1.40–1.27(m,1H),0.81–0.69(m,1H)。13C NMR(126MHz,DMSO-d6)δ172.88,145.87,144.47,142.22,139.50,127.39,127.18,125.97,125.48,125.31,122.80,61.03,56.95,55.35,44.79,36.47,36.30,29.46,29.13,22.86,11.60。
实施例69:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-甲基氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-65)的合成。
合成路线与实施例65类似，产率69％。1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝7.3Hz,3H),7.46–7.34(m,2H),7.29(s,6H),7.22(d,J＝8.5Hz,1H),6.80(d,J＝8.6Hz,1H),4.86(s,2H),4.31(d,J＝5.0Hz,1H),4.10–4.04(m,2H),3.67–3.61(m,2H),3.30(s,3H),3.27–3.20(m,4H),2.65(d,J＝5.4Hz,3H)。
实施例70:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-乙基氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-66)的合成。
合成路线与实施例65类似，产率57％。1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝7.5Hz,3H),7.45–7.35(m,2H),7.28(s,3H),7.22(d,J＝8.6Hz,2H),6.80(d,J＝8.6Hz,1H),4.86(s,2H),4.25(t,J＝5.7Hz,1H),4.09–4.05(m,2H),3.67–3.61(m,2H),3.30(s,3H),3.25(d,J＝6.4Hz,4H),3.04–2.95(m,2H),1.11(t,J＝7.2Hz,3H).
实施例71:N-(5-(N-丁基氨基磺酰基)-2，3-二氢-1H-茚-2-基)-N-(5-氯-2-(2-甲氧基乙氧基)苄基)苯并呋喃-2-甲酰胺(I-67)的合成。
合成路线与实施例65类似，产率48％。1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝7.4Hz,3H),7.46–7.34(m,2H),7.27(s,3H),7.25–7.19(m,2H),6.80(d,J＝8.6Hz,1H),4.86(s,2H),4.38(t,J＝5.9Hz,1H),4.10–4.04(m,2H),3.66–3.62(m,2H),3.30(s,3H),3.25(d,J＝6.2Hz,4H),2.95–2.88(m,2H),1.49–1.40(m,2H),1.33–1.27(m,2H),0.86(t,J＝7.3Hz,3H)。
实施例72::N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-己基氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-68)的合成。
合成路线与实施例65类似，产率63％。1H NMR(400MHz,Chloroform-d)δ7.63(d,J＝7.3Hz,3H),7.44–7.34(m,2H),7.28(d,J＝6.7Hz,3H),7.26–7.19(m,2H),6.80(d,J＝8.7Hz,1H),4.86(s,2H),4.41(t,J＝6.1Hz,1H),4.09–4.05(m,2H),3.66–3.62(m,2H),3.30(s,3H),3.24(d,J＝7.0Hz,4H),2.94–2.88(m,2H),1.49–1.40(m,2H),1.26–1.20(m,6H),0.84(t,J＝6.9Hz,3H)。
实施例73:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-异丁基氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-69)的合成。
合成路线与实施例65类似，产率49％。1H NMR(400MHz,Chloroform-d)δ7.63(d,J＝7.4Hz,3H),7.42–7.34(m,2H),7.28(s,2H),7.26–7.16(m,3H),6.80(d,J＝8.6Hz,1H),4.86(s,2H),4.58(t,J＝6.1Hz,1H),4.09–4.04(m,2H),3.66–3.61(m,2H),3.30(s,3H),3.27–3.17(m,4H),2.72(t,J＝6.6Hz,2H),1.29–1.18(m,1H),0.87(d,J＝6.7Hz,6H)。
实施例74:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(4-甲氧基苄基)氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-70)的合成。
合成路线与实施例65类似，产率55％。1H NMR(400MHz,Chloroform-d)δ7.69–7.61(m,3H),7.44–7.34(m,2H),7.28(d,J＝5.2Hz,2H),7.26–7.16(m,3H),6.80(d,J＝8.6Hz,1H),4.84(d,J＝11.2Hz,2H),4.81(s,1H),4.09–4.04(m,2H),3.81(dd,J＝6.0,2.4Hz,2H),3.67–3.61(m,2H),3.30(s,3H),3.26(s,4H),2.15(s,1H)。
实施例75:N-(5-氯-2-(2-甲氧基乙氧基)苄基)-N-(5-(N-(丙基-2-炔基)氨基磺酰基)-2，3-二氢-1H-茚-2-基)苯并呋喃-2-甲酰胺(I-71)的合成。
合成路线与实施例65类似，产率62％。1H NMR(400MHz,Chloroform-d)δ7.66–7.61(m,3H),7.44–7.34(m,2H),7.28(d,J＝7.8Hz,3H),7.25–7.19(m,3H),7.13–7.10(m,2H),6.82–6.77(m,3H),4.86(s,2H),4.71(t,J＝5.9Hz,1H),4.08–4.03(m,4H),3.76(s,3H),3.68–3.59(m,3H),3.30(s,3H),3.24(s,4H)。
实施例76:目标化合物抑制LPS/ATP诱导小鼠巨噬细胞J774A.1释放IL-1β的活性研究。
将J774A.1细胞铺到96孔板上，每孔10×105个细胞。12h后，加入细菌脂多糖(LPS)(1μg/mL)，37℃下孵育4.5h；加入不同浓度的目标化合物37℃孵育0.5h，随后加入腺嘌呤核苷三磷酸(ATP)。0.5h后，收集细胞上清液，采用IL-1βElisa试剂盒测定IL-1β含量，计算出目标化合物对NLRP3炎症小体的抑制活性。实验结果见下表：
表1目标化合物抑制LPS/ATP诱导小鼠巨噬细胞J774A.1释放IL-1β的活性(IC50:μM)
a表中IC50数值：+++++为≤0.1μM；++++为≤0.5μM；+++为≤1μM；++为≤10μM；+为≤30μM。表中数据为三次独立实验数据。
所设计的化合物均具有显著的抑制LPS/ATP诱导的小鼠巨噬细胞J774A.1产生IL-1β的活性。在这些活性中大部分化合物的抑制IC50都小于1μM，优于已报道的同类化合物格列本脲和JC-124。此外，代表性化合物I-41、I-59的抑制活性突出，IC50达到低于0.1μM。
实施例77:目标化合物I-41对LPS诱导的小鼠腹膜炎的抑制实验
实验方法：1、将4-8周雄性C57BL/6小鼠随机分成四组，每组5只，具体分组处理如下：
第一组：空白5只。
第二组：腹腔注射空白媒介物，1h后腹腔注射LPS(35mg/kg)，5只。
第三组：腹腔注射目标化合物I-41(10mg/kg)，1h后腹腔注射LPS(35mg/kg)，5只。
第四组：腹腔注射MCC950(10mg/kg)，1h后腹腔注射LPS(35mg/kg)，5只。
2、LPS腹腔注射2.5h后，眼球取血，将所取血液静置1h，然后离心3500r/min，20min。
3、将步骤2所得血液上清用ELISA的方法进行IL-1β、TNF-α含量测定
实验结果(如图1所示)：在体内抗炎实验中，代表性化合物I-41能显著的抑制LPS诱导的小鼠急性腹膜炎中的IL-1β的释放(图1a)，而不影响另一炎症因子TNF-α的释放(图1b)，表明化合物能特异性的抑制NLRP3炎症小体，具有一定的选择性。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (9)

1.一种如通式(I)所示的化合物，或其光学异构体、消旋体或其药学上可接受的盐、氘代物：
其中，R1选自
R2选自H、
R3选自
n＝0-3；
其中，R4取代基是一个或多个且在环上的位置不定，选自卤素、甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、2-甲氧基乙氧基、N,N-二甲基乙氧基、氰基、异丙基、三氟甲基；
R5取代基选自H、卤素、C1-C6的烷基、OH、CN、CF3、CHF2、NO2、 其中n＝0-6，X5为O、N或S；
R6取代基选自H、卤素、CF3、C1-C4的烷基；
R7取代基是一个或多个且在环上的位置不定，选自H、卤素、C1-C4的烷基、OH、羟基取代的C1-C3烷基；
R8取代基是一个或多个且在环上的位置不定，选自H、卤素、C1-C4的烷基、OH、OCH3、羟基取代的C1-C3烷基、
R9取代基是一个或多个且在环上的位置不定，选自H、卤素、OH、OCH3、
R10取代基选自H、卤素、C1-C4的烷基、OH、OCH3、羟基取代的C1-C3烷基、
R11取代基选自H、Boc；
X1取代基选自O、S、NH；X2取代基为N、CH；X3取代基选自O、S；X4取代基选自O、CH2、NH。
2.如权利要求1通式(I)所示的化合物，或其光学异构体、消旋体或其药学上可接受的盐、氘代物，其特征在于，R1选自R2选自/>R5为/>R6为氯、氟；R3选自/>其中X1取代基为O、S，n＝0-3，R10取代基为H、OCH3。
3.如权利要求1所述化合物或其光学异构体、消旋体或其药学上可接受的盐、氘代物，其特征在于，式(I)所示的化合物选自：
4.如权利要求1-3中任一项所述的化合物或其光学异构体、消旋体或其药学上可接受的盐、氘代物的制备方法，其特征在于包括以下步骤：
以化合物1为起始原料，先用三氟乙酰基保护氨基得到化合物2，进一步与氯磺酸反应得到中间体3；所述中间体3与氨基化合物反应得到化合物4，中间体4在碳酸钾存在的条件下将三氟乙酰基脱掉得到中间体5；中间体5与取代羧酸或者取代磺酰氯通过缩合反应得到目标化合物6，即通式(I)化合物；或者中间体5与取代苯甲醛经席夫碱还原生成仲胺后再与取代羧酸或取代磺酰氯缩合得到目标化合物6，即通式(I)化合物。
5.一种药物组合物，其特征在于包含如权利要求1-3中任一项所述的化合物或其光学异构体、消旋体或其药学上可接受的盐、氘代物以及药学上可接受的稀释剂或载体。
6.如权利要5所述的药物组合物，其特征在于所述的化合物或其光学异构体、或其药学上可接受的盐、氘代物的含量为0.1-99.9wt％。
7.如权利要求1-3中任一项所述的化合物或其光学异构体、消旋体或其药学上可接受的盐、氘代物在制备NLRP3炎症小体抑制剂中的用途。
8.如权利要求1-3中任一项所述的化合物或其光学异构体、消旋体或其药学上可接受的盐、氘代物在制备治疗与NLRP3炎症小体活性异常活化相关疾病的药物中的用途。
9.如权利要求8所述的用途，其特征在于所述与NLRP3炎症小体异常活化相关疾病包括阿尔兹海默症、帕金森氏症、多发性硬化、创伤性脑损伤、亨廷顿病及脑损伤；炎症性肠病、急性肺炎、非典型肺炎、风湿性关节炎、类风湿性关节炎、痛风性关节炎、骨性关节炎、非酒精性肝炎、急，慢性胃炎、急，慢性肾炎、腹膜炎、自身免疫性脑炎、脓毒症、感染休克；痛风、非酒精性脂肪肝、II型糖尿病；心力衰竭、动脉粥样硬化、急性心肌梗塞、冠状动脉疾病；肝纤维化、肺纤维化、慢性阻塞性肺病、哮喘、抑郁、冷吡啉相关周期性综合症或系统性红斑狼疮。
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