CN114685371A - 吡唑甲酰胺衍生物及其制备方法和用途 - Google Patents
吡唑甲酰胺衍生物及其制备方法和用途 Download PDFInfo
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- CN114685371A CN114685371A CN202210226137.3A CN202210226137A CN114685371A CN 114685371 A CN114685371 A CN 114685371A CN 202210226137 A CN202210226137 A CN 202210226137A CN 114685371 A CN114685371 A CN 114685371A
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- Prior art keywords
- pyrazole
- carboxamide
- methyl
- trifluoromethoxy
- phenyl
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- 150000003839 salts Chemical class 0.000 claims abstract description 7
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- -1 -OH Chemical group 0.000 claims description 189
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- 150000002367 halogens Chemical class 0.000 claims description 27
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 24
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Images
Classifications
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Abstract
本发明属于化学医药领域,公开一种吡唑甲酰胺类衍生物,具有通式I结构或其药学上可接受的盐或溶剂合物,式中:X、Y、Z为C或N;各基团定义详见说明书。其中大部分化合物对线粒体复合物I具有显著抑制作用,对人结直肠癌细胞株(HCT116、HCT15)等肿瘤细胞株显示出强效的体内外抗肿瘤作用。本发明要解决的技术问题是目前还没有靶向线粒体复合物I的抑制剂用于临床。本发明解决上述技术问题的方案是提供一种吡唑甲酰胺类衍生物,具有全新结构,显著抑制线粒体复合物I活性且抗恶性肿瘤活性高,在治疗恶性肿瘤药物开发上具有很大的价值。
Description
技术领域
本发明属于化学医药领域,具体涉及吡唑甲酰胺衍生物及其制备方法和用途。
背景技术
小分子靶向抗肿瘤药物由于疗效明确,安全性高,可以实现针对肿瘤患者的精准治疗,因此已经成为近年肿瘤药物研发的热点和趋势。
肿瘤细胞具有能量代谢重编程的显著性特征,尤其是线粒体在肿瘤细胞的能量代谢与物质代谢中均发挥着重要的功能。线粒体电子传递链(Electron Transport Chain,ETC)是线粒体发挥能量代谢调控的重要基础,线粒体复合物I(Complex I),也被称为NADH:泛醌氧化还原酶,是线粒体ETC的重要组成部分。其通过将电子从NADH转移到泛醌,并通过膜进行质子移位,从而促进细胞能量的产生。此外,线粒体复合物I也调控肿瘤细胞ROS的生成并维持其氧化还原稳态。因此,线粒体电子传递链复合物I与肿瘤细胞的发生发展密切相关。目前研究显示,线粒体复合物I在多种实体瘤包括神经胶质瘤、非小细胞肺癌、黑色素瘤、结直肠癌以及急性髓性白血病均有过表达,其过表达也与肿瘤组织分级,恶性程度或预后密切相关。用RNAi技术降低线粒体复合物I的表达或用小分子线粒体电子传递链复合物I抑制剂调控其的活性都能够抑制肿瘤细胞的生长和转移。因此,线粒体复合物I已经成为潜在的抗肿瘤治疗靶点,针对其进行特异性抑制剂的开发和研究具有重要的意义。
然而,迄今为止尚未有线粒体电子传递链复合物I抑制剂被国内外批准应用于临床肿瘤治疗。目前已有的线粒体复合物I抑制剂包括鱼藤酮、粉蝶霉素A等,但这些抑制剂均存在毒性大、靶点不单一、临床前效果差等问题。因此,研发高选择性、高效、低毒的线粒体复合物I抑制剂用于肿癌治疗具有特别重要的意义。
发明内容
本发明提供了一种吡唑甲酰胺衍生物,其结构如式Ⅰ所示
其中,X、Y、Z为C或N;
R1~R5为-H、卤素、烷基、卤代烷、烯烃、3-7元环烷基、3-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6为-H、卤素、三氟甲基、烷基、芳基;
R7~R11为-H、卤素、-OH、甲氧基、氨基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
应了解,本发明包括本发明定义的特定基团的所有组合和亚组,包括上文的简述中定义的、在整个说明书中的各个实施例中所示例的以及所附权利要求中所述的取代基。具体地,本发明通式I结构的吡唑甲酰胺衍生物的优选化合物选自:
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-((4'-(甲磺酰基)-[1,1'-联苯]-3-基)甲基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-((2'-甲氧基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-((2'-羟基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-吗啉基苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(3-甲磺酰基)氮杂环丁-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(1,1-二氧化硫吗啉)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(4-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-乙酰基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(4-(甲磺酰基)哌嗪-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(甲基(四氢-2H-吡喃-4-基)氨基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-(叔丁基)-1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-5-苯基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-环丙基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-苯基-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(对甲苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-环丙烷羰基)哌嗪-1-基)苯甲酰基)-N-(4-氟苯基)-5-甲基-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(吡啶-3-基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-N-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-甲酰胺;
或其上述化合物药学上可接受的盐或溶剂合物。
通式I结构的吡唑甲酰胺衍生物的制备方法,合成路线为:
路线一:
R1~R5为-H、卤素、烷基、卤代烷、3-7元环烷基、3-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6为-H、卤素、三氟甲基、烷基、芳基;
R7~R11为-H、卤素、-OH、甲氧基、氨基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
上述所示吡唑甲酰胺衍生物的制备操作步骤包括:
中间体1是原料1与不同取代的苄溴在碱性条件下得到,所述的碱为氢氧化钠、氢氧化钾等中的任意一种;所述的反应温度为60℃~90℃;所述的原料1、苄溴、碱的摩尔比为1︰1.5︰2.0;所述反应时间为2–4h;中间体2是中间体1经碱性条件下水解得到的5-R1基-1-(R2取代苯基)-1H-吡唑-3-羧酸,所述的溶剂主要选用甲醇-水、二氧六环-水等,所述的碱是氢氧化锂、氢氧化钠、氢氧化钾等中的任意一种,所述的反应温度在0℃~60℃;中间体2在HATU和DIEA作用下与取代的苯胺或者取代的杂环芳基胺发生缩合反应得到吡唑甲酰胺中间体3;最后,通式I目标产物由中间体3和不同取代的芳基硼酸、硼酸酯或氨基衍生物催化下得到,经柱层析纯化可得纯品,所述的催化剂为[1,1'-双(二苯基膦)二茂铁]二氯化钯,三(二亚苄基茚丙酮)二钯,醋酸钯等;所述的碱为碳酸铯、碳酸钾、磷酸钾、叔丁醇钠、叔丁醇钾等,所述的配体为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,2-双环己基膦-2',4',6'-三异丙基联苯等;所述的反应温度为80℃~140℃;所述的中间体3、氨基衍生物、钯催化剂、配体、碱的摩尔比为1︰1.5︰0.2︰0.3︰3;所述反应时间为12-24h;
附图说明
图1为I-1体内HCT116肿瘤细胞增殖抑制实验。
具体实施方式
实施例1、1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸乙酯(中间体1a)的制备
将原料3-甲基吡唑-5-甲酸乙酯300mg(2.0mmol)和氢氧化钾220mg(4.0mmol)置于5ml无水四氢呋喃(THF)中,回流下滴加间溴苄溴750mg(3.0mmol)的THF溶液,TLC监察反应完毕后,反应液冷却至室温,倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(10:1)洗脱,得淡黄色油状物478mg,产率为74%。1H NMR(400MHz,DMSO-d6)δ7.48-7.46(m,1H),7.31-7.29(m,2H),7.11-7.09(m,1H),6.59(s,1H),5.42(m,2H),4.24(q,J=7.1Hz,2H),2.24(s,3H),1.26(t,J=7.1Hz,3H).
实施例2、1-(3-溴苄基)-1H-吡唑-3-羧酸乙酯(中间体1b)的制备
将原料3-乙氧羰基吡唑280mg(2.0mmol)和氢氧化钾220mg(4.0mmol)置于5ml无水四氢呋喃(THF)中,回流下滴加间溴苄溴750mg(3.0mmol)的THF溶液,TLC监察反应完毕后,反应液冷却至室温,倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(10:1)洗脱,得淡白色固体462mg,产率为75%。1H NMR(400MHz,DMSO-d6)δ7.43-7.41(m,2H),7.36(d,J=7.5Hz,1H),7.22-7.19(m,2H),6.82(d,J=7.5Hz,1H),5.38(m,2H),4.39(q,J=7.1Hz,2H),1.39-1.32(m,3H).
实施例3、1-(3-溴苄基)-5-苯基-1H-吡唑-3-羧酸乙酯(中间体1c)的制备
将原料5-苯基-1H-吡唑-3-羧酸乙酯432mg(2.0mmol)和氢氧化钾220mg(4.0mmol)置于5ml无水四氢呋喃(THF)中,回流下滴加间溴苄溴750mg(3.0mmol)的THF溶液,TLC监察反应完毕后,反应液冷却至室温,倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(10:1)洗脱,得浅黄色油状物500mg,产率为65%。1H NMR(400MHz,DMSO-d6)δ7.50(s,1H),7.42-7.23(m,8H),7.11(s,1H),5.40(m,2H),4.39(q,J=7.1Hz,2H),1.37(t,J=8.0Hz,3H).
实施例4、1-(3-溴苄基)-5-(叔丁基)-1H-吡唑-3-羧酸乙酯(中间体1d)的制备
将原料5-(叔丁基)-1H-吡唑-3-羧酸乙酯393mg(2.0mmol)和氢氧化钾220mg(4.0mmol)置于5ml无水四氢呋喃(THF)中,回流下滴加间溴苄溴750mg(3.0mmol)的THF溶液,TLC监察反应完毕后,反应液冷却至室温,倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(10:1)洗脱,得无色油状物510mg,产率为70%。1H NMR(400MHz,DMSO-d6)δ7.50-7.48(m,1H),7.42(m,1H),7.31-7.23(m,2H),6.68(s,1H),5.36(m,2H),4.38(q,J=8.0Hz,2H),1.38(t,J=7.1Hz,3H),1.37(s,9H).
实施例5、1-(4-溴苄基)-5-甲基-1H-吡唑-3-羧酸乙酯(中间体1e)的制备
将原料3-甲基吡唑-5-甲酸乙酯300mg(2.0mmol)和氢氧化钾220mg(4.0mmol)置于5ml无水四氢呋喃(THF)中,回流下滴加对溴苄溴750mg(3.0mmol)的THF溶液,TLC监察反应完毕后,反应液冷却至室温,倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(10:1)洗脱,得淡黄色油状物498mg,产率为77%。1H NMR(400MHz,DMSO-d6)δ7.48(m,2H),7.17(m,2H),6.53(s,1H),5.28(m,2H),4.37(q,J=8.0Hz,2H),2.31(s,3H),1.27(t,J=7.1Hz,3H).
实施例6、1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸乙酯(中间体1a)1.6g(5.0mmol)溶解于甲醇-水(v/v=2/1)体系,冰浴下加入过量氢氧化锂,室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集水相,用2N盐酸调节PH至1,析出大量白色固体,抽滤,滤饼用少量水洗涤,减压干燥,得到白色固体1.19g,产率为81%。1HNMR(400MHz,DMSO-d6)δ12.66(s,1H),7.55(m,1H),7.46-7.32(m,2H),7.15(m,1H),6.59(s,1H),5.44(s,2H),2.29(s,3H).
实施例7、1-(3-溴苄基)-1H-吡唑-3-羧酸(中间体2b)的制备
将1-(3-溴苄基)-1H-吡唑-3-羧酸乙酯(中间体1b)1.5g(5.0mmol)溶解于甲醇-水(v/v=2/1)体系,冰浴下加入过量氢氧化锂,室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集水相,用2N盐酸调节PH至1,析出大量白色固体,抽滤,滤饼用少量水洗涤,减压干燥,得到白色固体1.19g,产率为85%。1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),7.43(m,2H),7.32-7.22(m,3H),6.66(s,1H),5.39(s,2H).
实施例8、1-(3-溴苄基)-5-苯基-1H-吡唑-3-羧酸(中间体2c)的制备
将1-(3-溴苄基)-5-苯基-1H-吡唑-3-羧酸乙酯(中间体1c)1.92g(5.0mmol)溶解于甲醇-水(v/v=2/1)体系,冰浴下加入过量氢氧化锂,室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集水相,用2N盐酸调节PH至1,析出大量白色固体,抽滤,滤饼用少量水洗涤,减压干燥,得到白色固体1.48g,产率为83%。1HNMR(400MHz,DMSO-d6)δ12.20(s,1H),7.63(s,1H),7.52-7.23(m,8H),7.08(s,1H),5.39(s,2H).
实施例9、1-(3-溴苄基)-5-(叔丁基)-1H-吡唑-3-羧酸(中间体2d)的制备
将1-(3-溴苄基)-5-(叔丁基)-1H-吡唑-3-羧酸乙酯(中间体1d)1.82g(5.0mmol)溶解于甲醇-水(v/v=2/1)体系,冰浴下加入过量氢氧化锂,室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集水相,用2N盐酸调节PH至1,析出大量白色固体,抽滤,滤饼用少量水洗涤,减压干燥,得到白色固体1.35g,产率为80%。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),7.48(m,1H),7.44(m,1H),7.30-7.23(m,2H),6.40(s,1H),5.35(s,2H),1.36(s,9H).
实施例10、1-(4-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2e)的制备
将1-(4-溴苄基)-5-甲基-1H-吡唑-3-羧酸乙酯(中间体1e)1.60g(5.0mmol)溶解于甲醇-水(v/v=2/1)体系,冰浴下加入过量氢氧化锂,室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用乙酸乙酯、饱和食盐水萃取2-3次,收集水相,用2N盐酸调节PH至1,析出大量白色固体,抽滤,滤饼用少量水洗涤,减压干燥,得到白色固体1.28g,产率为87%。1HNMR(400MHz,DMSO-d6)δ12.66(s,1H),7.58-7.34(m,2H),7.20-7.18(m,2H),6.22(s,1H),5.28(s,2H),2.31(s,3H).
实施例11、1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲氧基苯胺430mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得白色固体820mg,产率为90.3%。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.93(d,J=9.1Hz,2H),7.51(d,J=8.0Hz,1H),7.37-7.31(m,4H),7.12(d,J=7.7Hz,1H),6.67(s,1H),5.46(s,2H),2.26(s,3H).
实施例12、1-(3-溴苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3b)的制备
将1-(3-溴苄基)-1H-吡唑-3-羧酸(中间体2b)560mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲氧基苯胺430mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得白色固体205mg,产率为23.3%。1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.60-7.58(m,2H),7.49(m,1H),7.43-7.41(m,1H),7.39-7.37(m,1H),7.33–7.21(m,4H),6.75(d,J=7.5Hz,1H),5.41(s,2H).
实施例13、1-(3-溴苄基)-4-苯基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3c)的制备
将1-(3-溴苄基)-5-苯基-1H-吡唑-3-羧酸(中间体2c)714mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲氧基苯胺430mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得无色油状物837mg,产率为81.1%。1HNMR(400MHz,DMSO-d6)δ9.21(s,1H),7.98(s,1H),7.73-7.64(m,2H),7.63-7.57(m,2H),7.50-7.44(m,3H),7.43-7.32(m,2H),7.31-7.20(m,4H),5.37(s,2H).
实施例14、1-(3-溴苄基)-4-(叔丁基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3d)的制备
将1-(3-溴苄基)-5-(叔丁基)-1H-吡唑-3-羧酸(中间体2d)680mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲氧基苯胺430mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(8:1)洗脱,得无色油状物840mg,产率为84.6%。1HNMR(400MHz,DMSO-d6)δ10.23(s,1H),7.92(d,J=9.1Hz,2H),7.47(d,J=8.0Hz,1H),7.37–7.22(m,4H),6.97(d,J=7.8Hz,1H),6.70(s,1H),5.67(s,2H),1.31(s,9H).
实施例15、1-(4-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3e)的制备
将1-(4-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2e)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲氧基苯胺430mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得白色蜡状物747mg,产率为82.3%。1HNMR(400MHz,DMSO-d6)δ8.81(s,1H),7.58(d,J=7.6Hz,2H),7.46(d,J=7.6Hz,2H),7.28(d,J=7.5Hz,2H),7.18(d,J=6.5Hz,3H),5.36(s,2H),2.52(s,3H).
实施例16、1-(3-溴苄基)-5-甲基-N-苯基-1H-吡唑-3-甲酰胺(中间体3f)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入苯胺224mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物703mg,产率为95%。1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),7.75-7.63(m,2H),7.50(s,1H),7.45-7.38(m,1H),7.37-7.22(m,4H),7.13-7.01(m,1H),6.33(s,1H),5.33(s,2H),2.32(s,3H).
实施例17、1-(3-溴苄基)-5-甲基-N-(对甲苯基)-1H-吡唑-3-甲酰胺(中间体3g)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对甲基苯胺257mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物690mg,产率为90%。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.52-7.50(m,1H),7.49-7.45(m,2H),7.42-7.40(m,1H),7.32-7.22(m,2H),7.10-7.06(m,2H),6.36(s,1H),5.32(s,2H),2.35(s,3H),2.32(s,3H).
实施例18、1-(3-溴苄基)-5-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑-3-甲酰胺(中间体3h)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲基苯胺387mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物710mg,产率为81%。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.92-7.74(m,4H),7.51-7.47(m,1H),7.38-7.36(m,1H),7.32-7.21(m,2H),6.35(s,1H),5.34(s,2H),2.32(s,3H).
实施例19、1-(3-溴苄基)-N-(4-氟苯基)-5-甲基-1H-吡唑-3-甲酰胺(中间体3i)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对三氟甲基苯胺270mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物652mg,产率为84%。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.73-7.60(m,2H),7.57-7.49(m,1H),7.43-7.41(m,1H),7.36-7.18(m,2H),7.15-6.97(m,2H),6.35(s,1H),5.32(s,2H),2.31(s,3H).
实施例20、1-(3-溴苄基)-N-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-甲酰胺(中间体3j)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加入对甲基苯胺295mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物696mg,产率为87%。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.59-7.54(m,2H),7.52-7.50(m,1H),7.40-7.38(m,1H),7.33-7.20(m,2H),6.93-6.91(m,2H),6.38(s,1H),5.31(s,2H),3.80(s,3H),2.32(s,3H).
实施例21、1-(3-溴苄基)-5-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺(中间体3k)的制备
将1-(3-溴苄基)-5-甲基-1H-吡唑-3-羧酸(中间体2a)600mg(2.0mmol)、HATU1.14g(3.0mmol)溶解于20mL无水二氯甲烷中,冰浴下加入DIEA 390mg(3.0mmol),0℃搅拌1h后加3-氨基吡啶226mg(2.4mmol),室温反应8h,TLC监察反应完毕后反应液倒入分液漏斗,用二氯甲烷、饱和食盐水萃取2-3次,收集有机相并用无水Na2SO4干燥,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(5:1)洗脱,得浅黄色油状物460mg,产率为62%。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.33-8.31(m,2H),8.07-8.04(m,1H),7.51-7.49(m,1H),7.44-7.42(m,1H),7.38-7.22(m,3H),6.38(s,1H),5.33(s,2H),2.32(s,3H).
实施例22、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-1)的制备
将1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a)450mg(1.0mmol)、1-环丙甲酰基哌嗪盐酸盐285mg(1.5mmol)三(二亚苄基茚丙酮)二钯183mg(0.2mmol)、2-二环己基膦-2',4',6'-三异丙基联苯143mg(0.3mmol)、叔丁醇钾337mg(3.0mmol)溶解于无水甲苯5mL,氮气保护,140℃反应20h。TLC监察反应完毕反应液冷却至室温,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(1:2)洗脱,得白色固体140mg,产率为26.5%。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.95(d,J=9.1Hz,2H),7.33(d,J=8.6Hz,2H),7.20(t,J=7.9Hz,1H),6.91-6.89(m,1H),6.84(s,1H),6.65(s,1H),6.52(d,J=7.6Hz,1H),5.39(s,2H),3.81(s,2H),3.60(s,2H),3.16-3.10(m,4H),2.26(s,3H),2.04-2.01(m,1H),0.86-0.82(m,2H),0.76-0.72(m,2H).
实施例23、5-甲基-1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-2)的制备
操作过程同化合物I-1的制备,只是用4-甲烷磺酰基哌啶盐酸盐代替1-环丙甲酰基哌嗪盐酸盐,得到白色固体100mg,产率为18.6%。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.96(d,J=9.1Hz,2H),7.33(d,J=8.6Hz,2H),7.18(t,J=7.9Hz,1H),6.92-6.82(m,2H),6.65(s,1H),6.48(d,J=7.5Hz,1H),5.39(s,2H),3.85-3.81(m,2H),3.32-3.24(m,1H),2.95(s,3H),2.78-2.72(m,2H),2.27(s,3H),2.08-2.05(m,2H),1.73-1.63(m,2H).
实施例24、5-甲基-1-((4'-(甲磺酰基)-[1,1'-联苯]-3-基)甲基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-3)的制备
将1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a)450mg(1.0mmol)、4-(甲磺酰基)苯硼酸300mg(1.5mmol)[1,1'-双(二苯基膦)二茂铁]二氯化钯183mg(0.2mmol)、磷酸钾640mg(3.0mmol)溶解于无水N,N-二甲基甲酰胺5mL,氮气保护,90℃反应20h。TLC监察反应完毕反应液冷却至室温,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(1:1)洗脱,得灰白色固体179mg,产率为33.8%。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.95(d,J=8.4Hz,2H),7.88-7.82(m,4H),7.62(d,J=7.8Hz,1H),7.52(s,1H),7.45(t,J=7.7Hz,1H),7.26(d,J=8.7Hz,2H),7.12(d,J=7.7Hz,1H),6.61(s,1H),5.48(s,2H),3.18(s,3H),2.24(s,3H).
实施例25、1-((2'-甲氧基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-4)的制备
操作过程同化合物I-3的制备,只是用2-甲氧基苯硼酸代替4-(甲磺酰基)苯硼酸,得到棕色蜡状物360mg,产率为74.8%。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.95(d,J=9.1Hz,2H),7.41-7.39(m,2H),7.34-7.32(m,3H),7.27-7.25(m,2H),7.12-7.08(m,2H),7.05-6.97(m,1H),6.68(s,1H),5.51(s,2H),3.72(s,3H),2.31(s,3H).
实施例26、1-((2'-羟基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-5)的制备
操作过程同化合物I-3的制备,只是用2-羟基苯硼酸代替4-(甲磺酰基)苯硼酸,得到类白色固体220mg,产率为47%。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.53(s,1H),7.94(d,J=9.1Hz,2H),7.46(d,J=7.7Hz,1H),7.43-7.28(m,4H),7.24-7.13(m,2H),7.08(d,J=7.5Hz,1H),6.93(d,J=7.9Hz,1H),6.87(t,J=7.3Hz,1H),6.66(s,1H),5.50(s,2H),2.31(s,3H).
实施例27、5-甲基-1-(3-吗啉基苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-6)的制备
操作过程同化合物I-1的制备,只是用吗啉代替1-环丙甲酰基哌嗪盐酸盐,得到浅黄色蜡状物130mg,产率为28.2%。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.96(d,J=9.1Hz,2H),7.33(d,J=8.7Hz,2H),7.20(t,J=7.9Hz,1H),6.86(d,J=8.3Hz,1H),6.81(s,1H),6.66(s,1H),6.52(d,J=7.5Hz,1H),5.39(s,2H),3.78-3.63(m,4H),3.13-3.03(m,4H),2.26(s,3H).
实施例28、5-甲基-1-(3-(3-甲磺酰基)氮杂环丁-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-7)的制备
操作过程同化合物I-1的制备,只是用4-甲烷磺酰基环丁胺盐酸盐代替1-环丙甲酰基哌嗪盐酸盐,得到浅黄色蜡状物280mg,产率为55.1%。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.96(d,J=9.0Hz,2H),7.33(d,J=8.6Hz,2H),7.18(t,J=7.8Hz,1H),6.66(s,1H),6.50-6.39(m,2H),6.33(s,1H),5.38(s,2H),4.50-4.35(m,1H),4.12-4.08(m,2H),4.04-4.00(m,2H),3.04(s,3H),2.27(s,3H).
实施例29、1-(3-(1,1-二氧化硫吗啉)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-8)的制备
操作过程同化合物I-1的制备,只是用硫代吗啉-1,1-二氧化物代替1-环丙甲酰基哌嗪盐酸盐,得到浅黄色蜡状物120mg,产率为23.6%。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.94(d,J=9.1Hz,2H),7.33(d,J=8.6Hz,2H),7.22(t,J=7.9Hz,1H),6.97-6.95(m,2H),6.64(s,1H),6.50(d,J=7.5Hz,1H),5.38(s,2H),3.81-3.72(m,4H),3.15-3.08(m,4H),2.27(s,3H).
实施例30、5-甲基-1-(4-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-9)的制备
将1-(4-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3e)450mg(1.0mmol)、1-环丙甲酰基哌嗪盐酸盐285mg(1.5mmol)三(二亚苄基茚丙酮)二钯183mg(0.2mmol)、2-二环己基膦-2',4',6'-三异丙基联苯143mg(0.3mmol)、叔丁醇钾337mg(3.0mmol)溶解于无水甲苯5mL,氮气保护,140℃反应20h。TLC监察反应完毕反应液冷却至室温,过滤,浓缩后经柱层析纯化,以石油醚/乙酸乙酯(1:2)洗脱,得白色固体330mg,产率为61.5%。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.94(d,J=8.2Hz,2H),7.33(d,J=7.9Hz,2H),7.08-6.95(m,4H),6.62(s,1H),5.32(s,2H),3.84-3.81(m,2H),3.28-3.26(m,1H),2.94(s,3H),2.75-2.69(m,2H),2.25(s,3H),2.07-2.04(m,2H),1.68-1.65(m,2H).
实施例31、1-(3-(4-乙酰基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-10)的制备
操作过程同化合物I-1的制备,只是用1-乙酰哌嗪代替1-环丙甲酰基哌嗪盐酸盐,得到白色固体160mg,产率为31.9%。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.01-7.89(m,2H),7.33(d,J=8.6Hz,2H),7.20(t,J=7.9Hz,1H),6.89(d,J=9.8Hz,1H),6.83(s,1H),6.65(s,1H),6.52(d,J=7.5Hz,1H),5.38(s,2H),3.56(m,4H),3.15-3.07(m,4H),2.26(s,3H),2.03(s,3H).
实施例32、5-甲基-1-(3-(4-(甲磺酰基)哌嗪-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-11)的制备
操作过程同化合物I-1的制备,只是用1-甲烷磺酰哌嗪代替1-环丙甲酰基哌嗪盐酸盐,得到黄色固体260mg,产率为48.4%。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.94(d,J=9.1Hz,2H),7.34-7.32(m,2H),7.23-7.19(m,1H),6.92-6.88(m,2H),6.65(s,1H),6.55-6.52(m,1H),5.39(s,2H),3.24(s,8H),2.92(s,3H),2.27(s,3H).
实施例33、5-甲基-1-(3-(甲基(四氢-2H-吡喃-4-基)氨基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-12)的制备
操作过程同化合物I-1的制备,只是用N-甲基四氢-2H-吡喃-4-胺代替1-环丙甲酰基哌嗪盐酸盐,得到浅黄色蜡状物15mg,产率为3%。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.99(d,J=9.0Hz,2H),7.38(d,J=8.7Hz,2H),7.19(t,J=7.9Hz,1H),6.81-6.78(m,1H),6.70-6.66(m,2H),6.42(d,J=7.4Hz,1H),5.42(s,2H),3.96-3.93(m,2H),3.87-3.82(m,1H),3.48(s,2H),2.75(s,3H),2.31(s,3H),1.83-1.68(m,2H),1.58-1.55(m,2H).
实施例34、1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-5-苯基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-13)的制备
操作过程同化合物I-2的制备,只是1-(3-溴苄基)-4-苯基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3c)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体210mg,产率为35.1%。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.93(d,J=9.1Hz,2H),7.48-7.47(m,5H),7.32(d,J=8.6Hz,2H),7.10(t,J=7.9Hz,1H),6.97(s,1H),6.82(dd,J=8.3,1.8Hz,1H),6.56(s,1H),6.36(d,J=7.5Hz,1H),5.44(s,2H),3.69(d,J=12.7Hz,2H),3.28-3.17(m,1H),2.91(s,3H),2.69-2.63(m,2H),2.01-1.98(m,2H),1.70-1.49(m,2H).
实施例35、5-(叔丁基)-1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-14)的制备
操作过程同化合物I-2的制备,只是1-(3-溴苄基)-4-(叔丁基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3d)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体220mg,产率为44.7%。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.92(d,J=9.0Hz,2H),7.33(d,J=8.6Hz,2H),7.15(t,J=7.9Hz,1H),6.86(d,J=7.8Hz,1H),6.74(s,1H),6.68(s,1H),6.31(d,J=7.4Hz,1H),5.58(s,2H),3.82-3.79(m,2H),3.32-3.26(m,1H),2.94(s,3H),2.77-2.71(m,2H),2.06-2.03(m,2H),1.75-1.59(m,2H),1.31(s,9H).
实施例36、1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-15)的制备
操作过程同化合物I-2的制备,只是1-(3-溴苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3b)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到黄色蜡状物140mg,产率为26.8%。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.06-7.86(m,3H),7.33(d,J=8.5Hz,2H),7.20(t,J=7.9Hz,1H),7.01-6.89(m,2H),6.84(d,J=2.3Hz,1H),6.64(d,J=7.5Hz,1H),5.40(s,2H),3.85(d,J=12.7Hz,2H),3.30-3.25(m,1H),2.95(s,3H),2.76(t,J=12.3Hz,2H),2.09-2.07(m,2H),1.73-1.62(m,2H).
实施例37、1-(3-(4-环丙基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(化合物I-16)的制备
操作过程同化合物I-1的制备,只是用1-环丙基哌嗪代替1-环丙甲酰基哌嗪盐酸盐,得到浅黄色蜡状物142mg,产率为28.4%。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.94(d,J=8.8Hz,2H),7.32(d,J=8.3Hz,2H),7.15(t,J=7.8Hz,1H),6.90-6.74(m,2H),6.64(s,1H),6.47(d,J=7.2Hz,1H),5.36(s,2H),3.06-3.04(m,4H),2.64-2.62(m,4H),2.25(s,3H),1.62(s,1H),0.47-0.37(m,2H),0.32-0.30(m,2H).
实施例38、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-苯基-1H-吡唑-3-甲酰胺(化合物I-17)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-5-甲基-N-苯基-1H-吡唑-3-甲酰胺(中间体3f)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色蜡状物120mg,产率为27.1%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),7.81(d,J=7.8Hz,2H),7.32(t,J=7.4Hz,2H),7.21(t,J=7.7Hz,1H),7.07(t,J=6.9Hz,1H),6.97-6.79(m,2H),6.63(s,1H),6.53(d,J=7.3Hz,1H),5.38(s,2H),3.81(s,2H),3.60(s,2H),3.16-3.10(m,4H),2.26(s,3H),2.06-1.92(m,1H),0.88-0.58(m,4H).
实施例39、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑-3-甲酰胺(化合物I-18)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-5-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑-3-甲酰胺(中间体3h)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体135mg,产率为26.3%。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.06(d,J=8.4Hz,2H),7.69(d,J=8.5Hz,2H),7.21(t,J=7.8Hz,1H),6.96-6.79(m,2H),6.67(s,1H),6.53(d,J=7.4Hz,1H),5.40(s,2H),3.81(s,2H),3.60(s,2H),3.16-3.10(m,4H),2.27(s,3H),2.01-1.99(m,1H),0.79-0.63(m,4H).
实施例40、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(对甲苯基)-1H-吡唑-3-甲酰胺(化合物I-19)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-5-甲基-N-(对甲苯基)-1H-吡唑-3-甲酰胺(中间体3g)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体130mg,产率为28.3%。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),7.68(d,J=8.1Hz,2H),7.20(t,J=7.8Hz,1H),7.12(d,J=8.1Hz,2H),6.97-6.79(m,2H),6.61(s,1H),6.53(d,J=7.4Hz,1H),5.37(s,2H),3.81(s,2H),3.60(s,2H),3.16-3.10(m,4H),2.26(s,6H),2.01-1.99(m,1H),0.88-0.61(m,4H).
实施例41、1-(3-(4-环丙烷羰基)哌嗪-1-基)苯甲酰基)-N-(4-氟苯基)-5-甲基-1H-吡唑-3-甲酰胺(化合物I-20)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-N-(4-氟苯基)-5-甲基-1H-吡唑-3-甲酰胺(中间体3i)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体130mg,产率为28.1%。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.86-7.82(m,2H),7.22-7.14(m,3H),6.97-6.77(m,2H),6.63(s,1H),6.52(d,J=7.4Hz,1H),5.38(s,2H),3.81(s,2H),3.60(s,2H),3.16-3.10(m,4H),2.26(s,3H),2.01-1.99(m,1H),0.83-0.64(m,4H).
实施例42、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(吡啶-3-基)-1H-吡唑-3-甲酰胺(化合物I-21)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-5-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺(中间体3k)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到浅黄色固体27.5mg,产率为6.2%。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.98(s,1H),8.39-8.15(m,2H),7.38-7.35(m,1H),7.21(t,J=7.9Hz,1H),6.97-6.80(m,2H),6.66(s,1H),6.52(d,J=7.4Hz,1H),5.39(s,2H),3.81(s,2H),3.60(s,2H),3.17-3.10(m,4H),2.27(s,3H),2.07-1.94(m,1H),0.93-0.56(m,4H).
实施例43、1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-N-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-甲酰胺(化合物I-22)的制备
操作过程同化合物I-1的制备,只是用1-(3-溴苄基)-N-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-甲酰胺(中间体3j)代替1-(3-溴苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺(中间体3a),得到白色固体150mg,产率为28.5%。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.70(d,J=8.8Hz,2H),7.20(t,J=7.8Hz,1H),6.96-6.80(m,4H),6.60(s,1H),6.52(d,J=7.4Hz,1H),5.36(s,2H),3.80-3.73(dm,5H),3.60(s,2H),3.16-3.10(m,4H),2.26(s,3H),1.99(s,1H),0.75-0.71(m,4H).
实施例44、本发明吡唑甲酰胺衍生物的体外酶活性实验
1实验方法
本实验采用线粒体复合物I酶活检测试剂盒(Cayman,700930)进行检测。检查波长340nm,检测温度25℃,每20秒检测一次,总共检测15分钟;线粒体复合物I酶活计算公式:在反应时间内,根据时间和OD值,计算出每个孔的平均反应速率,线粒体复合I酶活(%)=(样品孔的平均反应速率/空白对照孔的平均反应速率)×100。该实验以鱼藤酮为阳性对照,每次实验至少设置3个平行。
2实验结果
采用以上方法检测,1μM化合物对体外酶水平抑制结果,化合物对酶活抑制作用结果见表1
表1为本发明化合物的体外酶水平抑制结果
从表1可以看出,本发明吡唑甲酰胺衍生物显示出良好的线粒体复合物I活性抑制作用。特别是化合物I-1、I-2、I-3、I-11、I-16和I-18具有强效的线粒体复合物I抑制活性。
实施例45、体外肿瘤细胞增殖抑制实验
本实验目的是检测发明化合物对体外肿瘤细胞增殖抑制活性,采用的方法为MTT(四甲基偶氮唑盐)比色法。
1实验方法
收集对数生长期细胞,以每孔1000-3000个将细胞接种于96孔板中,待细胞贴壁后,设置不同浓度化合物组、对照组和空白组处理细胞96h,加入5mg/mL MTT溶液,37℃,5%CO2孵育4h后,加入100μL 20%SDS溶液,37℃孵育过夜,用酶标仪测定570nm处各孔的吸光度值。计算抑制率和IC50:抑制率率%=100-((加药细胞OD-空白OD)/(对照细胞OD-空白OD))*100,用GraphPad Prism 9计算IC50及统计分析。
2实验结果
采用以上方法检测了发明化合物对HCT116、HCT15增殖抑制活性,发明化合物对细胞增殖抑制作用结果见表2。
表2化合物在体外对HCT116、HCT15增殖抑制活性
表2中的“ND”表示没有测定抑制作用。
数据表明本发明吡唑甲酰胺衍生物对于多种肿瘤细胞株都一定的抑制效果。
实施例46、本发明吡唑甲酰胺衍生物I-1体外肿瘤细胞增殖抑制实验
本实验采用MTT(四甲基偶氮唑盐)比色法检测了发明化合物I-1对结直肠癌HCT116、HCT15和正常细胞株NCM460、HCoEpiC增殖抑制活性,结果显示I-1对结直肠癌细胞株有显著增殖抑制效果,而对正常细胞没有明显增殖抑制效果,结果见表3。
表3化合物I-1在体外对HCT116、HCT15、NCM460、HCoEpiC增殖抑制活性
实施例47、本发明吡唑甲酰胺衍生物I-1体内肿瘤细胞增殖抑制实验
本实验用人结直肠癌细胞株HCT116建立皮下荷瘤小鼠模型,以8×106个细胞/100μL/只HCT116细胞悬液接种于裸鼠右侧颈背部皮下,待皮下瘤生长到100mm3左右时,随机分为2组,Control组和I-1组(给药剂量10mg/kg),以1周连续灌胃5天为一个给药周期,给药3个周期。每三天测量一次肿瘤体积和小鼠体重,并观察小鼠一般情况。肿瘤体积采用以下公式计算:肿瘤体积=肿瘤长径(mm)×肿瘤短径(mm)2×0.5,并计算肿瘤生长抑制率(Tumorgrowth inhibition,TGI),计算公式为TGI=1-Vtreated/Vcontrol试验。实验表明I-1可以显著抑制HCT116细胞的皮下瘤生长,TGI为34.7%(图1)。
Claims (8)
2.根据权利要求1所述的吡唑甲酰胺衍生物
R1~R5为-H、卤素、烷基、卤代烷、烯烃、3-7元环烷基、6-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、-OH、甲氧基、氨基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为-H、烯烃、3-7元环烷基、6-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、-OH、甲氧基、氨基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
进一步优选的,
R1~R5为烯烃、3-7元环烷基、6-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、-OH、甲氧基、氨基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为3-7元环烷基、6-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为6-7元含O、S或N的杂环烷基、苯甲酰基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为6-7元含O、S或N的杂环烷基、苯磺酰基、硝基、-OH、甲氧基、甲氧羰基、芳基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为6-7元含O、S或N的杂环烷基、苯磺酰基、硝基、-OH、甲氧基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基、烷基;
优选的,
R1~R5为6-7元含O、S或N的杂环烷基、苯磺酰基、硝基、甲氧基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基、芳基;
R7~R11独立地为-H、卤素、甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基;
最优选的,
R1~R5为6-7元含O、S或N的杂环烷基、苯磺酰基、甲氧基、杂环芳基、芳基胺、杂环芳基胺、脂肪胺、含氮杂环脂肪胺;
R6独立地为-H、卤素、三氟甲基、烷基;
R7~R11独立地为甲氧基、硝基、甲氧羰基、三氟甲氧基、三氟甲基、二氟甲氧基。
3.吡唑甲酰胺衍生物,其结构式名称为:
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-((4'-(甲磺酰基)-[1,1'-联苯]-3-基)甲基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-((2'-甲氧基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-((2'-羟基-[1,1'-联苯]-3-基)甲基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-吗啉基苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(3-甲磺酰基)氮杂环丁-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(1,1-二氧化硫吗啉)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(4-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-乙酰基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(4-(甲磺酰基)哌嗪-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-甲基-1-(3-(甲基(四氢-2H-吡喃-4-基)氨基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
5-(叔丁基)-1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-甲磺酰基)哌啶-1-基)苄基)-5-苯基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(甲磺酰基)哌啶-1-基)苄基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-环丙基哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-苯基-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(对甲苯基)-1H-吡唑-3-甲酰胺;
1-(3-(4-环丙烷羰基)哌嗪-1-基)苯甲酰基)-N-(4-氟苯基)-5-甲基-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-5-甲基-N-(吡啶-3-基)-1H-吡唑-3-甲酰胺;
1-(3-(4-(环丙烷羰基)哌嗪-1-基)苄基)-N-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-甲酰胺。
4.权利要求1~2任一项所述的吡唑甲酰胺衍生物药学上可接受的盐或水合物。
5.权利要求1~2任一项所述的吡唑甲酰胺衍生物的前药。
6.一种组合物,是由权利要求1~2任一项所述的吡唑甲酰胺衍生物、权利要求4所述的盐或水合物或权利要求5所述的前药添加药学上可以接受的辅助性成分制备而成的。
7.权利要求1~2任一项所述的吡唑甲酰胺衍生物、权利要求1~2所述的盐或水合物、权利要求5所述的前药或权利要求6所述的组合物在制备线粒体复合物I抑制剂中的用途;优选的,上述吡唑甲酰胺衍生物、它的盐或水合物在制备线粒体复合物I抑制剂中的用途。
8.权利要求1~2任一项所述的吡唑甲酰胺衍生物、权利要求1~2所述的盐或水合物、权利要求5所述的前药或权利要求6所述的组合物在制备治疗恶性肿瘤中的用途。
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