CN116925040A - 一种靶向冠状病毒3CL蛋白酶的PROTACs及其制备方法与应用 - Google Patents
一种靶向冠状病毒3CL蛋白酶的PROTACs及其制备方法与应用 Download PDFInfo
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
本发明公开了一种靶向冠状病毒3CL蛋白酶的PROTACs的制备方法和应用,属于药物化学领域。该靶向冠状病毒3CL蛋白酶的PROTACs具有如式Ⅰ或式Ⅱ所示的结构,本发明选用Cereblon蛋白(CRBN)的配体来那度胺与泊马度胺为E3连接酶配体,通过不同种类、不同链长的linker将冠状病毒3CL蛋白酶抑制剂与E3连接酶偶联,成功制备得到了靶向冠状病毒3CL蛋白酶的PROTACs,能有效靶向于目标蛋白。本发明克服了现有冠状病毒3CL蛋白酶抑制剂结构类型单一,发挥药效途径有限(仅具有抑制作用)等缺陷,对冠状病毒3CL蛋白酶具有较好的抑制和降解活性,可作为抗冠状病毒候选药物进行开发和研究。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种靶向冠状病毒3CL蛋白酶的PROTACs及其制备方法与应用。
背景技术
COVID-19(新型冠状病毒肺炎)具有高传染性和高致病性,其变异毒株德尔塔和奥密克戎等具有更强的传播能力,层出不穷的变异毒株让全球疫情形势更加复杂,新冠病毒已对人类健康、社会稳定和经济发展构成了严重威胁。
3CLpro(3C样蛋白酶,也称作主要蛋白酶Mpro)作为冠状病毒中重要的一个非结构蛋白,具有与microRNA病毒的3C蛋白酶相似的切割位点特异性,在子代病毒的复制和转录过程中起到极其关键的作用。3CLpro是由306个氨基酸构成的约33kDa的半胱氨酸蛋白酶(较S蛋白小很多),能够特异性地识别非结构蛋白NSP4-NSP16的11个切割位点并进行切割,从而释放出冠状病毒其它的非结构蛋白,经3CLpro自水解剪切释放出的非结构蛋白NSP4-NSP16是病毒基因组复制与转录的承载体,负责蛋白翻译后的切割、修饰以及核酸合成等重要生命过程。抑制3CLpro能够有效的阻断RNA复制和转录的过程,从而阻断病毒的增殖,因此3CLpro被认为是冠状病毒靶向性药物研发最具吸引力的靶标之一。
蛋白水解靶向嵌合分子(PROTACs)是近年来药物开发领域最具颠覆性的技术之一。蛋白水解靶向嵌合体(PROTAC)是一种对蛋白质进行化学降解的技术。它可以同时结合靶蛋白和E3泛素连接酶,让靶蛋白接近E3泛素连接酶,使靶蛋白泛素化,然后通过泛素-蛋白酶体系统(UPS)的降解作用对靶蛋白进行降解,值得一提的是,不管靶蛋白的功能如何,运用PROTAC技术都可将其降解。利用PROTAC技术降解外源性蛋白(如病毒蛋白等)的研究目前处于起步阶段,丙型肝炎病毒(HCV)NS3/4A蛋白酶降解剂DGY-08-097,抗病毒活性和抗耐药性特征显著优于传统药物Telaprevir,证实了PROTACs可以降解病毒相关蛋白。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供一种靶向冠状病毒3CL蛋白酶的PROTACs及其制备方法与应用,治疗冠状病毒所引起的疾病。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一种靶向冠状病毒3CL蛋白酶的PROTACs,为式Ⅰ或式Ⅱ所示化合物或其药学上可接受的盐,以及所述的式Ⅰ或式Ⅱ化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物,包括外消旋混合物;
所述式Ⅰ或式Ⅱ化合物的结构式为:
或
其中,Linker为以下链接基团之一:
其中,n=1-6。
优选地,所述代表性化合物选自如下化合物:
优选地,所述药学上可接受的盐为靶向冠状病毒3CL蛋白酶的PROTACs与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
本发明还公开了上述靶向冠状病毒3CL蛋白酶的PROTACs的制备方法,包括以下操作步骤:
(1)以3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮为原料,与2,4,5-三氟溴苄进行烷基化反应,得到化合物a1;然后在三嗪母核6位处引入6-氯-2-甲基-2H-吲唑单元,得到化合物a2;化合物a2的三嗪母核3位叔丁基在酸性溶剂中脱掉得到化合物a3;随后在化合物a3的三嗪母核3位引入3-丙炔基,最终得到化合物a4;
其中,a1为a2为/>a3为/>a4为/>
(2)以来那度胺为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b1-b6,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c1-c6;
或者,以泊马度胺为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b7-b12,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c7-c12;
其中,b1-b6为n=1-6;c1-c6为/>n=1-6;b7-b12为/>n=1-6;c7-c12为/>n=1-6;
或者,以来那度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d1-d3;
或者,以泊马度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d4-d6;
其中,d1-d3为n=1-6;d4-d6为/>n=1-6;
(3)化合物a4与化合物c1-c6或d1-d3反应,生成如式Ⅰ结构的靶向冠状病毒3CL蛋白酶的PROTACs;
或者,化合物a4与c7-c12或d4-d6反应,生成如式Ⅱ结构的靶向冠状病毒3CL蛋白酶的PROTACs。
优选地,步骤(1)中,3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮与2,4,5-三氟溴苄的摩尔比为1:1.1,化合物a1与6-氯-2-甲基-2H-吲唑-5-胺的摩尔比为1:1.3,化合物a3与3-溴丙炔的摩尔比为1:1.2;步骤(2)中,泊马度胺或来那度胺与不同长度的溴代烷酸的摩尔比为1:2,泊马度胺或来那度胺与叠氮-多聚乙二醇-乙酸类化合物的摩尔比为1:2;步骤(3)中,化合物a4与c1-c12或d1-d6的摩尔比为1:1.2。
优选地,步骤(1)中,化合物a2的合成过程中反应温度为0℃,所用催化剂为双三甲基硅基胺基锂;步骤(2)中,化合物b1-b6和b7-b12的合成过程中,用酰氯化试剂溶解不同长度的溴代烷酸,化合物d1-d3和d4-d6的合成过程中,所用缩合剂为氯化亚砜,所用溶剂为四氢呋喃;步骤(3)中所用溶剂为四氢呋喃和水的混合溶剂,混合溶剂中,四氢呋喃与水的体积比为10:1。
优选地,步骤(1)中,化合物a1的合成过程中所用的溶剂为乙腈,在碳酸钾和加热回流条件下反应;化合物a2的合成过程中所用溶剂为四氢呋喃;化合物a4的合成过程所用溶剂为DMF,反应温度为60℃;步骤(2)所述化合物b1-b6和b7-b12的合成过程中所用酰氯化试剂为氯化亚砜;化合物c1-c6和c7-c12的合成所用溶剂为DMF;步骤(3)中,催化剂为五水硫酸铜和抗坏血酸钠;反应条件为氩气保护下45℃反应。
进一步优选地,步骤(2)中,所用酰氯化试剂为氯化亚砜。
本发明还公开了上述靶向冠状病毒3CL蛋白酶的PROTACs在制备抗冠状病毒药物制剂中的应用。
优选地,所述冠状病毒为新型冠状病毒SARS-CoV-2。
优选地,所述制剂为单独使用或与其他抗冠状病毒药物联合使用,或与可药用的赋形剂、稀释剂混合制成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂、预混剂或微丸剂,或者制成非口服方式给药的搽剂或注射剂。
本发明还公开了一种药物组合物,所述药物组合物包含上述的靶向冠状病毒3CL蛋白酶的PROTACs作为活性成分。
与现有技术相比,本发明具有以下有益效果:
本发明提供的一种靶向冠状病毒3CL蛋白酶的PROTACs,选用Cereblon蛋白(CRBN)的配体来那度胺与泊马度胺为E3连接酶配体,通过不同种类、不同链长的linker将冠状病毒3CL蛋白酶抑制剂与E3连接酶偶联,成功制备得到了靶向冠状病毒3CL蛋白酶的PROTACs,能有效靶向于目标蛋白。3CLpro抑制活性测试结果表明,本发明合成的化合物对3CLpro有较强的抑制作用,优选化合物3、4、8、9、10、14和17对3CLpro的IC50值均在100nM以下;3CLpro降解活性实验结果表明,本发明合成的化合物对3CLpro均具有降解活性,优选化合物2、3、4、5、8、9、10、13、14、15、16和17的对于3CLpro的DC50值均在100nM以下。本发明提供的化合物克服了现有冠状病毒3CL蛋白酶抑制剂结构类型单一,发挥药效途径有限(仅具有抑制作用)等缺陷,对冠状病毒3CL蛋白酶具有较好的抑制和降解活性,可作为抗冠状病毒候选药物进行开发和研究。
本发明提供的一种靶向冠状病毒3CL蛋白酶的PROTACs的制备方法,该方法以各种可购买的低价合成砌块为原料,通过常见的化学反应,以较高的收率获得目标产物,所有反应均避免了高温高压以及高毒性试剂的使用,可在较为温和的条件下进行,对反应设备要求低,环境污染小;同时,原子经济性高,适合工业化生产。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面对本发明做进一步详细描述:
本发明提供的一种靶向冠状病毒3CL蛋白酶的PROTACs,为式Ⅰ或式Ⅱ所示化合物或其药学上可接受的盐,以及所述的式Ⅰ或式Ⅱ化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物,包括外消旋混合物;
所述式Ⅰ或式Ⅱ化合物的结构式为:
其中,Linker为以下链接基团之一:
其中,n=1~6;
所述药学上可接受的盐为靶向冠状病毒3CL蛋白酶的PROTACs与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
本发明提供的靶向冠状病毒3CL蛋白酶的PROTACs的制备方法如下:
(1)以3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮为原料,与2,4,5-三氟溴苄进行烷基化反应,得到化合物a1;然后在三嗪母核6位处引入6-氯-2-甲基-2H-吲唑单元,得到化合物a2;化合物a2的三嗪母核3位叔丁基在酸性溶剂中脱掉得到化合物a3;随后在化合物a3三嗪母核3位引入3-丙炔基,最终得到化合物a4,反应式如下:
其中,化合物a1的合成过程中所用的溶剂为乙腈,3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮与2,4,5-三氟溴苄的摩尔比为1:1.1,在碳酸钾和加热回流条件下反应;化合物a2的合成过程中,原料化合物a1与6-氯-2-甲基-2H-吲唑-5-胺的摩尔比为1:1.3,反应温度为0℃,所用溶剂为四氢呋喃,所用催化剂为双三甲基硅基胺基锂(LiHMDS);化合物a3的合成过程中所用的酸性溶剂为三氟乙酸(TFA);化合物a4的合成过程中,原料化合物a3与3-溴丙炔的摩尔比为1:1.2,所用溶剂为N,N-二甲基甲酰胺(DMF),反应温度为60℃;
(2)以来那度胺(购于上海麦克林生化科技有限公司)为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b1-b6,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c1-c6;
或者,以泊马度胺(购于上海麦克林生化科技有限公司)为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b7-b12,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c7-c12,反应式如下:
或者,以来那度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d1-d3;
或者,以泊马度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d4-d6,反应式如下:
其中,所述化合物b1-b6和b7-b12的合成过程中,泊马度胺或来那度胺与不同长度的溴代烷酸的摩尔比为1:2,不同长度的溴代烷酸用酰氯化试剂溶解,所用酰氯化试剂进一步优选为氯化亚砜;化合物c1-c6和c7-c12的合成所用溶剂为DMF,泊马度胺或来那度胺与叠氮-多聚乙二醇-乙酸类化合物的摩尔比为1:2,所用催化剂为碘化钾;所述化合物d1-d3和d4-d6的合成过程中,泊马度胺或来那度胺与叠氮-多聚乙二醇-乙酸类化合物的摩尔比为1:2,所用缩合剂为氯化亚砜,所用溶剂为四氢呋喃;
(3)化合物a4与化合物c1-c6或d1-d3反应,生成如式Ⅰ结构的靶向冠状病毒3CL蛋白酶的PROTACs;
或者,化合物a4与c7-c12或d4-d6反应,生成如式Ⅱ结构的靶向冠状病毒3CL蛋白酶的PROTACs,反应式如下:
其中,反应中化合物a4与c1-c12或d1-d6的摩尔比为1:1.2,反应所用溶剂为四氢呋喃和水的混合溶剂,体积比为四氢呋喃:水=10:1;催化剂为五水硫酸铜和抗坏血酸钠;反应条件为氩气保护下45℃反应。
1.合成化合物1-18的具体实施例
本发明代表性化合物结构式如下所示:
下面给出上述化合物合成的实施例。
实施例1
化合物1:(E)-3-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)丙酰胺的制备
(1)化合物a4的制备
步骤一:化合物a1的合成
将3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮(91.72mg,0.4mmol)、2,4,5-三氟溴苄(99.0mg,0.44mmol)和碳酸钾(66.3mg,0.48mmol)置于反应器中,使用10mL乙腈进行溶解,加热回流,搅拌反应3小时,TLC监测。反应结束后,将反应液减压浓缩除去溶剂,所得固体残留物经饱和氯化钠水溶液洗涤,乙酸乙酯萃取,收集有机相,柱层析分离纯化(正己烷:乙酸乙酯(V:V)为流动相=8:2),干燥得到a1 133.3mg,产率为89.25%。
步骤二:化合物a2的合成
将化合物a1(186.7mg,0.5mmol)和6-氯-2-甲基-2H-吲唑-5-胺(118.1mg,0.65mmol)置于反应器中,使用5mL四氢呋喃进行溶解,在0℃下向反应器中缓慢加入1mmol双三甲基硅基胺基锂(LiHMDS)(0.2mL,1mmol)的四氢呋喃溶液,搅拌反应3小时,TLC监测。反应结束后,冷却至室温,加入氯化铵水溶液进行淬灭,将反应液减压浓缩除去四氢呋喃,所得残留液经饱和氯化钠水溶液洗涤,乙酸乙酯萃取,收集有机相,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10;1为流动相),干燥得到a2 60.7mg,产率为24.63%。
步骤三:化合物a3的合成
将得到的化合物a2(246.4mg,0.5mmol)置于反应器中,加入3mL三氟乙酸(TFA),室温搅拌过夜,然后与甲苯共沸减压浓缩除去溶剂,干燥得到a3 201.0mg,产率为92.03%。
步骤四:化合物a4的合成
将化合物a3(436.8mg,1mmol)、3-溴丙炔(0.1mL,1.2mmol)和碳酸钾(165.9mg,1.2mmol)置于反应器中,使用10mL N,N-二甲基甲酰胺进行溶解,60℃加热搅拌反应5小时,TLC监测。反应结束后,所得反应液经饱和氯化钠水溶液洗涤,乙酸乙酯萃取,收集有机相,柱层析分离纯化(正己烷:乙酸乙酯(V:V)=6:4为流动相),干燥得到化合物a4 312.0mg,产率为65.71%。
(2)化合物c1的制备
步骤一:化合物b1的合成
将3-溴丙酸(305.9mg,2mmol)溶解于5mL氯化亚砜中,加热回流2小时,反应结束后,减压浓缩去除溶剂,随后加入来那度胺(1mmol,259.3mg),10mL四氢呋喃作溶剂,加热回流反应5小时,TLC监测。反应结束,冷却至室温,加入2mL甲醇后继续搅拌1小时。减压浓缩除去溶剂,柱层析分离得到b1 362.1mg(洗脱剂为二氯甲烷:甲醇(V:V)=20:1),产率为91.85%。
步骤二:化合物c1的合成
将化合物b1(197.1mg,0.5mmol)、叠氮化钠(97.5mg,1.5mmol)和碘化钾(8.3mg,0.05mmol)置于反应器中,使用10mL N,N-二甲基甲酰胺进行溶解,70℃加热搅拌反应5小时,TLC监测。反应结束后,所得反应液经饱和氯化钠水溶液洗涤,乙酸乙酯萃取,收集有机相,干燥得到化合物c1 151.6mg,产率为85.16%。
(4)化合物1的制备
将化合物a4(142.4mg,0.3mmol)、化合物c1(128.3mg,0.36mmol)和五水硫酸铜(30.0mg,0.12mmol)、抗坏血酸钠(23.8mg,0.12mmol)置于反应器中,使用10mL四氢呋喃和1mL水的混合溶液进行溶解,氩气保护,45℃加热搅拌过夜,TLC监测。反应结束后,所得反应液减压浓缩除去溶剂,柱层析分离纯化(二氯甲烷:甲醇(V:V)=15:1为流动相),干燥得到化合物1 95.7mg,产率为38.41%。
1H NMR(400MHz,DMSO)δ11.10(s,1H),9.79(s,1H),9.33(s,1H),8.32(s,1H),7.85(d,J=7.1Hz,1H),7.75(s,1H),7.62-7.50(m,2H),7.44–7.37(m,2H),7.30(s,1H),7.28-7.21(m,1H),5.22(s,2H),5.12(dd,J=13.3,4.8Hz,1H),5.03(s,2H),4.57(t,J=6.8Hz,2H),4.45–4.23(m,2H),4.12(3H,s),3.04–2.86(m,1H),2.70(d,J=17.3Hz,1H),2.33-2.12(m,2H),1.95–1.78(m,2H).
13C NMR(101MHz,DMSO)δ173.34,171.42,171.25,168.38,155.61,155.17,150.54,150.41,148.55,146.65,146.31,145.74,143.88,134.34,133.12,132.13,129.10,129.02,127.24,125.89,125.82,120.70,120.41,119.44,118.11,116.74,116.36,106.12,52.08,46.94,40.28,40.13,38.05,36.15,35.60,31.65,28.68.
实施例2
化合物2:(E)-4-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)丁酰胺的制备
制备方法参照实施例1,只需更换相应的原料即可。所得化合物2的产率:35.23%。
1H NMR(400MHz,DMSO)δ11.12(s,1H),9.77(s,1H),9.32(s,1H),8.29(s,1H),7.88(d,J=7.1Hz,1H),7.71(s,1H),7.65-7.53(m,2H),7.48–7.40(m,2H),7.35(s,1H),7.32-7.21(m,1H),5.28(s,2H),5.21(dd,J=13.3,4.8Hz,1H),5.05(s,2H),4.69(t,J=6.8Hz,2H),4.43–4.29(m,2H),4.16(3H,s),3.02–2.81(m,1H),2.60(d,J=17.3Hz,1H),2.50–2.38(m,3H),2.09–2.01(m,1H),1.92–1.80(m,2H).
13C NMR(101MHz,DMSO)δ173.35,171.46,171.26,168.39,155.65,155.15,150.56,150.42,148.57,146.69,146.34,145.77,143.89,134.36,133.15,132.16,129.12,129.00,127.23,125.91,125.80,120.71,120.43,119.46,118.10,116.79,116.32,106.11,52.06,46.84,40.21,40.10,38.06,36.12,35.59,31.61,27.58,24.65.
实施例3
化合物3:(E)-5-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)戊酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物3的产率:30.76%。
1H NMR(400MHz,DMSO)δ11.11(s,1H),9.79(s,1H),9.28(s,1H),8.36(s,1H),7.84(d,J=7.1Hz,1H),7.75(s,1H),7.63-7.52(m,2H),7.47–7.41(m,2H),7.36(s,1H),7.32-7.22(m,1H),5.24(s,2H),5.20(dd,J=13.3,4.8Hz,1H),5.07(s,2H),4.72(t,J=6.8Hz,2H),4.44–4.30(m,2H),4.18(3H,s),3.06–2.88(m,1H),2.61(d,J=17.3Hz,1H),2.51–2.40(m,3H),2.09–2.01(m,1H),1.82–1.70(m,2H),1.57–1.41(m,2H).
13C NMR(101MHz,DMSO)δ173.45,171.56,171.34,168.43,155.62,155.11,150.53,150.41,148.54,146.67,146.33,145.88,143.81,134.34,133.17,132.19,129.10,129.08,127.22,125.90,125.75,120.72,120.44,119.49,118.12,116.80,116.34,106.12,52.00,46.87,40.22,40.11,38.08,36.04,35.62,32.37,31.65,27.54,24.64.
实施例4
化合物4:(E)-6-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-
(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)己酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物4的产率:36.55%。
1H NMR(400MHz,DMSO)δ11.05(s,1H),9.81(s,1H),9.31(s,1H),8.40(s,1H),7.83(d,J=7.1Hz,1H),7.73(s,1H),7.65-7.54(m,2H),7.50–7.41(m,2H),7.38(s,1H),7.32-7.25(m,1H),5.26(s,2H),5.18(dd,J=13.3,4.8Hz,1H),5.04(s,2H),4.67(t,J=6.8Hz,2H),4.47–4.31(m,2H),4.15(3H,s),3.02–2.88(m,1H),2.64(d,J=17.3Hz,1H),2.44–2.30(m,3H),2.10–2.02(m,1H),1.92–1.81(m,2H),1.72–1.60(m,2H),1.57–1.41(m,2H).
13C NMR(101MHz,DMSO)δ173.35,171.68,171.56,168.33,155.58,155.22,150.50,150.43,148.52,146.60,146.38,145.98,143.84,134.26,133.17,132.35,129.12,129.10,127.21,125.93,125.79,120.76,120.54,119.53,118.12,116.70,116.46,106.16,52.00,46.96,40.29,40.06,38.04,36.08,35.61,32.47,31.69,27.66,24.71,23.15.
实施例5
化合物5:(E)-7-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)庚酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物5的产率:21.18%。
1H NMR(400MHz,DMSO)δ11.08(s,1H),9.79(s,1H),9.34(s,1H),8.42(s,1H),7.85(d,J=7.1Hz,1H),7.71(s,1H),7.67-7.54(m,2H),7.49–7.41(m,2H),7.37(s,1H),7.32-7.25(m,1H),5.24(s,2H),5.17(dd,J=13.3,4.8Hz,1H),5.02(s,2H),4.63(t,J=6.8Hz,2H),4.49–4.31(m,2H),4.16(3H,s),3.02–2.88(m,1H),2.65(d,J=17.3Hz,1H),2.42–2.29(m,2H),2.20–2.03(m,4H),1.90–1.79(m,2H),1.70–1.61(m,2H),1.54–1.39(m,2H).
13C NMR(101MHz,DMSO)δ173.39,171.62,171.49,168.36,155.49,155.23,150.51,150.43,148.54,146.62,146.39,145.90,143.81,134.22,133.19,132.29,129.09,129.03,127.26,125.90,125.75,120.72,120.54,119.52,118.11,116.76,116.41,106.14,52.08,46.95,40.30,40.05,38.03,36.12,35.59,32.45,31.70,28.90,27.62,24.74,23.35.
实施例6
化合物6:(E)-8-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)辛酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物2的产率:17.83%。
1H NMR(400MHz,DMSO)δ11.12(s,1H),9.76(s,1H),9.33(s,1H),8.41(s,1H),7.88(d,J=7.1Hz,1H),7.73(s,1H),7.67-7.54(m,2H),7.48–7.42(m,2H),7.36(s,1H),7.31-7.25(m,1H),5.25(s,2H),5.16(dd,J=13.3,4.8Hz,1H),5.04(s,2H),4.69(t,J=6.8Hz,2H),4.45–4.30(m,2H),4.17(3H,s),3.08–2.80(m,1H),2.69(d,J=17.3Hz,1H),2.44–2.29(m,2H),2.24–2.05(m,4H),1.95–1.76(m,4H),1.69–1.58(m,2H),1.49–1.38(m,2H).
13C NMR(101MHz,DMSO)δ173.38,171.58,171.46,168.35,155.43,155.24,150.50,150.41,148.53,146.61,146.36,145.91,143.83,134.23,133.18,132.29,129.12,129.02,127.24,125.95,125.78,120.71,120.56,119.52,118.14,116.72,116.44,106.18,52.12,46.98,40.33,40.10,38.08,36.16,35.61,32.46,31.77,30.15,28.96,27.65,24.76,23.42.
实施例7
化合物7:(E)-3-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)丙酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物7的产率:37.54%。
1H NMR(400MHz,DMSO)δ11.10(s,1H),9.84(s,1H),9.72(s,1H),8.42(d,J=8.3Hz,1H),8.33(s,1H),7.79(t,J=7.8Hz,1H),7.73(s,1H),7.69(d,J=7.2Hz,1H),7.64-7.53(m,2H),7.42(s,1H),7.32-7.22(m,1H),5.23(s,2H),5.14(dd,J=12.8,5.3Hz,1H),5.11(s,2H),4.68(t,J=6.5Hz,2H),4.21(s,3H),2.56–2.44(m,2H),2.33–2.21(m,2H),1.95–1.83(m,2H).
13C NMR(101MHz,DMSO)δ173.32,172.23,170.40,168.21,167.23,155.78,155.33,150.89,150.55,148.63,146.66,146.34,145.86,143.82,136.91,136.62,132.32,131.89,129.43,127.32,126.87,125.89,120.82,120.43,118.82,117.78,116.71,116.38,106.21,48.34,40.45,39.89,37.05,35.29,34.22,32.29,28.78.
实施例8
化合物8:(E)-4-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)丁酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物8的产率:33.77%。
1H NMR(400MHz,DMSO)δ11.09(s,1H),9.82(s,1H),9.74(s,1H),8.39(d,J=8.3Hz,1H),8.35(s,1H),7.86(t,J=7.8Hz,1H),7.70(s,1H),7.68(d,J=7.2Hz,1H),7.63-7.53(m,2H),7.33(s,1H),7.29-7.22(m,1H),5.20(s,2H),5.16(dd,J=12.8,5.3Hz,1H),5.09(s,2H),4.58(t,J=6.5Hz,2H),4.16(s,3H),2.95–2.88(m,1H),2.66–2.54(m,2H),2.43–2.31(m,1H),2.25–2.14(m,2H),1.98–1.84(m,2H).
13C NMR(101MHz,DMSO)δ173.29,172.19,170.29,168.12,167.21,155.45,155.23,150.55,150.44,148.55,146.62,146.31,145.90,143.85,136.89,136.57,132.34,131.95,129.12,127.31,126.92,125.91,120.75,120.52,118.80,117.69,116.69,116.42,106.17,49.33,40.31,40.12,38.03,35.73,35.20,32.09,30.41,24.45.
实施例9
化合物9:(E)-5-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)戊酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物9产率:27.64%。
1H NMR(400MHz,DMSO)δ11.13(s,1H),9.84(s,1H),9.73(s,1H),8.46(d,J=8.3Hz,1H),8.42(s,1H),7.86(t,J=7.8Hz,1H),7.72(s,1H),7.67(d,J=7.2Hz,1H),7.64-7.53(m,2H),7.36(s,1H),7.30-7.22(m,1H),5.24(s,2H),5.18(dd,J=12.8,5.3Hz,1H),5.06(s,2H),4.61(t,J=6.5Hz,2H),4.14(s,3H),2.98–2.87(m,1H),2.68–2.52(m,4H),2.13–2.01(m,1H),1.95–1.84(m,2H),1.81–1.64(m,2H).
13C NMR(101MHz,DMSO)δ173.24,172.17,170.26,168.07,167.14,155.57,155.20,150.51,150.42,148.51,146.64,146.37,145.97,143.81,136.91,136.56,132.35,131.97,129.10,127.36,126.94,125.93,120.76,120.54,118.86,117.65,116.70,116.46,106.16,49.38,40.29,40.06,38.04,35.78,35.17,32.02,31.41,23.81,22.45.
实施例10
化合物10:(E)-6-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)己酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物10的产率:22.19%。
1H NMR(400MHz,DMSO)δ11.14(s,1H),9.90(s,1H),9.83(s,1H),8.49(d,J=8.3Hz,1H),8.45(s,1H),7.87(t,J=7.8Hz,1H),7.74(s,1H),7.68(d,J=7.2Hz,1H),7.62-7.50(m,2H),7.39(s,1H),7.32-7.21(m,1H),5.25(s,2H),5.19(dd,J=12.8,5.3Hz,1H),5.16(s,2H),4.71(t,J=6.5Hz,2H),4.24(s,3H),3.02–2.87(m,2H),2.69–2.50(m,4H),2.23–2.11(m,2H),1.91–1.83(m,2H),1.72–1.65(m,2H).
13C NMR(101MHz,DMSO)δ173.19,172.09,170.32,168.12,167.10,155.63,155.22,150.49,150.43,148.55,146.67,146.39,146.02,143.79,136.88,136.52,132.38,132.01,129.14,127.38,126.96,125.95,120.78,120.55,118.88,117.66,116.74,116.42,106.14,50.02,40.39,40.16,38.24,35.92,35.27,32.32,31.44,25.72,23.89,22.55.
实施例11
化合物11:(E)-7-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)庚酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物11的产率:19.53%。
1H NMR(400MHz,DMSO)δ11.13(s,1H),9.88(s,1H),9.82(s,1H),8.44(d,J=8.3Hz,1H),8.41(s,1H),7.83(t,J=7.8Hz,1H),7.75(s,1H),7.69(d,J=7.2Hz,1H),7.61-7.52(m,2H),7.36(s,1H),7.31-7.20(m,1H),5.27(s,2H),5.21(dd,J=12.8,5.3Hz,1H),5.18(s,2H),4.74(t,J=6.5Hz,2H),4.22(s,3H),3.04–2.85(m,2H),2.72–2.55(m,4H),2.24–1.88(m,6H),1.82–1.68(m,2H).
13C NMR(101MHz,DMSO)δ173.20,172.12,170.34,168.16,167.12,155.67,155.34,150.83,150.52,148.67,146.80,146.42,146.12,143.80,136.81,136.12,132.42,132.10,129.21,127.42,126.93,125.91,120.92,120.51,118.82,117.76,116.77,116.38,106.16,50.09,40.42,40.18,38.32,35.88,35.42,32.43,31.54,27.34,25.56,23.92,22.45.
实施例12
化合物12:(E)-8-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)辛酰胺的制备
制备方法同实施例1,只需更换相应的原料即可。所得化合物12的产率:15.87%。
1H NMR(400MHz,DMSO)δ11.09(s,1H),9.91(s,1H),9.79(s,1H),8.46(d,J=8.3Hz,1H),8.39(s,1H),7.87(t,J=7.8Hz,1H),7.79(s,1H),7.71(d,J=7.2Hz,1H),7.64-7.50(m,2H),7.39(s,1H),7.32-7.23(m,1H),5.31(s,2H),5.24(dd,J=12.8,5.3Hz,1H),5.21(s,2H),4.78(t,J=6.5Hz,2H),4.25(s,3H),3.01–2.82(m,2H),2.68–2.35(m,4H),2.14–1.82(m,6H),1.74–1.54(m,4H).
13C NMR(101MHz,DMSO)δ173.22,172.15,170.42,168.23,167.17,155.71,155.39,150.97,150.58,148.71,146.89,146.56,146.09,143.85,136.79,136.09,132.45,132.14,129.19,127.45,126.88,125.89,120.89,120.49,118.79,117.81,116.79,116.41,106.21,50.11,40.52,40.21,38.41,35.91,35.32,32.63,31.44,28.21,27.34,25.56,22.92,21.65.
实施例13
化合物13:(E)-2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)乙酰胺的制备
(1)化合物a4的制备
制备方法同实施例1。
(2)化合物d1的制备
将2-(2-叠氮基乙氧基)乙酸(290.2mg,2mmol)溶解于5mL氯化亚砜中,加热回流2小时,反应结束后,减压浓缩去除溶剂,随后加入来那度胺(1mmol,259.3mg),10mL四氢呋喃作溶剂,加热回流反应5小时,TLC监测。反应结束,冷却至室温,加入2mL甲醇后继续搅拌1小时。减压浓缩除去溶剂,柱层析分离得到d1 296.8mg(洗脱剂为二氯甲烷:甲醇(V:V)=10:1),产率为76.83%。
(3)化合物13的制备
将化合物a4(142.4mg,0.3mmol)、化合物d1(139.1mg,0.36mmol)和五水硫酸铜(30.0mg,0.12mmol)、抗坏血酸钠(23.8mg,0.12mmol)置于反应器中,使用10mL四氢呋喃和1mL水的混合溶液进行溶解,氩气保护,45℃加热搅拌过夜,TLC监测。反应结束后,所得反应液减压浓缩除去溶剂,柱层析分离纯化(二氯甲烷:甲醇(V:V)=20:1为流动相),干燥得到化合物13 66.2mg,产率为25.63%。
1H NMR(400MHz,DMSO)δ11.12(s,1H),9.83(s,1H),9.30(s,1H),8.42(s,1H),7.95(d,J=7.1Hz,1H),7.75(s,1H),7.65-7.53(m,2H),7.46–7.35(m,2H),7.31(s,1H),7.26-7.13(m,1H),5.24(s,2H),5.17(dd,J=13.3,4.8Hz,1H),5.04(s,2H),4.58(s,2H),4.31(s,2H),4.12(3H,s),3.95–3.82(m,2H),3.75(t,J=7.1Hz,2H),2.80–2.65(m,2H),2.43-2.24(m,2H).
13C NMR(101MHz,DMSO)δ173.52,171.32,171.12,168.42,155.69,155.31,150.56,150.48,148.60,146.61,146.34,145.70,143.89,134.38,133.11,132.21,129.14,129.06,127.28,125.92,125.73,120.69,120.38,119.46,118.09,116.81,116.36,106.09,69.10,68.24,52.08,51.73,46.92,40.31,40.10,38.07,31.55,29.18.
实施例14
化合物14:(E)-2-(2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚啉-4-基)乙酰胺的制备
制备方法同实施例13,只需更换相应的原料即可。所得化合物14的产率:21.45%;。
1H NMR(400MHz,DMSO)δ11.23(s,1H),9.86(s,1H),9.33(s,1H),8.38(s,1H),7.89(d,J=7.1Hz,1H),7.73(s,1H),7.60-7.51(m,2H),7.41–7.32(m,2H),7.28(s,1H),7.22-7.14(m,1H),5.22(s,2H),5.16(dd,J=13.3,4.8Hz,1H),5.01(s,2H),4.49(s,2H),4.28(s,2H),4.09(3H,s),3.85–3.74(m,2H),3.64(t,J=7.1Hz,2H),3.35(s,4H),2.76–2.59(m,2H),2.23-2.04(m,2H).
13C NMR(101MHz,DMSO)δ173.68,171.42,171.23,168.38,155.71,155.34,150.61,150.52,148.63,146.66,146.31,145.72,143.91,134.42,133.12,132.24,129.16,129.01,127.32,125.91,125.77,120.71,120.42,119.51,118.11,116.84,116.32,106.14,69.16,68.45,68.34,68.16,52.12,51.75,46.96,40.34,40.09,38.12,31.56,29.23.
实施例15
化合物15:(E)-2-(2-(2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚啉-4-基)乙酰胺的制备
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制备方法同实施例13,只需更换相应的原料即可。所得化合物15的产率:16.36%。
1H NMR(400MHz,DMSO)δ11.18(s,1H),9.82(s,1H),9.41(s,1H),8.43(s,1H),7.92(d,J=7.1Hz,1H),7.71(s,1H),7.65-7.54(m,2H),7.44–7.33(m,2H),7.29(s,1H),7.24-7.16(m,1H),5.19(s,2H),5.12(dd,J=13.3,4.8Hz,1H),5.03(s,2H),4.51(s,2H),4.32(s,2H),4.08(3H,s),3.82–3.71(m,2H),3.63(t,J=7.1Hz,2H),3.39(s,8H),2.67–2.53(m,2H),2.24-2.07(m,2H).
13C NMR(101MHz,DMSO)δ173.71,171.46,171.25,168.42,155.78,155.41,150.69,150.58,148.67,146.72,146.35,145.71,144.02,134.46,133.21,132.25,129.22,129.08,127.34,126.02,125.81,120.77,120.45,119.53,118.17,116.84,116.36,106.16,70.41,70.12,69.21,68.46,68.37,68.21,52.18,51.82,47.03,40.42,40.19,38.17,31.62,29.27.
实施例16
化合物16:(E)-2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)乙酰胺的制备
制备方法同实施例13,只需更换相应的原料即可。所得化合物16的产率:26.44%。
1H NMR(400MHz,DMSO)δ11.11(s,1H),9.82(s,1H),9.75(s,1H),8.44(d,J=8.3Hz,1H),8.36(s,1H),7.81(t,J=7.8Hz,1H),7.72(s,1H),7.65(d,J=7.2Hz,1H),7.60-7.51(m,2H),7.43(s,1H),7.31-7.19(m,1H),5.26(s,2H),5.12(dd,J=12.8,5.3Hz,1H),5.16(s,2H),4.48(s,2H),4.19(s,3H),3.73–3.58(m,2H),3.51(t,J=6.8Hz,2H),2.32–2.19(m,2H),2.10–1.93(m,2H).
13C NMR(101MHz,DMSO)δ173.42,172.31,170.48,168.19,167.26,155.82,155.34,150.91,150.58,148.66,146.71,146.38,145.92,143.79,136.89,136.67,132.34,131.91,129.48,127.29,126.91,125.95,120.81,120.47,118.90,117.83,116.71,116.42,106.25,68.91,67.23,52.14,48.37,40.41,39.92,37.06,32.32,28.83.
实施例17
化合物17:(E)-2-(2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)乙酰胺的制备
制备方法同实施例13,只需更换相应的原料即可。所得化合物17的产率:20.81%。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.79(s,1H),9.70(s,1H),8.41(d,J=8.3Hz,1H),8.33(s,1H),7.82(t,J=7.8Hz,1H),7.71(s,1H),7.63(d,J=7.2Hz,1H),7.59-7.47(m,2H),7.42(s,1H),7.32-7.21(m,1H),5.28(s,2H),5.14(dd,J=12.8,5.3Hz,1H),5.19(s,2H),4.52(s,2H),4.21(s,3H),3.76–3.61(m,2H),3.48(t,J=6.8Hz,2H),3.39(s,4H),2.28–2.17(m,2H),2.11–1.95(m,2H).
13C NMR(101MHz,DMSO)δ173.38,172.28,170.51,168.21,167.22,155.84,155.36,150.89,150.62,148.65,146.73,146.42,145.91,143.80,136.94,136.72,132.36,131.88,129.54,127.34,126.85,125.88,120.79,120.52,118.93,117.80,116.74,116.42,106.21,69.74,69.12,68.85,67.22,52.16,48.39,40.38,39.91,37.10,32.24,28.90.
实施例18
化合物18:(E)-2-(2-(2-(2-(4-((4-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-2,6-二氧基-3-(2,4,5-三氟苄基)-1,3,5-三嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)乙酰胺的制备
制备方法同实施例13,只需更换相应的原料即可。所得化合物18的产率:17.26%。
1H NMR(400MHz,DMSO)δ11.15(s,1H),9.82(s,1H),9.75(s,1H),8.47(d,J=8.3Hz,1H),8.37(s,1H),7.84(t,J=7.8Hz,1H),7.73(s,1H),7.65(d,J=7.2Hz,1H),7.60-7.49(m,2H),7.42(s,1H),7.34-7.20(m,1H),5.33(s,2H),5.16(dd,J=12.8,5.3Hz,1H),5.21(s,2H),4.49(s,2H),4.18(s,3H),3.73–3.59(m,2H),3.53(t,J=6.8Hz,2H),3.42(s,8H),2.23–2.14(m,2H),2.06–1.87(m,2H).
13C NMR(101MHz,DMSO)δ173.42,172.33,170.49,168.28,167.23,155.92,155.34,150.90,150.63,148.67,146.76,146.44,145.96,143.83,136.92,136.71,132.38,131.90,129.51,127.36,126.87,125.91,120.83,120.54,118.91,117.87,116.72,116.48,106.25,71.01,70.87,69.68,69.32,68.90,67.43,52.25,48.46,40.52,39.98,37.11,32.27,28.96.
2.生物活性测定
(1)3CLpro抑制活性测试
使用荧光共振能量转移技术测定化合物对SARS-CoV-2 3CLpro的抑制活性。
将10μL不同浓度的制备的上述化合物溶液(终浓度为1000,500,250,125,62.5,31.25,15.63,7.81,3.90,1.95nM,DMSO配制)和40μL SARS-CoV-2 3CLpro(购于上海碧云天生物技术有限公司,终浓度为0.5μM,Tris-HCl缓冲液稀释(20mM Tris-HCl,100mM NaCl,1mM EDTA,pH值7.4))混合,加入黑色96孔板中,在37℃下孵育10min。加入50μL荧光底物Dabcyl-KTSAVLQSGFRKME-Edans(购于上海碧云天生物技术有限公司,终浓度为20μM)引发反应,孵育10min后在多功能酶标仪(赛默飞世尔科技有限公司,Varioskan Flash)上进行荧光检测,激发波长为340nm,发射波长为490nm,记录荧光值计算样品的抑制百分率。以不含化合物的DMSO为酶活性对照,不含SARS-CoV-2 3CLpro的Tris-HCl缓冲液为空白对照,其余处理方法相同。使用GraphPad Prism软件进行非线性回归分析计算得出样品(本发明合成的化合物1-18)的IC50值。
实验结果如表1所示(表1中,IC50所在列,A:IC50<100nM,B:IC50=100-1000nM),实施例化合物对3CLpro均具有抑制活性,其中化合物3、4、8、9、10、14和17对3CLpro的抑制作用较强,IC50值均在100nM以下。
(2)Western Blot测定3CLpro降解活性
将对数生长期的HEK293E细胞(购于中国科学院细胞库)以6.0×105细胞/孔密度接种于6孔板中,在含5%CO2的37℃温箱中孵育8-24h,待细胞长至密度为70%融合时,换入2mL预热的无血清培养基(购于上海奥浦迈生物科技股份有限公司)。用10μM PEI(聚乙烯亚胺,购于上海麦克林生化科技有限公司)溶液按质量体积比为3:4转染SARS-CoV-2 3CLpro表达质粒(2μg/孔,1×HBS配制,购于北京义翘神州科技股份有限公司),将PEI-质粒混合液逐滴加入上述无血清培养基中,轻摇混匀,置于含5%CO2的37℃温箱中孵育10h,后除去含转染试剂的培养基并加入含有梯度浓度待测样品的培养基(样品终浓度为1000,500,250,125,62.5,31.25,15.63,7.81,3.90,1.95nM)。37℃、5%CO2条件下培养24h后弃去上清,收集细胞,加入RIPA细胞裂解液(购于上海麦克林生化科技有限公司)冰上裂解细胞30min,用Western Blot检测3CLpro表达,Image J分析3CLpro相对表达量,计算蛋白降解率。以不含待测样品的培养基为对照组,其余处理方法相同。使用GraphPad Prism软件进行非线性回归分析计算得出样品的蛋白降解活性(DC50)。
实验结果如表1所示(表1中,DC50所在列,A:DC50<100nM,B:DC50=100-1000nM),实施例化合物对3CLpro均具有降解活性,其中化合物2、3、4、5、8、9、10、13、14、15、16和17的对于3CLpro的降解活性较强,DC50值均在100nM以下。
表1化合物1-18对3CLpro的抑制活性和降解活性
表1数据显示,化合物1-18对3CLpro均具有不同程度抑制作用和降解作用。其中化合物3、4、8、9、10、14和17对3CLpro的IC50值和DC50值均小于100nM。表明本发明中靶向冠状病毒3CL蛋白酶的PROTACs对3CLpro既具有的抑制活性,又具有良好的降解活性,可作为抗冠状病毒候选药物进行开发和研究。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (10)
1.一种靶向冠状病毒3CL蛋白酶的PROTACs,其特征在于,为式Ⅰ或式Ⅱ所示化合物或其药学上可接受的盐,以及所述的式Ⅰ或式Ⅱ化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物,包括外消旋混合物;
所述式Ⅰ或式Ⅱ化合物的结构式为:
其中,Linker为以下链接基团之一:
其中,n=1-6。
2.根据权利要求1所述的一种靶向冠状病毒3CL蛋白酶的PROTACs,其特征在于,所述代表性化合物选自如下化合物:
3.根据权利要求1所述的一种靶向冠状病毒3CL蛋白酶的PROTACs,其特征在于,所述药学上可接受的盐为靶向冠状病毒3CL蛋白酶的PROTACs与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
4.权利要求1-3任意一项所述的一种靶向冠状病毒3CL蛋白酶的PROTACs的制备方法,其特征在于,包括以下操作步骤:
(1)以3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮为原料,与2,4,5-三氟溴苄进行烷基化反应,得到化合物a1;然后在三嗪母核6位处引入6-氯-2-甲基-2H-吲唑单元,得到化合物a2;化合物a2的三嗪母核3位叔丁基在酸性溶剂中脱掉得到化合物a3;随后在化合物a3的三嗪母核3位引入3-丙炔基,最终得到化合物a4;
其中,a1为a2为/>a3为/>a4为/>
(2)以来那度胺为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b1-b6,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c1-c6;
或者,以泊马度胺为原料,与不同长度的溴代烷酸进行酸胺缩合反应,得到相应的化合物b7-b12,然后与叠氮化钠在碘化钾的催化下,得到相应的化合物c7-c12;
其中,b1-b6为n=1-6;c1-c6为/>n=1-6;b7-b12为/>n=1-6;c7-c12为/>n=1-6;
或者,以来那度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d1-d3;
或者,以泊马度胺为原料,与叠氮-多聚乙二醇-乙酸类化合物进行酸胺缩合反应,得到相应的化合物d4-d6;
其中,d1-d3为n=1-6;d4-d6为/>n=1-6;
(3)化合物a4与化合物c1-c6或d1-d3反应,生成如式Ⅰ结构的靶向冠状病毒3CL蛋白酶的PROTACs;
或者,化合物a4与c7-c12或d4-d6反应,生成如式Ⅱ结构的靶向冠状病毒3CL蛋白酶的PROTACs。
5.根据权利要求4所述的方法,其特征在于,步骤(1)中,3-叔丁基-6-(乙硫基)-1,3,5-三嗪-2,4(1H,3H)-二酮与2,4,5-三氟溴苄的摩尔比为1:1.1,化合物a1与6-氯-2-甲基-2H-吲唑-5-胺的摩尔比为1:1.3,化合物a3与3-溴丙炔的摩尔比为1:1.2;步骤(2)中,泊马度胺或来那度胺与不同长度的溴代烷酸的摩尔比为1:2,泊马度胺或来那度胺与叠氮-多聚乙二醇-乙酸类化合物的摩尔比为1:2;步骤(3)中,化合物a4与c1-c12或d1-d6的摩尔比为1:1.2。
6.根据权利要求4所述的方法,其特征在于,步骤(1)中,化合物a2的合成过程中反应温度为0℃,所用催化剂为双三甲基硅基胺基锂;步骤(2)中,化合物b1-b6和b7-b12的合成过程中,用酰氯化试剂溶解不同长度的溴代烷酸,化合物d1-d3和d4-d6的合成过程中,所用缩合剂为氯化亚砜,所用溶剂为四氢呋喃;步骤(3)中所用溶剂为四氢呋喃和水的混合溶剂,混合溶剂中,四氢呋喃与水的体积比为10:1。
7.权利要求1-3中任意一项所述的一种靶向冠状病毒3CL蛋白酶的PROTACs在制备抗冠状病毒药物制剂中的应用。
8.根据权利要求7所述的应用,其特征在于,所述冠状病毒为新型冠状病毒SARS-CoV-2。
9.根据权利要求7所述的应用,其特征在于,所述制剂为单独使用或与其他抗冠状病毒药物联合使用,或与可药用的赋形剂、稀释剂混合制成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂、预混剂或微丸剂,或者制成非口服方式给药的吸入剂、搽剂或注射剂。
10.一种药物组合物,其特征在于,所述药物组合物包含权利要求1-3任意一项所述的靶向冠状病毒3CL蛋白酶的PROTACs作为活性成分。
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