CN117917402A - 异吲哚酰胺类化合物及其药物组合物和应用 - Google Patents
异吲哚酰胺类化合物及其药物组合物和应用 Download PDFInfo
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- CN117917402A CN117917402A CN202311351469.5A CN202311351469A CN117917402A CN 117917402 A CN117917402 A CN 117917402A CN 202311351469 A CN202311351469 A CN 202311351469A CN 117917402 A CN117917402 A CN 117917402A
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Abstract
本发明提供了一种具有式(I)所示结构的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,及其应用。本发明涉及的化合物可以高效、高选择性地降解细胞中的GSPT1蛋白,从而能够显著抑制GSPT1高表达介导的肿瘤细胞增殖,可用于制备与GSPT1蛋白异常表达相关的癌症和其它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,具体涉及一类靶向泛素化降解GSPT1蛋白的异吲哚酰胺类化合物及其药物组合物和应用。
背景技术
蛋白质功能的异常、蛋白质表达水平的失衡是许多疾病的重要特征。在空间和时间上来讲,蛋白质的合成和降解是一个精密调控的过程。这些过程的错误调节很可能导致细胞异常生长、增殖和迁移,从而导致癌症的发生。例如,GSPT1它又名eF3a,是一种真核肽链释放因子,能够参与识别终止密码子,并与eRF1结合完成终止蛋白质的翻译过程。当终止密码子进入核糖体的A位点时,GSPT1与eRF1结合来终止蛋白质的翻译过程,并促进新生肽从核糖体中的释放。GSPT1除了在翻译终止中的作用外,GSPT1还参与如细胞周期调节、细胞骨架组织和细胞凋亡等过程。例如在酵母和黑腹果蝇中,GSPT1功能障碍已被证明可以导致细胞骨架组装和染色体分离缺陷(Cell Motil Cytoskel,2002,52,161-173)。此外,GSPT1能与ASK1相互作用并通过激活caspase-3增强ASK1诱导的凋亡活性(EMBOJ,1998,17,2596-2606.)。
GSPT1被认为是包括乳腺癌、肝细胞癌、胃癌和***癌在内的不同癌症类型的致癌驱动基因。(Brito,et al.,Carcinogenesis,2005,26(12),2046;Tavassoli,et al.,Med.Oncol.,2011,29,1581;Hoshino,et al.,Apoptosis,2012,17,1287;Liu,et.al.,PLOSOne,2014,9(1),e86371;Jean-Jean,et al.,Mol.Cell.Bio.,2007,27(16),5619;Ishii etal.,J.Biol.Chem.,2017,292(4),1240。因此,开发GSPT1蛋白降解剂有望对这些肿瘤发挥强效治疗作用,或者与其他药物联用共同用于肿瘤的治疗。
蛋白质降解在各种细胞功能中发挥作用,即通过蛋白降解来调节蛋白的浓度,以维持细胞的正常功能。因此,可以通过化合物调节蛋白质体内平衡是一种新的治疗方法。Cereblon(CRBN)是一种E3泛素连接酶复合物的蛋白质,该复合物泛素化各种其他蛋白质。CRBN作为抗肿瘤和免疫调节剂药物的重要靶点,已被证实在多发性骨髓瘤、慢性淋巴细胞白血病等多种血液性恶性肿瘤、麻风结节性红斑等皮肤病、和***性红斑狼疮等自身免疫性疾病具有明确的疗效。“分子胶”(Molecular glues),通过结合泛素化连接酶,从而识别并降解全新底物,如免疫调节类药物(IMiDs)就是靶向(IKZF1/3)的分子胶。最早出现的免疫调节类药物为(IMiDs)沙利度胺及其衍生物如来那度胺和泊马度胺。这类免疫调节剂药物包括沙利度胺(Thalidomide),来那度胺(Lenalidomide,Lena),和泊马度胺(Pomalidomide,Poma)利用戊二酰亚胺环结构***Cereblon(CRBN)泛素连接酶的口袋区域,招募转录因子lkaros(IKZFl)/Aiolos(IKZF3)并促进其泛素化降解,进而产生细胞毒作用。随后越来越多的免疫调节剂药物出现用于降解不同的底物蛋白,如IKZF1/3,CK1α,GSPT1等,通过降解不同的底物蛋白对不同的肿瘤类型发挥治疗作用。目前对GSPT1的降解剂有CC-885,CC-90009,MRT-2359,BTX-1188,SJ6986等分子。尽管此类免疫调节剂药物在癌症临床治疗方面的研究取得了进展,但仍然缺乏对不同种类癌症治疗有效的GSPT1降解剂分子。当前迫切需要开发新型GSPT1蛋白降解药物,用于不同种癌症的治疗。
发明内容
针对上述问题,本发明提供了一种新型靶向泛素化降解GSPT1蛋白的化合物,该化合物对GSPT1蛋白具有显著的降解作用,对多种肿瘤细胞具有较强的抑制作用。
具体地,本发明包括如下技术方案。
具有式(I)所示结构的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物:
其中:W选自:CR2,N;
A选自:
R1选自:H,C1-C6烷基,卤素取代的C1-C6烷基,卤素,C1-C6烷氧基,卤素取代的C1-C6烷氧基,羟基,C3-C6环烷基;
R2选自:H,C1-C6烷基,卤素,卤素取代的C1-C6烷基;
R3选自:H,-(CH2)O(C=O)R4;
R4选自:C1-C6烷基,氨基和/或羟基取代的C1-C6烷基;
R12选自:H,卤素取代的C1-C6烷基,
R’12选自:H,卤素,C1-C6烷基,R’13取代或者未取代的苯基,R’13取代或者未取代的5-6元杂芳基;
R”12选自:H,卤素,C1-C6烷基;
各R’13分别独立地选自:H,C1-C6烷基,卤素,氰基,卤素取代的C1-C6烷基;
R17和R18分别独立地选自:H,C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的3-12元杂环基;
各R14分别独立地选自:H,C1-C6烷基,R16取代或者未取代的3-8元杂环基,C1-C6烷基胺基,羟基;
各R16分别独立地选自:H,C1-C6烷基,C1-C6烷氧基;
m选自:0,1,2;
当A位于W的间位,R”12为卤素,R’12为C1-C6烷基时,R12不为氢,并且R17和R18与和其相连的氮原子不形成吗啉环。
在其中一些实施例中,W为CH。
在其中一些实施例中,R1选自:H,甲基,乙基,丙基,F,Cl,Br,环丙基,羟基,三氟甲基。
在其中一些实施例中,R4选自:H,甲基,乙基,丙基,叔丁基。
在其中一些实施例中,R2位于W的邻位。
在其中一些实施例中,所述异吲哚酰胺类化合物具有如下式(II)所示结构:
在其中一些实施例中,所述异吲哚酰胺类化合物具有如下式(III)所示结构:
在其中一些实施例中,所述异吲哚酰胺类化合物具有如下式(IV)所示结构:
在其中一些实施例中,R2选自:H,甲基,乙基,丙基,F,Cl,Br,环丙基,羟基,三氟甲基。
在其中一些实施例中,R”12选自:H,F,Cl,Br。
在其中一些实施例中,R’12选自:H,F,Cl,Br,甲基,乙基,丙基,R’13取代或者未取代的吡啶基,R’13取代或者未取代的苯基;
各R’13分别独立地选自:H,甲基,乙基,丙基,F,Cl,Br,氰基,三氟甲基。
在其中一些实施例中,R12选自:
H,卤素取代的C1-C3烷基,
R17和R18分别独立地选自:H,C1-C3烷基,C1-C3烷氧基取代的C1-C3烷基,C1-C3烷基胺基取代的C1-C3烷基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的3-8元杂环基;
各R14分别独立地选自:H,C1-C3烷基,R16取代或者未取代的3-8元杂环基,C1-C3烷基胺基,羟基;
各R16分别独立地选自:H,C1-C3烷基,C1-C3烷氧基;
m选自:0,1,2。
在其中一些实施例中,R12选自:
H,三氟甲基,
R17和R18分别独立地选自:甲基,乙基,甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的如下杂环烷基:哌啶基、哌嗪基、吗啉基、7元氮杂-氧杂螺环烷基、氮杂环丁基、二氧化硫代吗啉基、氧杂环丁基;
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃基。
在其中一些实施例中,R12选自:
H,三氟甲基,R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃。
在其中一些实施例中,R12选自:R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:甲基,吗啉基,氧杂环丁基,四氢吡喃。
在其中一些实施例中,R’12选自:H,R’13取代或者未取代的吡啶基,R’13取代或者未取代的苯基;
各R’13分别独立地选自:H,甲基,乙基,丙基,F,Cl,Br,氰基,三氟甲基;
R12选自:H,三氟甲基,R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃。
在其中一些实施例中,R’12选自:H,吡啶-4-基,吡啶-3-基,4-氰基苯基,4-氟苯基,4-三氟甲基苯基,苯基;
R12选自:H,三氟甲基,R17选自:甲基,R18选自:甲氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
本发明还提供了上述异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物的应用,包括如下技术方案。
上述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物在制备GSPT1蛋白降解剂中的应用。
上述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物在制备预防或治疗与GSPT1蛋白活性异常表达相关的疾病的药物中的应用。
在其中一些实施例中,与GSPT1蛋白活性异常表达相关的疾病为:肿瘤、高血糖、糖尿病、肥胖症、高血脂症、高胆固醇血症、高脂蛋白血症、高甘油三酯血症、高血压、高胰岛素血症、高尿酸血症、帕金森病、阿尔茨海默病。
在其中一些实施例中,所述肿瘤为:非小细胞肺癌、恶性黑色素瘤、***癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、***、肺癌、喉癌、鼻咽癌、口腔癌、皮肤癌、脑癌、神经癌、成骨肉瘤、软骨肉瘤、横纹肌肉瘤、食道癌、胰腺癌或多发性骨髓瘤、B淋巴瘤、白血病中的一种或几种。
本发明还提供了一种治疗或预防肿瘤的药物组合物,包括如下技术方案。
一种治疗或预防肿瘤的药物组合物,由活性成分和药学上可接受的辅料制备而成,所述活性成分含有上述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物。
基于上述技术方案,本发明具有以下有益效果:
本发明提供的异吲哚酰胺类化合物,具有抑制GST1蛋白活性与降解GSPT1蛋白活性的作用,因此本发明的化合物可用于与GSPT1蛋白异常表达相关的疾病,如各种癌症。
该化合物可以有效抑制GSPT1蛋白,并具有GSPT1靶蛋白降解功能。其蛋白降解机理是该类分子能够与E3连接酶结合,改变其表面和特异性,导致底物蛋白被招募、泛素化和随后的底物蛋白被蛋白酶体降解。该化合物为GSPT1作为药物开发靶点的研究与开发,白血病的治疗以及分子胶的开发应用可行性提供了重要的参考。
另外,本发明优选的部分化合物具有较好的溶解度,优异的药代动力学性质和较好的口服生物利用度,成药性好,有利于制备成抗肿瘤药物。
具体实施方式
本发明所述化合物中,当任何变量(例如R14)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***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***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”指环原子由碳原子组成的饱和或部分不饱和的单环、双环或多环环状烃基,双环或多环包括螺环、稠环和桥环。例如:“环烷基”包括但不限于以下基团:环丙基、环丁基、环戊基、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***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。
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,该芳香环可以是单环、双环或者多环,例如包括但不限于: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、哒嗪基等;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳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。
本发明提供了一种具有式(I)所示结构的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物:
其中:W选自:CR2,N;
A选自:
R1选自:H,C1-C6烷基,卤素取代的C1-C6烷基,卤素,C1-C6烷氧基,卤素取代的C1-C6烷氧基,羟基,C3-C6环烷基;
R2选自:H,C1-C6烷基,卤素,卤素取代的C1-C6烷基;
R3选自:H,-(CH2)O(C=O)R4;
R4选自:C1-C6烷基,氨基和/或羟基取代的C1-C6烷基;
R12选自:H,卤素取代的C1-C6烷基,
R’12选自:H,卤素,C1-C6烷基,R’13取代或者未取代的苯基,R’13取代或者未取代的5-6元杂芳基;
R”12选自:H,卤素,C1-C6烷基;
各R’13分别独立地选自:H,C1-C6烷基,卤素,氰基,卤素取代的C1-C6烷基;
R17和R18分别独立地选自:H,C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的3-12元杂环基;
各R14分别独立地选自:H,C1-C6烷基,R16取代或者未取代的3-8元杂环基,C1-C6烷基胺基,羟基;
各R16分别独立地选自:H,C1-C6烷基,C1-C6烷氧基;
m选自:0,1,2;
当A位于W的间位,R”12为卤素,R’12为C1-C6烷基时,R12不为氢,并且R17和R18与和其相连的氮原子不形成吗啉环。
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及立体异构体。术语“游离形式”指以非盐形式的化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式(I)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐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盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
在一个实施方案中,本发明提供了一种利用具有式(I)的化合物及其药学上可接受的盐治疗人或其它哺乳动物与GSPT1蛋白异常表达相关的肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等疾病。
在一个实施方案中,本发明的化合物及其药学上可接受的盐可以用于预防和/或治疗非小细胞肺癌、恶性黑色素瘤、***癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、***、肺癌、喉癌、鼻咽癌、口腔癌、皮肤癌、脑癌、神经癌、成骨肉瘤、软骨肉瘤、横纹肌肉瘤、食道癌、胰腺癌或多发性骨髓瘤、B淋巴瘤、白血病等肿瘤,或者用于防止肿瘤术后复发。
药物代谢物及前药
本发明所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本发明的权利要求中。例如:包括但不限于如下前药分子:
药物组合物
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体或者辅料。
本发明所述的“活性成分”是指本发明所述的式(I)化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明所述的“活性成分”和药物组合物可用作GSPT1蛋白降解剂,可用于制备预防和/或***、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等的药物。
“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体或者辅料”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
药学上可以接受的载体或者辅料部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中,本发明式(I)化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明式(I)化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:
(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;
(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;
(c)保湿剂,例如,甘油;
(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;
(e)缓溶剂,例如石蜡;
(f)吸收加速剂,例如,季胺化合物;
(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;
(h)吸附剂,例如,高岭土;和
(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
联合用药
式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式和剂量保持不变,而同时或随后服用式(I)化合物。当式(I)化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时,式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为:
***受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体、JAK抑制剂等。
在一个实施方案中,可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、***、磷酸***、戊酸***、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、***制剂、17-β-***、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟***、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化***、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、***磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替***龙、***、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、***、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
本发明的有益之处在于:
(1)提供一种结构新颖的化合物。
(2)该类化合物可以高效、高选择性地降解细胞中的GSPT1蛋白,可以有效抑制多种肿瘤细胞的生长,可用于制备抗肿瘤药物。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
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。
化合物的结构通过核磁共振(1H-NMR)和/或质谱(MS)来确定。NMR测定是用BrukerAV-400型核磁共振仪,测定溶剂为氘代氯仿(CDCl3)或氘代二甲亚砜(DMSO-d6),TMS为内标。MS的测定用LCQAD-40000型质谱仪。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
实施例1:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酰胺(WYY-1)的合成
步骤1:制备(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙-2-烯酸-2-甲基丙-2-基酯(2)
将3-(4-溴-1-氧亚基-2,3-二氢-1H-异吲哚-2-基)六氢吡啶-2,6-二酮(5g,15.48mmol),丙烯酸叔丁酯(4.96g,38.7mmol),三叔丁基膦四氟硼酸盐(0.225g,0.774mmol),催化量Pd2(dba)3(709mg),N,N-二环己基甲胺(6.04g,30.96mmol)加入100mLDMF中,于100℃下反应过夜。反应液旋干,柱层析得固体3.2g。
步骤2:制备3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酸-2-甲基丙-2-基酯(3)
将(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙-2-烯酸-2-甲基丙-2-基酯(2)(1g)溶于200mL甲醇,加入0.1gPd/C,于氢气氛围下室温反应过夜。硅藻土过滤,用甲醇洗涤,滤液旋干得白色固体0.93g。
步骤3:制备3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酸(4)
将3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酸-2-甲基丙-2-基酯(3)(0.3g)溶于10mL无水二氯甲烷中,加入5mL三氟乙酸,于室温下反应两小时。旋干溶剂,直接进行下一步反应。
步骤4:制备N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酰胺(WYY-1)
将3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酸(4)(0.2g,0.6mmol),3-氯-4-甲基苯胺(127mg,0.9mmol),HATU(0.262g,0.69mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.3mL,1.8mmol)于室温下反应三小时。旋干有机溶剂,柱层析分离得产物91.2mg。
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.06(s,1H),7.74(s,1H),7.63-7.41(m,3H),7.35-7.18(m,2H),5.12(dd,J=13.5,5.3Hz,1H),4.59-4.27(m,2H),2.96(t,J=7.5Hz,2H),2.89(d,J=14.3Hz,1H),2.68(t,J=7.7Hz,2H),2.61(d,J=18.3Hz,1H),2.41(d,J=12.4Hz,1H),2.24(s,3H),2.00(d,J=13.0Hz,1H)。
HRMS(ESI)for C23H22ClN3O4[M+H]+,calcd:440.1372;found:440.1372.
实施例2:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-2)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.04(s,1H),7.77(d,J=2.1Hz,1H),7.65(d,J=7.8Hz,1H),7.48(s,1H),7.40(d,J=7.8Hz,1H),7.31(dd,J=8.3,2.1Hz,1H),7.25(d,J=8.3Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.46-4.23(m,2H),3.02(t,J=7.6Hz,2H),2.90(ddd,J=17.2,13.6,5.4Hz,1H),2.67(t,J=7.6Hz,2H),2.64-2.55(m,1H),2.38(dd,J=13.2,4.5Hz,1H),2.25(s,3H),1.99(dd,J=8.0,5.3Hz,1H)。
HRMS(ESI)for C23H22ClN3O4[M+H]+,calcd:440.1372;found:440.1372.
实施例3:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酰胺(WYY-3)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.06(s,1H),7.87-7.80(m,2H),7.76(td,J=3.6,1.5Hz,2H),7.30(dd,J=8.3,2.1Hz,1H),7.24(d,J=8.3Hz,1H),5.13(dd,J=12.7,5.4Hz,1H),3.10(t,J=7.4Hz,2H),2.88(ddd,J=16.6,13.6,5.3Hz,1H),2.72(t,J=7.4Hz,2H),2.64-2.53(m,2H),2.25(s,3H),2.12-1.99(m,1H)。
HRMS(ESI)for C23H20ClN3O5[M+Na]+,calcd:476.0984;found,476.0975.
实施例4:N-(4-氯苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酰胺(WYY-4)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.09(s,1H),7.58(dd,J=8.2,3.9Hz,3H),7.52-7.43(m,2H),7.38-7.29(m,2H),5.13(dd,J=13.3,5.2Hz,1H),4.58-4.31(m,2H),2.97(t,J=7.5Hz,2H),2.94-2.84(m,1H),2.69(t,J=7.6Hz,2H),2.66-2.55(m,1H),2.48-2.35(m,1H),2.07-1.92(m,1H).
HRMS(ESI)for C22H20ClN3O4[M+H]+,calcd:426.1215;found:426.1215.
实施例5:N-(4-氯苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-5)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.09(s,1H),7.65(d,J=7.8Hz,1H),7.61-7.55(m,2H),7.48(s,1H),7.40(dd,J=7.8,1.5Hz,1H),7.36-7.30(m,2H),5.08(dd,J=13.3,5.1Hz,1H),4.48-4.22(m,2H),3.03(t,J=7.6Hz,2H),2.90(ddd,J=17.2,13.6,5.4Hz,1H),2.68(t,J=7.6Hz,2H),2.64-2.55(m,1H),2.38(qd,J=13.1,4.3Hz,1H),1.99(dt,J=9.4,2.7Hz,1H).
HRMS(ESI)for C22H20ClN3O4[M+H]+,calcd:426.1215;found:426.1215.
实施例6:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-6)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.06(s,1H),7.86-7.81(m,2H),7.78-7.74(m,2H),7.30(dd,J=8.3,2.1Hz,1H),7.24(d,J=8.3Hz,1H),5.12(dd,J=12.7,5.4Hz,1H),3.10(t,J=7.4Hz,2H),2.88(ddd,J=16.8,13.7,5.3Hz,1H),2.71(t,J=7.5Hz,2H),2.64-2.52(m,2H),2.25(s,3H),2.11-1.99(m,1H).
HRMS(ESI)for C23H20ClN3O5[M+H]+,calcd:454.1164;found:454.1164.
实施例7:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-7)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.05(s,1H),7.76(d,J=2.1Hz,1H),7.61(s,1H),7.51(s,2H),7.31(dd,J=8.3,2.1Hz,1H),7.24(d,J=8.3Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.48-4.21(m,2H),3.01(t,J=7.5Hz,2H),2.95-2.82(m,1H),2.66(t,J=7.5Hz,2H),2.63-2.55(m,1H),2.38(qd,J=13.2,4.4Hz,1H),2.25(s,3H),2.04-1.96(m,1H).
HRMS(ESI)for C23H22ClN3O4[M+H]+,calcd:440.1372;found:440.1372.
实施例8:N-(3-氯-4-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-1-氧亚基-2,3-二氢-1H-异吲哚-5-基]-2-甲基丙酰胺(WYY-8)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.95(d,J=7.8Hz,1H),7.76(d,J=2.2Hz,1H),7.64(d,J=7.7Hz,1H),7.44(s,1H),7.36(d,J=7.8Hz,1H),7.30(dd,J=8.3,2.4Hz,1H),7.24(d,J=8.3Hz,1H),5.09(dd,J=13.3,4.4Hz,1H),4.49-4.21(m,2H),3.14(q,J=7.5Hz,2H),3.07(dd,J=11.7,6.3Hz,1H),2.90(ddd,J=18.2,13.3,5.3Hz,1H),2.59(d,J=17.4Hz,1H),2.43-2.30(m,1H),2.25(s,3H),1.98(d,J=12.4Hz,1H),1.11(d,J=6.1Hz,3H).
HRMS(ESI)for C24H24ClN3O4[M+H]+,calcd:454.1528;found:454.1528.
实施例9:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧己基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(WYY-9)的合成
步骤1:制备(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸-2-甲基丙-2-基酯(5)
将3-(6-溴-1-氧亚基-2,3-二氢-1H-异吲哚-2-基)六氢吡啶-2,6-二酮(5g,15.48mmol),丙烯酸叔丁酯(4.96g,38.7mmol),三叔丁基膦四氟硼酸盐(0.225g,0.774mmol),催化量Pd2(dba)3(709mg),N,N-二环己基甲胺(6.04g,30.96mmol)加100mLDMF中,于100℃下反应过夜。反应液旋干,柱层析得固体3.6g。
步骤2:制备(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸(6)
将(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸-2-甲基丙-2-基酯(0.5g)溶于10mL二氯甲烷,加入5mL三氟乙酸,于室温下搅拌2小时,旋干溶剂,直接进行下一步反应。
步骤3:制备(2E)-N-(4-氯-3-甲基苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酰胺(WYY-9)
将(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸(0.4g,1.27mmol),3-氯-4-甲基苯胺(270mg,1.91mmol),HATU(0.55g,1.46mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.7mL,3.81mmol)于室温下反应三小时。旋干有机溶剂,柱层析分离得产物91.2mg。
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.31(s,1H),7.98(s,1H),7.93(s,1H),7.90(d,J=8.0Hz,1H),7.75-7.67(m,2H),7.44(d,J=8.4Hz,1H),7.32(d,J=8.3Hz,1H),6.93(d,J=15.7Hz,1H),5.14(dd,J=13.2,5.1Hz,1H),4.58-4.33(m,2H),2.98-2.85(m,1H),2.62(d,J=17.3Hz,1H),2.42-2.31(m,1H),2.29(s,3H),2.08-1.96(m,1H).
HRMS(ESI)for C23H20ClN3O4[M+Na]+,calcd:460.1035;found:460.1035.
实施例10:N-(3-氯-4-甲基苯基)-2-{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氨基}乙酰胺(WYY-10)的合成
步骤1:制备{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氨基}乙酸-2-甲基丙-2-基酯(7)
将3-(6-氨基-1-氧亚基-2,3-二氢-1H-异吲哚-2-基)六氢吡啶-2,6-二酮(4g,15.44mmol),溴乙酸叔丁酯(7.5g,38.6mmol),碘化钾(0.769g,4.63mmol),碳酸氢钾(3.86g,38.6mmol)溶于40mLDMF中,于100℃下反应过夜。反应液旋干,柱层析得产物2.1g
1H NMR(400MHz,DMSO-d6)δ10.96(d,J=4.3Hz,1H),7.29(d,J=8.1Hz,1H),6.87(dd,J=8.2,2.3Hz,1H),6.77(d,J=2.3Hz,1H),6.26(t,J=6.5Hz,1H),5.05(dd,J=13.2,4.7Hz,1H),4.32-4.10(m,2H),3.84(d,J=6.4Hz,2H),2.89(ddd,J=17.9,13.5,5.3Hz,1H),2.67-2.54(m,1H),2.36(qd,J=13.1,4.4Hz,1H),2.05-1.88(m,1H),1.41(s,9H).
步骤2:制备N-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]甘氨酸(8)
将{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氨基}乙酸-2-甲基丙-2-基酯(0.55g)溶于10mL二氯甲烷中,加入5mL三氟乙酸,于室温下搅拌2小时,旋干溶剂,直接进行下一步反应。
步骤3:制备N-(3-氯-4-甲基苯基)-2-{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氨基}乙酰胺(WYY-10)
将N-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]甘氨酸(0.5g,1.58mmol),3-氯-4-甲基苯胺(336mg,2.37mmol),HATU(0.69g,1.817mmol)溶于30mLDMF中,加入N,N-二异丙基乙胺(0.8mL,4.74mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物100.1mg。
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.13(s,1H),7.81(s,1H),7.40(d,J=8.4Hz,1H),7.29(dd,J=14.1,8.3Hz,2H),6.93(d,J=8.3Hz,1H),6.82(s,1H),6.36(t,J=6.2Hz,1H),5.06(dd,J=13.0,5.2Hz,1H),4.34-4.06(m,2H),3.94(d,J=6.1Hz,2H),2.99-2.81(m,1H),2.70-2.53(m,1H),2.44-2.30(m,1H),2.26(s,3H),2.04-1.87(m,1H).
HRMS(ESI)for C22H21ClN4O4[M+H]+,calcd:441.1324;found:441.1324.
实施例11:N-(3-氯-4-甲基苯基)-2-{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酰胺(WYY-11)的合成
步骤1:制备{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酸-2-甲基丙-2-基酯(9)
将3-(6-羟基-1-氧亚基-2,3-二氢-1H-异吲哚-2-基)六氢吡啶-2,6-二酮(3g,11.53mmol),溴乙酸叔丁酯(5.62g,28.8mmol),碘化钾(0.766g,4.612mmol),碳酸氢钾(4.036g,40.36mmol)溶于30mLDMF中,于100℃下反应过夜。反应液旋干,柱层析得产物1.2g。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.52(d,J=8.3Hz,1H),7.21(dd,J=8.3,2.5Hz,1H),7.16(d,J=0.1Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.77(s,2H),4.45-4.18(m,2H),2.91(ddd,J=17.2,13.6,5.4Hz,1H),2.67-2.54(m,1H),2.39(qd,J=13.2,4.5Hz,1H),2.04-1.87(m,1H),1.43(s,9H)。
步骤2:制备{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酸(10)
{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酸-2-甲基丙-2-基酯(0.55g)溶于10mL二氯甲烷,加入5mL三氟乙酸,于室温下搅拌2小时,旋干溶剂,直接进行下一步反应。
步骤3:制备N-(3-氯-4-甲基苯基)-2-{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酰胺(WYY-11)
{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酸(0.4g,1.26mmol),3-氯-4-甲基苯胺(267mg,1.89mmol),HATU(0.547g,1.44mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.7mL,3.78mmol)于室温下反应三小时。旋干有机溶剂,柱层析分离得产物82.1mg。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.21(s,1H),7.83(d,J=2.5Hz,1H),7.55(d,J=8.2Hz,1H),7.46(d,J=8.1Hz,1H),7.35-7.25(m,3H),5.11(dd,J=13.4,5.0Hz,1H),4.81(s,2H),4.44-4.22(m,2H),2.99-2.84(m,1H),2.69-2.55(m,1H),2.46-2.32(m,1H),2.28(s,3H),2.05-1.95(m,1H).
HRMS(ESI)for C22H20ClN3O5[M+H]+,calcd:442.1091;found:442.1164.
实施例12:N-(3-氯-4-甲基苯基)-2-{[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]氧基}乙酰胺(WYY-12)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.97(d,J=4.8Hz,1H),7.74(t,J=2.6Hz,1H),7.66-7.62(m,1H),7.56-7.51(m,2H),7.32-7.27(m,1H),7.23(d,J=8.7Hz,1H),5.10(dd,J=13.6,5.5Hz,1H),4.46-4.26(m,2H),2.95-2.86(m,1H),2.69-2.63(m,1H),2.63-2.57(m,1H),2.43-2.35(m,3H),2.25(s,3H),2.04-1.96(m,1H),1.28(s,3H).
HRMS(ESI)for C44H36FN7O10[M+H]+,calcd:454.1528;found,454.1515.
实施例13:N-{5-氯-4-甲基-3-[(4-甲基哌嗪-1-基)甲基]苯基}-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-13)的合成
步骤1:制备(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸-2-甲基丙-2-基酯(11)
将3-(6-溴-1-氧亚基-2,3-二氢-1H-异吲哚-2-基)六氢吡啶-2,6-二酮(5g,15.48mmol),丙烯酸叔丁酯(4.96g,38.7mmol),三叔丁基膦四氟硼酸盐(0.225g,0.774mmol),催化量Pd2(dba)3(709mg),N,N-二环己基甲胺(6.04g,30.96mmol)溶于100mLDMF中,于100℃下反应过夜。反应液旋干,柱层析得固体3.0g。
步骤2:制备3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸-2-甲基丙-2-基酯(12)
将(2E)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙-2-烯酸-2-甲基丙-2-基酯(11)(1g)溶于200mL甲醇,加入0.1gPd/C,于氢气范围下室温反应过夜。硅藻土过滤,用甲醇洗涤,滤液旋干得白色固体0.93g。
步骤3:制备3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸(13)
将3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸-2-甲基丙-2-基酯(12)(0.5g)溶于10mL无水二氯甲烷中,加入5mL三氟乙酸,于室温下反应两小时。旋干溶剂,直接进行下一步反应。
步骤4:制备2-甲基-3-氯-5-硝基苯甲酸(14)
将2-甲基-5-硝基苯甲酸(5g,27.6mmol)溶于10mL浓硫酸中,逐滴加入1,3-二氯-2-氧亚基四氢-1H-咪唑-5-酮(6.5g,33.1mmol),于80℃下搅拌12h,反应物冷却至室温,倒入100mL冰水中,过滤,取滤饼,用乙酸乙酯溶解,加水进行萃取,得到的有机层用饱和食盐水洗涤,后用无水硫酸钠干燥,抽滤得滤液,旋干得白色固体(8g)。
步骤5:制备(2-甲基-3-氯-5-硝基苯基)甲醇(15)
将2-甲基-3-氯-5-硝基苯甲酸(14)(8g,36.9mmol)溶于80mL四氢呋喃中,于0℃下逐滴加入7mLBH3S(CH3)2,于室温下搅拌10h。于0℃下向反应混合物中加入25mL水,用15%的碳酸氢钠溶液调节pH值为10,用EA萃取3次,有机层用饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,旋干,进行柱层析分离得黄色固体(2g)。
步骤6:制备2-氯-4-硝基-6-(氯甲基)甲苯(16)
将(2-甲基-3-氯-5-硝基苯基)甲醇(15)(2g,9.87mmol)溶于20mL无水二氯甲烷中,于0℃下加入二氯亚砜(5.87g,49.36mmol),后移至室温下搅拌2小时,旋干反应液。得到的粗品加入10mL水,用EA萃取3次,有机层用饱和食盐水洗涤1次,后用无水硫酸钠干燥,过滤,得到的滤液旋干得黄色油状液体(1.6g)。
步骤6:制备1-[(3-氯-2-甲基-5-硝基苯基)甲基]-4-甲基哌嗪(17)
将2-氯-4-硝基-6-(氯甲基)甲苯(16)(1.6g,7.24mmol)溶于20mL乙腈中,加入N-甲基哌嗪(0.94g,9.41mmol),三乙胺(1.83g,18mmol),于65℃下过夜回流,旋干反应液,进行柱层析分离得黄色固体(0.7g)。
步骤6:制备5-氯-4-甲基-3-[(4-甲基哌嗪-1-基)甲基]苯胺(18)
将1-[(3-氯-2-甲基-5-硝基苯基)甲基]-4-甲基哌嗪(17)(0.7g,2.47mmol),铁粉(0.69g,12.35mmol),氯化胺(0.13g,2.47mmol)加入30mL乙醇和15mL水的混合溶剂中,于90℃下回流搅拌4小时,反应液冷却至室温,过滤得滤液,加入饱和碳酸氢钠溶液,用EA萃取三次,饱和食盐水洗涤有机层,无水硫酸钠干燥,抽滤,滤液旋干得产物(0.5g)。
1H NMR(400MHz,DMSO-d6)δ6.49(dd,J=29.4,2.3Hz,2H),5.09(s,2H),3.27(s,2H),2.46-2.18(m,8H),2.15(s,3H),2.14(s,3H).
步骤7:制备N-{5-氯-4-甲基-3-[(4-甲基哌嗪-1-基)甲基]苯基}-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-13)
将3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸(13)(0.3g,0.949mmol),5-氯-4-甲基-3-[(4-甲基哌嗪-1-基)甲基]苯胺(18)(0.36g,1.42mmol),HATU(0.415g,1.09mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.5mL,2.95mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物95mg。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.03(s,1H),7.77(s,1H),7.62(s,1H),7.51(s,2H),7.30(s,1H),5.10(dd,J=13.3,5.1Hz,1H),4.47-4.19(m,2H),3.17(s,2H),3.02(t,J=7.5Hz,2H),2.91(ddd,J=18.1,13.5,5.3Hz,1H),2.67(t,J=7.6Hz,2H),2.63-2.54(m,5H),2.47-2.37(m,5H),2.35(s,3H),2.27(s,3H),2.04-1.86(m,1H).
HRMS(ESI)for C29H34ClN5O4[M+H]+,calcd:552.2372;found:552.2372.
实施例14:N-[5-氯-4-甲基-3-(1,4-氧杂氮杂环己-4-基甲基)苯基]-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-14)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.01(s,1H),7.78(d,J=2.2Hz,1H),7.62(s,1H),7.51(s,2H),7.31(s,1H),5.10(dd,J=13.3,5.1Hz,1H),4.46-4.24(m,2H),3.57(d,J=6.1Hz,4H),3.51(s,2H),3.02(t,J=7.5Hz,2H),2.90(ddd,J=18.0,13.5,5.3Hz,1H),2.67(t,J=7.4Hz,2H),2.63-2.56(m,1H),2.42(dd,J=13.0,4.4Hz,1H),2.39-2.30(m,4H),2.29(s,3H),2.04-1.94(m,1H).
HRMS(ESI)for C28H31ClN4O5[M+H]+,calcd:539.2056;found:539.2056.
实施例15:N-(5-氯-4-甲基-3-{[4-(1,4-氧杂氮杂环己-4-基)六氢吡啶-1-基]甲基}苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-16)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.05(s,1H),7.75(s,1H),7.62(s,1H),7.52(s,2H),7.37(s,1H),5.10(dd,J=13.3,5.1Hz,1H),4.47-4.22(m,2H),3.55(t,J=4.6Hz,4H),3.25(s,2H).3.02(t,J=7.5Hz,2H),2.96-2.84(m,4H),2.75(s,4H),2.67(t,J=7.6Hz,2H),2.60(d,J=17.9Hz,1H),2.39(qd,J=13.5,4.7Hz,1H),2.27(s,3H),2.19-2.03(m,3H),2.04-1.94(m,1H),1.87(d,J=12.1Hz,2H),1.49(q,J=12.4Hz,2H).
HRMS(ESI)for C33H40ClN5O5[M+H]+,calcd:622.2791;found:622.2791.
实施例16:N-[3-氯-4-甲基-5-(5-甲基-5-氮杂-2-氧杂己-6-基)苯基]-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-16)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.05(s,1H),7.77(s,1H),7.62(s,1H),7.51(s,2H),7.35(s,1H),5.10(dd,J=13.3,5.1Hz,1H),4.46-4.21(m,2H),3.58(s,2H),3.23(s,3H),3.02(t,J=7.4Hz,2H),2.96-2.84(m,1H),2.66(q,J=10.2,9.0Hz,4H),2.57(d,J=15.0Hz,1H),2.43-2.32(m,1H),2.28(s,3H),2.22(s,3H),2.04-1.95(m,1H).
HRMS(ESI)for C28H33ClN4O5[M+H]+,calcd:541.2212;found,541.2240.
实施例17:N-[5-氯-4-甲基-3-(6-氮杂-2-氧杂螺[3.3]庚-6-基甲基)苯基]-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-17)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.05(s,1H),7.76(d,J=2.1Hz,1H),7.63(s,1H),7.52(d,J=1.2Hz,2H),7.31(d,J=2.2Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.62(s,4H),4.46-4.23(m,2H),3.64(s,4H),3.17(s,2H),3.03(t,J=7.5Hz,2H),2.91(ddd,J=17.3,13.6,5.5Hz,1H),2.68(t,J=7.5Hz,2H),2.65-2.55(m,1H),2.39(qd,J=13.4,4.6Hz,1H),2.21(s,3H),2.06-1.94(m,1H).
HRMS(ESI)for C29H31ClN4O5[M+H]+,calcd:551.2056;found,551.2058.
实施例18:N-(5-氯-4-甲基-3-{[4-(氧杂环丁-3-基)哌嗪-1-基]甲基}苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-18)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.00(s,1H),7.78(s,1H),7.62(s,1H),7.51(s,2H),7.29(s,1H),5.10(dd,J=13.1,5.1Hz,1H),4.52(t,J=6.6Hz,2H),4.45-4.36(m,3H),4.28(d,J=17.1Hz,1H),3.42(s,3H),3.02(t,J=7.6Hz,2H),2.91(td,J=16.0,13.7,5.2Hz,1H),2.66(t,J=7.6Hz,2H),2.60(d,J=17.7Hz,1H),2.46-2.31(m,5H),2.27(s,6H),2.04-1.93(m,1H).
HRMS(ESI)for C31H36ClN5O5[M+H]+,calcd:594.2478;found:594.2478.
实施例19:N-(3-氯-4-甲基-5-{[3-(1,4-氧杂氮杂环己-4-基)氮杂环丁-1-基]甲基}苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-19)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.06(s,1H),7.75(s,1H),7.62(s,1H),7.51(s,2H),7.37(s,1H),5.09(dd,J=13.2,5.1Hz,1H),4.46-4.24(m,2H),3.78(s,2H),3.62-3.55(m,8H),3.17(s,1H),3.02(t,J=7.3Hz,2H),2.90(ddd,J=18.0,13.5,5.3Hz,1H),2.67(t,J=7.6Hz,2H),2.60(d,J=17.4Hz,1H),2.43-2.32(m,1H),2.28(s,4H),2.23(s,3H),1.99(dd,J=12.2,6.1Hz,1H).
HRMS(ESI)for C31H36ClN5O5[M+H]+,calcd:594.2478;found:594.2478.
实施例20:N-(3-氯-4-甲基-5-{[4-(3,4,5,6-四氢-2H-吡喃-4-基)哌嗪-1-基]甲基}苯基)-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-20)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.03(s,1H),7.74(s,1H),7.62(s,1H),7.51(s,2H),7.33(s,1H),5.09(dd,J=13.3,5.2Hz,1H),4.46-4.21(m,2H),3.97-3.86(m,2H),3.30-3.22(m,4H),3.02(t,J=7.5Hz,2H),2.90(ddd,J=18.6,13.7,5.3Hz,1H),2.78(s,4H),2.67(t,J=6.8Hz,2H),2.63-2.56(m,2H),2.42-2.31(m,3H),2.27(s,3H),2.00(dd,J=12.9,6.2Hz,1H),1.80(d,J=12.3Hz,2H),1.55-1.39(m,2H).
HRMS(ESI)for C33H40ClN5O5[M+H]+,calcd:622.2791;found:622.2791.
实施例21:N-{3-氯-5-[(3-羟基氮杂环丁-1-基)甲基]-4-甲基苯基}-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-21)的合成
合成方法参照实施例13。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.06(s,1H),7.75(s,1H),7.62(s,1H),7.52(s,2H),7.37(s,1H),5.57(s,1H),5.10(dd,J=13.4,5.1Hz,1H),4.47-4.23(m,2H),4.12(d,J=5.7Hz,1H),3.75(d,J=21.6Hz,2H),3.17(d,J=4.2Hz,2H),3.02(t,J=7.5Hz,2H),2.96-2.83(m,1H),2.71-2.64(m,2H),2.64-2.56(m,1H),2.42-2.30(m,1H),2.24(s,3H),2.05-1.95(m,1H).
HRMS(ESI)for C28H33ClN4O5[M+H]+,calcd:525.1899;found,525.1909.
实施例22:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-[3-(1,4-氧杂氮杂环己-4-基甲基)-4-(吡啶-4-基)苯基]丙酰胺(WYY-22)的合成
步骤1:制备1-溴-2-(溴甲基)-4-硝基苯(19)
将1-溴-2-甲基-4-硝基苯(10g,46.3mmol),N-溴代丁二酰亚胺(8.65g,48.6mmol),AIBN(3.8g,23.15mmol)溶于100mL1,2-二氯乙烷中,于100℃下回流反应9小时,旋干后进行柱层析分离得产物4g。
步骤2:制备1-[(2-溴-5-硝基苯基)甲基]-1,4-氧杂氮杂环己烷(20)
将1-溴-2-(溴甲基)-4-硝基苯(19)(4g,13.56mmol),***啉(1.54g,17.63mmol)溶于40mL四氢呋喃中,加入三乙胺(3.43g,33.9mmol),于65℃下回流6小时,反应液旋干,进行柱层析分离得产物3.1g。
步骤3:制备4-{[5-硝基-2-(吡啶-4-基)苯基]甲基}-1,4-氧杂氮杂环己烷(21)
将1-[(2-溴-5-硝基苯基)甲基]-1,4-氧杂氮杂环己烷(20)(1g,3.32mmol),4-吡啶硼酸(0.816g,6.64mmol),1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.24g,0.332mmol),碳酸钾(2.7g,19.92mmol)加入30mL1,4-二氧六环和10mL水的混合溶剂中,于100℃下反应2小时,反应液冷却至室温后,加入乙酸乙酯萃取3次,有机层用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,滤液旋干,进行柱层析分离得产物0.89g。
1H NMR(400MHz,DMSO-d6)δ8.75-8.63(m,2H),8.38(d,J=2.5Hz,1H),8.23(dd,J=8.4,2.5Hz,1H),7.58(d,J=8.4Hz,1H),7.52-7.46(m,2H),3.49(d,J=5.0Hz,6H),2.27(t,J=4.6Hz,4H).
步骤4:制备3-(1,4-氧杂氮杂环己-4-基甲基)-4-(吡啶-4-基)苯胺(22)
将4-{[5-硝基-2-(吡啶-4-基)苯基]甲基}-1,4-氧杂氮杂环己烷(21)(0.89g,2.59mmol),铁粉(0.725g,12.95mmol),氯化铵(0.138g,2.59mmol),加入30mL乙醇和15mL水的混合溶剂中,于90℃下回流反应4小时,反应液冷却至室温,过滤得滤液,加入饱和碳酸氢钠溶液20mL,用乙酸乙酯萃取得有机层,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,旋干得黄色固体(0.71g)。
步骤5:制备3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-[3-(1,4-氧杂氮杂环己-4-基甲基)-4-(吡啶-4-基)苯基]丙酰胺(WYY-22)
将1-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸(13)(0.25g,0.79mmol),3-(1,4-氧杂氮杂环己-4-基甲基)-4-(吡啶-4-基)苯胺(22)(0.27g,0.873mmol),HATU(0.318g,0.873mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.4mL,2.184mmol),于室温下搅拌反应2.5小时,反应液旋干,柱层析分离得产物105.2mg。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.10(s,1H),8.62-8.56(m,2H),7.70(dd,J=8.3,2.1Hz,1H),7.68-7.63(m,2H),7.53(s,2H),7.46-7.41(m,2H),7.22(d,J=8.3Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.46-4.24(m,2H),3.50(t,J=4.6Hz,6H),3.05(t,J=7.6Hz,2H),2.91(ddd,J=18.1,13.3,5.2Hz,1H),2.71(t,J=7.6Hz,2H),2.64-2.56(m,1H),2.46-2.32(m,1H),2.25(d,J=5.6Hz,4H),2.04-1.94(m,1H).
HRMS(ESI)for C32H33N5O5[M+H]+,calcd:568.2554;found:568.2554.
实施例23:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-[3-(1,4-氧杂氮杂环己-4-基甲基)-4-(吡啶-3-基)苯基]丙酰胺(WYY-23)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.06(s,1H),8.60-8.52(m,2H),7.83(dt,J=7.8,2.0Hz,1H),7.73-7.61(m,3H),7.53(s,2H),7.44(dd,J=7.9,4.8Hz,1H),7.21(d,J=8.3Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.47-4.23(m,2H),3.50(t,J=4.7Hz,4H),3.33(s,2H),3.05(t,J=7.5Hz,2H),2.91(ddd,J=18.0,13.5,5.4Hz,1H),2.71(t,J=7.5Hz,2H),2.65-2.56(m,1H),2.40(qd,J=13.2,4.5Hz,1H),2.24(s,4H),2.05-1.94(m,1H).
HRMS(ESI)for C32H33N5O5[M+H]+,calcd:568.2554;found:568.2554.
实施例24:N-[4-(4-氰基苯基)-3-(1,4-氧杂氮杂环己-4-基甲基)苯基]-3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酰胺(WYY-24)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.08(s,1H),7.87(d,J=7.9Hz,2H),7.69(d,J=8.7Hz,1H),7.67-7.57(m,4H),7.53(s,2H),7.20(d,J=8.3Hz,1H),5.11(dd,J=14.0,5.1Hz,1H),4.48-4.23(m,2H),3.49(s,4H),3.32(s,5H),3.05(t,J=7.5Hz,2H),2.98-2.84(m,1H),2.71(t,J=7.6Hz,2H),2.60(d,J=17.3Hz,1H),2.39(qd,J=12.9,12.5Hz,1H),2.24(s,4H),2.00(d,J=11.3Hz,1H).
HRMS(ESI)for C34H33N5O5[M+H]+,calcd:592.2554;found:592.2554.
实施例25:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-[4-(4-氟苯基)-3-(1,4-氧杂氮杂环己-4-基甲基)苯基]丙酰胺(WYY-25)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.02(s,1H),7.64(t,J=7.1Hz,3H),7.53(s,2H),7.41(t,J=6.7Hz,2H),7.23(t,J=8.8Hz,2H),7.15(d,J=8.2Hz,1H),5.11(dd,J=13.7,5.1Hz,1H),4.49-4.24(m,2H),3.52(d,J=4.7Hz,4H),3.29(s,2H),3.05(t,J=7.6Hz,2H),2.98-2.84(m,1H),2.70(t,J=7.8Hz,2H),2.65-2.55(m,1H),2.39(d,J=13.1Hz,1H),2.26(s,4H),2.05-1.93(m,1H).
HRMS(ESI)for C33H33FN4O5[M+H]+,calcd:585.2508;found:585.2508.
实施例26:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-[3-(1,4-氧杂氮杂环己-4-基甲基)-4-[4-(三氟甲基)苯基]苯基]丙酰胺(WYY-26)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.07(s,1H),7.77(d,J=7.9Hz,2H),7.69(d,J=8.6Hz,1H),7.65(d,J=7.4Hz,3H),7.62(s,1H),7.53(s,2H),7.21(d,J=8.2Hz,1H),5.11(dd,J=13.4,5.1Hz,1H),4.50-4.23(m,2H),3.51(t,J=4.3Hz,4H),3.29(s,2H),3.05(t,J=7.6Hz,2H),2.97-2.85(m,1H),2.71(t,J=7.6Hz,2H),2.60(dd,J=17.9,3.9Hz,1H),2.46-2.32(m,1H),2.26(s,4H),2.01(d,J=10.1Hz,1H).
HRMS(ESI)for C34H33F3N4O5[M+H]+,calcd:635.2476;found:635.2476.
实施例27:3-(2-(2,6-二氧哌啶-3-基)-3-氧异喹啉-5-基)-N-(2-(吗啉甲基)-(1,1'-联苯基)-4-基)丙酰胺(WYY-27)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.02(s,1H),7.66(d,J=8.9Hz,3H),7.53(s,2H),7.41(t,J=7.5Hz,2H),7.36(d,J=7.6Hz,3H),7.15(d,J=8.1Hz,1H),5.11(dd,J=13.1,5.0Hz,1H),4.49-4.20(m,2H),3.53(t,J=4.5Hz,4H),3.3(s,2H)3.05(t,J=7.6Hz,2H),2.91(s,1H),2.70(t,J=7.6Hz,2H),2.60(d,J=17.3Hz,1H),2.40(qd,J=14.8,13.9,5.5Hz,1H),2.25(s,4H),2.00(d,J=11.6Hz,1H).
HRMS(ESI)for C33H34N4O5[M+H]+,calcd:567.2602;found:567.2602.
实施例28:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N–[3-(5-甲基-5-氮杂-2-氧杂己-6-基)-4-(吡啶-4-基)苯基]丙酰胺(WYY-28)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.12(s,1H),8.60(d,J=5.0Hz,2H),7.75(s,1H),7.68(dd,J=8.4,2.2Hz,1H),7.64(s,1H),7.53(s,2H),7.43-7.38(m,2H),7.22(d,J=8.3Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.47-4.25(m,2H),3.17(s,3H),3.05(t,J=7.5Hz,2H),2.91(ddd,J=18.2,13.6,5.4Hz,1H),2.72(t,J=7.5Hz,2H),2.68-2.57(m,3H),2.45-2.32(m,2H),2.14(s,3H),2.00(ddd,J=11.4,6.0,3.8Hz,1H).
HRMS(ESI)for C32H35N5O5[M+Na]+,calcd:592.2530;found:592.2535.
实施例29:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-{3-[(1,1-二氧化硫代吗啉-4-基)甲基]-4-(吡啶-4-基)苯基}丙酰胺(WYY-29)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.09(s,1H),8.67-8.56(m,2H),7.69(d,J=6.7Hz,2H),7.65(s,1H),7.53(s,2H),7.46-7.40(m,2H),7.25-7.20(m,1H),5.11(dd,J=13.3,5.1Hz,1H),4.46-4.25(m,2H),3.56(s,2H),3.06(t,J=7.5Hz,2H),2.98(t,J=5.2Hz,4H),2.94-2.85(m,1H),2.72(q,J=7.8,6.6Hz,6H),2.65-2.56(m,1H),2.46-2.30(m,1H),2.05-1.94(m,1H).
HRMS(ESI)for C32H33N5O6S[M+H]+,calcd:616.2224;found:616.2230.
实施例30:3-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]-N-(4-联苯基)丙酰胺(WYY-30)的合成
化合物13的合成方法参照实施例13。
将4-[2-(2,6-二氧亚基六氢吡啶-3-基)-3-氧亚基-2,3-二氢-1H-异吲哚-5-基]丙酸(13)(0.3g,0.949mmol),联苯胺(0.24g,1.42mmol),HATU(0.415g,1.09mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.5mL,2.95mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物95mg。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.03(s,1H),7.68(s,1H),7.67-7.63(m,3H),7.62(d,J=2.1Hz,2H),7.59(d,J=1.8Hz,1H),7.53(s,2H),7.44(t,J=7.6Hz,2H),7.32(t,J=7.3Hz,1H),5.11(dd,J=13.6,5.0Hz,1H),4.46-4.24(m,2H),3.05(t,J=7.6Hz,2H),2.97-2.83(m,1H),2.71(t,J=7.6Hz,2H),2.60(dd,J=16.4,3.8Hz,1H),2.46-2.31(m,1H),2.05-1.94(m,1H).
HRMS(ESI)for C28H25N3O4[M+H]+,calcd:468.1918;found:468.1918.
实施例31:N-(3-氯-4-甲基苯基)-3-[6-(2,6-二氧亚基六氢吡啶-3-基)-5-氧亚基-6,7-二氢-5H-吡咯并[4,3-b]吡啶-3-基]丙酰胺(WYY-31)的合成
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将3-[6-(2,6-二氧亚基六氢吡啶-3-基)-5-氧亚基-6,7-二氢-5H-吡咯并[4,3-b]吡啶-3-基]丙酸(0.25g,0.788mmol),3-氯-4-甲基苯胺(0.134g,0.945mmol),HATU(0.344g,0.906mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.4mL,2.364mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物68mg。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.05(s,1H),8.69(s,1H),8.05(s,1H),7.76(s,1H),7.36-7.19(m,2H),5.16(dd,J=13.5,5.1Hz,1H),4.54-4.24(m,2H),3.05(t,J=7.5Hz,2H),2.91(td,J=15.0,13.4,5.9Hz,1H),2.71(t,J=7.3Hz,2H),2.60(dd,J=17.6,4.3Hz,1H),2.44-2.31(m,1H),2.25(s,3H),2.08-1.96(m,1H).
HRMS(ESI)for C22H21ClN4O4[M+H]+,calcd:441.1324;found:441.1324.
实施例32:3-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)-N-(3-(三氟甲氧基)苯基)丙酰胺(WYY-32)的合成
合成方法参照实施例1。
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.22(s,1H),7.77(s,1H),7.63(s,1H),7.52(s,2H),7.49-7.38(m,2H),7.01(d,J=7.9Hz,1H),5.11(dd,J=13.5,4.9Hz,1H),4.47-4.22(m,2H),3.04(t,J=7.2Hz,2H),2.97-2.83(m,1H),2.71(t,J=7.6Hz,2H),2.60(d,J=17.2Hz,1H),2.46-2.32(m,1H),2.05-1.94(m,1H).13C NMR(600MHz,DMSO-d6)δ173.38,171.51,171.23,168.58,148.94,141.67,141.17,140.39,132.57,132.35,130.92,123.88,122.96,118.03,115.54,111.51,52.07,47.48,38.37,31.69,30.80,22.95.HRMS(ESI)for C32H33N5O6S[M+H]+,calcd:476.1428;found:476.1438.HPLCpurity:99.8%,3.59min.
实施例33:3-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)-N-(3-((4-吗啉代哌啶-1-基)甲基)-4-(吡啶-4-基)苯基)丙酰胺(WYY-33)的合成
合成方法参照实施例22。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.09(s,1H),8.58(d,J=4.9Hz,2H),7.70(d,J=8.5Hz,1H),7.66-7.56(m,2H),7.52(d,J=6.3Hz,2H),7.41(d,J=5.0Hz,2H),7.20(d,J=8.9Hz,1H),5.18-5.03(m,1H),4.58-4.25(m,2H),4.18-4.08(m,2H),3.54(s,4H),3.48(s,2H),3.17(s,5H),3.10-2.99(m,2H),2.96-2.84(m,1H),2.77-2.66(m,4H),2.60(d,J=17.4Hz,1H),2.40(s,4H),2.30-2.21(m,1H),2.11-1.96(m,2H),1.80(t,J=11.4Hz,2H),1.68(d,J=12.0Hz,2H).13C NMR(600MHz,DMSO-d6)δ173.41,171.50,170.96,168.64,149.66,148.92,142.40,140.37,139.62,136.92,134.38,132.63,132.30,130.12,124.87,123.87,122.98,120.68,118.24,67.07,61.71,59.85,52.62,52.10,50.02,47.57,38.40,31.67,31.00,28.33,22.94.HRMS(ESI)for C31H36ClN5O5[M+H]+,calcd:651.3289;found:651.3285.HPLC purity:97.9%,3.0min.
实施例34:N-(3-氯-4-甲基苯基)-3-(2-(2,7-二氧杂环丙烷-3-基)-3-氧代异吲哚啉-5-基)丙酰胺(WYY-34)的合成
步骤1:制备3-(6-溴-1-氧代异吲哚啉-2-基)氮杂苯-2,7-二酮(24)
将化合物5-溴-2-(溴甲基)苯甲酸甲酯(1.69g,5.5mmol),3-氨基己内酰亚胺(1g,6.1mmol)溶于20mLDMF中,加入三乙胺(2.3mL,16.5mmol)于90℃下反应过夜,减压浓缩除去溶剂,进行柱层析分离纯化得到白色固体3-(6-溴-1-氧代异吲哚啉-2-基)氮杂苯-2,7-二酮(1.54g,产率为70.5%)。
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.93(d,J=8.5Hz,1H),7.80(t,J=6.3Hz,1H),7.76(s,1H),4.95(d,J=11.2Hz,1H),4.78-4.42(m,2H),2.64(s,2H),1.99(t,J=11.6Hz,2H),1.81(d,J=13.0Hz,2H),1.49(s,9H).MS(ESI),m/z:337.0[M+H]+
步骤2:制备(E)-3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚-5-基)丙烯酸叔丁酯(25)
将化合物3-(6-溴-1-氧代异吲哚啉-2-基)氮杂苯-2,7-二酮(1.4g,4.2mmol),丙烯酸叔丁酯(1.35g,10.5mmol),Pd2(dba)3(0.192g,0.21mmol),三叔丁基磷四氟硼酸盐(0.06g,0.21mmol)溶于25mLDMF中,加入N,N-二环己基甲胺(1.64g,8.4mmol)于105℃下反应7小时,减压浓缩除去溶剂,进行柱层析分离纯化,得到白色固体(E)-3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚-5-基)丙烯酸叔丁酯(1.0g,产率为76.5%)。
1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.96(d,J=8.5Hz,1H),7.82(t,J=6.3Hz,1H),7.70(s,1H),7.65(d,1H),6.64(d,J=16.0Hz,1H),4.91(d,J=11.0Hz,1H),4.77-4.45(m,2H),2.63(s,2H),1.99(t,J=11.5Hz,2H),1.79(d,J=13.0Hz,2H),1.49(s,9H).MS(ESI),m/z:385.1[M+H]+.
步骤3:制备3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚啉-5-基)丙酸叔丁酯(26)
将化合物(E)-3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚-5-基)丙烯酸叔丁酯(0.5g,1.3mmol)溶于100mL甲醇中,加入0.05g钯碳,于氢气保护下反应6小时,反应液经硅藻土过滤,甲醇洗涤滤饼,收集滤液,进行减压蒸馏除去溶剂,得到白色固体3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚啉-5-基)丙酸叔丁酯(0.42g,产率为84%)。
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.56(d,J=8.4Hz,1H),7.44(t,J=6.0Hz,1H),7.38(s,1H),4.95(d,J=11.0Hz,1H),4.76-4.40(m,2H),2.91-2.86(m,2H),2.78-2.64(m,4H),2.05-1.99(m,2H),1.79(d,J=13.0Hz,2H),1.49(s,9H).MS(ESI),m/z:387.1[M+H]+.
步骤4:制备3-(2-(2,7-二氧杂环戊烷-3-基)-3-氧代异吲哚啉-5-基)丙酸
将化合物3-(2-(2,7-二氧代环戊二烯-3-基)-3-氧代异吲哚啉-5-基)丙酸叔丁酯(0.25g,0.76mmol)溶于10mL无水二氯甲烷中,加入5mL三氟乙酸于室温下反应1小时,减压浓缩除去溶剂得到化合物3-(2-(2,7-二氧杂环戊烷-3-基)-3-氧代异吲哚啉-5-基)丙酸,无需纯化直接进行下一步反应。MS(ESI),m/z:331.1[M+H]+
步骤4:制备N-(3-氯-4-甲基苯基)-3-(2-(2,7-二氧杂环丙烷-3-基)-3-氧代异吲哚啉-5-基)丙酰胺(WYY-34)
将化合物3-(2-(2,7-二氧杂环戊烷-3-基)-3-氧代异吲哚啉-5-基)丙酸(0.25g,0.76mmol),对甲基间氯苯胺(0.123g,0.87mmol),HATU(0.33g,0.874mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.4mL,2.28mmol)于室温下反应3小时,旋干DMF,进行柱层析分离得到白色固体WYY-34(0.15g,产率为44.1%)。
1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.79(d,J=8.2Hz,2H),7.58(s,1H),7.54-7.45(m,2H),7.32(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,1H),4.89(d,J=11.0Hz,1H),4.64(d,J=17.0Hz,1H),4.42(d,J=17.1Hz,1H),3.01(t,J=7.7Hz,2H),2.66(t,J=7.5Hz,2H),2.25(s,3H),1.98(d,J=10.8Hz,2H),1.88-1.68(m,2H),1.35-1.20(m,2H).13CNMR(600MHz,DMSO-d6)δ174.89,170.91,167.42,141.39,140.89,138.72,133.40,132.78,132.11,131.61,130.11,123.70,122.80,119.88,118.10,53.86,47.62,41.28,38.43,30.94,29.45,29.01,28.29,19.36.HRMS(ESI)for C24H24ClN3O4[M+H]+,calcd:454.1528;found:454.1528.HPLC purity:99.2%,4.18min.
实施例35:N-(3--5-(((2-甲氧基乙基)(甲基)氨基)methyl)-4-甲基苯基)-3-(2-(2,6-二氧哌啶-3-基)-6-氟-3-氧代异吲哚-5-基)丙酰胺的合成(WYY-35)
将3-(2-(2,6-二氧哌啶-3-基)-6-氟-3-氧代异吲哚-5-基)丙酸(0.31g,0.95mmol),3-氯-5-(((2-甲氧基乙基)(甲基)氨基)甲基)-4-甲基苯胺(0.25g,1.45mmol),HATU(0.419g,1.1mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.52mL,2.98mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物97mg。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.04(s,1H),7.77(d,J=2.1Hz,1H),7.70(d,J=6.9Hz,1H),7.46(d,J=9.5Hz,1H),7.30(s,1H),5.09(dd,J=13.4,5.1Hz,1H),4.45-4.23(m,2H),3.51-3.40(m,5H),3.22(s,3H),3.01(t,J=7.6Hz,2H),2.96-2.83(m,1H),2.68(t,J=7.5Hz,2H),2.61-2.53(m,2H),2.45-2.32(m,1H),2.27(s,3H),2.14(s,3H),2.03-1.92(m,1H).
实施例36:3-(6-(3-((3-氯-5-(2-甲氧乙基)(甲基)氨基)甲基)-4-甲基苯基)氨基)-3-氧丙基)-1-氧异吲哚-2-基)-2,6-二氧吡吡啶-1-基)甲基新戊酸酯的合成(WYY-36)
将叔丁基3-(2-(2,6-二氧-哌啶-3-基)-3-氧异吲哚-5-基丙酸酯(0.375g,1.0mmol),新戊酸氯甲脂(0.21g,1.5mmol)溶于20mLDMF中,加入氢化钠(0.045g,1.1mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物336mg。将上述产物溶于二氯甲烷(5mL),然后加入三氟醋酸(2.0mL),在室温条件下搅拌1小时,溶剂蒸发后得到粗产物。将此粗产物210mg,3-氯-5-(((2-甲氧基乙基)(甲基)氨基)甲基)-4-甲基苯胺(0.25g,1.45mmol),HATU(0.419g,1.1mmol)溶于20mLDMF中,加入N,N-二异丙基乙胺(0.52mL,2.98mmol),于室温下反应三小时。旋干有机溶剂,柱层析分离得产物WYY-36(101mg)。
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),7.79(s,1H),7.64(s,1H),7.53(s,2H),7.30(s,1H),5.62(q,J=9.6Hz,2H),5.29(dd,J=13.3,5.1Hz,1H),4.44(d,J=16.9Hz,1H),4.25(d,J=17.0Hz,1H),3.49-3.41(m,4H),3.22(s,3H),3.16-3.05(m,1H),3.02(t,J=7.5Hz,2H),2.83(d,J=17.4Hz,1H),2.67(t,J=7.6Hz,2H),2.54(d,J=6.0Hz,2H),2.48-2.32(m,1H),2.27(s,3H),2.13(s,3H),2.10-2.03(m,1H),1.10(s,8H).
实施例37:体外肿瘤细胞增殖抑制活性
化合物对细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下:
1)细胞接种:处于细胞对数生长期的H1299(非小细胞肺癌细胞)、U937(人组织细胞淋巴瘤细胞)、MOLT4(人急性淋巴母细胞白血病细胞)、MV4-11(急性单核细胞白血病细胞)等肿瘤细胞分别按同样密度接种在不同96孔板中(3000-10000个细胞/100μL/孔)。
2)工作液配制:以细胞培养所需相应培养基作为稀释液(含或不含溶媒DMSO),稀释受试化合物和对照化合物储备液,获得所需浓度为终浓度3倍的系列浓度的工作液,各浓度组中的溶媒DMSO含量与溶媒对照组相一致。
3)共孵育:接种24hr后,向96孔板加入化合物系列浓度的母液100μL/孔,混匀后共培养72hr。所有组别至少3个复孔,每个化合物6个浓度。空白对照组:只加培养基,不加细胞和药物,排除培养基对比色的干扰。
4)吸光度测定:从96孔板吸走培养基后,每孔加入10μLCCK-8溶液,共培养4hr后,充分振荡使其均匀,在酶标仪上测定A450及A650处的吸光值。
5)数据处理:根据得到的A450-A650原始数据计算得到各处理孔的细胞存活率(计算方法如下);然后将细胞存活率数据及其对应的化合物浓度输入GraphPad Prism 8.0Demo软件,使用非线性回归模型计算化合物对不同细胞的IC50值。
细胞存活率的计算:细胞存活率(%)=[(As-Ac)/(Ab-Ac)]×100%](As:实验孔;Ab:溶媒对照孔;Ac:空白孔)。
结果如表1所示:本发明提供的异吲哚酰胺类化合物对各种肿瘤细胞都具有良好的抑制活性。
表1化合物对H1299、U937、MOLT4、MV4-11细胞的抑制活性
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实施例38:化合物对U937细胞中GSPT1表达的影响
细胞株:U937细胞株购自ATCC。
使用常规Western blot(免疫印迹法)进行检测,具体如下。将U937细胞按一定数量接种于12孔板,培养箱内贴壁培养过夜后,加入一定浓度的化合物作用6h,用裂解液裂解细胞,收样。然后取适量样品进行SDS-PAGE电泳,电泳结束后用半干电转移***将蛋白转移至硝酸纤维素膜,将硝酸纤维素膜置于封闭液(5%脱脂奶粉稀释于含0.1%Tween 20的TBS)中室温封闭2h,然后将膜分别置于一抗溶液(1:1000稀释于含0.1%Tween 20的TBS)中4℃孵育过夜。用含0.1%Tween 20的TBS洗涤三次,每次15min。将膜置于二抗溶液(辣根过氧化物酶标记羊抗兔的IgG,1:1000稀释于含0.1%Tween 20的TBS)中室温反应1h。同上,洗膜三次后,用ECL plus试剂发色,Amersham Imager 600system拍照。使用ImageJ软件分别进行灰度处理,得到灰度值,使用以下公式计算不同浓度下的蛋白降解率(Degradationrate,D)。DGSPT1=(1-GGSPT1/G0)*100%,其中,GGSPT1为不同浓度化合物处理组观察到目的蛋白降解的Density(GSPT1条带)/Density(对应GAPDH条带),G0=空白对照组Density(GSPT1条带)/Density(对应GAPDH条带)。通过GraphPadPrism8软件计算得到DC50。
检测结果如表2所示:本发明化合物能降解U937细胞中的GSPT1蛋白;尤其是化合物WYY-1、WYY-2、WYY-8、WYY-15~WYY-27、WYY-30等,其能显著降解U937细胞中的GSPT1蛋白。
表2化合物对U937细胞中GSPT1蛋白的降解活性
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实施例39:药代动力学实验
准备体重180-220g的SD(Sprague-Dawley)雄性大鼠3组,分别用于静脉注射(IV)和口服给药(PO),每组各3只。除了在口服给药前所有大鼠均禁食过夜10~14小时,在给药4小时给食外,试验期间动物自由进食。针对静脉注射给药的配药方法:将待测化合物溶于混合溶剂(5%DMSO+10%Solutol+85%Saline)中,浓度为1mg/mL。针对口服给药的配药方法:将待测化合物混悬于混合溶剂(0.5%CMC-Na)中,浓度为2mg/mL。分别以10mg/kg和10mg/kg的剂量静脉注射和口服给予化合物。静注给药采血时间点为:0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时和24小时。口服给药采血时间点为:0.25、0.5、1、2、4、6、8、10和24小时。经颈静脉或其它合适方式采血,每个样品采集约0.20mL,EDTA-K2抗凝,采集后置于冰上,并于1小时之内离心分离血浆(离心条件:6800g,6分钟,2-8℃)。通过不同时间点的血药浓度数据,运用Phoenix WinNonlin 7.0计算药代动力学参数,提供AUC0-t、AUC0-∞、MRT0-∞、Cmax、Tmax、和T1/2等参数及其平均值和标准差。剩余供试品及血浆样品在试验结束后1个月给予丢弃。
准备体重18~25g的SPF级的ICR雄性小鼠3只,用于腹膜内注射(IP)。实验期间,除了特定的禁食期外,动物可以自由进食。针对腹膜内注射给药的配药方法:将待测化合物溶于混合溶剂(5%DMSO+10%Solutol+85%Saline)中,浓度为2mg/mL。以20mg/kg剂量静脉注射给予化合物。腹膜内注射给药采血时间点为:0.5、1、2、4、8、12、24、36和48小时。从眼眶静脉丛在合适时间点采血0.03mL,血液样品存于加入了K2-EDTA的采血管中,置冰上直到离心环节开始。在1小时内离心分离血浆,并于-80℃下储存。离心条件为:6800转/分钟,6分钟,2~8℃。根据不同时间点的血药浓度数据,并利用Phoenix WinNonlin 7.0(Pharsight,USA)中的非隔室分析模块计算各药代动力学参数。
结果如表3所示,由于WWY-7溶解度很差,没有获得药代动力学参数。化合物WYY-16和WYY-35的AUC(0-∞)和Cmax远远高于化合物WYY-14,WYY-20和WYY-21,药代动力学性质更好。并且,以口服给药方式,化合物WYY-16和WYY-35的口服生物利用度分别为5.24%,10.52%,有一定的口服生物利用度并且优于其它化合物,表明本发明的化合物WYY-16和WYY-35可以口服给药。
表3.化合物的WYY-16,WYY-20,WYY-21和WYY-35的药物代谢动力学参数。
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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 (22)
1.具有式(I)所示结构的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物:
其中:W选自:CR2,N;
A选自:
R1选自:H,C1-C6烷基,卤素取代的C1-C6烷基,卤素,C1-C6烷氧基,卤素取代的C1-C6烷氧基,羟基,C3-C6环烷基;
R2选自:H,C1-C6烷基,卤素,卤素取代的C1-C6烷基;
R3选自:H,-(CH2)O(C=O)R4;
R4选自:C1-C6烷基,氨基和/或羟基取代的C1-C6烷基;
R12选自:H,卤素取代的C1-C6烷基,
R’12选自:H,卤素,C1-C6烷基,R’13取代或者未取代的苯基,R’13取代或者未取代的5-6元杂芳基;
R”12选自:H,卤素,C1-C6烷基;
各R’13分别独立地选自:H,C1-C6烷基,卤素,氰基,卤素取代的C1-C6烷基;
R17和R18分别独立地选自:H,C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的3-12元杂环基;
各R14分别独立地选自:H,C1-C6烷基,R16取代或者未取代的3-8元杂环基,C1-C6烷基胺基,羟基;
各R16分别独立地选自:H,C1-C6烷基,C1-C6烷氧基;
m选自:0,1,2;
当A位于W的间位,R”12为卤素,R’12为C1-C6烷基时,R12不为氢,并且R17和R18与和其相连的氮原子不形成吗啉环。
2.根据权利要求1所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,W为CH。
3.根据权利要求1所述述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R1选自:H,甲基,乙基,丙基,F,Cl,Br,环丙基,羟基,三氟甲基。
4.根据权利要求1所述述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R2位于W的邻位。
5.根据权利要求1所述述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,所述异吲哚酰胺类化合物具有如下式(II)所示结构:
6.根据权利要求1所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,所述异吲哚酰胺类化合物具有如下式(III)所示结构:
7.根据权利要求1所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,所述异吲哚酰胺类化合物具有如下式(IV)所示结构:
8.根据权利要求1-7任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R2选自:H,甲基,乙基,丙基,F,Cl,Br,环丙基,羟基,三氟甲基。
9.根据权利要求1-5任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R”12选自:H,F,Cl,Br。
10.根据权利要求1-5或者权利要求7任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R’12选自:H,F,Cl,Br,甲基,乙基,丙基,R’13取代或者未取代的吡啶基,R’13取代或者未取代的苯基;
各R’13分别独立地选自:H,甲基,乙基,丙基,F,Cl,Br,氰基,三氟甲基。
11.根据权利要求1-7任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R12选自:
H,卤素取代的C1-C3烷基,
R17和R18分别独立地选自:H,C1-C3烷基,C1-C3烷氧基取代的C1-C3烷基,C1-C3烷基胺基取代的C1-C3烷基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的3-8元杂环基;
各R14分别独立地选自:H,C1-C3烷基,R16取代或者未取代的3-8元杂环基,C1-C3烷基胺基,羟基;
各R16分别独立地选自:H,C1-C3烷基,C1-C3烷氧基;
m选自:0,1,2。
12.根据权利要求11所述述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R12选自:
H,三氟甲基,
R17和R18分别独立地选自:甲基,乙基,甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成R14取代或者未取代的如下杂环烷基:哌啶基、哌嗪基、吗啉基、7元氮杂-氧杂螺环烷基、氮杂环丁基、二氧化硫代吗啉基、氧杂环丁基;
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃基。
13.根据权利要求12所述述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R12选自:
H,三氟甲基,R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃。
14.根据权利要求6所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R12选自:R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:甲基,吗啉基,氧杂环丁基,四氢吡喃。
15.根据权利要求7所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,R’12选自:H,R’13取代或者未取代的吡啶基,R’13取代或者未取代的苯基;
各R’13分别独立地选自:H,甲基,乙基,丙基,F,Cl,Br,氰基,三氟甲基;
R12选自:H,三氟甲基,R17选自:甲基,乙基,R18选自:甲氧基取代的甲基,甲氧基取代的乙基,乙氧基取代的甲基,乙氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
各R14分别独立地选自:H,甲基,乙基,羟基,吗啉基,氧杂环丁基,四氢吡喃。
16.根据权利要求15所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,
R’12选自:H,吡啶-4-基,吡啶-3-基,4-氰基苯基,4-氟苯基,4-三氟甲基苯基,苯基;
R12选自:H,三氟甲基,R17选自:甲基,R18选自:甲氧基取代的乙基;或者R17和R18与和其相连的氮原子一起形成如下结构:
17.根据权利要求1所述异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物,其特征在于,选自如下化合物:
18.权利要求1~17任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物在制备GSPT1蛋白降解剂中的应用。
19.权利要求1~17任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物在制备预防或治疗与GSPT1蛋白活性异常表达相关的疾病的药物中的应用。
20.根据权利要求19所述的应用,其特征在于,与GSPT1蛋白活性异常表达相关的疾病为肿瘤、高血糖、糖尿病、肥胖症、高血脂症、高胆固醇血症、高脂蛋白血症、高甘油三酯血症、高血压、高胰岛素血症、高尿酸血症、帕金森病、阿尔茨海默病。
21.根据权利要求20所述的应用,其特征在于,所述肿瘤为:非小细胞肺癌、恶性黑色素瘤、***癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、***、肺癌、喉癌、鼻咽癌、口腔癌、皮肤癌、脑癌、神经癌、成骨肉瘤、软骨肉瘤、横纹肌肉瘤、食道癌、胰腺癌、多发性骨髓瘤、淋巴瘤、白血病。
22.一种治疗或预防肿瘤的药物组合物,其特征在于,由活性成分和药学上可接受的辅料制备而成,所述活性成分含有权利要求1~17任一项所述的异吲哚酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其溶剂合物。
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