CN110467637A - 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用 - Google Patents
一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用 Download PDFInfo
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- CN110467637A CN110467637A CN201810728287.8A CN201810728287A CN110467637A CN 110467637 A CN110467637 A CN 110467637A CN 201810728287 A CN201810728287 A CN 201810728287A CN 110467637 A CN110467637 A CN 110467637A
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Abstract
本发明的目的在于解决现有技术中激酶抑制剂药物耐药的问题,提供了一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用,具体涉及式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,其制备方法及其在制备作为激酶抑制剂的药物中的应用。本发明化合物对突变型EGFRT790M及EGFRC797S激酶均具有良好的抑制活性,同时展示出对野生型EGFR激酶也具有适度的抑制活性。
Description
技术领域
本发明属于医药技术领域,涉及一种双氨基取代的氯代嘧啶类化合物、制备方法及其应用。
背景技术
蛋白激酶是细胞生命活动重要的信号使者,可催化将ATP末端的γ-磷酸基团转移至底物氨基酸残基(丝氨酸、苏氨酸、酪氨酸)中的羟基受体上,从而激活目标蛋白(JohnsonL.N.,and Lewis R.J.,Structural basis for control by phosphorylation,Cheminform,2001,101,2209.)。蛋白激酶参与了众多的生理过程,包括细胞增殖、存活、凋亡、代谢、转录以及分化等(Adams J.A.,Kinetic and catalytic mechanismsof proteinkinases,Chemical reviews,2001,101,2271.)。在人体现有药物靶点中,蛋白激酶家族成员占比高达10%(Santos R.,Ursu O.,Gaulton A.,et al.,A comprehensive map ofmolecular drug targets,Nature Reviews Drug Discovery,2017,16,19.)。
表皮生长因子受体(ErbB)酪氨酸激酶可通过多种途径调节细胞增殖、迁移、分化、凋亡以及细胞移动。在多种形式的恶性肿瘤中,ErbB家族成员以及其部分配体通常过表达、扩增或突变,这使其成为重要的治疗靶标。该家族蛋白激酶包括:ErbB1/EGFR/HER1、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。其中EGFR是开发非小细胞肺癌的重要靶点(DienstmannR.,et.al.,Personalizing Therapy with Targeted Agents in Non-Small Cell LungCancer,ONCOTARGET,2001,2(3),165.)。
吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)是第一代靶向EGFR的可逆型激酶抑制剂,用于治疗非小细胞癌。该类抑制剂同时对野生型和激活突变型EGFR具有抑制作用,且在临床上取得了较大的成功,但是受体患者服用一段时间后耐药性的出现,尤其是T790M突变导致的耐药性使疗效降低或失效。第二代EGFR抑制剂阿法替尼(Afatinib)为非可逆型抑制剂,其含有迈克尔受体,可与位于ATP结合口袋入口处的半胱氨酸残基(Cys797)发生共价键结合,该抑制剂针对T790M突变型EGFR激酶和野生型EGFR激酶均表现出极强的活性,且对于T790M突变型EGFR激酶的抑制活性高于野生型EGFR激酶,这使得该药物临床应用中治疗窗口较窄,使用效果并不理想(Camidge,D.R.,et.al.,Acquiredresistance to TKIs in solid tumours:learning from lung cancer.Nature ReviewsClinical Oncology,2014,11,473.)。第三代的EGFR激酶抑制剂奥希替尼(Osimertinib)和奥莫替尼(Olmutinib)实现了对T790M突变型EGFR激酶相比野生型EGFR激酶的高选择性抑制,拉大了临床使用窗口,实现了对T790M突变病人的有效治疗。不幸的是,三代EGFR激酶抑制剂在临床上使用一段时间后也产生了耐药现象。其原因之一,是由于EGFR产生了C797S的二次突变。现有三代小分子EGFR抑制剂与靶标的作用机制是药物分子与EGFR的Cys797形成共价结合。但病人体内发生C797S的二次突变时,药物分子丧失了与Cys797的共价结合,导致药物的失效(Harun Patel.,et.al.,2017,Recent updates on third generation EGFRinhibitors and emergence of fourth generation EGFR inhibitors to combat C797Sresistance,Eur J Med Chem.,2017,142,32)。基于此,开发具有对T790M突变型EGFR激酶良好的抑制活性,同时具有对C797S突变型EGFR激酶良好抑制活性的新型药物分子具有重要意义。
Brigatinib是一种靶向的ALK抑制剂,由Ariad医药公司研发并于2017年获美国FDA批准上市用于治疗ALK阳性的非小细胞肺癌。根据文献报道,Brigatinib对C797S突变型EGFR激酶具有一定的抑制作用。
从蛋白质数据库(RCSB Protein Data Bank)中的晶体结构(5J7H)得知,Brigatinib化合物结构中的哌啶环在与ALK蛋白的相互作用中与其相连接的苯环形成了近于90度的二面角。然而,哌啶环中的氮原子与其相连接的苯环所形成的共轭体系使得哌啶环倾向于与其相连接的苯环形成近于0度的二面角。
如上述化合物结构(A)所示,在苯环的临位上引入取代集团(诸如甲氧基等)将有助于哌啶环与苯环之间的转置,使其化合物三维结构更有利于与ALK蛋白形成相互作用。这种结构修饰将会大大增加化合物(A)以及类似化合物对ALK蛋白的生物活性。出于同一道理,化合物(A)以及类似化合物对C797S突变的EGFR的生物活性也将大大提高。
发明内容
本发明一个目的在于解决现有技术中激酶抑制剂药物耐药和不良反应的问题,提供一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
式(I)中,
X为CH或N;
Y为CH或N;
R1为-H,-CF3,-CH2CF3,C1-C6烷基,C3-C6环烷基,C3-C4环烷基取代的C1-C2烷基,含一个氧原子的4-6元杂环基,或-(CH2)mR6,
其中m为1、2、3整数,
R6为-OH,-CN,-C(O)NH2,-S(=O)2CH3,C1-C3烷氧基,C1-C3烷硫基;
R2和R3分别独立的为-H、C1-C6烷基、C3-C6环烷基、含一个氮原子或含一个氧原子的4-6元杂环基或-(CH2)nR7,
其中n为1、2、3整数,
所述含一个氮原子或含一个氧原子的4-6元杂环为非取代或被C1-C3的烷基所取代,
R7为-OH,-CN,-C(O)NH2,-S(=O)2CH3,-NR'R”,C1-C3烷氧基,C1-C3烷硫基;
R'、R”分别独立的为H或C1-C3的烷基;
R2、R3也可以与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或分别被1-2个选自卤素、氰基、羟基、氨基、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、氰基取代的C1-C3烷基、羟基取代的C1-C3烷基、C1-C3烷氧基取代的C1-C3烷基所取代。
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环;
R4和R5分别独立的为-H,甲基,乙基,丙基,异丙基;
在一个优选的方案中,
R1选自-H,-CF3,-CH2CF3,甲基,乙基,丙基,异丙基,1-甲基丙基,2-甲基丙基,环丙基,环丁基,环戊基,环己基,环丙基甲基,环丙基乙基,环丁基甲基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基。
R2和R3分别独立的选自-H,甲基,乙基,丙基,异丙基,环丙基,环丁基,环戊基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,N-甲基哌啶-3-基,N-甲基哌啶-4-基,N-甲基吡咯烷-3-基,N-甲基氮(杂)环丁烷-3-基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基,甲氨基乙基,二甲氨基乙基,甲氨基丙基,二甲氨基丙基,或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R8选自–H,甲氨基,乙氨基,二甲氨基,
R9选自-H,甲基,乙基,丙基,异丙基,甲酰基,乙酰基或甲磺酰基。
R10和R11分别独立的选自-H,-F,-CF3,羟基,氨基,氰基,甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基,异丙氧基,氰基甲基,氰基乙基,甲氧基甲基,甲氧基乙基,甲氧基丙基,羟甲基,羟乙基,羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
R4和R5分别独立的为-H,甲基,乙基;
在另外一个优选的方案中,
R2选自:环丙基,环丁基,环戊基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,N-甲基哌啶-3-基,N-甲基哌啶-4-基,N-甲基吡咯烷-3-基,N-甲基氮(杂)环丁烷-3-基,
R3选自:-H,甲基,乙基,丙基,异丙基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基,甲氨基乙基,二甲氨基乙基,甲氨基丙基,二甲氨基丙基,
或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R8选自–H,甲氨基,乙氨基,二甲氨基,
R9选自-H,甲基,乙基,丙基,异丙基,甲酰基,乙酰基或甲磺酰基。
R10和R11分别独立的选自-H,-F,-CF3,羟基,氨基,氰基,甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基,异丙氧基,氰基甲基,氰基乙基,甲氧基甲基,甲氧基乙基,甲氧基丙基,羟甲基,羟乙基,羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
R4和R5分别独立的为-H,甲基,乙基;
本发明还提供了制备相应化合物的方法,可以使用多种合成方法制备本文所述的化合物,包括下述的方法,本发明的化合物或者其药学上可接受的盐,异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法,或通过本领域技术人员理解对这些方法的变化方法合成,优选方法包括但不限于下述方法。
一种制备本发明化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法,包括以下步骤,
其中,R1、R2、R3、R4、R5如前文所定义。
优选地,制备本发明化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法,包括以下步骤,
化合物的制备方案A如下:
反应条件:
步骤1)中的式(V)所示化合物与式(IV)所示化合物充分接触得到式(III)所示化合物;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:二氯甲烷、四氢呋喃、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、二氧六环、二氯乙烷、乙二醇二甲醚的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、醋酸钠、三乙胺、二异丙基乙基胺、三乙烯二胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉的一种或两种以上的组合;
步骤2)中的式(III)进行硝基还原反应得到式(II)所示化合物;
优选地,硝基还原反应的条件包含但不限于氢气与雷尼镍,氢气与钯碳,铁粉,锌粉或氯化亚锡;
步骤3)中的式(II)与(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧膦充分接触得到式(I)所示化合物;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、乙二醇二甲醚、异丙醇、正丁醇、2-丁醇、叔丁醇的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、醋酸钠、三乙胺、二异丙基乙基胺、三乙烯二胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉的一种或两种以上的组合;
优选地,该反应可在酸的存在下进行,所述的酸包含但不限于:三氟乙酸、对甲苯磺酸;
优选地,该反应可在钯金属催化偶联反应条件下进行,所述的钯金属催化偶联反应条件为常见的Buchward-Hartwig反应所用的钯配体、溶剂及碱;
化合物的制备方案B如下:
步骤1)中的式(V)所示化合物与式(VI’)所示化合物充分接触得到式(IV’)所示化合物;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:二氯甲烷、四氢呋喃、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、二氧六环、二氯乙烷、乙二醇二甲醚的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、醋酸钠、三乙胺、二异丙基乙基胺、三乙稀二胺、吡啶,4-二甲氨基吡啶,1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉的一种或两种以上的组合;
步骤2)中的式(IV’)所示化合物与带有离去集团的烷基化合物充分接触得到式(III)所示化合物,其中R1如权利要求中所述;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:四氢呋喃、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、二氧六环、乙二醇二甲醚的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、吡啶、4-二甲氨基吡啶的一种或两种以上的组合;
步骤3)中的式(III)进行硝基还原反应得到式(II)所示化合物;
优选地,硝基还原反应的条件包含但不限于氢气与雷尼镍,氢气与钯碳,铁粉,锌粉或氯化亚锡;
步骤4)中的式(II)与(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧磷充分接触得到式(I)所示化合物;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、乙二醇二甲醚、异丙醇、正丁醇、2-丁醇、叔丁醇的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、醋酸钠、三乙胺、二异丙基乙基胺、三乙稀二胺、吡啶,4-二甲氨基吡啶,1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉的一种或两种以上的组合;
优选地,该反应可在酸的存在下进行,所述的酸包含但不限于:三氟乙酸、对甲苯磺酸;
优选地,改反应可在钯金属催化偶联反应条件下进行,所述的钯金属催化偶联反应条件为常见的Buchward-Hartwig反应所用的钯配体、溶剂及碱;
实施例1.(2-((5-氯-2-((4-(4-(二甲基氨基)哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
将1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺25毫克(0.1mmol),(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦32毫克(0.1mmol),对甲苯磺酸17毫克(0.1mmol)置于反应瓶中,加热搅拌至反应完毕,旋蒸浓缩后柱层析得到产品27mg,产率50%。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.19(s,1H),8.62(s,1H),8.16(s,1H),7.62–7.54(m,1H),7.49–7.43(m,1H),7.18(s,3H),6.82–6.77(m,1H),3.66(s,3H),3.36–3.31(m,4H),2.48–2.45(m,1H),2.21(s,6H),1.83–1.80(m,2H),1.80(s,3H),1.77(s,3H),1.57–1.46(m,2H);MS:529[M+H]+.
实施例2.(2-((5-氯-2-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.19(s,1H),8.65–8.59(m,1H),8.16(s,1H),7.58(dd,J=13.8,7.6Hz,1H),7.46(t,J=8.0,8.0Hz,1H),7.20–7.15(m,3H),6.78(d,J=8.6Hz,1H),3.66(s,3H),3.32–3.29(m,4H),2.49–2.47(m,2H),2.47–2.44(m,1H),2.37–2.29(m,4H),2.29–2.21(m,2H),2.15(s,3H),1.84–1.80(m,2H),1.80(s,3H),1.77(s,3H),1.57–1.50(m,2H);MS:584[M+H]+.
实施例3.(2-((5-氯-2-((3-异丙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的3-异丙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.16(s,1H),8.63–8.56(m,1H),8.15(s,1H),7.58(dd,J=13.8,7.6Hz,1H),7.48(t,J=8.0,8.0Hz,1H),7.20–7.15(m,3H),6.77(d,J=8.2Hz,1H),4.44–4.38(m,1H),3.38(d,J=11.0Hz,2H),2.49–2.46(m,4H),2.46–2.43(m,1H),2.37–2.27(m,4H),2.27–2.18(m,2H),2.14(s,3H),1.85–1.81(m,2H),1.80(s,3H),1.76(s,3H),1.55–1.46(m,2H),1.23–1.20(m,6H).MS:612[M+H]+.
实施例4.(2-((5-氯-2-((3-(2-甲氧基乙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的3-(2-甲氧基乙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),9.17(s,1H),8.62–8.56(m,1H),8.15(s,1H),7.58(dd,J=14.0,8.0Hz,1H),7.47(t,J=8.0,8.0Hz,1H),7.20–7.14(m,3H),6.77(d,J=8.2Hz,1H),3.93(t,J=4.6,4.6Hz,2H),3.63(t,J=4.6,4.6Hz,2H),3.39(d,J=11.4Hz,2H),3.33(s,3H),2.50–2.47(m,4H),2.46–2.44(m,1H),2.37–2.29(m,4H),2.28–2.19(m,2H),2.15(s,3H),1.84–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.56–1.49(m,2H).MS:628[M+H]+.
实施例5.(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-((四氢-2H-吡喃-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-甲基-4-(1-(4-硝基-2-((四氢-2H-吡喃-4-基)氧基)苯基)哌啶-4-基)哌嗪的制备
将2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯酚320毫克(1mmol)、四氢-2H-吡喃-4-基4-甲基苯磺酸酯256毫克(1mmol)置于反应瓶中,加入2毫升DMF和碳酸钾138毫克(1mmol),搅拌至反应完毕,加水、抽滤得产品343毫克,产率85%。MS:405[M+H]+.
步骤2)4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-((四氢-2H-吡喃-4-基)氧基)苯胺的制备
将1-甲基-4-(1-(4-硝基-2-((四氢-2H-吡喃-4-基)氧基)苯基)哌啶-4-基)哌嗪343毫克(0.85mmol)置于反应瓶中,加入5毫升甲醇、铁粉476毫克(8.5mmol)和氯化铵450毫克(8.5mmol)加热至反应完毕,抽滤、加入碳酸钾水溶液调至碱性,乙酸乙酯萃取、浓缩得产品220毫克,产率70%。MS:375[M+H]+.
步骤3)(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-((四氢-2H-吡喃-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-((四氢-2H-吡喃-4-基)氧基)苯胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.16(s,1H),8.61–8.55(m,1H),8.15(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.48(t,J=8.0,8.0Hz,1H),7.25(s,1H),7.21–7.15(m,2H),6.80(d,J=8.6Hz,1H),4.40–4.35(m,1H),3.86–3.80(m,2H),3.44–3.38(m,4H),2.55–2.52(m,2H),2.48–2.47(m,1H),2.36–2.27(m,4H),2.27–2.18(m,2H),2.14(s,3H),1.90–1.82(m,5H),1.80(s,3H),1.77(s,3H),1.61–1.48(m,5H).MS:654[M+H]+.
实施例6.(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-异丙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-异丙氧基-4-硝基苯)-N,N-二甲基哌啶-4-胺的制备
将N,N-二甲基哌啶-4-胺128毫克(1mmol)、1-氟-2-异丙氧基-4-硝基苯199毫克(1mmol)置于反应瓶中,加入2毫升DMF和碳酸钾138毫克(1mmol),搅拌至反应完毕,加水、抽滤得产品260毫克,产率85%。MS:308[M+H]+.
步骤2)1-(4-氨基-2-异丙氧基苯基)-N,N-二甲基哌啶-4-胺的制备
参考实施例5的步骤2),以1-(2-异丙氧基-4-硝基苯)-N,N-二甲基哌啶-4-胺替代1-甲基-4-(1-(4-硝基-2-((四氢-2H-吡喃-4-基)氧基)苯基)哌啶-4-基)哌嗪。MS:278[M+H]+.
步骤3)(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-异丙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的1-(4-氨基-2-异丙氧基苯基)-N,N-二甲基哌啶-4-胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.16(s,1H),8.59(s,1H),8.15(s,1H),7.62–7.55(m,1H),7.51–7.46(m,1H),7.21–7.16(m,3H),6.80–6.76(m,1H),4.46–4.38(m,1H),3.42–3.32(m,4H),2.48–2.44(m,1H),2.22(s,6H),1.85–1.81(m,2H),1.78(d,J=13.6Hz,6H),1.56–1.44(m,2H),1.22(d,J=6.0Hz,6H).MS:557[M+H]+.
实施例7.(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的制备步骤1)至步骤3),起始物料以1-氟-2-(2-甲氧基乙氧基)-4-硝基苯替代1-氟-2-异丙氧基-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.18(s,1H),8.59(s,1H),8.16(s,1H),7.62–7.54(m,1H),7.50–7.44(m,1H),7.20–7.16(m,3H),6.78(d,J=8.4Hz,1H),3.93(t,J=4.8Hz,2H),3.64(d,J=4.3Hz,2H),3.39(d,J=10.9Hz,3H),3.33(s,4H),2.47–2.45(m,1H),2.20(s,6H),1.84–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.56–1.45(m,2H).MS:573[M+H]+.
实施例8.(2-((5-氯-2-((4-(4-(二甲氨基)哌啶-1-基)-3-((四氢-2H-吡喃-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的制备步骤1)至步骤3),起始物料以4-(5-氟-2-硝基苯氧基)四氢-2H-吡喃替代1-氟-2-异丙氧基-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.17(s,1H),8.59(s,1H),8.17(d,J=13.3Hz,1H),7.62–7.55(m,1H),7.51–7.46(m,1H),7.28–7.24(m,1H),7.23–7.14(m,2H),6.81(d,J=8.6Hz,1H),4.38(s,1H),3.87–3.80(m,2H),3.46–3.39(m,6H),2.57–2.53(m,1H),2.28(s,6H),1.90–1.85(m,4H),1.81(s,3H),1.77(s,3H),1.63–1.51(m,4H).MS:599[M+H]+.
实施例9.(2-((5-氯-2-((6-(4-(二甲氨基)哌啶-1-基)-5-甲氧基吡啶-3-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的制备步骤1)至步骤3),起始物料以2-氯-3-甲氧基-5-硝基吡啶替代1-氟-2-异丙氧基-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.24(s,1H),8.57(s,1H),8.16(s,1H),8.02(s,1H),7.58(dd,J=14.0,7.6Hz,1H),7.52(s,1H),7.41(t,J=8.0,8.0Hz,1H),7.15(t,J=7.4,7.4Hz,1H),3.81(d,J=12.4Hz,2H),3.67(s,3H),2.63(t,J=12.0,12.0Hz,2H),2.24–2.20(m,2H),2.18–2.15(m,1H),1.80(s,6H),1.77(s,6H),1.51–1.43(m,2H).MS:530[M+H]+.
实施例10.(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-乙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-乙氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺的制备
将2-(4-(二甲基氨基)哌啶-1-基)-5-硝基苯酚265毫克(1mmol)、溴乙烷108毫克(1mmol)置于反应瓶中,加入2毫升DMF和碳酸钾138毫克(1mmol),搅拌至反应完毕,加水、抽滤得产品235毫克,产率80%。MS:294[M+H]+.·
步骤2)1-(4-氨基-2-乙氧基苯基)-N,N-二甲基哌啶-4-胺的制备
将1-(2-乙氧基-4-硝基苯基)-N,N-二甲基哌啶-4-胺235毫克(0.8mmol)置于反应瓶中,加入5毫升甲醇、铁粉476毫克(8.5mmol)和氯化铵450毫克(8.5mmol)加热至反应完毕,抽滤、加入碳酸钾水溶液调至碱性,乙酸乙酯萃取、浓缩得产品147毫克,产率70%。MS:264[M+H]+.
步骤3)(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-乙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例1的制备方法,以等摩尔当量的1-(4-氨基-2-乙氧基苯基)-N,N-二甲基哌啶-4-胺替代1-(4-氨基-2-甲氧基苯基)-N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.18(s,1H),8.58(s,1H),8.16(s,1H),7.59(dd,J=13.8,7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.20–7.14(m,3H),6.77(d,J=8.5Hz,1H),3.88–3.82(m,2H),3.36(d,J=12.1Hz,2H),2.48–2.45(m,1H),2.20(s,6H),2.19–2.10(m,2H),1.85–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.55–1.46(m,2H),1.30(t,J=7.0Hz,3H);MS:543[M+H]+.
实施例11.(2-((5-氯-2-((3-环丁基-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例10的合成步骤1)至步骤3),起始原料中以等摩尔当量的碘代环丁烷替代溴乙烷。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.19(s,1H),8.57(s,1H),8.16(s,1H),7.60(dd,J=13.8,7.6Hz,1H),7.49(t,J=8.0Hz,1H),7.19–7.14(m,2H),7.07(s,1H),6.75(d,J=8.4Hz,1H),4.49–4.41(m,1H),3.38–3.34(m,2H),2.48–2.44(m,1H),2.39–2.31(m,2H),2.20(s,6H),2.19–2.09(m,2H),2.04–1.94(m,2H),1.85–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.77–1.68(m,2H),1.55–1.49(m,2H).MS:569[M+H]+.
实施例12.(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-(3-羟基丙基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例10的合成步骤1)至步骤3),起始原料中以等摩尔当量的3-溴代丙烷-1-醇替代溴乙烷。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.19(s,1H),8.61(s,1H),8.16(s,1H),7.59(dd,J=13.8,7.6Hz,1H),7.47(t,J=7.8Hz,1H),7.20–7.14(m,3H),6.77(d,J=8.4Hz,1H),4.50(t,J=5.2Hz,1H),3.87(t,J=6.2Hz,2H),3.61–3.56(m,2H),3.38–3.34(m,2H),2.47–2.45(m,1H),2.22(s,6H),2.21–2.14(m,2H),1.88–1.82(m,4H),1.80(s,3H),1.77(s,3H),1.55–1.47(m,2H);MS:573[M+H]+.
实施例13.2-(5-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(二甲基氨基)哌啶-1-基)苯氧基)乙腈的制备
参考实施例10的合成步骤1)至步骤3),起始原料中以等摩尔当量的2-溴代乙腈替代溴乙烷。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.34(s,1H),8.58(s,1H),8.17(s,1H),7.62–7.56(m,1H),7.53–7.49(m,1H),7.38(d,J=2.4Hz,1H),7.35(dd,J=8.6,2.4Hz,1H),7.20–7.16(m,1H),6.91(d,J=8.6Hz,1H),5.04(s,2H),3.30–3.26(m,2H),2.58–2.53(m,2H),2.20(s,6H),2.18–2.11(m,1H),1.86–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.58–1.50(m,2H);MS:554[M+H]+.
实施例14.(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-(3-(甲硫基)丙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化磷的制备
参考实施例10的合成步骤1)至步骤3),起始原料中以等摩尔当量的(3-溴丙基)(甲基)硫醚替代溴乙烷。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.21(s,1H),8.60(s,1H),8.16(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.47(t,J=8.0Hz,1H),7.22–7.15(m,3H),6.78(d,J=8.5Hz,1H),3.87(t,J=6.0Hz,2H),3.37–3.33(m,2H),2.64(t,J=7.2Hz,2H),2.48–2.45(m,1H),2.20(s,6H),2.18–2.09(m,2H),2.07(s,3H),1.97–1.92(m,2H),1.86–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.54–1.46(m,2H);MS:603[M+H]+.
实施例15.(2-((5-氯-2-((3-(环丙基甲氧基)-4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化磷的制备
参考实施例10的合成步骤1)至步骤3),起始原料中以等摩尔当量的(溴甲基)环丙烷替代溴乙烷。1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.17(s,1H),8.60(s,1H),8.15(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.46(t,J=8.0,8.0Hz,1H),7.18–7.14(m,3H),6.77(d,J=8.4Hz,1H),3.69(d,J=6.6Hz,2H),3.39(d,J=11.1Hz,2H),2.54–2.51(m,2H),2.49–2.46(m,1H),2.22(s,6H),2.18–2.12(m,1H),1.86–1.83(m,1H),1.81(s,3H),1.77(s,3H),1.57–1.48(m,2H),1.23–1.15(m,1H),0.56–0.51(m,2H),0.29(t,J=5.0Hz,2H);MS:569[M+H]+.
实施例16.(2-((5-氯-2-((3-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的溴代乙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.12(s,1H),8.52(s,1H),8.08(s,1H),7.55–7.49(m,1H),7.39(t,J=8.0Hz,1H),7.13–7.07(m,3H),6.69(d,J=8.4Hz,1H),3.81–3.74(m,2H),3.28–3.24(m,2H),2.43–2.39(m,4H),2.39–2.35(m,1H),2.31–2.20(m,4H),2.19–2.11(m,2H),2.07(s,3H),1.79–1.74(m,2H),1.73(s,3H),1.70(s,3H),1.50–1.41(m,2H),1.22(t,J=7.0Hz,3H);MS:598[M+H]+.
实施例17.(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-丙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的1-溴代丙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.19(s,1H),8.59(s,1H),8.16(s,1H),7.59(dd,J=13.8,7.6Hz,1H),7.45(t,J=8.0Hz,1H),7.19–7.13(m,3H),6.76(d,J=8.6Hz,1H),3.74(t,J=6.4Hz,2H),3.41–3.37(m,2H),2.49–2.47(m,4H),2.47–2.44(m,1H),2.38–2.26(m,4H),2.26–2.18(m,2H),2.14(s,3H),1.86–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.72–1.67(m,2H),1.57–1.48(m,2H),0.98(t,J=7.3Hz,3H);MS:612[M+H]+.
实施例18.(2-((5氯-2-((3-环丁基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的碘代环丁烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.13(s,1H),8.50(s,1H),8.09(s,1H),7.56–7.50(m,1H),7.42(t,J=7.8Hz,1H),7.13–7.09(m,2H),7.00(s,1H),6.68(d,J=8.6Hz,1H),4.41–4.33(m,1H),3.32–3.29(m,2H),2.41–2.38(m,2H),2.38–2.35(m,1H),2.32–2.23(m,6H),2.20–2.14(m,2H),2.08(s,3H),1.95–1.88(m,2H),1.77–1.74(m,2H),1.73(s,3H),1.70(s,3H),1.70–1.59(m,2H),1.53–1.41(m,4H);MS:624[M+H]+.
实施例19.(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-((四氢呋喃-3-基)氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的四氢呋喃-3-基4-甲基苯磺酸酯替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.20(s,1H),8.60–8.51(m,1H),8.17(s,1H),7.59(dd,J=13.8,7.6Hz,1H),7.48(t,J=8.0Hz,1H),7.22–7.15(m,3H),6.78(d,J=8.4Hz,1H),4.80(s,1H),3.83–3.72(m,4H),3.39–3.34(m,2H),2.50–2.46(m,4H),2.45–2.41(m,1H),2.40–2.27(m,4H),2.27–2.17(m,2H),2.15(s,3H),2.11–2.03(m,1H),1.99–1.92(m,1H),1.86–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.56–1.46(m,2H);MS:640[M+H]+.
实施例20.(2-((5-氯-2-((3-(2-羟基乙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的2-溴代乙烷-1-醇替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.20(s,1H),8.60(s,1H),8.16(s,1H),7.59(dd,J=13.8,7.8Hz,1H),7.48(t,J=8.0Hz,1H),7.21–7.15(m,3H),6.79(d,J=9.0Hz,1H),4.84(t,J=5.6Hz,1H),3.87(t,J=5.2Hz,2H),3.68–3.64(m,2H),3.42–3.36(m,2H),2.49–2.47(m,4H),2.47–2.44(m,1H),2.39–2.27(m,4H),2.27–2.19(m,2H),2.14(s,3H),1.85–1.80(m,2H),1.80(s,3H),1.77(s,3H),1.59–1.50(m,2H);MS:614[M+H]+.
实施例21.(2-((5-氯-2-((3-(3-羟基丙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的3-溴代丙烷-1-醇替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.19(s,1H),8.61(s,1H),8.16(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.47(t,J=8.0Hz,1H),7.19–7.14(m,3H),6.76(d,J=8.4Hz,1H),4.51(t,J=5.2Hz,1H),3.87(t,J=6.0Hz,2H),3.60–3.56(m,2H),3.39–3.34(m,2H),2.50–2.46(m,4H),2.46–2.43(m,1H),2.40–2.28(m,4H),2.28–2.18(m,2H),2.16(s,3H),1.87–1.81(m,4H),1.80(s,3H),1.77(s,3H),1.56–1.48(m,2H);MS:628[M+H]+.
实施例22.(2-((5-氯-2-((3-(3-甲氧基丙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的1-溴代-3-甲氧基丙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.18(s,1H),8.60(s,1H),8.15(s,1H),7.59(dd,J=13.8,7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.19–7.15(m,3H),6.77(d,J=8.8Hz,1H),3.85(t,J=6.2Hz,2H),3.50(t,J=6.3Hz,2H),3.38–3.33(m,2H),3.24(s,3H),2.50–2.47(m,4H),2.47–2.45(m,1H),2.37–2.28(m,4H),2.27–2.20(m,2H),2.14(s,3H),1.92(t,J=6.2Hz,2H),1.86–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.57–1.49(m,2H);MS:642[M+H]+.
实施例23.2-(5-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯氧基)乙腈的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的2-溴代乙腈替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.34(s,1H),8.58(s,1H),8.17(s,1H),7.61–7.57(m,1H),7.51(t,J=7.9Hz,1H),7.38(d,J=2.4Hz,1H),7.35(dd,J=8.6,2.4Hz,1H),7.20–7.17(m,1H),6.91(d,J=8.6Hz,1H),5.04(s,2H),3.30–3.27(m,2H),2.57–2.55(m,1H),2.55–2.51(m,4H),2.34–2.30(m,4H),2.27–2.23(m,2H),2.14(s,3H),1.85–1.82(m,2H),1.79(s,3H),1.77(s,3H),1.59–1.54(m,2H);MS:609[M+H]+.
实施例24.(2-((5-氯-2-((3-异丁基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧磷的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的1-溴代-2-甲基丙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(600MHz,DMSO-d6)δ11.19(s,1H),9.17(s,1H),8.62(s,1H),8.15(s,1H),7.60–7.56(m,1H),7.44(t,J=7.8Hz,1H),7.18–7.13(m,3H),6.76–6.74(m,1H),3.56(d,J=6.2Hz,2H),3.38–3.34(m,2H),2.50–2.47(m,4H),2.47–2.45(m,1H),2.39–2.25(m,4H),2.24–2.17(m,2H),2.13(s,3H),2.01–1.95(m,1H),1.84–1.81(m,2H),1.79(s,3H),1.77(s,3H),1.55–1.48(m,2H),0.98–0.95(m,6H);MS:626[M+H]+.
实施例25.(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-(3-(甲硫基)丙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧磷的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的(3-溴代丙基)(甲基)硫醚替代四氢-2H-吡喃-4-基-4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.20(s,1H),8.60(s,1H),8.16(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.47(t,J=8.0Hz,1H),7.22–7.15(m,3H),6.77(d,J=8.5Hz,1H),3.87(t,J=6.0Hz,2H),3.38–3.34(m,2H),2.64(t,J=7.2,7.2Hz,2H),2.58–2.51(m,4H),2.47–2.45(m,1H),2.44–2.32(m,4H),2.32–2.21(m,2H),2.19(s,3H),2.06(s,3H),1.97–1.91(m,2H),1.87–1.81(m,2H),1.80(s,3H),1.77(s,3H),1.57–1.48(m,2H);MS:658[M+H]+.
实施例26.(2-((5-氯-2-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-3-(3-(甲磺酰基)丙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧磷的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的1-溴代-3-(甲磺酰基)丙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.22(s,1H),8.59(s,1H),8.16(s,1H),7.59(dd,J=14.0,7.6Hz,1H),7.48(t,J=8.0Hz,1H),7.23–7.16(m,3H),6.79(d,J=8.4Hz,1H),3.93(t,J=6.0Hz,2H),3.38–3.32(m,4H),3.29–3.25(m,2H),3.01(s,3H),2.58–2.52(m,4H),2.49–2.46(m,1H),2.45–2.33(m,2H),2.33–2.22(m,2H),2.19(s,3H),2.14–2.08(m,2H),1.87–1.81(m,2H),1.81(s,3H),1.77(s,3H),1.61–1.51(m,2H);MS:690[M+H]+.
实施例27.(2-((5-氯-2-((3-(环丙基甲氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧磷的制备
参考实施例5的合成步骤1)至步骤3),起始原料中以等摩尔当量的(溴代甲基)环丙烷替代四氢-2H-吡喃-4-基4-甲基苯磺酸酯。1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),9.16(s,1H),8.65–8.56(m,1H),8.15(s,1H),7.60–7.54(m,1H),7.45(t,J=8.0Hz,1H),7.17–7.14(m,3H),6.75(d,J=8.4Hz,1H),3.69(d,J=6.4Hz,2H),3.42–3.36(m,2H),2.50–2.46(m,4H),2.46–2.45(m,1H),2.38–2.25(m,4H),2.25–2.18(m,2H),2.13(s,3H),1.84–1.80(m,2H),1.80(s,3H),1.77(s,3H),1.56–1.50(m,2H),1.20–1.15(m,1H),0.54–0.51(m,2H),0.29–0.27(m,2H);MS:624[M+H]+.
实施例28.(2-((5-氯-2-((4-(4-(环丁基(甲基)氨基)哌啶-1-基)-3-异丙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的合成步骤1)至步骤3),起始原料中以等摩尔当量的N-环丁基-N-甲基哌嗪-4-胺替代N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.11(s,1H),8.53(s,1H),8.08(s,1H),7.54–7.39(m,2H),7.14–7.08(m,3H),6.70(d,J=8.4Hz,1H),4.39–4.30(m,1H),3.34–3.30(m,4H),3.20–3.16(m,2H),2.53(t,J=6.2Hz,2H),2.41–2.32(m,3H),2.17(s,3H),1.74–1.71(m,9H),1.53–1.42(m,2H),1.15(d,J=6.0Hz,6H);MS:597[M+H]+.
实施例29.(2-((5-氯-2-((4-(4-羟基-4-甲基-[1,4'-联哌啶]-1'-基)-3-异丙氧基苯基氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的合成步骤1)至步骤3),起始原料中以等摩尔当量的4-甲基-[1,4'-联哌啶]-4-醇替代N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.16(s,1H),8.60(s,1H),8.15(s,1H),7.63–7.52(m,1H),7.49(t,J=8.0Hz,1H),7.22–7.16(m,3H),6.77(d,J=8.5Hz,1H),4.42(d,J=7.6Hz,1H),3.40(d,J=10.9Hz,2H),2.69–2.64(m,4H),2.36–2.30(m,2H),1.80–1.72(m,9H),1.59–1.55(m,2H),1.52–1.46(m,4H),1.25–1.20(m,7H),1.10(s,3H);MS:627[M+H]+.
实施例30.(2-((5-氯-2-((4-(4-(乙基(2-甲氧基乙基)氨基)哌啶-1-基)-3-异丙氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的合成步骤1)至步骤3),起始原料中以等摩尔当量的N-乙基-N-(2-甲氧基乙基)哌啶-4-胺替代N,N-二甲基哌啶-4-胺。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.18(s,1H),8.60(s,1H),8.16(s,1H),7.62–7.46(m,2H),7.23–7.12(m,3H),6.77(d,J=8.5Hz,1H),4.48–4.35(m,1H),3.41–3.35(m,2H),3.18–3.10(m,1H),2.48–2.41(m,3H),2.06(s,3H),1.98–1.92(m,2H),1.83–1.75(m,8H),1.64–1.56(m,8H),1.25–1.19(m,6H);MS:601[M+H]+.
实施例31.(2-((5-氯-2-((4-(4-(环丁基(甲基)氨基)哌啶-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的合成步骤1)至步骤3),第一步起始原料中以等摩尔当量的N-环丁基-N-甲基哌嗪-4-胺替代N,N-二甲基哌啶-4-胺,等摩尔当量的1-氟-2-甲氧基-4-硝基苯替代1-氟-2-异丙氧基-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.20(s,1H),8.67–8.56(m,1H),8.16(s,1H),7.64–7.54(m,1H),7.48–7.44(m,1H),7.24–7.11(m,3H),6.78(d,J=8.4Hz,1H),3.66(s,3H),3.32–3.28(m,2H),3.19–3.08(m,1H),2.49–2.41(m,3H),2.06(s,3H),1.99–1.88(m,2H),1.86–1.75(m,8H),1.66–1.53(m,6H);MS:569[M+H]+.
实施例32.(2-((5-氯-2-((3-甲氧基-4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
参考实施例6的合成步骤1)至步骤3),第一步起始原料中以等摩尔当量的4-(吡咯烷-1-基)哌啶替代N,N-二甲基哌啶-4-胺,等摩尔当量的1-氟-2-甲氧基-4-硝基苯替代1-氟-2-异丙氧基-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.14(s,1H),8.55(s,1H),8.09(s,1H),7.55–7.49(m,1H),7.42–7.37(m,1H),7.14–7.08(m,3H),6.74–6.71(m,1H),3.59(s,3H),3.20(d,J=11.6Hz,2H),2.50–2.44(m,6H),2.01–1.94(m,1H),1.83(d,J=12.4Hz,2H),1.73(s,3H),1.70(s,3H),1.64–1.59(m,4H),1.49–1.42(m,2H);MS:555[M+H]+.
实验例1.
小分子化合物抑制EGFRT790M激酶活性的测试,测试方法如下:
1)化合物的稀释
在96孔板a中,将化合物用DMSO溶液按3倍比例稀释,形成11个梯度,第12个梯度为纯DMSO溶液(作为阳性对照);取一块新的96孔板b,将上述溶液用超纯水稀释25倍(DMSO浓度为4%)。
2)将化合物转盘到384孔板
将上述96孔板b中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应的孔中。
3)加4×激酶溶液:用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中,混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照:在384孔板中设置阴性对照孔,每孔加入2.5μl 4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4%DMSO的超纯水。
6)离心混匀,避光室温反应2小时。
7)终止酶促反应:
吸取5μl上述4×终止液到384孔板相应孔,离心混匀,室温反应5分钟。
8)显色反应:
吸取5μl上述4×检测液加入到384孔板相应孔,离心混匀,室温反应1小时。
9)将384孔板放入读板仪,调取相应的程序检测信号。
10)IC50分析:
孔读值=10000*EU665值/EU615值
抑制率=(阳性对照孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)*100%
将药物浓度和相应抑制率输入GraphPad Prism 5处理可计算出相应的IC50。
EGFRT790M激酶活性抑制分子筛选实验条件:
反应体系中EGFR(T790M)激酶终浓度0.05nM,ATP的终浓度为5μM,底物ULightTM-labeled PolyGT的终浓度100nM,酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM,经3倍梯度稀释后共11个浓度,最低终浓度为0.042nM。DMSO终浓度为1%。
表(一)列出了本专利中部分化合物对酪氨酸激酶抑制活性的测定结果,其中A表示IC50小于或等于5nM,B表示IC50大于5nM但小于或等于50nM,C表示IC50大于50nM。
表(一):本发明化合物对EGFRT790M激酶抑制活性测定结果
实验例2.
小分子化合物抑制抑制BaF3-EGFR-L858R-T790M及BaF3-EGFR-L858R-T790M-C797S细胞增殖的测试,具体方法如下:
1)将细胞转移至15mL离心管中,以1000rpm离心4分钟。
2)弃去上清液,加入完全培养液,吹打均匀,取10μL细胞悬浮液和10μL0.4%胎盼蓝混匀,用细胞计数仪进行计数,记录细胞数及存活率。
3)每孔接种80μL的细胞悬液到96孔板中(不同细胞接种细胞密度见表二)。
表二:细胞密度
细胞名称 | 培养基 | 接种密度 |
BaF3-EGFR-L858R-T790M | RPMI 1640+10%FBS | 5000/well |
BaF3-EGFR-L858R-T790M-C797S | RPMI 1640+10%FBS | 5000/well |
4)在每孔中(B行到G行,第2列至第11列)加入20μL上述用培养液稀释过的5×化合物,混合摇匀。(每个化合物设置两平行,一个96孔板可测试三个化合物);
5)在含5%CO2的37℃培养箱中培养72小时后每孔加入10μL CCK-8试剂,培养2小时(可以根据颜色深浅来调节反应时间);
6)在多功能读板机于450nm处读其OD值。
7)数据处理:细胞存活率(%)=[(As-Ab)/(Ac-Ab)]*100%
As:实验孔(含有细胞的培养基、CCK-8、化合物)的OD值;
Ac:对照孔(含有细胞的培养基、CCK-8)的OD值;
Ab:空白孔(不含细胞和化合物的培养基、CCK-8)的OD值。
然后将数值导入Graphpad Prism5软件进行曲线拟合,计算IC50。
表(三)列出了本发明中代表性化合物对BaF3-EGFR-L858R-T790M及BaF3-EGFR-L858R-T790M-C797S细胞的活性测定结果。
表(三):本发明代表性化合物对细胞活性的测定结果
实验数据表明,本发明的化合物在苯环(相对于与其相连的哌啶环)的临位上引入取代基有效地增强了突变型EGFR的细胞活性,其部分化合物对EGFRT790M以及C797S突变细胞的抑制活性远远高于Brigatinib,有希望成为第四代EGFR突变介导的非小细胞肺癌候选药物化合物。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原则的前提下,本发明的实施方式还可以作出若干改进和修饰,这些改进和修饰也应视为本发明的保护范围。
Claims (9)
1.一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
式(I)中,
X为CH或N;
Y为CH或N;
R1为-H,-CF3,-CH2CF3,C1-C6烷基,C3-C6环烷基,C3-C4环烷基取代的C1-C2烷基,含一个氧原子的4-6元杂环基,或-(CH2)mR6,
其中m为1、2、3整数,
R6为-OH,-CN,-C(O)NH2,-S(=O)2CH3,C1-C3烷氧基,C1-C3烷硫基;
R2和R3分别独立的为-H、C1-C6烷基、C3-C6环烷基、含一个氮原子或含一个氧原子的4-6元杂环基或-(CH2)nR7,
其中n为1、2、3整数,
所述含一个氮原子或含一个氧原子的4-6元杂环为非取代或被C1-C3的烷基所取代,
R7为-OH,-CN,-C(O)NH2,-S(=O)2CH3,-NR'R”,C1-C3烷氧基,C1-C3烷硫基;
R'、R”分别独立的为H或C1-C3的烷基;
R2、R3也可以与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或分别被1-2个选自卤素、氰基、羟基、氨基、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、氰基取代的C1-C3烷基、羟基取代的C1-C3烷基、C1-C3烷氧基取代的C1-C3烷基所取代。
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环;
R4和R5分别独立的为-H,甲基,乙基,丙基,异丙基。
2.根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
R1选自-H,-CF3,-CH2CF3,甲基,乙基,丙基,异丙基,1-甲基丙基,2-甲基丙基,环丙基,环丁基,环戊基,环己基,环丙基甲基,环丙基乙基,环丁基甲基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基。
3.根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
R2和R3分别独立的选自-H,甲基,乙基,丙基,异丙基,环丙基,环丁基,环戊基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,N-甲基哌啶-3-基,N-甲基哌啶-4-基,N-甲基吡咯烷-3-基,N-甲基氮(杂)环丁烷-3-基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基,甲氨基乙基,二甲氨基乙基,甲氨基丙基,二甲氨基丙基,或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R8选自–H,甲氨基,乙氨基,二甲氨基,
R9选自-H,甲基,乙基,丙基,异丙基,甲酰基,乙酰基或甲磺酰基。
R10和R11分别独立的选自-H,-F,-CF3,羟基,氨基,氰基,甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基,异丙氧基,氰基甲基,氰基乙基,甲氧基甲基,甲氧基乙基,甲氧基丙基,羟甲基,羟乙基,羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
R4和R5分别独立的为-H,甲基,乙基。
4.根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
R2选自:环丙基,环丁基,环戊基,环氧丙烷-3-基,四氢呋喃-3-基,四氢吡喃-4-基,四氢吡喃-3-基,N-甲基哌啶-3-基,N-甲基哌啶-4-基,N-甲基吡咯烷-3-基,N-甲基氮(杂)环丁烷-3-基,
R3选自:-H,甲基,乙基,丙基,异丙基,甲硫基乙基,甲硫基丙基,甲氧基乙基,甲氧基丙基,乙氧基乙基,乙氧基丙基,异丙氧基乙基,异丙氧基丙基,氨基乙酰基,氨基丙酰基,甲磺酰乙基,甲磺酰丙基,羟乙基,羟丙基,氰基甲基,氰基乙基,氰基丙基,甲氨基乙基,二甲氨基乙基,甲氨基丙基,二甲氨基丙基,
或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R8选自–H,甲氨基,乙氨基,二甲氨基,
R9选自-H,甲基,乙基,丙基,异丙基,甲酰基,乙酰基或甲磺酰基。
R10和R11分别独立的选自-H,-F,-CF3,羟基,氨基,氰基,甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基,异丙氧基,氰基甲基,氰基乙基,甲氧基甲基,甲氧基乙基,甲氧基丙基,羟甲基,羟乙基,羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
R4和R5分别独立的为-H,甲基,乙基。
5.一种制备权利要求1-4所述化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法,包括以下步骤,
6.根据权利要求1-4任一项所述的式(I)的的化合物或其可药用的盐,其中所述的盐是酸性/阴离子盐或碱性/阳离子盐;药学上可接受的酸性/阴离子盐通常采取的形式是让其中的碱性氮被无机或有机酸质子化,代表性的有机或无机酸包括盐酸,氢溴酸,氢碘酸,高氯酸,硫酸,硝酸,磷酸,甲酸,乙酸,丙酸,羟基乙酸,乳酸,琥珀酸,马来酸,酒石酸,苹果酸,柠檬酸,富马酸,葡萄糖酸,安息香酸,扁桃酸,甲磺酸,羟乙基磺酸,苯磺酸,草酸,棕榈酸,2-萘磺酸,对甲苯磺酸,环己胺基磺酸,水杨酸,己糖酸,三氟乙酸;药学上可接受的碱性/阳离子盐类包括当然不仅限于此铝,钙,氯普鲁卡因,胆碱,二乙醇胺,乙二胺,锂,镁,钾,钠和锌。
7.一种治疗与酪氨酸激酶EGFR,HER2,或ALK突变或过表达相关疾病的药用组合物,其由权利要求1-4任一项所述的式(I)的化合物或其药学上可接受的盐或其水合物或其溶剂化物或其前药与药学上可接受的载体或赋形剂组成。
8.一种药用组合物:其中包含如权利要求1-4任一项所述的式(I)的化合物或其药学上可接受的盐、水合物、溶剂化物、或前药作为活性成分,一个或多个其它的治疗剂,以及一种或多种药学上可接受的载体或赋形剂。
9.根据权利要求1-4中任一项所述的式(I)的化合物或其药学上可接受的盐或其前药用于制备治疗与酪氨酸激酶EGFR,HER2,或ALK突变或过表达相关的癌症及自身免疫疾病的药物中的应用,其中所述癌症及自身免疫疾病包括但不限于,眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种等。
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