WO2013000280A1

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

Info

Publication number: WO2013000280A1
Application number: PCT/CN2012/000901
Authority: WO
Inventors: 余洛汀; 魏于全
Original assignee: 四川大学
Priority date: 2011-06-29
Filing date: 2012-06-30
Publication date: 2013-01-03
Also published as: CN102850355B; CN102850355A

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-sulfonyl ^9H-indole derivative and preparation method and use thereof

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. 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).

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.

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.

Summary of the invention

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:

Wherein, ~ is independently -H, -F, -Cl, -Br, -1, -N ₃ , -CF ₃ , -NH ₂ , -N0 ₂ ,

1 Confirmation S R. fluorenyl, C3 to C8 cycloalkyl, C1 to C8 alkoxy, C1 decyl substituted amine,

Or C1~C8 thiol;

^Rl2 w ^Rl1 R ₁₅丫s is Re R ₉ , R13 _3⁄4

, benzyl, C1~C8 thiol or C3-

C8 cycloalkyl;

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, -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;

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;

for

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 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 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;

R _2, R ₃ is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl group embankment,

^R 5, , R ₆

C1-C8 alkoxy group, C1-C8 alkyl-substituted amine group, ^_Ν ^. , ^R7 or C1~C8 thiol;

^Rl2 w ^Rl1 R ₁₅丫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 . Preferably, Ri is -H, C1~C8 alkyl or C3~C8 cycloalkyl;

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 alkoxy group, C1-C8 alkyl-substituted amine group, ^tN- or ^1,8 -alkylthio group; R ^L2 W ^RL1 R ₁₅丫s

^ is R ₈ R ₉ , 13 , ^J _;

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. Preferably, Ri is -H or C1~C4 fluorenyl;

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,

, '

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 R

Base, ^C ⁰ , ^^ ^ or C1~C4 thiol;

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 R

Substituted amine, †N3D, ^^^ or C1~C4 thiol;

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. _Η2Ν Λ _N , , .

0

Which does not include compounds

,

Optimal, 1^ is -11;

R ₂ is -H, -F, -Cl, -Br, -NH ₂ , -N ₃ , methyl, methoxy, C1~C4 fluorenyl substituted amine, ^{_ N} " ^ =< ^R6

Or methylthio;

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;

Further preferably, a C1~C8 fluorenyl group or a C3~C8 cyclodecyl group;

R ₂ and R ₃ are -H, -F, -Cl, -Br, -1, -NH ₂ , -N ₃ , -N0 ₂ , C1 to C8 fluorenyl,

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 is

, benzyl, C1~C4 thiol or C3- C6 cycloalkyl;

～ 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 ;}

Preferably, 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,

- , R

a C1~C8 methoxy group, a C1~C8 alkyl substituted amine group, or a C1~C8 sulfonium group;

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;

its

Preferably, 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 R

An alkyl substituted amine group, a hydrazine N3D, a ^_^ ⁶ or a C1~C4 thiol group;

R ₃ is -H, -F, -CK -Br, -NH ₂ or C1~C4 fluorenyl;

^Rl2 w ^{R 1} R ₁₅丫s ^ is Re R ₉ , 13 _χ

, benzyl, _{C 1} ～ _C4 thiol or

C6 ring thiol;

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~

Preferably,

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;

R ₃ is -H, -F, -Cl, -Br or -NH ₂ ;

R4 is

, benzyl, C1~C4 thiol or C3'

C4 ring thiol;

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;

Optimal, for -

R ₂ is -H, -F, -Cl, -Br, -1, -NH ₂ , -N ₃ , methyl, C1 to C4 alkoxy, C1 to C4 alkyl

^ =< ^R6

Amine, "^ ^{N 0} , ^SR 7 or A

R ₃ is -H, -H ₂ or -CI;

R4 is

, benzyl, C1~C4 thiol or C3-

C4 cycloalkyl;

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;

Further preferred, 9-sulfonyl-9H-

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;

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 base;

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. 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;

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 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, R ₃ is - H, -F, -CK -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~C8 cycloalkyl group embankment,

R ₅ R ₆

C! ~ C8 methoxy, C1~C8 fluorenyl substituted amine, ^{tN Q} , ^ ^R7 or C1~C8 thiol;

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 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;

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 . Preferably, 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

•| N 0

a C1-C8 alkoxy group, a C1-C8 alkyl-substituted amine group, a ^ ^R7 or a C1-C8 alkylthio group;

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 ;}

Preferably, 1^ is 11 or €1 to €4 alkyl;

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;

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 ;}

Further, when 1^ is a -11, 9-sulfonyl-9H-indole derivative has the structure shown in Formula III:

III wherein R ₂ is halogen;

R ₃ is -H, -NH _2;

R4 is

Benzyl, C1~C4 thiol or C3-

C6 ring thiol;

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 ;}

Preferably, 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-

C6 ring thiol;

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;

Preferably, 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-

C6 cycloalkyl;

~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;

Preferably, R ₂ is -F, -Cl, -Br or -I;

R ₃ is -H, -CI - H _{2 ;}

R4 is

Benzyl, C1~C4 thiol or C3-

C4 ring thiol;

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;

Ίi VN s

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

C4 ring thiol;

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;

Further, the above 9-sulfonyl-9H-oxime

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:

It is prepared from the compound 1 and the compound 2 by a sulfonylation reaction.

The reaction solvent is preferably a mixed solvent of tetrahydrofuran and dichloromethane, and the volume ratio of tetrahydrofuran to dichloromethane is

1: 1 The 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:

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;

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;

R ₃ is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl, C3~C8 cycloalkyl group embankment, Cl~

C8 methoxy, C1~C8 fluorenyl substituted amine, t^LJ^^ ^R7 or C1~C8 alkylthio;

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. 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;

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.

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:

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;

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;

R ₃ is -H, -F, -Cl, -Br, -N 3, - H 2, -N0 2, C1~C8 hospital group, C3~C8 cycloalkyl group embankment, Cl~ ^ ^>=< ^R6

a C8 alkoxy group, a C1 to C8 alkyl group substituted amine group, a ^ ^R7 or a C1~C8 sulfonium group;

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~

C8 alkoxy group, C1~C8 fluorenyl substituted amine group,

R _{5 to} R _{7 are} independently -H, C3-C8 cycloalkyl or C1 to C4 fluorenyl. Preferably, 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. 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;

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.

DRAWINGS

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 3. Compound 6-fluoro-9-(4-methoxybenzenesulfonyl)-9H-indole anti-HCV activity and cytotoxicity test results.

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

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.

Example 1 Intermediate 6-Dimethylamino Synthesis

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 (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).

Example 2 Synthesis of Intermediate 6-Diethylaminopurine

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, -CH ₃ ), 1.33 (m, 2H, -CH ₂ -), 7.97 (s, 1H): 8.40 (s, 1H), 13.66 (s, 1H).

Example 3 Intermediate Synthesis of 6-morpholinylfluorene

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(CH ₂ ) ₂ ), 4.21(s, 4H, -N(CH ₂ ) ₂ ), 8.14(s, 1H), 8.23( s, 1H), 13.07(s, 1H)»

Example 4 Synthesis of Intermediate 6-Methylthioguanidine

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, -CH ₃ ), 8.25 (s, 1H), 8.54 (s, 1H), 13.33 (s,

1H).

Example 5 Intermediate Synthesis of 6-allylthioguanidine

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, -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).

Example 6 Intermediate Synthesis of 6-azidofluorene

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).

ESI-MS (m/z, %): (M+H) ⁺ 162.05.

Synthesis of 6-fluoroindole in Example 7

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 (400 MHz, DMSO-D6) δ: 8.66 (d, 2H), 13.97 (s, 1H).

ESI-MS (m/z, %): (M+H) ⁺ 139.24. Example 8 Synthesis of Intermediate 6-Iodoindole

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%.

Example 9 Synthesis of Intermediate 6-Bromoindole

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%.

Example 10 Synthesis of target product 6-chloro-9-p-toluenesulfonyl-9H-indole

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.

Example 11 Target product 6-chloro-9-(4-methoxy-9H-oxime

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%.

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.

Example 12 Target product 6-azido-9-(4-yl)-9H-oxime

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%.

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.

Example 13 Target product 6-fluoro-9-(4-methoxybenzenesulfonyl)-9H-oxime

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, 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.

Example 14 Target product 6-Amino-9-(4-methyl)-9H-oxime

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, -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.

Example 15 Target product 6-chloro-9-(4-isopropoxybenzenesulfonyl)-9H-oxime

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%.

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.

Example 16 Target product 6-chloro-9-(4-tert-butyl-9H-oxime

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%.

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.

Example 17 Target product 6-chloro-9-(3-trifluoromethylbenzenesulfonyl)-9H-oxime

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, 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.

Example 18 Target product 6-chloro-9-(2-nitro-4-methoxybenzenesulfonyl)-9H-oxime

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, -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.

Example 19 Target product 6-chloro-9- (4- -9H-oxime

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 .

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.

Example 20 Target product 6-chloro-9-(2,4,6-triisopropylbenzenesulfonyl)-9H-indole

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, 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.

Example 21 Target product 6-chloro-9-(naphthalene-2-sulfonyl)-9H-oxime

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%.

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.

Example 22 Target product 6-chloro-9-(3-nitro)-9H-oxime

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:

ESI-MS (m/z, %): (M+H)+ 339.96.

Example 23 Target product 6-Chloro-9-(2-nitrophenylsulfonyl)-9H-indole

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, 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.

Example 24 Target product 6-chloro-9-(4-nitrophenylsulfonyl)-9H-oxime

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, 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.

Example 25 Target product 8-(6-chloro-9H-indol-9-ylsulfonyl)quinoline

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, 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.

Example 26 Target product 6-chloro-9-(benzylsulfonyl)-9H-oxime

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).

ESI-MS (m/z, %): (M+H) ⁺ 309.05.

Example 27 Target product 6-chloro-9-(cyclopropyl-9H-oxime

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%.

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.

Example 28 Target product 6-chloro-9-(n-butylsulfonyl)-9H-oxime

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%.

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.

Example 29 Target product 9-(4-Methoxybenzene-9H-oxime

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, 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.

Example 30 Target product 6-bromo-9-(4-methoxy-9H-indole

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, 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.

Example 31 Target product 6-iodo-9-(4-methoxy-9H-oxime

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, -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.

Example 32 Target product 6-Methoxy-9-yl-9H-indole

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%.

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.

Example 33 Target product 6-dimethylamino-9-p-toluenesulfonyl-9H-oxime

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 = 8.0 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.

Example 34 Target product 6-Diethylamino-9--9H-oxime

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, -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.

Example 35 Target product 2,6-Dichloro-9-p-toluenesulfonyl-9H-oxime

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%.

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.

Example 36 Target product 2-amino-6-chloro-9-p-toluenesulfonyl-9H-oxime

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 .

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.

Example 37 Target product 6-morpholinyl-9-p-toluenesulfonyl-9H-oxime

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 = 4.8 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.

Example 38 Target product 6-allylthio- - hydrazine

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-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.

Example 39 Target product 6-Methylthio-9--9H-oxime

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%.

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.

Example 40 Target product methyl 3-(6-chloro-9H-indol-9-ylsulfonyl)thiophene-2-carboxylate

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%.

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. Pharmacodynamics experimental part

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.

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.

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:

Table 1

Example 25 Compound 7.26 37.13 5.12

Example 26 Compound >100 >100 1

EXAMPLE 27 Compound 43.74 >100 > 2.29 Example 28 Compound 39.58 >100 >2.53 Example 29 Compound 49.93 >100 >2

EXAMPLE 30 Compound 7.84 75.86 9.68 Example 31 Compound 9.77 >100 >10.23 Example 32 Compound >100 >100 1

Example 33 Compound >100 >100 1

Example 34 Compound >100 >100 1

Example 35 Compound 98.4 96.9 1

Example 36 Compound 74.3 > 100 > 1.5 Example 37 Compound > 100 > 100 1

Example 38 Compound >100 >100 1

Example 39 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.

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).

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.

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

Claim

1, 9-sulfonyl-9H-indole derivative, the structure is as shown in formula I:

V. I ¹

I

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,

Or C1~C8 thiol;

^Rl2 w ^{R 1} R ₁₅丫s

R4 is ^{^{R9, Rl3, ^ ¾ ^,}} Ύ N, a benzyl group, _{C 1} ~ _C8 alkyl with or _C3 ~

C8 ring thiol;

C8:

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;

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.

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 cycloalkyl, C1~C8 decyloxy, C1~C8 fluorenyl substituted amine, ^NQ , ^ ^R7 or C1~C8 thiol;

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 ~ 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;

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. The 9-sulfonyl-9H-indole derivative according to claim 2, which is characterized in that:

1^ is -11, C1~C8 thiol or C3~C8 fluorenyl;

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 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;

～ 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. The 9-sulfonyl-9H-indole derivative according to claim 3, which is characterized in that:

Ri is -H, C1~C8 fluorenyl or C3~C8 cycloalkyl;

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 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;

R _{8 to} R _{12 are} independently -H, C1 to C8 fluorenyl, C1 to C8 decyloxy, -N0 ₂ , phenyl or -CF _{3 ;}

R _{13 to} R _{15 are} independently -H, C1 to C8 alkyl or C1 to C8 mercapto substituted oxycarbonyl.

The 9-sulfonyl-9H-indole derivative according to Claim 4, wherein - is -11 or. 1 to €4 垸 base;

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;

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~R _{12 are} independently -H, C1~C4 fluorenyl, C1~C4 decyloxy, -N0 ₂ , phenyl or -CF _{3 ;}

R _{13 to} R _{15 are} independently -H, C1 to C4 alkyl substituted oxycarbonyl or C1 to C4 fluorenyl.

6. The 9-sulfonyl-9H-indole derivative according to claim 5, characterized in that -

1^ is -11 or 1~€4 alkyl;

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;

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 alkoxy, phenyl or -CF _{3 ;}

R _{13 to} R _{15 are} independently an -H or a C1 to C4 alkyl group substituted with an oxycarbonyl group.

7. The 9-sulfonyl-9H-indole derivative according to claim 4, which is characterized in that:

Is -11 or C1~C4 sulfhydryl;

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;

R _{5 to} R _{7 are} independently -H;

R _{8 to} R _{12 are} independently -H, -N0 ₂ , CI C4, C1 to C4 alkoxy, phenyl or -CF _{3 ;}

Independent -H or C1~C4

Which does not include compounds

_o

8. The 9-sulfonyl-9H-indole derivative according to claim 7, wherein -

Ri is -H;

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;

Is -11, - H ₂ or -C1;

R _{5 to} R _{7 are} independently -H;

R _{8 to} Ri 2 are independently -H, -N0 ₂ , C1 to C4 fluorenyl, C1 to C4 decyloxy, phenyl or -CF _{3 ;}

R _{13 to} R _{15 are} independently -H or methyl substituted oxycarbonyl.

9. The 9-sulfonyl-9H-indole derivative according to claim 1, wherein -

C1~C8 thiol or C3~C8 cycloalkyl;

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 alkoxy group, C1-C8 alkyl-substituted amine group,

^R7 or C1~C8 sulfur-burning base;

for

, benzyl, C1~C4 thiol or C3-

C6 ring thiol;

1 ₅ 〜 is independently -H, C3~C8 cyclodecyl or C1~C8 alkyl;

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 ;}

The 9-sulfonyl-9H-indole derivative according to claim 9, which is characterized in that:

Rs~R _{12 are} independently -H, -N0 ₂ , C1~C8 fluorenyl, C1~C8 decyloxy, phenyl or -CF _{3 ;}

The 9-sulfonyl-9H-indole derivative according to claim 10, which is characterized in that:

-11 or 1 to €4 alkyl;

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

Mercapto substituted amine, †NQD, ^J^ _R or C1~C4 thiol;

R ₃ is -H, -F, -CK -Br, -NH ₂ or C1 to C4 alkyl;

R _{5 to} R _{7 are} independently -H or C1 to C4 alkyl;

Ri! ～ R _{12 is} independently -H, -N0 ₂ , C1 to C4 alkyl, C1 to C4 decyloxy, phenyl or -CF _{3 ;}

The 9-sulfonyl-9H-indole derivative according to claim 11, which is characterized in that -

Ri is -H;

R ₃ is -H, -F, -CK -Br -NH ₂ ;

^为

, benzyl, C1~C4 thiol or C3~

C4 ring thiol;

R _{5 to} R _{7 are} independently -H;

The 9-sulfonyl-9H-indole derivative according to Claim 12, which is characterized in that: (This item does not enjoy the priority)

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. ,

Or methylthio; R ₃ is -H, -H ₂ or -CI;

R _{13 to} R _{15 are} independently -H or methyl substituted oxycarbonyl.

The 9-sulfonyl-9H-indole derivative according to claim 1, wherein R4 is

The structure is as shown in Equation II:

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;

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;

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:

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.

The 9-sulfonyl-9H-indole derivative according to claim 14, which is characterized in that:

~ Is independently -H, -F, -Cl, -Br, -N 3, -CF 3, -NH 2, -N0 2, C1~C8 alkyl with, C3~

C8 cyclodecyl, C1~C8 decyloxy, C1~C8 alkyl substituted amine, †N. 0, ^ or C1~C8 hospital sulfur base;

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~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;

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.

The 9-sulfonyl-9H-indole derivative according to claim 15, wherein:

Is -11, C 1~C8 fluorenyl or C3~C8 cycloalkyl;

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,

R ₅ R ₆

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;

3⁄4 to R _{12 are} independently -H, C 1 to C8 fluorenyl, C1 to C8 decyloxy, -N0 ₂ , phenyl or -CF ₃ .

The 9-sulfonyl-9H-indole derivative according to claim 16, wherein - is 1 or. 1 to 04 垸 base;

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;

R ₃ is -H, -F, -Cl, -Br, C 1 -C4 alkyl or -NH ₂ ;

R ₅ to R _{7 are} independently -H or C1 to C4 fluorenyl;

R _{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. The 9-sulfonyl-9H-indole derivative according to claim 14, wherein -

R ₁ is -H, C ₁ -C8 alkyl or C3 to C8 cycloalkyl;

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 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~R _{12 are} independently -H, -N0 ₂ , C1~C8 alkyl, C 1~C8 alkoxy, phenyl or -CF _{3 ;}

The 9-sulfonyl-9Η-indole derivative according to claim 18, which is characterized in that:

Is 11 or C1~C4 thiol;

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;

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 fluorenyl;

～ ₂ independently is -11, -N0 ₂ , C1 to C4 alkyl, C1 to C4 alkoxy, phenyl or -CF ₃ .

The 9-sulfonyl-9H-indole derivative according to claim 19, which is characterized in that:

Ri is -H;

R ₂ is -H, -F, -Cl, -Br, -1, -N3⁄4, -N ₃ , methyl, C1 to C4 methoxy, C1 to C4 alkyl

R R

Amine group, †N^O, _s >= ^ or methylthio group;

R ₃ is -H, -H ₂ or -C1;

R _{5 to} R _{7 are} independently -H;

R8~R ₁₂ is independently -H, -N0 _2, C1~C4 firing group, C1~C4 alkoxy, phenyl, or -CF _3.

The 9-sulfonyl-9H-indole derivative according to claim 1, which has a structure of -11 and a structure of the formula III:

Wherein R ₂ is a halogen;

R ₃ is -H, halogen or -NH ₂

R4 is

Benzyl, C1 to C4 alkyl or C3

C6 ring thiol;

～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 ;}

The 9-sulfonyl-9Η-indole derivative according to claim 21, which is characterized in that:

R ₂ is -F, -Cl, -Br or -I;

R ₃ is -F, -Cl, -Br or -H ₂ ;

R4 is

, benzyl, C1~C4 fluorenyl or C3' C6 cyclodecyl;

〜 R _I2 independently is -H, -N0 ₂ , C1~C8 fluorenyl, C1~C8 decyloxy, phenyl or -CF _{3 ;}

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:

R ₂ is -F, -CK -Br or -I;

R ₃ is -H, -F, -CI or -NH ₂ ;

R ^l2 W ^Rl1 R ₁₅丫s

^ for Re R ₉ , Ri ₃

, benzyl, C1~C4 thiol or C3-

C6 ring yard base;

R _{8 to} R _{12 are} independently -H, -N0 ₂ , C1 to C4 alkyl, C1 to C4 decyloxy, phenyl or -CF _3;

R _{13 to} R _{15 are} independently -H, C1 to C4 fluorenyl substituted oxycarbonyl or C1 to C4 alkyl.

24. The 9-sulfonyl-9H-indole derivative according to claim 23, which is characterized in that:

R ₂ is -F, -CK -Br or -I; R ₃ is -H, -CI or -NH ₂ ;

^ is ^R 8 R ₉ ,

, '3⁄4^ ^, T ^N , benzyl, _C1 ~ _C4 thiol or o

C4 cycloalkyl;

R _{8 to} Ri 2 are independently -H, -N0 ₂ , C1 to C4' fluorenyl, C1 to C4 alkoxy, 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.

The 9-sulfonyl-9H-indole derivative according to claim 24, which is characterized in that:

R ₂ is -F, -CK -Br or -I; R ₃ is -H, -NH ₂ or -CI;

R is

Benzyl, C1~C4 fluorenyl or C3'C4 cyclodecyl;

Rs~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 methyl substituted oxycarbonyl.

26, 9-sulfonyl-9H-indole derivative, the structural formula is -

The method for producing a 9-sulfonyl-9H-indole derivative according to any one of claims 1 to 26, which is characterized in that:

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 -

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;

R _{5 to} R _{7 are} independently -H, C3 to C8 cycloalkyl or C1 to C8 fluorenyl.

The intermediate of a 9-sulfonyl-9H-indole derivative according to claim 28, wherein:

!^ is 11, C1~C8 fluorenyl or C3~C8 cycloalkyl;

R ₃ is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 alkyl, C3~C8 cycloalkyl, Cl~

C8 methoxy group, C1~C8 fluorenyl substituted amine group, ^_N . , ^ ^Rt or C1 ~ C8 thiol.

The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 29, which is characterized in that:

-11 or €1 to €4 alkyl;

R _{5 to} R _{7 are} independently -H, C3 to C8 cycloalkyl or C1 to C4 fluorenyl.

An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 30, which is characterized in that:

R ₃ is -H, -F, -Cl, -Br, C1~C4 fluorenyl or -NH _{2 ;}

R _{5 to} R _{7 are} independently -H or C1 to C4 fluorenyl.

An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 28, which is characterized in that:

Ri and R _{3 are} independently -H, -F, -Cl, -Br, -N ₃ , -N0 ₂ , C1-C8 fluorenyl, C3 to C8 cyclodecyl,

a C1-C8 alkoxy group, a C1~C8 thiol-substituted amino group, a †N>, ^ or a C1~C8 thiol group;

An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 32, which is characterized in that:

1^ is -:» or 1~〇4 alkyl; R ₃ is -H, -F, -Cl, -Br or C1~C4 fluorenyl;

R _{5 to} R _{7 are} independently -H or C1 to C4 alkyl.

The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 33, which is characterized in that:

R ₃ is -H or -C1;

R _{5 to} R _{7 are} independently -H.

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 -

V

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;

The intermediate of a 9-sulfonyl-9H-indole derivative according to claim 30, which is characterized in that:

! ^为-! !, C1~C8 thiol or C3~C8 cycloalkyl;

R ₃ is -H, -F, -Cl, -Br, -N 3, -NH 2, -N0 2, C1~C8 ' embankment group, C3~C8 cycloalkyl group embankment, Cl~

C8 decyloxy, C1~C8 alkyl substituted amine, ^t

An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 36, which is characterized in that:

-11 or €1 to 4 alkyl;

R _{5 to} R _{7 are} independently -H, C 2 -C 4 cycloalkyl or C 1 -C 4 fluorenyl.

38. The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 37, which is characterized in that:

R ₃ is -H, -F, -Cl, -Br, C1~C4 thiol or -Nit;

R _{5 to} R _{7 are} independently -Η or C1 to C4 fluorenyl.

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 alkoxy group, C1-C8 alkyl-substituted amine group, †N. 0, ^^^^ or C1~C8 alkylthio;

R _{5 to} R _{7 are} independently -H, C3 to C8 cyclodecyl or C1 to C8 fluorenyl.

40. The intermediate of the 9-sulfonyl-9H-indole derivative according to claim 41, which is characterized in that:

For -^1 or 1~04 垸 base;

R ₃ is -H, -F, -Cl, -Br or C1~C4 fluorenyl;

R _{5 to} R _{7 are} independently -H or C1 to C4 fluorenyl.

An intermediate of a 9-sulfonyl-9H-indole derivative according to claim 41, characterized in that -

R ₃ is -H or -CI;

R _{5 to} R _{7 are} independently -H.

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. 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.