CN117069696A - 一种双靶点小分子抑制剂及其制备方法和应用 - Google Patents

一种双靶点小分子抑制剂及其制备方法和应用 Download PDF

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CN117069696A
CN117069696A CN202311039264.3A CN202311039264A CN117069696A CN 117069696 A CN117069696 A CN 117069696A CN 202311039264 A CN202311039264 A CN 202311039264A CN 117069696 A CN117069696 A CN 117069696A
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孔令义
王小兵
李欣欣
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China Pharmaceutical University
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Abstract

本发明公开了一种双靶点小分子抑制剂及其制备方法和应用。包含结构如通式(V)所示的化合物或其药学上可接受的盐。本发明发现了一种新型双靶点小分子抑制剂，可作为肿瘤的单一治疗剂或者与其它抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。

Description

一种双靶点小分子抑制剂及其制备方法和应用
技术领域
本发明涉及药物化学领域，涉及一种双靶点小分子抑制剂及其制备方法和应用，具体为PARP1/EZH2双抑制剂、其制法和医药用途。
背景技术
三阴性乳腺癌(TNBC)占全球所有乳腺癌病理类型的15％，具有特殊的生物学行为和临床病理特征。三阴性乳腺癌由于***受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(HER2)表达阴性，内分泌治疗对其基本无效，靶向治疗也不敏感，因此三阴性乳腺癌也被称为“乳腺癌中的绝症”。PARP抑制剂被认为是靶向治疗TNBC最有潜力的药物，可对BRCA突变的TNBC细胞发挥"合成致死"作用。然而，约80％的TNBC患者不包含BRCA突变，不能发挥“合成致死”作用。开发有潜力的治疗TNBC的靶向药物，扩大PARPi的临床应用用于治疗BRCA野生型的TNBC具有很重大的意义。
发明内容
本发明的目的是提供一种双靶点小分子抑制剂。
本发明的另一目的是提供该双靶点小分子抑制剂的制备方法。
本发明的又一目的是提供该双靶点小分子抑制剂的应用。
本发明的目的可通过以下技术方案实现：
通式(V)所示的化合物或其药学上可接受的盐
其中，所述的R1选自C1-4的低级烷基；R2选自H、氨基或者C1-4的低级烷基；或者R1和R2及他们相连的原子形成含有1-2个氮原子的五元或六元杂环；R3选自H、C1-4的低级烷基、C1-4的低级酰基；n＝0、1、2或3。
作为本发明的一种优选，R1选自甲基或乙基，R2选自H，R3选自H、C1-3的低级烷基、C1-3的低级酰基，n＝0、1。
作为本发明的一种优选，R1选自甲基，R2选自H，R3选自乙基、异丙基、乙酰基或丙酰基，n＝0、1，结构如通式(I)或(III)所示：
作为本发明的一种优选，R1和R2及他们相连的原子形成含有1个或1个氮原子的五元不饱和含氮杂环，R3选自甲基、乙基、异丙基、乙酰基或丙酰基，n＝0、1，结构如通式(II)或(IV)所示：
本发明优选的部分化合物如下：
一种本发明所述的通式(V)所示的化合物的制备方法：路线1：目标化合物Ⅰ-1～Ⅰ-3的合成a.
a试剂及反应条件:(a)R3-O-R3,TEA,DCM，回流，12h；(b)NaOH,MeOH/H2O,r.t.,6h；(c)3-(氨基甲基)-4,6-二甲基-1H-吡啶-2-酮，HATU,DIPEA,DCM,r.t,12h；(d)4-硼苯甲酸甲酯，PdCl2(dppf)·CH2Cl2,K2CO3,Diox/H2O，回流，90℃，12h；(e)LiOH,MeOH/H2O,r.t,12h；(f)(i)HATU，DIPEA,DMF,r.t,12h；(ii)AcOH,120℃，1h。
路线2：目标化合物Ⅱ-1～Ⅱ-3的合成a.
a试剂及反应条件:(a)R3I,K2CO3,DMF，回流，75℃，12h；(b)NaOH,MeOH/H2O,r.t.，6h；(c)3-(氨基甲基)-4,6-二甲基-1H-吡啶-2-酮，HATU,DIPEA,DCM,r.t,12h；(d)4-硼苯甲酸甲酯，PdCl2(dppf)·CH2Cl2,K2CO3,Diox/H2O，回流，90℃，12h；(e)LiOH,MeOH/H2O,r.t,12h；(f)(i)HATU，DIPEA,DMF,r.t,12h；(ii)AcOH,120℃，1h。
路线3：目标化合物Ⅲ-1～Ⅲ-2的合成a.
a试剂及反应条件:(a)(4-甲氧基羰基甲基)苯硼酸，PdCl2(dppf)·CH2Cl2,K2CO3,DMF，回流，N2,90℃，6h；(b)LiOH,MeOH/H2O,r.t,12h；(c)(i)HATU，DIPEA,DMF,r.t,12h；(ii)AcOH,120℃，1h。
路线4：目标化合物Ⅳ-1～Ⅳ-3的合成a.
a试剂及反应条件:(a)(4-甲氧基羰基甲基)苯硼酸，PdCl2(dppf)·CH2Cl2,K2CO3,DMF，回流，N2,90℃，6h；(b)LiOH,MeOH/H2O,r.t,12h；(f)(i)HATU，DIPEA,DMF,r.t,12h；(ii)AcOH,120℃，1h。
本发明所述的通式(V)所示的化合物、所述的药物组合物在制备抗肿瘤药物中的用途，所述的肿瘤选自乳腺癌细胞。
有益效果：
本发明公开了一种双靶点小分子抑制剂——PARP1/EZH2抑制剂、其制备放法及其应用，可作为肿瘤的单一治疗剂或者与其它抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。
具体实施方式
将原料1a溶解于二氯甲烷中，加入R3-O-R3和三乙胺，在100ml圆底烧瓶中回流反应12h得到中间产物2a～2c。将2a～2c溶解于甲醇水溶液中，加入NaOH后室温反应6h得到中间产物3a～3c。然后将3a～3c在二氯甲烷中溶解，加入3-(氨基甲基)-4,6-二甲基-1H-吡啶-2-酮、HATU和DIPEA，室温下反应12h得到中间体4a～4c。将4a～4c用(4-(2-甲氧基-2-氧基乙基)苯基)硼酸、PdCl2(dppf)·CH2Cl2、K2CO3溶解于DMF中，在N2保护下于90℃回流反应6h得到中间体5a～5c；将4a～4b用(4-甲氧基羰基甲基)苯硼酸、PdCl2(dppf)·CH2Cl2、K2CO3溶解于DMF中，在N2保护下于90℃回流反应6h得到中间体5A～5B；。在甲醇水溶液中加入LiOH室温反应12h得到中间体6a～6c、6A～6B。最后将6a～6c、6A～6B和2,3-二氨基苯甲酰胺溶解于DMF中，加入HATU和DIPEA，室温反应12h后，将滤渣洗出，加入AcOH中，120℃反应1h，得到最终产物I-1～I-3和Ⅲ-1～Ⅲ-2。
将原料1b～1c溶解于DMF中，加入R3I和碳酸钾，在100ml圆底烧瓶中75℃回流反应12h得到中间产物2d～2g。将2d～2g溶解于甲醇水溶液中，加入NaOH后室温反应6h得到中间产物3d～3g。然后将3d～3g在二氯甲烷中溶解，加入3-(氨基甲基)-4,6-二甲基-1H-吡啶-2-酮、HATU和DIPEA，室温下反应12h得到中间体4d～4g。将4d～4f用(4-(2-甲氧基-2-氧基乙基)苯基)硼酸、PdCl2(dppf)·CH2Cl2、K2CO3溶解于DMF中，在N2保护下于90℃回流反应6h得到中间体5d～5f；将4d～4g用(4-甲氧基羰基甲基)苯硼酸、PdCl2(dppf)·CH2Cl2、K2CO3溶解于DMF中，在N2保护下于90℃回流反应6h得到中间体5D～5F；。在甲醇水溶液中加入LiOH室温反应12h得到中间体6d～6f、6D～6F。最后将6d～6f、6D～6F和2,3-二氨基苯甲酰胺溶解于DMF中，加入HATU和DIPEA，室温反应12h后，将滤渣洗出，加入AcOH中，120℃反应1h，得到最终产物Ⅱ-1～Ⅱ-3和Ⅳ-1～Ⅳ-3。
实施例1化合物(I-1)：2-(3'-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-5'-(乙氨基)-4'-甲基-[1,1'-联苯]-4-基)-1H-苯并[d]咪唑-4-甲酰胺。产率36％；1HNMR(600MHz,DMSO-d6)δ13.61(d,J＝24.8Hz,1H),11.49(s,1H),9.39(s,1H),8.34(dd,J＝19.8,8.1Hz,2H),8.12(t,J＝5.1Hz,1H),7.86(dd,J＝14.8,7.8Hz,3H),7.80–7.71(m,2H),7.36–7.16(m,2H),6.87(d,J＝11.1Hz,2H),5.87(d,J＝5.1Hz,1H),4.35–4.28(m,2H),3.25(q,J＝7.1Hz,2H),2.22(d,J＝6.5Hz,3H),2.11(s,3H),2.09(s,3H),1.29–1.21(m,3H)；13CNMR(151MHz,DMSO)δ169.03,165.78,162.62,151.34,149.01,146.91,142.30,141.13,139.00,138.34,136.50,135.01,127.26,126.98,126.70,122.50,121.90,121.25,118.77,114.57,112.72,107.29,106.98,37.28,34.52,18.37,17.67,13.92,13.26；HRMS[M+H]+calcdfor551.2765,found
551.2765；HPLCpurity98.87％(systemB；tR＝3.077min).
实施例2化合物(I-2)：2-(3'-乙酰氨基-5'-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-4'-甲基-[1,1'-联苯]-4-基)-1H-苯并[d]咪唑-4-甲酰胺。产率26％；1HNMR(600MHz,DMSO-d6)δ13.56(s,1H),11.49(s,1H),9.53(s,1H),9.37(s,1H),8.36(dd,J＝13.8,6.7Hz,3H),7.87(t,J＝7.8Hz,3H),7.80–7.78(m,2H),7.76(d,J＝8.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.35(t,J＝7.7Hz,1H),5.87(s,1H),4.32(d,J＝5.0Hz,2H),2.21(d,J＝7.0Hz,6H),2.11(d,J＝3.5Hz,6H)；13CNMR(151MHz,DMSO)δ168.80,166.49,163.29,151.87,151.41,149.88,143.09,141.50,139.40,137.89,136.32,135.71,129.86,128.35,127.84,127.34,124.60,123.23,122.64,121.82,121.01,115.33,109.17,107.67,35.26,23.56,19.24,18.48,14.81；HRMS[M+Na]+calcdforC32H30N6NaO4585.2221,found585.2219；HPLCpurity95.69％(systemB；tR＝3.082min).
实施例3化合物(I-3)：2-(3'-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-4'-甲基-5'-丙酰胺基-[1,1'-联苯]-4-基)-1H-苯并[d]咪唑-4-甲酰胺。产率31％；1HNMR(500MHz,DMSO-d6)δ13.89(s,1H),11.51(s,1H),9.35(s,1H),8.38(dd,J＝11.4,7.0Hz,3H),7.86(t,J＝7.4Hz,2H),7.78(q,J＝8.8Hz,3H),7.52–7.40(m,2H),7.38–7.28(m,2H),5.87(s,1H),4.31(dd,J＝8.8,5.1Hz,2H),2.21(d,J＝8.7Hz,6H),2.11(d,J＝3.8Hz,5H),1.31–1.21(m,3H)；13CNMR(151MHz,DMSO)δ168.94,166.63,163.43,152.01,151.55,150.02,143.23,141.64,139.54,138.03,136.46,135.20,130.00,128.49,127.98,127.48,124.74,123.37,122.78,121.96,120.22,115.47,109.31,107.81,35.40,23.70,19.38,18.62,14.95,8.91；HRMS[M+Na]+calcdforC33H32N6NaO4599.2377,found599.2376；HPLCpurity99.30％(systemB；tR＝3.094min).
实施例4化合物(II-1)：6-(4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-1-乙基-1H-吲唑-4-甲酰胺。产率27％；1HNMR(500MHz,DMSO-d6)δ13.58(s,1H),11.53(s,1H),9.38(s,1H),8.69(dd,J＝10.0,4.8Hz,1H),8.39(d,J＝6.7Hz,3H),8.23(s,1H),8.11(t,J＝12.1Hz,2H),7.98(d,J＝4.4Hz,1H),7.88(d,J＝7.6Hz,1H),7.79–7.74(m,2H),7.36(t,J＝7.8Hz,1H),5.88(s,1H),4.56(q,J＝7.3Hz,2H),4.40(d,J＝5.1Hz,2H),2.23(s,3H),2.11(s,3H),1.43(t,J＝7.2Hz,3H)；13CNMR(126MHz,DMSO)δ166.90,166.25,163.64,150.17,143.34,142.37,141.89,141.84,140.38,137.20,136.02,133.40,128.63,128.56,127.87,123.59,122.93,122.12,121.64,119.94,115.50,110.77,110.22,108.03,43.67,35.84,19.47,18.68,15.53；HRMS[M+Na]+calcdforC32H29N7NaO3582.2224,found582.2222；HPLCpurity96.42％(systemB；tR＝3.330min).
实施例5化合物(II-2)：6-(4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-1-异丙基-1H-吲唑-4-甲酰胺。产率28％；1HNMR(500MHz,DMSO-d6)δ13.58(s,1H),11.51(s,1H),9.36(s,1H),8.66(d,J＝5.7Hz,1H),8.42–8.31(m,3H),8.23(s,1H),8.06(dd,J＝24.0,8.1Hz,2H),7.98–7.93(m,1H),7.87(d,J＝7.5Hz,1H),7.76(d,J＝8.0Hz,2H),7.34(td,J＝7.8,2.8Hz,1H),5.87(s,1H),5.19(s,1H),4.39(t,J＝6.0Hz,2H),2.22(d,J＝2.3Hz,3H),2.10(s,3H),1.57(d,J＝6.7Hz,3H),1.51(d,J＝6.5Hz,3H)；13CNMR(126MHz,DMSO)δ166.20,165.88,163.13,151.64,149.63,148.58,142.80,142.22,141.52,135.71,135.47,128.00,127.92,127.67,127.44,122.87,122.33,122.24,121.67,121.03,120.44,119.47,118.75,117.93,115.04,110.11,107.53,54.82,35.30,22.96,22.16,18.98,18.17；HRMS[M+Na]+calcdforC33H31N7NaO3596.2381,found596.2380；HPLCpurity98.78％(systemB；tR＝3.417min).
实施例6化合物(II-3)：2-(4-(4-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-1-异丙基-1H-吲哚-6-基)苯基)-1H-苯并咪唑-4-甲酰胺。产率30％；1HNMR(600MHz,DMSO-d6)δ13.42(s,1H),11.57–11.54(m,1H),9.40(s,1H),8.35(dd,J＝12.1,6.6Hz,3H),8.10–8.00(m,3H),7.87(d,J＝7.5Hz,1H),7.83(d,J＝1.5Hz,1H),7.76(dd,J＝10.0,5.6Hz,2H),7.66(d,J＝3.2Hz,1H),7.34(t,J＝7.7Hz,1H),6.91(d,J＝3.2Hz,1H),5.89(s,1H),5.00(m,J＝6.7Hz,1H),4.40(d,J＝5.1Hz,2H),2.25(s,3H),2.12(s,3H),1.50(d,J＝6.6Hz,6H)；13CNMR(151MHz,DMSO)δ167.06,166.36,163.26,152.07,149.30,142.93,142.73,136.58,131.62,127.57,127.50,127.34,127.28,127.02,125.97,122.77,122.11,121.97,118.14,115.09,110.51,107.58,101.45,54.92,46.44,35.34,22.66,18.97,18.19；HRMS[M+Na]+calcdforC34H32N6NaO3595.2428,found595.2428；HPLCpurity95.85％(systemB；tR＝3.334min).
实施例7化合物(Ⅲ-1)：2-((3'-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-5'-(乙氨基)-4'-甲基-[1,1'-联苯]-4-基)甲基)-1H-苯并[d]咪唑-4-甲酰胺。产率32％；1HNMR(500MHz,DMSO-d6)δ12.79(s,1H),11.44(s,1H),9.29(s,1H),8.01(d,J＝5.0Hz,1H),7.81(dd,J＝7.6,4.0Hz,1H),7.73–7.61(m,2H),7.61–7.50(m,2H),7.42(d,J＝7.4Hz,2H),7.32–7.22(m,1H),6.73(d,J＝11.7Hz,2H),5.85(s,1H),4.90(s,1H),4.29(dd,J＝14.4,4.4Hz,4H),3.18(d,J＝8.3Hz,2H),2.19(s,3H),2.10(s,3H),2.05(s,3H),1.24(s,2H),1.20(d,J＝6.8Hz,3H)；13CNMR(126MHz,DMSO)δ168.89,165.64,162.49,151.25,148.83,146.63,142.15,138.24,136.41,134.88,127.25,126.86,126.54,122.36,121.76,121.12,114.41,112.68,107.37,106.85,37.38,34.43,28.44,18.38,17.64,13.81,13.20；HRMS[M+H]+calcdfor565.2922,found
565.2930；HPLCpurity96.07％(systemB；tR＝3.127min).
实施例8化合物(Ⅲ-2)：2-((3'-乙酰氨基-5'-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-4'-甲基-[1,1'-联苯]-4-基)甲基)-1H-苯并[d]咪唑-4-甲酰胺。产率29％；1HNMR(500MHz,DMSO-d6)δ13.71(s,1H),11.46(s,1H),9.33(s,1H),8.39–8.30(m,3H),7.85(t,J＝7.7Hz,3H),7.79–7.70(m,3H),7.42(d,J＝9.8Hz,1H),7.39–7.28(m,2H),5.86(s,1H),4.30(d,J＝5.1Hz,4H),2.23–2.14(m,6H),2.09(d,J＝5.2Hz,6H)；13CNMR(151MHz,DMSO)δ169.23,165.87,162.68,152.99,149.11,146.80,142.33,140.42,138.79,138.19,137.47,134.53,134.13,129.20,126.06,122.01,121.69,121.40,121.28,117.93,114.63,112.57,107.42,107.10,37.25,34.56,22.09,18.56,17.82,14.00；HRMS[M+Na]+calcdforC33H32N6NaO4599.2377,found599.2375；HPLCpurity99.59％(system B；tR＝3.029min).
实施例9化合物(Ⅳ-1)：6-(4-((4-氨基甲酰基-1H-苯并[d]咪唑-2-基)甲基)苯基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-1-乙基-1H-吲唑-4-甲酰胺。产率29％；1HNMR(500MHz,DMSO-d6)δ12.87(s,1H),11.52(s,1H),9.29(s,1H),8.62(t,J＝5.0Hz,1H),8.35(s,1H),8.07(s,1H),7.89–7.74(m,4H),7.74–7.61(m,2H),7.51(d,J＝8.3Hz,2H),7.27(t,J＝7.7Hz,1H),5.87(s,1H),4.52(q,J＝7.2Hz,2H),4.38(d,J＝4.9Hz,2H),4.35(s,2H),2.21(s,3H),2.11(s,3H),1.40(t,J＝7.2Hz,3H)；13CNMR(126MHz,DMSO)δ166.70,166.25,163.61,155.06,150.07,143.29,141.63,140.36,138.95,137.93,137.09,135.15,133.29,129.85,129.36,128.43,128.16,122.73,122.47,122.09,121.28,119.99,115.21,110.31,107.99,43.59,35.81,34.94,19.42,18.65,15.45；HRMS[M+Na]+calcdforC33H31N7NaO3596.2381,found596.2382；HPLCpurity99.07％(system B；tR＝3.200min).
实施例10化合物(Ⅳ-2)：6-(4-((4-氨基甲酰基-1H-苯并[d]咪唑-2-基)甲基)苯基)-N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-1-异丙基-1H-吲唑-4-甲酰胺。产率25％；1HNMR(500MHz,DMSO-d6)δ12.86(s,1H),11.51(s,1H),9.29(d,J＝3.6Hz,1H),8.61(t,J＝5.1Hz,1H),8.35(d,J＝4.2Hz,1H),8.06(d,J＝14.4Hz,1H),7.86–7.75(m,4H),7.72–7.62(m,4H),7.27(t,J＝7.8Hz,1H),5.87(s,1H),5.13(p,J＝6.6Hz,1H),4.40–4.30(m,4H),2.20(s,3H),2.11(s,3H),1.48(d,J＝6.6Hz,6H)；13CNMR(126MHz,DMSO)δ168.51,166.71,166.30,163.62,155.08,150.09,143.29,141.61,140.02,139.02,137.78,137.06,135.16,133.17,129.84,128.42,128.18,127.94,122.74,122.50,122.10,122.05,121.24,120.00,115.22,110.30,108.00,49.70,35.79,34.95,22.60,19.43,18.66；HRMS[M+Na]+calcdforC34H33N7NaO3610.2537,found610.2537；HPLC purity99.01％(systemB；tR＝3.231min).
实施例11化合物(Ⅳ-3)：2-(4-(4-(((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基甲酰基)-1-乙基-1H-吲哚-6-基)苄基)-1H-苯并咪唑-4-甲酰胺。产率31％；1HNMR(600MHz,DMSO-d6)δ12.93(s,1H),11.53(s,1H),9.30(s,1H),8.29(t,J＝5.2Hz,1H),7.85(s,1H),7.77(dd,J＝25.8,7.5Hz,3H),7.66(d,J＝22.3Hz,3H),7.50–7.44(m,3H),7.25(d,J＝8.4Hz,1H),6.82(d,J＝3.1Hz,1H),5.86(s,1H),4.35(d,J＝5.1Hz,2H),4.31(s,2H),4.28(q,J＝7.2Hz,2H),2.21(s,3H),2.10(s,3H),1.35(t,J＝7.2Hz,3H)；13CNMR(151MHz,DMSO)δ166.63,165.84,162.83,154.33,148.80,142.29,140.71,139.09,136.24,135.21,134.27,132.09,129.54,128.89,126.79,126.69,125.18,121.81,121.54,121.11,117.66,114.33,109.79,107.16,100.53,54.51,39.96,34.91,18.53,17.76,15.15；HRMS[M+Na]+calcd forC34H32N6NaO3595.2428,found 595.2429；HPLC purity 99.79％(system B；tR＝3.184min).
实施例12
本发明部分化合物的药理学实验及结果如下：
一、相关药理实验验证本发明化合物对三阴性乳腺癌细胞的抑制活性及对PARP1和EZH2的抑制活性：
实验方法：测定化合物对MDA-MB-231和BT-549细胞的抑制活性及对正常乳腺细胞MCF-10A的毒性。采用MTT法得到IC50。按照每个化合物设置三个副孔，每个实验重复三次，实验结果表达为平均值±SEM。
表1:本发明化合物对MDA-MB-231和BT-549细胞抑制活性及对正常乳腺细胞MCF-10A的毒性a
a处理72h后采用MTT法检测细胞活力；b用三个独立实验的剂量响应曲线的平均SD表示。
表2:本发明化合物对PARP1的双浓度抑制率及对EZH2的亲和力a
a用三个独立实验的剂量响应曲线的平均SD表示；b未检测到。
从表1,2可知，化合物II-2对两种细胞的抑制活性较好，对两种酶的作用效果较好，对人正常乳腺细胞MCF-10A基本没有毒性。接下来我们测定化合物II-2对PARP1和EZH2的半数抑制率。
表3：化合物II-2对PARP1和EZH2的抑制活性a
a用三个独立实验的剂量响应曲线的平均SD表示；b未检测到。
表3表明化合物II-2对PARP-1和EZH2有良好的体外抑制活性,有作为抗肿瘤药物的潜力。

Claims (10)

1.通式(V)所示的化合物或其药学上可接受的盐，
其中，所述的R1选自C1-4的低级烷基；R2选自H、氨基或者C1-4的低级烷基；或者
R1和R2及他们相连的原子形成含有1-2个氮原子的五元或六元杂环；R3选自H、C1-4的低级烷基、C1-4的低级酰基；n＝0、1、2或3。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于R1选自甲基或乙基，R2选自H，R3选自H、C1-3的低级烷基、C1-3的低级酰基，n＝0、1。
3.根据权利要求2所述的化合物或其药学上可接受的盐，其特征在于R1选自甲基，R2选自H，R3选自甲基、乙基、异丙基、乙酰基或丙酰基，n＝0、1。
4.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于R1和R2及他们相连的原子形成含有1个或1个氮原子的五元不饱和含氮杂环，R3选自乙基、异丙基、乙酰基或丙酰基，n＝0、1。
5.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于选自以下化合物或其药学上可接受的盐：
6.根据权利要求1～5中任一项所述的化合物或其药学上可接受的盐，其特征在于药学上可接受的盐为所述的化合物与酸形成的酸加成盐，所述的酸选自：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
7.一种药物组合物，其中含有权利要求1～5中任一项所述的化合物或其药学上可接受的盐及药学上可接受的载体。
8.根据权利要求7所述的药物组合物，其特征在于所述的药物组合物被制备成片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、冻干粉针或针剂中的任意一种剂型。
9.一种如权利要求1所述的化合物的制备方法，其特征在于反应路线如下：
10.权利要求1～5中任一项所述的化合物或其药学上可接受的盐、权利要求7所述的药物组合物在制备抗肿瘤药物中的用途，所述的肿瘤选自乳腺癌细胞。
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WO2002079192A1 (en) * 2001-03-28 2002-10-10 Bristol-Myers Squibb Company Novel tyrosine kinase inhibitors
WO2004031401A2 (en) * 2002-10-02 2004-04-15 Bristol-Myers Squibb Company Novel tyrosine kinases inhibitors
WO2013053983A1 (en) * 2011-10-10 2013-04-18 Orion Corporation Protein kinase inhibitors
CN105017221A (zh) * 2014-04-30 2015-11-04 中国医学科学院药物研究所 苯并咪唑衍生物及其制法和药物组合物与用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002079192A1 (en) * 2001-03-28 2002-10-10 Bristol-Myers Squibb Company Novel tyrosine kinase inhibitors
WO2004031401A2 (en) * 2002-10-02 2004-04-15 Bristol-Myers Squibb Company Novel tyrosine kinases inhibitors
WO2013053983A1 (en) * 2011-10-10 2013-04-18 Orion Corporation Protein kinase inhibitors
CN105017221A (zh) * 2014-04-30 2015-11-04 中国医学科学院药物研究所 苯并咪唑衍生物及其制法和药物组合物与用途

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