CN117886747A - 氟代甲基取代喹啉类化合物、应用、药物组合物、合成方法 - Google Patents
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Abstract
本发明属于化学药物及合成技术领域，具体涉及氟代甲基取代喹啉类化合物、应用、药物组合物、合成方法。本发明提供的化合物具有抑制Ramos癌细胞增殖的活性，提示本发明化合物对淋巴癌有抗癌活性，为药物筛选提供了新的结构单元，并且进一步筛选出同时具有抑制A‑549和Ramos癌细胞增殖活性的化合物，提示这类化合物对肺癌和淋巴癌的治疗均具有潜在的药用价值；同时本发明提供了合成方法，氟代甲基取代喹啉类化合物的合成是通过N‑芳基脒类化合物和氟代甲基炔酮类化合物之间的一锅串联反应完成的，反应条件温和，过程简单而高效。
Description
技术领域
本发明属于化学药物及合成技术领域，具体涉及氟代甲基取代喹啉类化合物、应用、药物组合物、合成方法。
背景技术
杂环化合物在设计用于医药应用的新结构实体中起重要作用。其中喹啉及其衍生物在天然存在的化合物中广泛存在而且具有广谱的生物活性。喹啉化合物在抗癌药物开发中起重要作用，通过不同的作用机制显示出优异的结果，例如通过细胞周期停滞、细胞凋亡、抑制血管生成、破坏细胞迁移和调节抑制生长等。DNA拓扑异构酶为催化DNA拓扑学异构体相互转变的酶之总称，是一种见于真核细胞和原核细胞中的重要生物酶，其对DNA转录、复制、染色体分离及基因表达等过程中的DNA拓扑结构起着重要的调控作用。研究发现，与正常细胞不同，DNA拓扑异构酶在肿瘤细胞中表现出不受其他因素影响的高水平表达，而许多抗肿瘤药物的作用机制也与DNA拓扑异构酶密切相关，因此它作为抗肿瘤药物的重要靶点引起了研究者的广泛关注。喹啉衍生物通过嵌入DNA而表现出细胞毒性进而干扰DNA复制过程。
对喹啉母体骨架上连接的基团进行结构改造一直是新药研发以及药物活性改进的重要途径。研究表明，将氟原子引入到喹啉结构中，可以极大地提高药物的活性，提高药效，尤其是三氟甲基结构单元的引入通常会对母体化合物的物理化学性质、生物活性以及代谢稳定性等产生显著影响，是新药设计的优势结构单元之一；一些氟代喹啉类化合物对很多生理疾病都有着良好的药物活性，是降低眼压制剂、肌球蛋白抑制剂、抗增殖药物等的有效成分。虽然氟代喹啉类化合物具有重要的应用价值，但是，目前合成该类化合物的方法不多，而且存在着路线繁琐，底物兼容性不好，条件苛刻等诸多问题，使得可进行活性筛选的氟代喹啉类化合物的数量有限，以致于阻碍了该类化合物在医药、农药等领域的应用研究。
因此，研究并开发从价廉易得的原料出发，通过简便的步骤和过程高效合成氟代甲基取代喹啉类化合物，无论是对于有机化学还是对于药物化学都具有重要的理论意义和实用前景。
发明内容
为了解决现有技术存在的问题，本发明的目的之一在于提供氟代甲基取代喹啉类化合物，该类化合物具有抗癌活性。
本发明的目的之二在于提供氟代甲基取代喹啉类化合物在制备抗癌药物方面的应用。
本发明的目的之三在于提供一种治疗肺癌和淋巴癌的药物组合物，其活性成分为本发明提供的氟代甲基取代喹啉类化合物。
本发明的目的之四在于提供氟代甲基取代喹啉类化合物的合成方法。
为了实现上述目的，本发明采用的技术方案如下：
一种氟代甲基取代喹啉类化合物，其化学结构通式为：
其中，R1为氢、一元或多元取代的C1-4烷基、C1-4烷氧基、C1-4烷硫基、苯基、卤素或亚乙基二氧基；或者R1与苯环共同组成萘环；
R2为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基；或者R2为苯基或取代的苯基时，喹啉4-位的R2与喹啉3位的炔基稠合为萘环或取代的萘环；
R3为氢、氟或三氟甲基。
可选的，R2为苯基或取代的苯基时，喹啉4-位的R2与喹啉3位的炔基稠合为萘环或取代的萘环，形成氟代甲基取代的苯并菲啶类化合物，其化学结构通式为：
其中X为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基。
作为优选的，所述R3为氟；R1为氢，或6位或7位一元取代的SMe、Cl或F；R2为苯基、对位F取代的苯基、间位甲氧基取代的苯基或噻吩基；或者R2为苯基时，4-位的R2与3位的炔基稠合为萘环。
进一步可选的，所述R2为苯基、对位F取代的苯基；或者R2为苯基时，4-位的R2与3位的炔基稠合为萘环。
作为优选的，上述化合物的化学结构式为：
可选的，本发明具体实施方案中通过细胞试验验证，该优选的化合物对Ramos癌细胞具有体外抗增殖作用，表明该优选的化合物作为药物活性成分，对淋巴癌具有预防、治疗、抑制恶化进程的作用。
更进一步优选的，上述化合物的化学结构式为：
可选的，本发明具体实施方案中通过细胞试验验证，该优选的化合物对A-549、Ramos癌细胞具有体外抗增殖作用，表明该优选的化合物作为药物活性成分，对肺癌、淋巴癌具有预防、治疗、抑制恶化进程的作用。
上述化合物的合成方法，包括以N-芳基脒类化合物1、氟代甲基炔酮类化合物2为原料制备而成。
可选的，包括将N-芳基脒类化合物1、氟代甲基炔酮类化合物2、催化剂、添加剂和溶剂混合，升温反应制得氟代甲基取代喹啉类化合物3，反应方程式为：
其中，R1为氢、一元或多元取代的C1-4烷基、C1-4烷氧基、C1-4烷硫基、苯基、卤素或亚乙基二氧基，或者R1与苯环共同组成萘环；R2为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基；R3为氢、氟或三氟甲基；
进一步地，在上述合成方法中，所述N-芳基脒类化合物1、氟代甲基炔酮类化合物2、催化剂、添加剂的投料摩尔比为1:1-2.5:0.03-0.05:1-3。
进一步地，在上述合成方法中，所述催化剂为二氯(五甲基环戊二烯基)合铑二聚体([RhCp*Cl2]2)。
进一步地，在上述合成方法中，所述添加剂为一水合醋酸铜、醋酸铜、1-金刚烷甲酸、苯甲酸、三甲基乙酸、2,4,6-三甲基苯甲酸或者两个及两个以上混合物。
进一步地，在上述合成方法中，所述溶剂为甲醇或乙醇。
进一步地，在上述合成方法中，所述反应温度为50-80℃。
进一步地，在上述合成方法中，所述气体氛围为空气或惰性气体氛围。
进一步地，上述合成方法还包括以氟代甲基取代喹啉类化合物3-1为原料在对甲苯磺酸存在下转变为氟代甲基取代的苯并菲啶类化合物4，反应方程式为：
其中，X为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基。
本发明有益效果：
(1)本发明提供的氟代甲基取代喹啉类化合物，通过对具有各种取代基的化合物进行筛选，并通过抗癌细胞活性试验验证，本发明提供的化合物具有抑制Ramos癌细胞增殖的活性，提示本发明化合物对淋巴癌有抗癌活性，为药物筛选提供了新的结构单元，并且进一步筛选出同时具有抑制A-549和Ramos癌细胞增殖活性的化合物，提示这类化合物对肺癌和淋巴癌的治疗均具有潜在的药用价值；
(2)本发明提供的合成方法，氟代甲基取代喹啉类化合物的合成是通过N-芳基脒类化合物和氟代甲基炔酮类化合物之间的一锅串联反应完成的，反应条件温和，过程简单而高效；
(3)本发明提供的合成方法合成的氟代甲基取代喹啉类化合物可进一步作为原料，通过一步反应转换为氟代甲基取代的苯并菲啶类化合物，本发明合成方法底物适用范围广，官能团耐受性好；原料价廉易得，反应条件温和，操作简便。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为实施例1中化合物3aa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
向35mL反应管中依次加入化合物1a、催化剂、添加剂1和/或添加剂2、溶剂以及化合物2a，将反应管密封，并置于油浴中升温搅拌反应12h。待反应结束后，冷却至室温，抽滤，浓缩滤液，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到白色固体产物3aa。
通过改变反应的物料比、添加剂1、添加剂2、催化剂、溶剂和反应温度等反应条件，得到一系列的结果，见表1。
表1各种条件下3aa的合成a
实施例2
向35mL反应瓶中依次加入1a(35.3mg,0.2mmol)、[RhCp*Cl2]2(3.7mg,0.006mmol)、一水合醋酸铜(40.0mg,0.2mmol)、三甲基乙酸(20.4mg,0.2mmol)、2a(99.1mg,0.5mmol)和甲醇(2mL)，盖上塞子密封，将其置于70℃油浴中搅拌反应12h。待反应结束后，冷却至室温，抽滤，浓缩滤液，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得白色固体产物3aa(48.7mg,65％)。该化合物的表征数据为：1H NMR(600MHz,CDCl3):δ8.25(d,J＝8.4Hz,1H),7.80-7.77(m,1H),7.69(d,J＝8.4Hz,1H),7.61-7.57(m,4H),7.50-7.49(m,2H),7.29-7.25(m,3H),7.21-7.19(m,2H).13C{1H}NMR(150MHz,CDCl3):δ153.4,147.2(q,2JC-F＝33.5Hz),145.1,135.8,131.5,130.8,130.5,130.0,129.1,128.93,128.85,128.4,128.3,127.5,126.4,122.6,121.6(q,1JC-F＝274.1Hz),113.7,100.0,83.3.19F NMR(565MHz,CDCl3):δ-66.14(s).HRMS(ESI)m/z:[M+H]+ Calcd for C24H15F3N 374.1151；Found 374.1141.
实施例3
依照实施例2的方法和步骤，通过改变反应物1和反应物2，可以合成出各种氟代甲基取代喹啉类化合物3，具体结果如下：
表2氟代甲基取代喹啉类化合物3的合成a,b
代表性产物表征数据如下：
6-Methyl-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ba)
1H NMR(600MHz,CDCl3):δ8.14(d,J＝9.0Hz,1H),7.63-7.57(m,4H),7.49-7.48(m,2H),7.41(s,1H),7.29-7.25(m,3H),7.19-7.18(m,2H),2.46(s,3H).13C{1H}NMR(150MHz,CDCl3):δ152.7,146.3(q,2JC-F＝33.5Hz),143.7,139.6,136.0,133.1,131.5,130.1,130.0,128.9,128.7,128.35,128.31,127.5,125.1,122.6,121.6(q,1JC-F＝275.6Hz),113.6,99.8,83.5,22.0.19F NMR(565MHz,CDCl3):δ-66.01(s).HRMS(ESI)m/z:[M+H]+ Calcd forC25H17F3N 388.1308；Found 388.1290.
6-Ethyl-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ca)
1H NMR(600MHz,CDCl3):δ8.17(d,J＝9.0Hz,1H),7.67(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.62-7.58(m,3H),7.50-7.49(m,2H),7.43(d,J＝1.2Hz,1H),7.30-7.25(m,3H),7.20-7.18(m,2H),2.75(q,J＝7.8Hz,2H),1.24(t,J＝7.8Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ152.8,146.4(q,2JC-F＝30.9Hz),145.7,143.9,136.1,132.0,131.5,130.3,130.0,128.8,128.7,128.33,128.30,127.5,123.9,122.6,121.7(q,1JC-F＝273.9Hz),113.6,99.8,83.5,29.2,15.4.19F NMR(565MHz,CDCl3):δ-66.00(s).HRMS(ESI)m/z:[M+H]+ Calcd forC26H19F3N 402.1464；Found 402.1469.
6-Methoxy-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3da)
1H NMR(400MHz,CDCl3):δ8.14(d,J＝9.2Hz,1H),7.62-7.56(m,3H),7.51-7.49(m,2H),7.43(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.30-7.24(m,3H),7.20-7.17(m,2H),6.89(d,J＝2.8Hz,1H),3.75(s,3H).13C{1H}NMR(150MHz,CDCl3):δ159.7,151.7,144.9(q,2JC-F＝32.1Hz),141.2,136.2,131.9,131.5,129.8,128.9,128.8,128.5,128.3,123.4,122.6,121.8(q,1JC-F＝274.8Hz),114.0,104.0,100.0,83.5,55.6.19F NMR(565MHz,CDCl3):δ-65.82(s).HRMS(ESI)m/z:[M+H]+Calcd for C25H17F3NO 404.1257；Found 404.1240.
6-(Methylthio)-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ea)
1H NMR(600MHz,CDCl3):δ8.12(d,J＝9.0Hz,1H),7.64(dd,J1＝9.0Hz,J2＝2.4Hz,1H),7.61-7.57(m,3H),7.50-7.49(m,2H),7.34(d,J＝1.8Hz,1H),7.31-7.25(m,3H),7.19(d,J＝6.6Hz,2H),2.41(s,3H).13C{1H}NMR(150MHz,CDCl3):δ151.7,146.2(q,2JC-F＝33.2Hz),143.2,141.3,135.7,131.5,130.4,129.9,129.7,128.95,128.92,128.4,128.3,127.9,122.5,121.6(q,1JC-F＝274.7Hz),120.3,114.3,100.2,83.3,15.2.19F NMR(565MHz,CDCl3):δ-65.98(s).HRMS(ESI)m/z:[M+H]+Calcd for C25H17F3NS 420.1028；Found420.1042.
4,6-Diphenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3fa)
1H NMR(400MHz,CDCl3):δ8.32(d,J＝8.8Hz,1H),8.06-8.03(m,1H),7.84(s,1H),7.61-7.53(m,7H),7.46-7.36(m,3H),7.29-7.20(m,5H).13C{1H}NMR(150MHz,CDCl3):δ153.5,147.1(q,2JC-F＝33.6Hz),144.4,142.0,139.9,135.8,131.6,130.9,130.6,130.0,129.1,129.0,128.9,128.4,128.3,128.2,127.6,123.9,122.5,121.6(q,1JC-F＝276.5Hz),114.1,100.2,83.4.19F NMR(565MHz,CDCl3):δ-66.06(s).HRMS(ESI)m/z:[M+H]+ Calcdfor C30H19F3N 450.1464；Found 450.1460.
6-Fluoro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ga)
1H NMR(600MHz,CDCl3):δ8.26(dd,J1＝9.0Hz,J2＝5.4Hz,1H),7.62-7.58(m,3H),7.57-7.53(m,1H),7.49-7.47(m 2H),7.32-7.26(m,4H),7.21-7.19(m,2H).13C{1H}NMR(150MHz,CDCl3):δ162.1(d,1JC-F＝250.2Hz),152.7(d,4JC-F＝5.4Hz),146.7(qd,2JC-F＝32.7Hz,6JC-F＝2.4Hz),142.1,135.4,133.2(d,3JC-F＝9.0Hz),131.6,129.8,129.1,128.7(d,3JC-F＝9.5Hz),128.6,128.3,122.3,121.5(q,1JC-F＝274.7Hz),121.0(d,2JC-F＝26.4Hz),114.5,109.9(d,2JC-F＝24.6Hz),100.7,83.1.19F NMR(565MHz,CDCl3):δ-66.19(s),-108.05–-108.09(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H14F4N 392.1057；Found392.1040.
6-Chloro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ha)
1H NMR(400MHz,CDCl3):δ8.19(d,J＝8.8Hz,1H),7.72(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),7.63-7.60(m,3H),7.49-7.47(m,2H),7.31-7.25(m,3H),7.20-7.18(m,2H).13C{1H}NMR(150MHz,CDCl3):δ152.5,147.4(q,2JC-F＝33.0Hz),143.4,135.4,135.2,132.0,131.7,131.6,129.9,129.2,129.1,128.6,128.4,128.3,125.1,122.3,121.4(q,1JC-F＝274.2Hz),114.7,100.9,83.0.19F NMR(565MHz,CDCl3):δ-66.28(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H14ClF3N 408.0761；Found 408.0756.
6-Bromo-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ia)
1H NMR(600MHz,CDCl3):δ8.11(d,J＝9.0Hz,1H),7.85(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.82(d,J＝2.4Hz,1H),7.63-7.59(m,3H),7.49-7.47(m,2H),7.32-7.26(m,3H),7.20-7.18(m,2H).13C{1H}NMR(150MHz,CDCl3):δ152.4,147.5(q,2JC-F＝32.9Hz),143.6,135.2,134.3,132.1,131.6,129.9,129.2,129.1,128.7,128.6,128.42,128.36,123.8,122.3,121.4(q,1JC-F＝276.2Hz),114.7,100.9,83.0.19F NMR(565MHz,CDCl3):δ-66.32(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H14BrF3N 452.0256；Found 452.0248.
7-Methyl-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ja)
1H NMR(400MHz,CDCl3):δ8.03(s,1H),7.58-7.56(m,4H),7.49-7.47(m,2H),7.39(d,J＝8.8Hz,1H),7.27-7.23(m,3H),7.20-7.18(m,2H),2.57(s,3H).13C{1H}NMR(150MHz,CDCl3):δ153.2,147.2(q,2JC-F＝33.8Hz),145.3,141.6,136.0,131.5,131.4,130.0,129.5,128.81,128.78,128.3,126.1,125.5,122.7,121.6(q,1JC-F＝275.9Hz),112.8,99.6,83.5,21.8.19F NMR(376MHz,CDCl3):δ-66.06(s).HRMS(ESI)m/z:[M+H]+Calcd for C25H17F3N388.1308；Found 388.1293.
7-Chloro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3ka)
1H NMR(400MHz,CDCl3):δ8.25(d,J＝2.0Hz,1H),7.64-7.58(m,4H),7.51(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.49-7.46(m,2H),7.30-7.25(m,3H),7.20-7.18(m,2H).13C{1H}NMR(150MHz,CDCl3):δ153.4,148.3(q,2JC-F＝32.4Hz),145.4,137.0,135.4,131.6,130.1,129.9,129.4,129.11,129.08,128.5,128.4,127.7,126.0,122.4,121.3(q,1JC-F＝275.1Hz),114.0,100.5,83.0.19F NMR(376MHz,CDCl3):δ-66.38(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H14ClF3N 408.0761；Found 408.0765.
7-Fluoro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3l)and5-Fluoro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3m)
1H NMR(600MHz,CDCl3):δ8.09(d,J＝8.4Hz,0.33H),7.88(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.75-7.72(m,0.33H),7.70(dd,J1＝9.0Hz,J2＝6.0Hz,1H),7.61-7.58(m,3H),7.54-7.53(m,0.99H),7.49-7.47(m,2H),7.42-7.41(m,0.66H),7.38-7.35(m,1H),7.31-7.24(m,4.32H),7.19-7.18(m,2H),7.14-7.12(m,0.66H).13C{1H}NMR(150MHz,CDCl3):δ163.7(d,1JC-F＝252.3Hz),157.7(d,1JC-F＝259.2Hz),153.5,150.8(d,3JC-F＝3.9Hz),148.4(q,2JC-F＝32.4Hz),147.8(q,2JC-F＝32.7Hz),146.2(d,3JC-F＝13.5Hz),146.0,138.4(d,4JC-F＝3.6Hz),135.6,131.6,131.5,130.6(d,3JC-F＝8.0Hz),129.9,129.08,129.06,129.0,128.9(d,3JC-F＝9.6Hz),128.5(d,4JC-F＝3.5Hz),128.5,128.34,128.32,128.30,127.8,126.9(d,3JC-F＝4.2Hz),124.7,122.4,121.4(q,1JC-F＝272.4Hz),121.3(q,1JC-F＝275.0Hz),119.7(d,2JC-F＝25.5Hz),118.3(d,2JC-F＝9.6Hz),115.7,114.5(d,2JC-F＝21.3Hz),114.2(d,2JC-F＝20.7Hz),113.3(d,4JC-F＝3.8Hz),101.5,100.1,83.0,82.7.19FNMR(565MHz,CDCl3):δ-66.34(s),-66.43(s),-105.53(dd,J1＝9.6Hz,J2＝6.8Hz),-106.97–-107.01(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H14F4N 392.1057；Found392.1065.8-Fluoro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3na)
1H NMR(600MHz,CDCl3):δ7.60-7.58(m,3H),7.53-7.46(m,5H),7.31-7.26(m,3H),7.21-7.19(m,2H).13C{1H}NMR(150MHz,CDCl3):δ158.4(d,1JC-F＝258.9Hz),153.3(d,4JC-F＝2.1Hz),147.4(q,2JC-F＝31.5Hz),135.5,135.3(d,3JC-F＝10.7Hz),131.6,129.9,129.2,129.08,129.07(d,2JC-F＝15.0Hz),128.44,128.37,122.3,122.1(d,3JC-F＝5.0Hz),121.3(q,1JC-F＝273.8Hz),114.93(d,2JC-F＝18.2Hz),114.87,100.9,83.0.19F NMR(565MHz,CDCl3):δ-66.24(s),-122.46–-122.49(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H14F4N392.1057；Found 392.1062.
8-Chloro-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3oa)
1H NMR(400MHz,CDCl3):δ7.89(dd,J1＝7.2Hz,J2＝1.2Hz,1H),7.61-7.58(m,4H),7.50-7.46(m,3H),7.31-7.25(m,3H),7.21-7.18(m,2H).13C{1H}NMR(150MHz,CDCl3):δ153.8,147.5(q,2JC-F＝32.4Hz),141.4,135.6,135.1,131.6,130.8,129.9,129.1,129.04,128.96,128.9,128.44,128.36,125.5,122.3,121.4(q,1JC-F＝277.7Hz),114.8,100.9,83.0.19F NMR(376MHz,CDCl3):δ-66.26(s).HRMS(ESI)m/z:[M+H]+Calcd forC24H14ClF3N408.0761；Found 408.0747.
6,7-Dimethyl-4-phenyl-3-(phenylethynyl)-2-(trifluoromethyl)quinoline(3pa)
1H NMR(400MHz,CDCl3):δ8.02(s,1H),7.59-7.54(m,3H),7.49-7.47(m,2H),7.39(s,1H),7.28-7.24(m,3H),7.19-7.17(m,2H),2.48(s,3H),2.36(s,3H).13C{1H}NMR(150MHz,CDCl3):δ152.4,146.4(q,2JC-F＝31.4Hz),144.2,141.6,139.6,136.2,131.5,130.0,129.8,128.72,128.65,128.3,126.0,125.4,122.7,121.7(q,1JC-F＝275.0Hz),112.7,99.4,83.6,20.41,20.37.19F NMR(565MHz,CDCl3):δ-65.92(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H19F3N 402.1464；Found 402.1448.
9-Phenyl-8-(phenylethynyl)-7-(trifluoromethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline(3qa)
1H NMR(400MHz,CDCl3):δ7.69(s,1H),7.58-7.54(m,3H),7.47-7.45(m,2H),7.27-7.24(m,3H),7.18-7.16(m,2H),7.06(s,1H),4.38-4.35(m,4H).13C{1H}NMR(150MHz,CDCl3):δ151.7,148.0,146.3,145.8(q,2JC-F＝32.4Hz),141.8,136.2,131.4,129.8,128.7,128.6,128.32,128.26,122.8,121.7(q,1JC-F＝273.0Hz),115.3,111.0,99.1,83.6,64.42,64.39.19F NMR(376MHz,CDCl3):δ-65.87(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H17F3NO2432.1206；Found 432.1216.
4-Phenyl-3-(phenylethynyl)-2-(trifluoromethyl)benzo[g]quinoline(3ra)
1H NMR(600MHz,CDCl3):δ8.87(s,1H),8.22(s,1H),8.11(d,J＝8.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.67-7.63(m,3H),7.60-7.57(m,3H),7.53(t,J＝7.8Hz,1H),7.31-7.27(m,3H),7.23-7.22(m,2H).13C{1H}NMR(150MHz,CDCl3):δ153.7,147.5(q,2JC-F＝33.5Hz),141.1,136.1,134.3,133.2,131.5,130.1,129.3,128.94,128.86,128.7,128.6,128.5,128.3,127.4,127.3,126.2,125.4,122.7,121.5(q,1JC-F＝274.4Hz),112.1,99.8,83.8.19FNMR(565MHz,CDCl3):δ-66.49(s).HRMS(ESI)m/z:[M+H]+Calcd for C28H17F3N424.1308；Found 424.1298.
4-(4-Butylphenyl)-3-((4-butylphenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ab)
1H NMR(400MHz,CDCl3):δ8.24(d,J＝8.0Hz,1H),7.79-7.75(m,1H),7.73(d,J＝8.0Hz,1H),7.59-7.55(m,1H),7.40(s,4H),7.12-7.06(m,4H),2.77(t,J＝7.6Hz,2H),2.58(t,J＝7.6Hz,2H),1.77-1.70(m,2H),1.58-1.52(m,2H),1.48-1.41(m,2H),1.35-1.30(m,2H),1.00(t,J＝7.2Hz,3H),0.91(t,J＝7.2Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ153.5,147.2(q,2JC-F＝33.0Hz),145.0,144.2,143.6,133.1,131.5,130.6,130.4,129.9,128.9,128.4,128.3,127.6,126.5,121.6(q,1JC-F＝274.5Hz),119.8,113.9,100.2,83.0,35.7,35.6,33.8,33.4,22.4,22.3,14.1,13.9.19F NMR(565MHz,CDCl3):δ-66.20(s).HRMS(ESI)m/z:[M+H]+Calcd for C32H31F3N 486.2403；Found 486.2399.
4-(4-Methoxyphenyl)-3-((4-methoxyphenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ac)
1H NMR(600MHz,CDCl3):δ8.23(d,J＝8.4Hz,1H),7.77-7.73(m,2H),7.57(t,J＝7.8Hz,1H),7.45(d,J＝9.0Hz,2H),7.21(d,J＝8.4Hz,2H),7.11(d,J＝8.4Hz,2H),6.81(d,J＝9.0Hz,2H),3.94(s,3H),3.80(s,3H).13C{1H}NMR(150MHz,CDCl3):δ160.2,160.0,152.5,147.2(q,2JC-F＝31.5Hz),144.9,133.1,131.5,130.5,130.4,129.0,128.0,127.8,126.4,121.6(q,1JC-F＝273.9Hz),114.8,114.0,113.7,100.1,82.5,55.5,55.3.19F NMR(565MHz,CDCl3):δ-66.23(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H19F3NO2 434.1362；Found 434.1368.
4-(4-Fluorophenyl)-3-((4-fluorophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ad)
1H NMR(600MHz,CDCl3):δ8.26(d,J＝8.4Hz,1H),7.82-7.79(m,1H),7.66(d,J＝7.8Hz,1H),7.61(t,J＝7.2Hz,1H),7.50-7.48(m,2H),7.30(t,J＝8.4Hz,2H),7.23-7.20(m,2H),7.00(t,J＝9.0Hz,2H).13C{1H}NMR(150MHz,CDCl3):δ163.1(d,1JC-F＝247.1Hz),163.0(d,1JC-F＝249.2Hz),152.1,147.2(q,2JC-F＝33.8Hz),145.1,133.5(d,3JC-F＝8.3Hz),131.9(d,3JC-F＝8.1Hz),131.7(d,4JC-F＝3.0Hz),130.9,130.6,129.4,127.4,126.1,121.5(q,1JC-F＝274.1Hz),118.5(d,4JC-F＝3.2Hz),115.8(d,2JC-F＝21.9Hz),115.5(d,2JC-F＝21.3Hz),113.7,99.1,82.9.19F NMR(565MHz,CDCl3):δ-66.24(s),-109.22–-109.27(m),-112.13–-112.18(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H13F5N410.0963；Found410.0966.
4-(4-Chlorophenyl)-3-((4-chlorophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ae)
1H NMR(600MHz,CDCl3):δ8.26(d,J＝8.4Hz,1H),7.83-7.81(m,1H),7.65-7.57(m,4H),7.45-7.43(m,2H),7.30-7.27(m,2H),7.16-7.14(m,2H).13C{1H}NMR(150MHz,CDCl3):δ152.0,147.2(q,2JC-F＝32.9Hz),145.1,135.3,135.2,134.1,132.7,131.4,131.1,130.6,129.5,128.8,128.7,127.2,126.0,121.4(q,1JC-F＝275.0Hz),120.8,113.3,99.1,84.0.19FNMR(565MHz,CDCl3):δ-66.20(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Cl2F3N 442.0372；Found 442.0387.
4-(4-Bromophenyl)-3-((4-bromophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3af)
1H NMR(400MHz,CDCl3):δ8.26(d,J＝8.4Hz,1H),7.84-7.80(m,1H),7.74(d,J＝8.8Hz,2H),7.66-7.59(m,2H),7.44(d,J＝8.4Hz,2H),7.38(d,J＝8.8Hz,2H),7.08(d,J＝8.4Hz,2H).13C{1H}NMR(150MHz,CDCl3):δ152.1,147.1(q,2JC-F＝33.3Hz),145.1,134.6,132.9,131.8,131.68,131.65,131.1,130.6,129.5,127.1,126.0,123.6,123.3,121.4(q,1JC-F＝274.8Hz),121.2,113.3,99.3,84.1.19F NMR(565MHz,CDCl3):δ-66.19(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Br2F3N 529.9361；Found 529.9371.
4-(m-Tolyl)-3-(m-tolylethynyl)-2-(trifluoromethyl)quinoline(3ag)
1H NMR(400MHz,CDCl3):δ8.25(d,J＝8.4Hz,1H),7.80-7.76(m,1H),7.72(d,J＝8.4Hz,1H),7.60-7.56(m,1H),7.48(t,J＝7.6Hz,1H),7.38(d,J＝7.6Hz,1H),7.32(s,1H),7.29(d,J＝7.6Hz,1H),7.16(t,J＝7.6Hz,1H),7.11(d,J＝7.6Hz,1H),7.03(s,1H),7.00(d,J＝7.2Hz,1H),2.47(s,3H),2.30(s,3H).13C{1H}NMR(150MHz,CDCl3):δ153.6,147.2(q,2JC-F＝32.1Hz),145.0,138.02,137.97,135.7,132.1,130.7,130.6,130.4,129.8,129.5,129.0,128.6,128.23,128.21,127.5,127.1,126.5,122.4,121.6(q,1JC-F＝276.2Hz),113.7,100.3,83.1,21.6,21.2.19F NMR(565MHz,CDCl3):δ-66.16(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H19F3N 402.1464；Found 402.1454.
4-(3-Methoxyphenyl)-3-((3-methoxyphenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ah)
1H NMR(600MHz,CDCl3):δ8.25(d,J＝8.4Hz,1H),7.80-7.78(m,1H),7.73(d,J＝8.4Hz,1H),7.60-7.57(m,1H),7.50(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.11-7.09(m,1H),7.07-7.04(m,2H),6.87-6.84(m,2H),6.712-6.706(m,1H),3.85(s,3H),3.77(s,3H).13C{1H}NMR(100MHz,CDCl3):δ159.6,159.3,153.4,147.1(q,2JC-F＝32.5Hz),145.1,137.1,130.8,130.4,129.5,129.4,129.2,127.4,126.4,124.1,123.5,122.4,121.5(q,1JC-F＝274.8Hz),116.2,115.7,115.3,114.7,113.5,100.1,83.1,55.4,55.3.19F NMR(565MHz,CDCl3):δ-66.10(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H19F3NO2 434.1362；Found 434.1376.
4-(3-Fluorophenyl)-3-((3-fluorophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ai)
1H NMR(600MHz,CDCl3):δ8.27(d,J＝8.4Hz,1H),7.84-7.81(m,1H),7.67(d,J＝7.8Hz,1H),7.64-7.61(m,1H),7.58(td,J1＝7.8Hz,J2＝6.0Hz,1H),7.32-7.22(m,4H),7.04-7.02(m,2H),6.91-6.89(m,1H).13C{1H}NMR(150MHz,CDCl3):δ162.7(d,1JC-F＝245.7Hz),162.3(d,1JC-F＝245.4Hz),152.0,147.2(q,2JC-F＝32.7Hz),145.2,137.7(d,3JC-F＝9.3Hz),131.2,130.6,130.2(d,3JC-F＝9.0Hz),130.1(d,3JC-F＝8.7Hz),129.5,127.4(d,4JC-F＝3.0Hz),127.1,126.1,125.8(d,4JC-F＝3.5Hz),124.1(d,3JC-F＝9.2Hz),121.4(q,1JC-F＝276.2Hz),118.2(d,2JC-F＝22.7Hz),117.1(d,2JC-F＝21.5Hz),116.5(d,2JC-F＝22.4Hz),116.0(d,2JC-F＝20.7Hz),113.2,98.9(d,4JC-F＝2.1Hz),83.7.19F NMR(565MHz,CDCl3):δ-66.18(s),-112.31–-112.35(m),-112.49–-112.53(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H13F5N 410.0963；Found 410.0969.
4-(3-Chlorophenyl)-3-((3-chlorophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3aj)
1H NMR(400MHz,CDCl3):δ8.27(d,J＝8.8Hz,1H),7.85-7.81(m,1H),7.69-7.61(m,2H),7.60-7.53(m,3H),7.39-7.36(m,1H),7.32-7.29(m,1H),7.26-7.22(m,2H),7.14-7.12(m,1H).13C{1H}NMR(150MHz,CDCl3):δ151.8,147.2(q,2JC-F＝32.7Hz),145.2,137.4,134.5,134.3,131.3,131.2,130.6,130.0,129.8,129.7,129.6,129.4,129.2,128.2,127.0,126.1,123.9,121.4(q,1JC-F＝276.6Hz),113.1,98.9,84.0.19F NMR(376MHz,CDCl3):δ-66.17(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Cl2F3N 442.0372；Found 442.0380.4-(3-Bromophenyl)-3-((3-bromophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3ak)
1H NMR(600MHz,CDCl3):δ7.27(d,J＝8.4Hz,1H),7.84-7.82(m,1H),7.74(d,J＝7.8Hz,1H),7.70(t,J＝1.8Hz,1H),7.68(d,J＝7.2Hz,1H),7.65-7.62(m,1H),7.49(t,J＝7.8Hz,1H),7.46-7.44(m,1H),7.42(d,J＝7.8Hz,1H),7.39(s,1H),7.20-7.16(m,2H).13C{1H}NMR(150MHz,CDCl3):δ151.7,147.1(q,2JC-F＝32.6Hz),145.2,137.6,134.2,132.9,132.3,132.1,131.2,130.7,130.1,130.0,129.9,129.6,128.7,127.0,126.1,124.2,122.5,122.2,121.4(q,1JC-F＝275.0Hz),113.1,98.9,84.1.19F NMR(565MHz,CDCl3):δ-66.14(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Br2F3N 529.9361；Found 529.9372.
2-(Trifluoromethyl)-4-(3-(trifluoromethyl)phenyl)-3-((3-(trifluoromethyl)phenyl)ethynyl)quinoline(3al)
1H NMR(400MHz,CDCl3):δ8.30(d,J＝8.4Hz,1H),7.89-7.84(m,3H),7.76(t,J＝7.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.66-7.61(m,2H),7.56(d,J＝7.6Hz,1H),7.42(t,J＝8.0Hz,1H),7.39-7.36(m,2H).13C{1H}NMR(150MHz,CDCl3):δ151.9,147.2(q,2JC-F＝32.9Hz),145.3,136.5,134.4,133.3,131.4,131.3(q,2JC-F＝32.9Hz),131.1(q,2JC-F＝32.7Hz),130.8,129.8,129.1,129.0,128.2(q,3JC-F＝4.1Hz),126.94,126.93(q,3JC-F＝3.9Hz),125.861,125.862(q,3JC-F＝3.7Hz),125.7(q,3JC-F＝3.6Hz),123.9(q,1JC-F＝270.2Hz),123.5(q,1JC-F＝270.9Hz),123.0,121.4(q,1JC-F＝274.8Hz),113.1,98.8,84.1.19F NMR(565MHz,CDCl3):δ-62.61(s),-63.18(s),-66.18(s).HRMS(ESI)m/z:[M+H]+Calcd for C26H13F9N 510.0899；Found 510.0889.
4-(2-Fluorophenyl)-3-((2-fluorophenyl)ethynyl)-2-(trifluoromethyl)quinoline(3am)
1H NMR(600MHz,CDCl3):δ8.28(d,J＝8.4Hz,1H),7.83-7.81(m,1H),7.64-7.61(m,2H),7.59-7.55(m,1H),7.44(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.37(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.33-7.27(m,2H),7.23-7.21(m,1H),7.07-7.04(m,1H),7.01(t,J＝7.8Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ162.6(d,1JC-F＝252.6Hz),159.7(d,1JC-F＝247.4Hz),148.0,147.1(q,2JC-F＝32.7Hz),145.0,133.5,131.8(d,4JC-F＝2.7Hz),131.2(d,3JC-F＝8.4Hz),131.1,130.8(d,3JC-F＝7.5Hz),130.6,129.5,127.4,126.0,124.3(d,3JC-F＝3.5Hz),123.9(d,3JC-F＝4.5Hz),123.2(d,2JC-F＝15.9Hz),121.4(q,1JC-F＝275.3Hz),116.1(d,2JC-F＝21.5Hz),115.6(d,2JC-F＝20.6Hz),114.3,111.1(d,2JC-F＝15.9Hz),93.5,87.5(d,4JC-F＝2.1Hz).19F NMR(565MHz,CDCl3):δ-66.16(s),-108.80–-108.84(m),-112.85–-112.88(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H13F5N 410.0963；Found 410.0961.
4-(3,4-Dimethoxyphenyl)-3-((3,4-dimethoxyphenyl)ethynyl)-2-(trifluoromethyl)quinoline(3an)
1H NMR(600MHz,CDCl3):δ8.24(d,J＝8.4Hz,1H),7.80-7.77(m,2H),7.59(td,J1＝8.4Hz,J2＝0.6Hz,1H),7.11(d,J＝1.8Hz,1H),7.09(d,J＝8.4Hz,1H),7.05(dd,J1＝7.8Hz,J2＝1.8Hz,1H),6.89(dd,J1＝8.4Hz,J2＝1.8Hz,1H),6.78(d,J＝8.4Hz,1H),6.67(d,J＝1.8Hz,1H),4.00(s,3H),3.89(s,3H),3.88(s,3H),3.85(s,3H).13C{1H}NMR(150MHz,CDCl3):δ152.7,150.1,149.4,148.8,148.7,147.0(q,2JC-F＝32.3Hz),145.0,130.6,130.5,129.1,128.3,127.7,126.4,124.9,122.9,121.6(q,1JC-F＝275.1Hz),114.7,114.0,113.9,113.5,111.0,110.8,100.5,82.5,56.1,56.0,55.9,55.8.19F NMR(565MHz,CDCl3):δ-66.16(s).HRMS(ESI)m/z:[M+H]+Calcd for C28H23F3NO4 494.1574；Found 494.1578.
4-(Naphthalen-2-yl)-3-(naphthalen-2-ylethynyl)-2-(trifluoromethyl)quinoline(3ao)
1H NMR(400MHz,CDCl3):δ8.29(d,J＝8.8Hz,1H),8.08(d,J＝8.4Hz,1H),8.06(s,1H),8.03(d,J＝8.0Hz,1H),7.96(d,J＝8.0Hz,1H),7.82-7.78(m,1H),7.75(d,J＝8.4Hz,1H),7.70-7.52(m,7H),7.47(s,1H),7.42-7.40(m,2H),7.08(dd,J1＝8.4Hz,J2＝1.6Hz,1H).13C{1H}NMR(100MHz,CDCl3):δ153.4,147.3(q,2JC-F＝32.3Hz),145.1,133.34,133.30,133.1,133.0,132.7,131.8,130.9,130.6,129.7,129.3,128.4,128.1,128.0,127.95,127.86,127.73,127.70,127.6,127.1,127.0,126.8,126.6,126.5,121.7(q,1JC-F＝275.6Hz),119.7,113.9,100.8,83.9.19F NMR(376MHz,CDCl3):δ-65.99(s).HRMS(ESI)m/z:[M+H]+Calcd for C32H19F3N 474.1464；Found 474.1447.
4-(Thiophen-2-yl)-3-(thiophen-2-ylethynyl)-2-(trifluoromethyl)quinoline(3ap)
1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H),7.81-7.77(m,1H),7.66-7.60(m,2H),7.32-7.27(m,3H),7.17(dd,J1＝3.6Hz,J2＝0.8Hz,1H),6.98(dd,J1＝5.2Hz,J2＝3.6Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ146.8(q,2JC-F＝32.6Hz),145.9,144.9,135.0,132.9,131.0,130.5,130.3,129.5,128.8,128.09,128.06,127.3,127.2,126.2,122.4,121.4(q,1JC-F＝274.2Hz),114.5,94.4,87.1.19F NMR(565MHz,CDCl3):δ-66.27(s).HRMS(ESI)m/z:[M+H]+Calcd for C20H11F3NS2 386.0280；Found386.0284.
4-(Thiophen-3-yl)-3-(thiophen-3-ylethynyl)-2-(trifluoromethyl)quinoline(3aq)
1H NMR(600MHz,CDCl3):δ8.23(d,J＝8.4Hz,1H),7.85(d,J＝8.4Hz,1H),7.80-7.78(m,1H),7.62-7.59(m,2H),7.56(dd,J1＝4.8Hz,J2＝3.0Hz,1H),7.39(dd,J1＝3.0Hz,J2＝1.2Hz,1H),7.34(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.26(dd,J1＝4.8Hz,J2＝2.4Hz,1H),7.01(dd,J1＝5.4Hz,J2＝1.2Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ148.4,147.2(q,2JC-F＝32.1Hz),145.0,135.4,130.8,130.5,129.7,129.6,129.2,127.7,126.7,126.2,125.61,125.56,121.7,121.5(q,1JC-F＝275.7Hz),113.8,95.3,83.0.19F NMR(565MHz,CDCl3):δ-66.27(s).HRMS(ESI)m/z:[M+H]+Calcd for C20H11F3NS2 386.0280；Found 386.0266.2-(Difluoromethyl)-4-phenyl-3-(phenylethynyl)quinoline(3ar)
1H NMR(400MHz,CDCl3):δ8.24(d,J＝8.4Hz,1H),7.79-7.75(m,1H),7.69(d,J＝8.4Hz,1H),7.60-7.53(m,4H),7.51-7.49(m,2H),7.31-7.21(m,5H),7.19(t,J＝54.4Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ152.5,151.2(t,2JC-F＝22.5Hz),146.0,135.9,131.5,130.5,130.3,130.0,128.9,128.8,128.5,128.4,128.3,127.3,126.4,122.5,114.2,113.6(t,1JC-F＝240.0Hz),99.8,83.5.19F NMR(565MHz,CDCl3):δ-116.64(d,J＝55.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H16F2N 356.1245；Found 356.1238.
2-(Perfluoroethyl)-4-phenyl-3-(phenylethynyl)quinoline(3as)
1H NMR(600MHz,CDCl3):δ8.24(d,J＝8.4Hz,1H),7.80-7.77(m,1H),7.66(d,J＝7.8Hz,1H),7.61-7.57(m,4H),7.49-7.47(m,2H),7.31-7.25(m,3H),7.17-7.15(m,2H).13C{1H}NMR(150MHz,CDCl3):δ153.6,146.8(t,2JC-F＝25.5Hz),145.1,135.9,131.5,130.7,130.6,130.0,129.2,128.85,128.76,128.33,128.29,127.2,126.4,122.6,119.4(qt,1JC-F＝285.6Hz,2JC-F＝36.5Hz),114.6,112.4(tq,1JC-F＝256.2Hz,2JC-F＝35.4Hz),100.1,83.5.19F NMR(565MHz,CDCl3):δ-80.80(s),-110.88(s).HRMS(ESI)m/z:[M+H]+Calcd forC25H15F5N 424.1119；Found 424.1132.
实施例4
本发明所合成的产物氟代甲基取代喹啉类化合物可以进行一系列反应，合成进一步的衍生物，从而显示出其在有机合成上的重要应用价值。例如：氟代甲基取代喹啉类化合物可以在对甲苯磺酸存在下转变为氟代甲基取代的苯并菲啶类化合物4。
利用化合物3aa合成化合物4a的过程如下：
向反应管中加入3aa(74.7mg，0.2mmol)和对甲苯磺酸一水合物(1.14g,6.0mmol)，然后在空气氛围中密封试管，并置于120℃油浴中搅拌反应24小时。反应结束后，将所得混合物冷却至室温，用饱和碳酸氢钠水溶液中和，并用乙酸乙酯萃取，合并有机相，水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)，得到白色固体产物4a(66.7mg,89％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3):δ8.96(d,J＝8.4Hz,1H),8.86(d,J＝7.8Hz,1H),8.27(dd,J1＝7.8Hz,J2＝1.2Hz,1H),8.06(q,J＝1.8Hz,1H),7.95(dd,J1＝8.4Hz,J2＝0.6Hz,1H),7.71(td,J1＝6.6Hz,J2＝1.2Hz,1H),7.67(td,J1＝7.8Hz,J2＝1.2Hz,1H),7.60(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.56-7.54(m,1H),7.48-7.43(m,4H),7.40-7.37(m,1H).13C{1H}NMR(150MHz,CDCl3):δ145.7(q,2JC-F＝31.5Hz),143.8,141.0,139.7,133.6,133.2,131.0,130.0,129.2,129.0,128.9,128.8,128.7,128.1,127.2,127.07,127.06,125.1,122.3(q,1JC-F＝275.9Hz),121.7(q,4JC-F＝3.2Hz),120.6.19F NMR(565MHz,CDCl3):δ-62.36(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H15F3N 374.1151；Found374.1141.
实施例5
依照实施例4的方法和步骤a,b，通过改变化合物3-1，可以合成出各种苯并菲啶类化合物4，具体结果如下：
a反应条件：3(0.2mmol)，对甲苯磺酸一水合物(6.0mmol)，120℃，24h,空气氛围；b分离收率。
代表性产物表征数据如下：
2-Ethyl-8-phenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4b)
1H NMR(400MHz,CDCl3):δ9.05(d,J＝8.4Hz,1H),8.75(s,1H),8.24(d,J＝8.4Hz,1H),8.08(q,J＝2.4Hz,1H),8.00(dd,J1＝8.0Hz,J2＝0.4Hz,1H),7.70-7.66(m,1H),7.64-7.58(m,2H),7.52-7.45(m,4H),7.44-7.40(m,1H),2.90(q,J＝7.6Hz,2H),1.33(t,J＝7.6Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ144.3,143.8(q,2JC-F＝32.0Hz),141.4,139.7,138.7,132.5,131.9,129.7,128.9,128.8,128.3,127.8,127.6,127.5,127.0,126.0,125.9,124.4,124.1,121.4(q,1JC-F＝275.4Hz),120.7(q,4JC-F＝2.9Hz),119.6,28.5,14.6.19F NMR(376MHz,CDCl3):δ-62.31(d,J＝2.6Hz).HRMS(ESI)m/z:[M+H]+Calcd forC26H19F3N 402.1464；Found 402.1478.
2-Methoxy-8-phenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4c)
1H NMR(400MHz,CDCl3):δ9.22(d,J＝8.4Hz,1H),8.46(d,J＝2.8Hz,1H),8.33(d,J＝9.2Hz,1H),8.16(q,J＝2.0Hz,1H),8.10(dd,J1＝8.4Hz,J2＝0.8Hz,1H),7.79-7.74(m,1H),7.72-7.68(m,1H),7.62-7.56(m,4H),7.54-7.50(m,2H),4.06(s,3H).13C{1H}NMR(150MHz,CDCl3):δ160.0,143.3(q,2JC-F＝30.8Hz),141.0,139.7,139.4,133.5,132.5,132.2,130.0,129.5,128.7,128.5,128.05,128.01,127.2,126.9,126.5,122.5(q,1JC-F＝274.2Hz),121.8(q,4JC-F＝3.0Hz),121.0,119.4,107.9,55.9.19F NMR(376MHz,CDCl3):δ-62.21(d,J＝2.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H17F3NO 404.1257；Found404.1266.
2,8-Diphenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4d)
1H NMR(400MHz,CDCl3):δ9.23(d,J＝1.6Hz,1H),9.20(d,J＝8.4Hz,1H),8.48(d,J＝8.4Hz,1H),8.20(q,J＝2.0Hz,1H),8.11(dd,J1＝8.4Hz,J2＝2.0Hz,2H),7.81-7.77(m,3H),7.74-7.70(m,1H),7.63-7.53(m,7H),7.46(t,J＝7.2Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ145.5(q,2JC-F＝33.2Hz),143.1,141.7,141.1,140.5,139.7,133.7,133.3,131.3,130.0,129.3,129.2,128.8,128.73,128.71,128.5,128.14,128.09,127.7,127.24,127.19,125.43,125.41,122.3(q,1JC-F＝276.3Hz),121.7(q,4JC-F＝2.6Hz),120.9.19F NMR(376MHz,CDCl3):δ-62.40(d,J＝2.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C30H19F3N450.1464；Found 450.1477.
2-Fluoro-8-phenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4e)
1H NMR(400MHz,CDCl3):δ9.05(d,J＝8.4Hz,1H),8.68(dd,J1＝10.8Hz,J2＝2.8Hz,1H),8.39(dd,J1＝8.8Hz,J2＝5.6Hz,1H),8.17(q,J＝2.0Hz,1H),8.09(d,J＝8.4Hz,1H),7.80-7.76(m,1H),7.73-7.69(m,1H),7.62-7.53(m,6H).13C{1H}NMR(150MHz,CDCl3):δ162.5(d,1JC-F＝274.7Hz),145.1(q,2JC-F＝32.7Hz),141.8,140.7,139.5,133.5(d,3JC-F＝8.9Hz),133.4,132.5(d,4JC-F＝4.4Hz),130.0,129.2,128.8,128.7,128.2,128.1,127.5,127.3,126.3(d,3JC-F＝10.2Hz),122.2(q,1JC-F＝275.6Hz),121.6(q,4JC-F＝3.3Hz),120.9,118.4(d,2JC-F＝24.8Hz),111.8(d,2JC-F＝25.2Hz).19F NMR(376MHz,CDCl3):δ-62.50(s),-109.38–-109.45(m).HRMS(ESI)m/z:[M+H]+Calcd for C24H14F4N 392.1057；Found392.1060.
3-Methyl-8-phenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4f)
1H NMR(400MHz,CDCl3):δ9.11(d,J＝8.4Hz,1H),8.91(d,J＝8.4Hz,1H),8.20(s,1H),8.16(q,J＝2.0Hz,1H),8.08(d,J＝8.0Hz,1H),7.77-7.72(m,1H),7.70-7.63(m,2H),7.60-7.51(m,5H),2.65(s,3H).13C{1H}NMR(150 MHz,CDCl3):δ145.6(q,2JC-F＝32.1Hz),144.0,140.5,139.8,139.5,133.6,133.3,130.8,130.3,130.0,129.2,128.9,128.7,128.6,128.0,127.03,126.96,126.9,123.0,122.4(q,1JC-F＝275.9Hz),121.8(q,4JC-F＝3.2Hz),120.2,21.4.19F NMR(376MHz,CDCl3):δ-62.42(s).HRMS(ESI)m/z:[M+H]+Calcdfor C25H17F3N 388.1308；Found 388.1300.
3-Chloro-8-phenyl-6-(trifluoromethyl)benzo[k]phenanthridine(4g)
1H NMR(600MHz,CDCl3):δ9.03(d,J＝8.4Hz,1H),8.96(d,J＝9.0Hz,1H),8.40(d,J＝2.4Hz,1H),8.16(q,J＝1.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.80-7.76(m,2H),7.74-7.71(m,1H),7.59-7.56(m,4H),7.54-7.51(m,1H).13C{1H}NMR(150MHz,CDCl3):δ146.8(q,2JC-F＝32.9Hz),144.4,141.4,139.5,134.8,133.8,133.1,130.0,129.9,129.4,129.01,128.98,128.7,128.6,128.5,128.2,127.35,127.25,123.6,122.1(q,1JC-F＝275.3Hz),121.6(q,4JC-F＝2.9Hz),120.6.19F NMR(565MHz,CDCl3):δ-62.63(s).HRMS(ESI)m/z:[M+H]+Calcdfor C24H14ClF3N 408.0761；Found 408.0758.
5-Phenyl-7-(trifluoromethyl)dibenzo[b,k]phenanthridine(4h)
1H NMR(400MHz,CDCl3):δ9.50(s,1H),9.28(d,J＝8.4Hz,1H),8.92(s,1H),8.19-8.11(m,4H),7.83-7.78(m,1H),7.73-6.92(m,1H),7.66-7.52(m,7H).13C{1H}NMR(150MHz,CDCl3):δ146.8(q,2JC-F＝31.2Hz),140.9,140.8,139.8,133.8,133.0,132.9,132.8,130.1,129.6,129.3,128.7,128.58,128.56,128.52,128.47,128.1,127.3,127.13,127.11,127.0,123.0,122.12(q,1JC-F＝275.7Hz),122.08(q,4JC-F＝3.5Hz),119.8.19F NMR(376MHz,CDCl3):δ-62.97(s).HRMS(ESI)m/z:[M+H]+Calcd for C28H17F3N 424.1308；Found424.1298.
10-Chloro-8-(4-chlorophenyl)-6-(trifluoromethyl)benzo[k]phenanthridine(4i)
1H NMR(600MHz,CDCl3):δ9.05(d,J＝9.0Hz,1H),8.92(d,J＝8.4Hz,1H),8.41(dd,J1＝7.8Hz,J2＝1.2Hz,1H),8.17(q,J＝1.2Hz,1H),7.99(d,J＝2.4Hz,1H),7.89(td,J1＝6.6Hz,J2＝1.2Hz,1H),7.86-7.84(m,1H),7.72(dd,J1＝9.0Hz,J2＝2.4Hz,1H),7.57(d,J＝8.4Hz,2H),7.51(d,J＝7.8 Hz,2H).13C{1H}NMR(150MHz,CDCl3):δ145.6(q,2JC-F＝33.2Hz),144.0,138.8,137.4,135.3,134.6,134.5,133.1,131.20,131.16,130.5,129.5,129.2,127.8,127.6,127.0,125.8,124.7,123.0(q,4JC-F＝3.0 Hz),122.1(q,1JC-F＝275.6Hz),120.4.19F NMR(565MHz,CDCl3):δ-62.43(s).HRMS(ESI)m/z:[M+H]+Calcd forC24H13Cl2F3N 442.0372；Found 442.0366
10-Bromo-8-(4-bromophenyl)-6-(trifluoromethyl)benzo[k]phenanthridine(4j)
1H NMR(400MHz,CDCl3):δ8.97(d,J＝9.2 Hz,1H),8.91(d,J＝8.0Hz,1H),8.40(dd,J1＝8.0Hz,J2＝1.2Hz,1H),8.151-8.147(m,2H),7.90-7.82(m,3H),7.73(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H).13C{1H}NMR(150MHz,CDCl3):δ145.6(q,2JC-F＝33.2Hz),144.0,138.7,137.8,134.7,133.2,132.2,131.5,131.2,130.6,130.5,129.5,129.2,129.0,127.9,126.9,124.6,123.7,123.0(q,4JC-F＝3.2Hz),122.8,122.1(q,1JC-F＝276.3Hz),120.4.19F NMR(376MHz,CDCl3):δ-62.42(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Br2F3N529.9361；Found 529.9374
11-Chloro-8-(3-chlorophenyl)-6-(trifluoromethyl)benzo[k]phenanthridine(4k)
1H NMR(400MHz,CDCl3):δ9.12(d,J＝2.0Hz,1H),8.99-8.95(m,1H),8.44-8.42(m,1H),8.15(q,J＝2.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.93-7.88(m,2H),7.68(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.56(d,J＝0.8Hz,1H),7.52-7.51(m,2H),7.47-7.44(m,1H).13C{1H}NMR(100MHz,CDCl3):δ145.6(q,2JC-F＝32.9Hz),143.9,141.0,139.2,134.8,133.9,132.4,131.6,131.2,130.2,130.1,129.9,129.5,129.4,128.5,128.4,128.13,128.07,126.7,124.7,122.14(q,4JC-F＝3.4Hz),122.11(q,1JC-F＝275.5Hz),120.9.19F NMR(376MHz,CDCl3):δ-62.47(d,J＝2.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Cl2F3N442.0372；Found 442.0376.
9-Chloro-8-(3-chlorophenyl)-6-(trifluoromethyl)benzo[k]phenanthridine(4l)
1H NMR(400MHz,CDCl3):δ9.04(d,J＝8.4Hz,1H),8.91(d,J＝7.6Hz,1H),8.42(dd,J1＝8.4Hz,J2＝1.6Hz,1H),8.12(q,J＝1.6Hz,1H),7.91-7.83(m,2H),7.80(dd,J1＝7.6Hz,J2＝0.8Hz,1H),7.68(t,J＝8.0Hz,1H),7.43-7.38(m,3H),7.35-7.32(m,1H).13C{1H}NMR(100MHz,CDCl3):δ145.3(q,2JC-F＝32.8Hz),144.3,144.2,137.8,133.9,133.8,132.35,132.31,131.7,131.1,130.1,129.5,129.3,129.24,129.15,128.5,127.6,127.4,127.1,125.8(q,4JC-F＝3.3Hz),124.7,122.0(q,1JC-F＝275.4Hz),119.8.19F NMR(376MHz,CDCl3):δ-62.54(s).HRMS(ESI)m/z:[M+H]+Calcd for C24H13Cl2F3N 442.0372；Found442.0364.
实施例6
本发明提供化合物的抗癌活性是利用CCK-8法或者CellTiter-Glo法，通过对癌细胞的抗增殖活性研究来评估的。选择Hela、A-549和Ramos三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。
具体方法为，CCK-8法：首先，将Hela或A-549细胞以每孔4000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20μL的CCK-8，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。所有的实验均布施两个平行样品，并重复两次。
CellTiter-Glo法：将Ramos细胞悬浮液稀释至所需密度，取100μL至96孔板。用培养基配置不同浓度梯度的测试化合物，并分别取100μL添加到96孔板中。接着，将细胞在37℃，5％ CO2环境下孵育72小时。然后，向每个孔中添加20μL的CellTiter-Glo试剂。使用振荡器轻轻摇晃孔板2分钟以诱导细胞溶解，然后在室温下孵育10分钟以稳定发光信号。使用EnVision multilatelbel Reader(Perkinermer)测量各孔的荧光强度，并用GraphPadPrism 6.0软件计算出IC50值。所有实验均布施两个平行样品，并重复两次。
部分化合物的抗癌活性结果如下：
该活性结果表明，本发明提供的氟代甲基取代喹啉类化合物3以及其衍生合成的苯并菲啶类化合物4具有较强地抗癌活性。其中，氟代甲基取代喹啉类化合物3具有显著地抗A-549和Ramos癌细胞活性，特别是化合物3ea、3ga、3ka和3ad具有显著地抑制A-549和Ramos癌细胞增殖的作用，提示该类化合物对癌症特别是肺癌、淋巴癌的预防/治疗/抑制恶化进程的药用价值；
氟代甲基取代苯并菲啶类化合物4对Ramos癌细胞表现出较强的抗增殖活性，提示该类化合物对癌症特别是淋巴癌的预防/治疗/抑制恶化进程的药用价值。
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
1.一种氟代甲基取代喹啉类化合物，其特征在于，其化学结构通式为：
其中，R1为氢、一元或多元取代的C1-4烷基、C1-4烷氧基、C1-4烷硫基、苯基、卤素或亚乙基二氧基；或者R1与苯环共同组成萘环；
R2为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基；或者R2为苯基或取代的苯基时，喹啉4-位的R2与喹啉3位的炔基稠合为萘环或取代的萘环；
R3为氢、氟或三氟甲基。
2.如权利要求1所述的氟代甲基取代喹啉类化合物，其特征在于，R2为苯基或取代的苯基时，喹啉4-位的R2与喹啉3位的炔基稠合为萘环或取代的萘环，其化学结构通式为：
其中X为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基。
3.如权利要求1或2所述的氟代甲基取代喹啉类化合物，其特征在于，所述R3为氟；R1为氢，或6位或7位一元取代的SMe、Cl或F；R2为苯基、对位F取代的苯基、间位甲氧基取代的苯基或噻吩基；或者R2为苯基时，4-位的R2与3位的炔基稠合为萘环。
4.如权利要求3所述的氟代甲基取代喹啉类化合物，其特征在于，所述R2为苯基、对位F取代的苯基；或者R2为苯基时，4-位的R2与3位的炔基稠合为萘环。
5.如权利要求3或4所述的氟代甲基取代喹啉类化合物，其特征在于，其化学结构式为
6.如权利要求5所述的氟代甲基取代喹啉类化合物，其特征在于，其化学结构式为：
7.如权利要求1～6任一项所述化合物在制备抗癌药物方面的应用，其特征在于，所述化合物作为药物活性成分。
8.如权利要求7所述应用，其特征在于，所述抗癌药物对淋巴癌具有预防、治疗、抑制恶化进程的作用；所述抗癌药物的活性成分为如权利要求3～5任一项所述的化合物；
或者，所述抗癌药物对肺癌、淋巴癌具有预防、治疗、抑制恶化进程的作用，所述抗癌药物的活性成分为如权利要求6所述的化合物。
9.一种药物组合物，其特征在于，其活性成分为如权利要求1～6任一项所述化合物；
可选的，其活性成分为如权利要求3～5任一项所述的化合物；
可选的，其活性成分为如权利要求6所述的化合物。
10.一种如权利要求1所述化合物的合成方法，其特征在于，包括以N-芳基脒类化合物1、氟代甲基炔酮类化合物2为原料制备而成；
可选的，包括将N-芳基脒类化合物1、氟代甲基炔酮类化合物2、催化剂、添加剂和溶剂混合，升温反应制得氟代甲基取代喹啉类化合物3，反应方程式为：
其中，R1为氢、一元或多元取代的C1-4烷基、C1-4烷氧基、C1-4烷硫基、苯基、卤素或亚乙基二氧基，或者R1与苯环共同组成萘环；R2为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基；R3为氢、氟或三氟甲基；
可选的，还包括以化合物3-1为原料持续反应合成化合物4，反应方程式为：
其中，X为一元或多元取代的C1-4烷基、C1-4烷氧基、卤素或三氟甲基；
优选的，所述N-芳基脒类化合物1、氟代甲基炔酮类化合物2、催化剂、添加剂的投料摩尔比为1:1-2.5:0.03-0.05:1-3；
优选的，所述催化剂为二氯(五甲基环戊二烯基)合铑二聚体([RhCp*Cl2]2)；
优选的，所述添加剂为一水合醋酸铜、醋酸铜、1-金刚烷甲酸、苯甲酸、三甲基乙酸、2,4,6-三甲基苯甲酸或者两个及两个以上混合物；
优选的，所述溶剂为甲醇或乙醇；
优选的，所述反应温度为50-80℃；
优选的，所述气体氛围为空气或惰性气体氛围。
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