CN107311933B - 一类苯并咪唑衍生物，及其制备方法和用途 - Google Patents
一类苯并咪唑衍生物，及其制备方法和用途 Download PDFInfo
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- CN107311933B CN107311933B CN201710508016.7A CN201710508016A CN107311933B CN 107311933 B CN107311933 B CN 107311933B CN 201710508016 A CN201710508016 A CN 201710508016A CN 107311933 B CN107311933 B CN 107311933B
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一类式I所示的苯并咪唑衍生物、其药学上可以接受的盐，溶剂合物，及其制备方法和用于制备肿瘤治疗药物、抗病毒药、抗菌药、抗寄生虫药和/或降血压药等药物的用途。根据本发明的化合物具有显著的抑制kras突变的肿瘤细胞的增殖能力，结构稳定，制备简便，具有开发为新型抗肿瘤药物的潜力。
Description
技术领域
本发明属于药学领域，具体涉及一类苯并咪唑衍生物，及其制备方法和作为肿瘤治疗药物、抗病毒药、抗菌药、抗寄生虫药和/或降血压药等药物的用途。
背景技术
恶性肿瘤是威胁人类生命健康的重大疾病。据世界卫生组织统计，2012年全世界约有1400万新发癌症病例，较2008年相比，全球癌症患者和死亡率均呈上升趋势，预计今后二十年新发病例数将增加约70％。癌症作为全球第二大人类死因，2015年导致880万人死亡，其中以肺癌、肝癌、结直肠癌、胃癌和乳腺癌发病率最高。大约70％的癌症死亡发生在低收入和中等收入国家，中国新增癌症病例和死亡人数均居世界首位。
现有的有机小分子抗癌药物容易引起骨髓抑制、胃肠道作用、皮疹和脱发等毒副反应，疗效也需要提高。原癌基因的激活和抑癌基因的失活是引起肿瘤的重要原因，根据肿瘤发生过程中涉及的原癌基因和相关分子的异常，研究靶向性的新型抗癌药物具有是发现高效低毒的抗肿瘤药物的新策略。
恶性肿瘤是一种由多因素疾病，基因突变是导致肿瘤的重要原因，现已知的诱发肿瘤的原癌基因高达100多种，主要包括MYC,Ras,HER2,BRAF,MET,BCR-ABL,PDGFR,KTT,FGFR3,ALK,RET,MITF,CUG2,FAM83,LAPTM4B,PLAG1等。其中，约1/3的癌症与Ras基因突变有关，Ras基因突变涉及约50％的结直肠癌、30％的肺癌以及20％的血癌诱发。
在人类Ras基因家族的36个基因中与肿瘤相关的三种特征性基因分别是H-Ras，K-Ras和N-Ras，分别负责编码H-Ras，K-Ras4A，K-Ras4B和N-Ras四种Ras蛋白质。其中K-Ras基因突变与肿瘤关系最为密切，由于K-Ras蛋白与底物GTP的亲和力极强(pmol·L-1级)，设计kras蛋白的抑制剂存在巨大的挑战，因此，临床上尚无有效靶向Ras治疗药物。
Ras基因翻译合成的Ras蛋白为蛋白前体，需要经过法尼基化修饰获得生物学功能。活化后的Ras蛋白是一种小GTP水解酶，定位于细胞内膜，刺激下游信号通路传递有丝分裂的信号，在调控细胞的生长、增殖、分化以及其它信号的传导上发挥重要作用。PDEδ(phosphodiesteraseδ)是磷酸二酯酶6的一个亚型，其空间结构中具有一个异戊二烯结合口袋，可以选择性的识别法尼基化的Ras蛋白，调节Ras蛋白的内膜定位，其作用机制主要包括维持K-Ras的空间结构，协助棕榈化的K-Ras定位到细胞膜及当K-Ras发挥作用而被去棕榈化后，PDEδ将其转运至高尔基体，促使其再一次棕榈化及膜定位，充分保证K-Ras在GTP活化态和GDP失活态之间的循环。
阻断kras与PDEδ的相互作用，可为K-Ras突变所致的肿瘤提供新的治疗策略。
发明内容
根据本发明的一个方面，提供式I所示的苯并咪唑衍生物、其药学上可以接受的盐，溶剂合物：
其中，A选自取代或者未取代的含有选自S、N和O中1至3个杂原子的五元至十元杂环基或-NH-R4。
当A为取代或者未取代的含有选自S、N和O中1至3个杂原子的五元至十元杂环基时，优选为取代或者未取代的含有选自S、N和O中1至3个杂原子的五元至七元杂环基；
当A为-NH-R4时，其中R4选自取代或者未取代的C1-C6烷基、取代或者未取代的C5-C10芳基、取代或者未取代的C6-C12烷基芳基、取代或者未取代的含有选自S、N和O中1至3个杂原子的五元至十元杂环基、取代或者未取代的含有选自S、N和O中1至3个杂原子的八元至十元杂并环基；
优选地，R4选自取代或者未取代的C1-C4烷基、取代或者未取代的C5-C8芳基、取代或者未取代的C6-C10烷基芳基、取代或者未取代的含有选自S、N和O中1至3个杂原子的五元至八元杂环基、取代或者未取代的含有选自S、N和O中1至3个杂原子的八元至十元并环基；
其中术语“取代的”是指被1至3个相同或不同的取代基取代，所述取代基选自羟基、氨基、卤素、硝基、羧基、磺酰基、C1-C6烷氧基、C5-C7芳基取代的C1-C6烷氧基，C5-C7芳基。
R2选自氢、C1-C6的烷基，Ar选自C5-10的芳环基，优选地，R2选自氢、C1-C3的烷基，Ar选自C5-C7的芳环基，更优选地，R2选自氢、甲基、乙基，Ar选自C5-C6的芳环基。
R3选自氢、C1-C6的烷基，优选地，R2选自氢、C1-C3的烷基，更优选地，R3选自氢、甲基、乙基。
所述卤素选自F、Cl、Br或I，优选为F、Cl或Br。
根据本发明的式I所示的苯并咪唑衍生物更加优选如下化合物：
所述“药学上可接受的盐”为通式(I)化合物与无机酸或有机酸反应形成的常规的无毒盐。例如，所述常规的无毒盐可通过通式(I)化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、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；或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再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；或者通式(I)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
根据本发明的另一个方面，本发明还提供式I所示化合物的合成方法，反应流程如下：
步骤1)甲酸甲酯基取代的邻硝基氟苯与相应的胺化合物
缩合得到式2的化合物，具体反应条件可以参考文献(Organic Letters,17(19),4734-4737)记载的方法；
步骤2)式2的化合物经过氢化还原得到式3的化合物，具体反应条件可以参考文献(Organic&Biomolecular Chemistry,7(24),5173-5183)；
步骤3)式3的化合物再与取代的苯甲醛
缩合关环得到式4的化合物，具体反应条件可以参考文献(Tetrahedron,71(4),532-538)；
步骤4)式4的化合物经过碱水解得到式5的化合物，具体反应条件可以参考文献(ChemMedChem,1(9),955-958)；
步骤5)式5的化合物再与相应的胺类化合物缩合，具体反应条件可以参考文献(Journal of Medicinal Chemistry,47(26),6451-6454)，得到目标产物式I的化合物。
其中取代基A、R2、R3和Ar的定义如上所述。
根据本发明的另一个方面，本发明还提供式I所示化合物用于制备肿瘤治疗药物、抗病毒药、抗菌药、抗寄生虫药和/或降血压药等药物的用途。
本发明的另一个方面是提供含有式I所示化合物、其药学上可接受的盐或溶剂合物作为活性成分的药物组合物。根据本发明的药物组合物，所述药物组合物包括治疗有效量的式I所示化合物、其药学上可接受的盐或溶剂合物以及药物辅料。术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。所述“药物辅料”是指药物中常规采用的各种辅料，例如赋形剂、控释剂、稳定剂等，这属于本领域技术人员常规知识范围。
优选地，所述包含根据本发明I式所示的化合物的药物组合物可以用于治疗与病毒相关的疾病、与细菌相关的疾病、与寄生虫相关的疾病、与动脉粥样硬化相关的疾病、与血栓相关的疾病、与高血压相关的疾病。
根据本发明的所述药物组合物可以是以下剂型：片剂例如但不限于普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片等；胶囊剂例如但不限于硬胶囊、软胶囊等；注射剂例如但不限于无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球等；喷雾剂例如但不限于口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂等；气雾剂例如但不限于肺吸入用气雾剂、局部皮肤气雾剂等；滴鼻剂例如但不限于滴鼻用溶液、滴鼻用凝胶等；粉雾剂例如但不限于空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂等；人体其他腔道如阴道、直肠、耳腔等用的栓剂、贴剂、凝胶剂。这些制剂的制备工艺是本领域技术人员根据已有的知识或者参考相关教科书或工具书或文献而可以制备的。
有益效果
基于kras的药物研究是肿瘤治疗药物的研究难点，目前尚未有成功的药物上市，本发明提供的化合物具有显著的抑制kras突变的肿瘤细胞的增殖能力，结构稳定，制备简便，具有开发为新型抗肿瘤药物的潜力。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
本发明涉及的1-苄基-2-苯基苯并咪唑类衍生物没有文献报道，根据本发明的式I所示化合物可以选择性杀死Ras基因突变的癌细胞或者抑制其增殖；式I所示药物作用的机制包括但不限于抑制kras蛋白与PDEδ的相互作用。
下述实施例中的实验方法，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径获得。
实施例1、N-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰吗啉的制备(ZXY8008-1)
N-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰吗啉的合成路线如下所示。
步骤a：3-苄胺基-4-硝基-苯甲酸甲酯的制备
9.9g(0.05mol)3-氟-4-硝基苯甲酸甲酯(10)溶于50ml DMF中，加入8.3g(0.06mol)碳酸钾，6.4g(0.06mol)苄胺，50℃反应至原料消失，将反应液倒入水中，过滤得橙红色固体，13.5g，收率：94.6％。1H-NMR(400MHz,DMSO-d6)δ(ppm):8.73-8.70(t,1H,J＝5.72Hz),8.19-8.17(d,1H,J＝8.68Hz),7.43-7.43(d,1H,J＝1.68Hz),7.39-7.33(m,4H),7.28-7.24(m,1H),7.14-7.12(dd,1H,J＝8.68,1.68Hz),4.67-4.65(d,2H,J＝5.88Hz),3.81(s,3H)。
步骤b：3-苄胺基-4-氨基-苯甲酸甲酯的制备
14.3g(0.05mol)3-苄胺基-4-硝基-苯甲酸甲酯置于500ml反应釜中，取催化剂雷尼镍3.6g(湿重)加入至200ml甲醇中，边搅拌边将甲醇倾倒入反应釜中，通入氢气于65℃反应3-5小时，反应液过滤(，适量甲醇洗滤饼。反应液减压浓缩得到淡黄色油状液体，乙醚超声析出灰白色固体，抽滤，干燥，得白色固体11.5g，收率：89.5％。1H-NMR(400MHz,CDCl3)δ(ppm):7.50-7.48(dd,1H,J＝8.12,1.96Hz),7.43-7.41(m,3H),7.39-7.35(m,2H),7.33-7.31(m,1H),6.72-6.70(d,1H,J＝8.16Hz),4.33(s,2H),3.86(s,3H),3.70(s,2H)。
步骤c：1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸甲酯的制备
9.3g(0.04mol)3-苄胺基-4-氨基-苯甲酸甲酯溶于100ml乙醇中，加入苯甲醛4.3g(0.04mol)，回流反应至原料消失，减压浓缩，固体粗品用乙醇：水＝7:3超声，过滤，滤饼干燥，得白色固体11.5g，收率：92.6％。1H-NMR(400MHz,CDCl3)δ(ppm):8.05-8.02(dd,1H,J＝8.44,1.4Hz),8.00-7.99(d,1H,J＝0.84Hz),7.88-7.86(d,1H,J＝8.4Hz),7.70-7.68(m,2H),7.50-7.43(m,3H),7.36-7.30(m,3H),7.09-7.07(dd,2H,J＝8.16,1.68Hz),5.501(s,2H),3.897(s,3H)。
步骤d：1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸的制备
取11.5g(0.03mol)1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸甲酯溶于300ml甲醇，加入1mol/L氢氧化钠溶液65ml，65℃反应过夜，稀盐酸酸化反应液至pH 4左右，析出大量白色固体，抽滤，水洗滤饼(25ml×2)，干燥，得白色固体10.9g，收率：98.5％。1H-NMR(400MHz,DMSO-d6)δ(ppm):12.92(s,1H),8.09-8.08(d,1H,J＝1.12Hz),7.92-7.90(dd,1H,J＝8.4,1.4Hz),7.83-7.81(d,1H,J＝8.68Hz),7.78-7.76(m,2H),7.59-7.53(m,3H),7.33-7.24(m,3H),7.03-7.02(d,2H,J＝6.72Hz),5.70(s,2H)。
步骤e：N-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰吗啉的制备
取263mg(0.80mmol)1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸和77mg(0.88mmol)吗啉溶于4ml DMF，加入184mg(0.96mmol)EDCI，130mg(0.96mmol)HOBt，30mg(0.24mmol)DMAP 50℃反应过夜。原料消失，停止加热，减压浓缩得浅棕色油状物，粗产品柱层析分离纯化，得白色固体，收率：76.9％，熔点：149-151℃。ESI-HRMS(m/z):398.1864[M+H]+,1H-NMR(400MHz,CDCl3)δ(ppm):7.90-7.89(d,1H,J＝1.12Hz),7.70-7.68(m,2H),7.51-7.45(m,3H),7.38-7.31(m,4H),7.27-7.24(d,1H,J＝8.96Hz),7.10-7.08(dd,2H,J＝7.84,1.68Hz),5.48(s,2H),3.73(s,8H),13C-NMR(400MHz,CDCl3)δ(ppm):170.8,162.6,156.0,144.4,136.0,135.8,130.4,129.8,129.6,129.3,129.3,129.0,128.1,126.1,122.1,120.0,110.6,67.0,48.7。
实施例2、N-(3-(苄氧基)-苯基)1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8008-3)
参照实施例1制备方法与条件，以3-苄氧基苯胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料进行酰胺缩合，原料消失，停止加热，减压浓缩除去溶剂，向浓缩后的油状液体中加入20ml水，超声15-20分钟，析出固体，干燥得白色固体，收率：91.0％，熔点：168-170℃。ESI-HRMS(m/z):510.2176[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(ppm):10.20(s,1H),8.15(s,1H),7.95-7.92(dd,1H,J＝8.68,1.4Hz),7.87-7.85(d,1H,J＝8.4Hz),7.77-7.75(m,2H),7.57-7.52(m,4H),7.47-7.45(m,2H),7.42-7.23(m,8H),7.02-7.01(d,2H,J＝7Hz),6.77-6.75(dd,1H,J＝8.12,2.24Hz),5.69(s,2H),5.10(s,2H),13C-NMR(400MHz,DMSO-d6)δ(ppm):165.6,158.5,155.6,145.0,140.5,137.1,136.8,129.4,129.3,129.1,128.9,128.9,128.5,127.8,127.7,127.6,126.0,122.0,118.9,113.0,111.3,109.9,107.1,69.1,47.6。
实施例3、(2-(1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺基)乙基)氨基甲酸叔丁酯的制备(ZXY8011-1)
参照实施例2实验条件及后处理方法，以N-Boc-乙二胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：90.2％，熔点：179-182℃。ESI-HRMS(m/z):471.2390[M+H]+,1H-NMR(400MHz,CDCl3)δ(ppm):7.91(s,1H),7.86-7.84(d,1H,J＝8.4Hz),7.72-7.67(m,3H),7.52-7.44(m,3H),7.33-7.28(m,4H),7.06-7.05(d,2H),5.49(s,2H),5.06(m,1H),3.57-3.53(m,2H),3.40-3.39(m,2H),1.41(s,9H),13C-NMR(400MHz,CDCl3)δ(ppm):168.0,157.6,156.3,145.5,136.2,136.1,130.4,129.7,129.4,129.3,129.2,129.0,128.0,126.0,121.3,119.7,110.8,80.0,48.5,42.2,40.1,28.5。
实施例4、N-(1H-苯并[d]咪唑-2-基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8011-5)
参照实施例2实验条件及后处理方法，以2-氨基-苯并咪唑和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：87.1％，熔点：250-253℃。ESI-HRMS(m/z):444.1819[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):12.22(s,2H),8.43(s,1H),8.13-8.11(d,1H,J＝8.4Hz),7.86-7.84(d,1H,J＝8.4Hz),7.77-7.75(dd,2H,J＝7.56,2.24Hz),7.56-7.55(m,3H),7.46-7.44(dd,2H,J＝5.88,3.36Hz),7.35-7.25(m,3H),7.13-7.11(dd,2H,J＝5.88,3.12Hz),7.07-7.06(d,2H,J＝7Hz),5.67(s,2H),13C-NMR(400MHz,DMSO-d6)δ(ppm):155.8,145.6,136.8,135.8,130.3,129.7,129.1,129.0,128.9,128.4,127.7,126.1,122.9,121.5,119.0,113.4,111.8,47.8。
实施例5、N-(3,4-二甲氧基苯乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑甲酰胺的制备(ZXY8013-1)
参照实施例2实验条件及后处理方法，以3,4-二甲氧基苯乙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，制得白色固体，收率：90.8％，熔点：164-166℃。ESI-HRMS(m/z):492.2281[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.55-8.52(t,1H,J＝5.6Hz),8.04(s,1H),7.82-7.77(m,2H),7.75-7.72(dd,2H,J＝7.04,1.68Hz),7.55-7.51(m,3H),7.33-7.26(m,3H),7.01-6.99(d,2H,J＝7.04Hz),6.84-6.82(d,2H,J＝8.12Hz),6.74-6.72(dd,1H,J＝8.12,1.68Hz),5.63(s,2H),3.70(s,3H),3.68(s,3H),3.49-3.44(m,2H),2.79-2.76(t,2H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.2,155.3,148.6,147.2,144.7,136.8,135.8,132.1,129.1,129.0,128.9,127.6,125.9,121.6,120.5,118.8,112.5,111.8,110.6,55.5,55.3,47.6,41.3,34.8。
实施例6、N-(4-苯氧基苯基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8013-2)
参照实施例2实验条件及后处理方法，以4-氨基-二苯醚和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：79.0％，熔点：216-218℃。ESI-HRMS(m/z):496.2020[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.3(s,1H),8.16(d,1H,J＝1.12Hz),7.96-7.94(dd,1H,J＝8.4,1.68Hz),7.87-7.85(d,1H,J＝8.4Hz),7.79-7.45(m,4H),7.56-7.52(m,3H),7.40-7.36(m,2H),7.33-7.23(m,3H),7.13-7.09(m,1H),7.05-6.98(m,6H),5.69(s,2H),13C-NMR(400MHz,DMSO-d6)δ(ppm):165.4,157.3,155.6,152.1,145.0,136.8,130.0,129.1,128.9,128.9,127.6,126.0,123.0,122.2,122.0,119.3,118.9,118.0,111.2,47.6。
实施例7、N-(4-氟苄基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8013-3)
参照实施例2实验条件及后处理方法，以对氟苄胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：80.5％，熔点：139-141℃。ESI-HRMS(m/z):436.1820[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):9.07-9.04(t,1H,J＝5.6Hz),8.10(s,1H),7.88-7.86(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.74-7.72(m,2H),7.57-7.51(m,3H),7.37-7.23(m,5H),7.17-7.12(m,2H),7.01-6.99(d,2H,J＝7.28Hz),5.64(s,2H),4.47-4.46(d,2H,J＝5.6Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.2,162.64,155.4,144.8,136.8,136.0,135.9,130.2,129.8,129.3,129.202,129.1,128.9,128.9,128.8,127.6,125.9,121.6,118.8,115.1,114.9,110.8,47.6,42.1。
实施例8、(S)-N-(1-苯基乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8015-1)
参照实施例2实验条件及后处理方法，以R(+)-α-苯乙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：92.5％，熔点：177-178℃。ESI-HRMS(m/z):432.2070[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.792-8.772(d,1H,J＝7.84Hz),8.079(s,1H),7.91-7.89(d,1H,J＝8.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(d,2H,J＝5.6Hz),7.59-7.52(m,3H),7.40-7.38(m,2H),7.33-7.19(m,6H),7.00-6.99(d,2H,J＝7.32Hz),5.65(s,2H),5.23-5.17(m,1H),1.50-1.48(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):165.5,155.3,145.1,144.8,136.8,135.9,130.2,129.8,129.1,128.9,128.9,128.3,127.6,126.6,126.1,126.0,121.8,118.7,110.9,48.6,47.6,22.3。
实施例9、(R)-N-(1-苯基丙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8015-2)
参照实施例2实验条件及后处理方法，以R(+)-1-苯丙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：92.1％，熔点：178-181℃。ESI-HRMS(m/z):446.2227[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.72-8.70(d,2H,J＝8.4Hz),8.05(s,1H),7.904-7.88(dd,1H,J＝8.4,1.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(m,2H),7.55-7.51(m,3H),7.40-7.38(d,2H,J＝7.28Hz),7.33-7.19(m,6H),7.01-6.99(d,2H,J＝7Hz),5.64(s,2H)4.96-4.92(m,1H),1.90-1.78(m,2H),0.92-0.88(t,3H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):165.93,155.3,144.7,144.2,136.8,135.8,130.2,129.8,129.1,129.1,128.9,128.2,127.6,126.6,126.0,121.7,118.7,111.0,55.0,47.6,29.0,11.5。
实施例10、(R)-N-(1-苯基乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8015-3)
参照实施例2实验条件及后处理方法，以S(-)-α-苯乙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得浅黄色固体,收率：95.9％，熔点：191-193℃。ESI-HRMS(m/z):432.2071[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.81-8.79(d,1H,J＝7.56Hz),8.09(s,1H),7.92-7.90(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.75-735(d,2H,J＝5.0Hz),7.53(s,3H),7.40-7.38(d,2H,J＝7Hz),7.33-7.21(m,6H),7.01-6.99(d,2H,J＝6.72Hz),5.65(s,2H),5.22-5.18(m,1H),1.50-1.48(d,3H,J＝6.44Hz),13C-NMR(400MHz,CDCl3)δ(ppm):166.7,156.4,143.4,136.3,136.0,130.5,129.6,129.4,129.3,129.2,129.0,128.8,128.0,127.5,126.4,126.0,120.9,119.6,111.1,49.5,48.5,21.9。
实施例11、(R)-N-(1-(1H-苯并[d]咪唑-2-基)乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8015-4)
参照实施例2实验条件及后处理方法，以(R)-(+)-2-(α-甲胺)-1H-苯并[d]咪唑和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：85.7％，熔点：290-292℃。ESI-HRMS(m/z):472.2132[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):12.28(s,1H),8.98-8.96(d,1H,J＝7.84Hz),8.19(s,1H),7.99-7.96(dd,1H,J＝8.44,1.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(m,2H),7.54-7.50(m,5H),7.32-7.22(m,3H),7.15-7.12(dd,2H,J＝5.88,3.08Hz),7.00-6.98(d,2H,J＝7.28Hz),5.66(s,2H),5.49-5.41(m,1H),1.66-1.65(d,3H,J＝7Hz)。
实施例12、N-(2-溴苯乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8015-5)
参照实施例2实验条件及后处理方法，以邻溴苯乙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：91.7％，熔点：147-149℃。ESI-HRMS(m/z):512.1161[M+H]+；1H-NMR(400MHz,CDCl3)δ(ppm):7.84-7.82(d,1H,J＝8.4Hz),7.81-7.81(d,1H,J＝1.12Hz),7.69-7.67(dd,2H,J＝8.4,1.12Hz),7.60-7.57(dd,1H,J＝8.4,1.4Hz),7.54-7.52(dd,1H,J＝8.12,1.12Hz),7.50-7.43(m,3H),7.35-7.29(m,3H),7.26-7.18(m,2H),7.10-7.05(m,3H),6.35-6.32(m,1H),5.49(s,2H),3.75-3.70(m,2H),3.10-3.07(t,2H,J＝6.72Hz),13C-NMR(400MHz,CDCl3)δ(ppm):167.8,156.3,138.5,133.0,131.1,130.4,129.5,129.3,129.2,128.9,128.4,128.0,127.7,125.9,121.1,119.6,110.7,48.4,40.1,35.7。
实施例13、N-(3H-1,2,4-三氮唑-3-基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8020-2)
向263mg(0.80mmol)1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸中加入5ml甲苯和0.5ml氯化亚砜，80℃反应2-3小时，减压浓缩除去氯化亚砜，3-氨基-1,2,4三氮唑75mg(0.88mmol)用二氯甲烷5ml溶解，加入0.5ml吡啶，0℃条件下，将新制备的酰氯用二氯甲烷稀释并缓慢滴至胺溶液中。反应完毕后，反应液转移至分液漏斗中，水洗有机相(15ml×2)，水相合并后再用10ml二氯甲烷萃取，合并有机相，饱和氯化钠洗，干燥，过滤，减压浓缩后柱层析分离纯化，得白色固体，收率：74.8％，熔点：200-203℃。ESI-HRMS(m/z):395.1615[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.318(s,1H),8.06-8.02(dd,1H,J＝8.68,1.4Hz),7.86-7.56(m,9H),7.32-7.25(m,3H),7.05-7.03(d,2H,J＝7Hz),5.66(s,2H),13C-NMR(400MHz,DMSO-d6)δ(ppm):167.7,158.4,156.5,151.2,146.0,136.4,135.1,130.4,129.5,129.2,128.9,127.7,126.3,125.8,125.3,118.5,115.2,47.8。
实施例14、(R)-N-(1-(3H-咪唑并[4,5-c]吡啶-2-基)乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8022)
参照实施例2实验条件及后处理方法，以(R)-(+)-2-(α-甲胺)-1H-吡啶并咪唑和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，得白色固体，收率：70.0％，熔点：270-273℃。ESI-HRMS(m/z):473.2082[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):12.68(s,1H),9.01-8.99(d,1H,J＝7.56Hz),8.85(s,1H),8.27-8.26(d,1H,J＝3.92Hz),8.17(s,1H),7.98-7.96(d,1H,J＝8.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(d,2H,J＝5.36Hz),7.54(s,3H),7.47(s,1H),7.30-7.24(m,3H),7.00-6.98(d,2H,J＝6.72Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.0,155.4,144.9,136.8,135.8,130.2,129.7,129.0,128.9,128.8,128.4,127.6,125.9,122.1,118.7,111.0,47.5,44.1,19.3。
实施例15、N-(4-(甲基磺酰基)苯基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8024)
参照实施例13实验条件及后处理方法，以4-甲磺酰基苯胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：77.8％，熔点：287-289℃。ESI-HRMS(m/z):482.1533[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.63(s,1H),8.20-8.19(d,1H,J＝1.28Hz),8.06-8.04(m,2H),7.99-7.96(dd,1H,J＝8.72,1.68Hz),7.92-7.88(m,3H),7.78-7.76(m,2H),7.57-7.53(m,3H),7.33-7.25(m,3H),7.03-7.01(d,2H,J＝7Hz),5.71(s,2H),3.19(s,3H),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.1,155.8,145.3,143.9,136.7,135.9,134.9,130.3,129.6,129.1,128.9,128.7,128.1,127.6,126.0,122.2,120.1,119.0,111.6,47.6,43.8。
实施例16、N-(2-(二甲基氨基)乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8026-3)
参照实施例13实验条件及后处理方法，以2-氨基咪唑和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：91.7％，熔点：125-128℃。ESI-HRMS(m/z):399.2179[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(ppm):8.42-8.39(t,1H,J＝5.6Hz),8.04(m,1H),7.83-7.72(m,4H),7.55-7.50(m,3H),7.33-7.23(m,3H),7.01-6.99(d,2H,J＝7.04Hz),5.64(s,2H),3.39-3.34(m,2H),2.43-2.39(t,2H,J＝7Hz),2.18(s,6H),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.1,155.3,144.7,136.8,135.8,130.2,129.8,129.1,129.0,128.9,127.6,125.9,121.5,118.7,110.7,58.3,47.5,45.3,37.5。
实施例17、(1-苄基-2-苯基-1H-苯并[d]咪唑-6-基)(4-乙基哌嗪-1-基)甲酮的制备(ZXY8026-4)
参照实施例13实验条件及后处理方法，以4-氨基-6-氯嘧啶和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：93.3％，熔点：126-128℃。ESI-HRMS(m/z):425.2336[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.78-7.74(m,3H),7.56-7.54(m,3H),7.51(s,1H),7.30-7.22(m,4H),7.01-6.99(d,2H,J＝7.28Hz),5.63(s,2H),3.58-3.27(m,5H),2.35-2.30(m,6H),1.01-0.97(t,3H,J＝7.28Hz)。
实施例18、N-(1-甲基哌啶-4-基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY5049-1)
参照实施例13实验条件及后处理方法，以4-氨基-1-甲基哌啶和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：79.9％，熔点：222-224℃。ESI-HRMS(m/z):425.2336[M+H]+；1H-NMR(400MHz,CDCl3)δ(ppm):7.86-7.83(m,2H),7.69-7.67(m,2H),7.63-7.61(d,1H,J＝8.44Hz),7.51-7.44(m,3H),7.32-7.28(m,3H),7.06-7.04(d,2H,J＝6.44Hz),6.18-6.16(d,1H,J＝7Hz),5.49-5.48(m,2H),3.99-3.97(m,1H),2.83-2.80(d,2H),2.30-2.30(s,3H),2.17-2.12(m,2H),2.04-2.01(m,2H),1.62-1.54(m,2H),13C-NMR(400MHz,CDCl3)δ(ppm):167.0,156.2,145.4,136.1,136.0,130.3,129.6,129.2,129.1,128.8,127.9,125.9,120.9,119.5,110.8,54.6,48.3,46.8,46.3,32.3。
实施例19、N-(3-氟苯乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY5049-2)
参照实施例13实验条件及后处理方法，以3-氟苯乙胺和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：83.8％，熔点：176-178℃。ESI-HRMS(m/z):450.1975[M+H]+；1H-NMR(400MHz,CDCl3)δ(ppm):7.83-7.80(m,2H),7.69-7.67(m,2H),7.56-7.53(dd,1H,J＝8.4,1.4Hz),7.54-7.43(m,3H),7.34-7.21(m,4H),7.06-7.04(dd,2H,J＝7.84,1.96Hz),6.99-6.98(d,1H,J＝7.56Hz),6.94-6.90(m,2H),6.35-6.32(t,1H,J＝5.6Hz),5.48(s,2H),3.71-3.66(m,2H),2.93-2.90(t,2H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):167.7,164.2,161.7,156.3,130.4,129.4,129.2,129.2,128.9,128.0,125.9,124.5,121.0,119.6,115.8,115.5,110.7,48.4,41.1,35.5。
实施例20、N-(2-吗啉基乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY5049-3)
参照实施例13实验条件及后处理方法，以N-(2-氨基乙基)吗啉和1-苄基-2-苯基-1H-苯并[d]咪唑-6-羧酸为原料，通过酰氯法制得白色固体，收率：83.8％，熔点：169-171℃。ESI-HRMS(m/z):441.2286[M+H]+；1H-NMR(400MHz,CDCl3)δ(ppm):7.89-7.87(d,1H,J＝8.44Hz),7.86-7.85(d,1H,J＝1.12Hz),7.71-7.69(m,2H),7.66-7.64(dd,1H,J＝8.68,1.68Hz),7.53-7.44(m,3H),7.35-7.29(m,3H),7.09-7.07(dd,2H,J＝8.12,1.96Hz),6.90(s,1H),5.51(s,2H),3.71-3.69(t,4H,J＝4.48Hz),3.57-5.33(m,2H),2.62-2.5(t,4H,J＝5.88Hz),2.50(s,4H),13C-NMR(400MHz,CDCl3)δ(ppm):167.5,156.4,145.5,136.2,136.0,130.4,129.6,129.5,129.3,129.2,129.0,128.0,125.9,120.9,119.7,110.8,67.1,56.9,53.3,48.5,36.2。
实施例21、N-(2-((7-硝基苯并[c][1,2,5]恶二唑)-4-氨基)乙基)1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺的制备(ZXY8027)
取400mg(2-(1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲酰胺基)乙基)氨基甲酸叔丁酯加入4mol/L盐酸5ml和二氯甲烷5ml，室温搅拌过夜，次日，用1mol/L氢氧化钠调pH 7-8左右，水层用二氯甲烷萃取(15ml×2)，合并有机相，饱和氯化钠洗，有机相干燥，过滤，减压浓缩，得白色固体。从中称取223mg(0.6mmol)与120mg(0.6mmol)4-氯-7-硝基苯并-2-氧杂-1,3二唑溶于10ml二氯甲烷，加入0.5ml三乙胺，室温反应3小时。反应液转移至分液漏斗中，水洗两次(10ml×2)，水相再用10ml二氯甲烷萃取，合并有机相，饱和氯化钠洗，干燥有机相，过滤，有机相减压浓缩，粗产品柱层析分离纯化，得深棕色固体91mg，收率：48.8％。ESI-HRMS(m/z):534.1885[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(ppm):9.56(s,1H),8.74-8.72(m,1H),8.52-8.50(d,1H,J＝8.96Hz),8.011(s,1H),7.79(s,2H),7.74-7.72(m,2H),7.56-7.51(m,3H),7.32-7.23(m,3H),6.99-6.97(d,2H,J＝6.72Hz),6.52-6.49(d,1H,J＝8.96Hz),5.63(s,2H),3.68-3,58(m,4H)。
实施例22、N-1-苄基-2-苯基-1H-苯并[d]咪唑-5-甲酰吗啉的制备
采用1-苄基-2-苯基-1H-苯并[d]咪唑-5-羧酸，利用类似于实施例1合成方法中步骤e的酰胺缩合法，以吗啉和1-苄基-2-苯基-1H-苯并[d]咪唑-5-羧酸为原料，制备目标化合物，经柱层析分离纯化得白色固体，收率：77.9％，熔点：147-150℃。ESI-HRMS(m/z):398.1863[M+H]+；1H-NMR(400MHz,DMSO-d6)(ppm):7.78(s,1H),7.75-7.73(m,2H),7.56-7.52(m,4H),7.32-7.24(m,4H),7.02-7.00(d,2H,J＝8.12Hz),5.62(s,2H),3.61(s,8H),13C-NMR(400MHz,DMSO-d6)δ(ppm):169.6,154.6,142.0,136.7,136.6,130.1,129.8,129.7,129.1,128.8,127.6,126.2,122.1,118.3,111.2,66.1,47.6。
实施例23、(S)-N-(1-(1H-苯并[d]咪唑-2-基)乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-5-甲酰胺的制备
采用上述方法制备1-苄基-2-苯基-1H-苯并[d]咪唑-5-羧酸，以(R)-(+)-2-(α-甲胺)-1H-苯并咪唑和1-苄基-2-苯基-1H-苯并[d]咪唑-5-羧酸为原料，利用类似于实施例11的方法制备目标化合物，得白色固体，收率：85.1％，熔点：250-252℃。ESI-HRMS(m/z):472.2132[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):12.26(s,1H),9.01-8.99(d,1H,J＝7.84Hz),8.43(s,1H),7.91-7.88(dd,1H,J＝8.4,1.12Hz),7.76-7.74(dd,2H,J＝7.56,3.92Hz),7.60-7.52(m,6H),7.30-7.23(m,3H),7.15-7.13(m,2H),6.98-6.96(d,2H,J＝7Hz),5.65(s,2H),5.50-5.43(m,1H),1.68-1.66(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.4,156.3,154.8,138.0,136.7,130.1,129.1,128.9,128.8,128.6,127.6,126.6,122.7,121.4,119.2,110.7,47.6,44.1,19.7。
实施例24、(S)-N-(1-(3H-咪唑并[4,5-c]吡啶-2-基)乙基)-1-苄基-2-苯基-1H-苯并[d]咪唑-5-甲酰胺的制备
以(R)-(+)-2-(α-甲胺)-1H-吡啶并咪唑(24)和1-苄基-2-苯基-1H-苯并[d]咪唑-5-羧酸为原料，利用类似于实施例14的方法制备目标化合物，得白色固体，收率：77.3％，熔点：155-157℃。ESI-HRMS(m/z):473.2084[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):12.71(s,1H),9.07～9.05(d,1H,J＝7.6Hz),8.86(s,1H),8.43～8.43(d,1H,J＝1.12Hz),8.28～8.26(d,1H,J＝5.6Hz),7.9～7.87(dd,1H,J＝8.4,1.4Hz),7.76～7.73(m,2H),7.60～7.58(d,1H,J＝8.4Hz),7.57～7.49(m,3H),7.30～7.23(m,3H),6.98～6.96(d,2H,J＝8.4Hz),5.65(s,2H),5.51～5.44(m,1H),1.70～1.68(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)δ(ppm):166.5,154.9,138.1,136.8,129.8,129.1,128.9,128.9,128.5,127.6,126.1,122.8,119.2,110.8,47.7,44.2,19.4。
试验实施例1：抗肿瘤活性测试
Kras基因突变导致其kras蛋白酶的功能增强，进而导致细胞增殖分化失控因此，kras突变阳性的肿瘤细胞株对本发明的kras抑制剂的细胞毒性更敏感。基于此，我们进行了生物活性测试，选取kras突变阳性的Panc-tu-1和kras阴性的PANC-1进行对比研究，测定细胞毒性。结果如下表1。
表1部分化合物细胞毒性实验结果
试验实施例2：化合物抗肿瘤活性测试
受试细胞:MDA-MB-231、LM3；细胞培养及实验方法:接种细胞于含10％胎牛血清的DMEM细胞培养液中(补充青链霉素原液5ml/500ml)，置于37℃含5％CO2的细胞培养箱中，每1-2天换液一次，0.25％胰蛋白酶消化，传代和收集细胞。将对数生长期细胞，用含10％胎牛血清的DMEM细胞培养液配制成适宜浓度的细胞悬液，按每孔2500-4000个细胞(100μl)加入到96孔细胞培养板中，培养过夜后，每孔加入含有不同浓度受试物的培养基100μl，每个浓度设4个平行孔。细胞加药培养72小时后弃上清，每孔加入100μl新配置的0.5-0.55mg/ml四氮唑蓝(MTT)的无血清培养液，37℃培养4h后弃上清，每孔加入200μl的DMSO溶解甲臜，酶标仪在570nm波长下测定吸光度值。药物配制：以《抗肿瘤药效学指导原则讨论稿》和《细胞毒类抗肿瘤化合物非临床研究技术指导原则》为指导，根据预备试验的结果，用助溶剂DMSO将受试化合物稀释成20mg/ml，取10μl稀释剂后再加入990μl培养基进行初步稀释，按所需浓度用培养基进一步稀释成不同的受试化合物浓度，另设空白对照组。数据处理:数据用±S表示；抑制率＝(对照组OD值－给药组OD值)/对照组OD值×100％；化合物效应指标用半数浓度(IC50)表示，并列出实测最大抑制率(Imax)。用Origin软件作图，及该软件中的四参数Logistic程序拟合肿瘤细胞生长曲线，求出半效浓度(IC50，μg/ml)。结果见下表2。
表2.化合物抑制肿瘤细胞增殖实验结果
在初筛的基础上，根据本发明的代表性化合物在恶性程度高的肿瘤细胞株MDA-MB-231和LM3进行测试，其抑制细胞增殖的IC50为nM级，显示了非常强的抑制肿瘤细胞增殖的能力，展示了良好的抗肿瘤药物开发潜力。
Claims (5)
1.一类式I所示的苯并咪唑衍生物、其药学上可以接受的盐：
其中，A为-NH-R4；
其中R4选自取代或者未取代的C5-C8芳基、取代或者未取代的C6-C10烷基芳基、取代或者未取代的含有选自S、N和O中1至3个杂原子的八元至十元并环基；
R2选自氢，Ar为苯基，
R3选自氢，
其中“取代的”是指被1至3个相同或不同的取代基取代，所述取代基选自氨基、卤素、硝基、磺酰基、C1-C6烷氧基、C5-C7芳基取代的C1-C6烷氧基，C5-C7芳基；
所述卤素选自F、Cl或Br。
2.一类苯并咪唑衍生物、其药学上可以接受的盐，其特征在于，所述苯并咪唑衍生物选自如下化合物：
3.一种根据权利要求1所述的式I所示的苯并咪唑衍生物、其药学上可以接受的盐的合成方法，反应流程如下：
步骤1)甲酸甲酯基取代的邻硝基氟苯与相应的胺化合物缩合得到式2的化合物；
步骤2)式2的化合物经过氢化还原得到式3的化合物；
步骤3)式3的化合物再与取代的苯甲醛缩合关环得到式4的化合物；
步骤4)式4的化合物经过碱水解得到式5的化合物；
步骤5)式5的化合物再与相应的胺类化合物缩合，得到目标产物式I的化合物；
其中取代基A、R2、R3和Ar的定义如权利要求1中所述。
4.根据权利要求1所述的式I所示的或权利要求2中所述的苯并咪唑衍生物、其药学上可以接受的盐用于制备肿瘤治疗药物的用途。
5.一种药物组合物，所述药物组合物包括治疗有效量的根据权利要求1所述的式I所示的或权利要求2中所述的苯并咪唑衍生物或其药学上可接受的盐以及药物辅料。
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