CN112745237B - 2-芳基胺类化合物及其制备方法和应用 - Google Patents

2-芳基胺类化合物及其制备方法和应用 Download PDF

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CN112745237B
CN112745237B CN202011149495.6A CN202011149495A CN112745237B CN 112745237 B CN112745237 B CN 112745237B CN 202011149495 A CN202011149495 A CN 202011149495A CN 112745237 B CN112745237 B CN 112745237B
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synthesis
cancer
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许叶春
邹毅
苏海霞
陈国峰
豆会霞
谢航
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Shanghai Institute of Materia Medica of CAS
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Abstract

本发明公开了一种2‑芳基胺类化合物及其制备方法和应用，2‑芳基胺类化合物结构如式I所示，式中，各取代基的定义如说明书和权利要求书中所述。本发明的化合物对脂肪酸结合蛋白4具有良好的抑制效果，可以用于预防、治疗或辅助治疗与FABP4活性或表达相关的代谢性疾病、炎症和癌症。

Description

2-芳基胺类化合物及其制备方法和应用
技术领域
本发明涉及药物化学领域，涉及一种新型脂肪酸结合蛋白4抑制剂及其制备方法和用途，具体涉及2-芳基胺类化合物或者其药学上可接受的盐或其前药分子的新型高效FABP4抑制剂，其可用于治疗或预防一些代谢相关性疾病、炎症和癌症等。
背景技术
脂肪酸在细胞中的转运是一个动态而复杂的过程，涉及细胞功能的多个方面。脂肪酸既是一种能量来源，又能作为信号分子，通过与酶及相关蛋白的相互作用控制基因转录，进而起到调节代谢的作用。脂肪酸结合蛋白(Fatty acid binding proteins,FABPs)是细胞中一类与脂质结合、介导脂质应答的分子伴侣，分子量为14～15kDa。它们可以与游离脂肪酸以及其它一些配体，如胆固醇、花生四烯酸及视磺酸等可逆地结合，并将这些配体转运到各个靶部位。FABPs在哺乳动物细胞中广泛表达且组织表达特异性明显。其中，脂肪酸结合蛋白4(A-FABP/aP2/FABP4)主要表达在脂肪细胞、内皮细胞和巨噬细胞，是脂肪酸结合蛋白家族中被研究最多的一员，近年来被证明与2型糖尿病、胰岛素抵抗、高血脂、动脉粥样硬化和癌症等疾病的发生发展密切相关。
大量的证据表明，在遗传或者饮食诱导的肥胖小鼠中，敲除FABP4可减轻高胰岛素血症和胰岛素抵抗。Tso等人对544例中国非糖尿病受试者进行长达10年的流行病学跟踪，发现糖耐量受损和空腹血糖增高受试者FABP4的血清水平显著升高，10年后患有2型糖尿病的受试者循环FABP4基线水平显著高于非糖尿病受试者，表明血清FABP4可预测糖尿病的发展。此外，在肥胖小鼠中敲除FABP4可降低血清甘油三酯和胆固醇水平，而在巨噬细胞中特异性敲除FABP4可抑制ApoE敲除引起的动脉粥样硬化，这些结果表明FABP4在与脂肪细胞以及巨噬细胞有关的代谢性疾病中发挥着重要的功能。因此对FABP4的抑制可能用于治疗2型糖尿病以及动脉粥样硬化等代谢性疾病。
近期越来越多的研究表明，FABP4在炎症的发生发展过程中起着重要作用。FABP4的敲除或抑制可以明显减轻慢性和急性炎症的症状。Zhang等人对正常小鼠和FABP4敲除小鼠进行长达9个月的高脂喂养，他们发现FABP4敲除小鼠相对于正常小鼠的骨关节炎症状明显减轻。此外，FABP4的抑制可以明显改善脂多糖诱导的非酒精性肝炎、急性肺炎的症状并且明显减轻缺血再灌注引起的急性肝损伤。因此，FABP4抑制剂可用于关节炎等慢性炎症以及急性肺损伤、急性肝损伤等急性炎症的治疗。
另外，FABP4在卵巢癌、***癌、膀胱癌、乳腺癌、肾细胞癌、白血病等多种肿瘤的发生发展中也起着重要的作用。例如，Liu等人报道了在急性髓系白血病(AML)细胞中，FABP4的上调能通过DNMT1依赖的DNA甲基化过程来促进AML的进展。Li等人还报道了在乳腺癌组织中监测到了FABP4在CD11b+F4/80+MHCII-Ly6C-型肿瘤相关巨噬细胞(TAM)中高表达，并且促进了肿瘤的发生发展。而将FABP4敲除的小鼠移植乳腺癌细胞则可显著抑制肿瘤生长和转移。
目前关于FABP4的抑制剂已经有不少报道，其中研究最多的小分子抑制剂BMS309403在饮食以及遗传引起的肥胖、糖尿病小鼠模型中能够有效的改善脂肪肝，提高胰岛素耐量和葡萄糖耐量，同时它还能减缓巨噬细胞形成泡沫细胞的过程，增加胆固醇的流出并减少与胰岛素敏感性密切相关的炎症因子(如MCP-1、IL-1β、IL-6、TNF-α)的产生，可见FABP4抑制剂在治疗糖尿病以及动脉粥样硬化方面有着极大的应用潜力。BMS309403还可在小鼠的白血病模型中抑制其进展，说明了FABP4抑制剂在肿瘤治疗中的潜力。
发明内容
本发明的目的在于提供一种具有良好的FABP4抑制活性的2-芳基胺类化合物或其药学上可接受的盐、其制备方法、药物组合物及应用，用于治疗和/或预防FABP4密切相关的代谢性疾病、炎症和肿瘤等多种疾病。
本发明的第一方面，提供一种通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，
Figure BDA0002740742780000021
式中，n为1或2；
A环为苯环或5-6元芳杂环；
Z1、Z2、Z3、Z4各自独立为N或CR4；各R4独立为氢、卤素、C1-C10烷基或C1-C10烷氧基；
R1为-COOH、-COOCH3、-COOC2H5、-CONH2、硝基、氨基或-NHSO2CH3甲磺酰胺基；
R2为氢、卤素、C1-C8卤代烷基、羟基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、-SH、-CN、硝基或-NR5R5a；其中R5和R5a各自独立地为氢、C1-C10烷基、C1-C8卤代烷基、C3-C10环烷基、3-8元杂环烷基、C6-C10芳基、3-8元芳杂环基、3-8元杂环烷基C1-C8亚烷基、3-8元环烷基C1-C8亚烷基或C6-C10芳基C1-C8亚烷基，或R5和R5a与它们共同连接的N原子一起形成3-8元的单环杂环烷基；
R3为氢、C1-C8烷基、卤素、-CN、-OR6、-NHR6、C5-C10芳基、3-10元杂芳基、3-10元含氮的杂环烷基、C1-C8烷硫基、-SH、硝基或C3-C8环烷基，其中各R6独立选自氢、C1-C8烷基、C3-8环烷基、3-8元杂环烷基、C5-C10芳基、C5-C10芳基C1-C8亚烷基、3-8元杂芳基、3-8元杂环烷基C1-C8亚烷基或C3-C8环烷基C1-C8亚烷基；
上述各烷基、各亚烷基、各烷氧基、各烷硫基、各杂环烷基、各环烷基、各芳基或各芳杂环基各自独立地为未取代的或被选自下组的1、2、3、4或5个取代基取代：卤素、C1-C8烷基、C1-C8卤代烷基、氰基、硝基、Boc、羟基或NR7R7a，其中R7和R7a各自独立地选自氢、C1-C8烷基、Boc、C1-C8卤代烷基、C3-C10环烷基、3-8元杂环烷基、C5-C10芳基、3-8元杂芳基、3-8元杂环烷基C1-C8亚烷基、3-8元环烷基C1-C8亚烷基或C6-C10芳基C1-C8亚烷基，或R7和R7a与它们共同连接的N原子一起形成3-8元的单环杂环烷基。
在另一优选例中，所述的杂芳基包含一个或多个选自O、S或N的杂原子。
在另一优选例中，当Z1、Z2、Z3、Z4其中的任意一个为N时，其余为CR4。
在另一优选例中，Z1为N，Z2、Z3、Z4为CR4；各R4独立为氢、氟、氯、溴、C1-C4烷基或C1-C4烷氧基。
在另一优选例中，Z1、Z2、Z4各自独立为CR4，Z3为N，各R4独立为氢、氟、氯、溴、C1-C4烷基或C1-C4烷氧基。
在另一优选例中，R4为氢、氟、氯、溴、C1-C4烷基或C1-C4烷氧基。
在另一优选例中，R4为氢、氟、氯、甲基或甲氧基。
在另一优选例中，R2为氢、氟、氯、溴、C1-C4卤代烷基、羟基、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、-SH、-CN、硝基或-NR5R5a；其中R5和R5a各自独立地为氢、C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、3-8元杂环烷基、C6-C10芳基、3-8元芳杂环基、3-8元杂环烷基C1-C4亚烷基、3-8元环烷基C1-C4亚烷基或C6-C10芳基C1-C4亚烷基，或R5和R5a与它们共同连接的N原子一起形成3-8元的单环杂环烷基。
在另一优选例中，R2为氢、氟、氯、溴、羟基、甲基、乙基、丙基、甲氧基、氰基、硝基、-NR5R5a；R5和R5a各自独立地选自氢、甲基、乙基、苯基，或R5和R5a与它们共同连接的N原子一起形成6元的单环杂环烷基。
在另一优选例中，R3为氢、C1-C4烷基、卤素、-CN、-OR6、-NHR6、C5-C10芳基、3-10元芳杂环基、3-8元含氮的杂环烷基、C1-C4烷硫基、-SH、硝基或C3-C8环烷基，其中各R6独立选自氢、C1-C4烷基、C3-8环烷基、3-8元杂环烷基、C5-C10芳基、C5-C10芳基C1-C4亚烷基、3-8元杂芳基、3-8元杂环烷基C1-C4亚烷基或C3-C8环烷基C1-C4亚烷基；
上述各烷基、各亚烷基、各烷氧基、各烷硫基、各杂环烷基、各环烷基、各芳基或各芳杂环基各自独立地为未取代的或被选自下组的1、2、3、4或5个取代基取代：卤素、C1-C4烷基、C1-C4卤代烷基、氰基、硝基、Boc、羟基或NR7R7a，其中R7和R7a各自独立地选自氢、C1-C4烷基、Boc、C1-C4卤代烷基、C3-C6环烷基、3-8元杂环烷基、C5-C10芳基、3-8元杂芳基、3-8元杂环烷基C1-C4亚烷基、3-8元环烷基C1-C4亚烷基或C6-C10芳基C1-C4亚烷基，或R7和R7a与它们共同连接的N原子一起形成3-8元的单环杂环烷基。
在另一优选例中，R3为氢、甲基、乙基、丙基、甲氧基、乙氧基、氯、氟、溴、三氟甲基、氰基、羟基、苯基、萘基(如
Figure BDA0002740742780000041
)、-OR6，或选自下组的任一基团：
Figure BDA0002740742780000042
其中R6为：
Figure BDA0002740742780000043
在另一优选例中，A环为苯环。
在另一优选例中，所述化合物为：
Figure BDA0002740742780000044
Figure BDA0002740742780000051
Figure BDA0002740742780000061
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明的第二方面，提供一种药物组合物，所述药物组合物包含第一方面所述的化合物或其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐；以及
药学上可接受的载体或赋形剂。
本发明提供新型的化合物，可以单独使用，或者将其与可药用的辅料(例如赋形剂、稀释剂等)混合，配制成口服给药的片剂、胶囊剂、颗粒剂或糖浆剂等。该药物组合物可以按照制药学上常规方法制得。
在另一优选例中，所述药物组合物进一步包含至少一种其他治疗剂。优选地，所述药物组合物中包含的所述至少一种其他治疗剂选自其他抗癌剂、免疫调节剂、抗过敏剂、止吐剂、疼痛缓解剂、细胞保护剂及其组合。
本发明的第三方面，提供第一方面所述的化合物或第二方面所述的药物组合物用途，用于制备脂肪酸结合蛋白4抑制剂，或者用于制备治疗或预防与脂肪酸结合蛋白4异常相关疾病的药物。
在另一优选例中，所述与脂肪酸结合蛋白4异常相关疾病为2型糖尿病、代谢综合征、动脉粥样硬化、血脂异常、肝脏疾病、肥胖症、脂营养不良、结节病、眼部疾病、肺部疾病、慢性肾脏疾病、慢性炎症、急性炎症、自身免疫性炎症疾病、先兆子痫、***或癌症。
在另一优选例中，所述药物用于治疗肝脏疾病、脂营养不良、眼部疾病、肺部疾病、慢性肾脏疾病或癌症。
在另一优选例中，所述的肝脏疾病包括炎症、脂肪变性和/或纤维化的肝脏疾病，如非酒精性脂肪肝病，尤其是非酒精性脂肪性肝炎。
在另一优选例中，所述的脂营养不良是遗传性或医源性脂营养不良。
在另一优选例中，所述的眼部疾病是由内皮增殖和血管新生维持的眼部疾病，特别是黄斑变性和视网膜病。
在另一优选例中，所述的肺部疾病包括但不限于哮喘、支气管肺发育异常、慢性阻塞性肺病的一种或多种。
在另一优选例中，所述的慢性肾脏疾病包括但不限于脉管炎、局灶性节段性肾小球硬化症、糖尿病肾病、狼疮肾炎、多囊性肾病和药物或毒素诱导的慢性小管间质性肾炎的一种或多种。
在另一优选例中，所述的急性炎症包括但不限于脓毒症、败血症、急性肾损伤、急性肺损伤、急性肝损伤。
在另一优选例中，所述的癌症包括但不限于：恶性黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、***癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、***、子宫内膜癌、间皮瘤、甲状腺癌、肝癌和食管癌中的一种或多种。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
附图说明
图1为化合物在3T3-L1细胞上促进脂堆积的作用图。
图2为化合物在3T3-L1细胞上对脂解的抑制作用图。
图3为化合物对THP-1细胞MCP-1分泌的抑制作用图。
图4为化合物对THP-1细胞IL-6分泌的抑制作用图。
图5为化合物对C57BL/KsJ雄性小鼠体内MCP-1分泌的抑制作用图。
图6为化合物对C57BL/KsJ雄性小鼠体内IL-6分泌的抑制作用图。
具体实施方式
本申请的发明人经过广泛而深入地研究，研发出一种2-芳基胺类化合物或其药学上可接受的盐，其中多个化合物在分子水平和多种细胞上表现出良好的FABP4抑制活性，化合物活性优于阳性抑制剂BMS309403；在动物体内具有较好的抑制炎症的效果，能够用于治疗和/或预防FABP4密切相关的代谢性疾病、炎症和肿瘤等多种疾病。在此基础上，完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C4”是指具有1、2、3或4个碳原子，“C1-C8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。“3-8元”是指具有3-8个环原子，依此类推。
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、正丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，“亚烷基”包括但不限于-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)-。
在本发明中，术语“烷氧基”表示-O-(C1-6烷基)基团。例如术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，术语“杂环烷基”表示包含至少一个环杂原子(例如N，O或S)的环烷基。
在本发明中，术语“芳基”表示包含一个或多个芳环的烃基部分。例如术语“C5-C10芳基”、“C6-C10芳基”是指在环上不含杂原子的具有5-10或6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“杂芳基”或“芳杂环基”表示环内具有1至15个碳原子和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团，如吡啶基、吡咯基等。
本发明中，所述取代为单取代或多取代，所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基，依此类推。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
在另一优选例中，“药学上可接受的盐”是指式I化合物同选自下组的酸形成的盐类：氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
化合物
在一优选实施方式中，本发明的2-芳基胺类化合物结构如下所示：
Figure BDA0002740742780000091
其中：m为1或2；B环为苯环或6元芳杂环；
Z1、Z2、Z3、Z4为N或C，当Z1、Z2、Z3、Z4其中的任意一个为N时，其余为C；
R1、R2、R3、R4的定义同前所述。
制备方法
本发明提供的2-芳基胺类化合物的制备方法，包括以下步骤：
a)当R1为-COOH，-COOCH3；R3为芳环时，通式(I)所示化合物的制备方法为：不同取代的邻硝基卤代苯与不同取代的苯硼酸发生Suzuki偶联反应制得中间体3，3经还原制得中间体4；4与不同取代的芳基苯甲酸甲酯5经Buchwald偶联反应得到中间体6，最后经水解反应得到目标产物；其合成路线如下：
Figure BDA0002740742780000092
其中，Z1、Z2、Z3、Z4、R2、R3和R4的定义如前所述；X选自氯、溴和碘，优选碘；
b)当R1为-COOH，-COOCH3；R3为-OR6时，通式(I)所示化合物的制备方法为：不同取代的邻氟硝基苯7与醇或酚反应得到9，9经还原制得10，10与不同取代的芳基苯甲酸甲酯5经Buchwald偶联反应得到中间体11，最后经水解反应得到目标产物；其合成路线如下：
Figure BDA0002740742780000101
其中，Z1、Z2、Z3、Z4、R2、R4和R6的定义如前所述；
c)当R1为-COOH，-COOCH3；R3为-NHR6时，通式(I)所示化合物的制备方法为：不同取代的邻氟硝基苯7与不同取代的伯胺或仲胺12反应得到13，13经还原制得14，14与不同取代的芳基苯甲酸甲酯5经Buchwald偶联反应得到中间体15，最后经水解反应得到目标产物；其合成路线如下：
Figure BDA0002740742780000102
其中，Z1、Z2、Z3、Z4、R2、R4和R6的定义如前所述；
d)当R1为硝基，氨基和甲磺酰胺基时，通式(I)所示化合物的制备方法为：不同取代的邻氟硝基苯16与不同取代的苯胺反应得到化合物18，随后，18经还原得到化合物19，最后19在甲磺酰氯存在下反应得到化合物；其合成路线如下：
Figure BDA0002740742780000111
其中，Z1、Z2、Z3、Z4、R2、R3和R4的定义如前所述；
e)当R1为-COOH，R3为甲基、氰基、三氟甲基和甲氧基时，通式(I)所示化合物的制备方法为：不同取代或未取代的邻卤代苯甲酸或邻卤代杂芳基甲酸和不同取代或未取代苯胺或杂芳胺经Ullmann反应制得目标化合物；其合成路线如下：
Figure BDA0002740742780000112
其中，Z1、Z2、Z3、Z4、R2、R3和R4的定义如前所述；X选自氯、溴和碘，优选氯。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
药物组合物
本发明的药物组合物，包含作为活性成分的本发明的化合物，或其药学上可接受的盐；和药学上可接受的载体。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure BDA0002740742780000113
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液和悬浮液)等，优选片剂、胶囊、液体、悬浮液、和针剂(溶液和悬浮液)。
为了使片剂、丸剂或栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油)，制成与血液等渗压的针剂。在制备针剂时，也可以使用本领域内任何常用的载体。例如：水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可以加入通常溶解剂和缓冲剂等。
本发明所述的化合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，优先为质量百分比的30～85％。
本发明的化合物或药物组合物的给药方法没有特殊限制。可根据患者年龄、性别和其它条件及症状，选择各种剂型的制剂给药。代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
本发明化合物可以单独给药，或者与其他治疗药物(如抗肿瘤药)联合给药。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
2-(邻甲苯胺)苯甲酸(1)的合成
Figure BDA0002740742780000121
将邻氯苯甲酸(200mg，1.27mmol)，邻甲基苯胺(137mg，1.27mmol)，铜粉(40.6mg，0.639mmol)和碳酸钾(353mg，2.55mmol)用5mL DMF混合，130℃下反应12h，随后降至室温，加入水(20mL)淬灭反应，用硅藻土过滤，滤液中滴加6N盐酸使溶液pH<7，乙酸乙酯萃取(3×20mL)，饱和食盐水洗涤，无水硫酸镁干燥，柱层析分离(二氯甲烷：无水甲醇＝500：1)，得白色固体180mg，收率59.2％。ESI-MS:226.2[M-H]-；1H NMR(500MHz,DMSO-d6)δ11.66(s,1H),7.90(dd,J＝7.7,1.8Hz,1H),7.32(dd,J＝8.0,1.2Hz,1H),7.17(dd,J＝7.5,1.5Hz,1H),7.10(qd,J＝8.2,1.8Hz,2H),7.04(dd,J＝8.2,1.3Hz,1H),6.85–6.79(m,1H),6.64–6.59(m,1H),2.22(s,3H).
实施例2
2-((2-甲基-3-三氟甲基苯基)-胺基苯甲酸(2)的合成
Figure BDA0002740742780000131
参照目标化合物1的合成方法，得白色固体，收率65％。ESI-MS:296.1[M+H]+；1HNMR(500MHz,DMSO-d6)δ10.12(s,1H),7.93(dd,J＝7.9,1.7Hz,1H),7.66–7.59(m,1H),7.46–7.36(m,2H),7.33(ddd,J＝8.6,7.1,1.7Hz,1H),6.88(dd,J＝8.5,1.1Hz,1H),6.78(ddd,J＝8.1,7.1,1.1Hz,1H),2.33–2.28(m,3H).
实施例3
2-((3-氟-2-甲苯基)-胺基苯甲酸(3)的合成
Figure BDA0002740742780000132
参照目标化合物1的合成方法，得白色固体，收率72％。ESI-MS:246.1[M+H]+；1HNMR(500MHz,Chloroform-d)δ9.19(s,1H),8.07(dd,J＝8.0,1.7Hz,1H),7.36(ddd,J＝8.7,7.0,1.7Hz,1H),7.17(td,J＝7.9,6.1Hz,2H),6.96–6.86(m,2H),6.78(ddd,J＝8.1,7.1,1.1Hz,1H),2.22(d,J＝2.1Hz,3H).
实施例4
2-((3-氟-2-甲苯基)-胺基苯甲酸(4)的合成
Figure BDA0002740742780000133
参照目标化合物1的合成方法，得白色固体，收率89％。ESI-MS:306.0[M+H]+；1HNMR(500MHz,Chloroform-d)δ11.59(s,1H),9.22(s,1H),8.08(dd,J＝8.3,1.8Hz,1H),7.47(d,J＝8.0Hz,1H),7.36(ddd,J＝8.6,7.1,1.7Hz,1H),7.31(d,J＝7.9Hz,1H),7.12(t,J＝7.9Hz,1H),6.79(dt,J＝7.4,3.1Hz,2H),2.41(s,3H).
实施例5
2-((2,3-二氯苯基)-胺基苯甲酸(5)的合成
Figure BDA0002740742780000134
参照目标化合物1的合成方法，得白色固体，收率87％。ESI-MS:280.0[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.40(s,1H),9.98(s,1H),7.97(dd,J＝7.9,1.8Hz,1H),7.56–7.46(m,2H),7.40–7.23(m,3H),6.95(t,J＝7.7Hz,1H).
实施例6
2-((3-氯-2,6-二乙基苯基)-胺基苯甲酸(6)的合成
Figure BDA0002740742780000141
参照目标化合物1的合成方法，得白色固体，收率71％。ESI-MS:302.1[M-H]-；1HNMR(500MHz,Chloroform-d)δ10.17(s,1H),9.02(s,1H),8.04(dd,J＝8.1,1.7Hz,1H),7.33(d,J＝8.3Hz,1H),7.27–7.24(m,1H),7.14(d,J＝8.3Hz,1H),6.69(ddd,J＝8.1,7.0,1.1Hz,1H),6.23(dd,J＝8.5,1.1Hz,1H),2.84(dq,J＝13.0,7.5Hz,1H),2.61(ddq,J＝27.7,15.0,7.6Hz,2H),2.47(dq,J＝15.0,7.6Hz,1H),1.14(t,J＝7.6Hz,3H),1.11(t,J＝7.5Hz,3H).
实施例7
2-((3-氯-2-甲氧基苯基)-胺基苯甲酸(7)的合成
Figure BDA0002740742780000142
参照目标化合物1的合成方法，得白色固体，收率75％。ESI-MS:276.0[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.15(s,1H),10.06(s,1H),7.94(dd,J＝7.9,1.7Hz,1H),7.45(td,J＝7.3,6.8,2.2Hz,2H),7.34(dd,J＝8.4,1.1Hz,1H),7.15–7.06(m,2H),6.87(ddd,J＝8.0,7.2,1.1Hz,1H),3.77(s,3H).
实施例8
2-((3-氯-2-三氟甲基苯基)-胺基苯甲酸(8)的合成
Figure BDA0002740742780000143
参照目标化合物1的合成方法，得淡黄色固体，收率80％。ESI-MS:314.0[M-H]-；1HNMR(500MHz,Chloroform-d)δ9.58(s,1H),8.07(ddd,J＝30.9,7.8,1.7Hz,1H),7.54–7.45(m,2H),7.39(ddq,J＝10.5,5.0,3.3,2.5Hz,2H),7.29(s,1H),7.06(dd,J＝8.5,1.1Hz,1H),6.88(ddd,J＝8.1,7.1,1.1Hz,1H).
实施例9
2-((2-氰基-3-三氟甲基苯基)-胺基苯甲酸(9)的合成
Figure BDA0002740742780000151
参照目标化合物1的合成方法，得白色固体，收率68％。ESI-MS:305.1[M+H]+；1HNMR(500MHz,Chloroform-d)δ10.16(s,1H),8.23–8.16(m,1H),7.78(d,J＝8.5Hz,1H),7.58(t,J＝8.1Hz,1H),7.51(t,J＝7.7Hz,1H),7.40(d,J＝8.3Hz,1H),7.35(d,J＝7.6Hz,1H),7.05(t,J＝7.5Hz,1H).
实施例10
Figure BDA0002740742780000152
2-((3,5-二氯-2-甲氧基苯基)-胺基苯甲酸(10)的合成
参照目标化合物1的合成方法，得到白色固体23mg，收率52％。ESI-MS:312.0[M+H]+；1H NMR(500MHz,DMSO-d6)δ13.36(s,1H),10.02(s,1H),7.96(dd,J＝7.9,1.7Hz,1H),7.53(ddd,J＝8.6,7.2,1.7Hz,1H),7.45–7.41(m,2H),7.19(t,J＝2.2Hz,1H),6.99–6.94(m,1H),3.79(s,3H).
2-((3,5-二氯-2-羟基苯基)-胺基苯甲酸(11)的合成
将2-((3,5-二氯-2-甲氧基苯基)-胺基苯甲酸(10，13mg，0.042mmol)溶于2mL的二氯甲烷中，体系降温至0℃后逐渐滴加三溴化硼(0.016mL，0.167mmol)至上述溶液，在此温度下反应20min后，再升温至室温再发应20min。反应使用10mL甲醇淬灭后，使用乙酸乙酯和水萃取，有机层合并后使用无水硫酸钠干燥，抽滤并旋干，得8mg目标产物，白色固体，收率61.2％。ESI-MS:296.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ11.28(s,1H),7.96(s,1H),7.94(dd,J＝7.7,1.8Hz,1H),7.48–7.32(m,1H),7.29–7.24(m,2H),7.22–7.19(m,1H),6.94(d,J＝2.4Hz,1H),6.78(t,J＝7.4Hz,1H).
实施例11
2-((3-氯-2-甲苯基)-胺基烟酸(12)的合成
Figure BDA0002740742780000153
参照目标化合物1合成方法，得淡褐色固体，收率66％。ESI-MS:261.1[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.80(s,1H),8.30(dd,J＝4.8,2.0Hz,1H),8.25(dd,J＝7.6,2.0Hz,1H),8.19(d,J＝8.1Hz,1H),7.19(t,J＝8.1Hz,1H),7.13(dd,J＝8.1,1.3Hz,1H),6.85(dd,J＝7.6,4.7Hz,1H),2.34(s,3H).
实施例12
2-苯胺基苯甲酸(13)的合成
Figure BDA0002740742780000161
参照目标化合物1合成方法，得白色固体，收率86％。ESI-MS:212.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ10.20(s,1H),7.89(dd,J＝7.5,1.5Hz,1H),7.31(td,J＝7.5,1.5Hz,1H),7.28–7.20(m,2H),7.15(dd,J＝7.5,1.5Hz,1H),7.07–7.00(m,2H),6.94(tt,J＝7.5,1.6Hz,1H),6.87(td,J＝7.5,1.6Hz,1H),6.21(s,1H).
实施例13
2-((3-氯-2-甲苯基)-胺基-5-氟烟酸(14)的合成
Figure BDA0002740742780000162
参照目标化合物1合成方法，得淡黄色固体，收率56％。ESI-MS:281.1[M+H]+；1HNMR(500MHz,DMSO-d6)δ13.95(s,1H),10.19(s,1H),8.39(d,J＝3.2Hz,1H),8.10(dd,J＝8.8,3.2Hz,1H),8.04(dd,J＝7.9,1.5Hz,1H),7.23–7.14(m,2H),2.31(s,3H).
实施例14
2-((3-氯-2-甲苯基)-胺基苯甲酸(15)的合成
Figure BDA0002740742780000163
参照目标化合物1合成方法，得白色固体，收率87％。ESI-MS:260.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.21(s,1H),7.89(dd,J＝7.4,1.6Hz,1H),7.37(dd,J＝6.1,2.8Hz,1H),7.34(td,J＝7.5,1.5Hz,1H),7.30–7.24(m,2H),7.21(td,J＝7.5,1.5Hz,1H),7.14(dd,J＝7.4,1.5Hz,1H),2.40(s,3H).
实施例15
Figure BDA0002740742780000164
3-氯-2-甲基-N-(2-硝基苯)苯胺(16)的合成
将邻溴硝基苯(500mg，2.475mmol)、3-氯-2-甲基苯胺(421mg，2.97mmol)、BINAP(231mg，0.371mmol)、Pd2(dba)3(227mg，0.248mmol)和Cs2CO3(1.61g，4.95mmol)置于8mL甲苯中，在氮气保护下加热至95℃反应12h。将体系温度冷却至室温后，加入水和乙酸乙酯萃取，饱和食盐水洗有机层，无水硫酸钠干燥，柱层析(石油醚：乙酸乙酯＝20：1)，得淡黄色固体480mg，收率74％。1H NMR(500MHz,Chloroform-d)δ9.26(s,1H),8.19–8.09(m,1H),7.32–7.22(m,2H),7.13(d,J＝6.2Hz,2H),6.70(t,J＝7.8Hz,2H),2.25(s,3H).
N-(3-氯-2-甲苯基)苯基-1,2-二胺(17)的合成
将3-氯-2-甲基-N-(2-硝基苯)苯胺(16，400mg，1.52mmol)溶于15mL乙醇，在室温下依次加入还原铁粉(680mg，12.18mmol)、氯化铵的水溶液(81mg氯化铵溶于5mL水)、冰醋酸(0.174mL，3.05mmol)，升温至50℃后反应1h。恢复至室温后使用硅藻土滤去不溶物，滤液使用乙酸乙酯和水萃取，饱和食盐水洗有机层，无水硫酸钠干燥，旋干得淡黄色固体300mg，收率85％。1H NMR(500MHz,Chloroform-d)δ6.97(td,J＝7.6,1.4Hz,1H),6.92–6.85(m,2H),6.82(d,J＝7.8Hz,1H),6.74(dd,J＝8.0,1.3Hz,1H),6.69(td,J＝7.6,1.4Hz,1H),6.40(d,J＝7.9Hz,1H),5.02(s,1H),3.66(s,2H),2.28(s,3H).
N-(2-((3-氯-2-甲苯基)胺基)苯基)甲磺酰胺(18)的合成
将N-(3-氯-2-甲苯基)苯基-1,2-二胺(17，50mg，0.215mmol)溶于6mL的无水***，在0℃下依次加入三乙胺(60μL，0.43mmol)和甲磺酰氯(17μL，0.215mmol)，在该温度下反应1h后加入10mL甲醇淬灭反应。使用乙酸乙酯和水萃取，饱和食盐水洗有机层，无水硫酸钠干燥，旋干后使用制备板分离提纯(二氯甲烷：甲醇＝10：1)，刮板得35mg白色固体，收率52.4％。1H NMR(500MHz,Chloroform-d)δ7.28(dd,J＝7.9,1.5Hz,1H),7.11(td,J＝7.8,1.6Hz,1H),7.01–6.89(m,4H),6.71(dd,J＝7.9,1.5Hz,1H),6.39(s,1H),6.10(s,1H),2.97(s,3H),2.26(s,3H).
实施例16
Figure BDA0002740742780000171
N-(3-氯-2-甲苯基)-3-硝基吡啶-2-胺(19)的合成
参照目标化合物16合成方法，得淡黄色固体，收率88％。1H NMR(500MHz,Chloroform-d)δ9.79(s,1H),8.47(dd,J＝8.4,1.8Hz,1H),8.36(dd,J＝4.4,1.8Hz,1H),7.55(dd,J＝8.0,1.3Hz,1H),7.23(dd,J＝8.1,1.3Hz,1H),7.13(t,J＝8.0Hz,1H),6.76(dd,J＝8.4,4.5Hz,1H),2.30(s,3H).
N-(3-氯-2-甲苯基)吡啶-2,3-二胺的合成
参照目标化合物17合成方法，得淡黄色固体，收率78％。1H NMR(500MHz,DMSO-d6)δ7.44(dd,J＝4.8,1.6Hz,1H),7.39–7.29(m,2H),7.20–7.10(m,2H),6.96(dd,J＝7.6,1.6Hz,1H),6.66(dd,J＝7.6,4.8Hz,1H),5.06(s,2H),2.23(s,3H).
N-(2-((3-氯-2-甲苯基)胺基)吡啶-3-基)甲磺酰胺(20)的合成
参照目标化合物18合成方法，得白色固体，收率50％。1H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.51(d,J＝3.3Hz,1H),7.94(d,J＝8.1Hz,1H),7.73(dd,J＝4.9,1.7Hz,1H),7.42(dd,J＝7.6,1.8Hz,1H),7.15(t,J＝8.0Hz,1H),7.10–7.04(m,1H),6.71(dd,J＝7.7,4.9Hz,1H),2.89(s,3H),2.24(s,3H).
实施例17
Figure BDA0002740742780000181
1-氯-2-(环丙基甲氧基)-3-硝基苯的合成
将环己基甲醇(288mg，3.99mmol)溶于10mL无水四氢呋喃，在0℃下加入NaH(NaH分散在矿物油中，含量60％，228mg，5.7mmol)，在该温度下反应15min后加入1-氯-2-氟-3-硝基苯(500mg，2.85mmol)，温度升至70℃反应1h。体系降至室温后，加入水(5mL)淬灭反应，乙酸乙酯萃取，饱和食盐水洗有机层，无水硫酸钠干燥，旋干后使用柱层析分离(石油醚：乙酸乙酯＝200：1)，得到淡黄色固体500mg，收率79％。1H NMR(500MHz,Chloroform-d)δ7.70(dd,J＝8.1,1.6Hz,1H),7.61(dd,J＝8.1,1.6Hz,1H),7.17(t,J＝8.1Hz,1H),4.01(d,J＝7.3Hz,2H),1.40–1.30(m,1H),0.68–0.57(m,2H),0.38–0.35(m,2H).
3-氯-2-(环丙基甲氧基)胺的合成
参照目标化合物17合成方法，得淡黄色固体，收率85％。
2-((3-氯-2-(环丙基甲氧基)苯基)胺基)苯甲酸甲酯的合成
参照目标化合物16合成方法，得白色固体，收率56％。ESI-MS:332.1[M+H]+
2-((3-氯-2-(环丙基甲氧基)苯基)胺基)苯甲酸(21)的合成
将2-((3-氯-2-(环丙基甲氧基)苯基)胺基)苯甲酸甲酯(47mg，0.142mmol)溶于甲醇(5mL)中，加入NaOH的水溶液(22.66mg的NaOH溶于5mL水)，升温至65℃后反应2h。待温度降至0℃后，使用6N盐酸调pH至酸性后析出大量白色固体，抽滤，干燥得白色固体35mg，收率78％。ESI-MS:316.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.00(s,1H),9.71(s,1H),7.69(dd,J＝8.0,1.7Hz,1H),7.26–7.17(m,2H),7.16–7.08(m,1H),6.92–6.81(m,2H),6.66–6.57(m,1H),3.51(d,J＝7.1Hz,2H),1.02–0.97(m,1H),0.28–0.18(m,2H),0.05–0.00(m,2H).
实施例18
2-((3-溴-2-(环丙基甲氧基)苯基)胺基)苯甲酸(22)的合成
Figure BDA0002740742780000182
参照目标化合物21合成方法，得白色固体，收率81％。ESI-MS:294.2[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.97(s,1H),9.70(s,1H),7.70(dd,J＝8.0,1.7Hz,1H),7.31–7.17(m,2H),7.10(d,J＝8.5Hz,1H),7.05–6.97(m,1H),6.81(t,J＝8.1Hz,1H),6.62(t,J＝7.5Hz,1H),3.49(d,J＝7.2Hz,2H),1.06–1.00(m,1H),0.29–0.20(m,2H),0.04–0.02(m,2H).
实施例19
2-((5-溴-3-氯-2-(环丙基甲氧基)苯基)胺基)苯甲酸(23)的合成
Figure BDA0002740742780000191
参照目标化合物21合成方法，得白色固体，收率78％。ESI-MS:360.3[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.32(s,1H),10.00(s,1H),7.96(dd,J＝8.1,1.6Hz,1H),7.58–7.48(m,2H),7.41(d,J＝8.3Hz,1H),7.31(d,J＝2.2Hz,1H),6.95(t,J＝7.6Hz,1H),3.78(d,J＝7.2Hz,2H),1.30-1.25(m,1H),0.54-0.44(m,2H),0.29–0.26(m,2H).
实施例20
2-((3-氯-2-(环丙基甲氧基)-5-三氟甲基苯基)胺基)苯甲酸(24)的合成
Figure BDA0002740742780000192
参照目标化合物21合成方法，得白色固体，收率80％。ESI-MS:386.0[M+H]+；1H NMR(500MHz,DMSO-d6)δ13.29(s,1H),10.13(s,1H),8.02(dt,J＝7.9,2.6Hz,1H),7.73(dd,J＝8.7,2.2Hz,1H),7.61–7.55(m,1H),7.52(d,J＝2.0Hz,1H),7.44(d,J＝8.4Hz,1H),7.03(dt,J＝11.6,7.5Hz,1H),3.92(d,J＝7.2Hz,2H),1.36–1.31(m,1H),0.62–0.53(m,2H),0.40–0.31(m,2H).
实施例21
2-((3-氯-2-(环丙基甲氧基)苯基)胺基)苯甲酸(25)的合成
Figure BDA0002740742780000193
参照目标化合物25合成方法，得白色固体，收率81％，ESI-MS:318.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.30(s,1H),9.87(d,J＝4.1Hz,1H),7.94(dt,J＝7.9,2.0Hz,1H),7.45(tt,J＝8.0,2.3Hz,2H),7.33–7.23(m,1H),7.19–7.05(m,2H),6.87(t,J＝7.6Hz,1H),5.02(h,J＝6.1Hz,1H),4.81–4.66(m,4H).
实施例22
2-((3-氯-2-(环戊基甲氧基)苯基)胺基)苯甲酸(26)的合成
Figure BDA0002740742780000201
参照目标化合物21合成方法，得白色固体，收率77％。ESI-MS:344.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),9.85(s,1H),7.92(dd,J＝8.0,1.7Hz,1H),7.47–7.37(m,2H),7.29(d,J＝8.4Hz,1H),7.19–7.01(m,2H),6.84(t,J＝7.5Hz,1H),3.73(d,J＝6.9Hz,2H),2.31(dq,J＝14.7,7.3Hz,1H),1.69(dtd,J＝12.3,7.1,6.3,3.0Hz,2H),1.57–1.42(m,4H),1.41–1.31(m,2H).
实施例23
2-((3-氯-2-(环丙基乙氧基)苯基)胺基)苯甲酸(27)的合成
Figure BDA0002740742780000202
参照目标化合物21合成方法，得白色固体，收率68％。ESI-MS:330.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),9.90(s,1H),7.93(dd,J＝7.9,1.7Hz,1H),7.44(td,J＝7.2,6.3,2.3Hz,2H),7.32(d,J＝8.4Hz,1H),7.11(q,J＝3.9,3.1Hz,2H),6.85(t,J＝7.5Hz,1H),3.93(t,J＝6.6Hz,2H),1.62(q,J＝6.7Hz,2H),0.82(pd,J＝7.5,3.8Hz,1H),0.43–0.26(m,2H),0.03–0.00(m,2H).
实施例24
2-((3-氯-2-(环丁基甲氧基)苯基)胺基)苯甲酸(28)的合成
Figure BDA0002740742780000203
参照目标化合物21合成方法，得白色固体，收率77％。ESI-MS:330.2[M-H]-；1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.01(dd,J＝7.9,1.7Hz,1H),7.57–7.46(m,2H),7.39(dd,J＝8.5,1.1Hz,1H),7.24–7.13(m,2H),6.99–6.89(m,1H),3.94(d,J＝6.6Hz,2H),2.79(ddd,J＝12.9,8.9,6.7Hz,1H),2.12–2.00(m,2H),1.99–1.78(m,4H).
实施例25
2-((3-氯-2-(2,2-二氟环丙基甲氧基)苯基)胺基)苯甲酸(29)的合成
Figure BDA0002740742780000211
参照目标化合物21的合成方法，得淡黄色固体，收率89％。ESI-MS:354.1[M+H]+；1HNMR(500MHz,DMSO-d6)δ13.18(s,1H),10.02(s,1H),8.00(d,J＝7.9Hz,1H),7.52(dd,J＝8.9,6.0Hz,2H),7.40(d,J＝8.4Hz,1H),7.26–7.12(m,2H),6.93(t,J＝7.5Hz,1H),4.11(ddd,J＝10.0,6.4,3.0Hz,1H),4.01(t,J＝9.7Hz,1H),2.24(tt,J＝12.5,6.8Hz,1H),1.71(tdd,J＝12.1,7.9,4.6Hz,1H),1.43(tdd,J＝12.6,8.2,4.4Hz,1H).
实施例26
2-((3-氯-2-(1-甲基环丙基甲氧基)苯基)胺基)苯甲酸(30)的合成
Figure BDA0002740742780000212
参照目标化合物21的合成方法，得淡黄色固体，收率87％。ESI-MS:330.3[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.28(s,1H),9.82(s,1H),7.98(dd,J＝8.0,1.7Hz,1H),7.52–7.45(m,2H),7.32(dd,J＝8.5,1.1Hz,1H),7.20–7.11(m,2H),6.93–6.86(m,1H),3.68(s,2H),1.25(s,3H),0.57–0.52(m,2H),0.40–0.33(m,2H).
实施例27
2-((3-氯-2-(环丙基甲氧基)苯基)胺基)-5-氟苯甲酸(31)的合成
Figure BDA0002740742780000213
参照目标化合物21的合成方法，得淡黄色固体，收率67％。ESI-MS:334.5[M-H]-；1HNMR(500MHz,DMSO-d6)δ9.76(s,1H),7.68–7.62(m,1H),7.42–7.38(m,1H),7.36(dd,J＝6.5,2.0Hz,2H),7.10(d,J＝4.7Hz,2H),3.76(d,J＝7.1Hz,2H),1.26–1.20(m,1H),0.54–0.43(m,2H),0.27–0.24(m,2H).
实施例28
4-((3-氯-2-(环丙基甲氧基)苯基)胺基)-2-氟烟酸(32)的合成
Figure BDA0002740742780000221
参照目标化合物21的合成方法，得白色固体，收率90％。ESI-MS:335.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.73(s,1H),10.19(s,1H),7.91(d,J＝6.0Hz,1H),7.43(dd,J＝8.0,1.5Hz,1H),7.34(dd,J＝8.1,1.5Hz,1H),7.19(t,J＝8.1Hz,1H),6.88(d,J＝6.0Hz,1H),3.75(d,J＝7.2Hz,2H),1.18-1.12(m,1H),0.50–0.39(m,2H),0.20–0.17(m,2H).
实施例29
3-((3-氯-2-(环丙基甲氧基)苯基)胺基)异烟酸(33)的合成
Figure BDA0002740742780000222
参照目标化合物21的合成方法，得白色固体，收率86％。ESI-MS:317.5[M-H]-；1HNMR(500MHz,DMSO-d6)δ9.56(s,1H),8.67(s,1H),8.10(d,J＝5.0Hz,1H),7.72(d,J＝5.0Hz,1H),7.49(d,J＝7.5Hz,1H),7.20–7.08(m,2H),3.76(d,J＝7.2Hz,2H),1.16-1.23(m,1H),0.48–0.44(m,2H),0.24-0.21(m,2H).
实施例30
6-(3-氯-2-(环丙基甲氧基)苯胺基)-3-氟-2-甲基苯甲酸(34)的合成
Figure BDA0002740742780000223
参照目标化合物21合成方法，得黄色固体，产率73％。ESI-MS:348.5[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.56(s,1H),7.51(d,J＝14.6Hz,1H),7.01–6.91(m,2H),6.79–6.70(m,2H),6.67(dd,J＝7.8,1.8Hz,1H),3.52(d,J＝7.2Hz,2H),2.03(d,J＝2.3Hz,3H),1.01–0.98(m,1H),0.29–0.25(m,2H),0.06–0.03(m,2H).
实施例31
2-(2-苯氧基苯胺基)苯甲酸(35)的合成
Figure BDA0002740742780000231
参照目标化合物21合成方法，得白色固体，产率92％。ESI-MS:304.5[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),9.97(s,1H),8.13(s,3H),7.94(d,J＝7.8Hz,1H),7.49(d,J＝3.9Hz,2H),7.36(d,J＝8.0Hz,1H),7.12(q,J＝9.2,8.1Hz,1H),6.98–6.86(m,2H),3.47(t,J＝11.8Hz,2H),3.17-3.11(m,2H),1.99–1.97(m,2H),1.85(tt,J＝14.6,7.2Hz,2H).
实施例32
2-(2-苄氧基-3-氯苯胺基)苯甲酸(36)的合成
Figure BDA0002740742780000232
参照目标化合物21合成方法，得白色固体，产率72％。ESI-MS:352.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.33(s,1H),10.05(s,1H),7.99(dd,J＝8.0,1.7Hz,1H),7.58–7.45(m,4H),7.43–7.29(m,4H),7.26–7.15(m,2H),6.99–6.88(m,1H),4.97(s,2H).
实施例33
2-(3-氯-2-(4-氯苯氧基)苯胺基)苯甲酸(37)的合成
Figure BDA0002740742780000233
参照目标化合物21合成方法，得白色固体，产率61％。ESI-MS:372.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.05(s,1H),9.88(s,1H),7.86(dd,J＝7.9,1.7Hz,1H),7.60(dd,J＝8.2,1.5Hz,1H),7.46(ddd,J＝8.7,7.1,1.8Hz,1H),7.40–7.29(m,4H),7.27(dd,J＝8.2,1.6Hz,1H),6.92–6.78(m,3H).
实施例34
Figure BDA0002740742780000241
(1-(2-氯-6-硝基苯基)哌啶-4-基)胺基甲酸叔丁酯的合成
将2-氟-3氯硝基苯(750mg，4.27mmol)，N-Boc-4-氨基哌啶(855.69mg，4.27mmol)，碳酸钾(1.18g，8.54mmol)溶于20mL乙腈，在85℃下反应5h。温度降至室温后，加入乙酸乙酯和水萃取，用无水硫酸钠干燥有机层，过滤，旋干后得到950mg褐色固体直接用于下一步。
(1-(2-胺基-6-氯苯基)哌啶-4-基)胺基甲酸叔丁酯的合成
参照目标化合物17的合成方法，得淡黄色固体，收率79％。
2-(2-(4-(叔丁氧酰胺)哌啶-1-基)-3-氯苯胺基)苯甲酸甲酯的合成
参照目标化合物16的合成方法，得棕色固体，收率68％。
2-(2-(4-(叔丁氧酰胺)哌啶-1-基)-3-氯苯胺基)苯甲酸(38)的合成
参照目标化合物21的合成方法，得白色固体，收率85％。ESI-MS:444.1[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.09(s,1H),7.97–7.90(m,1H),7.48(dt,J＝15.3,8.3Hz,2H),7.37(d,J＝8.2Hz,1H),7.09(t,J＝7.8Hz,1H),6.94–6.81(m,2H),6.76–6.65(m,1H),3.41(s,1H),2.80(d,J＝11.6Hz,2H),1.83(d,J＝11.6Hz,2H),1.69(d,J＝11.7Hz,2H),1.40(s,9H).
2-(2-(4-胺基哌啶-1-基)-3-氯苯胺基)苯甲酸(39)的合成
将2-(2-(4-(叔丁氧酰胺)哌啶-1-基)-3-氯苯胺基)苯甲酸(38，155mg，0.347mmol)溶于8mL二氯甲烷中，冰水浴中降至0℃。在体系中滴加氯化氢的二氧六环溶液(4M，1mL)，将温度升至室温反应3h，出现大量固体，抽滤，干燥，得白色固体100mg，收率83％。ESI-MS:344.2[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),9.97(s,1H),8.13(s,3H),7.94(d,J＝7.8Hz,1H),7.49(d,J＝3.9Hz,2H),7.35(t,J＝11.9Hz,1H),7.12(q,J＝9.2,8.1Hz,1H),6.98–6.86(m,2H),3.47(t,J＝11.8Hz,2H),3.14(d,J＝28.6Hz,2H),1.98(d,J＝11.7Hz,2H),1.85(tt,J＝14.6,7.2Hz,2H).
实施例35
2-((2-(1-(叔丁氧羰基)哌啶-3-基)胺基)-3-氯苯胺基)苯甲酸(40)的合成
Figure BDA0002740742780000251
参照目标化合物38合成方法，得白色固体，收率76％。1H NMR(400MHz,Methanol-d4)δ13.02(s,1H),9.53(s,1H),7.89(dd,J＝8.0,1.7Hz,1H),7.38(ddd,J＝8.7,7.1,1.7Hz,1H),7.28(dd,J＝8.0,1.4Hz,1H),7.15(dd,J＝8.0,1.4Hz,1H),7.08(d,J＝8.5Hz,1H),6.94(t,J＝8.0Hz,1H),6.81–6.74(m,1H),4.17(d,J＝10.0Hz,1H),3.62(d,J＝12.6Hz,1H),3.46(d,J＝13.4Hz,1H),3.14(s,1H),2.90(ddd,J＝13.3,9.8,3.1Hz,2H),1.78(d,J＝12.4Hz,1H),1.56(d,J＝13.0Hz,1H),1.44(d,J＝10.9Hz,1H),1.26(s,9H),1.16(s,1H).
2-(3-氯-2-(哌啶-3-基胺基)苯胺基)苯甲酸(41)的合成
Figure BDA0002740742780000252
参照目标化合物39合成方法，得白色固体，收率92％。ESI-MS:344.4[M-H]-；1H NMR(400MHz,Methanol-d4)δ13.17(s,1H),9.73(d,J＝2.6Hz,1H),9.05(d,J＝57.5Hz,1H),8.54(s,1H),7.93(dd,J＝8.0,1.7Hz,1H),7.44(ddd,J＝8.7,7.0,1.8Hz,1H),7.37(dd,J＝8.0,1.4Hz,1H),7.30(d,J＝8.4Hz,1H),7.10(dd,J＝8.1,1.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.83(t,J＝7.5Hz,1H),4.38(s,1H),3.23(s,2H),3.09(d,J＝12.4Hz,1H),2.87(q,J＝10.4Hz,1H),2.74–2.63(m,1H),1.92-1.80(m,2H),1.59–1.39(m,2H).
实施例36
2-(2-(4-(叔丁氧羰基)甲胺哌啶-1-基)-3-氯苯胺基)苯甲酸(42)的合成
Figure BDA0002740742780000253
参照目标化合物38合成方法，得白色固体，收率78％。ESI-MS:458.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.06(s,1H),10.20(s,1H),7.93(dd,J＝8.0,1.6Hz,1H),7.52–7.42(m,2H),7.39(dd,J＝8.1,1.3Hz,1H),7.11(t,J＝8.1Hz,1H),6.96–6.84(m,2H),2.88(d,J＝11.6Hz,2H),2.76(s,3H),1.99(d,J＝11.5Hz,2H),1.54(s,2H),1.42(s,9H).
2-(3-氯-2-(4-甲胺基哌啶-1-基)苯胺基)苯甲酸(43)的合成
Figure BDA0002740742780000261
参照目标化合物39合成方法，得白色固体，收率92％。ESI-MS:358.2[M-H]-；1H NMR(500MHz,Methanol-d4)δ8.03(dd,J＝7.9,1.6Hz,1H),7.53(d,J＝8.4Hz,1H),7.48–7.41(m,2H),7.37–7.20(m,1H),7.10(t,J＝8.1Hz,1H),6.90(t,J＝7.8Hz,2H),3.66–3.58(m,2H),3.25–3.20(m,2H),3.04(d,J＝12.0Hz,2H),2.76(s,3H),2.14–1.99(m,4H).
实施例37
2-(2-苯胺基苯胺基)苯甲酸(44)的合成
Figure BDA0002740742780000262
参照目标化合物38合成方法，得白色固体，收率72％。ESI-MS:303.6[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.85(s,1H),9.43(s,1H),7.86(dd,J＝8.0,1.7Hz,1H),7.57(s,1H),7.42–7.31(m,2H),7.26(d,J＝7.8Hz,1H),7.13(t,J＝7.8Hz,2H),7.11–6.97(m,3H),6.89(d,J＝8.0Hz,2H),6.73(q,J＝7.7Hz,2H).
实施例38
2-(3-氯-2-(环己基甲胺基)苯胺基)苯甲酸(45)的合成
Figure BDA0002740742780000263
参照目标化合物38合成方法，得淡黄色固体，收率78％。ESI-MS:315.1[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.84(s,1H),9.61(s,1H),7.89(dd,J＝8.0,1.7Hz,1H),7.41–7.32(m,1H),7.24(dd,J＝8.0,1.5Hz,1H),7.13(dd,J＝8.2,1.2Hz,1H),7.01(d,J＝8.4Hz,1H),6.90(t,J＝8.0Hz,1H),6.76(t,J＝7.5Hz,1H),4.34(s,1H),2.84(d,J＝7.0Hz,2H),0.94–0.86(m,1H),0.37–0.29(m,2H),0.06–0.03(m,2H).
实施例39
Figure BDA0002740742780000271
2-氯-6-硝基-1,1’-联苯的合成
将1,2-二氯-3-硝基苯(100mg，0.521mmol)，苯硼酸(63.5mg，0.521mmol)，Pd(PPh3)4(18.06mg，0.016mmol)和K2CO3(180mg，1.302mmol)溶于1,4-二氧六环(8mL)和水(4mL)的混合溶剂中，体系在氮气保护下温度升至90℃，反应15h后温度降至室温。加入水淬灭反应后，用乙酸乙酯萃取，有机层用无水硫酸钠干燥，抽滤，滤液旋干并进行柱层析(石油醚：乙酸乙酯＝10：1)，得到102mg淡棕色固体，收率84％。1H NMR(500MHz,Chloroform-d)δ7.63–7.58(m,3H),7.44(dd,J＝8.4,7.0Hz,3H),7.40–7.31(m,2H).
6-氯-[1,1’-联苯基]-2-胺的合成
参照目标化合物17的合成方法，得淡黄色固体，收率90％。
2-((6-氯-[1,1’-联苯基]-2-基)胺基)苯甲酸甲酯的合成
参照目标化合物16的合成方法，得棕色固体，收率56％。
2-((6-氯-[1,1’-联苯基]-2-基)胺基)苯甲酸(46)的合成
参照目标化合物21的合成方法，得白色固体，收率92％。ESI-MS:322.1[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.40(s,1H),7.81(dd,J＝7.7,1.7Hz,1H),7.43(t,J＝7.4Hz,3H),7.35(t,J＝7.4Hz,1H),7.29(t,J＝8.1Hz,1H),7.26–7.20(m,3H),7.18(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),6.70(t,J＝7.2Hz,1H).
实施例40
2-([1,1’-联苯基]-2-基胺基)苯甲酸(47)的合成
Figure BDA0002740742780000272
参照目标化合物46合成方法，得白色固体，收率92％。ESI-MS:288.5[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.83(s,1H),9.56(s,1H),7.82(dd,J＝7.9,1.7Hz,1H),7.48(dd,J＝8.1,1.3Hz,1H),7.43–7.28(m,8H),7.22(td,J＝7.4,1.3Hz,1H),7.11(dd,J＝8.5,1.1Hz,1H),6.76–6.67(m,1H).
实施例41
2-((6-氯-4’-氟-3’-甲基-[1,1’-联苯基]-2-基)胺基)苯甲酸(48)的合成
Figure BDA0002740742780000281
参照目标化合物46合成方法，得白色固体，收率68％。ESI-MS:354.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.96(s,1H),9.31(s,1H),7.81(dd,J＝7.9,1.7Hz,1H),7.50(d,J＝7.8Hz,1H),7.43–7.34(m,2H),7.30(d,J＝8.3Hz,1H),7.26–7.17(m,3H),7.09(ddd,J＝8.0,5.0,2.3Hz,1H),6.79(t,J＝7.3Hz,1H),2.25(d,J＝1.8Hz,3H).
实施例42
2-((3’,6-二氯-[1,1’-联苯基]-2-基)胺基)苯甲酸(49)的合成
Figure BDA0002740742780000282
参照目标化合物46合成方法，得白色固体，收率76％。ESI-MS:356.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.10(s,1H),9.39(s,1H),7.86(dd,J＝7.9,1.8Hz,1H),7.57(d,J＝8.0Hz,1H),7.55–7.50(m,2H),7.50–7.43(m,2H),7.40(d,J＝2.1Hz,1H),7.34(d,J＝8.2Hz,2H),7.28(dt,J＝6.6,1.9Hz,1H),6.86(t,J＝7.5Hz,1H).
实施例43
2-(2-(苯并[d][1,3]二氧代-5-基)-3-氯苯胺基)苯甲酸(50)的合成
Figure BDA0002740742780000283
参照目标化合物46合成方法，得白色固体，收率86％。ESI-MS:366.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.08(s,1H),9.37(s,1H),7.87(dd,J＝8.0,1.7Hz,1H),7.54(dd,J＝8.1,1.0Hz,1H),7.47(ddd,J＝8.7,7.0,1.8Hz,1H),7.43–7.35(m,2H),7.28(dd,J＝8.0,1.1Hz,1H),7.04(d,J＝7.9Hz,1H),6.89–6.83(m,2H),6.75(dd,J＝7.9,1.8Hz,1H),6.11(d,J＝7.8Hz,2H).
实施例44
2-(4’6-二氯-[1,1’-联苯基]-2-基胺基)苯甲酸(51)的合成
Figure BDA0002740742780000291
参照目标化合物46合成方法，得白色固体，收率71％。ESI-MS:356.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.10(s,1H),9.34(s,1H),7.86(dd,J＝7.9,1.7Hz,1H),7.57(dd,J＝8.5,1.9Hz,3H),7.50–7.42(m,2H),7.39–7.28(m,4H),6.90–6.81(m,1H).
实施例45
2-(3-氯-2-(萘-2-基)苯胺基)苯甲酸(52)的合成
Figure BDA0002740742780000292
参照目标化合物46合成方法，得白色固体，收率86％。ESI-MS:372.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.83(s,1H),9.44(s,1H),8.08–7.96(m,3H),7.92(d,J＝1.7Hz,1H),7.81(dd,J＝8.0,1.7Hz,1H),7.65–7.57(m,3H),7.48(t,J＝8.1Hz,2H),7.44–7.38(m,2H),7.35(d,J＝8.0Hz,1H),6.83(t,J＝7.4Hz,1H).
实施例46
2-(3-氯-2-(1H-吲唑-5-基)苯胺基)苯甲酸(53)的合成
Figure BDA0002740742780000293
参照目标化合物46合成方法，得白色固体，收率76％。ESI-MS:362.3[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.90(s,2H),9.20(s,1H),8.01(s,1H),7.67(dd,J＝7.9,1.7Hz,1H),7.59–7.56(m,1H),7.52(d,J＝8.5Hz,1H),7.44(d,J＝8.2Hz,1H),7.37–7.23(m,3H),7.17(d,J＝8.0Hz,1H),7.07(dd,J＝8.5,1.6Hz,1H),6.69(t,J＝7.4Hz,1H).
实施例47
2-(2-(苯并[c][1,2,5]氧杂二唑-5-基)-3-氯苯胺基)苯甲酸(54)的合成
Figure BDA0002740742780000301
参照目标化合物46合成方法，得淡黄色固体，收率66％。ESI-MS:364.0[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.95(s,1H),9.50(s,1H),8.21-8.08(m,2H),7.77(d,J＝7.8Hz,1H),7.59(d,J＝8.2Hz,1H),7.50–7.42(m,3H),7.35-7.31(m,2H),6.80(t,J＝7.5Hz,1H).
实施例48
2-(3-氯-2-(2,3-二氢苯并呋喃-5-基)苯胺基)苯甲酸(55)
Figure BDA0002740742780000302
参照目标化合物46合成方法，得淡黄色固体，收率81％。ESI-MS:364.0[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.03(s,1H),9.32(s,1H),7.87(dd,J＝7.9,1.7Hz,1H),7.57–7.50(m,1H),7.45(ddd,J＝8.7,7.0,1.8Hz,1H),7.41–7.34(m,2H),7.30–7.23(m,1H),7.13(d,J＝1.9Hz,1H),6.99(dd,J＝8.1,1.9Hz,1H),6.88–6.83(m,2H),4.61(t,J＝8.7Hz,2H),3.28–3.15(m,2H)；13C NMR(126MHz,DMSO-d6)δ169.94,159.85,146.37,141.39,134.52,134.42,133.23,132.19,129.79,129.36,128.17,127.67,126.79,123.57,118.82,118.57,114.75,113.86,109.58,71.48,29.49.
实施例49
2-((3’-氨基-6-氯-4’-羟基-[1,1’-联苯基]-2-基)胺基)苯甲酸(56)的合成
Figure BDA0002740742780000303
参照目标化合物46合成方法，得淡棕色固体，收率71％。ESI-MS:354.9[M+H]+；1HNMR(500MHz,DMSO-d6)δ9.65(s,1H),8.26-8.01(m,1H),8.01(d,J＝2.1Hz,1H),7.82-7.79(m,1H),7.47-7.42(m,J＝18.3,8.2Hz,1H),7.39-7.23(m,4H),7.15(t,J＝8.2Hz,1H),6.79-6.73(m,2H),6.70(d,J＝7.9Hz,1H),6.44(d,J＝2.1Hz,1H),6.24(dd,J＝7.9,2.1Hz,1H).
实施例50
2-(2-(苯并[d]噁唑-5-基)-3-溴苯胺基)苯甲酸(57)的合成
Figure BDA0002740742780000311
参照目标化合物46合成方法，得淡黄色固体，收率79％。ESI-MS:407.0[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.32(s,1H),9.65(d,J＝2.1Hz,1H),8.26(d,J＝2.0Hz,1H),8.00(d,J＝2.2Hz,1H),7.80(dt,J＝7.9,1.9Hz,1H),7.50(d,J＝8.1Hz,1H),7.41–7.30(m,3H),7.28–7.22(m,1H),6.95(d,J＝8.1Hz,1H),6.79–6.71(m,2H).
实施例51
2-(2-(苯并呋喃-5-基)-3-氯苯胺基)苯甲酸(58)的合成
Figure BDA0002740742780000312
参照目标化合物46合成方法，得白色固体，收率91％。ESI-MS:362.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),9.26(s,1H),8.03(d,J＝2.2Hz,1H),7.77(dd,J＝7.9,1.7Hz,1H),7.67(d,J＝8.4Hz,1H),7.59–7.48(m,2H),7.47–7.33(m,3H),7.26(d,J＝7.9Hz,1H),7.15(dd,J＝8.5,1.8Hz,1H),6.98(d,J＝2.1Hz,1H),6.83–6.74(m,1H).
实施例52
2-((6-氯-[1,1’-联苯基]-2-基)胺基)-5-氟-苯甲酸(59)的合成
Figure BDA0002740742780000313
参照目标化合物46合成方法，得白色固体，收率82％。ESI-MS:339.9[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.41(s,1H),9.09(s,1H),7.62–7.57(m,1H),7.57–7.52(m,3H),7.47(dt,J＝11.2,7.8Hz,2H),7.40(dd,J＝6.9,2.5Hz,2H),7.34(t,J＝7.5Hz,3H).
实施例53
6-((6-氯-[1,1’-联苯基]-2-基)胺基)-3-氟-2-甲基苯甲酸(60)的合成
Figure BDA0002740742780000321
参照目标化合物46合成方法，得淡黄色固体，收率89％。ESI-MS:353.9[M-H]-；1HNMR(500MHz,DMSO-d6)δ7.56(t,J＝7.5Hz,2H),7.49(t,J＝7.5Hz,1H),7.35–7.29(m,3H),7.24(dd,J＝7.0,4.4Hz,2H),7.14(t,J＝8.5Hz,2H),7.02(s,1H),2.25(d,J＝2.3Hz,3H).
实施例54
3-((6-氯-[1,1’-联苯基]-2-基)胺基)异烟酸(61)的合成
Figure BDA0002740742780000322
参照目标化合物46合成方法，得白色固体，收率79％。ESI-MS:323.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.63(s,1H),8.85(s,1H),8.61(s,1H),8.02(d,J＝5.0Hz,1H),7.61–7.53(m,2H),7.48–7.36(m,4H),7.34(d,J＝7.9Hz,1H),7.27(dd,J＝7.0,1.7Hz,2H).
实施例55
4-((6-氯-[1,1’-联苯基]-2-基)胺基)-2-氟烟酸(62)的合成
Figure BDA0002740742780000323
参照目标化合物46合成方法，得白色固体，收率76％。ESI-MS:297.1[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.09(s,1H),9.73(s,1H),7.83(d,J＝6.0Hz,1H),7.54–7.48(m,3H),7.44–7.39(m,2H),7.39–7.35(m,1H),7.27–7.22(m,2H),6.77(d,J＝6.1Hz,1H).
实施例56
4-氯-2-((6-氯-[1,1’-联苯基]-2-基)胺基)苯甲酸(63)的合成
Figure BDA0002740742780000324
参照目标化合物46合成方法，得白色固体，收率91％。ESI-MS:356.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.03(s,1H),9.46(s,1H),7.82(d,J＝8.5Hz,1H),7.57(dd,J＝8.2,1.1Hz,1H),7.53–7.46(m,3H),7.45–7.38(m,2H),7.29(dd,J＝7.0,1.8Hz,2H),7.16(d,J＝2.1Hz,1H),6.83(dd,J＝8.5,2.1Hz,1H).
实施例57
2-((6-氯-[1,1’-联苯基]-2-基)胺基)-5-甲氧基苯甲酸(64)的合成
Figure BDA0002740742780000331
参照目标化合物46合成方法，得白色固体，收率65％。ESI-MS:352.0[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.11(s,1H),8.73(s,1H),7.48(dd,J＝8.3,6.8Hz,2H),7.43–7.36(m,2H),7.35–7.29(m,3H),7.26(dd,J＝6.9,1.8Hz,2H),7.15(d,J＝7.8Hz,1H),7.10(dd,J＝9.1,3.1Hz,1H),3.71(s,3H).
实施例58
2-((6-氯-4’-氟-[1,1’-联苯基]-2-基)胺基)苯甲酸(65)的合成
Figure BDA0002740742780000332
参照目标化合物46合成方法，得白色固体，收率86％。ESI-MS:340.3[M-H]-；1H NMR(500MHz,DMSO-d6)δ12.99(s,1H),9.31(s,1H),7.85(dd,J＝8.0,1.7Hz,1H),7.56(d,J＝8.2Hz,1H),7.50–7.40(m,2H),7.39–7.27(m,6H),6.84(t,J＝7.5Hz,1H).
实施例59
2-((6-氯-4’-三氟甲基-[1,1’-联苯基]-2-基)胺基)苯甲酸(66)的合成
Figure BDA0002740742780000333
参照目标化合物46合成方法，得白色固体，收率70％。ESI-MS:340.3[M-H]-；1H NMR(500MHz,DMSO-d6)δ13.02(s,1H),9.28(s,1H),7.86(dd,J＝15.8,7.9Hz,3H),7.58(t,J＝8.2Hz,3H),7.48(q,J＝8.1Hz,2H),7.35(dd,J＝11.7,8.2Hz,2H),6.86(t,J＝7.5Hz,1H).
实施例60
2-氯-6-((6-氯-[1,1’-联苯基]-2-基)胺基)苯甲酸(67)的合成
Figure BDA0002740742780000341
参照目标化合物46合成方法，得白色固体，收率76％。ESI-MS:355.9[M-H]-；1H NMR(500MHz,DMSO-d6)δ7.55(t,J＝7.5Hz,2H),7.49(dd,J＝8.5,6.1Hz,1H),7.42–7.21(m,7H),7.10–7.01(m,2H).
实施例61
2-((6-氯-[1,1’-联苯基]-2-基)胺基)-6-甲氧基苯甲酸(68)的合成
Figure BDA0002740742780000342
参照目标化合物46合成方法，得白色固体，收率91％。ESI-MS:353.9[M]+；1H NMR(500MHz,DMSO-d6)δ12.96(s,1H),7.49(dd,J＝8.2,6.8Hz,2H),7.45–7.40(m,1H),7.33–7.22(m,6H),7.14(dd,J＝7.6,1.5Hz,1H),6.89(d,J＝8.3Hz,1H),6.62(d,J＝8.3Hz,1H),3.74(s,3H).
实施例62
6-(2-(苯并呋喃-5-基)-3-氯苯胺基)-3-氟-2-甲基苯甲酸(69)的合成
Figure BDA0002740742780000343
参照目标化合物46合成方法，得淡黄色固体，收率86％。ESI-MS:394.2[M-H]-；1HNMR(500MHz,DMSO-d6)δ8.05(d,J＝2.2Hz,1H),7.71(d,J＝8.4Hz,1H),7.56(d,J＝1.8Hz,1H),7.25(t,J＝8.1Hz,1H),7.22–7.17(m,3H),7.08(t,J＝8.8Hz,2H),7.01(d,J＝2.2Hz,2H),2.18(d,J＝2.4Hz,3H).
实施例63
6-(3-氯-2-(2,3-二氢苯并呋喃-5-基)苯胺基)-3-氟-2-甲基苯甲酸(70)的合成
Figure BDA0002740742780000351
参照目标化合物46合成方法，得淡黄色固体，收率61％。ESI-MS:396.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ13.71(s,1H),7.23–7.15(m,3H),7.13–7.00(m,4H),6.95(dd,J＝8.1,1.9Hz,1H),6.86(d,J＝8.1Hz,1H),4.61–4.51(m,2H),3.22(d,J＝8.7Hz,2H),2.20(d,J＝2.3Hz,3H).
实施例64
4-(3-氯-2-(2,3-二氢苯并呋喃-5-基)苯胺基)-2-氟烟酸(71)的合成
Figure BDA0002740742780000352
参照目标化合物46合成方法，得淡黄色固体，收率69％。ESI-MS:383.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.27(s,1H),7.77(d,J＝6.0Hz,1H),7.48–7.35(m,3H),7.08(d,J＝1.8Hz,1H),6.91(dd,J＝8.2,1.9Hz,1H),6.78(dd,J＝9.8,7.0Hz,2H),4.55(t,J＝8.7Hz,2H),3.20–3.13(m,2H).
实施例65
6-((6-氯-4’-氟-[1,1’-联苯]-2-基)胺基)-3-氟-2-甲基苯甲酸(72)的合成
Figure BDA0002740742780000353
参照目标化合物46合成方法，得淡黄色固体，收率78％。ESI-MS:372.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ7.32(d,J＝7.3Hz,4H),7.25(t,J＝8.2Hz,1H),7.22–7.14(m,2H),7.08(t,J＝8.3Hz,3H),2.20(d,J＝2.3Hz,3H).
实施例66
4-((6-氯-4’-氟-[1,1’-联苯]-2-基)胺基)-2-氟烟酸(73)的合成
Figure BDA0002740742780000361
参照目标化合物46合成方法，得淡黄色固体，收率68％。ESI-MS:359.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.52(s,1H),7.74(d,J＝5.9Hz,1H),7.41–7.46(m,3H),7.32–7.20(m,4H),6.78(d,J＝6.0Hz,1H).
实施例67
Figure BDA0002740742780000362
2,3-二氯-N-甲基-4-硝基苯胺的合成
将2,3-二氯-4-硝基苯胺(1.2g，5.8mmol)和K2CO3(2.4g，17.39mmol)溶于50mL的乙腈，随后逐滴加入碘甲烷(11.55mL，185mmol)，体系升温至90℃反应3d，降至室温后，将混合物旋干，使用柱层析分离(石油醚：乙酸乙酯＝3：1)得到黄色固体800mg，收率62.4％。1HNMR(500MHz,Chloroform-d)δ7.93(d,J＝9.3Hz,1H),6.49(d,J＝9.3Hz,1H),5.13(s,1H),2.95(d,J＝5.1Hz,3H).
2-氯-N-甲基-6-硝基-[1,1’-联苯]-3-胺的合成
参照中间体2-氯-6-硝基-1,1’-联苯的合成方法，得黄色固体，收率85％。
6-氯-N5-甲基-[1,1’-联苯]-2,5-二胺的合成
参照目标化合物17的合成方法，得淡黄色固体，收率80％。
2-((6-氯-5-甲胺基-[1,1’-联苯]-2-基)胺基)苯甲酸甲酯的合成
参照目标化合物16的合成方法，得淡黄色固体，收率56％。
2-((6-氯-5-甲胺基-[1,1’-联苯]-2-基)胺基)苯甲酸(74)的合成
参照目标化合物21的合成方法，得淡黄色固体，收率89％。ESI-MS:351.1[M-H]-；1HNMR(500MHz,DMSO-d6)δ8.93(s,1H),7.68(dd,J＝8.0,1.7Hz,1H),7.37–7.22(m,5H),7.17–7.09(m,2H),6.75(dd,J＝11.3,8.6Hz,2H),6.60–6.53(m,1H),5.56(q,J＝5.0Hz,1H),2.83(d,J＝4.6Hz,3H).
实施例68
2-((6-氯-5-二甲胺基-[1,1’-联苯]-2-基)胺基)苯甲酸(75)的合成
Figure BDA0002740742780000371
参照目标化合物74合成方法，得淡黄色固体，收率82％。ESI-MS:365.3[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.80(s,1H),9.06(s,1H),7.74(dd,J＝7.9,1.7Hz,1H),7.45–7.38(m,3H),7.37–7.31(m,2H),7.25(d,J＝8.8Hz,1H),7.21–7.14(m,2H),7.08(d,J＝8.4Hz,1H),6.69(t,J＝7.5Hz,1H),2.74(s,6H).
实施例69
2-((6-氯-5-乙胺基-[1,1’-联苯]-2-基)胺基)苯甲酸(76)的合成
Figure BDA0002740742780000372
参照目标化合物74合成方法，得淡黄色固体，收率67％。ESI-MS:365.2[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.66(s,1H),8.92(s,1H),7.98(dd,J＝7.9,1.1Hz,1H),7.70(ddd,J＝9.6,7.7,1.7Hz,2H),7.48(td,J＝7.6,1.2Hz,1H),7.33(dd,J＝8.1,6.4Hz,1H),7.30–7.26(m,1H),7.26–7.21(m,2H),7.13(dd,J＝6.9,1.9Hz,1H),6.83-6.76(m,1H),6.57(t,J＝7.5Hz,1H),5.23(s,1H),3.23(q,J＝7.1Hz,2H),1.22(t,J＝7.1Hz,3H).
实施例70
6-(3-氯-2-(2,3-二氢苯并呋喃-5-基)-4-甲胺基苯胺)-3-氟-2-甲基苯甲酸(77)的合成
Figure BDA0002740742780000373
参照目标化合物74合成方法，得淡黄色固体，收率56％。ESI-MS:425.2[M-H]-；1HNMR(500MHz,DMSO-d6)δ7.36–7.10(m,3H),7.09–7.02(m,1H),6.91(dt,J＝7.3,3.6Hz,2H),6.88–6.78(m,2H),4.67–4.56(m,2H),3.25–3.14(m,2H),2.87(s,3H),2.25(d,J＝2.4Hz,3H).
实施例71
2-(2-(苯并呋喃-5-基)-3-氯-4-甲胺基苯胺)苯甲酸(78)的合成
Figure BDA0002740742780000381
参照目标化合物74合成方法，得淡黄色固体，收率63％。ESI-MS:391.2[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.61(s,1H),8.93(s,1H),7.98(d,J＝2.2Hz,1H),7.66(dd,J＝8.0,1.7Hz,1H),7.55(d,J＝8.5Hz,1H),7.43(d,J＝1.7Hz,1H),7.31–7.23(m,2H),7.04(dd,J＝8.4,1.8Hz,1H),6.92(dd,J＝2.3,0.9Hz,1H),6.88–6.81(m,1H),6.75(d,J＝8.8Hz,1H),6.61–6.53(m,1H),5.54(d,J＝5.1Hz,1H),2.84(d,J＝4.8Hz,3H).
实施例72
2-(2-(苯并呋喃-5-基)-3-氯-4-甲胺基苯胺)-5-氟苯甲酸(79)的合成
Figure BDA0002740742780000382
参照目标化合物74合成方法，得淡黄色固体，收率69％。ESI-MS:409.2[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.98(s,1H),8.74(s,1H),7.98(d,J＝2.2Hz,1H),7.55(d,J＝8.4Hz,1H),7.41(d,J＝1.7Hz,1H),7.37–7.32(m,1H),7.26(d,J＝8.7Hz,1H),7.18(td,J＝8.6,3.2Hz,1H),7.03(dd,J＝8.5,1.8Hz,1H),6.92(d,J＝2.2Hz,1H),6.84–6.81(m,1H),6.75(d,J＝8.8Hz,1H),5.55(d,J＝5.8Hz,1H),2.84(d,J＝2.9Hz,3H).
实施例73
2-((6-氯-4’-氟-5-甲胺基-[1,1’-联苯]-2-基)胺基)苯甲酸(80)的合成
Figure BDA0002740742780000383
参照目标化合物74合成方法，得淡黄色固体，收率72％。ESI-MS:369.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.68(s,1H),8.94(s,1H),7.70(dd,J＝8.0,1.7Hz,1H),7.29–7.23(m,2H),7.23–7.10(m,4H),6.80–6.71(m,2H),6.63–6.54(m,1H),5.59(q,J＝4.9Hz,1H),2.83(d,J＝4.6Hz,3H).
实施例74
4-((6-氯-4’-氟-5-甲胺基-[1,1’-联苯]-2-基)胺基)-2-氟烟酸(81)的合成
Figure BDA0002740742780000391
参照目标化合物74合成方法，得淡黄色固体，收率52％。ESI-MS:388.3[M-H]-；1HNMR(500MHz,DMSO-d6)δ10.08(s,1H),7.61(d,J＝6.0Hz,1H),7.24–7.14(m,4H),6.75(d,J＝8.7Hz,1H),6.38(d,J＝6.1Hz,1H),5.70(d,J＝5.4Hz,1H),2.83(d,J＝4.6Hz,3H).
实施例75
2-(3-氯-2-(2,3-二氢苯并呋喃-5-基)-4-甲胺基苯胺)苯甲酸(82)的合成
Figure BDA0002740742780000392
参照目标化合物74合成方法，得淡黄色固体，收率78％。ESI-MS:393.4[M-H]-；1HNMR(500MHz,DMSO-d6)δ12.67(s,1H),8.94(s,1H),7.71(dd,J＝8.0,1.7Hz,1H),7.30–7.21(m,2H),6.96(d,J＝1.8Hz,1H),6.84–6.78(m,2H),6.73–6.68(m,2H),6.59(ddd,J＝8.0,7.0,1.1Hz,1H),5.51(d,J＝5.1Hz,1H),4.51(dd,J＝9.5,8.1Hz,2H),3.17-3.06(m,1H),2.82(d,J＝4.8Hz,3H).
实施例76
4-(3-氯-2-(2,3-二氢苯并呋喃-5-基)-4-甲胺基苯胺)-2-氟烟酸(83)的合成
Figure BDA0002740742780000393
参照目标化合物74合成方法，得淡黄色固体，收率87％。ESI-MS:412.3[M-H]-；1HNMR(500MHz,DMSO-d6)δ9.95(s,1H),7.63(d,J＝6.1Hz,1H),7.18(d,J＝8.7Hz,1H),7.00(s,1H),6.83(d,J＝8.1Hz,1H),6.70(dd,J＝8.4,2.6Hz,2H),6.40(d,J＝6.0Hz,1H),5.64(d,J＝5.2Hz,1H),4.52(t,J＝8.7Hz,2H),3.16–3.07(m,2H),2.82(d,J＝4.5Hz,3H).
实施例77
2-((3-氯-2-(2,3-二氢苯并呋喃-5-基)苯基)氨基)-5-氟苯甲酸(84)的合成
Figure BDA0002740742780000401
参照目标化合物46合成方法，得淡黄色固体，收率69％。ESI-MS:384.1[M+H]+；1HNMR(500MHz,DMSO-d6)δ13.33(s,1H),9.05(s,1H),7.57–7.49(m,1H),7.42(dd,J＝8.2,1.2Hz,1H),7.34–7.29(m,3H),7.21(dd,J＝8.0,1.0Hz,1H),7.08(d,J＝1.7Hz,1H),6.93(dd,J＝8.2,1.9Hz,1H),6.82(d,J＝8.1Hz,1H),4.59–4.53(t,2H),3.22–
3.12(t,2H).
实施例78
2-((6-氟-[1,1’-联苯]-2-基)氨基)苯甲酸(85)的合成
Figure BDA0002740742780000402
参照目标化合物46合成方法，得淡黄色固体，收率80％。ESI-MS:308.1[M+H]+；1HNMR(500MHz,DMSO-d6)δ12.99(s,1H),9.40(s,1H),7.82(dd,J＝7.9,1.7Hz,1H),7.48–7.27(m,9H),7.01(ddd,J＝9.4,7.8,1.5Hz,1H),6.79(ddd,J＝8.1,7.1,1.1Hz,1H).
实施例79
2-((6-三氟甲基-[1,1’-联苯]-2-基)氨基)苯甲酸(86)的合成
Figure BDA0002740742780000403
参照目标化合物46合成方法，得淡黄色固体，收率80％。ESI-MS:356.2[M+H]-；1HNMR(500MHz,DMSO-d6)δ12.98(s,1H),9.11(s,1H),7.84–7.76(m,2H),7.58(t,J＝8.0Hz,1H),7.53–7.47(m,1H),7.47–7.39(m,4H),7.30(dd,J＝8.5,1.1Hz,1H),7.26–7.18(m,2H),6.85–6.77(m,1H).
实施例80
2-((6-甲基-[1,1’-联苯]2-基)氨基)苯甲酸(87)的合成
Figure BDA0002740742780000411
参照目标化合物46合成方法，得淡黄色固体，收率82％。ESI-MS:302.2[M+H]-；1HNMR(500MHz,DMSO-d6)δ9.11(s,1H),7.76(dd,J＝7.9,1.8Hz,1H),7.42(t,J＝7.5Hz,2H),7.38–7.30(m,3H),7.27(t,J＝7.7Hz,1H),7.23–7.13(m,3H),7.05(d,J＝7.4Hz,1H),6.69(s,1H),2.02(s,3H).
实施例81
2-((6-甲氧基-[1,1’-联苯]-2-基)氨基)苯甲酸(88)的合成
Figure BDA0002740742780000412
参照目标化合物46合成方法，得淡黄色固体，收率85％。ESI-MS:318.3[M+H]-；1HNMR(500MHz,DMSO-d6)δ12.84(s,1H),9.19(s,1H),7.77(dd,J＝7.9,1.7Hz,1H),7.40–7.27(m,5H),7.20(m,3H),7.13–7.08(m,1H),6.86(d,J＝8.2Hz,1H),6.76–6.67(m,1H),3.69(s,3H).
实施例82
2-((6-溴-[1,1’-联苯]-2-基)氨基)苯甲酸(89)的合成
Figure BDA0002740742780000413
参照目标化合物46合成方法，得淡黄色固体，收率85％。ESI-MS:366.2[M+H]-；1HNMR(500MHz,DMSO-d6)δ9.20(s,1H),7.81–7.75(m,1H),7.53(d,J＝8.2Hz,1H),7.48–7.36(m,5H),7.33–7.27(m,2H),7.21(d,J＝7.2Hz,2H),6.78(m,1H).
实施例83
化合物对FABP4的抑制活性
pET-28-Fabp4原核表达质粒转化至Rosseta表达菌株，37℃条件下1mM IPTG诱导表达，收集菌体超声破碎，在15000rpm离心30min后，取上清上Ni-NTA层析柱，经含10mM、20mM咪唑的PBS洗柱后，以含80mM咪唑的PBS洗脱目的蛋白，获得的FABP4蛋白纯度大于95％。在96孔板200μL/孔的筛药体系中，1,8-ANS(8-苯胺-1-萘磺酸)底物的浓度为10μM，FABP4蛋白的终浓度为1μM，加入不同浓度的待测化合物共孵育3min后，在激发波长(EX)370nm/发射波长(EM)470nm检测荧光信号。根据体系的荧光吸收值计算待测样品对FABP4的抑制率(％)，并将抑制活性达50％时抑制剂的浓度定为IC50值。抑制率可根据下式进行：
抑制率(％)＝[1-(Fx-F背景)/(F0％-F背景)]×100％
上式中，Fx表示在化合物x存在下，测定的体系荧光值(fluorescence,F)，F背景表示荧光底物ANS的荧光值，F0％表示抑制率为0％时，即不加化合物时体系的荧光值。
实验设3个复孔。实验结果如表1所示。结果表明，本发明化合物对FABP4具有不同程度的抑制作用。IC50值报告的范围为：A表示<0.5μM，B表示0.5-1μM，C表示1-10μM，D表示>10μM。
表1本发明化合物对FABP4的抑制活性
Figure BDA0002740742780000421
实施例84
化合物对脂肪细胞脂质生成的影响
在脂肪细胞中，FABP4扮演着脂肪酸伴侣的角色，已有研究表明，使用基因敲除或药物抑制FABP4可抑制脂肪分解，促进脂肪细胞的脂质生成。为了研究化合物对脂肪细胞的影响，使用3T3-L1脂肪细胞作为模型分别对部分高活性化合物进行了油红染色实验。
首先将化合物孵育3T3-L1前脂肪细胞24小时，MTT法检测发现阳性药BMS309403在高浓度时对细胞活力有影响，而本申请的化合物几乎没有细胞毒性，故接下来的油红测定实验将化合物浓度设定为25μM。将3T3-L1细胞用待测化合物分别分化处理8天，然后用油红染色和定量测定法评价化合物对脂肪细胞脂滴形成的影响。
如图1所示，所有待测化合物在25μM下均具有一定促进3T3-L1前脂肪细胞脂质堆积的能力，其中化合物21、55和70促进脂堆积的能力均超过阳性药BMS309403。
实施例85
化合物对分化成熟的3T3-L1前脂肪细胞的脂解抑制活性
将3T3-L1前脂肪细胞接种于培养板，用含10％NCS的高糖-杜氏改良Eagle培养基(H-DMEM)在37℃、5％CO2中培养；待细胞长满后使其接触抑制剂两天，换含10％FBS的H-DMEM培养基培养，并加入终浓度为0.5mM 3-异丁基-1-甲基黄嘌呤(IBMX)、1μM***和5μg/mL胰岛素诱导48小时；48小时后换液为含终浓度5μg/mL的胰岛素继续培养48小时，每两天换液一次，诱导分化8～12天3T3-L1细胞90％多呈成熟脂肪细胞表型。换不含胰岛素的培养基培养4小时后分别加入10μM浓度的化合物孵育4小时；4小时后吸弃培养基，用预热的Krebs-Ringer bicarbonate HEPES(KRBH)缓冲液洗两遍，用含20μM毛喉素(forskolin,FSK)或无FSK的KRBH缓冲液继续孵育2小时；2小时后收集上清测甘油含量；同时用RadioImmunoprecipitation Assay(RIPA)裂解液收集细胞蛋白并使用比辛宁酸(BCA)蛋白浓度测定试剂盒进行蛋白校准。
如图2所示，化合物44和55在10μM浓度下能够明显降低FSK刺激下的上清甘油的含量。
实施例86
化合物对THP-1单核源性巨噬细胞单核细胞趋化因子-1(MCP-1)和白介素-6(IL-6)分泌的影响
首先，取对数生长期的单核细胞系THP-1，以5*105/mL细胞密度铺在96孔板上；随后加入100nM的佛波酯(PMA)诱导24小时使其分化成为巨噬细胞；接下来使用磷酸缓冲盐溶液(PBS)洗细胞1-2遍，加不同浓度化合物(1、5、10、25μM)孵育18小时；最后，使用100ng/mL的脂多糖(LPS)刺激6小时后收取上清液并稀释一定倍数使用酶联免疫吸附测定法(ELISA)检测其中MCP-1和IL-6的含量，同时收取细胞蛋白使用BCA法测蛋白浓度进行校准。
如图3和4所示，部分体外活性较好的化合物34、44、47、55和57能以剂量依赖性的方式显著降低THP-1单核细胞源性巨噬细胞中炎症因子MCP-1和IL-6的分泌。其中化合物44和55的活性均优于阳性药BMS309403，具有显著的抗炎效应。
实施例87
化合物55抗脂多糖(LPS)诱导C57小鼠急性炎症模型实验
使用6周龄C57BL/KsJ雄性小鼠，在无特定病原体动物(SPF级)实验动物房饲养。适应性饲养5天后进行随机分组，共分为4组：对照(control)组，LPS模型组，阳性药BMS309403组和待测化合物组，每组9-10只小鼠。其中给药组分别灌胃给予BMS309403(50mg/kg)和待测化合物(50mg/kg)，对照和LPS模型组给予同等体积的羧甲基纤维素钠(CMC-Na)；1小时后LPS模型组和化合物组腹腔注射LPS(5mg/kg)，对照组给予同等体积的生理盐水；5小时后眼眦取血，并于12000rpm，4℃下离心30分钟后取血清，使用ELISA法检测各组小鼠血清炎症因子MCP-1和IL-6的水平。
如图5和6所示，阳性药BMS309403和化合物55在50mg/kg剂量下，均能一定程度地下调炎症因子MCP-1和IL-6的水平，其中，化合物55效果优于阳性药BMS309403。
综上，本发明的绝大多数化合物对FABP4具有较强的体外活性；该类化合物可以促进3T3-L1前脂肪细胞脂质堆积并能抑制分化成熟的脂肪细胞脂解；同时显著降低THP-1细胞中炎症因子MCP-1和IL-6的分泌；体内抗炎实验则进一步证实了该类化合物能显著降低体内炎症因子的释放。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

1.一种化合物或其药学上可接受的盐，选自：
Figure FDF0000024964190000011
Figure FDF0000024964190000021
Figure FDF0000024964190000031
2.一种药物组合物，其特征在于，包含：
如权利要求1所述的化合物或其药学上可接受的盐；和
药学上可接受的载体。
3.如权利要求2所述的药物组合物，其特征在于，所述药物组合物进一步包含至少一种其他治疗剂，所述至少一种其他治疗剂为抗癌剂、免疫调节剂、抗过敏剂、止吐剂、疼痛缓解剂、细胞保护剂或其组合。
4.如权利要求1所述的化合物或其药学上可接受的盐或权利要求2所述的药物组合物的用途，用于制备脂肪酸结合蛋白4抑制剂，或者用于制备治疗或预防与脂肪酸结合蛋白4异常相关疾病的药物。
5.如权利要求4所述的用途，其特征在于，所述与脂肪酸结合蛋白4异常相关疾病为2型糖尿病、代谢综合征、动脉粥样硬化、血脂异常、肝脏疾病、肥胖症、脂营养不良、结节病、眼部疾病、肺部疾病、慢性肾脏疾病、慢性炎症、急性炎症、自身免疫性炎症疾病、先兆子痫、***或癌症。
6.如权利要求5所述的用途，其特征在于，所述的肝脏疾病包括炎症、脂肪变性和/或纤维化的肝脏疾病。
7.如权利要求5所述的用途，其特征在于，所述的肝脏疾病是非酒精性脂肪肝病。
8.如权利要求5所述的用途，其特征在于，所述的肝脏疾病是非酒精性脂肪性肝炎。
9.如权利要求5所述的用途，其特征在于，所述的脂营养不良是遗传性或医源性脂营养不良。
10.如权利要求5所述的用途，其特征在于，所述的眼部疾病是由内皮增殖和血管新生维持的眼部疾病。
11.如权利要求5所述的用途，其特征在于，所述的眼部疾病是黄斑变性或视网膜病。
12.如权利要求5所述的用途，其特征在于，所述的肺部疾病选自：哮喘、支气管肺发育异常、慢性阻塞性肺病。
13.如权利要求5所述的用途，其特征在于，所述的慢性肾脏疾病选自：脉管炎、局灶性节段性肾小球硬化症、糖尿病肾病、狼疮肾炎、多囊性肾病、药物或毒素诱导的慢性小管间质性肾炎。
14.如权利要求5所述的用途，其特征在于，所述的急性炎症为脓毒症、败血症、急性肾损伤、急性肺损伤、急性肝损伤。
15.如权利要求5所述的用途，其特征在于，所述的癌症选自：恶性黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、***癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、***、子宫内膜癌、间皮瘤、甲状腺癌、肝癌和食管癌。
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