CN103304555B - 一组苯-噁唑基衍生物及其制备方法和作为impdh抑制剂的相关应用 - Google Patents
一组苯-噁唑基衍生物及其制备方法和作为impdh抑制剂的相关应用 Download PDFInfo
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- CN103304555B CN103304555B CN201310065438.3A CN201310065438A CN103304555B CN 103304555 B CN103304555 B CN 103304555B CN 201310065438 A CN201310065438 A CN 201310065438A CN 103304555 B CN103304555 B CN 103304555B
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Abstract
本发明关于一组具有通式(I)的苯-噁唑基衍生物及其制备方法和作为IMPDH（次黄嘌呤核苷酸脱氢酶）抑制剂的相关应用。IMPDH抑制剂在免疫抑制、抗肿瘤、抗病毒、抗菌及抗寄生虫等方面均有良好的应用前景，本发明通过对以IMPDH为靶点的活性化合物的设计、合成与活性筛选研究，获得式（I）所示的一类新结构的IMPDH抑制剂，为该类化合物作为抗病毒、抗肿瘤、免疫抑制等相关作用的药物及其药用组合物的开发应用奠定了基础。
Description
优先权声明
本申请案要求申请日为2012年3月8日，申请号为201210060269.X，发明名称为“一组苯-噁唑基衍生物及其制备方法和作为IMPDH抑制剂的相关应用”的中国临时专利申请案的优先权，其说明书是以引用的方式全部并入本文中。
技术领域
本发明涉及一组苯-噁唑基衍生物及其制备方法，还涉及该苯-噁唑基衍生物作为次黄嘌呤核苷酸脱氢酶（IMPDH）抑制剂的相关应用，属于生物医药领域。
背景技术
次黄嘌呤核苷酸脱氢酶(inosinemonophosphatedehydrogenase，IMPDH)是嘌呤核苷酸生物合成的关键酶，依赖烟酰胺腺嘌呤二核苷酸(NAD)，催化鸟嘌呤核苷酸从头合成的限速步骤，将次黄嘌呤核苷酸(IMP)氧化为黄嘌呤核苷酸(XMP)。XMP随后被GMP合成酶作用转化为GMP。这是细胞生长和增殖的关键。除了少数原生动物寄生虫外，IMPDH/GMP在每一个生物体内存在。抑制IMPDH将导致抑制增殖和很多重要的胞内反应。人的IMPDH包括两种，I型(hIMPDH1)和II型(hIMPDH2)，具有84%的同源性。研究表明，hIMPDH2在增殖细胞内选择性上调，在激活的外周淋巴细胞中显著表达；在多数静态细胞中hIMPDH1表达占主导，hIMPDH1也被证明在血管生成中发挥关键作用。因此，IMPDH成为发现抗病毒、抗癌、免疫抑制等药物的重要靶点。
IMPDH抑制剂基于其结合活性中心可分为IMP点位和NAD点位两类。所有抑制作用的机制是通过阻断或通过IMP和NAD的点位构像改变，可以干扰甚至终止底物活性过程。
可逆的和不可逆的IMP点位抑制剂中包括一些化合物及其单磷酸物，如利巴韦林(HagerPW,BiochemPharmacol1995;49(9):1323-1329),3-脱氮鸟苷(3-deazaguanosine)(CookPD,JAmChemSoc1976,98(6):1492-1498.;StreeterDG,BiochemPharmacol1976,25(21):2413–2415.),咪唑立宾(mizoribine)(HagerPW,BiochemPharmacol1995;49(9):1323–132;KerrKM,Biochemistry1997,36(43):13365–13373.),6-氯嘌呤核苷(6-chloropurineriboside)(AntoninoLC,Biochemistry1994,33(7):1760–1765.)和2-乙烯肌苷(2-vinylinosines)(PalS,BioorgMedChem2002,10(11):3615–3618.;NairV,ClinMicrobiolRev2001,14(2):382–397.)等。利巴韦林已用于治疗呼吸道合胞病毒感染，与α-干扰素合用治疗丙肝。咪唑立宾已被用于批准器官移植排斥、类风湿关节炎、原发性肾病综合征、狼疮性肾炎、皮肌炎和自身免疫性皮肤病。与IMPDH复合物X射线晶体结构表明，6-氯嘌呤核苷磷酸或2-乙烯肌苷磷酸，均表现抑制剂与酶Cys331共价键的形成。
以靶点为NAD结合点位的抑制剂,如噻唑羧胺核苷(tiazofurin)(DeClercqE.ClinMicrobiolRev2001,14(2):382–397.;MinakawaN,CurrMedChem1999;6(7):615–628.)是NAD+的非竞争性IMPDH抑制剂，具有抗增殖和抗病毒活性，它的硒类似物显示体内外抗肿瘤活性。硒唑核苷(selenazole-nucleoside)(JayaramHN,BiochemPharmacol1983;32(17):2633–2636.;StreeterDG,BiochemlBiophysResCommun1983,115(2):544–550.)体外有抗DNA和RNA病毒活性。苯甲酰胺核苷通过其活性代谢物酰胺腺嘌呤二核苷酸显示其抑制活性，与IMPDH催化过程的NAD+竞争。
霉酚酸(Mycophenolicacid，MPA)不需要激活且适合在NAD结合位点的烟酰胺端。通过基于MPA等结合模式的结构基础的药物设计，已经得到了系列IMPDH抑制剂，如通过脲类连接的化合物VX-497(Merimepodib)，VX-148和AVN944等(LizbethHedstrom.Chem.Rev.2009,109,2903–2928)，进一步结构修改产生了含有噁唑吲哚、氰基吲哚、吡啶吲哚、异喹啉和吖啶酮等结构类型的IMPDH抑制剂。
MPA能够诱导淋巴细胞坏死，抑制肿瘤细胞生长。一系列霉酚酸腺嘌呤核苷酸，显示了更强的抗白血病效果和诱导细胞分化的能力，是有前景的治疗慢性粒细胞白血病的候选药物(SonjaBBraun-Sand,FutureMed.Chem.2010,2(1):81-92;RejmanD,JMedChem,2006,49(16):5018-5022.)。SAHA(Suberoylanilidehydroxamicacid)能够同时抑制IMPDH和HDAC，用于治疗皮肤T细胞淋巴瘤(LiqiangChen,JMedChem,2007,50,6685-6691)。AVN944是特异性的非竞争性IMPDH抑制剂，有望成为有前景的前列腺癌治疗药物。AVN944与吉西他滨合用用于胰腺癌的治疗已进入临床试验(FlorykD,IntJCancer,2008,123(10):2294-2302.)。
VX-497是一个抗病毒候选化合物，在对乙型肝炎病毒、人巨细胞病毒、呼吸道合胞病毒、1-型单纯疱疹病毒、脑心肌炎病毒、委内瑞拉马脑脊髓炎病毒的体外细胞实验中，VX-497的抗病毒活性均强于利巴韦林。VX-497与干扰素合用的实验中，也显示出比利巴韦林与干扰素合用更好的效果，其对丙肝的治疗作用已进入二期临床试验(MarklandW,AntimicrobAgentsChemother2000,44,(4)859–866)。
IMPDH抑制剂还应用于免疫抑制、抗菌和抗寄生虫药物的研究。MPA的前药霉酚酸酯应用于实体器官的移植。VX-497、VX-148等还用于免疫抑制疾病的治疗研究，有希望成为理想的侯选药物。
在以IMPDH为靶点的药物研究中，本发明证实，一系列新的具有苯-噁唑基的衍生物具有很强的IMPDH抑制活性，并显示有抗病毒(COX-B3)作用、抗肿瘤作用(肝癌细胞、人肺腺癌细胞)作用和免疫抑制作用。本发明所述化合物及其作用，迄今为止未见有国内外相关文献的报道。发展针对IMPDH的新药物将为临床提供更有效的新型抗病毒、抗癌和免疫抑制等治疗药物。
发明内容
本发明的目的是提供一组苯-噁唑基衍生物及其制备方法和作为次黄嘌呤核苷酸脱氢酶（IMPDH）抑制剂的相关应用。
为达到上述目的，本发明采用如下技术方案来实现：
一组苯-噁唑基衍生物或其药学上可接受的盐，具有通式(I)所示的结构：
式中：
R1代表：氢、卤素、羟基、C1-C3烷基、C1-C3烷氧基；
R2代表：氢、取代或未取代的C1-C12饱和或不饱和烃基、羰基或磺酰基，或不存在；
R代表：氢、氰基、取代或未取代的C1-C12饱和或不饱和烃基、C1-C12烷氧基或芳基氧基、C1-C12烷硫基或芳基巯基、氨基、取代的氨基、磺酸基、磺酰基、取代或未取代的单环至三环的芳香基、取代或未取代的杂环基；
所述的杂环基选自五到六元单环杂环基、五到六元环的双环杂环基或三环杂环基；
所述的杂环基中含有1-3个杂原子；
所述的杂原子是N、O、S；
j=0-1，m=0-3，n=0-6，j，m和n可相同也可以不同。
其中，所述的五元单环杂环基选自取代或不取代的噻吩基、呋喃基、吡咯基、异噁唑基、噻唑基、咪唑基、吡唑基或三唑基。
其中，所述的六元单环杂环基选自取代或不取代的哌啶基、吡啶基、吡喃基、哒嗪基、嘧啶基或吡嗪基。
其中，所述的双环杂环基选自取代或不取代的吲哚基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并吡喃基、硫苯并吡喃基、喹啉基、噌啉基、吲唑基、苯并噁二唑基或苯并噻二唑基。
其中，所述的三环杂环基选自取代或不取代的二苯并呋喃基、二苯并噻吩基、吖啶基或吩噻嗪基。
制备通式(I)化合物的方法，按以下反应方程式进行：
将化合物A与化合物B混合溶解于溶剂中，二者反应后再与化合物R2X反应，得到通式(I)化合物。
其中，R1，R2，R，j，m，n的定义如前，
M，X代表醛基、卤素、酰基。
苯-噁唑基衍生物在药学上可接受的盐，由所述通式(I)化合物与酸成盐，所述的酸选自无机酸或有机酸。所述无机酸优选盐酸、氢溴酸或硫酸；所述有机酸优选乙酸、三氟乙酸、乳酸、琥珀酸、富马酸、马来酸、柠檬酸、苯甲酸、甲磺酸或对甲苯磺酸。
一种药物组合物，由治疗有效量的通式(I)化合物或其药学上可接受的盐为活性成分，与一种或多种药学上可接受的载体所组成。
苯-噁唑基衍生物或其药学上可接受的盐在制备作为IMPDH抑制剂的药物中的应用，包括作为抗病毒药物、抗肿瘤药物或免疫抑制药物等。
一种药物组合物在制备作为IMPDH抑制剂的药物中的应用，包括作为抗病毒药物、抗肿瘤药物或免疫抑制药物等。
本发明采用上述技术方案，具有以下优点：
本发明通过对通式（I）所示的苯-噁唑基衍生物的设计、合成与构效关系研究，获得一类新结构的IMPDH抑制剂，为该类化合物作为抗病毒、抗肿瘤、免疫抑制等相关作用的药物及其药用组合物的开发应用奠定了基础。
具体实施方式
本发明的苯-噁唑基的衍生物及可药用盐可以根据目的物中R、R1和R2的结构设计来确定起始物和反应物，例如当R2不存在时，以目标产物是（噻吩-2-亚甲胺基）-3-甲氧基-4-(噁唑-5-基)-苯为例，具体的反应步骤如下：
3-甲氧基-4-(噁唑-5-基)苯胺(化合物A)溶解于无水乙醇中，加入2-噻吩甲醛(化合物B)，室温搅拌，至原料3-甲氧基-4-(噁唑-5-基)苯胺消失，得到产物席佛碱，用结晶法或层析法分离纯化。
当R2存在时，以目标产物是N-甲基-N-(5-甲基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺为例，具体步骤如下：
3-甲氧基-4-(噁唑-5-基)苯胺(化合物A)与5-甲基噻吩-3-甲醛(化合物B)混合溶解于乙醇中，室温搅拌至原料消失，制备中间产物席佛碱，将上述反应液温度降至0-10℃，缓慢加入还原剂(如NaBH4),至中间体席佛碱消失后，分离产物；再用丙酮溶解，无水K2CO3存在下,搅拌，缓慢加入碘甲烷（化合物R2X），原料消失后，产物用结晶法或层析法分离纯化。
以上两种合成步骤所代表的反应方程式如下：
其中，M，X，R，R1，R2及j,m和n同前。
上述过程中，起始原料3-甲氧基-4-(噁唑-5-基)苯胺、2-噻吩甲醛、5-甲基噻吩-3-甲醛等可以购买或由已知方法制备。
本发明从大量候选化合物筛选出所定义的苯-噁唑基的衍生物，其非限定性的结构示例可以是表1中的发明化合物：
表1部分发明化合物的结构
本发明另一方面还提供了一种抗病毒、抗肿瘤药物组合物，其包括治疗有效量的上述苯-噁唑基的衍生物或其药用盐及药学上可接受的药用辅料，可将化合物本身或其与药用赋形剂、稀释剂等混合物以片剂、胶囊、颗粒剂、散剂或糖浆剂的形式口服给药，或以注射剂的形式非口服给药。
上述制剂可通过常规制药方法制备。可用的药用辅剂的例子包括赋形剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羟甲基纤维素、羟甲基纤维素钙、羟甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝、磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)；粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)；崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)；润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)；矫味剂(例如常用的甜味剂、酸味剂和香料等)；稀释剂和注射液溶剂(例如水、乙醇和甘油等)。
本发明还提供了所述化合物的生物活性实验研究。发明化合物的IMPDH抑制活性进行了测定(表2)；还进行了部分化合物小鼠脾细胞增殖抑制活性检测，其中化合物63的IC50值为2.22μg/mL。
表2化合物对IMPDH抑制活性
| 编号 | 抑制率（%）10μg/mL |
| 1 | 65.7 |
| 2 | 68.7 |
| 4 | 74.9 |
| 5 | 58.9 |
| 9 | 38.1 |
| 11 | 69.6 |
| 20 | 47.7 |
| 42 | 60.7 |
| 53 | 39.2 |
| 56 | 37.4 |
| 57 | 45.1 |
| 61 | 73.7 |
| 65 | 32.0 |
根据以IMPDH为靶点的抗病毒药物研究进展，IMPDH抑制剂具有广谱抗病毒作用，对乙型肝炎病毒、丙型肝炎病毒、流感病毒、人巨细胞病毒、呼吸道合胞病毒、1-型单纯疱疹病毒、脑心肌炎病毒、委内瑞拉马脑脊髓炎病毒等多种病毒具有强抑制作用。化合物4在2215细胞株作为体外抗乙型肝炎病毒的实验模型中的TC50（半数有毒浓度）、IC50（对病毒半数抑制浓度）和SI（选择指数，SI=TC50/IC50）分别是100μg/mL、2.72μg/mL和36.76；并且对乙肝病毒A64(拉米夫定耐药)的TC50、IC50和SI分别是>50μg/mL、1.78μg/mL和>28.08。
以Vero(非洲绿猴肾)细胞为病毒宿主，测定了本发明化合物抑制柯萨奇病毒B3(COX-B3)、B6（COX-B6）型引起Vero细胞病变程度。发明化合物的抑制病毒活性测定结果见表3和表4;RBV:对照药利巴韦林。所测化合物抑制柯萨奇病毒B3、B6的活性均很强，活性较对照药利巴韦林强。
表3化合物抗柯萨奇病毒B3型(COX-B3)活性
| 编号 | IC50 | 编号 | IC50 | 编号 | IC50 | 编号 | IC50 |
| 1 | 0.44 | 28 | 1.23 | 55 | 1.88 | 82 | 0.33 |
| 2 | 0.23 | 29 | 10.68 | 56 | 5.75 | 83 | 0.42 |
| 3 | 0.35 | 30 | 0.54 | 57 | 2.47 | 84 | 0.34 |
| 4 | 0.44 | 31 | 0.88 | 58 | 3.22 | 85 | 0.44 |
| 5 | 0.47 | 32 | 0.68 | 59 | 1.90 | 86 | 0.34 |
| 6 | 0.47 | 33 | 0.64 | 60 | 0.57 | 87 | 0.35 |
| 7 | >66.67 | 34 | 0.57 | 61 | 0.64 | 88 | 0.36 |
| 8 | 0.45 | 35 | 0.57 | 62 | 0.63 | 89 | 0.26 |
| 9 | 12.83 | 36 | 0.59 | 63 | 0.47 | 90 | 0.26 |
| 10 | 0.27 | 37 | 0.63 | 64 | 4.28 | 91 | 0.28 |
| 11 | 0.44 | 38 | 0.88 | 65 | 1.23 | 92 | 0.63 |
| 12 | 0.23 | 39 | 11.12 | 66 | 1.43 | 93 | 0.88 |
| 13 | 0.30 | 40 | 0.26 | 67 | 1.88 | 94 | 0.68 |
| 14 | 0.44 | 41 | 0.63 | 68 | 1.53 | 95 | 0.55 |
| 15 | 0.46 | 42 | 1.43 | 69 | 0.98 | 96 | 1.43 |
| 16 | 0.45 | 43 | 1.03 | 70 | 155.21 | 97 | 0.23 |
| 17 | 2.56 | 44 | 0.69 | 71 | 1.25 | 98 | 0.88 |
| 18 | 0.25 | 45 | 0.88 | 72 | 0.44 | 99 | 0.78 |
| 19 | 12.83 | 46 | 0.76 | 73 | 0.35 | 100 | 0.46 |
| 20 | 0.64 | 47 | 0.56 | 74 | 0.63 | 101 | 0.48 |
| 21 | 2.47 | 48 | 0.50 | 75 | 0.45 | 102 | 0.35 |
| 22 | 0.82 | 49 | 0.82 | 76 | 0.24 | 103 | 0.40 |
| 23 | 0.76 | 50 | 0.46 | 77 | 0.35 | 104 | 0.45 |
| 24 | 0.57 | 51 | 2.47 | 78 | 0.36 | 105 | 1.23 |
| 25 | 0.53 | 52 | 3.25 | 79 | 0.35 | 106 | 0.44 |
| 26 | 0.57 | 53 | >2.47 | 80 | 0.24 | ||
| 27 | 1.47 | 54 | 1.43 | 81 | 0.29 | RBV | 222.22 |
注：IC50:μg/mL。
表4化合物抗柯萨奇病毒B6型(COX-B6)活性
| 编号 | IC50 | 编号 | IC50 | 编号 | IC50 | 编号 | IC50 |
| 1 | 0.44 | 10 | 0.36 | 52 | >2.47 | 61 | 1.06 |
| 2 | 0.63 | 11 | 1.33 | 53 | 7.41 | 62 | 1.43 |
| 3 | 1.43 | 20 | 0.82 | 54 | 3.18 | 63 | 2.47 |
| 4 | 0.27 | 21 | 3.25 | 55 | 3.25 | 64 | 17.24 |
| 5 | 0.44 | 22 | 3.83 | 56 | 4.28 | 65 | 5.75 |
| 6 | 0.27 | 41 | 1.88 | 57 | 1.88 | 66 | 4.28 |
| 7 | 18.50 | 42 | 1.93 | 59 | 1.05 | 68 | 7.41 |
| 9 | 12.83 | 49 | 1.53 | 60 | 3.15 | 71 | >0.82 |
| RBV | 222.22 |
注：IC50:μg/mL。
发明化合物对HCV、流感等也呈现强抑制活性。
IMPDH是嘌呤生物合成的关键酶，它将次黄嘌呤核苷酸IMP氧化为黄嘌呤核苷酸XMP，然后，XMP在GMP合成酶的催化下生成GMP。鸟嘌呤核苷酸对于DNA和RNA的合成是重要的酶底物，在细胞的生长分化、凋亡及在细胞信号传导中具有重要作用。抑制IMPDH将导致鸟嘌呤核苷酸缺乏，DNA合成受阻，使细胞静止于G1期，IMPDH的催化反应与细胞增殖有密切关系。因此，IMPDH抑制剂具有广谱抗肿瘤活性。
根据以IMPDH为靶点的抗肿瘤药物研究进展，本发明采用人肝癌细胞HepG2，测定了发明化合物的抑制人肝癌细胞HepG2活性；采用人肺腺癌细胞A549，测定了发明化合物对人肺腺癌细胞A549抑制作用，测定结果见表5：
表5化合物对肿瘤细胞的抑制作用
注：IC50:μg/mL，NT:未检测。
以上结果初步验证了本发明化合物或其药用盐对不同癌细胞的抑制活性，为其作为抗肿瘤药物的开发应用奠定了基础。
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
<实施例1>、N-(噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(1)的合成
在25ml的烧瓶中，3-甲氧基-4-(噁唑-5-基)苯胺(190.2mg,1mmol)溶解于无水乙醇(3ml)中，加入2-噻吩甲醛(1.1mmol)，室温搅拌，至原料3-甲氧基-4-(噁唑-5-基)苯胺消失。0-10℃，加入还原剂(如NaBH4,2mmol),后自然升至室温，至中间体消失。加入二氯甲烷(20ml×3)提取，加入10%的HCl溶液至酸性以除去过量的NaBH4，再用氨水碱化，水洗至中性。无水Na2SO4干燥。过滤，蒸除溶剂。Flash分离得到1产物165mg(57.6%)，黄色固体。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.57(s,2H,-CH2-),6.28(s,1H,2-Ph),6.37(d,J=8.5Hz,1H,6-Ph),6.98(m,1H,3-Th),7.04(m,1H,4-Th),7.24(m,1H,5-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例2>、N-(5-甲基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(2)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物2，收率74.0%。
1HNMR(CDCl3,δ)2.45(s,3H,CH3-Th),3.89(s,3H,-OCH3),4.29(br,1H,NH),4.47(s,2H,-CH2-),6.26(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.60(d,J=2.5Hz,1H,4-Th),6.80(d,J=3.0Hz,1H,3-Th),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例3>、N-(5-乙基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(3)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-乙基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物3，收率85.9%。
1HNMR(CDCl3,δ)1.29(t,3H,-CH2CH 3),2.81(q,2H,-CH 2CH3),3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.26(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.64(d,J=3.5Hz,1H,4-Th),6.82(d,J=3.5Hz,1H,3-Th),7.34(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例4>、N-(5-氯-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(4)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-氯噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物4，收率76.9%。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.47(s,2H,-CH2-),6.25(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),6.77(d,J=4Hz,1H,3-Th),6.80(d,J=4Hz1H,4-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例5>、N-(5-溴-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(5)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-溴噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物5，收率56.2%。
1HNMR(CDCl3,δ)3.91(s,3H,-OCH3),4.49(s,2H,-CH2-),6.25(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.79(d,J=3.5Hz,1H,3-Th),6.91(d,J=4Hz,1H,4-Th),7.35(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例6>、N-(5-苯基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(6)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-苯基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物6，收率72.1%。
1HNMR(CDCl3,δ)3.90(s,3H,-OCH3),4.56(s,2H,-CH2-),6.29(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),6.99(d,J=3.5Hz,1H,3-Th),7.17(d,J=3.5Hz,1H,4-Th),7.27(t,J=7.5Hz,J=7.5Hz,1H,4’-Ph),7.34(s,1H,4-Ox),7.36(t,J=7.5Hz,J=7.5Hz,2H,3’,5’-Ph),7.56(d,J=7.5Hz,2H,2’,6’-Ph),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例7>、5-{[3-甲氧基-4-(噁唑-5-基)-苯胺]-甲基}-噻吩-2-羧酸(7)的合成
3-甲氧基-4-(噁唑-5-基)苯胺(190.2mg,1mmol)溶解于无水乙醇(3ml)中，加入5-甲酰基-2-噻吩羧酸(1.1mmol)，室温搅拌，至原料3-甲氧基-4-(噁唑-5-基)苯胺消失。0-10℃，加入还原剂(如NaBH4，2mmol),后自然升至室温，至中间体消失。用无水乙醇加热溶解，过滤，蒸除部分溶剂，放置，得到54.6%黄色固体产物7。
1HNMR(DMSO-d6,δ)3.82(s,3H,-OCH3),4.39(br,1H,-NH),4.40(s,2H,-CH2-),6.32(d,J=8.5Hz,1H,6-Ph),6.39(s,1H,2-Ph),6.85(d,J=3Hz,1H,3-Th);7.03(d,J=3.5Hz,1H,4-Th),7.18(s,1H,4-Ox),7.37(d,J=8.5Hz,1H,5-Ph);8.21(s,1H,2-Ox).
<实施例8>、N-(苯并噻唑-2-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(8)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和苯并噻唑-2-甲醛为原料，按照实施例1的类似方法，得到化合物8。
1HNMR(CDCl3,δ)3.87(s,3H,-OCH3),4.65(s,2H,-CH2-),6.32(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),7.54(m,2H,5,6-Thia),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),8.11(m,1H,7-Thia),8.22(m,1H,4-Thia).
<实施例9>、（噻吩-2-亚甲胺基）-3-甲氧基-4-(噁唑-5-基)-苯(9)的合成
3-甲氧基-4-(噁唑-5-基)苯胺(190.2mg,1mmol)溶解于无水乙醇(3ml)中，加入2-噻吩甲醛(1.1mmol)，室温搅拌，至原料3-甲氧基-4-(噁唑-5-基)苯胺消失。加入二氯甲烷(20ml×3)提取，水洗至中性。无水Na2SO4干燥。过滤，蒸除溶剂，二氯甲烷/己烷重结晶，得到产物9，收率84.5%。
1HNMR(CDCl3,δ)4.00(s,3H,-OCH3),6.90(s,1H,2-Ph),6.91(d,J=10.5Hz,1H,6-Ph),7.16(dd,J=4.5Hz,J=4.5Hz,1H,4-Th),7.52(d,J=5Hz,1H,3-Th),7.55(d,J=5Hz,1H,5-Th),7.55(s,1H,4-Ox),7.78(d,J=10.5Hz,1H,5-Ph),7.90(s,1H,2-Ox),8.63(s,1H,N=CH-).
<实施例10>、N-(苯并噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(10)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和苯并噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物10，收率35.7%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.66(s,2H,-CH2-),6.31(s,1H,2-Ph),6.39(d,J=8.5Hz,1H,6-Ph),7.25(s,1H,3-Th),7.28(m,1H,5-Th),7.33(m,1H,6-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.70(m,1H,4-Th),7.78(m,1H,7-Th),7.82(s,1H,2-Ox).
<实施例11>、N-(噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(11)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和3-噻吩甲醛为原料，按照实施例1的类似方法，得到化合物11，收率62.9%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.39(s,2H,-CH2-),6.24(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),7.09(d,J=5Hz,1H,4-Th),7.22(s,1H,2-Th),7.33(d,J=5Hz,1H,5-Th),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例12>、N-甲基-N-(5-甲基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(12)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺(1mmol)和5-甲基噻吩-3-甲醛(1.1mmol)为原料，按照实施例1的类似方法，得到化合物N-(5-甲基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺,分离产物用丙酮溶解，无水K2CO3(2mmol),搅拌，缓慢加入碘甲烷(1mmol)的乙酸乙酯，原料消失后，用乙酸乙酯提取。Flash分离纯化，得到化合物12。
1HNMR(CDCl3,δ)2.43(s,3H,CH3-Th),2.86(s,3H,CH3-N),3.88(s,3H,-OCH3),4.61(s,2H,-CH2-),6.28(s,1H,2-Ph),6.45(d,J=8.5Hz,1H,6-Ph),6.87(s,1H,4-Th),7.20(s,1H,2-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例13>、N-(5-乙基-2-甲基-噻吩-3-甲基)-(3-甲氧基-4-噁唑-5-基-苯)-丙-2-炔胺(13)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-乙基-2-甲基-噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物N-(5-乙基-2-甲基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺;再用3-溴丙炔替代碘甲烷用实施例12的类似方法，得到化合物13。
1HNMR(CDCl3,δ)1.28(t,3H,-CH2CH 3),1.81(s,2H,-CH2CCH),2.41(s,3H,CH3),2.80(q,2H,-CH 2CH3),3.89(s,3H,-OCH3),4.09(s,2H,-CH 2CCH),4.60(s,2H,-CH2-),6.28(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.80(s,1H,4-Th),7.34(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例14>、N-(5-氯-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(14)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-氯噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物14。
1HNMR(CDCl3,δ)3.90(s,3H,-OCH3),4.38(s,2H,-CH2-),6.27(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.89(s,1H,4-Th),7.25(s,1H,2-Th),,7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例15>、N-(5-溴-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(15)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-溴噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物15。
1HNMR(CDCl3,δ)3.91(s,3H,-OCH3),4.39(s,2H,-CH2-),6.26(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),6.88(s,1H,4-Th),7.26(s,1H,2-Th),7.34(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例16>、N-(5-苯基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(16)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-苯基噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物16。
1HNMR(CDCl3,δ)3.91(s,3H,-OCH3),4.56(s,2H,-CH2-),6.29(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),7.16(s,1H,4-Th),7.26(s,1H,2-Th)，7.29(t,J=7.5Hz,J=7.5Hz,1H,4’-Ph),7.34(s,1H,4-Ox),7.37(t,J=7.5Hz,J=7.5Hz,2H,3’,5’-Ph),7.55(d,J=7.5Hz,2H,2’,6’-Ph),7.58(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例17>、N-(1-甲基-1H-咪唑-5-甲基)-3甲氧基-4-(噁唑-5-基)-苯胺(17)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和1-甲基-1H-5-醛基-咪唑为原料，按照实施例1的类似方法，得到化合物17。
1HNMR(CDCl3,δ)3.63(s,3H,-NCH3),3.90(s,3H,-OCH3),4.27(s,2H,-CH2-),6.28(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.67(s,1H,4-Imi),7.19(s,1H,2-Imi),7.33(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例18>、N-(5-甲氧基-噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(18)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲氧基噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物18。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),3.91(s,3H,CH3O-Th),4.48(s,2H,-CH2-),6.28(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),6.86(s,1H,4-Th),6.96(s,1H,2-Th),7.34(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例19>、(5-甲基-噻吩-3-亚甲胺基)-3-甲氧基-4-(噁唑-5-基)-苯(19)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲基噻吩-3-甲醛为原料，按照实施例9的类似方法，得到化合物19。
1HNMR(CDCl3,δ)2.45(s,3H,CH3-Th),3.99(s,3H,-OCH3),6.91(s,1H,2-Ph),6.92(d,J=10.5Hz,1H,6-Ph),7.39(s,1H,4-Th),7.52(s,1H,2-Th),7.56(s,1H,4-Ox),7.78(d,J=10.5Hz,1H,5-Ph),7.90(s,1H,2-Ox),8.62(s,1H,N=CH-).
<实施例20>、N-(苯并噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(20)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和苯并噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物20，收率47.6%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.25(br,1H,NH),4.61(s,2H,-CH2),6.28(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),7.35(s,1H,4-Ox),7.38(s,1H,2-Th),7.42(m,2H,5,6-Th),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox),7.83(m,1H,4-Th),7.86(m,1H,7-Th).
<实施例21>、N-(噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(21)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和2-噻吩甲醛为原料，按照实施例1的类似方法，得到化合物21，收率60.5%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.59(s,2H,-CH2-),4.85(s,1H,-NH),6.81(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),6.99(m,1H,3-Th),7.06(m,1H,4-Th),7.16(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.23(m,1H,5-Th),7.85(s,1H,2-Ox).
<实施例22>、N-(5-甲基-噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(22)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-甲基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物22，收率93.3%。
1HNMR(CDCl3,δ)2.46(s,3H,CH3-Th),3.87(s,3H,-OCH3),4.49(s,2H,-CH2-),4.74(s,1H,-NH),6.61(d,J=2Hz,3-Th),6.80(d,J=8.5Hz,1H,3-Ph),6.83(d,J=3Hz,4-Th),6.94(s,1H,6-Ph),7.18(s,1H,4-Ox),7.36(d,J=8.5Hz,1H,4-Ph),7.82(s,1H,2-Ox).
<实施例23>、N-(3，5-二甲基-异噁唑-4-甲基)-2-甲氧基-(5-噁唑-5-基)-苯胺(23)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和3,5-二甲基-4-异噁唑甲醛为原料，按照实施例1的类似方法，得到化合物23。
1HNMR(CDCl3,δ)2.35(s,6H,3,5-CH3-Isox),3.87(s,3H,-OCH3),4.48(s,2H,-CH2-),4.73(s,1H,-NH),6.81(d,J=8.5Hz,1H,3-Ph),6.93(s,1H,6-Ph),7.18(s,1H,4-Ox),7.35(d,J=8.5Hz,1H,4-Ph),7.81(s,1H,2-Ox).
<实施例24>、N-(5-氯甲基-噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(24)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-氯甲基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物24。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),4.62(s,1H,-CH2Cl),6.61(d,J=2Hz,3-Th),6.81(d,J=8.5Hz,1H,3-Ph),6.84(d,J=2Hz,4-Th)6.94(s,1H,6-Ph),7.17(s,1H,4-Ox),7.36(d,J=8.5Hz,1H,4-Ph),7.82(s,1H,2-Ox).
<实施例25>、N-(5-溴甲基-噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(25)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-溴甲基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物25。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),4.64(s,2H,-CH2Br),6.62(d,J=2Hz,3-Th),6.82(d,J=8.5Hz,1H,3-Ph),6.85(d,J=2Hz,4-Th)6.93(s,1H,6-Ph),7.18(s,1H,4-Ox),7.35(d,J=8.5Hz,1H,4-Ph),7.81(s,1H,2-Ox).
<实施例26>、N-(5-苯基-噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(26)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-苯基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物26。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),6.83(d,J=8.5Hz,1H,3-Ph),6.89(d,J=2Hz,3-Th),6.94(s,1H,6-Ph),7.05(d,J=2Hz,4-Th),7.18(s,1H,4-Ox),7.28(t,J=7.5Hz,J=7.5Hz,1H,4’-Ph),7.34(d,J=8.5Hz,1H,4-Ph),7.38(t,J=7.5Hz,J=7.5Hz,2H,3’,5’-Ph),7.54(d,J=7.5Hz,2H,2’,6’-Ph),7.82(s,1H,2-Ox).
<实施例27>、N-(5-氯-1,3-二甲基-1H-吡唑-4-基甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(27)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-氯-1,3-二甲基吡唑-4-甲醛为原料，按照实施例1的类似方法，得到化合物27。
1HNMR(CDCl3,δ)2.78(s,3H,3-CH3-Pyra),3.81(s,3H,N-CH3-Pyra),3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),6.82(d,J=8.5Hz,1H,3-Ph),6.94(s,1H,6-Ph),7.18(s,1H,4-Ox),7.36(d,J=8.5Hz,1H,4-Ph),7.82(s,1H,2-Ox).
<实施例28>、N-(2-甲氧基-5-噁唑-5-基-苯)-(2-苯基-2H-[1，2，3]三唑-4-基甲基)-胺(28)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和2-苯基-2H-[1,2,3]-三唑-4-甲醛为原料，按照实施例1的类似方法，得到化合物28。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.84(d,J=8.5Hz,1H,3-Ph),6.93(s,1H,6-Ph),7.19(s,1H,4-Ox),7.33(m,3H,3,4,5-Ph’),7.35(d,J=8.5Hz,1H,4-Ph),7.81(s,1H,2-Ox),7.84(s,1H,4-Tri),8.12(m,2H,2,6-Ph’).
<实施例29>、(4-氯-噻吩-2-亚甲胺基)-2-甲氧基-5-(噁唑-5-基)-苯(29)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和4-氯-噻吩-2-甲醛为原料，按照实施例9的类似方法，得到化合物29。
1HNMR(CDCl3,δ)3.99(s,3H,-OCH3),6.92(s,1H,3-Th),7.09(s,1H,5-Th),7.36(d,J=8.5Hz,1H,4-Ph),7.44(s,1H,6-Ph),7.49(d,J=8.5Hz,1H,3-Ph),7.38(s,1H,4-Ox),7.90(s,1H,2-Ox),8.13(s,1H,N=CH-).
<实施例30>、N-(5-氯-苯并噻吩-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(30)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-氯-苯并噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物30。
1HNMR(CDCl3,δ)3.87(s,3H,-OCH3),4.67(s,2H,-CH2-),6.84(d,J=8.5Hz,1H,3-Ph),6.98(s,1H,6-Ph),7.18(s,1H,4-Ox),7.26(s,1H,3-Th),7.33(m,1H,6-Th),7.40(d,J=8.5Hz,1H,4-Ph),7.71(s,1H,4-Th),7.82(m,1H,7-Th),7.82(s,1H,2-Ox).
<实施例31>、N-(噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(31)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物31。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.53(s,2H,-CH2-),6.82(d,J=8.5Hz,1H,3-Ph),6.94(s,1H,6-Ph),7.08(d,J=5Hz,1H,4-Th),7.15(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.21(s,1H,2-Th),7.33(d,J=5Hz,1H,5-Th),7.84(s,1H,2-Ox).
<实施例32>、N-(5-甲基-噻吩-3-甲基)-N-(2-甲氧基-5-噁唑-5-基)-丙酰胺(32)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺(1mmol)和5-甲基-噻吩-3-甲醛(1mmol)为原料，按照实施例1的类似方法，分离得到化合物N-(5-甲基-噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺，用四氢呋喃溶解，慢滴加丙酰氯，至中间体消失。分离纯化，得到化合物32。
1HNMR(CDCl3,δ)1.13(t,3H,COCH2CH 3),2.27(q,2H,COCH 2CH3),2.43(s,3H,CH3-Th),3.87(s,3H,-OCH3),4.65(s,2H,-CH2-),6.87(d,J=8.5Hz,1H,3-Ph),6.87(s,1H,4-Th),7.21(s,1H,6-Ph),7.34(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.20(s,1H,2-Th),7.82(s,1H,2-Ox).
<实施例33>、N-(2-甲氧基-5-噁唑-5-基-苯）-(1-甲基-哌啶-4-基甲基)-胺(33)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和1-甲基-哌啶-4-甲醛为原料，按照实施例1的类似方法，得到化合物33。
1HNMR(CDCl3,δ)1.46(m,4H,3,5-Pip),1.73(m,1H,4-Pip),2.24(m,4H,2,6-Pip),2.26(s,3H,N-CH3-Pip),3.02(m,2H,-CH2-),3.88(s,3H,-OCH3),6.82(d,J=8.5Hz,1H,3-Ph),6.94(s,1H,6-Ph),7.15(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.81(s,1H,2-Ox).
<实施例34>、N-(5-氯-噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(34)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-氯-噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物34。
1HNMR(CDCl3,δ)3.87(s,3H,-OCH3),4.48(s,2H,-CH2-),6.80(d,J=8.5Hz,1H,3-Ph),6.89(s,1H,4-Th),6.92(s,1H,6-Ph),7.16(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.24(s,1H,2-Th),7.81(s,1H,2-Ox).
<实施例35>、N-(5-溴-噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(35)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-溴-噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物35。
1HNMR(CDCl3,δ)3.87(s,3H,-OCH3),4.48(s,2H,-CH2-),6.80(d,J=8.5Hz,1H,3-Ph),6.92(s,1H,6-Ph),7.07(s,1H,4-Th),7.16(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.25(s,1H,2-Th),7.81(s,1H,2-Ox).
<实施例36>、N-(5-苯基-噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(36)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-苯基噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物36。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.83(d,J=8.5Hz,1H,3-Ph),6.88(s,1H,4-Th),6.95(s,1H,6-Ph),7.16(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.20(s,1H,2-Th),7.24(m,1H,4’-Ph),7.32(m,2H,3’,5’-Ph),7.48(m,2H,2’,6’-Ph),7.82(s,1H,2-Ox).
<实施例37>、N-(2-甲氧基-5-噁唑-5-基-苯)-(四氢吡喃-4-基甲基)-胺(37)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和四氢吡喃-4-甲醛为原料，按照实施例1的类似方法，得到化合物37。
1HNMR(CDCl3,δ)1.56(m,4H,3,5-Pyr),1.83(m,1H,4-Pyr),3.04(m,2H,-CH2-),3.59(m,4H,2,6-Pyr),3.87(s,3H,-OCH3),6.83(d,J=8.5Hz,1H,3-Ph),6.93(s,1H,6-Ph),7.16(d,J=8.5Hz,1H,4-Ph),7.19(s,1H,4-Ox),7.82(s,1H,2-Ox).
<实施例38>、N-(2-甲氧基-5-噁唑-5-基-苯)-(哒嗪-3-基甲基)-胺(38)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和哒嗪-3-甲醛为原料，按照实施例1的类似方法，得到化合物38。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.82(d,J=8.5Hz,1H,3-Ph),6.94(s,1H,6-Ph),7.14(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.58(m,2H,4,5-Pyr),7.82(s,1H,2-Ox),8.87(m,1H,6-Pyr).
<实施例39>、(噻吩-3-亚胺基)-2-甲氧基-5-(噁唑-5-基)-苯(39)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和噻吩-3-甲醛为原料，按照实施例9的类似方法，得到化合物39。
1HNMR(CDCl3,δ)3.98(s,3H,-OCH3),6.96(d,J=4Hz,1H,4-Th),7.10(d,J=4Hz,1H,5-Th),7.20(s,1H,3-Th),7.32(d,J=8.5Hz,1H,4-Ph),7.43(s,1H,6-Ph),7.44(d,J=8.5Hz,1H,3-Ph),7.35(s,1H,4-Ox),7.88(s,1H,2-Ox),8.13(s,1H,N=CH-).
<实施例40>、N-(6-溴-7-甲基-苯并噻吩-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(40)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和6-溴-7-甲基-苯并噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物40。
1HNMR(CDCl3,δ)2.35(s,3H,CH3-Th),3.88(s,3H,-OCH3),4.48(s,2H,-CH2-),6.82(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),7.06(d,J=8Hz,1H,5-Th),7.16(d,J=8.5Hz,1H,4-Ph),7.18(s,1H,4-Ox),7.29(d,J=8Hz,,1H,4-Th),7.38(s,1H,2-Th),7.82(s,1H,2-Ox).
<实施例41>N-(呋喃-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(41)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物41，收率51.8%。
1HNMR(CDCl3,δ)3.90(s,3H,-OCH3),4.37(s,2H,-CH2-),6.26(d,1H,3-Fu),6.27(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.34(m,1H,4-Fu),7.34(s,1H,4-Ox),7.38(m,1H,5-Fu),7.57(d,1H,J=8.5Hz,5-Ph),7.81(s,1H,2-Ox).
<实施例42>、N-(5-甲基-呋喃-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(42)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲基-2-呋喃甲醛为原料，按照实施例1的类似方法，得到化合物42，收率68.0%。
1HNMR(CDCl3,δ)2.28(s,3H,CH3-Fu),3.90(s,3H,-OCH3),4.30(s,2H,-CH2),5.91(d,J=2Hz,1H,4-Fu),6.13(d,J=2.5Hz,1H,3-Fu),6.28(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例43>、N-(2,4,6-三氯－嘧啶-5-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(43)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2,4,6-三氯-嘧啶-5-甲醛为原料，按照实施例1的类似方法，得到化合物43。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.31(s,2H,-CH2),6.29(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例44>、N-(3,5-二氯吡嗪-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(44)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和3,5-二氯吡嗪-2-甲基为原料，按照实施例1的类似方法，得到化合物44。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.30(s,2H,-CH2),6.29(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox)，8.50(s,1H,6-Pyra).
<实施例45>、N-(5-溴-呋喃-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(45)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-溴呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物45。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.45(d,J=3Hz,3-Fu),6.70(d,J=3Hz,1H,4-Fu),6.80(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),7.18(s,1H,4-Ox),7.37(d,J=8.5Hz,1H,4-Ph),7.82(s,1H,2-Ox).
<实施例46>、N-[5-(3-氯-苯基)-呋喃-2-甲基]-2-甲氧基-5-(噁唑-5-基)-苯胺(46)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-(3-氯苯)-呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物46。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),6.35(d,J=3Hz,3-Fu),6.70(d,J=3Hz,1H,4-Fu),6.82(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),7.18(s,1H,4-Ox),7.22(d,J=8Hz,1H,4’-Ph),7.25(dd,J=8Hz,8Hz,1H,5’-Ph),7.35(d,J=8.5Hz,1H,4-Ph),7.37(d,J=8Hz,1H,6’-Ph),7.48(s,1H,2’-Ph),7.81(s,1H,2-Ox).
<实施例47>、5-{[3-甲氧基-4-(噁唑-5-基)-苯胺]-甲基}-呋喃-2-甲酰-(3，4，5-三甲氧基)胺(47)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲酰-呋喃-2-羧酸为原料，按照实施例7的类似方法，得到化合物5-{[3-甲氧基-4-(噁唑-5-基)-苯胺]-甲基}-呋喃-2-羧酸,与3,4,5-三甲氧基苯胺，在DIC和HOBt存在下缩合反应，Flash分离纯化，得到产物47。
1HNMR(CDCl3,δ)3.90(s,3H,-OCH3),3.96(s,9H,3’,4’,5’-OCH3),4.32(s,2H,-CH2),6.28(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.37(d,J=3Hz,1H,4-Fu),6.61(s,2H,2’,6'-Ph),7.13(d,J=3Hz,1H,3-Fu),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),13.2(s,1H,-CONH).
<实施例48>、N-(5-甲氧基甲基-呋喃-2-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(48)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和5-甲氧基甲基-呋喃-2-甲基醛为原料，按照实施例1的类似方法，得到化合物48。
1HNMR(CDCl3,δ)3.24(s,3H,-OCH3-Fu),3.89(s,3H,-OCH3),4.15(s,2H,-CH2-),4.48(s,2H,-CH2-),6.45(d,J=3Hz,3-Fu),6.70(d,J=3Hz,1H,4-Fu),6.80(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),7.18(s,1H,4-Ox),7.37(d,J=8.5Hz,1H,4-Ph),7.82(s,1H,2-Ox).
<实施例49>、(5-硝基-呋喃-2-亚甲胺基)-3-甲氧基-4-(噁唑-5-基)-苯(49)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-硝基呋喃-2-甲醛为原料，按照实施例9的类似方法，得到化合物49，收率30.5%。
1HNMR(CDCl3,δ)4.00(s,3H,-OCH3),6.96(s,1H,2-Ph),6.98(d,J=8Hz,1H,6-Ph),7.23(d,J=4Hz,1H,3-Fu),7.44(d,J=3.5Hz,1H,4-Fu),7.60(s,1H,4-Ox),7.83(d,J=8Hz,1H,5-Ph),7.93(s,1H,2-Ox),8.47(s,1H,N=CH-).
<实施例50>、N-(苯并呋喃-3-甲基)-2-甲氧基-5-(噁唑-5-基)-苯胺(50)的合成
以2-甲氧基-5-(噁唑-5-基)苯胺和苯并呋喃-3-甲醛为原料，按照实施例1的类似方法，得到化合物50。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),6.81(d,J=8.5Hz,1H,3-Ph),6.95(s,1H,6-Ph),7.15(m,2H,5,6-Fu),7.18(s,1H,4-Ox),7.24(s,1H,2-Fu),7.36(d,J=8.5Hz,1H,4-Ph),7.45(m,2H,4,7-Fu),7.82(s,1H,2-Ox).
<实施例51>、N-(1-甲基-1H-吡咯-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(51)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和N-甲基-2-吡咯甲醛为原料，按照实施例1的类似方法，得到化合物51，收率14.1%。
1HNMR(CDCl3,δ)3.48(s,3H,N-CH3),3.88(s,3H,-OCH3),4.36(s,2H,-CH2),5.59(m,1H,3-Pyr),5.77(m,1H,4-Pyr),6.12(m,1H,5-Pyr),6.32(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例52>、N-(5-甲氧基-1H-吲哚-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(52)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲氧基-1H-吲哚-3-甲醛为原料，按照实施例1的类似方法，得到化合物52,收率28.6%。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),3.94(s,3H,CH3O-Ind),4.02(br,1H,-NH),4.20(s,2H,-CH2),6.31(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.69(m,1H,6-Ind),6.86(s,1H,2-Ind),7.07(m,1H,7-Ind),7.33(s,1H,4-Ox),7.40(m,1H,4-Ind),7.57(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox),8.05(br,1H,-NH-Ind).
<实施例53>、N-(1-H-吲哚-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(53)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和3-吲哚甲醛为原料，按照实施例1的类似方法，得到化合物53，收率16.7%。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.02(br,1H,NH),4.20(s,2H,-CH2),6.30(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.87(s,1H,2-Ind),7.07(m,1H,7-Ind),7.11(m,1H,6-Ind),7.19(m,1H,5-Ind),7.32(s,1H,4-Ox),7.40(m,1H,4-Ind),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),8.05(br,1H,-NH-Ind).
<实施例54>、N-(4-甲基-噻唑-5-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(54)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和4-甲基噻唑-5-甲醛为原料，按照实施例1的类似方法，得到化合物54，收率75.7%。
1HNMR(CDCl3,δ)2.51(s,3H,CH3-Thia),3.89(s,3H,-OCH3),4.50(s,2H,-CH2),6.24(s,1H,2-Ph),6.33(d,J=8.5Hz,1H,6-Ph),7.35(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox),8.64(s,1H,2-Thia).
<实施例55>、N-(噻唑-5-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(55)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和噻唑-5-甲醛为原料，按照实施例1的类似方法，得到化合物55，收率83.5%。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),4.64(s,2H,-CH2),6.27(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),7.35(s,1H,4-Ox),7.59(d,J=8Hz,1H,5-Ph),7.83(s,1H,2-Ox),7.85(s,1H,4-Thia),8.75(s,1H,2-Thia).
<实施例56>、N-(吡啶-4-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(56)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和4-吡啶甲醛为原料，按照实施例1的类似方法，得到化合物56，收率46.2%。
1HNMR(CDCl3,δ)3.84(s,3H,-OCH3),4.43(s,2H,-CH2-),6.18(s,1H,2-Ph),6.25(d,J=8.5Hz,1H,6-Ph),7.30(d,J=7.5Hz,2H,3,5-Py),7.33(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),8.57(d,J=7.5Hz,2H,2,6-Py).
<实施例57>、N-(6-甲基-吡啶-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(57)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和6-甲基-2-吡啶甲醛为原料，按照实施例1的类似方法，得到化合物57，收率73.8%。
1HNMR(CDCl3,δ)2.59(s,3H,CH3-Py),3.90(s,3H,-OCH3),4.46(s,2H,-CH2),5.10(br,1H,NH),6.29(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.07(d,J=7.5Hz,1H,5-Py),7.14(d,J=8Hz1H,3-Py),7.32(s,1H,4-Ox),7.56(t,J=7.5Hz,J=8Hz1H,4-Py),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例58>、2-甲氧基-4-(噁唑-5-基)-5-[(喹啉-4-基甲基)-氨基]-苯酚(58)的合成
以5-氨基-2-甲氧基-4-噁唑-5-基苯酚和喹啉-4-甲醛为原料，按照实施例1的类似方法，得到化合物58，收率45.8%。
1HNMR(CDCl3,δ)3.85(s,3H,-OCH3),4.11(br,1H,NH),4.42(s,2H,-CH2-),5.01(br,1H,OH),7.03(d,J=8Hz,1H,3-Qui),7.34(s,1H,4-Ox),7.41(m,1H,6-Qui),7.57(m,1H,7-Qui),7.77(m,1H,5-Qui),7.82(s,1H,2-Ox),8.02(m,1H,8-Qui),8.67(d,J=8Hz,1H,2-Qui).
<实施例59>、N-(2-氯-吡啶-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(59)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-氯-3-吡啶甲醛为原料，按照实施例1的类似方法，得到化合物59，收率56.2%。
1HNMR(CDCl3,δ)3.86(s,3H,-OCH3),4.50(s,2H,-CH2),6.19(s,1H,2-Ph),6.25(d,J=8.5Hz,1H,6-Ph),7.22(m,1H,5-Py),7.34(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.74(1H,m,4-Py),7.82(s,1H,2-Ox)，8.32(m,1H,6-Py).
<实施例60>、N-(6-甲氧基-吡啶-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(60)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-甲氧基-5-吡啶甲醛为原料，按照实施例1的类似方法，得到化合物60，收率51.7%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),3.94(s,3H,CH3O-Py),4.31(s,2H,-CH2),6.23(s,1H,2-Ph),6.33(d,J=8.5Hz,1H,6-Ph),6.75(d,J=8.5Hz,1H,3-Py),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.60(d,J=8.5Hz,1H,4-Py),7.82(s,1H,2-Ox),8.17(m,1H,6-Py).
<实施例61>、N-(4-甲氧苄基)-3-甲氧基-4-(噁唑-5-基)-苯胺(61)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和对甲氧基苯甲醛为原料，按照实施例1的类似方法，得到化合物61，收率67.7%。
1HNMR(CDCl3,δ)3.81(s,3H,CH3O-Ph’),3.87(s,3H,OCH3),4.31(s,2H,-CH2-),6.22(s,1H,2-Ph),6.32(d,J=8.5Hz,1H,6-Ph),6.89(d,J=8.5Hz,2H,2’,6’-Ph,),7.30(d,J=8.5Hz,2H,3’,5’-Ph),7.32(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例62>、N-(3-苯-烯丙基)-3-甲氧基-4-(噁唑-5-基)-苯胺(62)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和反-肉桂醛为原料，按照实施例1的类似方法，得到化合物62，收率15.7%。
1HNMR(CDCl3,δ)3.91(s,3H,-OCH3),4.00(d,J=5Hz,1H,-CH2-),6.31(s,1H,2-Ph),6.33(m,1H,-CH2-CH=CH-),6.39(d,J=8.5Hz,1H,6-Ph),6.65(d,J=16Hz,1H,-CH2-CH=CH-),7.21(m,1H,4’-Ph),7.31(t,J=7.5Hz,J=7.5Hz,2H,3’,5’-Ph),7.37(d,J=7Hz,2H,2’,6’-Ph),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例63>、N-[3-(2-甲氧基-苯)-烯丙基]-3-甲氧基-4-(噁唑-5-基)-苯胺(63)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和邻甲氧基肉桂醛为原料，按照实施例1的类似方法，得到化合物63，收率77.4%。
1HNMR(CDCl3,δ)3.85(s,3H,2’-OCH3),3.91(s,3H,-OCH3),4.00(d,J=6Hz,1H,-CH2-),6.30(s,1H,2-Ph),6.33(dd,J=6Hz,J=16Hz,1H,-CH2-CH=CH-),6.37(d,J=8.5Hz,1H,6-Ph),6.88(d,J=8Hz,1H,3’-Ph),6.92(t,J=8Hz,J=8Hz,1H,5’-Ph),6.97(d,J=16Hz,1H,-CH2-CH=CH-),7.23(t,J=8Hz,J=8Hz,1H,4’-Ph),7.33(s,1H,4-Ox),7.42(d,J=8Hz,1H,6’-Ph),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例64>、(4-氟苯-亚胺基)-3-甲氧基-4-(噁唑-5-基)-苯(64)
以3-甲氧基-4-(噁唑-5-基)苯胺和对氟苯甲醛为原料，按照实施例9的类似方法，得到化合物64，收率26.9%。
1HNMR(CDCl3,δ)4.01(s,3H,-OCH3),6.88(s,1H,2-Ph),6.98(d,J=10.5Hz,1H,6-Ph),7.19(m,,2H,2’,6’-Ph),7.92(m,2H,3’,5’-Ph),7.58(s,1H,4-Ox),7.80(d,J=11Hz,1H,5-Ph),7.91(s,1H,2-Ox),8.48(s,1H,N=CH-).
<实施例65>、(3-苯-烯丙亚胺)-3-甲氧基-4-(噁唑-5-基)-苯(65)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和反-肉桂醛为原料，按照实施例9的类似方法，得到化合物65，收率23.0%，黄色固体。
1HNMR(CDCl3,δ)4.01(s,3H,-OCH3),6.88(s,1H,2-Ph),6.89(d,J=8.5Hz,1H,6-Ph),7.21(m,1H,4’-Ph),,7.39(m,2H,3’,5’-Ph),7.44(m,2H,2’,6’-Ph),7.55(m,1H,C=CH-Ph),7.56(s,1H,4-Ox),7.57(m,1H,5-Ph),7.79(d,J=10.5Hz,1H,N=CH-CH),7.91(s,1H,2-Ox),8.35(d,J=10.5Hz,1H,N=CH-).
<实施例66>、2-[(3-甲氧基-4-(噁唑-5-基)-苯腙]-丙二腈(66)的合成
在25ml的烧瓶中,3-甲氧基-4-(噁唑-5-基)苯胺(190.2mg,1mmol)溶解于0.75N稀HCl(8.5ml)中，冰浴下低加NaNO2(1.5mmol)水溶液，搅拌10分钟，滴加丙二腈(1.5mmol)，室温搅拌2h，二氯甲烷提取。常规处理，得到70.5%收率的棕黄色固体产物66。
1HNMR(CDCl3,δ)4.04(s,3H,-OCH3),6.91(m,1H,6-Ph),7.03(s,1H,2-Ph),7.82(d,J=10Hz,1H,5-Ph),7.58(s,1H,4-Ox),7.90(s,1H,2-Ox),8.04(br,1H,NH).
<实施例67>、2-甲氧基-5-(噁唑-5-基)-苯胺(67)的合成
以5-(3-硝基-4-甲氧基苯)噁唑(3.3g,15mmol)，加入10%Pd/C(0.67g)和无水乙醇(33ml)，35-45psi，H2，氢化，反应至无原料，混合物过滤，无水乙醇(3×2.5ml)洗，浓缩至8ml，加入己烷(12ml)，放置，过滤，真空干燥，得到产物67，2.4g，收率84.1%。
1HNMR(CDCl3,δ)3.89(s,3H,-OCH3),3.98(br,2H,NH2),6.82(d,J=10Hz,1H,3-Ph),7.02(s,1H,6-Ph),7.04(d,J=10.5Hz,1H,4-Ph),7.19(s,1H,4-Ox),7.84(s,1H,2-Ox).
<实施例68>、N-[3-甲氧基-4-(噁唑-5-基)-苯]-甲磺酰胺(68)的合成
在25ml的烧瓶中，3-甲氧基-4-(噁唑-5-基)苯胺(380.4mg,2mmol)加入二氯甲烷(6.5ml)，吡啶(0.2ml)，2-4℃，慢滴加甲磺酰氯(0.2ml)，搅拌45分钟后慢升至室温。加入己烷(12ml)，水(12ml)，二氯甲烷(20ml×3)，过滤，水洗。真空干燥。得到产物68，240mg,收率44.8%，棕色固体。
1HNMR(CDCl3,δ)3.03(s,3H,-SO2CH3),3.98(s,3H,-OCH3),6.59(br,1H,-NH),6.97(s,1H,2-Ph),6.83(d,J=10.5Hz,1H,6-Ph),7.53(s,1H,4-Ox),7.54(d,J=10.5Hz,1H,5-Ph),7.92(s,1H,2-Ox).
<实施例69>、N-[3-甲氧基-4-(噁唑-5-基)-苯]-对甲苯磺酰胺(69)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和对甲苯磺酰氯为原料，按照实施例68的类似方法，得到化合物69。
1HNMR(CDCl3,δ)2.35(s,3H,4’-CH3),3.89(s,3H,-OCH3),6.26(s,1H,2-Ph),6.39(d,J=8.5Hz,1H,6-Ph),7.33(s,1H,4-Ox),7.34(m,2H,3’,5’-Ph),7.55(d,J=8.5Hz,1H,5-Ph),7.80(m,2H,4’,6’-Ph),7.82(s,1H,2-Ox).
<实施例70>、3-[3-甲氧基-4-(噁唑-5-基)-苯胺基]-丙-1-磺酸(70)的合成
在25ml的烧瓶中,3-甲氧基-4-(噁唑-5-基)苯胺(190.2mg,1mmol)和1，3-丙磺酸内酯（1.1mmol）溶解于甲醇中，回流6h，降温，冷却，过滤析出黄色固体产物70，收率30.5%。
1HNMR(DMSO-d6,δ)1.87(m,2H,-CH2CH 2CH2-),2.56(m,2H,-CH 2CH2CH2),3.22(m,2H,-CH2CH2CH 2-),3.87(s,3H,-OCH3),5.75(s,1H,-NH),6.46(m,1H,6-Ph),6.54(s,1H,2-Ph),7.47(d,J=10Hz,1H,5-Ph),7.27(s,1H,4-Ox),8.27(s,1H,2-Ox).
<实施例71>、N-(3,7-二甲基-辛-2,6-二烯基)-3-甲氧基-4-(噁唑-5-基)-苯胺(71)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和柠檬醛为原料，按照实施例1的类似方法，得到化合物71，收率35.3%。
1HNMR(CDCl3,δ)1.61(s,3H,3’-CH3),1.71(s,6H,7’-C(CH3)2),2.09(m,4H,4’,5’-CH2CH2-),3.76(m,2H,-CH2-),3.89(s,3H,-OCH3),5.11(m,1H,6’-H),5.35(1H,m,2’-H),6.20(s,1H,2-Ph),6.29(d,J=8.5Hz,1H,6-Ph),7.32(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例72>、N-[2-(5-甲基噻吩-2-基)-乙基]-3-甲氧基-4-(噁唑-5-基)-苯胺(72)的合成
3-甲氧基-4-(噁唑-5-基)苯胺(1mmol)用溶剂（如二氯甲烷）溶解，少量吡啶，三乙胺，低温，加入5-甲基-2-(2-氯乙基)噻吩(1mmol)，搅拌2小时，二氯甲烷提取，水洗，Flash分离，得到产物72，收率43.2%。
1HNMR(CDCl3,δ)2.44(s,3H,CH3-Th),2.78(t,2H,-CH2-),3.39(t,2H,-NHCH 2-),3.88(s,3H,-OCH3),6.25(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.61(d,J=3Hz,1H,4-Th),6.82(d,J=3Hz,1H,3-Th),7.34(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.80(s,1H,2-Ox).
<实施例73>、N-[2-(5-溴-噻吩-2-基)-乙基]-3-甲氧基-4-(噁唑-5-基)-苯胺(73)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-溴-5-(2-溴乙基)噻吩为原料，按照实施例72的类似方法，得到化合物73。
1HNMR(CDCl3,δ)2.77(t,2H,-CH2-),3.39(t,2H,-NHCH 2-),3.89(s,3H,-OCH3),6.24(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.67(d,J=3Hz,1H,4-Th),6.80(d,J=3Hz,1H,3-Th),7.34(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例74>、N-(2-苯并异噁唑-3-基-乙基)-3-甲氧基-4-(噁唑-5-基)-苯胺(74)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和3-(2-溴乙基)-苯并异噁唑为原料，按照实施例72的类似方法，得到化合物74。
1HNMR(CDCl3,δ)2.78(t,2H,-CH2-),3.39(t,2H,-NHCH 2-),3.88(s,3H,-OCH3),6.25(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.96(t,1H,5-Ben),7.16(t,1H,6-Ben),7.29(dd,J=8Hz,8Hz,2H,4,7-Ben),7.34(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.80(s,1H,2-Ox).
<实施例75>、N-(二苯并呋喃-4-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(75)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和二苯并呋喃-4-甲醛为原料，按照实施例1的类似方法，得到化合物75。
1HNMR(CDCl3,δ)4.38(s,2H,-CH2),6.48(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),6.99(d,J=8Hz,1H,3-Fu),7.02(dd,J=8Hz,8Hz,1H,2-Fu),7.16(m,2H,7,8-Fu),7.31(d,J=8Hz,1H,1-Fu),7.34(s,1H,4-Ox),7.43(d,J=8Hz,1H,6-Fu),7.49(d,J=8Hz,1H,9-Fu),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例76>、N-(5-甲基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(76)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-甲基噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物76，收率53.0%。
1HNMR(CDCl3,δ)2.43(s,3H,CH3-Th),3.81(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.88(s,3H,-OCH3),6.60(d,J=3Hz,1H,4-Th),6.62(s,1H,2-Ph),6.76(d,J=8.5Hz,1H,6-Ph),6.81(d,J=3Hz,1H,3-Th),7.34(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例77>、N-(5-氯-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(77)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-氯噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物77。
1HNMR(CDCl3,δ)3.81(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.89(s,3H,-OCH3),6.61(s,1H,2-Ph),6.71(d,J=3Hz,1H,4-Th),6.75(d,J=8.5Hz,1H,6-Ph),6.81(d,J=3Hz,1H,3-Th),7.35(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例78>、N-(苯并[1,2,5]噁二唑-4-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺78)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和苯并[1,2,5]噁二唑-4-甲醛为原料，按照实施例1的类似方法，得到化合物78。
1HNMR(CDCl3,δ)3.82(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.88(s,3H,-OCH3),6.62(s,1H,2-Ph),6.74(d,J=8.5Hz,1H,6-Ph),7.09(d,J=8Hz,1H,5-Ben),7.41(dd,J=8Hz,8Hz,1H,6-Ben),7.34(s,1H,4-Ox),7.59(d,J=8.5Hz,1H,5-Ph),7.73(d,J=8Hz,1H,7-Ben),7.82(s,1H,2-Ox).
<实施例79>、1-[(2-甲基-5-噁唑-5-基苯胺)-甲基]-萘-2-醇(79)的合成
以2-甲基-5-(噁唑-5-基)-苯胺和2-羟基-1-萘醛为原料，按照实施例1的类似方法，得到化合物79。
1HNMR(CDCl3,δ)2.36(s,3H,CH3),4.76(s,2H,-CH2-),4.03(s,1H,-NH),5.02(br,1H,OH),6.83(d,J=8Hz,1H,3-Naph),6.91(d,J=8.5Hz,1H,3-Ph),6.92(s,1H,6-Ph),7.19(s,1H,4-Ox),7.24(m,2H,6,7-Naph),7.36(d,J=8.5Hz,1H,4-Ph),7.45(d,J=8Hz,1H,4-Naph),7.61(dd,J=8Hz,8Hz,2H,5,8-Naph),7.81(s,1H,2-Ox).
<实施例80>、N-(2-苯并噻吩-2-基-乙基)-N-(3-甲氧基-4-噁唑-5-基)-2-溴丙酰胺(80)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-（2-溴乙基）-苯并噻吩为原料，按照实施例72的类似方法，得到N-(2-苯并噻吩-2-基-乙基)-3-甲氧基-4-(噁唑-5-基)-苯胺，再按照实施32的类似方法，用2-溴丙酰氯作酰化剂，得到化合物80。
1HNMR(CDCl3,δ)1.97(d,J=8Hz,3H,COBrCHCH 3),2.70(t,2H,-CH2-),3.71(t,2H,-NHCH 2-),3.89(s,3H,-OCH3),4.55(q,1H,COBrCHCH3),6.65(s,1H,2-Ph),6.72(d,J=8.5Hz,1H,6-Ph),7.24(s,1H,3-Th),7.27(m,1H,5-Th),7.32(m,1H,6-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.70(m,1H,4-Th),7.77(m,1H,7-Th),7.81(s,1H,2-Ox)。
<实施例81>、N-[2-(4-氯-噌啉-3-基)-乙基]-3-甲氧基-4-(噁唑-5-基)-苯胺(81)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和4-氯-3-(2-氯乙基)噌啉为原料，按照实施例72的类似方法，得到化合物81。
1HNMR(CDCl3,δ)2.78(t,2H,-CH2-),3.38(t,2H,-NHCH 2-),3.88(s,3H,-OCH3),6.24(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.63(dd,J=8Hz,8Hz,1H,7-Cin),7.73(dd,J=8Hz,8Hz,,1H,6-Cin),7.80(s,1H,2-Ox),8.07(d,J=8Hz,1H,5-Cin),.8.37(d,J=8Hz,1H,8-Cin).
<实施例82>、N-[2-(5-氯-苯并噻吩-2-基)-乙基]-3-甲氧基-4-(噁唑-5-基)-苯胺(82)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-(2-溴乙基)-5-氯-苯并噻吩为原料，按照实施例72的类似方法，得到化合物82。
1HNMR(CDCl3,δ)2.78(t,2H,-CH2-),3.38(t,2H,-NHCH 2-),3.88(s,3H,-OCH3),6.24(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),7.25(s,1H,3-Th),7.33(d,J=8Hz,1H,6-Th),7.34(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.71(s,1H,4-Th),7.72(d,J=8Hz,1H,7-Th),7.80(s,1H,2-Ox).
<实施例83>、N-(4,6-二氯-2H-硫苯并吡喃-3-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(83)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和4,6-二氯-2H-硫苯并吡喃-3-甲醛为原料，按照实施例1的类似方法，得到化合物83,收率46.2%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.10(dd,J=20Hz,20Hz,2H,2-Th),4.41(s,2H,-CH2-),7.22(d,J=8Hz,1H,7-Th),7.27(d,J=8Hz,,1H,8-Th),7.34(s,1H,4-Ox),7.41(s,1H,5-Th),7.81(s,1H,2-Ox).
<实施例84>、N-(3-甲氧基-4-噁唑-5-基-苄基)-N-(5-甲基-苯并噻吩-2-基甲基)-甲磺酰胺(84)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-甲基-苯并噻吩-2-甲醛为原料，按照实施例1的类似方法，分离得到N-(5-甲基-苯并噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺，加入无水乙腈,60%NaH,5℃,滴加MsCl,然后室温搅拌至中间体苄胺消失，分离纯化得到化合物84,收率33.2%。
1HNMR(CDCl3,δ)2.35(s,3H,CH3-Th),2.84(s,3H,SO2CH3),3.81(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.89(s,3H,-OCH3),6.63(s,1H,2-Ph),6.75(d,J=8.5Hz,1H,6-Ph),6.94(s,1H,3-Th),7.12(d,J=8Hz,1H,6-Th),7.33(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.58(s,1H,4-Th),7.80(s,1H,2-Ox),7.83(d,J=8Hz,1H,7-Th).
<实施例85>、N-(苯并噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(85)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和苯并噻吩-3-甲醛为原料，按照实施例1的类似方法，得到化合物85。
1HNMR(CDCl3,δ)3.81(s,2H,-NHCH 2-),3.82(s,2H,-CH 2NH-),3.86(s,3H,-OCH3),6.62(s,1H,2-Ph),6.74(d,J=8.5Hz,1H,6-Ph),7.33(s,1H,4-Ox),7.38(s,1H,2-Th),7.41(m,2H,5,6-Th),7.54(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),7.83(d,J=8Hz,1H,4-Th),7.86(d,J=8Hz,1H,7-Th).
<实施例86>、N-(1-甲基-1H-吲唑-5-基甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(86)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-(溴甲基)-1-甲基-1H-吲唑为原料，按照实施例72的类似方法，得到化合物86。
1HNMR(CDCl3,δ)3.80(s,H,CH3-Ind),3.81(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.88(s,3H,-OCH3),6.65(s,1H,2-Ph),6.74(d,J=8.5Hz,1H,6-Ph),7.15(d,J=8Hz,1H,6-Ind),7.34(s,1H,4-Ox),7.49(d,J=8Hz,1H,7-Ind),7.57(d,J=8.5Hz,1H,5-Ph),7.66(s,1H,4-Ind),7.81(s,1H,2-Ox),8.14(s,1H,3-Ind).
<实施例87>、N-甲基-N-(5-氯-苯并噻吩-3-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(87)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-氯-苯并噻吩-3-甲醛为原料，按照实施例12的类似方法，得到化合物87。
1HNMR(CDCl3,δ)2.27(s,3H,N-CH3),3.62(s,2H,-NHCH 2-),3.62(s,2H,-CH 2NH-),3.88(s,3H,-OCH3),6.64(s,1H,2-Ph),6.75(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.37(s,1H,2-Th),7.40(d,J=8Hz,1H,6-Th),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox),7.83(s,1H,4-Th),7.84(d,J=8Hz,1H,7-Th).
<实施例88>、N-(10-甲基-10H-吩噻嗪-3-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(88)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和10-甲基-10H-吩噻嗪-3-甲醛为原料，按照实施例1的类似方法，得到化合物88,收率41.5%。
1HNMR(CDCl3,δ)2.79(s,3H,NCH3-Phe),3.89(s,3H,-OCH3),4.42(s,2H,-CH2-),6.28(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),6.56(d,J=8Hz,1H,5-Phe),6.69(d,J=8Hz,1H,9-Phe),6.72(s,1H,2-Phe),6.76(dd,J=8Hz,8Hz,1H,7-Phe),6.79(d,J=8Hz,1H,4-Phe),6.92(d,J=8Hz,1H,6-Phe),6.99(dd,J=8Hz,8Hz,1H,8-Phe),7.34(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例89>、N-(5-甲基-噻吩-2-甲基)-3-氯-4-(噁唑-5-基)-苄胺(89)的合成
以3-氯-4-(噁唑-5-基)-苄胺和5-甲基-噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物89。
1HNMR(CDCl3,δ)2.43(s,3H,CH3-Th),3.81(s,2H,-NHCH 2-),3.82(s,2H,-CH 2NH-),6.61(d,J=3Hz,1H,4-Th),6.82(d,J=3Hz,1H,3-Th),7.06(d,J=8.5Hz,1H,6-Ph),7.12(s,1H,2-Ph),7.33(s,1H,4-Ox),7.61(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例90>、N-(二苯并噻吩-4-基甲基)-3-氯-4-(噁唑-5-基)-苯胺(90)的合成
以3-氯-4-(噁唑-5-基)苯胺和二苯并[B,D]噻吩-4-甲醛为原料，按照实施例1的类似方法，得到化合物90，收率48.1%。
1HNMR(CDCl3,δ)4.31(s,2H,-CH2),6.49(s,1H,2-Ph),6.37(d,J=8.5Hz,1H,6-Ph),7.12(d,J=8Hz,1H,3-Th),7.22(dd,J=8Hz,8Hz,1H,2-Th),7.30(m,2H,7,8-Th),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.59(d,J=8Hz,1H,1-Th),7.77(d,J=8Hz,1H,9-Th),7.81(s,1H,2-Ox),7.87(d,J=8Hz,1H,6-Th).
<实施例91>、N-(苯并[1,2,5]噻二唑-4-基甲基)-3-氯-4-(噁唑-5-基)-苄胺(91)的合成
以3-氯-4-(噁唑-5-基)-苄胺和2,1,3-苯并噻二唑-4-甲醛为原料，按照实施例1的类似方法，得到化合物91。
1HNMR(CDCl3,δ)3.81(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),7.02(d,J=8.5Hz,1H,6-Ph),7.10(s,1H,2-Ph),7.32(d,J=8Hz,1H,5-Ben),7.41(dd,J=8Hz,8Hz,1H,6-Ben),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.78(d,J=8Hz,1H,7-Ben),7.81(s,1H,2-Ox).
<实施例92>、3-[(3-甲氧基-4-噁唑-5-基-苯胺)-甲基]-4-H-苯并吡喃-6-醇(92)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和6-羟基苯并吡喃-3-甲醛为原料，按照实施例1的类似方法，得到化合物92,收率38.6%。
1HNMR(CDCl3,δ)3.22(m,2H,3-Chro),3.88(s,3H,-OCH3),6.22(s,1H,2-Chro),6.27(s,1H,2-Ph),6.36(s,1H,5-Chro),6.36(d,J=8.5Hz,1H,6-Ph),6.37(d,J=12Hz,7-Chro),6.45(d,J=12Hz,8-Chro),7.34(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例93>、N-(5-溴-呋喃-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(93)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和5-溴呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物93。
1HNMR(CDCl3,δ)3.66(s,2H,-NHCH 2-),3.81(s,2H,-CH 2NH-),3.89(s,3H,-OCH3),6.13(d,J=3Hz,1H,3-Fu),6.20(d,J=3Hz,1H,4-Fu),6.63(s,1H,2-Ph),6.74(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例94>、N-(2-甲基-吖啶-9-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(94)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2-甲基-9-吖啶甲醛为原料，按照实施例1的类似方法，得到化合物94。
1HNMR(CDCl3,δ)2.36(s,3H,CH3-Acr),3.88(s,3H,-OCH3),4.28(s,2H,-CH2-),6.28(s,1H,2-Ph),6.34(d,J=8.5Hz,1H,6-Ph),7.32(s,1H,4-Ox),7.41(m,1H,7-Acr),7.46(d,J=8Hz,1H,3-Acr),7.47(s,1H,1-Acr),7.56(d,J=8.5Hz,1H,5-Ph),7.59(m,1H,6-Acr),7.78(d,J=8Hz,1H,8-Acr),7.81(s,1H,2-Ox)7.99(d,J=8Hz,1H,4-Acr),8.03(d,J=8Hz,1H,5-Acr).
<实施例95>、N-(蒽-9-基甲基)-3-甲氧基-4-(噁唑-5-基)-苄胺(95)的合成
以3-甲氧基-4-(噁唑-5-基)-苄胺和9-蒽甲醛为原料，按照实施例1的类似方法，得到化合物95。
1HNMR(CDCl3,δ)3.87(s,3H,-OCH3),4.76(s,2H,-CH2-),6.29(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.31(s,1H,4-Ox),7.38(m,4H,2,3,6,7-Anth),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox),7.89(dd,J=8Hz,8Hz,2H,4,5-Anth),7.97(dd,J=8Hz,8Hz,2H,1,8-Anth),8.15(s,1H,10-Anth).
<实施例96>、{5-[(3-甲氧基-4-噁唑-5-基-苯胺)-甲基]-呋喃-2-基}-甲醇(96)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-羟甲基-呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物96。
1HNMR(CDCl3,δ)3.90(s,3H,-OCH3),4.30(s,2H,-CH2),4.63(s,2H,-CH 2OH)5.97(d,J=2.5Hz,1H,3-Fu),6.16(d,J=2.5Hz,1H,3-Fu),6.27(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.34(s,1H,4-Ox),7.56(d,J=8.5Hz,1H,5-Ph),7.80(s,1H,2-Ox).
<实施例97>、N-(4-溴-5-乙基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(97)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和4-溴-5-乙基-噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物97,收率56.2%。
1HNMR(CDCl3,δ)1.28(t,3H,-CH2CH 3),2.81(q,2H,-CH 2CH3),3.88(s,3H,-OCH3),4.48(s,2H,-CH2-),6.25(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.76(s,1H,3-Th),7.34(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例98>、噻吩-2-磺酰-(3-甲氧基-4-噁唑-5-基-苯)胺(98)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和噻吩-2-磺酰氯为原料，按照实施例68的类似方法，得到化合物98,收率53.3%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),6.25(s,1H,2-Ph),6.39(d,J=8.5Hz,1H,6-Ph),7.00(m,1H,3-Th),7.04(m,1H,4-Th),7.24(m,1H,5-Th),7.34(s,1H,4-Ox),7.53(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例99>、5-氯-4-硝基-噻吩-2-磺酰-(3-甲氧基-4-噁唑-5-基-苯)胺(99)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-氯-4-硝基-噻吩-2-磺酰氯为原料，按照实施例68的类似方法，得到化合物99,收率49.3%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),6.24(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),6.81(s,1H,3-Th),7.34(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例100>、N-(2，3-二氢-苯并呋喃-5-基甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(100)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和2,3-二氢-苯并呋喃-5-甲醛为原料，按照实施例1的类似方法，得到化合物100,收率68.3%。
1HNMR(CDCl3,δ)2.96(m,2H,3-Fu),3.89(s,3H,-OCH3),4.27(m,2H,2-Fu),4.49(s,2H,-CH2-),6.25(s,1H,2-Ph),6.38(d,J=8.5Hz,1H,6-Ph),6.60(d,J=8Hz,1H,7-Fu),6.78(d,J=8Hz,1H,6-Fu),6.81(s,1H,4-Fu),7.33(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例101>、1-{5-[(3-甲氧基-4-噁唑-5-基-苯胺)-甲基]-噻吩-2-基}-乙酮(101)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-乙酰基-噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物101,收率55.3%。
1HNMR(CDCl3,δ)2.54(s,3H,-COCH 3),3.88(s,3H,-OCH3),4.47(s,2H,-CH2-),6.25(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.64(d,J=4Hz,1H,3-Th),7.28(d,J=4Hz,1H,4-Th),7.34(s,1H,4-Ox),7.58(d,J=8.5Hz,1H,5-Ph),7.82(s,1H,2-Ox).
<实施例102>、N-(5-甲硫基-噻吩-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(102)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-甲硫基-噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物102,收率41.6%。
1HNMR(CDCl3,δ)2.47(s,3H,-SCH 3),3.89(s,3H,-OCH3),4.48(s,2H,-CH2-),6.26(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.42(d,J=4Hz,1H,3-Th),6.69(d,J=4Hz,1H,4-Th),7.34(s,1H,4-Ox),7.55(d,J=8.5Hz,1H,5-Ph),7.80(s,1H,2-Ox).
<实施例103>、1-{5-[(3-甲氧基-4-噁唑-5-基-苯胺)-甲基]-噻吩-2-基}-哌啶-4-醇(103)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-(4-羟基-呱啶-1-基)-噻吩-2-甲醛为原料，按照实施例1的类似方法，得到化合物103,收率33.8%。
1HNMR(CDCl3,δ)1.95(m,4H,3,5-Pyd),3.38(m,4H,2,6-Pyd),3.89(s,3H,-OCH3),3.95(m,1H,4-Pyd),4.46(s,2H,-CH2-),6.26(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),6.15(d,J=4Hz,1H,3-Th),5.78(d,J=4Hz,1H,4-Th),7.34(s,1H,4-Ox),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例104>、N-[5-(2-氯-4-三氟甲基苯)呋喃-2-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(104)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和5-(2-氯-4-三氟甲基苯)-呋喃-2-甲醛为原料，按照实施例1的类似方法，得到化合物104,收率48.8%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.29(s,2H,-CH2-),6.25(s,1H,2-Ph),6.36(d,J=8.5Hz,1H,6-Ph),6.13(d,J=4Hz,1H,3-Fu),6.20(d,J=4Hz,1H,4-Fu),7.33(s,1H,4-Ox),7.35(d,J=8Hz,1H,6’-Ph),7.39(d,J=8Hz,1H,5’-Ph),7.52(s,1H,3’-Ph),7.56(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例105>、N-(3-呋喃-3-基-烯丙基)-3-甲氧基-4-(噁唑-5-基)-苯胺(105)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和3-呋喃-3-基-丙醛为原料，按照实施例1的类似方法，得到化合物105,收率28.3%。
1HNMR(CDCl3,δ)3.91(s,3H,-OCH3),4.00(d,J=5Hz,1H,-CH2-),6.30(s,1H,2-Ph),6.33(m,1H,-CH2-CH=CH-),6.36(d,J=4Hz,1H,4-Fu),6.38(d,J=8.5Hz,1H,6-Ph),6.64(m,1H,-CH2-CH=CH-),7.34(s,1H,4-Ox),7.39(d,J=4Hz,5-Fu),7.50(s,1H,2-Fu),7.57(d,J=8.5Hz,1H,5-Ph),7.81(s,1H,2-Ox).
<实施例106>、N-(苯并噻吩-5-甲基)-3-甲氧基-4-(噁唑-5-基)-苯胺(106)的合成
以3-甲氧基-4-(噁唑-5-基)苯胺和苯并噻吩-5-甲醛为原料，按照实施例1的类似方法，得到化合物106,收率56.8%。
1HNMR(CDCl3,δ)3.88(s,3H,-OCH3),4.49(s,2H,-CH2-),6.25(s,1H,2-Ph),6.35(d,J=8.5Hz,1H,6-Ph),7.11(d,J=8Hz,1H,6-Th),7.29(d,J=4Hz,1H,3-Th),7.34(s,1H,4-Ox),7.40(d,J=4Hz,1H,2-Th),7.57(d,J=8.5Hz,1H,5-Ph),7.58(s,1H,4-Th),7.74(d,J=8Hz,1H,7-Th),7.81(s,1H,2-Ox).
<实施例107>、IMPDH抑制剂活性的测定
以NAD和IMP为底物，NADH为显色剂,在96孔板上测定样品对IMPDH抑制剂活性。在96孔板上,样品孔中加入2μl待测样品、20μl酶提取液和30μlIMP;对照孔中加入2μlDMSO，30μlIMP；空白孔中加入2μlDMSO和20μlIMPDH缓冲液代替酶提取液和30μlIMP。37℃保温15min，测定孔A340(OD1),然后每孔中加入50μlNAD，37℃保温50min,测定每孔A340(OD2)。样品对IMPDH抑制率的计算公式为:抑制率(%)=[对照(OD2-OD1)-样品(OD2-OD1)]/[对照(OD2-OD1)-空白(OD2-OD1)]×100%。
测定结果见表2。
<实施例108>、抗柯萨奇病毒B3、B6型(COX-B3、COX-B6)活性筛选
病毒株COX-B3（或COX-B6），化合物临用前DMSO配成母液，检测时用培养液稀释成一定浓度后再作3倍稀释，共8个稀释度。阳性对照药利巴韦林(RBV)。测试方法：Vero细胞种96孔培养板，24小时后感染柯萨奇病毒B3（或B6）型10-5，吸附2小时，弃病毒液，按以上稀释度加入样品及阳性对照药，同时设细胞对照孔和病毒对照孔，待病毒对照组病变程度(CPE)达4+时观察各组细胞病变程度(CPE)，用Reed-Muench法分别计算样品对柯萨奇病毒B3（或B6）型的半数抑制浓度(IC50)。筛选结果列于表3、表4
<实施例109>、体外抑瘤(人肝癌细胞HepG2)活性测定
收集生长良好的肿瘤细胞,用含10%胎牛血清的RPMI-1640或DMEM培养基配成6×104/ml细胞悬液,接种于96孔板内,每孔100μl,37℃，5%CO2孵箱培养24h后,加入待测药液(药物终浓度0.625、1.25、2.5、5.0、10μg/ml)，每浓度设3个平行孔,同时设阳性药物对照(顺铂10、1、0.1μg/ml)和空白对照。培养48h后弃上清,每孔加入MTT液10μl(5mg/ml)，RPMI-1640培养基配制)后继续培养4h，每孔加入100μl酸化异丙醇细胞裂解液，过夜培养，用Bio-TekMQX200型酶标仪在检测波长540nm、参考波长450nm下测吸光度(A)值，抑制率计算：(A空白对照－A样品)/A空白对照×100，采用GraphpadPrism5统计软件计算IC50。筛选结果列于表5。
<实施例110>、体外抑瘤(人肺腺癌细胞A549)活性测定
细胞株：人肺腺癌细胞A549。收集生长良好的肿瘤细胞，用含10%胎牛血清的Ham’sF12培养液配细胞悬液，接种于96孔板内，每孔100μl，5000细胞/孔，37℃，5%CO2孵箱培养24h后,加入2×药液100μl，每浓度设3个平行孔，设置空白对照。培养48h后,每孔加入MTT液20μl(5mg/ml)，继续培养4h，吸弃上清液，用Bio-Rad680型酶标仪在检测波长570nm下测吸光度(A)值，存活率(%)计算：A样品/A空白对照×100，采用GraphpadPrism5统计软件计算IC50。所有样品初筛后，IC50＜100μg/ml的样品调整浓度梯度后进行附筛，附筛平行两次。筛选结果列于表5。
Claims (7)
1.一组苯-噁唑基衍生物或其药学上可接受的盐，具有通式(I)所示的结构：
式中：
R1代表：氢、卤素、羟基、C1-C3烷基、C1-C3烷氧基；
R2代表：氢、取代或未取代的C1-C12饱和或不饱和烃基、羰基或磺酰基，或不存在；
R代表：氰基、取代或未取代的C1-C12饱和或不饱和烃基、C1-C12烷氧基或芳基氧基、C1-C12烷硫基、磺酸基、磺酰基、取代或未取代的杂环基；
所述的杂环基选自五到六元单环杂环基、五到六元环的双环杂环基或三环杂环基；
其中，所述的五元单环杂环基选自取代或不取代的噻吩基、呋喃基、吡咯基或吡唑基；
其中，所述的六元单环杂环基选自取代或不取代的哌啶基、吡啶基、吡喃基、哒嗪基、嘧啶基或吡嗪基；
其中，所述的双环杂环基选自取代或不取代的吲哚基、苯并噻吩基、苯并吡喃基、硫苯并吡喃基、喹啉基、噌啉基、吲唑基、苯并噁二唑基或苯并噻二唑基；
其中，所述的三环杂环基选自取代或不取代的二苯并呋喃基、二苯并噻吩基、吖啶基或吩噻嗪基；
j＝0-1，m＝0-3，n＝0-6，j，m和n可相同也可以不同。
2.如权利要求1所述的苯-噁唑基衍生物在药学上可接受的盐，其特征在于，由所述通式(I)化合物与酸成盐，所述的酸选自无机酸或有机酸。
3.如权利要求2所述的苯-噁唑基衍生物在药学上可接受的盐，其特征在于，所述无机酸为盐酸、氢溴酸或硫酸；所述有机酸为乙酸、三氟乙酸、乳酸、琥珀酸、富马酸、马来酸、柠檬酸、苯甲酸、甲磺酸或对甲苯磺酸。
4.制备如权利要求1所述通式(I)化合物的方法，其特征在于，按以下反应方程式进行：
其中，M，X代表醛基、卤素、酰基，
将化合物A与化合物B混合溶解于溶剂中，二者反应后，再与化合物R2X反应，得到通式(I)化合物。
5.一种药物组合物，其特征在于，由治疗有效量的通式(I)化合物或其药学上可接受的盐为活性成分，与一种或多种药学上可接受的载体所组成。
6.如权利要求1所述的苯-噁唑基衍生物或其药学上可接受的盐在制备作为IMPDH抑制剂的药物中的应用，其特征在于，包括作为抗病毒药物、抗肿瘤药物或免疫抑制药物。
7.如权利要求5所述的药物组合物在制备作为IMPDH抑制剂的药物中的应用，其特征在于，包括作为抗病毒药物、抗肿瘤药物或免疫抑制药物。
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| CN201310065438.3A CN103304555B (zh) | 2012-03-08 | 2013-03-01 | 一组苯-噁唑基衍生物及其制备方法和作为impdh抑制剂的相关应用 |
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| CN201210060269 | 2012-03-08 | ||
| CN201310065438.3A CN103304555B (zh) | 2012-03-08 | 2013-03-01 | 一组苯-噁唑基衍生物及其制备方法和作为impdh抑制剂的相关应用 |
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| CN103304555A CN103304555A (zh) | 2013-09-18 |
| CN103304555B true CN103304555B (zh) | 2016-03-30 |
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| US (1) | US20150031686A1 (zh) |
| CN (1) | CN103304555B (zh) |
| WO (1) | WO2013131409A1 (zh) |
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| CA3026241A1 (en) | 2016-06-02 | 2017-12-07 | Steven Baranowitz | Prevention and treatment of viral infections |
| US12011429B2 (en) | 2016-06-02 | 2024-06-18 | Steven Baranowitz | Prevention and treatment of viral infections |
| US10603299B2 (en) | 2016-06-02 | 2020-03-31 | Steven Baranowitz | Prevention and treatment of viral infections |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6344465B1 (en) * | 1996-04-23 | 2002-02-05 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
| US20020143176A1 (en) * | 1998-10-29 | 2002-10-03 | Chunjian Liu | Compounds derived from an amine nucleus and pharmaceutical compositions comprising same |
| US6518291B1 (en) * | 1997-03-14 | 2003-02-11 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000025780A1 (en) * | 1998-10-29 | 2000-05-11 | Bristol-Myers Squibb Company | Compounds derived from an amine nucleus that are inhibitors of impdh enzyme |
| EP1942888A2 (en) * | 2005-11-02 | 2008-07-16 | Cytokinetics, Inc. | Certain chemical entities, compositions, and methods |
| BRPI0710950A2 (pt) * | 2006-04-28 | 2012-06-26 | Shionogi & Co | derivado de amina tendo atividade antagonìstica de receptor y5 de npi 53 a61p 3/04 a61p 9/04 a61p 9/12 a61p 15/00 a61p 25/08 a61p 25/20 a61p 25/24 a61p 43/00 c07c 311/07 c07c 317/36 c07d 207/325 c07d 211/14 c07d 213/38 c07d 213/74 c07d 213/82 c07d 215/38 c07d 217/04 c07d 217/14 c07d 217/22 c07d 219/10 c07d 231/38 c07d 233/61 c07d 235/30 c07d 237/20 c07d 237/22 c07d 237/34 c07d 239/42 c07d 241/20 c07d 261/14 c07d 261/20 c07d 263/58 c07d 265/30 c07d 265/36 c07d 267/14 c07d 275/02 c07d 277/28 c07d 277/62 c07d 277/82 c07d 295/12 c07d 295/18 c07d 333/36 c07d 333/40 c07d 333/66 c07d 333/72 c07d 403/04 c07d 409/04 c07d 413/04 c07d 417/12 c07d 498/04 c07d 513/04 |
| SA08290668B1 (ar) * | 2007-10-25 | 2012-02-12 | شيونوجي آند كو.، ليمتد | مشتقات أمين لها نشاط مضاد لمستقبل npy y5 واستخداماتها |
| US8227618B2 (en) * | 2009-04-23 | 2012-07-24 | Shionogi & Co., Ltd. | Amine-derivatives having NPY Y5 receptor antagonistic activity and the uses thereof |
-
2013
- 2013-03-01 CN CN201310065438.3A patent/CN103304555B/zh not_active Expired - Fee Related
- 2013-03-06 US US14/383,616 patent/US20150031686A1/en not_active Abandoned
- 2013-03-06 WO PCT/CN2013/000234 patent/WO2013131409A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6344465B1 (en) * | 1996-04-23 | 2002-02-05 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
| US6518291B1 (en) * | 1997-03-14 | 2003-02-11 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
| US20020143176A1 (en) * | 1998-10-29 | 2002-10-03 | Chunjian Liu | Compounds derived from an amine nucleus and pharmaceutical compositions comprising same |
Non-Patent Citations (1)
| Title |
|---|
| Inhibitors of Inosine Monophosphate Dehydrogenase: SARs about the N-[3-Methoxy-4-(5-oxazolyl)phenyl Moiety;Edwin J. Iwanowicz等;《 Bioorganic & Medicinal Chemistry Letters》;20030616;第13卷(第12期);第2060-2061页表格1-3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20150031686A1 (en) | 2015-01-29 |
| WO2013131409A1 (zh) | 2013-09-12 |
| CN103304555A (zh) | 2013-09-18 |
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