CN114805301B - 2,4-二芳氨基嘧啶类化合物及其制备方法和应用 - Google Patents
2,4-二芳氨基嘧啶类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于医药领域，涉及通式I所示的2,4‑二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药，它们的制备方法和含有所述化合物的药物组合物及应用，其中取代基L、X、Y、Ra具有在说明书中给出的含义。本发明还涉及通式I的化合物在制备用于治疗和/或预防ALK介导的疾病药物中的应用，特别是在制备治疗淋巴瘤、非小细胞肺癌、小细胞肺癌、神经胶质瘤、成神经细胞瘤等的药物中的应用。
Description
技术领域:
本发明属于医药领域，涉及2,4-二芳氨基嘧啶类ALK抑制剂及其立体异构体以及药学上可接受的盐、它们的制备方法和含有所述化合物的药物组合物以及这类化合物或药物组合物在制备抗肿瘤药物中的应用。
背景技术：
间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)为胰岛素受体酪氨酸激酶家族中的一员，以NPM-ALK融合基因的形式在间变性大细胞淋巴瘤(anaplastic largecell lymphoma,ALCL)中首次被发现，是一种由1620个氨基酸组成，包括胞外配体结合域、跨膜域及胞内酪氨酸激酶结构域的跨膜蛋白。ALK可激活多个细胞内信号通路，包括磷脂酶Cγ、JAK激酶、信号转导和转录激活因子(signaltransducer and activator oftranscription-3,STAT3)、磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinase,PI3K)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)及丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)等，参与调节细胞生长、转化及抗细胞凋亡。在多种肿瘤中均发现了ALK基因重组、突变或扩增，包括淋巴瘤、神经母细胞瘤及非小细胞肺癌(non-small cell lung cancer，NSCLC)。截至目前，已有21个不同的基因被发现与ALK发生易位，不同的ALK融合蛋白可能引起不同信号通路的激活，导致癌细胞的增殖速率、侵袭及致瘤能力均不同。因此，靶向ALK抑制剂可以通过抑制ALK下游相关信号而达到抗肿瘤的目的。
Ceritinib是由诺华研发的第二代ALK抑制剂，于2014年4月29日经美国FDA批准上市。该药用于治疗ALK阳性、肿瘤病情有进展或不能耐受Crizotinib的转移性非小细胞肺癌患者。然而，随着在临床上的长期应用，大部分患者亦不可避免地对Ceritinib产生了耐药，超过半数耐药患者体内出现了ALK耐药突变。因此开发新型的抗ALK耐药突变的抑制剂迫在眉睫。
二硫代氨基甲酸酯是一类已报道具有较好抗肿瘤活性的片段，我们通过分子杂交的设计策略，在Ceritinib的哌啶端直接或通过linker引入二硫代氨基甲酸酯片段，发现了具有抗Ceritinib耐药突变的ALK抑制剂。
发明内容：
本发明涉及通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药。通式I为：
其中，L独立选自6–10元芳基、5–12元杂芳基、(C0–C8)烷基、(C2–C8)烯基、(C2–C8)炔基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基、芳基(C1–C6)烷基、杂芳基(C1–C6)烷基；所述的6–10元芳基、5–12元杂芳基、(C0–C8)烷基、(C2–C8)烯基、(C2–C8)炔基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基、芳基(C1–C6)烷基、杂芳基(C1–C6)烷基可被1–3个R1取代；
R1独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、羧基、氨基；
X、Y选自S、(C0–C4)烷基；
Ra独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、羧基、氨基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；
R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、氨基、羧基、–(C＝O)NR3R4或–NR3R4；
R3、R4独立地选自氢、(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基、氨基磺酰基(C1–C4)烷基、甲磺酰氨基(C1–C4)烷基、羧基(C1–C4)烷基；所述(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基、氨基磺酰基(C1–C4)烷基、甲磺酰氨基(C1–C4)烷基、羧基(C1–C4)烷基可任选被1–3个R5取代；
或者R3、R4和与它们相连的氮原子一起形成一个3–10元的含氮杂环，优选为5–6元含氮杂环；所述的含氮杂环含有0–3个选自N、O或S的杂原子，任选包括0～2个碳碳双键或叁键；所述的含氮杂环可任选被1–3个R6取代；
R5、R6独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、(C3–C8)环烷基、氰基、羟基、羧基、氨基。
本发明优选涉及通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药。
其中，L独立选自(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基；所述的(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基可被1–3个R1取代；
R1独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基；
X、Y选自S、(C0–C4)烷基；
Ra独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；
R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、氨基、羧基、–(C＝O)NR3R4或–NR3R4；
R3、R4独立地选自氢、(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基；所述(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基可任选被1–3个R5取代；
或者R3、R4和与它们相连的氮原子一起形成一个3–10元的含氮杂环，优选为5–6元含氮杂环；所述的含氮杂环含有0–3个选自N、O或S的杂原子，任选包括0～2个碳碳双键或叁键；所述的含氮杂环可任选被1–3个R6取代；
R5、R6独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、(C3–C8)环烷基、羟基、氨基。
本发明还优选涉及通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药。
其中，L独立选自(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基；所述的(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基可被1–3个R1取代；
R1独立地选自氢、(C1–C4)烷基；
X、Y选自S、(C0–C4)烷基；
Ra独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；
R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基、羧基、–(C＝O)NR3R4或–NR3R4；
–(C＝O)NR3R4或–NR3R4中的–NR3R4选自：
本发明更加优选涉及通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药。
其中，L独立选自(C0–C4)烷基、(C1–C4)烷基甲酰基、氨基(C1–C4)烷基；所述的(C0–C4)烷基、(C1–C4)烷基甲酰基、氨基(C1–C4)烷基可被1–3个R1取代；
R1独立地选自氢、(C1–C4)烷基；
X、Y选自S、(C0–C2)烷基；
Ra独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；
R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基、–(C＝O)NR3R4或–NR3R4；
–(C＝O)NR3R4或–NR3R4中的–NR3R4选自：
本发明特别优选涉及通式I的化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，其中，L为(C0–C2)烷基、氨基(C2–C3)烷基、(C1–C3)烷基甲酰基；
X、Y为S、(C0–C2)烷基；
Ra为–NR3R4、–(CH2)2NR3R4、–(CH2)3NR3R4、–(C＝O)NR3R4、–(CH2)2(C＝O)NR3R4、–(CH2)3(C＝O)NR3R4；
–NR3R4为：
本发明通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐、溶剂化物或其前药选自以下化合物，但这些化合物并不意味着对本发明的任何限制：
以上所述的通式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐，所述的药学上可接受的盐包括与无机酸、有机酸、碱金属离子形成的盐；所述的无机酸选自：盐酸、氢溴酸、氢氟酸、硫酸、磷酸；所述的有机酸选自：琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸或对甲苯磺酸；所属的碱金属离子选自锂离子、钠离子或钾离子。
此外，本发明还包括本发明化合物的前药。本发明化合物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘；“烷基”是指直链或支链的烷基；“杂芳基”是指含有碳原子和杂原子的单环或多环的环状体系，且环状体系具有芳香性，杂原子的种类和数目如权利要求所述；代表取代基连接处。
本发明所述通式I所述化合物中，L独立选自6–10元芳基、5–12元杂芳基、(C0–C8)烷基、(C2–C8)烯基、(C2–C8)炔基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基、芳基(C1–C6)烷基、杂芳基(C1–C6)烷基；所述的6–10元芳基、5–12元杂芳基、(C0–C8)烷基、(C2–C8)烯基、(C2–C8)炔基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基、芳基(C1–C6)烷基、杂芳基(C1–C6)烷基可被1–3个R1取代；
其中，R1独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、羧基、氨基；R1为任意位置取代。
本发明所述L有两个键合位，分别与Ceritinib哌啶上的N和X键合，例如，C1烷基实际指亚甲基–CH2–。
本发明所述“(C0–C8)烷基”中C0烷基实际指通式I所述化合物中，Ceritinib哌啶上的N直接与X键合。其他基团涉及C0的表达均为此含义。
本发明所述L中，“氨基(C1–C8)烷基”指“–NH–(C1–C8)烷基”，且–NH–侧键合X。例如，“氨基C2烷基”为“–NH–CH2–CH2–”。其他涉及类似表达方式的均为此含义。例如，“(C1–C8)烷基甲酰基”指“(C1–C8)烷基–CO–”；“C2烷基甲酰基”指“–CH2–CH2–CO–”，其中–CH2–侧键合X。
优选地，L独立选自(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基；所述的(C0–C8)烷基、(C1–C8)烷基甲酰基、氨基(C1–C8)烷基可被1–3个R1取代；进一步优选地，L独立选自(C0–C4)烷基、(C1–C4)烷基甲酰基、氨基(C1–C4)烷基；所述的(C0–C4)烷基、(C1–C4)烷基甲酰基、氨基(C1–C4)烷基可被1–3个R1取代。
优选地，R1独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基；进一步优选地，R1独立地选自氢、(C1–C4)烷基。
最优选地，L为(C0–C2)烷基、氨基(C2–C3)烷基、(C1–C3)烷基甲酰基，具体地，L为C0(即Ceritinib哌啶上的N直接与X键合)、–CH2、–CH2–CH2–、–NH–CH2–CH2–、–NH–CH2–CH2–CH2–、–CH2–CO–、–CH2–CH2–CO–或–CH2–CH2–CH2–CO–。
本发明所述通式I所述化合物中，X、Y选自S、(C0–C4)烷基。
本发明所述X有两个键合位，分别与L和碳键合，X的可选基团上的两个H原子分别被L和碳所取代。本发明所述Y有两个键合位，分别与碳和Ra键合，Y的可选基团上的两个H原子分别被Ra和碳所取代。
优选地，X、Y选自S、(C0–C2)烷基，具体地，X选自S、X为C0(即L直接与碳硫双键的碳键合)、–CH2、–CH2–CH2–；Y选自S、Y为C0(即L直接与碳硫双键的碳键合)、–CH2、–CH2–CH2–。
本发明所述通式I所述化合物中，Ra独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、羧基、氨基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；
本发明所述Ra有一个键合位。例如，“C1烷基”指“–CH3”。
优选地，Ra独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代；进一步优选地，Ra独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基；所述的(C1–C4)烷基、(C1–C4)烷氧基可任选被1–3个R2取代。R2为任意位置取代。
本发明所述通式I所述化合物中，R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、氰基、羟基、氨基、羧基、–(C＝O)NR3R4或–NR3R4；进一步优选地，R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基、羧基、–(C＝O)NR3R4或–NR3R4；更进一步优选R2独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、羟基、氨基、–(C＝O)NR3R4或–NR3R4；
本发明所述通式I所述化合物中，R3、R4独立地选自氢、(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基、氨基磺酰基(C1–C4)烷基、甲磺酰氨基(C1–C4)烷基、羧基(C1–C4)烷基；所述(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基、氨基磺酰基(C1–C4)烷基、甲磺酰氨基(C1–C4)烷基、羧基(C1–C4)烷基可任选被1–3个R5取代；R5为任意位置取代。
本发明所述R3、R4中，所述“羟基(C1–C4)烷基”指羟基任意取代的烷基，如“羟基C2烷基”指“–CH2–CH2–OH”。所述氨基(C1–C4)烷基、氨基磺酰基(C1–C4)烷基、甲磺酰氨基(C1–C4)烷基、羧基(C1–C4)烷基”分别为氨基取代的(C1–C4)、氨基磺酰基取代的(C1–C4)、甲磺酰氨基取代的(C1–C4)、羧基取代的(C1–C4)。例如，“氨基C2烷基”为“–CH2–CH2–NH2”。
或者R3、R4和与它们相连的氮原子一起形成一个3–10元的含氮杂环，优选为5–6元含氮杂环；所述的含氮杂环含有0–3个选自N、O或S的杂原子，任选包括0～2个碳碳双键或叁键；所述的含氮杂环可任选被1–3个R6取代。R6为任意位置取代。
优选地，R3、R4独立地选自氢、(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基；所述(C1–C4)烷基、(C3–C8)环烷基、羟基(C1–C4)烷基、氨基(C1–C4)烷基可任选被1–3个R5取代；
或者R3、R4和与它们相连的氮原子一起形成一个3–10元的含氮杂环，优选为5–6元含氮杂环；所述的含氮杂环含有0–3个选自N、O或S的杂原子，任选包括0～2个碳碳双键或叁键；所述的含氮杂环可任选被1–3个R6取代；
本发明所述通式I所述化合物中，R5、R6独立地选自氢、卤素、(C1–C4)烷基、(C1–C4)烷氧基、(C3–C8)环烷基、氰基、羟基、羧基、氨基；优选地，R5、R6独立地选自氢、(C1–C4)烷基、(C1–C4)烷氧基、(C3–C8)环烷基、羟基、氨基。
最优选地，Ra为–NR3R4、–(CH2)2NR3R4、–(CH2)3NR3R4、–(C＝O)NR3R4、–(CH2)2(C＝O)NR3R4、–(CH2)3(C＝O)NR3R4。
更进一步地，–(C＝O)NR3R4或–NR3R4中的–NR3R4选自：
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更进一步地，–(C＝O)NR3R4或–NR3R4中的–NR3R4选自：
更进一步地，–NR3R4为：
本发明可以含有上式I的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐作为活性成分，与药学上可接受的载体或赋形剂混合制备成组合物，所述载体或赋形剂包括本领域公知的稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂等。稀释剂包括但不限于淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、磷酸氢钙等；湿润剂包括水、乙醇、异丙醇等；粘合剂包括但不限于淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素、聚乙二醇等；崩解剂包括但不限于干淀粉、微品纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、十二烷基磺酸钠等；润滑剂和助流剂包括但不限于滑石粉、二氧化硅、聚乙二醇等。
本发明的药用组合物可配制成若干种剂型，所述剂型包括但不限于注射剂、片剂、胶囊剂等。
本发明的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐可以与其他活性成分组合使用，从而达到更优的治疗效果。
本发明的2,4-二芳氨基嘧啶类化合物及其立体异构体以及药学上可接受的盐可以用于预防或治疗淋巴瘤、非小细胞肺癌、小细胞肺癌、头颈部细胞癌、神经胶质瘤、成神经细胞瘤、肺鳞癌、肺腺癌、膀胱癌、胃癌、结肠癌、大肠癌、肾癌、胆管癌、胃癌、食管鳞癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌等癌症，包括其它远离肿瘤原发部位的组织或器官的转移病变。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线概括并描述了本发明的通式I化合物的制备，所有的原料都是通过有机化学领域普通技术人员熟知的方法制备或者可商购。本发明的化合物都是通过这些流程中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些流程中应用的全部可变因数如权利要求中的定义。
路线一：
以Ceritinib为起始原料，与卤代物在碱的作用下发生取代反应生成中间体A，中间体A与二硫化碳在叔丁醇钾的作用下生成中间体B，中间体B与氯代物反应制得通式I中的目标化合物。
路线二：
以Ceritinib为起始原料，与二卤代物在碱的作用下发生取代反应生成中间体C，中间体C与取代的二硫基氨基甲酸钠反应制得通式I中的目标化合物。
所述的L、X、Y、Ra的定义如权利要求所述，Z指卤素(氯、溴或碘)。本发明的具有通式I的2,4-二芳氨基嘧啶类化合物均可按照上述反应路线描述的方法或类似的方法制备得到。
具体实施方式:
在以下的实施例中，描绘了制备部分所述化合物的方法。应了解，以下方法及所属领域的普通技术人员已知的其他方法均可适用于本发明所述的所有化合物的制备。实施例旨在阐述而不是限制本发明的范围。
实施例1：
2-(二甲氨基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
步骤1：4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸钾盐
将Ceritinib(2g,3.58mmol)溶于40mL THF中，0℃下加入叔丁醇钾(0.48g,3.94mmol)，之后缓慢加入二硫化碳(0.52g,5.37mmol)，室温反应2h。反应完毕，析出固体，抽滤，滤渣用乙醚打浆，得白色固体1.74g，收率72.7％，无需进一步纯化。
步骤2：2-(二甲氨基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
将4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸钾(0.1g,0.15mmol)和2-氯-N,N-二甲基乙胺(0.02g,0.18mmol)溶于2mL DMF中，室温反应1h。反应完毕，加水，析出固体，抽滤，干燥，柱层析分离纯化得白色固体90mg，收率86.2％。
MS(ESI)m/z:705.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.50(d,J＝8.3Hz,1H),8.09(s,1H),7.97(s,1H),7.86(dd,J＝7.9,1.2Hz,1H),7.60–7.52(m,1H),7.48(s,1H),7.19(d,J＝15.1Hz,1H),6.60(s,1H),5.78(s,1H),4.80(s,1H),4.48(hept,J＝6.0Hz,1H),3.48(s,2H),3.26–3.13(m,2H),3.06(s,1H),3.00–2.92(m,1H),2.68(s,2H),2.31(s,6H),2.12(s,3H),1.82(d,J＝12.9Hz,2H),1.65(d,J＝38.7Hz,2H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ195.11,156.40,154.36,154.32,143.70,137.47,134.68,133.61,130.29,127.09,125.93,123.92,122.63,122.14,119.66,109.71,104.91,70.67,64.85,56.79,54.44,51.53,49.89,44.07,37.25,33.89,31.79,31.14,21.23,18.04,14.36.
类似实施例1的合成方法，以4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸钾为原料，与卤代物取代制备得到实施例2-19的化合物。
实施例2：
2-(二乙氨基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:733.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.50(d,J＝8.3Hz,1H),8.09(s,1H),7.97(s,1H),7.86(dd,J＝7.9,1.0Hz,1H),7.56(dd,J＝11.4,4.1Hz,1H),7.48(s,1H),7.19(t,J＝7.5Hz,1H),6.60(s,1H),5.75(s,1H),4.77(s,1H),4.53–4.42(m,1H),3.49(s,2H),3.19(tt,J＝13.6,6.6Hz,2H),3.07(s,1H),3.00–2.93(m,1H),2.84(s,2H),2.69(s,4H),2.12(s,3H),1.83(d,J＝13.0Hz,2H),1.65(s,2H),1.29(d,J＝6.0Hz,6H),1.25(d,J＝6.8Hz,6H),1.09(t,J＝6.3Hz,6H)；13C NMR(151MHz,CDCl3)δ194.99,156.40,154.35,154.31,143.70,137.46,134.66,133.62,130.28,127.11,125.96,123.90,122.62,122.14,119.68,109.73,104.91,70.69,64.84,54.44,51.61,50.33,49.89,45.95,37.24,32.83,31.77,31.10,28.68,21.23,18.04,14.36,10.23。
实施例3：
2-(四氢吡咯-1-基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:731.4[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.98(s,1H),7.87(dd,J＝7.9,1.4Hz,1H),7.58–7.53(m,1H),7.48(s,1H),7.20(d,J＝15.1Hz,1H),6.60(s,1H),5.75(s,1H),4.76(s,1H),4.48(hept,J＝6.0Hz,1H),3.59(s,2H),3.28–3.16(m,2H),3.14–2.44(m,8H),2.12(s,3H),1.83(d,J＝13.5Hz,6H),1.64(s,3H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.95,156.38,154.34,143.69,137.45,134.62,133.59,130.28,127.11,125.93,123.91,122.61,122.12,119.65,109.71,104.92,70.68,54.43,53.73,52.93,37.23,22.50,21.23,18.04,14.35。
实施例4：
2-(哌啶-1-基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:745.4[M+H]+；1H NMR(600MHz,CDCl3)δ9.51(s,1H),8.57(d,J＝8.3Hz,1H),8.16(s,1H),8.04(s,1H),7.93(d,J＝8.0Hz,1H),7.65–7.59(m,1H),7.55(s,1H),7.26(dd,J＝15.2,0.8Hz,1H),6.67(s,1H),5.84(s,1H),4.86(s,1H),4.55(hept,J＝6.0Hz,1H),3.55(s,2H),3.26(dp,J＝13.6,6.8Hz,2H),3.13(s,1H),3.03(tt,J＝12.0,3.5Hz,1H),2.73(s,2H),2.54(s,4H),2.19(s,3H),1.89(d,J＝13.1Hz,2H),1.64(s,6H),1.47(s,2H),1.36(d,J＝6.1Hz,6H),1.32(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ195.27,156.39,154.35,154.30,143.69,137.46,134.68,133.59,130.28,127.09,125.92,123.91,122.61,122.12,119.65,109.71,104.91,70.67,56.55,54.43,53.26,51.60,49.87,37.26,31.80,31.18,28.68,24.59,23.07,21.23,18.04,14.36。
实施例5：
2-吗啉基乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:747.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.98(s,1H),7.87(dd,J＝7.9,1.5Hz,1H),7.60–7.53(m,1H),7.48(s,1H),7.19(dd,J＝15.2,0.9Hz,1H),6.60(s,1H),5.75(s,1H),4.76(s,1H),4.48(hept,J＝6.2Hz,1H),3.70(s,4H),3.51(s,2H),3.27–3.15(m,2H),3.05(dd,J＝11.9,3.5Hz,1H),2.97(tt,J＝12.0,3.4Hz,1H),2.69(s,2H),2.51(s,4H),2.13(s,3H),1.84(d,J＝12.9Hz,2H),1.65(s,2H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ195.04,156.38,154.34,154.31,143.69,137.46,134.61,133.58,130.28,127.13,125.95,123.91,122.60,122.12,119.67,109.73,104.93,70.70,65.79,56.33,54.43,52.38,51.62,49.88,37.25,33.10,31.77,31.11,28.68,21.23,18.04,14.35。
实施例6：
2-(4-甲基哌嗪-1-基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:760.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.98(s,1H),7.87(dd,J＝7.9,1.4Hz,1H),7.60–7.52(m,1H),7.48(s,1H),7.22–7.18(m,1H),6.60(s,1H),5.76(s,1H),4.77(s,1H),4.48(hept,J＝6.1Hz,1H),3.46(s,2H),3.19(dp,J＝13.5,6.6Hz,2H),3.06(s,1H),2.96(tt,J＝11.9,3.3Hz,1H),2.68(t,J＝7.2Hz,3H),2.55(d,J＝54.3Hz,6H),2.29(s,3H),2.13(s,3H),1.83(d,J＝13.0Hz,2H),1.63(s,2H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ195.18,156.39,154.35,154.31,143.69,137.46,134.67,133.59,130.28,127.11,125.94,123.92,122.61,122.12,119.66,109.73,104.93,70.69,55.83,54.44,53.81,51.50,49.81,44.73,37.27,33.28,31.74,31.12,30.91,28.69,28.35,21.23,18.04,14.36。
实施例7：
2-甲氧基乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:692.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.47(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.96(s,1H),7.86(dd,J＝7.9,1.3Hz,1H),7.60–7.50(m,1H),7.20(t,J＝7.6Hz,2H),6.61(s,1H),5.78(s,1H),4.79(s,1H),4.48(hept,J＝6.0Hz,1H),3.64(s,2H),3.55(s,2H),3.33(s,3H),3.25–3.14(m,2H),3.07(s,1H),2.97(tt,J＝12.0,3.4Hz,1H),2.12(s,3H),1.83(d,J＝13.2Hz,2H),1.66(s,2H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.92,156.22,154.35,153.98,143.79,137.38,134.81,130.29,126.96,125.90,123.95,122.63,122.20,119.76,109.72,104.88,70.67,69.75,64.84,57.79,54.46,51.66,49.87,37.26,36.00,31.77,31.15,21.22,18.03,14.35。
实施例8：
2-(二乙氨基)丙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:747.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.98(s,1H),7.86(dd,J＝7.9,1.4Hz,1H),7.59–7.52(m,1H),7.49(s,1H),7.25–7.16(m,1H),6.61(s,1H),5.74(s,1H),4.73(s,1H),4.57–4.42(m,1H),3.43–3.26(m,2H),3.19(tt,J＝13.4,6.6Hz,2H),3.06(s,1H),2.97(ddd,J＝11.7,7.6,3.2Hz,1H),2.87(d,J＝6.1Hz,6H),2.13(s,3H),2.10(d,J＝7.4Hz,2H),1.84(d,J＝12.8Hz,2H),1.65(s,2H),1.29(d,J＝6.0Hz,6H),1.25(d,J＝6.9Hz,6H),1.22(d,J＝7.1Hz,6H)；13C NMR(151MHz,CDCl3)δ195.55,157.32,155.27,155.25,144.64,138.39,135.50,134.53,131.21,128.09,126.90,124.84,123.55,123.07,120.62,110.70,105.86,71.68,55.38,50.50,46.65,38.18,33.95,29.61,24.39,22.15,18.97,15.28,9.60。
实施例9：
2-氨基-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:691.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.46(s,1H),8.47(d,J＝7.9Hz,1H),8.25(s,1H),8.05(s,1H),7.84(dd,J＝8.0,1.4Hz,1H),7.64(t,J＝7.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.41–7.33(m,1H),7.17(s,1H),6.85(s,1H),5.54(s,1H),4.69(s,1H),4.62(dq,J＝12.0,6.0Hz,1H),4.02(d,J＝8.7Hz,2H),3.45(td,J＝13.6,6.8Hz,2H),3.26(s,1H),3.10(ddd,J＝11.9,7.6,3.1Hz,1H),2.18(s,3H),1.85(s,2H),1.69(s,2H),1.20(d,J＝6.0Hz,6H),1.16(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ192.48,167.22,156.73,154.19,153.65,145.36,136.78,136.77,133.65,129.72,125.80,125.34,123.28,122.51,122.47,122.41,110.47,103.09,69.39,53.59,50.91,49.27,39.40,38.84,36.06,30.98,30.59,20.67,17.29,13.64。
实施例10：
2-(二甲氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:719.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.52(s,1H),8.49(d,J＝8.3Hz,1H),8.07(s,1H),7.93(s,1H),7.87(dd,J＝7.9,1.5Hz,1H),7.68(s,1H),7.57–7.52(m,1H),7.22(d,J＝7.4Hz,1H),6.62(s,1H),5.71(s,1H),4.82(s,1H),4.50(dt,J＝12.1,6.1Hz,1H),4.27(s,2H),3.30–3.15(m,2H),3.13(s,3H),3.11–3.01(m,1H),2.97(dd,J＝9.5,6.0Hz,1H),2.94(s,3H),2.12(s,3H),1.83(d,J＝13.1Hz,2H),1.74–1.62(m,2H),1.30(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.05,166.29,155.84,154.47,144.02,137.23,135.08,133.62,130.32,126.69,125.82,124.04,123.81,122.68,122.38,119.99,109.72,104.84,70.69,54.52,51.80,50.02,39.95,37.21,36.73,35.05,31.73,31.17,21.21,18.02,14.35。
实施例11：
2-(二乙氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:747.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.46(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.86(dd,J＝7.9,1.1Hz,1H),7.56(dd,J＝17.6,10.4Hz,2H),7.20(t,J＝7.5Hz,1H),6.61(s,1H),5.72(s,1H),4.83(s,1H),4.55–4.44(m,1H),4.28(s,2H),3.46–3.40(m,2H),3.36(dd,J＝13.5,6.6Hz,2H),3.24–3.14(m,2H),3.07(s,1H),2.97(ddd,J＝12.0,8.8,3.4Hz,1H),2.12(s,3H),1.83(d,J＝13.5Hz,2H),1.68(dd,J＝24.9,12.5Hz,2H),1.29(d,J＝6.0Hz,6H),1.25(d,J＝6.9Hz,6H),1.22(d,J＝7.2Hz,3H),1.08(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ195.14,166.25,157.19,155.32,144.78,138.33,137.86,135.75,134.56,131.23,127.88,126.80,124.92,123.61,123.16,120.73,110.65,108.91,105.82,71.60,60.67,59.35,55.41,42.59,41.23,40.89,38.14,29.62,29.17,22.16,18.96,15.29,14.40,12.87。
实施例12：
2-(异丙氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:733.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.47(s,1H),8.48(d,J＝8.3Hz,1H),8.06(s,1H),7.94(s,1H),7.85(dd,J＝8.0,1.5Hz,1H),7.58(s,1H),7.55–7.51(m,1H),7.20–7.17(m,1H),6.58(s,1H),6.53(d,J＝7.7Hz,1H),5.66(s,1H),4.72(s,1H),4.46(hept,J＝6.1Hz,1H),4.04(s,1H),3.96(ddd,J＝14.3,13.2,6.6Hz,2H),3.26(s,1H),3.17(dt,J＝13.7,6.8Hz,1H),3.11(s,1H),2.97(ddd,J＝12.1,8.6,3.5Hz,1H),2.11(s,3H),1.84(d,J＝13.5Hz,2H),1.64(s,2H),1.27(d,J＝6.1Hz,6H),1.23(d,J＝6.9Hz,6H),1.08(d,J＝6.6Hz,6H)；13C NMR(151MHz,CDCl3)δ194.16,166.63,156.02,154.42,153.90,143.91,137.29,134.65,133.59,130.32,126.97,125.93,124.01,122.62,122.30,119.94,109.71,104.93,70.76,54.50,52.50,50.34,40.82,39.12,37.15,31.77,31.25,21.55,21.20,18.03,14.35。
实施例13：
2-(环己氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:773.3[M+H]+；1H NMR(600MHz,DMSO-d6)δ9.47(s,1H),8.47(d,J＝8.0Hz,1H),8.25(s,1H),8.07–8.00(m,2H),7.85(dd,J＝8.0,1.5Hz,1H),7.64(t,J＝7.4Hz,1H),7.56(s,1H),7.39–7.34(m,1H),6.84(s,1H),5.54(s,1H),4.68(s,1H),4.62(dt,J＝12.1,6.0Hz,1H),4.01(d,J＝4.4Hz,2H),3.60–3.39(m,3H),3.26(s,1H),3.14–3.06(m,1H),2.18(s,3H),1.85(s,2H),1.76–1.61(m,6H),1.27–1.12(m,18H)；13C NMR(151MHz,CDCl3)δ194.11,165.65,158.34,155.79,155.25,146.98,138.39,135.24,131.32,127.41,126.95,124.89,124.11,124.00,112.08,104.69,71.00,55.19,48.31,41.34,37.64,32.63,25.57,24.81,22.27,18.87,15.24。
实施例14：
2-(环丁氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:745.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.49(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.96(s,1H),7.87(d,J＝7.0Hz,1H),7.71–7.49(m,2H),7.21(d,J＝7.7Hz,1H),6.90(d,J＝7.7Hz,1H),6.61(s,1H),5.69(s,1H),4.74(s,1H),4.48(dt,J＝12.0,6.0Hz,1H),4.35–4.23(m,1H),4.07(s,1H),3.94(s,1H),3.34–3.05(m,3H),3.02–2.94(m,1H),2.27(dd,J＝16.4,7.6Hz,2H),2.13(s,3H),1.90–1.78(m,4H),1.73–1.60(m,4H),1.29(d,J＝6.0Hz,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ195.12,167.57,157.06,155.34,144.83,138.27,134.52,131.25,129.84,129.80,127.99,126.88,124.94,123.56,123.19,120.86,110.67,105.87,71.71,55.43,53.48,51.29,44.93,39.81,38.08,35.85,32.66,32.14,31.83,30.93,29.62,29.24,27.13,25.46,22.60,22.14,18.96,15.29,15.09,14.04。
实施例15：
2-(环戊氨基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:759.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.51(s,1H),8.50(d,J＝8.2Hz,1H),8.08(s,1H),7.95(s,1H),7.87(d,J＝7.4Hz,1H),7.70–7.45(m,2H),7.21(d,J＝7.6Hz,1H),6.76(d,J＝7.2Hz,1H),6.60(s,1H),5.68(s,1H),4.74(s,1H),4.48(dt,J＝12.0,6.0Hz,1H),4.18–4.09(m,1H),4.05(s,1H),3.95(s,1H),3.35–3.05(m,3H),2.99(t,J＝11.9Hz,1H),2.13(s,3H),1.87(dd,J＝12.3,7.9Hz,4H),1.72–1.58(m,4H),1.54(dd,J＝14.4,7.6Hz,2H),1.37(dd,J＝13.1,4.0Hz,2H),1.29(d,J＝6.0Hz,6H),1.25(d,J＝6.7Hz,6H)；13C NMR(151MHz,CDCl3)δ194.24,167.13,156.07,154.44,143.93,137.29,133.59,130.32,128.90,128.87,126.98,125.94,124.02,122.63,122.31,119.95,109.73,104.93,70.78,54.52,52.52,50.50,50.38,38.97,37.16,31.89,31.73,31.23,28.69,28.31,26.20,22.64,21.68,21.21,18.03,14.36,13.11。
实施例16：
2-吗啉-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:761.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.49(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.87(d,J＝7.9Hz,1H),7.74–7.43(m,2H),7.21(d,J＝7.4Hz,1H),6.61(s,1H),5.69(s,1H),4.80(s,1H),4.50(hept,J＝6.0Hz,1H),4.26(s,2H),3.72–3.67(m,2H),3.62(dq,J＝8.3,4.0Hz,6H),3.26(s,1H),3.19(dp,J＝13.7,6.9Hz,1H),3.08(s,1H),2.97(tt,J＝12.0,3.4Hz,1H),2.12(s,3H),1.84(d,J＝13.0Hz,2H),1.68(d,J＝10.6Hz,2H),1.30(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ193.60,165.13,156.12,154.39,153.79,143.86,137.33,134.73,133.60,130.30,126.94,125.87,123.98,122.64,122.25,119.83,109.69,104.89,70.70,65.77,65.65,54.48,51.95,50.12,45.64,41.64,39.27,37.16,31.73,31.17,21.22,18.03,14.35。
实施例17：
2-氧代-2-硫代吗啉乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:777.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.54(s,1H),8.56(d,J＝8.3Hz,1H),8.16(s,1H),8.02(s,1H),7.93(d,J＝7.8Hz,1H),7.62(t,J＝7.5Hz,2H),7.27(d,J＝7.7Hz,1H),6.67(s,1H),5.76(s,1H),4.86(s,1H),4.61–4.51(m,1H),4.35(s,2H),4.01–3.82(m,4H),3.33(s,1H),3.29–3.22(m,1H),3.15(s,1H),3.08–2.99(m,1H),2.79–2.70(m,2H),2.68–2.61(m,2H),2.19(s,3H),1.91(d,J＝12.8Hz,2H),1.75(s,2H),1.36(d,J＝6.0Hz,6H),1.32(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ193.59,164.89,156.10,154.40,153.70,143.90,137.32,134.75,133.60,130.30,126.88,125.86,123.99,122.64,122.27,119.88,109.69,104.90,70.69,54.49,52.00,50.09,48.01,44.10,39.87,37.18,31.80,31.15,26.92,26.33,21.22,18.03,14.35。
实施例18：
2-氧代-2-(哌啶-1-基)乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:759.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.48(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.87(dd,J＝8.0,1.5Hz,1H),7.65–7.49(m,2H),7.21(d,J＝7.3Hz,1H),6.61(s,1H),5.71(s,1H),4.82(s,1H),4.50(hept,J＝6.0Hz,1H),4.29(s,2H),3.55–3.47(m,4H),3.33–3.01(m,3H),2.97(tt,J＝12.0,3.5Hz,1H),2.12(s,3H),1.83(d,J＝13.1Hz,2H),1.68(d,J＝11.1Hz,2H),1.62–1.56(m,4H),1.51(s,2H),1.29(d,J＝6.1Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.10,164.41,156.15,154.40,153.98,143.88,137.35,134.85,133.63,130.31,126.90,125.86,123.99,122.67,122.27,119.82,109.71,104.88,70.67,54.48,51.77,50.07,46.33,42.42,40.40,37.21,31.72,31.15,25.49,24.50,23.44,21.22,18.03,14.36。
实施例19：
2-(4-甲基哌啶-1-基)-2-氧代乙基4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-碳二硫酸酯
MS(ESI)m/z:773.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.51(s,1H),8.49(d,J＝8.3Hz,1H),8.07(s,1H),7.93(s,1H),7.87(dd,J＝7.9,1.1Hz,1H),7.80–7.50(m,2H),7.21(d,J＝7.6Hz,1H),6.61(s,1H),5.71(s,1H),4.82(s,1H),4.54–4.45(m,2H),4.29(q,J＝15.1Hz,2H),3.96(d,J＝13.5Hz,1H),3.31–3.15(m,2H),3.12–3.02(m,2H),2.97(tt,J＝11.9,3.2Hz,1H),2.56(td,J＝12.9,2.5Hz,1H),2.12(s,3H),1.83(d,J＝12.9Hz,2H),1.75–1.60(m,4H),1.30(d,J＝6.0Hz,6H),1.25(d,J＝6.8Hz,6H),1.21–1.12(m,2H),1.06(ddd,J＝24.4,12.6,4.2Hz,1H),0.90(s,3H)；13C NMR(151MHz,CDCl3)δ194.07,164.40,156.02,154.43,153.34,143.94,137.27,134.96,133.61,130.30,126.78,125.83,124.01,122.67,122.32,119.91,109.71,104.85,70.67,54.50,51.80,50.04,45.58,41.79,40.42,37.21,33.62,32.68,31.70,31.14,30.00,21.21,20.68,18.02,14.35。
实施例20：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基二硫代氨基甲酸二乙酯
步骤1：2-氯-1-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1)乙烷-1-酮
将Ceritinib(2g,3.58mmol)溶于20mL干燥二氯甲烷中，0℃下加入三乙胺(0.54g,5.37mmol)，之后缓慢滴加氯乙酰氯(0.44g,3.94mmol)的二氯甲烷溶液，室温反应2h。反应完毕，加水，二氯甲烷萃取，合并有机相，有机层依次用水和饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压蒸干得淡黄色固体1.95g，收率86.2％，无需进一步纯化。MS(ESI)m/z:634.3[M+H]+。
步骤2：2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基二硫代氨基甲酸二乙酯
2-氯-1-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1)乙烷-1-酮(0.1g,0.16mmol)和二乙基二硫代氨基甲酸钠盐(0.033g,0.19mmol)溶于2mL DMF中，室温反应1h。反应完毕，加水，析出固体，抽滤，干燥，柱层析分离纯化得白色固体79mg，收率67.2％。
MS(ESI)m/z:746.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.49(s,1H),8.50(d,J＝8.3Hz,1H),8.07(s,1H),7.92(s,1H),7.87(dd,J＝8.0,1.6Hz,1H),7.72–7.46(m,2H),7.21(d,J＝8.1Hz,1H),6.64(s,1H),4.73(d,J＝13.3Hz,1H),4.50(hept,J＝6.1Hz,1H),4.37(d,J＝15.1Hz,1H),4.23(d,J＝15.1Hz,1H),4.13(d,J＝13.7Hz,1H),3.96(q,J＝6.8Hz,2H),3.74(q,J＝7.1Hz,2H),3.24–3.11(m,2H),2.87(ddd,J＝12.0,7.7,3.1Hz,1H),2.64(td,J＝12.9,2.2Hz,1H),2.11(s,3H),1.77(dd,J＝38.1,13.1Hz,2H),1.66(qd,J＝12.8,4.0Hz,1H),1.57(qd,J＝12.8,4.2Hz,1H),1.30(t,J＝6.3Hz,6H),1.26(t,J＝7.5Hz,9H),1.21(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ193.27,164.80,156.11,154.41,153.74,143.91,137.31,135.79,133.63,130.29,126.56,125.70,123.98,122.68,122.28,119.86,109.76,104.79,70.56,54.49,48.89,46.19,45.97,42.44,40.07,37.20,32.28,31.27,21.27,21.20,17.96,14.36,11.52,10.52。
类似实施20的合成方法，以Ceritinib为起始原料，与二氯代物在碱的作用下发生取代反应生成关键中间体，再与取代的二硫基氨基甲酸钠盐反应制得制得实施例21-35的化合物。
实施例21：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基四氢吡咯-1-碳二硫酸酯
MS(ESI)m/z:745.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.86(d,J＝7.9Hz,1H),7.80–7.50(m,2H),7.20(d,J＝15.2Hz,1H),6.64(s,1H),4.73(d,J＝12.4Hz,1H),4.50(hept,J＝6.0Hz,1H),4.38(d,J＝15.2Hz,1H),4.26(d,J＝15.3Hz,1H),4.14(d,J＝12.9Hz,1H),3.86(t,J＝6.9Hz,2H),3.70–3.62(m,2H),3.19(td,J＝13.6,7.0Hz,2H),2.85(dt,J＝11.9,3.2Hz,1H),2.64(t,J＝12.0Hz,1H),2.11(s,3H),2.03(dd,J＝13.7,6.8Hz,2H),1.92(p,J＝7.0Hz,2H),1.77(dd,J＝39.0,13.1Hz,2H),1.66(ddd,J＝25.3,12.7,3.8Hz,1H),1.57(ddd,J＝25.3,12.7,3.9Hz,1H),1.30(t,J＝6.9Hz,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ190.44,164.77,156.36,154.32,154.21,143.75,137.41,135.56,133.63,130.27,126.74,125.73,123.91,122.66,122.16,119.68,109.75,104.80,70.57,54.44,54.29,49.69,46.18,42.48,39.37,37.19,32.28,31.24,25.13,23.31,21.29,21.21,17.97,14.36。
实施例22：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基4-甲基哌嗪-1-碳二硫酸酯
MS(ESI)m/z:774.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.51(d,J＝8.2Hz,1H),8.09(s,1H),7.96(s,1H),7.86(dd,J＝8.0,1.5Hz,1H),7.58–7.52(m,1H),7.48(s,1H),7.19(dd,J＝15.3,1.0Hz,1H),6.64(s,1H),4.73(d,J＝13.2Hz,1H),4.49(hept,J＝6.0Hz,1H),4.44–4.18(m,4H),4.12(d,J＝13.5Hz,1H),3.97(s,2H),3.24–3.13(m,2H),2.86(tt,J＝12.0,3.3Hz,1H),2.65(td,J＝12.9,2.1Hz,1H),2.47(s,4H),2.28(s,3H),2.11(s,3H),1.77(dd,J＝41.6,13.0Hz,2H),1.65(qd,J＝12.8,4.0Hz,1H),1.57(qd,J＝12.8,4.2Hz,1H),1.32–1.27(m,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.78,164.50,156.42,154.35,154.31,143.70,137.46,135.42,133.61,130.27,126.84,125.77,123.90,122.65,122.12,119.64,109.73,104.84,70.58,54.43,53.29,50.31,48.81,46.17,44.52,42.48,40.07,40.07,37.18,32.30,31.25,21.30,21.22,17.98,14.36。
实施例23：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基吗啉-4-碳二硫酸酯
MS(ESI)m/z:761.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.48(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.94(s,1H),7.87(dd,J＝7.9,1.5Hz,1H),7.66–7.49(m,2H),7.20(t,J＝7.5Hz,1H),6.64(s,1H),4.73(d,J＝13.3Hz,1H),4.49(hept,J＝6.0Hz,1H),4.39(d,J＝15.4Hz,1H),4.20(dd,J＝91.7,14.4Hz,4H),3.97(s,2H),3.75–3.66(m,4H),3.25–3.15(m,2H),2.87(tt,J＝12.0,3.3Hz,1H),2.65(td,J＝12.8,1.8Hz,1H),1.30(dd,J＝7.4,6.4Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ195.35,164.37,156.15,154.39,153.73,143.87,137.34,135.62,133.62,130.29,126.66,125.76,123.97,122.66,122.25,119.84,109.77,104.83,70.61,65.27,65.10,54.48,50.59,49.54,46.16,42.50,39.90,37.18,32.29,31.24,21.28,21.21,17.97,14.36。
实施例24：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基4-(甲磺酰基)哌嗪-1-碳二硫酸酯
MS(ESI)m/z:838.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.52(s,1H),8.50(d,J＝8.3Hz,1H),8.07(s,1H),7.93(s,1H),7.87(d,J＝7.9Hz,1H),7.66(s,1H),7.57–7.51(m,1H),7.21(d,J＝7.5Hz,1H),6.64(s,1H),4.73(d,J＝13.0Hz,1H),4.56–4.45(m,1H),4.43–3.95(m,7H),3.29(s,4H),3.25–3.15(m,2H),2.91–2.83(m,1H),2.75(s,3H),2.66(t,J＝12.0Hz,1H),2.12(s,3H),1.79(dd,J＝44.0,13.0Hz,2H),1.66(ddd,J＝25.3,12.7,3.7Hz,1H),1.57(ddd,J＝25.6,12.9,4.0Hz,1H),1.30(dd,J＝8.0,6.3Hz,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ196.08,164.07,156.18,154.38,153.86,143.84,137.36,135.50,133.61,130.30,126.75,125.80,123.95,122.64,122.23,119.83,109.78,104.87,70.65,54.48,52.44,49.12,49.07,46.15,44.25,42.54,40.28,37.15,34.12,32.29,31.23,21.22,17.98,14.36。
实施例25：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基3,4,5-三甲基哌嗪-1-碳二硫酸酯
MS(ESI)m/z:802.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.96(s,1H),7.86(d,J＝7.8Hz,1H),7.56(t,J＝7.8Hz,1H),7.48(s,1H),7.19(d,J＝14.9Hz,1H),6.64(s,1H),4.73(d,J＝13.0Hz,1H),4.50(td,J＝12.0,5.9Hz,2H),4.33(dd,J＝66.3,15.1Hz,2H),4.12(d,J＝12.1Hz,1H),3.19(dd,J＝13.7,7.2Hz,2H),2.94–2.53(m,6H),1.30(t,J＝6.7Hz,6H),1.25(d,J＝6.8Hz,6H),1.18(s,3H),1.09(s,6H)；13C NMR(151MHz,CDCl3)δ194.24,164.52,156.40,154.33,154.28,143.68,137.44,135.40,133.59,130.24,126.82,125.75,123.88,122.62,122.09,119.61,109.72,104.82,70.55,66.72,65.15,63.84,56.62,55.39,54.41,49.79,49.50,46.15,42.44,42.28,40.06,37.86,37.14,32.27,31.22,29.47,28.66,27.95,22.94,21.93,21.27,21.19,17.95,14.34。
实施例26：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基4-(2-羟乙基)哌嗪-1-碳二硫酸酯
MS(ESI)m/z:804.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.96(s,1H),7.86(dd,J＝7.9,1.4Hz,1H),7.59–7.53(m,1H),7.48(s,1H),7.20(d,J＝15.1Hz,1H),6.64(s,1H),4.73(d,J＝13.1Hz,1H),4.53–4.45(m,1H),4.41–3.94(m,7H),3.69–3.59(m,2H),3.24–3.15(m,2H),2.92–2.84(m,1H),2.64(dd,J＝25.3,19.8Hz,8H),2.11(s,3H),1.78(dd,J＝42.1,12.9Hz,2H),1.65(ddd,J＝25.5,12.8,3.8Hz,1H),1.57(ddd,J＝16.5,13.0,4.2Hz,1H),1.32–1.28(m,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ195.02,164.40,156.41,154.34,154.31,143.71,137.46,135.39,133.61,130.27,126.86,125.79,123.90,122.64,122.12,119.65,109.74,104.86,70.59,58.23,56.76,54.43,51.33,49.93,48.61,46.17,42.50,40.12,37.16,32.30,31.24,28.69,21.30,21.22,17.98,14.36。
实施例27：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基二硫代氨基甲酸环丙酯
MS(ESI)m/z:731.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.59(s,1H),9.48(s,1H),8.50(d,J＝8.2Hz,1H),8.08(s,1H),7.95(s,1H),7.86(d,J＝7.7Hz,1H),7.68–7.50(m,1H),7.21(s,1H),6.62(s,1H),4.71(dd,J＝35.9,12.5Hz,1H),4.56–4.44(m,1H),4.41–4.04(m,1H),3.91–3.72(m,2H),3.32–3.10(m,3H),2.85(d,J＝11.4Hz,1H),2.67(dd,J＝22.6,10.6Hz,1H),2.11(s,3H),1.78(dd,J＝32.1,15.9Hz,2H),1.67–1.49(m,2H),1.30(t,J＝5.0Hz,6H),1.25(d,J＝6.7Hz,6H),0.88(dd,J＝19.7,5.9Hz,2H),0.73(d,J＝15.9Hz,2H)；13C NMR(151MHz,CDCl3)δ194.56,166.78,156.15,154.37,153.76,143.85,137.34,135.06,133.62,130.28,126.87,125.79,123.92,122.63,122.24,119.83,109.73,104.87,70.70,54.48,46.61,46.17,42.42,36.98,35.50,31.99,31.17,21.26,21.17,17.99,14.35,5.85,5.82。
实施例28：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基哌啶-1-碳二硫酸酯
MS(ESI)m/z:759.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.44(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.86(d,J＝7.9Hz,1H),7.55(t,J＝7.8Hz,1H),7.51(s,1H),7.20(d,J＝14.7Hz,1H),6.64(s,1H),4.73(d,J＝12.0Hz,1H),4.53–4.44(m,1H),4.38(d,J＝15.0Hz,1H),4.30–4.17(m,3H),4.14(d,J＝12.9Hz,1H),3.88(s,2H),3.24–3.13(m,2H),2.90–2.82(m,1H),2.64(t,J＝12.5Hz,1H),2.11(s,3H),1.77(dd,J＝39.7,12.9Hz,2H),1.69–1.52(m,8H),1.30(t,J＝6.0Hz,6H),1.25(dd,J＝6.8,1.9Hz,6H)；13CNMR(151MHz,CDCl3)δ193.22,164.76,156.33,154.30,154.15,143.73,137.40,135.55,133.60,130.25,126.71,125.72,123.88,122.64,122.14,119.66,109.73,104.78,70.54,54.42,52.28,50.52,46.16,42.42,40.02,37.17,32.27,31.24,25.03,24.41,23.19,21.27,21.19,17.95,14.34。
实施例29：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基硫代吗啉-4-碳二硫酸酯
MS(ESI)m/z:777.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.48(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.94(s,1H),7.86(dd,J＝7.9,1.5Hz,1H),7.56(dt,J＝8.6,5.8Hz,2H),7.22–7.19(m,1H),6.64(s,1H),4.73(d,J＝13.3Hz,1H),4.62–4.42(m,3H),4.41–4.19(m,4H),4.12(d,J＝13.5Hz,1H),3.24–3.15(m,2H),2.87(tt,J＝11.9,3.2Hz,1H),2.73–2.68(m,4H),2.68–2.62(m,1H),2.11(s,3H),1.78(dd,J＝42.8,13.0Hz,2H),1.69–1.61(m,1H),1.57(qd,J＝12.8,4.1Hz,1H),1.32–1.28(m,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ194.63,164.34,156.23,154.36,153.88,143.81,137.37,135.53,133.61,130.28,126.72,125.76,123.94,122.65,122.20,119.77,109.75,104.83,70.60,54.46,53.71,52.43,46.14,42.46,40.24,37.17,32.29,31.23,26.33,26.19,21.28,21.21,17.97,14.35。
实施例30：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基4-乙基哌嗪-1-碳二硫酸酯
MS(ESI)m/z:788.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.51(d,J＝8.3Hz,1H),8.09(d,J＝1.5Hz,1H),7.96(s,1H),7.86(d,J＝7.9Hz,1H),7.56(t,J＝7.8Hz,1H),7.48(s,1H),7.19(d,J＝15.2Hz,1H),6.63(s,1H),4.73(d,J＝12.3Hz,1H),4.55–4.44(m,1H),4.32(dd,J＝65.8,15.3Hz,4H),4.12(d,J＝13.5Hz,1H),3.98(s,2H),3.19(dd,J＝13.6,8.4Hz,2H),2.86(t,J＝11.9Hz,1H),2.65(t,J＝12.6Hz,1H),2.58–2.36(m,6H),2.11(s,3H),1.77(dd,J＝41.5,13.0Hz,2H),1.65(ddd,J＝25.4,12.7,3.7Hz,1H),1.56(ddd,J＝16.1,12.8,3.8Hz,1H),1.30(t,J＝6.6Hz,6H),1.25(d,J＝6.8Hz,6H),1.06(s,3H)；13CNMR(151MHz,CDCl3)δ194.57,164.50,156.40,154.33,154.28,143.68,137.44,135.41,133.59,130.24,126.81,125.74,123.88,122.62,122.09,119.61,109.71,104.81,70.55,54.41,51.01,50.88,50.32,48.85,46.15,42.46,40.00,37.15,32.27,31.22,28.66,21.27,21.19,17.95,14.34,10.82。
实施例31：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基4-环戊基哌嗪-1-碳二硫酸酯
MS(ESI)m/z:828.4[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.96(s,1H),7.86(dd,J＝7.9,0.9Hz,1H),7.59–7.52(m,1H),7.48(s,1H),7.19(d,J＝15.1Hz,1H),6.64(s,1H),4.73(d,J＝13.2Hz,1H),4.57–4.44(m,1H),4.40–4.18(m,4H),4.13(d,J＝13.3Hz,1H),3.97(s,2H),3.25–3.14(m,2H),3.25–3.14(m,2H),2.86(ddd,J＝12.0,8.9,3.3Hz,1H),2.70–2.40(m,6H),2.11(s,3H),1.81(d,J＝11.2Hz,3H),1.76–1.43(m,9H),1.30(t,J＝6.8Hz,6H),1.25(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ194.40,164.53,156.42,154.36,154.31,143.70,137.46,135.43,133.61,130.27,126.83,125.77,123.90,122.65,122.12,119.63,109.73,104.84,70.58,66.03,54.43,50.77,50.56,50.54,48.79,46.18,42.48,40.00,37.18,32.30,31.25,29.29,28.69,23.03,21.30,21.22,17.97,14.36。
实施例32：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基3-甲基哌嗪-1-碳二硫酸酯
MS(ESI)m/z:774.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.51(d,J＝8.3Hz,1H),8.09(s,1H),7.96(s,1H),7.86(d,J＝7.1Hz,1H),7.56(t,J＝7.4Hz,1H),7.48(s,1H),7.19(d,J＝14.9Hz,1H),6.64(s,1H),4.73(d,J＝12.8Hz,1H),4.49(dt,J＝12.0,6.0Hz,1H),4.38(dd,J＝15.2,5.1Hz,1H),4.27(dd,J＝15.2,5.2Hz,1H),4.13(d,J＝13.0Hz,1H),3.24–3.16(m,2H),3.05(d,J＝12.4Hz,1H),2.86(dd,J＝13.2,10.0Hz,3H),2.65(t,J＝12.1Hz,1H),2.21(s,1H),2.11(s,3H),1.84–1.72(m,2H),1.70–1.52(m,2H),1.30(t,J＝6.6Hz,6H),1.25(d,J＝6.8Hz,6H),1.09(d,J＝5.7Hz,3H)；13C NMR(151MHz,CDCl3)δ194.54,164.53,156.41,154.34,154.30,143.71,137.45,135.42,133.62,130.26,126.83,125.78,123.88,122.64,122.12,119.65,109.75,104.83,70.59,54.43,50.68,49.77,49.41,46.17,42.49,40.01,37.16,32.28,31.24,28.68,21.29,21.21,17.97,14.35,13.12。
实施例33：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基硫代吗啉-4-碳二硫酸酯1,1-二氧化物
MS(ESI)m/z:809.2[M+H]+；1H NMR(600MHz,CDCl3)δ9.50(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.94(s,1H),7.87(dd,J＝8.0,1.5Hz,1H),7.67–7.50(m,2H),7.22–7.20(m,1H),6.63(s,1H),4.72(d,J＝13.3Hz,1H),4.59(s,4H),4.47(dd,J＝12.2,6.1Hz,1H),4.31(dd,J＝46.8,15.6Hz,2H),4.09(d,J＝13.6Hz,1H),3.25–3.16(m,2H),3.15–3.11(m,4H),2.88(tt,J＝12.0,3.3Hz,1H),2.67(td,J＝12.9,2.0Hz,1H),2.12(s,3H),1.84(d,J＝14.1Hz,1H),1.76(d,J＝13.1Hz,1H),1.69–1.62(m,1H),1.60–1.52(m,1H),1.32–1.29(m,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ197.45,163.55,156.25,154.35,154.01,143.79,137.39,135.31,133.60,130.29,126.85,125.83,123.93,122.61,122.18,119.78,109.75,104.89,70.65,54.46,50.52,47.32,46.10,42.54,41.38,37.12,32.28,31.20,28.09,28.04,21.29,21.21,17.98,14.35。
实施例34：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基(2-(二甲氨基)乙基)(甲基)碳二硫酸酯
MS(ESI)m/z:776.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.43(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.95(s,1H),7.85(d,J＝7.9Hz,1H),7.55(t,J＝7.8Hz,1H),7.48(s,1H),7.18(d,J＝7.6Hz,1H),6.64(s,1H),4.72(d,J＝12.8Hz,1H),4.49(dt,J＝12.0,6.0Hz,1H),4.34(d,J＝15.3Hz,1H),4.21(d,J＝15.2Hz,1H),4.17–4.08(m,2H),3.86(d,J＝6.2Hz,1H),3.46(s,1H),3.37(s,2H),3.23–3.14(m,2H),2.90–2.82(m,1H),2.61(ddd,J＝21.0,19.2,9.9Hz,3H),2.25(d,J＝16.8Hz,6H),2.11(s,3H),1.80(d,J＝12.9Hz,1H),1.73(d,J＝12.9Hz,1H),1.66(ddd,J＝25.3,12.7,3.5Hz,1H),1.56(ddd,J＝16.3,12.8,4.0Hz,1H),1.29(t,J＝6.7Hz,6H),1.24(d,J＝6.8Hz,6H)；13C NMR(151MHz,CDCl3)δ195.36,164.54,156.41,154.34,154.28,143.69,137.44,135.47,133.62,130.24,126.78,125.74,123.86,122.63,122.11,119.63,109.72,104.79,70.53,55.07,54.42,54.25,53.89,46.17,44.65,44.48,42.47,40.41,37.16,32.26,31.25,21.29,21.21,17.97,14.35。
实施例35：
2-(4-(4-((5-氯-4-((2-(异丙磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-2-氧代乙基(S)-2-(羟甲基)四氢吡咯-1-碳二硫酸酯
MS(ESI)m/z:775.3[M+H]+；1H NMR(600MHz,CDCl3)δ9.47(s,1H),8.50(d,J＝8.3Hz,1H),8.08(s,1H),7.94(s,1H),7.86(dd,J＝7.9,1.5Hz,1H),7.63–7.49(m,2H),7.20(t,J＝7.6Hz,1H),6.64(s,1H),4.83(s,1H),4.72(d,J＝12.3Hz,1H),4.53–4.45(m,1H),4.35(dt,J＝17.2,8.7Hz,1H),4.27–4.18(m,1H),4.12(d,J＝13.2Hz,1H),3.92–3.68(m,4H),3.19(dt,J＝13.7,6.8Hz,2H),2.87(t,J＝11.2Hz,1H),2.71–2.60(m,2H),2.15(d,J＝7.7Hz,1H),2.11(s,3H),2.07–1.96(m,3H),1.80(d,J＝13.1Hz,1H),1.74(d,J＝13.1Hz,1H),1.66(dd,J＝20.7,7.9Hz,1H),1.57(qd,J＝12.7,3.8Hz,1H),1.30(t,J＝6.6Hz,6H),1.25(d,J＝6.9Hz,6H)；13C NMR(151MHz,CDCl3)δ192.95,164.53,156.20,154.36,153.86,143.83,137.36,135.60,133.62,130.27,126.67,125.73,123.93,122.66,122.22,119.78,109.76,104.81,70.59,62.59,62.40,54.47,46.18,42.56,39.45,37.16,32.23,31.24,28.68,26.72,23.11,21.28,21.21,17.97,14.35。
本发明化合物生物学活性研究
体外抗肿瘤细胞活性
对按照本发明的通式I的2,4-二芳氨基嘧啶类化合物进行了体外抑制人间变性大细胞淋巴瘤细胞Karpas299和人非小细胞肺癌细胞H2228活性的试验。
Karpas299细胞用CCK-8法进行测试。将处于对数生长期的细胞以6×104个/mL接种至96孔板中，细胞液体积为100μL/孔。向每孔加入100μL 5个不同浓度的药液，每个浓度设置四个复孔，于标准条件下孵育72h。孵育结束后取出96孔板，每孔加入20μL的CCK-8溶液，继续孵育4h后取出，置于微量振荡仪上振荡5min。在酶标仪上于450nm测得各孔的吸光度(OD)。
H2228细胞用MTT法进行测试。将处于对数生长期的细胞以1×104个/mL接种至96孔板中，细胞悬浮液体积为100μL/孔，置于标准条件下培养。24h后，每孔加入100μL 5个用培养液配制的不同浓度药液，每个浓度设置四个复孔，于标准条件下孵育96h。孵育结束后取出96孔板，每孔加入50μL的MTT溶液(2mg/mL)，继续孵育4h后取出，甩板弃去上清液后每孔加100μL的DMSO溶液，并置于微量振荡仪上振荡5min，使结晶物完全溶解。在酶标仪上于570nm测得各孔的吸光度(OD)。
按公式计算细胞体外增殖的抑制率(Inhibition Rate,IR)：
IR％＝(ODcontrol-ODsample)/(ODcontrol-ODblank)×100％
式中，ODcontrol：未加药孔的OD值；ODsample：加药孔的OD值；ODblank：在CCK-8法中为只加培养基孔的OD值，在MTT法中为只加DMSO孔的OD值。
最后，用SPSS软件输入数据并绘制抑制率-浓度曲线计算IC50。
化合物的抑制Karpas299和H2228细胞活性结果见表1。
表1
ALKWT、ALKL1196M和ALKG1202R酶活性试验
用于测量ALK酶活性的试验基于酶联免疫吸附试验。具体操作如下：室温下，在0.25mg/mL PGT包被的板上,将实施例化合物、50pM ALK和5μM ATP在试验缓冲液中(25mMMOPS,pH＝7.4,1mM DTT,5mM MgCl2,1mM MnCl2,0.1％NaN3)温育20min。通过冲洗除去反应混合液并用0.2μg/mL缀合辣根过氧化酶的磷酸酪氨酸特异性克隆抗体检测磷酸聚合物底物。加入1M磷酸终止显色后，于450nm处通过分光光度法定量显色的底物颜色。
部分实施例化合物对ALKWT、ALKL1196M和ALKG1202R酶的抑制数据见表2。
表2
从上述试验结果可以清楚地看出，本发明中通式I的化合物对Karpas299和H2228细胞具有较好的抗增殖活性，部分化合物对ALKWT、ALKL1196M和ALKG1202R酶具有显著的抑制活性。
Claims (5)
1.2,4-二芳氨基嘧啶类化合物或其立体异构体或其药学上可接受的盐，其中化合物具有下述化学结构式I或II：
2.权利要求1所述的2,4-二芳氨基嘧啶类化合物或其立体异构体或其药学上可接受的盐，所述的药学上可接受的盐包括与无机酸、有机酸、碱金属离子形成的盐；所述的无机酸选自：盐酸、氢溴酸、氢氟酸、硫酸、磷酸；所述的有机酸选自：琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸或对甲苯磺酸；所属的碱金属离子选自锂离子、钠离子或钾离子。
3.一种药物组合物，其特征在于，包含权利要求1或2中的化合物或其立体异构体、或其药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
4.权利要求1或2中的化合物或其立体异构体、或其药学上可接受的盐或权利要求3所述的药物组合物在制备ALK激酶抑制剂中的用途。
5.权利要求1或2中的化合物或其立体异构体、或其药学上可接受的盐或权利要求3所述的药物组合物在制备抗肿瘤药物中的用途，其特征在于，所述的肿瘤选自为淋巴瘤、非小细胞肺癌、小细胞肺癌、头颈部细胞癌、神经胶质瘤、成神经细胞瘤、肺鳞癌、肺腺癌、膀胱癌、胃癌、结肠癌、大肠癌、肾癌、胆管癌、胃癌、食管鳞癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌中的任一种。
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