CN114057630A - 吡非尼酮衍生物及其合成方法和应用 - Google Patents

吡非尼酮衍生物及其合成方法和应用 Download PDF

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CN114057630A
CN114057630A CN202111588533.2A CN202111588533A CN114057630A CN 114057630 A CN114057630 A CN 114057630A CN 202111588533 A CN202111588533 A CN 202111588533A CN 114057630 A CN114057630 A CN 114057630A
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dihydropyridin
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acetamide
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施秀芳
路翔
于震强
张振中
陈海歌
朱超然
姜琳琳
庞豪豪
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Zhengzhou University
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Abstract

本发明属于药物化学技术领域，公开了一类吡非尼酮衍生物及其制备方法和应用，结构通式如下所示，其中X、n、R1、R2如在说明书中所定义。此类吡非尼酮衍生物以2‑羟基‑5‑硝基吡啶为原料，经过C‑N偶联、硝基还原、成酰胺等反应得到目标化合物，整条路线制备方法简单、可靠，总收率在60%以上，纯化方法适合工业生产。此外，体外对小鼠胚成纤维细胞（NIH3T3）的抗增殖活性实验初步表明，此类化合物均具有良好的抗纤维化细胞增殖能力，并且大部分化合物优于临床上的吡非尼酮，可用于抗纤维化药物的研发。

Description

吡非尼酮衍生物及其合成方法和应用
技术领域
本发明涉及药物化学领域，具体涉及一类吡非尼酮衍生物、它们的制备方法及其作为抗纤维化药物的应用。
背景技术
特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)被称为“类肿瘤疾病”，诊断后生存期仅为2-3年，死亡率超过大多数肿瘤。其发病机制复杂，病毒、真菌、环境污染、药物诱导等都可能造成肺部重复性微损伤，引起成纤维细胞异常增殖和细胞外基质(extracellular matrix，ECM)沉积，导致肺纤维化，最终随着病程发展，患者由于肺功能损坏导致呼吸衰竭或死亡。尤其是COVID-19的出现，很大程度上会损伤肺部进而引起肺纤维化。
目前被FDA批准用于临床治疗IPF的药物只有两个：吡非尼酮(pirfenidone)和尼达尼布(nintedanib)，二者虽然可延缓疾病进展速度，但不能阻止或逆转其恶化。吡非尼酮作为一种新型广谱抗炎及抗纤维化药物，其作用机制尚未完全阐明，目前主要认为吡非尼酮是通过抑制转化生长因子-β(transforming growth factor-β,TGF-β)和炎症细胞因子分泌发挥疗效。吡非尼酮虽具有良好的抗纤维化、抗炎和抗氧化等作用，但其生物利用度较低，临床上所需每日剂量较大，容易出现较严重的副作用，例如胃肠道不适、光过敏、恶心和皮疹等问题。
研究表明吡非尼酮体内低生物利用度的原因是在于分子结构中非活性必需基团5-甲基容易被代谢为羟甲基或者羧基，生成非活性分子，进而影响药效和产生相关副作用。
发明内容
针对上述情况，本发明的目的在于提供一种具有较好的抗纤维化活性的新型吡非尼酮衍生物，并提供其合成方法及其在抗纤维化药物方面的应用。
为实现本发明目的，本发明以体内较为稳定的酰胺基团取代5位甲基，同时利用杂交原理，与抗炎化合物如阿司匹林、丙酮酸、熊果酸杂交，设计并合成了一系列吡非尼酮衍生物，旨在丰富吡非尼酮的构效关系，改善其代谢及生物利用度，减少副作用，同时有望提高其抗肺纤维化及抗炎等作用。
技术方案如下：
Figure BDA0003428924040000021
所述的吡非尼酮衍生物具有技术方案中的结构通式：
其中，n＝0,1；X＝H,卤素；优选氟。
(1)当n＝0时，R1为取代芳基、杂环芳基、取代脂肪环基及含O、N、S、P的杂环基团；所述取代基可以为羟基、氨基、卤素、甲氧基、乙氧基、甲基、三氟甲基、硝基、苯基、苄氧基等，可以是单取代或双取代。
(2)当n＝1，R2＝H时，R1为芳基、取代芳基、脂肪环基、取代脂肪环基、双取代链状胺基、环状胺基、取代环状胺基；所述取代基可以为羟基、氨基、卤素、甲氧基、乙氧基、甲基、三氟甲基、硝基、苯基、苄氧基等，可以是单取代或双取代。
(3)当n＝1，R1＝芳基，取代芳基；R2＝链状脂肪烃基，环状脂肪烃基，芳基，取代芳基等。所述取代基可以为羟基、氨基、卤素、甲氧基、乙氧基、甲基、三氟甲基、硝基、苯基、苄氧基等，可以是单取代或双取代。
优选如下方案：
(1)当X＝H，n＝0时，R1为苯基或被取代的苯基，吡啶基，喹啉基；C1-5烷基，C3-7饱和脂肪环基或被取代的C3-7饱和脂肪环基，金刚烷基。所述取代基可以为羟基、氨基、卤素、甲氧基、乙氧基、C1-4烷基、三氟甲基、硝基、苯基、苄氧基等，可以是单取代或多取代。优选如下化合物：
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A)；
2-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A1)；
2-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A2)；
2-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A3)；
2-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A4)；
2-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A5)；
2-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A6)；
3-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A7)；
3-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A8)；
3-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A9)；
3-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A10)；
3-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A11)；
3-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A12)；
4-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A13)；
4-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A14)；
4-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A15)；
4-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A16)；
4-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A17)；
4-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A18)；
4-硝基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A19)；
3-甲基-4-硝基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A20)；
4-乙氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A21)；
4-苯基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A22)；
4-苄氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A23)；
2,5-二甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A24)；
2-羟基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺(A25)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)吡啶甲酰胺(A26)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)异烟酰胺(A27)；
2-氧代-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺(A28)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)喹啉-6-甲酰胺(A29)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)烟酰胺(A30)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环丙烷甲酰胺(A31)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环丁烷甲酰胺(A32)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环戊烷甲酰胺(A33)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环己烷甲酰胺(A34)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环庚烷甲酰胺(A35)；
(3r，5r，7r)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)金刚烷-1-甲酰胺(A36)；
(2)当X＝H，n＝1，R2＝H时，R1为苯基或被取代的苯基，吡啶基或被取代的吡啶基，萘基或被取代的萘基；C1-5烷基，C3-7饱和脂肪环基或被取代的C3-7饱和脂肪环基，金刚烷基。所述取代基可以为羟基、氨基、卤素、甲氧基、乙氧基、C1-4烷基、三氟甲基、硝基、溴甲基等，可以是单取代或多取代。优选如下化合物：
2-(2-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B1)；
2-(2-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B2)；
2-(2-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B3)；
2-(2-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B4)；
2-(2-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B5)；
2-(2-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B6)；
2-(3-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B7)；
2-(3-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B8)；
2-(3-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B9)；
2-(3-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B10)；
2-(3-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B11)；
2-(3-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B12)；
2-(4-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B13)；
2-(4-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B14)；
2-(4-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B15)；
2-(4-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B16)；
2-(4-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B17)；
2-(4-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B18)；
2-(4-乙氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B19)；
2-(4-硝基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B20)；
2-([1,1’-联苯]-4-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B21)；
2-(4-苄氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B22)；
2-(2,5-二甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B23)；
2-(2-溴-4-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B24)；
2-(2,4,6-三甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B25)；
2-(3,4-二甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B26)；
2-(2,5-二氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B27)；
2-(3,4,5-三氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B28)；
2-(4-溴甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B29)；
2-(2,4,6-三氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B30)；
2-(4-叔丁基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B31)；
2-(萘-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B32)；
2-环丙基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B33)；
2-环戊基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B34)；
2-环己基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B35)；
2-((3r，5r，7r)-金刚烷-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B36)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-2-(吡咯烷-1-基)乙酰胺(B37)；
2-(2-甲基哌啶-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺(B38)；
(3)当X＝H，n＝1，R1＝苯基或被取代的苯基，萘基或被取代的萘基；R2＝C1-5直链烷基，C3-5环状烷基等。所述取代基可以为卤素、甲氧基、乙氧基、C1-4烷基等，可以是单取代或多取代。优选如下化合物：
(S)-2-(4-异丁基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺(C1)；
(S)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-2-苯基丙酰胺(C1)
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-1-苯基环丙烷-1-甲酰胺(C2)；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-1-苯基环戊烷-1-甲酰胺(C3)；
(S)-2-(6-甲氧基萘-2-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺(C4)；
(4)以上部分化合物当X＝F时，优选如下化合物：
1-(3-氟苯基)-5-硝基吡啶-2(1H)-酮(F-4)；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-甲氧基苯甲酰胺(F-A5)；
3-溴-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)苯甲酰胺(F-A9)；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-4-(三氟甲基)苯甲酰胺(F-A18)；
4-(苄氧基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)苯甲酰胺(F-A23)；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2，5-二甲基苯甲酰胺(F-A24)；
2-(2-溴苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B3)；
2-(4-氯苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B14)；
2-(4-乙氧基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B19)；
2-([1，1'-联苯]-4-基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B21)；
2-(4-苄氧基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B22)；
2-(2，5-二甲基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺(F-B23)；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-三甲基苯乙胺(F-B25)；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-(萘-1-基)乙酰胺(F-B32)；
(3r，5r，7r)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)金刚烷-1-甲酰胺(F-A36)；
所述的吡非尼酮衍生物或其可药用的盐的制备方法如下：
Figure BDA0003428924040000061
首先碘苯先和苯生成高碘盐，随后原料2-羟基-5-硝基吡啶和高碘盐进行C-N偶联反应得到关键中间体3，中间体3先后经过硝基还原，成酰胺反应得到目标终产物。
本发明化合物的结构及编号如下：
Figure BDA0003428924040000062
Figure BDA0003428924040000063
Figure BDA0003428924040000071
Figure BDA0003428924040000081
Figure BDA0003428924040000091
Figure BDA0003428924040000101
Figure BDA0003428924040000111
Figure BDA0003428924040000121
Figure BDA0003428924040000131
本发明优点：制备方法简单、可靠，总收率在60％以上，纯化方法适合工业生产。体外对小鼠胚成纤维细胞(NIH3T3)的抗增殖活性实验初步表明，此类化合物均具有良好的抗纤维化细胞增殖能力，并且大部分化合物优于临床上的吡非尼酮，可用于抗纤维化药物的研发。
具体实施方式
为了对本发明进行更好的说明，针对合成策略，举实例如下：
实例1、化合物2的制备
将5ml碘苯和5ml苯溶于适量的二氯甲烷中。冰浴条件下，加入8.5g间氯过氧苯甲酸，随后缓慢加入12.5ml三氟甲磺酸。之后移至室温反应10min，TLC检测反应完全后。减压蒸干溶剂，加入相同体积乙醚，室温下搅拌10min，之后置于冰箱30min，抽滤，滤饼用少量乙醚洗涤，真空干燥得类白色固体15.6g，产率为82.45％。
实例2、化合物3的制备
无水氮气保护条件下，将2.1g 2-羟基-5-硝基吡啶，0.29g碘化亚铜和8.3g化合物2分别加入烧瓶中，用140ml二氯甲烷溶解。随后在冰浴条件下，将4ml三乙胺溶于适量的无水二氯甲烷中缓慢滴加进入体系，滴加完毕室温反应10min，TLC检测反应完全后。减压蒸干溶剂，用200ml乙酸乙酯复溶，分别用含有少量醋酸的水和饱和食盐水萃取，无水硫酸钠干燥，减压蒸干溶剂得粗品，甲醇重结晶得淡黄色晶体2.7g，产率为83.3％。1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝3.1Hz,1H),8.24(dd,J＝10.1,3.1Hz,1H),7.58–7.52(m,5H),6.62(d,J＝10.1Hz,1H).
实例3、化合物4的制备
将0.5g化合物3，0.5g还原铁粉和0.19g氯化铵溶于乙醇和水混合溶剂中，加热回流2h，TLC检测反应完全后。铺硅藻土过滤，滤饼用二氯甲烷洗涤，蒸干溶剂得绿色粗品0.41g，产率为95.6％。1H NMR(400MHz,DMSO-d6)δ7.48(t,J＝7.5Hz,2H),7.41–7.35(m,3H),7.18(dd,J＝9.6,3.0Hz,1H),6.82(d,J＝2.9Hz,1H),6.36(d,J＝9.6Hz,1H),4.39(s,2H).13C NMR(101MHz,DMSO-d6)δ158.43,141.63,135.87,129.43,128.90,127.60,126.59,120.83,118.83.
实例4、目标化合物的制备
取干燥洁净的50ml圆底烧瓶，将285mg化合物4溶解于10ml二氯甲烷中，称取0.325g 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,0.229g 1-羟基苯并三唑加入反应瓶中，称量羧酸衍生物加入反应瓶中，室温搅拌过夜。反应完全后用二氯甲烷萃取，饱和食盐水洗涤有机相。快速柱层析(二氯甲烷：甲醇体积比＝25:1)，质量百分含量10％甲醇和乙酸乙酯混合溶剂重结晶。产率为45％～85％。部分目标化合物确证数据如下：
A橘黄色晶体(62％)。mp：247.2-247.6℃.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.29(d,J＝2.7Hz,1H),7.95–7.90(m,2H),7.78(dd,J＝9.8,2.8Hz,1H),7.62–7.51(m,5H),7.50–7.43(m,3H),6.57(d,J＝9.8Hz,1H).
A1无色透明晶体(产率82％)。196.2-196.8℃.1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.30(d,J＝2.7Hz,1H),7.71–7.64(m,2H),7.63–7.52(m,3H),7.51–7.43(m,3H),7.40–7.30(m,2H),6.57(d,J＝9.8Hz,1H).
A2无色透明晶体(产率84％)。mp:262.2-262.8℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.30(d,J＝2.8Hz,1H),7.63(dd,J＝9.8,2.9Hz,1H),7.60–7.53(m,4H),7.52–7.44(m,5H),6.58(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.14,159.91,141.62,136.67,136.55,131.81,130.45,130.21,129.71,129.47,129.16,128.79,127.76,127.18,121.40,120.30.
A3无色透明颗粒晶体(产率72％)。274.4-274.8℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.29(d,J＝2.7Hz,1H),7.72(dd,J＝7.9,0.9Hz,1H),7.62(dd,J＝9.8,2.9Hz,1H),7.55(ddd,J＝6.3,4.6,2.6Hz,3H),7.51–7.41(m,5H),6.58(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ166.04,159.90,141.61,138.85,136.54,133.28,131.90,129.72,129.40,129.13,128.79,128.23,127.18,121.41,120.30,119.49.
A4白色颗粒结晶(产率68％)。mp:228.2-228.6℃.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.33(d,J＝2.7Hz,1H),7.67(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.44(m,4H),7.40(dd,J＝11.1,3.7Hz,1H),7.33–7.27(m,2H),6.56(d,J＝9.8Hz,1H),2.38(s,3H).
A5绿色块状晶体(产率75％)。mp:184.9-185.3℃.1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.32(d,J＝2.7Hz,1H),7.71(dd,J＝9.8,2.8Hz,1H),7.67–7.62(m,1H),7.56–7.49(m,3H),7.46(dd,J＝8.5,6.8Hz,3H),7.17(d,J＝8.3Hz,1H),7.06(t,J＝7.4Hz,1H),6.55(d,J＝9.8Hz,1H),3.89(s,3H).13C NMR(101MHz,DMSO-d6)δ164.23,159.42,156.52,141.17,136.77,132.28,129.75,129.15,128.85,128.19,126.68,123.88,120.50,120.47,119.94,111.96,55.83.
A6浅蓝色晶体(产率72％)。mp:288.5-288.8℃.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.24(d,J＝2.7Hz,1H),7.88–7.78(m,2H),7.72(t,J＝7.5Hz,2H),7.60(dt,J＝6.1,3.1Hz,1H),7.55(t,J＝7.4Hz,2H),7.51–7.44(m,3H),6.58(d,J＝9.8Hz,1H).
A7淡黄色颗粒晶体(产率76％)。mp:223.1-223.6℃.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.27(d,J＝2.7Hz,1H),7.76(ddd,J＝21.0,9.4,6.2Hz,3H),7.58(ddd,J＝20.4,11.3,6.9Hz,3H),7.50–7.43(m,4H),6.57(d,J＝9.8Hz,1H).
A8淡黄色块状晶体(产率75％)。mp:179.1-179.6℃.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.26(d,J＝2.7Hz,1H),7.97(s,1H),7.88(d,J＝7.8Hz,1H),7.76(dd,J＝9.8,2.8Hz,1H),7.67(dd,J＝8.0,0.9Hz,1H),7.56(dd,J＝16.3,7.9Hz,3H),7.50–7.43(m,3H),6.57(d,J＝9.8Hz,1H).
A9白色针状晶体(产率83％)。mp:193.0-193.4℃.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.26(d,J＝2.7Hz,1H),8.11(s,1H),7.92(d,J＝7.8Hz,1H),7.82–7.74(m,2H),7.58–7.43(m,6H),6.57(d,J＝9.8Hz,1H).
A10淡黄色块状晶体(产率69％)。mp:172.1-172.4℃.1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.28(d,J＝2.7Hz,1H),7.78(dd,J＝9.8,2.8Hz,1H),7.75–7.69(m,2H),7.55(t,J＝7.4Hz,2H),7.50–7.44(m,3H),7.41(d,J＝5.5Hz,2H),6.57(d,J＝9.8Hz,1H),2.39(s,3H).
A11淡黄绿色块状晶体(产率64％)。mp:170.7-171.1℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.27(d,J＝2.7Hz,1H),7.78(dd,J＝9.8,2.8Hz,1H),7.58–7.47(m,4H),7.45(dd,J＝10.7,4.5Hz,4H),7.16(dd,J＝8.1,1.7Hz,1H),6.57(d,J＝9.8Hz,1H),3.83(s,3H).
A12白色絮状物(产率68％)。mp:227.0-227.2℃.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.24(dd,J＝12.9,5.4Hz,3H),7.97(d,J＝7.8Hz,1H),7.82–7.75(m,2H),7.55(t,J＝7.4Hz,2H),7.51–7.43(m,3H),6.58(d,J＝9.8Hz,1H).
A13淡黄色鳞状晶体(产率80％)。mp:223.7-224.0℃.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.26(d,J＝2.7Hz,1H),8.00(dd,J＝8.7,5.5Hz,2H),7.76(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),7.38(t,J＝8.8Hz,2H),6.57(d,J＝9.8Hz,1H).
A14白色絮状物(产率67％)。mp:226.9-227.1℃.1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.26(d,J＝2.7Hz,1H),7.95(d,J＝8.5Hz,2H),7.76(dd,J＝9.8,2.8Hz,1H),7.61(d,J＝8.5Hz,2H),7.54(t,J＝7.4Hz,2H),7.50–7.43(m,3H),6.56(d,J＝9.8Hz,1H).13CNMR(101MHz,DMSO-d6)δ164.15,159.43,141.08,137.01,136.53,132.81,129.65,129.39,129.16,128.54,128.22,126.62,120.47,119.73.
A15淡黄色晶体(产率75％)。mp:232.1-232.5℃.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.27(d,J＝2.7Hz,1H),7.87(d,J＝8.6Hz,2H),7.76(dd,J＝9.1,3.7Hz,3H),7.55(t,J＝7.4Hz,2H),7.50–7.42(m,3H),6.57(d,J＝9.8Hz,1H).
A16淡黄色晶体(产率49％)。mp:205.1-205.5℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.28(d,J＝2.7Hz,1H),7.84(d,J＝8.2Hz,2H),7.78(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),7.34(d,J＝8.0Hz,2H),6.56(d,J＝9.8Hz,1H),2.38(s,3H).
A17淡黄绿色针状晶体(产率62％)。mp:218.3-218.7℃.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.26(d,J＝2.7Hz,1H),7.92(d,J＝8.8Hz,2H),7.78(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),7.06(d,J＝8.8Hz,2H),6.56(d,J＝9.8Hz,1H),3.83(s,3H).
A18黄色晶体(产率63％)。mp:156.6-157.0℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.29(d,J＝2.8Hz,1H),8.12(d,J＝8.1Hz,2H),7.92(d,J＝8.3Hz,2H),7.78(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),6.58(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.04,159.46,141.06,137.88,136.93,131.61,129.80,129.17,128.38,128.24,126.62,125.49,125.21,120.53,119.61.
A19黄色晶体(产率46％)。mp:290.7-291.2℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.38(d,J＝8.8Hz,2H),8.29(d,J＝2.7Hz,1H),8.15(d,J＝8.8Hz,2H),7.77(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.51–7.43(m,3H),6.59(d,J＝9.8Hz,1H).
A20黄色颗粒晶体(产率46％)。mp:204.9-205.2℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.27(d,J＝2.7Hz,1H),8.12(d,J＝8.5Hz,1H),8.00(s,1H),7.93(d,J＝8.4Hz,1H),7.75(ddd,J＝11.0,7.9,2.7Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),6.58(d,J＝9.8Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO)δ163.65,159.45,150.54,141.04,137.99,136.88,132.80,131.79,129.84,129.19,128.27,126.62,126.38,124.58,120.56,119.54,19.35.
A21橘红色晶体(产率69％)。mp:229.2-229.6℃.1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.26(d,J＝2.7Hz,1H),7.90(d,J＝8.8Hz,2H),7.77(dd,J＝9.8,2.8Hz,1H),7.54(t,J＝7.4Hz,2H),7.50–7.43(m,3H),7.04(d,J＝8.8Hz,2H),6.56(d,J＝9.8Hz,1H),4.11(q,J＝7.0Hz,2H),1.35(t,J＝7.0Hz,3H).
A22淡黄色羽毛状晶体(产率78％)。mp:231.1-231.8℃.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.32(d,J＝2.5Hz,1H),8.03(d,J＝8.3Hz,2H),7.87–7.74(m,5H),7.58–7.40(m,8H),6.58(d,J＝9.8Hz,1H).
A23白色絮状物(产率81％)。mp:260.2-260.7℃.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.26(d,J＝2.7Hz,1H),7.91(d,J＝8.8Hz,2H),7.77(dd,J＝9.8,2.8Hz,1H),7.54(t,J＝7.4Hz,2H),7.44(ddd,J＝25.8,11.9,7.1Hz,7H),7.37–7.32(m,1H),7.15(d,J＝8.9Hz,2H),6.56(d,J＝9.8Hz,1H),5.20(s,2H).
A24白色针状晶体(产率52％)。mp:222.6-222.8℃.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.32(d,J＝2.7Hz,1H),7.67(dd,J＝9.8,2.9Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.44(m,3H),7.28(s,1H),7.23–7.16(m,2H),6.56(d,J＝9.8Hz,1H),2.32(s,6H).
A25淡黄色片状晶体(产率46％)。mp:237.3-237.8℃.1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.22(s,1H),8.19(d,J＝2.6Hz,1H),7.89(d,J＝6.9Hz,1H),7.74(dd,J＝9.8,2.8Hz,1H),7.54(t,J＝7.4Hz,2H),7.50–7.40(m,4H),7.01–6.92(m,2H),6.56(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ166.75,159.52,158.56,140.97,137.69,133.76,130.60,129.15,128.68,128.23,126.65,120.36,118.99,118.82,117.23,116.78.
A26红棕色块状晶体(产率63％)。mp:171.8-172.2℃.1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.73(d,J＝4.5Hz,1H),8.41(d,J＝2.8Hz,1H),8.10(d,J＝7.7Hz,1H),8.05(td,J＝7.6,1.6Hz,1H),7.98(dd,J＝9.8,2.9Hz,1H),7.67(ddd,J＝7.2,4.8,1.4Hz,1H),7.57–7.52(m,2H),7.47(dd,J＝7.6,5.8Hz,3H),6.56(d,J＝9.8Hz,1H).
A27淡黄色颗粒晶体(产率45％)。mp:227.3-228.1℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.82–8.77(m,2H),8.29(d,J＝2.7Hz,1H),7.83(dd,J＝4.6,1.4Hz,2H),7.76(dd,J＝9.8,2.8Hz,1H),7.55(t,J＝7.4Hz,2H),7.50–7.43(m,3H),6.59(d,J＝9.8Hz,1H).
A28淡黄绿色粉末(产率54％)。mp:228.5-229.1℃.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.29(d,J＝2.7Hz,1H),7.85(dd,J＝9.8,2.8Hz,1H),7.54(t,J＝7.4Hz,2H),7.48(d,J＝7.2Hz,1H),7.42(d,J＝7.3Hz,2H),6.55(d,J＝9.8Hz,1H),2.40(s,3H).
A29淡黄色颗粒晶体(产率56％)。mp:258.5-259.1℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.02(dd,J＝4.1,1.6Hz,1H),8.60(d,J＝1.5Hz,1H),8.53(d,J＝7.8Hz,1H),8.34(d,J＝2.7Hz,1H),8.24(dd,J＝8.8,1.8Hz,1H),8.15(d,J＝8.8Hz,1H),7.83(dd,J＝9.8,2.8Hz,1H),7.64(dd,J＝8.3,4.2Hz,1H),7.60–7.52(m,2H),7.49(dd,J＝5.1,2.8Hz,3H),6.61(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.79,159.46,152.30,148.74,141.12,137.12,136.98,131.96,129.58,129.20,129.17,128.31,128.22,127.75,127.04,126.64,122.32,120.52,119.94.
A30淡黄绿色颗粒晶体(产率46％)。mp:270.1-270.4℃.1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.08(d,J＝1.9Hz,1H),8.76(dd,J＝4.8,1.5Hz,1H),8.26(ddd,J＝7.9,4.5,2.4Hz,2H),7.75(dd,J＝9.8,2.9Hz,1H),7.60–7.52(m,3H),7.51–7.43(m,3H),6.58(d,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.78,159.45,152.22,148.49,141.06,136.93,135.23,129.80,129.74,129.18,128.25,126.62,123.55,120.56,119.60.
B1淡绿色针状晶体(产率65％)。mp:242.8-243.2℃.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.15(d,J＝2.7Hz,1H),7.53(dd,J＝7.1,2.7Hz,1H),7.50(dd,J＝5.4,3.9Hz,2H),7.45(dt,J＝4.7,1.9Hz,1H),7.40(dd,J＝5.3,3.2Hz,2H),7.36(dd,J＝7.8,1.6Hz,1H),7.30(dq,J＝5.5,1.8Hz,1H),7.19–7.12(m,2H),6.54(d,J＝9.8Hz,1H),3.69(s,2H).13C NMR(101MHz,DMSO-d6)δ168.40,162.29,159.81,141.61,136.54,132.42,129.61,129.37,128.75,127.07,124.71,123.18,123.02,121.29,120.39,115.58,36.24.
B2墨绿色粉末(产率58％)。mp:200.2-200.6℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.15(d,J＝2.7Hz,1H),7.55–7.48(m,3H),7.42(ddd,J＝18.0,7.8,5.7Hz,5H),7.32–7.27(m,2H),6.53(d,J＝9.7Hz,1H),3.79(s,2H).13C NMR(101MHz,DMSO-d6)δ167.77,159.30,141.12,136.05,133.59,132.10,129.10,128.96,128.87,128.62,128.22,128.14,127.03,126.57,120.80,119.92,40.24.
B3淡黄色块状晶体(产率76％)。mp:164.7-165.0℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.14(d,J＝2.7Hz,1H),7.60(d,J＝7.9Hz,1H),7.55–7.48(m,3H),7.44(t,J＝4.8Hz,1H),7.39(d,J＝7.7Hz,3H),7.34(t,J＝7.4Hz,1H),7.20(td,J＝7.8,1.8Hz,1H),6.54(d,J＝9.8Hz,1H),3.80(s,2H).13C NMR(101MHz,DMSO-d6)δ167.72,159.30,141.12,136.06,135.35,132.22,132.15,129.11,128.82,128.21,128.14,127.58,126.57,124.48,120.81,119.93,42.70.
B4蓝色絮状晶体(产率83％)。mp:204.2-204.7℃.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.15(d,J＝2.7Hz,1H),7.54–7.47(m,3H),7.43(dd,J＝8.4,5.9Hz,1H),7.41–7.37(m,2H),7.23–7.19(m,1H),7.17–7.10(m,3H),6.52(d,J＝9.7Hz,1H),3.63(s,2H),2.27(s,3H).13C NMR(101MHz,DMSO-d6)δ168.90,159.30,141.13,136.60,136.12,134.29,129.91,129.84,129.10,128.25,128.13,126.70,126.58,125.72,120.74,119.94,40.38,19.33.
B5黄绿色颗粒晶体(产率53％)。mp:183.4-183.7℃.1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.16(d,J＝2.7Hz,1H),7.56–7.48(m,3H),7.44(t,J＝6.8Hz,1H),7.42–7.38(m,2H),7.27–7.18(m,2H),6.97(d,J＝8.1Hz,1H),6.89(t,J＝7.4Hz,1H),6.53(d,J＝9.8Hz,1H),3.77(s,3H),3.59(s,2H).13C NMR(101MHz,DMSO-d6)δ168.97,159.29,157.15,141.16,136.10,130.74,129.10,128.12,128.07,128.01,126.57,123.78,120.72,120.15,120.11,110.63,55.38,37.14.
B6蓝色块状晶体(产率71％)。mp:185.6-185.9℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.13(d,J＝2.7Hz,1H),7.70(d,J＝7.8Hz,1H),7.63(t,J＝7.5Hz,1H),7.54–7.47(m,5H),7.46–7.42(m,1H),7.41–7.37(m,2H),6.54(d,J＝9.8Hz,1H),3.88(s,2H).
B7淡绿色鳞状晶体(产率85％)。mp:214.5-214.9℃.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.15(d,J＝2.7Hz,1H),7.54–7.48(m,3H),7.47–7.42(m,1H),7.41–7.38(m,2H),7.37–7.32(m,1H),7.14(d,J＝7.5Hz,2H),7.08(ddd,J＝9.1,2.8,1.3Hz,1H),6.53(d,J＝9.8Hz,1H),3.64(s,2H).13C NMR(101MHz,DMSO-d6)δ168.39,163.21,159.31,141.11,138.36,136.10,130.14,129.11,128.38,128.15,126.58,125.27,120.76,119.81,116.01,113.48,42.22.
B8淡黄色絮状物(产率59％)。mp:223.5-223.9℃.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.14(t,J＝6.6Hz,1H),7.54–7.48(m,3H),7.44(t,J＝7.3Hz,1H),7.39(d,J＝7.8Hz,3H),7.36–7.29(m,2H),7.26(d,J＝7.1Hz,1H),6.52(d,J＝9.8Hz,1H),3.63(s,2H).13C NMR(101MHz,DMSO-d6)δ168.37,159.31,141.10,138.02,136.07,132.78,130.09,129.11,129.02,128.36,128.23,128.16,127.89,126.58,120.77,119.80,42.06.
B9棕色絮状晶体(产率64％)。mp:223.1-223.7℃.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.16(d,J＝2.7Hz,1H),7.54–7.48(m,4H),7.44(t,J＝7.5Hz,2H),7.40(d,J＝7.3Hz,2H),7.33–7.26(m,2H),6.53(d,J＝9.8Hz,1H),3.63(s,2H).13C NMR(101MHz,DMSO-d6)δ168.37,159.30,141.10,138.31,136.06,131.89,130.39,129.46,129.11,128.34,128.27,128.16,126.59,121.43,120.78,119.81,42.03.
B10淡绿色针状晶体(产率68％)。mp:181.2-181.6℃.1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.16(d,J＝2.7Hz,1H),7.54–7.48(m,3H),7.43(dd,J＝8.6,6.0Hz,1H),7.41–7.37(m,2H),7.19(t,J＝7.5Hz,1H),7.12–7.03(m,3H),6.52(d,J＝9.8Hz,1H),3.54(s,2H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ168.97,159.29,141.13,137.32,136.04,135.51,129.66,129.11,128.18,128.16,128.10,127.19,126.59,126.09,120.76,119.97,42.74,20.93.
B11浅棕色鳞状晶体(产率56％)。mp:199.8-200.1℃.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.16(d,J＝2.7Hz,1H),7.52(dd,J＝12.2,5.2Hz,3H),7.44(t,J＝7.3Hz,1H),7.40(d,J＝7.3Hz,2H),7.23(t,J＝8.0Hz,1H),6.88(d,J＝6.6Hz,2H),6.82(dd,J＝8.9,1.9Hz,1H),6.53(d,J＝9.8Hz,1H),3.74(s,3H),3.56(s,2H).13C NMR(101MHz,DMSO-d6)δ168.80,159.30,159.17,141.13,137.06,136.05,129.29,129.11,128.20,128.15,126.59,121.25,120.76,119.94,114.85,111.94,54.93,42.82.
B12墨绿色絮状物(产率61％)。mp:190.6-190.9℃.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.16(d,J＝2.7Hz,1H),7.67(s,1H),7.64–7.59(m,2H),7.55(dd,J＝14.6,5.2Hz,2H),7.52–7.48(m,2H),7.44(dd,J＝8.6,6.1Hz,1H),7.41–7.37(m,2H),6.53(d,J＝9.8Hz,1H),3.75(s,2H).13C NMR(101MHz,DMSO-d6)δ168.34,159.31,141.10,136.97,136.06,133.40,129.26,129.11,128.76,128.37,128.15,126.58,125.81,125.57,123.38,120.79,119.79,42.02.
B13黄色针状晶体(产率74％)。mp:212.0-212.3℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.15(d,J＝2.7Hz,1H),7.54–7.48(m,3H),7.44(t,J＝7.3Hz,1H),7.39(d,J＝7.3Hz,2H),7.33(dd,J＝8.4,5.7Hz,2H),7.14(t,J＝8.9Hz,2H),6.53(d,J＝9.8Hz,1H),3.60(s,2H).13C NMR(101MHz,DMSO-d6)δ168.85,162.31,159.30,141.17,136.08,131.80,130.98,130.90,129.11,128.29,128.15,126.58,120.76,119.87,115.07,41.72.
B14白色针状晶体(产率76％)。mp:209.2-210.0℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.15(d,J＝2.7Hz,1H),7.54–7.49(m,3H),7.44(t,J＝7.3Hz,1H),7.39(dd,J＝7.6,5.7Hz,4H),7.32(d,J＝8.4Hz,2H),6.53(d,J＝9.8Hz,1H),3.61(s,2H).13C NMR(101MHz,DMSO-d6)δ168.57,159.30,141.10,136.09,134.63,131.31,130.97,129.11,128.34,128.18,128.16,126.58,120.76,119.83,41.86.
B15黄色针状晶体(产率65％)。mp:222.9-223.5℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14(d,J＝2.7Hz,1H),7.54–7.48(m,5H),7.44(t,J＝7.3Hz,1H),7.39(d,J＝7.4Hz,2H),7.26(d,J＝8.3Hz,2H),6.53(d,J＝9.8Hz,1H),3.59(s,2H).13C NMR(101MHz,DMSO-d6)δ168.50,159.30,141.10,136.08,135.06,131.36,131.11,129.12,128.34,128.16,126.58,120.76,119.82,119.77,41.93.
B16白色针状晶体(产率82％)。mp:240.5-240.9℃.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.15(d,J＝2.7Hz,1H),7.55–7.43(m,4H),7.39(d,J＝7.2Hz,2H),7.19(d,J＝7.9Hz,2H),7.12(d,J＝7.9Hz,2H),6.52(d,J＝9.8Hz,1H),3.54(s,2H),2.27(s,3H).13CNMR(101MHz,DMSO-d6)δ169.12,159.29,141.13,136.06,135.59,132.57,129.11,128.88,128.83,128.17,128.15,126.59,120.74,119.97,42.39,20.61.
B17棕黄色粉末(产率63％)。mp:199.1-199.5℃.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.15(d,J＝2.7Hz,1H),7.50(ddd,J＝22.0,13.5,5.0Hz,4H),7.39(d,J＝7.2Hz,2H),7.22(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),6.52(d,J＝9.8Hz,1H),3.73(s,3H),3.51(s,2H).13C NMR(101MHz,DMSO-d6)δ169.31,159.29,158.03,141.15,136.07,130.04,129.12,128.15,127.54,126.59,124.50,120.74,119.98,113.71,55.03,41.89.
B18蓝色针状晶体(产率67％)。mp:211.3-211.8℃.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.15(d,J＝2.7Hz,1H),7.69(d,J＝8.1Hz,2H),7.52(ddd,J＝7.7,6.2,3.1Hz,5H),7.44(t,J＝7.3Hz,1H),7.39(d,J＝7.2Hz,2H),6.53(d,J＝9.8Hz,1H),3.73(s,2H).13C NMR(101MHz,DMSO-d6)δ168.22,159.31,141.09,140.46,136.09,130.01,129.12,128.42,128.17,127.51,126.58,125.68,125.06,120.78,119.76,42.30.
B19白色羽毛状固体(产率67％)。mp:192.0-192.3℃.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.16(d,J＝2.7Hz,1H),7.54–7.43(m,4H),7.39(d,J＝7.3Hz,2H),7.20(d,J＝8.5Hz,2H),6.86(d,J＝8.6Hz,2H),6.52(d,J＝9.8Hz,1H),3.99(q,J＝7.0Hz,2H),3.51(s,2H),1.31(t,J＝7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ169.31,159.28,157.28,141.14,136.05,130.02,129.11,128.29,128.14,127.41,126.59,120.74,119.99,114.20,62.89,41.90,14.62.
B20棕色鳞状晶体(产率56％)。mp:211.1-211.5℃.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.19(d,J＝8.7Hz,2H),8.14(d,J＝2.7Hz,1H),7.59(d,J＝8.7Hz,2H),7.50(ddd,J＝23.8,14.4,5.0Hz,4H),7.39(d,J＝7.3Hz,2H),6.53(d,J＝9.8Hz,1H),3.80(s,2H).13C NMR(101MHz,DMSO-d6)δ167.81,159.32,146.37,143.63,141.07,136.10,130.53,129.12,128.50,128.17,126.58,123.33,120.79,119.70,42.23.
B21白色针状晶体(产率78％)。mp:209.7-210.2℃.1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.18(d,J＝2.6Hz,1H),7.63(dd,J＝11.6,7.9Hz,4H),7.56–7.44(m,6H),7.42–7.33(m,5H),6.54(d,J＝9.8Hz,1H),3.65(s,2H).13C NMR(101MHz,DMSO-d6)δ168.90,159.31,141.13,139.91,138.54,136.07,134.91,129.64,129.12,128.89,128.25,128.16,127.30,126.60,126.59,126.53,120.77,119.95,42.40.
B22白色絮状物(产率69％)。mp:203.8-204.2℃.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.16(d,J＝2.7Hz,1H),7.54–7.48(m,3H),7.47–7.41(m,3H),7.39(t,J＝7.3Hz,4H),7.32(t,J＝7.1Hz,1H),7.22(d,J＝8.5Hz,2H),6.96(d,J＝8.6Hz,2H),6.52(d,J＝9.8Hz,1H),5.08(s,2H),3.52(s,2H).13C NMR(101MHz,DMSO-d6)δ169.26,159.29,157.09,141.13,137.14,136.06,130.05,129.11,128.38,128.16,128.15,127.81,127.73,127.55,126.59,120.74,119.98,114.63,69.10,41.89.
B23淡黄色晶体(产率61％)。mp:172.8-173.0℃.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.16(d,J＝2.7Hz,1H),7.50(ddd,J＝28.1,15.0,5.0Hz,4H),7.40(d,J＝7.3Hz,2H),7.04(d,J＝7.5Hz,2H),6.95(d,J＝7.7Hz,1H),6.53(d,J＝9.8Hz,1H),3.59(s,2H),2.23(d,J＝3.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ168.95,159.32,141.13,136.09,134.47,134.05,133.41,130.63,129.75,129.12,128.25,128.15,127.28,126.61,120.76,119.99,40.38,20.52,18.92.
B24墨绿色块状晶体(产率68％)。mp:148.6-149.0℃.1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.14(d,J＝2.7Hz,1H),7.57(dd,J＝8.6,2.6Hz,1H),7.55–7.49(m,3H),7.45(dd,J＝8.4,6.2Hz,2H),7.40(d,J＝7.3Hz,2H),7.24(td,J＝8.5,2.6Hz,1H),6.54(d,J＝9.8Hz,1H),3.80(s,2H).13C NMR(101MHz,DMSO-d6)δ167.62,161.97,159.30,141.10,136.07,133.33,131.81,129.11,128.26,128.15,126.56,124.58,120.80,119.88,119.33,114.66,41.77.
B25黄色颗粒晶体(产率43％)。mp:194.3-194.7℃.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.13(d,J＝2.7Hz,1H),7.56–7.42(m,4H),7.39(d,J＝7.3Hz,2H),6.81(s,2H),6.53(d,J＝9.8Hz,1H),3.64(s,2H),2.22(s,6H),2.19(s,3H).13C NMR(101MHz,DMSO-d6)δ168.76,159.29,141.13,136.74,136.22,135.05,129.89,129.08,128.30,128.25,128.11,126.57,120.68,119.97,36.09,20.45,19.96.
B26淡黄色鳞状晶体(产率56％)。mp:186.6-187.3℃.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.16(d,J＝2.7Hz,1H),7.55–7.43(m,4H),7.40(t,J＝7.9Hz,2H),6.90(dd,J＝10.9,4.9Hz,2H),6.82(dd,J＝8.2,1.6Hz,1H),6.53(d,J＝9.8Hz,1H),3.74(s,3H),3.72(s,3H),3.51(s,2H).13C NMR(101MHz,DMSO-d6)δ169.22,159.30,148.50,147.63,141.13,136.10,129.12,128.18,128.15,127.98,126.59,121.02,120.73,119.99,112.98,111.79,55.50,55.42,42.36.
B27黄色针状晶体(产率68％)。201.0-201.7℃.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.14(d,J＝2.7Hz,1H),7.54–7.43(m,4H),7.41(t,J＝6.5Hz,2H),7.21(dddd,J＝28.4,12.8,7.5,4.2Hz,3H),6.54(d,J＝9.8Hz,1H),3.71(s,2H).13C NMR(101MHz,DMSO-d6)δ167.35,159.31,159.00,156.60,141.09,136.06,129.11,128.39,128.15,126.57,124.51,120.79,119.77,118.38,116.40,115.22,35.56.
B28淡绿色针状晶体(产率69％)。mp:181.3-181.7℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.13(d,J＝2.7Hz,1H),7.55–7.43(m,4H),7.39(d,J＝7.2Hz,2H),7.26(dd,J＝8.8,7.0Hz,2H),6.53(d,J＝9.8Hz,1H),3.65(s,2H).13C NMR(101MHz,DMSO-d6)δ167.80,159.32,151.04,148.68,141.07,136.18,132.84,129.12,128.58,128.17,126.57,120.74,119.66,114.06,41.28.
B30淡黄色针状晶体(产率64％)。mp:233.4-233.6℃.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.17(d,J＝2.7Hz,1H),7.59–7.48(m,4H),7.44(d,J＝7.2Hz,2H),7.23(t,J＝8.5Hz,2H),6.58(d,J＝9.8Hz,1H),3.74(s,2H).13C NMR(101MHz,DMSO-d6)δ166.60,162.36,159.87,159.30,141.08,135.98,129.09,128.38,128.15,126.56,120.82,119.71,108.10,100.25,28.98.
B31黄色颗粒晶体(产率70％)。mp:238.5-239.0℃.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.17(d,J＝2.7Hz,1H),7.54–7.42(m,4H),7.41–7.36(m,2H),7.33(d,J＝8.3Hz,2H),7.23(d,J＝8.2Hz,2H),6.52(d,J＝9.8Hz,1H),3.54(s,2H),1.26(s,9H).13CNMR(101MHz,DMSO-d6)δ169.09,159.28,148.88,141.14,136.01,132.63,129.11,128.68,128.14,128.12,126.58,125.03,120.76,119.99,42.34,34.09,31.12.
B32淡黄色颗粒晶体(产率53％)。mp:168.3-168.9℃.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.20(d,J＝2.8Hz,1H),8.15(d,J＝8.1Hz,1H),8.01–7.96(m,1H),7.92–7.87(m,1H),7.60(dd,J＝9.7,2.7Hz,2H),7.58–7.51(m,5H),7.47(dd,J＝7.6,5.0Hz,1H),7.44–7.41(m,2H),6.59(d,J＝9.8Hz,1H),4.16(s,2H).
A31白色棱状晶体(产率62％)。mp:230.6-231.0℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.15(d,J＝2.7Hz,1H),7.55–7.48(m,3H),7.45(t,J＝7.3Hz,1H),7.40(d,J＝7.2Hz,2H),6.52(d,J＝9.7Hz,1H),1.70(dq,J＝7.4,5.0Hz,1H),0.77(t,J＝5.8Hz,4H).
A32淡黄色块状晶体(产率51％)。mp:248.2-248.7℃.1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.20(d,J＝2.7Hz,1H),7.55–7.49(m,3H),7.46(t,J＝4.8Hz,1H),7.43–7.39(m,2H),6.51(d,J＝9.8Hz,1H),3.16(p,J＝8.4Hz,1H),2.22–2.05(m,4H),1.92(dd,J＝18.7,9.3Hz,1H),1.83–1.74(m,1H).
A33淡黄色透明块状晶体(产率72％)。mp:234.8-235.0℃.1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.20(d,J＝2.7Hz,1H),7.55–7.49(m,3H),7.46(d,J＝7.2Hz,1H),7.43–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.76–2.66(m,1H),1.87–1.76(m,2H),1.73–1.60(m,4H),1.58–1.47(m,2H).
A34淡黄色颗粒晶体(产率54％)。mp:247.2-247.4℃.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.21(d,J＝2.7Hz,1H),7.55–7.48(m,3H),7.45(dd,J＝8.2,5.7Hz,1H),7.42–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.29–2.21(m,1H),1.75(t,J＝12.2Hz,4H),1.63(d,J＝11.3Hz,1H),1.36(dd,J＝22.4,11.4Hz,2H),1.28–1.13(m,3H).
A35白色颗粒晶体(产率56％)。mp:220.6-221.5℃.1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.18(d,J＝2.7Hz,1H),7.51(dt,J＝10.5,5.0Hz,3H),7.45(dd,J＝8.2,5.8Hz,1H),7.42–7.38(m,2H),6.51(d,J＝9.7Hz,1H),2.46–2.38(m,1H),1.81(ddd,J＝13.5,7.1,3.4Hz,2H),1.75–1.65(m,2H),1.63–1.39(m,8H).
A36墨绿色棱状晶体(产率74％)。mp:213.2-213.8℃.1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.13(d,J＝2.8Hz,1H),7.68(dd,J＝9.8,2.8Hz,1H),7.52(t,J＝7.4Hz,2H),7.45(dd,J＝8.6,6.1Hz,1H),7.43–7.38(m,2H),6.49(d,J＝9.8Hz,1H),2.00(d,J＝3.3Hz,3H),1.86(d,J＝2.4Hz,6H),1.73–1.64(m,6H).
B33淡黄绿色棱状晶体(产率68％)。mp:219.7-220.6℃.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.18(d,J＝2.7Hz,1H),7.50(dt,J＝12.5,5.0Hz,3H),7.45(t,J＝6.9Hz,1H),7.43–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.15(d,J＝7.0Hz,2H),1.00(qd,J＝7.7,3.7Hz,1H),0.49–0.42(m,2H),0.16(q,J＝4.8Hz,2H).
B34淡黄色棱状晶体(产率64％)。mp:219.6-219.8℃.1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.17(d,J＝2.7Hz,1H),7.55–7.44(m,4H),7.43–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.25(d,J＝7.0Hz,2H),2.17(dd,J＝14.9,7.4Hz,1H),1.73(td,J＝11.4,6.4Hz,2H),1.63–1.45(m,4H),1.16(td,J＝14.6,7.2Hz,2H).
B35淡黄色棱状晶体(产率70％)。mp:217.7-217.9℃.1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.18(d,J＝2.7Hz,1H),7.55–7.44(m,4H),7.43–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.13(d,J＝6.9Hz,2H),1.73–1.58(m,6H),1.26–1.10(m,3H),1.00–0.89(m,2H).
B36淡粉色颗粒晶体(产率64％)。mp:260.8-261.3℃.1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.19(d,J＝2.7Hz,1H),7.55–7.44(m,4H),7.43–7.39(m,2H),6.51(d,J＝9.7Hz,1H),2.00(s,2H),1.92(s,3H),1.68–1.56(m,12H).
B37棕色块状固体(产率60％)。mp:130.6-131.1℃.1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.13(d,J＝2.7Hz,1H),7.67(dt,J＝6.4,3.2Hz,1H),7.52(t,J＝7.4Hz,2H),7.48–7.39(m,3H),6.49(d,J＝9.8Hz,1H),3.20(s,2H),2.56(s,4H),1.76–1.71(m,4H).13C NMR(101MHz,DMSO-d6)δ168.75,159.35,141.09,136.78,129.11,128.89,128.14,126.61,120.31,119.52,59.18,53.71,23.42.
B38淡黄色块状固体(产率64％)。mp:143.8-144.1℃.1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.11(d,J＝2.7Hz,1H),7.70(dd,J＝9.8,2.8Hz,1H),7.53(t,J＝7.4Hz,2H),7.48–7.38(m,3H),6.50(d,J＝9.8Hz,1H),3.26(d,J＝16.2Hz,1H),2.97(d,J＝16.2Hz,1H),2.80–2.73(m,1H),2.44–2.24(m,2H),1.67–1.46(m,4H),1.34–1.18(m,2H),1.00(d,J＝6.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ169.84,159.37,141.07,136.86,129.10,128.93,128.14,126.64,120.28,119.33,58.12,56.08,53.48,33.62,25.43,23.37,18.87.
C1白色块状固体(产率70％)。188.5-189.2℃.1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.20(d,J＝2.1Hz,1H),7.54–7.45(m,4H),7.39(d,J＝7.5Hz,2H),7.25(d,J＝7.8Hz,2H),7.10(d,J＝7.8Hz,2H),6.50(d,J＝9.7Hz,1H),3.72(q,J＝6.7Hz,1H),2.40(d,J＝7.1Hz,2H),1.80(dt,J＝13.4,6.7Hz,1H),1.37(d,J＝6.9Hz,3H),0.85(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ172.20,159.25,141.23,139.54,138.72,135.94,129.10,128.91,128.14,128.10,126.92,126.60,120.73,119.99,45.26,44.18,29.58,22.14,18.58.
C2白色块状固体(产率51％)。mp:176.5-177.8℃.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.18(d,J＝2.7Hz,1H),7.54–7.47(m,3H),7.44(dd,J＝8.6,6.0Hz,1H),7.41–7.29(m,6H),7.26–7.20(m,1H),6.50(d,J＝9.8Hz,1H),3.76(q,J＝6.9Hz,1H),1.39(d,J＝7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.03,159.26,141.55,141.15,135.96,129.10,128.38,128.17,128.15,127.20,126.74,126.60,120.74,119.94,45.62,18.59.
C3绿色簇状晶体(产率53％)。mp:205.5-206.3℃.1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.03(d,J＝2.7Hz,1H),7.58(dd,J＝9.8,2.8Hz,1H),7.51(t,J＝7.4Hz,2H),7.44(t,J＝7.3Hz,1H),7.40–7.30(m,6H),7.23(t,J＝7.1Hz,1H),6.45(d,J＝9.8Hz,1H),2.59(dd,J＝11.2,5.6Hz,2H),1.88(dd,J＝12.7,6.1Hz,2H),1.72–1.55(m,4H).13C NMR(101MHz,DMSO-d6)δ173.54,159.28,143.82,141.12,136.85,129.08,128.30,128.13,126.62,126.46,126.32,126.13,120.19,119.97,59.73,35.77,23.09.
C4淡黄绿色粉末(产率76％)。mp:92.7-93.2℃.1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.19(d,J＝2.7Hz,1H),7.78(dd,J＝11.7,8.9Hz,3H),7.53–7.41(m,5H),7.41–7.36(m,2H),7.28(d,J＝2.4Hz,1H),7.15(dd,J＝8.9,2.5Hz,1H),6.50(d,J＝9.8Hz,1H),3.93–3.88(m,1H),3.86(s,3H),1.47(d,J＝7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.17,159.26,157.06,141.14,136.65,136.02,133.23,129.11,129.10,128.34,128.22,128.14,126.80,126.60,126.23,125.37,120.70,119.97,118.66,105.65,55.13,45.58,18.59.
F-B14暗绿色针状晶体(产率76％)。mp:220.1-220.4℃.1H NMR(400MHz,DMSO-d6)δ10.09(d,J＝5.5Hz,1H),8.14(d,J＝2.3Hz,1H),7.57–7.50(m,2H),7.45(dd,J＝15.0,7.8Hz,1H),7.39(dd,J＝6.2,2.0Hz,2H),7.35(d,J＝14.7Hz,3H),7.31–7.24(m,1H),6.53(dd,J＝9.8,5.3Hz,1H),3.61(s,2H).
F-B23白色絮状晶体(产率78％)。mp:163.4-164.1℃.1H NMR(400MHz,DMSO-d6)δ10.03(d,J＝5.7Hz,1H),8.17(t,J＝2.5Hz,1H),7.55–7.48(m,2H),7.46–7.38(m,2H),7.38–7.23(m,1H),7.04(d,J＝7.0Hz,2H),6.95(d,J＝7.7Hz,1H),6.54(dd,J＝9.7,5.1Hz,1H),3.59(s,2H),2.23(d,J＝2.5Hz,6H).
NIH3T3(小鼠胚胎成纤维化细胞)是公认的体外筛选抗纤维化简便而有效的模型，本发明对所合成的化合物进行了体外抗纤维化活性的初步评价，结合实例5进行说明：
实例5、CCK-8法测化合物对NIH3T3(小鼠胚胎成纤维化细胞)的抗增殖能力
本发明首先初筛了所合成的吡非尼酮衍生物在1mM时对NIH3T3细胞增殖的抑制率，选择抑制率超过30％的化合物进行了IC50的筛选，具体步骤如下：将NIH3T3细胞以每孔5000个接种在96孔板中，在CM1-1培养基(质量百分含量90％DMEM-H+质量百分含量10％FBS)中培养12小时，然后用梯度浓度的化合物和阳性对照吡非尼酮作用48小时之后，向每个孔中加入质量百分含量0.5％的CCK溶液，并在37℃孵育4小时。IC50通过使用GraphPadPRISM的非线性回归分析确定。结果如下表所示：
表1化合物体外抗NIH3T3细胞增值结果：
Figure BDA0003428924040000291
Figure BDA0003428924040000301
实验结果表明：绝大多数化合物体外抗纤维细胞增殖活性优于阳性对照吡非尼酮，其中化合物C1活性最好，IC50约为吡非尼酮的350倍，值得进一步研究和开发。

Claims (6)

1.吡非尼酮衍生物或其药用的盐，其特征在于，具有如下通式所示结构：
Figure DEST_PATH_IMAGE001
，其中，n=0,1；X=H,卤素；
（1）当X=H，n=0时， R1为苯基或被取代的苯基，吡啶基，喹啉基；C1-5烷基，C3-7饱和脂肪环基或被取代的C3-7饱和脂肪环基，金刚烷基；所述取代基为羟基，氨基，卤素，甲氧基，乙氧基，C1-4烷基，三氟甲基，硝基，苯基，苄氧基；为单取代或多取代；
(2)当X=H，n=1，R2=H时，R1为苯基或被取代的苯基，吡啶基或被取代的吡啶基，萘基或被取代的萘基；C1-5烷基，C3-7饱和脂肪环基或被取代的C3-7饱和脂肪环基，金刚烷基；所述取代基为羟基，氨基，卤素，甲氧基，乙氧基，C1-4烷基，三氟甲基，硝基，溴甲基；为单取代或多取代；
（3）当X=H，n=1，R1=苯基或被取代的苯基，萘基或被取代的萘基；R2=C1-5直链烷基，C3-5环状烷基；所述取代基为卤素，甲氧基，乙氧基，C1-4烷基；为单取代或多取代。
2.根据权利要求1所述的吡非尼酮衍生物或其药用的盐，其特征在于，为如下任一种化合物：
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A）；
2-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A1）；
2-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A2）；
2-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A3）；
2-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A4）；
2-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A5）；
2-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A6）；
3-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A7）；
3-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A8）；
3-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A9）；
3-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A10）；
3-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A11）；
3-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A12）；
4-氟-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A13）；
4-氯-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A14）；
4-溴-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A15）；
4-甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A16）；
4-甲氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A17）；
4-三氟甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A18）；
4-硝基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A19）；
3-甲基-4-硝基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A20）；
4-乙氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A21）；
4-苯基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A22）；
4-苄氧基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A23）；
2,5-二甲基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A24）；
2-羟基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)苯甲酰胺（A25）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)吡啶甲酰胺（A26）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)异烟酰胺（A27）；
2-氧代-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺（A28）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)喹啉-6-甲酰胺（A29）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)烟酰胺（A30）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环丙烷甲酰胺（A31）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环丁烷甲酰胺（A32）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环戊烷甲酰胺（A33）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环己烷甲酰胺（A34）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)环庚烷甲酰胺（A35）；
(3r，5r，7r)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)金刚烷-1-甲酰胺（A36）；
2-(2-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B1）；
2-(2-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B2）；
2-(2-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B3）；
2-(2-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B4）；
2-(2-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B5）；
2-(2-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B6）；
2-(3-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B7）；
2-(3-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B8）；
2-(3-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B9）；
2-(3-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B10）；
2-(3-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B11）；
2-(3-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B12）；
2-(4-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B13）；
2-(4-氯苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B14）；
2-(4-溴苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B15）；
2-(4-甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B16）；
2-(4-甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B17）；
2-(4-三氟甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B18）；
2-(4-乙氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B19）；
2-(4-硝基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B20）；
2-([1,1’-联苯]-4-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B21）；
2-(4-苄氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B22）；
2-(2,5-二甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B23）；
2-(2-溴-4-氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B24）；
2-(2,4,6-三甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B25）；
2-(3，4-二甲氧基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B26）；
2-(2,5-二氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B27）；
2-(3,4,5-三氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B28）；
2-( 4-溴甲基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B29）；
2-(2，4，6-三氟苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B30）；
2-(4-叔丁基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B31）；
2-(萘-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B32）；
2-环丙基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B33）；
2-环戊基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B34）；
2-环己基-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B35）；
2-((3r，5r，7r)-金刚烷-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B36）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-2-(吡咯烷-1-基)乙酰胺（B37）；
2-(2-甲基哌啶-1-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)乙酰胺（B38）；
(S)-2-(4-异丁基苯基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺（C1）；
(S)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-2-苯基丙酰胺（C2）
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-1-苯基环丙烷-1-甲酰胺（C3）；
N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)-1-苯基环戊烷-1-甲酰胺（C4）；
(S)-2-(6-甲氧基萘-2-基)-N-(6-氧代-1-苯基-1，6-二氢吡啶-3-基)丙酰胺（C5）。
3.根据权利要求1所述的吡非尼酮衍生物或其药用的盐，其特征在于，为如下任一种化合物：
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-甲氧基苯甲酰胺（F-A5）；
3-溴-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)苯甲酰胺（F-A9）；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-4-(三氟甲基)苯甲酰胺（F-A18）；
4-苄氧基-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)苯甲酰胺（F-A23）；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2，5-二甲基苯甲酰胺（F-A24）；
2-(2-溴苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B3）；
2-(4-氯苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B14）；
2-(4-乙氧基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B19）；
2-([1，1 '-联苯]-4-基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B21）；
2-(4-苄氧基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B22）；
2-(2，5-二甲基苯基)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)乙酰胺（F-B23）；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-三甲基苯乙胺（F-B25）；
N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)-2-(萘-1-基)乙酰胺（F-B32）；
(3r，5r，7r)-N-(1-(3-氟苯基)-6-氧代-1，6-二氢吡啶-3-基)金刚烷-1-甲酰胺（F-A36）。
4.如权利要求1所述的吡非尼酮衍生物或其药用盐的制备方法，其特征在于，通过如下方法实现：
Figure DEST_PATH_IMAGE002
碘苯和苯氧化生成高碘盐，随后将原料2-羟基-5-硝基吡啶溶于有机溶剂，和高碘盐在碱和催化剂的作用下进行C-N偶联反应得到关键中间体3，中间体3先后经过硝基还原，成酰胺反应得到目标终产物；
所述催化剂为碘化亚铜；
所述的有机溶剂为：N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、丙酮、甲苯、甲醇、乙醇、乙腈、四氢呋喃的一种或两种；
所述的碱为：碳酸钾、碳酸铯、氢氧化钾、氢氧化钠、碳酸钠、三乙胺、N，N-二异丙基乙胺、4-二甲氨基吡啶、甲醇钠、乙醇钠、氢化钠的一种或两种；
所述硝基还原反应所用溶剂为甲醇、乙醇、乙腈、二氯甲烷、丙酮、水的一种或两种；还原剂为锡粉、锌粉、铁粉的一种；
所述成酰胺反应所用缩合剂为：DCC、HATU、HBTU、TBTU、DIC、EDCI的一种或两种；碱为碳酸钾、碳酸铯、氢氧化钾、氢氧化钠、碳酸钠、三乙胺、N，N-二异丙基乙胺、4-二甲氨基吡啶、甲醇钠、乙醇钠、氢化钠的一种或两种。
5.根据权利要求1-3其中之一所述的吡非尼酮衍生物或其药用盐在药物制备中的应用，其特征在于，将其作为活性成分，用于制备抗肺纤维化药物。
6.根据权利要求5所述的吡非尼酮衍生物或其药用盐在药物制备中的应用，其特征在于，用于制备治疗特发性肺纤维化或肺癌或新冠病毒引起的纤维化疾病药物。
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Publication number Priority date Publication date Assignee Title
CN1436172A (zh) * 2000-06-12 2003-08-13 卫材株式会社 1,2－二氢吡啶化合物及其制备方法和用途
CN1856467A (zh) * 2003-09-18 2006-11-01 阿斯利康(瑞典)有限公司 用作嗜中性白细胞弹性蛋白酶抑制剂的2－吡啶酮衍生物及其用途
CN106083702A (zh) * 2016-06-14 2016-11-09 四川大学 吡非尼酮衍生物及其制备方法
CN112739690A (zh) * 2018-07-24 2021-04-30 埃皮兹姆公司 用作smarca2拮抗剂的吡啶-2-酮化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1436172A (zh) * 2000-06-12 2003-08-13 卫材株式会社 1,2－二氢吡啶化合物及其制备方法和用途
CN1856467A (zh) * 2003-09-18 2006-11-01 阿斯利康(瑞典)有限公司 用作嗜中性白细胞弹性蛋白酶抑制剂的2－吡啶酮衍生物及其用途
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CN112739690A (zh) * 2018-07-24 2021-04-30 埃皮兹姆公司 用作smarca2拮抗剂的吡啶-2-酮化合物

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