CN116444495B 一类吲哚酮类flt3蛋白降解剂、其制备方法及其医药用途 （南京中医药大学）

basedderivativesaspotent,s页.本发明公开了一类吲哚酮类FLT3蛋白降解蛋白降解剂，对急性髓系白血病具有很好的疗而且对FLT3抑制剂耐药的急性髓系白血病细胞2。2.一种药物组合物，包括权利要求1中所述的一类吲哚酮类FLT3蛋白降解剂或其药学33.如权利要求1中所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐在制备4.如权利要求1中所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐，或根据权利要求2所述的药物组合物在制备用于治疗和/或预防与FLT3表达异常引起的相关疾5.如权利要求1中所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐，或根据权利要求2所述的药物组合物在制备用于治疗急性髓系白6.如权利要求1中所述的一类吲哚酮类FLT3蛋白降解剂或其药学上可接受的盐，或根据权利要求2所述的药物组合物在制备治疗FLT3抑制剂耐药的急性髓系白血病药物中的用4靶向治疗的重要靶标之一。目前已经有大量的FLT3抑制剂进入AML的临床研究并取得了较[0003]蛋白水解靶向嵌合体(proteolytictargetingchimera，PROTAC)技术是一种利[0004]2018年，Crews团队报道了一种基于Quizartinib设计的FLT3蛋白降解剂【JAm是目前AML治疗领域迫切需要解决的关键5AML效果显著的新型FLT3蛋白降解剂。[0007]针对上述问题，本发明提供了一种通式(I)所示的吲哚酮类FLT3蛋白降解剂或其6789反应温度为10℃~40℃,优选20℃。[0031]本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、及其药物组合物在制备FLT3蛋白降解剂中的用途；本发明的化合物或其药学上可接受的[0032]本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、[0033]本发明的另一目的在于提供所述吲哚酮类FLT3蛋白降解剂或药学上可接受的盐、[0034]本发明的有益效果是：本发明公开的一种口服有效的吲哚酮对急性髓系白血病具有很好的疗效，同等剂量下的抑瘤率明显优于FLT3抑制剂，而且对(4(2((5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙基)[0045]中间体V的合成：将化合物IV(0.26g，0.78mmol)和1_叔丁氧羰基哌嗪(0.79g，[0049]化合物A01的合成：取化合物III_1(110mg，0.25mmol)，化合物VI(103mg，169.23,167.36,167.19,165.93,159.58,157.71,155.46,140.06,137.41,135.17,133.49,125.74,125.71,125.65,120.85,119.52,117.24,116.52,116.52,115.73,115.29,111.00,(4(2((5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧代乙[0055]化合物A02的合成：取化合物III一2(120mg，0.25mmol)，化合物VI(103mg，169.22,167.67,167.35,167.18,165.90,157.72,155.42,137.39,135.17,133.50,127.58,127.51,125.70,125.66,124.28,121.22,120.82,119.52,117.24,116.51,115.70,112.81,42H46FN8O11[M+H]+:基)丙酰基)哌嗪1基)N(5(5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)[0059]中间体II一2的合成：将I一2(200mg，0.72mmol)以及聚乙二醇类的linker167.64,157.72,146.87,136.67,135.17,132.55,127.59,125.70,125.66,124.29,121.20,基)丙酰基)哌嗪1基)N(5(5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)[0065]中间体II一3的合成：将I一2(200mg，0.72mmol)以及聚乙二醇类的linker169.11,167.73,167.68,157.72,146.87,136.70,135.17,132.57,127.59,125.70,125.66,124.28,121.20,119.51,117.89,115.73,113.01,111.15,110.40,109.73,106.51,69.12,[0071]中间体II一4的合成：将I一2(200mg，0.72mmol)以及聚乙二醇类的linker157.72,146.86,136.67,135.18,132.55,127.48,125.68,124.16,121.15,119.48,117.90,115.76,112.85,111.13,110.49,109.71,106.32,70.29,70.25(3C),70.13,69.34,67.21,氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙基)哌嗪1基)壬酰粗品，柱层析分离(DCM:MeOH＝100:1～30:1)得纯品棕黄色固体粉末A06(33mg，yield:173.22,172.86,170.38,169.85,168.13,167.51,167.24,159.57,157.71,145.66,135.18,133.23,127.56,127.48,125.69,125.14,124.27,123.93,116.69,115.76,113.27,110.49,42H48FN8O7[M+H]+:哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙酰胺[0083]中间体II6的合成：将化合物I1(200mg，0.73mmol)，1,9二溴壬烷(250mg，粗品，柱层析分离(DCM:MeOH＝100:1～30:1)得纯品棕黄色固体粉末A07(36mg，yield:157.71,156.48,137.50,135.19,133.71,127.56,125.69,125.64,124.27,120.24,119.37,116.66,115.75,115.59,113.02,110.43,106.51,69.26,67.10,64.01,57.51,(2((5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙基)哌[0089]中间体II7的合成：将化合物I2(500mg，1.81mmol)，NBoc乙二胺(287μL，[0091]中间体III一3的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)在室温下搅拌[0093]化合物A08的合成：取化合物III一3(103mg，0.24mmol)，化合物VI(101mg，172.89,170.71,170.56,169.87,169.17,167.76,167.64,159.58,157.72,146.81,136.66,135.17,132.67,125.72,125.66,124.28,121.21,119.52,117.63,115.73,112.82,111.02,found:796.3207.[0095](Z)N(2((2,6二氧代哌啶3基)1,3二氧代异吲哚4基)氨基)乙基)6(4(2((5((5氟2氧异代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙[0097]中间体III一4的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)在室温下搅拌167.68,159.57,157.72,146.82,137.47,136.65,135.17,132.67,127.51,125.70,124.28,[0101](Z)N(2((2,6二氧代哌啶3基)1,3二氧代异吲哚4基)氨基)乙基)7(4(2((5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙基)[0103]中间体III一5的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)在室温下搅拌146.83,136.65,135.17,132.67,127.58,125.70,124.26,121.20,119.50,117.63,115.75,113.02,111.00,110.48,109.70,106.51,61.09,55.38,53.44,52.99,49.07,[0107](Z)N(2((2(2,6二氧代哌啶3基)1,3二氧代异吲哚4基)氨基)乙基)8(4(2((5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)氨基)2氧乙[0109]中间体III一6的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)在室[0111]化合物A11的合成：取化合物III一6(138mg，0.29mmol)，化合物VI(121mg，169.17,167.76,167.69,159.57,157.71,146.83,136.65,135.16,132.67,127.57,125.71,124.29,121.22,119.52,117.62,11838.3654.[0115]中间体III一7的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)[0117]化合物A12的合成：取化合物III一7(118mg，0.24mmol)，化合物VI(100mg，CNMR(126MHz,DMSOd6)δ173.28,173.24,171.42,170.54,169.83,169.14,167.77,162.35,159.57,157.71,146.83,136.67,135.30,132.64,125.67,125.63,123.70,120.90,119.29,117.68,116.21,113.00,111.01,[0119]((Z)N(2((2(2,6二氧代哌啶[0121]中间体III一8的合成：先将烷烃二酸类的linker(1.28mmol)，HBTU(180mg，0.47mmol)用5mLN,N一二甲基甲酰胺溶解，加入DIPEA(615μL，3.44mmol)159.58,157.72,146.83,136.63,135.17,132.66,127.58,125.66,124.27,121.19,119.50,866.3989.[0125](Z)2(4(6((2(基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙酰胺170.57,169.87,169.41,168.43,167.77,159.58,157.72,146.89,136.75,135.18,132.66,125.70,125.66,124.26,121.19,119.50,117.65,115.75,113.02,110.84,110.48,109.46,[0131](Z)2(4(7((2(2,酰)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙酰胺)δ173.28,171.05,170.56,169.96,169.86,169.41,167.76,159.58,157.71,146.89,136.74,135.17,132.66,127.57,125.70,124.24,121.18,119.50,117.64,115.75,112.83,110.84,110.47,found:767.3304.[0137](Z)2(4(8((2基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙酰胺171.07,170.56,169.99,169.87,169.42,167.76,159.58,157.71,146.89,136.73,135.17,132.65,127.58,125.70,124.27,121.19,119.50,117.64,115.73,113.01,110.83,110.47,41H46FN8O7[M+H]+:一烷基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙170.55,169.87,169.41,167.76,159.58,157.72,146.89,136.72,135.18,132.65,125.70,125.67,124.25,121.16,119.48,117.63,115.76,110.83,110.47,110.41,109.46,106.51,44H52FN8O7[M+H]+:二烷基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲基1H吡咯3基)乙[0152]化合物A18的合成：取化合物II一12(150mg，0.32mmol)，化合物VI(133mg，157.72,146.89,136.72,135.18,132.65,127.58,125.69,124.26,121.16,119.48,117.62,115.75,113.01,112.82,110.82,109.46,106.51,61.08,60.22,53.45,53.00,49.01(2C),[0154](Z)2(4((1(2(2,6二氧代哌啶3基)1,3二氧代异[0156]中间体II_13的合成：将化合物I_2(500mg，1.8mmol)，哌啶_4_基甲醇(255μL，中加入过量硫代硫酸钠饱和水溶液以及碳酸氢钠饱和水溶液，再搅拌10min，二氯甲烷萃[0162]化合物A19的合成：取化合物III_9(60mg，0.16mmol)，化合物VII(75mg，0.195mmol)以及乙酸(1mg，0.016mmol)溶于5mLN,N_二甲基甲酰胺中，在室温下先搅拌135.19,134.16,127.50,125.62,124.35,120.60,119.13,116.74,115.79,114.78,113.02,[0163](Z)2(4((1(2(2,6二氧代哌啶3基)1,3二氧代异[0165]中间体II14的合成：将化合物I4(500mg，1.8mmol)，哌啶4基甲醇(255μL，[0169]化合物A20的合成：取化合物III_10(60mg，0.16mmol)，化合物VII(75mg，0.195mmol)以及乙酸(1mg，0.016mmol)溶于5mLN,N_二甲基甲酰胺中，在室温下先搅拌155.48,135.19,134.51,127.58,125.66,125.45,124.31,120.61,119.14,118.04,117.82,115.79,113.02,110.48,108.18,106.51,106.30,64.13,61.44,53.75,53.43,49.22(2C),哌嗪_1_基)_N_(5_((5_氟_2_氧代吲哚_3_亚基)甲基)_4_甲基_1H_吡咯_3_基)乙酰胺[0173]中间体VIII_1的合成：取化合物VII(100mg，0.26mmol)，tert_butyl4_[0175]化合物A21的合成：取化合物VIII_1(126mg，0.22mmol)，化合物Ⅰ_4(130mg，CNMR(126MHz,134.49,127.57,125.69,125.46,124.30,120.76,119.25,118.11,118.05,115.74,112.83,[0179]中间体VIII_2的合成：取化合物VII(100mg，0.26mmol)，tert_butyl3_[0181]化合物A22的合成：取化合物VIII_2(82mg，0.15mmol)，化合物Ⅰ_4(82mg，100:1～30:1)得纯品棕黄色固体粉末A22(31mg，yield:29％)。1HNMR(500MHz,DMSO_d6)δ13CNMR(126MHz,DMSO_d6)δ173.28,170.59,169.86,167.93,167.62,159.57,157.71,155.38,135.17,134.29,127.57,125.62,125.31,124.31,120.82,119.30,117.32,115.75,114.64,112.83,110.48,106.52,106.32,104.94,[0185]中间体VIII_3的合成：取化合物VII(100mg，0.26mmol)，tert_butyl2_oxo_7_(乙酸乙酯:正己烷＝5:1)打浆得产物VIII_3_Boc(75mg，yield:47％)。1HNMR(500MHz,[0187]化合物A23的合成：取化合物VIII_3(143mg，0.23mmol)，化合物Ⅰ_4(130mg，100:1～30:1)得纯品棕黄色固体粉末A23(21mg，yield:12％)。1HNMR(500MHz,DMSO_d6)δ1.45(m,8H).13CNMR(126MHz,DMSO_d6)δ173.29,170.60,169.86,168.09,167.69,167157.71,155.36,135.17,134.50,127.57,125.70,125.46,124.31,120.65,119.20,118.08,[0191]中间体VIII_4的合成：取化合物VII(100mg，0.26mmol)，tert_butyl3_[0193]化合物A23的合成：取化合物VIII_4(147mg，0.25mmol)，化合物Ⅰ_4(140mg，100:1～30:1)得纯品棕黄色固体粉末A24(28mg，yield:16％)。1HNMR(500MHz,DMSO_d6)δ2.52(m,10H),2.28(s,3H),2.04–2.00(m,1H).13CNMR(126MHz,DMSO_d6)δ173.28,170.59,169.86,167.95,167.64,159.57,157.71,155.62,135.17,134.27,127.57,125.69,125.26,124.30,120.73,119.23,117.11,115.77,114.49,113.02,112.83,110.48,106.52,106.32,啶4基)甲基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)4甲[0197]中间体聂15的合成：将化合物I5(180mg，0.62mmol)，哌啶4基甲醇(85mg，1)，得产物III11(106mg，yield:46％)。HRMS(ESI):calcdforC19H18FN3O5[M+H]+:[0201]化合物A25的合成：取化合物III一11(106mg，2.73mmol)，化合物Ⅶ(87mg，2.27mmol)以及乙酸(13μL，2.27mmol)溶于5mLN,N一二甲基甲酰胺中，在室温下先搅拌CNMR(126MHz,DMSOd6)δ173.23,170.39,169.87,167.69,167.18,166.71,166.69,159.59,158.72,157.73,156.70,146.38,146.31,135.19,129.27,129.26,127.58,127.50,125.68,125.62,124.32,123.29,123.21,120.57,119.12,115.79,115.76,114.14,113.02,112.83,112.44,112.24,110.48,啶4基)甲基)哌嗪1基)N(5((5氟2氧代吲哚3亚基)甲基)2,4二甲基1H吡应体系中加入60mL水，有固体析出即产物，抽滤，烘干得棕黄色固体Ⅹ(140mg,yield:134.71,134.52,132.72,131.14,129.98,128.04,127.94,127.86,125.48,124.94,122.06,118.07,117.85,113.38,112.31,112.12,110.34,110.27,108.22,106.02,105.81,53.28,4二甲基1H吡咯3甲酰基)哌嗪1基)甲基)哌啶1基)异吲哚1,3二酮(A27)的合成MeOH＝100:1～30:1)得纯品棕黄色固体粉末A27(400mg，yield:26％)。1HNMR(500MHz,CNMR(126MHz,DMSOd6)δ173.29,170.82,170.59,170.02,168.10,167.43,159.63,157.77,155.41,135.06,134.50,127.62,126.51,125.47,125.25,found:722.31.4基)甲基)哌嗪1基)乙基)5((5氟2氧代吲哚3亚基)甲基)2,4二甲基1H吡MeOH＝100:1～30:1)得纯品棕黄色固体粉末A28(35mg，yield:30％)。1HNMR(500MHz,157.77,155.47,137.09,134.98,134.51,130.64,127.68,127.60,126.28,125.46,125.35,121.21,118.02,117.80,115.09,115.07,112.93,112.73,110.51,110.44,108.17,106.50,4基)甲基)哌嗪1基)丙基)5((5氟2氧代吲哚3亚基)甲基)2,4二甲基1H吡MeOH＝100:1～30:1)得纯品棕黄色固体粉末A29(130mg，yield:57％)。1HNMR(500MHz