CN101027051A - Methods for treating hepatitis C - Google Patents

Abstract

In accordance with the present invention, compounds that inhibit viral replication, preferably Hepatitis C Virus (HCV) replication, have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the treatment or prevention of a viral infection are provided. In another aspect of the invention, compounds useful in the treatment or prevention of HCV infection are provided.

Description

The method of treatment hepatitis C

The cross reference of related application

The application requires the rights and interests of following U.S. Patent application: on July 14th, 2004 submit the 60/587th, No. 487 U.S. Provisional Applications, in December in 2004 submitted in 13rd the 60/634th, No. 979 U.S. Provisional Applications, on January 24th, 2005 submit the 60/645th, No. 586 U.S. Provisional Applications, on March 28th, 2005 submit the 60/665th, No. 349 U.S. Provisional Applications and on April 28th, 2005 submit the 60/675th, No. 440 U.S. Provisional Applications, the whole contents of all these applications is incorporated herein by reference at this.It is 19025.037 the exercise question international application priority for " method (Methods for Treating Hepatitis C) of treatment hepatitis C " that the application also requires in the attorney docket that on July 14th, 2005 submitted, and the whole contents of this application is incorporated herein by reference at this.

Technical field

The present invention relates to use the benzazolyl compounds of the translation control that can improve hepatitis C virus to treat the method for hepatitis C.

Background technology

It is reported that nearly 100,000,000 7 thousand ten thousand populations in the whole world infect hepatitis C virus (HCV) is arranged, it is the pathogenic agent of hepatitis C.70-80% during HCV infects causes chronic liver to infect, and this can cause serious hepatopathy again, comprises that the liver cellulosic generates, hardens and hepatocarcinoma (115).

HCV belongs to the hepatovirus (Hepacivirus) (106) of flaviviridae (Flaviviridae), and comprises normal chain 9.6kb rna gene group.The genomic feature of HCV comprises the zone (UTR) of 5 '-unreacted, its internal ribosome entry site (IRES) of encoding, and the translation of the open reading-frame (ORF) of the single length of 3,010 amino acid whose polyproteins of this site-directed coding.After this HCV ORF then is 3 ' of variable-length-UTR, and it depends on the HCV variant, and coding causes the synthetic required sequence (79) of anti-genome chain.

All genome translations and duplicate needed zone in the coding RNA structure of HCV IRES and 3 '-UTR.The HCV polyprotein is treated at least 10 sophisticated virus proteins after translation, comprise structural protein nuclear (inferring nucleocapsid), E1 and E2 and non-structure (NS) albumen NS2-NS5B.

Three different factors have been confirmed in the translation of HCV IRES mediation, to relate to: the integrity of (1) HCV IRES chondritic, the genomic 3 ' end regions of (2) HCV; And (3) and HCV IRES factor interaction and help the trans-acting cytokine (35) of translation initiation.

The synthetic initial dependent AUG rule (61) of 5 ' medicated cap of mainly following of albumen in the eukaryotic cell.Yet, confirmed that increasing virus (6,12,28,31a, 50,95,97,98,105,128) and cell mRNA s (18,39,45,78,91,130) are to use the IRES factor to come directed translation initiation.In 1992, in 5 ' UTR of HCV rna gene group, reported IRES factor (129), show the synthetic initial of virus protein in the dependent mode of medicated cap.

Can use the bicistronic mRNA expression system to define and assess the effect of IRES factor.This test system comprises two kinds of different reporter genes, and wherein 5 '-nearside reporter gene is expressed by the dependent translating mechanism chain of medicated cap, and second kind of reporter gene just expressed when only spatial upstream sequence comprises IRES sequence factor between the embedding gene.By using this system, the IRES that infers among the HCV 5 ' UTR is not had the effect (133) that any query ground proof plays the IRES in the virus protein translation control.External translation, research takes place for RNA transfection and sudden change provides further evidence (23,41,42,108,129,132,133,134) for HCV 5 ' UTR comprises the IRES factor.Therefore in vitro study and all confirm the inside site (56,58,120) of HCV IRES with cell translation initiation factor guiding viral RNA based on the research of cell has functionally confirmed HCV IRES activity.In a word, these results confirm that HCV 5 '-UTR comprises the IRES factor, and the latter plays positive and crucial effect in the internal start mechanism of HCV protein translation.

IRES is one of zone the most conservative in the HCV genome, has shown it for virus replication and the synthetic fundamental property of albumen (13,118,122).As if though 5 ' and the 3 ' sequence of IRES is all in have an effect aspect the control of translation initiation (42,109,110,113,136), it is zone (40) between nucleotide 44-354 that the minmal sequence of HCV IRES function requires drawn.

Biochemical detection and computer model show that HCV IRES and 5 ' sequence thereof are folded into the different structure of being made up of four main territories and false knot (11,42,122).As if territory I comprises little stem-ring structure, and it is not the funtion part of IRES factor, and territory II, III and IV comprise HCV IRES activity (43,111).The secondary structure of HCV IRES and the relation between the tertiary structure and their function are identified (5,55,56,99,124) recently.Territory II and III are made up of a plurality of stems, ring and projection, and are important (23,40,51,52,54,56,64,74,75,93,107,108,110,124,127,131,139) for the IRES activity.The configuration that territory II can bring out on the ribosome changes, and this is considered to relate to decode procedure (124).Territory III has the structure conservative of top between different HCV strains.It comprises the nuclear of banzi virus IRES, and has 6 subdomains (40).Various researchs have shown that all subdomain IIId forms complicated secondary/tertiary structure, and are crucial (55,56,57,124,129) for initial activity.Territory IV has a stem-ring, and it strides across start codon, and is specific (41,122) for HCV IRES, but the accurate effect of territory IV in the IRES activity still has dispute (41,112).

The effect of HCV IRES is near the machine translator of start codon in the virus mRNA of location.The translation initiation mechanism of HCV IRES obviously is different from the mechanism (7,21,31,35,81,96,114,123) of the dependent translation initiation of 5 '-medicated cap.Most cell cap end mRNA utilizes multiple initiation factor (eIF), and they are essential for the translation initiation process.The initial step of this process need interact with 5 ' cap and 40S ribosomal subunit is raised the proteic medicated cap proximal region at mRNA.This complex then scans 3 ' of this medicated cap, until reaching the AUG codon, and will be in this initial translation (21,114).Yet if HCV, IRES functionally substitutes 5 ' cap, makes 40S ribosomal subunit and eIF3 directly combine with RNA.The subdomain IIId of HCV IRES is containing the binding site of 40S ribosomal subunit, and only the needed initiation factor of translation initiation is eIF2, eIF3 and eIF4E (15,58,94,100,120,124).

Poly-pyrimidine tract conjugated protein (track-binding protein) is the non-standard translation initiation factor with the La autoantigen (PTB), and it is in conjunction with also strengthening HCV IRES activity (1,2,3,4,5,30,48,49,53).PTB is related a kind of 57-kDa albumen in the RNA splicing, also is necessary (10,11,36,53,59,89,92) for the pico+ribonucleic acid+virus mRNA of IRES mediation and effective translation initiation of some cell mRNA.The non-winding albumen of the double-stranded RNA that described La autoantigen is a kind of 52kDa also increases the activity (38,85,86) of poliomyelitis virus and cell IRES.Other related cytokines comprise proteasome Alpha-subunit PSMA7 (62), ribosome protein s 5 (26), ribosomal protein S9 (24,25,100) and hnRNPL (33) in the translation initiation of HCV IRES mediation.Yet the effect of these these rna binding proteins in the translation initiation of HCV IRES mediation it be unclear that.Recently report that the activity that interferon (IFN) α antagonism HCV duplicates can be passed through to reduce the La protein level and the translation initiation (117) of targeting HCV IRES mediation.Therefore, the interactional inhibitor between blocking-up IRES and the non-standard factor might suppress HCV effectively and duplicates and do not have a cytotoxicity.

At present, only being combined in of interferon (IFN) α and nucleoside analogues 'Libaweilin ' has sale on the market, is used for the treatment of HCV and infects.But these two kinds of medicines are immunomodulators and have limited effectiveness, higher toxicity, and expense also high (80,83,84,138).Though therapeutic outcome is transformable in 6 main HCV genotype, the only only about half of patient that controlled responds to treatment, shows that this encoding viral can be directly or weaken the protein product of the antiviral activity of IFN indirectly.IFN is spontaneous when replying viral infection, and cellular exposure causes the expression of bringing out of gene (ISG) that various IFN stimulate in IFN, and the gene that many described IFN stimulate has the antiviral function.The ISG effect can be duplicated by a plurality of somes place limiting virus in replicative cycle.

Still need more effectively to treat the patient's who suffers from HCV means.Particularly, still need novel antiviral drugs, it does not have the resistant function of intersection with present treatment pattern, and has synergism with other anti-HCV medicaments.The applicant has identified and has suppressed the drug candidate that HCV infects, and successfully identifies the benzazolyl compounds that can be used as anti-HCV medicament.Be not limited to a kind of restriction of theory, it is believed that chemical compound of the present invention suppresses initial, the elongation of IRES mediation and stops, promptly, translation.

Chemical compound of the present invention also can be used for suppressing comprising the translation of other medicated cap dependoviruses of IRES factor.These viruses comprise the virus of Picornavirus, as poliomyelitis virus, hepatitis A virus and rhinovirus; The virus of coronavirus genus is as SARS; The virus that arbovirus belongs to; The virus of Flavivirus is as yellow fever virus, dengue virus and west Nile virus; Herpesvirus as herpes simplex virus and kaposi sarcoma associated herpesvirus, perhaps has other viruses of similar replication mode.In addition, chemical compound of the present invention also can be used for suppressing HIV or has other viruses of similar interpretive scheme.

All be incorporated by reference in this text at these all documents of quoting and examine.

Summary of the invention

According to not inventing, identified and can suppress the chemical compound that HCV duplicates.According to not inventing, also identify and to suppress the chemical compound that HCV infects, and their using method is provided.

In one aspect of the invention, provide the chemical compound of formula (I), it can be used for preventing and/or treating HCV and infects.Be not limited to a kind of restriction of theory, it is believed that chemical compound of the present invention suppresses initial, the elongation of IRES mediation and stops, promptly, translation.The chemical compound of formula (I) also can be used for suppressing and/or treats other viral infection that virus wherein comprises the IRES factor.These viruses comprise the virus of Picornavirus, such as but not limited to poliomyelitis virus, hepatitis A virus and rhinovirus; The virus of coronavirus genus is such as but not limited to SARS; The virus that arbovirus belongs to; The virus of Flavivirus is such as but not limited to yellow fever virus, dengue virus and west Nile virus; Herpesvirus such as but not limited to herpes simplex virus and kaposi sarcoma associated herpesvirus, perhaps has other viruses of similar replication mode.In addition, chemical compound of the present invention also can be used for suppressing HIV or has other viruses of similar interpretive scheme.

In another aspect of the present invention, provide the method that HCV infects that prevents and/or treats.

In another aspect of the present invention, provide pharmaceutical composition, it comprises and is used to prevent and/or treat the The compounds of this invention that HCV infects.

In one embodiment, the present invention relates to suppress the method for the initial sum translation of HCV IRES mediation, it comprises one or more chemical compounds of the present invention that effectively suppress the amount that the initial sum of IRES mediation translates to the individual administration that these needs are arranged.

Some embodiment

Embodiment 1: be used for the pharmaceutical composition that prevention or treatment hepatitis C virus (HCV) infect, it comprises at least a chemical compound or the acceptable salt of its materia medica that has with following formula for the treatment of effective dose, acceptable excipient of materia medica and optional at least a extra anti-HCV medicament:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and

R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Embodiment 2: as enforcement scheme 1 described pharmaceutical composition, wherein said optional at least a extra anti-HCV medicament is selected from following group: the interferon of Pegylation (pegylated), the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, anti-fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, glycosidase inhibitor, the unwindase inhibitor, Toll sample receptor stimulating agent, and their combination.

Embodiment 3. is as enforcement scheme 1 described pharmaceutical composition, and wherein X is selected from following group :-hydrogen;-cyano group; And-COR _aGroup, wherein R _aBe-C ₁-C ₆Alkyl or-dialkyl amido.

Embodiment 4. is as enforcement scheme 1 described pharmaceutical composition, and wherein Y is selected from following group:

Embodiment 5. is as enforcement scheme 1 described pharmaceutical composition, and wherein Y is selected from following group:

Embodiment 6. is as enforcement scheme 1 described pharmaceutical composition, and wherein R is a hydrogen.

Embodiment 7. is as enforcement scheme 1 described pharmaceutical composition, wherein R ₁Be selected from following group: hydrogen, nitro or alkoxyl.

Embodiment 8. is as enforcement scheme 1 described pharmaceutical composition, wherein R ₂Be selected from following group: hydroxyl, hydrogen, haloalkyl, nitro, amide ,-COOR _xOr alkoxyl.

Embodiment 9. is as enforcement scheme 1 described pharmaceutical composition, wherein R ₃Be hydrogen.

Embodiment 10. is as enforcement scheme 1 described pharmaceutical composition, and wherein said chemical compound is selected from the chemical compound in the Table A.

Embodiment 11: as enforcement scheme 1 described pharmaceutical composition, wherein said chemical compound is selected from chemical compound or acceptable salt of its materia medica and the acceptable excipient of materia medica among the table B.

Embodiment 12. is as enforcement scheme 11 described pharmaceutical compositions, and wherein said compositions further comprises at least a extra anti-HCV medicament that is selected from following group: the interferon of Pegylation (pegylated), the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, anti-long and slender dimension chemical medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, glycosidase inhibitor, the unwindase inhibitor, Toll sample receptor stimulating agent, and their combination.

The method that hepatitis C virus (HCV) infects in 13. 1 kinds of treatments of embodiment individuality, it comprises that comprising at least a of HCV amount of suppression to described individual administration has with the chemical compound of following formula or the pharmaceutical composition of acceptable salt of its materia medica and the acceptable excipient of materia medica:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, R wherein _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and

R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCO _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Embodiment 14. is as enforcement scheme 13 described methods, and wherein said pharmaceutical composition further comprises at least a extra anti-HCV medicament.

Embodiment 15. is as enforcement scheme 14 described methods, and wherein said at least a extra anti-HCV medicament is selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, glycosidase inhibitor, the unwindase inhibitor, Toll sample receptor stimulating agent, and their combination.

Embodiment 16. is as enforcement scheme 13 described methods, and wherein X is selected from following group :-hydrogen;-cyano group; And-COR _aGroup, wherein R _aBe :-C ₁-C ₆Alkyl or-dialkyl amido.

Embodiment 17. is as enforcement scheme 13 described methods, and wherein Y is selected from following group:

Embodiment 18. is as enforcement scheme 13 described methods, and wherein Y is selected from following group:

Embodiment 19. is as enforcement scheme 13 described methods, and wherein R is a hydrogen.

Embodiment 20. is as enforcement scheme 13 described method, wherein R ₁Be selected from following group :-hydrogen;-halogen;-nitro;-5 or 6 yuan of heterocycles; Optional quilt-C ₆-C ₈Aryl replaces-alkoxyl; Optional alkoxy replaces-C ₆-C ₈Aryl.

Embodiment 21. is as enforcement scheme 13 described method, wherein R ₂Be selected from following group :-nitro;-hydrogen;-halogen;-hydroxyl;-C ₁-C ₆Alkyl, it is chosen wantonly and is substituted one or more halogens;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens,--OCOR _xGroup, wherein R _xAs defined above, optional alkoxy replaces-dialkyl amido, and is optional by C ₁-C ₆-5 or 6 yuan of heterocycles that alkyl replaces, or-5 or 6 yuan of heteroaryls;-amide groups; And-NHSO ₂R _xGroup, wherein R _xAs defined above.

Embodiment 22. is as enforcement scheme 13 described method, wherein R ₃Be hydrogen.

Embodiment 23. is as enforcement scheme 13 described methods, and wherein said chemical compound is selected from the chemical compound in the Table A.

Embodiment 24. is as enforcement scheme 13 described methods, and wherein said chemical compound is selected from the chemical compound among the table B.

25. 1 kinds of treatments of embodiment or prevention are individual by the method for viral infection, wherein said virus comprises internal ribosome entry site (IRES), and this method comprises that one or more that comprise viral amount of suppression to described individual administration have with the chemical compound of following formula and/or the pharmaceutical composition of acceptable salt of its materia medica and the acceptable excipient of materia medica:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and

R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Embodiment 33. is as enforcement scheme 32 described methods, and wherein said pharmaceutical composition further comprises at least a extra antiviral drugs.

Embodiment 34. is as enforcement scheme 33 described methods, and wherein said at least a extra antiviral drugs is selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, glycosidase inhibitor, the unwindase inhibitor, and Toll sample receptor stimulating agent.

Embodiment 26. is selected from the chemical compound in following group:

Embodiment is used for influencing the active pharmaceutical composition of the viral IRES of the individuality of suffering from viral infection for 29. 1 kinds, and it comprises that one or more have with the chemical compound of following formula or the acceptable salt of its materia medica, the acceptable excipient of materia medica and the active chemical compound of one or more IRES of influence as known in the art randomly:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, R wherein _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and

R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, its optional quilt-individual or a plurality of halogens replace;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CHO ₂COR _x, and R _xAs defined above.

Embodiment 30. is as enforcement scheme 29 described pharmaceutical compositions, the translation of the single ORF of wherein said one or more coding polyproteins that influence the active compounds affect IRES mediation of IRES as known in the art.

The active method of viral IRES in the individuality of viral infection is suffered from 31. 1 kinds of influences of embodiment, and it comprises that to described individual administration one or more have with the chemical compound of following formula or the acceptable salt of its materia medica and the acceptable excipient of materia medica and the active chemical compound of one or more IRES of influence as known in the art randomly:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Embodiment 32. is as the method for enforcement scheme 31, the translation of the single ORF of the wherein said coding polyprotein that influences the active compounds affect IRES mediation of IRES as known in the art.

Embodiment is used for influencing the active pharmaceutical composition of the viral IRES of the individuality of suffering from viral infection for 33. 1 kinds, it comprises that one or more have chemical compound or acceptable salt of its materia medica and the acceptable excipient of materia medica with following formula, and the amount of wherein said chemical compound can influence viral IRES activity effectively:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, R wherein _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls, and R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Description of drawings

Fig. 1 has shown that the HCV-PV chimera makes up.The SANYE blade of grass sample RNA structure of PV is to connect the end capped basic cis acting reproducing signals of albumen VPg by genome, and it is positioned at this genomic 5 ' end.Solid (HCV) and hollow (PV) square has been described the open reading-frame of coding virus polypeptide.The position Δ kernel representation of HCV core fragment (first group of 123 aminoacid) gene.In a word, the HCV specific sequence span among this HCV-PV is nucleotide 18-710 (139).

The specific embodiment

According to the present invention, identified the chemical compound that changes the HCV translation and provide and used these chemical compounds to prevent or treat the method for HCV infection.Be not limited to a kind of restriction of theory, it is believed that chemical compound of the present invention suppresses the initial sum translation of IRES mediation.This HCV IRES relates to the translation of ORF of the single length of the polyprotein of encoding, and this polyprotein is processed at least 10 sophisticated virus proteins after translation, comprises described structural protein nuclear (inferring nucleocapsid), E1 and E2 and non-structure (NS) albumen NS2-NS5B.

A. chemical compound of the present invention

In one aspect of the invention, the The compounds of this invention that is provided can be used for prevention or treatment HCV infection.

The The compounds of this invention that is used to prevent or treats HCV to infect preferably includes the chemical compound with following formula (I).

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, R wherein _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

Group, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above;

Or the acceptable salt of its materia medica.

In another preferred embodiment, chemical compound of the present invention or compositions comprise the chemical compound of formula I, and wherein the chemical compound of this formula I is not following chemical compound 1.

Chemical compound 1

Typically refer to the saturated hydrocarbyl of straight chain, side chain or cyclic configuration or cyclic configuration and side chain or straight chain combination at this used term " alkyl ", comprise methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl group, positive decyl etc.In some embodiment just, alkyl substituent can be C ₁-C ₁₂Or C ₁-C ₈Or C ₁-C ₆Alkyl.

Typically refer to straight chain, side chain or ring-type thiazolinyl at this used term " thiazolinyl ", as C based on one or more carbon-to-carbon double bonds ₂-C ₆Thiazolinyl comprises the 3-acrylic.

Be meant the carbocyclic ring aromatic ring structure at this used term " aryl ".The scope of aryl comprises the aromatic rings with 5-20 carbon atom.The aryl rings structure comprises the chemical compound with one or more ring structures, for example monocyclic, bicyclic or tricyclic chemical compound.The example of aryl comprises phenyl, tolyl, anthryl, fluorenyl, indenyl, azulenyl, phenanthryl (phenanthrene promptly) and naphthyl (naphthalene promptly) ring structure.In certain embodiments, this aryl can be chosen wantonly and be substituted.

Be meant that at this used term " heteroaryl " atom in wherein one or more rings is the ring-type aromatic ring structure of the element (hetero atom) of non-carbon.Hetero atom is generally O, S or N atom.The heteroaryl scope comprises O, N and S heteroaryl ring structure, and can independently select.Described ring structure can comprise the chemical compound with one or more ring structures, for example monocyclic, bicyclic or tricyclic chemical compound.In certain embodiments, heteroaryl can be selected from and comprise 2 or more a plurality of hetero atom, 3 or more a plurality of hetero atom or 4 or more a plurality of heteroatomic heteroaryl.Heteroaryl can be selected from the heteroaryl that comprises 5 or more a plurality of atom, 6 or more a plurality of atom or 8 or more a plurality of atoms.The heteroaryl ring example of structure comprises: acridine, benzimidazole, benzoxazole, benzo dioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-benzodiazine, furan, furazan, imidazoles, indole isoxazole, isoquinolin, isothiazole, oxazole, purine, pyridazine, pyrazoles, pyridine, pyrazine, pyrimidine, pyrroles, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazines, 1,2,4-triazine, 1,2,3-triazine, tetrazolium and quinazoline.

Be meant that at this used term " heterocycle " atom is the cyclic rings structure of the element (hetero atom) of non-carbon in wherein one or more rings.Hetero atom is generally O, S or N atom.The heterocycle scope comprises O, N and S heterocyclic ring structure, and can independently select.Described ring structure can comprise the chemical compound with one or more ring structures, for example monocyclic, bicyclic or tricyclic chemical compound.The example of heterocyclic radical comprises and faces base, pyrrolidone-base, pyrrolidinyl, piperidyl, piperazinyl, hydantoin base, valerolactam base, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl or tetrahydro thiapyran base etc.In certain embodiments, this heterocycle can be chosen wantonly and be substituted.

Typically refer at this used term " alkoxyl " and to have-group of O-R structure, wherein R is an alkyl as defined above.

For the present invention, halogenic substituent can be independently selected from halogen, as fluorine, chlorine, bromine, iodine and astatine.Haloalkyl is meant the alkyl as defined above that is replaced by one or more halogens.Halogenated alkoxy is meant the alkoxyl as defined above that is replaced by one or more halogens.

For the present invention, if comprise X, Y, Z, R, R ₁, R ₂, and R ₃One or more functional groups be connected in formula (I) molecule, each functional group all appears at any position of disclosed chemical compound, then they can be selected independently, and can be suitably independent the replacement.In addition, if in molecule of the present invention, mentioned more upper substituent group, it will be appreciated that then on this that bit substituent can be by more specifically substituent group displacement, and the molecule of gained is still in the scope of molecule of the present invention.

Term " replacement " or " the optional replacement ", are meant that concrete substituent group can be replaced for the suitable chemical group of described substituent group by well known by persons skilled in the art, unless mention chemical group especially.

Exemplary X substituent group comprises following person, wherein symbol ^*The connecting key of representing this structure molecule.

Preferred X substituent group comprises :-hydrogen;-cyano group; And-COR _aGroup, wherein R _aBe-C ₁-C ₆Alkyl or-dialkyl amido.

Preferred X substituent group also comprises following person, wherein symbol ^*The connecting key of representing this structure molecule.

Preferred X substituent group comprises following person, wherein symbol ^*The connecting key of representing this structure molecule.

Exemplary Y substituent group comprises following person, wherein symbol ^*The connecting key of representing this structure molecule.

Preferred Y substituent group comprises following person, wherein symbol ^*Expression makes up the connecting key of molecule.

Preferred Y substituent group comprises following person, wherein symbol ^*Expression makes up the connecting key of molecule.

Exemplary Z substituent group comprises following person, wherein symbol ^*Expression makes up the connecting key of molecule.

Preferred Z substituent group comprises :-hydrogen;-C ₁-C ₆Alkyl, it is optional to be replaced by following group :-alkoxyl ,-one or more halogens or-C ₆-C ₈Aryl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

Preferred Z substituent group also comprises following person, wherein meets ^*Expression makes up the connecting key of molecule.

Preferred Z substituent group comprises :-hydrogen;-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group :-C ₆-C ₈Aryl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

Preferred Z substituent group comprises following person, wherein meets ^*Expression makes up the connecting key of molecule.

Exemplary R substituent group comprises following person:

Preferred R substituent group comprises following person:

Exemplary R ₁Substituent group comprises following person:

Preferred R ₁Substituent group comprises :-hydrogen;-halogen;-nitro;-5 or 6 yuan of heterocycles;-optional by C ₆-C ₈The alkoxyl that aryl replaces; The C of-optional alkoxy replacement ₆-C ₈Aryl.

Preferred R ₁Substituent group also comprises following person:

Preferred R ₁Substituent group comprises following person:

Exemplary R ₂Substituent group comprises following person:

Preferred R ₂Substituent group comprises :-nitro;-hydrogen;-halogen;-hydroxyl;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens,--OCOR _xGroup, wherein R _xAs defined above, the dialkyl amido of-optional alkoxy replacement ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, or-5 or 6 yuan of heteroaryls;-amide groups; And--NHSO ₂R _xGroup, wherein R _xAs defined above.

Preferred R ₂Substituent group also comprises following person:

Preferred R ₂Substituent group comprises :-hydrogen;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, perhaps-5 or 6 yuan heteroaryl.

Preferred R ₂Substituent group also comprises following person:

Exemplary R ₃Substituent group comprises following person:

Preferred R ₃Substituent group comprises following person:

*——H

Chemical compound of the present invention comprises following person:

Above-claimed cpd is to use synthetic route as described below and embodiment to make.The additive method for preparing these chemical compounds is known for those skilled in the art.

Preferred chemical compound comprises following chemical compound listed in the Table A:

Table A

Preferred chemical compound comprises the chemical compound among the following table B:

Table B

B. The preparation of The compounds of this invention

Benzazolyl compounds of the present invention can prepare by the known synthetic method of standard.Many indole starting materials can prepare by route as described below or route well known by persons skilled in the art.

The formula I chemical compound of structure I I representative can be prepared shown in following synthetic route A:

With alkali such as sodium tert-butoxide or potassium or sodium hydride handle Nitrocarbol. and the Nitrocarbol. anion that makes with activated carboxylic acid derivates such as acyl group imidazolide A1 processing, can obtain α-nitroketone derivant A2 thus.The reaction of α-nitroketone A2 and amine derivative A3 by blending constituent A3 and A4, is heated in suitable solvent such as alcohol or aprotic solvent then, can obtain Nitroenamine A4.In proton solvent such as acetic acid,, obtain the chemical compound of formula II in room temperature or near handling Nitroenamine A4 with quinone A5 under the room temperature.

Synthetic route A

The formula I chemical compound of structure III representative can be prepared shown in following synthetic route B:

In suitable solvent, under heating or the situation about not heating, when having alkali to exist, inorganic base for example, as sodium carbonate or potassium carbonate, perhaps organic base as triethylamine, with the reactive alkyl or aryl treatments B 1 that comprises leaving group L, can obtain the chemical compound of structure III.The example of leaving group includes but not limited to halogen (as chlorine, bromine or iodine) or alkyl or aryl sulphonic acid ester.

Synthetic route B

The formula I chemical compound of structure I V representative can be prepared shown in following synthetic route C:

The chemical compound of structure I V can carry out nitrated the preparation by the indole to structure C 1, to obtain 3-nitroindoline C2.This Nitrification can by with nitrating agent such as nitric acid or sodium nitrite in solvent such as acetic acid, acetic anhydride, sulphuric acid or comprising and handle C1 in the mixed solvent system of organic solvent such as dichloromethane and implement.This reaction can be held under-30 ℃ to+50 ℃ temperature.With the reactivity functional group R that comprises suitable leaving group L ₉(C3) handle the chemical compound that C2 forms structure I V.Reactive functional groups includes but not limited to alkyl and aralkyl.L can represent halogen, particularly chlorine, bromine or iodine or alkyl sulfonic ester.Hold under the situation that reaction between C2 and the C3 can have inorganic base such as potassium carbonate or sodium hydride or organic base such as trialkylamine to exist in suitable solvent.Perhaps, radicals R ₉Can represent aryl or heteroaryl, and L can represent halogen, as chlorine, bromine or iodine.This reaction can be in polarity or non-polar solven exists copper catalyst such as CuI, alkali such as Cs under the temperature of room temperature to 200 ℃ ₂CO ₃Or K ₃PO ₄, and randomly amine ligand is as 1, two (methylamino) ethane or 1 of 2-are held under the situation of 2-cyclohexane diamine.

Alternative method is according to being similar to aforesaid mode C1 to be converted into C4, holds nitration reaction then, to produce the chemical compound of structure I V.

Synthetic route C

The formula I chemical compound of structure V representative can be prepared shown in following synthetic route D:

With the beta-keto esters of amine D2 Processing Structure D1,, produce amino crotonates derivant D3 by in suitable solvent such as alcohol or aprotic solvent, heating.Reaction between D3 and the quinone D4 in polar aprotic solvent such as acetic acid produces the chemical compound of structure V.

Synthetic route D

The The compounds of this invention of structure VI chemical compound representative can prepare by the chemical method of describing among the following synthetic route E.

With for example acid or alkali in aqueous solvent or water-organic mixed solvent under the temperature of room temperature or rising the chemical compound of Processing Structure E1, perhaps in suitable solvent, handle, indole-3-carboxylic acid's ester E1 can be converted into indole-3-carboxylic acid E2 thus with nucleophilic reagent such as Boron tribromide or trimethyl silyl iodine.The chemical compound of E2 type then can activate, and handles with the amine of E3 type then, obtains compd E 4.The activation of carboxylic acid for example can be implemented by any standard method halogen.For example; described sour E2 can be activated when being with or without HOBt under the situation that has amine E3 with coupling agent such as EDCl or DCC; perhaps; this acid is activated and is acyl chlorides by handles acid with for example thionyl chloride or oxalyl chloride, perhaps passes through to be activated with the processing that carbonyl dimidazoles is handled acid and then held amine E3 to be acyl group imidazolide.As mentioned above, with the reactive functional groups R that comprises suitable leaving group L ₉(E5) handle E4, compd E 4 can be converted into the chemical compound of structure VI thus.Perhaps, the chemical compound of E1 type can be by handling the chemical compound that is converted into structure E6 with E5.Indole-3-carboxylic acid's ester E6 then can be converted into indole-3-carboxylic acid E7 by aforesaid method.E7 can finish by aforesaid activation and with the reaction of amine E3 to the conversion of compounds of structure VI.

Synthetic route E

The The compounds of this invention of structure VII chemical compound representative can prepare by the chemical method of describing among the following synthetic route F.

Benzazolyl compounds F1 can use such as the reagent of phosphoryl chloride phosphorus oxychloride in the presence of DMF and hold formylated, to form indole-3-formaldehyde F2.Can finish by handling F2 as previously mentioned to structure VII conversion of compounds with compound F 17-hydroxy-corticosterone 3.Perhaps, the chemical compound of F1 type can at first be converted into F4, is turned to the chemical compound of structure VII then by formyl.

Synthetic route F

The formula G chemical compound of structure VIII representative can be held preparation described in synthetic route G.

The indole-3-formaldehyde chemical compound of structure G1 can pass through to use under aqueous conditions to be held oxidation such as the reagent of potassium permanganate and is converted into indole-3-carboxylic acid's derivant.

VII. synthetic route G

The formula H chemical compound of structure I X representative can prepare shown in synthetic route H.

The indole-3-formaldehyde chemical compound of structure H1 can be converted into indole-3-carbonitrile derivatives H2 by the whole bag of tricks.In the presence of amine source, handle H1 with nitroparaffins such as nitropropane, form indole-3-nitrile H2 derivant such as ammonium hydrogen phosphate.The other approach that obtains compound H 2 is by intermediate H3.H1 can followingly carry out to the conversion of 9 oxime derivate H3: dehydration, for example use the described oxime of acetic anhydride and alkali treatment, or described oxime and thionyl chloride reaction, to form H2.Compound H 2 can be followed as previously mentioned and the reactive functional groups R that comprises suitable leaving group L ₉(H4) reaction, the chemical compound of formation structure I X.

Perhaps, H1 can with the reactive functional groups R that comprises suitable leaving group L ₉(H4) reaction, to form intermediate H5, it can react with nitroparaffins as mentioned above, forms indole-3-nitrile compound IX.Compound I X also can be as mentioned above by being converted into oxime H6, holding dehydration then and prepare.

VIII. synthetic route H

The The compounds of this invention of structure X representative also can prepare shown in following synthetic route I.

Benzazolyl compounds I1 can be at suitable solvent or solvent mixture such as DMF, CH ₃Carry out cyaniding with suitable cyanidization agent such as chloro sulfonyl isocyanate (I2) or dialkyl phosphoryl isocyanates in CN or the dioxane, to obtain the chemical compound of structure I 3.Compound I 3 can be followed as previously mentioned and the reactive functional groups R that comprises suitable leaving group L ₉(I4) reaction obtains compounds X.

Perhaps Compound I 1 can with the reactive functional groups R that comprises suitable leaving group L ₉Reaction, to form the chemical compound of structure I 5, it obtains the chemical compound of formula X then as mentioned above by cyaniding.

IX. synthetic route 1

The formula J chemical compound of structure XI representative can prepare shown in following synthetic route J.

Amino crotonates chemical compound J1 can form J3 with amine J2 reaction.The reaction in the presence of polar aprotic solvent such as acetic acid of J3 and quinone forms the chemical compound of structure XI.

X. synthetic route J

The The compounds of this invention of structure XII and XIII representative can prepare shown in following synthetic route K.

The aldehyde of structure K1 reacts by heat these compositions in appropriate organic solvent in the presence of organic or inorganic alkali with alkyl azide yl acetate K2, and described solvent for example is proton or aprotic solvent, to form α-azido acrylate K3.Heating K 3 in suitable non-reacted organic solvent such as toluene or dimethylbenzene can form 2-alkoxy carbonyl benzazolyl compounds K4.In suitable solvent such as ether or THF with appropriate reductant as ester functional group as described in the lithium aluminium hydride reduction, produce intermediate K5.As previously mentioned, with the reactive functional groups R that comprises suitable leaving group L ₉(K6) reduction K5 forms compound K 7.As previously mentioned, K7 is carried out cyaniding, form compounds X II with cyanidization agent such as chloro sulfonyl isocyanate.Perhaps, with chloro sulfonyl isocyanate K5 is carried out cyaniding, form K8, this chemical compound can be as previously mentioned and the reactive functional groups R that comprises suitable leaving group L ₉(K6) reaction obtains compounds X II.

Below illustrate the other using method of intermediate K4.2-alkoxy carbonyl to indole K4 under acidity or alkali condition is hydrolyzed, and decarboxylation forms intermediate K9 then.Decarboxylation can be implemented under the condition of heating, for example heats at suitable solvent such as toluene, dimethylbenzene or quinoline.Perhaps, can add the ketone source, as bronze, to promote the decarboxylation reaction.As mentioned above, K9 and the reactive functional groups R that comprises suitable leaving group L ₉(K6) reaction can form compound K 10.As previously mentioned, K10 is carried out cyaniding, form compounds X III with cyanidization agent such as chloro sulfonyl isocyanate.Perhaps, with chloro sulfonyl isocyanate K9 is carried out cyaniding, obtain K11, this chemical compound can be as previously mentioned and the reactive functional groups R that comprises suitable leaving group L ₉(K6) reaction obtains compounds X III.

XI. synthetic route K

The formula L chemical compound of structure XIV representative can prepare shown in following synthetic route L.

The chemical compound of formula L1 can be by halogenation on the 2-methyl, to form 2-bromomethyl or chloromethyl benzazolyl compounds L2.This halogenation can be used such as the reagent of N-bromo-or chlorosuccinimide and implement.This reaction can be carried out in suitable solvent such as chloroform, carbon tetrachloride or THF, and can implement in the scope of room temperature to 80 ℃.Randomly, can add radical initiator, as benzoyl peroxide base or AIBN.Compound L 2 is followed and nucleophilic reagent R ₅-W (L3) reaction, the chemical compound of formation structure XIV.This reaction can be at suitable solvent such as THF, CH ₂Cl ₂Or under 0 ℃-120 ℃ temperature range, implement among the DMF.Can use alkali such as inorganic base or organic base, described inorganic base for example is a potassium carbonate, and organic base for example is a trialkylamine, to remove the acid that forms in this reaction.Group W can be N, O or S atom.

XII. synthetic route L

The chemical compound of the present invention of structure XV representative can be prepared described in following synthetic route M.

The aniline compound of structure M1 can be by diazotising, and the diazol of gained, to form phenyl hydrazine chemical compound M2.Under acid condition, react between this hydrazine M2 and the ketone M3, form benzazolyl compounds M4.The condition of cyclization can be the representative condition that those skilled in the art use, and for example acid condition wherein uses acid, for example Bronstead acid, and as acetic acid, hydrochloric acid or polyphosphoric acid, perhaps Lewis acid is as zinc chloride.This reaction can be at cosolvent such as CH ₂Cl ₂Or THF exists the common down temperature range at 0 ℃-120 ℃ to implement.As previously mentioned, M4 and the reactive functional groups R that comprises suitable leaving group L ₉(M5), obtain chemical compound M6.Cyanidization agent such as chloro sulfonyl isocyanate carry out cyaniding to indole M6, form the chemical compound of structure XV.

Perhaps, described indole M4 can be by cyaniding, to form the chemical compound of structure M7.As mentioned above, M7 and the reactive functional groups R that comprises suitable leaving group L ₉(M5) reaction, the chemical compound of formation structure XV.

XIII. synthetic route M

The formula I chemical compound of structure XVI representative synthetic route N as shown below prepares.

The chemical compound of formula N1 can with dialkylformamide dialkyl acetal N2 (as dimethylformamide dimethyl acetal) randomly in the presence of suitable solvent such as DMF or dioxane in the temperature range internal reaction of room temperature to 150 ℃, to form the chemical compound of structure N3.The nitro of reduction N3 type chemical compound under standard conditions obtains the benzazolyl compounds of structure N4.This reduction reaction can implemented by hydrogenation in proton solvent or aprotic solvent in the presence of the hydrogen source, wherein uses hydrogenation catalyst such as the platinum or the palladium of substoichiometric amount.This reduction can be carried out in the temperature range of room temperature to 80 ℃.Perhaps, this reduction reaction can be undertaken by electronation, is for example carrying out this reaction in the temperature range of room temperature to 100 ℃ in the presence of the Fe of stoichiometry or the Sn chemical compound in suitable solvent.As previously mentioned, compound N 4 can be then and the reactive functional groups R that comprises suitable leaving group L ₉(N5) to obtain the chemical compound of structure N6.N6 carries out cyaniding with cyanidization agent such as chloro sulfonyl isocyanate in suitable solvent, can form the chemical compound of structure XVI.

Perhaps, the chemical compound of structure N4 can be by cyaniding, to form the chemical compound of structure N7.As mentioned above, N7 and the reactive functional groups R that comprises suitable leaving group L ₉(N5) react, can form the chemical compound of structure XVI.

XIV. synthetic route N

The formula I chemical compound of structure XVII representative can prepare by synthetic route O as shown below.

The chemical compound of structure O1 is converted into 2-iodo-or bromo indole chemical compound O2.Typically, use highly basic,, be formed on non-reactive solvent such as ether or THF or comprise the 2-indyl anion that produces in its solvent mixture as n-butyl lithium or s-butyl lithium or LDA or lithium or hexamethyl two silicon potassium nitrides.This reaction is carried out to the scope of room temperature at-78 ℃ usually.This 2-indyl anion is then carried out cancellation with the close power supply of halogen, and the close power supply of this halogen includes but not limited to iodine, bromine or N-bromine butanimide, to form the chemical compound of structure O2.2-iodo-or bromo indole chemical compound O2 and boric acid (being commonly referred to the Suzuki reaction) or trialkyl stannane (being commonly referred to the Stille reaction) reaction can form the chemical compound of structure XVII.Coupling reaction can be implemented according to method known to those skilled in the art, and is included under the situation of acid chloride of the phosphine part that has catalyst such as tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or have interpolation and carries out this reaction.This is reflected in suitable solvent such as DMF, toluene, dimethoxy-ethane or the dioxane in the temperature range of room temperature to 150 ℃ and carries out.For described Suzuki reaction, add alkali usually.This alkali can be in aqueous solution, for example aqueous sodium carbonate or sodium bicarbonate aqueous solution, and perhaps this alkali can use under anhydrous condition, as cesium fluoride or potassium fluoride.For described Stille reaction, can add the copper cocatalyst, as Copper diiodide.

Perhaps, aforesaid 2-indyl anion is reacted with trialkylboron acid esters or chlorine trialkyltin alkane derivatives respectively, thus benzazolyl compounds O1 is converted into indole-2-boric acid or indole-2-trialkyltin alkane derivatives O3.The chemical compound of O3 type can with aryl and heteroaryl bromide and iodide with the similar condition of above-mentioned condition under react, to form the chemical compound of structure XVII.

XV. synthetic route O

The formula I chemical compound of structure XVIII representative can prepare by synthetic route P as shown below.

P1 handles with aryl or heteroaryl halogenide (P2) in the presence of organo-metallic catalyst, and the chemical compound with structure P1 is converted into Compound P 3 thus.These catalyst combination can comprise palladium catalyst such as acid chloride and copper source such as Copper diiodide.This reaction can be implemented in the presence of alkali such as cesium carbonate.This reaction can be carried out in the temperature range of room temperature to 150 ℃.

XVI. synthetic route P

The The compounds of this invention of structure XIX representative can prepare shown in following synthetic route Q.

The chemical compound of structure XIX can prepare by the benzazolyl compounds (for example being the form of N-Boc derivant Q2) of protection structure Q1.Perhaps, other operable protecting groups include but not limited to for example benzyl, alkyl or aryl sulfonyl or trialkylsilkl.Q2 handles in aprotic solvent such as THF with highly basic such as LDA, uses the cancellation of trialkylboron acid ester derivant then, can form indyl-2-boric acid Q3.At palladium catalyst such as tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or have in the presence of the acid chloride of phosphine part of interpolation and aryl or heteroaryl halogenide Q4 reaction, can form compound Q 5.Remove protecting group and can form Q6.As mentioned above, Q6 and the reactive functional groups R that comprises suitable leaving group L ₉Reaction obtains the chemical compound of structure Q7.The cyaniding of compound Q 7 can make the chemical compound of structure XIX.

XVII. synthetic route Q

The formula I chemical compound of structure XX representative can prepare shown in following synthetic route R.

As mentioned above, the chemical compound of structure R1 can prepare by the benzazolyl compounds (for example being the form of N-Boc derivant R2) of protection structure R1.The chemical compound of structure R2 is converted into 2-iodo-or bromo indole compound R 3.

Typically, use highly basic,, be formed on non-reactive solvent such as ether or THF or comprise the 2-indyl anion that produces in their solvent mixture as n-butyl lithium or s-butyl lithium or LDA or lithium or hexamethyl two silicon potassium nitrides.This reaction is carried out to the scope of room temperature at-78 ℃ usually.This 2-indyl anion is then carried out cancellation with the close power supply of halogen, and the close power supply of this halogen includes but not limited to iodine, bromine or N-bromine butanimide, to form the chemical compound of structure R3.After removing protecting group, the chemical compound of R4 can with aryl or heteroaryl boric acid or ester (R5) reaction (being commonly referred to the Suzuki reaction), to form the chemical compound of structure R6.Coupling reaction can be implemented according to method known to those skilled in the art, and is included under the situation of acid chloride of the phosphine part that has catalyst such as tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or have interpolation and carries out this reaction.As mentioned above, R6 and the reactive functional groups R that comprises suitable leaving group L ₉Reaction can form the chemical compound of structure XX.

XVIII. synthetic route R

The The compounds of this invention of structure XXI representative can prepare shown in following synthetic route S.

The 2-iodo-of structure S1 or bromo indole chemical compound can be in the presence of palladium catalysts and olefine reaction (being commonly referred to the Heck reaction), to form the chemical compound of XXI type.Coupling reaction can be carried out according to method known to those skilled in the art.Described content before catalyst and choice of Solvent are similar to.

XIX. synthetic route S

The formula I chemical compound of structure XXII representative can prepare shown in following synthetic route T.

The 2-iodo-of structure T1 or 2-bromo indole chemical compound can react (being commonly referred to the Sonagashira reaction) with alkynes in the presence of palladium catalyst, with the compounds X XII of formation type.Coupling reaction can be carried out according to method known to those skilled in the art.The typical reaction condition of one cover comprises following benzazolyl compounds and the acetylide T2 reaction that makes structure T1: wherein have palladium source, copper cocatalyst and amine source.This is reflected in the suitable non-reactive solvent and implements, and carries out in the temperature range of room temperature to 150 ℃.

XX. synthetic route T

The formula I chemical compound of structure XXIII representative can prepare shown in following synthetic route U.

The chemical compound of structure XXIII can prepare by reducing compound XXI and XXII.The condition of this reduction reaction includes but not limited at suitable solvent such as CH ₂Cl ₂, the catalytic reduction in ether, THF, methanol or the solvent combination, as the hydrogenation on platinum or palladium source.

XXI. synthetic route U

The structure XXIV The compounds of this invention of representative can prepare shown in following synthetic route V.

The benzazolyl compounds of structure V1 can with suitable alkali such as LDA or the reaction of hexamethyl two silicon potassium nitrides with at suitable non-reactive solvent such as ether, THF or comprise in their solvent mixture and produce 2-indyl anion.This reaction is carried out to the temperature of room temperature at-78 ℃ usually.This 2-indyl anion can be then carried out cancellation with zinc halide source such as zinc halogenide metal or the solution that comprises them, to form the organic zinc compound of structure V2.V2 reacts (being commonly referred to the Negishi reaction) with aryl halide (V3) in the presence of palladium catalyst, form the chemical compound of structure XXIV.Perhaps, the 2-iodine of the structure V4 that is made by chemical compound V1 or bromo indole chemical compound can be in the presence of suitable palladium catalyst and the organic zinc compound reaction of structure V5 as previously mentioned, to form the chemical compound of structure XXIV.Organic zinc compound V5 can be obtained from for example alkyl or alkenyl halogenide after handling with activated zinc, perhaps be obtained from aryl or heteroaryl lithium or magnesium compound after handling with zinc halogenide.In addition, the reaction of V2 or V4 can carried out in suitable solvent and in the temperature range of room temperature to 150 ℃ in the presence of palladium source such as tetrakis triphenylphosphine palladium (0) or two (triphenylphosphine) palladium chloride (II).

XXII. synthetic route V

The formula I chemical compound of structure XXV-XXVIII representative can prepare shown in following synthetic route W.

The 2-iodo-of structure W1 or the chemical compound of bromo indole can be in the presence of palladium catalysts and the alkynes reaction (being commonly referred to the Sonagashira reaction) of structure W2, with the compounds X XV of formation type.Coupling reaction can be carried out according to method known to those skilled in the art.The typical reaction condition of one cover is included in the palladium source, there be benzazolyl compounds and the acetylide W2 reaction that makes structure W1 down in optional copper cocatalyst and amine source.This is reflected in the suitable non-reactive solvent and implements, and carries out in the temperature range of room temperature to 150 ℃.As mentioned above, XXV and the reactive functional groups R that comprises suitable leaving group L ₉Reaction can form the chemical compound of structure XXVI.

The 2-iodo-of structure W1 or bromo indole chemical compound also can be in the presence of palladium catalysts and olefine reaction (being commonly referred to the Heck reaction), with the compounds X XVII of formation type.Coupling reaction can be carried out according to method known to those skilled in the art.Catalyst and choice of Solvent and former described content class are seemingly.As mentioned above, XXVII and the reactive functional groups R that comprises suitable leaving group L ₉Reaction can form the chemical compound of structure XXVIII.

XXIII. synthetic route W

The formula I chemical compound of structure XXIX representative can prepare shown in following synthetic route X.

The carboxylic acid halides of the benzazolyl compounds possible constructions X2 of structure X1 carries out acidylate, forms the chemical compound of structure XXIX.This reaction can promote by Lewis acid.The selection of Lewis acid can be selected from but be not limited to aluminum chloride, iron chloride, stannic chloride or diethyl aluminum.This is reflected in the suitable non-reactive solvent and carries out, and comprises CH ₂Cl ₂, Carbon bisulfide or dichloromethane, and in-20 ℃ to 80 ℃ temperature range, implement usually.

XXIV. synthetic route X

The formula I chemical compound of structure XXX representative can prepare shown in following synthetic route Y.

Handle with for example Hydrazoic acid,sodium salt, thus the 3-cyanoindole chemical compound of structure Y1 is converted into the tetrazole compound of structure Y2.The mixture of heating Y2 and reagent Y3 can form 3-(1,2,4-4-oxadiazole base) benzazolyl compounds XXX.Reagent Y3 can for example be an acyl halide or with reagent such as dicyclohexylcarbodiimide or the activatory derivant of DIC.This reaction can be carried out in all kinds of solvents, for example comprises toluene, dioxane, pyridine and dichloromethane, and can implement by heating Y2 and Y3 under 30 °-130 ℃ temperature.

XXV. synthetic route Y

The structure XXXI formula I chemical compound of representative can prepare shown in following synthetic route Z.

The 3-cyanoindole chemical compound of structure Z1 can with azanol reaction, to form the hydroxyamidines chemical compound of formula Z2.The chemical compound reaction of the hydroxyamidines of structure Z2 and structure Z3 can form O-acyl group hydroxyamidines Z4.Chemical compound Z3 typical example such as carboxylic acid halides or use such as the activatory carboxylic acid of the reagent of dicyclohexylcarbodiimide or DIC.In non-reacted organic solvent such as toluene, dichloromethane or dioxane,, form the chemical compound of structure XXXI in the chemical compound of 30 ℃-150 ℃ temperature range internal heating structure Z4.

XXVI. synthetic route Z

The chemical compound of the present invention of structure XXXII representative can prepare shown in following synthetic route AA.

The ketone group benzazolyl compounds of AA1 type is converted into the oxime of structure AA2 by this ketone group benzazolyl compounds of heating and azanol (free alkali or hydrochlorate) in suitable solvent.Make the two deprotonations of chemical compound of AA2 type with strong organic base (as n-BuLi or s-butyl lithium or tert-butyl lithium),, form the chemical compound of formula XXXII then with the DMF reaction.

XXVII. synthetic route AA

The formula I chemical compound of structure XXXIII representative can prepare shown in following synthetic route AB.

The 3-ketone group benzazolyl compounds of structure AB1 can be vinylogy (vinylogous) amide compound of structure AB3 by isomorphismization (homologated) by the reaction with dialkyl amide dialkyl acetal AB2.This dialkyl amide can comprise for example low alkyl group amide, as Methanamide, acetamide and propionic acid amide..Example comprises dimethylformamide dimethyl acetal and dimethylacetamide dimethylacetal.This reaction can be by implementing when adding or not adding solvent AB1 and AB2 being reacted under the temperature of room temperature to 150 ℃.In suitable solvent, handle the chemical compound that AB3 produces structure XXXIII with azanol (free alkali or hydrochlorate).This reaction is usually carried out in the temperature range of room temperature to 120 ℃.

XXVIII. synthetic route AB

The formula I chemical compound of structure XXXIV representative can prepare shown in following synthetic route AC.

The vinylogous amide chemical compound of structure AC1 (as above preparation) can be in appropriate organic solvent (DMF, alcohol or acetic acid) be handled with hydrazine AC2 under the temperature of room temperature to 150 ℃, to form the chemical compound of structure XXXIV.

XXIX. synthetic route AC

The chemical compound of the present invention of structure XXXV representative can prepare shown in following synthetic route AD.

The indole-3-formaldehyde chemical compound of structure AD1 (as preparing among the synthetic route F) can react with p-(tosyl) methyl isocyanate (TOSMIC) in the presence of alkali, to form the chemical compound of structure XXXV.Described alkali can comprise potassium carbonate or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, and also this reaction can be in appropriate organic solvent be carried out under room temperature to 150 ℃.

XXX. synthetic route AD

The formula I chemical compound of structure XXXVI and XXXVII representative can prepare shown in following synthetic route AE.

The 3-indole-carboxylic acid of structure AE1 (by synthetic route E) is converted into the amide of structure AE2.The chemical compound of structure AE2 can activate by standard method arbitrarily.For example, sour AE1 can be in the presence of ammonia activates with coupling agent such as EDCI or DCC when being with or without HOBt.Perhaps, described acid can be activated as previously mentioned to acyl chlorides or acyl group imidazolide, uses ammonia treatment then.

The indole of structure AE2-3-Methanamide can be in suitable solvent under the temperature of room temperature to 200 ℃ with the aldehydes or ketones that is substituted (AE3) reaction that comprises suitable leaving group L.This reaction can be implemented under the situation of adding or not adding alkali, to obtain structure XXXVI De oxazole chemical compound.

Also can in suitable,, this primary amide chemical compound can be converted into the thioamides of structure AE4 thus at indole-3-benzamide compound of room temperature or usefulness Lawesson reagent of the temperature more than the room temperature or Phosphoric sulfide Processing Structure AE2.The thioamide compound AE4 of gained can be in suitable solvent under the temperature of room temperature-150 ℃ with the aldehydes or ketones that is substituted (AE3) reaction that comprises suitable leaving group L.This reaction can be implemented under the situation of adding or not adding alkali, to obtain the thiazolium compounds of structure XXXVII.

XXXI. synthetic route AE

The The compounds of this invention of structure XXXVIII and XXXIX representative can prepare shown in following synthetic route AF.

The 3-ketone group benzazolyl compounds of structure AF1 can be by halogenation (for example bromination), to form the chemical compound of structure AF3.Suitable bromating agent includes but not limited to phenyl trimethyl tribromide ammonium (AF2), N-bromine butanimide or bromine, and can implement in various organic solvents.

Adding or do not adding under the situation of alkali, in suitable solvent under the temperature of room temperature-200 ℃ with AF4 type amide-treated compd A F3, obtain structure XXXVIII De oxazole chemical compound thus.

Add or do not add alkali, to obtain the thiazolium compounds of structure XXXIX.Compd A F3 in suitable solvent under the temperature of room temperature-150 ℃ the thioamides with the AF5 type handle, obtain the thiazolium compounds of structure XXXIX.

XXXII. synthetic route AF

The formula I chemical compound of structure XL representative can prepare shown in following synthetic route AG.

The benzazolyl compounds of structure AG1 can be by bromination or iodate, to form the chemical compound of structure AG2.Bromating agent can include but not limited to bromine or N-bromine butanimide, and iodating agent can comprise single lodine chloride or two-trifluoroacetyl oxygen base iodobenzene.The reaction of 3-iodo-or bromo indole compd A G2 and boric acid AG3 (being commonly referred to the Suzuki reaction) can form the chemical compound of structure XL.Coupling reaction is undertaken by method known to those skilled in the art, and the acid chloride that is included in catalyst such as tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or has a phosphine part of increase exists and to implement this reaction down.This is reflected in suitable solvent such as DMF, toluene, dimethoxy-ethane or the dioxane in the temperature range of room temperature to 150 ℃ and implements, and there is alkali usually, for example aqueous carbonic acid sodium or sodium bicarbonate, perhaps this alkali can use under anhydrous condition, as cesium fluoride or potassium.

Perhaps, make 3-halogeno indole AG2 and strong organic base (lithium alkylide or grignard reagent) reaction, make the anion of gained and trialkylboron acid esters reagent A G4 reaction thus indole AG2 is converted into indole-3-boronic acid derivatives AG5 then.The chemical compound of AG5 type can with above similar condition under with aryl and heteroaryl bromide and iodide reaction, to form the chemical compound of structure XL.

XXXIII. synthetic route AG

The chemical compound of the present invention of structure XLI representative can prepare shown in following synthetic route AH.

The compound structure AH1 of 3-iodo-or bromo indole can react (being commonly referred to the Heck reaction) with alkene AH2 under the situation that has palladium catalyst to exist, to form the chemical compound of XLI type.Coupling reaction can be carried out according to method known to those skilled in the art.Catalyst and choice of Solvent are similar to described in the synthetic route AG.

XXXIV. synthetic route AH

The formula I chemical compound of structure XLII representative can prepare shown in following synthetic route AI.

The compound structure AI1 of 3-iodo-or bromo indole can react (being commonly referred to the Sonagashira reaction) with alkynes AI2 in the presence of palladium catalyst, to form the chemical compound of XLII type.Coupling reaction can be carried out according to method known to those skilled in the art.The typical reaction condition of one cover comprises that the benzazolyl compounds and the alkynyl compounds AI2 that make structure AI1 react in the presence of palladium source, copper cocatalyst and amine source, and this is reflected in the temperature range of room temperature to 150 ℃ and carries out.

XXXV. synthetic route AI

The chemical compound of the present invention of structure XLIII and XLIV representative can prepare shown in following synthetic route AJ.

The benzazolyl compounds that the nitroaniline chemical compound of structure AJ1 is converted into structure XLIII by eyeball condensation and cyclisation with structure AJ2.This reaction can be carried out in appropriate organic solvent such as DMF or dioxane.With the chemical compound of alkali treatment structure XLIII, then with the reactive functional groups R that comprises suitable leaving group L ₉React, can form the chemical compound of formula XLIV thus.

XXXVI. synthetic route AJ

The formula I chemical compound of structure XLV-XLVIII representative can prepare shown in following synthetic route AK.

The 2-amino indole chemical compound of structure XLV can be used the reactive functional groups R that comprises suitable leaving group L in the presence of alkali such as sodium hydride or potassium carbonate in appropriate organic solvent ₁₅Carry out alkylation, obtain the chemical compound of structure XLVI.Use comprises the reactive functional groups R ' of suitable leaving group L ₁₅Carry out the alkylation second time similarly, obtain the chemical compound of structure XLVII.

The chemical compound of structure XLV carry out acyl groupization with the acyl chlorides of structure AK1, can make the chemical compound of structure XLVIII thus.This reaction is carried out in appropriate organic solvent when organic base such as trialkylamine or inorganic base such as potassium carbonate exist usually.

XXXVII. synthetic route AK

The chemical compound of the present invention of structure XLIX representative can prepare shown in following synthetic route AL.

The indole-3-carboxylic acid of structure AL1 can activate, to obtain the chemical compound of structure AL2.The chemical compound of structure AL2 can for example be a carboxylic acid halides or through reagent such as dicyclohexylcarbodiimide or the activatory carboxylic acid of DIC.The hydroxyamidines reaction of the chemical compound of structure AL2 and structure AL3 forms O-acyl group hydroxyamidines AL4.Hydroxyamidines is available commercially or prepares by handling nitrile compound with azanol.In non-reacted organic solvent such as toluene, dichloromethane or dioxane under 30 ℃-150 ℃ temperature range the chemical compound of heating arrangement AL4, obtain the chemical compound of structure XLIX.

XXXVIII. synthetic route AL

C. method of the present invention

Method of the present invention generally includes one or more chemical compounds of the present invention of the individual drug treatment effective dose that infects to needs treatment HCV.In preferred embodiments, to the compositions of the individual drug treatment effective dose of needs treatments, said composition comprises formula I chemical compound described here.In a further preferred embodiment, chemical compound or compositions used in the method for the present invention comprise formula I chemical compound described here, and wherein this formula I chemical compound is not following chemical compound 1.

Chemical compound of the present invention can be by route of administration administration known in the art.That concrete exemplary route of administration comprises is oral, eye, rectum, cheek, part, nose, eye are interior with, subcutaneous, intramuscular, vein (single injection and infusion), brain, transdermal and pulmonary.Infection has the individual available compounds for treating of the present invention of HCV, with duplicating of further prevention or reduction HCV.

Be meant the amount that chemical compound of the present invention effectively suppresses the HCV translation and treats or improve the HCV infection thus effectively at this used term treatment effective dose.The effect of this chemical compound can be by analyzing the existence of (1) HCV-RNA; (2) existence of HCV antigen/antibody combination; (3) serum levels (ALT and AST raise in the patient who suffers from HCV for a long time) of alanine aminotransferase (ALT) and aspartate transaminase (AST); And (4) hepatocyte damages and measures.The accurate effective dose of each individuality will depend on this individual body weight, size and health.Certain patient's treatment effective dose can determine that this is within clinician's technical ability and judgement by routine test.

For chemical compound arbitrarily, the treatment effective dose can at first be estimated in the cell culture test or in relevant animal model (as Adeps seu carnis Rhiopithecus roxellanae monkey and tarmarins).Animal model also can be used for measuring proper concentration and route of administration.These information can be used for measuring useful dosage of man-hour and the approach of delivering medicine to that.Treatment is renderd a service and toxicity can be measured by the materia medica method of standard in cell culture and the laboratory animal, for example ED ₅₀(in 50% number, being the effective dosage of treatment) and LD ₅₀(causing the dosage of 50% number death).Dosage ratio between therapeutic effect and the toxic effect is a therapeutic index, and it can be expressed as ED ₅₀/ LD ₅₀Ratio.Pharmaceutical composition with big therapeutic index is preferred.The dosage that is comprised in these compositionss is preferably comprising ED ₅₀And almost do not have or do not have within the toxic circulation composition scope.This dosage can change within this scope, and this depends on used dosage form, patient's sensitivity and route of administration.

More specifically, show that with the viewed concentration of chemical compound of the present invention-biological agent relation initial target plasma concentration scope is the about 100 μ g/mL of about 0.1 μ g/ml-, be preferably the about 50 μ g/mL of about 1 μ g/mL-, the about 50 μ g/mL of more preferably about 5 μ g/mL-, even the about 25 μ g/mL of more preferably about 10 μ g/mL-.For reaching these plasma concentration, the dosage of The compounds of this invention can change between the 000mg at 0.1 μ g-100, and this depends on route of administration.Guidance to concrete dosage and medication is provided in the document, and normally available to those skilled in the art.Generally, for body weight for for the patient of the about 100kg of about 40-, described dosage is between about 1mg/ days-Yue 10g/ days, or between the about 3g/ of about 0.1g-days, or between the about 3g/ of about 0.3g-days, or between the about 2g/ of about 0.5g-days, its can be single dosage, fractionated dose or successive doses (this dosage for this more than weight range or under the patient can regulate, especially body weight is the following child of 40kg).

The correlative factor of Zhi Liao individuality as required, the clinicist can determine accurate dose.Dosage and administering mode all can be regulated, with activating agent that enough levels are provided or keep desirable effect.The factor that can be considered comprises the order of severity of morbid state, individual total health condition, age, body weight and sex, diet, time of administration and frequency, drug regimen, reaction sensitivity and the toleration/reaction to treating.The pharmaceutical composition of long term can every 3-4 days, administration weekly, and the patient is administered once in per two weeks, and this depends on the half-life and the clearance rate of concrete preparation.

D. the metabolite of chemical compound of the present invention

The interior metabolism product of The compounds of this invention also within the scope of the invention.This product can be for example owing to the oxidation of giving drug compound, reduction, hydrolysis, amidatioon, esterification etc. produce, main or because enzymatic processes.Therefore, the present invention includes the chemical compound that produces by the following method: make chemical compound of the present invention contact the sufficiently long time, to produce its metabolite with mammalian tissues or mammal.This product makes usually to be differentiated by the following method: prepare radiolabeledly (as C ¹⁴Or H ³) The compounds of this invention, with detectable dosage (as greater than about 0.5mg/kg) it is delivered medicine to mammal such as rat, mice, Cavia porcellus, monkey or delivers medicine to the people, allow time enough to carry out metabolism (about 30 seconds to 30 hours usually), from urine, blood or other biological sample, separate its converted product then.These products are easy to separate, and this is because they are labeled (can separate other materials in conjunction with the antibody of epi-position remaining in the metabolite by using).The metabolite structure is measured as MS or NMR in a conventional manner.Generally, the analysis of metabolite can be carried out according to the mode identical with conventional medicine metabolism research well known by persons skilled in the art.Converted product, as long as they are not to exist in the body, can the diagnostic test of being used for the treatment of property administration The compounds of this invention in, even they biologically active not itself.

E. pharmaceutical composition of the present invention

Though chemical compound of the present invention can purified form administration, preferably this chemical compound is formulated as the form of pharmaceutical composition.Therefore, of the present invention aspect another in, the pharmaceutical composition that can be used in the inventive method is provided.Pharmaceutical composition of the present invention can be prepared with the acceptable excipient of materia medica, and as carrier, solvent, solubilizing agent, adjuvant etc., this depends on concrete administering mode and dosage form.The preparation of pharmaceutical composition should realize the pH that the physiology is compatible usually, and the scope of pH is about 3-11, and preferably about 3-7 depends on the preparation and the approach of administration.In another embodiment, pH preferably is adjusted to about 5.0-8.0.

More specifically, pharmaceutical composition of the present invention comprises one or more chemical compounds of the present invention and the acceptable excipient of one or more materia medicas of treatment or prevention effective dose.The The compounds of this invention of treatment or prevention effective dose comprises the described chemical compound of viral amount of suppression or effectively influences the active amount of viral IRES.Term " viral amount of suppression " is meant and is enough to suppress virus replication or infective amount.Term " effectively influences the active amount of viral IRES " and is meant the amount that opens beginning and/or translation that is enough to suppress viral IRES mediation.Randomly, pharmaceutical composition of the present invention can comprise the combination of The compounds of this invention, perhaps can comprise second active component that is used for the treatment of viral infection, for example antiviral agent, it includes but not limited to: the interferon of Pegylation for example comprises the alpha-interferon of Pegylation; The interferon of Pegylation does not for example comprise the not alpha-interferon of Pegylation; Ribavirin or its prodrug or derivant; Alpha-glucosidase inhibitors; Protease inhibitor; AG14361; The p7 inhibitor; Entry inhibitor comprises fusion inhibitor, as Fuzeon ^TM(Trimeris); The unwindase inhibitor; Toll sample receptor stimulating agent, caspase inhibitor, fibrosis medicine; The medicine of IMPDH (targeting inosine phosplate dehydrogenase inhibitor) is as Merimepadib ^TM(Vertex Pharmaceuticals Inc.); Synthetic thymosin (ZADAXIN ^TM, SciClone Pharmaceuticals Inc.); Glycosidase inhibitor; Therapeutic vaccine is as the vaccine of being made by Chiron and Immunogenics; And immunomodulator, as resistance amine.

The present invention's the preparation that for example is used for parenteral route or oral administration usually great majority is solid, liquid solution, emulsion or suspension, and the inhalable formulations that is used for pulmonary administration normally liquid or powder formulation, wherein usually preferred powder formulation.The present invention's preferred pharmaceutical composition also can be mixed with the form of lyophilized solid, and this freeze dried solid can restore with the compatible solvent of physiology before administration.The present invention's interchangeable pharmaceutical composition can be mixed with forms such as syrup, emulsifiable paste, ointment, tablet.

Term " the acceptable excipient of materia medica " is meant the excipient that is used for administration medicine such as The compounds of this invention.This term is meant and can be used for administration and the how toxic drug excipient arbitrarily of no mistake in treatment.The acceptable excipient of materia medica partly is that the concrete method of using decides during by the concrete component of institute's administration and administration composition.Therefore, pharmaceutical composition of the present invention exist multiple appropriate formulation (for example referring to: Remington ' s Pharmaceutical Sciences).

Suitable excipient can be a carrier molecule, and it comprises big, slow metabolic macromole such as albumen, polysaccharide, polylactic acid, polyglycolic acid, polyamino acid, amino acid copolymer and non-activity virion.Other exemplary excipient comprise antioxidant such as ascorbic acid; Chelating agen such as EDTA; Carbohydrate such as dextrin, hydroxy alkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid; Liquid is as oil, water, saline, glycerol and ethanol; Wetting agent or emulsifying agent; PH buffer substance etc.Liposome is also included within the definition of the acceptable excipient of materia medica.

Pharmaceutical composition of the present invention can be mixed with any dosage form that is suitable for desired medication.For example when being used for oral administration, can be made into tablet, tablet, lozenge, aqueous suspensions or oil suspension, non-aqueous solution, dispersible powder or granule (comprising), Emulsion, hard or soft capsule, syrup or elixir through micronized granule and nano-particle.Being used for liquid preparations for oral administration can prepare according to any means that is used for pharmaceutical compositions well known by persons skilled in the art, and these compositionss can comprise the material that one or more comprise sweeting agent, flavoring agent, coloring agent and antiseptic, so that good to eat preparation to be provided.

The acceptable excipient of materia medica that is specially adapted in the tablet for example comprises inert diluent, as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; Disintegrating agent is as cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone (cross-linked povidone), corn starch or alginic acid; Binding agent is as polyvidone, starch, gelatin or arabic gum; And lubricant, as magnesium stearate, stearic acid or Talcum.Tablet can be not coating or comprise that by known technology little encapsulation techniques holds coating, postponing disintegrate and the absorption in gastrointestinal tract, and in the longer time, provide effect thus.For example, can use the time-delay material, as glycerol monostearate or glyceryl distearate, they can use separately or be used in combination with wax.

Oral formulations also can be the form of hard gelatin capsule, wherein active component and inert solid diluent such as cellulose, lactose, calcium phosphate or Kaolin mix, or the form of soft gelatin, wherein active component mixes with non-water or oily medium, as glycerol, propylene glycol, Polyethylene Glycol, Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil.

In another embodiment, pharmaceutical composition of the present invention can be mixed with the form of suspensoid, and it comprises and the compound of the present invention at least a acceptable excipient of materia medica that is applicable to the preparation suspensoid together.In another embodiment, pharmaceutical composition of the present invention can be mixed with dispersible powder and particulate form, and they are applicable to by adding suitable excipient and prepare suspensoid.

Be applicable to that the excipient in the suspensoid comprises suspending agent, as sodium carboxymethyl cellulose, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium alginate, polyvinyl pyrrolidone, Tragacanth, arabic gum, the condensation product of condensation product (as Myrj 45), oxirane and the long chain aliphatic of dispersant or wetting agent such as natural phospholipid (as lecithin), oxyalkylene and fatty acid (as 17 ethyleneoxy group ethanol), oxirane and derived from the condensation product (as polyoxyethylene sorbitan monooleate dehydration) of the part ester of fatty acid and hexitan; And thickening agent, as carbomer, Cera Flava, hard paraffin or spermol.This suspensoid also can comprise one or more antiseptic, as acetic acid, P-hydroxybenzoic acid methyl ester/n-propyl diester; One or more coloring agent; One or more flavoring agents; And one or more sweeting agents such as sucrose or glucide.

Pharmaceutical composition of the present invention also can be the form of oil in water emulsion.Oil phase can the water vegetable oil, as olive oil or Oleum Arachidis hypogaeae semen, and mineral oil, as liquid paraffin, the perhaps mixture of these materials.Suitable emulsifying agent comprises natural gum, as arabic gum and Tragacanth; Natural phospholipid is as soybean lecithin, the ester that is derived from fatty acid or part ester; Hexitan is as Arlacel-80; And the condensation product of these part esters and oxirane, as polyoxyethylene sorbitan monooleate dehydration.This Emulsion also can comprise sweeting agent and flavoring agent.Available sweeting agent such as glycerol, sorbitol or sucrose are mixed with syrup and elixir.These preparations also can comprise demulcen, antiseptic, flavoring agent or coloring agent.

In addition, pharmaceutical composition of the present invention can be the form of aseptic injection, as the aseptic injection aqueous emulsions or contain oil suspension.This Emulsion or suspensoid can be prepared by using those above-mentioned suitable dispersants or wetting agent and suspending agent according to known method.This aseptic injection also can be at atoxic gastrointestinal tract acceptable diluent or solvent as 1, the aseptic injectable solution in the 2-propylene glycol contains suspensoid.This aseptic injection can also be made the form of freeze-dried powder.In acceptable carrier and the solvent, can make water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic fixedly oil also can be used as solvent or suspension media.For this purpose, gentle arbitrarily fixing oil be can use, synthetic glyceryl monoacetate and two acid esters comprised.In addition, when the preparation injection, can use fatty acid such as oleic acid equally.

Generally, the The compounds of this invention that can be used in the inventive method is water insoluble basically, and is slightly soluble in acceptable proton solvent of most drug and the vegetable oil.But this chemical compound is dissolved in medium-chain fatty acid (as sad and capric acid) or the triglyceride usually, and has high dissolubility in the propylene glycol ester of medium-chain fatty acid.The present invention comprises that also these groups for example are more suitable in administration (for example increasing dissolubility, bioavailability, palatability, reduction negative response etc.) chemical compound by esterification, glycosylation, Pegylation etc. by the chemical compound that replaces or addition chemical group or biochemical group carry out modification.

In preferred embodiments, chemical compound of the present invention can be mixed with the lipid formulations that is used for oral administration, and they are suitable for the chemical compound of low solubility.The lipid based formulation can strengthen the oral administration biaavailability of these medicines usually.Therefore, preferred pharmaceutical compositions of the present invention comprises the The compounds of this invention and at least a acceptable excipient of materia medica that is selected from following group of treatment or prevention effective dose: medium-chain fatty acid or its propylene glycol ester (as edible fatty acid such as sad and propylene glycol ester capric acid) and materia medica acceptable surfactant such as polyoxy 40 castor oil hydrogenated.

In other embodiment preferred, can add cyclodextrin as the water solubility reinforcing agent.Preferred cyclodextrin comprise α-, β-and hydroxypropyl, hydroxyethyl, glucityl, malt-base and the maltotriose radical derivative of gamma-cyclodextrin.Particularly preferred cyclodextrin solubility reinforcing agent is hydroxypropyl-beta-schardinger dextrin-(HPBC), and it can be added into arbitrarily in the above-mentioned composition with the further water solubility characteristic of improving The compounds of this invention.In one embodiment, compositions of the present invention comprises hydroxypropyl-beta-schardinger dextrin-of 0.1%-20%, more preferably hydroxypropyl-beta-schardinger dextrin-of 1%-15%, and even more preferably hydroxypropyl-beta-schardinger dextrin-of 2.5%-10%.The use amount of solubility enhancing agent will depend on the amount of The compounds of this invention in said composition.

F. therapeutic alliance

Can also make up chemical compound of the present invention and one or more other be used for the treatment of the active component that HCV infects, be included in same dosage form or the different dosage form chemical compound, be used for simultaneously or the order administration to the patient of needs treatment.When the order administration, this combination can be administered twice or repeatedly.In another embodiment, can pass through different one or more chemical compounds of the present invention of administration and one or more extra active component.

Those skilled in the art will recognize that, various active component can with chemical compound combination medicine-feeding of the present invention, they can play and strengthen or the collaborative virus that strengthens The compounds of this invention suppresses activity.These active component comprise anti-HCV agent.Anti-HCV agent comprises the medicine of targeting virus and the medicine with immunoregulation effect.For example, anti-HCV agent includes but not limited to interferon, for example comprises IFN-α, ribavirin or its prodrug or derivant; Alpha-glucosidase inhibitors, protease inhibitor, AG14361, unwindase inhibitor, Toll sample receptor stimulating agent, caspase inhibitor and glycosidase inhibitor.In addition, chemical compound of the present invention also can with active other chemical compound combination medicine-feedings of IRES that influence well known by persons skilled in the art.

The method according to this invention, the combination of active component can be: (1) common preparation and administration or administration simultaneously in combination preparation; (2) replace or administration abreast with different preparations; Or (3) other combined therapy schemes arbitrarily known in the art.When administration in alternating treatment, method of the present invention can comprise administration sequentially or transmit active component, for example in different solution, emulsion, suspension, tablet pill or capsule, or by the injection in different syringes.Generally, during alternating treatment, each active component of administration effective dose in proper order (as a series of), and at the same time in the treatment, two or more active component of administration effective dose together.Also can use the combined therapy at intermittence of various orders.

For helping the understanding of the present invention, the present invention includes following examples.These relate to experiment of the present invention should not be understood that it is concrete restriction to the scope of the invention certainly; and these variations of the present invention; no matter be now known or later research and development; as long as they are within those skilled in the art's the ken, then also be considered to fall within this description and the claimed afterwards scope of the invention.

Embodiment

Describe the present invention in more detail with reference to following non-restrictive example, providing of these embodiment is for the present invention is described fully, and limits the scope of the present invention absolutely not.These embodiment have illustrated that the preparation of some The compounds of this invention and these chemical compounds are in external and/or intravital test.Those skilled in the art will appreciate that in these embodiments the technology that on behalf of the inventor, the technology of describing describe, implementing the present invention better, and constituted embodiment preferred thus.But it should be understood that those skilled in the art can carry out many improvement to concrete grammar disclosed herein according to disclosure of the present invention, and still can obtain identical or similar result, and do not break away from the spirit and scope of the present invention.

Embodiment 1: the preparation of The compounds of this invention

Embodiment 1A: preparation 1-ethyl-6-methoxyl group-1H-indole-3-nitrile (chemical compound 5).

Steps A: (10.0g, 68.0mmol) solution in DMF (120mL) is cooled to 0 ℃ also with chloro sulfonyl isocyanate (7.72mL, 88.4mmol) processing with 6-methoxyl group indole.After interpolation was finished, reactant mixture stirred 1 hour under this temperature.Dark solution is poured in the frozen water (600mL), and collects bright brown solid by filtering, with other H ₂The O washing is also dry, and with the 6-methoxyl group-1H-indole-3-nitrile that makes 9.9g (85%), it is bright brown solid.

Step B: to 6-methoxyl group-1H-indole-3-nitrile (9.9g, 57.6mmol) add in the solution in DMF (150mL) NaH (dispersion in 60% mineral oil, 3.45g, 86.3mmol).Reactant mixture stirred 15 minutes, and (5.53mL, 69.1mmol), and this mixture at room temperature stirs and spends the night to add ethyl iodide then.Reactant mixture is then used H ₂EtOAc (2X) extraction is used in the O dilution then.Organic facies H ₂O (3X) and saturated NaCl washing, dry then and be concentrated into semisolid.Crude product carries out pure system by column chromatography on silica gel (200g), wherein use CH ₂Cl ₂/ hexane (50-100%) is as eluant, and to make 6-methoxyl group-1-ethyl-1H-indole-3-nitrile, it is pale brown color solid.

Steps A more than using is with B and replace different benzazolyl compounds and alkyl halide, makes following chemical compound: chemical compound 43,45,51,52,108,109,115,118,120,123,126,179 and 714.

Embodiment 1B: preparation 6-ethyoxyl-1-ethyl-1H-indole-3-nitrile (chemical compound 9).

Steps A: (2.85g, 14.2mmol) (according to embodiment 1A, step B preparation) is at CH to 1-ethyl-6-methoxyl group-1H-indole-3-nitrile under 0 ℃ ₂Cl ₂Add the BBr of 1M in the solution (40mL) ₃At CH ₂Cl ₂(28.5mL, 28.5mmol) solution in.This mixture is warmed to room temperature and kept 2.5 hours.This dark reactant mixture is poured on ice, and adding enough 1M NaOH then is 8-9 until pH.This product CH ₂Cl ₂(3X) extraction, the saturated NaHCO of the organic facies of merging ₃, H ₂O and saturated NaCl washing.At MgSO ₄After the last drying, evaporating liquid, and product carries out pure system (EtOAc/CH by chromatograph ₂Cl ₂, 0-10%), with the 6-hydroxyl-1-ethyl-1H-indole-3-nitrile that makes 2.15g (82%), it is a yellow solid.

Step B: (80mg 0.43mmol) adds anhydrous K in the solution in the 5mL methyl ethyl ketone to 6-hydroxyl-1-ethyl-1H-indole-3-nitrile ₂CO ₃(71mg, 0.52mmol) and iodomethane (0.05mL, 0.60mmol).After the stirring that refluxes was spent the night, reactant mixture was cooled, and uses H ₂O dilutes and extracts with EtOAc (3X).The organic facies that merges is dry and concentrated.Flash chromatography (CH ₂Cl ₂) obtaining 6-ethyoxyl-1-ethyl-1H-indole-3-nitrile of 94mg (100%), it is a white wax.

In a comparable manner, after above steps A and B, make following chemical compound: chemical compound 6,10,11,12 and 24.

Embodiment 1C: preparation 5-(4-methoxyphenyl)-5H-[1,3] dioxole [4,5-f] indole-7-nitrile (chemical compound 44) also.

With the p-iodoanisole (85mg, 0.36mmol), anhydrous K ₃PO ₄(102mg, 0.48mmol), CuI (4.6mg, 0.024mmol) and N, N '-dimethyl cyclohexane-1, and the 2-diamidogen (14mg, mixture 0.096mmol) is added into 5H-[1,3] dioxole also [4,5-f] (45mg is 0.24mmol) in (according to embodiment 1A, the method preparation of describing in the steps A) solution in dry toluene (0.4mL) for indole-7-nitrile.After the reflux 24 hours, vacuum evaporating solvent.Residue CH ₂Cl ₂(5mL) dissolving, and filter this mixture.Concentrated filtrate, to make crude product, it carries out pure system by silica gel chromatography, wherein uses EtOAc/ petroleum ether (1: 4) as eluant, to make 5-(4-methoxyphenyl)-5H-[1,3] dioxole [4,5-f] indole-7-nitrile also.

Use said method and substitute different aryl iodides, make following chemical compound: chemical compound 4,8,102,103,111,112,117,119,124,125,127,154.

Embodiment 1D: preparation 1-ethyl-6-(pyrazine-2-base oxygen base)-1H-indole-3-nitrile (chemical compound 13).

To 1-ethyl-6-hydroxyl-1H-indole-3-nitrile (60mg, 0.32mmol) interpolation K in (according to as embodiment 1A, the method preparation described in the steps A) solution in DMF (5mL) ₂CO ₃(55mg, 0.40mmol) and 2-chlorine pyridazine (45mg, 0.40mmol).This mixture heated 18 hours down at 110 ℃.After being cooled to room temperature, reactant mixture H ₂O dilutes and extracts with EtOAc (3X).The organic facies H that merges ₂O and saturated NaCl washing, dry and concentrated.This product separates (EtOAc/CH in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel ₂Cl ₂, 1-3%), making the title compound of 76mg (96%), 1-ethyl-6-(pyrazine-2-base oxygen base)-1H-indole-3-nitrile, it is a beige solid.

Embodiment 1E: preparation 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid phenyl amide (chemical compound 15).

Steps A: 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid methyl ester (1.60g, 7.02mmol) (making by 1H-Indole-6-carboxylic acid methyl ester according to the method for describing among the embodiment 1A) solution in THF (35mL) 1N NaOH (7.7mL, 7.7mmol) handle, reflux is 2.5 hours then.After being cooled to room temperature, remove most THF, and solution H ₂Ether (2X) extraction is used in the O dilution then.Discard the ether extract.Water is acidified to pH2 with 6N HCl, then with EtOAc (3X) extraction.Merge the EtOAc layer, with saturated NaCl washing, dry then and concentrated, with the 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid who makes 1.43g (95%), it is a white solid.

Step B: (0.42g is 1.96mmol) at CH with 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid ₂Cl ₂Suspension (15mL) is cooled to 0 ℃.This suspension is handled with DMF (2 drops), (0.34mL 3.92mmol), removes ice bath afterwards to add oxalyl chloride by syringe in 2 minutes then, and making reactant mixture in 1.5 hours time, be warmed to room temperature, this reactant becomes yellow solution during this period.This solution is followed vacuum concentration, and with the 3-cyano group-1-ethyl-1H-indole-6-carbonyl chlorine that makes 0.46g (quantitative yield), it is a yellow solid.

Step C: (70mg, 0.30mmol) suspension in THF (5mL) is cooled to 0 ℃, uses aniline (0.08mL, 0.90mmol) processing then with 3-cyano group-1-ethyl-1H-indole-6-carbonyl chlorine.After interpolation was finished, this reaction was warmed to room temperature, and after stirring other 16 hours, reactant mixture H ₂O dilutes, and extracts with EtOAc (2X).The organic facies that merges is washed with saturated NaCl, and is dry then and concentrated, to make described product.Carry out chromatographically pure system (EtOAc/CH on the silica gel ₂Cl ₂, 2/98), obtain 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid phenyl amide of 44mg (51%).

Basically use above method, make following chemical compound: chemical compound 89.

Embodiment 1F: preparation (3-cyano group-1-ethyl-1H-indole-6-yl)-carbamic acid tertiary butyl ester (chemical compound 16).

3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid (0.60g, 2.80mmol) (by embodiment 1E, steps A obtains) solution Et in the tert-butyl alcohol (20mL) ₃N (0.46mL, 3.36mmol) and diphenyl phosphoryl azide (0.73mL 3.36mmol) handles, and reflux is 4 hours then.After being cooled to room temperature, vacuum is removed the most tert-butyl alcohol, to form a grease, it is dissolved among the EtOAc.Use H ₂After the O washing, organic facies is again with the EtOAc extraction, and the merging organic layer, sequentially uses other H ₂O, saturated NaHCO ₃And saturated NaCl washing.The organic facies drying concentrate, and the crude product of gained carry out chromatographically pure system on silica gel, wherein use EtOAc/CH ₂Cl ₂(0-1%), with the tert-butyl group (3-cyano group-1-ethyl-1H-indole-6-yl)-carbamate that makes 0.52g (65%), it is a white solid.

Prepare following chemical compound according to similar method: chemical compound 90.

Embodiment 1Ga: prepare 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (chemical compound 55) by the Suzuki approach.

Steps A: in the flame-dried flask of process, (3.9mL, 7.8mmol) solution in dilutes with THF (5mL) LDA of 2M at THF/ hexane (Acros).After this reactant was cooled to-30 ℃, ethyl-(1.30g, the 6.5mmol) solution in THF (10mL) remained on temperature-30 ℃ to 6-methoxyl group-1H-indole-3-nitrile to drip 1-in 10 minutes time.After 30 minutes, in 10 minutes time, add iodine (2.31g, 9.1mmol) solution in THF (5mL) at restir under this temperature.After interpolation is finished, in 1 hour time, make this reaction be warmed to room temperature.This reactant ice-H ₂EtOAc (2X) extraction is used in the O dilution then.The organic facies that merges is concentrated into brown solid then with 1M sodium thiosulfate and saturated NaCl washing.Carry out chromatographically pure system (CH on the silica gel ₂Cl ₂/ hexane, 1/1), obtain 1-ethyl-2-iodo-6-methoxyl group-1H-indole-3-nitrile of 1.31g (62%), it is a beige solid.

Step B: with 1-ethyl-2-iodo-6-methoxyl group-1H-indole-3-nitrile (1.25g, 3.83mmol), 4-(4,4,5, the 5-tetramethyl)-1,3-2-two oxa-bora rings penta-2-base-aniline (0.96g, 4.90mmol), CsF (1.46g, 9.58mmol) and Pd (PPh ₃) ₂Cl ₂(110mg, 0.15mmol) mixture in DME (20mL) is added in the flask, and randomly uses nitrogen aerofluxus and flushing.This reactant was followed reflux 24 hours, was cooled to room temperature then.Reactant mixture H ₂O dilutes, and extracts with EtOAc (2X).The organic facies H that merges ₂O and saturated NaCl washing, dry and concentrated on magnesium sulfate then.Thick reactant mixture carries out pure system by flash chromatography on silica gel, wherein use EtOAc/CH ₂Cl ₂(5/95) as eluant, with 2-(4-the aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile that makes 765mg (69%), it is a yellow solid.

Basically use method same as described above and replace different boric acid, make following chemical compound: chemical compound 19,20,21,22,53,63,70,71,74,76,77,79,80,100,110,229,239,240,247,250,254,255,256,257,258,259,260,281,282,283,284,286,335,336,337,338,339,347,348,426,427,428,429,476,543,578,758.

Embodiment 1Gb: prepare 2-(4-aminophenyl)-1-butyl-6-methoxyl group-1H-indole-3-nitrile by other Suzuki approach

To (i-Pr) ₂NH (1.35mL, 9.65mmol) in THF (30mL) be cooled to disposable interpolation n-BuLi in-78 ℃ the solution (3.7mL, the 2.5M hexane solution, 9.21mmol).Replace ice/water-bath with acetone/the dry ice bath, and this solution of restir 40 minutes.This solution is cooled to-78 ℃, drips 1-butyl-6-methoxyl group-1H-indole-3-nitrile (described in embodiment 1A, being prepared) (2.0g, 8.77mmol) solution in THF (10mL) then.This solution stirred 15 minutes down at-78 ℃, stirred 20 minutes down at-20 ℃ then.(1.0mL, 8.77mmol), reactant mixture stirred 15 minutes down at-20 ℃, removed cooling bath afterwards, and this solution of restir 1 hour at room temperature to add the trimethyl borine acid esters.Add K ₃PO ₄Solution (11.7mL, the 3M aqueous solution, 35.1mmol), add then the 4-Iodoaniline (2.5g, 11.40mmol) and PdCl ₂Dppf catalyst (640mg, 0.88mmol) solution in DMF (40mL adds 5mL rinse).Reactant mixture stirs and spends the night (about 18 hours), then adds water (80mL), and (3 * 50mL) extract and product is with EtOAc.The organic extract liquid that merges is dry on magnesium sulfate, filters and concentrating under reduced pressure.Crude product carries out pure system (5 → 60%EtOAc/ hexane is as eluant) by flash chromatography on silica gel, to make desirable 2-(4-aminophenyl)-1-butyl-6-methoxyl group-1H-indole-3-nitrile, it is pale brown color solid (2.4g, 86% productive rate).

Use other indole and aryl and heteroaryl bromide and the following chemical compound of iodide preparation according to similar method: chemical compound 656,659,660,661,682,683,712,731,732,733,806,807,808,809,810,811,812,813,814,827.

Embodiment 1Gc: prepare 2-(4-aminophenyl)-6-methoxyl group-1-propyl group-1H-indole-3-nitrile by the Negishi approach

Through nitrogen purge and barrier film is housed and the flask of nitrogen pin in charge into anhydrous THF (all interpolations are all implemented by syringe) (20mL).(Aldrich Sure-Seal, 2.00mL 14.3mmol), and are cooled to 0 ℃ with this solution to add diisopropylamine.Slow interpolation n-butyl lithium (the 1.6M hexane solution of 8.50mL, 13.6mmol).Make this flask fast warming to room temperature, be cooled to-78 ℃ then.Slowly add 6-methoxyl group-1-propyl group-1H-indole-3-nitrile (2.77g, 12.9mmol; The chemical compound 5 that is similar to embodiment 1A prepares) dense THF solution, gained solution kept 30 minutes down at-78 ℃.This flask is transferred in water-ice bath then, and make its reach 0 ℃ about 15 minutes.This solution is cooled to-78 ℃ again, and slowly adds ZnCl ₂(solution of 0.5M in THF, 27.0mL, 13.5mmol).Observe precipitation at this point, it might be two (indole) zinc compounds, but this solution becomes homogeneous when adding the liquor zinci chloridi of whole volume.After about 10 minutes, make this solution reach room temperature, add then the 4-Iodoaniline (3.47g, 15.8mmol) and triphenylphosphine (338mg, THF solution (5mL) 1.29mmol).Remove barrier film, add solid Pd then ₂(dba) ₃(295mg, 0.322mmol).On flask, install back flow condenser, and by three successive vacuum pump/N ₂Clean cycle makes this solution degassing.This vlil is spent the night.After being cooled to room temperature, this solution is poured in the water of 4 volumes, adds the ethyl acetate of 4 volumes then.The mixture vigorous stirring of gained 30 minutes is filtered (washing with ethyl acetate) to remove the material that solid comprises Zn and Pd by celite then.Separate each phase, and water reuse ethyl acetate extraction.Organic facies then with the saturated brine washing, merges, and is dry on anhydrous sodium sulfate, filters and evaporation.Form solid precipitation at this point, it is enough pure product, and by grinding and filter and collect with ether.Residuals carries out pure system (1: 2 ethyl acetate-hexane of eluting is on silica gel 60) by column chromatography.The gross production rate of product 2-(4-amino-phenyl)-6-methoxyl group-1-propyl group-1H-indole-3-nitrile is 2.75g (8.99mmol, 70%).

Use substantially the same method and replace other aryl or heteroaryl iodide or bromide, thus the following chemical compound of preparation: chemical compound 393,408,430,431,436,437,438,459,460,461,462,483,484,632,633,634,635,636,650,651.

Embodiment 1Gd: preparation 1-ethyl-2-(3-hydroxy phenyl)-6-methoxyl group-1H-indole-3-nitrile (chemical compound 288).

Steps A: (5.5mL, solution 39mmol) are cooled to-78 ℃ with THF (60mL) and diisopropylamine.Dropping n-butyl lithium in 5 minutes time (14.5mL, the 2.5M hexane solution, 36.2mmol).This LDA mixture stirred 10 minutes down at-78 ℃, then stirred 20 minutes down at 0 ℃.This solution is cooled to-78 ℃ again.(5.0g 25mmol) (prepares described in embodiment 1A) and puts into THF (30mL), drops in 15 minutes time in the described LDA mixture then with 1-ethyl-6-methoxyl group-1H-indole-3-nitrile.This reactant stirred 10 minutes down at-78 ℃, and stirred 30 minutes down at 0 ℃.This reactant mixture is cooled to-78 ℃ again.Dropping iodate tributyl tin (10mL, 35mmol).This mixture stirred 15 minutes down at-78 ℃, stirred 30 minutes down at 0 ℃ then.Reactant mixture is adsorbed on the silica gel and concentrates.Chromatographically pure system (CH ₂Cl ₂) generation 1-ethyl-6-methoxyl group-2-tributyl tin alkyl-1H-indole-3-nitrile (12.05g, 98%).

Step B: the 1-ethyl for preparing in the steps A-6-methoxyl group-2-tributyl tin alkyl-1H-indole-3-nitrile (1.0g, 2.05mmol) with the 3-iodophenol (474mg, 2.15mmol), Pd (PPh ₃) ₂Cl ₂(67mg, 0.102mmol), CuI (75mg, 0.39mmol) and THF (4.0mL) mix.This mixture is 65 ℃ of following heated overnight.Reactant mixture dilutes in EtOAc, filters by celite then.Concentrated filtrate, and residue by silica gel chromatography carry out pure system (4: 1, CH ₂Cl ₂/ EtOAc), to make crude product.Grind with ether, obtain 1-ethyl-2-(3-hydroxyl-phenyl)-6-methoxyl group-1H-indole-3-nitrile (430mg, 72%), it is a white-yellowish solid.

Use other commercially available iodide and bromides, perhaps use by one of p-iodophenyl sulfonic acid chloride and go on foot the iodide that amidatioon obtains, according to being similar to the following chemical compound of method for preparing: chemical compound 275,276,277,278,331,363,364,373,374,375,474,475,678.

Embodiment 1Ge: prepare ethyl sulfonic acid [4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indole-2-yl)-phenyl]-amide (chemical compound 519) by the Heck approach.

Steps A: with 6-difluoro-methoxy-1-ethyl-1H-indole (402.8mg, 2.04mmol), ethyl sulfonic acid (4-iodo-phenyl)-amide (712.1mg, 2.29mmol), cesium carbonate (733.2mg, 3.82mmol), triphenylphosphine (33.1mg, 0.13mmol) and acid chloride (5.7mg, 0.025mmol) solution in DMA (5ml) be heated to 135 ℃ totally 48 hours.The reactant mixture dilute with water is used EtOAc (2 * 10mL) extractions then.The organic facies salt water washing that merges is at MgSO ₄Last dry, concentrate then.Residue is gone up at silica gel (25g) and is carried out pure system by column chromatography, wherein use EtOAc/ hexane (10-20%) as eluant, with ethyl sulfonic acid [4-(6-difluoro-methoxy-1-ethyl-1H-iodo-2-yl)-the phenyl]-amide that makes 298.2mg (37.1% productive rate), chemical compound 516, it is bright brown solid.

Step B: according to method 1A, steps A is converted into ethyl sulfonic acid [4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indole-2-yl)-phenyl]-amide, chemical compound 519 with ethyl sulfonic acid [4-(6-difluoro-methoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide.

According to above steps A and B, prepare following chemical compound: chemical compound 343,344,345,346,409,410,411,412,413,414,415,416,417,418,419,463,464,465,466,467,468,469,470,471,472,473,515,517,518,520,521,522,523,524,575,577,579,580,611,612,613,614 by similar mode.

Embodiment 1H: preparation 1-ethyl-2-(4-fluorophenyl acetenyl)-6-methoxyl group-1H-indole-3-nitrile (chemical compound 67).

With 1-ethyl-2-iodo-6-methoxyl group-1H-indole-3-nitrile (150mg, 0.46mmol) (as embodiment 1Ga, prepare described in the steps A), 4-fluorophenyl acetylene (80mg, 0.0.69mmol), two (triphenylphosphine) palladium chloride (II) (6mg, 0.009mmol) and CuI (4mg, 0.018mmol) mixture be added in the sealable test tube and alternately emptying and use nitrogen purge.In this test tube, add DMF (4mL) and Et ₃(0.25mL, 1.84mmol), and this reactant is cooled to room temperature 80 ℃ of following heating 20 hours to N then.The reactant mixture dilute with water is used EtOAc (2X) extraction then.The organic facies H that merges ₂O (3X) and saturated NaCl washing, dry and concentrated on magnesium sulfate then.Thick reactant mixture is adsorbed on the silica gel (0.6g), and on silica gel, carry out chromatographically pure system, wherein use EtOAc/ hexane (10-20%) as eluant, with 1-ethyl-2-(4-fluorophenyl the acetenyl)-6-methoxyl group-1H-indole-3-nitrile that makes 120mg (82%), it is a yellow solid.

Use method same as described above basically and replace different acetylene-derivatives, make following chemical compound: chemical compound 64,65,66,68,69,91,92,93,94,95,96,133,134,135,136,137,143,144,145,146,147,148,149,150,151,158,159,160,161,169,170,171,172,173,174,175,176,177,178,184,185,186,187,188,196,197,198,199,200,201,202,223,230,231,232,233,234,235,236,237,238.

Embodiment 1I: preparation 1-ethyl-3-(5-ethyl-[1,2,4] oxadiazole-3-yl)-6-methoxyl group-1H-indole (chemical compound 28).

Steps A: (1.00g, 5.00mmol) (0.38mL 6.25mmol) handles the solution in MeOH (10mL) 1-ethyl-6-methoxyl group-1H-indole-3-nitrile, and reflux is 18 hours then with 50% aqueous hydroxylamine solution.After being cooled to room temperature, filter this multiphase mixture, to make the desirable product of 525mg, it is pale brown color solid.Concentrated filtrate is dissolved in CH with it then to grease ₂Cl ₂In, and on silica gel, carry out chromatographically pure system, wherein use EtOAc/CH ₂Cl ₂(15-50%), to make the product of other 295mg, it is pale brown color solid.The total output of 1-ethyl-N-hydroxyl-6-methoxyl group-1H-indole-3-carbonamidine is 820mg (70%).

Step B: above-mentioned N-hydroxy formamidine (50mg, 0.21mmol), (0.03mL is 0.32mmol) at CH for polystyrene-diisopropyl ethyl amine (165mg, 3.90mmol/g load) and propionyl chloride ₂Cl ₂Solution (10mL) is placed in the test tube, and at room temperature rotates 22 hours.After this time, add tris polyimide resin (77mg, 2.71mmol/g load), this test tube rotated under room temperature 30 minutes more then.Cross filter solid, concentrated filtrate with toluene (5mL) dilution, and stirs under 110 ℃ and spends the night then.Crude product mixture concentrates and carries out chromatographically pure system (EtOAc/CH ₂Cl ₂, 2/98), with 1-ethyl-3-of making 27mg (46%) (5-ethyl-[1,2,4] oxadiazole-3-yls)-6-methoxyl group-1H-indole, it is a white solid.

Use said method and replace suitable acyl halide, thus the following chemical compound of preparation: chemical compound 29.

Embodiment 1J: preparation 1-ethyl-6-methoxyl group-3-(5-ethyl-[1,3,4] oxadiazole-2-yl)-1H-indole (chemical compound 54).

Steps A: 1-ethyl-6-methoxyl group-1H-indole-3-nitrile (1.00g, 5.00mmol) mixture in toluene (30mL) with triethylamine hydrochloride (1.03g, 7.50mmol) and Hydrazoic acid,sodium salt (0.49g, 7.50mmol) processing, reflux is 16 hours then.After being cooled to room temperature, the saturated NaHCO of reactant mixture ₃Dilution extracts with EtOAc then.Organic layer is with other NaHCO ₃(2X) washing.The water that merges is acidified to pH2 with 6N HCl.The thick precipitate of gained extracts with the EtOAc (3X) of heat, and the organic facies of He Binging is also dry and concentrated with saturated NaCl washing then, and to form 0.55g (45%) of 1-ethyl-6-methoxyl group-3-(1H-tetrazolium-5-yl)-1H-indole, it is a yellow solid.

Step B: above-mentioned tetrazolium (50mg, 0.21mmol) and propionyl chloride (0.03mL, 0.31mmol) the suspension reflux in dichloromethane (5mL) is 21 hours.After reactant mixture was cooled to room temperature, (70mg, 3.4meq/g), this was reflected under the room temperature rotation 4 hours then to add polystyrene tris polyimide resin.Filter out resin also except that after desolvating, crude product is adsorbed on the silica gel, and by silica gel chromatography separated product (EtOAc/CH ₂Cl ₂, 5-10%), with 1-ethyl-6-methoxyl group-3-of making 30mg (53%) (5-ethyl-[1,3,4] oxadiazole-2-yls)-1H-indole, it is pale brown color solid.

Embodiment 1K: preparation 5-difluoro-methoxy-1-(4-methoxyphenyl)-2-Methyl-1H-indole-3-carboxylic acid ethyl ester (chemical compound 49).

Under 0 ℃ with Freon-22 (HCF ₂Cl) gas is blown into 5-hydroxyl-1-(4-methoxyphenyl)-2-Methyl-1H-indole-3-carboxylic acid, ethyl ester (250mg is 0.77mmol) at CH ₂Cl ₂In the solution (5mL), also comprise a spot of tetrabutyl ammonium bromide in this solution as phase transfer catalyst.At the NaOH of 0 ℃ of following Dropwise 5 0% solution.After interpolation was finished, this mixture stirred 2 hours down at 0 ℃.After adding water, separate organic facies and use the salt water washing, dry on magnesium sulfate then.Concentrated solvent, and residue carries out pure system by column chromatography on silica gel, wherein use EtOAc/ petroleum ether (1/2) as eluant, to make desirable product, productive rate is 40%.

Use said method and replace suitable oxyindole, thus the following chemical compound of preparation: chemical compound 18,46 and 50.Embodiment 1L: preparation 1-[5-methoxyl group-1-(4-methoxyphenyl)-1-H-indol-3-yl]-ethane ketone (chemical compound 42).

Down will (50mg 0.2mmol) be dissolved in the CH of 1mL according to 5-methoxyl group-1-(4-the methoxyphenyl)-1-H-indole of the method preparation of embodiment 1C at 0 ℃ ₂Cl ₂In.Add Et ₂AlCl (300 μ L, the 1M hexane solution, 0.3mmol).0 ℃ down stir 30 minutes after, (22 μ L are 0.3mmol) at the CH of 1mL for dripping acetyl chloride ₂Cl ₂In solution.It further stirred 90 minutes down at 0 ℃.The cancellation of reactant mixture water, and use CH ₂Cl ₂Extraction, vacuum concentration then.On silica gel, carry out the pure system of column chromatography EtOAc/CH ₂Cl ₂(5/95), make title compound, it is white solid (42mg, 71%).

Use method same as described above basically and replace different chloride compounds, thus the following chemical compound of preparation: chemical compound 32,33,34,37,38,39,47,48.

Embodiment 1M: preparation 1-ethyl-3-isoxazole-3-base-6-methoxyl group-1-H-indole (chemical compound 57).

Steps A: by the method described among the embodiment 1L by 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethane ketone (200mg that the 1-ethyl-the 6-methoxyl group-the 1H-indole makes, 0.92mmol), oxammonium hydrochloride. (128mg, 1.84mmol), NaOAc (151mg, 1.84mmol) and the mixture of EtOH (7mL) 85 ℃ of down heating 4 hours.Reactant mixture is then at H ₂Distribute between O and the EtOAc.Dry and the vacuum concentration of organic facies.Use EtOAc/CH ₂Cl ₂(1/9) carry out the pure system of column chromatography, obtain 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethane ketoxime, it is white solid (189mg, 92%).

Step B: (100mg 0.43mmol) is dissolved among the THF (900 μ L) with 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethane ketoxime under 0 ℃.(450 μ L, 2.5M hexane solution 1.12mol), produce solid sediment to drip n-BuLi.The DMF of dropping in 260 μ L (70 μ L, 0.9mol).It stirred 1 hour down at 0 ℃, at room temperature stirred then 1 hour.Reactant mixture is transferred to the H that comprises 1mL with pipet ₂The THF of O, 1mL and the dense H of 100 μ L ₂SO ₄Mixture in.This mixture heated 1 hour down at 75 ℃, then at H ₂Distribute between O and the EtOAc.Organic facies is dry and concentrated.Carry out pure system (CH by column chromatography ₂Cl ₂), obtaining 1-ethyl-3-isoxazole-3-base-6-methoxyl group-1-H-indole product, it is white solid (13mg, 12%).

Embodiment 1N: preparation 1-ethyl-3-isoxazole-5-base-6-methoxyl group-1H-indole (chemical compound 58).

(100mg is 0.46mmol) with pyrrolidine heated overnight under 110 ℃ of dimethylformamide dimethyl acetal and the 100 μ L of 1.5mL by 1-(1-ethyl-6-methoxyl group-1H-indol-3-yl) the ethane ketone of 1-ethyl-6-methoxyl group-1H-indole preparation according to the method for embodiment 1L.The vacuum concentration dimethylformamide dimethyl acetal.Residue is dissolved in the EtOH of 1.25mL and the H of 250 μ L again ₂Among the O, (66mg 0.95mmol) handles, and heats 2 hours down at 80 ℃ then with oxammonium hydrochloride..At H ₂Distribute between O and the EtOAc, dry and concentrated organic facies is carried out pure system (EtOAc/CH by silica gel chromatography then ₂Cl ₂, 5/95), obtain 1-ethyl-3-isoxazole-5-base-6-methoxyl group-1H-indole, it is white solid (72mg, 66%).

Use the following chemical compound of method preparation same as described above: chemical compound 60.

Embodiment 1O: preparation 1-ethyl-6-methoxyl group-3-(2H-pyrazole-3-yl)-1H-indole (chemical compound 59).

(100mg is 0.46mmol) with dimethylformamide dimethyl acetal and the 100 μ L pyrrolidines heated overnight under 110 ℃ of 1.5mL by 1-(1-ethyl-6-methoxyl group-1H-indol-3-yl)-ethane ketone that the 1-ethyl-the 6-methoxyl group-the 1H-indole makes by the method described among the embodiment 1L.Vacuum is removed the DMF dimethylacetal.Residue is dissolved in again in the acetic acid of 3mL, add hydrazine hydrate (70 μ L, 1.38mmol), then with this mixture heated to 100 ℃ totally 2 hours.Vacuum is removed acetic acid, and residue is at EtOAc and saturated NaHCO ₃Between distribute.Organic facies is dry and concentrated, and product passes through the pure system of silica gel chromatography (EtOAc/Hex, 1/1), and to form 1-ethyl-6-methoxyl group-3-(2H-pyrazole-3-yl)-1H-indole (54%) of 59mg, it is colourless semisolid.At Et ₂Grind among the O, obtain white crystalline powder.

Use the following chemical compound of method for preparing: chemical compound 61.

Embodiment 1P: preparation 1-ethyl-3-oxazole-5-base-1H-Indole-6-carboxylic acid methyl ester (chemical compound 72).

Steps A: (900mg 4.45mmol) is dissolved among the DMF (3.3mL) with 1-ethyl-1H-Indole-6-carboxylic acid methyl ester.It is dropped to POCl ₃(430 μ L are 4.5mmol) in the ice-cold solution in DMF (1.5mL).Reactant mixture at room temperature stirred 90 minutes.Reactant mixture is handled with 6N NaOH (3.5ml).This mixture is then at H ₂Distribute between O and the ethyl acetate.Carry out pure system (5-10%EtOAc/CH by silica gel chromatography ₂Cl ₂), obtaining 1-ethyl-3-formoxyl-1H-Indole-6-carboxylic acid methyl ester (985mg, 96%), it is a white solid.

Step B:1-ethyl-3-formoxyl-1H-Indole-6-carboxylic acid methyl ester (100mg, 0.42mmol), TOSMIC (100mg, 0.52mmol), K ₂CO ₃(178mg, 1.29mmol) and MeOH (800 μ L) 80 ℃ of following heated overnight.Reactant mixture is at H ₂Distribute between O and the ether.After the dry and concentrated organic facies, product carries out pure system (EtOAc/CH by silica gel chromatography ₂Cl ₂, 10/90), to form methyl 1-ethyl-3-oxazole-5-base-1H-Indole-6-carboxylic acid ester (26mg, 23%), it is a beige solid.

Embodiment 1Q: preparation methyl 1-ethyl-3-oxazole-2-base-1H-Indole-6-carboxylic acid ester (chemical compound 75).

Steps A: (800mg 3.5mmol) (as embodiment 1P, is prepared described in the steps A) and is dissolved in the acetone (98mL) 1-ethyl-3-formoxyl-1H-Indole-6-carboxylic acid methyl ester.Add KMnO ₄(655mg is 4.15mmol) at H ₂Solution among the O (31mL).Reactant mixture at room temperature stirred 90 minutes.Add KMnO again ₄(108mg) at H ₂Solution among the O (6mL), restir 45 minutes is so that react completely.Reactant mixture is then used 10%H ₂O ₂(1.5mL) cancellation.Mixture filters by celite.Filtrate under vacuum extracting to about 1/3 of volume.Residue extracts back in the ethyl acetate then with 6N HCl acidify.Grind with acetone by isolating solid in the ethyl acetate layer, making 1-ethyl-1H-indole-3,6-dicarboxylic acids 6-methyl ester (696mg, 79%), it is the bright orange solid.

Step B: with 1-ethyl-1H-indole-3, (600mg 2.43mmol) is suspended in CH to 6-dicarboxylic acids 6-methyl ester ₂Cl ₂(27ml) and in the solution of DMF (20 μ L).(470 μ L, 5.38mmol), and reactant mixture at room temperature stirred 1 hour to add oxalyl chloride.This mixture slowly is poured over dense NH ₄In the quick agitating solution of OH (10mL).It is then at H ₂Distribute among O and the EtOAc.The residue that ethyl acetate layer produces grinds with acetone, and to make 6-methoxycarbonyl-1-ethyl-1H-indole-3-Methanamide (511mg, 85%), it is a white solid.

Step C: (430 μ L, 3.7mmol) mixture in is 125 ℃ of heating 2 hours down at diethylene glycol dimethyl ether (3.6mL) and bromine acetal dimethylacetal with 6-methoxycarbonyl-1-ethyl-1H-indole-3-Methanamide of 150mg (0.61mmol).Reactant mixture cooling and at H ₂Distribute among O and the EtOAc.Organic facies is dry and concentrated, and product carries out pure system (EtOAc/CH by silica gel chromatography ₂Cl ₂5-10%).The each several part merging that comprises product concentrates then, and solid grinds with hexane, and to make methyl 1-ethyl-3-oxazole-2-base-1H-Indole-6-carboxylic acid ester (75mg, 46%), it is a yellow solid.

Embodiment 1R: preparation 1-ethyl-6-methoxyl group-3-thiazol-2-yl-1H-indole (chemical compound 73)

Steps A: (900mg 5.14mmol) is dissolved among the DMF (1.5mL) with 1-ethyl-6-methoxyl group-1H-indole.It is dropped to POCl ₃(500 μ L are 5.2mmol) in the ice-cold solution in DMF (1.75ml).After at room temperature stirring 90 minutes, reactant mixture cools off in ice bath again, slowly uses 6N NaOH (4mL) cancellation then.Reactant mixture is at EtOAc and H ₂Distribute between the O.Carry out pure system (EtOAc/CH by silica gel chromatography ₂Cl ₂, 5/95), obtain 1-ethyl-6-methoxyl group-1H-indole-3-formaldehyde (849mg, 81%), it is a yellow solid.

(600mg 2.95mmol) is dissolved in the acetone (85mL) step B:1-ethyl-6-methoxyl group-1H-indole-3-formaldehyde.Add KMnO ₄(450mg is 2.85mmol) at H ₂Solution among the O (28mL).It at room temperature stirred 5 hours, then added KMnO again ₄(450mg is 2.85mmol) at H ₂Solution among the O (25mL).At room temperature restir is after 1 hour, and this reaction is carried out fully.Reactant mixture 10%H ₂O ₂(1.5mL) cancellation is filtered by celite then.Filtrate under vacuum extracting to 1/3 of about volume.Residue extracts back in the ethyl acetate then with 6N HCl acidify.Carry out pure system (hexane/acetone/acetic acid, 70/30/1) by silicagel column, obtain crude product.Grind with ether, obtain pure 1-ethyl-6-methoxyl group-1H-indole-3-carboxylic acid (365mg, 56%), it is a yellow solid.

Step C: (250mg 1.14mmol) is suspended in CH with 1-ethyl-6-methoxyl group-1H-indole-3-carboxylic acid ₂Cl ₂(12.5mL) and in the solution of DMF (10 μ L).(230 μ L, 2.64mmol), reactant mixture at room temperature stirred 1 hour then to add oxalyl chloride.This mixture slowly is poured over dense NH ₄In the quick agitating solution of OH (5mL).It is then at H ₂Distribute among O and the EtOAc.The residue that ethyl acetate layer produces grinds with acetone, and to make 1-ethyl-6-methoxyl group-1H-indole-3-Methanamide (134mg, 54%), it is a white solid.

Step D:1-ethyl-6-methoxyl group-1H-indole-3-Methanamide (120mg, 0.55mmol), Lawesson reagent (240mg, 0.6mmol) and toluene (2mL) 90 ℃ of down heating 90 minutes.Reactant mixture concentrates and by the pure system (EtOAc/CH of silica gel chromatography ₂Cl ₂, 1/9), to make 1-ethyl-6-methoxyl group-1H-indole-3-thioformamide, it is yellow solid (92mg, 71%).

Step e: 1-ethyl-6-methoxyl group-1H-indole-3-thioformamide (83mg, 0.36mmol), (220 μ L are 1.86mmol) 80 ℃ of heating 16 hours down for diethylene glycol dimethyl ether (3.6mL) and bromine acetal dimethylacetal.Add bromine acetal dimethylacetal (250 μ L) again.80 ℃ of heating of its infra 2 hours.Add the bromine acetal dimethylacetal of 250 μ L again, and continue heating 2 hours.This reactant mixture is cooled to room temperature, is adsorbed on also to pass through the pure system of silica gel chromatography (hexane/EtOAc, 7/3) on the silicon dioxide, and to make 1-ethyl-6-methoxyl group-3-thiazol-2-yl-1H-indole, it is brown oil (44mg, 47%).

Prepare following chemical compound according to the method described above: chemical compound 78,101,104,105 and 106.

Embodiment 1S: preparation 1-ethyl-6-methoxyl group-2-phenoxymethyl-1H-indole-3-nitrile (chemical compound 99).

Steps A: under 0 ℃ to LiAlH ₄(7.6g 0.2mol) drips 6-methoxyl group-1H-indole-2-carboxylic acid methyl ester (8.2g, 0.04mol) solution in dioxane (50mL) in the suspension in dioxane (100mL).After interpolation was finished, this mixture at room temperature stirred 1 hour, and reflux is 5 hours then.After being cooled to 0 ℃, this reaction water (dropping), 15%NaOH aqueous solution cancellation then.After at room temperature stirring 1 hour, this mixture filters by celite.Solid washs with a large amount of EtOAc.Solvent salt water washing is at Na ₂SO ₄Last dry, vacuum evaporation then.Residue by the pure system of flash column chromatography, wherein uses EtOAc/ petroleum ether (1/5) as eluant on silica gel, to make 6-methoxyl group-2-Methyl-1H-indole of 61%.

Step B: (3.9g 24mmol) drips ClSO in the solution in acetonitrile (200mL) and DMF (20mL) to 6-methoxyl group-2-Methyl-1H-indole under 0 ℃ ₂NCO (4mL, 1.3eq.) solution in acetonitrile (31mL).After interpolation was finished, this mixture at room temperature stirred 3 hours.Then it is poured in the frozen water, and to wherein adding saturated NaHCO ₃Become alkalescence until it.Water CH ₂Cl ₂Extraction, evaporation then.Residue with flash column chromatography pure system, wherein uses EtOAc/ petroleum ether (1/5) as eluant on silica gel, to make 6-methoxyl group-2-Methyl-1H-indole-3-nitrile of 81%.

Step C: under 0 ℃ to NaH (0.6g, 2eq.) add in the suspension in DMF (7mL) 6-methoxyl group-2-Methyl-1H-indole-3-nitrile (1.3g, the 7.0mmol) solution in DMF (8mL), add then ethyl iodide (1.2mL, 2eq.).Stir after 1 hour, this mixture is poured in the frozen water, uses CH then ₂Cl ₂Extraction.Organic layer is with the salt water washing and use Na ₂SO ₄Dry.Vacuum evaporating solvent also on silica gel with the pure system of flash column chromatography, wherein use EtOAc/ petroleum ether (1/5) as eluant, to make 1-ethyl-6-methoxyl group-2-Methyl-1H-indole-3-nitrile of 92%.

Step D: to 1-ethyl-6-methoxyl group-2-Methyl-1H-indole-3-nitrile (1.38g, 6.45mmol) add in the solution in benzene (130mL) benzoyl peroxide (226mg) and NBS (1.21g, 1.05eq.).This mixture heated refluxed 3 hours.After cooling and the filtration, vacuum concentrated filtrate.Thick 2-bromomethyl-1-ethyl-6-methoxyl group-not further pure system of 1H-indole-3-nitrile (1.6g, 86%) promptly is used.

Step e: to NaH (44mg, 4eq.) add in the solution in DMF (0.5mL) 2-bromomethyl-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (80mg, 0.274mmol) and phenol (2eq.).Stir after 20 hours, this mixture is poured in the frozen water and uses CH ₂Cl ₂Extraction.Organic layer is with the salt water washing and use Na ₂SO ₄Dry.Vacuum evaporating solvent is also used the pure system of flash column chromatography on silica gel, wherein use EtOAc/ petroleum ether (1/5) as eluant, to make 1-ethyl-6-methoxyl group-2-phenoxymethyl-1H-indole-3-nitrile, chemical compound 99.

Embodiment 1T: preparation 6-nitro-2-pyrroles-1-base-1H-indole-3-nitrile (chemical compound 7).

Steps A: 2-fluoro-5-nitroaniline (11.7g, 74.9mmol) solution in dimethyl formamide (120mL) is with Cyanoacetyl-Cyacetazid (5.28g, 80.0mmol) and potassium carbonate (11.05g, 80.0mmol) processing (Modification of Chem.Heterocyclic Cpd. (Engl.Trans., 9 37(2001).The multiphase mixture of gained was heated to gentle reflux totally 3 hours, cooled off then and was poured in the water (500mL).The precipitate of gained is collected by filtering, and puts into ethyl acetate (300mL) then.This solution is at last Na ₂SO ₄Drying is filtered and the part evaporation, and to form precipitate, it is collected by filtering.Further evaporation and filtration form second batch of product.These two batches of products merge and vacuum drying, and to form 2-amino-1-ethyl-6-nitro-1H-indole-3-nitrile (7.90g, 52%), it is an orange powder.

Step B:2-amino-6-nitro-1H-indole-3-nitrile (362mg, 1.79mmol) solution in acetic acid (5mL) is with 2, and (0.30mL 2.27mmol) handles the 5-dimethoxy-tetrahydrofuran, and this vlil is 14 hours then.After being cooled to room temperature, this solution is poured in the water (100mL), adds solid sodium bicarbonate then until stopping to form CO ₂(2 * 100mL) extract this mixture, and extract washs with saturated brine, merges, at MgSO with EtOAc ₄Last dry, filter and concentrate.Residue separates (EtOAc/ hexane, 1/4) by silica gel chromatography, making 6-nitro-2-pyrroles-1-base-1H-indole-3-nitrile, and chemical compound 5, it is yellow solid (232mg, 51%).

Embodiment 1U: preparation N-(3-cyano group-1-ethyl-6-nitro-1H-indole-2-yl) acetamide (chemical compound 25).

Steps A: sodium hydride (42mg, 1.05mmol, 60%w/w mineral oil suspension) is put into dimethyl sulfoxide (1mL) then with hexane wash.2-amino-6-nitro-1H-indole-3-nitrile is according to the preparation of the method for 1T) solution in dimethyl sulfoxide (1mL) adds by syringe, and the mixture of gained stirred 20 minutes.(77 μ L, 0.96mmol), this mixture stirred 14 hours then to add iodoethane with syringe.This reactant is poured among the EtOAc (50mL), and this solution with water (3 * 50mL) and saturated brine (40mL) washing.Water with the EtOAc extraction, merges organic extract liquid again, and is dry on sodium sulfate, filters and evaporation.Residuals separates (EtOAc/ hexane, 1/1) by column chromatography on silica gel, at first make a spot of dialkyl group analog, be desirable chemical compound then, 2-amino-1-ethyl-6-nitro-1H-indole-3-nitrile (114mg, 52%), and last unreacted starting material.Separate desirable product, it is an orange powder.

Step B: sodium hydride (44mg, 1.10mmol is in the 60%w/w mineral oil) is with the washing hexane and be suspended in 1, in the 4-dioxane (3mL).(mixture of gained stirred 30 minutes for 120mg, the 0.521mmol) solution in dioxane (2mL) to add the 2-amino-1-ethyl-6-nitro-1H-indole-3-nitrile that makes among the above-mentioned steps B.By syringe add chloroacetic chloride (45 μ L, 0.63mmol), and this solution restir 12 hours.This is reflected between water and the EtOAc (20mL respectively) and distributes organic facies salt water washing then.Water is then used ethyl acetate extraction again, merges organic extract liquid, and is dry on magnesium sulfate, filters and evaporation.The solid Et of gained ₂O grinds, collects and vacuum drying by filtering, and making N-(3-cyano group-1-ethyl-6-nitro-1H-indole-2-yl)-acetamide (100mg, 71%), chemical compound 25, it is a cream-coloured powder.

Use this method and replace suitable acyl chlorides or chloro-formate, make following chemical compound: chemical compound 23,26,35,36,203,204,214,215,216.

Embodiment 1V: preparation N-ethyl-3-phenyl-5-nitroindoline (chemical compound 41).

Steps A: under-4 ℃ and blanket of nitrogen to 5-nitroindoline (5.00g, 30.8mmol) drip bromination in the solution in pyridine (200mL) and cross pyridinium bromide (pyridinium bromide perbromide) (10.99g, 34.3mmol) solution in pyridine (200mL), stir simultaneously.After interpolation was finished, reactant mixture stirred 5 minutes down at 0 ℃.Reactant mixture dilutes in 0 ℃ of water (200mL) and with the Et of 200mL ₂The O extraction.Organic layer 6M HCl (300mL), 5%NaHCO ₃(300mL) and saline (300mL) washing.Organic facies is at MgSO ₄Last dry, and remove and desolvate, to form 3-bromo-5-nitroindoline, it is a yellow powder, 80% is pure, contains 20%5-nitroindoline (6.80g, 74% productive rate).

Step B: the 3-bromo-5-nitroindoline that as above makes (625mg, 2.1mmol), phenylboric acid (381mg, 3.13mmol), triphenylphosphine (109.3mg, 0.417mmol) solution in dimethoxy-ethane (4.16mL) degassing.Add 2N sodium carbonate (6.25mL) in this mixture, this reactant mixture outgases again then.(23.4mg, 0.104mmol), this is reflected to reflux under the dry nitrogen atmosphere and stirred 8 hours then to add acid chloride (II) in this reactant.Reactant mixture then with 1M HCl (100mL) dilution, is used ethyl acetate (100mL) extraction then.Organic facies water (100mL) and saline (100mL) washing.Organic facies is at MgSO ₄Last dry and vacuum concentration.Crude product carries out chromatographically pure system (EtOAc/ hexane, 10/90) on silica gel, to make 3-phenyl-5-nitroindoline, it is orange powder (45mg, 9% productive rate).

Step C: to 60%NaH mineral oil (8.7mg, 0.630mmol) and the mixture among the DMF (1.0mL) drip 3-phenyl-5-nitroindoline (40.0mg, 2.1mmol) solution in DMF (0.75mL).Reactant mixture is at 0 ℃ and N ₂Under stirred 20 minutes.Drip ethyl iodide (14.8 μ L, 0.185mmol), and reactant mixture restir 3 hours.Reactant mixture water (250mL) dilutes, and extracts with EtOAc (30mL).Organic facies water (250mL) washing, dry on magnesium sulfate then, and solvent removed in vacuo.Obtain desirable N-ethyl-3-phenyl-5-nitroindoline, it is yellow powder (40.0mg, 89.5% productive rate).

Prepare following chemical compound according to similar method: chemical compound 40.

Embodiment 1W: preparation [3-cyano group-1-(4-methoxyphenyl)-1H-indole-6-yl]-carbamic acid propyl diester (chemical compound 97).

(30mg 0.12mmol) is suspended among the EtOH (300 μ L) with 6-amino-1-(4-methoxyphenyl)-1H-indole-3-nitrile.(168 μ L, 1.5mmol), this mixture at room temperature stirs and spends the night then to add propyl chloroformate..Add triethylamine (300 μ l), restir 1 hour is at room temperature finished reaction then.This reactant mixture directly is seated on the silicagel column, and uses CH ₂Cl ₂Eluting.Need another one silicagel column (3/2, ether/hexane) with complete pure system product [3-cyano group-1-(4-methoxyl group-phenyl)-1H-indole-6-yl]-carbamic acid propyl diester (19mg, 45%), it is a white solid.

Embodiment 1X: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-amsacrine (chemical compound 130).

At room temperature (50mg, 0.16mmol) (according to embodiment 1H preparation) is dissolved in the pyridine (550 μ L) with 2-(4-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.(17 μ L 0.21mmol), and at room temperature stir and spend the night to drip methane sulfonyl chloride.Reactant mixture dilutes with ethyl acetate, uses HCl aqueous solution, salt water washing then.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (9/1, CH ₂Cl ₂/ EtOAc), obtain N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-amsacrine (58mg, 92%), it is a beige solid.

Use said method and replace suitable aminophenyl Ethynylindole compounds and the following chemical compound of sulfonic acid chloride preparation: chemical compound 131,132,208,209 and 210.

Embodiment 1Y: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-amsacrine (chemical compound 129).

With 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (70mg, 0.24mmol) (as embodiment 1Ga, being prepared described in the step B) solution in THF (3mL) is cooled to 0 ℃, use triethylamine (0.04mL then, 0.31mmol) and methane sulfonyl chloride (0.02mL, 0.29mmol) under agitation handle, be warmed to ambient temperature overnight.Reactant mixture H ₂O dilutes and extracts with ethyl acetate (3X).Organic facies H ₂O and saturated NaCl washing, dry and concentrated, by the pure system of flash chromatography, wherein use EtOAc/ hexane (30-50%) then, with N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl that makes 60mg (68%)]-amsacrine, it is pale brown color solid.

Use method same as described above and replace suitable aminophenyl indole and sulfonic acid chloride, perhaps in as the pyridine of alkali and solvent, carry out this reaction, make following chemical compound: 83,85,86,87,88,243,251,252,272,273,287,289,365,366,367,368,369,370,371,394,439,440,448,449,451,452,477,487,488,495,505,510,548,549,550,551,552,562,563,598,599,601,602,608,609,610,615,616,617,621,622,623,629,630,631,639,655,657,658,662,669,670,671,674,675,701,702,703,706,707,708,709,710,711,713,715,720,789,790,791,850,851.

Embodiment 1Za: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-acetamide (chemical compound 138).

(95mg 0.29mmol) (is prepared described in embodiment 1H) and is dissolved among the THF (1.4mL) with 2-(4-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.Add triethylamine (84 μ L, 0.6mmol), then dripping acetyl chloride (44 μ L, 0.5mmol).It at room temperature stirred 1 hour.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.By the pure system of silica gel chromatography (9/1, CH ₂Cl ₂/ EtOAc), obtain N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-acetamide (103mg, 96%), it is a yellow solid.

According to above-described method and replace suitable aminophenyl Ethynylindole compounds and chloride compounds, prepare following chemical compound: chemical compound 82,139,152,153,162,163,165,167,205,206,207,211,212,213,219,224,225,228.

Embodiment 1Zb: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-Methanamide (chemical compound 241).

Acetic anhydride (2.5mL) and 98% formic acid (1.0mL) heated 1 hour down at 65 ℃, and it is cooled to 0 ℃.(100mg 0.32mmol) (is prepared as described in embodiment 1H) and puts into THF (1.2mL), and it is added in first and second acid anhydride mixtures with 2-(4-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.It stirred 0 minute down at 0 ℃.Reactant mixture is at H ₂Distribute between O and the EtOAc.The saturated NaHCO of EtOAc layer ₃, then saturated brine washing.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (4/1, CH ₂Cl ₂/ EtOAc), obtain N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-Methanamide (105mg, 96%), it is a yellow solid.

Be similar to the following chemical compound of preparation as mentioned above: chemical compound 218.

Embodiment 1AA: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-acetamide (chemical compound 128).

With 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (70mg, 0.24mmol) (as embodiment 1Ga, being prepared described in the step B) solution in THF (3mL) is cooled to 0 ℃, use triethylamine (0.04mL then, 0.31mmol) and chloroacetic chloride (0.02mL, 0.29mmol) handle, stir, be warmed to ambient temperature overnight.Reactant mixture H ₂O dilutes and extracts with ethyl acetate (3X).Organic facies H ₂O and saturated NaCl washing, dry and concentrated, by the pure system of flash chromatography, wherein use EtOAc/ hexane (30-50%) then, with N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl that makes 57mg (71%)] acetamide, it is pale brown color solid.

Use method same as described above and replace suitable aminophenyl benzazolyl compounds and chloride compounds, prepare following chemical compound: chemical compound 81,242,244,324,325,326,327,328,329,330,383,420,421,422,423,424,425,544,558,559,560,561,565,566 567,644,645,646,755,756,757,759,760,761,762,763,764,765,766,798,799,801,802,803,804,854,855,856,857,858,859.

Embodiment 1AB: preparation 1-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base) phenyl]-3-ethyl carbamide (chemical compound 220).

(100mg 0.32mmol) (is prepared described in embodiment 1H) and is dissolved in the pyridine (670 μ L) with 2-(3-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.The interpolation ethyl isocyanate (62 μ L, 0.75mmol).Reactant mixture heated 2 hours down at 100 ℃.This mixture dilutes in EtOAc, with moisture HCl, then salt water washing.Organic layer is dry and concentrated.By the pure system of silica gel chromatography (4/1, CH ₂Cl ₂/ EtOAc), use hexane/acetone (1/1) to grind then, obtain 1-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-3-ethyl carbamide (44mg, 36%), it is a white solid.

Embodiment 1AC: preparation 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl] urea (chemical compound 156).

(100mg 0.32mmol) (is prepared described in embodiment 1H) and is suspended in the toluene (600 μ L) with 2-(4-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.(32 μ L, 0.37mmol), this mixture heated 5 hours down at 100 ℃ then to add the 2-chloroethyl isocyanate.The reactant mixture cooling is diluted in acetone, is adsorbed on the silicon dioxide then.Carry out the pure system (CH of 5-10%EtOAc by column chromatography ₂Cl ₂Solution), obtain 1-(2-chloro-ethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl] urea (73mg, 54%), it is a yellow solid.

Use the following chemical compound of method for preparing: chemical compound 221.

Embodiment 1AD: preparation ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl] methyl nitrosourea (chemical compound 157).

Making N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base) phenyl] (70mg 0.17mmol) (is prepared described in embodiment 1X) and K ethane sulphonamide ₂CO ₃(49mg, 0.35mmol) and DMF (1.0mL) mix.(16 μ L, 0.26mmol), this mixture at room temperature stirred 1 hour then to add iodomethane.Reactant mixture dilutes in EtOAc, uses H ₂O, then salt water washing.Organic layer is dry and concentrated.By the pure system of silica gel chromatography (95/5, CH ₂Cl ₂/ EtOAc), obtain bright pale brown color solid.Grinding obtains ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl] methyl nitrosourea (61mg, 85%), and it is orange-white solid.

Use above method and replace the suitable following chemical compound of sulfonamide preparation: chemical compound 182,652,840.

Embodiment 1AE: preparation 1-ethyl-5-methoxyl group-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-nitrile (chemical compound 245).

Steps A: make 4-(3-cyano group-1-ethyl-5-methoxyl group-1H-indole-2-yl)-essence of Niobe (350mg, 1.05mmol) (described in embodiment 1Ga step B, prepare) with NaOH (40mg, 1mmol), H ₂O (0.8mL) and THF (3.4mL) mix, and 80 ℃ of heating of infra are 1 hour then.Reactant mixture is at H ₂Dilute among the O, then wash with ether.Water layer extracts back EtOAc then with moisture HCl acidify.Organic layer is dry and concentrated, and to make 4-(3-cyano group-1-ethyl-6-methoxyl group-1h-indole-2-yl)-benzoic acid (311mg, 92%), it is pure white solid.

Step B: (3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-(50mg 0.16mmol) is suspended in CH to benzoic acid with 4- ₂Cl ₂(2.2mL) and among the DMF (2 μ L) of catalytic amount.The interpolation oxalyl chloride (22 μ L, 0.25mmol).Reactant mixture at room temperature stirred 1 hour, and this moment is dissolving fully.This reactant mixture drips morpholine (1.0mL) in vigorous stirring at CH with pipet ₂Cl ₂In the solution (5ml).After interpolation was finished, reactant mixture washed with aqueous hydrochloric acid solution.Organic layer is dry and concentrated.By the pure system of silicagel column (1: 1 CH ₂Cl ₂/ EtOAc), obtain 1-ethyl-6-methoxyl group-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-nitrile (56mg, 90%), it is a white solid.

Be similar to the following chemical compound of preparation as mentioned above: chemical compound 113,114,246,270,271 290,291,292,323,377,378,379,380,381,382,384,385,386,387,388,389,390,391,392,432,433,564,568,569,570,571,572,573,647,648,853,860,861,862.

Embodiment 1AF: preparation cyclopropane-carboxylic acid [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-ethyl-acetylene base)-phenyl] amide (chemical compound 194).

[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-(60mg 0.16mmol) (prepares described in embodiment 1Za) at BBr amide at room temperature to make cyclopropane-carboxylic acid ₃(800 μ L, 1M CH ₂Cl ₂Solution, 0.8mmol) the middle stirring 1 hour.Reactant mixture H ₂CH is used in the O cancellation then ₂Cl ₂Extraction.Organic layer is dry and concentrated.Obtain impure product by the pure system of silica gel chromatography (EtOAC).These crude products grind with 1/1 hexane/acetone, and to make cyclopropane-carboxylic acid [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-ethyl-acetylene base)-phenyl]-amide (32mg, 54%), it is a beige solid.

Use said method and replace suitable sulfonamide compounds (deriving from embodiment 1X) or amide compound (deriving from embodiment 1Z), prepare following chemical compound: chemical compound 164,168,183,193,195.

Embodiment 1AG: preparation 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenylacetylene base]-1H-indole-3-nitrile (chemical compound 166).

Making 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl] (55mg 0.13mmol) (prepares described in embodiment 1AC) and K urea ₂CO ₃(50mg, 0.36mmol) and DMF (550 μ L) mix.This mixture at room temperature stirred 3 hours.Reactant mixture dilutes in EtOAc, uses H then ₂O, then use the salt water washing.Organic layer is dry and concentrated.By the pure system of silica gel chromatography (10-50%, EtOAc/CH ₂Cl ₂), obtain 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenylacetylene base]-1H-indole-3-nitrile (47mg, 94%), it is a white solid.

Use said method and replace the suitable following chemical compound of urea preparation: chemical compound 222.

Embodiment 1AH: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-dimethyl phosphine amide (chemical compound 227).

(100mg 0.32mmol) (prepares described in embodiment 1H) and is dissolved in pyridine (300 μ L) with 2-(3-aminophenyl acetenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile under 0 ℃.Add dimethyl phosphine acyl chlorides (60mg, 0.53mmol) solution in THF (300 μ L).This reaction was at room temperature stirred 2 hours.Reactant mixture dilutes in EtOAc, then with hydrochloric acid, then use the salt water washing.Organic layer is dry and concentrated.By the pure system of silica gel chromatography (acetone), obtain N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene base)-phenyl]-dimethyl phosphine amide (65mg, 52%), chemical compound 227, it is pure white solid.This silicagel column 9/1 CH ₂Cl ₂/ MeOH eluting is with N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-ethyl-acetylene the base)-phenyl that makes 9mg]-two-(dimethyl phosphonic acids) amide by-product.

Embodiment 1AI: preparation 1-ethyl-6-methoxyl group-3-[5-(4-methoxyphenyl)-isoxazole-3-base]-1H-indole (chemical compound 116).

Steps A: 1-ethyl-6-methoxyl group-1H-indole-3-carbaldehyde oxime (0.20g, 0.92mmol) (by the preparation of the aldehyde precursor substance among the embodiment 1R) mixture N-chloro-succinimide (0.12g in dichloromethane (3mL), 0.92mmol) and pyridine (0.04mL, 0.46mmol) handle, at room temperature stirred then 1 hour.Reactant mixture is poured over H ₂Among the O and to be acidified to pH with 1NHCl be 2.This mixture extracts with EtOAc, and organic facies H ₂O and saturated NaCl washing, drying also concentrates then, obtains the mixture of chlorine oxime, and its impure system promptly is used for next step.

Step B: this chlorine oxime mixture that as above makes is dissolved in CH ₂Cl ₂(5mL), then under 0 ℃ to wherein add 4-methoxybenzene ethyl-acetylene (0.24g, 1.84mmol) and triethylamine (0.25mL, 1.84mmol), this reactant then stirs and spends the night and be warmed to room temperature.This reactant H ₂O dilutes and extracts with EtOAc (3X).Organic facies H ₂O and saturated NaCl washing, dry then and concentrated.Chromatographically pure system on silica gel (the EtOAc/ hexane 10-20%), obtains 1-ethyl-6-methoxyl group-3-[5-(4-methoxyl group-phenyl)-isoxazole-3-base of 76mg (24%)]-the 1H-indole, it is pale brown color solid.

Embodiment 1AJ: preparation [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-carbamic acid ethyl ester (chemical compound 121).

0 ℃ down preparation 2-(4-amino-phenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (70mg, 0.24mmol) (described in embodiment 1Ga step B, prepare) and the chloro-carbonic acid ethyl ester (0.03mL is 0.29mmol) at EtOAc (3mL) and saturated NaHCO ₃Biphasic mixture (3mL) is warmed to room temperature then and stirred 24 hours.This reactant is then used H ₂O dilutes and extracts with EtOAc (2X).Organic facies H ₂O and saturated NaCl washing, dry then and concentrated.Flash chromatography (EtOAc/ hexane 20-40%) obtains 48mg's (55%) [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-carbamic acid ethyl ester, and it is a beige solid.

Prepare following chemical compound in a comparable manner: chemical compound 122,293,294,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,349,350,351,352,353,354,355,356,357,358,359,360,361,372,434,435,450,453,454,455,457,485,486,489,490,500,501,502,503,506,507,508,509,545,546,547,553,554,555,556,557,581,582,583,584,585,585,586,587,588,589,590,591,592,593,594,595,596,597,603,604,605,606,607,618,619,624,625,637,640,641,664,665,676,677,721,722,723,734,735,736,737,738,739,744,745,746,747,787,788,792,793,794,795,796,797,819,822,823,824,825,826,849.

Embodiment 1AK: preparation 1-ethyl-5-thiene-3-yl--1H-indole-3-nitrile (chemical compound 141).

Filling 5-bromo-1-ethyl-1H-indole-3-nitrile in test tube (100mg, 0.40mmol), thiophene-3-boric acid (72mg, 0.56mmol), PdCl ₂(PPh ₃) ₂(11mg, 0.016mmol) and CsF (152mg, mixture 1mmol), alternately emptying and pour nitrogen (3X) then, with dimethoxy-ethane (3mL) dilution, then be heated to 90 ℃ totally 19 hours.After the cooling, the saturated NaHCO of crude product mixture ₃Dilution also extracts with EtOAc (2X).The organic facies that merges is washed with saturated NaCl, and is dry then and concentrated.Pure system (the CH of flash chromatography on silica gel ₂Cl ₂/ hexane, 40/60), obtain 1-ethyl-5-thiene-3-yl--1H-indole-3-nitrile of 25mg (25%), it is a white solid.

Prepare following chemical compound according to similar method: chemical compound 140 and 142.

Embodiment 1AL: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-N-methylmethane sulfonamide (chemical compound 180).

N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amsacrine (130mg, 0.35mmol) (described in embodiment 1Y, preparing) solution in DMF (10mL) NaH (21mg, 0.53mmol) handle, at room temperature stirred then 10 minutes.(0.03mL, 0.53mmol), this mixture at room temperature stirred 18 hours then to add iodomethane.Reactant mixture is then used H ₂O dilutes, and extracts with EtOAc (2X).Organic facies H ₂O and saturated NaCl washing, dry then and concentrated.On silica gel, pass through the pure system (EtOAc/CH of flash chromatography ₂Cl ₂, 0-1%), obtain N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl of 60mg (45%)]-N-methylmethane sulfonamide, it is a white solid.

Prepare following chemical compound according to similar method: chemical compound 181,642,643,672,673,816,852.

Embodiment 1AM: preparation N-[4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-yl)-phenyl]-amsacrine (chemical compound 189).

With N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] (85mg is 0.23mmol) at CH for amsacrine ₂Cl ₂Solution (2mL) is cooled to-5 ℃.Add Boron tribromide solution (1.15mL, 1.15mmol, 1MCH ₂Cl ₂Solution), make reactant mixture be warmed to 10 ℃ totally 4 hours.Reactant mixture is poured over H ₂Extract among the O and with EtOAc (3X).The organic facies H that merges ₂O and saturated NaCl washing, dry then and concentrated.(the EtOAc/CH of chromatographically pure system on silica gel ₂Cl ₂, 5-10%), obtain N-[4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-yl)-phenyl of 18mg (22%)] and amsacrine, it is pale brown color solid.

Prepare following chemical compound similarly: chemical compound 190,191,192.

Embodiment 1AN: preparation methyl 3-[5-(3-cyano group-6-methoxyl group-1H-indole-2-yl)-[1,2,4] oxadiazole-3-yl] benzoate (chemical compound 226).

Steps A: to 6-methoxyl group-1H-indole-3-nitrile (5.88g, 40mmol) (preparation) as described above in Example and (Boc) ₂O (9.59g, 44.0mmol) add in the mixture in DCM (50mL) DMAP (0.10g, 0.8mmol).This mixture at room temperature stirred 48 hours, and water (30mL) is handled and in anhydrous Na then ₂SO ₄Last dry.Crude product carries out chromatographically pure system (hexane/EtOAc, 7/1) on silica gel, so that desirable intermediate product 3-cyano group-6-methoxyl group indole-1-carboxylic acid tertiary butyl ester (8.48g, 86%) to be provided.

Step B: with above-mentioned intermediate (2.72g 10.0mmol) is dissolved among the anhydrous THF (20mL), is cooled to-78 ℃ then, then add LDA (1.5M monoTHF in cyclohexane extraction, 10.0mL, 15mmol).Stir after 45 minutes, feed CO ₂Gas 2 hours.Make this mixture reach room temperature and solvent removed in vacuo, and residue is acidified to pH=2 with water treatment and with 6NHCl.The collecting precipitation thing also washes with water, and is dry then, to provide sour intermediate product 3-cyano group-6-methoxyl group-indole-1,2-dicarboxylic acids 1-tertiary butyl ester (2.40g, 73%).

Step C: to the 3-cyano group that as above makes-6-methoxyl group indole-1,2-dicarboxylic acids 1-tertiary butyl ester (474mg, 1.5mmol) and HOBt (200mg, 1.5mmol) add DCC (310mg in the solution in DCE/DMF (10mL/1mL), 1.5mmol), add then 3-(N-hydroxyl carbamimidoyl) benzoic acid methyl ester (291mg, 1.5mmol).This mixture at room temperature stirs and filtered then in 2 hours.Collect filtrate, replace described solvent with chlorobenzene then, then heated 48 hours down at 150 ℃.After being cooled to room temperature, solvent removed in vacuo, and residue carries out chromatographic isolation (silica gel, CH ₂Cl ₂/ EtOAc, 8/2), so that intermediate product 3-cyano group-6-methoxyl group-2-[3-(3-methoxycarbonyl phenyl)-[1,2,4] oxadiazole-5-yl]-indole-1-carboxylic acid tertiary butyl ester to be provided, it was at room temperature handled 1 hour with the solution of 50%TFA in DCM (10.0mL).After vacuum is removed volatile material, be suspended in residue in the water and use K ₂CO ₃Neutralization is to provide desirable product 3-[5-(3-cyano group-6-methoxyl group-1H-indole-2-base-) [1,2,4] oxadiazole-3-yl] essence of Niobe, chemical compound 226 (350mg, 62%).

Embodiment 1AO: preparation 1-ethyl-2-(4-methane sulfonyl phenyl)-6-methoxyl group-1H-indole-3-nitrile (chemical compound 265).

(4-methyl sulfane base phenyl)-(0.12g is 0.37mmol) at CH for 1H-indole-3-nitrile for 1-ethyl-6-methoxyl group-2- ₂Cl ₂Solution (5mL) use once m-chlorine benzylhydroperoxide (Aldrich,＜77%, 0.26g) handle, this reactant at room temperature stirred 10 hours then.H is then used in this reaction ₂O and saturated NaHCO ₃Dilution is then with EtOAc extraction 2 times.Organic facies NaHCO ₃(2X) and saturated NaCl washing, the semisolid of dry then and simmer down to dead color.Crude product is equipped with the pure system (EtOAc/CH of 5g silicagel column of 1g alkali alumina by the top by flash chromatography ₂Cl ₂, 0-3%), to form 1-ethyl-6-methoxyl group-2-(4-methyl sulfane base phenyl)-1H-indole-3-nitrile of 72mg (55%), it is a beige solid.

Embodiment 1AP: preparation N-{4-[3-cyano group-1-ethyl-6-(2-morpholine-4-base-ethyoxyl)-1H-indole-2-yl]-phenyl } amsacrine (chemical compound 478).

N-{4-[6-(2-chloroethoxy)-3-cyano group-1-ethyl-1H-indole-2-yl]-phenyl } amsacrine (90mg, 0.21mmol), morpholine (0.06mL, 0.65mmol), NaI (32mg, 0.21mmol) and diisopropyl ethyl amine (0.06mL is 0.32mmol) at CH ₃Solution among the CN (2mL) heated 25 hours down in 100 ℃ in sealed tube.This reactant mixture is cooled to room temperature, uses H ₂O dilutes and extracts with EtOAc (3X).The organic facies that merges is washed with saturated NaCl, and is dry and concentrated.Thick solid product grinds and filters with EtOAc, to form N-{4-[3-cyano group-1-ethyl-6-(2-morpholine-4-base-ethyoxyl)-1H-indole-2-yl of 41mg (41%)]-phenyl } amsacrine, it is pale brown color solid.

Prepare following chemical compound similarly: chemical compound 479,480,481,482,496,497 and 498.

Embodiment 1AQ: preparation 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide (chemical compound 653).

Steps A: 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (according to embodiment 1Ga step B preparation) (0.82mg at room temperature, 2.82mmol) solution in pyridine (10mL) dropwise drips with chloroethyl sulfonic acid chloride (0.38mL, 3.66mmol) handle, stir after 4 hours, reactant mixture goes out with ice-shrend, add enough 6N HCl then, be reduced to 2 until pH.This suspension extracts with the EtOAc (3X) of heat.Organic facies is sequentially used 1N HCl, H ₂O and saturated NaCl washing, dry then and concentrated, to form ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide, it is greenish orange color solid, not further pure system promptly is directly used in next step.

Step B: the ethyl sulfonic acid that as above makes [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide (70mg, 0.18mmol), (0.05mL is 0.55mmol) at CH for morpholine ₃Reflux is 1.5 hours among the CN (1.5mL).After being cooled to room temperature, this reactant concentrates, and residue is by flash chromatography pure system (acetone/EtOAc on silica gel, 2/98), with 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide that makes 89mg (100%), it is pale brown color foam.

Prepare following chemical compound similarly: chemical compound 654.

Embodiment 1AR: preparation 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] methyl nitrosourea (chemical compound 668).

2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide (embodiment 1AQ preparation) (60mg, 0.13mmol) the solution K in DMF (3mL) ₂CO ₃(35mg, 0.26mmol) and iodomethane (0.02mL 0.26mmol) handles.After at room temperature stirring 1.5 hours, the reactant mixture dilute with water is also used EtOAc (2X) extraction.Organic facies H ₂O (3X) and saturated NaCl washing, dry then and concentrated, to make residue.(acetone/EtOAc 0-2%), obtains 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] methyl nitrosourea of 31mg (50%) to the pure system of flash chromatography on silica gel, and it is a beige solid.

Prepare following chemical compound similarly: chemical compound 684,685,686,687,688,689,690,691,692,693,694,695,696,697,698.

Embodiment 1AS: preparation 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (chemical compound 84).

Steps A: 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (according to embodiment 1Ga step B preparation) (2.78g at room temperature, 9.55mmol) solution in pyridine (40mL) dropwise uses 3-chloropropane sulfonic acid chloride (1.45mL, 11.9mmol) handle, this reactant stirred 4 hours then.This reacts dilute with water, adds enough 6N HCl then so that pH is reduced to 2.Reactant mixture extracts with EtOAc (3X), and the organic layer that merges is sequentially with 1N HCl, water and saturated NaCl washing, dry then and concentrated, to form 3-chloropropane-1-sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide of 3.9g (95%), it is brown foam, and is directly used in next step.

Step B: the 3-chloropropane-1-sulfonic acid that as above makes [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amide (3.65g, 2.33mmol) the solution K in DMF (100mL) ₂CO ₃Handle, heated 2 hours down at 70 ℃ then.After being cooled to room temperature, reactant mixture H ₂O dilutes and extracts 3 times with hot EtOAc.This hot organic layer H of temperature ₂O (3X) and saturated NaCl washing, dry then and simmer down to solid.Grind (CH ₂Cl ₂/ hexane) obtain 2.27g (68%) 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile, it is bright brown solid.

Prepare following chemical compound similarly: chemical compound 649,775.

Embodiment 1AT: preparation 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (chemical compound 666).

Steps A: according to the method for embodiment 1B steps A, 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile uses down 1M BBr at-15 ℃ ₃At CH ₂Cl ₂In solution-treated 1.5 hours, be poured in middle ice-water, filter then and dry, with make near quantitative productive rate 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1 H-indole-3-nitrile.

Step B: according to the method for 1B step B, 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1H-indole-3-nitrile, K ₂CO ₃, 2-iodopropane and methyl ethyl ketone reflux, and at flash chromatography (EtOAc/CH ₂Cl ₂, obtain after 0-2%) 61% 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-nitrile, it is a beige solid.

Prepare following chemical compound similarly: chemical compound 667,699.

Embodiment 1AU: preparation 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl)-phenyl]-1-ethyl-6-(2-morpholine-4-base-ethyoxyl)-1 H-indole-3-nitrile (chemical compound 729).

According to the 2-[4-of the foregoing description 1AT preparation (1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1 H-indole-3-nitrile (70mg, 0.25mmol), K ₂CO ₃(75mg, 0.51mmol), sodium iodide (27mg, 0.18mmol), 4-(2-chloroethyl) morpholine hydrochloride (42mg, 0.25mmol) solution in methyl ethyl ketone (3mL) in sealed tube in 100 ℃ of down heating.After 13 hours, add DMF (3mL), and this reactant reheat 6 hours.After this time, add 4-(2-chloroethyl) morpholine hydrochloride of 42mg and the K of 135mg again ₂CO ₃, and this reactant reheat 6 hours is to reacting completely.This reactant mixture is cooled to room temperature, dilute with water, and extract with EtOAc (3X).Organic facies water (2X) that merges and saturated NaCl washing, dry then and concentrated.By flash chromatography (MeOH/CH ₂Cl ₂, 0-6%) obtain pure 2-[4-(1,1-dioxo-1 λ ⁶-isothiazolidine-2-yl)-phenyl]-1-ethyl-6-(2-morpholine-4-base-ethyoxyl)-1H-indole-3-nitrile, to form the pale brown color solid of 29mg (34%).

Prepare following chemical compound similarly: chemical compound 728 and 730.

Embodiment 1AV: preparation 2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile (chemical compound 779).

Steps A: 2-(4-aminophenyl)-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile (585mg, 1.92mmol) at 10mL1, (0.25mL 2.12mmol) handles solution in the 4-dioxane, and the vlil of gained is spent the night then with the NCO ethyl acetate.Make the cooling of this solution, and remove by rotary evaporation and to desolvate.Residue grinds with ether, and the precipitate of gained is by filtering collection and vacuum drying, to make chemical compound 773 (587mg, 1.35mmol, 70%).

Use similar method to prepare 2-{3-[4-(3-cyano group-6-ethyoxyl-1-ethyl-1H-indole-2-yl)-phenyl]-urea groups }-3-phenyl-methyl propionate (chemical compound 777).

Step B:{3-[4-(3-cyano group-6-ethyoxyl-1-ethyl-1H-indole-2-yl)-phenyl]-urea groups }-ethyl acetate (chemical compound 773,101mg, 0.232mmol) solution in THF (10mL) is with the solution (0.30mL of potassium tert-butoxide in the tert-butyl alcohol, 1.0M, 0.30mmol) handle, and the mixture stirring of gained is spent the night.Reactant mixture distributes between water and ethyl acetate (50mL respectively), and organic facies is washed with saturated brine.Water reuse ethyl acetate extraction, and extract merges, dry on anhydrous magnesium sulfate, filter and evaporation.Residue separates (eluting 2/1 ethyl acetate/hexane by column chromatography, on silica gel 60), to make 2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile, chemical compound 779, it is further by grinding with ether, collecting and dry next pure system (76mg, 0.196mmol, 84%) under fine vacuum by filtering.

Embodiment 1AW: preparation 2-[4-(2,4-dioxo-imidazolidine-1-yl) phenyl]-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile (chemical compound 776).

(319mg, 1.04mmol) 1, (0.10mL 1.17mmol) handles 2-(4-aminophenyl)-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile, and the solution of gained is warmed to 60 ℃ and spends the night with the chloracetyl isocyanates for solution in the 4-dioxane (3mL).This solution is cooled, add then DBU (0.20mL, 1.31mmol).This mixture at room temperature stirs and spends the night, and distributes between water and ethyl acetate (50mL respectively).Organic layer washs with saturated brine, and is dry on anhydrous magnesium sulfate then, filters and evaporation.Residue grinds with ether, and the solid by filtration of gained collection and dry under fine vacuum, to make title product (319mg, 0.821mmol, 79%).

Embodiment 1AX: preparation N, N-dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidine-1-yl)-phenyl]-6-ethyoxyl-1-ethyl-1H-indole-3-Methanamide (chemical compound 780) and N, N-dimethyl-6-ethyoxyl-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidine-1-yl)-phenyl]-1H-indole-3-Methanamide (chemical compound 781).

Steps A. at embodiment 1AV, make in the steps A 3-[4-(3-cyano group-6-ethyoxyl-1-ethyl-1H-indole-2-yl)-phenyl]-urea groups } ethyl acetate (chemical compound 773,325mg, 0.748mmol) solution in acetone (5mL) is with HCl (3mL, 6N) handle, and the vlil of gained is spent the night.Reactant mixture is cooled, and the precipitate of gained is collected by filtering, with ether washing and dry under fine vacuum, to make product 6-ethyoxyl-1-ethyl-2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-1H-indole-3-Methanamide (264mg, 0.650mmol, 87%).

The dispersion (75mg) of step B. sodium hydride in mineral oil used a spot of hexane wash, then the decant hexane layer.Be added on 6-ethyoxyl-1-ethyl-2-[4-(2,5-dioxo-imidazolidine-1-the yl)-phenyl in the dimethyl formamide (2mL)]-(190mg, 0.468mmol), and this mixture stirred 1 hour 1H-indole-3-Methanamide.By syringe add iodomethane (0.10mL, 1.61mmol).The mixture of gained at room temperature stirs and spends the night, and is poured over then in the ethyl acetate of 50mL.The organic facies water (3 * 50mL) and saturated brine (20mL) washing, dry on anhydrous magnesium sulfate then, filter also evaporation.Residue separates (1/1 ethyl acetate/hexane, eluting on silica gel 60) by column chromatography, to make title product, chemical compound 780 and 781.

Embodiment 1AY: preparation N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-N-(2-hydroxyethyl)-amsacrine (chemical compound 828).

Steps A: the dispersion (108mg) of sodium hydride in mineral oil used a spot of hexane wash, then the decant hexane layer.Slowly add N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amsacrine (chemical compound 129,500mg, 1.35mmol) solution in DMF (5mL).After gas produces fully, add the 2-bromoacetate (0.30mL, 2.64mmol) and sodium iodide (20mg).This mixture at room temperature stirs and spends the night, and is poured over then in the ethyl acetate of 50mL.Its water (3 * 50mL) and saturated brine (20mL) washing, dry on anhydrous magnesium sulfate then, filter also evaporation.Residue separates (1/1 ethyl acetate/hexane, eluting on silica gel 60) by column chromatography, to make chemical compound 815 (364mg, 0.799mmol, 59%).

Step B: make N-(2-acetoxyl group ethyl)-N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl] amsacrine (chemical compound 815,164mg, 0.360mmol) and hydronium(ion) oxidation lithium (45mg, 1.07mmol) mixture in 5mLTHF/1mL water is warmed to 60 ℃ and spends the night.This mixture cooling also is poured in the ethyl acetate (50mL).Its water (50mL) and saline (20mL) washing, dry on anhydrous magnesium sulfate, filter and evaporation, to make solid.This solid grinds with ether, by filtration collection and dry under fine vacuum, with system N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-N-(2-hydroxyethyl) amsacrine, chemical compound 828 (137mg, 0.331mmol, 92%).

Embodiment 1AZ: preparation 1-ethyl-6-methoxyl group-2-[4-(2-methoxy ethoxy)-phenyl]-1H-indole-3-nitrile (chemical compound 248).

(40mg 0.14mmol) (prepares described in embodiment 1Ga step B) and K 1-ethyl-2-(4-hydroxyl-phenyl)-6-methoxyl group-1H-indole-3-nitrile ₂CO ₃(77mg, 0.56mmol), bromo-ethyl-methyl ether (26 μ L, 0.28mmol) and DMF (450 μ L) mix, at room temperature stirred 1 hour, stirred 3 hours down at 75 ℃ then.Reactant mixture is then at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.Carry out pure system (CH by silica gel chromatography ₂Cl ₂, 0-5%EtOAc), to make 1-ethyl-6-methoxyl group-2-[4-(2-methoxy ethoxy)-phenyl]-1h-indole-3-nitrile (44mg, 90%), it is a white solid.

Following similarly chemical compound: chemical compound 249.

Embodiment 1BA: preparation 1-ethyl-6-methoxyl group-2-[4-(2-morpholine-4-base-ethyoxyl)-phenyl]-1H-indole-3-nitrile (chemical compound 261).

Steps A: 1-ethyl-6-methoxyl group-2-[4-(2-the hydroxyl-oxethyl)-phenyl that described in embodiment 1AZ, makes]-1H-indole-3-nitrile (450mg, 1.34mmol) and PPh ₃(878mg is 3.35mmol) at CH ₂Cl ₂Mix down in 0 ℃ (32mL).Disposable interpolation N-bromine butanimide (600mg, 3.37mmol).Reactant mixture at room temperature stirred 30 minutes.Reactant mixture NaHCO ₃Solution washing.Organic layer is dry and concentrated, then by the pure system (CH of silica gel chromatography ₂Cl ₂), to make 2-[4-(2-bromine oxethyl)-phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (506mg, 95%), chemical compound 253, it is a white solid.

Step B: the 2-[4-that in above-mentioned steps A, makes (2-bromine oxethyl)-phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (40mg, 0.1mmol) with morpholine (50 μ L, 0.58mmol) and acetonitrile (1.0mL) mix, and heated 2 hours down at 85 ℃.Reactant mixture is then at CH ₂Cl ₂And H ₂Distribute between the O.Organic layer is dry and concentrated.Carry out pure system (6/4, acetone/hexane) by silica gel chromatography, obtain 1-ethyl-6-methoxyl group-2-[4-(2-morpholine-4-base-ethyoxyl)-phenyl]-1 crowded indole-3-nitrile (39mg, 96%), it is a white solid.

Similarly with the different following chemical compounds of amines preparation: chemical compound 262,263,264.

Embodiment 1BB: preparation N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-ethyl } amsacrine (chemical compound 268).

Steps A:, the 2-[4-that makes in the steps A (2-bromine oxethyl) phenyl at embodiment 1BA]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (258mg, 0.65mmol) and NaN ₃(144mg, 2.2mmol) and MeOH (3.2mL) mix, and 75 ℃ of following heated overnight.Reactant mixture is at CH ₂Cl ₂And H ₂Distribute between the O.Organic layer is dry and concentrated.Carry out pure system (CH by silica gel chromatography ₂Cl ₂), obtain 2-[4-(2-azido ethyoxyl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (187mg, 80%), chemical compound 266, it is a white solid.

Step B: the 2-[4-that will in above-mentioned steps A, make (2-azido ethyoxyl) phenyl]-(410mg 1.14mmol) is suspended in the solution of MeOH (20mL) and dense HCl (500 μ L) 1-ethyl-6-methoxyl group-1H-indole-3-nitrile.Add Pd/C (150mg, 10%), this mixture hydrogenation 1 hour under 30p.s.i. then.It filters and concentrated filtrate.The filtrate residue distributes between EtOAc and 0.5N NaOH.Organic layer is dry and concentrated.Carry out pure system (10-30%, MeOH/CH by silica gel chromatography ₂Cl ₂), obtain 2-[4-(2-amino ethoxy) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (298mg, 78%), chemical compound 267,, it is a white solid.

Step C: the 2-[4-that will in above-mentioned steps B, make (2-amino ethoxy) phenyl]-(30mg 0.09mmol) is dissolved in the pyridine (300 μ L) 1-ethyl-6-methoxyl group-1H-indole-3-nitrile.(8 μ L 0.1mmol), and at room temperature stirred 45 minutes to add methane sulfonyl chloride.Add again methane sulfonyl chloride (4 μ L, 0.05mmol).Restir 1 hour.Reactant mixture distributes between EtOAc and moisture HCl.Organic layer is dry and concentrated.Carry out pure system (1/1CH by silica gel chromatography ₂Cl ₂/ EtOAc), obtain N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl) phenoxy group] ethyl } amsacrine, chemical compound 268 (32mg, 86%), it is a white solid.

Prepare following chemical compound similarly: chemical compound 269.

Embodiment 1BC: preparation N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-ethyl } acetamide (chemical compound 274).

Will be as embodiment 1BB, the 2-[4-for preparing described in the step B (2-amino ethoxy) phenyl]-(30mg 0.09mmol) is dissolved in THF (400 μ L) and Et to 1-ethyl-6-methoxyl group-1H-indole-3-nitrile ₃N (24 μ L, 0.17mmol) in.(10 μ L, 0.14mmol), reactant mixture at room temperature stirred 2 hours then to add chloroacetic chloride.Reactant mixture is at EtOAc and H ₂Distribute between the O.Organic layer is dry and concentrated.Carry out pure system (EtOAc) by silica gel chromatography, obtain N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl) phenoxy group] ethyl } acetamide (33mg, 97%), it is a white solid.

Embodiment 1BD: preparation 1-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group] ethyl }-3-ethyl-urea (chemical compound 279).

As the above-mentioned 2-[4-that makes (2-amino ethoxy) phenyl among the embodiment 1BB]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (30mg, 0.09mmol) with the Carbimide. ethyl ester (18 μ L, 0.21mmol) and pyridine (300 μ L) mixing.This mixture at room temperature stirred 90 minutes, distributed between EtOAc and moisture HCl then.Organic layer is dry and concentrated.Carry out pure system (EtOAc) by silica gel chromatography, obtain 1-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-ethyl }-3-ethyl-urea (34mg, 93%), it is a white solid.

Embodiment 1BE: preparation N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group] ethyl } Methanamide (chemical compound 280).

Acetic anhydride (700 μ L) and 98% formic acid (280 μ L) heated 1 hour down at 65 ℃, and were cooled to 0 ℃.2-[4-(2-amino ethoxy) phenyl that will described in embodiment 1BB, prepare]-(30mg 0.09mmol) puts into THF (400 μ L) to 1-ethyl-6-methoxyl group-1H-indole-3-nitrile, is added in the mixed acid anhydride then.Stirred 45 minutes down at 0 ℃.This mixture is then at EtOAc and moisture NaHCO ₃Between distribute.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (4/1, CH ₂Cl ₂/ acetone) produce N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl) phenoxy group]-ethyl } Methanamide (28mg, 86%), it is a white solid.

Embodiment 1BF: preparation 1-ethyl-2-{4-[2-(3-hydroxyl pyrrolidine-1-yl)-2-oxo-ethyoxyl] phenyl }-6-methoxyl group-1H-indole-3-nitrile (chemical compound 285).

Steps A: use identical with embodiment 1AZ basically method, by 1-ethyl-2-(4-hydroxy phenyl)-6-methoxyl group-1H-indole-3-nitrile (559mg, 1.91mmol) preparation [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-ra-butyl acetate (780mg, 100%).

Step B:[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-(745mg is 1.83mmol) at 20%TFA CH for ra-butyl acetate ₂Cl ₂Under room temperature, stirred 3 hours in the solution.It concentrates, and residue is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.Residue CH ₂Cl ₂Grind, to make [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-acetic acid (634mg, 99%), it is a white solid.

Step C: (40mg 0.12mmol) is suspended in CH with [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenoxy group]-acetic acid ₂Cl ₂(1.65mmol) and DMF (2 μ L).(17 μ L 0.19mmol), and at room temperature stirred 30 minutes to add oxalyl chloride.The solution of gained is transferred to S-3-hydroxyl pyrrolidine (150 μ L) and CH with pipet ₂Cl ₂In the agitating solution (3.0mL).This mixture washs with moisture HCl.Organic layer is dry and concentrated.Carry out pure system (3/2CH by silica gel chromatography ₂Cl ₂/ acetone), obtain 1-ethyl-2-{4-[2-(3-hydroxyl-pyrrolidine-1-yl)-2-oxo-ethyoxyl]-phenyl }-6-methoxyl group-1H-indole-3-nitrile (40mg, 79%), chemical compound 285, it is a white solid.

Embodiment 1BG: preparation 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazole-5-yl)-1H-indole-3-nitrile (chemical compound 332).

Steps A: (369mg is 1.1mmol) with EtOAc (20mL) and Pd/C (150mg, 10%) mixing with 1-ethyl-2-(4-hydroxyl-3-nitrobenzophenone)-6-methoxyl group-1H-indole-3-nitrile of preparing among the embodiment 1Gd.The hydrogenation 1 hour under 30p.s.i. of this mixture is filtered by celite then.Filtrate concentrates and grinds with ether, obtains 2-(3-amino-4-hydroxy phenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (307mg, 91%), chemical compound 322, and it is a white solid.

Step B: make 2-(3-amino-4-hydroxy phenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile of preparing in the steps A (100mg, 0.33mmol) with CDI (83mg, 0.51mmol) and THF (1.1mL) mix, and 65 ℃ of heating 1 hour down.Reactant mixture distributes between EtOAc and moisture HCl.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (9/1, CH ₂Cl ₂/ EtOAc), obtaining 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-5-yl)-1H-indole-3-nitrile (89mg, 81%), it is a white solid.

Embodiment 1BH: preparation 1-ethyl-6-methoxyl group-2-(3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indole-3-nitrile (chemical compound 334).

Steps A: bromoacetic acid (52mg, 0.37mmol) with the EDCI hydrochlorate (62mg, 0.4mmol) and acetonitrile (900 μ L) mix, with the formation homogeneous phase solution.Will be as embodiment 1BG, the 2-that makes described in the step B (3-amino-4-hydroxy phenyl)-(100mg 0.33mmol) is added in this solution 1-ethyl-6-methoxyl group-1H-indole-3-nitrile.Soon promptly form heavy-gravity pastel.Add the acetonitrile of 1.1mL again, this mixture at room temperature stirred 2 hours then.Reactant mixture is then at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (4/1, CH ₂Cl ₂/ EtOAc), obtain 2-chloro-N-[5-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-2-hydroxy phenyl] and acetamide (82mg, 60%), chemical compound 333,, it is a white solid.

Step B: the 2-chloro-N-[5-that in steps A, makes (3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-2-hydroxyl-phenyl] and acetamide (57mg, 0.13mmol) and K ₂CO ₃(55mg, 0.4mmol) and DMF (400 μ L) mix, and 80 ℃ of heating 1 hour down.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (9/1, CH ₂Cl ₂/ EtOAc), obtaining 1-ethyl-6-methoxyl group-2-(3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indole-3-nitrile (45mg, 90%), it is a white solid.

Embodiment 1BI: preparation 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazole-6-yl)-1H-indole-3-nitrile (chemical compound 340).

Steps A: (4.0g 26mmol) is suspended in H with the 4-aminosallcylic acid under-5 ℃ ₂SO ₄(26mL, 2.7M) in.(1.8g is 26.1mmol) at H with sodium nitrite ₂Be cooled to the ice bath temperature among the O (6.5mL), in 5 minutes time, drop in the above-mentioned aminosallcylic acid mixture then.The suspension of gained stirred 15 minutes down at-5 ℃.(6.8g is 41mmol) at H with KI ₂SO ₄(13mL, 1M) drips of solution in adds in the kazoe, produces a large amount of N simultaneously ₂Reactant mixture heated 20 minutes down at 70 ℃.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.Carry out pure system (7/3, hexane/acetone, 1% acetic acid) by silica gel chromatography, obtain 4-iodo-salicylic acid (5.33g, 85-90% is pure).

Step B: (1.0g 3.8mmol) is dissolved in THF (28mL) and Et with thick 4-iodo-salicylic acid ₃N (1.15mL, 8.2mmol) in.Interpolation DPPA (1.7mL, 7.8mmol), and 70 ℃ of following heated overnight.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (9/1, CH ₂Cl ₂/ EtOAc), obtain the thick intermediate product of 472mg.Grind with ether, obtain 6-iodo-3H-benzoxazole-2-ketone (369mg, 37%), it is a white solid.

Step C: use basically and identical method described in the embodiment 1Gd, with 6-iodo-3H-benzoxazole-2-ketone (118mg, 0.45mmol) preparation 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-6-yl)-1H-indole-3-nitrile, chemical compound 340 (75mg, 55%).

Embodiment 1BJ: preparation 1-ethyl-6-methoxyl group-2-(4-methyl-3-oxo-3,4 ,-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indole-3-nitrile (chemical compound 339).

(20mg, 0.058mmol) (14mg, 60% oil suspensions 0.35mmol) mix the 1-ethyl-6-methoxyl group-2-that makes described in embodiment 1 BH (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indole-3-nitrile with NaH.Add THF (300 μ L), and at room temperature stirred 5 minutes.Add the solution of iodomethane (4.4 μ L) in THF (100 μ L), and at room temperature stirred 1 hour.Reactant mixture distributes between EtOAc and moisture HCl.Organic layer is dry and concentrated.By silica gel chromatography carry out pure system (9/1, CH ₂Cl ₂/ EtOAc), obtaining 1-ethyl-6-methoxyl group-2-(4-methyl-3-oxo-3,4 ,-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indole-3-nitrile (16mg, 76%), it is a white solid.

Prepare following chemical compound similarly: chemical compound 341.

Embodiment 1BK: preparation 1-ethyl-2-iodo-6-methoxyl group-5-nitro-1H-indole-3-nitrile (chemical compound 499).

Will be under 0 ℃ as embodiment 1Ga, (50mg 0.15mmol) is suspended in acetic acid (620 μ L) to the 1-ethyl that makes described in the steps A-2-iodo-6-methoxyl group-1H-indole-3-nitrile.Add nitrous acid (4.25M AcOH solution), and at room temperature stirred 2 hours.Reactant mixture is at CH ₂Cl ₂And H ₂Distribute between the O.The moisture NaHCO of organic layer ₃Washing, dry then and concentrated.By silica gel chromatography carry out pure system (6/4, CH ₂Cl ₂/ hexane), grind with ether then, obtain 1-ethyl-2-iodo-6-methoxyl group-5-nitro-1H-indole-3-nitrile (16mg, 29%), it is a yellow solid.

Embodiment 1BL: preparation 1 '-ethane sulfonyl-1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] biindolyl base-3-nitrile (chemical compound 753).

Steps A: (3.0g 18.3mmol) is dissolved in THF (45mL) and Et with 6-nitro indoline under 0 ℃ ₃N (3.4mL, 24.4mmol) in.Dripping acetyl chloride (1.5mL, 21mmol).This mixture at room temperature stirred 30 minutes.This mixture distributes between EtOAc and moisture HCl.Organic layer is dry and concentrated, and to make 1-acetyl group-6-nitro indoline (3.8g, 100%), it is a yellow solid.

Step B: (3.8g 18.3mmol) is suspended among the EtOAc (200mL) with 1-acetyl group-6-nitro indoline.Add Pd/C (650mg, 10%), and under 40-55p.si.i. this mixture of hydrogenation 2 hours.This mixture filters by celite.Concentrated filtrate, and residue grinds with ether, to make the amino indoline (3.18g, 99%) of 1-acetyl group-6-, it is an orange solids.

Step C: with basically with embodiment 1BI, the method that steps A is identical is by the amino indoline of 1-acetyl group-6-(1.5g, 8.5mmol) preparation 1-acetyl group-6-iodine indoline (1.06g, 43%).

Step D:1-acetyl group-6-iodine indoline (1.06g, 3.7mmol), NaOH (1.16g, 29mmol), EtOH (8mL) and H ₂O (6mL) is 90 ℃ of following heated overnight.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is extracted among the moisture HCl.Alkalizing with NaOH in the water-bearing layer, and extracts with EtOAc.Organic layer is dry and concentrated.Hexane grinds, and obtains 6-iodine indoline (577mg, 64%), and it is a brown solid.

Step e: use basically and embodiment 1Gd, the method that step B is identical is by 1-iodine indoline (600mg, 2.45mmol) preparation 1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] biindolyl base-3-nitrile (535mg, 67%).

Step F: use the method among the embodiment 1Y; by 1-ethyl-6-methoxyl group-2 '; 3 '-dihydro-1H; 1H '-[2,6 '] biindolyl base-3-nitrile (30mg, 0.095mmol) preparation 1 '-ethane sulfonyl-1-ethyl-6-methoxyl group-2 '; 3 '-dihydro-1H; 1H '-[2,6 '] biindolyl base-3-nitrile (24mg, 62%).

Be similar to the above following chemical compound of method preparation: chemical compound 752 and 754.

Embodiment 1BM: preparation 5-acetyl group-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indole-3-nitrile (chemical compound 844).

(100mg 0.3mmol) is suspended in 1, in the 2-dichloromethane (500 μ L) at 0 ℃ of 1-ethyl-6-methoxyl group-2-(4-nitrobenzophenone)-1H-indole-3-nitrile that will make according to the method among the embodiment 1Gc down.The interpolation chloroacetic chloride (50 μ L, 0.69mmol), disposable then interpolation AlCl ₃(55mg, 0.4mmol).Reactant stirred 1 hour down at 0 ℃, at room temperature stirred 4 hours, spent the night under 45 ℃ then.Reactant mixture is at CH ₂Cl ₂And H ₂Distribute between the O.Organic layer is dry and concentrated.Carry out pure system (195: 5 CH by silica gel chromatography ₂Cl ₂/ EtOAc), obtaining 5-acetyl group-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indole-3-nitrile (33mg, 29%), it is an orange solids.

Embodiment 1BN: preparation 1-ethyl-6-methoxyl group-5-morpholine-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-nitrile (chemical compound 845).

Steps A: according to 1-ethyl-6-methoxyl group-2-(4-the nitrobenzophenone)-1H-indole-3-nitrile of the method for embodiment 1Gc preparation (100mg, 0.3mmol) with 1,3, the 5-trioxane (64mg, 0.71mmol) and acetic acid (2.0mL) mixing.Be added on the 33%HBr in the acetic acid (2.0mL), and at room temperature stirred 4 hours.Reactant mixture is at CH ₂Cl ₂And H ₂Distribute between the O.Organic layer NaHCO ₃Solution washing, dry then and concentrated.Crude product is used for next step.

Step B: thick 6-bromomethyl-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indole-3-nitrile (0.3mmol) and morpholine (150 μ L, 1.75mmol) and DCE (1.0mL) heated overnight together under 90 ℃.Reactant mixture is at H ₂Distribute between O and the EtOAc.Organic layer is dry and concentrated.Carry out pure system (50-100%, EtOAc/CH by silica gel chromatography ₂Cl ₂), grind with 1/1 hexane/acetone then, obtain 1-ethyl-6-methoxyl group-5-morpholine-4-ylmethyl-2-(4-nitrobenzophenone)-1H-indole-3-nitrile (57mg, 44% gross production rate), it is a yellow solid.

Embodiment 1BO:2-[4-(1,1-dioxo isothiazolidine-2-yl) phenyl]-1-cyclopropyl methyl-6-methoxyl group-1H-indole-3-nitrile (chemical compound 716).

Steps A: 40 ℃ and stir under to 6-methoxyl group indole (5.88g, 40.0mmol) and two-tert-butyl group, two carbonic esters (9.59g, 44.0mmol) interpolation DMAP (0.10g) solution in DCM (50mL) in.After stirring was spent the night, this mixture was sequentially used 0.1N HCl, water and salt water washing, and in last anhydrous Na ₂SO ₄Dry.Evaporating solvent, and residue carries out chromatographically pure system (silica gel, EtOAc/ hexane, 1/7), to obtain 6-methoxyl group-1H-indole-1-carboxylic acid tertiary butyl ester (8.48g, 86%).

Step B: (3.08g, 12.5mmol) (4.83mL 21.9mmol) is dissolved among the anhydrous THF (20mL), then this solution is cooled to 0 ℃ with the isopropyl borate with above-mentioned Boc-indole.Under agitation, and dropping LDA (12.5mL, the solution of 1.5M mono-THF complex in cyclohexane extraction, 18.7mmol).This mixture stirred 15 minutes down at 0 ℃, at room temperature stirred then 0.5 hour, then in ice-water-bath, add HCl (6N, 3.0mL, 18mmol).Vacuum is removed organic solvent, and residue is suspended in H ₂Among the O (100mL), use HCl (6N) to be acidified to pH4～5 then.Filter collecting precipitation thing and water and hexane wash,, produce 1-Boc-6-methoxyl group indole-2-boric acid (3.38g, 93%) then at air drying.

Step C: under 0 ℃ to the 4-Iodoaniline (3.18g, 14.5mmol) add in the solution in pyridine (15mL) 3-chlorine third sulfonic acid chloride (2.3mL, 18.9mmol).After interpolation was finished, this mixture at room temperature stirred 2 hours, was poured over then in ice-water (200mL).Separate organic facies, (2 * 50mL) extract and water layer is with DCM.The organic layer that merges sequentially use HCl (2N, 2 * 15mL), water (2 * 50mL) and saline (20mL) washing, then in anhydrous Na ₂SO ₄Last dry.Follow evaporating solvent, and residue carries out chromatographically pure system so that 3-chloro-N-(4-iodophenyl) propane-1-sulfonamide (4.68g, 90%) to be provided.(3.47g 9.6mmol) then uses K to the Clofenamide of gained ₂CO ₃(3.33g 24.1mmol) handled 2 hours down in 50 ℃ in DMF (50mL).This mixture is poured in ice-water (300mL), and the collecting precipitation thing, then at air drying, so that pure basically 2-(4-iodophenyl) isothiazolidine-1,1-dioxide (3.11g, 100%) to be provided.

Step D: to the 1-Boc-6-methoxyl group indole-2-boric acid that in above-mentioned steps B, makes (0.36g, 1.25mmol), 2-(4-iodophenyl) isothiazolidine-1, the 1-dioxide (0.32g, 1.0mmol) and PdCl ₂(dppf) (0.037g 0.05mmol) adds K in the mixture in DMF (4.0mL) ₂CO ₃Aqueous solution (1.5mL, 2.0M, 3.0mmol).This mixture at room temperature stirs and spends the night, and is poured over then in ice-water (100mL).The collecting precipitation thing also washes with water, by the pure system of flash column chromatography (silica gel, DCM/EtOAc, 9/1), provides 1-Boc-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl then]-6-methoxyl group-1H-indole (0.43g, 98%).

Prepare following chemical compound similarly: chemical compound 768.

Step D:1-Boc-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-(1.63g 3.7mmol) at room temperature uses TFA (25mL) to handle 4 hours in DCM (25mL) to 6-methoxyl group-1H-indole.After removing volatile material, residue carefully with saturated NaHCO ₃Stirred 0.5 hour.Thoroughly wash by filtering collecting precipitation thing and water, dry then, so that pure basically 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl to be provided]-6-methoxyl group indole (1.17g, 92%).

Step e: under 0 ℃ with 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-(0.95g 2.8mmol) is dissolved among the DMF (10mL) 6-methoxyl group indole, and (0.36mL 4.2mmol) handles to use chloro sulfonyl isocyanate then.This mixture then at room temperature stirs and spends the night, and is poured in ice-water (150mL), stirs then 0.5 hour.By filtration collecting precipitation thing, and the water thorough washing, then at air drying, provide 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-methoxyl group indole-3-nitrile (0.89g, 87%).

According to preparing following chemical compound similarly: chemical compound 829 with said method

Step F: to 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-methoxyl group indole-3-nitrile (73mg, 0.2mmol) and K ₂CO ₃(69mg, 0.5mmol) add in the solution in DMF (3.0mL) cyclopropyl methyl iodide (0.029mL, 0.3mmol).This mixture stirs down at 50 ℃ and spends the night, and is poured over then in ice-water (10mL).By filtering the collecting precipitation thing, wash with water, then by the pure system of column chromatography, so that 2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl to be provided]-6-methoxyl group-1-cyclopropyl methylindole-3-nitrile, chemical compound 716 (73mg, 87%).

Prepare following chemical compound according to method similar to the above: chemical compound 717,718,719,782,783,784.

Embodiment 1BP: preparation 2-[4-(1,1 '-dioxo-1 λ ⁶-isothiazolidine-2-yl)-6-methoxyl group-3-oxazole-5-base-1-propyl group-1H-indole (chemical compound 805).

Steps A: use basically and embodiment 1A, identical method described in the step B, by at embodiment 1BO, the 2-[4-that makes among the step D (1,1 '-dioxo-1 λ ⁶-isothiazolidine-2-yl)-6-methoxyl group-indole (900mg, 2.62mmol) preparation 2-[4-(1,1 '-dioxo-1 λ ⁶-isothiazolidine-2-yl)-6-methoxyl group-1-propyl group-1H-indole (608mg, 60%).

Step B: according to the method among the embodiment 1P, usefulness 2-[4-(1,1 '-dioxo-1 λ ⁶-isothiazolidine-2-yl)-6-methoxyl group-1-propyl group-1H-indole (50mg, 0.13mmol) preparation 2-[4-(1,1 '-dioxo-1 λ ⁶-isothiazolidine-2-yl)-6-methoxyl group-3-oxazole-5-base-1-propyl group-1H-indole (9mg, 15% gross production rate).

Embodiment B Q: preparation 2-[4-(cyclopropyl sulfonyl) piperazine-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-nitrile (chemical compound 842).

Steps A: the 1-ethyl that under-78 ℃, makes-6-trifluoro methyl indole-3-nitrile (2.54g to method according to route 1A, 10.0mmol) drip LDA (8.3mL in the solution in anhydrous THF (20.0mL), 1.5M the cyclohexane solution of mono-THF, 12.5mmol).Add finish after, this mixture continues 0.5 hour, adds hexachlorethane then, slowly makes this mixture reach room temperature then and stirs 0.5 hour.Follow evaporating solvent, and the residue water treatment.The organic facies dichloromethane extraction, water, salt water washing are then in anhydrous Na ₂SO ₄Last dry.Remove the crude product that obtains after desolvating and carry out chromatographically pure system (silica gel, dichloromethane/hexane, 3/2), so that 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-nitrile (1.75g, 64%) to be provided.

Step B: under 70 ℃, make the chloro-indole that as above makes (0.27g, 1.0mmol), K ₂CO ₃(0.35g, 2.5mmol) (0.28g 1.5mmol) stirred 3 days in DMF (5.0mL), was poured over then in the water (50mL) with the N-Boc-piperazine.By filtering the collecting precipitation thing and washing with water.This crude product carries out chromatographically pure system (silica gel, dichloromethane/ethyl acetate, 9/1), obtains 4-(3-cyano group-1-ethyl-6-Trifluoromethyl-1 H-indole-2-yl)-piperazine-1-carboxylic acid tertiary butyl ester, chemical compound 785 (0.30g, 71%).

According to preparing following chemical compound with other amines similarly: chemical compound 514,785,786 with said method.

Step C: at room temperature (0.26g 6.1mmol) handled 1 hour in dichloromethane (5mL) with TFA (5mL) 4-(3-cyano group-1-ethyl-6-Trifluoromethyl-1 H-indole-2-yl)-piperazine-1-carboxylic acid tertiary butyl ester.After removing volatile material, the saturated NaHCO of residue ₃Handle and pass through and filter the collecting precipitation thing, the water thorough washing then at air drying, provides pure basically 1-ethyl-2-piperazine-1-base-6-(trifluoromethyl)-1H-indole-3-nitrile (0.20g, 100%).

Step D: to 1-ethyl-2-piperazine-1-base-6-(trifluoromethyl)-1H-indole-3-nitrile (32mg, 0.1mmol), add the ring third sulfonic acid chloride (28mg in the solution of pyridine (0.1mL) in dichloromethane (1.0mL), 0.2mmol), this mixture at room temperature stirs and spends the night then.Then with dichloromethane (5mL) dilution; with HCl (2N; 2 * 2mL), water (2 * 5mL) and saline (5mL) washing; on silica gel, carry out chromatographically pure system (dichloromethane/ethyl acetate then; 9/1); so that 2-[4-(cyclopropyl sulfonyl) piperazine-1-yl to be provided]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-nitrile, chemical compound 842 (30mg, 70%).

According to using the following chemical compound of corresponding sulfonyl chloride compound preparation similarly: chemical compound 841,843. with said method

Embodiment 1BR: ethane sulfonic acid [3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-6-yl]-amide (chemical compound 835).

Steps A: in the test tube of sealing, make 6-bromo-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-3-nitrile of described in embodiment 1Gb, making by the 6-bromo indole (0.74g, 2.0mmol), chemical compound 831 and K ₂CO ₃(0.55g, 4.0mmol), CuI (0.02g, 0.1mmol), the carbamic acid tertiary butyl ester (0.35g, 3.0mmol), N, N '-dimethyl cyclohexane-1,2-two amine ligands (0.028g, 0.2mmol) and dry toluene (5.0mL) mix.Pour nitrogen in this reaction system, stir down at 110 ℃ then and spend the night.After the cooling, above-mentioned solvent is replaced the capable chromatographically pure system (silica gel, dichloromethane) that develops simultaneously with dichloromethane, so that [3-cyano group-2-(4-ethyoxyl-phenyl)-1-ethyl-1H-indole-6-yl]-carbamic acid tertiary butyl ester (0.68g, 84%), chemical compound 832 to be provided.

Step B: (0.63g 1.56mmol) at room temperature use TFA/DCM (7.5mL/7.5mL) to handle 2 hours, and vacuum is removed volatile material to the chemical compound that makes in above-mentioned steps A.The saturated NaHCO of residue ₃Handle also by filtering the collecting precipitation thing, water thorough washing then is at air drying, so that 6-amino-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-3-nitrile (0.45g, 96%), chemical compound 833 to be provided.

Step C: above-mentioned amine (31mg, 0.1mmol) with handling ethanesulfonyl chloride (19mg, 0.15mmol) in pyridine (1.0mL), under room temperature, handle and spend the night, after the pure system of column chromatography, obtain ethane sulfonic acid [3-cyano group-2-(4-ethyoxyl-phenyl)-1-ethyl-1H-indole-6-yl]-amide (83%), chemical compound 835.

According to preparing following chemical compound similarly: chemical compound 830,834,836 and 837 with said method.

Embodiment 1BS: preparation [3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-6-yl]-carbamic acid ethyl ester (chemical compound 838)

At embodiment 1BR, 6-amino-the 2-that makes among the step B (4-ethoxyl phenenyl)-1-ethyl-1H-indole-3-nitrile (31mg, 0.1mmol), chemical compound 833, with handling chloro-carbonic acid ethyl ester (16mg, 0.15mmol) in pyridine (1.0mL), under room temperature, handle and spend the night, after the pure system of column chromatography, obtain [3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-6-yl]-carbamic acid ethyl ester (30mg, 79%).

Embodiment 1BT: preparation 1-[3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-6-yl]-3-ethyl-urea (chemical compound 839).

(31mg, 0.1mmol) (14mg's usefulness ethyl isocyanate 0.2mmol) spends the night in 40 ℃ of following processing in dichloromethane (1.0mL) 6-amino-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indole-3-nitrile.By filtering the collecting precipitation thing, use washed with dichloromethane, then at air drying, obtain 1-[3-cyano group-2-(4-ethyoxyl-phenyl)-1-ethyl-1H-indole-6-yl]-3-ethyl-urea (36mg, 95%).

Embodiment 1BU: preparation 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-urea (chemical compound 442).

At room temperature to 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (50mg, 0.172mmole) add in the solution in THF (2mL) the 2-chloroethyl isocyanate (22uL, 0.258mmole).After the stirring that refluxes is spent the night, the vacuum concentration reactant mixture, and residue dilutes with ethyl acetate.The semisolid of gained grinds with hexane, collected precipitate is collected by filtering, use the solution thorough washing of 50% ethyl acetate in hexane then, and vacuum drying, obtain 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl of (62mg, 91%)]-urea.

Basically with the identical following chemical compound of method preparation: chemical compound 295,362,395,396,397,398,399,400,401,402,403,404,405,406,407,443,444,445,446,511,512,513,600,620,626,627,628,679,680,681,740,741,742,743,748,749,750,751,774,817,818,846,847,848.

Embodiment 1BV: preparation 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenyl]-1H-indole-3-nitrile (chemical compound 771).

To 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-(100mg 0.252mmol) adds 1M KOH aqueous solution (504uL) to urea in the solution in MeOH (10mL), and stirs 24 hours down at 49 ℃.Removal of solvent under reduced pressure.Residue is released with the acetic acid,diluted ethyl ester, washes with water then.Organic layer is at anhydrous MgSO ₄Last dry, filter, then concentrating under reduced pressure.Residue dilutes with ethyl acetate, then grind with hexane, by filtering the collecting precipitation thing, and with the solution thorough washing of 50% ethyl acetate in hexane, vacuum drying then, obtain 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenyl]-1H-indole-3-nitrile (56mg, 62%).

Basically with the identical following chemical compound of method preparation: chemical compound 770,778.

Embodiment 1BW: preparation 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidine-3-yl)-phenyl]-1H-indole-3-nitrile (chemical compound 638).

(30mg 0.07mmol) adds moisture K in the solution in DMF (1mL) to [4-(3-cyano group-1-ethyl-6-isopropoxy-1H-indole-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester ₂CO ₃(10mg), stirred 18 hours down at 50 ℃ then.Reactant mixture is poured in the cold water, and precipitate is collected by filtration, uses hexane wash, and vacuum drying obtains title compound (21mg, 81%) then.

Prepare following chemical compound according to similar method: chemical compound 820,821,863,864.

Embodiment 1BX: preparation 3-[3-cyano group-1-ethyl-6-(3-pyrrolidine-1-base-propoxyl group)-1H-indole-2-yl]-phenyl }-carbamic acid ethyl ester (chemical compound 530).

Steps A: (1.65g 4.37mmole) adds 1M BBr in the solution in DCM (20mL) to [3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-carbamic acid ethyl ester in 20 minutes time ₃Solution in DCM (13.12mL).This reactant mixture is restir 1 hour at room temperature, then removal of solvent under reduced pressure.Residue is dissolved among the MeOH, is poured in the cold water then.Filter the collecting precipitation thing,, obtain [3-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-yl)-phenyl]-carbamic acid ethyl ester (1.5g, 98%) with hexane wash and vacuum drying.

Step B: (1.2g 2.91mmol) adds K in the solution in DMF (10mL) to [3-(3-cyano group-1-ethyl-6-hydroxyl-1H-indole-2-yl)-phenyl]-carbamic acid ethyl ester ₂CO ₃(538mg, 3.9mmole) with 3-bromo-n-propyl chloride (383 μ L 3.9mmole), reactant mixture stirs down at 50 ℃ and spends the night then.Reactant mixture is poured in the cold water and by filtering the collecting precipitation thing, with hexane wash and vacuum drying, obtains 1.1g, 89% desirable product.

Step C: to 3-[3-cyano group-1-ethyl-6-(3-pyrrolidine-1-base-propoxyl group)-1H-indole-2-yl]-phenyl }-(50mg is 0.12mmole) at CH for carbamic acid ethyl ester ₃Add in the solution among the CN (2mL) DIEA (31 μ L, 0.18mmol), sodium iodide (20mg, 0.132mmol) and pyrrolidine (30 μ L, 0.36mmole).The mixture of gained stirs under reflux temperature and spends the night.Evaporating solvent, and residue grinds with the ethyl acetate dilution and with hexane, precipitate is by filter collecting and with the solution thorough washing of 50% ethyl acetate in hexane, vacuum drying then, obtain 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidines-3-yl)-phenyl]-1H-indole-3-nitrile, chemical compound 638 (46mg, 85%).

Prepare following chemical compound similarly according to above-mentioned steps A-C: chemical compound 441,447,491,492,493,504,525,526,527,528,529,531,532,533,534,535,536,537,538,539.

Embodiment 1BY: preparation [3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-thiourea (chemical compound 767).

Steps A: (187mg 0.642mmol) is dissolved in the anhydrous propanone (3.0mL) with starting material 2-(3-amino-phenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile.At room temperature (107mg 0.656mmol) is added in the above-mentioned solution, and stirs this mixture 17 hours, forms precipitate during this period with the benzoyl isothiocyanate.Filtering precipitate is used washing with acetone, and is dry then, obtains 1-benzoyl-3-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl of 264mg]-thiourea (90% productive rate), it is the glassy yellow solid.

Step B: at room temperature stir 1-benzoyl-3-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-thiourea (241mg; 0.530mmol) suspension in methanol (2.0ml) and water (0.5mL); add simultaneously sodium hydroxide (31mg, 0.78mmol).Reactant mixture be heated to 50 ℃ totally 17 hours.Reactant mixture concentrates to remove methanol.Water is added in this mixture, and crosses filter solid, wash drying then with water, obtain [3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl)-phenyl]-thiourea of 179mg, chemical compound 767 (96% productive rate), it is a white solid.

Embodiment 1BZ: preparation 1-ethyl-6-methoxyl group-2-[4-(2-phenylquinazoline-4-base is amino)-phenyl]-1H-indole-3-nitrile (chemical compound 458)

2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (100mg, 0.343mmol), 4-chloro-2-phenyl-quinazoline (83mg, 0.34mmol) and diisopropyl ethyl amine (0.10mL, 0.57mmol) vlil in dehydrated alcohol (3mL) is spent the night.This solution cooling is also evaporated, and residue is put into ethyl acetate (50mL).Water and saturated brine (50mL is respectively) washing, dry on anhydrous sodium sulfate then, filter and evaporation.The solid of gained grinds with ether, filters and collects, and vacuum drying obtains 1-ethyl-6-methoxyl group-2-[4-(2-phenylquinazoline-4-base is amino)-phenyl then]-1H-indole-3-nitrile (139mg, 0.280mmol, 82%).

Embodiment 1CA: preparation [4-(3-cyano group-6-ethyoxyl-1-ethyl-1H-indole-2-yl)-phenyl]-phosphoramidic acid diethyl ester (chemical compound 772).

2-(4-aminophenyl)-6-ethyoxyl-1-ethyl-1H-indole-3-nitrile (148mg, 0.484mmol), chlorine di(2-ethylhexyl)phosphate ethyl ester (0.086mL, 0.58mmol) and diisopropyl ethyl amine (0.10mL, 0.57mmol) 1, solution in the 4-dioxane (5mL) at room temperature stirs 12 hours, and then be heated to 80 ℃ totally 24 hours.The solution cooling also is poured in the ethyl acetate of 50mL.Its water and saturated brine (50mL is respectively) washing, dry on anhydrous magnesium sulfate, filter and evaporation.Residue separates (eluting 2/1 ethyl acetate/hexane by flash chromatography, on silica gel 60), after evaporation, obtain [4-(3-cyano group-6-ethyoxyl-1-ethyl-1H-indole-2-yl)-phenyl]-phosphoramidic acid diethyl ester (108mg, 0.245mmol, 51%), it is a white powder.

Embodiment 1CB: preparation 1-ethyl-6-methoxyl group-2-[4-(5-methyl isophthalic acid, 1-dioxo-1 λ ⁶-[1,2,5] thiadiazolidine-2-yl)-and phenyl]-1 H-indole-3-nitrile (chemical compound 726).

Steps A: to 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (202mg, 0.693mmol) add in the solution in pyridine (2.0mL) N-β-(chloroethyl amino) sulfonic acid chloride (222mg, 1.39mmol).This mixture at room temperature stirred 17 hours, then added water (12.0mL), and (3 * 2mL) extract this mixture with ethyl acetate then.Extract with 10% moisture HCl (2 * 2mL), water (2 * 2mL) washing, at MgSO ₄Last dry, filter, on rotary evaporator, concentrate then.Crude product is by the pure system (0-5% of flash chromatography, ethyl acetate/dichloromethane), obtain N-(2-chloro-ethyl)-N '-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl) phenyl] sulfonamide of 217mg, chemical compound 724, it is pale brown color solid (75% productive rate).

Prepare following chemical compound according to similar method: chemical compound 540,541,542,574,576,704.

Step B: to N-(2-chloro-ethyl)-N '-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indole-2-yl) phenyl] sulfonamide (100mg, 0.241mmol) add in the solution in dry DMF (1.25mL) potassium carbonate (71.0mg, 0.514mmol).This mixture at room temperature stirred 17 hours, water (7.5mL) dilution then.Reactant mixture with ethyl acetate (3 * 2mL) extraction, and the extract water (2 * 2mL) washing, at MgSO ₄Last dry and concentrate, obtain 2-[4-(1,1-dioxo-1 λ ⁶-[1,2,5] thiadiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile, chemical compound 725, it is white solid (84mg, 88% productive rate).

Prepare following chemical compound according to similar method: chemical compound 705.

Step C: to 2-[4-(1,1-dioxo-1 λ ⁶-[1,2,5] thiadiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indole-3-nitrile (34mg, 0.086mmol) add in the solution in dry DMF (1.0mL) potassium carbonate (25mg, 0.18mmol) and iodomethane (20.4mg, 0.144mmol).This mixture at room temperature stirred 2 hours, and then water (6.0mL) dilution produces precipitate.Filtering precipitate washes with water and drying, obtains 1-ethyl-6-methoxyl group-2-[4-(5-methyl isophthalic acid, 1-dioxo-1 λ ⁶-[1,2,5] thiadiazolidine-2-yl)-phenyl]-1H-indole-3-nitrile, chemical compound 726, it is white solid (35mg, 98% productive rate).

Prepare following chemical compound according to similar method: chemical compound 727.

Embodiment 2: use the HCV IRES monocistron translation experiment screening low molecular weight compound based on cell

Use is based on the translation experiment screen chemical libraries of the monocistron HCV IRES adjusting of cell, and this experimental design is used for the natural HCV mRNA translation of closely simulation, makes the also screening of analog of chemical compound then based on the coupling thing (hit) in this chemistry library.The preparation DNA construct is called pHCVIRESmono, wherein inserts HCV IRES sequence (HCV 2b, nucleotide 18-347) between promoter and Lampyridea luciferase (Fluc) reporter gene.Carry out transfection and select resistance with pHCVIRESmonoDNA, set up thus through the HepG 2 of stable transfection (hepatoblastoma) cell line (being called HepGmono-4) or Huh7 cell line (being called Huhmono 7) or Hela cell line (being called Helamono) to hygromycin.

Embodiment 3: use the selectivity of measuring the translation that HCV IRES is regulated based on the dependent translation experiment of the medicated cap of cell

Because use translation experiment to screen HCV IRES inhibitor, selected target can work to the translation that is driven by HCVIRES specifically, and perhaps the total protein in the scalable mammalian cell is synthetic.The chemical compound that should work to total translation will most possibly have significant cytotoxicity.For this probability is described, establish the dependent translation experiment of various medicated caps with the whole selected compounds of further assessment based on cell.Structure comprises the plasmid DNA of carrier the sequence 5 '-Fluc of 130 nucleotide.This construct is called pLuc at this.In the dependent translation experiment of medicated cap, set up stable cell line by use 293T cell (human embryonic kidney cell system).HepGmono-4 and pLuc use compound treatment 20 hours, measure activity by quantitative Fluc signal then.5 times selectivity is considered to make us wishing between HCV IRES and the dependent translation of medicated cap.For example, use based on the dependent translation experiment of the medicated cap of cell, the applicant has identified the IC in the dependent translation experiment of medicated cap ₅₀Value is at least than low 5 times chemical compound in HCV IRES translation experiment.Fig. 1 has shown that the selectivity of the translation that HCV IRES is regulated is higher than the example that optionally mates thing to the dependent pLuc translation of medicated cap.Importantly, the activity level of this chemical compound in HCV IRES monocistron 293T cell line and identical (data not shown) in HepGmono-4.Therefore, chemical compound can not be because used cell type different with selectivity between the dependent translation of medicated cap (293T) at HepGmono-4 (HepG 2).

In addition, use the western Blot experiment to confirm that further compound selective of the present invention ground suppresses the translation that is driven by HCV IRES.HepGmono-4 and the aforesaid compound treatment of pLuc cell were handled 20 hours with test compounds then, collecting cell, and in comprising the Laminin buffer of 0.5%SDS, dissolve.Protein isolate on 10%SDS-PAGE is then transferred on the NC Nitroncellulose film, uses the antibody of anti-Fluc (RDI) and beta-actin (Oncogene) to carry out engram analysis then.For example, test some chemical compounds of the present invention in this way, and as expected, chemical compound in the translation of using the Fluc signal optionally to suppress in as the experiment of terminal point to be driven by HCV IRES shows the comparable decline of luciferase report protein level in the HepGmono-4 cell, and is relative non-activity (data not shown) for pLuc in the Western trace.Importantly, these chemical compounds do not suppress the expression of endogenous beta-actin, and this proteic translation all is the medicated cap dependency in these two kinds of cell lines.Consistent is not show optionally chemical compound all Profilin accumulations (data not shown) in HCV IRES and the dependent translation experiment of medicated cap in this translation experiment.As expected, general protein translation inhibitor puromycin also all suppresses that HCV IRES drives and the dependent albumen formation of medicated cap (data not shown).Therefore, Western trace result has confirmed that compound selective of the present invention ground suppresses the translation that HCV IRES drives.

The test condition that is used for these cell lines all is optimised, and by the quantitative Fluc mRNA of RT PCR in real time level, controls the influence of mRNA level to compound activity thus.For example, test some chemical compounds of the present invention in this way, and between HepGmono-4 or Helamono cell or Huhmono cell and the used dependent translation cell line of medicated cap, all do not observed the significant difference (data not shown) of Fluc mRNA level.

Embodiment 4: the translation experiment that uses cell IRES to mediate is assessed the selectivity to the translation that is driven by HCV IRES

But various human mRNA has been proved grappling IRES element (18,19,39,44,45,91,126,130).Though the elementary introduction of HCVIRES and secondary structure are all different with cell IRES's, be to measure whether selected chemical compound is active for cell IRES for important test optionally.VEGF IRES has poor startup activity in experiment in vitro, but has tangible activity (18,45) in the translation experiment based on cell.For example, tested some chemical compounds of the present invention, and all dependent translation has well optionally chemical compound for medicated cap, it is to the IC of VEGF IRES ₅₀High at least 5 times (data not shown) of value comparison HCV IRES.These data show that selected chemical compound has selectivity for viral IRES.Except that having different structures, VEGF IRES also has and the different interaction of non-standard cell translation factor.These differences all have contribution for the HCV IRES selection of inhibitors that has identified.

Embodiment 5: the assessment cytotoxicity

The influence of on cell proliferation all is the problem of a key for any drug research.Therefore, use cell proliferation/cytotoxicity experiment to eliminate any chemical compound that mammalian cell is grown that influences.The effect of the selected coupling thing on cell proliferation of test in human cell line 293 T and Huh7 (people's hepatoblastoma cell line).Cell is grown in being supplemented with Dulbecco ' s improvement Eagle ' the s culture medium of 10% hyclone, L-glutaminate, penicillin and streptomycin.Handled 3 days with test compounds at the cell of logarithmic growth in mutually, wherein 250 μ M are the highest test concentrations of compound used therefor.(Promega, Madison WI) assess the influence of described chemical compound on cell proliferation to use CellTiter 96 AQueous One Solution Cell Proliferation Assay.With the IC among the HepGmono-4 ₅₀Value is compared its CC ₅₀The chemical compound that value is high at least 5 times is considered to have enough windows between activity and cytotoxicity, and is selected for further assessment thus.For example, tested some chemical compounds of the present invention in this way, and importantly, dependent translation has the good CC that optionally chemical compound showed to medicated cap for all ₅₀With IC ₅₀The ratio of value is higher than 5.

Embodiment 6: the effectiveness of assessment chemical compound in HCV replicon system

Because the cell culture and the small animal model that lack can be used for that HCV duplicates reliable and be easy to get have limited the research and development of new anti-HCV medicament.Recently existing people has described the sub-gene group HCV system of self replication, is called the HCV replicon, and has been widely used in assessing the effectiveness (8,70,104) of anti-HCV inhibitor.Have and report that the inhibitor of interferon (IFN) α and HCV protease and polymerase has activity (8,17,32,68,69,117) in HCV replicon system.

Discriminating comprises the HCV replicon of bicistronic mRNA and monocistron system, sets up the experiment that is used to test HCV IRES inhibitor then.In the bicistronic mRNA replicon, HCV IRES instructs the expression of selected marker thing (Neo and/or Fluc reporter gene), and the proteic expression of EMCV IRES mediation virus non structural.In the monocistron replicon, it is synthetic that HCVIRES directly mediates virus protein.HCV IRES inhibitor is analyzed by quantitative Fluc reporter gene signal in the bicistronic mRNA replicon.The cell that comprises replicon was cultivated 2 days with chemical compound of the present invention.Interferon (IFN) α is used as positive control.For example, chemical compound of the present invention is tested in this way, and these experiments show that the Fluc that the chemical compound of the translation of selectivity inhibition HCV IRES mediation suppresses in the bicistronic mRNA replicon expresses.

In following table (table 1),

*=replicon or HCV-PV IC50＞2uM

*=replicon or HCV-PV IC50 are between 0.5uM and 2uM

* *=replicon or HCV-PV IC50＜0.5uM

Replicon IC50 value Lampyridea luciferase signal measuring.

HCV-PV IC50 value reduces with viral RNA to be measured.

Table 1

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						1				*
2		311.1		*
						3		356.0		*
4		279.2		*
						5	64-66	201.3		*
6		201.1		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						7	304-305	251.1		**	1H NMR(300MHz，DMSO-d 6)：δ8.23 (1H，d，J＝2.1Hz)，8.08(1H，dd，J＝ 8.8，2.1Hz)，7.74(1H，d，J＝8.8Hz)， 7.55(2H，t，J＝2.2Hz)，6.51(2H，t，J＝ 2.2Hz).
8		277.3		**
						9	61-63	215.2		*
10	69-71	229.2		*
						11	78-80	243.2		*
12	94-97	277.2		**
						13	161-164	265.3		*
14	206-207	415.2		*	1H NMR(300MHz，CDCl 3：δ 8.09(1H， dd，J＝8.8，1.7Hz)，7.75(1H，d，J＝ 1.7Hz)，7.49(1H，d，J＝8.8Hz)，7.40 (2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.8 Hz)，7.17(2H，d，J＝8.8Hz)，6.93(2H， d，J＝8.8Hz)，6.15(1H，s)，3.93(3H， s)，3.83(3H，s).
						15	225-226	290.3		*
16	175-177	286.3		*
						17		248.1		*
18		237.3		*
						19		307.4		*
20	159-160	267.2		*
						21	125-125	277.3		*
22	146-149	321.1		**
						23	234-235	334.2		***
24	123-124	307.1		**
						25	291-293	271.2		*	1H NMR(300 MHz，DMSO-d 6)：δ10.81 (1H，s)，8.63(1H，d，J＝1.7Hz)，8.10 (1H，dd，J＝8.8，1.7Hz)，7.76(1H，d，J ＝8.8Hz)，4.35(2H，q，J＝7.0Hz)， 2.22(3H，s)，1.26(3H，t，J＝7.0Hz).
26	287-288	335.3		**	1H NMR(300MHz，CDCl 3)：δ10.83 (1H，s)，8.23(1H，s)，8.00(1H，d，J＝ 8.8Hz)，7.92(2H，d，J＝7.3Hz)，7.60 (1H，d，J＝8.5Hz)，7.53-7.43(1H，m)， 7.41-7.30(2H，m)，4.12(2H，q，J＝7.3 Hz)，1.31(3H，t，J＝7.3Hz).
						27	138-140	236.3		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						28	68-70	272.2		**
29	oil	284.3		*
						30	114-116	292.2		*	1H NMR(300MHz，DMSO-d 6)：δ8.19 (1H，d，J＝2.3Hz)，7.96(1H，dd，J＝ 8.8，2.3Hz)，7.69(1H，d，J＝8.8Hz)， 7.38(1H，t，J＝7Hz)，4.32(2H，q，J＝ 7.0Hz)，3.81(3H，s)，3.61(2H，pentet， J＝7Hz)，1.29(3H，t，J＝6.7Hz)，1.24 (3H，t，J＝7.0Hz).
31	189-190	264.1		*	1H NMR(300MHz，DMSO-d 6)：δ8.11 (1H，d，J＝2.0Hz)，7.94(1H，dd，J＝ 8.5，2.0Hz)，7.65(1H，d，J＝8.5Hz)， 7.54(2H，br s)，4.21(2H，q，J＝7.0 Hz)，3.79(3H，s)，1.20(3H，t，J＝7.0 Hz).
						32	oil	280.2		*
33	113-117	280.2		*
						34	137-141	232.1		*
35	318-319	411.0， 413.0 (M-H -)		*	1H NMR(300MHz，DMSO-d 6)：δ11.29 (1H，s)，8.71(1H，d，J＝2.0Hz)，8.13 (1H，dd，J＝8.8，2.0Hz)，7.98(2H，d，J ＝8.5Hz)，7.84(2H，d，J＝8.5Hz)， 7.83(1H，d，J＝8.8Hz)，4.41(2H，q，J ＝7.0Hz)，1.28(3H，t，J＝7.0Hz).
						36	273-274	380.1		*	1H NMR(300MHz，DMSO-d 6)：δ11.58 (1H，s)，8.87(1H，s)，8.72(1H，s)，8.53 (1H，d，J＝7.0Hz)，8.47(1H，d，J＝7.0 Hz)，8.14(1H，d，J＝8.5Hz)，7.91(1H， t，J＝8.2Hz)，7.86(1H，d，J＝8.8Hz)， 4.45(2H，q，J＝7.0Hz)，1.30(3H，t，J ＝7.0Hz).
37	56-60	246.2		*
						38	96-100	310.1		*
39	94-98	310.1		*
						40	176-180	269.1		*
41	155-175	267.1		*
						42	138-143	296.1		*
43		229.2		*
						44		293.2		*
45	130-131	215.5		*
						46		376.2		*
47	140-145	376.2		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						48	138-142	296.3		**
49	89-90	376.3		*
						50	91-92	259.3		*
51	95-96	229.4		*
						52		243.2		*
53	145-147	363.1		**
						54	99-101	272.3		*
55	183-185	292.2		*
						56	223-224	301.2		**
57	130-133	243.2		*
						58	76-79	243.2		*
59	81-85	242.2		*
						60	133-136	271.2		*
61	153-158	270.2		*
						62		262.0		*
63	188-192	333.4		*
						64	108-113	301.3		*
65	130-132	331.3		**
						66	119-122	331.3		*
67	132-136	319.3		**
						68	140-147	315.3		**
69	163-166	316.3		**
						70	142-141	321.2		*
71	199.4	348.2		*
						72	144-149	271.3		*
73	oil	259.2		*
						74	179-182	325.3		*
75	118-123	271.3		*
						76	118-120	293.3		*
77	117-118	307.3		*
						78	110-114	287.2		*
79	257-260	332.4		*
						80	292-294	356.5		**
81	209-211	360.5	***	***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						82	223-228	372.5	***	**
83	221-223	384.4	***	***
						84	232-237	396.4	***	***
85	163-165	398.3	***	***
						86	158-160	410.3		***
87	187-189	396.3	***	***
						88	209-213	398.4	***	**
89	148-155	308.3		**
						90	80-95	364.4		*
91	160-161	301.2		*
						92	155-156	317.2		*
93	172.4- 172.6	305.3		*
						94	262-265	314.4		**
95	248-251	344.4		**
						96	243-250	329.4		**
97	164-167	350.4		*
						98	180-185	363.2		*
99	123.4- 123.8	307.0		*
						100	128-129	277.2		*
101	204-209	426.6		**
						102	136.7- 136.9	267.2		*
103	90-93	263.2		*
						104	190-194	406.4		**
105	204-206	442.4		*
						106	230-243	494.4		*
107	157-158	327.1		*
						108	94-96	249.2 251.2		*
109	54-56	263.2 265.2		*
						110	128-130	349.3		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						111	208.5	374.3		*	1H NMR(CDCl 3，400MHz)，δ＝7.75-7.72 (m，2H)，7.13-7.10(m，2H)，6.97-6.88(m， 3H)，6.11(s，2H)
112	173.1- 173.5	277.3		**	1H NMR(CDCl 3，400MHz)，δ＝7.67(t， J＝8.4Hz，2H)，7.24(d，J＝14.8Hz，1H)，7.16 (d，J＝8.0Hz，1H)，6.96-6.90(m，3H)，6.10 (s，2H)，2.46(s，3H)
						113	193-194	374.3		*
114	207-298	390.3		*
						115	175-177	177.1		*
116	116-118	349.4		*
						117	120-123	249.3		*
118	62-65	205.2		**
						119	126-128	283.2		**
120	69-71	205.5		*
						121	167-169	364.5		**
122	163-169	426.5		*
						123	113-117	239.4		*
124	212.2- 212.3	295.3		*	CDCl 3，400MHz，δ＝7.61(dd，J＝8.4Hz and 4.4Hz，1H)，7.04-6.96(m，2H)，6.77 (m，3H)，6.12(s，2H)，2.42(s，3H)
						125	151.2- 151.7	291.3		**	CDCl 3，400MHz，δ＝7.57(d，J＝8.0Hz， 1H)，7.09(d，J＝8.0Hz，1H)，6.97(d， J＝8.0Hz，1H)，6.86(s，1H)，6.79(dd， J＝11.2Hz and 2.0Hz，2H)，6.12(s，2H)， 2.42(s，3H)，2.40(s，3H)
126	146-148	251.3		*
						127	173-175	327.3		*
128	218-220	334.5		*
						129	188-190	370.4		**
130	227-233	394.5		***
						131	199-204	408.5		**
132	209-212	422.5		**
						133	144-146	351.5		**
134	155-157	335.4		**
						135	168-170	369.5		**
136	159-161	381.4		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						137	129-132	345.5		**
138	235-239	358.5	***	**
						139	191-195	388.5	***	**
140	83-96	253.3		*
						141	145-146	253.4		*
142	103-105	237.4		*
						143	168-171	384.5		*
144	97-100	315.4		**
						145	110-113	357.5		**
146	169-172	335.3		**
						147	183-186	344.4		**
148	155-157	335.4		**
						149	134-136	345.4		**
150	141-143	319.4		**
						151	146-148	319.4		**
152	207-211	386.5		*
						153	225-228	398.5	*	**
154		293.1		**	DMSO，400MHz，δ＝8.13(d，J＝6.4Hz， 1H)，8.01(s，2H)，7.84(s，1H)，7.54(dd， J＝12.4Hz and 3.6Hz，1H)，7.15(d， J＝8.8Hz，2H)，3.83(s，3H)
						155				**	CDCl 3，300MHz，δ＝9.31(s，1H)，8.32(s， 1H)，8.19-8.17(m，1H)，7.75(s，1H)，2.70 (s，3H)
156	205-209	421.5		**
						157	149-153	422.5		**
158	153-156	317.5		**
						159	147-150	361.3		**
160	117-119	315.7		**
						161	174-176	340.3		**
162	185-190	413.5		*
						163	235-239	410.5		**
164	273-280	358.5		**
						165	211-225	373.5		*
166	236-240	385.5		***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						167	196-200	464.5		**
168	199-204	394.5		*
						169	147-150	316.5		**
170	148-151	307.4		**
						171	134-137	307.4		**
172	221-223	317.4		**
						173	150-153	316.5		**
174	139-142	302.4		**
						175	132-135	359.5		**
176	162-164	343.5		**
						177	125-130	331.4		**
178	119-123	369.4		*
						179	79-80	239.4		**
180	170-171	384.5	**	**
						181	177-178	398.5		**
182	148-154	408.5		***
						183	276-284	344.5		**
184	197-200	337.4		**
						185	157-160	355.4		**
186	166-169	317.4		**
						187	187-191	321.4		**
188	209-212	287.4		**
						189	252-253	356.4		*
190	234-236	370.4		**
						191	208-210	370.4	**	*
192	205-207	384.5		**
						193	228-232	378.5 [M-H]		**
194	278-284	370.4		**
						195	271-275	398.4		**
196	187-189	354.3		**
						197	147-149	373.6		*
198	163-165	395.7		*
						199	156-158.	369.2	***	*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						200	187-189	354.4		**
201	147-150	381.2		**
						202	137-139	369.4		**
203		257.9		**	DMSO，300MHz，δ＝10.34(s，1H)，7.42 (d，J＝8.7Hz，1H)，7.14(d，J＝2.1Hz，1H)， 6.87(dd，J＝8.7Hz and 2.1Hz，1H)，4.08(q， J＝7.2Hz，2H)，3.80(s，3H)，2.12(s，3H)， 1.21(t，J＝7.2Hz，3H)
						204		320.1		***	DMSO，300MHz，δ＝10.81(s，1H)，8.02 (t，J＝7.2Hz，2H)，7.67-7.47(m，4H)，7.21 (d，J＝2.4Hz，1H)，6.90(dd，J＝8.4Hz and 2.1Hz，1H)，4.12(q，J＝6.9Hz，2H)，3.83(s， 3H)，1.24(t，J＝7.5Hz，3H)
205	181-184	358.4		**
						206	187-191.	372.4		**
207	179-183.	386.4		**
						208	192-194.	394.4		**
209	180-183	408.4		**
						210	213-216	422.4		**
211	186-191.	384.4		**
						212	180-183	400.4		**
213	165-168	398.4		**
						214	254.8- 255.1	338.1		***	1H NMR(DMSO，300MHz)，δ＝7.88(d， J＝7.5Hz，1H)，7.82(d，J＝9.9Hz，1H)，7.64 (q，J＝8.1Hz，1H)，7.21(d，J＝2.4Hz，1H)， 7.56-7.48(m，2H)，7.21(d，J＝2.1Hz，1H)， 6.91(dd，J＝8.7Hz and 2.1Hz，1H)，4.12(q， J＝7.2Hz，2H)，4.13(s，3H)，1.23(t， J＝6.9Hz，3H)
215	245-246	345.1		**	1H NMR(DMSO，300MHz)，δ＝11.08 (s，1H)，8.16(d，J＝8.4Hz，2H)，8.07(d， J＝7.8Hz，2H)，7.49(d，J＝8.4Hz，1H)，7.21 (d，J＝2.1Hz，1H)，6.91(dd，J＝8.4Hz and 1.8Hz，1H)，4.08(q，J＝2.1Hz，2H)，3.80(s， 3H)，1.25(t，J＝7.2Hz，3H)
						216	261	283.9		**	1H NMR(DMSO，300MHz)，δ＝10.58 (br，1H)，7.42(d，J＝8.7Hz，1H)，7.15(d， J＝2.1Hz，1H)，6.86(dd，J＝8.7Hz and 2.4Hz，1H)，4.08(q，J＝7.2Hz，2H)，3.80(s， 3H)，2.04(br，1H)，1.21(t，J＝6.9Hz，3H)， 0.89-0.84(m，5H)

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						217	272-273	315.9		***	1H NMR(DMSO，300MHz)，δ＝9.94(s， 1H)，7.43(d，J＝8.7Hz，1H)，7.15(d， J＝2.1Hz，1H)，6.87(dd，J＝8.7Hz and 2.4Hz，1H)，4.12(q，J＝7.2Hz，2H)，3.91(d， J＝6.6Hz，2H)，3.80(s，3H)，1.89-1.92(m， 1H)，1.21(t，J＝7.2Hz，3H)，0.89(d， J＝6.6Hz，6H)
218	174-177	344.3		**
						219	145-149	388.4		**
220	219-223	387.7		**
						221	195-200	421.3		**
222	216-219	385.4		**
						223	210-216	316.4		**
224	245-249	358.3		**
						225	231-236	372.3		**
226	294-295	375.9		*	1H NMR(CDCl 3，300MHz)δ(ppm)，3.72 (s，3H)，3.80(s，3H)，6.75-6.91(m，2H)， 7.42-7.56(m，2H)，8.04(d，1H)，8.23(d， 1H)，8.67(d，1H).
						227	198-203	392.3		**
228	195-198	388.3		*
						229	142-147	321.3		*
230	218-220	323.4		*
						231	201-203	289.3		*
232	190-193	307.3		*
						233	232-234	329.4		**
234	221-223	288.3		*
						235	218-222	316.4		**
236	145-147	287.3		*
						237	146-148	303.3		*
238	189-191	273.3		*
						239	212-218	292.3		*
240	164-167	335.3		*
						241	184-188	344.3		*
242	242-248	334.3		*
						243	194-198	370.3		***
244	187-190	360.4		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						245	192-195	390.4		*
246	160-164	374.4		*
						247	212-217	293.3		*
248	117-121	351.4		**
						249	132-136	337.4		**
250	160-162	323.3		*
						251	186-187	398.4	***	**
252	176-177	432.4		**
						253	121-125	399.2		**
254	153-154	307.21		*
						255	149-151	435.5		**
256	230-232	331.3		*
						257	174-176.	330.3		*
258	146-148	330.3		*
						259	foam	358.3		*
260	109-111	359.3		*
						261	138-143	406.4		**
262	117-121	365.4		**
						263	121-127	419.4		**
264	glass	406.5		**
						265	204-206	355.3		*
266	96-99	362.4		**
						267	106-112	336.4		*
268	137-143	414.4		**
						269	153-158	428.4		**
270	175-177	404.4		*
						271	158-160	418.4		**
272	173-176	396.4		**
						273	207-209	404.4		*
274	166-172	378.4		*
						275	201-206	384.4		*
276	224-228	426.4		*
						277	186-191	370.4		*
278	234-240	356.4		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						279	197-202	407.5		*
280	89-95	364.4		*
						281	132-134	283.3		*
282	135-136	317.3		*
						283	215-218	353.4		*
284	112-114	267.3		*
						285	185-190	420.5		*
286	191-192	333.3		**	1H NMR(300 MHz，CDCl 3)：δ7.92-7.88 (2H，m)，7.67(1H，s)，7.66(1H，d，J＝ 8.8Hz)，7.46-7.42(2H，m)，6.98(1H， dd，J＝8.8，2.3Hz)，6.88(1H，d，J＝ 2.3Hz)，4.35(2H，q，J＝7.3Hz)，3.92 (3H，s)，1.46(3H，t，J＝7.3Hz).
						287	175-177	384.4		*
288	194-199	293.3		*
						289	173-175	432.2		*
290		433.1		*	1H NMR(CDCl3，300MHz)，δ7.97-7.92 (m，2H)，7.70-7.62(m，3H)，7.10(br，1H)， 6.98(dd，J＝8.7Hz and 2.1Hz，1H)，6.88(d， J＝2.1Hz，1H)，4.16(q，J＝7.5Hz，2H)，3.91 (s，3H)，3.77(t，J＝4.2Hz，4H)，3.62(q， J＝5.4Hz，2H)，2.68(t，J＝5.7Hz，2H)，2.59 (br，4H)，1.36(t，J＝7.2Hz，3H)
						291		319.9		*	1H NMR(CD 3OD，300MHz)，δ8.07(d， J＝7.2Hz，2H)，7.79-7.68(m，2H)，7.54(d， J＝8.7Hz，1H)，7.12(d，J＝2.1Hz，1H)，6.97 (dd，J＝8.7Hz and 2.1Hz，1H)，4.24(q， J＝7.5Hz，2H)，3.90(s，3H)，1.26(t， J＝7.2Hz，3H)
292	176-177	348.0		*	1H NMR(CDCl3，300MHz)，δ7.93-7.88 (m，2H)，7.69-7.60(m，3H)，6.98(dd， J＝8.7Hz and 2.1Hz，1H)，6.88(d，J＝2.1Hz， 1H)，6.17(br，1H)，4.15(q，J＝7.2Hz，2H)， 3.91(s，3H)，3.53(m，2H)，1.35(t， J＝7.2Hz，3H)，1.28(t，J＝7.2Hz，3H)
						293		412.5		*
294		364.4		***
						295		609.4		**
296		392.4		**
						297		378.4		**
298		394.4		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						299		376.4		**
300		392.4		**
						301		412.4		**
302		382.4		**
						303		374.2		*
304		426.4		**
						305		442.4		*
306		446.4		**
						307		430.4		**
308		424.3		*
						309		490.3		**
310		378.4		**
						311		392.1		*
312		378.1		*
						313		394.1		*
314		376.1		*
						315		412.0		*
316		474.1		*
						317		382.1		*
318		446.1		*
						319		430.1		*
320		426.1		*
						321		490.9		*
322	223-230	308.4		*
						323	102.9- 103.4	447.2		*	1H NMR(CD 3OD，300MHz，δ8.02-8.00 (m，2H)，7.78-7.68(m，2H)，7.55(d， J＝8.4Hz，1H)，7.12(s，1H)，6.97(dd， J＝6.6Hz and 1.5Hz，1H)，4.24(q，J＝7.5Hz， 2H)，3.90(s，3H)，3.68(t，J＝4.2Hz，4H)， 3.52(q，J＝5.4Hz，2H)，2.50(t，J＝6.9Hz， 6H)，1.86(br，2H)，1.28(t，J＝7.2Hz，3H)
324	165.3- 165.7	368.1		*	(DMSO，300MHz)，δ10.56(s，1H)，7.85 (s，1H)，7.73(d，J＝7.8Hz，1H)，7.54(q， J＝7.8Hz，2H)，7.31(d，J＝7.8Hz，1H)，7.23 (s，1H)，6.92(d，J＝8.7Hz，1H)，4.27(s， 2H)，4.18(q，J＝7.5Hz，2H)，3.83(s，3H) 1.20(t，J＝7.2Hz，3H)

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						325		462.1		*	(DMSO，300MHz)，δ10.30(s，1H)，8.02 (s，1H)，7.91(d，J＝7.5Hz，1H)，7.58-7.54 (m，4H)，7.5 1-7.49(m，2H)，7.04(d， J＝8.4Hz，1H)，6.92(dd，J＝8.7Hz and 1.8Hz，1H)，6.11(s，2H)，4.22(q，J＝7.5Hz， 2H)，3.83(s，3H)，1.21(t，J＝6.9Hz，3H)
326	137-138	396.1		*
						327	154-155	386.1		*	(DMSO，300MHz)，δ10.45(s，1H)，8.02 (s，1H)，7.95(d，J＝8.1Hz，2H)，7.55(q， J＝7.8Hz，2H)，7.33(q，J＝3.6Hz，2H)，7.25 (s，1H)，6.95(dd，J＝3.6 and J＝2.4Hz，1H)， 6.70(q，J＝1.8Hz，1H)，4.22(q，J＝7.5Hz， 2H)，3.84(s，3H)，1.22(t，J＝6.9Hz，3H)
328	174-175	401.1		*	(CDCl3，300MHz)，δ8.68(s，1H)，8.00 (s，1H)，7.65(m，2H)，7.55(t，J＝8.4Hz， 1H)，7.40(d，J＝7.2Hz，1H)，6.95(dd，J＝7.2 and 1.8Hz，1H)，6.90(d，J＝2.1，1H)，6.54 (s，1H)，4.20(q，J＝7.2Hz，2H)，3.92(s， 3H)，2.53(s，3H)，1.39(t，J＝7.2Hz，3H)
						329	175-176	334.0		*	(CDCl3，300MHz)，δ7.79(s，1H)，7.64 (d，J＝8.4Hz，1H)，7.58(d，J＝8.7Hz，1H)， 7.49(t，J＝7.8Hz，1H)，7.38(s，1H)，7.30(d， J＝4.5Hz，1H)，6.99(d，J＝2.1Hz，1H)，6.92 (d，J＝2.1Hz，1H)4.19(q，J＝6.9Hz，2H)， 3.91(s，3H)，2.22(s，3H)，1.39(t，J＝7.2Hz， 3H)
330	237-238	438.1		*	(DMSO，300MHz)，δ10.90(s，1H)，8.71 (s，1H)，8.18(d，J＝9.9Hz，1H)，8.06(s， 1H)，7.97(t，J＝9.3Hz，2H)，7.63(t， J＝8.1Hz，1H)，7.53(d，J＝8.7，1H)，7.39(d， J＝8.4Hz，1H)，7.27(d，J＝1.8Hz，1H)，6.94 (dd，J＝8.7Hz and 2.1Hz，1H)，4.23(q， J＝6.6Hz，2H)，3.84(s，3H)，1.23(t， J＝7.2Hz，3H)
						331	160-165.	370.5		**
332	239-145	334.5		*
						333	237-240	384.5		**
334	242-246	348.5		**
						335	87-88	297.5		**
336	129-132	384.5		*
						337	135-137	283.4		*
338	125-135	367.5 [M-H]		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						339	215-219	362.5		**
340	243-248	334.2		*
						341	227-230	348.3		**
342	258-261	337.3		*	1H NMR(300MHz，CDCl 3)：δ8.70(1H， s)，7.79(1H，d，J＝1.8Hz)，7.73(1H， dd，J＝8.5，1.8Hz)，7.07(1H，d，J＝ 8.5Hz)，6.95(2H，d，J＝8.8Hz)，6.65 (2H，d，J＝8.8Hz)，3.97(2H，q，J＝7.0 Hz)，3.54(3H，s)，1.12(3H，t，J＝7.0 Hz).
						343	131-133	373.5		*
344	177-178	356.5		**
						345	191-192	370.5		**
346	178-180	384.3		***
						347	146-148	357.3		*
348	126-128	267.2		*
						349		392.3		***
350		374.3		**
						351		390.3		**
352		388.3		**
						353		350.2		***
354		388.3		**
						355		384.2		*
356		404.3 [M-H]		*
						357		392.3		*
358		374.3		*
						359		390.3		*
360		388.3		*
						361		404.3		*
362		609.5 [M-H]		**
						363	201-207	394.2 [M-H]		**
364	183-188	398.2		**
						365	oil	408.2		***
366	223-225	420.2		***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						367	225-227	434.2		**
368	168-170	434.2		**
						369	174-177	470.2		**
370	159-164	432.2		*
						371	168-170	340.2		*	1H NMR(300MHz，DMSO-d 6)：δ10.24 (1H，s)，7.75-7.60(1H，m)，7.60(2H，d， J＝8.8Hz)，7.45-7.25(3H，m)，7.41 (2H，d，J＝8.8Hz)，4.21(2H，q，J＝7.0 Hz)，3.13(3H，s)，1.22(3H，t，J＝7.0 Hz).
372	211-212	334.3		**	1H NMR(300MHz，DMSO-d 6)：δ9.98 (1H，s)，7.73-7.62(2H，m)，7.69(2H，d， J＝8.4Hz)，7.54(2H，d，J＝8.4Hz)， 7.39-7.24(2H，m)，4.26-4.12(4H，m)， 1.26(3H，t，J＝7.0Hz)，1.20(3H，t，J＝ 7.3Hz).
						373	222-228	354.2 [M-H]		*
374	180-186	396.2 [M-H]		*
						375	161-166	425.6 [M-H]		*
376		278.4		*
						377	153-156	403.1		*	1H NMR(DMSO，300MHz)，δ7.66-7.51 (m，5H)，7.25(d，J＝2.1Hz，1H)，6.91(dd， J＝8.7Hz and 2.4Hz，1H)，4.20(q，J＝7.5Hz， 2H)，3.83(s，3H)，3.65-3.55(m，2H)，2.73- 2.68(m，4H)，1.71-1.54(m，4H)，1.18(t， J＝7.2Hz，3H).
378		376.7		*	1H NMR(DMSO，300MHz)，δ8.84(t， J＝1.8Hz，1H)，8.02(d，J＝8.1Hz，2H)，7.67 (d，J＝7.8Hz，2H)，7.49(d，J＝8.7Hz，1H)， 7.38(s，1H)，7.22(s，1H)，7.02(s，1H)， 6.89(d，J＝7.2Hz，1H)，4.17(q，J＝6.9Hz， 2H)，3.80-3.77(m，5H)，1.12(t，J＝7.2Hz， 3H).
						379	228-232	474.2		**	1H NMR(DMSO，300MHz)，δ7.72-7.67 (m，2H)，7.78-7.68(m，2H)，7.55(d， J＝8.4Hz，1H)，7.12(s，1H)，6.97(dd， J＝6.6Hz and 1.5Hz，1H)，4.20(q，J＝7.5Hz， 2H)，3.83(s，3H)，3.06(t，J＝4.2Hz，6H)， 2.76-2.69(m，6H)，2.50(s，6H)，1.96(br， 2H)，1.18(t，J＝7.2Hz，3H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						380				*	1H NMR(DMSO，300MHz)，δ10.67(s， 1H)，8.16(d，J＝2.4Hz，1H)，8.11(d， J＝4.5Hz，2H)，7.78(d，J＝8.4Hz，2H)，7.73 (d，J＝2.4Hz，1H)，7.61(d，J＝9.0Hz，1H)， 7.54(d，J＝9.0Hz，1H)，7.27(s，1H)，6.94 (d，J＝8.7Hz，1H)，4.28-4.26(m，2H)，3.84 (s，3H)，1.17(t，J＝7.2Hz，3H).
381	216-220	410.1		*	1H NMR(DMSO，300MHz)，δ10.34(s， 1H)，8.10(d，J＝8.1Hz，2H)，7.75(d， J＝8.1Hz，2H)，7.65(d，J＝8.4Hz，2H)，7.53 (d，J＝8.7Hz，1H)，7.26(s，1H)，7.14(d， J＝8.1Hz，2H)，6.94(dd，J＝8.7Hz and 2.4Hz，1H)，4.21(q，J＝6.9Hz，2H)，3.83(s， 3H)，2.25(s，3H)，1.17(t，J＝6.9Hz，3H).
						382	236-238			**	1H NMR(DMSO，300MHz)，δ10.55(s， 1H)，8.10(d，J＝7.8Hz，2H)，7.83-7.76(m， 4H)，7.54(d，J＝8.4Hz，1H)，7.41(d， J＝8.1Hz，2H)，7.27(s，1H)，6.93(dd， J＝9.9Hz and 1.2Hz，1H)，4.22(q，J＝6.9Hz， 2H)，3.84(s，3H)，1.17(t，J＝7.2Hz，3H).
383	161.2- 162.2	362.1		*	1H NMR(CDCl3，300MHz)，δ7.79(s， 1H)，7.65-7.59(m，2H)，7.48(t，J＝7.8Hz， 1H)，7.30(t，J＝11.4Hz，2H)，6.96(dd， J＝8.7Hz and 2.1Hz，1H)，6.88(d，J＝2.1Hz， 1H)，4.18(q，J＝7.2Hz，2H)，3.91(s，3H)， 2.57-2.52(m，1H)，1.36(t，J＝7.2Hz，3H) 1.28-1.23(m，6H).
						384	199-201	348.0		*	1H NMR(CDCl3，300MHz)，δ7.93(d， J＝8.4Hz，2H)，7.67-7.61(m，3H)，6.98(dd， J＝8.7Hz and 2.1Hz，1H)，6.88(d，J＝2.1Hz， 1H)，6.14(br，1H)，4.14(q，J＝7.5Hz，2H)， 3.93(s，3H)，3.57-3.53(m，2H)，1.36-1.26 (m，6H).
385	213-213.9	362.0		**	1H NMR(DMSO，300MHz)，δ8.37(d， J＝6.6Hz，1H)，7.98(d，J＝7.8Hz，2H)，7.65 (d，J＝7.8Hz，2H)，7.50(d，J＝9.0Hz，1H)， 7.23(s，1H)，6.90(d，J＝7.8Hz，1H)，4.19- 4.16(m，2H)，4.08-4.06(m，1H)，3.80(s， 3H)，1.14-1.12(m，9H).
						386	198-199	359.9		*	1H NMR(DMSO，300MHz)，δ8.59(d， J＝4.2Hz，1H)，7.97(d，J＝8.1Hz，2H)，7.67 (d，J＝8.1Hz，2H)，7.52(d，J＝8.7Hz，1H)， 7.25(d，J＝2.1Hz，1H)，6.92(dd，J＝8.7Hz and 2.1Hz，1H)，4.19(q，J＝7.2Hz，2H)， 3.83(s，3H)，2.90-2.80(m，1H)，1.16(t， J＝7.2Hz，3H)，0.69(q，J＝4.8Hz，2H)，0.57 (q，J＝3.3Hz，2H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						387	189-189.5	360.1		*	1H NMR(DMSO，300MHz)，δ7.81(d， J＝8.4Hz，2H)，7.67(d，J＝8.1Hz，2H)，7.53 (d，J＝8.7Hz，1H)，7.25(d，J＝1.8Hz，1H)， 6.93(dd，J＝8.7Hz and 2.1Hz，1H)，4.35(t， J＝6.8Hz，2H)，4.18(q，J＝7.2Hz，2H)，4.06 (t，J＝6.8Hz，2H)，3.83(s，3H)，2.24(m， 2H)，1.16(t，J＝7.2Hz，3H).
388	160.1- 161.8	363.9		*	1H NMR(DMSO，300MHz)，δ8.60(t， J＝2.1Hz，1H)，8.02(d，J＝8.4Hz，2H)，7.68 (d，J＝8.1Hz，2H)，7.53(d，J＝9.0Hz，1H)， 7.25(s，1H)，6.93(dd，J＝6.9Hz and 1.8Hz， 1H)，4.72(t，J＝5.4Hz，1H)，4.19(q， J＝7.2Hz，2H)，3.83(s，3H)，3.48(q， J＝6.0Hz，2H)，3.33(m，2H)，1.15(t， J＝7.2Hz，3H).
						389	130-132	447.1		*	1H NMR(CDCl3，300MHz)，δ8.36(br， 1H)，8.12(d，J＝7.2Hz，2H)，7.67-7.59(m， 3H)，6.97(dd，J＝9.3Hz and 1.8Hz，1H)， 6.89(s，1H)，4.18(q，J＝7.5Hz，2H)，3.98 (br，2H)，3.84(s，3H)，3.67(q，J＝6.9Hz， 2H)，2.87(br，4H)，2.17(s，1H)2.14(br， 1H)，2.09(s，1H)，1.40(t，J＝10.5Hz，3H)， 1.31(t，J＝7.5Hz，3H).
390	236-236.8	396.1		*	1H NMR(DMSO，300MHz)，δ10.42 (s， 1H)，8.12(d，J＝8.4Hz，2H)，7.79-7.75(m， 4H)，7.55(d，J＝8.7Hz，1H)，7.35(t， J＝10.6Hz，2H)，7.27(d，J＝2.1Hz，1H)，7.09 (t，J＝10.6Hz，1H)，6.94(dd，J＝8.7Hz and 2.1Hz，1H)，4.23(m，2H)，3.84(s，3H)， 1.18(t，J＝6.9Hz，3H).
						391	240-242			**	1H NMR(DMSO，300MHz)，δ10.55(s， 1H)，8.11(d，J＝8.1Hz，2H)，7.82(m，4H)， 7.55(d，J＝8.7Hz，1H)，7.41(d，J＝9.0Hz， 2H)，7.27(d，J＝1.8Hz，1H)，6.94(dd， J＝8.7Hz and 2.1Hz，1H)，4.23(q，J＝7.1Hz， 2H)，3.84(s，3H)，1.78(t，J＝7.1Hz，3H).
392	243-246	456.1		*	1H NMR(DMSO，300MHz)，δ10.27(s， 1H)，8.11(d，J＝8.4Hz，2H)，7.76(d， J＝8.4Hz，2H)，7.54(d，J＝8.7Hz，1H)，7.48 (d，J＝2.4Hz，1H)，7.33(d，J＝7.2Hz，1H)， 7.29(s，1H)，6.96-6.91(m，2H)，4.25(q， J＝8.5Hz，2H)，3.84(s，3H)，3.73(s，3H)， 3.72(s，3H)，1.18(t，J＝7.2Hz，3H).
						393	202-206	296.4		**
394	192-195	372.3 [M-H]		***
						395		397.4		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						396		377.2	***	***
397		377.5	***	***
						398		391.5		***
399		375.5		***
						400		411.3		**
401		363.3	***	***
						402		439.5		**
403		453.5		**
						404		425.5		*
405		425.5		**
						406		503.5		***
407		483.5		**
						408	231-235	358.1		**
409	163-164	398.3		**
						410	139-141	359.2		**
411	148-149	373.3		**
						412	143-144	373.3		*
413	184-185	370.4		***
						414	156-157	384.4		**
415	163-165	384.4		***
						416	173-175	398.4		***
417	199-201	398.4		***
						418	183-184	412.4		***
419	213-215	398.4		**
						420	241-243	372.5		**
421	214-216	406.3		*
						422	259-261	386.5		**
423	291-294	434.4		*
						424	150-153	443.5		*
425	273-275	398.4		**
						426	178-180	327.2		**
427	199-202	330.3		**
						428	144-146	319.2 [M-H]		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						429	200-206	314.3		**
430	180-186	372.4 [M-H]		**
						431	167-173	296.4		*
432	160-162	318.1		*	(DMSO，300MHz)，δ8.64(t，J＝5.4Hz， 1H)，8.02(d，J＝8.1Hz，2H)，7.80-7.65(m， 4H)，7.40-7.28(m，2H)，4.21(q，J＝6.9Hz， 2H)，3.29(q，J＝7.2Hz，2H)，1.20-1.08(m， 6H).
						433	187-189	329.9		*	(DMSO，300MHz)，δ8.61(d，J＝3.6Hz， 1H)，7.79(d，J＝8.1Hz，2H)，7.76-7.64(m， 4H)，7.40-7.27(m，2H)，4.20(q，J＝7.2Hz， 2H)，2.88-2.82(m，1H)，1.17(t，J＝7.2Hz， 3H)，0.69(q，J＝7.2Hz，2H)，0.56(q， J＝7.8Hz，2H).
434	170-175	368.4		*
						435	112-117	382.5		*
436	196-202	280.5		*
						437	220-227	342.3 [M-H]		*
438	188-194	356.3 [M-H]		*
						439	181-186	358.4		**
440	177-181	370.3 [M-H]		**
						441		459.5		**
442		397.5		*
						443		411.5		*
444		439.5		*
						445		453.5		**
446		503.5		*
						447		426.5		***
448	301-303	436.5		*	1H NMR(300MHz，DMSO-d 6)：δ10.65 (1H，s)，7.94(1H，s)，7.76(1H，s)，7.48 (1H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5 Hz)，7.33(2H，d，J＝8.5Hz)，7.21(1H， d，J＝2.0Hz)，6.90(1H，dd，J＝8.5， 2.0Hz)，4.13(2H，q，J＝7.0Hz)，3.82 (3H，s)，3.66(3H，s)，1.15(3H，t，J＝ 7.0Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						449	242-243	518.5		*	1H NMR(300MHz，DMSO-d 6)：δ10.59 (1H，s)，8.49(1H，d，J＝2.3Hz)，7.81 (1H，dd，J＝9.1，2.3Hz)，7.52-7.44 (3H，m)，7.29(2H，d，J＝8.5Hz)，7.21 (1H，d，J＝2.3 Hz)，6.90(2H，d，J＝8.8 Hz)，4.12(2H，q，J＝7.0Hz)，3.82(3H， s)，3.63-3.55(8H，m)，1.12(3H，t，J＝ 7.0Hz).
450	217-220	402.5		**
						451	179-182	438.4		*	1H NMR(300MHz，DMSO-d 6)：δ10.87 (1H，s)，7.94(1H，dt，J＝5.0，1.0Hz)， 7.66(1H，dt，J＝3.5，1.2Hz)，7.55-7.48 (3H，m)，7.33(2H，d，J＝8.0Hz)，7.22 (1H，d，J＝1.8Hz)，7.14(1H，ddd，J＝ 5.0，3.8，1.0Hz)，6.90(1H，dt，J＝8.8， 1.0Hz)，4.13(2H，q，J＝7.3Hz)，3.83 (3H，s)，1.13(3H，t，J＝7.3Hz).
452	299-301	483.4		*	1H NMR(300MHz，DMSO-d 6)：δ10.62 (1H，s)，9.12(1H，dd，J＝4.1，1.7Hz)， 8.53-8.45(2H，m)，8.29(1H，d，J＝8.5 Hz)，7.78-7.68(2H，m)，7.44(1H，d，J＝ 8.8Hz)，7.36(2H，d，J＝8.8Hz)，7.27 (2H，d，J＝8.8Hz)，7.16(1H，d，J＝20 Hz)，6.87(1H，dd，J＝8.8，2.0Hz)， 4.04(2H，q，J＝7.0Hz)，3.80(3H，s)， 1.06(3H，t，J＝7.0Hz).
						453	198-200	416.5		**
454	180-182	412.4		*	1H NMR(300MHz，CDCl 3)：δ7.44-7.11 (4.8H，m)，6.97(1.2H，d，J＝8.4Hz)， 6.78-6.69(2H，m)，4.00-3.90(2H，m)， 3.713(1.2H，s)，3.707(1.8H，s)，2.93 (1H，v br)，2.12(1.8H，s)，2.09(1.2H， s)，1.17(1.2H，t，J＝7.3Hz)，1.14 (1.8H，t，J＝7.3Hz).
						455	221-223	414.4		*
456	157-159	357.5		**
						457	156-158	464.5		**
458	272-273	496.5		*	1H NMR(300MHz，DMSO-d 6)：δ10.10 (1H，s)，8.62(1H，d，J＝8.2Hz)，8.49- 8.45(2H，m)，8.27(2H，d，J＝8.8Hz)， 7.90(2H，d，J＝3.8Hz)，7.72(2H，d，J ＝8.8Hz)，7.70-7.62(1H，m)，7.55-7.49 (4H，m)，7.26(1H，d，J＝2.0Hz)，6.94 (1H，dd，J＝8.8，2.0Hz)，4.27(2H，q，J ＝7.0Hz)，3.85(3H，s)，1.24(3H，t，J＝ 7.0Hz).
						459	158-163	368.5		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						460	oil	368.3 [M-H]		**
461	200-205	432.3		***
						462	135-140	444.2 [M-H]		***
463	178-179	359.5		*
						464	164-166	401.5		*
465	99-100	401.5		*
						466	164-166	385.5		**
467	169-170	399.5		**
						468	201-202	398.5	**	***
469	243-245	384.5		**
						470	178-180	426.5		***
471	154-156	412.2		***
						472	215-217	410.5		***
473	189-191	424.5		***
						474	218-222	293.5		*
475	178-181	293.5		***
						476	175-178	340.4		**
477	194-195	418.4		***
						478	172-175	469.5		***
479	190-192	467.5		*
						480	207-208	485.4		***
481	209-211	482.5		*
						482	128-130	471.5		**
483	149-150	292.2		*	1H NMR(300MHz，CDCl 3)：δ7.32-7.25 (2H，m)，7.19(1H，d，J＝2.4Hz)，6.97 (1H，dd，J＝8.9，2.4Hz)，6.92-6.80 (3H，m)，4.17(2H，q，J＝7.3Hz)，3.89 (3H，s)，3.80(2H，v br)，1.34(3H，t，J＝ 7.3Hz).
						484	156-157	334.2		*	1H NMR(300MHz，CDCl 3)：δ8.16(1H， d，J＝8.5Hz)，8.00(1H，d，J＝8.7Hz)， 7.68(1H，d，J＝8.8Hz)，7.60-7.50(2H， m)，7.25(1H，obscurred)，7.10(1H，d， J＝8.8Hz)，5.20(2H，q，J＝7.3Hz)， 4.02(3H，s)，1.55(3H，t，J＝7.3Hz).
485	128-133	440.2		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						486	116-123	454.2		**
487	175-179	446.2		**
						488	158-164	460.2		***
489		418.5		**
						490		404.5		**
491		445.2		*
						492		463.2		**
493		477.2		***
						494		336.2		*
495	126-128	444.3		**
						496	236-239			**
497	235-239			*
						498	192-194	427.5		**
499	235-250			***
						500		468.2		*
501		420.2		*
						502		406.2		*
503		406.2		*
						504		412.2		*
505	164-166	384.2		*	1H NMR(300MHz，CDCl 3)：δ7.52(1H， t，J＝7.9Hz)，7.47(1H，t，J＝1.9Hz)， 7.36-7.30(3H，m)，7.18(1H，d，J＝2.3 Hz)，7.00(1H，dd，J＝8.9，2.3Hz)， 6.91(1H，br s)，4.18(2H，q，J＝7.3 Hz)，3.90(3H，s)，3.25(2H，q，J＝7.3 Hz)，1.43(3H，t，J＝7.3Hz)，1.38(3H， t，J＝7.3Hz)
						506	156-157	364.2		*	1H NMR(300MHz，CDCl 3)：δ7.67(1H， s)，7.48-7.44(2H，m)，7.33(1H，d，J＝ 9.0Hz)，7.26-7.23(1H，m)，7.19(1H，d， J＝2.3Hz)，6.98(1H，dd，J＝9.0，2.3 Hz)，6.79(1H，s)，4.24(2H，q，J＝7.3 Hz)，4.19(2H，q，J＝7.3Hz)，1.36(3H， t，J＝7.3Hz)，1.32(3H，t，J＝7.3Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						507	152-153	378.2		*	1H NMR(300MHz，CDCl 3)：δ7.66(1H， s)，7.46(2H，d，J＝5.0Hz)，7.33(1H， d，J＝9.0Hz)，7.26-7.21(1H，m)，7.19 (1H，d，J＝2.3Hz)，6.98(1H，dd，J＝ 9.0，2.3Hz)，6.72(1H，s)，5.03(1H，hp， H＝6.1Hz)，4.19(2H，q，J＝7.3Hz)， 3.89(3H，s)，1.36(3H，t，J＝7.3Hz)， 1.30(6H，d，J＝6.1Hz).
508	glass	378.2		*	1H NMR(300MHz，CDCl 3)：δ7.67(1H， s)，7.48-7.45(2H，m)，7.33(1H，d，J＝ 9.0Hz)，7.27-7.23(1H，m)，7.19(1H，d， J＝2.3Hz)，6.98(1H，dd，J＝9.0，2.3 Hz)，6.77(1H，s)，4.19(2H，q，J＝7.0 Hz)，4.14(2H，t，J＝6.7Hz)，3.89(3H， s)，1.72(2H，m，J＝7.0Hz)，1.37(3H， t，J＝7.0Hz)，0.99(3H，t，J＝6.5Hz).
						509	92-95	412.1		*	1H NMR(300MHz，CDCl 3)：δ7.67(1H， s)，7.48-7.45(2H，m)，7.33(1H，d，J＝ 8.8Hz)，7.27-7.24(1H，m)，7.19(1H，d， J＝2.3Hz)，6.99(1H，dd，J＝8.8，2.3 Hz)，6.83(1H，s)，4.35(2H，t，J＝6.0 Hz)，4.19(2H，q，J＝7.3Hz)，3.89(3H， s)，3.66(2H，t，J＝6.5Hz)，2.16(2H，p， J＝6.1Hz)，1.37(3H，t，J＝7.3Hz).
510	210-211	368.3		**	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ9.64(1H，s)，7.28-7.17(3H，m)， 7.14(1H，d，J＝9.0Hz)，7.04(1H，d，J ＝7.3Hz)，6.91(1H，d，J＝2.0Hz)， 6.75(1H，dd，J＝9.0，2.0Hz)，3.95 (2H，q，J＝7.3Hz)，3.66(3H，s)，2.81 (3H，s)，1.15(3H，t，J＝7.3Hz).
						511	146-148	377.3		*	1H NMR(300MHz，CDCl 3)：δ7.34-7.27 (2H，m)，7.19(1H，d，J＝2.3Hz)，6.97 (1H，dd，J＝8.8，2.3Hz)，6.88-6.79 (3H，m)，4.17(2H，q，J＝7.0Hz)，3.89 (3H，s)，3.87(2H，vbr)，1.34(3H，t，J＝ 7.0Hz).
512	67-69	407.2		*	1H NMR(300MHz，CDCl 3)：δ10.06 (1H，s)，7.86(1H，s)，7.56-7.47(2H， m)，7.36-7.30(3H，m)，7.19(1H，d，J＝ 2.0Hz)，7.00-6.96(1H，m)，4.62(1H， br)，4.27(2H，q，J＝7.0Hz)，4.18(2H， q，J＝7.0Hz)，3.89(3H，s)，1.37(3H，t， J＝7.0Hz)，1.33(3H，t，J＝7.0Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						513	210-211	479.2		*	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ8.44(2H，d，J＝7.0Hz)，7.61 (1H，s)，7.45(1H，s)，7.36-7.13(3H， m)，7.10(2H，d，J＝8.8Hz)，6.93(1H， d，J＝7.6Hz)，6.89(1H，d，J＝7.9Hz)， 6.85(1H，d，J＝2.3Hz)，6.69(1H，dd， J＝8.8，2.3Hz)，3.94(2H，q，J＝7.0 Hz)，3.60(3H，s)，1.08(3H，t，J＝7.0 Hz). 19F NMR(300MHz，9∶1 CDCl 3- DMSO-d 6)：δ-63.02(3F，s).
514	248-250	268.2		*
						515	137-139	381.1		**
516	155-156	395.3		**	. 1H NMR(300MHz，CDCl 3)：δ7.57(1H， d，J＝8.5Hz)，7.45(2H，d，J＝8.2Hz)， 7.31(2H，d，J＝8.2Hz)，7.25(1H，s)，6.95 (1H，dd，J＝9.1，1.7Hz)，6.67(1H，s)，6.54 (1H，t，J＝74.8Hz)，6.48(1H，s)，4.15(2H， q)，3.23(2H，q)，1.45(3H，t，J＝7.5Hz)， 1.32(3H，t，J＝7.2Hz).
						517	160-161	409.1		*
518	197-199	392.1		**
						519	174-175	406.1		***
520	175-177	420.0		***	1H NMR(300MHz，CDCl 3)：δ7.73(1H，d， J＝8.4Hz)，7.52(2H，d，J＝8.2Hz)，7.39 (2H，d，J＝8.2Hz)，7.25(1H，s)，7.13(1H， dd，J＝7.5，2.4Hz)，6.96(1H，s)，6.56(1H， t，J＝74.1Hz)，4.16(2H，q)，3.26(2H，q)， 1.46(3H，t，J＝7.5Hz)，1.32(3H，t，J＝6.9 Hz).
						521	184-186	[NH-] 418.1		***
522	187-188	[NH-] 432.1		***
						523	190-192	[NH-] 418.1		***
524	186-188	434.2		***
						525		458.2		**
526		490.3		***
						527		493.3		**
528		475.3		**
						529		459.2		**
530		461.3		***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						531		479.5		**
532		458.2		**
						533		490.3		**
534		493.3		***
						535		475.3		***
536		459.2		**
						537		461.3		***
538		459.2		**
						539		477.3		***
540	182-183	385.2		**
						541	149-151	399.2		*
542	186-188	413.2		**
						543	197-200	324.2		**
544	263-265	392.2	***	***
						545	203-205	382.2		**
546	208-210	396.2		***
						547	180-182	410.2		***
548	171-174	402.1		**
						549	150-153	416.1		***
550	183-185	430.0		**
						551	187-190	462.3		**
552	185-188	428.1		***
						553		412.2		*
554		388.2		*
						555		408.2		*
556		440.2		*
						557		454.3 [M-H]		**
558	87-90	406.2		**
						559	92-94	386.2		*
560	207-210	434.2		*
						561	182-185	398.2		*
562	oil	420.1		***
						563	210-212	436.1		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						564	210-211	377.1		**	1H NMR(DMSO，300MHz)，δ8.61(t， J＝2.4Hz，1H)，8.35(br，2H)，8.04(d， J＝8.4Hz，2H)，7.73(d，J＝8.4Hz，2H)，7.52 (d，J＝8.7Hz，2H)，7.26(d，J＝2.4Hz，1H)， 6.94(dd，J＝8.7Hz and 2.1Hz，1H)，4.20(q， J＝7.5Hz，2H)，3.83(s，3H)，3.55(q， J＝6.0Hz，2H)，3.09(br，2H)，2.60-2.53(m， 3H)，1.15(t，J＝7.2Hz，3H).
565	228-229	304 2		*	1H NMR(DMSO，300MHz)，δ10.23(s， 1H)，7.79(d，J＝8.4Hz，2H)，7.69(d， J＝7.2Hz，1H)，7.62(d，J＝7.8Hz，1H)，7.54 (d，J＝7.8Hz，2H)，7.38-7.22(m，2H)，4.20 (q，J＝7.2Hz，2H)，2.07(s，3H)，1.19(t， J＝7.2Hz，3H).
						566		334.1		*	1H NMR(CDCl3，300MHz)，δ8.42(s， 1H)，7.80-7.76(m，3H)，7.54(d，J＝8.4Hz， 2H)，7.44(d，J＝7.8Hz，1H)，7.36-7.26(m， 2H)，4.20(q，J＝7.2Hz，2H)，4.07(s，2H)， 3.55(s，3H)，1.36(t，J＝7.2Hz，3H).
567	238.2- 238.6	344.2		**	1H NMR(CDCl3，300MHz)，δ7.78- 7.73(m，2H)，7.60(d，J＝5.7Hz，2H)，7.51 (d，J＝5.7Hz，1H)，7.38-7.28(m，2H)，4.20 (q，J＝6.8Hz，2H)，3.26(br，1H)，2.43(br， 2H)，2.27(br，2H)，2.06-1.90(m，2H)，1.36 (t，J＝6.9Hz，3H).
						568	195-200	320.0		*	1H NMR(CDCl3，400MHz)，δ7.99(d， J＝8.4Hz，2H)，7.66(d，J＝7.6Hz，2H)，7.35 (d，J＝9.2Hz，1H)，7.20(s，1H)，7.01(d， J＝9.0Hz，1H)，6.1 5(br，1H)，5.65(br，1H)， 4.17(q，J＝6.8Hz，2H)，3.90(s，3H)，1.36(t， J＝7.6Hz，3H).
569		348.1		**	1H NMR(CDCl3，400MHz)，δ7.93(d， J＝8.4Hz，2H)，7.62(d，J＝8.0Hz，2H)，7.34 (d，J＝8.8Hz，1H)，7.19(d，J＝2.0Hz，1H)， 7.01(dd，J＝8.8Hz and J＝2.4Hz，1H)，6.19 (br，1H)，4.16(q，J＝7.2Hz，2H)，3.90(s， 3H)，3.56-3.52(m，2H)，1.38-1.23(m，6H).
						570	220-222	362.1		**	1H NMR(CDCl3，300MHz)，δ7.92(d， J＝8.1Hz，2H)，7.62(d，J＝8.1Hz，2H)，7.34 (d，J＝9.0Hz，1H)，7.19(d，J＝2.1Hz，1H)， 7.00(dd，J＝9.0Hz and 2.4Hz，1H)，6.02(d， J＝7.8Hz，1H)，4.35(m，1H)，4.16(q， J＝7.2Hz，2H)，3.90(s，3H)，1.26-1.26(m， 9H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						571		360.0		**	1H NMR(CDCl3，400MHz)，δ7.91(d， J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，2H)，7.34 (d，J＝8.8Hz，1H)，7.19(d，J＝2.0Hz，1H)， 7.01(dd，J＝9.2Hz and 2.4Hz，1H)，6.34(s， 1H)，4.15(q，J＝7.2Hz，2H)，3.90(s，3H)， 2.97-2.93(m，1H)，1.34(t，J＝7.2Hz，3H)， 0.66(q，J＝7.2Hz，2H)，0.07(t，J＝2.1Hz， 2H).
572	168-171	378.0		**	1H NMR(CDCl3，300MHz)，δ7.96(d， J＝8.4Hz，2H)，7.63(d，J＝8.4Hz，2H)，7.34 (d，J＝8.7Hz，1H)，7.19(d，J＝2.1Hz，1H)， 7.02 (dd，J＝8.4Hz and 2.4Hz，1H)，6.60 (br，1H)，4.16(q，J＝6.6Hz，2H)，3.90(s， 3H)，3.68(q，J＝4.5Hz，2H)，3.59(t， J＝4.8Hz，2H)，3.41(s，3H)，1.35(t， J＝6.9Hz，3H).
						573		417.2		*	1H NMR(CDCl3，400MHz)，δ7.59(s， 4H)，7.34(d，J＝8.8Hz，1H)，7.20(s，1H)， 7.01(d，J＝8.4Hz，1H)，4.1 5(q，J＝6.4Hz， 2H)，3.90(s，3H)，3.90-3.79(m，2H)，3.60 (br，1H)，3.54(q，J＝5.6Hz，1H)，2.78(br， 1H)，2.69-2.67(m，1H)，2.61(br，2H)，2.41 (d，J＝18.4Hz，3H)，2.04(br，1H)，1.92(br， 1H)，1.34(t，J＝6.8Hz，3H).
574	155-161	427.4		*
						575	144-146	345.2		**
576	141-142	425.4		*
						577	171-173	345.4		**
578	171-173	317.4		**
						579	178-179	368.5 [M-H]		**
580	198-200	370.4		***
						581		378.5		**
582		392.5		**
						583		410.4		**
584		426.4		*
						585		406.5		**
586		440.4		**
						587		406.5		**
588		402.5		*
						589		422.5		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						590		446 5		**
591		420.5		*
						592		416.4		*
593		454.5		*
						594		412.4		*
595		420.5		*
						596		404.4		**
597		418.5		*
						598	169-170	382.5		*	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.8Hz)，7.53(1H，t，J＝7.9Hz)， 7.46(1H，t，J＝1.9Hz)，7.34-7.29(2H， m)，6.97(1H，dd，J＝8.8，2.3Hz)，6.95 (1H，s)，6.86(1H，d，J＝2.3Hz)，4.08 (2H，t，J＝7.6Hz)，3.91(3H，s)，3.13 (3H，s)，1.75(2H，hx，J＝6.6Hz)，0.80 (3H，t，J＝7.3Hz).
599	163-164	398.4		*	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.8Hz)，7.51(1H，dd，J＝8.5， 7.3Hz)，7.44(1H，t，J＝1.8Hz)，7.30 (2H，dd，J＝7.9，2.0Hz)，6.97(1H，dd， J＝8.8，2.3Hz)，6.86(1H，d，J＝2.3 Hz)，6.85(1H，s)，4.08(2H，t，J＝7.6 Hz)，3.91(3H，s)，3.25(2H，q，J＝7.3 Hz)，1.75(2H，hx，J＝7.6Hz)，1.42 (3H，t，J＝7.5Hz)，0.80(3H，t，J＝7.4 Hz).
						600	144-145	391.5		*	1H NMR(300MHz，CDCl 3)：δ7.60(1H， d，J＝8.8Hz)，7.57-7.54(1H，m)，7.35- 7.31(2H，m)，7.13-7.09(1H，m)，6.94 (1H，dd，J＝8.8，2.0Hz)，6.84(1H，d，J ＝2.0Hz)，4.07(2H，t，J＝7.4Hz)，3.89 (3H，s)，3.21(2H，t，J＝7.0Hz)，1.68 (2H，hx，J＝7.3Hz)，1.53(2H，hx，J＝ 7.3Hz)，0.91(3H，t，J＝7.3Hz)，0.73 (3H，t，J＝7.4Hz).
601	195-200	400.4 [M-H]		***
						602	179-184	398.4 [M-H]		***
603		422.4		*
						604		410.3		*
605	175-180	419.4		*
						606	166-170	433.4		***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						607	189-194	449.5		***
608	223-228	452.9		**
						609	230-234	439.4		**
610	226-231	424.8		**
						611	126-128	396.4		**
612	198-200	410.4		**
						613	116-117	[NH-] 430.4		***
614	176-177	[NH-] 444.4		***
						615	220-225	440.3 [M-H]		*
616	143-149	414.4 [M-H]		***
						617	164-167	433.8 [M-H]		***
618	205-211	368.4		***
						619	201-206	382.3		**
620	215-223	367.4		**
						621	187-188	412.4		**	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.8Hz)，7.50(2H，d，J＝8.5Hz)， 7.36(2H，d，J＝8.5Hz)，6.97(1H，dd， J＝8.8，2.3Hz)，6.86(1H，d，J＝2.3 Hz)，6.79(1H，s)，4.05(2H，t，J＝7.6 Hz)，3.91(3H，s)，3.23-3.17(2H，m)， 1.93(2H，hx，J＝7.3Hz)，1.73(2H，hx， J＝7.6Hz)，1.09(3H，t，J＝7.4Hz)， 0.79(3H，t，J＝7.4Hz).
622	182-183	412.4		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.48(2H，d，J＝8.5Hz)， 7.38(2H，d，J＝8.5Hz)，6.96(1H，dd， J＝8.8，2.3Hz)，6.86(1H，d，J＝2.3 Hz)，6.83(1H，s)，4.05(2H，t，J＝7.6 Hz)，3.90(3H，s)，3.43(1H，hp，J＝6.6 Hz)，1.73(2H，hx，J＝7.6Hz)，1.46 (6H，d，J＝6.6Hz)，0.79(3H，t，J＝7.5 Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						623	217-218	460.4		**	1H NMR(300MHz，CDCl 3)：δ7.65(1H， d，J＝8.8Hz)，7.47(2H，d，J＝8.5Hz)， 7.40-7.28(5H，m)，7.25(2H，d，J＝8.5 Hz)，6.97(1H，dd，J＝8.8，2.3Hz)， 6.86(1H，d，J＝2.3Hz)，6.55(1H，s)， 4.45(2H，s)，4.05(2H，t，J＝7.6Hz)， 3.91(3H，s)，1.74(2H，hx，J＝7.3Hz)， 0.80(3H，t，J＝7.4Hz).
624	187-188	378.5		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.5Hz)，7.57(2H，d，J＝8.8Hz)， 7.46(2H，d，J＝8.8Hz)，6.95(1H，dd， J＝8.8，2.3Hz)，6.85(1H，d，J＝2.3 Hz)，6.79(1H，s)，4.26(2H，q，J＝7.0 Hz)，4.05(2H，t，J＝7.5Hz)，3.90(3H， s)，1.72(2H，hx，J＝7.6Hz)，1.34(3H， t，J＝7.0Hz)，0.78(3H，t，J＝7.4Hz).
						625	152-153	392.4		***	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.5Hz)，7.57(2H，d，J＝8.5Hz)， 7.46(2H，d，J＝8.5Hz)，6.95(1H，dd， J＝8.5，2.3Hz)，6.85(1H，d，J＝2.3 Hz)，6.77(1H，s)，4.17(2H，t，J＝6.7 Hz)，4.05(2H，t，J＝7.4Hz)，3.90(3H， s)，1.73(2H，hx，J＝7.3Hz)，1.00(3H， t，J＝7.4Hz)，0.78(3H，t，J＝7.4Hz).
626	193-194	377.5		**	1H NMR(300 MHz，CDCl 3)：δ7.61(1H， d，J＝8.5Hz)，7.52(2H，d，J＝8.8Hz)， 7.41(2H，d，J＝8.8Hz)，7.30(1H，br)， 6.96(1H，dd，J＝8.8，2.0Hz)，6.86 (1H，d，J＝2.0Hz)，4.05(2H，t，J＝7.6 Hz)，3.90(3H，s)，3.32(2H，q，J＝7.3 Hz)，1.71(2H，hx，J＝7.3 Hz)，1.19 (3H，t，J＝7.3Hz)，0.77(3H，t，J＝7.3 Hz).
						627	188-189	391.5		***	1H NMR(300MHz，CDCl 3)：δ7.61(1H， d，J＝8.5Hz)，7.52(2H，d，J＝8.8Hz)， 7.41(2H，d，J＝8.8Hz)，7.34(1H，br)， 6.96(1H，dd，J＝8.5，2.0Hz)，6.86 (1H，d，J＝2.0Hz)，4.05(2H，t，J＝7.4 Hz)，3.90(3H，s)，3.24(2H，t，J＝7.0 Hz)，1.72(2H，hx，J＝7.6Hz)，1.57 (2H，hx，J＝7.0Hz)，0.95(3H，t，J＝ 7.3Hz)，0.77(3H，t，J＝7.3Hz).
628	221-226	381.4		**
						629	204-210	436.3		*
630	205-210	416.3		**
						631	177-182	428.5 [M-H]		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						632	176-178	366.4 [M-H]		**
633	159-161	380.5 [M-H]		**
						634	163-165	396.3		**
635	200-201	392.5 [M-H]		***
						636	97-98	428.4 [M-H]		**
637		398.4		***
						638		390.5		*
639	159-160	412.5		*	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.50(1H，t，J＝7.9Hz)， 7.44(1H，t，J＝1.8Hz)，7.33-7.28(2H， m)，7.18(1H，s)，6.96(1H，dd，J＝8.8， 2.3Hz)，6.86(1H，d，J＝2.3Hz)，4.08 (2H，t，J＝7.6Hz)，3.90(3H，s)，3.22- 3.16(2H，m)，1.90(2H，hx，J＝7.8Hz)， 1.74(2H，hx，J＝7.6Hz)，1.05(3H，t，J ＝7.4Hz)，0.79(3H，t，J＝7.5Hz).
						640	197-198	396.5		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.58(2H，d，J＝8.8Hz)， 7.48(2H，d，J＝8.8Hz)，6.95(1H，dd， J＝8.8，2.0Hz)，6.92(1H，s)，6.85(1H， d，J＝2.0Hz)，4.62(2H，dt，J＝74.3， 4.2Hz)，4.50(2H，dt，J＝55.8，4.2Hz)， 4.05(2H，t，J＝7.6Hz)，3.90(3H，s)， 1.72(2H，hx，J＝7.6Hz)，0.78(3H，t，J ＝7.4Hz). 19F NMR(300MHz， CDCl 3)：δ5.11(1F，m).
641	177-178	392.5		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.57(2H，d，J＝8.5Hz)， 7.46(2H，d，J＝8.5Hz)，6.95(1H，dd， J＝8.5，2.0Hz)，6.85(1H，d，J＝2.0 Hz)，6.72(1H，s)，5.05(1H，hp，J＝7.1 Hz)，4.05(2H，t，J＝7.6Hz)，3.90(3H， s)，1.72(2H，hx，J＝7.6Hz)，1.33(6H， d，J＝7.1Hz)，0.78(3H，t，J＝7.4Hz).
						642	152-153	426.5		**	1H NMR(300MHz，CDCl 3)：δ7.66-7.57 (3H，m)，7.53(2H，d，J＝8.8Hz)，6.97 (1H，dd，J＝8.8，2.0Hz)，6.86(1H，d，J ＝2.0Hz)，4.07(2H，t，J＝7.4Hz)，3.91 (3H，s)，3.46(3H，s)，3.40(1H，hp，J＝ 7.0Hz)，1.74(2H，hx，J＝7.3Hz)，1.40 (6H，d，J＝7.0Hz)，0.79(3H，t，J＝7.4 Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						643	150-151	412.4		**	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.8Hz)，7.58(2H，d，J＝9.0Hz)， 7.53(2H，d，J＝9.0Hz)，6.97(1H，dd， J＝8.8，2.0Hz)，6.86(1H，d，J＝2.0 Hz)，4.07(2H，t，J＝7.6Hz)，3.91(3H， s)，3.44(3H，s)，3.12(2H，q，J＝7.6 Hz)，1.75(2H，hx，J＝7.6Hz)，1.41 (3H，t，J＝7.3Hz)，0.79(3H，t，J＝7.5 Hz).
644		348.2		*	(DMSO，300MHz)，δ10.12(s，1H)，7.77 (d，J＝8.4Hz，2H)，7.58(d，J＝8.7Hz，1H)， 7.49(d，J＝8.7Hz，2H)，7.03(s，1H)，6.92 (d，J＝8.4Hz，1H)，4.13(q，J＝6.9Hz，2H)， 3.77(s，3H)，2.31(q，J＝7.5Hz，2H)，1.16(t， J＝8.7Hz，3H)，1.06(t，J＝7.5Hz，3H).
						645	242-244	410.2		*	(DMSO，300MHz)，δ10.33(s，1H)，7.99 (d，J＝8.4Hz，2H)，7.72(d，J＝7.8Hz，1H)， 7.64-7.56(m，4H)，7.51(d，J＝1.8Hz，1H)， 7.36-7.07(m，2H)，7.06(d，J＝8.1Hz，1H)， 6.12(s，2H)，4.22(q，J＝7.2Hz，2H)，1.21(t， J＝7.2Hz，3H).
646		356.2		**	(DMSO，300MHz)，δ10.47(s，1H)，8.01- 7.96(m，3H)，7.72(d，J＝8.4Hz，1H)，7.65- 7.59(m，3H)，7.38-7.29(m，3H)，6.71(dd， J＝3.9Hz and J＝1.8Hz，1H)，4.22(q， J＝6.9Hz，2H)，1.21(t，J＝7.2Hz，3H).
						647		430.1		*	(DMSO，300MHz)，δ10.56(s，1H)，8.12 (d，J＝8.4Hz，2H)，7.84-7.76(m，4H)，7.67 (d，J＝9.0Hz，1H)，7.41(d，J＝9.0Hz，2H)， 7.11(d，J＝8.7Hz，1H)，6.98(dd，J＝8.7Hz and 2.1Hz，1H)，4.22(q，J＝7.2Hz，2H)， 3.82(s，3H)，1.18(t，J＝7.2Hz，3H).
648		464.0		**	(DMSO，300MHz)，δ10.69(s，1H)， 8.18-8.09(m，3H)，7.82-7.72(m，3H)， 7.70-7.56(m，2H)，7.11(d，J＝2.1Hz，1H)， 6.96(dd，J＝8.1Hz and 2.4Hz，1H)，4.22(q， J＝7.2Hz，2H)，3.82(s，3H)，1.19(t， J＝7.2Hz，3H).
						649	210-212	410.5		**	1H NMR(300MHz，DMSO-d 6)：δ7.60 (2H，d，J＝8.8Hz)，7.50(1H，d，J＝8.8 Hz)，7.36(2H，d，J＝8.8Hz)，7.25(1H， d，J＝2.1Hz)，6.91(1H，dd，J＝8.8， 2.1Hz)，4.15(2H，t，J＝7.3Hz)，3.833 (2H，t，J＝6.4Hz)，3.831(3H，s)，3.57 (2H，t，J＝7.3Hz)，2.45-2.40(2H，m)， 1.54(2H，hx，J＝7.3Hz)，0.62(3H，t，J ＝7.3Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						650	165-166	384.5		**	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.8Hz)，7.54(4H，s)，6.96(1H， dd，J＝8.8，2.0Hz)，6.87(1H，d，J＝ 2.0Hz)，4.84(1H，brt，J＝6.1Hz)， 4.41(2H，d，J＝6.1Hz)，4.13(2H，q，J ＝7.3Hz)，3.90(3H，s)，2.97(3H，s)， 1.33(3H，t，J＝7.3Hz).
651	146-147	384.5		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.56-7.45(4H，m)，6.96 (1H，dd，J＝8.8，2.0Hz)，6.87(1H，d，J ＝2.0Hz)，4.89(1H，brt，J＝5.9Hz)， 4.42(2H，d，J＝5.9Hz)，4.13(2H，t，J ＝7.0Hz)，3.91(3H，s)，2.94(3H，s)， 1.34(3H，t，J＝7.0Hz).
						652	191-194	418.5		***
653	foam	469.5		*
						654	197-201	485.5		*
655	184-187	424.2		*
						656	159-161	346.2		*
657	196-198	388.2		*
						658	203-205	400.5		*
659	175-177	458.4		**
						660	215-217	394.5		**
661	156-158	458.5		***
						662		398.4		***
663		308.3		*
						664		424.4		*
665		444.5		*
						666	207-209	424.4		***
667	242-244	424.4		***
						668	171-174	483.0		**
669	213-215	461.5		***	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ9.73(1H，s)，8.76(1H，s)，8.54 (1H，d，J＝5.2Hz)，8.11(1H，d，J＝7.9 Hz)，7.58(1H，dd，J＝7.9，5.2Hz)， 7.45(1H，d，J＝9.3Hz)，7.28(4H，s)， 6.88-6.82(2H，m)，5.15(2H，s)，3.97 (2H，q，J＝7.2Hz)，2.99(2H，q，J＝7.3 Hz)，1.21(3H，t，J＝7.3Hz)，1.15(3H， t，J＝7.2Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						670	231-233	473.4		***	1H NMR(300 MHz，9∶1 CDCl 3-DMSO- d 6)：δ9.59(1H，s)，8.87(1H，s)，8.60 (1H，d，J＝5.2Hz)，8.35(1H，d，J＝7.6 Hz)，7.80(1H，dd，J＝7.6，5.2Hz)， 7.45(1H，d，J＝8.5Hz)，7.32-7.23(4H， m)，6.88(1H，d，J＝2.0Hz)，6.83(1H， dd，J＝8.5，2.0Hz)，5.21(2H，s)，3.97 (2H，q，J＝7.3Hz)，2.44-2.35(1H，m)， 1.14(3H，t，J＝7.3Hz)，1.07-0.99(2H， m)，0.84-0.78(2H，m).
671	221-222	461.4		***	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ9.72(1H，s)，8.56(1H，d，J＝5.0 Hz)，8.13(1H，brt，J＝7Hz)，7.87(1H， d，J＝7.6Hz)，7.53-7.50(1H，m)，7.41 (1H，d，J＝8.5Hz)，7.25(4H，s)，7.01 (1H，d，J＝2.0Hz)，6.86(1H，dd，J＝ 8.5，2.0Hz)，5.50(2H，s)，3.98(2H，q， J＝7.3Hz)，2.97(2H，q，J＝7.3Hz)， 1.19(3H，t，J＝7.3Hz)，1.11(3H，t，J＝ 7.3Hz).
						672	165-166	415.5		***	1H NMR(300MHz，CDCl 3)：δ7.65(1H， d，J＝8.8Hz)，7.55(4H，s)，6.97(1H， dd，J＝8.8，2.3Hz)，6.88(1H，d，J＝ 2.3Hz)，4.41(2H，s)，4.14(2H，q，J＝ 7.3Hz)，3.91(3H，s)，2.91(3H，s)，2.86 (3H，s)，1.35(3H，t，J＝7.3Hz).
673	131-132	398.4		*	1H NMR(300MHz，CDCl 3)：δ7.65(1H， d，J＝8.8Hz)，7.57-7.48(4H，m)，6.97 (1H，dd，J＝8.8，2.0Hz)，6.88(1H，d，J ＝2.0Hz)，4.42(2H，s)，4.15(2H，q，J＝ 7.3Hz)，3.91(3H，s)，2.89(3H，s)，2.87 (3H，s)，1.37(3H，t，J＝7.3Hz).
						674	159-160	414.4		*	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ 9.67(1H，s)，7.36(1H，d，J＝8.8 Hz)，7.31(2H，d，J＝8.8Hz)，7.23(2H， d，J＝8.8Hz)，6.76(1H，d，J＝2.0Hz)， 6.72(1H，dd，J＝8.8，2.0Hz)，4.05 (2H，t，J＝5.6Hz)，3.68(3H，s)，3.44 (2H，t，J＝5.6Hz)，3.00(3H，s)，2.95 (2H，q，J＝7.3Hz)，1.17(3H，t，J＝7.3 Hz).
675		460.4		**	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ9.83(1H，s)，7.61-7.27(5H，m)， 6.82-6.78(2H，m)，4.10(2H，t，J＝5.6 Hz)，3.74(3H，s)，3.56-3.47(4H，m)， 3.16(2H，t，J＝7.3Hz)，3.06(3H，s)， 2.21-2.01(2H，m).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						676	174-175	394.4		**	1H NMR(300MHz，9∶1 CDCl 3-DMSO- d 6)：δ8.77(1H，s)，7.51(2H，d，J＝8.5 Hz)，7.41(1H，d，J＝8.5Hz)，7.31(2H， d，J＝8.5Hz)，6.80(1H，d，J＝2.0Hz)， 6.77(1H，dd，J＝8.5，2.0Hz)，4.12- 4.04(4H，m)，3.72(3H，s)，3.46(2H，t， J＝5.6Hz)，3.04(3H，s)，1.18(3H，t，J ＝7.2Hz).
677	133-134	408.4		**	1H NMR(300MHz，CDCl 3)：δ7.64-7.51 (5H，m)，6.98-6.94(2H，m)，6.78(1H， s)，4.25(2H，t，J＝5.7Hz)，4.17(2H，t， J＝6.7Hz)，3.90(3H，s)，3.63(2H，t，J ＝5.7Hz)，3.22(3H，s)，1.73(2H，hx，J ＝7.3Hz)，1.00(3H，t，J＝7.4Hz).
						678	184-188	318.3		*
679	212-220	389.5		**
						680	163-168	403.3		***
681	192-197	403.3		**
						682	194-195	460.4		**
683	157-159	494.2		**
						684	175-176	412.5		*
685	140-141	448.4		**
						686	173-174	424.5		**
687	124-125	420.4		***
						688	178-179	410.4		**
689	204-205	409.5		**
						690	192-193	423.9		**
691	203-205	383.8		**
						692	175-176	397.8		**
693	163-164	411.8		***
						694	135-136	383.8		**
695	159-160	397.8		**
						696	194-196	397.8		**
697	foam	467.0		***
						698	foam	499.5		**
699	255-258	427.8		***
						701	188-194	395.8		**
702	147-150	409.8		**

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						703	160-165	424.5		**
704	169-170	433.4		*
						705	199-201	397.4		*
706	151-153	396.4		***
						707	159-161	412.5		**
708	175-177	426.5		**
						709	166-168	424.4		***
710	oil	458.5		*
						711	oil	424.5		*
712	259-261	316.5		*
						713	199-202	474.5		**
714	52-53	281.4		**
						715	174-175	424.1		***
716	204-205	422.4		***	1H NMR(CDCl 3，300MHz)δ(ppm)0.04- 0.12(m，2H)，0.41-0.50(m，2H)，0.98-1.13 (m，1H)，2.54-2.67(m，2H)，3.45(t，2H)， 3.87(t，3H)，3.91(s，2H)，3.99(d，2H)， 6.93-6.99(m，2H)，7.36-7.43(m，2H)， 7.49-7.56(m，2H)，7.61-7.66(m，1H).
						717	205-207	424.5		**
718	195-196	450.2		**
						719	192-193	410.2		*
720	172-178	410.5		**
						721	158-160	404.6		**
722	160-162	432.6		**
						723	175-180	418.6		**
724	168-170	416.4		**
						725	215-216	397.5		**
726	221-222	411.4		**
						727	217-218	487.5		**
728	197-199	479.5		***
						729	213-217	493.6		*
730	210-214	495.2		***
						731	173-174	388.5		***
732	219-221	378.2		**
						733	146-148	354.5		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						734	167-169	412.5		**
735	123-125	426.5		***
						736	125-126	[NH-] 438.5		***
737	153-155	[NH-] 438.5		**
						738	149-151	[NH-] 442.4		***
739	oil	456.5		*
						740	203-205	424.9		**
741	194-196	438.9		***
						742	171-173	[NH-] 451.5		**
743	129-129	465.5		***
						744	92-93	412.5		***
745	oil	426.5		***
						746	oil	440.5		*
747	136-137	410.5		***
						748	186-188	391.6		***
749	176-178	405.6		***
						750	173-174	419.6		***
751	159-162	405.6		**
						752	198-202	396.5		**
753	157-161	409.9		***
						754	146-150	424.5		**
755		357.2		***	1H NMR(DMSO，300MHz)，δ11.02(s， 1H)，8.83(d，J＝1.8Hz，1H)，8.01(d， J＝8.4Hz，2H)，7.71(d，J＝7.2Hz，1H)，7.66- 7.63(m，3H)，7.39-7.26(m，3H)，4.22(q， J＝7.5Hz，2H)，1.20(t，J＝6.9Hz，3H).
						756		388.0		***	1H NMR(CDCl3，300MHz)，δ8.04(s， 1H)，7.83(d，J＝8.4Hz，2H)，7.77(d， J＝7.5Hz，1H)，7.60(d，J＝8.7Hz，2H)，7.46 (d，J＝7.2Hz，1H)，7.42-7.31(m，2H)，4.23 (t，J＝7.8Hz，2H)，3.01(s，3H)，1.38(t， J＝7.2，3H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						757	218-225	358.2		***	1H NMR(CDCl3，300MHz)，δ7.79-7.76 (m，3H)，7.58(d，J＝8.4Hz，2H)，7.46(d， J＝7.5Hz，2H)，7.39-7.32(m，2H)，4.23(q， J＝7.5Hz，2H)，2.71(s，3H)，2.54(s，3H)， 1.38(t，J＝7.2Hz，3H).
758	149-153	320 2		***
						759		376.2		***	1H NMR(DMSO，300MHz)δ10.14(s， 1H)，7.79(d，J＝8.4Hz，2H)，7.58-7.45(m， 3H)，7.22(d，J＝1.5Hz，1H)，6.88(dd， J＝8.7Hz and 1.8Hz，1H)，4.75-4.67(m， 1H)，4.15(q，J＝6.9Hz，2H)，2.34(q， J＝7.6Hz，2H)，1.27(d，J＝6.0Hz，6H)，1.16- 1.07(m，6H).
760		402.2		***	(DMSO，300MHz)δ9.99(s，1H)，7.80(d， J＝8.7Hz，2H)，7.5 1-7.45(m，3H)，7.22(s， 1H)，6.87(dd，J＝9.0Hz and 1.8Hz，1H)， 4.72-4.69(m，1H)，4.15(q，J＝6.6Hz，2H)， 2.23-1.80(m，7H)，1.26(d，J＝6.0Hz，6H)， 1.13(t，J＝7.2Hz，3H).
						761	169-173	392.1		***	(DMSO，300MHz)δ10.06(s，1H)，7.90 (d，J＝8.7Hz，2H)，7.54-7.46(m，3H)，7.22 (d，J＝1.5Hz，1H)，6.88(dd，J＝8.4Hz and 2.1Hz，1H)，4.75-4.66(m，1H)，4.15(q， J＝7.2Hz，2H)，4.03(s，2H)，3.37(s，3H)， 1.26(d，J＝6.0Hz，6H)，1.16(t，J＝7.2Hz， 3H).
762	190-193	452.3		***	(DMSO，300MHz)δ10.20(s，1H)，7.78 (d，J＝8.7Hz，2H)，7.52-7.45(m，3H)，7.30- 7.21(m，5H)，7.18-7.14(m，1H)，6.88(dd， J＝8.4Hz and 2.1Hz，1H)，4.73-4.69(m， 1H)，4.15(q，J＝6.6Hz，2H)，2.91(t，J- 7.5Hz，2H)，2.65(t，J＝7.6Hz，2H)，1.27(d， J＝6.0Hz，6H)，1.14(t，J＝7.2Hz，3H).
						763	209.2- 209.7	424.3		***	(DMSO，300MHz)δ10.54(s，1H)，8.93- 7.96(m，4H)，7.62-7.49(m，6H)，7.26(d， J＝1.8Hz，1H)，6.91(dd，J＝8.7Hz and 2.1Hz，1H)，4.76-4.72(m，1H)，4.21(q， J＝7.2Hz，2H)，1.30(d，J＝6.0Hz，6H)，1.18 (t，J＝6.9Hz，3H).
764	213.5- 231 7	442.2		***	(DMSO，300MHz)δ10.52(s，1H)，8.06- 7.96(m，4H)，7.58(d，J＝8.4Hz，2H)，7.49 (d，J＝8.4Hz，1H)，7.37(t，J＝8.7Hz，2H)， 7.24(s，1H)，6.89(dd，J＝9.0Hz and 1.5Hz， 1H)，4.72-4.66(m，1H)，4.18(q，J＝7.2Hz， 2H)，1.27(d，J＝6.0Hz，6H)，1.16(t， J＝6.9Hz，3H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						765	288.5- 288.9	438.2		**	(DMSO，300MHz)δ10.91(s，1H)，8.72 (s，1H)，8.20(d，J＝9.3Hz，1H)，8.03-7.98 (m，3H)，7.65-7.62(d，J＝9.0Hz，3H)，7.08 (d，J＝2.4Hz，1H)，6.96(dd，J＝8.7Hz and 2.4Hz，1H)，4.20(q，J＝6.8Hz，2H)，3.81(s， 3H)，1.19(t，J＝7.2Hz，3H).
766	192.8- 193.1	440.1		**	(MeOD，300MHz)δ7.98(d，J＝8.7Hz， 2H)，7.60(d，J＝8.1Hz，2H)，7.50(d， J＝9.3Hz，1H)，7.11(s，1H)，6.99(d， J＝6.6Hz，1H)，6.60(s，1H)，4.24(q， J＝7.4Hz，2H)，3.87(s，3H)，2.54(s，3H)， 1.30(t，J＝6.9Hz，3H).
						767	204-205	350.9		***
768	170-175	429.4 [M-H]		*
						769	118-123	473.5		*
770		361.5		*
						771		361.5		***
772	211-212	442.4		***	1H NMR(300MHz，CDCl 3)：δ7.62(1H， d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)， 7.13(2H，d，J＝8.5Hz)，6.95(1H，dd， J＝8.5，1.8Hz)，6.87(1H，d，J＝1.8 Hz)，5.67(1H，d，J＝8.8Hz)，4.28-4.08 (8H，m)，1.47(3H，t，J＝6.9Hz)，1.37 (6H，td，J＝7.0，0.6Hz)，1.34(3H，t，J ＝7.3Hz).
						773	191-193	434.9		**	1H NMR(300MHz，CDCl 3)：δ7.60(1H， d，J＝8.8Hz)，7.52(2H，d，J＝8.8Hz)， 7.43(2H，d，J＝8.8Hz)，6.94(1H，dd， J＝8.8，2.2 Hz)，6.86(1H，d，J＝2.2 Hz)，4.24(2H，q，J＝7.0Hz)，4.22-4.06 (6H，m)，1.47(3H，t，J＝7.0Hz)，1.34- 1.25(6H，m).
774	205-206	410.9		**	1H NMR(300MHz，CDCl 3)：δ7.63(1H， d，J＝8.8Hz)，7.53(2H，d，J＝9.0Hz)， 7.46(2H，d，J＝9.0Hz)，6.98(1H，br s)，6.96(1H，dd，J＝8.8，2.0Hz)，6.88 (1H，d，J＝2.0Hz)，4.17-4.09(4H，m)， 3.71-3.61(4H，m)，1.48(3H，t，J＝7.0 Hz)，1.34(3H，t，J＝7.1Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						775		482.1		**	1H NMR(300MHz，CDCl 3)：δ7.64(1H， d，J＝8.5Hz)，7.52(2H，d，J＝9.0Hz)， 7.40(2H，d，J＝9.0Hz)，6.97(1H，dd， J＝8.5，2.2Hz)，6.90(1H，d，J＝2.2 Hz)，4.48(2H，t，J＝4.7Hz)，4.26(2H， t，J＝4.7Hz)，4.05(2H，t，J＝7.6Hz)， 3.87(2H，t，J＝6.6Hz)，3.45(2H，t，J＝ 6.9Hz)，2.61(2H，p，J＝7.3Hz)，2.13 (3H，s)，1.72(2H，hx，J＝7.3Hz)，0.79 (3H，t，J＝7.4Hz).
776	257-258	389.5		***	1H NMR(300MHz，DMSO-d 6)：δ11.32 (1H，s)，7.82(2H，d，J＝8.8Hz)，7.61 (2H，d，J＝8.8Hz)，7.50(1H，d，J＝8.8 Hz)，7.24(1H，d，J＝1.8Hz)，6.91(1H， dd，J＝8.8，1.8Hz)，4.52(2H，s)，4.18 (2H，q，J＝7.0Hz)，4.11(2H，q，J＝7.0 Hz)，1.36(3H，t，J＝7.0Hz)，1.16(3H， t，J＝7.0Hz).
						777	124-127	511.6		***	1H NMR(300MHz，CDCl 3)：δ7.58(1H， d，J＝8.8Hz)，7.45(2H，d，J＝8.8Hz)， 7.39(2H，d，J＝8.8Hz)，7.33(1H，br s)，7.31-7.15(5H，m)，6.94(1H，dd，J＝ 8.8，2.2Hz)，6.86(1H，d，J＝2.2Hz)， 4.84(1H，t，J＝6.0Hz)，4.11(2H，q，J ＝7.0Hz)，4.08(2H，q，J＝7.3Hz)， 3.74(3H，s)，3.18(1H，dd，J＝14.0，5.6 Hz)，3.07(1H，dd，J＝14.0，6.4Hz)， 1.47(3H，t，J＝7.0Hz)，1.30(3H，t，J＝ 7.3Hz).
778	225-227	375.5		***	1H NMR(300MHz，CDCl 3)：δ7.73(2H， d，J＝8.8Hz)，7.62(1H，d，J＝8.8Hz)， 7.52(2H，d，J＝8.8Hz)，6.95(1H，dd， J＝8.8，2.0Hz)，6.88(1H，d，J＝2.0 Hz)，4.13(2H，q，J＝7.0Hz)，4.12(2H， q，J＝7.0Hz)，4.04-3.99(2H，m)，3.67- 3.62(2H，m)，1.47(3H，t，J＝7.0Hz)， 1.34(3H，t，J＝7.0Hz).
						779	265-267	389.5		***	1H NMR(300MHz，DMSO-d 6)：δ8.42 (1H，s)，7.72(2H，d，J＝8.8Hz)，7.61 (2H，d，J＝8.8Hz)，7.53(1H，d，J＝8.5 Hz)，7.26(1H，d，J＝2.0Hz)，6.93(1H， dd，J＝8.5，2.0Hz)，4.25-4.08(6H，m)， 1.36(3H，t，J＝7.0Hz)，1.19(3H，t，J＝ 7.0Hz).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						780	219-220	463.6		**	1H NMR(300MHz，CDCl 3)：δ7.65(1H， d，J＝8.8Hz)，7.58(2H，d，J＝8.8Hz)， 7.48(2H，d，J＝8.8Hz)，6.97(1H，dd， J＝8.8，2.0Hz)，6.88(1H，d，J＝2.0 Hz)，4.18-4.08(5H，m)，3.09(3H，s)， 3.00(3H，s)，2.94(3H，s)，1.53(3H，d)， 1.47(3H，t，J＝7.0Hz)，1.34(3H，t，J＝ 7.0Hz).
781	207-208	449.8		***	1H NMR(300MHz，CDCl 3)：δ7.64(2H， d，J＝8.8Hz)，7.60(4H，s)，6.97(1H， d，J＝8.8，2.0Hz)，6.88(1H，d，J＝2.0 Hz)，4.12(2H，q，J＝7.0Hz)，4.11(2H， q，J＝7.0Hz)，3.36(3H，s)，3.23(2H， s)，3.14(3H，s)，2.88(3H，s)，1.48(3H， t，J＝7.0Hz)，1.33(3H，t，J＝7.0Hz).
						782	188-190	396.5		**
783	201-202	410.5		*
						784	245-246	410.5		**
785	151-153	423.5		**	1H NMR(CDCl 3，300MHz)δ(ppm)1.38 (t，3H)，3.30-3.37(m，4H)，3.51-3.58(m， 4H)，4.06-4.18(q，2H)，7.45(d，1H)，7.54 (s，1H)，7.66(d，1H).
						786	202-203	437.5		*
787	261-263	412.2		*
						788	112-114	453.9		*
789	154-156	398.2		***
						790		398.2		***
791	149-152	396.5		***
						792	182-185	350.5		***
793	154-155	364.5		***
						794	149-151	378.5		***
795	183-185	378.5		***
						796	124-125	392.6		**
797	209-212	277.9		**
						798	193.4- 193.7	429.2		*	(CD 3CN，400MHz)δ9.19(s，1H)，7.95(d， J＝7.6Hz，2H)，7.61(d，J＝8.0Hz，2H)，7.56 (d，J＝8.8Hz，1H)，7.10(s，1H)，6.92(dd， J＝8.8Hz and 0.8Hz，1H)，6.56(s，1H)， 4.74-4.64(m，1H)，4.18(q，J＝7.2Hz，2H)， 2.51(s，3H)，1.27(d，J＝6.0Hz，6H)，1.27(t， J＝7.2Hz，3H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						799		362.2		***	1H NMR(DMSO，300MHz)，δ10.14(s， 1H)，7.79(d，J＝8.4Hz，2H)，7.52-7.50(m， 3H)，7.22(s，1H)，6.91(d，J＝8.7Hz，1H)， 4.17(q，J＝7.5Hz，2H)，3.82(s，3H)，2.24(t， J＝7.2Hz，2H)，1.60(q，J＝7.2Hz，2H)，1.23 (t，J＝7.2Hz，3H)，0.90(t，J＝7.2Hz，3H).
801	199-219	374.2		***	1H NMR(CDCl3，300Hz)，7.72(d， J＝8.4Hz，2H)，7.63 (d，J＝8.7Hz，1H)，7.50 (d，J＝8.7Hz，2H)，7.22(s，1H)，6.91(dd， J＝6.6Hz and 2.1Hz，1H)，6.87(d，J＝2.1Hz， 1H)，4.14(q，J＝7.2Hz，2H)，3.90(s，3H)， 3.24-3.18(m，1H)，2.46-2.25(m，4H)， 2.06-1.97(m，2H)，1.33(t，J＝8.1Hz，3H).
						802	196-198	410.2		**	1H NMR(DMSO，300Hz)，δ10.45(s， 1H)，7.80(d，J＝8.4Hz，2H)，7.54-7.48(m， 3H)，7.33-7.21(m，6H)，6.92(dd，J＝6.6Hz and 2.1Hz，1H)，，4.17(q，J＝6.6Hz，2H)， 3.82(s，3H)，3.67(s，2H)，1.15(t，J＝7.2Hz， 3H).
803	216-217	386.1		*	1H NMR(DMSO，300Hz)，δ10.90(s， 1H)，8.71(s，1H)，8.19(d，J＝9.3Hz，1H)， 8.02-7.98(m，3H)，7.63(d，J＝8.7Hz，2H)， 7.51(d，J＝8.7Hz，1H)，7.24(d，J＝2.1Hz， 1H)，6.92(dd，J＝6.6Hz and 2.1Hz，1H)， 4.20(q，J＝6.6Hz，2H)，3.83(s，3H)，1.16(t， J＝6.6Hz，3H).
						804	214-216	401.2		*	1H NMR(DMSO，300Hz)，δ10.92(s， 1H)，8.00(d，J＝8.7Hz，2H)，7.59(d， J＝8.7Hz，2H)，7.51(d，J＝8.7Hz，1H)，7.23 (d，J＝2.1Hz，1H)，6.92(dd，J＝6.6Hz and 2.1Hz，1H)，6.69(s，1H)，4.19(q，J＝6.6Hz， 2H)，3.83(s，3H)，2.49(s，3H)，1.17(t， J＝7.2Hz，3H).
805	217-222	452.5		*
						806	157-159	422.5		**
807	171-172	396.5		***
						808	195-197	410.5		**
809	167-168	410.5		**
						810	209-211	422.5		**
811	166-168	354.5		*
						812	206-208	460.4		**
813	176-177	458.4		***
						814	164-165	[NH-] 458.5		*

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						815	153-154	473.5		*	1H NMR(300MHz，CDCl 3)：δ7.65(1H ， d，J＝8.8Hz)，7.61(2H，d，J＝8.8Hz)， 7.56(2H，d，J＝8.8Hz)，6.98(1H，dd， J＝8.8，2.3Hz)，6.89(1H，d，J＝2.3 Hz)，4.24(2H，t，J＝5.4Hz)，4.17(2H， q，J＝7.3Hz)，4.02(2H，q，J＝5.4Hz)， 3.91(3H，s)，3.00(3H，s)，2.01(3H，s)， 1.38(3H，t，J＝7.3Hz).
816	186-187	445.5		**	1H NMR(300MHz，CDCl 3)：δ7.66(1H， d，J＝8.5Hz)，7.60(2H，d，J＝8.8Hz)， 7.55(2H，d，J＝8.8Hz)，6.98(1H，dd， J＝8.5，2.0Hz)，6.89(1H，d，J＝2.0 Hz)，4.16(2H，q，J＝7.3Hz)，3.93(2H， t，J＝6.0Hz)，3.91(3H，s)，3.53(2H，t， J＝6.0Hz)，3.38(3H，s)，3.07(3H，s)， 1.38(3H，t，J＝7.3Hz).
						817	188-190	439.2		*
818	158-159	437.0		***
						819		438.9		*
820		408.4		**
						821		408.4		*
822	144-145	439.9		**
						823	93-94	456.2		*
824	169-170	428.2		*
						825	109-110	444.2		*
826	160-161	432.1		**
						827	189-191	446.1		***
828	198-200	431.2		**	1H NMR(300MHz，CDCl 3)：δ7.65(1H， d，J＝8.8Hz)，7.62(2H，d，J＝8.8Hz)， 7.57(2H，d，J＝8.8Hz)，6.98(1H，dd， J＝8.8，2.0Hz)，6.89(1H，d，J＝2.0 Hz)，4.17(2H，q，J＝7.2Hz)，3.93(2H， t，J＝5.3Hz)，3.91(3H，s)，3.77(2H，t， J＝5.3Hz)，3.06(3H，s)，1.38(3H，t，J ＝7.2Hz).
						829	271-275	422.1		**
830	178-179	420.1		**
						831	140-141	371.0		*
832	206-207	406.3		**	1H NMR(CDCl 3，300MHz)δ(ppm)1.34 (t，3H)，1.47(t，3H)，1.55(s，9H)，4.04- 4.25(m，4H)，6.62(s，1H)，6.86-6.92(m， 1H)，7.02-7.08(m，2H)，7.43-7.49(m，2H)， 7.62(d，1H)，7.95(d，1H).

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						833	183-185	306.3		**	1H NMR(CDCl 3，300MHz)δ(ppm)1.21 (t，3H)，1.37(t，3H)，3.84-4.09(m，6H)， 6.54-6.71(m，2H)，6.85-7.01(m，2H)， 7.23-7.45(m，3H).
834	179-180	384.2		**
						835	178-179	398.2		**	1H NMR(CDCl 3，300MHz)δ(ppm)， 1.32-1.52(m，9H)，3.06-3.17(q，2H)，4.07- 4.24(m 4H)，6.55(s，1H)，6.99-7.10(m， 3H)，7.42-7.50(m，2H)，7.52-7.53(m，1H)， 7.69(d，1H).
836	167-169	412.2		*
						837	144-145	410.2		*
838	193-194	378.1		**	1H NMR(CDCl 3，300MHz)δ(ppm)， 1.31-1.39(m，6H)，1.48(t，3H)，4.07-4.31 (m，6H)，6.73(s，1H)，6.88-6.95(m，1H)， 7.01-7.08(m，2H)，7.42-7.53(m，2H)，7.63 (d，1H)，7.99(s，1H).
						839	249-250	377.3		*	1H NMR(CDCl 3，300MHz)δ(ppm)，1.13 (t，3H)，1.32(t，3H)，1.43(t，3H)，3.20-3.32 (m，2H)，4.13-4.26(m，4H)，5.77(t，1H)， 7.06-7.18(m，3H)，7.48(d，1H)，7.52-7.59 (m，2H)，8.02(s，1H)，8.18(d，1H).
840	182-183	442.5		*
						841	140-141	429.2		*
842	170-171	427.2		*	1H NMR(CDCl 3，300MHz)δ(ppm)1.04- 1.13(m，2H)，1.20-1.28(m，2H)，1.44(t， 3H)，2.30-2.43(m，1H)3.44-3.61(m，8H)， 4.10-4.23(q，2H)，7.49(d，1H)，7.56(s， 1H)，7.72(d，1H).
						843	143-146	463.1		*
844	220-227	378.1		*
						845	210-215	435.0		*
846	201-202	391.5		**
						847	166-167	405.5		**
848	193-194	453.5		**
						849	159-161	364.5		**
850	179-180	446.4		**
						851	186-187	410.4		**
852	171-172	426.4		**
						853	159-161	346.2		***

Compound number	Fusing point (℃)	Mass spectrum [M+H]	HCV-PV IC50μM	Replicon IC50 μ M	The NMR data
						854		330.2		**
855		332.1		**
						856	202-202	368.1		*
857	192-192	364.2		**
						858		362.2		***
859	191-192	374.2		**
						860	242-244	334.1		**
861		346.2		**
						862		360.1		*
863		362.5		**
						864		362.5		**
865	187-192	412.9		*

Embodiment 7: the activity of using HCV-poliovirus chimera assessment chemical compound

In HCV-poliovirus (HCV-PV) chimera, shown in Fig. 1 (140), PV5 ' UTR is replaced by HCV5 ' UTR and part (123 aminoacid) core encoder sequences (the nucleotide 18-710 of HCV 1b).Consequently, the proteic expression of poliovirus is subjected to the regulation and control of HCV IRES.Poliovirus is a kind of picorna virus, and wherein the protein translation startup is to be mediated by the IRES element that is arranged in 5 ' UTR.At 5 ' end of HCV-PV mosaic gene group, there is the SANYE blade of grass sample RNA structure of PV, it is basic cis acting reproducing signals, the end is for connecting genomic albumen VPg.Being complementary of chimeric duplicating dynamics of HCV-PV and parental generation poliovirus (Mahoney), and in cell culture, cause CPE (CPE).Heptazyme, as the ribozyme of a kind of targeting HCV IRES, being proved for the embedded virus in the cell culture is activated (76,77).

Be the activity of assessment chemical compound, inoculation HeLa cell and at 37 ℃ and 5%CO to described embedded virus ₂Following incubation 24 hours.This cell then infected 30 minutes with HCV-PV, and wherein infection multiplicity (MOI) is 0.1, uses compound treatment then 1 day (processing time is with optimised).Variation (for example referring to table 1) during the activity of chemical compound forms by CPE, plaque assay and/or viral RNA is measured.

Embodiment 8: chemical compound is to the active assessment and the poliovirus of wild type poliovirus (WT-PV) IRES translation experiment (WT-PV mono luc)

The preparation DNA construct is called pPVIRESmono, and wherein PV IRES sequence is inserted (few nucleotide 1-742) between promoter and Lampyridea luciferase (Fluc) reporter gene.With pPVIRESmono DNA transfection and select resistance, set up 293 T cell lines thus through stable transfection to hygromycin.As previously mentioned, cell is used compound treatment 20 hours, measures activity by quantitative Fluc signal then.In addition, be the activity of assessment chemical compound, inoculation Hela cell and at 37 ℃ and 5%CO to the wild type poliovirus ₂Following incubation 24 hours.This cell then infected 30 minutes with the wild type poliovirus, and wherein MOI is 0.1, uses compound treatment then 1 day.The activity of chemical compound is measured (for example referring to table 2) by the variation among the RT-PCR of CPE, plaque assay and use poliovirus IRES primer and probe.

In addition, if chemical compound is active for poliovirus and other viral IRES, then this chemical compound can be used for treating the viral infection that the virus of any IRES of comprising causes.

Table 2
					Compound number	WT-PV CPE (100μM) *	WT-PV CPE (10μM) *	WT-PV CPE (1μM) *	WTPV mono luc IC 50(μM)
4	3	2	1	0.8
					5	3	2	1	9
9	3	2	2	＞100
					10	3	2	2	＞100
19	3	2	1	15
					24	3	2	2	1.5

Embodiment 9: external translation experiment

External translation experiment can be used for distinguishing the chemical compound that HCV IRES RNA or cell translation factor are worked.In exemplary experiment, with the mRNA that instructs translation be with Ambion RNA MegaTranscript test kit (Ambion, Inc., Austin, TX) T7 rna polymerase promoter that comes from the pHCVIRESmono plasmid DNA of Chan Shenging transcribes product out of control.According to method known to those skilled in the art, use the HeLa cell lysates to carry out external translation.PRELIMINARY RESULTS shows one or more The compounds of this invention, make this chemical compound and HCV IRES rna transcription thing at 37 ℃ of incubations after 30 minutes in advance, than with HeLa cell lysates incubation in advance behind the incubation or not in advance, the translation of regulating for HCVIRES has obviously higher activity (data not shown).This points out this chemical compound might interact with HCV IRES RNA in external translation experiment.For confirming whether this chemical compound optionally acts on the HCV IRES, and pLuc uses as in vitro translated contrast with cell IRES mRNA transcript.

All be incorporated herein by reference to same degree at these all publications quoted and patent application, seem that publication that each is independent or patent application all specifically and individually show to be incorporated by reference.

Though below described some specific embodiments in detail, those skilled in the art will be expressly understood, under the situation that does not break away from instruction of the present invention, also can hold many improvement in these embodiments.All these improvement all are included within claims scope of the present invention.

List of references:

1.Ali，N.，G.J.Pruijn，D.J.Kenan，J.D.Keene，and A.Siddiqui.2000.Human Laantigen is required for the hepatitis C virus internal ribosome entry site-mediatedtranslation.J Biol Chem 275：27531-27540.

2.Ali，N.and A.Siddiqui.1995.Interaction of polypyrimidine tract-binding protein with the5′noncoding region of the hepatitis C virus RNA genome and its functional requirement ininternal initiation of translation.J Virol 69：6367-6375.

3.Ali，N.and A.Siddiqui.1997.The La antigen binds 5′noncoding region of the hepatitis Cvirus RNA in the context of the initiator AUG codon and stimulates internal ribosome entrysite-mediated translation.Proc Natl Acad Sci USA 94：2249-2254.

4.Anwar，A.N.Ali，R.Tanveer，and A.Siddiqui.2000.Demonstration of functionalrequirement of polypyrimidine tract-binding protein by SELEX RNA during hepatitis Cvirus internal ribosome entry site-mediated translation initiation.J Biol Chem 275：34231-34235.

5.Beales，L.P.，D.J.Rowlands，and A.Holzenburg.2001.The internal ribosome entry site(IRES)of hepatitis C virus visualized by electron microscopy.RNA 7：661-670.

6.Belsham，G.J.and J.K.Brangwyn.1990.A region of the 5′noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis withincells：involvement with the role of L protease in translational control.J Virol 64：5389-5395.

7.Belsham，G.J.and R.J.Jackson.2000.Translation initiation on picornavirus RNA.，p.869-900.Cold Spring Harbor Laboratory Press，New York.

8.Blight, K.J., A.A.Kolykhalov, and C.M.R ice .2000.Efficient initiation of HCV RNAreplication in cell culture.Science 290:1972-1974.

9.Blight, K.J., J.A.McKeating, and C.M.R ice .2002.Highly permissive cell line s forsubgenomic and genomic hepatitis C virus RNA replication.J Virol 76:13001-13014.

10.Borvjagin，G.，T.Pestova，and I.Shatsky. 1994.Pyrimidine tract binding proteinstrongly stimulates in vitro encephalomyocarditis virus RNA translation at the level of thepreinitiation complex formation.FEBS Lett 351：291-302.

11.Brown，E.A.，H.Zhang，L.H.Ping，and S.M.Lemon.1992.Secondary structure of the5′nontranslated regions of hepatitis C virus and pestivirus genomic RNAs.Nucleic AcidsRes 20：5041-5045.

12.Buck CB，Shen X，Egan MA，Pierson TC，Walker CM，and Siliciano RF.2001.Thehuman immunodeficiency virus type 1 gag gene encodes an internal ribosome entry site.JVirol 75：181-191.

13.Bukh，J.，R.H.Purcell，and R.H.Miller.1992.Sequence analysis of the 5′noncodingregion of hepatitis C virus.Proc Natl Acad Sci USA 89：4942-4946.

14.Bukh，J.，R.H.Purcell，and R.H.Miller.1994.Sequence analysis ofthe core gene of 14hepatitis C virus genotypes.Proc Natl Acad Sci USA 91：8239-8243.

15.Buratti，E.，S.Tisminetzky，M.Zotti，and F.E.Baralle.1998.Functional analysis of theinteraction between HCV 5′UTR and putative subunits of eukaryotic translation initiationfactor eIF3.Nucleic Acids Res 26：3179-3187.

16.Chappell，S.A.，J.P.LeQuesne，F.E.Paulin，M.L.deSchoolmeester，M.Stoneley，R.L.Soutar，S.H.Ralston，M.H.Helfrich，and A.E.Willis.2000.A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma：a novelmechanism of oncogene de-regulation.Oncogene 19：4437-4440.

17.Chung，R.T.，W.He，A.Saquib，A.M.Contreras，R.J.Xavier，A.Chawla，T.C.Wang，and E.V.Schmidt.Hepatitis C virus replication is directly inhibited by IFN-alphain a full-length binary expression system.2001.Proc Natl Acad Sci USA 98：9847-9852.

18.Coldwell，M.J.，S.A.Mitchell，M.Stoneley，M.MacFarlane，and A.E.Willis.2000.Initiation of Apaf-1 translation by internal ribosome entry.Oncogene 19：899-905.

19.Creancier, L., D.Morello, P.Mercier, and A.C.Prats.2000.Fibroblast growth factor 2internal ribosome entry site (IRES) activity ex vivo and in transgenic m ice reveals astringent tissue-specific regulation.J Cell Biol 150:275-281.

20.Das，S.，M.Ott，A.Yamane，A.Venkatesan，S.Gupta，and A.Dasgupta.1998.Inhibition of internal entry site(IRES)-mediated translation by a small yeast RNA：a novelstrategy to block hepatitis C virus protein synthesis.Front Biosci 3：D1241-D1252.

21.Dever，T.E.2002.Gene-specific regulation by general translation factors.Cell 108：545-556.

22.Dumas，E.，C.Staedel，M.Colombat，S.Reigadas，S.Chabas，T.Astier-Gin，A.Cahour，S.Litvak，and M.Ventura.2003.A promoter activity is present in the DNAsequence corresponding to the hepatitis C virus 5′UTR.Nucleic Acids Res 31：1275-1281.

23.Fukushi，S.，K.Katayama，C.Kurihara，N.Ishiyama，F.B.Hoshino，T.Ando，and A.Oya.1994.Complete 5′noncoding region is necessary for the efficient internal initiation ofhepatitis C virus RNA.Biochem Biophys.Res Commun.199：425-432.

24.Fukushi，S.，C.Kurihara，N.Ishiyama，F.B.Hoshino，A.Oya，and K.Katayama.1997.The sequence element of the internal ribosome entry site and a 25-kilodalton cellularprotein contribute to efficient internal initiation of translation of hepatitis C virus RNA.JVirol 71：1662-1666.

25.Fukushi，S.，M.Okada，T.Kageyama，F.B.Hoshino，and K.Katayama.1999.Specificinteraction of a 25-kilodalton cellular protein，a 40S ribosomal subunit protein，with theinternal ribosome entry site of hepatitis C virus genome.Virus Genes 19：153-161.

26.Fukushi，S.，M.Okada，J.Stahl，T.Kageyama，F.B.Hoshino，and K.Katayama.2001.Ribosomal protein S5 interacts with the internal ribosomal entry site of hepatitis C virus.JBiol Chem 276：20824-20826.

27.Funkhouser，A.W.，D.E.Schultz，S.M.Lemon，R.H.Purcell，and S.U.Emerson.1999.Hepatitis A virus translation is rate-limiting for virus replication in MRC-5 cells.Virology 254：268-278.

28.Glass，M.J.，X.Y.Jia，and D.F.Summers.1993 Identification of the hepatitis A virusinternal ribosome entry site：in vivo and in vitro analysis of bicistronic RNAs containingthe HAV 5′noncoding region.Virology.193：842-852.

29.Gordon S.C.，B.R.Bacon，I.M.Jacobson，M.I.Shiffman，N.H.Afdhal，J.G.McHutchison，T.J.Kwoh，and F.A.Dorr.2002.A Phase II，12-week study of ISIS14803，an antisense inhibitor of HCV for the treatment of chronic hepatitis C.AASLDAbst.795.Hepatology 36：362A.

30.Gosert，R.，K.H.Chang，R.Rijnbrand，M.Yi，D.V.Sangar，and S.M.Lemon.2000.Transient expression of cellular polypyrimidine-tract binding protein stimulates cap-independent translation directed by both picornaviral and flaviviral internal ribosome entrysites In vivo.Mol Cell Biol 20：1583-1595.

31.Gray，N，and M.Wickens.1998.Control of translation initiation in animals.Annu RevCell Dev Biol 14：399-458.

31a.G riffith，A.，and D.M.Coen.2005.An unusual internal ribosome entry site in the herpessimplex virus thymidine kinase gene.Proc Natl Acad Sci U S A.102：9667-72.

32.Guo，J.T.，V.V.Bichko，and C.Seeger.2001.Effect of alpha interferon on the hepatitisC virus replicon.J Virol 75：8516-8523.

33.Hahm，B.，Y.K.Kim，J.H.Kim，T.Y.Kim，and S.K.Jang.1998.Heterogeneousnuclear ribonucleoprotein L interacts with the 3′border of the internal ribosomal entry siteof hepatitis C virus.J Virol 72：8782-8788.

34.Haller，A.A.，S.R.Stewart，and B.L.Semler.1 996.Attenuation stem-loop lesions in the5′noncoding region of poliovirus RNA：neuronal cell-specific translation defects.J Virol70：1467-1474.

35.Hellen，C.U.and T.V.Pestova.1999.Translation of hepatitis C virus RNA.J ViralHepat 6：79-87.

36.Hellen，C.U.，G.W.Witherell，M.Schmid，S.H.Shin，T.V.Pestova，A.Gil，and E.Wimmer.1993.A cytoplasmic 57-kDa protein that is required for translation ofpicornavirus RNA by internal ribosomal entry is identical to the nuclear pyrimidine tract-binding protein.Proc Natl Acad Sci USA 90：4672-7646

37.Hendrix，M.，E.S.Priestley，G.F.Joyce，and C.H.Wong.1997.Direct observation ofaminoglycoside-RNA interactions by surface plasmon resonance.Journal of the AmericanChemical Society 119：3641-8.

38.Holcik，M.and R.G.Kornelu k.2000.Functional characterization of the X-linkedinhibitor of apoptosis(XIAP)internal ribosome entry site element：role of La autoantigenin XIAP translation.Mol Cell Biol 20：4648-4657.

39.Holcik，M.，C.Lefebvre，C.Yeh，T.Chow，and R.G.Korneluk.1999.A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection.Nat Cell Biol 1：190-192.

40.Honda，M.，M.R.Beard，L.H.Ping，and S.M.Lemon.1999.A phylogeneticallyconserved stem-loop structure at the 5′border of the internal ribosome entry site ofhepatitis C virus is required for cap-independent viral translation.J Virol1 165-1174.

41.Honda，M.，E.A.Brown，and S.M.Lemon.1996.Stability of a stem-loop involving theinitiator AUG controls the efficiency of internal initiation of translation on hepatitis C virusRNA.RNA 2：955-968.

42.Honda，M.，L.H.Ping，R.C.Rijnbrand，E.Amphlett，B.Clarke，D.Rowlands，and S.M.Lemon.1996.Structural requirements for initiation of translation by internal ribosomeentry within genome-length hepatitis C virus RNA.Virology 222：31-42.

43.Honda，M.，R.Rijnbrand，G.Abell，D.Kim，and S.M.Lemon.1999.Natural variationin translational activities of the 5′nontranslated RNAs of hepatitis C virus genotyPes 1aand 1b：evidence for a long-range RNA-RNA interaction outside of the internal ribosomalentry site.J Virol 73：4941-4951.

44.Huez，I.，S.Bornes，D.Bresson，L.Creancier，and H.Prats.2001.New vascularendothelial growth factor isoform generated by internal ribosome entry site-driven CUGtranslation initiation.Mol Endocrinol.15：2197-2210.

45.Huez，I.，L.Creancier，S.Audigier，M.C.Gensac，A.C.Prats，and H.Prats.1998.Two independent internal ribosome entry sites are involved in translation initiation ofvascular endothelial growth factor mRNA.Mol Cell Biol 18：6178-6190

46.Ikeda, M., M.Yi, K.Li, and S.M.Lemon.2002.Selec table subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone ofthe HCV-N strain ofhepatitis C virus replicate efficiently in cultured Huh7 cells.J Virol 76:2997-3006.

47.Irvine，J.D.，L.Takahashi，K.Lockhart，J.Cheong，J.W.Tolan，H.E.Selick，and J.R.Grove.1999.MDCK(Madin-Darby canine kidney)cells：A tool for membranepermeability screening.J Pharm Sci 88：28-33.

48.Isoyama，T.，N.Kamoshita，K.Yasui，A.Iwai，K.Shiroki，H.Toyoda，A.Yamada，Y.Takasaki，and A.Nomoto.1999.Lower concentration of La protein required for internalribosome entry on hepatitis C virus RNA than on poliovirus RNA.J Gen Virol 80(Pt9)：2319-2327.

49.Ito，T.and M.M.Lai.1999.An internal polypyrimidine-tract-binding protein-binding sitein the hepatitis C virus RNA attenuates translation，which is relieved by the 3′-untranslatedsequence.Virology 254：288-296.

50.Jang，S.K.，H.G.Krausslich，M.J.Nicklin，G.M.Duke，A.C.Palmenberg，and E.Wimmer.1988.A segment of the 5′nontranslated region of encephalomyocarditis virusRNA directs internal entry ofribosomes during in vitro translation.J Virol 62：2636-2643.

51.Jubin，R.，N.E.Vantuno，J.S.Kieft，M.G.Murray，J.A.Doudna，J.Y.Lau，and B.M.Baroudy.2000.Hepatitis C virus internal ribosome entry site(IRES)stem loop IIIdcontains a phylogenetically conserved GGG triplet essential for translation and IRESfolding.J Virol 74：10430-10437.

52.Kalliampakou，K.I.，L.Psaridi-Linardaki，and P.Mavromara.2002.Mutationalanalysis of the apical region of domain II ofthe HCV IRES.FEBS Lett 511：79-84.

53.Kaminski，A.，S.L.Hunt，J.G.Patton，and R.J.Jackson.1995.Direct evidence thatpolypyrimidine tract binding protein(PTB)is essential for internal initiation of translationof encephalomyocarditis virus RNA.RNA 1：924-938

54.Kamoshita，N.，K.Tsukiyama-Kohara，M.Kohara，and A.Nomoto.1997.Geneticanalysis of internal ribosomal entry site on hepatitis C virus RNA：implication forinvolvement of the highly ordered structure and cell type-specific transacting factors.Virology 233：9-18.

55.Kieft，J.S.，K.Zhou，R.Jubin，M.G.Murray，J.Y.Lau，and J.A.Doudna.1999.Thehepatitis C virus internal ribosome entry site adopts an ion-dependent tertiary fold.J MolBiol 292：513-529.

56.Kieft，J.S.，K.Zhou，R.Jubin，M.G.Murray，J.Y.Lau，and J.A.Doudna.2001.Mechanism of ribosome recruitment by hepatitis C IRES RNA.RNA 7：194-206.

57.Klinck，R.，E.Westhof，S.Walker，M.Afshar，A.Collier，and F.Aboul-Ela.2000.Apotential RNA drug target in the hepatitis C virus internal ribosomal entry site.RNA6：1423-1431.

58.Kolupaeva VG，Pestova TV，and Hellen CUT.2000.An enzymatic foot-printing analysisof the interaction of 40S ribosomal subunits with the internal ribosomal entry site ofhepatitis C virus.J Virol 74：6242-6250.

59.Kolupaeva，V.G.，C.U.Hellen，and I.N.Shatsky.1996.Structural analysis of theinteraction of the pyrimidine tract-binding protein with the internal ribosomal entry site ofencephalomyocarditis virus and foot-and-mouth disease virus RNAs.RNA 2：1199-1212.

60.Kolupaeva，V.G.，T.V.Pestova，C.U.Hellen，and I.N.Shatsky.1998.Translationeukaryotic initiation factor 4G recognizes a specfic structural element within the internalribosome entry site of encephalomyocarditis virus RNA.J Biol Chem 273：18599-18604.

61.Kozak，M.1999.Initiation of translation in prokaryotes and eukaryotes.Gene 234：187-208.

62.Kruger，M.，C.Beger，P.J.Welch，J.R.Barber，M.P.Manns，and F.Wong-Staal.2001.Involvement of proteasome alpha-subunit PSMA7 in hepatitis C virus internalribosome entry site-mediated translation.Mol Cell Biol 21：8357-8364

63.La Monica, N.and V.R.Racaniello.1989.Differences in replication of attenuated andneurovirulent polioviruses in human neuroblastoma cell line SH-SY5Y.J Virol 63:2357-2360.

64.Le，S.Y.，N.Sonenberg，and J.V.Maizel，Jr.1995.Unusual folding regions andribosome landing pad within hepatitis C virus and pestivirus RNAs.Gene 154：137-143.65.Lerat，H.，Y.K.Shimizu，and S.M.Lemon.2000.Cell type-specific enhancement ofhepatitis C virus internal ribosome entry site-directed translation due to 5′nontranslatedregion substitutions selected during passage of virus in lymphoblastoid cells.J Virol74：7024-7031.

66.Li，K.，T.M.Davis，C.Bailly，A.Kumar，D.W.Boykin，and W.D.Wilson.2001.Aheterocyclic inhibitor of the REV-RRE complex binds to RRE as a dimer.Biochemistry40：1150-8.

67.Lipinski，J.2000.J.Pharm.Tox.Meth.44：235-249.

68.Llinàs-Brunet M.2002.NS3 serine protease inhibitors as potential antiviral agents for thetreatment of hepatitis C virus infections.The 3rd internatl antiviral & vaccine discoveryand development summit.March 13-14.Princeton，NJ.

69.Lohmann，V.，F.Korner，A.Dobierzewska，and R.Bartenschlager.2001.Mutations inhepatitis C virus RNAs conferring cell culture adaptation.J Virol 75：1437-1449.

70.Lohmann, V., F.Korner, J.Koch, U.Herian, L.Theilmann, and R.Bartenschlager.1999.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line .Science285:110-113.

71.Lopez，d.Q.，E.Lafuente，and E.Martinez-Salas.2001.IRES interaction withtranslation initiation factors：functional characterization of novel RNA contacts with eIF3，eIF4B，and eIF4GII.RNA 7：1213-1226.

72.Lopez，d.Q.and E.Martinez-Salas.2000.Interaction of the eIF4G initiation factor withthe aphthovirus IRES is essential for internal translation initiation in vivo.RNA 6：1380-1392.

73.Lu，H.H.and E.Wimmer.1996.Poliovirus chimeras replicating under the translationalcontrol of genetic elements of hepatitis C virus reveal unusual properties of the internalribosomal entry site of hepatitis C virus.Proc Natl Acad Sci USA 93：1412-7.

74.Lukavsky，P.J.，G.A.Otto，A.M.Lancaster，P.Sarnow，and J.D.Puglisi.2000.Structures of two RNA domains essential for hepatitis C virus internal ribosome entry sitefunction.Nat Struct Bio 7：1105-1110.

75.Lyons，A.J.，J.R.Lytle，J.Gomez，and H.D.Robertson.Hepatitis C virus internalribosome entry site RNA contains a tertiary structural element in a functional domain ofstem-loop II.Nucleic Acids Res 29：2535-2546.

76.Maceja k，D.G.，K.L.Jensen，S.F.Jamison，K.Domenico，E.C.Roberts，N.Chaudhary，I.von_Carlowitz，L.Bellon，M.J.Tong，A.Conrad，P.A.Pavco，and L.M.Blatt.2000.Inhibition of hepatitis C virus(HCV)-RNA-dependent translation andreplication of a chimeric HCV poliovirus using synthetic stabilized ribozymes.Hepatology(Baltimore，Md.)31：769-76.

77.Macejak，D.G.，K.L.Jensen，P.A.Pavco，K.M.Phipps，B.A.Heinz，J.M.Colacino，and L.M.Blatt.2001.Enhanced antiviral efiect in cell culture of type 1 interferon andribozymes targeting HCV RNA.J Viral Hepatitis 8：400-405.

78.Macejak，D.G.and P.Sarnow.1991.Internal initiation of translation mediated by the 5′leader of a cellular mRNA.Nature 353：90-94.

79.Major ME，Rehermann B，and Feinstone.2001.Hepatitis C viruses.，p.2535-2541.In D.Knipe and P.Howley(eds.)，Fields Virology.Lippincott Williams and Wilkins，Philadelphia，PA.

80.Manns MP，McHutchison JG，Gordon SC，Rustgi VK，Shiffman M，Reindollar R，Goodman ZD，Koury K，Ling M，and Albrecht JK.2003.Peginterferon alfa-2b plusribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronichepatitis C：a randomised trial.Lancet 358：958-965.

81.Martinez-Salas，E.，R.Ramos，E.Lafuente，and d.Q.Lopez.2001.Functionalinteractions in internal translation initiation directed by viral and cellular IRES elements.JGen Virol 82：973-984.

82.Mazur，S.，F.A.Tanious，D.Ding，A.Kumar，D.W.Boykin，I.J.Simpson，S.Neidle，and W.D.Wilson.2000.A thermodynamic and structural analysis of DNA minor-groovecomplex formation.Journal of Molecular Biology 300：321-37.

83.McHutchison JG and Poynard T.1999.Combination therapy with interferon plusribavirin for the initial treatment of chronic hepatitis C.Semin.Liver Dis.19 Suppl 1：57-65.

84.McHutchison，J.G.，T.Poynard，R.Esteban-Mur，G.L.Davis，Z.D.Goodman，J.Harvey，M.H.Ling，J.J.Garaud，J.K.Albrecht，K.Patel，J.L.Dienstag，and T.Morgan.2002.Hepatic HCV RNA before and after treatment with interferon alone orcombined with ribavirin.Hepatology 35：688-693.

85.Meerovitch，K.，J.Pelletier，and N.Sonenberg.1989.A cellular protein that binds to the5′-noncoding region of poliovirus RNA：implications for internal translation initiation.Genes Dev 3：1026-1034.

86.Meerovitch，K.，Y.V.Svitkin，H.S.Lee，F.Lejbkowicz，D.J.Kenan，E.K.Chan，V.I.Agol，J.D.Keene，and N.Sonenberg.1993.La autoantigen enhances and correctsaberrant translation of poliovirus RNA in reticulocyte lysate.J Virol 67：3798-3807.

87.Mercer, D.F., D.E.Schiller, J.F.Elliott, D.N.Douglas, C.Hao, A.Rinfret, W.R.Addison, K.P.Fischer, T.A.Churchill, J.R.Lakey, D.L.Tyrrell, and N.M.Kneteman.2001.Hepatitis C virus replication in m ice with chimeric human livers.NatureMedicine 7:927-33.

88.Michel，Y.M.，A.M.Borman，S.Paulous，and K.M.Kean.2001.Eukaryotic initiationfactor 4G-poly(A) binding protein interaction is required for poly(A)tail-mediatedstimulation of picornavirus internal ribosome entry segment-driven translation but not forX-mediated stimulation of hepatitis C virus translation.Mol Cell Biol 21：4097-4109.

89.Mitchell，S.A.，E.C.Brown，M.J.Coldwell，R.J.Jackson，and A.E.Willis.2001.Protein factor requirements of the Apaf-1 internal ribosome entry segment：roles ofpolypyrimidine tract binding protein and upstream of N-ras.Mol Cell Biol 21：3364-3374.

90.Moriguchi，e.al.1992.Chem Pharm Bull 40：127-130.

91.Nanbru，C.，I.Lafon，S.Audigier，M.C.Gensac，S.Vagner，G.Huez，and A.C.Prats.2003.Alternative translation of the proto-oncogene c-myc by an internal ribosome entrysite.J Biol Chem 272：32061-32066.

92.Niepmann，M.，A.Petersen，K.Meyer，and E.Bec k.1997.Functional involvement ofpolypyrimidine tract-binding protein in translation initiation complexes with the internalribosome entry site of foot-and-mouth disease virus.J Virol 71：8330-8339.

93.Odreman-Macchioli，F.，F.E.Baralle，and E.Buratti.2001.Mutational analysis of thedifferent bulge regions of hepatitis C virus domain II and their influence on internalribosome entry site translational ability.J Biol Chem 276：41648-41655.

94.Odreman-Macchioli，F.E.，S.G.Tisminetzky，M.Zotti，F.E.Baralle，and E.Buratti.2000.Influence of correct secondary and tertiary RNA folding on the binding of cellularfactors to the HCV IRES.Nucleic Acids Res 28：875-885.

95.Ohlmann，T.，M.Lopez-Lastra，and J.L.Darlix.2000.An internal ribosome entrysegment promotes translation of the simian immunodeficiency virus genomic RNA.J BiolChem 275：11899-11906.

96.Pain VM.1996.Initiation of protein synthesis in eukaryotic cells.Eur J Biochem 236：747-771.

97.Pelletier，J.and N.Sonenberg.1988.Internal initiation of translation of eukaryoticmRNA directed by a sequence derived from poliovirus RNA.Nature 334：320-325.

98.Pelletier，J.and N.Sonenberg.1989.Internal binding of eucaryotic ribosomes onpoliovirus RNA：translation in HeLa cell extracts.J Virol 63：441-444.

99.Pestova，T.V.，S.I.Borukhov，and C.U.Hellen.1998.Eukaryotic ribosomes requireinitiation factors 1 and 1A to locate initiation codons.Nature 394：854-859.

100.Pestova，T.V.，I.N.Shatsky，S.P.Fletcher，R.J.Jackson，and C.U.Hellen.1998.Aprokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codonduring internal translation initiation of hepatitis C and classical swine fever virus RNAs.Genes Dev 12：67-83.

101.Pestova，T.V.，I.N.Shatsky，and C.U.Hellen.1996.Functional dissection of eukaryoticinitiation factor 4F：the 4A subunit and the central domain of the 4G subunit are sufficientto mediate internal entry of 43S preinitiation complexes.Mol Cell Biol 16：6870-6878.

102.Peytou，V.，R.Condom，N.Patino，R.Guedj，A.M.Aubertin，N.Gelus，C.Bailly，R.Terreux，and D.Cabrol_Bass.1999.Synthesis and antiviral activity of ethidium-arginineconjugates directed against the TAR RNA of HIV-1.Journal of Medicinal Chemistry42：4042-53.

103.Pietschmann，T.，V.Lohmann，A.Kaul，N.Krieger，G.Rinck，G.Rutter，D.Strand，and R.Bartenschlager.2002.Persistent and transient replication of full-length hepatitis Cvirus genomes in cell culture.J Virol 76：4008-4021.

104.Pietschmann, T., V.Lohmann, G.Rutter, K.Kurpanek, and R.Bartenschlager.2001.Characterization of cell line s carrying self-replicating hepatitis C virus RNAs.J Virol75:1252-1264.

105.Poole，T.L.，C.Wang，R.A.Popp，L.N.Potgieter，A.Siddiqui，and M.S.Collett.1995.Pestivirus translation initiation occurs by interna ribosome entry.Virology 206：750-754.

106.Pringle，C.1999.Virus taxonomy--1999.The universal system of virus taxonomy，updatedto include the new proposals ratified by the International Committee on Taxonomy ofViruses during 1998.Arch Virol 144：421-429.

107.Psaridi，L.，U.Georgopoulou，A.Varaklioti，and P.Mavromara.1999.Mutationalanalysis of a conserved tetraloop in the 5′untranslated region of hepatitis C virus identifiesa novel RNA element essential for the internal ribosome entry site function.FEBS Lett453：49-53.

108.Reynolds，J.E.，A.Kaminski，A.R.Carroll，B.E.Clarke，D.J.Rowlands，and R.J.Jackson.1996.Internal initiation of translation of hepatitis C virus RNA：the ribosomeentry site is at the authentic initiation codon.RNA 2：867-878.

109.Reynolds，J.E.，A.Kaminski，H.J.Kettinen，K.Grace，B.E.Clarke，A.R.Carroll，D.J.Rowlands，and R.J.Jackson.1995.Unique features of internal initiation of hepatitis Cvirus RNA translation.EMBO J 14：6010-6020.

110.Rijnbrand R，Bredenbeek P，van derStraaten T，Whetter L，Inehauspe G，Lemon S，and Spaan W.1995.Almost the entire 5′non-translated region of hepatitis C virus isrequired for cap-independent translation.FEBS Lett 365：115-119.

111.Rijnbrand RC and Lemon SM.2000.Internal ribosome entry site-mediated translation inhepatitis C virus replication.Curr Top.Microbiol Immunol.242：85-116.

112.Rijnbrand，R.，P.J.Bredenbee k，P.C.Haasnoot，J.S.Kieft，W.J.Spaan，and S.M.Lemon.2001.The influence of downstream protein-coding sequence on internal ribosomeentry on hepatitis C virus and other flavivirus RNAs.RNA 7：585-597.

113.Rijnbrand，R.C.，T.E.Abbink，P.C.Haasnoot，W.J.Spaan，and P.J.Bredenbeek.1996.The influence of AUG codons in the hepatitis C virus 5′nontranslated region ontranslation and mapping of the translation initiation window.Virology 226：47-56.

114.Sachs，A.B.，P.Sarnow，and M.W.Hentze.1997.Starting at the beginning，middle，andend：translation initiation in eukaryotes.Cell 89：831-838.

115.Saito I，Miyamura T，Ohbayashi A，Harada H，Katayama T，Kikuchi S，Watanabe Y，Koi S，Onji M，Ohta Y，Choo Q，Houghton M，and Kuo G.2003.Hepatitis C virusinfection is associated with the development of hepatocellular carcinoma.Proc Natl AcadSci U.S.A 87：6547-6549.

116.Schultz，D.E.，M.Honda，L.E.Whetter，K.L.McKnight，and S.M.Lemon.1996.Mutations within the 5′nontranslated RNA of cell culture-adapted hepatitis A virus whichenhance cap-independent translation in cultured African green monkey kidney cells.J Virol70：1041-1049.

117.Shimazaki，T.，M.Honda，S.Kaneko，and K.Kobayashi.2002.Inhibition of internalribosomal entry site-directed translation of HCV by recombinant IFN-alpha correlates witha reduced La protein.Hepatology 35：199-208.

118.Simmonds，P.2003.Variability of hepatitis C virus.Hepatology 21：570-583.

119.Sinha，R.，P.Yang，S.Kodali，Y.Xiong，R.M.Kim，P.R.Griffin，H.R.Onishi，J.Kohler，L.L. Silver，and K.Chapman.2001.Direct interaction of a vancomycinderivative with bacterial enzymes involved in cell wall biosynthesis.Chem Biol 8：1095-1106.

120.Sizova，D.V.，V.G.Kolupaeva，T.V.Pestova，I.N.Shatsky，and C.U.Hellen.1998.Specific interaction of eukaryotic translation initiation factor 3 with the 5′nontranslatedregions of hepatitis C virus and classical swine fever virus RNAs.J Virol 72：4775-4782.

121.Smith.1994.EurJ Drug Metab Pharm 3：193-199.

122.Smith，D.B.，J.Mellor，L.M.Jarvis，F.Davidson，J.Kolberg，M.Urdea，P.L.Yap，and P.Simmonds.1995.Variation of the hepatitis C virus 5′non-coding region：implications for secondary structure，virus detection and typing.The International HCVCollaborative Study Group.J Gen Virol 76(Pt7)：1749-1761.

123.Sonenberg N，Mathews MB，and Hershey JWB.2000.Translational control of geneexpression.Cold Spring Harbor.Cold Spring Harbor Laboratory Press，New York.

124.Spahn，C.M.，J.S.Kieft，R.A.Grassucci，P.A.Penczek，K.Zhou，J.A.Doudna，andJ.Frank.2001.Hepatitis C virus IRES RNA-induced changes in the conformation of the40s ribosomal subunit.Science 291：1959-1962.

125.Spatzenegger，M.and W.Jaeger.1995.Clinical importance of hepatic cytochrome P450in drug metabolism.Drug Metab Rev 27：397-417.

126.Subkhankulova，T.，S.A.Mitchell，and A.E.Willis.2001.Internal ribosome entrysegment-mediated initiation of c-Myc protein synthesis following genotoxic stress.Biochem J 359：183-192.

127.Tang，S.，A.J.Collier，and R.M.Elliott.1999.Alterations to both the primary andpredicted secondary structure of stem-loop IIIc of the hepatitis C virus 1b 5′untranslatedregion(5′UTR)lead to mutants severely defective in translation which cannot becomplemented in trans by the wild-type 5′UTR sequence.J Virol 73：2359-2364.

128.Thiel，V.and S.G.Siddell.1994.Internal ribosome entry in the coding region of murinehepatitis virus mRNA 5.J Gen Virol.75(Pt11)：3041-3046.

129.Tsukiyama-Kohara，K.，N.Iizuka，M.Kohara，and A.Nomoto.1992.Internal ribosomeentry site within hepatitis C virus RNA.J Virol 66：1476-1483.

130.Vagner，S.，M.C.Gensac，A.Maret，F.Bayard，F.Amalric，H.Prats，and A.C.Prats.1995.Alternative translation of human fibroblast growth factor 2 mRNA occurs by internalentry of ribosomes.Mol Cell Biol 15：35-44.

131.Varaklioti A，Georgopoulou U，Kakkanas A，Psaridi L，Serwe M，Caselmann WH，and Mavromara P.1998.Mutational analysis of two unstructured domains of the 5，untranslated region of HCV RNA.Biochem Biophys.Res Commun.253：678-685.

132.Wang，C.，S.Y.Le，N.Ali，and A.Siddiqui.1995.An RNA pseudoknot is an essentialstructural element of the internal ribosome entry site located within the hepatitis C virus 5′noncoding region.RNA 1：526-537.

133.Wang，C.，P.Sarnow，and A.Siddiqui.1993.Translation of human hepatitis C virusRNA in cultured cells is mediated by an internal ribosome-binding mechanism.J Virol67：3338-3344.

134.Wang，C.，P.Sarnow，and A.Siddiqui.1994.A conserved helical element is essential forinternal initiation of translation of hepatitis C virus RNA.J Virol 68：7301-7307.

135.Wang，S.M.，S.C.Fears，L.Zhang，J.J.Chen，and J.D.Rowley.2000.Screeningpoly(dA/dT)-cDNAs for gene identfication.Proceedings of the National Academy ofSciences of the United States of America 97：4162-7.

136.Wang，T.H.，R.C.Rijnbrand，and S.M.Lemon.2000.Core protein-coding sequence，but not core protein，modulates the efficiency of cap-independent translation directed bythe internal ribosome entry site of hepatitis C virus.J Virol 74：11347-11358.

137.Wimmer，E.，C.U.Hellen，and X.Cao.1993.Genetics of poliovirus.Annu Rev Genet27：353-436.

138.Wong，J.B.，T.Poynard，M.H.Ling，J.K.Albrecht，and S.G.Pauker.2000.Cost-efiectiveness of 24 or 48 weeks of interferon alpha-2b alone or with ribavirin as initialtreatment of chronic hepatitis C.International Hepatitis Interventional Therapy Group.Am.J Gastroenterol.95：1524-1530.

139.Zhao，W.D.and E.Wimmer.2001.Genetic analysis of a poliovirus/hepatitis C viruschimera：new structure for domain II of the internal ribosomal entry site of hepatitis C virus.J Virol 75：3719-3730

140.Zhao，W.D.，E.Wimmer，and F.C.Lahser.1999.Poliovirus/Hepatitis C virus(internalribosomal entry site-core)chimeric viruses：improved growth properties throughmodification of a proteolytic cleavage site and requirement for core RNA sequences butnot for core-related polyPeptides.Journal of Virology 73：1546-54.

Claims (41)

1, is used for the pharmaceutical composition that prevention or treatment hepatitis C virus (HCV) infect, it comprises that at least a of treatment effective dose has with acceptable salt on the chemical compound of following formula or its materia medica, and the acceptable excipient of materia medica and one or more optional extra anti-HCV medicaments:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl-alkyl or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

2, pharmaceutical composition as claimed in claim 1, wherein said one or more extra anti-HCV medicaments are selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, the unwindase inhibitor, glycosidase inhibitor, Toll sample receptor stimulating agent, and their combination.

3, pharmaceutical composition as claimed in claim 1, wherein X is selected from following group :-hydrogen;-cyano group; And--COR _aGroup, wherein R _aBe :-C ₁-C ₆Alkyl, or-dialkyl-7-amino.

4, pharmaceutical composition as claimed in claim 3, wherein X be selected from cyano group and-COR _aGroup, wherein R _aBe-dialkyl-7-amino.

5, pharmaceutical composition as claimed in claim 4, wherein X is a cyano group.

6, pharmaceutical composition as claimed in claim 1, wherein Y is selected from the following chemical compound group:

7, pharmaceutical composition as claimed in claim 1, wherein Y is selected from the following chemical compound group:

8, pharmaceutical composition as claimed in claim 1, wherein Z is selected from following group :-hydrogen;-C ₁-C ₆Alkyl, it is optional to be replaced by following group :-alkoxyl ,-one or more halogens or-C ₆-C ₈Aryl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

9, pharmaceutical composition as claimed in claim 1, wherein Z is selected from following group :-hydrogen;-optional by C ₆-C ₈The C that aryl replaces ₁-C ₆Alkyl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

10, pharmaceutical composition as claimed in claim 1, wherein R is a hydrogen.

11, pharmaceutical composition as claimed in claim 1, wherein R ₁Be selected from following group :-hydrogen;-halogen;-nitro;-5 or 6 yuan of heterocycles;-optional by C ₆-C ₈The alkoxyl that aryl replaces; The C of-optional alkoxy replacement ₆-C ₈Aryl.

12, pharmaceutical composition as claimed in claim 1, wherein R ₂Be selected from following group :-nitro;-hydrogen;-halogen;-hydroxyl;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens,--OCOR _xGroup, wherein R _xAs defined above, the dialkyl-7-amino of-optional alkoxy replacement ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, or-5 or 6 yuan of heteroaryls;-amide groups; And--NHSO ₂R _xGroup, wherein R _xAs defined above.

13, pharmaceutical composition as claimed in claim 1, wherein R ₂Be selected from following group :-hydrogen;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, or-5 or 6 yuan of heteroaryls.

14, pharmaceutical composition as claimed in claim 1, wherein R ₃Be hydrogen.

15, be used for the treatment of the pharmaceutical composition that hepatitis C virus (HCV) infects, it comprises one or more the following chemical compounds or the acceptable salt of its materia medica for the treatment of effective dose, and the acceptable excipient of materia medica:

16, pharmaceutical composition as claimed in claim 15, wherein said composition also comprises the extra anti-HCV medicament that is selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, the unwindase inhibitor, glycosidase inhibitor, Toll sample receptor stimulating agent, and their combination.

17, the method that hepatitis C virus (HCV) infects in a kind of treatment individuality, it comprises that one or more that comprise the HCV amount of suppression to described individual administration have with the chemical compound of following formula and/or the pharmaceutical composition of acceptable salt of its materia medica and the acceptable excipient of materia medica:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above:

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

18, method as claimed in claim 17, wherein this method also comprises one or more extra anti-HCV medicaments of administration.

19, method as claimed in claim 18, wherein said one or more extra anti-HCV medicaments are to be selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, the unwindase inhibitor, glycosidase inhibitor, Toll sample receptor stimulating agent, and their combination.

20, method as claimed in claim 17, wherein X is selected from following group :-hydrogen;-cyano group; And--COR _aGroup, wherein R _aBe :-C _1-C ₆Alkyl, or-dialkyl-7-amino.

21, method as claimed in claim 17, wherein X be selected from cyano group and-COR _aGroup, wherein R _aBe-dialkyl-7-amino.

22, method as claimed in claim 17, wherein X is a cyano group.

23, method as claimed in claim 17, wherein Y is selected from the following chemical compound group:

24, method as claimed in claim 17, wherein Y is selected from the following chemical compound group:

25, method as claimed in claim 17, wherein Z is selected from following group :-hydrogen;-C ₁-C ₆Alkyl, it is optional to be replaced by following group :-alkoxyl ,-one or more halogens or-C ₆-C ₈Aryl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

26, method as claimed in claim 17, wherein Z is selected from following group :-hydrogen;-optional by C ₆-C ₈The C that aryl replaces ₁-C ₆Alkyl;-C ₂-C ₆Thiazolinyl; And-C that optional alkoxy replaces ₆-C ₈Aryl.

27, method as claimed in claim 17, wherein R is a hydrogen.

28, method as claimed in claim 17, wherein R ₁Be selected from following group :-hydrogen;-halogen;-nitro;-5 or 6 yuan of heterocycles;-optional by C ₆-C ₈The alkoxyl that aryl replaces; The C of-optional alkoxy replacement ₆-C ₈Aryl.

29, method as claimed in claim 17, wherein R ₂Be selected from following group :-nitro;-hydrogen;-halogen;-hydroxyl;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens,--OCOR _xGroup, wherein R _xAs defined above, the dialkyl-7-amino of-optional alkoxy replacement ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, or-5 or 6 yuan of heteroaryls;-amide groups; And--NHSO ₂R _xGroup, wherein R _xAs defined above.

30, method as claimed in claim 17, wherein R ₂Be selected from following group :-hydrogen;-optional the C that is replaced by one or more halogens ₁-C ₆Alkyl;-alkoxyl, it is chosen wantonly and is replaced by following group :-one or more halogens ,-optional by C ₁-C ₆5 or 6 yuan of heterocyclic radicals that alkyl replaces, or-5 or 6 yuan of heteroaryls.

31, method as claimed in claim 17, wherein R ₃Be hydrogen.

32, method as claimed in claim 17, wherein said chemical compound is selected from following chemical compound:

33, method as claimed in claim 17, wherein said chemical compound is selected from following chemical compound:

34, a kind of treatment or prevention are individual by the method for viral infection, wherein said virus comprises internal ribosome entry site (IRES), and this method comprises that one or more that comprise viral amount of suppression to described individual administration have with the chemical compound of following formula or the pharmaceutical composition of acceptable salt of its materia medica and the acceptable excipient of materia medica:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzo furan is fed;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocyclic radicals,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

35, method as claimed in claim 34, it further comprises one or more extra antiviral drugs of administration.

36, method as claimed in claim 35, wherein said one or more extra antiviral drugs are selected from following group: the interferon of Pegylation, the interferon of Pegylation not, ribavirin or its prodrug or derivant, alpha-glucosidase inhibitors, protease inhibitor, AG14361, the p7 inhibitor, entry inhibitor, fusion inhibitor, the fibrosis medicine, the caspase inhibitor, the medicine of targeting inosine list monophosphate dehydrogenase inhibitor (IMPDH), synthetic thymosin, therapeutic vaccine, immunomodulator, glycosidase inhibitor, the unwindase inhibitor, Toll sample receptor stimulating agent, and their combination.

37, the active pharmaceutical composition of viral IRES in the individuality of viral infection is suffered from a kind of influence, and it comprises that one or more have chemical compound or the acceptable salt of its materia medica and active chemical compound of the IRES of influence as known in the art and the acceptable excipient of materia medica with following formula:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzo furan is fed;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is chosen quilt wantonly

Following group replaces:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and

R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

38, pharmaceutical composition as claimed in claim 37, the translation of the ORF of the wherein said coding polyprotein that influences the active compounds affect IRES of IRES mediation known in the art.

39, the active method of viral IRES in the individuality of viral infection is suffered from a kind of influence, and it comprises that one or more have chemical compound and/or the acceptable salt of its materia medica and active chemical compound of the IRES of influence as known in the art and the acceptable excipient of materia medica with following formula to described individual administration:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzo furan is fed;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above, or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocyclic radicals, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

40, method as claimed in claim 39, the translation of the ORF of the wherein said coding polyprotein that influences the active compounds affect IRES of IRES mediation known in the art.

41, the active pharmaceutical composition of viral IRES in the individuality of viral infection is suffered from a kind of influence, it comprise the active amount of the viral IRES of effective influence one or more have chemical compound or acceptable salt of its materia medica and the acceptable excipient of materia medica with following formula:

Wherein:

X is:

-hydrogen;

-nitro;

-cyano group;

--COR _aGroup, wherein R _aBe:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or halogen replace, or

-dialkyl amido;

--COOR _xGroup, wherein R _xBe C ₁-C ₆Alkyl;

-formoxyl;

-C ₆-C ₈Aryl, its optional alkoxy replaces; Or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-C ₆-C ₈Aryl, its optional alkoxy or one or more halogen replace, or

-5-6 unit heteroaryl;

Y is:

-hydrogen;

-haloalkyl;

-halogen;

-optional by one or more C ₁-C ₆The amino that alkyl replaces;

-benzofuran;

-benzothiophene;

-dibenzofurans;

-dibenzothiophenes;

-benzothiazole;

-naphthalene;

-indole, it is chosen wantonly on nitrogen-atoms by C ₁-C ₆Alkyl replaces;

R wherein _bBe hydrogen or C ₁-C ₆Alkyl, and n is 0 or 1;

R wherein _cBe hydrogen ,-CONHR _x, R wherein _xAs defined above, or-SO ₂R _x, wherein

R _xAs defined above; Or

R wherein _dBe C ₁-C ₆Alkyl or C ₆-C ₈Aryl;

--NHCOR _eGroup, wherein R _eBe:

-C ₁-C ₆Alkyl;

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-alkoxyl,

-cyano group,

-nitro, or

-halogen;

--NHCOOR _xGroup, wherein R _xAs defined above;

--CH ₂O-R _fGroup, wherein R _fBe C ₆-C ₈Aryl;

--NR _gR _hGroup, wherein R _gBe C ₁-C ₆Alkyl or hydrogen, and R _hBe the C that optional alkoxy replaces ₆-C ₈Aryl;

-C ₁-C ₆Alkyl;

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

-C ₆-C ₈Aryl, its optional quilt-COOR _xReplace, wherein R _xAs defined above, or

-amino;

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

--COOR _xGroup, wherein R _xAs defined above, or

--NHCOOR _xGroup, wherein R _xAs defined above;

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-hydroxyl,

-one or more halogens,

-5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl, or

-hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _iSO ₂R _xGroup, wherein R _xAs defined above, and R _iBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _jCOR _kGroup, wherein R _kBe:

-C ₁-C ₆Alkyl,

-hydrogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

And R _jBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--N=N ⁺=N ^-Group, or

--COR ₁, R wherein ₁Be 5 or 6 yuan of heterocycles, it is chosen wantonly and is replaced by hydroxyl,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-nitro,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

--NHSO ₂R _xGroup, wherein R _xAs defined above, or

--NR _xSO ₂R _xGroup, wherein R _xAs defined above,

-halogenated alkoxy,

-halogen,

-hydroxyl,

--COOR _xGroup, wherein R _xAs defined above,

--COR _mGroup, wherein R _mBe:

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, wherein this C ₁-C ₆Alkyl is optional to be replaced by following group:

-hydroxyl

-5 or 6 yuan of heterocycles,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-alkoxyl,

-3-7 unit heterocycle, it is optional by C ₁-C ₆Alkyl replaces, chooses wantonly to be replaced by dialkyl amido,

--NHR _nGroup, wherein R _nBe:

--CH ₂CONH ₂, or

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkyl,

-one or more halogens,

-nitro, or

-one or more alkoxyls,

--NR _oCOR _pGroup, wherein R _pBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-alkoxyl, or

-C ₆-C ₈Aryl,

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heteroaryls, it is optional by one or more C ₁-C ₆Alkyl replaces,

-hydrogen,

And R wherein _oBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _qCONR _qR _rGroup, wherein R _qBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

And R wherein _rBe:

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-haloalkyl,

--OR _sGroup, wherein R _sBe C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

-C ₁-C ₆Alkyl, it is optional by one or more following groups replacements:

-halogen,

-thiazolinyl,

-C ₆-C ₈Aryl, or

--COOR _xGroup, wherein R _xAs defined above,

--COOR _xGroup, wherein R _xAs defined above,

--NR _tCOOR _uGroup, wherein R _uBe:

-C ₁-C ₁₂Alkyl, it is chosen wantonly and is replaced by following group:

-C ₆-C ₈Aryl, it is optional by C ₁-C ₆Alkyl or alkoxyl replace,

-thiazolinyl,

-alkoxyl,

-alkynyl,

-halogen, or

-5 or 6 yuan of heterocycles,

-C ₆-C ₈Aryl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-C ₁-C ₆Alkyl, or

-5 or 6 yuan of heterocycles,

And R _tBe:

-hydrogen,

-C ₁-C ₆Alkyl,

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl, or

-halogenated alkoxy,

--NR _vSO ₂R _wGroup, wherein R _vBe:

-hydrogen,

--COR _x, R wherein _xAs defined above or

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

--COR _xGroup, wherein R _xAs defined above,

--OCOR _xGroup, wherein R _xAs defined above,

-hydroxyl,

-hydroxyl, or

-alkoxyl,

And R wherein _wBe:

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-halogen,

-haloalkyl,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles,

-C ₂-C ₆Thiazolinyl,

-alkyl amino or dialkyl amido, it is chosen wantonly and is replaced by halogen,

-5 or 6 yuan of heterocycles, or

-5 or 6 yuan of heteroaryls, it is chosen wantonly and is replaced by following group:

-C ₁-C ₆Alkyl,

-5 or 6 yuan of heterocycles, or

It is optional by C ₁-C ₆Alkyl replaces, wherein R _yBe C ₁-C ₆Alkyl or hydrogen,

R wherein _zBe hydrogen or C ₁-C ₆Alkyl, it is optional by C ₆-C ₈Aryl replaces,

--SR _xGroup, wherein R _xAs defined above,

--SO ₂R _AaGroup, wherein R _AaBe:

-C ₁-C ₆Alkyl,

-amino,

-alkyl amino or dialkyl amido, its optional by hydroxyl or-COOR _xGroup replaces, wherein

R _xAs defined above,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, or

--NHR _BbGroup, wherein R _BbBe:

--C (=S) NH ₂, or

--PO (OR _x) ₂, R wherein _xAs defined above;

R _CcGroup, wherein R _CcBe:

-naphthalene,

-5 or 6 yuan of heteroaryls,

-C ₆-C ₈Aryl, it is optional by one or more following groups replacements:

-alkoxyl,

-hydroxyl,

-halogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by cyano group,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NHPOR _xR _x, R wherein _xAs defined above,

--NR _EeCONR _FfR _FfGroup, wherein R _EeBe hydrogen or C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by halogen, and R _FfBe:

-hydrogen,

-haloalkyl,

-halogenated alkoxy,

-C ₁-C ₆Alkyl, or

--COR _x, R wherein _xAs defined above,

--NR _GgCOR _HhGroup, wherein R _HhBe:

-hydrogen,

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-halogen, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces, and wherein said alkyl is optional to be replaced by halogen,

-5 or 6 yuan of heterocycles,

-5 or 6 yuan of heteroaryls,

And R _GgBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy, or

--COR _xGroup, wherein R _xAs defined above,

-haloalkyl,

-5 or 6 yuan of heterocyclic radicals,

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces,

--NR _IiSO ₂R _xGroup, wherein R _xAs defined above, and R _IiBe:

-hydrogen,

-C ₁-C ₆Alkyl,

-haloalkyl,

-halogenated alkoxy,

--COR _xGroup, wherein R _xAs defined above;

Z is:

-hydrogen;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by following group:

-alkoxyl,

-one or more halogens, or

-C ₆-C ₈Aryl;

-C ₂-C ₆Thiazolinyl;

-C ₆-C ₈Aryl, its optional alkoxy or one or more C ₁-C ₆Alkyl replaces;

--COOR _xGroup, wherein R _xAs defined above; Or

R is hydrogen, halogen or alkoxyl;

R ₁Be:

-hydrogen;

-hydroxyl;

-halogen;

-haloalkyl;

-nitro;

-5 or 6 yuan of heteroaryls;

-5 or 6 yuan of heterocycles;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

-C ₆-C ₈Aryl, or

-5 or 6 yuan of heterocycles;

-C ₆-C ₈Aryl, its optional alkoxy replaces;

--COR _xGroup, wherein R _xAs defined above;

-C ₁-C ₆Alkyl, it is optional by dialkyl amido or 5 or 6 yuan of heterocyclic substituted; Or

R ₁With R ₂Form together:

R ₂Be:

-nitro;

-hydrogen;

-halogen;

-hydroxyl;

-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens;

-amino;

-alkoxyl, it is chosen wantonly and is replaced by following group:

-one or more halogens,

--OCOR _xGroup, wherein R _xAs defined above,

-dialkyl amido, its optional alkoxy replaces,

-5 or 6 yuan of heterocycles, it is optional by C ₁-C ₆Alkyl replaces,

-5 or 6 yuan of heteroaryls, or

-C ₆-C ₈Aryl;

--COOR _xGroup, wherein R _xAs defined above;

-haloalkyl;

-amide groups, it is chosen wantonly and is replaced by following group:

-hydroxyl, or

-C ₆-C ₈Aryl;

-5 or 6 yuan of heteroaryls;

--OCOR _xGroup, wherein R _xAs defined above;

--NHCOR _JjGroup, wherein R _JjBe:

-alkoxyl, or

-amino, it is optional by one or more C ₁-C ₆Alkyl replaces;

--OR _KkGroup, wherein R _KkIt is 5-6 unit heteroaryl;

--NHSO ₂R _xGroup, wherein R _xAs defined above; Or

R ₂With R ₁Form together:

R ₃Be:

-hydrogen; Or

-CH ₂OCOR _x, and R _xAs defined above.

Images