CN113200947A - 苯并呋喃类化合物及其应用 - Google Patents
苯并呋喃类化合物及其应用 Download PDFInfo
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- CN113200947A CN113200947A CN202110513101.9A CN202110513101A CN113200947A CN 113200947 A CN113200947 A CN 113200947A CN 202110513101 A CN202110513101 A CN 202110513101A CN 113200947 A CN113200947 A CN 113200947A
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Abstract
本发明提供了一种式(I)所示的苯并呋喃类化合物或其药学上可接受的盐，以及其应用。该类化合物能够选择性抑制NLRP3炎症小体的激活，抑制炎症活化信号分子Caspase‑1、P20和炎症细胞因子IL‑1β的成熟和分泌，对于NLRP3炎症小体相关疾病具有良好的防治作用，尤其是对于腹膜炎和痛风性关节炎，具有显著的防治效果。从而可用于制备与NLRP3炎症小体相关疾病的治疗药物，例如抗炎或者辅助抗炎的药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类苯并呋喃类化合物及其应用。
背景技术
NLRP3炎症小体是一种模式识别受体(pattern recognition receptor，PRR)，是Caspase-1的炎症性激活平台。它能够识别外源性的病原体相关分子模式(pathogenassociated molecμlar pattern，PAMP)如脂多糖(LPS)、病毒RNA或内源性的损伤相关分子模式(damage-associated molecular pattern，DAMP)如DNA、内毒素、尿酸、ATP、Aβ和细胞碎片等。这些物质异常的出现在细胞外或细胞内的某个部位，使组织的稳态受到刺激而激活NLRP3炎症小体，抵抗外源性或内源性因素对机体的损害，但过度激活的NLRP3炎症小体会导致多种疾病发生发展，例如炎症性肠病、痛风、银屑病、2型糖尿病以及神经退行性疾病等。尽管在基础研究中许多抑制剂对NLRP3炎症小体相关的疾病都有一定的缓解作用，但目前临床上，仍缺乏抑制NLRP3炎症小体活化的药物。
发明内容
基于此，本发明提供了一类苯并呋喃类化合物，这类苯并呋喃类化合物能够抑制NLRP3炎症小体的激活，从而可以治疗或者改善与NLRP3炎症小体相关的疾病。
具体技术方案如下：
式(I)所示的苯并呋喃类化合物或其药学上可接受的盐；
其中，R1选自如下结构：
R2选自：C2-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R7取代的C6-C10芳基、R7取代的5-10元杂芳基、-N(R10)2；R7选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；并且，当R2为苯基时，R7不为甲基；各R10分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基；
R3选自：C2-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R8取代的C6-C10芳基、R8取代的5-10元杂芳基；R8选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；
R4选自：C1-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R9取代的C6-C10芳基、R9取代的5-10元杂芳基；R9选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；
R5选自：-N(R10)2，各R10分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基；
R6选自：-N(R11)2，各R11分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基。
在其中一些实施例中，R2选自：C2-C3烷基、C3-C6环烷基、C2烯基、苯基、5-6元杂芳基、R7取代的苯基；R7选自：H、C1-C3烷基、卤素、C1-C3烷氧基、三氟甲基。
在其中一些实施例中，R3选自：C2-C6烷基、C2烯基、苯基。
在其中一些实施例中，R4选自：C1-C4烷基、C3-C6环烷基、苯基、R9取代的苯基；R9选自：H、C1-C3烷基、卤素、C1-C3烷氧基、氰基。
在其中一些实施例中，R4选自：C1-C3烷基、环戊烷基、R9取代的苯基；R9选自：H、卤素、C1-C3烷氧基、氰基。
在其中一些实施例中，各R10分别独立地选自：H、C1-C3烷基。
在其中一些实施例中，一个R11为H，另一个R11为C1-C3烷基。
在其中一些实施例中，所述苯并呋喃类化合物选自：
本发明还提供了苯并呋喃类化合物的新应用。
具体技术方案如下：
苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备NLRP3炎症小体抑制剂中的应用，所述苯并呋喃类化合物选自上述的式(I)所示的苯并呋喃类化合物，或者选自如下化合物：
上述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备预防和/或治疗与NLRP3炎症小体相关的疾病的药物中的应用。
在其中一些实施例中，所述与NLRP3炎症小体相关的疾病为炎症性肠病、痛风、银屑病、2-型糖尿病、神经退行性疾病。
上述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备抗炎或者辅助抗炎的药物中的应用。
上述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备预防和/或治疗腹膜炎的药物中的应用。
在其中一些实施例中，所述腹膜炎为急性腹膜炎。
本发明还提供了一种抗炎或者辅助抗炎的药物组合物。
具体技术方案如下：
一种抗炎或者辅助抗炎的药物组合物，由活性成分和药学上可接受的辅料制备而成，所述活性成分包括有上述的式(I)所示的苯并呋喃类化合物或其药学上可接受的盐。
与现有技术相比，本发明具有以下有益效果：
本发明提供了一类苯并呋喃类化合物，该类化合物能够选择性抑制NLRP3炎症小体的激活，抑制炎症活化信号分子Caspase-1、P20和炎症细胞因子IL-1β的成熟和分泌，对于NLRP3炎症小体相关疾病具有良好的防治作用，尤其对于NLRP3过度激活相关的炎症疾病，如腹膜炎，具有显著的防治效果，从而可用于制备与NLRP3炎症小体相关疾病的治疗药物，例如抗炎或者辅助抗炎的药物。
附图说明
图1为化合物8c抑制NLRP3炎症小体诱导IL-1β分泌的结果。
图2为化合物8c抑制NLRP3炎症小体的活化结果。
图3为化合物8c和决奈达隆对NLRP3炎症小体抑制作用的体内研究结果。
具体实施方式
本发明所述化合物中，当任何变量(例如R7等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如，“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
本文所用术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。
本文所用术语“烷氧基”指具有-O-烷基结构的基团，如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
本文所用术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环，例如：喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基、苯并呋喃基、苯并噻吩基、苯并恶唑、吲哚基等。
正如本领域技术人员所理解的，本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明包括式(Ⅰ)化合物的游离形式，也包括其药学上可接受的盐。术语“游离形式”指以非盐形式的胺类化合物。本发明化合物的药学上可接受的盐包括与式(Ⅰ)化合物形成的季铵盐；或者包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸等的盐，也包括自有机酸例如甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸等制备的盐。
除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中的原料可以从商业途径获得，或者通过本领域已知的方法制备，或根据本文所述方法制备。
实施例1化合物的制备
路线一：化合物7a～7j、8a～8g、9a～9k的制备
路线二、化合物15a～15g的制备
化合物的合成路线如上述路线一和路线二所示：2-(溴甲基)-4-硝基苯酚(化合物1)进行Wittig反应得到化合物2。化合物2在二氯甲烷中与4-甲氧基苯甲酰氯反应生成化合物3，化合物3在AlCl3下去甲基生成化合物4。在碳酸钾存在下，化合物4与正丁基-N-(3-氯丙基)丁-1-胺的邻烷基化反应得到化合物5，再经过铁粉还原得到化合物6。化合物7a～7j,8a～8g,9a～9k由中间体6与各种底物(磺酰氯、酰氯、异氰酸或胺基磺酰氯)经酰化或亲核加成反应合成，收率为12％～85％。化合物11～13的合成应用上述化合物3～5的合成方法。化合物13发生磺酰反应得到化合物14。化合物14与草酰氯反应得到其磺酰氯中间体，并进一步与各种胺进行缩合反应得到化合物15a～15g，收率为25％～62％。
化合物2的合成：
第一步:向化合物1(10g,43.1mmol)的二氯甲烷溶液(140mL)中加入三苯基膦(11.9g,45.2mmol)。在40℃搅拌1小时。对反应混合物进行过滤，得到白色固体沉淀物(20.5g,96.5％)，可直接用于下一步。
第二步:将上述白色固体(20.5g,41.5mmol)加入甲苯(83mL)中，再加入戊酰氯(7.6mL,64.5mmol)和三乙胺(17.9ml,129mmol)。将混合物在110℃搅拌3小时。反应结束后，对反应进行过滤。滤液加入50mL水，用乙酸乙酯萃取。有机相经Na2SO4干燥、过滤、浓缩得到粗产物，经硅胶柱层析纯化[石油醚/乙酸乙酯＝70:1]得到化合物2(8.9g,93％)，为黄色状油物。1HNMR(400MHz,Chloroform-d)δ8.38–8.36(m,1H),8.13–8.09(m,1H),7.47–7.40(m,1H),6.51–6.47(m,J＝1.0Hz,1H),2.82–2.76(m,2H),1.77–1.69(m,2H),1.45–1.38(m,2H),0.97–0.92(m,3H).
化合物3的合成：
向化合物2(5.4g,24.83mmol)的二氯甲烷溶液(50mL)中加入4-甲氧基苯甲酰氯(4.4mL,32.28mmol)和三氯化铝(3.3g,24.83mmol)。混合物在室温下搅拌24小时。反应混合物用冰水猝灭后用二氯甲烷萃取。有机相经无水Na2SO4干燥、过滤、浓缩得到粗产物，经硅胶柱层析纯化[石油醚/乙酸乙酯＝10:1]得到化合物3(6.9g,78.9％)，为黄色固体。1H NMR(400MHz,CDCl3)δ8.32(d,J＝2.4Hz,1H),8.21–8.18(m,1H),7.83–7.80(m,2H),7.56–7.53(m,1H),6.99–6.96(m,2H),3.90(s,3H),2.93–2.87(m,2H),1.77–1.71(m,2H),1.36–1.31(m,2H),0.90–0.86(m,3H).
化合物4的合成：
向化合物3(1.9g,5.46mmol)的氯苯(11mL)溶液中加入三氯化铝(2.2g,16.38mmol)。在80℃搅拌2小时。反应混合物用二氯甲烷萃取。有机相经无水Na2SO4干燥、过滤、浓缩得到粗产物，经硅胶柱层析纯化[石油醚/乙酸乙酯＝5:1]得到化合物4(1.46g,78.5％)，为黄色固体。1H NMR(400MHz,CDCl3)δ8.32(dd,J＝2.4,0.5Hz,1H),8.22–8.18(m,1H),7.79–7.75(m,2H),7.55(dd,J＝9.0,0.5Hz,1H),6.97–6.93(m,2H),2.90(dd,J＝8.1,7.1Hz,2H),1.78–1.70(m,2H),1.37–1.29(m,2H),0.86(t,J＝7.3Hz,3H).
化合物5的合成：
在化合物4(2.0g,5.90mmol)的DMF(12mL)溶液中加入正丁基-N-(3-氯丙基)丁-1-胺(1.35mL,5.90mmol)，碘化钾(98mg,0.59mmol)和K2CO3(0.82g,5.90mmol)。混合物在65℃搅拌5小时。反应混合物用乙酸乙酯萃取。有机相用水(50ml)洗涤，经无水Na2SO4干燥、过滤、浓缩得到粗产物，经硅胶柱层析纯化[石油醚/乙酸乙酯＝1:1]纯化得到化合物5(2.17g,72.0％)，为黄色状油物。1H NMR(400MHz,CDCl3)δ8.32(d,J＝2.2Hz,1H),8.21–8.18(m,1H),7.83–7.78(m,2H),7.54(d,J＝9.0Hz,1H),6.96(d,J＝8.9Hz,2H),4.11(t,J＝6.2Hz,2H),2.90(t,J＝7.6Hz,2H),2.61(t,J＝7.0Hz,2H),2.45–2.40(m,4H),1.98–1.90(m,2H),1.78–1.70(m,2H),1.43–1.38(m,4H),1.32–1.22(m,6H),0.91–0.84(m,9H).
化合物6的合成：
在化合物5(2.17g,4.27mmol)的乙醇(21mL)溶液中加入铁(953mg,17.07mmol)，氯化铵水溶液(320mg,0.59mmol NH4Cl)。混合物在65℃搅拌1小时。将反应液过滤，滤液用二氯甲烷萃取。有机相经无水Na2SO4干燥、过滤、浓缩得到粗产物，经硅胶柱层析纯化[石油醚/乙酸乙酯＝1:1]得到化合物6(1.5g,74.2％)，为黄色状油物。1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.6Hz,2H),7.19(d,J＝8.5Hz,1H),6.89(d,J＝8.6Hz,2H),6.62–6.56(m,2H),4.05(t,J＝6.1Hz,2H),2.79(t,J＝7.6Hz,2H),2.65(t,J＝7.2Hz,2H),2.50–2.42(m,4H),1.98–1.91(m,2H),1.70–1.62(m,2H),1.40–1.37(m,4H),1.30–1.21(m,6H),0.84(dt,J＝11.6,7.3Hz,9H).
化合物7a～7j的合成：
在化合物6(1.0equiv.)的二甲苯溶液中加入三乙胺(4.0equiv.)和相应的磺酰氯(1.2equiv.)，在60℃搅拌2小时。反应完毕后加水，用二氯甲烷萃取反应混合物。有机相经无水Na2SO4干燥、过滤和浓缩得到粗产物，并用硅胶柱层析纯化[乙酸乙酯]得到化合物7a～7j。
(7a)黄色油状物(产率:37.5％)；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.8Hz,2H),7.38(d,J＝8.8Hz,1H),7.29(dd,J＝8.8,2.2Hz,1H),7.12(d,J＝2.1Hz,1H),6.90(d,J＝8.8Hz,2H),4.13(t,J＝5.9Hz,2H),2.99(m,4H),2.91–2.87(m,2H),2.80–2.73(m,4H),2.16–2.07(m,2H),1.72(m,2H),1.55(m,4H),1.30(m,9H),0.88(m,9H).13C NMR(100MHz,CDCl3)δ190.3,166.3,162.4,151.4,133.2,131.9,131.6,128.1,119.1,116.7,114.7,114.4,111.7,65.6,52.4,49.9,45.5,30.1,28.0,26.6,25.0,22.4,20.5,13.9,13.8,8.2.HRMS(ESI)计算值：C32H47N2O5S+(M+H)+571.3200,实验值571.3194.
(7b)黄色油状物(产率:40.8％)；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.9Hz,2H),7.40-7.37(m,1H),7.29(dd,J＝8.7,2.2Hz,1H),7.28–7.25(m,1H),6.91(d,J＝8.9Hz,2H),4.12(t,J＝5.7Hz,2H),2.93–2.80(m,4H),2.80–2.60(m,4H),2.40–2.35(m,1H),2.16–2.09(m,2H),1.75–1.67(m,2H),1.60–1.52(m,4H),1.34–1.26(m,6H),1.05–1.03(m,2H),0.92–0.84(m,11H).13C NMR(100MHz,CDCl3)δ190.3,166.0,162.7,151.8,132.8,131.8,131.7,128.0,120.8,116.8,116.3,114.4,111.6,65.9,53.2,50.3,30.1,29.8,29.5,28.0,22.4,20.5,13.9,13.8,5.6.HRMS(ESI)计算值C33H47N2O5S+(M+H)+583.3206,实验值583.3187.
(7c)黄色油状物(产率:35.5％)；1H NMR(400MHz,CDCl3)δ7.74(d,J＝4.7Hz,2H),7.37(dd,J＝8.7,3.9Hz,1H),7.25–7.20(m,1H),7.01(s,1H),6.92(d,J＝7.5Hz,2H),6.52–6.41(m,1H),6.08(dd,J＝16.5,3.6Hz,1H),5.81(dd,J＝9.8,3.7Hz,1H),4.21–4.13(m,2H),3.06–3.00(m,2H),2.94–2.89(m,2H),2.86–2.80(m,4H),2.20–2.14(m,2H),1.75–1.70(m,2H),1.63–1.56(m,4H),1.37–1.31(m,6H),0.94–0.87(m,9H).13C NMR(100MHz,CDCl3)δ190.3,166.5,162.2,151.5,135.5,132.6,132.0,131.6,127.9,127.6,119.5,116.7,115.3,114.5,111.5,65.4,52.2,49.9,30.2,27.94,26.2,22.5,20.4,13.9,13.8.HRMS(ESI)计算值C32H45N2O5S+(M+H)+569.3049,实验值569.3035.
(7d)黄色油状物(产率:21.8％)；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.8Hz,2H),7.37(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.2Hz,1H),7.06(d,J＝2.1Hz,1H),6.90(d,J＝8.8Hz,2H),4.10(t,J＝6.1Hz,2H),2.86(t,J＝7.6Hz,3H),2.77(t,J＝7.2Hz,2H),2.63–2.56(m,4H),2.08–2.00(m,4H),1.83–1.76(m,2H),1.73–1.66(m,2H),1.50–1.42(m,6H),1.33–1.21(m,8H),1.15–1.10(m,2H),0.89–0.83(m,9H).13C NMR(100MHz,CDCl3)δ190.4,166.3,162.5,151.2,133.5,131.9,131.7,128.0,118.5,116.8,114.4,114.1,111.7,65.7,60.0,52.5,50.0,30.2,28.0,26.9,26.4,25.2,22.4,20.5,20.5,13.9,13.8.HRMS(ESI)计算值C36H53N2O5S+(M+H)+625.3675,实验值625.3648.
(7e)黄色油状物(产率:66.1％)；1H NMR(400MHz,CDCl3)δ7.69–7.64(m,4H),7.46(t,J＝7.4Hz,1H),7.34(t,J＝7.8Hz,2H),7.29(d,J＝8.8Hz,1H),7.13(dd,J＝8.8,2.0Hz,1H),6.90–6.85(m,3H),4.17(t,J＝5.8Hz,2H),3.08–3.00(m,2H),2.87(m,6H),2.19(m,2H),1.70(m,2H),1.59(m,4H),1.37–1.30(m,6H),0.90(m,9H).13C NMR(100MHz,CDCl3)δ190.2,166.5,162.1,151.4,139.6,132.9,132.7,131.9,131.6,128.9,127.7,127.2,119.5,116.7,115.4,114.4,111.4,65.4,52.2,49.9,30.2,27.9,26.2,24.7,22.5,20.4,13.9,13.8.HRMS(ESI)计算值C36H47N2O5S+(M+H)+619.3206,实验值619.3194.
(7f)黄色油状物(产率:31.6％)；1H NMR(400MHz,CDCl3)δ8.89(d,J＝1.9Hz,1H),8.70–8.66(m,1H),7.91(d,J＝8.1Hz,1H),7.65(d,J＝8.7Hz,2H),7.35(d,J＝8.8Hz,1H),7.31–7.28(m,1H),7.22(dd,J＝8.8,2.0Hz,1H),6.89(d,J＝8.7Hz,2H),6.86–6.81(m,1H),4.19(t,J＝5.7Hz,2H),2.93(m,4H),2.81–2.73(m,4H),2.13(mz,2H),1.75–1.68(m,2H),1.56(m,4H),1.34(m,6H),0.95–0.87(m,9H).13C NMR(100MHz,CDCl3)δ190.2,166.8,162.2,153.1,151.6,148.2,136.2,135.0,132.3,131.8,131.5,127.9,123.6,119.7,116.6,115.7,114.5,111.7,65.4,52.4,50.0,30.1,27.9,26.7,25.1,22.5,20.5,13.9,13.8.HRMS(ESI)计算值C35H46N3O5S+(M+H)+620.3158,实验值620.3131.
(7g)黄色油状物(产率:27.8％)；1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.9Hz,2H),7.52(d,J＝7.8Hz,2H),7.30–7.26(m,1H),7.15–7.09(m,3H),6.89(d,J＝7.9Hz,2H),6.85–6.83(m,1H),4.18(t,J＝5.6Hz,2H),3.10–3.02(m,2H),2.90–2.86(m,4H),2.33(s,3H),2.26–2.16(m,2H),1.76–1.68(m,2H),1.63–1.59(m,2H),1.38–1.30(m,6H),1.26–1.21(m,2H),0.93(t,J＝6.9Hz,6H),0.88(t,J＝6.2Hz,3H).13C NMR(100MHz,CDCl3)δ190.3,166.5,162.1,151.3,143.4,136.6,132.9,131.9,131.6,129.5,127.7,127.3,119.3,116.7,115.3,114.4,111.4,65.3,52.1,49.9,30.2,27.9,26.0,24.5,22.5,21.6,20.4,13.8.HRMS(ESI)计算值C37H49N2O5S+(M+H)+633.3362,实验值633.3357.
(7h)黄色油状物(产率:85.1％)；1H NMR(400MHz,CDCl3)δ7.69–7.64(m,4H),7.29(d,J＝8.8Hz,1H),7.12(dd,J＝8.8,2.2Hz,1H),6.99(t,J＝8.6Hz,2H),6.93(d,J＝2.1Hz,1H),6.87(d,J＝8.8Hz,2H),4.14(t,J＝5.8Hz,2H),3.02–2.95(m,2H),2.89–2.84(m,2H),2.82–2.75(m,4H),2.18–2.11(m,2H),1.73–1.66(m,2H),1.61–1.53(m,4H),1.37–1.28(m,6H),0.92–0.84(m,9H).13C NMR(100MHz,CDCl3)δ190.2,168.8,165.0(d,J＝255.1Hz),162.4,151.5,135.6(d,J＝3.2Hz),132.7,131.8,131.6,130.0(d,J＝9.5Hz),127.8,119.7,116.7,116.1(d,J＝22.6Hz),115.5,114.4,111.5,65.6,52.5,50.1,30.1,29.4,27.9,25.1,22.4,20.4,13.9,13.8.HRMS(ESI)计算值C36H46FN2O5S+(M+H)+637.3111,实验值637.3099.
(7i)黄色油状物(产率:60.0％)；1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.2Hz,2H),7.69(d,J＝8.8Hz,2H),7.59(d,J＝8.3Hz,2H),7.27(d,J＝8.8Hz,1H),7.11(dd,J＝8.8,2.2Hz,1H),7.05(d,J＝2.1Hz,1H),6.88(d,J＝8.9Hz,2H),4.16(t,J＝5.8Hz,2H),3.11–2.98(m,2H),2.92–2.79(m,6H),2.30–2.17(m,2H),1.68(m,6H),1.32(m,6H),0.88(m,9H).13C NMR(100MHz,CDCl3)δ190.2,166.3,162.3,151.6,143.1,134.16(q,J＝32.9Hz),132.2,131.8,131.7,127.9,127.8,126.0(q,J＝3.5Hz),123.3(q,J＝273.0Hz),119.9,116.7,115.9,114.4,111.5,65.5,52.8,50.3,30.1,29.8,27.9,26.4,22.4,20.4,13.81,13.76.HRMS(ESI)计算值C37H46F3N2O5S+(M+H)+687.3080,实验值687.3060.
(7j)黄色油状物(产率:45.7％)；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.6Hz,2H),7.69(d,J＝8.5Hz,2H),7.24(d,J＝7.7Hz,1H),7.14(d,J＝8.5Hz,2H),7.08(d,J＝8.8Hz,2H),6.87(d,J＝8.6Hz,2H),4.20–4.15(m,2H),3.24–3.18(m,2H),3.03–2.96(m,4H),2.87(t,J＝7.6Hz,2H),2.38–2.30(m,2H),1.75–1.66(m,6H),1.38–1.30(m,6H),0.91(t,J＝7.3Hz,6H),0.85(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ190.1,166.4,162.1,152.0,151.5,137.8,132.4,132.0,131.7,129.6,127.7,120.6,120.2(q,J＝260Hz)119.9,116.7,115.9,114.4,111.4,65.2,52.6,50.5,30.1,27.9,25.6,22.4,20.2,13.8,13.7.HRMS(ESI)计算值C37H46F3N2O6S+(M+H)+703.3029,实验值703.2999.
化合物8a～8g的合成：
在化合物6(1equiv.)的二甲苯溶液中加入三乙胺(4equiv.)和相应的酰氯(1.2equiv.)，将混合物在室温下搅拌5小时，用二氯甲烷萃取反应混合物，有机相经无水Na2SO4干燥，过滤和浓缩得到粗产物，并用硅胶柱层析纯化[乙酸乙酯]得到化合物8a～8g。
(8a)黄色油状物(产率:35.9％)；1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.9Hz,2H),7.71–7.64(m,1H),7.37(d,J＝8.9Hz,1H),7.17(s,1H),6.89(d,J＝8.4Hz,2H),4.08(t,J＝5.9Hz,2H),2.91–2.84(m,4H),2.74–2.59(m,4H),2.11–2.03(m,5H),1.76–1.68(m,2H),1.58–1.48(m,4H),1.36–1.26(m,6H),0.93–0.85(m,9H).13C NMR(100MHz,CDCl3)δ190.4,168.7,165.8,162.5,150.6,134.2,131.9,131.8,127.4,118.0,116.8,114.3,112.8,111.0,65.7,52.8,50.1,30.2,28.0,27.2,24.3,22.4,20.6,14.0,13.8.HRMS(ESI)计算值C32H45N2O4 +(M+H)+521.3379,实验值521.3371.
(8b)黄色油状物(产率:59.50％)；1H NMR(400MHz,CDCl3)δ7.81–7.75(m,3H),7.39(d,J＝8.8Hz,1H),7.22(d,J＝1.6Hz,1H),6.83(d,J＝8.7Hz,2H),6.37–6.21(m,2H),5.64(dd,J＝9.8,1.8Hz,1H),3.97(t,J＝5.7Hz,2H),2.91–2.86(m,2H),2.85–2.79(m,2H),2.68–2.61(m,4H),2.03–1.98(m,2H),1.76–1.68(t,J＝7.6Hz,2H),1.54–1.47(m,4H),1.35–1.28(m,6H),0.92–0.85(m,9H).13C NMR(100MHz,CDCl3)δ190.3,165.8,163.8,162.6,150.6,134.1,131.8,131.6,131.5,127.4,127.2,117.9,116.9,114.2,112.8,111.0,65.8,52.8,49.9,30.2,29.8,27.9,27.3,22.5,20.6,14.0,13.8.HRMS(ESI)计算值C33H45N2O4 +(M+H)+533.3379,实验值533.3367.
(8c)黄色油状物(产率:38.86％)；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.8Hz,2H),7.74(dd,J＝8.8,1.7Hz,1H),7.37(d,J＝8.9Hz,1H),7.22(d,J＝1.8Hz,1H),6.89(d,J＝8.7Hz,2H),4.07(t,J＝5.8Hz,2H),2.94–2.88(m,2H),2.87–2.82(m,2H),2.75–2.67(m,4H),2.52–2.44(m,1H),2.12–2.06(m,2H),1.75–1.67(m,2H),1.56–1.50(m,4H),1.35–1.28(m,6H),1.17(d,J＝6.8Hz,6H),0.91(t,J＝7.3Hz,6H),0.86(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ190.4,175.5,165.5,162.5,150.6,134.4,131.9,131.8,127.4,118.0,116.8,114.3,112.5,111.0,65.7,52.6,50.0,36.4,30.2,28.0,27.0,25.3,22.4,20.5,19.7,13.9,13.8.HRMS(ESI)计算值C34H49N2O4 +(M+H)+549.3692,实验值549.3684.
(8d)黄色油状物(产率:59.03％)；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.7Hz,2H),7.64(d,J＝8.9Hz,1H),7.35(d,J＝8.9Hz,1H),7.27(s,1H),6.90(d,J＝8.6Hz,2H),4.04(t,J＝6.1Hz,2H),2.82(t,J＝7.5Hz,2H),2.67(t,J＝7.1Hz,2H),2.52–2.47(m,4H),2.26(t,J＝7.6Hz,2H),1.99–1.93(m,2H),1.74–1.66(m,2H),1.66–1.59(m,2H),1.47–1.40(m,4H),1.36–1.32(m,2H),1.30–1.23(dd,J＝14.9,7.7Hz,6H),0.90–0.83(m,12H).13C NMR(100MHz,CDCl3)δ190.41,171.65,165.27,163.00,150.65,134.09,131.77,131.58,127.48,118.14,116.90,114.27,112.77,110.97,66.38,53.43,50.14,37.33,30.15,28.45,27.99,27.80,22.69,22.46,22.41,20.71,14.07,13.88,13.76.HRMS(ESI)计算值C35H51N2O4 +(M+H)+563.3849,实验值563.3830.
(8e)黄色油状物(产率:76.51％)；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.6Hz,2H),7.63–7.59(m,1H),7.39–7.35(m,2H),6.91(d,J＝8.7Hz,2H),4.09(t,J＝6.0Hz,2H),2.87–2.79(m,2H),2.79–2.75(m,2H),2.69–2.59(m,4H),2.15–2.04(m,2H),1.71–1.65(m,2H),1.54(p,J＝7.7Hz,4H),1.34–1.27(m,6H),1.26(s,9H),0.90(t,J＝7.3Hz,6H),0.83(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ190.4,176.7,164.9,162.8,150.8,134.1,131.8,131.8,127.6,118.5,116.9,114.3,113.1,111.0,66.0,53.3,50.4,39.5,31.5,30.1,29.8,28.1,27.7,22.4,20.6,14.0,13.8.HRMS(ESI)计算值C37H47N2O4 +(M+H)+583.3536,实验值583.3522.
(8f)黄色油状物(产率:68.75％)；1H NMR(400MHz,CDCl3)δ7.77(t,J＝8.9Hz,4H),7.70(d,J＝8.8Hz,1H),7.33–7.46(m,5H),6.87(d,J＝8.7Hz,2H),4.01(t,J＝6.2Hz,2H),2.84–2.77(m,2H),2.54(t,J＝7.0Hz,2H),2.40–2.34(m,4H),1.91–1.84(m,2H),1.69(q,J＝7.5Hz,2H),1.39–1.31(m,4H),1.28–1.21(m,6H),0.83(t,J＝7.2Hz,9H).13C NMR(100MHz,CDCl3)δ190.4,165.9,165.2,163.1,150.8,134.9,133.9,131.7,131.6,131.3,128.6,127.5,127.1,118.5,116.9,114.2,113.4,111.0,66.4,53.8,50.2,30.1,29.1,27.9,26.8,22.3,20.7,14.1,13.7.HRMS(ESI)计算值C37H47N2O4 +(M+H)+583.3536,实验值583.3522.
(8g)黄色油状物(产率:66.49％)；1H NMR(400MHz,CDCl3)δ7.80–7.76(m,4H),7.72(dd,J＝9.0,2.0Hz,1H),7.41–7.38(m,2H),6.92–6.86(m,4H),4.04(t,J＝6.3Hz,2H),3.81(s,3H),2.85–2.81(m,2H),2.58(t,J＝7.0Hz,2H),2.43–2.38(m,4H),1.94–1.88(m,2H),1.75–1.67(m,2H),1.43–1.35(m,4H),1.30–1.24(m,6H),0.88–0.84(m,9H).13C NMR(100MHz,CDCl3)δ190.4,165.5,165.3,163.2,162.4,150.8,134.1,131.8,131.5,129.1,127.6,127.2,118.6,117.0,114.3,113.9,113.3,111.1,66.6,55.5,53.9,50.4,30.2,29.2,28.0,27.0,22.4,20.8,14.2,13.8.HRMS(ESI)计算值C38H49N2O5 +(M+H)+613.3641,实验值613.3627.
化合物9a～9h的合成：
在化合物6(1equiv)的二氯甲烷溶液中加入三乙胺(1.1equiv)和各种异氰酸(1.1equiv)。0℃下搅拌1小时，继续在室温反应11小时,将反应混合物浓缩得到粗产物，并用硅胶柱层析纯化[乙酸乙酯:二氯甲烷:甲醇＝10:10:1]得到化合物9a～9h。
(9a)黄色油状物(产率:11.8％)；1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.8Hz,2H),7.43(dd,J＝8.9,1.9Hz,1H),7.35(d,J＝8.8Hz,1H),6.98(s,1H),6.88(d,J＝8.8Hz,2H),4.06(t,J＝6.1Hz,2H),3.94–3.85(m,1H),2.90–2.85(m,2H),2.77(t,J＝7.1Hz,2H),2.61–2.54(m,4H),2.03–1.96(m,2H),1.76–1.68(m,2H),1.52–1.44(m,4H),1.34–1.27(m,6H),1.07(d,J＝6.5Hz,6H),0.92–0.85(m,9H).13C NMR(100MHz,CDCl3)δ190.4,168.1,166.1,161.9,156.0,149.9,135.7,132.2,131.7,127.3,117.8,114.1,112.2,111.0,64.9,51.8,49.6,41.7,30.2,27.9,25.3,23.9,23.4,22.5,20.3,13.8,13.8.HRMS(ESI)计算值C34H50N3O4 +(M+H)+564.3801,实验值564.3781.
(9b)黄色油状物(产率:16.5％)；1H NMR(400MHz,CDCl3)δ8.47(s,1H),8.03(s,1H),7.72(d,J＝8.7Hz,2H),7.57(dd,J＝8.9,2.1Hz,1H),7.30(d,J＝8.9Hz,1H),6.79(m,3H),3.97(t,J＝5.6Hz,2H),3.10–3.03(m,4H),2.93–2.86(m,6H),2.15–2.07(m,2H),1.76–1.69(m,2H),1.64–1.57(m,4H),1.41–1.31(m,8H),0.93(t,J＝7.3Hz,6H),0.87(t,J＝7.3Hz,3H),0.81(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ190.4,168.5,166.0,162.0,156.8,149.9,135.8,132.1,131.7,127.3,117.7,116.6,114.1,111.0,64.9,51.9,49.6,41.8,30.2,27.9,25.6,24.1,23.5,22.5,20.3,13.8,13.8,11.4.HRMS(ESI)计算值C34H50N3O4 +(M+H)+564.3801,实验值564.3783.
(9c)黄色油状物(产率:13.7％)；1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.75(d,J＝8.2Hz,2H),7.60–7.53(m,2H),7.32(d,J＝8.8Hz,1H),6.84(m,3H),4.05–3.97(m,3H),3.00–2.94(m,2H),2.91(t,J＝7.6Hz,2H),2.81–2.71(m,4H),2.11–2.05(m,2H),1.90–1.82(m,2H),1.77–1.68(m,2H),1.61–1.48(m,8H),1.38–1.26(m,8H),0.94–0.85(m,9H).13C NMR(100MHz,CDCl3)δ190.4,168.8,166.0,162.3,156.3,150.1,135.5,132.0,131.7,127.4,118.1,114.2,112.5,111.1,65.3,52.4,51.8,49.8,33.5,30.2,28.0,26.5,24.8,23.6,22.5,20.4,13.9,13.8.HRMS(ESI)计算值C36H52N3O4 +(M+H)+590.3958,实验值590.3945.
(9d)黄色油状物(产率:16.6％)；1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.74(d,J＝8.8Hz,3H),7.56(dd,J＝8.9,2.0Hz,1H),7.31(d,J＝8.9Hz,1H),6.83–6.79(m,3H),3.98(t,J＝5.6Hz,2H),3.53(s,1H),3.03–2.96(m,2H),2.93–2.89(m,2H),2.83–2.77(m,4H),2.10–2.04(m,2H),1.84–1.78(m,2H),1.76–1.69(m,2H),1.63–1.56(m,6H),1.36–1.30(m,6H),1.11–0.95(m,4H),0.92(t,J＝7.3Hz,6H),0.88(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ190.4,168.8,166.0,162.2,155.9,150.0,135.6,132.0,131.7,127.3,117.9,116.6,114.1,111.0,65.2,52.2,49.7,48.6,33.8,30.2,27.9,26.2,25.7,24.9,24.5,22.5,20.4,13.9,13.8.HRMS(ESI)计算值C37H54N3O4 +(M+H)+604.4114,实验值604.4097.
(9e)黄色油状物(产率:13.9％)1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.6Hz,2H),7.38(dd,J＝8.8,1.8Hz,1H),7.25(s,1H),7.10–7.08(m,3H),6.91(d,J＝8.3Hz,2H),6.83(d,J＝8.7Hz,2H),4.00(t,J＝6.0Hz,2H),2.84(t,J＝7.6Hz,2H),2.74(t,J＝7.2Hz,2H),2.59–2.53(m,4H),2.19(s,3H),2.00–1.95(m,2H),1.74–1.66(m,2H),1.51–1.43(m,4H),1.34–1.25(m,7.3Hz,6H),0.86(t,J＝7.3Hz,9H).13C NMR(100MHz,CDCl3)δ190.5,165.5,162.7,154.3,150.4,136.1,134.6,132.7,131.7,129.4,127.5,120.3,118.6,116.8,114.3,113.3,111.1,65.9,53.6,50.4,30.2,28.0,26.0,22.5,20.8,20.6,14.0,13.8.HRMS(ESI)计算值C38H50N3O4 +(M+H)+612.3801,实验值612.3781.
(9f)黄色油状物(产率:26.8％)；1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.07(s,1H),7.69(d,J＝8.8Hz,2H),7.62(dd,J＝8.9,2.0Hz,1H),7.30(d,J＝8.9Hz,1H),7.15(d,J＝8.9Hz,2H),6.82(d,J＝2.0Hz,1H),6.78(d,J＝8.8Hz,2H),6.67(d,J＝9.0Hz,2H),4.00(t,J＝5.5Hz,2H),3.68(s,3H),3.16–3.15–3.11(m,2H),2.95–2.89(m,6H),2.16–2.09(m,2H),1.76–1.69(m,2H),1.65–1.57(m,4H),1.37–1.27(m,6H),0.92–0.85(m,9H).13C NMR(100MHz,CDCl3)δ190.4,168.3,166.2,161.8,155.5,149.9,135.5,132.3,131.7,127.2,121.6,117.4,116.6,114.1,114.1,111.8,111.0,64.7,55.5,51.8,49.7,30.2,27.9,25.2,23.8,22.5,20.2,13.8,13.7.HRMS(ESI)计算值C38H50N3O5 +(M+H)+632.3255,实验值632.3236.
(9g)黄色油状物(产率:13.6％)；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.8Hz,2H),7.37–7.32(m,5H),7.27(d,J＝8.7Hz,1H),7.18(s,1H),6.84(d,J＝8.8Hz,2H),4.01(t,J＝6.1Hz,2H),2.75(t,J＝7.6Hz,2H),2.67(t,J＝7.1Hz,2H),2.51–2.46(m,4H),1.96–1.91(m,2H),1.68–1.63(m,2H),1.45–1.38(m,4H),1.28–1.23(m,6H),0.86–0.82(m,9H).13C NMR(100MHz,CDCl3)δ190.5,169.0,166.3,161.9,153.4,150.2,144.3,134.9,133.0,132.3,131.6,127.3,119.6,118.3,116.4,114.2,111.8,111.2,104.3,64.8,52.4,50.0,30.1,28.1,25.8,24.5,22.5,20.3,13.8,13.8.HRMS(ESI)计算值C38H47N4O4 +(M+H)+623.3597,实验值623.35756.
(9h)黄色油状物(产率:14.3％)；1H NMR(400MHz,CDCl3)δ8.05(d,J＝19.2Hz,2H),7.70(d,J＝8.6Hz,2H),7.41(dd,J＝8.8,1.7Hz,1H),7.27(d,J＝8.8Hz,1H),7.18(d,J＝8.8Hz,2H),7.06(s,1H),7.04(d,J＝8.8Hz,2H),6.83(d,J＝8.7Hz,2H),4.04(t,J＝5.9Hz,2H),2.86–2.79(m,4H),2.69–2.59(m,4H),2.06–1.98(m,2H),1.74–1.66(m,2H),1.54–1.46(m,4H),1.31–1.25(m,6H),0.89–0.84(m,9H).13C NMR(100MHz,CDCl3)δ190.6,165.8,162.5,153.9,150.5,137.7,134.4,131.9,131.7,128.7,127.5,127.5,120.6,118.5,116.6,114.3,111.2,65.6,53.5,50.4,30.1,28.0,27.6,25.7,22.5,20.5,13.9,13.8.HRMS(ESI)计算值C37H47ClN3O4 +(M+H)+632.3255,实验值632.3236.
化合物9i～9k的合成：
在化合物6(1.0equiv.)的二甲苯溶液中加入三乙胺(4.0equiv.)和相应的胺基磺酰氯(1.2equiv.)，在60℃搅拌2小时，反应完毕后加水，用二氯甲烷萃取反应混合物，有机相经无水Na2SO4干燥、过滤和浓缩得到粗产物，并用硅胶柱层析纯化[乙酸乙酯]得到化合物9i～9k。
(9i)黄色油状物(产率:44.7％)；1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.8Hz,2H),7.35(d,J＝8.8Hz,1H),7.23(dd,J＝8.8,2.2Hz,1H),7.16(d,J＝2.1Hz,1H),6.90(d,J＝8.8Hz,2H),4.13(t,J＝5.8Hz,2H),3.03–2.93(m,2H),2.86(t,J＝7.6Hz,2H),2.82–2.72(m,4H),2.61(s,3H),2.21–2.12(m,2H),1.74–1.66(m,2H),1.63–1.55(q,J＝8.0Hz,4H),1.35–1.28(m,6H),0.92–0.84(m,9H).13C NMR(100MHz,CDCl3)δ190.4,166.1,162.6,151.2,133.4,131.8,131.7,127.9,118.8,114.3,114.2,111.6,65.8,60.5,52.9,50.3,30.1,29.4,29.2,28.0,22.4,20.4,14.0,13.8.HRMS(ESI)计算值C31H46N3O5S+(M+H)+6572.3158,实验值572.3134.
(9j)黄色油状物(产率:33.9％)；1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.7Hz,2H),7.35(d,J＝8.8Hz,1H),7.19(dd,J＝8.8,2.2Hz,1H),7.09(d,J＝2.2Hz,1H),6.90(d,J＝8.7Hz,2H),4.09(t,J＝6.1Hz,2H),2.88–2.83(m,2H),2.80–2.75(m,2H),2.72(s,6H),2.62–2.55(m,4H),2.02(p,J＝6.1Hz,2H),1.73–1.66(m,2H),1.49–1.42(m,4H),1.33–1.26(m,6H),0.89–0.82(m,9H).13C NMR(100MHz,CDCl3)δ190.4,166.2,162.5,151.1,133.6,131.9,131.7,127.9,118.6,116.8,114.4,114.1,111.5,65.8,52.6,50.0,38.2,30.2,28.0,27.0,25.3,22.4,20.5,13.9,13.8.HRMS(ESI)计算值C32H48N3O5S+(M+H)+586.3315,实验值586.3297.
(9k)黄色油状物(产率:52.4％)；1H NMR(400MHz,CDCl3)δ7.75–7.72(m,3H),7.37–7.34(m,1H),7.23–7.20(m,1H),7.01(d,J＝2.5Hz,1H),6.91–6.87(m,2H),4.20–4.10(m,2H),3.15–3.11(m,1H),2.94–2.90(m,8H),1.77–1.71(m,2H),1.66–1.58(m,4H),1.37–1.33(m,8H),1.05–1.01(m,6H),0.94–0.91(m,9H).13C NMR(100MHz,CDCl3)δ190.4,166.4,162.2,150.8,134.0,132.0,131.7,127.8,117.6,116.7,114.4,113.2,111.4,65.4,51.7,49.7,46.217,30.2,28.0,25.5,24.1,23.6,22.5,20.3,13.8.HRMS(ESI)计算值C33H50N3O5S+(M+H)+600.3471,实验值600.3448.
化合物11的合成：
按照化合物3合成过程相同的方法，从2-丁基苯并呋喃(5.6mL,32.56mmol)合成得到化合物11(7.1g,71.0％)。1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.9Hz,2H),7.46(d,J＝8.2Hz,1H),7.34(dd,J＝8.4,1.3Hz,1H),7.28–7.23(m,1H),7.19–7.14(m,1H),6.95(d,J＝8.9Hz,2H),3.88(s,3H),2.93–2.88(m,2H),1.78–1.70(m,2H),1.58(s,1H),1.38–1.31(m,2H),0.88(t,J＝7.4Hz,3H).
化合物12的合成：
按照化合物4合成过程相同的方法，从化合物11(5.52g,17.90mmol)制备化合物12(4.83g,91.6％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.6Hz,2H),7.46(d,J＝8.2Hz,1H),7.34(d,J＝9.1Hz,1H),7.28–7.23(m,1H),7.19–7.15(m,1H),6.88(d,J＝8.6Hz,2H),2.92–2.87(m,2H),1.76–1.70(m,2H),1.37–1.32(m,2H),0.89–0.86(m,3H).
化合物13的合成：
按照化合物5合成过程相同的方法，从化合物12(2.1g,7.13mmol)制备得到化合物13(3g,91.9％)。1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.9Hz,2H),7.45(d,J＝8.6Hz,1H),7.34(dd,J＝8.1,1.0Hz,1H),7.27–7.23(m,1H),7.18–7.14(m,1H),6.93(d,J＝8.9Hz,2H),4.09(t,J＝6.3Hz,2H),2.94–2.86(m,4H),2.60(t,J＝7.0Hz,2H),2.44–2.39(m,4H),1.96–1.90(m,2H),1.78–1.70(m,2H),1.44–1.38(m,4H),1.32–1.27(m,4H),0.90–0.86(m,9H).
化合物14的合成：
在化合物13(3g,6.55mmol)的二氯甲烷溶液(22mL)中加入氯磺酸(1.3mL,19.65mmol)。0℃在氮气条件下搅拌1h，室温继续反应24h，反应混合物用二氯甲烷萃取，有机相用无水Na2SO4干燥，过滤、浓缩得到粗产物，经硅胶柱层析[二氯甲烷/甲醇＝10:1]纯化得到化合物14(2.91g,81.6％)，为黄色油状物。1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.61(d,J＝8.7Hz,3H),7.06(d,J＝8.1Hz,1H),6.78(d,J＝8.8Hz,2H),3.98(t,J＝5.6Hz,2H),2.84(t,J＝8.4Hz,2H),2.78–2.72(m,2H),2.68–2.63(m,4H),2.02–1.98(m,2H),1.60–1.55(m,2H),1.50–1.43(m,4H),1.28–1.21(m,6H),0.84(t,J＝7.3Hz,6H),0.77(t,J＝7.3Hz,3H).
化合物15a～15g的合成：
第一步:向化合物14(1equiv.)的二氯甲烷溶液中加入氯磺酸(1.5equiv.)。室温搅拌12h。反应完毕后加入水，用二氯甲烷萃取反应混合物。有机相用无水Na2SO4干燥，过滤、浓缩得到粗产物，直接用于下一步。
第二步:向化合物2-丁基-3-(4-(3-(二丁基氨基)丙氧基)苯甲酰)苯并呋喃-5-磺酰氯(1equiv.)的二氯甲烷溶液中加入三乙胺(2equiv.)和相应的各种胺(1equiv.)。将混合物在室温下搅拌过夜，将得到的混合物浓缩为粗品，并用硅胶柱层析纯化[二氯甲烷:甲醇＝10:1]得到化合物15a～15g。
(15a)黄色油状物(产率:27.6％)；1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.78(d,J＝8.7Hz,2H),7.73(dd,J＝8.4,1.5Hz,1H),7.45(d,J＝8.3Hz,1H),6.94(d,J＝8.7Hz,2H),4.10(t,J＝6.2Hz,2H),2.92(t,J＝7.6Hz,2H),2.65(t,J＝6.9Hz,2H),2.50–2.43(m,4H),2.00–1.95(m,2H),1.77–1.71(m,2H),1.42(m,4H),1.26(m,6H),0.88(m,9H).13C NMR(100MHz,CDCl3)δ189.6,168.0,163.5,152.5,137.9,131.8,131.4,131.1,121.9,121.6,116.9,114.4,110.2,66.6,53.9,50.4,30.1,29.0,28.1,26.8,22.4,20.7,14.1,13.7.HRMS(ESI)计算值C30H43N2O5S+(M+H)+543.2893,实验值543.2881.
(15b)黄色油状物(产率:24.5％)；1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.75(d,J＝8.6Hz,2H),7.63(d,J＝8.3Hz,1H),7.44(d,J＝8.3Hz,1H),6.91(d,J＝8.7Hz,2H),4.07(t,J＝6.1Hz,2H),2.88(t,J＝7.6Hz,2H),2.62(s,3H),2.48–2.42(m,4H),1.98–1.91(m,2H),1.75–1.67(m,2H),1.44–1.36(m,4H),1.32–1.20(m,8H),0.86–0.81(m,9H).13C NMR(100MHz,CDCl3)δ189.7,167.8,163.5,152.7,134.7,131.8,131.4,131.1,122.3,121.8,116.9,114.4,111.0,66.6,53.9,50.4,30.1,29.5,29.1,28.1,26.9,22.4,20.8,14.1,13.7.HRMS(ESI)计算值C31H45N2O5S+(M+H)+557.3049,实验值557.3033.
(15c)黄色油状物(产率:28.8％)；1H NMR(400MHz,CDCl3)δ7.91(d,J＝1.2Hz,1H),7.79(d,J＝8.8Hz,2H),7.59(dd,J＝8.3,1.4Hz,1H),7.51(d,J＝8.3Hz,1H),6.95(d,J＝8.8Hz,2H),4.12(t,J＝6.1Hz,2H),2.92(d,J＝7.5Hz,2H),2.76(m,2H),2.71(s,6H),2.61–2.55(m,4H),2.06(m,2H),1.77–1.72(m,2H),1.53–1.46(m,4H),1.37–1.30(m,6H),0.88(m,9H).13C NMR(100MHz,CDCl3)δ189.7,167.7,163.3,152.8,131.8,131.5,131.4,131.3,122.8,121.6,116.9,114.4,111.3,66.3,53.6,50.4,38.1,30.1,28.1,26.2,22.4,20.6,14.0,13.7.HRMS(ESI)计算值C32H47N2O5S+(M+H)+571.3206,实验值571.3192.
(15d)黄色油状物(产率:35.9％)；1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.79(d,J＝8.7Hz,2H),7.68(dd,J＝8.3,1.4Hz,1H),7.47(d,J＝8.4Hz,1H),6.94(d,J＝8.7Hz,2H),4.11(t,J＝6.1Hz,2H),3.53–3.43(m,1H),2.91(t,J＝7.6Hz,2H),2.77–2.73(m,2H),2.59–2.54(m,4H),2.06–2.00(m,2H),1.78–1.71(m,2H),1.51–1.44(m,4H),1.37–1.27(m,6H),1.07(d,J＝6.5Hz,6H),0.89(m,9H).13C NMR(100MHz,CDCl3)δ189.7,167.7,163.3,152.6,137.1,131.8,131.3,131.1,122.1,121.8,116.9,114.4,110.7,66.4,53.4,50.2,46.3,30.1,28.3,28.3,28.1,26.3,23.9,22.4,20.7,14.1,13.7.HRMS(ESI)计算值C33H49N2O5S+(M+H)+585.3362,实验值585.3346.
(15e)黄色油状物(产率:55.1％)；1H NMR(400MHz,CDCl3)δ8.34(s,1H),8.07(d,J＝1.1Hz,1H),7.76(d,J＝8.8Hz,2H),7.72(dd,J＝8.3,1.4Hz,1H),7.42(d,J＝8.3Hz,1H),6.92(d,J＝8.8Hz,2H),4.14(t,J＝5.4Hz,2H),3.78(s,3H),3.29–3.23(m,2H),3.06–3.01(m,4H),2.94–2.89(m,2H),2.32–2.25(m,2H),1.75–1.65(m,6H),1.41–1.32(m,6H),0.96(t,J＝7.3Hz,6H),0.87(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ189.5,168.6,166.8,162.5,152.4,132.1,131.8,131.8,123.4,121.6,116.8,114.4,112.4,65.4,65.1,52.0,50.0,30.0,28.1,25.1,23.9,22.4,20.2,13.7,13.7.HRMS(ESI)计算值C31H45N2O6S+(M+H)+573.2998,实验值573.2982.
(15f)黄色油状物(产率:33.7％)；1H NMR(400MHz,CDCl3)δ7.98–7.96(m,1H),7.74(d,J＝8.9Hz,2H),7.64(dd,J＝8.3,1.5Hz,1H),7.42(d,J＝8.3Hz,1H),6.89(d,J＝8.9Hz,2H),4.08(t,J＝5.9Hz,2H),3.00–2.94(m,2H),2.87(t,J＝7.6Hz,4H),2.69–2.63(m,4H),2.40–2.34(m,2H),2.10(s,6H),1.74–1.66(m,2H),1.54–1.47(m,4H),1.33–1.25(m,6H),1.22–1.18(m,2H),0.89–0.81(m,9H).13C NMR(100MHz,CDCl3)δ189.7,168.7,162.9,152.6,135.8,131.8,131.5,131.1,122.1,121.8,116.8,114.4,110.8,65.9,57.2,52.3,49.8,44.4,39.8,30.0,29.7,28.1,26.4,22.4,20.4,13.9,13.7.HRMS(ESI)计算值C34H52N3O5S+(M+H)+614.3628,实验值614.3607.
(15g)黄色油状物(产率:62.0％)；1H NMR(400MHz,CDCl3)7.87(s,1H),7.72(d,J＝8.3Hz,2H),7.54(d,J＝8.3Hz,1H),7.39(d,J＝8.3Hz,1H),6.87(d,J＝8.4Hz,2H),4.06(t,J＝5.4Hz,2H),3.05–2.98(m,4H),2.98–2.92(m,2H),2.84(t,J＝7.5Hz,2H),2.78–2.70(m,4H),2.15–2.06(m,2H),1.72–1.65(m,2H),1.55–1.45(m,8H),1.32–1.23(m,6H),0.86(t,J＝7.3Hz,6H),0.83–0.77(m,9H).13C NMR(100MHz,CDCl3)δ189.7,167.8,166.6,162.5,152.7,136.2,131.8,130.8,122.2,121.6,116.8,114.3,110.6,65.3,51.9,50.3,49.9,30.0,28.1,25.1,23.9,22.4,22.2,20.2,13.7,13.7,11.3.HRMS(ESI)计算值C36H55N2O5S+(M+H)+627.3832,实验值627.3821.
实施例2：苯并呋喃类化合物或其盐对NLRP3炎症小体抑制作用的体外研究
1.第一天，将J774A.1细胞分到96孔板上，每个孔5×105个细胞；
2.种板过夜，弃上清，每孔加入100μL含细菌脂多糖(LPS)(1μg/ml)的含10％血清的DMEM培养基，然后分别加入不同化合物处理1小时，再加入尼日利亚菌素(10μM)或ATP(5mM)处理1小时；
3.步骤2处理后，收集细胞上清液，采用Mouse IL-1βELISA试剂盒测定IL-1β含量，其操作步骤按照试剂盒说明书进行，结果见表1。
表1结果显示，在LPS预处理和第二信号尼日利亚菌素或ATP的共同作用下，NLRP3炎症小体活化，IL-1β成熟并分泌到上清之中。随着不同化合物加入，有效地抑制IL-1β成熟和分泌。因此，本发明的苯并呋喃类化合物具有抑制IL-1β成熟和分泌的作用。
表1化合物对IL-1β的抑制能力
实施例3化合物8c抑制NLRP3炎症小体诱导的IL-1β分泌
1.第一天，将J774A.1细胞分到96孔板上，每个孔5×105个细胞
2.种板过夜，弃上清，每孔加入100μL含细菌脂多糖(LPS)(1μg/ml)的含10％血清的DMEM培养基，加入化合物8c(1.25μM、2.5μM、5μM、10μM和20μM)处理1小时，再加入尼日利亚菌素(10μM)或ATP(5mM)处理1小时；
3.步骤2处理后，收集细胞上清液，采用Mouse IL-1βELISA试剂盒测定IL-1β含量，其操作步骤按照试剂盒说明书进行，结果见图1。
实施例4化合物8c抑制NLRP3炎症小体的活化
1.第一天，将J774A.1细胞分到6孔板上，每个孔2×106个细胞；
2.种板过夜，弃上清，每孔加入1mL含细菌脂多糖(LPS)(1μg/ml)的含10％血清的DMEM培养基，然后弃上清，加入不同浓度的8c(1μM、3μM、6μM)的opti-MEM培养基处理1小时，再加入尼日利亚菌素(10μM)处理1小时；
3.步骤2处理后，收集细胞上清液和细胞裂解液，上清液和裂解液按常规方法提取蛋白，用抗IL-1β抗体、抗Caspase-1抗体、抗NLRP3抗体和抗ASC抗体进行westernblot分析，结果见图2。
图2结果显示，在LPS预处理和第二信号尼日利亚菌素的共同作用下，炎症小体活化，P20和IL-1β成熟并分泌到上清之中，随着不同浓度的8c加入，有效地抑制P20和IL-1β成熟和分泌，并且，这种抑制效果是剂量依赖的。因此，测试化合物8c具有抑制NLRP3炎性小体的作用。
实施例5化合物8c和决奈达隆对NLRP3炎症小体抑制作用的体内研究
1.取6-8周龄C57BL/6雌鼠，称重，并进行编号。实验组灌胃化合物8c或决奈达隆(100mg/kg，每组6只)，对照组灌胃PBS(6只)，每天一次，连续三天，第三天灌胃1h后，腹腔注射LPS，20mg/kg每只鼠；
2.6小时后，摘除眼球放血，并收集血液，放血完毕后颈椎脱臼处死小鼠。血液放于室温静置30min，然后3000rpm离心30min，收集血清；
3.用1ml生理盐水冲洗腹腔，吸出的生理盐水，3000rpm离心5分钟，收集上清液；
4.步骤2得到的血清和步骤3得到的腹腔灌洗上清液用ELISA的方法进行IL-1β、IL-6和TNF-α含量的测定(*P<0.05,**P<0.01,***P<0.001,****P<0.0001)，结果见图3。
图3的结果表明，腹腔注射LPS后，IL-1β、IL-6和TNF-α等炎性因子水平有明显的升高，而8c或决奈达隆的加入特异性的抑制炎性因子IL-1β的水平而不影响其他炎性因子的分泌，表明化合物8c和决奈达隆可以有效地抑制LPS诱导的急性腹膜炎。化合物8c和决奈达隆具有治疗腹膜炎的作用。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对以下实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.式(I)所示的苯并呋喃类化合物或其药学上可接受的盐；
其中，R1选自如下结构：
R2选自：C2-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R7取代的C6-C10芳基、R7取代的5-10元杂芳基、-N(R10)2；R7选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；并且，当R2为苯基时，R7不为甲基；各R10分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基；
R3选自：C2-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R8取代的C6-C10芳基、R8取代的5-10元杂芳基；R8选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；
R4选自：C1-C6烷基、C3-C8环烷基、C2-C6烯基、C6-C10芳基、5-10元杂芳基、R9取代的C6-C10芳基、R9取代的5-10元杂芳基；R9选自：H、C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷基、氰基；
R5选自：-N(R10)2，各R10分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基；
R6选自：-N(R11)2，各R11分别独立地选自：H、C1-C6烷基、C1-C6烷氧基、二甲胺基取代的C1-C6烷基。
2.根据权利要求1所述的苯并呋喃类化合物或其药学上可接受的盐，其特征在于，R2选自：C2-C3烷基、C3-C6环烷基、C2烯基、苯基、5-6元杂芳基、R7取代的苯基；R7选自：H、C1-C3烷基、卤素、C1-C3烷氧基、三氟甲基；和/或，
R3选自：C2-C6烷基、C2烯基、苯基；和/或，
R4选自：C1-C4烷基、C3-C6环烷基、苯基、R9取代的苯基；R9选自：H、C1-C3烷基、卤素、C1-C3烷氧基、氰基。
3.根据权利要求1所述的苯并呋喃类化合物或其药学上可接受的盐，其特征在于，R4选自：C1-C3烷基、环戊烷基、R9取代的苯基；R9选自：H、卤素、C1-C3烷氧基、氰基。
4.根据权利要求1所述的苯并呋喃类化合物或其药学上可接受的盐，其特征在于，各R10分别独立地选自：H、C1-C3烷基；和/或，
一个R11为H，另一个R11为C1-C3烷基。
5.根据权利要求1所述的苯并呋喃类化合物或其药学上可接受的盐，其特征在于，所述苯并呋喃类化合物选自：
6.苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备NLRP3炎症小体抑制剂中的应用，所述苯并呋喃类化合物选自权利要求1-5任一项所述的苯并呋喃类化合物，或者选自如下化合物：
7.权利要求6中所述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备预防和/或治疗与NLRP3炎症小体相关的疾病的药物中的应用。
8.权利要求6中所述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备抗炎或者辅助抗炎的药物中的应用。
9.权利要求6中所述的苯并呋喃类化合物或其药学上可接受的盐作为活性成分在制备预防和/或治疗腹膜炎的药物中的应用；优选地，所述腹膜炎为急性腹膜炎。
10.一种抗炎或者辅助抗炎的药物组合物，其特征在于，由活性成分和药学上可接受的辅料制备而成，所述活性成分包括有权利要求1-5任一项所述的苯并呋喃类化合物或其药学上可接受的盐。
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| CN112618535B (zh) * | 2020-12-30 | 2022-04-12 | 中山大学附属第六医院 | 决奈达隆在制备防治结肠炎的药物中的应用 |
| CN115433172A (zh) * | 2022-09-29 | 2022-12-06 | 广西中医药大学 | 苯并呋喃衍生物及其应用 |
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