[go: up one dir, main page]

CN111285844A - 具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法和应用 - Google Patents

具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法和应用 Download PDF

Info

Publication number
CN111285844A
CN111285844A CN202010110738.9A CN202010110738A CN111285844A CN 111285844 A CN111285844 A CN 111285844A CN 202010110738 A CN202010110738 A CN 202010110738A CN 111285844 A CN111285844 A CN 111285844A
Authority
CN
China
Prior art keywords
nmr
dmso
substituted amide
thiophene
biological activity
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010110738.9A
Other languages
English (en)
Other versions
CN111285844B (zh
Inventor
时蕾
杨晓岚
龚晓峰
江经纬
袁胜涛
孙立
张贵生
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Henan Normal University
Original Assignee
Henan Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Henan Normal University filed Critical Henan Normal University
Priority to CN202010110738.9A priority Critical patent/CN111285844B/zh
Publication of CN111285844A publication Critical patent/CN111285844A/zh
Application granted granted Critical
Publication of CN111285844B publication Critical patent/CN111285844B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法和应用，该苯并噻唑取代酰胺类化合物的结构通式如下：

Description

具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方 法和应用
技术领域
本发明属于具有生物活性的化合物及其应用技术领域，具体涉及一种具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法和应用。
背景技术
苯并杂环类化合物由于具有特殊的共轭结构和独特的药理和生物活性，而且来源广泛，既能各处提炼出来，也能通过合成得到，因而在药学、农学和材料科学中都有着广泛应用[1]。苯并噻吩不仅可以作除草剂、杀虫剂[2]、植物生长调节剂[3]，还具有治疗哮喘[4]、预防骨质疏松[5]等生物活性。
含有酰胺键的化合物称为酰胺化合物，既可看作羧酸的含氮衍生物，也可看作氨或胺的衍生物。由于酰胺具有较突出的杀虫[6]、杀菌[7]、除草[8]等活性，所以在农药研究和开发中占有举足轻重的地位，而且研究生产出的药剂大多具有高效、低毒、低残留、环境友好等优点。酰胺类化合物也是临床上最为常用的抗肿瘤药之一，属于细胞周期非特异性广谱抗肿瘤药，当前在肺癌、胃癌、结肠癌、乳腺癌、恶性淋巴瘤等肿瘤的治疗中取得了很好的效果[9-11]。
考虑到酰胺和噻吩衍生物都是具有应用价值的潜在的具有生物活性的化合物，本发明设计合成了新型苯并噻吩取代酰胺衍生物并研究了它们对抗癌PIMI靶点的抑制率和初步生物活性。
参考文献：
[1]T.Y.Zhang,J.O'toole,C.S.Proctor.RecentAdvances in the SynthesisandApplications of Benzo[b]thiophenes[J].Sulfurreports,1999,22,1-47。
[2]宋宝安,吴刚.新杂环农药:杀虫剂[M].北京:化学工业出版社,2010。
[3]L.R.M.Saniere,M.R.Pizzonero,N.Triballeau,etal.Preparationofazetidine derivatives as GPR43 antagonists useful in thetreatment of metabolic andinflammatorydiseases[J].PCTInt.Appl.WO2012098033,2012。
[4]A.Rossi,C.Pergola,A.Koeberle,et al.The 5-lipoxygenase inhibitor,zileuton,suppresses prostaglandin biosynthesis by inhibition ofarachidonicacid release in macrophages[J].British journalofpharmacology,2010,161,555。
[5]Z.Qin,I.Kastrati,R.E.P.Chandrasena,et al.Benzothiophene selectiveestrogen receptor modulators with modulated oxidative activity and receptoraffinity[J].Journal ofMedicinal Chemistry,2007,50,2682。
[6]W.Zhao,J.H.Xing,T.M.Xu,et al.Synthesis and in vivo nematocidalevaluation ofnovel3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives[J].Frontiers of Chemical Science andEngineering,2017,11,363。
[7]X.H.Liu,L.Qiao,Z.W.Zhai,et al.Novel 4-Pyrazole CarboxamideDerivatives Containing Flexible Chain Motif:Design,Synthesis and AntifungalActivity[J].Pest Management Science,2019,doi:10.1002/ps.5463。
[8]L.P.Duan,Q.F.Zhao,H.B.Zhang,et al.Novel 2H-[1,2,4]Thiadiazolo[2,3-a]Pyrimidine Derivatives Bearing Chiral S(-)-2-(4-Chlorophenyl)-3-Methylbutyric Acid Moiety:Design,Synthesis andHerbicidalActivity[J].ArabianJournal ofChemistry,2010,3,225。
[9]A.Iqubal，M.K.Iqubal，S.Sharma，et al.Molecular Mechanism Involved inCyclophosphamide－Induced Cardiotoxicity:Old Drug with a New Vision[J].LifeScience,2019,218,112。
[10]赵培培，禚映辰，赵雪，等.环磷酰胺在节律性化疗中的研究进展[J].中国医院药学杂志,2018,38,104。
[11]S.Bae，C.Charles-Schoeman.Oral Cyclophosphamide in Treatment ofPatients with Refractory Idiopathic Inflammatory Myopathies:a RetrospectiveObservational Study[J].ClinicalRheumatology,2018,37,2113。
发明内容
本发明解决的技术问题是提供了一种具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法，该方法根据活性拼接原理将噻吩基团引入到酰胺中得到具有生物活性的新型苯并噻唑取代酰胺类化合物，制得的新型苯并噻唑取代酰胺类化合物对PIM抑制剂的酶具有抑制活性，在制备抗癌药物领域具有较好的应用前景。
本发明为解决上述技术问题采用如下技术方案，具有生物活性的新型苯并噻唑取代酰胺类化合物，其特征在于该苯并噻唑取代酰胺类化合物的结构通式如下：
Figure BDA0002389893710000021
5a R＝H，R1＝Ph，
Figure BDA0002389893710000022
5b R＝H，R1＝Ph，
Figure BDA0002389893710000023
5c R＝H，R1＝Ph，
Figure BDA0002389893710000024
5d R＝Ph，R1＝H，
Figure BDA0002389893710000031
5e R＝H，R1＝4-OCH3Ph，
Figure BDA0002389893710000032
5fR＝H，R1＝4-OCH3Ph，
Figure BDA0002389893710000033
5g R＝H，R1＝4-OCH3Ph，
Figure BDA0002389893710000034
5h R＝H，R1＝4-OCH3Ph，
Figure BDA0002389893710000035
5i R＝H，R1＝4-CF3Ph，
Figure BDA0002389893710000036
5j R＝H，R1＝4-CF3Ph，
Figure BDA0002389893710000037
5k R＝H，R1＝4-CF3Ph，
Figure BDA0002389893710000038
5l R＝H，R1＝4-CF3Ph，
Figure BDA0002389893710000039
5m R＝H，
Figure BDA00023898937100000310
Figure BDA00023898937100000311
5n R＝H，
Figure BDA00023898937100000312
5o R＝CH3，R1＝H，
Figure BDA00023898937100000313
5p R＝CH3，R1＝H，
Figure BDA00023898937100000314
5q R＝CH3，R1＝H，
Figure BDA00023898937100000315
5r R＝CH3，R1＝H，
Figure BDA00023898937100000316
5s R＝CH3，R1＝4-OCH3Ph，
Figure BDA00023898937100000317
5t R＝CH3，R1＝4-OCH3Ph，
Figure BDA00023898937100000318
5u R＝CH3，R1＝4-OCH3Ph，
Figure BDA00023898937100000319
5v R＝CH3，R1＝4-CF3Ph，
Figure BDA00023898937100000320
5w R＝CH3，R1＝4-CF3Ph，
Figure BDA00023898937100000321
5x R＝CH3，
Figure BDA00023898937100000322
5y R＝CH3，
Figure BDA00023898937100000323
Figure BDA00023898937100000324
5z R＝CH3，
Figure BDA00023898937100000325
5A R＝CH3，R1＝4-N(CH3)Ph，
Figure BDA00023898937100000326
5B R＝CH3，R1＝4-N(CH3)Ph，
Figure BDA00023898937100000327
本发明所述的具有生物活性的新型苯并噻唑取代酰胺类化合物的合成方法，其特征在于具体合成路线为：
Figure BDA0002389893710000041
本发明所述的具有生物活性的新型苯并噻唑取代酰胺类化合物在制备抗癌药物中的应用，所述新型苯并噻唑取代酰胺类化合物对PIM抑制剂的酶具有抑制活性，其中活性较优的化合物及对应化合物对PIM I靶点的抑制率分别为：
Figure BDA0002389893710000042
(84.62±0.24)％；
Figure BDA0002389893710000043
(74.07±2.22)％；
Figure BDA0002389893710000044
(70.77±2.11)％；
Figure BDA0002389893710000045
(68.26±1.17)％；
Figure BDA0002389893710000046
(66.79±0.86)％；
Figure BDA0002389893710000047
(63.60±1.53)％；
Figure BDA0002389893710000048
(62.47±2.82)％。
本发明与现有技术相比具有以下优点：本发明合成的新型苯并噻唑取代酰胺类化合物对PIM抑制剂的酶具有抑制活性，其中部分化合物具有较优的生物活性，在制备抗癌药物领域具有较好的应用前景。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例
1、化合物的合成
(1)6-苯基苯并噻吩类化合物1的合成
Figure BDA0002389893710000051
在氮气氛围下，取代苯硼酸(12mmol)、6-溴苯并噻吩(10mmol)、氟化铯(30mmol)和四三苯基磷钯(0.9mmol)溶解在30mL干燥的乙二醇二甲醚溶剂中，反应混合物在100℃的油浴中加热回流。通过TLC监测反应直至不再检测到6-溴苯并噻吩。然后将反应混合物冷却，用乙酸乙酯和水萃取，再将有机层干燥并浓缩。然后采用柱色谱分离(石油醚)粗产物得到产物6-苯基苯并噻吩类化合物1。
(2)2,3-二溴-6-苯基苯并[b]噻吩类化合物2的合成
Figure BDA0002389893710000052
在氮气氛围下，10mmol 6-苯基苯并噻吩类化合物1溶解在30mL干燥的乙醚中，然后向混合物中滴加30mmol液溴。将混合物置于室温下反应，通过TLC监测反应直至不再检测到6-苯基苯并噻吩类化合物1。向反应体系中加入饱和的硫代硫酸钠溶液，然后用乙酸乙酯萃取，再将有机层干燥并浓缩。然后采用柱色谱分离(石油醚)粗产物得到产物2,3-二溴-6-苯基苯并[b]噻吩类化合物2。
(3)3-溴-2,6-二苯基苯并[b]噻吩类化合物3的合成
Figure BDA0002389893710000053
在氮气氛围下，10mmol 2,3-二溴-6-苯基苯并[b]噻吩类化合物2和10mmol取代硼酸溶解在35mL 1,4-二氧六环溶剂中，然后向混合物中加入0.5mmol四三苯基磷钯，再加22mL 2M的碳酸钠溶液。将混合物置于110℃的油浴中加热回流，通过TLC监测反应直至不再检测到2,3-二溴-6-苯基苯并[b]噻吩类化合物2。向反应体系中加入饱和的氯化铵溶液猝灭反应，然后用乙酸乙酯萃取，再将有机层干燥并浓缩。然后采用柱色谱分离(石油醚)粗产物得到产物3-溴-2,6-二苯基苯并[b]噻吩类化合物3。
(4)2,6-二苯基苯并[b]噻吩-3-羧酸类化合物4的合成
Figure BDA0002389893710000061
在氮气氛围下，将3-溴-2,6-二苯基苯并[b]噻吩类化合物3(5.0mmol)用35mL无水四氢呋喃溶解后放置于-78℃的低温仪中，然后向混合物中逐滴加入正丁基锂(5.76mmol)。加完后，溶液在-78℃下继续搅拌2小时。用固体CO2(5.0g，113.6mmol)淬灭反应混合物，并搅拌过夜，使温度升至20℃。向反应体系中加入水猝灭反应，然后用37wt％盐酸溶液将该溶液酸化至pH＜2，并将产物用乙酸乙酯(4×50mL)萃取，再将有机层干燥并浓缩。然后采用柱色谱分离(石油醚：乙酸乙酯)粗产物得到产物2,6-二苯基苯并[b]噻吩-3-羧酸类化合物4。
(5)N-(R2)-2,6-二苯基苯并[b]噻吩-3-甲酰胺类化合物5的合成
Figure BDA0002389893710000062
将0.5mmol 2,6-二苯基苯并[b]噻吩-3-羧酸类化合物4溶解于5mL无水二氯甲烷中，加入5mmol二氯亚砜，混合物置于45℃的油浴锅中加热回流，反应通过TLC检测。反应结束后，减压蒸干溶剂，直接进行下一步。在氮气氛围下，用无水二氯甲烷溶解上步所得固体，并向其中加入三乙胺(1.5mmol)和取代氨基化合物(0.5mmol)，然后将反应体系置于室温下反应，并用TLC检测。反应结束后，用饱和氯化铵溶液和二氯甲烷萃取，再将有机层干燥并浓缩。然后采用柱色谱(石油醚：乙酸乙酯)分离粗产物得到产物N-(R2)-2,6-二苯基苯并[b]噻吩-3-甲酰胺类化合物5。
2、化合物数据
Figure BDA0002389893710000071
N-(苯并[b]噻吩-5-基)-2,6-二苯基苯并[b]噻吩-3-甲酰胺(5a)：白色固体，产率：80％；m.p.220-222℃.1H NMR(600MHz,DMSO)δ10.70(s,1H),8.43(s,1H),8.40(s,1H),7.94(d,J＝9.0Hz,1H),7.89(d,J＝8.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.81(d,J＝7.8Hz,2H),7.78(d,J＝5.4Hz,1H),7.71(d,J＝7.2Hz,2H),7.54–7.49(m,3H),7.48(d,J＝7.0Hz,3H),7.41(dd,J＝12.8,7.2Hz,2H).13C NMR(150MHz,DMSO)δ163.4,142.0,139.7,139.6,138.7,138.0,137.3,135.7,134.7,132.8,129.6,129.1,129.1,128.4,128.2,127.7,126.9,124.4,124.1,123.2,122.7,120.3,117.6,114.2.HRMS(ESI),m/z calcd.forC29H19NNaOS2([M+Na]+)484.0800,found:484.0791.
Figure BDA0002389893710000072
2,6-二苯基-N-(吡啶-4-基)苯并[b]噻吩-3-甲酰胺(5b)：白色固体，产率：89％；m.p.229-231℃.1H NMR(600MHz,CDCl3)δ8.37(d,J＝4.8Hz,2H),8.30(d,J＝8.4Hz,1H),8.02(s,1H),7.71(d,J＝8.4Hz,1H),7.67(d,J＝7.2Hz,3H),7.60(d,J＝7.2Hz,2H),7.48(t,J＝7.8Hz,5H),7.39(t,J＝7.2Hz,1H),7.21(d,J＝4.8Hz,2H).13C NMR(150MHz,CDCl3)δ163.2,150.7,146.3,144.8,140.6,139.6,138.9,137.9,132.6,130.0,129.6,129.5,129.1,127.8,127.5,127.2,125.3,124.5,120.2,113.6.HRMS(ESI),m/z calcd.forC26H29N2OS([M+H]+)407.1213,found:407.1203.
Figure BDA0002389893710000073
N-(1H-吲哚-5-基)-2,6-二苯基苯并[b]噻吩-3-甲酰胺(5c)：白色固体，产率：79％；m.p.230-232℃.1H NMR(600MHz,DMSO)δ11.06(s,1H),10.37(s,1H),8.41(s,1H),7.98(s,1H),7.88(d,J＝8.4Hz,1H),7.84–7.78(m,3H),7.73(d,J＝7.2Hz,2H),7.50(dt,J＝15.4,7.8Hz,4H),7.41(dd,J＝14.4,7.2Hz,2H),7.35(d,J＝6.0Hz,2H),7.25(d,J＝9.0Hz,1H),6.43(s,1H).13C NMR(150MHz,DMSO)δ162.9,141.4,141.4,139.6,138.7,138.3,137.2,133.1,132.9,130.8,130.2,129.0,128.9,128.1,127.6,127.4,126.9,126.1,124.3,123.2,120.2,115.3,111.5,111.2,101.2.HRMS(ESI),m/z calcd.for C29H20N2NaOS([M+Na]+)467.1189,found:467.1176.
Figure BDA0002389893710000081
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2,6-二苯基苯并[b]噻吩-3-甲酰胺(5d)：白色固体，产率：86％；m.p.223-225℃.1HNMR(600MHz,DMSO)δ10.39(s,1H),8.41(s,1H),7.88–7.73(m,4H),7.66(d,J＝8.0Hz,2H),7.54–7.46(m,4H),7.42(dt,J＝14.6,7.4Hz,2H),7.29(d,J＝3.0Hz,1H),7.03(d,J＝8.4Hz,1H),6.81(d,J＝9.0Hz,1H),4.38–4.02(m,4H).13C NMR(150MHz,DMSO)δ163.4,146.4,143.4,142.3,140.4,140.0,139.2,138.5,137.7,133.2,133.0,130.1,129.6,129.5,129.5,128.6,127.4,124.9,120.7,117.3,113.5,109.4,64.7,64.5.HRMS(ESI),m/z calcd.for C27H22NNaO3S([M+Na]+)486.1110,found:486.1116.
Figure BDA0002389893710000082
N-(苯并[b]噻吩-5-基)-2-(甲氧基苯基)-6-苯基苯并[b]噻吩-3-甲酰胺(5e)：白色固体，产率：82％；m.p.174-176℃.1H NMR(600MHz,DMSO)δ10.68(s,1H),8.42(s,1H),8.39(s,1H),7.95(d,J＝7.8Hz,1H),7.84(d,J＝7.8Hz,1H),7.79(d,J＝6.6Hz,4H),7.64(d,J＝7.8Hz,2H),7.50(t,J＝7.8Hz,4H),7.40(d,J＝6.6Hz,1H),7.04(d,J＝7.2Hz,2H),3.77(s,3H).13C NMR(150MHz,DMSO)δ163.7,159.9,142.1,139.9,139.6,138.4,138.2,137.0,135.8,134.5,129.5,129.1,128.6,128.4,127.6,126.9,125.1,124.3,124.2,122.9,122.7,120.2,117.7,114.6,114.1,55.3.HRMS(ESI),m/z calcd.for C30H21NNaO2S2([M+Na]+)514.0906,found:514.0894.
Figure BDA0002389893710000091
2-(4-甲氧基苯基)-6-苯基-N-(吡啶-4-基)苯并[b]噻吩-3-甲酰胺(5f)：白色固体，产率：80％；m.p.185-187℃.1H NMR(600MHz,CDCl3)δ8.39(d,J＝5.2Hz,2H),8.27(d,J＝8.4Hz,1H),7.99(s,1H),7.69(d,J＝7.2Hz,2H),7.65(d,J＝7.2Hz,2H),7.52(d,J＝8.4Hz,2H),7.46(t,J＝7.8Hz,2H),7.37(t,J＝7.2Hz,1H),7.25(s,2H),6.97(d,J＝8.4Hz,2H),3.84(s,3H).13C NMR(150MHz,CDCl3)δ163.4,161.0,150.7,146.6,144.9,140.6,139.3,138.7,138.0,130.9,129.1,127.7,127.4,126.4,125.2,124.6,124.3,120.1,114.9,113.6,55.6.HRMS(ESI),m/z calcd.for C27H21N2O2S([M+H]+)437.1318,found:437.1311.
Figure BDA0002389893710000092
N-(1H-吲哚-5-基)-2-(4-甲氧基苯基)-6-苯基苯并[b]噻吩-3-甲酰胺(5g)：白色固体，产率：84％；m.p.201-203℃.1H NMR(600MHz,DMSO)δ11.06(s,1H),10.36(s,1H),8.37(s,1H),8.01(s,1H),7.84(d,J＝8.4Hz,1H),7.79(d,J＝8.4Hz,3H),7.66(d,J＝8.4Hz,2H),7.51(t,J＝7.8Hz,2H),7.40(t,J＝7.2Hz,1H),7.35(d,J＝7.8Hz,2H),7.27(d,J＝8.4Hz,1H),7.05(d,J＝9.0Hz,2H),6.43(s,1H),3.78(s,3H).13C NMR(150MHz,DMSO)δ163.1,159.8,141.4,139.7,138.5,138.4,136.9,133.0,130.9,129.5,129.1,129.1,129.0,127.6,127.4,126.9,126.0,125.3,124.2,123.0,120.1,115.3,114.5,111.5,111.2,101.2,55.3.HRMS(ESI),m/z calcd.for C30H22N2NaO2S([M+Na]+)497.1294,found:497.1277.
Figure BDA0002389893710000093
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-(4-甲氧基苯基)-6-苯基苯并[b]噻吩-3-甲酰胺(5h)：黄色固体，产率：83％；m.p.180-182℃.1H NMR(400MHz,DMSO)δ10.39(s,1H),8.37(s,1H),7.79(d,J＝4.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.50(t,J＝7.6Hz,1H),7.39(t,J＝7.4Hz,1H),7.33(s,1H),7.05(d,J＝8.8Hz,1H),6.82(d,J＝8.8Hz,1H),4.23(q,J＝5.2Hz,1H),3.79(s,1H).13C NMR(100MHz,DMSO)δ163.1,159.9,142.9,141.8,139.8,139.6,138.3,138.2,136.9,132.6,129.4,129.0,128.6,127.6,126.9,125.1,124.3,122.9,120.1,116.8,114.6,113.0,108.9,64.2,64.0,55.3,45.3.HRMS(ESI),m/zcalcd.for C30H23NNaO3S([M+Na]+)516.1240,found:516.1231.
Figure BDA0002389893710000101
N-(苯并[b]噻吩-5-基)-6-苯基-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5i)：白色固体，产率：80％；m.p.211-213℃.1HNMR(400MHz,DMSO)δ10.79(s,1H),8.48(s,1H),8.40(s,1H),7.94(dd,J＝13.6,6.4Hz,3H),7.87(t,J＝8.4Hz,4H),7.80(t,J＝7.6Hz,3H),7.56–7.45(m,4H),7.41(t,J＝7.2Hz,1H).13C NMR(100MHz,DMSO)δ163.1,140.1,139.9,139.4,139.1,137.8,136.8,135.6,134.7,131.1,129.1,129.0,128.5,127.8,127.0,126.0(d,J＝3.6Hz),124.7,124.1,123.5,122.8,120.4,117.7,114.3.HRMS(ESI),m/z calcd.for C30H18F3NNaOS2([M+Na]+)552.0674,found:552.0646.
Figure BDA0002389893710000102
6-苯基-N-(吡啶-4-基)-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5J)：白色固体，产率：80％；m.p.173-175℃.1H NMR(600MHz,DMSO)δ11.06(s,1H),8.49(s,3H),7.95–7.83(m,6H),7.80(s,2H),7.64(s,2H),7.51(d,J＝6.6Hz,2H),7.42(d,J＝6.6Hz,1H).13C NMR(150MHz,DMSO)δ164.5,151.0,145.7,141.6,139.8,139.6,138.4,137.9,137.0,130.5,129.6,129.6,128.3,127.5,126.6(d,J＝3.6Hz),125.3,123.9,121.0,114.2.HRMS(ESI),m/z calcd.for C27H18F3N2OS([M+H]+)475.1098,found:475.1073.
Figure BDA0002389893710000111
N-(1H-吲哚-5-基)-6-苯基-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5k)：浅黄色固体，产率：79％；m.p.242-244℃.1HNMR(600MHz,DMSO)δ11.08(s,1H),10.47(s,1H),8.00(s,1H),7.92(d,J＝10.2Hz,3H),7.87(d,J＝8.4Hz,3H),7.81(d,J＝7.8Hz,2H),7.52(t,J＝7.8Hz,2H),7.41(t,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,2H),7.26(d,J＝8.4Hz,1H),6.44(s,1H).13C NMR(150MHz,DMSO)δ162.5,139.5,139.1138.0,137.7,137.0,133.2,131.6,130.6,129.1,128.9,127.8,127.5,127.0,126.1,125.99(dd,J＝7.5,3.6Hz),124.6,123.6,120.4,115.3,111.7,111.3,101.2.HRMS(ESI),m/z calcd.forC30H19F3N2NaOS([M+Na]+)535.1036,found:535.1036..
Figure BDA0002389893710000112
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-6-苯基-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5l)：白色固体，产率：80％；m.p.230-232℃.1H NMR(600MHz,DMSO)δ10.49(s,1H),8.46(s,1H),7.88(q,J＝9.0Hz,5H),7.81(d,J＝7.2Hz,2H),7.52(t,J＝7.8Hz,2H),7.41(t,J＝7.8Hz,1H),7.31(s,1H),7.03(d,J＝8.4Hz,1H),6.82(d,J＝8.4Hz,1H),4.23(dd,J＝12.0,4.9Hz,5H).13C NMR(150MHz,DMSO)δ162.5,143.0,140.0,139.9,139.4,139.1,137.8,136.8,132.3,131.0,129.1,128.9,127.8,127.0,126.04(dd,J＝7.5,3.9Hz),124.6,123.5,120.4,116.9,113.1,109.0,64.2,64.0.HRMS(ESI),m/z calcd.forC30H20F3NNaO2S([M+Na]+)554.1008,found:554.1003.
Figure BDA0002389893710000113
2-(二苯并[b,d]呋喃-4-基)-6-苯基-N-(吡啶-4-基)苯并[b]噻吩-3-甲酰胺(5m)：白色固体，产率：91％；m.p.261-263℃.1H NMR(400MHz,DMSO)δ10.93(s,1H),8.49(s,1H),8.35(d,J＝6.0Hz,2H),8.21(d,J＝7.6Hz,1H),8.14(d,J＝7.2Hz,1H),8.05(d,J＝8.4Hz,1H),7.87(d,J＝8.4Hz,1H),7.82(d,J＝7.2Hz,2H),7.75(d,J＝7.6Hz,1H),7.54(t,J＝4.4Hz,2H),7.51(dd,J＝7.8,3.6Hz,3H),7.46(d,J＝8.0Hz,1H),7.44–7.34(m,3H).13CNMR(100MHz,DMSO)δ164.1,155.5,152.3,150.2,145.9,139.6,139.5,138.7,137.68(s),137.2,130.4,129.3,128.2,127.9,127.1,124.7,124.5,123.8,123.8,123.6,122.4,121.6,120.4,117.4,113.7,111.5.HRMS(ESI),m/z calcd.for C32H21N2O2S([M+H]+)497.1318,found:497.1330.
Figure BDA0002389893710000121
2-(二苯并[b,d]呋喃-4-基)-N-(1H-吲哚-5-基)-6-苯基苯并[b]噻吩-3-甲酰胺(5n)：白色固体，产率：80％；m.p.211-213℃.1H NMR(400MHz,DMSO)δ10.99(s,1H),10.28(s,1H),8.49(s,1H),8.21(d,J＝7.6Hz,1H),8.18(d,J＝7.6Hz,1H),8.07(d,J＝8.4Hz,1H),7.88(d,J＝8.4Hz,1H),7.83(dd,J＝10.4,7.6Hz,4H),7.63(d,J＝8.4Hz,1H),7.52(dt,J＝10.2,6.8Hz,4H),7.41(t,J＝7.6Hz,2H),7.29(t,J＝2.8Hz,1H),7.26(d,J＝8.8Hz,1H),7.18(d,J＝8.8Hz,1H),6.34(t,J＝2.0Hz,1H).13C NMR(150MHz,DMSO)δ162.5,139.2,139.1,137.8,137.6,137.2,137.0,136.6,129.7,128.9,127.5,126.8,126.0,126.0,124.4,123.5,120.0,115.3,111.7,111.2,101.2,20.7.HRMS(ESI),m/z calcd.forC35H22N2NaO2S([M+Na]+)557.1294,found:557.1267.
Figure BDA0002389893710000122
N-(苯并[b]噻吩-5-基)-2-苯基-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5o)：白色固体，产率：89％；m.p.218-220℃.1H NMR(600MHz,DMSO)δ10.69(s,1H),8.39(d,J＝4.4Hz,2H),7.94(d,J＝9.0Hz,1H),7.87(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.77(s,1H),7.70(d,J＝8.4Hz,4H),7.49(d,J＝4.8Hz,1H),7.47(d,J＝6.0Hz,3H),7.41(t,J＝7.4Hz,1H),7.31(d,J＝7.8Hz,2H).13C NMR(150MHz,DMSO)δ163.5,141.8,139.8,138.8,137.8,137.2,137.0,136.6,135.7,134.6,132.8,129.6,129.1,129.1,129.0,128.4,128.1,126.7,124.2,124.1,123.1,122.7,119.9,117.6,114.2,20.7.HRMS(ESI),m/z calcd.forC30H21NNaOS2([M+Na]+)498.0957,found:498.0967.
Figure BDA0002389893710000131
2-苯基-N-(吡啶-4-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5p)：白色固体，产率：90％；m.p.294-296℃.1H NMR(600MHz,DMSO)δ10.94(s,1H),8.48(d,J＝3.6Hz,2H),8.40(s,1H),7.84(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,2H),7.64(d,J＝7.2Hz,4H),7.48(t,J＝7.6Hz,2H),7.42(t,J＝7.2Hz,1H),7.31(d,J＝7.8Hz,2H),2.36(s,3H).13C NMR(150MHz,DMSO)δ164.6,160.0,150.5,145.4,142.9,138.4,137.6,137.0,136.6,129.6,129.6,127.6,126.69(s),124.8,124.2,122.8,119.8,114.6,113.6,55.3,20.7.HRMS(ESI),m/z calcd.for C27H21N2OS([M+H]+)421.1369,found:421.1379.
Figure BDA0002389893710000132
N-(1H-吲哚-5-基)-2-苯基-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5q)：白色固体，产率：85％；m.p.243-245℃.1H NMR(600MHz,DMSO)δ11.06(s,1H),10.36(s,1H),8.38(s,1H),7.98(s,1H),7.86(d,J＝8.4Hz,1H),7.79(d,J＝8.4Hz,1H),7.71(dd,J＝12.6,7.8Hz,4H),7.48(t,J＝7.6Hz,2H),7.41(t,J＝7.2Hz,1H),7.34(d,J＝6.6Hz,2H),7.31(d,J＝7.8Hz,2H),7.25(d,J＝8.6Hz,1H),6.42(s,1H),2.37(s,3H).13C NMR(150MHz,DMSO)δ162.9,141.1,138.7,138.1,137.1,137.0,136.7,133.1,133.0,130.8,130.2,129.6,129.0,128.9,128.1,127.4,126.7,126.1,124.1,123.2,119.8,1153,111.5,111.2,101.2,20.7.HRMS(ESI),m/z calcd.for C30H22N2NaOS([M+Na]+)481.1345,found:481.1333.
Figure BDA0002389893710000141
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-苯基-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5r)：白色固体，产率：84％；m.p.228-230℃.1HNMR(600MHz,DMSO)δ10.38(s,1H),8.37(s,1H),7.80(q,J＝8.4Hz,1H),7.67(dd,J＝19.2,7.8Hz,2H),7.48(t,J＝7.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.35–7.25(m,1H),7.04(d,J＝9.0Hz,1H),6.81(d,J＝9.0Hz,1H),4.23(dd,J＝12.0,5.4Hz,2H),2.36(s,2H).13C NMR(150MHz,DMSO)δ163.0,143.0,141.6,139.9,138.7,137.8,137.2,137.0,136.6,132.8,132.5,129.6,129.1,129.0,128.1,126.7,124.2,123.1,119.9,116.8,113.0,108.9,64.2,64.0,HRMS(ESI),m/z calcd.forC30H23NNaO3S([M+Na]+)500.1291,found:500.1268.
Figure BDA0002389893710000142
2-(4-甲氧基苯基)-N-(吡啶-4-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5s)：白色固体，产率：84％；m.p.294-296℃.1H NMR(600MHz,DMSO)δ10.93(s,1H),8.48(d,J＝4.2Hz,2H),8.36(s,1H),7.79(dd,J＝19.8,8.4Hz,2H),7.68(d,J＝7.8Hz,4H),7.65(d,J＝3.6Hz,2H),7.57(d,J＝8.2Hz,2H),7.31(d,J＝7.7Hz,2H),7.04(d,J＝8.3Hz,2H),3.78(s,3H),2.36(s,3H).13C NMR(150MHz,DMSO)δ164.6,160.0,150.5,145.4,142.9,138.4,137.6,137.0,136.6,129.6,129.6,127.6,126.7,124.8,124.2,122.8,119.8,114.6,113.6,55.3,20.7.HRMS(ESI),m/z calcd.for C28H23N2O2 S([M+H]+)451.1475,found:451.1467.
Figure BDA0002389893710000143
N-(1H-吲哚-5-基)-2-(4-甲氧基苯基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5t)：白色固体，产率：81％；m.p.230-232℃.1HNMR(600MHz,DMSO)δ11.05(s,1H),10.34(s,1H),8.33(s,1H),8.01(s,1H),7.82(d,J＝8.4Hz,1H),7.77(d,J＝8.4Hz,1H),7.69(d,J＝7.8Hz,2H),7.65(d,J＝8.4Hz,2H),7.34(s,2H),7.31(d,J＝7.8Hz,2H),7.27(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,2H),6.43(s,1H),3.78(s,3H),2.36(s,3H).13C NMR(150MHz,DMSO)δ163.1,159.8,141.2,138.4,138.2,136.9,136.8,136.8,133.0,130.9,129.6,129.4,129.1,127.4,126.7,126.0,125.3,124.0,122.9,119.7,115.2,114.5,111.4,111.2,101.2,55.3,20.7.HRMS(ESI),m/z calcd.for C31H24N2NaO2S([M+Na]+)511.1451,found:511.1436.
Figure BDA0002389893710000151
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-(4-甲氧基苯基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5u)：白色固体，产率：78％；m.p.193-195℃.1H NMR(400MHz,DMSO)δ10.38(s,1H),8.33(s,1H),7.76(s,2H),7.68(d,J＝8.4Hz,2H),7.59(d,J＝8.8Hz,2H),7.31(d,J＝8.8Hz,3H),7.05(d,J＝8.8Hz,3H),6.81(d,J＝8.8Hz,1H),4.23(dd,J＝8.4,4.8Hz,4H),3.79(s,3H),2.36(s,3H).13C NMR(100MHz,DMSO)δ163.6,160.3,143.4,142.1,140.3,138.8,138.5,137.4,137.3,137.2,133.0,130.1,129.9,129.0,127.2,125.6,124.5,123.3,123.3,120.2,117.3,115.0,113.5,109.4,64.7,64.5,55.8,45.8,21.2.HRMS(ESI),m/z calcd.for C31H25NNaO4S([M+Na]+)530.1396,found:530.1380.
Figure BDA0002389893710000152
N-(1H-吲哚-5-基)-6-(对甲苯基)-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5v)：白色固体，产率：60％；m.p.242-244℃.1H NMR(400MHz,DMSO)δ11.07(s,1H),10.44(s,1H),8.43(s,1H),7.98(s,1H),7.87(dt,J＝14.8,8.4Hz,5H),7.71(d,J＝7.8Hz,2H),7.35(dt,J＝12.8,11.6Hz,4H),7.23(d,J＝6.8Hz,1H),6.42(s,1H),2.37(s,3H).13C NMR(100MHz,DMSO)δ162.5,139.2,139.1,137.8,137.6,137.2,137.0,136.6,133.2,131.6,130.6,129.7,129.7,128.9,127.4,126.8,126.1,126.0(d,J＝3.9Hz),124.4,124.4,123.5,120.0,115.3,111.6,111.2,101.2,20.7.HRMS(ESI),m/z calcd.for C31H22F3N2OS([M+H]+)527.1399,found:527.1373.
Figure BDA0002389893710000161
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-6-(对甲苯基)-2-(4-(三氟甲基)苯基)苯并[b]噻吩-3-甲酰胺(5w)：白色固体，产率：50％；m.p.270-272℃.1H NMR(400MHz,DMSO)δ10.48(s,1H),8.42(s,1H),7.88–7.80(m,6H),7.70(d,J＝8.4Hz,2H),7.32(d,J＝7.2Hz,3H),7.03(d,J＝8.8Hz,1H),6.82(d,J＝8.8Hz,1H),4.23(q,J＝4.8Hz,4H),2.37(s,3H).13CNMR(100MHz,DMSO)δ163.0,143.5,140.5,140.1,139.6,138.2,138.0,137.7,137.3,137.0,132.8,131.5,130.2,129.4,127.2,126.5,124.9,123.9,120.5,117.3,113.6,109.5,64.7,64.5,21.2.HRMS(ESI),m/z calcd.for C31H22F3NNaO3S([M+Na]+)568.1165,found:568.1151.
Figure BDA0002389893710000162
2-(二苯并[b,d]呋喃-2-基)-N-(吡啶-4-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5x)：白色固体，产率：85％；m.p.312-314℃.1HNMR(600MHz,DMSO)δ10.89(s,1H),8.48(s,1H),8.35(d,J＝4.8Hz,2H),8.22(d,J＝7.8Hz,1H),8.16(d,J＝7.8Hz,1H),8.03(d,J＝8.4Hz,1H),7.86(d,J＝8.4Hz,1H),7.75(d,J＝7.8Hz,1H),7.73(d,J＝7.2Hz,2H),7.52(m,3H),7.48(t,J＝7.8Hz,1H),7.42(d,J＝8.4Hz,1H),7.39(t,J＝7.2Hz,1H),7.33(d,J＝7.8Hz,2H),2.37(s,3H).13C NMR(150MHz,DMSO)δ164.0,155.4,152.2,150.3,145.6,139.4,138.2,137.5,137.2,136.9,136.6,130.4,129.8,128.1,126.8,124.4,124.4,123.7,123.6,123.5,123.2,122.2,121.5,119.9,117.3,113.6,111.4,20.7.HRMS(ESI),m/zcalcd.for C33H23N2O2([M+H]+)511.1475,found:511.1465.
Figure BDA0002389893710000163
2-(二苯并[b,d]呋喃-2-基)-N-(1H-吲哚-5-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5y)：白色固体，产率：80％；m.p.303-305℃.1H NMR(400MHz,DMSO)δ10.99(s,1H),10.26(s,1H),8.46(s,1H),8.28–8.12(m,2H),8.04(d,J＝8.4Hz,1H),7.85(d,J＝10.4Hz,2H),7.81(d,J＝7.6Hz,1H),7.74(d,J＝8.0Hz,2H),7.63(d,J＝8.4Hz,1H),7.55–7.47(m,2H),7.41(t,J＝7.4Hz,1H),7.33(d,J＝8.0Hz,2H),7.29(t,J＝2.8Hz,1H),7.25(d,J＝8.8Hz,1H),7.17(d,J＝8.8Hz,1H),6.33(s,1H),2.38(s,3H).13C NMR(150MHz,DMSO)δ163.0,155.9,152.8,140.0,137.8,137.8,137.6,137.2,136.8,133.4,132.4,131.2,130.2,128.5,127.8,127.3,126.4,124.9,124.5,124.2,123.9,123.9,123.8,122.3,121.9,120.3,118.2,115.9,112.2,111.5,101.5,21.2.HRMS(ESI),m/z calcd.forC36H24N2NaO2S([M+Na]+)571.1451,found:571.1430.
Figure BDA0002389893710000171
2-(二苯并[b,d]呋喃-2-基)-N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5z)：白色固体，产率：75％；m.p.264-266℃.1H NMR(400MHz,DMSO)δ10.31(s,1H),8.45(s,1H),8.21(dd,J＝11.6,7.6Hz,2H),7.99(d,J＝8.4Hz,1H),7.84(d,J＝8.4Hz,1H),7.80–7.69(m,3H),7.53(d,J＝5.2Hz,2H),7.50(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.33(d,J＝8.0Hz,2H),7.18(d,J＝2.4Hz,1H),6.95(d,J＝8.8Hz,1H),6.72(d,J＝8.8Hz,1H),4.17(s,4H),2.37(s,3H).13C NMR(100MHz,DMSO)δ163.0,155.9,152.8,143.3,140.1,139.9,137.8,137.6,137.2,137.1,133.0,131.9,130.2,128.5,128.4,127.2,124.9,124.6,124.1,124.0,123.9,123.8,122.4,121.9,120.3,118.0,117.1,113.6,112.0,109.4,64.6,64.4,52.5,45.8,21.2.HRMS(ESI),m/zcalcd.for C36H25NNaO4S([M+Na]+)590.1396,found:590.1390.
Figure BDA0002389893710000172
2-(4-(二甲基氨基)苯基)-N-(吡啶-4-基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5A)：白色固体，产率：77％；m.p.221-223℃.1H NMR(400MHz,CDCl3)δ8.39(d,J＝5.2Hz,2H),8.22(d,J＝8.4Hz,2H),7.94(s,1H),7.63(d,J＝8.4Hz,1H),7.54(d,J＝8.0Hz,2H),7.44(d,J＝8.8Hz,2H),7.35(d,J＝6.0Hz,2H),7.25(d,J＝7.6Hz,1H),6.70(d,J＝8.8Hz,2H),2.99(s,6H),2.39(s,3H).13C NMR(150MHz,DMSO)δ163.5,151.2,146.6,140.3,139.1,138.5,138.1,138.0,137.3,135.7,134.9,130.6,129.7,127.6,127.3,126.0,124.7,124.2,124.1,122.7,119.7,117.8,114.8,112.4,40.4,29.8,21.3.HRMS(ESI),m/zcalcd.for C29H26N3OS([M+H]+)464.1791,found:464.1793.
Figure BDA0002389893710000181
N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-(4-(二甲基氨基)苯基)-6-(对甲苯基)苯并[b]噻吩-3-甲酰胺(5B)：白色固体，产率：81％；m.p.230-232℃.1H NMR(600MHz,DMSO)δ10.35(s,1H),8.28(s,1H),7.71(q,J＝8.4Hz,2H),7.67(d,J＝7.8Hz,2H),7.49(d,J＝8.4Hz,2H),7.36(s,1H),7.30(d,J＝7.8Hz,2H),7.08(d,J＝8.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.77(d,J＝8.4Hz,2H),4.23(d,J＝9.0Hz,4H),2.94(s,6H),2.36(s,3H).13CNMR(150MHz,DMSO)δ164.1,151.0,143.4,143.2,140.2,138.9,138.3,137.3,136.8,133.2,130.1,129.3,127.4,127.1,124.4,122.9,120.4,120.1,117.3,113.4,112.6,109.3,64.7,64.5,21.2.HRMS(ESI),m/z calcd.for C32H29N2O3S([M+H]+)521.1893,found:521.1873.
3、活性测试
活性测试过程
酶促反应操作步骤
1)酶促步骤：依次用激酶缓冲液稀释待测化合物(包括阳性药)、激酶、底物及ATP，以制备酶促步骤所需最终浓度为(2.5倍、5倍、5倍、5倍)的工作溶液。将待测物4μL、激酶、底物及ATP各2μL依次加入384孔板中(阴性对照组不加化合物，加入4μL激酶缓冲液；空白对照组不加化合物和激酶)，反应体系为10μL。最后以薄膜封板(防止蒸发及灰尘)，用离心机甩板30s，室温孵育1h。
2)终止步骤：用检测缓冲液稀释Sa-XL665储备溶液(16.67μM)，以制备浓度为试验所需最终浓度4倍的工作溶液，按照1/50的比例稀释STK-抗体储备溶液，以获得工作溶液。待激酶反应结束后，依次加入5μL的Sa-XL665及5μL的STK-Antibody(含EDTA)，总反应体系为20μL，封板，室温终止反应1h。
3)上机检测：终止反应结束后，用酶标仪上机检测，分别检测620nm及665nm处的荧光度值，并计算665/620的比值。
4)酶活抑制率计算：根据反应原理，阴性对照组的酶促反应完全，即665/620的比值最大，而对于化合物组，比值越小说明酶促反应进行得越少，即酶活抑制越明显。空白对照孔读值最小，计算酶活抑制率时各组均要去除空白对照的影响。因此，酶活抑制率按照以下公式进行计算：
Figure BDA0002389893710000191
比值＝(665nm/620nm)×104
5)活性测试结果
活性测试结果如下表所示：
表1化合物对PIM I靶点的抑制率
Figure BDA0002389893710000192
Figure BDA0002389893710000201
Figure BDA0002389893710000211
Figure BDA0002389893710000221
Figure BDA0002389893710000231
结果表明，该系列化合物对PIM抑制剂的酶均具有一定的抑制活性，其中5r、5A、5w、5m、5o、5t、5p活性较优。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (4)

1.具有生物活性的新型苯并噻唑取代酰胺类化合物，其特征在于该苯并噻唑取代酰胺类化合物的结构通式如下：
Figure FDA0002389893700000011
5a R＝H，R1＝Ph，
Figure FDA0002389893700000012
5b R＝H，R1＝Ph，
Figure FDA0002389893700000013
5c R＝H，R1＝Ph，
Figure FDA0002389893700000014
5d R＝Ph，R1＝H，
Figure FDA0002389893700000015
5e R＝H，R1＝4-OCH3Ph，
Figure FDA0002389893700000016
5fR＝H，R1＝4-OCH3Ph，
Figure FDA0002389893700000017
5g R＝H，R1＝4-OCH3Ph，
Figure FDA0002389893700000018
5h R＝H，R1＝4-OCH3Ph，
Figure FDA0002389893700000019
5i R＝H，R1＝4-CF3Ph，
Figure FDA00023898937000000110
5j R＝H，R1＝4-CF3Ph，
Figure FDA00023898937000000111
5k R＝H，R1＝4-CF3Ph，
Figure FDA00023898937000000112
5l R＝H，R1＝4-CF3Ph，
Figure FDA00023898937000000113
5m R＝H，
Figure FDA00023898937000000114
Figure FDA00023898937000000115
5n R＝H，
Figure FDA00023898937000000116
5o R＝CH3，R1＝H，
Figure FDA00023898937000000117
5p R＝CH3，R1＝H，
Figure FDA00023898937000000118
5q R＝CH3，R1＝H，
Figure FDA00023898937000000119
5r R＝CH3，R1＝H，
Figure FDA00023898937000000120
5s R＝CH3，R1＝4-OCH3Ph，
Figure FDA00023898937000000121
5t R＝CH3，R1＝4-OCH3Ph，
Figure FDA00023898937000000122
5u R＝CH3，R1＝4-OCH3Ph，
Figure FDA00023898937000000123
5v R＝CH3，R1＝4-CF3Ph，
Figure FDA00023898937000000124
5w R＝CH3，R1＝4-CF3Ph，
Figure FDA00023898937000000125
5x R＝CH3，
Figure FDA00023898937000000126
5y R＝CH3，
Figure FDA00023898937000000127
Figure FDA0002389893700000021
5z R＝CH3，
Figure FDA0002389893700000022
5A R＝CH3，R1＝4-N(CH3)Ph，
Figure FDA0002389893700000023
5B R＝CH3，R1＝4-N(CH3)Ph，
Figure FDA0002389893700000024
2.一种权利要求1所述的具有生物活性的新型苯并噻唑取代酰胺类化合物的合成方法，其特征在于具体合成路线为：
Figure FDA0002389893700000025
3.权利要求1所述的具有生物活性的新型苯并噻唑取代酰胺类化合物在制备抗癌药物中的应用。
4.根据权利要求3所述的应用，其特征在于：所述具有生物活性的新型苯并噻唑取代酰胺类化合物对PIM抑制剂的酶具有抑制活性，其中活性较优的化合物及对应化合物对PIM I靶点的抑制率分别为：
Figure FDA0002389893700000026
Figure FDA0002389893700000031
CN202010110738.9A 2020-02-24 2020-02-24 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用 Active CN111285844B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010110738.9A CN111285844B (zh) 2020-02-24 2020-02-24 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010110738.9A CN111285844B (zh) 2020-02-24 2020-02-24 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用

Publications (2)

Publication Number Publication Date
CN111285844A true CN111285844A (zh) 2020-06-16
CN111285844B CN111285844B (zh) 2022-08-12

Family

ID=71028243

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010110738.9A Active CN111285844B (zh) 2020-02-24 2020-02-24 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用

Country Status (1)

Country Link
CN (1) CN111285844B (zh)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022595A1 (en) * 2000-09-18 2002-03-21 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
CN1731993A (zh) * 2002-11-01 2006-02-08 维洛药品公司 苯并呋喃化合物、组合物以及治疗和预防丙型肝炎病毒感染及相关疾病的方法
CN1901902A (zh) * 2003-10-09 2007-01-24 阿托恩药品公司 噻吩和苯并噻吩异羟肟酸衍生物
US20090082308A1 (en) * 2005-04-20 2009-03-26 Jed Lee Hubbs Benzothiophene derivatives
US20120328569A1 (en) * 2010-03-02 2012-12-27 Mccomas Casey Cameron Inhibitors of hepatitis c virus ns5b polymerase
AU2011329485A1 (en) * 2010-11-18 2013-04-18 Glaxo Group Limited Compounds
US20140213571A1 (en) * 2011-09-08 2014-07-31 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of viral diseases
WO2017153789A1 (en) * 2016-03-11 2017-09-14 Vichem Chemie Kutató Kft. Benzo[b]thiophene derivatives and their use for the inhibition of fibroblast growth factor receptor kinases (fgfrs) for the use of neo- and hyperplasia therapies
CN109912571A (zh) * 2019-05-06 2019-06-21 河南师范大学 具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用
CN110612298A (zh) * 2017-05-11 2019-12-24 百时美施贵宝公司 用作irak4抑制剂的噻吩并吡啶及苯并噻吩化合物

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022595A1 (en) * 2000-09-18 2002-03-21 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
CN1731993A (zh) * 2002-11-01 2006-02-08 维洛药品公司 苯并呋喃化合物、组合物以及治疗和预防丙型肝炎病毒感染及相关疾病的方法
CN1901902A (zh) * 2003-10-09 2007-01-24 阿托恩药品公司 噻吩和苯并噻吩异羟肟酸衍生物
US20090082308A1 (en) * 2005-04-20 2009-03-26 Jed Lee Hubbs Benzothiophene derivatives
US20120328569A1 (en) * 2010-03-02 2012-12-27 Mccomas Casey Cameron Inhibitors of hepatitis c virus ns5b polymerase
AU2011329485A1 (en) * 2010-11-18 2013-04-18 Glaxo Group Limited Compounds
US20140213571A1 (en) * 2011-09-08 2014-07-31 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of viral diseases
JP2014526445A (ja) * 2011-09-08 2014-10-06 メルク・シャープ・アンド・ドーム・コーポレーション 四環式複素環化合物およびウイルス疾患の治療のためのその使用方法
WO2017153789A1 (en) * 2016-03-11 2017-09-14 Vichem Chemie Kutató Kft. Benzo[b]thiophene derivatives and their use for the inhibition of fibroblast growth factor receptor kinases (fgfrs) for the use of neo- and hyperplasia therapies
CN110612298A (zh) * 2017-05-11 2019-12-24 百时美施贵宝公司 用作irak4抑制剂的噻吩并吡啶及苯并噻吩化合物
CN109912571A (zh) * 2019-05-06 2019-06-21 河南师范大学 具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATEL, HITISHA K 等: "A Chimeric SERM-Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy", 《CHEMMEDCHEM》 *
RYO MIZOJIRI 等: "Design and synthesis of a novel 1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative as an orally available ACC1 inhibitor", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
张国威: "苯并噻吩和喹啉衍生物的合成研究", 《中国优秀博硕士学位论文全文数据库(硕士) 工程科技Ⅰ辑》 *

Also Published As

Publication number Publication date
CN111285844B (zh) 2022-08-12

Similar Documents

Publication Publication Date Title
AU753067B2 (en) Prostaglandin receptor ligands
MXPA02000822A (es) Amidas de acidos carboxilicos, medicamentos que contienen estos compuestos, su utilizacion y su preparacion.
CZ297253B6 (cs) Derivát amidu aminothiofenkarboxylové kyseliny, zpusob jeho prípravy a farmaceutický prostredek, který ho obsahuje
CN107176932A (zh) 苯并恶嗪酮衍生物及其制备方法和用途
CN104230905A (zh) 一类含苯并二噁烷骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用
CN101282957B (zh) 药物化合物
CN111285844B (zh) 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用
CN102180845B (zh) 含丁烯内酯结构的苄氨基二硫代甲酸酯类化合物、其制备方法及其用途
CN110256451A (zh) 一种苯并呋喃并[2,3-b]喹啉衍生物的合成方法
CN102030761B (zh) 普拉格雷中间体及其制备方法
CN103382196A (zh) (e)-1-（8-苯并吡喃基)-2-丙烯-1-酮及其类似物以及它们的用途
CN103553957B (zh) 含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及制备方法和用途
CN103113174B (zh) 一种酚类化合物的制备方法
CN101941943A (zh) 2-氯-3-氰基吡啶的合成方法
CN117946007A (zh) 一种姜黄素-氨基酸甲酯类衍生物及其制备方法和应用
CN101220005A (zh) 一种苯并噻嗪类化合物的制备方法
CN107118140A (zh) 一种β‑酰基‑烯丙基甲硫醚衍生物及其制备方法
CN114621204A (zh) 一种含有嘧啶二酮酰基多取代哌嗪类衍生物及其制备方法与应用
KR20080086482A (ko) 글루코코르티코이드 수용체와의 상호 작용에 의한 약효를갖는 화합물
CN101143853B (zh) 联苯四氮唑类化合物及其制备方法
CN119371416B (zh) 一种通过氧杂环丁烷开环以构建4-取代异香豆素及其类似物的合成方法
CN105130923A (zh) 一种多取代2-亚氨基噻唑类化合物的制备方法
WO2016082737A1 (zh) 一种取代的噻吩并嘧啶化合物及其制备方法
CN113214199B (zh) 一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法
CN111303195B (zh) 一类含硼小分子化合物、其制备方法及应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant