CN104447625B - 苯甲酰胺类化合物或其药学上可接受的盐及其应用 - Google Patents
苯甲酰胺类化合物或其药学上可接受的盐及其应用 Download PDFInfo
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- CN104447625B CN104447625B CN201310422397.9A CN201310422397A CN104447625B CN 104447625 B CN104447625 B CN 104447625B CN 201310422397 A CN201310422397 A CN 201310422397A CN 104447625 B CN104447625 B CN 104447625B
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- Prior art keywords
- piperazine
- chloro
- replacement
- nitrophenyl
- ketone
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- 206010022000 influenza Diseases 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明公开式Ⅰ所示的苯甲酰胺类化合物或其药学上可接受的盐及其应用,属于药物化学技术领域。所述苯甲酰胺类化合物或其药学上可接受的盐,在体外能够显著阻断病毒核蛋白进入宿主细胞核,表现出显著抑制流感病毒的活性。
Description
技术领域
本发明涉及化学医药技术领域,特别是涉及苯甲酰胺类化合物或其药学上可接受的盐及其应用。
背景技术
流行性感冒简称流感,是由流感病毒引起的一种常见的急性呼吸道传染病,也是一种传染性强、传播速度快的疾病,以冬春季多见。典型的临床特点是急起高热、显著乏力,全身肌肉酸痛,而鼻塞、流涕和喷嚏等上呼吸道症状相对较轻。本病具有自限性,但在婴幼儿、老年人和存在心肺基础疾病的患者容易并发肺炎等严重并发症而导致死亡。据世界卫生组织公布的数据显示,流感会导致总人口5%~15%的人感染,,300万―500万患者因此发生肺炎、心肌炎、呼吸衰竭等并发症,25万―50万患者因而死亡;我国每年有超过10%的人感染流感。
禽流感,全称为鸟禽类流行性感冒,是由病毒引起的动物性传染病,通常只感染鸟类,少数情况下会感染猪。禽流感病毒高度针对特定物种,但在罕有情况下会跨越物种障碍感染人。自从1997年在香港发现人类也会感染禽流感之后,此病症引起全世界卫生组织的高度关注。其后,该病一直在亚洲地区零星爆发。2003年12月开始,禽流感在东亚多国,尤其是在越南、韩国、泰国等地严重爆发,并造成越南多名病人丧生。现在包括东欧多个国家都有禽流感的案例发生。2012年3月,台湾首度发生H5N2高致病性禽流感,引起重视。2012年9月,广东省农业厅通报,湛江发生高致病性禽流感。高致病性禽流感的发病率和死亡率都非常高,人感染高致病性禽流感死亡率约是60%,而家禽感染的死亡率几乎是100%。2013年3月,上海和安徽两地又发现H7N9禽流感病例,到目前为止已造成100多人感染,其中已有36人死亡。
目前,注射流感疫苗仍然是预防流感的最主要方式。然而,由于流感病毒具有广泛的宿主和多个分段的基因组,在其感染和复制的过程中容易发生基因突变或基因重组而产生变种,因此,我们很难获得对流感具有稳定而且持久的免疫能力。目前使用的流感疫苗对流感的预防效率仅达60%-70%,对老年人或伴发基础疾病者保护力仅为40%。临床上,还是以药物治疗流感为主,尤其是在流感爆发期间,药物治疗显得尤为重要。
目前已经开发出的抗流感药物主要有两类,一类是以离子通道M2蛋白为药物靶点,包括金刚烷胺和金刚乙胺两种。这类药物通过改变宿主细胞的表面电荷,调节宿主细胞的PH值,抑制病毒M2通道的打开,阻止了病毒释放核酸,从而抑制病毒的繁殖。但这种药物具有明显的中枢神经系统等副作用,且只对甲型流感有效。同时,使用该类药物治疗流感约有三分之一的患者出现了耐药现象,并且存在金刚烷胺和金刚乙胺两种药物交叉耐药的情况。因此,在临床上,该类药物的使用受到了限制。另一类是以病毒表面的糖蛋白神经氨酸酶为药物靶点,主要包括扎那米韦(Zanamivir)和奥司他韦(Oseltamivir)等。该类药物能够竞争性的与流感病毒神经氨酸酶的活性位点结合,进而干扰病毒从被感染的宿主细胞中释放,从而减少流感病毒的复制。神经氨酸酶抑制剂类药物是目前最为有效的治疗流感的药物之一,然而,该类药物同样面临着中枢神经系统等毒副作用的困扰,并且,该类药物的耐药株也被分离出来了。面对具有高突变率的流感病毒,和现有药物的毒副作用的困扰,因此,开发新的抗流感靶点及新型抗流感药物变得极为迫切。
流感病毒是一种RNA病毒,其遗传物质RNA主要依赖核蛋白运输到宿主细胞核内进行复制和重组。因此,只要能抑制病毒核蛋白进入细胞核内,就能有效的抑制流感病毒的复制。2010年Ricard Y Kao(Nature Biotechnology,2010,28,600)和Ching-Yao Su(PNAS,2011,108,15366)分别报道了以核蛋白为靶点的小分子抑制剂Nucleozin及其类似物能够有效的抑制流感病毒的复制。2012年,程辉敏博士也在此基础上通过骨架迁移及电子等排策略研究发现了1,2,3-三氮唑-4(5)苯甲酰胺类化合物同样具有很好的抗流感病毒效应(JMC,2012,55,2144)。
发明内容
基于此,本发明的目的在于克服现有技术的缺陷,提供一种苯甲酰胺类化合物或其药学上可接受的盐。
为实现上述目的,本发明采取以下技术方案:
式Ⅰ所示的苯甲酰胺类化合物或其药学上可接受的盐:
其中,Ar2选自0-3个R2取代的苯基;
R2选自:卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基;
R1选自:0-3个R3取代的苯基,0-3个R3取代的萘,0-3个R3取代的连苯基,0-3个R3取代的氮杂芳香环,苯并呋喃环,环戊烷,环己烷,吲哚,吡嗪;
R3选自:卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基。
在其中一些实施例中,所述苯甲酰胺类化合物选自式II所示化合物:
其中:R4、R5、R6各自任选自:氢,卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基。
R7、R8、R9各自任选自:氢,卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基。
在其中一些实施例中,所述苯甲酰胺类化合物选自式III所示化合物:
其中:R7、R8、R9各自任选自:氢,卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R4选自:甲氧基,卤素;
R5选自:硝基。
在其中一些实施例中,所述苯甲酰胺类化合物选自式IV所示化合物:
其中:R7、R8、R9各自任选自:氢,卤素,C1-C4烷基,C1-C5烷氧基,氰基,硝基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,苯酚基,1-甲基哌嗪基;
R4选自:甲氧基,卤素;
R5选自:硝基。
在其中一些实施例中,所述苯甲酰胺类化合物选自式V所示化合物:
其中:R7选自:C1-C4烷基,C1-C5烷氧基,卤素;
R9选自:氢,卤素,氨基;
R4选自:甲氧基,卤素;
R5选自:硝基。
在其中一些实施例中,所述R1选自0-2个R3取代的吡啶,R3选自卤素,氨基。
在其中一些实施例中,所述R1选自:苯并呋喃环,环己烷,环戊烷,吲哚,吡嗪。
本发明的另一个目的在于提供上述苯甲酰胺类化合物或其药学上可接受的盐在制备预防和治疗流感药物中的应用。
本发明的另一个目的在于提供一种预防和治疗流感的药物组合物,其活性成分包括上述的苯甲酰胺类化合物或其药学上可接受的盐。
与现有技术相比,本发明具有以下有益效果:
本发明所提供的苯甲酰胺类化合物或其药学上可接受的盐,其在体外能够显著阻断病毒核蛋白进入宿主细胞核,表现出显著抑制流感病毒的活性。从而为临床治疗流感提供了新的药物选择。
附图说明
图1为实施例88中核蛋白进入细胞核实验不加药物4小时共聚焦显微镜下照片;
图2为实施例88中核蛋白进入细胞核实验加入实施例13制备得到的化合物4小时共聚焦显微镜下照片;
图3为实施例88中核蛋白进入细胞核实验加入实施例29制备得到的化合物4小时共聚焦显微镜下照片;
具体实施方式
以下结合附图和具体实施例来详细说明本发明,但该实施例并非用于限制本发明的保护范围。
本发明以取代苯甲酸为原料,通过酰化或是缩合反应,生成苯甲酰胺类化合物。
实施例1(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(苯基)甲酮的合成
步骤1)1-(2-氯-4-硝基苯基)哌嗪的合成
分别称取18.69g(96.2mmol)六水哌嗪和8.66g(45.1mmol)3,4-二氯硝基苯溶于40mlDMF中,加热到100℃。反应3小时后,停止反应。在旋转蒸发仪上旋蒸掉大部分的溶剂,加入100ml的水,用乙酸乙酯多次萃取,合并有机相,洗涤,干燥,旋干溶剂,柱层析得产物8.46g(77.8%)。
其表征数据为:1H NMR(400MHz,CDCl3),δ8.22(d,J=2.4Hz,1H),8.07(dd,J=2.4,9.2Hz,1H),7.02(d,J=9.2Hz,1H),3.18(s,4H),3.07(s,4H),2.43(s,1H)。
步骤2)(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(苯基)甲酮的合成
称取241mg(1mmol)1-(2-氯-4-硝基苯基)哌嗪和183mg(1.5mmol)苯甲酸于10ml的二氯甲烷中,加入383mg(2mmol)EDCI,270mg(2mmol)HOBT及200mg(2mmol)NEt3,室温反应,TLC跟踪至反应结束。反应液减压浓缩,柱层析得产物。
其表征数据为:1H NMR(400MHz,CDCl3),δ8.26(d,J=2.8Hz,1H),8.11(dd,J=2.4,8.8Hz,1H),7.46-7.43(m,5H),7.05(d,J=9.2Hz,1H),3.99(br.,2H),3.66(br.,2H),3.25(br.,2H),3.17(br.,2H)。
实施例2(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.24(d,J=2.0Hz,1H),8.16(d,J=8.8Hz,1H),7.32-7.21(m,5H),3.84-3.11(m,8H),2.25(s,3H);13C NMR(125MHz,DMSO-d6),δ168.7,154.2,141.8,136.1,133.8,130.2,128.7,126.4,125.9,125.8,125.7,123.7,120.8,50.4,50.1,46.2,40.8,40.0,39.9,39.84,39.76,39.7,39.5,39.3,39.2,39.0,18.6。
实施例3(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.24(d,J=2.8Hz,1H),8.17(dd,J=2.4,8.8Hz,1H),7.35-7.21(m,5H),3.68-3.19(m,8H),2.34(s,3H);13C NMR(125MHz,DMSO-d6),δ169.2,154.3,141.8,137.8,135.6,130.2,128.3,127.4,126.3,125.9,124.0,123.7,120.8,50.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0,20.9。
实施例4(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.23(d,J=2.4Hz,1H),8.16(dd,J=2.4,8.8Hz,1H),7.35-7.25(m,5H),3.75-3.19(m,8H),2.33(s,3H);13C NMR(125MHz,DMSO-d6),δ169.2,154.2,141.8,139.3,132.7,138.9,127.2,126.3,128.9,123.7,120.7,50.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0,20.9。
实施例5(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-乙基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.19(dd,J=2.8,9.2Hz,1H),7.39-7.29(m,5H),3.83-3.15(m,8H),2.68(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H);13CNMR(125MHz,DMSO-d6),δ169.2,154.3,145.5,141.8,133.0,129.4,127.9,127.7,127.2,126.3,125.9,123.7,120.7,50.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0,28.1,15.3。
实施例6(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-异丙基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.27(d,J=2.0Hz,1H),8.13(dd,J=2.0,8.8Hz,1H),7.38(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),7.06(d,J=8.8Hz,1H),3.88(br.,4H),3.03(s,4H),2.98(m,1H),1.27(d,J=7.2Hz,6H)。
实施例7(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.17(dd,J=2.8,9.2Hz,1H),7.31(d,J=7.2Hz,1H),7.13(dt,J=1.2,8.0Hz,1H),7.06(dd,J=7.6Hz,1H),6.73(d,J=8.0Hz,1H),6.60(t,J=7.2Hz,1H),5.24(br.,2H),3.65-3.22(m,8H);13C NMR(125MHz,DMSO-d6),δ168.7,154.3,145.7,141.7,130.1,127.8,126.3,125.9,123.7,120.6,119.0,115.50,115.48,50.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例8(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(s,1H),8.18(d,J=8.8Hz,1H),7.32(d,J=8.8Hz,1H),7.09(t,J=7.6Hz,1H),6.63-6.59(m,2H),6.53(d,J=7.2Hz,1H),5.27(br.,2H),3.80-3.19(m,8H)。
实施例9(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.24(d,J=2.8Hz,1H),8.17(dd,J=8.8,2.4Hz,1H),7.3(d,J=5.2Hz,1H),7.19(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),5.55(br.,2H),3.68(4,4H),3.20(s,4H);13C NMR(125MHz,DMSO-d6),δ170.0,154.3,150.6,141.7,129.3,126.3,125.9,123.7,121.5,120.7,112.6,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例10(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-羟基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.24(s,1H),8.17(d,J=8.0Hz,1H),7.31(d,J=8.8Hz,1H),7.26(t,J=8.8Hz,1H),7.18(d,J=6.8Hz,1H),6.90(t,J=8.0Hz,2H),3.80-3.20(m,8H);13C NMR(125MHz,DMSO-d6),δ167.3,154.3,153.2,141.7,130.3,128.2,126.3,125.9,123.7,123.6,120.7,119.1,115.7,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例11(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-羟基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.32(d,J=9.2Hz,1H),7.27(t,J=8.0Hz,1H),6.87-6.81(m,3H),3.78-3.17(m,8H)。
实施例12(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-羟基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(d,J=7.2Hz,1H),7.32-7.31(m,3H),6.83-6.81(m,2H),3.68-3.21(m,8H),2.54(s,1H);13C NMR(125MHz,DMSO-d6),δ169.4,158.9,154.3,141.8,131.4,129.3,126.9,125.9,125.8,123.8,120.7,115.3,114.9,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例13(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.26(d,J=2.4Hz,1H),8.13(dd,J=8.8,2.4Hz,1H),7.62(d,J=7.6Hz,1H),7.42(t,J=7.6Hz,1H),7.31-7.28(m,2H),7.06(d,J=9.2Hz,1H),4.15-4.09(m,1H),3.99-3.93(m,1H),3.54-3.11(m,6H);13C NMR(125MHz,CDCl3),δ167.8,154.1,142.7,137.5,132.8,130.5,127.9,127.8,127.7,126.5,123.4,119.7,119.0,77.3,77.0,76.7,50.8,50.3,46.7,41.4。
实施例14(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.26(d,J=2.4Hz,1H),8.12(dd,J=2.4,8.8Hz,1H),7.59-7.57(m,2H),7.37-7.26(m,2H),7.06(d,J=8.8Hz,1H),3.97-3.18(m,8H)。
实施例15(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.69(d,J=8.4Hz,1H),7.44(d,J=8.0Hz,1H),7.31(d,J=8.8Hz,1H),3.80-3.01(m,8H)13CNMR(125MHz,DMSO-d6),δ168.1,154.2,141.8,134.8,131.4,129.2,126.3,125.9,123.71230.0,120.7,50.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例16(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.27(d,J=2.8Hz,2H),8.25(d,J=8.0Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),7.91(t,J=8.0Hz,1H),7.76(dt,J=1.2,8.4Hz,1H),7.63(dd,J=1.2,7.6Hz,1H),7.35(d,J=9.2Hz,1H),3.85-3.3.82(m,2H),3.44-3.26(m,4H),3.18-3.12(m,2H);13C NMR(125MHz,DMSO-d6),δ165.6,154.2,145.3,141.9,134.9,132.1,130.4,128.1,126.4,125.9,124.8,123.8,120.7,50.0,49.7,46.4,41.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例17(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.32-8.22(m,3H),8.17(dd,J=8.8,2.8Hz,1H),7.93(d,J=7.6Hz,1H),7.79(t,J=8.0Hz,1H),7.31(d,J=8.8Hz,1H),3.84-3.19(m,8H)。
实施例18(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.31(d,J=8.4Hz,2H),8.23(d,J=2.8Hz,1H),8.17(dd,J=2.4,8.8Hz,1H),7.74(d,J=8.8Hz,2H),7.30(d,J=9.2Hz,2H),3.83-3.17(m,8H);13C NMR(125MHz,DMSO-d6),δ167.2,154.1,147.8,142.0,141.8,128.4,126.3,125.9,123.7,120.7,50.2,49.9,46.9,41.5,40.1,40.0,39.9,39.84,39.76,39.7,39.5,39.3,39.2,39.0。
实施例19(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-氰基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.27(d,J=2.8Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),7.97(d,J=8.0Hz,2H),7.67(d,J=8.4Hz,2H),7.32(d,J=9.2Hz,1H),3.85-3.18(m,8H);13CNMR(125MHz,DMSO-d6),δ167.6,154.2,141.8,140.2,132.6,127.9,126.4,125.9,123.7,120.7,118.3,112.2,54.9,50.2,49.9,46.9,41.5,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例20(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-甲氧基羰氧基苯基)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),8.05(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),7.32(d,J=8.8Hz,1H),3.88(s,3H),3.83-3.17(m,8H);13C NMR(125MHz,DMSO-d6),δ168.2,165.7,154.2,141.8,140.1,130.4,129.3,127.3,126.3,125.9,123.7,120.7,52.3,50.3,50.0,46.9,41.5,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例21(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.44(dt,J=1.6,8.8Hz,1H),7.33(d,J=9.2Hz,1H),7.25(dd,J=1.6,7.2Hz,1H),7.12(d,J=7.6Hz,1H),7.04(t,J=7.6Hz,1H),3.86-3.79(m,5H),3.34-3.41(m,2H),3.26(t,J=4.8Hz,2H),3.14(t,J=4.8Hz,2H);13C NMR(125MHz,DMSO-d6),δ166.6,154.9,154.2,141.8,130.5,127.8,126.3,125.9,125.3,123.7,120.7,120.6,111.4,55.5,50.4,50.1,46.2,40.9,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例22(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-甲氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.40(t,J=8.0Hz,1H),7.32(d,J=8.8Hz,1H),7.05-6.99(m,3H),3.85-3.76(m,5H),3.56-3.12(m,6H);13C NMR(125MHz,DMSO-d6),δ168.8,159.1,154.2,141.8,137.0,129.7,126.3,125.9,123.7,120.7,118.7,115.2,112.3,55.2,50.1,47.0,41.4,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例23(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-甲氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.44(d,J=8.4Hz,1H),7.33(d,J=9.2Hz,1H),7.02(d,J=8.8Hz,1H),3.81(s,3H),3.77-3.22(m,8H)。
实施例24(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-乙氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.27(s,1H),8.13(d,J=8.8Hz,1H),7.42(d,J=8.4Hz,2H),7.06(d,J=8.8Hz,1H),7.00(d,J=8.0Hz,2H),4.10(q,J=6.8Hz,2H),3.84(s,4H),3.21(s,4H),1.45(t,J=6.8Hz,3H)。
实施例25(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-异丙氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.27(d,J=2.0Hz,1H),8.12(d,J=8.8Hz,1H),7.41(d,J=8.4Hz,2H),7.04(d,J=8.8Hz,1H),6.91(d,J=8.0Hz,2H),4.62(m,1H),3.84(s,4H),3.21(s,4H),1.36(d,J=6.0Hz,6H)。
实施例26(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-(戊基-3-氧代)苯基)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.26(s,1H),8.12(d,J=4.8Hz,1H),7.40(s,2H),7.06(d,J=7.2Hz,1H),6.91(s,2H),4.17(m,1H),3.85-3.22(m,8H),1.71-1.62(m,4H),0.98(t,J=7.2Hz,6H);。
实施例27(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,6-二甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.34(d,J=5.2Hz,1H),7.22(t,J=7.6Hz,1H),7.10(d,J=7.6Hz,1H),3.89(t,J=4.8Hz,2H),3.28(t,J=4.8Hz,4H),3.13(t,J=4.8Hz,2H),2.20(s,6H)。
实施例28(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-乙酰氧基-6-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.24(d,J=1.6Hz,1H),8.09(dd,J=6.0,8.8Hz,1H),6.98(d,J=8.8Hz,1H),6.85(m,3H),3.84(s,2H),3.80(s,3H),3.77(s,3H),3.14(s,2H),2.99(s,3H)。
实施例29(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-6-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.22(d,J=2.4Hz,1H),8.15(dd,J=8.8,2.4Hz,1H),7.29(d,J=9.2Hz,1H),6.96(t,J=8.0Hz,1H),6.54(d,J=8.0Hz,1H),6.44(d,J=7.6Hz,1H),4.89(s,2H),3.86(t,J=4.8Hz,2H),3.40-3.05(m,6H),2.10(s,3H);13C NMR(125MHz,DMSO-d6),δ167.6,154.3,144.1,141.7,134.1,128.8,126.3,125.9,123.7,120.8,120.7,117.6,112.5,50.7,50.1,45.4,40.5,40.0,39.8,39.7,39.5,39.3,39.2,39.0,19.0。
实施例30(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-硝基-6-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.27(d,J=2.8Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),8.08(d,J=8.0Hz,1H),7.77(d,J=7.6Hz,1H),7.63(t,J=8.0Hz,1H),7.35(d,J=9.2Hz,1H),3.86-3.85(m,2H),3.46-3.15(m,6H),2.35(s,3H)。
实施例31(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.17(dd,J=2.4,8.8Hz,1H),7.51(d,J=7.6Hz,1H),7.33-7.25(m,3H),3.90-3.80(m,2H),3.34-3.13(m,6H),2.26(s,3H);13C NMR(125MHz,DMSO-d6),δ166.1,154.1,141.9,137.1,136.4,130.2,129.7,129.4,126.5,125.9,123.7,120.8,118.5,50.3,50.0,45.5,40.6,40.0,39.8,39.7,39.5,39.3,39.2,39.0,19.0。
实施例32(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲氧基-6-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.25(s,1H),8.11(d,J=8.4Hz,1H),7.09(d,J=8.4Hz,1H),7.04(d,J=8.8Hz,1H),6.32(d,J=8.0Hz,1H),6.23(s,1H),3.97(s,2H),3.78(s,3H),3.50-3.12(m,8H)。
实施例33(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-6-甲氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.25(d,J=2.8Hz,1H),8.11(dd,J=2.4,8.8Hz,1H),7.21-7.19(m,2H),7.06(d,J=8.8Hz,1H),6.90(dd,J=7.6,1.2Hz,1H),4.15-4.11(m,1H),3.96-3.90(m,1H),3.83(s,3H),3.46-3.12(m,6H);13C NMR(125MHz,CDCl3),δ165.5,156.6,154.3,142.6,130.8,127.9,126.8,126.6,124.8,123.4,120.1,119.7,109.9,77.3,77.0,76.7,56.1,50.9,50.3,46.3,41.3。
实施例34(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,6-二氯苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+Na]+=437.2。
实施例35(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-羟基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ9.59(s,1H),8.26(d,J=2.4Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.33(d,J=8.8Hz,1H),7.03(d,J=8.0Hz,1H),6.65-6.61(m,2H),3.81-3.11(m,8H),2.17(s,3H);13C NMR(125MHz,DMSO-d6),δ169.2,157.6,154.3,151.8,135.9,127.4,126.7,126.4,125.9,123.7,120.8,116.8,112.5,50.2,40.9,40.0,39.8,39.7,39.5,39.3,39.2,39.0,18.9。
实施例36(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.33(d,J=9.2Hz,1H),6.88(d,J=8.0Hz,1H),6.42-6.39(m,2H),5.25(s,2H),3.80-3.15(m,8H),2.11(s,3H)。
实施例37(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基4-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.21(d,J=2.0Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),8.14(dd,J=2.4,8.0Hz,1H),7.58(d,J=8.4Hz,1H),7.33(d,J=9.2Hz,1H),3.90-3.84(m,2H),3.48-3.39(m,4H),3.16-3.11(m,2H),2.39(s,3H);13C NMR(125MHz,DMSO-d6),δ166.9,154.1,147.4,142.5,141.9,136.4,137.3,126.4,125.9,125.0,123.7,121.2,120.8,50.3,50.0,46.1,40.9,40.0,39.8,39.7,39.5,39.3,39.2,39.0,18.5。
实施例38(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.55(s,1H),7.48(d,J=2.0,8.0Hz,1H),7.32(d,J=9.2Hz,1H),7.22(d,J=8.0Hz,1H),3.89-3.80(m,2H),3.40-3.24(m,4H),3.20-3.06(m,2H),2.25(s,3H)。
实施例39(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,4-二硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+H]+=436.2。
实施例40(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.57(d,J=2.0Hz,1H),7.38(dd,J=2.0,8.0Hz,1H),7.31-7.28(m,2H),5.90(s,2H),3.85-3.17(m,8H);13C NMR(125MHz,DMSO-d6),δ166.6,154.2,148.6,146.4,141.,128.9,126.3,125.9,125.2,123.8,120.7,109.6,110.0,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例41(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-4-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.53(d,J=2.0Hz,1H),8.34(dd,J=2.0,8.4Hz,1H),8.27(d,J=2.8Hz,1H),8.19(dd,J=2.8,9.2Hz,1H),7.75(d,J=8.4Hz,1H),7.34(d,J=9.2Hz,1H),3.91-3.82(m,2H),3.36-3.25(m,4H),3.21-3.15(m,2H);13C NMR(125MHz,DMSO-d6),δ165.1,154.0,148.0,143.7,141.9,129.1,127.5,126.4,125.9,123.7,123.3,120.8,119.0,50.1,49.8,46.1,41.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例42(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(d,J=2.4,8.8Hz,1H),7.30(d,J=8.8Hz,1H),7.00(d,J=8.0Hz,1H),6.92(d,J=1.6Hz,1H),6.73(dd,J=1.6,8.4Hz,1H),5.54(br.,2H),3.71-3.52(m,4H),3.28-3.17(m,4H);13C NMR(125MHz,DMSO-d6),δ167.7,154.2,147.3,141.7,129.7,126.3,125.9,123.7,123.2,120.6,118.2,117.9,117.3,50.2,40.0,39.8,39.6,39.7,39.5,39.3,39.2,39.0。
实施例43(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯-4-氟苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.18(d,J=2.4,8.8Hz,1H),7.60(dd,J=2.4,8.8Hz,1H),7.54(dd,J=2.0,8.4Hz,1H),7.37-7.31(m,2H),3.86-3.81(m,2H),3.32-3.14(m,6H);13C NMR(125MHz,DMSO-d6),δ165.1,162.9,160.9,154.1,141.9,132.14,132.12,130.5,130.4,129.8,129.7,126.4,125.9,123.7,120.8,117.0,116.8,115.1,115.0,50.3,49.9,46.2,41.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例44(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氟-4-氯苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.27(d,J=2.8Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.62(dd,J=1.6,9.2Hz,1H),7.54(d,J=8.0Hz,1H),7.43(dd,J=1.6,8.0Hz,1H),7.33(d,J=8.8Hz,1H),3.84-3.15(m,8H);13C NMR(125MHz,DMSO-d6),δ163.2,158.6,156.6,154.1,141.9,135.1,135.0,130.3,125.9,125.3,123.7,122.9,122.8,120.8,116.7,116.5,50.4,49.9,46.5,41.4,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例45(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氟-4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.72(dd,J=1.6,9.6Hz,1H),7.56(dd,J=1.6,8.4Hz,1H),7.46(t,J=7.6Hz,1H),7.32(d,J=9.2Hz,1H),3.84(t,J=4.4Hz,2H),3.47-3.21(m,6H)。
实施例46(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲氧基-4氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.33(d,J=8.8Hz,1H),6.90(d,J=8.0Hz,1H),6.24(d,J=1.6Hz,1H),6.19(dd,J=2.0,8.0Hz,1H),5.45(br.,2H),3.77-3.72(m,4H),3.42-3.09(m,7H);13C NMR(125MHz,DMSO-d6),δ167.5,156.3,154.4,151.4,141.7,129.5,126.3,125.9,123.7,120.7,112.3,105.8,96.3,54.89,54.86,50.5,46.4,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例47(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-硝基-4-三氟甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.55(s,1H),8.31-8.27(m,2H),8.20(dd,J=2.4,8.8Hz,1H),7.91(d,J=8.0Hz,1H),7.35(d,J=9.2Hz,1H),3.91-3.08(m,8H)。
实施例48(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,4-二溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.27(s,1H),8.13(d,J=7.2Hz,1H),7.79(s,1H),7.55(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),7.06(d,J=8.8Hz,1H),4.11-3.13(m,8H)。
实施例49(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-氯苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=6.4Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.31(dd,J=3.6,9.2Hz,1H),7.07(d,J=8.4Hz,1H),6.77(d,J=2.0Hz,1H),6.60(dd,J=1.6,8.0Hz,1H),5.56(br.,2H),3.65-3.22(m,8H)。
实施例50(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(d,J=2.4,8.8Hz,1H),7.30(d,J=8.8Hz,1H),7.00(d,J=8.0Hz,1H),6.92(d,J=1.6Hz,1H),6.73(dd,J=1.6,8.4Hz,1H),5.54(br.,2H),3.71-3.52(m,4H),3.28-3.17(m,4H);13C NMR(125MHz,DMSO-d6),δ167.7,154.2,147.3,141.7,129.7,126.3,125.9,123.7,123.2,120.6,118.2,117.9,117.3,50.2,40.0,39.8,39.6,39.7,39.5,39.3,39.2,39.0。
实施例51(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-羟基-4-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ9.72(s,1H),8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.31(d,J=8.8Hz,1H),6.93(d,J=8.0Hz,1H),6.08-6.06(m,2H),5.40(s,2H),3.67-3.62(m,4H),3.23-3.16(m,4H)。
实施例52(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-乙酰氧基-4-乙酰氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,CDCl3),δ8.29(d,J=2.8Hz,1H),8.15(dd,J=2.4,8.8Hz,1H),7.96(s,1H),7.49(s,1H),7.25(q,J=8.8,16.8Hz,2H),7.08(d,J=8.8Hz,1H),3.97-3.14(m,8H),2.30(s,3H),2.18(s,3H);13C NMR(125MHz,DMSO-d6),δ168.9,168.8,165.6,154.2,147.0,141.8,141.1,128.4,126.4,126.0,123.8,123.4,120.8,116.1,113.0,54.9,50.3,50.1,46.7,41.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0,24.1,20.7。
实施例53(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯-4-氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.17(dd,J=2.8,8.8Hz,1H),7.32(d,J=8.8Hz,1H),7.03(d,J=8.4Hz,1H),6.63(d,J=2.0Hz,1H),6.56(dd,J=2.0,8.4Hz,1H),5.67(br.,2H),3.78-3.14(m,8H)。
实施例54(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,4-二氯苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.76(d,J=5.6Hz,1H),7.56(dd,J=1.6,8.4Hz,1H),7.50(d,J=8.4Hz,1H),7.33(d,J=9.2Hz,1H),3.84-3.15(m,8H)。
实施例55(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-硝基-4-甲基氨基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.40(d,J=5.2Hz,1H),8.27(d,J=2.8Hz,1H),8.19-8.16(m,2H),7.68(dd,J=2.0,8.8Hz,1H),7.33(d,J=9.2Hz,1H),7.07(d,J=8.8Hz,1H),3.75-3.68(m,4H),3.26-3.19(m,4H),3.01(d,J=4.8Hz,3H);13C NMR(125MHz,DMSO-d6),δ167.6,154.2,146.4,141.7,135.4,130.1,126.3,126.1,125.9,123.7,121.2,120.7,114.2,50.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0,29.8。
实施例56(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-硝基-4-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),8.06(d,J=1.2Hz,1H),7.74(dd,J=1.6,8.0Hz,1H),7.32(d,J=9.2Hz,1H),3.82-3.21(m,8H),2.56(s,3H);13C NMR(125MHz,DMSO-d6),δ166.9,154.2,148.8,141.8,134.7,134.1,133.0,131.6,126.3,125.9,123.8,123.1,120.7,49.9,47.1,41.6,40.0,39.8,39.7,39.5,39.3,39.2,39.0,19.3。
实施例57(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氯-4-溴苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),7.89(d,J=8.4Hz,1H),7.74(d,J=1.6Hz,1H),7.38(d,J=2.0,8.4Hz,1H),7.32(d,J=8.8Hz,1H),3.80-3.19(m,8H)。
实施例58(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-硝基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),8.02-7.96(m,2H),7.31(d,J=9.2Hz,1H),6.79-6.76(m,3H),3.65-3.24(m,8H);13C NMR(125MHz,DMSO-d6),δ166.1,154.2,151.7,141.7,135.5,126.4,126.3,125.9,125.1,123.7,120.6,118.3,114.4,50.0,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例59(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.32(d,J=9.2Hz,1H),6.94(dd,J=1.2,8.4Hz,1H),6.86(d,J=1.6Hz,1H),6.65(d,J=8.0Hz,1H),5.02(br.,2H),3.64-3.22(m,8H),2.16(s,3H);13C NMR(125MHz,DMSO-d6),δ168.8,154.3,143.1,141.7,130.7,127.9,126.3,125.9,124.1,123.7,120.7,119.3,115.7,50.3,40.0,39.83,39.76,39.5,39.3,39.2,39.0,19.9。
实施例60(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-氯苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.32(d,J=9.2Hz,1H),7.15(d,J=2.4,8.8Hz,1H),7.07(d,J=2.4Hz,1H),6.74(d,J=8.8Hz,1H),5.39(br.,2H),3.63-3.23(m,8H)。
实施例61(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-3,4-二甲基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.31(d,J=8.8Hz,1H),6.84(dd,J=7.6Hz,1H),6.50(d,J=7.6Hz,1H),3.65-3.20(m,8H),2.20(s,3H),2.02(s,3H);13C NMR(125MHz,DMSO-d6),δ169.5,154.3,143.8,141.7,137.7,126.3,125.9,124.7,123.7,120.8,120.7,117.8,117.0,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0,20.4,12.9。
实施例62(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4,5-二氟苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.31(d,J=8.8Hz,1H),7.18(dd,J=2.0,10.8Hz,1H),6.69-6.64(m,1H),5.41(br.,2H),3.63-3.22(m,8H)。
实施例63(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4,5-二甲氧基苯基)甲酮的合成
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.32(dd,J=9.2Hz,1H),6.67(s,1H),6.40(s,1H),5.09(br.,2H),3.72(s,3H),3.69-3.61(m,7H),3.24-3.22(m,4H);13C NMR(125MHz,DMSO-d6),δ169.0,154.3,151.2,141.7,141.6,139.6,126.3,125.9,123.7,120.7,113.0,109.2,100.3,56.4,55.2,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例64(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,3,4-三氟苯基)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.27(d,J=2.8Hz,1H),8.19(dd,J=2.8,9.2Hz,1H),7.49-7.31(m,3H),3.84-3.16(m,8H)。
实施例65(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(1H-吲哚-5-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.19(dd,J=2.8,9.2Hz,1H),7.69(s,1H),7.46-7.43(m,2H),7.34(d,J=8.8Hz,1H),7.21(dd,J=1.6,8.4Hz,1H),6.51(s,1H),3.78-3.71(m,4H),3.26-3.21(m,4H);13C NMR(125MHz,DMSO-d6),δ170.7,154.3,141.7,136.4,126.9,126.6,126.3,126.0,125.9,123.7,120.7,120.5,119.7,111.1,101.8,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例66(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氨基萘-2-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.18(dd,J=2.4,8.8Hz,1H),7.72(d,J=8.0Hz,1H),7.67(s,1H),7.56(d,J=8.4Hz,1H),7.36-7.30(m,2H),7.18(t,J=7.2Hz,1H),7.01(s,1H),5.34(s,2H),3.89-3.15(m,8H);13C NMR(125MHz,DMSO-d6),δ167.9,154.3,123.2,121.7,134.9,127.9,127.0,126.8,126.3,125.9,125.6,125.0,124.1,123.7,121.8,120.7,107.9,50.2,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例67(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-(4-甲基哌嗪-1-取代)苯基)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.8Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.35-7.30(m,3H),7.00(d,J=8.8Hz,1H),3.77-3.65(m,4H),3.28-3.17(m,8H),2.46-2.43(m,4H),2.22(s,3H);13C NMR(125MHz,DMSO-d6),δ169.4,154.3,151.8,141.7,128.8,126.3,125.9,124.5,123.7,120.7,13.9,54.4,50.3,47.2,45.7,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例68(4-(2-甲氧基-4-硝基苯基)哌嗪-1-取代)环己基甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.4Hz,1H),8.18(dd,J=2.4,9.2Hz,1H),7.31(d,J=9.2Hz,1H),3.68-3.13(m,8H),2.63-2.60(m,1H),1.72-1.63(m,5H),1.39-1.116(m,5H);13C NMR(125MHz,DMSO-d6),δ173.6,154.3,141.7,126.3,125.9,123.7,120.6,50.7,20.3,44.7,40.0,39.8,39.7,39.5,39.3,39.2,39.0,29.1,25.6,25.1。
实施例69(4-(2-甲氧基-4-硝基苯基)哌嗪-1-取代)环戊基甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.0Hz,1H),8.18(dd,J=2.8,8.8Hz,1H),7.31(d,J=8.4Hz,1H),3.69-3.13(m,8H),3.04(t,J=7.6Hz,1H),1.79-1.53(m,10H);13CNMR(125MHz,DMSO-d6),δ173.6,154.3,141.7,126.3,125.9,123.7,120.7,50.6,50.1,44.8,41.1,40.04,40.0,39.8,39.7,39.5,39.3,39.2,39.0,29.5,25.6。
实施例70(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯-5-溴吡啶-3-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.67(s,1H),8.33(d,J=2.8Hz,1H),8.27(d,J=2.4Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.34(d,J=8.8Hz,1H),3.88-3.13(m,8H)。
实施例71(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氨基吡啶-4-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.24(d,J=2.8Hz,1H),8.17(dd,J=2.8,8.8Hz,1H),8.09(s,1H),7.80(d,J=4.8Hz,1H),7.30(d,J=9.2Hz,1H),7.01(d,J=0.8Hz,1H),5.46(br.,2H),3.78-3.06(m,8H)。
实施例72(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-氨基吡啶-3-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:13C NMR(125MHz,DMSO-d6),δ164.6,154.1,146.1,141.9,134.7,134.4,130.8,129.7,126.4,125.9,124.8,123.8,120.7,50.0,49.7,46.4,41.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例73(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2'-羟基-[1,1'-联苯]-4-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ9.67(s,1H),8.27(d,J=2.4Hz,1H),8.19(dd,J=2.8,8.8Hz,1H),7.65(d,J=8.4Hz,2H),7.50(d,J=8.0Hz,2H),7.34-7.29(m,2H),7.21(dt,J=1.2,8.0Hz,1H),6.98(d,J=7.6Hz,1H),6.92(t,J=7.6Hz,1H),3.79-3.24(m,8H);13C NMR(125MHz,DMSO-d6),δ169.2,154.4,154.3,141.8,140.0,133.6,130.3,129.01,128.96,126.9,126.9,126.4,126.0,123.8,120.8,119.6,116.1,50.3,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例74(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3'-羟基-[1,1'-联苯]-4-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),M+=437.3。
实施例75(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(5-苯基呋喃-2-取代)甲酮
合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.25(d,J=2.8Hz,1H),8.17(dd,J=2.8,9.2Hz,1H),7.31(d,J=7.2Hz,1H),7.13(dt,J=1.2,8.0Hz,1H),7.06(dd,J=7.6Hz,1H),6.73(d,J=8.0Hz,1H),6.60(t,J=7.2Hz,1H),5.24(br.,2H),3.65-3.22(m,8H)。
实施例76(4-(2-甲氧基-4-硝基苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,不同在于,步骤1中,将加入的1-(2-氯-4-硝基苯基)哌嗪替换1-(2-甲氧基-4-硝基苯基)哌嗪,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ7.86(dd,J=2.4,8.8Hz,1H),7.72(d,J=2.4Hz,1H),7.51(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),7.285(t,J=8.0Hz,1H),7.07(d,J=8.8Hz,1H),3.92(s,3H),3.87-3.76(m,2H),3.45-3.12(m,6H),2.26(s,3H)。
实施例77(4-(2-硝基苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,不同在于,步骤1中,将加入的1-(2-氯-4-硝基苯基)哌嗪替换1-(2-硝基苯基)哌嗪,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ7.69(s,1H),7.64(d,J=8.0Hz,1H),7.52(t,J=8.0Hz,2H),7.44(d,J=8.0Hz,1H),7.34(d,J=7.2Hz,1H),7.29(t,J=8.0Hz,1H),3.86-3.24(m,8H),2.25(s,3H)。
实施例78(4-(4-甲氧基苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,不同在于,步骤1中,将加入的1-(2-氯-4-硝基苯基)哌嗪替换1-(4-甲氧基苯基)哌嗪,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ7.51(d,J=8.0Hz,1H),7.33(d,J=7.6Hz,1H),7.27(t,J=8.0Hz,1H),6.93(d,J=9.2Hz,2H),6.84(d,J=9.2Hz,2H),3.85-3.76(m,2H),3.69(s,3H),3.38-2.87(m,6H),2.25(s,3H);13C NMR(125MHz,DMSO-d6),δ165.8,153.4,144.9,137.3,136.3,130.1,129.7,129.3,118.5,118.1,114.3,55.2,20.1,49.8,45.5,40.7,40.0,39.8,39.7,39.5,39.3,39.2,39.0,18.9。
实施例79(4-(2,4-二氯苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,不同在于,步骤1中,将加入的1-(2-氯-4-硝基苯基)哌嗪替换1-(2,4-二氯苯基)哌嗪,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.54(t,J=8.4Hz,1H),8.13(d,J=8.4Hz,1H),8.06(t,J=8.0Hz,1H),7.80(t,J=8.0Hz,1H),7.65-7.18(m,9H),3.86-3.60(m,8H),2.25(s,3H),1.21(s,1H);13C NMR(125MHz,DMSO-d6),δ166.1,163.7,147.5,137.6,137.2,136.3,134.4,134.1,132.9,132.2,131.9,130.1,129.7,129.6,129.5,129.3,128.7,128.0,127.5,122.5,118.7,118.4,115.6,50.9,50.6,45.7,40.8,40.0,39.8,39.7,39.5,39.3,39.2,39.0,19.01,18.96。
实施例80(4-(3,5-二氯吡啶-2-取代)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮的合成
合成方法如实施例1,不同在于,步骤1中,将加入的1-(2-氯-4-硝基苯基)哌嗪替换1-(3,5-二氯吡啶-2-取代)哌嗪,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ9.02(t,J=2.4Hz,1H),8.53(d,J=2.4Hz,1H),7.51(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),7.28(t,J=8.0Hz,1H),3.86-3.60(m,8H),2.25(s,3H),1.21(s,1H)。
实施例81(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯苯基)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.18(dd,J=2.8,9.2Hz,1H),7.57-7.45(m,4H),7.34(d,J=9.2Hz,1H),3.86-3.16(m,8H);13C NMR(125MHz,DMSO-d6),δ165.7,154.1,141.9,135.5,130.6,129.4,129.1,128.0,127.6,126.4,125.9,123.7,120.8,50.2,50.0,46.2,41.0,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例82(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氯苯基)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.56-7.49(m,3H),7.43(d,J=7.2Hz,1H),7.33(d,J=8.8Hz,1H),3.85-3.16(m,8H);13C NMR(125MHz,DMSO-d6),δ167.5,154.2,141.8,137.8,133.2,130.5,129.5,126.8,126.3,125.9,125.6,123.7,120.7,50.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例83(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(4-氯苯基)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:1H NMR(400MHz,DMSO-d6),δ8.26(d,J=2.4Hz,1H),8.19(dd,J=2.4,8.8Hz,1H),7.55(dd,J=2.0,6.4Hz,2H),7.51(dd,J=2.0,6.4Hz,2H),3.85-3.17(m,8H);13C NMR(125MHz,DMSO-d6),δ168.1,154.2,141.8,134.4,134.3,129.0,128.5,126.3,125.9,123.7,120.7,50.1,40.0,39.8,39.7,39.5,39.3,39.2,39.0。
实施例84(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(吡啶-3-取代)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+H]+=347.0。
实施例85(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(吡啶-4-取代)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+H]+=347.0。
实施例86(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(吡啶-2-取代)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+H]+=347.0。
实施例87(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(吡嗪-2-取代)甲酮的合成
合成方法如实施例1合成方法如实施例1,步骤2中加入的反应物如表1所示,得到目标化合物,其表征数据为:MS(ESI),[M+H]+=348.1。
实施例88生物活性测定实验
一,细胞活性试验
1.实验材料:
MDCK细胞,A/WS/33H1N1病毒,A/Hong Kong/8/68H3N2病毒,胎牛血清,BSA,TPCK,DMEM培养基,青霉素链霉素双抗,Hanks液,PBS,胰酶,CCK-8,MTT,酶标仪,生物安全柜,细胞培养箱,细胞计数仪,显微镜,恒温水浴锅,96孔板。
2.实验方法:
1)MDCK细胞的准备:
把培养好的MDCK细胞消化5-10min,待细胞变圆,用完全培养基终止消化,然后用细胞计数板或细胞计数仪计数,以每孔2.5×104个细胞计算,每块96孔板以120孔计算制备细胞悬液,然后每孔加100μl铺板。放到37℃孵箱培养24h贴壁备用。
2)病毒感染液的准备(实验前准备):
50 ml体系用量:
DMEM(Dulbecco's Modified Eagle Medium)培养基 48ml
7.5%BSA 2ml
1mg/mlTPCK胰酶 50μl
3)稀释流感病毒:用事先准备好的病毒感染液稀释流感病毒,3#(H1N1)释释至MOI约为0.01,,4#(H3N2)稀释至MOI约为0.01,每块板约准备6 ml。
4)洗板:把实验用的铺有MDCK细胞的96孔板培养上清吸掉,每孔加100μl Hanks液,轻轻拍打,然后吸掉上清,再加入100 μl Hanks液。
5)把稀释的流感病毒以每孔50 μl加到96孔板中,设不加化合物的对照孔,不加流感病毒的对照孔,37℃孵箱培养120min。
6)稀释化合物,用病毒感染液稀释化合物,以每孔70μl计算,每种浓度化合物须做二个复孔,用AMD(金刚烷胺)作阳性对照,从100μm开始3倍稀释共7个梯度。
7)加病毒后2h后加入化合物,每孔50μl,设不加化合物和不加病毒对照。37度培养箱培养三天。
8)加入CCK-8(Cell Counting Kit-8),37℃孵育2h后于酶标仪上检测光吸收,波长为450nM。
9)检测得到的OD值(吸光值)用prism软件分析并计算每个化合物的IC50值,结果如下表1所示。
表1.各化合物细胞活性结果
注:NA指没有进行检测。
由上表中的活性数据可以看出,在本发明所述通式中,R1取代的芳环上2、4、6位有取代基时,活性优于未取代以及3、5位取代。同时2,6位双取代的活性整体优于2,4位双取代。
二、化合物抑制流感病毒的核蛋白(NP 蛋白细胞)进入细胞核的实验
1、NP 蛋白细胞免疫荧光实验
实验材料:MDCK细胞,H1N1病毒,胎牛血清,BSA,TPCK胰酶,DMEM培养基,青霉素链霉素双抗,Hanks液,PBS,NP抗体,洗涤液,福尔马林固定液,抗荧光淬灭封片剂,DAPI(4',6-二脒基-2-苯基吲哚),载玻片,盖玻片,一抗稀释液,封闭液,共聚焦荧光显微镜,生物安全柜,细胞培养箱,细胞计数仪,显微镜,35mm皿或6孔板。
实验方法:
1)取普通洁净盖玻片于70%乙醇中浸泡5分钟或更长时间,无菌超净台内吹干或用细胞培养级PBS或0.9%NaCl等溶液洗涤三遍,再用细胞培养液洗涤一遍。将盖玻片置于六孔板内,种入细胞培养过夜,使约为50%-80%满。
2)吸去培养基,用Hanks液洗两遍,按照上述方法配置感染液,用感染液按照一定的比例(使MOI约为10)稀释病毒,然后感染液按一定的比例(终浓度为60uM)稀释化合物或DMSO,吸去Hanks液,加入病毒和化合物溶液,处理组分为对照组和加药组,处理时间设置为感染后2h,4h,6h。在37℃孵育2h。然后每组取出一皿吸去感染液,加入固定液于4℃固定;同时其它处理组用感染液稀释的化合物或DMSO换液,并继续在培养箱分别孵育2h或4h,在2h或4h后每组取出一皿吸去感染液,加入固定液4℃固定。
3)去固定液,用洗涤液洗3次,每次3-5min,吸尽液体。洗涤时宜用摇床,或手动晃动数次。
4)用封闭液封闭60min,可以在摇床上轻轻摇动。
5)去封闭液,用稀释的NP抗体作用120mim,稀释比例为1:20,可以在摇床上轻轻摇动。期间适当注意避光操作。
6)去除抗体,用洗涤液洗涤3-5次,每次3-5min。每次洗涤时都可以在摇床上轻轻摇动。
7)去除洗涤液,加入DAPI作用3-5min。
8)吸除DAPI,用洗涤液洗涤2-3次,每次3-5min,期间适当注意避光操作。每次洗涤时都可以在摇床上轻轻摇动。
9)滴一滴本试剂盒提供的抗荧光淬灭封片液于载玻片上,盖上贴有细胞的盖玻片,尽量避免气泡。使细胞接触封片液,切勿弄反。
10)在共聚焦显微镜下进行观察并拍照。
结果请参见图1-图3。其中,图1为不加药物4小时结果;图2为加入实施例13制备得到的化合物10μM4小时的结果;图3加入实施例29制备得到的化合物10μM4小时的结果,图中浅色荧光为核蛋白。
从图1、图2、图3,三张图图可以看出,在不加药物4小时,流感病毒的核蛋白集中在MDCK细胞核中,而加入实施例13(图2)或实施例29(图3)制备得到的化合物4小时后,流感病毒的核蛋白未能进入MDCK细胞的细胞核内。从而证明了本发明化合物能够阻止流感病毒的核蛋白进入细胞核内,起到抑制流感病毒复制的作用。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (6)
1.式II所示的苯甲酰胺类化合物或其药学上可接受的盐:
其中:R4、R5、R6各自任选自:氢,卤素,硝基;
R7选自:氢,氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R8、R9各自任选自:氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基。
2.根据权利要求1所述的苯甲酰胺类化合物或其药学上可接受的盐,其特征在于,选自式III所示化合物:
其中:R7选自:氢,氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R8、R9各自任选自:氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R4选自:卤素;
R5选自:硝基。
3.式IV所示的苯甲酰胺类化合物或其药学上可接受的盐,其特征在于,选自式IV所示化合物:
其中:R7选自:氢,卤素,C1-C5烷氧基,氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R8、R9各自任选自:卤素,C1-C5烷氧基,氰基,羟基,氨基,三氟甲基,甲氧基羰甲基,乙酰氧基,乙酰胺基,甲基取代氨基,二甲基取代氨基,1-甲基哌嗪基;
R4选自:卤素;
R5选自:硝基。
4.一种苯甲酰胺类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:
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,6-二甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-乙酰氧基-6-甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-6-甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-硝基-6-甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-6-甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲氧基-6-氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-6-甲氧基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,6-二氯苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-羟基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-硝基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲基-4-溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-硝基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-溴-4-硝基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯-4-氟苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氟-4-氯苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氟-4-溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-甲氧基-4-氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-硝基-4-三氟甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,4-二溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-氯苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4-溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-羟基-4-氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-乙酰氧基-4-乙酰氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氯-4-氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,4-二氯苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-硝基-4-甲氨基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(3-氯-4-溴苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-硝基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-5-氯苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-3,4-二甲基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4,5-二氟苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2-氨基-4,5-二甲氧基苯基)甲酮
(4-(2-氯-4-硝基苯基)哌嗪-1-取代)(2,3,4-三氟苯基)甲酮。
5.权利要求1-4任一项所述的苯甲酰胺类化合物或其药学上可接受的盐在制备预防和治疗流感药物中的应用。
6.一种预防和治疗流感的药物组合物,其特征在于,其活性成分包括有权利要求1-4任一项所述的苯甲酰胺类化合物或其药学上可接受的盐。
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