CN112961100B - 光学活性的吲哚化合物、合成方法及其应用 - Google Patents

光学活性的吲哚化合物、合成方法及其应用 Download PDF

Info

Publication number
CN112961100B
CN112961100B CN202110207147.8A CN202110207147A CN112961100B CN 112961100 B CN112961100 B CN 112961100B CN 202110207147 A CN202110207147 A CN 202110207147A CN 112961100 B CN112961100 B CN 112961100B
Authority
CN
China
Prior art keywords
methylsulfonyl
oxo
nmr
cdcl
carbonitrile
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.)
Active
Application number
CN202110207147.8A
Other languages
English (en)
Other versions
CN112961100A (zh
Inventor
刘文博
胡旭东
夏宇尘
华容
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.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
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 Wuhan University WHU filed Critical Wuhan University WHU
Priority to CN202110207147.8A priority Critical patent/CN112961100B/zh
Publication of CN112961100A publication Critical patent/CN112961100A/zh
Application granted granted Critical
Publication of CN112961100B publication Critical patent/CN112961100B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 ring system
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种光学活性的吲哚化合物、合成方法及其应用。所述的吲哚化合物是指含氰基季碳手性中心的吲哚化合物，其合成方法是钯催化炔基胺钯化不对称氰基加成反应。该类化合物对乙肝病毒(HBV)有的明显的抑制作用，是潜在的制备治疗HBV药物的新化合物。

Description

光学活性的吲哚化合物、合成方法及其应用
技术领域
本发明涉及有机合成技术领域，具体涉及一种光学活性的吲哚化合物、合成方法及其应用。
背景技术
吲哚是许多具有重要生物学意义和立体化学结构丰富的生物碱和药物分子的重要骨架[(a) M.Usman,X.-D.Hu,W.-B.Liu,Chin.J.Chem.2020,38,737；(b)R.Littell,E.N.Greenblatt,G. R.Allen,J.Med.Chem.1972,15,875；(c)T.S.Kam,G.Subramaniam,W.Chen,Phytochemistry 1999,51,159；(d)T.Zeng,X.-Y.Wu,S.-X.Yang,W.-C.Lai,S.-D.Shi,Q.Zou,Y.Liu,L.-M.Li,J. Nat.Prod.2017,80,864；(e)W.-S.Yap,C.-Y.Gan,K.-S.Sim,S.-H.Lim,Y.-Y.Low,T.-S.Kam,J. Nat.Prod.2016,79,230.]。到目前为止，利用吲哚作为关键中间体，已经实现了十种以上 Aspidosperma和Kopsia家族生物碱的全合成，而这些方法都是利用C20位置全碳季碳中心作为立体化学的关键，进而发生一系列环化反应，突出了对映体的吲哚类化合物在汇聚式合成中多种天然产物巨大潜力。目前，并没有有效合成含氰基季碳手性中心的吲哚的方法。鉴于氰基和杂环的在药物化学中的重要作用，设计合成含氰基季碳手性中心的吲哚，并发现其具有良好的抗乙肝病毒(HBV)活性。
发明内容
针对现有技术的不足，本发明要解决的技术问题是提供光学活性的吲哚化合物、合成方法及其应用。
为实现上述目的，本发明提供的技术方案如下：
第一方面，本发明的目的提供一种含氰基季碳手性中心的吲哚化合物，具有如下结构(通式I)：
Figure BDA0002949691860000011
通式(I)中，其中R1任选自烷基或芳基或者烯基；R2任选自氢、酰基、酯基、酰胺、烷基、芳基、杂芳基、烯基、杂原子、卤素(氟、氯、溴)；R3任选自烷基磺酰基，芳基磺酰基，酰基，或者氢原子。Z任选自亚甲基或杂原子；其中m任取自0、1、或2；其中n任取自0、 1、或2；*表示手性中心；
第二方面，本发明的目的是提供一种上述含氰基季碳手性中心的吲哚化合物的合成方法如下：
(1)在催化剂前体和配体络合形成的催化剂催化下，原料II在溶剂中发生反应；(2) 反应结束后，加入稀盐酸溶液搅拌后处理；(3)萃取并浓缩溶剂，分离提纯，生成含氰基季碳手性中心的吲哚化合物I；其反应方程式如下(方程式A)：
Figure BDA0002949691860000021
其中[Pd]为钯催化剂前体；Ligand为配体；solvent为有机溶剂；additive为添加剂；
其中R1任选自烷基或芳基或者烯基；R2任选自氢、酰基、酯基、酰胺、烷基、芳基、杂芳基、烯基、杂原子、卤素(氟、氯、溴)；R3任选自烷基磺酰基，芳基磺酰基，酰基，或者氢原子。Z任选自亚甲基或杂原子；其中m任取自0、1、或2；其中n任取自0、1、或2； *表示手性中心；
催化剂前体钯为二价钯，包括Pd(OAc)2、Pd(OTs)2、Pd(TFA)2、PdCl2、Pd(acac)2、Pd(BF4)2或者这些物质的水合物。
所述的配体具有下式A-J所示结构或者其对映异构体，式A-J中Ar为芳基，Y任选自氧或R15取代的氮原子，所述的取代基R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15是独立的取代基；其中R5、R8、R13、R14任选自氢、氟、烷基、卤代烷基、卤代烷氧基、环烷基、杂环基、烷氨基、烷氧基、芳基或杂芳基；R6、R7、R9、任选自氢、甲基、乙基、异丙基、叔丁基、环己基、芳基或芐基；R10、R11、R12任选自甲基、乙基、异丙基、叔丁基、环己基、芳基；
优选地，所述配体为具有如式A、式C、式D、式E、式F、式H或者式J所示结构的配体
Figure BDA0002949691860000031
所述催化剂为所催化剂前体含金属钯元素与配体的摩尔比为1:0.5～1:2；
优选地，催化剂前体中所含金属钯元素与配体的摩尔比为1:1～1:1.2；
所述反应在有机溶剂中进行，所述有机溶剂为苯、甲苯、1,2-二氯乙烷、氯苯、乙腈、二甲基甲酰胺、乙二醇二甲醚、四氢呋喃、1,4-二氧六环以及其中二种或二种以上混合溶剂；
优选地，所述反应在苯或1,4-二氧六环中进行；
所述添加剂是指氯化锌、对甲基苯磺酸、四丁基氯化铵、六氟磷酸胺、三氟甲烷磺酰亚胺、水；
优选地，所述反应的添加剂为2当量的水；
所述金属催化剂中金属元素的物质量与式II所示原料的物质量之比为0.01:1～0.2:1，优选 0.25:1～0.1:1；
所述添加剂和原料II的物质量之比为0.3:1～2:1；
所述反应的温度为80℃～120℃；
所述反应的时间为1～48小时。
上述制备方法步骤所述分离提纯方法为柱层析、薄层层析。
上述柱层析使用的洗脱液为乙酸乙酯、丙酮、或者石油醚和乙酸乙酯的混合液。石油醚和乙酸乙酯的体积比为100:10～1:1。
第三方面，本发明的目的是提供上述含氰基季碳手性中心的吲哚化合物在制备抗乙肝病毒药物中的应用。含氰基季碳手性中心的吲哚化合物的对乙肝病毒的活性，包括抑制HBV转录，抑制HBeAg的分泌；抑制转录出的HBVpgRNA水平，抑制分泌到细胞外的HBV DNA的水平，而且这些化合物对细胞的毒性较小，是潜在的制备治疗HBV药物的新的化合物。
本发明的优点及有益效果如下：
本发明提供了一种光学活性的氰基季碳手性中心的吲哚化合物；本发明给提供了一种高效不对称催化的合成方法，从简单易得的原料高效合成光学活性的氰基季碳手性中心的吲哚化合物；本发明提供的光学活性的氰基季碳手性中心的吲哚化合物具有良好的抗乙肝病毒活性，可用于制备治疗乙肝的药物。
附图说明
图1：200MOI HBV感染HepG2-NTCP，同时用10uM化合物HXD-1、HXD-2、HXD-3、 HXD-4、HXD-5、HXD-6、HXD-7、HXD-8、HXD-9、HXD-10、2uMAM80或DMSO处理细胞，24h后换成含10uM化合物HXD-1、HXD-2、HXD-3、HXD-4、HXD-5、HXD-6、HXD-7、 HXD-8、HXD-9、HXD-10、2uMAM80或DMSO的培养基，在感染后第7天，图1A.检测上清中HBeAg水平；图 1B.检测不同化合物对HepG2-NTCP细胞毒性的影响。注：*代表p<0.05； **代表p<0.01。
图2：用10uM化合物HXD-7、HXD-8、HXD-9、2uMAM80或DMSO处理HepAD38细胞，在处理后第6天，检测不同化合物对HepAD38细胞转录出的HBVpgRNA的影响。注：* 代表p<0.05。
图3：用10uM化合物HXD-7、HXD-8、HXD-9、2uMAM80或DMSO处理HepAD38细胞，在处理后第6天，检测上清中，不同化合物对HepAD38细胞分泌出的HBV DNA的影响。注：*代表p<0.05；**代表p<0.01。
图4：含氰基季碳手性中心吲哚化合物的结构式。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应溶剂研究：
Figure BDA0002949691860000051
Figure BDA0002949691860000052
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，括号内的为分离收率，条件10配体用量为12mol％，条件11配体用量为5mol％，er由高效液相测定，条件5或条件10为最佳反应条件。
实施例2：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应催化剂前体研究：
Figure BDA0002949691860000053
Figure BDA0002949691860000054
Figure BDA0002949691860000061
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，条件7添加20mol％AgSbF6，条件1为最佳反应条件，er由高效液相测定。
实施例3：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应配体研究：
Figure BDA0002949691860000062
Figure BDA0002949691860000063
Figure BDA0002949691860000071
Figure BDA0002949691860000072
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，er由高效液相测定，条件2为最佳反应条件。
实施例4：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应添加剂研究：
Figure BDA0002949691860000081
Figure BDA0002949691860000082
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，er由高效液相测定，条件1为最佳反应条件。
实施例5：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应温度研究：
Figure BDA0002949691860000083
Figure BDA0002949691860000084
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，er由高效液相测定，条件2为最佳反应条件。
实施例6：以N-(2-(5,5-二氰基-6-苯基己烷-1-炔-烷基)苯基)-4-甲基苯磺酰胺为标准底物，对钯催化的β位含氰基手性季碳中心的吲哚合成的反应浓度研究：
Figure BDA0002949691860000091
Figure BDA0002949691860000092
其中mol％指的相对摩尔量，equiv代表当量，收率为核磁收率，er由高效液相测定，条件4为最佳反应条件。
实施例7：
制备方法包括以下要素：取干燥的10mL装有磁力搅拌子的反应封管，于手套箱氩气氛围中加入10mol％活化的三氟乙酸钯(3.4mg,0.01mmol)和12mol％配体(S)-tBu-Phox(记为L2)(4.7mg,0.012mmol)和2mL苯，室温下搅拌30分钟。再加入反应物II(0.1mmol)，最后再补加1mL苯和H2O(4uL,0.2mmol)。100℃油浴条件下反应，至TLC监测原料反应完全(约24h)。体系恢复至室温，加入1mL乙酸乙酯稀释和1M盐酸水溶液(1.0mL)进行后处理，并搅拌10分钟.混合体系用乙酸乙酯(10mLx 3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤。旋转蒸发除去溶剂，选用200-300目的硅胶和石油醚与乙酸乙酯的混合溶剂作为洗脱液进行柱层析分离，得到目标产物II，产物的ee由配备手性分离柱的高相液相色谱测定。
实施例8：
在本实施例中，制备(R)-3-苄基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-benzyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000101
白色固体(33.4mg,88％收率)，其er＝97:3.比旋光度[α]D 25＝7.33(c 0.5,CHCl3).Rf＝0.3 (PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.35–8.25(m,1H),7.96(ddd,J＝7.6,3.5,2.2Hz,1H),7.49–7.41(m,2H),7.41–7.29(m,5H),3.61–3.48(m,2H),3.38(ddd,J＝19.3,9.0,4.9Hz,1H),3.26(s, 3H),3.13(BA,J＝13.9Hz,1H),2.45(dt,J＝13.9,5.1Hz,1H),2.22(ddd,J＝13.9,9.0,5.0Hz, 1H).13C NMR(100MHz,CDCl3)δ185.9,150.0,136.0,134.3,130.6,128.9,127.9,126.5,125.8, 125.7,122.3,118.6,115.7,113.5,48.4,42.3,39.2,31.4,21.9.HRMS(ESI)m/z calc’d for C21H18N2O3SNa[M+Na]+:401.0930,found 401.0922.
实施例9：
在本实施例中，制备(R)-9-(甲磺酰基)-4-氧代-3-(3,4,5-三甲氧基苄基)-2,3,4,9-四氢-1H- 咔唑-3-腈 [(R)-9-(Methylsulfonyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carbo nitrile]，其结构式如下：
Figure BDA0002949691860000102
白色固体(36.1mg,80％收率)，其er＝96:4.比旋光度[α]D 25＝25.43(c 1.0,CH3CN).Rf＝ 0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.33–8.23(m,1H),8.01–7.91(m,1H),7.49–7.37(m,2H),6.52(s,2H),3.83(s,3H),3.82(s,6H),3.62–3.32(m,3H),3.26(s,3H),3.09(BA,J＝14.0Hz,1H), 2.47(dt,J＝13.9,5.1Hz,1H),2.29–2.15(m,1H).13C NMR(100MHz,CDCl3)δ185.9,153.3, 150.0,137.6,135.9,129.9,126.5,125.8,125.6,122.1,118.9,115.6,113.5,107.5,61.0,56.3,48.3, 42.2,39.7,31.4,21.9.HRMS(ESI+)m/z calc’d forC24H24N2O6SNa[M+Na]+:491.1247,found 491.1237.
实施例10：
在本实施例中，制备(R)-9-(甲磺酰基)-3-(萘-1-基甲基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-9-(Methylsulfonyl)-3-(naphthalen-1-ylmethyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbon itrile]，其结构式如下：
Figure BDA0002949691860000111
白色固体(40.5mg,94％收率)，其er＝96:4.比旋光度[α]D 25＝7.87(c 1.0,CH3CN).Rf＝0.4 (PE:EA＝2:1).1H NMR(400MHz,CDCl3)δ8.36–8.29(m,1H),8.14–8.06(m,1H),8.01– 7.93(m,1H),7.91–7.86(m,1H),7.86–7.81(m,1H),7.58(dd,J＝7.1,1.3Hz,1H),7.55–7.41 (m,5H),4.14(AB,J＝14.6Hz,1H),3.64(BA,J＝14.6Hz,1H),3.50(dt,J＝19.4,4.5Hz,1H), 3.29(ddd,J＝19.3,10.1,5.0Hz,1H),3.22(s,3H),2.39(dt,J＝13.8,4.5Hz,1H),2.28(ddd,J＝ 13.9,10.1,4.9Hz,1H).13C NMR(100MHz,CDCl3)δ186.0,150.2,136.0,134.1,132.8,130.9, 129.3,129.2,128.7,126.49,126.46,126.0,125.8,125.7,125.5,123.9,122.3,118.6,115.9,113.5, 48.6,42.2,34.4,32.2,22.1.HRMS(ESI+)m/zcalc’d for C25H20N2O3SNa[M+Na]+:451.1087,found 451.1077.
实施例11：
在本实施例中，制备(R)-3-((1-甲基-1H-吲哚-3-基)甲基)-9-(甲基磺酰基)-4-氧代-2,3,4,9- 四氢-1H-咔唑-3-腈 [(R)-3-((1-Methyl-1H-indol-3-yl)methyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole -3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000112
白色固体(38.3mg,89％收率)，其er＝96:4.比旋光度[α]D 25＝34.60(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.40–8.27(m,1H),8.03–7.90(m,1H),7.62–7.52(m,1H),7.50–7.39(m,2H),7.32(dt,J＝8.4,0.9Hz,1H),7.28–7.20(m,1H),7.19–7.04(m,2H),3.77(s, 3H),3.61(AB,J＝14.7Hz,1H),3.56–3.44(m,2H),3.35(ddd,J＝19.2,9.8,4.9Hz,1H),3.21(s, 3H),2.52(dt,J＝13.9,4.7Hz,1H),2.36–2.23(m,1H).13C NMR(100MHz,CDCl3)δ186.3, 150.3,136.8,136.0,129.4,128.7,126.4,125.69,125.66,122.2,121.9,119.6,119.4,118.7,116.0, 113.5,109.6,107.0,49.0,42.2,33.0,31.7,29.0,22.0.HRMS(ESI+)m/z calc’d for C24H21N3O3SNa [M+Na]+:454.1196,found 454.1187.
实施例12：
在本实施例中，制备(R)-9-(甲磺酰基)-4-氧代-3-(噻吩-2-基甲基)-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-9-(Methylsulfonyl)-4-oxo-3-(thiophen-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitr ile]，其结构式如下：
Figure BDA0002949691860000121
白色固体(35.5mg,93％收率)，其er＝97:3.比旋光度[α]D 25＝43.63(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.33–8.26(m,1H),8.00–7.93(m,1H),7.49–7.40(m,2H),7.24(dd,J＝5.1,1.2Hz,1H),7.06–7.02(m,1H),7.02–6.97(m,1H),3.67(AB,J＝15.0Hz,1H), 3.63–3.49(m,2H),3.43(ddd,J＝19.3,9.7,4.9Hz,1H),3.27(s,3H),2.53(dt,J＝13.9,4.8Hz, 1H),2.26(ddd,J＝14.2,9.6,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ185.4,150.2,136.0,135.5, 128.7,127.5,126.5,125.85,125.81,125.6,122.3,118.5,115.7,113.5,48.2,42.3,33.5,31.4,21.9. HRMS(ESI+)m/z calc’d for C19H16N2O3S2Na[M+Na]+:407.0495,found 407.0483.
实施例13：
在本实施例中，制备(R)-3-(呋喃-2-基甲基)-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-(Furan-2-ylmethyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000122
白色固体(33.7mg,90％收率)，其er＝97:3.比旋光度[α]D 25＝35.40(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.34–8.23(m,1H),8.03–7.91(m,1H),7.49–7.40(m,2H),7.39(d,J＝1.8Hz,1H),6.42–6.28(m,2H),3.66–3.38(m,3H),3.35–3.29(m,1H),3.28(s,3H), 2.57(dt,J＝13.8,4.8Hz,1H),2.26(ddd,J＝14.0,9.2,4.9Hz,1H).13C NMR(100MHz,CDCl3)δ 185.3,150.2,148.9,142.8,136.0,126.5,125.8,125.6,122.3,118.3,115.5,113.5,111.0,110.0,47.8, 42.3,32.0,31.8,21.9.HRMS(ESI+)m/z calc’d forC19H16N2O4SNa[M+Na]+:391.0723,found 391.0718.
实施例14：
在本实施例中，制备(R)-3-(3-甲基-2-烯-1-基)-9-(甲基磺酰基)-4-氧代-2,3,4,9-四氢-1H- 咔唑-3-腈 [(R)-3-(3-Methylbut-2-en-1-yl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carboni trile]，其结构式如下：
Figure BDA0002949691860000131
白色固体(33.7mg,90％收率)，其er＝95:5.比旋光度[α]D 25＝19.90(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.33–8.21(m,1H),8.02–7.92(m,1H),7.47–7.36(m,2H),5.33–5.19(m,1H),3.58–3.37(m,2H),3.27(s,3H),2.88(dd,J＝14.6,7.2Hz,1H),2.64–2.50 (m,2H),2.34(ddd,J＝13.7,8.1,5.4Hz,1H),1.78(d,J＝1.3Hz,3H),1.68(d,J＝1.4Hz,3H).13C NMR(100MHz,CDCl3)δ186.4,149.7,138.1,135.8,126.3,125.6,125.5,122.1,118.9,116.5, 115.5,113.3,47.6,42.1,32.0,31.4,26.1,21.7,18.3.HRMS(ESI+)m/z calc’d for C19H20N2O3SNa [M+Na]+:379.0187,found 379.0182.
实施例15：
在本实施例中，制备(S)-9-(甲磺酰基)-4-氧代-3-(4-苯基-3-炔基)-2,3,4,9-四氢-1H-咔唑-3-腈 [(S)-9-(Methylsulfonyl)-4-oxo-3-(4-phenylbut-3-yn-1-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboni trile]，其结构式如下：
Figure BDA0002949691860000141
白色固体(22.5mg,59％收率)，其er＝95:5.比旋光度[α]D 25＝32.63(c 0.3,EA).Rf＝0.2 (PE:EA＝5:1).
1H NMR(400MHz,CDCl3)δ8.31–8.22(m,1H),8.02–7.93(m,1H),7.49–7.39(m,2H),7.39–7.32(m,2H),7.31–7.20(m,3H),3.66–3.42(m,2H),3.28(s,3H),2.85–2.65(m,3H),2.59–2.42(m,2H),2.29–2.14(m,1H).13C NMR(100MHz,CDCl3)δ186.1,149.5,136.0,131.6,128.4,128.1,126.5,125.8,125.6,123.3,122.3,118.5,115.3,113.4,87.7,82.2,47.6,42.3,32.5,32.1, 21.8,16.0.HRMS(ESI+)m/z calc’d for C24H20N2O3SNa[M+Na]+:439.1087,found 439.1082.
实施例16：
在本实施例中，制备(S)-9-(甲磺酰基)-4-氧代-3-丙基-2,3,4,9-四氢-1H-咔唑-3-腈 [(S)-9-(Methylsulfonyl)-4-oxo-3-propyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000142
白色固体(26.7mg,83％收率)，其er＝94.5:5.5.比旋光度[α]D 25＝43.03(c 1.0,CH3CN).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.30–8.24(m,1H),8.00–7.93(m,1H),7.47–7.40(m,2H),3.47(t,J＝6.1Hz,2H),3.28(s,3H),2.64(dt,J＝13.9,6.1Hz,1H),2.39(dt,J＝13.9,6.2Hz,1H), 2.18–2.05(m,1H),1.86–1.74(m,1H),1.70–1.57(m,2H),1.02(t,J＝7.3Hz,3H).13C NMR (100MHz,CDCl3)δ186.9,149.4,135.9,126.4,125.74,125.69,122.3,119.2,115.4,113.4,48.0, 42.3,35.4,32.0,21.7,18.6,14.1.HRMS(ESI+)m/z calc’d forC17H18N2O3SNa[M+Na]+:353.0930, found 353.0931.
实施例17：
在本实施例中，制备(R)-3-(环己基甲基)-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-(Cyclohexylmethyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile] ，其结构式如下：
Figure BDA0002949691860000151
白色固体(33.6mg,86％收率)，其er＝95:5.比旋光度[α]D 25＝48.13(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.31–8.23(m,1H),8.00–7.92(m,1H),7.47–7.38(m,2H),3.47(t,J＝6.1Hz,2H),3.28(s,3H),2.64(dt,J＝13.9,6.0Hz,1H),2.42(dt,J＝13.9,6.1Hz,1H), 2.02(dd,J＝14.4,6.5Hz,1H),1.94–1.85(m,1H),1.85–1.58(m,6H),1.36–1.21(m,2H),1.21– 0.97(m,3H).13C NMR(100MHz,CDCl3)δ187.2,149.2,135.9,126.4,125.74,125.72,122.3, 119.7,115.3,113.4,47.0,42.3,40.1,34.8,34.6,34.0,32.3,26.3,26.2,26.1,21.8.HRMS(ESI+)m/z calc’d for C21H24N2O3SNa[M+Na]+:407.1400,found407.1936.
实施例18：
在本实施例中，制备(R)-3-(环丙基甲基)-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑 -3-腈 [(R)-3-(Cyclopropylmethyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitril e]，其结构式如下：
Figure BDA0002949691860000152
白色固体(27.4mg,81％收率)，其er＝96:4.比旋光度[α]D 25＝31.00(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.32–8.21(m,1H),8.01–7.87(m,1H),7.49–7.35(m,2H),3.60–3.37(m,2H),3.28(s,3H),2.75(dt,J＝13.8,5.7Hz,1H),2.51(dt,J＝13.9,6.5Hz,1H), 2.07(dd,J＝14.4,7.2Hz,1H),1.82(dd,J＝14.4,6.8Hz,1H),1.04–0.85(m,1H),0.71–0.53(m, 2H),0.31–0.17(m,2H).13C NMR(100MHz,CDCl3)δ186.8,149.5,135.9,126.4,125.73,125.65, 122.3,119.2,115.5,113.4,48.3,42.3,38.2,32.0,21.9,6.9,5.0,4.7.HRMS(ESI+)m/z calc’d for C18H18N2O3SNa[M+Na]+:365.0930,found 365.0927.
实施例19：
在本实施例中，制备(S)-3-甲基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(S)-3-Methyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000161
白色固体(27.3mg,93％收率)，其er＝95.5:4.5.比旋光度[α]D 25＝15.33(c 1.0,CH3CN).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.33–8.18(m,1H),8.05–7.88(m,1H),7.52–7.33(m,2H),3.61–3.42(m,2H),3.27(s,3H),2.62(dt,J＝13.8,4.9Hz,1H),2.40–2.25(m,1H),1.68(s,3H). 13C NMR(100MHz,CDCl3)δ186.6,149.9,136.0,126.4,125.7,125.6,122.2,119.6,115.3,113.4, 42.8,42.2,34.8,22.1,20.7.HRMS(ESI+)m/z calc’d for C15H14N2O3SNa[M+Na]+:325.0617,found 325.0615.
实施例20：
在本实施例中，制备(R)-3-异丙基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-Isopropyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000162
白色固体(26.8mg,82％收率)，其er＝95.5:4.5.比旋光度[α]D 25＝149.50(c 0.7,CH3CN).Rf＝0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.35–8.23(m,1H),8.00–7.91(m,1H),7.51–7.37(m,2H),3.43(td,J＝5.9,1.6Hz,2H),3.28(s,3H),2.55(t,J＝6.1Hz,2H),2.52–2.42(m,1H),1.20–1.06 (m,6H).13C NMR(100MHz,CDCl3)δ187.2,149.1,135.9,126.4,125.7,122.3,118.4,115.6,113.4, 53.4,42.3,30.1,28.9,21.5,18.5,18.4.HRMS(ESI+)m/z calc’d forC17H18N2O3SNa[M+Na]+: 353.0930,found 353.0930.
实施例21：
在本实施例中，制备(R)-9-(甲磺酰基)-4-氧代-3-苯基-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-9-(Methylsulfonyl)-4-oxo-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000171
白色固体(25.9mg,71％收率)，其er＝96.5:3.5.比旋光度[α]D 25＝147.17(c 1.0,CH3CN).Rf＝0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.37–8.29(m,1H),8.05–7.94(m,1H),7.49–7.36(m,7H),3.56(ddd,J＝19.2,7.1,4.9Hz,1H),3.36(ddd,J＝19.2,7.0,4.8Hz,1H),3.27(s,3H),2.94(ddd,J ＝13.9,7.2,4.8Hz,1H),2.85(ddd,1H).13C NMR(100MHz,CDCl3)δ185.6,149.9,136.0,134.1, 129.4,129.1,127.2,126.6,125.9,125.6,122.4,118.6,116.3,113.5,53.2,42.3,35.8,22.1.HRMS (ESI+)m/z calc’d for C20H16N2O3SNa[M+Na]+:387.0774,found 387.0770.
实施例22：
在本实施例中，制备(R)-9-(甲磺酰基)-4-氧代-3-(3-氧代丁基)-2,3,4,9-四氢-1H-咔唑-3- 腈[(R)-9-(Methylsulfonyl)-4-oxo-3-(3-oxobutyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000172
白色固体(19.7mg,56％收率)，其er＝96:4.比旋光度[α]D 25＝17.73(c 1.0,CH3CN).Rf＝ 0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.24(dd,J＝6.3,3.0Hz,1H),8.01–7.92(m,1H),7.49–7.38 (m,2H),3.58–3.43(m,2H),3.28(s,3H),2.94–2.75(m,2H),2.64(dt,J＝13.1,6.2Hz,1H),2.47 –2.33(m,2H),2.21(s,3H),2.18–2.09(m,1H).13C NMR(100MHz,CDCl3)δ206.5,186.7, 149.4,136.0,126.5,125.8,125.6,122.2,118.8,115.2,113.5,47.2,42.3,39.4,33.1,30.2,27.5,21.7. HRMS(ESI+)m/z calc’d for C18H18N2O4SNa[M+Na]+:381.0879,found 381.0880..
实施例23：
在本实施例中，制备(R)-3-(2-(1,3-二氧戊环-2-基)乙基)-9-(甲磺酰基)-4-氧代-2,3,4,9- 四氢-1H-咔唑-3-腈 [(R)-3-(2-(1,3-Dioxolan-2-yl)ethyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-car bonitrile]，其结构式如下：
Figure BDA0002949691860000181
黄色固体(33.6mg,84％收率)，其er＝95:5.比旋光度[α]D 25＝28.50(c 1.0,CH3CN).Rf＝ 0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.31–8.20(m,1H),8.01–7.90(m,1H),7.48–7.36(m,2H),4.96(t,J＝3.8Hz,1H),4.02–3.91(m,2H),3.91–3.80(m,2H),3.54–3.40(m,2H),3.28(s,3H), 2.64(dt,J＝13.7,6.0Hz,1H),2.39(dt,J＝13.8,6.2Hz,1H),2.32–2.21(m,1H),2.09–1.89(m, 3H).13C NMR(100MHz,CDCl3)δ186.4,149.3,135.8,126.3,125.6,125.5,122.2,118.7,115.2, 113.3,103.2,65.1,47.3,42.2,32.0,29.3,27.2,21.6.HRMS(ESI+)m/z calc’d for C19H20N2O5SNa [M+Na]+:411.0985,found 411.0983.
实施例24：
在本实施例中，制备(R)-3-(3-羟丙基)-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3- 碳腈 [(R)-3-(3-Hydroxypropyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000182
白色固体(28.4mg,84％收率)，其er＝95.5:4.5.比旋光度[α]D 25＝28.83(c 1.0,CH3CN).Rf＝0.2(PE:EA＝1:1).
1H NMR(400MHz,CDCl3)δ8.24(dd,J＝6.2,3.0Hz,1H),8.00–7.90(m,1H),7.47–7.37 (m,2H),3.83–3.63(m,2H),3.48(t,J＝6.0Hz,2H),3.28(s,3H),2.64(dt,J＝13.9,5.9Hz,1H), 2.41(dt,J＝13.3,6.1Hz,1H),2.29–2.16(m,1H),2.07–1.91(m,1H),1.91–1.77(m,2H).13C NMR(100MHz,CDCl3)δ186.9,149.6,135.9,126.4,125.7,125.6,122.2,119.0,115.3,113.4,62.1, 47.7,42.3,32.2,30.1,28.2,21.7.HRMS(ESI+)m/z calc’dfor C17H18N2O4SNa[M+Na]+:369.0879, found 369.0881.
实施例25：
在本实施例中，制备(R)-3-(3-(1,3-二氧异吲哚-2-基)丙基)-9-(甲磺酰基)-4-氧代-2,3,4,9- 四氢-1H-咔唑-3-腈 [(S)-3-(3-(1,3-Dioxoisoindolin-2-yl)propyl)-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazo le-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000191
白色固体(40.7mg,87％收率)，其er＝95.5:4.5.比旋光度[α]D 25＝29.30(c 1.0,CH3CN).Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.29–8.18(m,1H),8.00–7.90(m,1H),7.89–7.78(m,2H),7.76–7.67(m,2H),7.47–7.35(m,2H),3.88–3.68(m,2H),3.48(t,J＝6.1Hz,2H),3.27(s,3H), 2.62(dt,J＝13.8,5.6Hz,1H),2.36(dt,J＝13.5,6.4Hz,1H),2.28–2.15(m,1H),2.10–1.84(m, 3H).13C NMR(100MHz,CDCl3)δ186.1,168.4,149.5,135.9,134.2,132.1,126.5,125.8,125.6, 123.5,122.3,118.6,115.4,113.4,47.3,42.2,37.6,32.3,30.8,24.5,21.8.HRMS(ESI+)m/z calc’d for C25H21N3O5SNa[M+Na]+:498.1094,found 498.1096.
实施例26：
在本实施例中，制备叔丁基-(S)-(2-(苄氧基)乙基)(3-(3-氰基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-基)丙基)氨基甲酸酯[tert-Butyl (S)-(2-(benzyloxy)ethyl)(3-(3-cyano-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl) propyl)carbamate]，其结构式如下：
Figure BDA0002949691860000201
白色固体(46.1mg,83％收率)，其er＝95:5.比旋光度[α]D 25＝42.19(c 2.0,CH3CN).Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.30–8.22(m,1H),8.02–7.91(m,1H),7.48–7.38(m,2H),7.37–7.21(m,5H),4.50(s,2H),3.83–3.19(m,11H),2.69–2.44(m,1H),2.43–2.15(m,1H),2.14–2.00(m,1H),1.90–1.69(m,3H),1.60–1.35(m,9H).13C NMR(100MHz,CDCl3)(Chemical shifts ofthe lised tautomer in theparentheses)δ186.7(186.5),155.6,149.5,138.2,135.8, 128.4,127.7,127.6,126.3,125.6,125.5,122.1,118.8,115.1,113.3,79.8,73.1,69.1(68.9),48.3, 47.6,47.4,42.2,31.9,30.7(30.5),28.5,24.4(24.0),21.5.HRMS(ESI+)m/z calc’d for C31H37N3O6SNa[M+Na]+:602.2295,found602.2287.
实施例27：
在本实施例中，制备苄基-(S)-N-[(叔丁氧基)羰基]-N-(3-(3-氰基-9-(甲磺酰基)-4- 氧代-2,3,4,9-四氢-1H-咔唑-3-基)丙基)氨基甲酸酯[Benzyl(S) -N-[(tert-butoxy)carbonyl]-N-(3-(3-cyano-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazol- 3-yl)propyl)carbamate]，其结构式如下：
Figure BDA0002949691860000202
黄色固体(51.1mg,85％收率)，其er＝95.5:4.5.比旋光度[α]D 25＝23.73(c 1.0,CH3CN).Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.31–8.18(m,1H),8.02–7.88(m,1H),7.47–7.28(m,7H),5.21(s,2H),3.72(td,J＝6.9,2.1Hz,2H),3.51–3.36(m,2H),3.26(s,3H),2.56(dt,J＝13.8,5.7 Hz,1H),2.38–2.23(m,1H),2.17–2.05(m,1H),1.94–1.71(m,3H),1.47(s,9H).13CNMR(100 MHz,CDCl3)δ186.3,153.9,151.9,149.4,135.9,135.5,128.7,128.5,128.4,126.4,125.7,125.6, 122.2,118.7,115.2,113.4,83.3,68.6,47.4,46.0,42.2,32.0,30.5,28.0,24.7,21.6.HRMS(ESI+) m/z calc’d for C30H33N3O7SNa[M+Na]+:602.1931,found 602.1927.
实施例28：
在本实施例中，制备(R)-3-苄基-6-甲基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-benzyl-6-methyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000211
白色固体(35.5mg,91％收率)，其er＝97:3.比旋光度[α]D 25＝30.20(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.19–8.03(m,1H),7.82(d,J＝8.5Hz,1H),7.45–7.28(m,5H),7.28–7.21(m,1H),3.58–3.46(m,2H),3.35(ddd,J＝19.3,9.1,5.0Hz,1H),3.23(s,3H), 3.13(BA,J＝13.9Hz,1H),2.49(s,3H),2.43(dt,J＝13.9,5.1Hz,1H),2.21(ddd,J＝14.0,9.0,5.0 Hz,1H).13C NMR(100MHz,CDCl3)δ186.0,150.0,135.8,134.3,134.1,130.6,128.8,127.9, 127.7,125.8,122.1,118.7,115.5,113.1,48.4,42.1,39.1,31.3,21.8,21.4.HRMS(ESI+)m/z calc’d for C22H20N2O3SNa[M+Na]+:415.1087,found 415.1079.
实施例29：
在本实施例中，制备(R)-3-苄基-7-甲基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-Benzyl-7-methyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000212
白色固体(36.7mg,94％收率)，其er＝97:3.比旋光度[α]D 25＝18.60(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.1Hz,1H),7.77(s,1H),7.41–7.29(m,5H),7.29 –7.25(m,1H),3.58–3.45(m,2H),3.36(ddd,J＝19.3,9.0,5.0Hz,1H),3.25(s,3H),3.12(BA,J ＝13.9Hz,1H),2.51(s,3H),2.43(dt,J＝13.9,5.1Hz,1H),2.28–2.16(m,1H).13C NMR(100 MHz,CDCl3)δ186.0,149.4,136.9,136.4,134.4,130.6,128.8,127.9,127.2,123.3,121.8,118.7, 115.7,113.5,48.3,42.2,39.2,31.4,22.2,21.9.HRMS(ESI+)m/zcalc’d for C22H20N2O3SNa [M+Na]+:415.1087,found 415.1085.
实施例30：
在本实施例中，制备(R)-3-苄基-7-甲氧基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3- 腈
[(R)-3-Benzyl-7-methoxy-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000221
白色固体(36.6mg,89％收率)，其er＝96:4.比旋光度[α]D 25＝21.93(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,1H),7.49(d,J＝2.3Hz,1H),7.42–7.27(m, 5H),7.04(dd,J＝8.7,2.3Hz,1H),3.89(s,3H),3.57–3.42(m,2H),3.34(ddd,J＝19.3,8.9,5.0Hz, 1H),3.23(s,3H),3.11(d,J＝13.9Hz,1H),2.43(dt,J＝13.9,5.1Hz,1H),2.21(ddd,J＝13.9,8.9, 5.0Hz,1H).13C NMR(100MHz,CDCl3)δ186.0,159.1,148.9,137.1,134.3,130.6,128.8,127.9, 122.8,119.1,118.7,115.8,114.0,98.3,56.0,48.3,42.0,39.1,31.4,21.9.HRMS(ESI+)m/z calc’d for C22H20N2O4SNa[M+Na]+:431.1036,found431.1040.
实施例31：
在本实施例中，制备(R)-3-苄基-6-氟-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈[(R)-3-Benzyl-6-fluoro-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000222
白色固体(31.5mg,79％收率)，其er＝96:4.比旋光度[α]D 25＝20.13(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ7.98(dd,J＝8.4,2.7Hz,1H),7.93(dd,J＝9.2,4.2Hz,1H), 7.41–7.27(m,5H),7.16(td,J＝8.9,2.7Hz,1H),3.60–3.47(m,2H),3.37(ddd,J＝19.4,9.3,5.0 Hz,1H),3.26(s,3H),3.14(BA,J＝13.9Hz,1H),2.45(dt,J＝13.9,5.0Hz,1H),2.22(ddd,J＝ 14.1,9.3,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ185.7,161.0(d,J＝243.8Hz),151.2,134.2, 132.2,130.6,128.9,128.0,126.8(d,J＝11.2Hz),118.5,115.5(d,J＝4.0Hz),114.7(d,J＝9.4Hz), 114.4(d,J＝25.6Hz),108.3(d,J＝25.4Hz),48.2,42.4,39.1,31.3,22.0.19F NMR(376MHz, CDCl3)δ–116.0––116.1(m).HRMS(ESI+)m/zcalc’d for C21H17FN2O3SNa[M+Na]+:419.0836, found419.0831.
实施例32：
在本实施例中，制备3-苄基-7-氟-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈[(R)-3-Benzyl-7-fluoro-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000231
白色固体(33.2mg,82％收率)，其er＝97:3.比旋光度[α]D 25＝14.27(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.24(dd,J＝8.7,5.5Hz,1H),7.72(dd,J＝9.6,2.3Hz,1H), 7.43–7.27(m,5H),7.20(td,J＝8.9,2.3Hz,1H),3.59–3.45(m,2H),3.36(ddd,J＝14.3,9.2,4.6 Hz,1H),3.26(s,3H),3.13(BA,J＝14.0Hz,1H),2.45(dt,J＝13.9,5.0Hz,1H),2.22(ddd,J＝ 14.0,9.1,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ185.8,161.7(d,J＝245.0Hz),150.2(d,J＝ 3.1Hz),136.3(d,J＝12.3Hz),134.2,130.6,128.9,128.0,123.3(d,J＝9.6Hz),121.8,118.5,115.5, 114.1(d,J＝23.9Hz),101.4(d,J＝29.2Hz),48.3,42.4,39.1,31.4,21.9.19F NMR(376MHz, CDCl3)δ–112.9––113.0(m).HRMS(ESI+)m/zcalc’d for C21H17FN2O3SNa[M+Na]+:419.0836, found419.0829.
实施例33：
在本实施例中，制备(R)-3-苄基-6-氯-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-Benzyl-6-chloro-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000241
白色固体(34.1mg,83％收率)，其er＝97.5:2.5.比旋光度[α]D 25＝28.43(c 1.0,CH3CN).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.28(d,J＝2.2Hz,1H),7.89(d,J＝8.9Hz,1H),7.45–7.28(m, 6H),3.60–3.46(m,2H),3.36(ddd,J＝19.3,9.2,5.0Hz,1H),3.26(s,3H),3.14(BA,J＝14.0Hz, 1H),2.44(dt,J＝13.9,5.0Hz,1H),2.22(ddd,J＝14.0,9.2,5.0Hz,1H).13C NMR(100MHz, CDCl3)δ185.6,150.9,134.3,134.1,131.9,130.6,128.9,128.0,126.8,126.7,121.9,118.4,115.0, 114.6,48.3,42.4,39.1,31.3,21.9.HRMS(ESI+)m/z calc’d forC21H17ClN2O3SNa[M+Na]+: 435.0541,found 435.0532.
实施例34：
在本实施例中，制备(R)-3-苄基-6-溴-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-Benzyl-6-bromo-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000242
白色固体(32.8mg,71％收率)，其er＝97.5:2.5.比旋光度[α]D 25＝28.23(c 1.0,CH3CN).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.44(d,J＝2.0Hz,1H),7.83(d,J＝8.9Hz,1H),7.52(dd,J＝ 8.9,2.0Hz,1H),7.46–7.27(m,5H),3.61–3.44(m,2H),3.37(ddd,J＝14.4,9.2,4.6Hz,1H), 3.26(s,3H),3.14(BA,J＝14.0Hz,1H),2.44(dt,J＝13.9,5.0Hz,1H),2.22(ddd,J＝14.0,9.1,5.0 Hz,1H).13C NMR(100MHz,CDCl3)δ185.6,150.8,134.7,134.1,130.6,129.4,128.9,128.0, 127.2,124.9,119.5,118.4,114.9,48.3,42.5,39.1,31.3,21.9.HRMS(ESI+)m/z calc’d for C21H17BrN2O3SNa[M+Na]+:479.0035,found 479.0025.
实施例35：
在本实施例中，制备(R)-3-苄基-9-(甲磺酰基)-4-氧代-6-(三氟甲基)-2,3,4,9-四氢-1H- 咔唑-3-腈 [(R)-3-Benzyl-9-(methylsulfonyl)-4-oxo-6-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carb onitrile]，其结构式如下：
Figure BDA0002949691860000251
白色固体(26.9mg,61％收率)，其er＝98:2.比旋光度[α]D 25＝20.20(c 1.0,CH3CN).Rf＝ 0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.71–8.55(m,1H),8.10(d,J＝8.8Hz,1H),7.69(dd,J＝8.9, 1.9Hz,1H),7.44–7.29(m,5H),3.65–3.48(m,2H),3.40(ddd,J＝19.3,9.4,4.8Hz,1H),3.30(s, 3H),3.17(d,J＝14.0Hz,1H),2.47(dt,J＝13.9,4.7Hz,1H),2.24(ddd,J＝14.1,9.4,4.9Hz,1H). 13C NMR(100MHz,CDCl3)δ185.6,151.5,137.6,134.1,130.6,128.9,128.3(d,J＝32.7Hz), 128.0,125.6,124.2(d,J＝272.5Hz),123.3(q,J＝3.6Hz),119.8(q,J＝4.0Hz),118.3,115.6, 114.0,48.2,42.7,39.1,31.4,22.0.19F NMR(376MHz,CDCl3)δ–61.49.HRMS(ESI+)m/z calc’d for C22H17F3N2O3SNa[M+Na]+:469.0804,found 469.0791.
实施例36：
在本实施例中，制备(R)-3-苄基-3-氰基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-7-羧酸甲酯[(R)- 3-benzyl-3-cyano-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-7-carboxylate]，其结构式如下：
Figure BDA0002949691860000252
白色固体(31.7mg,73％收率)，其er＝97:3.比旋光度[α]D 25＝14.70(c 1.0,CH3CN).Rf＝ 0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.35(d,J＝8.0Hz,1H),8.14(dd,J＝8.3,1.6Hz, 1H),7.42–7.28(m,5H),3.97(s,3H),3.64–3.49(m,2H),3.47–3.35(m,1H),3.35–3.26(m,3H), 3.15(BA,J＝14.0Hz,1H),2.47(dt,J＝14.2,5.1Hz,1H),2.24(ddd,J＝14.2,9.3,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ185.7,166.8,152.4,135.6,134.1,130.6,129.2,128.9,128.3,128.0, 127.0,122.0,118.4,115.4,115.1,52.6,48.3,42.7,39.1,31.3,22.1.HRMS(ESI+)m/z calc’d for C23H20N2O5SNa[M+Na]+:459.0985,found 459.0980.
实施例37：
在本实施例中，制备(R)-9-苄基-5-(甲磺酰基)-10-氧代-5,6,7,8,9,10-六氢环庚[b]吲哚-9- 腈
[(R)-9-Benzyl-5-(methylsulfonyl)-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-9-carbonitrile]，其结构式如下：
Figure BDA0002949691860000261
白色固体(29.2mg,75％收率)，其er＝94.5:5.5.比旋光度[α]D 25＝26.37(c 1.0,CH3CN).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.09–7.94(m,2H),7.47–7.36(m,2H),7.29(s,5H),3.57(ddd, J＝19.2,8.9,4.7Hz,1H),3.47–3.29(m,2H),3.27–2.99(m,4H),2.32–2.06(m,3H),2.03–1.91 (m,1H).13C NMR(100MHz,CDCl3)δ192.4,146.9,135.9,134.0,130.6,128.7,127.9,127.7,126.2, 125.3,121.5,121.2,119.4,113.9,57.2,43.2,41.8,33.1,29.7,23.1.HRMS(ESI+)m/z calc’d for C22H20N2O3SNa[M+Na]+:415.1087,found 415.1082.
实施例38：
在本实施例中，制备(R)-3-苄基-4-氧代-9-甲苯磺酰基-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-3-Benzyl-4-oxo-9-tosyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000262
白色固体(33.0mg,73％收率)，，其er＝94:6.Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.26–8.21(m,1H),8.18–8.12(m,1H),7.77(d,
J＝8.2hz,2H),7.45–7.27(m,9H),3.61(dt,J＝19.2,5.1Hz,1H),3.50(AB,J＝14.0
Hz,1H),3.41(ddd,J＝19.2,9.0,4.9Hz,1H),3.07(BA,J＝13.9Hz,1H),2.45–2.36
(m,4H),2.19(ddd,J＝13.9,9.0,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ185.9,149.9, 146.5,136.3,135.0,134.3,130.6,130.5,128.8,127.9,126.8,126.2,125.6,125.5,121.9,114.1,48.4, 39.1,31.3,22.1,21.8.HRMS(ESI)m/z calcd forC27H22N2O3SNa+[M+Na]+:477.1243,found 477.1240.
实施例39：
在本实施例中，制备(R)-3-苄基-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈[(R)- 3-Benzyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000271
白色固体，其er＝96:4.比旋光度[α]D 25＝35.33(c 0.1,CH3CN).Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CD3COCD3)δ11.15(s,1H),8.20–8.03(m,1H),7.57–7.08(m,8H),3.48(AB,J＝13.8Hz,1H),3.37–3.14(m,3H),2.41(dt,J＝13.6,5.4Hz,1H),2.31(ddd,J＝13.8, 8.7,5.2Hz,1H).13C NMR(100MHz,CD3COCD3)δ185.2,152.2,137.6,136.6,131.4,129.2, 128.1,126.2,124.4,123.3,121.7,120.6,112.6,111.0,49.5,39.8,32.3,21.0.HRMS(ESI+)m/z calc’d for C20H16N2ONa[M+Na]+:323.1155,found 323.1142.
实施例40：
在本实施例中，制备叔丁基-(S)-3-氰基-3-(3-(1,3-二氧异吲哚-2-基)丙基)-4-氧代-1,2,3,4- 四氢-9H-咔唑-9-羧酸酯[tert-butyl (S)-3-Cyano-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-oxo-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate]，其结构式如下：
Figure BDA0002949691860000272
白色固体，其er＝96:4.Rf＝0.2(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.24–8.16(m,1H),8.12–8.04(m,1H),7.83(dd,J＝5.4,3.0 Hz,2H),7.76–7.65(m,2H),7.41–7.30(m,2H),3.84–3.69(m,2H),3.60–3.39(m,2H),2.64–2.53(m,1H),2.33(ddd,J＝13.3,7.6,5.1Hz,1H),2.28–2.15(m,1H),2.10–1.95(m,2H),1.95– 1.83(m,1H),1.72(s,9H).13C NMR(100MHz,CDCl3)δ186.4,168.4,150.6,149.5,136.2,134.2, 132.1,125.8,125.6,125.0,123.5,121.6,119.0,115.5,114.8,86.4,47.2,37.7,32.4,30.9,28.3,24.6, 23.3.
实施例41：
在本实施例中，制备(R)-3-甲基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-咔唑-3-甲酰胺 [(R)-3-Methyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide]，其结构式如下：
Figure BDA0002949691860000281
白色固体，其er＝96.5:3.5.比旋光度[α]D 25＝–113.43(c 0.3,CH3CN).Rf＝0.3(PE:EA＝1: 1).
1H NMR(400MHz,CDCl3)δ8.36–8.23(m,1H),8.03–7.92(m,1H),7.48–7.34(m,2H),6.52(s,1H),5.38(s,1H),3.54–3.31(m,2H),3.24(s,3H),2.80(dt,J＝13.9,4.8Hz,1H),2.25– 2.10(m,1H),1.57(s,3H).13C NMR(100MHz,CDCl3)δ196.2,172.9,152.2,136.1,125.94, 125.87,125.5,122.1,116.5,113.5,53.1,42.2,32.6,23.7,22.1.HRMS(ESI+)m/zcalc’d for C15H16N2O4SNa[M+Na]+:343.0723,found 343.0719.
实施例42：
在本实施例中，制备(S)-3-苄基-3-异氰酸酯-9-(甲磺酰基)-1,2,3,9-四氢-4H-咔唑-4-酮 [(S)-3-Benzyl-3-isocyanato-9-(methylsulfonyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one]，其结构式如下：
Figure BDA0002949691860000282
黄色固体，其er＝95:5.比旋光度[α]D 25＝–9.47(c 0.5,CHCl3).Rf＝0.3(PE:EA＝5:1).
1H NMR(400MHz,CDCl3)δ8.35–8.23(m,1H),8.04–7.95(m,1H),7.52–7.41(m,2H),7.37–7.28(m,3H),7.22–7.12(m,2H),3.53–3.34(m,2H),3.28(s,3H),3.15(AB,J＝13.7Hz,1H),3.03(BA,J＝13.7Hz,1H),2.40–2.28(m,2H).13C NMR(100MHz,CDCl3)δ191.9,149.1,136.3,134.4,130.5,128.60,128.56,127.7,126.3,125.7,125.6,122.2,114.9,113.5,67.9,42.6,42.3, 34.1,22.6.HRMS(ESI+)m/z calc’d for C21H19N2O4S[M+H]+:395.1060,found 395.1057.
实施例43：
在本实施例中，制备(S)-7-(甲磺酰基)-2-氧代-2,3,4,5,6,7-六氢-苯并[c]咔唑-4a-腈 [(S)-7-(Methylsulfonyl)-2-oxo-2,3,4,5,6,7-hexahydro-4H-benzo[c]carbazole-4a-carbonitrile]，其结构式如下：
Figure BDA0002949691860000291
白色固体。比旋光度[α]D 25＝–90.67(c 0.1,CH3CN).Rf＝0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.14–8.03(m,1H),7.96–7.85(m,1H),7.50–7.35(m,2H),6.79(s,1H),3.62(ddd,J＝19.3,5.3,1.8Hz,1H),3.42(ddd,J＝19.2,11.9,5.2Hz,1H),3.19(s, 3H),2.93(ddd,J＝17.2,14.8,4.7Hz,1H),2.76–2.64(m,1H),2.60–2.47(m,2H),2.29–2.15(m, 1H),2.15–2.03(m,1H).13C NMR(100MHz,CDCl3)δ196.6,146.8,141.7,136.8,126.11,126.06, 125.2,122.9,120.9,119.3,114.2,114.0,41.7,36.8,34.7,34.4,33.6,22.7.HRMS(ESI+)m/z calc’d for C18H17N2O3S[M+H]+:341.0954,found 341.0946.
实施例44：
在本实施例中，制备(S)-9-(甲磺酰基)-1,6'，7'，9-四氢-5'H-螺环[咔唑-3,8'-四唑[1,5-a] 吡啶]-4(2H)-酮 [(S)-9-(Methylsulfonyl)-1,6',7',9-tetrahydro-5'H-spiro[carbazole-3,8'-tetrazolo[1,5-a]pyridin]-4(2H)- one]，其结构式如下：
Figure BDA0002949691860000292
白色固体。其er＝94.5:5.5.比旋光度[α]D 25＝–84.33(c 0.5,CH3CN).Rf＝0.2(PE:EA＝1: 1).
1H NMR(400MHz,CDCl3)δ8.23–8.13(m,1H),8.06–7.96(m,1H),7.48–7.31(m,2H),4.60(dt,J＝13.4,5.2Hz,1H),4.41–4.25(m,1H),3.65(dt,J＝19.3,5.6Hz,1H),3.56–3.39(m, 1H),3.32(s,3H),3.01–2.86(m,1H),2.72–2.59(m,1H),2.55–2.31(m,2H),2.25–2.10(m,1H), 1.99–1.87(m,1H).13C NMR(100MHz,CDCl3)δ191.5,153.2,150.6,136.2,126.1,126.0,125.6, 122.2,115.6,113.5,45.8,45.6,42.2,34.0,29.4,21.8,19.3.HRMS(ESI+)m/z calc’d for C17H17N5O3SNa[M+Na]+:394.0944,found 394.0938.
实施例45：
在本实施例中，制备(S)-3-苄基-9-(甲磺酰基)-2,3,4,9-四氢-1H-咔唑-3-腈[(S)-3-Benzyl-9-(Methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000301
白色固体。其er＝96.5:3.5.比旋光度[α]D 25＝–147.63(c 0.25,CH3CN).Rf＝0.3(PE:EA＝ 5:1).
1H NMR(400MHz,CDCl3)δ8.03–7.94(m,1H),7.47–7.27(m,8H),3.36–3.22(m,1H),3.19–2.90(m,7H),2.74(d,J＝16.2Hz,1H),2.40–2.28(m,1H),1.97–1.85(m,1H).13C NMR(100MHz,CDCl3)δ136.6,134.8,134.1,130.4,129.5,128.8,127.8,125.0,124.0,122.5,118.3, 115.2,114.2,44.7,40.3,38.0,32.1,31.3,22.3.HRMS(ESI+)m/z calc’d forC21H20N2O2SNa [M+Na]+:387.1138,found 387.1134.
实施例46：
在本实施例中，制备(7S，12R)-10,11,12-三甲氧基-5-(甲磺酰基)-6,7,8,12b-四氢茚并[2,1-c] 咔唑-7a(5H)-腈 [(7S,12R)-10,11,12-Trimethoxy-5-(methylsulfonyl)-6,7,8,12b-tetrahydroindeno[2,1-c]carbazole-7a(5 H)-carbonitrile]，其结构式如下：
Figure BDA0002949691860000311
黄色固体，其er＝97:3.比旋光度[α]D 25＝156.53(c 0.5,CH3CN).Rf＝0.3(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.05–7.98(m,1H),7.85–7.78(m,1H),7.39–7.31(m,2H),6.60(s,1H),4.76(s,1H),3.85(s,3H),3.80(s,3H),3.52(d,J＝15.2Hz,1H),3.33–3.22(m,1H), 3.20–3.08(m,1H),3.12(s,3H),3.08–2.98(m,1H),3.01(s,3H),2.29–2.06(m,2H).13CNMR (100MHz,CDCl3)δ154.0,151.4,141.9,136.5,134.7,134.6,130.5,126.6,124.7,123.5,122.5, 121.3,116.5,113.5,104.5,61.0,60.4,56.3,46.1,42.6,41.2,40.4,28.5,22.0.HRMS(ESI+)m/z calc’d for C24H24N2O5SNa[M+Na]+:475.1298,found 475.1295.
实施例47：
在本实施例中，制备(R)-7-(甲磺酰基)-2,3,4,5,6,7-六氢-4aH-吡啶并[3,2-c]咔唑-4a- 腈[(R)-7-(Methylsulfonyl)-2,3,4,5,6,7-hexahydro-4aH-pyrido[3,2-c]carbazole-4a-carbonitrile]，其结构式如下：
Figure BDA0002949691860000312
白色固体，其er＝95.5:4.5.比旋光度[α]D 25＝–76.00(c 0.5,CH3CN).Rf＝0.4(PE:EA＝2: 1).
1H NMR(400MHz,CDCl3)δ8.42–8.31(m,1H),8.02–7.89(m,1H),7.42–7.29(m,2H),4.22(dd,J＝19.1,5.5Hz,1H),3.81(ddd,J＝18.3,11.4,5.6Hz,1H),3.48(ddd,J＝18.9,5.4,1.9 Hz,1H),3.43–3.30(m,1H),3.11(s,3H),2.41(ddd,J＝13.4,5.0,1.9Hz,1H),2.35–2.26(m,1H), 2.15–1.88(m,3H),1.70(td,J＝13.5,3.1Hz,1H).13C NMR(100MHz,CDCl3)δ154.5,141.3, 136.4,126.9,125.6,124.8,122.6,120.0,116.6,113.4,49.7,41.2,36.8,34.1,31.2,22.5,20.0. HRMS(ESI+)m/z calc’d for C17H18N3O2S[M+H]+:328.1114,found 328.1106.
实施例48：
在本实施例中，制备(4R，11S)-7-(甲磺酰基)-1,2,3,4,5,6,7,11c-八氢-4aH-吡啶并[3,2-c] 咔唑-4a-腈[(4R,11S)-7-(Methylsulfonyl)-1,2,3,4,5,6,7,11c-octahydro-4aH-pyrido[3,2-c]carbazole-4a-carbonitril e]，其结构式如下：
Figure BDA0002949691860000321
白色固体，其er＝96:4.比旋光度[α]D 25＝–39.64(c 0.3,EA).Rf＝0.4(PE:EA＝2:1).
1H NMR(400MHz,CDCl3)δ8.17–8.05(m,1H),7.99(d,J＝8.1Hz,1H),7.37–7.18(m,2H),3.88(s,1H),3.45–3.17(m,3H),2.98(s,3H),2.95–2.79(m,1H),2.28–2.13(m,2H),2.03– 1.81(m,2H),1.81–1.56(m,3H).13C NMR(100MHz,CDCl3)δ136.7,134.6,128.9,124.7,123.8, 122.0,121.3,118.4,114.0,61.3,46.2,42.6,40.3,34.1,31.8,24.7,22.9.HRMS(ESI+)m/z calc’d for C17H20N3O2S[M+H]+:330.1271,found 330.1273.
实施例49：
在本实施例中，制备苄基(4R，11R)-4a-氰基-7-(甲磺酰基)-2,3,4,4a，5,6,7,11c-八氢-1H- 吡啶并[3,2-c]咔唑-1-羧酸脂[Benzyl (4R,11R)-4a-cyano-7-(methylsulfonyl)-2,3,4,4a,5,6,7,11c-octahydro-1H-pyrido[3,2-c]carbazole-1-carboxylate]，其结构式如下：
Figure BDA0002949691860000322
白色固体，其er＝95:5.比旋光度[α]D 25＝–39.64(c 0.3,EA).Rf＝0.4(PE:EA＝2:1).
[α]D 25＝–10.73(c 0.5,EA).Rf＝0.4(PE:EA＝1:1).
1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.4Hz,1H),7.51–7.27(m,6H),7.24–7.08(m,2H),5.94(s,1H),5.35(s,2H),4.21(s,1H),3.23–3.11(m,1H),3.11–2.93(m,4H),2.51–2.27(m, 3H),2.06–1.91(m,1H),1.90–1.82(m,2H),1.66–1.53(m,1H).13C NMR(100MHz,CDCl3)δ 155.6,136.7,136.4,134.4,128.7,128.44,128.37,127.5,125.1,124.4,122.3,119.5,113.8,113.7, 68.3,53.5,41.2,39.4,36.6,31.7,26.6,22.3,20.6.HRMS(ESI+)m/zcalc’d for C25H25N3O4SNa [M+Na]+:486.1458,found 486.1451.
实施例50：
在本实施例中，制备(R)-4a-氰基-2,3,4,4a，5,6-六氢-7H-吡啶并[3,2-c]咔唑-7-羧酸叔丁酯 [tert-Butyl(R)-4a-Cyano-2,3,4,4a,5,6-hexahydro-7H-pyrido[3,2-c]carbazole-7-carboxylate]，其结构式如下：
Figure BDA0002949691860000331
白色固体，比旋光度[α]D 25＝–69.33(c 0.1,CH3CN).Rf＝0.3(PE:EA＝5:1).
1H NMR(400MHz,CDCl3)δ8.40–8.29(m,1H),8.16–8.08(m,1H),7.36–7.24(m,2H),4.22(dd,J＝18.9,5.5Hz,1H),3.84(ddd,J＝18.2,11.4,5.5Hz,1H),3.56–3.39(m,2H),2.46–2.35(m,1H),2.31(ddd,J＝13.2,4.7,2.2Hz,1H),2.17–2.00(m,2H),1.98–1.89(m,1H),1.80– 1.67(m,10H).13C NMR(100MHz,CDCl3)δ155.2,150.0,142.4,136.3,126.4,124.8,123.9,121.8, 120.2,115.2,115.0,84.9,49.4,36.6,34.3,31.3,28.3,24.0,20.0.HRMS(ESI+)m/z calc’d for C21H24N3O2[M+H]+:350.1863,found 350.1865.
实施例51：
在本实施例中，制备(3S，10S)-12,13-二氧基-2,3,5,6,12,13-六氢-1H-恶唑[3'，2'：1,2]吡啶[3,2-c]咔唑-3a(4H)-腈 [(3S,10S)-12,13-Dioxo-2,3,5,6,12,13-hexahydro-1H-oxazolo[3',2':1,2]pyrido[3,2-c]carbazole-3a(4H) -carbonitrile]，其结构式如下：
Figure BDA0002949691860000332
白色固体，比旋光度[α]D 25＝–10.17(c 0.2,EA).Rf＝0.3(PE:EA＝1:2).
1H NMR(400MHz,CDCl3)δ9.06(s,1H),7.43(d,J＝8.1Hz,1H),7.25–7.17(m,1H),7.17 –7.11(m,1H),7.12–7.04(m,1H),4.42(dd,J＝12.5,3.7Hz,1H),3.17–2.89(m,2H),2.89–2.69 (m,2H),2.43–2.26(m,1H),2.16–1.92(m,3H),1.84–1.70(m,1H).13C NMR(100MHz,CDCl3) δ158.4,152.0,138.5,136.7,123.7,123.4,121.8,118.5,117.3,112.2,100.5,90.0,46.0,39.3,28.9, 28.7,21.7,18.7.HRMS(ESI+)m/z calc’d for C18H15N3O3Na[M+Na]+:344.1006,found 344.1002.
实施例52：
在本实施例中，制备(S)-3-苄基-4-亚氨基-9-(甲磺酰基)-2,3,4,9-四氢-1H-咔唑-3-腈 [(S)-3-Benzyl-4-imino-9-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000341
HRMS(ESI+)m/z calc’d for C21H19N3O2SNa[M+Na]+:400.1096,found 400.1091.
实施例53：
在本实施例中，制备(R)-9-(甲磺酰基)-4-氧代-3-乙烯基-2,3,4,9-四氢-1H-咔唑-3-腈 [(R)-9-(Methylsulfonyl)-4-oxo-3-vinyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000342
HRMS(ESI+)m/z calc’d for C16H14N2NaO3S[M+Na]+:337.0623,found 337.0631.
实施例54：
在本实施例中，制备(R)-9-乙酰基-3-苄基-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈[(R)-9-Acetyl-3-benzyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000343
HRMS(ESI+)m/z calc’d for C22H18N2NaO2[M+Na]+:365.1260,found 365.1266.
实施例55：
在本实施例中，制备(R)-3-苄基-9-甲基-4-氧代-2,3,4,9-四氢-1H-咔唑-3-腈[(R)-3-Benzyl-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000351
HRMS(ESI+)m/z calc’d for C21H18N2NaO[M+Na]+:337.1311,found 337.1314.
实施例56：
在本实施例中，制备(R)-3-苄基-4-氧代-9-苯基-2,3,4,9-四氢-1H-咔唑-3-腈[(R)-3-Benzyl-4-oxo-9-phenyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000352
HRMS(ESI+)m/z calc’d for C26H20N2NaO[M+Na]+:399.1468,found 399.1462.
实施例57：
在本实施例中，制备(S)-3-苄基-9-(甲磺酰基)-4-氧代-1,3,4,9-四氢吡喃[3,4-b]吲哚-3-腈 [(S)-3-Benzyl-9-(methylsulfonyl)-4-oxo-1,3,4,9-tetrahydropyrano[3,4-b]indole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000353
HRMS(ESI+)m/z calc’d for C20H16N2NaO4S[M+Na]+:403.0723,found 403.0722.
实施例58：
在本实施例中，制备(S)-3-苄基-2-甲基-9-(甲磺酰基)-4-氧代-2,3,4,9-四氢-1H-吡啶[3,4-b] 吲哚-3-腈 [(S)-3-Benzyl-2-methyl-9-(methylsulfonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carb onitrile]，其结构式如下：
Figure BDA0002949691860000361
HRMS(ESI+)m/z calc’d for C21H19N3NaO3S[M+Na]+:416.1039,found 416.1042.
实施例59：
在本实施例中，制备(S)-3-苄基-9-(甲磺酰基)-4-氧代-1,3,4,9-四氢硫代吡喃[3,4-b]吲哚-3- 腈[(S)-3-Benzyl-9-(methylsulfonyl)-4-oxo-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-3-carbonitrile]，其结构式如下：
Figure BDA0002949691860000362
HRMS(ESI+)m/z calc’d for C20H16N2NaO3S2[M+Na]+:419.0495,found 419.0495.
实施例60：
在本实施例中，制备(R)-4-苄基-10-(甲磺酰基)-5-氧代-3,4,5,10-四氢-1H-氧代匹诺[3,4-b] 吲哚-4-腈 [(R)-4-Benzyl-10-(methylsulfonyl)-5-oxo-3,4,5,10-tetrahydro-1H-oxepino[3,4-b]indole-4-carbonitril e]，其结构式如下：
Figure BDA0002949691860000363
HRMS(ESI+)m/z calc’d for C21H18N2NaO4S[M+Na]+:417.0879,found 417.0879.
实施例61：
在本实施例中，制备(S)-4-苄基-10-(甲磺酰基)-5-氧代-2-甲苯基-1,2,3,4,5,10-六氢氮杂环[3,4-b]吲哚-4-腈 [(S)-4-Benzyl-10-(methylsulfonyl)-5-oxo-2-tosyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indole-4-carb onitrile]，其结构式如下：
Figure BDA0002949691860000371
HRMS(ESI+)m/z calc’d for C28H25N3NaO5S2[M+Na]+:570.1128,found 570.1121.
实施例62：
在本实施例中，制备(S)-4-苄基-10-(甲磺酰基)-5-氧代-3,4,5,10-四氢-1H-噻吩并[3,4-b] 吲哚-4-腈 [(S)-4-Benzyl-10-(methylsulfonyl)-5-oxo-3,4,5,10-tetrahydro-1H-thiepino[3,4-b]indole-4-carbonitril e]，其结构式如下：
Figure BDA0002949691860000372
HRMS(ESI+)m/z calc’d for C21H18N2NaO3S2[M+Na]+:433.0651,found 433.0639.
实施例63：
在本实施例中，制备(R)-10-苄基-5-(甲磺酰基)-11-氧代-6,7,8,9,10,11-六氢-5H-环辛[b] 吲哚-10-腈 [(R)-10-Benzyl-5-(methylsulfonyl)-11-oxo-6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-10-carbo nitrile]，其结构式如下：
Figure BDA0002949691860000373
1H NMR(400MHz,CDCl3)δ8.08–7.97(m,1H),7.46–7.35(m,2H),7.35–7.20(m,6H),3.38–3.10(m,6H),2.66(BA,J＝13.3Hz,1H),2.24–1.95(m,3H),1.81(ddt,J＝15.2,8.5,4.9Hz, 3H).13C NMR(100MHz,CDCl3)δ198.4,142.3,135.7,133.1,130.6,128.7,128.3,128.1,125.8, 124.8,119.2,118.3,115.7,113.8,57.6,43.1,41.7,29.5,29.1,26.0,22.5.HRMS(ESI+)m/z calc’d for C23H22N2NaO3S[M+Na]+:429.1243,found 429.1249.
实施例64：
在本实施例中，制备(S)-苄基-11-(甲磺酰基)-6-氧代-1,3,4,5,6,11-六氢氧代[3,4-b]吲哚-5- 腈
[(S)-5-Benzyl-11-(methylsulfonyl)-6-oxo-1,3,4,5,6,11-hexahydrooxocino[3,4-b]indole-5-carbonitrile] ，其结构式如下：
Figure BDA0002949691860000381
HRMS(ESI+)m/z calc’d for C22H20N2NaO4S[M+Na]+:431.1036,found 431.1035.
实施例65：
在本实施例中，制备(S)-2-乙酰基-5-苄基-11-(甲磺酰基)-6-氧代-2,3,4,5,6,11-六氢-1H- 偶氮[3,4-b]吲哚-5-腈 [(S)-2-Acetyl-5-benzyl-11-(methylsulfonyl)-6-oxo-2,3,4,5,6,11-hexahydro-1H-azocino[3,4-b]indole- 5-carbonitrile]，其结构式如下：
Figure BDA0002949691860000382
HRMS(ESI+)m/z calc’d for C24H23N3NaO4S[M+Na]+:472.1301,found 472.1305.
实施例66：
在本实施例中，制备(S)-5-苄基-11-(甲磺酰基)-6-氧代-1,3,4,5,6,11-六氢噻吩[3,4-b]吲哚 -5-腈[(S)-5-Benzyl-11-(methylsulfonyl)-6-oxo-1,3,4,5,6,11-hexahydrothiocino[3,4-b]indole-5-carbonitrile] ，其结构式如下：
Figure BDA0002949691860000383
HRMS(ESI+)m/z calc’d for C22H20N2NaO3S2[M+Na]+:447.0808,found 447.0813.
实施例67：
在本实施例中，制备(R)-6-苄基-9-(甲磺酰基)-5-氧代-6,7,8,9-四氢-5H-吡啶并[2,3-b]吲哚 -6-腈 [(R)-6-Benzyl-9-(methylsulfonyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile]，其结构式如下：
Figure BDA0002949691860000391
1H NMR(400MHz,CDCl3)δ8.46–8.41(m,1H),8.41–8.32(m,1H),7.85–7.70(m,1H),7.37–7.23(m,5H),3.71(s,3H),3.63–3.52(m,1H),3.50–3.33(m,2H),3.05(BA,J＝13.9Hz,1H),2.46–2.32(m,1H),2.22–2.10(m,1H).HRMS(ESI+)m/z calc’d for C22H20N2NaO3S2 [M+Na]+:447.0808,found 447.0813.
实施例68：β位含氰基手性季碳中心的吲哚抑制HBV的活性测试。
Figure BDA0002949691860000392
(1)实验方法
HBV感染实验：在96孔板中铺HepG2-NTCP细胞，待细胞密度达70-80％时，用2.5％DMSO培养基继续培养至细胞密度达100％，每孔加入100ul含200MOI HBV、5％PEG8000、2.5％DMSO的培养基孵育24h，弃去培养基，用PBS洗3次，换成新鲜的2.5％DMSO培养基继续培养，每2天换一次新鲜的培养基。
CCK8检测化合物对细胞的毒性：HepG2-NTCP细胞用化合物处理7天后，弃去培养基，每孔加入10ul CCK8试剂+90ul培养基，37度培养箱孵育1h后，酶标仪检测每孔培养基的OD450。
HBeAg检测：收集细胞上清，按照乙型肝炎病毒e抗原检测试剂盒(酶联免疫法)说明书，检测上清中HBeAg的相对含量。
HBVpgRNA检测：HepAD38细胞用化合物处理6天后，弃上清，用PBS洗两次，用RNA 抽提试剂盒提取细胞中的RNA，用逆转录试剂盒将RNA逆转成cDNA，实时定量PCR检测细胞中HBVpgRNA的含量(相对于内参基因ACTB)。
HBV上清DNA检测：HepAD38细胞用化合物处理6天后的上清，用HBV DNA检测试剂盒检测HBV DNA浓度。
(2)实验结果
化合物抑制HBeAg的分泌：在HBV感染的HepG2-NTCP细胞中，10uM化合物HXD 1-10处理细胞7天后，对于HBV e抗原HBeAg的分泌的影响，化合物HXD-7、HXD-8、HXD-9 与已知的能抑制HBV转录的化合物AM80类似，能明显抑制HBeAg的分泌(如图1A所示)，而HXD-1、HXD-2、HXD-3、HXD-4、HXD-5、HXD-6、HXD-10对HBeAg分泌的影响并不明显；随后通过CCK8检测化合物HXD-7、HXD-8、HXD-9对HepG2-NTCP细胞毒性的影响，发现化合物HXD-7、HXD-8、HXD-9对HepG2-NTCP无细胞毒性(如图1B所示)。
化合物抑制HBVpgRNA：HBV基因组在肝细胞中能转录出HBVpgRNA，因为前面的实验表明化合物HXD-7、HXD-8、HXD-9能明显抑制HBV e抗原的分泌，因此本发明在整合了HBV基因组的肝癌细胞系HepAD38中，检测化合物HXD-7、HXD-8、HXD-9对HBVpgRNA 的影响。用10uM化合物HXD-7、HXD-8、HXD-9处理细胞6天后，发现化合物能明显抑制转录出来的HBVpgRNA水平(如图2所示)。
化合物抑制分泌出细胞的HBV DNA：在HBV生活周期中，包裹子代rcDNA的子代HBV病毒颗粒将分泌出细胞外。本发明在整合了HBV基因组的肝癌细胞系HepAD38中，用10uM 化合物HXD-7、HXD-8、HXD-9处理细胞6天后，发现化合物能明显抑制分泌到细胞外的HBV DNA的水平(如图3所示)。
在本发明的这项研究中，化合物HXD-7、HXD-8、HXD-9对HBeAg、HBVpgRNA、HBV DNA都有明显的抑制作用，而且这些化合物对细胞的毒性较小，是潜在的治疗HBV的新的化合物。
本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可以是在本发明范围内所作的修改或在权利要求中所添加的等同内容。

Claims (7)

1.一种化合物，其特征在于，选自如下结构式之一：
Figure FDA0003618712330000011
2.一种如权利要求1所述化合物的合成方法，其特征在于：
所述合成方法包括以下步骤：
(1)在催化剂前体钯和配体络合形成的催化剂催化下，原料II在溶剂中发生反应；
(2)反应结束后，加入稀盐酸溶液搅拌后处理；
(3)萃取并浓缩溶剂，分离提纯，生成化合物I；
所述反应式为：
Figure FDA0003618712330000021
R1-R3的结构如权利要求1中所示，Z选自亚甲基，m取自1，n取自0；*表示手性中心；
其中[Pd]为催化剂前体钯；Ligand为配体；solvent为有机溶剂；additive为添加剂；
所述催化剂前体钯为Pd(OAc)2或Pd(TFA)2；
所述配体选自下式之一：
Figure FDA0003618712330000022
所述添加剂选自：氯化锌、对甲基苯磺酸、四丁基氯化铵、六氟磷酸胺、三氟甲烷磺酰亚胺或水。
3.根据权利要求2所述的一种式I化合物的合成方法，其特征在于：所述催化剂前体钯中含金属钯元素与配体的摩尔比为1:0.5～1:2。
4.根据权利要求2或3所述的一种式I化合物的合成方法，其特征在于：所述反应在有机溶剂中进行，所述有机溶剂为苯、甲苯、1,2-二氯乙烷、氯苯、乙腈、二甲基甲酰胺、乙二醇二甲醚、四氢呋喃、1,4-二氧六环以及其中二种或二种以上混合溶剂。
5.根据权利要求2或3所述的一种式I化合物的合成方法，其特征在于：所述催化剂中Pd元素的物质量与II所示原料的物质量之比为0.01:1～0.2:1。
6.根据权利要求5所述的一种式I化合物的合成方法，其特征在于：所述添加剂和原料II的物质量之比为0.3:1～2:1；所述反应的温度为80℃～120℃；所述反应的时间为1～48小时；所述分离提纯方法为柱层析、薄层层析；所述柱层析使用的洗脱液为乙酸乙酯、丙酮、或者石油醚和乙酸乙酯的混合液。
7.一种如权利要求1所述化合物在制备抗乙肝病毒药物中的应用，其特征在于：所述化合物具有抗乙肝病毒的活性，所述抗乙肝病毒的活性选自抑制HBV转录、抑制HBeAg的分泌、抑制转录出的HBVpgRNA水平和抑制分泌到细胞外的HBVDNA的水平。
CN202110207147.8A 2021-02-24 2021-02-24 光学活性的吲哚化合物、合成方法及其应用 Active CN112961100B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110207147.8A CN112961100B (zh) 2021-02-24 2021-02-24 光学活性的吲哚化合物、合成方法及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110207147.8A CN112961100B (zh) 2021-02-24 2021-02-24 光学活性的吲哚化合物、合成方法及其应用

Publications (2)

Publication Number Publication Date
CN112961100A CN112961100A (zh) 2021-06-15
CN112961100B true CN112961100B (zh) 2022-06-14

Family

ID=76285963

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110207147.8A Active CN112961100B (zh) 2021-02-24 2021-02-24 光学活性的吲哚化合物、合成方法及其应用

Country Status (1)

Country Link
CN (1) CN112961100B (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111499542A (zh) * 2020-04-01 2020-08-07 武汉大学 一种含α-氰基取代季碳中心的环烯酮化合物的制备方法
CN111646992A (zh) * 2020-06-05 2020-09-11 武汉大学 一种季碳中心的全取代吡啶化合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111499542A (zh) * 2020-04-01 2020-08-07 武汉大学 一种含α-氰基取代季碳中心的环烯酮化合物的制备方法
CN111646992A (zh) * 2020-06-05 2020-09-11 武汉大学 一种季碳中心的全取代吡啶化合物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Enantioselective Synthesis of α-All-Carbon Quaternary Center-Containing Carbazolones via Amino-palladation/Desymmetrizing Nitrile Addition Cascade";Xu-Dong Hu et al.;《JACS》;20210308;第143卷;第3734-3740页 *

Also Published As

Publication number Publication date
CN112961100A (zh) 2021-06-15

Similar Documents

Publication Publication Date Title
Han et al. Total synthesis, stereochemical assignment, and biological activity of all known (−)-trigonoliimines
Ziegler et al. Chiral aziridinyl radicals: an application to the synthesis of the core nucleus of FR-900482
Wang et al. A biomimetic total synthesis of (−)-spirotryprostatin B and related studies
Cui Recent progress in the synthesis of pyrrolo [2, 1-a] isoquinolines
Zhang et al. Silver-catalyzed intramolecular hydroamination of alkynes in aqueous media: Efficient and regioselective synthesis for fused benzimidazoles
Xu et al. Gold-catalyzed Michael addition/intramolecular annulation cascade: an effective pathway for the chemoselective-and regioselective synthesis of tetracyclic indole derivatives in water
FI74002C (fi) Foerfarande foer framstaellning av - karbolinderivat.
Miller et al. A concise, enantioselective approach for the synthesis of yohimbine alkaloids
CN110551136A (zh) 一种氮杂环卡宾催化的含吲哚骨架手性螺环化合物的制备方法及用途
Xia et al. One-pot asymmetric synthesis of a spiro [dihydrofurocoumarin/pyrazolone] scaffold by a Michael addition/I 2-mediated cyclization sequence
CN114516881B (zh) 一种氮杂环卡宾催化的含吡唑并吡喃骨架手性化合物及制备方法
Bolte et al. Total Syntheses of the 3 H-Pyrrolo [2, 3-c] quinolone-Containing Alkaloids Marinoquinolines A–F, K, and Aplidiopsamine A Using a Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Pathway
Hajinasiri A review of the synthesis of 1, 2-dihydroisoquinoline,[2, 1-a] isoquinoline and [5, 1-a] isoquinoline since 2006
CN113105468B (zh) 一种含苯并吡喃酮的多环螺吲哚酮类化合物及其制备方法和应用
Peng et al. Enantioselective total synthesis of spirotryprostatin A
CN112961100B (zh) 光学活性的吲哚化合物、合成方法及其应用
CN114716438B (zh) 具有苯并[7,8]吲嗪[1,2-c]喹啉骨架衍生物及其合成方法
CN110776510B (zh) 一种1-(2-喹啉基)-β-咔啉天然产物及衍生物的制备方法
CN109160914B (zh) 一种双吲哚并吡啶类衍生物的合成方法及在抗肿瘤中的应用
CN113214136A (zh) 一种含螺环戊二烯-2-羟吲哚类化合物及其制备方法和应用
CN113149984B (zh) 一种吡啶并咪唑衍生物的绿色合成方法及其在制备抗肿瘤药物中的应用
CN114249724B (zh) 一种唑吡坦中间体的制备方法
CN115368349B (zh) 一种新型n-取代靛红衍生物及其制备以及其在制备抗肿瘤药物中的应用
Depa et al. Epoxydibenzo [b, f][1, 5] diazocines: From a Hidden Structural Motif to an Efficient Solvent-Free Synthetic Protocol
CN115611901B (zh) 一种氮杂䓬类化合物或其药学上可接受的盐及其制备方法和应用

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