CN115947693A - 一种fgfr4抑制剂及其制备与应用 - Google Patents
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Abstract
本发明属于药物化学领域，具体涉及一种FGFR4抑制剂及其制备与应用。所述的FGFR4抑制剂如通式I所示，具有良好的FGFR4抑制活性和FGFR4高选择性，能够用于治疗与此激酶密切联系的恶性肿瘤，
Description
技术领域
本发明属于药物化学领域，具体涉及一种FGFR4抑制剂及其制备与应用。
背景技术
FGFR(成纤维细胞生长因子受体)是一种受体型蛋白酪氨酸激酶，包含FGFR1，FGFR2，FGFR3、FGFR4和其他18种不同FGF配体的高亲和力受体，对维持细胞的生长、增殖、凋亡、迁移等起关键作用。各亚型均具有与配体结合的胞外区、跨膜区和受体磷酸化的胞内区的结构特点，是负责细胞增殖和分化的酪氨酸激酶信号通路的一部分。它们通过与18种不同的成纤维细胞生长因子(FGF)形成三元复合物，进而引发一系列的信号传导途径。FGFR分子改变可导致异常的FGF/FGFR信号，促进细胞增殖、新血管生成、侵袭、转移、抗凋亡等，与广泛的人类恶性肿瘤有关。
研究发现，FGF19/FGFR4信号通路通过多种途径促进肝细胞癌细胞生存，增殖，侵袭与转移，表明FGF19/FGFR4信号通路在肝癌进程中的作用机制可为其靶向治疗提供依据。因此，迫切需求开发FGFR4选择性抑制剂来治疗由异常FGFR4信号驱动的癌症患者。新型选择性FGFR4小分子激酶抑制剂逐渐成为一种很有前途的治疗方法，其研发受到越来越多的关注。
发明内容
本发明的一个目的是提供通式I所示的一种FGFR4抑制剂或其药学上可接受的盐，通式I所示的3-取代乙炔基苯酰胺类化合物具有良好的FGFR4抑制活性和FGFR4高选择性，能够用于治疗与此激酶密切联系的恶性肿瘤。
本发明的另一个目的是提供制备本发明的通式I的化合物或其药学上可接受的盐的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其药学上可接受的盐和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其药学上可接受的盐和另一种或多种药物的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其药学上可接受的盐治疗和/或预防FGFR4相关的疾病的方法，以及本发明的通式I的化合物或其药学上可接受的盐在制备用于治疗和/或预防FGFR4相关的疾病的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供式I所示的一种FGFR4抑制剂或其药学上可接受的盐：
其中，
R1选自氢、卤素、烷基；
R2选自乙烯基、烷基、卤代烷基、环烷基，所述乙烯基可以被烷基、烷氨基烷基取代；
R3选自氢、烷基、烷氧基；
R4选自杂环烷基或杂环芳基。
在一些优选实施方案中，R1选自氢、C1-6烷基；优选地，R1选自氢、甲基。
在一些优选实施方案中，R2选自乙烯基、丙烯基、N,N-二甲基丙烯-1-基、甲基、乙基、氯代甲基、环丙基；优选地，R2为乙烯基。
在一些优选实施方案中，R3选自氢、甲基、甲氧基。
在一些优选实施方案中，R4选自N-甲基哌嗪基、吗啉基、1,2,4三氮唑基。
在一些具体实施方案中，本发明提供式I-1所示的一种FGFR4抑制剂或其药学上可接受的盐：
其中，
R1选自氢、甲基；
R3选自氢、甲基、甲氧基。
第二方面，本发明提供下述化合物：
第三方面，本发明提供式I化合物的制备方法，所述方法包括：
(1)式(1)的化合物与式(2)的化合物反应生成式(3)的化合物；
(2)式(4)的化合物与式(5)的化合物反应生成式(6)的化合物；
(3)式(3)的化合物与式(6)的化合物缩合反应生成式(7)的化合物；
(4)式(7)的化合物水解得到式(8)的化合物；
(5)式(8)的化合物与式(9)的化合物缩合反应得到式(10)的化合物；
(6)式(10)的化合物还原得到式(11)的化合物；
(7)式(11)的化合物与取代酰氯反应得到式(I)的化合物，反应路线的如下：
第四方面，本发明提供一种药物组合物，其包含治疗有效剂量的通式(I)的化合物或其药学上可接受的盐。
第五方面，本发明涉及一种通式(I)化合物或其药学可接受的盐在制备治疗或预防FGFR4相关疾病药物中的应用，尤其是在制备治疗和预防肝癌药物中的应用。
术语解释
本发明所述的“烷基”是指直链或支链的饱和烃基，优选为C1-6烷基，进一步优选为C1-3烷基，合适的C1-3烷基为甲基、乙基、丙基或异丙基。
本发明所述的“卤素”是指氟、氯、溴或碘。
本发明所述的“烷氧基”是指烷基-O-，优选为C1-6烷氧基，进一步优选为C1-3烷氧基，合适的C1-3烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基。
本发明所述的“卤代烷基”是指至少被一个卤素取代的烷基，优选为卤素取代的C1-6烷基，进一步优选为卤素取代的C1-3烷基。
本发明所述的“药物组合物”是指包含任何一种本文所述化合物和一种或多种药学上可接受的载体和/或赋形剂的混合物。药物组合物的目的是促进化合物对生物体的给药。所述组合物通常用于治疗和/或预防由FGFR介导的疾病。
具体实施方式
一种制备上述的一类以FGFR4为靶点的苯乙炔类化合物的方法，步骤如下：实施例1：3-((2-((2-丙烯酰胺基-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备
3-乙炔基-4-甲基苯甲酸甲酯的合成
在冰浴条件下，将3-碘-4-甲基苯甲酸甲酯(4g，14.5mmol)溶解于N，N-二甲基甲酰胺(15ml)中，加入双(三苯基膦)二氯化钯(0.2g，0.28mmol)和碘化亚铜(0.275g，1.44mmol)，滴入三乙胺溶液(4.39g，43.46mmol)，体系用氮气置换3次，在冰浴状态反应下，向其中缓慢滴入乙炔基三甲基硅烷，搅拌10分钟后撤掉冰浴，反应混合物在室温下反应2h，然后向其中加入四丁基氟化铵(10％四氢呋喃溶液，4.6克，17.6mmol)。室温下搅拌反应30min。TLC监测显示反应完毕。冷却反应至室温，缓慢加入100ml乙酸乙酯淬灭反应，反应液经过硅藻土抽滤得母液，向滤液中加水萃取(100ml×3)，合并有机层，加饱和食盐水洗涤有机层，然后用无水硫酸钠干燥，减压抽除溶剂，浓缩得固体，残余物经硅胶柱层析纯化得到2.3g白色固体化合物，收率91％。
5-碘-N-(2-甲基-6-硝基苯基)嘧啶-2-胺的合成
在冰浴条件下，称取2-氨基-5-碘嘧啶(3g，13.57mmol)于烧瓶中，加入DMF搅拌使其分散均匀，反应20min，随后向反应瓶中缓慢滴加2-氟-3-硝基甲苯(2.74g，17.67mmol)，搅拌5min，置于60℃外温反应2h，反应完毕后，冷却至室温，将反应体系加到水中，用乙酸乙酯萃取两遍，合并有机层并用饱和食盐水洗涤，然后用无水硫酸钠干燥，减压抽除溶剂，浓缩后经硅胶柱层析纯化得到淡黄色固体化合物3.8g，产率78％。
4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)苯甲酸甲酯的合成
依次称取化合物3-乙炔基-4-甲基苯甲酸甲酯(2g,11.5mmol)、5-碘-N-(2-甲基-6-硝基苯基)嘧啶-2-胺(2.72g,7.66mmol)、双(三苯基膦)二氯化钯(0.12g，1.17mmol)和碘化亚铜(0.33g，1.7mmol)，于250mL反应瓶中，加入15mL干燥的DMF溶液使其溶解，滴入三乙胺溶液(2.67g，26.4mmol)，体系用氮气置换3次，随后于氮气保护下室温反应2h。TLC监控至原料反应完全，加入150ml乙酸乙酯淬灭反应，反应液经过硅藻土抽滤得母液，向滤液中加水萃取(150ml×3)，合并有机层，加饱和食盐水洗涤有机层，然后用无水硫酸钠干燥，减压抽除溶剂，浓缩得固体，残余物经硅胶柱层析纯化得到2.6g黄色固体化合物，产率56％。
4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)苯甲酸的合成
于250mL反应瓶中依次加入4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)苯甲酸甲酯(2.6g,6.5mmol)、氢氧化钾(2.21g，39.5mmol)、15ml乙醇和3mL水，在60℃下反应1h，TLC监控至反应完全，减压抽除溶剂，残余物于冰浴条件下缓慢加入4mol/L盐酸调PH，搅拌5min后析出棕色固体，抽滤干燥得目标化合物，经硅胶柱层析纯化得到2g黄色固体化合物，收率79.7％。
4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
向250mL反应瓶中依次加入化合物4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)苯甲酸(1.9g，4.89mmol)、HATU(2.23g，5.87mmol)和15mL干燥的DMF，缓慢滴加DIEA(1.26g，9.76mmol),室温下搅拌1h，加入4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺,再将反应升温至60℃反应5h，TLC监控至原料反应完全，加入150mL水淬灭反应，乙酸乙酯(150mL×3)萃取,合并有机相,依次用饱和NaCl洗涤，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到2.5g淡黄色固体化合物，收率79.4％
3-((2-((2-氨基-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
往250mL反应瓶中加入化合物4-甲基-3-(2-(2-甲基-6-硝基苯基)氨基)嘧啶-5-基)乙炔基)-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(2.5g，3.88mmol)、铁粉(1.09g，19.46mmol)、氯化铵(1.05g，19.44mmol)，15mL乙醇和3mL水，于90℃外温加热回流反应1h，TLC监控至反应完全，反应液趁热经过硅藻土抽滤得母液，减压抽除溶剂，加饱和碳酸钠、水、乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥，残余物经硅胶柱层析纯化得到600mg化合物，淡黄色固体，收率25.2％。
3-((2-((2-丙烯酰胺基-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
取化合物3-((2-((2-氨基-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(300mg，0.48mmol)于25mL反应瓶中，加入10mL干燥的DCM，三乙胺(98mg，0.97mmol)，氮气保护，在冰盐浴下搅拌10min，缓慢滴加丙烯酰氯(88mg，0.97mmol)的二氯甲烷(1mL)溶液，TLC监控原料至反应完全，加入2mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，依次用饱和碳酸钠、饱和NaCl洗涤，合并有机相，无水硫酸钠干燥，减压抽除溶剂，残余物经硅胶柱层析纯化得到80mg白色粉末，收率14.7％。1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.49(s,1H),8.82(s,1H),8.57(s,2H),8.20(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(m,1H),7.90(m,1H),7.70(d,J＝8.6Hz,2H),7.50(d,J＝8.1Hz,1H),7.20(m,1H),7.12-7.07(m,1H),6.53(m,1H),6.23(m,1H),5.71(m,1H),3.56(s,2H),2.52(s,3H),2.47-2.24(m,8H),2.16(s,3H),2.14(s,3H).13CNMR(151MHz,DMSO-d6)165.15,163.91,160.22,143.87,138.64,137.13,135.39,132.61,132.53,132.28,131.67,130.74,130.37,128.47,127.72,127.30,126.97,126.76,123.95,122.75,117.73,107.86,90.94,89.65,57.92,55.15,53.13,46.14,20.87,18.84.
实施例2：3-(2-(2-(2-氯乙酰胺)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到83mg白色固体。1H NMR(600MHz,DMSO-d6)δ10.49(s,1H),9.39(s,1H),8.97(s,1H),8.58(m,2H),8.20(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(m,1H),7.90(m,1H),7.71(m,2H),7.49(d,J＝8.1Hz,1H),7.21(t,J＝7.9Hz,1H),7.15-7.09(m,1H),4.29(s,2H),3.57(s,2H),2.53(s,3H),2.38-2.36(m,8H),2.20(s,3H),2.16(s,3H).13C NMR(151MHz,DMSO-d6)165.19,160.74,160.29,143.87,138.67,137.01,135.06,132.64,132.47,131.72,130.79,130.37,128.46,128.02,127.82,127.12,126.92,123.98,123.58,123.18,122.76,121.07,117.82,116.09,108.04,91.01,89.57,57.88,55.05,52.90,45.89,43.75,20.84,18.68.
实施例3：(E)-3-(2-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到60mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.60(s,1H),8.91(s,1H),8.57(s,2H),8.24(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),8.09(m,1H),7.93(m,1H),7.71(t,J＝8.7Hz,2H),7.49(d,J＝8.1Hz,1H),7.19(t,J＝7.8Hz,1H),7.11-7.06(m,1H),6.73(m,1H),6.42(m,1H),3.59(s,2H),3.15-3.10(m,2H),2.53(s,3H),2.28(s,3H),2.22(s,6H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ165.18,163.86,160.64,160.18,143.84,140.83,138.74,137.12,135.47,132.57,132.27,131.69,130.80,130.35,129.71,128.48,127.98,127.78,127.04,126.82,126.72,125.70,123.99,123.89,122.76,121.48,117.79,117.75,107.85,90.93,89.64,59.81,57.74,54.72,52.41,45.38,45.21,20.86,18.85.
实施例4：4-甲基-3-((2-((2-甲基-6-丙酰胺苯基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到78mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.21(s,1H),8.75(s,1H),8.57(s,2H),8.20(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.05(m,1H),7.90(m,1H),7.70(d,J＝8.5Hz,1H),7.58(d,J＝8.1Hz,1H),7.50(d,J＝8.1Hz,1H),7.16(t,J＝7.8Hz,1H),7.06(d,J＝7.6Hz,1H),3.56(s,2H),2.53(s,3H),2.50-2.32(m,8H),2.29(m,2H),2.16(s,3H),2.14(s,3H),1.01(t,J＝7.5Hz,3H).13CNMR(151MHz,DMSO-d6)δ174.21,172.70,165.14,160.65,160.16,143.83,138.65,137.01,135.54,132.61,132.48,131.66,130.74,130.35,128.45,127.96,127.76,126.67,126.61,125.71,123.93,122.75,121.57,117.73,107.82,90.93,89.64,57.90,55.13,53.05,46.05,20.86,18.84,17.69,10.25.
实施例5：3-((2-((2-丙烯酰胺基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到50mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.84(s,1H),9.10(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),8.06(m,1H),7.91(m,1H),7.74-7.68(m,2H),7.64-7.57(m,1H),7.51(d,J＝8.1Hz,1H),7.20(m,2H),6.52(m,1H),6.29(m,1H),5.81-5.74(m,1H),3.57(s,2H),2.54(s,3H),2.45-2.22(m,8H),2.16(s,3H).13C NMR(151MHz,DMSO-d6)δ165.13,164.24,160.59,159.31,143.87,138.66,132.65,132.53,131.99,131.68,131.15,130.83,130.36,128.52,128.00,127.80,127.59,125.73,125.59,125.55,124.97,123.95,123.91,122.67,117.79,117.74,108.83,91.28,89.42,57.94,55.18,53.12,46.11,20.86.
实施例6：3-((2-((2-丙烯酰胺-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到120mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.42(s,1H),9.51(s,1H),8.80(s,1H),8.52(s,2H),8.17(m,2H),8.04(m,2H),7.70(t,J＝7.5Hz,2H),7.25(d,J＝8.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.54(m,1H),6.23(m,1H),5.77-5.69(m,1H),3.94(s,3H),3.56(s,2H),2.36(s,8H),2.16(s,3H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ164.76,163.93,162.43,160.55,160.10,138.76,137.12,135.36,132.73,132.33,131.65,130.93,129.84,127.93,127.74,127.54,127.31,126.98,126.88,126.74,125.73,123.88,121.52,117.67,111.74,111.58,108.09,89.08,88.80,57.92,56.69,55.17,53.12,46.13,18.84.
实施例7：3-((2-((2-丙烯酰胺-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到130mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.57(s,1H),9.48(s,1H),8.75-8.82(m,1H),8.55(s,2H),8.21(d,J＝2.3Hz,1H),8.13(d,J＝1.8Hz,1H),8.05(m,1H),7.98(m,1H),7.76-7.67(m,3H),7.60(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.5Hz,1H),6.53(m,1H),6.22(m,1H),5.71(m,1H),3.57(s,2H),2.37(m,8H),2.17(s,3H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ165.29,163.93,160.76,160.15,138.64,137.12,135.36,135.33,134.63,132.41,132.30,131.74,130.51,129.80,129.58,128.51,128.00,127.81,127.30,126.98,126.75,123.98,123.86,122.96,121.55,117.78,107.62,92.10,85.93,57.73,54.75,52.43,45.40,18.85.
实施例8：5-((2-((2-丙烯酰胺-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-2-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到100mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.61(s,1H),9.47(s,1H),8.70-8.79(m,1H),8.51(s,2H),8.18(d,J＝2.3Hz,1H),7.95(m,1H),7.74-7.61(m,3H),7.54(m,1H),7.37(d,J＝8.1Hz,1H),7.19(t,J＝7.8Hz,1H),7.12-7.04(m,1H),6.52(m,1H),6.22(m,1H),5.76-5.64(m,1H),3.57(s,2H),2.41(s,3H),2.40-2.31(m,8H),2.21(s,3H),2.13(s,3H).13CNMR(151MHz,DMSO-d6)δ167.47,163.92,160.65,160.09,138.67,137.29,137.12,136.95,135.34,132.72,132.43,132.29,131.82,131.73,130.40,128.07,127.31,126.96,126.74,125.66,123.84,123.45,121.52,120.15,117.15,113.37,107.84,92.15,85.32,57.80,54.95,52.74,45.75,19.84,18.84.
实施例9：4-((2-((2-丙烯酰胺-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-3-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1，经柱层析分离得到77mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.78(d,J＝4.2Hz,1H),9.91(s,1H),9.02(s,1H),8.56(s,2H),8.29(d,J＝2.2Hz,1H),8.14(m,1H),8.03(d,J＝1.8Hz,1H),7.90(m,1H),7.69(t,J＝9.7Hz,2H),7.61(d,J＝8.0Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.59(m,1H),6.24(m,1H),5.71(m,1H),3.61(s,2H),2.70(s,3H),2.53(s,8H),2.43(s,3H),2.13(s,3H).
实施例10:(E)-3-((6-((2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)吡啶-3-基)乙炔基)-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到101mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.50(s,1H),8.52-8.40(m,1H),8.22(d,J＝2.3Hz,2H),8.12(s,1H),8.06(m,1H),7.97(m,1H),7.74(d,J＝8.2Hz,1H),7.71(m,2H),7.63(m,1H),7.57(t,J＝7.8Hz,1H),7.17(t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.68(m,1H),6.47(s,1H),6.37-6.31(m,1H),3.57(s,2H),3.00(m,2H),2.37(m,8H),2.16(s,3H),2.14(s,6H),2.13(s,3H).13C NMR(151MHz,DMSO-d6)δ165.24,163.91,157.30,151.37,143.68,141.41,140.12,138.69,136.92,135.70,132.56,132.41,131.69,130.59,130.44,130.30,128.11,127.97,127.78,126.95,126.66,126.50,125.71,123.96,123.90,123.20,121.59,117.77,117.72,108.27,92.96,88.24,60.02,57.85,55.01,52.87,49.06,45.43,18.83.
实施例11:(E)-3-((2-(2-(丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到88mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.54(s,1H),9.37(s,1H),8.81(s,1H),8.57(s,2H),8.22(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.08(m,1H),7.91(m,1H),7.69(m,2H),7.50(d,J＝8.1Hz,1H),7.18(t,J＝7.8Hz,1H),7.10-7.05(m,1H),6.78(m,1H),6.24(m,1H),3.58(s,2H),2.51-2.53(s,3H),2.45(s,8H),2.29(s,3H),2.13(s,3H),1.84(m,3H).13C NMR(151MHz,DMSO-d6)δ172.45,165.16,164.24,160.67,160.17,143.86,140.47,138.72,137.12,135.55,132.59,132.28,131.72,130.75,130.37,129.69,128.46,127.99,127.79,126.75,126.35,125.70,123.96,122.75,121.37,117.77,107.86,90.94,89.66,57.74,54.76,52.45,45.41,20.87,18.85,17.92.
实施例12:3-((2-((2-丙烯酰胺-4-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到65mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.49(s,1H),9.76(s,1H),8.98(s,1H),8.61(s,2H),8.20(s,1H),8.14(d,J＝2.0Hz,1H),8.06(m,1H),7.91(m,1H),7.70(d,J＝8.5Hz,1H),7.56(d,J＝8.2Hz,1H),7.50(d,J＝8.1Hz,1H),7.43(s,1H),7.03(m,1H),6.51(m,1H),6.27(m,1H),5.76(m,1H),3.57(s,2H),2.54(s,3H),2.40(s,8H),2.31(s,3H),2.18(s,3H).13C NMR(151MHz,DMSO-d6)δ165.14,164.16,160.57,159.45,143.85,138.67,134.37,132.63,132.48,132.03,131.69,131.14,130.81,130.35,129.32,128.49,128.00,127.80,127.49,126.24,125.65,125.17,123.95,122.71,117.79,117.75,108.54,91.19,89.50,57.91,55.10,53.00,45.98,21.05,20.85.
实施例13:3-((6-((2-丙烯酰胺-6-甲基苯基)氨基)吡啶-3-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到110mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.49(s,1H),9.53(s,1H),8.35(s,1H),8.27-8.19(m,2H),8.10(d,J＝2.0Hz,1H),8.06(m,1H),7.90-7.86(m,1H),7.73(d,J＝8.1Hz,1H),7.69(d,J＝8.5Hz,1H),7.65(m,1H),7.47(d,J＝8.0Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.55-6.41(m,2H),6.20(m,1H),5.69(m,1H),3.56(s,2H),2.51(s,3H),2.43-2.23(m,8H),2.16(s,3H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ165.22,163.88,157.26,151.34,143.64,140.08,138.69,136.97,135.47,132.58,132.49,132.43,131.65,130.61,130.26,128.12,127.97,127.77,127.04,126.43,125.73,123.98,123.92,123.20,121.68,117.81,117.77,108.34,92.95,88.28,57.95,55.20,53.17,46.16,20.85,18.86.
实施例14:(E)-3-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到100mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.30-10.24(m,1H),9.56(s,1H),8.88(s,1H),8.55(s,2H),8.10(d,J＝2.0Hz,1H),7.94-7.87(m,1H),7.77-7.64(m,3H),7.46(d,J＝8.0Hz,1H),7.25(d,J＝8.2Hz,2H),7.18(t,J＝7.8Hz,1H),7.07(d,J＝7.5Hz,1H),6.71(m,1H),6.38(m,1H),3.41(s,2H),3.02(d,J＝6.1Hz,2H),2.51(s,3H),2.33(m,8H),2.15(s,6H),2.14(s,3H),2.13(s,3H).13C NMR(151MHz,DMSO-d6)δ164.81,164.01,160.61,160.18,143.40,141.85,138.36,137.11,135.50,134.05,133.16,130.82,130.22,129.79,129.46,128.40,126.79,126.67,126.41,122.69,121.51,120.72,107.94,91.05,89.53,62.16,60.19,55.23,52.98,46.20,45.60,20.82,18.84.
实施例15:(E)-3-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(吗啉甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到90mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.31(t,J＝3.6Hz,1H),9.70-9.57(m,1H),8.96-8.86(m,1H),8.55(s,2H),8.11(d,J＝1.9Hz,1H),7.92(m,1H),7.72(m,3H),7.46(d,J＝8.1Hz,1H),7.27(d,J＝8.4Hz,2H),7.17(t,J＝7.8Hz,1H),7.07(d,J＝7.1Hz,1H),6.71(m,1H),6.39(m,1H),3.57(t,J＝4.6Hz,4H),3.43(s,2H),3.02(m,2H),2.51(s,3H),2.35(t,J＝4.7Hz,4H),2.15(s,6H),2.13(s,3H).13C NMR(151MHz,DMSO-d6)δ164.83,164.00,160.61,160.15,143.41,141.84,138.47,137.10,135.47,133.50,133.13,130.84,130.22,129.81,129.58,128.42,126.79,126.65,126.41,122.69,121.55,120.74,107.93,91.05,89.53,66.69,62.54,60.19,53.61,45.60,20.81,18.85.
实施例16:(E)-3-(2-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到70mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.14(s,1H),9.71(s,1H),8.95(s,1H),8.55(s,2H),8.13-8.07(m,1H),7.94-7.88(m,1H),7.68(d,J＝8.1Hz,1H),7.64(d,J＝8.7Hz,2H),7.45(d,J＝8.0Hz,1H),7.17(t,J＝7.8Hz,1H),7.07(d,J＝7.6Hz,1H),6.91(d,J＝8.7Hz,2H),6.71(m,1H),6.39(m,1H),3.32(s,3H),3.10(t,J＝4.9Hz,4H),3.02(d,J＝6.0Hz,2H),2.46(s,4H),2.22(s,3H),2.14-2.17(s,6H),2.13(s,3H).13C NMR(151MHz,DMSO-d6)δ164.30,164.00,160.60,160.12,148.01,143.11,141.80,137.10,135.43,133.30,131.43,130.75,130.16,129.92,129.85,128.31,126.80,126.61,126.44,122.63,122.04,115.88,107.95,91.11,89.43,60.19,55.12,48.98,46.24,45.60,20.79,18.86.
实施例17:(E)-N-(4-((1H-1,2,4-***-1-基)甲基)苯基)-3-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺的制备；
操作同实施例1经柱层析分离得到86mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.36(d,J＝7.1Hz,1H),9.58(t,J＝9.2Hz,1H),8.89(d,J＝9.3Hz,1H),8.65(s,1H),8.55(s,2H),8.11(d,J＝2.0Hz,1H),7.97(s,1H),7.91(m,1H),7.79(m,2H),7.70(d,J＝8.1Hz,1H),7.47(d,J＝8.0Hz,1H),7.29(d,J＝8.4Hz,2H),7.18(t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.71(m,1H),6.38(m,1H),5.39(s,2H),3.02(d,J＝4.3Hz,2H),2.51(s,3H),2.14-2.16(s,6H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ164.94,164.02,160.62,160.18,152.11,144.53,143.53,141.86,139.33,137.11,135.50,132.97,131.86,130.83,130.25,129.79,128.76,128.44,126.79,126.67,126.40,122.71,121.52,121.02,107.92,91.01,89.56,60.18,52.28,45.60,20.82,18.84.
实施例18:3-(2-((2-(2-(环丙烷甲酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到102mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.58-10.50(m,1H),9.73-9.54(m,1H),8.80(d,J＝6.2Hz,1H),8.57(s,2H),8.22(s,1H),8.14(s,1H),8.07(d,J＝8.7Hz,1H),7.92(m,1H),7.69(d,J＝8.5Hz,1H),7.59(d,J＝8.2Hz,1H),7.49(d,J＝8.0Hz,1H),7.15(t,J＝7.8Hz,1H),7.06(d,J＝7.6Hz,1H),3.56(s,2H),2.53(s,3H),2.36(m,8H),2.15-2.19(m,6H),1.89(s,1H),0.83-0.77(m,2H),0.70-0.77(m,2H).13C NMR(151MHz,DMSO-d6)δ172.49,165.17,160.66,160.22,143.82,138.69,137.10,135.61,132.64,132.53,131.66,130.81,130.33,129.67,128.47,127.98,127.79,126.67,126.57,125.74,123.99,123.92,122.79,121.45,117.82,117.78,107.90,90.96,89.66,57.96,55.21,53.17,46.16,20.85,18.84,14.75,7.70.
实施例19:(E)-3-(2-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-甲基-4-(4-甲基哌嗪-1-羰基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到60mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.30(d,J＝6.5Hz,1H),9.43(s,1H),8.82(s,1H),8.56(s,2H),8.10(s,1H),7.89(d,J＝8.0Hz,1H),7.69(m,3H),7.48(d,J＝8.2Hz,1H),7.18(t,J＝7.9Hz,1H),7.13(d,J＝8.2Hz,1H),7.08(d,J＝7.6Hz,1H),6.71(m,1H),6.37(m,1H),3.65(s,2H),3.16(s,2H),3.02(d,J＝6.0Hz,2H),2.52(s,3H),2.36(s,2H),2.22(s,5H),2.19(s,3H),2.15(s,6H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ168.87,165.01,163.92,160.62,160.18,143.59,141.38,139.73,137.10,135.49,134.76,132.94,132.10,130.79,130.27,129.66,128.42,126.78,126.71,126.68,122.70,122.10,121.43,118.07,107.86,90.97,89.57,59.98,55.28,54.78,46.02,45.40,20.83,19.40,18.83.
实施例20:(E)-3-(2-((2-(2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-(4-甲基哌嗪-1-羰基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到88mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.82(t,J＝3.0Hz,1H),9.71-9.61(m,1H),8.93(s,1H),8.56(s,2H),8.35(d,J＝2.1Hz,1H),8.20(m,1H),8.17(d,J＝2.0Hz,1H),7.98(m,1H),7.69(d,J＝8.1Hz,1H),7.50(d,J＝8.0Hz,1H),7.43(d,J＝8.4Hz,1H),7.18(t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.71(m,1H),6.39(m,1H),3.63(m,2H),3.19-3.12(m,1H),3.10-3.04(m,1H),3.02(m,2H),2.53(s,3H),2.40(m,1H),2.34-2.22(m,2H),2.19(s,3H),2.15(s,7H),2.13(s,3H).13C NMR(151MHz,DMSO-d6)δ166.50,165.44,164.00,160.63,160.16,143.99,141.79,140.50,137.10,135.45,132.41,130.97,130.35,130.04,129.82,128.63,128.59,126.80,126.64,126.44,126.29,126.08,125.00,124.08,123.54,123.19,122.82,118.09,118.05,107.87,90.92,89.69,60.18,54.62,47.07,46.04,45.59,20.86,18.85.
实施例21:3-((2-((2-丙烯酰胺基-6-氯苯基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到75mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),9.59(s,1H),9.03(s,1H),8.59(s,2H),8.19(d,J＝2.3Hz,1H),8.12(d,J＝2.0Hz,1H),8.05(m,1H),7.96(m,1H),7.90(m,1H),7.70(d,J＝8.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.35-7.28(m,2H),6.59(m,1H),6.25(m,1H),5.74(m,1H),3.57(s,2H),2.53(s,3H),2.37(m,8H),2.17(s,3H).13C NMR(151MHz,DMSO-d6)δ165.16,164.13,160.54,160.23,143.91,138.67,137.68,133.53,132.67,132.55,132.14,131.71,130.81,130.36,128.51,128.41,128.01,127.99,127.82,127.77,125.75,125.73,123.97,123.92,122.71,122.32,117.81,117.76,108.56,91.10,89.46,57.94,55.18,53.12,46.11,20.85.
实施例22:(E)-3-((6-((2-(4-(二甲氨基)丁-2-烯酰胺基)-6-甲基苯基)氨基)吡啶-3-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备；
操作同实施例1经柱层析分离得到78mg白色粉末。1H NMR(600MHz,DMSO-d6)δ10.53(s,1H),9.46(s,1H),8.35(s,1H),8.24(d,J＝2.4Hz,1H),8.23(s,1H),8.11(d,J＝2.0Hz,1H),8.07(m,1H),7.88(m,1H),7.75(d,J＝8.0Hz,1H),7.70(d,J＝8.6Hz,1H),7.65(m,1H),7.48(d,J＝8.1Hz,1H),7.18(t,J＝7.8Hz,1H),7.12-7.07(m,1H),6.69(m,1H),6.43(s,1H),6.35(m,1H),3.57(s,2H),3.04(m,2H),2.51(s,3H),2.41(s,8H),2.21(s,3H),2.16(s,6H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ165.24,163.91,157.30,151.37,143.68,141.41,140.12,138.69,136.92,135.70,132.56,132.41,131.69,130.59,130.44,130.30,128.11,127.97,127.78,126.95,126.66,126.50,125.71,123.96,123.90,123.20,121.59,117.77,117.72,108.27,92.96,88.24,60.02,57.85,55.01,52.87,49.06,45.43,20.85,18.83.
实验例1FGFR4激酶抑制活性测试
在384孔反应板中，设阳性对照孔和阴性对照孔，其余每孔加入不同浓度的化合物及FGFR4激酶，离心后室温孵育15min，加入荧光底物和ATP，反应结束后加入终止液停止反应，用Caliper EZ reader读取转化率。进而计算百分比抑制率，计算公式如下：酶抑制率＝Mean(最大)-样品信号/Mean(最大)-空白乘以100％。实验结果见表1
表1.化合物在100和10nM浓度下对FGFR4和FGFR1的抑制率a
结果显示：化合物I-5，I-7在100nM浓度下对FGFR4激酶的抑制活性达到了90％以上，说明该化合物对FGFR4抑制活性较强。
实验例2细胞增殖抑制活性测试
实验设溶剂对照组及药物实验组，药物实验组每组设8个浓度，每个浓度下设3个平行孔。每个实验重复三次。在96孔板中，每孔加入细胞浓度为1×105个/mL的细胞悬液100μL，即每孔含细胞3×103个，接种时注意使细胞均匀分布在各孔中。为防止液体蒸发，96孔板周围一圈孔不接种细胞，加入PBS保湿。细胞贴壁后，药物实验组中每孔中加入不同浓度的目标化合物100μL。将96孔板置于37℃、5％CO2孵箱内继续培养，于72h后终止培养。分别于药物处理细胞72h后，取出96孔板，每孔中加入MTT法溶液，在细胞培养箱内继续孵育4小时后，在自动酶标仪上570nm处测定每孔吸光度值(A)。通过公式计算抑制率。以抑制率对药物浓度作直线回归分析，用直线方程求算IC50值。检测所得结果以均数±标准偏差表示，实验结果采用SPSS15.0软件进行统计分析，以P<0.05表示有显著性差异。结果见表2，表明化合物I-7、I-21对Huh-7细胞和Hep3B细胞的IC50与Ponatinib相当(麦克林公司购买)。
表2.化合物对不同肿瘤细胞株的增殖抑制活性a
a The data reported are the mean values from three independentexperiments。
Claims (8)
1.式I所示的一种FGFR4抑制剂或其药学上可接受的盐，
其中，
R1选自氢、卤素、烷基；
R2选自乙烯基、烷基、卤代烷基、环烷基，所述乙烯基可以被烷基、烷氨基烷基取代；
R3选自氢、烷基、烷氧基；
R4选自杂环烷基或杂环芳基。
2.根据权利要求1所述的抑制剂或其药学上可接受的盐，其特征在于：R1选自氢、C1-6烷基，R2选自乙烯基、丙烯基、N,N-二甲基丙烯-1-基、甲基、乙基、氯代甲基、环丙基，R3选自氢、甲基、甲氧基。
3.根据权利要求1所述的抑制剂或其药学上可接受的盐，其特征在于：R1选自氢、甲基，R2为乙烯基，R3选自氢、甲基、甲氧基。
4.根据权利要求1所述的抑制剂或其药学上可接受的盐，其特征在于：R4选自N-甲基哌嗪基、吗啉基、1,2,4三氮唑基。
5.式I-1所示的一种FGFR4抑制剂或其药学上可接受的盐，
其中，
R1选自氢、甲基；
R3选自氢、甲基、甲氧基。
6.根据权利要求1-5任一项所述的抑制剂，其中所述的抑制剂为选自以下的化合物：
7.一种药物组合物，其包含权利要求1-5任一项所述的抑制剂或其药学上可接受的盐，或权利要求6所述的化合物或其药学上可接受的盐，和药学上可接受的载体。
8.权利要求1-5任一项所述的抑制剂或其药学上可接受的盐，或权利要求6所述的化合物或其药学上可接受的盐，或权利要求7所述的组合物在制备治疗和/或预防肿瘤药物中的应用。
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