CN101080404B - 嘧啶基异噁唑衍生物 - Google Patents

嘧啶基异噁唑衍生物 Download PDF

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CN101080404B
CN101080404B CN2005800435089A CN200580043508A CN101080404B CN 101080404 B CN101080404 B CN 101080404B CN 2005800435089 A CN2005800435089 A CN 2005800435089A CN 200580043508 A CN200580043508 A CN 200580043508A CN 101080404 B CN101080404 B CN 101080404B
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phenyl
pyrimidyl
isoxazole
kharophen
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莲见幸市
太田修治
斋藤教久
佐藤秀一郎
加藤淳也
佐藤润
铃木弘幸
浅野创
冈田真美
松本康浩
代田和彦
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Aska Pharmaceutical Co Ltd
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Abstract

本发明公开了式(I)所示的具有优异的P38MAP激酶抑制作用的异噁唑衍生物或其制药学上可接受的盐。式中,R1表示氢原子、低级烷基、氨基、卤素原子、低级烷氧基等;R2表示取代或未取代的芳基等;R3表示氢原子或低级烷基;R4表示取代或未取代的苯基等;Y表示-CH2-、-CO-、-CH(CH3)-、-O-、-NH-等。

Description

嘧啶基异噁唑衍生物 
技术领域
本发明涉及新型的嘧啶基异噁唑衍生物或其盐、其制备方法以及用途。本发明的化合物具有P38MAP激酶抑制作用和基于该作用的肿瘤坏死因子-α(以下称为“TNF-α”)、白细胞介素-1(以下称为“IL-1”)、白细胞介素-6(以下称为“IL-6”)、白细胞介素-8(以下称为“IL-8”)、环加氧酶-II(以下称为“COX-II”)等的生成抑制作用,作为TNF-α关连疾病、IL-1关连疾病、IL-6关连疾病、IL-8关连疾病、COX-II关连疾病等的处置剂有效。
背景技术
已知TNF-α、IL-1、IL-6、IL-8和COX-II为主要由巨噬细胞、中性粒细胞等免疫系统的细胞产生的蛋白质(细胞因子),除了具有免疫调节功能或炎症症状等之外,还是参与造血系统、内分泌系统、神经系统等的重要因子之一。
另一方面,P38MAP激酶具有激活NF-кB、AP-1、CREB等转录因子的作用,这些转录因子与TNF-α、IL-1、IL-6、IL-8、COX-II等上共通的序列的DNA结合,促进合成各自的细胞因子的mRNA的转录,因此P38MAP激酶具有促进TNF-α等细胞因子生成的作用。另外,转录的mRNA与特定的蛋白质结合而失活,然后迅速分解,而P38MAP激酶具有使mRNA与特定的蛋白质的结合解离的作用,单从这一点也可以说P38MAP激酶有助于TNF-α等细胞因子的产生。
因此,P38MAP激酶的抑制与抑制TNF-α等细胞因子的生成相关,结果,期待对下述的与TNF-α等细胞因子相关的疾病的处置或预防有效,所述疾病例如有:急性炎症、慢性炎症、类风湿性关节炎、变形性膝关节症、痛风、炎症性肠疾病、节段性肠炎、溃疡性大肠炎、胃炎、结肠息肉、大肠癌、结肠癌、哮喘、支气管炎、支气管哮喘、过敏性鼻炎、急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺疾病、肺纤维变性、充血性心脏病、局部缺血性心脏病、心肌梗死、动脉硬化、高血压、心绞痛、早老性痴呆、再灌流损伤、血管炎、脑血管障碍、脑膜炎、多发性大脑硬化、骨质疏松症、骨硬化、贝切特氏病、骨转移、多发性骨髓瘤、急性感染、内毒素休克、败血病、毒素性休克综合征、结核、弥散性血管内凝血病(DIC)、银屑病、特应性皮炎、肝硬化、肾纤维变性、恶病质、艾滋病(AIDS)、恶性肿瘤、自体免疫疾病、糖尿病、巨大淋巴结增生症(Castleman病)、肾小球膜细胞增殖性肾炎、子宫内膜异位、早产等。
到目前为止,作为具有P38MAP激酶抑制作用的化合物,已提案的有:咪唑衍生物(参照Bioorganic & Medicinal Chemistry,Vol.5,No.1,49-64(1997)和日本特表平7-503017号公报)、吡唑衍生物(参照PCT国际公开WO98/52940小册子和PCT国际公开WO00/39116小册子)、异噁唑衍生物(参照日本特表平11-503722号公报、日本特开2002-179656号公报、PCT国际公开WO2004/17968小册子、日本特开2000-86657号公报和PCT国际公开WO2004/22555小册子)等。但是,这些化合物有许多副作用,还不能作为药品在市。
最近,Katerina Leftheris等人发表:某种三嗪衍生物既具有强力的P38MAP激酶抑制作用又能够迅速代谢,因此有望减轻副作用,可作为抗风湿病药(参照J.Med.Chem.,Vol.47,6283-6291(2004))。
发明内容
本发明的目的在于提供既具有优异的P38MAP激酶抑制作用叉可以减轻副作用的嘧啶基异噁唑衍生物。
本发明人这次发现:某种新型的4-(4-嘧啶基)异噁唑衍生物既具有优异的P38MAP激酶抑制作用且在血液中的代谢消失速度迅速,因此P38MAP激酶抑制剂可以减轻目前成为问题的副作用,从而完成了本发明。
因此,本发明提供式(I)所示的嘧啶基异噁唑衍生物或其制药学上可接受的盐:
Figure G05843508920070620D000031
式中,
R1表示氢原子、低级烷基、氨基、低级烷基氨基、二低级烷基氨基、苯基低级烷基氨基、酰基氨基、卤素原子、低级烷氧基、低级烷基硫基或低级烷基亚硫酰基;
R2表示未取代的芳基或杂芳基,或者被选自卤素原子、低级烷基、低级烷氧基、低级卤代烷基、低级亚烷基二氧基或苄氧基的1~3个取代基取代的芳基或杂芳基;
R3表示氢原子或低级烷基;
R4表示取代或未取代的苯基或者取代或未取代的杂环基;
Y表示-(CH2)n-、-CO-、-CH(CH3)-、-O-、-NH-、
Figure G05843508920070620D000032
或 
Figure G05843508920070620D000033
,其中n表示0~3的整数。
本发明还提供P38MAP激酶抑制剂,其特征在于:该抑制剂含有式(I)的嘧啶基异噁唑衍生物或其制药学上可接受的盐。
本说明书中,所说的“低”是指带有该词语下的基团的碳原子数为6个以下、优选为4个以下。
“低级烷基”可以是直链或支链,例如有:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等,其中,优选甲基、乙基、正丙基、异丙基和正丁基,“低级烷氧基”是被该低级烷基取代的氧(O)基,例如有:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、正戊氧基、正己氧基等,其中,优选甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基。
“卤素原子”包含氟、氯、溴和碘原子,特别优选氟、氯和溴原子。
R1定义中的“低级烷基氨基”是指被1个上述的低级烷基取代的氨基,“二低级烷基氨基”是指被2个上述的低级烷基取代的氨基。其中,二低级烷基氨基中的2个低级烷基可以相同、也可以相互不同。另外,“苯基低级烷基氨基”是指上述低级烷基氨基中的低级烷基部分进一步被1个苯基取代的基团。
R1定义中的“低级烷基硫基”和“低级烷基亚硫酰基”分别是指被上述的低级烷基取代的硫(S)基和亚硫酰(SO)基。
R1定义中的“酰基氨基”是指酰基化的氨基,作为酰基,例如有:甲酰基、乙酰基、丙酰基、丁酰基等低级烷酰基或苯甲酰基等芳酰基等,其中,优选乙酰基和苯甲酰基。
R2定义中的“芳基”例如有苯基、萘基等,其中,优选苯基。R2 定义中的“杂芳基”包含具有选自N、O和S的1~2个杂原子的5~6元杂芳基,根据情况可与苯环稠合,例如有:吡啶基、喹啉基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基等,其中,特别优选吡啶基。
R2定义中的“低级卤代烷基”是指被1个或1个以上相同或不同的卤素原子取代的上述低级烷基,例如有:氟甲基、三氟甲基、1,2-二氯乙基、1-氯-2-溴乙基、五氟乙基、1-氯-正丙基、2-溴-2-甲基乙基、3-氯-正戊基、2-溴-3-氯-正己基等,其中,特别优选被1~5个相同或不同的卤素原子取代的碳数为1或2个的低级烷基。
R2定义中的“低级亚烷基二氧基”例如有:亚甲基二氧基、亚乙基二氧基、三亚甲基二氧基等,特别优选亚甲基二氧基。
R4定义中的“杂环基”包含具有选自N、O和S的1~3个杂原子的饱和或不饱和的5~7元杂环基,可根据情况形成稠合环,例如有:吡啶基、嘧啶基、氮杂基(アゼピニル)、喹啉基、吲哚基、喹唑啉基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、异噁唑基、噻唑基、吡咯烷基、异苯并二氢吡喃基等,其中,优选噻吩基和异噁唑基。
作为R4定义中的“取代或未取代的苯基”的苯基上的取代基例如有:卤素原子、低级烷基、低级烷氧基、硝基、低级卤代烷基、低级卤代烷基硫基、羟基、氨基等,其中,优选卤素原子、低级烷基、低级烷氧基、硝基、低级卤代烷基和低级卤代烷基硫基,特别优选卤素原子和低级烷基。作为R4定义中的“取代或未取代的杂环基”的杂环基上的取代基,例如有:卤素原子、低级烷基、低级烷氧基、硝基、低级卤代烷基、氨基等,特别优选卤素原子和低级烷基。
本发明中优选的一组化合物为R1表示氢原子、氨基、低级烷基氨基或二低级烷基氨基时的式(I)化合物,其中,更优选的是R1表示氢原子时的式(I)化合物。R1的优选取代位置为嘧啶环的2位。
本发明中优选的另一组化合物为R2表示被选自卤素原子、低级烷基、低级烷氧基和低级亚烷基二氧基的1~3个取代基取代的苯基时的式(I)化合物,其中,更优选R2表示被选自卤素原子、低级烷基和低级亚烷基二氧基的1或2个取代基取代的苯基时的式(I)化合物,特别优选R2为4-氟苯基、2,4-二氟苯基、4-氯苯基、3-甲基苯基、2-氟-5-甲基苯基、4-氟-3-甲基苯基、2-氟-4-甲氧基苯基或2,3-亚甲基二氧基苯基时的式(I)化合物。
本发明中优选的又一组化合物为R3表示氢原子时的式(I)化合物。
本发明中优选的又一组化合物为R4表示取代或未取代的苯基时的式(I)化合物,其中,更优选R4表示未取代的苯基或被选自卤素原 子、低级烷基和低级烷氧基的1或2个取代基取代的苯基时的式(I)化合物,特别优选R4为未取代的苯基、2-卤代苯基、2,6-二卤代苯基、2-低级烷基苯基、3-低级烷基苯基、3-低级烷氧基苯基或2,5-二低级烷基苯基时的式(I)化合物。
本发明中优选的又一组化合物为Y表示-CH2-时的式(I)化合物。
本发明提供的上述式(I)化合物的代表例除了后述实施例中揭示的例子之外,还例举如下。
3-(4-氟苯基)-4-[4-(2-甲基氨基嘧啶基)]-5-(苯基乙酰氨基)异噁唑、
5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)-4-[4-(2-甲基氨基嘧啶基)]异噁唑、
4-[4-(2-二甲基氨基嘧啶基)]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑、
5-[(2-氯苯基)乙酰氨基]-4-[4-(2-二甲基氨基嘧啶基)]-3-(4-氟苯基)异噁唑、
4-[4-(2-苄基氨基嘧啶基)]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑、
4-[4-(2-苄基氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑、
4-[4-(2-乙酰氨基嘧啶基)]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑、
4-[4-(2-乙酰氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑、
4-[4-(2-苯甲酰氨基嘧啶基)]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑、
4-[4-(2-苯甲酰氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑、
3-(4-氟苯基)-5-(N-甲基-苯基乙酰氨基)-4-(4-嘧啶基)异噁唑、
3-(4-氟苯基)-5-[(2-氯苯基)乙酰基-N-甲基氨基]-4-(4-嘧啶基)异噁唑、
5-(N-乙基-苯基乙酰氨基)-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰基-N-乙基氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑、
3-[4-(2-甲基吡啶基)]-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰氨基]-3-[4-(2-甲基吡啶基)]-4-(4-嘧啶基)异噁唑、
3-[2-(6-甲基吡啶基)]-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰氨基]-3-[2-(6-甲基吡啶基)]-4-(4-嘧啶基)异噁唑、
3-[2-(4-甲基吡啶基)]-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑、
5-[(2-氯苯基)乙酰氨基]-3-[2-(4-甲基吡啶基)]-4-(4-嘧啶基)异噁唑等。
本发明的式(I)化合物根据情况可以以盐的形态存在,其盐例如有:与盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸的盐;与乙酸、草酸、柠檬酸、乳酸、酒石酸、对甲苯磺酸等有机酸的盐等,其中,优选制药学上可接受的盐。
本发明的式(I)化合物例如可以通过下述方法(a)或(b)来制备。
方法(a):上述式(I)中R3表示氢原子时的化合物,即,下述式的化合物:
Figure G05843508920070620D000071
式中,R1、R2、R4和Y具有上述的定义,
可以通过使下述式的化合物:
式中,R1和R2具有上述的定义,
与下述式的羧酸化合物或其反应性衍生物(例如酰卤、酸酐、混合酸酐、活性酰胺、活性酯等)反应制备。
Figure G05843508920070620D000082
式中,R4和Y具有上述的定义。
方法(b):上述式(I)中R3表示低级烷基时的式(I)化合物,即,下述式的化合物:
式中,R1、R2、R4和Y具有上述的定义,R表示低级烷基,
可以通过将上述式(I-1)的化合物进行N-低级烷基化来制备。
方法(a)中,式(III)的羧酸化合物优选事先利用例如1,1-羰基二咪唑(CDI)、1,1-亚硫酰二咪唑等进行处理,然后再变换为活性酰胺等反应性衍生物。使用酰基卤、例如酰基氯作为上述式(III)的羧酸化合物的反应性衍生物时,该酰基卤可以事先利用例如咪唑和DBU等进行处理,然后再变换为咪唑烷酮(イミダゾリド)等其它反应性衍生物。
应说明的是,上述式(II)的化合物中R1表示氨基或低级烷基氨基时,根据需要,该氨基或该低级烷基氨基可以是事先利用适当的保护基进行保护的状态,例如制成使用二碳酸二叔丁基酯(BOC)、丙酮 基丙酮、苄氧基羰基氯(Z-氯)等进行保护的状态,反应结束后将该保护基脱离。
上述式(II)的化合物与上述式(III)的羧酸化合物或其反应性衍生物的反应通常在惰性有机溶剂,例如二噁烷、四氢呋喃、二甲氧基乙烷等醚类;苯、甲苯、二甲苯等芳族烃类;二氯甲烷、氯仿等卤代烃类;二甲基甲酰胺、二甲基乙酰胺等酰胺类;二甲基亚砜等中,根据需要在碱例如1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺、二异丙基乙胺、吡啶等存在下进行。反应温度通常适合在0℃至反应混合物的回流温度,优选冰冷却下至50℃范围内的温度。
通常每1摩尔式(II)的化合物中,式(III)的羧酸化合物或其反应性衍生物可以在至少1摩尔、优选1.5~10摩尔、进一步优选2~5摩尔的范围内使用。另外,通常每1摩尔式(III)的羧酸化合物或其反应性衍生物中,碱的使用比例可以为至少1摩尔、优选1~2摩尔的范围。
应说明的是,作为起始物质使用的上述式(II)的化合物可以按照其本身已知的合成方法,例如下述反应式1中所示的途径容易地合成。关于反应式1中的反应条件等细节请参照后述实施例1的a)~c)。
反应式1:
Figure G05843508920070620D000091
式中,R1和R2具有上述的定义、X表示卤素原子。
方法(b)中,上述式(I-1)的化合物的N-低级烷基化反应通常在惰性有机溶剂,例如甲醇、乙醇、异丙醇等醇类;二噁烷、四氢呋喃、二甲氧基乙烷等醚类;苯、甲苯、二甲苯等芳族烃类;二甲基甲酰胺、二甲基乙酰胺等酰胺类;二甲基亚砜等中,在适当的碱例如氢氧化钠、碳酸钾、吡啶等存在下,使低级烷基卤,例如碘甲烷、溴乙烷、溴丙烷等反应。反应温度,通常在0℃至反应混合物的回流温度,优选室温至50℃范围内的温度。
通常每1摩尔式(I-1)的化合物中,低级烷基卤可以在至少1摩尔、优选1.1~5摩尔、进一步优选1.2~4摩尔的范围内使用。另外,通常每1摩尔式(I-1)的化合物中,碱的使用比例可以为至少1摩尔、优选1~5摩尔的范围。
按照上述方法制备的本发明的式(I)化合物可以通过其本身已知的手段,例如重结晶、柱层析、薄层色谱等方法,从反应混合物中分离、纯化。
本发明的由式(D所示的嘧啶基异噁唑衍生物或其制药学上可接受的盐既具有优异的P38MAP激酶抑制作用又可以减轻副作用,对处置或预防人、其他哺乳动物的下述的与TNF-α、IL-1、IL-6、IL-8、COX-II等相关的疾病有效,所述疾病例如:急性炎症、慢性炎症、类风湿性关节炎、变形性膝关节症、痛风、炎症性肠疾病、节段性肠炎、溃疡性大肠炎、胃炎、结肠息肉、大肠癌、结肠癌、哮喘、支气管炎、支气管哮喘、过敏性鼻炎、急性呼吸窘迫综合征、慢性阻塞性肺疾病、肺纤维变性、充血性心脏病、局部缺血性心脏病、心肌梗死、动脉硬化、高血压、心绞痛、早老性痴呆、再灌流损伤、血管炎、脑血管障碍、脑膜炎、多发性大脑硬化、骨质疏松症、骨硬化、贝切特氏病、骨转移、多发性骨髓瘤、急性感染、内毒素休克、败血病、毒素性休克综合征、结核、弥散性血管内凝血病、银屑病、特应性皮炎、肝硬化、肾纤维变性、恶病质、艾滋病、恶性肿瘤、自体免疫疾病、糖尿病、巨大淋巴结增生症、肾小球膜细胞增殖性肾炎、子宫内膜异位、早产等。
本发明的式(I)化合物所具有的TNF-α生成抑制作用、本发明的式(I)化合物在血液中的代谢消失速度和本发明的式(I)化合物所具有的P38MAP激酶抑制作用可以通过下述实验显示。
(1)TNF-α生成抑制作用的测定:
将来自人的培养细胞THP-1(购自大日本制药)悬浮在RPMI 1640培养基(含有10%胎牛血清、100单位/mL青霉素)(1×105细胞/mL)中。在培养用24孔板上接种1.6mL THP-1细胞悬浮液,再加入溶解于RPMI 1640培养基的0.2mL受试物质和0.2mL 10μg/mL浓度的LPS(E.coli 055:来自B5、溶解于RPMI 1640培养基、Difco),然后在37℃、5%CO2条件下培养2小时。离心(500×g、5分钟),利用ELISA(酶联免疫吸附测定,Amersham Biosciences,TNF-αHuman,ELISABiotrak System)法测定得到的上清液,进行TNF-α的定量。各受试物质的50%抑制浓度(IC50)如下求出。首先,通过下式求出各种浓度下的TNF-α的生成抑制率(%)。
Figure G05843508920070620D000111
由该式得到的TNF-α的生成抑制率(%)和此时的受试物质浓度通过Prism 4 for WIndows Ver 4.02(Graph Pad Software,Inc)计算,算出IC50值。其结果与下述(2)化合物代谢速度的测定结果一起如后述表A所示。
(2)化合物的代谢速度的测定:
向含有NADPH生成物(含有3.3mmol/L MgCL2、3.3mmol/L葡糖-6-磷酸酯、1.3mmol/L β-NADP+和0.4单位/mL葡糖-6-磷酸脱氢酶)的磷酸钾缓冲液(50mmol/L,pH7.4)中添加化合物(此时,使终浓度为1μmol/L),在37℃下温育2分钟。温育后,添加人肝脏S9(人 肝脏细胞破碎液在9000×g下离心而得到的上清液组分)的磷酸钾缓冲液悬浮液,使终浓度为0.5mg蛋白/mL。将该反应混合液在37℃下温育5分钟,然后添加反应混合液的4倍容积的乙腈,混合、冰冷却。冰冷却后离心(2000×g、10分钟),采集上清液的一部分,利用LC/MS/MS进行分析,算出反应溶液中的未变化体的残留率。其结果与上述(1)的TNF-α生成抑制作用的测定结果一起如下述表A所示。
表A
Figure G05843508920070620D000131
(3)P38MAP激酶抑制活性的测定:
使用人P38MAP激酶在大杆菌中表达的重组蛋白作为酶源,使用10μg/mL髓鞘碱性蛋白(MBP)作为底物。温育缓冲液使用50mmol/L HEPES、20mmol/L MgCl2、0.2mmol/L Na3VO4、1mmol/L二硫苏糖醇(DTT)、pH7.4。利用ELISA法测定P38MAP激酶引起的MBP的磷酸化。温育温度和时间为:25℃下预温育15分钟、25℃下温育60分钟。各化合物的浓度为1nmol/L~10μmol/L,使用1%DMSO作为载体。测定结果如下述表B所示。
表B
  化合物   对P38MAP激酶α的IC50值(nM)
  实施例13   19.0
  实施例201   9.32
因此,本发明的式(I)表示的嘧啶基异噁唑衍生物或其制药学上可接受的盐作为既具有优异的作用代谢速度又快的P38MAP激酶抑制剂,作为用于人或人以外的哺乳物的疾病的治疗、处置、疾病预防等药品,可以对患者口服或肠道外给药(例如肌肉注射、静脉注射、直肠给药、经皮给药等)。
本发明的化合物作为药品使用时,根据其用途,可以与无毒性的添加剂一起制成下述任一种制剂形态:固体形态(例如片剂、硬胶囊剂、软胶囊剂、颗粒剂、散剂、细粒剂、丸剂、糖锭等)、半固体形态(例如栓剂、软膏等)或液体形态(例如注射剂、乳剂、悬浮液、洗液、喷雾剂等)。上述制剂中可使用的无毒性添加物例如有:淀粉、明胶、葡萄糖、乳糖、果糖、麦芽糖、碳酸镁、滑石粉、硬脂酸镁、甲基纤维素、羧甲基纤维素或其盐、阿拉伯树胶、聚乙二醇、对羟基苯甲酸烷基酯、糖浆、乙醇、丙二醇、凡士林、聚乙二醇、甘油、氯化钠、亚硫酸钠、磷酸钠、柠檬酸等。该制剂还可以含有治疗学上有效的其它药物。
该制剂中本发明的化合物的含量根据其剂型而不同,通常,固体和半固体形态时优选为0.1~50%重量的范围内,液体形态时优选为0.05~10%重量的范围内。
本发明的化合物的给药量可以根据对象为以人为代表的恒温动物的种类、年龄、体重、给药途径、症状的轻重、医师的诊断等可广范围地改变,一般来说,每日给药量可以在0.02~20mg/kg、优选0.2~8mg/kg的范围内。但是,根据患者症状的轻重、医师的诊断等,当然可以给予低于上述范围下限的量或高于上限的量。上述给药量可以每日给药1次或分数次给药。
实施例
以下,通过实施例和制剂例更具体地说明本发明。
实施例1
3-(4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:二甲基-[(E)-2-(4-嘧啶基)乙烯基]胺的合成
将10g 4-甲基嘧啶与38g N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)和46.6g DMF的混合物在140℃密封管中搅拌24小时。将反应溶液冷却,然后减压下馏去溶剂,得到15.08g(收率:95%)茶色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.73(bs,1H),8.22(d,J=5.5Hz,1H),7.77(d,J=12.9Hz,1H),6.72(dd,J=5.5Hz,12.9Hz,1H),5.00(d,J=12.9Hz,1H),2.96(s,6H)。
b:4-嘧啶基乙腈的合成
向5g二甲基-[(E)-2-(4-嘧啶基)乙烯基]胺的70mL水溶液中加入9.48g羟胺-O-磺酸,50℃下搅拌30分钟。冰冷却下向反应溶液中加入饱和碳酸氢钠水溶液,使溶液呈碱性,然后用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用30g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=30∶1)纯化,得到1.56g(收率:39%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:9.21(d,J=1.2Hz,1H),8.80(d,J=5.2Hz,1H),7.51(dd,J=1.2Hz,5.2Hz,1H),3.93(s,2H)。
c:5-氨基-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的合成
将2.50g甲醇钠溶解于50mL甲醇中,滴入5g 4-嘧啶基乙腈的50mL THF溶液,然后室温下搅拌30分钟。接着,滴入7.29g 4-氟苯甲酰氯(4-フルオロベンズヒドロキシモイルクロリド)的50mL甲醇溶液,然后室温下搅拌7小时。减压下馏去反应溶液中的溶剂,然后加水、滤取析出的残余物,水洗后减压下干燥。将所得残余物用80g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=50∶1~30∶1)纯化,用乙醚洗涤,得到7.86g(收率:73%)淡灰色结晶的标题化合物。
1H-NMR(CDCl3)δ:9.03(d,J=1.4Hz,1H),8.32(d,J=5.6Hz,1H),7.54~7.49(m,2H),7.24~7.18(m,2H),6.88(bs,2H),6.70(dd,J=1.4Hz,5.6Hz,1H)。
Mass,m/e:256(M+),111(base)。
d:3-(4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑的合成
将0.43g咪唑和1.9g DBU溶解于40mL THF中,冰冷却搅拌下,滴入0.97g苯乙酰氯,然后室温下搅拌20分钟。随后,滴入0.8g 5-氨基-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的40mL THF溶液,然后室温下搅拌6小时。减压下馏去反应溶液中的溶剂,加水,用乙酸乙酯萃取。用无水硫酸镁干燥有机层,然后减压下馏去溶剂。将所得残余物用40g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=100∶1)纯化,然后用乙醚洗涤,得到0.77g(收率:66%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.39(s,1H),8.49(s,1H),8.36(d,J=5.6Hz,1H),7.50~7.38(m,7H),7.20(t,J=8.5Hz,2H),6.73(dd,J=1.3Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:374(M+),240(base)。
实施例2
3-(4-氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
向0.12g 2’-氟苯基乙酸的5mL THF溶液中加入0.126g CDI,室温下搅拌1小时。接着,加入0.237g DBU与0.1g 5-氨基-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的5mL THF溶液,室温下搅拌11小时。减压下馏去反应溶液中的溶剂,加水用乙酸乙酯萃取。用无水硫酸镁干燥有机层,然后减压下馏去溶剂。将所得残余物用15g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=100∶1)纯化,然后用乙醚·己烷洗涤,得到0.090g(收率:59%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.57(s,1H),8.62(s,1H),8.39(d,J=5.7Hz,1H),7.50~7.40(m,4H),7.30~7.17(m,4H),6.76(dd,J=1.6Hz,5.7Hz,1H),3.97(s,2H)。
Mass,m/e:392(M+),109(base)。
以下,与实施例2进行同样地操作,合成实施例3~43的化合物。
实施例3
3-(4-氟苯基)-5-[(3-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.66(s,1H),8.39(d,J=5.4Hz,1H),7.48~7.43(m,3H),7.22~7.18(m,3H),7.15~7.12(m,2H),6.76(dd,J=1.2Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:392(M+),109(base。)
实施例4
3-(4-氟苯基)-5-[(4-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(bs,1H),8.65(s,1H),8.40(d,J=5.8Hz,1H),7.48~7.44(m,2H),7.39~7.36(m,2H),7.22~7.13(m,4H),6.76(dd,J=1.5Hz,5.8Hz,1H),3.91(s,2H)。
Mass,m/e:392(M+),109(base)。
实施例5
5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(bs,1H),8.54(s,1H),8.38(d,J=5.7Hz,1H),7.55~7.38(m,6H),7.20(t,J=8.7Hz,2H),6.75(dd,J=1.3Hz,5.7Hz,1H),4.06(s,2H)。
Mass,m/e:408(M+),240(base)。
实施例6
5-[(3-氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.69(s,1H),8.40(d,J=5.4Hz,1H),7.50~7.38(m,5H),7.29(dt,J=1.9Hz,6.6Hz,1H),7.21(t,J=8.7Hz,2H),6.77(dd,J=1.3Hz,5.4Hz,1H),3.92(s,2H)。
Mass,m/e:408(M+),240(base)。
实施例7
5-[(4-氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.65(s,1H),8.42(d,J=5.5Hz,1H),7.50~7.42(m,4H),7.35(d,J=8.6Hz,2H),7.21(t,J=8.6Hz,2H),6.77(dd,J=1.4Hz,5.5Hz,1H),3.92(s,2H)。
Mass,m/e:408(M+),240(base)。
实施例8
5-[(2-溴苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.53(s,1H),8.38(d,J=5.5Hz,1H),7.72(dd,J=1.2Hz,7.7Hz,1H),7.50~7.43(m,4H),7.37~7.31(m,1H),7.20(t,J=8.7Hz,2H),6.75(dd,J=1.3Hz,5.5Hz,1H),4.09(s,2H)。
Mass,m/e:454(M+),240(base)。
实施例9
5-[(2-碘苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.51(s,1H),8.38(d,J=5.5Hz,1H),8.00(d,J=7.7Hz,1H),7.52~7.43(m,4H),7.24~7.13(m,3H),6.75(dd,J=1.3Hz,5.5Hz,1H),4.10(s,2H)。
Mass,m/e:500(M+),240(base)。
实施例10
3-(4-氟苯基)-5-[(2,5-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.62(bs,1H),8.80(s,1H),8.43(d,J=5.6Hz,1H),7.50~7.46(m,2H),7.23~7.06(m,5H),6.79(dd,J=1.5Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:410(M+),240(base)。
实施例11
5-[(2,6-二氟苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.65(s,1H),8.70(s,1H),8.41(d,J=5.4Hz,1H),7.48(dd,J=5.2Hz,8.6Hz,2H),7.45~7.36(m,1H),7.21(t,J=8.6Hz,2H),7.04(t,J=7.7Hz,2H),6.79(dd,J=1.3Hz,5.4Hz,1H),4.02(s,2H)。
Mass,m/e:410(M+),240(base)。
实施例12
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.72(s,1H),8.42(d,J=5.4Hz,1H),7.51~7.43(m,4H),7.30~7.18(m,2H),7.12(dt,J=2.7Hz,8,1Hz,1H),6.79(dd,J=1.5Hz,5.4Hz,1H),4.04(s,2H)。
Mass,m/e:426(M+),240(base)。
实施例13
5-[(2-氯-6-氟苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(s,1H),8.64(s,1H),8.40(d,J=5.7Hz,1H),7.51~7.45(m,2H),7.43~7.34(m,2H),7.26~7.13(m,3H),6.78(dd,J=1.3Hz,5.7Hz,1H),4.14(s,2H)。
Mass,m/e:426(M+),240(base)。
实施例14
5-[(2,4-二氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(s,1H),8.71(s,1H),8.42(d,J=5.6Hz,1H),7.54(d,J=1.9Hz,1H),7.48(dd,J=5.4Hz,8.9Hz,2H),7.43~7.35(m,2H),7.21(t,J=8.9Hz,2H),6.79(dd,J=5.6Hz,1H),4.04(s,2H)。
Mass,m/e:442(M+),240(base)。
实施例15
5-[(3,4-二氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.78(s,1H),8.43(d,J=5.7Hz,1H),7.54~7.51(m,2H),7.48(dd,J=5.2Hz,8.7Hz,2H),7.27~7.19(m,3H),6.79(dd,J=1.4Hz,5.7Hz,1H),3.91(s,2H)。
Mass,m/e:442(M+),240(base)。
实施例16
5-[(2,6-二氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.62(s,1H),8.41(d,J=5.6Hz,1H),7.49(t,J=7.5Hz,4H),7.37(dd,J=7.3Hz,8.5Hz,1H),7.2 3(t,J=8.5Hz,2H),6.79(dd,J=1.5Hz,5.6Hz,1H),4.33(s,2H)。
Mass,m/e:442(M+),240(base)。
实施例17
3-(4-氟苯基)-5-[(2-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.34(s,1H),8.46(s,1H),8.35(d,J=5.5Hz,1H),7.49~7.42(m,3H),7.34(dd,J=1.7Hz,7.5Hz,1H),7.19(t,J=8.6Hz,2H),7.09(dt,J=1.0Hz,7.5Hz,1H),6.99(d,J=8.6Hz,1H),6.72(dd,J=1.3Hz,5.5Hz,1H),3.88(s,2H),3.81(s,3H)。
Mass,m/e:404(M+),148(base)。
实施例18
5-[(3-甲氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(s,1H),8.60(d,J=1.3Hz,1H),8.37(d,J=5.5Hz,1H),7.49~7.43(m,2H),7.40(t,J=7.9Hz,1H),7.20(t,J=8.7Hz,2H),7.00~6.93(m,3H),6.73(dd,J=1.3Hz,5.5Hz,1H),3.90(s,2H),3.84(s,3H)。
Mass,m/e:404(M+),240(base)。
实施例19
5-[(4-甲氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.57(d,J=1.3Hz,1H),8.37(d,J=5.5Hz,1H),7.49~7.43(m,2H),7.31(d,J=8.8Hz,2H),7.20(t,J=8.8Hz,2H),7.00(d,J=8.8Hz,2H),6.74(dd,J=1.3Hz,5.5Hz,1H),3.87(s,2H),3.86(s,3H)。
Mass,m/:404(M+),148(base)。
实施例20
5-[(2-乙氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.33(bs,1H),8.43(d,J=1.5Hz,1H),8.34(d,J=5.8Hz,1H),7.48~7.40(m,3H),7.34(dd,J=1.5Hz,7.3Hz,1H),7.22~7.16(m,2H),7.07(dt,J=1.2Hz,7.7Hz,1H),6.97(d,J=7.7Hz,1H),6.71(dd,J=1.5Hz,5.8Hz,1H),4.03(q,J=6.9H,2H),3.88(s,2H),1.32(t,J=6.9Hz,3H)。
Mass,m/e:418(M+),240(base)。
实施例21
5-[(3-乙氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(bs,1H),8.61(d,J=1.3Hz,1H),8.37(d,J=5.6Hz,1H),7.48~7.43(m,2H),7.27(t,J=8.1Hz,1H),7.22~7.16(m,2H),6.97~6.92(m,3H),6.73(dd,J=1.3Hz,5.6Hz,1H),4.05(q,J=7.3Hz,2H),3.88(s,2H),1.41(t,J=7.3Hz,3H)。
Mass,m/e:418(M+),162(base)。
实施例22
3-(4-氟苯基)-5-[(2-丙氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.33(bs,1H),8.42(d,J=1.3Hz,1H),8.34(d,J=5.8Hz,1H),7.47~7.41(m,3H),7.34(dd,J=1.5Hz,7.3Hz,1H),7.21~7.16(m,2H),7.07(dt,J=0.8Hz,7.3Hz,1H),6.97(d,J=8.1Hz,1H),6.71(dd,J=1.3Hz,5.8Hz,1H),3.92~3.88(m,4H),3.88(s,2H),1.72(dt,J=7.3Hz,13.8Hz,2H),0.92(t,J=7.3Hz,3H)。
Mass,m/e:432(M+),107(base)。
实施例23
3-(4-氟苯基)-5-[(3-丙氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.61(d,J=1.2Hz,1H),8.37(d,J=5.6Hz,1H),7.47~7.44(m,2H),7.37(t,J=8.1Hz,1H),7.21~7.17(m,2H),6.98~6.94(m,3H),6.73(dd,J=1.2Hz,5.6Hz,1H),3.94(t,J=6.6Hz,2H),3.88(s,2H),1.85~1.76(m,2H),1.02(t,J=7.3Hz,3H)。
Mass,m/e:432(M+),240(base)。
实施例24
3-(4-氟苯基)-5-[(2-异丙氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.31(bs,1H),8.39(d,J=1.0Hz,1H),8.34(d,J=5.6Hz,1H),7.48~7.40(m,3H),7.33(dd,J=1.5Hz,7.7Hz,1H),7.20~7.16(m,2H),7.02(t,J=7.3Hz,1H),6.97(d,J=8.5Hz,1H),6.70(dd,J=1.0Hz,5.6Hz,1H),4.55(m,J=6.2Hz,1H),3.85(s,2H),1.24(d,J=6.2Hz,6H)。
Mass,m/e:432(M+),134(base)。
实施例25
3-(4-氟苯基)-5-[(3-异丙氧基苯基)乙酰氨基]-4-(嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(bs,1H),8.63(d,J=1.4Hz,1H),8.37(d,J=5.4Hz,1H),7.48~7.43(m,2H),7.36(t,J=8.1Hz,1H),7.22~7.16(m,2H),6.96~6.92(m,3H),6.72(dd,J=1.4Hz,5.4Hz,1H),4.58(m,J=5.8Hz,1H),3.87(s,2H),1.33(d,J=5.8Hz,6H)。
Mass,m/e:432(M+),240(base)。
实施例26
5-[(2,3-二甲氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(s,1H),8.62(d,J=1.4Hz,1H),8.36(d,J=5.5Hz,1H),7.49~7.43(m,2H),7.23~7.16(m,2H),7.14(d,J=7.7Hz,1H),7.00(dd,J=1.4Hz,8.3Hz,1H),6.95(dd,J=1.4Hz,7.7Hz,1H),6.72(dd,J=1.4Hz,5.5Hz,1H),3.90(s,3H),3.89(s,3H)。
Mass,m/e:434(M+),178(base)。
实施例27
5-[(2,5-二甲氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(s,1H),8.58(d,J=1.3Hz,1H),8.36(d,J=5.5Hz,1H),7.46(dd,J=5.2Hz,8.7Hz,2H),7.19(t,J=8.7Hz,2H),6.97~6.89(m,3H),6.73(dd,J=1.3Hz,5.5Hz,1H),3.86(s,2H),3.81(s,3H),3.77(s,3H)。
Mass,m/e:434(M+),178(base)。
实施例28
5-[(3,5-二甲氧基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.70(d,J=1.3Hz,1H),8.38(d,J=5.7Hz,1H),7.49~7.43(m,2H),7.23~7.17(m,2H),6.74(dd,J=1.3Hz,5.7Hz,1H),6.54(d,J=2.2Hz,2H),6.51(t,J=2.2Hz,1H),3.84(s,2H),3.81(s,6H)。
Mass,m/e:434(M+),178(base)。
实施例29
3-(4-氟苯基)-4-(4-嘧啶基)-5-[(3,4,5-三甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.71(s,1H),8.40(d,J=5.5Hz,1H),7.50~7.44(m,2H),7.24~7.17(m,2H),6.75(dd,J=1.0Hz,5.5Hz,1H),6.60(s,2H),3.89(s,2H),3.87(s,6H),3.86(s,3H)。
Mass,m/e:464(M+),208(base)。
实施例30
3-(4-氟苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(s,1H),8.42(s,1H),8.35(d,J=5.5Hz,1H),7.48~7.30(m,6H),7.19(t,J=8.7Hz,2H),6.71(dd,J=1.3Hz,5.5Hz,1H),3.92(s,2H),2.36(s,3H)。
Mass,m/e:388(M+),240(base)。
实施例31
3-(4-氟苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(bs,1H),8.48(s,1H),8.36(d,J=5.4Hz,1H),7.45(dd,J=5.4Hz,8.5Hz,2H),7.37(t,J=7.7Hz,1H),7.27(s,1H),7.21~7.17(m,4H),6.73(dd,J=1.2Hz,5.4Hz,1H),3.88(s,2H),2.39(s,3H)。
Mass,m/e:388(M+),240(base)。
实施例32
5-[(2,5-二甲基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.32(s,1H),8.39(d,J=1.4Hz,1H),8.35(d,J=5.4Hz,1H),7.49~7.43(m,2H),7.23~7.14(m,5H),6.72(dd,J=1.4Hz,5.4Hz,1H),3.88(s,2H),2.39(s,3H),2.31(s,3H)。
Mass,m/e:402(M+),240(base)。
实施例33
5-[(3,5-二甲基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.36(s,1H),8.46(s,1H),8.36(d,J=5.7Hz,1H),7.49~7.43(m,2H),7.20(t,J=8.7Hz,2H),7.08(s,1H),7.00(s,2H),6.73(dd,J=1.3Hz,5.7Hz,1H),3.84(s,2H),2.35(s,6H)。
Mass,m/e:402(M+),283(base)。
实施例34
3-(4-氟苯基)-5-[(2-硝基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(s,1H),8.89(bs,1H),8.89(s,1H),8.44(d,J=5.4Hz,1H),8.20(d,J=8.5Hz,1H),7.72(dt,J=1.5Hz,7.7Hz,1H),7.59(t,J=7.7Hz,2H),7.53~7.47(m,2H),7.22(t,J=8.7Hz,1H),6.80(dd,J=1.5Hz,5.4Hz,1H),4.31(s,2H)。
Mass m/e:419(M+),240(base)。
实施例35
3-(4-氟苯基)-5-[(4-硝基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.88(s,1H),8.45(d,J=5.5Hz,1H),8.29(d,J=8.9Hz,2H),7.59(d,J=8.9Hz,2H),7.52~7.46(m,2H),7.25~7.20(m,2H),6.82(dd,J=1.3Hz,5.5Hz,1H),4.10(s,2H)。
Mass,m/e:419(M+),240(base)。
实施例36
3-(4-氟苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.58(s,1H),8.39(d,J=5.7Hz,1H),7.82(d,J=8.1Hz,1H),7.67(t,J=7.3Hz,1H),7.61~7.53(m,2H),7.50~7.44(m,2H),7.20(t,J=8.7Hz,2H),6.76(dd,J=1.4Hz,5.7Hz,1H),4.12(s,2H)。
Mass,m/e:442(M+),240(base)。
实施例37
3-(4-氟苯基)-4-(4-嘧啶基)-5-[(3-三氟甲基苯硫基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.47(s,1H),8.64(s,1H),8.41(d,J=5.5Hz,1H),7.74~7.68(m,2H),7.57~7.45(m,4H),7.25~7.18(m,2H),6.78(dd,J=1.3Hz,5.5Hz,1H),3.99(s,2H)。
Mass,m/e:474(M+),240(base)。
实施例38
3-(4-氟苯基)-5-(2-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(bs,1H),8.57(d,J=1.4Hz,1H),8.35(d,J=5.6Hz,1H),7.50~7.38(m,7H),7.19(t,J=8.7Hz,2H),6.72(dd,J=1.4Hz,5.6Hz,1H),3.93(q,J=7.3Hz,1H),1.68(d,J=7.3Hz,3H)。
Mass,m/e:388(M+),240(base)。
实施例39
3-(4-氟苯基)-5-(2-甲基-2-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.32(s,1H),8.43(d,J=1.4Hz,1H),8.33(d,J=5.4Hz,1H),7.52~7.42(m,6H),7.41~7.36(m,1H),7.19(t,J=8.7Hz,2H),6.70(dd,J=1.4Hz,5.4Hz,1H),1.74(s,6H)。
Mass,m/e:402(M+),240(base)。
实施例40
3-(4-氟苯基)-5-[2-(4-异丁基苯基)丙酰基氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.62(d,J=1.4Hz,1H),8.36(d,J=5.4Hz,1H),7.46(dd,J=5.4Hz,8.9Hz,2H),7.31(d,J=8.3Hz,2H),7.22(d,J=8.3Hz,2H),7.18(d,J=8.9Hz,2H),6.72(dd,J=1.4Hz,5.4Hz,1H),3.89(q,J=7.1Hz,1H),2.51(d,J=7.3Hz,2H),1.94~1.82(m,1H),1.66(d,J=7.1Hz,3H),0.89(dd,J=3.9Hz,6.6Hz,6H)。
Mass,m/e:444(M+),240(base)。
实施例41
3-(4-氟苯基)-4-(4-嘧啶基)-5-[(2-噻吩基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.62(bs,1H),8.68(s,1H),8.39(d,J=5.6Hz,1H),7.47(dd,J=5.4Hz,8.9Hz,2H),7.42(dd,J=1.5Hz,5.0Hz,1H),7.22~7.14(m,4H),6.76(dd,J=1.5Hz,5.6Hz,1H),4.13(s,2H)。
Mass,m/e:380(M+),240(base)。
实施例42
3-(4-氟苯基)-5-{[5-(3-甲基异噁唑基)]乙酰氨基}-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.96(bs,1H),9.13(d,J=1.4Hz,1H),8.46(d,J=5.6Hz,1H),7.49(dd,J=5.4Hz,8.9Hz,2H),7.22(t,J=8.9Hz,2H),6.81(dd,J=1.4Hz,5.6Hz,1H),6.21(s,1H),4.09(s,2H),2.35(s,3H)。
Mass,m/e:379(M+),240(base)。
实施例43
3-(4-氟苯基)-4-(4-嘧啶基)-5-[(3-噻吩基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.75(s,1H),8.40(d,J=5.4Hz,1H),7.50~7.44(m,3H),7.37~7.35(m,1H),7.20(t,J=8.5Hz,2H),7.13(d,J=5.0Hz,1H),6.76(dd,J=1.2Hz,5.4Hz,1H),3.97(s,2H)。
Mass,m/e:380(M+),240(base)。
以下,与实施例1和实施例2进行同样地操作,合成实施例44~299的化合物。
实施例44
3-苯基-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-苯基-4-(4-嘧啶基)异噁唑
1H-NMR(DMSO-d6)δ:8.99(d,J=1.4Hz,1H),8.35(d,J=5.4Hz,1H),8.29(bs,2H),7.59~7.50(m,5H),6.56(dd,J=1.4Hz,5.4Hz,1H)。
Mass,m/e:238(M+),77(base)。
b:3-苯基-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.48(s,1H),8.32(d,J=5.6Hz,1H),7.53~7.39(m,10H),6.73(dd,J=1.5Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:356(M+),222(base)。
实施例45
5-[(2-氯苯基)乙酰氨基]-3-苯基-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.52(s,1H),8.34(d,J=5.4Hz,1H),7.54~7.39(m,9H),6.75(dd,J=0.8Hz,5.4Hz,1H),4.06(s,2H)。
Mass,m/e:390(M+),222(base)。
实施例46
5-[(2,6-二氯苯基)乙酰氨基]-3-苯基-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(bs,1H),8.59(s,1H),8.36(d,J=5.4Hz,1H),7.55~7.46(m,7H),7.35(dd,J=7.3Hz,8.5Hz,1H),6.79(dd,J=1.6Hz,5.4Hz,1H),4.32(s,2H)。
Mass,m/e:424(M+),222(base)。
实施例47
5-[(3-甲基苯基)乙酰氨基]-3-苯基-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(s,1H),8.47(s,1H),8.33(d,J=5.4Hz,1H),7.56~7.44(m,5H),7.40~7.36(m,1H),7.28~7.18(m,3H),6.74(dd,J=1.5Hz,5.4Hz,1H),3.90(s,2H),2.40(s,3H)。
Mass,m/e:370(M+),77(base)。
实施例48
5-[(2,5-二甲基苯基)乙酰氨基]-3-苯基-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(s,1H),8.37(d,J=1.4Hz,1H),8.33(d,J=5.4Hz,1H),7.56~7.44(m,5H),7.40~7.36(m,1H),7.21~7.16(m,2H),6.74(dd,J=1.4Hz,5.4Hz,1H),3.88(s,2H),2.39(s,3H),2.31(s,3H)。
Mass,m/e:384(M+),222(base)。
实施例49
3-(3-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.5Hz,1H),8.33(d,J=5.7Hz,1H),7.53~7.46(m,1H),7.31(dt,J=1.3Hz,8.1Hz,1H),7.28~7.21(m,3H),6.92~6.82(bs,2H),6.71(dd,J=1.5Hz,5.7Hz,1H)。
Mass,m/e:256(M+),111(base)。
b:3-(3-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.52~8.47(bs,1H),8.37(d,J=5.4Hz,1H),7.52~7.39(m,6H),7.28~7.17(m,3H),6.74(dd,J=1.5Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:374(M+),91(base)。
实施例50
3-(3-氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.62(s,1H),8.40(d,J=5.5Hz,1H),7.52~7.39(m,3H),7.29~7.17(m,5H),6.77(dd,J=1.3Hz,5.5Hz,1H),3.97(s,2H)。
Mass,m/e:392(M+),109(base)。
实施例51
5-[(2-氯苯基)乙酰氨基]-3-(3-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.57~8.52(bs,1H),8.39(d,J=5.5Hz,1H),7.55~7.38(m,5H),7.28~7.18(m,3H),6.76(dd,J=1.3Hz,5.5Hz,1H),4.07(s,2H)。
Mass,m/e:408(M+),240(base)。
实施例52
3-(2-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.3Hz,1H),8.29(d,J=5.6Hz,1H),7.58~7.40(m,4H),6.92(bs,2H),6.41(dd,J=1.3Hz,5.6Hz,1H)。
Mass,m/e:272(M+),237(base)。
b:3-(2-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.47(bs,1H),8.33(d,J=5.7Hz,1H),7.55~7.40(m,9H),6.46(dd,J=1.3Hz,5.7Hz,1H),3.95(s,2H)。
Mass,m/e:390(M+),91(base)。
实施例53
3-(2-氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(s,1H),8.59(s,1H),8.36(d,J=5.7Hz,1H),7.56~7.40(m,5H),7.29~7.18(m,3H),6.49(dd,J=1.3Hz,5.7Hz,1H),3.98(s,2H)。
Mass,m/e:408(M+),109(base)。
实施例54
3-(2-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(s,1H),8.52(s,1H),8.35(d,J=5.5Hz,1H),7.56~7.38(m,8H),6.49(dd,J=1.3Hz,5.5Hz,1H),4.08(s,2H)。
Mass,m/e:424(M+),256(base)。
实施例55
3-(3-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.3Hz,1H),8.34(d,J=5.5Hz,1H),7.56~7.50(m,2H),7.45(t,J=7.5Hz,1H),7.41(dt,J=1.5Hz,7.5Hz,1H),6.88(bs,2H),6.69(dd,J=1.3Hz,5.5Hz,1H)。
Mass,m/e:272(M+),127(base)。
b:3-(3-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.50(bs,1H),8.38(d,J=5.7Hz,1H),7.55~7.32(m,9H),6.73(dd,J=1.5Hz,5.7Hz,1H),3.94(s,2H)。
Mass,m/e:390(M+),91(base)。
实施例56
3-(3-氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.59(s,1H),8.62(bs,1H),8.41(d,J=5.5Hz,1H),7.55~7.34(m,6H),7.29~7.17(m,2H),6.76(dd,J=1.3Hz,5.5Hz,1H),3.97(s,2H)。
Mass,m/e:408(M+),256(base)。
实施例57
3-(3-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.55(bs,1H),8.40(d,J=5.5Hz,1H),7.56~7.33(m,8H),6.75(dd,J=1.3Hz,5.5Hz,1H),4.07(s,2H)。
Mass,m/e:424(M+),256(base)。
实施例58
3-(4-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.2Hz,1H),8.32(d,J=5.4Hz,1H),7.51~7.45(m,4H),6.88(s,2H),6.70(dd,J=1.2Hz,5.4Hz,1H)。
Mass,m/e:272(M+),127(base)。
b:3-(4-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(bs,1H),8.49(s,1H),8.37(d,J=5.6Hz,1H),7.51~7.39(m,9H),6.73(dd,J=1.5Hz,5.6Hz,1H),3.93(s,2H)。
Mass,m/e:390(M+),91(base)。
实施例59
3-(4-氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(bs,1H),8.61(s,1H),8.40(d,J=5.6Hz,1H),7.50~7.40(m,6H),7.27~7.17(m,2H),6.77(dd,J=1.5Hz,5.6Hz,1H),3.96(s,2H)。
Mass,m/e:408(M+),109(base)。
实施例60
3-(4-氯苯基)-5-[(3-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.66(s,1H),8.40(d,J=5.4Hz,1H),7.49(d,J=8.7Hz,2H),7.46~7.40(m,1H),7.42(d,J=8.7Hz,2H),7.20~7.12(m,3H),6.77(dd,J=1.5Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:408(M+),109(base)。
实施例61
3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.53(s,1H),8.39(d,J=5.6Hz,1H),7.54~7.39(m,8H),6.76(dd,J=1.5Hz,5.6Hz,1H),4.06(s,2H)。
Mass,m/e:424(M+),256(base)。
实施例62
5-[(2-溴苯基)乙酰氨基]-3-(4-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.52(s,1H),8.39(d,J=5.4Hz,1H),7.72(d,J=8.1Hz,1H),7.50~7.40(m,6H),7.36~7.31(m,1H),6.76(dd,J=1.2Hz,5.4Hz,1H),4.08(s,2H)。
Mass,m/e:468(M+),256(base)。
实施例63
3-(4-氯苯基)-5-[(2-碘苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(bs,1H),8.50(s,1H),8.38(d,J=5.6Hz,1H),8.00(d,J=7.7Hz,1H),7.50~7.46(m,4H),7.42(d,J=8.5Hz,2H),7.18~7.14(m,1H),6.76(dd,J=1.5Hz,5.6Hz,1H),4.09(s,2H)。
Mass,m/e:516(M+),256(base)。
实施例64
3-(4-氯苯基)-5-[(2,5-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.61(bs,1H),8.80(s,1H),8.44(d,J=5.8Hz,1H),7.50(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.17~7.06(m,3H),6.80(dd,J=1.6Hz,5.8Hz,1H),3.94(s,2H)。
Mass,m/e:426(M+),127(base)。
实施例65
3-(4-氯苯基)-5-[(3,5-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(bs,1H),8.82(s,1H),8.44(d,J=5.4Hz,1H),7.50(d,J=8.9Hz,2H),7.43(d,J=8.9Hz,2H),6.98~6.93(m,2H),6.90~6.84(m,1H),6.80(dd,J=1.2Hz,5.4Hz,1H),3.93(s,2H)。
Mass,m/e:426(M+),256(base)。
实施例66
3-(4-氯苯基)-5-[(2,6-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.64(bs,1H),8.70(s,1H),8.42(d,J=5.4Hz,1H),7.50(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.40~7.37(m,1H),7.07~7.01(m,2H),6.80(dd,J=1.5Hz,5.4Hz,1H),4.01(s,2H)。
Mass,m/e:426(M+),127(base)。
实施例67
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(4-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.72(s,1H),8.43(d,J=5.6Hz,1H),7.51~7.41(m,5H),7.27(dd,J=2.7Hz,8.5Hz,1H),7.11(dt,J=2.7Hz,8.1Hz,1H),6.73(dd,J=1.5Hz,5.6Hz,1H),4.03(s,2H)。
Mass,m/e:442(M+),256(base)。
实施例68
5-[(2-氯-6-氟苯基)乙酰氨基]-3-(4-氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.64(s,1H),8.41(d,J=5.4Hz,1H),7.49(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.40~7.34(m,2H),7.17(dt,J=1.2Hz,8.9Hz,1H),6.79(dd,J=1.2Hz,5.4Hz,1H),4.13(s,2H)。
Mass,m/e:442(M+),256(base)。
实施例69
3-(4-氯苯基)-5-[(2,4-二氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.70(s,1H),8.43(d,J=5.6Hz,1H),7.54~7.48(m,3H),7.44~7.36(m,4H),6.79(dd,J=1.5Hz,5.6Hz,1H),4.04(s,2H)。
Mass,m/e:458(M+),256(base)。
实施例70
3-(4-氯苯基)-5-[(2,6-二氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.60(s,1H),8.40(d,J=5.4Hz,1H),7.51~7.47(m,4H),7.42(d,J=8.5Hz,2H),7.35(dd,J=7.3Hz,8.4Hz,1H),6.78(dd,J=1.5Hz,5.4Hz,1H),4.31(s,2H)。
Mass,m/e:458(M+),256(base)。
实施例71
3-(4-氯苯基)-5-[(2-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.33(bs,1H),8.46(d,J=1.4Hz,1H),8.37(d,J=5.6Hz,1H),7.49~7.40(m,5H),7.34(dd,J=1.4Hz,7.5Hz,1H),7.08(dt,J=1.4Hz,7.5Hz,1H),6.99(d,J=8.1Hz,1H),6.73(dd,J=1.4Hz,5.6Hz,1H),3.88(s,2H),3.80(s,3H)。
Mass,m/e:420(M+),91(base)。
实施例72
3-(4-氯苯基)-5-[(3-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(bs,1H),8.60(d,J=1.4Hz,1H),8.38(d,J=5.4Hz,1H),7.48(d,J=8.9Hz,2H),7.42~7.37(m,3H),6.99~6.94(m,3H),6.74(dd,J=1.4Hz,5.4Hz,1H),3.89(s,2H),3.83(s,3H)。
Mass,m/e:420(M+),148(base)。
实施例73
3-(4-氯苯基)-5-[(2,3-二甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(bs,1H),8.61(d,J=1.5Hz,1H),8.36(d,J=5.4Hz,1H),7.47(d,J=8.5Hz,2H),7.27(d,J=8.5Hz,2H),7.14(t,J=8.1Hz,1H),7.00(dd,J=1.5Hz,8.1Hz,1H),6.95(dd,J=1.5Hz,7.7Hz,1H),6.72(dd,J=1.5Hz,5.4Hz,1H),3.89(s,2H),3.89(s,3H),3.88(s,3H)。
Mass,m/e:450(M+),178(base)。
实施例74
3-(4-氯苯基)-5-[(2,5-二甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.34(bs,1H),8.58(d,J=1.3Hz,1H),8.37(d,J=5.4Hz,1H),7.48(d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H),6.96~6.89(m,3H),6.74(dd,J=1.3Hz,5.4Hz,1H),3.85(s,2H),3.81(s,3H),3.76(s,3H)。
Mass,m/e:450(M+),178(base)。
实施例75
3-(4-氯苯基)-5-[(3,5-二甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.70(d,J=1.3Hz,1H),8.39(d,J=5.4Hz,1H),7.48(d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H),6.74(dd,J=1.3Hz,5.4Hz,1H),6.54~6.50(m,3H),3.84(s,2H),3.81(s,6H)。
Mass,m/e:450(M+),178(base)。
实施例76
3-(4-氯苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(bs,1H),8.41(d,J=1.4Hz,1H),8.36(d,J=5.6Hz,1H),7.48(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.37~7.31(m,4H),6.74(dd,J=1.4Hz,5.6Hz,1H),3.92(s,2H),2.35(s,3H)。
Mass,m/e:404(M+),256(base)。
实施例77
3-(4-氯苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.48(d,J=1.2Hz,1H),8.38(d,J=5.8Hz,1H),7.50~7.47(m,2H),7.43~7.36(m,3H),7.27~7.19(m,3H),6.74(dd,J=1.5Hz,5.8Hz,1H),3.89(s,2H),2.39(s,3H)。
Mass,m/e:404(M+),105(base)。
实施例78
3-(4-氯苯基)-5-[(2,5-二甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.31(bs,1H),8.38(d,J=1.4Hz,1H),8.36(d,J=5.4Hz,1H),7.48(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.20(s,2H),7.15(s,1H),6.73(dd,J=1.4Hz,5.4Hz,1H),3.87(s,2H),2.38(s,3H),2.30(s,3H)。
Mass,m/e:418(M+),146(base)。
实施例79
3-(4-氯苯基)-4-(4-嘧啶基)-5-[(2-三氟苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.37(bs,1H),8.57(s,1H),8.40(d,J=5.6Hz,1H),7.81(d,J=8.1Hz,1H),7.68~7.54(m,3H),7.49(d,J=8.5Hz,2H),7.42(d,J=8.5Hz,2H),6.77(dd,J=1.5Hz,5.6Hz,1H),4.12(s,2H)。
Mass,m/e:458(M+),256(base)。
实施例80
3-(4-氯苯基)-5-(2-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(bs,1H),8.56(d,1.3Hz,1H),8.36(d,J=5.4Hz,1H),7.49~7.38(m,9H),6.72(dd,J=1.3Hz,5.4Hz,1H),3.92(q,J=7.1Hz,1H),1.68(d,J=7.1Hz,3H)。
Mass,m/e:404(M+),91(base)。
实施例81
3-(4-氯苯基)-5-(3-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),9.07(d,J=1.3Hz,1H),8.46(d,J=5.4Hz,1H),7.51(d,J=8.5Hz,2H),7.45(d,J=8.5Hz,2H),7.31~7.27(m,4H),7.20~7.16(m,1H),6.77(dd,J=1.3Hz,5.4Hz,1H),3.12(t,J=7.5Hz,2H),2.97(t,J=7.5Hz,2H)。
Mass,m/e:404(M+),105(base)。
实施例82
3-(4-氯苯基)-5-[(1-苯基-环丙烷)羰基氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(bs,1H),8.21(d,J=1.4Hz,1H),8.32(d,J=5.4Hz,1H),7.56~7.45(m,7H),7.40~7.37(m,2H),6.69(dd,J=1.4Hz,5.4Hz,1H),1.81(q,J=3.5Hz,2H),1.31(q,J=3.5Hz,2H)。
Mass,m/e:416(M+),117(base)。
实施例83
3-(3-溴苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-溴苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.4Hz,1H),8.34(d,J=5.7Hz,1H),7.71~7.66(m,2H),7.46(dt,J=1.3Hz,7.7Hz,1H),7.39(t,J=7.7Hz,1H),6.90(bs,2H),6.71(dd,J=1.4Hz,5.7Hz,1H)。
Mass,m/e:316(M+),76(base)。
b:3-(3-溴苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.50(bs,1H),8.39(d,J=5.7Hz,1H),7.68(dt,J=1.9Hz,6.9Hz,1H),7.65~7.63(m,1H),7.52~7.35(m,7H),6.73(dd,J=1.3Hz,5.7Hz,1H),3.94(s,2H)。
Mass,m/e:434(M+),91(base)。
实施例84
3-(3-溴苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.62(s,1H),8.41(d,J=5.7Hz,1H),7.69(dt,J=1.9Hz,7.3Hz,1H),7.66~7.64(m,1H),7.47~7.36(m,4H),7.29~7.17(m,2H),6.77(dd,J=1.3Hz,5.7Hz,1H),3.97(s,2H)。
Mass,m/e:452(M+),109(base)。
实施例85
3-(3-溴苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.55(dd,J=1.3Hz,1H),8.40(d,J=5.5Hz,1H),7.68(dt,J=1.9Hz,7.3Hz,1H),7.67~7.64(m,1H),7.56~7.45(m,2H),7.45~7.35(m,4H),6.76(dd,J=1.3Hz,5.5Hz,1H),4.07(s,2H)。
Mass,m/e:468(M+),125(base)。
实施例86
3-(3-溴苯基)-5-[(2-溴苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.53(s,1H),8.40(d,J=5.5Hz,1H),7.72(dd,J=0.8Hz,8.8Hz,1H),7.68(dt,J=1.9Hz,6.9Hz,1H),7.67~7.64(m,1H),7.51~7.31(m,5H),6.76(dd,J=1.5Hz,5.5Hz,1H),4.09(s,2H)。
Mass,m/e:512(M+),300(base)。
实施例87
3-(3-溴苯基)-5-[(2-氯-4-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.73(s,1H),8.44(d,J=5.4Hz,1H),7.69(dt,J=1.9Hz,7.3Hz,1H),7.67~7.65(m,1H),7.48~7.36(m,3H),7.28(dd,J=2.7Hz,8.1Hz,1H),7.12(td,J=2.7Hz,8.1Hz,1H),6.79(dd,J=1.5Hz,5.4Hz,1H),4.04(s,2H)。
Mass,m/e:486(M+),143(base)。
实施例88
3-(3-溴苯基)-5-[(2-氯-6-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.56(s,1H),8.65(s,1H),8.43(d,J=5.7Hz,1H),7.69(dt,J=1.8Hz,7.1Hz,1H),7.67~7.64(m,1H),7.44~7.34(m,4H),7.17(td,J=1.7Hz,8.1Hz,1H),6.79(dd,J=1.3Hz,5.7Hz,1H),4.15(d,J=1.5Hz,2H)。
Mass,m/e:486(M+),143(base)。
实施例89
3-(3-溴苯基)-5-[(2,6-二氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.61(s,1H),8.42(d,J=5.4Hz,1H),7.69(dt,J=1.9Hz,7.3Hz,1H),7.67~7.64(m,1H),7.49(d,J=8.1Hz,2H),7.44~7.33(m,3H),6.78(dd,J=1.3Hz,5.5Hz,1H),4.32(s,2H)。
Mass,m/e:502(M+),300(base)。
实施例90
3-(3-溴苯基)-5-[(3-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.61(d,J=1.3Hz,1H),8.39(d,J=5.5Hz,1H),7.68(dt,J=2.1Hz,6.9Hz,1H),7.66~7.62(m,1H),7.43~7.36(m,3H),7.00~6.93(m,3H),6.74(dd,J=1.3Hz,5.5Hz,1H),3.90(s,2H),3.84(s,3H)。
Mass,m/e:464(M+),148(base)。
实施例91
3-(3-溴苯基)-5-[(2,5-二甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.36(s,1H),8.59(d,J=1.4Hz,1H),8.39(d,J=5.7Hz,1H),7.67(dt,J=1.9Hz,7.3Hz,1H),7.66~7.63(m,1H),7.42~7.34(m,2H),6.98~6.89(m,3H),6.74(dd,J=1.4Hz,5.7Hz,1H),3.86(s,2H),3.81(s,3H),3.77(s,3H)。
实施例92
3-(3-溴苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(s,1H),8.42(d,J=1.4Hz,1H),8.37(d,J=5.5Hz,1H),7.68(dt,J=2.1Hz,6.6Hz,1H),7.65~7.62(m,1H),7.43~7.31(m,6H),6.72(dd,J=1.4Hz,5.5Hz,1H),3.93(s,2H),2.36(s,3H)。
Mass,m/e:448(M+),132(base)。
实施例93
3-(3-溴苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.49(s,1H),8.39(d,J=5.7Hz,1H),7.68(dt,J=2.1Hz,6.9Hz,1H),7.66~7.63(m,1H),7.42~7.35(m,3H),7.29~7.18(m,3H),6.74(dd,J=1.3Hz,5.7Hz,1H),3.89(s,2H),2.40(s,3H)。
Mass,m/e:448(M+),132(base)。
实施例94
3-(3-溴苯基)-5-[(2,5-二甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.33(s,1H),8.39(d,J=1.4Hz,1H),8.37(d,J=5.7Hz,1H),7.68(dt,J=1.9Hz,6.9Hz,1H),7.65~7.62(m,1H),7.41~7.34(m,2H),7.21(bs,2H),7.15(bs,1H),6.72(dd,J=1.4Hz,5.7Hz,1H),3.88(s,2H),2.39(s,3H),2.31(s,3H)。
Mass,m/e:462(M+),119(base)。
实施例95
3-(3-溴苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.58(s,1H),8.41(d,J=5.4Hz,1H),7.82(d,J=8.1Hz,1H),7.71~7.63(m,3H),7.61~7.54(m,2H),7.43~7.36(m,2H),6.76(dd,J=1.5Hz,5.4Hz,1H),4.13(s,2H)。
Mass,m/e:502(M+),159(base)。
实施例96
3-(4-溴苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-溴苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.5Hz,1H),8.34(d,J=5.8Hz,1H),7.66(dt,J=2.3Hz,8.5Hz,2H),7.41(dt,J=2.3Hz,8.5Hz,2H),6.87(bs,2H),6.80(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:315(M+),173(base)。
b:3-(4-溴苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.50(s,1H),8.38(d,J=5.8Hz,1H),7.66~7.63(m,2H),7.51~7.34(m,7H),6.74(dd,J=1.5Hz,5.8Hz,1H),3.94(s,2H)。
Mass,m/e:434(M+),91(base)。
实施例97
3-(4-溴苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.62(s,1H),8.42(d,J=5.4Hz,1H),7.67~7.63(dt,J=2.1Hz,8.5Hz,2H),7.47~7.40(m,2H),7.38~7.34(m,2H),7.28~7.18(m,2H),6.78(dd,J=1.5Hz,5.4Hz,1H),3.97(s,2H)。
Mass,m/e:452(M+),109(base)。
实施例98
3-(4-溴苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.54(s,1H),8.40(d,J=5.8Hz,1H),7.67~7.63(m,2H),7.54~7.40(m,4H),7.37~7.34(m,2H),6.77(dd,J=1.5Hz,5.8Hz,1H),4.07(s,2H)。
Mass,m/e:468(M+),125(base)。
实施例99
3-(2,3-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,3-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.5Hz,1H),8.36(d,J=5.4Hz,1H),7.41~7.24(m,3H),6.92(bs,2H),6.60(dt,J=1.5Hz,5.4Hz,1H)。
Mass,m/e:274(M+),52(base)。
b:3-(2,3-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.49(d,J=1.2Hz,1H),8.41(d,J=5.4Hz,1H),7.52~7.35(m,6H),7.30~7.24(m,2H),6.74(dt,J=1.5Hz,5.4Hz,1H),3.95(s,2H)。
Mass,m/e:392(M+),91(base)。
实施例100
3-(2,3-二氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.63(s,1H),8.62(d,J=1.2Hz,1H),8.44(d,J=5.8Hz,1H),7.47~7.36(m,3H),7.31~7.19(m,4H),6.68(dt,J=1.5Hz,5.8Hz,1H),3.98(d,J=1.2Hz,2H)。
Mass,m/e:410(M+),109(base)。
实施例101
5-[(2-氯苯基)乙酰氨基]-3-(2,3-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.55(d,J=0.8Hz,1H),8.43(d,J=5.4Hz,1H),7.55~7.36(m,5H),7.29~7.24(m,2H),6.67(dt,J=1.5Hz,5.4Hz,1H),4.08(s,2H)。
Mass,m/e:426(M+),125(base)。
实施例102
3-(2,4-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.2Hz,1H),8.35(d,J=5.4Hz,1H),7.51(dt,J=6.6Hz,8.5Hz,1H),7.08~6.97(m,2H),6.92(bs,2H),6.60(td,J=1.2Hz,5.4Hz,1H)。
Mass,m/e:274(M+),129(base)。
b:3-(2,4-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.48(s,1H),8.40(d,J=5.6Hz,1H),7.54~7.39(m,6H),7.06(dt,J=1.9Hz,8.1Hz,1H),6.97(dt,J=2.3Hz,9.3Hz,1H),6.65(td,J=1.5Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:392(M+),91(base)。
实施例103
3-(2,4-二氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.61(bs,1H),8.61(d,J=1.4Hz,1H),8.42(d,J=5.6Hz,1H),7.51(dt,J=6.2Hz,8.1Hz,1H),7.44~7.41(m,2H),7.28~7.24(m,1H),7.20(t,J=9.6Hz,1H),7.09~7.04(m,1H),7.00~6.95(m,1H),6.71(td,J=1.4Hz,5.6Hz,1H),3.96(s,2H)。
Mass,m/e:410(M+),109(base)。
实施例104
3-(2,4-二氟苯基)-5-[(3-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(s,1H),8.65(s,1H),8.43(d,J=5.4Hz,1H),7.52(dt,J=6.2Hz,8.1Hz,1H),7.47~7.43(m,1H),7.19(d,J=7.7Hz,1H),7.16~7.12(m,2H),7.07(dt,J=2.3Hz,7.7Hz,1H),6.98(dt,J=2.3Hz,8.5Hz,1H),6.68(td,J=1.9Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:410(M+),258(base)。
实施例105
5-[(2-氯苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(bs,1H),8.53(s,1H),8.41(d,J=5.4Hz,1H),7.54~7.40(m,5H),7.09~7.04(m,1H),6.98(dt,J=2.3Hz,8.5Hz,1H),6.67(td,J=1.5Hz,5.4Hz,1H),4.07(s,2H)。
Mass,m/e:426(M+),258(base)。
实施例106
5-[(2-溴苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),9.02(d,J=1.5Hz,1H),8.52(s,1H),8.41(d,J=5.2Hz,1H),7.72(d,J=8.1Hz,1H),7.54~7.45(m,3H),7.36~7.32(m,1H),7.09~6.95(m,1H),6.67(td,J=1.5Hz,5.2Hz,1H),4.09(s,2H)。
Mass,m/e:470(M+),258(base)。
实施例107
3-(2,4-二氟苯基)-5-[(2-碘苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.51(s,1H),8.41(d,J=5.4Hz,1H),8.00(d,J=7.7Hz,1H),7.52(dt,J=6.2Hz,8.5Hz,1H),7.49~7.48(m,2H),7.18~7.14(m,1H),7.06(dt,J=2.7Hz,8.9Hz,1H),6.98(dt,J=2.3Hz,8.9Hz,1H),6.67(td,J=1.5Hz,5.4Hz,1H),4.10(s,2H)。
Mass,m/e:518(M+),258(base)。
实施例108
3-(2,4-二氟苯基)-5-[(2,4-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.64(s,1H),8.79(d,J=1.2Hz,1H),8.46(d,J=5.6Hz,1H),7.53(dt,J=6.2Hz,8.5Hz,1H),7.40(dt,J=6.6Hz,8.5Hz,1H),7.10~7.05(m,1H),7.01~6.92(m,3H),6.72(td,J=1.2Hz,5.6Hz,1H),3.93(s,2H)。
Mass,m/e:428(M+),254(base)。
实施例109
3-(2,4-二氟苯基)-5-[(2,5-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(s,1H),8.79(s,1H),8.46(d,J=5.6Hz,1H),7.53(dt,J=6.2Hz,8.5Hz,1H),7.18~7.05(m,4H),6.99(dt,J=2.7Hz,8.9Hz,1H),6.72(td,J=1.9Hz,5.6Hz,1H),3.95(s,2H)。
Mass,m/e:428(M+),258(base)。
实施例110
3-(2,4-二氟苯基)-5-[(2,6-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.69(s,1H),8.69(s,1H),8.46(d,J=5.4Hz,1H),7.53(dt,J=6.2Hz,8.1Hz,1H),7.45~7.37(m,1H),7.10~6.96(m,4H),6.71(td,J=1.5Hz,5.4Hz,1H),4.01(s,2H)。
Mass,m/e:428(M+),258(base)。
实施例111
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.52(bs,1H),8.71(s,1H),8.45(d,J=5.4Hz,1H),7.53(dt,J=6.2Hz,8.1Hz,1H),7.45(dd,J=5.8Hz,8.5Hz,1H),7.28(dd,J=2.7Hz,8.1Hz,1H),7.14~7.05(m,2H),6.99(dt,J=2.3Hz,9.6Hz,1H),6.71(td,J=1.9Hz,5.4Hz,1H),4.04(s,2H)。
Mass,m/e:444(M+),258(base)。
实施例112
3-(2,4-二氟苯基)-5-[(2-氯-6-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.59(s,1H),8.64(s,1H),8.44(d,J=5.2Hz,1H),7.53(dt,J=6.2Hz,8.1Hz,1H),7.42~7.35(m,2H),7.16(dt,J=1.5Hz,8.9Hz,1H),7.10~7.05(m,1H),6.99(dt,J=2.3Hz,8.5Hz,1H),6.78(td,J=1.9Hz,5.2Hz,1H),4.14(s,2H)。
Mass,m/e:444(M+),258(base)。
实施例113
5-[(2,4-二氯苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:10.11(bs,1H),8.70(s,1H),8.46(d,J=5.6Hz,1H),7.55~7.50(m,2H),7.42~7.36(m,2H),7.10~7.05(m,1H),7.01~6.96(m,1H),6.71(td,J=1.6Hz,5.6Hz,1H),4.04(s,2H)。
Mass,m/e:460(M+),258(base)。
实施例114
5-[(2,6-二氯苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(bs,1H),8.60(s,1H),8.43(d,J=5.4Hz,1H),7.55~7.48(m,3H),7.35(dd,J=7.7Hz,8.5Hz,1H),7.07(dt,J=1.5Hz,7.7Hz,1H),6.98(dt,J=2.7Hz,9.6Hz,1H),6.70(td,J=1.9Hz,5.4Hz,1H),4.31(s,2H)。
Mass,m/e:460(M+),258(base)。
实施例115
3-(2,4-二氟苯基)-5-[(2-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.46(d,J=1.2Hz,1H),8.38(d,J=5.6Hz,1H),7.51(dt,J=6.6Hz,8.5Hz,1H),7.45(dt,J=1.5Hz,8.1Hz,1H),7.34(dd,J=1.5Hz,7.3Hz,1H),7.11~7.03(m,2H),7.00~6.94(m,2H),6.64(td,J=1.5Hz,5.6Hz,1H),3.88(s,2H),3.81(s,3H)。
Mass,m/e:422(M+),91(base)。
实施例116
3-(2,4-二氟苯基)-5-[(3-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.59(d,J=1.4Hz,1H),8.39(d,J=5.6Hz,1H),7.51(dt,J=6.6Hz,8.5Hz,1H),7.40(t,J=7.7Hz,1H),7.06(dt,J=1.5Hz,7.7Hz,1H),6.99~6.94(m,4H),6.66(td,J=1.4Hz,5.6Hz,1H),3.90(s,2H),3.83(s,3H)。
Mass,m/e:422(M+),148(base)。
实施例117
3-(2,4-二氟苯基)-5-[(2,3-二甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.62(d,J=1.7Hz,1H),8.39(d,J=5.4Hz,1H),7.50(dt,J=6.2Hz,8.5Hz,1H),7.14(t,J=7.7Hz,1H),7.08~7.03(m,1H),7.01~6.94(m,3H),6.64(td,J=1.7Hz,5.4Hz,1H),3.90(s,2H),3.89(s,3H),3.89(s,3H)。
Mass,m/e:452(M+),178(base)。
实施例118
3-(2,4-二氟苯基)-5-[(2,5-二甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.58(d,J=1.4Hz,1H),8.40(d,J=5.6Hz,1H),7.51(dt,J=6.2Hz,8.5Hz,1H),7.06(dt,J=2.3Hz,8.5Hz,1H),6.99~6.90(m,4H),6.65(td,J=1.4Hz,5.6Hz,1H),3.86(s,2H),3.81(s,3H),3.77(s,3H)。
Mass,m/e:452(M+),178(base)。
实施例119
3-(2,4-二氟苯基)-5-[(3,5-二甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.70(d,J=1.7Hz,1H),8.41(d,J=5.6Hz,1H),7.51(dt,J=6.2Hz,8.5Hz,1H),7.09~7.04(m,1H),7.00~6.95(m,1H),6.66(td,J=1.7Hz,5.6Hz,1H),6.54(d,J=2.3Hz,2H),6.51(t,J=2.3Hz,1H),3.84(s,2H),3.81(s,6H)。
Mass,m/e:452(M+),178(base)。
实施例120
3-(2,4-二氟苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.41(d,J=1.54Hz,1H),8.38(d,J=5.4Hz,1H),7.50(dt,J=6.2Hz,8.5Hz,1H),7.42~7.31(m,4H),7.08~7.03(m,1H),6.97(dt,J=2.3Hz,8.9Hz,1H),6.64(td,J=1.9Hz,5.4Hz,1H),3.92(s,2H),2.36(s,3H)。
Mass,m/e:406(M+),258(base)。
实施例121
3-(2,4-二氟苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.48(s,1H),8.40(d,J=5.4Hz,1H),7.54~7.49(m,1H),7.40~7.36(m,1H),7.28~7.20(m,3H),7.09~7.04(m,1H),7.00~6.95(m,1H),6.76(dt,J=1.5Hz,5.4Hz,1H),3.89(s,2H),2.40(s,3H)。
Mass,m/e:406(M+),258(base)。
实施例122
3-(2,4-二氟苯基)-5-[(2,5-二甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.36(s,1H),8.39(d,J=5.4Hz,1H),8.38(s,1H),7.50(dt,J=6.2Hz,8.1Hz,1H),7.20(bs,2H),7.15(s,1H),7.06(dt,J=2.7Hz,8.9Hz,1H),6.97(dt,J=2.7Hz,8.9Hz,1H),6.64(td,J=1.9Hz,5.4Hz,1H),3.88(s,2H),2.38(s,3H),2.31(s,3H)。
Mass,m/e:420(M+),258(base)。
实施例123
3-(2,4-二氟苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.57(s,1H),8.42(d,J=5.4Hz,1H),7.82(d,J=8.1Hz,1H),7.67(t,J=6.9Hz,1H),7.59~7.49(m,3H),7.07(dt,J=2.7Hz,8.9Hz,1H),6.98(dt,J=2.7Hz,8.9Hz,1H),6.68(td,J=1.9Hz,5.4Hz,1H),4.12(s,2H)。
Mass,m/e:460(M+),258(base)。
实施例124
3-(2,4-二氟苯基)-5-(3-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(bs,1H),9.07(d,J=1.5Hz,1H),8.48(d,J=5.4Hz,1H),7.55(dt,J=6.2Hz,8.5Hz,1H),7.31~7.26(m,5H),7.11~7.06(m,1H),7.03~6.98(m,1H),6.73(td,J=1.5Hz,5.4Hz,1H),3.12(t,J=7.5Hz,2H),2.98(t,J=7.5Hz,2H)。
Mass,m/e:406(M+),91(base)。
实施例125
3-(2,4-二氟苯基)-5-(1-苯基环丙烷羰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.35(d,J=5.8Hz,1H),8.21(d,J=1.3Hz,1H),7.57~7.46(m,6H),7.05(dt,J=2.5Hz,8.5Hz,1H),6.95(dt,J=2.5Hz,9.3Hz,1H),6.61(td,J=1.3Hz,5.8Hz,1H),1.85(q,J=3.9Hz,2H),1.31(q,J=3.9Hz,2H)。
Mass,m/e:418(M+),117(base)。
实施例126
3-(2,6-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,6-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.5Hz,1H),8.34(d,J=5.4Hz,1H),7.58~7.50(m,1H),7.11~7.07(m,2H),6.94(bs,2H),6.57~6.54(m,1H)。
Mass,m/e:274(M+),129(base)。
b:3-(2,6-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.48(d,J=1.2Hz,1H),8.38(d,J=5.4Hz,1H),7.58~7.41(m,6H),7.11~7.06(m,2H),6.60(dd,J=1.2Hz,5.4Hz,1H),3.95(s,2H)。
Mass,m/e:392(M+),91(base)。
实施例127
5-[(2-氯苯基)乙酰氨基]-3-(2,6-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.53(s,1H),8.54(bs,1H),8.40(d,J=5.8Hz,1H),7.59~7.38(m,5H),7.10~7.06(m,2H),6.62(d,J=4.6Hz,1H),4.08(s,2H)。
Mass,m/e:426(M+),258(base)。
实施例128
3-(3,4-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-二氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.4Hz,1H),8.37(d,J=5.7Hz,1H),7.55~7.10(m,3H),6.90(bs,2H),6.71(dd,J=1.4Hz,5.7Hz,1H)。
Mass,m/e:274(M+),129(base)。
b:3-(3,4-二氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(s,1H),8.50(d,J=0.8Hz,1H),8.40(d,J=5.5Hz,1H),7.52~7.20(m,8H),6.74(dd,J=1.3Hz,5.5Hz,1H),3.94(s,1H)。
Mass,m/e:392(M+),91(base)。
实施例129
3-(2-氯-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氯-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.6Hz,1H),8.32(d,J=5.6Hz,1H),7.47(dd,J=6.2Hz,8.5Hz,1H),7.31(dd,J=2.7Hz,8.5Hz,1H),7.16(dt,J=2.7Hz,8.5Hz,1H),6.93(bs,2H),6.42(dd,J=1.6Hz,5.6Hz,1H),2.41(s,3H)。
Mass,m/e:290(M+),255(base)。
b:3-(2-氯-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(bs,1H),8.47(d,J=1.3Hz,1H),8.37(d,J=5.6Hz,1H),7.51~7.40(m,6H),7.29(dd,J=2.3Hz,8.1Hz,1H),7.15(dt,J=2.7Hz,8.5Hz,1H),6.47(dd,J=1.3Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:408(M+),91(base)。
实施例130
3-(2-氯-4-氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.65(s,1H),8.60(d,J=1.2Hz,1H),8.40(d,J=5.8Hz,1H),7.46~7.41(m,3H),7.31~7.16(m,4H),6.50(dd,J=1.2Hz,5.8Hz,1H),3.96(s,2H)。
Mass,m/e:426(M+),109(base)。
实施例131
3-(2-氯-4-氟苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.52(s,1H),8.52(d,J=1.2Hz,1H),8.41(d,J=5.6Hz,1H),7.54~7.52(m,1H),7.49~7.40(m,4H),7.29(dd,J=2.7Hz,8.3Hz,1H),7.16(td,J=2.7Hz,8.3Hz,1H),6.49(dd,J=1.2Hz,5.6Hz,1H),4.07(s,2H)。
Mass,m/e:442(M+),274(base)。
实施例132
3-(3-氯-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-氯-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.4Hz,1H),8.37(d,J=5.6Hz,1H),7.75~7.15(m,3H),6.89(bs,2H),6.71(dd,J=1.4Hz,5.6Hz,1H)。
Mass,m/e:290(M+),145(base)。
b:3-(3-氯-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.50(d,J=1.4Hz,1H),8.41(d,J=5.6Hz,1H),7.56(dd,J=2.3Hz,6.9Hz,1H),7.52~7.32(m,6H),7.28(t,J=8.5Hz,1H),6.74(dd,J=1.4Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:408(M+),91(base)。
实施例133
3-(3-氯-4-氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(s,1H),8.63(s,1H),8.44(d,J=5.4Hz,1H),7.55(t,J=7.7Hz,1H),7.47~7.40(m,2H),7.30(dd,J=1.9Hz,8.9Hz,1H),7.27(dd,J=1.2Hz,7.7Hz,1H),7.24~7.17(m,2H),6.78(dd,J=1.2Hz,5.4Hz,1H),3.96(s,2H)。
Mass,m/e:426(M+),109(base)。
实施例134
3-(2-氟-4-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-氯-2-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.3Hz,1H),8.36(d,J=5.6Hz,1H),7.47(t,J=7.7Hz,1H),7.32(dd,J=1.9Hz,8.5Hz,1H),7.28(dd,J=1.9Hz,9.2Hz,1H),6.91(bs,2H),6.61(dd,J=1.3Hz,5.6Hz,1H)。
Mass,m/e:290(M+),145(base)。
b:3-(2-氟-4-氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.49(d,J=1.4Hz,1H),8.41(d,J=5.4Hz,1H),7.51~7.39(m,6H),7.32(dd,J=2.3Hz,8.5Hz,1H),7.25(dd,J=1.9Hz,9.3Hz,1H),6.66(td,J=1.4Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:384(M+),91(base)。
实施例135
3-(4-氯-2-氟苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.62(s,1H),8.61(d,J=1.5Hz,1H),8.44(d,J=5.2Hz,1H),7.49~7.40(m,3H),7.33(dd,J=1.9Hz,7.7Hz,1H),7.28~7.24(m,2H),7.20(t,J=8.5Hz,1H),6.69(td,J=1.5Hz,5.2Hz,1H),3.96(s,2H)。
Mass,m/e:426(M+),109(base)。
实施例136
3-(4-氯-2-氟苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.54(s,1H),8.42(d,J=5.8Hz,1H),7.54~7.52(m,1H),7.49~7.45(m,2H),7.42~7.40(m,2H),7.32(dd,J=1.9Hz,8.5Hz,1H),7.26(dd,J=2.3Hz,8.9Hz,1H),6.49(td,J=1.5Hz,5.8Hz,1H),4.07(s,2H)。
Mass,m/e:442(M+),274(base)。
实施例137
3-(4-氯-3-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-氯-3-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.5Hz,1H),8.36(d,J=5.8Hz,1H),7.55(t,J=8.1Hz,1H),7.35(dd,J=1.9Hz,9.3Hz,1H),7.28~7.26(m,1H),6.91(bs,2H),6.72(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:290(M+),145(base)。
b:3-(4-氯-3-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(bs,1H),8.50(d,J=1.3Hz,1H),8.41(d,J=5.6Hz,1H),7.54(t,J=8.5Hz,1H),7.49~7.45(m,3H),7.41~7.39(m,2H),7.29(dd,J=1.9Hz,8.9Hz,1H),7.22~7.20(m,1H),6.75(dd,J=1.3Hz,5.6Hz,1H),3.93(s,2H)。
Mass,m/e:408(M+),91(base)。
实施例138
3-(4-氯-3-氟苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.55(d,J=1.2Hz,1H),8.42(d,J=5.6Hz,1H),7.57~7.52(m,2H),7.48~7.46(m,1H),7.43~7.40(m,2H),7.30(dd,J=1.9Hz,8.9Hz,1H),7.23~7.21(m,1H),6.77(dd,J=1.2Hz,5.6Hz,1H),4.06(s,2H)。
Mass,m/e:442(M+),274(base)。
实施例139
3-(3-溴-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-溴-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.5Hz,1H),8.36(d,J=5.8Hz,1H),7.77(dd,J=1.5Hz,6.4Hz,1H),7.48~7.44(m,1H),7.28~7.25(m,1H),6.88(bs,2H),6.71(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:334(M+),94(base)。
b:3-(3-溴-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.51(bs,1H),8.41(d,J=5.4Hz,1H),7.71(dd,J=6.6Hz,2.3Hz,1H),7.51~7.39(m,6H),7.25~7.23(m,1H),6.74(dd,J=5.4Hz,1.5Hz,1H),3.94(s,2H)。
Mass,m/e:452(M+),91(base)。
实施例140
3-(3-溴-4-氟苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:10.09(s,1H),8.55(bs,1H),8.42(d,J=5.4Hz,1H),7.72(dd,J=2.1Hz,6.4Hz,1H),7.54~7.52(m,1H),7.47~7.39(m,4H),7.28~7.24(m,1H),6.76(dd,J=1.2Hz,5.4Hz,1H),4.06(s,2H)。
Mass,m/e:486(M+),125(base)。
实施例141
3-(3,4-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.5Hz,1H),8.37(d,J=5.8Hz,1H),7.66(d,J=1.9Hz,1H),7.60(d,J=8.1Hz,1H),7.37(dd,J=1.9Hz,8.1Hz,1H),6.89(bs,2H),6.72(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:305(M+),161(base)。
b:3-(3,4-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.51(s,1H),8.42(d,J=5.6Hz,1H),7.60~7.57(m,2H),7.52~7.39(m,5H),7.30(dd,J=1.9Hz,8.1Hz,1H),6.75(dd,J=1.5Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:424(M+),91(base)。
实施例142
3-(3,4-二氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.56(s,1H),8.63(s,1H),8.45(d,J=5.8Hz,1H),7.62~7.59(m,2H),7.47~7.41(m,2H),7.32(dd,J=1.9Hz,8.1Hz,1H),7.28~7.18(m,2H),6.79(dd,J=1.5Hz,5.8Hz,1H),3.96(s,2H)。
Mass,m/e:442(M+),109(base)。
实施例143
5-[(2-氯苯基)乙酰氨基]-3-(3,4-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.56(d,J=1.2Hz,1H),8.43(d,J=5.6Hz,1H),7.61~7.58(m,2H),7.55~7.38(m,4H),7.32(dd,J=1.9Hz,8.1Hz,1H),6.78(dd,J=1.5Hz,5.6Hz,1H),4.07(s,2H)。
Mass,m/e:459(M++1),125(base)。
实施例144
3-(3,5-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,5-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.05(d,J=1.3Hz,1H),8.39(d,J=5.5Hz,1H),7.54(t,J=1.9Hz,1H),7.43(d,J=1.9Hz,2H),6.91(bs,2H),6.71(dd,J=1.3Hz,5.5Hz,1H)。
Mass,m/e:306(M+),161(base)。
b:3-(3,5-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.51(d,J=1.3Hz,1H),8.44(d,J=5.4Hz,1H),7.54(t,J=1.9Hz,1H),7.52~7.39(m,5H),7.37(d,J=1.9Hz,2H),6.74(dd,J=1.3Hz,5.4Hz,1H),3.94(s,2H)。
Mass,m/e:424(M+),91(base)。
实施例145
3-(3,5-二氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.64(d,J=1.4Hz,1H),8.47(d,J=5.5Hz,1H),7.55(t,J=1.9Hz,1H),7.48~7.40(m,2H),7.38(d,J=1.9Hz,2H),7.30~7.24(m,1H),7.20(t,J=8.9Hz,1H),6.77(dd,J=1.4Hz,5.5Hz,1H),3.97(d,J=1.2Hz,2H)。
Mass,m/e:442(M+),109(base)。
实施例146
5-[(2-氯苯基)乙酰氨基]-3-(3,5-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.56(d,J=1.3Hz,1H),8.45(d,J=5.4Hz,1H),7.56~7.52(m,2H),7.50~7.40(m,3H),7.38(d,2H),6.75(dd,J=1.3Hz,5.4Hz,1H),4.07(s,2H)。
Mass,m/e:458(M+),125(base)。
实施例147
3-(2,6-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,6-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.4Hz,1H),8.30(d,J=5.6Hz,1H),7.50~7.43(m,3H),7.00(bs,2H),6.29(dd,J=1.4Hz,5.6Hz,1H)。
Mass,m/e:306(M+),271(base)。
b:3-(2,6-二氯苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.47(s,1H),8.35(d,J=5.6Hz,1H),7.52~7.42(m,8H),6.34(dd,J=1.5Hz,5.6Hz,1H),3.96(s,2H)。
Mass,m/e:424(M+),91(base)。
实施例148
3-(2,6-二氯苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.68(s,1H),8.60(s,1H),8.38(d,J=5.6Hz,1H),7.50~7.43(m,5H),7.29~7.19(m,2H),6.37(dd,J=1.2Hz,5.6Hz,1H),3.99(s,2H)。
Mass,m/e:442(M+),109(base)。
实施例149
5-[(2-氯苯基)乙酰氨基]-3-(2,6-二氯苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(s,1H),8.54(s,1H),8.36(d,J=5.6Hz,1H),7.55~7.40(m,7H),6.36(dd,J=1.5Hz,5.6Hz,1H),4.09(s,2H)。
Mass,m/e:460(M+),125(base)。
实施例150
5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(2,3,4-三氟苯基)异噁唑
a:5-氨基-4-(4-嘧啶基)-3-(2,3,4-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.5Hz,1H),8.39(d,J=5.8Hz,1H),7.31~7.25(m,1H),7.21~7.13(m,1H),6.92(bs,2H),6.60(dt,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:292(M+),147(base)。
b:5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(2,3,4-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.50(d,J=1.2Hz,1H),8.44(d,J=5.8Hz,1H),7.52~7.39(m,5H),7.30~7.13(m,2H),6.64(dt,J=1.2Hz,5.8Hz,1H),3.95(s,2H)。
Mass,m/e:410(M+),91(base)。
实施例151
5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)-3-(2,3,4-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.61(s,1H),8.63(d,J=1.2Hz,1H),8.47(d,J=5.4Hz,1H),7.48~7.41(m,2H),7.31~7.14(m,4H),6.68(dt,J=1.2Hz,5.4Hz,1H),3.97(s,2H)。
Mass,m/e:428(M+),109(base)。
实施例152
5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)-3-(2,3,4-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.56(d,J=1.2Hz,1H),8.46(d,J=5.4Hz,1H),7.55~7.41(m,3H),7.31~7.25(m,2H),7.20~7.13(m,1H),6.67(dt,J=1.2Hz,5.4Hz,1H),4.07(s,2H)。
Mass,m/e:444(M+),125(base)。
实施例153
3-(2,4,5-三氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-4-(4-嘧啶基)-3-(2,4,5-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.5Hz,1H),8.39(d,J=5.4Hz,1H),7.43~7.37(m,1H),7.16~7.09(m,1H),6.91(bs,2H),6.63(dt,J=1.5Hz,5.4Hz,1H)。
Mass,m/e:292(M+),147(base)。
b:3-(2,4,5-三氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.50(bs,1H),8.44(d,J=5.4Hz,1H),7.52~7.36(m,6H),7.13~7.07(m,1H),6.68~6.67(m,1H),3.94(s,2H)。
Mass,m/e:410(M+),91(base)。
实施例154
5-[(2-氟苯基)乙酰氨基]-3-(2,4,5-三氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.61(s,1H),8.63(d,J=1.2Hz,1H),8.46(d,J=5.4Hz,1H),7.45~7.37(m,3H),7.29~7.18(m,2H),7.14~7.09(m,1H),6.71(dt,J=1.2Hz,5.4Hz,1H),3.97(s,2H)。
Mass,m/e:428(M+),109(base)。
实施例155
5-[(2-氯苯基)乙酰氨基]-3-(2,4,5-三氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.55(bs,1H),8.45(d,J=5.4Hz,1H),7.55~7.36(m,5H),7.14~7.08(m,1H),6.71~6.69(m,1H),4.07(s,2H)。
Mass,m/e:444(M+),276(base)。
实施例156
5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(2,4,6-三氟苯基)异噁唑
a:5-氨基-4-(4-嘧啶基)-3-(2,4,6-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.3Hz,1H),8.38(d,J=5.7Hz,1H),7.07~6.50(m,5H)。
Mass,m/e:292(M+),147(base)。
b:5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(2,4,6-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.49(d,J=1.2Hz,1H),8.42(d,J=5.4Hz,1H),7.52~7.40(m,5H),6.89~6.82(m,2H),6.61(dd,J=5.4Hz,1.2Hz,1H),3.95(s,2H)。
Mass,m/e:410(M+),91(base)。
实施例157
5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)-3-(2,4,6-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.64(s,1H),8.62(bs,1H),8.45(d,J=5.4Hz,1H),7.47~7.41(m,2H),7.29~7.18(m,2H),6.90~6.83(m,2H),6.65(dd,J=1.2Hz,5.4Hz,1H),3.98(s,2H)。
Mass,m/e:428(M+),276(base)。
实施例158
5-[(2-氯苯基)乙酰氨基]-3-(2,4,6-三氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.52(s,1H),8.55(bs,1H),8.44(d,J=5.4Hz,1H),7.55~7.53(m,1H),7.49~7.47(m,1H),7.43~7.40(m,2H),6.87(dd,J=7.3Hz,8.5Hz,2H),6.64(d,J=5.4Hz,1H),4.08(s,2H)。
Mass,m/e:444(M+),276(base)。
实施例159
5-[(3-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)-3-(2,4,6-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.60(d,J=1.5Hz,1H),8.43(d,J=5.4Hz,1H),7.40(t,J=7.9Hz,1H),7.00~6.95(m,3H),6.89~6.84(m,2H),6.61(dd,J=1.5Hz,5.4Hz,1H),3.91(s,2H),3.84(s,3H)。
Mass,m/e:440(M+),148(base)。
实施例160
5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(3,4,5-三氟苯基)异噁唑
a:5-氨基-4-(4-嘧啶基)-3-(3,4,5-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:9.04(d,J=1.5Hz,1H),8.40(d,J=5.4Hz,1H),7.19(t,J=7.7Hz,2H),6.94(bs,2H),6.71(dd,J=1.5Hz,5.4Hz,1H)。
Mass,m/e:292(M+),147(base)。
b:5-(苯基乙酰氨基)-4-(4-嘧啶基)-3-(3,4,5-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.35(bs,1H),8.51(d,J=1.2Hz,1H),8.45(d,J=5.4Hz,1H),7.51~7.44(m,3H),7.41~7.38(m,2H),7.14(t,J=6.2Hz,2H),6.75(dd,J=1.2Hz,5.4Hz,1H),3.93(s,2H)。
Mass,m/e:410(M+),91(base)。
实施例161
5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)-3-(3,4,5-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.54(s,1H),8.64(d,J=1.4Hz,1H),8.47(d,J=5.6Hz,1H),7.47~7.39(m,2H),7.28~7.13(m,4H),6.73(dd,J=1.4Hz,5.6Hz,1H),3.96(s,2H)。
Mass,m/e:428(M+),109(base)。
实施例162
5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)-3-(3,4,5-三氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.41(s,1H),8.56(d,J=1.2Hz,1H),8.41(d,J=5.4Hz,1H),7.54~7.52(m,1H),7.48~7.40(m,3H),7.15(t,J=6.6Hz,2H),6.77(dd,J=1.2Hz,5.4Hz,1H),4.10(s,2H)。
Mass,m/e:444(M+),125(base)。
实施例163
3-(2-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.99(d,J=1.5Hz,1H),8.26(d,J=5.8Hz,1H),7.51(td,J=1.7Hz,7.7Hz,1H),7.42(dd,J=1.7Hz,1H),7.09(ddd,J=1.0Hz,7.7Hz,15.7Hz,1H),7.02(d,J=7.7Hz,1H),6.83(bs,2H),6.55(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:268(M+),123(base)。
b:3-(2-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.47(bs,1H),8.31(d,J=5.7Hz,1H),7.55~7.22(m,6H),7.16~7.05(m,2H),6.98(d,J=8.5Hz,1H),6.60(dd,J=1.5Hz,5.7Hz,1H),3.94(s,2H),3.62(s,3H)。
Mass,m/e:386(M+),252(base)。
实施例164
5-[(2-氟苯基)乙酰氨基]-3-(2-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.63(s,1H),8.59(s,1H),8.33(d,J=5.5Hz,1H),7.55~7.49(m,1H),7.47~7.39(m,3H),7.29~7.16(m,2H),7.09(td,J=1.0Hz,7.3Hz,1H),6.99(d,J=8.1Hz,1H),6.63(dd,J=1.3Hz,5.5Hz,1H),3.97(s,2H),3.63(s,3H)。
Mass,m/e:404(M+),252(base)。
实施例165
5-[(2-氯苯基)乙酰氨基]-3-(2-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.52(s,1H),8.32(d,J=5.5Hz,1H),7.55~7.45(m,3H),7.44~7.38(m,3H),7.09(td,J=0.9Hz,7.3Hz,1H),6.99(d,J=8.1Hz,1H),6.63(dd,J=1.3Hz,5.5Hz,1H),4.07(s,2H)。
Mass,m/e:420(M+),252(base)。
实施例166
3-(3-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.3Hz,1H),8.30(d,J=5.7Hz,1H),7.42(t,J=7.9Hz,1H),7.11(m,3H),6.87(bs,2H),6.76(dd,J=1.3Hz,5.7Hz,1H),3.83(s,3H)。
Mass,m/e:268(M+),77(base)。
b:3-(3-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.49(s,1H),8.35(d,J=5.5Hz,1H),7.52~7.37(m,6H),7.10~6.95(m,3H) ,6.78(dd,J=1.3Hz,5.5Hz,1H),3.94(s,2H),3.81(s,3H)。
Mass,m/e:386(M+),91(base)。
实施例167
5-[(2-氟苯基)乙酰氨基]-3-(3-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.61(s,1H),8.37(d,J=5.7Hz,1H),7.47~7.38(m,3H),7.29~7.16(m,2H),7.09~6.97(m,3H),6.81(dd,J=1.3Hz,5.7Hz,1H),3.97(s,2H),3.82(s,3H)。
Mass,m/e:404(M+-1),252(base)。
实施例168
5-[(2-氯苯基)乙酰氨基]-3-(3-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.56~8.50(bs,1H),8.36(d,J=5.6Hz,1H),7.56~7.37(m,5H),7.09(m,3H),6.79(dd,J=1.3Hz,5.6Hz,1H),4.07(s,2H),3.81(s,3H)。
Mass,m/e:420(M+),252(base)。
实施例169
3-(4-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.5Hz,1H),8.30(d,J=5.8Hz,1H),7.46~7.43(m,2H),7.04~7.00(m,2H),6.84(bs,2H),6.79(dd,J=1.5Hz,5.8Hz,1H),3.88(s,3H)。
Mass,m/e:268(M+),123(base)。
b:3-(4-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.48(s,1H),8.35(d,J=5.4Hz,1H),7.50~7.36(m,7H),7.02~6.98(m,2H),6.82(dd,J=1.5Hz,5.4Hz,1H),3.93(s,2H),3.87(s,3H)。
Mass,m/e:386(M+),91(base)。
实施例170
5-[(2-氟苯基)乙酰氨基]-3-(4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.60(s,1H),8.38(d,J=5.4Hz,1H),7.46~7.38(m,4H),7.27~7.17(m,2H),7.03~6.99(m,2H),6.83(dd,J=1.5Hz,5.4Hz,1H),3.96(s,2H),3.87(s,3H)。
Mass,m/e:404(M+),109(base)。
实施例171
5-[(2-氯苯基)乙酰氨基]-3-(4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.53(s,1H),8.36(d,J=5.4Hz,1H),7.54~7.52(m,1H),7.48~7.46(m,1H),7.42~7.38(m,4H),7.03~7.00(m,2H),6.84(dd,J=1.5Hz,5.4Hz,1H),4.06(s,2H),3.87(s,3H)。
Mass,m/e:420(M+),135(base)。
实施例172
3-(2-氟-4-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.98(d,J=1.5Hz,1H),8.41(d,J=5.8Hz,1H),8.31(bs,2H),7.47(t,J=8.5Hz,1H),7.06(dd,J=2.3Hz,11.9Hz,1H),6.97(dd,J=2.3Hz,8.5Hz,1H),6.57(td,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:286(M+),141(base)。
b:3-(2-氟-4-甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.47(s,1H),8.38(d,J=5.8Hz,1H),7.51~7.38(m,6H),6.83(dd,J=2.7Hz,8.5Hz,1H),6.75~6.71(m,2H),3.93(s,2H),3.86(s,3H)。
Mass,m/e:404(M+),91(base)。
实施例173
3-(2-氟-4-甲氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.62(bs,1H),8.59(s,1H),8.41(d,J=5.8Hz,1H),7.45~7.39(m,3H),7.27~7.24(m,1H),7.19(t,J=9.3Hz,1H),6.84(dd,J=2.3Hz,8.5Hz,1H),6.77~6.72(m,2H),3.96(s,2H),3.87(s,3H)。
Mass,m/e:422(M+),270(base)。
实施例174
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.52(s,1H),8.39(d,J=5.8Hz,1H),7.54~7.51(m,1H),7.48~7.46(m,1H),7.43~7.39(m,3H),6.84(dd,J=2.3Hz,8.5Hz,1H),6.76~6.72(m,2H),4.06(s,2H),3.87(s,3H)。
Mass,m/e:438(M+),270(base)。
实施例175
3-(2-氟-4-甲氧基苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(bs,1H),8.40(d,J=1.2Hz,1H),8.37(d,J=5.4Hz,1H),7.42~7.31(m,5H),6.83(dd,J=1.9Hz,8.1Hz,1H),6.75~6.70(m,2H),3.92(s,2H),3.86(s,3H),2.36(s,3H)。
Mass,m/e:418(M+),270(base)。
实施例176
3-(2-氟-4-甲氧基苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.46(s,1H),8.38(d,J=5.8Hz,1H),7.40(t,J=8.5Hz,2H),7.37(t,J=7.3Hz,1H),7.26(d,J=7.3Hz,1H),7.21(d,J=7.3Hz,1H),6.83(dd,J=2.7Hz,8.9Hz,1H),6.75~6.71(m,2H),3.88(s,2H),3.86(s,3H),2.39(s,3H)。
Mass,m/e:418(M+),270(base)。
实施例177
5-[(2,5-二甲基苯基)乙酰氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.36(bs,1H),8.37(s,1H),8.37(d,J=5.4Hz,1H),7.40(t,J=8.1Hz,1H),7.20(s,2H),7.15(s,1H),6.83(dd,J=2.3Hz,8.5Hz,1H),6.75~6.71(m,2H),3.87(s,2H),3.86(s,3H),2.38(s,3H),2.31(s,3H)。
Mass,m/e:432(M+),270(base)。
实施例178
3-(4-乙基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-乙氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.5Hz,1H),8.30(d,J=5.8Hz,1H),7.45~7.41(m,2H),7.02~6.99(m,2H),6.83(bs,2H),6.79(dd,J=1.5Hz,5.8Hz,1H),4.11(q,J=6.9Hz,2H),1.46(t,J=6.9Hz,3H)。
Mass,m/e:282(M+),137(base)。
b:3-(4-乙基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.48(s,1H),8.34(d,J=5.8Hz,1H),7.50~7.35(m,7H),7.00~6.97(m,2H),6.82(dd,J=1.5Hz,5.8Hz,1H),4.09(q,J=6.9Hz,2H),3.92(s,2H),1.45(t,J=6.9Hz,3H)。
Mass,m/e:400(M+),266(base)。
实施例179
3-(4-乙氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.60(s,1H),8.37(d,J=5.4Hz,1H),7.46~7.36(m,4H),7.27~7.17(m,2H),7.01~6.97(m,2H),6.85(dd,J=1.5Hz,5.4Hz,1H),4.09(q,J=6.9Hz,2H),3.92(s,2H),1.45(t,J=6.9Hz,3H)。
Mass,m/e:418(M+),266(base)。
实施例180
3-(4-乙氧基苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.53(s,1H),8.36(d,J=5.4Hz,1H),7.54~7.36(m,6H),7.01~6.97(m,2H),6.85(dd,J=1.5Hz,5.4Hz,1H),4.12~4.06(m,4H),1.45(t,J=6.9Hz,3H)。
Mass,m/e:434(M+),266(base)。
实施例181
3-(3-苄氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-苄氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.99(d,J=1.5Hz,1H),8.29(d,J=5.6Hz,1H),7.43~7.29(m,7H),7.11~7.07(m,2H),6.95(bs,2H),6.45(dd,J=1.5Hz,5.6Hz,1H),5.06(s,2H)。
Mass,m/e:344(M+),91(base)。
b:3-(3-苄氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(bs,1H),8.46(d,J=1.4Hz,1H),8.33(d,J=5.6Hz,1H),7.51~7.29(m,12H),7.09(dd,J=3.1Hz,8.9Hz,1H),7.04(d,J=3.1Hz,1H),6.50(dd,J=1.4Hz,5.6Hz,1H),5.05(s,2H),3.94(s,2H)。
Mass,m/e:461(M+),91(base)。
实施例182
3-(3-苄氧基苯基)-5-[(2-氯-4-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.56(bs,1H),8.69(s,1H),8.39(d,J=5.6Hz,1H),7.48~7.26(m,9H),7.14~7.09(m,2H),7.06(d,J=3.1Hz,1H),6.55(dd,J=1.5Hz,5.6Hz,1H),5.06(s,2H),4.05(s,2H)。
Mass,m/e:513(M+),91(base)。
实施例183
3-(3-苄氧基苯基)-5-[(2,4-二氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(bs,1H),8.68(s,1H),8.39(d,J=5.6Hz,1H),7.54(d,J=1.9Hz,1H),7.43~7.31(m,9H),7.10(dd,J=3.1Hz,8.9Hz,1H),7.06(d,J=3.1Hz,1H),6.56(dd,J=1.5Hz,5.6Hz,1H),5.06(s,2H),4.05(s,2H)。
Mass,m/e:529(M+),91(base)。
实施例184
3-(3-苄氧基苯基)-5-[(2,6-二氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(bs,1H),8.58(s,1H),8.37(d,J=5.6Hz,1H),7.49(d,J=8.1Hz,2H),7.42~7.29(m,8H),7.10(dd,J=3.1Hz,8.9Hz,1H),7.06(d,J=3.1Hz,1H),6.55(dd,J=1.2Hz,5.6Hz,1H),5.06(s,2H),4.32(s,2H)。
Mass,m/e:529(M+),91(base)。
实施例185
3-(2,3-二甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,3-二甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.97(d,J=1.3Hz,1H),8.26(d,J=5.8Hz,1H),7.19(t,J=7.8Hz,1H),7.10(dd,J=1.5Hz,8.5Hz,1H),6.97(dd,J=1.5Hz,7.8Hz,1H),6.86(bs,2H),6.56(dd,J=1.3Hz,5.8Hz,1H),3.93(s,3H),3.72(s,3H)。
Mass,m/e:298(M+),267(base)。
b:3-(2,3-二甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.44(s,1H),8.31(d,J=5.7Hz,1H),7.52~7.40(m,5H),7.18(t,J=7.8Hz,1H),7.10(dd,J=1.5Hz,8.5Hz,1H),6.93(dd,J=1.5Hz,7.8Hz,1H),6.61(dd,J=1.5Hz,5.7Hz,1H),3.95(s,2H),3.91(s,3H),3.65(s,3H)。
Mass,m/e:416(M+),91(base)。
实施例186
3-(2,3-二甲氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.69(s,1H),8.56(s,1H),8.34(d,J=5.5Hz,1H),7.47~7.40(m,2H),7.31~7.15(m,4H),6.94(dd,J=1.5Hz,7.3Hz,1H),6.64(dd,J=1.5Hz,5.5Hz,1H),3.98(s,2H),3.92(s,3H),3.66(s,3H)。
Mass,m/e:434(M+),109(base)。
实施例187
3-(2,3-二甲氧基苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.32(s,1H),8.49(s,1H),8.32(d,J=5.4Hz,1H),7.55~7.38(m,4H),7.19(t,J=8.5Hz,1H),7.10(dd,J=1.5Hz,8.5Hz,1H),6.94(dd,J=1.5Hz,7.2Hz,1H),6.64(dd,J=1.5Hz,5.4Hz,1H),4.08(s,2H),3.92(s,3H),3.66(s,3H)。
Mass,m/e:450(M+),282(base)。
实施例188
3-(3,4-二甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-二甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.3Hz,1H),8.31(d,J=5.5Hz,1H),7.08(dd,J=1.9Hz,8.4Hz,1H),7.02(s,1H),7.00(t,J=8.4Hz,1H),6.85(bs,2H),6.81(dd,J=1.3Hz,5.5Hz,1H),3.96(s,3H),3.87(s,3H)。
Mass,m/e:298(M+),153(base)。
b:3-(3,4-二甲氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.50(bs,1H),8.36(d,J=5.7Hz,1H),7.52~7.38(m,5H),7.04~6.93(m,3H),6.84(dd,J=1.3Hz,5.7Hz,1H),3.94(s,3H),3.94(s,2H),3.84(s,3H)。
Mass,m/e:416(M+),91(base)。
实施例189
3-(3,4-二甲氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.61(s,1H),8.38(d,J=5.5Hz,1H),7.47~7.39(m,2H),7.30~7.16(m,2H),7.03(dd,J=1.9Hz,8.1Hz,1H),6.99~6.95(m,2H),6.87(dd,J=1.3Hz,5.5Hz,1H),3.97(s,2H),3.95(s,3H),3.85(s,3H)。
Mass,m/e:434(M+),282(base)。
实施例190
5-[(2-氯苯基)乙酰氨基]-3-(3,4-二甲氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.54(s,1H),8.37(d,J=5.5Hz,1H),7.55~7.50(m,1H),7.49~7.45(m,1H),7.45~7.38(m,2H),7.02(dd,J=1.7Hz,8.3Hz,1H),6.99~6.94(m,2H),6.86(dd,J=5.5Hz,1H),4.07(s,2H),3.95(s,3H),3.84(s,3H)。
Mass,m/e:450(M+),282(base)。
实施例191
3-(2,3-亚甲基二氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,3-亚甲基二氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.5Hz,1H),8.39(d,J=5.8Hz,1H),7.04~6.91(m,1H),6.83~6.81(m,2H),6.87(bs,2H),6.63(dd,J=1.5Hz,5.8Hz,1H),5.95(s,2H)。
Mass,m/e:282(M+),137(base)。
b:3-(2,3-亚甲基二氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.50(bs,1H),8.41(d,J=5.8Hz,1H),7.51~7.40(m,5H),6.99~6.95(m,3H),6.84(dd,J=1.4Hz,5.8Hz,1H),5.89(s,2H),3.94(s,2H)。
Mass,m/e:400(M+),91(base)。
实施例192
5-[(2-氯苯基)乙酰氨基]-3-(2,3-亚甲基二氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.54(bs,1H),8.42(d,J=5.4Hz,1H),7.54~7.52(m,1H),7.48~7.46(m,1H),7.42~7.39(m,2H),6.99~6.96(m,3H),6.87(dd,J=1.5Hz,5.4Hz,1H),5.89(s,2H),4.07(s,2H)。
Mass,m/e:434(M+),266(base)。
实施例193
3-(3,4-亚甲基二氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-亚甲基二氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.1Hz,1H),8.34(d,J=5.7Hz,1H),7.05~6.70(m,6H),6.06(s,2H)。
Mass,m/e:282(M+),137(base)。
b:3-(3,4-亚甲基二氧基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(s,1H),8.48(s,1H),8.38(d,J=5.8Hz,1H),7.52~7.38(m,5H),6.97~6.85(m,4H),6.05(s,2H),3.93(s,1H)。
Mass,m/e:400(M+),91(base)。
实施例194
3-(3,4-亚乙基二氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-亚乙基二氧基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.2Hz,1H),8.32(d,J=5.8Hz,1H),7.04(bs,1H),6.98(d,J=1.2Hz,2H),6.86(dd,J=1.2Hz,5.6Hz,1H),6.82(bs,2H),4.35~4.30(m,4H)。
Mass,m/e:296(M+),151(base)。
b:3-(3,4-亚乙基二氧基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.60(s,1H),8.40(d,J=5.4Hz,1H),7.46~7.40(m,2H),7.28~7.17(m,2H),7.00~6.91(m,4H),4.34~4.28(m,4H),3.96(s,2H)。
Mass,m/e:432(M+),280(base)。
实施例195
3-(2-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.99(d,J=1.5Hz,1H),8.23(d,J=5.7Hz,1H),7.46~7.43(m,1H),7.36~7.29(m,3H),6.90(bs,2H),6.34(dd,J=1.5Hz,5.7Hz,1H),2.22(s,3H)。
Mass,m/e:252(M+),130(base)。
b:3-(2-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.46(bs,1H),8.28(d,J=5.7Hz,1H),7.52~7.40(m,6H),7.34~7.25(m,3H),6.39(dd,J=1.5Hz,5.7Hz,1H),3.96(s,2H),2.13(s,3H)。
Mass,m/e:370(M+),91(base)。
实施例196
5-[(2-氟苯基)乙酰氨基]-3-(2-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(s,1H),8.58(s,1H),8.31(d,J=1.5Hz,1H),7.48~7.40(m,3H),7.35~7.18(m,5H),6.42(dd,J=1.5Hz,5.4Hz,1H),3.99(d,J=0.8Hz,2H),2.14(s,3H)。
Mass,m/e:388(M+),236(base)。
实施例197
5-[(2-氯苯基)乙酰氨基]-3-(2-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(s,1H),8.51(s,1H),8.29(d,J=5.7Hz,1H),7.56~7.19(m,8H),6.41(dd,J=1.3Hz,5.7Hz,1H),4.09(s,2H),2.14(s,3H)。
Mass,m/e:404(M+),236(base)。
实施例198
3-(3-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.6Hz,1H),8.28(d,J=5.6Hz,1H),7.40~7.28(m,4H),6.86(bs,2H),6.73(dd,J=1.6Hz,5.6Hz,1H),2.41(s,3H)。
Mass,m/e:252(M+),91(base)。
b:3-(3-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.48(s,1H),8.32(d,J=5.6Hz,1H),7.48~7.21(m,9H),6.75(dd,J=1.5Hz,5.6Hz,1H),3.93(s,2H),2.39(s,3H)。
Mass,m/e:370(M+),91(base)。
实施例199
5-[(2-氟苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.60(s,1H),8.35(d,J=5.4Hz,1H),7.45~7.17(m,8H),6.79(dd,J=1.5Hz,5.4Hz,1H),3.96(s,2H),2.39(s,3H)。
Mass,m/e:388(M+),236(base)。
实施例200
5-[(3-氟苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.65(s,1H),8.36(d,J=5.4Hz,1H),7.47~7.33(m,3H),7.29(s,1H),7.24~7.13(m,4H),6.79(dd,J=1.2Hz,5.4Hz,1H),3.94(s,2H),2.40(s,3H)。
Mass,m/e:388(M+),236(base)。
实施例201
5-[(2-氯苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.52(s,1H),8.34(d,J=5.4Hz,1H),7.54~7.20(m,8H),6.78(dd,J=1.5Hz,5.4Hz,1H),4.07(s,2H),2.39(s,3H)。
Mass,m/e:404(M+),236(base)。
实施例202
5-[(2-溴苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(bs,1H),8.51(s,1H),8.34(d,J=5.5Hz,1H),7.41(d,J=8.1Hz,1H),7.49~7.31(m,5H),7.29(s,1H),7.23(d,J=7.3Hz,1H),6.77(dd,J=1.2Hz,5.5Hz,1H),4.09(s,2H),2.39(s,3H)。
Mass,m/e:448(M+),236(base)。
实施例203
5-[(2-碘苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(bs,1H),8.49(s,1H),8.33(d,J=5.6Hz,1H),8.00(d,J=7.7Hz,1H),7.48(d,J=3.9Hz,2H),7.39~7.32(m,2H),7.29(s,1H),7.24(d,J=9.3Hz,1H),7.18~7.12(m,1H),6.77(dd,J=1.2Hz,5.6Hz,1H),4.12(s,2H),2.39(s,3H)。
Mass,m/e:496(M+),236(base)。
实施例204
5-[(2,4-二氟苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.62(bs,1H),8.78(s,1H),8.39(d,J=5.6Hz,1H),7.42~7.34(m,3H),7.30(s,1H),7.24(d,J=6.6Hz,1H),7.00~6.91(m,2H),6.82(dd,J=1.6Hz,5.6Hz,1H),3.94(s,2H),2.40(s,3H)。
Mass,m/e:406(M+),236(base)。
实施例205
5-[(2,5-二氟苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.65(bs,1H),8.79(s,1H),8.39(d,J=5.6Hz,1H),7.40~7.34(m,2H),7.30(bs,1H),7.25~7.24(m,1H),7.17~7.05(m,3H),6.82(dd,J=1.2Hz,5.6Hz,1H),3.95(s,2H),2.40(s,3H)。
Mass,m/e:406(M+),236(base)。
实施例206
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.70(s,1H),8.38(d,J=5.6Hz,1H),7.45(dd,J=5.8Hz,8.5Hz,1H),7.40~7.33(m,2H),7.30~7.23(m,3H),7.11(dt,J=2.3Hz,7.7Hz,1H),6.81(dd,J=1.5Hz,5.6Hz,1H),4.04(s,2H),2.40(s,3H)。
Mass,m/e:422(M+),236(base)。
实施例207
5-[(2-氟-6-氯苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.63(s,1H),8.37(d,J=5.6Hz,1H),7.41~7.33(m,4H),7.30(s,1H),7.24(d,J=5.8Hz,1H),7.16(dt,J=1.5Hz,8.9Hz,1H),6.80(dd,J=1.5Hz,5.6Hz,1H),4.14(d,J=1.5Hz,2H),2.40(s,3H)。
Mass,m/e:422(M+),236(base)。
实施例208
5-[(2,6-二氯苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.59(s,1H),8.36(d,J=5.4Hz,1H),7.48(d,J=7.7Hz,2H),7.40~7.32(m,3H),7.30(s,1H),7.25~7.23(m,1H),6.80(dd,J=1.9Hz,5.4Hz,1H),4.32(s,2H),2.40(s,3H)。
Mass,m/e:438(M+),236(base)。
实施例209
5-[(2-甲氧基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.36(s,1H),8.44(d,J=1.2Hz,1H),8.31(d,J=5.6Hz,1H),7.44(dt,J=1.5Hz,8.1Hz,1H),7.38~7.31(m,3H),7.28(s,1H),7.22(d,J=7.3Hz,1H),7.08(t,J=7.3Hz,1H),6.99(d,J=8.1Hz,1H),6.74(dd,J=1.2Hz,5.6Hz,1H),3.88(s,2H),3.80(s,3H),2.38(s,3H)。
Mass,m/e:400(M+),91(base)。
实施例210
5-[(3-甲氧基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.58(s,1H),8.33(d,J=5.6Hz,1H),7.41~7.32(m,3H),7.28(s,1H),7.22(d,J=7.3Hz,1H),6.99~6.94(m,3H),6.76(dd,J=1.2Hz,5.6Hz,1H),3.89(s,2H),3.83(s,3H),2.39(s,3H)。
Mass,m/e:400(M+),236(base)。
实施例211
5-[(2,5-二甲氧基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(s,1H),8.56(d,J=1.4Hz,1H),8.33(d,J=5.4Hz,1H),7.38~7.31(m,2H),7.28(s,1H),7.22(d,J=7.3Hz,1H),6.94~6.92(m,3H),6.76(dd,J=1.4Hz,5.4Hz,1H),3.86(s,2H),3.81(s,3H),3.77(s,3H),2.39(s,3H)。
Mass,m/e:430(M+),178(base)。
实施例212
5-[(2,3-二甲氧基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.59(d,J=1.5Hz,1H),8.32(d,J=5.4Hz,1H),7.38~7.31(m,2H),7.28(s,1H),7.22(d,J=6.9Hz,1H),7.14(t,J=8.1Hz,1H),7.00(dd,J=1.2Hz,8.1Hz,1H),6.95(dd,J=1.2Hz,7.3Hz,1H),6.74(dd,J=1.5Hz,5.4Hz,1H),3.90(s,2H),3.89(s,3H),3.88(s,3H),2.42(s,3H)。
Mass,m/e:430(M+),178(base)。
实施例213
5-[(3,5-二甲氧基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.69(d,J=1.3Hz,1H),8.34(d,J=5.6Hz,1H),7.36(q,J=7.3Hz,1H),7.33(d,J=7.3Hz,1H),7.28(s,1H),7.22(d,J=7.3Hz,1H),6.76(dd,J=1.3Hz,5.6Hz,1H),6.54(d,J=2.3Hz,2H),6.50(t,J=2.3Hz,1H),3.84(s,2H),3.81(s,6H),2.39(s,3H)。
Mass,m/e:430(M+),178(base)。
实施例214
3-(3-甲基苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.40(d,J=1.4Hz,1H),8.31(d,J=5.6Hz,1H),7.41~7.31(m,6H),7.27(bs,1H),7.21(dd,J=7.7Hz,1H),6.74(dd,J=1.4Hz,5.6Hz,1H),3.92(s,2H),2.38(s,3H),2.36(s,3H)。
Mass,m/e:384(M+),236(base)。
实施例215
3-(3-甲基苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.47(s,1H),8.33(d,J=5.4Hz,1H),7.39~7.32(m,3H),7.28~7.19(m,5H),6.76(dd,J=1.5Hz,5.4Hz,1H),3.89(s,2H),2.39(s,6H)。
Mass,m/e:384(M+),236(base)。
实施例216
5-[(2,5-二甲基苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.34(s,1H),8.31(d,J=5.8Hz,1H),8.37(d,J=1.4Hz,1H),7.38~7.32(m,2H),7.28(s,1H),7.22~7.20(m,3H),7.15(s,1H),6.74(dd,J=1.4Hz,5.8Hz,1H),3.87(s,2H),2.39(s,6H),2.31(s,3H)。
Mass,m/e:398(M+),236(base)。
实施例217
3-(3-甲基苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.41(bs,1H),8.56(s,1H),8.35(d,J=5.6Hz,1H),7.81(d,J=7.7Hz,1H),7.66(t,J=7.7Hz,1H),7.58(d,J=6.9Hz,1H),7.54(d,J=7.7Hz,1H),7.39~7.32(m,2H),7.29(s,1H),7.23(d,J=6.9Hz,1H),6.78(dd,J=1.5Hz,5.6Hz,1H),4.12(s,2H),2.35(s,3H)。
Mass,m/e:438(M+),236(base)。
实施例218
3-(3-甲基苯基)-5-(3-苯基丙酰基氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(bs,1H),9.06(d,J=1.4Hz,1H),8.41(d,J=5.4Hz,1H),7.41~7.25(m,8H),7.20~7.17(m,1H),6.83(dd,J=1.4Hz,5.4Hz,1H),3.12(t,J=7.5Hz,2H),2.98(t,J=7.5Hz,2H),2.41(s,3H)。
Mass,m/e:384(M+),91(base)。
实施例219
3-(3-甲基苯基)-5-[(1-苯基-环丙烷)羰基氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(bs,1H),8.28(d,J=5.6Hz,1H),8.19(d,J=1.5Hz,1H),7.57~7.50(m,5H),7.37~7.30(m,2H),7.26(s,1H),7.20(d,J=7.3Hz,1H),6.72(dd,J=1.5Hz,5.6Hz,1H),2.38(s,3H),1.84(q,J=3.9Hz,2H),1.30(q,J=3.9Hz,2H)。
Mass,m/e:396(M+),117(base)。
实施例220
3-(4-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.4Hz,1H),8.29(d,J=5.7Hz,1H),7.50~7.20(m,4H),6.87(bs,2H),6.76(dd,J=1.4Hz,5.7Hz,1H),2.45(s,3H)。
Mass,m/e:252(M+),107(base)。
b:3-(4-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(s,1H),8.48(s,1H),8.33(d,J=5,6Hz,1H),7.51~7.38(m,5H),7.36~7.27(m,4H),6.79(dd,J=1.4Hz,5.6Hz,1H),3.94(s,2H),2.43(s,3H)。
Mass,m/e:370(M+),236(base)。
实施例221
3-(4-乙基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-乙基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.2Hz,1H),8.30(d,J=5.4Hz,1H),7.43(d,J=8.1Hz,2H),7.33(d,J=8.1Hz,2H),6.85(bs,2H),6.77(dd,J=1.2Hz,5.4Hz,1H),2.74(q,J=7.7Hz,2H),1.30(t,J=7.7Hz,3H)。
Mass,m/e:266(M+),106(base)。
b:3-(4-乙基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.48(s,1H),8.34(d,J=5.8Hz,1H),7.49~7.30(m,9H),6.80(dd,J=1.5Hz,5.8Hz,1H),3.94(s,2H),2.56(q,J=7.7Hz,2H),1.27(t,J=7.7Hz,3H)。
Mass,m/e:384(M+),250(base)。
实施例222
3-(4-乙基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.61(s,1H),8.37(d,J=5.4Hz,1H),7.46~7.17(m,8H),6.84(dd,J=1.5Hz,5.4Hz,1H),4.00(s,2H),2.73(q,J=7.7Hz,2H),1.29(t,J=7.7Hz,3H)。
Mass,m/e:402(M+),250(base)。
实施例223
3-(4-乙基苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.53(s,1H),8.36(d,J=5.8Hz,1H),7.54~7.31(m,8H),6.83(dd,J=1.5Hz,5.8Hz,1H),4.07(s,2H),2.73(q,J=7.7Hz,2H),1.28(t,J=7.7Hz,3H)。
Mass,m/e:418(M+),250(base)。
实施例224
3-(2-氟-5-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.5Hz,1H),8.32(d,J=5.4Hz,1H),7.10(t,J=9.3Hz,1H),7.34~7.30(m,2H),6.88(bs,2H),6.65(td,J=1.5Hz,5.4Hz,1H)。
Mass,m/e:270(M+),125(base)。
b:3-(2-氟-5-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(bs,1H),8.47(s,1H),8.37(d,J=5.4Hz,1H),7.51~7.40(m,5H),7.34~7.28(m,2H),7.07(t,J=9.3Hz,1H),6.70(td,J=1.9Hz,5.4Hz,1H),3.94(s,2H),2.37(s,3H)。
Mass,m/e:388(M+),254(base)。
实施例225
3-(2-氟-5-甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.64(s,1H),8.60(s,1H),8.39(d,J=5.8Hz,1H),7.42(t,J=6.9Hz,2H),7.33~7.26(m,3H),7.20(t,J=9.6Hz,1H),7.08(t,J=8.9Hz,1H),6.73(d,J=5.8Hz,1H),3.97(s,2H),2.38(s,3H)。
Mass,m/e:406(M+),254(base)。
实施例226
3-(2-氟-5-甲基苯基)-5-[(3-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(bs,1H),8.64(s,1H),8.40(d,J=6.0Hz,1H),7.47~7.42(m,1H),7.35~7.29(m,2H),7.20(d,J=7.7Hz,1H),7.16~7.11(m,2H),7.08(t,J=9.3Hz,1H),6.73(td,J=1.5Hz,6.0Hz,1H),3.94(s,2H),2.38(s,3H)。
Mass,m/e:406(M+),254(base)。
实施例227
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.52(s,1H),8.38(d,J=5.6Hz,1H),7.54~7.51(m,1H),7.49~7.46(m,1H),7.42~7.39(m,2H),7.34~7.29(m,2H),7.07(t,J=9.3Hz,1H),6.72(td,J=1.5Hz,5.6Hz,1H),4.07(s,2H),2.37(s,3H)。
Mass,m/e:422(M+),254(base)。
实施例228
5-[(2-溴苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(bs,1H),8.51(s,1H),8.38(d,J=5.2Hz,1H),7.72(dd,J=1.2Hz,7.7Hz,1H),7.50~7.43(m,2H),7.35~7.29(m,3H),7.08(t,J=9.3Hz,1H),6.72(td,J=1.9Hz,5.2Hz,1H),4.09(s,2H),2.38(s,3H)。
Mass,m/e:466(M+),254(base)。
实施例229
3-(2-氟-5-甲基苯基)-5-[(2-碘苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(bs,1H),8.49(s,1H),8.38(d,J=5.4Hz,1H),8.00(d,J=7.7Hz,1H),7.48(d,J=4.2Hz,2H),7.34~7.30(m,2H),7.18~7.13(m,1H),7.08(t,J=8.5Hz,1H),6.72(td,J=1.9Hz,5.4Hz,1H),4.10(s,2H),2.38(s,3H)。
Mass,m/e:514(M+),254(base)。
实施例230
3-(2-氟-5-甲基基基)-5-[(2,4-二氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.66(bs,1H),8.77(s,1H),8.43(d,J=5.6Hz,1H),7.40(dt,J=6.2Hz,8.5Hz,1H),7.36~7.30(m,2H),7.09(t,J=8.9Hz,1H),7.01~6.92(m,2H),6.78(d,J=5.6Hz,1H),3.94(s,2H),2.38(s,3H)。
Mass,m/e:424(M+),254(base)。
实施例231
5-[(2,5-二氟苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.69(bs,1H),8.78(s,1H),8.43(d,J=5.4Hz,1H),7.36~7.29(m,2H),7.18~7.06(m,4H),6.77(td,J=1.9Hz,5.4Hz,1H),3.95(s,2H),2.39(s,3H)。
Mass,m/e:424(M+),254(base)。
实施例232
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.70(s,1H),8.42(d,J=5.6Hz,1H),7.45(dd,J=6.2Hz,8.9Hz,1H),7.36~7.26(m,3H),7.14~7.06(m,2H),6.75(td,J=1.5Hz,5.6Hz,1H),4.04(s,2H),2.38(s,3H)。
Mass,m/e:440(M+),254(base)。
实施例233
5-[(2-氯-6-氟苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.61(bs,1H),8.63(s,1H),8.41(d,J=5.4Hz,1H),7.42~7.29(m,4H),7.16(dd,J=2.3Hz,6.9Hz,1H),7.09(t,J=9.3Hz,1H),6.75(td,J=1.9Hz,5.4Hz,1H),4.14(d,J=1.9Hz,2H),2.38(s,3H)。
Mass,m/e:440(M+),254(base)。
实施例234
5-[(2,6-二氯苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.59(s,1H),8.40(d,J=5.4Hz,1H),7.48(d,J=8.1Hz,2H),7.37~7.30(m,3H),7.09(t,J=8.9Hz,1H),6.74(td,J=1.9Hz,5.4Hz,1H),4.31(s,2H),2.38(s,3H)。
Mass,m/e:456(M+),254(base)。
实施例235
3-(2-氟-5-甲基苯基)-5-[(3-甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(bs,1H),8.58(d,J=1.5Hz,1H),8.37(d,J=5.2Hz,1H),7.39(t,J=7.7Hz,1H),7.34~7.28(m,2H),7.07(t,J=9.2Hz,1H),7.00~6.94(m,3H),6.70(td,J=1.5Hz,5.2Hz,1H),3.90(s,2H),3.83(s,3H),2.37(s,3H)。
Mass,m/e:418(M+),148(base)。
实施例236
5-[(2,3-二甲氧基苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.60(d,J=1.7Hz,1H),8.36(d,J=5.6Hz,1H),7.33~7.28(m,2H),7.14(t,J=8.1Hz,1H),7.06(t,J=9.3Hz,1H),7.00(dd,J=1.4Hz,8.1Hz,1H),6.96(dd,J=1.4Hz,7.7Hz,1H),6.69(td,J=1.7Hz,5.6Hz,1H),3.91(s,2H),3.89(s,3H),3.88(s,3H),2.37(s,3H)。
Mass,m/e:448(M+),178(base)。
实施例237
5-[(2,5-二甲氧基苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(bs,1H),8.56(J=1.5Hz,1H),8.36(d,J=5.4Hz,1H),7.33~7.29(m,2H),7.07(t,J=8.9Hz,1H),6.96~6.90(m,3H),6.70(td,J=1.5Hz,5.4Hz,1H),3.86(s,2H),3.81(s,3H),3.77(s,3H),2.37(s,3H)。
Mass,m/e:448(M+),178(base)。
实施例238
3-(2-氟-5-甲基苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.40(d,J=1.3Hz,1H),8.35(d,J=5.4Hz,1H),7.41~7.28(m,6H),7.07(t,J=8.9Hz,1H),6.68(td,J=1.3Hz,5.4Hz,1H),3.92(s,2H),2.37(s,3H),2.36(s,3H)。
Mass,m/e:402(M+),254(base)。
实施例239
5-[(2,5-二甲基苯基)乙酰氨基]-3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(bs,1H),8.37~8.35(m,2H),7.34~7.28(m,2H),7.20(t,J=8.1Hz,2H),7.15(s,1H),7.07(t,J=9.2Hz,1H),6.69(td,J=1.9Hz,5.8Hz,1H),3.88(s,2H),2.38(s,3H),2.37(s,3H),2.31(s,3H)。
Mass,m/e:416(M+),254(base)。
实施例240
3-(2-氟-5-甲基苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.45(bs,1H),8.55(s,1H),8.39(d,J=5.6Hz,1H),7.81(d,J=8.1Hz,1H),7.67(t,J=7.7Hz,1H),7.58(d,J=6.9Hz,1H),7.55(d,J=7.7Hz,1H),7.35~7.29(m,2H),7.08(t,J=9.3Hz,1H),6.73(td,J=1.9Hz,5.6Hz,1H),4.12(s,2H),2.38(s,3H)。
Mass,m/e:456(M+),254(base)。
实施例241
3-(3-甲基-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.5Hz,1H),8.32(d,J=5.4Hz,1H),7.37(dd,J=7.3Hz,1.6Hz,1H),7.32~7.28(m,1H),7.13(t,J=8.5Hz,1H),6.89(bs,2H),6.73(dd,J=1.2Hz,5.4Hz,1H),2.33(d,J=1.5Hz,3H)。
Mass,m/e:270(M+),125(base)。
b:3-(3-甲基-4-氟苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(bs,1H),8.48(s,1H),8.35(d,J=5.8Hz,1H),7.51~7.39(m,4H),7.34~7.30(m,1H),7.26~7.21(m,2H),7.11(t,J=8.5Hz,1H),6.76(dd,J=1.5Hz,5.8Hz,1H),3.93(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:388(M+),91(base)。
实施例242
5-[(2-氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(bs,1H),8.61(s,1H),8.38(d,J=5.8Hz,1H),7.46~7.40(m,3H),7.32(dd,J=1.9Hz,7.3Hz,1H),7.28~7.17(m,2H),7.12(t,J=8.5Hz,1H),6.78(dd,J=1.5Hz,5.8Hz,1H),3.96(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:406(M+),254(base)。
实施例243
5-[(3-氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(bs,1H),8.65(s,1H),8.39(d,J=5.6Hz,1H),7.47~7.40(m,2H),7.32(dd,J=1.9Hz,7.3Hz,1H),7.28~7.17(m,3H),7.12(t,J=8.5Hz,1H),6.78(dd,J=1.5Hz,5.6Hz,1H),3.96(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:406(M+),254(base)。
实施例244
5-[(2-氯苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(bs,1H),8.53(s,1H),8.37(d,J=5.6Hz,1H),7.54~7.51(m,1H),7.48~7.45(m,1H),7.42~7.39(m,2H),7.32(d,J=7.3Hz,1H),7.26~7.22(m,1H),7.12(t,J=8.9Hz,1H),6.77(dd,J=1.6Hz,5.6Hz,1H),4.06(s,2H),2.31(d,J=1.5Hz,3H)。
Mass,m/e:422(M+),254(base)。
实施例245
5-[(2-溴苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(bs,1H),8.51(s,1H),8.37(d,J=5.8Hz,1H),7.71(d,J=8.1Hz,1H),7.49~7.43(m,2H),7.35~7.31(m,2H),7.26~7.22(m,1H),7.12(t,J=8.9Hz,1H),6.77(dd,J=1.6Hz,5.8Hz,1H),4.08(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:468(M+),254(base)。
实施例246
5-[(2-碘苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(bs,1H),8.50(s,1H),8.37(d,J=5.4Hz,1H),8.00(d,J=7.7Hz,1H),7.49~7.46(m,2H),7.32(d,J=6.9Hz,1H),7.26~7.22(m,1H),7.18~7.10(m,2H),6.76(dd,J=1.2Hz,5.4Hz,1H),4.09(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:514(M+),254(base)。
实施例247
5-[(2,4-二氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.59(s,1H),8.79(s,1H),8.42(d,J=5.4Hz,1H),7.39(t,J=6.6Hz,8.5Hz,1H),7.33(dd,J=1.9Hz,7.3Hz,1H),7.29~7.24(m,1H),7.13(t,J=8.9Hz,1H),7.00~6.91(m,2H),6.82(dd,J=1.2Hz,5.4Hz,1H),3.97(s,2H),2.32(d,J=1.9Hz,3H)。
Mass,m/e:424(M+),254(base)。
实施例248
5-[(2,5-二氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.62(bs,1H),8.79(s,1H),8.42(d,J=5.4Hz,1H),7.33(dd,J=1.5Hz,7.3Hz,1H),7.28~7.24(m,1H),7.17~7.06(m,4H),6.82(dd,J=1.6Hz,5.4Hz,1H),3.94(s,2H),2.32(d,J=1.5Hz,3H)。
Mass,m/e:424(M+),254(base)。
实施例249
5-[(2-氯-4-氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(bs,1H),8.71(s,1H),8.41(d,J=5.6Hz,1H),7.45(dd,J=6.2Hz,8.9Hz,1H),7.33(dd,J=1.9Hz,7.3Hz,1H),7.28~7.23(m,2H),7.15~7.09(m,2H),6.81(dd,J=1.5Hz,5.6Hz,1H),4.03(s,2H),2.32(d,J=1.9Hz,3H)。
Mass,m/e:440(M+),254(base)。
实施例250
5-[(2-氯-6-氟苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.55(bs,1H),8.63(s,1H),8.40(d,J=5.4Hz,1H),7.42~7.32(m,3H),7.27~7.23(m,1H),7.18~7.11(m,2H),6.80(dd,J=1.2Hz,5.4Hz,1H),4.14(s,2H),2.32(d,J=1.9Hz,3H)。
Mass,m/e:440(M+),254(base)。
实施例251
5-[(2,6-二氯苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.60(s,1H),8.39(d,J=5.6Hz,1H),7.48(d,J=8.1Hz,2H),7.37~7.32(m,2H),7.27~7.23(m,1H),7.13(t,J=9.3Hz,1H),6.80(dd,J=1.5Hz,5.6Hz,1H),4.31(s,2H),2.32(d,J=1.9Hz,3H)。
Mass,m/e:456(M+),254(base)。
实施例252
5-[(2-甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.34(bs,1H),8.45(d,J=1.4Hz,1H),8.34(d,J=5.6Hz,1H),7.45(dt,J=1.9Hz,8.1Hz,1H),7.35~7.30(m,2H),7.24~7.20(m,1H),7.13~7.06(m,2H),6.99(d,J=8.1Hz,1H),6.73(dd,J=1.4Hz,5.6Hz,1H),3.88(s,2H),3.80(s,3H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:418(M+),148(base)。
实施例253
5-[(3-甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.41(s,1H),8.59(s,1H),8.36(d,J=5.8Hz,1H),7.39(t,J=8.1Hz,1H),7.31(d,J=7.0Hz,1H),7.25~7.22(m,1H),7.11(t,J=9.3Hz,1H),6.98~6.94(m,3H),6.76(dd,J=1.2Hz,5.8Hz,1H),3.89(s,2H),3.83(s,3H),2.31(s,3H)。
Mass,m/e:418(M+),254(base)。
实施例254
5-[(2,3-二甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(bs,1H),8.60(d,J=1.4Hz,1H),8.39(d,J=5.6Hz,1H),7.31(dd,J=1.9Hz,6.9Hz,1H),7.24~7.21(m,1H),7.16~7.09(m,2H),7.00(dd,J=1.5Hz,8.1Hz,1H),6.95(dd,J=1.5Hz,7.7Hz,1H),6.74(dd,J=1.4Hz,5.6Hz,1H),3.90(s,2H),3.89(s,3H),3.88(s,3H),2.31(s,3H)。
Mass,m/e:448(M+),178(base)。
实施例255
5-[(2,5-二甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(bs,1H),8.57(d,J=1.4Hz,1H),8.35(d,J=5.4Hz,1H),7.32(dd,J=1.5Hz,6.9Hz,1H),7.25~7.21(m,1H),7.11(t,J=8.5Hz,1H),6.96~6.91(m,3H),6.75(dd,J=1.4Hz,5.4Hz,1H),3.85(s,2H),3.81(s,3H),3.76(s,3H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:448(M+),178(base)。
实施例256
5-[(3,5-二甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(bs,1H),8.69(d,J=1.5Hz,1H),8.37(d,J=5.8Hz,1H),7.31(dd,J=1.9Hz,7.3Hz,1H),7.25~7.21(m,1H),7.12(t,J=8.9Hz,1H),6.76(dd,J=1.5Hz,5.8Hz,1H),6.53(d,J=2.3Hz,2H),6.50(t,J=2.3Hz,1H),3.84(s,2H),3.81(s,6H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:448(M+),178(base)。
实施例257
3-(3-甲基-4-氟苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.35(bs,1H),8.41(d,J=1.4Hz,1H),8.34(d,J=5.4Hz,1H),7.41~7.30(m,5H),7.24~7.20(m,1H),7.11(t,J=9.3Hz,1H),6.74(dd,J=1.4Hz,5.4Hz,1H),3.92(s,2H),2.35(s,3H),2.30(d,J=1.9Hz,3H)。
Mass,m/e:402(M+),254(base)。
实施例258
3-(3-甲基-4-氟苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.37(bs,1H),8.48(s,1H),8.35(d,J=5.6Hz,1H),7.37(t,J=7.3Hz,1H),7.31(d,J=7.3Hz,1H),7.27~7.18(m,4H),7.11(t,J=8.9Hz,1H),6.76(dd,J=1.2Hz,5.6Hz,1H),3.88(s,2H),2.39(s,3H),2.31(s,3H)。
Mass,m/e:402(M+),254(base)。
实施例259
5-[(2,5-二甲基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.32(bs,1H),8.38(d,J=1.2Hz,1H),8.35(d,J=5.6Hz,1H),7.31(dd,J=1.5Hz,7.3Hz,1H),7.24~7.20(m,3H),7.15(s,1H),7.11(t,J=8.9Hz,1H),6.74(dd,J=1.2Hz,5.6Hz,1H),3.87(s,2H),2.38(s,3H),2.31(s,3H),2.31(s,3H)。
Mass,m/e:416(M+),254(base)。
实施例260
3-(3-甲基-4-氟苯基)-5-[(2-硝基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(bs,1H),8.88(s,1H),8.43(d,J=5.8Hz,1H),8.20(d,J=8.5Hz,1H),7.72(t,J=7.7Hz,1H),7.58(t,J=7.7Hz,2H),7.35(d,J=7.3Hz,1H),7.29~7.25(m,1H),7.14(t,J=8.9Hz,1H),6.83(dd,J=1.5Hz,5.8Hz,1H),4.31(s,2H),2.33(d,J=1.5Hz,3H)。
Mass,m/e:433(M+),254(base)。
实施例261
3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)-5-[(2-三氟甲基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.38(bs,1H),8.57(s,1H),8.38(d,J=5.4Hz,1H),7.81(d,J=8.1Hz,1H),7.66(t,J=6.9Hz,1H),7.58~7.54(m,2H),7.32(dd,J=1.5Hz,6.9Hz,1H),7.26~7.22(m,1H),7.12(t,J=8.9Hz,1H),6.78(dd,J=1.5Hz,5.4Hz,1H),4.12(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:456(M+),254(base)。
实施例262
3-(3-氟-4-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-氟-4-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.4Hz,1H),8.32(d,J=5.8Hz,1H),7.32(t,J=8.1Hz,1H),7.20~7.17(m,2H),6.87(bs,2H),6.75(dd,J=1.4Hz,5.8Hz,1H),2.46(s,3H)。
Mass,m/e:270(M+),125(base)。
b:3-(3-氟-4-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.39(bs,1H),8.49(s,1H),8.37(d,J=5.4Hz,1H),7.51~7.39(m,5H),7.30(t,J=7.1Hz,1H),7.13(d,J=9.3Hz,2H),6.78(dd,J=1.5Hz,5.4Hz,1H),3.93(s,2H),2.35(d,J=1.5Hz,3H)。
Mass,m/e:388(M+),254(base)。
实施例263
3-(3-氟-4-甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.61(s,1H),8.40(d,J=5.4Hz,1H),7.46~7.40(m,2H),7.39~7.13(m,5H),6.82(dd,J=1.5Hz,5.4Hz,1H),3.96(d,J=0.8Hz,2H),2.36(d,J=1.6Hz,3H)。
Mass,m/e:406(M+),109(base)。
实施例264
5-[(2-氯苯基)乙酰氨基]-3-(3-氟-4-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.53(s,1H),8.38(d,J=5.4Hz,1H),7.54~7.51(m,1H),7.48(m,1H),7.42~7.39(m,1H),7.33(t,J=7.7Hz,2H),7.15~7.13(m,2H),6.81(dd,J=1.2Hz,5.4Hz,1H),4.06(s,2H),2.35(d,J=1.9Hz,3H)。
Mass,m/e:422(M+),254(base)。
实施例265
3-(4-氯-3-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-氯-3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.02(d,J=1.5Hz,1H),8.33(d,J=5.8Hz,1H),7.48(d,J=8.1H,1H),7.41(d,J=1.9Hz,1H),7.28(dd,J=1.5Hz,8.1Hz,1H),6.86(bs,2H),6.74(dd,J=1.5Hz,5.8Hz,1H),2.43(s,3H)。
Mass,m/e:286(M+),141(base)。
b:3-(4-氯-3-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.49(s,1H),8.37(d,J=5.7Hz,1H),7.51~7.36(m,7H),7.20(dd,J=1.5Hz,8.1Hz,1H),6.76(dd,J=1.5Hz,5.7Hz,1H),3.97(s,2H),2.39(s,3H)。
Mass,m/e:404(M+),91(base)。
实施例266
3-(4-氯-3-甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.61(s,1H),8.40(d,J=5.8Hz,1H),7.48~7.37(m,5H),7.28~7.18(m,2H),6.80(dd,J=1.5Hz,5.8Hz,1H),3.96(s,2H),2.42(s,3H)。
Mass,m/e:422(M+),109(base)。
实施例267
5-[(2-氯苯基)乙酰氨基]-3-(4-氯-3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.53(s,1H),8.39(d,J=5.4Hz,1H),7.54~7.36(m,6H),7.21(dd,J=1.9Hz,8.1Hz,1H),6.79(dd,J=1.5Hz,5.4Hz,1H),4.07(s,2H),2.42(s,3H)。
Mass,m/e:438(M+),270(base)。
实施例268
3-(4-甲氧基-3-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-甲氧基-3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(bs,1H),8.31(d,J=5.4Hz,1H),7.32~7.29(m,2H),6.92(d,J=8.1Hz,1H),6.83~6.81(m,3H),3.90(s,3H),2.26(s,3H)。
Mass,m/e:282(M+),137(base)。
b:3-(4-甲氧基-3-甲基苯基)-5-(苯基基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.40(s,1H),8.48(s,1H),8.34(d,J=5.4Hz,1H),7.51~7.39(m,5H),7.23~7.22(m,1H),6.90(d,J=8.1Hz,1H),6.85(dd,J=1.5Hz,5.4Hz,1H),6.67(dt,J=1.5Hz,5.4Hz,1H),3.93(s,2H),3.89(s,3H),2.23(s,3H)。
Mass,m/e:400(M+),91(base)。
实施例269
5-[(2-氟苯基)乙酰氨基]-3-(4-甲氧基-3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.60(s,1H),8.37(d,J=5.4Hz,1H),7.45~7.40(m,2H),7.27~7.17(m,3H),6.91(d,J=8.1Hz,1H),6.80(dd,J=1.5Hz,5.8Hz,1H),6.67(dt,J=1.5Hz,5.4Hz,1H),4.00(s,2H),3.89(s,3H),2.24(s,3H)。
Mass,m/e:418(M+),109(base)。
实施例270
5-[(2-氯苯基)乙酰氨基]-3-(4-甲氧基-3-甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.46(s,1H),8.53(s,1H),8.36(d,J=5.8Hz,1H),7.54~7.39(m,4H),7.26~7.24(m,1H),6.91(d,J=8.5Hz,1H),6.87(dd,J=1.5Hz,5.8Hz,1H),6.67(dt,J=1.5Hz,5.4Hz,1H),4.06(s,2H),3.89(s,3H),2.24(s,3H)。
Mass,m/e:434(M+),121(base)。
实施例271
3-(2,3-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,3-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.97(d,J=1.5Hz,1H),8.22(d,J=5.6Hz,1H),7.31(d,J=7.3Hz,1H),7.22(d,J=7.3Hz,1H),7.15(d,J=9.3Hz,1H),6.93(bs,2H),6.33(dd,J=1.5Hz,5.6Hz,1H),2.35(s,3H),2.11(s,3H)。
Mass,m/e:266(M+),77(base)。
b:3-(2,3-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(bs,1H),8.45(s,1H),8.27(d,J=5.4Hz,1H),7.49~7.41(m,5H),7.31(d,J=7.3Hz,1H),7.20(t,J=7.3Hz,1H),7.10(d,J=6.9Hz,1H),6.39(dd,J=1.5Hz,5.4Hz,1H),3.95(s,2H),2.32(s,3H),2.02(s,3H)。
Mass,m/e:384(M+),94(base)。
实施例272
3-(2,3-二甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.67(bs,1H),8.57(s,1H),8.29(d,J=5.4Hz,1H),7.46(m,2H),7.32(d,J=7.7Hz,1H),7.28~7.18(m,3H),7.11(d,J=6.9Hz,1H),6.42(dd,J=1.2Hz,5.4Hz,1H),3.98(s,2H),2.33(s,6H),2.04(s,3H)。
Mass,m/e:402(M+),250(base)。
实施例273
3-(2,5-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,5-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.97(d,J=1.3Hz,1H),8.24(d,J=5.4Hz,1H),7.26~7.20(m,2H),7.15(s,1H),6.91(bs,2H),6.38(dd,J=1.3Hz,5.4Hz,1H),2.35(s,3H),2.15(s,3H)。
Mass,m/e:266(M+),77(base)。
b:3-(2,5-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(bs,1H),8.45(s,1H),8.28(d,J=5.8Hz,1H),7.51~7.41(m,5H),7.24~7.18(m,2H),7.08(bs,1H),6.42(dd,J=1.5Hz,5.8Hz,1H),3.95(s,2H),2.33(s,3H),2.06(s,3H)。
Mass,m/e:384(M+),91(base)。
实施例274
3-(2,5-二甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.66(bs,1H),8.57(s,1H),8.31(d,J=5.4Hz,1H),7.45~7.41(m,2H),7.28~7.17(m,4H),7.09(bs,1H),6.45(dd,J=1.5Hz,5.4Hz,1H),3.98(s,2H),2.33(s,3H),2.07(s,3H)。
Mass,m/e:402(M+),109(base)。
实施例275
5-[(2-氯苯基)乙酰氨基]-3-(2,5-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.50(s,1H),8.30(d,J=5.4Hz,1H),7.54~7.52(m,1H),7.50~7.46(m,1H),7.44~7.38(m,2H),7.22~7.19(m,2H),7.09(bs,1H),6.45(dd,J=1.6Hz,5.4Hz,1H),4.08(s,2H),2.33(s,3H),2.07(s,3H)。
Mass,m/e:418(M+),250(base)。
实施例276
3-(2,6-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2,6-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.97(d,J=1.2Hz,1H),8.21(d,J=5.6Hz,1H),7.31(t,J=7.5Hz,1H),7.16(d,J=7.5Hz,2H),6.96(bs,2H),6.21(dd,J=1.2Hz,5.6Hz,1H),2.15(s,6H)。
Mass,m/e:266(M+),77(base)。
b:3-(2,6-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.54(bs,1H),8.45(s,1H),8.26(d,J=5.4Hz,1H),7.52~7.43(m,5H),7.31(t,J=7.5Hz,1H),7.14(d,J=7.5Hz,2H),6.26(dd,J=1.6Hz,5.4Hz,1H),3.96(s,2H),2.06(s,6H)。
Mass,m/e:384(M+),91(base)。
实施例277
3-(2,6-二甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.71(s,1H),8.56(s,1H),8.29(d,J=5.6Hz,1H),7.47~7.41(m,2H),7.33~7.19(m,3H),7.15(d,J=7.7Hz,2H),6.29(td,J=1.5Hz,5.6Hz,1H),3.99(s,2H),2.07(s,6H)。
Mass,m/e:402(M+),250(base)。
实施例278
5-[(2-氯苯基)乙酰氨基]-3-(2,6-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.50(s,1H),8.28(d,J=5.6Hz,1H),7.55~7.53(m,1H),7.51~7.49(m,1H),7.44~7.39(m,2H),7.31(t,J=7.5Hz,1H),7.15(d,J=7.5Hz,2H),6.28(td,J=1.2Hz,5.6Hz,1H),4.09(s,2H),2.07(s,6H)。
Mass,m/e:418(M+),250(base)。
实施例279
3-(3,4-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,4-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.01(d,J=1.3Hz,1H),8.29(d,J=5.7Hz,1H),7.34~7.12(m,3H),7.00~6.70(m,3H),2.35(s,3H),2.32(s,3H)。
Mass,m/e:266(M+),121(base)。
b:3-(3,4-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(s,1H),8.48(bs,1H),8.33(d,J=5.4Hz,1H),7.51~7.39(m,5H),7.24~7.22(m,2H),7.16~7.14(m,1H),6.85(dd,J=1.4Hz,5.4Hz,1H),4.07(s,2H),2.34(s,3H),2.29(s,3H)。
Mass,m/e:384(M+),91(base)。
实施例280
3-(3,4-二甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.59(s,1H),8.60(bs,1H),8.36(d,J=5.4Hz,1H),7.45~7.40(m,2H),7.27~7.16(m,5H),6.82(dd,J=1.5.Hz,5.4Hz,1H),3.97(s,2H),2.38(s,3H),2.34(s,3H)。
Mass,m/e:402(M+),109(base)。
实施例281
5-[(2-氯苯基)乙酰氨基]-3-(3,4-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.47(s,1H),8.52(bs,1H),8.35(d,J=5.4Hz,1H),7.54~7.52(m,1H),7.49~7.46(m,1H),7.43~7.38(m,2H),7.25~7.23(m,2H),7.17~7.15(m,1H),6.84(dd,J=1.4Hz,5.4Hz,1H),4.07(s,2H),2.34(s,3H),2.29(s,3H)。
Mass,m/e:418(M+),250(base)。
实施例282
3-(3,5-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3,5-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.00(d,J=1.4Hz,1H),8.28(d,J=5.8Hz,1H),7.14(s,1H),7.11(s,2H),6.88(bs,2H),6.75(dd,J=1.4Hz,5.8Hz,1H),2.34(s,6H)。
Mass,m/e:266(M+),121(base)。
b:3-(3,5-二甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.48(s,1H),8.33(d,J=5.6Hz,1H),7.48~7.39(m,5H),7.14(s,1H),7.04(s,2H),6.78(dd,J=1.5Hz,5.6Hz,1H),3.93(s,2H),2.34(s,6H)。
Mass,m/e:384(M+),250(base)。
实施例283
3-(3,5-二甲基苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.60(s,1H),8.36(d,J=5.4Hz,1H),7.46~7.40(m,2H),7.27~7.23(m,1H),7.19~7.17(m,1H),7.15(s,1H),7.06(s,2H),6.81(dd,J=1.2Hz,5.4Hz,1H),3.96(d,J=0.8Hz,2H),2.34(s,6H)。
Mass,m/e:402(M+),250(base)。
实施例284
5-[(2-氯苯基)乙酰氨基]-3-(3,5-二甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.48(s,1H),8.52(s,1H),8.34(d,J=5.6Hz,1H),7.53(m,1H),7.48(m,1H),7.41~7.39(m,2H),7.15(s,1H),7.05(s,2H),6.80(dd,J=1.5Hz,5.6Hz,1H),4.08(s,2H),2.34(s,6H)。
Mass,m/e:418(M+),250(base)。
实施例285
3-(4-联苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(4-联苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.5Hz,1H),8.32(d,J=5.4Hz,1H),7.75~7.38(m,9H),6.88(bs,2H),6.84(dd,J=1.5Hz,5.4Hz,1H)。
Mass,m/e:314(M+),169(base)。
b:3-(4-联苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(s,1H),8.51(s,1H),8.37(d,J=5.8Hz,1H),7.73~7.71(m,2H),7.65~7.63(m,2H),7.55~7.38(m,10H),6.87(dd,J=1.5Hz,5.8Hz,1H),3.95(s,2H)。
Mass,m/e:432(M+),298(base)。
实施例286
3-(4-联苯基)-5-[(2-氟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.61(s,1H),8.63(s,1H),8.40(d,J=5.4Hz,1H),7.74~7.72(m,2H),7.66~7.64(m,2H),7.57~7.54(m,2H),7.50~7.38(m,5H),7.29~7.18(m,2H),6.89(dd,J=1.5Hz,5.4Hz,1H),3.98(s,2H)。
Mass,m/e:450(M+),298(base)。
实施例287
3-(4-联苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.49(s,1H),8.55(s,1H),8.38(d,J=5.8Hz,1H),7.75~7.72(m,2H),7.66~7.64(m,2H),7.56~7.38(m,9H),6.90(dd,J=1.5Hz,5.8Hz,1H),4.08(s,2H)。
Mass,m/e:466(M+),298(base)。
实施例288
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-3-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氟-3-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(d,J=1.7Hz,1H),8.34(d,J=5.2Hz,1H),7.83(t,J=7.7Hz,1H),7.75(t,J=7.7Hz,1H),7.43(t,J=7.7Hz,1H),6.98(bs,2H),6.53(td,J=1.7Hz,5.2Hz,1H)。
Mass,m/e:324(M+),179(base)。
b:5-[(2-氯苯基)乙酰氨基]-3-(2-氟-3-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.54(d,J=1.5Hz,1H),8.41(d,J=5.2Hz,1H),7.84(t,J=8.1Hz,1H),7.75(t,J=7.7Hz,1H),7.54~7.40(m,5H),6.60(td,J=1.5Hz,5.2Hz,1H),4.07(s,2H)。
Mass,m/e:476(M+),351(base)。
实施例289
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-4-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氟-4-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.04(s,1H),8.37(d,J=5.6Hz,1H),7.69(t,J=7.7Hz,1H),7.60(t,J=8.1Hz,1H),7.52(d,J=9.3Hz,1H),6.94(bs,2H),6.56(td,J=5.6Hz,1H)。
Mass,m/e:324(M+),52(base)。
b:5-[(2-氯苯基)乙酰氨基]-3-(2-氟-4-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.55(d,J=1.5Hz,1H),8.43(d,J=5.4Hz,1H),7.69(t,J=7.7Hz,1H),7.61(d,J=8.1Hz,1H),7.54~7.40(m,5H),6.63(td,J=5.4Hz,1H),4.10(s,2H)。
Mass,m/e:476(M+),308(base)。
实施例290
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(DMSO-d6)δ:8.98(d,J=1.5Hz,1H),8.43(d,J=5.6Hz,1H),8.37(bs,2H),8.10(m,1H),8.02(dd,J=2.3Hz,6.2Hz,1H),7.69(t,J=9.3Hz,1H),6.59(td,J=1.5Hz,5.6Hz,1H)。
Mass,m/e:324(M+),179(base)。
b:5-[(2-氯苯基)乙酰氨基]-3-(2-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.50(s,1H),8.55(d,J=1.5Hz,1H),8.42(d,J=5.4Hz,1H),7.87~7.83(m,2H),7.55~7.52(m,1H),7.49~7.47(m,1H),7.43~7.40(m,2H),7.35(t,J=9.3Hz,1H),6.62(td,J=1.5Hz,5.4Hz,1H),4.08(s,2H)。
Mass,m/e:476(M+),308(base)。
实施例291
3-(3-氟-5-三氟甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(3-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.05(d,J=1.4Hz,1H),8.37(d,J=5.6Hz,1H),7.62(s,1H),7.51(d,J=8.1Hz,1H),7.46(d,J=8.5Hz,1H),7.00(bs,2H),6.65(dd,J=1.4Hz,5.6Hz,1H)。
Mass,m/e:324(M+),59(base)。
b:3-(3-氟-5-三氟甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.38(s,1H),8.52(d,J=1.4Hz,1H),8.42(d,J=5.6Hz,1H),7.56(s,1H),7.53~7.39(m,7H),6.68(dd,J=1.4Hz,5.6Hz,1H),3.94(s,2H)。
Mass,m/e:442(M+),91(base)。
实施例292
5-[(2-氟苯基)乙酰氨基]-3-(3-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.57(s,1H),8.65(d,J=1.4Hz,1H),8.44(d,J=5.8Hz,1H),7.57(s,1H),7.52(d,J=8.1Hz,1H),7.47~7.41(m,3H),7.28(d,J=7.3Hz,1H),7.20(t,J=9.6Hz,1H),6.71(dd,J=1.4Hz,5.8Hz,1H),3.97(s,2H)。
Mass,m/e:460(M+),109(base)。
实施例293
5-[(2-氯苯基)乙酰氨基]-3-(3-氟-5-三氟甲基苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.44(s,1H),8.56(d,J=1.2Hz,1H),8.43(d,J=5.4Hz,1H),7.57(s,1H),7.55~7.41(m,6H),6.70(dd,J=1.2Hz,5.4Hz,1H),4.07(s,2H)。
Mass,m/e:476(M+),308(base)。
实施例294
3-(1-萘基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(1-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:8.97(d,J=1.5Hz,1H),8.05~8.00(m,2H),7.95(d,J=8.1Hz,1H),7.73(d,J=8.1Hz,1H),7.62~7.58(m,2H),7.55~7.50(m,1H),7.45~7.41(m,1H),7.00(bs,2H),6.06(dd,J=1.5Hz,5.8Hz,1H)。
Mass,m/e:288(M+),143(base)。
b:3-(1-萘基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.58(s,1H),8.44(s,1H),8.06~8.03(m,2H),7.93(d,J=8.5Hz,1H),7.60~7.37(m,10H),6.10(dd,J=1.5Hz,5.4Hz,1H),3.99(s,2H)。
Mass,m/e:406(M+),91(base)。
实施例295
5-[(2-氟苯基)乙酰氨基]-3-(1-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.76(s,1H),8.56(s,1H),8.08(d,J=5.4Hz,1H),8.04(dd,J=2.3Hz,7.3Hz,1H),7.94(d,J=8.5Hz,1H),7.61~7.20(m,9H),6.13(dd,J=1.5Hz,5.6Hz,1H),4.02(s,2H)。
Mass,m/e:424(M+),109(base)。
实施例296
5-[(2-氯苯基)乙酰氨基]-3-(1-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.63(s,1H),8.49(s,1H),8.07~8.03(m,2H),7.94(d,J=8.1Hz,1H),7.61~7.38(m,9H),6.12(dd,J=1.5Hz,5.6Hz,1H),4.12(s,2H)。
Mass,m/e:440(M+),127(base)。
实施例297
3-(2-萘基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
a:5-氨基-3-(2-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:9.03(s,1H),8.23(d,J=5.8Hz,1H),8.07(s,1H),7.98(d,J=8.5Hz,1H),7.94~7.89(m,2H),7.62~7.55(m,3H),6.90(bs,2H),6.72(dd,J=1.2Hz,5.8Hz,1H)。
Mass,m/e:288(M+),127(base)。
b:3-(2-萘基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.45(s,1H),8.50(s,1H),8.27(d,J=5.4Hz,1H),8.01(s,1H),7.96(d,J=8.5Hz,1H),7.93~7.87(m,2H),7.62~7.55(m,2H),7.52~7.42(m,6H),6.74(dd,J=1.4Hz,5.4Hz,1H),3.96(s,2H)。
Mass,m/e:406(M+),108(base)。
实施例298
5-[(2-氟苯基)乙酰氨基]-3-(2-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.63(s,1H),8.62(s,1H),8.30(d,J=5.4Hz,1H),8.03(s,1H),7.98~7.88(m,3H),7.62~7.55(m,2H),7.49(dd,J=1.5Hz,8.5Hz,1H),7.47~7.42(m,2H),7.29~7.18(m,2H),6.78(dd,J=1.5Hz,5.4Hz,1H),4.00(s,2H)。
Mass,m/e:424(M+),109(base)。
实施例299
5-[(2-氯苯基)乙酰氨基]-3-(2-萘基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.51(s,1H),8.55(s,1H),8.29(d,J=5.4Hz,1H),8.03(s,1H),7.97(d,J=8.5Hz,1H),7.93~7.87(m,2H),7.62~7.39(m,7H),6.77(dd,J=1.5Hz,5.4Hz,1H),4.09(s,2H)。
Mass,m/e:440(M+),272(base)。
实施例300
3-(4-氟苯基)-5-[(2-甲氧基甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
a:(2-甲氧基甲氧基苯基)乙酸乙酯的合成
向0.6g 2’-羟苯基乙酸乙酯的30mL无水丙酮溶液中加入2g碳酸钾,室温下搅拌15分钟。接着冰冷却下滴入1.02mL甲氧基甲基氯,然后升温至室温,搅拌过夜。向反应溶液中加水,用醚萃取法萃取。用无水硫酸镁干燥醚萃取液,然后减压下馏去溶剂。将所得残余物用60g硅胶层析(洗脱溶剂,乙酸乙酯∶己烷=1∶3)纯化,得到0.69g(收率:93%)油状物的标题化合物。
1H-NMR(CDCl3)δ:7.31~6.86(m,4H),5.17(s,2H),4.15(q,J=7.1Hz,2H),3.64(s,2H),3.45(s,3H),1.24(t,J=7.1Hz,3H)。
Mass;m/e:224(M+),134(base)。
b:(2-甲氧基甲氧基苯基)乙酸的合成
向0.69g(2-甲氧基甲氧基苯基)乙酸乙酯的20mL甲醇溶液中加入16mL 1M氢氧化钠水溶液,室温下搅拌5小时。减压下馏去反应溶液中的溶剂,加入2M柠檬酸水溶液使溶液呈酸性,进行乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂,得到0.47g(收率:77%)油状物的标题化合物。
1H-NMR(CDCl3)δ:8.40~8.00(bs,1H),7.35~6.86(m,4H),5.18(s,2H),3.68(s,2H),3.44(s,3H)。
Mass;m/e:196(M+),134(base)。
c:3-(4-氟苯基)-5-[(2-甲氧基甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑的合成
将0.47g(2-甲氧基甲氧基苯基)乙酸和0.5g CDI溶解于16mLTHF,室温下搅拌2小时。接着,加入0.92g DBU、0.31g 5-氨基-3-(4-氟苯基)-4-嘧啶基异噁唑的16mL THF溶液,室温下搅拌21小时。减压下馏去反应溶液中的溶剂,向残余物中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用50g硅胶层析(洗脱溶剂,氯仿∶甲醇=100∶1)纯化,然后残余物用醚-己烷洗涤,得到0.32g(收率:60%)标题化合物。
1H-NMR(CDCl3)δ:11.38(bs,1H),8.44(d,J=1.5Hz,1H),8.35(d,J=5.6Hz,1H),7.47~7.41(m,3H),7.35(dd,J=1.5Hz,7.3Hz,1H),7.24~7.12(m,4H),6.72(dd,J=1.5Hz,5.6Hz,1H),5.18(s,2H),3.91(s,2H),3.32(s,3H)。
Mass,m/e:434(M+),240(base)。
实施例301
3-(4-氟苯基)-5-[(2-羟基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
将50mg 3-(4-氟苯基)-5-[(2-甲氧基甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑溶解于30mL二氯甲烷中,加入460mg固定于硅胶上的硫酸氢钠试剂,室温下搅拌4小时。向反应溶液中加入饱和碳酸氢钠水溶液,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂。用醚-己烷洗涤所得残余物,得到16mg(收率:34%)标题化合物。
1H-NMR(CDCl3)δ:11.60(bs,1H),8.73(s,1H),8.37(d,J=5.6Hz,1H),7.45(dd,J=5.4Hz,8.7Hz,2H),7.31~7.26(m,2H),7.19(t,J=8.7Hz,2H),7.00(dt,J=0.8Hz,7.3Hz,1H),6.93(d,J=8.1Hz,1H),6.76(dd,J=1.6Hz,5.6Hz,1H),3.92(s,2H)。
Mass,m/e:390(M+),78(base)。
实施例302
3-(4-氟苯基)-5-[(3-甲氧基甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
与实施例300进行同样的操作,合成标题化合物。
1H-NMR(CDCl3)δ:11.42(bs,1H),8.61(d,J=1.3Hz,1H),8.37(d,J=5.6Hz,1H),7.48~7.43(m,2H),7.39(t,J=7.7Hz,1H),7.22~7.17(m,2H),7.12(dd,J=1.9Hz,8.5Hz,1H),7.70(t,J=1.9Hz,1H),7.03(d,J=7.7Hz,1H),6.73(dd,J=1.3Hz,5.6Hz,1H),5.19(s,2H),3.89(s,2H),3.45(s,3H)。
Mass,m/e:434(M+),240(base)。
实施例303
3-(4-氟苯基)-5-[(3-羟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
与实施例301进行同样的操作,合成标题化合物。
1H-NMR(DMSO-d6)δ:11.36(bs,1H),9.48(s,1H),8.93(d,J=1.5Hz,1H),8.59(d,J=5.4Hz,1H),7.58~7.54(m,2H),7.37~7.33(m,2H),7.19(t,J=7.7Hz,1H),6.94(dd,J=1.5Hz,5.4Hz,1H),6.80~6.78(m,2H),6.76~6.73(m,1H),3.73(s,2H)。
Mass,m/e:390(M+),240(base)。
实施例304
3-(4-氟苯基)-5-[(4-甲氧基甲氧基苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
与实施例300同样地操作,合成标题化合物。
1H-NMR(CDCl3)δ:11.40(bs,1H),8.58(s,1H),8.37(d,J=5.6Hz,1H),7.47~7.43(m,2H),7.32~7.30(m,2H),7.22~7.12(m,4H),6.73(dd,J=1.6Hz,5.6Hz,1H),5.23(s,2H),3.87(s,2H),3.52(s,3H)。
Mass,m/e:434(M+),178(base)。
实施例305
3-(4-氟苯基)-5-[(4-羟苯基)乙酰氨基]-4-(4-嘧啶基)异噁唑
与实施例301同样地操作,合成标题化合物。
1H-NMR(DMSO-d6)δ:11.31(bs,1H),9.42(s,1H),8.87(d,J=1.5Hz,1H),8.59(d,J=5.4Hz,1H),7.56(dd,J=5.8Hz,8.9Hz,2H),7.35(t,J=8.9Hz,2H),7.17(d,J=8.5Hz,2H),6.93(dd,J=1.5Hz,5.4Hz,1H),6.79(d,J=8.5Hz,2H),3.70(s,2H)。
Mass,m/e:390(M+),107(base)。
实施例306
5-[(4-氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
a:4-叔丁氧基羰基氨基苯基乙酸乙酯的合成
向1.94g 4-氨基苯基乙酸乙酯的23mL DMF溶液中加入0.15gDMAP、4.6mL三乙胺和3g二碳酸二叔丁酯,室温下搅拌15小时。向反应溶液中加水,用乙醚萃取。用无水硫酸镁干燥乙醚萃取液,然后减压下馏去溶剂。将所得残余物用200g硅胶层析(洗脱溶剂,乙酸乙酯∶己烷=1∶5)纯化,得到0.70g(收率:17%)油状物的标题化合物。
1H-NMR(CDCl3)δ:7.29(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,2H),6.44(bs,1H),4.12(q,J=7.3Hz,2H),3.53(s,2H),1.50(s,9H),1.22(t,J=7.3Hz,3H)。
Mass,m/e:279(M+),57(base)。
b:5-[(4-叔丁氧基羰基氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的合成
向0.7g 4-叔丁氧基羰基氨基苯基乙酸乙酯的20mL甲醇溶液中加入13mL 1M氢氧化钠水溶液,室温下搅拌24小时。减压下浓缩反应溶液,加入2M柠檬酸水溶液,使溶液呈酸性。冰冷却下,滤取析出的结晶,得到淡黄色结晶的0.40g 4-叔丁氧基羰基氨基苯基乙酸。将本化合物溶解于13mL THF,加入0.40g CDI,室温下搅拌2小时。接着,加入0.71g DBU、0.26g 5-氨基-3-(4-氟苯基)-4-嘧啶基异噁唑的13mL THF溶液,室温下搅拌过夜。减压下馏去反应溶液中的溶剂,向残余物中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用30g硅胶层析(洗脱溶剂,氯仿∶甲醇=100∶1)纯化,然后用乙醚-己烷洗涤结晶残余物,得到0.364g(收率:46%)标题化合物。
1H-NMR(CDCl3)δ:11.41(bs,1H),8.61(d,1H),8.37(d,J=5.6Hz,1H),7.49~7.44(m,4H),7.32~7.30(m,2H),7.22~7.17(m,2H),6.73(dd,J=1.2Hz,5.6Hz,1H),6.59(bs,1H),3.86(s,2H),1.52(s,9H)。
Mass,m/e:489(M+),57(base)。
c:5-[(4-氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑的合成
冰冷却下向59mg 5-[(4-叔丁氧基羰基氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑中加入1mL TFA,然后升温至室温,搅 拌20分钟。冰冷却下,用饱和碳酸氢钠水溶液中和反应溶液,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用二乙醚-己烷洗涤,得到24mg(收率:51%)标题化合物。
1H-NMR(CDCl3)δ:11.41(bs,1H),8.62(s,1H),8.36(d,J=5.6Hz,1H),7.47~7.44(m,2H),7.20(d,J=8.5Hz,2H),7.15(d,J=8.5Hz,2H),6.75(d,J=8.5Hz,2H),6.72(dd,J=1.5Hz,5.6Hz,1H),3.79(s,2H)。
Mass,m/e:389(M+),133(base)。
实施例307
5-[(3-氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
与实施例306同样地操作,合成标题化合物。
a:5-[(3-叔丁氧基羰基氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.43(bs,1H),8.62(d,J=1.2Hz,1H),8.36(d,J=5.4Hz,1H),7.63(s,1H),7.47~7.43(m,2H),7.37(t,J=8.1Hz,1H),7.28~7.26(m,1H),7.22~7.16(m,2H),7.06(d,J=7.7Hz,1H),6.72(dd,J=1.2Hz,5.4Hz,1H),6.58(bs,1H),3.89(s,2H),1.50(s,9H)。
Mass,m/e:489(M+),57(base)。
b:5-[(3-氨基苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.42(bs,1H),8.68(d,J=1.2Hz,1H),8.36(d,J=5.4Hz,1H),7.47~7.44(m,2H),7.27~7.17(m,3H),6.76~6.69(m,4H),3.81(s,2H)。
Mass,m/e:389(M+),133(base)。
实施例308
3-(4-氟苯基)-5-[2-(2-氯苯基)丙酰基氨基]-4-[4-嘧啶基]异噁唑
a:2-(2-氯苯基)丙酸的合成
冰冷却下,向1g 2-氯苯基乙酸中滴入8.8mL 2M的LDA庚烷、THF、乙基苯溶液,再加入1.58g HMPA和5mL THF,室温下搅拌1小时。接着,冰冷却下加入1.25g甲基碘,室温下搅拌30分钟。向反应溶液中注入冰水,加入10%盐酸水溶液使溶液呈酸性,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用30g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=20∶1)纯化,得到0.928g(收率:86%)淡黄色油状性物质的标题化合物。
1H-NMR(CDCl3)δ:7.50~7.10(m,4H),4.27(q,J=7.2Hz,1H),1.52(d,J=7.2Hz,3H)。
Mass,m/e:184(M+),139(base)。
b:3-(4-氟苯基)-5-[2-(2-氯苯基)丙酰基氨基]-4-[4-嘧啶基]异噁唑的合成
将0.144g 2-(2-氯苯基)丙酸和0.126g CDI溶解于5mL THF,室温下搅拌1小时。接着,加入0.237g DBU、0.1g 5-氨基-3-(4-氟苯基)-4-嘧啶基异噁唑的5mL THF溶液,室温下搅拌3小时。减压下馏去反应溶液中的溶剂,向残余物中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用20g硅胶层析(洗脱溶剂,氯仿∶甲醇=50∶1)纯化,然后用乙醚洗涤残余物,得到0.118g(收率:72%)标题化合物。
1H-NMR(CDCl3)δ:11.53(s,1H),8.66(d,J=1.5Hz,1H),8.38(d,J=5.8Hz,1H),7.52~7.43(m,4H),7.39~7.30(m,2H),7.23~7.17(m,2H),6.73(dd,J=1.5Hz,5.8Hz,1H),4.45(q,J=7.1Hz,1H),1.67(d,J=7.1Hz,3H)。
Mass,m/e:422(M+),240(base)。
实施例309
3-(4-氟苯基)-5-[2-(2,6-二氯苯基)丙酰基氨基]-4-(4-嘧啶基)异噁唑
与实施例308同样地操作,合成标题化合物。
a:2-(2,6-二氯苯基)丙酸
1H-NMR(CDCl3)δ:7.45~7.00(m,3H),4.58(q,J=7.2Hz,1H),1.54(d,J=7.2Hz,3H)。
Mass,m/e:218(M+),183(base)。
b:3-(4-氟苯基)-5-[2-(2,6-二氯苯基)丙酰基氨基]-4-(4-嘧啶基)异噁唑
1H-NMR(CDCl3)δ:11.65(s,1H),8.37~8.34(m,2H),7.52~7.38(m,4H),7.31(t,J=8.1Hz,1H),7.20(t,J=8.7Hz,2H),6.75(dd,J=1.4Hz,5.6Hz,1H),4.77(q,J=6.9Hz,1H),1.70(d,J=6.9Hz,3H)。
Mass,m/e:456(M+),240(base)。
实施例310
3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]-5-(苯基乙酰氨基)异噁唑
a:4-甲基-2-甲硫基嘧啶的合成
向25.5g 2-(4-甲基嘧啶)硫醇的400mL甲苯溶液加入50mLDMFDMA,接着加入42mL二异丙基乙胺,加热回流6.5小时。将反应溶液冷却,然后减压下馏去溶剂,向残余物中加水,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用120g硅胶柱层析(洗脱溶剂,氯仿)纯化,得到24.13g(收率:85%)褐色油状性物质的标题化合物。
1H-NMR(CDCl3)δ:8.36(d,J=5.1Hz,1H),6.80(d,J=5.1Hz,1H),2.56(s,3H),2.45(s,3H)。
b:1-氟-4-[4-(2-甲硫基嘧啶基)乙酰基]苯的合成
在-78℃下,向12.64g 4-甲基-2-甲硫基嘧啶的100mL THF溶液中滴入54.1mL 2M的LDA庚烷、THF、乙基苯溶液,滴完后在-78℃下搅拌15分钟。接着,在-78℃下滴入15.17g 4-氟苯甲酸乙酯的100mL THF溶液,滴完后一边缓慢升温至室温一边搅拌1小时。向反应溶液中加入50mL饱和氯化铵水溶液和50mL水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物溶解于氯仿,用120g硅胶柱层析(洗脱溶剂,己烷∶乙酸乙酯=4∶1)纯化,然后用己烷洗涤,得到3.39g(收率:14%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:14.61(s,1H),8.30(d,J=5.4Hz,1H),7.83(dd,J=5.3Hz,8.9Hz,2H),7.10(t,J=8.9Hz,2H),6.63(d,J=5.4Hz,1H),5.90(s,1H),2.61(s,3H)。
c:5-(4-氟苯基)-4-[4-(2-甲硫基嘧啶基)]异噁唑的合成
将6.12g 1-氟-4-[4-(2-甲硫基嘧啶基)乙酰基]苯和13.90gDMFDMA的混合物加热回流45分钟。将反应溶液冷却,然后减压下馏去DMFDMA。向残余物中加入100mL乙醇,接着加入8.12g羟胺盐酸盐,加热回流30分钟。减压下馏去反应溶液中的溶剂,向残余物中加水,滤取沉淀的固体。残余物水洗后溶解于氯仿,用无水硫酸镁干燥,减压下馏去溶剂。将所得残余物用乙醚-己烷洗涤,得到5.10g(收率:76%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.73(s,1H),8.45(d,J=5.2Hz,1H),7.90~7.65(m,2H),7.35~7.05(m,2H),6.98(d,J=5.2Hz,1H),2.50(s,3H)。
Mass,m/e:287(M+),95(base)。
d:3-(4-氟苯基)-2-[4-(甲硫基嘧啶基)]-3-羟丙腈的合成
向5.09g 5-(4-氟苯基)-4-[4-(2-甲硫基嘧啶基)]异噁唑的60mL乙醇溶液中加入30mL 1N NaOH水溶液,60℃、搅拌2.5小时。将反 应溶液冷却,然后减压下浓缩至约1/3,加入冰水(10mL),然后加入10%HCl水溶液使溶液呈中性,滤取沉淀的固体。水洗后减压下干燥,得到4.95g(收率:97%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.15(d,J=6.4Hz,1H),7.80(dd,J=5.6Hz,9.0Hz,2H),7.80~7.55(m,1H),7.29(t,J=9.0Hz,2H),2.64(s,3H)。
e:4-(2-甲硫基嘧啶基)乙腈的合成
向4.94g 2-(4-氟苯基)-[4-(2-甲硫基嘧啶基)]乙腈的200mL乙醇溶液中加入1.29g肼一水合物,加热回流3.5小时。减压下馏去反应溶液中的溶剂,将所得残余物用50g硅胶柱层析(洗脱溶剂,氯仿)纯化,得到2.44g(收率:86%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.55(d,J=5.1Hz,1H),7.11(d,J=5.1Hz,1H),3.83(s,2H),2.57(s,3H)。
f:5-氨基-3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]异噁唑的合成
向0.54g乙醇钠的30mL乙醇溶液中加入1.20g 4-(2-甲硫基嘧啶基)乙腈的20mL THF溶液,室温下搅拌1小时。接着,冰冷却下加入1.26g 4-氟苯甲酰氯的20mL乙醇溶液,室温下搅拌1.5小时。减压下馏去反应溶液中的溶剂,向残余物中加水,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,用活性炭脱色,然后减压下馏去溶剂。将所得残余物用50g硅胶柱层析(洗脱溶剂,氯仿)纯化,然后用乙醚-己烷洗涤,得到1.57g(收率:71%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.14(d,J=5.6Hz,1H),7.62~7.08(m,4H),6.85~6.70(bs,2H),6.36(d,J=5.6Hz,1H),2.57(s,3H)。
Mass,m/e:302(M+,base)。
g:3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]-5-(苯基乙酰氨基)异噁唑的合成
将0.48g咪唑和4.26g DBU溶解于30mL THF,冰冷却搅拌下加入0.99g苯乙酰氯,室温下搅拌1小时。接着,加入1.06g 5-氨基-3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]异噁唑的20mL THF溶液,室温下搅拌24小时。向反应溶液中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用60g硅胶柱层析(洗脱溶剂:氯仿)纯化,然后用乙醚-己烷洗涤,得到0.080g(收率:29%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.35~11.31(bs,1H),8.25(d,J=5.5Hz,1H),7.60~7.05(m,9H),6.45(d,J=5.5Hz,1H),3.92(s,2H),2.62(s,3H)。
实施例311
3-(4-氟苯基)-4-[4-(2-甲基亚硫酰基)嘧啶基]-5-(苯基乙酰氨基)异噁唑
向0.18g 3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]-5-(苯基乙酰氨基)异噁唑的20mL甲醇悬浮液中加入0.79g OXONE的10mL水溶液,室温下搅拌2.5小时。减压下将反应溶液浓缩至液量的约1/4,加入30mL饱和NaHCO3水溶液,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用乙醚洗涤,得到0.15g(收率:78%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:12.50~12.35(bs,1H),8.48(d,J=5.4Hz,1H),7.65~7.10(m,9H),6.82(d,J=5.4Hz,1H),4.01(s,2H),2.98(s,3H)。
Mass,m/e:436(M+),91(base)。
实施例312
3-(4-氟苯基)-4-[4-(2-甲氧基嘧啶基)]-5-(苯基乙酰氨基)异噁唑
a:5-氨基-3-(4-氟苯基)-4-[4-(2-甲基亚硫酰基)嘧啶基]异噁唑的合成
向0.7g 5-氨基-3-(4-氟苯基)-4-[4-(2-甲硫基)嘧啶基]异噁唑的100mL甲醇溶液中加入1.71g OXONE的50mL水溶液,室温下搅拌20分钟。减压下将反应溶液浓缩至液量的约1/3,加入50mL饱和NaHCO3水溶液,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂,得到0.74g(收率:100%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.33(d,J=5.6Hz,1H),7.70~7.05(m,6H),6.68(d,J=5.6Hz,1H),2.93(s,3H)。
b:5-氨基-3-(4-氟苯基)-4-[4-(2-甲氧基嘧啶基)]异噁唑的合成
向0.055g 5-氨基-3-(4-氟苯基)-4-[4-(2-甲基亚硫酰基)嘧啶基]异噁唑中加入0.014g甲醇钠的5mL甲醇溶液,加热回流20分钟。将反应溶液冷却,然后减压下馏去溶剂。向残余物中加水,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用己烷洗涤,得到0.032g(收率:65%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.13(d,J=5.6Hz,1H),7.51(dd,J=5.4Hz,8.7Hz,2H),7.20(t,J=8.7Hz,2H),6.85~6.75(bs,2H),6.34(d,J=5.6Hz,1H),4.00(s,3H)。
Mass,m/e:286(M+),111(base)。
c:3-(4-氟苯基)-4-[4-(2-甲氧基嘧啶基)]-5-(苯基乙酰氨基)异噁唑的合成
将0.014g咪唑和0.124g DBU溶解于3mL THF,冰冷却搅拌下,加入0.028g苯乙酰氯,室温下搅拌2小时。接着,加入0.029g 5-氨基-3-(4-氟苯基)-4-[4-(2-甲氧基嘧啶基)]异噁唑的3mL THF溶液,室温下搅拌26小时。向反应溶液中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用薄层色谱(展开溶剂:氯仿)纯化,得到0.019g(收率:46%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.58(s,1H),8.22(d,J=5.5Hz,1H),7.52~7.43(m,5H),7.38(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,1H),7.20(t,J=8.6Hz,2H),4.04(s,3H),3.92(s,2H)。
Mass,m/e:404(M+),270(base)。
实施例313
4-[4-(2-氨基)嘧啶基]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑
a:2-[1-(2,5-二甲基吡咯基)]-4-甲基嘧啶的合成
将10.28g 2-氨基-4-甲基嘧啶和12.90g丙酮基丙酮的混合物在200℃下搅拌8小时。冷却后,向残余物中加入乙醚,过滤固体。进一步用乙醚洗涤残余物,然后将滤液与洗液合并,减压下馏去溶剂。向过滤的固体中加入8.02g丙酮基丙酮,200℃下搅拌3小时。冷却后,向残余物中加入乙醚,过滤固体,用乙醚洗涤。将滤液与洗液合并,减压下馏去溶剂。将二次的残余物合在一起,溶解于氯仿,用150g硅胶柱层析(洗脱溶剂,己烷∶乙酸乙酯=5∶1→10∶1)纯化,得到6.97g(收率:40%)淡黄色油状性物质的标题化合物。
1H-NMR(CDCl3)δ:8.59(d,J=4.8Hz,1H),7.03(d,J=4.8Hz,1H),5.88(s,2H),2.55(s,3H),2.32(s,6H)。
b:4-{2-[1-(2,5-二甲基吡咯基)]嘧啶基}乙腈的合成
将8.18g 2-[1-(2,5-二甲基吡咯基)]-4-甲基嘧啶和22.83g叔丁氧基双二甲氨基甲烷的混合物在110℃下搅拌45分钟。将反应溶液冷却,然后减压下馏去叔丁氧基双二甲氨基甲烷。向所得残余物中加入150mL水和12.36g羟胺-O-磺酸,室温下搅拌45分钟。向反应溶液中加入碳酸氢钠使溶液呈碱性,然后用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物溶解于氯仿,用120g硅胶柱层析(洗脱溶剂,己烷∶乙酸乙酯=4∶1→2∶1)纯化,得到1.923g(收率:21%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.79(d,J=5.3Hz,1H),7.28(d,J=5.3Hz,1H),5.91(s,2H),3.92(s,2H),2.38(s,6H)。
c:5-氨基-4-(4-{2-[1-(2,5-二甲基吡咯基)]嘧啶基})-3-(4-氟苯基)异噁唑的合成
向0.12g甲醇钠的10mL甲醇溶液中加入0.38g 4-{2-[1-(2,5-二甲基吡咯基)]嘧啶基}乙腈的10mL THF溶液,室温下搅拌30分钟。接着,冰冷却下加入0.31g 4-氟苯甲酰氯的10mL甲醇溶液,室温下搅拌1小时。减压下馏去反应溶液中的溶剂,向残余物中加水,用氯仿萃取。用无水硫酸镁干燥氯仿萃取液,用活性炭脱色,然后减压下馏去溶剂。将所得残余物用25g硅胶柱层析(洗脱溶剂,氯仿)纯化,然后用乙醚-己烷洗涤,得到0.21g(收率:35%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.38(d,J=5.5Hz,1H),7.70~7.10(m,4H),6.85~6.65(bs,2H),6.60(d,J=5.5Hz,1H),5.91(s,2H),2.30(s,6H)。
Mass,m/e:349(M+,base)。
d:4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑的合成
将0.058g咪唑和0.261g DBU溶解于5mL THF,冰冷却搅拌下,加入0.121g苯乙酰氯,室温下搅拌30分钟。接着,加入0.06g 5-氨基-4-(4-{2-[1-(2,5-二甲基吡咯基)]嘧啶基})-3-(4-氟苯基)异噁唑的5mLTHF溶液,室温下搅拌3小时。向反应溶液中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,减压下馏去溶剂。将所得残余物用10g硅胶柱层析(洗脱溶剂,氯仿)纯化,用乙醚-己烷洗涤,得到0.066g(收率:82%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.32(s,1H),8.49(d,J=5.3Hz,1H),7.53(dd,J=5.3Hz,9.0Hz,2H),7.25~7.15(m,5H),7.07~7.02(m,2H),6.67(d,J=5.3Hz,1H),6.05(s,2H),3.73(s,2H),2.34(s,6H)。
Mass,m/e:467(M+),91(base)。
e:4-[4-(2-氨基嘧啶基)]-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑的合成
向0.05g 4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)-5-(苯基乙酰氨基)异噁唑、1mL TFA和1mL苯的混合物中加数滴水,40℃下搅拌过夜。冰冷却下向反应溶液中加水,加入饱和碳酸氢钠水溶液使溶液呈碱性,然后用氯仿萃取。用无水硫酸钠干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用薄层色谱(展开溶剂,氯仿∶甲醇=50∶1)纯化,然后用乙醚-己烷洗涤,得到0.020g(收率:48%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.16(s,1H),7.96(d,J=5.2Hz,1H),7.52~7.38(m,7H),7.17(t,J=8.7Hz,2H),6.06(d,J=5.2Hz,1H),4.35~4.20(bs,2H),3.97(s,2H)。
Mass,m/e:389(M+),255(base)。
实施例314
4-[4-(2-氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑
a:5-[(2-氯苯基)乙酰氨基]-4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)异噁唑的合成
向0.195g 2’-氯苯基乙酸的10mL THF溶液中加入0.186g CDI,室温下搅拌1.5小时。接着,加入0.347g DBU与0.2g 5-氨基-4-(4-{2-[1-(2,5-二甲基吡咯基)]嘧啶基})-3-(4-氟苯基)异噁唑的10mL THF溶液,室温下搅拌2.5小时。减压下馏去反应溶液中的溶剂,加水, 用乙酸乙酯萃取。用无水硫酸镁干燥有机层,然后减压下馏去溶剂。将所得残余物用20g硅胶柱层析(洗脱溶剂,氯仿)纯化,然后用乙醚-己烷洗涤,得到0.248g(收率:86%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.13(s,1H),8.49(d,J=5.4Hz,1H),7.53(dd,J=5.2Hz,8.7Hz,2H),7.30~7.07(m,6H),6.68(d,J=5.4Hz,1H),5.97(s,2H),3.92(s,2H)2.31(s,6H)。
Mass,m/e:501(M+),94(base)。
b:4-[4-(2-氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑的合成
向0.2g 5-[(2-氯苯基)乙酰氨基]-4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)异噁唑、2mL TFA和2mL苯的混合物中加入数滴水,50℃下搅拌4小时。冰冷却下向反应溶液中加入水,加入饱和碳酸氢钠水溶液使溶液呈碱性,然后用氯仿萃取。用无水硫酸钠干燥氯仿萃取液,然后减压下馏去溶剂。将所得残余物用10g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=50∶1)纯化,然后用乙醚洗涤,得到0.083g(收率:49%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.17(s,1H),8.00(d,J=5.4Hz,1H),7.54~7.45(m,4H),7.40~7.34(m,2H),7.23~7.16(m,2H),6.11(d,J=5.4Hz,1H),4.66~4.56(bs,2H),4.09(s,2H)。
Mass,m/e:423(M+),255(base)。
以下,与实施例314同样地操作,合成实施例315~317的化合物。
实施例315
4-[4-(2-氨基嘧啶基)]-5-[(2,6-二氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑
a:5-[(2,6-二氯苯基)乙酰氨基]-4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.12(s,1H),8.51(d,J=5.4Hz,1H),7.54(dd,J=5.4Hz,8.8Hz,2H),7.28~7.21(m,4H),7.13(dd,J=7.5Hz,8.8Hz,1H),6.70(d,J=5.4Hz,1H),5.94(s,2H),4.22(s,2H),2.32(s,6H)。
Mass,m/e:535(M+),94(base)。
b:4-[4-(2-氨基嘧啶基)]-5-[(2,6-二氯苯基)乙酰氨基]-3-(4-氟苯基)异噁唑
1H-NMR(CDCl3)δ:11.25~11.10(bs,1H),8.03(d,J=5.4Hz,1H),7.49(dd,J=5.2Hz,8.7Hz,2H),7.42(d,J=7.9Hz,2H),7.28(d,J=7.9Hz,1H),7.19(t,J=8.7Hz,2H),6.13(d,J=5.4Hz,1H),4.90~4.75(bs,2H),4.38(s,2H)。
Mass,m/e:457(M+),255(base)。
实施例316
4-[4-(2-氨基)嘧啶基]-3-(4-氟苯基)-5-[(2-甲氧基苯基)乙酰氨基]异噁唑
a:4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)-5-[(2-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:10.89(s,1H),8.46(d,J=5.4Hz,1H),7.51(dd,J=5.0Hz,8.9Hz,2H),7.26~7.15(m,3H),7.00(dd,J=1.5Hz,7.3Hz,1H),6.79~6.72(m,2H),6.65(d,J=5.4Hz,1H),5.97(s,2H),3.76(s,2H),3.67(s,3H),2.31(s,6H)。
Mass,m/e:497(M+),91(base)。
b:4-[4-(2-氨基)嘧啶基]-3-(4-氟苯基)-5-[(2-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.09(s,1H),7.95(d,J=5.4Hz,1H),7.48~7.36(m,4H),7.16(t,J=8.6Hz,2H),7.05(t,J=7.3Hz,1H),7.00(d,J=8.1Hz,1H),6.05(d,J=5.4Hz,1H),4.37(bs,2H),3.88(s,2H),3.84(s,3H)。
Mass,m/e:419(M+),148(base)。
实施例317
3-(4-氟苯基)-5-(2-苯基丙酰基氨基)-4-{4-(2-氨基嘧啶基)}异噁唑
a:4-(4-{2-[1-(2,5-二甲基吡咯基)]}嘧啶基)-3-(4-氟苯基)-5-(2-苯基丙酰基氨基)异噁唑
1H-NMR(CDCl3)δ:11.30(s,1H),8.46(d,J=5.4Hz,1H),7.55~7.48(m,2H),7.25~7.12(m,5H),7.02~6.97(m,2H),6.65(d,J=5.4Hz,1H),6.07(s,2H),3.66(q,J=7.0Hz,1H),2.30(s,6H),1.54(d,J=7.0Hz,3H)。
Mass,m/e:481(M+),105(base)。
b:3-(4-氟苯基)-5-(2-苯基丙酰基氨基)-4-{4-(2-氨基嘧啶基)}异噁唑
1H-NMR(CDCl3)δ:11.21(s,1H),7.96(d,J=5.4Hz,1H),7.50~7.37(m,7H),7.17(t,J=8.7Hz,2H),6.06(d,J=5.4Hz,1H),4.33(s,2H),3.95(q,J=6.9Hz,1H),1.63(d,J=6.9Hz,3H)。
Mass,m/e:403(M+),255(base)。
实施例318
4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-(苯基乙酰氨基)异噁唑
a:2-(二-叔丁氧基羰基氨基)-4-甲基嘧啶的合成
向9.15g 2-氨基-4-甲基嘧啶的200mL乙腈溶液中加入40.26g二碳酸二叔丁酯、18.65g三乙胺和1.02g DMAP,室温下搅拌2小时。减压下馏去反应溶液中的溶剂。将残余物溶解于乙酸乙酯,用10%硫酸氢钾水溶液、接着用饱和盐水洗涤,然后用无水硫酸镁干燥,减压下馏去溶剂。将所得残余物用乙醚洗涤,得到15.35g(收率:59%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.59(d,J=5.1Hz,1H),7.06(d,J=5.1Hz,1H),2.54(s,3H),1.45(s,18H)。
b:4-(2-二-叔丁氧基羰基氨基嘧啶基)乙腈的合成
将15.34g 2-(二-叔丁氧基羰基氨基)-4-甲基嘧啶和25.91g叔丁氧基双二甲氨基甲烷的混合物在110℃下搅拌40分钟。将反应溶液冷却,然后减压下馏去叔丁氧基双二甲氨基甲烷。向所得残余物中加入150mL水和16.83g羟胺-O-磺酸,室温下搅拌1小时。向反应溶液中加入碳酸氢钠使溶液呈碱性,然后用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,减压下馏去溶剂。将所得残余物用120g硅胶柱层析(洗脱溶剂,氯仿∶甲醇=50∶1)纯化,得到5.27g(收率:32%)黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.80(d,J=5.1Hz,1H),7.37(d,J=5.1Hz,1H),3.92(s,2H),1.48(s,18H)。
c:5-氨基-3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑的合成
向0.136g甲醇钠的10mL甲醇溶液中加入0.7g 4-[2-(二-叔丁氧基羰基氨基)嘧啶基]乙腈的10mL THF溶液,室温下搅拌45分钟。接着,冰冷却下加入0.439g 4-氯苯甲酰氯的10mL甲醇溶液,室温下搅拌2小时。减压下馏去反应溶液中的溶剂,向残余物中加水,滤取沉淀的固体。将滤取的固体水洗,然后溶解于氯仿-甲醇,用无 水硫酸镁干燥,用活性炭脱色后减压下馏去溶剂。将所得残余物用乙醚-己烷洗涤,得到0.444g(收率:43%)淡黄色结晶的标题化合物。
1H-NMR(CDCl3)δ:8.21(d,J=5.6Hz,1H),7.48(s,4H),7.07(bs,2H),6.44(d,J=5.6Hz,1H),1.53(s,18H)。
Mass,m/e:487(M+),57(base)。
d:3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-5-(苯基乙酰氨基)异噁唑的合成
将0.042g咪唑和0.187g DBU溶解于5mLTHF,冰冷却搅拌下,加入0.095g苯乙酰氯,室温下搅拌40分钟。接着,加入0.1g 5-氨基-3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑的5mLTHF溶液,室温下搅拌1.5小时。向反应溶液中加水,用乙酸乙酯萃取。用无水硫酸镁干燥乙酸乙酯萃取液,然后减压下馏去溶剂。将所得残余物用薄层色谱(展开溶剂,氯仿)纯化,然后用乙醚-己烷洗涤,得到0.095g(收率:77%)无色固体的标题化合物。
1H-NMR(CDCl3)δ:11.61(s,1H),8.29(d,J=5.4Hz,1H),7.50~7.24(m,9H),6.52(d,J=5.4Hz,1H),4.05(s,2H),1.57(s,18H)。
Mass,m/e:605(M+-91),57(base)。
e:4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-(苯基乙酰氨基)异噁唑的合成
向0.093g 3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-5-(苯基乙酰氨基)异噁唑中加入0.5mL TFA,室温下搅拌1小时。冰冷却下,向反应溶液中加入饱和碳酸氢钠水溶液,滤取沉淀的固体。将滤取的固体水洗后减压下干燥。用乙醚洗涤所得残余物,得到0.080g(收率:90%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.51(s,1H),7.97(d,J=5.4Hz,1H),7.51~7.38(m,9H),6.07(d,J=5.4Hz,1H),4.30(bs,2H),3.97(s,2H)。
Mass,m/e:405(M+),270(base)。
实施例319
4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]异噁唑
a:3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑的合成
向0.094g 2’-氯苯基乙酸的5mL THF溶液中加入0.09g CDI,室温下搅拌1.5小时。接着,加入0.168g DBU和0.09g 5-氨基-3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑的5mL THF溶液,60℃下搅拌3.5小时。减压下馏去反应溶液中的溶剂,加水用乙酸乙酯萃取。用无水硫酸镁干燥有机层,然后减压下馏去溶剂。将所得残余物用薄层色谱(展开溶剂,氯仿)纯化,得到0.088g(收率:75%)无色固体的标题化合物。
1H-NMR(CDCl3)δ:11.76(s,1H),8.30(d,J=5.4Hz,1H),7.48(dd,J=8.8Hz,12.3Hz,4H),7.41~7.35(m,2H),7.27~7.23(m,2H),6.54(d,J=5.4Hz,1H),4.22(s,2H),1.55(s,18H)。
Mass,m/e:514(M+-125),57(base)。
b:4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]异噁唑的合成
向0.086g 3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑中加入0.5mL TFA,室温下搅拌1小时。冰冷却下向反应溶液中加入饱和碳酸氢钠水溶液,滤取沉淀的固体。将滤取的固体水洗后减压下干燥。将所得残余物用乙醚洗涤,得到0.043g(收率:73%)无色结晶的标题化合物。
1H-NMR(CDCl3)δ:11.05(s,1H),7.92(d,J=5.4Hz,1H),7.55~7.35(m,8H),6.13(d,J=5.4Hz,1H),4.08(s,2H),2.55(bs,2H)。
Mass,m/e:439(M+),271(base)
以下,与实施例318和319同样地操作,合成实施例320~326的化合物。
实施例320
4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-[3-甲氧基苯基)乙酰氨基]异噁唑
a:3-(4-氯苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.61(s,1H),8.28(d,J=5.4Hz,1H),7.47(dd,J=8.7Hz,14.8Hz,4H),7.25~7.21(m,1H),7.00~6.94(m,2H),6.81(dd,J=2.3Hz,8.1Hz,1H),6.52(d,J=5.4Hz,1H),4.03(s,2H),3.79(s,3H),1.57(s,18H)。
Mass,m/e:514(M+-121),56(base)。
b:4-[4-(2-氨基嘧啶基)]-3-(4-氯苯基)-5-[3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:10.77(s,1H),7.71(d,J=6.4Hz,1H),7.50(d,J=8.5Hz,2H),7.46~7.37(m,3H),7.02~6.94(m,3H),6.16(d,J=6.5Hz,1H),3.94(s,2H),3.84(s,3H),3.60(bs,2H)。
Mass,m/e:435(M+),271(base)。
实施例321
4-[4-(2-氨基嘧啶基)]-5-(苯基乙酰氨基)-3-(4-氟-3-甲基苯基)异噁唑
a:5-氨基-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基])-3-(4-氟-3-甲基苯基)异噁唑
1H-NMR(CDCl3)δ:8.20(d,J=5.4Hz,1H),7.39~7.34(m,1H),7.33~7.27(m,1H),7.12(t,J=8.9Hz,1H),7.03(bs,2H),6.47(d,J=5.4Hz,1H),2.33(s,3H),1.53(s,18H)。
Mass,m/e:485(M+),57(base)。
b:4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-3-(4-氟-3-甲基苯基)-5-(苯基乙酰氨基)异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.28(d,J=5.4Hz,1H),7.42~7.24(m,7H),7.12(t,J=8.9Hz,1H),6.54(d,J=5.4Hz,1H),4.05(s,2H),2.32(d,J=1.9Hz,3H),1.57(s,18H)。
Mass,m/e:512(M+-91),57(base)。
c:4-[4-(2-氨基嘧啶基)]-5-(苯基乙酰氨基)-3-(4-氟-3-甲基苯基)异噁唑
1H-NMR(CDCl3)δ:11.16(s,1H),7.95(d,J=5.4Hz,1H),7.51~7.38(m,5H),7.34~7.29(m,1H),7.27~7.20(m,1H),7.09(t,J=8.9Hz,1H),6.09(d,J=5.4Hz,1H),4.36(bs,2H),3.98(s,2H),2.31(d,J=1.9Hz,3H)。
Mass,m/e:403(M+),269(base)。
实施例322
4-[4-(2-氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟-3-甲基苯基)异噁唑
a:4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基])-3-(4-氟-3-甲基苯基)-5-[(2-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.74(s,1H),8.29(d,J=5.4Hz,1H),7.41~7.35(m,3H),7.31~7.21(m,3H),7.12(t,J=8.9Hz,1H),6.56(d,J=5.4Hz,1H),4.22(s,2H),2.32(s,3H),1.55(s,18H)。
Mass,m/e:512(M+-125),57(base)。
b:4-[4-(2-氨基嘧啶基)]-5-[(2-氯苯基)乙酰氨基]-3-(4-氟-3-甲基苯基)异噁唑
1H-NMR(CDCl3)δ:11.03(s,1H),7.88(d,J=5.8Hz,1H),7.55~7.46(m,2H),7.42~7.36(m,2H),7.34~7.30(m,1H),7.27~7.21(m,1H),7.12(t,J=8.9Hz,1H),6.16(d,J=5.8Hz,1H),4.09(s,2H),2.48(bs,2H),2.32(d,J=1.5Hz,3H)。
Mass,m/e:437(M+),125(base)。
实施例323
4-[4-(2-氨基嘧啶基)]-3-(4-氟-3-甲基苯基)-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
a:4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-3-(4-氟-3-甲基苯基)-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.60(s,1H),8.27(d,J=5.4Hz,1H),7.40~7.20(m,3H),7.12(t,J=8.9Hz,1H),7.02~6.94(m,2H),6.81(dd,J=1.7Hz,8.3Hz,1H),6.54(d,J=5.4Hz,1H),4.03(s,2H),3.79(s,3H),2.32(s,3H),1.57(s,18H)。
Mass,m/e:512(M+-121),57(base)。
b:4-[4-(2-氨基嘧啶基)]-3-(4-氟-3-甲基苯基)-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:10.75(s,1H),7.68(d,J=6.6Hz,1H),7.43(t,J=7.9Hz,1H),7.31~7.18(m,2H),7.14(t,J=8.7Hz,1H),7.02~6.93(m,3H),6.19(d,J=6.6Hz,1H),3.95(s,2H),3.85(s,3H),2.32(s,3H)。
Mass,m/e:433(M+),269(base)。
实施例324
4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-(苯基乙酰氨基)异噁唑
a:5-氨基-3-(3-苄氧基苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑
1H-NMR(CDCl3)δ:8.17(d,J=5.6Hz,1H),7.45~7.27(m,7H),7.11~7.05(m,4H),6.19(d,J=5.6Hz,1H),5.07(s,2H),1.51(s,18H)。
Mass,m/e:459(M+-1),91(base)。
b:3-(3-苄氧基苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-5-(苯基乙酰氨基)异噁唑
1H-NMR(CDCl3)δ:11.73(s,1H),8.24(d,J=5.4Hz,1H),7.44~7.30(m,12H),7.11~7.07(m,2H),6.30(d,J=5.4Hz,1H),5.07(s,2H),4.07(s,2H),1.56(s,18H)。
Mass,m/e:677(M+-175),59(base)。
c:4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-(苯基乙酰氨基)异噁唑
1H-NMR(CDCl3)δ:11.23(s,1H),7.90(d,J=5.4Hz,1H),7.54~7.28(m,12H),7.10~7.02(m,2H),5.87(d,J=5.4Hz,1H),5.05(s,2H),4.43(bs,2H),3.99(s,2H)。
Mass,m/e:476(M+-1),91(base)。
实施例325
4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-[(2-氯苯基)乙酰氨基]异噁唑
a:3-(3-苄氧基苯基)-5-[(2-氯苯基)乙酰氨基]-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}异噁唑
1H-NMR(CDCl3)δ:11.87(s,1H),8.24(d,J=5.4Hz,1H),7.43~7.20(m,11H),7.12~7.07(m,2H),6.31(d,J=5.4Hz,1H),5.08(s,2H),4.24(s,2H),1.54(s,18H)。
Mass,m/e:536(M+-175),91(base)。
b:4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-[(2-氯苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.26(bs,1H),7.95(d,J=5.4Hz,1H),7.54~7.48(m,2H),7.43~7.29(m,9H),7.10~7.03(m,2H),5.91(d,J=5.4Hz,1H),5.06(s,2H),4.69(bs,2H),4.10(s,2H)。
Mass,m/e:393(M+-102),91(base)。
实施例326
4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
a:3-(3-苄氧基苯基)-4-{4-[2-(二-叔丁氧基羰基氨基)嘧啶基]}-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.73(s,1H),8.23(d,J=5.4Hz,1H),7.44~7.20(m,8H),7.12~7.04(m,2H),7.04~6.95(m,2H),6.84~6.79(m,1H),6.30(d,J=5.4Hz,1H),5.07(s,2H),4.05(s,2H),3.79(s,3H),1.56(s,18H)。
Mass,m/e:541(M+-166),91(base)。
b:4-[4-(2-氨基嘧啶基)]-3-(3-苄氧基苯基)-5-[(3-甲氧基苯基)乙酰氨基]异噁唑
1H-NMR(CDCl3)δ:11.22(s,1H),7.93(d,J=5.4Hz,1H),7.43~7.29(m,8H),7.10~6.90(m,5H),5.87(d,J=5.4Hz,1H),5.05(s,2H),4.49(bs,2H),3.94(s,2H),3.83(s,3H)。
Mass,m/e:420(M+-87),91(base)。
制剂例1
将活性成分粉碎成70μm以下的粒度,向其中加入淀粉、乳糖和羧甲基纤维素钙并充分混合。将10%的淀粉糊加入到上述混合粉体中,搅拌混合,制造颗粒。干燥后整粒,使粒径在1000μm左右,向其中混合滑石粉和硬脂酸镁,压片。

Claims (13)

1.式(I)所示的异
Figure FSB00000250683900011
唑衍生物或其制药学上可接受的盐:
式中,
R1表示氢原子;
R2表示未取代的苯基、或者被选自卤素原子、C1-6烷基和C1-6烷氧基的1~3个取代基取代的苯基;
R3表示氢原子;
R4表示未取代的苯基或者被选自卤素原子、C1-6烷基和C1-6烷氧基的1个或2个取代基取代的苯基;
Y表示-(CH2)n-,其中n表示1~3的整数。
2.权利要求1的异
Figure FSB00000250683900013
唑衍生物或其制药学上可接受的盐,其中R2表示被选自卤素原子、C1-6烷基和C1-6烷氧基的1~3个取代基取代的苯基。
3.权利要求2的异
Figure FSB00000250683900014
唑衍生物或其制药学上可接受的盐,其中R2为4-氟苯基、2,4-二氟苯基、4-氯苯基、3-甲基苯基、2-氟-5-甲基苯基、4-氟-3-甲基苯基或2-氟-4-甲氧基苯基。
4.权利要求1或2的异
Figure FSB00000250683900015
唑衍生物或其制药学上可接受的盐,其中R4表示未取代的苯基、2-卤代苯基、2,6-二卤代苯基、2-C1-6烷基苯基、3-C1-6烷基苯基、3-C1-6烷氧基苯基或2,5-二C1-6烷基苯基。
5.选自下述的异唑衍生物或它们的制药学上可接受的盐:
5-[(2-氯苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900017
唑、
5-[(2-氯-6-氟苯基)乙酰氨基]-3-(4-氟苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900018
唑、
3-(4-氯苯基)-5-[(2-氯苯基)乙酰氨基]-4-(4-嘧啶基)异唑、
5-[(2-氯苯基)乙酰氨基]-3-(2,4-二氟苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900021
唑、
3-(2,4-二氟苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异
Figure FSB00000250683900022
唑、
5-[(2-氯苯基)乙酰氨基]-3-(2-氟-4-甲氧基苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900023
唑、
5-[(2-氯苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900024
唑、
5-[(2-溴苯基)乙酰氨基]-3-(3-甲基苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900025
唑、
3-(3-甲基苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异
Figure FSB00000250683900026
唑、
3-(3-甲基苯基)-5-[(3-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异
Figure FSB00000250683900027
唑、
3-(2-氟-5-甲基苯基)-5-(苯基乙酰氨基)-4-(4-嘧啶基)异
Figure FSB00000250683900028
唑、
5-[(3-甲氧基苯基)乙酰氨基]-3-(3-甲基-4-氟苯基)-4-(4-嘧啶基)异
Figure FSB00000250683900029
唑、和
3-(3-甲基-4-氟苯基)-5-[(2-甲基苯基)乙酰氨基]-4-(4-嘧啶基)异
Figure FSB000002506839000210
唑。
6.P38MAP激酶抑制剂,其特征在于:该抑制剂含有权利要求1~5中任一项的异
Figure FSB000002506839000211
唑衍生物或其制药学上可接受的盐作为有效成分。
7.药物,该药物含有权利要求1~5中任一项的异唑衍生物或其制药学上可接受的盐。
8.肿瘤坏死因子-α关连疾病、白细胞介素-1关连疾病、白细胞介素-6关连疾病、白细胞介素-8关连疾病或环加氧酶-II关连疾病的处置剂,其特征在于:该处置剂含有权利要求1~5中任一项的异
Figure FSB000002506839000213
唑衍生物或其制药学上可接受的盐作为有效成分,其中肿瘤坏死因子-α关连疾病、白细胞介素-1关连疾病、白细胞介素-6关连疾病、白细胞介素-8关连疾病或环加氧酶-II关连疾病为急性炎症、慢性炎症、变形性膝关节症、痛风、炎症性肠疾病、胃炎、结肠息肉、哮喘、支气管炎、过敏性鼻炎、急性呼吸窘迫综合征、慢性阻塞性肺疾病、肺纤维变性、充血性心脏病、局部缺血性心脏病、心肌梗死、动脉硬化、高血压、心绞痛、早老性痴呆、再灌流损伤、血管炎、脑血管障碍、脑膜炎、多发性大脑硬化、骨质疏松症、骨硬化、贝切特氏病、骨转移、多发性骨髓瘤、急性感染、内毒素休克、败血病、毒素性休克综合征、结核、弥散性血管内凝血病、银屑病、特应性皮炎、肝硬化、肾纤维变性、恶病质、艾滋病、恶性肿瘤、自体免疫疾病、糖尿病、巨大淋巴结增生症、肾小球膜细胞增殖性肾炎、子宫内膜异位或早产。
9.权利要求8所述的处置剂,其中慢性炎症为类风湿性关节炎。
10.权利要求8所述的处置剂,其中哮喘为支气管哮喘。
11.权利要求8所述的处置剂,其中炎症性肠疾病为节段性肠炎或溃疡性大肠炎。
12.权利要求8所述的处置剂,其中恶性肿瘤为大肠癌或结肠癌。
13.权利要求1~5中任一项的异
Figure FSB00000250683900031
唑衍生物或其制药学上可接受的盐在制备用于处置肿瘤坏死因子-α关连疾病、白细胞介素-1关连疾病、白细胞介素-6关连疾病、白细胞介素-8关连疾病或环加氧酶-II关连疾病的药物中的应用。
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