CN116444495A - 一类吲哚酮类flt3蛋白降解剂、其制备方法及其医药用途 - Google Patents
一类吲哚酮类flt3蛋白降解剂、其制备方法及其医药用途 Download PDFInfo
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- CN116444495A CN116444495A CN202310433921.6A CN202310433921A CN116444495A CN 116444495 A CN116444495 A CN 116444495A CN 202310433921 A CN202310433921 A CN 202310433921A CN 116444495 A CN116444495 A CN 116444495A
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- China
- Prior art keywords
- methyl
- fluoro
- dioxopiperidin
- ylidene
- dioxoisoindol
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明公开了一类吲哚酮类FLT3蛋白降解剂、其制备方法及其医药用途。涉及药物化学领域;本发明公开的一种体内有效的吲哚酮类FLT3蛋白降解剂,对急性髓系白血病具有很好的疗效,同等剂量下的抑瘤率明显优于FLT3抑制剂,而且对FLT3抑制剂耐药的急性髓系白血病细胞具有很好的增殖抑制活性,具有良好的产业化前景。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,以及含有这些化合物的药物组合物,它们的制备方法以及在抗急性髓系白血病方面的用途。
背景技术
FMS样受体酪氨酸激酶3(Fms-like tyrosine kinase 3,FLT3)的异常激活与急性髓系白血病(Acute myeloid leukemia,AML)的发生、发展及不良预后密切相关,已成为AML靶向治疗的重要靶标之一。目前已经有大量的FLT3抑制剂进入AML的临床研究并取得了较好的治疗效果,但是短期用药后出现的耐药性问题严重影响了FLT3抑制剂的疗效。临床研究表明,①FLT3的二次点突变,如D835V/Y/F/H、F691I/L、Y842C/H、A848P和A627P等,会导致患者对FLT3抑制剂耐药;②FLT3的表达增高、骨髓微环境中FLT3配体浓度升高,促进两者的结合,重新激活FLT3信号通路导致耐药;③骨髓基质细胞中的CYP3A4将游离的FLT3抑制剂快速代谢,降低药物浓度导致耐药;④其他信号通路的旁路激活也是产生耐药的重要因素。因此,AML患者对FLT3抑制剂产生耐药是多种因素共同作用的结果,传统的可逆FLT3抑制剂难以达到理想的治疗效果,迫切需要开发一种全新作用机制的抗AML药物,从根源上解决现有药物治疗AML出现的耐药性问题。
蛋白水解靶向嵌合体(proteolytic targeting chimera,PROTAC)技术是一种利用化学小分子诱导靶蛋白泛素化标记后经蛋白酶体降解的新型治疗策略,是近年来药物研发领域的一个新兴方向。与传统小分子抑制剂通过―占据驱动”的作用模式抑制靶蛋白的功能发挥治疗疾病的作用相比,PROTAC是―事件驱动”的瞬时作用模式,不是影响蛋白的功能,而是介导致病靶蛋白被降解。只要PROTAC介导三元复合物的形成并给靶蛋白打上泛素化的标签,理论上是可以循环反复使用的,因此催化剂量即可发挥作用,避免了长时间、大剂量给药导致靶蛋白表达量增加、靶蛋白突变以及旁路信号激活所引起的耐药性。因此,开发靶向降解FLT3蛋白的FLT3-PROTACs,有望从源头上解决FLT3突变或者高表达导致的耐药性。
2018年,Crews团队报道了一种基于Quizartinib设计的FLT3蛋白降解剂【J AmChem Soc,2018,140,16428-16432】,2021年Yang课题组报道了一种基于Dovitinib设计的FLT3蛋白降解剂【J Med Chem,2021,64,16497-16511】。这两种PROTACs分子能够有效降解MV4-11细胞内的FLT3蛋白,对携带FLT3-ITD突变的AML细胞的抗增殖活性显著增强,遗憾的是这两种FLT3降解剂无相关的体内药效数据,也未开展相关的抗耐药性研究。实践证明,开发FLT3降解剂是可行的,但是成药性问题一直是制约PROTACs发展的难题,目前尚无体内有效的FLT3降解剂进入临床研究阶段,现有的FLT3降解剂在体内药效和成药性方面存在严重不足。因此,如何设计合成一种体内有效的FLT3降解剂,克服传统FLT3抑制剂的耐药性依然是目前AML治疗领域迫切需要解决的关键科学问题。
本发明在前期发现的FLT3抑制剂候选化合物PX-A13的基础上,采用沙利度胺作为E3连接酶CRBN的配体,通过优化Linker的种类、长度、连接方式,设计合成了一系列靶向降解FLT3蛋白的PROTACs,通过系统的生物活性和成药性评价,成功发现了一类体内有效、抗AML效果显著的新型FLT3蛋白降解剂。
发明内容
针对上述问题,本发明提供了一种通式(I)所示的吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐。
本发明的技术方案是:本发明公开了一种吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐、多晶型物或溶剂化物,其特征在于,所述衍生物的化学结构式如式(I)所示:
其中:
R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或氨基中的一种或几种;
R2选自氢原子、甲基或卤代甲基;
R3选自氢原子或卤素;
R4选自氢原子或与相邻的碳形成羰基;
X选自-NHCO-、-CONH-或-NH-;
m是0-6;
Linker选自
n是1-12;
本发明优选的典型化合物如下,但不限于:
本发明的一个目的在于提供了制备方法;其具体制备步骤如下:
由化合物Ⅱ与柔性的脂肪链或者聚乙二醇Linker反应制备化合物Ⅲ的过程,所需缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾,优选DIPEA;反应溶剂选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)或二甲亚砜(DMSO),优选DMA;反应温度为70℃~100℃,优选80℃。
由化合物Ⅲ与化合物Ⅳ反应制备化合物I的过程,所用的缩合剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)、1-羟基苯并三唑(HOBT)/1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、二环己基碳二亚胺(DCC)或N,N'-羰基二咪唑(CDI),优先PyBOP;缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾,优选DIPEA;反应溶剂选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)或二甲亚砜(DMSO),优选DMF;反应温度为10℃~50℃,优选20℃~30℃。
由化合物Ⅳ与刚性杂环Linker反应制备化合物Ⅴ的过程分为两步,第一步是在酸性条件下,胺与羰基反应形成席夫碱,所用的酸选自乙酸(AcOH)、甲酸(HCOOH)、对甲苯磺酸(PTSA),优选AcOH;第二步所用的还原剂选自三乙酰氧基硼氢化钠(STAB)、氰基硼氢化钠、硼氢化钠,优选STAB;反应溶剂选自甲醇、二氯甲烷(DCM)、四氢呋喃(THF)、二甲基亚砜(DMSO)或其中任意两到三种溶剂的混合溶剂,优选DMSO;反应温度为10℃~50℃,优选20℃~30℃;脱掉Boc保护基所用的酸选自盐酸、三氟乙酸、硫酸、对甲苯磺酸,优选盐酸;反应溶剂选择乙酸乙酯、甲醇、二氯甲烷、丙酮、二氧六环或任意几种的混合溶剂,优选乙酸乙酯;反应温度为10℃~40℃,优选20℃。
由化合物Ⅴ与化合物Ⅵ反应制备化合物I的过程,所需缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾,优选DIPEA;反应溶剂选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)或二甲亚砜(DMSO),优选DMSO;反应温度为70℃~100℃,优选80℃。
由化合物I经成盐制备化合物I·A的过程,反应物A为氯化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸,优选氯化氢;溶剂为甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯、四氢呋喃、或任意几种的混合溶剂,优选乙酸乙酯。
本发明的第二目的在于提供一种药物组合物,包括所述的吲哚酮类FLT3蛋白降解剂、其药学上可接受的盐,以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、及其药物组合物在制备FLT3蛋白降解剂中的用途;本发明的化合物或其药学上可接受的盐,及其药物组合物对FLT3具有很强的降解活性,因此可以用于制备治疗FLT3表达异常引起的相关肿瘤疾病的药物。
本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、及其药物组合物在制备治疗急性髓系白血病药物中的用途。体外抗肿瘤活性实验表明,本发明的化合物能够显著抑制急性髓系白血病细胞的增殖;整体动物试验表明,本发明化合物对急性髓系白血病具有很好的疗效;因此,本发明的化合物或其药学上可接受的盐,及其药物组合物可作为单一治疗剂,或者与其它抗肿瘤药物联合使用,用于急性髓系白血病的治疗。
本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、及其药物组合物在制备治疗FLT3抑制剂耐药的急性髓系白血病药物中的用途;体外抗肿瘤活性实验表明,本发明的化合物对FLT3抑制剂耐药的急性髓系白血病细胞具有显著的抗增殖作用;因此,本发明的化合物或其药学上可接受的盐,及其药物组合物可作为单一治疗剂,或者与其它抗肿瘤药物联合使用,用于对FLT3抑制剂耐药的急性髓系白血病的治疗。
本发明的有益效果是:本发明公开的一种口服有效的吲哚酮类FLT3蛋白降解剂,对急性髓系白血病具有很好的疗效,同等剂量下的抑瘤率明显优于FLT3抑制剂,而且对FLT3抑制剂耐药的急性髓系白血病细胞具有很好的增殖抑制活性,能够克服FLT3抑制剂的耐药性,具有良好的产业化前景。
附图说明
图1是本发明的制备流程图;
图2是本发明实施例32中化合物A1-A29对MV-4-11、MOLM-13细胞中FLT3蛋白的降解作用的对比图;其中,(a)是化合物A1-A29对MV-4-11中FLT3蛋白的降解作用的示意图;(b)是化合物A1-A29对MOLM-13细胞中FLT3蛋白的降解作用的示意图。
具体实施方式
为了更清楚地说明本发明的技术方案,下面对本发明的技术方案做进一步的详细说明:
实施例1
(Z)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(2-(3-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-3-氧丙氧基)乙基)乙酰胺(A01)的合成:
中间体II-1的合成:将2-羟基乙酸叔丁酯(0.51g,3.85mmol)和三苯基膦(1.35g,5.15mmol)溶于10mL无水THF,将反应体系降至0℃后,加入DTBAD(1.15g,5.15mmol)的无水THF溶液,再加入化合物Ⅰ-1(1.1g,3.85mmol)的无水THF溶液,将反应体系在0℃下搅拌1h,然后恢复至室温,过夜反应,LC-MS监控反应完成,旋去溶剂后用10mL二氯甲烷溶解,再加入13mL甲酸,将体系升温至40℃反应36h,TLC(石油醚:乙酸乙酯=1:1)监控反应完成,减压浓缩,然后柱层析分离,得白色固体粉末(700mg,yield:60%)。
中间体III-1的合成:将化合物II-1(0.2g,0.63mmol)和linker(0.63mmol)溶解于5mL N,N-二甲基甲酰胺,再加入HATU(0.23g,0.98mmol)以及DIPEA(0.3mL,1.26mmol),然后反应体系在室温下反应2h,TLC(石油醚:乙酸乙酯=1:1)监控反应完成,将反应倒入水中,乙酸乙酯(30mL×3)萃取,合并有机相,水洗(30mL×2),饱和食盐水洗,无水硫酸钠干燥,抽滤,真空浓缩滤液,然后向其中加入5mL二氯甲烷,再加入4ml甲酸,然后将反应体系升温至40℃,在该温度下酸解,直至完全反应,反应完成后,将反应倒入水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩即得粗品,直接投下步反应。
中间体V的合成:将化合物IV(0.26g,0.78mmol)和1-叔丁氧羰基哌嗪(0.79g,3.9mmol)用N,N-二甲基甲酰胺(10mL)溶解,升温至50℃反应12h,LC-MS监控反应完成,向反应体系中加入30mL水,有固体析出即产物,抽滤,烘干得棕黄色固体V(0.37g,yield:90%)。1HNMR(500MHz,DMSO-d6)δ13.45(s,1H),10.89(s,1H),9.22(s,1H),7.77(dd,J=9.4,2.6Hz,1H),7.74(s,1H),7.64(d,J=3.0Hz,1H),6.96–6.91(m,1H),6.84(dd,J=8.4,4.5Hz,1H),3.39(t,J=4.9Hz,4H),3.17(s,2H),2.50–2.41(m,4H),2.28(s,3H),1.41(s,9H).
中间体VI的合成:取化合物V(0.35g,0.72mmol)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得棕黄色化合物VI(0.26g,yield:85%)。1H NMR(500MHz,DMSO-d6)δ13.54(s,1H),10.96(s,1H),9.27(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.62(d,J=3.0Hz,1H),6.94(ddd,J=9.5,8.4,2.6Hz,1H),6.82(dd,J=8.4,4.5Hz,1H),3.43(t,J=4.8Hz,6H),3.21(s,2H),2.50–2.41(m,4H),2.23(s,3H).
化合物A01的合成:取化合物III-1(110mg,0.25mmol),化合物VI(103mg,0.25mmol)以及PyBOP(195mg,0.375mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(180μL,1.0mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A01(47mg,yield:23%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.13(s,1H),10.89(s,1H),9.24(s,1H),8.01(t,J=5.7Hz,1H),7.81(t,J=7.9Hz,1H),7.77(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.1Hz,1H),7.50(d,J=7.3Hz,1H),7.41(d,J=8.4Hz,1H),6.93(t,J=9.1Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),5.12(dd,J=12.8,5.4Hz,1H),4.80(s,2H),3.64(t,J=6.6Hz,2H),3.56–3.47(m,4H),3.46(t,J=5.7Hz,2H),3.31(t,J=15.0Hz,2H),3.17(s,2H),2.94–2.86(m,1H),2.65–2.61(m,1H),2.60–2.52(m,6H),2.28(s,3H),2.09–2.03(m,2H).13C NMR(126MHz,DMSO-d6)δ173.23,170.34,169.86,169.23,167.36,167.19,165.93,159.58,157.71,155.46,140.06,137.41,135.17,133.49,125.74,125.71,125.65,120.85,119.52,117.24,116.52,116.52,115.73,115.29,111.00,110.41,69.05,68.02,67.01,63.91,62.93,52.89,52.87,49.28,38.83,33.19,31.42,22.47,9.11.HR-MS(ESI):calcd for C40H42FN8O10[M+H]+:813.3002;found:813.3009.
实施例2
(Z)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(2-(3-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧代乙基)哌嗪-1-基)-3-氧代丙氧基)乙基)乙酰胺(A02)的合成
中间体III-2的合成:将化合物II-1(0.2g,0.63mmol)和linker(0.63mmol)溶解于5mL N,N-二甲基甲酰胺,再加入HATU(0.23g,0.98mmol)以及DIPEA(0.3mL,1.26mmol),然后反应体系在室温下反应2h,TLC(石油醚:乙酸乙酯=1:1)监控反应完成,将反应倒入水中,乙酸乙酯(30mL×3)萃取,合并有机相,水洗(30mL×2),饱和食盐水洗,无水硫酸钠干燥,抽滤,真空浓缩滤液,然后向其中加入5mL二氯甲烷,再加入4ml甲酸,然后将反应体系升温至40℃,在该温度下酸解,直至完全反应,反应完成后,将反应倒入水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩即得粗品,直接投下步反应。
化合物A02的合成:取化合物III-2(120mg,0.25mmol),化合物VI(103mg,0.25mmol)以及PyBOP(195mg,0.375mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(180μL,1.0mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A02(56mg,yield:26%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.12(s,1H),10.88(s,1H),9.24(s,1H),8.00(t,J=5.6Hz,1H),7.81(t,J=7.9Hz,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.63(d,J=3.1Hz,1H),7.50(d,J=7.3Hz,1H),7.41(d,J=8.5Hz,1H),6.93(td,J=9.4,9.0,2.6Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),5.12(dd,J=12.7,5.4Hz,1H),4.80(s,2H),3.63(t,J=6.6Hz,2H),3.48(s,8H),3.47(d,J=5.7Hz,2H),3.32(d,J=5.6Hz,2H),3.17(s,2H),2.94–2.86(m,1H),2.62(s,1H),2.60–2.52(m,6H),2.28(s,3H),2.09–1.99(m,2H).13C NMR(126MHz,DMSO-d6)δ173.22,170.32,169.86,169.22,167.67,167.35,167.18,165.90,157.72,155.42,137.39,135.17,133.50,127.58,127.51,125.70,125.66,124.28,121.22,120.82,119.52,117.24,116.51,115.70,112.81,110.47,106.50,106.30,70.07(2C),69.29,67.99,67.24,61.13,53.40,52.93,49.29(2C),45.52,41.52,33.22,31.42,22.47,9.10.HR-MS(ESI):calcd for C42H46FN8O11[M+H]+:857.3265;found:857.3265.
实施例3
(Z)-2-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A03)的合成
中间体II-2的合成:将I-2(200mg,0.72mmol)以及聚乙二醇类的linker(0.66mmol)溶于DMA5mL中,再加入DIPEA(300μL,1.72mmol),然后将反应体系升温至80℃,在此条件下反应4h,反应完成降温至室温,将反应液倒入水(20mL)中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空浓缩除去溶剂,然后向其中加入5mL二氯甲烷,再加入4mL甲酸,然后将反应体系升温至40℃,在该温度下酸解,直至完全反应,反应完成后,将反应倒入水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩即得粗品,直接投下步反应。
化合物A03的合成:取化合物II-2(110mg,0.25mmol),化合物VI(103mg,0.25mmol)以及PyBOP(195mg,0.375mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(180μL,1.0mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A03(63mg,yield:31%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.12(s,1H),10.88(s,1H),9.24(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.0Hz,1H),7.58(t,J=7.9Hz,1H),7.15(d,J=8.4Hz,1H),7.04(d,J=7.1Hz,1H),6.93(t,J=7.7Hz,1H),6.84(dd,J=8.5,4.4Hz,1H),6.61(t,J=5.9Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),3.64–3.62(m,4H),3.57–3.56(m,2H),3.53–3.51(m,6H),3.48–3.45(m,2H),3.17(s,2H),2.94–2.86(m,1H),,2.61(s,1H),2.55(t,J=18.5Hz,4H),2.48–2.45(m,2H),2.28(s,3H),2.06–1.99(m,2H).13C NMR(126MHz,DMSO-d6)δ173.26,170.54,169.87,169.40,169.20,167.74,167.64,157.72,146.87,136.67,135.17,132.55,127.59,125.70,125.66,124.29,121.20,119.51,117.91,115.73,113.01,112.82,111.13,109.72,107.24,70.17(2C),69.36,67.31,61.13,60.22,53.39,52.93,49.03(2C),45.49,33.23,31.46,22.61,9.10.HR-MS(ESI):calcd for C40H44FN8O9[M+H]+:799.3210;found:799.3195.
实施例4
(Z)-2-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A04)的合成
中间体II-3的合成:将I-2(200mg,0.72mmol)以及聚乙二醇类的linker(0.66mmol)溶于DMA5mL中,再加入DIPEA(300μL,1.72mmol),然后将反应体系升温至80℃,在此条件下反应4h,反应完成降温至室温,将反应液倒入水(20mL)中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空浓缩除去溶剂,然后向其中加入5mL二氯甲烷,再加入4mL甲酸,然后将反应体系升温至40℃,在该温度下酸解,直至完全反应,反应完成后,将反应倒入水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩即得粗品,直接投下步反应。
化合物A04的合成:取化合物II-3(75mg,0.19mmol),化合物VI(81mg,0.19mmol)以及PyBOP(150mg,0.29mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(140μL,0.77mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A04(44mg,yield:31%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.11(s,1H),10.89(s,1H),9.23(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.1Hz,1H),7.59(t,J=8.0Hz,1H),7.16(d,J=8.6Hz,1H),7.05(d,J=7.0Hz,1H),6.93(td,J=9.4,9.0,2.6Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),6.59(t,J=5.8Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),3.69(t,J=6.6Hz,2H),3.61(t,J=5.4Hz,2H),3.55–3.50(m,4H),3.47(t,J=5.5Hz,2H),3.16(s,2H),2.94–2.86(m,1H),2.61(s,1H),2.60–2.53(m,4H),2.50–2.46(m,2H),2.28(s,3H),2.06–1.99(m,2H).13C NMR(126MHz,DMSO-d6)δ173.25,170.51,169.87,169.40,169.11,167.73,167.68,157.72,146.87,136.70,135.17,132.57,127.59,125.70,125.66,124.28,121.20,119.51,117.89,115.73,113.01,111.15,110.40,109.73,106.51,69.12,67.17,61.11,60.22,53.41,52.92,49.04(2C),42.15,33.20,31.45,22.63,9.09.HR-MS(ESI):calcd for C38H40FN8O8[M+H]+:755.2948;found:755.2951.
实施例5
(Z)-2-(4-(3-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A05)的合成
中间体II-4的合成:将I-2(200mg,0.72mmol)以及聚乙二醇类的linker(0.66mmol)溶于DMA5mL中,再加入DIPEA(300μL,1.72mmol),然后将反应体系升温至80℃,在此条件下反应4h,反应完成降温至室温,将反应液倒入水(20mL)中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空浓缩除去溶剂,然后向其中加入5mL二氯甲烷,再加入4mL甲酸,然后将反应体系升温至40℃,在该温度下酸解,直至完全反应,反应完成后,将反应倒入水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩即得粗品,直接投下步反应。
化合物A05的合成:取化合物II-4(80mg,0.17mmol),化合物VI(70mg,0.17mmol)以及PyBOP(135mg,0.26mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(120μL,0.68mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A05(55mg,yield:38%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.90(s,1H),9.29(s,1H),7.76(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.65(d,J=3.1Hz,1H),7.58(t,J=7.8Hz,1H),7.14(d,J=8.5Hz,1H),7.04(d,J=7.0Hz,1H),6.94(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),6.61(t,J=5.8Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.63(dd,J=6.5,3.2Hz,4H),3.61–3.39(m,16H),3.31–3.04(m,1H),2.93–2.85(m,1H),2.61(t,J=3.3Hz,1H),2.56(dt,J=9.7,5.3Hz,4H),2.29(s,2H),2.10–1.99(m,2H).13CNMR(126MHz,DMSO-d6)δ173.27,170.80,170.54,169.86,169.39,169.27,167.75,159.58,157.72,146.86,136.67,135.18,132.55,127.48,125.68,124.16,121.15,119.48,117.90,115.76,112.85,111.13,110.49,109.71,106.32,70.29,70.25(3C),70.13,69.34,67.21,60.22,52.84,52.82,49.03(2C),42.16,33.21,31.45,21.23,9.13.HR-MS(ESI):calcd forC42H48FN8O10[M+H]+:843.3471;found:843.3478.
实施例6
(Z)-N-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)-9-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)壬酰胺(A06)的合成
中间体II-5的合成:取化合物I-3(250mg,0.92mmol),9-溴壬酸(200mg,0.84mmol)溶于5mL乙腈中,再加入TCFH(356mg,1.27mmol),NMI(203μL,2.5mmol)在室温下搅拌反应2h左右,LC-MS监控反应完成,将反应液倒入20mL水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤真空除去溶剂,将产物简单纯化得到粗品化合物II-5,直接投下一步反应。
化合物A06的合成:取化合物Ⅱ-5(113mg,0.23mmol),化合物Ⅵ(80mg,0.19mmol),碳酸氢钠(50mg,0.8mmol)溶解于5mL N,N-二甲基甲酰胺中,将反应体系升温至90℃,在此条件下反应4h,LC-MS监控反应完成,将反应体系冷却至室温,向其中加入20mL水,析出固体粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A06(33mg,yield:22%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.13(s,1H),10.91(s,1H),10.67(s,1H),9.24(s,1H),8.28(s,1H),7.93(d,J=10.1Hz,1H),7.87(d,J=8.2Hz,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.65(d,J=3.1Hz,1H),6.94(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),5.13(dd,J=12.9,5.4Hz,1H),3.20(d,J=5.0Hz,2H)3.06(q,J=7.2Hz,4H),2.94–2.84(m,2H),2.62–2.54(m,4H),2.41(t,J=7.4Hz,4H),2.28(s,3H),2.07–1.99(m,2H),1.65–1.59(m,2H),1.38–1.26(m,10H).13C NMR(126MHz,DMSO-d6)δ173.22,172.86,170.38,169.85,168.13,167.51,167.24,159.57,157.71,145.66,135.18,133.23,127.56,127.48,125.69,125.14,124.27,123.93,116.69,115.76,113.27,110.49,110.42,106.51,106.31,60.22,49.42,49.06,45.97(4C),36.98,31.42,29.51,29.13,28.99,25.26,22.53,21.24,14.56,9.08.HR-MS(ESI):calcd for C42H48FN8O7[M+H]+:795.3625;found:795.3603.
实施例7
(Z)-2-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)壬基哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A07)的合成
中间体II-6的合成:将化合物I-1(200mg,0.73mmol),1,9-二溴壬烷(250mg,0.88mmol)以及DIPEA(390μL,2.2mmol)溶解于5mL N,N-二甲基甲酰胺中,将反应体系升温至85℃反应4h,LC-MS监控反应完成,将反应体系降至室温,然后倒入水中,乙酸乙酯萃取,合并有机相,水洗,食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,将产物简单纯化得到粗品化合物II-6,直接投下步反应。
化合物A07的合成:取化合物II-6(115mg,0.24mmol),化合物Ⅵ(84mg,0.20mmol),碳酸氢钠(50mg,0.8mmol)溶解于5mL N,N-二甲基甲酰胺中,将反应体系升温至90℃,在此条件下反应4h,LC-MS监控反应完成,将反应体系冷却至室温,向其中加入20mL水,析出固体粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A07(36mg,yield:23%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H)11.13(s,1H),10.90(s,1H),9.24(s,1H),7.81(t,J=7.9Hz,1H),7.76(dd,J=9.5,2.6Hz,1H),7.73(s,1H),7.65(d,J=3.1Hz,1H),7.51(d,J=8.6Hz,1H),7.44(d,J=7.7Hz,1H),6.98–6.89(m,1H),6.85(dd,J=8.6,4.4Hz,1H),5.09(dd,J=12.9,5.5Hz,1H),4.20(t,J=6.4Hz,2H),3.19(s,2H),2.94–2.86(m,2H),2.77–2.49(m,10H),2.28(s,3H),2.10–2.01(m,2H),1.52–1.43(m,4H),1.39–1.25(m,10H).13C NMR(126MHz,DMSO-d6)δ173.25,170.42,169.86,167.58,167.31,165.78,159.57,157.71,156.48,137.50,135.19,133.71,127.56,125.69,125.64,124.27,120.24,119.37,116.66,115.75,115.59,113.02,110.43,106.51,69.26,67.10,64.01,57.51,49.20(2C),31.43(2C),29.33,29.19,29.08,28.88,27.00,25.74,22.53,22.48,14.44,9.09.HR-MS(ESI):calcd for C42H49FN7O7[M+H]+:782.3672;found:782.3670.
实施例8
(Z)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-5-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-5-氧戊酰胺(A08)的合成
中间体II-7的合成:将化合物I-2(500mg,1.81mmol),N-Boc乙二胺(287μL,1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA 10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC(二氯甲烷:甲醇=10:1)监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单纯化后将得到的产物用少量乙酸乙酯溶解,再加入15mL HCl-EA,然后密封在室温下反应,TLC监控反应完成后,真空除去溶剂,再加15mL乙酸乙酯,然后搅拌1h,再真空除去溶剂,然后加入大量的乙酸乙酯,搅拌0.5h后,抽滤,滤饼再用大量乙酸乙酯,正己烷冲洗,油泵拉干,即得黄色固体II-7。
中间体III-3的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A08的合成:取化合物III-3(103mg,0.24mmol),化合物VI(101mg,0.24mmol)以及PyBOP(190mg,0.36mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(170μL,0.96mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A08(46mg,yield:24%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.11(s,1H),10.89(s,1H),9.25(s,1H),8.05(t,J=5.7Hz,1H),7.76(dd,J=9.3,2.6Hz,1H),7.74(s,1H),7.65(d,J=3.0Hz,1H),7.59(t,J=7.9Hz,1H),7.18(d,J=8.6Hz,1H),7.03(d,J=7.2Hz,1H),6.98–6.90(m,1H),6.84(dd,J=8.6,4.5Hz,1H),6.74(t,J=6.1Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),3.52(s,2H),3.47(s,2H),3.44–3.36(m,4H),3.26(t,J=6.1Hz,2H),3.18(d,J=4.6Hz,2H),2.94–2.86(m,1H),2.64–2.60(m,1H),2.59–2.52(m,4H),2.28(s,3H),2.17–1.96(m,4H),1.73(q,J=7.4Hz,2H).13C NMR(126MHz,DMSO-d6)δ173.27,172.89,170.71,170.56,169.87,169.17,167.76,167.64,159.58,157.72,146.81,136.66,135.17,132.67,125.72,125.66,124.28,121.21,119.52,117.63,115.73,112.82,111.02,110.47,109.70,106.32,61.12,53.42,52.98,49.00,45.37,42.00,41.51,38.45,35.07,32.13,31.46,22.64,21.37,9.11.HR-MS(ESI):calcd for C39H41FN9O8[M+H]+:796.3213;found:796.3207.
实施例9
(Z)-N-(2-((2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-6-(4-(2-((5-((5-氟-2-氧异代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-6-氧己酰胺(A09)的合成
中间体III-4的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A09的合成:取化合物III-4(93mg,0.21mmol),化合物Ⅵ(92mg,0.21mmol)以及PyBOP(164mg,0.32mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(150μL,0.84mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A09(51mg,yield:30%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.11(s,1H),10.89(s,1H),9.24(s,1H),8.05(t,J=5.7Hz,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.0Hz,1H),7.59(dd,J=8.6,7.1Hz,1H),7.18(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.93(td,J=9.1,2.5Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),6.74(t,J=6.2Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),3.54–3.47(m,4H),3.38(d,J=6.3Hz,2H),3.25(q,J=6.2Hz,2H),3.17(s,2H),2.94–2.86(m,1H),2.63–2.58(m,1H),2.54(d,J=5.0Hz,2H),2.49(s,2H),2.30(d,J=7.3Hz,2H),2.28(s,3H),2.07–1.99(m,2H),1.48(dq,J=21.3,7.7Hz,4H).13CNMR(126MHz,DMSO-d6)δ173.27,173.08,170.92,170.56,169.87,169.17,167.76,167.68,159.57,157.72,146.82,137.47,136.65,135.17,132.67,127.51,125.70,124.28,121.21,119.51,117.61,115.73,112.82,110.99,110.47,109.70,61.15,53.47,53.01,49.07,49.00,45.45,41.95,38.47,35.66,32.49,31.45,25.42,24.90,22.64,9.10.HR-MS(ESI):calcd for C41H45FN9O8[M+H]+:810.3370;found:810.3364.
实施例10
(Z)-N-(2-((2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-7-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-7-氧庚酰胺(A10)的合成
中间体III-5的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A10的合成:取化合物III-5(82mg,0.18mmol),化合物VI(76mg,0.18mmol)以及PyBOP(140mg,0.27mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(127μL,0.72mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A10(47mg,yield:32%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.89(s,1H),9.27(s,1H),8.03(t,J=5.7Hz,1H),7.76(dd,J=9.5,2.6Hz,1H),7.73(s,1H),7.65(d,J=3.0Hz,1H),7.59(t,J=7.9Hz,1H),7.18(d,J=8.5Hz,1H),7.03(d,J=6.1Hz,1H),6.93(t,J=9.2Hz,1H),6.84(dt,J=7.9,3.3Hz,1H),6.73(t,J=6.1Hz,1H),5.07(dd,J=13.3,5.6Hz,1H),3.51(d,J=12.8Hz,4H),3.46–3.38(m,2H),3.25(d,J=6.6Hz,2H),3.18(s,2H),2.94–2.85(m,1H),2.64–2.60(m,1H),2.59–2.52(m,4H),2.28(s,3H),2.26(d,J=7.6Hz,2H),2.11–1.98(m,4H),1.56–1.42(m,4H),1.25–1.21(m,2H).13C NMR(126MHz,DMSO-d6)δ173.27,173.17,171.04,170.55,169.87,169.17,167.79,167.76,159.58,157.72,146.83,136.65,135.17,132.67,127.58,125.70,124.26,121.20,119.50,117.63,115.75,113.02,111.00,110.48,109.70,106.51,61.09,55.38,53.44,52.99,49.07,49.00,41.95,38.44,35.79,32.58,31.45,28.89,25.56,25.06,22.64,9.11.HR-MS(ESI):calcd forC42H47FN9O8[M+H]+:824.3527;found:824.3522.
实施例11
(Z)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-8-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-8-氧辛酰胺(A11)的合成
中间体III-6的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A11的合成:取化合物III-6(138mg,0.29mmol),化合物VI(121mg,0.29mmol)以及PyBOP(225mg,0.44mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(205μL,1.16mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A11(64mg,yield:26%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.11(s,1H),10.89(s,1H),9.24(s,1H),8.02(t,J=5.7Hz,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.0Hz,1H),7.59(t,J=8.7Hz,1H),7.18(d,J=8.7Hz,1H),7.03(d,J=7.0Hz,1H),6.96–6.90(m,1H),6.84(dd,J=8.4,4.5Hz,1H),6.72(t,J=6.2Hz,1H),5.06(dd,J=12.7,5.5Hz,1H),3.51(dt,J=10.2,4.6Hz,4H),3.38(d,J=6.4Hz,2H),3.25(q,J=6.1Hz,2H),3.18(s,2H),2.94–2.86(m,1H),2.65–2.58(m,1H),2.54(d,J=5.0Hz,4H),2.49(s,2H),2.28(s,3H),2.26(d,J=7.5Hz,2H),2.07–2.03(m,2H),1.56–1.38(m,4H),1.31–1.20(m,4H).13C NMR(126MHz,DMSO-d6)δ173.28,173.20,171.06,170.56,169.87,169.17,167.76,167.69,159.57,157.71,146.83,136.65,135.16,132.67,127.57,125.71,124.29,121.22,119.52,117.62,115.72,112.81,111.01,110.39,109.69,106.51,61.15,53.49,53.01,48.99,45.47,41.92,41.51,38.44,35.84,32.67,31.44,29.03,28.99,25.58,25.16,22.64,9.10.HR-MS(ESI):calcd for C43H49FN9O8[M+H]+:838.3682;found:838.3654.
实施例12
(Z)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-9-(4-(2-((5-((5-氟-2-氧代异、吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-9-氧壬酰胺(A12)的合成
中间体III-7的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A12的合成:取化合物III-7(118mg,0.24mmol),化合物VI(100mg,0.24mmol)以及PyBOP(135mg,0.26mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(120μL,0.68mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A12(45mg,yield:22%)。1H NMR(500MHz,DMSO-d6)δ13.50(s,1H),11.11(s,1H),10.96(s,1H),10.34(s,1H),8.08(t,J=5.7Hz,1H),7.77(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.71(d,J=3.1Hz,1H),7.59(t,J=7.8Hz,1H),7.18(d,J=8.5Hz,1H),7.03(d,J=6.9Hz,1H),6.95(td,J=9.0,2.5Hz,1H),6.86(dd,J=8.4,4.5Hz,1H),6.72(t,J=6.2Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.60–3.51(m,4H),3.34–3.20(m,4H),3.11(s,2H),2.93–2.85(m,1H),2.61(s,1H),2.58–2.51(m,4H),2.50(s,2H),2.34(s,3H),2.10–1.97(m,4H),1.56–1.40(m,4H),1.23(q,J=7.1,6.6Hz,6H).13C NMR(126MHz,DMSO-d6)δ173.28,173.24,171.42,170.54,169.83,169.14,167.77,162.35,159.57,157.71,146.83,136.67,135.30,132.64,125.67,125.63,123.70,120.90,119.29,117.68,116.21,113.00,111.01,110.61,109.65,106.41,56.78,52.15,51.96,49.06,48.98,42.10,41.96,38.43,35.82,32.36,31.47,29.10,29.06,29.01,25.63,24.96,22.66,9.49.HR-MS(ESI):calcd forC44H51FN9O8[M+H]+:852.3840;found:852.3819.
实施例13
((Z)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-10-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-10-氧葵酰胺(A13)的合成
中间体III-8的合成:先将烷烃二酸类的linker(1.28mmol),HBTU(180mg,0.47mmol)用5mL N,N-二甲基甲酰胺溶解,加入DIPEA(615μL,3.44mmol)在室温下搅拌5min,然后加入II-7(150mg,0.43mmol),在室温下反应2h后,LC-MS监控反应完成,简单处理后可直接投下一步反应。
化合物A13的合成:将化合物Ⅲ-8(116mg,0.23mmol),化合物Ⅵ(96mg,0.23mmol)以及PyBOP(182mg,0.35mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(163μL,0.92mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A13(54mg,yield:27%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.11(s,1H),10.89(s,1H),9.25(s,1H),8.02(t,J=5.6Hz,1H),7.76(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.1Hz,1H),7.58(t,J=8.6Hz,1H),,7.17(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.93(td,J=9.5,9.0,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),6.72(t,J=6.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),3.51(q,J=6.0,5.0Hz,4H),3.37(d,J=6.3Hz,2H),3.24(q,J=6.1Hz,2H),3.18(s,2H),2.94–2.86(m,1H),2.61(d,J=3.3Hz,1H),2.58–2.51(m,4H),2.50–2.45(m,2H),2.28(s,3H),2.06–1.98(m,4H),1.50–1.44(m,4H),1.22(s,8H).13C NMR(126MHz,DMSO-d6)δ173.26,173.21,171.07,170.80,170.53,169.87,169.16,167.76,159.58,157.72,146.83,136.63,135.17,132.66,127.58,125.66,124.27,121.19,119.50,117.61,115.74,112.81,110.99,110.47,109.68,106.51,61.15,60.22,53.48,53.02,49.07,48.99,41.94,38.45,35.87,32.72,31.45,29.24,29.21,29.09,25.68,25.29,22.65,21.23,9.10.HR-MS(ESI):calcd for C45H53FN9O8[M+H]+:866.3996;found:866.3989.
实施例14
(Z)-2-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)己基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A14)的合成
中间体II-8的合成:取I-2(500mg,1.81mmol),氨基烷烃酸类linker(1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA 10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
化合物A14的合成:取化合物II-8(110mg,0.26mmol),化合物VI(110mg,0.26mmol)以及PyBOP(203mg,0.39mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(190μL,1.04mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A14(75mg,yield:38%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.89(s,1H),9.27(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.74(s,1H),7.65(d,J=3.0Hz,1H),7.59(t,J=8.0Hz,1H),7.10(d,J=8.6Hz,1H),7.02(d,J=7.1Hz,1H),6.94(t,J=9.2Hz,1H),6.84(dd,J=8.7,4.5Hz,1H),6.54(t,J=6.0Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),3.52(s,4H),3.30(d,J=7.6Hz,2H),3.20(s,2H),2.93–2.84(m,1H),2.61(s,1H),2.59–2.52(m,4H),2.33(t,J=7.6Hz,2H),2.28(s,3H),2.10–1.99(m,2H),1.60(t,J=7.5Hz,2H),1.54(q,J=8.1,7.6Hz,2H),1.37(p,J=7.4Hz,2H).13C NMR(126MHz,DMSO-d6)δ173.28,171.00,170.57,169.87,169.41,168.43,167.77,159.58,157.72,146.89,136.75,135.18,132.66,125.70,125.66,124.26,121.19,119.50,117.65,115.75,113.02,110.84,110.48,109.46,106.31,61.06,55.38,53.45,53.00,49.01(2C),42.24,32.61,31.45,29.03,26.57,25.02,22.63,9.11.HR-MS(ESI):calcd for C39H42FN8O7[M+H]+:753.3155;found:753.3144.
实施例15
(Z)-2-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)庚酰)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A15)的合成
中间体II-9的合成:取I-2(500mg,1.81mmol),氨基烷烃酸类linker(1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA 10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
化合物A15的合成:取化合物II-9(85mg,0.21mmol),化合物VI(90mg,0.21mmol)以及PyBOP(165mg,0.32mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(150μL,0.84mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A15(45mg,yield:28%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.89(s,1H),9.27(s,1H),7.76(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.0Hz,1H),7.58(t,J=7.8Hz,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.1Hz,1H),6.93(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),6.54(t,J=5.9Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.57–3.44(m,4H),3.29(t,J=6.8Hz,2H),3.20(s,2H),2.92–2.85(m,1H),2.61(t,J=3.3Hz,1H),2.59–2.51(m,4H),2.31(t,J=7.5Hz,2H),2.28(s,3H),2.12–1.97(m,2H),1.57(q,J=7.2Hz,2H),1.50(q,J=7.3Hz,2H),1.40–1.30(m,4H).13C NMR(126MHz,DMSO-d6)δ173.28,171.05,170.56,169.96,169.86,169.41,167.76,159.58,157.71,146.89,136.74,135.17,132.66,127.57,125.70,124.24,121.18,119.50,117.64,115.75,112.83,110.84,110.47,109.48,106.31,61.03,60.96,53.43,53.42,52.98,49.01(2C),32.61,31.45,29.06,28.97,26.63,25.22,22.63,9.11.HRMS(ESI):calcd for C40H44FN8O7[M+H]+:767.3311;found:767.3304.
实施例16
(Z)-2-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)辛基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A16)的合成
中间体II-10的合成:取I-2(500mg,1.81mmol),氨基烷烃酸类linker(1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA 10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
化合物A16的合成:取化合物II-10(80mg,0.19mmol),化合物VI(82mg,0.19mmol)以及PyBOP(150mg,0.29mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(140μL,0.76mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A16(52mg,yield:35%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.89(s,1H),9.25(s,1H),7.76(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.1Hz,1H),7.59(t,J=8.0Hz,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.93(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),6.53(t,J=5.9Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.51(s,4H),3.29(q,J=6.7Hz,2H),3.18(s,2H),2.94–2.86(m,1H),2.65–2.58(m,1H),2.59–2.51(m,4H),2.31(d,J=7.4Hz,2H),2.28(s,3H),2.09–1.96(m,2H),1.61–1.54(m,2H),1.52–1.46(m,2H),1.31(q,J=13.2,10.8Hz,6H).13C NMR(126MHz,DMSO-d6)δ173.27,171.07,170.56,169.99,169.87,169.42,167.76,159.58,157.71,146.89,136.73,135.17,132.65,127.58,125.70,124.27,121.19,119.50,117.64,115.73,113.01,110.83,110.47,109.47,106.51,61.13,60.22,55.38,53.47,53.02,49.01(2C),32.68,31.45,29.21,29.13,29.06,26.72,25.24,22.62,9.10.HR-MS(ESI):calcd for C41H46FN8O7[M+H]+:781.3468;found:781.3465.实施例17
(Z)-2-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)十一烷基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A17)的合成
中间体II-11的合成:取I-2(500mg,1.81mmol),氨基烷烃酸类linker(1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA 10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
化合物A17的合成:取化合物II-11(71mg,0.16mmol),化合物VI(66mg,0.16mmol)以及PyBOP(125mg,0.23mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(110μL,0.62mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A17(55mg,yield:41%)。1H NMR(500MHz,DMSO-d6)δ13.46(s,1H),11.11(s,1H),10.89(s,1H),9.27(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.65(d,J=3.1Hz,1H),7.58(t,J=7.8Hz,1H),7.08(d,J=8.6Hz,1H),7.02(d,J=7.1Hz,1H),6.93(t,J=9.2Hz,1H),6.84(dd,J=8.6,4.5Hz,1H),6.52(t,J=5.9Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.52(s,4H),3.29(t,J=6.8Hz,2H),3.20(s,2H),2.94–2.86(m,1H),2.61(s,1H),2.59–2.52(m,4H),2.29(d,J=10.0Hz,5H),2.10–1.99(m,2H),1.57(t,J=7.2Hz,2H),1.50–1.44(m,2H),1.35–1.31(m,2H),1.30–1.20(m,10H).13C NMR(126MHz,DMSO-d6)δ173.27,171.09,170.80,170.55,169.87,169.41,167.76,159.58,157.72,146.89,136.72,135.18,132.65,125.70,125.67,124.25,121.16,119.48,117.63,115.76,110.83,110.47,110.41,109.46,106.51,60.22(2C),53.43,52.99,49.01(2C),42.30,32.70,31.45,29.44,29.39,29.34,29.26,29.22,29.13,26.79,25.30,21.23,9.11.HR-MS(ESI):calcd for C44H52FN8O7[M+H]+:823.3938;found:823.3909.
实施例18
(Z)-2-(4-(12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)十二烷基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A18)的合成
中间体II-12的合成:取I-2(500mg,1.81mmol),氨基烷烃酸类linker(1.81mmol)以及DIPEA(650μL,3.62mmol)溶于DMA10mL中,然后将反应体系升温至80℃,在此条件下反应2h,TLC监控反应完成,将体系降至室温,然后倒入水中,乙酸乙酯(100mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
化合物A18的合成:取化合物II-12(150mg,0.32mmol),化合物VI(133mg,0.32mmol)以及PyBOP(250mg,0.48mmol)溶解于5mL N,N-二甲基甲酰胺中,搅拌状态下加入DIPEA(230μL,1.28mmol),该体系在室温下反应2h,LC-MS监控反应完成,向反应体系中加15mL水析出固体,抽滤,烘干得粗品,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A18(88mg,yield:33%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.10(s,1H),10.88(s,1H),9.24(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.0Hz,1H),7.58(t,J=8.6Hz,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.93(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),6.52(t,J=5.9Hz,1H),5.05(dd,J=12.7,5.5Hz,1H),3.51(s,4H),3.31–3.27(m,2H),3.18(s,2H),2.92–2.85(m,1H),2.61(d,J=3.3Hz,1H),2.59–2.52(m,4H),2.30(d,J=7.2Hz,2H),2.28(s,3H),2.10–1.99(m,2H),1.57(t,J=7.2Hz,2H),1.48(t,J=7.4Hz,2H),1.36–1.32(m,4H),1.28–1.22(m,10H).13C NMR(126MHz,DMSO-d6)δ173.26,171.08,170.79,170.55,169.87,169.41,167.76,159.58,157.72,146.89,136.72,135.18,132.65,127.58,125.69,124.26,121.16,119.48,117.62,115.75,113.01,112.82,110.82,109.46,106.51,61.08,60.22,53.45,53.00,49.01(2C),42.30,32.71,31.45,29.46,29.43,29.36,29.26,29.23,29.14,26.78,25.31,22.63,21.23,9.10.HR-MS(ESI):calcd for C45H54FN8O7[M+H]+:837.4093;found:837.4074.
实施例19
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A19)的合成
中间体II-13的合成:将化合物I-2(500mg,1.8mmol),哌啶-4-基甲醇(255μL,2.2mmol)以及DIPEA(1.6mL,9mmol)溶于5mL二甲亚砜中,将反应体系升温至80℃,在此条件下反应4h,LC-MS监控反应完成,将反应体系降至室温,然后倒入水中,乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
中间体III-9的合成:将II-13(540mg,1.45mmol)溶于15mL二氯甲烷中,然后缓慢加入戴斯-马丁试剂(1.24g,2.9mmol),室温下反应2h,LC-MS监控反应完成后,向反应体系中加入过量硫代硫酸钠饱和水溶液以及碳酸氢钠饱和水溶液,再搅拌10min,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,简单处理后可直接投下一步反应。
中间体VII的合成:取化合物VI(0.1g,0.24mmol)溶于10mL水中,再搅拌状态下加入饱和碳酸氢钠水溶液,直至体系呈碱性,然后向体系加入乙酸乙酯30mL,再搅拌0.5h左右,分液漏斗分层,再用乙酸乙酯(30mL×2)萃取,合并有机相,用水和盐水洗涤有机相,无水硫酸钠干燥,抽滤,浓缩滤液,即得化合物VII(0.06g,yield:65%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),10.90(s,1H),9.24(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.74(s,1H),7.65(d,J=3.2Hz,1H),6.94(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),3.11(s,2H),2.82(t,J=4.7Hz,4H),2.50–2.41(m,4H),2.28(s,3H),1.24(brs,1H).
化合物A19的合成:取化合物III-9(60mg,0.16mmol),化合物VII(75mg,0.195mmol)以及乙酸(1mg,0.016mmol)溶于5mL N,N-二甲基甲酰胺中,在室温下先搅拌10min,然后缓慢加入三乙酰氧硼氢化钠(42mg,0.195mmol),再在室温下反应,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A19(44mg,yield:37%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.09(s,1H),10.88(s,1H),9.19(s,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.69–7.65(m,2H),7.32(dd,J=7.8,5.4Hz,2H),6.93(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),5.09(dd,J=12.7,5.5Hz,1H),3.69(d,J=11.6Hz,2H),3.14(s,2H),2.92–2.83(m,3H),2.67–2.53(m,6H),2.49–2.37(m,3H),2.28(s,3H),2.23(s,2H),2.03(ddd,J=12.3,6.8,4.1Hz,1H),1.82(d,J=12.5Hz,2H),1.73(s,1H),1.41–1.22(m,3H).13C NMR(126MHz,DMSO-d6)δ173.25,170.48,169.87,167.56,166.74,159.59,157.72,150.64,136.17,135.19,134.16,127.50,125.62,124.35,120.60,119.13,116.74,115.79,114.78,113.02,112.83,110.48,106.51,106.30,64.35,61.43,53.79,53.45,51.48,51.46,51.43,49.25(2C),32.70,31.44,30.94(2C),22.56,8.98.HR-MS(ESI):calcd for C39H42FN8O6[M+H]+:737.3206;found:737.3196.实施例20
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A20)的合成
中间体II-14的合成:将化合物I-4(500mg,1.8mmol),哌啶-4-基甲醇(255μL,2.2mmol)以及DIPEA(1.6mL,9mmol)溶于5mL二甲亚砜中,将反应体系升温至80℃,在此条件下反应4h,LC-MS监控反应完成,将反应体系降至室温,然后倒入水中,乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,柱层析分离得化合物II-14(340mg,yield:81%)。1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.68(d,J=8.5Hz,1H),7.29(d,J=2.4Hz,1H),7.06(dd,J=8.6,2.4Hz,1H),4.95(dd,J=12.1,5.4Hz,1H),3.99(dt,J=13.3,3.3Hz,2H),3.55(d,J=6.3Hz,2H),3.00(ddd,J=15.3,12.0,2.7Hz,2H),2.91–2.77(m,3H),2.14(ddd,J=10.4,4.8,2.6Hz,1H),1.93–1.77(m,3H),1.37(td,J=12.4,4.0Hz,2H),1.27(t,J=7.1Hz,1H).
中间体III-10的合成:将II-14(210mg,0.57mmol)溶于10mL二氯甲烷中,然后缓慢加入DMP(480mg,1.13mmol),室温下反应2h,LC-MS监控反应完成后,向反应体系中加入过量硫代硫酸钠饱和水溶液以及碳酸氢钠饱和水溶液,再搅拌10min,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,然后柱层析分离,得产物III-10(190mg,yield:90%)。1H NMR(500MHz,CDCl3)δ9.74(d,J=0.9Hz,1H),8.09(s,1H),7.72(d,J=8.5Hz,1H),7.31(d,J=2.3Hz,1H),7.09(dd,J=8.6,2.4Hz,1H),4.96(dd,J=12.4,5.4Hz,1H),3.88(dt,J=13.4,4.3Hz,2H),3.20(ddd,J=13.4,10.5,3.1Hz,2H),2.95–2.72(m,4H),2.18–2.07(m,3H),1.85–1.77(m,2H).
化合物A20的合成:取化合物III-10(60mg,0.16mmol),化合物VII(75mg,0.195mmol)以及乙酸(1mg,0.016mmol)溶于5mL N,N-二甲基甲酰胺中,在室温下先搅拌10min,然后缓慢加入三乙酰氧硼氢化钠(42mg,0.195mmol),再在室温下反应,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A20(36mg,yield:30%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.08(s,1H),10.88(s,1H),9.18(s,1H),7.76(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.68–7.63(m,2H),7.31(d,J=2.3Hz,1H),7.23(dd,J=8.8,2.3Hz,1H),6.93(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.04(d,J=12.9Hz,2H),3.14(s,2H),2.96(t,J=12.5Hz,2H),2.91–2.84(m,1H),2.67–2.54(m,6H),2.45(s,3H),2.28(s,3H),2.21–2.15(m,2H),2.04–2.00(m,1H),1.80(d,J=13.2Hz,3H),1.27–1.12(m,3H).13CNMR(126MHz,DMSO-d6)δ173.24,170.55,169.87,168.10,167.69,167.42,157.72,155.48,135.19,134.51,127.58,125.66,125.45,124.31,120.61,119.14,118.04,117.82,115.79,113.02,110.48,108.18,106.51,106.30,64.13,61.44,53.75,53.43,49.22(2C),47.72,32.99,31.46,30.06(2C),22.67,22.52,14.42,8.97.HR-MS(ESI):calcd forC39H42FN8O6[M+H]+:737.3206;found:737.3193.
实施例21
(Z)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A21)的合成
中间体VIII-1的合成:取化合物VII(100mg,0.26mmol),tert-butyl4-oxopiperidine-1-carboxylate(80mg,0.40mmol)以及AcOH(1μL,0.03mmol)溶4mL二甲亚砜中,然后在25℃条件下搅拌10min,再加入三乙酰氧硼氢化钠(80mg,0.40mmol),再在25℃条件下反应2h,LC-MS监控反应完成,向反应体系中倒入20mL水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤真空除去溶剂,将粗产物用(乙酸乙酯:正己烷=5:1)打浆得产物VIII-1-Boc(126mg,yield:88%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),10.89(s,1H),9.23(d,J=37.4Hz,1H),7.77(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.62(dd,J=24.5,3.1Hz,1H),6.94(td,J=9.1,2.5Hz,1H),6.84(dd,J=8.4,4.5Hz,1H),4.02–3.88(m,2H),3.61(t,J=6.3Hz,2H),3.12(s,2H),2.92(d,J=12.1Hz,1H),2.77–2.54(m,8H),2.27(s,3H),1.75(d,J=12.4Hz,2H),1.40(s,9H),1.31–1.23(m,2H).VIII-1由VIII-1-Boc用TFA脱去Boc所得,直接投下一步反应。
化合物A21的合成:取化合物VIII-1(126mg,0.22mmol),化合物Ⅰ-4(130mg,0.44mmol)以及DIPEA(240μL,1.32mmol)溶于3mL二甲亚砜中,升温至80℃并在此条件下反应4h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A21(40mg,yield:25%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.10(s,1H),10.90(s,1H),9.19(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.73(s,1H),7.71–7.60(m,2H),7.33(d,J=2.3Hz,1H),7.25(dd,J=8.7,2.3Hz,1H),6.94(td,J=9.1,2.6Hz,1H),6.84(dd,J=8.5,4.6Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.08(d,J=12.7Hz,2H),3.11(s,2H),3.04–2.81(m,4H),2.67–2.51(m,10H),2.27(s,3H),2.04–1.98(m,1H),1.87(d,J=12.2Hz,2H),1.46(qd,J=12.2,11.8,3.6Hz,2H).13C NMR(126MHz,DMSO-d6)δ173.28,170.58,169.85,168.07,167.71,167.42,157.71,155.21,135.17,134.49,127.57,125.69,125.46,124.30,120.76,119.25,118.11,118.05,115.74,112.83,110.48,108.25,106.52,106.31,61.47,60.98,60.23,53.74,51.19,49.21(2C),47.05,31.45,27.73(2C),22.66,14.56,9.02.HR-MS(ESI):calcd for C38H39FN8O6[M+H]+:723.3049;found:723.3039.
实施例22
(Z)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)氮杂环丁烷-3-基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A22)的合成
中间体VIII-2的合成:取化合物VII(100mg,0.26mmol),tert-butyl3-oxoazetidine-1-carboxylate(70mg,0.40mmol)以及AcOH(1μL,0.03mmol)溶4mL二甲亚砜中,然后在25℃条件下搅拌10min,再加入三乙酰氧硼氢化钠(80mg,0.40mmol),再在25℃条件下反应2h,LC-MS监控反应完成,向反应体系中倒入20mL水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤真空除去溶剂,将粗产物用(乙酸乙酯:正己烷=5:1)打浆得产物VIII-2-Boc(80mg,yield:57%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),10.89(s,1H),9.29–9.14(m,1H),7.76(dd,J=9.4,2.6Hz,1H),7.73(d,J=2.1Hz,1H),7.64(dd,J=9.6,3.2Hz,1H),6.97–6.88(m,1H),6.84(dd,J=8.5,4.5Hz,1H),3.84(s,2H),3.66(s,2H),3.14(s,2H),3.06(dt,J=7.0,3.8Hz,2H),2.70(td,J=10.8,8.9,5.8Hz,2H),2.56(s,4H),2.41–2.34(m,1H),2.27(s,3H),1.38(s,9H).VIII-2由VIII-2-Boc用TFA脱去Boc所得,直接投下一步反应。
化合物A22的合成:取化合物VIII-2(82mg,0.15mmol),化合物Ⅰ-4(82mg,0.30mmol)以及DIPEA(160μL,0.90mmol)溶于3mL二甲亚砜中,升温至80℃并在此条件下反应4h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A22(31mg,yield:29%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.10(s,1H),10.90(s,1H),9.21(s,1H),7.77(dd,J=9.4,2.7Hz,1H),7.74(s,1H),7.71–7.62(m,2H),6.94(td,J=9.0,2.6Hz,1H),6.86–6.81(m,1H),6.82–6.78(m,1H),6.65(dd,J=8.5,2.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.11(t,J=7.8Hz,2H),3.86(dd,J=8.7,4.9Hz,2H),3.16(s,2H),2.91–2.84(m,1H),2.77–2.51(m,8H),2.48–2.40(m,2H),2.28(s,3H),2.12–1.97(m,2H).13C NMR(126MHz,DMSO-d6)δ173.28,170.59,169.86,167.93,167.62,159.57,157.71,155.38,135.17,134.29,127.57,125.62,125.31,124.31,120.82,119.30,117.32,115.75,114.64,112.83,110.48,106.52,106.32,104.94,61.36,60.23,55.55,54.60,52.97,49.59,49.17,31.45,22.67,14.56,9.04.HR-MS(ESI):calcd for C36H35FN8O6[M+H]+:695.2736;found:695.2726.
实施例23
(Z)-2-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-7-氮杂螺环[3.5]壬-2-基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A23)的合成
中间体VIII-3的合成:取化合物VII(100mg,0.26mmol),tert-butyl2-oxo-7-azaspiro[3.5]nonane-7-carboxylate(96mg,0.40mmol)以及AcOH(1μL,0.03mmol)溶4mL二甲亚砜中,然后在25℃条件下搅拌10min,再加入三乙酰氧硼氢化钠(80mg,0.40mmol),再在25℃条件下反应2h,LC-MS监控反应完成,向反应体系中倒入20mL水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤真空除去溶剂,将粗产物用(乙酸乙酯:正己烷=5:1)打浆得产物VIII-3-Boc(75mg,yield:47%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),10.91(s,1H),9.31(s,1H),7.77(dd,J=9.4,2.6Hz,1H),7.73(s,1H),7.64(d,J=3.2Hz,1H),6.94(td,J=9.4,8.9,2.6Hz,1H),6.85(dd,J=8.4,4.5Hz,1H),3.29(q,J=5.7Hz,5H),3.20(d,J=6.8Hz,3H),3.09–2.92(m,2H),2.81(s,2H),2.75–2.62(m,2H),2.28(s,3H),2.19–2.00(m,4H),1.91(s,2H),1.53–1.45(m,4H),1.39(s,9H).VIII-3由VIII-3-Boc用TFA脱去Boc所得,直接投下一步反应。
化合物A23的合成:取化合物VIII-3(143mg,0.23mmol),化合物Ⅰ-4(130mg,0.46mmol)以及DIPEA(250μL,1.38mmol)溶于3mL二甲亚砜中,升温至100℃并在此条件下反应4h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A23(21mg,yield:12%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.10(s,1H),10.90(s,1H),9.20(s,1H),7.77(d,J=9.4Hz,1H),7.74(s,1H),7.65(d,J=10.2Hz,2H),7.32(s,1H),7.24(d,J=8.8Hz,1H),6.94(t,J=9.0Hz,1H),6.84(dd,J=8.6,4.7Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),3.47(d,J=6.4Hz,4H),3.14(s,2H),2.89(t,J=13.5Hz,1H),2.67–2.51(m,8H),2.27(s,3H),2.04–1.95(m,4H),1.70–1.45(m,8H).13C NMR(126MHz,DMSO-d6)δ173.29,170.60,169.86,168.09,167.69,167.41,157.71,155.36,135.17,134.50,127.57,125.70,125.46,124.31,120.65,119.20,118.08,117.86,115.76,113.03,110.48,108.23,106.52,106.33,61.43,60.24,54.89,53.03,49.78,49.19(2C),45.08,44.86,36.68,31.61(2C),31.45,29.52,22.66,14.45,9.00.HR-MS(ESI):calcd for C41H43FN8O6[M+H]+:763.3362;found:763.3351.
实施例24
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)氮杂环丁烷-3-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A24)的合成
中间体VIII-4的合成:取化合物VII(100mg,0.26mmol),tert-butyl3-formylazetidine-1-carboxylate(75mg,0.40mmol)以及AcOH(1μL,0.03mmol)溶4mL二甲亚砜中,然后在25℃条件下搅拌10min,再加入三乙酰氧硼氢化钠(80mg,0.40mmol),再在25℃条件下反应2h,LC-MS监控反应完成,向反应体系中倒入20mL水中,乙酸乙酯(30mL×2)萃取,合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤真空除去溶剂,将粗产物用(乙酸乙酯:正己烷=5:1)打浆得产物VIII-4-Boc(95mg,yield:66%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),10.91(s,1H),9.27(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.74(s,1H),7.65(d,J=3.1Hz,1H),6.94(td,J=9.5,9.1,2.6Hz,1H),6.85(dd,J=8.4,4.5Hz,1H),3.95–3.79(m,4H),3.65–3.51(m,4H),3.24(dt,J=19.8,6.6Hz,2H),2.69–2.55(m,4H),2.28(s,2H),1.92(s,1H),1.38(s,9H),1.25(q,J=4.1,2.8Hz,2H).VIII-4由VIII-4-Boc用TFA脱去Boc所得,直接投下一步反应。
化合物A23的合成:取化合物VIII-4(147mg,0.25mmol),化合物Ⅰ-4(140mg,0.50mmol)以及DIPEA(310μL,1.75mmol)溶于4mL二甲亚砜中,升温至80℃并在此条件下反应4h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A24(28mg,yield:16%)。1H NMR(500MHz,DMSO-d6)δ13.45(s,1H),11.09(s,1H),10.90(s,1H),9.20(s,1H),7.77(dd,J=9.4,2.6Hz,1H),7.74(s,1H),7.70–7.61(m,2H),6.93(td,J=9.1,2.7Hz,1H),6.84(dd,J=8.4,4.4Hz,1H),6.77(d,J=2.1Hz,1H),6.64(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.7,5.5Hz,1H),4.13(t,J=8.1Hz,2H),3.73–3.66(m,2H),3.14(s,2H),3.09–2.94(m,2H),2.94–2.81(m,2H),2.70–2.52(m,10H),2.28(s,3H),2.04–2.00(m,1H).13C NMR(126MHz,DMSO-d6)δ173.28,170.59,169.86,167.95,167.64,159.57,157.71,155.62,135.17,134.27,127.57,125.69,125.26,124.30,120.73,119.23,117.11,115.77,114.49,113.02,112.83,110.48,106.52,106.32,62.19,61.40,60.23,56.14,55.39,53.33,49.16,31.45,27.49,22.68,21.24,14.56,9.02.HR-MS(ESI):calcd for C37H37FN8O6[M+H]+:709.2893;found:709.2894.
实施例25
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(A25)的合成
中间体Ⅱ-15的合成:将化合物I-5(180mg,0.62mmol),哌啶-4-基甲醇(85mg,0.74mmol)以及DIPEA(500μL,3.10mmol)溶于5mL二甲亚砜中,将反应体系升温至80℃,在此条件下反应4h,LC-MS监控反应完成,将反应体系降至室温,然后倒入水中,乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,浓缩有机相得II-15(233mg,yield:96%)。
中间体Ⅲ-11的合成:将II-15(233mg,0.60mmol)溶于10mL二氯甲烷中,然后缓慢加入DMP(507mg,1.20mmol),室温下反应4h,LC-MS监控反应完成后,向反应体系中加入过量硫代硫酸钠饱和水溶液以及碳酸氢钠饱和水溶液,再搅拌10min,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤,真空除去溶剂,然后柱层析分离(DCM:MeOH=100:1~20:1),得产物III-11(106mg,yield:46%)。HR-MS(ESI):calcd for C19H18FN3O5[M+H]+:388.12;found:388.13.
化合物A25的合成:取化合物III-11(106mg,2.73mmol),化合物Ⅶ(87mg,2.27mmol)以及乙酸(13μL,2.27mmol)溶于5mL N,N-二甲基甲酰胺中,在室温下先搅拌20min,然后缓慢加入三乙酰氧硼氢化钠(58mg,2.73mmol),再在室温下反应,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品橙黄色固体粉末A25(45mg,yield:26%)。1H NMR(500MHz,DMSO-d6)δ13.44(s,1H),11.12(s,1H),10.89(s,1H),9.19(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.74–7.69(m,2H),7.66(d,J=3.1Hz,1H),7.44(d,J=7.4Hz,1H),6.94(ddd,J=9.6,8.4,2.6Hz,1H),6.84(dd,J=8.5,4.5Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),3.61(d,J=11.2Hz,2H),3.13(s,2H),2.94–2.85(m,3H),2.62–2.51(m,6H),2.48(d,J=4.4Hz,3H),2.28(s,3H),2.22(d,J=7.1Hz,2H),2.07–2.01(m,1H),1.83(d,J=12.4Hz,3H),1.32–1.21(m,3H).13C NMR(126MHz,DMSO-d6)δ173.23,170.39,169.87,167.69,167.18,166.71,166.69,159.59,158.72,157.73,156.70,146.38,146.31,135.19,129.27,129.26,127.58,127.50,125.68,125.62,124.32,123.29,123.21,120.57,119.12,115.79,115.76,114.14,113.02,112.83,112.44,112.24,110.48,110.41,106.52,106.31,64.22,61.46,53.79,53.43,50.40,49.51,32.75,31.43,30.70,22.56,8.97.HR-MS(ESI):calcd for C39H40F2N8O6[M+H]+:755.30;found:755.31.
实施例26
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺(A26)的合成
中间体Ⅹ的合成:将化合物Ⅸ(320mg,0.90mmol)和1-叔丁氧羰基哌嗪(860mg,3.9mmol)用N,N-二甲基甲酰胺(10mL)溶解,升温至50℃反应12h,LC-MS监控反应完成,向反应体系中加入60mL水,有固体析出即产物,抽滤,烘干得棕黄色固体Ⅹ(140mg,yield:31%)。
中间体Ⅺ的合成:取化合物Ⅹ(140mg,0.28mmol)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得棕黄色化合物Ⅺ(74mg,yield:66%)。
化合物A26的合成:取化合物III-10(60mg,0.22mmol),化合物XI(74mg,0.19mmol)以及乙酸(11μL,0.19mmol)溶于5mL N,N-二甲基甲酰胺中,在室温下先搅拌20min,然后缓慢加入三乙酰氧硼氢化钠(50mg,0.195 0.22mmol),再在室温下反应,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A26(40mg,yield:29%)。1H NMR(500MHz,DMSO-d6)δ13.61(s,1H),11.08(s,1H),10.82(s,1H),9.01(d,J=31.9Hz,1H),7.73–7.61(m,3H),7.32(s,1H),7.23(s,1H),6.93–6.87(m,1H),6.84(dd,J=8.4,4.6Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.05(d,J=12.5Hz,2H),3.15(s,2H),2.97(t,J=12.2Hz,2H),2.87(d,J=16.8Hz,1H),2.69–2.52(m,7H),2.19(d,J=14.8Hz,7H),2.04–1.98(m,1H),1.81(d,J=13.1Hz,2H),1.51–1.00(m,7H).13C NMR(126MHz,DMSO-d6)δ173.27,170.58,169.97,168.11,167.44,157.71,155.46,134.71,134.52,132.72,131.14,129.98,128.04,127.94,127.86,125.48,124.94,122.06,118.07,117.85,113.38,112.31,112.12,110.34,110.27,108.22,106.02,105.81,53.28,49.21,47.68,32.01,31.62,31.46,29.99,29.90,29.48,22.67,12.31,9.65.HR-MS(ESI):calcd for C40H43FN8O6[M+H]+:751.33;found:751.34.
实施例27
(Z)-2-(2,6-二氧代哌啶-3-基)-5-(4-((4-(5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰基)哌嗪-1-基)甲基)哌啶-1-基)异吲哚-1,3-二酮(A27)的合成
中间体ⅫⅠ-1的合成:取化合物Ⅻ(1.65g,5.63mmol)溶解于8mL N,N-二甲基甲酰胺中,再向其中加入DIPEA(1.5mL,8.45mmol),HATU(2.14g,5.63mmol),在室温下搅拌20min后再向体系中加入N-Boc哌嗪(1.05g,5.63mmol)的DMF溶液,接着体系在室温下反应12h,LC-MS监测反应完成,向反应体系中加40mL水析出固体,抽滤,烘干得黄色粉末ⅫⅠ-1-Boc(1.57g,yield:67%)化合物ⅩIII-1-Boc(1.50g)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得棕黄色化合物ⅪII-1(0.80g,yield:68%)。1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),10.95(s,1H),7.78(dd,J=9.4,2.6Hz,1H),7.73(s,1H),6.95(td,J=9.5,9.0,2.6Hz,1H),6.86(dd,J=8.4,4.5Hz,1H),3.69(s,4H),2.32(d,J=16.5Hz,6H).
化合物A27的合成:取化合物III-10(950mg,2.61mmol),化合物XIII-1(800mg,2.17mmol)以及乙酸(125μL,2.17mmol)溶于5mL N,N-二甲基甲酰胺中,再向体系中加入5mL三乙胺,在室温下先搅拌30min,然后缓慢加入三乙酰氧硼氢化钠(550mg,2.61mmol),再在室温下反应12h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A27(400mg,yield:26%)。1H NMR(500MHz,DMSO-d6)δ13.64(s,1H),11.10(s,1H),10.90(s,1H),7.76(dd,J=9.3,2.6Hz,1H),7.71(s,1H),7.65(d,J=8.5Hz,1H),7.31(d,J=2.3Hz,1H),7.23(dd,J=8.9,2.4Hz,1H),6.92(dd,J=9.2,2.5Hz,1H),6.85(dd,J=8.5,4.5Hz,1H),5.07(dd,J=12.8,5.5Hz,1H),2.55–1.74(m,25H),1.36–1.04(m,5H).13C NMR(126MHz,DMSO-d6)δ173.29,170.82,170.59,170.02,168.10,167.43,159.63,157.77,155.41,135.06,134.50,127.62,126.51,125.47,125.25,118.10,113.00,110.53,108.27,106.51,106.31,60.23,49.21,47.61,31.46,29.98,22.66,21.24,14.56,13.00,10.58.HR-MS(ESI):calcd for C39H40FN7O6[M+H]+:722.30;found:722.31.
实施例28
(Z)-N-(2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)乙基)-5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(A28)的合成
中间体ⅫⅠ-2的合成:取化合物Ⅻ(300mg,1.00mmol)溶解于6mL N,N-二甲基甲酰胺中,再向其中加入DIPEA(261μL,1.50mmol),HATU(380mg,1.00mmol),在室温下搅拌20min后再向体系中加入4-N-(2-胺乙基)-1-N-BOC-哌嗪(230mg,1.00mmol)的DMF溶液,接着体系在室温下反应12h,LC-MS监测反应完成,向反应体系中加40mL水析出固体,抽滤,烘干得黄色粉末ⅫⅠ-2-Boc(125mg,yield:25%)化合物ⅩIII-2-Boc(120mg)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得棕黄色化合物ⅪII-2(65mg,yield:64%)。1H NMR(500MHz,DMSO-d6)δ13.75(s,1H),10.96(s,1H),7.85–7.64(m,2H),6.94(td,J=9.0,2.5Hz,1H),6.86(dd,J=8.5,4.4Hz,1H),4.02–3.24(m,16H),2.48(s,3H).
化合物A28的合成:取化合物III-10(70mg,0.18mmol),化合物XIII-2(65mg,0.15mmol)以及乙酸(20μL,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,再向体系中加入3mL三乙胺,在室温下先搅拌30min,然后缓慢加入三乙酰氧硼氢化钠(50mg,0.18mmol),再在室温下反应12h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A28(35mg,yield:30%)。1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),11.09(s,1H),10.90(s,1H),7.82–7.72(m,2H),7.65(d,J=8.5Hz,1H),7.46(d,J=5.8Hz,1H),7.31(d,J=2.3Hz,1H),7.23(dd,J=8.7,2.3Hz,1H),6.96–6.90(m,1H),6.85(dd,J=8.4,4.5Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.04(d,J=12.6Hz,2H),3.00–2.87(m,3H),2.62–2.51(m,6H),2.50(s,3H),2.45(d,J=7.4Hz,9H),2.14(s,2H),2.04–1.98(m,1H),1.79(d,J=12.8Hz,3H),1.14(q,J=13.4,12.0Hz,2H).13CNMR(126MHz,DMSO-d6)δ173.28,170.59,170.04,168.11,167.44,164.93,159.63,157.77,155.47,137.09,134.98,134.51,130.64,127.68,127.60,126.28,125.46,125.35,121.21,118.02,117.80,115.09,115.07,112.93,112.73,110.51,110.44,108.17,106.50,106.29,64.21,57.22,53.70,53.10,49.20,47.70,36.54,32.90,31.46,30.07,22.67,13.81,11.10.HR-MS(ESI):calcd for C41H45FN8O6[M+H]+:765.34;found:765.35.
实施例29
(Z)-N-(3-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)丙基)-5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(A29)的合成
中间体ⅫⅠ-3的合成:取化合物Ⅻ(300mg,1.00mmol)溶解于6mL N,N-二甲基甲酰胺中,再向其中加入DIPEA(261μL,1.50mmol),HATU(380mg,1.00mmol),在室温下搅拌20min后再向体系中加入4-N-(2-胺乙基)-1-N-BOC-哌嗪(230mg,1.00mmol)的DMF溶液,接着体系在室温下反应12h,LC-MS监测反应完成,向反应体系中加40mL水析出固体,抽滤,烘干得黄色粉末ⅫⅠ-3-Boc(200mg,yield:37%)化合物ⅩIII-3-Boc(200mg)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得棕黄色化合物ⅪII-3(120mg,yield:74%)。1H NMR(500MHz,DMSO-d6)δ13.72(s,1H),10.95(s,1H),7.78(dd,J=9.4,2.6Hz,1H),7.73(s,1H),6.96–6.91(m,1H),6.86(dd,J=8.4,4.5Hz,1H),3.70(d,J=12.9Hz,1H),3.53(s,1H),3.48–3.41(m,2H),3.25–3.06(m,3H),2.98(d,J=9.0Hz,1H),2.45(d,J=9.7Hz,6H),2.03–1.91(m,3H),1.42(s,4H).
化合物A29的合成:取化合物III-10(130mg,0.18mmol),化合物XIII-3(120mg,0.15mmol)以及乙酸(17μL,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,再向体系中加入3mL三乙胺,在室温下先搅拌30min,然后缓慢加入三乙酰氧硼氢化钠(74mg,0.18mmol),再在室温下反应12h,LC-MS监控反应完成,将反应液倒入水中,乙酸乙酯萃取,柱层析分离(DCM:MeOH=100:1~30:1)得纯品棕黄色固体粉末A29(130mg,yield:57%)。1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),11.09(s,1H),10.90(s,1H),7.77(dd,J=9.4,2.6Hz,1H),7.72(s,1H),7.65(d,J=8.4Hz,1H),7.30(s,1H),7.22(d,J=8.7Hz,1H),6.93(td,J=9.0,2.6Hz,1H),6.85(dd,J=8.4,4.5Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.04(s,2H),3.25(q,J=6.6Hz,2H),2.98–2.85(m,3H),2.62–2.51(m,4H),2.50(s,2H),2.43(d,J=8.8Hz,13H),2.12(s,2H),2.04–1.98(m,1H),1.77(d,J=13.1Hz,3H),1.67(s,2H),1.13(d,J=13.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ173.29,170.60,170.04,168.11,167.44,165.19,159.63,157.77,155.45,136.83,134.97,134.50,130.67,127.67,127.60,126.26,125.46,125.37,121.47,118.03,117.81,115.01,112.93,112.73,110.52,110.45,108.19,106.50,106.29,49.19,47.68,37.54,32.87,31.45,30.02,22.66,13.79,11.04.HR-MS(ESI):calcd forC41H45FN8O6[M+H]+:778.36;found:778.36.
实施例30
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺盐酸盐(A20.HCl)的合成
化合物A20盐酸盐的合成:取化合物A20(0.05g,0.07mmol)用少量二氯甲烷和甲醇的混合体系溶解,再加入盐酸乙酸乙酯溶液,密封,在室温下反应,TLC监控反应完成,真空浓缩除去溶剂,再用乙酸乙酯(10mL)搅拌0.5h,真空浓缩除去乙酸乙酯,最后用大量乙酸乙酯打浆,抽滤,滤饼用大量乙酸乙酯洗涤,再用少量正己烷洗,油泵拉干。得红棕色化合物A20.HCl(0.04g,yield:73%)。1H NMR(500MHz,DMSO-d6)δ13.54(s,1H),11.08(s,1H),10.94(s,1H),10.34(s,1H),7.77(dd,J=9.3,2.6Hz,1H),7.75–7.69(m,2H),7.67(d,J=8.5Hz,1H),7.36(d,J=2.3Hz,1H),7.28(dd,J=8.7,2.3Hz,1H),6.95(td,J=9.1,2.6Hz,1H),6.86(dd,J=8.4,4.5Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.31(s,2H),3.83–3.74(m,6H),3.45(s,2H),3.13(s,2H),3.00(t,J=12.0Hz,2H),2.93–2.86(m,1H),2.62–2.51(m,4H),2.35(s,3H),2.18(s,1H),2.05–1.97(m,3H),1.29(q,J=10.5,8.9Hz,2H).
实施例31
化合物对人源AML细胞株的增殖抑制活性
实验方法:人源急性髓系白血病MV-4-11、MOLM-13是FLT3突变细胞株。采用CCK-8方法测定化合物对MV-4-11和MOLM-13的体外抗增殖活性:用培养基2倍梯度稀释受试化合物至终浓度的两倍,取200μL至2mL EP管中备用。取适量处于对数生长期的细胞重悬于培养基中,等体积加入到含有受试化合物的培养基中,上下颠倒10次混匀,依次加入96孔板中,每孔100μL。于37℃、5% CO2孵箱培养48h后,每孔加入10μL CCK-8,继续孵育2h。酶标仪读取OD450吸光度值,重复三次实验。采用Graphpad Prism 5软件分析处理数据,求得IC50。
结果显示:烷基连接剂优于聚乙二醇(PEG)和烷基酰胺连接剂,具有8或9个原子长度连接链的化合物对人源AML细胞的增殖抑制活性较强,具有杂环的刚性链的化合物的活性显著提高,其中,化合物A20对MV4-11和MOLM-13细胞的抗增殖活性最强,IC50值分别为39.9nM和169.9nM。
表1.实施例化合物A1-A24对人源AML细胞的增殖抑制活性
表2.实施例化合物A25-A30对人源AML细胞的增殖抑制活性
实施例32
化合物对MV-4-11、MOLM-13细胞中FLT3蛋白的降解作用
实验方法:分别用溶剂对照DMSO,化合物100nM处理对数生长期的MV-4-11、MOLM-13细胞,于37℃、5% CO2孵箱培养24h后,用RIPA裂解液裂解细胞收取蛋白并超声,WesternBlot检测细胞FLT3蛋白的表达情况。
结果显示:化合物能显著降解MV-4-11、MOLM-13细胞中FLT3蛋白,其中A10、A19、A20、A26、A28表现出较强的FLT3降解活性(图2)。
实施例33
化合物A20、A26、A28在MV-4-11裸鼠皮下移植瘤模型上的抗肿瘤效果
实验方法:MV-4-11细胞体外扩增培养,取适量处于对数生长期的细胞重悬于无血清IMDM培养基与Matrigel(1:1)混悬液中,无菌条件下制备成5×106/100μL细胞悬液,用注射器将100μL细胞悬液接种于雄性Balb/c裸小鼠前左肢腋窝皮下;待肿瘤体积生长至100-200mm3时,选取肿瘤大小适中的动物随机分组,每组6只;分别为空白溶剂对照组、A20(5mg/kg/d)组、A26(5mg/kg/d)组、A28(5mg/kg/d)组;每天灌胃给药一次,给药12天;给药期间,每天测量裸小鼠体重和瘤径;实验结束后颈椎脱臼处死,取瘤称重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,a表示肿瘤长径;b表示肿瘤短径。
结果显示:在MV-4-11裸鼠皮下移植瘤模型上,连续给药12天,A20、A26、A28均能有效抑制肿瘤的生长,并且对小鼠体重没有影响。A20、A26与A28给药组的抑瘤率分别为98.57%、82.73%和65.07%。
表4.A20在MV-4-11裸鼠皮下移植瘤模型上的抗肿瘤效果
*,p<0.05;**,p<0.01;***,p<0.001(与溶剂对照比较)。
实施例34
化合物A20在MV-4-11裸鼠皮下移植瘤模型上的抗肿瘤效果
实验方法:MV-4-11细胞体外扩增培养,取适量处于对数生长期的细胞重悬于无血清IMDM培养基与Matrigel(1:1)混悬液中,无菌条件下制备成5×106/100μL细胞悬液,用注射器将100μL细胞悬液接种于雄性Balb/c裸小鼠前左肢腋窝皮下;待肿瘤体积生长至100-200mm3时,选取肿瘤大小适中的动物随机分组,每组6只;分别为空白溶剂对照组、A20(1.25mg/kg/d)组、A20(2.5mg/kg/d)组、A20(5mg/kg/d)组、A20(10mg/kg/d)组、PX-A13(1.6mg/kg/d)组;每天灌胃给药一次,给药12天。给药期间,每天测量裸小鼠体重和瘤径;实验结束后颈椎脱臼处死,取瘤称重;肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,a表示肿瘤长径;b表示肿瘤短径。
结果显示:在MV-4-11裸鼠皮下移植瘤模型上,连续给药12天,A20能够剂量依赖性地抑制肿瘤的生长,并且对小鼠体重没有影响;其中1.25mg/kg/d低剂量组的抑瘤率为51.43%,2.5mg/kg/d剂量下的抑瘤率达到84.34%,明显优于相同摩尔剂量下(1.6mg/kg/d)化合物PX-A13的抑瘤率(39.76%);5mg/kg/d的剂量可使部分肿瘤消失,10mg/kg/d的剂量8天即可使全部肿瘤消失。
表4.A20在MV-4-11裸鼠皮下移植瘤模型上的抗肿瘤效果
*,p<0.05;**,p<0.01;***,p<0.001(与溶剂对照比较)。
实施例35
A20在Sunitinib或Quizartinib耐药的MOLM-13细胞上的增殖抑制活性
实验方法:通过药物持续诱导三个月以上构建对FLT3抑制剂耐药的AML细胞株,其中MOLM-13-Suni-R、MOLM-13-Quiz-R是对FLT3抑制剂Sunitinib或Quizartinib耐药的细胞株;采用CCK-8方法测定化合物A20对MOLM-13-Suni-R和MOLM-13-Quiz-R的体外抗增殖活性:用培养基2倍梯度稀释受试化合物至终浓度的两倍,取200μL至2mL EP管中备用;取适量处于对数生长期的细胞重悬于培养基中,等体积加入到含有受试化合物的培养基中,上下颠倒10次混匀,依次加入96孔板中,每孔100μL;于37℃、5% CO2孵箱培养48h后,每孔加入10μL CCK-8,继续孵育2h;酶标仪读取OD450吸光度值,重复三次实验;采用Graphpad Prism5软件分析处理数据,求得IC50。
结果显示:MOLM-13细胞在药物诱导后对Sunitinib或Quizartinib产生耐药性,FLT3抑制剂PX-A13对这两种耐药细胞系也表现出较弱的抗增殖活性;然而,化合物A20对Sunitinib或Quizartinib耐药细胞仍表现出较强的抗增殖活性,IC50值分别为147nM和483nM(表5)。
表5.A20在Sunitinib或Quizartinib耐药的MOLM-13细胞上的增殖抑制活性
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理前提下的若干改进和润饰,应视为本发明的保护范围。
Claims (10)
1.一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,其特征在于,所述化合物的化学结构式如式(I)所示:
其中:
R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或氨基中的一种或几种;
R2选自氢原子、甲基或卤代甲基;
R3选自氢原子或卤素;
R4选自氢原子或与相邻的碳形成羰基;
X选自-NHCO-、-CONH-或-NH-;
n是0-6;
Linker选自
上式中,m取值是1-12。
2.根据权利要求1所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,其特征在于,
R1选自氢原子、卤代烷基或氨基中的一种或几种;
R2选自氢原子或卤代甲基;
R3选自氢原子;
R4选自氢原子。
3.根据权利要求1所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,其特征在于,
X选自-NHCO-或-NH-;
n是3;
Linker选自
上式中,m取值是6。
4.根据权利要求1所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,其特征在于,所述的化合物选自:
(Z)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(2-(3-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-3-氧丙氧基)乙基)乙酰胺;
(Z)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(2-(3-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧代乙基)哌嗪-1-基)-3-氧代丙氧基)乙基)乙酰胺;
(Z)-2-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(3-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-N-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)-9-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)壬酰胺;
(Z)-2-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)壬基哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-5-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-5-氧戊酰胺;
(Z)-N-(2-((2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-6-(4-(2-((5-((5-氟-2-氧异代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-6-氧己酰胺;
(Z)-N-(2-((2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-7-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-7-氧庚酰胺;
(Z)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-8-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-8-氧辛酰胺;
(Z)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-9-(4-(2-((5-((5-氟-2-氧代异、吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-9-氧壬酰胺;
(Z)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)-10-(4-(2-((5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)氨基)-2-氧乙基)哌嗪-1-基)-10-氧葵酰胺;
(Z)-2-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)己基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)庚酰)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)辛基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)十一烷基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)十二烷基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)氮杂环丁烷-3-基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-7-氮杂螺环[3.5]壬-2-基)哌嗪-1-基)-N-(5-(5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)氮杂环丁烷-3-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-N-(5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺;
(Z)-2-(2,6-二氧代哌啶-3-基)-5-(4-((4-(5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰基)哌嗪-1-基)甲基)哌啶-1-基)异吲哚-1,3-二酮;
(Z)-N-(2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)乙基)-5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺;
(Z)-N-(3-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)丙基)-5-((5-氟-2-氧代吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺。
5.如权利要求1-4任意一项所述的吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐的制备方法,其特征在于,其具体步骤如下:
6.一种药物组合物,包括权利要求1-4中任一权利要求中所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐。
7.如权利要求1-4中任一项所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐在制备FLT3蛋白降解剂中的用途。
8.如权利要求1-4中任一项所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,或根据权利要求6所述的药物组合物在制备用于治疗和/或预防与FLT3表达异常引起的相关疾病的药物中的用途。
9.如权利要求1-4中任一项所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,或根据权利要求6所述的药物组合物在制备用于治疗急性髓系白血病的药物中的用途。
10.如权利要求1-4中任一项所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐,或根据权利要求6所述的药物组合物在制备治疗FLT3抑制剂耐药的急性髓系白血病药物中的用途。
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