CN115894381A - 一种2,4,5-三取代嘧啶类化合物及其制备方法和用途 - Google Patents
一种2,4,5-三取代嘧啶类化合物及其制备方法和用途 Download PDFInfo
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- CN115894381A CN115894381A CN202211413247.7A CN202211413247A CN115894381A CN 115894381 A CN115894381 A CN 115894381A CN 202211413247 A CN202211413247 A CN 202211413247A CN 115894381 A CN115894381 A CN 115894381A
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- amino
- phenyl
- chloro
- pyrimidin
- methylpiperazin
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Images
Abstract
Description
技术领域
本发明属于药物化学领域,具体涉及一类以FGFR1为靶点的2,4,5-三取代嘧啶类化合物及其制备方法和用途。
背景技术
在蛋白激酶这个领域,成纤维细胞生长因子受体FGFR1家族在肿瘤治疗中是一个非常有吸引力的靶点。受体酪氨酸激酶的FGFR1家族包括四个成员,分别是FGFR1-4。它们具有高度相似的序列同源性。FGFR1激酶的过表达与多种恶性肿瘤密切相关,如乳腺癌、膀胱癌、胃癌、***癌、直肠癌等,因此肿瘤医学不断对其研究和对癌症的诊断和治疗。抑制与疾病相关的蛋白激酶,阻断并破坏肿瘤细胞的信号传递,可通过多种方法来实现,但由于合成的反义寡核苷酸易受核酶的攻击而降解,RNA干扰技术存在安全性、稳定性和脱靶效应等问题,因此新药研发人员尝试从有机合成小分子中筛选FGFR1的化学小分子抑制剂。目前为止已有4款FGFR抑制剂上市,包括erdafitinib、pemigatinib、infigrarinib以及TAS-120。其中TAS-120作为首个上市的不可逆FGFR抑制剂,用于治疗携带FGFR2基因重排(包括基因融合)的局部晚期或转移性胆管癌患者,这一成功的共价键应用为我们提供设计灵感,不可逆结合被认为是一种实用的机制,用于可逆抑制剂对耐药突变体以及对ATP具有高亲和力的酪氨酸激酶无效的情况。因此靶向FGFR1的不可逆抑制剂尚有很大前景,目前开发能够克服上述缺点的新型FGFR1抑制剂是亟待解决的问题。
发明内容
本发明的目的之一是为解决上述技术问题,提供一类以FGFR1为靶点的2,4,5-三取代嘧啶类化合物及其制备方法和用途。该化合物可以选择性地抑制FGFR激酶的磷酸化从而用于治疗与此激酶密切联系的恶性肿瘤。
一种2,4,5-三取代嘧啶类化合物,具有下列结构通式:
其中,R1可以选自卤素、三氟甲基、C1-C6烷基或者C1-C6烷氧基中的一个;
R2可以选自为H或者C1~C5烷基中的任意一种;
其中m为0或1或2;
作为优选:R1可以选自F,Cl,CH3,OCH3或CF3中的任意一种;
作为优选,R2可以选自H,CH3,CH2CH3中的任意一种;
作为优选,m=0;
R3选自下列任一取代基团:
其中,R6选自Cl或甲基;R7选自H或Cl;R5选自乙烯基、丙烯基、丁烯基、三氟乙烯基、甲基、乙基、苯基、四氢呋喃-2-基或丙烯酰胺基。
R3进一步选自下列任一取代基团:
R4选自下列任一取代基团:
以上R1,R2,R3,R4中的取代基可以任意组合。
作为优选,所述的R1为Cl;
所述的R2为H;
m为0;
所述的R4选自下列任一取代基团:
本申请的化合物可以以其药学上可接受的盐的形式存在。
所述药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于:乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于:铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。
本发明还提供了一种所述的2,4,5-三取代嘧啶类化合物在药物制备中的应用,所述的药物为抗肿瘤药物。
作为优选,所述的抗肿瘤药物以FGFR1为靶点。
作为优选,所述的药物用来治疗肝细胞癌、乳腺癌、膀胱癌、结直肠癌、黑色素瘤、间皮瘤、肺癌、***癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成纤维细胞瘤、子宫癌、横纹肌肉瘤、皮肤癌、肾癌、淋巴瘤、***、头颈部鳞癌、恶性***、绒毛膜上皮癌、卵巢癌、胃癌、白血病中的一种或者多种,作为进一步的优选,所述的药物用来治疗非小细胞肺癌。
附图说明
图1为实施例9中部分化合物对FGFR1野生型的抑制活性;
图2为实施例9中部分化合物对FGFR1突变型V561M的抑制活性;
图3为实施例9中部分化合物对FGFR1突变型V561F的抑制活性。
具体实施方式
以下在本文中阐述的实施例仅仅为了说明目的,用以举例说明本发明的各个方面以及实施方式,并不意欲以任何方式限制本发明所要求保护的范围。
除非另有声明,所有起始原料和试剂均从商业途径获得,市售原料和试剂均不经进一步纯化直接使用。合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
1H-NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=宽峰,dd=双二重峰,dt=双三重峰。若提供偶合常数时,其单位为Hz。
质谱是用高分辨质谱仪测定得到,离子化方式可为ESI。
纯度是用高效液相色谱仪(安捷伦1260)测定得到,流动相为色谱甲醇和超纯水体系。
氢气,氮气环境下是指反应瓶连接一个约1L容积的气球。
实施例中无特殊说明,反应中的溶液是指水溶液。
实施例1:N-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(化合物1)的制备
合成中间体1-1:N1-(2-氯-5-氟嘧啶-4-基)苯-1,4-二胺
将2,4-二氯-5-氟嘧啶(166.0mg,1.00mmol)和对苯二胺(129.7mg,1.20mmol),以及无水碳酸钠(318.0mg,3.00mmol),于无水乙醇溶剂(10mL)中充分溶解,80℃下冷凝回流,3h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得白色固体化合物1-1,产率为88.8%。
合成中间体1-2:N4-(4-氨基苯基)-5-氟-N2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺
将化合物1-1(210.7mg,0.88mmol)和4-(4-乙基哌嗪-1-基)苯胺(201.9mg,1.06mmol),于仲丁醇(10mL)中充分溶解,滴加三氟乙酸(196μL,2.64mmol),100℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得浅褐色固体化合物1-2,产率为40.6%。
合成化合物1:N-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺
将化合物1-2(137.7mg,0.35mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(111.3mg,1.05mmol),于0℃搅拌5min后滴加丙烯酰氯(44μL,0.53mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得灰绿色固体化合物1,产率为64.1%。实施例2:N-(4-(2-(5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺(化合物33)的制备
合成中间体2-1:2,5-二氯-N-(4-硝基苯乙基)嘧啶-4-胺
将2,4,5-三氯嘧啶(167.0mg,1.00mmol)和2-(4-硝基苯基)乙烷-1-胺盐酸盐(242.5mg,1.20mmol),以及无水碳酸钠(318.0mg,3.00mmol),于无水乙醇溶剂(10mL)中充分溶解,室温下搅拌,2h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得鹅黄色固体化合物2-1,产率为87.0%。
合成中间体2-2:N-(4-氨基苯乙基)-2,5-二氯嘧啶-4-胺
将化合物2-1(271.5mg,0.87mmol)和无水氯化铵(234.9mg,4.35mmol)充分溶解于EtOH:H2O=3:1的混合溶液(10mL)中,于60℃下冷凝回流30min后,加入Fe粉(48.7mg,4.35mmol)后升温至80℃。3h反应结束后,抽滤,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得黄色固体化合物2-2,产率为95.1%。
合成中间体2-3:N-(4-(2-(2,5-二氯嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺
将化合物2-2(225.0mg,0.80mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(254.4mg,2.40mmol),于0℃搅拌5min后滴加丙烯酰氯(100μL,1.20mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得固体化合物2-3,产率为72.2%。
合成化合物33:N-(4-(2-(5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺
将化合物2-3(168.0mg,0.50mmol)和4-(4-乙基哌嗪-1-基)苯胺(114.8mg,0.60mmol),于仲丁醇(5mL)中充分溶解,滴加三氟乙酸(75μL,1.00mmol),100℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得淡黄色固体化合物33,产率为37.3%。
实施例3:N-((5-氯-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺(化合物11)的制备
中间体3-1:2,5-二氯-N-(2-甲基-6-硝基苯基)嘧啶-4-胺
将2-甲基-6-硝基苯胺(182.5mg,1.20mmol)溶于无水DMF(5mL)中,于0℃中充分搅拌。将NaH(72.0mg,3.00mmol)溶于无水DMF(1mL)中,混匀后滴入反应体系,活化30min后加入2,4,5-三氯嘧啶(167.0mg,1.00mmol),1h后反应结束。用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得白色固体化合物3-1,产率为76.2%。
合成中间体3-2:N1-(2,5-二氯嘧啶-4-基)-6-甲基苯-1,2-二胺
将化合物3-1(208.6mg,0.70mmol)和无水氯化铵(189.0mg,3.50mmol)充分溶解于EtOH:H2O=3:1的混合溶液(8mL)中,于60℃下冷凝回流30min后,加入Fe粉(196.0mg,3.50mmol)后升温至80℃。3h反应结束后,抽滤,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得淡黄色固体化合物3-2,产率为90.9%。
合成中间体3-3:N-(2-((2,5-二氯嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺
将化合物3-2(134.0mg,0.50mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(159.0mg,1.50mmol),于0℃搅拌5min后滴加丙烯酰氯(60μL,0.75mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得固体化合物3-3,产率为94.6%。
合成化合物11:N-((5-氯-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺
将化合物3-3(144.9mg,0.45mmol)和4-(4-乙基哌嗪-1-基)苯胺(114.8mg,0.60mmol),于仲丁醇(5mL)中充分溶解,滴加三氟乙酸(75μL,1.00mmol),100℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得灰白色固体化合物11,产率为16.7%。
实施例4:1-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(化合物19)的制备
合成中间体4-1:4-((2-氯-5-氟嘧啶-4-基)氨基)哌啶-1-羧酸叔丁酯
将2,4-二氯-5-氟嘧啶(166.0mg,1.00mmol)和4-氨基哌啶-1-羧酸叔丁酯(240.2mg,1.20mmol),以及无水碳酸钠(318.0mg,3.00mmol),于无水乙醇溶剂(10mL)中充分溶解,70℃下冷凝回流,2h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得油状化合物4-1,产率为82.1%。
合成中间体4-2:2-氯-5-氟-N-(哌啶-4-基)嘧啶-4-胺
将化合物4-1(264.1mg,0.80mmol)溶于二氯甲烷(4mL)中,室温下充分搅拌后滴加4mol/LHCl,30min反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得油状化合物4-2,产率为85.3%.
合成中间体4-3:1-(4-((2-氯-5-氟嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮
将化合物4-2(147.0mg,0.60mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(159.0mg,1.50mmol),于0℃搅拌5min后滴加丙烯酰氯(75μL,0.90mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得淡黄色固体化合物4-3,产率为90.4%。
合成化合物19:1-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮
将化合物4-3(142.0mg,0.50mmol)和4-(4-乙基哌嗪-1-基)苯胺(114.8mg,0.60mmol),于仲丁醇(5mL)中充分溶解,滴加三氟乙酸(75μL,1.00mmol),100℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得白色固体化合物19,产率为27.5%。
实施例5:N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)(甲基)氨基)苯基)乙酰胺(化合物27)的制备
合成中间体5-1:2-氯-N-(3-氯-4-硝基苯基)-5-氟嘧啶-4-胺
将2,4-二氯-5-氟嘧啶(166.0mg,1.00mmol)和3-氯-4-硝基苯胺(206.4mg,1.20mmol),以及无水碳酸钠(318.0mg,3.00mmol),于无水乙醇溶剂(10mL)中充分溶解,80℃下冷凝回流,2h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得黄色固体化合物5-1,产率为93.4%.
合成中间体5-2:2-氯-N-(3-氯-4-硝基苯基)-5-氟-N-甲基嘧啶-4-胺
将化合物5-1(271.8mg,0.90mmol)和碳酸铯(879.7mg,2.70mmol)溶于无水DMF(5mL)中,室温下充分搅拌,往体系中滴加碘甲烷(184.5mg,1.30mmol),1h反应结束后,倒入冰水后有大量固体析出,静置,抽滤,水洗,烘干后得黄色固体化合物5-2,产率为91.5%.
合成中间体5-3:3-氯-N1-(2-氯-5-氟嘧啶-4-基)-N1-甲基苯-1,4-二胺
将化合物5-2(252.8mg,0.80mmol)和无水氯化铵(189.0mg,3.50mmol)充分溶解于EtOH:H2O=3:1的混合溶液(8mL)中,于60℃下冷凝回流30min后,加入Fe粉(196.0mg,3.50mmol)后升温至80℃。3h反应结束后,抽滤,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得固体化合物5-3,产率为95.1%.
合成中间体5-4:N-(2-氯-4-((2-氯-5-氟嘧啶-4-基)(甲基)氨基)苯基)乙酰胺
将化合物5-3(200.2mg,0.70mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(254.4mg,2.40mmol),于0℃搅拌5min后滴加丙烯酰氯(100μL,1.20mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得淡黄色固体化合物5-4,产率为73.0%。
合成化合物27:N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)(甲基)氨基)苯基)乙酰胺
将化合物5-4(142.0mg,0.50mmol)和4-(4-乙基哌嗪-1-基)苯胺(114.8mg,0.60mmol),于仲丁醇(5mL)中充分溶解,滴加三氟乙酸(75μL,1.00mmol),100℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得黄褐色固体化合物27,产率为20.6%.
实施例6:N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(化合物46)的制备
合成中间体6-1:2,5-二氯-N-(3-氯-4-硝基苯基)嘧啶-4-胺
将2,4.5-三氯嘧啶(167.0mg,1.00mmol)和3-氯-4-硝基苯胺(206.4mg,1.20mmol),以及无水碳酸钠(318.0mg,3.00mmol),于无水乙醇溶剂(10mL)中充分溶解,室温下反应,2h反应结束后,减压蒸馏,用乙酸乙酯萃取,合并有机层,干燥,减压浓缩。经柱层析色谱法分离纯化得黄色固体化合物6-1,产率为92.3%.
合成中间体6-2:3-氯-N1-(2,5-二氯嘧啶-4-基)苯-1,4-二胺
将化合物6-1(287.5mg,0.90mmol)和无水氯化铵(189.0mg,3.50mmol)充分溶解于EtOH:H2O=3:1的混合溶液(8mL)中,于60℃下冷凝回流30min后,加入Fe粉(196.0mg,3.50mmol)后升温至80℃。3h反应结束后,抽滤,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得土黄色固体化合物6-2,产率为94.2%.
合成中间体6-3:N-(2-氯-4-((2,5-二氯嘧啶-4-基)氨基)苯基)丙烯酰胺
将化合物6-2(202.6mg,0.70mmol)溶于无水四氢呋喃(5mL)中充分溶解,加入无水碳酸钠(254.4mg,2.40mmol),于0℃搅拌5min后滴加丙烯酰氯(100μL,1.20mmol),1h反应结束后,加NH4Cl溶液淬灭反应。减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得固体化合物6-3,产率为72.0%
合成中间体6-4:(3R,5S)-1-(2-甲氧基-4-硝基苯基)-3,5-二甲基哌嗪
将1-氟-2-甲氧基-4-硝基苯(171.1mg,1.00mmol)和(2R,6S)-2,6-二甲基哌嗪(114.2mg,1.0mmol)以及无水碳酸钾(414.6mg,3.0mmol)溶解于DMSO(5mL)中,于80℃下冷凝回流,2h反应结束后,倒入冰水有固体析出,静置,抽滤,水洗,烘干后得黄色化合物6-4,产率为63.1%
合成中间体6-5:4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯胺
将化合物6-4(132.6mg,0.5mmol)溶于甲醇(5mL)中,加入13mgPdC,在H2保护下室温反应,1h反应结束后,抽滤,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得固体化合物6-5,产率为89.2%
合成化合物46:N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺
将化合物6-3(171.0mg,0.5mmol)和化合物6-5(117.6mg,0.5mmol),于仲丁醇(5mL)中充分溶解,滴加三氟乙酸(75μL,1.0mmol),120℃下冷凝回流,8h反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得灰白色固体化合物46,产率为36.9%.
实施例7:N-(2-氯-4-((5-氯-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)氨基)苯基)丙烯酰胺(化合物45)
将化合物6-3(171.0mg,0.50mmol)和5-(4-甲基哌嗪-1-基)吡啶-2-胺(115.4mg,0.60mmol),pd2(dba)3(22.9mg,0.025mmol),BINAP(31.1mg,0.05mmol)和NaOtBu(72.1mg,0.75mmol)加入无水1,4-二氧六环(5mL)中,在N2保护下于110℃冷凝回流反应,反应结束后,减压蒸馏,用乙酸乙酯萃取,减压浓缩。经柱层析色谱法分离纯化得灰白色固体化合物45,产率为11.8%.
按照实施列1-7类似的合成路线和方法,通过改变起始原料合成下列2,4,5-三取代嘧啶类化合物。
实施例8化合物对FGFR1激酶活性的测定
通过LANCE ULTRA Assay方法测定化合物对FGFR1的抑制活性,筛选出活性好的化合物。FGFR1为CARNA公司购买。具体方法:所测试的化合物、ATP、特异性底物以及FGFR1激酶用激酶稀释液稀释。激酶反应混合物中含FGFR1、ATP、底物、HEPES(PH=7.5)、MgCl2、EGTA、Tween-20。不加任何化合物组作100%磷酸化对照,加入FGFR1激酶后马上加EDTA终止反应组作为0%磷酸化对照。激酶反应混合物室温下共孵育1h后,加EDTA终止反应5分钟。再加入特异性抗体,室温下继续共孵育1h,用PerkinElmer Envision激酶仪检测激发光。根据激酶仪检测所得信号值,用公式计算得抑制率或者GraphPad计算受试化合物IC50值。
实验结果表明:以上测试的化合物均显示出对体外FGFR1激酶的抑制活性。
实施例9活性化合物对FGFR1野生型和突变型抑制活性
按照实施例8的方法,测试部分化合物对FGFR1野生型和突变型V561M、V561F的抑制活性,结果见图1~3。
以上测试的各实施例化合物对FGFR1野生型和突变型V561M、V561F均显示出与BGJ398相似或更好的抑制活性。
实施例10活性化合物对细胞MRC-5、H1581、A549增殖的影响
通过采用MTT法进行测定。实验方法简述如下受试化合物首先溶解于DMSO中制备为储备液,随后以对应细胞的培养基进行梯度稀释,配制成测试样品,化合物的终浓度范围在20μM。将处于对数培养期的细胞以适宜的密度接种至96孔细胞培养板中,在对应的条件下培养过夜后,加入测试化合物样品后继续培养72小时。培养结束后,向每孔加入适宜体积的MTT检测液,并在37℃下孵育1-4小时,小心弃去培养基,然后每孔加入100μL DMSO溶解孔底部的结晶,置于微量振荡器上避光室温下震荡10min,待结晶充分溶解后,用酶标仪检测各个孔在490nm处的吸光值,计算各化合物抑制肺癌细胞的抑制率或IC50值。
本发明的优选化合物对FGFR1异常的肺癌细胞H1581和A549具有显著的增殖抑制作用,相对于阳性对照药BGJ398具有更优秀的抑制细胞增殖活性。
实施例12测定化合物编号1-52的性状、产率、氢谱、碳谱和质谱
N-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(1),灰绿色固体,产率:23.1%.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.27(s,1H),8.92(s,1H),8.03(d,J=3.7Hz,1H),7.76(d,J=8.8Hz,2H),7.65(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),6.84(d,J=8.9Hz,2H),6.47(dd,J=16.9,10.1Hz,1H),6.33–6.22(m,1H),5.76(dd,J=10.1,1.6Hz,1H),3.13-2.97(m,4H),2.50–2.41(m,4H),2.24(s,3H).13CNMR(101MHz,DMSO)δ163.41,156.34,150.17,150.06,146.41,135.22,134.83,133.63,132.48,130.15,127.00,122.22,120.74,120.04,116.32,55.20,49.47,46.23,40.63.HRMS(ESI)m/z:calcd for C24H26FN7O+,448.2261;found,448.2261.HPLC purity:99.8%
N-(4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(2),土黄色固体,产率:25.2%.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.09(s,1H),8.77(s,1H),8.07(s,1H),7.71(d,J=8.6Hz,2H),7.60(d,J=7.8Hz,2H),7.46(d,J=8.4Hz,2H),6.83(d,J=8.7Hz,2H),6.56(dd,J=16.9,10.1Hz,1H),6.28(d,J=17.0Hz,1H),5.77(d,J=10.3Hz,1H),3.21(s,6H),2.87(s,5H).13C NMR(101MHz,DMSO)δ163.53,158.38,156.52,154.94,145.66,135.70,134.75,133.59,132.53,127.03,124.43,124.42,121.01,119.94,116.52,53.93,48.01,44.34.HRMS(ESI)m/z:calcd for C24H26ClN7O+,464.1966;found,464.1963.HPLC purity:99.1%
N-(4-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(3),黄色固体,产率:17.6%.1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),9.03(s,1H),8.53(s,1H),7.84(s,1H),7.73(d,J=8.9Hz,2H),7.64(d,J=8.6Hz,2H),7.51(d,J=8.7Hz,2H),6.87(d,J=8.9Hz,2H),6.66(dd,J=17.0,10.2Hz,1H),6.27(d,J=16.9Hz,1H),5.77–5.69(m,1H),3.27(s,4H),2.77(s,4H),2.11(s,3H),1.24(s,3H).13C NMR(101MHz,DMSO)δ163.57,160.14,157.37,157.33,144.93,135.36,133.94,132.70,130.17,126.78,123.69,121.05,119.89,116.92,105.91,52.75,46.81,42.54,14.05.HRMS(ESI)m/z:calcd for C25H29N7O+,444.2512;found,444.2512.HPLC purity:94.8%
N-(4-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(4),灰绿色固体,产率:18.2%.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.64(s,2H),7.86–7.77(m,3H),7.63(d,J=8.9Hz,2H),7.53(d,J=8.9Hz,2H),6.83(d,J=9.0Hz,2H),6.46(dd,J=16.9,10.1Hz,1H),6.27(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,1.9Hz,1H),3.85(s,3H),3.09–2.99(m,4H),2.50–2.43(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ163.35,154.57,152.11,145.85,136.95,135.84,134.75,134.46,134.32,132.50,126.96,121.87,120.01,119.96,116.47,57.39,55.24,49.63,46.25.HRMS(ESI)m/z:calcd for C25H29N7O2 +,460.2461;found,460.2462.HPLC purity:99.3%
N-(2-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(5),灰色固体,产率:21.1%.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.87(s,1H),8.69(s,1H),8.05(d,J=3.5Hz,1H),7.73(d,J=7.7Hz,1H),7.65(d,J=7.2Hz,1H),7.43(d,J=9.0Hz,2H),7.35–7.19(m,2H),6.75(d,J=9.0Hz,2H),6.55(dd,J=17.0,10.2Hz,1H),6.30(dd,J=17.0,1.7Hz,1H),5.80(d,J=11.8Hz,1H),3.08–2.94(m,4H),2.49–2.40(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ164.48,156.29,150.85,150.74,146.12,142.38,141.26,141.07,139.95,133.76,132.09,131.87,131.19,127.91,127.23,125.65,124.64,120.15,116.31,55.13,49.42,46.13.HRMS(ESI)m/z:calcd for C24H26FN7O+,448.2261;found,448.2261.HPLC purity:99.0%
N-(2-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(6),黄色固体,产率:20.7%.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.39(s,1H),7.90(s,1H),7.75(d,J=8.9Hz,1H),7.61(d,J=7.4Hz,2H),7.36–7.33(m,2H),7.29(s,1H),7.27(s,1H),6.85(d,J=8.8Hz,2H),6.57(dd,J=17.0,10.2Hz,1H),6.31(d,J=18.5Hz,1H),5.81(d,J=11.7Hz,1H),2.88(s,4H),2.52(s,4H),2.12(s,3H),1.25(s,3H).13C NMR(101MHz,DMSO)δ164.58,162.18,159.55,159.24,153.69,143.87,133.14,131.71,130.17,128.65,128.20,127.28,125.60,124.49,118.99,116.86,107.62,52.84,46.56,42.62,13.39.HRMS(ESI)m/z:calcd for C25H29N7O+,444.2512;found,448.2512.HPLCpurity:99.9%
N-(2-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(7),土黄色固体,产率:19.4%.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.61(s,1H),8.23(s,1H),8.00–7.93(m,1H),7.81(s,1H),7.48(d,J=9.0Hz,2H),7.40(d,J=7.7Hz,1H),7.36–7.27(m,1H),7.20(td,J=7.8,1.3Hz,1H),6.82–6.71(m,2H),6.50(dd,J=17.0,10.1Hz,1H),6.33(dd,J=17.0,2.0Hz,1H),5.82(d,J=11.8Hz,1H),3.80(s,3H),3.08–2.95(m,4H),2.49–2.40(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ164.59,154.69,152.48,145.80,138.07,134.80,134.39,133.13,131.59,130.45,128.00,126.25,125.93,125.47,124.65,119.75,116.43,57.80,55.25,49.65,46.29.HRMS(ESI)m/z:calcd forC25H29FN7O2 +,460.2461;found,460.2442.HPLC purity:97.7%
N-(2-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺(8),白色固体,产率:11.5%.1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.66(s,1H),8.50(s,1H),8.28(s,1H),7.65(d,J=9.2Hz,1H),7.49(d,J=6.9Hz,1H),7.27(d,J=8.8Hz,2H),7.08(ddd,J=6.6,3.5,2.1Hz,2H),6.87(d,J=9.0Hz,2H),6.49(dd,J=17.0,10.2Hz,1H),6.27(d,J=18.7Hz,1H),5.78(d,J=11.8Hz,1H),3.17–3.08(m,4H),2.50–2.46(m,4H),2.25(s,3H).13C NMR(101MHz,DMSO)δ164.22,161.58,157.79,156.06,156.00,148.85,132.25,131.97,130.36,129.86,127.71,126.44,125.68,125.56,124.90,124.41,115.56,55.09,48.92,46.26.HRMS(ESI)m/z:calcd for C25H26F3N7O+,498.2229;found,498.2215.HPLC purity:99.7%
N-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(9),土黄色固体,产率:22.5%.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.06(s,1H),8.47(s,1H),8.09(s,1H),7.79(d,J=7.9Hz,1H),7.45(d,J=7.7Hz,1H),7.40(d,J=8.8Hz,2H),7.35(d,J=7.7Hz,1H),7.28(t,J=8.2Hz,1H),6.74(d,J=9.0Hz,2H),6.53(dd,J=17.0,10.1Hz,1H),6.34(dd,J=17.0,1.6Hz,1H),5.83(dd,J=10.1,1.7Hz,1H),3.03(d,J=4.6Hz,4H),2.49–2.40(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ164.78,158.39,156.44,154.94,146.51,133.06,132.31,131.63,131.46,128.24,127.68,126.13,125.83,125.04,120.67,116.18,103.84,55.20,49.42,46.28.HRMS(ESI)m/z:calcd forC24H26ClN7O+,464.1966;found,464.1942.HPLC purity:99.5%
N-(2-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺(10),深绿色固体,产率:14.4%.1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.78(s,1H),8.51(s,1H),8.00(d,J=3.6Hz,1H),7.78(d,J=7.9Hz,1H),7.36–7.23(m,3H),7.17(d,J=7.4Hz,1H),6.61(dd,J=26.3,9.6Hz,3H),6.25(dd,J=17.0,1.8Hz,1H),5.79–5.69(m,1H),3.03–2.92(m,4H),2.48–2.40(m,4H),2.20(d,J=14.1Hz,6H).13C NMR(101MHz,DMSO)δ164.16,156.38,151.77,151.65,145.84,142.61,140.39,137.58,135.65,134.07,132.33,129.34,127.46,127.05,121.26,119.48,116.22,55.25,49.57,46.31,19.05.HRMS(ESI)m/z:calcd for C25H28FN7O+,462.2418;found,462.2402.HPLC purity:99.6%
N-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺(11),灰白色固体,产率:16.7%.1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.99(s,1H),8.24(s,1H),8.04(s,1H),7.54(d,J=7.8Hz,1H),7.32(t,J=7.8Hz,1H),7.28–7.19(m,3H),6.61(d,J=8.7Hz,2H),6.54(dd,J=17.0,10.2Hz,1H),6.29(dd,J=17.0,1.7Hz,1H),5.82–5.69(m,1H),3.07–2.87(m,4H),2.49–2.41(m,4H),2.21(d,J=19.1Hz,6H).13C NMR(101MHz,DMSO)δ164.45,158.39,157.23,154.49,146.03,137.75,134.89,133.48,131.88,130.96,130.16,127.85,127.72,127.17,121.88,119.75,116.14,55.14,49.37,46.19,19.05.HRMS(ESI)m/z:calcd for C25H28ClN7O+,478.2122;found,478.2115.HPLC purity:99.6%
N-(3-甲基-2-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(12),黑色固体,产率:15.3%.1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.57(s,1H),7.77(d,J=8.1Hz,2H),7.59(d,J=7.9Hz,1H),7.33–7.25(m,3H),7.21(d,J=7.2Hz,1H),6.60(d,J=9.0Hz,2H),6.53(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,1.7Hz,1H),5.75(d,J=11.8Hz,1H),3.00–2.92(m,4H),2.49–2.39(m,4H),2.22(s,3H),2.17(s,3H),2.07(s,3H).13C NMR(101MHz,DMSO)δ164.37,160.72,159.00,155.46,145.34,137.82,134.95,134.54,132.05,131.71,127.70,127.48,126.64,121.53,119.25,116.35,104.81,55.04,49.44,45.97,19.16,13.53.HRMS(ESI)m/z:calcd for C26H31N7O+,458.2668;found,458.2657.HPLC purity:94.3%
N-(2-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺(13),白色固体,产率:14.8%.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.66(d,J=19.7Hz,2H),7.91–7.70(m,2H),7.33(t,J=7.8Hz,1H),7.19(d,J=7.5Hz,1H),7.11(d,J=8.8Hz,2H),6.73(d,J=8.7Hz,2H),6.57(dd,J=16.9,10.2Hz,1H),6.25(d,J=16.9Hz,1H),5.82–5.67(m,1H),3.89(s,3H),3.17(s,4H),2.86(s,4H),2.51(s,3H),2.15(s,3H).13C NMR(101MHz,DMSO)δ164.23,159.86,156.63,149.42,146.34,136.97,135.19,134.80,132.09,131.11,127.99,127.80,127.15,121.76,121.58,118.84,116.88,57.74,52.85,46.55,42.61,18.74.HRMS(ESI)m/z:calcd for C26H31N7O2 +,474.2617;found,474.2602.HPLC purity:99.3%
N-(3-甲基-2-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺(14),黄色油状液体,产率:9.2%.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.28(s,1H),8.05(s,1H),7.36(s,2H),7.33–7.26(m,1H),7.19(d,J=28.7Hz,2H),6.63(d,J=43.8Hz,2H),6.47(dd,J=17.0,10.1Hz,1H),6.29(d,J=17.0Hz,1H),5.78(d,J=10.1Hz,1H),5.34(s,1H),3.00(s,4H),2.47–2.41(m,4H),2.23(s,3H),2.18(s,3H).13CNMR(101MHz,DMSO)δ174.85,164.41,161.03,158.12,155.70,155.66,137.78,134.27,132.48,131.64,131.51,130.15,128.17,127.93,127.30,122.41,115.91,55.17,49.25,46.27,18.91.HRMS(ESI)m/z:calcd for C26H28F3N7O+,512.2386;found,512.2372.HPLCpurity:94.9%
N-(3-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(15),浅绿色固体,产率:22.8%.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.36(s,1H),8.91(s,1H),8.07(d,J=3.7Hz,1H),7.96(s,1H),7.48(dd,J=14.0,8.8Hz,4H),7.29(t,J=8.1Hz,1H),6.78(d,J=9.0Hz,2H),6.49(dd,J=17.0,10.1Hz,1H),6.28(dd,J=17.0,1.9Hz,1H),5.83–5.73(m,1H),3.06–2.96(m,4H),2.49–2.40(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ163.58,156.28,150.26,146.30,141.94,141.27,139.59,139.49,133.55,132.44,129.15,127.36,120.40,117.80,116.28,115.28,113.99,55.20,49.48,46.29.HRMS(ESI)m/z:calcd for C24H26FN7O+,448.2261;found,448.2250.HPLC purity:99.6%
N-(3-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(16),浅黄色固体,产率:20.3%.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.68(s,1H),8.32(s,1H),7.94(s,1H),7.86(s,1H),7.52(d,J=9.0Hz,2H),7.45(d,J=7.9Hz,1H),7.39(d,J=8.0Hz,1H),7.28(t,J=8.0Hz,1H),6.73(d,J=9.0Hz,2H),6.48(dd,J=17.0,10.1Hz,1H),6.28(dd,J=17.0,2.0Hz,1H),5.77(dd,J=10.1,2.0Hz,1H),3.03–2.92(m,4H),2.48–2.38(m,4H),2.23(s,3H),2.11(s,3H).13C NMR(101MHz,DMSO)δ163.54,159.79,158.86,156.40,145.87,140.63,139.37,134.05,132.49,128.93,127.26,120.05,118.48,116.35,114.85,114.78,105.36,55.23,49.58,46.30,14.07.HRMS(ESI)m/z:calcd forC25H29N7O+,444.2512;found,444.2504.HPLC purity:99.9%
N-(4-(2-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺(17),粉色固体,产率:18.1%.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.79(s,1H),7.83(d,J=3.7Hz,1H),7.64(d,J=8.4Hz,2H),7.56(d,J=9.0Hz,2H),7.51(t,J=5.6Hz,1H),7.23(d,J=8.4Hz,2H),6.79(d,J=9.0Hz,2H),6.46(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,2.0Hz,1H),5.76(dd,J=10.1,2.0Hz,1H),3.67–3.53(m,2H),3.07–2.98(m,4H),2.90–2.83(m,2H),2.49–2.43(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ163.49,156.66,152.46,145.97,139.90,139.13,137.70,135.03,134.15,132.44,129.44,127.17,120.02,119.85,116.32,55.21,49.49,46.24,41.92,34.93.HRMS(ESI)m/z:calcd forC26H30FN7O+,476.2574;found,476.2560.HPLC purity:99.5%
N-(4-(((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)甲基)苯基)丙烯酰胺(18),浅黄色固体,产率:19.6%.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.75(s,1H),7.94(t,J=5.9Hz,1H),7.85(d,J=3.7Hz,1H),7.63(d,J=8.5Hz,2H),7.44(d,J=9.0Hz,2H),7.31(d,J=8.5Hz,2H),6.78(d,J=9.1Hz,2H),6.44(dd,J=17.0,10.1Hz,1H),6.26(dd,J=17.0,2.0Hz,1H),5.75(dd,J=10.1,2.0Hz,1H),4.55(d,J=5.9Hz,2H),3.09–2.98(m,4H),2.49–2.40(m,4H),2.22(s,3H).13C NMR(101MHz,DMSO)δ163.53,156.57,152.43,152.31,146.01,139.89,138.16,135.27,134.04,132.40,128.04,127.22,119.97,119.75,116.33,55.23,49.52,46.26,43.18.HRMS(ESI)m/z:calcd for C25H28FN7O+,462.2418;found,448.2403.HPLC purity:98.4%
1-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(19),白色固体,产率:27.3%.1H NMR(400MHz,CDCl3)δ7.80(d,J=3.2Hz,1H),7.45(d,J=8.9Hz,2H),6.93(d,J=8.9Hz,2H),6.84(s,1H),6.63(dd,J=16.8,10.6Hz,1H),6.33(dd,J=16.8,1.8Hz,1H),5.74(dd,J=10.6,1.8Hz,1H),4.86(d,J=7.2Hz,1H),4.67(d,J=12.2Hz,1H),4.28–3.98(m,2H),3.33–3.16(m,5H),2.94(t,J=12.8Hz,1H),2.75–2.64(m,4H),2.43(s,3H),2.20(s,4H).13C NMR(101MHz,CDCl3)δ165.57,156.17,146.68,142.30,139.39,139.19,133.23,128.01,127.65,120.70,117.19,55.00,49.67,47.90,45.79,31.80,29.75.HRMS(ESI)m/z:calcd for C23H30FN7O+,440.2574;found,440.2561.HPLC purity:95.7%
N-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺,淡黄色固体(20),产率:24.9%.1H NMR(400MHz,DMSO-d6)δ9.91(d,J=10.0Hz,1H),9.22(s,1H),8.91(s,1H),8.03(d,J=3.7Hz,1H),7.73(d,J=8.8Hz,2H),7.57–7.43(m,4H),6.84(d,J=9.0Hz,2H),3.12–3.01(m,4H),2.27(s,4H),2.05(d,J=5.1Hz,3H),1.25(s,3H).13CNMR(101MHz,DMSO)δ168.47,156.33,150.18,150.07,146.32,140.58,135.22,134.73,133.72,122.14,120.69,119.66,116.36,55.13,49.41,46.11,24.44.HRMS(ESI)m/z:calcdfor C23H26FN7O+,436.2261;found,436.2255.HPLC purity:99.0%
N-(2,6-二氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(21),黄色固体,产率:26.4%.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.54(s,1H),9.11(s,1H),8.21–8.12(m,1H),7.98(s,2H),7.43(d,J=8.8Hz,2H),6.89(d,J=9.0Hz,2H),3.11–2.98(m,4H),2.49–2.39(m,4H),2.23(s,3H),2.07(s,3H).13C NMR(101MHz,DMSO)δ168.94,156.47,149.49,149.39,146.74,139.69,139.37,133.91,133.03,127.73,121.30,120.10,116.61,55.23,49.43,46.29,22.91.HRMS(ESI)m/z:calcd forC23H24Cl2FN7O+,504.1482;found,504.1470.HPLC purity:99.7%
N-(2,6-二氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(22),白色固体,产率:28.2%.1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.26(s,1H),8.98(s,1H),8.17(s,1H),7.89(s,2H),7.42(d,J=8.8Hz,2H),6.87(d,J=9.0Hz,2H),3.13–2.99(m,4H),2.50–2.42(m,4H),2.23(s,3H),2.08(s,3H).13C NMR(101MHz,DMSO)δ168.92,158.48,155.92,155.87,146.91,139.44,133.70,132.46,128.44,121.93,121.44,116.51,103.74,55.21,49.32,46.29,
22.93.HRMS(ESI)m/z:calcd for C23H24Cl3N7O+,520.1186;found,520.1176.HPLCpurity:99.2%
N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(23),白色固体,产率:22.7%.1H NMR(400MHz,DMSO-d6)δ9.44(d,J=25.8Hz,2H),9.02(s,1H),8.16–7.96(m,2H),7.72(d,J=8.3Hz,1H),7.59(d,J=8.7Hz,1H),7.47(d,J=8.8Hz,2H),6.88(d,J=8.9Hz,2H),3.15–2.99(m,4H),2.50–2.38(m,4H),2.24(s,3H),2.10(s,3H).13C NMR(101MHz,DMSO)δ169.09,156.40,149.80,146.59,141.89,139.44,137.52,133.33,130.28,127.18,126.98,121.43,121.03,120.28,116.52,55.23,49.47,46.28,23.75.HRMS(ESI)m/z:calcd for C23H25ClFN7O+,470.1871;found,470.1861.HPLCpurity:99.5%
N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙酰胺(24),白色固体,产率:21.1%.1H NMR(400MHz,DMSO-d6)δ9.40(s,2H),9.02(s,1H),8.25–7.86(m,2H),7.83–7.25(m,4H),6.87(s,2H),3.19–2.94(m,4H),2.46(s,6H),2.23(s,3H),1.12(s,3H).13C NMR(101MHz,DMSO)δ172.79,156.43,149.83,149.73,146.58,139.43,137.48,133.31,130.32,127.36,127.07,121.57,121.01,120.45,116.48,55.25,49.46,46.31,29.35,10.25.HRMS(ESI)m/z:calcd for C24H27ClFN7O+,484.2028;found,448.2022.HPLC purity:99.8%
N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)苯甲酰胺(25),淡黄色固体,产率:20.5%.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.48(s,1H),9.06(s,1H),8.12(d,J=3.4Hz,1H),8.05(dd,J=14.3,4.6Hz,3H),7.78(d,J=7.4Hz,1H),7.64(t,J=7.2Hz,1H),7.57(t,J=7.4Hz,2H),7.49(t,J=8.3Hz,3H),6.89(d,J=8.9Hz,2H),3.14–2.97(m,4H),2.49–2.36(m,4H),2.21(s,3H).13C NMR(101MHz,DMSO)δ166.00,156.42,149.84,149.74,146.60,141.91,141.74,141.55,139.47,138.65,134.55,133.30,132.29,130.14,130.10,128.99,128.18,121.66,121.03,120.44,116.50,55.22,49.45,46.28.HRMS(ESI)m/z:calcd for C28H27ClFN7O+,532.2028;found,532.2029.HPLCpurity:99.8%
N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(26),黄褐色固体,产率:22.1%.1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.16(s,1H),8.86(s,1H),8.12(s,1H),7.85(s,1H),7.62(s,2H),7.43(d,J=8.8Hz,2H),6.85(d,J=9.0Hz,2H),3.14–2.96(m,4H),2.50–2.43(m,4H),2.24(s,3H),2.11(s,3H).13C NMR(101MHz,DMSO)δ166.00,156.42,149.84,149.74,146.60,141.77,139.47,138.65,134.55,133.30,132.29,130.14,128.99,128.18,121.66,121.03,120.44,116.50,55.22,49.45,46.28.HRMS(ESI)m/z:calcd for C23H25Cl2N7O+,486.1576;found,486.1563.HPLC purity:95.1%
N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)(甲基)氨基)苯基)乙酰胺(27),黄褐色固体,产率:20.6%.1H NMR(400MHz,Chloroform-d)δ8.40(d,J=8.8Hz,1H),7.83(d,J=5.4Hz,1H),7.66(s,1H),7.44(d,J=8.9Hz,2H),7.26(d,J=1.9Hz,1H),7.16(dd,J=8.8,2.2Hz,1H),7.00(s,1H),6.92(d,J=8.9Hz,2H),3.48(s,3H),3.25–3.16(m,4H),2.69–2.63(m,4H),2.41(s,3H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ168.26,155.96,151.68,146.81,143.47,143.23,140.54,132.96,132.78,125.98,124.89,122.66,121.94,120.62,117.11,55.13,49.84,46.00,40.11,24.86.HRMS(ESI)m/z:calcdfor C24H27ClFN7O+,484.2028;found,484.2027.HPLC purity:99.7%
N-(2-氯-4-(乙基(5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(28),黄色固体,产率:18.7%.1H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.7Hz,1H),7.82(d,J=5.5Hz,1H),7.66(s,1H),7.43(d,J=8.9Hz,2H),7.25(d,J=2.1Hz,1H),7.15(dd,J=8.8,2.2Hz,1H),6.93(s,1H),6.90(d,J=5.2Hz,2H),3.97(q,J=7.0Hz,2H),3.25–3.17(m,4H),2.71–2.64(m,4H),2.42(s,3H),2.29(s,3H),1.26(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ168.28,155.94,151.09,146.69,143.52,143.28,140.18,133.13,132.96,126.91,125.92,122.59,121.82,120.50,117.12,55.12,49.84,47.01,45.98,24.91,12.88.HRMS(ESI)m/z:calcd for C25H29ClFN7O+,498.2184;found,498.2176.HPLC purity:99.6%
N-(2-氯-4-(乙基(5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(29),白色固体,产率:20.3%.1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.27(s,1H),9.03(s,1H),8.10(d,J=3.4Hz,1H),8.04–7.97(m,1H),7.83(d,J=8.8Hz,1H),7.77(d,J=8.2Hz,1H),7.46(d,J=8.6Hz,2H),6.87(d,J=8.8Hz,2H),4.49(dd,J=8.0,5.5Hz,1H),4.04(q,J=6.8Hz,1H),3.90(q,J=7.0Hz,1H),3.07(s,4H),2.47(s,4H),2.24(s,4H),2.04(dq,J=12.4,6.2Hz,1H),1.92(p,J=6.6Hz,2H).13C NMR(101MHz,DMSO)δ171.91,156.40,149.79,146.60,141.63,139.44,137.43,133.28,129.44,126.04,124.76,121.49,121.09,120.61,116.44,78.44,69.54,55.25,49.45,46.31,30.48,25.57.HRMS(ESI)m/z:calcd for C26H29ClFN7O+,526.2134;found,526.2127.HPLC purity:97.0%
N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(30),黄色固体,产率:23.1%.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.16(s,1H),8.90(s,1H),8.13(s,1H),7.86(s,1H),7.70(t,J=9.8Hz,2H),7.43(d,J=8.3Hz,2H),6.85(d,J=8.6Hz,2H),6.64(dd,J=16.5,10.5Hz,1H),6.30(d,J=16.9Hz,1H),5.81(d,J=10.2Hz,1H),3.06(s,4H),2.45(s,4H),2.23(s,3H).13CNMR(101MHz,DMSO)δ164.05,158.44,156.18,155.48,146.67,137.45,132.75,131.91,130.63,127.70,126.98,126.72,123.60,122.45,121.19,116.36,103.52,55.13,49.22,46.17.HRMS(ESI)m/z:calcd forC24H25Cl2N7O+,498.1576;found,498.1569.HPLC purity:98.2%
N-(2,6-二氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(31),白色固体,产率:21.9%.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.27(s,1H),9.02(s,1H),8.18(s,1H),7.91(s,2H),7.42(d,J=8.6Hz,2H),6.88(d,J=8.9Hz,2H),6.51(dd,J=17.1,10.2Hz,1H),6.29(d,J=17.0Hz,1H),5.83(d,J=10.3Hz,1H),3.06(s,4H),2.50–2.42(m,4H),2.24(s,3H).13C NMR(101MHz,DMSO)δ164.01,158.44,156.03,155.93,146.80,139.60,133.57,132.50,131.20,128.03,127.88,122.21,121.32,116.51,103.68,55.12,49.19,46.17.HRMS(ESI)m/z:calcd for C24H24Cl3N7O+,532.1186;found,532.1174.HPLC purity:99.2%
N-(3-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(32),黄色固体,产率:23.5%.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.10(s,1H),8.86(s,1H),8.10(s,1H),7.91(s,1H),7.56(s,1H),7.47(d,J=8.0Hz,2H),7.31(s,2H),6.73(d,J=7.8Hz,2H),6.50(dd,J=16.7,10.1Hz,1H),6.28(d,J=16.8Hz,1H),5.78(d,J=9.9Hz,1H),3.01(s,4H),2.48(s,4H),2.26(s,3H).13CNMR(101MHz,DMSO)δ163.61,158.30,156.57,155.26,146.36,139.50,139.38,133.09,132.43,130.15,129.07,127.37,120.62,119.46,116.18,115.90,103.49,55.05,49.24,46.09.HRMS(ESI)m/z:calcd forC24H26ClN7O+,464.1966;found,464.1958.HPLC purity:98.5%
N-(4-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺(33),淡黄色固体,产率:18.6%.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.97(s,1H),7.90(s,1H),7.65(d,J=8.1Hz,2H),7.56(d,J=8.6Hz,2H),7.22(d,J=8.0Hz,3H),6.78(d,J=8.7Hz,2H),6.46(dd,J=16.9,10.1Hz,1H),6.28(d,J=16.8Hz,1H),5.77(d,J=9.8Hz,1H),3.69–3.56(m,2H),3.04(s,4H),2.92–2.80(m,2H),2.47(s,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ163.49,158.75,157.79,153.55,146.25,137.71,135.00,133.52,132.45,129.41,127.16,120.54,119.84,116.22,103.17,55.16,49.34,46.20,42.31,34.90.HRMS(ESI)m/z:calcd for C26H30ClN7O+,492.2279;found,492.2271.HPLC purity:95.9%
(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)但-2-烯酰胺(34),白色固体,产率:19.3%.1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.17(s,1H),8.89(s,1H),8.13(s,1H),7.85(s,1H),7.67(d,J=14.0Hz,2H),7.52–7.31(m,2H),6.98–6.72(m,3H),6.33(d,J=13.0Hz,1H),3.06(s,4H),2.46(s,4H),2.24(s,3H),1.99–1.79(m,3H).13C NMR(101MHz,DMSO)δ164.29,158.45,156.19,155.44,146.71,140.72,137.19,132.75,130.94,126.85,126.63,126.04,123.61,122.42,121.19,116.36,103.47,55.20,49.30,46.27,18.08.HRMS(ESI)m/z:calcd for C25H27Cl2N7O+,512.1732;found,512.1719.HPLC purity:98.3%
N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-3-甲基丁-2-烯酰胺(35),白色固体,产率:19.1%.1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),9.16(s,1H),8.89(s,1H),8.12(s,1H),7.85–7.74(m,1H),7.73–7.57(m,2H),7.43(d,J=8.8Hz,2H),6.85(d,J=9.0Hz,2H),6.06(s,1H),3.11–3.00(m,4H),2.49–2.38(m,4H),2.23(s,3H),2.18(s,3H),1.90(s,3H).13C NMR(101MHz,DMSO)δ164.29,158.45,156.19,155.44,146.71,140.72,137.19,132.75,130.94,126.85,126.63,126.04,123.61,122.42,121.19,116.36,103.47,55.20,49.30,46.27,18.08.HRMS(ESI)m/z:calcd forC26H29Cl2N7O+,526.1889;found,526.1875.HPLC purity:96.4%
(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-2-甲基丁-2-烯酰胺(36),白色固体,产率:19.2%.1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.18(s,1H),8.92(s,1H),8.13(s,1H),7.82(s,1H),7.67–7.58(m,1H),7.48(d,J=8.6Hz,1H),7.43(d,J=8.0Hz,2H),6.86(d,J=8.5Hz,2H),6.61(d,J=6.5Hz,1H),3.07(s,4H),2.47(s,4H),2.24(s,3H),1.89(s,3H),1.82(d,J=6.4Hz,3H).13C NMR(101MHz,DMSO)δ169.25,167.93,158.42,156.25,155.47,146.61,137.68,136.88,132.79,132.28,131.70,131.32,129.14,129.03,127.95,121.07,116.37,55.15,49.21,46.18,14.42,12.92.HRMS(ESI)m/z:calcd for C26H29Cl2N7O+,526.1889;found,526.1872.HPLC purity:98.4%
(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-4,4,4-三氟丁-2-烯酰胺(37),黄色油状液体,产率:14.4%.1H-NMR(400MHz,Chloroform-d)δ8.11–7.90(m,1H),7.82(d,J=24.3Hz,1H),7.56–7.34(m,3H),7.26(d,J=25.5Hz,2H),7.11(dq,J=17.8,10.0,9.5Hz,2H),7.02–6.71(m,4H),3.26(s,4H),2.73(s,4H),2.47(s,3H).13C NMR(101MHz,CDCl3)δ158.30,155.55,154.10,153.66,146.91,145.57,133.13,132.26,127.86,122.93,122.42,122.15,121.45,121.06,120.66,117.35,115.74,104.37,77.41,77.09,76.77,54.94,49.49,45.76.HPLC purity:98.5%
N-丙烯酰基-2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯甲酰胺(38),黄色油状液体,产率:11.2%.1H-NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.95(s,1H),8.16(s,1H),7.91(s,1H),7.83(s,1H),7.80–7.71(m,1H),7.53(s,1H),7.48–7.34(m,4H),6.88(d,J=8.7Hz,3H),3.08(s,4H),2.50(d,J=5.6Hz,4H),2.26(s,3H).13C-NMR(101MHz,DMSO)δ168.47,158.50,155.88,155.77,146.85,141.29,133.24,132.60,131.77,130.29,130.16,129.31,127.07,122.81,121.55,120.60,116.46,103.83,55.09,49.20,46.13.HPLC purity:94.5%
N-(2-氯-4-((5-氯-2-((3-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(39),黄色固体,产率:20.7%.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.24(s,1H),8.96(s,1H),8.19(s,1H),7.80(d,J=50.5Hz,3H),7.38–6.92(m,3H),6.60(d,J=41.1Hz,2H),6.30(d,J=16.1Hz,1H),5.81(s,1H),3.06(s,4H),2.52(s,4H),2.27(s,3H).13C NMR(101MHz,DMSO)δ164.05,158.27,156.02,155.43,151.68,141.42,137.28,131.96,130.63,129.89,129.37,127.75,126.49,123.36,121.89,110.97,109.82,106.97,104.43,54.78,48.31,45.78.HRMS(ESI)m/z:calcd for C24H25Cl2N7O+,498.1576;found,498.1561.HPLC purity:99.6%
N-(2-氯-4-((5-氯-2-((2-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(40),黄褐色固体,产率:21.3%.1H NMR(400MHz,Chloroform-d)δ8.50(d,J=8.2Hz,1H),8.35(d,J=7.9Hz,1H),8.25(s,1H),8.15(d,J=12.5Hz,1H),7.78(s,1H),7.36–7.30(m,1H),7.22–7.14(m,1H),7.11(s,1H),6.99(ddt,J=23.2,15.0,7.7Hz,2H),6.77(t,J=8.0Hz,1H),6.50(d,J=16.8Hz,1H),6.35(dd,J=16.9,10.2Hz,1H),5.94–5.77(m,1H),3.05–2.94(m,4H),2.87–2.55(m,4H),2.44(d,J=8.4Hz,3H).13C NMR(101MHz,CDCl3)δ163.33,157.67,155.35,154.62,141.51,140.78,134.55,131.10,128.30,125.40,124.81,122.00,121.84,120.47,120.00,118.71,118.38,115.21,104.90,55.77,51.93,46.01.HRMS(ESI)m/z:calcd for C24H25Cl2N7O+,498.1576;found,498.1574.HPLC purity:98.0%
N-(2-氯-4-((5-氯-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(41),紫色固体,产率:20.0%.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.15(s,1H),8.90(s,1H),8.19(s,1H),8.12(s,1H),7.87–7.75(m,2H),7.67(s,2H),6.78(d,J=9.1Hz,1H),6.63(dd,J=16.9,10.3Hz,1H),6.29(dd,J=17.0,1.6Hz,1H),5.85–5.73(m,1H),3.44–3.39(m,4H),2.46–2.35(m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ164.05,158.78,158.13,156.17,155.71,155.50,140.59,137.43,131.92,131.59,130.57,128.28,127.69,127.04,126.73,123.36,122.16,107.34,54.83,46.19,45.59.HRMS(ESI)m/z:calcd for C24H24Cl2N8O+,499.1528;found,499.1526.HPLC purity:96.7%
N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(42),白色固体,产率:19.5%.1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.17(s,1H),8.91(s,1H),8.13(s,1H),7.83(s,1H),7.69(s,2H),7.43(d,J=8.6Hz,2H),6.86(d,J=9.0Hz,2H),6.64(dd,J=16.9,10.2Hz,1H),6.30(dd,J=17.0,1.6Hz,1H),5.85–5.75(m,1H),3.50(d,J=10.4Hz,4H),2.19(t,J=11.0Hz,2H),1.08(d,J=6.2Hz,7H).13C NMR(101MHz,DMSO)δ164.04,158.47,156.18,155.49,146.50,137.45,132.72,131.99,130.63,127.61,126.98,126.66,123.64,122.64,122.50,121.35,116.49,55.63,50.77,19.08.HRMS(ESI)m/z:calcd for C25H27Cl2N7O+,512.1732;found,512.1731.HPLCpurity:94.6%
N-(2-氯-4-((5-氯-2-((4-(4-乙基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(43),米黄色固体,产率:18.3%.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.22(s,1H),8.92(s,1H),8.16(s,1H),7.92(s,1H),7.70(s,2H),7.25–7.18(m,1H),7.15(s,1H),6.80(d,J=8.6Hz,1H),6.64(dd,J=17.0,10.3Hz,1H),6.30(dd,J=17.0,1.9Hz,1H),5.80(dd,J=10.2,1.8Hz,1H),3.64(s,3H),2.93(s,4H),2.55–2.52(m,4H),2.45–2.33(m,2H),1.04(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ164.03,158.35,156.04,155.44,152.36,137.43,136.33,135.90,132.05,131.93,130.57,127.70,126.97,126.63,123.26,121.97,118.38,112.33,105.19,104.03,55.59,53.07,52.17,50.70,12.31.HRMS(ESI)m/z:calcd for C26H29Cl2N7O+,542.1838;found,542.1837.HPLC purity:99.0%
N-(2-氯-4-((5-氯-2-((4-(4-(2-甲氧基乙基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(44),米黄色固体,产率:17.4%.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.16(s,1H),8.89(s,1H),8.12(s,1H),7.87(s,1H),7.70(t,J=10.7Hz,2H),7.43(d,J=8.5Hz,2H),6.85(d,J=8.8Hz,2H),6.65(dd,J=16.7,10.1Hz,1H),6.30(d,J=16.9Hz,1H),5.81(d,J=10.2Hz,1H),3.49(t,J=5.6Hz,2H),3.27(s,4H),3.06(s,4H),2.58(s,5H).13C NMR(101MHz,DMSO)δ164.05,158.45,156.18,155.48,146.71,137.45,132.77,131.94,130.63,127.69,126.98,126.70,123.59,122.43,121.24,116.38,103.56,70.28,58.54,57.47,53.61,49.32,40.64,40.43,40.22,40.01,39.81,39.60,39.39.HRMS(ESI)m/z:calcd for C26H29Cl2N7O2 +,542.1838;found,542.1834.HPLC purity:97.9%
N-(2-氯-4-((5-氯-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(45),灰白色固体,产率:10.6%.1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.49(s,1H),9.01(s,1H),8.20(s,1H),7.99(s,1H),7.89(s,1H),7.78(d,J=9.1Hz,1H),7.75–7.64(m,2H),7.43–7.31(m,1H),6.64(dd,J=16.5,10.3Hz,1H),6.30(d,J=17.1Hz,1H),5.81(d,J=10.2Hz,1H),3.15(s,4H),2.57(s,4H),2.30(s,3H).13C NMR(101MHz,DMSO)δ164.09,157.49,156.27,155.42,146.00,142.84,137.39,135.70,131.89,130.79,127.72,127.16,126.89,125.85,123.85,122.73,114.37,104.69,54.69,48.62,45.84.HRMS(ESI)m/z:calcd for C24H24Cl2N8O+,499.1528;found,499.1527.HPLC purity:94.8%
N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基))氨基)苯基)丙烯酰胺(46),灰白色固体,产率:19.9%.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.21(s,1H),8.91(s,1H),8.16(s,1H),7.89(s,1H),7.70(s,2H),7.26–7.08(m,2H),6.78(d,J=8.6Hz,1H),6.64(dd,J=17.0,10.2Hz,1H),6.30(dd,J=17.0,1.8Hz,1H),5.80(dd,J=10.2,1.8Hz,1H),3.64(s,3H),3.15(d,J=9.6Hz,2H),2.99–2.87(m,2H),2.09(t,J=10.5Hz,2H),0.99(d,J=6.3Hz,7H).13C NMR(101MHz,DMSO)δ164.02,158.37,156.04,155.45,152.39,137.44,136.54,135.74,131.94,130.56,127.68,126.96,126.62,123.25,122.00,118.57,112.46,105.34,104.00,57.95,55.64,50.85,19.78.HRMS(ESI)m/z:calcd for C26H29Cl2N7O2 +,542.1838;found,542.1832.HPLC purity:96.8%
N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基))氨基)苯基)丙烯酰胺(47),褐色固体,产率:17.3%.1H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.1Hz,1H),8.02(s,1H),7.90(d,J=2.1Hz,1H),7.70(s,1H),7.33(d,J=8.8Hz,2H),7.02(s,1H),6.89(s,1H),6.82(d,J=8.9Hz,2H),6.44(d,J=16.8Hz,1H),6.32(dd,J=16.9,10.1Hz,1H),5.83(d,J=10.1Hz,1H),5.30(s,1H),3.59(t,J=11.6Hz,1H),3.48(s,2H),3.11(d,J=11.3Hz,2H),2.78(s,3H),2.43(s,3H),2.02(d,J=15.5Hz,4H).13C NMR(101MHz,CDCl3)δ163.92,163.27,158.70,155.28,154.61,146.86,131.20,130.33,128.20,122.90,121.87,121.22,120.28,120.23,115.59,115.19,104.16,56.54,55.29,45.45,29.75,29.37,28.14.HRMS(ESI)m/z:calcd for C26H29Cl2N7O+,526.1889;found,526.1884.HPLC purity:94.2%.
N-(2-氯-4-((5-氯-2-((4-(4-甲基-1,4-二氮杂-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(48),黄色固体,产率:16.5%.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.02(s,1H),8.85(s,1H),8.09(s,1H),7.86(s,1H),7.69(s,2H),7.34(d,J=8.2Hz,2H),6.62(d,J=8.7Hz,3H),6.29(d,J=17.0Hz,1H),5.85–5.74(m,1H),3.48(d,J=19.6Hz,6H),2.68(s,2H),2.32(s,3H),1.98–1.85(m,2H).13CNMR(101MHz,DMSO)δ164.04,158.68,156.09,155.50,144.96,137.52,131.97,130.49,129.53,127.63,126.96,126.63,123.36,122.35,122.23,111.97,103.13,57.60,56.66,48.20,47.98,46.07,26.92.HRMS(ESI)m/z:calcd for C25H27Cl2N7O+,512.1732;found,512.1733.HPLC purity:82.0%
N-(2-氯-4-((5-氯-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(49),白色固体,产率:20.6%.1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.42(s,1H),9.00(s,1H),8.20(s,1H),7.87(d,J=1.9Hz,1H),7.81–7.63(m,2H),7.48(d,J=15.1Hz,1H),7.34(d,J=8.7Hz,1H),6.95(t,J=9.4Hz,1H),6.66(dd,J=16.9,10.2Hz,1H),6.37–6.26(m,1H),5.82(d,J=11.9Hz,1H),2.96(s,4H),2.59–2.51(m,4H),2.26(s,3H).13C NMR(101MHz,DMSO)δ164.08,158.01,156.25,155.40,153.92,137.25,135.97,134.32,131.92,130.86,127.74,126.65,123.75,122.44,119.71,115.66,108.00,107.75,104.51,55.12,50.66,46.03.HRMS(ESI)m/z:calcd for C24H24Cl2FN7O+,516.1482;found,516.1481.HPLC purity:99.1%
N-(4-((2-((3-((4-乙酰哌嗪-1-基)磺酰基)苯基)氨基)-5-氯嘧啶-4-基)氨基)-2-氯苯基)丙烯酰胺(50),白色固体,产率:14.8%.1H NMR(400MHz,DMSO-d6)δ9.89–9.55(m,2H),9.08(s,1H),8.36–8.07(m,2H),8.06–7.79(m,2H),7.70(d,J=27.8Hz,2H),7.50(t,J=7.8Hz,1H),7.25(d,J=7.4Hz,1H),6.63(dd,J=16.3,10.4Hz,1H),6.31(d,J=16.9Hz,1H),5.81(d,J=10.2Hz,1H),3.52(s,4H),2.90(d,J=12.1Hz,4H),1.94(s,3H).13C NMR(101MHz,DMSO)δ168.89,164.13,157.78,156.40,155.23,141.89,137.20,135.53,131.87,130.98,130.08,127.84,126.84,123.97,123.42,122.49,120.24,117.90,105.74,60.28,46.31,45.42,21.57,14.59.HRMS(ESI)m/z:calcd for C25H25Cl2N7O4S+,590.1144;found,590.1140.HPLC purity:99.7%
N-(2-氯-4-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺(51),深褐色固体,产率:19.3%.1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.22(s,1H),8.93(s,1H),8.17(s,1H),7.91(s,1H),7.70(s,2H),7.26–7.12(m,2H),6.81(d,J=8.5Hz,1H),6.66(dd,J=16.7,10.1Hz,1H),6.31(d,J=17.1Hz,1H),5.87–5.75(m,1H),3.65(s,3H),3.35(d,J=11.0Hz,4H),2.35(s,7H),1.88(d,J=10.5Hz,2H),1.58(q,J=11.3,10.8Hz,2H).13C NMR(101MHz,DMSO)δ164.02,158.35,156.05,155.43,152.40,137.44,136.59,135.89,131.94,130.58,127.67,127.00,126.67,123.28,122.00,118.67,112.26,105.06,104.00,62.31,55.57,50.59,41.38,28.40.HRMS(ESI)m/z:calcd for C27H31Cl2N7O2 +,556.1995;found,556.1988.HPLC purity:94.7%
N-(4-((2-((4-([1,4'-双哌啶]-1'-基)-3-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)-2-氯苯基)丙烯酰胺(52),淡黄色固体,产率:17.7%.1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.23(s,1H),8.93(s,1H),8.16(s,1H),7.90(s,1H),7.69(s,2H),7.24–7.11(m,2H),6.81(d,J=8.6Hz,1H),6.65(dd,J=16.7,10.3Hz,1H),6.36–6.24(m,1H),5.86–5.76(m,1H),3.64(s,3H),2.90(s,4H),2.48(s,1H),1.97(q,J=12.4,10.5Hz,4H),1.70(s,8H),1.50(s,2H).13C NMR(101MHz,DMSO)δ164.05,158.31,156.06,155.43,152.39,137.44,136.19,136.07,131.92,130.59,127.73,127.05,126.69,123.29,122.00,118.77,118.70,112.17,104.96,62.93,55.58,50.50,49.77,27.38,24.52,22.60.HRMS(ESI)m/z:calcdfor C30H35Cl2N7O2 +,596.2308;found,596.2308.HPLC purity:93.4%
上述详细说明是针对发明的可行实施例的具体说明,该实施例并非用以限制本发明的专利范围,凡未脱离本发明的等效实施或变更,均应当包含于本发明的专利范围内。
另外,本领域技术人员还可在本发明权利要求公开的范围和精神内做其他形式和细节上的各种修改、添加和替换。当然,这些依据本发明精神所做的各种修改、添加和替换等变化,都应包含在本发明所要求保护的范围内。
Claims (10)
3.根据权利要求1所述的2,4,5-三取代嘧啶类化合物,其特征在于,所述的R1选自F,Cl或者CH3,OCH3或CF3。
4.根据权利要求1所述的2,4,5-三取代嘧啶类化合物,其特征在于,所述的R2为H,CH2或C2H5。
6.根据权利要求1所述的2,4,5-三取代嘧啶类化合物,其特征在于,为以下化合物、其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐,或其前药、或其代谢物中的一种:N-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(4-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(4-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(2-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺;N-(3-甲基-2-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-((5-甲氧基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-3-甲基苯基)丙烯酰胺;N-(3-甲基-2-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(3-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(3-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(4-(2-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺;N-(4-(((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)甲基)苯基)丙烯酰胺;1-(4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮;N-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2,6-二氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2,6-二氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙酰胺;N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)苯甲酰胺;
N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2-氯-4-((5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)(甲基)氨基)苯基)乙酰胺;N-(2-氯-4-(乙基(5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2-氯-4-(乙基(5-氟-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2,6-二氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(3-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(4-(2-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)乙基)苯基)丙烯酰胺;(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)但-2-烯酰胺;N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-3-甲基丁-2-烯酰胺;(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-2-甲基丁-2-烯酰胺;
(E)-N-(2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-4,4,4-三氟丁-2-烯酰胺;N-丙烯酰基-2-氯-4-((5-氯-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯甲酰胺;N-(2-氯-4-((5-氯-2-((3-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((2-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-(4-乙基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-(4-(2-甲氧基乙基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基))氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-((3R,5S)-3,5-二甲基哌嗪-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基))氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-(4-甲基-1,4-二氮杂-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺N-(4-((2-((3-((4-乙酰哌嗪-1-基)磺酰基)苯基)氨基)-5-氯嘧啶-4-基)氨基)-2-氯苯基)丙烯酰胺;N-(2-氯-4-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(4-((2-((4-([1,4'-双哌啶]-1'-基)-3-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)-2-氯苯基)丙烯酰胺。
7.一种含有权利要求1~6任一项所述的2,4,5-三取代嘧啶类化合物的药物组合物,其特征在于,所述的药物组合物的制剂形式为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂、纳米制剂的任一种。
8.一种如权利要求1-6任一项所述的2,4,5-三取代嘧啶类化合物在药物制备中的应用,其特征在于,所述的药物用于治疗与FGFR相关的疾病或病症;
所述药物以所述的2,4,5-三取代嘧啶类化合物为活性成分。
9.根据权利要求8所述的应用,其中所述与FGFR相关的疾病和病症选自癌症、骨骼障碍或软骨细胞障碍、低磷血症障碍和纤维化疾病。
10.根据权利要求8所述的应用,其中所述与FGFR相关的癌症选自肝细胞癌、乳腺癌、膀胱癌、结直肠癌、黑色素瘤、间皮瘤、肺癌、***癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成纤维细胞瘤、子宫癌、横纹肌肉瘤、皮肤癌、肾癌、淋巴瘤、***、头颈部鳞癌、恶性***、绒毛膜上皮癌、卵巢癌、胃癌、白血病中的一种或者多种。
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