CN114057814B - 核苷类似物及其应用 - Google Patents
核苷类似物及其应用 Download PDFInfo
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- CN114057814B CN114057814B CN202110897435.0A CN202110897435A CN114057814B CN 114057814 B CN114057814 B CN 114057814B CN 202110897435 A CN202110897435 A CN 202110897435A CN 114057814 B CN114057814 B CN 114057814B
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/14—Pyrrolo-pyrimidine radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
Abstract
本发明涉及一种核苷类似物及其应用，属于药物化学技术领域。该化合物具有式I结构特征的核苷类似物或其药学上可接受的盐或立体异构体或溶剂化物或前药，具有RNA病毒，特别是冠状病毒抑制活性，能够作为抑制RNA病毒引发感染疾病的药物候选物。部分在体外细胞活性试验中，其对SARS‑CoV‑2病毒的活性与瑞德西韦相当，具有较好的应用前景。
Description
技术领域
本发明涉及药物化学技术领域，特别是涉及一种核苷类似物及其应用。
背景技术
冠状病毒(CoVs)是一大类有包膜的正链单链RNA病毒，在自然界中广泛存在，可感染包括人类在内的多类脊椎动物。根据系统发育树，CoVs可分为α、β、γ和δ四个属。目前已知的7种可感染人类的CoVs中，可引起重症的SARS-CoV、MERS-CoV和SARS-CoV-2均属于β属冠状病毒。
由于人类感染CoVs(HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1)后，通常仅有类似流感的一般呼吸道症状，因此早前(2001年以前)CoVs并未引起人们的过多关注，临床上也没有针对性的药物。然而，近20年来CoVs引起的疾病已在全球范围内引发三次疫情，并造成大量人员死亡。
世界卫生组织(WHO)于2020年3月11日将COVID-19疫情评估为“全球大流行(pandemic)”。同时，COVID-19疫情对世界经济也产生了严重的消极影响。国际货币基金组织(IMF)的报告认为：COVID-19引发的影响将造成九十年来最严重的经济衰退，并预测到2022年将造成总计9万亿美元的损失。但是，由于缺乏疫苗和有效药物，此次COVID-19疫情仍在蔓延中。因此，开发针对CoVs的药物，不仅是一个对人类公共卫生和健康至关重要的课题，同时也是一个对国民经济发展举足轻重的课题。
发明内容
基于此，有必要针对上述问题，提供一种核苷类似物，该核苷类似物具有RNA病毒，特别是冠状病毒抑制活性，能够作为抑制RNA病毒引发感染疾病的药物候选物。
一种具有式I结构特征的核苷类似物或其药学上可接受的盐或立体异构体或溶剂化物或前药：
其中，
R1选自：H，D，COR2，PONHR3(OAr2)；
Z选自：H，D，F，CH2Cl，CN，N3，CF3，CH2OR4，CH2CF3，炔基；
Y选自：Me，卤素，C1-C4烷基，C3-C4环烷基，NHR5，OR5，SR5，NR5NHR5，NR5OR5，N(R5)2；
W选自：C2炔基，C2烯基，5-6元芳环或杂芳环，CF2，C3-C6环烷基，CO或没有；
X选自：N，CH；
Ar选自：卤素，C1-C6直链烷基或支链烷基，C3-C6环烷基，5-6元芳环或杂芳环，取代5-6元芳环或杂芳环，五元并六元芳环或杂芳环，萘基或没有；
Ar2选自：芳基、萘基、取代芳基或取代萘基；
R2选自：C1-C10烷基或取代烷基，C1-C10烯基或取代烯基，天然或非天然氨基酸基；
R3选自：天然以及非天然氨基酸链接氨基的基团，其中羧酸和C1-C6醇成酯；
R4选自：C1-C3烷基；
R5选自：H，D，C1-C6直链烷基或支链烷基，C2-C3烯基或炔基，C3-C6环烷基，C3-C6杂环烷基，苄基，芳基，取代苄基或芳基，杂芳基，取代杂芳基，环丙基甲基或取代环丙基甲基，C2-C3炔基，氨基、酰氨基或磺酰氨基。
在其中一个实施例中，R1选自：H，D，COR2，PONHR3(OAr2)；
Z选自：H，F，CN，N3，C2-C3炔基；
Y选自：Me，卤素，NHR5，OR5，SR5，环丙基，NR5NHR5，NR5OR5；
W选自：C2炔基，C2烯基，R6取代C2烯基，C3-C6环烷基，5-6元芳环或杂芳环，或没有；
X选自：N；
Ar选自：卤素，C1-C6直链烷基或支链烷基，C3-C6环烷基，5-6元芳环或杂芳环，至少一个R6取代5-6元芳环或杂芳环，五元并六元芳环或杂芳环，萘基，或没有；所述杂芳环选自至少一个N、S、O杂原子取代杂芳环；
Ar2选自：芳基，萘基；
R2选自：C1-C10氨基取代烷基，
R3选自：天然氨基酸链接氨基的基团，且其中羧酸和C1-C6醇成酯；
R5选自：H，C1-C6直链烷基或支链烷基，C2-C3烯基或炔基，C3-C6环烷基，C3-C6杂环烷基，苄基，芳基，取代苄基或芳基，杂芳基，取代杂芳基，环丙基甲基或取代环丙基甲基，C2-C3炔基，氨基、酰氨基或磺酰氨基；
R6任选自：甲基，卤素，CF3，甲氧基，甲氧基甲基，乙氧基羰基，苯基，C3-C6环烷基。
可以理解的，上述R3基团，为天然存在的氨基酸链接氨基的基团，以其中羧酸与C1-C6的醇成酯所得基团，例如丙酸(S)异丙酯等。天然存在的氨基酸优选人体必需20种氨基酸之一。
在其中一个实施例中，
R1选自：H，PONHR3(OAr2)；
Z选自：H，F，N3；
Y选自：Me，NHR5，OR5，SR5，NR5NHR5，NR5OR5；
W选自：C2炔基或没有；
X选自：N；
Ar选自：5-6元芳环或杂芳环，至少一个R6取代5-6元芳环或杂芳环，萘基，或没有；所述杂芳环选自至少一个N、S、O杂原子取代杂芳环；
Ar2选自：芳基，萘基；
R3选自：天然氨基酸链接氨基的基团，且其中羧酸和C1-C6醇成酯；
R5选自：H，甲基，C2-C3烯基，C3-C6环烷基，C3-C6杂环烷基，苄基，取代杂芳基，取代芳基，C2-C3炔基，氨基、酰氨基或磺酰氨基；
R6任选自：卤素，甲基，CF3，苯基，甲氧基，甲氧基甲基，乙氧基羰基，C3-C6环烷基。
在其中一个实施例中，R1选自：H，PONHR3(OAr2)；
Z选自：H，F，N3；
Y选自：Me，NHR5，SR5，NR5NHR5，NR5OR5；
W选自：C2炔基；
X选自：N；
Ar选自：芳环，至少一个R6取代芳环，芳杂环，至少一个R6取代芳环，所述杂芳环选自至少一个N、S、O杂原子取代杂芳环；
Ar2选自：苯基，萘基；
R3选自：天然氨基酸链接氨基的基团，且其中羧酸和C1-C6醇成酯；
R5选自：H，甲基，C3-C6环烷基，C3-C6杂环烷基，苄基，取代杂芳基，取代芳基，C2-C3炔基，氨基、酰氨基或磺酰氨基；
R6任选自：卤素。
在其中一个实施例中，R1选自：PONHR3(OAr2)；
R3选自：丙酸(S)异丙酯；
Ar2选自：苯基；
Y选自：NHR5，NR5NHR5，NR5OR5；
R5选自：H，C3-C6环烷基，C3-C6杂环烷基，甲磺酰胺基，酰胺基。
在其中一个实施例中，所述的核苷类似物选自如下化合物：
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本发明还公开了上述的核苷类似物或其药学上可接受的盐或立体异构体或溶剂化物或前药在制备用于预防和治疗RNA病毒感染疾病的药物中的应用。
在其中一个实施例中，所述RNA病毒为冠状病毒科或黄病毒。
在其中一个实施例中，所述冠状病毒包括：SARS-CoV、MERS-CoV和SARS-CoV-2。
本发明还公开了一种药物组合物，包括上述的核苷类似物或其药学上可接受的盐或立体异构体或溶剂化物或前药，以及药学上可以接受的辅料或载体。
与现有技术相比，本发明具有以下有益效果：
本发明的一种具有式I结构特征的核苷类似物或其药学上可接受的盐或立体异构体或溶剂化物或前药，该核苷类似物具有RNA病毒，特别是冠状病毒抑制活性，在体外细胞活性试验中，其对SARS-CoV-2病毒的活性与瑞德西韦相当，能够作为抑制RNA病毒引发感染疾病的药物候选物，具有广泛的应用前景。
具体实施方式
为了便于理解本发明，下面将参照实施例对本发明进行更全面的描述。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
实施例1
1、化合物2的制备。
取化合物1(6.477g，17.40mmol)溶于无水THF(50mL)中，置于-20℃，氮气保护，缓慢滴加Li(Ot-Bu)3AlH的THF溶液(1M，21mmol，21mL，1.2当量)，搅拌6h。加入1M稀盐酸(10mL)淬灭反应，升至室温，搅拌0.5h，EA萃取，收集有机相，再用饱和食盐水洗，干燥，旋干，过柱(PE:EA＝4:1)，得无色油状液体6.481g，产率100％。
化合物2的表征数据为：1H NMR(400MHz,CDCl3)δ8.11–8.05(m,2H),8.04–7.98(m,2H),7.64–7.52(m,2H),7.41(m,4H),6.18(d,J＝2.1Hz,1H),5.26(t,J＝6.0Hz,1H),4.79–4.62(m,2H),4.56(dd,J＝12.2,4.9Hz,1H),2.18(s,3H),1.71(d,J＝22.4Hz,3H).
2、化合物3的制备。
取一50mL的两口瓶，加入化合物2(1g，2.6mmol)，氩气保护，加入无水DCM(10mL)溶解，置于-25℃下，加入PPh3(1.03g，3.64mmol，3当量)的无水DCM(8mL)溶液，搅拌15min，再加入CBr4(1.4g，3.9mmol，3当量)的无水DCM(8mL)溶液，在-20℃下搅拌10min，直至原料反应完毕。加入硅胶，用湿法上柱，过柱(PE：EA＝12:1)，得无色透明液体1.115g(α构型)，产率为95％。
化合物3的表征数据为：1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.2Hz,2H),8.02(d,J＝7.6Hz,2H),7.63–7.56(m,2H),7.507.42(m,4H),6.34(s,1H),5.29(dd,J＝5.3,2.8Hz,1H),4.89-4.86(m,1H),4.80–4.76(m,1H),4.65–4.61(m,1H),1.72(d,J＝21.2Hz,3H).
3、化合物5的制备。
取一50mL两口瓶，在上述化合物3中加入化合物4(1.76g，7.47mmol，2.95当量)，氩气保护，加入无水的tBuOH溶液(3mL)，搅拌，加入tBuOK(0.85g，7.7mmol，3当量)的无水tBuOH溶液(5mL)，搅拌30min，反应物溶解，变澄清，将化合物3(1.1g，2.5mmol)溶于无水MeCN(12ml)，加入，缓慢升温至50℃，搅拌5h，直至TLC显示化合物反应完毕，冷却至常温，加入醋酸，调至中性，过滤掉生成的无机盐，旋干，过柱(PE：EA＝10:1)，得白色固体产物0.65g，产率为50％。
化合物5的表征数据为：1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.12(d,J＝7.6Hz,2H),8.05(d,J＝4Hz,2H),7.64–7.57(m,2H),7.49–7.41(m,5H)，6.64(d,J＝16Hz,1H),6.59(s,1H),6.02(dd,J＝8,12Hz,1H),4.92(dd,J＝4,4Hz,1H),4.79–4.75(m,1H),4.67-4.11(m,1H),1.22(d,J＝20Hz).MS(ESI+)m/z:510.1(M+H+).
4、化合物6的制备。
将化合物5(0.65g，1.27mmol)溶于无水THF(5mL)中，加入Pd(PPh3)4(0.147g，0.127mmol，0.1当量)，加入AlMe3的正己烷溶液(1.6M，0.1524mmol，0.91mL，1.2当量)，置于100℃下，回流反应5min，冷却至常温，加入EA稀释，再加入1M稀盐酸(10mL)，萃取，干燥，旋干，过柱得白色固体产物0.59g，产率为96％。
化合物6的表征数据为：1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.10(d,J＝8Hz,2H),8.04(d,J＝8Hz,2H),7.58–7.52(m,2H),7.46–7.34(m,5H),6.64(d,J＝20Hz),6.53(d,J＝4Hz,1H),6.07(dd,J＝12,8Hz,1H),4.90(dd,J＝4.4Hz,1H),4.77–4.73(m,1H),4.68–4.63(m,1H),2.70(s,3H),1.20(d,J＝20Hz).MS(ESI+)m/z:490.1(M+H+).
5、化合物8-1的制备。
按照以下路线合成：
取一50mL两口瓶，加入化合物6(0.62g，1.26mmol)，氩气保护，加入无水DMF(5mL)溶解，将NIS/NBS(2g，8.87mmol，7当量)溶于无水DMF(5mL)，缓慢加入，置于50℃下，反应5h，用油泵旋去大部分DMF，EA溶解，加入饱和硫代硫酸钠溶液(10mL)淬灭反应，加入EA(20mL)，收集有机相，加入饱和食盐水，萃取，干燥，旋干，过柱(PE：EA＝5:1)，得白色固体产物(化合物7)。
将上述白色化合物(化合物7)用NH3的甲醇溶液(5mL)溶解，常温搅拌30min，旋干，过柱(DCM：iPrOH＝10:1)，得白色固体产物(化合物8-1)0.323g，两步产率为65％。
化合物8-1的表征数据为：1H NMR(400MHz,MeOD-d4)δ8.66(s,1H),8.13(s,1H),6.53(d,J＝20Hz,1H),4.22(dd,J＝8,8Hz,1H),4.06–4.03(m,1H),3.87(d,J＝4Hz,2H),2.98(s,3H),1.00(d,J＝24Hz,3H).13CNMR(125MHz,MeOD-d4)δ161.8,152.0,151.1,132.8,119.7,101.6(d,JC-F＝180Hz),89.8(d,J＝39Hz),83.4,72.3(d,J＝18Hz),60.4,53.6,20.6,16.6(d,J＝25Hz).MS(ESI+)m/z:408.0(M+H+).
6、化合物8-2的制备。
参照上述方法合成化合物8-2，两步产率为55％。
化合物8-2的表征数据为：1HNMR(400MHz,DMSO)δ8.13(s,1H),7.73(s,1H),6.69(br,2H),6.36(d,J＝18Hz,1H),5.65(d,J＝6.8Hz,1H),5.28(s,1H),4.15–4.05(m,1H),3.90–3.84(m,2H),3.69–3.66(m,1H),0.98(d,J＝22Hz,3H).13CNMR(125MHz,DMSO)δ157.0,152.7,149.1,120.6,100.8,100.4(d,JC-F＝179Hz),87.2,81.7,70.2(d,J＝18Hz),64.8,58.9,16.1(d,J＝25Hz).MS MS(ESI+)m/z:361.0(M+H+).
7、化合物10-1的制备。
按照以下路线合成：
氩气保护下，往25ml的两口瓶中加化合物8-1(50mg,0.13mmol)、Pd(PPh3)Cl2(9.3mg,0.013mmol)、CuI(5.1mg,98％,0.026mmol)、干燥THF(3ml)置于室温下搅拌，接着加入干燥的三乙胺(26.3mg,0.26mmol)和化合物9(0.26mmol，2eq)，加完后室温搅拌过夜,浓缩除去溶剂，过柱得白色固体10。
根据目标化合物结构的差异，选择具有预定R基团的化合物9，制备得到28.2mg目标化合物10-1，收率为66.4％。
化合物10-1的表征数据为：1H NMR(400MHz,Methanol-d4)δ8.62(s,1H),7.93(s,1H),6.51(d,J＝17.8Hz,1H),4.24(dd,J＝24.3,9.5Hz,1H),4.13–4.00(m,2H),3.86(dd,J＝12.6,2.9Hz,1H),2.87(s,3H),1.50(td,J＝8.3,4.3Hz,1H),1.01(d,J＝22.2Hz,3H),0.94–0.83(m,2H),0.79–0.69(m,2H).13C NMR(101MHz,MeOD)δ162.10,152.42,150.68,130.47,103.21,101.42,100.09,97.14,90.06,89.67,83.41,72.62,72.44,68.89,60.59,20.67,16.70,16.45,8.76,0.86.MS(ESI+)m/z:346.3(M+H+).
8、化合物10-2的制备。
参照上述方法制备得到30.1mg化合物10-2，收率为67.7％。
化合物10-2的表征数据为：1H NMR(400MHz,Methanol-d4)δ8.66(s,1H),7.96(s,1H),6.54(d,J＝17.9Hz,1H),4.26(dd,J＝24.4,9.3Hz,1H),4.15–3.93(m,2H),3.93–3.72(m,1H),2.92(s,3H),1.34(s,9H),1.02(d,J＝22.2Hz,3H).13C NMR(101MHz,MeOD)δ162.04,152.40,150.71,129.97,118.83,103.22,101.88,101.42,100.04,90.00,89.62,83.38,72.92,72.57,72.39,60.53,31.21,29.23,20.74,16.71,16.46.MS(ESI+)m/z:362.2(M+H+).
9、化合物10-3的制备。
参照上述方法制备得到29.0mg化合物10-3，收率为73.8％。
化合物10-3的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.10(s,1H),6.45(d,J＝17.7Hz,1H),5.67(d,J＝7.1Hz,1H),5.30(t,J＝4.9Hz,1H),4.15(ddd,J＝25.6,9.3,7.1Hz,1H),4.00–3.79(m,2H),3.70(ddd,J＝12.5,5.0,2.9Hz,1H),2.83(s,3H),2.09(s,3H),0.94(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ160.35,151.74,148.98,128.72,116.84,102.09,100.30,97.33,88.56,87.85,87.47,81.95,72.57,70.42,70.24,58.86,20.65,16.28,16.04,3.97.
10、化合物10-4的制备。
参照上述方法制备得到40.6mg化合物10-4，收率为82.6％。
化合物10-4的表征数据为：1H NMR(400MHz,DMSO)δ8.79(s,1H),8.36(s,1H),7.64(s,1H),7.48(s,1H),7.41–7.12(m,2H),6.51(d,J＝17.6Hz,1H),5.71(d,J＝6.4Hz,1H),5.37(s,1H),4.20(d,J＝25.3Hz,1H),3.94(dd,J＝23.2,8.9Hz,2H),3.76(s,1H),2.93(s,3H),1.00(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ163.55,161.14,161.07,152.64,149.82,133.33,131.32,131.24,130.51,125.41,125.38,116.37,116.16,111.39,111.24,102.61,100.82,96.44,88.60,88.53,88.50,88.22,85.35,82.59,70.97,70.80,59.44,21.28,16.87,16.63.
11、化合物10-5的制备。
参照上述方法制备得到化合物10-5。
化合物10-5的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.27(s,1H),7.44(d,J＝7.8Hz,2H),7.25(d,J＝7.8Hz,2H),6.49(d,J＝17.7Hz,1H),5.71(d,J＝7.1Hz,1H),5.36(t,J＝5.0Hz,1H),4.19(dt,J＝25.6,8.3Hz,1H),4.03–3.82(m,2H),3.73(dt,J＝12.7,3.8Hz,1H),2.92(s,3H),2.34(s,3H),0.98(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ160.64,152.13,149.34,138.51,130.84,129.53,129.34,119.51,
116.83,102.22,100.42,96.65,91.65,88.11,87.72,82.34,82.15,70.58,70.41,59.05,54.98,21.12,20.93,16.46,16.21.
12、化合物10-6的制备。
参照上述方法制备得到39.6mg化合物10-6，收率为80.6％。
化合物10-6的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.29(s,1H),7.62(dd,J＝8.4,5.4Hz,2H),7.29(t,J＝8.7Hz,2H),6.49(d,J＝17.6Hz,1H),5.70(d,J＝7.2Hz,1H),5.34(t,J＝5.1Hz,1H),4.18(dt,J＝25.6,8.4Hz,1H),4.04–3.82(m,2H),3.73(dt,J＝12.6,3.8Hz,1H),2.92(s,3H),0.98(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ163.66,161.20,161.05,152.57,149.75,133.72,133.64,130.03,119.39,119.36,117.23,116.70,116.48,102.59,100.80,96.73,90.83,88.55,88.16,83.14,82.56,71.00,70.82,59.46,21.39,16.86,16.61.
13、化合物10-7的制备。
参照上述方法制备得到33.0mg化合物10-7，收率为59.7％。
化合物10-7的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.41(s,1H),7.83(dd,J＝10.8,7.7Hz,2H),7.75(t,J＝7.6Hz,1H),7.62(t,J＝7.7Hz,1H),6.50(d,J＝17.6Hz,1H),5.71(s,1H),5.37(s,1H),4.33–4.08(m,1H),3.94(dd,J＝23.1,11.0Hz,2H),3.73(dd,J＝12.7,3.0Hz,1H),2.89(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.00,152.64,149.84,134.39,133.19,131.39,130.10,129.70,129.40,129.37,129.11,126.70,126.65,126.59,126.55,125.47,122.76,120.90,120.88,120.04,116.97,102.59,100.80,96.18,88.89,88.66,88.28,87.49,82.58,70.89,70.72,59.35,21.30,16.88,16.63.
14、化合物10-8的制备。
参照上述方法制备得到40.6mg化合物27.1mg，收率为57.6％。
化合物10-8的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.62(d,J＝4.8Hz,1H),8.41(s,1H),7.86(t,J＝7.8Hz,1H),7.63(d,J＝7.8Hz,1H),7.52–7.31(m,1H),6.50(d,J＝17.5Hz,1H),5.71(d,J＝7.0Hz,1H),5.38(d,J＝5.1Hz,1H),4.20(dt,J＝25.6,8.3Hz,1H),4.07–3.81(m,2H),3.74(d,J＝12.6Hz,1H),2.94(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.15,152.67,150.69,149.85,142.94,137.29,131.14,127.18,123.84,117.28,102.62,100.82,96.01,91.90,88.22,82.77,82.61,70.93,70.76,59.41,21.42,16.86,16.62.
15、化合物10-9的制备。
参照上述方法制备得到35.5mg化合物10-9，收率为74.5％。
化合物10-9的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.32(s,1H),7.68(d,J＝5.1Hz,1H),7.43(d,J＝3.6Hz,1H),7.15(t,J＝4.4Hz,1H),6.50(d,J＝17.6Hz,1H),5.71(d,J＝7.1Hz,1H),5.34(t,J＝5.2Hz,1H),4.19(dt,J＝25.5,8.2Hz,1H),4.09–3.83(m,2H),3.74(d,J＝12.7Hz,1H),2.89(s,3H),0.99(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ161.00,152.60,149.80,132.67,130.21,130.10,129.20,128.29,122.45,117.16,102.61,100.81,96.48,88.55,88.16,86.93,85.16,82.59,70.98,70.80,59.47,21.29,16.85,16.60.
16、化合物10-10的制备。
参照上述方法制备得到12.2化合物10-10，收率为31.4％。
化合物10-10的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.50(s,1H),7.95(dd,J＝20.1,3.3Hz,2H),6.50(d,J＝17.5Hz,1H),5.72(s,1H),5.37(s,1H),4.20(dd,J＝25.8,9.2Hz,1H),3.94(dd,J＝25.4,10.9Hz,2H),3.74(dd,J＝12.4,3.1Hz,1H),2.90(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.06,152.80,149.91,147.80,144.46,144.43,131.95,123.19,117.12,102.61,100.80,95.02,94.99,88.64,88.25,87.98,85.22,82.68,70.93,70.75,59.45,21.37,16.86,16.62.
17、化合物10-11的制备。
参照上述方法制备得到24.0mg化合物10-11，收率为50.9％。
化合物10-11的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.99–8.74(m,3H),8.54(s,1H),7.51(t,J＝4.9Hz,1H),6.51(d,J＝17.3Hz,1H),5.72(d,J＝7.1Hz,1H),5.41(s,1H),4.22(dt,J＝25.4,8.6Hz,1H),3.95(dd,J＝23.6,10.8Hz,2H),3.75(d,J＝12.6Hz,1H),2.95(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.19,158.26,152.80,149.96,132.54,120.90,117.35,102.64,100.84,95.13,91.69,88.64,88.26,82.68,81.21,70.83,70.66,59.35,21.37,16.87,16.63.
18、化合物10-12的制备。
参照上述方法制备得到43.9mg化合物10-12，收率为90.3％。
化合物10-12的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.33(s,1H),7.52(d,J＝7.5Hz,1H),7.35-7.30(m,2H),7.28-7.23(m,1H),6.50(d,J＝17.7Hz,1H),5.71(d,J＝7.1Hz,1H),5.36(t,J＝4.8Hz,1H),4.21(dt,J＝25.6,7.9Hz,1H),4.04–3.85(m,2H),3.74(dt,J＝12.6,3.9Hz,1H),2.94(s,3H),2.51(s,3H),1.01(d,J＝22.4Hz,3H).13CNMR(101MHz,DMSO)δ160.96,152.51,149.79,139.71,131.87,130.24,130.19,129.06,126.49,122.78,117.09,102.59,100.80,97.05,90.70,88.58,88.18,87.02,82.55,71.00,70.83,59.46,21.51,20.89,16.89,16.64.
19、化合物10-13的制备。
参照上述方法制备得到46.4mg化合物10-13，收率为91.7％。
化合物10-13的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.26(s,1H),7.48(dd,J＝7.5,1.6Hz,1H),7.40(td,J＝7.9,7.5,1.7Hz,1H),7.11(d,J＝8.4Hz,1H),7.06–6.93(m,1H),6.50(d,J＝17.8Hz,1H),5.70(d,J＝7.1Hz,1H),5.36(s,1H),4.20(dt,J＝25.5,8.1Hz,1H),4.00–3.83(m,5H),3.78-3.69(m,1H),2.96(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.21,160.22,152.41,149.78,132.73,130.60,129.58,121.04,111.99,111.83,102.61,100.81,97.45,88.92,88.55,88.17,86.91,82.53,71.00,70.82,59.44,56.08,21.08,16.87,16.62.
20、化合物10-14的制备。
参照上述方法制备得到42.4mg化合物10-14，收率为81.0％。
化合物10-14的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.36(s,1H),7.57(dd,J＝7.5,1.5Hz,1H),7.49(dd,J＝7.6,1.5Hz,1H),7.45-7.35(m,2H),6.51(d,J＝17.6Hz,1H),5.71(s,1H),5.37(s,1H),4.64(s,2H),4.21(dd,J＝25.3,9.3Hz,1H),4.02–3.85(m,2H),3.74(dd,J＝12.4,3.0Hz,1H),3.38(s,3H),2.95(s,3H),1.01(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ160.92,152.43,149.77,139.96,132.10,130.51,129.09,128.40,128.22,121.75,117.05,102.60,100.80,96.90,89.55,88.6,88.20,87.40,82.56,72.46,70.94,70.76,59.40,58.46,21.42,16.88,16.63.
21、化合物10-4的制备。
参照上述方法制备得到43.8mg化合物10-15，收率为86.6％。
化合物10-15的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.25(s,1H),7.57–7.42(m,2H),7.09–6.94(m,2H),6.50(d,J＝17.8Hz,1H),5.71(d,J＝7.1Hz,1H),5.34(t,J＝5.0Hz,1H),4.23-4.13(m,1H),4.01–3.86(m,2H),3.81(s,3H),3.75-3.70(m,1H),2.92(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.03,159.97,152.48,149.72,132.93,129.45,117.26,114.98,114.85,102.60,100.81,97.28,91.95,88.51,88.12,82.53,81.84,71.02,70.84,59.47,55.77,21.30,16.85,16.60.
22、化合物10-16的制备。
参照上述方法制备得到47.6mg化合物10-16，收率为94.1％。
化合物10-16的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.30(s,1H),7.36(t,J＝8.0Hz,1H),7.14(dt,J＝7.7,1.0Hz,1H),7.09(dd,J＝2.6,1.4Hz,1H),7.02(ddd,J＝8.4,2.7,1.0Hz,1H),6.50(d,J＝17.8Hz,1H),5.71(d,J＝7.1Hz,1H),5.35(t,J＝5.0Hz,1H),4.19(dt,J＝25.5,8.2Hz,1H),4.01–3.86(m,2H),3.80(s,3H),3.76-3.71(m,1H),2.93(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.07,159.73,152.56,149.77,130.49,130.05,123.97,123.75,117.24,116.21,115.47,102.59,100.80,96.81,91.85,88.54,88.16,83.24,82.56,71.02,70.84,59.47,55.72,21.35,16.86,16.61.
23、化合物10-17的制备。
参照上述方法制备得到48.4mg化合物10-17，收率为85.5％。
化合物10-17的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.41(s,1H),7.76(dd,J＝8.0,1.2Hz,1H),7.67(dd,J＝7.7,1.7Hz,1H),7.47(td,J＝7.6,1.2Hz,1H),7.36(td,J＝7.7,1.7Hz,1H),6.51(d,J＝17.6Hz,1H),5.71(d,J＝7.1Hz,1H),5.38(t,J＝4.9Hz,1H),4.26-4.16(m,1H),4.02–3.84(m,2H),3.77-3.77(m,1H),2.96(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.09,152.61,149.83,133.72,133.05,130.98,130.74,128.39,124.90,124.65,117.04,102.59,100.80,96.39,90.32,88.63,88.25,87.71,82.57,70.93,70.76,59.39,55.35,21.77,16.88,16.64.
24、化合物10-18的制备。
参照上述方法制备得到44.0mg化合物10-18，收率为89.6％。
化合物10-18的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.33(s,1H),7.53-7.47(m,1H),7.41(d,J＝8.4Hz,2H),7.35–7.23(m,1H),6.51(d,J＝17.7Hz,1H),5.71(d,J＝7.1Hz,1H),5.35(t,J＝5.1Hz,1H),4.19(dt,J＝25.6,8.3Hz,1H),4.04–3.85(m,2H),3.74(dt,J＝12.6,4.0Hz,1H),2.93(s,3H),1.00(d,J＝22.3Hz,3H).13CNMR(101MHz,DMSO)δ163.64,161.21,161.12,152.63,149.79,131.50,131.41,130.44,127.75,127.72,124.92,124.82,117.97,117.75,117.24,116.52,116.31,102.59,100.80,96.41,90.67,90.63,88.58,88.19,84.52,82.58,70.99,70.81,59.45,21.46,16.86,16.61.
25、化合物10-19的制备。
参照上述方法制备得到化合物10-19，收率为74％。
化合物10-19的表征数据为：1H NMR(400MHz,DMSO)δ8.78(s,1H),8.34(s,1H),7.78(t,J＝7.9Hz,1H),7.60(dd,J＝9.5,1.6Hz,1H),7.35(dd,J＝8.3,1.6Hz,1H),6.50(d,J＝17.7Hz,1H),5.70(d,J＝7.1Hz,1H),5.34(t,J＝4.8Hz,1H),4.25–4.10(m,1H),4.01–3.82(m,2H),3.78–3.65(m,1H),2.91(s,3H),0.98(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.15,159.84,157.40,152.68,149.81,134.54,130.68,129.10,129.06,124.33,124.24,119.29,119.06,117.18,109.37,109.16,102.60,100.80,96.22,89.97,89.94,88.60,88.21,85.57,82.59,70.98,70.80,59.44,21.51,16.86,16.61.
26、化合物10-20的制备。
参照上述方法制备得到化合物10-20，收率为58％。
化合物10-20的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.63(d,J＝4.8Hz,1H),8.42(s,1H),7.87(t,J＝7.8Hz,1H),7.63(d,J＝7.8Hz,1H),7.50–7.36(m,1H),6.51(d,J＝17.5Hz,1H),5.72(d,J＝7.0Hz,1H),5.39(d,J＝5.1Hz,1H),4.21(dt,J＝25.6,8.3Hz,1H),4.05–3.82(m,2H),3.75(d,J＝12.6Hz,1H),2.95(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.15,152.67,150.69,149.85,142.94,137.29,131.14,127.18,123.84,117.28,102.62,100.82,96.01,91.90,88.22,82.77,82.61,70.93,70.76,59.41,21.42,16.86,16.62.
27、化合物10-21的制备。
参照上述方法制备得到化合物10-21，收率为41％。
化合物10-21的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.40(s,1H),7.78(d,J＝4.0Hz,1H),7.47(d,J＝4.0Hz,1H),6.50(d,J＝17.5Hz,1H),5.71(d,J＝7.1Hz,1H),5.35(t,J＝5.0Hz,1H),4.34-4.29(m,2H),4.19(dt,J＝25.5,8.3Hz,1H),4.05–3.84(m,2H),3.74(dt,J＝12.7,3.9Hz,1H),2.89(s,3H),1.31(t,J＝7.1Hz,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.07,161.04,152.74,149.87,134.37,134.03,133.23,131.08,129.03,117.14,102.59,100.79,95.74,90.09,88.62,88.24,84.47,82.64,70.97,70.79,61.85,59.47,21.39,16.86,16.61,14.60.
28、化合物10-22的制备。
参照上述方法制备得到化合物10-22，收率为89％。
化合物10-22的表征数据为：1H NMR(400MHz,DMSO)δ8.77(s,1H),8.29(s,1H),7.33(dd,J＝17.6,10.4Hz,3H),7.23(d,J＝6.8Hz,1H),6.49(d,J＝17.7Hz,1H),5.71(d,J＝7.1Hz,1H),5.36(t,J＝4.7Hz,1H),4.31–4.04(m,1H),4.05–3.84(m,2H),3.83–3.65(m,1H),2.92(s,3H),2.33(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ160.67,152.16,149.37,138.28,131.27,129.52,128.82,128.06,122.39,116.84,111.13,102.22,100.43,99.60,96.54,91.65,88.13,87.75,82.69,82.16,70.57,70.40,59.04,20.96,20.83,16.46,16.22.
29、化合物10-23的制备。
参照上述方法制备得到化合物10-23，收率为78％。
化合物10-23的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.33(s,1H),7.72–7.60(m,2H),7.55–7.44(m,2H),6.50(d,J＝17.7Hz,1H),5.73(d,J＝7.1Hz,1H),5.37(t,J＝4.9Hz,1H),4.24-4.14(m,1H),4.02–3.82(m,2H),3.76-3.71(m,1H),2.92(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ160.67,152.21,149.36,132.80,131.98,129.89,122.05,121.74,116.77,102.20,100.41,96.16,90.46,88.14,87.75,84.34,82.16,70.55,70.37,59.03,21.02,16.46,16.21.
30、化合物10-24的制备。
参照上述方法制备得到化合物10-24，收率为80％。
化合物10-24的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.34(s,1H),7.75(d,J＝2.1Hz,1H),7.70–7.49(m,2H),7.41(t,J＝7.9Hz,1H),6.50(d,J＝17.7Hz,1H),5.73(d,J＝7.1Hz,1H),5.37(s,1H),4.19(dt,J＝26.1,7.5Hz,1H),3.94(dd,J＝23.5,10.9Hz,2H),3.74(d,J＝12.4Hz,1H),2.93(s,3H),0.99(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ160.74,152.25,149.38,133.06,131.70,131.01,130.15,130.02,124.76,121.90,116.80,102.21,100.42,95.99,89.91,88.17,87.79,84.56,82.18,70.57,70.39,59.05,21.09,16.48,16.23.
31、化合物10-25的制备。
参照上述方法制备得到化合物10-25，收率为72％。
化合物10-25的表征数据为：1H NMR(400MHz,DMSO)δ8.78(s,1H),8.38(s,1H),7.80–7.67(m,1H),7.62–7.45(m,2H),6.49(d,J＝17.6Hz,1H),5.82–5.67(m,1H),5.39(t,J＝4.6Hz,1H),4.34–4.05(m,1H),4.05–3.83(m,2H),3.73(dd,J＝8.0,3.1Hz,1H),2.90(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ162.94,162.83,160.73,160.42,156.01,152.31,150.75,149.43,141.10,134.07,132.86,130.38,128.32,128.29,124.44,122.42,122.32,119.58,119.34,116.72,113.31,110.53,110.38,102.23,100.44,99.60,95.76,89.43,88.20,87.81,84.13,82.20,70.51,70.33,59.00,55.00,20.92,16.48,16.23.
32、化合物10-26的制备。
参照上述方法制备得到化合物10-6，收率为69％。
化合物10-26的表征数据为：1H NMR(400MHz,DMSO)δ8.79(s,1H),8.40(s,1H),7.74(t,J＝7.7Hz,1H),7.43(d,J＝7.7Hz,1H),7.27(d,J＝7.8Hz,1H),6.50(d,J＝17.6Hz,1H),5.72(d,J＝7.1Hz,1H),5.37(t,J＝4.8Hz,1H),4.28–4.13(m,1H),4.03–3.86(m,2H),3.82–3.67(m,1H),2.91(d,J＝17.5Hz,3H),2.50(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.14,159.17,152.65,149.84,142.17,137.48,131.09,130.12,124.33,123.34,117.22,102.62,100.83,96.14,91.97,88.57,82.61,82.27,70.94,70.76,59.42,24.47,21.39,16.85,16.60.MS(ESI+)m/z:397.2(M+H+).
33、化合物10-27的制备。
参照上述方法制备得到化合物10-27，收率为82.6％。
化合物10-27的表征数据为：收率:61％。1H NMR(400MHz,DMSO)δ8.78(s,1H),8.44(s,2H),7.74(d,J＝7.7Hz,1H),7.31(dd,J＝7.6,4.7Hz,1H),6.50(d,J＝17.5Hz,1H),5.73(d,J＝7.1Hz,1H),5.40(s,1H),4.32–4.12(m,1H),3.94(dd,J＝23.2,9.7Hz,2H),3.74(d,J＝12.1Hz,1H),2.94(s,2H),2.49(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.04,152.63,149.87,147.96,142.69,137.81,135.74,131.42,130.11,123.58,117.06,102.62,100.83,96.22,90.69,88.60,88.22,86.26,82.60,70.89,70.72,59.37,21.58,19.43,16.87,16.62.MS(ESI+)m/z:397.2(M+H+).
34、化合物10-28的制备。
参照上述方法制备得到化合物10-28，收率为67％。
化合物10-28的表征数据为：1H NMR(400MHz,DMSO)δ8.79(s,1H),8.46(d,J＝5.0Hz,1H),8.40(s,1H),7.47(s,1H),7.24(d,J＝4.9Hz,1H),6.50(d,J＝17.6Hz,1H),5.71(d,J＝7.1Hz,1H),5.37(t,J＝4.8Hz,1H),4.29–4.11(m,1H),4.01–3.84(m,2H),3.74(ddd,J＝12.4,4.7,3.0Hz,1H),2.94(s,3H),2.35(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ161.15,152.67,150.38,149.86,148.12,142.77,131.08,127.73,124.70,117.24,102.63,100.84,96.10,91.98,88.59,88.21,82.62,82.33,70.92,70.74,59.39,21.43,20.69,16.86,16.62.MS(ESI+)m/z:397.2(M+H+).
35、化合物10-29的制备。
参照上述方法制备得到化合物10-29，收率为78％。
化合物10-29的表征数据为：1H NMR(400MHz,DMSO)δ8.79(s,1H),8.40(s,1H),7.86–7.72(m,1H),7.24(d,J＝7.2Hz,1H),6.86(d,J＝8.3Hz,1H),6.50(d,J＝17.7Hz,1H),5.70(d,J＝7.1Hz,1H),5.36(t,J＝4.8Hz,1H),4.28–4.12(m,1H),4.01–3.92(m,1H),3.88(s,3H),3.78–3.69(m,1H),2.94(s,3H),1.00(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ163.88,161.15,152.68,149.87,140.08,139.97,130.96,120.65,111.55,102.62,100.83,96.05,91.79,88.59,88.20,82.66,82.63,70.98,70.81,59.47,53.71,21.37,16.86,16.61.MS(ESI+)m/z:413.2(M+H+).
36、化合物10-4的制备。
参照上述方法制备得到化合物10-30，收率为57％。
化合物10-30的表征数据为：1H NMR(400MHz,DMSO)δ8.76(s,1H),8.31(s,1H),7.53(d,J＝5.1Hz,1H),7.01(d,J＝5.1Hz,1H),6.49(d,J＝17.7Hz,1H),5.71(d,J＝7.0Hz,1H),5.34(s,1H),4.29–4.06(m,1H),3.93(dd,J＝24.1,10.6Hz,2H),3.73(d,J＝12.3Hz,1H),2.89(s,3H),2.35(s,3H),0.99(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ160.95,152.56,149.80,142.83,130.26,130.15,127.75,117.86,102.60,100.80,96.78,89.02,88.56,88.17,84.74,82.57,71.01,70.84,59.49,55.34,21.36,16.87,16.62,15.26.MS(ESI+)m/z:402.4(M+H+).
37、化合物10-31的制备。
参照上述方法制备得到化合物10-31，收率为63％。
化合物10-31的表征数据为：1H NMR(400MHz,DMSO)δ8.76(s,1H),8.28(s,1H),7.22(d,J＝3.4Hz,1H),6.83(d,J＝2.6Hz,1H),6.48(d,J＝17.7Hz,1H),5.69(d,J＝7.1Hz,1H),5.33(t,J＝4.7Hz,1H),4.29–4.08(m,1H),4.03–3.81(m,2H),3.73(dd,J＝8.1,3.4Hz,1H),2.86(s,3H),2.47(s,3H),0.98(d,J＝22.4Hz,3H).13C NMR(101MHz,DMSO)δ160.99,152.58,149.79,142.71,132.86,129.99,126.68,120.04,102.61,100.81,96.65,88.54,88.15,86.24,85.48,82.59,70.99,70.82,59.48,21.25,16.84,16.59,15.47.MS(ESI+)m/z:402.3(M+H+).
38、化合物10-32的制备。
参照上述方法制备得到化合物10-32，收率为55％。
化合物10-32的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.29(s,1H),7.56(d,J＝5.6Hz,2H),7.44(d,J＝5.2Hz,3H),6.51(d,J＝17.6Hz,1H),5.71(d,J＝6.4Hz,1H),5.35(s,1H),4.24–4.13(m,1H),3.97–3.88(m,2H),3.74-3.71(m,1H),2.92(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(125MHz,DMSO-d6)δ160.5,152.0,149.2,130.8,129.5,128.8,128.6,122.4,116.7,100.4(d,JC-F＝180Hz),96.3,91.4,87.7(d,J＝40Hz),82.9,82.0,0.3(d,J＝17Hz),58.9,30.6,20.8,16.1(d,J＝25Hz).MS(ESI+)m/z:382.2(M+H+).
39、化合物10-33的制备。
参照上述方法制备得到化合物10-33，收率为82.6％。
化合物10-33的表征数据为：MS(ESI+)m/z:478.1(M+H+).
40、化合物10-34的制备。
参照上述方法制备得到化合物10-34，收率为46.3％。
化合物10-34的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.34(s,1H),7.73–7.61(m,2H),7.42(d,J＝8.4Hz,1H),6.50(d,J＝17.8Hz,1H),5.72(d,J＝7.1Hz,1H),5.37(s,1H),4.27–4.09(m,1H),4.05–3.85(m,2H),3.81–3.68(m,1H),2.91(s,3H),0.98(d,J＝22.1Hz,3H).MS(ESI+)m/z:434.1(M+H+).
41、化合物10-35的制备。
参照上述方法制备得到化合物10-35，收率为51.0％。
化合物10-35的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.37(s,1H),8.05–7.88(m,2H),7.76(d,J＝8.3Hz,1H),6.50(d,J＝17.6Hz,1H),5.73(d,J＝7.2Hz,1H),5.36(s,1H),4.27–4.10(m,1H),4.01–3.83(m,2H),3.73(d,J＝13.6Hz,1H),2.92(s,3H),0.98(d,J＝22.4Hz,3H).MS(ESI+)m/z:528.0(M+H+).
42、化合物10-36的制备。
参照上述方法制备得到化合物10-36，收率为55.7％。
化合物10-36的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.36(s,1H),7.50(d,J＝8.1Hz,2H),6.49(d,J＝17.8Hz,1H),5.73(d,J＝7.2Hz,1H),5.37(s,1H),4.24–4.07(m,1H),4.03–3.85(m,2H),3.78–3.65(m,1H),2.90(s,3H),0.98(d,J＝22.1Hz,3H)..MS(ESI+)m/z:496.0(M+H+).
实施例2
1、化合物12的制备。
按照以下线路合成：
氩气保护下，在10ml的双口瓶中加入化合物8-1(50mg,0.13mmol)、化合物11(39.6mg,0.2mmol)、DMSO(3ml)置于室温搅拌，接着加入Pd(dppf)Cl2(15mg,0.013mmol)、KOAc(120mg,0.45mmol)的水溶液(0.3ml),加完后将体系加热至80℃搅拌1h后，降至室温，加入EA，洗涤，干燥，过滤，浓缩，过柱分离纯化得白色固体12。
2、化合物12-1的制备。
参照上述方法制备得到化合物12-1，收率为54.5％。
化合物12-1的表征数据为：收率54.5％.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.65–7.49(m,1H),6.41(d,J＝18.3Hz,1H),5.62(d,J＝7.2Hz,1H),5.27(t,J＝5.1Hz,1H),4.15(ddd,J＝25.9,9.4,7.2Hz,1H),3.96–3.80(m,2H),3.68(ddd,J＝12.4,5.1,3.1Hz,1H),2.86(s,3H),2.06(tt,J＝8.3,5.0Hz,1H),0.89(d,J＝22.3Hz,3H),0.69–0.47(m,2H).13C NMR(101MHz,DMSO)δ160.03,151.38,150.52,122.33,118.68,117.80,102.62,100.83,88.09,87.70,82.20,71.08,70.91,59.50,22.60,16.77,16.52,7.96,7.34,6.98.MS(ESI+)m/z:322.4(M+H+).
3、化合物12-2的制备。
参照上述方法制备得到化合物12-2，收率为40.7％。
化合物12-2的表征数据为：1H NMR(400MHz,Chloroform-d)δ8.67(s,1H),7.30(td,J＝7.6,2.1Hz,2H),7.24–7.06(m,4H),6.30(dd,J＝19.7,12.9Hz,1H),4.75–4.45(m,1H),4.17(d,J＝12.4Hz,1H),4.09(d,J＝9.2Hz,1H),4.04–3.90(m,1H),2.28(dt,J＝7.1,3.6Hz,1H),2.14–1.94(m,1H),1.39(t,J＝7.1Hz,2H),1.10(d,J＝22.7Hz,3H).13C NMR(101MHz,CDCl3)δ160.69,150.94,150.00,149.95,141.56,128.58,126.01,125.46,123.24,118.61,118.15,102.64,100.87,91.09,82.46,72.13,71.95,60.23,29.69,26.08,25.99,22.29,19.89,16.74,16.70,16.49,16.45,16.40,16.37.MS(ESI+)m/z:398.5(M+H+).
4、化合物12-3的制备。
参照上述方法制备得到化合物12-3，收率为30.9％。
化合物12-3的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.87(d,J＝4.9Hz,2H),8.76(s,1H),8.65(s,1H),7.38(t,J＝4.9Hz,1H),6.60(d,J＝18.0Hz,1H),5.70(d,J＝7.1Hz,1H),5.31(t,J＝4.8Hz,1H),4.27-4.17(m,1H),3.97(d,J＝9.4Hz,1H),3.98-3.88(m,1H),3.74-3.68(m,1H),2.99(s,3H),0.99(d,J＝22.2Hz,3H).13C NMR(101MHz,DMSO)δ161.41,161.37,157.33,151.24,150.87,129.38,118.76,116.65,114.82,102.13,100.33,88.06,87.67,81.88,70.54,70.37,58.72,25.46,16.44,16.19.
5、化合物12-4的制备。
参照上述方法制备得到40.6mg化合物12-4，收率为88.7％。
化合物12-4的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.98(s,1H),7.76(t,J＝8.4Hz,4H),7.61(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,2H),7.39(t,J＝7.4Hz,1H),6.58(d,J＝18.2Hz,1H),5.66(d,J＝7.1Hz,1H),5.24(s,1H),4.37–4.14(m,1H),3.96(d,J＝9.4Hz,1H),3.88(d,J＝12.4Hz,1H),3.70(d,J＝12.4Hz,1H),2.54(s,3H),1.03(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO)δ160.03,151.38,150.52,122.33,118.68,117.80,102.62,100.83,88.09,87.70,82.20,71.08,70.91,59.50,22.60,16.77,16.52,7.96,7.34,6.98.MS(ESI+)m/z:433.5(M+H+).
6、化合物12-5的制备。
参照上述方法制备得到化合物12-5，收率为70.2％。
化合物12-5的表征数据为：1H NMR(400MHz,MeOD-d4)δ8.62(s,1H),8.07(s,1H),7.10(dd,J＝11.2,10.8Hz,1H),6.59(d,J＝18Hz,1H),5.67(dd,J＝1.2,1.6Hz,1H),5.29(dd,J＝1.6,1.2Hz,1H),4.35(dd,J＝9.2,9.6Hz,1H),4.08–4.04(m,1H),3.89(dd,J＝2.8,2.8Hz,2H),2.82(s,3H),1.05(d,J＝22.4Hz,3H).13C NMR(125MHz,MeOD-d4)δ161.2,151.7,151.6,129.3,123.6,117.6,117.4,115.7,101.6(d,JC-F＝180Hz),89.7(d,J＝39Hz),83.3,72.5(d,J＝18Hz),60.6,22.6,16.4(d,J＝25Hz).MS(ESI+)m/z:308.1(M+H+).
7、化合物12-6的制备。
参照上述方法制备得到化合物12-6，收率为54％。
化合物12-6的表征数据为：1HNMR(400MHz,MeOD-d4)δ8.70(s,1H),7.89(s,1H),7.52(t,J＝6.4Hz,2H),7.22(t,J＝6.8Hz,2H),6.68(d,J＝14.4Hz,1H),4.36(dd,J＝7.6,7.6Hz,1H),4.08(t,J＝4.4Hz,2H),3.88(d,J＝10Hz,1H),2.52(s,3H),1.13(d,J＝18Hz,3H).13CNMR(125MHz,MeOD-d4)δ164.9,162.9,161.3,151.8,151.6,133.0(d,J＝8.1Hz),131.6,131.6,125.7,118.9,117.7,116.0(d,J＝21.6Hz),101.7(d,JC-F＝179Hz),89.7(d,J＝38.6Hz),83.3,72.5(d,J＝17.8Hz),60.5,22.5,16.5(d,J＝25.3Hz).MS(ESI+)m/z:376.3(M+H+).
8、化合物12-7的制备。
参照上述方法制备得到化合物12-7，收率为73％。
化合物12-7的表征数据为：1HNMR(400MHz,MeOD-d4)δ8.73(s,1H),8.03(s,1H),7.79(d,J＝6.4Hz,2H),7.73(d,J＝6.8Hz,1H),6.70(d,J＝14.4Hz,1H),4.38(dd,J＝7.6,7.6Hz,1H),4.09(t,J＝4Hz,2H),3.89(dd,J＝1.6,2Hz,1H),2.56(s,3H),1.15(d,J＝18.4Hz,3H).13CNMR(125MHz,MeOD-d4)δ161.3,152.0,151.9,139.7,131.6,130.4(d,J＝32.3Hz),126.3(d,J＝14Hz),126.2,126.2,124.7(d,JC-F3＝269.5Hz),118.5,117.4,101.7(d,JC-F＝179.4Hz),89.7(d,J＝39.1Hz),83.4,72.5(d,J＝17.8Hz),60.5,22.9,16.5(d,J＝25.3Hz).MS(ESI+)m/z:426.1(M+H+).
9、化合物12-8的制备。
参照上述方法制备得到化合物12-8，收率为40％。
化合物12-8的表征数据为：收率:40％。1HNMR(400MHz,MeOD-d4)δ8.68(s,1H),7.81(s,1H),7.40(d,J＝6.4Hz,2H),7.03(d,J＝6.4Hz,2H),6.68(d,J＝14.4Hz,1H),4.36(dd,J＝7.6,7.6Hz,1H),4.07(t,J＝4.4Hz,2H),3.86(s,4H),2.52(s,3H),1.13(d,J＝18Hz,3H).13CNMR(125MHz,MeOD-d4)δ161.3,160.9,151.6,151.6,132.3,127.5,125.2,119.8,117.9,114.8,101.7(d,JC-F＝179.1Hz),89.7(d,J＝38Hz),83.3,72.6(d,J＝17.9Hz),60.6,55.7,22.4,16.5(d,J＝25.4Hz).MS(ESI+)m/z:388.3(M+H+).
10、化合物12-9的制备。
参照上述方法制备得到化合物12-9，收率为55％。
化合物12-9的表征数据为：1HNMR(400MHz,MeOD-d4)δ8.76(s,1H),8.61(s,2H),8.17(s,1H),7.62(s,2H),6.66(d,J＝14Hz,1H),4.38(dd,J＝7.8,8.2Hz,1H),4.10(d,J＝10Hz,2H),3.90(d,J＝10Hz,1H),2.637(s,3H),1.14(d,J＝18Hz,3H,).13CNMR(125MHz,MeOD-d4)δ161.4,152.2,150.1,145.0,127.2,126.3,117.0,116.9,101.7(d,JC-F＝179.5Hz),89.8(d,J＝38.8Hz),83.5,72.4(d,J＝17.9Hz),60.5,23.2,16.5(d,J＝25.4Hz).MS(ESI+)m/z:359.1(M+H+).
11、化合物12-10的制备。
参照上述方法制备得到化合物12-10，收率为49％。
化合物12-10的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.25(s,1H),7.59(d,J＝7.6Hz,2H),7.50(d,J＝16Hz,1H),7.40(t,J＝7.2Hz,2H),7.29(t,J＝7.2Hz,1H),7.04(d,J＝16Hz,1H),6.53(d,J＝18.4Hz,1H),5.68(d,J＝7.2Hz,1H),5.35(t,J＝4.8Hz,1H),4.29–4.18(m,1H),3.97-3.90(m,2H),3.76–-3.73(m,1H),2.87(s,3H),1.01(d,J＝22.4Hz,3H).13C NMR(125MHz,DMSO-d6)δ206.3,159.8,151.0,150.0,137.0,128.7,127.3,126.1,121.8,119.8,115.5,114.7,100.5(d,JC-F＝180Hz),87.5(d,J＝36Hz),81.9,70.6(d,J＝18Hz),59.2,30.6,23.0,16.1(d,J＝25Hz).MS(ESI+)m/z:384.2(M+H+).
12、化合物12-11的制备。
参照上述方法制备得到化合物12-11。
化合物12-11的表征数据为：1H NMR(500MHz,CDCl3+Methanol-d4)δ9.01(s,1H),8.68(s,2H),8.60(s,1H),7.80(s,1H),6.46(d,J＝17.8Hz,1H),4.18(dd,J＝24.2,9.2Hz,1H),3.98–3.92(m,2H),3.77–3.70(m,1H),3.27(s,br,2H),2.39(s,3H),0.98(d,J＝22.3Hz,3H).13C NMR(101MHz,CDCl3+Methanol-d4)δ159.78,156.84,156.74,151.43,150.60,128.90,125.63,116.10,110.20,101.17(d,J＝180.5Hz),88.96(d,J＝38.7Hz),82.03,71.01(d,J＝18.0Hz),59.19,22.78,16.25(d,J＝25.3Hz).MS(ESI+)m/z:360.1(M+H+).12、化合物12-11的制备。
13、参照上述方法制备得到化合物12-12。
化合物12-12的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.74(s,1H),8.46(s,1H),7.92(d,J＝3.4Hz,1H),7.61(d,J＝3.4Hz,1H),6.64(d,J＝17.2Hz,1H),4.34(dd,J＝24.5,9.1Hz,1H),4.14–4.02(m,2H),3.94–3.83(m,1H),2.85(s,3H),1.09(d,J＝22.2Hz,3H).MS(ESI+)m/z:365.1(M+H+).
14、参照上述方法制备得到化合物12-13。
化合物12-13的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.68(s,1H),8.03(s,1H),7.72(s,1H),6.64(d,J＝18.0Hz,1H),4.89(s,2H),4.32(dd,J＝24.4,9.2Hz,1H),4.13–4.00(m,2H),3.93–3.76(m,1H),2.66(s,3H),1.08(d,J＝22.3Hz,3H).MS(ESI+)m/z:348.1(M+H+).
15、参照上述方法制备得到化合物12-14。
化合物12-14的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.74(s,1H),8.09(s,1H),7.58(d,J＝1.9Hz,1H),6.65(d,J＝17.6Hz,1H),6.44(d,J＝1.9Hz,1H),4.31(dd,J＝24.5,9.4Hz,1H),4.14–4.01(m,2H),3.86(dd,J＝12.5,2.7Hz,1H),3.72(s,3H),2.41(s,3H),1.11(d,J＝22.2Hz,3H).MS(ESI+)m/z:362.1(M+H+).
16、参照上述方法制备得到化合物12-15。
化合物12-15的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.71(s,1H),7.77(s,1H),7.26(d,J＝2.3Hz,1H),6.57(d,J＝18.6Hz,1H),6.19(d,J＝2.2Hz,1H),5.16(s,1H),4.89–4.38(m,2H),4.17–4.01(m,2H),3.83(dd,J＝13.1,2.0Hz,1H),3.73(s,3H),2.69(s,3H),1.11(d,J＝22.7Hz,3H).MS(ESI+)m/z:362.2(M+H+).
16、参照上述方法制备得到化合物12-16。
化合物12-16的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.75(s,1H),8.73(s,1H),6.63(d,J＝17.0Hz,1H),4.31(dd,J＝24.3,9.1Hz,1H),4.15–4.05(m,2H),3.94–3.87(m,1H),3.08(s,3H),2.61(s,3H),1.09(d,J＝22.2Hz,3H).MS(ESI+)m/z:364.1(M+H+).
18、参照上述方法制备得到化合物12-17。
化合物12-17的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.74(s,1H),8.59(s,1H),7.96(d,J＝0.9Hz,1H),7.29(d,J＝1.0Hz,1H),6.65(d,J＝17.5Hz,1H),4.33(dd,J＝24.4,9.2Hz,1H),4.16–4.04(m,2H),3.89(dd,J＝13.1,3.2Hz,1H),3.05(s,3H),1.08(d,J＝22.2Hz,3H).MS(ESI+)m/z:349.1(M+H+).
19、参照上述方法制备得到化合物12-18。
化合物12-18的表征数据为：1H NMR(400MHz,Methanol-d4)δ9.04(s,1H),8.71(s,1H),8.58(s,1H),6.63(dd,J＝17.4,1.8Hz,1H),4.28(dd,J＝24.1,9.1Hz,1H),4.18–4.02(m,2H),3.96–3.83(m,1H),3.03(s,3H),1.09(d,J＝22.2Hz,3H).MS(ESI+)m/z:350.1(M+H+).
20、参照上述方法制备得到化合物12-19。
化合物12-19的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.74(s,1H),8.56(s,1H),6.66(d,J＝17.6Hz,1H),4.31(dd,J＝24.2,9.2Hz,1H),4.17–4.07(m,2H),3.91(dd,J＝12.9,3.1Hz,1H),3.05(s,3H),2.66(s,3H),1.10(d,J＝22.2Hz,3H).MS(ESI+)m/z:364.1(M+H+).
21、参照上述方法制备得到化合物12-20。
化合物12-20的表征数据为：1H NMR(400MHz,DMSO-d6)δ18.74(s,1H),18.64(d,J＝2.1Hz,1H),18.01(d,J＝7.4Hz,2H),17.64–17.46(m,3H),16.40(d,J＝17.1Hz,1H),15.57(d,J＝7.1Hz,1H),15.33(t,J＝4.4Hz,1H),14.17–13.98(m,1H),13.87–13.75(m,2H),13.63–13.51(m,1H),12.84(s,2H),10.83(d,J＝22.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ174.48,164.47,160.97,151.94,150.80,133.45,129.63,128.60,127.99,123.32,114.34,102.62,101.34(d,J＝180.8Hz),88.04(d,J＝38.9Hz),82.10,70.10(d,J＝17.3Hz),58.55,24.14,16.31(d,J＝24.9Hz).MS(ESI+)m/z:426.1(M+H+).
实施例3
1、化合物13的制备。
在100ml的烧瓶中，加入6(4.5g)和约50ml NH3的甲醇溶液，室温搅拌过夜。TLC显示反应完全，减压浓缩后，过柱得2.5g白色泡状固体，即为化合物13，收率96.6％.
化合物13的表征数据为：1HNMR(400MHz,D2O)δ8.56(s,1H),7.60(d,J＝3.6Hz,1H),6.77(d,J＝3.2Hz,1H),6.23(d,J＝6.4Hz,1H),4.71(t,J＝5.6Hz,1H),4.39(q,J＝1.6,1.6Hz,1H),4.24(d,J＝3.2Hz,1H),3.84–3.80(m,2H),2.66(s,3H).13CNMR(125MHz,MeOD-d4)δ160.9,151.7,151.4,127.4,119.6,101.8,101.7(d,JC-F＝179.4Hz),89.9(d,J＝38.4Hz),83.3,72.7(d,J＝18Hz),60.8,20.9,16.4(d,J＝25.4Hz).MS(ESI+)m/z:382.1(M+H+).
2、化合物14的制备。
I2(676.7mg，2.67mmol，1.5eq)加入PPh3(746.0mg，2.84mmol，1.6eq)和无水THF(10ml)，室温搅拌20min后，加入化合物13(500mg，1.78mmol)，继续室温搅拌过夜。减压浓缩干，过柱得白色固体591mg(化合物14)，收率：84.9％。
化合物14的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.72(d,J＝3.8Hz,1H),6.84(d,J＝3.7Hz,1H),6.49(d,J＝20.3Hz,1H),5.97(d,J＝6.9Hz,1H),4.02(q,J＝7.2Hz,1H),3.88(t,J＝7.3Hz,1H),3.70(dd,J＝11.1,2.7Hz,1H),3.59(dd,J＝11.1,7.3Hz,1H),2.67(s,3H),0.96(d,J＝22.6Hz,3H).MS(ESI+)m/z:292.0(M+H+).
3、化合物15的制备。
化合物14(600mg，1.53mmol)加入12ml乙腈中，然后加入DBU(233mg，1eq)，加热回流4h，减压浓缩后加EA和水，萃取，有机相干燥，减压浓缩，过柱得320mg白色固体(化合物15)，收率：79.2％.
化合物15的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.77(d,J＝1.6Hz,1H),7.13–6.97(m,1H),6.73–6.57(m,2H),4.98–4.80(m,1H),4.71(q,J＝2.0Hz,1H),4.54(q,J＝1.8Hz,1H),3.04(d,J＝9.4Hz,1H),2.73(d,J＝1.7Hz,3H),1.20(dd,J＝22.5,1.6Hz,3H).13C NMR(126MHz,CDCl3)δ160.55,160.17,151.85,150.25,124.11,118.31,101.67,99.71,98.27,89.19,88.89,85.34,73.46,73.31,21.47,16.11,15.91.MS(ESI+)m/z:264.6(M+H+).
4、化合物16的制备。
化合物15(420mg，1.60mmol)加入乙腈(10ml)中，置于0℃下搅拌，依次加入NIS(432.0mg，1.92mmol，1.2eq)和ZH或ZNa(1.2eq)，然后室温搅拌2h，加入饱和Na2SO3淬灭，然后加EA萃取，有机相干燥浓缩，过柱得白色固体(化合物16)。
5、化合物16-1的制备。
参照上述方法制备得到化合物16-1，收率：36.7％
化合物,16-1的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.72(s,1H),7.73(d,J＝3.8Hz,1H),6.87(d,J＝3.7Hz,1H),6.71(d,J＝18.9Hz,1H),6.27(d,J＝8.7Hz,1H),3.86–3.65(m,2H),2.68(s,3H),1.03(d,J＝22.6Hz,3H).13C NMR(126MHz,DMSO)δ160.21,151.59,150.11,118.47,114.97,113.11,101.74,100.56,99.09,75.16,75.03,74.98,74.85,21.58,17.85,17.65,5.31,5.05.MS(ESI+)m/z:410.4(M+H+).
6、化合物18的制备。
将化合物16(1eq)和吡啶(2eq)加入DCM中，室温搅拌下加入BzCl(1.2eq)，继续室温搅拌2h后，加水萃取，干燥有机相，减压浓缩得棕色粘稠物化合物17，无需过柱，将粗品化合物17、BzONa(3eq)、15-冠-5(3eq)加入DMF中，加热至95度搅拌过夜，冷却至室温后，加EA和水萃取，有机相干燥、减压浓缩，过柱得白色固体(化合物18)。
7、化合物18-1的制备。
参照上述方法制备得到化合物18-1。
化合物18-1的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.03(d,J＝7.7Hz,2H),7.88(d,J＝3.7Hz,1H),7.74(dd,J＝22.5,7.6Hz,3H),7.56(q,J＝8.0Hz,3H),7.25(t,J＝7.7Hz,2H),6.97(d,J＝19.2Hz,1H),6.89–6.70(m,2H),4.90(dd,J＝18.1,12.1Hz,1H),4.78(t,J＝11.2Hz,1H),2.68(s,3H),1.22(d,J＝22.8Hz,3H).13C NMR(126MHz,DMSO)δ165.21,165.09,160.58,151.56,149.86,134.66,134.03,130.15,129.65,129.60,129.42,129.36,129.14,128.98,128.93,128.68,128.60,127.31,119.00,114.75,112.86,101.49,99.44,97.95,74.63,74.51,74.47,74.36,64.17,63.90,21.66,18.00,17.80.MS(ESI+)m/z:508.3(M+H+).
8、化合物19的制备。
将化合物18(1eq)溶于DMF，搅拌下加入NIS(2eq)，加热至70℃搅拌5h，降至室温后，加EA和亚硫酸钠溶液搅拌3min，分液，将有机相干燥、浓缩，过柱得白色固体(化合物19)。
9、化合物19-1的制备。
参照上述方法制备得到化合物19-1。
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化合物19-1的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.65(s,1H),8.10(td,J＝8.2,1.4Hz,4H),7.67–7.57(m,3H),7.49(td,J＝7.7,6.0Hz,4H),6.64(d,J＝18.4Hz,1H),5.89(dd,J＝22.0,9.4Hz,1H),4.91(dd,J＝12.7,2.8Hz,1H),4.81–4.71(m,1H),4.62(dd,J＝12.7,3.9Hz,1H),1.21(d,J＝22.4Hz,3H).MS(ESI+)m/z:634.4(M+H+).
10、化合物20的制备。
将化合物19(1eq)加入NH3的甲醇溶液，室温搅拌过夜，减压浓缩后，过柱纯化得白色固体(化合物20)。
11、化合物20-1的制备。
参照上述方法制备得到化合物20-1。
化合物20-1的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.73(s,1H),7.95(s,1H),6.76(d,J＝17.2Hz,1H),6.05(d,J＝8.6Hz,1H),5.81(s,1H),4.41(s,1H),3.82–3.60(m,2H),2.89(s,3H),1.01(d,J＝22.3Hz,3H).13C NMR(126MHz,DMSO)δ160.68,151.89,149.99,130.92,130.55,128.63,127.89,118.18,118.06,116.21,99.83,98.36,89.35,71.74,59.78,59.44,55.63,55.35,21.02,17.48,17.28.MS(ESI+)m/z:426.2(M+H+).
12、化合物21的制备。
化合物21的合成方法同上述化合物10或者化合物12.
13、化合物21-1的制备。
参照上述方法制备得到化合物21-1。
化合物21-1的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.80(s,1H),8.14(s,1H),7.77(t,J＝7.9Hz,1H),7.58(d,J＝9.5Hz,1H),7.34(d,J＝8.3Hz,1H),6.81(d,J＝16.9Hz,1H),6.09(d,J＝8.6Hz,1H),5.84(s,1H),4.45(s,1H),3.74(q,J＝5.1Hz,2H),2.91(s,3H),1.05(d,J＝22.4Hz,3H).13C NMR(126MHz,DMSO)δ161.35,159.58,157.62,152.89,149.95,134.52,130.09,129.08,129.06,124.16,124.09,119.26,119.07,118.15,117.12,116.29,109.45,109.29,99.88,98.41,96.88,90.23,90.20,89.74,85.20,71.77,59.84,59.50,21.51,17.48,17.28.MS(ESI+)m/z:496.0(M+H+).
14、化合物21-2的制备。
参照上述方法制备得到化合物21-2。
化合物21-2的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.74(s,1H),7.69(s,1H),7.51(t,J＝7.5Hz,1H),7.20(dd,J＝9.0,2.1Hz,1H),7.12(d,J＝8.2Hz,1H),6.65(s,1H),4.64(d,J＝22.2Hz,1H),4.42(s,1H),4.10(d,J＝12.0Hz,1H),3.96(dd,J＝12.4,5.6Hz,1H),2.96(s,3H),1.87(s,1H),1.15(d,J＝22.7Hz,3H).13C NMR(126MHz,CDCl3)δ162.04,159.77,157.79,152.40,149.38,133.71,132.12,128.64,127.89,127.87,127.32,123.79,123.72,118.84,118.65,109.90,109.73,100.66,99.21,98.32,97.99,90.63,90.60,83.56,73.12,72.98,62.51,21.23,17.40,17.19.MS(ESI+)m/z:519.2(M+H+).
实施例4
1、化合物23的制备。
Ar保护下，化合物21(1eq)溶于无水THF中，置于0℃下搅拌，慢慢加入t-BuMgCl(2eq)，加完后维持0℃搅拌20min后，滴加化合物22(1eq)的THF(2ml)溶液，恢复至室温搅拌过夜，加1ml甲醇淬灭反应，减压浓缩后过柱得白色固体(化合物23).
2、化合物23-1的制备。
参照上述方法制备得到化合物23-1。
化合物23-1的表征数据为：1H NMR(400MHz,DMSO)δ8.78(s,1H),8.12(s,1H),7.75(t,J＝7.9Hz,1H),7.42(dd,J＝9.4,1.5Hz,1H),7.32(t,J＝7.8Hz,2H),7.23(d,J＝8.2Hz,3H),7.15(t,J＝7.2Hz,1H),6.53(d,J＝18.9Hz,1H),6.03(dd,J＝12.8,10.2Hz,1H),5.88(d,J＝7.0Hz,1H),4.78(dt,J＝12.5,6.2Hz,1H),4.44(dd,J＝10.4,6.1Hz,1H),4.37-4.23(m,2H),4.16-4.12(m,1H),3.91–3.72(m,1H),2.91(s,3H),1.21(d,J＝7.1Hz,3H),1.09(dd,J＝13.0,6.3Hz,6H),1.03(d,J＝22.6Hz,3H).13C NMR(101MHz,DMSO)δ172.67,172.62,160.81,159.36,156.91,152.31,150.74,150.68,149.44,134.05,130.55,129.61,128.55,128.52,124.61,123.90,123.81,120.25,120.20,118.74,118.50,116.76,108.90,108.69,101.67,99.87,96.24,89.63,89.61,88.70,88.28,84.99,79.97,79.89,71.70,71.52,67.98,65.13,49.88,21.36,21.08,19.87,19.80,16.45,16.20.MS(ESI+)m/z:747.3(M+H+).
2、化合物23-2的制备。
参照上述方法制备得到化合物23-2。
化合物23-2的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),7.71(s,1H),7.47(t,J＝7.7Hz,1H),7.24-7.30(m,4H),7.14(t,J＝7.2Hz,1H),7.09(d,J＝9.1Hz,1H),7.03(d,J＝8.3Hz,1H),6.61(d,J＝18.2Hz,1H),4.62(dd,J＝12.1,6.8Hz,1H),4.56–4.41(m,1H),4.35–4.15(m,2H),4.15–3.97(m,4H),3.92(dd,J＝11.1,5.7Hz,1H),2.97(s,3H),1.41-1.46(m,1H),1.38(d,J＝6.3Hz,3H),1.22-1.28(m,4H),1.12(d,J＝22.5Hz,3H),0.78-0.82(m,6H).13C NMR(126MHz,CDCl3)δ173.91,173.85,161.44,159.82,157.85,152.63,150.53,150.48,149.98,133.67,129.97,128.90,128.02,128.00,125.40,124.26,124.19,120.25,120.21,118.94,118.76,117.72,109.63,109.46,101.88,100.44,97.84,90.18,90.16,89.03,88.72,84.55,80.16,80.10,72.44,72.30,67.96,64.79,50.52,40.27,23.26,23.21,21.39,21.21,21.17,16.55,16.35,11.02,10.97.MS(ESI+)m/z:789.5(M+H+).
3、化合物23-3的制备。
参照上述方法制备得到化合物23-3。
化合物23-3的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.13(s,1H),7.72(dd,J＝9.3,1.9Hz,1H),7.51–7.39(m,2H),7.37–7.28(m,2H),7.28–7.19(m,2H),7.14(t,J＝7.3Hz,1H),6.52(d,J＝19.2Hz,1H),6.02(dd,J＝13.1,10.0Hz,1H),5.89(d,J＝7.1Hz,1H),4.77(p,J＝6.2Hz,1H),4.49–4.18(m,3H),4.13(t,J＝7.5Hz,1H),3.85–3.74(m,1H),2.90(s,3H),1.26–1.14(m,3H),1.13–0.96(m,9H).13CNMR(101MHz,DMSO)δ173.06,173.01,163.33,161.18,160.81,152.72,151.15,151.09,149.87,134.37,130.09,130.00,129.55,129.21,128.61,128.57,124.98,122.77,122.68,120.62,120.57,119.92,119.68,117.16,110.91,110.75,102.04,100.24,96.62,89.58,89.55,84.64,80.41,80.33,72.24,72.07,68.37,65.76,50.29,21.77,21.26,20.25,20.18,16.90,16.65.
4、化合物23-4的制备。
参照上述方法制备得到化合物23-4。
化合物23-4的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.72(s,1H),7.45(s,1H),7.31(q,J＝8.0Hz,2H),7.22(d,J＝8.2Hz,2H),7.16(t,J＝7.6Hz,2H),6.93(dd,J＝17.4,10.9Hz,1H),6.58(d,J＝19.1Hz,1H),5.59(d,J＝17.4Hz,1H),5.20(d,J＝10.9Hz,1H),4.97-4.93(m,1H),4.64–4.53(m,1H),4.53–4.41(m,1H),4.33(dd,J＝23.2,9.4Hz,1H),4.21(d,J＝9.2Hz,1H),4.03–3.95(m,1H),3.83(t,J＝10.5Hz,1H),2.82(s,3H),1.34(d,J＝7.1Hz,3H),1.19(dd,J＝12.9,6.3Hz,6H),1.12(d,J＝22.6Hz,3H).MS(ESI+)m/z:577.6(M+H+).
5、化合物23-5的制备。
参照上述方法制备得到化合物23-5。
化合物23-5的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.75(s,1H),7.55(s,1H),7.40(d,J＝6Hz,1H),7.32–7.20(m,10H),7.14(t,J＝5.6Hz,1H),6.98(d,J＝12.8Hz,1H),6.65(d,J＝15.2Hz,1H),4.95–4.90(m,1H),4.65–4.61(m,1H),4.50–4.37(m,1H),4.32(d,J＝38.4Hz,1H),4.23(d,J＝6.8Hz,1H),3.99–3.94(m,1H),3.75(t,J＝8.8Hz,1H),3.32(s,1H),2.90(s,3H),1.31(d,J＝5.6Hz,3H),1.18–1.14(m,9H).
13C NMR(125MHz,Chloroform-d)δ202.7,202.7,189.9,180.4,180.3,180.2,167.0,160.2,159.0,158.0,156.9,155.8,154.5,151.4,149.8,149.8,148.4,146.2,146.0,129.6(d,JC-F＝181Hz),109.4(d,J＝7.7Hz),101.8,101.7(d,J＝52.4Hz),98.4,94.7,80.0,51.2,50.2,50.1,48.9,48.8,44.9(d,J＝25Hz).MS(ESI+)m/z:653.1(M+H+).
10、化合物23-6的制备。
参照上述方法制备得到化合物23-6。
化合物23-6的表征数据为：1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.77(d,J＝4.1Hz,2H),8.44(s,1H),7.29–7.22(m,J＝8.1Hz,2H),7.21–7.16(m,J＝7.7Hz,2H),7.16–7.07(m,2H),6.73(d,J＝17.4Hz,1H),5.12(t,J＝9.6Hz,1H),4.96–4.87(m,J＝12.0,5.9Hz,1H),4.67–4.59(m,J＝13.9,7.5Hz,2H),4.41(dd,J＝23.9,8.6Hz,1H),4.33–4.26(m,J＝8.4Hz,1H),4.22–4.08(m,J＝15.8,8.1Hz,1H),3.11(s,3H),2.52(s,1H),1.31(d,J＝6.9Hz,3H),1.22(d,J＝22.5Hz,3H),1.17(s,6H).13C NMR(126MHz,CDCl3)δ173.24(d,J＝7.7Hz),162.61,162.08,157.25,151.75(d,J＝7.5Hz),150.69(d,J＝7.1Hz),129.77,129.04,125.16,120.42(d,J＝4.7Hz),118.2,117.24,115.92,101.44(d,J＝181.4Hz),88.87(d,J＝37.9Hz),80.59(d,J＝6.8Hz),72.06(d,J＝17.9Hz),69.21,65.13(d,J＝5.2Hz),50.62,26.08,21.72(d,J＝3.7Hz),21.00(d,J＝4.5Hz),16.52(d,J＝25.0Hz).MS(ESI+)m/z:629.6(M+H+).
11、化合物23-7的制备。
参照上述方法制备得到化合物23-7。
化合物23-7的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.79(d,J＝7.0Hz,1H),7.64–7.41(m,2H),7.34–7.21(m,4H),7.17–7.10(m,1H),7.07-6.89(m,2H),5.03–4.90(m,1H),4.81–4.13(m,3H),4.06–3.87(m,2H),3.67(d,br,J＝73.3Hz,1H),2.98(d,J＝8.7Hz,3H),1.34(dd,J＝20.1,6.6Hz,3H),1.22–1.06(m,9H).MS(ESI+)m/z:765.1(M+H+).
12、化合物23-8的制备。
参照上述方法制备得到化合物23-8。
化合物23-8的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.82(s,1H),7.69(s,1H),7.49(t,J＝7.7Hz,1H),7.29(d,J＝8.6Hz,4H),7.16(d,J＝7.1Hz,1H),7.11–6.97(m,2H),6.83(s,1H),5.04–4.90(m,1H),4.76–4.33(m,3H),4.01(q,J＝7.9Hz,1H),3.92(t,J＝10.7Hz,1H),3.55–3.30(m,1H),3.00(s,3H),1.36(d,J＝7.0Hz,3H),1.23–1.15(m,9H).MS(ESI+)m/z:788.1(M+H+).
实施例5
1、化合物25的制备。
按照以下路线合成：
化合物25的合成方法同化合物8。得到以下化合物25-1，其表征数据为：MS(ESI+)m/z:427.9(M+H+)。
2、化合物26的制备。
按照以下路线合成：
化合物26的合成方法同化合物10或化合物12。得到以下化合物26-1，
化合物26-1的表征数据为：1H NMR(500MHz,DMSO)δ8.77(s,1H),8.51(s,1H),7.76(t,J＝7.8Hz,1H),7.55(d,J＝9.3Hz,1H),7.34(d,J＝8.2Hz,1H),6.50(d,J＝17.2Hz,1H),5.74(d,J＝6.1Hz,1H),5.40(s,1H),4.18(dt,J＝25.6,8.2Hz,1H),3.98(d,J＝9.3Hz,1H),3.91(d,J＝8.9Hz,1H),3.74(d,J＝12.0Hz,1H),1.02(d,J＝22.5Hz,3H).13C NMR(126MHz,DMSO)δ158.09(d,J＝246.0Hz),151.91(d,J＝7.0Hz),150.18,134.03,131.77,128.57(d,J＝3.3Hz),123.66(d,J＝9.0Hz),118.58(d,J＝23.8Hz),116.07,108.89(d,J＝21.0Hz),101.18(d,J＝181.0Hz),95.65,90.04(d,J＝3.0Hz),88.32(d,J＝39.2Hz),83.46,82.28,70.21(d,J＝17.5Hz),58.80,16.21(d,J＝24.9Hz).MS(ESI+)m/z:498.0(M+H+).
3、化合物27的制备。
按照以下路线合成：
在碱的作用下，将YH(或者Y的钠盐等)加入化合物26的溶液中，得化合物27，及以下具体化合物：
化合物27-1的表征数据为：1H NMR(500MHz,DMSO)δ8.53(s,1H),8.20(s,1H),7.75(t,J＝7.7Hz,1H),7.52(d,J＝9.4Hz,1H),7.31(d,J＝8.2Hz,1H),6.45(d,J＝17.6Hz,1H),5.70(s,1H),5.32(s,1H),4.23–4.13(m,1H),4.11(s,3H),3.95(d,J＝9.2Hz,1H),3.90(d,J＝12.4Hz,1H),3.73(d,J＝12.3Hz,1H),0.97(d,J＝22.3Hz,3H).13C NMR(126MHz,DMSO)δ162.92,158.08(d,J＝245.8Hz),152.25,150.80,133.96,128.73(d,J＝3.3Hz),128.27,124.10(d,J＝9.0Hz),118.67(d,J＝23.7Hz),108.52(d,J＝20.9Hz),104.83,101.93,100.49,95.02,88.40(d,J＝2.9Hz),88.17(d,J＝38.0Hz),85.06,82.06,70.30(d,J＝17.5Hz),58.90,54.02,16.19(d,J＝25.0Hz).MS(ESI+)m/z:494.0(M+H+)
4、化合物27-2的制备。
参照上述方法合成化合物27-2。
化合物27-2的表征数据为：1H NMR(500MHz,CDCl3)δ8.63(s,1H),7.58(s,1H),7.54(s,1H),7.31(d,J＝8.4Hz,1H),7.22(d,J＝7.5Hz,1H),6.35(d,J＝19.3Hz,1H),4.52(d,J＝15.5Hz,1H),4.18(d,J＝9.2Hz,1H),4.11(d,J＝8.5Hz,1H),4.00(d,J＝12.2Hz,1H),2.89(s,1H),2.70(s,3H),1.13(d,J＝22.7Hz,3H).13CNMR(126MHz,CDCl3)δ164.80,158.89(d,J＝247.9Hz),151.79,147.27,133.70,128.55,128.02(d,J＝3.4Hz),124.40(d,J＝8.8Hz),118.87(d,J＝23.8Hz),116.99,109.58(d,J＝21.2Hz),101.76(d,J＝178.8Hz),97.72,91.23,90.88(d,J＝2.9Hz),84.01,82.63,72.07(d,J＝18.4Hz),60.27,16.65(d,J＝25.1Hz),12.32.MS(ESI+)m/z:510.0(M+H+).
5、化合物27-3的制备。
参照上述方法合成化合物27-3。
化合物27-3的表征数据为：1H NMR(500MHz,DMSO)δ8.33(s,1H),8.01(s,1H),7.78(t,J＝7.5Hz,1H),7.61(d,J＝9.4Hz,1H),7.34(d,J＝8.1Hz,1H),6.54(s,1H),6.38(d,J＝17.9Hz,1H),5.67(d,J＝6.7Hz,1H),5.31(s,1H),4.14(d,J＝25.9Hz,1H),3.98–3.82(m,2H),3.71(d,J＝11.9Hz,1H),2.94(s,1H),0.97(d,J＝22.3Hz,3H),0.82(d,J＝5.6Hz,2H),0.60(s,2H).13C NMR(126MHz,DMSO)δ158.03(d,J＝245.6Hz),157.4,153.1,148.8,134.0,128.7(d,J＝3.2Hz),126.4,123.8(d,J＝9.1Hz),118.8(d,J＝24.0Hz),108.7(d,J＝20.9Hz),101.4(d,J＝232.0Hz),100.5,94.3,89.6(d,J＝2.8Hz),88.0(d,J＝38.2Hz),85.1,81.9,70.4(d,J＝17.9Hz),59.0,54.9,24.0,16.2(d,J＝25.1Hz),7.1,7.0.MS(ESI+)m/z:533.1(M+H+).
6、化合物27-2的制备。
参照上述方法合成化合物27-4。
化合物27-4的表征数据为：1H NMR(500MHz,DMSO)δ8.29(s,1H),8.03(s,1H),7.69(t,J＝7.8Hz,1H),7.47–7.39(m,3H),7.37–7.23(m,3H),7.15(d,J＝8.2Hz,1H),6.78(s,1H),6.39(d,J＝17.9Hz,1H),5.68(d,J＝6.8Hz,1H),5.32(s,1H),4.78(d,J＝4.4Hz,2H),4.22–4.08(m,1H),3.97–3.86(m,2H),3.71(d,J＝12.0Hz,1H),0.99(d,J＝22.3Hz,3H).MS(ESI+)m/z:569.1(M+H+).
7、化合物27-5的制备。
参照上述方法合成化合物27-5。
该化合物27-5表征数据为：MS(ESI+)m/z:473.2(M+H+).
8、化合物27-6的制备。
参照上述方法合成化合物27-6。
该化合物27-6的表征数据为：MS(ESI+)m/z:414.1(M+H+).
9、化合物27-7的制备。
参照上述方法合成化合物27-7。
该化合物27-7的表征数据为：MS(ESI+)m/z:398.1(M+H+).
10、化合物27-8的制备。
参照上述方法合成化合物27-8。
化合物27-8的表征数据为：1H NMR(500MHz,CDCl3)δ8.27(s,1H),7.55(t,J＝7.3Hz,1H),7.32(s,1H),7.25(d,J＝10.7Hz,1H),7.16(d,J＝8.2Hz,1H),6.28–6.02(m,2H),5.15–4.40(m,2H),4.18(d,J＝12.5Hz,1H),4.09(d,J＝9.0Hz,1H),3.97(d,J＝12.4Hz,1H),3.45(t,J＝5.2Hz,2H),2.97(s,1H),1.09(d,J＝16.8Hz,4H),0.57(d,J＝7.3Hz,2H),0.31(d,J＝3.8Hz,2H).MS(ESI+)m/z:534.3(M+H+).
11、化合物27-9的制备。
参照上述方法合成化合物27-9。
化合物27-9的表征数据为：1H NMR(500MHz,CDCl3)δ8.35(s,1H),7.43(t,J＝7.7Hz,1H),7.38–7.30(m,J＝8.0Hz,2H),7.26(s,2H),7.19(d,J＝7.5Hz,1H),7.13(d,J＝9.4Hz,1H),7.05(t,J＝8.4Hz,1H),6.87(dd,J＝8.9,1.5Hz,1H),6.81(d,J＝8.3Hz,1H),6.22(t,J＝4.8Hz,1H),6.17(d,J＝19.7Hz,1H),4.79(d,J＝5.0Hz,2H),4.67(d,J＝23.8Hz,1H),4.24–4.15(m,1H),4.09(d,J＝9.1Hz,1H),3.99(d,J＝7.9Hz,1H),2.32(s,1H),1.16(d,J＝22.9Hz,3H).MS(ESI+)m/z:587.0(M+H+).
12、化合物27-10的制备。
参照上述方法合成化合物27-10。
化合物27-10的表征数据为：1H NMR(500MHz,MeOD)δ8.64(s,1H),8.53(d,J＝3.8Hz,1H),8.32(s,1H),7.85(d,J＝7.8Hz,1H),7.72(s,1H),7.48(t,J＝7.7Hz,1H),7.37(dd,J＝7.6,5.0Hz,1H),6.92(d,J＝8.9Hz,1H),6.88(d,J＝8.4Hz,1H),6.39(d,J＝18.3Hz,1H),4.84(s,2H),4.32(dd,J＝24.0,9.5Hz,1H),4.10(d,J＝6.4Hz,2H),3.91(d,J＝11.0Hz,1H),1.12(d,J＝22.3Hz,3H).MS(ESI+)m/z:570.1(M+H+).
13、化合物27-11的制备。
参照上述方法合成化合物27-11。
化合物27-11的表征数据为：1H NMR(500MHz,MeOD)δ8.25(s,1H),7.64–7.55(m,2H),7.26(dd,J＝8.9,1.4Hz,1H),7.18(d,J＝8.2Hz,1H),6.31(d,J＝18.6Hz,1H),4.69–4.62(m,1H),4.35(dd,J＝24.0,9.1Hz,1H),4.15–4.06(m,2H),3.91(d,J＝11.2Hz,1H),2.58–2.48(m,2H),1.99–1.88(m,2H),1.88–1.79(m,2H),1.10(d,J＝22.4Hz,3H).MS(ESI+)m/z:533.1(M+H+).
14、化合物27-12的制备。
参照上述方法合成化合物27-12。
化合物27-12的表征数据为：1H NMR(500MHz,CDCl3)δ8.29(s,1H),7.60(t,J＝7.7Hz,1H),7.43(s,1H),7.27(dd,J＝9.6,2.1Hz,1H),7.19(d,J＝8.3Hz,1H),6.44(d,J＝6.6Hz,1H),6.21(d,J＝19.6Hz,1H),5.39–5.32(m,1H),5.10(t,J＝6.9Hz,2H),4.73–4.36(m,4H),4.20(d,J＝12.3Hz,1H),4.10(d,J＝9.1Hz,1H),4.02–3.94(m,1H),2.79(d,J＝7.4Hz,1H),1.15(d,J＝22.8Hz,3H).MS(ESI+)m/z:535.1(M+H+).
15、化合物27-13的制备。
参照上述方法合成化合物27-13。
化合物27-13的表征数据为：1H NMR(500MHz,CDCl3)δ8.31(s,1H),7.55(t,J＝7.7Hz,1H),7.32(s,1H),7.23(d,J＝8.9Hz,1H),7.14(d,J＝8.2Hz,1H),6.14(d,J＝19.7Hz,1H),5.97(d,J＝4.7Hz,1H),4.93–4.40(m,2H),4.18(d,J＝12.4Hz,1H),4.09(d,J＝8.9Hz,1H),3.97(d,J＝12.3Hz,1H),3.16(d,J＝4.9Hz,3H),2.80(s,1H),1.12(d,J＝22.8Hz,3H).MS(ESI+)m/z:493.1(M+H+).
16、化合物27-14的制备。
参照上述方法合成化合物27-14。
化合物27-14的表征数据为：1H NMR(500MHz,CDCl3)δ8.67(s,1H),8.51(s,1H),8.38–8.27(m,2H),7.55(t,J＝7.6Hz,1H),7.41(d,J＝9.0Hz,1H),7.38–7.31(m,2H),7.22(d,J＝8.1Hz,1H),6.20(d,J＝19.5Hz,1H),4.97(d,J＝3.3Hz,2H),4.63(d,J＝16.1Hz,1H),4.20(d,J＝12.4Hz,1H),4.10(d,J＝9.0Hz,1H),3.98(d,J＝12.5Hz,1H),2.77(s,1H),1.13(d,J＝22.8Hz,3H).MS(ESI+)m/z:571.1(M+H+).
17、化合物27-15的制备。
参照上述方法合成化合物27-15。
化合物27-15的表征数据为：1H NMR(500MHz,DMSO)δ9.53(s,1H),9.02(s,1H),8.41(s,1H),8.15(s,1H),7.76(t,J＝7.9Hz,1H),7.64(d,J＝9.7Hz,1H),7.38(d,J＝9.2Hz,1H),6.43(d,J＝17.8Hz,1H),5.70(d,J＝7.1Hz,1H),5.35(t,J＝4.6Hz,1H),4.24–4.08(m,1H),3.96–3.84(m,2H),3.75–3.65(m,1H),3.02(s,3H),0.99(d,J＝22.4Hz,3H).MS(ESI+)m/z:572.0(M+H+).
18、化合物27-16的制备。
参照上述方法合成化合物27-16。
化合物27-16的表征数据为：1H NMR(CDCl3+CD3OD):8.86(s,1H),8.66(d,J＝1.7Hz,1H),8.26(s,1H),7.78-7.72(m,1H),7.57-7.54(m,1H),7.47(brs,1H),7.38(d,J＝9.0Hz,1H),7.24(d,J＝8.0Hz,1H),6.41-6.37(m,1H),4.49-4.34(m,4H),4.29-4.23(m,1H),4.09-4.05(m,3H),3.86(d,J＝10.9Hz,1H),1.07(d,J＝22.3Hz,3H).MS(ESI+)m/z:571.1(M+H+).
19、化合物27-17的制备。
参照上述方法合成化合物27-17。
化合物27-17的表征数据为：1H NMR(CDCl3+CD3OD):8.28(d,J＝4.7Hz,1H),8.25(s,1H),7.68-7.65(m,1H),7.60(s,1H),7.48(t,J＝7.7Hz,1H),7.34-7.28(m,2H),7.20-7.15(m,2H),6.32(d,J＝18.6Hz,1H),4.27(dd,J＝9.3,24.0Hz,1H),4.09-4.04(m,6H),3.86(d,J＝11.0Hz,1H),1.05(d,J＝22.4Hz,3H).MS(ESI+)m/z:570.1(M+H+).
20、化合物27-18的制备。
参照上述方法合成化合物27-18。
化合物27-18的表征数据为：1H NMR(CDCl3+CD3OD):8.27(s,1H),7.65(s,1H),7.39-7.35(m,3H),7.03(t,J＝8.5Hz,2H),6.74(d,J＝8.9Hz,1H),6.64(d,J＝8.2Hz,1H),6.33(d,J＝18.3Hz,1H),4.29-4.21(m,6H),4.08-4.04(m,2H),3.85(d,J＝11.3Hz,1H),1.06(d,J＝22.3Hz,3H).MS(ESI+)m/z:587.1(M+H+).
21、化合物27-19的制备。
参照上述方法合成化合物27-19。
化合物27-19的表征数据为：1H NMR(CDCl3+CD3OD):8.19(s,1H),7.52-7.48(m,2H),7.14(d,J＝8.9Hz,1H),7.07(d,J＝8.3Hz,1H),6.22(d,J＝18.7Hz,1H),4.29(dd,J＝9.0,23.6Hz,1H),4.06-4.01(m,2H),3.91-3.82(m,3H),3.50-3.45(m,5H),3.31(t,J＝11.4Hz,2H),1.87-1.83(m,1H),1.65(d,J＝12.4Hz,2H),1.39-1.31(m,2H),1.04(d,J＝22.4Hz,3H).MS(ESI+)m/z:577.1(M+H+).
22、化合物27-20的制备。
参照上述方法合成化合物27-20。
化合物27-20的表征数据为：1H NMR(CDCl3+CD3OD):8.26(s,1H),7.61(s,1H),7.51(s,1H),7.46-7.42(m,2H),6.80-6.77(m,2H),6.31(d,J＝18.3Hz,1H),4.30-4.23(m,1H),4.07-4.03(m,7H),3.86-3.81(m,4H),1.05(d,J＝22.3Hz,3H).MS(ESI+)m/z:573.1(M+H+).
23、化合物27-21的制备。
参照上述方法合成化合物27-21。
化合物27-21的表征数据为：1H NMR(CDCl3+CD3OD):8.40(s,1H),7.82(s,1H),7.51-7.00(m,8H),6.47(d,J＝18.3Hz,1H),4.26-3.85(m,4H),1.31-1.18(m,2H),1.05(d,J＝22.3Hz,3H),1.03-0.96(m,2H).MS(ESI+)m/z:595.1(M+H+).
24、化合物27-22的制备。
参照上述方法合成化合物27-22。
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化合物27-22的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.26(s,1H),7.64(s,1H),7.52(t,J＝7.7Hz,1H),7.27(dd,J＝9.1,1.9Hz,1H),7.16(dd,J＝8.2,1.8Hz,1H),6.34(d,J＝18.3Hz,1H),4.36(d,J＝2.5Hz,2H),4.27(dd,J＝24.0,9.3Hz,1H),4.07–4.01(m,2H),3.91–3.83(m,1H),2.43(s,1H),1.06(d,J＝22.3Hz,3H).MS(ESI+)m/z:517.1(M+H+).
25、化合物27-23的制备。
参照上述方法合成化合物27-23。
化合物27-23的表征数据为：1H NMR(400MHz,DMSO-d6)δ10.48(d,J＝4.0Hz,1H),8.82(d,J＝4.9Hz,2H),8.52(s,1H),8.26(s,1H),7.32(t,J＝4.9Hz,1H),6.46(d,J＝18.3Hz,1H),5.67(d,J＝7.1Hz,1H),5.32(t,J＝4.8Hz,1H),4.28–4.07(m,1H),4.00–3.83(m,2H),3.77–3.60(m,1H),3.10–2.94(m,1H),0.98(d,J＝22.3Hz,3H),0.86–0.76(m,2H),0.67–0.55(m,2H).MS(ESI+)m/z:401.2(M+H+).
26、化合物27-24的制备。
参照上述方法合成化合物27-24。
化合物27-24的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.23(s,1H),8.06(s,1H),7.65(d,J＝3.4Hz,1H),7.21(d,J＝3.4Hz,1H),6.36(d,J＝17.9Hz,1H),4.30(dd,J＝24.1,9.3Hz,1H),4.13–3.99(m,2H),3.87(dd,J＝12.6,2.0Hz,1H),2.97–2.84(m,1H),1.08(d,J＝22.3Hz,3H),0.92–0.84(m,2H),0.65–0.58(m,2H).MS(ESI+)m/z:406.1(M+H+).
27、化合物27-25的制备。
参照上述方法合成化合物27-25。
化合物27-25的表征数据为：1H NMR(500MHz,DMSO-d6)δ12.97(s,1H),10.08(d,J＝3.9Hz,1H),8.21(s,1H),7.97(s,1H),7.82(t,J＝2.0Hz,1H),6.53(t,J＝2.0Hz,1H),6.39(d,J＝18.4Hz,1H),5.64(d,J＝7.3Hz,1H),5.35(t,J＝5.1Hz,1H),4.26–4.12(m,1H),3.97–3.89(m,2H),3.77–3.69(m,1H),3.04–2.94(m,1H),0.97(d,J＝22.3Hz,3H),0.86–0.79(m,2H),0.60–0.52(m,2H).MS(ESI+)m/z:389.2(M+H+).
28、化合物27-26的制备。
参照上述方法合成化合物27-26。
化合物27-26的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.31(s,1H),7.83(s,1H),7.59(d,J＝1.9Hz,1H),6.50(d,J＝17.7Hz,1H),6.39(d,J＝1.9Hz,1H),4.29(dd,J＝24.5,9.2Hz,1H),4.11–3.98(m,2H),3.92–3.83(m,1H),3.79(s,3H),2.82–2.73(m,1H),1.09(d,J＝22.2Hz,3H),0.85–0.76(m,2H),0.52–0.40(m,2H).MS(ESI+)m/z:403.2(M+H+).
29、化合物27-27的制备。
参照上述方法合成化合物27-27。
化合物27-27的表征数据为：1H NMR(400MHz,DMSO-d6)δ9.91(d,J＝3.9Hz,1H),8.22(s,1H),7.97(s,1H),7.76(d,J＝2.3Hz,1H),6.49(d,J＝2.3Hz,1H),6.39(d,J＝18.2Hz,1H),5.65(d,J＝7.2Hz,1H),5.35(t,J＝5.2Hz,1H),4.27–4.07(m,1H),3.95–3.88(m,5H),3.78–3.66(m,1H),3.09–2.93(m,1H),0.96(d,J＝22.3Hz,3H),0.88–0.78(m,2H),0.63–0.52(m,2H).MS(ESI+)m/z:403.2(M+H+).
30、化合物27-28的制备。
参照上述方法合成化合物27-28。
化合物27-28的表征数据为：1H NMR(500MHz,MeOD)δ8.25(s,1H),7.73(s,2H),7.50(s,1H),6.46(d,J＝18.4Hz,1H),4.28(dd,J＝24.4,9.5Hz,1H),4.08–3.97(m,2H),3.92–3.76(m,J＝12.6,2.8Hz,1H),2.89–2.66(m,J＝7.0,3.7Hz,1H),1.07(d,J＝22.2Hz,3H),0.84–0.78(m,J＝6.7,3.3Hz,2H),0.54–0.38(m,2H).MS(ESI+)m/z:389.2(M+H+).
31、化合物27-29的制备。
参照上述方法合成化合物27-29。
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化合物27-29的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.21(s,1H),7.97(s,1H),6.48(d,J＝18.6Hz,1H),4.24(dd,J＝24.1,9.5Hz,1H),4.17–4.02(m,2H),4.01–3.88(m,1H),3.03–2.86(m,1H),1.09(d,J＝22.3Hz,3H),0.97–0.84(m,2H),0.81–0.63(m,2H).MS(ESI+)m/z:391.2(M+H+).
32、化合物27-30的制备。
参照上述方法合成化合物27-30。
化合物27-30的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.98(d,J＝3.6Hz,1H),8.39(s,1H),8.32(s,1H),6.45(d,J＝17.9Hz,1H),5.67(d,J＝7.2Hz,1H),5.38(t,J＝4.7Hz,1H),4.42(s,3H),4.27–4.13(m,1H),3.99–3.85(m,2H),3.78–3.65(m,1H),3.07–2.95(m,1H),0.98(d,J＝22.3Hz,3H),0.91–0.76(m,2H),0.65–0.48(m,2H).MS(ESI+)m/z:405.2(M+H+).
33、化合物27-31的制备。
参照上述方法合成化合物27-31。
化合物27-31的表征数据为：1H NMR(500MHz,Methanol-d4)δ8.25(s,1H),8.23(s,1H),7.84(d,J＝0.9Hz,1H),7.23(d,J＝0.9Hz,1H),6.46(d,J＝17.7Hz,1H),4.29(dd,J＝24.4,9.3Hz,1H),4.12–4.00(m,2H),3.93–3.84(m,1H),2.96–2.85(m,1H),1.06(d,J＝22.2Hz,3H),0.92–0.87(m,2H),0.67–0.59(m,2H).MS(ESI+)m/z:390.2(M+H+).
34、化合物27-32的制备。
参照上述方法合成化合物27-32。
化合物27-32的表征数据为：1H NMR(400MHz,Methanol-d4)δ8.54(d,J＝3.0Hz,1H),8.25(s,1H),6.44(d,J＝17.1Hz,1H),4.28(dd,J＝24.4,9.3Hz,1H),4.18–3.99(m,2H),3.95–3.81(m,1H),2.98–2.85(m,1H),2.40(d,J＝3.3Hz,3H),1.07(d,J＝22.2Hz,3H),0.96–0.87(m,2H),0.71–0.55(m,2H).MS(ESI+)m/z:405.2(M+H+).
35、化合物27-33的制备。
参照上述方法合成化合物27-33。
化合物27-33的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.68(d,J＝3.6Hz,1H),8.42(s,1H),8.33(s,1H),6.44(d,J＝17.7Hz,1H),5.67(d,J＝7.1Hz,1H),5.37(t,J＝4.7Hz,1H),4.28–4.10(m,1H),4.00–3.85(m,2H),3.77–3.65(m,1H),3.07–2.91(m,1H),2.66(s,3H),0.97(d,J＝22.3Hz,3H),0.91–0.80(m,2H),0.60–0.51(m,2H).MS(ESI+)m/z:405.2(M+H+).
36、化合物27-34的制备。
参照上述方法合成化合物27-34。
化合物27-34的表征数据为：1H NMR(500MHz,DMSO-d6)δ9.25(d,J＝3.5Hz,1H),8.38(s,1H),8.34(s,1H),6.41(d,J＝17.6Hz,1H),5.67(d,J＝7.2Hz,1H),5.41(t,J＝4.6Hz,1H),4.17(dd,J＝21.1,12.6Hz,1H),3.99–3.86(m,2H),3.78–3.67(m,1H),3.03–2.92(m,1H),2.55(s,3H),1.00(d,J＝22.4Hz,3H),0.90–0.81(m,2H),0.58–0.48(m,2H).MS(ESI+)m/z:405.2(M+H+).
37、化合物27-35的制备。
参照上述方法合成化合物27-35。
化合物27-35的表征数据为：1H NMR(500MHz,DMSO-d6)δ8.65–8.60(m,2H),8.35(s,1H),8.16(d,J＝7.1Hz,2H),7.84–7.75(m,1H),7.73–7.67(m,2H),6.45(d,J＝17.5Hz,1H),5.69(d,J＝7.1Hz,1H),5.47(d,J＝4.8Hz,1H),4.22(dd,J＝21.8,13.2Hz,1H),4.05–3.90(m,2H),3.80–3.70(m,1H),3.09–2.96(m,1H),1.01(d,J＝22.3Hz,3H),0.93–0.86(m,2H),0.64–0.54(m,2H).MS(ESI+)m/z:467.2(M+H+).
实施例6
1、化合物29的制备。
取化合物24(0.393mmol)置于10mL封管中，溶于1，4-二氧六环(1mL)，加入氨水(2mL)，拧紧，置于100℃下搅拌2h，冷却至常温，旋干，过柱(DCM：iPrOH＝10:1)，得白色固体产物(化合物29).
2、化合物29-1的制备。
参照上述方法制备得到82.1mg化合物29-1，收率为51％。
化合物29-1的表征数据为：mg,收率51％。1HNMR(400MHz,DMSO-d6)δ8.13(s,1H),7.76(s,1H),6.72(br,2H),6.34(d,J＝18Hz,1H),5.63(d,J＝7.2Hz,1H’),5.28(t,J＝4.8Hz,1H’),4.15–4.05(m,1H),3.89–3.83(m,2H),3.68–3.65(m,1H),0.96(d,J＝22Hz,3H).13CNMR(125MHz,DMSO-d6)δ157.2,152.2,149.6,126.0,102.9,100.4(d,JC-F＝179Hz),87.6,81.7,70.3(d,J＝17Hz),58.9,52.3,16.1(d,J＝25Hz).(ESI+)m/z:409.0(M+H+).
3、化合物29-2的制备。
参照上述方法制备得到78.1mg化合物29-2，收率为55％。
化合物29-2的表征数据为：1HNMR(400MHz,DMSO)δ8.13(s,1H),7.73(s,1H),6.69(br,2H),6.36(d,J＝18Hz,1H),5.65(d,J＝6.8Hz,1H’),5.28(s,1H),4.15–4.05(m,1H),3.90–3.84(m,2H),3.69–3.66(m,1H),0.98(d,J＝22Hz,3H).
13CNMR(125MHz,DMSO)δ157.0,152.7,149.1,120.6,100.8,100.4(d,JC-F＝179Hz),87.2,81.7,70.2(d,J＝18Hz),64.8,58.9,16.1(d,J＝25Hz).MS(ESI+)m/z:361.0(M+H+).
实施例7
1、化合物30的制备。
化合物30的合成方法同化合物10或化合物12。得到如下具体化合物30-19(收率：37％)。
化合物30-1的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.12(s,1H),8.07(d,J＝7.2Hz,2H),6.49(d,J＝18Hz),4.35(dd,J＝9.2,9.6Hz,1H),4.09(t,J＝5.2Hz,2H),3.92(d,J＝12Hz,1H),1.12(d,J＝22.4Hz,3H).13CNMR(125MHz,DMSO-d6)δ157.8,152.5,150.5,120.4,101.9,100.5,99.5,90.0(d,JC-F＝180.3Hz),87.5(d,J＝40.1Hz),81.8,71.0,59.7,54.8,16.2(d,J＝25Hz).MS(ESI+)m/z:350.1(M+H+).
2、化合物30-2的制备。
参照上述方法制备得到化合物30-2，收率为49％。
化合物30-2的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.19(s,1H),7.71(s,1H),7.47(d,J＝2Hz,1H),7.17(s,2H),6.52(d,J＝14.4Hz,1H),4.34(dd,J＝7.2,7.6Hz,1H),4.11(t,J＝14.8Hz,2H),3.87(d,J＝8.4Hz,1H),1.13(d,J＝17.6Hz,3H).13CNMR(125MHz,MeOH-d4)δ158.9,153.1,151.3,136.5,129.0,127.9,126.9,122.8,111.4,102.4,101.7(d,JC-F＝179.2Hz),90.3(d,J＝41Hz),83.2,72.5(d,J＝17.8Hz),60.5,16.5(d,J＝25.3Hz).MS(ESI+)m/z:365.1(M+H+).
3、化合物30-3的制备。
参照上述方法制备得到化合物30-3，收率为55％。
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化合物30-3的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.18(s,1H),7.60(s,1H),7.54(q,J＝4.8Hz,2H),7.24(t,J＝6.8Hz,2H),6.53(d,J＝14.4Hz,1H),4.34(dd,J＝7.6,7.6Hz,1H),4.11(d,J＝9.6Hz,2H),3.88(t,J＝8.4Hz,1H),1.13(d,J＝17.6Hz,3H).
13CNMR(125MHz,MeOH-d4)δ173.0,164.8,162.8,158.9,152.8,151.5,131.7(d,J＝8.1Hz),121.8,118.3,116.7(d,J＝21.8Hz),102.2,101.7(d,JC-F＝179.1Hz),90.0(d,J＝38.6Hz),83.2,72.6(d,J＝18Hz),60.6,16.6(d,J＝25.3Hz).MS(ESI+)m/z:377.1(M+H+).
4、化合物30-4的制备。
参照上述方法制备得到化合物30-4，收率为44％。
化合物30-4的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.17(s,1H),7.53(s,1H),7.44(d,J＝6.8Hz,2H),7.06(d,J＝6.8Hz,2H),6.53(d,J＝14.4Hz,1H),4.34(dd,J＝7.6,7.6Hz,1H),4.07(d,J＝6Hz,2H),3.87(t,J＝4.4Hz,4H),1.13(d,J＝18Hz,3H).13CNMR(125MHz,MeOH-d4)δ160.8,158.9,152.6,151.3,131.1,127.7,121.2,119.1,115.5,102.4,101.7(d,JC-F＝179.3Hz),90.0(d,J＝38.8Hz),83.2,72.6(d,J＝17.9Hz),60.7,55.8,16.5(d,J＝25.3Hz).MS(ESI+)m/z:389.2(M+H+).
5、化合物30-5的制备。
参照上述方法制备得到化合物30-5，收率为44％。
化合物30-5的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.61(d,J＝4.4Hz,2H),8.24(s,1H),7.93(s,1H),7.61(d,J＝4.4Hz,2H),6.55(d,J＝14.4Hz,1H),4.36(dd,J＝7.6,7.6Hz,1H),4.09(d,J＝9.2Hz,2H),3.90(t,J＝8Hz,1H),1.14(d,J＝17.6Hz,3H).13CNMR(125MHz,MeOH-d4)δ159.0,153.2,152.3,150.5,144.8,124.7,123.8,116.4,101.7(d,JC-F＝179.5Hz),101.5,90.0(d,J＝41.4Hz),83.3,72.4(d,J＝18Hz),60.5,16.6(d,J＝25.3Hz,3H).MS(ESI+)m/z:360.1(M+H+).
6、化合物30-6的制备。
参照上述方法制备得到化合物30-6，收率为44％。
化合物30-6的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.21(s,1H),8.00(d,J＝6Hz,2H),7.78(d,J＝6.8Hz,1H),7.66(d,J＝8.8Hz,1H),7.61–7.54(m,3H),7.50(d,J＝5.2Hz,1H),6.61(d,J＝15.2Hz,1H),4.37–4.28(m,1H),4.08–4.02(m,2H),3.85(t,J＝9.6Hz,1H),1.24(t,J＝16.8Hz,3H).13CNMR(125MHz,MeOH-d4)δ173.5,167.0,162.4,157.2,152.2,150.0,138.7,131.7,131.6,131.3,128.6,128.3,128.1,126.7,126.2,125.6,100.7(d,JC-F＝180Hz),87.7(d,J＝48.8Hz),81.7,67.4,59.0,16.3(d,J＝22.5Hz).MS(ESI+)m/z:408.0(M+H+).
7、化合物30-7的制备。
参照上述方法制备得到化合物30-7，收率为44％。
化合物10-5的表征数据为：1HNMR(400MHz,MeOH-d4)δ8.22(s,1H),7.80(t,J＝6.4Hz,3H),7.73(d,J＝6.4Hz,2H),6.55(d,J＝14.4Hz,1H),4.36(dd,J＝7.6,7.6Hz,1H),4.08(t,J＝5.6Hz,2H),3.88(d,J＝8.4Hz,1H),1.15(d,J＝17.6Hz,3H).13CNMR(125MHz,MeOH-d4)δ158.9,153.0,151.9,130.2,130.1(d,J＝32.375Hz),127.0,126.9(d,J＝7.7Hz),122.7,122.3(d,JC-F3＝297.9Hz),118.0,101.9,101.7(d,JC-F＝179.5Hz),90.0(d,J＝39.5Hz),83.3,72.5(d,J＝18Hz),60.6,16.6(d,J＝25.4Hz).MS(ESI+)m/z:427.1(M+H+).
8、化合物30-8的制备。
参照上述方法制备得到化合物30-8，表征数据为：MS(ESI+)m/z:426.5(M+H+).
9、化合物30-9的制备。
参照上述方法制备得到化合物30-9，表征数据为：MS(ESI+)m/z:413.4(M+H+).
9、化合物30-10的制备。
参照上述方法制备得到化合物30-10，表征数据为：MS(ESI+)m/z:401.3(M+H+).
10、化合物30-11的制备。
参照上述方法制备得到化合物30-11，表征数据为：.MS(ESI+)m/z:384.4(M+H+).
11、化合物30-12的制备。
参照上述方法制备得到化合物30-12，表征数据为：MS(ESI+)m/z:433.5(M+H+).
12、化合物30-13的制备。
参照上述方法制备得到化合物30-13。
化合物30-13的表征数据为：1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.96(s,1H),7.58(s,2H),7.42(s,3H),6.79(brs,2H),6.38(d,J＝13.6Hz,1H),5.66(s,1H),5.30(s,1H),4.17–4.12(m,1H),3.91–3.87(m,1H),3.91–3.71(m,2H),1.00(d,J＝17.6Hz,3H).13CNMR(125MHz,DMSO-d6)δ157.6,152.1,150.3,134.1,128.6,128.5,125.8,122.3,100.5(d,JC-F＝179Hz),95.2,91.2,87.7(d,J＝41Hz),82.7,81.8,70.3(d,J＝18Hz),59.0,16.1(d,J＝25Hz).MS(ESI+)m/z:383.0(M+H+).
实施例8
1、化合物28的制备。
化合物28的合成方法同化合物23，并参照上述方法，制备得到以下列些具体化合物：
化合物28-1的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.66(s,1H),7.60(s,1H),7.48(t,J＝7.6Hz,1H),7.33–7.23(m,4H),7.19–7.09(m,3H),6.57(d,J＝18.3Hz,1H),5.02–4.92(m,1H),4.65–4.55(m,1H),4.53–4.45(m,1H),4.31–4.19(m,2H),4.04–3.93(m,2H),3.76(s,1H),2.71(s,3H),1.37(d,J＝6.7Hz,3H),1.17(d,J＝6.3Hz,6H),1.12(d,J＝22.5Hz,3H).13C NMR(126MHz,Chloroform-d)δ173.18(d,J＝6.9Hz),164.10,158.83(d,J＝247.9Hz),152.09,150.49(d,J＝6.3Hz),147.91,133.58,130.00,128.03(d,J＝3.5Hz),127.41,125.46,124.51(d,J＝8.7Hz),120.27,120.23,118.84(d,J＝23.7Hz),116.59,109.40(d,J＝21.0Hz),101.18(d,J＝181.4Hz),97.82,90.67(d,J＝3.0Hz),88.98(d,J＝39.3Hz),84.39,80.12(d,J＝7.0Hz),72.39(d,J＝17.8Hz),69.80,64.80,50.61,21.73(d,J＝7.9Hz),21.12(d,J＝5.0Hz),16.44(d,J＝25.2Hz),12.3.MS(ESI+)m/z:780.6(M+H+).
化合物28-2的表征数据为：1H NMR(500MHz,CDCl3)δ8.51(s,1H),7.57(s,1H),7.49(t,J＝7.6Hz,1H),7.35–7.24(m,4H),7.20–7.12(m,2H),7.08(d,J＝8.2Hz,1H),6.58(d,J＝18.4Hz,1H),5.04–4.95(m,1H),4.68–4.59(m,1H),4.56–4.48(m,1H),4.34–4.21(m,2H),4.19(s,3H),4.02(d,J＝10.4Hz,2H),3.89(s,1H),1.39(d,J＝2.9Hz,3H),1.19(d,J＝6.1Hz,6H),1.13(d,J＝22.6Hz,3H).MS(ESI+)m/z:764.3(M+H+).
化合物28-3的表征数据为：1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.48–7.37(m,6H),7.34–7.23(m,5H),7.15(t,J＝6.7Hz,1H),6.67(d,J＝8.9Hz,1H),6.53(d,J＝8.8Hz,2H),6.14(s,1H),5.01–4.93(m,1H),4.78(s,2H),4.66–4.58(m,1H),4.53–4.46(m,1H),4.35–4.17(m,2H),4.11–3.91(m,3H),1.38(d,J＝4.8Hz,3H),1.20–1.11(m,9H).MS(ESI+)m/z:839.5(M+H+).
化合物28-4的表征数据为：MS(ESI+)m/z:661.2(M+H+).
化合物28-5的表征数据为：1H NMR(500MHz,CDCl3)δ8.42(s,1H),7.50(t,J＝7.5Hz,1H),7.43(s,1H),7.33–7.20(m,4H),7.12(t,J＝6.7Hz,1H),7.05(d,J＝8.8Hz,1H),7.00(d,J＝8.2Hz,1H),6.49(d,J＝18.3Hz,1H),6.20(s,1H),5.00–4.91(m,J＝11.9,5.8Hz,1H),4.65–4.55(m,1H),4.50–4.43(m,1H),4.22(d,J＝21.7Hz,2H),3.99(d,J＝10.7Hz,2H),2.97(s,1H),1.35(d,J＝4.1Hz,3H),1.16(d,J＝6.1Hz,6H),1.12(d,J＝22.7Hz,3H),0.94(d,J＝6.3Hz,2H),0.61(s,2H).MS(ESI+)m/z:789.4(M+H+).
化合物28-6的表征数据为：1H NMR(500MHz,CDCl3)δ8.35(s,1H),7.51(t,J＝7.4Hz,1H),7.45(s,1H),7.35–7.22(m,5H),7.18–7.11(m,2H),7.07(d,J＝8.1Hz,1H),6.52(d,J＝18.4Hz,1H),6.10(s,1H),5.04–4.92(m,1H),4.67–4.56(m,1H),4.54–4.45(m,1H),4.33–4.16(m,2H),4.14–3.97(m,2H),3.48(d,J＝4.8Hz,2H),1.39(d,J＝6.5Hz,3H),1.21–1.11(m,10H),0.59(d,J＝6.9Hz,2H),0.34(s,2H).MS(ESI+)m/z:803.4(M+H+).
化合物28-7的表征数据为：1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.45(s,1H),7.35(dd,J＝14.6,6.9Hz,2H),7.31–7.23(m,4H),7.20(d,J＝7.6Hz,1H),7.16–7.10(m,2H),7.04(t,J＝7.8Hz,1H),6.73(d,J＝8.8Hz,1H),6.66(d,J＝8.1Hz,1H),6.51(d,J＝18.4Hz,1H),6.15(s,1H),5.02–4.92(m,1H),4.85–4.71(m,2H),4.66–4.56(m,1H),4.52–4.43(m,1H),4.30–4.15(m,2H),4.04–3.90(m,2H),3.77(s,1H),1.35(d,J＝5.3Hz,3H),1.20–1.09(m,9H).MS(ESI+)m/z:856.2(M+H+).
化合物28-8的表征数据为：1H NMR(500MHz,CDCl3)δ8.71(s,1H),8.60(s,1H),8.40(s,1H),7.77(d,J＝7.6Hz,1H),7.47(s,1H),7.38(t,J＝7.6Hz,1H),7.34–7.20(m,5H),7.13(t,J＝6.7Hz,1H),6.77(d,J＝8.8Hz,1H),6.69(d,J＝8.1Hz,1H),6.52(d,J＝18.3Hz,1H),6.14(t,J＝4.9Hz,1H),5.00–4.92(m,6.1Hz,1H),4.90–4.77(m,2H),4.68–4.56(m,1H),4.54–4.43(m,1H),4.35–4.05(m,4H),3.99(dd,J＝15.3,7.6Hz,1H),1.35(d,J＝6.8Hz,3H),1.19–1.10(m,9H).MS(ESI+)m/z:839.2(M+H+).
化合物28-9的表征数据为：1H NMR(500MHz,CDCl3)δ8.34(s,1H),7.52(t,J＝7.6Hz,1H),7.44(s,1H),7.34–7.24(m,4H),7.14(t,J＝7.0Hz,1H),7.10(d,J＝8.9Hz,1H),7.05(d,J＝8.2Hz,1H),6.49(d,J＝18.4Hz,1H),6.13(d,J＝7.1Hz,1H),5.02–4.93(m,1H),4.72(dd,J＝15.5,7.8Hz,1H),4.65–4.58(m,1H),4.52–4.43(m,1H),4.23(d,J＝21.4Hz,2H),4.13–3.82(m,,3H),2.53(d,J＝3.8Hz,2H),1.97–1.87(m,J＝18.7,9.0Hz,2H),1.87–1.77(m,2H),1.37(d,J＝6.8Hz,3H),1.18(d,J＝6.2Hz,6H),1.12(d,J＝22.6Hz,3H).MS(ESI+)m/z:802.2(M+H+).
化合物28-10的表征数据为：1H NMR(500MHz,MeOD)δ8.58(s,1H),7.98(d,J＝1.6Hz,1H),7.56(t,J＝7.8Hz,1H),7.35–7.29(m,1H),7.28–7.24(m,4H),7.21–7.15(m,1H),7.15–7.09(m,1H),6.53(d,J＝17.8Hz,1H),4.92–4.91(m,1H),4.83–4.76(m,1H),4.70–4.57(m,3H),4.50–4.41(m,1H),4.32–4.20(m,2H),3.97–3.85(m,2H),3.81–3.74(m,1H),1.30(d,J＝7.1Hz,3H),1.18–1.11(m,9H).MS(ESI+)m/z:804.2(M+H+).
化合物28-11的表征数据为：1H NMR(500MHz,CDCl3)δ8.36(s,1H),7.49(t,J＝7.7Hz,1H),7.43(s,1H),7.30–7.21(m,4H),7.15–7.05(m,2H),7.02(d,J＝8.2Hz,1H),6.49(d,J＝18.4Hz,1H),5.92(d,J＝4.8Hz,1H),5.00–4.90(m,1H),4.64–4.55(m,1H),4.50–4.43(m,1H),4.29–4.14(m,2H),4.10–3.84(m,3H),3.17(d,J＝4.9Hz,3H),1.35(d,J＝6.9Hz,3H),1.16(d,J＝6.2Hz,6H),1.11(d,J＝22.6Hz,3H).MS(ESI+)m/z:762.2(M+H+).
化合物28-12的表征数据为：1H NMR(500MHz,CDCl3)δ8.69(s,1H),8.51(s,1H),8.40(s,1H),8.33(s,1H),7.55–7.43(m,2H),7.32–7.20(m,6H),7.17–7.06(m,,2H),6.52(d,J＝18.4Hz,1H),5.01(d,J＝4.3Hz,2H),4.99–4.92(m,1H),4.66–4.56(m,1H),4.54–4.42(m,1H),4.31–4.16(m,2H),4.10–3.79(m,3H),1.36(d,J＝6.8Hz,3H),1.19–1.08(m,J＝16.3Hz,9H).MS(ESI+)m/z:840.2(M+H+).
化合物28-13的表征数据为：1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.78(br,s,2H),7.58(s,1H),7.46(t,J＝7.7Hz,1H),7.30–7.22(m,4H),7.14(t,J＝6.7Hz,1H),7.09–7.04(m,2H),6.51(d,J＝18.2Hz,1H),5.02–4.93(m,1H),4.67–4.59(m,1H),4.53–4.43(m,1H),4.29–4.17(m,2H),4.16–4.08(m,1H),4.05–3.92(m,1H),3.07(s,3H),1.36(d,J＝6.9Hz,3H),1.20–1.16(m,6H),1.12(d,J＝22.5Hz,3H).MS(ESI+)m/z:841.1(M+H+).
化合物28-14的表征数据为：1H NMR(500MHz,CDCl3)δ8.40(s,1H),8.35(d,J＝4.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.52(t,J＝3.7Hz,1H),7.50–7.42(m,2H),7.36–7.23(m,6H),7.23–7.18(m,1H),7.17–7.09(m,2H),6.52(d,J＝18.5Hz,1H),5.01–4.89(m,3H),4.65–4.56(m,1H),4.48(t,J＝8.9Hz,1H),4.32–4.16(m,2H),4.11–3.89(m,3H),1.37(d,J＝6.7Hz,3H),1.19–1.08(m,9H).MS(ESI+)m/z:839.2(M+H+).
化合物28-15的表征数据为：1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.47–7.37(m,3H),7.33(t,J＝7.6Hz,1H),7.29–7.20(m,4H),7.12(t,J＝6.9Hz,1H),7.06(t,J＝8.4Hz,2H),6.67(d,J＝8.8Hz,1H),6.57–6.43(m,2H),6.09(s,1H),5.00–4.91(m,1H),4.74(d,J＝4.3Hz,2H),4.65–4.55(m,1H),4.52–4.42(m,1H),4.29–4.16(m,2H),4.13–3.88(m,3H),1.35(d,J＝6.9Hz,3H),1.19–1.08(m,9H).MS(ESI+)m/z:856.2(M+H+).
化合物28-16的表征数据为：1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.51(t,J＝7.7Hz,1H),7.45(s,1H),7.32–7.21(m,4H),7.13(t,J＝6.8Hz,1H),7.08(dd,J＝8.9,1.3Hz,1H),7.02(d,J＝8.3Hz,1H),6.50(d,J＝18.4Hz,1H),6.06(t,J＝5.6Hz,1H),5.02–4.92(m,1H),4.66–4.57(m,1H),4.52–4.44(m,1H),4.32–4.16(m,2H),4.08–3.92(m,5H),3.56(t,J＝6.2Hz,2H),3.38(t,J＝11.5Hz,2H),1.99–1.86(m,1H),1.77–1.65(m,2H),1.50–1.39(m,2H),1.37(d,J＝6.6Hz,3H),1.21–1.08(m,9H).MS(ESI+)m/z:846.2(M+H+).
化合物28-17的表征数据为：1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.55(s,1H),7.46–7.36(m,93H),7.31–7.21(m,4H),7.12(t,J＝7.1Hz,1H),6.73(d,J＝9.0Hz,1H),6.66(d,J＝8.2Hz,1H),6.50(d,J＝18.4Hz,1H),6.01(s,1H),4.99–4.91(m,1H),4.62(d,J＝4.7Hz,2H),4.61–4.55(m,1H),4.51–4.43(m,1H),4.32–4.16(m,2H),4.08–3.93(m,3H),3.87(s,3H),1.35(d,J＝6.5Hz,3H),1.18–1.07(m,9H).MS(ESI+)m/z:842.2(M+H+).
化合物28-18的表征数据为：1H NMR(500MHz,CDCl3)δ8.38(s,1H),7.51–7.42(m,2H),7.33–7.21(m,4H),7.17–7.08(m,2H),7.05(d,J＝8.2Hz,1H),6.50(d,J＝18.3Hz,1H),6.05(t,J＝4.8Hz,1H),5.00–4.91(m,1H),4.64–4.54(m,1H),4.50–4.43(m,1H),4.43–4.38(m,2H),4.31–4.14(m,2H),4.13–4.05(m,1H),4.05–3.88(m,J＝16.2,8.0Hz,2H),2.35(t,J＝2.3Hz,1H),1.36(d,J＝7.0Hz,3H),1.16(d,J＝6.2Hz,6H),1.11(d,J＝22.6Hz,3H).MS(ESI+)m/z:786.1(M+H+).
化合物28-19的表征数据为：1H NMR(400MHz,Chloroform-d)δ8.85(d,J＝3.0Hz,1H),8.48(s,1H),8.17–8.11(m,2H),8.09(s,1H),7.67–7.59(m,1H),7.56–7.48(m,2H),7.31–7.27(m,4H),7.18–7.08(m,1H),6.57(d,J＝18.0Hz,1H),4.90–4.81(m,1H),4.62–4.53(m,2H),4.50–4.32(m,2H),4.28–4.21(m,1H),4.15–4.06(m,1H),3.10–3.02(m,1H),1.31(d,J＝7.1Hz,3H),1.24(d,J＝3.5Hz,3H),1.10(dd,J＝12.9,6.3Hz,6H),1.01–0.94(m,2H),0.74–0.66(m,2H).MS(ESI+)m/z:695.2(M+H+).
实施例9
化合物31的制备。
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化合物31的合成方法为：
将27(1eq)加入吡啶和DCM(1/1)的混合溶液中，室温下搅拌，缓慢滴加异丁酸酐(1.2eq)的DCM(1ml)溶液，然后继续搅拌1h，减压浓缩，柱层析得到化合物31.
得到如下具体化合物：
化合物31-1的表征数据为：1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.69(d,J＝4.9Hz,2H),8.39(s,1H),7.06(t,J＝4.9Hz,1H),6.61(d,J＝18.6Hz,1H),5.67(dd,J＝22.3,9.1Hz,1H),4.32(d,J＝9.3Hz,1H),4.13(d,J＝13.1Hz,1H),3.84–3.77(m,1H),3.02(s,3H),2.74–2.64(m,1H),1.23–1.19(m,6H),1.14(d,J＝22.5Hz,3H).13C NMR(101MHz,CDCl3)δ176.84,162.79,162.07,157.10,151.72,151.44,129.77,118.37,117.58,116.05,100.81(d,J＝185.3Hz),90.21(d,J＝39.8Hz),80.52,71.63(d,J＝16.0Hz),60.35,33.99,25.87,19.12,18.99,17.47(d,J＝25.0Hz).MS(ESI+)m/z:430.2(M+H+).
实施例10
化合物32的制备。
化合物32的合成方法为：
将27(1eq)、33(1.5eq)、DCC(1.5eq)、DMAP(0.1eq)加入无水DMF中，室温搅拌过夜，加EA稀释后，依次用饱和NaHCO3、水洗，干燥、浓缩，柱层析得32。得到如下具体化合物：
化合物32-1的表征数据为：1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.66(d,J＝4.7Hz,2H),8.38(s,1H),7.01(t,J＝4.9Hz,1H),6.65(d,J＝19.1Hz,1H),5.84(dd,J＝22.2,9.1Hz,1H),4.35(d,J＝9.2Hz,1H),4.14(d,J＝13.2Hz,1H),3.82(d,J＝13.1Hz,1H),3.52(d,J＝4.9Hz,1H),3.21(s,3H),3.01(s,3H),2.22–2.09(m,1H),1.19(d,J＝22.8Hz,3H),1.03(d,J＝7.1Hz,3H),0.96(d,J＝6.9Hz,3H),0.06(d,J＝1.7Hz,4H).13C NMR(101MHz,CDCl3)δ175.20,162.88,162.00,157.12,151.81,151.45,129.81,118.40,117.50,116.06,100.87(d,J＝185.2Hz),90.34(d,J＝39.4Hz),80.54,72.16(d,J＝15.8Hz),60.22,60.03,32.34,25.88,19.37,17.56(d,J＝24.9Hz),17.27.MS(ESI+)m/z:459.2(M+H+).
实验例
化合物抑制冠状病毒复制活性试验。
以下活性筛选试验委托中国科学院武汉病研究毒所P3实验室进行，按照常规病毒活性测试条件进行。
1、技术内容：在Vero E6细胞模型中验证上述合成化合物的抗病毒(SARS-CoV-2)活性。
2、技术方法和路线：Vero E6细胞接种至24孔板，18h后加入药物处理(上述化合物选择5个浓度梯度、终浓度10μM)，以0.01MOI的SARS-CoV-2病毒感染，37℃5％CO2培养箱孵育1h后换成含药物培养基，继续培养24h后收取部分上清，qPCR检测病毒RNA含量；48h、72h显微镜观察细胞的病变情况。设置DMSO溶剂对照、阳性药物对照。
3、实验结果。
结果如下表所示。
表1.化合物活性筛选结果
注：a表示24hr病毒RNA含量下降超过2个log，b表示24hr病毒RNA含量下降1-2个log，c表示24hr病毒RNA含量下降1个log以内。
从上述结果可以看出，本发明得到的化合物，部分化合物可以在24h使病毒RNA降低超过2个log，与阳性药物瑞德西韦活性相当，部分化合物可以在24h使病毒RNA降低约1-2个log，具有较好的抑制活性。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (3)
1.一种核苷类似物或其药学上可接受的盐，其特征在于，选自如下化合物：
2.权利要求1所述的核苷类似物或其药学上可接受的盐在制备用于预防和治疗RNA病毒感染疾病的药物中的应用，所述RNA病毒为SARS-CoV-2。
3.一种药物组合物，其特征在于，包括权利要求1所述的核苷类似物或其药学上可接受的盐，以及药学上可以接受的辅料或载体。
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| Publication number | Priority date | Publication date | Assignee | Title |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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Non-Patent Citations (2)
| Title |
|---|
| Junxing Shi，et al..Synthesis and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5’-triphosphates.《Bioorganic & Medicinal Chemistry Letters》.2011,第21卷7094-7098. * |
| Natalia Dyatkina，et al..5'-Triphosphate of 7-deaza-7-ethynyl-2'-deoxy-2'-fluoro- 2'-C-methyladenosine: New potent chain terminator of hepatitis C virus RNA polymerase.《Collection Symposium Series》.2008,第10卷341-342. * |
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