WO2013000280A1 - 9-sulfonyl-9h-purine derivative, preparation method and use thereof - Google Patents

9-sulfonyl-9h-purine derivative, preparation method and use thereof Download PDF

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WO2013000280A1
WO2013000280A1 PCT/CN2012/000901 CN2012000901W WO2013000280A1 WO 2013000280 A1 WO2013000280 A1 WO 2013000280A1 CN 2012000901 W CN2012000901 W CN 2012000901W WO 2013000280 A1 WO2013000280 A1 WO 2013000280A1
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independently
alkyl
group
fluorenyl
substituted
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PCT/CN2012/000901
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French (fr)
Chinese (zh)
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余洛汀
魏于全
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四川大学
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28Oxygen atom
    • C07D473/30Oxygen atom attached in position 6, e.g. hypoxanthine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32Nitrogen atom
    • C07D473/34Nitrogen atom attached in position 6, e.g. adenine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36Sulfur atom
    • C07D473/38Sulfur atom attached in position 6
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/40Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • the present invention relates to a 9-sulfonyl-9H-indole derivative, a preparation method and use thereof, and belongs to the field of chemical medicine. Background technique
  • Chronic hepatitis C is a chronic liver disease caused by hepatitis C virus (HCV), a major cause of liver cirrhosis and liver cancer, and is the leading cause of liver transplantation.
  • HCV hepatitis C virus
  • WHO World Health Organization
  • HCV anti-hepatitis C virus
  • the first technical problem to be solved by the present invention is to provide a novel class of 9-sulfonyl-9H-indole derivatives having the structure shown in Formula I:
  • is independently -H, -F, -Cl, -Br, -1, -N 3 , -CF 3 , -NH 2 , -N0 2 ,
  • Rl2 w Rl1 R 15 ⁇ s is Re R 9 , R13 3 ⁇ 4 , benzyl, C1 ⁇ C8 thiol or C3-
  • R 5 to R 7 are independently -H, -F, -Cl, -Br, -H 2 > -N0 2 , -N 3 , -CF 3 , C3 to C8 cyclodecyl or Cl to C8 fluorenyl;
  • R8 ⁇ R 15 is independently -H, -F, -Cl, -Br, -N3 ⁇ 4, -N0 2, -N 3, -CF 3, with R 16 Cl ⁇ C8 alkyl with a substituent, substituted with R 16 cyclic alkyl with C3 ⁇ C8 group, optionally substituted with R 16 C1 ⁇ C8 alkyl with an oxygen probe substituent group, C3 ⁇ C8 cycloalkyl with R 16 substituted alkyl with a substituted oxycarbonyl group, substituted with R 16 group C1 ⁇ C8 a fluorenyloxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
  • R 16 is -H, C1 to C8 'decyl, -NH 2 > -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 fluorene A group or a C1 to C8 alkyl group substituted with an amine group.
  • R 5 to R 7 are independently -H, -F, -Cl, -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cyclodecyl or C! ⁇ C8 hospital base;
  • R 15 are independently -H, -F, -Cl, -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , Cl to C8 alkyl group having an R 16 substituent, and R 16 C3 ⁇ C8 cycloalkyl group substituted with a substituent R 16 C1 ⁇ C8 alkyl with a substituted oxycarbonyl group, substituted with a group R 16 C3 ⁇ C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 group C1 ⁇ C8
  • An alkoxy group or a ring skeleton having a substituent of R 16 is an aromatic ring group of 3 to 8 carbon atoms;
  • C1 to C8 alkyl -NH 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy
  • the C3 ⁇ C8 cyclodecyl group or the C1 ⁇ C8 fluorenyl group is substituted with an amine group.
  • it is -11, C1 ⁇ C8 alkyl or C3 ⁇ C8 cycloalkyl;
  • R 2 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1 ⁇ C8 alkyl with, C3 ⁇ C8 cycloalkyl group embankment,
  • Rl2 w Rl1 R 15 ⁇ s is Re R 9 , R 13 ,
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
  • ⁇ R 15 is independently -H, C1 ⁇ C8 fluorenyl, C1 ⁇ C8 decyloxy, -N0 2 , phenyl, C1 ⁇ C8 fluorenyl substituted oxycarbonyl, C3 ⁇ C8 cycloalkyl substituted oxo group or - CF 3 .
  • Ri is -H, C1 ⁇ C8 alkyl or C3 ⁇ C8 cycloalkyl;
  • is R 8 R 9 , 13 , ⁇ J ;
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
  • Rs ⁇ R 12 are independently -H, C1 ⁇ C8 alkyl, C1 ⁇ C8 decyloxy, -N0 2 , phenyl or -CF 3;
  • R 13 to R 15 are independently -H, C1 to C8 fluorenyl or C1 to C8 fluorenyl substituted oxycarbonyl.
  • Ri is -H or C1 ⁇ C4 fluorenyl;
  • R 3 is -H, -F, -Cl, -Br, C1 ⁇ C4 fluorenyl or -NH 2;
  • R4 is, , '
  • R 5 to R 7 are independently -H or C1 to C4 fluorenyl
  • R 8 to Ri 2 are independently -H, C1 to C4 alkyl, C1 to C4 methoxy, -N0 2 , phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H, C1 to C4 fluorenyl substituted oxycarbonyl or C1 to C4 fluorenyl. Preferably, it is -11 or €1 to 4 alkyl;
  • R 2 is -H, -F, -Cl, -Br, -N 3 , C1 to C4 alkyl, C1 to C4 nonyloxy, C1 to C4 alkyl substituted amine
  • R 3 is -H, -F, -Cl, -Br or C1 to C4 alkyl
  • R 5 to R 7 are independently -H
  • Rs ⁇ R 12 are independently C1 ⁇ C4 alkyl, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently an -H or a C1 to C4 fluorenyl group substituted with an oxycarbonyl group. Preferably, it is -11 or 01 ⁇ 04 thiol;
  • R 2 is -H, -F, -Cl, -Br, -NH 2 , -N 3 , C1 to C4 fluorenyl, C1 to C4 decyloxy, C1 to C4 fluorenyl
  • R 3 is -H, -F, -Cl, -Br, -NH 2 or C1 to C4 alkyl;
  • R 5 to R 7 are independently -H
  • R « ⁇ Ri 2 are independently -H, -N0 2 , C1 ⁇ C4 alkyl, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H or C1 to C4 fluorenyl substituted oxycarbonyl; x. ⁇ 2 ⁇ ⁇ N , , .
  • Optimal, 1 ⁇ is -11;
  • R 3 is -H, -NH 2 or -C1;
  • R 5 to R 7 are independently -H
  • ⁇ R 12 is independently -H, -N0 2 , C1 ⁇ C4, CI 4 alkoxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H or methyl substituted oxycarbonyl
  • R 2 and R 3 are -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , -N0 2 , C1 to C8 fluorenyl,
  • R4 is , benzyl, C1 ⁇ C4 thiol or C3- C6 cycloalkyl
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
  • ⁇ R 15 is independently -H, -N0 2 , C1 ⁇ C8 alkyl, C1 ⁇ C8 decyloxy, phenyl, C1 ⁇ C8 fluorenyl, C3 ⁇ C8 cyclodecyl substituted oxycarbonyl or -CF 3 ;
  • Ri is -H, C1 ⁇ C8 fluorenyl or C3 ⁇ C8 cycloalkyl
  • R 2 and R 3 are -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , -N0 2 , C3 to C8 cycloalkyl,
  • R4 is , benzyl, C1 ⁇ C4 fluorenyl or C3 C6 cycloalkyl
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl;
  • Rs ⁇ R 12 are independently -H, -N0 2 , C1 ⁇ C8 'decyl, C1 ⁇ C8 alkoxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H, C1 to C8 alkyl or C1 to C8 alkyl substituted oxycarbonyl;
  • 1 ⁇ is - ⁇ 1 or €1 ⁇ 4 alkyl
  • R 2 is -H, -F, -CK -Br, -1, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4
  • R 3 is -H, -F, -CK -Br, -NH 2 or C1 ⁇ C4 fluorenyl;
  • Rl2 w R 1 R 15 ⁇ s ⁇ is Re R 9 , 13 ⁇ , benzyl, C 1 ⁇ C4 thiol or
  • R 5 to R 7 are independently -H or C1 to C4 alkyl
  • Rs ⁇ R 12 are independently -H, -N0 2 , C1 ⁇ C4 fluorenyl, C1 ⁇ C4 alkoxy, phenyl or -CF 3 ;
  • R 15 is independently -H, C1 ⁇ C4 carbonyl or C1 ⁇
  • R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 decyloxy, C1 to C4 Substituted amine group, ⁇ 3>, ⁇ 111 ⁇ or C1 ⁇ C4 thiol;
  • R 3 is -H, -F, -Cl, -Br or -NH 2 ;
  • R4 is , benzyl, C1 ⁇ C4 thiol or C3'
  • R 5 to R 7 are independently -H
  • Rg ⁇ R 12 are independently -H, -N0 2 , C1 ⁇ C4, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H or C1 to C4 fluorenyl substituted oxycarbonyl
  • R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , methyl, C1 to C4 alkoxy, C1 to C4 alkyl
  • R 3 is -H, -H 2 or -CI
  • R4 is , benzyl, C1 ⁇ C4 thiol or C3-
  • R 5 to R 7 are independently -H
  • ⁇ R 12 is independently -H, -N0 2 , C1 ⁇ C4 fluorenyl, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • ⁇ R 15 is independently -H or methyl substituted oxycarbonyl;
  • R 5 to R 7 are independently -H, -F, -CK -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cycloalkyl or Cl ⁇
  • R 8 ⁇ R 12 is independently -H, -F, -CK -Br, -NH 2, -N0 2, -N 3, -CF 3, with R 16 Cl ⁇ C8 alkyl with a substituted group, with R 16 embankment C3 ⁇ C8 cycloalkyl substituent, substituted with R 16 C1 ⁇ C8 alkyl with a substituted oxycarbonyl group, substituted with a group R 16 C3 ⁇ C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 group C1 ⁇ C8 a fluorenyloxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
  • R 16 is -H, C1 to C8 alkyl, -H 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 cycloalkyl Or a C1 ⁇ C8 thiol group substituted with an amine group.
  • Ri ⁇ R 3 is independently -H, -F, -CK -Br, -N 3, -CF 3, -NH 2, -N0 2, C1 ⁇ C8 alkyl with, C3 ⁇ C8 cycloalkyl, C1-C8 decyloxy, C1-C8 alkyl-substituted amine group, ⁇ N ⁇ JD, ⁇ R7 or C1 ⁇ C8 thiol;
  • R 5 to R 7 are independently -H, -F, -CK -Br, - ⁇ 2 , - ⁇ 0 2 , - ⁇ 3 , -CF 3 , C3 ⁇ C8 cyclodecyl or Cl ⁇ C8 alkyl;
  • ⁇ R is independently -H, -F, -CK -Br, -NH 2, -N0 2, -N 3, -CF 3, with R 16 Cl ⁇ C8 alkyl group substituted with a substituent R 16 C1 ⁇ C8 alkyl with embankment C3 ⁇ C8 cycloalkyl group with a substituent group R 16 substituted oxycarbonyl group, substituted with a group R 16 C3 ⁇ C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 C1 ⁇ C8 alkoxy group embankment Or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
  • Ri 6 is -H, C1 to C8 fluorenyl, -NH 2 , -N0 2 , -N 3 , -F, -CK -Br, -CF 3 , C1 to C8 decyloxy,
  • the C3 ⁇ C8 cyclodecyl group or the C1 ⁇ C8 fluorenyl group is substituted with an amine group.
  • Preferred, ! ⁇ is -H, C1 ⁇ C8 thiol or C3 ⁇ C8 fluorenyl;
  • R 2 is - H, -F, -CK -Br, -N 3, -NH 2, -N0 2, C1 ⁇ C8 alkyl with, C3 ⁇ C8 cycloalkyl group embankment,
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 alkyl;
  • R 8 to R 12 are independently -H, C1 to C8 'decyl, C1 to C8 decyloxy, -N0 2 , phenyl or -CF 3 . Preferably, it is 11 or €1 to €4;
  • R 3 is -H, -F, -CK -Br, C1 ⁇ C4 fluorenyl or -NH 2 ;
  • R 5 to R 7 are independently -H or C1 to C4 alkyl
  • ⁇ Ri2 is independently -H, C1 to C4 alkyl, C1 to C4 alkoxy, -N0 2 , phenyl or -CF 3 .
  • Ri is -H, C1 ⁇ C8 fluorenyl or C3 ⁇ C8 cyclodecyl;
  • R 2 and R 3 are -H, -F, -CK -Br, -1, -NH 2 , -N 3 , -N0 2 , C1 to C8 fluorenyl, C3 to C8 cyclodecyl, R ⁇ R 6
  • R 5 to R 7 independently -H, C3 to C8 cyclodecyl or C1 to C8 alkyl
  • R 8 to R 12 are independently -H, -N0 2 , C1 to C8, C1 to C8 alkoxy, phenyl or -CF 3 ;
  • 1 ⁇ is 11 or €1 to €4 alkyl
  • R 3 is -H, -F, -Cl, -Br, -NH 2 or C1 to C4 fluorenyl;
  • R 5 to R 7 are independently -H or C1 to C4 alkyl
  • ⁇ Ri2 is independently -H, -N0 2 , C1 ⁇ C4, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • Optimal, for - R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , methyl, methoxy, C1 to C4 mercapto substituted amine, f or methylthio;
  • R 3 is -H, - H 2 or -C1;
  • R 5 to R 7 are independently -H
  • Rg ⁇ R 12 are independently -H, -N0 2 , C1 ⁇ C4 fluorenyl, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • R 3 is -H, -NH 2;
  • R4 is Benzyl, C1 ⁇ C4 thiol or C3-
  • Rs ⁇ R 15 are independently -H, -N0 2 , C1 ⁇ C8, C1 ⁇ C8 alkoxy, phenyl, C1 ⁇ C8 alkyl substituted oxycarbonyl, C3 ⁇ C8 cycloalkyl substituted oxycarbonyl or - CF 3 ;
  • R 2 is -F, -Cl, -Br or -I;
  • R 3 is -H, -F, -CK -Br or -NH 2 ;
  • R4 is R 9 , Benzyl, C1 ⁇ C4 thiol or C3-
  • Rs ⁇ Ri2 are independently -H, -N0 2 , CI' 8 fluorenyl, C1 to C8 alkoxy, phenyl or -CF 3 ;
  • R 15 is independently -H, C1-C8 alkyl or C1 to C8 alkyl substituted oxycarbonyl;
  • R 2 is -F, -CK -Br or -I;
  • R 3 is -H, -F, -CI or -NH 2 ;
  • R4 is , benzyl, C1 ⁇ C4 thiol or C3-
  • ⁇ Rn is independently -H, -N0 2 , C1 ⁇ C4, C1 ⁇ C4 decyloxy, phenyl or -CF 3 ;
  • R 13 to R 15 are independently -H, CI to C 4 alkyl substituted oxycarbonyl or CI C4 fluorenyl;
  • R 2 is -F, -Cl, -Br or -I;
  • R 3 is -H, -CI - H 2 ;
  • R4 is Benzyl, C1 ⁇ C4 thiol or C3-
  • R 8 to R 12 are independently -H, -N0 2 , C1 to C4 alkyl, C1 to C4 alkoxy, phenyl or -CF 3
  • R 13 to R 15 are independently -H or C to C4 fluorenyl Substituting an oxycarbonyl group
  • N0 2 is optimal, R 2 is -F, -Cl, -Br or -I;
  • R 3 is -H, -NH 2 or -CI
  • R4 is Benzyl, C1 ⁇ C4 thiol or C3
  • R « ⁇ R 12 are independently -H, -N0 2 , C1 ⁇ C4, CI' C4 methoxy, phenyl or -CF 3 ;
  • R 13 ⁇ R 15 are independently -H or methyl substituted oxygen Carbonyl;
  • a second technical problem to be solved by the present invention is to provide a process for producing the 9-sulfonyl-9H-indole derivative represented by the above formula I, formula II and formula III, and the synthesis route is as follows:
  • the reaction solvent is preferably a mixed solvent of tetrahydrofuran and dichloromethane, and the volume ratio of tetrahydrofuran to dichloromethane is
  • reaction temperature is room temperature and requires nitrogen protection.
  • a third technical problem to be solved by the present invention is to provide the use of the 9-sulfonyl-9H-indole derivative represented by the above formula I, formula II and formula III for the preparation of a medicament for anti-chronic hepatitis C.
  • a fourth technical problem to be solved by the present invention is to provide an intermediate which is used in the preparation of the 9-sulfonyl-9H-indole derivative represented by the above formula I and formula II, and has the structure shown in Formula IV:
  • Ra and R 3 are independently -H, -F, -Cl, -Br, - ⁇ 3 , - ⁇ 2 , - ⁇ 0 2 , C1 ⁇ C8 thiol, C3 ⁇ C8 cyclodecyl, C1 ⁇ C8 ⁇ An oxy group, a C1 ⁇ C8 fluorenyl substituted amine group, a ⁇ , ⁇ or a C1 ⁇ C8 sulphur-burning group;
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl.
  • 1 ⁇ is 11, C1 ⁇ C8 alkyl or C3 ⁇ C8 cyclodecyl;
  • R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1 ⁇ C8 alkyl, C3 ⁇ C8 cycloalkyl group embankment, Cl ⁇
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl. Preferably, it is -11 or €1 to €4 alkyl;
  • R 3 is -H, -F, -Cl, -Br, -N 3, - H 2, -N0 2, C1 ⁇ C8 alkyl, C3 ⁇ C8 cycloalkyl group embankment, C! ⁇ C8 alkoxy, C1 ⁇ C8 mercapto substituted amine, ⁇ f]0, ⁇ or C1 ⁇ C8 thiol;
  • R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C4 fluorenyl. Preferably, it is -11 or €1 to €4 alkyl;
  • R 3 is -H, -F, -Cl, -Br, C1 to C4 alkyl or -R 5 to R 7 are independently -H or C1 to C4 alkyl.
  • R 3 is independently -H, -F, -Cl, -Br, -N 3 , -N0 2 , C1 ⁇ C8 fluorenyl, C3 ⁇ C8 cyclodecyl, C1 ⁇ C8 decyloxy, C1 ⁇ C8 alkyl substituted amine group, ⁇ ND, ⁇ or C1 ⁇ C8 thiol group;
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl. Preferably, it is a -11 or a C1 to C4 alkyl group;
  • R 3 is -H, -F, -Cl, -Br or C1 ⁇ C4 fluorenyl
  • R 5 to R 7 are independently -H or C1 to C4 fluorenyl. Optimal, R ⁇ H;
  • R 3 is -H or -C1
  • R 5 to R 7 are independently -H.
  • R 3 is independently -H, -F, -Cl, -Br, -N 3 , -NH 2 -N0 2 , C1 ⁇ C8 'decyl, C3 ⁇ C8 cycloalkyl, C1 ⁇ C8 ⁇ oxygen a group, a C1 ⁇ C8 thiol group substituted with an amine group, ⁇ ⁇ ⁇ . 0, ⁇ or C1 ⁇ C8 alkylthio;
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl.
  • Ri is -H, C1 ⁇ C8 alkyl or C3 ⁇ C8 cyclodecyl;
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl. Preferably, it is -11 or ⁇ 4 alkyl;
  • R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1 ⁇ C8 hospital group, C3 ⁇ C8 cycloalkyl group embankment, Cl ⁇
  • R 5 to R 7 are independently -H, C3-C8 cycloalkyl or C1 to C4 fluorenyl.
  • Ri is -H or C1 ⁇ C4 alkyl;
  • R 3 is -H, -F, -Cl, -Br, C1 ⁇ C4 fluorenyl or -N3 ⁇ 4;
  • R 5 to R 7 are independently -H or C1 to C4 alkyl.
  • R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl. Preferably, it is a -11 or a C1 to C4 alkyl group;
  • R 3 is -H, -F, -Cl, -Br or C1 ⁇ C4 fluorenyl
  • R 5 to R 7 are independently -H or C1 to C4 alkyl. Optimal, RH;
  • R 3 is -H or -CI
  • R 5 to R 7 are independently -H.
  • the present invention also provides a pharmaceutical composition prepared by adding a pharmaceutically acceptable auxiliary component to the 9-sulfonyl-9H-indole derivative represented by the above formula I and formula II.
  • the pharmaceutical composition can be used to prepare an anti-chronic hepatitis C drug.
  • the invention obtains 9-sulfonyl-9H-indole derivative on the basis of a large number of screenings, has anti-HCV activity, and provides a new choice for the development and application of anti-chronic hepatitis C drugs.
  • Figure 1 Compound 6-chloro-9-(4-methoxybenzenesulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.
  • Fig. 2 shows the results of anti-HCV activity and cytotoxicity test of the compound methyl 3-(6-chloro-9H-indol-9-ylsulfonyl)thiophene-2-carboxylate.
  • Figure 4 Compound 6-chloro-9-(3-nitrophenylsulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.
  • Figure 5 Compound 6-chloro-9-(2-nitrophenylsulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.
  • 6-chloroindole 0.465 g Ommol was dissolved in ethanol, followed by 1.25 g (9 mmol) of potassium carbonate and 0.725 g (9 mmol) of dimethylamine hydrochloride, followed by heating under reflux for 12 h. After completion of the reaction, the solvent was evaporated under reduced pressure. The remaining solid was suspended in water and stirred for 2 h, then filtered to give the product 6-dimethylaminoindole, with a net weight of 0.392 g and a yield of 80.05%. Purity (HPLC) ⁇ 94%.
  • the raw material is replaced by 6-chloropurine and diethylamine, and the reaction is washed. Polyester and filtration directly gave 6-diethylaminopurine in a yield of 85.37%. Purity (HPLC) ⁇ 95%.
  • the starting material was replaced with 6-chloroindole and morpholine, and after the reaction, washing and filtration directly gave 6-morpholinylhydrazine in a yield of 89.42%. Purity (HPLC) ⁇ 96%.
  • 6-chloroindole 1.545 g (10 mmol) was dissolved in THF (30 mL), then 3 mL (33%, 30 mmol) of trimethylamine aqueous solution was added thereto, and stirred at room temperature for 24 h. After completion of the reaction, it was filtered and dried in vacuo to give intermediate.
  • 6-Trimethylaminoguanidine hydrochloride The intermediate 6-trimethylaminoguanidine hydrochloride 1.130 g (5 mmol) was dissolved in DMSO (15 mL), and then tetrabutylammonium fluoride (TBAF, 7.5 mmol) was added thereto, and reacted at room temperature for 24 hours, followed by ethyl acetate.
  • 6-Chloropurine (0.465 & 3 mmol) was dissolved in a mixed solvent of dichloromethane/tetrahydrofuran (20 mL, V/V-1/1), and then p-toluenesulfonyl chloride ( 1.143 g, 6 mmol) and triethylbenzene were sequentially added thereto.
  • the amine (0.606 g, 6 mmol) was stirred at room temperature for 4 h under nitrogen. The solvent was evaporated under reduced pressure. The residue was purified from methylene chloride and water.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.643 g, yield 66.15%, purity (HPLC) ⁇ 99%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-azidofluorene and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.135 g, yield: 13.60%, purity (HPLC) ⁇ 96%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-fluoroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.174 g, yield 56.49%, purity (HPLC) ⁇ 95%.
  • Example 10 In the same manner as in Example 10, the starting material was replaced with 6-fluoroindole and the corresponding sulfonyl chloride. After the reaction was completed, the solvent was removed under reduced pressure. The residual oily solid was stirred in 4 mol of aqueous ammonia for 2 h, then dichloromethane and water. The organic layer was washed with 4 mol/L aqueous ammonia solution (20 mL ⁇ 2) and saturated brine (30 mL ⁇ 2), dried over anhydrous magnesium sulfate, and filtered and filtered to afford white solid product 0.077 g, yield 50.32%. , purity (HPLC) ⁇ 96%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and after the column was passed, the product was obtained, 0.684 g, yield: 64.77%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.587 g, yield 55.90%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the raw material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product was obtained after passing through the column. g, yield 59.12%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.342 g, the yield was 30.89%, and the purity (HPLC) was ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.489 g, the yield was 44.05%, and the purity (HPLC) was ⁇ 96. / 0 .
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.718 g, yield 56.98%, purity (HPLC) >97%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.547 g, yield 53.00%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and after the column was passed, the product was obtained in a yield of 58.38 g. , purity (HPLC) ⁇ 99%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.513 g, yield 50.44%, purity (HPLC) >99%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in the form of 0.912 g, yield: 67.25%, purity (HPLC) ⁇ 99%.
  • Example 10 According to the preparation method of Example 10, the raw material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product was obtained after passing through the column. g, yield 36.09%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.098 g, yield 31.82%, purity (HPLC) ⁇ 95%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.262 g, the yield was 50.77%, and the purity (HPLC) was >97%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.195 g, yield: 35.58%, purity (HPLC) ⁇ 97%.
  • 6-Chloro-9-(4-methoxybenzenesulfonyl)-9H-indole (Example 11, 0.325 g, 1 mmol) was dissolved in tetrahydrofuran (20 mL) and then taken three times (0 h, 6 after the start of the reaction) h, 12 h) 5% palladium on carbon was added thereto, and the mixture was reacted under reflux for 24 hours. The palladium carbon was removed by filtration, and the filtrate was subjected to silica gel column chromatography to afford white crystals (yield: s.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-bromoindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.041 g, the yield was 15.91%, and the purity (HPLC) was ⁇ 96%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-iodonium and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.133 g, yield: 31.97%, purity (HPLC) ⁇ 96%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-methoxyanthracene and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in an amount of 0.318 g, the yield was 34.87%, and the purity (HPLC) was ⁇ 96%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-dimethylaminopurine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.458 g, yield 48.16%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-diethylaminopurine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.575 g, yield 55.72%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 2,6-dichloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.498 g, yield 48.54%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 2-amino 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained to be 0.456 g, the yield was 47.06%, and the purity (HPLC) was ⁇ 97. / 0 .
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-morpholinylfluorene and the corresponding sulfonyl chloride, and the product was subjected to a column yield of 0.758 g, yield 70.38%, purity (HPLC) ⁇ 99%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-propanylsulfonyl hydrazide and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.421 g, yield 40.56%, purity (HPLC) ⁇ 99%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-methylthioguanidine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.789 g, yield: 82.19%, purity (HPLC) ⁇ 98%.
  • Example 10 According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.478 g, yield 44.51%, purity (HPLC) ⁇ 98%.
  • Test Examples Compounds in vitro HCV Replicon luciferase Assay and HCV Replicon MTT Assay.
  • the HCV Replicon luciferase Assay is a compound that is tested for anti-HCV activity using the luciferase assay.
  • the principle is to infect an in vitro infectious replication system formed by fusing a subgenome of the HCV NS3-NS5 encoding gene containing the genotype lb with a luciferase encoding gene, and infecting Huh7.0 cells by electroporation.
  • System can In intracellular replication, HCV replicon activity can be determined by testing luciferase activity in cells.
  • MTT is a yellow dye that accepts gas ions and acts on the respiratory chain in the mitochondria of living cells.
  • succinate dehydrogenase and cytochrome C Under the action of succinate dehydrogenase and cytochrome C, the tetrazolium ring is cracked to form blue formazan crystals. The amount of production is only proportional to the number of living cells.
  • the formed formazan crystals are dissolved in dimethyl sulfoxide (DMSO), and the optical density OD value at 570 nm is measured by a microplate reader to reflect the number of living cells.
  • DMSO dimethyl sulfoxide
  • the half-lethal lethal dose of CC50 and HCV half-inhibitory concentration IC50 is the safety index of the compound. The larger the ratio, the safer the compound, and the inhibition of HCV by the compound is not due to its cytotoxicity.
  • Table 1 shows the results of HCV Replicon luciferase Assay and HCV Replicon MTT Assay for Example 10-Compound 40:
  • Example 36 Compound 74.3 > 100 > 1.5
  • Example 37 Compound > 100 > 100 1
  • Example 40 Compound 3.851 31.92 8.29 As can be seen from the above table, the control CSA and Clemizole test results are in the normal range. As can be seen from the test data, the compound of Example 11, the compound of Example 13, the compound of Example 22, and the examples The compound of Example 23 and the compound of Example 40 had good HCV inhibitory ability at low micromolar concentrations, and the cytotoxicity was low. Furthermore, the inhibitory effect of the compound on HCV was dose dependent, see Figure 1 - Figure 5.
  • the above active compounds have a strong inhibitory effect on HCV, and some compounds have low cytotoxicity and a high selectivity index.
  • the preparation method of the 9-sulfonyl-9H-indole derivative according to the present invention has the advantages of mild reaction conditions, abundant raw materials, easy operation and post-treatment, high total yield, and low environmental pollution.

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Abstract

Disclosed are a 9-sulfonyl-9H-purine derivative as represented by Formula (I), a preparation method and use thereof. The compound represented by Formula (I) is provided with anti-chronic hepatitis C virus activity. [Formula I]

Description

9-磺酰基 ^9H-嘌呤衍生物及其制备方法和用途 技术领域  9-sulfonyl ^9H-indole derivative and preparation method and use thereof
本发明涉及 9-磺酰基 -9H-嘌呤衍生物及其制备方法和用途, 属于化学医药领域。 背景技术  The present invention relates to a 9-sulfonyl-9H-indole derivative, a preparation method and use thereof, and belongs to the field of chemical medicine. Background technique
慢性丙型肝炎是由丙型肝炎病毒(HCV)引起的一种慢性肝脏疾病, 是肝硬化和肝 癌的主要原因, 也是目前肝脏移植的首要原因。 据世界卫生组织 (WHO) 1999年的调 査显示, 全球约有 3%的人 (1.7亿人)感染了 HCV (J. Viral. Hepat. 1999, 6: 35-47 ), 中国 的感染率约为 3.2% (4000万人) (Lancet Jnfeci. Dis. 2005. 5: 558-67 ) , 而且感染人数有 逐年增多的趋势。 这些感染了 HCV的人群, 经过 10-20年的潜伏期后, 约有 80%的人 将发展为慢性丙型肝炎, 20%的人将进一步发展成肝硬化, 1%-4%的人将最终恶化转变 为肝癌 iMed. Res. Rev. 2007, 27: 353-73 )。  Chronic hepatitis C is a chronic liver disease caused by hepatitis C virus (HCV), a major cause of liver cirrhosis and liver cancer, and is the leading cause of liver transplantation. According to a 1999 survey by the World Health Organization (WHO), about 3% of the world's (170 million people) are infected with HCV (J. Viral. Hepat. 1999, 6: 35-47), and the infection rate in China is about It is 3.2% (40 million people) (Lancet Jnfeci. Dis. 2005. 5: 558-67), and the number of infected people is increasing year by year. After HCV-infected people, after 80-20 years of incubation, about 80% will develop chronic hepatitis C, 20% will develop cirrhosis, and 1%-4% will eventually Deterioration into liver cancer iMed. Res. Rev. 2007, 27: 353-73).
在我国, HCV的感染水平略高于世界平均水平, 但由于 HCV感染潜伏期很长, 大 多数病例被确诊为慢性丙型肝炎患者时己发展成为肝硬化和肝癌,故目前我国慢性丙型 肝炎的治疗形势相当严峻, 迫切需要开发具有自主知识产权的抗 HCV新药。  In China, the level of HCV infection is slightly higher than the world average, but due to the long incubation period of HCV infection, most cases have been diagnosed as chronic hepatitis C patients have developed into cirrhosis and liver cancer, so the current chronic hepatitis C in China The treatment situation is quite severe, and there is an urgent need to develop new anti-HCV drugs with independent intellectual property rights.
本发明者通过大量化合物筛选及结构优化,找到了一类新型结构的抗丙型肝炎病毒 ( HCV) 活性化合物, 这一类化合物在体外 HCV Replicon luciferase Assay禾 f] HCV Replicon MTT Assay两项测试中表现出了较好的 HCV抑制效果, 同时表现出了较低的 细胞毒性。 有望被开发成为新型的抗慢性丙型肝炎药物。  The inventors have found a new class of anti-hepatitis C virus (HCV) active compounds through a large number of compound screening and structural optimization. This compound is tested in vitro by HCV Replicon luciferase Assay and HCV Replicon MTT Assay. It showed better HCV inhibition and showed lower cytotoxicity. It is expected to be developed into a new type of anti-chronic hepatitis C drug.
发明内容 Summary of the invention
本发明所要解决的第一个技术问题是提供一类新的 9-磺酰基 -9H-嘌呤衍生物, 结构 如式 I所示:  The first technical problem to be solved by the present invention is to provide a novel class of 9-sulfonyl-9H-indole derivatives having the structure shown in Formula I:
Figure imgf000002_0001
Figure imgf000002_0001
其中, 〜 独立的为 -H、 -F、 -Cl、 -Br、 -1、 -N3、 -CF3、 -NH2、 -N02Wherein, ~ is independently -H, -F, -Cl, -Br, -1, -N 3 , -CF 3 , -NH 2 , -N0 2 ,
1 确 认 本 S R. 垸基、 C3〜C8环烷基、 C1〜C8烷氧基、 C1 垸基取代胺基、
Figure imgf000003_0001
或 C1〜C8垸硫基;
1 Confirmation S R. fluorenyl, C3 to C8 cycloalkyl, C1 to C8 alkoxy, C1 decyl substituted amine,
Figure imgf000003_0001
Or C1~C8 thiol;
Rl2wRl1 R15丫 s 为 Re R9 、 R13 ¾
Figure imgf000003_0002
、苄基、 C1〜C8垸基或 C3-
Rl2 w Rl1 R 15丫s is Re R 9 , R13 3⁄4
Figure imgf000003_0002
, benzyl, C1~C8 thiol or C3-
C8环烷基; C8 cycloalkyl;
R5〜R7独立的为 -H、 -F、 -Cl、 -Br、 - H2> -N02、 -N3、 -CF3、 C3〜C8环垸基或 Cl〜 C8垸基; R 5 to R 7 are independently -H, -F, -Cl, -Br, -H 2 > -N0 2 , -N 3 , -CF 3 , C3 to C8 cyclodecyl or Cl to C8 fluorenyl;
R8〜R15独立的为 -H、 -F、 -Cl、 -Br、 -N¾、 -N02、 -N3、 -CF3、带 R16取代基的 Cl〜 C8垸基、 带 R16取代基的 C3〜C8环垸基、 带 R16取代基的 C1〜C8垸基取代氧探基、 带 R16取代基的 C3〜C8环垸基取代氧羰基、 带 R16取代基的 C1〜C8垸氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; R8~R 15 is independently -H, -F, -Cl, -Br, -N¾, -N0 2, -N 3, -CF 3, with R 16 Cl~ C8 alkyl with a substituent, substituted with R 16 cyclic alkyl with C3~C8 group, optionally substituted with R 16 C1~C8 alkyl with an oxygen probe substituent group, C3~C8 cycloalkyl with R 16 substituted alkyl with a substituted oxycarbonyl group, substituted with R 16 group C1~C8 a fluorenyloxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
R16为 -H、 C1〜C8 '垸基、 -NH2> -N02、 -N3、 -F、 -Cl、 -Br、 -CF3、 C1〜C8垸氧基、 C3〜C8环垸基或 C1〜C8烷基取代胺基。 优选的, Ri〜R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -CF3、 -N¾、 -N02、 C1〜C8烷 基、 C3〜C8环烷基、 C1〜C8垸氧基、 C1〜C8烷基取代胺基、 †N^O、 S_ =<R^或 C1〜C8烷硫基; R 16 is -H, C1 to C8 'decyl, -NH 2 > -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 fluorene A group or a C1 to C8 alkyl group substituted with an amine group. Preferably, Ri~R 3 are independently -H, -F, -Cl, -Br, -N 3 , -CF 3 , -N3⁄4, -N0 2 , C1~C8 alkyl, C3~C8 cycloalkyl, a C1-C8 decyloxy group, a C1-C8 alkyl-substituted amine group, †N^O, S _=< R ^ or a C1~C8 alkylthio group;
Figure imgf000003_0003
for
Figure imgf000003_0003
R5〜R7独立的为 -H、 -F、 -Cl、 -Br、 -NH2、 -N02、 -N3、 -CF3、 C3〜C8环垸基或 C!〜 C8院基; R 5 to R 7 are independently -H, -F, -Cl, -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cyclodecyl or C! ~ C8 hospital base;
Rs〜R15独立的为 -H、 -F、 -Cl、 -Br、 -NH2、 -N02、 -N3、 -CF3、带 R16取代基的 Cl〜 C8烷基、 带 R16取代基的 C3〜C8环烷基、 带 R16取代基的 C1〜C8垸基取代氧羰基、 带 R16取代基的 C3〜C8环烷基取代氧羰基、 带 R16取代基的 C1〜C8烷氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; Rs to R 15 are independently -H, -F, -Cl, -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , Cl to C8 alkyl group having an R 16 substituent, and R 16 C3~C8 cycloalkyl group substituted with a substituent R 16 C1~C8 alkyl with a substituted oxycarbonyl group, substituted with a group R 16 C3~C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 group C1~C8 An alkoxy group or a ring skeleton having a substituent of R 16 is an aromatic ring group of 3 to 8 carbon atoms;
Rie % H, C1〜C8烷基、 -NH2、 -N02、 -N3、 -F、 -Cl、 -Br、 -CF3、 C1〜C8垸氧基、 C3〜C8环垸基或 C1~C8垸基取代胺基。 优选的, 为-11、 C1〜C8烷基或 C3〜C8环烷基; Rie % H, C1 to C8 alkyl, -NH 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, The C3~C8 cyclodecyl group or the C1~C8 fluorenyl group is substituted with an amine group. Preferably, it is -11, C1~C8 alkyl or C3~C8 cycloalkyl;
R2、 R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8垸基、 C3〜C8环垸基、R 2, R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl group embankment,
R5、 ,R6 R 5, , R 6
C1〜C8烷氧基、 C1〜C8烷基取代胺基、 ^。、 R7或 C1〜C8垸硫基; C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group, ^. , R7 or C1~C8 thiol;
Rl2wRl1 R15丫 s 为 Re R9 、 R13 Rl2 w Rl1 R 15丫s is Re R 9 , R 13 ,
Figure imgf000004_0001
Figure imgf000004_0001
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8垸基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
〜R15独立的为 -H、 C1〜C8焼基、 C1〜C8垸氧基、 -N02、 苯基、 C1〜C8垸基 取代氧羰基、 C3〜C8环烷基取代氧揆基或 -CF3。 优选的, Ri为 -H、 C1〜C8烷基或 C3〜C8环烷基; ~R 15 is independently -H, C1~C8 fluorenyl, C1~C8 decyloxy, -N0 2 , phenyl, C1~C8 fluorenyl substituted oxycarbonyl, C3~C8 cycloalkyl substituted oxo group or - CF 3 . Preferably, Ri is -H, C1~C8 alkyl or C3~C8 cycloalkyl;
R2、 R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1-C8垸基、 C3〜C8环垸基、 - ^>= R6 R 2 and R 3 are -H, -F, -Cl, -Br, -N 3 , -NH 2 , -N0 2 , C1-C8 fluorenyl, C3~C8 cyclodecyl, -^>= R6
C1〜C8烷氧基、 C1〜C8烷基取代胺基、 tN— 、 或 1〜 8烷硫基; RL2WRL1 R15丫 s C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group, tN- or 1,8 -alkylthio group; R L2 W RL1 R 15丫s
^为 R8 R9 、 13 、 ^J; ^ is R 8 R 9 , 13 , ^J ;
R5〜R7独立的为 -H、 C3~C8环垸基或 C1〜C8垸基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
Rs〜R12独立的为 -H、 C1〜C8烷基、 C1〜C8垸氧基、 -N02、 苯基或 -CF3; Rs~R 12 are independently -H, C1~C8 alkyl, C1~C8 decyloxy, -N0 2 , phenyl or -CF 3;
R13〜R15独立的为 -H、 C1〜C8垸基或 C1〜C8垸基取代氧羰基。 优选的, Ri为 -H或 C1〜C4垸基; R 13 to R 15 are independently -H, C1 to C8 fluorenyl or C1 to C8 fluorenyl substituted oxycarbonyl. Preferably, Ri is -H or C1~C4 fluorenyl;
R2为 -H、 -F、 -Cl、 -Br、 -N3、 - H2、 C1〜C4'垸基、 C1〜C4垸氧基、 C1〜C4垸基 取代胺基、 -N ^、 ^^=^或 〜 4垸硫基; R3为 -H、 -F、 -Cl、 -Br、 C1〜C4垸基或 -NH2; R4为 、
Figure imgf000005_0001
、 '
R 2 is -H, -F, -Cl, -Br, -N 3 , -H 2 , C1 to C4' fluorenyl, C1 to C4 decyloxy, C1 to C4 fluorenyl substituted amine, -N ^, ^^ = ^ or ~ 4 thiol; R 3 is -H, -F, -Cl, -Br, C1~C4 fluorenyl or -NH 2; R4 is,
Figure imgf000005_0001
, '
R5〜R7独立的为 -H或 C1〜C4垸基; R 5 to R 7 are independently -H or C1 to C4 fluorenyl;
R8〜Ri2独立的为 -H、 C1〜C4烧基、 C1〜C4垸氧基、 -N02、 苯基或 -CF3 ; R 8 to Ri 2 are independently -H, C1 to C4 alkyl, C1 to C4 methoxy, -N0 2 , phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C4垸基取代氧羰基或 C1〜C4垸基。 优选的, 为-11或€1〜 4烷基; R 13 to R 15 are independently -H, C1 to C4 fluorenyl substituted oxycarbonyl or C1 to C4 fluorenyl. Preferably, it is -11 or €1 to 4 alkyl;
R2为- H、 -F、 -Cl、 -Br、 -N3、 C1〜C4烷基、 C1〜C4垸氧基、 C1〜C4烷基取代胺 R 2 is -H, -F, -Cl, -Br, -N 3 , C1 to C4 alkyl, C1 to C4 nonyloxy, C1 to C4 alkyl substituted amine
R R  R R
基、 ,^C0、 ^^ ^或 C1〜C4焼硫基; Base, ^C 0 , ^^ ^ or C1~C4 thiol;
R3为- H、 -F、 -Cl、 -Br或 C1〜C4烷基; R 3 is -H, -F, -Cl, -Br or C1 to C4 alkyl;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
Rs〜R12独立的为 C1〜C4烷基、 C1〜C4垸氧基、 苯基或 -CF3 ; Rs~R 12 are independently C1~C4 alkyl, C1~C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或 C1〜C4垸基取代氧羰基。 优选的, 为-11或01〜04垸基; R 13 to R 15 are independently an -H or a C1 to C4 fluorenyl group substituted with an oxycarbonyl group. Preferably, it is -11 or 01~04 thiol;
R2为- H、 -F、 -Cl、 -Br、 -NH2、 -N3、 C1〜C4垸基、 C1〜C4垸氧基、 C1 ~C4垸基 R 2 is -H, -F, -Cl, -Br, -NH 2 , -N 3 , C1 to C4 fluorenyl, C1 to C4 decyloxy, C1 to C4 fluorenyl
R R  R R
取代胺基、 †N3D、 ^^ ^或 C1~C4垸硫基; Substituted amine, †N3D, ^^^ or C1~C4 thiol;
R3为 -H、 -F、 -Cl、 -Br、 -NH2或 C1〜C4烷基; R 3 is -H, -F, -Cl, -Br, -NH 2 or C1 to C4 alkyl;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
R«〜Ri2独立的为 -H、 -N02、 C1〜C4烷基、 C1〜C4垸氧基、 苯基或 -CF3; R«~Ri 2 are independently -H, -N0 2 , C1~C4 alkyl, C1~C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或 C1〜C4垸基取代氧羰基; x 。 Η2ΝΛ N 、、 。 R 13 to R 15 are independently -H or C1 to C4 fluorenyl substituted oxycarbonyl; x. Η2Ν Λ N , , .
0  0
其中不包括化合物
Figure imgf000005_0002
Which does not include compounds
Figure imgf000005_0002
,
Figure imgf000006_0001
最优的, 1^为-11;
Figure imgf000006_0001
Optimal, 1^ is -11;
R2为 -H、 -F、 -Cl、 -Br、 -NH2、 -N3、 甲基、甲氧基、 C1〜C4垸基取代胺基、 _ N」 ^ =<R6 R 2 is -H, -F, -Cl, -Br, -NH 2 , -N 3 , methyl, methoxy, C1~C4 fluorenyl substituted amine, _ N " ^ =< R6
; 或甲硫基;  Or methylthio;
R3为 -H、 -NH2或 -C1; R 3 is -H, -NH 2 or -C1;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
〜R12独立的为 -H、 -N02、 C1〜C4院基、 CI 4烷氧基、 苯基或 -CF3 ; ~R 12 is independently -H, -N0 2 , C1~C4, CI 4 alkoxy, phenyl or -CF 3 ;
R13~R15独立的为 -H或甲基取代氧羰基; R 13 to R 15 are independently -H or methyl substituted oxycarbonyl;
Figure imgf000006_0002
进一步优选的, C1〜C8垸基或 C3〜C8环垸基;
Figure imgf000006_0002
Further preferably, a C1~C8 fluorenyl group or a C3~C8 cyclodecyl group;
R2、 R3为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 -N02、 C1〜C8垸基、 R 2 and R 3 are -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , -N0 2 , C1 to C8 fluorenyl,
C1〜C8烷氧基、 C1〜C8垸基取代胺基、 fN Q、 ^ R7或 C1〜C8烷硫基; a C1-C8 alkoxy group, a C1~C8 fluorenyl substituted amine group, a f NQ , a R 7 or a C 1 ~ C 8 alkylthio group;
R4为
Figure imgf000006_0003
、苄基、 C1~C4垸基或 C3- C6环烧基;
R4 is
Figure imgf000006_0003
, benzyl, C1~C4 thiol or C3- C6 cycloalkyl;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8垸基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
〜R15独立的为 -H、 -N02、 C1~C8烷基、 C1〜C8垸氧基、 苯基、 C1~C8垸基 、 C3〜C8环垸基取代氧羰基或 -CF3 ; ~ R 15 is independently -H, -N0 2 , C1~C8 alkyl, C1~C8 decyloxy, phenyl, C1~C8 fluorenyl, C3~C8 cyclodecyl substituted oxycarbonyl or -CF 3 ;
Figure imgf000007_0001
优选的, Ri为 -H、 C1〜C8垸基或 C3~C8环烷基;
Figure imgf000007_0001
Preferably, Ri is -H, C1~C8 fluorenyl or C3~C8 cycloalkyl;
R2、 R3为- H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 -N02、 C3〜C8环烷基、 R 2 and R 3 are -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , -N0 2 , C3 to C8 cycloalkyl,
- 、 R - , R
C1〜C8垸氧基、 C1〜C8烷基取代胺基、 或 C1〜C8垸硫基;  a C1~C8 methoxy group, a C1~C8 alkyl substituted amine group, or a C1~C8 sulfonium group;
R4为
Figure imgf000007_0002
、苄基、 C1〜C4垸基或 C3 C6环烷基;
R4 is
Figure imgf000007_0002
, benzyl, C1~C4 fluorenyl or C3 C6 cycloalkyl;
R5〜R7独立的为 -H、 C3~C8环烷基或 C1〜C8烷基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl;
Rs〜R12独立的为 -H、 -N02、 C1〜C8 '垸基、 C1〜C8烷氧基、 苯基或 -CF3 ; Rs~R 12 are independently -H, -N0 2 , C1~C8 'decyl, C1~C8 alkoxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C8烷基或 C1〜C8烷基取代氧羰基; R 13 to R 15 are independently -H, C1 to C8 alkyl or C1 to C8 alkyl substituted oxycarbonyl;
Figure imgf000007_0003
its
Figure imgf000007_0003
Figure imgf000008_0001
优选的, 1^为-^1或€1〜 4烷基;
Figure imgf000008_0001
Preferably, 1^ is -^1 or €1~4 alkyl;
R2为 -H、 -F、 -CK -Br、 -1、 -NH2、 -N3、 C1〜C4烷基、 C1〜C4烷氧基、 C1〜C4 R 2 is -H, -F, -CK -Br, -1, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4
R R  R R
烷基取代胺基、 †N3D、 ^_ ^ 6或 C1〜C4垸硫基; An alkyl substituted amine group, a hydrazine N3D, a ^_^ 6 or a C1~C4 thiol group;
R3为 -H、 -F、 -CK -Br、 -NH2或 C1〜C4垸基; R 3 is -H, -F, -CK -Br, -NH 2 or C1~C4 fluorenyl;
Rl2wR 1 R15丫 s ^为 Re R9 、 13 χ
Figure imgf000008_0002
、苄基、 C 1C4垸基或
Rl2 w R 1 R 15丫s ^ is Re R 9 , 13 χ
Figure imgf000008_0002
, benzyl, C 1C4 thiol or
C6环垸基; C6 ring thiol;
R5〜R7独立的为 -H或 C1〜C4烷基; R 5 to R 7 are independently -H or C1 to C4 alkyl;
Rs〜R12独立的为 -H、 -N02、 C1〜C4垸基、 C1〜C4烷氧基、 苯基或 -CF3 ; Rs~R 12 are independently -H, -N0 2 , C1~C4 fluorenyl, C1~C4 alkoxy, phenyl or -CF 3 ;
R15独立的为 -H、 C1〜C4 羰基或 C1〜R 15 is independently -H, C1~C4 carbonyl or C1~
Figure imgf000008_0003
优选的,
Figure imgf000008_0003
Preferably,
R2为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 C1〜C4烷基、 C1〜C4垸氧基、 C1〜C4 院基取代胺基、 ·Ν3>、 ^^^^111 ^或 C1〜C4垸硫基; R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 decyloxy, C1 to C4 Substituted amine group, ·Ν3>, ^^^^ 111 ^ or C1~C4 thiol;
R3为 -H、 -F、 -Cl、 -Br或 -NH2; R 3 is -H, -F, -Cl, -Br or -NH 2 ;
R4为
Figure imgf000009_0001
、苄基、 C1〜C4垸基或 C3'
R4 is
Figure imgf000009_0001
, benzyl, C1~C4 thiol or C3'
C4环垸基; C4 ring thiol;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
Rg〜R12独立的为 -H、 -N02、 C1〜C4院基、 C1〜C4垸氧基、 苯基或 -CF3 ; Rg~R 12 are independently -H, -N0 2 , C1~C4, C1~C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或 C1〜C4垸基取代氧羰基; R 13 to R 15 are independently -H or C1 to C4 fluorenyl substituted oxycarbonyl;
Figure imgf000009_0002
最优的, 为-
Figure imgf000009_0002
Optimal, for -
R2为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 甲基、 C1〜C4烷氧基、 C1〜C4烷基取代 R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , methyl, C1 to C4 alkoxy, C1 to C4 alkyl
^ =<R6 ^ =< R6
胺基、 "^N 0 , S R7或甲 Amine, "^ N 0 , SR 7 or A
R3为- H、 - H2或 -CI; R 3 is -H, -H 2 or -CI;
R4为
Figure imgf000009_0003
、苄基、 C1〜C4垸基或 C3-
R4 is
Figure imgf000009_0003
, benzyl, C1~C4 thiol or C3-
C4环烷基; C4 cycloalkyl;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
〜R12独立的为 -H、 -N02、 C1〜C4垸基、 C1〜C4垸氧基、 苯基或 -CF3; 〜R15独立的为 -H或甲基取代氧羰基; ~R 12 is independently -H, -N0 2 , C1~C4 fluorenyl, C1~C4 decyloxy, phenyl or -CF 3 ; ~R 15 is independently -H or methyl substituted oxycarbonyl;
Figure imgf000010_0001
进一步优选的, 9-磺酰基 -9H-
Figure imgf000010_0001
Further preferred, 9-sulfonyl-9H-
Figure imgf000010_0002
Figure imgf000010_0002
其中, 〜 独立的为 -H、 -F、 -CK -Br、 -1、 -Ν3、 -CF3、 - Η2、 -Ν02、 C1 -C8 烷基、 C3〜C8环烷基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 †N D、 ^^>=<^ 或 C1〜C8垸硫基; Wherein, ~ is independently -H, -F, -CK -Br, -1, -Ν 3 , -CF 3 , - Η 2 , -Ν0 2 , C1 -C8 alkyl, C3~C8 cycloalkyl, C1 ~C8 methoxy, C1~C8 thiol substituted amine, †ND, ^^>=<^ or C1~C8 thiol;
R5〜R7独立的为 -H、 -F、 -CK -Br、 -NH2、 -N02、 -N3、 -CF3、 C3〜C8环烷基或 Cl〜R 5 to R 7 are independently -H, -F, -CK -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cycloalkyl or Cl~
C8焼基; C8 base;
R8〜R12独立的为 -H、 -F、 -CK -Br、 -NH2、 -N02、 -N3、 -CF3、 带 R16取代基的 Cl〜 C8垸基、 带 R16取代基的 C3〜C8环垸基、 带 R16取代基的 C1〜C8垸基取代氧羰基、 带 R16取代基的 C3〜C8环烷基取代氧羰基、 带 R16取代基的 C1〜C8垸氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; R 8 ~R 12 is independently -H, -F, -CK -Br, -NH 2, -N0 2, -N 3, -CF 3, with R 16 Cl~ C8 alkyl with a substituted group, with R 16 embankment C3~C8 cycloalkyl substituent, substituted with R 16 C1~C8 alkyl with a substituted oxycarbonyl group, substituted with a group R 16 C3~C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 group C1~C8 a fluorenyloxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
R16为 -H、 C1〜C8烧基、 - H2、 -N02、 -N3、 -F、 -Cl、 -Br、 -CF3、 C1〜C8垸氧基、 C3〜C8环烷基或 C1〜C8垸基取代胺基。 优选的, Ri〜R3独立的为 -H、 -F、 -CK -Br、 -N3、 -CF3、 -NH2、 -N02、 C1〜C8垸 基、 C3〜C8环烷基、 C1〜C8垸氧基、 C1〜C8烷基取代胺基、 †N^JD、 ^^<R7或 C1〜C8垸硫基; R 16 is -H, C1 to C8 alkyl, -H 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 cycloalkyl Or a C1~C8 thiol group substituted with an amine group. Preferably, Ri~R 3 is independently -H, -F, -CK -Br, -N 3, -CF 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl, C1-C8 decyloxy, C1-C8 alkyl-substituted amine group, †N^JD, ^^< R7 or C1~C8 thiol;
R5〜R7独立的为 -H、 -F、 -CK -Br、 -ΝΉ2、 -Ν02、 -Ν3、 -CF3、 C3〜C8环垸基或 Cl〜 C8烷基; R 5 to R 7 are independently -H, -F, -CK -Br, -ΝΉ 2 , -Ν0 2 , -Ν 3 , -CF 3 , C3~C8 cyclodecyl or Cl~C8 alkyl;
〜R 独立的为 -H、 -F、 -CK -Br、 -NH2、 -N02、 -N3、 -CF3、带 R16取代基的 Cl〜 C8烷基、 带 R16取代基的 C3〜C8环垸基、 带 R16取代基的 C1〜C8垸基取代氧羰基、 带 R16取代基的 C3〜C8环烷基取代氧羰基、 带 R16取代基的 C1〜C8垸氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; ~R is independently -H, -F, -CK -Br, -NH 2, -N0 2, -N 3, -CF 3, with R 16 Cl~ C8 alkyl group substituted with a substituent R 16 C1~C8 alkyl with embankment C3~C8 cycloalkyl group with a substituent group R 16 substituted oxycarbonyl group, substituted with a group R 16 C3~C8 cycloalkyl substituted oxycarbonyl group, substituted with R 16 C1~C8 alkoxy group embankment Or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
Ri6为 -H、 C1〜C8垸基、 -NH2、 -N02、 -N3、 -F、 -CK -Br、 -CF3、 C1〜C8垸氧基、Ri 6 is -H, C1 to C8 fluorenyl, -NH 2 , -N0 2 , -N 3 , -F, -CK -Br, -CF 3 , C1 to C8 decyloxy,
C3〜C8环垸基或 C1〜C8垸基取代胺基。 优选的, !^为-H、 C1〜C8垸基或 C3〜C8环垸基; The C3~C8 cyclodecyl group or the C1~C8 fluorenyl group is substituted with an amine group. Preferred, ! ^ is -H, C1~C8 thiol or C3~C8 fluorenyl;
R2、 R3为- H、 -F、 -CK -Br、 -N3、 -NH2、 -N02、 C1〜C8垸基、 C3〜C8环垸基、 R 2, R 3 is - H, -F, -CK -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl group embankment,
R5 R6 R 5 R 6
C!〜 C8垸氧基、 C1〜C8垸基取代胺基、 tN Q、 ^ R7或 C1〜C8垸硫基;C! ~ C8 methoxy, C1~C8 fluorenyl substituted amine, tN Q , ^ R7 or C1~C8 thiol;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8烷基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 alkyl;
R8〜R12独立的为 -H、 C1〜C8 '垸基、 C1〜C8垸氧基、 -N02、 苯基或 -CF3。 优选的, 为11或€1〜€4垸基; R 8 to R 12 are independently -H, C1 to C8 'decyl, C1 to C8 decyloxy, -N0 2 , phenyl or -CF 3 . Preferably, it is 11 or €1 to €4;
R2为- H、 -F、 -CK -Br、 -N3、 -NH2、 C1〜C4 '烷基、 C1〜C4垸氧基、 C1〜C4垸基 取代胺基、 †N、 p、 S^=<R7或 C1〜C4烷硫基; R 2 is -H, -F, -CK -Br, -N 3 , -NH 2 , C1~C4 'alkyl, C1~C4 decyloxy, C1~C4 fluorenyl substituted amine, †N, p, S ^=< R7 or C1~C4 alkylthio;
R3为 -H、 -F、 -CK -Br、 C1〜C4垸基或 -NH2; R 3 is -H, -F, -CK -Br, C1~C4 fluorenyl or -NH 2 ;
R5〜R7独立的为 -H或 C1〜C4烷基; R 5 to R 7 are independently -H or C1 to C4 alkyl;
〜Ri2独立的为 -H、 C1〜C4烷基、 C1〜C4烷氧基、 -N02、 苯基或 -CF3。 优选的, Ri为 -H、 C1〜C8垸基或 C3〜C8环垸基; ~Ri2 is independently -H, C1 to C4 alkyl, C1 to C4 alkoxy, -N0 2 , phenyl or -CF 3 . Preferably, Ri is -H, C1~C8 fluorenyl or C3~C8 cyclodecyl;
R2、 R3为 -H、 -F、 -CK -Br、 -1、 -NH2、 -N3、 -N02、 C1〜C8垸基、 C3〜C8环垸基、 R^R6 R 2 and R 3 are -H, -F, -CK -Br, -1, -NH 2 , -N 3 , -N0 2 , C1 to C8 fluorenyl, C3 to C8 cyclodecyl, R^R 6
•| N 0  •| N 0
C1〜C8烷氧基、 C1〜C8烷基取代胺基、 ^ R7或 C1〜C8烷硫基;a C1-C8 alkoxy group, a C1-C8 alkyl-substituted amine group, a ^ R7 or a C1-C8 alkylthio group;
R5〜R7独立的 -H、 C3〜C8环垸基或 C1〜C8烷基; R 5 to R 7 independently -H, C3 to C8 cyclodecyl or C1 to C8 alkyl;
R8〜R12独立的为 -H、 -N02、 C1〜C8院基、 C1〜C8烷氧基、 苯基或 -CF3 ; R 8 to R 12 are independently -H, -N0 2 , C1 to C8, C1 to C8 alkoxy, phenyl or -CF 3 ;
Figure imgf000012_0001
优选的, 1^为11或€1〜€4烷基;
Figure imgf000012_0001
Preferably, 1^ is 11 or €1 to €4 alkyl;
R2为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 C1〜C4垸基、 C1〜C4垸氧基、 C1〜C4 垸基取代胺基、 †N、 p、 S^=<R 或 〜 4垸硫基; R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , C1 to C4 fluorenyl, C1 to C4 decyloxy, C1 to C4 fluorenyl substituted amine, †N , p, S ^=< R or ~ 4 thiol;
R3为 -H、 -F、 -Cl、 -Br、 -NH2或 C1〜C4垸基; R 3 is -H, -F, -Cl, -Br, -NH 2 or C1 to C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4烷基; R 5 to R 7 are independently -H or C1 to C4 alkyl;
〜Ri2独立的为 -H、 -N02、 C1〜C4院基、 C1〜C4垸氧基、 苯基或 -CF3 ; ~Ri2 is independently -H, -N0 2 , C1~C4, C1~C4 decyloxy, phenyl or -CF 3 ;
Figure imgf000012_0002
最优的, 为- R2为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、甲基、甲氧基、 C1~C4垸基取代胺基、 f 或甲硫基;
Figure imgf000012_0002
Optimal, for - R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , methyl, methoxy, C1 to C4 mercapto substituted amine, f or methylthio;
Figure imgf000013_0001
Figure imgf000013_0001
R3为 -H、 - H2或 -C1; R 3 is -H, - H 2 or -C1;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
Rg〜R12独立的为 -H、 -N02、 C1〜C4浣基、 C1〜C4垸氧基、 苯基或 -CF3 ; Rg~R 12 are independently -H, -N0 2 , C1~C4 fluorenyl, C1~C4 decyloxy, phenyl or -CF 3 ;
Figure imgf000013_0002
进一步的, 当 1^为-11, 9-磺酰基 -9H-嘌呤衍生物的结构如式 III所示:
Figure imgf000013_0002
Further, when 1^ is a -11, 9-sulfonyl-9H-indole derivative has the structure shown in Formula III:
Figure imgf000013_0003
Figure imgf000013_0003
III 其中, R2为卤素; III wherein R 2 is halogen;
R3为 -H、 -NH2; R 3 is -H, -NH 2;
R4为
Figure imgf000013_0004
苄基、 C1〜C4垸基或 C3-
R4 is
Figure imgf000013_0004
Benzyl, C1~C4 thiol or C3-
C6环垸基; C6 ring thiol;
Rs〜R15独立的为 -H、 -N02、 C1〜C8院基、 C1〜C8烷氧基、 苯基、 C1〜C8烷基 取代氧羰基、 C3〜C8环烷基取代氧羰基或 -CF3 ;
Figure imgf000014_0001
优选的, R2为 -F、 -Cl、 -Br或 -I;
Rs~R 15 are independently -H, -N0 2 , C1~C8, C1~C8 alkoxy, phenyl, C1~C8 alkyl substituted oxycarbonyl, C3~C8 cycloalkyl substituted oxycarbonyl or - CF 3 ;
Figure imgf000014_0001
Preferably, R 2 is -F, -Cl, -Br or -I;
R3为 -H、 -F、 -CK -Br或 -NH2; R 3 is -H, -F, -CK -Br or -NH 2 ;
R4为 R9 、
Figure imgf000014_0002
苄基、 C1〜C4垸基或 C3-
R4 is R 9 ,
Figure imgf000014_0002
Benzyl, C1~C4 thiol or C3-
C6环垸基; C6 ring thiol;
Rs〜Ri2独立的为 -H、 -N02、 CI' 8焼基、 C1〜C8烷氧基、 苯基或 -CF3 ; Rs~Ri2 are independently -H, -N0 2 , CI' 8 fluorenyl, C1 to C8 alkoxy, phenyl or -CF 3 ;
R15独立的为 -H、 C1-C8烷基或 C1〜C8烷基取代氧羰基; R 15 is independently -H, C1-C8 alkyl or C1 to C8 alkyl substituted oxycarbonyl;
Figure imgf000014_0003
优选的, R2为 -F、 -CK -Br或 -I;
Figure imgf000014_0003
Preferably, R 2 is -F, -CK -Br or -I;
R3为- H、 -F、 -CI或 -NH2; R4为
Figure imgf000015_0001
、苄基、 C1〜C4垸基或 C3-
R 3 is -H, -F, -CI or -NH 2 ; R4 is
Figure imgf000015_0001
, benzyl, C1~C4 thiol or C3-
C6环烷基; C6 cycloalkyl;
〜Rn独立的为 -H、 -N02、 C1〜C4院基、 C1〜C4垸氧基、 苯基或 -CF3; ~Rn is independently -H, -N0 2 , C1~C4, C1~C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H、 CI〜C4烷基取代氧羰基或 CI C4垸基; R 13 to R 15 are independently -H, CI to C 4 alkyl substituted oxycarbonyl or CI C4 fluorenyl;
Figure imgf000015_0002
优选的, R2为 -F、 -Cl、 -Br或 -I;
Figure imgf000015_0002
Preferably, R 2 is -F, -Cl, -Br or -I;
R3为 -H、 -CI - H2 ; R 3 is -H, -CI - H 2 ;
R4为
Figure imgf000015_0003
苄基、 C1〜C4垸基或 C3-
R4 is
Figure imgf000015_0003
Benzyl, C1~C4 thiol or C3-
C4环垸基; C4 ring thiol;
R8〜R12独立的为 -H、 -N02、 C1〜C4烧基、 C1〜C4烷氧基、 苯基或 -CF3 R13〜R15独立的为 -H或 C 〜 C4垸基取代氧羰基; R 8 to R 12 are independently -H, -N0 2 , C1 to C4 alkyl, C1 to C4 alkoxy, phenyl or -CF 3 R 13 to R 15 are independently -H or C to C4 fluorenyl Substituting an oxycarbonyl group;
Figure imgf000015_0004
ίi V N s
Figure imgf000015_0004
Ίi VN s
N02 最优的, R2为 -F、 -Cl、 -Br或 -I; N0 2 is optimal, R 2 is -F, -Cl, -Br or -I;
R3为 -H、 -NH2或 -CI; R 3 is -H, -NH 2 or -CI;
R4为
Figure imgf000016_0001
、苄基、 C1〜C4垸基或 C3
R4 is
Figure imgf000016_0001
Benzyl, C1~C4 thiol or C3
C4环垸基; C4 ring thiol;
R«〜R12独立的为 -H、 -N02、 C1〜C4院基、 CI' C4垸氧基、 苯基或 -CF3 ; R13〜R15独立的为 -H或甲基取代氧羰基; R«~R 12 are independently -H, -N0 2 , C1~C4, CI' C4 methoxy, phenyl or -CF 3 ; R 13 〜R 15 are independently -H or methyl substituted oxygen Carbonyl;
Figure imgf000016_0002
进一步的, 上述 9-磺酰基 -9H-嘌呤
Figure imgf000016_0002
Further, the above 9-sulfonyl-9H-oxime
Figure imgf000016_0003
Figure imgf000016_0003
Figure imgf000017_0001
Figure imgf000017_0001
本发明所要解决的第二个技术问题是提供上述式 I、 式 II和式 III所示的 9-磺酰基 -9H-嘌呤衍生物的制备方法, 合成路线如下所示:  A second technical problem to be solved by the present invention is to provide a process for producing the 9-sulfonyl-9H-indole derivative represented by the above formula I, formula II and formula III, and the synthesis route is as follows:
Figure imgf000017_0002
Figure imgf000017_0002
由化合物 1与化合物 2通过氮磺酰化反应制备得到。  It is prepared from the compound 1 and the compound 2 by a sulfonylation reaction.
反应溶剂优选为四氢呋喃与二氯甲烷的混合溶剂, 四氢呋喃与二氯甲烷的体积比为 The reaction solvent is preferably a mixed solvent of tetrahydrofuran and dichloromethane, and the volume ratio of tetrahydrofuran to dichloromethane is
1: 1 , 反应温度为室温, 需氮气保护。 1: 1 The reaction temperature is room temperature and requires nitrogen protection.
本发明所要解决的第三个技术问题是提供上述式 I、 式 II和式 III所示的 9-磺酰基 -9H-嘌呤衍生物在制备抗慢性丙型肝炎药物中的用途。  A third technical problem to be solved by the present invention is to provide the use of the 9-sulfonyl-9H-indole derivative represented by the above formula I, formula II and formula III for the preparation of a medicament for anti-chronic hepatitis C.
本发明所要解决的第四个技术问题是提供制备上述式 I、式 II所示的 9-磺酰基 -9H- 嘌呤衍生物时使用的中间体, 结构如式 IV所示:  A fourth technical problem to be solved by the present invention is to provide an intermediate which is used in the preparation of the 9-sulfonyl-9H-indole derivative represented by the above formula I and formula II, and has the structure shown in Formula IV:
Figure imgf000018_0001
Figure imgf000018_0001
其中, Ra、 R3独立的为 -H、 -F、 -Cl、 -Br、 -Ν3、 -ΝΗ2、 -Ν02、 C1〜C8浣基、 C3〜 C8环垸基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 · ·Ν^Ο、 ^^^^或 C1〜C8 烧硫基; Wherein, Ra and R 3 are independently -H, -F, -Cl, -Br, -Ν 3 , -ΝΗ 2 , -Ν0 2 , C1~C8 thiol, C3~C8 cyclodecyl, C1~C8垸An oxy group, a C1~C8 fluorenyl substituted amine group, a Ν^Ο, ^^^^ or a C1~C8 sulphur-burning group;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 优选的, 1^为11、 C1〜C8烷基或 C3〜C8环垸基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl. Preferably, 1^ is 11, C1~C8 alkyl or C3~C8 cyclodecyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8烷基、 C3〜C8环垸基、 Cl〜 R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl, C3~C8 cycloalkyl group embankment, Cl~
C8垸氧基、 C1〜C8垸基取代胺基、 t^LJ^ ^ R7或 C1〜C8烷硫基; C8 methoxy, C1~C8 fluorenyl substituted amine, t^LJ^^ R7 or C1~C8 alkylthio;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1~C8垸基。 优选的, 为-11或€1〜€4烷基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl. Preferably, it is -11 or €1 to €4 alkyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 - H2、 -N02、 C1〜C8烷基、 C3~C8环垸基、 C!〜 C8烷氧基、 C1〜C8垸基取代胺基、 †f 〕0、 ^或 C1〜C8垸硫基; R 3 is -H, -F, -Cl, -Br, -N 3, - H 2, -N0 2, C1~C8 alkyl, C3 ~ C8 cycloalkyl group embankment, C! ~ C8 alkoxy, C1~C8 mercapto substituted amine, †f]0, ^ or C1~C8 thiol;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C4垸基。 优选的, 为-11或€1〜€4烷基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C4 fluorenyl. Preferably, it is -11 or €1 to €4 alkyl;
R3为 -H、 -F、 -Cl、 -Br、 C1〜C4烷基或- R5〜R7独立的为 -H或 C1〜C4烷基。 优选的, 、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -N02、 C1〜C8 垸基、 C3〜C8 环垸基、 C1〜C8垸氧基、 C1〜C8烷基取代胺基、 †N D、 ^或 C1〜C8垸 硫基; R 3 is -H, -F, -Cl, -Br, C1 to C4 alkyl or -R 5 to R 7 are independently -H or C1 to C4 alkyl. Preferably, R 3 is independently -H, -F, -Cl, -Br, -N 3 , -N0 2 , C1~C8 fluorenyl, C3~C8 cyclodecyl, C1~C8 decyloxy, C1 ~C8 alkyl substituted amine group, †ND, ^ or C1~C8 thiol group;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 优选的, 为-11或 C1~C4烷基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl. Preferably, it is a -11 or a C1 to C4 alkyl group;
R3为 -H、 -F、 -Cl、 -Br或 C1〜C4垸基; R 3 is -H, -F, -Cl, -Br or C1~C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4垸基。 最优的, R^ H; R 5 to R 7 are independently -H or C1 to C4 fluorenyl. Optimal, R^ H;
R3为 -H或 -C1; R 3 is -H or -C1;
R5〜R7独立的为 -H。 R 5 to R 7 are independently -H.
制备上述式 I、 式 II所示的 9-磺酰基 -9H-嘌呤衍生物时使用的中间体, 结构如式 V 所示:  The intermediate used in the preparation of the 9-sulfonyl-9H-indole derivative represented by the above formula I and formula II has the structure shown by the formula V:
Figure imgf000019_0001
其中, 、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2 -N02、 C1〜C8 '垸基、 C3〜 C8环烷基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 · ·Ν。0、 ^或 C1〜C8 烷硫基;
Figure imgf000019_0001
Wherein, R 3 is independently -H, -F, -Cl, -Br, -N 3 , -NH 2 -N0 2 , C1~C8 'decyl, C3~C8 cycloalkyl, C1~C8垸 oxygen a group, a C1~C8 thiol group substituted with an amine group, · · Ν. 0, ^ or C1 ~ C8 alkylthio;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8烷基。 优选的, Ri为 -H、 C1〜C8烷基或 C3〜C8环垸基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl. Preferably, Ri is -H, C1~C8 alkyl or C3~C8 cyclodecyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 - H2、 -N02、 C1〜C8院基、 C3〜C8环垸基、 Cl〜 ^ ^>=<R6 R 3 is -H, -F, -Cl, -Br, -N 3, - H 2, -N0 2, C1~C8 hospital group, C3~C8 cycloalkyl group embankment, Cl~ ^ ^>=< R6
C8烷氧基、 C1〜C8烷基取代胺基、 ^ R7或 C1〜C8垸硫基; a C8 alkoxy group, a C1 to C8 alkyl group substituted amine group, a ^ R7 or a C1~C8 sulfonium group;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8烷基。 优选的, 为-11或 〜 4烷基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 alkyl. Preferably, it is -11 or 〜4 alkyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8院基、 C3〜C8环垸基、 Cl〜 R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 hospital group, C3~C8 cycloalkyl group embankment, Cl~
C8烷氧基、 C1〜C8垸基取代胺基、
Figure imgf000020_0001
C8 alkoxy group, C1~C8 fluorenyl substituted amine group,
Figure imgf000020_0001
R5〜R7独立的为 -H、 C3-C8环烷基或 C1〜C4垸基。 优选的, Ri为 -H或 C1〜C4烷基; R 5 to R 7 are independently -H, C3-C8 cycloalkyl or C1 to C4 fluorenyl. Preferably, Ri is -H or C1~C4 alkyl;
R3为 -H、 -F、 -Cl、 -Br、 C1〜C4垸基或 -N¾; R 3 is -H, -F, -Cl, -Br, C1~C4 fluorenyl or -N3⁄4;
R5~R7独立的为 -H或 C1〜C4烷基。 优选的, Ri、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -N02、 C1 -C8垸基、 C3〜C8 环烷基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 †N D、 ^_ =< ^或 C1〜C8垸 硫基; R 5 to R 7 are independently -H or C1 to C4 alkyl. Preferably, Ri and R 3 are independently -H, -F, -Cl, -Br, -N 3 , -N0 2 , C1 -C8 fluorenyl, C3~C8 cycloalkyl, C1~C8 decyloxy, a C1-C8 thiol-substituted amine group, †ND, ^_=<^ or a C1~C8 thiol group;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 优选的, 为-11或 C1~C4烷基; R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl. Preferably, it is a -11 or a C1 to C4 alkyl group;
R3为 -H、 -F、 -Cl、 -Br或 C1〜C4垸基; R 3 is -H, -F, -Cl, -Br or C1~C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4烷基。 最优的, R H; R 5 to R 7 are independently -H or C1 to C4 alkyl. Optimal, RH;
R3为 -H或 -CI; R 3 is -H or -CI;
R5〜R7独立的为 -H。 R 5 to R 7 are independently -H.
本发明还提供了一种药物组合物, 是由上述式 I、 式 II所示的 9-磺酰基 -9H-嘌呤衍 生物添加药学上可以接受的辅助性成分制备而成的。该药物组合物可用于制备抗慢性丙 型肝炎药物。 本发明在大量筛选的基础上得到 9-磺酰基 -9H-嘌呤衍生物, 具有抗 HCV活性, 为 抗慢性丙型肝炎药物的开发和应用提供了新的选择。 The present invention also provides a pharmaceutical composition prepared by adding a pharmaceutically acceptable auxiliary component to the 9-sulfonyl-9H-indole derivative represented by the above formula I and formula II. The pharmaceutical composition can be used to prepare an anti-chronic hepatitis C drug. The invention obtains 9-sulfonyl-9H-indole derivative on the basis of a large number of screenings, has anti-HCV activity, and provides a new choice for the development and application of anti-chronic hepatitis C drugs.
附图说明 DRAWINGS
图 1 化合物 6-氯 -9- (4-甲氧基苯磺酰基) -9H-嘌呤抗 HCV活性及细胞毒性测试结 果。  Figure 1 Compound 6-chloro-9-(4-methoxybenzenesulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.
图 2化合物甲基 3-(6-氯 -9H-嘌吟 -9-基磺酰基)噻吩 -2-羧酸酯抗 HCV活性及细胞毒 性测试结果。  Fig. 2 shows the results of anti-HCV activity and cytotoxicity test of the compound methyl 3-(6-chloro-9H-indol-9-ylsulfonyl)thiophene-2-carboxylate.
图 3 化合物 6-氟 -9- (4-甲氧基苯磺酰基) -9H-嘌呤抗 HCV活性及细胞毒性测试结 果。  Figure 3. Compound 6-fluoro-9-(4-methoxybenzenesulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.
图 4化合物 6-氯 -9- (3-硝基苯磺酰基) -9H-嘌吟抗 HCV活性及细胞毒性测试结果。 图 5 化合物 6-氯 -9- (2-硝基苯磺酰基) -9H-嘌呤抗 HCV活性及细胞毒性测试结果。 具体实施方式  Figure 4. Compound 6-chloro-9-(3-nitrophenylsulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results. Figure 5 Compound 6-chloro-9-(2-nitrophenylsulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results. detailed description
以下结合实施例对本发明作进一步的阐述。 实施例仅用于说明本发明, 而不是以任 何方式来限制本发明。  The invention is further illustrated by the following examples. The examples are merely illustrative of the invention and are not intended to limit the invention in any way.
实施例 1中间体 6-二甲氨基 合成 Example 1 Intermediate 6-Dimethylamino Synthesis
Figure imgf000021_0001
Figure imgf000021_0001
将 6-氯噤呤 0.465 g Ommol) 溶于乙醇中, 随后依次加入碳酸钾 1.25 g (9mmol) 及盐酸二甲胺 0.725 g (9mmol), 然后加热回流 12h, 反应完成后减压蒸出溶剂, 剩余 固体悬浮于水中搅拌 2h,然后过滤得产物 6-二甲氨基嘌呤,净重 0.392 g,产率 80.05%。 纯度 (HPLC)≥94%。  6-chloroindole 0.465 g Ommol) was dissolved in ethanol, followed by 1.25 g (9 mmol) of potassium carbonate and 0.725 g (9 mmol) of dimethylamine hydrochloride, followed by heating under reflux for 12 h. After completion of the reaction, the solvent was evaporated under reduced pressure. The remaining solid was suspended in water and stirred for 2 h, then filtered to give the product 6-dimethylaminoindole, with a net weight of 0.392 g and a yield of 80.05%. Purity (HPLC) ≥ 94%.
1H-NMR (400MHz, DMSO-D6) 6:2.47(s, 6H, N(CH3)2), 7.96(s, 1H), 8.38(s, 1H), 13.71(s, 1H)。 1H-NMR (400 MHz, DMSO-D6) 6: 2.47 (s, 6H, N (CH 3 ) 2 ), 7.96 (s, 1H), 8.38 (s, 1H), 13.71 (s, 1H).
实施例 2 中间体 6-二乙氨基嘌呤的合成 Example 2 Synthesis of Intermediate 6-Diethylaminopurine
Figure imgf000021_0002
Figure imgf000021_0002
按中间体 6-二甲氨基嘌呤的制备方法,将原料替换为 6-氯嘌呤与二乙胺, 反应后洗 涤、 过滤直接得到 6-二乙氨基嘌呤, 产率 85.37%。 纯度 (HPLC)≥95%。 According to the preparation method of the intermediate 6-dimethylamino hydrazine, the raw material is replaced by 6-chloropurine and diethylamine, and the reaction is washed. Polyester and filtration directly gave 6-diethylaminopurine in a yield of 85.37%. Purity (HPLC) ≥ 95%.
1H-NMR (400MHz, DMSO-D6) 5:1.33(t, 6H, -CH3), 1.33(m, 2H, -CH2-), 7.97(s, 1H): 8.40(s, 1H), 13.66(s, 1H)。 1H-NMR (400MHz, DMSO-D6) 5: 1.33 (t, 6H, -CH 3 ), 1.33 (m, 2H, -CH 2 -), 7.97 (s, 1H): 8.40 (s, 1H), 13.66 (s, 1H).
实施例 3 中间体 6-吗啉基嘌呤的合成 Example 3 Intermediate Synthesis of 6-morpholinylfluorene
Figure imgf000022_0001
按中间体 6-二甲氨基嘌吟的制备方法,将原料替换为 6-氯嘌呤与吗啉,反应后洗涤、 过滤直接得到 6-吗啉基嘌呤, 产率 89.42%。 纯度 (HPLC)≥96%。
Figure imgf000022_0001
According to the preparation method of the intermediate 6-dimethylaminopurine, the starting material was replaced with 6-chloroindole and morpholine, and after the reaction, washing and filtration directly gave 6-morpholinylhydrazine in a yield of 89.42%. Purity (HPLC) ≥ 96%.
^- MR (400MHz, DMSO-D6) 6:3.71(s, 4H, 0(CH2)2), 4.21(s, 4H, -N(CH2)2), 8.14(s, 1H), 8.23(s, 1H), 13.07(s, 1H)» ^- MR (400MHz, DMSO-D6) 6:3.71(s, 4H, 0(CH 2 ) 2 ), 4.21(s, 4H, -N(CH 2 ) 2 ), 8.14(s, 1H), 8.23( s, 1H), 13.07(s, 1H)»
实施例 4 中间体 6-甲硫基嘌昤的合成 Example 4 Synthesis of Intermediate 6-Methylthioguanidine
Figure imgf000022_0002
将中间体 6-巯基嘌呤 0.455 g (3mmol)溶于 2N的 NaOH ( 10mL) 中, 然后向其中 加入碘甲烷 0.550g (3.6mmol),常温下搅拌 12h, 反应结束后用冰醋酸调 pH至 5, 过滤 直接得到 6-甲硫基嘌呤, 净重 0.34 g, 产率 69.13%。 纯度 (HPLC)≥96%。
Figure imgf000022_0002
The intermediate 6-mercaptopurine 0.455 g (3 mmol) was dissolved in 2N NaOH (10 mL), and then 0.550 g (3.6 mmol) of iodomethane was added thereto, and stirred at normal temperature for 12 hours, and the pH was adjusted to 5 with glacial acetic acid. Filtration directly gave 6-methylthioguanidine, a net weight of 0.34 g, and a yield of 69.13%. Purity (HPLC) ≥ 96%.
Ή-NMR (400MHz, DMSO-D6) 6:2.68(s, 3H, -CH3), 8.25(s, 1H), 8.54(s, 1H), 13.33(s,Ή-NMR (400MHz, DMSO-D6) 6: 2.68 (s, 3H, -CH 3 ), 8.25 (s, 1H), 8.54 (s, 1H), 13.33 (s,
1H)。 1H).
实施例 5 中间体 6-烯丙硫基嘌呤的合成  Example 5 Intermediate Synthesis of 6-allylthioguanidine
Figure imgf000022_0003
Figure imgf000022_0003
将中间体 6-巯基嘌呤 0.456 g Ommol)溶于 2N的 NaOH ( lOmL) 中, 然后向其中 加入烯丙基氯 0.276g (3.6mmol),常温下搅拌 12h, 反应结束后用冰醋酸调 pH至 5, 过 滤直接得到 6-烯丙硫基嘌呤, 净重 0.504 g, 产率 87.50%。 纯度 (HPLC)≥96%。 The intermediate 6-mercaptopurine 0.456 g Ommol) was dissolved in 2N NaOH (10 mL) and then 0.276 g (3.6 mmol) of allyl chloride was added, and the mixture was stirred at normal temperature for 12 hours. After the reaction was completed, the pH was adjusted to 5 with glacial acetic acid, and then filtered to give 6-ethyl propyl sulfonium sulphate, with a net weight of 0.504 g, yield 87.50%. Purity (HPLC) ≥ 96%.
1H- MR (400MHz, DMSO-D6) 5:4.03(d, 2H, -SCH2-), 5.13(d, 1H, =CH2), 5.35(d, 1H, =CH2), 5.97(m, 1H, =CH-), 8.58(s, 1H), 8.84(s, 1H), 13.42(s, 1H)。 1H-MR (400MHz, DMSO-D6) 5:4.03(d, 2H, -SCH 2 -), 5.13(d, 1H, =CH 2 ), 5.35(d, 1H, =CH 2 ), 5.97(m, 1H, =CH-), 8.58(s, 1H), 8.84(s, 1H), 13.42(s, 1H).
实施例 6 中间体 6-叠氮基噤呤的合成 Example 6 Intermediate Synthesis of 6-azidofluorene
Figure imgf000023_0001
将中间体 6-氯噤呤 1.545 g ( lOmmol) 溶于 DMF (20mL) 中, 然后向其中加入叠 氮钠 0.783g ( 12mmol),升温至 60°C搅拌 12h, 反应结束后降至室温, 用乙酸乙酯与水 萃取, 乙酸乙酯层分别用水 (50 mLx2) 、 饱和碳酸氢钠溶液 (50 mIX2) 、 饱和食盐 水 (50 mLx2) 洗涤, 无水硫酸镁千燥, 后拌样过柱 (乙酸乙酯 /石油醚 =1/3 ),得产品 0.851 g, 产率 52.53%。 纯度 (HPLC) >97%
Figure imgf000023_0001
The intermediate 6-chloropurine 1.545 g (10 mmol) was dissolved in DMF (20 mL), then sodium azide 0.783 g (12 mmol) was added thereto, and the mixture was heated to 60 ° C for 12 h, and then cooled to room temperature after the reaction was completed. The ethyl acetate layer was extracted with water, and the ethyl acetate layer was washed with water (50 mL×2), saturated sodium hydrogen carbonate solution (50 mIX2) and saturated brine (50 mL×2), dried over anhydrous magnesium sulfate, Ethyl acetate / petroleum ether = 1/3) gave the product 0.851 g, yield 52.53%. Purity (HPLC) >97%
1H-NMR (400MHz, D S0-D6) δ: 8.58(s, 1H), 8.73(s, 1H), 13.87(s, 1H)。  1H-NMR (400MHz, D S0-D6) δ: 8.58 (s, 1H), 8.73 (s, 1H), 13.87 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 162.05。 ESI-MS (m/z, %): (M+H) + 162.05.
实施例 7 中 6-氟嘌呤的合成 Synthesis of 6-fluoroindole in Example 7
Figure imgf000023_0002
Figure imgf000023_0002
将中间体 6-氯嘌呤 1.545 g ( lOmmol)溶于 THF (30mL) 中, 然后向其中加入三甲 胺水溶液 3mL (33%, 30mmol) ,常温搅拌 24h, 反应结束后过滤, 真空干燥, 得中间 体 6-三甲氨基嘌呤盐酸盐。取中间体 6-三甲氨基嘌呤盐酸盐 1.130 g( 5mmol)溶于 DMSO ( 15mL) 中, 后向其中加入四丁基氟化铵 (TBAF, 7.5mmol) , 常温反应 24h后用乙 酸乙酯与水萃取, 乙酸乙酯层分别用水 (50 mLx2) 、 饱和食盐水 (50 mLx2) 洗涤, 无水硫酸镁干燥, 减压蒸出溶剂后得产品 0.153 g, 产率 22.17%。 纯度(HPLC)≥92%。  The intermediate 6-chloroindole 1.545 g (10 mmol) was dissolved in THF (30 mL), then 3 mL (33%, 30 mmol) of trimethylamine aqueous solution was added thereto, and stirred at room temperature for 24 h. After completion of the reaction, it was filtered and dried in vacuo to give intermediate. 6-Trimethylaminoguanidine hydrochloride. The intermediate 6-trimethylaminoguanidine hydrochloride 1.130 g (5 mmol) was dissolved in DMSO (15 mL), and then tetrabutylammonium fluoride (TBAF, 7.5 mmol) was added thereto, and reacted at room temperature for 24 hours, followed by ethyl acetate. The water was extracted, and the ethyl acetate layer was washed with water (50 mL×2) and brine (50 mL×2), dried over anhydrous magnesium sulfate, and evaporated. Purity (HPLC) ≥ 92%.
Ή-NMR (400MHz, DMSO-D6) δ: 8.66(d, 2H), 13.97(s, 1H)。  Ή-NMR (400 MHz, DMSO-D6) δ: 8.66 (d, 2H), 13.97 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 139.24。 实施例 8 中间体 6-碘嘌呤的合成 ESI-MS (m/z, %): (M+H) + 139.24. Example 8 Synthesis of Intermediate 6-Iodoindole
Figure imgf000024_0001
Figure imgf000024_0001
称取中间体6-氯嘌呤4.650 g (30mmol), 然后向其中加入氢碘酸溶液 30mL (45%, m/m),常温搅拌 2h, 反应结束后过滤, 蒸馏水洗涤滤饼(10mLX 3 ) , 真空干燥, 得黑 色中间体 6-碘嘌吟, 产品重量 5.235 g, 产率 70.93%。 该中间体未经纯化直接用于后续 反应, 纯度 (HPLC)≥95%。  The intermediate 6-chloropurine 4.650 g (30 mmol) was weighed, and then 30 mL (45%, m/m) of hydroiodic acid solution was added thereto, and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filter cake (10 mL×3) was washed with distilled water. Drying in vacuo gave a black intermediate 6-iodoindole, product weight 5.235 g, yield 70.93%. This intermediate was used in the subsequent reaction without purification, purity (HPLC) ≥ 95%.
实施例 9 中间体 6-溴嘌呤的合成 Example 9 Synthesis of Intermediate 6-Bromoindole
Figure imgf000024_0002
Figure imgf000024_0002
称取中间体 6-氯嘌呤 1.550 g ( lOmmol) , 然后向其中加入三溴氧磷 30 g, 氮气保 护下升温至 120°C, 搅拌 12h后将反应液缓慢倒入饱和碳酸钠溶液中并于冰水浴下剧烈 搅拌, 后用乙酸乙酯萃取该混合液, 水层用乙酸乙酯洗涤 (100mLX 3 ) , 合并有机层, 并用饱和食盐水洗涤 (100mLX 3 ) , 无水硫酸镁干燥, 过滤后减压移除溶剂, 得灰白 色固体 6-溴嘌呤, 产品重量 0.204 g, 产率 10.25%。 该中间体未经纯化直接用于后续反 应, 纯度 (HPLC)≥90%。  Weigh the intermediate 6-chloropurine 1.550 g (10 mmol), then add 30 g of phosphorus oxybromide, and heat to 120 ° C under nitrogen. After stirring for 12 h, slowly pour the reaction into saturated sodium carbonate solution and After stirring vigorously in an ice-water bath, the mixture was extracted with EtOAc. EtOAc (EtOAc) The solvent was removed under reduced pressure to give 6-bromo succine as an off-white solid, product weight 0.204 g, yield 10.25%. This intermediate was used directly in the subsequent reaction without purification, purity (HPLC) ≥ 90%.
实施例 10 目标产物 6-氯 -9-对甲苯磺酰 -9H-嘌呤的合成 Example 10 Synthesis of target product 6-chloro-9-p-toluenesulfonyl-9H-indole
Figure imgf000024_0003
Figure imgf000024_0003
将 6-氯嘌呤(0.465 & 3mmol)溶于二氯甲烷 /四氢呋喃(20mL, V/V-1/1 )混合溶剂 中, 后向其中依次加入对甲苯磺酰氯 ( 1.143 g, 6mmol)及三乙胺 (0.606 g,6mmol) , 氮气保护下于常温搅拌 4h, 减压移除溶剂, 残留油状固体用二氯甲烷与水萃取,有机层 用饱和碳酸氢钠溶液 (30mLX 2) 及饱和食盐水 (30mLX 2) 洗涤, 无水硫酸镁干燥, 2h后过滤并过柱, 得白色固体 0.476 g, 产率 51.51%, 纯度 (HPLC)≥99%。 Ή NMR (400MHz, CDC13): 52.39(s, 3H, -CH3), 7.5 l(d, J = 8.0Hz, 2H), 8.12(d, J = 8.4Hz, 2H), 8.66 (s, 1H), 8.87(s, 1H)。 6-Chloropurine (0.465 & 3 mmol) was dissolved in a mixed solvent of dichloromethane/tetrahydrofuran (20 mL, V/V-1/1), and then p-toluenesulfonyl chloride ( 1.143 g, 6 mmol) and triethylbenzene were sequentially added thereto. The amine (0.606 g, 6 mmol) was stirred at room temperature for 4 h under nitrogen. The solvent was evaporated under reduced pressure. The residue was purified from methylene chloride and water. After washing with 30 mL of X 2), dried over anhydrous magnesium sulfate, and filtered and then passed to the column to afford white solids, 0.476 g, yield 51.51%, purity (HPLC) ≥99%. NMR NMR (400MHz, CDC1 3 ): 52.39(s, 3H, -CH 3 ), 7.5 l(d, J = 8.0Hz, 2H), 8.12(d, J = 8.4Hz, 2H), 8.66 (s, 1H ), 8.87(s, 1H).
ESI-MS (m/z, %): (M+Na)+ 331.15。 ESI-MS (m/z, %): (M+Na) + 331.15.
实施例 11 目标产物 6-氯 -9- (4-甲氧 -9H-嘌昤 Example 11 Target product 6-chloro-9-(4-methoxy-9H-oxime
Figure imgf000025_0001
Figure imgf000025_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.643 g, 产率 66.15%, 纯度 (HPLC) ≥99%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.643 g, yield 66.15%, purity (HPLC) ≥ 99%.
Ή NMR (400MHz, CDCI3): 63.90 (s, 3H, -OCH3), 7.05 (d, J = 8.8Hz, 2H), 8.23(d, J = 8.8Hz, 2H), 8.59(s, 1H), 8.86(s, 1H)。  NMR NMR (400MHz, CDCI3): 63.90 (s, 3H, -OCH3), 7.05 (d, J = 8.8Hz, 2H), 8.23 (d, J = 8.8Hz, 2H), 8.59(s, 1H), 8.86 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 325.11。 ESI-MS (m/z, %): (M+H) + 325.11.
实施例 12 目标产物 6-叠氮基 -9- (4- 基) -9H-嘌呤 Example 12 Target product 6-azido-9-(4-yl)-9H-oxime
Figure imgf000025_0002
Figure imgf000025_0002
按实施例 10的制备方法, 将原料替换为 6-叠氮基嘌呤与相应磺酰氯, 过柱后得产 物 0.135 g, 产率 13.60%, 纯度 (HPLC) ≥96%。  According to the preparation method of Example 10, the starting material was replaced with 6-azidofluorene and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.135 g, yield: 13.60%, purity (HPLC) ≥ 96%.
Ή NMR (400MHz, DMSO-i¾): 53.86 (s, 3H, -OCH3), 7.24 (d, J= 8.8Hz, 2H), 8.23(d, J = 8.8Hz, 2H), 9.16(s, 1H), 10.22(s, 1H;)。 NMR NMR (400MHz, DMSO-i3⁄4): 53.86 (s, 3H, -OCH 3 ), 7.24 (d, J = 8.8Hz, 2H), 8.23 (d, J = 8.8Hz, 2H), 9.16(s, 1H ), 10.22(s, 1H;).
ESI-MS (m/z, %): (M+H)+ 332.06。 ESI-MS (m/z, %): (M+H) + 332.06.
实施例 13 目标产物 6-氟 -9- (4-甲氧基苯磺酰基) -9H-嘌呤 Example 13 Target product 6-fluoro-9-(4-methoxybenzenesulfonyl)-9H-oxime
Figure imgf000026_0001
Figure imgf000026_0001
按实施例 10的制备方法,将原料替换为 6-氟嘌呤与相应磺酰氯,过柱后得产物 0.174 g, 产率 56.49%, 纯度 (HPLC)≥95%。  According to the preparation method of Example 10, the starting material was replaced with 6-fluoroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.174 g, yield 56.49%, purity (HPLC) ≥ 95%.
1H NMR (400MHz, CDC13): 63.88 (s, 3H, -OCH3), 7.05 (d, J = 9.6Hz, 2H), 8.24(d, J = 9.2Hz, 2H), 8.56(s, 1H), 8.75(s, 1H)。 1H NMR (400MHz, CDC1 3 ): 63.88 (s, 3H, -OCH3), 7.05 (d, J = 9.6Hz, 2H), 8.24 (d, J = 9.2Hz, 2H), 8.56(s, 1H), 8.75 (s, 1H).
ESI-MS (m/z, %): (M+Na)+ 331.10。 ESI-MS (m/z, %): (M+Na) + 331.10.
实施例 14 目标产物 6-氨基 -9- (4-甲 ) -9H-嘌吟 Example 14 Target product 6-Amino-9-(4-methyl)-9H-oxime
Figure imgf000026_0002
Figure imgf000026_0002
按实施例 10中的方法, 将原料替换为 6-氟嘌呤与相应磺酰氯, 反应结束后减压移 除溶剂, 残留油状固体先于 4mol L的氨水中搅拌 2h, 后用二氯甲烷与水萃取, 有机层 用 4mol/L的氨水溶液 (20mLX 2)及饱和食盐水 (30mLX 2) 洗涤, 无水硫酸镁千燥, 2h后过滤并过柱, 得白色固体产物 0.077 g, 产率 50.32%, 纯度 (HPLC)≥96%。  In the same manner as in Example 10, the starting material was replaced with 6-fluoroindole and the corresponding sulfonyl chloride. After the reaction was completed, the solvent was removed under reduced pressure. The residual oily solid was stirred in 4 mol of aqueous ammonia for 2 h, then dichloromethane and water. The organic layer was washed with 4 mol/L aqueous ammonia solution (20 mL×2) and saturated brine (30 mL×2), dried over anhydrous magnesium sulfate, and filtered and filtered to afford white solid product 0.077 g, yield 50.32%. , purity (HPLC) ≥ 96%.
1H NMR (400MHz, DMSO-i/6): 63.84 (s, 3H, -OCH3), 7.18 (d, J = 9.2Hz, 2H), 7.65 (s, 2H, -NH2), 8.13(d, J= 9.2Hz, 2H), 8.21(d, J= 2.4Hz , 1H), 8.59(d, J= 2.4Hz, 1H)。 1H NMR (400MHz, DMSO-i/ 6 ): 63.84 (s, 3H, -OCH3), 7.18 (d, J = 9.2Hz, 2H), 7.65 (s, 2H, -NH 2 ), 8.13 (d, J = 9.2 Hz, 2H), 8.21 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H).
ESI-MS (m/z, %): (M+H)+ 306.07。 ESI-MS (m/z, %): (M+H) + 306.07.
实施例 15 目标产物 6-氯 -9- (4-异丙氧基苯磺酰基) -9H-嘌呤
Figure imgf000027_0001
Example 15 Target product 6-chloro-9-(4-isopropoxybenzenesulfonyl)-9H-oxime
Figure imgf000027_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.684 g, 产率 64.77%, 纯度 (HPLC)≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and after the column was passed, the product was obtained, 0.684 g, yield: 64.77%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, CDC13): 61.355 (d, J = 6.0Hz, 6H, -CH3), 4.64 (m, J = 6.0Hz, 3H, -CH=), 6.99 (d, J= 8.8Hz, 2H), 8.19(d, J= 8.8Hz, 2H), 8.57(s, 1H), 8.85(s, 1H)。 NMR NMR (400MHz, CDC1 3 ): 61.355 (d, J = 6.0Hz, 6H, -CH 3 ), 4.64 (m, J = 6.0Hz, 3H, -CH=), 6.99 (d, J= 8.8Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 8.57 (s, 1H), 8.85 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 353.03。  ESI-MS (m/z, %): (M+H) + 353.03.
实施例 16 目标产物 6-氯 -9- (4-叔丁 -9H-嘌昤  Example 16 Target product 6-chloro-9-(4-tert-butyl-9H-oxime
Figure imgf000027_0002
Figure imgf000027_0002
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.587 g, 产率 55.90%, 纯度 (HPLC)≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.587 g, yield 55.90%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, CDC13): 51.32 (s, 9H, -CH3), 7.61 (d, J = 8.8Hz, 2H), 8.21(d, J = 8.8Hz, 2H), 8.58(s, 1H), 8.86(s, 1H)。 NMR NMR (400MHz, CDC1 3 ): 51.32 (s, 9H, -CH 3 ), 7.61 (d, J = 8.8Hz, 2H), 8.21 (d, J = 8.8Hz, 2H), 8.58(s, 1H) , 8.86(s, 1H).
ESI-MS (m/z, %): (M+H)+ 351.07。 ESI-MS (m/z, %): (M+H) + 351.07.
实施例 17 目标产物 6-氯 -9- (3-三氟甲基苯磺酰基) -9H-嘌呤  Example 17 Target product 6-chloro-9-(3-trifluoromethylbenzenesulfonyl)-9H-oxime
Figure imgf000027_0003
Figure imgf000027_0003
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.642 g, 产率 59.12%, 纯度 (HPLC ) ≥98%。 According to the preparation method of Example 10, the raw material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product was obtained after passing through the column. g, yield 59.12%, purity (HPLC) ≥ 98%.
1H MR (400MHz, CDC13): 57.80 (t, J = 8.0Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 8.55(d, J = 8.0Hz, 1H), 8.59(s, 1H), 8.61(d, J= 8.0Hz, 1H), 8.88(s, 1H)。 1H MR (400MHz, CDC1 3 ): 57.80 (t, J = 8.0Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 8.55 (d, J = 8.0Hz, 1H), 8.59(s, 1H ), 8.61 (d, J = 8.0 Hz, 1H), 8.88 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 362.98。 ESI-MS (m/z, %): (M+H) + 362.98.
实施例 18 目标产物 6-氯 -9- ( 2-硝基 -4-甲氧基苯磺酰基) -9H-嘌呤 Example 18 Target product 6-chloro-9-(2-nitro-4-methoxybenzenesulfonyl)-9H-oxime
Figure imgf000028_0001
Figure imgf000028_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌吟与相应磺酰氯,过柱后得产物 0.342 g, 产率 30.89%, 纯度 (HPLC ) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.342 g, the yield was 30.89%, and the purity (HPLC) was ≥98%.
1H NMR (400MHz, CDCI3): δ 3.99(s, 3H, -OCH3), 7.29-7.32 (m, 2H), 8.62 (s, 1H), 8.73(d, J = 9.2Hz, 1H), 8.79(s, 1H)。 1H NMR (400MHz, CDCI3): δ 3.99(s, 3H, -OCH 3 ), 7.29-7.32 (m, 2H), 8.62 (s, 1H), 8.73 (d, J = 9.2Hz, 1H), 8.79 ( s, 1H).
ESI-MS (m/z, %): (M+H)+ 369.97。 ESI-MS (m/z, %): (M+H) + 369.97.
实施例 19 目标产物 6-氯 -9- (4- -9H-嘌呤 Example 19 Target product 6-chloro-9- (4- -9H-oxime
Figure imgf000028_0002
Figure imgf000028_0002
按实施例 10 的制备方法, 将原料替换为 6-氯嘌呤与相应磺酰氯, 过柱后得产物 0.489g, 产率 44.05%, 纯度 (HPLC ) ≥96。/0According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.489 g, the yield was 44.05%, and the purity (HPLC) was ≥96. / 0 .
Ή NMR (400MHz, CDCI3): 67.42-7.53 (m, 3H), 7.56-7.58(m, 2H), 7.79(d, J = 8.8Hz, 2H), 8.35 (d, J= 8.4Hz, 2H), 8.62 (s, 1H), 8.88 (s, 1H)。  NMR NMR (400MHz, CDCI3): 67.42-7.53 (m, 3H), 7.56-7.58 (m, 2H), 7.79 (d, J = 8.8 Hz, 2H), 8.35 (d, J = 8.4 Hz, 2H), 8.62 (s, 1H), 8.88 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 371.05。 ESI-MS (m/z, %): (M+H) + 371.05.
实施例 20 目标产物 6-氯 -9- (2,4,6-三异丙基苯磺酰基) -9H-嘌呤
Figure imgf000029_0001
Example 20 Target product 6-chloro-9-(2,4,6-triisopropylbenzenesulfonyl)-9H-indole
Figure imgf000029_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.718 g, 产率 56.98%, 纯度 (HPLC ) >97%„  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.718 g, yield 56.98%, purity (HPLC) >97%.
!H NMR (400MHz, CDC13): 61.16-1.57(m, 18H), 2.92 (t, J = 6.8Hz, 1H), 4.26-4.33(m, 2H), 7.24 (d, J= 10.4Hz, 2H), 8.67 (d, J= 2.8Hz, 2H)。 ! H NMR (400MHz, CDC1 3 ): 61.16-1.57 (m, 18H), 2.92 (t, J = 6.8Hz, 1H), 4.26-4.33 (m, 2H), 7.24 (d, J = 10.4Hz, 2H ), 8.67 (d, J = 2.8 Hz, 2H).
ESI-MS (m/z, %): (M+H)+ 421.21。 ESI-MS (m/z, %): (M+H) + 421.21.
实施例 21 目标产物 6-氯 -9- (萘 -2-磺酰基) -9H-噤呤 Example 21 Target product 6-chloro-9-(naphthalene-2-sulfonyl)-9H-oxime
Figure imgf000029_0002
Figure imgf000029_0002
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.547 g, 产率 53.00%, 纯度 (HPLC) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.547 g, yield 53.00%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, CDCI3): 67.60 (t, J= 8.0Hz, 1H), 7.7 l(q, J = 8.0Hz, 2H), 7.96 (d, J = 8.0Hz, 1H), 8.23 (d, J= 8.4Hz, 1H), 8.66 (d, J = 8.8Hz, 1H), 8.71(s, 1H), 8.83 (s, 1H), 8.88 (dd, J= 1.2, 7.6Hz, 1H)。  NMR NMR (400MHz, CDCI3): 67.60 (t, J= 8.0Hz, 1H), 7.7 l(q, J = 8.0Hz, 2H), 7.96 (d, J = 8.0Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.71 (s, 1H), 8.83 (s, 1H), 8.88 (dd, J = 1.2, 7.6 Hz, 1H).
ESI-MS (m/z, %): (M+H)+ 345.09。 ESI-MS (m/z, %): (M+H) + 345.09.
实施例 22 目标产物 6-氯 -9- (3-硝基 基) -9H-嘌呤 Example 22 Target product 6-chloro-9-(3-nitro)-9H-oxime
Figure imgf000029_0003
Figure imgf000029_0003
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.592 g, 产率 58.38°/。, 纯度 (HPLC ) ≥99%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and after the column was passed, the product was obtained in a yield of 58.38 g. , purity (HPLC) ≥ 99%.
lH NMR (400MHz, CDCI3): 57.95 (t, J = 8.0Hz, 1H), 8.11 (d, J = 8.0Hz, 1H), 8.55(d, J = 8.0Hz, 1H), 8.59(s, 1H), 8.88(s, 1H) , 8.98(d, J= 8.0Hz: lH NMR (400MHz, CDCI3): 57.95 (t, J = 8.0Hz, 1H), 8.11 (d, J = 8.0Hz, 1H), 8.55(d, J = 8.0Hz, 1H), 8.59(s, 1H), 8.88(s, 1H) , 8.98(d, J= 8.0Hz:
ESI-MS (m/z, %): (M+H)+ 339.96。  ESI-MS (m/z, %): (M+H)+ 339.96.
实施例 23 目标产物 6-氯 -9- (2-硝基苯磺酰基) -9H-嘌呤 Example 23 Target product 6-Chloro-9-(2-nitrophenylsulfonyl)-9H-indole
Figure imgf000030_0001
Figure imgf000030_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.513 g, 产率 50.44%, 纯度 (HPLC) >99%o  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.513 g, yield 50.44%, purity (HPLC) >99%.
1H NMR (400MHz, CDC13): 57.62 (t, J = 8.0Hz, 1H), 7.97 (t, J = 8.0Hz, 1H), 8.25 (d, J = 8.0Hz, 1H), 8.50(d, J= 8.0Hz, 1H), 8.58(s, 1H), 8.86(s, 1H)。 1H NMR (400MHz, CDC1 3 ): 57.62 (t, J = 8.0Hz, 1H), 7.97 (t, J = 8.0Hz, 1H), 8.25 (d, J = 8.0Hz, 1H), 8.50(d, J = 8.0 Hz, 1H), 8.58 (s, 1H), 8.86 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 339.98。 ESI-MS (m/z, %): (M+H) + 339.98.
实施例 24 目标产物 6-氯 -9- (4-硝基苯磺酰基) -9H-嘌呤 Example 24 Target product 6-chloro-9-(4-nitrophenylsulfonyl)-9H-oxime
Figure imgf000030_0002
Figure imgf000030_0002
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.912 g, 产率 67.25%, 纯度 (HPLC)≥99%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in the form of 0.912 g, yield: 67.25%, purity (HPLC) ≥ 99%.
1H NMR (400MHz, CDC13): 58.45 (d, J = 9.2Hz, 2H), 8.55(d, J = 8.8Hz, 2H), 8.59(s, 1H), 8.88(s, 1H)。 1H NMR (400MHz, CDC1 3 ): 58.45 (d, J = 9.2Hz, 2H), 8.55 (d, J = 8.8Hz, 2H), 8.59 (s, 1H), 8.88 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 339.95。 ESI-MS (m/z, %): (M+H) + 339.95.
实施例 25 目标产物 8- (6-氯 -9H-嘌呤 -9-基磺酰基) 喹啉 Example 25 Target product 8-(6-chloro-9H-indol-9-ylsulfonyl)quinoline
Figure imgf000030_0003
Figure imgf000030_0003
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.249 g, 产率 36.09%, 纯度 (HPLC) ≥98%。 According to the preparation method of Example 10, the raw material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product was obtained after passing through the column. g, yield 36.09%, purity (HPLC) ≥ 98%.
1H MR (400MHz, CDC13): 57.51 (dd, J = 4.0Hz, 1H), 7.78 (t, J = 8.0Hz, 1H); 8.19-8.25 (m, 2H), 8.66(s, 1H), 8.92-8.95(m, 2H), 9.16(s, 1H)。 1H MR (400MHz, CDC1 3 ): 57.51 (dd, J = 4.0Hz, 1H), 7.78 (t, J = 8.0Hz, 1H) ; 8.19-8.25 (m, 2H), 8.66(s, 1H), 8.92 -8.95 (m, 2H), 9.16 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 346.10。 ESI-MS (m/z, %): (M+H) + 346.10.
实施例 26 目标产物 6-氯 -9- (苄磺酰基) -9H-嘌昤 Example 26 Target product 6-chloro-9-(benzylsulfonyl)-9H-oxime
Figure imgf000031_0001
Figure imgf000031_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.098 g, 产率 31.82%, 纯度 (HPLC) ≥95%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.098 g, yield 31.82%, purity (HPLC) ≥ 95%.
lH NMR (400MHz, CDCI3): 54.97 (s, 2H), 7.02 (d, J = 7.6Hz, 2H), 7.29 (d, J = 7.6Hz, 2H), 7.36(t, J= 7.2Hz, 1H), 8.00(s, 1H), 8.97(s, 1H)。  lH NMR (400MHz, CDCI3): 54.97 (s, 2H), 7.02 (d, J = 7.6Hz, 2H), 7.29 (d, J = 7.6Hz, 2H), 7.36 (t, J = 7.2Hz, 1H) , 8.00 (s, 1H), 8.97 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 309.05。 ESI-MS (m/z, %): (M+H) + 309.05.
实施例 27 目标产物 6-氯 -9- (环丙基 -9H-嘌呤 Example 27 Target product 6-chloro-9-(cyclopropyl-9H-oxime
Figure imgf000031_0002
Figure imgf000031_0002
按实施例 10的制备方法,将原料替换为 6-氯嘌吟与相应磺酰氯,过柱后得产物 0.262 g, 产率 50.77%, 纯度 (HPLC ) >97%o  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.262 g, the yield was 50.77%, and the purity (HPLC) was >97%.
Ή NMR (400MHz, CDCI3): δΙ .27-1.32 (m, 2H), 1.72-1.77 (m, 2H), 3.09-3.16 (m, 1H), 8.46(s, 1H), 8.90(s, 1H)。  NMR NMR (400MHz, CDCI3): δΙ .27-1.32 (m, 2H), 1.72-1.77 (m, 2H), 3.09-3.16 (m, 1H), 8.46(s, 1H), 8.90(s, 1H) .
ESI-MS (m/z, %): (M+Na)+ 280.98。 ESI-MS (m/z, %): (M+Na) + 280.98.
实施例 28 目标产物 6-氯 -9- (正丁基磺酰基) -9H-嘌呤 Example 28 Target product 6-chloro-9-(n-butylsulfonyl)-9H-oxime
Figure imgf000032_0001
Figure imgf000032_0001
按实施例 10的制备方法,将原料替换为 6-氯嘌呤与相应磺酰氯,过柱后得产物 0.195 g, 产率 35.58%, 纯度 (HPLC) ≥97%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.195 g, yield: 35.58%, purity (HPLC) ≥ 97%.
Ή NMR (400MHz, CDC13): 50.92 (t, J=7.2Hz, 3H, -CH3), 1.43-1.52 (m, 2H), 1.77-1.85 (m, 2H) , 3.78 (t, J=8.0Hz, 2H), 8.49(s, 1H), 8.91(s, 1H)。 NMR NMR (400MHz, CDC1 3 ): 50.92 (t, J=7.2Hz, 3H, -CH 3 ), 1.43-1.52 (m, 2H), 1.77-1.85 (m, 2H) , 3.78 (t, J=8.0 Hz, 2H), 8.49(s, 1H), 8.91(s, 1H).
ESI-MS (m/z, %): (M+H)+ 275.05。 ESI-MS (m/z, %): (M+H) + 275.05.
实施例 29 目标产物 9- (4-甲氧基苯 -9H-嘌呤 Example 29 Target product 9-(4-Methoxybenzene-9H-oxime
Figure imgf000032_0002
Figure imgf000032_0002
将 6-氯 -9- (4-甲氧基苯磺酰基) -9H-嘌呤 (实施例 11, 0.325 g, lmmol) 溶于四氢 呋喃(20mL) 中, 然后分三次 (反应开始后 0 h、 6 h、 12 h)向其中加入 5%钯碳, 回流状 态下反应 24h,过滤除去钯碳,滤液用硅胶过柱,得白色固体产物 0.063 g,产率 21.73%, 纯度 (HPLC) ≥96%。  6-Chloro-9-(4-methoxybenzenesulfonyl)-9H-indole (Example 11, 0.325 g, 1 mmol) was dissolved in tetrahydrofuran (20 mL) and then taken three times (0 h, 6 after the start of the reaction) h, 12 h) 5% palladium on carbon was added thereto, and the mixture was reacted under reflux for 24 hours. The palladium carbon was removed by filtration, and the filtrate was subjected to silica gel column chromatography to afford white crystals (yield: s.
lR NMR (400MHz, CDC13): 53.87 (s, 3H, -OCH3), 7.02 (d, J = 9.2Hz, 2H), 8.23(d, J = 9.2Hz, 2H), 8.55(s, 1H), 9.09(s, 1H) , 9.15(s, 1H)。 lR NMR (400MHz, CDC1 3 ): 53.87 (s, 3H, -OCH3), 7.02 (d, J = 9.2Hz, 2H), 8.23 (d, J = 9.2Hz, 2H), 8.55(s, 1H), 9.09(s, 1H), 9.15(s, 1H).
ESI-MS (m/z, %): (M+Na)+ 313.05。 ESI-MS (m/z, %): (M+Na) + 313.05.
实施例 30 目标产物 6-溴 -9- (4-甲氧 -9H-嘌呤 Example 30 Target product 6-bromo-9-(4-methoxy-9H-indole
Figure imgf000032_0003
按实施例 10的制备方法,将原料替换为 6-溴嘌呤与相应磺酰氯,过柱后得产物 0.041 g, 产率 15.91%, 纯度 (HPLC) ≥96%。
Figure imgf000032_0003
According to the preparation method of Example 10, the starting material was replaced with 6-bromoindole and the corresponding sulfonyl chloride, and the product obtained after the column was 0.041 g, the yield was 15.91%, and the purity (HPLC) was ≥96%.
Ή MR (400MHz, CDC13): 63.89 (s, 3H, -OCH3), 7.03 (d, J = 8.8Hz, 2H), 8.22(d, J = 8.8Hz, 2H), 8.59(s, 1H), 8.80(s, 1H)。 Ή MR (400MHz, CDC1 3 ): 63.89 (s, 3H, -OCH 3 ), 7.03 (d, J = 8.8Hz, 2H), 8.22 (d, J = 8.8Hz, 2H), 8.59(s, 1H) , 8.80(s, 1H).
ESI-MS (m/z, %): (M+H)+ 369.02。 ESI-MS (m/z, %): (M+H) + 369.02.
实施例 31 目标产物 6-碘 -9- (4-甲氧 -9H-嘌呤 Example 31 Target product 6-iodo-9-(4-methoxy-9H-oxime
Figure imgf000033_0001
Figure imgf000033_0001
按实施例 10的制备方法,将原料替换为 6-碘嘌呤与相应磺酰氯,过柱后得产物 0.133 g, 产率 31.97%, 纯度 (HPLC) ≥96%。  According to the preparation method of Example 10, the starting material was replaced with 6-iodonium and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.133 g, yield: 31.97%, purity (HPLC) ≥ 96%.
1H NMR (400MHz, CDCI3): 53.88 (s, 3H, -OCH3), 7.03 (d, J = 8.8Hz, 2H), 8.21(d, J = 8.8Hz, 2H), 8.58(s, 1H), 8.73(s, 1H)。 1H NMR (400MHz, CDCI3): 53.88 (s, 3H, -OCH 3 ), 7.03 (d, J = 8.8Hz, 2H), 8.21 (d, J = 8.8Hz, 2H), 8.58(s, 1H), 8.73 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 416.91。 ESI-MS (m/z, %): (M+H) + 416.91.
实施例 32 目标产物 6-甲氧基 -9- 基 -9H-噤呤 Example 32 Target product 6-Methoxy-9-yl-9H-indole
Figure imgf000033_0002
Figure imgf000033_0002
按实施例 10的制备方法, 将原料替换为 6-甲氧基嘌呤与相应磺酰氯, 过柱后得产 物 0.318 g, 产率 34.87%, 纯度 (HPLC)≥96%。  According to the preparation method of Example 10, the starting material was replaced with 6-methoxyanthracene and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in an amount of 0.318 g, the yield was 34.87%, and the purity (HPLC) was ≥96%.
Ή NMR (400MHz, DMSO- ): 62.39(s, 3H), 4.09(s, 3H), 7.51(d, J = 8.0Hz , 2H), 8.12(d, J= 8.4Hz, 1H), 8.66 (s, 1H), 8.87(s, 1H)。  NMR NMR (400MHz, DMSO-): 62.39 (s, 3H), 4.09 (s, 3H), 7.51 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.66 (s , 1H), 8.87(s, 1H).
ESI-MS (m/z, %): (M+H)+ 305.08。 ESI-MS (m/z, %): (M+H) + 305.08.
实施例 33 目标产物 6-二甲氨基 -9-对甲苯磺酰基 -9H-嘌呤
Figure imgf000034_0001
Example 33 Target product 6-dimethylamino-9-p-toluenesulfonyl-9H-oxime
Figure imgf000034_0001
按实施例 10的制备方法, 将原料替换为 6-二甲氨基嘌呤与相应磺酰氯, 过柱后得 产物 0.458 g, 产率 48.16%, 纯度 (HPLC) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-dimethylaminopurine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.458 g, yield 48.16%, purity (HPLC) ≥ 98%.
1H NMR (400MHz, DMSO-^)- 62.39(s, 3H), 3.60(s, 6H), 7.49(d, J = 8.0Hz, 2H), 8.08(d, J = 8.4Hz, 1H), 8.68 (s, 1H), 8.86(s, 1H)。  1H NMR (400MHz, DMSO-^) - 62.39 (s, 3H), 3.60 (s, 6H), 7.49 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 8.68 ( s, 1H), 8.86(s, 1H).
ESI-MS (m/z, %): (M+H)+ 318.12。 ESI-MS (m/z, %): (M+H) + 318.12.
实施例 34 目标产物 6-二乙胺基 -9- -9H-嘌呤 Example 34 Target product 6-Diethylamino-9--9H-oxime
Figure imgf000034_0002
Figure imgf000034_0002
按实施例 10的制备方法, 将原料替换为 6-二乙氨基嘌呤与相应磺酰氯, 过柱后得 产物 0.575 g, 产率 55.72%, 纯度 (HPLC) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-diethylaminopurine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.575 g, yield 55.72%, purity (HPLC) ≥ 98%.
1H NMR (400MHz, DMSO-i 6): 61.35(t, J = 6.8Hz, 6H), 2.39(s, 3H), 3.60(q, J = 6.8Hz, 4H, -NCH2 -), 7.52(d, J= 8.0Hz , 2H), 8.13(d, J= 8.4Hz, 1H), 8.67 (s, 1H), 8.88(s, 1H)。 1H NMR (400MHz, DMSO-i 6 ): 61.35 (t, J = 6.8Hz, 6H), 2.39(s, 3H), 3.60 (q, J = 6.8Hz, 4H, -NCH 2 -), 7.52(d , J = 8.0 Hz, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H), 8.88 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 345.25。 ESI-MS (m/z, %): (M+H) + 345.25.
实施例 35 目标产物 2,6-二氯 -9-对甲苯磺酰基 -9H-嘌呤 Example 35 Target product 2,6-Dichloro-9-p-toluenesulfonyl-9H-oxime
Figure imgf000034_0003
Figure imgf000034_0003
按实施例 10的制备方法, 将原料替换为 2,6-二氯嘌呤与相应磺酰氯, 过柱后得产 物 0.498 g, 产率 48.54%, 纯度 (HPLC) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 2,6-dichloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.498 g, yield 48.54%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, DMSO- 6): 62.39(s, 3H, -CH3), 7.51(d, J = 8.0Hz , 2H), 8.12(d, J = 8.4Hz, 2H), 8.72 (s, 1H)。 NMR NMR (400MHz, DMSO- 6 ): 62.39 (s, 3H, -CH 3 ), 7.51 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H), 8.72 (s, 1H) ).
ESI-MS (m/z, %): (M+H)+ 343.01。  ESI-MS (m/z, %): (M+H) + 343.01.
实施例 36 目标产物 2-氨基 -6-氯 -9-对甲苯磺酰基 -9H-噤呤
Figure imgf000035_0001
Example 36 Target product 2-amino-6-chloro-9-p-toluenesulfonyl-9H-oxime
Figure imgf000035_0001
按实施例 10的制备方法, 将原料替换为 2-氨基 6-氯嘌呤与相应磺酰氯, 过柱后得 产物 0.456 g, 产率 47.06%, 纯度 (HPLC)≥97。/0According to the preparation method of Example 10, the starting material was replaced with 2-amino 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained to be 0.456 g, the yield was 47.06%, and the purity (HPLC) was ≥97. / 0 .
Ή MR (400MHz, DMSO- ): 62.41(s, 3H), 7.42 (s, 2H, - H2), 7.5 l(d, J= 9.6Hz, 2H): 8.11 (d, J= 8.4Hz,2H),8.52(s, 1H)。 Ή MR (400MHz, DMSO- ): 62.41(s, 3H), 7.42 (s, 2H, - H 2 ), 7.5 l(d, J= 9.6Hz, 2H): 8.11 (d, J= 8.4Hz, 2H ), 8.52 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 324.06。  ESI-MS (m/z, %): (M+H)+ 324.06.
实施例 37 目标产物 6-吗啉基 -9-对甲苯磺酰基 -9H-嘌呤 Example 37 Target product 6-morpholinyl-9-p-toluenesulfonyl-9H-oxime
Figure imgf000035_0002
Figure imgf000035_0002
按实施例 10的制备方法, 将原料替换为 6-吗啉基嘌呤与相应磺酰氯, 过柱后得产 物 0.758g, 产率 70.38%, 纯度 (HPLC)≥99%。  According to the preparation method of Example 10, the starting material was replaced with 6-morpholinylfluorene and the corresponding sulfonyl chloride, and the product was subjected to a column yield of 0.758 g, yield 70.38%, purity (HPLC) ≥ 99%.
1H NMR (400MHz, DMSO-cfe): 62.39(s, 3H), 3.69(t, J = 4.8Hz , 4H), 4.15(sbr, 4H), 7.50(d, J= 8.4Hz, 2H), 8.08 (d, J= 8.4Hz, 2H), 8.33(s, IH), 8.68(s, 1H)。  1H NMR (400MHz, DMSO-cfe): 62.39 (s, 3H), 3.69 (t, J = 4.8 Hz, 4H), 4.15 (sbr, 4H), 7.50 (d, J = 8.4 Hz, 2H), 8.08 ( d, J = 8.4 Hz, 2H), 8.33 (s, IH), 8.68 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 360.18。 ESI-MS (m/z, %): (M+H) + 360.18.
实施例 38 目标产物 6-烯丙硫基 - - 呤 Example 38 Target product 6-allylthio- - hydrazine
Figure imgf000035_0003
Figure imgf000035_0003
按实施例 10的制备方法, 将原料替换为 6-炼丙硫基嘌吟与相应磺酰氯, 过柱后得 产物 0.421g, 产率 40.56%, 纯度 (HPLC)≥99%。  According to the preparation method of Example 10, the starting material was replaced with 6-propanylsulfonyl hydrazide and the corresponding sulfonyl chloride. After the column was passed, the product was obtained in a yield of 0.421 g, yield 40.56%, purity (HPLC) ≥ 99%.
lH NMR (400MHz, DMSO-i¾): 62.33 (s, 3H), 4.03 (d, J = 6.4Hz, 2H), 5.13 (d, J = 16.8Hz, IH), 5.91-5.99 (m, IH ), 7.52 (d, J= 8.0Hz, 2H), 8.12(d, J= 8.0Hz, 2H), 8.84(s, IH), 8.95(s, 1H)。 lH NMR (400MHz, DMSO-i3⁄4): 62.33 (s, 3H), 4.03 (d, J = 6.4Hz, 2H), 5.13 (d, J = 16.8Hz, IH), 5.91-5.99 (m, IH ), 7.52 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H), 8.84 (s, IH), 8.95 (s, 1H).
ESI-MS (m/z, %): (M+H)+ 347.12。 ESI-MS (m/z, %): (M+H) + 347.12.
实施例 39 目标产物 6-甲硫基 -9- -9H-嘌呤 Example 39 Target product 6-Methylthio-9--9H-oxime
Figure imgf000036_0001
Figure imgf000036_0001
按实施例 10的制备方法, 将原料替换为 6-甲硫基嘌呤与相应磺酰氯, 过柱后得产 物 0.789 g, 产率 82.19%, 纯度 (HPLC ) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-methylthioguanidine and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.789 g, yield: 82.19%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, CDC13): 52.43(s, 3H), 2.68(s, 3H), 7.36(d, J= 8.0Hz, 2H), 8.14 (d, J = 8.4Hz, 2H), 8.41(s, 1H), 8.80(s, 1H)。 NMR NMR (400MHz, CDC1 3 ): 52.43(s, 3H), 2.68(s, 3H), 7.36(d, J= 8.0Hz, 2H), 8.14 (d, J = 8.4Hz, 2H), 8.41(s , 1H), 8.80(s, 1H).
ESI-MS (m/z, %): (M+H)+ 321.09。 ESI-MS (m/z, %): (M+H) + 321.09.
实施例 40 目标产物甲基 3-(6-氯 -9H-嘌 -9-基磺酰基)噻吩 -2-羧酸酯 Example 40 Target product methyl 3-(6-chloro-9H-indol-9-ylsulfonyl)thiophene-2-carboxylate
Figure imgf000036_0002
Figure imgf000036_0002
按实施例 10 的制备方法, 将原料替换为 6-氯嘌呤与相应磺酰氯, 过柱后得产物 0.478g, 产率 44.51%, 纯度 (HPLC ) ≥98%。  According to the preparation method of Example 10, the starting material was replaced with 6-chloroindole and the corresponding sulfonyl chloride. After the column was passed, the product was obtained, 0.478 g, yield 44.51%, purity (HPLC) ≥ 98%.
Ή NMR (400MHz, DMSO-i/6): 63.80 (s, 3H), 7.96 (d, J= 5.6Hz, 1H), 8.18(d, J= 5.2Hz, 1H), 8.83(s, 1H), 9.14(s, 1H)。 NMR NMR (400MHz, DMSO-i/ 6 ): 63.80 (s, 3H), 7.96 (d, J = 5.6Hz, 1H), 8.18 (d, J = 5.2Hz, 1H), 8.83(s, 1H), 9.14(s, 1H).
ESI-MS (m/z, %): (M+H)+ 359.02。 药效学实验部分 ESI-MS (m/z, %): (M+H) + 359.02. Pharmacodynamics experimental part
试验例 化合物体外 HCV Replicon luciferase Assay和 HCV Replicon MTT Assay。 Test Examples Compounds in vitro HCV Replicon luciferase Assay and HCV Replicon MTT Assay.
HCV Replicon luciferase Assay是利用荧光素酶法测试化合物抗 HCV活性。 其原理 是将含有基因型 lb的 HCV NS3-NS5编码基因的亚基因组与荧光素酶编码基因融合而形 成的体外可感染的复制子系统, 通过电穿孔技术感染 Huh7.0细胞后, 该复制子系统可 在胞内复制, 通过测试细胞中荧光素酶活性从而可以确定 HCV复制子活性。 The HCV Replicon luciferase Assay is a compound that is tested for anti-HCV activity using the luciferase assay. The principle is to infect an in vitro infectious replication system formed by fusing a subgenome of the HCV NS3-NS5 encoding gene containing the genotype lb with a luciferase encoding gene, and infecting Huh7.0 cells by electroporation. System can In intracellular replication, HCV replicon activity can be determined by testing luciferase activity in cells.
后者则是通过 MTT方法测试活细胞数目而反应化合物在不同浓度下对 Huh7.0细胞 的毒性效应。 MTT是一种接受氣离子的黄色染料, 可作用于活细胞线粒体中的呼吸链, 在琥珀酸脱氢酶和细胞色素 C的作用下 tetrazolium环开裂,生成蓝色的甲瓒结晶, 甲瓒 结晶的生成量仅与活细胞数目成正比, 生成的甲瓒结晶在二甲亚砜 (DMSO) 中溶解, 利用酶标仪测定 570nm处的光密度 OD值, 即可反映出活细胞数目。  The latter is the toxic effect of the reactive compounds on Huh7.0 cells at different concentrations by measuring the number of viable cells by the MTT method. MTT is a yellow dye that accepts gas ions and acts on the respiratory chain in the mitochondria of living cells. Under the action of succinate dehydrogenase and cytochrome C, the tetrazolium ring is cracked to form blue formazan crystals. The amount of production is only proportional to the number of living cells. The formed formazan crystals are dissolved in dimethyl sulfoxide (DMSO), and the optical density OD value at 570 nm is measured by a microplate reader to reflect the number of living cells.
两测试得到的细胞半数致死量 CC50与 HCV半数抑制浓度 IC50的比值即为化合物 的安全指数, 该比值越大说明化合物越安全, 也可说明化合物对 HCV的抑制作用不是 源于其细胞毒性。  The half-lethal lethal dose of CC50 and HCV half-inhibitory concentration IC50 is the safety index of the compound. The larger the ratio, the safer the compound, and the inhibition of HCV by the compound is not due to its cytotoxicity.
表 1 为实施例 10-实施例 40化合物进行 HCV Replicon luciferase Assay禾卩 HCV Replicon MTT Assay结果:  Table 1 shows the results of HCV Replicon luciferase Assay and HCV Replicon MTT Assay for Example 10-Compound 40:
表 1  Table 1
Figure imgf000037_0001
实施例 25化合物 7.26 37.13 5.12
Figure imgf000037_0001
Example 25 Compound 7.26 37.13 5.12
实施例 26化合物 >100 >100 1  Example 26 Compound >100 >100 1
实施例 27化合物 43.74 >100 >2.29 实施例 28化合物 39.58 >100 >2.53 实施例 29化合物 49.93 >100 >2  EXAMPLE 27 Compound 43.74 >100 > 2.29 Example 28 Compound 39.58 >100 >2.53 Example 29 Compound 49.93 >100 >2
实施例 30化合物 7.84 75.86 9.68 实施例 31化合物 9.77 >100 >10.23 实施例 32化合物 >100 >100 1  EXAMPLE 30 Compound 7.84 75.86 9.68 Example 31 Compound 9.77 >100 >10.23 Example 32 Compound >100 >100 1
实施例 33化合物 >100 >100 1  Example 33 Compound >100 >100 1
实施例 34化合物 >100 >100 1  Example 34 Compound >100 >100 1
实施例 35化合物 98.4 96.9 1  Example 35 Compound 98.4 96.9 1
实施例 36化合物 74.3 >100 >1.5 实施例 37化合物 >100 >100 1  Example 36 Compound 74.3 > 100 > 1.5 Example 37 Compound > 100 > 100 1
实施例 38化合物 >100 >100 1  Example 38 Compound >100 >100 1
实施例 39化合物 >100 >100 1  Example 39 Compound >100 >100 1
实施例 40化合物 3.851 31.92 8.29 由上表可以看出, 对照物 CSA与 Clemizole测试结果均处于正常范围, 从测试数据 可以看出, 实施例 11化合物、实施例 13化合物、实施例 22化合物、实施例 23化合物、 实施例 40化合物在低微摩尔浓度下均具有较好的 HCV抑制能力, 而细胞毒性较低。并 且化合物对 HCV的抑制作用具有剂量依赖性, 见图 1-图 5。  Example 40 Compound 3.851 31.92 8.29 As can be seen from the above table, the control CSA and Clemizole test results are in the normal range. As can be seen from the test data, the compound of Example 11, the compound of Example 13, the compound of Example 22, and the examples The compound of Example 23 and the compound of Example 40 had good HCV inhibitory ability at low micromolar concentrations, and the cytotoxicity was low. Furthermore, the inhibitory effect of the compound on HCV was dose dependent, see Figure 1 - Figure 5.
随后, 我们研究了活性化合物实施例 11化合物、 实施例 13化合物、 实施例 22化 合物、 实施例 23化合物、 实施例 40化合物在部分常用溶剂中的溶解性, 发现这些化合 物在非极性溶剂二氯甲烷及氯仿中溶解性较好 (溶解度>1000 8 11^), 在乙酸乙酯中能 溶解(溶解度>5mg/mL),而在乙醇或甲醇等醇类溶剂中溶解性稍差(溶解度 <5mg/mL)。 在剂型制备过程中, 我们发现这类化合物在受试剂型 PEG400/乙醇 (V/V=80/20) 溶液 中的饱和溶解度〉^^^!!^, 在受试剂型 PEG400/水(V/V=80/20)溶液中的饱和溶解度 >3mg/mL (化合物 SKLB-HCV-75、 76未进行上述测定)。 Subsequently, we investigated the solubility of the active compound of Example 11 compound, the compound of Example 13, the compound of Example 22, the compound of Example 23, and the compound of Example 40 in some common solvents, and found that these compounds are in a non-polar solvent Good solubility in methane and chloroform (solubility >100 0 8 11^), soluble in ethyl acetate (solubility >5mg/mL), and slightly less soluble in alcohol solvents such as ethanol or methanol (solubility < 5 mg / mL). During the preparation of the dosage form, we found that the saturation solubility of this compound in the reagent type PEG400/ethanol (V/V=80/20) solution is ^^^^!!^, in the reagent type PEG400/water (V/ V = 80/20) Saturated solubility in solution > 3 mg/mL (Compound SKLB-HCV-75, 76 was not subjected to the above measurement).
接下来, 我们在 SD大鼠体内对实施例 23化合物进行了初步的急性毒性试验, (给 药量: 2g/kg, 观察两周后解剖并 HE染色), 大鼠在两周的观察中未表现出明显的毒性 反应, HE染色未发现明显异常。 Next, we performed a preliminary acute toxicity test on the compound of Example 23 in SD rats (administered amount: 2 g/kg, observed after two weeks of anatomy and HE staining), and the rats were not observed in two weeks. Shows significant toxicity Reaction, no significant abnormalities were found in HE staining.
综上所述, 上述活性化合物对 HCV具有较强的抑制作用, 且部分化合物细胞毒性 较低, 选择性指数较高。 另外, 本发明所述的 9-磺酰基 -9H-嘌呤衍生物的制备方法具有 反应条件温和、原料丰富易得,操作及后处理简单、总产率较高、环境污染较小等优点。  In summary, the above active compounds have a strong inhibitory effect on HCV, and some compounds have low cytotoxicity and a high selectivity index. In addition, the preparation method of the 9-sulfonyl-9H-indole derivative according to the present invention has the advantages of mild reaction conditions, abundant raw materials, easy operation and post-treatment, high total yield, and low environmental pollution.

Claims

权利要求书 Claim
1、 9-磺酰基 -9H-嘌呤衍生物, 结构如式 I所示: 1, 9-sulfonyl-9H-indole derivative, the structure is as shown in formula I:
V。 I 1 V. I 1
I I
其中, R〜R3独立的为 -H、 -F、 -CK -Br、 -1、 -N3、 -CF3、 -N¾、 -N0、 C1〜C8 烷基、 C3〜C8环烷基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 †N。0、Wherein R to R 3 are independently -H, -F, -CK -Br, -1, -N 3 , -CF 3 , -N3⁄4, -N0, C1 to C8 alkyl, C3 to C8 cycloalkyl, C1~C8 decyloxy, C1~C8 fluorenyl substituted amine group, †N. 0,
Figure imgf000040_0001
或 C1〜C8垸硫基;
Figure imgf000040_0001
Or C1~C8 thiol;
Rl2wR 1 R15丫 s Rl2 w R 1 R 15丫s
R4为 R9Rl3 、 ^¾ ^、 Ύ N 、苄基、 C 1C8垸基或 C3R4 is R9, Rl3, ^ ¾ ^, Ύ N, a benzyl group, C 1 ~ C8 alkyl with or C3 ~
C8环垸基; C8 ring thiol;
R5〜R7独立的为 -H、 -F、 -CK -Br、 -NH2、 -N02、 -N3、 -CF3、 C3〜C8环烷基或 Cl~R 5 to R 7 are independently -H, -F, -CK -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cycloalkyl or Cl~
C8 某: C8:
R8〜R15独立的为 -H、 -F、 -CK -Br、 - H2、 -N02、 -N3、 -CF3、 带 R16取代基的 Cl〜 C8垸基、 带 R16取代基的 C3〜C8环烷基、 带 R16取代基的 C1〜C8烷基取代氧羰基、 带 R16取代基的 C3〜C8环垸基取代氧羰基、 带 R16取代基的 C1〜C8烷氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; R 8 ~R 15 is independently -H, -F, -CK -Br, - H 2, -N0 2, -N 3, -CF 3, with R 16 Cl~ C8 alkyl with a substituent, with R 16 C3~C8 cycloalkyl group, substituted with R 16 C1~C8 alkyl group substituted oxycarbonyl group, C3~C8 cycloalkyl with R 16 substituted alkyl with a substituted oxycarbonyl group, substituted with R 16 group C1~C8 An alkoxy group or a ring skeleton having a substituent of R 16 is an aromatic ring group of 3 to 8 carbon atoms;
R16为 -H、 C1〜C8烷基、 - H2、 -N02、 -N3、 -F、 -CK -Br、 -CF3 C1〜C8烷氧基、 C3〜C8环垸基或 C1〜C8垸基取代胺基。 R 16 is -H, C1 to C8 alkyl, -H 2 , -N0 2 , -N 3 , -F, -CK -Br, -CF 3 C1 to C8 alkoxy, C3 to C8 cyclodecyl or C1 ~C8 thiol substituted amine group.
2、 根据权利要求 1所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于: 〜 独立的为 -H、 -F、 -CK -Br、 -N3、 -CF3、 -N¾、 -N02、 C1〜C8垸基、 C3〜 k ^Re The 9-sulfonyl-9H-indole derivative according to claim 1, wherein: - independently, -H, -F, -CK-Br, -N 3 , -CF 3 , -N3⁄4, -N0 2 , C1~C8 垸 base, C3~ k ^ Re
C8环烷基、 C1〜C8垸氧基、 C1〜C8垸基取代胺基、 N Q、 ^ R7或 C1〜C8 垸硫基;
Figure imgf000040_0002
为 R5〜R7独立的为 -H、 -F、 -Cl、 -Br、 -N 、 -N02、 -N3、 -CF3、 C3〜C8环垸基或 Cl〜 C8垸基;
C8 cycloalkyl, C1~C8 decyloxy, C1~C8 fluorenyl substituted amine, NQ , ^ R7 or C1~C8 thiol;
Figure imgf000040_0002
for R 5 to R 7 are independently -H, -F, -Cl, -Br, -N, -N0 2 , -N 3 , -CF 3 , C3 to C8 cyclodecyl or Cl to C8 fluorenyl;
Rs~R15独立的为 -H、 -F、 -Cl、 -Br、 -NH2、 -N02、 -N3、 -CF3、 带 R16取代基的 Cl〜 C8垸基、 带 R16取代基的 C3~C8环垸基、 带 R16取代基的 C1〜C8烷基取代氧羰基、 带 R16取代基的 C3〜C8环垸基取代氧羰基、 带 R16取代基的 C1〜C8烧氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; Rs ~ R 15 is independently -H, -F, -Cl, -Br, -NH 2, -N0 2, -N 3, -CF 3, with Cl~ C8 alkyl with a substituent R 16, with R 16 a C3~C8 cyclodecyl group of a substituent, a C1~C8 alkyl group substituted with an R 16 substituent, an oxycarbonyl group, a C3~C8 cyclodecyl group having an R 16 substituent, an oxycarbonyl group, and a C1 to C8 group having an R 16 substituent. An alkoxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
R16为 -H、 C1〜C8烷基、 -NH2、 -N02、 -N3、 -F、 -Cl、 -Br、 -CF3、 C1〜C8垸氧基、 C3〜C8环垸基或 C1〜C8垸基取代胺基。 R 16 is -H, C1 to C8 alkyl, -NH 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 cyclodecyl Or a C1~C8 thiol group substituted with an amine group.
3、 根据权利要求 2所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  3. The 9-sulfonyl-9H-indole derivative according to claim 2, which is characterized in that:
1^为-11、 C1〜C8垸基或 C3〜C8环垸基;  1^ is -11, C1~C8 thiol or C3~C8 fluorenyl;
R2、 R3为 -H、 -F、 -CK -Br、 -N3、 -N¾、 -N02、 C1〜C8垸基、 C3〜C8环垸基、 R 2 and R 3 are -H, -F, -CK -Br, -N 3 , -N3⁄4, -N0 2 , C1 to C8 fluorenyl, C3 to C8 cyclodecyl,
C1〜C8垸氧基、 C1〜C8烷基取代胺基、 N^、 ^ R7或 C1〜C8垸硫基; R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8烷基; C1~C8 methoxy, C1~C8 alkyl substituted amine, N ^, ^ R7 or C1~C8 thiol; R 5 〜R 7 are independently -H, C3~C8 cyclodecyl or C1~C8 alkyl;
〜R15独立的为 -H、 C1〜C8烷基、 C1〜C8烷氧基、 -N02、 苯基、 C1〜C8垸基 取代氧羰基、 C3〜C8环烷基取代氧羰基或 -CF3~ R 15 is independently -H, C1 to C8 alkyl, C1 to C8 alkoxy, -N0 2 , phenyl, C1 to C8 alkyl substituted oxycarbonyl, C3~C8 cycloalkyl substituted oxycarbonyl or -CF 3 .
4、 根据权利要求 3所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  4. The 9-sulfonyl-9H-indole derivative according to claim 3, which is characterized in that:
Ri为 -H、 C1〜C8垸基或 C3〜C8环烷基;  Ri is -H, C1~C8 fluorenyl or C3~C8 cycloalkyl;
R2、 R3为- H、 -F、 -CK -Br、 -N3、 -NH2、 -N02、 C1〜C8烷基、 C3〜C8环垸基、 R 2, R 3 is - H, -F, -CK -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl, C3~C8 cycloalkyl group embankment,
C1 ~C8垸氧基、 C1〜C8垸基取代胺基、 Ν^、 ^ R7或 C1〜CS垸硫基; R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8垸基; C1 ~ C8 decyloxy, C1~C8 fluorenyl substituted amine, Ν ^, ^ R7 or C1~CS thiol; R 5 〜R 7 independently -H, C3~C8 cyclodecyl or C1~C8垸基;
R8〜R12独立的为 -H、 C1〜C8焼基、 C1〜C8垸氧基、 -N02、 苯基或 -CF3 ; R 8 to R 12 are independently -H, C1 to C8 fluorenyl, C1 to C8 decyloxy, -N0 2 , phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C8烷基或 C1〜C8垸基取代氧羰基。 R 13 to R 15 are independently -H, C1 to C8 alkyl or C1 to C8 mercapto substituted oxycarbonyl.
5、 根据权利要求 4所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 为-11或。1〜€4垸基;  The 9-sulfonyl-9H-indole derivative according to Claim 4, wherein - is -11 or. 1 to €4 垸 base;
R2为 -H、 -F、 -CK -Br、 -N3、 -NH2、 C1~C4烷基、 C1〜C4烷氧基、 C1〜C4垸基 取代胺基、 †N3D、 ^^<^或 C1〜C4烷硫基; R 2 is -H, -F, -CK -Br, -N 3 , -NH 2 , C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4 alkyl substituted amine, †N3D, ^^< ^ or C1~C4 alkylthio;
R3为 -H、 -F、 -CK -Br、 C1〜C4烷基或 -ΝΉ2; R5〜R7独立的为 -H或 C1〜C4垸基; R 3 is -H, -F, -CK -Br, C1 to C4 alkyl or -ΝΉ 2 ; R 5 to R 7 are independently -H or C1 to C4 fluorenyl;
Rs〜R12独立的为 -H、 C1〜C4浣基、 C1〜C4垸氧基、 -N02、 苯基或 -CF3 ; Rs~R 12 are independently -H, C1~C4 fluorenyl, C1~C4 decyloxy, -N0 2 , phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C4烷基取代氧羰基或 C1〜C4垸基。 R 13 to R 15 are independently -H, C1 to C4 alkyl substituted oxycarbonyl or C1 to C4 fluorenyl.
6、 根据权利要求 5所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 6. The 9-sulfonyl-9H-indole derivative according to claim 5, characterized in that -
1^为-11或 1〜€4烷基; 1^ is -11 or 1~€4 alkyl;
R2为 -H、 -F、 -Cl、 -Br、 -N3、 C1〜C4垸基、 C1〜C4烷氧基、 C1~C4烷基取代胺 基、 —^(^0、 ^-^ ^或 C1〜C4垸硫基; R 2 is -H, -F, -Cl, -Br, -N 3 , C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4 alkyl substituted amine, -^(^ 0 , ^-^ ^ or C1 ~ C4 thiol;
R3为 -H、 -F、 -Cl、 -Br或 C1〜C4烷基; R 3 is -H, -F, -Cl, -Br or C1 to C4 alkyl;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
Rs〜R12独立的为 C1〜C4烷基、 C1〜C4烷氧基、 苯基或 -CF3 ; Rs~R 12 are independently C1~C4 alkyl, C1~C4 alkoxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或 C1〜C4烷基取代氧羰基。 R 13 to R 15 are independently an -H or a C1 to C4 alkyl group substituted with an oxycarbonyl group.
7、 根据权利要求 4所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  7. The 9-sulfonyl-9H-indole derivative according to claim 4, which is characterized in that:
为-11或 C1〜C4垸基;  Is -11 or C1~C4 sulfhydryl;
R2为- H、 -F、 -C -Br, -NH2、 -N3、 C1〜C4烷基、 C1〜C4烷氧基、 C1〜C4垸基 取代胺基、 †N3D、 ^^^^或 〜。 垸硫基; ;
Figure imgf000042_0001
R 2 is -H, -F, -C -Br, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4 alkyl substituted amine, †N3D, ^^^ ^ or ~. Thiothio group;
Figure imgf000042_0001
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
R8〜R12独立的为 -H、 -N02、 CI C4院基、 C1〜C4烷氧基、 苯基或 -CF3 ; R 8 to R 12 are independently -H, -N0 2 , CI C4, C1 to C4 alkoxy, phenyl or -CF 3 ;
独立的为 -H或 C1〜C4  Independent -H or C1~C4
其中不包括化合物
Figure imgf000042_0002
Figure imgf000043_0001
o
Which does not include compounds
Figure imgf000042_0002
Figure imgf000043_0001
o
8、 根据权利要求 7所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 8. The 9-sulfonyl-9H-indole derivative according to claim 7, wherein -
Ri为 -H; Ri is -H;
R2为 -H、 -F、 -Cl、 -Br, -N¾、 -N3、 甲基、 C1〜C4垸氧基、 C1〜C4垸基取代胺 基、 t^J 、 S R 7或甲硫基; R 2 is -H, -F, -Cl, -Br, -N3⁄4, -N 3 , methyl, C1~C4 decyloxy, C1~C4 fluorenyl substituted amine, t^J, SR 7 or methyl sulfide base;
为-11、 - H2或 -C1; Is -11, - H 2 or -C1;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
R8〜Ri2独立的为 -H、 -N02、 C1〜C4垸基、 C1 ~C4垸氧基、 苯基或 -CF3 ; R 8 to Ri 2 are independently -H, -N0 2 , C1 to C4 fluorenyl, C1 to C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或甲基取代氧羰基。 R 13 to R 15 are independently -H or methyl substituted oxycarbonyl.
9、 根据权利要求 1所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 9. The 9-sulfonyl-9H-indole derivative according to claim 1, wherein -
C1〜C8垸基或 C3〜C8环烷基; C1~C8 thiol or C3~C8 cycloalkyl;
R2、 R3为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 -N02、 C1〜C8烷基、 C3〜C8环烷基、 R 2 and R 3 are -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , -N0 2 , C1 to C8 alkyl, C3 to C8 cycloalkyl,
C1〜C8烷氧基、 C1〜C8烷基取代胺基、
Figure imgf000043_0002
R7或 C1〜C8烧硫基;
C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group,
Figure imgf000043_0002
R7 or C1~C8 sulfur-burning base;
Figure imgf000043_0003
、苄基、 C1〜C4垸基或 C3-
for
Figure imgf000043_0003
, benzyl, C1~C4 thiol or C3-
C6环垸基; C6 ring thiol;
1 5〜 独立的为 -H、 C3〜C8环垸基或 C1〜C8烷基; 1 5 〜 is independently -H, C3~C8 cyclodecyl or C1~C8 alkyl;
Rs〜R15独立的为 -H、 -N02、 C1〜C8烧基、 C1〜C8垸氧基、 苯基、 C1〜C8垸基 取代氧羰基、 C3〜C8环烷基取代氧羰基或 -CF3 ; Rs~R 15 are independently -H, -N0 2 , C1~C8 alkyl, C1~C8 decyloxy, phenyl, C1~C8 fluorenyl substituted oxycarbonyl, C3~C8 cycloalkyl substituted oxycarbonyl or - CF 3 ;
Figure imgf000043_0004
Figure imgf000044_0001
Figure imgf000043_0004
Figure imgf000044_0001
10、 根据权利要求 9所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9H-indole derivative according to claim 9, which is characterized in that:
Rs〜R12独立的为 -H、 -N02、 C1〜C8垸基、 C1〜C8垸氧基、 苯基或 -CF3 ; Rs~R 12 are independently -H, -N0 2 , C1~C8 fluorenyl, C1~C8 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C8烷基或 C1〜C8垸基取代氧羰基。 R 13 to R 15 are independently -H, C1 to C8 alkyl or C1 to C8 mercapto substituted oxycarbonyl.
11、 根据权利要求 10所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于: The 9-sulfonyl-9H-indole derivative according to claim 10, which is characterized in that:
为-11或 1〜€4烷基;  -11 or 1 to €4 alkyl;
R2为 -H、 -F、 -Cl、 -Br、 -1、 - H2、 -N3、 C1〜C4垸基、 C1〜C4垸氧基、 C1〜C4 R 2 is -H, -F, -Cl, -Br, -1, -H 2 , -N 3 , C1 to C4 fluorenyl, C1 to C4 decyloxy, C1 to C4
R R  R R
垸基取代胺基、 †NQD 、 ^J^R 或 C1〜C4垸硫基; Mercapto substituted amine, †NQD, ^J^ R or C1~C4 thiol;
R3为- H、 -F、 -CK -Br、 -NH2或 C1〜C4烷基; R 3 is -H, -F, -CK -Br, -NH 2 or C1 to C4 alkyl;
R5〜R7独立的为 -H或 C1~C4烷基; R 5 to R 7 are independently -H or C1 to C4 alkyl;
Ri!〜 R12独立的为 -H、 -N02、 C1〜C4烷基、 C1〜C4垸氧基、 苯基或 -CF3 ; Ri! ~ R 12 is independently -H, -N0 2 , C1 to C4 alkyl, C1 to C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C4烷基取代氧羰基或 C1〜C4垸基。 R 13 to R 15 are independently -H, C1 to C4 alkyl substituted oxycarbonyl or C1 to C4 fluorenyl.
12、 根据权利要求 11所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于-The 9-sulfonyl-9H-indole derivative according to claim 11, which is characterized in that -
Ri为 -H; Ri is -H;
R3为 -H、 -F、 -CK -Br -NH2; R 3 is -H, -F, -CK -Br -NH 2 ;
^为
Figure imgf000044_0002
、苄基、 C1〜C4垸基或 C3〜
^为
Figure imgf000044_0002
, benzyl, C1~C4 thiol or C3~
C4环垸基; C4 ring thiol;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
R13〜R15独立的为 -H或 C1~C4烷基取代氧羰基。 R 13 to R 15 are independently an -H or a C1 to C4 alkyl group substituted with an oxycarbonyl group.
13、 根据权利要求 12所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于: (此项不能享受优 先权) The 9-sulfonyl-9H-indole derivative according to Claim 12, which is characterized in that: (This item does not enjoy the priority)
R2为 -H、 -F、 -CK -Br、 -1、 -NH2、 -N3、 甲基、 C1〜C4烷氧基、 C1〜C4垸基取代 胺基、 †Nu。 、
Figure imgf000044_0003
或甲硫基; R3为- H、 - H2或 -CI;
R 2 is -H, -F, -CK -Br, -1, -NH 2 , -N 3 , methyl, C1 to C4 alkoxy, C1 to C4 mercapto substituted amino group, †N u. ,
Figure imgf000044_0003
Or methylthio; R 3 is -H, -H 2 or -CI;
Rs〜R12独立的为 -H、 -N02、 C1〜C4浣基、 C1〜C4烷氧基、 苯基或 -CF3 ; Rs~R 12 are independently -H, -N0 2 , C1~C4 fluorenyl, C1~C4 alkoxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或甲基取代氧羰基。 R 13 to R 15 are independently -H or methyl substituted oxycarbonyl.
14、根据权利要求 1所述的 9-磺酰基 -9H-嘌呤衍生物,其特征在于: R4为The 9-sulfonyl-9H-indole derivative according to claim 1, wherein R4 is
Figure imgf000045_0001
Figure imgf000045_0001
结构如式 II所示: The structure is as shown in Equation II:
Figure imgf000045_0002
其中, 〜 独立的为 -H、 -F、 -Cl、 -Br、 -1、 -N3、 -CF3、 -NH2、 -N02、 C1〜C8 垸基、 C3〜C8环垸基、 C1〜C8烷氧基、 C1〜C8烷基取代胺基、 · ·Ν。0、 ^^ =<^ 或 C1〜C8垸硫基;
Figure imgf000045_0002
Wherein ~ is independently -H, -F, -Cl, -Br, -1, -N 3, -CF 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl group embankment, C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group, · · hydrazine. 0, ^^ =<^ or C1~C8 thiol;
R5〜R7独立的为 -H、 -F、 -Cl、 -Br、 -NH2、 -N02、 -N3、 -CF3、 C3〜C8环烷基或 Cl〜 C8烷基; R 5 to R 7 are independently -H, -F, -Cl, -Br, -NH 2 , -N0 2 , -N 3 , -CF 3 , C3 to C8 cycloalkyl or Cl to C8 alkyl;
R8〜Ri2独立的为 -H、 -F、 -Cl、 -Br、 - H2、 -N02、 -N3、 -CF3、带 R16取代基的 Cl〜 C8烷基、 带 R16取代基的 C3~C8环烷基、 带 R16取代基的 C1〜C8垸基取代氧羰基、 带 R16取代基的 C3〜C8环垸基取代氧羰基、 带 R16取代基的 C1〜C8烷氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基: R 8 to Ri 2 are independently -H, -F, -Cl, -Br, -H 2 , -N0 2 , -N 3 , -CF 3 , Cl to C8 alkyl group having an R 16 substituent, and R 16 C3 ~ C8 cycloalkyl group, optionally substituted with R 16 C1~C8 alkyl with a substituted oxycarbonyl group, C3~C8 cycloalkyl with R 16 substituted alkyl with a substituted oxycarbonyl group, substituted with R 16 group C1~C8 The alkoxy group or the ring skeleton having the R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms:
R16为 -H、 C1〜C8垸基、 -NH2、 -N02、 -N3、 -F、 -Cl、 -Br. -CF3、 C1〜C8垸氧基、 C3〜C8环烷基或 C1〜C8烷基取代胺基。 R 16 is -H, C1 to C8 fluorenyl, -NH 2 , -N0 2 , -N 3 , -F, -Cl, -Br. -CF 3 , C1 to C8 decyloxy, C3 to C8 cycloalkyl Or a C1~C8 alkyl substituted amine group.
15、 根据权利要求 14所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9H-indole derivative according to claim 14, which is characterized in that:
〜 独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -CF3、 -NH2、 -N02、 C1〜C8垸基、 C3〜 ~ Is independently -H, -F, -Cl, -Br, -N 3, -CF 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~
C8环垸基、 C1〜C8垸氧基、 C1〜C8烷基取代胺基、 †N。0、 ^或 C1〜C8 院硫基; C8 cyclodecyl, C1~C8 decyloxy, C1~C8 alkyl substituted amine, †N. 0, ^ or C1~C8 hospital sulfur base;
R5〜R7独立的为 -H、 -F、 -Cl、 -Br、 -N¾、 -N02、 -N3、 -CF3、 C3-C8环烷基或 Cl〜 C8烷基; R 5 to R 7 are independently -H, -F, -Cl, -Br, -N3⁄4, -N0 2 , -N 3 , -CF 3 , C3-C8 cycloalkyl or Cl~ C8 alkyl;
Rs〜R12独立的为 -H、 -F、 -Cl、 -Br、 -N¾、 -N02、 -N3、 -CF3、 带 R16取代基的 Cl〜 C8垸基、 带 R16取代基的 C3〜C8环烷基、 带 R16取代基的 C1〜C8垸基取代氧羰基、 带 R16取代基的 C3〜C8环烷基取代氧羰基、 带 R16取代基的 C 1〜C8垸氧基或带 R16取 代基的环骨架为 3〜8个碳原子的芳环基; Rs~R 12 is independently -H, -F, -Cl, -Br, -N¾, -N0 2, -N 3, -CF 3, with R 16 Cl~ C8 alkyl with a substituent, substituted with R 16 a C3~C8 cycloalkyl group of the group, a C1~C8 alkyl group substituted with an R 16 substituent, an oxycarbonyl group, a C3 to C8 cycloalkyl group having an R 16 substituent, an oxycarbonyl group, and a C 1 to C8 group having an R 16 substituent; a fluorenyloxy group or a ring skeleton having an R 16 substituent is an aromatic ring group of 3 to 8 carbon atoms;
R16为 -H、 C1〜C8垸基、 -NH2、 -N02、 -N3、 -F、 -Cl、 -Br、 -CF3、 C1〜C8垸氧基、 C3〜C8环垸基或 C 1〜C8烷基取代胺基。 R 16 is -H, C1 to C8 fluorenyl, -NH 2 , -N0 2 , -N 3 , -F, -Cl, -Br, -CF 3 , C1 to C8 decyloxy, C3 to C8 cyclodecyl Or a C 1 -C8 alkyl substituted amine group.
16、 根据权利要求 15所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9H-indole derivative according to claim 15, wherein:
为-11、 C 1〜C8垸基或 C3〜C8环烷基;  Is -11, C 1~C8 fluorenyl or C3~C8 cycloalkyl;
R2、 R3为 -H、 -F、 -Cl、 -Br、 -N3、 - H2、 -N02、 C 1〜C8垸基、 C3〜C8环垸基、 R 2 and R 3 are -H, -F, -Cl, -Br, -N 3 , -H 2 , -N0 2 , C 1 to C8 fluorenyl, C3 to C8 cyclodecyl,
R5 R6 R 5 R 6
C 1〜C8烷氧基、 C1〜C8垸基取代胺基、 tN Q、 "V? 或 C1〜C8垸硫基;a C 1 -C8 alkoxy group, a C1 to C8 alkyl group-substituted amine group, t NQ , "V? or a C1 to C8 thiol group;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8垸基; R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl;
¾〜R12独立的为 -H、 C 1〜C8焼基、 C1〜C8垸氧基、 -N02、 苯基或 -CF33⁄4 to R 12 are independently -H, C 1 to C8 fluorenyl, C1 to C8 decyloxy, -N0 2 , phenyl or -CF 3 .
17、 根据权利要求 16所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 为1^或。1〜04垸基;  The 9-sulfonyl-9H-indole derivative according to claim 16, wherein - is 1 or. 1 to 04 垸 base;
R2为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 C卜 C4烷基、 C卜 C4烷氧基、 C1〜C4垸基 取代胺基、 ·ΐ{^0、 ^或 C1〜C4垸硫基; R 2 is -H, -F, -Cl, -Br, -N 3 , -NH 2 , CBu C4 alkyl, CBu C4 alkoxy, C1~C4 mercapto substituted amine, ·ΐ{^0 , ^ or C1 ~ C4 thiol;
R3为 -H、 -F、 -Cl、 -Br、 C 1〜C4烷基或 -NH2; R 3 is -H, -F, -Cl, -Br, C 1 -C4 alkyl or -NH 2 ;
R5~R7独立的为 -H或 C1〜C4垸基; R 5 to R 7 are independently -H or C1 to C4 fluorenyl;
R8〜R12独立的为 -H、 C 1〜C4烷基、 C1〜C4垸氧基、 -N02、 苯基或 -CF3R 8 to R 12 are independently -H, C 1 to C 4 alkyl, C 1 to C 4 decyloxy, -N 2 2 , phenyl or -CF 3 .
】8、 根据权利要求 14所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于- 8. The 9-sulfonyl-9H-indole derivative according to claim 14, wherein -
R1为-H、 C 1〜C8烷基或 C3〜C8环烷基; R 1 is -H, C 1 -C8 alkyl or C3 to C8 cycloalkyl;
R2、 R3为 -H、 -F -Cl、 -Br、 -1、 - H2、 -N3、 -N02、 C1〜C8垸基、 C3〜C8环垸基、 R 2 and R 3 are -H, -F -Cl, -Br, -1, -H 2 , -N 3 , -N0 2 , C1 to C8 fluorenyl, C3 to C8 cyclodecyl,
C 1〜C8烷氧基、 C 1〜C8垸基取代胺基、 ^Ν、_^0、 ^ R7或 C1〜C8垸硫基; R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8烷基; C 1 -C8 alkoxy, C 1~C8 decyl substituted amine, ^ Ν , _^0, ^ R7 or C1~C8 thiol; R 5 〜R 7 are independently -H, C3~C8 ring Alkyl or C1 to C8 alkyl;
Rs〜R12独立的为 -H、 -N02、 C1〜C8烷基、 C 1〜C8烷氧基、 苯基或 -CF3 ;
Figure imgf000047_0001
Rs~R 12 are independently -H, -N0 2 , C1~C8 alkyl, C 1~C8 alkoxy, phenyl or -CF 3 ;
Figure imgf000047_0001
19、 根据权利要求 18所述的 9-磺酰基 -9Η-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9Η-indole derivative according to claim 18, which is characterized in that:
为11或 C1〜C4垸基;  Is 11 or C1~C4 thiol;
R2为 -H、 -F、 -Cl、 -Br、 -1、 -NH2、 -N3、 C1〜C4烷基、 C1〜C4垸氧基、 C1〜C4 垸基取代胺基、 †N: ;0、 S_ =<R:或 C1〜C4垸硫基; R 2 is -H, -F, -Cl, -Br, -1, -NH 2 , -N 3 , C1 to C4 alkyl, C1 to C4 decyloxy, C1 to C4 decyl substituted amine, †N : ; 0, S _ = < R : or C1 ~ C4 thiol;
R3为 -H、 -F、 -Cl、 -Br、 -NH2或 C1〜C4垸基; R 3 is -H, -F, -Cl, -Br, -NH 2 or C1 to C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4垸基; R 5 to R 7 are independently -H or C1 to C4 fluorenyl;
2独立的为-11、 -N02、 C1~C4烷基、 C1〜C4烷氧基、 苯基或 -CF32 independently is -11, -N0 2 , C1 to C4 alkyl, C1 to C4 alkoxy, phenyl or -CF 3 .
20、 根据权利要求 19所述的 9-磺酰基 -9H-嘌昤衍生物, 其特征在于: The 9-sulfonyl-9H-indole derivative according to claim 19, which is characterized in that:
Ri为 -H;  Ri is -H;
R2为 -H、 -F、 -Cl、 -Br、 -1、 -N¾、 -N3、 甲基、 C1〜C4垸氧基、 C1〜C4烷基取代 R 2 is -H, -F, -Cl, -Br, -1, -N3⁄4, -N 3 , methyl, C1 to C4 methoxy, C1 to C4 alkyl
R R  R R
胺基、 †N^O、 s >= ^或甲硫基; Amine group, †N^O, s >= ^ or methylthio group;
R3为- H、 - H2或 -C1; R 3 is -H, -H 2 or -C1;
R5〜R7独立的为 -H; R 5 to R 7 are independently -H;
R8〜R12独立的为 -H、 -N02、 C1〜C4焼基、 C1〜C4烷氧基、 苯基或 -CF3R8~R 12 is independently -H, -N0 2, C1~C4 firing group, C1~C4 alkoxy, phenyl, or -CF 3.
21、根据权利要求 1所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于: 为-11, 其结构如 式 III所示:
Figure imgf000048_0001
The 9-sulfonyl-9H-indole derivative according to claim 1, which has a structure of -11 and a structure of the formula III:
Figure imgf000048_0001
其中, R2为卤素; Wherein R 2 is a halogen;
R3为 -H、 卤素或 -NH2 R 3 is -H, halogen or -NH 2
R4为
Figure imgf000048_0002
苄基、 C1〜C4烷基或 C3
R4 is
Figure imgf000048_0002
Benzyl, C1 to C4 alkyl or C3
C6环垸基; C6 ring thiol;
〜Ri5独立的为 -H、 -N02、 C1〜C8烷基、 C1〜C8烷氧基、 苯基、 C1〜C8垸基 取代氧羰基、 C3〜C8环垸基取代氧羰基或 -CF3 ; ~Ri5 is independently -H, -N0 2 , C1~C8 alkyl, C1~C8 alkoxy, phenyl, C1~C8 fluorenyl substituted oxycarbonyl, C3~C8 cyclodecyl substituted oxycarbonyl or -CF 3 ;
Figure imgf000048_0003
Figure imgf000048_0003
22、 根据权利要求 21所述的 9-磺酰基 -9Η-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9Η-indole derivative according to claim 21, which is characterized in that:
R2为- F、 -Cl、 -Br或 -I; R 2 is -F, -Cl, -Br or -I;
R3为 - -F、 -Cl、 -Br或 - H2; R 3 is -F, -Cl, -Br or -H 2 ;
R4为
Figure imgf000048_0004
、苄基、 C1〜C4垸基或 C3' C6环垸基;
R4 is
Figure imgf000048_0004
, benzyl, C1~C4 fluorenyl or C3' C6 cyclodecyl;
〜RI2独立的为 -H、 -N02、 C1〜C8垸基、 C1〜C8垸氧基、 苯基或 -CF3 ; 〜 R I2 independently is -H, -N0 2 , C1~C8 fluorenyl, C1~C8 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H、 C1〜C8垸基或 C1〜C8垸基取代氧羰基。 23、 根据权利要求 22所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于: R 13 to R 15 are independently -H, C1 to C8 fluorenyl or C1 to C8 fluorenyl substituted oxycarbonyl. The 9-sulfonyl-9H-indole derivative according to claim 22, which is characterized in that:
R2为- F、 -CK -Br或 -I; R 2 is -F, -CK -Br or -I;
R3为 -H、 -F、 -CI或 -NH2; R 3 is -H, -F, -CI or -NH 2 ;
Rl2WRl1 R15丫 s R l2 W Rl1 R 15丫s
^为 Re R9 、 Ri3
Figure imgf000049_0001
、苄基、 C1〜C4垸基或 C3-
^ for Re R 9 , Ri 3
Figure imgf000049_0001
, benzyl, C1~C4 thiol or C3-
C6环院基; C6 ring yard base;
R8〜R12独立的为 -H、 -N02、 C1〜C4烷基、 C1〜C4垸氧基、 苯基或 -CF3; R 8 to R 12 are independently -H, -N0 2 , C1 to C4 alkyl, C1 to C4 decyloxy, phenyl or -CF 3;
R13〜R15独立的为 -H、 C1〜C4垸基取代氧羰基或 C1〜C4烷基。 R 13 to R 15 are independently -H, C1 to C4 fluorenyl substituted oxycarbonyl or C1 to C4 alkyl.
24、 根据权利要求 23所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  24. The 9-sulfonyl-9H-indole derivative according to claim 23, which is characterized in that:
R2为 -F、 -CK -Br或 -I; R3为- H、 -CI或 -NH2; R 2 is -F, -CK -Br or -I; R 3 is -H, -CI or -NH 2 ;
^为 R8 R9
Figure imgf000049_0002
、'¾^ ^、 T N 、苄基、 C1~C4垸基或 o
^ is R 8 R 9 ,
Figure imgf000049_0002
, '3⁄4^ ^, T N , benzyl, C1 ~ C4 thiol or o
C4环烷基; C4 cycloalkyl;
R8〜Ri2独立的为 -H、 -N02、 C1〜C4'垸基、 C1〜C4烷氧基、 苯基或 -CF3; R 8 to Ri 2 are independently -H, -N0 2 , C1 to C4' fluorenyl, C1 to C4 alkoxy, phenyl or -CF 3;
R13〜R15独立的为 -H或 C1〜C4垸基取代氧羰基。 R 13 to R 15 are independently an -H or a C1 to C4 fluorenyl group substituted with an oxycarbonyl group.
25、 根据权利要求 24所述的 9-磺酰基 -9H-嘌呤衍生物, 其特征在于:  The 9-sulfonyl-9H-indole derivative according to claim 24, which is characterized in that:
R2为 -F、 -CK -Br或 -I; R3为- H、 -NH2或 -CI; R 2 is -F, -CK -Br or -I; R 3 is -H, -NH 2 or -CI;
R 为
Figure imgf000049_0003
、苄基、 C1〜C4垸基或 C3' C4环垸基;
R is
Figure imgf000049_0003
Benzyl, C1~C4 fluorenyl or C3'C4 cyclodecyl;
Rs〜R12独立的为 -H、 -N02、 C1〜C4院基、 C1〜C4垸氧基、 苯基或 -CF3; Rs~R 12 are independently -H, -N0 2 , C1~C4, C1~C4 decyloxy, phenyl or -CF 3 ;
R13〜R15独立的为 -H或甲基取代氧羰基。 R 13 to R 15 are independently -H or methyl substituted oxycarbonyl.
26、 9-磺酰基 -9H-嘌呤衍生物, 其结构式为- 26, 9-sulfonyl-9H-indole derivative, the structural formula is -
Figure imgf000050_0001
Figure imgf000050_0001
、 权利要求 1〜26任一项所述的 9-磺酰基 -9H-嘌呤衍生物的制备方法, 其特征在于: The method for producing a 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26, which is characterized in that:
Figure imgf000050_0002
由化合物 1与化合物 2通过氮磺酰化反应制备得到。
Figure imgf000050_0002
It is prepared from the compound 1 and the compound 2 by a sulfonylation reaction.
28、 制备权利要求 1〜26任一项所述的 9-磺酰基 -9H-嘌呤衍生物时所用的中间体, 结构 如式 IV所示- The intermediate used in the preparation of the 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26, which has the structure shown in Formula IV -
Figure imgf000051_0001
其中, 、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8院基、 C3〜 C8环烷基、 C1〜C8烷氧基、 C1〜C8烷基取代胺基、 NQD、 ^或 C1〜C8 院硫基;
Figure imgf000051_0001
Wherein,, R 3 is independently -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 hospital group, C3~ C8 cycloalkyl, C1~C8 alkoxy a C1-C8 alkyl substituted amine group, NQD, ^ or C1~C8 thiol;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl.
29、 根据权利要求 28所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于: 一  The intermediate of a 9-sulfonyl-9H-indole derivative according to claim 28, wherein:
!^为11、 C1〜C8垸基或 C3〜C8环烷基;  !^ is 11, C1~C8 fluorenyl or C3~C8 cycloalkyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8烷基、 C3〜C8环烷基、 Cl〜 R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl, C3~C8 cycloalkyl, Cl~
C8垸氧基、 C1〜C8垸基取代胺基、 _N 。、 ^ Rt或 C1〜C8垸硫基。 C8 methoxy group, C1~C8 fluorenyl substituted amine group, _N . , ^ Rt or C1 ~ C8 thiol.
30、 根据权利要求 29所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 29, which is characterized in that:
为-11或€1〜€4烷基;  -11 or €1 to €4 alkyl;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C4垸基。 R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C4 fluorenyl.
31、 根据权利要求 30所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 30, which is characterized in that:
R3为 -H、 -F、 -Cl、 -Br、 C1~C4垸基或 -NH2 ; R 3 is -H, -F, -Cl, -Br, C1~C4 fluorenyl or -NH 2 ;
R5〜R7独立的为 -H或 C1〜C4垸基。 R 5 to R 7 are independently -H or C1 to C4 fluorenyl.
32、 根据权利要求 28所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 28, which is characterized in that:
Ri、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -N02、 C1-C8垸基、 C3〜C8环垸基、 Ri and R 3 are independently -H, -F, -Cl, -Br, -N 3 , -N0 2 , C1-C8 fluorenyl, C3 to C8 cyclodecyl,
C1〜C8烷氧基、 C1〜C8垸基取代胺基、 †N >、 ^或 C1〜C8垸硫基; a C1-C8 alkoxy group, a C1~C8 thiol-substituted amino group, a †N>, ^ or a C1~C8 thiol group;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl.
33、 根据权利要求 32所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 32, which is characterized in that:
1^为-:»或 1〜〇4烷基; R3为 -H、 -F、 -Cl、 -Br或 C1〜C4垸基; 1^ is -:» or 1~〇4 alkyl; R 3 is -H, -F, -Cl, -Br or C1~C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4烷基。 R 5 to R 7 are independently -H or C1 to C4 alkyl.
34、 根据权利要求 33所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 33, which is characterized in that:
R3为 -H或 -C1; R 3 is -H or -C1;
R5〜R7独立的为 -H。 R 5 to R 7 are independently -H.
35、 制备权利要求 1〜26任一项所述的 9-磺酰基 -9H-嘌呤衍生物时所用的中间体, 结构 如式 V所示-  The intermediate used in the preparation of the 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26, which has the structure shown in Formula V -
Figure imgf000052_0001
Figure imgf000052_0001
V  V
其中, 、 R3独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8院基、 C3〜 C8环烷基、 C1〜C8烷氧基、 C1〜C8垸基取代胺基、 · ·Ν。0、 ^或 C 1〜C8 院硫基; Wherein,, R 3 is independently -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 hospital group, C3~ C8 cycloalkyl, C1~C8 alkoxy a group, a C1~C8 thiol group substituted with an amine group, · · Ν. 0, ^ or C 1 ~ C8 hospital sulfur;
R5〜R7独立的为 -H、 C3〜C8环烷基或 C1〜C8垸基。 R 5 to R 7 are independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl.
36、 根据权利要求 30所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  The intermediate of a 9-sulfonyl-9H-indole derivative according to claim 30, which is characterized in that:
!^为-!!、 C1〜C8垸基或 C3〜C8环烷基;  ! ^为-! !, C1~C8 thiol or C3~C8 cycloalkyl;
R3为 -H、 -F、 -Cl、 -Br、 -N3、 -NH2、 -N02、 C1〜C8 '垸基、 C3〜C8环垸基、 Cl〜 R 3 is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 ' embankment group, C3~C8 cycloalkyl group embankment, Cl~
C8垸氧基、 C1〜C8烷基取代胺基、 t
Figure imgf000052_0002
C8 decyloxy, C1~C8 alkyl substituted amine, t
Figure imgf000052_0002
37、 根据权利要求 36所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 36, which is characterized in that:
为-11或€1〜 4烷基;  -11 or €1 to 4 alkyl;
R5〜R7独立的为 -H、 C2〜C4环烷基或 C1〜C4垸基。 R 5 to R 7 are independently -H, C 2 -C 4 cycloalkyl or C 1 -C 4 fluorenyl.
38、 根据权利要求 37所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于:  38. The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 37, which is characterized in that:
R3为- H、 -F、 -Cl、 -Br、 C1〜C4垸基或 -Nit; R 3 is -H, -F, -Cl, -Br, C1~C4 thiol or -Nit;
R5〜R7独立的为 -Η或 C1〜C4垸基。 R 5 to R 7 are independently -Η or C1 to C4 fluorenyl.
39、 根据权利要求 35所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于: 独立的为 -H、 -F、 -Cl、 -Br、 -N3、 -N02、 C1〜C8烷基、 C3〜C8环垸基、 39. The intermediate of a 9-sulfonyl-9H-indole derivative according to claim 35, which is characterized in that: Independently -H, -F, -Cl, -Br, -N 3 , -N0 2 , C1 to C8 alkyl, C3 to C8 cyclodecyl,
C1〜C8烷氧基、 C1〜C8烷基取代胺基、 †N。0、 ^^^^或 C1〜C8烷硫基; C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group, †N. 0, ^^^^ or C1~C8 alkylthio;
R5〜R7独立的为 -H、 C3〜C8环垸基或 C1〜C8垸基。 R 5 to R 7 are independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl.
40、 根据权利要求 41所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于: 40. The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 41, which is characterized in that:
为-^1或 1〜04垸基;  For -^1 or 1~04 垸 base;
R3为 -H、 -F、 -Cl、 -Br或 C1~C4垸基; R 3 is -H, -F, -Cl, -Br or C1~C4 fluorenyl;
R5〜R7独立的为 -H或 C1〜C4垸基。 R 5 to R 7 are independently -H or C1 to C4 fluorenyl.
42、 根据权利要求 41所述的 9-磺酰基 -9H-嘌呤衍生物的中间体, 其特征在于-  An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 41, characterized in that -
R3为 -H或 -CI; R 3 is -H or -CI;
R5〜R7独立的为 -H。 R 5 to R 7 are independently -H.
43、权利要求 1〜26任一项所述的 9-磺酰基 -9H-嘌呤衍生物在制备抗慢性丙型肝炎药物 中的用途。  The use of the 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26 for the preparation of a medicament for anti-chronic hepatitis C.
44、 药物组合物, 是由权利要求 1〜26任一项所述的 9-磺酰基 -9H-嘌呤衍生物添加药学 上可以接受的辅助性成分制备而成的。  44. A pharmaceutical composition prepared by adding a pharmaceutically acceptable auxiliary component to the 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26.
PCT/CN2012/000901 2011-06-29 2012-06-30 9-sulfonyl-9h-purine derivative, preparation method and use thereof WO2013000280A1 (en)

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