TW201817700A - 二苯乙烯衍生物及其製備方法 - Google Patents

二苯乙烯衍生物及其製備方法 Download PDF

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TW201817700A
TW201817700A TW106133720A TW106133720A TW201817700A TW 201817700 A TW201817700 A TW 201817700A TW 106133720 A TW106133720 A TW 106133720A TW 106133720 A TW106133720 A TW 106133720A TW 201817700 A TW201817700 A TW 201817700A
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alkyl
aryl
hydrogen
cycloalkyl
heterocyclyl
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TWI786064B (zh
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李珉京
李鎭珏
韓元碩
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耐諾爾米克斯企業股份有限公司
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Abstract

本發明係關於二苯乙烯衍生物及其製備方法，且更特地而言係關於用於抑制親環蛋白之功能的新穎二苯乙烯衍生物及其製備方法，該新穎二苯乙烯衍生物在預防親環蛋白相關疾病或在治療此種疾病之症狀方面為有效的。

Description

二苯乙烯衍生物及其製備方法
本發明係關於用於抑制親環蛋白(cyclophilin)之功能的具有改良醫藥概況的新穎二苯乙烯衍生物及其製備方法。
親環蛋白已知為用於許多疾病之有效藥物標靶，該等疾病包括病毒感染疾病，諸如B型肝炎病毒(hepatitis B virus；HBV)、C型肝炎病毒(hepatitis C virus；HCV)、人類免疫缺陷病毒(human immunodeficiency virus；HIV)、流感病毒等等；藉由發炎反應引起的疾病，諸如心血管疾病；類風濕性關節炎；敗血症；哮喘；齒根骨膜炎；老化；禿髮(alopecia)；藉由粒線體功能異常引起的神經退化性疾病；癌症及類似者(Nigro P等人，Cell Death Dis 2013,4,e888)。
親環蛋白(CyP)屬於免疫親和蛋白家族之蛋白質，在所有生物體(原核生物及真核生物兩種)之所有細胞中皆 發現該親環蛋白，且其歷經演化已在結構上得以良好保存。人類含有總共16種存在於人類中之內源蛋白質，包括七種主要CyP，即CyP A、CyP B、CyP C、CyP D、CyP E、CyP 40、及CyP NK。
親環蛋白在人體內的大多數細胞中被發現，且哺乳動物中之CyP A及CyP 40具有細胞質訊息序列，而CyP B及CyP C具有靶向至內質網之N-末端訊息序列。CyP D具有導向至粒線體之訊息序列，CyP E具有胺基末端RNA結合結構域且位於核內，而CyP 40具有TPR且位於細胞質。人類CyP NK為最大的CyP，其具有大的親水性及帶正電羧基末端，且位於細胞質內。
親環蛋白係涉及細胞過程之多功能蛋白質且負責細胞中之必需功能。已證明親環蛋白具有催化肽醯基-脯胺醯基鍵之順反異構化的酶性質。因此，親環蛋白稱為肽醯基脯胺醯基順反異構酶(PPIase)，其可充當新合成蛋白質之恰當折疊中之加速因子。PPIase亦涉及修復歸因於包括熱應力之環境應力、紫外輻射、細胞環境pH之改變、及氧化劑處理之受損蛋白質。此功能係稱為分子伴護蛋白(chaperone)活性。親環蛋白之PPIase活性亦已被證明涉及細胞內蛋白質通行、粒線體功能及前驅傳訊RNA處理。
環孢素係可利用親環蛋白抑制劑之一種，其結合於CyP A之疏水性凹穴中以因此抑制PPIase活性。CyP A為親環蛋白家族之原型，且在人類中展示與CyP B、CyP C、及CyP D之極高序列同源性。所有親環蛋白之結合凹穴係藉由相應於高度保守區域的大致109個胺基酸形成，且CyP A與CyP D之間的序列同源性為100%。因此，CyP A結合親和力為CyP D結合親和力之最佳預測物且反之亦然。
親環蛋白之間的此種序列同源性暗示不僅CyP D而且所有親環蛋白為針對具有對CyP A之結合親和力的功能抑制劑之潛在標靶，此指示CyP A之功能抑制劑可適用於治療藉由與親環蛋白相關的眾多細胞內過程引起的許多疾病。
[先前技術文獻]
[專利文獻]
專利文獻1：韓國專利第1309409號。
因此，本發明意欲提供一種用於抑制親環蛋白之功能的具有改良醫藥概況使得能預防疾病或治療此種疾病之症狀的化合物且亦提供其製備方法，該等疾病包括病毒感染疾病，諸如HBV、HCV、HIV、流行性感冒及類似者； 心血管疾病；類風濕性關節炎；敗血症；哮喘；齒根骨膜炎；老化；禿髮；神經退化性疾病；癌症等等。
因此，本發明提供一種能夠抑制親環蛋白之功能的化合物。本發明提供由下文化學式1表示的二苯乙烯衍生物、其醫藥學上可接受的鹽、水合物、水合鹽、多態晶體結構、外消旋物、非對映異構物、或鏡像異構物。其係用於預防親環蛋白相關疾病或用於治療此種疾病之症狀。
在化學式1中，A為CRa或N，B為CRb或N，G為CRe或N，J為CRf或N， M為CRg或N，D、E、及L為CRh或N，Rx為H、CH3、CN、NH2、F、Cl、Br或I，其中當Rx為H、CH3、NH2、F、Cl、Br或I時，Ra為氫、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、 C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Rd為鹵素、NO2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)， Rf為氫、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12雜環基、-NHR11(R11為C1-C2烷基)、-COOR12(R12為C1-C2烷基)、-OCOR13(R13為C1-C2烷基)、或-COR14(R14為C1-C2烷基)，Rg為氫、NH2、OH、鹵素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，及Rh為氫、NH2、OH、C1-C5烷基或C2-C10烯基，當Rx為CN時，Ra為氫， Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基、或C5-C12雜環基)，Rd為氫、鹵素、NO2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、 C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf及Rg各自為氫，及Rh為氫、C1-C5烷基或C2-C10烯基，雜環基之雜原子可為選自由氮、氧及硫組成之群的至少一者，烷基可經選自由以下各項組成之群的至少一個取代基取代：OH、胺、C6-C12芳基、C5-C10雜環基及C3-C10環烷基， 烷氧基可經選自由以下各項組成之群的至少一個取代基取代：鹵素、C6-C12芳基、C3-C10環烷基、胺及胺基羰基，雜環基可經選自由以下各項組成之群的至少一個取代基取代：烷基、經胺取代之烷基、胺、醯胺基及羧基，芳基可經選自由以下各項組成之群的至少一個取代基取代：鹵素、烷基、羥基、烷氧基、羧基、酯基、硝基及胺基，A、B、D、E、G、J、L及M可與相鄰基團連接來形成稠合環，及當Rb為CH3時，Rd不可為NO2。
根據本發明，二苯乙烯衍生物在抑制親環蛋白之功能方面為有效的，且因此適用於預防親環蛋白相關疾病，或用於治療此種疾病之症狀，該等疾病包括病毒感染疾病，諸如C型肝炎病毒(HCV)、B型肝炎病毒(HBV)、人類免疫缺陷病毒(HIV)、家禽流行性感冒(avian influenza；AI)病毒及類似者；心血管疾病；類風濕性關節炎；敗血症；哮喘；齒根骨膜炎；老化；禿髮；神經退化性疾病；癌症等等。此外，本發明之二苯乙烯衍生物可用於與現存治療劑組合 來由此增加治療效果。
下文，將給出本發明之詳細描述。
本發明針對由下文化學式1表示的二苯乙烯衍生物。本發明之二苯乙烯衍生物具有適於結合至維持在具有親環蛋白之功能的任何蛋白質中之活性凹穴的結構且因此適於用作親環蛋白抑制劑。
在化學式1中，A為CRa或N，B為CRb或N，G為CRe或N， J為CRf或N，M為CRg或N，D、E、及L為CRh或N，Rx為H、CH3、CN、NH2、F、Cl、Br或I，其中當Rx為H、CH3、NH2、F、Cl、Br或I時，Ra為氫、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12 芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Rd為鹵素、NO2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、 C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf為氫、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12雜環基、-NHR11(R11為C1-C2烷基)、-COOR12(R12為C1-C2烷基)、-OCOR13(R13為C1-C2烷基)、或-COR14(R14為C1-C2烷基)，Rg為氫、NH2、OH、鹵素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，及Rh為氫、NH2、OH、C1-C5烷基或C2-C10烯基，當Rx為CN時， Ra為氫，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基、或C5-C12雜環基)，Rd為氫、鹵素、NO2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4可連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為 C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O)2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf及Rg各自為氫，及Rh為氫、C1-C5烷基或C2-C10烯基，雜環基之雜原子可為選自由氮、氧及硫組成之群的至少一者，烷基可經選自由以下各項組成之群的至少一個取代基取代：OH、胺、C6-C12芳基、C5-C10雜環基及C3-C10環烷基， 烷氧基可經選自由以下各項組成之群的至少一個取代基取代：鹵素、C6-C12芳基、C3-C10環烷基、胺及胺基羰基，雜環基可經選自由以下各項組成之群的至少一個取代基取代：烷基、經胺取代之烷基、胺、醯胺基及羧基，芳基可經選自由以下各項組成之群的至少一個取代基取代：鹵素、烷基、羥基、烷氧基、羧基、酯基、硝基及胺基，A、B、D、E、G、J、L及M可與相鄰基團連接來形成稠合環，及當Rb為CH3時，Rd不可為NO2。
本發明之化合物可經由各種方法合成，且典型地其中化學式1之Rx為CN的狀況之合成過程可不同於其他狀況之彼等合成過程。
當Rx為CN時，由化學式1表示的二苯乙烯衍生物可藉由使由下文化學式2表示的苯基乙腈衍生物與由下文化學式3表示的苯甲醛衍生物反應來製備。
由化學式2表示的苯基乙腈衍生物及由化學式3表示的苯甲醛衍生物可為可商購產品，或可在經由此項技術中所知的方法製備之後使用。
上文反應可在有機溶劑存在下或在無任何溶劑的情況下進行。在此狀況下，使用微波時，反應時間可減少且產率可增加。
有機溶劑不受限制，但較佳地包括醇，且更佳地為丁醇、甲醇、乙醇、或丙醇。諸如三苯基膦、哌啶或類似物之催化劑可添加來促進反應。
Rx=CN
[化學式2]
在化學式2及化學式3中，A、B、D、E、G、J、L、M、Rc及Rd係如化學式1之A、B、D、E、G、J、L、M、Rc及Rd中所定義。
當Rx為H、CH3、NH2、F、Cl、Br或I時，由化學式1表示的二苯乙烯衍生物可藉由使由下文化學式4表示的烯烴衍生物與由下文化學式5表示的有機鹵化物衍生物反應來製備。
由化學式4表示的烯烴衍生物及由化學式5表示的有機鹵化物衍生物可為可商購產品，或可在經由此項技術中所知的製程製備之後使用。
上文反應較佳地使用三乙醇胺有機溶劑在乙酸鈀(II)催化劑存在下進行。
Rx=H、CH3、NH2、F、Cl、Br、I
在化學式4及化學式5中， Rx為氫、CH3、NH2、F、Cl、Br或I，X為F、Cl、Br或I，及A、B、D、E、G、J、L、M、Rc及Rd係如化學式1之A、B、D、E、G、J、L、M、Rc及Rd中所定義。
根據本發明之由化學式1表示的二苯乙烯衍生物可連同醫藥學上可接受的載劑一起用作親環蛋白相關疾病之預防劑或治療劑。
此外，根據本發明之由化學式1表示的二苯乙烯衍生物可用作用於親環蛋白相關疾病之治療劑之效力的比較參考材料。
在本發明中，烷基或烯基可為直鏈或支鏈。
如本文所使用，術語「鹵素原子」可指氟、氯、溴或碘。
在本發明中，當A、B、D、E、G、J、L及M與相鄰基團連接以形成稠合環時，該稠合環較佳地為六員環或五員環。此外，稠合環可含有諸如N、O及S之雜原子之至少一者。稠合環可為呋喃或噻吩。
在本發明之實施例中，A較佳為CRa或N，B較佳為CRb，G較佳為CRe，J較佳為CRf，M較佳為CRg或N，且D、E及L較佳為CH，但本發明不限於此。
在本發明之另一實施例中，Rb較佳為氫或C1-C8烷基，但本發明不限於此。
在本發明之又一實施例中，Rc較佳為C1-C20烷基、C2-C10烷氧基、苯基烷基、硝基、C3-C10環烷基、C5-C12雜環基或C1-C10烷基酮，但本發明不限於此。
在本發明之另一實施例中，Rd較佳為C2-C20烷基；C3-C10酯基；C3-C10環烷基；經環烷基取代之甲氧基；經胺基取代之乙氧基；羧基；經苯基取代之C2-C20烷基，該苯基為未經取代的或經C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪(N-methylpiperazine)；哌啶；嗎啉；或-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)，但本發明不限於此。
在本發明之又一實施例中，Re較佳為氫、OH、C1-C20烷基、或C1-C10烷氧基，但本發明不限於此。
在本發明之另一實施例中，Rg較佳為氫、OH、C1-C20烷基；C3-C10酯基；C3-C10環烷基；經環烷基取代之甲氧基；經胺基取代之乙氧基；經苯基取代之C2-C20烷基，該苯基為未經取代的或經C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；嗎啉；或羧基，但本發明不限於此。
在本發明之另一實施例中，Rh較佳為氫，但本發明不限於此。
在本發明中，烷基可為經取代或未經取代之烷基，諸如-CH3、-CH2CH3、-CH2CH2CH3、-CH2(CH2)2CH3、-CH2(CH2)3CH3、-CH(CH3)CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)2、-CH(CH3)2、-C(CH3)3、-CH2C(CH3)3、-CH2CH(CH3)2、-CH(CH3)CH(CH3)2、-CH(CH3)C(CH3)3、-C(CH3)2CH2CH3、-C(CH3)2CH(CH3)2、-C(CH3)2C(CH3)3、-CH2CH2C(CH3)3、-CH2CH(CH3)CH(CH3)2、-CH2CH2C(CH3)2CH2CH3、-CH2CH2CH(CH3)CH2C(CH3)3、-CH2Ph、CH2CH2Ph、 或，但本發明不限於此。
在本發明中，烷氧基可為經取代或未經取代之烷氧基，諸如-OCH3、-OCF3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、-OCH(CH3)CH2CH3、-OCH2CONH2、-OCH2CH2N(CH3)2、 或，但本發明不限於此。
在本發明中，雜環基可為 、或，但本發明不限於此。
在本發明中，-NR3R4可為-NH2、-NHCH3、-N(CH3)2、或，但本發明不限於此。
在本發明中，-COOR5可為COOCH3、-COOCH2CH3、COO(CH2)2CH3、-COO(CH2)3CH3、COO(CH2)4CH3、 COOCH(CH3)2、或，但本發明不限於此。
在本發明中，-OCOR6可為 或，但本發明不限於此。
在本發明中，-NR7CYR8基團可為 或，但本發明不限於此。
在本發明中，-NHS(O)2R9基團可為 或，但本發明不限於此。
在本發明中，COR10可為COC(CH3)3，但本發明不限於此。
如本文所使用，術語「醫藥學上可接受的載劑」可定義為不損害組成物之生物活性或性質的載劑或稀釋劑。
醫藥學上可接受的載劑或添加劑可包括典型使用的稀釋劑或賦形劑之至少一者，諸如穩定劑、填料、增量劑、潤濕劑、崩解劑、潤滑劑、黏合劑、表面活性劑、及類似者。
崩解劑可包括瓊脂、澱粉、海藻酸或其鈉鹽、無水磷酸氫鈣、及類似者。潤滑劑可包括矽石、滑石、硬脂酸或其鎂鹽或鈣鹽、聚乙二醇、偏矽酸鎂鋁、及類似者。黏合劑可包括矽酸鎂鋁、澱粉糊、明膠、黃芪膠、甲基纖維素、羧甲基纖維素鈉、聚乙烯吡咯啶酮、低級經取代羥丙基纖維素、及類似者。
除此之外，乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素或甘胺酸可用作稀釋劑。在一些狀況下，通常已知的煎鹽(boiling salt)、吸收劑、著色劑、調味劑、甜味劑及類似者可與其一起使用。
此外，穩定劑可包括無鈉(Na)穩定劑，其實例包括偏矽酸鎂鋁、矽酸鎂鋁、鋁酸鎂、無水氫氧化鋁、合成水滑石、合成矽酸鋁、碳酸鎂、沉澱碳酸鈣、氧化鎂、氫氧化鋁、L-精胺酸、磷酸鉀、磷酸氫二鉀、磷酸二氫鉀、氯化銨、氯化鋁、及類似者，其可單獨使用或以其兩個或兩個以上者之組合使用。
含有本發明之化學式1之二苯乙烯衍生物的醫藥組成物可以促進將化合物投與至生物體中之各種方式來投與。含有本發明之化合物的醫藥組成物可經由口服投與、直腸內投與、陰道內投與、鼻內投與、眼內投與、口內投與、舌下投與、皮下投與、肌肉內投與、靜脈內投與、鞘內投與、真皮內投與、硬膜上投與、及類似者來投與。
含有本發明之化合物的醫藥組成物可以錠劑、膠囊、粉末、滴丸、散劑、推注劑、酊劑或泥罨劑(cataplasm)之劑型來提供。較佳錠劑可為典型錠劑、包衣錠劑、可分散錠劑、發泡性錠劑等等，或可為多壓縮錠劑，諸如雙錠劑、嵌套錠劑(tablet-in-tablet)、多層錠劑等等。
包括在含有本發明之化合物的醫藥組成物中的二苯乙烯衍生物或其醫藥學上可接受的鹽之較佳投與量取決於患者之狀態及體重、疾病之嚴重性、藥物之類型、投與路線及持續時間而變化，但可藉由熟習此項技術者做出適當選擇。
本發明之更好理解可經由以下非限制性實例達成，該等非限制性實例僅僅闡述來說明但不意欲解釋為限制本發明之範疇。以下實例可經適當修飾且在本發明之範疇內更改。
實例1.其中Rx為CN的二苯乙烯衍生物之製備
1)溶劑之使用
將1當量之化學式2之苯基乙腈衍生物及1.3當量之化學式3之苯甲醛衍生物與0.2當量之三苯基膦在丁醇溶劑中回流，繼之以Knoevenagel縮合反應，因此產生化學式1之化合物。
2)微波之使用
將1當量之化學式2之苯基乙腈衍生物、1.3當量之化學式3之苯甲醛衍生物及0.2當量之三苯基膦利用微波處理，因此產生化學式1之化合物。當使用微波時，反應時間可縮短且產率可增加。
實例2.其中Rx為氫、CH3、NH2、F、Cl、Br、I的衍生物之製備
將1當量之化學式4之烯烴衍生物及1當量之化學式5之有機鹵化物衍生物與0.01當量之乙酸鈀(II)在三乙醇胺溶劑中回流，繼之以Heck烯化反應，因此產生化學式1之化合物。
測試實例1.二苯乙烯衍生物之順反異構酶抑制活性之評估
胰凝乳蛋白酶分解反式丙胺酸-脯胺酸肽鍵。當Suc-AAPF-pNA(肽受質)及胰凝乳蛋白酶混合時，反式肽受質經分解，且順式肽受質保留。剩餘的順式肽受質藉由順反異構酶轉化成反式，且隨後再次藉由胰凝乳蛋白酶分解。當存在順反異構酶時，胰凝乳蛋白酶能夠在預定時間段內分解較大量的反式肽受質，由此可測定順反異構酶之 活性。經分解的反式肽受質之量係使用在390nm下之吸光度來量測。
親環蛋白具有順反異構酶活性，且促進反式肽受質藉由胰凝乳蛋白酶之分解。當本發明之二苯乙烯衍生物連同親環蛋白一起處理時，未觀察到肽受質藉由胰凝乳蛋白酶之分解加速。由此，可斷定本發明之二苯乙烯衍生物抑制親環蛋白之活性。
下文化合物1至化合物155(表1至表10)可如下基於順反異構酶抑制活性(IC50)值來分組：A組(GA)：2000nM或更小但超過200nM之IC50，B組(GB)：200nM或更小但超過20nM之IC50，及C組(GC)：20nM或更小之IC50。
測試實例2.二苯乙烯衍生物之細胞毒性之評估
量測二苯乙烯衍生物之細胞毒性。將穩定複製C型肝炎病毒基因組之複製子細胞塗覆至96孔板且在CO2培養器中在37℃下培養24小時。將培養一天的複製子細胞用磷 酸鹽緩衝鹽水(phosphate buffered saline；PBS)溶液洗滌，用本發明之化合物處理，且隨後培養72小時。其後，經由MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物]細胞毒性測試，量測本發明之化合物之CC50值。本發明之化合物之CC50值為200μM或更大。例如，化合物64具有320μM之CC50，化合物65具有284μM之CC50，且化合物66具有245μM之CC50。因此，本發明之化學式1之化合物不展現細胞毒性。
測試實例3.二苯乙烯衍生物之抗病毒活性之評估
量測二苯乙烯衍生物對C型肝炎病毒之抗病毒活性。將穩定複製C型肝炎病毒基因組之複製子細胞塗覆至培養板且在CO2培養器中在37℃下培養24小時。將培養一天的複製子細胞用PBS溶液洗滌，用本發明之化合物處理，且隨後培養72小時。將二苯乙烯衍生物處理的複製子細胞用冷PBS溶液洗滌，且添加20μL之細胞溶解溶液以使得細胞溶解在冰中達20min。向其添加100μL之Renilla螢光素酶受質，之後量測其發光且由此估計C型肝炎病毒基因組之量。展示根據本發明之二苯乙烯衍生物處理的複製子細胞中C型肝炎病毒基因組之量相對於二甲亞碸(dimethylsulfoxide；DMSO)處理的複製子細胞中C型肝炎病毒基因組之量。
表1至表10之化合物1至化合物155可如下基於抗病毒活性(EC50)值分組：D組(GD)：50μM或更小但超過5μM之EC50，E組(GE)：5μM或更小但超過0.5μM之EC50，及F組(GF)：0.5μM或更小之EC50。
因此，本發明之化學式1之化合物展現抗病毒效果。
測試實例4.對粒線體腫脹之抑制活性測試
親環蛋白為用於形成粒線體中之通透性轉變孔(permeability transition pore；PTP)的關鍵蛋白質。當形成通透性轉變孔時，粒線體腫脹，其外膜藉此破裂且因此細胞死亡進展。此種粒線體功能異常引起包括神經退化性疾病、癌症、及類似者之許多疾病。環孢素係一種已知的親環蛋白抑制劑，其能夠防止通透性轉變孔之形成以由此抑制粒線體腫脹。
粒線體腫脹測試如下執行。特定而言，使用Dounce組織磨碎器破壞肝細胞。在700xg下將所破壞細胞離心 10min且將上清液轉移至新的管中。在12,000xg下將上清液離心15min，進而獲得粒線體。
當將所萃取粒線體添加鈣時，其腫脹，從而可藉由量測520nm下之吸光度來觀察。二苯乙烯衍生物歸因於鈣而在抑制粒線體腫脹方面為有效的。
表1至表10之化合物1至化合物155對抑制粒線體腫脹之活性可基於IC50值判定，且可如下分組：G組(GG)：500μM或更小但超過50μM之IC50，H組(GH)：50μM或更小但超過5μM之IC50，及I組(GI)：5μM或更小之IC50。
相應於在實例1及實例2中製備的二苯乙烯衍生物之化合物1至化合物155的NMR(核磁共振；nuclear magnetic resonance)分析及LCMS(液相層析-質譜法；liquid chromatography mass spectrometry)分析之結果如下。
化合物1： NMR(400MHz,CDCl3)：8.03(d,1H),7.84(s,1H),7.63(d,2H),7.37(m,1H)7.27(m,2H),7.10(m,2H),2.78(s,6H),2.42ppm(s,3H)
LCMS：MH+=263.1
化合物2：NMR(400MHz,DMSO-D6)：8.41(s,1H),8.05(d,1H),7.78(m,2H),7.62(m,3H)7.36(d,2H),2.65(m,2H),1.20ppm(m,3H)
LCMS：MH+=260.1
化合物3：NMR(400MHz,CDCl3)：8.03(d,1H),7.85(s,1H),7.66(d,2H),7.38(m,1H)7.28(m,2H),7.12(m,2H),2.78(s,6H),2.70(m,2H),1.28ppm(m,3H)
LCMS：MNa+=300.1
化合物4：NMR(400MHz,CDCl3)：8.11(m,1H),7.87(s,1H),7.65(d,2H),7.47(d,1H)7.39(m,2H),7.27(s,2H),2.98(m,1H),1.29ppm(d,6H)
LCMS：MH+=282.0
化合物5： NMR(400MHz,CDCl3)：8.33(s,1H),8.24(m,1H),7.91(d,1H),7.72(m,1H)7.67(d,2H),7.56(m,1H),7.33(d,2H),2.98(m,1H),1.29ppm(d,6H)
LCMS：MNa+=314.1
化合物6：NMR(400MHz,CDCl3)：8.13(d,1H),7.93(s,1H),7.63(m,2H),7.41(m,1H)7.31(m,2H),7.27(m,1H),6.94(d,1H),3.89(s,3H),2.97(m,1H),1.28ppm(d,6H)
LCMS：MH+=278.1
化合物7：NMR(400MHz,CDCl3)：8.31(m,2H),8.10(m,2H),7.91(d,2H),7.44(m,1H)7.14(m,2H),2.80ppm(s,6H)
LCMS：MH+=294.1
化合物8：NMR(400MHz,DMSO-D6)：8.41(s,1H),8.04(m,1H),7.76(m,2H),7.62(m,3H)7.35(d,2H),2.63(m,2H),1.58(m,2H),1.32(m,2H),0.92ppm(m,3H)
LCMS：MH+=304.1
化合物9： NMR(400MHz,CDCl3)：8.33(s,1H),8.23(d,1H),7.92(d,1H),7.73(m,1H)7.67(d,2H),7.56(m,1H),7.28(m,2H),2.67(m,1H),1.66(m,2H),1.28(d,3H),0.860ppm(m,3H)
LCMS：MNa+=288.1
化合物10：NMR(400MHz,CDCl3)：8.34(s,1H),8.23(m,1H),7.92(d,1H),7.73(d,1H)7.68(d,2H),7.49(m,1H),7.27(s,2H),1.37ppm(s,9H)
LCMS：MNa+=328.3
化合物11：NMR(400MHz,CDCl3)：8.15(d,1H),7.95(s,1H),7.64(d,2H),7.46(d,2H)7.27(s,1H),7.07(m,1H),6.94(d,1H),3.89(s,3H),1.36ppm(s,9H)
LCMS：MH+=292.2
化合物12：NMR(300MHz,CDCl3)：7.83(d,1H),7.53(m,1H),7.40(m,1H),7.31(d,1H)7.16(m,2H),7.08(d,2H),3.70(s,3H),2.30ppm(d,6H)
LCMS：MH+=264.1
化合物13：NMR(300MHz,CDCl3)：7.85(d,1H),7.49(m,1H),7.37(m,1H),7.28(d,1H)7.15(m,2H),7.02(d,2H),2.28ppm(d,6H)
LCMS：MNa+=299.1
化合物14：NMR(300MHz,CDCl3)：7.58(d,2H),7.55(d,1H),7.36(m,1H),7.32(d,1H)7.01(m,2H),6.91(d,2H),3.89(s,3H),1.38ppm(s,9H)
LCMS：MH+=320.2
化合物15：NMR(300MHz,CDCl3)：7.75(d,1H),7.72(m,2H),7.65(d,2H),7.61(d,1H)7.43(d,2H),7.39(s,1H),1.37ppm(s,9H)
LCMS：MNa+=355.1
化合物16：NMR(300MHz,CDCl3)：7.83(d,1H),7.80(s,1H),7.75(d,2H),7.60(m,1H)7.25(d,1H),7.19(m,1H),7.08(d,2H),4.12(m,2H),3.89(s,3H),1.42ppm(m,3H)
LCMS：MH+=280.1
化合物17：NMR(300MHz,CDCl3)：7.94(d,1H),7.90(s,1H),7.83(d,2H),7.65(m,1H)7.30(d,1H),7.22(m,1H),7.14(d,2H)4.17(m,2H),1.43ppm(m,3H)
LCMS：MNa+=315.1
化合物18：NMR(300MHz,CDCl3)：7.82(d,1H),7.67(s,1H),7.55(m,1H),7.50(d,2H)7.17(m,2H),6.97(m,2H),3.92(m,2H),3.63(s,3H),1.77(m,2H),1.50(m,2H),0.99ppm(m,3H)
LCMS：MH+=308.2
化合物19：NMR(300MHz,CDCl3)：7.90(d,1H),7.79(s,1H),7.60(m,1H),7.53(d,2H)7.24(m,2H),7.04(m,2H),4.02(m,2H),1.83(m,2H0,1.57(m,2H),1.01ppm(m,3H)
LCMS：MNa+=343.1
化合物20：NMR(300MHz,CDCl3)：7.84(d,1H),7.81(s,1H),7.75(m,3H),7.59(m,1H)7.26(m,3H),7.20(m,4H),7.09(m,1H),4.04(s,2H),3.89ppm(s,3H)
LCMS：MH+=326.2
化合物21：NMR(300MHz,CDCl3)：7.86(d,1H),7.82(s,1H),7.78(m,3H),7.59(m,1H)7.28(m,3H),7.23(m,4H),7.11(m,1H),4.09ppm(s,2H)
LCMS：MNa+=361.1
化合物22：NMR(300MHz,CDCl3)：8.23(d,2H),8.15(s,1H),7.83(d,2H),7.67(m,1H)7.53(m,2H),7.38(m,1H),2.76(m,2H),1.23ppm(m,3H)
LCMS：MH+=279.1
化合物23：NMR(300MHz,CDCl3)：8.22(d,2H),8.16(s,1H),7.84(d,2H),7.66(m,1H)7.53(m,2H),7.37(m,1H),2.96(m,1H),1.24ppm(d,6H)
LCMS：MH+=293.1
化合物24：NMR(300MHz,CDCl3)：8.30(d,1H),7.57(d,1H),7.50(s,1H),7.35(m,2H)6.78(m,2H),6.69(m,2H),6.15ppm(s,2H)
LCMS：MH+=266.1
化合物25：NMR(300MHz,CDCl3)：8.36(d,2H),8.16(d,1H),8.13(s,1H),7.91(d,2H)7.52(m,1H),7.25(d,1H),7.19(d,1H),3.07(m,4H),2.62(broad s,4H),2.41ppm(s,3H)
LCMS：MH+=349.2
化合物26：NMR(300MHz,CDCl3)：8.29(d,2H),8.23(m,2H),7.84(d,2H),7.48(m,1H)7.07(m,1H),7.00(m,1H),4.50(m,1H),1.86(m,2H),1.39(d,3H),1.07ppm(m,3H)
LCMS：MH+=323.1
化合物27：NMR(300MHz,CDCl3)：8.38(d,2H),8.28(m,1H),8.24(s,1H),7.88(d,2H)7.64(m,1H),6.84(m,1H),6.69(d,1H),3.93(d,2H),0.92(m,1H),0.72(m,2H),0.42ppm(m,2H)
LCMS：MH+=339.1
化合物28： NMR(300MHz,CDCl3)：8.34(d,2H),8.26(d,1H),8.20(s,1H),7.88(d,2H)7.50(m,1H),7.13(m,1H),7.03(d,1H),4.15(m,2H),2.53(m,2H),2.31ppm(s,6H)
LCMS：MH+=338.1
化合物29：NMR(300MHz,CDCl3)：8.35(d,2H),8.17(d,1H),8.14(s,1H),7.92(d,2H)7.48(m,1H),7.18(m,2H),2.98(m,4H),1.74ppm(m,6H)
LCMS：MH+=334.2
化合物30：NMR(300MHz,CDCl3)：8.36(d,2H),8.18(d,1H),8.15(s,1H),7.91(d,2H)7.55(m,1H),7.26(m,1H),7.19(d,1H),3.89(m,4H),3.03ppm(m,4H)
LCMS：MH+=336.1
化合物31：NMR(300MHz,CDCl3)：8.35(d,2H),8.10(s,1H),7.89(m,3H),7.46(m,3H)2.72(m,1H),1.87(m,4H),1.60ppm(m,6H)
LCMS：MH+=333.2
化合物32： NMR(300MHz,CDCl3)：8.34(d,2H),7.88(d,2H),7.68(s,1H),7.56(s,1H)7.46(m,2H),7.08(d,1H),4.10(m,2H),1.92(m,1H),1.88(m,2H),1.02ppm(d,6H)
LCMS：MH+=337.2
化合物33：NMR(300MHz,CDCl3)：8.27(d,2H),7.82(d,2H),7.64(s,1H),7.52(s,1H)7.41(m,3H),4.07(m,2H),2.48(m,2H),2.28(d,6H),2.03ppm(m,2H)
LCMS：MH+=352.2
化合物34：NMR(300MHz,CDCl3)：8.34(d,2H),8.02(d,2H),7.88(d,2H),7.46(m,2H)7.36(m,1H),2.65(d,2H),1.86(m,1H),0.96ppm(d,6H)
LCMS：MH+=307.1
化合物35：NMR(400MHz,CDCl3)：8.36(m,3H),8.05(d,1H),7.94(d,1H),7.87(d,2H)7.75(d,1H),7.45(m,2H),2.68(s,2H),0.94ppm(s,9H)
LCMS：MH+=321.2
化合物36： NMR(300MHz,CDCl3)：8.35(d,2H),8.02(d,2H),7.90(d,2H),7.39(m,3H)2.76(m,2H),1.67(m,1H),1.52(m,2H),0.98ppm(d,6H)
LCMS：MH+=321.2
化合物37：NMR(400MHz,CDCl3)：8.30(m,3H),7.87(s,1H),7.75(d,2H),7.63(m,2H)7.53(m,2H),7.08(d,2H),3.98ppm(s,2H)
LCMS：MH+=409.0
化合物38：NMR(400MHz,CDCl3)：8.29(m,3H),7.88(s,1H),7.75(d,2H),7.63(m,2H)7.54(m,2H),7.24(m,2H),7.06(d,2H),3.07(m,2H),2.96ppm(m,2H)
LCMS：MH+=355.1
化合物39：NMR(300MHz,CDCl3)：8.34(d,2H),8.27(d,1H),8.02(d,2H),7.88(d,2H)7.46(m,1H),7.35(m,1H),2.77(m,2H),1.83(m,5H),1.55(m,2H),1.34(m,4H),1.02ppm(m,2H)
LCMS：MH+=361.2
化合物40：NMR(300MHz,CDCl3)：8.38(d,2H),8.26(d,1H),8.02(d,2H),7.88(d,2H),7.43(m,1H),7.36(m,1H),2.73(m,2H),1.67(m,8H),1.27(m,3H),1.16(m,2H),1.04ppm(m,2H)
LCMS：MH+=375.2
化合物41：NMR(300MHz,CDCl3)：8.36(d,2H),8.03(d,2H),7.87(d,2H),7.42(m,3H),2.65(d,2H),1.89(m,1H),1.72ppm(m,10H)
LCMS：MH+=347.2
化合物42：NMR(300MHz,CDCl3)：8.33(d,2H),8.02(d,1H),7.79(s,1H),7.70(d,2H)7.47(m,1H),7.40(d,2H),7.30(m,5H),2.7(m,4H),1.99ppm(m,2H)
LCMS：MH+=369.2
化合物43：NMR(300MHz,CDCl3)：8.37(d,2H),8.03(d,2H),7.88(d,2H),7.46(m,1H)7.35(m,2H),2.72(m,2H),1.49(m,2H),1.00ppm(s,9H)
LCMS：MH+=335.2
化合物44：LCMS：MH+=385.2
化合物45：LCMS：MH+=411.2
化合物46：LCMS：MH+=389.1
化合物47：LCMS：MH+=389.1
化合物48：LCMS：MH+=389.1
化合物49：LCMS：MH+=385.2
化合物50：LCMS：MH+=385.2
化合物51：LCMS：MNa+=420.1
化合物52：LCMS：MH+=369.2
化合物53：LCMS：MH+=370.2
化合物54： NMR(300MHz,CDCl3)：7.99(d,1H),7.82(s,1H),7.61(d,2H),7.32(m,1H)7.25(m,2H),7.12(m,2H),2.21(s,2H),0.97ppm(s,9H)
LCMS：MH+=320.1
化合物55：NMR(300MHz,CDCl3)：8.23(d,2H),7.81(d,2H),7.61(s,1H),7.50(s,1H)7.39(m,3H),2.77(m,1H),2.08(m,1H),1.22(s,3H),0.76ppm(m,6H)
LCMS：MH+=320.1
化合物56：NMR(300MHz,CDCl3)：8.19(d,1H),7.83(s,1H),7.63(d,2H),7.54(m,1H)7.45(m,2H),7.37(m,2H),2.99(m,1H),1.32(m,3H),1.03ppm(s,9H)
LCMS：MH+=334.1
化合物57：NMR(300MHz,CDCl3)：8.31(s,1H),8.23(m,1H),7.94(d,1H),7.71(m,1H)7.68(d,2H),7.53(m,1H),7.34(d,2H),2.88(m,2H),1.69(m,2H),0.98ppm(s,9H)
LCMS：MH+=334.1
化合物58： NMR(300MHz,CDCl3)：8.26(d,2H),7.87(d,2H),7.61(s,1H),7.55(s,1H)7.40(m,3H),2.67(m,2H),2.08(m,1H),1.88(m,1H),0.96ppm(m,9H)
LCMS：MH+=334.1
化合物59：NMR(300MHz,CDCl3)：8.35(s,1H),8.24(m,1H),7.91(d,1H),7.73(m,1H)7.66(d,2H),7.57(m,1H),7.38(d,2H),2.65(d,2H),1.77(m,1H),1.71ppm(m,10H)
LCMS：MH+=346.1
化合物60：NMR(300MHz,CDCl3)：8.33(s,1H),8.22(m,1H),7.92(d,1H),7.74(m,1H)7.67(d,2H),7.56(m,1H),7.36(d,2H),2.71(s,2H),1.67(m,8H),1.29(m,3H),1.17(m,2H),1.06ppm(m,2H)
LCMS：MH+=360.1
化合物61：NMR(300MHz,CDCl3)：8.32(s,1H),8.20(m,1H),7.92(d,1H),7.74(m,1H)7.64(d,2H),7.53(m,1H),7.34(d,2H),2.62(s,2H),1.66(m,1H),0.43(m,2H),0.20ppm(m,2H)
LCMS：MH+=304.1
化合物62：NMR(300MHz,CDCl3)：8.34(s,1H),8.21(m,1H),7.94(d,1H),7.74(m,1H)7.65(d,2H),7.53(m,1H),7.35(d,2H),2.67(s,2H),1.69(m,2H),0.40(m,3H),0.15ppm(m,2H)
LCMS：MH+=318.1
化合物63：NMR(300MHz,CDCl3)：8.36(s,1H),8.23(m,1H),7.96(d,1H),7.76(m,1H)7.64(d,2H),7.56(m,1H),7.34(d,2H),2.68(s,2H),1.22(d,2H),1.02(s,6H),0.40(m,3H),0.15ppm(m,2H)
LCMS：MH+=360.1
化合物64：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=351.2
化合物65： NMR(400MHz,CDCl3)：7.93(d,1H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.46(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=365.2
化合物66：NMR(400MHz,CDCl3)：7.93(d,1H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.60(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),1.25(m,3H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=379.2
化合物67：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.52(m,1H),7.44(m,1H),7.35(m,1H),7.13(m,1H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=365.2
化合物68： NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.52(m,1H),7.44(m,1H),7.35(m,1H),7.13(m,1H),7.00(d,1H),4.36(m,2H),2.60(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),1.25(m,3H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=379.2
化合物69：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=365.2
化合物70：NMR(400MHz,CDCl3)：7.92(m,1H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),2.22(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=379.2
化合物71：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00 (d,1H),4.36(m,2H),2.53(s,2H),1.85(m,2H),1.05(m,3H),0.94ppm(s,9H)
LCMS：MH+=337.2
化合物72：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.43(m,4H),0.99(s,9H),0.97ppm(m,3H)
LCMS：MH+=351.2
化合物73：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),5.33(m,1H),2.54(s,2H),1.42(d,6H),0.96ppm(s,9H)
LCMS：MH+=337.2
化合物74：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.03(m,2H),2.41(s,2H),2.03(m,1H),1.53(m,4H),1.48(m,2H),1.43(m,2H),1.27(m,2H),0.94ppm(s,9H)
LCMS：MH+=391.2
化合物75：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H4.46(m,1H),4.21(m,1H),3.33(m,1H),2.79(m,1H),2.69(m,1H),2.41(s,2H),1.55(m,1H),1.48(m,2H),1.45(m,1H),0.94ppm(s,9H)
LCMS：MH+=392.2
化合物76：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.47(m,4H),7.38(m,4H),7.13(d,2H),7.00(d,1H),5.26(m,2H),2.53(s,2H),0.98ppm(s,9H)
LCMS：MH+=385.2
化合物77：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),3.91(m,1H),2.53(s,2H),1.99(m,2H),1.74(m,2H),1.53(m,2H),1.48(m,2H),1.43(m,2H),0.94ppm(s,9H)
LCMS：MH+=377.2
化合物78：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.63(m,1H),2.38(m,1H),2.04(m,1H),1.80(m,2H),1.55(m,2H),1.45(m,2H),0.96(m,3H),0.90ppm(m,6H)
LCMS：MH+=351.2
化合物79：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.54(m,2H),1.89(m,1H),1.80(m,2H),1.60(m,2H),1.56(m,2H),1.46(m,4H),1.35(m,2H),0.90ppm(m,3H)
LCMS：MH+=363.2
化合物80：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.29(m,2H),1.81(m,1H),1.53(m,4H),1.48(m,2H),1.44(m,2H),1.27(m,2H),0.90ppm(m,3H)
LCMS：MH+=377.2
化合物81： NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,3H),7.23(m,3H),7.13(d,2H),7.00(d,1H),4.36(m,2H),1.79(m,2H),1.51(m,2H),0.90ppm(m,3H)
LCMS：MH+=371.2
化合物82：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),1.80(m,2H),1.45(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=365.2
化合物83：NMR(400MHz,CDCl3)：7.92(m,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2,48(s,3H),2.42(m,5H),1.80(m,2H),1.45(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=379.2
化合物84：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.50(m,1H),7.46(m,1H),7.35(m,1H),7.13(m,1H), 7.00(d,1H),4.36(m,2H),2.48(s,3H),2.42(m,5H),1.80(m,2H),1.45(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=379.2
化合物85：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),2.34(s,3H),1.80(m,2H),1.45(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=379.2
化合物86：NMR(400MHz,CDCl3)：7.92(m,1H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),2.34(s,3H),2.22(s,3H),1.80(m,2H),1.45(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=393.2
化合物87：NMR(400MHz,CDCl3)：77.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),1.91(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=351.2
化合物88：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),1.80(m,2H),1.39(m,2H),1.31(m,2H),0.94(s,9H),0.90ppm(m,3H)
LCMS：MH+=379.2
化合物89：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),5.33(m,1H),2.54(s,2H),2.42(m,3H),1.42(d,6H),0.96ppm(s,9H)
LCMS：MH+=351.2
化合物90：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,5H),2.03(m,1H),1.53(m,4H),1.43(m,2H),1.27(m,2H),1.48(m,2H),0.94ppm(s,9H)
LCMS：MH+=405.2
化合物91： NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),3.33(m,1H),2.79(m,1H),2.69(m,1H),2.42(m,5H),1.55(m,1H),1.48(m,2H),1.45(m,1H),0.94ppm(s,9H)
LCMS：MH+=406.3
化合物92：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(m,4H)7.36(m,4H),7.13(d,2H),7.00(d,1H),5.26(m,2H),2.53(s,2H),0.98ppm(s,9H)
LCMS：MH+=399.2
化合物93：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),3.91(m,1H),2.42(s,2H),1.99(m,2H),1.74(m,2H),1.53(m,2H),1.48(m,2H),1.43(m,2H),0.94ppm(s,9H)
LCMS：MH+=391.3
化合物94：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.63(m,1H),2.42(m,3H),2.38(m,1H),2.04(m, 1H),1.80(m,2H),1.55(m,2H),1.45(m,2H),0.96(m,3H),0.90ppm(m,6H)
LCMS：MH+=365.2
化合物95：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.54(m,2H),2.42(m,3H),1.89(m,1H),1.80(m,2H),1.60(m,2H),1.56(m,2H),1.46(m,4H),1.35(m,2H),0.90ppm(m,3H)
LCMS：MH+=377.2
化合物96：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.42(m,3H),1.81(m,3H),1.53(m,4H),1.48(m,2H),1.44(m,4H),0.90ppm(m,3H)
LCMS：MH+=391.2
化合物97：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),1.79(m,2H),1.51(m,2H),0.92ppm(m,3H)
LCMS：MH+=385.2
化合物98：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=366.2
化合物99：NMR(400MHz,CDCl3)：7.94(m,1H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=380.2
化合物100：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.48(m,1H),7.36(m,1H),7.17(m,1H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=380.3
化合物101： NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=380.3
化合物102：NMR(400MHz,CDCl3)：7.96(m,1H),7.63(m,1H),7.49(d,2H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),2.22(s,3H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=394.3
化合物103：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(s,2H),2.02(s,2H),1.79(m,2H),1.50(m,4H),0.98(s,9H),0.96ppm(m,3H)
LCMS：MH+=380.3
化合物104：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),5.33 (m,1H),2.54(s,2H),2.02(s,2H),1.43(d,6H),0.96ppm(s,9H)
LCMS：MH+=352.2
化合物105：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.03(m,2H),2.53(s,2H),2.02(m,3H),1.52(m,4H),1.48(m,2H),1.43(m,2H),1.27ppm(m,2H)
LCMS：MH+=406.3
化合物106：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(m,4H),7.36(m,4H),7.17(d,2H),6.84(m,1H),5.26(m,2H),2.53(s,2H),2.02(s,2H),0.98ppm(s,9H)
LCMS：MH+=400.2
化合物107：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),3.91(m,1H),2.53(s,2H),2.02(s,2H),1.99(m,2H),1.74(m,2H),1.53(m,2H),1.48(m,2H),1.43(m,1H),0.98ppm(s,9H)
LCMS：MH+=392.3
化合物108：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.63(m,1H),2.38(m,1H),2.02(m,3H),1.79(m,2H),1.55(m,2H),1.51(m,2H),0.96(m,3H),0.92ppm(m,6H)
LCMS：MH+=366.2
化合物109：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(d,2H),2.02(s,2H),1.89(m,1H),1.79(m,2H),1.57(m,4H),1.51(m,2H),1.40(m,4H),0.99ppm(m,3H)
LCMS：MH+=378.2
化合物110：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,1H),7.17(d,2H),6.84(m,1H),4.36(m,2H),2.53(d,2H),2.02(s,2H),1.80(m,3H),1.51(m,6H),1.48(m,2H),1.43(m,2H),0.98ppm(m,3H)
LCMS：MH+=392.3
化合物111：NMR(400MHz,CDCl3)：7.98(m,2H),7.63(m,1H),7.49(d,2H),7.36(m,3H),7.23(m,3H),7.17(d,2H),6.84(m,1H),4.36(m,2H),3.96(s,2H),2.02(s,2H),1.79(m,2H),1.51(m,2H),0.98ppm(m,3H)
LCMS：MH+=386.2
化合物112：NMR(400MHz,CDCl3)：7.97(m,2H),7.62(m,1H),7.48(d,2H),7.36(m,1H),7.17(d,2H),6.90(m,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=369.2
化合物113：NMR(400MHz,CDCl3)：7.92(m,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(m,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=399.2
化合物114：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.50(m,1H),7.46(m,1H),7.35(m,1H),7.13(m,1H), 7.00(d,1H),4.36(m,2H),2.53(s,2H),2.48(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=443.2
化合物115：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=491.1
化合物116：NMR(400MHz,CDCl3)：7.94(m,1H),7.62(m,1H),7.48(d,2H),7.17(d,2H),6.90(m,1H),4.36(m,2H),2.53(s,2H),2.34(s,3H),2.22(s,3H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=397.3
化合物117：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.54(s,2H),1.79(m,2H),1.48(m,4H),0.98(s,9H),0.96ppm(m,3H)
LCMS：MH+=399.2
化合物118：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),5.33(m,1H),2.53(s,2H),1.42(d,6H),0.96ppm(s,9H)
LCMS：MH+=415.1
化合物119：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.03(m,2H),2.41(s,2H),2.03(m,1H),1.53(m,4H),1.48(m,2H),1.43(m,2H),1.27(m,2H),0.94ppm(s,9H)
LCMS：MH+=517.2
化合物120：NMR(400MHz,CDCl3)：7.97(m,2H),7.62(m,1H),7.47(m,4H),7.37(m,4H),7.17(d,2H),6.90(m,1H),5.26(m,2H),2.42(s,2H),0.94ppm(s,9H)
LCMS：MH+=403.2
化合物121：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),3.91 (m,1H),2.53(s,2H),1.99(m,2H),1.74(m,2H),1.49(m,4H),1.43(m,3H),0.96ppm(s,9H)
LCMS：MH+=411.2
化合物122：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.63(m,1H),2.38(m,1H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.96ppm(m,6H)
LCMS：MH+=429.1
化合物123：NMR(400MHz,CDCl3)：7.94(m,2H),7.59(m,1H),7.48(d,2H),7.34(m,3H),7.24(m,3H),7.13(d,2H),7.00(d,1H),4.36(m,2H),3.96(s,2H),1.79(m,2H),1.51(m,2H),0.98ppm(m,3H)
LCMS：MH+=497.1
化合物124：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.96(s,3H),2.53(s,2H),0.94ppm(m,9H)
LCMS：MH+=309.2
化合物125：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.95(s,3H),2.63(m,1H),2.38(m,1H),1.65(m,1H),1.21(m,2H),0.94(m,3H),0.87ppm(d,3H)
LCMS：MH+=309.2
化合物126：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.95(s,3H),2.63(m,2H),2.11(m,1H),1.65ppm(m,6H)
LCMS：MH+=321.2
化合物127：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.92(s,3H),2.48(d,2H),2.14(m,1H),1.24ppm(m,10H)
LCMS：MH+=335.2
化合物128： NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.34(m,3H),7.25(m,3H),7.13(d,2H),7.00(d,1H),3.92(s,3H),3.89ppm(s,2H)
LCMS：MH+=329.2
化合物129：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.93(s,3H),2.48(d,2H),1.88(m,1H),0.91ppm(d,6H)
LCMS：MH+=295.2
化合物130：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),3.92(s,3H),2.60(m,2H),1,62(m,2H),1.33(m,4H),0.90ppm(m,3H)
LCMS：MH+=309.2
化合物131：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),4.35(m,2H),2.49(d,2H),1.91(m,1H),1.78(m,2H),1.50(m,2H),0.95(m,3H),0.91ppm(d,6H)
LCMS：MH+=337.2
化合物132：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H)7.35(m,1H),7.13(d,2H),7.00(d,1H),4.37(m,2H),2.64(m,2H),1.85(m,2H),1.68(m,2H),1.53(m,2H),1.37(m,4H),098(m,3H),0.92ppm(m,3H)
LCMS：MH+=351.2
化合物133：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),2.53(s,2H),3.27(m,4H),1.92(m,4H),0.96ppm(s,9H)
LCMS：MH+=364.2
化合物134：NMR(400MHz,CDCl3)：8.11(m,2H),7.78(d,1H),7.65(m,1H),7.52(d,2H),7.37(m,1H),7.17(d,2H),7.06(d,1H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=295.2
化合物135： NMR(400MHz,CDCl3)：8.07(d,1H),7.78(d,1H),7.59(m,1H),7.52(d,2H),7.17(d,2H),7.06(d,1H),6.84(m,1H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=311.2
化合物136：NMR(400MHz,CDCl3)：8.09(m,2H),7.78(d,1H),7.52(d,2H),7.17(d,2H),7.07(m,2H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=311.2
化合物137：NMR(400MHz,CDCl3)：8.07(d,1H),7.78(d,1H),7.60(m,1H),7.52(d,2H),7.17(d,2H),7.13(m,1H),7.06(d,1H),6.55(s,2H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=310.2
化合物138：NMR(400MHz,CDCl3)：8.06(m,2H),7.78(d,1H),7.52(d,2H),7.41(m,1H),7.17(d,2H),7.06(d,1H),6.55(s,2H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=310.2
化合物139： NMR(400MHz,CDCl3)：8.07(d,1H),7.78(d,1H),7.59(m,1H),7.52(d,2H),7.21(m,1H),7.17(d,2H),7.06(d,1H),2.54(s,2H),2.48(s,3H),0.96ppm(s,9H)
LCMS：MH+=309.2
化合物140：NMR(400MHz,CDCl3)：8.04(m,2H),7.78(d,1H),7.55(m,1H),7.52(d,2H),7.17(d,2H),7.06(d,1H),2.54(s,2H),2.34(s,3H),0.96ppm(s,9H)
LCMS：MH+=309.2
化合物141：NMR(400MHz,CDCl3)：7.72(d,1H),7.59(m,2H),7.47(m,1H),7.46(d,2H),7.32(m,1H),7.13(d,2H),7.07(d,1H),6.60(s,1H),6.10(s,1H),2.53(s,2H),0.95ppm(s,9H)
LCMS：MH+=294.2
化合物142：NMR(400MHz,CDCl3)：8.34(s,1H),8.17(m,1H),8.04(m,2H),7.74(m,3H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=401.2
化合物143：NMR(400MHz,CDCl3)：8.37(s,1H),7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(m,1H),7.35(m,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物144：NMR(400MHz,CDCl3)：8.39(s,1H),7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(m,1H),7.35(m,1H),7.13(m,1H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物145：NMR(400MHz,CDCl3)：8.61(m,1H),7.92(m,1H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物146： NMR(400MHz,CDCl3)：9.17(s,1H),8.27(m,1H),7.94(m,1H),7.74(d,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物147：NMR(400MHz,CDCl3)：8.90(s,1H),8.00(m,1H),7.94(d,1H),7.74(d,1H),7.48(d,2H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物148：NMR(400MHz,CDCl3)：8.76(m,1H),7.94(m,1H),7.74(d,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00(d,1H),4.36(m,2H),2.53(s,2H),1.79(m,2H),1.51(m,2H),0.99(m,3H),0.98ppm(s,9H)
LCMS：MH+=352.2
化合物149：NMR(400MHz,CDCl3)：7.94(m,2H),7.74(d,1H),7.59(m,1H),7.48(d,2H),7.35(m,1H),7.13(d,2H),7.00 (d,1H),4.36(m,4H),2.53(s,2H),1.79(m,4H),1.51(m,4H),0.99(m,6H),0.98ppm(s,9H)
LCMS：MH+=451.3
化合物150：NMR(400MHz,CDCl3)：8.15(d,1H),7.78(d,1H),7.52(d,2H),7.31(m,1H),7.17(d,2H),7.06(d,1H),7.12(m,1H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=311.2
化合物151：NMR(400MHz,CDCl3)：8.15(d,1H),7.78(d,1H),7.52(d,2H),7.41(m,1H),7.32(m,1H),7.17(d,2H),7.06(d,1H),6.55(s,2H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=310.2
化合物152：NMR(400MHz,CDCl3)：8.15(d,1H),7.78(d,1H),7.52(d,2H),7.49(m,1H),7.29(m,1H),7.17(d,2H),7.06(d,1H),2.54(s,2H),2.48(s,3H),0.96ppm(s,9H)
LCMS：MH+=309.2
化合物153： NMR(400MHz,CDCl3)：8.09(m,2H),7.78(d,1H),7.52(d,2H),7.17(d,2H),7.06(d,1H),6.81(m,1H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=311.2
化合物154：NMR(400MHz,CDCl3)：8.10(m,2H),7.78(d,1H),7.52(d,2H),7.17(d,2H),7.14(m,1H),7.06(d,1H),6.55(s,2H),2.54(s,2H),0.96ppm(s,9H)
LCMS：MH+=310.2
化合物155：NMR(400MHz,CDCl3)：8.10(m,2H),7.78(d,1H),7.52(d,2H),7.21(m,1H),7.17(d,2H),7.06(d,1H),2.54(s,2H),2.34(s,3H),0.96ppm(s,9H)
LCMS：MH+=309.2

Claims (18)

  1. 一種由以下化學式1表示的二苯乙烯衍生物或其醫藥學上可接受的鹽： 在化學式1中，A為CRa或N，B為CRb或N，G為CRe或N，J為CRf或N，M為CRg或N，D、E、及L為CRh或N，Rx為H、CH 3、CN、NH 2、F、Cl、Br或I，其中當Rx為H、CH 3、NH 2、F、Cl、Br或I時，Ra為氫、NO 2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)， Rc為OH、NO 2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Rd為鹵素、NO 2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為 C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、NH 2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf為氫、NH 2、OH、NO 2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12雜環基、-NHR11(R11為C1-C2烷基)、-COOR12(R12為C1-C2烷基)、-OCOR13(R13為C1-C2烷基)、或-COR14(R14為C1-C2烷基)，Rg為氫、NH 2、OH、鹵素、NO 2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或 C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，及Rh為氫、NH 2、OH、C1-C5烷基或C2-C10烯基，當Rx為CN時，Ra為氫，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO 2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基、或C5-C12雜環基)，Rd為氫、鹵素、NO 2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4 連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf及Rg各自為氫，及Rh為氫、C1-C5烷基或C2-C10烯基，前述雜環基之雜原子為選自由氮、氧及硫組成之群的至少一者，前述烷基經選自由以下各項組成之群的至少一個取代基取代：OH、胺、C6-C12芳基、C5-C10雜環基及C3-C10環烷基，前述烷氧基經選自由以下各項組成之群的至少一個取代基取代：鹵素、C6-C12芳基、C3-C10環烷基、胺及胺基羰基， 前述雜環基經選自由以下各項組成之群的至少一個取代基取代：烷基、經胺取代之烷基、胺、醯胺基及羧基，前述芳基經選自由以下各項組成之群的至少一個取代基取代：鹵素、烷基、羥基、烷氧基、羧基、酯基、硝基及胺基，A、B、D、E、G、J、L及M與相鄰基團連接來形成稠合環，及當Rb為CH 3時，Rd不為NO 2。
  2. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中A為CRa或N，B為CRb，G為CRe，J為CRf，M為CRg或N，且D、E及L為CH。
  3. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中Rb為氫或C1-C8烷基。
  4. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中Rc為C1-C20烷基、C2-C10烷氧基、苯基烷基、硝基、C3-C10環烷基、C5-C12雜環基或C1-C10烷基酮。
  5. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中Rd為C2-C20烷基；C3-C10酯基；C3-C10環烷基；經環烷基取代之甲氧基；經胺基取代之乙氧基；羧基；經苯基取代之C2-C20烷基，前述苯基為未經取代的或經C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；嗎啉；或 -COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)。
  6. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中Re為氫、OH、C1-C20烷基或C1-C10烷氧基。
  7. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中Rg為氫、OH、C1-C20烷基；C3-C10酯基；C3-C10環烷基；經環烷基取代之甲氧基；經胺基取代之乙氧基；經苯基取代之C2-C20烷基，前述苯基為未經取代的或經C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；嗎啉；或羧基。
  8. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中前述烷基為-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH 2(CH 2) 2CH 3、-CH 2(CH 2) 3CH 3、-CH(CH 3)CH 2CH 3、-CH 2CH(CH 3)CH 2CH 3、-CH 2CH 2CH(CH 3) 2、-CH(CH 3) 2、-C(CH 3) 3、-CH 2C(CH 3) 3、-CH 2CH(CH 3) 2、-CH(CH 3)CH(CH 3) 2、-CH(CH 3)C(CH 3) 3、-C(CH 3) 2CH 2CH 3、-C(CH 3) 2CH(CH 3) 2、-C(CH 3) 2C(CH 3) 3、-CH 2CH 2C(CH 3) 3、-CH 2CH(CH 3)CH(CH 3) 2、-CH 2CH 2C(CH 3) 2CH 2CH 3、-CH 2CH 2CH(CH 3)CH 2C(CH 3) 3、-CH 2Ph、CH 2CH 2Ph、 或
  9. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中前述烷氧基為-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2CH 3、-OCH(CH 3)CH 2CH 3、-OCH 2CONH 2、-OCH 2CH 2N(CH 3) 2、 或
  10. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可 接受的鹽，其中前述雜環基為 、或
  11. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中-COOR5為COOCH 3、-COOCH 2CH 3、COO(CH 2) 2CH 3、-COO(CH 2) 3CH 3、COO(CH 2) 4CH 3、 COOCH(CH 3) 2、 或
  12. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可 接受的鹽，其中-OCOR6為 或
  13. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其中-NR3R4為-NH 2、-NHCH 3、-N(CH 3) 2、 或
  14. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可 接受的鹽，其中-NR7CYR8為 或
  15. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可 接受的鹽，其中-NHS(O) 2R9為 或
  16. 如請求項1所記載之二苯乙烯衍生物或其醫藥學上可接受的鹽，其為選自由以下化合物1至化合物155組成之群的任一者： 。
  17. 一種製備由以下化學式1表示的二苯乙烯衍生物之方法，其包含以下步驟：使由以下化學式2表示的苯基乙腈衍生物與由以下化學式3表示的苯甲醛衍生物反應： 在化學式1、化學式2及化學式3中，A為CRa或N，B為CRb或N，G為CRe或N，J為CRf或N，M為CRg或N， D、E、及L為CRh或N，Rx為CN，Ra為氫，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO 2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基、或C5-C12雜環基)，Rd為氫、鹵素、NO 2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環 烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)或-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf及Rg各自為氫，Rh為氫、C1-C5烷基或C2-C10烯基，前述雜環基之雜原子為選自由氮、氧及硫組成之群的至少一者，前述烷基經選自由以下各項組成之群的至少一個取代基取代：OH、胺、C6-C12芳基、C5-C10雜環基及C3-C10環烷基，前述烷氧基經選自由以下各項組成之群的至少一個取代基取代：鹵素、C6-C12芳基、C3-C10環烷基、胺及胺基羰基， 前述雜環基經選自由以下各項組成之群的至少一個取代基取代：烷基、經胺取代之烷基、胺、醯胺基及羧基，前述芳基經選自由以下各項組成之群的至少一個取代基取代：鹵素、烷基、羥基、烷氧基、羧基、酯基、硝基及胺基，A、B、D、E、G、J、L及M與相鄰基團連接來形成稠合環，及當Rb為CH 3時，Rd不為NO 2。
  18. 一種製備由以下化學式1表示的二苯乙烯衍生物之方法，其包含以下步驟：使由以下化學式4表示的烯烴衍生物與由以下化學式5表示的有機鹵化物衍生物反應： Rx=H,CH 3,NH 2,F,Cl,Br,I 在化學式1、化學式4及化學式5中，A為CRa或N，B為CRb或N，G為CRe或N，J為CRf或N，M為CRg或N，D、E、及L為CRh或N，X為F、Cl、Br或I，Rx為H、CH 3、NH 2、F、Cl、Br或I，Ra為氫、NO 2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rb為氫、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1為氫或C1-C5烷基)或-OCOR2(R2為C1-C5烷基)，Rc為OH、NO 2、C1-C20烷基、C3-C10環烷基、C2-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為 C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Rd為鹵素、NO 2、COOH、CN、C2-C20烷基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Re為氫、NH 2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或 C5-C12雜環基)或-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)，Rf為氫、NH 2、OH、NO 2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12雜環基、-NHR11(R11為C1-C2烷基)、-COOR12(R12為C1-C2烷基)、-OCOR13(R13為C1-C2烷基)、或-COR14(R14為C1-C2烷基)，Rg為氫、NH 2、OH、鹵素、NO 2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10環烷基、C1-C10烷氧基、C6-C12芳基、C5-C12雜環基、-NR3R4(R3為氫、C1-C20烷基或C6-C12芳基，R4為氫、C1-C20烷基或C6-C12芳基，且R3及R4連接來形成雜環，進一步含有至少一個雜原子)、-COOR5(R5為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-OCOR6(R6為C1-C20烷基、C6-C12芳基或C3-C10環烷基)、-NR7CYR8(Y為O或S，R7為氫或C1-C5烷基，且R8為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)、-NHS(O) 2R9(R9為C6-C12芳基或C5-C12雜環基)、或-COR10(R10為C1-C20烷基、C6-C12芳基、C3-C10環烷基或C5-C12雜環基)，Rh為氫、NH 2、OH、C1-C5烷基或C2-C10烯基，前述雜環基之雜原子為選自由氮、氧及硫組成之群的至少一者， 前述烷基經選自由以下各項組成之群的至少一個取代基取代：OH、胺、C6-C12芳基、C5-C10雜環基及C3-C10環烷基，前述烷氧基經選自由以下各項組成之群的至少一個取代基取代：鹵素、C6-C12芳基、C3-C10環烷基、胺及胺基羰基，前述雜環基經選自由以下各項組成之群的至少一個取代基取代：烷基、經胺取代之烷基、胺、醯胺基及羧基，前述芳基經選自由以下各項組成之群的至少一個取代基取代：鹵素、烷基、羥基、烷氧基、羧基、酯基、硝基及胺基，及A、B、D、E、G、J、L及M與相鄰基團連接來形成稠合環。
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Publication number Priority date Publication date Assignee Title
US3201481A (en) * 1964-04-15 1965-08-17 Gen Aniline & Film Corp Method of preparing 4-nitrostilbenes
US3555071A (en) * 1967-10-17 1971-01-12 Upjohn Co Isocyanatostilbenes
JPS61175646A (ja) 1985-01-31 1986-08-07 Canon Inc 電子写真感光体
BR0109107A (pt) 2000-03-09 2002-12-03 Aventis Pharma Gmbh Usos terapêuticos de mediadores ppar
DK1324970T3 (da) 2000-10-02 2009-01-05 Hoffmann La Roche Retinoider til behandling af emfysem
JP2003020477A (ja) * 2001-07-09 2003-01-24 Toyo Ink Mfg Co Ltd 有機エレクトロルミネッセンス素子用材料およびそれを使用した有機エレクトロルミネッセンス素子
JP4500689B2 (ja) * 2002-12-26 2010-07-14 エーザイ・アール・アンド・ディー・マネジメント株式会社 選択的エストロゲン受容体モジュレーター
EP2332527A3 (en) * 2004-10-20 2011-11-16 Resverlogix Corp. Flavanoids and Isoflavanoids for the prevention and treatment of cardiovascular diseases
CN1817863A (zh) 2006-03-13 2006-08-16 中国科学院上海药物研究所 3－取代的1，2，3，4－四氢喹啉衍生物及其合成方法和用途
CN100586937C (zh) * 2007-06-13 2010-02-03 山东大学 川芎嗪茋类衍生物、制备方法和药物组合物与应用
JP5630013B2 (ja) * 2009-01-30 2014-11-26 ソニー株式会社 液晶表示装置の製造方法
WO2010113005A2 (en) 2009-03-27 2010-10-07 Council Of Scientific & Industrial Research One pot multicomponent synthesis of some novel hydroxy stilbene derivatives with alpha, beta-carbonyl conjugation under microwave irradiation
EP2289883A1 (en) * 2009-08-19 2011-03-02 Phenex Pharmaceuticals AG Novel FXR (NR1H4) binding and activity modulating compounds
WO2011141515A1 (en) * 2010-05-14 2011-11-17 Bayer Pharma Aktiengesellschaft Diagnostic agents for amyloid beta imaging
JO3063B1 (ar) 2011-03-29 2017-03-15 Neurovive Pharmaceutical Ab مركب مبتكر وطرق لانتاجه
DE102011118606A1 (de) 2011-11-15 2013-05-16 Philipps-Universität Marburg Stilben-Verbindungen als PPAR beta/delta Inhibitoren für die Behandlung von PPAR beta/delta-vermittelten Erkrankungen
EP2801347B1 (en) * 2013-05-10 2019-08-07 Rahn Ag Carboxylated stilbenes for activating AMPK and sirtuins
EP2801357A1 (en) * 2013-05-10 2014-11-12 IMD Natural Solutions GmbH Carboxylated stilbenes for activating AMPK and sirtuins
EP3074481A2 (en) 2013-11-28 2016-10-05 Rolic AG Conducting and semi-conducting alignment materials
CN104193596B (zh) 2014-08-28 2016-04-27 浙江大学 反式邻羟基二苯乙烯衍生物及其制备方法和应用
GB201416273D0 (en) 2014-09-15 2014-10-29 Isis Innovation Therapeutic compounds
JP2017222576A (ja) * 2014-10-31 2017-12-21 石原産業株式会社 有害生物防除剤
CN105503652B (zh) 2015-12-30 2017-12-05 延边大学 含氰基白藜芦醇类似物及其制备方法和用途
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CN105837388B (zh) * 2016-04-22 2018-08-28 同济大学 烷基和烯基修饰的双官能团化联苯类化合物的制备方法
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