CN113230240B - 1,3-二苯基丙-2-烯-1-酮衍生物及其应用 - Google Patents
1,3-二苯基丙-2-烯-1-酮衍生物及其应用 Download PDFInfo
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- CN113230240B CN113230240B CN202110317148.8A CN202110317148A CN113230240B CN 113230240 B CN113230240 B CN 113230240B CN 202110317148 A CN202110317148 A CN 202110317148A CN 113230240 B CN113230240 B CN 113230240B
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Abstract
本发明提供了一种式(I)所示的1,3‑二苯基丙‑2‑烯‑1‑酮衍生物或其药学上可接受的盐，及其作为活性成分在制备NLRP3炎症小体抑制剂中的应用。该类化合物能够选择性抑制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，例如：急性腹膜炎和结肠炎，从而可用于制备与NLRP3炎症小体相关疾病的治疗药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类1,3-二苯基丙-2-烯-1-酮衍生物及其应用。
背景技术
NLRP3炎症小体是一种NOD样受体，由炎症小体传感器分子(NLRP3蛋白)，接头蛋白ASC，以及效应分子caspase-1前体蛋白(pro-caspase-1)三部分组成，是存在于胞浆中的一种多蛋白复合物。NLRP3炎症小体激活后，Pro-caspase-1自剪切为有活性的caspase-1，进一步将pro-IL-1β和Pro-IL-18切割为有活性的白介素-1β(IL-1β)和白介素-18(IL-18)，最终导致炎症反应和细胞焦亡。大量证据表明很多人类疾病，如阿尔茨海默症，痛风，多发性硬化，II型糖尿病，炎症性肠病等，与NLRP3炎症小体有着密切关联。到目前为止，已经有多种NLRP3炎症小体抑制剂被发现，但并没有一个可用于临床。因此，发现新的NLRP3炎症小体抑制剂对治疗NLRP3相关疾病具有重要意义。
发明内容
基于此，本发明发现了一类1,3-二苯基丙-2-烯-1-酮衍生物，这类1,3-二苯基丙-2-烯-1-酮衍生物能够选择性抑制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，例如：急性腹膜炎和结肠炎。
具体技术方案如下：
式(I)所示的1,3-二苯基丙-2-烯-1-酮衍生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；
其中，
Q选自：-COOH、-OR4；
R1选自：C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氨基、C1-C6烷基胺基、苯基、R7取代的苯基、卤素、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、噻唑基、R7取代的噻唑基、R7取代的苯磺酰胺基、C1-C6烷基氨基磺酰胺基、C1-C6烷基磺酰胺基、丙烯酰胺基、C1-C6烷基酰胺基、或-NHCONH-R8；
R2、R3、R5、R6、R7各自分别独立地选自：氢、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、卤素、羧基；
R4选自：氢、C1-C6烷基、羧基取代的C1-C6烷基、羟基取代的C1-C6烷基、5-6元杂环基取代的C1-C6烷基、-CONH-R9、羧基取代的烯丙基，或者R4与R3连接形成5-6元杂环结构；
R8选自：氢、C1-C6烷基、R7取代的苯基；
R9选自：氢、C1-C6烷基。
在其中一些实施例中，R1选自：C1-C3烷硫基、氨基、C1-C3烷基胺基、卤素、C1-C3烷基亚磺酰基、C1-C3烷基磺酰基、卤素取代的苯磺酰胺基、C1-C3烷基氨基磺酰胺基、C1-C3烷基磺酰胺基、丙烯酰胺基、C1-C3烷基酰胺基、或-NHCONH-R8。
在其中一些实施例中，R1选自：甲硫基、氨基、二甲胺基、苯基、氟、氯、碘、溴、甲基亚磺酰基、甲磺酰基、噻唑基、甲基取代的噻唑基、乙基磺酰胺基、对氟苯磺酰胺基、异丙基氨基磺酰胺基、丙烯酰胺基、-NHCONH-R8，其中，R8选自：异丙基、丙基、氟苯基、甲苯基。
在其中一些实施例中，R2、R3、R5、R6、R7各自分别独立地选自：氢、羟基、C1-C3烷基、C1-C3烷氧基、卤素。
在其中一些实施例中，R2、R3、R5、R6、R7各自分别独立地选自：氢、羟基、甲基、甲氧基、乙基、卤素。
在其中一些实施例中，R2选自：氢、卤素、C1-C3烷基。
在其中一些实施例中，R2选自：氢、氟、甲基。
在其中一些实施例中，R3选自：氢、卤素、C1-C3烷基、C1-C3烷氧基、羟基。
在其中一些实施例中，R3选自：氢、甲基、甲氧基、氯、氟，乙基、羟基。
在其中一些实施例中，R5选自：氢、C1-C3烷基、C1-C3烷氧基。
在其中一些实施例中，R5选自：氢、甲基、乙基、甲氧基。
在其中一些实施例中，R6选自：氢、C1-C3烷基。
在其中一些实施例中，R6选自：氢、甲基。
在其中一些实施例中，R7选自：氢、卤素、C1-C3烷基。
在其中一些实施例中，R7选自：氢、氟、甲基。
在其中一些实施例中，R4选自：氢、C1-C3烷基、羧基取代的C1-C6烷基、羟基取代的C1-C3烷基、6元杂环基取代的C1-C3烷基、-CONH-R9、羧基取代的烯丙基，或者R4与R3连接形成5元杂环结构；其中，R9选自：氢、C1-C3烷基。
在其中一些实施例中，R4选自：氢、甲基、或以下结构：
在其中一些实施例中，Q选自：-OH、COOH、羟基取代的乙氧基，并且，R2和R6不同时为C1-C6烷基，R3和R5不同时为C1-C6烷氧基。
在其中一些实施例中，所述1,3-二苯基丙-2-烯-1-酮衍生物具有式(II)所示结构：
其中，Q选自：-OH、COOH、羟基取代的乙氧基，并且，R2和R6不同时为C1-C6烷基，R3和R5不同时为C1-C6烷氧基。
在其中一些实施例中，所述1,3-二苯基丙-2-烯-1-酮衍生物具有式(III)所示结构：
R1选自：C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氨基、C1-C6烷基胺基、卤素、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、R7取代的苯磺酰胺基、C1-C6烷基氨基磺酰胺基、C1-C6烷基磺酰胺基、丙烯酰胺基、C1-C6烷基酰胺基、或-NHCONH-R8。
在其中一些实施例中，R1选自：C1-C3烷硫基、氨基、C1-C3烷基胺基、卤素、C1-C3烷基亚磺酰基、C1-C3烷基磺酰基、卤素取代的苯磺酰胺基、C1-C3烷基氨基磺酰胺基、C1-C3烷基磺酰胺基、丙烯酰胺基、C1-C3烷基酰胺基、或-NHCONH-R8。
在其中一些实施例中，R1选自：C1-C3烷基亚磺酰基、卤素取代的苯磺酰胺基、C1-C3烷基氨基磺酰胺基、丙烯酰胺基。
在其中一些实施例中，R1选自：甲硫基、氨基、二甲胺基、氟、氯、甲基亚磺酰基、甲磺酰基、乙基磺酰胺基、对氟苯磺酰胺基、异丙基氨基磺酰胺基、丙烯酰胺基、-NHCONH-R8，其中，R8选自：异丙基、氟苯基。
在其中一些实施例中，所述1,3-二苯基丙-2-烯-1-酮衍生物具有式(IV)所示结构：
其中，R4选自：C1-C3烷基、羟基取代的C1-C3烷基、6元杂环基取代的C1-C3烷基、-CONH-R9、羧基取代的烯丙基、羧基取代的C4-C6烷基；其中，R9选自：氢、C1-C3烷基。
在其中一些实施例中，所述1,3-二苯基丙-2-烯-1-酮衍生物具有式(V)所示结构：
上述的1,3-二苯基丙-2-烯-1-酮衍生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腹膜炎和结肠炎。
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防治NLRP3炎症小体相关的疾病的药物组合物。
具体技术方案如下：
一种防治NLRP3炎症小体相关的疾病的药物组合物，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1,3-二苯基丙-2-烯-1-酮衍生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：
本发明发现了一类1,3-二苯基丙-2-烯-1-酮衍生物，该类化合物能够选择性抑制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，例如：急性腹膜炎和结肠炎，从而可用于制备与NLRP3炎症小体相关疾病的治疗药物。
附图说明
图1为化合物40在体外特异性抑制NLRP3炎性体的活化并抑制细胞焦亡的结果图。
图2为化合物40抑制LPS诱导的急性腹膜炎的结果图。
图3为化合物40改善硫酸葡聚糖钠(DSS)诱导的结肠炎的结果图。
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“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“烷硫基”指具有-S-烷基结构的基团，如-SCH3、-SCH2CH3、-SCH2CH2CH3、-S-CH2CH(CH3)2、-SCH2CH2CH2CH3、-S-CH(CH3)2等。
本文所用术语“烷基胺基”指氨基中的一个或两个氢原子被烷基取代后的基团，如二甲胺基、二乙胺基、甲胺基、乙胺基等。
本文所用术语“杂环基”指饱和或部分不饱和的单环、双环或多环环状取代基，其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，双环或多环包括螺环、稠环和桥环。例如：吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基等，及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
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。
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。
本发明化合物的合成路线如下：
其中，中间体1h-1l的合成路线如下：
实施例1：(E)-3-(4-甲氧基-3,5-二甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物1)的制备
将4-甲巯基苯乙酮(200mg,1.20mmol)和3，5-二甲基-4-甲氧基苯甲醛(197mg,1.20mmol)溶于5mL甲醇中，然后加入氢氧化钠(481mg,12.03mmol)，室温下搅拌24小时，析出固体并用甲醇重结晶得到白色固体270mg，产率77％。1H NMR(400MHz,CDCl3)δ7.97–7.93(m,2H),7.72(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.33–7.27(m,2H),3.75(s,3H),2.53(s,3H),2.32(s,6H)；13C NMR(100MHz,CDCl3)δ189.4,159.4,145.6,144.6,134.8,131.7,130.6,129.4,129.1,125.2,120.7,59.9,16.4,15.0；HRMS(ESI)calcd forC19H20O2S(M+H)+313.1257,found 313.1278.
实施例2：(E)-1-(4-氨基苯基)-3-(4-甲氧基-3,5-二甲基苯基)丙-2-烯-1-酮(化合物2)的制备
参照实施例1的方法，得到黄色固体，产率63％。1HNMR(400MHz,DMSO-d6)δ7.97–7.87(m,2H),7.75(d,J＝15.4Hz,1H),7.57–7.42(m,3H),6.69–6.56(m,2H),6.15(s,2H),3.68(s,3H),2.25(s,3H)；13C NMR(100MHz,DMSO-d6)δ185.8,158.3,153.8,141.3,131.1,130.9,130.6,129.2,125.5,121.1,112.7,59.4,15.9；HRMS(ESI)calcd for C18H19NO2(M+H)+282.1489,282.1489.
实施例3：(E)-1-(4-(二甲基氨基)苯基)-3-(4-甲氧基-3,5-二甲基苯基)丙-2-烯-1-酮(化合物3)的制备
参照实施例1的方法，得到黄色固体，产率75％。1HNMR(400MHz,DMSO-d6)δ8.14–8.00(m,2H),7.78(d,J＝15.5Hz,1H),7.59–7.51(m,3H),6.80–6.70(m,2H),3.68(s,3H),3.04(s,6H),2.26(s,6H)；13C NMR(100MHz,DMSO-d6)δ186.1,158.4,153.3,141.5,130.9,130.7,130.6,129.2,125.3,121.1,110.8,59.4,39.6,15.8；HRMS(ESI)calcd for C20H23NO2(M+H)+310.1802,found 310.1804.
实施例4：(E)-3-(2,3-二氢苯并呋喃-5-基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物4)的制备
参照实施例1的方法，得到黄色固体，产率74％。1HNMR(400MHz,DMSO-d6)δ8.12–8.05(m,2H),7.85(d,J＝1.7Hz,1H),7.77(d,J＝15.4Hz,1H),7.69(d,J＝15.4Hz,1H),7.61(dd,J＝8.3,1.9Hz,1H),7.42–7.36(m,2H),6.84(d,J＝8.3Hz,1H),4.61(t,J＝8.7Hz,2H),3.23(t,J＝8.7Hz,2H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.7,162.2,145.2,144.2,134.1,130.7,128.9,128.6,127.5,125.4,124.9,118.6,109.3,71.8,28.6,14.0；HRMS(ESI)calcd for C18H16O2S(M+H)+297.0944,found297.0967.
实施例5：(E)-1-异丙基-3-(4-(3-(4-甲氧基-3,5-二甲基苯基)丙烯酰基)苯基)脲(化合物5)的制备
将化合物2(50mg,0.18mmol)和异氰酸异丙酯(18mg,0.21mmol)溶解于1.5mL甲苯中。反应液加热到70℃搅拌过夜后，将形成的沉淀物过滤并用甲苯洗涤，干燥，得到黄色固体48mg，产率74％。1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.10–8.03(m,2H),7.80(d,J＝15.5Hz,1H),7.63–7.52(m,5H),6.19(d,J＝7.5Hz,1H),3.84–3.74(m,1H),3.69(s,3H),2.26(s,6H),1.11(d,J＝6.5Hz,6H)；13C NMR(100MHz,DMSO-d6)δ187.1,158.7,154.0,145.3,142.7,131.0,130.4,130.3,130.1,129.5,120.8,116.6,59.4,41.1,22.9,15.9；HRMS(ESI)calcd for C22H26N2O3(M+H)+367.2016,found 367.2013.
实施例6：(E)-1-(4-(3-(4-甲氧基-3,5-二甲基苯基)丙烯酰基)苯基)-3-丙基脲(化合物6)的制备
参照实施例5的方法，得到黄色固体，产率74％。1HNMR(400MHz,DMSO-d6)δ8.91(s,1H),8.11–8.00(m,2H),7.80(d,J＝15.5Hz,1H),7.69–7.49(m,5H),6.33(t,J＝5.7Hz,1H),3.69(s,3H),3.11–3.02(m,2H),2.26(s,6H),1.54–1.39(m,2H),0.88(t,J＝7.4Hz,3H)；13CNMR(100MHz,DMSO-d6)δ187.1,158.7,154.8,145.4,142.7,131.0,130.4,130.4,129.5,120.8,116.6,59.4,40.9,22.9,15.9,11.4；HRMS(ESI)calcd for C22H26N2O3(M+H)+367.2016,found367.2019.
实施例7：(E)-1-(4-氟苯基)-3-(4-(3-(4-甲氧基-3,5-二甲基苯基)丙烯酰基)苯基)脲(化合物7)的制备
参照实施例5的方法，得到黄色固体，产率95％。1HNMR(400MHz,DMSO-d6)δ9.14(s,1H),8.85(s,1H),8.18–8.04(m,2H),7.82(d,J＝15.5Hz,1H),7.67–7.55(m,5H),7.53–7.44(m,2H),7.21–7.08(m,2H),3.69(s,3H),2.26(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.2,158.7,157.6(d,J＝237.0Hz),152.3,144.4,142.9,135.6(d,J＝2.6Hz),131.2,130.9,130.3,130.0,129.5,120.3(d,J＝7.9Hz),120.3,117.3,115.4(d,J＝22.3Hz)59.4,15.8；HRMS(ESI)calcd for C25H23FN2O3(M+H)+419.1765,found419.1777.
实施例8：(E)-1-(4-(3-(4-甲氧基-3,5-二甲基苯基)丙烯酰基)苯基)-3-(对甲苯基)脲(化合物8)的制备
参照实施例5的方法，得到黄色固体，产率90％。1HNMR(400MHz,DMSO-d6)δ9.10(s,1H),8.70(s,1H),8.18–8.01(m,2H),7.82(d,J＝15.4Hz,1H),7.67–7.50(m,5H),7.41–7.28(m,2H),7.16–7.02(m,2H),3.69(s,3H),2.27(s,6H),2.25(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.2,158.7,152.2,144.5,142.9,136.7,131.1,131.1,130.9,130.3,130.0,129.5,129.2,120.7,118.6,117.2,59.4,20.4,15.8；HRMS(ESI)calcd for C26H26N2O3(M+H)+415.2016,found415.2021.
实施例9：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物9)的制备
将4-甲巯基苯乙酮(2.33g,14.00mmol)和3,5-二甲基-4-羟基苯甲醛(2.10g,14.00mmol)加入到20mL氯化氢甲醇溶液(4mol/L)中，在室温下搅拌24h，将所形成的沉淀物过滤并干燥得到黄色固体3.20g，产率77％。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.14–8.02(m,2H),7.71(d,J＝15.4Hz,1H),7.60(d,J＝15.4Hz,1H),7.49(s,2H),7.43–7.34(m,2H),2.55(s,3H),2.20(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.8,156.3,145.2,144.6,134.2,129.7,129.0,125.8,125.0,124.7,118.2,16.7,14.0；HRMS(ESI)calcd forC18H18O2S(M+H)+299.1100,found 299.1106.
实施例10：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸(化合物10)的制备
将化合物9(200mg,0.67mmol)和溴乙酸乙酯(224mg,1.34mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(463mg,3.35mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到中间体羧酸酯，为黄色油状物，183mg，产率71％。将上述羧酸酯(300mg，0.78mmol)溶解于THF/H2O(8mL/8mL)中，加入氢氧化锂(112mg，4.68mmol)，并在50℃下搅拌过夜，然后用盐酸(1mol/L)将溶液调节至pH＝2，并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到化合物10，为黄色固体，180mg，产率65％。1HNMR(400MHz,DMSO-d6)δ8.14–8.03(m,2H),7.80(d,J＝15.5Hz,1H),7.61(d,J＝15.5Hz,1H),7.56(s,2H),7.43–7.29(m,2H),4.43(s,2H),2.55(s,3H),2.27(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.9,170.2,157.4,145.5,143.5,133.9,131.1,130.5,129.7,129.1,125.0,120.8,68.8,16.1,14.0；HRMS(ESI)calcd for C20H20O4S(M+H)+357.1155,found357.1159.
实施例11：(E)-3-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物11)的制备
将化合物9(100mg,0.34mmol)和2-溴乙醇(125mg,1.00mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(232mg,1.68mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到黄色固体65mg,产率57％。1HNMR(400MHz,DMSO-d6)δ8.12–8.06(m,2H),7.80(d,J＝15.5Hz,1H),7.62(d,J＝15.5Hz,1H),7.56(s,2H),7.42–7.37(m,2H),4.91(t,J＝5.5Hz,1H),3.84–3.79(m,2H),3.74–3.68(m,2H),2.56(s,3H),2.28(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.8,157.9,145.4,143.6,133.9,131.2,130.0,129.7,129.0,125.0,120.5,74.0,60.5,16.0,14.0；HRMS(ESI)calcd for C20H22O3S(M+H)+343.1362,found 343.1364.
实施例12：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯氧基)丁酸(化合物12)的制备
将化合物9(200mg,0.67mmol)和2-溴丁酸甲酯(363mg,2.01mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(463mg,3.35mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到中间体羧酸酯，为黄色油状物，210mg，产率79％。将上述羧酸酯(200mg,0.50mmol)溶解于THF/H2O(5mL/5mL)中，加入氢氧化锂(72mg,3.00mmol)，并在50℃下搅拌过夜，然后用盐酸(1mol/L)将溶液调节至pH＝2，并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到化合物12，为黄色固体，120mg，产率62％。1HNMR(400MHz,DMSO-d6)δ8.14–8.04(m,2H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.55(s,2H),7.44–7.35(m,2H),4.44(t,J＝5.9Hz,1H),2.55(s,3H),2.28(s,6H),1.97–1.81(m,2H),0.98(t,J＝7.4Hz,3H)；13C NMR(100MHz,DMSO-d6)δ187.8,172.1,157.0,145.5,143.5,133.9,130.8,129.9,129.9,129.1,125.0,120.6,81.2,25.7,16.9,14.0,9.0；HRMS(ESI)calcd for C22H24O4S(M+H)+385.1468,found 385.1473.
实施例13：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(化合物13)的制备
将化合物9(150mg,0.50mmol)和2-溴-2-甲基丙酸叔丁酯(336mg,1.51mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(347mg,2.51mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到中间体羧酸酯，为黄色油状物，180mg，产率82％。将上述羧酸酯(180mg,0.41mmol)溶解于二氯甲烷中，加入三氟乙酸(466mg,4.08mmol)，并在常温下搅拌过夜，浓缩并通过硅胶柱纯化，得到化合物13，为黄色固体，110mg，产率70％。1HNMR(400MHz,DMSO-d6)δ8.21–7.99(m,2H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.55(s,2H),7.42–7.36(m,2H),2.56(s,3H),2.22(s,6H),1.39(s,6H)；13C NMR(101MHz,DMSO-d6)δ187.78,174.96,154.94,145.40,143.32,133.87,133.14,130.19,129.33,129.00,124.93,120.84,80.69,24.99,17.53,13.94；HRMS(ESI)calcd for C22H24O4S(M+H)+385.1468,found 385.1468.
实施例14：(E)-2-((2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯氧基)甲基)丙烯酸(化合物14)的制备
将化合物9(200mg,0.67mmol)和2-(溴甲基)丙烯酸甲酯(239mg,1.34mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(463mg,3.35mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到中间体羧酸酯，为黄色油状物，185mg，产率70％。将上述羧酸酯(185mg,0.47mmol)溶解于THF/H2O(5mL/5mL)中，加入氢氧化锂(67mg,2.80mmol)，并在50℃下搅拌过夜，然后用盐酸(1mol/L)将溶液调节至pH＝2，并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到化合物14，为黄色固体，55mg，产率31％。1HNMR(400MHz,CDCl3)δ7.98–7.94(m,2H),7.73(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.35–7.28(m,4H),6.60–6.56(m,1H),6.29–6.25(m,1H),4.56–4.52(m,2H),2.54(s,3H),2.31(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.9,166.8,157.5,145.5,143.6,137.6,133.9,131.3,130.4,129.7,129.1,126.7,125.0,120.8,70.2,16.1,14.0；HRMS(ESI)calcd for C22H22O4S(M+H)+383.1312,found 383.1315.
实施例15：(E)-5-(2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯氧基)戊酸(化合物15)的制备
将化合物9(200mg,0.67mmol)和5-溴戊酸乙酯(420mg,2.01mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(463mg,3.35mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到中间体羧酸酯，为黄色油状物，240mg，产率84％。将上述羧酸酯(180mg,0.42mmol)溶解于THF/H2O(4mL/4mL)中，加入氢氧化锂(50mg,2.10mmol)，并在50℃下搅拌过夜，然后用盐酸(1mol/L)将溶液调节至pH＝2，并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到化合物15，为黄色固体，121mg，产率72％。1HNMR(400MHz,DMSO-d6)δ8.12–8.06(m,2H),7.80(d,J＝15.5Hz,1H),7.62(d,J＝15.5Hz,1H),7.57(s,2H),7.43–7.36(m,2H),3.77(t,J＝5.8Hz,2H),2.56(s,3H),2.31(t,J＝6.9Hz,2H),2.25(s,6H),1.77–1.70(m,4H)；13C NMR(100MHz,DMSO-d6)δ187.8,174.5,157.9,145.4,143.6,133.9,131.1,130.1,129.6,129.0,124.9,120.5,71.5,33.5,29.4,21.3,16.0,14.0；HRMS(ESI)calcd for C23H26O4S(M+H)+399.1625,found 399.1629.
实施例16：(E)-2,6-二甲基-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯基丙基氨基甲酸酯(化合物16)的制备
将化合物9(50mg,0.17mmol)和三乙胺(3mg,0.03mmol)溶解在无水CH2Cl2中，加入异氰酸丙酯，并在室温下搅拌5h，然后将反应液浓缩并通过硅胶柱纯化得到白色固体46mg,产率72％。1HNMR(400MHz,CDCl3)δ7.99–7.90(m,2H),7.72(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.36–7.27(m,4H),5.21(t,J＝6.1Hz,1H),3.29–3.17(m,2H),2.53(s,3H),2.22(s,6H),1.66–1.53(m,2H),0.97(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ189.3,153.8,150.1,145.6,144.3,134.6,132.3,132.0,129.1,128.8,125.2,121.3,43.1,23.3,16.4,14.9,11.3；HRMS(ESI)calcd for C22H25NO3S(M+H)+384.1628,found 384.1631.
实施例17：(E)-3-(3,5-二甲基-4-(3-吗啉代丙氧基)苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物17)的制备
将化合物9(100mg,0.34mmol)和4-(3-氯丙基)吗啉(110mg,0.67mmol)溶解于2mL无水DMF溶液中，加入碳酸钾(232mg,1.68mmol)，90℃搅拌6h，然后将该反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体101mg,产率71％。1HNMR(400MHz,CDCl3)δ8.00–7.86(m,2H),7.71(d,J＝15.6Hz,1H),7.41(d,J＝15.6Hz,1H),7.34–7.27(m,4H),3.84(t,J＝6.3Hz,2H),3.73(t,J＝4.7Hz,4H),2.59(t,J＝7.3Hz,2H),2.53(s,3H),2.48(t,J＝4.7Hz,4H),2.30(s,6H),2.05–1.95(m,2H)；13C NMR(100MHz,CDCl3)δ189.3,158.3,145.5,144.6,134.8,131.8,130.5,129.3,129.0,125.2,120.6,70.3,67.1,55.5,53.8,27.5,16.5,15.0；HRMS(ESI)calcd for C25H31NO3S(M+H)+426.2097,found426.2101.
实施例18：(E)-4-(3-(4-(甲硫基)苯基)-3-氧代丙-1-烯-1-基)苯甲酸(化合物18)的制备
将4-甲巯基苯乙酮(366mg,2.20mmol)和4-甲酰基苯甲酸(300mg,2.00mmol)溶解在10mL甲醇中，加入4mL40％的氢氧化钠溶液，室温下搅拌24h,随后，将溶液调节至pH＝2，然后过滤沉淀，用甲醇洗涤并干燥,得到黄色固体415mg,产率70％。1H NMR(400MHz,DMSO-d6)δ8.14–8.10(m,2H),8.03(d,J＝15.6Hz,1H),8.00–7.97(m,4H),7.76(d,J＝15.6Hz,1H),7.47–7.35(m,2H),2.56(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.9,167.2,145.9,142.4,138.4,133.6,129.7,129.2,128.8,125.0,123.8,14.0；HRMS(ESI)calcd forC17H14O3S(M+H)+299.0736,found 299.0740.
实施例19：(E)-3-(4-羟苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物19)的制备
参照实施例9的方法，得到黄色固体，产率60％。1HNMR(400MHz,DMSO-d6)δ10.11(s,1H),8.10–8.03(m,2H),7.76–7.64(m,4H),7.43–7.32(m,2H),6.88–6.80(m,2H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.8,160.1,145.1,144.2,134.1,131.0,128.9,125.9,124.9,118.3,115.9,14.0；HRMS(ESI)calcd for C16H14O2S(M+H)+271.0787,found271.0812.
实施例20：(E)-3-(4-羟基-3-甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物20)的制备
参照实施例9的方法，得到黄色固体，产率63％。1HNMR(400MHz,DMSO-d6)δ10.00(s,1H),8.12–7.99(m,2H),7.73–7.66(m,2H),7.63(d,J＝15.4Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.41–7.35(m,2H),6.85(d,J＝8.3Hz,1H),2.55(s,3H),2.17(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.7,158.4,145.0,144.4,134.2,131.3,128.9,125.7,124.9,124.7,118.0,114.9,15.9,14.0；HRMS(ESI)calcd for C17H16O2S(M+H)+285.0944,found285.0968.
实施例21：(E)-3-(4-羟基-3-甲氧基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物21)的制备
参照实施例9的方法，得到黄色固体，产率51％。1HNMR(400MHz,DMSO-d6)δ9.68(s,1H),8.11–8.02(m,2H),7.75(d,J＝15.4Hz,1H),7.67(d,J＝15.4Hz,1H),7.51(d,J＝2.0Hz,1H),7.43–7.35(m,2H),7.28(dd,J＝8.3,1.9Hz,1H),6.84(d,J＝8.1Hz,1H),3.87(s,3H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.8,149.7,148.0,145.1,144.6,134.2,128.9,126.3,124.9,124.1,118.5,115.6,111.7,55.8,14.0；HRMS(ESI)calcd forC17H16O3S(M+H)+301.0893,found 301.0911.
实施例22：(E)-3-(3-氟-4-羟基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物22)的制备
参照实施例9的方法，得到黄色固体，产率30％。1HNMR(400MHz,DMSO-d6)δ10.51(s,1H),8.12–8.03(m,2H),7.85(dd,J＝12.6,2.1Hz,1H),7.79(d,J＝15.5Hz,1H),7.64(d,J＝15.5Hz,1H),7.52–7.47(m,1H),7.41–7.36(m,2H),7.06–6.88(m,1H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.7,151.2(d,J＝241.6Hz),147.5(d,J＝12.5Hz),145.3,143.0(d,J＝2.5Hz),133.9,129.0,126.9(d,J＝2.6Hz),126.7(d,J＝6.6Hz),124.9,120.0,117.8(d,J＝3.3Hz),115.8(d,J＝18.6Hz),14.0；HRMS(ESI)calcd for C16H13FO2S(M+H)+289.0693,found289.0712.
实施例23：(E)-3-(2-氟-4-羟基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物23)的制备
参照实施例9的方法，得到黄色固体，产率18％。1HNMR(400MHz,DMSO-d6)δ10.58(s,1H),8.09–8.01(m,2H),7.94(t,J＝8.8Hz,1H),7.81–7.70(m,2H),7.43–7.35(m,2H),6.72(dd,J＝8.6,2.3Hz,1H),6.66(dd,J＝12.6,2.3Hz,1H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.7,162.2(d,J＝250.0Hz),,161.7(d,J＝12.6Hz),145.4,135.5(d,J＝3.7Hz),133.9,130.3(d,J＝4.5Hz),128.9,125.0,120.1(d,J＝4.3Hz),113.4(d,J＝11.5Hz),112.64(d,J＝2.3Hz),102.9(d,J＝24.1Hz),14.0；HRMS(ESI)calcd for C16H13FO2S(M+H)+289.0693,found 289.0708.
实施例24：(E)-3-(3-氯-4-羟基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物24)的制备
参照实施例9的方法，得到黄色固体，产率23％。1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.14–8.06(m,2H),8.02(d,J＝2.1Hz,1H),7.81(d,J＝15.5Hz,1H),7.67–7.60(m,2H),7.41–7.36(m,2H),7.02(d,J＝8.4Hz,1H),2.55(s,1H)；13C NMR(100MHz,DMSO-d6)δ187.7,155.3,145.3,142.7,133.9,130.1,129.7,129.0,127.2,124.9,120.5,119.8,116.7,14.0；HRMS(ESI)calcd for C16H13ClO2S(M+H)+305.0398,found 305.0411.
实施例25：(E)-3-(4-羟基-2,5-二甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物25)的制备
参照实施例9的方法，得到黄色固体，产率71％。1HNMR(400MHz,DMSO-d6)δ9.87(s,1H),8.17–8.01(m,2H),7.92(d,J＝15.3Hz,1H),7.81(s,1H),7.64(d,J＝15.3Hz,1H),7.45–7.28(m,2H),6.67(s,1H),2.55(s,3H),2.33(s,3H),2.15(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.7,158.1,145.0,141.0,137.8,134.2,129.5,128.9,124.9,123.9,122.4,118.4,116.6,19.0,15.5,14.0；HRMS(ESI)calcd for C18H18O2S(M+H)+299.1100,found299.1114.
实施例26：(E)-3-(4-羟基-2,6-二甲基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物26)的制备
参照实施例9的方法，得到黄色固体，产率48％。1HNMR(400MHz,DMSO-d6)1HNMR(400MHz,DMSO-d6)δ9.73(s,1H),δ8.02–7.95(m,2H),7.85(d,J＝15.8Hz,1H),7.40–7.35(m,2H),7.28(d,J＝15.8Hz,1H),6.56(s,2H),2.53(s,3H),2.34(s,6H)；13C NMR(100MHz,DMSO-d6)δ188.1,158.0,145.4,141.6,139.8,134.1,129.0,125.1,124.6,124.4,115.8,21.6,14.0；HRMS(ESI)calcd for C18H18O2S(M+H)+299.1100,found 299.1113.
实施例27：(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物27)的制备
参照实施例9的方法，得到黄色固体，产率45％。1HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.13–8.06(m,2H),7.78(d,J＝15.4Hz,1H),7.67(d,J＝15.4Hz,1H),7.43–7.36(m,2H),7.20(s,2H),3.85(s,6H),2.56(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.8,148.1,145.1,145.0,138.7,134.1,129.0,125.1,124.9,118.9,106.9,56.2,14.0；HRMS(ESI)calcd for C18H18O4S(M+H)+331.0999,found 331.1000.
实施例28：(E)-3-(3,5-二乙基-4-羟苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物28)的制备
参照实施例9的方法，得到黄色固体，产率69％。1HNMR(400MHz,DMSO-d6)δ8.81(s,1H),8.19–7.99(m,2H),7.72(d,J＝15.4Hz,1H),7.64(d,J＝15.4Hz,1H),7.48(s,2H),7.42–7.34(m,2H),2.63(q,J＝7.5Hz,4H),2.55(s,3H),1.17(t,J＝7.5Hz,6H)；13C NMR(100MHz,DMSO-d6)δ187.7,155.2,145.0,144.8,134.2,130.9,128.9,128.1,126.1,124.9,118.1,23.0,14.4,14.0；HRMS(ESI)calcd for C20H22O2S(M+H)+327.1413,found 327.1429.
实施例29：(E)-3-(3,4-二羟基苯基)-1-(4-(甲硫基)苯基)丙-2-烯-1-酮(化合物29)的制备
参照实施例9的方法，得到黄色固体，产率46％。1HNMR(400MHz,DMSO-d6)δ9.61(s,1H),9.25(s,1H),8.14–7.93(m,2H),7.66–7.53(m,2H),7.43–7.34(m,2H),7.26(d,J＝2.1Hz,1H),7.18(dd,J＝8.2,2.1Hz,1H),6.81(d,J＝8.2Hz,1H),2.55(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.8,148.7,145.6,145.1,144.7,134.2,128.9,126.4,125.0,122.2,118.3,115.8,115.6,14.0；HRMS(ESI)calcd for C16H14O3S(M+H)+287.0736,found287.0740.
实施例30：(E)-1-(4-氟苯基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(化合物30)的制备
参照实施例9的方法，得到黄色固体，产率63％。1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.29–8.09(m,2H),7.71(d,J＝15.4Hz,1H),7.62(d,J＝15.4Hz,1H),7.48(s,2H),7.41–7.31(m,2H)；13C NMR(100MHz,DMSO-d6)δ187.4,164.9(d,J＝251.3Hz),156.4,145.1,134.7(d,J＝2.9Hz),131.3(d,J＝9.2Hz),129.7,125.7,124.7,118.0,115.7(d,J＝21.7Hz),16.6；HRMS(ESI)calcd for C17H15FO2(M+H)+271.1129,found 271.1131.
实施例31：(E)-1-(4-氯苯基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(化合物31)的制备
参照实施例9的方法，得到黄色固体，产率67％。1HNMR(400MHz,DMSO-d6)δ8.18–8.10(m,2H),7.70(d,J＝15.4Hz,1H),7.65–7.58(m,3H),7.49(s,2H),2.21(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.7,156.5,145.4,137.7,136.7,130.3,129.8,128.8,125.6,124.7,117.9,16.5；HRMS(ESI)calcd for C17H15ClO2(M+H)+287.0833,found 287.0832.
实施例32：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-碘苯基)丙-2-烯-1-酮(化合物32)的制备
参照实施例9的方法，得到黄色固体，产率44％。1HNMR(400MHz,DMSO-d6)δ7.96–7.92(m,2H),7.91–7.86(m,2H),7.67(d,J＝15.5Hz,1H),7.61(d,J＝15.5Hz,3H),7.49(s,2H),2.20(s,6H)；13C NMR(100MHz,DMSO-d6)δ188.3,156.5,145.4,137.7,137.3,130.2,129.8,125.7,124.7,117.9,101.4,16.6；HRMS(ESI)calcd for C17H15IO2(M+H)+379.0189,found379.0197.
实施例33：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲基亚磺酰基)苯基)丙-2-烯-1-酮(化合物33)的制备
在0℃搅拌条件下，将化合物9(500mg，1.68mmol)溶解在15mL无水CH2Cl2溶液中，然后将3-氯过氧苯甲酸(289mg，1.68mmol)缓慢加入到上述溶液中并在室温下继续搅拌5h，然后将溶液过滤，滤饼通过色谱柱纯化得到黄色固体354mg，产率67％。1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.31–8.25(m,2H),7.87–7.82(m,2H),7.73(d,J＝15.5Hz,1H),7.65(d,J＝15.5Hz,1H),7.50(s,2H),2.81(s,3H),2.21(s,6H)；13C NMR(100MHz,DMSO-d6)δ188.4,156.6,151.0,145.7,139.8,129.9,129.1,125.6,124.7,123.9,118.2,43.1,16.6；HRMS(ESI)calcd for C18H18O3S(M+H)+315.1049,found 315.1051.
实施例34：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲基磺酰基)苯基)丙-2-烯-1-酮(化合物34)的制备
在搅拌条件下，将化合物9(500mg，1.68mmol)溶解在15mL无水CH2Cl2溶液中，然后将3-氯过苯甲酸(754mg，4.37mmol)缓慢加入到上述溶液中丙在室温搅拌5h，然后将溶液过滤，滤饼通过色谱柱纯化得到黄色固体338mg,产率61％。1H NMR(400MHz,DMSO-d6)δ8.38–8.27(m,2H),8.15–8.02(m,2H),7.72(d,J＝15.6Hz,1H),7.66(d,J＝15.6Hz,1H),7.52(s,2H),3.31(s,3H),2.20(s,6H)；13C NMR(100MHz,DMSO-d6)δ188.4,156.9,146.4,143.9,142.0,130.1,129.3,127.5,125.5,124.8,118.1,43.4,16.7；HRMS(ESI)calcd forC18H18O4S(M+H)+331.0999,found 331.0996.
实施例35：(E)-1-([[1,1'-联苯]-4-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(化合物35)的制备
参照实施例9的方法，得到黄色固体，产率47％。1HNMR(400MHz,DMSO-d6)δ8.27–8.18(m,2H),7.87–7.81(m,2H),7.80–7.71(m,3H),7.65(d,J＝15.5Hz,1H),7.55–7.47(m,4H),7.46–7.39(m,1H),2.21(s,6H)；13C NMR(100MHz,DMSO-d6)δ188.5,156.5,145.0,144.3,139.1,136.9,129.9,129.3,128.5,127.1,127.0,125.8,124.8,118.4,16.7；HRMS(ESI)calcd for C23H20O2(M+H)+329.1536,found 329.1537.
实施例36：
中间体1-(4-(噻吩-2-基)苯基)乙-1-酮(中间体1h)的制备
N2保护下，将4-溴苯乙酮(200mg,1.01mmol)，噻吩2-基硼酸(386mg,3.02mmol)，碳酸钾(277mg,2.01mmol)，和四(三苯基膦)钯(116mg,0.10mmol)溶解于5mLDME溶液中，并在90℃条件下搅拌过夜，然后将反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体145mg,产率71％。1H NMR(400MHz,CDCl3)δ7.99–7.95(m,2H),7.73–7.67(m,2H),7.44(dd,J＝3.6,1.1Hz,1H),7.37(dd,J＝5.1,1.1Hz,1H),7.12(dd,J＝5.1,3.6Hz,1H),2.62(s,3H).
(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(噻吩-2-基)苯基)丙-2-烯-1-酮(化合物36)的制备的制备
参照实施例9的方法，得到黄色固体，产率38％。1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.24–8.12(m,2H),7.88–7.79(m,2H),7.78–7.70(m,2H),7.69–7.60(m,2H),7.51(s,2H),7.20(dd,J＝5.1,3.7Hz,1H),2.22(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.9,156.4,144.9,142.2,137.7,136.7,129.8,129.4,128.9,127.5,125.7,125.5,125.4,124.7,118.2,16.6；HRMS(ESI)calcd for C21H18O2S(M+H)+335.1100,found 35.1103.
实施例37：
中间体1-(4-(5-甲基噻吩-2-基)苯基)乙-1-酮(中间体1i)的制备
N2保护下，将4-溴苯乙酮(200mg,1.01mmol)，(5-甲基噻吩-2-基)硼酸(285mg,2.01mmol)，碳酸钾(277mg,2.01mmol)，和四(三苯基膦)钯(116mg,0.10mmol)溶解于5mLDME溶液中，并在90℃条件下搅拌过夜，然后将反应液用水稀释并用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体148mg,产率68％。1HNMR(400MHz,CDCl3)δ7.98–7.90(m,2H),7.69–7.57(m,2H),7.24(d,J＝3.6Hz,1H),6.77(m,1H),2.60(s,3H),2.53(d,J＝1.1Hz,3H).
(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(5-甲基噻吩-2-基)苯基)丙-2-烯-1-酮(化合物37)的制备
参照实施例9的方法，得到黄色固体，产率34％。1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.18–8.08(m,2H),7.80–7.68(m,3H),7.62(d,J＝15.4Hz,1H),7.55–7.46(m,3H),6.94–6.81(m,1H),2.50–2.46(m,3H),2.21(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.8,156.3,144.7,141.2,139.7,138.0,136.3,129.7,129.4,127.4,125.8,125.5,124.8,124.7,118.2,16.6,15.2；HRMS(ESI)calcd for C22H20O2S(M+H)+349.1257,found349.1261.
实施例38：
中间体N-(4-乙酰基苯基)-4-氟苯磺酰胺(中间体1j)的制备
0℃搅拌条件下，将对氨基苯乙酮(100mg,0.74mmol)溶解于1.5mL无水THF溶液中，加入吡啶(175mg,2.22mmol)，再缓慢加入对氟苯磺酰氯(172mg,0.89mmol)，并在室温下继续搅拌5h，然后将溶液用水稀释，用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体205mg,产率77％。1HNMR(400MHz,CDCl3)δ7.90–7.83(m,4H),7.39(s,1H),7.19–7.11(m,4H),2.54(s,3H)。
(E)-4-氟-N-(4-(3-(4-羟基-3,5-二甲基苯基)丙烯酰基)苯基)苯磺酰胺(化合物38)的制备
参照实施例9的方法，得到黄色固体，产率49％。1HNMR(400MHz,DMSO-d6)δ8.93(s,1H),8.07–7.99(m,2H),7.95–7.86(m,2H),7.62(d,J＝15.4Hz,1H),7.55(d,J＝15.4Hz,1H),7.49–7.37(m,4H),7.32–7.20(m,2H),2.19(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.4,164.6(d,J＝252.3Hz),156.3,144.5,141.8,135.7(d,J＝2.9Hz),133.4,130.0,129.9(d,J＝9.7Hz),129.6,125.8,124.7,118.4,118.1,116.8(d,J＝23.0Hz),16.6；HRMS(ESI)calcdfor C23H20FNO4S(M+H)+426.1170,found426.1175.
实施例39：
中间体N-(4-乙酰基苯基)异丙基氨基磺酰胺(中间体1k)的制备
0℃搅拌条件下，将对氨基苯乙酮(50mg,0.37mmol)溶解于2mL无水CH2Cl2溶液中，加入三乙胺(74mg,0.74mmol)，再缓慢加入异丙基氨基磺酰氯(70mg,0.44mmol)，并在室温下继续搅拌5h，然后将溶液用水稀释，用乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体54mg,产率57％。1HNMR(400MHz,CDCl3)δ7.98–7.86(m,2H),7.21–7.13(m,2H),7.07(s,1H),4.56(d,J＝7.7Hz,1H),3.64–3.50(m,1H),2.57(s,3H),1.13(d,J＝6.5Hz,6H).
(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-{[((丙-2-基)氨磺酰基]氨基}苯基)丙-2-烯-1-酮(化合物39)的制备
参照实施例9的方法，得到黄色固体，产率37％。1HNMR(400MHz,DMSO-d6)δ10.22(s,1H),8.90(s,1H),8.13–8.01(m,2H),7.77–7.64(m,2H),7.57(d,J＝15.4Hz,1H),7.47(s,2H),7.29–7.17(m,2H),3.34–3.29(m,1H),2.20(s,6H),0.99(d,J＝6.5Hz,6H)；13C NMR(100MHz,DMSO-d6)δ187.4,156.2,144.1,143.6,131.5,129.9,129.6,125.9,124.7,118.3,116.5,45.2,23.1,16.6；HRMS(ESI)calcd for C20H24N2O4S(M+H)+389.1560,found389.1532.
实施例40：
中间体N-(4-乙酰基苯基)丙烯酰胺(中间体1l)的制备
0℃搅拌条件下，将对氨基苯乙酮(405mg,3.00mmol)溶解于7mL无水THF溶液中，加入三乙胺(413mg,4.20mmol)，再缓慢加入丙烯酰氯(299mg,3.30mmol)，并在室温下继续搅拌5h，然后将溶液过滤，将滤液用水和乙酸乙酯萃取，合并有机层，浓缩并通过硅胶柱纯化，得到白色固体428mg,产率75％。1HNMR(400MHz,CDCl3)δ7.99–7.89(m,3H),7.74–7.67(m,2H),6.47(dd,J＝16.9,1.2Hz,1H),6.30(dd,J＝16.9,10.2Hz,1H),5.81(dd,J＝10.2,1.2Hz,1H),2.58(s,3H).
(E)-N-(4-(3-(4-羟基-3,5-二甲基苯基)丙烯酰基)苯基)丙烯酰胺(化合物40)的制备
参照实施例9的方法，得到黄色固体，产率66％。1HNMR(400MHz,DMSO-d6)δ10.51(s,1H),8.94(s,1H),8.17–8.11(m,2H),7.87–7.81(m,2H),7.71(d,J＝15.4Hz,1H),7.60(d,J＝15.4Hz,1H),7.48(s,2H),6.48(dd,J＝17.0,10.0Hz,1H),6.32(dd,J＝17.0,2.0Hz,1H),5.82(dd,J＝10.0,2.0Hz,1H),2.20(s,6H)；13C NMR(100MHz,DMSO-d6)δ187.5,163.7,156.3,144.4,143.2,133.1,131.6,129.8,129.7,128.0,125.9,124.8,118.9,118.3,16.6；HRMS(ESI)calcd for C20H19NO2(M+H)+322.1438,found 322.1437.
实施例41：1,3-二苯基丙-2-烯-1-酮衍生物对NLRP3炎症小体抑制作用的体外研究
将J774A.1细胞分到96孔板上，每个孔5×105个细胞，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，然后加入不同浓度的(1μM、2μM、5μM、10μM、20μM、40μM)1,3-二苯基丙-2-烯-1-酮衍生物处理1小时，再加入尼日利亚菌素(Nigericin，10μM)处理1小时，之后收集细胞上清液，采用Mouse IL-1βELISA试剂盒测定IL-1β含量，计算出本发明化合物对NLRP3炎症小体的抑制作用，结果见表1。
表1 1,3-二苯基丙-2-烯-1-酮衍生物对J774A.1细胞中NLRP3炎症小体活化介导的IL-1β释放的抑制活性(IC50，μM)
实施例42:化合物40在体外特异性抑制NLRP3炎性体的活化并抑制细胞焦亡
1、NLRP3炎症小体激活及IL-1β检测：将J774A.1细胞或小鼠骨髓来源的巨噬细胞(BMDMs)分到96孔板上，每个孔5×105个细胞，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，然后加入不同浓度的(1μM、2μM、5μM)化合物40处理1h，再加入尼日利亚菌素(Nigericin，10μM)处理1h，之后收集细胞上清液，采用Mouse IL-1βELISA试剂盒测定IL-1β含量。
2、细胞焦亡检测：如前所述处理J774A.1细胞，然后使用LDH检测试剂盒评估细胞上清液中LDH的释放。
3、蛋白质免疫印迹分析：将步骤1处理后的J774A.1细胞样品在带有蛋白酶抑制剂的RIPA裂解缓冲液中于4℃裂解30min。裂解液或上清液中的蛋白质用12％SDS-聚丙烯酰胺凝胶分离，转移到PVDF膜上，并与抗鼠IL-1β抗体，抗ASC抗体，抗casepase-1抗体，抗NLRP3抗体，抗β-actin抗体进行蛋白免疫印迹分析。
4、NLRC4和AIM2炎症小体激活及IL-1β检测:对于NLRC4或AIM2炎性体激活，用1μg/mLLPS刺激J774A.1细胞5h，然后加入不同浓度的(1μM、2μM、5μM)化合物40处理1h，然后用细菌鞭毛蛋白(FLA-STUltrapure)(2.5μg/mL)感染细胞4h，或用poly(dA：dT)(0.25μg/mL)转染细胞4h，之后收集细胞上清液，采用Mouse IL-1βELISA试剂盒测定IL-1β含量。
结果如图1所示，从图1的结果来看，在NLRP3炎症小体激活的J774A.1和BMDMs细胞模型中，化合物40可以浓度依赖性地抑制IL-1β的分泌(图1中的A图和B图)。蛋白质免疫印迹实验显示化合物40抑制caspase-1p20成熟和IL-1β分泌的作用呈剂量依赖性，但不影响细胞裂解物中的pro-IL-1β，pro-caspase-1，NLRP3或ASC(图1中的C图)。化合物40还可以抑制LPS/尼日利亚霉素诱导的细胞焦亡(图1中的D图和E图)。与此同时，化合物40对AIM2或NLRC4炎性小体的激活没有抑制作用(图1中的F图)。以上结果表明，化合物40可以特异性抑制NLRP3炎性小体依赖性的caspase-1激活和IL-1β分泌。
实施例43：化合物40抑制LPS诱导的急性腹膜炎
1、6-8周雌性C57BL/6小鼠分成4组，每组6只，具体分组处理如下：
第一组：连续三天灌胃空白媒介物；
第二组：连续三天灌胃空白媒介物，第三天腹腔内注射LPS(20mg/kg)；
第三组：连续三天灌胃化合物40(25mg/kg/天，第三天腹腔内注射LPS(20mg/kg)；
第四组：连续三天灌胃化合物40(100mg/kg/天)，第三天腹腔内注射LPS(20mg/kg)；
2、LPS腹腔注射6h后，收集血液，同时对每组小鼠腹腔灌注1mlPBS，取腹腔灌洗液，对血液和腹腔灌洗液离心。
3、将步骤2所得血液上清和腹腔灌洗液上清用ELISA的方法进行IL-1β含量测定，结果见图2。
从图2的结果看，注射LPS后，小鼠血液中和腹腔液中的IL-1β含量明显上升，而灌胃化合物40可以剂量依赖性降低IL-1β水平，表明化合物40可以有效抑制LPS诱导的急性腹膜炎。
实施例44：化合物40改善硫酸葡聚糖钠(DSS)诱导的结肠炎
1、6-8周雌性C57BL/6小鼠分成4组，每组5只，具体分组处理如下：
第一组：第1-10天在饮食中给予蒸馏水，同时每天灌胃媒介物；
第二组：第1-3天饮食中给予蒸馏水，第4-10天开始每天在饮食中给予2％DSS的蒸馏水，同时每天灌胃媒介物；
第三组：连续10天灌胃化合物40(25mg/kg/天)，第四天开始每天在饮食中给予2％DSS的蒸馏水；
第四组:连续10天灌胃化合物40(100mg/kg/天)，第四天开始每天在饮食中给予2％DSS的蒸馏水；
2、从给药后开始每天监测每组小鼠的便血程度和体重，并在第11天取小鼠结肠进行长度测量及对结肠中的IL-1β含量测定。
结果如图3所示，从图3的结果来看，在饮食中给予2％DSS后，小鼠的便血严重程度增加，而且小鼠结肠长度缩短，结肠中IL-1β显著升高，灌胃化合物40可以剂量依赖性改善小鼠便血，改善结肠长度缩短，降低结肠中IL-1β水平。
活性测试结果表明，本发明的1,3-二苯基丙-2-烯-1-酮类化合物对受试细胞J774A.1细胞显示出抑制NLRP3炎症小体的活性。同时代表性化合物40可以选择性抑制NLRP3炎症小体的激活，同时可以改善LPS诱导的急性腹膜炎和DSS诱导的结肠炎，可见，本发明的1,3-二苯基丙-2-烯-1-酮类化合物具有用于治疗NLRP3炎症小体相关疾病的用途。
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 (4)
1.1,3-二苯基丙-2-烯-1-酮衍生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1,3-二苯基丙-2-烯-1-酮衍生物选自如下化合物：
2.权利要求1中所述的1,3-二苯基丙-2-烯-1-酮衍生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。
3.根据权利要求2所述的应用，其特征在于，所述与NLRP3炎症小体相关的疾病为腹膜炎和结肠炎。
4.根据权利要求3所述的应用，其特征在于，所述腹膜炎为急性腹膜炎。
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