CN113105366A - 一类含苯基羟肟结构衍生物及其制法与用途 - Google Patents
一类含苯基羟肟结构衍生物及其制法与用途 Download PDFInfo
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- CN113105366A CN113105366A CN202110240224.XA CN202110240224A CN113105366A CN 113105366 A CN113105366 A CN 113105366A CN 202110240224 A CN202110240224 A CN 202110240224A CN 113105366 A CN113105366 A CN 113105366A
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- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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Abstract
本发明公开了一种含苯基羟肟结构衍生物及其制法与用途，该衍生物为通式(I)的化合物或其药学上可接受的盐，活性高以及副作用小的抗肿瘤候选化合物，这些化合物通过与其他抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。药理实验显示，本发明的化合物可以对IDO1产生抑制作用，可用于制备治疗癌症等疾病的药物。
Description
技术领域
本发明涉及一类含羟肟结构衍生物及其制法与用途，尤其涉及一类含苯基羟肟结构衍生物及其制法与用途。
背景技术
当前，癌症已成为人类死亡的主要原因之一。2020年12月15日，世界卫生组织下属的国际癌症研究机构发布最新数据显示，2020年全球新增癌症病例约1930万、死亡人数约1000万。而在其管理的“全球癌症观察”网站上新增了2040年癌症负担预测数据，该预测显示，2040年，全球新增癌症病例将达到2840万例，与2020年相比上升47％，且发展程度较低或中等的国家病例增幅最大。因此，癌症已成为一个引起高度社会关注的公共卫生议题，开发有效的癌症治疗手段迫在眉睫。人体的免疫系统负责保卫机体健康，其中T细胞在肿瘤的监控和杀伤中起着至关重要的作用。然而肿瘤细胞能通过多种机制来抑制T细胞的抗肿瘤活性，从而逃避免疫系统的攻击，产生了免疫逃逸。随着肿瘤免疫相关研究的不断深入，免疫治疗成为改善癌症患者预后的新希望。
吲哚胺2,3-双加氧酶-1(IDO1)是一种分解色氨酸(tryptophan)的重要酶，在多种肿瘤细胞中表达，介导肿瘤诱导的免疫抑制。这种酶可局部降解色氨酸，钝化免疫系统的肿瘤监视作用及防止肿瘤排斥。IDO1在多种肿瘤细胞中过度表达，可以抑制T细胞功能、增强Treg细胞功能以及诱导NK细胞功能紊乱，导致肿瘤细胞不断发展与转移。抑制IDO1的活性对于肿瘤的治疗有着显著的促进作用，针对这种酶的特异性抑制剂，具有治疗各种类型肿瘤的潜力。目前，IDO1已经成为抗肿瘤免疫疗法中重要的小分子调控靶点。
发明内容
发明目的：本发明的第一目的为提供一种活性高以及副作用小的抗肿瘤含苯基羟肟结构衍生物，本发明的第二目的为提供该含苯基羟肟结构衍生物的制备方法，本发明的第三目的为提供该含苯基羟肟结构衍生物的用途。
技术方案：本发明公开了通式(I)的化合物及其药学上可接受的盐，
其中n＝0、1或2；
R代表氢、C1-C6烷基、C3-C6环烷基、任意取代的苯环或芳杂环，芳杂环是六元或五元芳杂环，取代基是卤素、C1～C3的烷基、烷氧基或卤代烷基；
R1、R2代表氢、卤素、C1～C3的烷基、烷氧基、卤代烷基、氰基、OH、NO2、或NR4R5，其中R4、R5代表氢或C1～C6烷基；
R3代表氢、卤素、C1～C3的烷基、烷氧基、卤代烷基、氰基或NR6R7，其中R6、R7代表氢或C1～C6烷基。
作为优选，n＝0或1；
R代表C1-C6烷基、C3-C6环烷基、任意取代的苯环或芳杂环，芳杂环是六元或五元芳杂环，取代基是卤素、C1～C3的烷基、卤代烷基；
R1、R2各自独立地选自氢、卤素、C1～C3的烷基；
R3代表氢或NR6R7，其中R6、R7代表氢、C1～C6烷基。
上述化合物的药学上可接受的盐为通式(I)的酸加成盐，其中用于成盐的酸为：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
本发明优选的化合物如下：
当R3不为NR6R7时，本发明化合物可用下列方法制备：
其中：n、R、R1、R2的定义同前；
由化合物Ⅱ与羟胺(NH2OH)水溶液反应制备化合物Ⅲ，所用羟胺水溶液使用三乙胺与盐酸羟胺溶液中和而得；所用溶剂为乙醇和水。
由化合物Ⅲ、亚硝酸钠(NaNO2)与6N盐酸水溶液制备化合物Ⅳ；所用溶剂为水。
由化合物Ⅳ与化合物Ⅴ制备得化合物Ⅵ，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选碳酸钠；溶剂选自甲醇、乙醇、乙腈、二氧六环、N,N-二甲基甲酰胺或任意两者组成的混合溶剂，优选乙醇。
由化合物VI与羰基二咪唑(CDI)制备化合物VII，所用溶剂选自乙腈、丙酮、1,4-二氧六环、乙酸乙酯或任意二者组成的混合溶剂，优选乙酸乙酯。
由化合物VII经还原得化合物VIII，所用还原剂为二水合氯化亚锡(SnCl2·H2O)，所用溶剂为甲醇、乙醇、乙酸乙酯、1,4-二氧六环或任意两者组成的混合溶剂，优选乙醇。
化合物X由化合物VIII与化合物IX反应制备而得，所用催化剂选自三乙胺、三亚乙基亚胺、4-二甲氨基吡啶、吡啶，优选三乙胺；溶剂为四氢呋喃、丙酮、二氯甲烷、1,2-二氯乙烷或任意二者组成的混合溶剂，优选四氢呋喃。
终产物I由化合物X经碱水解制备而得，所用碱选自氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠，优选氢氧化钠；所用溶剂选自N,N-二甲基甲酰胺、1,4-二氧六环、四氢呋喃、甲醇、乙腈、丙酮，优选N,N-二甲基甲酰胺，并与水组成混合溶剂。
当R3为NR6R7时，化合物II可用下列方法制备：
其中n、R6、R7的定义同前；
由化合物XI与化合物XII经亲核取代反应制备化合物II，所用溶剂选自N,N-二甲基甲酰胺、1,4-二氧六环、二甲基亚砜、乙腈、1,2-二氯乙烷或任意两者组成的混合溶剂，优选N,N-二甲基甲酰胺；所用碱选自三乙胺、碳酸钾、碳酸铯、叔丁醇钠，优选碳酸铯。
本发明还公开了一种药物组合物，其含有上述通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明通式(I)化合物及其水合物、溶剂合物或结晶在制备IDO1抑制剂药物中的应用也在本发明的保护范围内。
进一步地，其中的IDO1抑制剂可用于治疗肿瘤。
有益效果：与现有技术相比，本发明具有如下显著优点：活性高以及副作用小的抗肿瘤候选化合物，这些化合物通过与其他抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。药理实验显示，本发明的化合物可以对IDO1产生抑制作用，可用于制备治疗癌症等疾病的药物。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
3-[3-(对甲苯基)脲基]-4-(二异丁胺)-N'-羟基-N-(对甲苯基)苯甲脒(I-1)
4-二异丁胺-3-硝基苯甲腈(II-1)的合成
向装有4-氟-3-硝基苯甲腈(5.00g,30.1mmol)的单颈瓶中加入40mL DMF，搅拌溶解，缓慢加入碳酸铯(14.73g,45.2mmol)，二异丁胺(11.67g,90.3mmol)，搅拌，升温至100℃反应1h。冷却至室温，加入80mL水稀释，用乙酸乙酯(3×40mL)萃取，饱和NaCl溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得到黄色油状物，柱层析分离(淋洗剂，石油醚:乙酸乙酯＝20:1)，得黄色固体8.20g，收率63.7％。
1H-NMR(300MHz,CDCl3),δ(ppm):8.04(d,J＝2.1Hz,1H,ArH),7.54(dd,J＝9.0,2.1Hz,1H ArH),7.10(d,J＝9.0Hz,1H,ArH),3.00(d,J＝7.3Hz,4H,-NCH2-),1.96(m,2H,-CH2CH-),0.84(d,J＝6.6Hz,12H,-CHCH 3).
4-二异丁胺-N'-羟基-3-硝基苯甲脒(III-1)的合成
盐酸羟胺(9.66g，0.14mol)用20mL水溶解，加入三乙胺(14.05g，0.14mol)中和。向装有4-二异丁胺-3-硝基苯甲腈(II-1)(15.30g，55.56mmol)的三颈瓶中加入100mL乙醇，搅拌，滴加新鲜制备的羟胺水溶液，滴完，升温至45℃反应6h，减压蒸除溶剂，加100mL水稀释，超声，析出红色固体，抽滤，45℃真空干燥，得16.91g，收率98.7％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.61(s,1H,-NOH),7.96(d,J＝1.4Hz,1H,ArH),7.74(dd,J＝8.8,1.7Hz,1H,ArH),7.31(d,J＝8.9Hz,1H,ArH),5.83(s,2H,-CNH2),2.93(d,J＝7.1Hz,4H,-NCH2-),1.79-1.88(m,2H,-CH2CH-),0.77(d,J＝6.5Hz,12H,-CHCH3).1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.10(d,J＝2.4Hz,1H,ArH),7.69(dd,J＝9.1,2.4Hz,1H,ArH),7.46(d,J＝9.1Hz,1H,ArH),3.01(d,J＝7.0Hz,4H,-NCH2-),1.89-1.81(m,2H,-CH2CH-),0.76(d,J＝6.5Hz,12H,-CHCH3).
4-二异丁胺-N-羟基-3-硝基亚氨代苯甲酰氯(IV-1)的合成
将4-二异丁胺-N’-羟基-3-硝基苯甲脒(III-1)(7.78g,22.6mmol)在45℃下溶于250mL的6N HCl，溶清后降温至0℃以下，开始缓慢滴加亚硝酸钠(1.56g,22.6mmol)的20mL水溶液，控制温度低于0℃，0℃以下反应2h后升至3-5℃反应过夜，TLC监测III-1反应完全，抽滤，水洗滤饼，柱层析分离(淋洗剂，石油醚:乙酸乙酯＝20:1)，得红色固体4.45g，收率60.2％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):12.31(s,1H,-NOH),8.03(d,J＝2.4Hz,1H,ArH),7.81(dd,J＝9.1,2.3Hz,1H,ArH),7.40(d,J＝9.1Hz,1H,ArH),2.98(d,J＝7.2Hz,4H,-NCH2-),1.91-1.82(m,2H,-CH2CH-),0.78(d,J＝6.5Hz,12H,-CHCH3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.00(d,J＝2.2Hz,1H,ArH),7.80(dd,J＝9.0,2.2Hz,1H,ArH),7.36(d,J＝9.1Hz,1H,ArH),2.95(d,J＝7.0Hz,4H,-NCH2-),1.90–1.78(m,2H,-CH2CH-),0.74(d,J＝6.5Hz,12H,-CHCH3).
4-二异丁胺-N’-羟基-3-硝基-N-(对甲苯基)苯甲脒(VI-1)的合成
将4-二异丁胺-N-羟基-3-硝基亚氨代苯甲酰氯(IV-1)(1.80g,5.5mmol)溶于25mL乙醇中，加入对甲苯胺(0.71g,6.6mmol)，而后加入碳酸氢钠(1.16g,13.8mmol)的水溶液，升温至60℃反应2h，冷却，减压蒸除乙醇，加入15mL水稀释，用乙酸乙酯萃取(3×5mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体，柱层析分离(淋洗剂，石油醚:乙酸乙酯＝8:1)，得黄色固体1.46g，收率69.1％。
1H-NMR(300MHz,CDCl3),δ(ppm):7.86(d,J＝1.9Hz,1H,ArH),7.45(br,1H,-NOH),7.35(dd,J＝9.1,2.4Hz,1H,ArH),7.01-6.93(m,3H,ArH),6.69(d,J＝8.2Hz,2H,ArH),2.92(d,J＝7.2Hz,4H,-NCH2-),2.27(s,3H,-ArCH3),1.95-1.88(m,2H,-CH2CH-),0.81(d,J＝6.6Hz,12H,-CHCH3).
3-[4-(二异丁胺)-3-硝基苯基]-4-(对甲苯基)-1,2,4-噁二唑-5(4H)-酮(VII-1)的合成
将4-二异丁胺-N’-羟基-3-硝基-N-(对甲苯基)苯甲脒(VI-1)(1.30g，3.38mmol)溶于5mL乙酸乙酯中，加入CDI(0.82g，5.07mmol)，25℃反应2h,用5mL 1N HCl洗涤2次，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体，乙醇重结晶纯化，得黄色固体1.36g，收率95.1％。
1H-NMR(300MHz,CDCl3),δ(ppm):7.75(d,J＝2.3Hz,1H,ArH),7.33(dd,J＝9.0,2.3Hz,2H,ArH),7.29(s,1H,ArH),7.17(d,J＝8.3Hz,2H,ArH),7.01(d,J＝9.1Hz,1H,ArH),2.95(d,J＝7.3Hz,4H,-NCH2 -),2.43(s,3H,-ArCH3 ),2.00–1.83(m,2H,-CH2CH-),0.82(d,J＝6.6Hz,12H,-CHCH 3).
3-[3-氨基-4-(二异丁胺)苯基]-4-(对甲苯基)-1,2,4-噁二唑-5(4H)-酮(VIII-1)的合成
将3-[4-(二异丁胺)-3-硝基苯基]-4-(对甲苯基)-1,2,4-噁二唑-5(4H)-酮(VII-1)(1.32g，3.1mmol)溶于30mL无水乙醇中，加入二水合氯化亚锡(3.51g，15.5mmol)，25℃反应过夜，TLC监测反应，至原料反应完全，结束反应。用1N NaOH水溶液调pH至9-10，用乙酸乙酯萃取(3×50mL)，饱和NaCl溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色油状物1.01g，收率82.6％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):7.29(s,4H,ArH),6.94(d,J＝8.3Hz,1H,ArH),6.84(d,J＝2.0Hz,1H,ArH),6.35(dd,J＝8.0,1.6Hz,1H,ArH),4.98(s,2H,-NH2 ),2.56(d,J＝7.1Hz,4H,-NCH2 -),2.34(s,3H,-ArCH3 ),1.74–1.54(m,2H,-CH2CH-),0.79(d,J＝6.5Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.26(s,4H,ArH),6.92(d,J＝8.3Hz,1H,ArH),6.81(d,J＝2.0Hz,1H,ArH),6.36(dd,J＝8.1,1.9Hz,1H,ArH),2.54(d,J＝7.2Hz,4H,-NCH2 -),2.32(s,3H,-ArCH3 ),1.73–1.47(m,2H,-CH2CH-),0.77(d,J＝6.5Hz,12H,-CHCH 3).
1-[2-(二异丁胺)-5-[5-氧代-4-(对甲苯基)-4,5-二氢-1,2,4-噁二唑-3-基]苯基]-3-(对甲苯基)脲(X-1)的合成
将3-[3-氨基-4-(二异丁胺)苯基]-4-(对甲苯基)-1,2,4-噁二唑-5(4H)-酮(VIII-1)(0.39g，1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入对甲苯异氰酸酯(0.16g,1.2mmol)，25℃反应，TLC监测反应，至原料VIII-1反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl水溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝3:1)，得黄色固体0.51g，收率96.2％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.36(s,1H,-NHCO-),8.18(d,J＝1.7Hz,1H,ArH),7.73(s,1H,-CONH-),7.46–7.21(m,6H,ArH),7.16(d,J＝8.5Hz,1H,ArH),7.09(d,J＝8.3Hz,2H,ArH),6.77(dd,J＝8.3,1.4Hz,1H,ArH),2.74(d,J＝6.8Hz,4H,-NCH2 -),2.33(s,3H,-ArCH3 ),2.24(s,3H,-ArCH3 ),1.70-1.54(m,2H,-CH2CH-),0.77(d,J＝6.5Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.12(d,J＝1.8Hz,1H,ArH),7.46–7.18(m,6H,ArH),7.14(d,J＝8.5Hz,1H,ArH),7.08(d,J＝8.3Hz,2H,ArH),6.77(dd,J＝8.3,2.1Hz,1H,ArH),2.71(d,J＝6.8Hz,4H,-NCH2 -),2.30(s,3H,-ArCH3 ),2.22(s,3H,-ArCH3 ),1.70-1.50(m,2H,-CH2CH-),0.74(d,J＝6.6Hz,12H,-CHCH 3).
3-[3-(对甲苯基)脲基]-4-(二异丁胺)-N'-羟基-N-(对甲苯基)苯甲脒(I-1)的合成
将1-[2-(二异丁胺)-5-[5-氧代-4-(对甲苯基)-4,5-二氢-1,2,4-噁二唑-3-基]苯基]-3-(对甲苯基)脲(X-1)(0.40g,0.76mmol)溶于3mL DMF中，加氢氧化钠(0.04g,0.91mmol)，1mL水，45℃反应，TLC监测反应，至原料化合物X-1反应完全，结束反应。加25mL水析出固体，抽滤，用(乙酸乙酯:石油醚＝1:5)打浆得白色固体0.18g，收率47.2％，将0.10g游离的I-1溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出白色固体，抽滤，45℃真空干燥。得0.09g白色固体，收率83.9％，纯度：96.5％。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.32(s,1H,-NHCO-),9.36(s,1H,-CONH-),8.15(s,1H,-NHAr-),8.04(d,J＝1.8Hz,1H,ArH),7.88(s,1H,-NOH),7.37(d,J＝8.3Hz,2H,ArH),7.17-7.10(m,3H,ArH),6.89-6.83(m,3H,ArH),6.57(d,J＝8.3Hz,2H,ArH),2.73(d,J＝6.6Hz,4H,-NCH2 -),2.27(s,3H,-ArCH3 ),2.16(s,3H,-ArCH3 ),1.78–1.63(m,2H,-CH2CH-),0.85(d,J＝6.5Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.05(d,J＝1.8Hz,1H,ArH),7.32(d,J＝8.2Hz,2H,ArH),7.18-7.05(m,3H,ArH),6.92–6.78(m,3H,ArH),6.54(d,J＝8.2Hz,2H,ArH),2.69(d,J＝6.7Hz,4H,-NCH2 -),2.24(s,3H,-ArCH3 ),2.13(s,3H,-ArCH3 ),1.70-1.56(m,2H,-CH2CH-),0.81(d,J＝6.6Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):11.62(br,1H,-NHCO-),10.85(s,1H,-CONH-),9.77(s,1H,-NHAr-),8.15(s,1H,ArH),7.98(s,1H,-NOH),7.36(d,J＝8.3Hz,2H,ArH),7.18(d,J＝8.5Hz,1H,ArH),7.08(d,J＝8.3Hz,2H,ArH),6.98(d,J＝8.2Hz,2H,ArH),6.90–6.76(m,3H,ArH),2.81(d,J＝6.6Hz,4H,-NCH2 -),2.23(s,3H,-ArCH3 ),2.18(s,3H,-ArCH3 ),1.72–1.57(m,2H,-CH2CH-),0.75(d,J＝6.6Hz,12H,-CHCH 3).
实施例2
N-(3-溴-4-氟苯基)-4-(二异丁胺)-N'-羟基-3-[3-(对甲苯基)脲基]苯甲脒(I-2)
N-(3-溴-4-氟苯基)-4-(二异丁胺)-N'-羟基-3-硝基苯甲脒(VI-2)的合成
将4-二异丁胺-N-羟基-3-硝基亚氨代苯甲酰氯(IV-1)(4.35g，13.3mmol)溶于100mL乙醇中，加入3-溴-4-氟苯胺(3.02g，15.9mmol)，而后加入碳酸氢钠(2.79g，33.2mmol)的水溶液，升温至60℃反应过夜，冷却，减压蒸除乙醇，加入50mL水稀释，用乙酸乙酯萃取(3×20mL)，饱和NaCl水溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体，柱层析分离(淋洗剂，石油醚:乙酸乙酯＝8:1)，得黄色固体2.10g，收率32.8％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.66(s,1H,-NH-),8.54(s,1H,-NOH-),7.72(d,J＝2.1Hz,1H,ArH),7.36(dd,J＝8.9,2.1Hz,1H,ArH),7.28(d,J＝8.9Hz,1H,ArH),7.10(t,J＝8.8Hz,1H,ArH),6.87(dd,J＝6.1,2.7Hz,1H,ArH),6.74–6.63(m,1H,ArH),2.93(d,J＝7.1Hz,4H,-NCH2 -),1.93–1.73(m,2H,-CH2CH-),0.76(d,J＝6.5Hz,12H,-CHCH 3).1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.67(d,J＝2.1Hz,1H,ArH),7.35(dd,J＝8.9,2.1Hz,1HArH,),7.25(d,J＝9.0Hz,1H,ArH),7.08(t,J＝8.8Hz,ArH),6.81(dd,J＝6.0,2.7Hz,1H,ArH),6.74–6.65(m,1H,ArH),2.90(d,J＝7.2Hz,4H,-NCH2 -),1.89–1.70(m,2H,-CH2CH-),0.73(d,J＝6.5Hz,12H,-CHCH 3).
3-[4-(二异丁胺)-3-硝基苯基]-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(VII-2)的合成
将N-(3-溴-4-氟苯基)-4-(二异丁胺)-N'-羟基-3-硝基苯甲脒(VI-2)(2.00g,4.1mmol)溶于20mL乙酸乙酯中，加入CDI(1.01g,6.2mmol)，25℃反应2h，用1N HCl洗涤(2×20mL)，饱和NaCl水溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体，乙醇重结晶纯化，得黄色固体1.90g，收率90.2％。
1H-NMR(300MHz,CDCl3)δ(ppm):7.82(d,J＝2.3Hz,1H,ArH),7.56-7.50(m,1H,ArH),7.27(s,1H,ArH),7.25(d,J＝1.5Hz,1H,ArH),7.22(d,J＝2.3Hz,1H,ArH),7.04(d,J＝9.0Hz,1H,ArH),2.97(d,J＝7.3Hz,4H,-NCH2 -),2.01–1.85(m,2H,-CH2CH-),0.83(d,J＝6.6Hz,12H,-CHCH 3).
3-[3-氨基-4-(二异丁胺)苯基]-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(VIII-2)的合成
将3-[4-(二异丁胺)-3-硝基苯基]-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(VII-2)(1.25g,2.4mmol)溶于30mL无水乙醇中，加二水合氯化亚锡(2.78g,12.3mmol)，25℃反应过夜，TLC监测反应，至原料VII-2反应完全，结束反应。用1N NaOH水溶液调pH至10，乙酸乙酯萃取(3×50mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色油状物1.02g，收率86.8％。
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.83(d,J＝6.4Hz,1H,ArH),7.51(d,J＝7.1Hz,2H,ArH),6.98(d,J＝8.0Hz,1H,ArH),6.77(s,1H,ArH),6.37(d,J＝7.6Hz,1H,ArH),2.58(d,J＝6.7Hz,4H,-NCH2 -),1.76–1.52(m,2H,-CH2CH-),0.79(d,J＝6.5Hz,12H,-CHCH 3).
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(对甲苯基)脲(X-2)的合成
将3-[3-氨基-4-(二异丁胺)苯基]-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(VIII-2)(0.47g，1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入对甲苯异氰酸酯(0.20g,1.5mmol)，25℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl水溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚：乙酸乙酯＝3:1)，得黄色固体0.46g，收率73.7％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.40(s,1H,-NHCO-),8.12(d,J＝1.7H,1H,ArH),7.96(dd,J＝6.1,2.2Hz,1H,ArH),7.78(s,1H,-CONH-),7.68–7.49(m,2H,ArH),7.38(d,J＝8.3Hz,2H,ArH),7.28(d,J＝8.4Hz,1H,ArH),7.13(d,J＝8.2Hz,2H,ArH),6.95(dd,J＝8.5,1.7Hz,1H,ArH),2.81(d,J＝6.8Hz,4H,-NCH2 -),2.29(s,3H,-ArCH3 ),1.74–1.62(m,2H,-CH2CH-),0.82(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.02(d,J＝1.9Hz,1H,ArH),7.87(d,J＝6.0Hz,1H,ArH),7.60–7.44(m,2H,ArH),7.34(d,J＝8.1Hz,2H,ArH),7.24(d,J＝8.4Hz,1H,ArH),7.12(d,J＝8.1Hz,2H,ArH),6.98(d,J＝8.4Hz,1H,ArH),2.77(d,J＝6.7Hz,4H,-NCH2 -),2.26(s,3H,-ArCH3 ),1.71-1.58(m,2H,-CH2CH-),0.78(d,J＝6.5Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-4-(二异丁胺)-N'-羟基-3-[3-(对甲苯基)脲基]苯甲脒(I-2)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(对甲苯基)脲(X-2)(0.35g，0.57mmol)溶于3mL DMF中，加入氢氧化钠(0.03g，0.68mmol)，1mL水，45℃反应，TLC监测反应，至原料X-2反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝3:1)，得灰色固体0.16g，收率48.0％。将0.09g游离的化合物I-2溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出黄色固体，抽滤，45℃真空干燥。得0.09g黄色固体，收率94.1％，纯度：94.0％。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.75(br,1H,-NHCO-),9.41(s,1H,-CONH-),8.91(br,1H,-NHAr-),8.17(s,1H,ArH),7.91(s,1H,-NOH-),7.38(d,J＝8.0Hz,2H,ArH),7.23(d,J＝8.4Hz,1H,ArH),7.18–7.02(m,3H,ArH),7.00–6.86(m,2H,ArH),6.85-6.74(m,1H,ArH),2.78(d,J＝6.3Hz,4H,-NCH2 -),2.28(s,3H,-ArCH3 ),1.77–1.63(m,2H,-CH2CH-),0.85(d,J＝6.4Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.06(s,1H,ArH),7.32(d,J＝7.7Hz,2H,ArH),7.20(d,J＝7.7Hz,1H,ArH),7.11(d,J＝8.1Hz,3H,ArH),6.95-6.90(m,1H,ArH),6.83-6.79(m,2H,ArH),2.73(d,J＝6.1Hz,4H,-NCH2 -),2.25(s,3H,-ArCH3 ),1.72–1.57(m,2H,-CH2CH-),0.81(d,J＝6.3Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):11.32(s,1H,-NHCO-),10.13(s,1H,-CONH-),9.64(s,1H,-NHAr-),8.11(s,1H,ArH),7.93(s,1H,-NOH-),7.35(d,J＝8.3Hz,2H,ArH),7.25–7.13(m,2H,ArH),7.07(d,J＝8.1Hz,3H,ArH),6.92(d,J＝7.1Hz,2H,ArH),2.79(d,J＝6.3Hz,4H,-NCH2 -),2.23(s,3H,-ArCH3 ),1.71–1.58(m,2H,-CH2CH-),0.77(d,J＝6.5Hz,12H,-CHCH 3).
实施例3
N-(3-溴-4-氟苯基)-3-[3-(4-氯苯基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-3)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(4-氯苯基)脲(X-3)的合成
将VIII-2(0.47g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入对氯苯异氰酸酯(0.23g,1.5mmol)，25℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝3:1)，得白色固体0.35g，收率55.3％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.63(s,1H,-NHCO-),8.06(d,J＝2.0Hz,1H,ArH),7.93(dd,J＝6.2,2.2Hz,1H,ArH),7.81(s,1H,-CONH-),7.64–7.44(m,4H,ArH),7.32(d,J＝8.8Hz,2H,ArH),7.25(d,J＝8.4Hz,1H,ArH),6.93(dd,J＝8.4,2.0Hz,1H,ArH),2.77(d,J＝6.8Hz,4H,-NCH2 -),1.72-1.57(m,2H,-CH2CH-),0.77(d,J＝6.6Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-[3-(4-氯苯基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-3)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(4-氯苯基)脲(X-3)(0.22g，0.35mmol)溶于3mL DMF中，加氢氧化钠(0.02g，0.42mmol)，1mL水，45℃反应，TLC监测反应，至原料X-3反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝4:1)，得黄色固体0.14g，收率66.1％。将0.08g游离的I-3溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出棕色固体，抽滤，45℃真空干燥。得0.08g棕色固体，收率94.4％。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):11.01(br,1H,-NHCO-),9.77(s,1H,-CONH-),9.41(br,1H,-NHAr-),8.10(d,J＝1.7Hz,1H,ArH),7.96(s,1H,-NOH-),7.49(d,J＝8.8Hz,2H,ArH),7.31(d,J＝8.8Hz,2H,ArH),7.21(d,J＝8.3Hz,1H,ArH),7.12(t,J＝8.7Hz,1H,ArH),7.05–6.88(m,2H,ArH),6.88–6.76(m,1H,ArH),2.77(d,J＝6.6Hz,4H,-NCH2 -),1.73–1.55(m,2H,-CH2CH-),0.79(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.02(d,J＝1.9Hz,1H,ArH),7.45(d,J＝8.9Hz,2H,ArH),7.30(d,J＝8.8Hz,2H,ArH),7.19(d,J＝8.2Hz,1H,ArH),7.10(t,J＝8.7Hz,1H,ArH),7.02–6.76(m,3H,ArH),2.73(d,J＝6.8Hz,4H,-NCH2 -),1.67–1.52(m,2H,-CH2CH-),0.76(d,J＝6.6Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.02(s,1H,ArH),7.46(d,J＝7.6Hz,2H,ArH),7.31(d,J＝8.7Hz,2H,ArH),7.25-7.09(m,2H,ArH),7.04(d,J＝3.4Hz,1H,ArH),6.94(d,J＝6.8Hz,2H,ArH),2.77(d,J＝5.7Hz,4H,-NCH2 -),1.71-1.53(m,2H,-CH2CH-),0.74(d,J＝6.1Hz,12H,-CHCH 3).
实施例4
N-(3-溴-4-氟苯基)-3-[3-(4-三氟甲基苯基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-4)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(对三氟甲基苯基)脲(X-4)的合成
将VIII-2(0.40g,0.8mmol)溶于5mL四氢呋喃中，加三乙胺(0.16g,1.6mmol)，搅拌，加入对三氟甲基异氰酸酯(0.47g,2.5mmol)，45℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝3:1)，得白色固体0.40g，收率72.5％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.89(s,1H,-NHCO-),8.04(s,1H,ArH),7.93(d,J＝5.0Hz,1H,ArH),7.89(s,1H,-CONH-),7.76–7.60(m,4H,ArH),7.59–7.46(m,2H,ArH),7.26(d,J＝8.2Hz,1H,ArH),6.95(d,J＝7.6Hz,1H,ArH),2.78(d,J＝6.2Hz,4H,-NCH2 -),1.81–1.48(m,2H),0.77(d,J＝5.9Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.88(s,1H,ArH),7.77(d,J＝5.8Hz,1H,ArH),7.59(s,4H,ArH),7.50–7.35(m,2H,ArH),7.18(d,J＝8.4Hz,1H),6.99(d,J＝7.9Hz,1H,ArH),2.72(d,J＝6.1Hz,4H,-NCH2 -),1.67-1.51(m,2H,-CH2CH-),0.71(d,J＝6.4Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-[3-(4-三氟甲基苯基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-4)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-(对三氟甲基苯基)脲(X-4)(0.35g,0.53mmol)溶于3mL DMF中，加氢氧化钠(0.03g,0.64mmol)，1mL水，45℃反应，TLC监测反应，至原料X-4反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝4:1)，得棕色固体0.15g，收率44.3％，纯度：91.6％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.57(s,1H,-CONH-),9.92(s,1H,-NHCO-),8.51(s,1H,-NHAr),8.13(d,J＝2.0Hz,1H,ArH),8.04(s,1H,-NOH),7.66(q,J＝9.0Hz,4H,ArH),7.21(d,J＝8.4Hz,1H,ArH),7.07(t,J＝8.8Hz,1H,ArH),6.92(dd,J＝8.2,2.0Hz,1H,ArH),6.77(dd,J＝6.0,2.6Hz,1H,ArH),6.75–6.63(m,1H,ArH),2.75(d,J＝6.8Hz,4H,-NCH2 -),1.74–1.59(m,2H,-CH2CH-),0.83(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):δ8.04(d,J＝2.0Hz,1H,ArH),7.73–7.56(m,4H,ArH),7.17(d,J＝8.4Hz,1H,ArH),7.09–6.98(m,1H,ArH),6.90(dd,J＝8.3,2.0Hz,1H,ArH),6.76–6.65(m,2H,ArH),2.70(d,J＝6.8Hz,4H,-NCH2 -),1.69–1.53(m,2H,-CH2CH-),0.78(d,J＝6.6Hz,12H,-CHCH 3).
实施例5
4-(二异丁胺)-N'-羟基-3-[3-(嘧啶-5-基)脲基]-N-(对甲苯基)-苯甲脒(I-5)
5-嘧啶异氰酸酯(IX-5)的合成
将5-氨基嘧啶(0.20g,2.0mmol)溶于5mL四氢呋喃中，加二异丙基乙胺(0.36g,1.4mmol)，搅拌，加入三光气(0.20g,6.8mmol)，5℃反应，TLC监测反应，至5-氨基嘧啶反应完全，结束反应。未经纯化直接投下一步反应。
1-[2-(异丁胺基)-5-[5-氧代-4-(对甲苯基)-4,5-二氢-1,2,4-噁二唑-3-基]苯基]-3-(嘧啶基-5-基)脲(X-5)的合成
将化合物VIII-1(0.39g,1.0mmol)溶于10mL四氢呋喃中，加三乙胺(0.15g,1.5mmol)，搅拌，加入5-嘧啶异氰酸酯(IX-5)(0.24g,2mmol)，25℃反应，TLC监测反应，至原料VIII-1反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂,二氯甲烷:乙酸乙酯＝10:1,加三乙胺)，得黄色固体0.22g，收率42.7％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.86(s,1H,-NHCO-),8.93(s,2H,ArH),8.87(s,1H,ArH),8.19(d,J＝2.2Hz,1H,ArH),8.03(s,1H,-CONH-),7.34(q,J＝8.4Hz,4H,ArH),7.25(d,J＝8.4Hz,1H,ArH),6.90(d,J＝8.2Hz,1H,ArH),2.83(d,J＝6.7Hz,4H,-NCH2 -),2.37(s,3H,-ArCH3 ),1.76–1.63(m,2H,-CH2CH-),0.82(d,J＝6.5Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.89(s,2H,ArH),8.82(s,1H,ArH),8.06(d,J＝2.0Hz,1H,ArH),7.29(s,4H,ArH),7.21(d,J＝8.7Hz,1H,ArH),6.94(d,J＝8.0Hz,1H,ArH),2.77(d,J＝6.8Hz,4H,-NCH2 -),2.33(s,3H,-ArCH3 ),1.71–1.58(m,2H,-CH2CH-),0.78(d,J＝6.5Hz,12H,-CHCH 3).
4-(二异丁胺)-N'-羟基-3-[3-(嘧啶-5-基)脲基]-N-(对甲苯基)-苯甲脒(I-5)的合成
将1-[2-(异丁胺基)-5-[5-氧代-4-(对甲苯基)-4,5-二氢-1,2,4-噁二唑-3-基]苯基]-3-(嘧啶基-5-基)脲(X-5)(0.15g,0.29mmol)溶于3mL DMF中，加氢氧化钠(0.05g,1.2mmol)，1mL水，45℃反应，TLC监测反应，至原料X-5反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，二氯甲烷:乙酸乙酯＝10:1，加三乙胺)，得黄色色固体0.13g，收率92.8％。将0.06g游离的I-5溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出棕色固体，抽滤，45℃真空干燥。得0.06g棕色固体，收率，91.4％。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.32(s,1H,-CONH-),9.87(s,1H,-NHCO-),8.90(s,2H,ArH),8.80(s,1H,ArH),8.13(d,J＝2.0Hz,1H,ArH),8.11(s,1H,-NHAr-),8.03(s,1H,-NOH),7.15(d,J＝8.4Hz,1H,ArH),6.86(dd,J＝8.2,1.9Hz,1H,ArH),6.80(d,J＝8.3Hz,2H,ArH),6.53(d,J＝8.4Hz,2H,ArH),2.72(d,J＝6.8Hz,4H,-NCH2 -),2.12(s,3H,-ArCH3 ),1.71–1.58(m,2H,-CH2CH-),0.82(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.87(s,2H,ArH),8.78(s,1H,ArH),8.07(d,J＝1.9Hz,1H,ArH),7.14(d,J＝8.4Hz,1H,ArH),6.87(dd,J＝8.2,1.9Hz,1H,ArH),6.80(d,J＝8.2Hz,2H,ArH),6.51(d,J＝8.4Hz,2H,ArH),2.69(d,J＝6.8Hz,4H,-NCH2 -),2.10(s,3H,-ArCH3 ),1.66–1.55(m,2H,-CH2CH-),0.79(d,J＝6.6Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.93(s,1H,-NHCO-),10.81(s,1H,-CONH-),9.01(s,2H,ArH),8.86(s,1H,ArH),8.37(s,1H,-NHAr-),8.16(s,1H,ArH),7.23(d,J＝8.4Hz,1H,ArH),7.03(d,J＝8.1Hz,2H,ArH),6.96(d,J＝8.2Hz,1H,ArH),6.89(d,J＝8.1Hz,2H,ArH),2.91(d,J＝6.6Hz,4H,-NCH2 -),2.23(s,3H,-ArCH3 ),1.77–1.63(m,2H,-CH2CH-),0.80(d,J＝6.5Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.95(s,2H,ArH),8.85(s,1H,ArH),8.10(s,1H,ArH),7.24(d,J＝8.4Hz,1H,ArH),7.08–6.94(m,3H,ArH),6.88(d,J＝8.1Hz,2H,ArH),2.86(d,J＝6.7Hz,4H,-NCH2 -),2.21(s,3H,-ArCH3 ),1.73–1.59(m,2H,-CH2CH-),0.77(d,J＝6.5Hz,12H,-CHCH 3).
实施例6
N-(3-溴-4-氟苯基)-3-[3-(嘧啶-5-基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-6)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)]-3-(嘧啶基-5-基)脲(X-6)的合成
将VIII-2(0.47g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌加入5-嘧啶异氰酸酯(0.24g,2mmol)，25℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl溶液洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，二氯甲烷:乙酸乙酯＝10:1，加三乙胺)，得黄色固体0.33g，收率55.1％。1H-NMR(300MHz,DMSO-d6),δ(ppm):9.87(s,1H,-NHCO-),8.89(s,2H,ArH),8.82(s,1H,ArH),8.03(d,J＝2.1Hz,1H,ArH),8.00(s,1H,-CONH-),7.92(dd,J＝6.1,2.1Hz,1H,ArH),7.63–7.48(m,2H,ArH),7.28(d,J＝8.5Hz,1H,ArH),6.97(dd,J＝8.4,2.1Hz,1H,ArH),2.80(d,J＝6.8Hz,4H,-NCH2 -),1.70–1.59(m,2H,-CH2CH-),0.78(d,J＝6.6Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-[3-(嘧啶-5-基)脲基]-4-(二异丁胺)-N'-羟基苯甲脒(I-6)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)]-3-(嘧啶基-5-基)脲(X-6)(0.25g，0.42mmol)溶于3mL DMF中，加氢氧化钠(0.02g,0.50mmol)，1mL水，45℃反应，TLC监测反应，至原料X-6反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。(淋洗剂，二氯甲烷：乙酸乙酯＝10:1，加三乙胺)，得黄色色固体0.16g，收率66.5％。将0.08g游离的I-6溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出黄色固体，抽滤，45℃真空干燥。得0.08g黄色固体，收率94.0％。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.56(s,1H,-CONH-),9.90(s,1H,-NHCO-),8.90(s,2H,ArH),8.80(s,1H,-NHAr-),8.50(s,1H,-NOH),8.13(d,J＝1.8Hz,2H,ArH),7.21(d,J＝8.4Hz,1H,ArH),7.05(t,J＝8.8Hz,1H,ArH),6.91(dd,J＝8.4,1.9Hz,1H,ArH),6.76(dd,J＝6.0,2.5Hz,1H,ArH),6.73–6.63(m,1H,ArH),2.75(d,J＝6.8Hz,4H,-NCH2 -),1.73–1.54(m,2H，-CH2CH-),0.82(d,J＝6.6Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.34(s,1H,-NHCO-),8.97(s,2H,ArH),8.85(s,1H,ArH),8.25(s,1H,-NHAr-),8.14(d,J＝1.6Hz,1H,ArH),7.28(d,J＝8.3Hz,1H,ArH),7.20(t,J＝8.8Hz,1H,ArH),7.13–7.07(m,1H,ArH),7.05–6.91(m,2H,ArH),2.87(d,J＝6.7Hz,4H,-NCH2 -),1.79–1.62(m,2H,-CH2CH-),0.83(d,J＝6.6Hz,12H,-CHCH 3).1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.93(s,2H,ArH),8.84(s,1H,ArH),8.06(d,J＝1.6Hz,1H,ArH),7.27(d,J＝8.3Hz,1H,ArH),7.19(t,J＝8.8Hz,1H,ArH),7.11–6.90(m,3H,ArH),2.83(d,J＝6.7Hz,4H,-NCH2 -),1.74–1.60(m,2H,-CH2CH-),0.80(d,J＝6.5Hz,12H,-CHCH 3).
实施例7
N-(3-溴-4-氟苯基)-3-(3-乙基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-7)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-乙基脲(X-7)的合成
将VIII-2(0.48g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入乙基异氰酸酯(0.21g,3.0mmol)，45℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝3:1)，得黄色固体0.51g，收率92.7％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.16(s,1H,-CONH-),7.86(d,J＝6.1Hz,1H,ArH),7.67–7.49(m,2H,ArH),7.47(s,1H,-CH2NH-),7.29–7.04(m,2H,ArH),6.73(d,J＝8.1Hz,1H,ArH),3.07(p,J＝7.1Hz,2H,-CH2 CH3),2.68(d,J＝6.4Hz,4H,-NCH2 -),1.70-1.46(m,2H,-CH2CH-),1.04(t,J＝7.2Hz,3H,-CH2CH3 ),0.77(d,J＝6.2Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-(3-乙基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-7)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-乙基脲(X-7)(0.41g,0.75mmol)溶于5mL DMF中，加(0.04g,0.90mmol)氢氧化钠，1mL水，45℃反应，TLC监测反应，至原料X-7反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝4:1)，得棕黄色固体0.21g，收率43.8％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.52(s,1H,-CONH-),8.48(s,1H，-NHAr),8.13(d,J＝2.0Hz,1H,ArH),7.60(s,1H,-NOH),7.19–7.10(m,2H,ArH),7.06(t,J＝8.8Hz,1H,ArH),6.81(dd,J＝8.2,2.0Hz,1H,ArH),6.74(dd,J＝6.0,2.6Hz,1H,-CH2NH-),6.72–6.65(m,1H,ArH),3.14–3.01(m,2H,-CH2 NH-),2.65(d,J＝6.9Hz,4H,-NCH2 -),1.69–1.55(m,2H,-CH2CH-),1.04(t,J＝7.2Hz,3H,-CH2CH3 ),0.83(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.03(d,J＝2.0Hz,1H,ArH),7.11(d,J＝8.3Hz,1H,ArH),7.03(t,J＝8.9Hz,ArH),6.79(dd,J＝8.2,2.0Hz,1H,ArH),6.73–6.64(m,2H,ArH),3.04(q,J＝7.2Hz,2H,-CH2 CH3),2.61(d,J＝6.9Hz,4H,-NCH2 -),1.65–1.52(m,2H,-CH2CH-),1.01(t,J＝7.2Hz,3H,-CH2CH3 ),0.78(d,J＝6.6Hz,12H,-CHCH 3).
实施例8
N-(3-溴-4-氟苯基)-3-(3-丙基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-8)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-正丙基脲(X-8)的合成
将VIII-2(0.47g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入正丙基异氰酸酯(0.26g,3mmol)，45℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚乙:酸乙酯＝3:1)，得黄色固体0.42g，收率74.6％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.13(d,J＝2.1Hz,1H,ArH),7.87(dd,J＝6.2,2.2Hz,1H,ArH),7.60–7.53(m,1H,ArH),7.51(s,1H,-NHCO-),7.47(s,1H,-CONH-),7.22–7.11(m,2H,ArH),6.73(dd,J＝8.3,2.1Hz,1H,ArH),3.04-2.98(m,2H,-NHCH2 -),2.68(d,J＝6.9Hz,4H,-NCH2 -),1.65-1.56(m,2H,-CH2 CH3),1.45-1.36(m,2H,-CHCH3),0.85(t,J＝7.4Hz,3H,-CH2CH3 ),0.77(d,J＝6.6Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-(3-丙基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-8)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-正丙基脲(X-8)(0.30g,0.53mmol)溶于5mL DMF中，加氢氧化钠(0.03g,0.6mmol)，1mL水，45℃反应，TLC监测反应，至原料X-8反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝4:1)，得黄色固体0.15g，收率52.7％。将0.07g游离的I-8溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出黄色固体，抽滤，45℃真空干燥。得0.06g黄色固体，收率80.2％，
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.71(s,1H,-CONH-),8.87(s,1H,-NHAr-),8.09(d,J＝2.0Hz,1H,ArH),7.59(s,1H,-NOH),7.13(t,J＝8.0Hz,2H,-CH2NH-,ArH),7.06(d,J＝8.6Hz,1H,ArH),6.90–6.78(m,2H,ArH),6.78–6.70(m,1H,ArH),3.03-2.98(m,2H,-NHCH2 -),2.66(d,J＝6.8Hz,4H,-NCH2 -),1.69–1.52(m,2H,-CH2CH-)),1.47–1.36(m,2H,-CH2 CH3),0.91–0.74(m,15H,-CH2CH3 ,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.99(s,1H,ArH),7.11(t,J＝8.2Hz,1H,ArH),7.04(d,J＝8.9Hz,1H,ArH),6.81(d,J＝8.0Hz,1H,ArH),6.78–6.68(m,2H,ArH),2.98(t,J＝6.7Hz,2H,-NHCH2 -),2.64(d,J＝6.9Hz,4H,-NCH2 -),1.65–1.52(m,2H,-CH2CH-),1.43–1.33(m,2H,-CH2 CH3),0.87–0.73(m,15H,-CH2CH3 ,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.97(br,1H,-CONH-),8.13(s,1H,ArH),7.67(br,1H,-NHAr-),7.36–7.14(m,3H,-CH2NH-,ArH),7.07(dd,J＝5.9,2.4Hz,1H,ArH),7.01–6.84(m,2H,ArH),3.06(t,J＝6.7Hz,2H,-NHCH2 -),2.78(d,J＝5.7Hz,4H,-NCH2 -),1.76–1.59(m,2H,-CH2CH-),1.53–1.41(m,2H,-CH2 CH3),0.90(t,J＝7.3Hz,3H,-CH2CH3 ),0.83(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.02(s,1H,ArH),7.30–7.11(m,2H,ArH),7.05(dd,J＝5.9,2.2Hz,1H,ArH),7.01–6.85(m,2H,ArH),3.04(t,J＝6.9Hz,2H,-NHCH2 -),2.76(d,J＝5.7Hz,4H,-NCH2 -),1.70–1.56(m,2H,-CH2CH-),1.51–1.38(m,2H,-CH2 CH3),0.87(t,J＝7.4Hz,3H,-CH2CH3 ),0.80(d,J＝6.6Hz,12H,-CHCH 3).
实施例9
N-(3-溴-4-氟苯基)-3-(3-正丁基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-9)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-正丁基脲(X-9)的合成
将VIII-2(0.47g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入异氰酸正丁酯(0.29g,3mmol)，45℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝5:1)，得黄色固体0.48g，收率83.2％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.12(d,J＝1.2Hz,1H,ArH),7.86(d,J＝6.0Hz,1H,ArH),7.60–7.49(m,2H,ArH),7.46(s,1H,-NHCO-),7.17(d,J＝8.5Hz,1H,ArH),7.12(s,1H,-CONH-),6.74(d,J＝8.0Hz,1H,ArH),3.07-3.02(m,2H,-NHCH2 -),2.68(d,J＝6.9Hz,4H,-NCH2 -),1.65-1.57(m,2H,-CH2CH-),1.43–1.11(m,4H,-CH2 CH2 -),0.88(t,J＝7.0Hz,3H,-CH2CH3 ),0.77(d,J＝6.6Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-(3-正丁基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-9)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-正丁基脲(X-9)(0.38g,0.53mmol)溶于5mL DMF中，加氢氧化钠(0.03g,0.6mmol)，1mL水，45℃反应，TLC监测反应，至原料X-9反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝4:1)，得黄色固体0.18g，收率53.2％。将0.10g游离的I-9溶于5mL乙酸乙酯，冰浴，滴加HCl的饱和乙酸乙酯溶液，至pH为2，析出黄色固体，抽滤，45℃真空干燥。得0.09g黄色固体，收率82.3％。成盐前m.p.102-104℃，成盐后m.p.118-120℃。
成盐前
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.77(br,1H,-CONH-),8.96(br,1H,-NHAr-),8.08(d,J＝2.1Hz,1H,ArH),7.58(s,1H,-NOH),7.27–7.00(m,3H,-CH2NH-,ArH),6.93–6.67(m,3H,ArH),3.19–2.97(m,2H,-CH2 NH-),2.67(d,J＝6.8Hz,4H,-NCH2 -),1.70–1.53(m,2H,-CH2CH-),1.43–1.20(m,4H,-CH2 CH2 -),0.87(t,J＝7.2Hz,3H,-CH2CH3 ),0.80(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.99(d,J＝1.6Hz,1H,ArH),7.16–7.08(m,1H,ArH),7.05(d,J＝8.1Hz,1H,ArH),6.86–6.73(m,3H,ArH),3.02(t,J＝6.2Hz,2H,-CH2 NH-),2.64(d,J＝6.0Hz,4H-NCH2 -),1.64–1.52(m,2H,-CH2CH-),1.37–1.22(m,4H,-CH2 CH2 -),0.84(t,J＝6.8Hz,3H,-CH2CH3 ),0.77(d,J＝5.6Hz,12H,-CHCH 3).
成盐后
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.50(s,1H,-CONH-),8.45(s,1H,-NHAr-),8.13(d,J＝1.7Hz,1H,ArH),7.61(s,1H,-NOH),7.17(d,J＝8.3Hz,1H,ArH),7.12-7.00(m,2H,ArH),6.86(dd,J＝8.2,1.6Hz,1H,ArH),6.80(dd,J＝5.9,2.7Hz,1H，-CH2NH-),6.76–6.65(m,1H,ArH),3.09(t,J＝6.7Hz,2H,-CH2 NH-),2.69(d,J＝6.8Hz,4H,-NCH2 -),1.71-1.62(m,2H,-CH2CH-),1.43-1.27(m,4H,-CH2 CH2 -),0.92(t,J＝7.1Hz,3H,-CH2CH3 ),0.86(d,J＝6.6Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.04(s,1H,ArH),7.15(d,J＝8.3Hz,1H,ArH),7.09-7.03(m,1H,ArH),6.85(dd,J＝8.1,1.8Hz,1H,ArH),6.74(dd,J＝5.8,2.6Hz,2H,ArH),3.16–3.03(m,2H,-CH2 NH-),2.69(d,J＝6.8Hz,4H,-NCH2 -),1.75-1.59(m,2H,-CH2CH-),1.45–1.25(m,4H,-CH2 CH2 -),0.92(t,J＝7.1Hz,3H,-CH2CH3 ),0.86(d,J＝6.6Hz,12H,-CHCH 3).
实施例10
N-(3-溴-4-氟苯基)-3-(3-环己基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-10)
1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-环己基脲(X-10)的合成
将VIII-2(0.47g,1.0mmol)溶于5mL四氢呋喃中，加三乙胺(0.20g,2.0mmol)，搅拌，加入异氰酸环己酯(0.29g,3mmol)，45℃反应，TLC监测反应，至原料VIII-2反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝5:1)，得黄色固体0.52g，收率86.9％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.06(d,J＝2.1Hz,1H,-CHNH-),7.87(dd,J＝6.3,2.3Hz,1H,ArH),7.59–7.52(m,1H,ArH),7.49(d,J＝9.0Hz,1H,ArH),7.38(s,1H,-CONH-),7.15(d,J＝8.3Hz,1H,ArH),7.03(d,J＝7.4Hz,1H,ArH),6.73(dd,J＝8.3,2.2Hz,1H,ArH),3.46–3.37(m,1H,-CHNH-),2.69(d,J＝6.8Hz,4H,-NCH2 -),1.79(d,J＝10.1Hz,2H,-CHCH3),1.70-1.55(m,4H,-CHCH2 -),1.34–1.07(m,6H,-(CH2 )3),0.76(d,J＝6.5Hz,12H,-CHCH 3).
N-(3-溴-4-氟苯基)-3-(3-环己基脲基)-4-(二异丁胺)-N'-羟基苯甲脒(I-10)的合成
将1-[5-[4-(3-溴-4-氟苯基)-5-氧代4,5-二氢-1,2,4-噁二唑-3-基]-2-(异丁胺基)苯基)-3-环己基脲(X-10)(0.44g,0.73mmol)溶于5mL DMF中，加氢氧化钠(0.08g,2.1mmol)，1mL水，45℃反应，TLC监测反应，至原料X-10反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝5:1)，得棕色固体0.19g，收率45.1％，纯度：96.6％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):10.49(s,1H,-CONH-),8.45(s,1H,-NHAr-),8.01(s,1H,ArH),7.49(s,1H,-NOH),7.15–7.06(m,1H,ArH),7.06–6.93(m,2H,-CHNH-,ArH),6.81(d,J＝8.0Hz,1H,ArH),6.77–6.71(m,1H,ArH),6.71–6.59(m,1H,ArH),3.51–3.35(m,1H,-CHNH-),2.64(d,J＝6.3Hz,4H,-NCH2 -),1.85–1.71(m,2H,-CH2CH-),1.68–1.54(m,4H,-CH2 CH-),1.26–1.08(m,6H,-(CH2 )3-),0.80(d,J＝6.3Hz,12H,-CHCH 3).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.86(d,J＝1.8Hz,1H,ArH),7.08(d,J＝8.3Hz,1H,ArH),7.01(t,J＝8.8Hz,1H,ArH),6.79(dd,J＝8.2,1.7Hz,1H,ArH),6.74–6.66(m,1H,ArH),6.63(dd,J＝6.0,2.6Hz,1H,ArH),3.42–3.29(m,1H,-CHNH-),2.59(d,J＝6.7Hz,4H,-NCH2 -),1.77–1.67(m,2H,-CH2CH-),1.65–1.51(m,4H,-CH2 CH-),1.23–1.02(m,6H,-(CH2 )3-),0.75(d,J＝6.6Hz,12H,-CHCH 3)).
实施例11
N-(3-溴-4-氟苯基)-2-[3-[3-(4-氯苯基)脲基]苯基]--N'-羟基乙酰胺(I-11)
N'-羟基-2-(3-硝基苯基)乙酰胺(III-2)的合成
盐酸羟胺(5.36g,77.1mmol)用15mL水溶解，加入三乙胺(7.79g,77.1mmol)中和，向装有3-硝基苯乙腈(II-2)(5.00g,30.8mmol)的单颈瓶中加入100mL乙醇，搅拌，滴加羟胺，滴完，升温至25℃反应6h,减压蒸除溶剂，加100mL水稀释，超声，析出绿色固体，抽滤，55℃真空干燥，柱层析分离(淋洗剂，二氯甲烷:甲醇＝150:1)，重2.52g，收率41.9％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.00(s,1H,-NOH),8.15(d,J＝1.9Hz,1H,ArH),8.08(dq,J＝8.1,1.1Hz,ArH),7.72(dt,J＝7.6,1.4Hz,1H,ArH),7.58(t,J＝7.9Hz,1H,ArH),5.55(s,2H,-NH2 )3.41(s,2H,-ArCH2 -).
1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):8.12(t,J＝2.2Hz,1H,ArH),8.06(dd,J＝8.1,2.1Hz,1H,ArH),7.70(d,J＝7.6Hz,1H,ArH),7.57(t,J＝7.9Hz,1H,ArH),3.39(s,2H,-ArCH2 -).
N-羟基-2-(3-硝基苯基)乙酰氯(IV-2)的合成
N'-羟基-2-(3-硝基苯基)乙酰胺(III-2)(1.91g,9.7mmol)用6N HCl(50mL)溶解，降温至-5℃，析出白色固体，缓慢滴加Na2NO2(1.80g,19.5mmol)的5mL水溶液，-5℃反应过夜，点板检测反应完全，直接抽滤，用20mL水洗涤，55℃真空干燥，得灰白色固体，重1.51g，收率71.5％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):11.86(s,1H,-NOH),8.22–8.08(m,2H,ArH),7.74(d,J＝7.7Hz,1H,ArH),7.69–7.60(m,1H,ArH),4.03(s,2H,-ArCH2 -).
N-(3-溴-4-氟)-N'-羟基-2-(3-硝基苯基)乙酰胺(VI-3)的合成
N-羟基-2-(3-硝基苯基)乙酰氯(IV-2)(2.10g,9.7mmol)用50mL乙醇溶解，加入3-溴-4氟苯胺(2.23g,11.7mmol)，NaHCO3(2.05g,24.45mmol)的5mL水溶液，25℃搅拌过夜，析出白色固体，抽滤，用20mL水洗涤，55℃真空干燥，得浅黄色固体，重2.61g，收率72.2％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.70(s,1H,-NHAr),8.56(s,1H，-NOH),8.20(s,1H,ArH),8.12–8.05(m,2H,ArH),7.78(d,J＝7.8Hz,1H,ArH),7.61(t,J＝7.9Hz,1H,ArH),7.35–7.27(m,1H,ArH),7.23–7.19(m,1H,ArH),3.89(s,2H,-ArCH2-).
4-(3-溴-4-氟苯基)-3-(3-硝基苄基)1,2,4-噁二唑-5(4H)-酮(VII-3)的合成
N-(3-溴-4-氟)-N'-羟基-2-(3-硝基苯基)乙酰胺(VI-3)(2.60g,7.0mmol)用80mL乙酸乙酯溶解，加入CDI(1.72g,10.6mmol)，室温搅拌，点板检测反应完全，用1N HCl洗涤(2×100mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体，乙醇重结晶纯化，得黄色固体2.49g，收率89.8％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.09(d,J＝7.1Hz,1H,ArH),7.97(s,1H,ArH),7.86(d,J＝5.9Hz,1H,ArH),7.71–7.37(m,4H,ArH),4.10(s,2H,-ArCH2-).
4-(3-溴-4-氟苯基)-3-(3-氨基苄基)1,2,4-噁二唑-5(4H)-酮(VIII-3)的合成
将4-(3-溴-4-氟苯基)-3-(3-硝基苄基)1,2,4-噁二唑-5(4H)-酮(VII-3)(5.02g，0.013mmol)溶于100mL无水乙醇中，加二水合氯化亚锡(14.31g,0.063mmol)，25℃反应过夜，TLC监测反应，至原料VII-3反应完全，结束反应。加400mL水稀释，抽滤，除去絮状物，用DCM(3×150mL)萃取，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色油状物，乙醇重结晶得白色固体3.41g，收率72.02％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):7.78(d,J＝5.5Hz,1H,ArH),7.47(d,J＝6.6Hz,2H,ArH),6.82(t,J＝7.7Hz,1H,ArH),6.37(d,J＝7.9Hz,1H,ArH),6.26(s,1H,ArH),6.07(d,J＝7.2Hz,1H,ArH),5.05(s,2H,-NH2 ),3.72(s,2H,-ArCH2-).
1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-(4-氯苯基)脲(X-11)的合成
将4-(3-溴-4-氟苯基)-3-(3-氨基苄基)1,2,4-噁二唑-5(4H)-酮(VIII-3)(0.50g,1.4mmol)溶于5mL四氢呋喃中，加三乙胺(0.21g,2.1mmol)，搅拌，加入4-氯苯基异氰酸酯(0.63g,4.1mmol)，25℃反应，TLC监测反应，至原料VIII-3反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝4:1)，得黄色固体0.45g，收率65.4％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):8.76(s,1H,-NHCO-),8.65(s,1H,-CONH-),7.80(dd,J＝6.7,1.8Hz,1H,ArH),7.55–7.42(m,4H,ArH),7.37–7.27(m,2H,ArH),7.27–7.18(m,2H,ArH),7.17–7.05(m,1H,ArH),6.63(d,J＝7.7Hz,1H,ArH),3.88(s,2H,-ArCH2 -).
N-(3-溴-4-氟苯基)-2-[3-[3-(4-氯苯基)脲基]苯基]--N'-羟基乙酰胺(I-11)的合成
将1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-(4-氯苯基)脲(X-11)(0.35g,0.68mmol)溶于5mL DMF中，加氢氧化锂(0.02g,1.0mmol)，1mL水，25℃反应，TLC监测反应，至原料X-11反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝3:1)，得白色固体0.11g，收率32.9％。
1H NMR(300MHz,DMSO-d6)δ9.49(s,1H,HO-N＝C-),8.70(s,1H,-NHCO-),8.65(s,1H,-CONH-),8.40(s,1H,-N＝C-NH-),8.12(dd,J＝6.3,2.8Hz,1H,ArH),7.49–7.41(m,2H,ArH),7.38–7.27(m,4H,ArH),7.24–7.14(m,3H,ArH),6.94(d,J＝8.0Hz,1H,ArH),3.72(s,2H,-CH2-).
实施例12
N-(3-溴-4-氟苯基)-2-[3-[3-(4-嘧啶基)脲基]苯基]--N'-羟基乙酰胺(I-2)
1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-嘧啶基脲(X-12)的合成
将VIII-3(0.50g,1.4mmol)溶于5mL四氢呋喃中，加三乙胺(0.21g,2.1mmol)，搅拌，加入5-嘧啶异氰酸酯(0.50g,4.1mmol)，25℃反应，TLC监测反应，至原料VIII-3反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得绿色油状物。柱层析分离(淋洗剂，二氯甲烷:甲醇＝60:1)，得淡绿色固体0.38g，收率55.9％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.64(s,1H,-NHCO-),9.40(s,1H,-CONH-),8.88(s,2H,ArH),8.78(s,1H,ArH),7.83(dd,J＝6.2,1.8Hz,1H,ArH),7.57–7.47(m,2H,ArH),7.29–7.21(m,2H,ArH),7.17–7.07(m,1H,ArH),6.67(d,J＝7.5Hz,1H,ArH),3.88(s,2H,-ArCH2 -).
N-(3-溴-4-氟苯基)-2-[3-[3-(4-嘧啶基)脲基]苯基]--N'-羟基乙酰胺(I-12)的合成
将1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-嘧啶基脲(X-12)(0.30g,0.62mmol)溶于5mL DMF中，加氢氧化锂(0.02g,0.93mmol)，1mL水，25℃反应，TLC监测反应，至原料X-12反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，二氯甲烷:甲醇＝30:1，加三乙胺)，得白色固体0.15g，收率52.6％。
1H NMR(300MHz,DMSO-d6)δ9.51(s,1H,HO-N＝C-),8.97(s,1H,-CONH-),8.91(s,1H,-CONH-),8.89(s,2H,ArH),8.79(s,1H,ArH),8.42(s,1H,-N＝C-NH-),8.13(dd,J＝6.3,2.5Hz,1H,ArH),7.42–7.29(m,3H,ArH),7.20(d,J＝8.9Hz,2H,ArH),6.98(d,J＝7.3Hz,1H,ArH),3.74(s,2H,-CH2-).
实施例13
N-(3-溴-4-氟苯基)-2-[3-[3-(4-三氟甲基苯基)脲基]苯基]--N'-羟基乙酰胺(I-13)
1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-[4-(三氟甲基)苯基]脲(X-13)的合成
将VIII-3(0.50g,1.4mmol)溶于5mL四氢呋喃中，加三乙胺(0.21g,2.1mmol)，搅拌，加入对三氟甲基异氰酸酯(0.38g,2.1mmol)，25℃反应，TLC监测反应，至原料VIII-3反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝4:1)，得白色固体0.37g，收率47.9％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.08(s,1H,-NHCO-),8.78(s,1H,-CONH-),,7.81(dd,J＝6.4,2.0Hz,1H,ArH),7.72–7.57(m,4H,ArH),7.56–7.44(m,2H,ArH),7.29–7.19(m,2H,ArH),7.13(t,J＝8.1Hz,1H,ArH),6.65(d,J＝7.4Hz,1H,ArH),3.89(s,2H,-ArCH2 -).
N-(3-溴-4-氟苯基)-2-[3-[3-(4-三氟甲基苯基)脲基]苯基]--N'-羟基乙酰胺(I-13)的合成
将1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-[4-(三氟甲基)苯基]脲(X-13)(0.30g,0.54mmol)溶于5mL DMF中，加氢氧化锂(0.02g,0.82mmol)，1mL水，25℃反应，TLC监测反应，至原料X-13反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝3:1)，得白色固体0.16g，收率56.4％。
1H NMR(300MHz,DMSO-d6)δ9.50(s,1H,HO-N＝C-),9.04(s,1H,-NHCO-),8.80(s,1H,-CONH-),8.42(s,1H,-N＝C-NH-),8.13(dd,J＝6.4,2.6Hz,1H,ArH),7.68–7.56(m,4H,ArH),7.37–7.30(m,2H,ArH),7.26–7.15(m,3H,ArH),6.96(d,J＝7.7Hz,1H,ArH),3.73(s,2H,-CH 2-)..
实施例14
N-(3-溴-4-氟苯基)-2-[3-(3-丙基脲基)苯基]--N'-羟基乙酰胺(I-14)
1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-丙基脲(X-14)的合成
将VIII-3(0.50g,1.4mmol)溶于5mL四氢呋喃中，加三乙胺(0.21g,2.1mmol)，搅拌，加入正丙基异氰酸酯(0.35g,4.1mmol)，25℃反应，TLC监测反应，至原料VIII-3反应完全，结束反应。50℃减压蒸除四氢呋喃，加水稀释，用乙酸乙酯萃取(3×10mL)，饱和NaCl洗两次，无水Na2SO4干燥保存过夜，减压蒸除溶剂得黄色固体。柱层析分离(淋洗剂，石油醚:乙酸乙酯＝4:1)，得白色固体0.35g，收率55.6％。
1H-NMR(300MHz,DMSO-d6),δ(ppm):9.09(s,1H,-CONH-),7.81(dd,J＝6.2,1.9Hz,1H,ArH),7.59–7.45(m,2H,ArH),7.19(d,J＝7.2Hz,2H,ArH),7.05–6.97(m,1H,ArH),6.71–6.62(m,1H,-CH2NH-),6.48(d,J＝7.9Hz,1H,ArH),3.82(s,2H,-ArCH2 -),3.03-2.97(m,2H,-NHCH2 -),1.44-1.35(m,2H,-CH2 CH3),0.86(t,J＝7.5Hz,3H,-CH2CH3 ).
N-(3-溴-4-氟苯基)-2-[3-(3-丙基脲基)苯基]--N'-羟基乙酰胺(I-14)的合成
将1-[3-[[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]甲基苯基]苯基]-3-丙基脲(X-14)(0.30g,0.67mmol)溶于5mL DMF中，加氢氧化锂(0.02g,1.0mmol)，1mL水，25℃反应，TLC监测反应，至原料X-14反应完全，结束反应。加25mL水析出固体，抽滤，45℃真空干燥。柱层析分离纯化(淋洗剂，石油醚:乙酸乙酯＝3:1)，得黄色固体0.25g，收率88.2％。
1H NMR(500MHz,DMSO-d6)δ(ppm):9.46(s,1H,HO-N＝C-),8.37(s,1H,-N＝C-NH-),8.32(s,1H,-CO-NH-Ar),8.12(dd,J＝6.4,2.7Hz,1H,ArH),7.36–7.30(m,2H,ArH),7.23(s,1H,ArH),7.19(t,J＝8.8Hz,1H,ArH),7.12–7.09(m,1H,ArH),6.85(d,J＝7.5Hz,1H,ArH),6.04(t,J＝6.0Hz,1H,-CH2NH-),3.70(s,2H,ArCH2 -),3.02(q,J＝6.6Hz,2H,-NHCH2 -),1.47–1.38(m,2H,-CH2 CH3),0.86(t,J＝7.4Hz,3H,-CH2CH3 ).
本发明部分化合物的药理学实验及结果如下：
1)检测部分目标化合物在酶水平抑制IDO1的活性
实验试剂：IDO 1(NOVUS BioscienceInc.#H00003620-P01)
实验方法：1μM用大肠杆菌表达的全长人重组IDO1蛋白(rhIDO1)与测试化合物或DMSO在50mM磷酸钾缓冲液(pH6.5)中37℃下预孵育40min后加入反应体系：10mM抗坏血酸，10μM亚甲基蓝，2mM L-Trp和100μg/mL过氧化氢酶。37℃孵育60min后，立刻加入TCA(终浓度为7％)。37℃孵育30min后，加入等体积2％((w/v))的Ehrlich试剂的乙酸溶液。避光振摇10min，在492nM测定吸光度。酶活性百分率(％)＝(OD值给药孔－OD值本底)/(OD值对照孔－OD值本底)×100％，然后用Prism GraphPad软件拟合计算IC50值。
2)检测部分目标化合物对HeLa细胞的抑制活性
实验试剂：HeLa细胞、胎牛血清(Sciencell)、DMEM培养基。
实验方法：按每孔5×103个细胞的密度将HeLa细胞接种在96孔培养板中，贴壁后弃旧培养基，先加入IFN-γ(100ng/mL),后加入L-Trp(15μg/mL)、受试化合物至200μL体系，培养48小时。收集上清液(140μL)，加入6.1mmol/L三氯乙酸(10μL)，50℃孵育30min，4000rpm离心20min。取上清液(100μL)转移至另一96孔板，避光条件下与等体积2％(w/v)对二甲氨基苯甲醛的醋酸溶液混合。多功能酶标仪测定492nm下吸光度，用Prism GraphPad进行非线性回归分析。抑制率(％)＝(OD对照-OD给药)/OD对照×100％，并计算IC50。
3)实验结果见表1
表1.部分目标化合物对IDO1和HeLa细胞的抑制活性IC50
Claims (10)
1.一类通式(I)的化合物或其药学上可接受的盐：
其中：
n＝0、1或2；
R代表氢、C1-C6烷基、C3-C6环烷基、任意取代的苯环或芳杂环，所述芳杂环是六元或五元芳杂环，所述取代基是卤素、C1～C3的烷基、烷氧基或卤代烷基；
R1、R2代表氢、卤素、C1～C3的烷基、烷氧基、卤代烷基、氰基、OH、NO2、或NR4R5，其中R4、R5代表氢或C1～C6烷基；
R3代表氢、卤素、C1～C3的烷基、烷氧基、卤代烷基、氰基或NR6R7，其中R6、R7代表氢或C1～C6烷基。
2.根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐，其特征在于：n＝0或1；R代表C1-C6烷基、C3-C6环烷基、任意取代的苯环或芳杂环，所述芳杂环是六元或五元芳杂环，所述取代基是卤素、C1～C3的烷基或卤代烷基；
R1、R2代表氢、卤素或C1～C3的烷基；
R3代表氢或NR6R7，其中R6、R7代表氢或C1～C6烷基。
3.权利要求2的化合物或其药学上可接受的盐，其特征在于：n＝1；R代表任意取代的苯环或嘧啶环，所述取代基是F、Cl、Br、CH3或CF3；R1、R2代表氢、F、Cl、Br、I、CH3或C2H5；R3代表NR6R7，其中R6、R7代表异丁基。
4.根据权利要求2的化合物或其药学上可接受的盐，其特征在于n＝1，R代表任意取代的苯环或嘧啶环，所述取代基是F、Cl、Br、CH3或CF3；R1、R2代表氢、F、Br、或CH3；R3代表NR6R7，其中R6、R7代表氢或异丁基。
5.根据权利要求2的化合物或其药学上可接受的盐，其特征在于：所述通式(I)的化合物选自以下任意一种化合物：
6.根据权利要求1～5中任一项的化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐为权利要求1～5中任一项的化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
7.一种权利要求1所述通式(I)的化合物的制备方法，其特征在于，所述化合物的合成路线如下：
8.一种药物组合物，其特征在于，含有权利要求1～5中任何一项的化合物或其药学上可接受的盐，及药学上可接受的载体。
9.一种权利要求1～5中任何一项的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备IDO1抑制剂药物中的用途。
10.一种权利要求1～5中任一项的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备抗肿瘤药物中的应用。
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| CN101212967A (zh) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | 吲哚胺2,3-双加氧酶调节剂及其用法 |
| CN106866571A (zh) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | 杂环脲类化合物及其药物组合物和应用 |
| WO2018044663A1 (en) * | 2016-08-29 | 2018-03-08 | Merck Sharp & Dohme Corp. | Novel substituted n'-hydroxycarbamimidoyl-1,2,5-oxadiazole compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
| CN111909107A (zh) * | 2019-05-10 | 2020-11-10 | 中国药科大学 | Ido/hdac双重抑制剂及其药物组合物和应用 |
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| CN101212967A (zh) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | 吲哚胺2,3-双加氧酶调节剂及其用法 |
| WO2018044663A1 (en) * | 2016-08-29 | 2018-03-08 | Merck Sharp & Dohme Corp. | Novel substituted n'-hydroxycarbamimidoyl-1,2,5-oxadiazole compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
| CN106866571A (zh) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | 杂环脲类化合物及其药物组合物和应用 |
| CN111909107A (zh) * | 2019-05-10 | 2020-11-10 | 中国药科大学 | Ido/hdac双重抑制剂及其药物组合物和应用 |
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