CN112939988A - 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究 - Google Patents

茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究 Download PDF

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CN112939988A
CN112939988A CN202110232463.0A CN202110232463A CN112939988A CN 112939988 A CN112939988 A CN 112939988A CN 202110232463 A CN202110232463 A CN 202110232463A CN 112939988 A CN112939988 A CN 112939988A
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张新迎
张凌华
赵杰
范学森
姜玉钦
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Abstract

本发明公开了一类新型具有抗癌活性的茚并吡唑并吡唑啉酮类化合物，其结构通式为：
Figure DDA0002957668440000011
该类化合物表现出显著的抗REC‑1和Ramos等癌细胞活性。芳基偶氮甲碱亚胺和炔丙醇类化合物，在铑或钌催化剂和添加剂存在下，三氟乙醇溶剂中，发生串联反应一步即可得到茚并吡唑并吡唑啉酮类化合物。本发明所提供茚并吡唑并吡唑啉酮类化合物的合成方法，具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，该类化合物表现出良好抗癌活性，为药物研究开发提供了一类新的结构单元。

Description

茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究
技术领域
本发明属于有机合成和药物发现技术领域，具体涉及茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性。
背景技术
茚并吡唑是一类重要的含氮稠杂环，不仅在天然产物中广泛存在，而且也是许多抗抑郁、抗真菌、抗精神病、抗高血压、抗肿瘤和抗菌药物的核心结构单元。另一方面，N,N-双环吡唑啉酮则不仅具有独特的结构，而且表现出显著的抗锥体细胞和抗菌性能。尽管以上两种结构单元表现出多样生物性能，然而这两种优势结构单元拼合形成的新结构单元茚并吡唑并吡唑啉酮具有何种生物活性仍是未知的。
另一方面，目前关于茚并吡唑并吡唑啉酮这类化合物的合成方法也很少有报道。最近，Kim等报道了利用钌催化下芳基偶氮甲碱亚胺与烯丙基缩醛反应制备氢化茚并吡唑并吡唑啉酮。该方法存在的问题是所用原料不易合成且不稳定，应用范围受到影响。另外，该方法所得产物氢化茚并吡唑并吡唑啉酮因在茚环上缺少一个碳碳双键而将与茚并吡唑并吡唑啉酮表现出不同的生化性能。
基于以上原因，研究并开发从简单易得的原料出发，经过简便的步骤合成茚并吡唑并吡唑啉酮类化合物的绿色高效新方法，同时研究该类化合物的生物活性，具有十分重要的理论意义和实用前景。
发明内容
为了克服上述技术缺陷，本发明首先提供了一类新的茚并吡唑并吡唑啉酮类化合物，并研究了其抗癌活性。其次还提供了茚并吡唑并吡唑啉酮类化合物的合成方法，通过芳基偶氮甲碱亚胺和炔丙醇类化合物之间发生的串联反应，可以高效合成茚并吡唑并吡唑啉酮类化合物，合成方法具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，该类化合物具有显著的抗癌活性，因此具有潜在的药用价值。
本发明第一个目的，提供了具有抗癌活性的茚并吡唑并吡唑啉酮类化合物，其结构通式为：
Figure BDA0002957668420000021
其中，R1为氢、卤素、C1-6烷基、C1-6烷氧基或C1-6烷氧羰基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6烷基、C3-6环烷基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5和R6各自独立为氢、C1-4烷基、苯基或共同组成C5-6环烷基。
本发明还提供了上述结构3化合物及其在药学上可接受的盐在抗癌活性药物中的应用。
本发明中药学上可接受的盐(下同)包括茚并吡唑并吡唑啉酮类化合物3与有机酸或无机酸形成的盐。有机酸选自苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸或草酸中的一种或多种，有机酸选自磷酸、氢卤酸、硫酸或硝酸中一种或多种。
进一步地，在上述技术方案中，所述抗癌活性是指抗REC-1和Ramos等癌细胞活性。
本发明第二个目的还提供了用于治疗REC-1和Ramos癌症的药物，包括茚并吡唑并吡唑啉酮类化合物其结构通式为：
Figure BDA0002957668420000022
和相应药学上可接受的盐。
其中，R1为氢、卤素、C1-6烷基、C1-6烷氧基或C1-6烷氧羰基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6烷基、C3-6环烷基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5和R6各自独立为氢、C1-4烷基、苯基或共同组成C5-6环烷基。
本发明第三个目的，还提供了上述茚并吡唑并吡唑啉酮类化合物的合成方法，采用的技术方案为：
茚并吡唑并吡唑啉酮类化合物的合成方法，包括如下操作：将芳基偶氮甲碱亚胺1、炔丙醇类化合物2、铑或钌催化剂、添加剂和溶剂混合，常温或升温反应制得茚并吡唑并吡唑啉酮类化合物3。反应方程式为：
Figure BDA0002957668420000031
其中R1为氢、卤素、C1-6烷基、C1-6烷氧基或C1-6烷氧羰基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6烷基、C3-6环烷基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5和R6各自独立为氢、C1-4烷基、苯基或共同组成C5-6环烷基。
进一步地，在上述技术方案中，所述反应溶剂为起到溶解原料的作用，优选2,2,2-三氟乙醇或六氟异丙醇。
进一步地，在上述技术方案中，所述添加剂为乙酸银、醋酸铜、醋酸钠或六氟锑酸银。
进一步地，在上述技术方案中，所述催化剂为[Ru(p-cymene)Cl2]2{二氯双(4-甲基异丙基苯基)钌(II)}或[RhCp*Cl2]2{二氯(五甲基环戊二烯基)合铑(III)二聚体}。采用其他催化剂，例如CoCp*(CO)I2或MnBr(CO)5等时，反应未检测到需要产物，采用[IrCp*Cl2]2时，仅检测到少量目标产物。
进一步地，在上述技术方案中，所述芳基偶氮甲碱亚胺1、炔丙醇类化合物2、添加剂和铑或钌催化剂的投料摩尔比为1-2:1:0.075-0.25:0.02-0.03。
进一步地，在上述技术方案中，所述反应温度为20-100℃。
发明有益效果：
本发明与现有技术相比具有以下优点：1)合成过程简单、高效，通过芳基偶氮甲碱亚胺和炔丙醇类化合物的一锅串联反应，即可合成茚并吡唑并吡唑啉酮类化合物；2)原料价廉易得，反应条件温和，操作简便，底物的适用范围广；3)茚并吡唑并吡唑啉酮类化合物具有显著的抗癌活性，为药物筛选提供了新的结构单元。
说明书附图
图1为实施例1-3中化合物3a的X-射线单晶衍射图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0002957668420000041
向15mL反应瓶中依次加入化合物1a、溶剂、催化剂、添加剂和化合物2a，盖上塞子密封，在一定温度下搅拌反应。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得白色固体产物3a。
通过改变反应的溶剂、添加剂、催化剂、反应物之间的当量比和反应温度等反应条件，得到一系列的结果，见表1。
表1化合物3a的合成条件筛选试验a
Figure BDA0002957668420000042
Figure BDA0002957668420000051
实施例2
Figure BDA0002957668420000052
向15mL反应瓶中依次加入1a(60.6mg,0.3mmol)、六氟异丙醇(2mL)、二氯双(4-甲基异丙基苯基)钌(II)(4.6mg,0.0075mmol)、六氟锑酸银(10.7mg,0.03mmol)和2a(48.1mg,0.3mmol)，盖上塞子密封，将其置于60℃油浴中搅拌反应2h。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得白色固体产物3a(89.8mg,87％)。该化合物的表征数据为：1H NMR(400MHz,CDCl3):δ7.48-7.39(m,6H),7.33(t,J＝7.6Hz,1H),7.27-7.23(m,2H),4.70(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.96(s,3H),1.56(s,3H),1.54(s,3H),1.35(s,3H).13C{1H}NMR(100MHz,CDCl3):δ162.8,154.6,148.6,139.7,137.1,133.5,128.9,128.7,128.6,128.5,125.9,125.3,121.4,65.7,60.3,58.7,50.1,27.7,27.4,22.5,21.1HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O 345.1961；found 345.1960.
实施例3
依照实施例2的方法和步骤a,b，通过改变反应物1和反应物2，可以合成出各种茚并吡唑并吡唑啉酮类化合物3a-3z和3aa-3hh，具体结果如下：
Figure BDA0002957668420000061
a反应条件:1(0.3mmol),2(0.3mmol),[Ru(p-cymene)Cl2]2(0.0075mmol),AgSbF6(0.03mmol),HFIP(1mL),60℃,2h；b分离收率.
_____________________________________________________________________
代表性产物表征数据如下：
3,3,7,10,10-Pentamethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3b)
White solid(90.3mg,84％).1H NMR(400MHz,CDCl3):δ7.49-7.40(m,5H),7.34(d,J＝8.0Hz,1H),7.06-7.04(m,2H),4.66(s,1H),2.77(d,J＝15.6Hz,1H),2.40(d,J＝15.6Hz,1H),2.35(s,3H),1.94(s,3H),1.54(s,3H),1.52(s,3H),1.33(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.0,148.9,138.7,137.2,136.9,133.8,129.0,128.8,128.5,126.6,125.1,122.2,65.4,60.3,58.8,50.2,27.8,27.5,22.6,21.7,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O 359.2118；found 359.2106.
7-(tert-Butyl)-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3c)
White solid(110.5mg,92％).1H NMR(600MHz,CDCl3):δ7.49-7.46(m,2H),7.44-7.41(m,3H),7.39(d,J＝8.4Hz,1H),7.29-7.27(m,2H),4.67(s,1H),2.77(d,J＝16.2Hz,1H),2.40(d,J＝15.6Hz,1H),1.94(s,3H),1.55(s,3H),1.53(s,3H),1.32(s,3H),1.29(s,9H).13C{1H}NMR(150MHz,CDCl3):δ162.8,154.9,152.2,148.5,137.4,136.8,133.7,128.9,128.7,128.4,124.8,122.8,118.4,65.2,60.2,58.7,50.1,34.9,31.5,27.7,27.4,22.5,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C27H33N2O 401.2587；found 401.2573.
7-Methoxy-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3d)
White solid(87.6mg,78％).1H NMR(400MHz,CDCl3):δ7.48-7.39(m,5H),7.35(d,J＝8.0Hz,1H),6.79(d,J＝2.4Hz,1H),6.76(dd,J1＝8.0Hz,J2＝2.4Hz,1H),4.65(s,1H),3.77(s,3H),2.77(d,J＝15.6Hz,1H),2.39(d,J＝15.6Hz,1H),1.94(s,3H),1.54(s,3H),1.52(s,3H),1.33(s,3H).13C{1H}NMR(150MHz,CDCl3):δ163.0,160.6,156.2,150.4,137.1,133.6,131.9,129.0,128.8,128.6,126.0,111.1,107.7,65.1,60.4,58.8,55.7,50.2,27.8,27.4,22.6,21.2.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 375.2067；found:375.2053.
7-Fluoro-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3e)
White solid(84.7mg,78％).1H NMR(400MHz,CDCl3):δ7.50-7.38(m,6H),6.97-6.91(m,2H),4.67(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.96(s,3H),1.55(s,3H),1.52(s,3H),1.35(s,3H).13C{1H}NMR(100MHz,CDCl3):δ163.6(d,1JC-F＝244.9Hz),162.8,156.9,151.0(d,3JC-F＝8.7Hz),136.6(d,4JC-F＝2.9Hz),135.2(d,4JC-F＝2.9Hz),132.9,128.83,128.78,128.7,126.2(d,3JC-F＝9.4Hz),112.4(d,2JC-F＝22.4Hz),108.9(d,2JC-F＝23.8Hz),65.0,60.3,58.7,50.0,27.6,27.4,22.4,21.1.19F NMR(376MHz,CDCl3):δ-112.65(td,J1＝8.3Hz,J2＝4.1Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H24FN2O363.1867；found363.1857.
7-Chloro-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3f)
White solid(80.5mg,71％).1H NMR(400MHz,CDCl3):δ7.50-7.43(m,3H),7.41-7.36(m,3H),7.24-7.21(m,2H),4.67(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝16.0Hz,1H),1.95(s,3H),1.55(s,3H),1.51(s,3H),1.34(s,3H).13C{1H}NMR(100MHz,CDCl3):δ162.8,156.5,150.5,137.9,136.4,134.9,132.8,128.9,128.8,128.7,126.1,125.7,121.6,65.1,60.3,58.7,50.0,27.6,27.4,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcd forC23H24ClN2O 379.1572；found 379.1561.
7-Bromo-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3g)
White solid(73.4mg,58％).1H NMR(400MHz,CDCl3):δ7.50-7.44(m,3H),7.42-7.37(m,4H),7.31(d,J＝8.0Hz,1H),4.64(s,1H),2.77(d,J＝16.0Hz,1H),2.41(d,J＝15.6Hz,1H),1.94(s,3H),1.54(s,3H),1.51(s,3H),1.33(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,156.4,150.7,138.4,136.4,132.8,128.9,128.8,128.7,128.6,126.5,124.5,123.0,65.2,60.3,58.7,49.9,27.6,27.4,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcdfor C23H24BrN2O 423.1067；found 423.1060.
Methyl
3,3,10,10-tetramethyl-1-oxo-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]-pyrazole-7-carboxylate(3h)
White solid(57.9mg,48％).1H NMR(400MHz,CDCl3):δ7.97(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.90(d,J＝1.2Hz,1H),7.54-7.41(m,6H),4.73(s,1H),3.90(s,3H),2.79(d,J＝15.6Hz,1H),2.42(d,J＝15.6Hz,1H),1.96(s,3H),1.57(s,3H),1.54(s,3H),1.35(s,3H).13C{1H}NMR(100MHz,CDCl3):δ166.9,162.8,155.7,149.1,144.4,136.8,132.9,130.7,128.9,128.80,128.77,127.6,125.1,122.1,65.5,60.4,58.7,52.3,50.0,27.6,27.4,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C25H27N2O3 403.2016；found 403.2012.
3,3,6,10,10-Pentamethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3i)
White solid(90.3mg,84％).1H NMR(600MHz,CDCl3):δ7.46-7.39(m,5H),7.27(s,1H),7.14(s,2H),4.67(s,1H),2.78(d,J＝15.6Hz,1H),2.42-2.39(m,4H),1.94(s,3H),1.55(s,3H),1.54(s,3H),1.34(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,153.6,145.9,139.9,137.1,135.7,133.7,129.2,128.9,128.6,128.4,126.3,121.0,65.5,60.3,58.6,50.1,27.7,27.5,22.6,21.5,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O 359.2118；found 359.2106.
6-Chloro-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3j)
White solid(86.2mg,76％).1H NMR(600MHz,CDCl3):δ7.47(d,J＝7.8Hz,1H),7.42(s,1H),7.40(d,J＝4.8Hz,2H),7.35(t,J＝7.8Hz,1H),7.32-7.30(m,1H),7.26(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.95(s,3H),1.56(s,3H),1.53(s,3H),1.37(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,156.5,150.5,137.9,136.4,134.9,132.8,128.9,128.8,128.7,126.1,125.7,121.6,65.1,60.3,58.7,50.0,27.6,27.4,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcdfor C23H24ClN2O 379.1572；found 379.1565.
6-Bromo-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3k)
Light yellow solid(98.8mg,78％).1H NMR(600MHz,CDCl3):δ7.57(s,1H),7.47-7.41(m,4H),7.39(d,J＝7.2Hz,2H),7.12(d,J＝7.8Hz,1H),4.67(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.94(s,3H),1.55(s,3H),1.53(s,3H),1.33(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,155.0,147.5,141.6,136.6,132.9,131.6,128.80,128.76,128.6,122.5,119.8,65.4,60.3,58.6,50.0,27.57,27.53,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H24BrN2O 423.1067；found 423.1055.
6-Methoxy-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3l)
White solid(85.3mg,76％).1H NMR(600MHz,CDCl3):δ7.46-7.39(m,5H),7.16(d,J＝9.0Hz,1H),7.05(d,J＝1.8Hz,1H),6.86(dd,J1＝8.4Hz,J2＝2.4Hz,1H),4.66(s,1H),3.83(s,3H),2.78(d,J＝15.6Hz,1H),2.40(d,J＝15.6Hz,1H),1.94(s,3H),1.54(s,6H),1.33(s,3H).13C{1H}NMR(100MHz,CDCl3):δ162.8,158.5,152.2,141.42,141.35,137.0,133.7,128.8,128.6,128.4,121.7,113.3,112.7,65.4,60.3,58.6,55.7,50.1,27.7,27.5,22.6,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 375.2067；found 375.2063.
8-Methoxy-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3m)
White solid(18.0mg,16％).1H NMR(400MHz,CDCl3):δ7.36(br s,5H),7.21(t,J＝7.6Hz,1H),7.10(d,J＝7.2Hz,1H),6.87(d,J＝8.4Hz,1H),4.66(s,1H),3.57(s,3H),2.78(d,J＝15.6Hz,1H),2.40(d,J＝15.6Hz,1H),1.89(s,3H),1.54(s,6H),1.21(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.0,153.7,141.8,137.0,135.45,135.39,127.8,127.4,127.3,118.3,112.6,65.9,60.4,58.9,55.6,50.3,27.8,27.6,22.5,21.2.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 375.2067；found 375.2063.
3,3,5,10,10-Pentamethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3n)
White solid(83.8mg,78％).1H NMR(600MHz,CDCl3):δ7.46-7.40(m,5H),7.24(t,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,2H),4.69(s,1H),2.72(d,J＝15.6Hz,1H),2.56(s,3H),2.37(d,J＝15.6Hz,1H),1.89(s,3H),1.65(s,3H),1.50(s,3H),1.34(s,3H).13C{1H}NMR(100MHz,CDCl3):δ163.1,153.0,149.2,138.3,137.4,135.2,133.9,129.2,129.1,128.6,128.4,119.1,64.5,60.8,57.3,51.5,27.8,25.7,22.5,21.8,20.0.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O 359.2118；found 359.2108.
5-Fluoro-3,3,10,10-tetramethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3o)
White solid(71.7mg,66％).1H NMR(400MHz,CDCl3):δ7.49-7.40(m,5H),7.35-7.30(m,1H),7.05(d,J＝7.6Hz,1H),6.97-6.93(m,1H),4.77(s,1H),2.77(d,J＝16.0Hz,1H),2.42(d,J＝15.6Hz,1H),1.95(s,3H),1.59(s,3H),1.50(s,3H),1.34(s,3H).13C{1H}NMR(100MHz,CDCl3):δ163.0,159.6(d,1JC-F＝246.3Hz),155.1,151.9(d,3JC-F＝5.8Hz),136.9(d,4JC-F＝2.9Hz),133.1,131.3(d,3JC-F＝8.0Hz),128.8,128.73,128.71,124.4(d,2JC-F＝16.6Hz),117.5(d,4JC-F＝2.9Hz),113.7(d,2JC-F＝22.4Hz),63.0,60.6,58.2,50.6,27.6,25.7(d,JC(H3)-F＝8.6Hz),22.4,20.5(d,JC(H3)-F＝2.1Hz).19F NMR(565MHz,CDCl3)δ-112.29(dd,J1＝10.2Hz,J2＝4.0Hz,).HRMS(ESI)m/z:[M+H]+Calcd for C23H24FN2O363.1867；found 363.1860.
3,10,10-Trimethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3p-one isomer)
White solid(42.0mg,42％).1H NMR(600MHz,CDCl3):δ7.53(d,J＝7.2Hz,1H),7.47-7.41(m,5H),7.34(t,J＝7.2Hz,1H),7.27-7.24(m,2H),4.35(s,1H),3.56-3.51(m,1H),2.74(dd,J1＝15.6Hz,J2＝7.2Hz,1H),2.60(dd,J1＝15.6Hz,J2＝13.2Hz,1H),1.99(s,3H),1.55(d,J＝6.0Hz,3H),1.31(s,3H).13C{1H}NMR(150MHz,CDCl3):δ163.3,154.2,148.6,139.0,137.6,133.4,128.8,128.7,128.6,126.0,125.5,121.3,75.3,63.1,59.1,44.4,27.9,23.0,18.7.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O 331.1805；found331.1801.
3,10,10-Trimethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3p-the other isomer)
White solid(44.2mg,45％).1H NMR(600MHz,CDCl3):δ7.47-7.41(m,6H),7.35(t,J＝7.2Hz,1H),7.29-7.24(m,2H),4.73(s,1H),4.07-4.02(m,1H),3.12(dd,J1＝16.2Hz,J2＝7.8Hz,1H),2.35(d,J＝16.2Hz,1H),1.95(s,3H),1.52(d,J＝7.2Hz,3H),1.33(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.7,154.7,148.4,139.6,137.7,133.6,128.9,128.8,128.7,128.5,126.0,124.2,121.5,65.3,59.0,53.1,43.7,27.5,22.5,14.9.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O 331.1805；found 331.1801.
10,10-Dimethyl-9-phenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3q)
Yellow solid(79.7mg,84％).1H NMR(600MHz,CDCl3):δ7.46-7.41(m,6H),7.35(t,J＝7.2Hz,1H),7.27-7.24(m,2H),4.26(s,1H),3.88(t,J＝7.8Hz,1H),3.22-3.17(m,1H),2.97-2.91(m,1H),2.70(dd,J1＝15.6Hz,J2＝7.8Hz,1H),2.00(s,3H),1.30(s,3H).13C{1H}NMR(150MHz,CDCl3):δ163.4,154.3,148.2,139.2,137.9,133.5,129.0,128.7,128.6,126.1,124.4,121.4,75.4,59.6,53.8,37.2,27.7,23.0.HRMS(ESI)m/z:[M+H]+Calcd forC21H21N2O 317.1648；found 317.1647.
3,3,10,10-Tetramethyl-9-(p-tolyl)-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3r)
White solid(81.7mg,76％).1H NMR(600MHz,CDCl3):δ7.46(d,J＝7.2Hz,1H),7.34-7.31(m,3H),7.27-7.22(m,4H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.42-2.39(m,4H),1.95(s,3H),1.56(s,3H),1.53(s,3H),1.36(s,3H).13C{1H}NMR(150MHz,CDCl3)δ:162.8,154.1,148.7,139.7,138.4,137.1,130.5,129.4,128.8,128.6,125.8,125.3,121.4,65.6,60.3,58.7,50.1,27.7,27.4,22.5,21.4,21.1.HRMS(ESI)m/z:[M+H]+Calcdfor C24H27N2O 359.2118；found 359.2119.
9-(4-Methoxyphenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3s)
White solid(83.1mg,74％).1H NMR(600MHz,CDCl3):δ7.46(d,J＝7.8Hz,1H),7.37-7.35(m,2H),7.33(t,J＝7.8Hz,1H),7.28-7.27(m,1H),7.24(td,J1＝7.2Hz,J2＝1.2Hz,1H),6.99(d,J＝8.4Hz,2H),4.68(s,1H),3.86(s,3H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.95(s,3H),1.55(s,3H),1.53(s,3H),1.37(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,159.8,153.6,148.7,139.7,136.8,130.1,128.6,125.8,125.7,125.3,121.3,114.1,65.5,60.3,58.7,55.3,50.1,27.7,27.4,22.5,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 375.2067；found:375.2053.
9-(4-Fluorophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3t)
White solid(93.4mg,86％).1H NMR(400MHz,CDCl3):δ7.48(d,J＝7.2Hz,1H),7.42-7.39(m,2H),7.35(td,J1＝7.6Hz,J2＝0.8Hz,1H),7.28-7.24(m,1H),7.22(d,J＝7.6Hz,1H),7.18-7.14(m,2H),4.70(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.94(s,3H),1.56(s,3H),1.54(s,3H),1.35(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,162.8(d,1JC-F＝246.2Hz),154.9,148.4,139.6,136.1,130.6(d,3JC-F＝7.7Hz),129.5(d,4JC-F＝3.3Hz),128.7,126.0,125.3,121.1,115.8(d,2JC-F＝21.9Hz),65.7,60.3,58.5,50.0,27.7,27.4,22.5,21.0.19F NMR(565MHz,CDCl3):δ-112.58–-112.63(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H24FN2O363.1867；found 363.1858.
9-(4-Chlorophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3u)
White solid(82.8mg,73％).1H NMR(600MHz,CDCl3):δ7.47-7.39(m,6H),7.32(t,J＝7.8Hz,1H),7.25-7.23(m,1H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.95(s,3H),1.55(s,3H),1.53(s,3H),1.35(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,154.7,148.6,139.7,137.1,133.5,128.9,128.7,128.6,128.5,125.9,125.3,121.4,65.7,60.3,58.7,50.1,27.7,27.4,22.5,21.1.HRMS(ESI)m/z:[M+H]+Calcdfor C23H24ClN2O 379.1572；found 379.1565.
9-(4-Bromophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazl-1-one(3v)
White solid(95.0mg,75％).1H NMR(600MHz,CDCl3):δ7.60(d,J＝8.4Hz,2H),7.47(d,J＝7.2Hz,1H),7.35-7.33(m,1H),7.30(d,J＝8.4Hz,2H),7.27-7.25(m,1H),7.21(d,J＝7.2Hz,1H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.94(s,3H),1.56(s,3H),1.53(s,3H),1.36(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.3,148.1,139.6,136.0,132.4,132.0,130.5,128.7,126.1,125.4,122.6,121.1,65.8,60.3,58.6,50.0,27.7,27.4,22.6,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H24BrN2O423.1067；found 423.1048.
3,3,10,10-Tetramethyl-9-(4-(trifluoromethyl)phenyl)-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3w)
White solid(94.0mg,76％).1H NMR(600MHz,CDCl3):δ7.74(d,J＝7.8Hz,2H),7.56(d,J＝8.4Hz,2H),7.49(d,J＝7.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.29-7.27(m,1H),7.20(d,J＝7.8Hz,1H),4.73(s,1H),2.79(d,J＝15.6Hz,1H),2.42(d,J＝15.6Hz,1H),1.96(s,3H),1.57(s,3H),1.54(s,3H),1.34(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,156.3,148.0,139.6,137.4,135.8,130.6(q,2JC-F＝32.7Hz),129.2,128.8,126.2,125.7(q,3JC-F＝3.2Hz),125.5,124.0(q,1JC-F＝270.2Hz),121.1,65.9,60.3,58.5,50.0,27.6,27.4,22.7,21.1.19F NMR(565MHz,CDCl3):δ-62.61(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H24F3N2O413.1835；found 413.1823.
3,3,10,10-Tetramethyl-9-(m-tolyl)-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3x)
White solid(98.9mg,92％).1H NMR(600MHz,CDCl3):δ7.46(d,J＝7.2Hz,1H),7.35-7.32(m,2H),7.27-7.21(m,5H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.42-2.39(m,4H),1.95(s,3H),1.56(s,3H),1.53(s,3H),1.36(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.8,154.4,148.7,139.7,138.3,137.3,133.4,129.4,129.3,128.61,128.56,126.0,125.8,125.3,121.4,65.6,60.3,58.7,50.1,27.7,27.4,22.5,21.5,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O 359.2118；found 359.2106.
9-(3-Chlorophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3y)
White solid(91.9mg,81％).1H NMR(600MHz,CDCl3):δ7.47(d,J＝7.8Hz,1H),7.42-7.40(m,3H),7.35(t,J＝7.8Hz,1H),7.32-7.30(m,1H),7.28-7.25(m,1H),7.22(d,J＝7.8Hz,1H),4.70(s,1H),2.78(d,J＝15.6Hz,1H),2.42(d,J＝15.6Hz,1H),1.95(s,3H),1.56(s,3H),1.53(s,3H),1.37(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.8,148.1,139.6,135.7,135.4,134.7,130.0,128.80,128.78,128.7,127.1,126.1,125.4,121.2,65.8,60.3,58.6,50.0,27.7,27.4,22.6,21.1.HRMS(ESI)m/z:[M+H]+Calcd forC23H24ClN2O 379.1572；found 379.1560.
9-(3-Bromophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3z)
White solid(110.2mg,87％).1H NMR(600MHz,CDCl3):δ7.58(s,1H),7.55(dt,J1＝7.2Hz,J1＝1.8Hz,1H),7.47(d,J＝7.2Hz,1H),7.36-7.32(m,3H),7.28-7.25(m,1H),7.22(d,J＝7.2Hz,1H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.41(d,J＝15.6Hz,1H),1.94(s,3H),1.56(s,3H),1.53(s,3H),1.37(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.8,148.1,139.6,135.7,135.6,131.7,131.6,130.3,128.8,127.5,126.1,125.4,122.8,121.1,65.8,60.3,58.6,50.0,27.7,27.4,22.7,21.1.HRMS(ESI)m/z:[M+H]+Calcd forC23H24BrN2O 423.1067；found 423.1056.
9-(2-Bromophenyl)-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3aa)
White solid(110.2mg,87％).1H NMR(600MHz,CDCl3):δ7.70(dd,J1＝7.8Hz,J1＝0.6Hz,1H),7.46(d,J＝7.2Hz,1H),7.39-7.34(m,2H),7.29-7.26(m,2H),7.23(td,J1＝7.8Hz,J2＝1.2Hz,1H),6.86(d,J＝7.8Hz,1H),4.78(s,1H),2.80(d,J＝15.6Hz,1H),2.41(d,J＝15.0Hz,1H),1.88(s,3H),1.56(s,3H),1.54(s,3H),1.39(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.5,149.4,139.6,134.62,134.57,133.1,131.0,129.8,128.7,127.3,125.8,125.0,123.5,120.9,65.6,60.6,58.7,50.0,27.4,25.0,23.5,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H24BrN2O423.1067；found 423.1060.
3,3,10,10-Tetramethyl-9-(thiophen-2-yl)-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3bb)
White solid(57.8mg,55％).1H NMR(600MHz,CDCl3):δ7.48-7.46(m,2H),7.43(d,J＝5.4Hz,1H),7.38(t,J＝7.8Hz,1H),7.28-7.25(m,1H),7.21(d,J＝3.6Hz,1H),7.16(t,J＝4.8Hz,1H),4.69(s,1H),2.78(d,J＝15.6Hz,1H),2.42(d,J＝15.6Hz,1H),1.99(s,3H),1.56(s,3H),1.53(s,3H),1.50(m,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,155.7,148.0,139.2,133.8,129.7,128.8,127.7,127.6,126.5,126.2,125.3,121.4,65.9,60.1,58.9,50.1,27.7,27.5,21.9,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C21H23N2OS 351.1526；found351.1522.
9-Cyclopentyl-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3cc)
White solid(70.6mg,70％).1H NMR(600MHz,CDCl3):δ7.40(d,J＝7.2Hz,1H),7.33(d,J＝7.2Hz,1H),7.29(t,J＝7.2Hz,1H),7.17(td,J1＝7.2Hz,J2＝1.2Hz,1H),4.48(s,1H),3.22-3.16(m,1H),2.78(d,J＝15.6Hz,1H),2.40(d,J＝15.0Hz,1H),2.02-1.87(m,6H),1.83(s,3H),1.81(s,3H),1.77-1.73(m,2H),1.504(s,3H),1.496(s,3H).13C{1H}NMR(150MHz,CDCl3):δ162.9,153.5,147.3,140.1,137.3,128.0,125.0,124.8,121.8,65.5,60.0,58.5,50.3,38.4,31.2,30.2,27.5,26.80,26.76,26.2,23.6,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C22H29N2O 337.2274；found 337.2264.
9-Cyclopropyl-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3dd)
White solid(80.4mg,87％).1H NMR(600MHz,CDCl3):δ7.46(d,J＝7.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.35(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),4.48(s,1H),2.77(d,J＝15.6Hz,1H),2.39(d,J＝15.6Hz,1H),1.92(s,3H),1.82(m,3H),1.68-1.66(m,1H),1.49(s,3H),1.48(s,3H),0.99-0.92(m,2H),0.75-0.71(m,1H),0.53-0.49(m,1H).13C{1H}NMR(150MHz,CDCl3):δ162.8,154.0,149.5,139.1,136.8,128.6,125.5,124.8,121.0,65.2,60.1,58.4,50.1,27.4,25.5,23.6,21.0,7.3,5.7,5.0.HRMS(ESI)m/z:[M+H]+Calcdfor C20H25N2O 309.1961；found 309.1958.
9-Butyl-3,3,10,10-tetramethyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3ee)
Yellow syrup(73.9mg,76％).1H NMR(600MHz,CDCl3):δ7.39(d,J＝7.2Hz,1H),7.34(t,J＝7.2Hz,1H),7.27(d,J＝7.2Hz,1H),7.19(td,J1＝7.2Hz,J2＝0.6Hz,1H),4.52(s,1H),2.78(d,J＝15.6Hz,1H),2.61-2.52(m,2H),2.39(d,J＝15.6Hz,1H),1.83(s,6H),1.62-1.57(m,2H),1.50(s,3H),1.49(s,3H)1.47-1.39(m,2H),0.96(t,J＝7.2Hz,3H).13C{1H}NMR(100MHz,CDCl3):δ162.8,152.6,149.2,139.4,135.1,128.4,125.2,124.8,120.1,65.5,60.1,58.4,50.2,31.1,27.4,26.5,25.5,23.0,22.99,21.0,13.9.HRMS(ESI)m/z:[M+H]+Calcd for C21H29N2O 325.2274；found 325.2274.
3,3-Dimethyl-9,10-diphenyl-10-propyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3ff)
White solid(71.6mg,55％).1H NMR(600MHz,CDCl3):δ7.84(d,J＝7.8Hz,2H),7.49(d,J＝7.2Hz,1H),7.41-7.25(m,11H),4.81(s,1H),2.80(d,J＝15.6Hz,1H),2.66-2.62(m,1H),2.41(d,J＝15.6Hz,1H),1.70-1.64(m,1H),1.52(s,3H),1.46(s,3H),1.29-1.17(m,2H),0.48(t,J＝6.6Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ163.4,150.8,148.6,143.1,140.2,137.6,133.1,128.8,128.61,128.56,128.5,127.6,127.3,125.9,125.5,121.6,67.7,65.8,60.3,50.0,35.3,27.5,20.8,17.8,13.3.HRMS(ESI)m/z:[M+H]+Calcdfor C30H31N2O 435.2431；found 435.2428.
3,3-Dimethyl-9,10-diphenyl-2,3,4a,10-tetrahydro-1H-indeno[1,2-c]pyrazolo[1,2-a]pyrazol-1-one(3gg)
Light yellow solid(52.9mg,45％).1H NMR(600MHz,CDCl3):δ7.58-7.55(m,3H),7.50(d,J＝7.2Hz,1H),7.43-7.33(m,7H),7.31-7.26(m,3H),5.38(s,1H),5.00(s,1H),2.77(d,J＝15.6Hz,1H),2.42(d,J＝15.6Hz,1H),1.61(s,3H),1.56(s,3H).13C{1H}NMR(150MHz,CDCl3):δ163.7,148.5,147.2,141.0,139.9,138.6,132.8,128.9,128.8,128.73,128.69,128.62,128.57,128.2,126.2,125.7,122.2,65.9,60.7,57.1,49.7,27.3,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C27H25N2O 393.1961；found 393.1958.
3',3'-Dimethyl-9'-phenyl-2',3'-dihydro-1'H,4a'H-spiro[cyclohexane-1,10'-indeno[1,2-c]pyrazolo[1,2-a]pyrazol]-1'-one(3hh)
Yellow solid(92.2mg,80％).1H NMR(600MHz,CDCl3):δ7.46-7.43(m,3H),7.42-7.39(m,1H),7.36-7.35(m,2H),7.26-7.24(m,1H),7.21(td,J1＝7.8Hz,J1＝1.2Hz,1H),6.82(d,J＝7.8Hz,1H),4.72(s,1H),2.83(d,J＝15.6Hz,1H),2.59(td,J1＝12.6Hz,J1＝3.6Hz,1H),2.41-2.36(m,2H),1.94-1.92(m,1H),1.85-1.79(m,2H),1.55(s,3H),1.53(s,3H),1.49-1.43(m,1H),1.34-1.25(m,3H),0.41-0.35(m,1H).13C{1H}NMR(150MHz,CDCl3):δ162.9,153.6,150.8,138.5,136.9,135.0,129.3,128.64,128.60,128.1,125.7,124.7,121.5,65.9,63.4,60.5,50.3,35.9,31.7,27.3,24.5,23.0,22.1,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C26H29N2O385.2274；found 385.2268.
实施例4
化合物的抗癌活性是利用CCK8分析，通过细胞抗增殖活性研究来评估的。首先，将细胞以每孔5000个细胞的密度接种到每孔装有100μL培养基的96孔板中，并在37℃和5％CO2环境下孵育过夜。第二天，在每孔中加入100μL用培养基稀释的待测化合物(浓度为0.03nM-30μM)，接着，细胞在37℃和5％CO2环境下孵育72小时。然后，向每个孔中加入10μL的CCK8，并将96孔板置于37℃孵育2小时。使用EnVision multilatelbel Reader(Perkinermer)在450nm处测量吸光度(用630nm作为参考波长)，并用GraphPad Prism 6.0软件计算出IC50值。所有的实验均布施三个平行样品，并重复三次。选择REC-1和Ramos两种癌细胞作为研究对象，5-氟尿嘧啶(5-FU)被用作药物的阳性对照品。
部分化合物的抗癌活性结果如下：
Figure BDA0002957668420000181
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (10)

1.茚并吡唑并吡唑啉酮类化合物，其结构通式为：
Figure FDA0002957668410000011
其中，R1为氢、卤素、C1-6烷基、C1-6烷氧基或C1-6烷氧羰基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6烷基、C3-6环烷基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、三氟甲基或卤素，R5和R6各自独立为氢、C1-4烷基、苯基或共同组成C5-6环烷基。
2.如权利要求1所述茚并吡唑并吡唑啉酮类化合物及其在药学上可接受的盐在抗癌活性药物中的应用。
3.如权利要求2所述茚并吡唑并吡唑啉酮类化合物及其在药学上可接受的盐在抗癌活性药物中的应用，其特征在于，所述抗癌活性是指抗REC-1和Ramos两种癌细胞活性。
4.用于治疗REC-1和Ramos癌症的药物，包括茚并吡唑并吡唑啉酮类化合物其结构通式为：
Figure FDA0002957668410000012
和相应药学上可接受的盐；其中R1-R6取代基同权利要求1。
5.如权利要求1所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于，包括如下操作：将芳基偶氮甲碱亚胺1、炔丙醇类化合物2、铑或钌催化剂、添加剂和溶剂混合，常温或升温反应制得茚并吡唑并吡唑啉酮类化合物3；反应方程式为：
Figure FDA0002957668410000013
其中R1-R6取代基同权利要求1。
6.根据权利要求5所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于：铑催化剂选自二氯(五甲基环戊二烯基)合铑(III)，钌催化剂选自二氯双(4-甲基异丙基苯基)钌(II)。
7.根据权利要求5所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于：所述添加剂选自乙酸银、醋酸铜、醋酸钠或六氟锑酸银。
8.根据权利要求5所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于：所述反应溶剂选自2,2,2-三氟乙醇或六氟异丙醇。
9.根据权利要求5所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于：所述芳基偶氮甲碱亚胺1、炔丙醇类化合物2、添加剂和铑或钌催化剂摩尔比为1-2:1:0.075-0.25:0.02-0.03。
10.根据权利要求5所述茚并吡唑并吡唑啉酮类化合物的合成方法，其特征在于：所述反应温度为20-100℃。
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