CN108530391B - 一种酰胺类芳基哌嗪衍生物及其制备方法与应用 - Google Patents

一种酰胺类芳基哌嗪衍生物及其制备方法与应用 Download PDF

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CN108530391B
CN108530391B CN201810478869.5A CN201810478869A CN108530391B CN 108530391 B CN108530391 B CN 108530391B CN 201810478869 A CN201810478869 A CN 201810478869A CN 108530391 B CN108530391 B CN 108530391B
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袁牧
陈洪
叶碧波
邵斌豪
黄珺珺
刘夏雯
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Abstract

本发明属于药物化学技术领域，具体涉及一种酰胺类芳基哌嗪衍生物，并进一步公开其制备方法，以及用于制备治疗良性前列腺增生药物的应用。本发明所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐，经初步药理学研究，通过大鼠离体组织(脾、胸主动脉、输精管)生物功能测试，所述衍生物对α1A‑AR，α1D‑AR表现出了较强的拮抗活性及良好的选择性，而对α1B亚型的拮抗能力较弱，可在保证药物疗效的同时有效减少药物副作用，可为新型抗良性前列腺增生药物的研制、开发提供更为高效、安全的选择。

Description

一种酰胺类芳基哌嗪衍生物及其制备方法与应用
技术领域
本发明属于药物化学技术领域，具体涉及一种酰胺类芳基哌嗪衍生物，并进一步公开其制备方法，以及用于制备治疗良性前列腺增生药物的应用。
背景技术
良性前列腺增生(Benign prostatic hyperplasia，BPH)，是一种常见的老年男性泌尿障碍症，BPH的主要临床表现为下尿路症状(LUTS)，包括尿频、尿急、尿等待、夜尿增多、尿无力等症；严重者可导致并发症，如急性尿潴留、尿失禁、反复发作的尿路感染、血尿、肾衰竭、膀胱结石等。近年来，随着国民生活水平的提高，，人口平均寿命的延长及人口老龄化的加速，其发病率有逐渐增加的趋势，在国外50-60岁的老年男性中约50％患有前列腺增生症，而80岁时可达80％-90％。因此，BPH的治疗药物研究已成为老年疾病研究的新热点(J.Med.Chem.1988,31,1087-1093；Br.J.Pharmacol.2000,129,653-660；Pharmacol.Ther.2000,88,281-309)。
α1 adrenergic receptors(α1-ARs)，是G蛋白偶联受体(GPCRs)家族的重要成员之一，其具有调节心血管系统和中枢神经系统活动的功能，这类7次跨膜受体在药物研发中占据核心的位置。α1-ARs按照其生理调节特点可分为α1A、α1B和α1D三种亚型。α1-ARs的病理生理学研究表明：膀胱颈、前列腺包膜及增生的前列腺基质中的平滑肌细胞以α1-AR为主(The Atlas of Clinical Urology.1990,17,641-649)。而α1-AR引起的平滑肌收缩则是引发BPH的主要原因(Reviews in urology.2005.7(Suppl 8)::p.S34～42)。另有研究表明，拮抗α1A-AR可以缓解尿路梗阻，拮抗α1D-AR对逼尿肌功能失调的刺激性和灌注性排泄症状有改善作用，而α1B则与小阻力血管的控制有关，拮抗α1B将产生低体位性低血压、心悸、昏厥等副作用。因此，选择性的作用于α1A及α1D亚型是目前公认的有效治疗BPH有效靶标(Curr.Med.Chem.2006,13,3395-3416；B.J..U International.2000,86Suppl 2:p.23-8,discussion 28-30)。
然而，目前应用的α1-AR拮抗剂主要都是对α1-AR三种亚型存在普遍拮抗性(Eur.J.Pharmacol.1999,374,495–502)，难以区分血管和尿路α肾上腺素受体，常在治疗BPH的同时易导致患者产生一系列心血管副作用。因而，开发出新一代的高效、低毒、高选择性的α1-AR拮抗剂具有重大意义。
发明内容
为此，本发明所要解决的技术问题在于提供一种酰胺类芳基哌嗪衍生物，所述酰胺类芳基哌嗪衍生物具有高效、低毒，且α1-AR高选择性的优势。
本发明所要解决的第二个技术问题在于提供上述酰胺类芳基哌嗪衍生物用于制备治疗良性前列腺增生药物的应用。
为解决上述技术问题，本发明所述的一种酰胺类芳基哌嗪衍生物及其药学上可接受的盐，所述衍生物具有如下式(Ⅰ)所示的结构：
Figure BDA0001664513180000021
其中，m选自1-4的整数，n选自0-2的整数；
R1选自取代或未取代的C1-C4的烷基；
R2选自取代或未取代的C6-C10的芳基，或取代或未取代的C3-C9的杂芳基。
所述R1选自甲基、三氟甲基、乙基、异丙基或叔丁基之一。
所述R2选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的咪唑基、取代或未取代的吲哚基、取代或未取代的噻唑基、取代或未取代的2,3-二氢苯并呋喃、取代或未取代的苯并呋喃、取代或未取代的萘基、取代或未取代的3,4-乙撑二氧噻吩、取代或未取代的2,3-二氢-1,4-苯并二噁烷、取代或未取代的吗啉基、取代或未取代的己内酰胺基。
所述酰胺类芳基哌嗪衍生物中，m＝2，n＝0。
所述酰胺类芳基哌嗪衍生物中，所述R1为异丙基，所述R2选自如下式1-29所示的结构：
Figure BDA0001664513180000031
进一步的，所述药学上可接受的盐具有如下式(Ⅱ)所示的结构：：
Figure BDA0001664513180000032
其中，所述药学上可接受的盐包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、草酸盐、磷酸盐、琥珀酸盐、墟泊酸盐、乳酸盐中的一种。
本发明还公开了一种制备所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐的方法，包括如下步骤：
(1)以4-溴-1-丁胺氢溴酸为原料，在DMAP和三乙胺存在下，通过二碳酸二叔丁基酯保护，制得中间体Ⅱ；
(2)所述中间体Ⅱ在碱催化下与2-异丙氧基苯基哌嗪进行反应，得到中间体Ⅲ；
(3)所述中间体Ⅲ在三氟乙酸存在下，脱保护生成中间体Ⅳ；
(4)所述中间体Ⅳ与选定的羧基经缩合反应得到所需的酰胺类芳基哌嗪衍生物；
Figure BDA0001664513180000041
所述的制备酰胺类芳基哌嗪衍生物及其药学上可接受的盐的方法，还包括将将所述酰胺类芳基哌嗪衍生物溶于有机溶剂中，并加入选定的HX酸进行反应，析出的固体即为所需的酰胺类芳基哌嗪衍生物的盐。
本发明还公开了所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐用于制备α1-AR拮抗剂的用途。
本发明还公开了所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐用于制备治疗良性前列腺增生药物的用途。
本发明所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐，经初步药理学研究，通过大鼠离体组织(脾、胸主动脉、输精管)生物功能测试，所述衍生物对α1A-AR表现出了较强的抑制活性及良好的抑制选择性，对α1A及α1D亚型具有BPH有效靶标性能，而对α1B亚型的拮抗性能稍弱，可在保证药物疗效的同时有效减少药物副作用，为新型抗良性前列腺增生药物的研制开发提供更为高效、安全的选择。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中，
图1为化合物对脾脏拮抗活性实验的数据图；
图2为化合物对胸主动脉拮抗活性实验的数据图；
图3为化合物对输精管拮抗活性实验的数据图。
具体实施方式
本发明下述实施例中涉及仪器包括：
熔点测定用a Fisher Johns hot-stage测定仪(温度计未校正)；
1HNMR，13C NMR用瑞士Bruker AVANCE AV-400NB，TMS做内标；
ESI-MS用Angilent 6330型超高速液相色谱-离子阱质谱联用仪测定。
制备例1 中间体Ⅱ的制备
Figure BDA0001664513180000051
将5g 4-溴正丁烷-1-氨氢溴酸盐与4.686g(1.5eq)二碳酸二叔丁基酯溶于二氯甲烷溶液中，搅拌溶解，缓慢滴加含有193mg(0.1eq)4-二甲氨基吡啶和8.688g(4eq)三乙胺的二氯甲烷溶液，室温反应1.5h。最后在分液漏斗中分别用0.5N盐酸水溶液和饱和食盐水洗涤反应液，经无水硫酸钠干燥后，过滤，减压蒸馏除去有机溶剂，得到5.387g中间Ⅱ。
制备例2 中间体Ⅲ的制备
Figure BDA0001664513180000052
将中间体Ⅱ(5.387g)(1.5eq)溶于乙腈，并加入5.923g(3eq)碳酸钾固体和3.150g2-异丙氧基苯基哌嗪，80℃回流反应过夜。反应液过滤后拌样上硅胶柱，用石油醚和乙酸乙脂梯度洗脱，得4.502g中间体Ⅲ。
制备例3 中间体Ⅳ的制备
Figure BDA0001664513180000053
将4.502g中间体Ⅲ溶于120ml二氯甲烷，缓慢滴加30ml三氟乙酸室温搅拌，点板监控反应终点。反应完全后，加入20％氢氧化钠水溶液调节反应液呈碱性，然后用二氯甲烷萃取3次，经无水硫酸钠干燥，减压蒸馏除去有机溶剂得到3.203g中间体Ⅳ，未经进一步纯化，直接用于一下步反应。
实施例
本发明下述实施例1～29用于合成所述衍生物结构式中m＝2，n＝0，R1为异丙基，R2选自如下式1～29所示的结构的衍生物，分别记为衍生物1～29，其具体制备过程包括：
Figure BDA0001664513180000061
取90mg上述中间体Ⅳ溶解于20ml二氯甲烷中，加入60mg(1eq)具有相应R2结构的酸、以及117mg(1eq)2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯、0.6ml N,N-二异丙基乙胺，常温下搅拌6h，反应完全后，用碳酸氢钠水溶液和水清洗反应液，经无水硫酸钠干燥后，用300目硅胶层析柱分离纯化，先用200ml乙酸乙酯-石油醚(体积比2：1)冲洗副产物，然后用甲醇-二氯甲烷体系梯度洗脱，分别得到相应的化合物1-29。
实施例1 化合物1的制备
Figure BDA0001664513180000062
按照上述合成方法，选取选定R2结构的酸进行反应，得到80mg淡黄色油状物。
ESI-MS(m/z)：469.7[M+H]+；1H NMR(400MHz,DMSO)δ7.91(t,J＝5.4Hz,1H,N-H),6.95–6.82(m,6H,Ar-H),6.77(dd,J＝8.2,1.9Hz,1H,Ar-H),4.57(dq,J＝12.1,6.1Hz,1H,O-CH-(CH3)2),3.72(d,J＝8.4Hz,6H,Ar-(O-CH3 )2),3.31(s,2H,Ar-CH2),3.06(dd,J＝11.6,5.9Hz,2H,NH-CH2 ),2.97(s,4H,piperazinyl-H),2.54–2.40(m,4H,piperazinyl-H),2.30(s,2H,piperazinyl-CH2 ),1.43(s,4H,CH2-(CH2 )2-CH2),1.25(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ170.12(s),149.77(s),148.51(s),147.47(s),139.71(s),129.04(s),122.11–121.97(m),121.42(s),120.89(s),118.19(s),116.50(s),112.95(s),111.87(s),69.64(s),57.55(s),55.56(s),55.43(s),53.00(s,2C),49.84(s,2C),42.09(s),38.45(s),27.05(s),23.62(s),22.03(s,2C)。可见，化合物结构正确。
实施例2 化合物2的制备
Figure BDA0001664513180000071
按照上述合成方法，选取选定R2结构的酸进行反应，得到97mg淡黄色固体。
ESI-MS(m/z)：477.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.0Hz,2H,Ar-H),7.41(d,J＝7.9Hz,2H,Ar-H),6.99–6.83(m,4H,Ar-H),6.26(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.59(s,2H,Ar-CH2),3.27(q,J＝5.9Hz,2H,NH-CH2 ),3.13(s,4H,piperazinyl-H),2.64(s,4H,piperazinyl-H),2.44(t,J＝6.7Hz,2H,piperazinyl-CH2 ),1.65–1.50(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.86(s),150.31(s),142.34(s),139.25(s),129.64(s,2C),129.42(q,J＝32.6Hz,),125.71(q,J＝3.7Hz,2C),124.11(q,J＝272.2Hz,CF3),122.70(s),121.40(s),118.42(s),115.86(s),70.25(s),57.91(s),53.45(s,2C),50.14(s,2C),43.46(s),39.50(s),27.31(s),24.00(s),22.29(s,2C)。可见，化合物结构正确。
实施例3 化合物3的制备
Figure BDA0001664513180000072
按照上述合成方法，选取选定R2结构的酸进行反应，得到132mg淡黄色固体。
ESI-MS(m/z)：477.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.57–7.38(m,4H,Ar-H),7.00–6.80(m,4H,Ar-H),6.26(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.59(s,2H,Ar-CH2),3.31–3.23(m,2H,NH-CH2 ),3.13(s,4H,piperazinyl-H),2.63(s,4H,piperazinyl-H),2.43(t,J＝6.5Hz,2H,piperazinyl-CH2 ),1.62–1.48(m,4H,CH2-(CH2 )2-CH2),1.35(t,J＝6.7Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.89(s),150.32(s),142.43(s),136.17(s),132.72(s),131.07(q,J＝32.5Hz),129.25(s),125.95(q,J＝3.7Hz),124.02(q,J＝3.9Hz),122.64(s),121.42(s),118.41(s),115.93(s),70.26(s),57.94(s),53.47(s,2C),50.20(s,2C),43.39(s),39.54(s),27.34(s),24.07(s),22.29(s,2C)。可见，化合物结构正确。
实施例4 化合物4的制备
Figure BDA0001664513180000081
按照上述合成方法，选取选定R2结构的酸进行反应，得到128mg淡黄色固体。
ESI-MS(m/z)：443.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.31–7.22(m,3H,Ar-H),7.16(d,J＝5.6Hz,1H,Ar-H),6.98–6.83(m,4H,Ar-H),6.07(s,1H,N-H),4.65–4.52(m,1H,O-CH-(CH3)2),3.52(s,2H,Ar-CH2),3.32–3.22(m,2H,NH-CH2 ),3.12(s,4H,piperazinyl-H),2.62(s,4H,piperazinyl-H),2.41(t,J＝6.4Hz,2H,piperazinyl-CH2 ),1.54(d,J＝2.7Hz,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ170.03(s),150.32(s),142.51(s),137.13(s),134.64(s),130.12(s),129.41(s),127.51(s),127.43(s),122.59(s),121.44(s),118.43(s),115.97(s),70.26(s),58.00(s),53.49(s,2C),50.24(s,2C),43.39(s),39.54(s),27.39(s),24.08(s),22.32(s,2C)。可见，化合物结构正确。
实施例5 化合物5的在制备
Figure BDA0001664513180000082
按照上述合成方法，选取选定R2结构的酸进行反应，得到124mg淡黄色固体。
ESI-MS(m/z)：423.6[M+H]+；1H NMR(400MHz,DMSO)δ7.95(s,1H,N-H),7.15(d,J＝8.0Hz,2H,Ar-H),7.09(d,J＝8.0Hz,2H,Ar-H),6.93–6.85(m,4H,Ar-H),4.63–4.51(m,1H,O-CH-(CH3)2),3.34(s,2H,Ar-CH2),3.06(dd,J＝11.8,6.1Hz,2H,NH-CH2 ),2.99(s,4H,piperazinyl-H),2.60–2.43(m,4H,piperazinyl-H),2.34(s,3H,Ar-CH3),2.26(s,2H,piperazinyl-CH2 ),1.48–1.36(m,4H,CH2-(CH2 )2-CH2),1.26(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ170.51(s),150.27(s),143.16(s),135.64(s),134.01(s),129.21(s,2C),129.16(s,2C),122.60(s),121.90(s),118.71(s),116.95(s),70.15(s),57.87(s),53.42(s,2C),50.27(s,2C),42.60(s),38.92(s),27.50(s),23.94(s),22.53(s,2C),21.08(s)。可见，化合物结构正确。
实施例6 化合物6的制备
Figure BDA0001664513180000091
按照上述合成方法，选取选定R2结构的酸进行反应，得到107mg淡黄色固体。
ESI-MS(m/z)：427.6[M+H]+；1H NMR(400MHz,DMSO)δ8.01(t,J＝5.1Hz,1H,N-H),7.33–7.23(m,2H,Ar-H),7.15–7.06(m,2H,Ar-H),6.93–6.80(m,4H,Ar-H),4.63–4.51(m,1H,O-CH-(CH3)2),3.39(s,2H,Ar-CH2),3.05(t,J＝11.2Hz,2H,NH-CH2 ),2.98(s,4H,piperazinyl-H),2.53–2.39(m,4H,piperazinyl-H),2.32(s,2H,piperazinyl-CH2 ),1.43(s,4H,CH2-(CH2 )2-CH2),1.25(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ170.23(s),161.44(d,J＝241.8Hz),150.27(s),143.17(s),133.23(d,J＝3.0Hz),131.18(s),131.10(s),122.55(s),121.90(s),118.68(s),116.96(s),115.37(s),115.16(s),70.13(s),57.96(s),53.48(s,2C),50.31(s,2C),41.98(s),38.97(s),27.50(s),24.04(s),22.52(s,2C)。可见，化合物结构正确。
实施例7 化合物7的制备
Figure BDA0001664513180000092
按照上述合成方法，选取选定R2结构的酸进行反应，得到123mg淡黄色油状物。
ESI-MS(m/z)：410.6[M+H]+；1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.7Hz,1H,Ar-H),7.66(t,J＝7.7Hz,1H,Ar-H),7.45(s,1H,N-H),7.29(d,J＝8.1Hz,1H,Ar-H),7.23–7.16(m,Ar-H),7.00–6.81(m,4H,Ar-H),4.65–4.52(m,1H,O-CH-(CH3)2),3.72(s,2H,Ar-CH2),3.34–3.24(m,2H,NH-CH2 ),3.13(s,4H,piperazinyl-H),2.63(s,4H,piperazinyl-H),2.42(t,J＝6.5Hz,2H,piperazinyl-CH2 ),1.56(s,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.25(s),155.89(s),150.30(s),149.10(s),142.59(s),137.16(s),124.13(s),122.52(s),121.43(s),118.46(s),115.99(s),70.23(s),58.13(s),53.47(s,2C),50.17(s,2C),45.45(s),39.34(s),27.43(s),24.02(s),22.32(s,2C)。可见，化合物结构正确。
实施例8 化合物8的制备
Figure BDA0001664513180000101
按照上述合成方法，选取选定R2结构的酸进行反应，得到71mg黄色油状物。
ESI-MS(m/z)：454.6[M+H]+；1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.3Hz,2H,Ar-H),7.47(d,J＝8.3Hz,2H,Ar-H),6.99–6.81(m,4H,Ar-H),6.56(s,1H,N-H),4.65–4.53(m,1H,O-CH-(CH3)2),3.63(s,2H,Ar-CH2),3.29(q,J＝5.8Hz,2H,NH-CH2 ),3.14(s,4H,piperazinyl-H),2.66(s,4H,piperazinyl-H),2.49–2.36(m,2H,piperazinyl-CH2 ),1.67–1.53(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.07(s),150.31(s),147.11(s),142.77(s),142.30(s),130.14(s),123.85(s),122.75(s),121.41(s),118.39(s),115.89(s),70.28(s),57.84(s),53.45(s,2C),50.17(s,2C),43.30(s),39.55(s),27.28(s),24.07(s),22.31(s,2C)。可见，化合物结构正确。
实施例9 化合物9的制备
Figure BDA0001664513180000102
按照上述合成方法，选取选定R2结构的酸进行反应，得到106mg淡黄色固体。
ESI-MS(m/z)：468.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.1Hz,1H,Ar-H),7.44(d,J＝7.6Hz,1H,Ar-H),7.31(t,J＝7.8Hz,1H,Ar-H),6.98–6.81(m,4H,Ar-H),6.08(s,1H,N-H),4.64–4.53(m,1H,O-CH-(CH3)2),3.65(s,2H,Ar-CH2),3.34–3.22(m,2H,NH-CH2 ),3.12(s,4H,piperazinyl-H),2.60(d,J＝19.9Hz,4H,piperazinyl-H),2.46–2.38(m,2H,piperazinyl-CH2 ),1.52(d,J＝24.2Hz,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.16(s),151.54(s),150.31(s),142.51(s),136.72(s),134.40(s),131.40(s),126.76(s),123.25(s),122.59(s),121.43(s),118.36(s),115.99(s),70.27(s),58.01(s),53.53(s,2C),50.28(s,2C),41.80(s),39.61(s),27.48(s),24.16(s),22.32(s,2C),15.25(s)。可见，化合物结构正确。
实施例10 化合物10的制备
Figure BDA0001664513180000111
按照上述合成方法，选取选定R2结构的酸进行反应，得到111mg淡黄色固体。
ESI-MS(m/z)：454.6[M+H]+；1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.2Hz,1H,Ar-H),7.59(t,J＝7.5Hz,1H,Ar-H),7.52–7.39(m,2H,Ar-H),7.00–6.81(m,4H,Ar-H),6.54(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.84(s,2H,Ar-CH2),3.29(q,J＝5.9Hz,2H,NH-CH2 ),3.14(s,4H,piperazinyl-H),2.65(s,4H,piperazinyl-H),2.45(t,J＝6.6Hz,2H,piperazinyl-CH2 ),1.65–1.53(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.1Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ168.81(s),150.32(s),148.92(s),142.58(s),133.52(s),133.48(s),130.66(s),128.31(s),125.07(s),122.54(s),121.45(s),118.43(s),116.03(s),70.27(s),57.99(s),53.48(s,2C),50.24(s,2C),41.04(s),39.61(s),27.44(s),24.12(s),22.32(s,2C)。可见，化合物结构正确。
实施例11 化合物11的制备
Figure BDA0001664513180000112
按照上述合成方法，选取选定R2结构的酸进行反应，得到119mg淡黄色固体。
ESI-MS(m/z)：443.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.43–7.32(m,2H,Ar-H),7.30–7.19(m,2H,Ar-H),6.98–6.82(m,4H,Ar-H),6.00(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.68(s,2H,Ar-CH2),3.27(q,J＝6.0Hz,2H,NH-CH2 ),3.12(s,4H,piperazinyl-H),2.66(s,4H,piperazinyl-H),2.46(t,J＝6.7Hz,2H,piperazinyl-CH2 ),1.62–1.47(m,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.70(s),150.32(s),142.37(s),134.39(s),133.28(s),131.76(s),129.74(s),128.87(s),127.36(s),122.66(s),121.42(s),118.48(s),115.94(s),70.27(s),57.98(s),53.45(s,2C),49.99(s,2C),41.53(s),39.41(s),27.35(s),23.72(s),22.31(s,2C)。可见，化合物结构正确。
实施例12 化合物12的制备
Figure BDA0001664513180000121
按照上述合成方法，选取选定R2结构的酸进行反应，得到111mg淡黄色固体。
ESI-MS(m/z)：451.6[M+H]+；1H NMR(400MHz,DMSO)δ7.90(t,J＝5.1Hz,1H,N-H),7.11(s,1H,Ar-H),6.94(dd,J＝12.9,5.9Hz,1H,Ar-H),6.88(dt,J＝11.9,6.2Hz,4H,Ar-H),6.66(d,J＝8.1Hz,1H,Ar-H),4.63–4.54(m,1H,O-CH-(CH3)2),4.48(t,J＝8.7Hz,2H,O-CH2 -CH2),3.29(s,2H,Ar-CH2),3.14(t,J＝8.7Hz,2H,O-CH2-CH2 ),3.06(dd,J＝11.8,6.2Hz,2H,NH-CH2 ),2.99(s,4H,piperazinyl-H),2.57–2.42(m,4H,piperazinyl-H),2.33(s,2H,piperazinyl-CH2 ),1.48–1.35(m,4H,CH2-(CH2 )2-CH2),1.25(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ170.82(s),158.74(s),150.27(s),143.18(s),128.78(s),128.63(s),127.50(s),125.99(s),122.58(s),121.90(s),118.70(s),116.96(s),108.83(s),71.21(s),70.14(s),53.47(s,2C),50.28(s,2C),42.38(s),38.94(s),29.58(s),27.52(s),23.98(s),22.53(s,2C)。可见，化合物结构正确。
实施例13 化合物13的制备
Figure BDA0001664513180000122
按照上述合成方法，选取选定R2结构的酸进行反应，得到75mg淡黄色固体。
ESI-MS(m/z)：443.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.31(d,J＝8.2Hz,2H,Ar-H),7.20(d,J＝8.2Hz,2H,Ar-H),6.96–6.83(m,4H,Ar-H),5.98(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.51(s,2H,Ar-CH2),3.25(q,J＝5.7Hz,2H,NH-CH2 ),3.11(s,4H,piperazinyl-H),2.59(s,4H,pipearzinyl-H),2.38(t,J＝6.3Hz,2H,piperazinyl-CH2 ),1.59–1.46(m,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ170.23(s),150.32(s),142.64(s),133.62(s),133.18(s),130.67(s,2C),129.03(s,2C),122.52(s),121.45(s),118.38(s),116.06(s),70.27(s),58.09(s),53.54(s,2C),50.36(s,2C),43.11(s),39.61(s),27.48(s),24.24(s),22.33(s,2C)。可见，化合物结构正确。
实施例14 化合物14的制备
Figure BDA0001664513180000131
按照上述合成方法，选取选定R2结构的酸进行反应，得到116mg淡黄色固体。
ESI-MS(m/z)：453.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.01–6.82(m,8H,Ar-H),6.76(d,J＝5.1Hz,1H,N-H),4.68(dd,J＝7.0,2.5Hz,1H,1,4-dioxane-H),4.65–4.54(m,1H,O-CH-(CH3)2),4.36(ddd,J＝18.5,11.4,4.8Hz,2H,1,4-dioxane-H),3.36(d,J＝5.9Hz,2H,NH-CH2 ),3.17(s,4H,pipearzinyl-H),2.75(s,4H,piperazinyl-H),2.56(s,2H,piperazinyl-CH2 ),1.60(s,4H,CH2-(CH2 )2-CH2),1.33(t,J＝10.4Hz,6H,O-CH-(CH3 )2)；13CNMR(101MHz,CDCl3)δ167.36(s),150.33(s),143.33(s),142.10(s),141.66(s),122.82(s),122.40(s),121.97(s),121.37(s),118.57(s),117.65(s),117.18(s),115.75(s),73.31(s),70.24(s),65.40(s),57.95(s),53.52(s,2C),49.79(s,2C),38.81(s),27.26(s),23.40(s),22.29(s,2C)。可见，化合物结构正确。
实施例15 化合物15的制备
Figure BDA0001664513180000132
按照上述合成方法，选取选定R2结构的酸进行反应，得到107mg淡黄色固体。
ESI-MS(m/z)：511.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.8Hz,1H,Ar-H),7.58(d,J＝7.6Hz,1H,Ar-H),7.36(t,J＝7.8Hz,1H,Ar-H),6.97–6.81(m,4H,Ar-H),6.30(s,1H,N-H),4.64–4.53(m,1H,O-CH-(CH3)2),3.73(s,2H,Ar-CH2),3.33–3.24(m,2H,NH-CH2 ),3.13(s,4H,piperazinyl-H),2.64(s,4H,piperazinyl-H),2.44(t,J＝6.4Hz,2H,piperazinyl-CH2 ),1.64–1.53(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ168.73(s),150.32(s),142.47(s),135.98(s),135.10(s),132.23(s),129.13(q,J＝31.1Hz),126.89(s),126.73(q,J＝5.4Hz),122.86(q,J＝273.2Hz),122.60(s),121.42(s),118.41(s),115.95(s),70.26(s),57.98(s),53.50(s,2C),50.20(s,2C),41.43(s),39.59(s),27.39(s),24.08(s),22.30(s,2C)。可见，化合物结构正确。
实施例16 化合物16的制备
Figure BDA0001664513180000141
按照上述合成方法，选取选定R2结构的酸进行反应，得到104mg棕黄色油状。
ESI-MS(m/z)：399.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.53(s,1H,imidazolyl-H),7.12(s,1H,imidazolyl-H),7.01–6.96(m,1H,imidazolyl-H),6.96–6.83(m,4H,Ar-H),6.35(s,1H,N-H),4.63(s,2H,imidazolyl-CH2),4.58(dt,J＝12.0,6.0Hz,1H,O-CH-(CH3)2),3.33–3.23(m,2H,NH-CH2 ),3.12(s,4H,pipearzinyl-H),2.63(s,4H,piperazinyl-H),2.41(t,J＝6.5Hz,2H,piperazinyl-CH2 ),1.58–1.47(m,4H,CH2-(CH2 )2-CH2),1.33(t,J＝8.7Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ166.68(s),150.30(s),142.45(s),138.08(s),130.38(s),122.63(s),121.42(s),119.82(s),118.42(s),115.92(s),70.25(s),57.93(s),53.49(s,2C),50.20(s,2C),50.14(s),39.42(s),27.25(s),23.93(s),22.31(s,2C)。可见，化合物结构正确。
实施例17 化合物17的制备
Figure BDA0001664513180000142
按照上述合成方法，选取选定R2结构的酸进行反应，得到96mg淡黄色油状物。
ESI-MS(m/z):444.7[M+H]+；1H NMR(400MHz,CDCl3)δ7.00–6.82(m,4H,Ar-H),6.72(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.98(s,2H,2-oxoazepan-CH2),3.49(d,J＝8.7Hz,2H,2-oxoazepan-H),3.32–3.21(m,2H,NH-CH2),3.15(s,4H,piperazinyl-H),2.65(d,J＝20.8Hz,4H,piperazinyl-H),2.62–2.54(m,2H,2-oxoazepan-H),2.46(t,J＝6.8Hz,2H,piperazinyl-CH2 ),1.78–1.71(m,2H,2-oxoazepan-H),1.71–1.65(m,2H,2-oxoazepan-H),1.63–1.52(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13CNMR(101MHz,CDCl3)δ176.95(s),169.43(s),150.30(s),142.51(s),122.56(s),121.41(s),118.46(s),115.93(s),70.23(s),58.01(s),53.46(s,2C),53.36(s),51.32(s),50.12(s,2C),39.20(s),36.85(s),29.83(s),27.94(s),27.34(s),24.00(s),23.26(s),22.31(s,2C).可见，化合物结构正确。
实施例18 化合物18的制备
Figure BDA0001664513180000151
按照上述合成方法，选取选定R2结构的酸进行反应，得到57mg淡黄色固体。
ESI-MS(m/z):470.7[M+H]+；1H NMR(400MHz,DMSO)δ8.12(t,J＝5.6Hz,1H,N-H),7.44(dd,J＝8.3,5.8Hz,2H,Ar-H),7.14(t,J＝8.8Hz,2H,Ar-H),6.93–6.81(m,4H,Ar-H),4.57(dq,J＝12.2,6.1Hz,1H,O-CH-(CH3)2),3.62(s,1H,Ar-CH),3.10–3.01(m,2H,NH-CH2 ),2.96(s,4H,piperazinyl-H),2.45(s,4H,piperazinyl-H),2.27(s,2H,piperazinyl-CH2),2.09(s,6H,N-(CH3 )2),1.45–1.29(m,4H,CH2-(CH2 )2-CH2),1.25(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ170.72(s),162.06(d,J＝243.4Hz),150.22(s),143.12(s),135.11(s),130.77(s),130.69(s),122.58(s),121.88(s),118.66(s),116.85(s),115.40(s),115.19(s),75.72(s),70.03(s),57.95(s),53.44(s,2C),50.28(s,2C),43.72(s,2C),38.61(s),27.46(s),23.93(s),22.51(s,2C).可见，化合物结构正确。
实施例19 化合物19的制备
Figure BDA0001664513180000152
按照上述合成方法，选取选定R2结构的酸进行反应，得到77mg淡黄色固体。
ESI-MS(m/z):470.7[M+H]+；1H NMR(400MHz,CDCl3)δ7.29(dd,J＝12.4,5.6Hz,1H,Ar-H),7.20(s,1H,N-H),7.12(d,J＝7.6Hz,1H,Ar-H),7.06(d,J＝9.7Hz,1H,Ar-H),7.02–6.96(m,1H,Ar-H),6.95–6.84(m,4H,Ar-H),4.60(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.71(s,1H,Ar-CH),3.35–3.25(m,2H,NH-CH2 ),3.13(s,4H,piperazinyl-H),2.61(s,4H,piperazinyl-H),2.42(t,J＝5.9Hz,2H,piperazinyl-CH2 ),2.20(s,6H,N-(CH3 )2),1.63–1.50(m,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ171.08(s),162.79(d,J＝246.2Hz),150.32(s),142.75(s),139.21(d,J＝7.0Hz),129.92(d,J＝8.2Hz),124.60(d,J＝2.7Hz),122.45(s),121.46(s),118.39(s),116.09(s),115.49(d,J＝21.9Hz),115.03(d,J＝21.1Hz),76.65(s),70.26(s),58.20(s),53.59(s,2C),50.33(s,2C),43.84(s,2C),38.98(s),27.64(s),24.25(s),22.32(s,2C).可见，化合物结构正确。
实施例20 化合物20的制备
Figure BDA0001664513180000161
按照上述合成方法，选取选定R2结构的酸进行反应，得到92mg淡黄色油状物。
ESI-MS(m/z):470.7[M+H]+；1H NMR(400MHz,CDCl3)δ7.53–7.43(m,1H,N-H),7.33–7.23(m,2H,Ar-H),7.16–7.02(m,2H,Ar-H),6.97–6.82(m,4H,Ar-H),4.66–4.51(m,1H,O-CH-(CH3)2),4.28(s,1H,Ar-CH),3.45–3.23(m,2H,NH-CH2),3.14(s,4H,piperazinyl-H),2.64(s,4H,piperazinyl-H),2.50–2.39(m,2H,piperazinyl-CH2),2.25–2.12(m,6H,N-(CH3)2),1.61(t,J＝3.1Hz,4H,CH2-(CH2)2-CH2),1.35(d,J＝6.1Hz,6H,O-CH-(CH3)2)；13CNMR(101MHz,CDCl3)δ170.65(s),161.43(d,J＝246.6Hz),150.31(s),142.66(s),131.29(d,J＝4.0Hz),129.62(d,J＝8.4Hz),123.93(d,J＝3.4Hz),122.50(s),122.26(d,J＝14.3Hz),121.44(s),118.42(s),116.02(s),115.78(s),115.55(s),70.23(s),68.39(s),58.23(s),53.56(s,2C),50.25(s,2C),43.21(s,2C),39.03(s),27.72(s),24.16(s),22.32(s,2C).可见，化合物结构正确。
实施例21 化合物21的制备
Figure BDA0001664513180000162
按照上述合成方法，选取选定R2结构的酸进行反应，得到75mg黄色固体。
ESI-MS(m/z):554.5[M+H]+；1H NMR(400MHz,CDCl3)δ8.51(s,1H,Ar-H),7.81(d,J＝8.5Hz,1H,Ar-H),7.67(d,J＝8.5Hz,1H,Ar-H),7.06(d,J＝5.2Hz,1H,N-H),6.99–6.80(m,4H,Ar-H),4.66–4.54(m,1H,O-CH-(CH3)2),3.75(s,2H,S-CH2 ),3.35–3.23(m,2H,NH-CH2 ),3.15(dd,J＝14.7,7.3Hz,4H,piperazinyl-H),2.70(s,4H,piperazinyl-H),2.47(d,J＝6.6Hz,2H,piperazinyl-CH2),1.56(dd,J＝11.0,8.2Hz,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ166.84(s),150.33(s),145.18(s),142.18(s),140.95(s),130.30(s),128.01(d,J＝34.6Hz),127.54(s),123.51(s),122.78(s),121.38(s),118.45(s),115.82(s),70.28(s),57.89(s),53.51(s,2C),49.97(s,2C),39.74(s),36.50(s),27.16(s),23.73(s),22.28(s,2C).可见，化合物结构正确。
实施例22 化合物22的制备
Figure BDA0001664513180000171
按照上述合成方法，选取选定R2结构的酸进行反应，得到135mg淡黄色固体。
ESI-MS(m/z):448.6[M+H]+；1H NMR(400MHz,CDCl3)δ8.82(s,1H,indole-NH),7.55(d,J＝7.9Hz,1H,Ar-H),7.36(d,J＝8.1Hz,1H,Ar-H),7.20(t,J＝7.5Hz,1H,Ar-H),7.13(t,J＝7.5Hz,1H,Ar-H),7.08(s,1H,Ar-H),6.98–6.81(m,4H,Ar-H),5.94(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.72(s,2H,indole-CH2 ),3.21(d,J＝5.8Hz,2H,NH-CH2 ),3.09(s,4H,piperazinyl-H),2.54(s,4H,piperazinyl-H),2.33(d,J＝6.4Hz,2H,piperazinyl-CH2 ),1.51–1.38(m,4H,CH2-(CH 2)2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ171.59(s),150.30(s),142.51(s),136.48(s),127.07(s),123.90(s),122.60(s),122.47(s),121.44(s),119.95(s),118.68(s),118.48(s),115.93(s),111.52(s),108.92(s),70.24(s),58.10(s),53.40(s,2C),50.14(s,2C),39.33(s),33.52(s),27.45(s),23.84(s),22.32(s,2C).可见，化合物结构正确。
实施例23 化合物23的制备
Figure BDA0001664513180000181
按照上述合成方法，选取选定R2结构的酸进行反应，得到114mg淡黄色固体。
ESI-MS(m/z):482.6[M+H]+；1H NMR(400MHz,CDCl3)δ9.10(s,1H,indole-NH),7.52(s,1H,indole-H),7.23(d,J＝8.6Hz,1H,indole-H),7.13(d,J＝8.6Hz,1H,indole-H),7.08(s,1H,indole-H),6.98–6.82(m,4H,Ar-H),6.07(t,J＝5.1Hz,1H,N-H),4.58(dq,J＝12.0,6.0Hz,1H,O-CH-(CH3)2),3.65(s,2H,indole-CH2 ),3.24(d,J＝5.5Hz,2H,NH-CH2 ),3.08(s,4H,piperazinyl-H),2.56(s,4H,piperazinyl-H),2.36(s,2H,piperazinyl-CH2 ),1.46(s,4H,CH2-(CH2 )2-CH2),1.33(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ171.26(s),150.29(s),142.46(s),134.81(s),128.18(s),125.61(s),125.25(s),122.70(s),122.64(s),121.43(s),118.47(s),118.13(s),115.88(s),112.60(s),108.67(s),70.23(s),58.06(s),53.40(s,2C),50.20(s,2C),39.43(s),33.37(s),27.43(s),23.93(s),22.30(s,2C).可见，化合物结构正确。
实施例24 化合物24的制备
Figure BDA0001664513180000182
按照上述合成方法，选取选定R2结构的酸进行反应，得到43mg淡黄色固体。
ESI-MS(m/z):454.6[M+H]+；1H NMR(400MHz,DMSO)δ8.21–8.13(m,2H,Ar-H,N-H),8.10(d,J＝8.2Hz,1H,Ar-H),7.72(d,J＝7.6Hz,1H,Ar-H),7.61(t,J＝7.9Hz,1H,Ar-H),6.92–6.84(m,4H,Ar-H),4.57(dq,J＝12.0,6.0Hz,1H,O-CH-(CH3)2),3.58(s,2H,Ar-CH2 ),3.08(d,J＝5.3Hz,2H,NH-CH2 ),2.96(s,4H,piperazinyl-H),2.46(s,4H,piperazinly-H),2.29(s,2H,piperazinyl-CH2 ),1.43(s,4H,CH2-(CH2 )2-CH2),1.25(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,DMSO)δ169.50(s),150.22(s),148.09(s),143.13(s),139.29(s),136.42(s),130.10(s),124.05(s),122.58(s),121.88(s,2C),118.67(s),116.85(s),70.03(s),57.97(s),53.49(s,2C),50.33(s,2C),42.09(s),39.04(s),27.44(s),24.07(s),22.51(s,2C).可见，化合物结构正确。
实施例25 化合物25的制备
Figure BDA0001664513180000191
按照上述合成方法，选取选定R2结构的酸进行反应，得到91mg黄色固体。
ESI-MS(m/z):418.6[M+H]+；1H NMR(400MHz,CDCl3)δ7.18(s,1H,N-H),6.97–6.83(m,4H,Ar-H),4.60(hept,J＝6.0Hz,1H,O-CH-(CH3)2),3.77–3.69(m,4H,morpholinyl-H),3.36–3.27(m,2H,NH-CH2 ),3.14(s,4H,piperazinyl-H),3.01(s,2H,morpholinyl-CH2 ),2.65(s,4H,piperazinyl-H),2.57–2.49(m,4H,morpholinyl-H),2.45(t,J＝6.6Hz,2H,piperazinyl-CH2 ),1.55(t,J＝18.8Hz,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.77(s),150.30(s),142.58(s),122.54(s),121.42(s),118.43(s),115.96(s),70.23(s),66.98(s,2C),62.09(s),58.22(s),53.89(s,2C),53.55(s,2C),50.23(s,2C),38.80(s),27.77(s),24.14(s),22.31(s,2C).可见，化合物结构正确。
实施例26 化合物26的制备
Figure BDA0001664513180000192
按照上述合成方法，选取选定R2结构的酸进行反应，得到106mg淡黄色固体。
ESI-MS(m/z):431.5[M+H]+；1H NMR(400MHz,CDCl3)δ7.04(s,1H,N-H),6.97–6.82(m,4H,Ar-H),6.26(s,1H,thiazole-H),5.51(s,2H,thiazole-NH2 ),4.67–4.52(m,1H,O-CH-(CH3)2),3.45(s,2H,thiazole-CH2 ),3.26(dt,J＝20.1,10.2Hz,2H,NH-CH2 ),3.14(s,4H,piperazinyl-H),2.67(s,4H,piperazinyl-H),2.50–2.37(m,2H,piperazinyl-CH2 ),1.64–1.45(m,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ169.56(s),168.54(s),150.28(s),145.65(s),142.44(s),122.63(s),121.40(s),118.47(s),115.88(s),105.08(s),70.23(s),58.10(s),53.40(s,2C),50.07(s,2C),39.29(s),39.21(s),27.29(s),23.85(s),22.31(s,2C).可见，化合物结构正确。
实施例27 化合物27的制备
Figure BDA0001664513180000201
按照上述合成方法，选取选定R2结构的酸进行反应，得到86mg淡黄色固体。
ESI-MS(m/z):453.7[M+H]+；1H NMR(400MHz,CDCl3)δ7.15(d,J＝8.3Hz,2H,Ar-H),6.99–6.80(m,6H,Ar-H),5.75(s,1H,N-H),4.59(hept,J＝6.0Hz,1H,O-CH-(CH3)2),4.01(q,J＝7.0Hz,2H,O-CH2 -CH3),3.50(s,2H,Ar-CH2 ),3.28–3.19(m,2H,NH-CH2 ),3.11(s,4H,piperazinyl-H),2.59(s,4H,piperazinyl-H),2.38(t,J＝6.4Hz,2H,piperazinyl-CH2 ),1.59–1.44(m,4H,CH2-(CH2 )2-CH2),1.40(t,J＝7.0Hz,3H,O-CH2-CH3 ),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ171.39(s),158.22(s),150.32(s),142.66(s),130.50(s),126.88(s),122.49(s),121.45(s),118.41(s),116.07(s),114.97(s),70.26(s),63.48(s),58.12(s),53.52(s,2C),50.28(s,2C),43.00(s),39.47(s),27.50(s),24.08(s),22.32(s,2C),14.84(s).可见，化合物结构正确。
实施例28 化合物28的制备
Figure BDA0001664513180000202
按照上述合成方法，选取选定R2结构的酸进行反应，得到136mg黄色油状物。
ESI-MS(m/z):605.6[M+H]+；1H NMR(400MHz,CDCl3)δ8.11(s,1H,Ar-H),8.03(d,J＝8.1Hz,1H,Ar-H),7.63(d,J＝7.6Hz,1H,Ar-H),7.41(t,J＝7.9Hz,1H,Ar-H),7.00–6.78(m,4H,Ar-H),5.93(t,J＝5.1Hz,1H,N-H),5.89(s,1H,NH-CH2),4.94(s,1H,Ar-CH),4.65–4.52(m,1H,O-CH-(CH3)2),3.62(s,3H,O-CH3 ),3.28–3.17(m,2H,NH-CH2 ),3.09(s,4H,piperazinyl-H),2.55(d,J＝11.0Hz,3H,piperazinyl-H),2.35(d,J＝4.4Hz,2H,piperazinyl-CH2 ),2.31(s,3H,NH-C-CH3 ),2.20(s,3H,NH-C-CH3 ),1.47(s,4H,CH2-(CH2 )2-CH2),1.35(d,J＝6.1Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ168.13(s),167.69(s),150.30(s),148.83(s),148.60(s),146.31(s),142.59(s),136.75(s),133.79(s),129.25(s),122.52(s),122.41(s),121.72(s),121.43(s),118.34(s),116.03(s),108.04(s),100.50(s),70.26(s),57.95(s),53.47(s,2C),51.03(s),50.18(s,2C),41.45(s),39.39(s),27.43(s),24.14(s),22.30(s,2C),19.95(s),18.21(s).可见，化合物结构正确。
实施例29 化合物29的制备
Figure BDA0001664513180000211
按照上述合成方法，选取选定R2结构的酸进行反应，得到82mg黄色油状物。
ESI-MS(m/z):459.6[M+H]+；1H NMR(400MHz,CDCl3)δ6.97–6.88(m,3H,Ar-H),6.88–6.83(m,1H,Ar-H),6.81(s,1H,N-H),6.54(s,1H,thiophene-H),4.65–4.53(m,1H,O-CH-(CH3)2),4.41–4.33(m,2H,1,4-dioxane-H),4.24(d,J＝4.1Hz,2H,1,4-dioxane-H),3.46(q,J＝5.8Hz,2H,NH-CH2 ),3.14(s,4H,piperazinyl-H),2.67(s,4H,piperazinyl-H),2.50(d,J＝6.7Hz,2H,piperazinyl-CH2 ),1.71–1.60(m,4H,CH2-(CH2 )2-CH2),1.34(d,J＝6.0Hz,6H,O-CH-(CH3 )2)；13C NMR(101MHz,CDCl3)δ161.33(s),150.32(s),142.59(s),140.98(s),140.58(s),122.54(s),121.43(s),118.44(s),116.02(s),114.39(s),104.74(s),70.26(s),65.59(s),64.08(s),58.32(s),53.59(s,2C),50.20(s,2C),39.28(s),27.86(s),24.13(s),22.32(s,2C).可见，化合物结构正确。
实验例 化合物1-29对α1A-AR、α1B-AR和α1D-AR三种亚型的拮抗活性
1、提取分离组织
取8周龄的SPF级SD大鼠，腹腔注射0.8mL 5％戊巴比妥水溶液，麻醉后对大鼠进行解剖，打开胸腔和腹腔，快速取出胸主动脉、脾脏、输精管(睾丸侧细端)放入富氧(持续通入5％CO2，95％O2混合气)的krebs溶液中(氯化钠120mmol/L，氯化钾5.5mmol/L，氯化钙2.5mmol/L，氯化镁1.2mmol/L，磷酸二氢钠1.2mmol/L，碳酸氢钠25.0mmol/L，葡萄糖11.0mmol/L，醋酸去氧皮质酮3.0μmol/L，盐酸地昔帕敏0.1μmol/L，盐酸普萘洛尔1.0μmol/L，pH7.3-7.4)。
取胸主动脉固定于培养皿中，用组织剪小心剥离附着的血丝和筋膜之后，将动脉切成长5mm的血管环并用镊子剥离血管内皮。用等腰三角形支架将血管环串起，挂在张力测试仪的双层恒温槽上并浸泡在10ml krebs缓冲液中，给予1.5g的前负荷，恒温槽温度设定为37℃。取脾脏固定于培养皿中，用组织剪剥离附着的粘膜和脂肪组织，将脾脏横切成两等分，用丝线结扎悬挂于张力测试仪的双层恒温槽并浸泡在10mL krebs缓冲液中，给予1g的前负荷，恒温槽温度设定为37℃。取输精管固定于培养皿中，用组织剪分离附着的黏膜于血管，切取细端约5mm长度，用细线结扎悬挂于张力测试仪的双层恒温槽并浸泡在10mL krebs缓冲液中，给予0.5g的前负荷，恒温槽温度设定为37℃。
2、张力测试
维持组织预设张力并平衡至少1小时，每隔15分钟更换一次krebs缓冲液。
组织平衡后进行机械调零，加入200μL、4mol/L的KCl水溶液预刺激，待组织收缩到达平台期后，更换krebs缓冲液。平衡至少30分钟，期间每隔15分钟更换一次krebs缓冲液，直至组织恢复刺激前的张力。
组织恢复刺激前张力后，加入100μL、1*10-3mol/L的去甲肾上腺素溶液预刺激组织，组织收缩达到平台期后，更换krebs缓冲液，平衡组织至少1小时，平衡期间每15分钟更换一次缓冲液，直至组织恢复刺激前的张力，再重复一次刺激。
三次预刺激结束，组织张力恢复刺激前水平后，分别给予脾、胸主动脉、输精管，30μL 10-2mol/L、30μL 10-3mol/L、100μL 10-5mol/L浓度的去甲肾上腺素，待组织收缩张力达到平台期后记录收缩张力值作为给药前数据(输精管收缩张力取峰值)，更换krebs缓冲液。平衡组织至少1小时，每隔15分钟换液一次至组织恢复刺激前张力。
给予组织3*10-8mol/L浓度的受试化合物，加受试化合物后不再换液，孵育20分钟。
孵育受试化合物完成后，分别再次给予脾、胸主动脉、输精管，30μL 10-2mol/L、30μL 10-3mol/L、100μL 10-5mol/L浓度的去甲肾上腺素，待组织收缩张力达到平台期后并记录组织收缩张力值作为给药后数据(输精管收缩张力取峰值)。通过如下公式计算受试化合物对三种组织的收缩抑制率：
药物抑制率＝(1-给药后刺激张力/给药前刺激张力)*100％。
化合物分别对脾脏胸主动脉、输精管的拮抗活性数据分别见图1-3所示，图中纵坐标为张力，单位为g；横坐标为时间，图中6条虚线，分别代表5次给药刺激与1次孵育受试化合物。根据附图数据分别计算其化合物1～29对三种组织的抑制率，记录于下表1。
表1 化合物1～29对三种组织的抑制率
Figure BDA0001664513180000231
Figure BDA0001664513180000241
从表1的活性初筛结果，可以看出芳基哌嗪衍生物均具有不同程度的松弛平滑肌的作用，提示这些化合物具有拮抗去甲肾上腺素兴奋受体引起的平滑肌收缩效应，表明上述化合物具有不同程度的α1-受体拮抗活性。芳基哌嗪衍生物在3*10-8浓度下对脾(α1B-AR)的抑制活性绝大多数都低于30％，与坦索罗辛相当，略高于萘哌地尔，说明这批化合物对α1B-AR的抑制活性普遍不高，而对α1B-AR的抑制作用会引起许多心血管方面的不良反应。
芳基哌嗪衍生物对胸主动脉(α1D-AR)的抑制活性也都低于30％，远低于坦索罗辛(93.25％)，但是与萘哌地尔较接近。
对α1A-AR选择活性，化合物22和29对α1A-AR选择活性最好的，其对大鼠输精管(α1A-AR)的抑制活性都达到了90％以上，与坦索罗辛(97.20％)相近，且远高于萘哌地尔(57.62％)，对输精管收缩的高抑制率显示出这3个化合物对α1A-AR的抑制活性较好。
以化合物22和29为例进一步探讨其对α1-AR亚型受体的抑制情况，对比情况记录于下表2。
表2 化合物22、29、坦索罗辛和萘哌地尔对α1-AR亚型受体抑制率的比值
名称 α<sub>1A</sub>-AR/α<sub>1B</sub>-AR α<sub>1A</sub>-AR/α<sub>1D</sub>-AR
化合物22 10.91 7.59
化合物29 2.78 6.93
坦索罗辛 3.71 1.04
萘哌地尔 6.79 16.85
从表2对比情况可看出，在α1A-AR/α1D-AR的相对选择性方面，化合物22和化合物29要优于坦索罗辛，而较萘哌地尔稍低，其选择性强弱依次为：萘哌地尔＞化合物22≈化合物29＞坦索罗辛。
在α1A-AR/α1B-AR的相对选择性方面，化合物22优于坦索罗辛和萘哌地尔，其选择性强弱依次为：化合物22＞萘哌地尔＞坦索罗辛＞化合物29。
总体上来看，这三个化合物对于α1A-AR的相对选择活性要比坦索罗辛好，且抑制活性比萘哌地尔强。
在这三个受试化合物中，化合物29对α1B-AR的拮抗活性要比化合物22稍强，可以推测化合物29可能会引起较多心血管方面的副作用，而化合物22可能更具有成药潜力。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (6)

1.一种酰胺类芳基哌嗪衍生物及其药学上可接受的盐，其特征在于，所述衍生物具有如下式（Ⅰ）所示的结构：
Figure DEST_PATH_IMAGE001
；
其中，m=3，n=0；
所述R1选自为异丙基；
所述R2选自如下式所示的结构：
Figure DEST_PATH_IMAGE003
。
2.根据权利要求1所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐，其特征在于，所述药学上可接受的盐包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、草酸盐、磷酸盐、琥珀酸盐、墟泊酸盐、乳酸盐中的一种。
3.一种制备权利要求1所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐的方法，其特征在于，包括如下步骤：
（1）以4-溴-1-丁胺氢溴酸为原料，在DMAP和三乙胺存在下，通过二碳酸二叔丁基酯保护，制得中间体Ⅱ；
（2）所述中间体Ⅱ在碱催化下与2-异丙氧基苯基哌嗪进行反应，得到中间体Ⅲ；
（3）所述中间体Ⅲ在三氟乙酸存在下，脱保护生成中间体Ⅳ；
（4）所述中间体Ⅳ与选定的羧基经缩合反应得到所需的酰胺类芳基哌嗪衍生物；
Figure 859921DEST_PATH_IMAGE004
。
4.根据权利要求3所述的制备酰胺类芳基哌嗪衍生物及其药学上可接受的盐的方法，其特征在于，还包括将所述酰胺类芳基哌嗪衍生物溶于有机溶剂中，并加入选定的HX酸进行反应，析出的固体即为所需的酰胺类芳基哌嗪衍生物的盐。
5.权利要求1或2所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐用于制备α1-AR拮抗剂的用途。
6.权利要求1或2所述的酰胺类芳基哌嗪衍生物及其药学上可接受的盐用于制备治疗良性前列腺增生药物的用途。
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