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CN109160896B - 一种亲水性吡啶类化合物中间体及其制备方法 - Google Patents

一种亲水性吡啶类化合物中间体及其制备方法 Download PDF

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CN109160896B
CN109160896B CN201810468610.2A CN201810468610A CN109160896B CN 109160896 B CN109160896 B CN 109160896B CN 201810468610 A CN201810468610 A CN 201810468610A CN 109160896 B CN109160896 B CN 109160896B
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蔡玲玲
蔡勇全
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Kunshan ruxu Biotechnology Co.,Ltd.
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Abstract

本发明公开了一种亲水性吡啶类化合物中间体及其制备方法。利用本发明的中间体化合物D，可制备得到亲水性吡啶类化合物A；该亲水性吡啶类化合物A与前列腺癌细胞PSMA蛋白具有良好的结合能力；其经18F放射性标记后可作为PSMA蛋白成像显影剂应用于正电子断层扫描技术(PET)，从而用于对前列腺癌的诊断或对药物疗效的跟踪。

Description

一种亲水性吡啶类化合物中间体及其制备方法
技术领域
本发明涉及一种亲水性吡啶类化合物中间体及其制备方法。
背景技术
前列腺癌(英文：Prostate cancer)是起源于人体前列腺组织的一种恶性肿瘤。大多数前列腺癌生长速度较为缓慢，但仍有些生长较快。癌细胞可以转移到骨头和淋巴结等部位。前列腺癌早期可能没有症状，晚期可能导致排尿困难、尿血、背痛、骨盆疼痛等症状。前列腺肥大也会导致类似的症状。晚期症状还包括因血液中红细胞数量低导致的疲倦。
前列腺癌的风险因子包含高龄、家族病史、种族等。约99％的病例中患者年龄超过50岁。父母、兄弟等亲属患有此病时，发病风险较常人高出2至3倍。美国疾病控制中心统计显示美国非裔前列腺癌发病率最高，欧裔其次，亚裔族群前列腺癌发病率最低。但是亚裔男性死于前列腺癌位于所有癌症的首位。其他风险因子包含饮食中有大量乳肉制品(红肉、加工肉品、乳制品)或缺乏某些蔬菜。前列腺癌可以由活体组织切片确诊。医学影像技术可检测癌细胞是否扩散到身体其他部位。
前列腺癌筛查效果尚不明确。前列腺特异抗原(PSA)检测可增加癌症检测率，但不会降低死亡率。由于大多数确诊的前列腺癌没有症状，美国预防医学工作组(USPSTF)为防止过度诊断和过度治疗而不建议使用PSA检测。USPSTF认为检测的益处并不超过可能存在的弊端。5α还原酶抑制剂可能降低较低级的前列腺癌风险，但并不影响高风险前列腺癌，因此不建议用于预防前列腺癌。带有矿物质或维生素的补充剂对前列腺癌风险没有作用。
大多数前列腺癌病例可安全通过主动监测或观察等待追查。其他治疗方法包括手术、放射治疗、荷尔蒙治疗、化学治疗，这几种疗法可以合并运用，当癌细胞仅存在于前列腺内部时本病有治愈可能。对于癌细胞已扩散至骨骼的患者，可使用镇痛药、双膦酸盐类药物以及靶向治疗。前列腺癌的治疗效果取决于患者的年龄、健康状况、以及癌症的侵略性与癌细胞的扩散情况。大多数前列腺癌患者并不会最终因前列腺癌而去世。在美国，前列腺癌患者的五年存活率约为99％。在全世界，前列腺癌是第二常见的癌症，也是男性与癌症相关的第五大死因。在2012年，约有110万男性患前列腺癌，又有30.7万人因前列腺癌去世。前列腺癌在84个国家是男性最常见的癌症，且更常发于发达国家，但发展中国家的患病率正在上升。在中国前列腺癌的发病率位于所有癌症的第六位。因PSA检测的推广，1980年代和1990年代前列腺癌的发现率显着提升。研究显示并非死于前列腺癌的60岁以上男性，约30％至70％已有前列腺癌变。
由于前列腺癌患病病期长达数十年，临床诊断显得特别重要，特别是是否扩散到其他器官如骨头、淋巴结等。和前列腺癌有关的放射性诊断试剂，美国FDA批准过至少5种，包括[18F]FDG(2004)诊断葡萄糖代谢异常、[18F]NaF(1972,2012)诊断癌细胞骨转移、[111In]Prostascint(1996)诊断前列腺癌细胞受体PSMA、[11C]Choline(2012)诊断前列腺癌细胞对胆碱的吸收、[18F]Axumin诊断前列腺癌细胞对氨基酸Axumin的吸收。新的一类诊断试剂是基于前列腺特异性膜抗原(PSMA)的抗原，比较新颖的包括[18F]DCFPyL和[68Ga]Ga-PSMA-617。
Figure BDA0001662472550000021
但是这两个显影剂给出的信号均比较微弱，所显示的动力学范围以及针对PSMA的特异性也都有待提高。开发低背景噪音、能更好地聚集癌细胞，特别是对有表达PSMA的癌细胞、提高放射性标记效率、增加信号动力学范围、以及针对PSMA有高度的选择性、特异性、可逆性的结合率的18F放射性标记的显影剂，具有十分重要的意义。
发明内容
本发明所要解决的技术问题是针对目前已有的经放射性标记的显影剂对有表达PSMA的前列腺癌细胞成像信号微弱，所显示的动力学范围低以及针对靶点的特异性有待提高等问题，因而提供了一种亲水性吡啶类化合物、中间体、其制备方法及应用。本发明的亲水性吡啶类化合物与前列腺癌细胞的PSMA受体蛋白具有良好的结合能力；其经18F放射性标记后可作为PSMA受体成像显影剂，应用于正电子断层扫描技术(PET)，从而用于对前列腺癌的诊断及对药物疗效的跟踪。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种亲水性吡啶类化合物A，其结构如下所示：
Figure BDA0001662472550000031
其中，X为-COOH、-CONH2或-CONHC2H4NH2。
所述的化合物A优选为式I_5、式II_5或式III_5：
Figure BDA0001662472550000032
在某一方案中，所述的化合物A的某些基团的定义如下，未定义的基团如前任一方案所述：
所述的18F在吡啶氮的邻位或者对位。
在某一方案中，所述的化合物A的某些基团的定义如下，未定义的基团如前任一方案所述：
所述的化合物A为式I_5
Figure BDA0001662472550000033
时，所述的X可为-CO2H或-CONH2。
在某一方案中，所述的化合物A的某些基团的定义如下，未定义的基团如前任一方案所述：
所述的化合物A为式II_5
Figure BDA0001662472550000041
时，所述的X可为-CO2H或-CONH2。
在某一方案中，所述的化合物A的某些基团的定义如下，未定义的基团如前任一方案所述：
所述的化合物A为式III_5
Figure BDA0001662472550000042
时，所述的X可为-CO2H或-CONH2。
当所述的化合物A为式I_5时，所述的化合物A可为如下任一化合物：
Figure BDA0001662472550000043
Figure BDA0001662472550000051
当所述的化合物A为式II_5时，所述的化合物A可为如下任一化合物：
Figure BDA0001662472550000061
当所述的化合物A为式III_5时，所述的化合物A可为如下任一化合物：
Figure BDA0001662472550000071
本发明提供了一种所述的亲水性吡啶类化合物A的制备方法，其包含下列步骤：在溶剂中，在K2CO3存在下，将化合物B与18F氟化试剂进行如下所示的氟化反应，得到所述的化合物A，即可，
Figure BDA0001662472550000072
其中，X为-CO2H、-CONH2或-CONH(C2H4NH2)；
Y为Cl、F、NO2或NMe3 +。
本发明中，所述的氟化反应可采用本领域此类反应的常规方法和条件。
所述的氟化反应中，所述的溶剂可为本领域该类反应常规的溶剂，例如酰胺类溶剂(例如DMF)和/或亚砜类溶剂(例如DMSO)。
所述的18F氟化试剂可为本领域该类反应常规的18F氟化试剂，例如由回旋加速器生产的18F负离子；核反应如下：
18O+p＝>18F。
所述18F氟化试剂的摩尔数与放射化学标记时的放射性用量有关；一般放射量在1至10居里；所述的化合物B可控制在1至3毫克。
所述的氟化反应中，所述的反应温度可为本领域该类反应常规的温度，例如60～150℃。
K2CO3与所述化合物B的摩尔比可为本领域常规的摩尔比，较佳地为3:1～6:1；或者K2CO3用量可为10毫克/次。
所述的氟化反应的进程可采用本领域中的常规监测方法，例如采用放射性监测器(例如美国的Bioscan和德国的Eckert&Ziegler)进行监测。
所述亲水性吡啶类化合物A的制备方法，所述的反应结束后还可包括以下后处理步骤：将氟化反应结束后的反应液通过半制备型HPLC柱分离纯化，得到所述的化合物A即可。
所述的半制备型HPLC柱分离纯化可采用本领域该类制备方法中常规的HPLC柱分离纯化方法。
所述的亲水性吡啶类化合物A的制备方法，还可包括如下步骤：在溶剂中，将化合物C与脱保护试剂进行如下所示脱保护反应，得到所述的化合物B即可，
Figure BDA0001662472550000081
所述的脱保护基反应可为本领域该类反应中的常规方法和条件。在本发明中，所述的溶剂可为本领域该类反应中常规的溶剂，例如卤代烃类溶剂(例如氯仿)。所述的反应温度可为本领域该类反应常规的温度，例如20～40℃。所述的脱保护试剂可为本领域该类反应中常规的试剂，例如三氟甲磺酸(TFA)。所述的化合物C与所述的脱保护试剂的摩尔比可为本领域该类反应中常规的摩尔比，例如所述的化合物C与所述的脱保护试剂的摩尔比为1:5～1:20。
所述的亲水性吡啶类化合物A的制备方法，还可包括如下任一方法1、方法2、方法3或方法4，制备得到所述的化合物C；
方法1包括如下步骤：在溶剂中，在碱存在下，将化合物IV与化合物F进行偶联反应，得到“X为-CO2H、Y为F、Cl或NO2”的所述化合物C，即可；
Figure BDA0001662472550000091
其中，N1和N2中，任意一个为N时，另一个为CH；Y为F、Cl或NO2；
方法2包括如下步骤：包括如下步骤：在溶剂中，在Me3SiOTf存在下，将“X为-CO2H、Y为F、Cl或NO2”的所述化合物C与Me3N进行取代反应，得到“X为-CO2H、Y为NMe3 +”的所述化合物C，即可；
方法3包括如下步骤：在溶剂中，将化合物D与脱保护剂试剂进行如下所示选择性脱保护反应，得到“X为-CO2H”的所述化合物C，即可；
Figure BDA0001662472550000092
其中，X’为
Figure BDA0001662472550000093
Y为Cl，F、NO2或NMe3 +；
方法4包括如下步骤：在溶剂中，在偶联剂存在下，将“X为-CO2H、Y为Cl，F、NO2或NMe3 +”的所述化合物C与胺类化合物X’-H进行偶联反应，当X’为-NH2时，得到“X为-CONH2、Y为Cl，F、NO2或NMe3 +”的所述化合物C；当X’为-NH(C2H4NH)-(C＝O)O-C(CH3)3时，得到“X为-CONHC2H4NH2、Y为Cl，F、NO2或NMe3 +”的所述化合物C，即可。
方法1中，所述的偶联反应可采用本领域此类反应的常规方法和条件。
方法1中，所述的碱可为本领域此类反应常规的碱，例如有机碱(例如三乙胺、吡啶和N,N-二甲基-对-吡啶(DMAP)中的一种或多种)和/或酸式碱金属盐(例如K2CO3、KOAc、K3PO4和Na2CO3中的一种或多种)。
方法1中，所述的碱的用量可为本领域此类反应常规的，例如为100％～300％，所述的百分比为所述催化剂与所述的化合物IV的摩尔百分比。
方法1中，所述的溶剂可为本领域此类反应常规的，例如卤代烃类溶剂(例如二氯甲烷)。
方法1中，所述反应的温度可为本领域此类反应常规的温度，例如20～40℃。
方法1中，所述的化合物IV、所述的化合物F的摩尔比可为本领域此类反应常规的摩尔比，例如1:2～1:3。
方法2中，所述X为-CO2H、Y为F、Cl或NO2”的化合物C与Me3N的摩尔比可为本领域此类反应常规的摩尔比，例如1:1～1:5。
方法2中，所述X为-CO2H、Y为F、Cl或NO2”的化合物C与Me3SiOTf的摩尔比可为本领域此类反应常规的摩尔比，例如1:1～1:2(又例如1:1.1)。
方法2中，所述的溶剂可为本领域该类反应中常规的溶剂，例如腈类溶剂(例如乙腈)。
方法2中，所述的取代反应的反应温度可为本领域该类反应中常规的温度，例如20～40℃。
方法3中，所述的选择性脱保护可采用本领域此类反应的常规方法和条件。
方法3中，较佳地，所述的脱保护试剂可为本领域此类反应常规的脱保护试剂，例如为哌啶。
方法3中，较佳地，所述的选择性脱保护反应中，所述的化合物D与所述的脱保护试剂的摩尔比可为本领域此类反应常规的摩尔比，例如1:1。
方法3中，所述的溶剂可为本领域该类反应中常规的溶剂，例如腈类溶剂(例如乙腈)。
方法4中，所述的偶联反应可为本领域该类反应中常规方法和条件。在本发明中，所述的溶剂可为本领域该类反应中常规的溶剂，例如卤代烃类溶剂(例如二氯甲烷)。
方法4中，所述的偶联剂可为本领域该类反应中常规的偶联剂，例如1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC，C2H5N＝C＝N(CH2)3NMe2)和/或N,N’-二环己基碳二亚胺(DCC，C6H11N＝C＝NC6H11)。所述偶联反应的反应温度可为本领域该类反应中常规的温度，例如20～40℃。“X为-CO2H、Y为Cl，F、NO2或NMe3 +”的所述化合物C与所述的胺类化合物X’-H的摩尔比可为本领域该类反应中常规的摩尔比，例如1:2～1:3)。“X为-CO2H、Y为Cl，F、NO2或NMe3 +”的所述化合物C与所述的偶联剂的摩尔比可为本领域该类反应中常规的摩尔比，例如1:3～1:4。
所述的亲水性吡啶类化合物A的制备方法，其还可包括如下步骤：在溶剂中，在催化剂存在下，将化合物I与氧化剂进行如下所示氧化反应，得到所述的化合物F即可，
Figure BDA0001662472550000111
其中，N1和N2中任意一个为N时，另一个为CH；Y为F、Cl或NO2。
所述的氧化反应可为领域该类反应中常规常规方法和条件。
所述的溶剂可为本领域该类反应中常规的溶剂，例如四氯化碳和/或水。
所述的催化剂可为本领域该类反应中常规的催化剂，例如RuCl3。
所述的氧化剂可为本领域该类反应中常规的氧化剂，例如H5IO6。
所述的亲水性吡啶类化合物A的制备方法，还可包括如下方法A或方法B，制备得到所述的化合物D；其中，当目标化合物D中Y为F、Cl或NO2时，采用方法A；当目标化合物D中Y为NMe3 +时，采用方法B；
方法A包括下列步骤：在溶剂中，在偶联剂存在下，将化合物IV与Y为F、Cl或NO2的化合物H进行如下所示偶联反应，得到Y为F、Cl或NO2的所述化合物D，即可；
Figure BDA0001662472550000112
方法B包括下列步骤：在溶剂中，在Me3SiOTf存在下，将Y为F、Cl或NO2的所述化合物D与Me3N进行取代反应，得到Y为NMe3 +的所述化合物D，即可。
方法A中，所述的偶联反应可为本领域该类反应中常规常规方法和条件。
方法A中，所述的溶剂可为本领域该类反应中常规的溶剂，例如腈类溶剂(例如乙腈)。
方法A中，所述的偶联剂可为本领域该类反应中常规的偶联剂，例如1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC，C2H5N＝C＝N(CH2)3NMe2)和/或N,N’-二环己基碳二亚胺(DCC，C6H11N＝C＝NC6H11)。
方法A中，所述偶联反应的反应温度可为本领域该类反应中常规的温度，例如20～40℃。
方法A中，所述的化合物IV与所述的化合物H的摩尔比可为本领域该类反应中常规的摩尔比，例如1:1～1.6:3(又例如1:1.2)。
方法A中，所述的化合物IV与所述的偶联剂的摩尔比可为本领域该类反应中常规的摩尔比，例如1:1～1:4(又例如1:3)。
方法B中，“Y为F、Cl或NO2”的所述化合物D与Me3N的摩尔比可为本领域此类反应常规的摩尔比，例如1:1～1:5。
方法B中，“Y为F、Cl或NO2”的所述化合物D与Me3SiOTf的摩尔比可为本领域此类反应常规的摩尔比，例如1:1～1:2(又例如1:1.1)。
方法B中，所述的溶剂可为本领域该类反应中常规的溶剂，例如腈类溶剂(例如乙腈)。
方法B中，所述取代反应的反应温度可为本领域该类反应中常规的温度，例如20～40℃。
所述的亲水性吡啶类化合物A的制备方法，其还可包括如下步骤：在溶剂中，在碱存在下，将化合物G与脱保护剂试剂进行如下所示脱保护反应，得到所述的化合物H，即可，
Figure BDA0001662472550000121
其中，X’为
Figure BDA0001662472550000122
Y为F、Cl或NO2。
所述的脱保护可采用本领域此类反应的常规方法和条件。
本发明中，较佳地，所述的脱保护试剂可为本领域此类反应常规的脱保护试剂，例如为哌啶。
较佳地，所述的选择性脱保护反应中，所述的化合物G与所述的脱保护试剂的摩尔比可为本领域此类反应常规的摩尔比，例如1:1。
所述的溶剂可为本领域该类反应中常规的溶剂，例如腈类溶剂(例如乙腈)。
所述的化合物G由相应的二酸原料
Figure BDA0001662472550000131
通过本领域常规的酯化反应制备得到。
本发明提供了一种化合物B，其结构如下所示：
Figure BDA0001662472550000132
其中，X为-CO2H、-CONH2或-CONH(C2H4NH2)；
Y＝Cl、F、NO2或NMe3 +。
所述的化合物B可为如下任一化合物：
Figure BDA0001662472550000141
Figure BDA0001662472550000151
Figure BDA0001662472550000161
本发明还提供了一种所述化合物B的制备方法，其采用如上所述的制备方法制备得到。
本发明还提供了一种化合物C，其结构如下所示：
Figure BDA0001662472550000171
其中，X为-CO2H、-CONH2或-CONH(C2H4NH2)；
Y为Cl、F、NO2或NMe3 +。
所述的化合物C可为如下任一化合物：
Figure BDA0001662472550000172
Figure BDA0001662472550000181
Figure BDA0001662472550000191
Figure BDA0001662472550000201
本发明还提供了一种所述化合物C的制备方法，其采用如上所述的制备方法制备得到。
本发明提供了一种化合物F，其结构如下所示：
Figure BDA0001662472550000202
但不为
Figure BDA0001662472550000203
其中，N1和N2中任意一个为N时，另一个为CH；Y为F、Cl或NO2。
所述的F可为如下任一化合物：
Figure BDA0001662472550000204
本发明还提供了一种所述化合物F的制备方法，其采用如上所述的制备方法制备得到。
本发明提供了一种化合物D，其结构如下所示：
Figure BDA0001662472550000211
其中，X’为
Figure BDA0001662472550000212
Y为Cl，F、NO2或NMe3 +。
所述的D可为如下任一化合物：
Figure BDA0001662472550000213
Figure BDA0001662472550000221
其中，X’为
Figure BDA0001662472550000231
本发明还提供了一种所述化合物D的制备方法，其采用如上所述的制备方法制备得到。
本发明提供了一种化合物H，其结构如下所示：
Figure BDA0001662472550000232
其中，X’为
Figure BDA0001662472550000233
Y为F、Cl或NO2。
所述的H可为如下任一化合物：
Figure BDA0001662472550000234
Figure BDA0001662472550000241
本发明还提供了一种所述化合物H的制备方法，其采用如上所述的制备方法制备得到。
本发明提供了一种化合物G，其结构如下所示：
Figure BDA0001662472550000242
其中，X’为
Figure BDA0001662472550000243
Y为F、Cl或NO2。
所述的化合物G可为如下任一化合物：
Figure BDA0001662472550000251
所述的化合物G由相应的二酸原料
Figure BDA0001662472550000252
通过本领域常规的酯化反应制备得到。
本发明中，所述的如式A所示的亲水性吡啶类化合物及中间体均可通过本领域常规制备方法制得，本领域技术人员在上述公开内容的基础上，可自行选择具体反应条件，并得到目标化合物。
本发明还进一步提供了如上所述的亲水性吡啶化合物A，其药学上可接受的盐、其水合物、其溶剂化物、或其代谢产物作为成像显影剂在正电子断层扫描技术中的应用。
所述的成像显影剂可作为PSMA受体成像显影剂用于对前列腺癌的诊断或对药物疗效的跟踪。
本发明中，如无特别说明，所述的F代表19F；所述的18F意指回旋加速器生产的没有加入载体的18F。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
除特殊说明外，本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的亲水性吡啶类化合物与PSMA蛋白具有良好的结合能力；其经18F放射性标记后可作为PSMA受体成像显影剂，应用于正电子断层扫描技术(PET)，从而用于对前列腺癌诊断或对药物疗效的跟踪。
附图说明
图1为效果实施例2中骨扫描，一年前后比较：多发骨转移；
图2为效果实施例2中PSMA PET/CT，发现了更多直径<1cm的病灶。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1化合物V---VIII的制备
Figure BDA0001662472550000261
一般合成步骤：在一般实验室条件下，1.0mmol底物1-4，5.0mmol氧化剂H5IO6，0.2mmol RuCl3催化剂，加入100mL CCl4与250mL的水。搅拌24小时后，收集水层并用3N HCl酸化至pH＝1。然后将水层用乙酸乙酯萃取，用Na2SO4干燥，蒸发除去挥发物，得到产物0.40-0.60mmol，为黄色脂状(40-60％收率)。1H NMR和MS数据与文献报道相符。加入5mL二氯亚砜回流1-2小时，溶剂抽干，用氯仿溶解并过滤，取溶液抽干定量，继续使用。
实施例2化合物IX-XVIII系列的制备
Figure BDA0001662472550000271
Figure BDA0001662472550000281
化合物IX-XVIII合成步骤：1.0mmol底物，1.0mmol哌啶，5.0mL CH3CN，反应混合物在80℃反应10-20小时，搅拌直至反应完成。反应混合物在乙酸乙酯和饱和食盐水中分离。有机溶剂相在硫酸镁中干燥，抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。其中，原料底物5～10由各自二酸酯化而来，未纯化分离。
实施例3化合物I1_3AAA-I1_3DDD和II3_3AAA-II3_3DDD的制备
Figure BDA0001662472550000291
一般合成步骤：1.0mmol底物IV，1.2eq V，3.0eq吡啶，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000292
1.0mmol底物I1_3BBB或者II3_3BBB，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_3AAA,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),9.01(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3BBB,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),9.03(d,3JHH＝8.9Hz,1H,Ar-H),8.03(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3CCC,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),9.28(d,3JHH＝8.9Hz,1H,Ar-H),8.82(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3DDD,产率25％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),8.30(d,3JHH＝8.9Hz,1H,Ar-H),7.36(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3AAA,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.88(d,3JHH＝8.9Hz,1H,Ar-H),7.64(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3BBB,产率42％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.90(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3CCC,产率36％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),9.16(d,3JHH＝8.9Hz,1H,Ar-H),8.86(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3DDD,产率18％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.32(d,3JHH＝8.9Hz,1H,Ar-H),7.24(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例4化合物I3_3AAA-I3_3DDD和III3_3AAA-III3_3DDD的制备
Figure BDA0001662472550000311
一般合成步骤：1.0mmol底物IV，1.2eq VI，3.0eq吡啶，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000312
1.0mmol底物I3_3BBB或者III3_3BBB，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I3_3AAA,产率58％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3BBB,产率43％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3CCC,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3DDD,产率27％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3AAA,产率50％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.99(s,1H,Ar-H),7.98(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3BBB,产率39％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),9.32(s,1H,Ar-H),7.74(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3CCC,产率33％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),9.38(s,1H,Ar-H),9.16(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3DDD,产率22％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.64(s,1H,Ar-H),7.40(s,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例5化合物I6_3AAA-I6_3DDD和III2_3AAA-III2_3DDD的制备
Figure BDA0001662472550000331
一般合成步骤：1.0mmol底物IV，1.2eq VII，3.0eq吡啶，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000332
1.0mmol底物I6_3BBB或者III2_3BBB，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I6_3AAA,产率62％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3BBB,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3CCC,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3DDD,产率24％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3AAA,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.88(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3BBB,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),8.05(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3CCC,产率38％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),9.33(d,3JHH＝8.9Hz,1H,Ar-H),8.50(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3DDD,产率20％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.59(d,3JHH＝8.9Hz,1H,Ar-H),6.98(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例6化合物I7_3AAA-I7_3DDD和II6_3AAA-II6_3DDD的制备
Figure BDA0001662472550000351
一般合成步骤：1.0mmol底物IV，1.2eq VIII，3.0eq吡啶，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000352
1.0mmol底物I7_3BBB或者II6_3BBB，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I7_3AAA,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.81(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3BBB,产率41％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),9.07(d,3JHH＝8.9Hz,1H,Ar-H),8.16(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3CCC,产率39％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,CO2H),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3DDD,产率18％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.2(brs,1H,CO2H),8.49(d,3JHH＝8.9Hz,1H,Ar-H),7.42(d,3JHH＝8.9Hz,1H,Ar-H),8.3(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3AAA,产率61％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.88(d,3JHH＝8.9Hz,1H,Ar-H),7.64(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3BBB,产率42％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.90(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3CCC,产率33％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),9.16(d,3JHH＝8.9Hz,1H,Ar-H),8.86(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3DDD,产率15％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,CO2H),8.32(d,3JHH＝8.9Hz,1H,Ar-H),7.24(d,3JHH＝8.9Hz,1H,Ar-H),9.0(brs,1H,CONH),6.5(brs,2H,CONH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(m,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(t,3JHH＝7.1Hz,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例7化合物I2_2A-I2_2D的制备
Figure BDA0001662472550000371
一般合成步骤：1.0mmol底物IV，1.2eq I2_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000381
1.0mmol底物I2_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I2_2A,产率52％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I2_2B,产率41％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),9.21(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I2_2C,产率37％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.59(d,3JHH＝8.9Hz,1H,Ar-H),9.38(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I2_2D,产率17％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),8.61(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例8化合物I4_2A-I4_2D的制备
Figure BDA0001662472550000391
一般合成步骤：1.0mmol底物IV，1.2eq I4_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000392
1.0mmol底物I4_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I4_2A,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.01(d,3JHH＝8.9Hz,1H,Ar-H),6.55(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I4_2B,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),6.72(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I4_2C,产率33％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),7.75(d,3JHH＝8.9Hz,1H,Ar-H),7.38(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I4_2D,产率11％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.30(d,3JHH＝8.9Hz,1H,Ar-H),5.65(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例9化合物I5_2A-I5_2D的制备
Figure BDA0001662472550000401
一般合成步骤：1.0mmol底物IV，1.2eq I5_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000411
1.0mmol底物I5_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I5_2A,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.32(s,1H,Ar-H),8.94(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I5_2B,产率44％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.27(s,1H,Ar-H),9.21(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I5_2C,产率31％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.59(s,1H,Ar-H),9.33(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I5_2D,产率17％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.61(s,1H,Ar-H),8.59(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例10化合物I8_2A-I8_2D的制备
Figure BDA0001662472550000421
一般合成步骤：1.0mmol底物IV，1.2eq I8_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000422
1.0mmol底物I8_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I8_2A,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.33(s,1H,Ar-H),9.28(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I8_2B,产率40％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.35(s,1H,Ar-H),9.30(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I8_2C,产率37％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.56(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I8_2D,产率19％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.20(s,1H,Ar-H),9.15(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例11化合物I9_2A-I9_2D的制备
Figure BDA0001662472550000431
一般合成步骤：1.0mmol底物IV，1.2eq I9_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000441
1.0mmol底物I9_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I9_2A,产率50％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),8.31(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I9_2B,产率43％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.20(s,1H,Ar-H),8.65(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I9_2C,产率33％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.53(s,1H,Ar-H),9.46(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物I9_2D,产率13％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(s,1H,Ar-H),7.70(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例12化合物II1_2A-II1_2D的制备
Figure BDA0001662472550000451
一般合成步骤：1.0mmol底物IV，1.2eq II1_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000452
1.0mmol底物II1_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_2A,产率61％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.08(d,3JHH＝8.9Hz,1H,Ar-H),8.72(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II1_2B,产率41％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.97(d,3JHH＝8.9Hz,1H,Ar-H),8.89(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II1_2C,产率38％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.30(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II1_2D,产率9％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.82(d,3JHH＝8.9Hz,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例13化合物II2_2A-II2_2D的制备
Figure BDA0001662472550000461
一般合成步骤：1.0mmol底物IV，1.2eq II2_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000471
1.0mmol底物II2_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II2_2A,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II2_2B,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II2_2C,产率31％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II2_2D,产率14％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例14化合物II4_2A-II4_2D的制备
Figure BDA0001662472550000481
一般合成步骤：1.0mmol底物IV，1.2eq II4_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000482
1.0mmol底物II4_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II4_2A,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.10(s,1H,Ar-H),8.37(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II4_2B,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.71(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II4_2C,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.59(s,1H,Ar-H),9.38(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II4_2D,产率19％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.97(s,1H,Ar-H),7.76(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.89(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例15化合物II5_2A-II5_2D的制备
Figure BDA0001662472550000491
一般合成步骤：1.0mmol底物IV，1.2eq II5_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000501
1.0mmol底物II5_2B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II5_2A,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.62(s,1H,Ar-H),8.49(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II5_2B,产率62％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.96(s,1H,Ar-H),8.83(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II5_2C,产率41％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.84(s,1H,Ar-H),9.71(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物II5_2D,产率12％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.01(s,1H,Ar-H),7.88(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例16化合物III1_2A-III1_2D的制备
Figure BDA0001662472550000511
一般合成步骤：1.0mmol底物IV，1.2eq III1_1A-C，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
Figure BDA0001662472550000512
1.0mmol底物III1_1B，5eq Me3N，1.1eq Me3SiOTf，5.0mL CH2Cl2，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_2A,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(s,1H,Ar-H),8.34(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物III1_2B,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.22(s,1H,Ar-H),8.10(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物III1_2C,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.67(s,1H,Ar-H),9.53(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
化合物III1_2D,产率17％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.15(s,1H,Ar-H),7.76(s,1H,Ar-H),4.87(d,3JHH＝7.1Hz,2H,CH2),4.46(m,1H,CH),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3),7.90(d,3JHH＝8.9Hz,1H,Fluoren),7.55(d,3JHH＝8.9Hz,1H,Fluoren),7.38(m,2H,Fluoren),7.28(m,2H,Fluoren).
实施例17化合物I2_3AAA-I2_3DDD的制备
Figure BDA0001662472550000521
一般合成步骤：1.0mmol底物I2_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I2_3AAA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.14(s,1H,Ar-H),8.85(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3BBB,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),9.13(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3CCC,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.41(s,1H,Ar-H),9.24(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.50(s,1H,Ar-H),8.43(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例18化合物I4_3AAA-I4_3DDD的制备
Figure BDA0001662472550000531
一般合成步骤：1.0mmol底物I4_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I4_3AAA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.01(d,3JHH＝8.9Hz,1H,Ar-H),6.65(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3BBB,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),6.72(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3CCC,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.28(d,3JHH＝8.9Hz,1H,Ar-H),7.17(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.30(d,3JHH＝8.9Hz,1H,Ar-H),5.65(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例19化合物I5_3AAA-I5_3DDD的制备
Figure BDA0001662472550000541
一般合成步骤：1.0mmol底物I5_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I5_3AAA,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.14(s,1H,Ar-H),8.77(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3BBB,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.10(s,1H,Ar-H),9.03(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3CCC,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.41(s,1H,Ar-H),9.16(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3DDD,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.45(s,1H,Ar-H),8.26(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例20化合物I8_2AAA-I8_2DDD的制备
Figure BDA0001662472550000551
一般合成步骤：1.0mmol底物I8_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I8_3AAA,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.19(s,1H,Ar-H),9.11(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3BBB,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.21(s,1H,Ar-H),9.13(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3CCC,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.47(s,1H,Ar-H),9.39(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3DDD,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.98(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例21化合物I9_3AAA-I9_3DDD的制备
Figure BDA0001662472550000561
一般合成步骤：1.0mmol底物I9_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I9_3AAA,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),8.31(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3BBB,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),8.65(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3CCC,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.53(s,1H,Ar-H),9.46(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3DDD,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(s,1H,Ar-H),7.70(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例22化合物II1_3AAA-II1_3DDD的制备
Figure BDA0001662472550000571
一般合成步骤：1.0mmol底物II1_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_3AAA,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),8.61(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3BBB,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.80(d,3JHH＝8.9Hz,1H,Ar-H),8.68(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3CCC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.23(d,3JHH＝8.9Hz,1H,Ar-H),9.17(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3DDD,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.19(d,3JHH＝8.9Hz,1H,Ar-H),7.71(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例23化合物II2_3AAA-II2_3DDD的制备
Figure BDA0001662472550000591
一般合成步骤：1.0mmol底物II2_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II2_3AAA,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3BBB,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3CCC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3DDD,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例24化合物II4_3AAA-II4_3DDD的制备
Figure BDA0001662472550000601
一般合成步骤：1.0mmol底物II4_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II4_3AAA,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.93(s,1H,Ar-H),8.26(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3BBB,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.95(s,1H,Ar-H),8.60(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3CCC,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.48(s,1H,Ar-H),9.21(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3DDD,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.80(s,1H,Ar-H),7.65(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例25化合物II5_3AAA-II5_3DDD的制备
Figure BDA0001662472550000611
一般合成步骤：1.0mmol底物II5_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II5_3AAA,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.62(s,1H,Ar-H),8.49(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3BBB,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.96(s,1H,Ar-H),8.83(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3CCC,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.84(s,1H,Ar-H),9.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3DDD,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.01(s,1H,Ar-H),7.88(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例26化合物III1_3AAA-III1_3DDD的制备
Figure BDA0001662472550000621
一般合成步骤：1.0mmol底物III1_2，1.0eq哌啶，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_3AAA,产率92％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(s,1H,Ar-H),8.34(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3BBB,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.22(s,1H,Ar-H),8.10(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3CCC,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.67(s,1H,Ar-H),9.53(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3DDD,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,12.8)，8.3(brs,1H,CONH),6.5(brs,2H,CONH),815(s,1H,Ar-H),7.76(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例27化合物I1_3A-I1_3D至I9_3A-I9_3D的制备
Figure BDA0001662472550000631
一般合成步骤：1.0mmol底物I_3，2.0eq NH3的乙腈溶液，3.0eq
C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_3A,产率93％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3B,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3C,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I1_3D,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3A,产率93％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3B,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3C,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I2_3D,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.68(s,1H,Ar-H),8.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3A,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3B,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3C,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I3_3D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3A,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3B,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3C,产率46％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.22(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I4_3D,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3A,产率53％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3B,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3C,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I5_3D,产率27％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.58(s,1H,Ar-H),8.55(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3A,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3B,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3C,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I6_3D,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3A,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3B,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3C,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I7_3D,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3A,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.24(s,1H,Ar-H),9.20(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3B,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.26(s,1H,Ar-H),9.22(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3C,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.52(s,1H,Ar-H),9.41(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I8_3D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.11(s,1H,Ar-H),9.07(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3A,产率95％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3B,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3C,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物I9_3D,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例28化合物I1_3AA-I1_3DD至I9_3AA-I9_3DD的制备
Figure BDA0001662472550000691
一般合成步骤：1.0mmol底物I_3，2.0eq BocNHC2H4NH2的乙腈溶液，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_3AA,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I1_3BB,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I1_3CC,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I1_3DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I2_3AA,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I2_3BB,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I2_3CC,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I2_3DD,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.58(s,1H,Ar-H),8.50(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I3_3AA,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I3_3BB,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I3_3CC,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I3_3DD,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I4_3AA,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I4_3BB,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.71(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I4_3CC,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.20(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I4_3DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I5_3AA,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I5_3BB,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I5_3CC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I5_3DD,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.58(s,1H,Ar-H),8.38(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I6_3AA,产率70％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I6_3BB,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I6_3CC,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I6_3DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I7_3AA,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I7_3BB,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I7_3CC,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I7_3DD,产率61％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I8_3AA,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.24(s,1H,Ar-H),9.14(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I8_3BB,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH),6.5(brs,2H,CONH),9.26(s,1H,Ar-H),9.16(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I8_3CC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.52(s,1H,Ar-H),9.42(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I8_3DD,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.11(s,1H,Ar-H),9.00(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I9_3AA,产率55％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I9_3BB,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I9_3CC,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物I9_3DD,产率55％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
实施例29化合物II1_3A-II1_3D至II6_3A-II6_3D的制备
Figure BDA0001662472550000761
一般合成步骤：1.0mmol底物II_3，2.0eq NH3的乙腈溶液，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_3A,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3B,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.71(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3C,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.22(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II1_3D,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3A,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3B,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3C,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II2_3D,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3A,产率53％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.95(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3B,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3C,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II3_3D,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3A,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3B,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3C,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II4_3D,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3A,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.57(s,1H,Ar-H),8.37(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3B,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.91(s,1H,Ar-H),8.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3C,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.79(s,1H,Ar-H),9.59(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II5_3D,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),7.96(s,1H,Ar-H),7.76(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3A,产率70％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3B,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3C,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_3D,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例30化合物II1_3AA-II1_3DD至II6_3AA-II6_3DD的制备
Figure BDA0001662472550000801
一般合成步骤：1.0mmol底物II_3，2.0eq BocNHC2H4NH2的乙腈溶液，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_3AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II1_3BB,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II1_3CC,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.16(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II1_3DD,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II2_3AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II2_3BB,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II2_3CC,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II2_3DD,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II3_3AA,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.95(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II3_3BB,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II3_3CC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II3_3DD,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II4_3AA,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II4_3BB,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II4_3CC,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II4_3DD,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II5_3AA,产率53％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.57(s,1H,Ar-H),8.37(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II5_3BB,产率41％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.91(s,1H,Ar-H),8.71(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II5_3CC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.79(s,1H,Ar-H),9.59(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II5_3DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.8(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),7.96(s,1H,Ar-H),7.76(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II6_3AA,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II6_3BB,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II6_3CC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物II6_3DD,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ9.0(brs,1H,CONH),8.7(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
实施例31化合物III1_3A-III1_3D至III3_3A-III3_3D的制备
Figure BDA0001662472550000851
一般合成步骤：1.0mmol底物III_3，2.0eq NH3的乙腈溶液，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_3A,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.5(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3B,产率68％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.5(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3C,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.5(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III1_3D,产率62％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.5(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3A,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3B,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3C,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III2_3D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3A,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3B,产率44％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3C,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物III3_3D,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例32化合物III1_3AA-III1_3DD至III3_3AA-III3_3DD的制备
Figure BDA0001662472550000871
一般合成步骤：1.0mmol底物III_3，2.0eq BocNHC2H4NH2的乙腈溶液，3.0eq C2H5N＝C＝N(CH2)3N(CH3)2，5.0mL CH3CN，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_3AA,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.5(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III1_3BB,产率55％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.5(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III1_3CC,产率43％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.5(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),8.48(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III1_3DD,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.8(brs,1H,CONH),8.5(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III2_3AA,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III2_3BB,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III2_3CC,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.39(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III2_3DD,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III3_3AA,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III3_3BB,产率45％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III3_3CC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
化合物III3_3DD,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.8(brs,2H,CONH)，6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，3.33(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,36H,CH3).
实施例33化合物I1_4AAA-I1_4DDD至I9_4AAA-I9_4DDD的制备
Figure BDA0001662472550000901
一般合成步骤：1.0mmol底物I_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_4AAA,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.01(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.33(t,3JHH＝7.1Hz,2H,CH2),2.05(m,2H,CH2),1.76(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4BBB,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,2H,CONH2)，6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),8.03(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4CCC,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,2H,CONH2)，6.5(brs,2H,CONH),9.28(d,3JHH＝8.9Hz,1H,Ar-H),8.82(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4DDD,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,2H,CONH2)，6.5(brs,2H,CONH),8.30(d,3JHH＝8.9Hz,1H,Ar-H),7.36(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4AAA,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.14(s,1H,Ar-H),8.85(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4BBB,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),9.03(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4CCC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.41(s,1H,Ar-H),9.24(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4DDD,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.50(s,1H,Ar-H),8.43(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4AAA,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4BBB,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4CCC,产率58％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4AAA,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.01(d,3JHH＝8.9Hz,1H,Ar-H),6.55(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4BBB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),6.72(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4CCC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.28(d,3JHH＝8.9Hz,1H,Ar-H),7.16(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4DDD,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.29(d,3JHH＝8.9Hz,1H,Ar-H),5.65(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4AAA,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.14(s,1H,Ar-H),8.77(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4BBB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.10(s,1H,Ar-H),9.03(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4CCC,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.41(s,1H,Ar-H),9.16(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4DDD,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.44(s,1H,Ar-H),8.40(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_3AAA,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4BBB,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4CCC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ13.3(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.65(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.07(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4AAA,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.82(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4BBB,产率45％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.07(d,3JHH＝8.9Hz,1H,Ar-H),8.16(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4CCC,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.33(d,3JHH＝8.9Hz,1H,Ar-H),9.04(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4DDD,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.49(d,3JHH＝8.9Hz,1H,Ar-H),7.42(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4AAA,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.19(s,1H,Ar-H),9.11(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4BBB,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.21(s,1H,Ar-H),9.13(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4CCC,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.47(s,1H,Ar-H),9.39(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4DDD,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.98(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4AAA,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.18(s,1H,Ar-H),8.31(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4BBB,产率39％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.20(s,1H,Ar-H),8.65(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4CCC,产率53％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.53(s,1H,Ar-H),9.46(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.07(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_3DDD,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.05(s,1H,Ar-H),7.77(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.07(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例34化合物I1_4A-I1_4D至I9_4A-I9_4D的制备
Figure BDA0001662472550000971
一般合成步骤：1.0mmol底物I_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_4A,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4B,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4C,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4A,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4B,产率94％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4C,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4D,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.58(s,1H,Ar-H),8.55(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4A,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4B,产率68％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4C,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4D,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4A,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4B,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4C,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.16(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4D,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4A,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4B,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4C,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4D,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.58(s,1H,Ar-H),8.38(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_3A,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4B,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4C,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.68(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4D,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4A,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4B,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4C,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4D,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4A,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.24(s,1H,Ar-H),9.14(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4B,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.26(s,1H,Ar-H),9.16(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4C,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.52(s,1H,Ar-H),9.42(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4D,产率61％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.11(s,1H,Ar-H),9.01(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4A,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4B,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4C,产率48％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_3D,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例35化合物I1_4AA-I1_4DD至I9_4AA-I9_4DD的制备
Figure BDA0001662472550001041
一般合成步骤：1.0mmol底物I_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物I1_4AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.6(brs,2H,CONH)，1.5(brs,2H,NH2),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4BB,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.6(brs,2H,CONH)，1.5(brs,2H,NH2),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4CC,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.6(brs,2H,CONH)，1.5(brs,2H,NH2),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I1_4DD,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.6(brs,2H,CONH)，1.5(brs,2H,NH2),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4BB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4CC,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I2_4DD,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.58(s,1H,Ar-H),8.55(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4AA,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4BB,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.45(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4CC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I3_4DD,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4AA,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4BB,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.91(d,3JHH＝8.9Hz,1H,Ar-H),8.71(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4CC,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.16(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I4_4DD,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4AA,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.29(s,1H,Ar-H),8.90(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4BB,产率89％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.23(s,1H,Ar-H),9.18(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4CC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.56(s,1H,Ar-H),9.29(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I5_4DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.58(s,1H,Ar-H),8.55(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4AA,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4BB,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4CC,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I6_4DD,产率57％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4AA,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4BB,产率92％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4CC,产率58％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I7_4DD,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4AA,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.24(s,1H,Ar-H),9.14(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4BB,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.26(s,1H,Ar-H),9.16(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4CC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.52(s,1H,Ar-H),9.42(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I8_4DD,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.11(s,1H,Ar-H),9.00(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4AA,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4BB,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4CC,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物I9_4DD,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH),8.3(brs,1H,CONH),6.5(brs,2H,CONH)，1.5(brs,2H,NH2),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.42(t,3JHH＝7.1Hz,2H,CH2)，2.76(t,3JHH＝7.1Hz,2H,CH2)，3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例36化合物II1_4AAA-II1_4DDD至II6_4AAA-II6_4DDD的制备
Figure BDA0001662472550001121
一般合成步骤：1.0mmol底物II_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_4AAA,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),8.61(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4BBB,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，6.5(brs,2H,CONH),8.80(brs,2H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4CCC,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，6.5(brs,2H,CONH),9.23(d,3JHH＝8.9Hz,1H,Ar-H),9.17(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4DDD,产率47％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，6.5(brs,2H,CONH),8.19(d,3JHH＝8.9Hz,1H,Ar-H),7.71(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4AAA,产率56％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4BBB,产率49％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4CCC,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.75(s,1H,Ar-H),8.48(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4DDD,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,3H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4AAA,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),7.83(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4BBB,产率54％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.79(d,3JHH＝8.9Hz,1H,Ar-H),7.85(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4CCC,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.17(d,3JHH＝8.9Hz,1H,Ar-H),8.64(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.19(d,3JHH＝8.9Hz,1H,Ar-H),7.18(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4AAA,产率45％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.93(s,1H,Ar-H),8.26(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4BBB,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.95(s,1H,Ar-H),8.60(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4CCC,产率66％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.48(s,1H,Ar-H),9.21(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4DDD,产率62％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.80(s,1H,Ar-H),7.65(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4AAA,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.62(s,1H,Ar-H),8.49(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4BBB,产率58％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.96(s,1H,Ar-H),8.83(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4CCC,产率61％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.20(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.84(s,1H,Ar-H),9.71(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4DDD,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.01(s,1H,Ar-H),7.88(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_3AAA,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.88(d,3JHH＝8.9Hz,1H,Ar-H),7.64(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4BBB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.90(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4CCC,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),9.16(d,3JHH＝8.9Hz,1H,Ar-H),8.86(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4DDD,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),6.5(brs,2H,CONH),8.32(d,3JHH＝8.9Hz,1H,Ar-H),7.24(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例37化合物II1_4A-II1_4D至II6_4A-II6_4D的制备
Figure BDA0001662472550001161
一般合成步骤：1.0mmol底物II_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_4A,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.78(d,3JHH＝8.9Hz,1H,Ar-H),8.40(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4B,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.86(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4C,产率65％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),9.52(d,3JHH＝8.9Hz,1H,Ar-H),9.06(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.2(brs,2H,CONH2)，6.5(brs,2H,CONH),8.82(d,3JHH＝8.9Hz,1H,Ar-H),8.04(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4A,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4B,产率94％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4C,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),8.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4D,产率82％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4A,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4B,产率68％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4C,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4D,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,1H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4A,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4B,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4C,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4D,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3)，2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4A,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4B,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4C,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4D,产率51％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),8.4(brs,2H,CONH2)，6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_3A,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4B,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4C,产率86％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
化合物II6_4D,产率64％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH),7.8(brs,2H,CONH2)，6.5(brs,2H,CONH),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2),1.42(s,27H,CH3).
实施例38化合物II1_4AA-II1_4DD至II6_4AA-II6_4DD的制备
Figure BDA0001662472550001211
一般合成步骤：1.0mmol底物II_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物II1_4AA,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.05(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4BB,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.94(d,3JHH＝8.9Hz,1H,Ar-H),8.74(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4CC,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.36(d,3JHH＝8.9Hz,1H,Ar-H),9.26(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II1_4DD,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.84(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4AA,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4BB,产率92％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4CC,产率79％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II2_4DD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4AA,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.05(d,3JHH＝8.9Hz,1H,Ar-H),7.96(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4BB,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.98(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4CC,产率71％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.32(d,3JHH＝8.9Hz,1H,Ar-H),8.77(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II3_4DD,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.34(d,3JHH＝8.9Hz,1H,Ar-H),7.31(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4AA,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.06(s,1H,Ar-H),8.39(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4BB,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.08(s,1H,Ar-H),8.73(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4CC,产率72％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.61(s,1H,Ar-H),9.34(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II4_4DD,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.93(s,1H,Ar-H),7.78(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4AA,产率93％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.57(s,1H,Ar-H),8.37(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4BB,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.91(s,1H,Ar-H),8.71(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4CC,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.79(s,1H,Ar-H),9.59(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II5_4DD,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),7.96(s,1H,Ar-H),7.76(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_3AA,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.93(d,3JHH＝8.9Hz,1H,Ar-H),7.77(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_4BB,产率75％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.95(d,3JHH＝8.9Hz,1H,Ar-H),8.11(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_4CC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.21(d,3JHH＝8.9Hz,1H,Ar-H),8.99(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物II6_4DD,产率74％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),9.0(brs,1H,CONH)，8.7(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.37(d,3JHH＝8.9Hz,1H,Ar-H),7.37(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例39化合物III1_4AAA-III1_4DDD至III3_4AAA-III3_4DDD的制备
Figure BDA0001662472550001261
一般合成步骤：1.0mmol底物III_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_4AAA,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，6.5(brs,2H,CONH),9.05(s,1H,Ar-H),8.34(d,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.06(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4BBB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，6.5(brs,2H,CONH),9.22(s,1H,Ar-H),8.10(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4CCC,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，6.5(brs,2H,CONH),9.67(s,1H,Ar-H),9.53(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4DDD,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.2(brs,1H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，6.5(brs,2H,CONH),8.15(s,1H,Ar-H),7.76(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4AAA,产率70％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.94(d,3JHH＝8.9Hz,1H,Ar-H),7.88(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4BBB,产率53％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.63(d,3JHH＝8.9Hz,1H,Ar-H),8.05(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.05(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4CCC,产率76％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.33(d,3JHH＝8.9Hz,1H,Ar-H),8.50(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.04(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4DDD,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.58(d,3JHH＝8.9Hz,1H,Ar-H),6.98(d,3JHH＝8.9Hz,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.03(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4AAA,产率69％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.99(s,1H,Ar-H),7.98(d,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.04(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4BBB,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.32(s,1H,Ar-H),7.74(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.04(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4CCC,产率59％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),9.38(s,1H,Ar-H),9.17(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.04(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4DDD,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.8(brs,1H,COOH),12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH),6.5(brs,2H,CONH),8.64(s,1H,Ar-H),7.40(s,1H,Ar-H),4.55(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.33(m,2H,CH2),2.04(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例40化合物III1_4A-III1_4D至III3_4A-III3_4D的制备
Figure BDA0001662472550001281
一般合成步骤：1.0mmol底物III_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_4A,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，8.2(brs,2H,CONH2),6.5(brs,2H,CONH),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4B,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，8.2(brs,2H,CONH2),6.5(brs,2H,CONH),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4C,产率89％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，8.2(brs,2H,CONH2),6.5(brs,2H,CONH),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4D,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.5(brs,1H,CONH)，8.2(brs,2H,CONH2),6.5(brs,2H,CONH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4A,产率80％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4B,产率73％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4C,产率67％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4D,产率89％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4A,产率78％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4B,产率94％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),9.46(s,1H,Ar-H),7.87(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4C,产率90％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4D,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.3(brs,1H,CONH)，7.8(brs,2H,CONH2),6.5(brs,2H,CONH),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例41化合物III1_4AA-III1_4DD至III3_4AA-III3_4DD的制备
Figure BDA0001662472550001311
一般合成步骤：1.0mmol底物III_3，1mL TFA/CHCl3(1：1体积比)，反应混合物在室温下，搅拌直至反应完成。抽干溶剂，粗产品用硅胶柱分离，使用乙酸乙酯和甲醇(90-95:10-5,v/v)作为流动相。
化合物III1_4AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH)，8.5(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.13(s,1H,Ar-H),8.29(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4BB,产率89％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH)，8.5(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.30(s,1H,Ar-H),8.05(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4CC,产率85％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH)，8.5(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.75(s,1H,Ar-H),9.48(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III1_4DD,产率94％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.8(brs,1H,CONH)，8.5(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4AA,产率81％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.99(d,3JHH＝8.9Hz,1H,Ar-H),8.01(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4BB,产率83％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.68(d,3JHH＝8.9Hz,1H,Ar-H),8.18(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4CC,产率77％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.38(d,3JHH＝8.9Hz,1H,Ar-H),8.63(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III2_4DD,产率87％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.64(d,3JHH＝8.9Hz,1H,Ar-H),7.11(d,3JHH＝8.9Hz,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4AA,产率88％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.12(s,1H,Ar-H),8.11(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4BB,产率84％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.46(s,1H,Ar-H),7.87(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4CC,产率91％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),9.51(s,1H,Ar-H),9.30(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
化合物III3_4DD,产率70％,纯度>95％,1H NMR(400MHz；DMSO-d6),δ12.7(brs,2H,COOH),12.0(brs,1H,COOH),8.7(brs,1H,CONH)，8.3(brs,1H,CONH),6.5(brs,1H,CONH),1.5(brs,2H,NH2),8.77(s,1H,Ar-H),7.53(s,1H,Ar-H),3.42(t,3JHH＝7.1Hz,2H,CH2),2.76(t,3JHH＝7.1Hz,2H,CH2),4.51(m,2H,CH),3.06(t,3JHH＝7.1Hz,2H,CH2),2.86(s,9H,NCH3),2.35(t,3JHH＝7.1Hz,2H,CH2),2.29(m,2H,CH2),1.88(m,2H,CH2),1.53(m,2H,CH2),1.25(m,2H,CH2).
实施例42放射性化合物[18F]I1_5A-I9_5A至[18F]III1_5AA-III3_5DD的制备
Figure BDA0001662472550001341
Figure BDA0001662472550001351
Figure BDA0001662472550001361
Figure BDA0001662472550001371
一般合成步骤：3.0mg前体，>3eq K2CO3+K222试剂，1.0mL DMF，反应混合物加热至120～150℃，反应10-30min。反应混合物酸化后，用HPLC分离，做成制剂后使用。
放射性试剂的纯度和比活度由本领域常规的放射性HPLC的紫外光谱确定。比活度由测定注入HPLC试剂的放射性量测定，试剂的摩尔数由非放射性标准品试剂的吸收峰制定的标准曲线来确定.比活度由放射性的量与试剂的摩尔数的比值计算。
对比实施例1
用Na2CO3代替K2CO3，重复实施例42的操作步骤及反应条件，制备放射性化合物[18F]I1_5A-I9_5A至[18F]III1_5AA-III3_5DD。结果发现，Na2CO3效果不好，无法制备得到目标化合物。
效果实施例1：体外实验
由于[18F]放射性化合物具有放射性，且半衰期只有109分钟。而对于[18F]标记化合物与[19F]标记化合物来说，[18F]与[19F]对于化合物的油水分配系数、体外结合实验测定没有影响。因此，以下实验使用非放射性[19F]化合物代替[18F]放射性化合物进行测定，结果数据可以直接等同。
油水分配系数的具体测试方法：l升正辛醇中，加入100毫升PBS(10mM)，溶液在超声波水浴中超声混匀10分钟。然后用分液漏斗分离出正辛醇，放置待用。在1升PBS(10mM)中加入100毫升正辛醇，溶液在超声波水浴中超声混匀10分钟。然后用分液漏斗分离出PBS，放置待用。取上述正PBS溶液5毫升，加入5毫克本发明中的待测化合物，待溶解完全后，加入上述正辛醇40毫升。溶液在涡旋式振荡器上振荡5分钟，分别取0.1毫升水溶液或1毫升正辛醇溶液，注入HPLC进行紫外吸收测量。各溶液中的试剂量由试剂化合物的标准曲线进行定量。分配系数由正辛醇溶液的浓度和水溶液的浓度的比率，再进行所用体积进行校正。油水分配系数由LogP进行计算。本专利所保护化合物的LogP值见下表。
体外结合实验：前列腺肿瘤组织匀浆在1:500PBS(10mM)中，在每个试管中使用900μL。将[3H]DCFPyL浓度用乙醇从1mCi/mL原液稀释到1μCi/100μL，进一步用PBS稀释至2.7×10-2μCi/100μL，每管中使用100μL。将非放射性的化合物DCFPyL或其他待测化合物溶于二甲亚砜中，得到1×10-3M溶液，用二甲亚砜配制1×10-4至1×10-10M溶液，每管中使用10μL。组装后，涡旋试管，并在37℃下反应2h。使用细胞收集器分离，用含10％乙醇的PBS洗涤滤纸。将滤纸放入4mL塑料瓶，加入2mL闪烁液(购自CytoScint,Fisheries Scientific,US)。对样品进行计数。使用GraphPad对数据进行分析，从而得到结合常数。本发明的各种化合物I-III及各对比化合物的结合常数Ki列于下表(具体结果请见下表)。
Figure BDA0001662472550001391
Figure BDA0001662472550001401
对照品结构如下：
Figure BDA0001662472550001402
结论：本发明描述了新一类放射性标记化合物的合成。新增加的亲水性基团，给这类小分子化合物带来了的多重性质改变，包括与目标蛋白质的结合常数，以及非特异性吸收的强弱。但是负离子亲水基团与正离子亲水基团表现不同，并且各种异构体表现也各不相同。部分放射性标记化合物在前列腺肿瘤组织匀浆的体外结合实验中，显示有强的结合能力，部分化合物具有纳摩尔以下的结合常数(Ki<1nM)。非特异性吸收的强弱,由蛋白质结合实验中,饱和曲线中的线性部分大小与蛋白质浓度的比值衡量,比值越小越有利于PET成像中背景峰的消除。有些化合物具有良好PET显影剂的特征，有望为前列腺肿瘤的疾病分级和药物临床效果的跟踪提供灵敏的分子探针。
效果实施例2：使用[18F]I1_5AAA成像剂进行PET成像
临床病例：男性，67岁，近一年来tPSA逐渐升高至13.89，骨扫描发现多发骨转移；图1为一年前后的比较。由图2可知，使用新试剂[18F]I1_5AAA的PSMA PET/CT成像，发现了更多直径<1cm的病灶。成像清晰度和灵敏度，超过同类产品[18F]DCFPyL。

Claims (10)

1.一种化合物D，其结构如下所示：
Figure FDA0001662472540000011
其中，X’为
Figure FDA0001662472540000012
Y为Cl，F、NO2或NMe3 +。
2.如权利要求1所述的化合物D，其为如下任一化合物：
Figure FDA0001662472540000013
Figure FDA0001662472540000021
Figure FDA0001662472540000031
3.一种如权利要求1或2所述的化合物D的制备方法，其特征在于，其包括下列步骤：在溶剂中，在偶联剂存在下，将化合物IV与化合物H进行如下所示偶联反应，得到化合物D，即可；
Figure FDA0001662472540000032
。
4.如权利要求3所述的化合物D的制备方法，其特征在于，所述的偶联剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺和/或N,N’-二环己基碳二亚胺；
和/或，所述偶联反应的反应温度为20～40℃；
和/或，所述的化合物IV与所述的化合物H的摩尔比为1:1～1.6:3；
和/或，所述的化合物IV与所述的偶联剂的摩尔比为1:1～1:4。
5.一种如权利要求1或2所述的化合物D的制备方法，其特征在于，包括下列步骤：在溶剂中，在Me3SiOTf存在下，将“Y为F、Cl或NO2”的化合物D与Me3N进行取代反应，得到“Y为NMe3 +”的所述化合物D，即可。
6.如权利要求5所述的化合物D的制备方法，其特征在于，“Y为F、Cl或NO2”的所述化合物D与Me3N的摩尔比为1:1～1:5；
和/或，“Y为F、Cl或NO2”的所述化合物D与Me3SiOTf的摩尔比为1:1～1:2；
和/或，所述的溶剂为腈类溶剂；
和/或，所述的取代反应的反应温度为20～40℃。
7.一种化合物H，其结构如下所示：
Figure FDA0001662472540000041
其中，X’为
Figure FDA0001662472540000042
Y为F、Cl或NO2。
8.如权利要求7所述的化合物H，其为如下任一化合物：
Figure FDA0001662472540000043
Figure FDA0001662472540000051
9.一种如权利要求7或8所述的化合物H的制备方法，其特征在于，其包括如下步骤：在溶剂中，在碱存在下，将化合物G与脱保护剂试剂进行如下所示脱保护反应，得到所述的化合物H，即可，
Figure FDA0001662472540000052
10.如权利要求9所述的化合物H的制备方法，其特征在于，所述的脱保护试剂为哌啶；
和/或，所述的化合物G与所述的脱保护试剂的摩尔比为1:1；
和/或，所述的溶剂为腈类溶剂。
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