CN109790107A - 二苯乙烯衍生物及其制备方法 - Google Patents

二苯乙烯衍生物及其制备方法 Download PDF

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CN109790107A
CN109790107A CN201780057502.XA CN201780057502A CN109790107A CN 109790107 A CN109790107 A CN 109790107A CN 201780057502 A CN201780057502 A CN 201780057502A CN 109790107 A CN109790107 A CN 109790107A
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alkyl
aryl
heterocycle
hydrogen
naphthenic base
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李珉京
李镇珏
韩元硕
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Ozil Co
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Ozil Co
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Priority claimed from PCT/KR2017/010998 external-priority patent/WO2018062953A1/ko
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Abstract

本发明涉及二苯乙烯衍生物及其制备方法。更具体地，本发明涉及抑制亲环蛋白之功能且有效预防亲环蛋白相关疾病或治疗其症状的新颖的二苯乙烯衍生物，以及制备该二苯乙烯衍生物的方法。

Description

二苯乙烯衍生物及其制备方法
技术领域
本发明涉及用于抑制亲环蛋白(cyclophilin)之功能的具有改良医药概况的新颖二苯乙烯衍生物及其制备方法。
背景技术
亲环蛋白已知为用于许多疾病的有效药物标靶，该等疾病包括病毒感染疾病，诸如B型肝炎病毒(hepatitis B virus；HBV)、C型肝炎病毒(hepatitis C virus；HCV)、人类免疫缺陷病毒(human immunodeficiency virus；HIV)、流感病毒等等；藉由发炎反应引起的疾病，诸如心血管疾病；类风湿性关节炎；败血症；哮喘；牙周炎；老化；秃发(alopecia)；藉由粒线体功能异常引起的神经退化性疾病；癌症及类似者(Nigro P等人,Cell DeathDis 2013,4,e888)。
亲环蛋白(CyP)属于免疫亲和蛋白家族的蛋白质，在所有生物体(原核生物及真核生物两种)的所有细胞中皆发现该亲环蛋白，且其历经演化已在结构上得以良好保存。人类含有总共16种存在于人类中的内源蛋白质，包括七种主要CyP，即CyP A、CyP B、CyP C、CyPD、CyP E、CyP 40、及CyP NK。
亲环蛋白在人体内的大多数细胞中被发现，且哺乳动物中的CyP A及CyP 40具有细胞质讯息序列，而CyP B及CyP C具有靶向至内质网的N-末端讯息序列。CyP D具有导向至粒线体的讯息序列，CyP E具有胺基末端RNA结合结构域且位于核内，而CyP 40具有TPR且位于细胞质。人类CyP NK为最大的CyP，其具有大的亲水性及带正电羧基末端，且位于细胞质内。
亲环蛋白是涉及细胞过程的多功能蛋白质且负责细胞中的必需功能。已证明亲环蛋白具有催化肽酰基-脯胺酰基键的顺反异构化的酶性质。因此，亲环蛋白称为肽酰基脯胺酰基顺反异构酶(PPIase)，其可充当新合成蛋白质的恰当折迭中的加速因子。PPIase亦涉及修复归因于包括热应力的环境应力、紫外辐射、细胞环境pH的改变、及氧化剂处理的受损蛋白质。此功能称为分子伴护蛋白(chaperone)活性。亲环蛋白的PPIase活性亦已被证明涉及细胞内蛋白质通行、粒线体功能及前驱传讯RNA处理。
环孢素是可利用亲环蛋白抑制剂之一，其结合于CyP A的疏水性凹穴中以因此抑制PPIase活性。CyP A为亲环蛋白家族的原型，且在人类中展示与CyP B、CyP C、及CyP D的极高序列同源性。所有亲环蛋白的结合凹穴是藉由相应于高度保守区域的大致109个胺基酸形成，且CyP A与CyP D之间的序列同源性为100％。因此，CyP A结合亲和力为CyP D结合亲和力的最佳预测物且反之亦然。
亲环蛋白之间的此种序列同源性暗示不仅CyP D而且所有亲环蛋白为针对具有对CyP A的结合亲和力的功能抑制剂的潜在标靶，此指示CyP A的功能抑制剂可适用于治疗藉由与亲环蛋白相关的众多细胞内过程引起的许多疾病。
发明内容
因此，本发明意欲提供一种用于抑制亲环蛋白之功能的具有改良医药概况使得能预防疾病或治疗此种疾病的症状的化合物且还提供其制备方法，该等疾病包括病毒感染疾病，诸如HBV、HCV、HIV、流行性感冒及类似者；心血管疾病；类风湿性关节炎；败血症；哮喘；牙周炎；老化；秃发；神经退化性疾病；癌症等等。
因此，本发明提供一种能够抑制亲环蛋白之功能的化合物。本发明提供由下文化学式1表示的二苯乙烯衍生物、其医药学上可接受的盐、水合物、水合盐、多态晶体结构、外消旋物、非对映异构物、或镜像异构物。其是用于预防亲环蛋白相关疾病或用于治疗此种疾病的症状。
[化学式1]
在化学式1中，
A为CRa或N，
B为CRb或N，
G为CRe或N，
J为CRf或N，
M为CRg或N，
D、E、及L为CRh或N，
Rx为H、CH3、CN、NH2、F、Cl、Br或I，
其中当Rx为H、CH3、NH2、F、Cl、Br或I时，
Ra为氢、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Rd为卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf为氢、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12杂环基、-NHR11(R11为C1-C2烷基)、-COOR12(R12为C1-C2烷基)、-OCOR13(R13为C1-C2烷基)、或-COR14(R14为C1-C2烷基)，
Rg为氢、NH2、OH、卤素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，及
Rh为氢、NH2、OH、C1-C5烷基或C2-C10烯基，
当Rx为CN时，
Ra为氢，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基、或C5-C12杂环基)，
Rd为氢、卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf及Rg各自为氢，及
Rh为氢、C1-C5烷基或C2-C10烯基，
杂环基的杂原子可为选自由氮、氧及硫组成之群的至少一者，
烷基可经选自由以下各项组成之群的至少一个取代基取代：OH、胺、C6-C12芳基、C5-C10杂环基及C3-C10环烷基，
烷氧基可经选自由以下各项组成之群的至少一个取代基取代：卤素、C6-C12芳基、C3-C10环烷基、胺及胺基羰基，
杂环基可经选自由以下各项组成之群的至少一个取代基取代：烷基、经胺取代的烷基、胺、酰胺基及羧基，
芳基可经选自由以下各项组成之群的至少一个取代基取代：卤素、烷基、羟基、烷氧基、羧基、酯基、硝基及胺基，
A、B、D、E、G、J、L及M可与相邻基团连接来形成稠合环，及
当Rb为CH3时，Rd不可为NO2。
根据本发明，二苯乙烯衍生物在抑制亲环蛋白之功能方面为有效的，且因此适用于预防亲环蛋白相关疾病，或用于治疗此种疾病的症状，该等疾病包括病毒感染疾病，诸如C型肝炎病毒(HCV)、B型肝炎病毒(HBV)、人类免疫缺陷病毒(HIV)、家禽流行性感冒(avianinfluenza；AI)病毒及类似者；心血管疾病；类风湿性关节炎；败血症；哮喘；牙周炎；老化；秃发；神经退化性疾病；癌症等等。此外，本发明的二苯乙烯衍生物可用于与现存治疗剂组合来由此增加治疗效果。
具体实施方式
下文，将给出本发明的详细描述。
本发明针对由下文化学式1表示的二苯乙烯衍生物。本发明的二苯乙烯衍生物具有适于结合至维持在具有亲环蛋白之功能的任何蛋白质中的活性凹穴的结构且因此适于用作亲环蛋白抑制剂。
[化学式1]
在化学式1中，
A为CRa或N，
B为CRb或N，
G为CRe或N，
J为CRf或N，
M为CRg或N，
D、E、及L为CRh或N，
Rx为H、CH3、CN、NH2、F、Cl、Br或I，
其中当Rx为H、CH3、NH2、F、Cl、Br或I时，
Ra为氢、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Rd为卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf为氢、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12杂环基、-NHR11(R11为C1-C2烷基)、-COOR12(R12为C1-C2烷基)、-OCOR13(R13为C1-C2烷基)、或-COR14(R14为C1-C2烷基)，
Rg为氢、NH2、OH、卤素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，及
Rh为氢、NH2、OH、C1-C5烷基或C2-C10烯基，
当Rx为CN时，
Ra为氢，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基、或C5-C12杂环基)，
Rd为氢、卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4可连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf及Rg各自为氢，及
Rh为氢、C1-C5烷基或C2-C10烯基，
杂环基的杂原子可为选自由氮、氧及硫组成之群的至少一者，
烷基可经选自由以下各项组成之群的至少一个取代基取代：OH、胺、C6-C12芳基、C5-C10杂环基及C3-C10环烷基，
烷氧基可经选自由以下各项组成之群的至少一个取代基取代：卤素、C6-C12芳基、C3-C10环烷基、胺及胺基羰基，
杂环基可经选自由以下各项组成之群的至少一个取代基取代：烷基、经胺取代的烷基、胺、酰胺基及羧基，
芳基可经选自由以下各项组成之群的至少一个取代基取代：卤素、烷基、羟基、烷氧基、羧基、酯基、硝基及胺基，
A、B、D、E、G、J、L及M可与相邻基团连接来形成稠合环，及
当Rb为CH3时，Rd不可为NO2。
本发明的化合物可经由各种方法合成，且典型地其中化学式1的Rx为CN的状况的合成过程可不同于其他状况的彼等合成过程。
当Rx为CN时，由化学式1表示的二苯乙烯衍生物可藉由使由下文化学式2表示的苯基乙腈衍生物与由下文化学式3表示的苯甲醛衍生物反应来制备。
由化学式2表示的苯基乙腈衍生物及由化学式3表示的苯甲醛衍生物可为可商购产品，或可在经由此项技术中所知的方法制备之后使用。
上文反应可在有机溶剂存在下或在无任何溶剂的情况下进行。在此状况下，使用微波时，反应时间可减少且产率可增加。
有机溶剂不受限制，但优选地包括醇，且更优选地为丁醇、甲醇、乙醇、或丙醇。诸如三苯基膦、哌啶或类似物的催化剂可添加来促进反应。
[化学式1]
Rx＝CN
[化学式2]
[化学式3]
在化学式2及化学式3中，
A、B、D、E、G、J、L、M、Rc及Rd是如化学式1的A、B、D、E、G、J、L、M、Rc及Rd中所定义。
当Rx为H、CH3、NH2、F、Cl、Br或I时，由化学式1表示的二苯乙烯衍生物可藉由使由下文化学式4表示的烯烃衍生物与由下文化学式5表示的有机卤化物衍生物反应来制备。
由化学式4表示的烯烃衍生物及由化学式5表示的有机卤化物衍生物可为可商购产品，或可在经由此项技术中所知的制程制备之后使用。
上文反应优选地使用三乙醇胺有机溶剂在乙酸钯(II)催化剂存在下进行。
[化学式1]
Rx＝H、CH3、NH2、F、Cl、Br、I
[化学式4]
[化学式5]
在化学式4及化学式5中，
Rx为氢、CH3、NH2、F、Cl、Br或I，
X为F、Cl、Br或I，及
A、B、D、E、G、J、L、M、Rc及Rd是如化学式1的A、B、D、E、G、J、L、M、Rc及Rd中所定义。
根据本发明的由化学式1表示的二苯乙烯衍生物可连同医药学上可接受的载剂一起用作亲环蛋白相关疾病的预防剂或治疗剂。
此外，根据本发明的由化学式1表示的二苯乙烯衍生物可用作用于亲环蛋白相关疾病的治疗剂之效力的比较参考材料。
在本发明中，烷基或烯基可为直链或支链。
如本文所使用，术语“卤素原子”可指氟、氯、溴或碘。
在本发明中，当A、B、D、E、G、J、L及M与相邻基团连接以形成稠合环时，该稠合环优选地为六员环或五员环。此外，稠合环可含有诸如N、O及S的杂原子之至少一者。稠合环可为呋喃或噻吩。
在本发明的实施例中，A优选为CRa或N，B优选为CRb，G优选为CRe，J优选为CRf，M优选为CRg或N，且D、E及L优选为CH，但本发明不限于此。
在本发明的另一实施例中，Rb优选为氢或C1-C8烷基，但本发明不限于此。
在本发明的又一实施例中，Rc优选为C1-C20烷基、C2-C10烷氧基、苯基烷基、硝基、C3-C10环烷基、C5-C12杂环基或C1-C10烷基酮，但本发明不限于此。
在本发明的另一实施例中，Rd优选为C2-C20烷基；C3-C10酯基；C3-C10环烷基；经环烷基取代的甲氧基；经胺基取代的乙氧基；羧基；经苯基取代的C2-C20烷基，该苯基为未经取代的或经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；吗啉；或-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)，但本发明不限于此。
在本发明的又一实施例中，Re优选为氢、OH、C1-C20烷基、或C1-C10烷氧基，但本发明不限于此。
在本发明的另一实施例中，Rg优选为氢、OH、C1-C20烷基；C3-C10酯基；C3-C10环烷基；经环烷基取代的甲氧基；经胺基取代的乙氧基；经苯基取代的C2-C20烷基，该苯基为未经取代的或经C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；吗啉；或羧基，但本发明不限于此。
在本发明的另一实施例中，Rh优选为氢，但本发明不限于此。
在本发明中，烷基可为经取代或未经取代的烷基，诸如-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、 但本发明不限于此。
在本发明中，烷氧基可为经取代或未经取代的烷氧基，诸如-OCH3、-OCF3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、-OCH(CH3)CH2CH3、-OCH2CONH2、-OCH2CH2N(CH3)2、 但本发明不限于此。
在本发明中，杂环基可为 但本发明不限于此。
在本发明中，-NR3R4可为-NH2、-NHCH3、-N(CH3)2、 但本发明不限于此。
在本发明中，-COOR5可为COOCH3、-COOCH2CH3、COO(CH2)2CH3、-COO(CH2)3CH3、COO(CH2)4CH3、COOCH(CH3)2、但本发明不限于此。
在本发明中，-OCOR6可为 但本发明不限于此。
在本发明中，-NR7CYR8基团可为 但本发明不限于此。
在本发明中，-NHS(O)2R9基团可为 但本发明不限于此。
在本发明中，COR10可为COC(CH3)3，但本发明不限于此。
如本文所使用，术语“医药学上可接受的载剂”可定义为不损害组合物之生物活性或性质的载剂或稀释剂。
医药学上可接受的载剂或添加剂可包括典型使用的稀释剂或赋形剂的至少一者，诸如稳定剂、填料、增量剂、润湿剂、崩解剂、润滑剂、黏合剂、表面活性剂、及类似者。
崩解剂可包括琼脂、淀粉、海藻酸或其钠盐、无水磷酸氢钙、及类似者。润滑剂可包括硅石、滑石、硬脂酸或其镁盐或钙盐、聚乙二醇、偏硅酸镁铝、及类似者。黏合剂可包括硅酸镁铝、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯啶酮、低级经取代羟丙基纤维素、及类似者。
除此之外，乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素或甘胺酸可用作稀释剂。在一些状况下，通常已知的煎盐(boiling salt)、吸收剂、着色剂、调味剂、甜味剂及类似者可与其一起使用。
此外，稳定剂可包括无钠(Na)稳定剂，其实例包括偏硅酸镁铝、硅酸镁铝、铝酸镁、无水氢氧化铝、合成水滑石、合成硅酸铝、碳酸镁、沉淀碳酸钙、氧化镁、氢氧化铝、L-精胺酸、磷酸钾、磷酸氢二钾、磷酸二氢钾、氯化铵、氯化铝、及类似者，其可单独使用或以其两个或两个以上者之组合使用。
含有本发明的化学式1的二苯乙烯衍生物的药物组合物可以促进将化合物给予至生物体中的各种方式来给药。含有本发明的化合物的药物组合物可经由口服给药、直肠内给药、阴道内给药、鼻内给药、眼内给药、口内给药、舌下给药、皮下给药、肌肉内给药、静脉内给药、鞘内给药、真皮内给药、硬膜上给药、及类似者来给药。
含有本发明的化合物的药物组合物可以锭剂、胶囊、粉末、滴丸、散剂、推注剂、酊剂或泥罨剂(cataplasm)的剂型来提供。优选锭剂可为典型锭剂、包衣锭剂、可分散锭剂、发泡性锭剂等等，或可为多压缩锭剂，诸如双锭剂、嵌套锭剂(tablet-in-tablet)、多层锭剂等等。
包括在含有本发明的化合物的药物组合物中的二苯乙烯衍生物或其医药学上可接受的盐的优选给药量取决于患者的状态及体重、疾病的严重性、药物的类型、给药路线及持续时间而变化，但可藉由熟习此项技术者做出适当选择。
本发明的更好理解可经由以下非限制性实例达成，该等非限制性实例仅仅阐述来说明但不意欲解释为限制本发明的范畴。以下实例可经适当修饰且在本发明的范畴内更改。
实例1.其中Rx为CN的二苯乙烯衍生物的制备
1)溶剂的使用
将1当量的化学式2的苯基乙腈衍生物及1.3当量的化学式3的苯甲醛衍生物与0.2当量的三苯基膦在丁醇溶剂中回流，继之以Knoevenagel缩合反应，因此产生化学式1的化合物。
2)微波的使用
将1当量的化学式2的苯基乙腈衍生物、1.3当量的化学式3的苯甲醛衍生物及0.2当量的三苯基膦利用微波处理，因此产生化学式1的化合物。当使用微波时，反应时间可缩短且产率可增加。
[方案1]
实例2.其中Rx为氢、CH3、NH2、F、Cl、Br、I的衍生物的制备
将1当量的化学式4的烯烃衍生物及1当量的化学式5的有机卤化物衍生物与0.01当量的乙酸钯(II)在三乙醇胺溶剂中回流，继之以Heck烯化反应，因此产生化学式1的化合物。
[方案2]
测试实例1.二苯乙烯衍生物的顺反异构酶抑制活性的评估
胰凝乳蛋白酶分解反式丙胺酸-脯胺酸肽键。当Suc-AAPF-pNA(肽底物)及胰凝乳蛋白酶混合时，反式肽底物经分解，且顺式肽底物保留。剩余的顺式肽底物藉由顺反异构酶转化成反式，且随后再次藉由胰凝乳蛋白酶分解。当存在顺反异构酶时，胰凝乳蛋白酶能够在预定时间段内分解较大量的反式肽底物，由此可测定顺反异构酶的活性。经分解的反式肽底物的量是使用在390nm下的吸亮度来量测。
亲环蛋白具有顺反异构酶活性，且促进反式肽底物藉由胰凝乳蛋白酶的分解。当本发明的二苯乙烯衍生物连同亲环蛋白一起处理时，未观察到肽底物藉由胰凝乳蛋白酶的分解加速。由此，可断定本发明的二苯乙烯衍生物抑制亲环蛋白的活性。
下文化合物1至化合物155(表1至表10)可如下基于顺反异构酶抑制活性(IC50)值来分组：
A组(GA)：2000nM或更小但超过200nM的IC50，
B组(GB)：200nM或更小但超过20nM的IC50，及
C组(GC)：20nM或更小的IC50。
[表1]
[表2]
[表3]
[表4]
[表5]
[表6]
[表7]
[表8]
[表9]
[表10]
测试实例2.二苯乙烯衍生物的细胞毒性的评估
量测二苯乙烯衍生物的细胞毒性。将稳定复制C型肝炎病毒基因组的复制子细胞涂覆至96孔板且在CO2培养器中在37℃下培养24小时。将培养一天的复制子细胞用磷酸盐缓冲盐水(phosphate buffered saline；PBS)溶液洗涤，用本发明的化合物处理，且随后培养72小时。其后，经由MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物]细胞毒性测试，量测本发明的化合物的CC50值。本发明的化合物的CC50值为200μM或更大。例如，化合物64具有320μM的CC50，化合物65具有284μM的CC50，且化合物66具有245μM的CC50。因此，本发明的化学式1的化合物不展现细胞毒性。
测试实例3.二苯乙烯衍生物的抗病毒活性的评估
量测二苯乙烯衍生物对C型肝炎病毒的抗病毒活性。将稳定复制C型肝炎病毒基因组的复制子细胞涂覆至培养板且在CO2培养器中在37℃下培养24小时。将培养一天的复制子细胞用PBS溶液洗涤，用本发明的化合物处理，且随后培养72小时。将二苯乙烯衍生物处理的复制子细胞用冷PBS溶液洗涤，且添加20μL的细胞溶解溶液以使得细胞溶解在冰中达20min。向其添加100μL的Renilla荧光素酶底物，之后量测其发光且由此估计C型肝炎病毒基因组的量。展示根据本发明的二苯乙烯衍生物处理的复制子细胞中C型肝炎病毒基因组的量相对于二甲亚砜(dimethylsulfoxide；DMSO)处理的复制子细胞中C型肝炎病毒基因组的量。
表1至表10的化合物1至化合物155可如下基于抗病毒活性(EC50)值分组：
D组(GD)：50μM或更小但超过5μM的EC50，
E组(GE)：5μM或更小但超过0.5μM的EC50，及
F组(GF)：0.5μM或更小的EC50。
因此，本发明的化学式1的化合物展现抗病毒效果。
测试实例4.对粒线体肿胀的抑制活性测试
亲环蛋白为用于形成粒线体中的通透性转变孔(permeability transitionpore；PTP)的关键蛋白质。当形成通透性转变孔时，粒线体肿胀，其外膜藉此破裂且因此细胞死亡进展。此种粒线体功能异常引起包括神经退化性疾病、癌症、及类似者的许多疾病。环孢素是一种已知的亲环蛋白抑制剂，其能够防止通透性转变孔的形成以由此抑制粒线体肿胀。
粒线体肿胀测试如下执行。特定而言，使用Dounce组织磨碎器破坏肝细胞。在700xg下将所破坏细胞离心10min且将上清液转移至新的管中。在12,000xg下将上清液离心15min，进而获得粒线体。
当将所萃取粒线体添加钙时，其肿胀，从而可藉由量测520nm下的吸亮度来观察。二苯乙烯衍生物归因于钙而在抑制粒线体肿胀方面为有效的。
表1至表10的化合物1至化合物155对抑制粒线体肿胀的活性可基于IC50值判定，且可如下分组：
G组(GG)：500μM或更小但超过50μM的IC50，
H组(GH)：50μM或更小但超过5μM的IC50，及
I组(GI)：5μM或更小的IC50。
相应于在实例1及实例2中制备的二苯乙烯衍生物的化合物1至化合物155的NMR(核磁共振；nuclear magnetic resonance)分析及LCMS(液相层析-质谱法；liquidchromatography mass spectrometry)分析的结果如下。
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
工业实用性
本发明的新颖二苯乙烯衍生物可以用作具有改良医药概况的亲环蛋白的功能抑制剂。

Claims (18)

1.由以下化学式1表示的二苯乙烯衍生物或其医药学上可接受的盐：
[化学式1]
在化学式1中，
A为CRa或N，
B为CRb或N，
G为CRe或N，
J为CRf或N，
M为CRg或N，
D、E、及L为CRh或N，
Rx为H、CH3、CN、NH2、F、Cl、Br或I，
其中当Rx为H、CH3、NH2、F、Cl、Br或I时，
Ra为氢、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Rd为卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf为氢、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12杂环基、-NHR11(R11为C1-C2烷基)、-COOR12(R12为C1-C2烷基)、-OCOR13(R13为C1-C2烷基)、或-COR14(R14为C1-C2烷基)，
Rg为氢、NH2、OH、卤素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，及
Rh为氢、NH2、OH、C1-C5烷基或C2-C10烯基，
当Rx为CN时，
Ra为氢，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基、或C5-C12杂环基)，
Rd为氢、卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf及Rg各自为氢，及
Rh为氢、C1-C5烷基或C2-C10烯基，
所述杂环基的杂原子为选自由氮、氧及硫组成之群的至少一者，
所述烷基可经选自由以下各项组成之群的至少一个取代基取代：OH、胺、C6-C12芳基、C5-C10杂环基及C3-C10环烷基，
所述烷氧基可经选自由以下各项组成之群的至少一个取代基取代：卤素、C6-C12芳基、C3-C10环烷基、胺及胺基羰基，
所述杂环基可经选自由以下各项组成之群的至少一个取代基取代：烷基、经胺取代的烷基、胺、酰胺基及羧基，
所述芳基可经选自由以下各项组成之群的至少一个取代基取代：卤素、烷基、羟基、烷氧基、羧基、酯基、硝基及胺基，
A、B、D、E、G、J、L及M可与相邻基团连接来形成稠合环，及
当Rb为CH3时，Rd不可为NO2。
2.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中A为CRa或N，B为CRb，G为CRe，J为CRf，M为CRg或N，且D、E及L为CH。
3.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中Rb为氢或C1-C8烷基。
4.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中Rc为C1-C20烷基、C2-C10烷氧基、苯基烷基、硝基、C3-C10环烷基、C5-C12杂环基或C1-C10烷基酮。
5.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中Rd为C2-C20烷基；C3-C10酯基；C3-C10环烷基；经环烷基取代的甲氧基；经胺基取代的乙氧基；羧基；经苯基取代的C2-C20烷基，所述苯基为未经取代的或经C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；吗啉；或-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)。
6.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中Re为氢、OH、C1-C20烷基或C1-C10烷氧基。
7.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中Rg为氢、OH、C1-C20烷基；C3-C10酯基；C3-C10环烷基；经环烷基取代的甲氧基；经胺基取代的乙氧基；经苯基取代的C2-C20烷基，所述苯基为未经取代的或经C1-C5烷基、C1-C5烷氧基、羧基或胺基取代；胺；N-甲基哌嗪；哌啶；吗啉；或羧基。
8.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中所述烷基为-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、
9.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中所述烷氧基为-OCH3、-OCF3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、-OCH(CH3)CH2CH3、-OCH2CONH2、-OCH2CH2N(CH3)2、
10.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中所述杂环基为
11.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中-COOR5为COOCH3、-COOCH2CH3、COO(CH2)2CH3、-COO(CH2)3CH3、COO(CH2)4CH3、COOCH(CH3)2、
12.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中-OCOR6为
13.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中-NR3R4为-NH2、-NHCH3、-N(CH3)2、
14.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中-NR7CYR8为
15.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其中-NHS(O)2R9为
16.如权利要求1所述的二苯乙烯衍生物或其医药学上可接受的盐，其为选自由以下化合物1至化合物155组成之群的任一者：
17.制备由以下化学式1表示的二苯乙烯衍生物的方法，其包含以下步骤：
使由以下化学式2表示的苯基乙腈衍生物与由以下化学式3表示的苯甲醛衍生物反应：
[化学式1]
[化学式2]
[化学式3]
在化学式1、化学式2及化学式3中，
A为CRa或N，
B为CRb或N，
G为CRe或N，
J为CRf或N，
M为CRg或N，
D、E、及L为CRh或N，
Rx为CN，
Ra为氢，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基、或C5-C12杂环基)，
Rd为氢、卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、CN、C2-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf及Rg各自为氢，
Rh为氢、C1-C5烷基或C2-C10烯基，
所述杂环基的杂原子为选自由氮、氧及硫组成之群的至少一者，
所述烷基可经选自由以下各项组成之群的至少一个取代基取代：OH、胺、C6-C12芳基、C5-C10杂环基及C3-C10环烷基，
所述烷氧基可经选自由以下各项组成之群的至少一个取代基取代：卤素、C6-C12芳基、C3-C10环烷基、胺及胺基羰基，
所述杂环基可经选自由以下各项组成之群的至少一个取代基取代：烷基、经胺取代的烷基、胺、酰胺基及羧基，
所述芳基可经选自由以下各项组成之群的至少一个取代基取代：卤素、烷基、羟基、烷氧基、羧基、酯基、硝基及胺基，
A、B、D、E、G、J、L及M可与相邻基团连接来形成稠合环，及
当Rb为CH3时，Rd不可为NO2。
18.备由以下化学式1表示的二苯乙烯衍生物的方法，其包含以下步骤：
使由以下化学式4表示的烯烃衍生物与由以下化学式5表示的有机卤化物衍生物反应：
[化学式1]
Rx＝H,CH3,NH2,F,Cl,Br,I
[化学式4]
[化学式5]
在化学式1、化学式4及化学式5中，
A为CRa或N，
B为CRb或N，
G为CRe或N，
J为CRf或N，
M为CRg或N，
D、E、及L为CRh或N，
X为F、Cl、Br或I，
Rx为H、CH3、NH2、F、Cl、Br或I，
Ra为氢、NO2、CN、OH、C1-C5烷基、C2-C10烯基、C1-C2烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rb为氢、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、-COOR1(R1为氢或C1-C5烷基)或-OCOR2(R2为C1-C5烷基)，
Rc为OH、NO2、C1-C20烷基、C3-C10环烷基、C2-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Rd为卤素、NO2、COOH、CN、C2-C20烷基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Re为氢、NH2、OH、CN、C1-C20烷基、C2-C10烯基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)或-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)，
Rf为氢、NH2、OH、NO2、C1-C4烷基、C2-C10烯基、C1-C4烷氧基、C6-C12芳基、C5-C12杂环基、-NHR11(R11为C1-C2烷基)、-COOR12(R12为C1-C2烷基)、-OCOR13(R13为C1-C2烷基)、或-COR14(R14为C1-C2烷基)，
Rg为氢、NH2、OH、卤素、NO2、COOH、CN、C1-C20烷基、C2-C10烯基、C3-C10环烷基、C1-C10烷氧基、C6-C12芳基、C5-C12杂环基、-NR3R4(R3为氢、C1-C20烷基或C6-C12芳基，R4为氢、C1-C20烷基或C6-C12芳基，且R3及R4连接来形成杂环，进一步含有至少一个杂原子)、-COOR5(R5为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-OCOR6(R6为C1-C20烷基、C6-C12芳基或C3-C10环烷基)、-NR7CYR8(Y为O或S，R7为氢或C1-C5烷基，且R8为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)、-NHS(O)2R9(R9为C6-C12芳基或C5-C12杂环基)、或-COR10(R10为C1-C20烷基、C6-C12芳基、C3-C10环烷基或C5-C12杂环基)，
Rh为氢、NH2、OH、C1-C5烷基或C2-C10烯基，
所述杂环基的杂原子为选自由氮、氧及硫组成之群的至少一者，
所述烷基可经选自由以下各项组成之群的至少一个取代基取代：OH、胺、C6-C12芳基、C5-C10杂环基及C3-C10环烷基，
所述烷氧基可经选自由以下各项组成之群的至少一个取代基取代：卤素、C6-C12芳基、C3-C10环烷基、胺及胺基羰基，
所述杂环基可经选自由以下各项组成之群的至少一个取代基取代：烷基、经胺取代的烷基、胺、酰胺基及羧基，
所述芳基可经选自由以下各项组成之群的至少一个取代基取代：卤素、烷基、羟基、烷氧基、羧基、酯基、硝基及胺基，及
A、B、D、E、G、J、L及M可与相邻基团连接来形成稠合环。
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CN113116872A (zh) * 2021-03-17 2021-07-16 广东省第二人民医院（广东省卫生应急医院） 紫檀芪在抗甲型流感病毒药物方面的应用
CN113116872B (zh) * 2021-03-17 2022-06-24 广东省第二人民医院（广东省卫生应急医院） 紫檀芪在抗甲型流感病毒药物方面的应用

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