CN107266388A - 一种氨基噻唑类衍生物 - Google Patents
一种氨基噻唑类衍生物 Download PDFInfo
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- CN107266388A CN107266388A CN201610209655.9A CN201610209655A CN107266388A CN 107266388 A CN107266388 A CN 107266388A CN 201610209655 A CN201610209655 A CN 201610209655A CN 107266388 A CN107266388 A CN 107266388A
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- C07D277/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类氨基噻唑类杂环衍生物，其制备方法，以及在制备治疗或预防进行性认知障碍和/或记忆力缺失疾病的药物中的用途。
Description
技术领域
本发明属于有机合成与药物化学技术领域，涉及一类新的氨基噻唑类杂环衍生物，其制备方法，以及在制备治疗或预防进行性认知障碍和/或记忆力缺失疾病的药物中的用途。
背景技术
老年痴呆症又称阿尔茨海默病(Alzheimerc’s disease,AD),是一种慢性神经退行性或脑血管损伤等引起脑实质损害、脑功能失调或缺失的老年病症。AD患者脑组织的病理变化主要表现为脑的普遍萎缩,特别是与认知能力相关的区域(如海马及相应皮质部位)尤为明显,此区域的神经元和神经突触明显减少或消失,并且伴有典型特征性的神经细胞外淀粉样斑块和神经细胞内神经纤维缠结。
在老年人口中，AD患病率占总人口的4％～5％。在80岁以上的老年人中，患病率可占17％～20％。而我国人口老龄化问题日趋凸显。据统计，我国60岁以上的老年人口已达1.32亿，占全国人口的10.23％，预计到2040年我国老年人口将增至3.8亿，占全国人口的25％。随着老年人口的的快速增长，老年痴呆的发病率必然增加。因此，必须加快AD治疗药物的研发步伐，改善老年人的生活质量，减轻病患家属和社会压力。
从1906年阿尔茨海默发现该病以来,人们对AD的发病机理进行了广泛深入的研究,也开发了一些治疗药物，然而，研究和发现新的治疗药物依旧是临床需求所在。
发明内容
本发明涉及具有式(vii)的化合物或者其药学上可接收的盐，
其中，
R1独立选自氢、卤素、烷基、烷氧基、羟基、苯基、杂环基、烯基、卤素取代的烷基；
R2、R3各自独立地为氢、卤素、烷基、烷氧基、苯基、杂环基、环烷基，其中苯基可任选的被一个或多个独立选自以下的取代基取代：
氢、卤素、烷基、烷氧基、羟基、杂环基、环烷基、卤素取代的烷基；
n＝0、1、2、3、4、5。进一步的，R1为氯、溴、C1-10烷基、C1-10烷氧基、三氟甲基；R2、R3各自独立地为C1-10烷基、C1-10烷氧基、C3-8环烷基、苯基、杂环基，其中苯基任选的被一个或多个独立选自以下的取代基取代：氯、溴、C1-10烷基、C1-10烷氧基、杂环基、三氟甲基。
更进一步的，n＝0、1、2；R2、R3各自独立地为呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚、喹啉、蝶啶、吖啶、苯基，其中苯基可任选的被一个或多个独立选自以下的取代基取代：呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚、喹啉、蝶啶、吖啶。
本发明优选的化合物或者其药学上可接收的盐，其选自：
本发明的式(vii)的化合物可用于但不局限于治疗或预防进行性认知障碍和/或记忆力缺失疾病，特别是阿尔兹海默症。
本发明式(vii)的化合物可以单独地或者以药物组合物的形式给药于人患者，在药物组合物的情况中，它们以各种用于治疗或改善如本文中所述的疾病或状况的剂量混合以生物学合适的载体或赋形剂。
本发明式(vii)的化合物可以单独地或者以药物组合物的形式给药于人患者，在药物组合物的情况中，它们以各种用于治疗或改善如本文中所述的疾病或状况的剂量混合以生物学合适的载体或赋形剂。配制和给药本申请的化合物的技术可见于本领域技术人员众所周知的参考文献中。
适当的给药途径可以例如包括口服，眼药水，直肠，穿粘膜，局部，或肠给药；肠胃外输送，包括肌内，皮下，髓内注射，以及鞘内，直接心室内，静脉，腹内，鼻内，或眼球内注射。此外，可以在靶向药物输送系统中给药药物。
本发明的药物组合物可以以本身已知的方式制造，例如通过常规的混合，溶解，粒化，糖衣化，细磨，乳化，封装，捕集或冻干方法。
用于本发明的药物组合物可以以常规方式配制，使用一种或多种生理学可接受的载体，包括赋形剂和助剂，其促进将活性化合物加工成可以药用使用的制剂。适当的制剂取决于所选择的给药途径。
对于注射来说，本发明的药剂可以配制在水溶液中，优选地生理学相容的缓冲液如汉克斯氏液，林格氏液，或生理盐水缓冲液。对于穿粘膜给药来说，适合于待渗透的阻隔物的渗透剂用于制剂中。这样的渗透剂通常是本领域已知的。
对于口服来说，通过将活性化合物与本领域众所周知的药用可接受的载体结合，可以容易地配制化合物。这样的载体使得本发明的化合物能够被配制为片剂，丸剂，糖衣丸，胶囊，液体，凝胶，糖浆，淤浆，悬浮液等等，以便待治疗的患者口服摄取。用于口服使用的药物制剂可以通过下述方式获得，将活性化合物与固体赋形剂结合，任选地研磨所得的混合物，和加工颗粒混合物，之前添加适当的助剂，如果期望的话，以便获得片剂或糖衣丸芯。适当的赋形剂是，特别地，填料如糖，包括乳糖，蔗糖，甘露糖醇，或山梨糖醇；纤维素制剂，例如玉米淀粉，麦淀粉，米淀粉，马铃薯淀粉，明胶，黄蓍树胶，甲基纤维素，羟丙基甲基-纤维素，羧甲基纤维素钠，和/或聚乙烯吡咯烷酮(PVP)。如果期望的话，可以添加崩解剂，例如，交联的聚乙烯基吡咯烷酮，琼脂，或藻酸或其盐如藻酸钠。
糖衣丸芯具有适当的涂层。为此，可以使用浓缩糖液，其可以任选地包含阿拉伯树胶，滑石，聚乙烯基吡咯烷酮，卡巴浦尔凝胶，聚乙二醇，和/或二氧化钛，漆溶液，和适当的有机溶剂或溶剂混合物。染料或颜料可以加入片剂或糖衣丸涂层以便识别或表征活性化合物剂量的不同组合。
可以口服使用的药物制剂包括由明胶制成的硬胶囊，以及由明胶和增塑剂，如甘油或山梨糖醇制成的软密封胶囊。硬胶囊可以包含活性成分，混合以填料如乳糖，粘结剂如淀粉，和/或润滑剂如滑石或硬脂酸镁和，任选地稳定剂。在软胶囊中，活性化合物可以溶解或悬浮于适当的液体，如脂肪油，液状石蜡，或液体聚乙二醇中，另外，可以添加稳定剂。全部的口服制剂应当处于适用于这样的给药的剂量中。
对于通过吸入给药来说，用于本发明的化合物便利地以从加压包或雾化器的气溶胶喷射呈现的形式递送，借助于合适的推进剂，例如，二氯二氟甲烷，三氯氟甲烷，二氯四氟乙烷，二氧化碳或其他适合的气体。在加压气溶胶的情况下，剂量单位可以通过提供阀来确定，以便递送计量的数量。用于吸入器或吹入器的例如明胶的胶囊和药筒可以被配制，其包含化合物和合适的粉末基础材料如乳糖或淀粉的粉末混合物。
化合物可以被配制以便肠胃外给药，通过注射，例如弹丸注射或连续输注。用于注射的制剂可以以单位剂量形式存在，例如，在安瓿中或者在多剂量容器中，其中添加有防腐剂。组合物可以采取这样的形式如悬浮液，溶液或乳液，在油或水性赋形剂中，并且可以包含配制剂如悬浮、稳定和/或分散剂。
对于肠胃外给药的药物制剂包括水溶性形式的活性化合物的水溶液。另外，活性化合物的悬浮液可以被制备为合适的油性注射悬浮液。适当的亲油溶剂或赋形剂包括脂肪油如芝麻油，或合成脂肪酸酯，如油酸乙酯或甘油三酯，或脂质体。水性注射悬浮液可以包含这样的物质，其提高悬浮液的粘度，如羧甲基纤维素钠盐，山梨糖醇，或右旋糖酐。任选地，悬浮液还可包含适当的稳定剂或提高化合物的溶解性以便制备高浓度溶液的试剂。
备选地，可以使用疏水药用化合物用的其它输送系统。脂质体和乳液是疏水药物用的输送赋形剂或载体的众所周知的实例。某些有机溶剂如二甲亚砜也可以使用，尽管通常以更大的毒性为代价。另外，化合物可以使用持续释放系统来递送，如含治疗剂的固体疏水聚合物的半透性基质。各种的持续释放材料已经被证实并且是本领域技术人员众所周知的。
许多本发明的化合物可以以具有药用相容反离子的盐的形式提供。药用相容盐可以用许多酸形成，包括但不限于盐酸、硫酸、乙酸、乳酸、酒石酸、苹果酸、琥珀酸，等等。相比于相应的游离碱形式，盐往往更可溶于水性或其它质子溶剂。
本发明的式(vii)的化合物可与各种其他药剂组合以治疗或预防进行性认知障碍和/或记忆力缺失疾病，所述药剂例如胆碱酯酶抑制药、M胆碱受体激动药、脑代谢激活药、改善微循环药等，具体包括多奈哌齐、利凡斯的明、加兰他敏、他克林、美金刚、石杉碱甲、占诺美林、吡拉西坦、双氢麦角碱等。所述组合，其是本发明的一部分，可以是本发明的化合物和至少一种另外的选自以上列表的药剂。所述组合还可以包括多于一种的另外的药剂，例如，两或三种另外的药剂，条件是所述组合使得所形成的组合物可以通过试验证实或实现其预期功能。以上所述的药剂的目的在于举例说明，而非意图进行限制。
具体实施方式
合成路线1：
(X为氯或溴)
反应条件：a:硫氰酸胺,盐酸,水,80℃.b:甲苯，-25℃.c:对甲苯磺酸，N-卤代丁二酰亚胺，乙腈，80℃.d:乙醇，80℃
中间体化合物(i)的合成
向化合物i-a(0.5mol,1eq.)的水溶液(100ml)中加入5M盐酸(100ml,1eq.),搅拌至溶液澄清，然后向反应液中缓慢加入硫氰酸胺(0.5mol,1eq.)水溶液(100ml)，将反应液在80℃回流20h，冷却至室温，过滤并用水洗涤，得到目标化合物i。
中间体化合物(ii-c)的合成:
-25℃条件下，向化合物ii-a(0.5mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b(0.6mol,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c。
中间体化合物(ii)的合成：
向化合物ii-c(0.5mol,1eq.)的乙腈(50ml)溶液中加入对甲苯磺酸(0.75mol,1.5eq.)和N-卤代丁二酰亚胺(0.5mol,1eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii。
化合物(vii)的合成：
向化合物ii(0.5mol,1eq.)的乙醇(100ml)溶液中加入化合物i(0.75mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii。
合成路线2：
(X为氯或溴)
反应条件：e:N-卤代丁二酰亚胺,氯仿，-50℃.f:碳酸钠，醋酸钯，4,5-双二苯基膦-9,9-二甲基氧杂葸，N,N-二甲基甲酰胺，水，80℃.
中间体化合物iii-c的合成：
-25℃条件下，向化合物iii-a(0.5mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物iii-b(0.6mol,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物iii-c。
中间体化合物iii的合成：
向化合物iii-c(0.5mol,1eq.)的乙腈(50ml)溶液中加入对甲苯磺酸(0.75mol,1.5eq.)和N-卤代丁二酰亚胺(0.5mol,1eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物iii。
中间体化合物iv的合成：
向化合物iii(0.5mol,1eq.)的乙醇(100ml)溶液中加入化合物i(0.75mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物iv
中间体化合物v的合成：
-20℃条件下，向化合物iv(0.5mol,1eq.)的氯仿(50ml)溶液中缓慢加入N-卤代丁二酰亚胺(0.5mol,1eq.),将反应液在-20℃条件下搅拌6h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物v。
化合物vii的合成：
向化合物v(0.5mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,20ml)溶液中，加入化合物vi(2mol,4eq.)，碳酸钠(1.25mol,2.5eq.)，醋酸钯(0.05mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(0.15mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii。
实施例1：化合物1-(4-甲基苯基)硫脲的合成
向化合物i-a-1(5g,0.05mol,1eq.)的水溶液(10ml)中加入5M盐酸(9ml,1eq.),搅拌至溶液澄清，然后向反应液中缓慢加入硫氰酸胺(3.55g,0.05mol,1eq.)水溶液(10ml)，将反应液在80℃回流20h后，冷却至室温，过滤并用水洗涤，得到目标化合物i-1(产率90％)。Rf＝0.22(石油醚/乙酸乙酯＝5/1)；1H NMR(400MHz,DMSO)δ9.581(s,1H),7.230(d,J＝8Hz,2H),7.121(d,J＝8Hz,2H),2.267(s,3H)；LC/MS(ESR)m/z167.13[M+H]+
实施例2：化合物1-(2,6-二甲氧基苯基)硫脲的合成
向化合物i-a-2(5g,0.03mol,1eq.)的水溶液(10ml)中加入5M盐酸(6ml,1eq.),搅拌至溶液澄清，然后向反应液中缓慢加入硫氰酸胺(2.48g,0.05mol,1eq.)水溶液(10ml)，将反应液在80℃回流20h后，冷却至室温，过滤并用水洗涤，得到目标化合物i-2(产率92％)。Rf＝0.20(石油醚/乙酸乙酯＝5/1)；1H NMR(400MHz,CDCl3)δ7.694(s,1H),6.909(m,2H),6.757(m,1H),6.129(s,2H),3.819(s,3H),3.768(s,3H)；LC/MS(ESR)m/z213.19[M+H]+
实施例3：化合物1-(4-三氟甲基苯基)硫脲的合成
向化合物i-a-3(5g,0.03mol,1eq.)的水溶液(10ml)中加入5M盐酸(6ml,1eq.),搅拌至溶液澄清，然后向反应液中缓慢加入硫氰酸胺(2.48g,0.05mol,1eq.)水溶液(10ml)，将反应液在80℃回流20h后，冷却至室温，过滤并用水洗涤，得到目标化合物i-3(产率90％)。Rf＝0.20(石油醚/乙酸乙酯＝4/1)；1H NMR(400MHz,CDCl3)δ8.577(s,1H),7.701(d,J＝8Hz,2H),7.391(d,J＝8Hz,2H),6.297(s,2H)；LC/MS(ESR)m/z219.11[M-H]-
实施例4：化合物1-叔丁基硫脲的合成
向化合物i-a-4(5g,0.07mol,1eq.)的水溶液(10ml)中加入5M盐酸(14ml,1eq.),搅拌至溶液澄清，然后向反应液中缓慢加入硫氰酸胺(5.2g,0.07mol,1eq.)水溶液(10ml)，将反应液在80℃回流20h后，冷却至室温，过滤并用水洗涤，得到目标化合物i-4(产率89％)。1H NMR(400MHz,CDCl3)δ7.648(s,2H),1.270(s,9H)；LC/MS(ESR)m/z133.07[M+H]+
实施例5：化合物1-(3，4-二氯苯基)-1-戊酮的合成
-25℃条件下，向化合物ii-a-1(17g,0.1mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b-1(48ml,2.5M,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c-1(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝150/1)；1H NMR(400MHz,CDCl3)δ8.031(m,1H),7.782(m,1H),7.540(m,1H),2.921(t,J＝7.2Hz,2H),1.711(m,2H),1.410(m,2H),0.955(t,J＝7.2Hz,3H)；LC/MS(ESR)m/z229.08[M-H]-
实施例6：化合物1-苯基-1-戊酮的合成
-25℃条件下，向化合物ii-a-2(10.3g,0.1mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b-2(48ml,2.5M,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c-2(产率90％)。Rf＝0.20(石油醚/乙酸乙酯＝150/1)；1H NMR(400MHz,CDCl3)δ7.960(m,2H),7.552(m,1H),7.456(m,2H),2.966(t,J＝7.2Hz,2H),1.707(m,2H),1.406(m,2H),0.946(t,J＝7.2Hz,3H)；LC/MS(ESR)m/z163.19[M+H]+
实施例7：化合物1-(4-氯苯基)-1-戊酮的合成
-25℃条件下，向化合物ii-a-3(13.7g,0.1mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b-3(48ml,2.5M,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c-1(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝150/1)；1H NMR(600MHz,CDCl3)δ7.885(m,2H),7.411(m,2H),2.923(t,J＝7.2Hz,2H),1.702(m,2H),1.410(m,2H),0.943(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ199.225,139.224,135.353,129.437,128.808,38.251,26.334,22.394,13.872；LC/MS(ESR)m/z197.01[M+H]+
实施例8：化合物1-(3-氟-4-氯苯基)-1-戊酮的合成
-25℃条件下，向化合物ii-a-4(15.5g,0.1mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b-4(48ml,2.5M,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c-4(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝150/1)；1H NMR(400MHz,CDCl3)δ7.705(m,2H),7.481(m,1H),2.915(t,J＝7.2Hz,2H),1.707(m,2H),1.410(m,2H),0.949(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ197.142,159.412,156.924,137.320,126.274,124.385,124.347,116.078,115.866,38.324,26.362,13.865；LC/MS(ESR)m/z213.32[M-H]-
实施例9：化合物1-(3-氯苯基)-1-戊酮的合成
-25℃条件下，向化合物ii-a-5(13.7g,0.1mol,1eq.)的干燥甲苯(100ml)溶液中缓慢加入化合物ii-b-5(48ml,2.5M,1.2eq.)，-25℃条件下搅拌2h后，将反应液倒入冰水中，加入浓硫酸(3ml)，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-c-5(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝150/1)；1H NMR(400MHz,CDCl3)δ7.915(s,1H),7.825(m,1H),7.501(m,1H),7.394(m,1H),2.934(t,J＝7.2Hz,2H),1.711(m,2H),1.413(m,2H),0.950(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ199.141,138.624,134.876,132.759,129.869,128.169,126.098,38.398,26.260,22.383,13.878；LC/MS(ESR)m/z197.01[M+H]+
实施例10：化合物2-氯-1-(3，4-二氯苯基)-1-戊酮的合成
向化合物ii-c-1(23.0g,0.1mol,1.0eq.)的乙腈(100ml)溶液中加入对甲苯磺酸(25.8g,0.15mol,1.5eq.)和N-氯代丁二酰亚胺(13.4g,0.1mol,1.0eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-1(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝200/1)；1H NMR(400MHz,CDCl3)δ8.081(m,1H),7.835(m,1H),7.570(m,1H),4.985(m,1H),2.061(m,2H),1.573(m,1H),1.463(m,1H),1.248(m,3H)；13CNMR(100MHz,CDCl3)δ191.479,138.351,134.019,133.534,130.886,130.848,127.897,57.184,35.191,29.684,19.488,13.547；LC/MS(ESR)m/z263.10[M-H]-
实施例11：化合物2-溴-1-(3，4-二氯苯基)-1-乙酮的合成
向化合物ii-c-2(18.8g,0.1mol,1.0eq.)的乙腈(100ml)溶液中加入对甲苯磺酸(25.8g,0.15mol,1.5eq.)和N-溴代丁二酰亚胺(17.7g,0.1mol,1.0eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-2(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝40/1)；1H NMR(400MHz,CDCl3)δ8.075(m,1H),7.803(m,1H),7.585(m,1H),4.375(s,2H)；13C NMR(100MHz,CDCl3)δ189.286,138.715,133.435,130.992,130.909,127.943,29.919；LC/MS(ESR)m/z267.09[M+H]+
实施例12：化合物2-氯-1-(4-氯苯基)-1-戊酮的合成
向化合物ii-c-3(19.6g,0.1mol,1.0eq.)的乙腈(100ml)溶液中加入对甲苯磺酸(25.8g,0.15mol,1.5eq.)和N-氯代丁二酰亚胺(13.4g,0.1mol,1.0eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-3(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝200/1)；1H NMR(600MHz,CDCl3)δ7.930(m,2H),7.436(m,2H),5.036(m,1H),2.063(m,1H),1.975(m,1H),1.563(m,1H),1.454(m,1H),0.962(m,3H)；13CNMR(150MHz,CDCl3)δ190.373,140.113,132.755,130.257,129.023,57.311,35.331,19.459,13.481；LC/MS(ESR)m/z229.10[M-H]-
实施例13：化合物2-氯-1-(3-氟-4-氯苯基)-1-戊酮的合成
向化合物ii-c-4(21.4g,0.1mol,1.0eq.)的乙腈(100ml)溶液中加入对甲苯磺酸(25.8g,0.15mol,1.5eq.)和N-氯代丁二酰亚胺(13.4g,0.1mol,1.0eq.),将反应液在80℃回流5h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物ii-4(产率95％)。Rf＝0.20(石油醚/乙酸乙酯＝200/1)；1H NMR(600MHz,CDCl3)δ7.792(m,1H),7.737(m,1H),7.534(m,1H),4.988(m,1H),2.080(m,1H),2.014(m,1H),1.590(m,1H),1.466(m,1H),0.987(m,3H)；13C NMR(150MHz,CDCl3)δ191.475,159.043,157.372,134.687,134.648,131.085,127.283,127.161,125.252,125.229,117.006,116.860,57.219,35.254,19.497,13.527；LC/MS(ESR)m/z247.10[M-H]-
实施例14：化合物4-(3，4-二氯苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-2(26.6g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物iv-1(产率85％)。Rf＝0.20(石油醚/乙酸乙酯＝30/1)；1H NMR(600MHz,CDCl3)δ10.676(m,1H),7.842(m,1H),7.720(m,1H),7.560(m,1H),7.251(m,4H),6.684(s,1H),2.379(s,3H)；13C NMR(150MHz,CDCl3)δ168.293,140.458,137.538,134.418,133.790,131.560,130.755,128.180,127.628,125.145,121.298,100.160,21.061；LC/MS(ESR)m/z333.15[M-H]-
实施例15：化合物4-(3，4-二氯苯基)-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-1(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.09(s,1H),7.75(s,1H),7.68(d,J＝8.3Hz,1H),7.54(d,J＝8.3Hz,1H),7.45(d,J＝8.1Hz,2H),7.08(d,J＝8.1Hz,2H),2.74(t,J＝7.5Hz,2H),2.21(s,3H),1.58(m,2H),0.89(t,J＝7.2Hz,3H)；LC/MS(ESR)m/z377.23[M+H]+,379.23[M+H]+,380.23[M+H]+.
实施例16：化合物4-(3，4-二氯苯基)-5-丙基-N-(4-三氟甲基苯基)噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-3(33.0g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-2(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝30/1)；1H NMR(400MHz,CDCl3)δ7.703(d,J＝2Hz,1H),7.564(d,J＝8.8Hz,2H),7.479(d,J＝8.4Hz,1H),7.425(d,J＝8.4Hz,2H),7.419(d,J＝8Hz,1H),2.809(t,J＝8Hz,2H),1.691(m,2H),1.000(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ159.625,143.975,143.079,135.070,135.031,132.541,131.575,130.433,130.287,127.720,126.670,126.341,125.988,116.738,28.955,25.299,13.795；LC/MS(ESR)m/z431.19[M+H]+,433.18[M+H]+,435.18[M+H]+.
实施例17：化合物4-(3，4-二氯苯基)-N-(2，6-二甲氧基苯基)噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-2(31.8g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-3(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.760(d,J＝1.6Hz,1H),7.703(d,J＝2.8Hz,1H),7.467(m,2H),6.809(d,J＝9.2Hz,1H),6.489(dd,J＝8.8,2.8Hz,1H),3.862(s,3H),3.815(s,3H),2.804(t,J＝8Hz,2H),1.691(m,2H),0.994(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ159.886,154.107,143.692,141.576,135.491,132.380,131.153,130.701,130.425,130.180,127.582,125.068,110.867,105.441,103.180,56.300,55.687,28.985,25.276,13.803；LC/MS(ESR)m/z423.28[M+H]+,425.26[M+H]+,426.24[M+H]+.
实施例18：化合物N-丁基-4-(3，4-二氯苯基)-5-丙基噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-5(19.8g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-4(产率85％)。Rf＝0.20(石油醚/乙酸乙酯＝50/1)；1H NMR(600MHz,CDCl3)δ7.655(s,1H),7.436(d,J＝8.4Hz,1H),7.361(d,J＝8.4Hz,1H),5.090(s,1H),3.225(m,2H),2.713(t,J＝7.2Hz,2H),1.626(m,5H),1.410(m,2H),0.960(m,5H)；13C NMR(150MHz,CDCl3)δ168.622,143.868,135.783,132.270,130.954,130.402,130.065,127.674,123.436,45.792,31.530,29.062,25.268,20.019,13.765,13.726；LC/MS(ESR)m/z 343.24[M+H]+,345.24[M+H]+,347.26[M+H]+.
实施例19：化合物4-(3，4-二氯苯基)-N-苯基-5-丙基噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-6(22.8g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-5(产率80％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.621(d,J＝1.6Hz,1H),7.345(m,2H),7.237(m,4H),6.988(t,J＝7.2Hz,1H),2.698(t,J＝8Hz,2H),1.590(m,2H),0.908(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ161.717,143.692,140.297,135.346,132.410,131.291,130.418,130.188,129.421,127.743,124.517,123.045,118.301,28.947,25.261,13.780；LC/MS(ESR)m/z363.20[M+H]+,365.18[M+H]+,367.20[M+H]+.
实施例20：化合物4-苯基-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-5(19.6g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-6(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(600MHz,CDCl3)δ7.573(d,J＝7.8Hz,2H),7.398(t,J＝7.8Hz,2H),7.315(t,J＝7.8Hz,1H),7.149(d,J＝7.2Hz,2H),7.108(d,J＝7.2Hz,2H),2.784(t,J＝7.8Hz,2H),2.316(s,3H),1.670(m,2H),0.967(t,J＝5.2Hz,3H)；13C NMR(150MHz,CDCl3)δ162.139,146.045,138.143,135.445,132.564,129.874,128.617,128.257,127.329,122.945,118.730,29.001,25.391,20.754,13.811；LC/MS(ESR)m/z309.30[M+H]+,310.31[M+H]+,311.28[M+H]+.
实施例21：化合物4-(3,4-二氯苯基)-N-(4-甲氧基苯基)-5-丙基噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-7(27.3g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-7(产率70％)。Rf＝0.20(石油醚/乙酸乙酯＝30/1)；1H NMR(600MHz,CDCl3)δ7.653(s,1H),7.388(m,2H),7.189(d,J＝8.4Hz 2H),6.864(d,J＝8.4Hz,2H),3.813(s,3H),2.714(t,J＝7.2Hz,2H),1.637(m,6H),0.951(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ164.215,156.497,143.676,135.399,133.598,132.364,131.191,130.394,130.133,127.727,123.818,122.293,114.668,55.533,28.939,25.214,13.756；LC/MS(ESR)m/z393.05[M+H]+,394.05[M+H]+,396.05[M+H]+.
实施例22：化合物4-(3-氟-4-氯苯基)-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-4(24.8g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-8(产率70％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(600MHz,CDCl3)δ7.393(m,2H),7.311(m,1H),7.184(d,J＝8.4Hz 2H),7.140(d,J＝8.4Hz,2H),2.764(t,J＝7.2Hz2H),2.332(s,3H),1.659(m,2H),0.973(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ162.261,157.889,143.837,137.836,135.997,135.943,133.054,130.295,129.973,124.808,124.792,124.271,119.765,119.650,118.960,116.699,116.554,29.001,25.230,20.793,13.803；LC/MS(ESR)m/z361.27[M+H]+,363.28[M+H]+,364.28[M+H]+.
实施例23：化合物4-(4-氯苯基)-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-3(23.0g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-9(产率70％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.510(m,2H),7.360(m,2H),7.185(m,4H),2.756(t,J＝8Hz,2H),2.329(s,3H),1.650(m,2H),0.963(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ162.083,144.823,137.935,133.846,133.171,132.890,129.969,129.833,128.467,123.505,118.809,29.023,25.305,20.784,13.804；LC/MS(ESR)m/z343.27[M+H]+,345.27[M+H]+,346.27[M+H]+.
实施例24：化合物4-(3-氯-4-氟苯基)-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-6(24.8g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-10(产率70％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.630(m,1H),7.420(m,1H),7.158(m,5H),2.741(t,J＝8Hz,2H),2.329(s,3H),1.650(m,2H),0.963(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ162.083,158.593,143.823,137.935,133.019,132.662,130.750,129.969,128.247,128.179,123.687,120.918,118.946,116.404,116.195,29.023,25.260,20.784,13.774；LC/MS(ESR)m/z361.28[M+H]+,363.32[M+H]+,364.32[M+H]+
实施例25：化合物4-(3，4-二氯苯基)-5-丙基-N-(3，5-二甲基苯基)噻唑-2-胺的合成
向化合物ii-1(26.4g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-8(27.0g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-11(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.704(m,1H),7.470(m,1H),7.200(m,1H),6.902(s,2H),6.722(s,1H),2.772(t,J＝8Hz,2H),2.320(s,3H),1.680(m,2H),1.254(s,2H),0.963(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ161.848,143.572,140.188,139.293,135.409,132.404,131.221,130.394,130.189,127.670,124.985,124.484,116.131,28.690,28.993,25.275,21.421,13.797；LC/MS(ESR)m/z391.29[M+H]+,393.23[M+H]+,395.26[M+H]+.
实施例26：化合物4-(3-氯苯基)-5-丙基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-7(23.0g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-12(产率75％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.575(m,1H),7.449(m,1H),7.314(m,2H),7.140(m,4H),2.765(t,J＝8Hz,2H),2.321(s,3H),1.650(m,2H),0.966(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ162.280,144.664,137.935,137.207,134.180,132.890,129.969,129.468,128.672,127.382,126.646,123.961,118.878,28.947,25.298,20.769,13.774；LC/MS(ESR)m/z343.31[M+H]+,345.27[M+H]+,346.27[M+H]+.
实施例27：化合物4-(4-氯苯基)-5-甲基-N-(3,5-二甲基苯基)噻唑-2-胺的合成
向化合物ii-8(20.2g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-8(27.0g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-13(产率80％)。Rf＝0.20(石油醚/乙酸乙酯＝15/1)；1H NMR(400MHz,CDCl3)δ7.580(m,2H),7.540(s,1H),7.380(m,2H),6.864(s,2H),6.712(s,1H),2.450(s,3H),2.307(s,6H)；13C NMR(100MHz,CDCl3)δ161.848,140.346,139.200,133.632,129.641,128.443,124.763,115.993,21.389,12.338；LC/MS(ESR)m/z329.29[M+H]+,331.23[M+H]+,332.26[M+H]+.
实施例28：化合物4-(3,4-二氯苯基)-5-甲基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物ii-9(23.6g,0.1mol,1eq.)的乙醇(100ml)溶液中加入化合物i-1(24.9g,0.15mol,1.5eq.)，将反应液在80℃回流12h后，通过硅胶柱色谱分离得到目标化合物vii-14(产率80％)。Rf＝0.20(石油醚/乙酸乙酯＝15/1)；1H NMR(400MHz,CDCl3)δ7.725(m,1H),7.440(m,2H),7.159(m,4H),2.419(s,3H),2.324(s,3H)；13C NMR(100MHz,CDCl3)δ161.908,143.875,137.814,135.196,133.064,132.404,131.122,130.159,129.977,127.519,118.916,117.755,20.784,12.378；LC/MS(ESR)m/z349.29[M+H]+,351.23[M+H]+,353.26[M+H]+.
实施例29：化合物5-溴-4-(3，4-二氯苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
-20℃条件下，向化合物iv-1(33.4g,0.1mol,1eq.)的氯仿(100ml)溶液中缓慢加入N-溴代丁二酰亚胺(17.7g,0.1mol,1eq.),将反应液在-20℃条件下搅拌6h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物v-1(产率87％)。Rf＝0.20(石油醚/乙酸乙酯＝50/1)；1H NMR(400MHz,CDCl3)δ8.048(m,1H),7.850(m,1H),7.480(m,1H),7.190(m,4H),2.350(s,3H)；13C NMR(100MHz,CDCl3)δ164.888,145.748,136.872,134.384,133.420,132.411,132.183,130.211,130.128,127.495,119.810,91.164,29.691,20.845；LC/MS(ESR)m/z410.10[M-H]-
实施例30：化合物5-氯-4-(3，4-二氯苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
-20℃条件下，向化合物iv-1(33.4g,0.1mol,1eq.)的氯仿(100ml)溶液中缓慢加入N-氯代丁二酰亚胺(13.4g,0.1mol,1eq.),将反应液在-20℃条件下搅拌6h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物v-1(产率85％)。Rf＝0.20(石油醚/乙酸乙酯＝50/1)；1H NMR(400MHz,CDCl3)δ8.043(m,1H),7.785(m,1H),7.460(m,1H),7.243(s,1H),7.168(M,4H),2.346(s,3H)；13C NMR(100MHz,CDCl3)δ161.772,143.139,136.896,134.316,132.973,132.480,132.040,130.227,129.931,127.223,119.758,108.997,20.845；LC/MS(ESR)m/z367.12[M-H]-,369.16[M-H]-,370.99[M-H]-.
实施例31：化合物4-(3，4-二氯苯基)-5-苯基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-1(4.9g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-15(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,CDCl3)δ7.672(s,1H),7.466(s,1H),7.280(m,6H),7.175(m,4H),2.340(s,3H)；13C NMR(100MHz,CDCl3)δ163.710,142.987,137.469,135.031,133.591,132.387,131.721,131.468,130.678,130.073,130.027,129.467,128.847,128.027,127.935,122.401,119.351,20.816；LC/MS(ESR)m/z409.26[M-H]-,411.26[M-H]-,412.10[M-H]-
实施例32：化合物4-(3，4-二氯苯基)-5-(4-吡啶基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-2(4.9g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-16(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.364(s,1H),8.530(m,2H),7.636(m,1H),7.534(m,2H),7.424(m,2H),7.357(m,2H),7.149(m,2H),2.266(s,3H)；13C NMR(100MHz,DMSO)δ162.305,149.193,148.081,138.193,136.755,135.145,131.087,130.879,130.689,130.356,129.491,128.482,123.854,117.504,20.352；LC/MS(ESR)m/z412.25[M+H]+,414.25[M+H]+,415.25[M+H]+.
实施例33：化合物化合物4-(3，4-二氯苯基)-5-(3-氟苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-3(5.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-17(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.322(s,1H),7.613(m,2H),7.500(m,2H),7.414(m,2H),7.199(m,5H),1.989(s,3H)；13C NMR(100MHz,DMSO)δ163.848,162.346,161.413,143.410,138.707,135.702,134.177,134.094,131.636,131.533,131.454,131.279,131.059,130.718,130.521,129.952,128.958,126.068,126.045,120.613,120.590,117.935,116.539,116.319,115.492,115.287,20.820；LC/MS(ESR)m/z429.25[M+H]+,431.25[M+H]+,432.25[M+H]+.
实施例34：化合物化合物4-(3，4-二氯苯基)-5-(4-氟苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-4(5.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-18(产率51％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.232(s,1H),7.555(m,2H),7.470(m,2H),7.330(m,3H),7.209(m,2H),7.110(m,2H),2.227(s,3H)；13C NMR(100MHz,DMSO)δ163.470,162.013,161.019,142.774,138.787,135.702,132.107,131.425,131.144,131.022,130.491,130.362,129.930,128.807,128.193,121.061,117.852,116.676,116.456,20.814；LC/MS(ESR)m/z429.25[M+H]+,431.25[M+H]+,432.25[M+H]+.
实施例35：化合物化合物4-(3，4-二氯苯基)-5-(2-氟苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-5(5.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-19(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.323(s,1H),7.560(m,4H),7.472(m,2H),7.328(m,3H),7.170(m,2H),2.267(s,3H)；13C NMR(100MHz,DMSO)δ162.470,162.013,160.628,144.174,138.238,135.431,132.503,131.038,130.947,130.811,130.591,130.112,129.480,129.127,127.594,125.144,119.059,118.908,117.481,116.442,116.222,113.855,20.344；LC/MS(ESR)m/z429.25[M+H]+,431.25[M+H]+,432.25[M+H]+.
实施例36：化合物化合物4-(3，4-二氯苯基)-5-(4-甲氧基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-6(6.1g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-20(产率56％)。Rf＝0.20(石油醚/乙酸乙酯＝25/1)；1H NMR(400MHz,DMSO)δ10.173(s,1H),7.625(m,1H),7.540(m,1H),7.490(m,2H),7.373(m,1H),7.240(m,2H),7.120(m,2H),6.941(m,2H),3.758(s,3H),2.237(s,3H)；13C NMR(100MHz,DMSO)δ161.081,159.124,141.356,138.413,135.621,130.864,130.720,130.462,129.749,129.438,128.186,123.194,121.950,117.277,114.561,55.204,20.337；LC/MS(ESR)m/z441.31[M+H]+,443.25[M+H]+,445.30[M+H]+.
实施例37：化合物化合物4-(3，4-二氯苯基)-5-(3-甲氧基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-7(6.1g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-21(产率53％)。Rf＝0.20(石油醚/乙酸乙酯＝25/1)；1H NMR(400MHz,DMSO)δ10.259(s,1H),7.630(m,1H),7.538(m,1H),7.430(m,2H),7.362(m,1H),7.230(m,2H),7.121(m,2H),6.801(m,2H),3.708(s,3H),2.263(s,3H)；13C NMR(100MHz,DMSO)δ161.491,159.450,142.107,138.321,135.477,132.548,130.841,130.662,130.454,130.227,129.961,129.908,129.445,128.383,121.586,117.375,114.667,113.756,55.098,20.337；LC/MS(ESR)m/z441.31[M+H]+,443.25[M+H]+,445.30[M+H]+.
实施例38：化合物化合物4-(3，4-二氯苯基)-5-(2-甲氧基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-8(6.1g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-22(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝25/1)；1H NMR(400MHz,DMSO)δ10.182(s,1H),7.581(m,1H),7.524(m,3H),7.389(m,2H),7.225(m,1H),7.135(m,3H),6.968(m,1H),3.678(s,3H),2.260(s,3H)；13C NMR(100MHz,DMSO)δ162.037,156.916,142.949,138.488,135.909,131.903,130.697,130.424,130.287,129.498,129.430,128.967,127.480,120.865,119.765,117.861,117.269,111.996,55.439,20.329；LC/MS(ESR)m/z441.31[M+H]+,443.25[M+H]+,445.30[M+H]+.
实施例39：化合物化合物4-(3，4-二氯苯基)-5-(3-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-9(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-23(产率52％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.240(s,1H),7.643(m,1H),7.530(m,3H),7.390(m,1H),7.262(m,1H),7.175(m,4H),7.090(m,1H),2.290(s,3H),2.260(s,3H)；13C NMR(100MHz,DMSO)δ161.899,142.288,138.898,138.829,135.976,131.683,131.326,131.091,130.916,130.287,130.233,129.930,129.414,129.308,128.754,126.933,122.457,117.822,21.324,20.814；LC/MS(ESR)m/z425.31[M+H]+,427.25[M+H]+,428.30[M+H]+.
实施例40：化合物化合物4-(3，4-二氯苯基)-5-(4-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-10(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-24(产率59％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.225(s,1H),7.660(m,1H),7.540(m,3H),7.390(m,1H),7.216(m,4H),7.141(m,2H),2.323(s,3H),2.261(s,3H)；13C NMR(100MHz,DMSO)δ161.786,142.138,138.852,138.085,136.075,131.364,131.038,130.931,130.317,130.127,129.915,129.649,128.762,122.480,117.807,51.258,21.246,20.814；LC/MS(ESR)m/z425.31[M+H]+,427.25[M+H]+,428.30[M+H]+.
实施例41：化合物化合物4-(3，4-二氯苯基)-5-(4-氯苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-11(6.2g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-25(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.281(s,1H),7.636(m,1H),7.575(m,1H),7.490(m,2H),7.430(m,2H),7.330(m,3H),7.130(m,2H),2.239(s,3H)；13C NMR(100MHz,DMSO)δ162.641,143.199,138.715,135.764,133.094,131.493,131.242,131.091,130.765,130.681,130.507,129.945,129.573,128.936,120.766,117.913,20.821；LC/MS(ESR)m/z445.23[M+H]+,447.23[M+H]+,449.23[M+H]+.
实施例42：化合物化合物4-(3，4-二氯苯基)-5-(1-萘基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-12(6.9g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-26(产率51％)。Rf＝0.20(石油醚/乙酸乙酯＝30/1)；1H NMR(400MHz,DMSO)δ10.306(s,1H),8.030(m,2H),7.740(m,1H),7.608(m,5H),7.530(m,2H),7.375(m,1H),7.185(m,3H),2.263(s,3H)；13C NMR(150MHz,DMSO)δ162.130,143.315,138.387,135.169,133.452,131.659,130.754,130.624,130.386,129.658,129.620,129.490,129.421,128.854,128.562,128.432,127.160,126.493,125.834,124.868,119.097,117.373,20.356；LC/MS(ESR)m/z461.28[M+H]+,463.28[M+H]+,465.28[M+H]+
实施例43：化合物化合物4-(3，4-二氯苯基)-5-(2-噻吩基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-13(5.1g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-27(产率60％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.305(s,1H),7.700(m,1H),7.636(m,1H),7.575(m,1H),7.495(m,3H),7.109(m,4H),2.249(s,3H)；13C NMR(100MHz,DMSO)δ161.619,143.677,138.109,135.135,131.827,130.940,130.902,130.598,130.477,130.083,129.468,128.596,128.413,127.920,127.594,117.557,114.174,20.344；LC/MS(ESR)m/z417.27[M+H]+,419.25[M+H]+,421.25[M+H]+.
实施例44：化合物化合物4-(3，4-二氯苯基)-5-(2-萘基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-14(6.9g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-28(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.303(s,1H),7.908(m,4H),7.691(m,1H),7.528(m,5H),7.369(m,2H),7.150(m,2H),2.255(s,3H)；13C NMR(150MHz,DMSO)δ161.701 142.311,138.326,135.506,133.046,132.195,130.946,130.708,130.501,130.049,129.980,129.470,128.808,128.493,128.409,128.072,127.873,127.612,126.999,126.738,126.623,121.810,117.434,20.346；LC/MS(ESR)m/z461.32[M+H]+,463.32[M+H]+,465.32[M+H]+
实施例45：化合物化合物4-(3，4-二氯苯基)-5-(3-噻吩基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-15(5.1g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-29(产率61％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(600MHz,DMSO)δ10.237(s,1H),7.637(m,3H),7.570(m,1H),7.508(m,2H),7.451(m,1H),7.145(m,2H),6.985(m,1H),1.986(s,3H)；13C NMR(150MHz,DMSO)δ161.103,142.342,138.326,135.582,130.885,130.616,130.517,130.018,129.712,129.444,128.233,128.011,127.528,124.830,117.350,116.706,20.344；LC/MS(ESR)m/z417.24[M+H]+,419.25[M+H]+,421.25[M+H]+.
实施例46：化合物4-(3，4-二氯苯基)-5-(2-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-16(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-30(产率51％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.225(s,1H),7.501(m,4H),7.326(m,5H),7.151(m,2H),2.253(s,3H),2.071(s,3H)；13C NMR(150MHz,DMSO)δ161.686,142.181,138.403,137.299,135.437,131.191,130.885,130.708,130.601,130.547,130.509,129.649,129.451,129.191,128.547,126.976,126.616,120.714,117.273,20.340,19.620；LC/MS(ESR)m/z425.31[M+H]+,427.35[M+H]+,428.30[M+H]+.
实施例47：化合物4-(3，4-二氯苯基)-5-(2-吡咯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-17(4.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-31(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝15/1)；1H NMR(400MHz,DMSO)δ11.021(s,1H),10.171(s,1H),7.562(m,2H),7.505(m,2H),7.453(m,1H),7.130(m,2H),6.854(s,1H),6.123(s,2H),2.250(s,3H)；13C NMR(150MHz,DMSO)δ161.065,142.181,138.395,135.567,130.770,130.494,129.453,129.436,129.045,127.589,119.734,119.588,117.243,114.652,109.832,108.989,20.333；LC/MS(ESR)m/z400.26[M+H]+,402.30[M+H]+,403.13[M+H]+.
实施例48：化合物4-(3，4-二氯苯基)-5-(5-嘧啶基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-18(5.0g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-32(产率52％)。Rf＝0.20(石油醚/乙酸乙酯＝15/1)；1H NMR(400MHz,DMSO)δ10.441(s,1H),9.115(s,1H),8.729(s,2H),7.685(s,1H),7.600(d,J＝8Hz,1H),7.511(d,J＝8Hz,2H),7.362(d,J＝8Hz,1H),7.155(d,J＝8Hz,2H),2.250(s,3H)；13C NMR(150MHz,DMSO)δ163.130,157.029,156.569,145.173,138.076,134.796,131.294,131.133,130.849,130.757,130.297,129.546,128.650,126.680,117.675,113.881,20.374；LC/MS(ESR)m/z413.26[M+H]+,415.26[M+H]+,416.26[M+H]+.
实施例49：化合物4-(3-[3,-甲基苯基]-4-氯苯基)-5-(3-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-3(4.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-9(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-33(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝25/1)；1H NMR(400MHz,DMSO)δ10.20(s,1H),7.52(m,4H),7.27(m,3H),7.10(m,7H),6.94(s,1H),2.27(m,9H)；13C NMR(150MHz,DMSO)δ161.78,138.77,132.22,131.60,130.93,130.55,130.36,130.35,129.95,129.88,129.40,129.17,129.07,128.84,128.39,127.12,126.55,117.73,109.98,21.35,31.32,20.81；LC/MS(ESR)m/z481.14[M+H]+,483.14[M+H]+,484.14[M+H]+.
实施例50：化合物4-(3，4-二氯苯基)-5-(3,5-二氯苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-20(7.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-34(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.355(s,1H),7.681(s,1H),7.596(m,3H),7.491(d,J＝8Hz,2H),7.342(d,J＝8Hz,1H),7.256(d,J＝8Hz,1H),7.132(d,J＝8Hz,2H),2.243(s,3H)；13C NMR(150MHz,DMSO)δ162.57,144.05,138.60,132.65,132.06,131.58,131.38,131.20,131.12,130.91,130.64,129.97,129.02,119.18,117.97,20.83；LC/MS(ESR)m/z479.31[M+H]+,481.35[M+H]+,482.30[M+H]+.
实施例51：化合物4-(3，4-二氯苯基)-5-吗啉基-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-21(5.2g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-35(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝30/1)；1H NMR(400MHz,DMSO)δ9.99(s,1H),8.37(s,1H),8.10(d,J＝8Hz,1H),7.65(d,J＝8Hz,1H),7.47(d,J＝8Hz,2H),7.10(d,J＝8Hz,2H),3.72(m,4H),2.78(m,4H),2.242(s,3H)；13C NMR(150MHz,DMSO)δ157.92,140.15,138.97,136.36,135.22,131.37,131.06,130.81,129.84,129.39,129.03,127.67,117.77,66.70,55.14,20.80；LC/MS(ESR)m/z420.06[M+H]+,422.06[M+H]+,423.06[M+H]+.
实施例52：化合物4-(3，4-二氯苯基)-5-[5-(1,3-苯并二氧戊环)基]-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-22(6.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-36(产率52％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.20(s,1H),7.66(m,1H),7.57(d,J＝8Hz,1H),7.50(d,J＝8Hz,2H),7.39(m,1H),7.13(d,J＝8Hz,2H),6.94(d,J＝8Hz,1H),6.87(m,1H),6.82(m,1H),6.06(s,2H),2.25(s,3H)；13C NMR(150MHz,DMSO)δ161.56,148.16,147.75,142.13,138.86,135.93,131.38,131.00,130.93,130.28,129.91,128.69,125.10,123.89,122.24,117.74,110.11,109.38,101.89,20.83；LC/MS(ESR)m/z455.31[M+H]+,457.35[M+H]+,459.30[M+H]+.
实施例53：化合物4-(3，4-二氯苯基)-5-(3,5-二甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-23(6.0g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-37(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.20(s,1H),7.67(s,1H),7.53(m,3H),7.39(d,J＝8Hz,1H),7.14(d,J＝8Hz,2H),6.99(s,1H),6.95(s,2H),2.24(m,9H)；13C NMR(150MHz,DMSO)δ161.72,142.02,138.84,138.67,135.95,131.57,131.29,131.02,130.84,130.26,130.21,130.13,129.91,128.64,127.42,122.61,117.77,21.21,20.83；LC/MS(ESR)m/z455.31[M+H]+,457.35[M+H]+,459.30[M+H]+.
实施例54：化合物4-(3，4-二氯苯基)-5-(4-三氟甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-24(7.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-38(产率50％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.37(s,1H),7.70(d,J＝8Hz,2H),7.65(s,1H),7.59(d,J＝8Hz,1H),7.50(m,4H),7.34(m,1H),7.14(d,J＝8Hz,2H),2.24(s,3H)；13C NMR(150MHz,DMSO)δ162.74,144.21,138.64,136.24,135.67,131.60,131.49,131.16,130.99,130.70,130.21,129.95,129.11,128.42,128.21,126.36,126.33,125.43,123.63,120.28,118.02,20.83；LC/MS(ESR)m/z479.03[M+H]+,481.03[M+H]+,482.03[M+H]+.
实施例55：化合物4-(3，4-二氯苯基)-5-(2-氟-3-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-25(6.2g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-39(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.28(s,1H),7.60(s,1H),7.52(m,3H),7.33(m,2H),7.19(m,1H),7.11(m,3H),2.23(m,6H)；13CNMR(150MHz,DMSO)δ162.97,158.96,157.33,144.41,138.70,135.87,132.70,132.66,131.40,131.26,131.00,130.51,130.36,129.95,129.61,128.05,119.17,119.06,117.92,114.76,20.81,14.71,14.69；LC/MS(ESR)m/z443.03[M+H]+,445.03[M+H]+,446.03[M+H]+.
实施例56：化合物4-(3，4-二氯苯基)-5-(1-哌嗪基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-2(3.7g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-26(5.2g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-40(产率50％)。Rf＝0.10(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ9.96(s,1H),8.44(s,1H),8.09(d,J＝8Hz,1H),7.66(d,J＝8Hz,1H),7.49(d,J＝8Hz,2H),7.11(d,J＝8Hz,2H),2.85(m,4H),2.71(m,4H),2.24(s,3H)；13C NMR(100MHz,DMSO)δ157.14,141.36,139.02,135.64,135.47,131.46,131.00,130.76,129.89,129.22,128.81,127.55,117.23,56.42,46.21,20.88；LC/MS(ESR)m/z419.08[M+H]+,421.08[M+H]+,422.08[M+H]+.
实施例57：化合物4-(3，4-二氯苯基)-5-(3-三氟甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-1(4.1g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-27(7.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-41(产率52％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.35(s,1H),7.69(m,1H),7.60(m,5H),7.51(d,J＝8Hz,2H),7.36(m,1H),7.14(d,J＝8Hz,2H),2.25(s,3H)；13C NMR(150MHz,DMSO)δ162.55,143.89,138.64,135.54,133.82,133.04,131.49,131.36,131.09,130.84,130.73,130.55,129.97,129.01,125.93,124.96,120.16,117.98,20.83；LC/MS(ESR)m/z479.03[M+H]+,481.03[M+H]+,482.03[M+H]+.
实施例58：化合物4-(3-氯-4-溴苯基)-5-(3-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-4(4.6g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-9(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-42(产率55％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.23(s,1H),7.68(m,1H),7.63(m,1H),7.50(m,2H),7.27(m,2H),7.14(m,4H),7.09(m,1H),2.27(m,6H)；13C NMR(100MHz,DMSO)δ161.88,142.33,138.84,136.50,134.11,133.33,130.16,129.90,129.34,128.82,126.91,122.47,120.66,117.81,21.30,20.80；LC/MS(ESR)m/z469.01[M+H]+,471.01[M+H]+,472.02[M+H]+
实施例59：化合物4-(3,4-二氯苯基)-5-(3-甲基苯基)-N-(3-氟-4-甲基苯基)噻唑-2-胺的合成
向化合物v-5(4.3g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-9(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-42(产率59％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.45(s,1H),7.62(m,2H),7.56(m,1H),7.38(m,1H),7.23(m,5H),7.09(m,1H),2.16(s,3H),1.97(s,6H)；13C NMR(100MHz,DMSO)δ162.21,161.26,159.86,142.26,140.61,140.50,138.89,135.81,132.14,132.07,131.44,131.36,130.95,130.45,130.25,129.41,128.67,126.95,123.15,117.07,116.89,113.32,104.45,104.17,21.30,14.01；LC/MS(ESR)m/z443.05[M+H]+,445.05[M+H]+,447.05[M+H]+
实施例60：化合物4-(3,4-二氯苯基)-5-(2-氟苯基)-N-(3-氟-4-甲基苯基)噻唑-2-胺的合成
向化合物v-5(4.3g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-5(5.6g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-44(产率59％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.52(s,1H),7.64(m,1H),7.56(m,2H),7.44(m,2H),7.26(m,5H),2.16(s,3H)；13C NMR(100MHz,DMSO)δ162.18,160.36,158.76,141.27,140.91,140.46,139.22,136.51,132.14,131.71,131.66,131.33,130.26,130.20,128.96,128.47,125.85,124.35,118.97,117.89,115.32,102.61,101.07,21.26,；LC/MS(ESR)m/z447.02[M+H]+,449.02[M+H]+,450.02[M+H]+
实施例61：化合物4-(3-溴-4-氯苯基)-5-(3-甲基苯基)-N-(4-甲基苯基)噻唑-2-胺的合成
向化合物v-6(4.6g,0.01mol,1eq.)的N,N-二甲基甲酰胺/水(3/1,50ml)混合溶液中，加入化合物vi-9(5.4g,0.04mol,4eq.)，碳酸钠(2.7g,0.025mol,2.5eq.)，醋酸钯(0.2g,0.001mol,0.1eq.)和4,5-双二苯基膦-9,9-二甲基氧杂葸(1.7g,0.003mol,0.3eq.)，将反应液在80℃回流2h，萃取并浓缩有机相，通过硅胶柱色谱分离得到目标化合物vii-45(产率53％)。Rf＝0.20(石油醚/乙酸乙酯＝20/1)；1H NMR(400MHz,DMSO)δ10.23(s,1H),7.78(m,1H),7.63(m,1H),7.52(m,3H),7.42(m,1H),7.25(m,1H),7.12(m,4H),2.27(m,6H)；13C NMR(100MHz,DMSO)δ161.78,142.12,138.64,136.31,134.25,133.33,130.46,129.40,129.14,128.33,126.56,122.47,120.46,117.90,21.20,20.70；LC/MS(ESR)m/z469.01[M+H]+,471.01[M+H]+,472.02[M+H]+
实施例62：生物学测定
本发明采用果蝇行为学测试来进行生物学测定，主要采用转基因果蝇，进行巴普洛夫果蝇嗅觉实验，以市售抗阿尔兹海默药物“美金刚”作为对照组，测试其记忆恢复效果。
在本研究中,果蝇组织特异性表达模式Gal4-UAS(下文称H29.3)系统被用来构建所需要的阿尔兹海默症转基因果蝇(下文称AD果蝇)模型，其中Elav-Gal4c155(下文称P35)为控制Aβ42表达的基因。w1118(isoCJ1)(下文称2U)为在实验中普遍用作对照的一种近等基因系。实验所用转基因果蝇为2U×H29.3(对照组果蝇)、P35×2U(对照组果蝇)和P35×H29.3(AD果蝇)杂交而成的第一代果蝇。
实验所用果蝇在24℃,40-60％相对湿度(RH)条件下培养。在其羽化后第二天，挑选出雄性对照组果蝇((+/Y；UAS-Aβ42/+)和雄性AD果蝇(elav/Y；UAS-Aβ42/+)，分装并储存在不同果蝇管中(约100只/管)进行化合物喂养(29℃,40±15％RH)。
所有化合物的储存液和阳性对照药物美金刚(10mM储存液)都在冰箱中保存。在药物喂养实验开始前一天，用4％蔗糖和1％DMSO溶液稀释储存液至100μM，并将其保存在冰箱中。已有研究显示，所用4％蔗糖和1％DMSO溶液不会对果蝇的记忆能力产生影响。
在果蝇羽化后第2天至第8天内，每天对果蝇进行化合物喂养4h，新鲜食物喂养20h。在每个药物喂养日中，给与每管果蝇50μl的化合物溶液(100μM)或50μl的美金刚溶液(100μM)。每个数据点，如表现指数(PI),由2管果蝇观察得到。
巴普洛夫果蝇嗅觉实验在25℃,70％相对湿度的暗室中进行。在训练环节，每一管的所有果蝇依次接触两种不同的中性气味(如正辛醇和甲基环己醇等)，每种气味接触时间为60s，不同气味接触间隔时间为45s。当果蝇接触第一种气味时，同时给予60V方波脉冲电刺激，每次脉冲持续1.5s，脉冲间隔3.5s。
训练阶段结束后，立即将果蝇转入T型迷宫中，使其在两种气味中进行选择。2min后对选择不同气味的果蝇数量进行统计。
由T型迷宫中果蝇的分布可计算得出表现指数(PI)。PI＝0表示两种气味的果蝇分布比例为50：50，即果蝇无法记忆带有电击的中性气味。PI＝100表示所有果蝇都可记忆带有电击的中性气味。
部分化合物测定结果：
表现指数(PI)＝(选择正确的果蝇-选择错误的果蝇)/所有果蝇的数量*100％
归一化挽救率＝(喂药果蝇PI-疾病果蝇组PI)/(健康果蝇组PI-疾病果蝇组PI)*100％
研究结果显示,所述化合物皆可有效改善转基因果蝇记忆能力,且效果接近或好于市售对照药物“美金刚”。
在此说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域的普通技术人员应当理解，可以在形式上和细节上对其做出各种各样的改变，而不偏离本发明的精神和范围。
Claims (10)
1.一种具有式(vii)的化合物或者其药学上可接收的盐：
其中，
R1独立选自氢、卤素、烷基、烷氧基、羟基、苯基、杂环基、烯基、卤素取代的烷基；
R2、R3各自独立地为氢、卤素、烷基、烷氧基、苯基、杂环基、环烷基，其中苯基可任选的被一个或多个独立选自以下的取代基取代：
氢、卤素、烷基、烷氧基、羟基、杂环基、环烷基、卤素取代的烷基；
n＝0、1、2、3、4、5。
2.根据权利要求1的化合物或者其药学上可接收的盐：
其中R1为氯、溴、C1-10烷基、C1-10烷氧基、三氟甲基。
3.根据权利要求2的化合物或者其药学上可接收的盐：
其中n＝0、1、2。
4.根据权利要求1的化合物或者其药学上可接收的盐：
其中R2、R3各自独立地为C1-10烷基、C1-10烷氧基、C3-8环烷基、苯基、杂环基，其中苯基任选的被一个或多个独立选自以下的取代基取代：
氯、溴、C1-10烷基、C1-10烷氧基、杂环基、三氟甲基。
5.根据权利要求4的化合物或者其药学上可接收的盐：
其中R2、R3各自独立地为呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚、喹啉、蝶啶、吖啶、苯基，其中苯基可任选的被一个或多个独立选自以下的取代基取代：
呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚、喹啉、蝶啶、吖啶。
6.根据权利要求1的化合物或者其药学上可接收的盐，其选自：
7.药物组合物，其由权利要求1-6中任一项所述的化合物或者其药学上可接收的盐、以及药学上可接受的辅料或载体组成。
8.根据权利要求7的药物组合物，其中还可以加入任选的其它治疗性成分。
9.根据权利要求1-6中任一项所述的化合物或者其药学上可接收的盐，在制备治疗或预防进行性认知障碍和/或记忆力缺失疾病的药物中的用途。
10.根据权利要求9所述的化合物或者其药学上可接收的盐，在制备治疗或预防阿尔兹海默症的药物中的用途。
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| MAKAM, PARAMESHWAR ET AL.: "2-Aminothiazole derivatives as antimycobacterial agents: Synthesis, characterization, in vitro and in silico studies", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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